# Patent

## Title
Solid antiviral dosage forms

## Abstract

The present disclosure relates to solid dosage forms comprising antiviral compounds and methods of using such dosage forms to treat antiviral infection.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of U.S. patent application Ser. No. 14/677,611 filed Apr. 2, 2015, now issued as U.S. Pat. No. 9,333,204, which is incorporated herein by reference in its entirety, and which is a continuation of International Application No. PCT/US2015/010060 with an international filing date of Jan. 2, 2015, which is incorporated herein by reference in its entirety, and claims priority to U.S. Provisional Application No. 61/976,934 filed Apr. 8, 2014, and U.S. Provisional Application No. 61/923,544 filed Jan. 3, 2014, both of which are incorporated herein by reference in their entirety.


FIELD OF THE INVENTION
The present disclosure relates to solid dosage forms comprising antiviral compounds, methods of preparing the solid dosage forms, and methods of using such dosage forms to treat antiviral infection.
BACKGROUND OF THE INVENTION
Hepatitis C virus (“HCV”) infection is associated with progressive liver pathology, including cirrhosis and hepatocellular carcinoma. Standard of care for treating chronic HCV infection generally comprises administration of peginterferon-alpha in combination with ribavirin to the patient. Treatment often additionally comprises administering a hepatitis C protease inhibitor to genotype 1-infected patients. Many patients, however, suffer side effects from the treatment, and viral elimination from the body is often inadequate. In view of the limited efficacy and tolerability of such standard of care treatment, there remains a need for new drugs to treat HCV infection.
BRIEF DESCRIPTION OF THE INVENTION
The present disclosure relates to solid dosage forms comprising Compound 1, Compound 2, Compound 3, and Compound 4 (as those compounds are defined in the disclosure below).
In an aspect, the present disclosure relates to solid dosage forms comprising Compound 1, Compound 2, and Compound 3 in a first composition, and Compound 4 in a second composition.
In one aspect, the present disclosure relates to solid dosage forms comprising Compound 1, Compound 2, Compound 3, and Compound 4, wherein the weight ratio (free acid or free base) of Compound 1:Compound 2:Compound 3 is from 10:1:2 to 2:1:3.
In another aspect, the disclosure relates to solid dosage forms comprising:

    
    
        (a) 40 mg to 180 mg (free acid equivalent weight) of Compound 1;
        (b) 5 mg to 30 mg (free base equivalent weight) of Compound 2;
        (c) 25 mg to 120 mg (free base equivalent weight) of Compound 3; and
        (d) 75 mg to 900 mg (free acid equivalent weight) of Compound 4.
    
    


In another aspect, the disclosure relates to solid dosage forms comprising:

    
    
        (a) a first composition comprising:
        
            (i) 40 mg to 90 mg (free acid equivalent weight) of Compound 1;
            (ii) 5 mg to 15 mg (free base equivalent weight) of Compound 2; and
            (iii) 25 mg to 60 mg (free base equivalent weight) of Compound 3; and
        
        
        (b) a second composition comprising:
        
            (i) 75 mg to 450 mg (free acid equivalent weight) of Compound 4;
            (ii) a pharmaceutically acceptable stabilizing polymer, or combination of pharmaceutically acceptable stabilizing polymers, in an amount of at least 5% by weight of the second composition; and
            (iii) a pharmaceutically acceptable release rate-modifying polymer, or combination of pharmaceutically acceptable release rate-modifying polymers, in an amount of at least 5% by weight of the second composition;
            wherein the stabilizing polymer, or combination of stabilizing polymers, and the release rate-modifying polymer, or combination of release rate-modifying polymers, can be the same or different.
        
        
    
    


In another aspect, the disclosure relates to methods for treating HCV infection in a subject in need of such treatment, wherein the methods comprise administering at least one dosage form of the present disclosure once daily to the subject. In one aspect, the methods comprise administering two dosage forms of the present disclosure once daily to the subject. In another aspect, the methods comprise administering three dosage forms of the present disclosure once daily to the subject.
In another aspect, the disclosure relates to methods for treating liver disease in a subject in need of such treatment, wherein the methods comprise administering at least one dosage form of the present disclosure once daily to the subject. In one aspect, the methods comprise administering two dosage forms of the present disclosure once daily to the subject. In another aspect, the methods comprise administering three dosage forms of the present disclosure once daily to the subject.
In another aspect, the disclosure relates to kits comprising one or more of the dosage forms of the present disclosure.
In another aspect, the disclosure relates to processes for making the dosage forms of the present disclosure, wherein the processes comprise:

    
    
        (a) preparing a melt comprising Compound 1, Compound 2, Compound 3, a hydrophilic polymer, and a surfactant;
        (b) solidifying the melt to provide an amorphous solid dispersion;
        (c) preparing a first composition comprising the amorphous solid dispersion;
        (d) preparing a second composition comprising Compound 4 and a pharmaceutically acceptable stabilizing polymer, or combination of pharmaceutically acceptable stabilizing polymers; and
        (e) formulating the first composition and the second composition to provide the dosage form.
    
    


In another aspect, the disclosure relates to solid dosage forms prepared in accordance with the above processes.


DETAILED DESCRIPTION OF THE INVENTION
This written description uses examples to illustrate the invention and also to enable any person skilled in the art to practice the invention, including making and using any compositions and performing any related methods. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims or if they include equivalent structural elements with insubstantial differences from the literal language of the claims.
I. DEFINITIONS
Section headings as used in this section and the entire disclosure are not intended to be limiting.
Where a numeric range is recited, each intervening number within the range is explicitly contemplated with the same degree of precision. For example, for the range 6 to 9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 and 7.0 are explicitly contemplated. In the same manner, all recited ratios also include all sub-ratios falling within the broader ratio.
The term “AUC∞” refers to the area under the plasma concentration-time curve from the time 0 (time of dosing) to infinity (∞), as calculated by the linear trapezoidal method.
The term “Cmax” refers to the maximum observed plasma concentration over the entire sampling period.
The term “C24” refers to the plasma concentration at 24 hours.
The term “particle size” refers to particle size as measured by conventional particle size measuring techniques such as laser light scattering. The term “D10 particle size” means the particle size distribution of at least 10% of the particles as measured by laser light scattering particle size measuring techniques. The term “D50 particle size” means the particle size distribution of at least 50% of the particles as measured by laser light scattering particle size measuring techniques. The term “D90 particle size” means the particle size distribution of at least 90% of the particles as measured by laser light scattering particle size measuring techniques.
The term “subject” refers to a human subject.
The term “Tmax” refers to the time of the maximum observed plasma concentration (Cmax).
The abbreviation “cTAB” means cetyltrimethylammonium bromide.
The abbreviation “FeSSIF” means Fed-State Simulated Intestinal Fluid.
The abbreviation “HCV” means hepatitis C virus.
The abbreviation “HLB” means Hydrophobic-Lipophilic Balance.
The abbreviation “HPMC” means hydroxypropyl methylcellulose.
The abbreviation “PXRD” means powder X-ray diffraction.
The abbreviation “Tg” means glass transition temperature.
The abbreviation “v/v” refers to volume/volume.
The abbreviation “w/v” refers to weight/volume.
The abbreviation “w/w” refers to weight/weight.
II. SOLID DOSAGE FORMS
Combination therapy treatment of HCV-infected adult human subjects comprising the administration to those subjects of Compound 1, Compound 2, Compound 3, and Compound 4 (which are further described below) was evaluated in Phase III clinical trials. The Phase III trials employed two separate dosage forms, a first tablet comprising Compound 1, Compound 2, and Compound 3 (the “Triple Tablet”), and a second tablet comprising Compound 4 as the only active ingredient (the “Single Tablet”). The daily dosing regimen under evaluation in the Phase III clinical trials has required administration to the subject of two Triple Tablets and one Single Tablet in the morning and the administration of one Single Tablet to the subject in the evening. Initial results have indicated that such combination therapy treatment is effective.
A. Active Ingredients
Compound 1:
The compound (2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-6-(5-methylpyrazine-2-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide (also known as ABT-450 or paritaprevir) is an HCV protease inhibitor and has the structure shown below:




For convenience, this compound and its pharmaceutically acceptable salts are collectively referred to as Compound 1 throughout this disclosure. The synthesis and formulation of Compound 1 are described, for example, in U.S. Patent Application Publication Nos. 2010/0144608 and 2011/0312973.

Compound 2:
The compound dimethyl (2S,2′S)-1,1′-((2S,2′S)-2,2′-(4,4′-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis-(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)-dicarbamate (also known as ABT-267 or ombitasvir) is an HCV NS5A inhibitor and has the structure shown below:




For convenience, this compound and its pharmaceutically acceptable salts are collectively referred to as Compound 2 throughout this disclosure. The synthesis and formulation of Compound 2 are described, for example, in U.S. Patent Application Publication Nos. 2010/0317568 and 2012/0258909.
Compound 3: The compound 1,3-thiazol-5-ylmethyl N-[(2S,3S,5S)-3-hydroxy-5-[(2S)-3-methyl-2-{[methyl({[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl})carbamoyl]-amino}butanamido]-1,6-diphenylhexan-2-yl]carbamate (also known as ritonavir) is a protease inhibitor and has the structure shown below:




For convenience, this compound and its pharmaceutically acceptable salts are collectively referred to as Compound 3 throughout this disclosure. The synthesis and formulation of Compound 3 are described, for example, in U.S. Pat. No. 5,541,206 and U.S. Pat. No. 8,268,349. Compound 3 is the active ingredient in the commercially available product NORVIR®.

Compound 4:
The compound N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (also known as ABT-333 or dasabuvir) is a polymerase inhibitor and has the structure shown below:




For convenience, this compound and its pharmaceutically acceptable salts are collectively referred to as Compound 4 throughout this disclosure. The synthesis and formulation of Compound 4 are described, for example, in International Application Publication WO2009/039134.

Unless otherwise stated, any reference in this disclosure to an amount of Compound 1, Compound 2, Compound 3, or Compound 4 is intended to refer to the free acid or free base equivalent weight of the compound. For example, 350 mg of Compound 4 refers to 350 mg of the free acid of Compound 4 or an equivalent amount of a salt (e.g., a sodium salt) of Compound 4.
The present disclosure relates, in part, to one or more solid dosage forms that comprise all four of the active ingredients (Compound 1, Compound 2, Compound 3, and Compound 4) employed in the combination therapy evaluated in Phase III clinical trials discussed above. Such solid dosage forms, inter alia, can be administered to the subject pursuant to a once-daily dosing regimen, provide substantially comparable efficacy relative to, and are preferably bioequivalent to, the Triple Tablet/Single Tablet dosing regimen, and/or result in improved patient compliance. However, co-formulation of all four active ingredients in a single solid dosage form has been challenging in view of a number of factors, including the following:
(a) Total Daily Dose:
The combined daily dose of Compound 1 (150 mg), Compound 2 (25 mg), Compound 3 (100 mg), and Compound 4 (500 mg) administered to the subject in Phase III clinical trials is relatively large, totaling 775 mg and must be administered in four tablets.
(b) Dosage Form Size:
The Triple Tablet (1117 mg) and Single Tablet (697 mg) administered to subjects in Phase III clinical trials are large in size.
(c) Drug Loading:
Drug loading limitations previously impacted the development of the Triple Tablet. Consolidating the four active ingredients into a single dosage form only exacerbates that problem.

    
    
        (d) Different Pharmacokinetic Profiles:
    
    


The daily dosing regimen for the Triple Tablet (once-daily dosing regimen) and the Single Tablet (twice-daily dosing regimen) differ, and deliver a specific pharmacokinetic profile for each of the four compounds.

    
    
        (e) Solubility:
    
    


Compound 1, Compound 2, Compound 3, and Compound 4 have low solubility. They generally exhibit lower bioavailability and/or higher variability in bioavailability relative to more soluble compounds due to their poor aqueous solubility and low dissolution.
(f) Free Acid Conversion (Compound 4):
The free acid of Compound 4 exhibits good permeability but poor solubility in the gastrointestinal tract. Administering a salt of Compound 4 (such as the sodium salt) rather than the free acid form of Compound 4, however, does not improve Compound 4 solubility and uptake in the gastrointestinal tract to the extent expected due to unknown reasons.
(g) Regional Absorption (Compound 4):
The rate and extent of Compound 4 absorption varies throughout the gastrointestinal tract, making it difficult to design a once daily dosing that is bioequivalent to twice daily dosing.
Individually, the above considerations present significant challenges to co-formulating all four active ingredients in a suitable solid dosage form. Collectively, these considerations further increase the difficulty of co-formulating all four active ingredients in a suitable solid dosage form without adversely impacting dosage form size and/or the number of unit dosage forms that must be administered on a daily basis while achieving suitable efficacy and bioavailability.
B. Therapeutic Dose and Regimen
The dosage forms of the present invention are administered in accordance with a daily dosing regimen that orally delivers a therapeutic amount of Compounds 1, 2, 3, and 4 to a subject. This daily dosing regimen generally delivers an amount of Compounds 1, 2, 3, and 4 within the ranges set forth in Table A below.







TABLE A







Daily Therapeutic Dose










ACTIVE INGREDIENT
DAILY THERAPEUTIC DOSE (mg)







Compound 1
80 to 180 (e.g., 150)



Compound 2
10 to 30 (e.g., 25)



Compound 3
50 to 120 (e.g., 100)



Compound 4
450 to 900 (e.g., 500 or 600)










Due to drug loading limitations and dosage form size constraints, administration of two or more of the dosage forms of the present invention typically will be required to deliver the necessary daily therapeutic dose to the subject. In one aspect, daily administration of two of the dosage forms will provide the necessary daily therapeutic dose to the subject. In another aspect, daily administration of three of the dosage forms will provide the necessary daily therapeutic dose to the subject. If desired, however, daily administration of four or more of the dosage forms can be employed to provide the necessary daily therapeutic dose to the subject.

C. Dosage Form
Illustrative Embodiments
The present disclosure relates, in part, to a solid dosage form comprising:

    
    
        (a) 40 mg to 180 mg (free acid equivalent weight) of Compound 1, wherein Compound 1 is:
    
    






or a pharmaceutically acceptable salt thereof;

    
    
        (b) 5 mg to 30 mg (free base equivalent weight) of Compound 2, wherein Compound 2 is:
    
    






or a pharmaceutically acceptable salt thereof;

    
    
        (c) 25 mg to 120 mg (free base equivalent weight) of Compound 3, wherein Compound 3 is ritonavir, or a pharmaceutically acceptable salt thereof; and
        (d) 75 mg to 900 mg (free acid equivalent weight) of Compound 4, wherein Compound 4 is:
    
    






or a pharmaceutically acceptable salt thereof.

The dosage form generally will comprise Compounds 1, 2, and 3 at a weight ratio (free acid or free base) of 3:2:24 to 60:3:5 (Compound 1:Compound 2:Compound 3). In one aspect, the weight ratio is 10:1:2 to 2:1:3 (Compound 1:Compound 2:Compound 3). In another aspect, the weight ratio is 6:1:4 (Compound 1:Compound 2:Compound 3).
Suitable dosage forms (e.g., tablets, capsules, sachets, etc.) and representative examples of such dosage form types are discussed in greater detail in Section II.J below.
As mentioned above, the dosage forms of the present disclosure may be administered pursuant to a daily dosing regimen that comprises, for example, either administering two of the dosage forms daily to the subject or administering three of the dosage forms daily to the subject. In one aspect, the two or three dosage forms are administered to the subject substantially simultaneously each day. In one aspect, the two or three dosage forms are administered to the subject substantially sequentially each day. Representative embodiments of dosage forms that can be employed in each regimen are set forth below.
In one embodiment, the dosage forms comprises:

    
    
        (a) 40 mg to 90 mg (free acid equivalent weight) of Compound 1;
        (b) 5 mg to 15 mg (free base equivalent weight) of Compound 2;
        (c) 25 mg to 60 mg (free base equivalent weight) of Compound 3; and
        (d) 75 mg to 450 mg (free acid equivalent weight) of Compound 4.
    
    


In another embodiment, the dosage form comprises:

    
    
        (a) a first composition comprising:
        
            (i) 40 mg to 90 mg (free acid equivalent weight) of Compound 1;
            (ii) 5 mg to 15 mg (free base equivalent weight) of Compound 2; and
            (iii) 25 mg to 60 mg (free base equivalent weight) of Compound 3; and
        
        
        (b) a second composition comprising:
        
            (i) 75 mg to 450 mg (free acid equivalent weight) of Compound 4;
            (ii) a pharmaceutically acceptable stabilizing polymer, or combination of pharmaceutically acceptable stabilizing polymers, in an amount of at least 5% by weight of the second composition; and
            (iii) a pharmaceutically acceptable release rate-modifying polymer, or combination of pharmaceutically acceptable release rate-modifying polymers, in an amount of at least 5% by weight of the second composition;
            wherein the stabilizing polymer, or combination of stabilizing polymers, and the release rate-modifying polymer, or combination of release rate-modifying polymers, can be the same or different.
        
        
    
    


The first composition may further comprise a portion of the total amount of Compound 4 present in the dosage form. The amount of Compound 4 present in the first composition may not exceed the amount of Compound 4 present in the second composition. In one aspect, the amount of Compound 4 present in the first composition is less than or equal to 45% of the amount of Compound 4 present in the dosage form. In another aspect, the amount of Compound 4 present in the first composition is less than or equal to 40% of the amount of Compound 4 present in the dosage form. In another aspect, the amount of Compound 4 present in the first composition is less than or equal to 35% of the amount of Compound 4 present in the dosage form. In another aspect, the amount of Compound 4 present in the first composition is less than or equal to 30% of the amount of Compound 4 present in the dosage form. In another aspect, the amount of Compound 4 present in the first composition is less than or equal to 25% of the amount of Compound 4 present in the dosage form. In another aspect, the amount of Compound 4 present in the first composition is less than or equal to 20% of the amount of Compound 4 present in the dosage form. In another aspect, the amount of Compound 4 present in the first composition is less than or equal to 15% of the amount of Compound 4 present in the dosage form. In another aspect, the amount of Compound 4 present in the first composition is 25% of the amount of Compound 4 present in the dosage form.
In another embodiment of the dosage form:

    
    
        the first composition comprises (i) 60 mg to 90 mg (free acid equivalent weight) of Compound 1; (ii) 10 mg to 15 mg (free base equivalent weight) of Compound 2; and (iii) 40 mg to 60 mg (free base equivalent weight) of Compound 3; and the second composition comprises 225 mg to 450 mg (free acid equivalent weight) of Compound 4.
    
    


In another embodiment of the dosage form:

    
    
        the first composition comprises (i) 70 mg to 80 mg (free acid equivalent weight) of Compound 1; (ii) 11 mg to 14 mg (free base equivalent weight) of Compound 2; and (iii) 45 mg to 55 mg (free base equivalent weight) of Compound 3; and
        the second composition comprises 225 mg to 400 mg (free acid equivalent weight) of Compound 4.
    
    


In another embodiment of the dosage form:

    
    
        the first composition comprises (i) 75 mg (free acid equivalent weight) of Compound 1; (ii) 12.5 mg (free base equivalent weight) of Compound 2; and (iii) 50 mg (free base equivalent weight) of Compound 3; and
        the second composition comprises 300 mg to 400 mg (free acid equivalent weight) of Compound 4.
    
    


In another embodiment of the dosage form:

    
    
        the first composition comprises (i) 75 mg (free acid equivalent weight) of Compound 1; (ii) 12.5 mg (free base equivalent weight) of Compound 2; and (iii) 50 mg (free base equivalent weight) of Compound 3; and
        the second composition comprises 300 mg to 400 mg (free acid equivalent weight) of Compound 4; and
        the stabilizing polymer comprises copovidone.
    
    


In another embodiment of the dosage form:

    
    
        the first composition comprises (i) 75 mg (free acid equivalent weight) of Compound 1; (ii) 12.5 mg (free base equivalent weight) of Compound 2; and (iii) 50 mg (free base equivalent weight) of Compound 3; and
        the second composition comprises 300 mg to 400 mg (free acid equivalent weight) of Compound 4;
        the stabilizing polymer comprises copovidone; and
        the release rate-modifying polymer comprises hydroxypropyl methylcellulose.
    
    


In another embodiment of the dosage form:

    
    
        the first composition comprises (i) 60 mg to 90 mg (free acid equivalent weight) of Compound 1; (ii) 10 mg to 15 mg (free base equivalent weight) of Compound 2; and (iii) 40 mg to 60 mg (free base equivalent weight) of Compound 3; and
        the first composition further comprises 25 mg to 225 mg (free acid equivalent weight) of Compound 4;
        wherein the dosage form comprises a total amount of Compound 4 (free acid equivalent weight) from 225 mg to 450 mg; and
        the amount of Compound 4 (free acid equivalent weight) in the first composition is less than or equal to the amount of Compound 4 (free acid equivalent weight) in the second composition.
    
    


In another embodiment of the dosage form:

    
    
        the first composition comprises (i) 70 mg to 80 mg (free acid equivalent weight) of Compound 1; (ii) 11 mg to 14 mg (free base equivalent weight) of Compound 2; and (iii) 45 mg to 55 mg (free base equivalent weight) of Compound 3; and
        the first composition further comprises 25 mg to 225 mg (free acid equivalent weight) of Compound 4;
        wherein the dosage form comprises a total amount of Compound 4 (free acid equivalent weight) from 225 mg to 450 mg; and
        the amount of Compound 4 (free acid equivalent weight) in the first composition is less than or equal to the amount of Compound 4 (free acid equivalent weight) in the second composition.
    
    


In another embodiment of the dosage form:

    
    
        the first composition comprises (i) 75 mg (free acid equivalent weight) of Compound 1; (ii) 12.5 mg (free base equivalent weight) of Compound 2; and (iii) 50 mg (free base equivalent weight) of Compound 3; and
        the first composition further comprises 25 mg to 200 mg (free acid equivalent weight) of Compound 4;
        wherein the dosage form comprises a total amount of Compound 4 (free acid equivalent weight) from 300 mg to 400 mg; and
        the amount of Compound 4 (free acid equivalent weight) in the first composition is less than or equal to the amount of Compound 4 (free acid equivalent weight) in the second composition.
    
    


In another embodiment of the dosage form:

    
    
        the first composition comprises (i) 75 mg (free acid equivalent weight) of Compound 1; (ii) 12.5 mg (free base equivalent weight) of Compound 2; and (iii) 50 mg (free base equivalent weight) of Compound 3; and
        the first composition further comprises 25 mg to 200 mg (free acid equivalent weight) of Compound 4;
        wherein the dosage form comprises a total amount of Compound 4 (free acid equivalent weight) from 300 mg to 400 mg;
        the amount of Compound 4 (free acid equivalent weight) in the first composition is less than or equal to the amount of Compound 4 (free acid equivalent weight) in the second composition; and
        the stabilizing polymer comprises copovidone.
    
    


In another embodiment of the dosage form:

    
    
        the first composition comprises (i) 75 mg (free acid equivalent weight) of Compound 1; (ii) 12.5 mg (free base equivalent weight) of Compound 2; and (iii) 50 mg (free base equivalent weight) of Compound 3; and
        the first composition further comprises 25 mg to 200 mg (free acid equivalent weight) of Compound 4;
        wherein the dosage form comprises a total amount of Compound 4 (free acid equivalent weight) from 300 mg to 400 mg;
        the amount of Compound 4 (free acid equivalent weight) in the first composition is less than or equal to the amount of Compound 4 (free acid equivalent weight) in the second composition;
        the stabilizing polymer comprises copovidone; and
        the release rate-modifying polymer comprises hydroxypropyl methylcellulose.
    
    


In another embodiment of the dosage form:

    
    
        the first composition comprises (i) 40 mg to 60 mg (free acid equivalent weight) of Compound 1; (ii) 6.5 mg to 10.5 mg (free base equivalent weight) of Compound 2; and (iii) 25 mg to 40 mg (free base equivalent weight) of Compound 3; and
        the second composition comprises 150 mg to 300 mg (free acid equivalent weight) of Compound 4.
    
    


In another embodiment of the dosage form:

    
    
        the first composition comprises (i) 45 mg to 55 mg (free acid equivalent weight) of Compound 1; (ii) 7.5 mg to 9.5 mg (free base equivalent weight) of Compound 2; and (iii) 30 mg to 37 mg (free base equivalent weight) of Compound 3; and
        the second composition comprises 150 mg to 300 mg (free acid equivalent weight) of Compound 4.
    
    


In another embodiment of the dosage form:

    
    
        the first composition comprises (i) 50 mg (free acid equivalent weight) of Compound 1; (ii) 8.3 mg (free base equivalent weight) of Compound 2; and (iii) 33.3 mg (free base equivalent weight) of Compound 3; and
        the second composition comprises 190 mg to 250 mg (free acid equivalent weight) of Compound 4.
    
    


In another embodiment of the dosage form:

    
    
        the first composition comprises (i) 50 mg (free acid equivalent weight) of Compound 1; (ii) 8.3 mg (free base equivalent weight) of Compound 2; and (iii) 33.3 mg (free base equivalent weight) of Compound 3; and
        the second composition comprises 190 mg to 250 mg (free acid equivalent weight) of Compound 4; and
        the stabilizing polymer comprises copovidone.
    
    


In another embodiment of the dosage form:

    
    
        the first composition comprises (i) 50 mg (free acid equivalent weight) of Compound 1; (ii) 8.3 mg (free base equivalent weight) of Compound 2; and (iii) 33.3 mg (free base equivalent weight) of Compound 3; and
        the second composition comprises 190 mg to 250 mg (free acid equivalent weight) of Compound 4;
        the stabilizing polymer comprises copovidone; and
        the release rate-modifying polymer comprises hydroxypropyl methylcellulose.
    
    


In another embodiment of the dosage form:

    
    
        the first composition comprises (i) 40 mg to 60 mg (free acid equivalent weight) of Compound 1; (ii) 6.5 mg to 10.5 mg (free base equivalent weight) of Compound 2; and (iii) 25 mg to 40 mg (free base equivalent weight) of Compound 3; and
        the first composition further comprises 25 mg to 150 mg (free acid equivalent weight) of Compound 4;
        wherein the dosage form comprises a total amount of Compound 4 (free acid equivalent weight) from 150 mg to 300 mg; and
        the amount of Compound 4 (free acid equivalent weight) in the first composition is less than or equal to the amount of Compound 4 (free acid equivalent weight) in the second composition.
    
    


In another embodiment of the dosage form:

    
    
        the first composition comprises (i) 45 mg to 55 mg (free acid equivalent weight) of Compound 1; (ii) 7.5 mg to 9.5 mg (free base equivalent weight) of Compound 2; and (iii) 30 mg to 37 mg (free base equivalent weight) of Compound 3; and
        the first composition further comprises 25 mg to 150 mg (free acid equivalent weight) of Compound 4;
        wherein the dosage form comprises a total amount of Compound 4 (free acid equivalent weight) from 150 mg to 300 mg; and
        the amount of Compound 4 (free acid equivalent weight) in the first composition is less than or equal to the amount of Compound 4 (free acid equivalent weight) in the second composition.
    
