Transmucosal delivery of macromolecular drugs

• US 5,516,523 A
• Filed: 05/16/1994
• Issued: 05/14/1996
• Est. Priority Date: 02/22/1993
• Status: Expired due to Fees

• Current Assignee: Theratech, Inc. (Dynatronics Corporation)
• Original Assignee: Theratech, Inc. (Dynatronics Corporation)
• Inventors: Dave, Sirish C., Ebert, Charles D., Heiber, Sonia J.
• Primary Examiner(s): AZPURU, CARLOS A
• Application Number:
  US08/243,415
• Time in Patent Office: 729 Days
• Field of Search: 424/434, 424/435, 514/953
• US Class Current: 424/435
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays

Abstract

A method and system for mucosally administering a macromolecular drug to mucosa of the oral cavity is shown. The system comprises an inner drug/enhancer/polymer layer having one surface adapted to contact and adhere to the mucosal tissue of the oral cavity and an opposing surface in contact with and adhering to an overlying inert layer. The inner layer contains from about two to sixty percent by weight of a bile salt enhancer, five to sixty five percent by weight of a hydrophilic polymer which is water soluble or swellable and an effective amount of a macromolecular drug having a molecular weight of at least 500 daltons. Polysaccharides, polypeptides and proteins are preferred forms of macromolecular drugs. The bile salt enhancer facilitates the delivery of macromolecules such as low molecular weight heparin and calcitonin. The polymer serves as a plasticizer to prevent the crystallization and/or aggregation of such macromolecular drugs. Hydroxypropyl cellulose is a particularly suitable polymer.

Claims

1. A method for mucosally administering a macromolecular drug to the oral cavity comprising applying to a oral cavity mucosa a system comprising an inner drug/enhancer/polymer layer having one surface in contact with and adhering to the mucosal tissue of the oral cavity and an opposing surface in contact with and adhering to an overlying inert layer, said inner layer containing from about two to sixty percent by weight of a bile salt enhancer, five to sixty five percent by weight of a hydrophilic polymer and an effective amount of a macromolecular drug having a molecular weight of at least 500 daltons.

2. A method according to claim 1 wherein said bile salt enhancer is a steroidal detergent comprising the natural or synthetic salts of cholanic acid and mixtures thereof.

3. A method according to claim 2 wherein said macromolecular drug is a member selected from the group consisting of polysaccharides, polypeptides and proteins.

4. A method according to claim 3 wherein said hydrophilic polymer is a member selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxy ethylcellulose, ethylcellulose, carboxymethyl cellulose, dextran, gaur-gum, polyvinyl pyrrolidone, pectins, starches, gelatin, casein, acrylic acid, acrylic acid esters, acrylic acid copolymers, vinyl polymers, vinyl copolymers, vinyl alcohols, alkoxy polymers, polyethylene oxide polymers, polyethers, and mixtures thereof.

5. A method according to claim 4 wherein the system is in the form of a bilayer tablet wherein said inner layer additionally contains one or more members selected from the group consisting of binding agents, flavoring agents and fillers and wherein said inert layer is nonadhesive to mucosal tissues and is substantially impermeable to the bile salt enhancer or macromolecular drug.

6. A method according to claim 5 wherein said bile salt enhancer is a salt of a conjugate of a bile acid with taurine.

7. A method according to claim 6 wherein said hydrophilic polymer is hydroxypropyl cellulose.

8. A method according to claim 7 wherein the macromolecular drug is a polysaccharide.

9. A method according to claim 8 wherein the polysaccharide is heparin having a molecular weight of between about 4000 and 6000.

10. A method according to claim 7 wherein the macromolecular drug is a polypeptide.

11. A method according to claim 10 wherein the polypeptide is calcitonin.

12. A method according to claim 4 wherein the system is in the form of a filmpatch wherein said inert layer is a polymeric membrane which is nonadhesive to mucosal tissues and is substantially impermeable to the bile salt enhancer or macromolecular drug.

13. A method according to claim 12 wherein said membrane is a molecular weight cutoff membrane.

14. A method according to claim 13 wherein said membrane has a molecular weight cutoff of between about 100 and 500.

15. A method according to claim 14 wherein said bile salt enhancer is a salt of a conjugate of a bile acid with taurine.

16. A method according to claim 15 wherein said hydrophilic polymer is hydroxypropyl cellulose.

17. A method according to claim 16 wherein the macromolecular drug is a polysaccharide.

18. A method according to claim 17 wherein the polysaccharide is heparin having a molecular weight of between about 4000 and 6000.

19. A method according to claim 16 wherein the macromolecular drug is a polypeptide.

20. A method according to claim 19 wherein the polypeptide is calcitonin.

21. A method according to claim 13 wherein an additional membrane overlays and extends beyond the periphery of said molecular weight cutoff membrane and contains an adhesive on the portion of the inner surface thereof extending beyond said inert layer for adhering said system to mucosal tissues.

22. A method according to claim 21 wherein said additional membrane is also a molecular weight cutoff membrane.

23. A method according to claim 22 wherein the molecular weight cutoff of said inert membrane is between about 100 and 500 and wherein the molecular weight cutoff of said inert membrane and said additional membrane are different.

24. A method according to claim 23 wherein each of the inert layer and additional layer is a molecular weight cutoff membrane having a molecular weight cutoff of between 100 and 500.