Method of administering amantadine prior to a sleep period

• US 9,867,791 B2
• Filed: 02/09/2017
• 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:
  US15/428,899
• Publication Number:
  US 20170151184A1
• Time in Patent Office: 341 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 administering a dose of a pharmaceutical composition of a drug selected from the group consisting of amantadine and pharmaceutically acceptable salts thereof to a human patient in need thereof, comprising administering said dose of said pharmaceutical composition to said human patient orally, once daily 0 to 4 hours before bedtime, wherein said dose of said pharmaceutical composition comprises:

(i) 250 mg to 600 mg of the drug; and

(ii) one or more excipients, wherein at least one of said one or more excipients modifies the release of said drug to provide an extended release dosage form, and

wherein when said pharmaceutical composition is dosed in a single dose, fasted, human pharmacokinetic study in healthy subjects, the fractional AUC_0-4 for amantadine is less than 5% of AUC_0-inf and the Tmax of amantadine is 8 to 20 hours.

5. The method of claim 1, wherein when said pharmaceutical composition is dosed in a single dose, fasted, human pharmacokinetic study in healthy subjects, the Cmax for amantadine is 1.0 to 2.4 ng/ml per mg of amantadine.

6. The method of claim 1, wherein when said pharmaceutical composition is dosed in a single dose, fasted, human pharmacokinetic study in healthy subjects, the AUC_0-inf for amantadine is 40 to 75 ng*h/ml per mg of amantadine.

7. The method of claim 5, wherein when said pharmaceutical composition is dosed in a single dose, fasted, human pharmacokinetic study in healthy subjects, the AUC_0-inf for amantadine is 40 to 75 ng*h/ml per mg of amantadine.

8. The method of claim 1, wherein when said pharmaceutical composition is dosed in a multiple dose, fasted, human pharmacokinetic study in healthy subjects, the steady state AUC_0-24 for amantadine is 44 to 83 ng*h/ml per mg of amantadine.

9. The method of claim 5, wherein when said pharmaceutical composition is dosed in a multiple dose, fasted, human pharmacokinetic study in healthy subjects, the steady state AUC_0-24 for amantadine is 44 to 83 ng*h/ml per mg of amantadine.

10. The method of claim 1, wherein said patient is being treated for Parkinson'"'"'s disease.

11. The method of claim 5, wherein said patient is being treated for Parkinson'"'"'s disease.

12. The method of claim 8, wherein said patient is being treated for Parkinson'"'"'s disease.

13. The method of claim 10, wherein said patient suffers from levodopa-induced dyskinesia.

14. The method of claim 13, wherein the method reduces the frequency or severity of levodopa-induced dyskinesia in said patient.

15. The method of claim 1, wherein said dose of said pharmaceutical composition comprises 1 or 2 unit dosage forms.

16. The method of claim 15, wherein said unit dosage form comprises a capsule.

45. The method of claim 1, wherein said fractional AUC_0-4 for amantadine, said AUC_0-inf for amantadine and said Tmax for amantadine are determined from one subject of said human pharmacokinetic study.

46. The method of claim 1, wherein said fractional AUC_0-4 for amantadine and said AUC_0-inf for amantadine are mean values determined from said human pharmacokinetic study, and said Tmax for amantadine is the median value determined from said human pharmacokinetic study.

53. The method of claim 1, wherein said pharmaceutical composition is selected from the group consisting of one unit dosage form comprising 340 mg of said drug and two unit dosage forms each comprising 170 mg of said drug.

2. A method of administering a dose of a pharmaceutical composition of a drug selected from the group consisting of amantadine and pharmaceutically acceptable salts thereof to a human patient in need thereof, comprising administering said dose of said pharmaceutical composition to said human patient orally, once daily 0 to 4 hours before bedtime, wherein said dose of said pharmaceutical composition comprises:

(i) 250 mg to 600 mg of the drug; and

(ii) one or more excipients, wherein at least one of said one or more excipients modifies the release of said drug to provide an extended release dosage form, and

wherein when said pharmaceutical composition is dosed in a single dose, fasted, human pharmacokinetic study in healthy subjects, the fractional AUC_0-8 for amantadine is 5% to 15% of AUC_0-inf and the Tmax for amantadine is 8 to 20 hours.

