Patent Description:
The complement system plays a central role in the clearance of immune complexes and in immune responses to infectious agents, foreign antigens, virus infected cells and tumor cells. Inappropriate or excessive activation of the complement system can lead to harmful, and even potentially life-threatening consequences due to severe inflammation and resulting tissue destruction. These consequences are clinically manifested in various disorders including septic shock; myocardial, as well as, intestinal ischemia/reperfusion injury; graft rejection; organ failure; nephritis; pathological inflammation; and autoimmune diseases.

The complement system is composed of a group of proteins that are normally present in the serum in an inactive state. Activation of the complement system encompasses mainly three distinct pathways, i.e., the classical, the alternative, and the lectin pathway (<NPL>): <NUM>) The classical pathway is a calcium/magnesium-dependent cascade, which is normally activated by the formation of antigen-antibody complexes. It can also be activated in an antibody-independent manner by the binding of C-reactive protein, complexed with ligand, and by many pathogens including gram-negative bacteria. <NUM>) The alternative pathway is a magnesium-dependent cascade which is activated by deposition and activation of C3 on certain susceptible surfaces (e.g. cell wall polysaccharides of yeast and bacteria, and certain biopolymer materials). <NUM>) The lectin pathway involves the initial binding of mannose-binding lectin and the subsequent activation of C2 and C4, which are common to the classical pathway (<NPL>); <NPL>)).

The activation of the complement pathway generates biologically active fragments of complement proteins, e.g. C3a, C4a and C5a anaphylatoxins and C5b-<NUM> membrane attack complexes (MAC), all which mediate inflammatory responses by affecting leukocyte chemotaxis; activating macrophages, neutrophils, platelets, mast cells and endothelial cells; and increasing vascular permeability, cytolysis and tissue injury.

Complement C5a is one of the most potent proinflammatory mediators of the complement system. (The anaphylactic C5a peptide is <NUM> times more potent, on a molar basis, in eliciting inflammatory responses than C3a. ) C5a is the activated form of C5 (<NUM> kD, molecular weight). C5a is present in human serum at approximately <NUM>µg/ml (<NPL>)). It is composed of two polypeptide chains, α and β, with approximate molecular weights of <NUM> kD and <NUM> kD, respectively (<NPL>)). Biosynthesized as a single-chain promolecule, C5 is enzymatically cleaved into a two-chain structure during processing and secretion. After cleavage, the two chains are held together by at least one disulphide bond as well as noncovalent interactions (<NPL>)).

Recent work has identified Compound <NUM>
<CHM>
as useful for treating C5a mediated diseases. Compound <NUM> is classed as a compound belonging to Class II of the Biopharmaceutics Classification System (BCS) having poor solubility in the aqueous environment of the gastrointestinal (GI) tract but high permeability across membranes. Thus, its resorption is controlled by its solubility and rate of dissolution in the GI tract. Despite the disclosure of this compound, a pharmaceutical formulation that provides manufacturability, consistent stability, bioavailability, and pharmacokinetics has not been developed.

As such, there exists a need to produce pharmaceutical formulations that meet the necessary manufacturability, stability, bioavailability, and pharmacokinetic requirements to make them suitable for oral administration to humans or other animals. The present disclosure addresses these needs and provides related advantages as well. <CIT> relates to C5AR antagonists.

In one aspect, provided herein is a solid solution capsule comprising Compound <NUM> as a free base, in its neutral form
<CHM>
and a vehicle comprising.

Also disclosed herein is a method of preparing a solid solution capsule comprising Compound <NUM> a free base, in its neutral form or in the form of a pharmaceutically acceptable salt
<CHM>.

Also disclosed herein is a solid solution capsule comprising Compound <NUM> as a free base, in its neutral form or in the form of a pharmaceutically acceptable salt
<CHM>.

In one aspect, provided herein is a solid solution capsule of the present invention for use in a method of treating an individual suffering from or susceptible to a disease or disorder involving pathologic activation of C5a receptors, the method comprising administering to the individual an effective amount of the solid solution capsule.

In one aspect, provided herein is a single unit dosage capsule comprising about <NUM> to <NUM> of Compound <NUM> as a free base, in its neutral form
<CHM>
and a vehicle comprising.

In one aspect, provided herein are kits comprising a solid solution capsule of the present invention, or a single unit dosage capsule of the present invention.

Other objects, features, and advantages of the present invention will be apparent to one of skill in the art from the following detailed description and figures.

Compound <NUM> has been found to possess extremely poor solubility across a broad pH range. Additionally, Compound <NUM> lacked solubility in a number of excipients tested. Compound <NUM> has been successfully formulated as a liquid; however, such formulations included ethanol. Ethanol readily evaporates during both dose preparation and storage, thereby introducing dosing inaccuracies and, at times, causing Compound <NUM> to crash out of solution. In order to overcome the difficulties in formulating Compound <NUM> for pharmaceutical uses, the present disclosure provides a solid solution capsule formulation of Compound <NUM> and methods of making the same.

The solid solution capsules described herein provide Compound <NUM> completely and molecularly dissolved in a matrix, dispersed in a matrix, or a mixture thereof. That is, the drug product is a solid solution of drug substance in the amorphous capsule fill matrix. In some embodiments, dissolution of Compound <NUM> in the matrix can be determined through visual inspection of the capsule fill matrix. Thus, completely and molecularly dissolved Compound <NUM> can include a solid solution capsule fill matrix that does not have observable clusters of undissolved Compound <NUM> and appears as a uniform solid solution to the naked eye.

Advantageously, the solid solution capsule formulations described herein avoids or reduces crystallization of the drug substance in the molecularly dissolved or dispersed matrix and provides excellent stability, bioavailability, and pharmacokinetic properties. A key feature of the formulations described herein is the ratio of the at least one non-ionic surfactant and the at least one water-soluble solubilizer that provide a useful pharmaceutical composition.

The term "treating" or "treatment" encompasses both disease-modifying treatment and symptomatic treatment, either of which may be prophylactic (i.e., before the onset of symptoms, in order to prevent, delay or reduce the severity of symptoms) or therapeutic (i.e., after the onset of symptoms, in order to reduce the severity and/or duration of symptoms).

