Drug delivery system and method of making the same

• US 4,897,268 A
• Filed: 08/03/1987
• Issued: 01/30/1990
• Est. Priority Date: 08/03/1987
• Status: Expired due to Term

• Current Assignee: Southwest Research Institute
• Original Assignee: Southwest Research Institute
• Inventors: Tice, Thomas R., Gilley, Richard M.
• Primary Examiner(s): Robinson, Ellis P.
• Assistant Examiner(s): Prater, P. L.
• Application Number:
  US07/081,289
• Time in Patent Office: 911 Days
• Field of Search: 424/426, 424/78, 424/497, 424/489, 424/486, 424/488, 424/422, 424/455, 514/800
• US Class Current: 424/422
• CPC Class Codes: A61K 38/09 Luteinising hormone-releasing hormone [LHRH] , i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077

Abstract

A compatible, biodegradable microcapsule delivery system for active ingredients, including hormonally active peptides, proteins, or other bioactive molecules, and a method of making the same. The ingredients are encapsulated in biodegradable copolymer excipients of varying mole ratios and the blend of the microcapsules are administered to an animal. Delivery of the ingredient occurs over a prolonged period of time at a constant rate as a result of the varying break-down rates of the copolymer excipients.

Claims

1. A method of preparing a composition for delivering a an effective amount of a constant dose of an active ingredient to an animal over a preselected, prolonged period of time, comprising the steps of:

(a) encapsulating effective amounts of said ingredient in first and second separate biodegradable and biocompatible copolymer excipients having different monomers ratios to form first and second microcapsules, each of said microcapsules having of a different rate of release therefrom of said ingredient; and

(b) combining an effective amount of said first and second microcapsules to form said composition having a delivery profile wherein the release of said ingredient through said second microcapsule begins as the release of said ingredient through said first microcapsule declines.

2. A method as claimed in claim 1, further including the step of administering an effective amount of said composition to the animal.

3. A method as claimed in claim 1, wherein said excipient is selected from the group consisting of polyacetal polymers, polyorthoesters, polyesteramides, polycaprolactone and copolymers thereof, polycarbonates, polyhydroxybuterate and copolymers thereof, polymaleamides, copolyaxalates, and polysaccharides.

4. The method as claimed in claim 1, wherein a copolymer excipient is poly(D,L-lactide-co-glycolide).

6. The method as claimed in claim 1, wherein said active ingredient is a bioactive molecule.

7. The method as claimed in claim 1, wherein said active ingredient is a peptide.

8. The method of claim 7, wherein said peptide is hormonally active.

9. The method as claimed in claim 7, wherein said peptide is a luteinizing hormone releasing hormone or an analogue thereof.

10. The method of claim 1, wherein said active ingredient is a protein.

11. The method as claimed in claim 7, wherein said peptide is [D-Trp⁶, des-Gly¹⁰ ]-LHRH ethylamide.

12. The method as claimed in claim 1, wherein said first microcapsule comprises 3 percent by weight loaded [D-Trp⁶, des-Gly¹⁰ ]-LHRH ethylamide encapsulated in a copolymer excipient having a mole ratio of 52 percent lactide to 48 percent glycolide and wherein said second microcapsule comprises 10 percent by weight loaded [D-Trp⁶, des-Gly¹⁰ ]-LHRH ethylamide encapsulated in a copolymer excipient having a mole ratio of 68 percent lactide to 32 percent glycolide.

13. The method as claimed in claim 12, wherein said combining step further comprises adding to said composition an effective amount of 8 percent by weight loaded [D-Trp⁶, des-Gly¹⁰ ]-LHRH ethylamide encapsulated in a copolymer excipient having a mole ratio of 85 percent lactide to 15 percent glycolide.

14. The method as claimed in claim 13, wherein [D-Trp⁶, des-Gly¹⁰ ]-LHRH ethylamide is delivered at a constant rate ranging from 50 μ

g to 250 μ

g per day for approximately 180 days.

15. The method as claimed in claim 7, wherein said peptide is [D-N-Ac-4-Cl-Phe², D-Trp⁶, D-Ala¹⁰ ]-LHRH.

16. The method as claimed in claim 15, wherein said [D-N-Ac-4-Cl-Phe², D-Trp⁶, D-Ala¹⁰ ]-LHRH is delivered at a constant rate of about 200 μ

g to 500 μ

g per day for at least 90 days.

17. The method as claimed in claim 1, wherein said administering step is parenterally.

18. The method as claimed in claim 1, wherein said administering step is intramuscularly.

5. The method as claimed in claim 5, wherein the copolymer excipients have mole ratios of lactide to glycolide of 40:

60 to 85;

15, respectively.

19. A composition capable of delivering an effective amount of a constant dose of an active ingredient to an animal over a preselected, prolonged period of time, comprising a blend of effective amounts of an active ingredient encapsulated in at least two biodegradable and biocompatible copolymer excipients having different monomers ratios to form first and second microcapsules, each excipient having of a different rate of release of said ingredient therethrough, said composition having a delivery profile wherein the release of said ingredient through said second microcapsule begins as the release of said ingredient through said first microcapsule declines.

20. A composition as claimed in claim 19, wherein said copolymer excipients are poly(D,L-lactide-co-glycolide).

21. A composition as claimed in claim 20, wherein said copolymer excipients have mole ratios of lactide to glycolide of 40:

60 to 85;

15 respectively.

22. A composition as claimed in claim 19, wherein said active ingredient is a bioactive molecule.

23. A composition as claimed in claim 19, wherein said active ingredient is a peptide.

24. A composition as claimed in claim 23, wherein said peptide is hormonally active.

25. A composition as claimed in claim 23, wherein said peptide is a luteinizing hormone releasing hormone or an analog thereof.

26. A composition as claimed in claim 25, wherein said luteinizing hormone releasing hormone is [D-Trp⁶, des-Gly¹⁰ ]-LHRH ethylamide.

27. A composition as claimed in claim 19, wherein said active ingredient is a protein.

28. A composition as claimed in claim 19, wherein said blend of microencapsulated peptide is comprised of appropriate amounts of 3% by weight loaded [D-Trp⁶, des-Gly¹⁰ ]-LHRH ethylamide encapsulated in a copolymer excipient having a mole ratio of 52% lactide to 48% glycolide, and 10% by weight loaded [D-Trp⁶, des-Gly¹⁰ ]-LHRH ethylamide encapsulated in a copolymer excipient having a mole ratio of 68% lactide to 32% glycolide.

29. A composition as claimed in claim 28 and further comprising an appropriate amount of 8% by weight loaded [D-Trp⁶, des-Gly¹⁰ ]-LHRH ethylamide encapsulated in a copolymer excipient having a mole ratio of 85% lactide to 15% glycolide added to said blend.

30. A composition as claimed in claim 29, wherein said blend delivers [D-Trp⁶, des-Gly¹⁰ ]-LHRH ethylamide at a constant rate of about 50 μ

g to 250 μ

g per day for 180 days.

31. A composition as claimed in claim 23, wherein said peptide is [D-N-Ac-4-Cl-Phe², D-Trp⁶, D-Ala¹⁰ ]-LHRH.

32. A composition as claimed in claim 31, wherein said blend delivers [D-N-Ac-4-Cl-Phe², D-Trp⁶, D-Ala¹⁰ ]-LHRH at a constant rate of about 200 μ

g to 500 μ

g per day for at least 90 days.