SUBLINGUAL FILMS

• US 20160338972A1
• Filed: 08/02/2016
• Published: 11/24/2016
• Est. Priority Date: 12/16/2010
• Status: Active Grant

• Current Assignee: Sunovion Pharmaceuticals Inc. (Sumitomo Chemical Company Limited)
• Original Assignee: Cynapsus Therapeutics Inc. (Sumitomo Chemical Company Limited)
• Inventors: BRYSON, Nathan John, GIOVINAZZO, Anthony John, BARNHART, Scott David, KOONS, Michael Clinton
• Granted Patent: US 10,285,953 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61F 13/00063 comprising medicaments or additives, e.g. odor control, PH control, debriding, antimicrobic drug delivery dressings A61K9/70; chemical aspect of the additives A61L15/00
• CPC Class Codes: A61J 1/03 for pills or tablets containers for pills or tablets with special dispensing means therefor B65D83/04
• CPC Class Codes: A61J 7/0053 Syringes, pipettes or oral dispensers
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/381 having five-membered rings
• CPC Class Codes: A61K 31/4045 Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• CPC Class Codes: A61K 31/428 condensed with carbocyclic rings
• CPC Class Codes: A61K 31/4415 Pyridoxine, i.e. Vitamin B6 pyridoxal phosphate A61K31/675
• CPC Class Codes: A61K 31/473 ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• CPC Class Codes: A61K 31/48 Ergoline derivatives, e.g. lysergic acid, ergotamine
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• 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 47/12 Carboxylic acids; Salts or anhydrides thereof
• 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 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• 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 9/209 : containing drug in at least two layers or in the core and in at least one outer layer
• 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
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: B29C 39/18 : incorporating preformed parts or layers, e.g. casting around inserts or for coating articles B29C39/206 takes precedence
• CPC Class Codes: B29C 39/38 : Heating or cooling
• CPC Class Codes: B29C 43/305 : Making multilayered articles
• CPC Class Codes: B29C 43/52 : Heating or cooling
• CPC Class Codes: B29C 65/70 : by moulding using a particular moulding technique, see the relevant technique , e.g. by injection B29C45/14467
• CPC Class Codes: B29C 66/45 : Joining of substantially the whole surface of the articles methods or apparatus for laminating B32B37/00
• CPC Class Codes: B29K 2001/00 : Use of cellulose, modified cellulose or cellulose derivatives, e.g. viscose, as moulding material
• CPC Class Codes: B29L 2007/008 : Wide strips, e.g. films, webs
• CPC Class Codes: B29L 2009/00 : Layered products
• CPC Class Codes: B29L 2031/753 : Medical equipment; Accessories therefor bloodbags, medical bags B29L2031/7148; artificial eyes B29L2011/0008
• CPC Class Codes: B29L 2031/755 : Membranes, diaphragms
• CPC Class Codes: B65D 65/38 : Packaging materials of special type or form

Abstract

The invention features sublingual film formulations of dopamine agonists and methods of treating Parkinson'"'"'s disease, tremors, restless leg syndrome, sexual dysfunction, and depressive disorders therewith.

Claims

1. A pharmaceutical composition in unit dosage form formulated for sublingual administration, wherein said unit dosage form is a film comprising 30±

5% (w/w) one or more disintegrants and a plasticizing agent, said film having a first portion comprising apomorphine hydrochloride, and a second portion comprising pH neutralizing agent, wherein said unit dosage form comprises from 0.5 to 5 mg, from 4 to 10 mg, or from 8 to 20 mg of apomorphine hydrochloride and said pH neutralizing agent is present in an amount sufficient to produce a solution having a pH of between 3.0 and 6.5 when said unit dosage form is placed in unbuffered water at pH 7.

2. The pharmaceutical composition of claim 1, wherein said unit dosage form further comprises a high molecular weight polymer having a weight average molecular weight of greater than 60 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose.

3. The pharmaceutical composition of claim 1 or 2, wherein said unit dosage form further comprises a low molecular weight polymer having a weight average molecular weight of from 5 KDa to 50 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose.

6. The pharmaceutical composition of any one of claims 1-3 or 5, wherein said pH neutralizing agent is meglumine, pyridoxine, or magnesium hydroxide.

7. The pharmaceutical composition of claim 6, wherein said pH neutralizing agent is pyridoxine.

8. The pharmaceutical composition of any one of claims 1-7, further comprising 1±

0.5% (w/w) permeation enhancer.

9. The pharmaceutical composition of claim 8, wherein said permeation enhancer is glycerol monostereate.

10. The pharmaceutical composition of any one of claims 1-9, wherein said pharmaceutical composition comprises from 3 to 15% (w/w) plasticizing agent.