The term "pharmaceutically acceptable salts" is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, Examples of salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, <NUM>-diethylaminoethanol, <NUM>-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperadine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, <NPL> or <NPL>).

The neutral form of Compound <NUM> may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of Compound <NUM> differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of Compound <NUM> for the purposes of the present disclosure.

"Solid solution capsule" refers to a formulation comprising the drug substance dissolved or dispersed in an excipient matrix that is encapsulated. The drug substance is completely and molecularly dissolved or dispersed in the excipient matrix, or a mixture thereof. In the present invention, the drug substance, i.e. Compound <NUM> as a free base, in its neutral form, is dissolved or dispersed in an excipient matrix, which is a vehicle comprising at least one non-ionic surfactant as defined herein and at least one water-soluble solubilizer as defined herein.

"Nonionic surfactant" refers to a surfactant in which the hydrophilic portion of the surfactant carries no charge. Two non-limiting classes of nonionic surfactants useful in the present disclosure are (a) polyoxyethylene castor oil derivatives, and (b) polyoxyethylene derivatives of a fatty acids containing from about <NUM> to about <NUM> carbon atoms. The carbon atoms of the fatty acid can include one or more points of unsaturation or one or more points of substitution (e.g. ricinoleic acid).

The term "hydrophilic-lipophilic balance" ("HLB") is a relative measure of the ratio of polar and non-polar groups present in a surfactant. In some embodiments, the HLB value is calculated by the Griffin method using the formula: <MAT> where Mh is the molecular mass of the hydrophilic portion of the molecule, and M is the molecular mass of the whole molecule, giving a result on a scale of <NUM> to <NUM>. An HLB value of <NUM> corresponds to a completely lipophilic/hydrophobic molecule, and a value of <NUM> corresponds to a completely hydrophilic/lipophobic molecule. Further details of Griffin's method can be found in <NPL>) and <NPL>). In some embodiments, the HLB value is calculated by the Davies method when is described in <NPL>). In some embodiments, when determining the HLB values of compositions where the hydrophilic portions consists of ethylene oxide only, the HLB value is calculated using the formula <MAT> where E is the weight percent of the oxyethylene content. Further information for this calculation is described in "The HLB system: a time-saving guide to emulsifier selection. Wilmington. ICI Americas, Inc.

"Water-soluble solubilizer" refers to compositions that that are readily molecularly soluble in water at neutral pH and ambient temperature. For example, water-soluble solubilizers have a solubility in water of at least <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM>/L at <NUM>. In some embodiments, water-soluble solubilizers have a solubility in water of at least <NUM>/L at <NUM>. Typical water-soluble solubizers having a melting point at or above <NUM> are polyethylene glycols having an average molecular weight of <NUM> to <NUM>. Additional water-soluble solubilizers having a melting point at or above <NUM>° C also include poloxamers such as poloxamer <NUM>, poloxamer <NUM>, poloxamer <NUM> and poloxamer <NUM>.

The "total fill weight" refers to the amount of material that is encapsulated within a capsule shell as described herein. The "total fill weight" does not include the weight of the capsule itself nor any other additives used to seal the capsule.

"Compound <NUM>" is a chemical compound having an IUPAC name of (2R,<NUM>)-<NUM>-(<NUM>-(cyclopentylamino)phenyl)-<NUM>-(<NUM>-fluoro-<NUM>-methylbenzoyl)-N-(<NUM>-methyl-<NUM>-(trifluoromethyl)phenyl)piperidine-<NUM>-carboxamide, and the structure shown below:
<CHM>.

As used herein, a condition is considered "responsive to C5a receptor modulation" if modulation of C5a receptor activity results in the reduction of inappropriate activity of a C5a receptor.

The term "individual" refers to mammals, which includes primates (especially humans), domesticated companion animals (such as dogs, cats, horses, and the like) and livestock (such as cattle, pigs, sheep, and the like), with dosages as described herein. In some embodiments, the term "individual" refers to a human.

In some aspects, provided herein are solid solution capsule formulations comprising Compound <NUM> as a free base, in its neutral form or in the form of a pharmaceutically acceptable salt
<CHM>
and a vehicle comprising.

Without wishing to be bound by any particular theory, it is thought that a capsule formulation comprising a non-ionic surfactant as defined herein, which may have an HLB value of at least <NUM>, and a water-soluble solubilizer as defined herein, which may have a melting point at or above <NUM>° C, provides a so-called self-emulsifying or self-solubilizing system. Upon oral administration, the capsule shell dissolves in the gastrointestinal tract followed by dissolution of the solubilizing agent in the gastric fluid with simultaneous formation of micelles comprising molecularly dissolved Compound <NUM>. Thus, a microemulsion or a nanoemulsion is formed that permits Compound <NUM> to remain in solution despite being surrounded by gastric fluid having a pH value of <NUM> or above, at which pH value Compound <NUM> is normally insoluble.

In some embodiments, the solid solution capsule formulations comprising Compound <NUM> as a free base, in its neutral form, and a vehicle, said vehicle comprising macrogol-<NUM>-glycerol hydroxystearate and PEG-<NUM>.

In some embodiments, the vehicle comprises about <NUM> to <NUM>% by weight of the total fill weight of said solid solution capsule. In some embodiments, the vehicle comprises about <NUM>% by weight of the total fill weight of said solid solution capsule.

In some embodiments, the solid solution capsule comprises about <NUM> to <NUM>% of Compound <NUM> by weight of the total fill weight of said solid solution capsule. In some embodiments, the solid solution capsule comprises about <NUM> to <NUM>% of Compound <NUM> by weight of the total fill weight of said solid solution capsule. In some embodiments, the solid solution capsule comprises about <NUM>% of Compound <NUM> by weight of the total fill weight of said solid solution capsule.

