# Patent

## Title
Solid dispersion formulations and methods of use thereof

## Abstract

The present invention relates to formulations and methods for increasing the bioavailability of 1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one, 1-(3,3-diphenylpropanoyl)piperazine, or a salt thereof. In particular, the formulation can include one or more pharmaceutically acceptable matrix polymers to form a solid dispersion, e.g., a spray dried dispersion or a hot melt extrusion.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part of U.S. patent application Ser. No. 13/414,369, filed on Mar. 7, 2012, which claims benefit of U.S. Provisional Application No. 61/450,479, filed on Mar. 8, 2011, and U.S. Provisional Application No. 61/485,405, filed on May 12, 2011, each of which is hereby incorporated by reference in its entirety.


BACKGROUND OF THE INVENTION
The present invention relates to formulations and methods for increasing the bioavailability of 1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one or a metabolite thereof, as well as salts thereof. In particular, the formulations and methods relate to the use of solid dispersions to improve mean bioavailability in fasted or fed subjects and/or to reduce food effect.
Ion channels mediate a variety of normal physiological functions and are also implicated in a number of human disorders. Examples of human disorders mediated by calcium channels include but are not limited to congenital migraine, cerebellar ataxia, angina, epilepsy, hypertension, ischemia, and some arrhythmias (see, e.g., Janis et al., Ion Calcium Channels Their Properties, Functions, Regulation and Clinical Relevance (1991) CRC Press, London); and those mediated by sodium channels include but are not limited to epilepsy, cancer, pain, migraine, Parkinson's Disease, mood disorders, schizophrenia, psychosis, tinnitus, amyotrophic lateral sclerosis, glaucoma, ischaemia, spasticity disorders, obsessive compulsive disorder, restless leg syndrome, and Tourette syndrome. Modulators of ion channels, e.g., such as 1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one, a metabolite thereof, or a salt thereof, are thus desired. In particular, formulations of such modulators having improved oral bioavailability and/or reduced patient-to-patient variability in pharmacokinetic behavior are needed.
SUMMARY OF THE INVENTION
The invention provides formulations and methods for administering 1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one (compound 1), a metabolite thereof (e.g., 1-(3,3-diphenylpropanoyl)piperazine (compound 2)), or a salt thereof. Compound 1 is a potent N-type calcium channel antagonist having selectivity over other types of calcium channels (e.g., L-type or P/Q-type calcium channels). The invention also provides use of these formulations for acting at ion channels (e.g., calcium channels (e.g., N-type calcium channels) and/or sodium channels) and for treating various conditions associated with these channels, such as pain and epilepsy.
In a first aspect, the invention relates to a pharmaceutical composition in unit dosage form for oral administration, the composition including from about 20 mg to about 250 mg of substantially amorphous compound 1, compound 2, or a salt thereof, and a pharmaceutically acceptable excipient (e.g., any described herein, such as one or more pharmaceutically acceptable matrix polymers described herein), where, following administration of the pharmaceutical composition to subjects, the ratio of the mean bioavailability for fed subjects to the mean bioavailability for fasted subjects is from about 1.0 to about 2.0.
In a second aspect, the invention relates to a pharmaceutical composition in unit dosage form for oral administration, the composition including from about 20 mg to about 250 mg (e.g., from 20 mg to 30 mg, from 20 mg to 40 mg, from 20 mg to 50 mg, from 20 mg to 75 mg, from 20 mg to 100 mg, from 20 mg to 125 mg, from 20 mg to 150 mg, from 20 mg to 175 mg, from 20 mg to 200 mg, from 20 mg to 225 mg, from 30 mg to 40 mg, from 30 mg to 50 mg, from 30 mg to 75 mg, from 30 mg to 100 mg, from 30 mg to 125 mg, from 30 mg to 150 mg, from 30 mg to 175 mg, from 30 mg to 200 mg, from 30 mg to 225 mg, from 30 mg to 250 mg, from 40 mg to 50 mg, from 40 mg to 75 mg, from 40 mg to 100 mg, from 40 mg to 125 mg, from 40 mg to 150 mg, from 40 mg to 175 mg, from 40 mg to 200 mg, from 40 mg to 225 mg, from 40 mg to 250 mg, from 50 mg to 75 mg, from 50 mg to 100 mg, from 50 mg to 125 mg, from 50 mg to 150 mg, from 50 mg to 175 mg, from 50 mg to 200 mg, from 50 mg to 225 mg, from 50 mg to 250 mg, from 60 mg to 75 mg, from 60 mg to 100 mg, from 60 mg to 125 mg, from 60 mg to 150 mg, from 60 mg to 175 mg, from 60 mg to 200 mg, from 60 mg to 225 mg, from 60 mg to 250 mg, from 70 mg to 75 mg, from 70 mg to 100 mg, from 70 mg to 125 mg, from 70 mg to 150 mg, from 70 mg to 175 mg, from 70 mg to 200 mg, from 70 mg to 225 mg, from 70 mg to 250 mg, from 80 mg to 100 mg, from 80 mg to 125 mg, from 80 mg to 150 mg, from 80 mg to 175 mg, from 80 mg to 200 mg, from 80 mg to 225 mg, from 80 mg to 250 mg, from 90 mg to 100 mg, from 90 mg to 125 mg, from 90 mg to 150 mg, from 90 mg to 175 mg, from 90 mg to 200 mg, from 90 mg to 225 mg, from 90 mg to 250 mg, from 100 mg to 125 mg, from 100 mg to 150 mg, from 100 mg to 175 mg, from 100 mg to 200 mg, from 100 mg to 225 mg, and from 100 mg to 250 mg) of substantially amorphous compound 1, compound 2, or a salt thereof, in a pharmaceutically acceptable matrix polymer. In some preferred embodiments, the unit dosage form comprises about 70 mg to about 250 mg (e.g., from 70 mg to 75 mg, from 70 mg to 100 mg, from 70 mg to 125 mg, from 70 mg to 150 mg, from 70 mg to 175 mg, from 70 mg to 200 mg, from 70 mg to 225 mg, from 70 mg to 250 mg, from 80 mg to 100 mg, from 80 mg to 125 mg, from 80 mg to 150 mg, from 80 mg to 175 mg, from 80 mg to 200 mg, from 80 mg to 225 mg, from 80 mg to 250 mg, from 90 mg to 100 mg, from 90 mg to 125 mg, from 90 mg to 150 mg, from 90 mg to 175 mg, from 90 mg to 200 mg, from 90 mg to 225 mg, from 90 mg to 250 mg, from 100 mg to 125 mg, from 100 mg to 150 mg, from 100 mg to 175 mg, from 100 mg to 200 mg, from 100 mg to 225 mg, and from 100 mg to 250 mg) of compound 1, compound 2, or a salt thereof.
In some embodiments of any of the aspects herein, the percentage loading of compound 1 or compound 2 is from about 1% to about 90% (w/w) (e.g., from 1% to 19%, from 10% to 19%, from 10% to 20%, from 10% to 30%, from 10% to 40%, from 10% to 50%, from 10% to 60%, from 10% to 70%, from 10% to 80%, from 10% to 90%, from 20% to 30%, from 20% to 40%, from 20% to 50%, from 20% to 60%, from 20% to 70%, from 20% to 80%, from 20% to 90%, from 21% to 30%, from 21% to 34%, from 21% to 40%, from 21% to 50%, from 21% to 60%, from 21% to 70%, from 21% to 80%, from 21% to 90%, from 30% to 40%, from 30% to 50%, from 30% to 60%, from 30% to 70%, from 30% to 80%, from 30% to 90%, from 36% to 40%, from 36% to 49%, from 36% to 60%, from 36% to 70%, from 36% to 80%, from 36% to 90%, from 40% to 50%, from 40% to 60%, from 40% to 70%, from 40% to 80%, from 40% to 90%, from 50% to 60%, from 50% to 70%, from 50% to 80%, from 50% to 90%, 51% to 60%, from 51% to 70%, from 51% to 80%, from 51% to 90%, from 60% to 70%, from 60% to 80%, from 60% to 90%, from 70% to 80%, and from 70% to 90%). In some preferred embodiments, the percentage loading of compound 1 or compound 2 is from about 10% to about 60% (w/w) (e.g., from 10% to 20%, from 10% to 30%, from 10% to 40%, from 10% to 50%, from 10% to 60%, from 20% to 30%, from 20% to 40%, from 20% to 50%, from 20% to 60%, from 30% to 40%, from 30% to 50%, from 30% to 60%, from 40% to 50%, and from 40% to 60%).
In some embodiments, following administration of the pharmaceutical composition to subjects (e.g., fed subjects or fasted subjects), the mean bioavailability is greater than about 20% (e.g., greater than 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or even 99%) or between about 20% to about 90% (e.g., from 20% to 30%, from 20% to 40%, from 20% to 50%, from 20% to 60%, from 20% to 70%, from 20% to 80%, from 20% to 90%, from 30% to 40%, from 30% to 50%, from 30% to 60%, from 30% to 70%, from 30% to 80%, from 30% to 90%, from 40% to 50%, from 40% to 60%, from 40% to 70%, from 40% to 80%, from 40% to 90%, from 50% to 60%, from 50% to 70%, from 50% to 80%, from 50% to 90%, from 60% to 70%, from 60% to 80%, from 60% to 90%, from 70% to 80%, from 70% to 90%, and from 80% to 90%).
In some embodiments, the ratio of the mean bioavailability for fed subjects to the mean bioavailability for fasted subjects is from about 1.0 to about 2.0 (e.g., from 1.0 to 1.1, from 1.0 to 1.2, from 1.0 to 1.3, from 1.0 to 1.4, from 1.0 to 1.5, from 1.0 to 1.6, from 1.0 to 1.7, from 1.0 to 1.8, from 1.0 to 1.9, from 1.3 to 1.4, from 1.3 to 1.5, from 1.3 to 1.6, from 1.3 to 1.7, from 1.3 to 1.8, from 1.3 to 1.9, from 1.3 to 2.0, from 1.5 to 1.6, from 1.5 to 1.7, from 1.5 to 1.8, from 1.5 to 1.9, from 1.5 to 2.0, from 1.7 to 1.8, from 1.7 to 1.9, from 1.7 to 2.0, from 1.8 to 1.9, and from 1.8 to 2.0).
In some embodiments, administration of the pharmaceutical composition to fed and fasted subjects produces a coefficient of variation in Cmax and/or AUC∞ of less than about 60% (e.g., less than 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, and 15%). In particular embodiments, the coefficient of variation in Cmax and/or AUC∞ is of from about 20% to about 60% (e.g., from 20% to 30%, from 20% to 35%, from 20% to 40%, from 20% to 45%, from 20% to 50%, from 20% to 55%, from 30% to 35%, from 30% to 40%, from 30% to 45%, from 30% to 50%, from 30% to 55%, from 30% to 60%, from 35% to 40%, from 35% to 45%, from 35% to 50%, from 35% to 55%, from 35% to 60%, from 40% to 45%, from 40% to 50%, from 40% to 55%, from 40% to 60%, from 45% to 50%, from 45% to 55%, from 45% to 60%, from 50% to 55%, from 50% to 60%, and from 55% to 60%).
In some embodiments, administration of the pharmaceutical composition to fasted or fed subjects produces a coefficient of variation in Cmax and/or AUC∞ of less than about 65% (e.g., less than 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, and 15%). In some embodiments, administration of the pharmaceutical composition to fasted or fed subjects produces a coefficient of variation in Cmax and/or AUC∞ of from about 30% to about 65% (e.g., from 30% to 35%, from 30% to 40%, from 30% to 45%, from 30% to 50%, from 30% to 55%, from 30% to 60%, from 30% to 65%, from 35% to 40%, from 35% to 45%, from 35% to 50%, from 35% to 55%, from 35% to 60%, from 35% to 65%, from 40% to 45%, from 40% to 50%, from 40% to 55%, from 40% to 60%, from 45% to 50%, from 45% to 55%, from 45% to 60%, from 45% to 65%, from 50% to 55%, from 50% to 60%, from 50% to 65%, from 55% to 60%, from 55% to 65%, and from 60% to 65%).
In some embodiments, administration of the pharmaceutical composition to a fasted subject produces a Cmax that is greater than about 400 ng/mL (e.g., greater than about 450, 500, 550, 600, 650, 700, 750, or 800 ng/mL and/or up to about 900, 1,000, or 1,500 ng/mL, e.g., from 400 ng/mL to 1,500 ng/mL, from 400 ng/mL to 1,000 ng/mL, from 400 ng/mL to 800 ng/mL, from 400 ng/mL to 700 ng/mL, from 500 ng/mL to 1,500 ng/mL, from 500 ng/mL to 1,000 ng/mL, from 500 ng/mL to 800 ng/mL, and from 500 ng/mL to 700 ng/mL) and/or an AUC∞ that is greater than about 4,000 hr*ng/mL (e.g., greater than 4,500, 5,000, 5,500, 6,000, 6,500, 7,000, 7,500, or 8,000 hr*ng/mL and/or up to 8,000 hr*ng/mL, e.g., from 4,000 hr*ng/mL to 8,000 hr*ng/mL, from 4,500 hr*ng/mL to 8,000 hr*ng/mL, from 5,000 hr*ng/mL to 8,000 hr*ng/mL, from 4,000 hr*ng/mL to 7,000 hr*ng/mL, from 4,500 hr*ng/mL to 7,000 hr*ng/mL, and from 5,000 hr*ng/mL to 7,000 hr*ng/mL) for a 225 mg dose of compound 1 or compound 2.
In any of the above aspects, the pharmaceutical composition includes a solid dispersion of the compound 1, compound 2, or the salt thereof, and a pharmaceutically acceptable matrix polymer, where the weight ratio of the compound 1, compound 2, or the salt thereof, to the pharmaceutically acceptable matrix polymer is from about 1:6 to about 1:1.5 (e.g., from 1:6 to 1:2, from 1:6 to 1:2.5, from 1:6 to 1:3, from 1:6 to 1:3.5, from 1:6 to 1:4, from 1:6 to 1:4.5, from 1:6 to 1:5, from 1:5 to 1:2, from 1:5 to 1:2.5, from 1:5 to 1:3, from 1:5 to 1:3.5, from 1:5 to 1:4, from 1:5 to 1:4.5, from 1:5 to 1:1.5, from 1:4 to 1:1.5, from 1:4 to 1:2, from 1:4 to 1:2.5, from 1:4 to 1:3, from 1:4 to 1:3.5, from 1:3 to 1:1.5, from 1:3 to 1:2, from 1:3 to 1:2.5, and from 1:2 to 1:1.5).
In some embodiments, at least about 90% (e.g., at least 95%, 96%, 97%, 98%, 99%, 99.5%, or even 99.9%, such as from 90% to 99.9%, from 90% to 99.5%, from 90% to 99%, from 90% to 98%, from 90% to 97%, from 90% to 96%, from 90% to 95%, from 95% to 99.9%, from 95% to 99.5%, from 95% to 99%, from 95% to 98%, from 95% to 97%, and from 95% to 96%) of the compound 1, compound 2, or the salt thereof, is in amorphous form.
In some embodiments, the pharmaceutically acceptable matrix polymer includes a polymer selected from a cellulose derivative, a polyacrylate, a polyvinyl pyrrolidone, a polyvinyl acetate, or a copolymer of a polyvinyl pyrrolidone and a polyvinyl acetate.
In further embodiments, the cellulose derivative is a cellulose acetate having from about 10% to about 50% (e.g., from 10% to 15%, from 10% to 20%, from 10% to 25%, from 10% to 30%, from 10% to 35%, from 10% to 40%, from 10% to 45%, from 20% to 25%, from 20% to 30%, from 20% to 35%, from 20% to 40%, from 20% to 45%, from 20% to 50%, from 25% to 30%, from 25% to 35%, from 25% to 40%, from 25% to 45%, from 25% to 50%, from 30% to 35%, from 30% to 40%, from 30% to 45%, from 30% to 50%, from 35% to 40%, from 35% to 45%, from 35% to 50%, from 40% to 45%, and from 40% to 50%) acetyl. In further embodiments, the cellulose acetate is cellulose acetate phthalate (CAP) (e.g., having about 35% phthalyl/24% acetyl), methylcellulose acetate phthalate, hydroxypropylmethyl cellulose acetate, and hydroxypropylmethyl cellulose acetate succinate (HPMCAS) (e.g., having about 9% acetyl/11% succinoyl, 12% acetyl/6% succinoyl, and 8% acetyl/15% succinoyl).
In some embodiments, the mean particle size of the matrix polymer is about 1 mm or about 5 μm. In particular embodiments, the matrix polymer is HPMCAS having a mean particle size of about 1 mm (e.g., grade MG) or about 5 μm (e.g., grade MF).
In other embodiments, the cellulose derivative is selected from an alkyl cellulose (e.g., methyl cellulose and ethyl cellulose), a hydroxyalkyl cellulose (e.g., hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, such as those having 11% hydroxypropyl or 8% hydroxypropyl, and hydroxybutyl cellulose), a hydroxyalkylalkyl cellulose (e.g., hydroxyethylmethyl cellulose and hydroxypropylmethyl cellulose (HPMC) having 19-24% methoxyl/7-12% hydroxypropxyl, 28-30% methoxyl/7-12% hydroxypropxyl, 23% methoxyl/10% hydroxypropxyl, 23%-29% methoxyl/8%-9% hydroxypropxyl, 29% methoxyl/9% hydroxypropxyl, and 23% methoxyl/6% hydroxypropxyl), a hydroxyalkylalkyl cellulose ester (e.g., hydroxypropylmethyl cellulose phthalate (HPMCP)), a carboxyalkyl cellulose (e.g., carboxymethyl cellulose and alkali metal salts thereof, such as sodium salts), a carboxyalkylalkyl cellulose (e.g., carboxymethylethyl cellulose), and a carboxyalkyl cellulose ester (e.g., carboxymethyl cellulose butyrate, carboxymethyl cellulose propionate, carboxymethyl cellulose acetate butyrate, and carboxymethyl cellulose acetate propionate). In further embodiment, the cellulose derivative is further cross-linked or copolymerized (e.g., with any matrix polymer described herein).
In some embodiments, the matrix polymer is the polyacrylate selected from a polymethacrylate, a methacrylate copolymer (e.g., a methacrylic acid-methyl methacrylate copolymer having a 1:1 ratio of free carboxyl groups to ester groups and a 1:2 ratio of free carboxyl groups to ester groups, a dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer, and a diethylaminoethyl methacrylic acid-methyl methacrylate copolymer), and an ethacrylate copolymer (e.g., a methacrylic acid ethacrylate copolymer having a 50:50 ratio of methacrylic acid to ethacrylate).
In some embodiments, the matrix polymer is the polyvinyl acetate selected from a polyvinyl pyrrolidone (e.g., povidone) having a molecular weight more than about 2,000 (e.g., about 2,500, about 9,000, about 50,000, and about 1,250,000), a polyvinyl acetate ester (e.g., polyvinyl acetate phthalate (PVAP)), and a polyethylene glycol polyvinylacetate copolymer (e.g., polyethylene glycol-polyvinylcaprolactam-polyvinylacetate copolymer).
In other embodiments, the matrix polymer is the copolymer of a polyvinyl pyrrolidone and a polyvinyl acetate and the copolymer has from about 10:90 to about 70:30 ratio (e.g., 20:80, 30:70, 40:60, 50:50, and 60:40) of N-vinyl-2-pyrrolidone to vinyl acetate.
In some embodiments, the pharmaceutical composition further includes a plasticizer. Exemplary plasticizers include those selected from a polyalkylene oxide (e.g., polyethylene glycols, such as PEG 300, PEG 400, PEG 4000, and PEG 8000, and polypropylene glycols), a copolymer of ethylene oxide and propylene oxide (e.g., ethoxylated propoxylated block copolymers having the formula H(OCH2CH2)a(OCHCH3CH2)b(OCH2CH2)aOH, where a is between 10 and 150 and b is between 10 and 100 (e.g., where a is about 12 and b is about 20, a is about 38 and b is about 29, a is about 80 and b is about 27, a is about 64 and b is about 37, a is about 141 and b is about 44, a is about 49 and b is about 57, and a is about 101 and b is about 56), and a polyethoxylated glyceryl ester (e.g., polyoxyl 35 castor oil and polyoxyl 40 castor oil having 40-45 moles of ethylene oxide).
In some embodiments, the composition further includes a surfactant. Exemplary surfactants include those selected from a polyethoxylated ester of one or more fatty acids, a polyethoxylated alkyl ether, a polyethoxylated glyceryl ester, a polyoxyethylene glyceryl ester of one or more fatty acids, a sorbitan ester, a polyethoxylated sorbitan ester, a polyethoxylated vitamin analog (e.g., a pegylated vitamin E compound, e.g., D-alpha-tocopheryl PEG 1000 succinate), and an ethoxylated propoxylated block copolymer.
In other embodiments, the solid dispersion is formed by spray drying a liquid mixture including compound 1, compound 2, or the salt thereof, and the pharmaceutically acceptable matrix polymer. In some embodiments, the matrix polymer is a cellulose derivative (e.g., any described herein).
In some embodiments, the solid dispersion is formed by hot melt extrusion of a mixture including compound 1, compound 2, or the salt thereof, and the pharmaceutically acceptable matrix polymer. In some embodiments, the matrix polymer is a cellulose derivative (e.g., hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethyl cellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), hydroxypropylmethyl cellulose acetate succinate (HPMCAS), or any described herein), a polyacrylate (e.g., a polymethacrylate, a methacrylate copolymer, or any described herein, e.g., a methacrylic acid-methyl methacrylate copolymer (e.g., Eudragit® L 100 or Eudragit® S 100, MW  ̃125,000 g/mol), a dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer (e.g., Eudragit® E PO, Eudragit® E 100, or Eudragit® E 12.5, respectively), a diethylaminoethyl methacrylic acid-methyl methacrylate copolymer (e.g., Eudragit® E), or an ethacrylate copolymer, such as a methacrylic acid ethacrylate copolymer (e.g., Kollicoat® MAE 100P or Eudragit®L 100-55), a polyvinyl pyrrolidone, a polyvinyl acetate, or a copolymer of a polyvinyl pyrrolidone and a polyvinyl acetate.
In a third aspect, the invention features a method for reducing the food effect exhibited by compound 1, compound 2, or a salt thereof, following administration to a subject, the method including administering a unit dosage form including any pharmaceutical composition described herein to the subject.
In a fourth aspect, the invention features a method to treat a disease or condition (e.g., pain, epilepsy, or any described herein), the method including administering to a subject (e.g., a fasted subject or a fed subject) in need of such treatment an effective amount of any pharmaceutical composition described herein.
In a fifth aspect, the invention features a method to treat a disease or condition (e.g., pain, epilepsy, or any described herein) modulated by ion channel activity, the method including administering to a subject (e.g., a fasted subject or a fed subject) in need of such treatment an effective amount of any pharmaceutical composition described herein.
In a sixth aspect, the invention features a method of inhibiting an ion channel, the method including contacting a cell (e.g., a cell from a fasted subject or a cell from a fed subject) with any pharmaceutical composition described herein (e.g., an effective amount of any pharmaceutical composition described herein).
In some embodiments of the above aspects, the ion channel is a calcium channel or a sodium channel. In some embodiments, the calcium channel is an N-type calcium channel (e.g., the CaV 2.2 channel). In some embodiments, the sodium channel is a voltage-gated sodium channel (e.g., the NaV1.7 channel or the NaV1.8, channel).
In some embodiments, the condition is pain, epilepsy, Parkinson's disease, a mood disorder (e.g., a major depressive disorder (e.g., atypical depression, melancholic depression, psychotic major depression, catatonic depression, postpartum depression, seasonal affective disorder, dysthymia, and depressive disorder not otherwise specified (DD-NOS)), recurrent brief depression, minor depressive disorder, or a bipolar disorder), psychosis (e.g., schizophrenia), tinnitus, amyotrophic lateral sclerosis, glaucoma, ischaemia, a spasticity disorder, obsessive compulsive disorder, restless leg syndrome, or Tourette syndrome. In particular embodiments, the condition is pain or epilepsy.
In some embodiments, the pain is inflammatory pain (e.g., caused by rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease, primary dysmenorrhea, or endometriosis) or neuropathic pain. In other embodiments, the pain is chronic pain. In further embodiments, the chronic pain is peripheral neuropathic pain (e.g., post-herpetic neuralgia, diabetic neuropathic pain, neuropathic cancer pain, HIV-associated neuropathy, erythromelalgia, failed back-surgery syndrome, trigeminal neuralgia, or phantom limb pain), central neuropathic pain (e.g., multiple sclerosis related pain, Parkinson disease related pain, post-stroke pain, post-traumatic spinal cord injury pain, lumbosacral radiculopathy, cervical radiculopathy, brachial radiculopathy, or pain in dementia), musculoskeletal pain (e.g., osteoarthritic pain or fibromyalgia syndrome), headache (e.g., migraine, cluster headache, tension headache syndrome, facial pain, or headache caused by other diseases), visceral pain (e.g., interstitial cystitis, irritable bowel syndrome, or chronic pelvic pain syndrome), or mixed pain (e.g., lower back pain, neck and shoulder pain, burning mouth syndrome, or complex regional pain syndrome). In still other embodiments, the pain is acute pain. In further embodiments, the acute pain is nociceptive pain or post-operative pain.