11. The pharmaceutical composition of any one of claims 1-3 or 10, wherein said plasticizing agent is a polyol, oleic acid, or triacetin.

12. The pharmaceutical composition of claim 11, wherein said plasticizing agent is a polyol selected from sorbitol, mannitol, maltitol, xylitol, glycerol, propylene glycol, and polyethylene glycol.

14. The pharmaceutical composition of any one of claims 1-3 or 13, wherein said hydrolyzed starch is a dextrin.

15. The pharmaceutical composition of claim 14, wherein said hydrolyzed starch is a maltodextrin.

16. The pharmaceutical composition of any one of claims 1-15, wherein said pharmaceutical composition further comprises an antioxidant.

17. The pharmaceutical composition of claim 16, wherein said pharmaceutical further comprises from 0.05 to 2.5% (w/w) metabisulfite.

18. The pharmaceutical composition of any one of claims 1-17, wherein said pharmaceutical composition has a sublingual bioavailability of greater than 40%.

19. The pharmaceutical composition of any one of claims 1-18, wherein said pharmaceutical composition has a T_max of from 10 to 25 minutes.

20. The pharmaceutical composition of claim 19, wherein following sublingual administration to a subject said unit dosage form produces an average circulating apomorphine concentration of at least 3 ng/mL within a period of from 5 to 15 minutes.

21. The pharmaceutical composition of any of claims 1-18, wherein said unit dosage form when administered sublingually to a subject is non-irritating.

22. The pharmaceutical composition of any of claims 1-18, wherein said unit dosage form is an individual film packaged in a sealed plastic-lined aluminum foil, wherein said unit dosage form is stable for a period of at least 2 months at 40 PC.

4. A pharmaceutical composition in unit dosage form formulated for sublingual administration, wherein said unit dosage form is a film comprising:

(i) apomorphine hydrochloride;

(ii) a low molecular weight polymer having a weight average molecular weight of from 5 KDa to 50 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose; and

(iii) a high molecular weight polymer having a weight average molecular weight of greater than 60 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose,

wherein said unit dosage form comprises from 0.5 to 5 mg, from 4 to 10 mg, or from 8 to 20 mg of apomorphine hydrochloride.

13. The pharmaceutical composition of any one of claims 4-9, wherein said pharmaceutical composition further comprises from 1 to 50% (w/w) hydrolyzed starch.

5. A pharmaceutical composition in unit dosage form formulated for sublingual administration, wherein said unit dosage form is a bilayer film having a first layer and a second layer, said second layer comprising a pH neutralizing agent and said first layer comprising:

(i) apomorphine hydrochloride;

(ii) a low molecular weight polymer having a weight average molecular weight of from 5 KDa to 50 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose; and

(iii) a high molecular weight polymer having a weight average molecular weight of greater than 60 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose,

wherein said unit dosage form comprises from 0.5 to 5 mg, from 4 to 10 mg, or from 8 to 20 mg of apomorphine hydrochloride and said pH neutralizing agent is present in an amount sufficient to produce a solution having a pH of between 3.0 and 6.5 when said unit dosage form is placed in unbuffered water at pH 7.

23. A pharmaceutical composition in unit dosage form formulated for sublingual administration, said unit dosage form having a first portion comprising an acid addition salt of a dopamine agonist, and a second portion comprising a pH neutralizing agent, wherein said dopamine agonist is selected from bromocriptine, cabergoline, dihydroergocryptine, lisuride, piribedil, pergolide, pramipexole, rotigotine, and ropinirol.

24. The pharmaceutical composition of claim 23, wherein said unit dosage form is a lozenge, a pill, a tablet, a film, or a strip.

51. The pharmaceutical composition of any of claims 23-50, wherein said dopamine agonist is selected from apomorphine, an apomorphine prodrug, bromocriptine, cabergoline, dihydroergocryptine, lisuride, piribedil, pergolide, pramipexole, rotigotine, and ropinirol.

70. The pharmaceutical composition of any of claims 23-69, wherein said unit dosage form when administered sublingually to a subject is non-irritating.

72. The pharmaceutical composition of any of claims 23-69, wherein said dopamine agonist in said unit dosage form has a sublingual bioavailability of greater than 40%.

73. The pharmaceutical composition of any of claims 23-69, wherein said unit dosage form is an individual film packaged in a sealed plastic-lined aluminum foil, wherein said unit dosage form is stable for a period of at least 2 months at 40 PC.

