Claims for Patent: 10,959,943

Summary for Patent: 10,959,943

Title:	Methods of treating Parkinson's disease by administration of apomorphine to an oral mucosa
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.times.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.
Inventor(s):	Barnhart; Scott David (York, PA), Koons; Michael Clinton (York, PA), Hariharan; Madhu Sudan (Greensboro, NC), Dubow; Jordan (Glencoe, IL), Bilbault; Thierry (Cambridge, MA), Giovinazzo; Anthony John (Caledon, CA)
Assignee:	Sunovion Pharmaceuticals Inc. (Marlborough, MA)
Application Number:	16/564,864
Patent 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 an acid addition salt of apomorphine and a second portion comprising a pH neutralizing agent; and (b) determining an effective dose of said film by uptitration of said subject; and (c) sublingually administering said effective dose of said film to said subject, wherein said effective dose of said film comprises an acid addition salt of apomorphine in an amount sufficient to produce, on average, following administration to subjects: (i) an apomorphine plasma concentration of at least 2.64 ng/mL within 30 minutes, (ii) an apomorphine Cmax of less than 10 ng/mL, and (iii) an apomorphine T.sub.max of from 20 to 60 minutes. 2. 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 an acid addition salt of apomorphine and a second portion comprising a pH neutralizing agent; and (b) determining an effective dose of said film by uptitration of said subject; and (c) sublingually administering said effective dose of said film to said subject, wherein said effective dose of said film comprises an acid addition salt of apomorphine in an amount sufficient to produce, on average, following administration to subjects: (i) an apomorphine plasma concentration of at least 2.64 ng/mL within 30 minutes, (ii) an apomorphine Cmax of less than 10 ng/mL, and (iii) an apomorphine plasma concentration of at least 2.64 ng/mL for a period of at least 60 minutes. 3. The method of claim 1, wherein said film comprises 12.5.+-.2.5 mg of an acid addition salt of apomorphine. 4. The method of claim 1, wherein said film comprises 17.5.+-.2.5 mg of an acid addition salt of apomorphine. 5. The method of claim 1, wherein said film comprises 25.0.+-.5.0 mg of an acid addition salt of apomorphine. 6. The method of claim 1, wherein said film comprises 35.+-.10.0 mg of an acid addition salt of apomorphine. 7. 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 an acid addition salt of apomorphine and a second portion comprising a pH neutralizing agent; and (b) determining an effective dose of said film by uptitration of said subject; and (c) sublingually administering said effective dose of said film to said subject, wherein said effective dose of said film comprises an acid addition salt of apomorphine in an amount sufficient to produce, on average, following administration to subjects: (i) an apomorphine plasma concentration of at least 2.64 ng/mL within 30 minutes, and (ii) an apomorphine Cmax of less than 10 ng/mL; and wherein an effective amount of an antiemetic is administered to said subject prior to administering said film. 8. The method of claim 7, wherein an effective amount of said antiemetic is administered to said subject for at least 2 days prior to administering said film. 9. The method of claim 1, wherein said film has a toughness greater than or equal to 100 g.times.mm. 10. The method of claim 1, wherein said second portion comprises a permeation enhancer. 11. The method of claim 1, wherein said film comprises less than 10% (w/w) of a permeation enhancer. 12. The method of claim 1, wherein said first portion comprises a permeation enhancer. 13. The method of claim 10, wherein said first portion is free of a permeation enhancer. 14. The method of claim 10, wherein said permeation enhancer is menthol, an ionic surfactant, a nonionic surfactant, a polysorbate, a tocopherol derivative, a poloxamer, a monoglyceride, a diglyceride, a fatty acid, or a fatty alcohol, or a combination thereof. 15. The method of claim 14, wherein said permeation enhancer is a mixture of menthol and glycerol monostearate. 16. 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. 17. The method of claim 16, wherein said film comprises from 20% (w/w) to 40% (w/w) of said pharmaceutically acceptable high molecular weight polymer. 