In a seventh aspect, the invention features a method of preparing any pharmaceutical composition described herein, the method including preparing a mixture (e.g., a liquid mixture) or a solution including compound 1, compound 2, or a salt thereof, and a pharmaceutically acceptable matrix polymer; and spray drying the mixture or the solution to form a solid dispersion (e.g., a spray dried dispersion).
In an eighth aspect, the invention features a method of preparing any pharmaceutical composition described herein, the method including preparing a mixture or a solution including compound 1, compound 2, or a salt thereof, and a pharmaceutically acceptable matrix polymer; heating (e.g., up to or above the transition glass temperature or melting temperature of the matrix polymer) the mixture to form a homogenous molten mass; extruding the molten mass; and cooling the molten mass to form a solid dispersion (e.g., a hot melt extrusion).
In some embodiments of the seventh and eighth aspects, the mixture or the solution further includes a solvent (e.g., one or more of dimethyl acetamide, dimethyl formamide, pyrrolidone, methylpyrrolidone, methanol, ethanol, and acetone).
In some embodiments, the mixture or the solution further includes a pharmaceutically acceptable excipient (e.g., butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol). Further exemplary excipients include an inert diluent or filler (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, a starch including potato starch, kaolin, calcium carbonate, sodium chloride, lactose, such as lactose monohydrate, calcium phosphate, calcium sulfate, and sodium phosphate); a granulating agent or a disintegrating agent (disintegrant) (e.g., a cellulose derivative including microcrystalline cellulose, a starch including potato starch and sodium starch glycolate, croscarmellose sodium, alginate, and alginic acid); a binding agent (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, lactose, such as lactose monohydrate, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, and polyethylene glycol); a lubricant (e.g., magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumurate, sodium lauryl sulfate, stearic acid, hydrogenated vegetable oil, mineral oil, PEG 4000-6000, sodium benzoate, glyceryl palmitostearate, glyceryl behenate, and talc); a wetting agent or a surfactant (e.g., sodium lauryl sulfate, polysorbate 80, and a pegylated vitamin E compound, as described herein); a glidant (e.g., magnesium stearate, calcium stearate, zinc stearate, colloidal silicon dioxide, magnesium carbonate, silica, such as fumed silica, and talc); an antiadhesive (e.g., magnesium stearate, calcium stearate, zinc stearate, fumed silica, and talc); a colorant; a flavoring agent; a plasticizer; a humectant; a buffering agent; an antioxidant; a coating or a film former; a compression aid; an emollient; an emulsifier; a fragrance; a preservative; a printing ink; a sorbent; a suspensing or dispersing agent; a sweetener; and waters of hydration.
In some embodiments, the composition includes of from about 1% to about 30% (w/w) of compound 1, compound 2, or a salt thereof (e.g., at any useful weight percentage range, as described herein). In further embodiments, the composition further includes of from about 25% to about 85% (w/w) of one or more pharmaceutically acceptable matrix polymers (e.g., from 25% to 50%, from 25% to 60%, from 25% to 70%, from 25% to 80%, from 35% to 50%, from 35% to 60%, from 35% to 70%, from 35% to 80%, from 35% to 85%, from 50% to 60%, from 50% to 70%, from 50% to 80%, from 50% to 85%, from 60% to 70%, from 60% to 80%, from 60% to 85%, from 70% to 80%, and from 70% to 85%); from about 15% to about 40% (w/w) of one or more binding agents; from about 1% to about 5% (w/w) of one or more disintegrating agents; from about 0.1% to about 2% (w/w) of one or more wetting agents; from about 0.1% to about 1% (w/w) of a glidant; and from about 0.1% to about 1% (w/w) of a lubricant. In particular embodiments, the composition further included of from about 1% to about 5% (w/w) of one or more surfactants (e.g., vitamin E TPGS).
In further embodiments of the seventh and eighth aspects, the method further includes filling the unit dosage form with the solid dispersion.
In some embodiments, the matrix polymer is selected from the group consisting of a cellulose derivative (e.g., a cellulose acetate having from about 10% to about 50% acetyl, an alkyl cellulose, a hydroxyalkyl cellulose, a hydroxyalkylalkyl cellulose, a hydroxyalkylalkyl cellulose ester, a carboxyalkyl cellulose, a carboxyalkylalkyl cellulose, and a carboxyalkyl cellulose ester, or any described herein), a polyacrylate (e.g., a polymethacrylate, a methacrylate copolymer, and an ethacrylate copolymer, or any described herein), a polyvinyl pyrrolidone (e.g., povidone, copovidone, or any described herein), a polyvinyl acetate (e.g., polyvinyl acetate ester, such as polyvinylacetate phthalate (PVAP), and a polyethylene glycol-polyvinylcaprolactam-polyvinylacetate copolymer, or any described herein), or a copolymer of a polyvinyl pyrrolidone and a polyvinyl acetate (e.g., having from 10:90 to 70:30 ratio of N-vinyl-2-pyrrolidone to vinyl acetate). In some embodiments, the cellulose acetate is selected from cellulose acetate phthalate (CAP), methylcellulose acetate phthalate, hydroxypropylmethyl cellulose acetate, and hydroxypropylmethyl cellulose acetate succinate (HPMCAS).
In some embodiments, the mixture or the solution further includes a plasticizer selected from a polyalkylene oxide (e.g., polyethylene glycols, such as PEG 300, PEG 400, and PEG 8000, and polypropylene glycols), a copolymer of ethylene oxide and propylene oxide (e.g., ethoxylated propoxylated block copolymers having the formula H(OCH2CH2)a(OCHCH3CH2)b(OCH2CH2)aOH, where a is about 38 and b is about 29 and where a is about 49 and b is about 57), and a polyethoxylated glyceryl ester (e.g., polyoxyl 35 castor oil and polyoxyl 40 castor oil having 40-45 moles of ethylene oxide).
In any of the aspects described herein, the composition includes compound 1 or a salt thereof.
In any of the aspects described herein, the composition includes compound 2 or a salt thereof.
In any of the aspects described herein, the composition includes HPMCAS.
In any of the above aspects, the unit dosage form includes from about 20 mg to about 100 mg (e.g., about 75 mg) of compound 1, compound 2, or a salt thereof.
In any of the above aspects, the compound 1, compound 2, or the salt thereof, is the hydrochloride salt of compound 1, the hydrochloride salt of compound 2, the free base form of compound 1, or the free base form of compound 2.
In any of the above aspects, the compound 1 is the free base form of compound 1.
In any of the above aspects, the unit dosage form is a tablet, hard gelatin capsule, a hard hydroxypropyl methylcellulose capsule, or a soft gelatin capsule.
In any of the above aspects, the unit dosage form includes from about 20 mg to about 250 mg of compound 1, compound 2, or a salt thereof, such as from 20 mg to 30 mg, from 20 mg to 40 mg, from 20 mg to 50 mg, from 20 mg to 75 mg, from 20 mg to 100 mg, from 20 mg to 125 mg, from 20 mg to 150 mg, from 20 mg to 175 mg, from 20 mg to 200 mg, from 20 mg to 225 mg, from 30 mg to 40 mg, from 30 mg to 50 mg, from 30 mg to 75 mg, from 30 mg to 100 mg, from 30 mg to 125 mg, from 30 mg to 150 mg, from 30 mg to 175 mg, from 30 mg to 200 mg, from 30 mg to 225 mg, from 30 mg to 250 mg, from 40 mg to 50 mg, from 40 mg to 75 mg, from 40 mg to 100 mg, from 40 mg to 125 mg, from 40 mg to 150 mg, from 40 mg to 175 mg, from 40 mg to 200 mg, from 40 mg to 225 mg, from 40 mg to 250 mg, from 50 mg to 75 mg, from 50 mg to 100 mg, from 50 mg to 125 mg, from 50 mg to 150 mg, from 50 mg to 175 mg, from 50 mg to 200 mg, from 50 mg to 225 mg, from 50 mg to 250 mg, from 60 mg to 75 mg, from 60 mg to 100 mg, from 60 mg to 125 mg, from 60 mg to 150 mg, from 60 mg to 175 mg, from 60 mg to 200 mg, from 60 mg to 225 mg, from 60 mg to 250 mg, from 70 mg to 75 mg, from 70 mg to 100 mg, from 70 mg to 125 mg, from 70 mg to 150 mg, from 70 mg to 175 mg, from 70 mg to 200 mg, from 70 mg to 225 mg, from 70 mg to 250 mg, from 80 mg to 100 mg, from 80 mg to 125 mg, from 80 mg to 150 mg, from 80 mg to 175 mg, from 80 mg to 200 mg, from 80 mg to 225 mg, from 80 mg to 250 mg, from 90 mg to 100 mg, from 90 mg to 125 mg, from 90 mg to 150 mg, from 90 mg to 175 mg, from 90 mg to 200 mg, from 90 mg to 225 mg, from 90 mg to 250 mg, from 100 mg to 125 mg, from 100 mg to 150 mg, from 100 mg to 175 mg, from 100 mg to 200 mg, from 100 mg to 225 mg, and from 100 mg to 250 mg.
In any of the above aspects, the unit dosage form is administered to achieve a daily amount of from about 25 mg to about 1,600 mg (e.g., from 40 mg to 1,600 mg, from 40 mg to 1,000 mg, from 40 mg to 800 mg, from 40 mg to 700 mg, from 40 mg to 600 mg, from 40 mg to 500 mg, from 40 mg to 400 mg, from 40 mg to 300 mg, from 40 mg to 200 mg, from 50 mg to 1,600 mg, from 50 mg to 1,000 mg, from 50 mg to 800 mg, from 50 mg to 700 mg, from 50 mg to 600 mg, from 50 mg to 500 mg, from 50 mg to 400 mg, from 50 mg to 300 mg, from 50 mg to 200 mg, from 60 mg to 1,600 mg, from 60 mg to 1,000 mg, from 60 mg to 800 mg, from 60 mg to 700 mg, from 60 mg to 600 mg, from 60 mg to 500 mg, from 60 mg to 400 mg, from 60 mg to 300 mg, from 60 mg to 200 mg, from 80 mg to 1,600 mg, from 80 mg to 1,000 mg, from 80 mg to 800 mg, from 80 mg to 700 mg, from 80 mg to 600 mg, from 80 mg to 500 mg, from 80 mg to 400 mg, from 80 mg to 300 mg, from 80 mg to 200 mg, from 100 mg to 1,600 mg, from 100 mg to 1,000 mg, from 100 mg to 800 mg, from 100 mg to 700 mg, from 100 mg to 600 mg, from 100 mg to 500 mg, from 100 mg to 400 mg, from 100 mg to 300 mg, from 100 mg to 200 mg, from 150 mg to 1,600 mg, from 150 mg to 1,000 mg, from 150 mg to 800 mg, from 150 mg to 700 mg, from 150 mg to 600 mg, from 150 mg to 500 mg, from 150 mg to 400 mg, from 150 mg to 300 mg, and from 150 mg to 200 mg, such as from 40 mg to 800 mg and from 80 mg to 320 mg) of compound 1, compound 2, or a salt thereof. In additional aspects, the unit dosage form is administered to achieve a daily amount of up to 1,600 mg (e.g., up to 1,500 mg, up to 1,250 mg, up to 1,000 mg, up to 750 mg, up to 500 mg, up to 450 mg, up to 400 mg, up to 350 mg, up to 300 mg, up to 250 mg, up to 200 mg, up to 150 mg, up to 100 mg, and up to 50 mg, preferably up to 400 mg) or a daily amount of from about 50 mg to about 1,600 mg (e.g., from 150 mg to 200 mg, from 150 mg to 225 mg, from 150 mg to 500 mg, from 150 mg to 750 mg, from 150 mg to 900 mg, from 150 mg to 1,000 mg, from 150 mg to 1,250 mg, from 150 mg to 1,500 mg, from 150 mg to 1,600 mg, from 200 mg to 225 mg, from 200 mg to 500 mg, from 200 mg to 750 mg, from 200 mg to 900 mg, from 200 mg to 1,000 mg, from 200 mg to 1,250 mg, from 200 mg to 1,500 mg, from 200 mg to 1,600 mg, from 225 mg to 500 mg, from 225 mg to 750 mg, from 225 mg to 900 mg, from 225 mg to 1,000 mg, from 225 mg to 1,250 mg, from 225 mg to 1,500 mg, from 225 mg to 1,600 mg, from 500 mg to 750 mg, from 500 mg to 900 mg, from 500 mg to 1,000 mg, from 500 mg to 1,250 mg, from 500 mg to 1,500 mg, from 500 mg to 1,600 mg, from 750 mg to 900 mg, from 750 mg to 1,000 mg, from 750 mg to 1,250 mg, from 750 mg to 1,500 mg, from 750 mg to 1,600 mg, from 900 mg to 1,000 mg, from 900 mg to 1,250 mg, from 900 mg to 1,500 mg, from 900 mg to 1,600 mg, from 1,000 mg to 1,250 mg, from 1,000 mg to 1,500 mg, from 1,000 mg to 1,600 mg, from 1,250 mg to 1,500 mg, from 1,250 mg to 1,600 mg, and from 1,500 mg to 1,600 mg, e.g., about 225 mg) of compound 1, compound 2, or a salt thereof. In further aspects, the unit dosage form is administered one to five times daily (e.g., one, two, three, four, or five times daily).
DEFINITIONS
By “pharmaceutically acceptable excipient” is meant any ingredient other than the active ingredient and capable of maintaining the active ingredient in a substantially amorphous form.
By “pharmaceutically acceptable matrix polymer” is meant a polymer suitable for pharmaceutical formulation and capable of forming a solid dispersion.
As used herein, the term “substantially amorphous” refers to a solid dosage form containing compound 1, compound 2, or a salt thereof, in which less than 20% (w/w) of the compound 1, compound 2, or a salt thereof, is present in a crystalline form (e.g., less than 15%, 12%, 10%, 8%, 5%, 3%, or 1% (w/w) is present in a crystalline form, such as between 0.01% and 20%, 0.01% and 15%, 0.01% and 12%, 0.01% and 10%, 0.01% and 8%, 0.01% and 5%, 0.01% and 3%, and 0.01% and 1% (w/w) in crystalline form). The crystalline content of a solid dosage form can be assessed using x-ray diffraction techniques.
As used herein, the term “solid dispersion” encompasses systems having substantially amorphous active ingredient dispersed in a matrix polymer. In certain dosage forms of the invention, the solid dispersion is a form having homogenously dispersed active ingredient throughout the matrix polymer in a manner that results in a single glass transition temperature Tg.
As used herein, “about” means+/−10% of the recited value.
As used herein, “bioavailability” refers to the fraction of drug absorbed following administration to a subject or patient under a fasted state. Under fasted states, the bioavailability of compound 1, compound 2, or a salt thereof, formulated as described herein is at least about 15%, but may be greater than 20%, 25%, 30%, 35%, 40%, 45%, or 50% of the dose administered.
By “coefficient of variation” is meant the arithmetic standard deviation divided by the arithmetic mean for a particular pharmacokinetic parameter, where the data is obtained from a pharmacokinetic study involving 10, 12, or more subjects or patients.
By “mean” is meant the arithmetic mean for a particular pharmacokinetic parameter, where the data is obtained from a pharmacokinetic study involving 10, 12, or more subjects or patients.
By “Cmax” is meant the mean peak concentration of a drug achieved in plasma after dosing.
By “Tmax” is meant the mean time after oral administration of a drug when the maximum plasma concentration of the drug or Cmax is reached.
By “AUC∞,” “AUC0-∞,” or “Area Under the Curve∞” is meant the mean integrated area under the curve for the plasma concentration of a drug, versus time from t=0 to ∞ following dosing.
By “food effect” is meant is meant a difference between any one or more of Cmax, Tmax, AUC∞, and bioavailability for a drug, administered under fasted states in comparison to the drug administered under fed states.
As used herein, “reducing the food effect” refers to narrowing the difference between any one of Cmax, Tmax, AUC∞, and bioavailability for a drug administered under fasted states in comparison to the drug administered under fed states.
By “fasted” or “fasted states” is meant a subject has not eaten for at least about four hours prior and about four hours subsequent to drug administration.
By “fed” or “fed states” is meant a subject has eaten within about 30 minutes prior to drug administration. The meal can be a fatty meal, and the resulting mean pharmacokinetic parameters can be characteristic of consuming a fatty meal. For example, the “fed state” can be a human who has eaten a United States Food and Drug Administration (FDA) standard high fat breakfast (or another meal containing a comparable quantity of fat and calories) within 30 minutes prior to drug administration. A typical FDA standard breakfast consists of 2 eggs fried in butter, 2 strips of bacon, 2 slices of toast with butter, 4 ounces of hash brown potatoes, and 8 ounces of whole milk. The meal is high in both fat (approximately 50% of total calorie content of the meal) and calories (approximately 800-1,000 calories).
By “pegylated vitamin E compound” is meant a compound or mixture of compounds containing one or more vitamin E moieties (e.g., a tocopherol, tocomonoenol, tocodienol, or tocotrienol) bonded to (e.g., by an ester, amide, or thioester bond) to one or more polyethylene glycol (PEG) moieties via a linker (e.g., a dicarboxylic or tricarboxylic acid). The vitamin E moiety can be any naturally occurring or synthetic form of vitamin E, including α-, β-, γ-, and δ-isoforms, and all stereoisomers of tocopherol, tocomonoenol, tocodienol, and tocotrienol. Linkers include, for example, dicarboxylic acids (e.g., succinic acid, sebacic acid, dodecanedioic acid, suberic acid, or azelaic acid, citraconic acid, methylcitraconic acid, itaconic acid, maleic acid, glutaric acid, glutaconic acid, fumaric acids, and phthalic acids). Exemplary tocopherol polyethylene glycol diesters are D-alpha-tocopheryl PEG succinate, tocopherol sebacate polyethylene glycol, tocopherol dodecanodioate polyethylene glycol, tocopherol suberate polyethylene glycol, tocopherol azelaate polyethylene glycol, tocopherol citraconate polyethylene glycol, tocopherol methylcitraconate polyethylene glycol, tocopherol itaconate polyethylene glycol, tocopherol maleate polyethylene glycol, tocopherol glutarate polyethylene glycol, tocopherol glutaconate polyethylene glycol, and tocopherol phthalate polyethylene glycol. Each of the PEG moieties of the pegylated vitamin E compound can be any polyethylene glycol or any PEG derivative, and can have a molecular weight of 200-6,000 kDa (e.g., 400-4,000 kDa, 500-2,000 kDa, 750-1,500 kDa, 800-1,200 kDa, 900-1,100 kDa, or about 1,000 kDa). The PEG moieties can be polydisperse; that is, they can have a variety of molecular weights. PEG derivatives include, for example, methylated PEG, propylene glycol, PEG-NHS, PEG-aldehyde, PEG-SH, PEG-NH2, PEG-CO2H, PEG-OMe and other ethers, branched PEGs, and PEG copolymers (e.g., PEG-b-PPG-b-PEG-1100, PEG-PPG-PEG-1900, PPG-PEG-MBE-1700, and PPG-PEG-PPG-2000). Any known source of pegylated vitamin E compound can be used in the present invention. An exemplary pegylated vitamin E compound is tocopheryl PEG-1000 succinate (TPGS-1000), which has a PEG moiety having a molecular weight of 1,000 kDa. A food grade TPGS-1000 is available, for example, under the trade name Eastman Vitamin E TPGS® (Eastman Chemical Company, Kingsport, Tenn.). This TPGS is water-soluble form of natural-source vitamin E, which is prepared by esterification of crystalline D-α-tocopheryl acid succinate with polyethylene glycol 1000 (PEG 1000), and contains between 260 and 300 mg/g total tocopherol. Another exemplary pegylated vitamin E compound is Water Soluble Natural Vitamin E (ZMC-USA, The Woodlands, Tex.). Methods of preparing pegylated vitamin E are described in U.S. Pat. Nos. 2,680,749 and 3,102,078 and in U.S. Publication Nos. 2007/0184117 and 2007/0141203, which are herein incorporated by reference. Pegylated vitamin E compounds also include analogs that differ in chemical composition from tocopheryl PEG succinate (e.g., TPGS-1000) by the substitution, addition, or removal of one or more atoms, methylene (CH2)n units, or functional groups. Pegylated vitamin E compounds also include chromanol derivatives (e.g., 6-chromanol PEG-1000 succinate and 6-chromanol PEG-400 succinate), steroid derivatives (e.g., cholesteryl PEG-1000 succinate, cholic acid PEG-1000, dihydro cholic acid PEG-1000, litho-cholic acid PEG-1000, ursodeoxycholic acid PEG-1000, chenodeoxycholic acid PEG-1000), and others (e.g., indomethacin PEG-1000, chromone-2-carboxylic acid PEG-1000, chromone-2-carboxylic acid PEG-1100-OMe, chromone-2-carboxylic acid PEG-1500, chromone-2-carboxylic acid PEG-2000, naproxen PEG-1000, probenecid PEG-1000, 7-carboxymethoxy-4-methyl-coumarin PEG-1000, 5-(4-chlorophenyl)-2-furoic acid PEG-1000, probenecid tocopheryl PEG-1000 succinate, lithocholic acid PEG-1000, and chromone-3-carboxylic acid PEG-1000, 7-hydroxy-coumarinyl-4-acetic acid PEG-1000).
The term “unit dosage form” refers to a physically discrete unit suitable as a unitary dosage, such as a tablet, caplet, hard capsule, or soft capsule, each unit containing a predetermined quantity of a drug.
As used herein, the term “administration” or “administering” refers to peroral (e.g., oral) administration of a drug to a subject or patient.
By “effective” amount is meant the amount of a drug sufficient to treat, prevent, or ameliorate a condition in a subject or patient. The effective amount of compound 1, compound 2, or salt thereof, used to practice the present invention for therapeutic management of a condition varies depending upon one or more of the manner of administration, the age, body weight, sex, and/or general health or malady of the patient. The prescribers will primarily decide the appropriate amount and dosage regimen. Such amount is referred to as an “effective” amount.
As used herein, and as well understood in the art, “to treat” a condition or “treatment” of the condition (e.g., the conditions described herein such as pain (e.g., chronic or acute pain), epilepsy, Alzheimer's disease, Parkinson's disease, cardiovascular disease, diabetes, cancer, sleep disorders, obesity, mood disorders, psychosis such as schizophrenia, tinnitus, amyotrophic lateral sclerosis, glaucoma, ischaemia, spasticity disorders, obsessive compulsive disorder, restless leg syndrome, Tourette syndrome, overactive bladder, renal disease, neuroprotection, addiction, or male birth control) is an approach for obtaining beneficial or desired results, such as clinical results. Beneficial or desired results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions; diminishment of extent of disease, disorder, or condition; stabilized (i.e., not worsening) state of disease, disorder, or condition; preventing spread of disease, disorder, or condition; delay or slowing the progress of the disease, disorder, or condition; amelioration or palliation of the disease, disorder, or condition; and remission (whether partial or total), whether detectable or undetectable. “Palliating” a disease, disorder, or condition means that the extent and/or undesirable clinical manifestations of the disease, disorder, or condition are lessened and/or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment.
Other features and advantages of the invention will be apparent from the following detailed description, the drawings, and the claims.



