Mucoadhesive erodible drug delivery device for controlled administration of pharmaceuticals and other active compounds

• US 6,585,997 B2
• Filed: 08/16/2001
• Issued: 07/01/2003
• Est. Priority Date: 08/16/2001
• Status: Expired due to Term

• Current Assignee: Uluru Inc.
• Original Assignee: Access Pharmaceuticals Inc.
• Inventors: Moro, Daniel G., Nowotnik, David, Callahan, Howard
• Primary Examiner(s): Azpuru, Carlos A.
• Application Number:
  US09/931,319
• Publication Number:
  US 20030044446A1
• Time in Patent Office: 684 Days
• Field of Search: 424/434, 424/435, 424/448, 424/449
• US Class Current: 424/434
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/12 Keratolytics, e.g. wart or anti-corn preparations
• CPC Class Codes: A61P 23/02 Local anaesthetics
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The present invention relates to a layered pharmaceutical delivery device for the administration of pharmaceuticals or other active compounds to mucosal surfaces. The device may also be used by itself without the incorporation of a therapeutic. The device of the present invention consists of a water-soluble adhesive layer, a non-adhesive, bioerodable backing layer and one or more pharmaceuticals if desired in either or both layers. Upon application, the device adheres to the mucosal surface, providing protection to the treatment site and localized drug delivery. The “Residence Time”, the length of time the device remains on the mucosal surface before complete erosion, can be easily regulated by modifications of the backing layer.

Claims

1. A mucoadhesive, erodible multi-layered device comprising a first, water-soluble adhesive layer to be placed in contact with a mucosal surface and a second, water-erodible non-adhesive backing layer that controls residence time of the device;

wherein said first layer comprises at least one water-soluble film-forming polymer in combination with at least one mucoadhesive polymer; and

said second, water-erodible non-adhesive backing layer comprises a precast film containing at least one of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyethylene glycol, polyethylene oxide, and ethylene oxide-propylene oxide co-polymer, said backing layer being coated with at least one hydrophobic polymer, alone or in combination with at least one hydrophilic polymer, such that the backing layer is bioerodible.

2. The device of claim 1 defined further as for use with or without an incorporated pharmaceutical agent.

3. The device of claim 1 defined further as being for protection of a mucosal site or the administration of a pharmaceutical agent locally, regionally or systemically.

4. The mucoadhesive, erodible multi-layered device of claim 1, wherein said first water-soluble adhesive layer comprises at least one water-soluble film-forming polymer selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and hydroxyethyl methylcellulose, in combination with at least one mucoadhesive polymer selected from the group consisting of polyacrylic acid, polyvinyl pyrrolidone, and sodium carboxymethyl cellulose.

5. The mucoadhesive, erodible multi-layered device of claim 1, wherein said second water-erodible non-adhesive backing layer acts as a casting and support surface on which the adhesive layer is prepared, and comprises a premade film of hydroxypropyl methyl cellulose in combination with a coating consisting of at least one hydrophobic polymer selected from the family of quaternary ammonium acrylate/methacrylate co-polymers, (Eudragit RS) ethyl cellulose and methyl cellulose, alone or in combination with at least one hydrophilic polymer, selected from the group consisting of polyvinyl pyrrolidone, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and polyvinyl alcohol.

6. The mucoadhesive, erodible multi-layered device of claim 1, wherein said second water-erodible non-adhesive backing layer comprises a premade film of hydroxypropyl methylcellulose and a coating of a hydrophobic and hydrophilic polymer mixture at a ratio of 0.5:

1 to 18;

1.

7. The device of claim 1 wherein said second water-erodible non-adhesive backing layer comprises a premade film of hydroxypropyl methylcellulose and a coating of a hydrophobic and hydrophilic polymer mixture at a ratio of 1:

0 to 10;

1.

8. The device of claim 6 where the non-adhesive backing layer comprises a precast film of hydroxypropyl methylcellulose and coating mixture of hydrophobic and hydrophilic polymers at a ratio of 1:

0 to 10;

1, wherein the coating contains at least one of propylene glycol, polyethylene glycol, or glycerine, as a plasticizer to improve flexibility.

9. The device of claim 6 where the non-adhesive backing layer comprises a premade film of hydroxypropyl methylcellulose and coating mixture of hydrophobic and hydrophilic polymers at a ratio of 1:

0 to 10;

1, wherein the coating mixture contains at least one of hyaluronic acid and alpha hydroxyl acid as a humectant to improve softness or feel.

