# US 11,077,073 B2 · Methods of using amantadine compositions > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,077,073 B2 - Document ID: US11077073B2 - Status: Granted - Kind: B2 - Application number: 16/409,554 - Filed: 2019-05-10 - Published: 2019-08-29 - Granted: 2021-08-03 - Earliest claimed: 2017-08-24 - Assignees: Adamas Pharma, LLC - Applicants: Adamas Pharma, LLC - Inventors: Gregory T. Went; Timothy J. Fultz; Sangita Ghosh; Natalie McClure - Web page: https://patentgrep.com/patent/US11077073B2 ## CPC - A61K 31/136: having the amino group directly attached to the aromatic ring, e.g. benzeneamine - A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration} - A61K 9/501: {Inorganic compounds} - A61K 9/5015: {Organic compounds, e.g. fats, sugars} - A61K 9/5026: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates} - A61K 9/5031: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)} - A61K 9/5042: {Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose} - A61K 9/5047: {Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose} - A61K 9/5078: {with drug-free core} - A61K 31/13: Amines {(A61K31/04 takes precedence)} - A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia - A61P 25/16: Anti-Parkinson drugs - A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract Provided herein are oral pharmaceutical compositions comprising amantadine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, and which have a low level of organic solvent. Provided are also methods of orally administrating a composition comprising amantadine, or a pharmaceutically acceptable salt thereof, to a subject, which has reduced gastrointestinal side effects or sleep disturbances. Further provided are extended release oral compositions comprising amantadine, or a pharmaceutically acceptable salt thereof, that are suitable for once daily administration. ## Claims ### Claim 1 A method of reducing levodopa-induced dyskinesia (LID) in a subject with Parkinson's disease in need thereof, comprising orally administering once daily to the subject an oral pharmaceutical composition comprising: a drug, wherein the drug is amantadine or a pharmaceutically acceptable salt thereof, and wherein said oral pharmaceutical composition comprises from 50 mg to 500 mg of the amantadine or an equivalent amount of the pharmaceutically acceptable salt thereof, and at least one excipient that modifies the release of at least a portion of said drug; wherein said oral pharmaceutical composition has a dissolution profile of said drug which shows: (i) 0% to 10% in 2 hours, (ii) 3% to 14% in 4 hours, (iii) 23% to 40% in 6 hours, and (iv) not less than 80% in 12 hours; wherein the dissolution profile is determined with a USP Type 2 apparatus (paddles) at 50 rpm at 37.0±0.5° C. with 500 ml water as the dissolution medium; and wherein said oral pharmaceutical composition provides (i) a Tmax for amantadine of 11 to 19 hours, and (ii) an AUC0-inf for amantadine of 44 to 72 ng*hr/ml per mg of said drug and (iii) a pAUC0-8 for amantadine of 1.0 to 2.0 ng*hr/ml per mg of said drug, when said oral pharmaceutical composition is dosed in healthy subjects of a single dose, human pharmacokinetic study, wherein the subjects are dosed in the morning after an overnight fast; wherein said oral pharmaceutical composition comprises less than 2000 ppm of organic solvent; and wherein LID is reduced in the subject. ### Claim 2 A method of increasing ON time without troublesome dyskinesia in a subject with Parkinson's disease in need thereof, wherein the subject has levodopa-induced dyskinesia (LID), the method comprising orally administering once daily to the subject an oral pharmaceutical composition comprising: a drug, wherein the drug is amantadine or a pharmaceutically acceptable salt thereof, and wherein said oral pharmaceutical composition comprises from 50 mg to 500 mg of the amantadine or an equivalent amount of the pharmaceutically acceptable salt thereof; and at least one excipient that modifies the release of at least a portion of said drug; wherein said oral pharmaceutical composition has a dissolution profile of said drug which shows: (i) not more than 9% dissolution at 2 hours, (ii) 3% to 14% dissolution at 4 hours, (iii) 20% to 43% dissolution at 6 hours, and (iv) at least 82% dissolution at 12 hours; wherein the dissolution profile is determined with a USP Type 2 apparatus (paddles) at 50 rpm at 37.0±0.5° C. with 500 ml water as the dissolution medium; wherein said oral pharmaceutical composition provides (i) a Tmax for amantadine of 11 to 19 hours, and (ii) an AUC0-inf for amantadine of 44 to 72 ng*hr/ml per mg of said drug and (iii) a pAUC0-8 for amantadine of 1.0 to 2.0 ng*hr/ml per mg of said drug, when said oral pharmaceutical composition is dosed in healthy subjects of a single dose, human pharmacokinetic study, wherein the subjects are dosed in the morning after an overnight fast; and wherein said oral pharmaceutical composition comprises less than 2000 ppm of organic solvent. ### Claim 3 A method of reducing OFF time in a subject with Parkinson's disease in need thereof, wherein the subject has levodopa-induced dyskinesia (LID), the method comprising orally administering once daily to the subject an oral pharmaceutical composition comprising: a drug, wherein the drug is amantadine or a pharmaceutically acceptable salt thereof, and