BRIEF DESCRIPTION OF THE DRAWINGS
FIGS. 1A-1H are graphs showing the dissolution rate in gastric media for solid dispersion formulations having 20% (w/w) loading of compound 1 and a gastric-to-FaSSIF (pH 1.0-to-6.5) media transition at 13 minutes. The following solid dispersion formulations were tested: carboxymethylethyl cellulose (CMEC, FIG. 1A), cellulose acetate phthalate (CAP, FIG. 1B), hydroxypropylmethyl cellulose acetate succinate M grade (HPMCAS-M, FIG. 1C), polyvinyl acetate phthalate (PVAP, FIG. 1D), methacrylic acid-methyl methacrylate copolymer (Eudragit® L 100, FIG. 1E), polyethylene glycol-polyvinylcaprolactam-polyvinylacetate copolymer (Soluplus®, FIG. 1F), hydroxypropylmethyl cellulose phthalate (HPMCP-H55, FIG. 1G), and polyvinylpyrrolidone vinylacetate copolymer (PVP-VA, FIG. 1H). The total drug species are represented by open circles with error bars, and the free drug species are represented by closed circles with error bars. The solubility of unformulated compound 1 in the gastric and FaSSIF media is shown in FIG. 1A.
FIGS. 2A-2C are graphs showing the dissolution rate in gastric media for solid dispersion formulations having 35% (w/w) loading of compound 1 and a gastric-to-FaSSIF (pH 1.0-to-6.5) media transition at 13 minutes. The following solid dispersion formulations were tested: cellulose acetate phthalate (CAP, FIG. 2A), hydroxypropylmethyl cellulose acetate succinate M grade (HPMCAS-M, FIG. 2B), and polyvinyl acetate phthalate (PVAP, FIG. 2C). The total drug species are represented by open circles with error bars, and the free drug species are represented by closed circles with error bars.
FIGS. 3A-3D are graphs showing the dissolution rate in gastric media for solid dispersion formulations having 50% (w/w) loading of compound 1 and a gastric-to-FaSSIF (pH 1.0-to-6.5) media transition at 13 minutes. The following solid dispersion formulations were tested: cellulose acetate phthalate (CAP, FIG. 3A), hydroxypropylmethyl cellulose acetate succinate M grade (HPMCAS-M, FIG. 3B), methacrylic acid-methyl methacrylate copolymer (Eudragit® L 100, FIG. 3C), and polyvinyl acetate phthalate (PVAP, FIG. 3D). The total drug species are represented by open circles with error bars, and the free drug species are represented by closed circles with error bars. The solubility of unformulated compound 1 in the gastric and FaSSIF media is shown in FIG. 3A.
FIGS. 4A-4B are graphs showing results from computer modeling of fraction absorbed (FIG. 4A) and fed-fasted ratio (FIG. 4B) for 20%, 35%, and 50% (w/w) loading of compound 1. Data are shown for solid dispersion formulations of carboxymethylethyl cellulose (CMEC), hydroxypropylmethyl cellulose acetate succinate M grade (HPMCAS-M), cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), methacrylic acid-methyl methacrylate copolymer (Eudragit® L 100), polyethylene glycol-polyvinylcaprolactam-polyvinylacetate copolymer (Soluplus®), polyvinylpyrrolidone vinylacetate copolymer (PVP-VA), and hydroxypropylmethyl cellulose phthalate (HPMCP-H44), and for crystalline compound 1 (API).
FIGS. 5A-5B are graphs showing the dissolution rate in gastric media for solid dispersion formulations having 20% (w/w) loading of compound 1 and a gastric-to-FaSSIF (pH 1.0-to-6.5) media transition at 30 minutes. The following solid dispersion formulations were tested: cellulose acetate phthalate (CAP, FIG. 5A) and hydroxypropylmethyl cellulose acetate succinate M grade (HPMCAS-M, FIG. 5B). The total drug species are represented by open circles with error bars, and the free drug species are represented by closed circles with error bars.
FIG. 6 is a graph showing modulated differential scanning calorimetry measurements at ambient relative humidity for solid dispersion formulations having 20% (w/w) loading of compound 1. Glass transition temperature Tg is shown for formulations of carboxymethylethyl cellulose (CMEC), hydroxypropylmethyl cellulose acetate succinate M grade (HPMCAS-M), cellulose acetate phthalate (CAP), and polyvinyl acetate phthalate (PVAP).
FIG. 7 is a graph showing powder x-ray diffraction measurements for crystalline compound 1 and solid dispersion formulations having 20% (w/w) loading of compound 1 with hydroxypropylmethyl cellulose acetate succinate M grade (HPMCAS-M) or cellulose acetate phthalate (CAP).
FIGS. 8A-8C are graphs showing mean concentration of compound 1 in plasma for various formulations in an in vivo studies in rats. Data are shown for formulation 1 having cellulose acetate phthalate (CAP) (FIG. 8A), formulation 2 having hydroxypropylmethyl cellulose acetate succinate M grade (HPMCAS-M) (FIG. 8B), and control (FIG. 8C) with doses of 10 mg/kg, 30 mg/kg, and 100 mg/kg.
FIGS. 9A-9C are graphs showing mean concentration of compound 1 in plasma for various doses in an in vivo study in rats. Data are shown for formulations 1, 2, and control with doses of 10 mg/kg (FIG. 9A), 30 mg/kg (FIG. 9B), and 100 mg/kg (FIG. 9C).
FIG. 10 is a graph showing mean concentration of compound 1 in plasma for various formulations in an in vivo study in dogs with a 10 mg/kg dose. Data are shown for 20% (w/w) compound 1 with hydroxypropylmethyl cellulose acetate succinate M grade (HPMCAS-MG, Group 2) or cellulose acetate phthalate (CAP, Group 3) and control (Group 1).
FIGS. 11A-11B are graphs comparing AUC0-24 values for two formulations in fasted or fed conditions. Data are provided for compound 1 (free base) in a spray dried dispersion (SDD) formulation (“SDD”) to compound 1 (HCl salt) in a micronized formulation (“Micronized”). FIG. 11A shows the ratio of AUC0-24 for fasted to fed conditions (i.e., [AUC0-24 fasted]/[AUC0-24 fed]) for SDD or Micronized. FIG. 11B shows the ratio of AUC0-24 for SDD to Micronized (i.e., [AUC0-24 SDD]/[AUC0-24 Micronized]) for fasted or fed conditions.
FIG. 12 is a series of box plots showing the mean, median and distributions of the AUC0-∞ for all treatments in groups 1 and 2 of Examples 10 and 11, comparing treatment with the hot melt extrusion (HME) formulation under fasted or fed conditions and, separately, comparing treatment with the HME or SDD formulations under fed conditions. Formulation details are provided in Examples 7 and 8.
FIG. 13 is a series of box plots showing the mean, median and distributions of the Cmax for all treatments in groups 1 and 2 of Examples 10 and 11, comparing treatment with the HME formulation under fasted or fed conditions and, separately, comparing treatment with the HME or SDD formulations under fed conditions. Formulation details are provided in Examples 7 and 8.



DETAILED DESCRIPTION
The invention provides methods for treating conditions related to N-type calcium channels, involving administration of 1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one (compound 1), a metabolite thereof (e.g., 1-(3,3-diphenylpropanoyl)piperazine (compound 2), or a salt thereof. Non-limiting examples of conditions treatable by this administration are pain and epilepsy.
Compound 1 is a potent and selective N-type calcium channel antagonist, and doses of up to 1,600 mg provided no adverse effects. Yet, compound 1 is also known to have decreased oral bioavailability in the fasted state, as compared to the fed state. Accordingly, the invention provides formulations to increase the oral bioavailability or to reduce patient-to-patient variability in pharmacokinetic behavior of compound 1, compound 2, or a salt thereof. Generally, amorphous forms of a drug are more readily absorbed within the gastric and intestinal system and, thus, have increased bioavailability, as compared to crystalline forms of the drug. These formulations include use of a solid dispersion system to provide a matrix polymer capable of maintaining therapeutically effective amounts of compound 1, compound 2, or a salt thereof, in an amorphous form.
Previously Determined Characteristics of Compound 1
Compound 1 has the following previously determined characteristics:
(i) physical appearance: white to off-white powder;
(ii) solubility: slightly soluble in water (0.2 μg/ml to 2.0 μg/ml at pH of 6.8, 0.03 μg/ml at pH of 6.5, 1.5 μg/ml at pH of 6.5 in FaSSIF, and 55 μg/ml at pH of 1.0) and soluble in acetone (up to 50 mg/ml), propylene glycol, ethanol, and tetrahydrofuran;
(iii) pKa: 5.4;
(iv) log P: 2.6;
(v) M.P.: 123° C. (for free base) and 126° C. (for HCl salt);
(vi) Tg: 41.6° C.;
(vii) hygroscopicity (for free base): 0.09% at 70% relative humidity (RH);
(viii) potential isomerism: none;
(ix) Tmax (for HCl salt): <2 hours (fasted state), 2-5 hours (fed state with normal fat meal), and 4-5 hours (fed state with high fat meal); and
(x) t1/2 for absorption (for HCl salt): 0.05-0.17 hours (fasted state), 0.5-1.6 hours (fed state with normal fat meal), and 0.8-2.8 hours (fed state with high fat meal). The fed-fasted pharmacokinetic data were collected using a “normal fat” meal consisting of toast with 1 pat of butter, a banana, 2% milk, apple juice, and Honey Nut Cheerios®, where the meal has about 501 calories with 99 calories from fat, 346 calories from carbohydrates, and 56 calories from protein; and using a “high fat” meal consisting of 2 eggs fried in butter, 2 strips of bacon, 2 slices of toast with butter, 4 ounces of hash brown potatoes and 8 ounces of whole milk, where the meal has about 1,000 calories with 500-600 calories from fat, 250 calories from carbohydrates, and 150 calories from protein.
The relative oral bioavailability of compound 1 (HCl salt) has been previously determined in various fed and fasted states in a micronized formulation. This micronized formulation included the following for a 100 mg dose in a #1 HPMC (white opaque) capsule: compound 1 HCl micronized (100.00 mg), Lactose Fast Flo® Fast Flo® composed of a spray-dried mixture of crystalline and amorphous lactose monohydrate (184.80 mg); sodium starch glycolate (19.20 mg); polysorbate 80 (14.40 mg); purified water (used as the granulating fluid and was removed during processing) (QS); and magnesium stearate (1.60 mg), where the resultant fill weight was 320.00 mg. For a 25 mg dose in a #1 gelatin (white opaque) capsule, the formulation included the following: compound 1 HCl micronized (25.00 mg), Lactose Fast Flo® Fast Flo® composed of a spray-dried mixture of crystalline and amorphous lactose monohydrate (264.60 mg); sodium starch glycolate (19.20 mg); polysorbate 80 (9.60 mg); purified water (used as the granulating fluid and was removed during processing) (QS); and magnesium stearate (1.60 mg), where the resultant fill weight was 320.00 mg.
For the micronized formulation, typical values for relative bioavailability included 0.682 for a fasted state relative to a fed state with a normal fat meal; 1.48 for a 25 mg capsule relative to a 100 mg capsule; 5.60 for a fed state with a high fat meal relative to a fed state with a normal fat meal; and




  1
  -
  
    0.363
    ×
    
      
        log
        10
      
      ⁡
      
        (
        
          dose
          100
        
        )
      
    
  




as a function of dose (mg) relative to a 100 mg dose. Typical values were computed as 100%×√ω2, where ω2=variance (eta), and 68% of the study population were within the range of these typical values. Relative bioavailability values derived from the provided typical values are provided in Table 1.










TABLE 1









Meal*













Dosage form
Dose (mg)
Fasted
Normal fat
High fat

















100 mg
100
0.682
1.000
5.600



capsule
200
0.607
0.891
4.988




400
0.533
0.781
4.376




800
0.458
0.672
3.764




1,600
0.384
0.563
3.152



25 mg
25
1.230
NA
10.10



capsule
50
1.120
NA
9.19




100
1.009
NA
8.29




200
0.899
NA
7.38




400
0.789
NA
6.48




800
0.678
NA
5.57




1,600
0.568
NA
4.67







*Values are expressed relative to the 100 mg dose administered with a normal fat meal.






