Patent Publication Number: US-2013231350-A1

Title: Solid dispersion formulations and methods of use thereof

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation of U.S. patent application Ser. No. 13/494,545, filed on Jun. 12, 2012, which 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&#39;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 C max  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 C max  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 C max  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 C max  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 C max  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(OCH 2 CH 2 ) a (OCHCH 3 CH 2 ) b (OCH 2 CH 2 ) a OH, 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 Ca V  2.2 channel). In some embodiments, the sodium channel is a voltage-gated sodium channel (e.g., the Na V 1.7 channel or the Na V 1.8, channel). 
     In some embodiments, the condition is pain, epilepsy, Parkinson&#39;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(OCH 2 CH 2 ) a (OCHCH 3 CH 2 ) b (OCH 2 CH 2 ) a OH, 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 T g . 
     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 “C max ” is meant the mean peak concentration of a drug achieved in plasma after dosing. 
     By “T max ” is meant the mean time after oral administration of a drug when the maximum plasma concentration of the drug or C max  is reached. 
     By “AUC ∞ ” “AUC 0-∞ ,” 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 C max , T max , 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 C max , T max , 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-NH 2 , PEG-CO 2 H, 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 (CH 2 ) 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&#39;s disease, Parkinson&#39;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 T g  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 AUC 0-24  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 AUC 0-24  for fasted to fed conditions (i.e., [AUC 0-24  fasted]/[AUC 0-24  fed]) for SDD or Micronized.  FIG. 11B  shows the ratio of AUC 0-24  for SDD to Micronized (i.e., [AUC 0-24  SDD]/[AUC 0-24  Micronized]) for fasted or fed conditions. 
         FIG. 12  is a series of box plots showing the mean, median and distributions of the AUC 0-∞  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 C max  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) T g : 41.6° C.; 
     (vii) hygroscopicity (for free base): 0.09% at 70% relative humidity (RH); 
     (viii) potential isomerism: none; 
     (ix) T max  (for HCl salt): &lt;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) t 1/2  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 
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                   10 
                 
                 ( 
                 
                   dose 
                   100 
                 
                 ) 
               
             
           
         
       
     
     as a function of dose (mg) relative to a 100 mg dose. Typical values were computed as 100%×√ω 2 , where ω 2 =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 T g  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 T g  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 T g  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 (T g =133° C.), cellulose acetate phthalate (CAP, T g =171° C.), hydroxypropylmethyl cellulose acetate (T g =177° C.), hydroxypropylmethyl cellulose acetate succinate (HPMCAS, T g =115° C.), hydroxypropylmethyl cellulose phthalate (HPMCP, T g =133° C.), polyvinylpyrrolidone (T g =174° C.), crospovidone (T g =190° C. to 195° C.), polyvinyl alcohol (T g =75° C.), and polyvinyl acetate phthalate (T g =55° C.). Exemplary solid dispersions are those having 20% (w/w) of compound 1 and CMEC (T g =89.4° C.), HPMCAS-M (T g =91.3° C.), CAP (T g =129.9° C.), or PVAP (T g =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 (Methocel™ 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 (Methocel™ K, including those having apparent viscosity (2% in water at 20° C.) of 80-120 cP (Methocel™ K100), 3,000-5,600 cP (Methocel™ K4M), 11,250-21,000 cP (Methocel™ K15M), 80,000-120,000 cP (Methocel™ K100M), available from Dow Chemical Co.), 28-30% methoxyl/7-12% hydroxypropxyl (Methocel™ E, including those having apparent viscosity (2% in water at 20° C.) of 3,000-5,600 cP (Methocel™ E4M) and 7,500-14,000 cP (Methocel™ 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+Σ i N i   h −Σ i N i   l , where i is the number of groups, N i   h  is a value for each i th  hydrophilic group, and N i   l  is the value for each i th  lipophilic group. Values of N h  and N l  depend on the type of hydrophilic and lipophilic group, respectively. Exemplary values for N h  include 38.7 for —SO 4 Na, 21.1 for —CO 2 K, 19.1 for —CO 2 Na, 9.4 for tertiary amine N, 6.8 for ester (sorbitan ring), 2.4 for ester (free), 2.1 for —CO 2 H, 1.9 for —OH (free), 1.3 for —O—, 0.5 for —OH (sorbitan ring), and 0.33 for —(CH 2 CH 2 O)—; and for N l  include −1.66 for benzyl, −0.475 for —CH—, —CH 2 —, —CH 3 , and ═CH—, and −0.13 for —(CH 2 CH 2 CH 2 O)—. 
     Plasticizers 
     The formulations of the invention optionally include one or more plasticizers. Generally, plasticizers can be used to reduce the glass transition temperature T g  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(OCH 2 CH 2 ) a (OCHCH 3 CH 2 ) b (OCH 2 CH 2 ) a OH, 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® HS 15, 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 &lt;2% C 6 /50%-80% C 8 /20%-50% C 10 /&lt;3% C 12 /&lt;1% C 14  (Softigen® 767, HLB=19), a mixture of PEG 8 caprylic/capric glyceryl esters having 50%-80% C 8 /20%-50% C 10 /&lt;3% C 12 /&lt;1% C 18  (Labrasol®, HLB=14), a mixture of PEG 32 lauryl glyceryl esters having 40%-50% C 12 /14%-24% C 14 /4%-10% C 8 /3-9% C 10 /4%-14% C 16 /5%-15% C 18  (Gelucire® 44/14, HLB=14), and a mixture of PEG 32 stearyl glyceryl esters having 40%-50% C 16 /48%-58% C 18  (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(OCH 2 CH 2 ) a (OCHCH 3 CH 2 ) b (OCH 2 CH 2 ) a OH, 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-NH 2 , PEG-CO 2 H, 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 T g  or melting temperature T m  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 &amp; 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&#39;s disease, Parkinson&#39;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&#39;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. Behav.  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 (CCI) 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% CO 2  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 (P app ), percent recovery, and efflux ratio were calculated as follows: 
     
