Sublingual films

• US 8,414,922 B2
• Filed: 04/12/2012
• Issued: 04/09/2013
• Est. Priority Date: 12/16/2010
• Status: Active Grant

• Current Assignee: Sunovion Pharmaceuticals Inc. (Sumitomo Chemical Company Limited)
• Original Assignee: ARx, LLC (Adhesives Research Inc.), Cynapsus Therapeutics Inc. (Sumitomo Pharma America, Inc.)
• Inventors: Bryson, Nathan John, Giovinazzo, Anthony John, Barnhart, Scott David, Koons, Michael Clinton
• Primary Examiner(s): Wax, Robert A
• Assistant Examiner(s): Park, Sarah
• Application Number:
  US13/445,656
• Publication Number:
  US 20120195955A1
• Time in Patent Office: 362 Days
• Field of Search: None
• US Class Current: 424/472
• 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:

(A) a first layer comprising;

(i) from 10 to 75% (w/w) apomorphine hydrochloride;

(ii) from 0.5 to 10% (w/w) 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 35% (w/w) 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

(B) a second layer comprising;

(iv) from 6 to 65% (w/w) a pH neutralizing agent that is an organic base having a pKa of 5±

2, and

(v) 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,

wherein said first layer comprises from 2 to 60 mg of apomorphine hydrochloride,

wherein, following sublingual administration to subjects, said unit dosage form produces an average circulating concentration of 3 to 6 ng/mL within a period of from 7 to 20 minutes, and

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 4.5 and 6.5.

2. The pharmaceutical composition of claim 1, wherein said film further comprises from 3 to 12% (w/w) plasticizing agent.

3. The pharmaceutical composition of claim 2, wherein said plasticizing agent is a polyol, oleic acid, or triacetin.

4. The pharmaceutical composition of claim 3, wherein said plasticizing agent is a polyol selected from sorbitol, mannitol, maltitol, xylitol, glycerol, propylene glycol, and polyethylene glycol.

5. The pharmaceutical composition of claim 1, wherein said film comprises from 1 to 50% (w/w) hydrolyzed starch.

6. The pharmaceutical composition of claim 5, wherein said hydrolyzed starch is a dextrin or a maltodextrin.

7. The pharmaceutical composition of claim 1, wherein said film further comprises an antioxidant.

8. The pharmaceutical composition of claim 7, wherein said film further comprises from 0.05 to 2.5% (w/w) metabisulfite.

9. The pharmaceutical composition of claim 1, wherein said film further comprises from 0.2 to 5% (w/w) of a permeation enhancer.

10. The pharmaceutical composition of claim 9, wherein said permeation enhancer is glycerol monostearate.

11. The pharmaceutical composition of claim 1, wherein said low molecular weight polymer is hydroxypropyl methyl cellulose, hydroxypropyl cellulose, or hydroxyethyl cellulose.

12. The pharmaceutical composition of claim 11, wherein said hydroxypropyl methylcellulose has about 20% to about 35% methoxyl substitution and about 5% to about 15% hydroxypropyl substitution.

13. The pharmaceutical composition of claim 1, wherein said high molecular weight polymer is hydroxypropyl methyl cellulose or hydroxyethyl cellulose.

14. The pharmaceutical composition of claim 13, 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.

15. The pharmaceutical composition of claim 13, wherein said high molecular weight polymer is hydroxyethyl cellulose having a weight average molecular weight of from 60 KDa to 1,000 KDa.

16. The pharmaceutical composition of claim 1, wherein said organic base selected from pyridoxine, citrate, acetate, and histidine.

17. The pharmaceutical composition of claim 1, 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.

18. A method of treating Parkinson'"'"'s disease in a subject, said method comprising sublingual administration of a pharmaceutical composition of claim 1 in an amount effective to treat said subject.

19. The pharmaceutical composition of claim 16, wherein said organic base is pyridoxine.

20. The pharmaceutical composition of claim 1, wherein said unit dosage form comprises 12±

3 mg of apomorphine hydrochloride.

21. The pharmaceutical composition of claim 1, wherein said unit dosage form comprises 22±

4 mg of apomorphine hydrochloride.

22. The pharmaceutical composition of claim 1, wherein said unit dosage form comprises 30±

5 mg of apomorphine hydrochloride.

23. The pharmaceutical composition of claim 1, wherein said unit dosage form comprises 35±

5 mg of apomorphine hydrochloride.