wherein said oral pharmaceutical composition comprises from 50 mg to 500 mg of the amantadine or an equivalent amount of the pharmaceutically acceptable salt thereof; and at least one excipient that modifies the release of at least a portion of said drug; wherein said oral pharmaceutical composition has a dissolution profile of said drug which shows: (i) not more than 9% dissolution at 2 hours, (ii) 3% to 14% dissolution at 4 hours, (iii) 20% to 43% dissolution at 6 hours, and (iv) at least 82% dissolution at 12 hours; wherein the dissolution profile is determined with a USP Type 2 apparatus (paddles) at 50 rpm at 37.0±0.5° C. with 500 ml water as the dissolution medium; and wherein said oral pharmaceutical composition provides (i) a Tmax for amantadine of 11 to 19 hours, and (ii) an AUC0-inf for amantadine of 44 to 72 ng*hr/ml per mg of said drug and (iii) a pAUC0-8 for amantadine of 1.0 to 2.0 ng*hr/ml per mg of said drug, when said oral pharmaceutical composition is dosed in healthy subjects of a single dose, human pharmacokinetic study, wherein the subjects are dosed in the morning after an overnight fast; wherein said oral pharmaceutical composition comprises less than 2000 ppm of organic solvent; and wherein OFF time is reduced in the subject. ### Claim 4 A method of reducing levodopa-induced dyskinesia (LID) in a subject with Parkinson's disease in need thereof, comprising orally administering once daily to the subject an oral pharmaceutical composition comprising: a drug, wherein the drug is amantadine or a pharmaceutically acceptable salt thereof, and wherein said oral pharmaceutical composition comprises from 50 mg to 500 mg of the amantadine or an equivalent amount of the pharmaceutically acceptable salt thereof; and at least one excipient that modifies the release of at least a portion of said drug; wherein said oral pharmaceutical composition has a dissolution profile of said drug which shows: (i) not more than 10% dissolution at 2 hours; (ii) 5% to 13% dissolution at 4 hours; (iii) 20% to 43% dissolution at 6 hours; and (iv) at least 80% dissolution at 12 hours; wherein the dissolution profile is determined with a USP Type 2 apparatus (paddles) at 50 rpm at 37.0±0.5° C. with 500 ml water as the dissolution medium; and wherein said oral pharmaceutical composition provides (i) a Tmax for amantadine of 11 to 19 hours, and (ii) an AUC0-inf for amantadine of 44 to 72 ng*hr/ml per mg of said drug and (iii) a pAUC0-8 for amantadine of 1.0 to 2.0 ng*hr/ml per mg of said drug, when said oral pharmaceutical composition is dosed in healthy subjects of a single dose, human pharmacokinetic study, wherein the subjects are dosed in the morning after an overnight fast; wherein said oral pharmaceutical composition comprises less than 2000 ppm of organic solvent; and wherein LID is reduced in the subject. ### Claim 5 A method of reducing levodopa-induced dyskinesia (LID) in a subject with Parkinson's disease in need thereof, comprising orally administering once daily to the subject an oral pharmaceutical composition comprising: a drug, wherein the drug is amantadine or a pharmaceutically acceptable salt thereof, and wherein said oral pharmaceutical composition comprises from 50 mg to 500 mg of the amantadine or an equivalent amount of the pharmaceutically acceptable salt thereof; and at least one excipient that modifies the release of at least a portion of said drug; wherein said oral pharmaceutical composition has a dissolution profile of said drug which shows: (i) not more than 9% dissolution at 2 hours, (ii) 3% to 14% dissolution at 4 hours, (iii) 20% to 43% dissolution at 6 hours, and (iv) at least 82% dissolution at 12 hours; wherein the dissolution profile is determined with a USP Type 2 apparatus (paddles) at 50 rpm at 37.0±0.5° C. with 500 ml water as the dissolution medium; and wherein said oral pharmaceutical composition provides (i) a Tmax for amantadine of 11 to 19 hours, and (ii) an AUC0-inf for amantadine of 44 to 72 ng*hr/ml per mg of said drug and (iii) a pAUC0-8 for amantadine of 1.0 to 2.0 ng*hr/ml per mg of said drug, when said oral pharmaceutical composition is dosed in healthy subjects of a single dose, human pharmacokinetic study, wherein the subjects are dosed in the morning after an overnight fast; wherein said oral pharmaceutical composition comprises less than 2000 ppm of organic solvent; and wherein LID is reduced in the subject. ### Claim 6 (depends on 1) The method of claim 1, wherein the oral pharmaceutical composition comprises from 100 mg to 450 mg of amantadine, or an equivalent amount of a pharmaceutically acceptable salt thereof. ### Claim 7 (depends on 1) The method of claim 1, wherein the oral pharmaceutical composition comprises one, two, three, or four unit dosage forms. ### Claim 8 (depends on 1) The method of claim 1, wherein the oral pharmaceutical composition comprises one or two unit dosage forms. ### Claim 9 (depends on 1) The method of claim 1, wherein the drug is a pharmaceutically acceptable salt of amantadine. ### Claim 10 (depends on 1) The method of claim 1, wherein the drug is amantadine hydrochloride. ### Claim 11 (depends on 1) The method of claim 1, wherein the oral pharmaceutical composition comprises: a plurality of coated pellets, wherein each coated pellet comprises amantadine or a pharmaceutically acceptable salt thereof; and a capsule shell.