    


In another embodiment of the dosage form:

    
    
        the first composition comprises (i) 50 mg (free acid equivalent weight) of Compound 1; (ii) 8.3 mg (free base equivalent weight) of Compound 2; and (iii) 33.3 mg (free base equivalent weight) of Compound 3; and
        the first composition further comprises 25 mg to 135 mg (free acid equivalent weight) of Compound 4;
        wherein the dosage form comprises a total amount of Compound 4 (free acid equivalent weight) from 190 mg to 250 mg; and
        the amount of Compound 4 (free acid equivalent weight) in the first composition is less than or equal to the amount of Compound 4 (free acid equivalent weight) in the second composition.
    
    


In another embodiment of the dosage form:

    
    
        the first composition comprises (i) 50 mg (free acid equivalent weight) of Compound 1; (ii) 8.3 mg (free base equivalent weight) of Compound 2; and (iii) 33.3 mg (free base equivalent weight) of Compound 3; and
        the first composition further comprises 25 mg to 135 mg (free acid equivalent weight) of Compound 4;
        wherein the dosage form comprises a total amount of Compound 4 (free acid equivalent weight) from 190 mg to 250 mg;
        the amount of Compound 4 (free acid equivalent weight) in the first composition is less than or equal to the amount of Compound 4 (free acid equivalent weight) in the second composition; and
        the stabilizing polymer comprises copovidone.
    
    


In another embodiment of the dosage form:

    
    
        the first composition comprises (i) 50 mg (free acid equivalent weight) of Compound 1; (ii) 8.3 mg (free base equivalent weight) of Compound 2; and (iii) 33.3 mg (free base equivalent weight) of Compound 3; and
        the first composition further comprises 25 mg to 135 mg (free acid equivalent weight) of Compound 4;
        wherein the dosage form comprises a total amount of Compound 4 (free acid equivalent weight) from 190 mg to 250 mg;
        the amount of Compound 4 (free acid equivalent weight) in the first composition is less than or equal to the amount of Compound 4 (free acid equivalent weight) in the second composition;
        the stabilizing polymer comprises copovidone; and
        the release rate-modifying polymer comprises hydroxypropyl methylcellulose.
    
    


D. Compound 4
The dosage form typically will comprise a pharmaceutically acceptable salt of Compound 4. In one aspect, the salt is an alkali metal salt. In another aspect, the salt is a sodium salt. In another aspect, the salt is a crystalline salt. In another aspect, the salt is a pattern B crystalline monosodium salt having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 5.4±0.2, 10.8±0.2, 14.4±0.2, 16.3±0.2, 17.0±0.2, 21.6±0.2, 22.1±0.2, and 23.7±0.2 degrees two theta when measured at 25° C. with monochromatic Cu—Kα1 radiation; or an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 5.4±0.2, 10.8±0.2, 14.4±0.2, 16.3±0.2, 17.0±0.2, 18.8±0.2, 19.2±0.2, 19.6±0.2, 21.6±0.2, 22.1±0.2, 23.7±0.2, 28.8±0.2, 29.1±0.2, and 31.8±0.2 degrees two theta when measured at 25° C. with monochromatic Cu—Kα1 radiation; or an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 5.4±0.2, 10.8±0.2, 16.3±0.2, 22.1±0.2, and 23.7±0.2 degrees two theta when measured at 25° C. with monochromatic Cu—Kα1 radiation; or an X-ray powder diffraction pattern comprising peaks at 5.4±0.2, 10.8±0.2, 16.3±0.2, and 22.1±0.2 degrees two theta when measured at 25° C. with monochromatic Cu—Kα1 radiation. In another aspect, the pattern B monosodium salt is a pattern B monosodium salt monohydrate. In another aspect, the salt is an amorphous salt. In another aspect, the salt is an amorphous monosodium salt.
The amount of Compound 4 (free acid equivalent weight) in the second composition generally is at least 20% by weight of the second composition. In one aspect, the amount of Compound 4 (free acid equivalent weight) in the second composition is at least 25% by weight of the second composition. In another aspect, the amount of Compound 4 (free acid equivalent weight) in the second composition is at least 30% by weight of the second composition. In another aspect, the amount of Compound 4 (free acid equivalent weight) in the second composition is at least 35% by weight of the second composition. In another aspect, the amount of Compound 4 (free acid equivalent weight) in the second composition is at least 40% by weight of the second composition. In another aspect, the amount of Compound 4 (free acid equivalent weight) in the second composition is 20% to 60% percent by weight of the second composition. In another aspect, the amount of Compound 4 (free acid equivalent weight) in the second composition is 25% to 55% percent by weight of the second composition. In another aspect, the amount of Compound 4 (free acid equivalent weight) in the second composition is 35% to 50% percent by weight of the second composition.
E. Stabilizing Polymer
The amount of the stabilizing polymer, or combination of stabilizing polymers, in the second composition generally is at least 5% by weight of the second composition. In one aspect, the amount of the stabilizing polymer, or combination of stabilizing polymers, in the second composition is at least 10% by weight. In another aspect, the amount of the stabilizing polymer, or combination of stabilizing polymers, in the second composition is at least 15% by weight. In another aspect, the amount of the stabilizing polymer, or combination of stabilizing polymers, in the second composition is at least 20% by weight. In another aspect, the amount of the stabilizing polymer, or combination of stabilizing polymers, in the second composition is at least 25% by weight. In another aspect, the amount of the stabilizing polymer, or combination of stabilizing polymers, in the second composition is at least 30% by weight. In another aspect, the amount of the stabilizing polymer, or combination of stabilizing polymers, in the second composition is 10% to 60% percent by weight. In another aspect, the amount of the stabilizing polymer, or combination of stabilizing polymers, in the second composition is 15% to 55% percent by weight. In another aspect, the amount of the stabilizing polymer, or combination of stabilizing polymers, in the second composition is 20% to 50% percent by weight. In another aspect, the amount of the stabilizing polymer, or combination of stabilizing polymers, in the second composition is 25% to 45% percent by weight. In another aspect, the amount of the stabilizing polymer, or combination of stabilizing polymers, in the second composition is 25% to 40% percent by weight.
In one embodiment, the weight ratio of the stabilizing polymer, or combination of stabilizing polymers, to Compound 4 (free acid equivalent weight) in the second composition is from 4:1 to 1:8. In one aspect, the weight ratio of the stabilizing polymer, or combination of stabilizing polymers, to Compound 4 (free acid equivalent weight) in the second composition is 2:1 to 1:4. In another aspect, the weight ratio of the stabilizing polymer, or combination of stabilizing polymers, to Compound 4 (free acid equivalent weight) in the second composition is 1:1 to 1:3.5. In another aspect, the weight ratio of the stabilizing polymer, or combination of stabilizing polymers, to Compound 4 (free acid equivalent weight) in the second composition is 1:1.5 to 1:3.5. In another aspect, the weight ratio of the stabilizing polymer, or combination of stabilizing polymers, to Compound 4 (free acid equivalent weight) in the second composition is 1:2 to 1:3.
When Compound 4 is present in both the first composition and the second composition of the dosage form, the first composition may further comprise a stabilizing polymer, or combination of stabilizing polymers, in the same manner as previously described for the second composition. In such dosage forms, the weight ratio of the stabilizing polymer, or combination of stabilizing polymers, to Compound 4 (free acid equivalent weight) in the first composition is from 4:1 to 1:8, or as otherwise described above for the various aspects of the second composition.
The stabilizing polymer, or combination of stabilizing polymers, selected generally will inhibit precipitation of Compound 4. In one aspect, the stabilizing polymer, or combination of stabilizing polymers, inhibits precipitation of Compound 4 by at least 10% to 80% relative to a substantially identical dosage form that does not contain the stabilizing polymer, or combination of stabilizing polymers. In one aspect, the stabilizing polymer, or combination of stabilizing polymers, inhibits precipitation of Compound 4 by at least 10% relative to a substantially identical dosage form that does not contain the stabilizing polymer, or combination of stabilizing polymers. In another aspect, the stabilizing polymer, or combination of stabilizing polymers, inhibits precipitation of Compound 4 by at least 20%. In another aspect, the stabilizing polymer, or combination of stabilizing polymers, inhibits precipitation of Compound 4 by at least 30%. In another aspect, the stabilizing polymer, or combination of stabilizing polymers, inhibits precipitation of Compound 4 by at least 40%. In another aspect, the stabilizing polymer, or combination of stabilizing polymers, inhibits precipitation of Compound 4 by at least 50%. In another aspect, the stabilizing polymer, or combination of stabilizing polymers, inhibits precipitation of Compound 4 by at least 60%. In another aspect, the stabilizing polymer, or combination of stabilizing polymers, inhibits precipitation of Compound 4 by at least 70%. In another aspect, the stabilizing polymer, or combination of stabilizing polymers, inhibits precipitation of Compound 4 by at least 80%.
In one embodiment, the stabilizing polymer, or combination of stabilizing polymers, selected for the dosage form inhibits precipitation of Compound 4 as determined by the process comprising:

    
    
        (a) preparing a test solution comprising Compound 4, or a salt thereof, and the stabilizing polymer, or combination of stabilizing polymers;
        (b) preparing a control solution, the control solution being substantially identical to the test solution except that the control solution does not contain the stabilizing polymer, or combination of stabilizing polymers;
        (c) maintaining the test mixture and the control solution under the same conditions for a test period; and
        (d) determining at the end of the test period the extent to which precipitation of Compound 4, or a salt thereof, is inhibited in the test solution relative to the control solution.
    
    


Suitable methods for determining whether precipitation of Compound 4 has been inhibited in the test solution relative to the control solution include UV/Vis spectrophotometry using an in situ UV/Vis probe; HPLC assay of the supernatant solution after removing particles; and other conventional methods known to those of skill in the art.
In one aspect, the stabilizing polymer, or combination of stabilizing polymers, inhibits precipitation of Compound 4 by at least 10% to 80% relative to a substantially identical dosage form that does not contain the stabilizing polymer, or combination of stabilizing polymers, as determined by the process comprising: (a) preparing a test solution comprising Compound 4, or a salt thereof, and the stabilizing polymer, or combination of stabilizing polymers; (b) preparing a control solution, the control solution being substantially identical to the test solution except that the control solution does not contain the stabilizing polymer, or combination of stabilizing polymers; (c) maintaining the test mixture and the control solution under the same conditions for a test period; and (d) determining at the end of the test period the extent to which precipitation of Compound 4, or a salt thereof, is inhibited in the test solution relative to the control solution by UV/Vis spectrophotometry using an in situ UV/Vis probe.
It is hypothesized that in dosage forms comprising a salt of Compound 4 but lacking a sufficient amount of the stabilizing polymer, or combination of stabilizing polymers, the salt is rapidly converted to the relatively insoluble free acid when the salt comes into contact with the acidic environment of the stomach. The free acid then precipitates on the surface of the solid dosage form without being released into the surrounding medium and/or precipitates out of the surrounding medium. This precipitation of the free acid results in a smaller amount of the administered dose of Compound 4 dissolving in the medium and being available for uptake and lowers the overall bioavailability of Compound 4. It is further hypothesized that the incorporation of the stabilizing polymer, or combination of stabilizing polymers, in the dosage form creates a microenvironment in the gastrointestinal tract in which the salt of Compound 4 dissolves to provide the free acid and the stabilizing polymer, or combination of stabilizing polymers, then functions to maintain the free acid in a supersaturated state in solution rather than precipitating out of solution. Because the amount of dissolved free acid increases and free acid precipitation is reduced, a larger amount of the administered dose is absorbed and the bioavailability of Compound 4 is increased.
As a result, the drug loading in a unit dose formulation comprising a salt of Compound 4 and a stabilizing polymer, or combination of stabilizing polymers, can be reduced without a reduction in Compound 4 bioavailability relative to a similar unit dose formulation having a higher drug loading but otherwise lacking a sufficient amount of the stabilizing polymer, or combination of stabilizing polymers. By facilitating a reduction in the required drug loading of the unit dosage form, the stabilizing polymer, or combination of stabilizing polymers, effectively facilitates a corresponding reduction in the size of the unit dosage form where desirable.
Pharmaceutically acceptable stabilizing polymers, or combinations of pharmaceutically acceptable stabilizing polymers, generally will include, for example, compressible stabilizing polymers, or compressible combinations of stabilizing polymers, and non-acidic stabilizing polymers, or non-acidic combinations of stabilizing polymers. In one aspect, the stabilizing polymer, or combination of pharmaceutically acceptable stabilizing polymers, comprises a compressible stabilizing polymer, or compressible combination of stabilizing polymers. In another aspect, the stabilizing polymer, or combination of pharmaceutically acceptable stabilizing polymers, comprises a non-acidic polymer, or non-acidic combination of stabilizing polymers.
Specific pharmaceutically acceptable stabilizing polymers, or combinations of pharmaceutically acceptable stabilizing polymers, include stabilizing polymers, or combinations of stabilizing polymers, selected from the group consisting of copovidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (SOLUPLUS®), and combinations thereof; wherein the hydroxypropyl methylcellulose has a viscosity less than 100 centipoise in a 2% solution (i.e., a 2% aqueous solution) at a temperature of 20° C. In one aspect, the stabilizing polymer, or combination of stabilizing polymers, is selected from the group consisting of copovidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, and combinations thereof; wherein the hydroxypropyl methylcellulose has a viscosity less than 100 centipoise in a 2% solution at a temperature of 20° C. In another aspect, the stabilizing polymer, or combination of stabilizing polymers, is selected from the group consisting of homopolymers or copolymers of N-vinyl pyrrolidone and cellulose esters. In another aspect, the stabilizing polymer, or combination of stabilizing polymers, comprises copovidone. In another aspect, the stabilizing polymer, or combination of stabilizing polymers, comprises polyvinylpyrrolidone. In another aspect, the stabilizing polymer, or combination of stabilizing polymers, comprises hydroxypropyl methylcellulose having a viscosity less than 100 centipoise in a 2% solution at a temperature of 20° C. In another aspect, the stabilizing polymer, or combination of stabilizing polymers, comprises polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (SOLUPLUS®). In another aspect, the dosage form comprises two or more stabilizing polymers selected from the group consisting of copovidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (SOLUPLUS®); wherein the hydroxypropyl methylcellulose has a viscosity less than 100 centipoise in a 2% solution at a temperature of 20° C.
F. Release Rate-Modifying Polymer
The amount of the release rate-modifying polymer, or combination of release rate-modifying polymers, in the second composition generally is at least 5% by weight of the second composition. In one aspect, the amount of the release rate-modifying polymer, or combination of release rate-modifying polymers, in the second composition is at least 10% by weight. In another aspect, the amount of the release rate-modifying polymer, or combination of release rate-modifying polymers, in the second composition is at least 15% by weight. In another aspect, the amount of the release rate-modifying polymer, or combination of release rate-modifying polymers, in the second composition is at least 20% by weight. In another aspect, the amount of the release rate-modifying polymer, or combination of release rate-modifying polymers, in the second composition is 5% to 60% percent by weight. In another aspect, the amount of the release rate-modifying polymer, or combination of release rate-modifying polymers, in the second composition is 10% to 50% percent by weight. In another aspect, the amount of the release rate-modifying polymer, or combination of release rate-modifying polymers, in the second composition is 15% to 40% percent by weight. In another aspect, the amount of the release rate-modifying polymer, or combination of release rate-modifying polymers, in the second composition is 15% to 30% percent by weight.
In one embodiment, the weight ratio of the release rate-modifying polymer, or combination of release rate-modifying polymers, to Compound 4 (free acid equivalent weight) in the second composition is from 4:1 to 1:8. In one aspect, the weight ratio of the release rate-modifying polymer, or combination of release rate-modifying polymers, to Compound 4 (free acid equivalent weight) in the second composition is 1:4 to 4:1. In another aspect, the weight ratio of the release rate-modifying polymer, or combination of release rate-modifying polymers, to Compound 4 (free acid equivalent weight) in the second composition is the weight ratio of the release rate-modifying polymer, or combination of release rate-modifying polymers, to Compound 4 (free acid equivalent weight) in the second composition is 1:3 to 2:1. In another aspect, the weight ratio of the release rate-modifying polymer, or combination of release rate-modifying polymers, to Compound 4 (free acid equivalent weight) in the second composition is 1:2.5 to 1:1.
Pharmaceutically acceptable release rate-modifying polymers, or combinations of pharmaceutically acceptable release rate-modifying polymers, generally will include, for example, compressible release rate-modifying polymers, or compressible combinations of release rate-modifying polymers, and non-acidic release rate-modifying polymers, or non-acidic combinations of release rate-modifying polymers. In one aspect, the release rate-modifying polymer, or combination of pharmaceutically acceptable release rate-modifying polymers, comprises a compressible release rate-modifying polymer, or compressible combination of release rate-modifying polymers. In another aspect, the release rate-modifying polymer, or combination of pharmaceutically acceptable release rate-modifying polymers, comprises a non-acidic polymer, or non-acidic combination of release rate-modifying polymers.
Specific pharmaceutically acceptable release rate-modifying polymers, or combinations of pharmaceutically acceptable release rate-modifying polymers, include release rate-modifying polymers, or combinations of release rate-modifying polymers, selected from the group consisting of polyvinylpyrolidone, hydroxypropyl methylcellulose, ethylcellulose polymers, copovidone, polyvinyl acetate, methacrylate/methacrylic free acid copolymers, polyethylene glycols, polyethylene oxides, and polaxamers. In one aspect, the release rate-modifying polymers, or combinations of pharmaceutically acceptable release rate-modifying polymers, are selected from the group consisting of polyvinylpyrolidone (such as polyvinylpyrolidone (PVP) K17, PVP K25, PVP K30, and PVP K90); hydroxypropyl methylcellulose (such as hydroxypropyl methylcellulose (HPMC) E3, HPMC E5, HPMC E6, HPMC E15, HPMC E4M, HPMC E10M, HPMC K3, HPMC A4, HPMC A15, HPMC acetate succinate (AS) LF, HPMC AS MF, HPMC AS HF, HPMC AS LG, HPMC AS MG, HPMC AS HG, HPMC phthalate (P) 50, and HPMC P550; ethylcellulose polymers (such as Ethocel 4, Ethocel 7, Ethocel 10, Ethocel 14, and Ethocel 20); copovidone (vinylpyrrolidone-vinyl acetate copolymer 60/40), polyvinyl acetate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (SOLUPLUS®), methacrylate/methacrylic free acid copolymers (such as Eudragit L100-55, Eudragit L100, and Eudragit S100); polyethylene glycols (such as polyethylene glycol (PEG) 400, PEG 600, PEG 1450, PEG 3350, PEG 4000, PEG 6000, and PEG 8000); and polaxamers (such as poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407). In another aspect, the release rate-modifying polymer, or combination of release rate-modifying polymers, is selected from the group consisting of copovidone, polyvinylpyrrolidone, and hydroxypropyl methylcellulose. In another aspect, the release rate-modifying polymer, or combination of release rate-modifying polymers, comprises hydroxypropyl methylcellulose. In another aspect, the release rate-modifying polymer, or combination of release rate-modifying polymers, comprises hydroxypropyl methylcellulose giving an apparent viscosity at 2% weight in water at 20° C. of 80 centipoise to 120,000 centipoise at 20° C. In another aspect, the release rate-modifying polymer, or combination of release rate-modifying polymers, comprises a hydroxypropyl methylcellulose selected from the group consisting of K100, K4M, K15M, and K100M hydroxypropyl methylcelluloses.
In one embodiment of the dosage forms of the present disclosure, the stabilizing polymer comprises copovidone and the release rate-modifying polymer comprises hydroxypropyl methylcellulose.
G. Granulation
The Compound 4 starting material employed in the preparation of the dosage form can be granulated or ungranulated. It may be beneficial to use granulated Compound 4, for example, to improve bulk handling properties of the Compound 4 starting material during the preparation of the dosage form. In one embodiment, at least a portion of the Compound 4 used in the preparation of the dosage form (e.g., as the Compound 4 starting material for the first composition, the second composition, or both) is provided in the form of granules comprising Compound 4, wherein the granules are prepared by granulating Compound 4 with at least a portion of one or more of the excipients (see Section II.I. below) present in the dosage form.
In one embodiment, the dosage form is prepared by a process comprising:

    
    
        granulating (i) a mixture comprising at least a portion of the Compound 4 with at least a portion of the stabilizing polymer, or combination of stabilizing polymers, to provide granules comprising Compound 4; (ii) a mixture comprising at least a portion of the Compound 4 with at least a portion of the release rate-modifying polymer, or combination of release rate-modifying polymers, to provide granules comprising Compound 4; or (iii) a mixture comprising at least a portion of the Compound 4 with at least a portion of the stabilizing polymer, or combination of stabilizing polymers, and at least a portion of the release rate-modifying polymer, or combination of stabilizing polymers, to provide granules comprising Compound 4; and
        preparing the second composition using the granules as a source of at least a portion of the Compound 4 present in the second composition.
    
    


As previously discussed, a portion of the total amount of Compound 4 in the dosage form also may be present in the first composition. In such dosage forms, at least a portion of the Compound 4 used in the preparation of the first composition can be provided in the form of granules comprising Compound 4, wherein the granules are prepared by granulating Compound 4 with at least a portion of the stabilizing polymer, or combination of stabilizing polymers. In one embodiment, the dosage form is prepared by a process comprising:

    
    
        granulating a mixture comprising at least a portion of the Compound 4 with at least a portion of the stabilizing polymer, or combination of stabilizing polymers, to provide granules comprising Compound 4; and
        preparing the first composition using the granules as a source of at least a portion of the Compound 4 present in the first composition.
    
    


In another embodiment, the dosage form is prepared by a process comprising:

    
    
        granulating a mixture comprising at least a portion of the Compound 4 with at least a portion of the stabilizing polymer, or combination of stabilizing polymers, to provide granules comprising Compound 4;
        preparing the first composition using the granules as a source of at least a portion of the Compound 4 present in the first composition; and
        preparing the second composition using the granules as a source of at least a portion of the Compound 4 present in the second composition.
    
    


In another embodiment, the dosage form is prepared by a process comprising:

    
    
        granulating (i) a mixture comprising at least a portion of the Compound 4 with at least a portion of the stabilizing polymer, or combination of stabilizing polymers, to provide a first population of granules comprising Compound 4;
        granulating (i) a mixture comprising at least a portion of the Compound 4 with at least a portion of the release rate-modifying polymer, or combination of release rate-modifying polymers, to provide a second population of granules comprising Compound 4; or (ii) a mixture comprising at least a portion of the Compound 4 with at least a portion of the stabilizing polymer, or combination of stabilizing polymers, and at least a portion of the release rate-modifying polymer, or combination of stabilizing polymers, to provide a second population of granules comprising Compound 4;
        preparing the first composition using the first population of granules as a source of at least a portion of the Compound 4 present in the first composition; and
        preparing the second composition using the second population of granules as a source of at least a portion of the Compound 4 present in the second composition.
    