76. A method of treating Parkinson'"'"'s disease in a subject, said method comprising sublingual administration of a pharmaceutical composition of any of claims 23-73 in an amount effective to treat said subject.

77. A method of treating tremor in a subject, said method comprising sublingual administration of a pharmaceutical composition of any of claims 23-73 in an amount effective to treat said subject.

78. A method of treating restless leg syndrome in a subject, said method comprising sublingual administration of a pharmaceutical composition of any of claims 23-73 in an amount effective to treat said subject.

79. A method for alleviating dyskinesia in a subject afflicted with Parkinson'"'"'s disease, said method comprising sublingual administration of a pharmaceutical composition of any of claims 23-73 in an amount effective to alleviate said dyskinesia.

80. A method for alleviating akinesia in a subject afflicted with Parkinson'"'"'s disease, said method comprising sublingual administration of a pharmaceutical composition of any of claims 23-73 in an amount effective to alleviate said akinesia.

81. A method of treating sexual dysfunction in a subject, said method comprising sublingual administration of a pharmaceutical composition of any of claims 23-73 in an amount effective to treat said subject.

82. A method of treating a depressive disorder in a subject, said method comprising sublingual administration of a pharmaceutical composition of any of claims 23-73 in an amount effective to treat said subject.

83. The method of any of claims 76-82, further comprising the administration of an effective amount of an anti-emetic agent.

84. The method of claim 83, wherein said anti-emetic agent is selected from nicotine, lobeline sulfate, pipamazine, oxypendyl hydrochloride, ondansetron, buclizine hydrochloride, cyclizine hydrochloride, dimenhydrinate, scopolamine, metopimazine, benzauinamine hydrochloride, and diphenidol hydrochloride.

25. A pharmaceutical composition in unit dosage form formulated for sublingual administration, wherein said unit dosage form is a film comprising:

(i) from 30 to 75% (w/w) dopamine agonist, or an acid addition salt thereof;

(ii) from 0.5 to 10% (w/w) of a low molecular weight polymer having a weight average molecular weight of from 5 KDa to 50 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose; and

(iii) from 4 to 20% (w/w) of a high molecular weight polymer having a weight average molecular weight of greater than 60 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose.

27. The pharmaceutical composition of claim 25 or 26, wherein said film further comprises from 3 to 12%/o (w/w) plasticizing agent.

28. The pharmaceutical composition of claim 27, wherein said plasticizing agent is a polyol, oleic acid, or triacetin.

29. The pharmaceutical composition of claim 28, wherein said plasticizing agent is a polyol selected from sorbitol, mannitol, maltitol, xylitol, glycerol, propylene glycol, and polyethylene glycol.

30. The pharmaceutical composition of claim 25 or 26, wherein said film further comprises from 1 to 50% (w/w) hydrolyzed starch.

31. The pharmaceutical composition of claim 30, wherein said hydrolyzed starch is a dextrin.

32. The pharmaceutical composition of claim 30, wherein said hydrolyzed starch is a maltodextrin.

33. The pharmaceutical composition of claim 25 or 26, wherein said film further comprises an antioxidant.

34. The pharmaceutical composition of claim 33, wherein said film further comprises from 0.05 to 2.5% (w/w) metabisulfite.

35. The pharmaceutical composition of claim 25 or 26, wherein said film further comprises from 0.2 to 5% (w/w) of a permeation enhancer.

36. The pharmaceutical composition of claim 35, wherein said permeation enhancer is selected from ionic surfactants, nonionic surfactants, polysorbates, derivatives of tocopherol, poloxamers, monoglycerides, diglycerides, fatty acids, and fatty alcohols.

37. The pharmaceutical composition of claim 25 or 26, wherein said low molecular weight polymer is hydroxypropyl methyl cellulose, hydroxypropyl cellulose, or hydroxyethyl cellulose.

38. The pharmaceutical composition of claim 37, wherein said hydroxypropyl methylcellulose has about 20% to about 35% methoxyl substitution and about 5% to about 15% hydroxypropyl substitution.

39. The pharmaceutical composition of claim 25 or 26, wherein said high molecular weight polymer is hydroxypropyl methyl cellulose or hydroxyethyl cellulose.

40. The pharmaceutical composition of claim 39, wherein said high molecular weight polymer is hydroxypropyl methyl cellulose having about 20% to about 35% methoxyl substitution and about 5% to about 15% hydroxypropyl substitution.

41. The pharmaceutical composition of claim 39, wherein said high molecular weight polymer is hydroxyethyl cellulose having a weight average molecular weight of from 60 KDa to 1,000 KDa.

