Method of administering amantadine prior to a sleep period

• US 9,867,793 B2
• Filed: 02/10/2017
• Issued: 01/16/2018
• Est. Priority Date: 12/02/2009
• Status: Active Grant

• Current Assignee: Adamas Pharma, LLC (Supernus Pharmaceuticals, Inc.)
• Original Assignee: Adamas Pharma, LLC (Supernus Pharmaceuticals, Inc.)
• Inventors: Went, Gregory T., Sathyan, Gayatri, Vermani, Kavita, Ganapati, Gangadhara, Coffee, Michael, Shek, Efraim, Katdare, Ashok
• Primary Examiner(s): Orwig, Kevin S
• Application Number:
  US15/430,084
• Publication Number:
  US 20170151190A1
• Time in Patent Office: 340 Days
• Field of Search: None
• 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. A method of treating levodopa-induced dyskinesia (LID) in a human patient with Parkinson'"'"'s disease, comprising orally administering to said human patient with Parkinson'"'"'s disease and levodopa-induced dyskinesia, once daily 0 to 4 hours before bedtime, a pharmaceutical composition comprising 220 mg to 455 mg of a drug selected from the group consisting of amantadine and pharmaceutically acceptable salts thereof, in an extended release dosage form,

wherein said extended release dosage form comprises one or more capsules each containing one or more pellets wherein each of said one or more pellets comprises:

a) a pellet core comprising said drug; and

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

wherein said drug is present at a weight percent of from 40% to 80% based on the combined weight of said pellet core and said extended release coating layer,

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

wherein said one or more capsules have an in vitro dissolution profile of said drug 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 Apparatus II (Paddles) at 50 rpm with 500 ml of water at 37°

C. as the dissolution medium, and

wherein the extended release dosage form has a Tmax for amantadine of 8 hours to 18 hours when the Tmax of the extended release form is determined in a fasted single dose human pharmacokinetic study.

4. The method of claim 1, wherein the one or more capsules have an in vitro dissolution profile of said drug of 25% to 55% at 6 hours.

5. The method of claim 1, wherein said extended release coating polymer comprises ethyl cellulose.

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

7. The method of claim 1, wherein the pharmaceutical composition comprises 260 mg to 420 mg of amantadine or a pharmaceutically acceptable salt thereof.

8. The method of claim 1, wherein the method reduces the severity or frequency of dyskinesia.

9. The method of claim 1, wherein said Tmax for amantadine is 12 hours to 18 hours.

10. The method of claim 1, wherein said pellet core further comprises a seed core and a binder.

11. The method of claim 10, wherein said seed core is a cellulose sphere.

12. The method of claim 10, wherein said binder comprises hydroxypropyl methylcellulose.

13. The method of claim 1, wherein said extended release dosage form comprises one, two,. or three capsules.

32. The method of claim 1, wherein said extended release dosage form is selected from the group consisting of one capsule comprising 340 mg of said drug and two capsules each comprising 170 mg of said drug.

33. The method of claim 32, wherein said drug is a pharmaceutically acceptable salt of amantadine.

34. The method of claim 32, wherein said drug is amantadine hydrochloride.

41. The method of claim 1, wherein said drug is present at a weight percent of from 40% to 65% based on the combined weight of said pellet core and said extended release coating layer.

2. A method of administering amantadine, or a pharmaceutically acceptable salt thereof, to a patient in need thereof, comprising orally administering to said patient in need thereof, once daily 0 to 4 hours before bedtime, a pharmaceutical composition comprising 220 mg to 455 mg of a drug selected from the group consisting of amantadine and pharmaceutically acceptable salts thereof, in an extended release dosage form,

wherein said extended release dosage form comprises one or more capsules each containing one or more pellets, wherein each of said one or more pellets comprises:

a) a pellet core comprising said drug; and

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

wherein said drug is present at a weight percent of from 40% to 80% based on the combined weight of said pellet core and said extended release coating layer,

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

wherein the one or more capsules have an in vitro dissolution profile of said drug 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 Apparatus II (Paddles at 50 rpm with 500 ml of water at 37°

C. as the dissolution medium, and

wherein the extended release dosage form has a Tmax for amantadine of 8 hours to 18 hours when the Tmax of the extended release form is determined in a fasted single dose human pharmacokinetic study.