    


In another embodiment, at least a portion of the Compound 4 is dry granulated during the preparation of the dosage form with at least a portion of one or more of the excipients that are present in the final dosage form.
In another embodiment, at least a portion of the Compound 4 is wet granulated during the preparation of the dosage form with at least a portion of one or more of the excipients that are present in the final dosage form. In one aspect, at least a portion of the Compound 4 is wet (high shear) granulated with at least a portion of one or more of the excipients that are present in the final dosage form. In another aspect, a liquid comprising water is added to the granulation mixture during wet granulation.
In another embodiment, at least a portion of the Compound 4 is fluid bed granulated during the preparation of the dosage form with at least a portion of one or more of the excipients that are present in the final dosage form. In one aspect, a liquid comprising water is added to the granulation mixture during the fluid bed granulation. In another aspect, the granulation mixture is sprayed with a liquid comprising water during the fluid bed granulation.
In general, the moisture content of the granulation mixture during fluid bed granulation is controlled to provide an acceptable level of adhesion between the Compound 4 particles and the copovidone particles. As the weight ratio of Compound 4 to total polymer in the granulation mixture increases (i.e., as the relative amount of Compound 4 present in the granulation mixture increases), the target moisture content selected for the granulation mixture during granulation typically will increase. In addition, it may be beneficial to maintain the granulation mixture in the fluid bed at the specified moisture content for an additional period of time (i.e., a “hold period”) to further facilitate additional growth, tighter particle size distribution, and/or improved mechanical properties of the granules. In one aspect, the granulation mixture comprises no more than 20 weight percent liquid during the granulation. In another aspect, the granulation mixture comprises no more than 14 weight percent liquid during the granulation. In another aspect, the granulation mixture comprises from 5 weight percent liquid to 20 weight percent liquid when the addition of the liquid to the granulation mixture has been completed (i.e., prior to drying the granulation mixture). In another aspect, the granulation mixture comprises from 8 weight percent liquid to 14 weight percent liquid when the addition of the liquid to the granulation mixture has been completed.
In each and every embodiment, example, preference and aspect described herein, at least a portion of the Compound 4 can be, for example, fluid bed granulated with (a) at least a portion of the pharmaceutically acceptable stabilizing polymer, or combination of pharmaceutically acceptable stabilizing polymers, and/or (b) at least a portion of the pharmaceutically acceptable release rate-modifying polymer, or combination of pharmaceutically acceptable stabilizing polymers, prior to blending with the other components of the formulation; and the weight ratio of Compound 4 (free acid equivalent weight) to total polymer (i.e., the combined weight of stabilizing polymer and release rate-modifying polymer) in the resulting granules is from 4:1 to 1:8.
In each and every embodiment, example, preference and aspect described herein, the Compound 4 starting material used in the granulation can, for example, have a particle size distribution that satisfies one or more of the following conditions: (a) a D10 particle size distribution less than 20 μm, (b) a D50 particle size distribution less than 50 μm, and/or (c) a D90 particle size distribution less than 150 μm. In one aspect, the Compound 4 starting material has a D90 particle size distribution less than 100 μm. In another aspect, the Compound 4 starting material has a particle size distribution that satisfies one or more of the following conditions: (a) a D10 particle size distribution from 1 μm to 20 μm, (b) a D50 particle size distribution from 10 μm to 50 μm, and/or (c) a D90 particle size distribution from 40 μm to 100 μm.
In each and every embodiment, example, preference, and aspect described herein, the granules comprising Compound 4 can, for example, have a particle size distribution after granulation, sieving, and/or milling and prior to compression that satisfies one or more of the following conditions: (a) a D10 particle size distribution less than 100 μm, (b) a D50 particle size distribution less than 300 μm, and/or (c) a D90 particle size distribution less than 600 μm. In one aspect, the granules comprising Compound 4 have a particle size distribution after granulation, sieving, and/or milling and prior to compression that satisfies one or more of the following conditions: (a) a D10 particle size distribution from 1 μm to 100 μm, (b) a D50 particle size distribution from 40 μm to 300 μm, and/or (c) a D90 particle size distribution from 100 μm to 600 μm. In another aspect, the Compound 4 granules have a particle size distribution after granulation, sieving, and/or milling and prior to compression that satisfies one or more of the following conditions: (a) a D10 particle size distribution from 5 μm to 50 μm, (b) a D50 particle size distribution from 80 μm to 130 μm, and/or (c) a D90 particle size distribution from 180 μm to 250 μm.
Further discussion on granulation unit operations can be found, for example, in Food and Drug Administration Guidance for Industry, SUPAC-IR/MR: Immediate Release and Modified Release Solid Oral Dosage Forms, Manufacturing Equipment Addendum (January 1999, CMC 9, Revision 1).
H. Compounds 1, 2, and 3
The total drug loading in the first composition of the dosage form generally will be at least 5% by weight of the first composition. In one aspect, the total amount of Compound 1 (free acid equivalent weight), Compound 2 (free base equivalent weight), and Compound 3 (free base equivalent weight) in the first composition is at least 6% by weight of the first composition. In another aspect, the total amount is at least 8% by weight. In another aspect, the total amount is at least 10% by weight. In another aspect, the total amount is at least 12% by weight. In another aspect, the total amount is 6% to 15% percent by weight. In another aspect, the total amount is 8% to 15% percent by weight. In another aspect, the total amount is 10% to 40% percent by weight. In another aspect, the total amount is 15% to 30% percent by weight. In another aspect, the total amount is 15% to 25% percent by weight. In another aspect, the total amount is 20% to 30% percent by weight. In another aspect, the first composition comprises Compound 1, Compound 2, and Compound 3 at a weight ratio (free acid or free base) of 3:2:24 to 60:3:5 (Compound 1:Compound 2:Compound 3). In another aspect, the first composition comprises Compound 1, Compound 2, and Compound 3 at a weight ratio (free acid or free base) of 10:1:2 to 2:1:3 (Compound 1:Compound 2:Compound 3). In another aspect, the weight ratio is 6:1:4 (Compound 1:Compound 2:Compound 3).
In order to achieve the desired total drug loading, the first composition typically will comprise Compound 1, Compound 2, and Compound 3 in the form of an amorphous solid dispersion. In one embodiment, separate amorphous solid dispersions are prepared for each of Compound 1, Compound 2, and Compound 3 (e.g., individual mono-extrudates) and the separate amorphous solid dispersions are used to prepare the first composition. In another embodiment, a single amorphous solid dispersion comprising Compound 1, Compound 2, and Compound 3 (e.g., a co-extrudate) is prepared and used to prepare the first composition.
1. Individual Mono-Extrudates
In one embodiment of the present disclosure, each of the Compound 1, Compound 2, and Compound 3 components of the first composition is prepared as a separate amorphous solid dispersion comprising the active ingredient using hot melt extrusion technology and is milled prior to blending with the other two amorphous dispersions to form the first composition. Accordingly, in one aspect of the dosage form, the first composition comprises particles of a first amorphous solid dispersion comprising Compound 1; particles of a second amorphous solid dispersion comprising Compound 2; and particles of a third amorphous solid dispersion comprising Compound 3. In another aspect, the first amorphous solid dispersion, second amorphous solid dispersion, and the third amorphous solid dispersion each independently comprise at least one pharmaceutically acceptable hydrophilic polymer and at least one pharmaceutically acceptable surfactant. In another aspect, each hydrophilic polymer has a Tg value of at least 50° C. In another aspect, each hydrophilic polymer is a homopolymer or copolymer of N-vinyl pyrrolidone. In another aspect, the hydrophilic polymer is copovidone. In another aspect, each surfactant has a Hydrophilic-Lipophilic Balance value of at least 10. In another aspect, one or more of the first amorphous solid dispersion, second amorphous solid dispersion, and the third amorphous solid dispersion further comprises another surfactant having a Hydrophilic-Lipophilic Balance value of below 10. In another aspect, the first amorphous solid dispersion comprises propylene glycol monolaurate as the surfactant. In another aspect, the first amorphous solid dispersion further comprises vitamin E tocopheryl polyethylene glycol succinate. In another aspect, the second amorphous solid dispersion comprises vitamin E tocopheryl polyethylene glycol succinate as the surfactant. In another aspect, the third amorphous solid dispersion comprises sorbitan monolaurate as the surfactant.
Additional information regarding the preparation of a Compound 1 mono-extrudate, a Compound 2 mono-extrudate, and a Compound 3 mono-extrudate can be found, for example, in published U.S. application US2011/0312973 and published international application WO2011/156578, both of which are incorporated by reference.
2. Co-Extrudate
In another embodiment of the present disclosure, Compound 1, Compound 2, and Compound 3 are prepared as a single amorphous solid dispersion comprising those three active ingredients using hot melt extrusion technology. The amorphous solid dispersion is milled and used to prepare the first composition.
Drug loads in conventional amorphous solid dispersions of poorly soluble compounds are generally no more than 15% by weight because higher drug loads can lead to a substantial reduction in drug release. Consequently, the Triple Tablet used in clinical trials was prepared from separate solid dispersions of Compound 1, Compound 2, and Compound 3, with each of the three solid dispersions having no more than 15% drug loading. As a result of the low drug loading, the Triple Tablet was relatively large in size.
Moreover, hot melt extrusion, a method commonly used to prepare amorphous solid dispersions, often involves the use of high temperature to assist the formation of a melt that is composed of all components of the final solid dispersion. Certain drug substances, such as Compound 3, can reach unacceptable degradation levels at temperatures of beyond 140° C., which considerably limits the use of the hot melt extrusion process to co-formulate Compound 3 with other drug substance(s) when the other drug substance(s) requires higher temperatures to form a suitable melt.
In contrast to conventional understanding, however, it has been found that Compound 1, Compound 2, and Compound 3 can be co-formulated in an amorphous solid dispersion having an increased total drug loading without compromising drug release. This allows the preparation of smaller solid dosage forms (e.g., tablets) comprising all three drug substances. In addition, when Compound 1, Compound 2, and Compound 3 were co-extruded in the hot melt extrusion process, Compound 3 became less susceptible to degradation at high temperatures. Even at a temperature of 165° C., Compound 3 degradation was well within the acceptable levels.
In one embodiment of the present disclosure, the total weight of Compound 1, Compound 2, and Compound 3 in the amorphous solid dispersion is at least 6% by weight relative to the total weight of the amorphous solid dispersion. In one aspect, the total weight is at least 8% by weight relative to the total weight of the amorphous solid dispersion. In another aspect, the total weight is at least 10% by weight relative to the total weight of the amorphous solid dispersion. In another aspect, the total weight is at least 12% by weight relative to the total weight of the amorphous solid dispersion. In another aspect, the total weight is at least 15% by weight relative to the total weight of the amorphous solid dispersion. In another aspect, the total weight is in excess of 15% by weight relative to the total weight of the amorphous solid dispersion. In another aspect, the total weight ranges from 10% to 40% by weight relative to the total weight of the amorphous solid dispersion. In another aspect, the total weight ranges from 15% to 40% by weight relative to the total weight of the amorphous solid dispersion. In another aspect, the total weight ranges from 20% to 40% by weight relative to the total weight of the amorphous solid dispersion. In another aspect, the total weight ranges from 20% to 30% by weight relative to the total weight of the amorphous solid dispersion. In another aspect, the total weight ranges from 25% to 30% by weight relative to the total weight of the amorphous solid dispersion.
In another embodiment, Compound 1 in the amorphous solid dispersion can range from 10% to 20% by weight relative to the total weight of the amorphous solid dispersion; Compound 2 in the amorphous solid dispersion can range from 2% to 5% by weight relative to the total weight of the amorphous solid dispersion; and Compound 3 in the amorphous solid dispersion can range from 5% to 15% by weight relative to the total weight of the amorphous solid dispersion. In one aspect, Compound 1 in the amorphous solid dispersion can range from 15% to 20% by weight relative to the total weight of the amorphous solid dispersion; Compound 2 in the amorphous solid dispersion can range from 2% to 3% by weight relative to the total weight of the amorphous solid dispersion; and Compound 3 in the amorphous solid dispersion can range from 10% to 15% by weight relative to the total weight of the amorphous solid dispersion. In another aspect, Compound 1 in the amorphous solid dispersion can be 15% by weight relative to the total weight of the amorphous solid dispersion; Compound 2 in the amorphous solid dispersion can range from 2% to 3% by weight relative to the total weight of the amorphous solid dispersion; and Compound 3 in the amorphous solid dispersion can be 10% by weight relative to the total weight of the amorphous solid dispersion.
In another embodiment, the amount of Compound 1 in the amorphous solid dispersion can be, for example, 75 mg; the amount of Compound 2 in the amorphous solid dispersion can be, for example, 12.5 mg; and the amount of Compound 3 in the amorphous solid dispersion can be, for example, 50 mg.
In another embodiment, the amorphous solid dispersion can comprise from 50% to 75% by weight, relative to the total weight of the amorphous solid dispersion, of the polymer, and from 2% to 15% by weight, relative to the total weight of the amorphous solid dispersion, of the surfactant. In one aspect, the amorphous solid dispersion can comprise from 50% to 70% by weight, relative to the total weight of the amorphous solid dispersion, of the polymer, and from 5% to 15% by weight, relative to the total weight of the amorphous solid dispersion, of the surfactant. In another aspect, the amorphous solid dispersion can comprise from 55% to 65% by weight, relative to the total weight of the amorphous solid dispersion, of the polymer, and from 5% to 10% by weight, relative to the total weight of the amorphous solid dispersion, of the surfactant. In another aspect, the amorphous solid dispersion can comprise from 60% to 65% by weight, relative to the total weight of the amorphous solid dispersion, of the polymer, and from 5% to 10% by weight, relative to the total weight of the amorphous solid dispersion, of the surfactant.
In another embodiment, the amorphous solid dispersion can be prepared as a compressed core (e.g., a tablet core, layer, or the like), onto which another layer of other excipients or ingredients can be optionally added. For example, the amorphous solid dispersion can be milled, mixed with other excipients or ingredients to form the first composition, and the first composition compressed to form the core. In one aspect, the polymer in the amorphous solid dispersion can range from 50% to 75% by weight relative to the total weight of the compressed core, and the surfactant in the amorphous solid dispersion can range from 5 to 15% by weight relative to the total weight of the compressed core. In another aspect, the polymer in the amorphous solid dispersion can range from 50% to 70% by weight relative to the total weight of the compressed core, and the surfactant in the amorphous solid dispersion can range from 5 to 15% by weight relative to the total weight of the compressed core. In another aspect, the polymer in the amorphous solid dispersion can range from 55% to 65% by weight relative to the total weight of the compressed core, and the surfactant in the amorphous solid dispersion can range from 5 to 10% by weight relative to the total weight of the compressed core. In another aspect, the polymer in the amorphous solid dispersion can range from 60% to 65% by weight relative to the total weight of the compressed core, and the surfactant in the amorphous solid dispersion can range from 5 to 10% by weight relative to the total weight of the compressed core.
In another embodiment, the total weight of Compound 1, Compound 2, and Compound 3 in the amorphous solid dispersion can range from 20% to 40% by weight relative to the total weight of the compressed core. In one aspect, the total weight of Compound 1, Compound 2, and Compound 3 in the amorphous solid dispersion can range from 20% to 30% by weight relative to the total weight of the compressed core. In another aspect, the total weight of Compound 1, Compound 2, and Compound 3 in the amorphous solid dispersion can range from 25% to 30% by weight relative to the total weight of the compressed core. In another aspect, Compound 1 in the amorphous solid dispersion can range from 10% to 20% by weight relative to the total weight of the compressed core; Compound 2 in the amorphous solid dispersion can range from 2% to 5% by weight relative to the total weight of the compressed core; and Compound 3 in the amorphous solid dispersion can range from 5% to 15% by weight relative to the total weight of the compressed core. In another aspect, Compound 1 in the amorphous solid dispersion can range from 15% to 20% by weight relative to the total weight of the compressed core; Compound 2 in the amorphous solid dispersion can range from 2% to 3% by weight relative to the total weight of the compressed core; and Compound 3 in the amorphous solid dispersion can range from 10% to 15% by weight relative to the total weight of the compressed core. In another aspect, Compound 1 in the amorphous solid dispersion can be 15% by weight relative to the total weight of the compressed core; Compound 2 in the amorphous solid dispersion can range from 2% to 3% by weight relative to the total weight of the compressed core; and Compound 3 in the amorphous solid dispersion can be 10% by weight relative to the total weight of the compressed core.
In another embodiment, the hydrophilic polymer can have a Tg of at least 50° C. In one aspect, the hydrophilic polymer has a Tg of at least 80° C. In another aspect, the hydrophilic polymer has a Tg of at least 100° C. In another aspect, the hydrophilic polymer can have a Tg of from 80° C. to 180° C. In another aspect, the hydrophilic polymer can have a Tg of from 100° C. to 150° C.
Although the first composition can comprise a poorly water-soluble or water-insoluble polymer (such as a cross-linked polymer), the first composition generally will comprise a hydrophilic polymer that is a water-soluble polymer. In one aspect, the hydrophilic polymer has an apparent viscosity, when dissolved at 20° C. in an aqueous solution at 2% (w/v), of 1 to 5000 mPa·s. In another aspect, the hydrophilic polymer has an apparent viscosity, when dissolved at 20° C. in an aqueous solution at 2% (w/v), of 1 to 700 mPa·s. In another aspect, the hydrophilic polymer has an apparent viscosity, when dissolved at 20° C. in an aqueous solution at 2% (w/v), of 5 to 100 mPa·s.
The hydrophilic polymer can be selected, for example, from the group consisting of homopolymer of N-vinyl lactam, copolymer of N-vinyl lactam, cellulose ester, cellulose ether, polyalkylene oxide, polyacrylate, polymethacrylate, polyacrylamide, polyvinyl alcohol, vinyl acetate polymer, oligosaccharide, polysaccharide, or combinations thereof. Non-limiting examples of suitable hydrophilic polymers include homopolymer of N-vinyl pyrrolidone, copolymer of N-vinyl pyrrolidone, copolymer of N-vinyl pyrrolidone and vinyl acetate, copolymer of N-vinyl pyrrolidone and vinyl propionate, polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxyalkylcelluloses, hydroxypropylcellulose, hydroxyalkylalkylcellulose, hydroxypropyl methylcellulose, cellulose phthalate, cellulose succinate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose succinate, hydroxypropyl methylcellulose acetate succinate, polyethylene oxide, polypropylene oxide, copolymer of ethylene oxide and propylene oxide, methacrylic acid/ethyl acrylate copolymer, methacrylic acid/methyl methacrylate copolymer, butyl methacrylate/2-dimethylaminoethyl methacrylate copolymer, poly(hydroxyalkyl acrylate), poly(hydroxyalkyl methacrylate), copolymer of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate, carrageenan, galactomannan, xanthan gum, and combinations thereof. In one aspect, the hydrophilic polymer is copovidone. In another aspect, the hydrophilic polymer is a homopolymer or copolymer of N-vinyl pyrrolidone.
Although the first composition can comprise a surfactant having a Hydrophobic-Lipophilic Balance (“HLB”) value less than 10, the first composition generally will comprise a surfactant having an HLB value of at least 10. In one embodiment, the first composition comprises a first surfactant having an HLB of at least 10 and a second surfactant having an HLB value of less than 10, and both surfactants are co-formulated in the amorphous solid dispersion.
The surfactant can be selected, for example, from the group consisting of polyoxyethylene castor oil derivates, mono fatty acid ester of polyoxyethylene sorbitan, polyoxyethylene alkyl ether, polyoxyethylene alkylaryl ether, polyethylene glycol fatty acid ester, alkylene glycol fatty acid mono ester, sucrose fatty acid ester, sorbitan fatty acid mono ester, and combinations thereof. Non-limiting examples of suitable surfactants include polyoxyethyleneglycerol triricinoleate or polyoxyl 35 castor oil (Cremophor® EL; BASF Corp.) or polyoxyethyleneglycerol oxystearate such as polyethylenglycol 40 hydrogenated castor oil (Cremophor® RH 40, also known as polyoxyl 40 hydrogenated castor oil or macrogolglycerol hydroxystearate) or polyethylenglycol 60 hydrogenated castor oil (Cremophor® RH 60), mono fatty acid ester of polyoxyethylene sorbitan, such as mono fatty acid ester of polyoxyethylene (20) sorbitan, e.g. polyoxyethylene (20) sorbitan monooleate (Tween® 80), polyoxyethylene (20) sorbitan monostearate (Tween® 60), polyoxyethylene (20) sorbitan monopalmitate (Tween® 40) or polyoxyethylene (20) sorbitan monolaurate (Tween® 20), polyoxyethylene (3) lauryl ether, polyoxyethylene (5) cetyl ether, polyoxyethylene (2) stearyl ether, polyoxyethylene (5) stearyl ether, polyoxyethylene (2) nonylphenyl ether, polyoxyethylene (3) nonylphenyl ether, polyoxyethylene (4) nonylphenyl ether, polyoxyethylene (3) octylphenyl ether, PEG-200 monolaurate, PEG-200 dilaurate, PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearate, PEG-300 dioleate, propylene glycol monolaurate (e.g., Lauroglycol), sucrose monostearate, sucrose distearate, sucrose monolaurate, sucrose dilaurate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalnitate, sorbitan stearate, or combinations thereof. In one aspect, the surfactant is D-alpha-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS).
In one embodiment, the polymer is copovidone, and the surfactant is vitamin E TPGS. In another aspect, the polymer is copovidone, the surfactant is vitamin E TPGS, and the amorphous solid dispersion further comprises propylene glycol monolaurate (e.g., Lauroglycol). Propylene glycol monolaurate can range, for example, from 1% to 5% by weight relative to the total weight of the amorphous solid dispersion. Propylene glycol monolaurate can also range, for example, from 1% to 3% by weight relative to the total weight of the amorphous solid dispersion.
In another embodiment, first composition comprises 75 mg of Compound 1, 12.5 mg of Compound 2, and 50 mg of Compound 3, all of which are co-formulated with a pharmaceutically acceptable hydrophilic polymer and a pharmaceutically acceptable surfactant in amorphous solid dispersion, wherein the polymer in the amorphous solid dispersion ranges from 50% to 70% by weight relative to the total weight of the amorphous solid dispersion, and the surfactant in the amorphous solid dispersion ranges from 5% to 15% by weight relative to the total weight of the amorphous solid dispersion. In one aspect, the polymer is copovidone, and the surfactant is vitamin E TPGS. In another aspect, the amorphous solid dispersion further comprises from 1% to 5% by weight of propylene glycol monolaurate, relative to the total weight of the amorphous solid dispersion. In another aspect, the amorphous solid dispersion further comprises from 1% to 3% by weight of propylene glycol monolaurate.
In another embodiment, the first composition comprises 75 mg of Compound 1, 12.5 mg of Compound 2, and 50 mg of Compound 3, all of which are co-formulated with a pharmaceutically acceptable hydrophilic polymer and a pharmaceutically acceptable surfactant in amorphous solid dispersion, wherein the polymer in the amorphous solid dispersion ranges from 55% to 65% by weight relative to the total weight of the amorphous solid dispersion, and the surfactant in the amorphous solid dispersion ranges from 5% to 10% by weight relative to the total weight of the amorphous solid dispersion. In one aspect, the polymer is copovidone, and the surfactant is vitamin E TPGS. In another aspect, the amorphous solid dispersion further comprises from 1% to 5% by weight of propylene glycol monolaurate, relative to the total weight of the amorphous solid dispersion. In another aspect, the amorphous solid dispersion further comprises from 1% to 3% by weight of propylene glycol monolaurate.
In another embodiment, the first composition comprises 75 mg of Compound 1, 12.5 mg of Compound 2, and 50 mg of Compound 3, all of which are co-formulated with a pharmaceutically acceptable hydrophilic polymer and a pharmaceutically acceptable surfactant in amorphous solid dispersion, wherein the polymer in the amorphous solid dispersion ranges from 60% to 65% by weight relative to the total weight of the amorphous solid dispersion, and the surfactant in the amorphous solid dispersion ranges from 5% to 10% by weight relative to the total weight of the amorphous solid dispersion. In one aspect, the polymer is copovidone, and the surfactant is vitamin E TPGS. In another aspect, the amorphous solid dispersion further comprises from 1% to 5% by weight of propylene glycol monolaurate, relative to the total weight of the amorphous solid dispersion. In another aspect, the amorphous solid dispersion further comprises from 1% to 3% by weight of propylene glycol monolaurate.
In another embodiment, the first composition comprises a compressed core which includes 75 mg of Compound 1, 12.5 mg of Compound 2, and 50 mg of Compound 3, all of which are co-formulated with a pharmaceutically acceptable hydrophilic polymer and a pharmaceutically acceptable surfactant in amorphous solid dispersion, wherein the total weight of the compressed core is no more than 800 mg. In one aspect, the polymer is copovidone, and the surfactant is vitamin E TPGS, and the amorphous solid dispersion further comprises propylene glycol monolaurate.
In another embodiment, the first composition comprises a compressed core which includes 75 mg of Compound 1, 12.5 mg of Compound 2, and 50 mg of Compound 3, all of which are co-formulated with a pharmaceutically acceptable hydrophilic polymer and a pharmaceutically acceptable surfactant in amorphous solid dispersion, wherein the total weight of the compressed core is no more than 700 mg. In one aspect, the polymer is copovidone, and the surfactant is vitamin E TPGS, and the amorphous solid dispersion further comprises propylene glycol monolaurate.
In another embodiment, the first composition comprises a compressed core which includes 75 mg of Compound 1, 12.5 mg of Compound 2, and 50 mg of Compound 3, all of which are co-formulated with a pharmaceutically acceptable hydrophilic polymer and a pharmaceutically acceptable surfactant in amorphous solid dispersion, wherein the total weight of the compressed core is no more than 600 mg. In one aspect, the polymer is copovidone, and the surfactant is vitamin E TPGS, and the amorphous solid dispersion further comprises propylene glycol monolaurate.
In another embodiment, the first composition comprises a compressed core which includes 75 mg of Compound 1, 12.5 mg of Compound 2, and 50 mg of Compound 3, all of which are co-formulated with a pharmaceutically acceptable hydrophilic polymer and a pharmaceutically acceptable surfactant in amorphous solid dispersion, wherein the total weight of the compressed core is no more than 500 mg. In one aspect, the polymer is copovidone, and the surfactant is vitamin E TPGS, and the amorphous solid dispersion further comprises propylene glycol monolaurate.
In another embodiment, the first composition comprises a compressed core which includes 75 mg of Compound 1, 12.5 mg of Compound 2, and 50 mg of Compound 3, all of which are co-formulated with a pharmaceutically acceptable hydrophilic polymer and a pharmaceutically acceptable surfactant in amorphous solid dispersion, wherein the total weight of the compressed core ranges from 400 mg to 500 mg. In one aspect, the polymer is copovidone, and the surfactant is vitamin E TPGS, and the amorphous solid dispersion further comprises propylene glycol monolaurate.
In another embodiment, the first composition comprises a compressed core which includes 75 mg of Compound 1, 12.5 mg of Compound 2, and 50 mg of Compound 3, all of which are co-formulated with a pharmaceutically acceptable hydrophilic polymer and a pharmaceutically acceptable surfactant in amorphous solid dispersion, wherein the total weight of the compressed core ranges from 500 mg to 600 mg. In one aspect, the polymer is copovidone, and the surfactant is vitamin E TPGS, and the amorphous solid dispersion further comprises propylene glycol monolaurate.
In another embodiment, the first composition comprises a compressed core which includes 75 mg of Compound 1, 12.5 mg of Compound 2, and 50 mg of Compound 3, all of which are co-formulated with a pharmaceutically acceptable hydrophilic polymer and a pharmaceutically acceptable surfactant in amorphous solid dispersion, wherein the total weight of the compressed core ranges from 600 mg to 700 mg. In one aspect, the polymer is copovidone, and the surfactant is vitamin E TPGS, and the amorphous solid dispersion further comprises propylene glycol monolaurate
In another embodiment, the first composition comprises a compressed core which includes 75 mg of Compound 1, 12.5 mg of Compound 2, and 50 mg of Compound 3, all of which are co-formulated with a pharmaceutically acceptable hydrophilic polymer and a pharmaceutically acceptable surfactant in amorphous solid dispersion, wherein the total weight of the compressed core ranges from 450 mg to 500 mg. In one aspect, the polymer is copovidone, and the surfactant is vitamin E TPGS, and the amorphous solid dispersion further comprises propylene glycol monolaurate.
In another embodiment, the first composition comprises a compressed core which includes 75 mg of Compound 1, 12.5 mg of Compound 2, and 50 mg of Compound 3, all of which are co-formulated with a pharmaceutically acceptable hydrophilic polymer and a pharmaceutically acceptable surfactant in amorphous solid dispersion, wherein the total weight of the compressed core is 500 mg. In one aspect, the polymer is copovidone, and the surfactant is vitamin E TPGS, and the amorphous solid dispersion further comprises propylene glycol monolaurate.
In one embodiment, the amorphous solid dispersion is a solid solution, glass solution, or glass suspension. These types of amorphous solid dispersions are discussed, for example, in Chiou, W. L. and Riegelman, S. (1971), Pharmaceutical applications of solid dispersion systems. J. Pharm. Sci., 60: 1281-1302. In one aspect, the amorphous solid dispersion is a solid solution. In another embodiment, the amorphous solid dispersion is a glassy solution.
In another embodiment, the amorphous solid dispersion comprises or consists of a single-phase (as defined in thermodynamics) in which Compound 1, Compound 2, and Compound 3 are molecularly dispersed in a matrix containing the pharmaceutically acceptable hydrophilic polymer and the pharmaceutically acceptable surfactant. Thermal analysis of the amorphous solid dispersion using differential scanning calorimetry (DSC) typically shows only one single Tg, and the amorphous solid dispersion typically does not contain any detectable crystalline compound as measured by X-ray powder diffraction spectroscopy.
I. Additional Excipients
The dosage form optionally may comprise other excipients such as, for example, fillers, disintegrants, glidants, and lubricants. The term “excipient” is used in this disclosure to describe any ingredient other than Compound 1, Compound 2, Compound 3, or Compound 4. The choice of additional excipient(s) will depend to a large extent on factors such as, for example, the effect of the excipient on solubility and stability. The drug loading requirements and resulting dosage form size, however, may effectively limit the amount of additional excipients that may be included in the dosage form.
Examples of pharmaceutically acceptable fillers include, without limitation, microcrystalline cellulose, such as Avicel PH 101, Avicel PH102, Avicel PH 200, Avicel PH 105, Avicel DG, Ceolus KG 802, Ceolus KG 1000, SMCC50 and Vivapur 200; lactose monohydrate, such as Lactose FastFlo; microcrystalline cellulose co-processed with other excipeints, such as microcrystalline cellulose co-processed with lactose monohydrate (MicroceLac 100) and microcrystalline cellulose co-processed with colloidal silicon dioxide (SMCC50, Prosolv 50 and Prosolv HD 90); mixtures of isomaltulose derivatives such as galenIQ; natural or pre-gelatinized potato or corn starch; and other suitable fillers and combinations thereof.
Examples of pharmaceutically acceptable disintegrants include, without limitation, cross-linked polymers such as cross-linked polyvinyl pyrrolidone and cross-linked sodium carboxymethylcellulose (including croscarmellose sodium).
Examples of pharmaceutically acceptable glidants include, without limitation, colloidal silicon dioxide (such as highly dispersed silica (Aerosil®)) and any other suitable glidant such as animal or vegetable fats or waxes.
Examples of pharmaceutically acceptable lubricants include, without limitation, polyethylene glycol (e.g., having a molecular weight of from 1000 to 6000), magnesium stearate, calcium stearate, sodium stearyl fumarate, and talc.
J. In Vitro and In Vivo Properties of Dosage Form
1. In Vitro Properties
In one aspect, the pharmaceutically acceptable release rate-modifying polymer, or combination of pharmaceutically acceptable release rate-modifying polymers, modifies an in vitro release rate from the dosage form of at least one of the compounds within the dosage form to be less than 75% to less than 35% of the in vitro release rate of the compound from an otherwise identical dosage form lacking the release rate-modifying polymer, or combination of release rate-modifying polymers.
In one aspect, the pharmaceutically acceptable release rate-modifying polymer, or combination of pharmaceutically acceptable release rate-modifying polymers, modifies an in vitro release rate from the dosage form of at least one of the compounds within the dosage form to be less than 75% to less than 35% of the in vitro release rate of the compound from an otherwise identical dosage form lacking the release rate-modifying polymer, or combination of release rate-modifying polymers as determined by a dissolution test conducted in 900 mL of a dissolution medium comprising a 0.05 M sodium phosphate buffer pH 6.8 with 15 mM cTAB as a surfactant using a standard USP dissolution Apparatus 2 (paddle) with sinker operating at 100 RPM at 37±0.5° C.
In one aspect, the pharmaceutically acceptable release rate-modifying polymer, or combination of pharmaceutically acceptable release rate-modifying polymers, modifies an in vitro release rate from the dosage form of at least one of the compounds within the dosage form to be an average in vitro release rate for the compound of 1.0 weight percent/hour (based on the total weight of the compound in the dosage form) to 6.0 weight percent/hour over a sixteen-hour period. In one aspect, the pharmaceutically acceptable release rate-modifying polymer, or combination of pharmaceutically acceptable release rate-modifying polymers, modifies an in vitro release rate from the dosage form of at least one of the compounds within the dosage form to be an average in vitro release rate for the compound of 1.0 weight percent/hour (based on the total weight of the compound in the dosage form) to 6.0 weight percent/hour over a sixteen-hour period as determined by a dissolution test conducted in 900 mL of a dissolution medium comprising a 0.05 M sodium phosphate buffer pH 6.8 with 15 mM cTAB as a surfactant using a standard USP dissolution Apparatus 2 (paddle) with sinker operating at 100 RPM at 37±0.5° C.
In one aspect, the pharmaceutically acceptable release rate-modifying polymer, or combination of pharmaceutically acceptable release rate-modifying polymers, modifies an in vitro release rate from the dosage form of at least one of the compounds within the dosage form to be an average in vitro release rate for the compound of 5 mg/hour to 16 mg/hour over a sixteen-hour period.
In one aspect, the pharmaceutically acceptable release rate-modifying polymer, or combination of pharmaceutically acceptable release rate-modifying polymers, modifies an in vitro release rate from the dosage form of at least one of the compounds within the dosage form to be an average in vitro release rate for the compound of 5 mg/hour to 16 mg/hour over a sixteen-hour period as determined by a dissolution test conducted in 900 mL of a dissolution medium comprising a 0.05 M sodium phosphate buffer pH 6.8 with 15 mM cTAB as a surfactant using a standard USP dissolution Apparatus 2 (paddle) with sinker operating at 100 RPM at 37±0.5° C.
a. Compound 4
In one aspect, the pharmaceutically acceptable release rate-modifying polymer, or combination of pharmaceutically acceptable release rate-modifying polymers, modifies an in vitro release rate of Compound 4 from the dosage form to be less than less than 75% to less than 35% of the in vitro release rate of Compound 4 from an otherwise identical dosage form lacking the release rate-modifying polymer, or combination of release rate-modifying polymers.
In one embodiment, the dosage forms of the present disclosure exhibit an in vitro release rate that is less than 75% of the in vitro release rate exhibited by an otherwise identical dosage form lacking the release rate-modifying polymer, or combination of release rate-modifying polymers, wherein the in vitro release rate is determined using the dissolution test described below in Section II.J.1.c, and represents the average in vitro release rate (mg/hour) for Compound 4 over a four-hour period. In one aspect, the in vitro release rate is less than 65% of the in vitro release rate exhibited by an otherwise identical dosage form lacking the release rate-modifying polymer, or combination of release rate-modifying polymers. In another aspect, the in vitro release rate is less than 55% of the in vitro release rate exhibited by an otherwise identical dosage form lacking the release rate-modifying polymer, or combination of release rate-modifying polymers. In another aspect, the in vitro release rate is less than 45% of the in vitro release rate exhibited by an otherwise identical dosage form lacking the release rate-modifying polymer, or combination of release rate-modifying polymers. In another aspect, the in vitro release rate is less than 35% of the in vitro release rate exhibited by an otherwise identical dosage form lacking the release rate-modifying polymer, or combination of release rate-modifying polymers. In one aspect, the pharmaceutically acceptable release rate-modifying polymer, or combination of pharmaceutically acceptable release rate-modifying polymers, modifies an in vitro release rate of Compound 4 from the dosage form to be an average in vitro release rate for of Compound 4 of 1.0 weight percent/hour (based on the total weight of the compound in the dosage form) to 6.0 weight percent/hour over a sixteen-hour period.
In another embodiment, the dosage forms of the present disclosure exhibit an average in vitro release rate for Compound 4 over a 16 hour period of 1.0 weight percent/hour (based on the total weight of Compound 4 in the dosage form) to 6.0 weight percent/hour as determined using the dissolution test described below in Section II.J.1.c. In one aspect, the average in vitro release rate over a 16 hour period is 1.5 weight percent/hour to 5.5 weight percent/hour. In another aspect, the average in vitro release rate over a 16 hour period is 2.0 weight percent/hour to 5.0 weight percent/hour. In another aspect, the average in vitro release rate over a 16 hour period is 2.0 weight percent/hour to 4.5 weight percent/hour. In another aspect, the average in vitro release rate over a 16 hour period is 2.0 weight percent/hour to 4.0 weight percent/hour. In another aspect, the average in vitro release rate over a 16 hour period is 3.0 weight percent/hour to 3.5 weight percent/hour.
In one aspect, the pharmaceutically acceptable release rate-modifying polymer, or combination of pharmaceutically acceptable release rate-modifying polymers, modifies an in vitro release rate of Compound 4 from the dosage form to be an average in vitro release rate for the compound over a 16 hour period of 1.0 weight percent/hour (based on the total weight of Compound 4 in the dosage form) to 6.0 weight percent/hour as determined by a dissolution test conducted in 900 mL of a dissolution medium comprising a 0.05 M sodium phosphate buffer pH 6.8 with 15 mM cTAB as a surfactant using a standard USP dissolution Apparatus 2 (paddle) with sinker operating at 100 RPM at 37±0.5° C. In one aspect, the pharmaceutically acceptable release rate-modifying polymer, or combination of pharmaceutically acceptable release rate-modifying polymers, modifies an in vitro release rate of Compound 4 from the dosage form to be an average in vitro release rate of 5 mg/hour to 16 mg/hour over a sixteen-hour period.
In one aspect, the pharmaceutically acceptable release rate-modifying polymer, or combination of pharmaceutically acceptable release rate-modifying polymers, modifies an in vitro release rate of Compound 4 from the dosage form to be an average in vitro release rate of 5 mg/hour to 16 mg/hour over a 16 hour period.
In another embodiment, the dosage forms of the present disclosure exhibit an average in vitro release rate for Compound 4 over a 16 hour period of 10 mg/hour to 16 mg/hour as determined using the dissolution test described below in Section II.J.1.c. In one aspect, the average in vitro release rate over a 16 hour period is 10 mg/hour to 14 mg/hour. In another aspect, the average in vitro release rate over a 16 hour period is 10 mg/hour to 12 mg/hour. In another aspect, the average in vitro release rate over a 16 hour period is 5 mg/hour to 10 mg/hour. In another aspect, the average in vitro release rate over a 16 hour period is 6 mg/hour to 9 mg/hour. In another aspect, the average in vitro release rate over a 16 hour period is 7 mg/hour to 9 mg/hour.
In one aspect, the pharmaceutically acceptable release rate-modifying polymer, or combination of pharmaceutically acceptable release rate-modifying polymers, modifies an in vitro release rate of Compound 4 from the dosage form to be an average in vitro release rate for the compound of 5 mg/hour to 16 mg/hour over a sixteen-hour period as determined by a dissolution test conducted in 900 mL of a dissolution medium comprising a 0.05 M sodium phosphate buffer pH 6.8 with 15 mM cTAB as a surfactant using a standard USP dissolution Apparatus 2 (paddle) with sinker operating at 100 RPM at 37±0.5° C.
b. Compounds 1, 2, and 3
In one embodiment, the dosage forms of the present disclosure release at least 40% by weight of each of Compounds 1, 2, and 3 within five hours as determined using the dissolution test described below in Section II.J.1.c. In one aspect, the dosage form releases at least 70% of each of Compounds 1, 2, and 3 within ten hours. In one embodiment, the dosage forms of the present disclosure release at least 40% by weight of each of Compounds 1, 2, and 3 within five hours, and at least 70% of each of Compounds 1, 2, and 3 within ten hours.
In one embodiment, the dosage forms of the present disclosure release at least 40% by weight of each of Compounds 1, 2, and 3 within five hours, and the dosage form releases at least 70% of each of Compounds 1, 2, and 3 within ten hours as determined by a dissolution test conducted in 900 mL of a dissolution medium comprising a 0.05 M sodium phosphate buffer pH 6.8 with 15 mM cTAB as a surfactant using a standard USP dissolution Apparatus 2 (paddle) with sinker operating at 100 RPM at 37±0.5° C.
c. Dissolution Test
The in vitro dissolution test used for evaluating the in vitro release properties of the dosage form as described above in Sections II.J.1.a and II.J.1.b is conducted in 900 mL of a dissolution medium comprising a 0.05 M sodium phosphate buffer pH 6.8 with 15 mM cTAB as a surfactant using a standard USP dissolution Apparatus 2 (paddle) with sinker operating at 100 RPM at 37±0.5° C.
2. In Vivo Properties
While the dosage forms of the present disclosure generally will be administered pursuant to a dosage regimen that comprises administering one to four of the dosage forms once daily to the subject or administering two or three of the dosage forms once daily to the subject, each regimen is designed to provide in vivo results within a targeted therapeutic window.
a. Compound 4
In one embodiment, the present disclosure relates to dosage forms that, when administered once daily to a population of human subjects in accordance with a dosing regimen that provides a daily therapeutic amount of Compounds 1, 2, 3, and 4 to the subject, satisfy one or more of the following conditions:

