Formulations of cycloserine compounds and applications thereof

Abstract

A solid dosage form comprises an inner core containing a cycloserine compound and an outer layer attached to the inner core. The dosage form can be enteric tablet or transdermal patch, suitable for treating a neuropsychiatric disorder or tuberculosis.

1 . A solid dosage form, comprising:
 (i) an inner core, which comprises a cycloserine compound and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient comprises a filler, a binder, a disintegrating agent, a lubricant, a carrier, a pH adjuster, a dispersion reagent, an anti-sedimentation reagent, an enhancer, a sustained release reagent, or a mixture thereof; and   (ii) an outer layer attached to the inner core;   wherein the solid dosage form contains about 10 mg to about 1500 mg of the cycloserine compound.   
     
     
         2 . The solid dosage form of  claim 1 , wherein the outer layer is an enteric layer, which comprises polymethacrylate, phthalate, cellulose ester, shellac, alginate, or a mixture thereof. 
     
     
         3 . The solid dosage form of  claim 2 , further comprising (iii) an isolation layer between the inner core and the enteric layer, wherein the isolation layer comprises a cellulose polymer. 
     
     
         4 . The solid dosage form of  claim 2 , wherein in the inner core:
 (a) the filler is selected from the group consisting of starch, lactose, sucrose, glucose, mannitol, calcium phosphate, microcrystalline cellulose, and a mixture thereof;   (b) the binder is selected from the group consisting of carboxymethylcellulose, microcrystalline cellulose (MCC), hydroxypropyl cellulose, alginates, gelatin, polyvinylpyrrolidinone, acacia, and a mixture thereof;   (c) the disintegrating agent is selected from the group consisting of agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium starch glycolate (SSG), croscarmellose, crospovidone, sodium carbonate, and a mixture thereof; and/or   (d) the lubricant is selected from the group consisting of magnesium stearate, colloidal silicon dioxide, talc, calcium stearate, solid polyethylene glycol, sodium lauryl sulfate, and a mixture thereof.   
     
     
         5 . The solid dosage form of  claim 2 , wherein the pharmaceutically acceptable excipient in the inner core comprises about 50-500 mg of the filler, about 10-100 mg of the binder, about 10-200 mg of the disintegrating agent, and about 5-100 mg of the lubricant. 
     
     
         6 . The solid dosage form of  claim 2 , wherein the filler comprises microcrystalline cellulose (MCC) pH 102, the binder comprises hydroxylpropyl cellulose (HPC), the disintegrating agent comprises croscarmellose, and the lubricant comprises magnesium stearate. 
     
     
         7 . The solid dosage form of  claim 2 , wherein the enteric layer comprises:
 (a) polymethacrylate, which is selected from the group consisting of poly(methacrylic acid-co-ethyl acrylate) in a molar ratio of 1:1, poly(methacylic acid-co-methyl methacrylate) in a molar ratio of 1:1, poly(methacylic acid-co-methyl methacrylate) in a molar ratio of 1:2, and poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) in a molar ratio of 7:3:1;   (b) phthalate, which is selected from the group consisting of polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, diethyl phthalate, and cellulose acetate phthalate; and/or   (c) cellulose ester, which is selected from the group consisting of cellulose acetate trimellitate, cellulose acetate succinate, and hydroxypropyl methylcellulose acetate succinate.   
     
     
         8 . The solid dosage form of  claim 2 , wherein the enteric layer comprises 90.5%-98.49% of poly(methacrylic acid-co-ethyl acrylate) in a ratio of 1:1 by weight, 0.5%-2% of sodium lauryl sulfate by weight, 0.01%-2.5% of triethyl citrate by weight, 0.5%-2.5% of colloidal silicon dioxide by weight, and 0.5%-2.5% of talc by weight. 
     
     
         9 . The solid dosage form of  claim 2 , wherein the cellulose polymer is hydroxypropyl methylcellulose (HPMC). 
     
     
         10 . The solid dosage form of  claim 9 , wherein the HPMC has an average molecular weight of 50,000 to 125,000 Dalton. 
     
     
         11 . The solid dosage form of  claim 3 , wherein the isolation layer comprises 95.5%-99.49% of hydroxypropyl methylcellulose by weight, 0.5%-2.5% of talc by weight, and 0.01%-2% of triacetin by weight. 
     
     
         12 . The solid dosage form of  claim 3 , which comprises about 10 mg to about 300 mg of the enteric layer and/or about 10 mg to about 100 mg of the isolation layer. 
     
     
         13 . The solid dosage form of  claim 3 , wherein the pharmaceutically acceptable excipient comprises MCC pH 102, croscarmellose, hydroxypropyl cellulose (HPC), and magnesium stearate; wherein the enteric layer comprises polymethacrylate; and wherein the isolation layer comprises HPMC having a molecular weight of 50,000 to 125,000 Dalton. 
     
     
         14 . The solid dosage form of  claim 1 , wherein the solid dosage form is a transdermal patch and wherein the outer layer is a backing layer of the transdermal patch. 
     
