Compositions and methods for mucosal delivery

• US 6,552,024 B1
• Filed: 11/05/1999
• Issued: 04/22/2003
• Est. Priority Date: 01/21/1999
• Status: Expired due to Fees

• Current Assignee: Thallium Holding Company, LLC
• Original Assignee: Lavipharm Laboratories Inc (Lavipharm SA)
• Inventors: Tao, Li, Tan, Hock Seng, Buranachokpaisan, Thitiwan, Renn, Donald W., Osborne, James, Pfister, William R., Chen, Li-Lan H.
• Primary Examiner(s): Dees, Jose' G.
• Assistant Examiner(s): CHOI, FRANK I
• Application Number:
  US09/434,878
• Time in Patent Office: 1,264 Days
• Field of Search: 424/400, 424/443, 424/444, 424/484, 424/485, 424/486, 424/487, 424/488, 514/182, 514/252.16, 514/258, 514/289, 514/343, 514/534
• US Class Current: 514/252.16
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 9/0007 Effervescent A61K9/0065 takes precedence
• CPC Class Codes: A61K 9/0031 Rectum, anus
• CPC Class Codes: A61K 9/0034 Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• 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: A61K 9/7015 Drug-containing film-forming compositions, e.g. spray-on
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Mucosal surface-coat-forming film dosage units containing a water-soluble hydrocolloid, an effective dose of an active agent and a mucosal adhesion enhancer; wherein the active agent is encapsulated within a polymer which is chemically or physically distinct from the hydocolloid; wherein the mucosal adhesion enhancer is a starch graft copolymer; wherein the film exhibits a dry tack value of less than 3.5 g, a wet tack of greater than 35 g, a gelation temperature that is greater than 70° C. for a 2% polymer solution, a dry film thickness of less than 20 mil, a water content of 0.5 to 10%, a tensile strength greater than 1500 psi, a modulus in the range of 35,000 to 300,000 psi, a % elongation of less than 20%, a tear probagation resistance of 0.001 to 1 N, and a dissolution time in the range of 1 to 600 seconds upon application to an oral mucosal surface.

Claims

1. A dosage unit, comprising:

an effective dose of sildenafil citrate;

the sildenafil citrate being formed in a solid dispersion with a water soluble inert filler, the solid dispersion being mixed with film forming reagents including a hydropolymer so as to form a film, the film being capable of dissolving on a mucosal surface so as to release the sildenafil citrate;

wherein the film exhibits a dry tack value of less than 3.5 g, a wet tack of greater than 35 g, a gelation temperature that is greater than 70°

C. for a 2% polymer solution, a dry film thickness of not more than 20 mil, a water content of 0.5 to 10%, a tensile strength greater than 1500 psi, a modulus in the range of 35,000 to 300,000 psi, a % elongation of less than 20%, a tear propagation resistance of 0.001 to 1 N, and a dissolution time of not more than 600 seconds upon application to an oral mucosal surface.

2. A dosage unit comprising a mucosal surface-coat-forming film, wherein the mucosal surface-coat-forming film comprises a water-soluble hydrocolloid, an effective dose of an active agent and a mucosal adhesion enhancer;

wherein the active agent is encapsulated within a polymer which is chemically or physically distinct from the hydocolloid;

wherein the mucosal adhesion enhancer is a starch graft copolymer;

wherein the film exhibits a dry tack value of less than 3.5 g, a wet tack of greater than 35 g, a gelation temperature that is greater than 70°

C. for a 2% polymer solution, a dry film thickness of no more than 20 mil, a water content of 0.5 to 10%, a tensile strength greater than 1500 psi, a modulus in the range of 35,000 to 300,000 psi, a % elongation of less than 20%, a tear propagation resistance of 0.001 to 1 N, and a dissolution time of not more than 600 seconds upon application to an oral mucosal surface.

3. The dosage unit of claim 2, wherein the mucosal adhesion enhancer is a copolymer of starch and acrylic acid.

4. The dosage unit of claim 2, wherein the film exhibits a dry tack value of less than 2.0 g.

5. The dosage unit of claim 2, wherein the water-soluble hydrocolloid exhibits a hydration rate in 24 hours of 5-20% at 75% humidity at room temperature.

6. The dosage unit of claim 2, wherein the water-soluble hydrocolloid is a polymer selected from the group consisting of a natural, semi-natural and synthetic biopolymer.

7. The dosage unit of claim 6, wherein the water-soluble hydrocolloid is selected from the group consisting of a polysaccharade and a polypeptide.

8. The dosage unit of claim 6, wherein the water-soluble hydrocolloid comprises a hydroxypropylmethylcellulose polymer.

9. The dosage unit of claim 8, wherein the hydroxypropylmethylcellulose polymer has a molecular weight of less than 200,000 Daltons.

10. The dosage unit of claim 2, wherein the film further comprises at least one of an emulsifier, a plasticizer, a taste modifying agent, a water soluble inert filler, a preservative, a coloring agent, a stabilizer and a buffering agent.

11. The dosage unit of claim 2, wherein the film further comprises an emulsifier present at a concentration in the range of 0.1 to 10 wt % of the dosage unit.

12. The dosage unit of claim 2, wherein the film further comprises a taste modifying agent comprising at least one of a sweetening agent, a flavoring agent and a taste masking agent.

13. The dosage unit of claim 2, wherein the film further comprises a water soluble inert filler present at a concentration in the range of 0.5 to 50 wt % of the dosage unit.

14. The dosage unit of claim 2, wherein the film further comprises a preservative present at a concentration in the range of 0.01 to 10 wt % of the dosage unit.