In some embodiments, the total weight of the vehicle comprises a <NUM>:<NUM> to <NUM>:<NUM> ratio of at least one non-ionic surfactant as defined herein and at least one water-soluble solubilizer as defined herein. In a preferred embodiment, the ratio of macrogol-<NUM>-glycerol hydroxystearate to polyethylene glycol <NUM> (PEG-<NUM>) is from <NUM>:<NUM> and <NUM>:<NUM>. In some embodiments, the total weight of the vehicle comprises a <NUM>:<NUM> to <NUM>:<NUM> ratio of at least one non-ionic surfactant as defined herein and at least one water-soluble solubilizer as defined herein. In a preferred embodiment, the ratio of macrogol-<NUM>-glycerol hydroxystearate to polyethylene glycol <NUM> (PEG-<NUM>) is from <NUM>:<NUM> to <NUM>:<NUM>. In some embodiments, the total weight of the vehicle comprises a <NUM>:<NUM> to <NUM>:<NUM> ratio of at least one non-ionic surfactant as defined herein and at least one water-soluble solubilizer as defined herein. In a preferred embodiment, the ratio of macrogol-<NUM>-glycerol hydroxystearate to polyethylene glycol <NUM> (PEG-<NUM>) is from <NUM>:<NUM> to <NUM>:<NUM>. In some embodiments, the total weight of the vehicle comprises about a <NUM>:<NUM> ratio of at least one non-ionic surfactant as defined herein and at least one water-soluble solubilizer as defined herein. In a preferred embodiment, the ratio of macrogol-<NUM>-glycerol hydroxystearate to polyethylene glycol <NUM> (PEG-<NUM>) is <NUM>:<NUM>. In some embodiments, the total weight of the vehicle comprises about a <NUM>:<NUM> ratio of at least one non-ionic surfactant as defined herein and at least one water-soluble solubilizer as defined herein. In a preferred embodiment, the ratio of macrogol-<NUM>-glycerol hydroxystearate to polyethylene glycol <NUM> (PEG-<NUM>) is <NUM>:<NUM>. In some embodiments, the total weight of the vehicle comprises about a <NUM>:<NUM> ratio of at least one non-ionic surfactant as defined herein and at least one water-soluble solubilizer as defined herein. In a preferred embodiment, the ratio of macrogol-<NUM>-glycerol hydroxystearate to polyethylene glycol <NUM> (PEG-<NUM>) is <NUM>:<NUM>.

In some embodiments, the total fill weight of said solid solution capsule is about <NUM> to about <NUM>,<NUM>. In some embodiments, the total fill weight of said solid solution capsule is about <NUM> to about <NUM>. In some embodiments, the total fill weight of said solid solution capsule is about <NUM> to about <NUM>. In some embodiments, the total fill weight of said solid solution capsule is about <NUM>.

In some embodiments, the solid solution capsule does not include ethanol.

In some embodiments, the solid solution capsule is in a capsule of size #<NUM>, #<NUM>, #<NUM>, #<NUM>, #<NUM>, #<NUM>, or #<NUM>. In some embodiments, the solid solution capsule is in a capsule of size #<NUM>. In some embodiments, the solid solution capsule is in a capsule of size #<NUM>. In some embodiments, the solid solution capsule is in a capsule of size #<NUM>.

In some embodiments, the capsule is a hard capsule. In some embodiments, the capsule is a soft capsule.

Capsules of the present disclosure can be sealed using known techniques in the art. For example, a gelatin sealing band comprising a plasticizer such as polysorbate <NUM> can be used to seal the capsules disclosed herein.

Also disclosed herein are methods for making solid solution capsules comprising Compound <NUM> as a free base, in its neutral form or in the form of a pharmaceutically acceptable salt. The solid solution capsule formulations described herein are manufactured by filling hard shell capsules with warmed drug solution. After filling the warmed drug solution into the capsules, the solution solidifies and forms an amorphous matrix.

Also disclosed herein are methods of preparing a solid solution capsule comprising Compound <NUM> as a free base, in its neutral form or in the form of a pharmaceutically acceptable salt
<CHM>
and a vehicle comprising.

Melting the vehicle is achieved using standard techniques in the art. The temperature for melting will depend on the identity of the vehicle. Typical melting techniques include direct heating oven and jacketed mixing tanks. The vehicle in step (a) may be heated to about <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or more degrees C. The vehicle in step (a) may be heated to about <NUM>° to <NUM>° C. The vehicle in step (a) may be heated to about <NUM>° C. The vehicle in step (a) may be heated to about <NUM>° C. The vehicle in step (a) may be heated to about <NUM>° C. The vehicle in step (a) may be heated to about <NUM>° C.

As described above, the melting of step (a) can be performed using standard heating techniques in the art. This also applies to steps (i) and (ii). The heating temperatures of steps (i) and (ii) may be the same. The heating temperatures of steps (i) and (ii) may be different.

The at least one non-ionic surfactant having an HLB value of at least <NUM> in step (i) may be heated to about <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or more degrees C. The at least one non-ionic surfactant having an HLB value of at least <NUM> in step (i) may be heated to about <NUM>° to <NUM>° C. The at least one non-ionic surfactant having an HLB value of at least <NUM> in step (i) may be heated to about <NUM>° to <NUM>° C. The at least one non-ionic surfactant having an HLB value of at least <NUM> in step (i) may be heated to about <NUM>° C. The at least one non-ionic surfactant having an HLB value of at least <NUM> in step (i) may be heated to about <NUM>° C. The at least one non-ionic surfactant having an HLB value of at least <NUM> in step (i) may be heated to about <NUM>° C. The at least one non-ionic surfactant having an HLB value of at least <NUM> in step (i) may be heated to about <NUM>° C.

The at least one water-soluble solubilizer in step (ii) may be heated to about <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or more degrees C. The at least one water-soluble solubilizer in step (ii) may be heated to about <NUM>° to <NUM>° C. The at least one water-soluble solubilizer in step (ii) may be heated to about <NUM>° to <NUM>° C. The at least one water-soluble solubilizer in step (ii) may be heated to about <NUM>° C. The at least one water-soluble solubilizer in step (ii) may be heated to about <NUM>° C. The at least one water-soluble solubilizer in step (ii) may be heated to about <NUM>° C. In some embodiments, the at least one water-soluble solubilizer in step (ii) may be heated to about <NUM>° C.

The at least one non-ionic surfactant having an HLB value of at least <NUM> in step (i) may be heated to about <NUM> to <NUM>° C, and the at least one water-soluble solubilizer in step (ii) may be heated to about <NUM> to <NUM>° C. The at least one non-ionic surfactant having an HLB value of at least <NUM> in step (i) may be heated to about <NUM>° C, and the at least one water-soluble solubilizer in step (ii) may be heated to about <NUM>° C.