       
         
           
             
               
                 
                   P 
                   app 
                 
                  
                 
                   [ 
                   
                     cm 
                      
                     
                         
                     
                      
                     
                       s 
                       
                         - 
                         1 
                       
                     
                   
                   ] 
                 
               
               = 
               
                 
                   
                      
                     
                       C 
                       r 
                     
                   
                   
                      
                     t 
                   
                 
                 × 
                 
                   
                     V 
                     r 
                   
                   
                     A 
                     × 
                     
                       C 
                       0 
                     
                   
                 
               
             
             , 
             
               
 
             
              
             
               
                 Percent 
                  
                 
                     
                 
                  
                 
                   recovery 
                    
                   
                       
                   
                   [ 
                   % 
                   ] 
                 
               
               = 
               
                 100 
                 × 
                 
                   
                     
                       ( 
                       
                         
                           V 
                           r 
                         
                         × 
                         
                           C 
                           
                             r 
                             , 
                             final 
                           
                         
                       
                       ) 
                     
                     + 
                     
                       ( 
                       
                         
                           V 
                           d 
                         
                         × 
                         
                           C 
                           
                             d 
                             , 
                             final 
                           
                         
                       
                       ) 
                     
                   
                   
                     
                       V 
                       d 
                     
                     × 
                     
                       C 
                       N 
                     
                   
                 
               
             
             , 
             and 
           
         
       
       
         
           
             
               
                 Efflux 
                  
                 
                     
                 
                  
                 ratio 
               
               = 
               
                 
                   
                     P 
                     app 
                   
                    
                   
                     ( 
                     
                       B 
                        
                       
                         - 
                       
                        
                       to 
                        
                       
                         - 
                       
                        
                       A 
                     
                     ) 
                   
                 
                 
                   
                     P 
                     app 
                   
                    
                   
                     ( 
                     
                       A 
                        
                       
                         - 
                       
                        
                       to 
                        
                       
                         - 
                       
                        
                       B 
                     
                     ) 
                   
                 
               
             
             , 
           
         
       
     
     where 
     
       
         
           
             
               
                  
                 Cr 
               
               
                  
                 t 
               
             
              
             
                 
             
             [ 
             
               μ 
                
               
                   
               
                
               M 
                
               
                   
               
                
               
                 s 
                 
                   - 
                   1 
                 
               
             
             ] 
           
         
       
     
     is the slope of me cumulative concentration in the receiver chamber as a function of time; V r  [cm 3 ] is the volume of the receiver chamber; V d  [cm 3 ] is the volume of the donor chamber; A [cm 2 ] is the area of the cell monolayer, which is estimated to be about 1.13 cm 2  for the 12-well Costar Transwell® plates; C 0  [μM] is the measured concentration in the donor chamber at t=0 hours; C N  [μM] is the nominal concentration of the dosing solution; C r,final  [μM] is the cumulative concentration in the receiver chamber at the end of the incubation period; and C d,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 P app (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 
                 P app  (10 −6  cm/s) 
                 (P app (B-to-A)/P app (A- 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Direction 
                 Conc. (μM) 
                 (%) 
                 R1 
                 R2 
                 R3 
                 Avg. 
                 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 C max  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 C max  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 I 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 T g  values, which can be used to understand the molecular mobility of a drug within the dispersion.  FIG. 6  shows the MDSC traces and T g  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 T g  is likely greater than 150° C. due to polymer degradation above this temperature. All recorded T g  values were at least twice as high as compound 1 alone (T g =41.6° C.). Lower T g  values could indicate potential stability issues over long periods of time or at an increased temperature or pressure. Table 3 provides T g  values for CAP (formulation 1), HPMCAS-M (formulation 2), and PVAP. 
     