    
    
        (a) the average Cmax value for Compound 4 in the population of human subjects is from 400 ng/mL to 2,000 ng/mL;
        (b) the average AUC∞ value for Compound 4 in the population of human subjects is from 4,000 ng·hr/mL to 30,000 ng·hr/mL;
        (c) the average Tmax value for Compound 4 in the population of human subjects is from 2.5 hours to 10 hours; and/or
        (d) the average C24 value for Compound 4 in the population of human subjects is from 20 ng/mL to 400 ng/mL.

In one aspect, the daily dosing regimen comprises administering two of the dosage forms once daily to the subject. In another aspect, the daily dosing regimen comprises administering three of the dosage forms once daily to the subject. In another aspect, the dosage forms are administered under non-fasting conditions. In another aspect, the dosage forms are administered under fasting conditions. In another aspect, the daily dosing regimen comprises administering the two or more dosage forms at substantially the same time.

    
    


In another embodiment, the present disclosure relates to dosage forms that, when administered once daily to a population of human subjects in accordance with a dosing regimen that provides a daily therapeutic amount of Compounds 1, 2, 3, and 4 to the subject, satisfy one or more of the following conditions:

    
    
        (a) the average Cmax value for Compound 4 in the population of human subjects is from 750 ng/mL to 1,500 ng/mL;
        (b) the average AUC∞ value for Compound 4 in the population of human subjects is from 6,000 ng·hr/mL to 20,000 ng·hr/mL;
        (c) the average Tmax value for Compound 4 in the population of human subjects is from 4 hours to 10 hours; and/or
        (d) the average C24 value for Compound 4 in the population of human subjects is from 150 ng/mL to 400 ng/mL.
    
    


b. Compound 1
In one embodiment, the present disclosure relates to dosage forms that, when administered once daily to a population of human subjects in accordance with a dosing regimen that provides a daily therapeutic amount of Compounds 1, 2, 3, and 4 to the subject, satisfy one or more of the following conditions:

    
    
        (a) the average Cmax value for Compound 1 in the population of human subjects is from 200 ng/mL to 4,000 ng/mL;
        (b) the average AUC∞ value for Compound 1 in the population of human subjects is from 2,000 ng·hr/mL to 25,000 ng·hr/mL; and/or
        (c) the average Tmax value for Compound 1 in the population of human subjects is from 3 hours to 8 hours.

In one aspect, the daily dosing regimen comprises administering two of the dosage forms once daily to the subject. In another aspect, the daily dosing regimen comprises administering three of the dosage forms once daily to the subject. In another aspect, the dosage forms are administered under non-fasting conditions. In another aspect, the dosage forms are administered under fasting conditions. In another aspect, the daily dosing regimen comprises administering the two or more dosage forms at substantially the same time.

    
    


In another embodiment, the present disclosure relates to dosage forms that, when administered once daily to a population of human subjects in accordance with a dosing regimen that provides a daily therapeutic amount of Compounds 1, 2, 3, and 4 to the subject, satisfy one or more of the following conditions:

    
    
        (a) the average Cmax value for Compound 1 in the population of human subjects is from 350 ng/mL to 2,200 ng/mL;
        (b) the average AUC∞ value for Compound 1 in the population of human subjects is from 2,500 ng·hr/mL to 15,000 ng·hr/mL; and/or
        (c) the average Tmax value for Compound 1 in the population of human subjects is from 4 hours to 7 hours.
    
    


c. Compound 2
In one embodiment, the present disclosure relates to dosage forms that, when administered once daily to a population of human subjects in accordance with a dosing regimen that provides a daily therapeutic amount of Compounds 1, 2, 3, and 4 to the subject, satisfy one or more of the following conditions:

    
    
        (a) the average Cmax value for Compound 2 in the population of human subjects is from 50 ng/mL to 200 ng/mL;
        (b) the average AUC∞ value for Compound 2 in the population of human subjects is from 800 ng·hr/mL to 2,000 ng·hr/mL; and/or
        (c) the average Tmax value for Compound 2 in the population of human subjects is from 3 hours to 7 hours.

In one aspect, the daily dosing regimen comprises administering two of the dosage forms once daily to the subject. In another aspect, the daily dosing regimen comprises administering three of the dosage forms once daily to the subject. In another aspect, the dosage forms are administered under non-fasting conditions. In another aspect, the dosage forms are administered under fasting conditions. In another aspect, the daily dosing regimen comprises administering the two or more dosage forms at substantially the same time.

    
    


In another embodiment, the present disclosure relates to dosage forms that, when administered once daily to a population of human subjects in accordance with a dosing regimen that provides a daily therapeutic amount of Compounds 1, 2, 3, and 4 to the subject, satisfy one or more of the following conditions:

    
    
        (a) the average Cmax value for Compound 2 in the population of human subjects is from 90 ng/mL to 180 ng/mL;
        (b) the average AUC∞ value for Compound 2 in the population of human subjects is from 1,000 ng·hr/mL to 2,000 ng·hr/mL; and/or
        (c) the average Tmax value for Compound 2 in the population of human subjects is from 4 hours to 6 hours.
    
    


d. Compound 3
In one embodiment, the present disclosure relates to dosage forms that, when administered once daily to a population of human subjects in accordance with a dosing regimen that provides a daily therapeutic amount of Compounds 1, 2, 3, and 4 to the subject, satisfy one or more of the following conditions:

    
    
        (a) the average Cmax value for Compound 3 in the population of human subjects is from 500 ng/mL to 2,500 ng/mL;
        (b) the average AUC∞ value for Compound 3 in the population of human subjects is from 3,000 ng·hr/mL to 18,000 ng·hr/mL; and/or
        (c) the average Tmax value for Compound 3 in the population of human subjects is from 3 hours to 7 hours.
    
    


In one aspect, the daily dosing regimen comprises administering two of the dosage forms once daily to the subject. In another aspect, the daily dosing regimen comprises administering three of the dosage forms once daily to the subject. In another aspect, the dosage forms are administered under non-fasting conditions. In another aspect, the dosage forms are administered under fasting conditions. In another aspect, the daily dosing regimen comprises administering the two or more dosage forms at substantially the same time.
In another embodiment, the present disclosure relates to dosage forms that, when administered once daily to a population of human subjects in accordance with a dosing regimen that provides a daily therapeutic amount of Compounds 1, 2, 3, and 4 to the subject, satisfy one or more of the following conditions:

    
    
        (a) the average Cm, value for Compound 3 in the population of human subjects is from 700 ng/mL to 2.000 ng/mL;
        (b) the average AUC∞ value for Compound 3 in the population of human subjects is from 4,000 ng·hr/mL to 12,000 ng·hr/mL; and/or
        (c) the average Tmax value for Compound 3 in the population of human subjects is from 3.5 hours to 6 hours.
    
    


K. Dosage Form Size and Type
The dosage forms of the present disclosure generally will have a weight less than 1500 mg. In one aspect, oral dosage form has a weight less than 1450 mg. In another aspect, the dosage form has a weight less than 1400 mg. In another aspect, the oral dosage form has a weight less than 1350 mg.
In one embodiment, the dosage form is a tablet. In one aspect, the dosage form is a tablet having a weight from 500 mg to 1500 mg. In another aspect, the dosage form is a tablet having a weight from 900 mg to 1500 mg. In another aspect, the tablet is coated with a polymer coating. In another aspect, the tablet hardness is from 15 kP to 45 kP. In another aspect, the tablet hardness is from 25 kP to 35 kP.
In another embodiment, the dosage form is a tablet comprising at least a first layer and a second layer. The first layer comprises the previously described first composition, and the second layer comprises the previously described second composition.
In another embodiment, the dosage form is a bilayer tablet comprising a first layer comprising the previously described first composition and a second layer comprising the previously described second composition.
In another embodiment, the dosage form is a trilayer tablet comprising a first layer comprising the first composition, a second layer comprising the second composition, and a third layer comprising an immediate release composition comprising Compound 4.
In another embodiment, the dosage form is a tablet comprising a core and at least one exterior layer, wherein the core comprises the first composition and the second composition; and the exterior layer comprises Compound 4. In one aspect, the dosage form is a tablet comprising a core and an exterior layer, wherein the core comprises the first composition and the second composition; and the exterior layer comprises an immediate release composition comprising Compound 4.
In another embodiment, the dosage form is a tablet comprising at least one outer layer comprising the active ingredients Compound 1, Compound 2, Compound 3, and Compound 4, and a second inner core tablet comprising a delayed release composition comprising Compound 4.
In another embodiment, the dosage form is a capsule comprising the first composition and the second composition.
In another embodiment, the dosage form is a sachet comprising the first composition and the second composition.
In another embodiment, the dosage form is a combination of mini-tablets. In one aspect, the dosage form comprising the combination of mini-tablets is selected from the group consisting of a compressed disintegrable tablet, an orally dispersible dosage form, a capsule, and a sachet. In another aspect, the dosage form comprising the combination of mini-tablets is a compressed disintegrable tablet. In another aspect, the dosage form comprising the combination of mini-tablets is an orally dispersible dosage form. In another aspect, the dosage form comprising the combination of mini-tablets is a capsule. In another aspect, the dosage form comprising the combination of mini-tablets is a sachet. In another aspect, the combination of the mini-tablets comprises: (a) at least one mini-tablet comprising the first composition; and (b) at least one mini-tablet comprising the second composition. In another aspect, the combination of the mini-tablets comprises: (a) at least one mini-tablet comprising Compound 1; (b) at least one mini-tablet comprising Compound 2; (c) at least one mini-tablet comprising Compound 3; and (d) at least one mini-tablet comprising Compound 4.
In another embodiment, the dosage form comprises:

    
    
        (a) a first population of particles comprising Compound 1;
        (b) a second population of particles comprising Compound 2;
        (c) a third population of particles comprising Compound 3; and
        (d) a fourth population of particles comprising Compound 4;
        wherein the fourth population comprises at least two sub-populations of particles comprising Compound 4, and wherein each sub-population exhibits a different in vitro release profile for Compound 4 relative to the other sub-populations of particles comprising Compound 4.
    
    


In one aspect of the above embodiment, the fourth population comprises at least one sub-population of particles exhibiting an immediate release in vitro release profile for Compound 4; at least one sub-population of particles exhibiting a delayed-release in vitro release profile for Compound 4; at least one sub-population of particles exhibiting an extended-release in vitro release profile for Compound 4. In another aspect, the particles comprising Compound 4 further comprise a pharmaceutically acceptable stabilizing polymer, or combination of pharmaceutically acceptable stabilizing polymers. In another aspect, at least one of the sub-populations of particles comprising Compound 4 further comprises a pharmaceutically acceptable release rate-modifying polymer, or combination of pharmaceutically acceptable release rate-modifying polymers. In another aspect, the particles comprising Compound 1 are in the form of an amorphous solid dispersion. In another aspect, the particles comprising Compound 2 are in the form of an amorphous solid dispersion. In another aspect, the particles comprising Compound 3 are in the form of an amorphous solid dispersion. In another aspect, the weight ratio (free acid or free base) of Compound 1:Compound 2:Compound 3 is from 10:1:2 to 2:1:3 (Compound 1:Compound 2:Compound 3). In another aspect, the weight ratio is 6:1:4 (Compound 1:Compound 2:Compound 3).
In another embodiment, the dosage form is a sachet comprising the first population of particles, the second population of particles, the third population of particles, and the fourth population of particles.
In another embodiment, the dosage form comprises:

    
    
        (a) a first population of particles comprising Compound 1, Compound 2, and Compound 3; and
        (d) a second population of particles comprising Compound 4;
        wherein the second population comprises at least two sub-populations of particles comprising Compound 4, and wherein each sub-population exhibits a different in vitro release profile for Compound 4 relative to the other sub-populations of particles comprising Compound 4.
    
    


In one aspect of the above embodiment, the second population comprises at least one sub-population of particles exhibiting an immediate release in vitro release profile for Compound 4; at least one sub-population of particles exhibiting a delayed-release in vitro release profile for Compound 4; at least one sub-population of particles exhibiting an extended-release in vitro release profile for Compound 4. In another aspect, the particles comprising Compound 4 further comprise a pharmaceutically acceptable stabilizing polymer, or combination of pharmaceutically acceptable stabilizing polymers. In another aspect, at least one of the sub-populations of particles comprising Compound 4 further comprises a pharmaceutically acceptable release rate-modifying polymer, or combination of pharmaceutically acceptable release rate-modifying polymers. In another aspect, the particles comprising Compound 1, Compound 2, and Compound 3 are in the form of an amorphous solid dispersion. In another aspect, the weight ratio (free acid or free base) of Compound 1:Compound 2:Compound 3 is from 3:2:24 to 60:3:5 (Compound 1:Compound 2: Compound 3). In another aspect, the weight ratio (free acid or free base) of Compound 1:Compound 2:Compound 3 is from 10:1:2 to 2:1:3 (Compound 1:Compound 2:Compound 3). In another aspect, the weight ratio is 6:1:4 (Compound 1:Compound 2:Compound 3).
In another embodiment, the dosage form is a sachet comprising the first population of particles and the second population of particles.
In another embodiment, the dosage form is an orally dispersible dosage form. The larger dosage form dimensions associated with a fixed dose combination product due to the higher-drug loading can present challenges (such as swallowing difficulties) for certain patients, especially pediatric and geriatric patients. As a result, patient compliance and use in pediatric patients may be limited. An orally dispersible dosage form (e.g., a dispersible dosage form that can disintegrate to fine dispersion within 30 seconds when in contact with water) can overcome such problems associated with dosage form size. Since the dispersible dosage form yields a fine dispersion upon immersion in water, the tablet dimensions should not impact patient compliance. In general, the dispersible dosage form can be prepared in any suitable manner including freeze-drying and direct compression methods. Excipients may include a pharmaceutically acceptable dispersing agent (such as lactose, glucose, cyclodextrin, sucrose, xylitol, mannitol, and sorbitol), a pharmaceutically acceptable disintegrant (such as croscarmellose sodium, cross-linked PVP, sodium starch glycolate, maize starch, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, and microcrystalline cellulose), and, optionally, a pharmaceutically acceptable lubricant (such as magnesium stearate, calcium stearate, aluminum stearate, stearic acid, sodium stearyl fumarate, talc, sodium benzoate, glyceryl mono fatty acid, glyceryl monostearate, glyceryl dibehenate, glyceryl palmito-stearic esters, polyethylene glycol, hydrogenated cotton seed oil, castor seed oil, and sucrose esters). The resulting blend can be incorporated into any suitable dosage form which facilitates the release of the active ingredients. Examples of such dosage forms include but are not limited to freeze-dried tablets, directly-compressed tablets, and lyophilized powders. The active ingredients can be provided, for example, in the form of individual mono-extrudates (Compounds 1, 2, and 3), co-extrudates (Compounds 1, 2, and 3), and mini-tablets.
L. Additional Representative Embodiments
In one embodiment, the solid dosage form comprises:

    
    
        (a) Compound 1, wherein Compound 1 is:
    
    






or a pharmaceutically acceptable salt thereof;

    
    
        (b) Compound 2, wherein Compound 2 is:
    
    






or a pharmaceutically acceptable salt thereof;

    
    
        (c) Compound 3, wherein Compound 3 is ritonavir, or a pharmaceutically acceptable salt thereof;
        (d) Compound 4, wherein Compound 4 is:
    
    






or a pharmaceutically acceptable salt thereof; and

    
    
        (e) a pharmaceutically acceptable stabilizing polymer, or combination of pharmaceutically acceptable stabilizing polymers.
    