After performing steps (i) and (ii), the melted solubilizer may have the temperature adjusted to a temperature within the tolerances of the capsule shell. For example, the temperature tolerance of a gelatin capsule shell is about <NUM>° C. Difference capsule shells can tolerate different temperatures, a person of skill in the art would readily identify appropriate temperatures based on the capsule shell being used.

When contacting the melted solubilizer and the melted surfactant, agitation is generally applied to ensure mixing of the melted surfactant and melted solubilizer. Typically, stirring is employed. The time of agitation/stirring will vary depending on the components of the melted surfactant and melted solubilizer, the size of the preparation, and the heating temperatures used. Stirring may be performed for <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or more hours. Agitation may be performed under vacuum during this step to dearate the solution.

Returning to step (b), when contacting the melted vehicle with Compound <NUM> in step (b), the drug is dissolved in the heated vehicle. Dissolution of Compound <NUM> can be achieved by a number of techniques including waiting an appropriate amount of time or agitating the solution to increase the rate of dissolution. The heated vehicle with Compound <NUM> in step (b) may be agitated by stirring. Stirring times can be between one to six or more hours. The stirring time may be for <NUM>, <NUM>, <NUM>, <NUM>, <NUM><NUM> or more hours. The stirring time may be for about <NUM> hours.

Encapsulation of the drug solution is performed using known techniques in the art. One such machine useful for encapsulating is a Shionogi F40 filler. A person of skill in the art will be aware of additional equivalent machines.

There are a number of means known in the art for cooling a desired substance. The cooling in recited step (d) can include passive activities such as allowing the encapsulated drug solution to equilibrate to room temperature or more active steps such as placing the encapsulated drug solution in a refrigerated area to increase the rate of cooling.

A person of skill in the art will recognize the each of the above steps does not need to be performed in the recited order to prepare a solid solution capsule comprising Compound <NUM>. For example, after dissolution of Compound <NUM> in the heated vehicle (step (b)), to form a drug mixture, the drug mixture can be cooled to form a solid solution. As discussed above, cooling can include passive activities such as allowing the encapsulated drug solution to equilibrate to room temperature or more active steps such as placing the encapsulated drug solution in a refrigerated area to increase the rate of cooling.

In some embodiments, the total weight of the vehicle comprises a <NUM>:<NUM> to <NUM>:<NUM> ratio of at least one non-ionic surfactant as defined herein and at least one water-soluble solubilizer as defined herein. In a preferred embodiment, the ratio of macrogol-<NUM>-glycerol hydroxystearate to polyethylene glycol <NUM> (PEG-<NUM>) is from <NUM>:<NUM> and <NUM>:<NUM>. In some embodiments, wherein the total weight of the vehicle comprises a <NUM>:<NUM> to <NUM>:<NUM> ratio of at least one non-ionic surfactant as defined herein and at least one water-soluble solubilizer as defined herein. In a preferred embodiment, the ratio of macrogol-<NUM>-glycerol hydroxystearate to polyethylene glycol <NUM> (PEG-<NUM>) is from <NUM>:<NUM> to <NUM>:<NUM>. In some embodiments, the total weight of the vehicle comprises a <NUM>:<NUM> to <NUM>:<NUM> ratio of at least one non-ionic surfactant as defined herein and at least one water-soluble solubilizer as defined herein. In a preferred embodiment, the ratio of macrogol-<NUM>-glycerol hydroxystearate to polyethylene glycol <NUM> (PEG-<NUM>) is from <NUM>:<NUM> to <NUM>:<NUM>. In some embodiments, the total weight of the vehicle comprises about a <NUM>:<NUM> ratio of at least one non-ionic surfactant as defined herein and at least one water-soluble solubilizer as defined herein. In a preferred embodiment, the ratio of macrogol-<NUM>-glycerol hydroxystearate to polyethylene glycol <NUM> (PEG-<NUM>) is <NUM>:<NUM>. In some embodiments, the total weight of the vehicle comprises about a <NUM>:<NUM> ratio of at least one non-ionic surfactant as defined herein and at least one water-soluble solubilizer as defined herein. In a preferred embodiment, the ratio of macrogol-<NUM>-glycerol hydroxystearate to polyethylene glycol <NUM> (PEG-<NUM>) is <NUM>:<NUM>. In some embodiments, the total weight of the vehicle comprises about a <NUM>:<NUM> ratio of at least one non-ionic surfactant as defined herein and at least one water-soluble solubilizer as defined herein. In a preferred embodiment, the ratio of macrogol-<NUM>-glycerol hydroxystearate to polyethylene glycol <NUM> (PEG-<NUM>) is <NUM>:<NUM>.

As described in the preceding paragraphs, these methods are used to prepare a solid solution capsule. Accordingly, in some aspects, also provided herein is a solid solution capsule of the present invention prepared according to the methods describe herein.

In some embodiments, provided herein is a solid solution capsule comprising Compound <NUM> as a free base, in its neutral form
<CHM>
and a vehicle comprising.

References herein to methods of treatment of the human or animal body by therapy are to be interpreted as referring to the solid solution capsules of the present invention or the single unit dosage capsules of the present invention for use in those methods.

Also provided herein are methods of treating individuals suffering from conditions that are responsive to C5a receptor modulation.

In some aspects provided herein are methods of treating an individual suffering from or susceptible to a disease or disorder involving pathologic activation of C5a receptors, comprising administering to the individual an effective amount of a solid solution capsule of the present invention.

In some embodiments, the solid solution capsules of the present invention are used for treating patients suffering from conditions that are responsive to C5a receptor modulation.

Autoimmune disorders-- e.g., Rheumatoid arthritis, systemic lupus erythematosus, Guillain-Barre syndrome, pancreatitis, C3 glomerulopathy (C3G), hidradenitis suppurativa (HS), lupus nephritis, lupus glomerulonephritis, immunoglobulin A (IgA) nephropathy, psoriasis, Crohn's disease, vasculitis, irritable bowel syndrome, dermatomyositis, multiple sclerosis, bronchial asthma, pemphigus, pemphigoid, scleroderma, myasthenia gravis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome (and associated glomerulonephritis and pulmonary hemorrhage), immunovasculitis, tissue graft rejection, hyperacute rejection of transplanted organs; and the like.

