Microencapsulation and sustained release of biologically active polypeptides

1. A composition for the sustained release of a biologically active polypeptide comprising: a biocompatible polymer having dispersed therein a biologically active polypeptide, a sugar and a salting-out salt, and a corticosteroid wherein the corticosteroid is unencapsulated but commingled with the sustained release composition and wherein the biologically active polypeptide is a glucoregulatory peptide.

2. The sustained release composition of claim 1 , wherein the glucoregulatory peptide is selected from GLP-1, GLP-2, exendin-3, exendin-4 or a combination thereof.

3. The sustained release composition of claim 1 , wherein the biologically active polypeptide is present from about 0.01% (w/w) to about 50% (w/w) of the total weight of the composition.

4. The sustained release composition of claim 3 , wherein the biologically active polypeptide is present in a range from about 0.1% (w/w) to about 30% (w/w) of the total weight of the composition.

5. The sustained release composition of claim 4 , wherein the polypeptide is present from about 0.1% (w/w) to about 10% (w/w) of the total weight of the sustained release composition.

6. The sustained release composition of claim 5 , wherein the polypepticle is present from about 0.5% (w/w) to about 5% (w/w) of the total weight of the sustained release composition.

7. The sustained release composition of claim 1 , wherein the sugar is present from about 0.01% to about 50% w/w of the total weight of the sustained release composition.

8. The sustained release composition of claim 7 , wherein the sugar is present from about 0.01% to about 10% w/w of the total weight of the sustained release composition.

9. The sustained release composition of claim 8 , wherein the sugar is present from about 0.1% to about 5% w/w of the total weight of the sustained release composition.

10. The sustained release composition of claim 1 , wherein the sugar is selected from a monosaccharide, a disaccharide, a sugar alcohol or a combination thereof.

11. The sustained release composition of claim 10 , wberein the sugar is selected from sucrose, trebalose, mannitol and combinations thereof.

12. The sustained release composition of claim 10 , wherein the sugar is a disaccharide.

13. The sustained release composition of claim 12 , wherein the disaccharide is sucrose, trehalose or a combination thereof.

14. The sustained release composition of claim 1 , wherein the salting-out salt comprises a salt containing a cation selected from Mg +2 , Li + , Na + , K + and NH 4 + and combinations thereof.

15. The sustained release composition of claim 1 , wherein the salting-out salt comprises a salt containing an anion selected from SC 4 −2 , HPO 4 −2 , acetate, citrate, tartrate, Cl − , NO 3 − , ClO 3 − , I − , ClO 4 − and SCN − and combinations thereof.

16. The sustained release composition of claim 1 , wherein the salting-out salt is ammonium sulfate.

17. The sustained release composition of claim 1 , wherein the salting-out salt is present from about 0.01% to about 50% w/w of the total weight of the sustained release composition.

18. The sustained release composition of claim 17 , wherein the salting-out salt is present from about 0.0 1% to about 10% w/w of the total weight of the sustained release composition.

19. The sustained release composition of claim 1 , wherein the bioconipatible polymer is selected from the group consisting of poly(lactides), poly(glycolides), poly(lactide-co-glycolides), poly(actic acid)s, poly(glycolic acid)s, poly(actic acid-co-glycolic acid)s, polycaprolactone, polycarbonates, polyesterarnides, polyanhydrides, poly(amino acids), polyorthoesters, polycyanoacryl ates, poly(p-dioxanone), poly(allcylene oxalate)s, biodegradable polyurethanes, blends thereof and copolymers thereof.

20. The sustained release composition of claim 19 , wherein said polymer comprises poly(lactide-co-glycolide).

21. The sustained release composition of claim 1 , where the corticasteroid is selected from 21-Acetoxypregnenolone, Aiclometasone, Algestone. Amcinonide, Beclomethasone, Betamethasone, Budesonide, Chioroprednisone, Clobetasol, Clobetasone, Clocortolone, Cloprednol, Corticosterone, Cortisone, Cortivazol, Deflazacort, Desonide, Desoximetasone, Dexatnethasone, Disfiorasone, Diflucortolone, Difluprednate, Enoxolone, Fluazacort, Flucloronide, Fluinethasone, Flunisolide, Flucinolone Acetonide, Fluocinonide, Fluocortin Butyl, Flucortolone, Fluorometholone, Fluperolone Acetate, Fluprednidence Acetate, Fluprednisolone, Flurandrenolide, Fluticasone Propionate, Formocortal, Halcinonide, Halobetasol Propionate, Haloinetasone, Halopredone Acetate, Hydrocortamate, Hydrocortisone, Loteprednol Etabonate, Mazipredone, Medrysone, Meprednisone, Methyiprednisolone, Mometasone Furoate, Paramethasone, Prednicarbate, Prednisolone, Prednisolone 25-Diethylarnino-acetate, Predrilsolone Sodium Phosphate, Prednisone, Prednival, Prednylidene, Rhuexolone, Tixocortol, Triarocinolone, Triarncinolone Acetonide, Trinincinolone Acetonide 21-oic acid methyl ester, Triameinolone Benetonide, Triameinolone Hexacetonide, Triameinolone Diacetate, pharmaceutically acceptable mixtures and salts thereof.

22. The sustained release composition of claim 21 , wherein the corticosteroid is selected from Triamcinolone, Triarecinolone Acetonide, Triamcinolone Acetonide 21-ole acid methyl ester, Triamcinolone Benetonide, Triameinolone Hexacetonide, Triamoinolone Diacetate, pharmaceutically acceptable mixtures and salts thereof.

23. A composition for the sustained release of biologically active polypeptide comprising: a biocompatible polymer having dispersed therein exendin-4, sucrose and ammonium sulfate and a corticosteroid wherein the corticosteroid is unencapsulated but comminaled with the sustained release composition.

24. The composition of claim 23 , wherein the biocompatible polymer is selected from poly(lactides), poly(glycolides), poly(lactide-co-glycolides), poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s and blends and copolymers thereof.

25. The composition of claim 23 , wherein the sucrose is present at a concentration from about 0.01% w/w to about 10% w/w of the total weight of the sustained release composition.

26. The composition of claim 23 , wherein the aunnonium sulfite is present at a concentration of from about 0.01% w/w to about 10% w/w of the total weight of the sustained release composition.

27. The sustained release composition of claim 23 , wherein the exendin-40 is present at a concentration of about 0.1% to about 10% of the total weight of the composition.

28. A method of treating a patient suffering from Type 2diabetes comprising administering a therapeutically effective amount of a sustained release composition comprising a biocompatible polymer having dispersed therein a biologically active exendin-4, a sugar and a salting-out salt, and a corticosteroid wherein the corticosteroid is unencapsulated but comminaled with the sustained release composition.

29. The method of claim 28 , wherein the biocoinpatible polymer of the sustained release composition is selected from poly(lactides), poly(gllycolides), poly(actide-co-glycolides), poly(lactic acid)s, poly(glyeolic acid)s, poly(lactic acid-co-glycolic acid)s and blends and copolymers thereof.

30. The method of claim 28 , wherein the sugar is present in the sustained release composition at a concentration from about 0.01% w/w to about 10% w/w of the total weight of the sustained release composition.

31. The method of claim 28 . wherein the salting-out salt in the sustained release composition is present at a concentration of from about 0.01% w/w to about 10% w/w of the total weight of the sustained release composition.

32. The method of claim 28 , wherein the exendin-4 is present in the sustained release composition at a concentration of about 0.1% to about 10% of the total weight of the composition.