42. The pharmaceutical composition of claim 25, wherein said first layer is separated from said second layer by a barrier.

43. The pharmaceutical composition of claim 42, wherein said barrier is a third layer.

44. The pharmaceutical composition of claim 25, wherein said film has a surface coated with a pH neutralizing agent.

46. The pharmaceutical composition of claim 44 or 45, wherein said pH neutralizing agent is an inorganic base.

47. The pharmaceutical composition of claim 46, wherein said inorganic base is selected from aluminum hydroxide, aluminosilicates, calcium hydroxide, magnesium hydroxide, potassium hydroxide, sodium hydroxide, calcium carbonate, iron carbonate, magnesium carbonate, zinc carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate monobasic, sodium phosphate dibasic, sodium phosphate tribasic, potassium phosphate monobasic, potassium phosphate dibasic, potassium phosphate tribasic, and mixtures thereof.

48. The pharmaceutical composition of claim 47, wherein said pH neutralizing agent is an organic base.

49. The pharmaceutical composition of claim 48, wherein said organic base is selected from amines, acetate salts, citrate salts, stearate salts, laurate salts, proprionate salts, lactate salts, succinate salts, oxalate salts, tartrate salts, glycolate salts, galacturonate salts, glucuronate salts, alginate salts, sorbate salts, caprylate salts, carboxymethyl cellulose, polyacrylate, and mixtures thereof.

50. The pharmaceutical composition of claim 49, wherein said organic base is an amine selected from pyridoxine, meglumine, lysine, Eudragit E, diethanolamine, glycine, citrate, acetate, histidine, N-methyl glucamine, and tris(hydroxymethyl)aminomethane.

52. The pharmaceutical composition of any of claim 25 or 26, wherein said dopamine agonist is selected from an acid addition salt of apomorphine, an apomorphine prodrug, bromocriptine, cabergoline, dihydroergocryptine, lisuride, piribedil, pergolide, pramipexole, rotigotine, and ropinirol.

53. The pharmaceutical composition of claim 25 or 26, wherein said film comprises a solid solution of an acid addition salt of ropinirol.

54. The pharmaceutical composition of claim 25 or 26, wherein said film comprises a solid solution of an acid addition salt of said dopamine agonist.

55. The pharmaceutical composition of claim 25 or 26, wherein said film comprises dopamine agonist particles having an effective particle size of from 20 nm to 10 μ

m, wherein said dopamine agonist particles comprise apomorphine, an apomorphine prodrug, bromocriptine, cabergoline, dihydroergocryptine, lisuride, piribedil, pergolide, pramipexole, rotigotine, ropinirol, or a salt thereof.

56. The pharmaceutical composition of claim 25 or 26, wherein said film comprises apomorphine particles having an effective particle size of from 20 nm to 10 μ

m, wherein said apomorphine particles comprise apomorphine, an apomorphine prodrug, or a salt thereof.

57. The pharmaceutical composition of claim 25 or 26, wherein said film comprises apomorphine hydrochloride.

58. The pharmaceutical composition of claim 25 or 26, wherein said film comprises ropinirol hydrochloride.

59. The pharmaceutical composition of claim 25 or 26, wherein said unit dosage form comprises from 0.1 to 100 mg of a dopamine agonist selected from apomorphine, an apomorphine prodrug, or an acid addition salt thereof.

60. The pharmaceutical composition of claim 25 or 26, wherein said unit dosage form comprises from 0.1 to 100 mg of a dopamine agonist selected from ropinirol, or an acid addition salt thereof.

61. The pharmaceutical composition of claim 25 or 26, wherein said unit dosage form comprises from 0.1 to 100 mg of a dopamine agonist selected from bromocriptine, or an acid addition salt thereof.

62. The pharmaceutical composition of claim 25 or 26, wherein said unit dosage form comprises from 0.1 to 100 mg of a dopamine agonist selected from cabergoline, or an acid addition salt thereof.

63. The pharmaceutical composition of claim 25 or 26, wherein said unit dosage form comprises from 0.1 to 100 mg of a dopamine agonist selected from dihydroergocryptine, or an acid addition salt thereof.

64. The pharmaceutical composition of claim 25 or 26, wherein said unit dosage form comprises from 0.1 to 100 mg of a dopamine agonist selected from lisuride, or an acid addition salt thereof.

65. The pharmaceutical composition of claim 25 or 26, wherein said unit dosage form comprises from 0.1 to 100 mg of a dopamine agonist selected from piribedil, or an acid addition salt thereof.