17. The method of claim 2, wherein when said pharmaceutical composition is dosed in a single dose, fasted, human pharmacokinetic study in healthy subjects, the Cmax for amantadine is 1.0 to 2.4 ng/ml per mg of amantadine.

18. The method of claim 2, wherein when said pharmaceutical composition is dosed in a single dose, fasted, human pharmacokinetic study in healthy subjects, the AUC_0-inf for amantadine is 40 to 75 ng*h/ml per mg of amantadine.

19. The method of claim 17, wherein when said pharmaceutical composition is dosed in a single dose, fasted, human pharmacokinetic study in healthy subjects, the AUC_0-inf for amantadine is 40 to 75 ng*h/ml per mg of amantadine.

20. The method of claim 2, wherein when said pharmaceutical composition is dosed in a multiple dose, fasted, human pharmacokinetic study in healthy subjects, the steady state AUC_0-24 for amantadine is 44 to 83 ng*h/ml per mg of amantadine.

21. The method of claim 17, wherein when said pharmaceutical composition is dosed in a multiple dose, fasted, human pharmacokinetic study in healthy subjects, the steady state AUC_0-24 for amantadine is 44 to 83 ng*h/ml per mg of amantadine.

22. The method of claim 2, wherein said patient is being treated for Parkinson'"'"'s disease.

23. The method of claim 17, wherein said patient is being treated for Parkinson'"'"'s disease.

24. The method of claim 20, wherein said patient is being treated for Parkinson'"'"'s disease.

25. The method of claim 22, wherein said patient suffers from levodopa-induced dyskinesia.

26. The method of claim 25, wherein the method reduces the frequency or severity of levodopa-induced dyskinesia in said patient.

27. The method of claim 2, wherein said dose of said pharmaceutical composition comprises 1 or 2 unit dosage forms.

28. The method of claim 27, wherein said unit dosage form comprises a capsule.

47. The method of claim 2, wherein said fractional AUC_0-8 for amantadine, said AUC_0-inf for amantadine, and said Tmax for amantadine are determined from one subject of said human pharmacokinetic study.

48. The method of claim 2, wherein said fractional AUC_0-8 for amantadine and said AUC_0-inf for amantadine are mean values determined from said human pharmacokinetic study, and said Tmax for amantadine is the median value determined from said human pharmacokinetic study.

54. The method of claim 2, wherein said pharmaceutical composition is selected from the group consisting of one unit dosage form comprising 340 mg of said drug and two unit dosage forms each comprising 170 mg of said drug.

3. A method of administering a dose of a pharmaceutical composition of a drug selected from the group consisting of amantadine and pharmaceutically acceptable salts thereof to a human patient in need thereof, comprising administering said dose of said pharmaceutical composition to said human patient orally, once daily 0 to 4 hours before bedtime, wherein said dose of said pharmaceutical composition comprises:

(i) 250 mg to 600 mg of the drug; and

(ii) one or more excipients, wherein at least one of said one or more excipients modifies the release of said drug to provide an extended release dosage form, and

wherein when said pharmaceutical composition is dosed in a single dose, fasted, human pharmacokinetic study in healthy subjects, the fractional AUC_0-4 for amantadine is less than 5% of AUC_0-inf and the Cmax for amantadine is 1.0 to 2.4 ng/ml per mg of amantadine.

29. The method of claim 3, wherein when said pharmaceutical composition is dosed in a single dose, fasted, human pharmacokinetic study in healthy subjects, the AUC_0-inf for amantadine is 40 to 75 ng*h/ml per mg of amantadine.