     
         15 . The solid dosage form of  claim 14 , wherein the backing layer comprises a polymer of polyethylene, polyurethane, ethylene vinyl acetate, polyvinyl chloride, polyethylene, terephthalate, or a mixture therefore. 
     
     
         16 . The solid dosage form of  claim 14 , wherein the inner core comprises a carrier, a dispersion reagent, an anti-sedimentation reagent, an enhancer, a sustained release reagent, a pH adjuster, or a mixture thereof. 
     
     
         17 . The solid dosage form of  claim 16 , wherein the carrier is selected from the group consisting of propylene glycerol, dipropylene glycol, hexylene glycerol, tetrathyleneglycol monomethylether, copolymers of acrylic and methacrylic acids or esters, hydroxypropyl methylcellulose, ethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, cellulose acetate phthalate, cellulose acetate, polymerized rosin, crosslinked polyacrylic acid polymers, acrylate copolymer, polyisobutylene, xanthan gum, and silicon gum, or combination thereof. 
     
     
         18 . The solid dosage form of  claim 16 , wherein the dispersion reagent is selected from the group consisting of sodium lauroyl sarcosinate, polyethylene glycol, sodium dodecyl sulfate, and cetyltrimethylammonium bromide, or combination thereof. 
     
     
         19 . The solid dosage form of  claim 16 , wherein the anti-sedimentation reagent is selected from the group consisting of corn oil, eucalyptus oil, peppermint oil, benzyl benzoate, and sesame oil, or combination thereof. 
     
     
         20 . The solid dosage form of  claim 16 , wherein the enhancer is selected from the group consisting of terpene, fatty acid, ester, essential oil, pyrrolidone, mannitol, 2-pyrrolidone, 1-methyl-2-pyrrolidone, and vitamin E, or combination thereof. 
     
     
         21 . The solid dosage form of  claim 16 , wherein the sustained released reagent is polyvinylpyrrolidone (PVP), ethyl cellulose (EC), HPMC, polyacrylate, or a combination thereof. 
     
     
         22 . The solid dosage form of any one of  claims 16 - 21 , wherein the pH adjuster comprises a pharmaceutically acceptable base. 
     
     
         23 . The solid dosage form of  claim 22 , wherein the pH adjuster is sodium hydroxide, sodium acetate, or sodium bicarbonate. 
     
     
         24 . The solid dosage form of  claim 1 , wherein the cycloserine compound is in nanocrystalline form. 
     
     
         25 . The solid dosage form of  claim 1 , wherein the cycloserine compound is in particle form having a D 90  value ranging from about 0.05 μm to about 500 μm. 
     
     
         26 . The solid dosage form of  claim 1 , wherein the cycloserine compound is D-cycloserine or L-cycloserine, or a pharmaceutically acceptable salt thereof. 
     
     
         27 . The solid dosage form of  claim 1 , which is a pharmaceutical composition, a nutraceutical composition, a health food, or a medical food. 
     
     
         28 . A method for alleviating a symptom associated with a neuropsychiatric disease or tuberculosis, the method comprising administering to a subject in need thereof an effective amount of the solid dosage form of  claim 1 . 
     
     
         29 . The method of  claim 28 , wherein the neuropsychiatric disorder is selected from the group consisting of schizophrenia, psychotic disorders, Alzheimer's disease, frontotemporal dementia, vascular dementia, dementia with Lewy bodies, senile dementia, mild cognitive impairment, benign forgetfulness, ataxia symptoms, spinocerebellar, degeneration, closed head injury, autistic spectrum disorder, Asperger's disorder, pervasive developmental disorder—not otherwise specified (PDD-NOS), fragile X syndrome, attention deficit hyperactivity disorders, attention deficit disorder, obsessive compulsive disorder, tic disorders, childhood learning disorders, premenstrual syndrome, depression, major depressive disorder, anhedonia, suicidal ideation and/or behaviors, bipolar disorder, anxiety disorders, panic disorder, anorexia, nervosa, phobia, agoraphobia, claustrophobia, post-traumatic stress disorder, chronic mild and unpredictable stress, eating disorders, addiction disorders, personality disorders, Parkinson's disorder, Huntington's disorder, multiple sclerosis, amyotrophic lateral sclerosis, Tourette's syndrome, nocturnal enuresis, non-epileptic seizures, blepharospasm, Duchenne muscular dystrophy, stroke, chronic pain, neuropathic pain including hyperalgesia and allodynia, diabetic polyneuropathy, and chronic pain syndromes. 
     
     
         30 . The method of  claim 28 , wherein the solid dosage form is administered to the subject three times a day to one time every three months. 
     
     
         31 . The method of  claim 28 , wherein the subject is on an additional treatment for the neuropsychiatric disorder or wherein the subject is on an additional treatment of tuberculosis. 
     
     
         32 . The method of  claim 28 , further comprising administering to the subject an additional therapeutic agent for treating the neuropsychiatric disorder or tuberculosis.