    


In one aspect of the solid dosage form: (a) Compound 1 is present in an amount of 40 mg to 180 mg (free acid equivalent weight); (b) Compound 2 is present in an amount of 5 mg to 30 mg (free base equivalent weight); (c) Compound 3 is present in an amount of 25 mg to 120 mg (free base equivalent weight); (d) Compound 4 is present in an amount of 75 mg to 900 mg (free acid equivalent weight) of Compound 4; and (e) the dosage form comprises a pharmaceutically acceptable polymer, or combination of pharmaceutically acceptable polymers in an amount of 350 mg to 2500 mg. In another aspect of the solid dosage form: (a) Compound 1 is present in an amount of 40 mg to 90 mg (free acid equivalent weight); (b) Compound 2 is present in an amount of 5 mg to 15 mg (free base equivalent weight); (c) Compound 3 is present in an amount of 25 mg to 60 mg (free base equivalent weight); (d) Compound 4 is present in an amount of 75 mg to 450 mg (free acid equivalent weight) of Compound 4; and (e) the dosage form comprises a pharmaceutically acceptable polymer, or combination of pharmaceutically acceptable polymers in an amount of 400 mg to 1500 mg. In another aspect of the solid dosage form: (a) Compound 1 is present in an amount of 40 mg to 60 mg (free acid equivalent weight); (b) Compound 2 is present in an amount of 6.5 mg to 10.5 mg (free base equivalent weight); (c) Compound 3 is present in an amount of 25 mg to 40 mg (free base equivalent weight); (d) Compound 4 is present in an amount of 150 mg to 300 mg (free acid equivalent weight) of Compound 4; and (e) the dosage form comprises a pharmaceutically acceptable polymer, or combination of pharmaceutically acceptable polymers in an amount of 500 mg to 1000 mg. In another aspect of the solid dosage form: (a) Compound 1 is present in an amount of 45 mg to 55 mg (free acid equivalent weight); (b) Compound 2 is present in an amount of 7.5 mg to 9.5 mg (free base equivalent weight); (c) Compound 3 is present in an amount of 30 mg to 37 mg (free base equivalent weight); (d) Compound 4 is present in an amount of 150 mg to 300 mg (free acid equivalent weight) of Compound 4; and (e) the dosage form comprises a pharmaceutically acceptable polymer, or combination of pharmaceutically acceptable polymers in an amount of 550 mg to 750 mg.
In one aspect of the embodiment, the solid dosage form comprises a first composition comprising Compound 1, Compound 2, and Compound 3; and a second composition comprising Compound 4. In another aspect, the solid dosage form comprises a first composition comprising Compound 1, Compound 2, Compound 3, and Compound 4; and a second composition comprising Compound 4. In one aspect, the dosage form is a bilayer tablet comprising at least a first layer comprising the first composition and at least a second layer comprising the second composition. Unless otherwise specified, the terms “first layer” and “second layer” are used in a non-limiting manner and are intended to encompass bilayer tablets prepared in any tableting sequence (i.e., the first layer can prepared first followed by the second layer or the second layer can be prepared first followed by the first layer).
In one aspect, (a) the solid dosage form comprises a first composition comprising Compound 1, Compound 2, and Compound 3; and a second composition comprising Compound 4; (b) Compound 1 is present in an amount of 40 mg to 180 mg (free acid equivalent weight); (c) Compound 2 is present in an amount of 5 mg to 30 mg (free base equivalent weight); (d) Compound 3 is present in an amount of 25 mg to 120 mg (free base equivalent weight); (e) Compound 4 is present in an amount of 75 mg to 900 mg (free acid equivalent weight) of Compound 4; and (f) the second composition comprises a pharmaceutically acceptable stabilizing polymer, or combination of pharmaceutically acceptable stabilizing polymers in an amount of 20 mg to 500 mg. In another aspect, (a) the solid dosage form comprises a first composition comprising Compound 1, Compound 2, and Compound 3; and a second composition comprising Compound 4; (b) Compound 1 is present in an amount of 40 mg to 90 mg (free acid equivalent weight); (c) Compound 2 is present in an amount of 5 mg to 15 mg (free base equivalent weight); (d) Compound 3 is present in an amount of 25 mg to 60 mg (free base equivalent weight); (e) Compound 4 is present in an amount of 75 mg to 450 mg (free acid equivalent weight) of Compound 4; and (f) the second composition comprises a pharmaceutically acceptable stabilizing polymer, or combination of pharmaceutically acceptable stabilizing polymers in an amount of 25 mg to 400 mg. In another aspect, (a) the solid dosage form comprises a first composition comprising Compound 1, Compound 2, and Compound 3; and a second composition comprising Compound 4; (b) Compound 1 is present in an amount of 40 mg to 60 mg (free acid equivalent weight); (c) Compound 2 is present in an amount of 6.5 mg to 10.5 mg (free base equivalent weight); (d) Compound 3 is present in an amount of 25 mg to 40 mg (free base equivalent weight); (e) Compound 4 is present in an amount of 150 mg to 300 mg (free acid equivalent weight) of Compound 4; and (f) the second composition comprises a pharmaceutically acceptable stabilizing polymer, or combination of pharmaceutically acceptable stabilizing polymers in an amount of 30 mg to 250 mg. In another aspect, (a) the solid dosage form comprises a first composition comprising Compound 1, Compound 2, and Compound 3; and a second composition comprising Compound 4; (b) Compound 1 is present in an amount of 45 mg to 55 mg (free acid equivalent weight); (c) Compound 2 is present in an amount of 7.5 mg to 9.5 mg (free base equivalent weight); (d) Compound 3 is present in an amount of 30 mg to 37 mg (free base equivalent weight); (e) Compound 4 is present in an amount of 150 mg to 300 mg (free acid equivalent weight) of Compound 4; and (f) the second composition comprises a pharmaceutically acceptable stabilizing polymer, or combination of pharmaceutically acceptable stabilizing polymers in an amount of 50 mg to 150 mg. In each of these aspects, the dosage form can be, for example, a bilayer tablet comprising the first composition and the second composition.
In one aspect of the embodiment, the second composition further comprises the pharmaceutically acceptable stabilizing polymer, or combination of pharmaceutically acceptable stabilizing polymers, in an amount of at least 5% by weight of the second composition. In another aspect, the stabilizing polymer, or combination of stabilizing polymers are selected from the group consisting of homopolymers or copolymers of N-vinyl pyrrolidone and cellulose esters. In another aspect, the stabilizing polymer, or combination of stabilizing polymers, comprises a stabilizing polymer selected from the group consisting of copovidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (SOLUPLUS®), and combinations thereof; wherein the hydroxypropyl methylcellulose has a viscosity less than 100 centipoise in a 2% solution of at a temperature of 20° C. In another aspect, the stabilizing polymer, or combination of stabilizing polymers, comprises copovidone.
In one aspect of the embodiment, the second composition further comprises a pharmaceutically acceptable release rate-modifying polymer, or combination of pharmaceutically acceptable release rate-modifying polymers, in an amount of at least 5% by weight of the second composition. In another aspect, the release rate-modifying polymer, or combination of release rate-modifying polymers, comprises a release rate-modifying polymer selected from the group consisting of copovidone, polyvinylpyrrolidone, and hydroxypropyl methylcellulose. In another aspect, the stabilizing polymer, or combination of stabilizing polymers, comprises copovidone; and the release rate-modifying polymer, or combination of release rate-modifying polymers comprises hydroxypropyl methylcellulose. In another aspect, the stabilizing polymer, or combination of stabilizing polymers, and the release rate-modifying polymer, or combination of release rate-modifying polymers, are the same.
In one aspect of the embodiment, the second composition further comprises the pharmaceutically acceptable stabilizing polymer, or combination of pharmaceutically acceptable stabilizing polymers, in an amount of at least 5% by weight of the second composition; and further comprises a pharmaceutically acceptable release rate-modifying polymer, or combination of pharmaceutically acceptable release rate-modifying polymers, in an amount of at least 5% by weight of the second composition. In another aspect, the stabilizing polymer, or combination of stabilizing polymers are selected from the group consisting of homopolymers or copolymers of N-vinyl pyrrolidone and cellulose esters; and the release rate-modifying polymer, or combination of release rate-modifying polymers, comprises a release rate-modifying polymer selected from the group consisting of copovidone, polyvinylpyrrolidone, and hydroxypropyl methylcellulose. In another aspect, the stabilizing polymer, or combination of stabilizing polymers, comprises a stabilizing polymer selected from the group consisting of copovidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (SOLUPLUS®), and combinations thereof; wherein the hydroxypropyl methylcellulose has a viscosity less than 100 centipoise in a 2% solution of at a temperature of 20° C.; and the release rate-modifying polymer, or combination of release rate-modifying polymers, comprises a release rate-modifying polymer selected from the group consisting of copovidone, polyvinylpyrrolidone, and hydroxypropyl methylcellulose. In another aspect, the stabilizing polymer, or combination of stabilizing polymers, comprises copovidone; and the release rate-modifying polymer, or combination of release rate-modifying polymers comprises hydroxypropyl methylcellulose.
In one aspect of the embodiment, the first composition comprises an amorphous solid dispersion comprising one or more of Compound 1, Compound 2, and/or Compound 3. In another aspect, the amorphous solid dispersion further comprises at least one pharmaceutically acceptable hydrophilic polymer and at least one pharmaceutically acceptable surfactant.
In one aspect of the embodiment, the D90 particle size distribution for Compound 4 is less than 150 μm. In another aspect of the solid dosage form, the D90 particle size distribution for Compound 4 is less than 100 μm.
In one embodiment, the solid dosage form comprises:

    
    
        (a) a first composition comprising:
        (i) 40 mg to 90 mg (free acid equivalent weight) of Compound 1;
        (ii) 5 mg to 15 mg (free base equivalent weight) of Compound 2; and
        (iii) 25 mg to 60 mg (free base equivalent weight) of Compound 3; and
        (b) a second composition comprising:
        (i) 75 mg to 450 mg (free acid equivalent weight) of Compound 4;
        (ii) a pharmaceutically acceptable stabilizing polymer, or combination of pharmaceutically acceptable stabilizing polymers, in an amount from 10% by weight to 60% by weight of the second composition; and
        (iii) a pharmaceutically acceptable release rate-modifying polymer, or combination of pharmaceutically acceptable release rate-modifying polymers, in an amount from 5% by weight to 60% by weight of the second composition.
    
    


In one embodiment, the solid dosage form comprises:

    
    
        (a) a first composition comprising:
        (i) 40 mg to 60 mg (free acid equivalent weight) of Compound 1;
        (ii) 6.5 mg to 10.5 mg (free base equivalent weight) of Compound 2; and
        (iii) 25 mg to 40 mg (free base equivalent weight) of Compound 3; and
        (b) a second composition comprising:
        (i) 150 mg to 300 mg (free acid equivalent weight) of Compound 4;
        (ii) a pharmaceutically acceptable stabilizing polymer, or combination of pharmaceutically acceptable stabilizing polymers, in an amount from 15% by weight to 55% by weight of the second composition; wherein the stabilizing polymer, or combination of stabilizing polymers, comprises a stabilizing polymer selected from the group consisting of copovidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (SOLUPLUS®), and combinations thereof; wherein the hydroxypropyl methylcellulose has a viscosity less than 100 centipoise in a 2% solution of at a temperature of 20° C.; and
        (iii) a pharmaceutically acceptable release rate-modifying polymer, or combination of pharmaceutically acceptable release rate-modifying polymers, in an amount from 10% by weight to 50% by weight of the second composition; wherein the release rate-modifying polymer, or combination of release rate-modifying polymers, comprises a release rate-modifying polymer selected from the group consisting of polyvinylpyrolidone, hydroxypropyl methylcellulose, ethylcellulose polymers, copovidone, polyvinyl acetate, methacrylate/methacrylic free acid copolymers, polyethylene glycols, and polaxamers.
    
    


In one embodiment, the solid dosage form comprises:

    
    
        (a) a first composition comprising:
        (i) 45 mg to 55 mg (free acid equivalent weight) of Compound 1;
        (ii) 7.5 mg to 9.5 mg (free base equivalent weight) of Compound 2; and
        (iii) 30 mg to 37 mg (free base equivalent weight) of Compound 3; and
        (b) a second composition comprising:
        (i) 150 mg to 300 mg (free acid equivalent weight) of Compound 4;
        (ii) a pharmaceutically acceptable stabilizing polymer, or combination of pharmaceutically acceptable stabilizing polymers, in an amount from 15% by weight to 55% by weight of the second composition; wherein the stabilizing polymer, or combination of stabilizing polymers, comprises a stabilizing polymer selected from the group consisting of copovidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (SOLUPLUS®), and combinations thereof; wherein the hydroxypropyl methylcellulose has a viscosity less than 100 centipoise in a 2% solution of at a temperature of 20° C.; and
        (iii) a pharmaceutically acceptable release rate-modifying polymer, or combination of pharmaceutically acceptable release rate-modifying polymers, in an amount from 10% by weight to 50% by weight of the second composition; wherein the release rate-modifying polymer, or combination of release rate-modifying polymers, comprises a release rate-modifying polymer selected from the group consisting of copovidone, polyvinylpyrrolidone, and hydroxypropyl methylcellulose.
    
    


In one embodiment, the solid dosage form comprises:

    
    
        (a) a first composition comprising:
        (i) 45 mg to 55 mg (free acid equivalent weight) of Compound 1;
        (ii) 7.5 mg to 9.5 mg (free base equivalent weight) of Compound 2; and
        (iii) 30 mg to 37 mg (free base equivalent weight) of Compound 3; and
        (b) a second composition comprising:
        (i) 150 mg to 300 mg (free acid equivalent weight) of Compound 4;
        (ii) a pharmaceutically acceptable stabilizing polymer, or combination of pharmaceutically acceptable stabilizing polymers, in an amount from 20% by weight to 50% by weight of the second composition; wherein the stabilizing polymer, or combination of stabilizing polymers, comprises copovidone; and
        (iii) a pharmaceutically acceptable release rate-modifying polymer, or combination of pharmaceutically acceptable release rate-modifying polymers, in an amount from 15% by weight to 40% by weight of the second composition; wherein the release rate-modifying polymer, or combination of release rate-modifying polymers, comprises hydroxypropyl methylcellulose.
    
    


In one embodiment, the solid dosage form comprises:

    
    
        (a) a first composition comprising:
        
            (i) 50 mg (free acid equivalent weight) of Compound 1;
            (ii) 8.3 mg (free base equivalent weight) of Compound 2; and
            (iii) 33.3 mg (free base equivalent weight) of Compound 3; and
        
        
        (b) a second composition comprising:
        
            (i) 150 mg to 300 mg (free acid equivalent weight) of Compound 4; wherein the D90 particle size distribution for the Compound 4 present in the dosage form is less than 100 μm;
            (ii) a pharmaceutically acceptable stabilizing polymer, or combination of pharmaceutically acceptable stabilizing polymers, in an amount from 20% by weight to 50% by weight of the second composition; wherein the stabilizing polymer, or combination of stabilizing polymers, comprises copovidone; and
            (iii) a pharmaceutically acceptable release rate-modifying polymer, or combination of pharmaceutically acceptable release rate-modifying polymers, in an amount from 15% by weight to 40% by weight of the second composition; wherein the release rate-modifying polymer, or combination of release rate-modifying polymers, comprises hydroxypropyl methylcellulose.
        
        
    
    


