Sustained release microspheres

• US 6,458,387 B1
• Filed: 10/18/1999
• Issued: 10/01/2002
• Est. Priority Date: 10/18/1999
• Status: Expired due to Term

• Current Assignee: Baxter Healthcare SA (Baxter International Inc.), Baxter International Inc.
• Original Assignee: Epic Therapeutics, Inc. (Baxter International Inc.)
• Inventors: Scott, Terrence L., Blizzard, Charles D., Rashba-Step, Julia, Riske, Frank J., Brown, Larry R.
• Primary Examiner(s): Kishore, Gollamudi S.
• Assistant Examiner(s): Pulliam, Amy E
• Application Number:
  US09/420,361
• Time in Patent Office: 1,079 Days
• Field of Search: 424/484, 424/488, 424/489, 424/499, 424/490
• US Class Current: 424/489
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/1658 Proteins, e.g. albumin, gelatin
• CPC Class Codes: Y10S 977/799 Containing biological material

Abstract

Methods for forming sustained release microspheres and the products produced thereby are provided. The microspheres have a smooth surface that includes a plurality of channel openings that are less than 1000 angstroms in diameter.

Claims

1. A method for forming a microsphere comprising:

(1) forming an aqueous mixture containing;

(a) a carrier protein;

(b) a water soluble polymer;

(c) a polyanionic polysaccharide first complexing agent; and

(d) a divalent metal cation second completing agent selected from the group consisting of calcium and magnesium;

(2) allowing the microspheres to form in the aqueous mixture; and

(3) stabilizing the microspheres, by contacting the microspheres with a crosslinking agent, under conditions sufficient to stabilize the microspheres.

2. The method of claim 1, wherein forming the aqueous mixture is performed by combining the carrier protein, the water soluble polymer, the first-complexing agent, and the second complexing agent essentially simultaneously.

3. The method of claim 1, further comprising the step of:

(4) contacting the microsphere with a solution of an active agent, to incorporate the active agent into the microsphere.

4. The method of claim 3, wherein the step of contacting the microsphere with the solution of active agent results in a yield of incorporation of at least 60%, of the active agent.

5. The method of claim 3, wherein the active agent is selected from the group consisting of:

a hormone, an antibiotic, an antiinfective agent, a hematopoietic, a thrombopoictic agent, an antidementia agent, an antiviral agent, an antitumoral agent, an antipyretic, an analgesic, an antiflammatory agent, an antiulcer agent, an antiallergic agent, an antidepressant, a psychotropic agent, a cardiotonic, an antiaarythmic agent a vasodilator, an antihypcrtensive agent, an antidiabetic agent, an anticoagulant, a cholesterol lowering agent, a therapeutic agent for osteoporosis, an enzyme, a vaccine, an immunological agent, an adjuvant, a cytokine, a growth factor, a nucleotide, a nucleic acid;

a carbohydrate, a polysaccharide;

a virus, and a virus particle.

6. The method of claim 3, wherein the active agent is a luteinizing hormone releasing hormone or analog thereof.

7. The method of claim 3, wherein the active agent is leuprolide.

8. The method of claim 3, wherein the step of contacting the microsphere with the solution of active agent results in a yield of incorporation of at least 70% of the active agent.

9. The method of claim 3, wherein the step of contacting the microsphere with the solution of active agent results in a yield of incorporation of at least 80% of the active agent.

10. The method of claim 3, wherein the step of contacting the microaphere with the solution of active agent results in a yield of incorporation of at least 90% of the active agent.

11. The method of claim 3, wherein the step of contacting the microsphere with the solution of active agent results in a yield of incorporation of at least 95% of the active agent.

12. The method of claim 3, wherein the step of contacting the microsphere with the solution of active agent results in a yield of incorporation of at least 98% of the active agent.

13. The method of claim 1, wherein the step of stabilizing further comprises exposing the microspheres to an energy source.

14. The method of claim 1, wherein the step of stablizing further comprises exposing the microspheres to heat.

15. A method for forming a microsphere comprising:

(1) forming an aqueous mixture containing;

(a) a carrier protein;

(b) a water soluble polymer;

(c) a polyanionic polysaccharide first complexing agent; and

(d) a divalent metal cation second complexing agent selected from the group consisting of calcium and magnesium;

(2) allowing the microspheres to form in the aqueous mixture; and

(3) stabile the microspheres by exposing the microspheres to an energy source, under conditions sufficient to stabilize the microspheres.

16. The method of claim 15, wherein the energy source is heat.

17. The method of claim 15 or claim 16, wherein forming the aqueous mixture is performed by combining the carrier protein, the water soluble polymer, the first-complexing agent, and the second complexing agent essentially simultaneously.

18. The method of claim 15, or claim 16, further comprising the step of:

(4) contacting the microsphere with a solution of an active agent to incorporate the active agent into the microsphere.

19. The method of claim 18, wherein the active agent is selected from the group consisting of:

a hormone, an antibiotic, an antiinfective agent a hematopoietic, a thrombopoietic agent, an antidementia agent, an antiviral agent, an antitumoral agent, an antipyretic, an analgesic, an ammatory agent, an antiulcer agent, an antiallergic agent an antidepressant, a psychotropic agent, a cardiotonic, an antiarrythmic agent, a vasodilator, an antihypertensive agent, an antidiabetic agent, an anticoagulnt, a cholesterol lowering agent, a therapeutic agent for osteoporosis, an enzyme, a vaccine, an immunological agent, an adjuvant, a cytokine, a growth factor, a nucleotide, a nucleic acid;

a carbohydrate, a polysaccharide;

a virus, and a virus particle.

20. The method of claim 18, wherein the active agent is a luteinizg hormone releasing hormone or analog thereof.

21. The method of claim 18, wherein the active agent is leuprolide.

22. The method of claim 15, further comprising the step of:

(5) stabilizing the microspheres, by contacting the microspheres with a crosslinking agent under conditions sufficient to stabilize the microsphere.

23. The method of claim 18, wherein the step of contacting the microsphere with the solution of active agent results in a yield of incorporation of at least 60% of the active agent.

24. The method of claim 18, wherein the step of contacting the microsphere with the solution of active agent results in a yield of incorporation of at least 700% of the active agent.

25. The method of claim 18, wherein the stop of contacting the microsphere with the solution of active, agent results in a yield of incorporation of at least 80% of the active agent.

26. The method of claim 18, wherein the step of contacting the microsphere with the solution of active agent results in a yield of incorporation of at least 90% of the active agent.

27. The method of claim 18, wherein the step of contacting the microsphere with the solution of active agent results in a yield of incorporation of at least 95% of the active agent.

28. The method of claim 18, wherein the step of contacting the microsphere with the solution of active agent results in a yield of incorporation of at least 98% of the active agent.