Inflammatory disorders and related conditions-- e.g., Neutropenia, sepsis, septic shock, Alzheimer's disease, multiple sclerosis, stroke, inflammatory bowel disease (IBD), age-related macular degeneration (AMD, both wet and dry forms), inflammation associated with severe burns, lung injury, and ischemia-reperfusion injury, osteoarthritis, as well as acute (adult) respiratory distress syndrome (ARDS), chronic pulmonary obstructive disorder (COPD), systemic inflammatory response syndrome (SIRS), atopic dermatitis, psoriasis, chronic urticaria and multiple organ dysfunction syndrome (MODS). Also included are pathologic sequellae associated with insulin-dependent diabetes mellitus (including diabetic retinopathy), lupus nephropathy, Heyman nephritis, membranous nephritis and other forms of glomerulonephritis, contact sensitivity responses, and inflammation resulting from contact of blood with artificial surfaces that can cause complement activation, as occurs, for example, during extracorporeal circulation of blood (e.g., during hemodialysis or via a heart-lung machine, for example, in association with vascular surgery such as coronary artery bypass grafting or heart valve replacement), or in association with contact with other artificial vessel or container surfaces (e.g., ventricular assist devices, artificial heart machines, transfusion tubing, blood storage bags, plasmapheresis, plateletpheresis, and the like). Also included are diseases related to ischemia/reperfusion injury, such as those resulting from transplants, including solid organ transplant, and syndromes such as ischemic reperfusion injury, ischemic colitis and cardiac ischemia. The solid solution capsules comprising Compound <NUM> described herein may also be useful in the treatment of age-related macular degeneration (<NPL>).

Cardiovascular and Cerebrovascular Disorders--e.g., myocardial infarction, coronary thrombosis, vascular occlusion, post-surgical vascular reocclusion, atherosclerosis, traumatic central nervous system injury, and ischemic heart disease. In one embodiment, an effective amount of a solid solution capsule comprising Compound <NUM> described herein may be administered to a patient at risk for myocardial infarction or thrombosis (i.e., a patient who has one or more recognized risk factor for myocardial infarction or thrombosis, such as, but not limited to, obesity, smoking, high blood pressure, hypercholesterolemia, previous or genetic history of myocardial infarction or thrombosis) in order reduce the risk of myocardial infarction or thrombosis.

Diseases of Vasculitis - Vasculitic diseases are characterized by inflammation of the vessels. Infiltration of leukocytes leads to destruction of the vessel walls, and the complement pathway is believed to play a major role in initiating leukocyte migration as well as the resultant damage manifested at the site of inflammation (<NPL>). The solid solution capsules comprising Compound <NUM> described herein can be used to treat vasculitis, including anti-neutrophil cytoplasmic antibody associate vasculitis (or ANCA-associated vasculitis, which includes microscopic polyangiitis, eosinophilic granulomatosis with polyangitis, and granulomatosis with polyangiitis, which is also known as Wegener's disease), Churg-Strauss syndrome, Henoch-Schonlein purpura, polyateritis nodosa, Rapidly Progressive Glomerulonephritis (RPGN), cryoglobulinaemia, giant cell arteritis (GCA), Behcet's disease and Takayasu's arteritis (TAK).

HIV infection and AIDS -- the solid solution capsules comprising Compound <NUM> described herein may be used to inhibit HIV infection, delay AIDS progression or decrease the severity of symptoms or HIV infection and AIDS.

Neurodegenerative disorders and related diseases-- Within further embodiments, the solid solution capsules comprising Compound <NUM> described herein may be used to treat Alzheimer's disease, multiple sclerosis, and cognitive function decline associated with cardiopulmonary bypass surgery and related procedures.

Cancers-The solid solution capsules comprising Compound <NUM> described herein are also useful for the treatment of cancers and precancerous conditions in a subject. Specific cancers that can be treated include, but are not limited to, sarcomas, carcinomas, and mixed tumors. Exemplary conditions that may be treated according to the present invention include fibrosarcomas, liposarcomas, chondrosarcomas, osteogenic sarcomas, angiosarcomas, lymphangiosarcomas, synoviomas, mesotheliomas, meningiomas, leukemias, lymphomas, leiomyosarcomas, rhabdomyosarcomas, squamous cell carcinomas, basal cell carcinomas, adenocarcinomas, papillary carcinomas, cystadenocarcinomas, bronchogenic carcinomas, melanomas, renal cell carcinomas, hepatocellular carcinomas, transitional cell carcinomas, choriocarcinomas, seminomas, embryonal carcinomas, wilm's tumors, pleomorphic adenomas, liver cell papillomas, renal tubular adenomas, cystadenomas, papillomas, adenomas, leiomyomas, rhabdomyomas, hemangiomas, lymphangiomas, osteomas, chondromas, lipomas and fibromas.

In some embodiments, the solid solution capsules of the present invention can be used for the treatment of diseases selected from the group consisting of sepsis (and associated disorders), COPD, rheumatoid arthritis, lupus nephritis and multiple sclerosis.

In some embodiments, the solid solution capsules co of the present invention can be used for the treatment of diseases selected from the group consisting of anti-neutrophil cytoplasmic antibody associate (ANCA) vasculitis, C3 glomerulopathy, hidradenitis suppurativa, and lupus nephritis.

Treatment methods provided herein include, in general, administration to a patient an effective amount of one or more solid solution capsules of the present invention. Suitable patients include those patients suffering from or susceptible to (i.e., prophylactic treatment) a disorder or disease identified herein. Typical patients for treatment as described herein include mammals, particularly primates, especially humans. Other suitable patients include domesticated companion animals such as a dog, cat, horse, and the like, or a livestock animal such as cattle, pig, sheep and the like.