Synthesis of Compound 1

Compound 1, or a salt thereof, can be synthesized by any useful method, including those described in U.S. Pat. Nos. 6,294,533; 6,387,897; 6,492,375; 6,617,322; 6,949,554; 6,951,862; and 7,064,128; and U.S. Patent Publication Nos. 2006/0084660 and 2004/0259866, incorporated herein by reference in their entirety.
Scheme 1 provides an exemplary schematic for the synthesis of compound 1 (free base). Briefly, the first and second steps provide purified 3,3-diphenylpropionic acid, and these steps can optionally include a recrystallization step in ethyl acetate/heptanes (70/30). Then, the third step provides compound 1, and this step can optionally include use of a toluene azeotrope to remove residual solvents, such as ethanol, tetrahydrofuran (THF), ethyl acetate, commercial grade heptanes, toluene, or isopropanol.




Synthesis of Compound 2

Compound 2, or a salt thereof, can be synthesized by any useful method, including those described in U.S. Pat. Nos. 6,011,035; 6,951,862; and 7,186,726; U.S. Patent Application Publication Nos. 2006/0084660 and 2004/0259866; International Publications Nos. WO 2008/066803, WO 2011/006073, and WO 2007/118323; J. Am. Chem. Soc. 77:3142, 1955; and J. Am. Pharm. Assoc. 46:279, 1957; incorporated herein by reference in their entirety.
Scheme 2 provides an exemplary schematic for the synthesis of compound 2 (free base). Briefly, the first step provides a protected carbamate compound. The second step provides compound 2. These steps can optionally include a purification step (e.g., where the starting material, 3,3-diphenylpropanoic acid, can be optionally purified, as shown in Scheme 1), a recrystallization step in ethyl acetate/heptanes (e.g., in a ratio of 70/30), or use of a toluene azeotrope to remove residual solvents, such as ethanol, tetrahydrofuran (THF), ethyl acetate, commercial grade heptanes, toluene, or isopropanol.




Pharmaceutically Acceptable Matrix Polymer

Pharmaceutically acceptable matrix polymers include one or more polymers capable of forming a solid dispersion with compound 1, compound 2, or a salt thereof. Two or more matrix polymers can be used to together and can optionally include one or more surfactants and/or plasticizers. Generally, optimal Tg values include from 50° C. to 180° C., which is higher than the melting temperature of compound 1 or compound 2 but lower than the temperature at which compound 1 or compound 2 decomposes. Exemplary Tg values for matrix polymers are from 50° C. to 180° C. (e.g., from 50° C. to 170° C., from 50° C. to 160° C., from 50° C. to 150° C., from 50° C. to 145° C., from 50° C. to 140° C., from 50° C. to 135° C., from 50° C. to 130° C., from 50° C. to 125° C., from 50° C. to 120° C., from 50° C. to 115° C., from 50° C. to 110° C., from 50° C. to 105° C., from 50° C. to 100° C., from 50° C. to 95° C., from 50° C. to 90° C., from 50° C. to 85° C., from 50° C. to 80° C., from 50° C. to 75° C., from 50° C. to 70° C., from 50° C. to 65° C., from 50° C. to 60° C., from 75° C. to 180° C., from 75° C. to 170° C., from 75° C. to 160° C., from 75° C. to 150° C., from 75° C. to 145° C., from 75° C. to 140° C., from 75° C. to 135° C., from 75° C. to 130° C., from 75° C. to 125° C., from 75° C. to 120° C., from 75° C. to 115° C., from 75° C. to 110° C., from 75° C. to 105° C., from 75° C. to 100° C., from 75° C. to 95° C., from 75° C. to 90° C., from 75° C. to 85° C., from 75° C. to 80° C., from 80° C. to 180° C., from 80° C. to 170° C., from 80° C. to 160° C., from 80° C. to 150° C., from 80° C. to 145° C., from 80° C. to 140° C., from 80° C. to 135° C., from 80° C. to 130° C., from 80° C. to 125° C., from 80° C. to 120° C., from 80° C. to 115° C., from 80° C. to 110° C., from 80° C. to 105° C., from 80° C. to 100° C., from 80° C. to 95° C., from 80° C. to 90° C., from 80° C. to 85° C., from 85° C. to 180° C., from 85° C. to 170° C., from 85° C. to 160° C., from 85° C. to 150° C., from 85° C. to 145° C., from 85° C. to 140° C., from 85° C. to 135° C., from 85° C. to 130° C., from 85° C. to 125° C., from 85° C. to 120° C., from 85° C. to 115° C., from 85° C. to 110° C., from 85° C. to 105° C., from 85° C. to 100° C., from 85° C. to 95° C., from 85° C. to 90° C., from 90° C. to 180° C., from 90° C. to 170° C., from 90° C. to 160° C., from 90° C. to 150° C., from 90° C. to 145° C., from 90° C. to 140° C., from 90° C. to 135° C., from 90° C. to 130° C., from 90° C. to 125° C., from 90° C. to 120° C., from 90° C. to 115° C., from 90° C. to 110° C., from 90° C. to 105° C., from 90° C. to 100° C., from 90° C. to 95° C., from 95° C. to 180° C., from 95° C. to 170° C., from 95° C. to 160° C., from 95° C. to 150° C., from 95° C. to 145° C., from 95° C. to 140° C., from 95° C. to 135° C., from 95° C. to 130° C., from 95° C. to 125° C., from 95° C. to 120° C., from 95° C. to 115° C., from 95° C. to 110° C., from 95° C. to 105° C., from 95° C. to 100° C., from 100° C. to 180° C., from 100° C. to 170° C., from 100° C. to 160° C., from 100° C. to 150° C., from 100° C. to 145° C., from 100° C. to 140° C., from 100° C. to 135° C., from 100° C. to 130° C., from 100° C. to 125° C., from 100° C. to 120° C., from 100° C. to 115° C., from 100° C. to 110° C., from 100° C. to 105° C., from 110° C. to 180° C., from 110° C. to 170° C., from 110° C. to 160° C., from 110° C. to 150° C., from 110° C. to 145° C., from 110° C. to 140° C., from 110° C. to 135° C., from 110° C. to 130° C., from 110° C. to 125° C., from 110° C. to 120° C., from 110° C. to 115° C., from 120° C. to 180° C., from 120° C. to 170° C., from 120° C. to 160° C., from 120° C. to 150° C., from 120° C. to 145° C., from 120° C. to 140° C., from 120° C. to 135° C., from 120° C. to 130° C., from 120° C. to 125° C., from 125° C. to 180° C., from 125° C. to 170° C., from 125° C. to 160° C., from 125° C. to 150° C., from 125° C. to 145° C., from 125° C. to 140° C., from 125° C. to 135° C., from 125° C. to 130° C., from 130° C. to 180° C., from 130° C. to 170° C., from 130° C. to 160° C., from 130° C. to 150° C., from 130° C. to 145° C., from 130° C. to 140° C., from 130° C. to 135° C., from 135° C. to 150° C., from 135° C. to 145° C., from 135° C. to 140° C., from 150° C. to 180° C., from 150° C. to 170° C., from 150° C. to 160° C., and from 175° C. to 180° C.).
Exemplary Tg values for a solid dispersion including compound 1 or compound 2 and one or more matrix polymers are from 80° C. to 150° C. (e.g., from 80° C. to 145° C., from 80° C. to 140° C., from 80° C. to 135° C., from 80° C. to 130° C., from 80° C. to 125° C., from 80° C. to 120° C., from 80° C. to 115° C., from 80° C. to 110° C., from 80° C. to 105° C., from 80° C. to 100° C., from 80° C. to 95° C., from 80° C. to 90° C., from 80° C. to 85° C., from 85° C. to 150° C., from 85° C. to 145° C., from 85° C. to 140° C., from 85° C. to 135° C., from 85° C. to 130° C., from 85° C. to 125° C., from 85° C. to 120° C., from 85° C. to 115° C., from 85° C. to 110° C., from 85° C. to 105° C., from 85° C. to 100° C., from 85° C. to 95° C., from 85° C. to 90° C., from 90° C. to 150° C., from 90° C. to 145° C., from 90° C. to 140° C., from 90° C. to 135° C., from 90° C. to 130° C., from 90° C. to 125° C., from 90° C. to 120° C., from 90° C. to 115° C., from 90° C. to 110° C., from 90° C. to 105° C., from 90° C. to 100° C., from 90° C. to 95° C., from 95° C. to 150° C., from 95° C. to 145° C., from 95° C. to 140° C., from 95° C. to 135° C., from 95° C. to 130° C., from 95° C. to 125° C., from 95° C. to 120° C., from 95° C. to 115° C., from 95° C. to 110° C., from 95° C. to 105° C., from 95° C. to 100° C., from 120° C. to 150° C., from 120° C. to 145° C., from 120° C. to 140° C., from 120° C. to 135° C., from 120° C. to 130° C., from 120° C. to 125° C., from 125° C. to 150° C., from 125° C. to 145° C., from 125° C. to 140° C., from 125° C. to 135° C., from 125° C. to 130° C., from 130° C. to 150° C., from 130° C. to 145° C., from 130° C. to 140° C., from 130° C. to 135° C., from 135° C. to 150° C., from 135° C. to 145° C., and from 135° C. to 140° C.).
Exemplary matrix polymers are one or more of ethyl cellulose (Tg=133° C.), cellulose acetate phthalate (CAP, Tg=171° C.), hydroxypropylmethyl cellulose acetate (Tg=177° C.), hydroxypropylmethyl cellulose acetate succinate (HPMCAS, Tg=115° C.), hydroxypropylmethyl cellulose phthalate (HPMCP, Tg=133° C.), polyvinylpyrrolidone (Tg=174° C.), crospovidone (Tg=190° C. to 195° C.), polyvinyl alcohol (Tg=75° C.), and polyvinyl acetate phthalate (Tg=55° C.). Exemplary solid dispersions are those having 20% (w/w) of compound 1 and CMEC (Tg=89.4° C.), HPMCAS-M (Tg=91.3° C.), CAP (Tg=129.9° C.), or PVAP (Tg=116.1° C.).
Examples of matrix polymers which can be used in the formulations of the invention are, without limitation, cellulose derivatives, polyacrylates, polyvinyl pyrrolidones, polyvinyl acetates, and copolymers thereof.
Cellulose Derivatives
The formulations of the invention can include one or more cellulose derivatives. Cellulose derivatives generally include those having any number of modifications to the free hydroxyl groups in cellulose.
In some examples, the cellulose derivative is a cellulose acetate having from 10% to 50% acetyl. Referring to cellulose derivatives, % refers to the proportion of the free hydroxyl groups esterified with a functional group. For example, “10% acetyl” refers to a derivative having 10% of the free hydroxyl groups in cellulose esterified with an acetyl group.
Particular examples of cellulose acetates are cellulose acetate phthalates (CAP), such as those having 35% phthalyl, 24% acetyl (available as Cellacefate from Eastman Chemical Company, Kingsport, Tenn.); methylcellulose acetate phthalates; hydroxypropylmethyl cellulose acetates; and hydroxypropylmethyl cellulose acetate succinates (HPMCAS), such as M grade having 9% acetyl/11% succinoyl (e.g., HPMCAS having a mean particle size of 5 μm (i.e., HPMCAS-MF, fine powder grade) or having a mean particle size of 1 mm (i.e., HPMCAS-MG, granular grade)), H grade having 12% acetyl/6% succinoyl (e.g., HPMCAS having a mean particle size of 5 μm (i.e., HPMCAS-HF, fine powder grade) or having a mean particle size of 1 mm (i.e., HPMCAS-HG, granular grade)), and L grade having 8% acetyl/15% succinoyl (e.g., HPMCAS having a mean particle size of 5 μm (i.e., HPMCAS-LF, fine powder grade) or having a mean particle size of 1 mm (i.e., HPMCAS-LG, granular grade)).
Additional exemplary cellulose derivatives are alkyl celluloses, such as methyl cellulose (MethocelTM A) or ethylcellulose (Ethocel®); hydroxyalkyl celluloses, such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC, e.g., low-substituted HPC having 11% hydroxypropyl or 8% hydroxypropyl), and hydroxybutyl cellulose; hydroxyalkylalkyl celluloses, such as hydroxyethylmethyl cellulose and hydroxypropylmethyl cellulose (hypromellose, HPMC, e.g., those having about 19-24% methoxyl/7-12% hydroxypropxyl (MethocelTM K, including those having apparent viscosity (2% in water at 20° C.) of 80-120 cP (MethocelTM K100), 3,000-5,600 cP (MethocelTM K4M), 11,250-21,000 cP (MethocelTM K15M), 80,000-120,000 cP (MethocelTM K100M), available from Dow Chemical Co.), 28-30% methoxyl/7-12% hydroxypropxyl (MethocelTM E, including those having apparent viscosity (2% in water at 20° C.) of 3,000-5,600 cP (MethocelTM E4M) and 7,500-14,000 cP (MethocelTM E10M), also available from Dow Chemical Co.), 23% methoxyl/10% hydroxypropxyl (Metolose® SR, available from Shin-Etsu Chemical Co., Ltd., Tokyo, Japan), 23%-29% methoxyl/8%-9% hydroxypropxyl (Metolose®, also available from Shin-Etsu Chemical Co., Ltd.), 29% methoxyl/9% hydroxypropxyl (Hypromellose USP, substitution 2910), and 23% methoxyl/6% hydroxypropxyl (Hypromellose USP, substitution 2208)); hydroxyalkylalkyl cellulose esters, such as hydroxypropylmethyl cellulose phthalate (HPMCP) (e.g., HP 55 grade having 31% nominal phthalyl content and HP-55S or HP-50 grades having 24% nominal phthalyl content); carboxyalkyl celluloses, such as carboxymethyl cellulose and alkali metal salts thereof, such as sodium salts; carboxyalkylalkyl celluloses, such as carboxymethylethyl cellulose; and carboxyalkyl cellulose esters, such as carboxymethyl cellulose butyrate, carboxymethyl cellulose propionate, carboxymethyl cellulose acetate butyrate, and carboxymethyl cellulose acetate propionate.
Any of the cellulose derivatives herein can be further cross-linked or copolymerized (e.g., with any matrix polymer described herein).
Polyacrylates
The formulations of the invention can include one or more polyacrylates or copolymers thereof.
Exemplary polyacrylates are polymethacrylates; methacrylate copolymers, such as methacrylic acid-methyl methacrylate copolymers having a 1:1 ratio of free carboxyl groups to ester groups (e.g., Eudragit® L 100, MW  ̃125,000 g/mol) and a 1:2 ratio of free carboxyl groups to ester groups (Eudragit® S 100, MW  ̃125,000 g/mol), dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymers (e.g., having a ratio of 2:1:1 of dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate and in powder, granule, or solution forms, i.e., Eudragit® E PO, Eudragit® E 100, or Eudragit® E 12.5, respectively), and diethylaminoethyl methacrylic acid-methyl methacrylate copolymers (e.g., Eudragit® E); and ethacrylate copolymers, such as methacrylic acid ethacrylate copolymers having a 50:50 ratio of methacrylic acid to ethacrylate (e.g., Kollicoat® MAE 100P or Eudragit®L 100-55, MW  ̃320,000 g/mol)
Polyvinyl Pyrrolidones and Polyvinyl Acetates
The formulations of the invention can include one or more polyvinyl pyrrolidones, polyvinyl acetates, or copolymers thereof.
Exemplary polyvinyl pyrrolidones and polyvinyl acetates are polyvinyl pyrrolidones (e.g., povidone, PVP, or soluble povidone) having molecular weights of about 2,500 (Kollidon®12 PF, weight-average molecular weight between 2,000 to 3,000), about 9,000 (Kollidon®17 PF, weight-average molecular weight between 7,000 to 11,000), about 25,000 (Kollidon®25, weight-average molecular weight between 28,000 to 34,000), about 50,000 (Kollidon®30, weight-average molecular weight between 44,000 to 54,000), and about 1,250,000 (Kollidon®90 or Kollidon®90F, weight-average molecular weight between 1,000,000 to 1,500,000); polyvinyl acetate esters, such as polyvinyl acetate phthalate (PVAP); polyethylene glycol-polyvinyl acetate copolymers, such as polyethylene glycol-polyvinylcaprolactam-polyvinylacetate copolymer (Soluplus®); and polyvinylpyrrolidone-polyvinyl acetate copolymers (PVP-VA), such as those having a 60:40 ratio of N-vinyl-2-pyrrolidone to vinyl acetate (copovidone, also available as Kollidon® VA 64) and a 20:80 ratio of N-vinyl-2-pyrrolidone to vinyl acetate (Kollidon® SR).
Hydrophobic-Lipophilic Balance
The matrix polymers, plasticizers, and surfactants used in the formulations of the invention can be characterized by the hydrophobic-lipophilic balance (“HLB”). HLB generally provides the degree of hydrophobicity or lipophilicity for a given molecule. HLB can be determined by any useful method, including the formula HLB=20×Mh/M, where Mh is the molecular mass of the hydrophilic region of the molecule and M is the molecule mass of the molecule, and the formula HLB=7+ΣiNih−ΣiNil, where i is the number of groups, Nih is a value for each ith hydrophilic group, and Nil is the value for each ith lipophilic group. Values of Nh and Nl depend on the type of hydrophilic and lipophilic group, respectively. Exemplary values for Nh include 38.7 for —SO4Na, 21.1 for —CO2K, 19.1 for —CO2Na, 9.4 for tertiary amine N, 6.8 for ester (sorbitan ring), 2.4 for ester (free), 2.1 for —CO2H, 1.9 for —OH (free), 1.3 for —O—, 0.5 for —OH (sorbitan ring), and 0.33 for —(CH2CH2O)—; and for Nl include −1.66 for benzyl, −0.475 for —CH—, —CH2—, —CH3, and —CH—, and −0.13 for —(CH2CH2CH2O)—.
Plasticizers
The formulations of the invention optionally include one or more plasticizers. Generally, plasticizers can be used to reduce the glass transition temperature Tg or to decrease viscosity of the mixture of compound 1, compound 2, or a salt thereof, with the matrix polymer. Exemplary plasticizers are polyalkylene oxides, such as polyethylene glycols (e.g., PEG 300, PEG 400, PEG 4000, or PEG 8000) and polypropylene glycols; copolymers of ethylene oxide and propylene oxide, such as ethoxylated propoxylated block copolymers having the formula H(OCH2CH2)a(OCHCH3CH2)b(OCH2CH2)aOH, where a is about 12 and b is about 20 (Poloxamer® 124), where a is about 38 and b is about 29, where a is about 80 and b is about 27 (Poloxamer® 188), where a is about 64 and b is about 37 (Poloxamer® 237), where a is about 141 and b is about 44 (Poloxamer® 338), where a is about 49 and b is about 57, and where a is about 101 and b is about 56 (Poloxamer® 407); and polyethoxylated glyceryl esters, such as polyoxyl 35 castor oil (Cremophor® EL, HLB=12 to 14) and polyoxyl 40 castor oil having 40-45 moles of ethylene oxide (Cremophor® RH-40, HLB=14 to 16).
Surfactants
Exemplary surfactants are liquid and solid polyethoxylated esters of fatty acids, such as polyoxyl 40 stearate (Myrj® 52, hydrophobic-lipophilic balance (“HLB”)=17), PEG 400 monostearate, also known as polyoxyl 8 stearate (Myrj® 45, HLB=11), and PEG 660 hydroxystearate, also known as PEG 15 hydroxystearate (Solutol® HS15, HLB=14 to 16); polyethoxylated alkyl ethers, such as polyoxyl 10 oleyl ether (Brij® 97, HLB=12.4) and PEG 25 cetostearyl ether (Cremophor® A 25, HLB=15 to 17); polyethoxylated sorbitan esters, such as polysorbate 20 (Tween® 20, HLB=15) and polysorbate 80 (Tween® 80, HLB=11.5); polyethoxylated glyceryl esters having high HLB values (e.g., from 10 to 20), such as polyoxyl 35 castor oil (Cremophor® EL, HLB=12 to 14) and polyoxyl 40 castor oil having 40-45 moles of ethylene oxide (Cremophor® RH-40, HLB=14 to 16); polyethoxylated glyceryl esters of fatty acids having high HLB values (e.g., from 10 to 20), such as a mixture of PEG 6 caprylic/capric glyceryl esters having <2% C6/50%-80% C8/20%-50% C10/<3% C12/<1% C14 (Softigen® 767, HLB=19), a mixture of PEG 8 caprylic/capric glyceryl esters having 50%-80% C8/20%-50% C10/<3% C12/<1% C18 (Labrasol®, HLB=14), a mixture of PEG 32 lauryl glyceryl esters having 40%-50% C12/14%-24% C14/4%-10% C8/3-9% C10/4%-14% C16/5%-15% C18 (Gelucire® 44/14, HLB=14), and a mixture of PEG 32 stearyl glyceryl esters having 40%-50% C16/48%-58% C18 (Gelucire® 50/13, HLB=13); polyethoxylated vitamin analogs, such as D-alpha-tocopheryl PEG 1000 succinate (HLB=13); and ethoxylated propoxylated block copolymers having formula H(OCH2CH2)a(OCHCH3CH2)b(OCH2CH2)aOH, where a is about 12 and b is about 20 (Poloxamer® 124), where a is about 38 and b is about 29, where a is about 80 and b is about 27 (Poloxamer® 188), where a is about 64 and b is about 37 (Poloxamer® 237), where a is about 141 and b is about 44 (Poloxamer® 338), where a is about 49 and b is about 57, and where a is about 101 and b is about 56 (Poloxamer® 407).
Tocopheryl polyethylene glycol succinate (tocopheryl PEG-1000 succinate) and related pegylated vitamin E compounds can be used in the pharmaceutical composition of the invention. Tocopheryl PEG-1000 succinate has the following structure:




where n is an integer (e.g., the molecular weight is about 1513 for tocopheryl PEG-1000 succinate).

