AMANTADINE COMPOSITIONS AND METHODS OF USE

• US 20170151190A1
• Filed: 02/10/2017
• Published: 06/01/2017
• Est. Priority Date: 12/02/2009
• Status: Active Grant

• Current Assignee: Adamas Pharma, LLC (Supernus Pharmaceuticals, Inc.)
• Original Assignee: Adamas Pharmaceuticals, Inc. (Supernus Pharmaceuticals, Inc.)
• Inventors: WENT, Gregory T., SATHYAN, Gayatri, VERMANI, Kavita, GANAPATI, Gangadhara, COFFEE, Michael, SHEK, Efraim, KATDARE, Ashok
• Granted Patent: US 9,867,793 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/13 Amines A61K31/04 takes precedence
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 9/0002 Galenical forms characterised by the drug release technique; Application systems commanded by energy
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61K 9/48 Preparations in capsules, e.g. of gelatin, of chocolate A61K9/0004 takes precedence; bite capsules A61K9/0056
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/4891 Coated capsules; Multilayered drug free capsule shells with drug coating for immediate release A61K9/4808; osmotic devices A61K9/0004
• CPC Class Codes: A61K 9/50 Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals A61K9/2081 takes precedence; particles with a single coating comprising drug A61K9/167
• CPC Class Codes: A61K 9/5015 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5047 Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: 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

Abstract

Methods of nighttime administration of amantadine to reduce sleep disturbances in patient undergoing treatment with amantadine are described, as well as compositions of extended release amantadine that are suitable for nighttime administration.

Claims

1-28. -28. (canceled)

29. A method of treating dyskinesia, comprising:

orally administering to a human patient with Parkinson'"'"'s disease who is taking levodopa, a pharmaceutical composition comprising 50 mg to 500 mg of a drug selected from the group consisting of amantadine and pharmaceutically acceptable salts thereof in an extended release dosage form, once daily 0 to 4 hours before bedtime,

said extended release dosage form comprising a capsule containing a plurality of pellets wherein said pellets comprise;

a) a pellet core comprising amantadine or a pharmaceutically acceptable salt thereof; and

b) an extended release coating layer comprising an extended release coating polymer, a pore former, and a plasticizer surrounding the pellet core,

wherein said amantadine or pharmaceutically acceptable salt thereof is present at a weight percent of from 40% to 65% based on the combined weight of said pellet cores and said extended release coating layers,

wherein said extended release coating layer is present at a weight percent from 10% to 30% based on the combined weight of said pellet cores and said extended release coating layers, and

said pharmaceutical composition having an in vitro dissolution profile of amantadine of not more than 10% at 1 hour, not more than 25% at 2 hours, and at least 80% at 12 hours, using a USP type 2 (paddle) dissolution system at 50 rpm with 500 ml of water at 37°

C. as the dissolution medium.

32. The method of claim 29, wherein said pharmaceutical composition has an in vitro dissolution profile of amantadine of 25% to 55% at 6 hours using a USP type 2 (paddle) dissolution system at 50 rpm with 500 ml of water at 37°

C. as the dissolution medium.

33. The method of claim 29, wherein said extended release coating polymer is ethyl cellulose.

34. The method of claim 33, wherein said ethyl cellulose is present in an amount of 5 to 20% based on the combined weight of said pellet cores and said extended release coating layers.

35. The method of claim 29, wherein 200mg to 500mg of amantadine or a pharmaceutically acceptable salt is administered daily to said human subject.

36. The method of claim 29, wherein the method reduces the severity or frequency of dyskinesia.

37. The method of claim 29, wherein the extended release dosage form provides a Tmax of 8 hours to 18 hours when the Tmax of the extended release dosage form is determined in a single dose human pharmacokinetic study.

38. The method of claim 29, wherein said pellet core additionally comprises a seed core and a binder.

39. The method of claim 38, wherein said seed core is a cellulose sphere.

40. The method of claim 38, wherein said binder comprises hydroxypropyl methylcellulose.

41. The method of claim 29, wherein said pharmaceutical composition is encapsulated in one, two or three capsules, and said one, two, or three capsules are administered to said human subject once daily.

