Claims for Patent: 11,065,213

Summary for Patent: 11,065,213

Title:	Amantadine compositions and preparations thereof
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.
Inventor(s):	Went; Gregory T. (San Francisco, CA), Fultz; Timothy J. (Big Canoe, GA), Ghosh; Sangita (Foster City, CA), McClure; Natalie (Portola Valley, CA)
Assignee:	Adamas Pharma, LLC (Emeryville, CA)
Application Number:	16/677,431
Patent Claims:	1. 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.degree. 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 AUC.sub.0-inf for amantadine of 44 to 72 ng*hr/ml per mg of said drug, and (iii) a pAUC.sub.0-8 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 the oral pharmaceutical composition comprises less than 2000 ppm of organic solvent. 2. 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.degree. 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 AUC.sub.0-inffor amantadine of 44 to 72 ng*hr/ml per mg of said drug, and (iii) a pAUC.sub.0-8 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 the oral pharmaceutical composition comprises less than 2000 ppm of organic solvent. 3. 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.degree. 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 AUC.sub.0-inffor amantadine of 44 to 72 ng*hr/ml per mg of said drug, and (iii) a pAUC.sub.0-8 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 the oral pharmaceutical composition comprises less than 2000 ppm of organic solvent. 4. The oral pharmaceutical composition of claim 1, comprising from 100 mg to 450 mg of amantadine, or an equivalent amount of a pharmaceutically acceptable salt thereof. 5. The oral pharmaceutical composition of claim 1, comprising one, two, three, or four unit dosage forms. 6. The oral pharmaceutical composition of claim 1, comprising one or two unit dosage forms. 7. The oral pharmaceutical composition of claim 1, wherein the drug is a pharmaceutically acceptable salt of amantadine. 8. The oral pharmaceutical composition of claim 1, wherein the drug is amantadine hydrochloride. 9. The oral pharmaceutical composition of claim 1, comprising: a plurality of coated pellets, wherein each coated pellet comprises amantadine or a pharmaceutically acceptable salt thereof; and a capsule shell.