In another embodiment, the present invention features a pharmaceutical solid dosage form comprising two compositions. The first composition comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second composition comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first composition comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first composition. The second composition comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second composition.
In another embodiment, the present invention features a pharmaceutical solid dosage form comprising two compositions. The first composition comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second composition comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first composition comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first composition. The second composition comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second composition.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form comprising two compositions. The first composition comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second composition comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first composition comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first composition. The second composition comprises 216.2 mg Compound 4 monosodium salt monohydrate, 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second composition.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form comprising two compositions. The first composition comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second composition comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first composition comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first composition. The second composition comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second composition.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form comprising two compositions. The first composition comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second composition comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first composition comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first composition. The second composition comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second composition.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form comprising two compositions. The first composition comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second composition comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first composition comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first composition. The second composition comprises 216.2 mg Compound 4 monosodium salt monohydrate, 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second composition.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form comprising two compositions. The first composition comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second composition comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first composition comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first composition. The second composition comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second composition.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form comprising two compositions. The first composition comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second composition comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first composition comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first composition. The second composition comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second composition.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form comprising two compositions. The first composition comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second composition comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first composition comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first composition. The second composition comprises 216.2 mg Compound 4 monosodium salt monohydrate, 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second composition.
In another embodiment, the present invention features a pharmaceutical solid dosage form comprising two compositions. The first composition comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second composition comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first composition comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first composition, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises (1) the hydrophilic polymer or the combination of hydrophilic polymers and (2) the surfactant or the combination of surfactants. The amorphous solid dispersion can be milled and compressed into the first composition. The second composition comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second composition.
In another embodiment, the present invention features a pharmaceutical solid dosage form comprising two compositions. The first composition comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second composition comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first composition comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first composition, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises (1) the hydrophilic polymer or the combination of hydrophilic polymers and (2) the surfactant or the combination of surfactants. The amorphous solid dispersion can be milled and compressed into the first composition. The second composition comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second composition.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form comprising two compositions. The first composition comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second composition comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first composition comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first composition, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises (1) the hydrophilic polymer or the combination of hydrophilic polymers and (2) the surfactant or the combination of surfactants. The amorphous solid dispersion can be milled and compressed into the first composition. The second composition comprises 216.2 mg Compound 4 monosodium salt monohydrate, 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second composition.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form comprising two compositions. The first composition comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second composition comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first composition comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first composition, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises copovidone, vitamin E TPGS, lauroglycol and sorbitan monolaurate. The amorphous solid dispersion can be milled and compressed into the first composition. The second composition comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second composition.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form comprising two compositions. The first composition comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second composition comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first composition comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first composition, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises copovidone, vitamin E TPGS, lauroglycol and sorbitan monolaurate. The amorphous solid dispersion can be milled and compressed into the first composition. The second composition comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second composition.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form comprising two compositions. The first composition comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second composition comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first composition comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first composition, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises copovidone, vitamin E TPGS, lauroglycol and sorbitan monolaurate. The amorphous solid dispersion can be milled and compressed into the first composition. The second composition comprises 216.2 mg Compound 4 monosodium salt monohydrate, 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second composition.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form comprising two compositions. The first composition comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second composition comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first composition comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first composition, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises copovidone, vitamin E TPGS, lauroglycol and sorbitan monolaurate. The amorphous solid dispersion can be milled and compressed into the first composition. The second composition comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second composition.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form comprising two compositions. The first composition comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second composition comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first composition comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first composition, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises copovidone, vitamin E TPGS, lauroglycol and sorbitan monolaurate. The amorphous solid dispersion can be milled and compressed into the first composition. The second composition comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second composition.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form comprising two compositions. The first composition comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second composition comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first composition comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first composition, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises copovidone, vitamin E TPGS, lauroglycol and sorbitan monolaurate. The amorphous solid dispersion can be milled and compressed into the first composition. The second composition comprises 216.2 mg Compound 4 monosodium salt monohydrate, 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second composition.
In another embodiment, the present invention features a pharmaceutical solid dosage form comprising two compositions. The first composition comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second composition comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first composition comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first composition, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions, and each solid dispersion comprises (1) the hydrophilic polymer or the combination of hydrophilic polymers and (2) the surfactant or one of the combination of surfactants. These amorphous solid dispersions can be milled and then compressed into the first composition. The second composition comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second composition.
In another embodiment, the present invention features a pharmaceutical solid dosage form comprising two compositions. The first composition comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second composition comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first composition comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first composition, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions, and each solid dispersion comprises (1) the hydrophilic polymer or one of the combination of hydrophilic polymers and (2) the surfactant or one of the combination of surfactants. These amorphous solid dispersions can be milled and then compressed into the first composition. The second composition comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second composition.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form comprising two compositions. The first composition comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second composition comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first composition comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first composition, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions, and each solid dispersion comprises (1) the hydrophilic polymer or one of the combination of hydrophilic polymers and (2) the surfactant or one of the combination of surfactants. These amorphous solid dispersions can be milled and then compressed into the first composition. The second composition comprises 216.2 mg Compound 4 monosodium salt monohydrate, 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second composition.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form comprising two compositions. The first composition comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second composition comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first composition comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first composition, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions. The solid dispersion comprising Compound 1 can comprise copovidone, vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound 2 can comprise copovidone and vitamin E TPGS; and the solid dispersion comprising Compound 3 can comprise copovidone and sorbitan monolaurate. These amorphous solid dispersions can be milled and then compressed into the first composition. The second composition comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second composition.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form comprising two compositions. The first composition comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second composition comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first composition comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first composition, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions. The solid dispersion comprising Compound 1 can comprise copovidone, vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound 2 can comprise copovidone and vitamin E TPGS; and the solid dispersion comprising Compound 3 can comprise copovidone and sorbitan monolaurate. These amorphous solid dispersions can be milled and then compressed into the first composition. The second composition comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second composition.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form comprising two compositions. The first composition comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second composition comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first composition comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first composition, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions. The solid dispersion comprising Compound 1 can comprise copovidone, vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound 2 can comprise copovidone and vitamin E TPGS; and the solid dispersion comprising Compound 3 can comprise copovidone and sorbitan monolaurate. These amorphous solid dispersions can be milled and then compressed into the first composition. The second composition comprises 216.2 mg Compound 4 monosodium salt monohydrate, 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second composition.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form comprising two compositions. The first composition comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second composition comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first composition comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first composition, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions. The solid dispersion comprising Compound 1 can comprise copovidone, vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound 2 can comprise copovidone and vitamin E TPGS; and the solid dispersion comprising Compound 3 can comprise copovidone and sorbitan monolaurate. These amorphous solid dispersions can be milled and then compressed into the first composition. The second composition comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second composition.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form comprising two compositions. The first composition comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second composition comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first composition comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first composition, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions. The solid dispersion comprising Compound 1 can comprise copovidone, vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound 2 can comprise copovidone and vitamin E TPGS; and the solid dispersion comprising Compound 3 can comprise copovidone and sorbitan monolaurate. These amorphous solid dispersions can be milled and then compressed into the first composition. The second composition comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second composition.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form comprising two compositions. The first composition comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second composition comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first composition comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first composition, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions. The solid dispersion comprising Compound 1 can comprise copovidone, vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound 2 can comprise copovidone and vitamin E TPGS; and the solid dispersion comprising Compound 3 can comprise copovidone and sorbitan monolaurate. These amorphous solid dispersions can be milled and then compressed into the first composition. The second composition comprises 216.2 mg Compound 4 monosodium salt monohydrate, 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second composition.
In another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first layer. The second layer comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second layer.
In another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first layer. The second layer comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second layer.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first layer. The second layer comprises 216.2 mg Compound 4 monosodium salt monohydrate, 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second layer.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first layer. The second layer comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first layer. The second layer comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first layer. The second layer comprises 216.2 mg Compound 4 monosodium salt monohydrate, 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first layer. The second layer comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first layer. The second layer comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first layer. The second layer comprises 216.2 mg Compound 4 monosodium salt monohydrate, 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer.
In another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises (1) the hydrophilic polymer or the combination of hydrophilic polymers and (2) the surfactant or the combination of surfactants. The amorphous solid dispersion can be milled and compressed into the first layer. The second layer comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second layer.
In another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises (1) the hydrophilic polymer or the combination of hydrophilic polymers and (2) the surfactant or the combination of surfactants. The amorphous solid dispersion can be milled and compressed into the first layer. The second layer comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second layer.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises (1) the hydrophilic polymer or the combination of hydrophilic polymers and (2) the surfactant or the combination of surfactants. The amorphous solid dispersion can be milled and compressed into the first layer. The second layer comprises 216.2 mg Compound 4 monosodium salt monohydrate, 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second layer.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises copovidone, vitamin E TPGS, lauroglycol and sorbitan monolaurate. The amorphous solid dispersion can be milled and compressed into the first layer. The second layer comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises copovidone, vitamin E TPGS, lauroglycol and sorbitan monolaurate. The amorphous solid dispersion can be milled and compressed into the first layer. The second layer comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises copovidone, vitamin E TPGS, lauroglycol and sorbitan monolaurate. The amorphous solid dispersion can be milled and compressed into the first layer. The second layer comprises 216.2 mg Compound 4 monosodium salt monohydrate, 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises copovidone, vitamin E TPGS, lauroglycol and sorbitan monolaurate. The amorphous solid dispersion can be milled and compressed into the first layer. The second layer comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises copovidone, vitamin E TPGS, lauroglycol and sorbitan monolaurate. The amorphous solid dispersion can be milled and compressed into the first layer. The second layer comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises copovidone, vitamin E TPGS, lauroglycol and sorbitan monolaurate. The amorphous solid dispersion can be milled and compressed into the first layer. The second layer comprises 216.2 mg Compound 4 monosodium salt monohydrate, 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer.
In another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions, and each solid dispersion comprises (1) the hydrophilic polymer or the combination of hydrophilic polymers and (2) the surfactant or one of the combination of surfactants. These amorphous solid dispersions can be milled and then compressed into the first layer. The second layer comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second layer.
In another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions, and each solid dispersion comprises (1) the hydrophilic polymer or one of the combination of hydrophilic polymers and (2) the surfactant or one of the combination of surfactants. These amorphous solid dispersions can be milled and then compressed into the first layer. The second layer comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second layer.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions, and each solid dispersion comprises (1) the hydrophilic polymer or one of the combination of hydrophilic polymers and (2) the surfactant or one of the combination of surfactants. These amorphous solid dispersions can be milled and then compressed into the first layer. The second layer comprises 216.2 mg Compound 4 monosodium salt monohydrate, 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second layer.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions. The solid dispersion comprising Compound 1 can comprise copovidone, vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound 2 can comprise copovidone and vitamin E TPGS; and the solid dispersion comprising Compound 3 can comprise copovidone and sorbitan monolaurate. These amorphous solid dispersions can be milled and then compressed into the first layer. The second layer comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions. The solid dispersion comprising Compound 1 can comprise copovidone, vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound 2 can comprise copovidone and vitamin E TPGS; and the solid dispersion comprising Compound 3 can comprise copovidone and sorbitan monolaurate. These amorphous solid dispersions can be milled and then compressed into the first layer. The second layer comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions. The solid dispersion comprising Compound 1 can comprise copovidone, vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound 2 can comprise copovidone and vitamin E TPGS; and the solid dispersion comprising Compound 3 can comprise copovidone and sorbitan monolaurate. These amorphous solid dispersions can be milled and then compressed into the first layer. The second layer comprises 216.2 mg Compound 4 monosodium salt monohydrate, 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions. The solid dispersion comprising Compound 1 can comprise copovidone, vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound 2 can comprise copovidone and vitamin E TPGS; and the solid dispersion comprising Compound 3 can comprise copovidone and sorbitan monolaurate. These amorphous solid dispersions can be milled and then compressed into the first layer. The second layer comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions. The solid dispersion comprising Compound 1 can comprise copovidone, vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound 2 can comprise copovidone and vitamin E TPGS; and the solid dispersion comprising Compound 3 can comprise copovidone and sorbitan monolaurate. These amorphous solid dispersions can be milled and then compressed into the first layer. The second layer comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions. The solid dispersion comprising Compound 1 can comprise copovidone, vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound 2 can comprise copovidone and vitamin E TPGS; and the solid dispersion comprising Compound 3 can comprise copovidone and sorbitan monolaurate. These amorphous solid dispersions can be milled and then compressed into the first layer. The second layer comprises 216.2 mg Compound 4 monosodium salt monohydrate, 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer.
In each and every embodiment, aspect and example described herein, when the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can, for example, have the following release profile: 50-60% Compound 1 in the solid dosage form is released within 1 hour, 50-60% Compound 2 in the solid dosage form is released within 1 hour, 50-60% Compound 3 in the solid dosage form is released within 1 hour, and 0.5-2% Compound 4 in the solid dosage form is released within 1 hour. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In each and every embodiment, aspect and example described herein, when the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can, for example, have the following release profile: 95-100% Compound 1 in the solid dosage form is released within 4 hours, 95-100% Compound 2 in the solid dosage form is released within 4 hours, 95-100% Compound 3 in the solid dosage form is released within 4 hours, and 10-15% Compound 4 in the solid dosage form is released within 4 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In each and every embodiment, aspect and example described herein, when the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can, for example, have the following release profile: 95-100% Compound 1 in the solid dosage form is released within 6 hours, 95-100% Compound 2 in the solid dosage form is released within 6 hours, 95-100% Compound 3 in the solid dosage form is released within 6 hours, and 15-20% Compound 4 in the solid dosage form is released within 6 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In each and every embodiment, aspect and example described herein, when the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can, for example, have the following release profile: 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% Compound 3 in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, and 40-60% Compound 4 in the solid dosage form is released within 16 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In each and every embodiment, aspect and example described herein, when the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can, for example, have the following release profile: 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% Compound 3 in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, 40-60% Compound 4 in the solid dosage form is released within 16 hours, and 60-80% Compound 4 in the solid dosage form is released within 24 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
Accordingly, in another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first layer. The second layer comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second layer. When the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can have the following release profile: 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% Compound 3 in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, 40-60% Compound 4 in the solid dosage form is released within 16 hours, and 60-80% Compound 4 in the solid dosage form is released within 24 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first layer. The second layer comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second layer. When the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can have the following release profile: 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% Compound 3 in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, 40-60% Compound 4 in the solid dosage form is released within 16 hours, and 60-80% Compound 4 in the solid dosage form is released within 24 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first layer. The second layer comprises 216.2 mg Compound 4 monosodium salt monohydrate, 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second layer. When the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can have the following release profile: 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% Compound 3 in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, 40-60% Compound 4 in the solid dosage form is released within 16 hours, and 60-80% Compound 4 in the solid dosage form is released within 24 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first layer. The second layer comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can have the following release profile: 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% Compound 3 in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, 40-60% Compound 4 in the solid dosage form is released within 16 hours, and 60-80% Compound 4 in the solid dosage form is released within 24 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first layer. The second layer comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can have the following release profile: 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% Compound 3 in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, 40-60% Compound 4 in the solid dosage form is released within 16 hours, and 60-80% Compound 4 in the solid dosage form is released within 24 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first layer. The second layer comprises 216.2 mg Compound 4 monosodium salt monohydrate, 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can have the following release profile: 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% Compound 3 in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, 40-60% Compound 4 in the solid dosage form is released within 16 hours, and 60-80% Compound 4 in the solid dosage form is released within 24 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first layer. The second layer comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can have the following release profile: 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% Compound 3 in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, 40-60% Compound 4 in the solid dosage form is released within 16 hours, and 60-80% Compound 4 in the solid dosage form is released within 24 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first layer. The second layer comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can have the following release profile: 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% Compound 3 in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, 40-60% Compound 4 in the solid dosage form is released within 16 hours, and 60-80% Compound 4 in the solid dosage form is released within 24 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first layer. The second layer comprises 216.2 mg Compound 4 monosodium salt monohydrate, 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can have the following release profile: 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% Compound 3 in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, 40-60% Compound 4 in the solid dosage form is released within 16 hours, and 60-80% Compound 4 in the solid dosage form is released within 24 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises (1) the hydrophilic polymer or the combination of hydrophilic polymers and (2) the surfactant or the combination of surfactants. The amorphous solid dispersion can be milled and compressed into the first layer. The second layer comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second layer. When the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can have the following release profile: 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% Compound 3 in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, 40-60% Compound 4 in the solid dosage form is released within 16 hours, and 60-80% Compound 4 in the solid dosage form is released within 24 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises (1) the hydrophilic polymer or the combination of hydrophilic polymers and (2) the surfactant or the combination of surfactants. The amorphous solid dispersion can be milled and compressed into the first layer. The second layer comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second layer. When the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can have the following release profile: 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% Compound 3 in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, 40-60% Compound 4 in the solid dosage form is released within 16 hours, and 60-80% Compound 4 in the solid dosage form is released within 24 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises (1) the hydrophilic polymer or the combination of hydrophilic polymers and (2) the surfactant or the combination of surfactants. The amorphous solid dispersion can be milled and compressed into the first layer. The second layer comprises 216.2 mg Compound 4 monosodium salt monohydrate, 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second layer. When the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can have the following release profile: 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% Compound 3 in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, 40-60% Compound 4 in the solid dosage form is released within 16 hours, and 60-80% Compound 4 in the solid dosage form is released within 24 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises copovidone, vitamin E TPGS, lauroglycol and sorbitan monolaurate. The amorphous solid dispersion can be milled and compressed into the first layer. The second layer comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can have the following release profile: 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% Compound 3 in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, 40-60% Compound 4 in the solid dosage form is released within 16 hours, and 60-80% Compound 4 in the solid dosage form is released within 24 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises copovidone, vitamin E TPGS, lauroglycol and sorbitan monolaurate. The amorphous solid dispersion can be milled and compressed into the first layer. The second layer comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can have the following release profile: 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% Compound 3 in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, 40-60% Compound 4 in the solid dosage form is released within 16 hours, and 60-80% Compound 4 in the solid dosage form is released within 24 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises copovidone, vitamin E TPGS, lauroglycol and sorbitan monolaurate. The amorphous solid dispersion can be milled and compressed into the first layer. The second layer comprises 216.2 mg Compound 4 monosodium salt monohydrate, 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can have the following release profile: 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% Compound 3 in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, 40-60% Compound 4 in the solid dosage form is released within 16 hours, and 60-80% Compound 4 in the solid dosage form is released within 24 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises copovidone, vitamin E TPGS, lauroglycol and sorbitan monolaurate. The amorphous solid dispersion can be milled and compressed into the first layer. The second layer comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can have the following release profile: 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% Compound 3 in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, 40-60% Compound 4 in the solid dosage form is released within 16 hours, and 60-80% Compound 4 in the solid dosage form is released within 24 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises copovidone, vitamin E TPGS, lauroglycol and sorbitan monolaurate. The amorphous solid dispersion can be milled and compressed into the first layer. The second layer comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can have the following release profile: 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% Compound 3 in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, 40-60% Compound 4 in the solid dosage form is released within 16 hours, and 60-80% Compound 4 in the solid dosage form is released within 24 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises copovidone, vitamin E TPGS, lauroglycol and sorbitan monolaurate. The amorphous solid dispersion can be milled and compressed into the first layer. The second layer comprises 216.2 mg Compound 4 monosodium salt monohydrate, 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can have the following release profile: 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% Compound 3 in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, 40-60% Compound 4 in the solid dosage form is released within 16 hours, and 60-80% Compound 4 in the solid dosage form is released within 24 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions, and each solid dispersion comprises (1) the hydrophilic polymer or the combination of hydrophilic polymers and (2) the surfactant or one of the combination of surfactants. These amorphous solid dispersions can be milled and then compressed into the first layer. The second layer comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second layer. When the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can have the following release profile: 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% Compound 3 in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, 40-60% Compound 4 in the solid dosage form is released within 16 hours, and 60-80% Compound 4 in the solid dosage form is released within 24 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions, and each solid dispersion comprises (1) the hydrophilic polymer or one of the combination of hydrophilic polymers and (2) the surfactant or one of the combination of surfactants. These amorphous solid dispersions can be milled and then compressed into the first layer. The second layer comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second layer. When the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can have the following release profile: 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% Compound 3 in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, 40-60% Compound 4 in the solid dosage form is released within 16 hours, and 60-80% Compound 4 in the solid dosage form is released within 24 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions, and each solid dispersion comprises (1) the hydrophilic polymer or one of the combination of hydrophilic polymers and (2) the surfactant or one of the combination of surfactants. These amorphous solid dispersions can be milled and then compressed into the first layer. The second layer comprises 216.2 mg Compound 4 monosodium salt monohydrate, 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second layer. When the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can have the following release profile: 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% Compound 3 in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, 40-60% Compound 4 in the solid dosage form is released within 16 hours, and 60-80% Compound 4 in the solid dosage form is released within 24 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions. The solid dispersion comprising Compound 1 can comprise copovidone, vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound 2 can comprise copovidone and vitamin E TPGS; and the solid dispersion comprising Compound 3 can comprise copovidone and sorbitan monolaurate. These amorphous solid dispersions can be milled and then compressed into the first layer. The second layer comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can have the following release profile: 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% Compound 3 in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, 40-60% Compound 4 in the solid dosage form is released within 16 hours, and 60-80% Compound 4 in the solid dosage form is released within 24 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions. The solid dispersion comprising Compound 1 can comprise copovidone, vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound 2 can comprise copovidone and vitamin E TPGS; and the solid dispersion comprising Compound 3 can comprise copovidone and sorbitan monolaurate. These amorphous solid dispersions can be milled and then compressed into the first layer. The second layer comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can have the following release profile: 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% Compound 3 in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, 40-60% Compound 4 in the solid dosage form is released within 16 hours, and 60-80% Compound 4 in the solid dosage form is released within 24 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions. The solid dispersion comprising Compound 1 can comprise copovidone, vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound 2 can comprise copovidone and vitamin E TPGS; and the solid dispersion comprising Compound 3 can comprise copovidone and sorbitan monolaurate. These amorphous solid dispersions can be milled and then compressed into the first layer. The second layer comprises 216.2 mg Compound 4 monosodium salt monohydrate, 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can have the following release profile: 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% Compound 3 in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, 40-60% Compound 4 in the solid dosage form is released within 16 hours, and 60-80% Compound 4 in the solid dosage form is released within 24 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions. The solid dispersion comprising Compound 1 can comprise copovidone, vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound 2 can comprise copovidone and vitamin E TPGS; and the solid dispersion comprising Compound 3 can comprise copovidone and sorbitan monolaurate. These amorphous solid dispersions can be milled and then compressed into the first layer. The second layer comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can have the following release profile: 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% Compound 3 in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, 40-60% Compound 4 in the solid dosage form is released within 16 hours, and 60-80% Compound 4 in the solid dosage form is released within 24 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions. The solid dispersion comprising Compound 1 can comprise copovidone, vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound 2 can comprise copovidone and vitamin E TPGS; and the solid dispersion comprising Compound 3 can comprise copovidone and sorbitan monolaurate. These amorphous solid dispersions can be milled and then compressed into the first layer. The second layer comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can have the following release profile: 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% Compound 3 in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, 40-60% Compound 4 in the solid dosage form is released within 16 hours, and 60-80% Compound 4 in the solid dosage form is released within 24 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions. The solid dispersion comprising Compound 1 can comprise copovidone, vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound 2 can comprise copovidone and vitamin E TPGS; and the solid dispersion comprising Compound 3 can comprise copovidone and sorbitan monolaurate. These amorphous solid dispersions can be milled and then compressed into the first layer. The second layer comprises 216.2 mg Compound 4 monosodium salt monohydrate, 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When the pharmaceutical solid dosage form is dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosage form can have the following release profile: 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% Compound 3 in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, 40-60% Compound 4 in the solid dosage form is released within 16 hours, and 60-80% Compound 4 in the solid dosage form is released within 24 hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.
In each and every embodiment, aspect and example described in this disclosure, when a single dose consisting of the same three solid dosage forms is administered to humans under non-fasting conditions, it can, for example, produce the following pharmacokinetics profile: the AUC∞ for Compound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.
Accordingly, in another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first layer. The second layer comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second layer. When a single dose consisting of three solid dosage forms of this embodiment is administered to humans under non-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.
In another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first layer. The second layer comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second layer. When a single dose consisting of three solid dosage forms of this embodiment is administered to humans under non-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first layer. The second layer comprises 216.2 mg Compound 4 monosodium salt monohydrate, 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second layer. When a single dose consisting of three solid dosage forms of this embodiment is administered to humans under non-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first layer. The second layer comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When a single dose consisting of three solid dosage forms of this embodiment is administered to humans under non-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first layer. The second layer comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When a single dose consisting of three solid dosage forms of this embodiment is administered to humans under non-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first layer. The second layer comprises 216.2 mg Compound 4 monosodium salt monohydrate, 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When a single dose consisting of three solid dosage forms of this embodiment is administered to humans under non-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first layer. The second layer comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When a single dose consisting of three solid dosage forms of this embodiment is administered to humans under non-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first layer. The second layer comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When a single dose consisting of three solid dosage forms of this embodiment is administered to humans under non-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first layer. The second layer comprises 216.2 mg Compound 4 monosodium salt monohydrate, 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When a single dose consisting of three solid dosage forms of this embodiment is administered to humans under non-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.
In another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises (1) the hydrophilic polymer or the combination of hydrophilic polymers and (2) the surfactant or the combination of surfactants. The amorphous solid dispersion can be milled and compressed into the first layer. The second layer comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second layer. When a single dose consisting of three solid dosage forms of this embodiment is administered to humans under non-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.
In another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises (1) the hydrophilic polymer or the combination of hydrophilic polymers and (2) the surfactant or the combination of surfactants. The amorphous solid dispersion can be milled and compressed into the first layer. The second layer comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second layer. When a single dose consisting of three solid dosage forms of this embodiment is administered to humans under non-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises (1) the hydrophilic polymer or the combination of hydrophilic polymers and (2) the surfactant or the combination of surfactants. The amorphous solid dispersion can be milled and compressed into the first layer. The second layer comprises 216.2 mg Compound 4 monosodium salt monohydrate, 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second layer. When a single dose consisting of three solid dosage forms of this embodiment is administered to humans under non-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises copovidone, vitamin E TPGS, lauroglycol and sorbitan monolaurate. The amorphous solid dispersion can be milled and compressed into the first layer. The second layer comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When a single dose consisting of three solid dosage forms of this embodiment is administered to humans under non-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises copovidone, vitamin E TPGS, lauroglycol and sorbitan monolaurate. The amorphous solid dispersion can be milled and compressed into the first layer. The second layer comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When a single dose consisting of three solid dosage forms of this embodiment is administered to humans under non-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises copovidone, vitamin E TPGS, lauroglycol and sorbitan monolaurate. The amorphous solid dispersion can be milled and compressed into the first layer. The second layer comprises 216.2 mg Compound 4 monosodium salt monohydrate, 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When a single dose consisting of three solid dosage forms of this embodiment is administered to humans under non-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises copovidone, vitamin E TPGS, lauroglycol and sorbitan monolaurate. The amorphous solid dispersion can be milled and compressed into the first layer. The second layer comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When a single dose consisting of three solid dosage forms of this embodiment is administered to humans under non-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises copovidone, vitamin E TPGS, lauroglycol and sorbitan monolaurate. The amorphous solid dispersion can be milled and compressed into the first layer. The second layer comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When a single dose consisting of three solid dosage forms of this embodiment is administered to humans under non-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are formulated in the same amorphous solid dispersion which comprises copovidone, vitamin E TPGS, lauroglycol and sorbitan monolaurate. The amorphous solid dispersion can be milled and compressed into the first layer. The second layer comprises 216.2 mg Compound 4 monosodium salt monohydrate, 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When a single dose consisting of three solid dosage forms of this embodiment is administered to humans under non-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.
In another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions, and each solid dispersion comprises (1) the hydrophilic polymer or the combination of hydrophilic polymers and (2) the surfactant or one of the combination of surfactants. These amorphous solid dispersions can be milled and then compressed into the first layer. The second layer comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second layer. When a single dose consisting of three solid dosage forms of this embodiment is administered to humans under non-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.
In another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions, and each solid dispersion comprises (1) the hydrophilic polymer or one of the combination of hydrophilic polymers and (2) the surfactant or one of the combination of surfactants. These amorphous solid dispersions can be milled and then compressed into the first layer. The second layer comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second layer. When a single dose consisting of three solid dosage forms of this embodiment is administered to humans under non-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer or a combination of pharmaceutically acceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions, and each solid dispersion comprises (1) the hydrophilic polymer or one of the combination of hydrophilic polymers and (2) the surfactant or one of the combination of surfactants. These amorphous solid dispersions can be milled and then compressed into the first layer. The second layer comprises 216.2 mg Compound 4 monosodium salt monohydrate, 20-40% a pharmaceutically acceptable stabilizing polymer or a combination of pharmaceutically acceptable stabilizing polymers, and 20-40% a pharmaceutically acceptable release rate-modifying polymer or a combination of pharmaceutically acceptable release rate-modifying polymers, wherein all percentages are weight percentages relative to the total weight of the second layer. When a single dose consisting of three solid dosage forms of this embodiment is administered to humans under non-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions. The solid dispersion comprising Compound 1 can comprise copovidone, vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound 2 can comprise copovidone and vitamin E TPGS; and the solid dispersion comprising Compound 3 can comprise copovidone and sorbitan monolaurate. These amorphous solid dispersions can be milled and then compressed into the first layer. The second layer comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When a single dose consisting of three solid dosage forms of this embodiment is administered to humans under non-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions. The solid dispersion comprising Compound 1 can comprise copovidone, vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound 2 can comprise copovidone and vitamin E TPGS; and the solid dispersion comprising Compound 3 can comprise copovidone and sorbitan monolaurate. These amorphous solid dispersions can be milled and then compressed into the first layer. The second layer comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When a single dose consisting of three solid dosage forms of this embodiment is administered to humans under non-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions. The solid dispersion comprising Compound 1 can comprise copovidone, vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound 2 can comprise copovidone and vitamin E TPGS; and the solid dispersion comprising Compound 3 can comprise copovidone and sorbitan monolaurate. These amorphous solid dispersions can be milled and then compressed into the first layer. The second layer comprises 216.2 mg Compound 4 monosodium salt monohydrate, 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When a single dose consisting of three solid dosage forms of this embodiment is administered to humans under non-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions. The solid dispersion comprising Compound 1 can comprise copovidone, vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound 2 can comprise copovidone and vitamin E TPGS; and the solid dispersion comprising Compound 3 can comprise copovidone and sorbitan monolaurate. These amorphous solid dispersions can be milled and then compressed into the first layer. The second layer comprises 30-50% a pharmaceutically acceptable salt of Compound 4, 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When a single dose consisting of three solid dosage forms of this embodiment is administered to humans under non-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions. The solid dispersion comprising Compound 1 can comprise copovidone, vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound 2 can comprise copovidone and vitamin E TPGS; and the solid dispersion comprising Compound 3 can comprise copovidone and sorbitan monolaurate. These amorphous solid dispersions can be milled and then compressed into the first layer. The second layer comprises a pharmaceutically acceptable salt of Compound 4 in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When a single dose consisting of three solid dosage forms of this embodiment is administered to humans under non-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.
In yet another embodiment, the present invention features a pharmaceutical solid dosage form which is a tablet comprising two layers. The first layer comprises Compound 1, Compound 2 and Compound 3, each of which is formulated in amorphous solid dispersion, and the second layer comprises a pharmaceutically acceptable salt of Compound 4 in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% a combination of vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein all percentages are weight percentages relative to the total weight of the first layer, and wherein Compound 1, Compound 2 and Compound 3 are each formulated in separate amorphous solid dispersions. The solid dispersion comprising Compound 1 can comprise copovidone, vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound 2 can comprise copovidone and vitamin E TPGS; and the solid dispersion comprising Compound 3 can comprise copovidone and sorbitan monolaurate. These amorphous solid dispersions can be milled and then compressed into the first layer. The second layer comprises 216.2 mg Compound 4 monosodium salt monohydrate, 30% copovidone, and 30% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second layer. When a single dose consisting of three solid dosage forms of this embodiment is administered to humans under non-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.
In each and every embodiment, aspect and example described in this application, the size of the pharmaceutical solid dosage form can be, for example, 1000-1600 mg.
In each and every embodiment, aspect and example described in this disclosure, the size of the pharmaceutical solid dosage form can be, for example, 1200-1400 mg.
In each and every embodiment, aspect and example described in this disclosure, the size of the pharmaceutical solid dosage form can be, for example, 1300-1400 mg.
III. METHODS OF TREATMENT
In one embodiment, the disclosed solid dosage forms can be used for treating a disease that can be treated by inhibiting HCV RNA polymerase.
In another embodiment, the disclosed solid dosage forms can be used for treating HCV infection in a subject in need of such treatment. In one aspect, the subject is suffering from both HCV infection and human immunodeficiency virus (HIV) infection.
In another embodiment, the disclosed solid dosage forms can be used for treating liver disease in a subject in need of such treatment. In one aspect, the liver disease is end-stage liver disease. In another aspect, the liver disease is cirrhosis. In another aspect, the liver disease is hepatocellular carcinoma. In another aspect, the treatment delays the progression of the liver disease.
These methods of treatment comprise administering to the subject one or more of the disclosed solid dosage forms, and, optionally, one or more additional therapeutic agents. In one aspect, the method comprises administering at least one of the dosage forms once daily to the subject. In one aspect, the at least one dosage forms administered once daily to the subject is a tablet. In another aspect, the method comprises administering two of the dosage forms once daily to the subject. In one aspect, the at least one dosage forms administered once daily to the subject are tablets. In another aspect, the method comprises administering three of the dosage forms once daily to the subject. In one aspect, the at least three dosage forms administered once daily to the subject are tablets. In another aspect, the dosage forms are administered under non-fasting conditions. In another aspect, the dosage forms are administered under fasting conditions. In another aspect, the method comprises administering the two or more dosage forms once daily at substantially the same time. In another aspect, the subject in need of treatment is suffering from, or is susceptible to, HCV infection.
IV. COMBINATION THERAPY
The methods of treatment of the present disclosure also comprise combination therapy in which the disclosed solid dosage forms are co-administered with a second (or even a third, fourth, etc.) composition, such as, for example, a composition containing another therapeutic agent used to treat HCV infection (e.g., interferon or interferon/ribavirin combination, or an HCV inhibitor such as, for example, an HCV polymerase inhibitor or an HCV protease inhibitor or an NS5a inhibitor). The disclosed solid dosage forms also can be co-administered with therapeutic agents other than therapeutic agents used to treat HCV infection (e.g., anti-HIV agents). In these co-administration embodiments, the disclosed solid dosage forms and the second, etc. composition(s) may be administered in a substantially simultaneous manner (e.g., or within about five minutes of each other), in a sequential manner, or both. It is contemplated that such combination therapies may include administering the additional therapeutic agent(s) multiple times between the administration of the disclosed solid dosage forms. The time period between the administration of each additional therapeutic agent(s) may range from a few seconds (or less) to several hours or days, and will depend on, for example, the properties of the additional therapeutic agent as formulated (e.g., potency, solubility, bioavailability, half-life, and kinetic profile), as well as the condition of the patient.
V. KITS
The present disclosure also relates to kits comprising one or more solid dosage forms of the present disclosure. The kit optionally can comprise one or more additional therapeutic agents and/or instructions, for example, instructions for using the kit. In one embodiment, the kit comprises a plurality of separate packages with each package containing a daily dose of the solid dosage forms (e.g., a package containing two or three of the solid dosage forms).
VI. METHODS OF PREPARATION
The present disclosure also relates to methods for preparing the solid dosage forms described in this specification, including those methods described in the Examples below.
In one embodiment, the disclosure relates to methods for preparing a single amorphous solid dispersion comprising Compounds 1, 2 and 3 that can be used to in the preparation of the dosage form. The amorphous solid dispersion can be prepared by a variety of techniques such as, without limitation, melt-extrusion, spray-drying, co-precipitation, freeze drying, or other solvent evaporation techniques, with melt-extrusion and spray-drying being preferred.
In another embodiment, the method generally comprises, for example: (1) preparing a melt comprising Compound 1, Compound 2, Compound 3, a pharmaceutically acceptable hydrophilic polymer, and a pharmaceutically acceptable surfactant; and (2) solidifying the melt. The solidified melt can comprise any amorphous solid dispersion described or contemplated herein. The method can further comprise milling the solidified melt, followed by compressing the milled product with one or more other excipients or ingredients to form a tablet core. These other excipients or ingredients can include, for example, coloring agents, flavoring agents, lubricants or preservatives. In one aspect, the melt is formed at a temperature from 150° C. to 180° C. In another aspect, the melt is formed at a temperature from 150° C. to 170° C. In another aspect, the melt is formed at a temperature from 150° C. to 160° C. In another aspect, the melt is formed at a temperature from 160° C. to 170° C.
The melt-extrusion process typically comprises the steps of preparing a melt which includes the active ingredients (i.e., Compound 1, Compound 2, and Compound 3), the hydrophilic polymer(s) and optionally the surfactant(s), and then cooling the melt until it solidifies. “Melting” means a transition into a liquid or rubbery state in which it is possible for one component to get embedded, such as homogeneously embedded, in the other component or components. In many cases, the polymer component(s) will melt and the other components including the active ingredients and surfactant(s) will dissolve in the melt thereby forming a solution. Melting usually involves heating above the softening point of the polymer(s). The preparation of the melt can take place in a variety of ways. The mixing of the components can take place before, during or after the formation of the melt. For example, the components can be mixed first and then melted or be simultaneously mixed and melted. The melt can also be homogenized in order to disperse the active ingredients efficiently. In addition, it may be convenient first to melt the polymer(s) and then to mix in and homogenize the active ingredients. In one example, all materials except surfactant(s) are blended and fed into an extruder, while the surfactant(s) is molten externally and pumped in during extrusion.
In the melt-extrusion process, the active ingredients can be employed in their solid forms, such as their respective crystalline forms. The active ingredients can also be employed as a solution or dispersion in a suitable liquid solvent such as alcohols, aliphatic hydrocarbons, esters or, in some cases, liquid carbon dioxide. The solvent can be removed, e.g. evaporated, upon preparation of the melt.
Various additives can also be included in the melt, for example, flow regulators (e.g., colloidal silica), binders, lubricants, fillers, disintegrants, plasticizers, colorants, or stabilizers (e.g., antioxidants, light stabilizers, radical scavengers, and stabilizers against microbial attack).
The melting and/or mixing can take place in an apparatus customary for this purpose such as extruders or kneaders. Suitable extruders may include single screw extruders, intermeshing screw extruders or multi-screw extruders, such as twin screw extruders, which can be co-rotating or counter-rotating and, optionally, be equipped with kneading disks. It will be appreciated that the working temperatures will be determined by the kind of extruder or the kind of configuration within the extruder that is used. Friction and shearing of the material in the extruder may provide a substantial amount of energy to the mixture and aid in the formation of a homogeneous melt of the components. However, part of the energy needed to melt, mix and dissolve the components in the extruder can be provided by heating elements.
The consistency of the melt can range from thin to pasty to viscous. Shaping of the extrudate can be conveniently carried out by a calendar with two counter-rotating rollers with mutually matching depressions on their surface. The extrudate can be cooled and allowed to solidify. The extrudate can also be cut into pieces, either before solidification (hot-cut) or after solidification (cold-cut).
The solidified extrusion product can be further milled, ground or otherwise reduced to granules. The solidified extrudate, as well as each granule produced, comprises a solid dispersion, such as a solid solution, of the active ingredients in a matrix comprised of the hydrophilic polymer(s) and the pharmaceutically acceptable surfactant(s). The extrusion product can also be blended with other active ingredient(s) and/or additive(s) before being milled or ground into granules. The granules can be further processed into suitable solid oral dosage forms.
In one example, copovidone and one or more surfactants (e.g., vitamin E TPGS in combination with propylene glycol monolaurate) are mixed and granulated, followed by the addition of aerosil and Compound 1, Compound 2, and Compound 3. The mixture is milled, and then subjected to extrusion. The extrudate thus produced can be milled and sieved for further processing to make capsules or tablets. Surfactant(s) employed in this example can be added, for example, through liquid dosing during extrusion.
Alternatively, the amorphous solid dispersion can be prepared using the approach of solvent evaporation, via spray-drying, which provides the advantage of allowing for processing at lower temperatures, if needed, and also allows for other modifications to the process in order to further improve powder properties. The spray-dried powder can then be formulated further, if needed, and final drug product is flexible with regards to whether capsule, tablet or any other solid dosage form is desired.
Exemplary spray-drying processes and spray-drying equipment are described in K. Masters, SPRAY DRYING HANDBOOK (Halstead Press, New York, 4th ed., 1985). Non-limiting examples of spray-drying devices that are suitable for the present invention include spray dryers manufactured by Niro Inc. or GEA Process Engineering Inc., Buchi Labortechnik AG, and Spray Drying Systems, Inc. A spray-drying process generally involves breaking up a liquid mixture into small droplets and rapidly removing solvent from the droplets in a container (spray drying apparatus) where there is a strong driving force for evaporation of solvent from the droplets. Atomization techniques include, for example, two-fluid or pressure nozzles, or rotary atomizers. The strong driving force for solvent evaporation can be provided, for example, by maintaining the partial pressure of solvent in the spray drying apparatus well below the vapor pressure of the solvent at the temperatures of the drying droplets. This may be accomplished by either (1) maintaining the pressure in the spray drying apparatus at a partial vacuum; (2) mixing the liquid droplets with a warm drying gas (e.g., heated nitrogen); or (3) both.
The temperature and flow rate of the drying gas, as well as the spray dryer design, can be selected so that the droplets are dry enough by the time they reach the wall of the apparatus to be essentially solid and to form a fine powder to avoid sticking to the apparatus wall. The spray-dried product can be collected by removing the material manually, pneumatically, mechanically or by other suitable means. The actual length of time to achieve the desired level of dryness depends on the size of the droplets, the formulation, and spray dryer operation. Following the solidification, the solid powder may stay in the spray drying chamber for additional time (e.g., 5 seconds to 60 seconds) to further evaporate solvent from the solid powder. The final solvent content in the solid dispersion as it exits the dryer is generally at a sufficiently low level so as to improve the stability of the final product. For instance, the residual solvent content of the spray-dried powder can be less than 2% by weight. The residual solvent content may be within the limits set forth in the International Conference on Harmonization (ICH) Guidelines. In addition, it may be useful to subject the spray-dried composition to further drying to lower the residual solvent to even lower levels. Methods to further lower solvent levels include, but are not limited to, fluid bed drying, infra-red drying, tumble drying, vacuum drying, and combinations of these and other suitable processes.
Like the solid extrudate described above, the spray dried product contains a solid dispersion, such as a solid solution, of the active ingredients in a matrix comprised of the hydrophilic polymer(s) and the pharmaceutically acceptable surfactant(s).
Before feeding into a spray dryer, the active ingredients, the hydrophilic polymer(s), as well as other excipients such as the pharmaceutically acceptable surfactant(s), can be dissolved in a solvent. Suitable solvents include, but are not limited to, alkanols (e.g., methanol, ethanol, 1-propanol, 2-propanol or mixtures thereof), acetone, acetone/water, alkanol/water mixtures (e.g., ethanol/water mixtures), or combinations thereof. The solution can also be preheated before being fed into the spray dryer.
The solid dispersion produced by melt-extrusion, spray-drying or other techniques can be prepared into any suitable solid oral dosage forms. In one embodiment, the solid dispersion prepared by melt-extrusion, spray-drying or other techniques (e.g., the extrudate or the spray-dried powder) can be compressed into tablets. The solid dispersion can be either directly compressed, or milled or ground into granules or powders before compression. Compression can be performed in a tablet press, such as in a steel die between two moving punches.
At least one additive selected from flow regulators, binders, lubricants, fillers, disintegrants, or plasticizers may be used in compressing the solid dispersion. These additives can be mixed with ground or milled solid dispersion before compacting. Disintegrants promote a rapid disintegration of the compact in the stomach and keeps the liberated granules separate from one another. Non-limiting examples of suitable disintegrants are cross-linked polymers such as cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethylcellulose or sodium croscarmellose. Non-limiting examples of suitable fillers (also referred to as bulking agents) are lactose monohydrate, calcium hydrogenphosphate, microcrystalline cellulose (e.g., Avicell), silicates (such as silicium dioxide), magnesium oxide, talc, potato or corn starch, isomalt, or polyvinyl alcohol. Non-limiting examples of suitable flow regulators include highly dispersed silica (e.g., colloidal silica such as Aerosil), and animal or vegetable fats or waxes. Non-limiting examples of suitable lubricants include polyethylene glycol (e.g., having a molecular weight of from 1000 to 6000), magnesium and calcium stearates, sodium stearyl fumarate, and the like.
Various other additives or ingredients may also be used in preparing a solid composition of the present invention, for example dyes such as azo dyes, organic or inorganic pigments such as aluminium oxide or titanium dioxide, or dyes of natural origin; stabilizers such as antioxidants, light stabilizers, radical scavengers, stabilizers against microbial attack; or other active pharmaceutical ingredients.
Accordingly, one representative embodiment relates to a method of making the dosage forms described in this specification, wherein the method comprises:

    
    
        (a) preparing a melt comprising Compound 1, Compound 2, Compound 3, a hydrophilic polymer, and a surfactant;
        (b) solidifying the melt to form an amorphous solid dispersion;
        (c) preparing a first composition comprising the amorphous solid dispersion;
        (d) preparing a second composition comprising Compound 4; and
        (e) formulating the first composition and the second composition to provide the dosage form.

In one aspect, the preparing the first composition step further comprises: (a) milling the solidified melt to provide particles of the amorphous solid dispersion; and (b) optionally combining the particles of the amorphous solid dispersion with one or more excipients to provide the first composition. In another aspect, the melt is prepared at a temperature of 150° C. to 170° C. In another aspect, the melt is prepared at a temperature of 160° C. to 170° C.

    
    


Another representative embodiment relates to a method of making the dosage forms described in this specification, wherein the method comprises:

    
    
        (a) preparing the first composition comprising Compound 1, Compound 2, and Compound 3;
        (b) granulating (i) a mixture comprising at least a portion of the Compound 4 with at least a portion of the stabilizing polymer, or combination of stabilizing polymers, to provide granules comprising Compound 4; (ii) a mixture comprising at least a portion of the Compound 4 with at least a portion of the release rate-modifying polymer, or combination of release rate-modifying polymers, to provide granules comprising Compound 4; or (iii) a mixture comprising at least a portion of the Compound 4 with at least a portion of the stabilizing polymer, or combination of stabilizing polymers, and at least a portion of the release rate-modifying polymer, or combination of stabilizing polymers, to provide granules comprising Compound 4;
        (c) preparing the second composition using the granules as a source of at least a portion of the Compound 4 present in the second composition; and
        (d) formulating the first composition and the second composition to provide the dosage form.
    
    


VII. PRODUCT-BY-PROCESS
The present disclosure also relates to solid dosage forms prepared in accordance with any of the methods described in this specification, including the methods described in the Examples below.
In one embodiment, the dosage form is prepared by a process comprising:

    
    
        granulating (i) a mixture comprising at least a portion of the Compound 4 with at least a portion of the stabilizing polymer, or combination of stabilizing polymers, to provide granules comprising Compound 4; (ii) a mixture comprising at least a portion of the Compound 4 with at least a portion of the release rate-modifying polymer, or combination of release rate-modifying polymers, to provide granules comprising Compound 4; or (iii) a mixture comprising at least a portion of the Compound 4 with at least a portion of the stabilizing polymer, or combination of stabilizing polymers, and at least a portion of the release rate-modifying polymer, or combination of stabilizing polymers, to provide granules comprising Compound 4; and
        preparing the second composition using the granules as a source of at least a portion of the Compound 4 present in the second composition.
    
    


VIII. EXAMPLES
Unless otherwise stated, in the formulations described in the Examples below: (i) the Compound 1 free acid was used; (ii) the Compound 2 free base was used; (iii) the Compound 3 free base was used; and the Compound 4 monosodium salt monohydrate was used.
Example 1: Bilayer Tablet (Formulation C5-12)
Bilayer tablets (Formulation C5-12) comprising a first bilayer blend containing Compound 1, Compound 2, and Compound 3, and a second bilayer containing Compound 4 were prepared. The specific composition of the resulting Formulation C5-12 is set forth in Table 1-A below.







TABLE 1-A







Bilayer Tablet (Formulation C5-12)











FORMU-




LATION




C5-12




(mg/


COMPONENT
FUNCTION
TABLET)










BILAYER 1









Compound 1 Mono-Extrudate




Compound 1
Drug Substance
50.00


Copovidone
Polymer Carrier
256.67


Vitamin E, TPGS
Surfactant/Plasticizer
16.67


Lauroglycol FCC
Surfactant/Plasticizer
6.67


Colloidal Silicon Dioxide
Glidant
3.33


Compound 2 Mono-Extrudate


Compound 2
Drug Substance
8.33


Copovidone
Polymer Carrier
144.9


Vitamin E, TPGS
Surfactant/Plasticizer
11.67


Colloidal Silicon Dioxide
Glidant
1.67


Compound 3 Mono-Extrudate


Compound 3
Drug Substance
33.33


Copovidone
Polymer Carrier
164.44


Sorbitan Monolaurate
Surfactant/Plasticizer
22.22


Colloidal Silicon Dioxide
Glidant
2.22


Colloidal Silicon Dioxide
Glidant
1.8








Total Bilayer 1 Weight
723.9







BILAYER 2 (200 mg Compound 4)









Compound 4 granules:
Drug Substance
216.21


Compound 4 (55.7%)
(Compound 4)


Copovidone Type K 28 (44.3%)
Polymer (Copovidone)
172.0


Hypromellose 2208, USP/EP,
Polymer
173.2


20,700 mPa · S (Premium CR)


Colloidal Silicon Dioxide
Glidant
1.44


Magnesium Stearate, NF/EP,
Lubricant
14.46


Impalpable Powder (Veget. Grade)










Total Bilayer 2 Weight
577.3


TABLET WEIGHT(mg)
1301.2





1Equivalent to 200.0 mg of Compound 4 (free acid).






Each of the Compound 1, Compound 2, and Compound 3 components was prepared as a separate amorphous solid dispersion comprising the active ingredient using hot melt extrusion technology and milled prior to blending with the other two amorphous solid dispersions. The Compound 1 mono-extrudate and the Compound 3 mono-extrudate were prepared as described in Example 4 of published U.S. application US2011/0312973. The Compound 2 mono-extrudate was prepared as described in Example 1 of published international application WO2011/156578.
A. Compound 1 Mono-Extrudate
As stated above, the Compound 1 mono-extrudate was prepared using hot melt extrusion technology in which Compound 1 was converted from crystalline to amorphous form and uniformly distributed in a polymer-surfactant matrix. The Compound 1 mono-extrudate prepared contained: (i) copovidone as a carrier polymer, (ii) colloidal silicon dioxide as a glidant to aid in powder flow into the extruder, and (iii) vitamin E tocopheryl polyethylene glycol succinate (vitamin E TPGS) and propylene glycol monolaurate, type I (LauroglycolTM FCC) as surfactants/plasticizers. The specific composition of the Compound 1 mono-extrudate prepared is set forth below in Table 1-B.







TABLE 1-B







Compound 1 Mono-Extrudate









COMPONENT
FUNCTION
WEIGHT PERCENT





Compound 1
Drug Substance
151 


Copovidone
Polymer Carrier
77 


Vitamin E, TPGS
Surfactant/Plasticizer
5


Lauroglycol FCC
Surfactant/Plasticizer
2


Colloidal Silicon Dioxide
Glidant
1





1Weight/weight % based on free acid equivalent amount of Compound 1.






B. Compound 2 Mono-Extrudate
As stated above, the Compound 2 mono-extrudate was prepared using hot melt extrusion technology in which Compound 2 was converted from crystalline to amorphous form and uniformly distributed in a polymer-surfactant matrix. The Compound 2 mono-extrudate contains: (i) copovidone as a carrier polymer, (ii) colloidal silicon dioxide as a glidant to aid in powder flow into the extruder, and (iii) vitamin E tocopheryl polyethylene glycol succinate (vitamin E TPGS) as a surfactant/plasticizer. The specific composition of the Compound 2 mono-extrudate prepared is set forth below in Table 1-C.







TABLE 1-C







Compound 2 Mono-Extrudate









COMPONENT
FUNCTION
WEIGHT PERCENT





Compound 2
Drug Substance
 51


Copovidone
Polymer Carrier
87 


Vitamin E, TPGS
Surfactant/Plasticizer
7


Colloidal Silicon Dioxide
Glidant
1





1Weight/weight % based on free base equivalent amount of Compound 2.






C. Compound 3 Mono-Extrudate
As stated above, the Compound 3 mono-extrudate was prepared using hot melt extrusion technology in which Compound 3 was converted from crystalline to amorphous form and uniformly distributed in a polymer-surfactant matrix. The Compound 3 mono-extrudate prepared contained: (i) copovidone as a carrier polymer, (ii) colloidal silicon dioxide as a glidant to aid in powder flow into the extruder, and (iii) sorbitan monolaurate as a surfactant/plasticizer. The specific composition of the Compound 3 mono-extrudate prepared is set forth below in Table 1-D.







TABLE 1-D







Compound 3 Mono-Extrudate









COMPONENT
FUNCTION
WEIGHT PERCENT





Compound 3
Drug Substance
 151


Copovidone
Polymer Carrier
74


Sorbitan Monolaurate
Surfactant/Plasticizer
10


Colloidal Silicon Dioxide
Glidant
 1





1Weight/weight % based on free acid equivalent amount of Compound 3.






D. First Bilayer Blend
A first bilayer blend comprising the Compound 1 mono-extrudate, the Compound 2 mono-extrudate, and the Compound 3 mono-extrudate was prepared. The mono-extrudates were each milled, combined in a 46:23:31 ratio (Compound 1:Compound 2:Compound 3) based on the weight percent of active ingredient, and blended with additional colloidal silicon dioxide to form the first bilayer blend having the composition reported in Table 1-E below.







TABLE 1-E







First Bilayer Blend (Formulation C5-12)










COMPONENT
AMOUNT (mg/TABLET)














Compound 1 Mono-Extrudate
333.3



Compound 2 Mono-Extrudate
166.7



Compound 3 Mono-Extrudate
222.2



Colloidal Silicon Dioxide, NF/EP
1.8



TOTAL
724.0










E. Compound 4 Granules
Compound 4 was granulated with copovidone in a fluid bed granulation process. Compound 4 was added together with copovidone to the fluid bed granulator. The powders were fluidized with heated air at approximately 35° C. to 55° C. and water was subsequently sprayed from the top onto the fluidized powder bed. The water was sprayed at a rate sufficient to increase the moisture content of the granulation to a target of approximately 8% to 14% moisture. The water spray rate was then slightly reduced to maintain the granulation at the target moisture content for a hold period of approximately 15 minutes or longer. The spraying was subsequently stopped. The heated air temperature was increased and the granulation was dried until the moisture content was reduced to no greater than about 2 w/w %. The D50 particle size distribution of the granules was between 80 and 130 microns. This method of granulation improved the bulk handling properties of the resulting combination of Compound 4 and copovidone while maintaining the intrinsic small particle size of Compound 4. The resulting Compound 4 granules had the composition reported in Table 1-F below.







TABLE 1-F







Compound 4 Granules (Formulation C5-12)








COMPONENT
WEIGHT PERCENT











Compound 4 (monosodium salt monohydrate)
55.7


Copovidone Type K 28
44.3


Purified Water
—


TOTAL
100









The Compound 4 granules prepared as described above were then blended with HPMC Hypromellose 2208, colloidal silicon dioxide, and magnesium stearate to form the second bilayer blend used in the preparation of Formulation C5-12. The specific composition of the second bilayer blend is set forth in Table 1-G below.







TABLE 1-G





Second Bilayer Blend (Formulation C5-12)


BlLAYER 2 (200 mg Compound 4)



















Compound 4 granules:
Compound 4
216.21



Compound 4 (55.7%)
Copovidone)
172.0



Copovidone Type K 28 (44.3%)



Hypromellose 2208, USP/EP, 20,700

173.2



mPa · S (Premium CR)



Colloidal Silicon Dioxide

1.44



Magnesium Stearate, NF/EP,

14.46



Impalpable Powder (Veget. Grade)










Total
577.3





1Equivalent to 200.0 mg of Compound 4 (free acid).






F. Tablet Preparation (Formulation C5-12)
Formulation C5-12 was prepared by loading a unit dose of the second bilayer blend into the tablet die (oval, concave tooling, 10 mm width×18.8 mm length) on an automated bilayer tablet press, compressing the second bilayer blend with a compression force of approximately 4 kN, loading a unit dose of the first bilayer blend into the same tablet die on top of the previously compressed second bilayer blend, and compressing the first bilayer blend with a compression force of approximately 25 kN.
Example 2: Sink Conditions Dissolution Testing
The release profiles of Formulation C5-12 of Example 1 were evaluated in a Sink Conditions dissolution study. The study was conducted in 900 mL of dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37±0.5° C. The dissolution medium was a 0.05 M sodium phosphate buffer pH 6.8 with 15 mM cTAB as a surfactant.
Results for the Compound 1 component of Formulation C5-12 of Example 1 are reported in Table 2-A below.
Results for the Compound 2 component of Formulation C5-12 of Example 1 are reported in Table 2-B below.
Results for the Compound 3 component of Formulation C5-12 of Example 1 are reported in Table 2-C below.
Results for the Compound 4 component of Formulation C5-12 of Example 1 are reported in Table 2-D (% Released) and Table 2-E (mg Released) below.







TABLE 2-A







Sink Conditions Dissolution Release Profile (Compound 1)













Time (Hours)
1
4
6
8
12
16
















% Released
54
98
99
102
102
101


Std. Dev. (N = 6)
3.2
2.1
2.3
2.4
2.2
2.2
















TABLE 2-B







Sink Conditions Dissolution Release Profile (Compound 2)













Time (Hours)
1
4
6
8
12
16
















% Released
55
98
99
103
102
102


Std. Dev. (N = 6)
2.8
1.8
1.9
2.1
2.2
2.1
















TABLE 2-C







Sink Conditions Dissolution Release Profile (Compound 3)













Time (Hours)
1
4
6
8
12
16
















% Released
58
99
100
103
102
100


Std. Dev. (N = 6)
2.9
2.1
1.9
2.2
2.2
2.0
















TABLE 2-D







Sink Conditions Dissolution Release Profile


(Compound 4: Percent Released)















Time (Hours)
1
4
6
8
12
16
24
30


















% Released
1
11
18
25
39
51
70
81


Std. Dev. (N = 6)
0.1
0.7
1.4
1.9
2.6
3.1
3.8
3.9
















TABLE 2-E







Sink Conditions Dissolution Release


Profile (Compound 4: mg Released)















Time (Hours)
1
4
6
8
12
16
24
30


















mg Released
2.3
25.7
42.0
58.3
91.0
119.0
163.3
189.0


Std. Dev. (N = 6)
0.2
1.6
3.3
4.4
6.1
7.2
8.9
9.1









Example 3: FeSSIF Dissolution Testing
Release profiles are obtained for Formulation C5-12 of Example 1 using a Fed-State Simulated Intestinal Fluid (“FeSSIF”) dissolution protocol under non-sink conditions. The study is conducted in 450 mL of dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 75 RPM at 37±0.5° C. The dissolution medium is a 0.04 M sodium phosphate buffer pH 6.8 with 11.2 g/L Phares SIF Original Powder (biorelevant.com, Croydon, Surrey, UK) to simulate FeSSIF conditions. Although the Sink Conditions dissolution method discussed in Example 2 provides results that are acceptable for general comparisons of release profiles, that method does not account for the conversion of a Compound 4 salt to the insoluble Compound 4 free acid in vivo and the resulting reduction in Compound 4 bioavailability that has been observed in vivo. The FeSSIF dissolution method provides results that more closely correlate with the observed in vivo results than the Sink Conditions dissolution method.
Example 4: Human Pharmacokinetic Study (Formulation C5-12)
A Phase 1, non-fasting, open-label, single-dose, two-arm, three-period, randomized, crossover study was conducted to evaluate the pharmacokinetics of Formulation C5-12 of Example 1 and several other formulations containing Compounds 1, 2, 3, and 4.
Methodology:
Formulation C5-12 and a second formulation were tested in Arm II of the study. Adult male and female subjects (N=30 for combined Arm I and Arm II studies) in general good health were selected to participate in the study according to the selection criteria. Subjects meeting the selection criteria were randomly assigned to one of the Regimen sequences as shown below in Table 4-A.











TABLE 4-A









SEQUENCE
NUMBER OF
REGIMENS












ARM
NUMBER
SUBJECTS
PERIOD 1
PERIOD 2
PERIOD 3





II
1
5
A
*
B



2
5
*
B
A



3
5
B
A
*





* Second formulation.






Study drug was administered as provided below in Table 4-B.








TABLE 4-B







REGI-
One Single Tablet (i.e., Compound 4 250 mg immediate release


MEN A
tablet) + Two Triple Tablets (each co-formulated tablet


(Refer-
contains Compound 1 (75 mg), Compound 2 (12.5 mg), and


ence
Compound 3 (50 mg)) are administered under non-fasting


Regi-
conditions in the morning and one Single Tablet is


men)
administered under non-fasting conditions in the evening



(Day 1 of each period in Arm I and II).


REGI-
Three Formulation C5-12 tablets (bi-layer tablet/total dose


MEN B
of Compound 1 (150 mg)/Compound 2 (25 mg)/Compound 3



(100 mg)/Compound 4 (600 mg)) are administered in the



morning under non-fasting conditions (Day 1 of each period



in Arm II).