10. The device of claim 9 where the humectant is glycolic acid.

11. The device of claim 1 where the non-adhesive backing layer comprises a precast film of hydroxypropyl methylcellulose and coating mixture of hydrophobic and hydrophilic polymers at a ratio of 1:

0 to 10;

1, wherein the coating mixture contains titanium dioxide, zinc oxide, or zirconium silicate as an opacifier one or less FD&

C Red, Yellow, Green or Blue as a coloring agent to help distinguish the backing layer from the mucoadhesive layer.

12. The mucoadhesive, erodible multi-layered device of claim 1 wherein said backing layer comprises a premade film of hydroxypropyl methyl cellulose, a coating comprising a mixture of hydrophobic and hydrophilic polymers at a ratio of 1:

0 to 10;

1, a plasticizer, and a coloring agent or an opacifier whose combined total is less than about 4% by weight of the device.

13. The mucoadhesive, erodible multi-layered device of claim 1 further comprising at least one pharmaceutical agent incorporated within said first or second layer.

14. The multi-layered pharmaceutical carrier device of claim 13, wherein said first or second layer contains a flavoring agent to mask the taste of the pharmaceutical agent or to improve patient compliance.

15. The multi-layered pharmaceutical carrier device of claim 13, wherein said pharmaceutical agent comprises an anti-allergic agent.

16. The multi-layered pharmaceutical carrier device of claim 15, wherein said anti-allergic agent is amlexanox, astemizole, azelastinep, emirolast, alopatadine, cromolyn, fenpiprane, repirinast, tranilast, or traxanox.

17. The multi-layered pharmaceutical carrier device of claim 13, wherein said pharmaceutical agent comprises an anti-inflammatory analgesic agent.

18. The multi-layered pharmaceutical carrier device of claim 17, wherein said anti-inflammatory analgesic agent is acetaminophen, methyl salicylate, monoglycol salicylate, aspirin, mefenamic acid, flufenamic acid, indomethacin, diclofenac, alclofenac, diclofenac sodium, ibuprofen, ketoprofen, naproxen, pranoprofen, fenoprofen, sulindac, fenclofenac, clidanac, flubiprofen, fentiazac, bufexamac, piroxicam, phenylbutazone, oxyphenbutazone, clofezone, pentazocine, mepirizole, or tiaramide hydrochloride.

19. The multi-layered pharmaceutical carrier device of claim 13, wherein said pharmaceutical agent comprises an antianginal agent.

20. The multi-layered pharmaceutical carrier device of claim 19, wherein said antianginal agent is nifedipine, atenolol, bepridil, carazolol, or epanolol.

21. The multi-layered pharmaceutical carrier device of claim 13, wherein said pharmaceutical agent comprises a steroidal anti-inflammatory agent.

22. The multi-layered pharmaceutical carrier device of claim 21, wherein said steroidal anti-inflammatory agent is hydrocortisone, predonisolone, dexamethasone, triamcinolone acetonide, fluocinolone acetonide, hydrocortisone acetate, predonisolone acetate, methylpredonisolone, dexamethasone acetate, betamethasone, betamethasone valerate, flutetasone, fluormetholone, or orbeclomethasone dipropionate.

23. The multi-layered pharmaceutical carrier device of claim 13, wherein said pharmaceutical agent comprises an antihistamine.

24. The multi-layered pharmaceutical carrier device of claim 23, wherein said antihistamine is diphenhydramine hydrochloride, chlorpheniramine maleate, isothipendyl hydrochloride, tripelennamine hydrochloride, promethazine hydrochloride, or methdilazine hydrochloride.

25. The multi-layered pharmaceutical carrier device of claim 13, wherein said pharmaceutical agent comprises a local anesthetic.

26. The multi-layered pharmaceutical carrier device of claim 25, wherein said local anesthetic is dibucaine hydrochloride, dibucaine, lidocaine hydrochloride, lidocaine, benzocaine, p-buthylaminobenzoic acid, 2-(di-ethylamino) ethyl ester hydrochloride, procaine hydrochloride, tetracaine, tetracaine hydrochloride, chloroprocaine hydrochloride, oxyprocaine hydrochloride, mepivacaine, cocaine hydrochloride, piperocaine hydrochloride, dyclonine, or dyclonine hydrochloride.