18. The method of claim 16, wherein said pharmaceutically acceptable high molecular weight polymer has a weight average molecular weight from 60 kDa to 1,000 kDa. 19. The method of claim 16, wherein said pharmaceutically acceptable high molecular weight polymer is carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, or methyl cellulose, or a combination thereof. 20. 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. 21. The method of claim 20, wherein said film comprises from 0.01% (w/w) to 5% (w/w) of said pharmaceutically acceptable low molecular weight polymer. 22. The method of claim 20, wherein said pharmaceutically acceptable low molecular weight polymer has a weight average molecular weight of from .sub.5 kDa to 50 kDa. 23. The method of claim 20, wherein said pharmaceutically acceptable low molecular weight polymer is carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, or methyl cellulose, or a combination thereof. 24. The method of claim 23, wherein said pharmaceutically acceptable low molecular weight polymer is hydroxypropyl cellulose. 25. The method of claim 1, wherein said second portion is free of a pharmaceutically acceptable low molecular weight polymer. 26. The method of claim 1, wherein said film disintegrates in aqueous media in 2 minutes or less. 27. The method of claim 1, wherein said film disintegrates in aqueous media in 30 seconds or more. 28. The method of claim 7, wherein said film comprises 12.5.+-.2.5 mg of an acid addition salt of apomorphine. 29. The method of claim 7, wherein said film comprises 17.5.+-.2.5 mg of an acid addition salt of apomorphine. 30. The method of claim 7, wherein said film comprises 25.0.+-.5.0 mg of an acid addition salt of apomorphine. 31. The method of claim 7, wherein said film comprises 35.+-.10.0 mg of an acid addition salt of apomorphine. 32. The method of claim 7, wherein said film has a toughness greater than or equal to 100 g.times.mm. 33. The method of claim 7, wherein said second portion comprises a permeation enhancer. 34. The method of claim 7, wherein said film comprises less than 10% (w/w) of a permeation enhancer. 35. The method of claim 7, wherein said first portion comprises a permeation enhancer. 36. The method of claim 33, wherein said first portion is free of a permeation enhancer. 37. The method of claim 33, wherein said permeation enhancer is menthol, an ionic surfactant, a nonionic surfactant, a polysorbate, a tocopherol derivative, a poloxamer, a monoglyceride, a diglyceride, a fatty acid, or a fatty alcohol, or a combination thereof. 38. The method of claim 37, wherein said permeation enhancer is a mixture of menthol and glycerol monostearate. 39. The method of claim 7, 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. 40. The method of claim 39, wherein said film comprises from 20% (w/w) to 40% (w/w) of said pharmaceutically acceptable high molecular weight polymer. 41. The method of claim 39, wherein said pharmaceutically acceptable high molecular weight polymer has a weight average molecular weight from 60 kDa to 1,000 kDa. 42. The method of claim 39, wherein said pharmaceutically acceptable high molecular weight polymer is carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, or methyl cellulose, or a combination thereof. 43. The method of claim 7, 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. 44. The method of claim 43, wherein said film comprises from 0.01% (w/w) to 5% (w/w) of said pharmaceutically acceptable low molecular weight polymer. 45. The method of claim 43, wherein said pharmaceutically acceptable low molecular weight polymer has a weight average molecular weight of from 5 kDa to 50 kDa. 46. The method of claim 43, wherein said pharmaceutically acceptable low molecular weight polymer is carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, or methyl cellulose, or a combination thereof. 47. The method of claim 46, wherein said pharmaceutically acceptable low molecular weight polymer is hydroxypropyl cellulose. 48. The method of claim 40, wherein said second portion is free of a pharmaceutically acceptable low molecular weight polymer. 49. The method of claim 2, wherein said film comprises 12.5.+-.2.5 mg of an acid addition salt of apomorphine. 50. The method of claim 2, wherein said film comprises 17.5.+-.2.5 mg of an acid addition salt of apomorphine. 51. The method of claim 2, wherein said film comprises 25.0.+-.5.0 mg of an acid addition salt of apomorphine. 52. The method of claim 2, wherein said film comprises 35.+-.10.0 mg of an acid addition salt of apomorphine.