15. The dosage unit of claim 2, wherein the active agent is present at a concentration in the range of 0.01 to 75 wt % of the dosage unit.

16. The dosage unit of claim 2, wherein the active agent is selected from the group consisting of a therapeutic agent, a dietary supplement and a hygiene aid.

17. The dosage unit of claim 16, wherein the therapeutic agent is sildenafil citrate.

18. The dosage unit of claim 16, wherein the therapeutic agent is selected from the group consisting of nicotine, hydromorphone, oxybutynine and estradiol.

19. The dosage unit of claim 2, wherein the film has a dry film thickness in the range of 1 to 20 mil.

20. The dosage unit of claim 19, wherein the film has a dry film thickness of less than 10 mils.

21. The dosage unit of claim 2, wherein the film exhibits a dissolution time in the range of 10 to 600 seconds upon application to an oral mucosal surface.

22. The dosage unit of claim 2, wherein the film further exhibits a disintegration time in the range of 1 to 300 seconds upon application to an oral mucosal surface.

23. The dosage unit of claim 2, wherein the active agent is encapsulated within a polymer, wherein the polymer is chemically or physically distinct from the hydrocolloid.

24. The dosage unit of claim 2, wherein the dosage unit comprises at least two active agents.

25. The dosage unit of claim 2, wherein the mucosal adhesion enhancer is present at a concentration of up to 50wt %.

26. A dosage unit comprising a mucosal surface-coat-forming film, wherein the mucosal surface-coat-forming film comprises a water soluble hydrocolloid and an effective dose of an active agent, wherein the active agent comprises sildenafil citrate;

wherein the mucosal surface-coat-forming film exhibits a dry tack value of less than 3.5 g, a wet tack of greater than 35 g, a gelation temperature that is greater than 70°

C. for a 2% polymer solution, a dry film thickness of not more than 20 mil, a water content of 0.5 to 10%, a tensile strength greater than 1500 psi, a modulus in the range of 35,000 to 300,000 psi, a % elongation of less than 20%, a tear propagation resistance of 0.001 to 1 N, and a dissolution time of not more than 600 seconds upon application to an oral mucosal surface.

27. The dosage unit of claim 26, wherein the active agent further comprises xylitol and wherein the xylitol and sildenafil citrate form a solid dispersion.

28. The dosage unit of claim 27, wherein the mass ratio of sildenafil citrate to xylitol is 9/1.

29. The dosage form of claim 27, wherein the dosage unit further comprises a mucosal adhesion enhancer.

30. The dosage unit of claim 29, wherein the mucosal adhesion enhancer is a starch graft copolymer.

31. The dosage unit of claim 29, wherein the mucosal adhesion enhancer is a copolymer of starch and acrylic acid.

32. The dosage unit of claim 27, wherein the film exhibits a dry tack value of less than 2.0 g.

33. The dosage unit of claim 27, wherein the water-soluble hydrocolloid exhibits a gelation temperature that is greater than 70°

C. for a 2% polymer solution.

34. The dosage unit of claim 27, wherein the water-soluble hydrocolloid exhibits a hydration rate in 24 hours of 5-20% at 75% humidity at room temperature.

35. The dosage unit of claim 27, wherein the water-soluble hydrocolloid is a polymer selected from the group consisting of a natural, semi-natural and synthetic biopolymer.

36. The dosage unit of claim 35, wherein the water-soluble hydrocolloid is selected from the group consisting of a polysaccharade and a polypeptide.

37. The dosage unit of claim 35, wherein the water-soluble hydrocolloid comprises a hydroxypropylmethylcellulose polymer.

38. The dosage unit of claim 37, wherein the hydroxypropylmethylcellulose polymer has a molecular weight of less than 200,000 Daltons.

39. The dosage unit of claim 27, wherein the film further comprises at least one of an emulsifier, a plasticizer, a taste modifying agent, a water soluble inert filler, a preservative, a coloring agent, a stabilizer and a buffering agent.

40. The dosage unit of claim 27, wherein the film further comprises an emulsifier present at a concentration in the range of 0.1 to 10 wt % of the dosage unit.

41. The dosage unit of claim 27, wherein the film further comprises a taste modifying agent comprising at least one of a sweetening agent, a flavoring agent and a taste masking agent.

42. The dosage unit of claim 27, wherein the film further comprises a water soluble inert filler present at a concentration in the range of 0.5 to 50 wt % of the dosage unit.

43. The dosage unit of claim 27, wherein the film further comprises a preservative present at a concentration in the range of 0.01 to 10 wt % of the dosage unit.

44. The dosage unit of claim 27, wherein the active agent is present at a concentration in the range of 0.01 to 75 wt % of the dosage unit.

45. The dosage unit of claim 27, wherein the film has a dry film thickness in the range of 1 to 20 mil.

46. The dosage unit of claim 45, wherein the film has a dry film thickness of less than 10 mils.

47. The dosage unit of claim 27, wherein the film exhibits a dissolution time in the range of 10 to 600 seconds upon application to an oral mucosal surface.

48. The dosage unit of claim 27, wherein the film further exhibits a disintegration time in the range of 1 to 300 seconds upon application to an oral mucosal surface.

49. The dosage unit of claim 27, wherein the active agent is encapsulated within a polymer, wherein the polymer is chemically or physically distinct from the hydrocolloid.

50. The dosage unit of claim 27, wherein the dosage unit comprises at least two active agents.

51. The dosage unit of claim 27, wherein the mucosal adhesion enhancer is present at a concentration of up to 50 wt %.