Biodegradable oxidized cellulose esters and their uses as microspheres

• US 20050131225A1
• Filed: 10/28/2004
• Published: 06/16/2005
• Est. Priority Date: 12/06/2001
• Status: Active Grant

• Current Assignee: University of Iowa Research Foundation
• Original Assignee: University of Iowa Research Foundation
• Inventors: Kumar, Vijay, Dong, Yang
• Granted Patent: US 7,649,089 B2
• Time in Patent Office: Days
• US Class Current: 536/56
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/5042 Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
• CPC Class Codes: C08B 15/00 Preparation of other cellulose derivatives or modified cellulose , e.g. complexes
• CPC Class Codes: C08B 3/00 Preparation of cellulose esters of organic acids rendering cellulose suitable for esterification C08B1/02

Abstract

A new cellulose excipient, OCCAE, suitable for use as a binder, filler, and/or disintegrant in the development of solid dosage forms and as a bodying agent or a drug carrier in the preparation of topical formulations is described. The cellulose excipient is formed by reacting an oxidized cellulose ester with an alcohol in the presence of a catalyst. The invention also describes the formation of controlled release microspheres using OCCAE and/or oxidized cellulose esters that may be used to control the release of drug in a patient over a time period of several hours to several days.

Claims

1. A biodegradable, oxidized cellulose carboxylate alkyl/aryl ester (OCCAE).

2. An OCCAE according to claim 1 having one of the following general formulas I or II the general formula:

3. An OCCAE according to claim 1 that is present in a product selected from the group consisting of a pharmaceutical, an agricultural product, and a veterinary composition.

4. An OCCAE according to claim 1 that is soluble in at least one solvent selected from the group consisting of water, ketones, esters, glycol ethers, glycol ether acetates, alcohols, methylene chloride, halogenated solvents, and aprotic solvents.

5. An OCCAE according to claim 4 whereby the aprotic solvents are selected from the group consisting of DMSO, DMA, DMF, and n-methyl-2-pyrrolidone.

14. A pharmaceutical comprising the OCCAE of claim 1.

15. The pharmaceutical of claim 14 comprising microspheres.

16. The pharmaceutical of claim 15 comprising controlled release microspheres.

17. The pharmaceutical of claim 15 further comprising a drug.

18. The pharmaceutical of claim 17 comprising drug that is released over a time period of between about 150 days to 6 months or longer.

27. A method of providing a patient with a drug in a controlled release manner comprising:

administering to a patient the pharmaceutical of claim 14.

28. The method of claim 27 whereby the patient receives the drug over a time period of between about 150 hours to 6 months or more.

29. The method of claim 27 whereby the patient is provided with a chemotherapeutic drug.

30. The method of claim 27 whereby the patient is provided with a drug selected from the group consisting of camptothecin and 5-fluorouracil.

6. A method of making an OCCAE comprising:

forming a biodegradable oxidized cellulose ester (OCE); and

reacting the OCE with an alcohol in the presence of a coupling agent and a basic catalyst.

7. The method of claim 6 whereby the coupling agent is a carbodiimide.

8. The method of claim 7 wherein the carbodiimide is 1,3-dicyclohexylcarbodiimide (DCC).

9. The method of claim 6 whereby the basic catalyst is 4-(dimethylamino) pyridine (DMAP).

10. The method of claim 6 whereby the OCE and the alcohol are reacted for at least 30 minutes.

11. The method of claim 6 whereby the OCE and the alcohol are reacted at a temperature ranging from about −

5°

to about 75°

C.

12. The method of claim 6 whereby the alcohol is a C₁-C₁₆ alcohol.

13. The method of claim 12 whereby the alcohol is methanol or ethanol.

19. A pharmaceutical comprising:

controlled release microspheres comprising at least one oxidized cellulose ester.

20. The pharmaceutical of claim 19 comprising a drug that is released over a time period of between about 24-150 hours.

21. The pharmaceutical of claim 19 comprising from about 1-10% by weight of a drug.

31. A method of providing a patient with a drug in a controlled release manner comprising:

administering to a patient the pharmaceutical of claim 19.

32. The method of claim 31 whereby the patient receives the drug over a time period of between about 24-150 hours.

33. The method of claim 32 whereby the patient is provided with a chemotherapeutic drug.

34. The method of claim 33 whereby the patient is provided with a drug selected from the group consisting of camptothecin and 5-fluorouracil.

22. A method of manufacturing a pharmaceutical comprising:

suspending or dissolving a drug in a solvent to form a drug suspension or solution;

combining the drug suspension or solution with an OCE or an OCCAE to form a mixture;

combining the mixture with an emulsifying agent to form an emulsion; and

agitating the emulsion to form microspheres.

23. The method of claim 22 whereby the emulsifying agent is a solution of polyvinylalcohol.

24. The method of claim 22 whereby the drug suspension is combined with an OCE having the following general formula I or II:

25. The method of claim 22 whereby the drug suspension is combined with an OCCAE having one of the following general formulas:

26. The method of claim 22 further including the step of filtering and drying the micro spheres.