METHODS OF TREATING PARKINSON'S DISEASE BY ADMINISTRATION OF APOMORPHINE TO AN ORAL MUCOSA

• US 20180133146A1
• Filed: 10/20/2017
• Published: 05/17/2018
• Est. Priority Date: 04/21/2015
• Status: Active Grant

• Current Assignee: Sunovion Pharmaceuticals Inc. (Sumitomo Chemical Company Limited)
• Original Assignee: Sunovion Pharmaceuticals Inc. (Sumitomo Chemical Company Limited)
• Inventors: BARNHART, Scott David, Koons, Michael Clinton, Hariharan, Madhu Sudan, Dubow, Jordan, Bilbault, Thierry, Giovinazzo, Anthony John
• Granted Patent: US 10,449,146 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/473 ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 47/38 Cellulose; Derivatives thereof
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61K 9/7007 Drug-containing films, membranes or sheets A61K9/0041, A61K9/0043, A61K9/006, A61K9/0063 take precedence
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs

Abstract

Methods and pharmaceutical unit dosage forms for treating Parkinson'"'"'s disease in a subject (e.g., an “off” episode in a subject having Parkinson'"'"'s disease) are described. The pharmaceutical unit dosage forms are films having a first portion including particles containing an acid addition salt of apomorphine and a second portion containing a pH neutralizing agent. The pharmaceutical unit dosage forms can be flexible and have toughness greater than 100 g×mm. The methods can involve administering to a subject having Parkinson'"'"'s disease a therapeutic dose sufficient to produce an apomorphine plasma concentrate of at least 2.64 ng/mL within 45 minutes after the administration. The subject may be identified as having low uptake, medium uptake, or high uptake of apomorphine administered via oral mucosa.

Claims

1. A method of treating an “

off”

episode in a subject having Parkinson'"'"'s disease, said method comprising;

(a) providing a film having a first portion comprising apomorphine particles comprising an acid addition salt of apomorphine and a second portion comprising a pH neutralizing agent; and

(b) sublingually administering said film to said subject,

wherein said film comprises an acid addition salt of apomorphine in an amount sufficient to produce, on average, following administration to the subject;

(i) an apomorphine plasma concentration of at least 2.64 ng/mL within 30 minutes, and (ii) an apomorphine Cmax is less than 10 ng/mL.

2. The method of claim 1, wherein the apomorphine T_max is from 20 to 60 minutes following said sublingually administering said film to said subject.

3. The method of claim 1, wherein the film maintains an apomorphine plasma concentration of at least 2.64 ng/mL is maintained for a period of at least 60 minutes.

12. The method of claim 1, wherein said film has a toughness greater than or equal to 100 g×

mm.

13. The method of claim 1, wherein said second portion comprises a permeation enhancer.

15. The method of claim 1, wherein said first portion comprises a permeation enhancer.

16. The method of claim 1, wherein said first portion is free of a permeation enhancer.

19. The method of claim 1, wherein said film comprises 20% (w/w) or more of a pharmaceutically acceptable high molecular weight polymer having a weight average molecular weight of 60 kDa or greater.

20. The method of claim 19, wherein said film comprises from 20% (w/w) to 40% (w/w) of said pharmaceutically acceptable high molecular weight polymer.

21. The method of claim 19, wherein said pharmaceutically acceptable high molecular weight polymer has a weight average molecular weight from 60 kDa to 1,000 kDa.

23. The method of claim 1, wherein said film comprises 5% (w/w) or less of a pharmaceutically acceptable low molecular weight polymer having a weight average molecular weight of less than 60 kDa.

29. The method of claim 1, wherein said film disintegrates in aqueous media in 2 minutes or less.

61. The method of claim 1, wherein said film has a toughness greater than or equal to 100 g×

mm.

62. The method of claim 1, wherein said film comprises 10±

2.5 mg, 15±

2.5 mg, 20.0±

2.5 mg, 25.0±

2.5 mg, 30.0±

5.0 mg, or 35.0±

5.0 mg of said acid addition salt of apomorphine.

4-7. -7. (canceled)

8. A method of treating Parkinson'"'"'s disease in a subject, said method comprising:

(a) providing a subject identified by titration as having low uptake, medium uptake, or high uptake in response to sublingually administered apomorphine; and

(b) (1) if said subject is a subject identified as having low uptake in response to sublingually administered apomorphine, sublingually administering a therapeutic dose comprising 10±

2.5 mg, 12.5±

2.5 mg, or 15±

2.5 mg of an acid addition salt of apomorphine to said subject;

(2) if said subject is a subject identified as having medium uptake in response to sublingually administered apomorphine, sublingually administering a therapeutic dose comprising 15.0±

2.5 mg, 20.0±

2.5 mg, or 25.0±

2.5 mg of an acid addition salt of apomorphine to said subject;

or

(3) if said subject is a subject identified as having high uptake in response to sublingually administered apomorphine, sublingually administering a therapeutic dose comprising 30.0±

5.0 mg, 35.0±

5.0 mg, or 40.0±

5.0 mg of an acid addition salt of apomorphine to said subject;

wherein said therapeutic dose is administered as a film having a first portion comprising apomorphine particles comprising an acid addition salt of apomorphine and a second portion comprising a pH neutralizing agent.

9-11. -11. (canceled)

14. (canceled)

17-18. -18. (canceled)

22. (canceled)

24-28. -28. (canceled)

30-31. -31. (canceled)

32. A pharmaceutical unit dosage form that is a film comprising a first portion comprising particles of an acid addition salt of apomorphine and a second portion comprising a pH neutralizing agent and a permeation enhancer, wherein said film has a toughness greater than or equal to 100 g×

mm.

37. The pharmaceutical unit dosage form of claim 32, wherein said first portion is free of a permeation enhancer.

39. The pharmaceutical unit dosage form of claim 32, wherein said permeation enhancer is a combination of menthol and glycerol monostearate.

57. The pharmaceutical unit dosage form of claim 32, wherein said film disintegrates in aqueous media in 2 minutes or less.

58. The pharmaceutical unit dosage form of claim 32, wherein said film disintegrates in aqueous media in 30 seconds or more.

33-36. -36. (canceled)

38. (canceled)

40-56. -56. (canceled)

59-60. -60. (canceled)