30. A method of administering amantadine to a patient in need thereof, comprising:

orally administering to said patient, a pharmaceutical composition comprising 50 mg to 500 mg of a drug selected from the group consisting of amantadine and pharmaceutically acceptable salts thereof in an extended release dosage form, once daily 0-4 hours before bedtime,

said extended release dosage form comprising a capsule containing a plurality of pellets wherein said pellets comprise;

a) a pellet core comprising amantadine or a pharmaceutically acceptable salt thereof; and

b) an extended release coating layer comprising an extended release coating polymer, a pore former, and a plasticizer surrounding the pellet core,

wherein said amantadine or pharmaceutically acceptable salt thereof is present at a weight percent of from 40% to 65% based on the combined weight of said pellet cores and said extended release coating layers,

wherein said extended release coating layer is present at a weight percent from 10% to 30% based on the combined weight of said pellet cores and said extended release coating layers, and

said pharmaceutical composition having an in vitro dissolution profile of amantadine of not more than 10% at 1 hour, not more than 25% at 2 hours, and at least 80% at 12 hours, using a USP type 2 (paddle) dissolution system at 50 rpm with 500 ml of water at 37°

C. as the dissolution medium.

42. The method of claim 30, wherein said pharmaceutical composition has an in vitro dissolution profile of amantadine of 25% to 55% at 6 hours using a USP type 2 (paddle) dissolution system at 50 rpm with 500 ml of water at 37°

C. as the dissolution medium.

43. The method of claim 30, wherein said extended release coating polymer is ethyl cellulose.

44. The method of claim 43, wherein said ethyl cellulose is present in an amount of 5 to 20% based on the combined weight of said pellet cores and said extended release coating layers.

45. The method of claim 30, wherein 200mg to 500mg of amantadine or a pharmaceutically acceptable salt is administered daily to said human subject.

46. The method of claim 30, wherein the extended release dosage form provides a Tmax of 8 hours to 18 hours when the Tmax of the extended release dosage form is determined in a single dose human pharmacokinetic study.

47. The method of claim 30, wherein said pellet core additionally comprises a seed core and a binder.

48. The method of claim 47, wherein said seed core is a cellulose sphere.

49. The method of claim 47, wherein said binder comprises hydroxypropyl methylcellulose.

50. The method of claim 30, wherein one, two or three capsules containing said pharmaceutical composition are administered to said human subject once daily.

31. A method of reducing sleep disturbances in a subject taking amantadine, comprising:

orally administering to said subject, a pharmaceutical composition comprising 50 mg to 500 mg of a drug selected from the group consisting of amantadine and pharmaceutically acceptable salts thereof in an extended release dosage form, once daily 0-4 hours before bedtime,

said extended release dosage form comprising a capsule containing a plurality of pellets wherein said pellets comprise;

a) a pellet core comprising amantadine or a pharmaceutically acceptable salt thereof; and

b) an extended release coating layer comprising an extended release coating polymer, a pore former, and a plasticizer surrounding the pellet core,

wherein said amantadine or pharmaceutically acceptable salt thereof is present at a weight percent of from 40% to 65% based on the combined weight of said pellet cores and said extended release coating layers,

wherein said extended release coating layer is present at a weight percent from 10% to 30% based on the combined weight of said pellet cores and said extended release coating layers, and

said pharmaceutical composition having an in vitro dissolution profile of amantadine of not more than 10% at 1 hour, not more than 25% at 2 hours, and at least 80% at 12 hours, using a USP type 2 (paddle) dissolution system at 50 rpm with 500 ml of water at 37°

C. as the dissolution medium.

51. The method of claim 31, wherein said pharmaceutical composition has an in vitro dissolution profile of amantadine of 25% to 55% at 6 hours using a USP type 2 (paddle) dissolution system at 50 rpm with 500 ml of water at 37°

C. as the dissolution medium.

52. The method of claim 31, wherein said extended release coating polymer is ethyl cellulose.

53. The method of claim 52, wherein said ethyl cellulose is present in an amount of 5 to 20% based on the combined weight of said pellet cores and said extended release coating layers.

54. The method of claim 31, wherein 200mg to 500mg of amantadine or a pharmaceutically acceptable salt is administered daily to said human subject.

55. The method of claim 31, wherein the extended release dosage form provides a Tmax of 8 hours to 18 hours when the Tmax of the extended release dosage form is determined in a single dose human pharmacokinetic study.

56. The method of claim 31, wherein said pellet core additionally comprises a seed core and a binder.

57. The method of claim 56, wherein said seed core is a cellulose sphere.

58. The method of claim 56, wherein said binder comprises hydroxypropyl methylcellulose.

59. The method of claim 31, wherein one, two or three capsules containing said pharmaceutical composition are administered to said human subject once daily.