Related pegylated vitamin E compounds include additives formed using different diacid linkers, different length polyethylene glycol tails, and different isoforms (e.g. α-, β-, γ-, or δ-) of tocopherol, tocomonoenol, tocodienol, and tocotrienol. These include α-tocopherol, α-tocomonoenol, α-tocodienol, α-tocotrienol, β-tocopherol, β-tocomonoenol, β-tocodienol, β-tocotrienol, γ-tocopherol, γ-tocomonoenol, γ-tocodienol, γ-tocotrienol, δ-tocopherol, δ-tocomonoenol, δ-tocodienol, δ-tocotrienol, and any stereoisomer thereof. Suitable vitamin E compounds of the present invention also include desmethyl-tocopherol, desmethyl-tocomonoenol, desmethyl-tocodienol, desmethyl-tocotrienol, and any stereoisomer thereof. Furthermore, when a compound disclosed herein contains one or more chiral atoms where stereochemistry is unspecified, it will be understood that each stereoisomer of the compound is individually disclosed as if the structure of each stereoisomer were explicitly drawn. In certain embodiments of the invention, the vitamin E compound may be a naturally-occurring D-stereoisomer of vitamin E.
The vitamin E moieties of the present invention may be naturally occurring or synthetic. Certain embodiments of the invention include a naturally occurring vitamin E compound such as an extract from a food source. For example, α-tocopherol, α-tocotrienol, β-tocopherol, β-tocotrienol, γ-tocopherol, γ-tocotrienol, δ-tocopherol, and δ-tocotrienol are available naturally from fortified cereals, green vegetables, nuts, seeds, and vegetable oils. Methods of extracting vitamin E from natural sources have been described, for example, in U.S. Pat. Nos. 6,743,450; 6,838,104; 7,161,055; and 7,544,822, which are hereby incorporated by reference.
The pegylated vitamin E compound can include synthetic vitamin E moieties. An exemplary method for making α-tocopherol is the reaction of trimethylhydroquinone (TMHQ) with iso-phytol (3,7,11,15-tetramethylhexadec-1-en-3-ol) in a condensation reaction with a catalyst. It will be apparent to one skilled in the art that other tocopherol, tocomonoenol, tocodienol, and tocotrienol isoforms and their derivatives can also be prepared using a similar strategy starting from appropriate precursors. For example, the starting compounds may be TMHQ and 3,7,11,15-tetramethylhexadec-2-en-1-ol. An additional method of making vitamin E with isophytol under relatively mild conditions has been described by Wehrli et al., J. Org. Chem. 36:2910 (1971). Methods for synthesizing unsaturated side chains of vitamin E are described in U.S. Pat. No. 4,168,271, which is hereby incorporated by reference. Additional methods of synthesizing vitamin E side chains have been reviewed by Stalla-Bourdillon, Ind. Chim. Belg. 35, 13 (1970). Additional methods of synthesizing tocopherols are described in U.S. Pat. Nos. 5,523,420 and 6,005,122, each of which is incorporated herein by reference. Additional methods of synthesizing tocotrienols are described in U.S. Pat. No. 7,038,067, which is hereby incorporated by reference.
Pegylated vitamin E compounds can include different linkers, for example, dicarboxylic acids (e.g., succinic acid, sebacic acid, dodecanedioic acid, suberic acid, or azelaic acid, citraconic acid, methylcitraconic acid, itaconic acid, maleic acid, glutaric acid, glutaconic acid, fumaric acids, and phthalic acids). Exemplary tocopherol polyethylene glycol diesters are TPGS-1000, tocopherol sebacate polyethylene glycol, tocopherol dodecanodioate polyethylene glycol, tocopherol suberate polyethylene glycol, tocopherol azelaate polyethylene glycol, tocopherol citraconate polyethylene glycol, tocopherol methylcitraconate polyethylene glycol, tocopherol itaconate polyethylene glycol, tocopherol maleate polyethylene glycol, tocopherol glutarate polyethylene glycol, tocopherol glutaconate polyethylene glycol, and tocopherol phthalate polyethylene glycol.
The PEG moiety of the pegylated vitamin E compound can be any polyethylene glycol or derivative thereof, and can have a molecular weight of 200-6,000 kDa (e.g., 400-4,000 kDa, 500-2,000 kDa, 750-1,500 kDa, 800-1,200 kDa, 900-1,100 kDa, or about 1,000 kDa). PEG derivatives include, for example, methylated PEG, polypropylene glycol (PPG), PEG-NHS, PEG-aldehyde, PEG-SH, PEG-NH2, PEG-CO2H, PEG-OMe, as well as other ethers, branched PEGs, and PEG copolymers (e.g., PEG-b-PPG-b-PEG-1100, PEG-PPG-PEG-1900, PPG-PEG-MBE-1700, and PPG-PEG-PPG-2000).
Any known source of pegylated vitamin E compound can be used in the present invention. Pegylated vitamin E compounds typically have an HLB value of between about 16 and about 18 (e.g., between 18 and 18). An exemplary pegylated vitamin E compound is tocopheryl PEG-1000 succinate (also referred to herein as “TPGS 1000”), which has a PEG moiety having a molecular weight of 1,000 kDa. A food grade TPGS 1000 is available, for example, under the trade name Eastman Vitamin E TPGS® (Eastman Chemical Company, Kingsport, Tenn.). This TPGS is water-soluble form of natural-source vitamin E, which is prepared by esterification of crystalline D-α-tocopheryl acid succinate with polyethylene glycol 1000 (PEG 1000), and contains between 260 and 300 mg/g total tocopherol. Another exemplary pegylated vitamin E compound is Water Soluble Natural Vitamin E (ZMC-USA, The Woodlands, Tex.). Methods of preparing pegylated vitamin E compounds are described in U.S. Pat. Nos. 2,680,749 and 3,102,078 and in U.S. Publication Nos. 2007/0184117 and 2007/0141203, which are herein incorporated by reference.
Pegylated vitamin E compounds also include chromanol derivatives (e.g., 6-chromanol PEG-1000 succinate and 6-chromanol PEG-400 succinate), steroid derivatives (e.g., cholesteryl PEG-1000 succinate, cholic acid PEG-1000, dihydrocholic acid PEG-1000, litho-cholic acid PEG-1000, ursodeoxycholic acid PEG-1000, chenodeoxycholic acid PEG-1000), and others (e.g., indomethacin PEG-1000, chromone-2-carboxylic acid PEG-1000, chromone-2-carboxylic acid PEG-1100-OMe, chromone-2-carboxylic acid PEG-1500, chromone-2-carboxylic acid PEG-2000, naproxen PEG-1000, probenecid PEG-1000, 7-carboxymethoxy-4-methyl-coumarin PEG-1000, 5-(4-chlorophenyl)-2-furoic acid PEG-1000, probenecid tocopheryl PEG-1000 succinate, lithocholic acid PEG-1000, and chromone-3-carboxylic acid PEG-1000, 7-hydroxy-coumarinyl-4-acetic acid PEG-1000).
Pharmaceutically Acceptable Excipients
Pharmaceutically acceptable excipients include one or more other ingredient capable of maintaining compound 1, compound 2, or a salt thereof, in a substantially amorphous form. In particular embodiments, the excipient is a pharmaceutically acceptable matrix polymer, as described herein.
Exemplary excipients are antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, and waters of hydration. Additional non-limiting exemplary excipients are: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.
These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, kaolin, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, and sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, and alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, and polyethylene glycol); and lubricants, glidants, and antiadhesives (e.g., magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumurate, sodium lauryl sulfate, stearic acid, silicas, hydrogenated vegetable oils, and talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.
Methods of Making Solid Dispersion Systems
The pharmaceutical composition including the solid dispersion (e.g., a spray dried dispersion (SDD) or a hot melt extrusion (HME)) can be made using any useful method. Generally, one or more matrix polymers and compound 1, compound 2, or a salt thereof, are combined either with or without a solvent (e.g., one or more of dimethyl acetamide, dimethyl formamide, pyrrolidone, methylpyrrolidone, methanol, ethanol, and acetone) to form a mixture (e.g., a liquid mixture) or a solution. Optionally, the matrix polymer and compound 1 or compound 2, either with or without additional excipients, can be heated near or past the glass transition temperature Tg or melting temperature Tm to form a liquid mixture. Then, the resultant solution can be spray dried to form a solid dispersion. Alternatively, the method includes a hot-melt extrusion process, where the mixture is heated to form a homogenous molten mass, extruded, and cooled to form a solid dispersion. The extrudates can optionally be pelletized or milled to form a solid dispersion amenable for further processing in a suitable unit dosage form.
Finally, the solid dispersion is used for filling any one of the unit dosage forms described herein (e.g., a capsule) or for tabletting. The solid dispersion can optionally be further processed before filling or tabletting. Exemplary further processing includes spheronizing, pelletizing, milling, injection molding, sieving, and/or calendaring the solid dispersion.
Spray Dried Processes
The compositions of the invention can be prepared by any useful process, such as spray drying to form a spray dried dispersion (SDD). In one example, one or more matrix polymers and compound 1 or compound 2 are combined with one or more solvents (e.g., acetone) to form a solution having about 4% (w/w) to about 15% (w/w) of total solids. Percentage (w/w) total solids is determined by dividing the total mass of the compound and one or more matrix polymers by the total mass of the compound, one or more matrix polymers, and one or more solvents. The solution can then be spray dried to form a SDD, which can optionally be further drying steps. In particular embodiments, the SDD includes about 20% (w/w) of compound 1 or compound 2 with the one or more matrix polymers (i.e., the weight ratio of compound 1 or compound 2 to the matrix polymer is about 1:4).
For example, to produce a 20% (w/w) compound 1 in a SDD, a solution was prepared having about 2% (w/w) compound 1 and about 8% (w/w) of a pharmaceutically acceptable matrix polymer or a combination of a pharmaceutically acceptable matrix polymer in acetone. The solution was then spray dried at the appropriate temperature (e.g., between about 95° C. and 110° C. for HPMCAS at the appropriate solution flow rate).
Exemplary matrix polymers for SDD include a cellulose derivative, such as HPMCAS, e.g., type MG or MF, or CAP; and a polyvinyl acetate, such as PVAP.
The resultant SDD can be blended with one or more excipients, as described herein, and then granulated and/or compacted to produce a final blend for encapsulating or tabletting. In particular embodiments, the one or more excipients include a binding agent, a filler, a disintegrating agent, a wetting agent, a glidant, and a lubricant.
Hot Melt Extrusion Processes
In some embodiments, the compositions of the invention are prepared by hot melt extrusion (HME). In one example, one or more matrix polymers and compound 1 or compound 2 are combined to form a mixture, where this mixture can optionally include a surfactant. The mixture can then be fed into a pre-heated extruder (e.g., an extruder having temperature zones between about 75° C. to about 145° C.) to produce an initial extrudate. The extrudate is then pelletized and milled (e.g., to a size less than about 500 μm) to produce a fine milled extrudate.
For example, to produce a 20% (w/w) compound 1 extrudate, a pre-blend was prepared having 20% (w/w) compound 1 and 80% (w/w) of a pharmaceutically acceptable matrix polymer or a combination of a pharmaceutically acceptable matrix polymer with a surfactant (e.g., any pharmaceutically acceptable matrix polymer and/or surfactant described herein, e.g., a combination of 75% (w/w) HPMCAS-MF with 5% (w/w) vitamin E TPGS). Any component of the pre-blend can be pre-milled or pre-sieved. For example, the pharmaceutically acceptable matrix polymer and/or surfactant can be milled through a bar rotor and rasping screen to reduce particle size (e.g., reduce down to ≦600 microns); and/or compound 1 can be pre-sieved. Then, the pre-blend was processed using a co-rotating twin screw extruder, and the resultant extrudate was processed further by milling (pelletizing) to reduce its particle size (e.g., ≦500 microns). The milled/pelletized extrudate was sieved and blended with various pharmaceutically acceptable excipients (e.g., any described herein), where the resultant blend was then co-milled. The co-milled blend can be further processed by adding a lubricant (e.g., magnesium stearate), and the resultant, processed blend can be used to fill a unit dosage form (e.g., a capsule).
Matrix polymers for hot melt extrusion include a cellulose derivative, such as HPMCAS, e.g., type MG or MF; a polyvinyl pyrrolidone (PVP), such as povidone having a molecular weight of about 50,000 (Kollidon®30, weight-average molecular weight between 44,000 to 54,000); a polyvinyl acetate; or a copolymer of a polyvinyl pyrrolidone and a polyvinyl acetate (PVP-VA), such as those having a 60:40 ratio of N-vinyl-2-pyrrolidone to vinyl acetate (copovidone, also available as Kollidon® VA 64) and a 20:80 ratio of N-vinyl-2-pyrrolidone to vinyl acetate (Kollidon® SR).
In particular embodiments, any surfactant or wetting agent described herein can be included in the mixture to enhance dissolution and/or enhance stability. An exemplary surfactant includes a pegylated vitamin E compound, such as any described herein (e.g., D-alpha-tocopheryl PEG 1000 succinate), in a useful amount (e.g., from about 3% to about 10% (w/w), e.g., about 5% (w/w)).
The resultant extrudate can be blended with one or more excipients, as described herein, and then milled, blended, granulated and/or compacted to produce a final blend for encapsulating or tabletting. In particular embodiments, the one or more excipients include a binding agent, a filler, a surfactant (e.g., a pegylated vitamin E compound), a disintegrating agent, a wetting agent, a glidant, and a lubricant.
Dosage and Administration
For administration to animal or human subjects, the dosage of compound 1, compound 2, or a salt thereof, is typically 0.1 to 15 mg/kg, more preferably 3 to 5 mg/kg. However, dosage levels can be highly dependent on the nature of the condition, drug efficacy, the condition of the patient, the judgment of the practitioner, and the frequency and mode of administration.
Compound 1, compound 2, or a salt thereof, is preferably provided in a therapeutically effective amount, which may be, for example, a daily amount of from 25 mg to 1,600 mg, more preferably 40 mg to 800 mg, and even more preferably 80 mg to 320 mg. In one embodiment, a pharmaceutical composition comprising a compound 1, compound 2, or a salt thereof, comprises a capsule, for example in unit dosage form having from 20 mg to 250 mg of compound 1, compound 2, or a salt thereof, (e.g., from 20 mg to 250 mg, such as from 20 mg to 30 mg, from 20 mg to 40 mg, from 20 mg to 50 mg, from 20 mg to 75 mg, from 20 mg to 100 mg, from 20 mg to 125 mg, from 20 mg to 150 mg, from 20 mg to 175 mg, from 20 mg to 200 mg, from 20 mg to 225 mg, from 30 mg to 40 mg, from 30 mg to 50 mg, from 30 mg to 75 mg, from 30 mg to 100 mg, from 30 mg to 125 mg, from 30 mg to 150 mg, from 30 mg to 175 mg, from 30 mg to 200 mg, from 30 mg to 225 mg, from 30 mg to 250 mg, from 40 mg to 50 mg, from 40 mg to 75 mg, from 40 mg to 100 mg, from 40 mg to 125 mg, from 40 mg to 150 mg, from 40 mg to 175 mg, from 40 mg to 200 mg, from 40 mg to 225 mg, from 40 mg to 250 mg, from 50 mg to 75 mg, from 50 mg to 100 mg, from 50 mg to 125 mg, from 50 mg to 150 mg, from 50 mg to 175 mg, from 50 mg to 200 mg, from 50 mg to 225 mg, from 50 mg to 250 mg, from 60 mg to 75 mg, from 60 mg to 100 mg, from 60 mg to 125 mg, from 60 mg to 150 mg, from 60 mg to 175 mg, from 60 mg to 200 mg, from 60 mg to 225 mg, from 60 mg to 250 mg, from 70 mg to 75 mg, from 70 mg to 100 mg, from 70 mg to 125 mg, from 70 mg to 150 mg, from 70 mg to 175 mg, from 70 mg to 200 mg, from 70 mg to 225 mg, from 70 mg to 250 mg, from 80 mg to 100 mg, from 80 mg to 125 mg, from 80 mg to 150 mg, from 80 mg to 175 mg, from 80 mg to 200 mg, from 80 mg to 225 mg, from 80 mg to 250 mg, from 90 mg to 100 mg, from 90 mg to 125 mg, from 90 mg to 150 mg, from 90 mg to 175 mg, from 90 mg to 200 mg, from 90 mg to 225 mg, from 90 mg to 250 mg, from 100 mg to 125 mg, from 100 mg to 150 mg, from 100 mg to 175 mg, from 100 mg to 200 mg, from 100 mg to 225 mg, and from 100 mg to 250 mg). These unit dosage forms can be administered to achieve any daily amount described herein, such as by administering one to five times daily (e.g., one, two, three, four, or five times daily).
Unit Dosage Forms
For use as treatment of human and animal subjects, compound 1, compound 2, or a salt thereof, can be formulated as pharmaceutical or veterinary compositions. Depending on the subject to be treated, the mode of administration, and the type of treatment desired (e.g., prevention, prophylaxis, or therapy) the compounds are formulated in ways consonant with these parameters. A summary of such techniques is found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, (2005); and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, each of which is incorporated herein by reference.
Compound 1, compound 2, or a salt thereof, may be present in amounts totaling 1-95% by weight of the total weight of the composition. The composition including compound 1, compound 2, or a salt thereof, and a pharmaceutically acceptable matrix polymer may be provided in a dosage form that is suitable for oral administration. Alternatively, the unit dosage form of the invention includes substantially amorphous compound 1, compound 2, or a salt thereof, and a pharmaceutically acceptable excipient (e.g., fillers, diluents, lubricants, and/or glidants). Thus, the pharmaceutical composition may be in the form of, e.g., hard capsules (e.g., hard gelatin capsules or hard hydroxypropyl methylcellulose capsules), soft gelatin capsules, tablets, caplets, enteric coated tablets, chewable tablets, enteric coated hard gelatin capsules, enteric coated soft gelatin capsules, minicapsules, lozenges, films, strips, gelcaps, dragees, suspensions, syrups, or sprinkles. The compositions may be formulated according to conventional pharmaceutical practice.
In particular embodiments, compound 1, compound 2, or a salt thereof, and a matrix polymer are included in a capsule or compressed into a tablet. Compound 1, compound 2, or a salt thereof, in combination with a matrix polymer can be in any form, such as a semi-solid suspension, a solid suspension, a homogenous melt, solid particles, or semi-solid particles. The form of the compound 1, compound 2, or a salt thereof, can be determined based on dose. For example, a capsule filled with a solid dispersion can be used for approximately 10-50% drug loading.
Exemplary unit dosage forms are hard capsules (e.g., hard gelatin capsules or hard hydroxypropyl methylcellulose capsules) and soft gelatin capsules. When soft gelatin capsules are used, it is preferred that when a composition contains a polyethylene glycol, the composition of the soft gelatin capsule shell contains a humectant, for example, sorbitol, to prevent brittleness of the soft gelatin capsule.
Utility and Treatment of Conditions
Conditions that can be treated using the compositions or formulations described herein include pain (e.g., chronic or acute pain), epilepsy, Alzheimer's disease, Parkinson's disease, diabetes, cancer, sleep disorders, obesity, mood disorders, psychosis such as schizophrenia, tinnitus, amyotrophic lateral sclerosis, glaucoma, ischaemia, spasticity disorders, obsessive compulsive disorder, restless leg syndrome, Tourette syndrome, overactive bladder, renal disease, neuroprotection, and addiction. For example, the condition can be pain (e.g., neuropathic pain or post-surgery pain), epilepsy, migraine, Parkinson's disease, depression, schizophrenia, psychosis, or tinnitus.
Epilepsy as used herein includes but is not limited to partial seizures such as temporal lobe epilepsy, absence seizures, generalized seizures, and tonic/clonic seizures.
Cancer as used herein includes but is not limited to breast carcinoma, neuroblastoma, retinoblastoma, glioma, prostate carcinoma, esophageal carcinoma, fibrosarcoma, colorectal carcinoma, pheochromocytoma, adenocarcinoma, insulinoma, lung carcinoma, melanoma, and ovarian cancer.
Acute pain as used herein includes but is not limited to nociceptive pain and post-operative pain. Chronic pain includes, but is not limited to, neuropathic pain, peripheral neuropathic pain such as post-herpetic neuralgia, diabetic neuropathic pain, neuropathic cancer pain, HIV-associated neuropathy, erythromelalgia, failed back-surgery syndrome, trigeminal neuralgia, and phantom limb pain; central neuropathic pain such as multiple sclerosis related pain, Parkinson disease related pain, post-stroke pain, post-traumatic spinal cord injury pain, lumbosacral radiculopathy, cervical radiculopathy, brachial radiculopathy, and pain in dementia; musculoskeletal pain such as osteoarthritic pain and fibromyalgia syndrome; inflammatory pain such as rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease, primary dysmenorrhea, and endometriosis; headache such as migraine, cluster headache, tension headache syndrome, facial pain, and headache caused by other diseases; visceral pain such as interstitial cystitis, irritable bowel syndrome, and chronic pelvic pain syndrome; and mixed pain such as lower back pain, neck and shoulder pain, burning mouth syndrome, and complex regional pain syndrome.
In treating osteoarthritic pain, joint mobility can also improve as the underlying chronic pain is reduced. Thus, use of compositions and formulations of the present invention to treat osteoarthritic pain includes use of such compositions or formulations to improve joint mobility in patients suffering from osteoarthritis or other condition presenting with decreased joint mobility.
The compositions and formulations described herein can be tested for efficacy in any standard animal model of pain. Various models test the sensitivity of normal animals to intense or noxious stimuli (physiological or nociceptive pain). These tests include responses to thermal, mechanical, or chemical stimuli. Thermal stimuli usually involve the application of hot stimuli (typically varying between 42-55° C.) including, for example: radiant heat to the tail (the tail flick test), radiant heat to the plantar surface of the hindpaw (the Hargreaves test), the hotplate test, and immersion of the hindpaw or tail into hot water. Immersion in cold water, acetone evaporation, or cold plate tests may also be used to test cold pain responsiveness. Tests involving mechanical stimuli typically measure the threshold for eliciting a withdrawal reflex of the hindpaw to graded strength monofilament von Frey hairs or to a sustained pressure stimulus to a paw (e.g., the Ugo Basile analgesiometer). The duration of a response to a standard pinprick may also be measured. When using a chemical stimulus, the response to the application or injection of a chemical irritant (e.g., capsaicin, mustard oil, bradykinin, ATP, formalin, or acetic acid) to the skin, muscle joints, or internal organs (e.g., bladder or peritoneum) is measured.
In addition, various tests assess pain sensitization by measuring changes in the excitability of the peripheral or central components of the pain neural pathway. In this regard, peripheral sensitization (i.e., changes in the threshold and responsiveness of high threshold nociceptors) can be induced by repeated heat stimuli as well as the application or injection of sensitizing chemicals (e.g., prostaglandins, bradykinin, histamine, serotonin, capsaicin, or mustard oil). Central sensitization (i.e., changes in the excitability of neurons in the central nervous system induced by activity in peripheral pain fibers) can be induced by noxious stimuli (e.g., heat), chemical stimuli (e.g., injection or application of chemical irritants), or electrical activation of sensory fibers.
Various pain tests developed to measure the effect of peripheral inflammation on pain sensitivity can also be used to study the efficacy of the compositions (Stein et al., Pharmacol. Biochem. Behay. 31: 445-451, 1988; Woolf et al., Neurosci. 62:327-331, 1994). Additionally, various tests assess peripheral neuropathic pain using lesions of the peripheral nervous system. One such example is the “axotomy pain model” (Watson, J. Physiol. 231:41, 1973). Other similar tests include the SNL test which involves the ligation of a spinal segmental nerve (Kim and Chung, Pain 50: 355, 1992), the Seltzer model involving partial nerve injury (Seltzer, Pain 43: 205-18, 1990), the spared nerve injury (SNI) model (Decosterd and Woolf, Pain 87:149, 2000), chronic constriction injury (CCl) model (Bennett, Muscle Nerve 16:1040, 1993), tests involving toxic neuropathies such as diabetes (streptozocin model), pyridoxine neuropathy, taxol, vincristine, and other antineoplastic agent-induced neuropathies, tests involving ischemia to a nerve, peripheral neuritis models (e.g., CFA applied peri-neurally), models of post-herpetic neuralgia using HSV infection, and compression models.
In all of the above tests, outcome measures may be assessed, for example, according to behavior, electrophysiology, neurochemistry, or imaging techniques to detect changes in neural activity.
EXAMPLES
Example 1
In Vitro Absorption of Compound 1
Absorption of particular drugs may be limited by biological factors, such as reduced cellular permeability in the intestine. Many cellular mechanisms can influence permeability, such as reduced passive paracellular and transcellular transport or increased active export by the efflux transporter protein P-glycoprotein. Thus, the use of self-emulsifying carriers may not be beneficial for drugs having limited cellular permeability, where methods to increase the solubilization of a drug may not increase its permeability in the gastrointestinal tract. Experiments were conducted to assess the apparent intestinal permeability of compound 1 using a Caco-2 cell model. Overall, the data herein suggest that compound 1 is not limited by permeability in the intestine, and formulations that promote delivery of compound 1 to the gastrointestinal tract may reduce food effects or increase bioavailability.
Briefly, Caco-2 cells were used as an in vitro model for predicting absorption through the intestinal epithelium. Confluent monolayers of Caco-2 cells were grown on collagen-coated, microporous, polycarbonate membranes (12-well Costar Transwell® plates) that are placed between two chambers. The apical side of the monolayer was exposed to the buffer solution in a first chamber, but the basolateral side of the monolayer adhered to microporous membranes fluidically connected to a second chamber. The dosing solution was added to the first chamber for measurements in the apical-to-basolateral direction (A-to-B) and to the second chamber for measurements in the basolateral-to-apical direction (B-to-A). Accordingly, for A-to-B measurements, the first chamber was the receiver chamber and the second chamber was the donor chamber; for B-to-A measurements, the first chamber was the donor chamber and the second chamber was the receiver chamber. The permeability assay buffer was Hanks Balanced Salt Solution containing 10 mM HEPES and 15 mM glucose at a pH of 7.4. The buffer in the receiver chamber also contained 1% bovine serum albumin. The dosing solution concentration was 1 μM of compound 1 in the assay buffer. All donor chambers were first pre-incubated for five minutes with dosing solution to attempt to saturate any non-specific binding sites on the device with test compound. After five minutes, the solution was removed and replaced with fresh dosing solution, and time was recorded as 0. Cell monolayers were dosed on the apical side/first chamber (for A-to-B measurements) or basolateral side/second chamber (for B-to-A measurements) and incubated at 37° C. with 5% CO2 in a humidified incubator. At 30 and 60 minutes, aliquots were taken from the receiver chambers and replaced with fresh assay buffer. Samples were taken from the donor chamber at 0 and 60 minutes. Each experiment was performed in triplicate.
The apparent permeability (Papp), percent recovery, and efflux ratio were calculated as follows:



  
    
      
        
          P
          app
        
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            ⁢
            
              
            
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    ,
    
      

    
    ⁢
    
      
        Percent
        ⁢
        
          
        
        ⁢
        
          recovery
          ⁢
          
            
          
          [
          %
          ]
        
      
      =
      
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        ×
        
          
            
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                  r
                
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                    r
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                    final
                  
                
              
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    ,
    and
  




  
    
      
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        ⁢
        
          
        
        ⁢
        ratio
      
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    ,
  



where





  
    
      d
      Cr
    
    
      d
      t
    
  
  ⁡
  
    [
    
      μ
      ⁢
      
        
      
      ⁢
      M
      ⁢
      
        
      
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    ]
  




is the slope of the cumulative concentration in the receiver chamber as a function of time; Vr [cm3] is the volume of the receiver chamber; Vd [cm3] is the volume of the donor chamber; A [cm2] is the area of the cell monolayer, which is estimated to be about 1.13 cm2 for the 12-well Costar Transwell® plates; C0 [μM] is the measured concentration in the donor chamber at t=0 hours; CN [μM] is the nominal concentration of the dosing solution; Cr final [μM] is the cumulative concentration in the receiver chamber at the end of the incubation period; and Cd final [μM] is the cumulative concentration in the donor chamber at the end of the incubation period.

Table 2 shows the apparent permeability for the apical-to-basolateral direction (A-to-B), the basolateral-to-apical direction (B-to-A), and cell-free condition. Compound 1 was classified as having a high permeability coefficient, due to an apparent permeability value Papp(A-to-B) more than 1.0×10−6 cm/s. Efflux of compound 1 was not considered significant, due to an efflux ratio of less than 3. Thus, absorption of compound 1 in humans is not expected to be permeability limited.












TABLE 2










Percent

Efflux Ratio



Initial Donor
Recovery
Papp (10−6 cm/s)
(Papp(B-to-A)/Papp














Direction
Conc. (μM)
(%)
R1
R2
R3
Avg.
(A-to-B))





A-to-B
0.69
28
4.37
4.31
6.78
5.15
0.8


B-to-A
0.59
37
5.04
3.48
4.45
4.32


Cell-free
0.68
54
1.71
2.21
1.69
1.87









Example 2
Solubility of Solid Dispersion Formulations in Gastric and Intestinal Media
Eight solid dispersion formulations were tested at 20% (w/w) loading of compound 1. As shown in FIG. 1A, unformulated compound 1 rapidly precipitated from the FaSSIF media following exposure to gastric media.
Various formulations were tested to reduce precipitation. As shown in FIGS. 1A-1H, solubility was measured for the following formulations: carboxymethylethyl cellulose (CMEC, FIG. 1A), cellulose acetate phthalate (CAP, FIG. 1B), hydroxypropylmethyl cellulose acetate succinate M grade (HPMCAS-M, FIG. 1C), polyvinyl acetate phthalate (PVAP, FIG. 1D), methacrylic acid-methyl methacrylate copolymer (Eudragit® L 100, FIG. 1E), polyethylene glycol-polyvinylcaprolactam-polyvinylacetate copolymer (Soluplus®, FIG. 1F), hydroxypropylmethyl cellulose phthalate (HPMCP-H55, FIG. 1G), and polyvinylpyrrolidone vinylacetate copolymer (PVP-VA, FIG. 1H). At approximately 13 minutes, the media was transferred from gastric media (pH of 1.0) to Fasted State Simulated Intestinal Fluid media (FaSSIF media, pH of 6.5).
In all instances, the solid dispersion formulations provided improvements in solubility of compound 1. Dispersions having the highest Cmax included CMEC, CAP, HPMCAS-M, PVAP, and Eudragit® L 100 (FIGS. 1A-1E). Among these, PVAP had the fastest precipitation rate, and HPMCAS-M and Eudragit® L 100 had the slowest dissolution rates.
Further tests were conducted with different % loading of compound 1. Dissolution rates were measured for formulations have 35% (w/w) loading (FIGS. 2A-2C) and 50% (w/w) loading (FIGS. 3A-3D). CAP, HPMCAS-M, Eudragit® L 100, and PVAP were further analyzed for these tests. Generally, increased % loading exhibited lower free drug concentrations in the media (shown as open circles). Without wishing to be limited by theory, as % loading increases, the amount of matrix polymer needed to inhibit precipitation of compound 1 also increases. Overall, dissolution rates for 35% and 50% loading were comparable to those for 20% loading of the same polymers, and PVAP provided the highest Cmax and the most rapid precipitation.
Physiological-based pharmacokinetic (PBPK) modeling (GastroPlus® v.6.1) was conducted to predict the in vivo fraction absorbed and the fed-fasted ratio at 10 mg/kg and 100 mg/kg doses. These predictive estimates are provided for fraction absorbed (FIG. 4A) and fed-fasted ratio (FIG. 4B) for 20%, 35%, and 50% (w/w) loading of compound 1. These data suggest enhanced absorption and reduced fed-fasted ratio for a range of formulations at 20% and 35% loading of compound 1.
Example 3
Solubility of Formulations 1 and 2
Based on the dissolution data provided herein, formulations for 20% (w/w) loading of formula 1 in CAP (formulation 1) and HPMCAS-M (formulation 2) were further tested with media transition times longer than 13 minutes to better represent human physiological gastric emptying times. At approximately 30 minutes, the media was transferred from gastric media (pH of 1.0) to Fasted State Simulated Intestinal Fluid media (FaSSIF media, pH of 6.5). FIGS. 5A-5B show that formulations 1 and 2 performed similarly to experiments performed at shorter times.
Example 4
Physical Characterization of Formulations
Various solid dispersion formulations were tested using modulated differential scanning calorimetry (MDSC). MDSC measurements provide glass transition temperature Tg values, which can be used to understand the molecular mobility of a drug within the dispersion. FIG. 6 shows the MDSC traces and Tg values for CMEC, HPMCAS-M, CAP, and PVAP formulations having 20% (w/w) loading of compound 1. Data for Eudragit® L 100 are not shown, but Tg is likely greater than 150° C. due to polymer degradation above this temperature. All recorded Tg values were at least twice as high as compound 1 alone (Tg=41.6° C.). Lower Tg values could indicate potential stability issues over long periods of time or at an increased temperature or pressure. Table 3 provides Tg values for CAP (formulation 1), HPMCAS-M (formulation 2), and PVAP.










TABLE 3






Percentage (w/w)
Tg (° C.)
Tg (° C.)



of compound 1
at ambient
at 75%


Formulation
with polymer
relative humidity
relative humidity







CAP
20
130-132
83


(formulation 1)
35
116
N.D.



50
N.D.
N.D.


HPMCAS-M
20
88-91
54


(formulation 2)
35
63
N.D.



50
55
N.D.


PVAP
20
116
N.D.



35
106
N.D.



50
90
N.D.





N.D.: not determined






Formulations having CAP and HPMCAS-M were further analyzed using powder X-ray diffraction (PXRD). As shown in FIG. 7, no evidence of crystalline compound 1 was detected in either formulation 1 or 2.
Example 5
In Vivo Study in Rats
The pharmacokinetics of formulations having 20% (w/w) of compound 1 in matrix polymer were studied in rats. Table 4 provides a summary of the results for this in vivo study. Formulation 1 is 20% (w/w) of compound 1 in CAP. Formulation 2 is 20% (w/w) compound 1 in HPMCAS-M. Control indicates compound 1 in 0.5% Tween® 80 in 0.5% carboxy methylcellulose (CMC). Doses included 10 to 100 mg of compound 1 to kg of the subject (mg/kg).













TABLE 4







Cmax
Tmax
t1/2
AUC∞
AUC0-last




(ng/mL,
(hr,
(hr,
(h * mg/mL,
(h * mg/mL,


Dose
Formulation
mean)
mean)
mean)
mean)
mean)





















 10 mg/kg
Control
89
3.33
1.54
503
466


dose
1 (CAP)
82.0
6.67
1.99
540
385



2 (HPMCAS-M)
157
4.67
2.15
914
732


 30 mg/kg
Control
152
3.33
4.07
1262
831


dose
1 (CAP)
392
3.33
2.07
2215
1925



2 (HPMCAS-M)
417
3.00
4.18
3970
2449


100 mg/kg
Control
450
5.33
3.22
3461
2155


dose
1 (CAP)
591
2.67
4.06
5179
3807



2 (HPMCAS-M)
714
3.00
2.64
4628
3667









Data for each animal are provided for formulation 1 (Table 5 and FIG. 8A), formulation 2 (Table 6 and FIG. 8B), and control (Table 7 and FIG. 8C) for three doses. FIGS. 9A-9C provides data for these formulations for each dose. Overall, both formulations 1 and 2 showed enhanced oral bioavailability of compound 1, compared to control.








TABLE 5







Dose of



Form-


ulation 1


(CAP)
Pharmacokinetic parameters













(20%

Cmax
Tmax
t1/2
AUC∞
AUC0-last


(w/w))
Animal
(ng/mL)
(hr)
(hr)
(h * ng/mL)
(h * ng/mL)
















 10 mg/kg
10
70.8
8.00
NC
NC
336



11
72.1
6.00
1.75
451
369



12
103
6.00
2.23
629
451



Mean
82.0
6.67
1.99
540
385



SD
18.2
1.15
0.341
126
59.5



SEM
10.5
0.667
0.241
89.1
34.4


 30 mg/kg
13
361
2.00
1.74
1912
1778



14
492
4.00
1.18
2191
2111



15
324
4.00
3.28
2542
1885



Mean
392
3.33
2.07
2215
1925



SD
88.3
1.15
1.08
316
170



SEM
51.0
0.667
0.626
182
97.9


100 mg/kg
16
661
2.00
4.06
5179
3633



17
540
4.00
NC
NC
3709



18
572
2.00
NC
NC
4080



Mean
591
2.67
4.06
5179
3807



SD
62.7
1.15
n/a
n/a
239



SEM
36.2
0.667
n/a
n/a
138


















TABLE 6







Dose of




Formulation 2

Pharmacokinetic parameters













(HPMCAS-M)

Cmax
Tmax
t1/2
AUC∞
AUC0-last


(20% (w/w))
Animal
(ng/mL)
(hr)
(hr)
(h * ng/mL)
(h * ng/mL)
















10 mg/kg
19
119
6.00
2.09
690
505



20
174
2.00
2.25
845
762



21
178
6.00
2.10
1206
928



Mean
157
4.67
2.15
914
732



SD
33.0
2.31
0.0868
265
213



SEM
19.0
1.33
0.0501
153
123


30 mg/kg
22
342
1.00
2.10
2068
1845



23
468
4.00
8.15
6620
2706



24
440
4.00
2.27
3222
2795



Mean
417
3.00
4.18
3970
2449



SD
66.2
1.73
3.44
2366
525



SEM
38.2
1.00
1.99
1366
303


100 mg/kg 
25
574
6.00
2.74
5112
3745



26
893
2.00
2.55
4143
3479



27
674
1.00
NC
NC
3778



Mean
714
3.00
2.64
4628
3667



SD
163
2.65
0.136
685
164



SEM
94.2
1.53
0.0963
484
94.8


















TABLE 7









Pharmacokinetic parameters













Dose of

Cmax
Tmax
t1/2
AUC∞
AUC0-last


Control
Animal
(ng/mL)
(hr)
(hr)
(h * ng/mL)
(h * ng/mL)
















 10 mg/kg
1
96.7
6.00
0.858
558
534



2
110
2.00
1.65
559
517



3
60.6
2.00
2.13
391
346



Mean
89
3.33
1.54
503
466



SD
26
2.3
0.64
97.0
104



SEM
15
1.3
0.37
56.0
60.0


 30 mg/kg
4
125
2.00
8.28
1888
845



5
169
4.00
1.34
898
857



6
162
4.00
2.59
998
790



Mean
152
3.33
4.07
1262
831



SD
23.6
1.15
3.70
545
35.3



SEM
13.7
0.667
2.14
315
20.4


100 mg/kg
7
434
4.00
2.88
2812
2121



8
361
6.00
2.49
2637
1893



9
554
6.00
4.29
4934
2453



Mean
450
5.33
3.22
3461
2155



SD
97.4
1.15
0.945
1279
282



SEM
56.3
0.667
0.545
738
163









Example 6
In Vivo Study in Dogs
The pharmacokinetics of formulations 1 and 2 were studied in dogs using a dosage of 10 mg/kg (mg of compound 1/kg of subject). Table 8 provides a summary of the results for this in vivo study. Control indicates compound 1HCl in 0.5% Tween 80 in 0.5% CMC. FIG. 10 shows enhanced oral bioavailability for formulations 1 and 2.
