In general, treatment methods provided herein comprise administering to a patient an effective amount of one or more solid solution capsules of the present invention. In a preferred embodiment, the solid solution capsules of the present invention are administered to a patient (e.g., a human) orally. The effective amount may be an amount sufficient to modulate C5a receptor activity and/or an amount sufficient to reduce or alleviate the symptoms presented by the patient. Preferably, the amount administered is sufficient to yield a plasma concentration of the compound (or its active metabolite, if the compound is a pro-drug) high enough to detectably inhibit white blood cell (e.g., neutrophil) chemotaxis in vitro. Treatment regimens may vary depending on the compound used and the particular condition to be treated; for treatment of most disorders, a frequency of administration of <NUM> times daily or less is preferred. In some embodiments, a dosage regimen of <NUM> times daily is used. In some embodiments, once daily administration is used. The patient may be administered solid solution capsules of the present invention in a fed or fasted state. In some embodiments, the patient takes the solid solution capsules of the present invention with food. In some embodiments, the patient takes the solid solution capsules of the present invention without food. It will be understood, however, that the specific dose level and treatment regimen for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination (i.e., other drugs being administered to the patient) and the severity of the particular disease undergoing therapy, as well as the judgment of the prescribing medical practitioner. In general, the use of the minimum dose sufficient to provide effective therapy is preferred. Patients may generally be monitored for therapeutic effectiveness using medical or veterinary criteria suitable for the condition being treated or prevented.

Dosage levels of the order of from about <NUM> to about <NUM> per kilogram of body weight per day are useful in the treatment or preventions of conditions involving pathogenic C5a activity (about <NUM> to about <NUM> per human patient per day). Dosage unit forms will generally contain between from about <NUM> to about <NUM> of Compound <NUM>. In some embodiments, the dosage unit form comprises <NUM> of Compound <NUM>. It is preferred that sufficient amount of Compound <NUM> be administered to achieve a serum concentration of <NUM> ng (nanograms)/mL-<NUM>µg (micrograms)/mL serum, more preferably sufficient Compound <NUM> to achieve a serum concentration of <NUM> ng-<NUM>µg/ml serum should be administered, most preferably sufficient Compound <NUM> to achieve a serum concentration of <NUM> ng/ml-<NUM> ng/ml serum should be administered.

The present disclosure includes pharmaceutical dosage forms of Compound <NUM> as a free base, in its neutral form. The dosage forms described herein are solid solution capsules for oral administration to a subject.

As described above, the solid solution capsules can comprise about <NUM> to <NUM>% of compound <NUM> by weight of the total fill wait of said solution capsule. In some embodiments, the total fill weight of said solid solution capsule is about <NUM> to about <NUM>. Thus, in some embodiments, single unit dosage capsules can include <NUM> to <NUM> of Compound <NUM> as a free base, in its neutral form.

In some aspects, the present disclosure provides a single unit dosage capsule comprising about <NUM> to <NUM> of Compound <NUM> as a free base, in its neutral form
<CHM>
and a vehicle comprising.

In some embodiments, the solid solution capsules comprise about <NUM>% of compound <NUM> by weight of the total fill wait of said solution capsule. In some embodiments, the total fill weight of said solid solution capsule is about <NUM> to about <NUM>. In such embodiments, single unit dosage capsules can include <NUM> to <NUM> of Compound <NUM> as a free base, in its neutral form. In some embodiments, single unit dosage capsules can include <NUM> of Compound <NUM> as a free base, in its neutral form.

The total fill weight of the single unit dosage capsule is about <NUM> to about <NUM>,<NUM>. In some embodiments, the total fill weight of the single unit dosage capsule is about <NUM> to about <NUM>. In some embodiments, the total fill weight of the single unit dosage capsule is about <NUM> to about <NUM>. In some embodiments, the total fill weight of the single unit dosage capsule is about <NUM>.

In some embodiments, the single unit dosage capsule is size #<NUM>, #<NUM>, #<NUM>, #<NUM>, #<NUM>, or #<NUM>. In some embodiments, the single unit dosage capsule is size #<NUM>. In some embodiments, the single unit dosage capsule is size #<NUM>. In some embodiments, the single unit dosage capsule is size #<NUM>. In some embodiments, the single unit capsule is size #<NUM>. In some embodiments, the single unit dosage capsule is size #<NUM>. In some embodiments, the single unit dosage capsule is size #<NUM>. In some embodiments, the single unit dosage capsule is size #<NUM>.

In some embodiments, the capsule dosage form is a hard capsule. In some embodiments, the capsule dosage form is a soft capsule.

In the single unit dosage capsule of the present invention, the total weight of the vehicle comprises about a <NUM>:<NUM> ratio of macrogol-<NUM>-glycerol hydroxystearate and PEG-<NUM>. In a preferred embodiment, the ratio of macrogol-<NUM>-glycerol hydroxystearate to polyethylene glycol <NUM> (PEG-<NUM>) is <NUM>:<NUM>.

The disclosure also encompasses kits comprising a solid solution capsule of the present invention, or a single unit dosage capsule of the present invention.

In some aspects, provided herein are kits comprising a solid solution capsule of the present invention. In some embodiments, provided herein are one or more unit dosage capsules of the present invention.

Some of the kits described herein include a label describing a method of administering a solid solution capsule of the present invention. Some of the kits described herein include a label describing a method of treating a disease or disorder involving pathologic activation of C5a receptors. In some embodiments, the kits described herein include a label describing a method of treating ANCA-associated vasculitis.

The solid solution capsule of the present inventioncan be packaged in a bottle, jar, vial, ampoule, tube, blister pack, or other container-closure system approved by the Food and Drug Administration (FDA) or other regulatory body, which may provide one or more unit dosages containing solid solution of the present invention. In some embodiments, the solid solution capsule of the present inventionis packaged ina bottle. The package or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, the notice indicating approval by the agency. In certain aspects, the kit may include a solid solution capsule of the present invention, a container closure system including the formulation or one or more dosage units form including the formulation, and a notice or instructions describing a method of use as described herein.

The solubility of Compound <NUM> in pH adjusted buffer solutions (from pH <NUM> to <NUM>), in water, in <NUM> HCl, and in Simulated Gastric Fluid (SGF), in Fed- and Fasted-State Simulated Intestinal Fluid (FeSSIF, FaSSIF) were evaluated, the data are shown in Table <NUM>, below, and <FIG>.

Compound <NUM> free base has very poor aqueous solubility across full spectrum of pH range, including the biorelevant media and water (no salt effect).

Liquid formulations of PEG400/EtOH and Compound <NUM> can be preapred using general methods for making liquid formulations known in the art. For example, Compound <NUM> was dissolved in EtOH with agitation and ambient temperature, then the desired amount of PEG400 was added to achieve the desired ratios.