       
         
           
               
               
               
               
             
               
                 TABLE 3 
               
               
                   
               
               
                   
                 Percentage (w/w) of 
                 T g  (° C.) 
                 T g  (° C.) 
               
               
                   
                 compound 1 with 
                 at ambient 
                 at 75% relative 
               
               
                 Formulation 
                 polymer 
                 relative humidity 
                 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 
               
               
                   
               
               
                   
                   
                 C max   
                 T max   
                 t 1/2   
                 AUC ∞   
                 AUC 0-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 
                   
               
               
                 Formu- 
               
               
                 lation 1 
               
               
                 (CAP) 
                 Pharmacokinetic parameters 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 (20% 
                   
                 C max   
                 T max   
                 t 1/2   
                 AUC ∞   
                 AUC 0-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 
                 Pharmacokinetic parameters 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Formulation 2 
                   
                   
                   
                   
                 AUC ∞   
                 AUC 0-last   
               
               
                 (HPMCAS-M) 
                   
                 C max   
                 T max   
                 t 1/2   
                 (h * ng/ 
                 (h * ng/ 
               
               
                 (20% (w/w)) 
                 Animal 
                 (ng/mL) 
                 (hr) 
                 (hr) 
                 mL) 
                 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 
                   
                 C max   
                 T max   
                 t 1/2   
                 AUC ∞   
                 AUC 0-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 1 HCl in 0.5% Tween 80 in 0.5% CMC.  FIG. 10  shows enhanced oral bioavailability for formulations 1 and 2. 
     
       
         
           
               
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 8 
               
               
                   
                   
               
               
                   
                   
                   
                 T max   
                 t 1/2   
                 C max   
                 AUC 0-last   
                 AUC 0-24   
                 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 (R 2  &lt; 0.8) for elimination phase. 
               
            
           
         
       
     
     In Table 8 above, the AUC 0-24  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 AUC 0-∞ , C max , and T max  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 (T max ), as well as AUC 0-∞  and C max  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* 
               
             
            
               
                   
                   
               
               
                   
                 AUC 0-∞   
                 C max   
                 T max   
               
               
                   
                 (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 C max  values have been corrected for carry-over effect. 
               
            
           
         
       
     
     In Table 11 above, the ratio of mean AUC 0-∞ , C max , and T max  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 AUC 0-∞  and C max  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 C max  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 AUC 0-24  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 AUC 0-24  and C max  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 
               
             
            
               
                   
                   
               
               
                   
                 AUC 0-24   
                 C max   
                 Mean T max   
               
               
                   
                 (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 dose a   
                 (30%) 
                 (27%) 
                 (30%) 
                 (29%) 
               
               
                 Micronized 
                 489 
                 2311 
                 65 
                 336 
                 3.0 
                 5.0 
               
               
                 (HCl salt), 
                 (82%) 
                 (26%) 
                 (94%) 
                 (33%) 
               
               
                 200 mg dose b   
               
               
                 Micronized 
                 394 
                 2703 
                 51 
                 389 
                 3.0 
                 7.0 
               
               
                 (HCl salt), 
                 (42%) 
                 (39%) 
                 (56%) 
                 (35%) 
               
               
                 400 mg dose c   
               
               
                   
               
               
                 *CV provided in parentheses. 
               
               
                   a Data for AUC 0-24 , C max , and T max  for SDD are corrected for the carry-over effect and truncated Period 2 (as in Table 11 above). 
               
               
                   b Data for AUC 0-24  and C max  from a 200 mg dose were normalized to a 225 mg dose. 
               
               
                   c Data for AUC 0-24  and C max  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* 
               
               
                   
               
               
                   
                   
                   
                 C max   
                 AUC 0-24   
                 AUC 0-120   
                 AUC 0-168   
                 AUC 0-∞   
               
               
                 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  14 C-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 
               
               
                   
               
               
                   
                   
                   
                   
                   
                 AUC 0-4 hr   
               
               
                   
                 Processing 
                 C max   
                   
                   
                 (mg * 
               
               
                 Sample 
                 Conditions 
                 (μg/mL) 
                 SD 
                 T max   
                 hr/mL) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Control 
                 na 
                 2.645 
                 2.0 
                  2 hours 
                 0.008 
               
               
                 (free base) 
               
               
                 20% 
                 150° C., no 
                 178.6 
                 15.8 
                 20 minutes 
                 0.483 
               
               
                 compound 1/ 
                 vacuum 
               
               
                 80% 
                 150° C., 
                 150.5 
                 21.1 
                 40 minutes 
                 0.445 
               