TABLE 8









Tmax
t1/2
Cmax
AUC0-last
AUC0-24
AUC∞



Animal
Rsq
(hr)
(hr)
(ng/mL)
(hr * ng/mL)
(hr * ng/mL)
(hr * ng/mL)
























Group 1
1311019
NC
1
NC
  14.4
   7.82
  15.0
NC


(control)
1311108
0.03
2
NR
111
470
470
NR



1457366
NC
1
NC
  17.3
131
131
NC



Mean
0.03
  1.3
NC
  47.6
203
205
NC



SD
NA
  0.6
NA
 55
239
236
NA


Group 2
1376382
0.99
1
8.9
603
1740 
1740 
1820


(formulation 2
1401603
0.25
1
NR
160
800
800
NR


(HPMCAS-M))
1408951
0.96
2
12.8 
300
1230 
1230 
1480



Mean
0.73
  1.3
10.9 
354
1260 
1260 
1650



SD
0.41
  0.6
NA
226
472
472
NA


Group 3
1296265
0.88
1
1.5
169
384
399
 400


(formulation 1
1502906
0.14
2
NR
135
600
600
NR


(CAP))
5955823
0.43
1
NR
254
1330 
1330 
NR



Mean
0.48
  1.3
1.5
186
773
777
 400



SD
0.37
  0.6
NA
  61.3
498
492
NA





NC = Not calculated by WinNonlin due to insufficient data points for elimination phase.


NR = Not reported, due to poor goodness-of-fit (R2 < 0.8) for elimination phase.






In Table 8 above, the AUC0-24 was about six times greater for Group 2 (HPMCAS) and more than three times greater for Group 3 (CAP), as compared to Group 1 (control).
Example 7
Phase 1 (part 1) Study in Healthy Human Subjects
The pharmacokinetics of a spray dried dispersion (SDD) formulation having HPMCAS were studied in healthy, human subjects using an oral dosage of 225 mg of compound 1 (three 75-mg capsules).
Compound 1 (free base) was supplied in #00 white opaque hard gelatin shell capsules. Each capsule contained 75 mg of compound 1 (free base) in hypromellose acetate succinate (HPMCAS-MG) as a spray dried dispersion, which was dry blended with lactose, microcrystalline cellulose, sodium lauryl sulphate, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate. The spray dried dispersion was prepared by using a solution of compound 1 with hypromellose acetate succinate, grade MG (HPMCAS-MG), with acetone as the spray drying solvent. The quantitative composition of these SDD capsules is shown in Table 9.










TABLE 9








Quantity per


Component
Function
Standard
Capsule (mg)


















compound 1 (free base)
API
C of A
75.00


Hypromellose acetate
Polymer component of
Ph. Eur., NF, JP
300.00


succinate Type MG
the solid dispersion


Lactose monohydrate
Binder-Filler
Ph. Eur., NF, JP
38.24


Microcrystalline cellulose
Binder-Filler
Ph. Eur., NF, JP
78.24


Croscarmellose sodium
Disintegrant
Ph. Eur., NF, JP
17.00


Sodium lauryl sulphate
Wetting agent
Ph. Eur., NF, JP
4.24


Colloidal silicon dioxide
Flow aid/Glidant
NF
2.14


Magnesium stearate
Lubricant
Ph. Eur., NF, JP
2.14


Capsule Shell, hard gelatin
Dosage form

na


white opaque size 00







Total Fill Weight:
517.0





Abbreviations: API = Active Pharmaceutical Ingredient; C of A—Certificate of Analysis; Ph. Eur. = European Pharmacopoeia; NF = National Formulary; JP = Japanese Pharmacopeia






This single-center, open-label, crossover design study was conducted to determine the relative bioavailability, safety, and tolerability of the oral, SDD formulation under fasted and fed conditions in healthy subjects. The study comprised of an up to 21-day screening period, two 4-day inpatient clinic stays, and 35-days outpatient follow-up period. Sixteen subjects were randomized to the fed state or fasted state.
On Day 1 in Period 1, subjects received capsules either in the fasted state (defined as no food consumption for 10 hours and no water for 2 hours prior to oral dosing) or the fed state (defined as consumption of a high-fat meal 30 minutes prior to oral dosing and must completely consume the meal before taking the capsules). Subjects were administered 225 mg of compound 1 in capsules. Immediately prior to dosing, vital signs were measured, a 12-lead ECG was obtained, and a pharmacokinetics (PK) blood sample was obtained. Subjects were then administered 225 mg of compound 1. Blood samples for PK determinations were obtained at 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 16 hours post-oral dose; vital signs and 12-lead ECGs were obtained at 3, 4, and 5 hours post-dose; and any concomitant medications and adverse events (AE) were recorded.
During Days 1-4 (inpatient period) and Days 5-6 (outpatient period) in Period 1, blood samples for PK determinations, vital signs, and 12-lead ECGs were obtained at various time points; and adverse events (AE) were recorded. In particular, blood samples for PK determinations were obtained at 24 and 36 hours post-dose on Period 1/Day 2, at 48 and 60 hours post-dose on Period 1/Day 3, and at 72 hours post-dose on Period 1/Day 4. After completion of all of the Period 1/Day 4 assessments, the subjects were discharged from the clinical testing facility. Subjects reported back to the clinical testing facility on the mornings of Period 1/Days 5 and 6 for collection of PK blood samples at 96 hours (Period 1/Day 5) and 120 hours (Period 1/Day 6) post-dose.
After a one week washout period, subjects who received capsules in the fed state in Period 1 then received capsules in the fasted state in Period 2 (defined as no food consumption for 10 hours and no water for 2 hours preceding oral dosing); and subjects who received capsules in the fasted state in Period 1 received capsules in the fed state in Period 2.
A PK blood sample was taken at 168 hours after the first oral dose of study drug in Period 1; this sample, which was drawn immediately before the subject takes the 225-mg oral dose on the morning of Period 2/Day 1, was used as the pre-dose sample for Period 2. After collection of the pre-dose PK blood sample, subjects took a single oral dose of 225 mg of compound 1 (free base). Blood samples for PK determinations were obtained at 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 16 hours post-oral dose; vital signs and 12-lead ECGs were obtained at 3, 4, and 5 hours post-oral dose; and any concomitant medications and AEs were recorded.
During Days 1-4 (inpatient period) in Period 2, blood samples for PK determinations, vital signs, and 12-lead ECGs were obtained at various time points; and adverse events (AE) were recorded. In particular, blood samples for PK determinations were obtained at 24 and 36 hours post-oral dose on Period 2/Day 2, at 48 and 60 hours post-dose on Period 2/Day 3, and at 72 hours post-oral dose on Period 2/Day 4. After completion of all of the Period 2/Day 4 assessments, the subjects were discharged from the clinical testing facility. Subjects returned to the clinical testing facility in the fasted state for an end of study (EOS) visit on Period 2/Day 36 or at the time of premature termination from the study. A fasting blood sample for PK determinations (840 hours post-oral dosing) and fasting blood and urine samples for safety laboratory determinations were obtained, vital signs were measured, and a physical examination was performed. A pregnancy test (β-hCG) was performed for female subjects.
For the data in Table 10, PK blood samples were collected to 168 hours for Period 1 and to 840 hours for Period 2. Table 10 shows the effect of Period 1 versus Period 2 on the estimation of terminal half-life.









TABLE 10









Half-Life (hr)












Subject
Period 1
Period 2
Ratio
















3001
130
316
41%



3002
99
306
32%



3003
199
296
67%



3004
126
178
71%



3005
72
388
19%



3006
129
493
26%



3007
265
220
121% 



3008
115
357
32%



3009
100
309
33%



3010
98
186
53%



3011
111
282
39%



3012
122
402
30%



3013
79
231
34%



3014
86
207
41%



3015
97
377
26%



3016
116
370
31%



Mean
122
307
40%



CV %
40%
29%
138% 










For the data in Table 11, corrected AUC0-∞, Cmax, and Tmax values are provided for all samples in Period 1 and in Period 2. Table 11 shows the effect of food on the time to reach maximum concentration (Tmax), as well as AUC0-∞ and Cmax values that have been corrected for carry-over effect and the truncated observation period of Period 2. Carry-over effects were observed in Period 2, likely due to incomplete washout.











TABLE 11*









AUC0-∞
Cmax
Tmax



(hr * ng/mL)
(ng/mL)
(hr)



















Fasted


Fasted


Fed −


Subject
Fasted
Fed
Fed
Fasted
Fed
Fed
Fasted
Fed
Fasted



















3001
5019
5298
95%
528
608
87%
1.3
5.0
3.7


3002
5544
10031
55%
916
649
141%
2.5
5.0
2.5


3003
7399
11462
65%
431
519
83%
10.0
6.0
−4.0


3004
6296
7591
83%
685
823
83%
2.0
4.0
2.0


3005
6841
14742
46%
806
1054 
76%
5.0
5.0
0.0


3006
5161
4381
118% 
563
328
172%
2.5
8.0
5.5


3007
6210
8572
72%
250
915
27%
4.0
5.0
1.0


3008
2634
7282
36%
423
591
72%
1.8
6.0
4.2


3009
4099
8667
47%
530
806
66%
3.0
6.0
3.0


3010
5854
6730
87%
473
449
105%
1.3
6.0
4.7


3011
3432
8157
42%
372
882
42%
3.0
5.0
2.0


3012
4287
4419
97%
595
613
97%
1.5
5.0
3.5


3013
3604
7244
50%
556
570
98%
3.0
4.0
1.0


3014
4110
5884
70%
719
787
91%
1.5
6.0
4.5


3015
4180
10551
40%
425
920
46%
3.0
5.0
2.0


3016
5254
6346
83%
576
531
109%
1.8
5.0
3.2


Mean
4992
7960
68%
553
690
87%
3.0
5.4
2.4


Median
n/a
n/a
n/a
n/a
n/a
n/a
2.5
5.0
2.8


% CV
27%
34%
36%
30%
29%
41%
0.7
0.2
94%


Geometric
4820
7551
65%
529
662
80%
2.5
5.3
n/a


Mean





*AUC and Cmax values have been corrected for carry-over effect.






In Table 11 above, the ratio of mean AUC0-∞, Cmax, and Tmax are 1.59, 1.25, and 1.8, respectively, for fed subjects to fasted subjects. Furthermore, administration of the SDD formulation produced a coefficient of variation in AUC0-∞, and Cmax of less than 35% in fasted subjects (i.e., 27% and 30%, respectively) and in fed subjects (i.e., 34% and 29%, respectively). Finally, administration of the SDD composition to fed and fasted subjects produced a coefficient of variation in AUC∞ of less than 40% (i.e., 36%) and in Cmax of less than 60% (i.e., 41%).
FIGS. 11A-11B show that compound 1 in an SDD formulation (as a free base) has improved PK properties, compared to a micronized formulation (as an HCl salt). As shown in FIG. 11A, the ratio of these values for fasted versus fed subjects was about three-fold higher for the SDD formulation compared to the micronized formulation. Thus, use of the SDD formulation reduced the food effect of compound 1, as compared to the micronized formulation. Furthermore, the SDD formulation provided improved AUC values relative to the micronized formulation. As shown in FIG. 11B, the AUC0-24 values for the SDD formulation were more than 900% and 150% greater for fasted and fed states, respectively, than that for the micronized formulation. Additional data comparing SDD and micronized formulations are provided in Table 12. Overall, both AUC0-24 and Cmax for the SDD formulation were increased, and significant improvements were observed in intersubject variability (e.g., improved CV) relative to the micronized formulation.











TABLE 12









AUC0-24
Cmax
Mean Tmax



(hr * ng/mL)*
(ng/mL)*
(hr)*













Formulation
Fasted
Fed
Fasted
Fed
Fasted
Fed





SDD (free base),
2574 
3954
553 
690
3.0
5.0


225 mg dosea
(30%)
(27%)
(30%)
(29%)


Micronized
489
2311
65
336
3.0
5.0


(HCl salt),
(82%)
(26%)
(94%)
(33%)


200 mg doseb


Micronized
394
2703
51
389
3.0
7.0


(HCl salt),
(42%)
(39%)
(56%)
(35%)


400 mg dosec





*CV provided in parentheses.


aData for AUC0-24, Cmax, and Tmax for SDD are corrected for the carry-over effect and truncated Period 2 (as in Table 11 above).


bData for AUC0-24 and Cmax from a 200 mg dose were normalized to a 225 mg dose.


cData for AUC0-24 and Cmax from a 400 mg dose were normalized to a 225 mg dose.






Table 13 provides additional data that are corrected for carry-over effect and includes all the data from both periods (i.e., samples from entire Period 1 and Period 2).














TABLE 13*








Cmax
AUC0-24
AUC0-120
AUC0-168
AUC0-∞


Treatment
Period
Subject
(ng/mL)
(hr * ng/mL)
(hr * ng/mL)
(hr * ng/mL)
(hr * ng/mL)






















Fasted
1
3002
916
3648
4582
4864
5544




3003
431
3479
4757
5159
7399




3005
806
4473
5940
6226
6841




3008
423
1725
2162
2279
2634




3009
530
2654
3417
3599
4099




3011
372
2107
2868
3014
3432




3013
556
2275
3064
3237
3604




3015
425
2793
3660
3813
4180




Mean
557
2894
3806
4024
4717




CV %
36
32
32
32
36


Fasted
2
3001
528
2186
2743
2916
5019




3004
685
3233
4219
4480
6296




3006
563
2046
2867
3009
5161




3007
250
1876
2706
2922
6210




3010
473
2617
3612
3825
5854




3012
595
1808
2291
2438
4287




3014
719
2107
2769
2969
4110




3016
576
2159
2993
3170
5254




Mean
549
2254
3025
3216
5274




CV %
26
21
20
20
16


Fed
1
3001
608
3169
4091
4361
5298




3004
823
4363
5935
6313
7591




3006
328
2876
3538
3740
4381




3007
915
3577
4968
5400
8572




3010
449
3949
5473
5820
6730




3012
613
2809
3562
3778
4419




3014
787
4160
5154
5371
5884




3016
531
3524
4710
5067
6346




Mean
632
3553
4679
4981
6153




CV %
32
16
19
19
24


Fed
2
3002
649
4450
5887
6278
10031




3003
519
3381
4691
5239
11462




3005
1054
6737
8707
9139
14742




3008
591
2947
3984
4272
7282




3009
806
3857
5116
5451
8667




3011
882
4716
5994
6236
8157




3013
570
3102
4528
4916
7244




3015
920
5605
6819
7126
10551




Mean
749
4349
5716
6082
9767




CV %
26
30
27
25
26





*Values were corrected for the carry-over effect.






Additional studies can be conducted to determine absolute bioavailability of a single dose of compound 1 in a SDD formulation using a microdose of 14C-labeled compound 1 (free base).
Example 8
Manufacturing Process for Hot Melt Extrusion Formulations
Various hot melt extrusion (HME) formulations were prepared. The preferred polymers were found to be Kollidon® VA 64 (Copovidone), HPMCAS-MF (Hypromellose Acetate Succinate), and Kollidon® K30 (Povidone, PVP). Dissolution properties of these formulations are provided below in Example 9.
Briefly, the following process was developed to prepare an HME formulation with 20% (w/w) compound 1 with HPMCAS-MF. Vitamin E TPGS was pre-milled to reduce particle size down to ≦600 micron, and compound 1 was pre-sieved. Then, a pre-blend was prepared having 20% (w/w) sieved compound 1, 75% (w/w) HPMCAS-MF, and 5% (w/w) milled vitamin E TPGS. The pre-blend was processed using a co-rotating twin screw extruder having the following heating zone set points: 75° C., 110° C., 130° C., 140° C., and 95° C.; and the resultant extrudate was collected and processed further by milling (pelletizing) to reduce its particle size to ≦500 microns. Approximately half of the milled/pelletized extrudate was sieved and blended with half of the microcrystalline cellulose. Then, various pharmaceutically acceptable excipients (i.e., lactose, sodium lauryl sulphate, colloidal silicon dioxide, and croscarmellose sodium) were added and blended. The remaining milled/pelletized extrudate and microcrystalline cellulose were added and blended, where the resultant blend was co-milled and further processed by adding a lubricant (i.e., magnesium stearate). Finally, the blend was used to fill hard gelatin shell capsules.
Each capsule contained 75 mg of compound 1 (free base) in a HPMCAS-MF and Vitamin E TPGS amorphous solid dispersion prepared by hot melt extrusion (HME). The quantitative composition of these HME capsules is shown in Table 14.










TABLE 14








Quantity per


Component
Function
Standard
Capsule (mg)


















Compound 1 (free base)
API
C of A
75.00


Hypromellose acetate
Polymer component of
Ph. Eur., NF, JP
281.25


succinate Type MF
the solid dispersion


(HPMCAS-MF)


Vitamin E TPGS (d-alpha
Surfactant
Ph. Eur., NF, JP
18.75


tocopheryl polyethylene


glycol 1000 succinate)


Lactose monohydrate
Binder-Filler
Ph. Eur., NF, JP
74.74


Microcrystalline cellulose
Binder-Filler
Ph. Eur., NF, JP
74.74


Croscarmellose sodium
Disintegrant
Ph. Eur., NF, JP
17.00


Sodium lauryl sulphate
Wetting agent
Ph. Eur., NF, JP
4.24


Colloidal silicon dioxide
Flow aid/Glidant
NF
2.14


Magnesium stearate
Lubricant
Ph. Eur., NF, JP
2.14


Capsule Shell, hard gelatin
Dosage form

Na


white opaque size 00







Total Fill Weight:
550.0





Abbreviations: API = Active Pharmaceutical Ingredient; C of A—Certificate of Analysis; Ph. Eur. = European Pharmacopoeia; NF = National Formulary; JP = Japanese Pharmacopeia






The formulation development materials were tested for dissolution enhancement and for stability. The 1:4 ratio of API:polymer with a 5% surfactant was confirmed suitable. Solid-state characterization was performed on these formulations, including modulated dynamic scanning calorimetry (mDSC) polarized light microscopy, kinetic solubility, and X-ray powder diffraction (XRRD), each to confirm that the API was dispersed in an amorphous form.
Example 9
Dissolution Studies of Hot Melt Extrusion Formulations
Supersaturation dissolution kinetics provides valuable information regarding the performance of different matrix polymers in combination with an active agent. In particular, such studies could provide insight on which formulations could provide enhanced bioavailability. Accordingly, dissolution studies were conducted on the following three HME formulations: Kollidon® VA 64 (Copovidone), HPMCAS-MF (Hypromellose Acetate Succinate), and Kollidon® K30 (Povidone, PVP).
Briefly, the target concentration of the dissolution sample solution was 1.1 mg/mL, or ten times the estimated sink dissolution sample solution concentration produced by a 100 mg dose when dissolved in 900 mL of dissolution media. Triplicate preparations of about 10 mg of extrudate (2 mg of compound 1 in the three HME formulations) were transferred into separate micro-centrifuge tubes. About 1.8 mL of dissolution media was preheated to 37° C. and added to each tube, where the tube was then placed into an incubator shaker at 37° C. and 250 rpm. Samples were centrifuged at 13,000 rpm for one minute, and 25 μL aliquots of the clear supernatant were transferred into HPLC vials and diluted with 1.0 mL of HPLC mobile phase (30%/70% of pH 6.6 buffer/acetonitrile) at 10′ (minutes), 20′, 40′, 1 hr (hour), 1.5 hrs, 2 hrs, 4 hrs, and 24 hrs. An isocratic HPLC method was applied for quantitation against a five point calibration curve in the range of 5.5-220 μg/mL (C18, 5 μm, 4.6×150 mm column, and UV 216 nm detection). The HPLC sample solution target concentration was 27.1 μg/mL. Table 15 provides these data.