14. The method of claim 2, wherein the one or more capsules have an in vitro dissolution profile of said drug of 25% to 55% at 6 hours.

15. The method of claim 2, wherein said extended release coating polymer comprises ethyl cellulose.

16. The method of claim 15, wherein said ethyl cellulose is present in an amount of 5 to 20% based on the combined weight of said pellet core and said extended release coating layer.

17. The method of claim 2, wherein the pharmaceutical composition comprises 260 mg to 420 mg of amantadine or a pharmaceutically acceptable salt thereof.

18. The method of claim 2, wherein the said Tmax for amantadine is 12 hours to 18 hours.

19. The method of claim 2, wherein said pellet core further comprises a seed core and a binder.

20. The method of claim 19, wherein said seed core is a cellulose sphere.

21. The method of claim 20, wherein said binder comprises hydroxypropyl methylcellulose.

22. The method of claim 2, wherein the extended release dosage form comprises one, two, or three capsules.

35. The method of claim 2, wherein said extended release dosage form is selected from the group consisting of one capsule comprising 340 mg of said drug and two capsules each comprising 170 mg of said drug.

36. The method of claim 35, wherein said drug is a pharmaceutically acceptable salt of amantadine.

37. The method of claim 35, wherein said drug is amantadine hydrochloride.

42. The method of claim 2, wherein said drug is present at a weight percent of from 40% to 65% based on the combined weight of said pellet core and said extended release coating layer.

3. A method of reducing sleep disturbances in a subject taking amantadine, comprising orally administering to said subject taking amantadine a pharmaceutical composition once daily 0 to 4 hours before bedtime, the pharmaceutical composition comprising 220 mg to 455 mg of a drug selected from the group consisting of amantadine and pharmaceutically acceptable salts thereof, in an extended release dosage form,

wherein said extended release dosage form comprises one or more capsules each containing one or more pellets wherein each of said one or more pellets comprises:

a) a pellet core comprising said drug; and

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

wherein said drug is present at a weight percent of from 40% to 80% based on the combined weight of said pellet core and said extended release coating layer,

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

wherein the one or more capsules have an in vitro dissolution profile of said drug 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 Apparatus II (Paddles) at 50 rpm with 500 ml of water at 37°

C. as the dissolution medium, and

wherein the extended release dosage form has a Tmax for amantadine of 8 hours to 18 hours when the Tmax of the extended release form is determined in a fasted single dose human pharmacokinetic study.

23. The method of claim 3, wherein the one or more capsules have an in vitro dissolution profile of said drug of 25% to 55% at 6 hours.

24. The method of claim 3, wherein said extended release coating polymer comprises ethyl cellulose.

25. The method of claim 24, wherein said ethyl cellulose is present in an amount of 5 to 20% based on the combined weight of said pellet core and said extended release coating layer.

26. The method of claim 3, wherein the pharmaceutical composition comprises 260 mg to 420 mg of amantadine or a pharmaceutically acceptable salt thereof.

27. The method of claim 3, wherein said Tmax for amantadine is 12 hours to 18 hours.

28. The method of claim 3, wherein said pellet core further comprises a seed core and a binder.

29. The method of claim 28, wherein said seed core is a cellulose sphere.

30. The method of claim 28, wherein said binder comprises hydroxypropyl methylcellulose.

31. The method of claim 3, wherein said extended release dosage form comprises one, two, or three capsules.

38. The method of claim 3, wherein said extended release dosage form is selected from the group consisting of one capsule comprising 340 mg of said drug and two capsules each comprising 170 mg of said drug.

39. The method of claim 38, wherein said drug is a pharmaceutically acceptable salt of amantadine.

40. The method of claim 38, wherein said drug is amantadine hydrochloride.

43. The method of claim 3, wherein said drug is present at a weight percent of from 40% to 65% based on the combined weight of said pellet core and said extended release coating layer.