               
                 Kollidon ® 
                 vacuum 
               
               
                 VA64 
                 140° C., no 
                 116.5 
                 8.1 
                 40 minutes 
                 0.309 
               
               
                 (Copovidone) 
                 vacuum 
               
               
                 20% 
                 150° C., no 
                 115.2 
                 62.1 
                 40 minutes 
                 0.203 
               
               
                 compound 1/ 
                 vacuum 
               
               
                 Kollidon ® 
                 150° C., 
                 32.8 
                 1.2 
                 20 minutes 
                 0.092 
               
               
                 K30 
                 vacuum 
               
               
                 (Povidone) 
                 140° C., no 
                 101.0 
                 13.5 
                 40 minutes 
                 0.137 
               
               
                   
                 vacuum 
               
               
                 20% 
                 150° C., no 
                 691.8 
                 22.5 
                  4 hours 
                 1.68 
               
               
                 compound 1/ 
                 vacuum 
               
               
                 80% 
                 150° C., 
                 647.4 
                 26.2 
                  4 hours 
                 1.63 
               
               
                 HPMCAS-MF 
                 vacuum 
               
               
                   
                 140° C., no 
                 661.6 
                 29.0 
                  4 hours 
                 1.66 
               
               
                   
                 vacuum 
               
               
                   
               
            
           
         
       
     
     As shown in Table 15, HPMCAS-MF (20% (w/w) compound 1) outperformed the other two polymers (copovidone or PVP) with a C max  of 647-692 μg/mL. All the tested formulations provided enhanced C max  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&#39;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 AUC 0-∞ , AUC 0-24 , and C max  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, t max  is shown in Table 18 for fasted and fed conditions, as well as the difference between t max  fasted and t max  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 AUC 0-∞ , AUC 0-24 , and C max  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 
               
               
                   
               
             
            
               
                 C max   
                 The peak drug concentration, obtained directly from the data 
               
               
                   
                 without interpolation. 
               
               
                 t max   
                 Time to maximum plasma concentration. 
               
               
                 t 1/2   
                 The terminal elimination half-life, derived from the terminal 
               
               
                   
                 portion of the plasma concentration versus time curve. 
               
               
                 AUC 0 t   
                 Area under the plasma concentration versus time curve 
               
               
                   
                 computed up to the last measurable concentration, where 
               
               
                   
                 time is post-dose. 
               
               
                 AUC 0-24   
                 Area under the plasma concentration versus time curve 
               
               
                   
                 computed up to 24 hours postdose. 
               
               
                 AUC 0-120   
                 Area under the plasma concentration versus time curve 
               
               
                   
                 computed up to 120 hours postdose. 
               
               
                 AUC 0-168   
                 Area under the plasma concentration versus time curve 
               
               
                   
                 computed up to 168 hours postdose. 
               
               
                 AUC 0-∞   
                 Area under the plasma concentration versus time curve, 
               
               
                   
                 from time of dosing to infinity. 
               
               
                 AUC extrap   
                 Percentage of the area extrapolated beyond the last 
               
               
                   
                 quantifiable plasma concentration. 
               
               
                 λ z   
                 Terminal first-order elimination rate constant. 
               
               
                 Cl/F 
                 Apparent plasma clearance after oral administration. 
               
               
                 V z /F 
                 Apparent volume of distribution after oral administration. 
               
               
                 t lag   
                 The time prior to the first measurable (non zero) 
               
               
                   
                 concentration. 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
             
               
                   
                 TABLE 17 
               
             
            
               
                   
                   
               
               
                   
                 AUC 0-∞   
                 AUC 0-24   
                 C max   
               
               
                   
                 (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 
               
             
            
               
                   
                   
               
               
                   
                 t max   
               
               
                   
                 (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 
               
             
            
               
                   
                   
               
               
                   
                 AUC 0-∞   
                 AUC 0-24   
                 C max   
               
               
                   
                 (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 
                 4257 
                 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 ⅝ 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&#39;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 AUC O-∞ , mean AUC 0-24 , and mean C max  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 AUC 0-∞  data for the HME formulation under fasted and fed conditions (as in Example 10), as well as AUC 0-∞  data for HME and SDD formulations under fed conditions (as in this Example).  FIG. 13  displays box plot representations of C max  data for the HME formulation under fasted and fed conditions (as in Example 10), as well as C max  data for HME and SDD formulations under fed conditions (as in this Example). 
     The time to reach maximum concentration, t max , is shown in Table 22 for all HME and SDD samples, as well as the difference between t max  HME and t max  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 
               
             
            
               
                   
                   
               
               
                   
                 AUC 0-∞   
                 AUC 0-24   
                 C max   
               
               
                   
                 (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 
               
             
            
               
                   
                   
               
               
                   
                 t max   
               
               
                   
                 (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.