TABLE 15






Processing
Cmax


AUC0-4 hr


Sample
Conditions
(μg/mL)
SD
Tmax
(mg * hr/mL)





















Control
na
2.645
2.0
2
hours
0.008


(free base)


20%
150° C.,
178.6
15.8
20
minutes
0.483


compound 1/
no vacuum


80%
150° C.,
150.5
21.1
40
minutes
0.445


Kollidon ®
vacuum


VA64
140° C.,
116.5
8.1
40
minutes
0.309


(Copovidone)
no vacuum


20%
150° C.,
115.2
62.1
40
minutes
0.203


compound 1/
no vacuum


Kollidon ®
150° C.,
32.8
1.2
20
minutes
0.092


K30
vacuum


(Povidone)
140° C.,
101.0
13.5
40
minutes
0.137



no vacuum


20%
150° C.,
691.8
22.5
4
hours
1.68


compound 1/
no vacuum


80%
150° C.,
647.4
26.2
4
hours
1.63


HPMCAS-MF
vacuum



140° C.,
661.6
29.0
4
hours
1.66



no vacuum









As shown in Table 15, HPMCAS-MF (20% (w/w) compound 1) outperformed the other two polymers (copovidone or PVP) with a Cmax of 647-692 μg/mL. All the tested formulations provided enhanced Cmax values, as compared to the Control (free base, compound 1).
Example 10
Phase I (Group 1) Study in Healthy Human Subjects to Determine the Pharmacokinetics and Bioavailability of Compound 1 Following Treatment with the HME Formulation Under Fasted or Fed Conditions
Bioavailability of the ion channel modulator compound 1 was studied in healthy human subjects using the HME formulation, with subjects in either a fed or a fasted state. The effect of food on bioavailability from a single oral dose of the HME formulation was thereby evaluated. Safety and tolerability of compound 1 were also evaluated.
This study utilized a single-center, single-dose open-label, 2-group, 2-period randomized crossover design to address bioavailability under fasted and fed conditions. A total of 16 subjects were selected for the study. Inclusion criteria required men and women between 18 and 55 years of age, inclusive, with BMI between 18.0 and 30.0 kg/m2, inclusive, with a body weight not less than 50.0 kg, utilizing a reliable method of contraception, and that had signed an informed consent document. Subjects were screened for eligibility by safety and clinical assessments, including informed consent, medical history, medication history, demongraphics, physical examination, height, weight, BMI, serum pregnancy, clinical laboratory, HIV, Hepatitis B, Hepatitis C, vital signs, 12-lead ECG, urine drug screen, breath alcohol, concomitant medications, haematology, and adverse event monitoring. Subjects were excluded on the basis of clinically significant pulmonary history, medical conditions that potentially alter drug metabolism, malignancy within the previous 5 years, clinically significant allergies, creatine clearance, HIV, hepatitis B, hepatitis C, substance abuse, planned surgery during the course of the study, smoking, alcohol abuse, donation or loss of whole blood, caffeine consumption, experimental drug use, experimental medical device use, breast-feeding, use of non-prescription medication, use of prescription medication, use of natural health products, sodium intake, fluid intake, calcium intake, phosphorous intake, monoamine oxidase inhibitors, tricyclic antidepressants, febrile illness, abnormal body temperature, inability to swallow large capsules, inability to perform study requirements, employment by the principle investigator, inadequate venous access, and other exclusion criteria. Subjects were treated with an oral dose of 225 mg compound 1 as a hot melt extrusion (225 mg HME) formulation, administered in a 75 mg API dosage form as described in Example 8, Table 14. Dose was administered with approximately 8 fluid ounces of water to subjects in either a fed (high-fat meal) or a fasted state. Subjects were randomized between fed and fasted states during period 1 of the trial in equal numbers, and, following a washout period, assigned to the opposite state during period 2. The fed condition is defined as the state of a subject following an overnight fast of at least 10 hours with a test meal provided 30 minutes prior to administration of the study drug. The subject must completely consume their respective meal before being dosed. Meals were standardized high-fat meals and served according to a pre-determined schedule throughout the inpatient portion of the study. The time of food intake before and after study drug administration was documented. The standardized FDA-recommended high-fat meal will derive approximately 50% of total caloric content of the meal from fat with approximately 150, 250, and 500 to 600 calories derived from protein, carbohydrate, and fat, respectively (total of approximately 900 to 1000 calories). An example test meal would include two eggs fried in butter, two strips of bacon, two slices of white toast with butter and jam, 4 ounces of hash brown potatoes, and 8 ounces of whole milk. The fasted condition is defined as the state of a subject following an overnight fast of at least 10 hours prior to the administration of the study drug without a meal prior to drug administration. Following drug administration, subjects were not allowed food for at least 4 hours. Water was allowed as desired except for one hour before and after drug administration. Outside of these restrictions, subjects in both fed and fasted conditions were provided fluid intake according to the subject's individual needs, with documentation. Fasted and fed groups were dosed and evaluated simultaneously.
Treatments of 225 mg HME were administered on day 1 of period 1 of the trial, and subjects were admitted to the clinical research unit (CRU) for four days of inpatient evaluation. Subjects were discharged from the CRU upon completion of assessments on day 4, and reported to the CRU for additional pharmacokinetic blood sampling and safety assessment on days 5 and 6, completing period 1. There was a 7-day washout between the first and second period drug administrations. In the second period, subjects in a fed (high-fat meal) or fasted state were treated with an oral dose of 225 mg HME. The treatment was administered on day 1 of period 2 of the trial, and subjects were admitted to the CRU. Subjects were discharged from the CRU upon completion of assessments on day 4, and reported to the CRU for additional and follow-up pharmacokinetic blood sampling and safety assessment on days 5, 6, 8, 15, 22, 29, and 36 of period 2.
Pharmacokinetic assessments conducted during each treatment period were performed by the collection of venous blood samples via indwelling catheter or direct venipuncture. The plasma concentration of the drug was determined for each sample using a validated liquid chromatography coupled with tandem mass (LC/MS/MS) assay, with a lower limit of quantitation (LLOQ) of 0.1 ng/mL. The pharmacokinetic properties of the drug were measured by the parameters listed in Table 16. Descriptive statistics were calculated for these parameters and tabulated by feeding regimen and period. Safety of the trial subjects was assessed by the following endpoints: adverse events, vital signs, ECG parameters, laboratory parameters, medical history and physical examination.
Table 17 displays AUC0-∞, AUC0-24, and Cmax values from both periods for all subjects, each subject having been cumulatively treated under both fasted and fed conditions. Mean, median, CV %, and geometric mean are calculated for each parameter as measured under fasted and fed conditions. The ratio of the fasted to the fed value of each parameter is shown for each subject and for summary statistics. The time to reach maximum concentration, tmax is shown in Table 18 for fasted and fed conditions, as well as the difference between tmax fasted and tmax fed (fed minus fasted). Mean, median, CV %, and geometric mean are calculated for fasted and fed conditions. In Table 19, half-life values of the drug are provided for all subjects in period 1 and period 2; the ratio between the two and summary statistics are calculated. Table 20 presents geometric mean AUC0-∞, AUC0-24, and Cmax values for both HME and SDD formulations under fasted and fed conditions, as well as the ratio of the fasted to fed values of the geometric mean for each parameter.








TABLE 16





Parameter
Description







Cmax
The peak drug concentration, obtained directly from the data



without interpolation.


tmax
Time to maximum plasma concentration.


t1/2
The terminal elimination half-life, derived from the terminal



portion of the plasma concentration versus time curve.


AUC0 t
Area under the plasma concentration versus time curve



computed up to the last measurable concentration,



where time is post-dose.


AUC0-24
Area under the plasma concentration versus time curve



computed up to 24 hours postdose.


AUC0-120
Area under the plasma concentration versus time curve



computed up to 120 hours postdose.


AUC0-168
Area under the plasma concentration versus time curve



computed up to 168 hours postdose.


AUC0-∞
Area under the plasma concentration versus time curve,



from time of dosing to infinity.


AUCextrap
Percentage of the area extrapolated beyond the last



quantifiable plasma concentration.


λz
Terminal first-order elimination rate constant.


Cl/F
Apparent plasma clearance after oral administration.


VZ/F
Apparent volume of distribution after oral administration.


tlag
The time prior to the first measurable (non zero)



concentration.




















TABLE 17









AUC0-∞
AUC0-24
Cmax



(hr * ng/mL)
(hr * ng/mL)
(ng/mL)



















Fasted


Fasted


Fasted


Subject
Fasted
Fed
Fed
Fasted
Fed
Fed
Fasted
Fed
Fed



















1003
6039
6406
94%
3423
3753
91%
630
544
116%


1006
5443
6532
83%
3422
3747
91%
621
399
156%


1007
6651
10547
63%
4310
5794
74%
804
813
99%


1008
7579
8510
89%
3880
4811
81%
811
833
97%


1009
7199
11878
61%
3557
4877
73%
757
649
117%


1012
7809
14463
54%
4687
6947
67%
780
592
132%


1013
5240
7619
69%
3452
5147
67%
712
1210
59%


1014
7257
7744
94%
4379
4583
96%
830
611
136%


1018

8262


6122


1180


1021
8180


4396


850


1022
7781
9441
82%
3806
3781
101%
917
397
231%


1024
4023
7386
54%
2679
4161
64%
417
921
45%


1025
9487
7625
124%
3466
4361
79%
688
696
99%


1026
3372
6428
52%
1959
4486
44%
487
751
65%


1027
6497
15124
43%
4432
8684
51%
583
1327
44%


1028
3472
5870
59%
1933
2819
69%
294
628
47%


Mean
6402
8922
73%
3585
4938
75%
679
770
103%


Median
6651
7744
66%
3557
4583
74%
712
696
99%


CV %
28%
32%
31%
24%
30%
22%
26%
37%
50%


Geometric
6134
8550
70%
3472
4757
73%
653
724
92%


Mean


















TABLE 18









tmax (hr)












Subject
Fasted
Fed
Fed − Fasted
















1003
2
6
4



1006
2.5
10
7.5



1007
3
8
5



1008
4
8
4



1009
3
6
3



1012
3
5
2



1013
2.5
5
2.5



1014
5
6
1



1018

6



1021
5



1022
3
5
2



1024
5
8
3



1025
4
6
2



1026
2.5
6
3.5



1027
6
5
−1



1028
5
5
0



Mean
3.7
6.3
2.8



Median
3
6
2.8



CV %
33%
24%
77%



Geometric
3.5
6.2



Mean



















TABLE 19









Half-Life (hr)












Subject
Period 1
Period 2
Ratio
















1003
88
97
91%



1006
191
125
153% 



1007
49
129
38%



1008
95
92
103% 



1009
103
130
79%



1012
70
129
54%



1013
91
87
105% 



1014
161
175
92%



1018
39



1021
89



1022
303
73
415% 



1024
37
193
19%



1025
91
552
16%



1026
64
89
72%



1027
39
124
31%



1028
99
298
33%



Mean
101
164
93%



CV %
68
77
101% 





















TABLE 20









AUC0-∞
AUC0-24
Cmax



(hr * ng/mL)
(hr * ng/mL)
(ng/mL)





















Fasted


Fasted


Fasted


Form.
Subject
Fasted
Fed
Fed
Fasted
Fed
Fed
Fasted
Fed
Fed





HME
Geometric
6134
8550
70%
3472
4757
73%
653
724
92%



Mean



CV %
28%
32%
31%
24%
30%
22%
26%
37%
50%


SDD
Geometric
4279
6560
65%
2481
3837
65%
529
662
80%



Mean



CV %
29%
24%
18%
31%
27%
22%
30%
29%
41%









Example 11
Phase I (Group 2) Study in Healthy Human Subjects to Determine the Pharmacokinetics and Bioavailability of Compound 1 Following Treatment with the HME or SDD Formulations Under Fed Conditions
Bioavailability of the ion channel modulator compound 1 was studied in healthy human subjects using SDD and HME formulations, with subjects in a fed state. The effect the SDD or HME formulation on bioavailability following a single oral dose under fed conditions was thereby evaluated and compared. Safety and tolerability of compound 1 was also evaluated.
This study utilized a single-center, single-dose open-label, 2-group, 2-period randomized crossover design to determine bioavailability following treatment with the SDD or HME formulation under fed conditions. A total of 16 subjects were selected by the criteria described in Example 10.
Subjects were treated with an oral dose of 225 mg HME (as described in Example 8, Table 14) or 225 mg SDD (as described in Example 7) with approximately 8 fluid ounces of water in the fed (standard meal) state. Subjects were randomized between HME and SDD formulations in equal numbers during period 1 of the trial, and, following a washout period, assigned to the opposite formulation during period 2. The fed condition is defined as the state of a subject following an overnight fast of at least 10 hours with a test meal provided 30 minutes prior to administration of the study drug. The subject must completely consume their respective meal before being dosed. Meals were standardized and standard meals were served according to a pre-determined schedule throughout the inpatient portion of the study. A standardized meal derived approximately 35% of total caloric content of the meal from fat, approximately 15-20% from protein, and approximately 45-50% from carbohydrates, with a total caloric content of approximately 400-450 calories. An example test meal would have included 5⁄8 ounces Cheerios®, 1 egg, 1 strip of bacon, 1 slice of toast with margarine, 6 ounces of low fat milk, and 4 ounces of orange juice. The time of food intake before and after study drug administration was documented. Water was allowed as desired except for one hour before and after drug administration. Outside of these restrictions, subjects in both fed and fasted conditions were provided fluid intake according to the subject's individual needs, with documentation. HME and SDD groups were dosed and evaluated simultaneously.
Treatments of 225 mg HME or SDD were administered on day 1 of period 1 of the trial and subjects were admitted to the clinical research unit (CRU) for four days of inpatient evaluation. Subjects were discharged from the CRU upon completion of assessments on day 4, and reported to the CRU for additional pharmacokinetic blood sampling and safety assessment on days 5 and 6, completing period 1. There was a 7-day washout between the first and second period drug administrations. In the second period, subjects were treated with an oral dose of 225 mg HME or 225 mg SDD in the fed (standard meal) state. The treatment was administered on day 1 of period 2 of the trial and subjects were admitted to the clinical research unit (CRU). Subjects were discharged from the CRU upon completion of assessments on day 4, and reported to the CRU for additional and followup pharmacokinetic blood sampling and safety assessment on days 5, 6, 8, 15, 22, 29, and 36 of period 2.
Pharmacokinetic assessments conducted during each treatment period were performed by the collection of venous blood samples via indwelling catheter or direct venipuncture. The plasma concentrations of the drug was determined for each sample. Concentration of the drug was determined using a validated liquid chromatography coupled with tandem mass (LC/MS/MS) assay, with a lower limit of quantitation (LLOQ) of 0.1 ng/mL. The pharmacokinetic properties of the drug were measured by the parameters listed in Table 16. Descriptive statistics were calculated for these parameters and tabulated by formulation and period. Safety of the trial subjects was assessed by the following endpoints: adverse events, vital signs, ECG parameters, laboratory parameters, medical history, and physical examination.
In Table 21, the mean AUC0-∞, mean AUC0-24, and mean Cmax values from both periods for all subjects, each subject having been cumulatively treated with both HME and SDD formulations. Mean, median, CV %, and geometric mean are calculated for each parameter as measured following treatment with the HME or SDD formulation. The ratio of the HME and SDD value for each parameter is shown for each subject and for summary statistics. FIG. 12 displays box plot representations of AUC0-∞ data for the HME formulation under fasted and fed conditions (as in Example 10), as well as AUC0-∞ data for HME and SDD formulations under fed conditions (as in this Example). FIG. 13 displays box plot representations of Cmax data for the HME formulation under fasted and fed conditions (as in Example 10), as well as Cmax data for HME and SDD formulations under fed conditions (as in this Example).
The time to reach maximum concentration, tmax, is shown in Table 22 for all HME and SDD samples, as well as the difference between tmax HME and tmax SDD (fed minus fasted). Mean, median, CV %, and geometric mean are calculated for the HME and SDD formulations. The effect of period on terminal half-life is displayed in Table 23, which shows the half-life value of each subject in each period; the ratio between the two and summary statistics are calculated.











TABLE 21









AUC0-∞
AUC0-24
Cmax



(hr * ng/mL)
(hr * ng/mL)
(ng/mL)



















HME


HME


HME


Subject
HME
SDD
SDD
HME
SDD
SDD
HME
SDD
SDD



















1001
12161
10620
115%
6033
6591
92%
1242
1470
84%


1002
9824
7188
137%
6492
4484
145%
1450
894
162%


1004
9922
12851
77%
6198
7150
87%
1730
1302
133%


1005
6415
5405
119%
3589
3672
98%
915
904
101%


1010
6627
5450
122%
4028
3967
102%
862
788
109%


1011

23084


6840


1420


1015
6932
8153
85%
4561
4969
92%
467
858
54%


1016
4863
5940
82%
3220
3447
93%
765
873
88%


1017
7865
7287
108%
4188
5094
82%
909
1040
87%


1019
10983
10317
106%
5276
6208
85%
1124
1570
72%


1020
5603
5771
97%
3376
3440
98%
442
873
51%


1023
5884
5899
100%
3770
3746
101%
697
901
77%


1029
7615
7935
96%
4284
4243
101%
772
908
85%


1030
8878
9163
97%
5879
5200
113%
1470
1122
131%


1031
6897
6241
111%
4492
4263
105%
1365
967
141%


1032
10377
7568
137%
3282
3292
100%
909
811
112%


Mean
8056
8680
93%
4578
4788
100%
1008
1044
99%


Median
7615
7427
106%
4284
4373
98%
909
906
88%


CV %
27
51
17%
25
27
15%
37
24
32%


Geometric
7786
8004
97%
4454
4636
99%
939
1018
94%


Mean


















TABLE 22









tmax (hr)















HME



Subject
HME
SDD
SDD
















1001
5
3
167%



1002
3
3
100%



1004
5
3
167%



1005
5
5
100%



1010
4
3
133%



1011

5



1015
10
5
200%



1016
5
5
100%



1017
5
3
167%



1019
5
5
100%



1020
5
5
100%



1023
5
3
167%



1029
5
5
100%



1030
5
4
125%



1031
5
5
100%



1032
5
5
100%



Mean
5
4
128%



Median
5
5
100%



CV %
28
23
 28%



Geometric
5
4.1
124%



Mean



















TABLE 23









Half-Life (hr)












Subject
Period 1
Period 2
Ratio
















1001
96
193
50%



1002
114
98
116% 



1004
72
71
101% 



1005
105
116
91%



1010
77
114
68%



1011
617



1015
79
104
76%



1016
75
171
44%



1017
75
176
43%



1019
270
417
65%



1020
73
82
89%



1023
115
106
108% 



1029
112
149
75%



1030
92
155
59%



1031
94
137
69%



1032
163
400
41%



Mean
139
166
73%



CV %
98
63
33%










Other Embodiments
While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth.
All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

## Claims

1. A pharmaceutical composition in unit dosage form for oral administration comprising a solid dispersion of from about 20 mg to about 250 mg of substantially amorphous 1-(4-benzhydrylpiperazine-1-yl)-3,3-diphenylpropan-1-one in a matrix polymer, wherein said matrix polymer comprises a member selected from the group consisting of a cellulose derivative, a polyacrylate, a polyvinyl pyrrolidone, a polyvinyl acetate, or a copolymer of a polyvinyl pyrrolidone and a polyvinyl acetate and wherein the percentage loading of said 1-(4-benzhydrylpiperazine-1-yl)-3,3-diphenylpropan-1-one in said solid dispersion is from about 10% to about 80% (w/w).

2. The pharmaceutical composition of claim 1, wherein the percentage loading of said compound 1 in said solid dispersion is from about 10% to about 50% (w/w).

3. The pharmaceutical composition of claim 1, wherein said unit dosage form comprises from about 70 mg to about 250 mg of 1-(4-benzhydrylpiperazine-1-yl)-3,3-diphenylpropan-1-one.

4. A method to treat pain in a subject in need thereof, said method comprising administering to said subject an effective amount of the pharmaceutical composition of claim 1.