All three concentration formulations in PEG-<NUM>/Ethanol stored at Refrigerated Stability (<NUM>/Ambient), Room Temperature (<NUM>° C/<NUM>% RH), Normal Laboratory Light Conditions, and Accelerated Stability (<NUM>° C/<NUM>% RH) appeared stable after <NUM> week, the Compound <NUM> assay values ranged from <NUM>-<NUM> % of label claim. The total impurities found in all formulations after <NUM> week were in the range of <NUM>-<NUM>% a/a of the total peaks; the highest individual impurity was reported at <NUM>% a/a with a relative retention time of <NUM>-<NUM>.

Despite these results, formulations with ethanol can introduce dosing inaccuracy and undissolved drugs due to evaporation of the ethanol during both dose preparation and storage. As such, formulations with ethanol do not provide the needed attributes.

The liquid formulations of the present example are prepared as described in Example <NUM>. When additional excipients are included, they are added after dissolution of Compound <NUM> in ethanol.

The data from this test is summarized in Table <NUM>, below.

Particular formulations tested herein provided completely dissolved Compound <NUM>. Despite this promise, the most positive formulations each included ethanol, which as described in Example <NUM> can introduce dosing inaccuracy and undissolved drugs due to evaporation of the ethanol during both dose preparation and storage.

Manufacture of Compound <NUM> solid solution capsules utilized a traditional pharmaceutical oral dosage form equipment suitable for filling hard gelatin capsules. The capsule fill mass is a standard heated stainless steel vessel with agitator / homogenizer.

A list of typical equipment required for the manufacturing process is found in Table <NUM>. Equipment examples are listed for information purpose only.

The in-process controls for the drug product manufacturing process are summarized in Table <NUM>.

In addition to the visual test for verification of the drug substance dissolution, a centrifuge test was performed. From the vessel a sample was taken, centrifuged and controlled for absence of undissolved drug substance. If the drug substance is not fully dissolved, white particles are visible at the tip of the centrifuge tube.

Solid solution <NUM> capsules of Compound <NUM> are prepared with the components summarized in Table <NUM>.

The solid solution formulations of Table <NUM> were prepared according the manufacturing process shown in <FIG>. The steps used are further detailed below:.

The composition of the Gelatin Capsule Shell and Gelatin sealing solution are described in Table <NUM> and Table <NUM>, respectively.

Using the general procedures outlined in Example <NUM>, formulations of macrogol-<NUM>-glycerol hydroxystearate:PEG-<NUM> were prepared (<NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, and <NUM>: <NUM> (w/w) macrogol-<NUM>-glycerol hydroxystearate:PEG-<NUM>).

Each of the prepared formulations were characterized using differential scanning calorimetry (DSC). Formulations comprising macrogol-<NUM>-glycerol hydroxystearate:PEG-<NUM> at <NUM>:<NUM> & <NUM>:<NUM> appear to have one broad endothermic peak in the DSC thermograms, implying one miscible solid phase (see, <FIG> and <FIG>, respectively). Comparatively, formulations comprising macrogol-<NUM>-glycerol hydroxystearate:PEG-<NUM> formulations having <NUM>: <NUM> & <NUM>:<NUM> show two separate endothermic peaks in the DSC thermograms, indicating potential phase separation (see, <FIG> and data not show).

Solid Solution capsules of Compound <NUM> comprising <NUM>:<NUM>, and <NUM>:<NUM> (w/w) macrogol-<NUM>-glycerol hydroxystearate:PEG-<NUM> were prepared as described in Example <NUM>.

The USP Apparatus II (paddles) with <NUM> media volume at <NUM> ±<NUM> was selected for the dissolution development studies. Vessels are <NUM>, clear glass, round-bottom. Media represents physiologic conditions. Paddles with sinkers were selected over baskets to ensure sufficient agitation during the dissolution test and to maintain the capsule in the paddle agitation zone during disintegration.

<FIG> plots the dissolution of each sample tested. The <NUM>:<NUM> macrogol-<NUM>-glycerol hydroxystearate:PEG-<NUM> sample demonstrated rapid dissolution, while the <NUM>:<NUM> macrogol-<NUM>-glycerol hydroxystearate:PEG-<NUM> sample demonstrated slower initial dissolution characteristics.

To confirm reproducibility of the <NUM>:<NUM> macrogol-<NUM>-glycerol hydroxystearate:PEG-<NUM> blend, samples from multiple lots preparing the <NUM>:<NUM> formulation were tested. Indeed, <FIG> demonstrates that fast, reproducible release of Compound <NUM> is achieved.

The identification of forced degradation products in Compound <NUM> solid solution capsules was performed using HPLC with photodiode array detection. Capsules were exposed to stress conditions (acid, base, peroxide, heat, light, heat and humidity) and chromatograms and data from the stressed samples were then compared to an unstressed control sample. Only those degradation products found in the stressed samples but not in the unstressed control sample were reported. A summary of the results under the stressed conditions are summarized in Table <NUM> for the capsule and in Table <NUM> for the degradation products found for the stressed capsules. Details of each condition tested are shown in Table <NUM>. Under all of the stress conditions studied, the Compound <NUM> peak showed no co-elution or interference from potential degradation products based upon the peak purity results from diode array detection.

No degradation was observed for placebo capsules at the stress conditions evaluated.

Compound <NUM> capsules were found to degrade the most under oxidative stress, where a total of fifteen (<NUM>) degradants were observed. Acid hydrolysis resulted in three (<NUM>) degradants, base hydrolysis produced two (<NUM>) degradants, and heat and heat/humidity produced a single degradant (RRT <NUM>). The impurity at an RRT of <NUM> increased only slightly under heat (<NUM>) and oxidative stress but did not change under acidic, or basic conditions.

Overall, this study shows that the Compound <NUM> solid solution capsules are quite stable when exposed to all stress conditions, with the exception of oxidative stress.