27. The multi-layered pharmaceutical carrier device of claim 13, wherein said pharmaceutical agent comprises a bactericide or disinfectant.

28. The multi-layered pharmaceutical carrier of claim 27, wherein said bactericide or disinfectant is thimerosal, phenol, thymol, benzalkonium chloride, chlorhexidine, povidone iodine, cetylpyridinium chloride, eugenol, trimethylammonium bromide, benzoic acid or sodium benzoate.

29. The multi-layered pharmaceutical carrier device of claim 13, wherein said pharmaceutical agent comprises a vasoconstrictor.

30. The multi-layered pharmaceutical carrier device of claim 29, wherein said vasoconstrictor is naphazoline nitrate, tetrahydrozoline hydrochloride, oxymetazoline hydrochloride, phenylephrine hydrochloride, or tramazolinehydrochloride.

31. The multi-layered pharmaceutical carrier device of claim 13, wherein said pharmaceutical agent comprises a hemostatic agent.

32. The multi-layered pharmaceutical carrier device of claim 31, wherein said hemostatic agent is thrombin, phytonadione, protamine sulfate, aminocaproic acid, tranexamic acid, carbazochrome, carbaxochrome sodium sulfate, rutin, or hesperidin.

33. The multi-layered pharmaceutical carrier device of claim 13, wherein said pharmaceutical agent comprises a chemotherapeutic agent.

34. The multi-layered pharmaceutical device of claim 33, wherein said chemotherapeutic agent is sulfamine, sulfathiazole, sulfadiazine, homosulfamine, sulfisoxazole, sulfisomidine, sulfamethizole, nitrofurazone, taxanes, platinum compound, topoisomerase 1 inhibitor, or anthracycline.

35. The multi-layered pharmaceutical carrier device of claim 13, wherein said pharmaceutical agent comprises an antibiotic.

36. The multi-layered pharmaceutical carrier device of claim 35, wherein said antibiotic is penicillin, meticillin, oxacillin, cefalotin, cefalordin, erythromycin, lincomycin, tetracycline, chlortetracycline, oxytetracycline, chloramphenicol, kanamycin, streptomycin, gentamicin, bacitracin, cycloserine, or clindamycin.

37. The multi-layered pharmaceutical carrier device of claim 13, wherein said pharmaceutical agent comprises a keratolytic agent.

38. The multi-layered pharmaceutical carrier device of claim 37, wherein said keratolytic agent is salicylic acid, podophyllum resin, podolifox, or cantharidin.

39. The multi-layered pharmaceutical carrier device of claim 13, wherein said pharmaceutical agent comprises a cauterizing agent.

40. The multi-layered pharmaceutical carrier device of claim 39, wherein said cauterizing agent is chloroacetic acid or silver nitrate.

41. The multi-layered pharmaceutical carrier device of claim 13, wherein said pharmaceutical agent comprises a hormone.

42. The multi-layered pharmaceutical carrier device of claim 41, wherein said hormone is estrone, estradiol, testosterone, equilin, or human growth hormone.

43. The multi-layered pharmaceutical carrier device of claim 13, wherein said pharmaceutical agent comprises a growth hormone inhibitor.

44. The multi-layered pharmaceutical carrier device of claim 43, wherein said growth hormone inhibitor is octreotide or somatostatin.

45. The multi-layered pharmaceutical carrier device of claim 13, wherein said pharmaceutical agent comprises an analgesic narcotic.

46. The multi-layered pharmaceutical carrier device of claim 45, wherein said analgesic narcotic is fentanyl, buprenorphine, codeine sulfate, levophanol, or morphine hydrochloride.

47. The multi-layered pharmaceutical carrier device of claim 13, wherein said pharmaceutical agent comprises an antiviral drug.

48. The multi-layered pharmaceutical carrier device of claim 47, wherein said antiviral drug is a protease inhibitor, thymidine kinase inhibitor, sugar or glycoprotein synthesis inhibitor, structural protein synthesis inhibitor, attachment and adsorption inhibitor, or nucleoside analogue.

49. The device of claim 48 where the analogue is acyclovir, penciclovir, valacyclovir, or ganciclovir.

50. The multi-layered pharmaceutical carrier device of claim 13, wherein the pharmaceutical agent comprises between about 0.001 and about 30 percent by weight of the device.

51. The multi-layered pharmaceutical carrier device of claim 13 wherein the pharmaceutical agent comprises between about 0.005 and about 20 percent by weight of the device.