30. The method of claim 3, wherein when said pharmaceutical composition is dosed in a multiple dose, fasted, human pharmacokinetic study in healthy subjects, the steady state AUC_0-24 for amantadine is 44 to 83 ng*h/ml per mg of amantadine.

31. The method of claim 3, wherein said patient is being treated for Parkinson'"'"'s disease.

32. The method of claim 29, wherein said patient is being treated for Parkinson'"'"'s disease.

33. The method of claim 31, wherein said patient suffers from levodopa-induced dyskinesia.

34. The method of claim 33, wherein the method reduces the frequency or severity of levodopa-induced dyskinesia in said patient.

35. The method of claim 3, wherein said dose of said pharmaceutical composition comprises 1 or 2 unit dosage forms.

36. The method of claim 35, wherein said unit dosage form comprises a capsule.

49. The method of claim 3, wherein said fractional AUC_0-4 for amantadine, said AUC_0-inf for amantadine, and said Cmax for amantadine are determined from one subject of said human pharmacokinetic study.

50. The method of claim 3, wherein said fractional AUC_0-4 for amantadine, said AUC_0-inf for amantadine, and said Cmax for amantadine are mean values determined from said human pharmacokinetic study.

55. The method of claim 3, wherein said pharmaceutical composition is selected from the group consisting of one unit dosage form comprising 340 mg of said drug and two unit dosage forms each comprising 170 mg of said drug.

4. A method of administering a dose of a pharmaceutical composition of a drug selected from the group consisting of amantadine and pharmaceutically acceptable salts thereof to a human patient in need thereof, comprising administering said dose of said pharmaceutical composition to said human patient orally, once daily 0 to 4 hours before bedtime, wherein said dose of said pharmaceutical composition comprises:

(i) 250 mg to 600 mg of the drug; and

(ii) one or more excipients, wherein at least one of said one or more excipients modifies the release of said drug to provide an extended release dosage form, and

wherein when said pharmaceutical composition is dosed in a single dose, fasted, human pharmacokinetic study in healthy subjects, the fractional AUC_0-8 for amantadine is 5% to 15% of AUC_0-inf and the Cmax for amantadine is 1.0 to 2.4 ng/ml per mg of amantadine.

37. The method of claim 4, wherein when said pharmaceutical composition is dosed in a single dose, fasted, human pharmacokinetic study in healthy subjects, the AUC_0-inf for amantadine is 40 to 75 ng*h/ml per mg of amantadine.

38. The method of claim 4, wherein when said pharmaceutical composition is dosed in a multiple dose, fasted, human pharmacokinetic study in healthy subjects, the steady state AUC_0-24 for amantadine is 44 to 83 ng*h/ml per mg of amantadine.

39. The method of claim 4, wherein said patient is being treated for Parkinson'"'"'s disease.

40. The method of claim 37, wherein said patient is being treated for Parkinson'"'"'s disease.

41. The method of claim 39, wherein said patient suffers from levodopa-induced dyskinesia.

42. The method of claim 41, wherein the method reduces the frequency or severity of levodopa-induced dyskinesia in said patient.

43. The method of claim 4, wherein said dose of said pharmaceutical composition comprises 1 or 2 unit dosage forms.

44. The method of claim 43, wherein said unit dosage form comprises a capsule.

51. The method of claim 4, wherein said fractional AUC_0-8 for amantadine, said AUC_0-inf for amantadine, and said Cmax for amantadine are determined from one subject of said human pharmacokinetic study.

52. The method of claim 4, wherein said fractional AUC_0-8 for amantadine, said AUC_0-inf for amantadine, and said Cmax for amantadine are mean values determined from said human pharmacokinetic study.

56. The method of claim 4, wherein said pharmaceutical composition is selected from the group consisting of one unit dosage form comprising 340 mg of said drug and two unit dosage forms each comprising 170 mg of said drug.