Solid Solution capsules of Compound <NUM> comprising <NUM>:<NUM> macrogol-<NUM>-glycerol hydroxystearate:PEG-<NUM> or <NUM>% macrogol-<NUM>-glycerol hydroxystearate were prepared using the general procedures described in Example <NUM>. The PEG heating steps were omitted for the <NUM>% macrogol-<NUM> glycerol hydroxystearate formulations. These formulations were dosed in beagle dogs (male) at <NUM> per dog to evaluate the pharmacokinetic profile. The results are summarized in Table <NUM> (below, and shown in <FIG> (<NUM>:<NUM> macrogol-<NUM>-glycerol hydroxystearate:PEG-<NUM> and <FIG> (<NUM>% macrogol-<NUM>-glycerol hydroxystearate).

Although the <NUM>% macrogol-<NUM>-glycerol hydroxystearate formulation provided high bioavailability (as determined by AUC comparison), the <NUM>% macrogol-<NUM>-glycerol hydroxystearate formulation is not as stable. In a side-by side comparison of stability, both formulations dosed in dogs were stored for <NUM> months at <NUM>° C. The <NUM>% macrogol-<NUM>-glycerol hydroxystearate formulation showed an increase in an impurity (RRT <NUM>), whereas the <NUM>:<NUM> macrogol-<NUM>-glycerol hydroxystearate formulation:PEG-<NUM> formulation remained unchanged. This demonstrates that the <NUM>% macrogol-<NUM>-glycerol hydroxystearate formulation is not suitable for pharmaceutical use, while the <NUM>:<NUM> formulation is suitable for pharmaceutical use.

Solid Solution capsules of Compound <NUM> comprising <NUM>:<NUM> macrogol-<NUM>-glycerol hydroxystearate:PEG-<NUM> were prepared using the general procedures described in Example <NUM>.

Patients with AAV were randomized and double-blind in placebo-controlled clinical trial conducted in a step-wise manner to evaluate the efficacy and safety of Compound <NUM> formulated in a solid solution as described above with reduced or no prednisone in comparison with the standard of care full dose prednisone. All patients received either cyclophosphamide (CYC) or rituximab (RTX) intravenously. <NUM> subjects received <NUM> of Compound <NUM> as described above b. for <NUM> days and no prednisone (prednisone-matching placebo), <NUM> subjects received <NUM> Compound <NUM> as described above b. for <NUM> days plus a reduced starting dose (i.e., <NUM>/day) of prednisone, and <NUM> subjects received Compound <NUM> as described above -matching placebo b. for <NUM> days plus a full starting dose of prednisone (i.e., <NUM>/day). All subjects received IV cyclophosphamide or rituximab.

The PK parameters of Compound <NUM> and its mean trough concentration are shown in Table <NUM>. Following the first dose of <NUM> Compound <NUM> on Day <NUM>, Compound <NUM> was absorbed rapidly. The AUC<NUM>-6hr and Cmax of Compound <NUM> were <NUM> ± <NUM> ng•hr/mL and <NUM> ± <NUM> ng/mL, respectively (these PK exposures were calculated using data from patients dosed both with and without prednisone). The Day <NUM> Cmax of Compound <NUM> in these AAV patients (without prednisone co-administration: Cmax = <NUM> ± <NUM> ng/mL) was similar to that in healthy subjects who were dosed with the same dosage form, suggesting that there is no meaningful difference between AAV patients and healthy subjects in the exposure of Compound <NUM> after a single oral dose.

No significant drug-drug interaction was observed in this study between Compound <NUM> and concomitant medications prednisone, cyclophosphamide, and rituximab.

An open-label study in <NUM> healthy volunteers to evaluate the pharmacokinetic effect of a high fat (~<NUM>% of total caloric content of the meal), high calorie meal on the solid solution capsule of Compound <NUM> in a <NUM>:<NUM> mixture of macrogol-<NUM>-glycerol hydroxystearate:PEG-<NUM>. Subjects received a single oral dose of <NUM> Compound <NUM>, given in the fed or fasted state. Blood samples were collected for measurement of Compound <NUM> plasma concentrations.

The results of this study showed that administration of a high fat, high calorie meal with <NUM> Compound <NUM> increased plasma Compound <NUM> AUC by approximately <NUM>% compared to administration under fasted conditions. Cmax was more comparable, with only an <NUM>% increase under fed conditions compared to fasted; however, Tmax was delayed by approximately <NUM> hours in the fed population (<FIG> and Table <NUM>).

The physical state of the drug substance in solid solution capsules of Compound <NUM> comprising <NUM>:<NUM> macrogol-<NUM>-glycerol hydroxystearate:PEG-<NUM> prepared as described in Example <NUM> was assessed in capsules stored for more than <NUM> years under <NUM>% RH and at <NUM>.

The capsule fill of select capsules were removed from capsule shells and analyzed using <NUM>F solid state nuclear magnetic resonance (SS-NMR). As shown in <FIG>, no coupling phenomena of the trifluoromethyl (-CF<NUM>) and aryl fluoride (CF) groups in the -<NUM> ppm or at -<NUM> ppm regions respectively is observed, which are characteristic of crystalline Compound <NUM> drug substance. Thus, the drug substance in the capsule fill matrix remained molecularly dissolved in the matrix without any signs of crashing out.

Using the general procedures outlined in Example <NUM>, a batch size manufacturing <NUM>,<NUM> units of <NUM> hard capsules was prepared. Amounts used for preparation are shown in Table <NUM> and Table <NUM>.

Claim 1:
A solid solution capsule formulation comprising Compound <NUM> as a free base, in its neutral form
<CHM>
and a vehicle comprising
at least one non-ionic surfactant selected from the group consisting of polyoxyethylene <NUM> castor oil, macrogol-<NUM>-glycerol hydroxystearate, macrogolglycerol ricinoleate, macrogol-<NUM>-hydroxystearate, polyoxyethylene <NUM> castor oil, polyoxyethylene <NUM> hydrogenated castor oil, polyoxyethylene <NUM> hydrogenated castor oil, polyoxyethylene <NUM> castor oil, and polyoxyethylene <NUM> hydrogenated castor oil, and
at least one water-soluble solubilizer selected from the group consisting of PEG-<NUM>, PEG-<NUM>, PEG-<NUM>, PEG-<NUM>, PEG-<NUM>, PEG-<NUM>, PEG-<NUM>, PEG-<NUM>, PEG-<NUM>, PEG-<NUM>, PEG-<NUM>, poloxamer <NUM>, poloxamer <NUM>, poloxamer <NUM>, and poloxamer <NUM>.