66. The pharmaceutical composition of claim 25 or 26, wherein said unit dosage form comprises from 0.1 to 100 mg of a dopamine agonist selected from pergolide, or an acid addition salt thereof.

67. The pharmaceutical composition of claim 25 or 26, wherein said unit dosage form comprises from 0.1 to 100 mg of a dopamine agonist selected from pramipexole, or an acid addition salt thereof.

68. The pharmaceutical composition of claim 25 or 26, wherein said unit dosage form comprises from 0.1 to 100 mg of a dopamine agonist selected from rotigotine, or an acid addition salt thereof.

71. The pharmaceutical composition of claim 25 or 26, wherein said dopamine agonist is selected from apomorphine, an apomorphine prodrug, or a salt thereof, and wherein following sublingual administration to a subject said unit dosage form produces an average circulating concentration of at least 3 ng/mL within a period of from 5 to 15 minutes.

74. A kit comprising:

(i) a first film of claim 25;

(ii) a pH neutralizing agent; and

(iii) instructions for administering said first film and said pH neutralizing agent simultaneously to a subject.

75. The kit according to claim 74, wherein said pH neutralizing agent is pyridoxine.

26. A pharmaceutical composition in unit dosage form formulated for sublingual administration, wherein said unit dosage form is a bilayer film having a first layer and a second layer, said first layer comprising:

(i) from 30 to 75% (w/w) dopamine agonist, or an acid addition salt thereof;

(ii) from 0.5 to 10% (w/w) of a low molecular weight polymer having a weight average molecular weight of from 5 KDa to 50 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose; and

(iii) from 4 to 20% (w/w) of a high molecular weight polymer having a weight average molecular weight of greater than 60 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose,

and wherein said second layer comprises a pH neutralizing agent and from 15 to 50% (w/w) of a high molecular weight polymer having a weight average molecular weight of greater than 60 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose.

45. The pharmaceutical composition of claim 26, wherein said second layer comprises from 10 to 50% (w/w) pH neutralizing agent.

69. The pharmaceutical composition of claim 26, wherein said unit dosage form when placed in 1 mL of unbuffered water at pH 7 results in a solution having a pH of between 2.5 and 8.0.

85. A method of preparing a bilayer film having a first layer and a second layer, said method comprising:

(i) forming a first viscous solution by mixing an aqueous solution comprising a volatile organic solvent with (a) from 30 to 75% (w/w) dopamine agonist, or an acid addition salt thereof;

(b) from 0.5 to 10% (w/w) of a low molecular weight polymer having a weight average molecular weight of from 5 KDa to 50 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose;

(c) from 4 to 20% (w/w) of a high molecular weight polymer having a weight average molecular weight of greater than 60 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose;

(d) from 3 to 12% (w/w) of a plasticizing agent; and

(e) from 1 to 50% (w/w) hydrolyzed starch;

(ii) casting said first viscous solution onto an inert support, and drying the solution to form a first film layer;

(iii) forming a second viscous solution by mixing an aqueous solution comprising a volatile organic solvent with (a) from 15 to 50% (w/w) of a high molecular weight polymer having a weight average molecular weight of greater than 60 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose;

(b) from 10 to 50% (w/w) pH neutralizing agent;

(c) from 3 to 12% (w/w) of a plasticizing agent; and

(d) from 1 to 50% (w/w) hydrolyzed starch;

(iv) casting said second viscous solution onto an inert support, and drying the solution to form a second film layer;

(v) contacting faces of said first film layer and said second film layer with a volatile organic solvent, pressing said faces together such that said volatile organic solvent is sandwiched between said first film layer and said second film layer, and drying the layers to form a bilayer film.

86. The method of claim 85, wherein said plasticizing agent is a polyol, oleic acid, or triacetin.

87. The method of claim 86, wherein said plasticizing agent is a polyol selected from sorbitol, mannitol, maltitol, xylitol, glycerol, propylene glycol, and polyethylene glycol.

88. The method of claim 85, wherein said hydrolyzed starch is a dextrin.

89. The method of claim 85, wherein said hydrolyzed starch is a maltodextrin.

90. The method of any of claims 85-89, wherein said volatile organic solvent comprises acetone, ethanol, isopropyl alcohol, dimethyl ether, diethyl ether, butanol, propanol, ethyl acetate, or combinations thereof.

91. The method of any of claims 85-90, wherein said dopamine agonist is selected from an acid addition salt of apomorphine, an apomorphine prodrug, bromocriptine, cabergoline, dihydroergocryptine, lisuride, piribedil, pergolide, pramipexole, rotigotine, ropinirol, and acid addition salts thereof.