Each study regimen was taken orally with approximately 240 mL of water approximately 30 minutes after the start of standardized breakfast. Study regimens were administered orally in the morning on Study Day 1 of each period. For Regimen A the evening dose of the Single Tablet was taken orally with approximately 240 mL of water approximately 30 minutes after the start of the evening snack. Serial blood samples for pharmacokinetic analysis were collected 72 hours after dosing in each period.
Tables 4-C, 4-D, 4-E, and 4-F below report the Arm II pharmacokinetic data for Formulation C5-12 (separately reported for each of Compounds 1, 2, 3, and 4). Table 4-G presents the relative bioavailability and 90% confidence intervals results for the pharmacokinetic data of Formulation C5-12 relative to the reference regimen. The data presented in Tables 4-C through 4-G are preliminary data and are subject to database lock and final data verification.
Arm II Pharmacokinetic Data (C5-12):







TABLE 4-C







Compound 1 Pharmacokinetic Data (C5-12)









GEOMETRIC MEAN (ARITHMETIC



MEAN, % CV) (N = 13)














REGIMEN A




PARAMETER

(REFERENCE
REGIMEN E



(UNIT)

REGIMEN)
(C5-12)

















Cmax (ng/mL)
900
(1340, 100)
647
(1050, 96)



Tmax (h)
4.8
(30)
5.7
(47)



t1/2 (h)
5.2
(16)
5.1
(20)



AUCt (ng · h/mL)
4670
(6120, 79)
4310
(5930, 82)



AUC∞ (ng · h/mL)
4690
(6140, 79)
4330
(5950, 81)



C24 (ng/mL)
24.3
(27.2, 53)
24.5
(28.2, 60)

















TABLE 4-D







Compound 2 Pharmacokinetic Data (C5-12)









GEOMETRIC MEAN (ARITHMETIC



MEAN, % CV) (N = 13)














REGIMEN A




PARAMETER

(REFERENCE
REGIMEN E



(UNIT)

REGIMEN)
(C5-12)

















Cmax (ng/mL)
113
(117, 27)
117
(122, 31)



Tmax (h)
4.5
(25)
5.2
(18)



t1/2 (h)
26.6
(40)
23.2
(35)



AUCt (ng · h/mL)
1450
(1500, 24)
1510
(1560, 25)



AUC∞ (ng · h/mL)
1640
(1700, 28)
1670
(1740, 29)



C24 (ng/mL)
17.9
(18.7, 29)
18.7
(19.4, 29)

















TABLE 4-E







Compound 3 Pharmacokinetic Data (C5-12)









GEOMETRIC MEAN (ARITHMETIC



MEAN, % CV) (N = 13)














REGIMEN A




PARAMETER

(REFERENCE
REGIMEN E



(UNIT)

REGIMEN)
(C5-12)

















Cmax (ng/mL)
1170
(1330, 57)
1160
(1390, 57)



Tmax (h)
4.0
(27)
4.9
(35)



t1/2 (h)
4.9
(27)
4.2
(26)



AUCt (ng · h/mL)
7710
(8630, 51)
8160
(9470, 54)



AUC∞ (ng · h/mL)
7900
(8790, 50)
8270
(9560, 53)



C24 (ng/mL)
37.0
(42.6, 55)
38.8
(46.3, 62)

















TABLE 4-F







Compound 4 Pharmacokinetic Data (C5-12)









GEOMETRIC MEAN (ARITHMETIC



MEAN, % CV) (N = 13)










REGIMEN A



PARAMETER
(REFERENCE
REGIMEN E


(UNIT)
REGIMEN)
(C5-12)














Cmax (ng/mL)
1240
(1260, 22)
1350
(1480, 46)


Tmax (h)
3.1
(34)
9.7
(39)


t1/2 (h)
5.5
(9)
6.4
(19)


AUCt (ng · h/mL)
18200
(18800, 26)
18400
(20200, 47)


AUC∞ (ng · h/mL)
18400
(18900, 26)
18600
(20300, 47)


C24 (ng/mL)
361
(392, 42)
290
(344, 64)
















TABLE 4-G







Relative Bioavailability and 90% Confidence Intervals (C5-12)












COM-
COM-
COM-
COM-


PARAMETER
POUND 1
POUND 2
POUND 3
POUND 4





Cmax
0.714a
1.038
1.001
1.094



(0.482-
(0.933-
(0.821-
(0.856-



1.056)b
1.155)
1.220)
1.398)


AUCinf
0.919
1.022
1.056
1.012



(0.724-
(0.963-
(0.935-
(0.832-



1.167)
1.084)
1.192)
1.231)





aPoint Estimate


b90% Confidence Interval






Arm III Pharmacokinetic Data (C5-12):
After completion of the Arm 11 study, an Arm III study was conducted to evaluate the steady-state pharmacokinetics of Formulation C5-12 in a 14-day multiple-dose, single period, randomized design (N=12). Three Formulation C5-12 tablets were administered under non-fasting conditions to subjects for 14 days (Study Days 1 through 14).
Tables 4-H, 4-I, 4-J, and 4-K below report the Arm III pharmacokinetic data for Formulation C5-12 (separately reported for each of Compounds 1, 2, 3, and 4). The data presented in Tables 4-H through 4-K are preliminary data and are subject to database lock and final data verification.







TABLE 4-H







Compound 1 Pharmacokinetic Data (C5-12)









GEOMETRIC MEAN (ARITHMETIC


PARAMETER
MEAN, % CV) (N = 14)










(UNIT)
DAY 1
DAY 14
RATIO















AUC24 (ng · h/mL)
4640
(6070, 64)
10600
(15100, 88)
2.28


Cmax (ng/mL)
651
(991, 77)
1640
(2530, 95)
2.52


C24 (ng/mL)
33.7
(38.3, 56)
33.7
(44.9, 103)
1.00


Tmax (h)
6.7
(41)
5.1
(27)











β (1/h)
—
0.151
(19)



t1/2 (h)
—
4.6
(19)
















TABLE 4-I







Compound 2 Pharmacokinetic Data (C5-12)









GEOMETRIC MEAN


PARAMETER
(ARITHMETIC MEAN, % CV) (N = 14)










(UNIT)
DAY 1
DAY 14
RATIO





AUC24 (ng · h/mL)
1280 (1320, 26)
1720 (1780, 26)
1.34


Cmax (ng/mL)
123 (127, 28)
135 (141, 34)
1.10


C24 (ng/mL)
23.4 (24.4, 30)
40.2 (41.5, 24)
1.72


Tmax (h)
5.5 (29)   
5.6 (18)   



β (1/h)
—
0.023 (41)    



t1/2 (h)
—
29.8 (43)    
















TABLE 4-J







Compound 3 Pharmacokinetic Data (C5-12)









GEOMETRIC MEAN


PARAMETER
(ARITHMETIC MEAN, % CV) (N = 14)










(UNIT)
DAY 1
DAY 14
RATIO





AUC24 (ng · h/mL)
7230 (7970, 41)
10700 (11200, 29)
1.48


Cmax (ng/mL)
 921 (1030, 44)
1430 (1500, 28)
1.55


C24 (ng/mL)
34.7 (41.1, 53)
40.0 (42.3, 36)
1.15


Tmax (h)
5.4 (38)   
4.7 (17)   



β (1/h)
—
0.174 (23)    



t1/2 (h)
—
4.0 (23)   
















TABLE 4-K







Compound 4 Pharmacokinetic Data (C5-12)









GEOMETRIC MEAN


PARAMETER
(ARITHMETIC MEAN, % CV) (N = 14)










(UNIT)
DAY 1
DAY 14
RATIO





AUC24 (ng · h/mL)
13600 (15500, 50)
12000 (13900, 50)
0.88


Cmax (ng/mL)
1320 (1480, 44)
1250 (1400, 44)
0.95


C24 (ng/mL)
272 (313, 55)
172 (210, 61)
0.63


Tmax (h)
9.0 (20)   
9.4 (19)   



β (1/h)
—
0.117 (22)    



t1/2 (h)
—
5.9 (22)   









Example 5: Human Pharmacokinetic Study (Formulation C5-12)
A Phase 1, non-fasting, open-label, two-arm, four-period, randomized, crossover study was conducted to compare and characterize the pharmacokinetics of (i) Triple Tablet when co-administered with Single Tablet, and (ii) Formulation C5-12 as discussed below. Part 1 was a single dose, two-treatment, randomized, four period, two sequence replicated crossover study with 88 subjects. Doses in the four periods were separated by at least 10 days. Part 2 was a multiple-dose, two-treatment, two period, randomized crossover study with 66 subjects. Dosing in each period was 14 days and doses in the two periods were separated by at least 10 days.
Methodology:
Adult male and female subjects in general good health were selected to participate in the study according to the selection criteria. Subjects meeting the selection criteria were randomly assigned to one of the sequences of Regimens A and B (four sequences for Arm I and two sequences for Arm II) as shown below in Table 5-A.








TABLE 5-A








REGIMENS












ARM
N
PERIOD 1
PERIOD 2
PERIOD 3
PERIOD 4





I
44
A
B
A
B



44
B
A
B
A


II
33
A
B





33
B
A









Study drug was administered as provided below in Table 5-B.








TABLE 5-B







REGIMEN 
Three Film-Coated Formulation C5-12 tablets (total dose of


A
Compound 1 (150 mg)/Compound 2 (25 mg)/Compound 3 


(Test
(100 mg)/Compound 4 (600 mg)) were administered in the 


Regimen)
morning under non-fasting conditions on Day 1 of each 



corresponding period in Arm I, and Days 1 through 14



of each corresponding period in Arm II.


REGIMEN 
One Single Tablet (i.e., Compound 4 250 mg immediate 


B
release tablet) + Two Triple Tablets (each co-formulated 


(Reference
tablet contains Compound 1 (75 mg), Compound 2 


Regimen)
(12.5 mg), and Compound 3 (50 mg)) are administered 



under non-fasting conditions in the morning and 



one Single Tablet is administered under non-fasting



conditions in the evening on Day 1 of each



corresponding period in Arm I, and Days 1 through 



14 of each corresponding period in Arm II.









Each study regimen was taken orally with approximately 240 mL of water approximately 30 minutes after the start of standardized breakfast. Study regimens were administered orally in the morning on Study Day 1 of each period. Serial blood samples for pharmacokinetic analysis were collected 72 hours after dosing in each period.
Arm I Pharmacokinetic Data (Single Dose Study):
Tables 5-C, 5-D, 5-E, and 5-F below report the Arm I pharmacokinetic data for Formulation C5-12 (separately reported for each of Compounds 1, 2, 3, and 4). Table 5-G presents the results of a relative bioavailability and 90% confidence interval analysis of the pharmacokinetic data for Formulation C5-12 relative to the reference regimen. The data presented in Tables 5-C through 5-G are preliminary data and are subject to database lock and final data verification by the statistician.







TABLE 5-C







Compound 1 Pharmacokinetic Data (Arm I: C5-12)









GEOMETRIC MEAN



(ARITHMETIC MEAN, % CV)










REGIMEN A
REGIMEN B


PARAMETER
(C5-12)
(REFERENCE REGIMEN)


(UNIT)
(N = 172)
N = 171)





Cmax (ng/mL)
618 (996, 97)
 935 (1360, 82)


Tmax (h)
5.0 (5.8, 32)
5.0 (5.1, 27)


t1/2 (h)
6.15 (1.46)  
6.02 (1.36)  


AUCt (ng · h/mL)
4460 (6450, 86)
5470 (7170, 75)


AUC∞ (ng · h/mL)
4490 (6480, 85)
5490 (7270, 74)
















TABLE 5-D







Compound 2 Pharmacokinetic Data (Arm I: C5-12)









GEOMETRIC MEAN



(ARITHMETIC MEAN, % CV)










REGIMEN A
REGIMEN B


PARAMETER
(C5-12)
(REFERENCE REGIMEN)


(UNIT)
(N = 172)
N = 171)





Cmax (ng/mL)
124 (133, 33)
131 (136, 33)


Tmax (h)
5.0 (5.3, 17)
5.0 (5.1, 15)


t1/2 (h)
37.9 (15.3)  
39.2 (14.2)  


AUCt (ng · h/mL)
1660 (1770, 32)
1630 (1680, 31)


AUC∞ (ng · h/mL)
1800 (1910, 33)
1760 (1840, 30)
















TABLE 5-E







Compound 3 Pharmacokinetic Data (Arm I: C5-12)









GEOMETRIC MEAN



(ARITHMETIC MEAN, % CV)










REGIMEN A
REGIMEN B


PARAMETER
(C5-12)
(REFERENCE REGIMEN)


(UNIT)
(N = 172)
N = 171)





Cmax (ng/mL)
1130 (1320, 48)
1430 (1540, 42)


Tmax (h)
4.0 (4.9, 32)
4.0 (4.5, 23)


t1/2 (h)
4.52 (0.99)  
4.47 (0.86)  


AUCt (ng · h/mL)
7450 (9140, 61)
8610 (9690, 58)


AUC∞ (ng · h/mL)
8090 (9360, 59)
8750 (9920, 56)
















TABLE 5-F







Compound 4 Pharmacokinetic Data (Arm I: C5-12)









GEOMETRIC MEAN



(ARITHMETIC MEAN, % CV)










REGIMEN A
REGIMEN B


PARAMETER
(C5-12)
(REFERENCE REGIMEN)


(UNIT)
(N = 172)
N = 171)





Cmax (ng/mL)
1060 (1210, 46)
1030 (1110, 36)


Tmax (h)
8.0 (8.4, 32)
4.0 (4.2, 28)


t1/2 (h)
6.91 (1.99)  
5.80 (1.17)  


AUCt (ng · h/mL)
12700 (15200, 54)
14800 (15900, 38)


AUC∞ (ng · h/mL)
12900 (15300, 54)
14900 (16100, 38)
















TABLE 5-G







Relative Bioavailability and 90% Confidence Intervals (Arm I: C5-12)












POINT
90% CONFIDENCE


REGIMEN
PARAMETER
ESTIMATE
INTERVAL










COMPOUND 1










A vs. B
Cmax
0.685
0.625-0.750




0.689
0.091



AUCt
0.849
0.790-0.911



AUCinf
0.850
0.792-0.912







COMPOUND 2










A vs. B
Cmax
0.960
0.926-0.995



AUCt
1.037
1.011-1.064



AUC24
1.035
1.009-1.062







COMPOUND 3










A vs. B
Cmax
0.821
0.777-0.867



AUCt
0.914
0.880-0.949



AUC24
0.923
0.893-0.953







COMPOUND 4










A vs. B
Cmax
1.032
0.950-1.121



AUCt
0.859
0.787-0.936



AUC24
0.863
0.793-0.939









Arm II Pharmacokinetic Data (Multiple Dose Study):
Tables 5-H, 5-I, 5-J, and 5-K below report the Arm II pharmacokinetic data for Formulation C5-12 (separately reported for each of Compounds 1, 2, 3, and 4). Table 5-L presents the results of a relative bioavailability and 90% confidence interval analysis of the pharmacokinetic data for Formulation C5-12 relative to the reference regimen. The data presented in Tables 5-H through 5-L are preliminary data and are subject to database lock and final data verification by the statistician.







TABLE 5-H







Compound 1 Pharmacokinetic Data (Arm II: C5-12)









GEOMETRIC MEAN



(ARITHMETIC MEAN, % CV)



(N = 63)









PARAMETER
REGIMEN A
REGIMEN B


(UNIT)
(C5-12)
(REFERENCE REGIMEN)





AUC24 (ng · h/mL)
 8900 (13500, 96)
 9240 (13200, 82)


Cmax (ng/mL)
1500 (2290, 86)
1947 (2810, 85)


Tmax (h)
5.0 (5.2, 30)
4.0 (4.2, 22)


C24 (ng/mL)
 34.6 (54.2, 141)
30.4 (38.9, 73)


β (1/h)
0.129 (0.132, 20)
0.128 (0.130, 17)


t1/2 (h)
5.2 (20)   
5.3 (17)   
















TABLE 5-I







Compound 2 Pharmacokinetic Data (Arm II: C5-12)









GEOMETRIC MEAN



(ARITHMETIC MEAN, % CV)



(N = 63)









PARAMETER
REGIMEN A
REGIMEN B


(UNIT)
(C5-12)
(REFERENCE REGIMEN)





AUC24 (ng · h/mL)
1390 (1470, 34)
1240 (1330, 37)


Cmax (ng/mL)
128 (135, 31)
117 (127, 35)


Tmax (h)
5.0 (5.0, 11)
5.0 (4.8, 18)


C24 (ng/mL)
30.5 (33.5, 46)
26.6 (29.6, 49)


β (1/h)
0.019 (0.020, 34)
0.019 (0.020, 34)


t1/2 (h)
35.1 (34)    
35.0 (34)    
















TABLE 5-J







Compound 3 Pharmacokinetic Data (Arm II: C5-12)









GEOMETRIC MEAN



(ARITHMETIC MEAN, % CV)



(N = 63)









PARAMETER
REGIMEN A
REGIMEN B


(UNIT)
(C5-12)
(REFERENCE REGIMEN)





AUC24 (ng · h/mL)
8670 (9470, 43)
9580 (10700, 50)


Cmax (ng/mL)
1340 (1440, 39)
1680 (1800, 44)


Tmax (h)
4.0 (4.6, 21)
4.0 (4.1, 19)


C24 (ng/mL)
36.2 (44.3, 76)
35.1 (43.2, 73)


β (1/h)
0.147 (0.152, 25)
0.142 (0.145, 23)


t1/2 (h)
4.6 (25)   
4.8 (23)   
















TABLE 5-K







Compound 4 Pharmacokinetic Data (Arm II: C5-12)









GEOMETRIC MEAN



(ARITHMETIC MEAN, % CV)



(N = 63)









PARAMETER
REGIMEN A
REGIMEN B


(UNIT)
(C5-12)
(REFERENCE REGIMEN)





AUC24 (ng · h/mL)
 8810 (10300, 55)
 9770 (10600, 42)


Cmax (ng/mL)
799 (896, 46)
879 (932, 40)


Tmax (h)
8.0 (8.4, 35)
4.0 (5.2, 79)


C24 (ng/mL)
116 (155, 87)
162 (183, 55)


β (1/h)
0.104 (0.111, 30)
0.122 (0.127, 44)


t1/2 (h)
6.2 (30)   
5.5 (24)   
















TABLE 5-L







Relative Bioavailability and 90% Confidence Intervals (Arm II: C5-12)












POINT
90% CONFIDENCE


REGIMEN
PARAMETER
ESTIMATE
INTERVAL










COMPOUND 1










A vs. B
Cmax
0.727
0.642-0.823



AUC24
0.903
0.817-0.998



C24
1.055
0.970-1.147







COMPOUND 2










A vs. B
Cmax
1.087
1.006-1.174



AUCt
1.091
1.065-1.119



AUC24
1.098
1.064-1.132







COMPOUND 3










A vs. B
Cmax
0.793
0.747-0.843



AUCt
0.894
0.847-0.944



AUC24
1.009
0.946-1.075







COMPOUND 4










A vs. B
Cmax
0.905
0.823-0.995



AUCt
0.893
0.810-0.986



AUC24
0.710
0.622-0.812









With respect to the observed pharmacokinetics of Formulation C5-12 relative to the reference regimen in Arm I of the study:
(1) Cmax for Compound 1 was lower (by 30%) than Cmax for the reference regimen. Otherwise, the exposures for Compound 1, Compound 2, Compound 3, and Compound 4 were comparable (less than 20% difference) to exposures from the reference regimen. Based on the exposures-efficacy of Compound 1, Compound 2, and Compound 3, however, these differences were not deemed clinically significant.
(2) For the AUC of Compound 4 and Compound 1 and the Cmax of Compound 3, the lower 90% confidence bounds were slightly lower than 0.80 (less than 2% difference) and the geometric mean exposures were within 20% of the exposures from the reference regimen. These differences were not deemed clinically significant.
With respect to the observed pharmacokinetics of Formulation C5-12 relative to the reference regimen in Arm II of the study:
(1) Compound 1 and Compound 3 exposures (C24,ss and AUC24,ss) were bioequivalent (point estimate and 90% confidence interval for the geometric mean ratio (“GMR”) within 0.80-1.25) to exposures from the reference regimen except for Cmax,ss, which was lower (by 27% and 21%, respectively) than Cmax,ss for the reference regimen. Based on the exposures-efficacy, however, the difference in Cmax,ss was not deemed clinically significant.
(2) Compound 2 exposures were bioequivalent (point estimate and 90% confidence interval for the GMR within 0.80-1.25) to exposures from the reference regimen.
(3) Compound 4 exposures (Cmax,ss and AUC24,ss) were bioequivalent (point estimate and 90% confidence interval for the GMR within 0.80-1.25) to exposures from the reference regimen except for the C24,ss (Ctrough) which was lower (by 29%) than the C24,ss (Ctrough) for the reference regimen. Based on the exposures-efficacy, however, the difference in Ctrough was not deemed clinically significant.
It should be understood that the above-described embodiments and the examples are given by way of illustration, not limitation. Various changes and modifications within the scope of the present invention will become apparent to those skilled in the art from the present description.
All references (patent and non-patent) cited above are incorporated by reference into this patent disclosure. The discussion of those references is intended merely to summarize the assertions made by their authors. No admission is made that any reference (or a portion of any reference) is relevant prior art (or prior art at all). Applicants reserve the right to challenge the accuracy and pertinence of the cited references.

## Claims

1. A solid dosage form comprising a first composition and a second composition, wherein:
the first composition comprises from 40 mg to 180 mg of





from 5 mg to 30 mg of




from 25 mg to 120 mg of ritonavir, 70-85% by weight of copovidone; and 5% to 10% by weight of a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first composition, and wherein Compound 1, Compound 2 and ritonavir are formulated in an amorphous solid dispersion;
the second composition comprises from 75 mg to 900 mg (free acid equivalent) of a sodium monohydrate salt of





20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second composition;
when dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., 50-60% Compound 1 in the solid dosage form is released within 1 hour, 50-60% Compound 2 in the solid dosage form is released within 1 hour, 50-60% ritonavir in the solid dosage form is released within 1 hour, and 0.5-2% Compound 4 in the solid dosage form is released within 1 hour, wherein the dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cetyltrimethylammonium bromide (cTAB), and
the total weight of the solid dosage form is from 1000 mg to 1600 mg.

2. The solid dosage form of claim 1, wherein the first composition comprises from 45 mg to 55 mg of Compound 1, from 7.5 mg to 9.5 mg of Compound 2, and from 30 mg to 37 mg of ritonavir, and the second composition comprises from 150 mg to 300 mg (free acid equivalent) of the sodium monohydrate salt of Compound 4.

3. A method for treating hepatitis C virus (HCV) infection in a patient in need of such treatment, wherein the method comprises administering once daily to the patient at least one solid dosage form of claim 1.

4. A method for treating HCV infection in a patient in need of such treatment, wherein the method comprises administering once daily to the patient three solid dosage forms of claim 1.

5. A solid dosage form comprising a first composition and a second composition, wherein:
the first composition comprises from 40 mg to 180 mg of Compound 1, from 5 mg to 30 mg of Compound 2, from 25 mg to 120 mg of ritonavir, 70-85% by weight of copovidone; and 5% to 10% by weight of a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first composition, and wherein Compound 1, Compound 2 and ritonavir are formulated in an amorphous solid dispersion;
the second composition comprises from 75 mg to 900 mg (free acid equivalent) of a sodium monohydrate salt of Compound 4, 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second composition;
when dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., 95-100% Compound 1 in the solid dosage form is released within 4 hours, 95-100% Compound 2 in the solid dosage form is released within 4 hours, 95-100% ritonavir in the solid dosage form is released within 4 hours, and 10-15% Compound 4 in the solid dosage form is released within 4 hours, wherein the dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB, and
the total weight of the solid dosage form is from 1000 mg to 1600 mg.

6. The solid dosage form of claim 5, wherein the first composition comprises from 45 mg to 55 mg of Compound 1, from 7.5 mg to 9.5 mg of Compound 2, and from 30 mg to 37 mg of ritonavir, and the second composition comprises from 150 mg to 300 mg (free acid equivalent) of the sodium monohydrate salt of Compound 4.

7. A method for treating HCV infection in a patient in need of such treatment, wherein the method comprises administering once daily to the patient at least one solid dosage form of claim 5.

8. A method for treating HCV infection in a patient in need of such treatment, wherein the method comprises administering once daily to the patient three solid dosage forms of claim 5.

9. A solid dosage form comprising a first composition and a second composition, wherein:
the first composition comprises from 40 mg to 180 mg of Compound 1, from 5 mg to 30 mg of Compound 2, from 25 mg to 120 mg of ritonavir, 70-85% by weight of copovidone; and 5% to 10% by weight of a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first composition, and wherein Compound 1, Compound 2 and ritonavir are formulated in an amorphous solid dispersion;
the second composition comprises from 75 mg to 900 mg (free acid equivalent) of a sodium monohydrate salt of Compound 4, 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second composition;
when dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., 95-100% Compound 1 in the solid dosage form is released within 6 hours, 95-100% Compound 2 in the solid dosage form is released within 6 hours, 95-100% ritonavir in the solid dosage form is released within 6 hours, and 15-20% Compound 4 in the solid dosage form is released within 6 hours, wherein the dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB, and
the total weight of the solid dosage form is 1000 mg to 1600 mg.

10. The solid dosage form of claim 9, wherein the first composition comprises from 45 mg to 55 mg of Compound 1, from 7.5 mg to 9.5 mg of Compound 2, and from 30 mg to 37 mg of ritonavir, and the second composition comprises from 150 mg to 300 mg (free acid equivalent) of the sodium monohydrate salt of Compound 4.

11. A method for treating HCV infection in a patient in need of such treatment, wherein the method comprises administering once daily to the patient at least one solid dosage form of claim 9.

12. A method for treating HCV infection in a patient in need of such treatment, wherein the method comprises administering once daily to the patient three solid dosage forms of claim 9.

13. A solid dosage form comprising a first composition and a second composition, wherein:
the first composition comprises from 40 mg to 180 mg of Compound 1, from 5 mg to 30 mg of Compound 2, from 25 mg to 120 mg of ritonavir, 70-85% by weight of copovidone; and 5% to 10% by weight of a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first composition, and wherein Compound 1, Compound 2 and ritonavir are formulated in an amorphous solid dispersion;
the second composition comprises from 75 mg to 900 mg (free acid equivalent) of a sodium monohydrate salt of Compound 4, 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second composition;
when dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% ritonavir in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, and 40-60% Compound 4 in the solid dosage form is released within 16 hours, wherein the dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB, and
the total weight of the solid dosage form is from 1000 mg to 1600 mg.

14. The solid dosage form of claim 13, wherein the first composition comprises from 45 mg to 55 mg of Compound 1, from 7.5 mg to 9.5 mg of Compound 2, and from 30 mg to 37 mg of ritonavir, and the second composition comprises from 150 mg to 300 mg (free acid equivalent) of the sodium monohydrate salt of Compound 4.

15. A method for treating HCV infection in a patient in need of such treatment, wherein the method comprises administering once daily to the patient at least one solid dosage form of claim 13.

16. A method for treating HCV infection in a patient in need of such treatment, wherein the method comprises administering once daily to the patient three solid dosage forms of claim 13.

17. A solid dosage form comprising a first composition and a second composition, wherein:
the first composition comprises from 40 mg to 180 mg of Compound 1, from 5 mg to 30 mg of Compound 2, from 25 mg to 120 mg of ritonavir, 70-85% by weight of copovidone; and 5% to 10% by weight of a pharmaceutically acceptable surfactant or a combination of pharmaceutically acceptable surfactants, wherein all percentages are weight percentages relative to the total weight of the first composition, and wherein Compound 1, Compound 2 and ritonavir are formulated in an amorphous solid dispersion;
the second composition comprises from 75 mg to 900 mg (free acid equivalent) of a sodium monohydrate salt of Compound 4, 20-40% copovidone, and 20-40% hypromellose, wherein all percentages are weight percentages relative to the total weight of the second composition;
when dissolved in 900 mL of a dissolution medium using a standard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., 100% Compound 1 in the solid dosage form is released within 8 hours, 100% Compound 2 in the solid dosage form is released within 8 hours, 100% ritonavir in the solid dosage form is released within 8 hours, 20-30% Compound 4 in the solid dosage form is released within 8 hours, 30-40% Compound 4 in the solid dosage form is released within 12 hours, 40-60% Compound 4 in the solid dosage form is released within 16 hours, and 60-80% Compound 4 in the solid dosage form is released within 24 hours, wherein the dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB, and
the total weight of the solid dosage form is from 1000 mg to 1600 mg.

18. The solid dosage form of claim 17, wherein the first composition comprises from 45 mg to 55 mg of Compound 1, from 7.5 mg to 9.5 mg of Compound 2, and from 30 mg to 37 mg of ritonavir, and the second composition comprises from 150 mg to 300 mg (free acid equivalent) of the sodium monohydrate salt of Compound 4.

19. A method for treating HCV infection in a patient in need of such treatment, wherein the method comprises administering once daily to the patient at least one solid dosage form of claim 17.

20. A method for treating HCV infection in a patient in need of such treatment, wherein the method comprises administering once daily to the patient three solid dosage forms of claim 17.