Agent delivering system comprised of microparticle and biodegradable gel with an improved releasing profile and methods of use thereof

• US 6,287,588 B1
• Filed: 04/27/2000
• Issued: 09/11/2001
• Est. Priority Date: 04/29/1999
• Status: Expired due to Term

• Current Assignee: BTG International Limited (Boston Scientific Corporation)
• Original Assignee: Macromedia Incorporated (Protherics Incorporated)
• Inventors: Zentner, Gaylen M., Shih, Chung
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): FUBARA, BLESSING M
• Application Number:
  US09/559,507
• Time in Patent Office: 502 Days
• Field of Search: 424/425, 424/423, 424/497, 424/501, 424/426, 424/486, 424/561, 424/424, 525/415
• US Class Current: 424/426
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00

Abstract

A composition and method for releasing a bio-active agent or a drug within a biological environment in a controlled manner is disclosed. The composition is a dual phase polymeric agent-delivery composition comprising a continuous biocompatible gel phase, a discontinuous particulate phase comprising defined microparticles and an agent to be delivered. A microparticle containing a bio-active agent is releasably entrained within a biocompatible polymeric gel matrix. The bio-active agent release may be contained in the microparticle phase alone or in both the microparticles and the gel matrix. The release of the agent is prolonged over a period of time, and the delivery may be modulated and/or controlled. In addition, a second agent may be loaded in some of the microparticles and/or the gel matrix.

Claims

1. A dual phase polymeric agent-delivery composition comprising:

(a) a continuous biocompatible gel phase,

(b) a discontinuous particulate phase comprising defined microparticles; and

(c) an agent to be delivered contained in both the continuous biocompatible gel phase and the discontinuous particulate phase.

2. The composition according to claim 1 wherein the biocompatible gel phase is biodegradable.

3. The composition according to claim 2 wherein said biodegradable gel comprises a hydrogel.

4. The composition according to claim 3 wherein said hydrogel is a stimuli responsive gel.

5. The composition according to claim 4 wherein said stimuli responsive gel is sensitive to stimuli selected from the group consisting of temperature, pH, ionic strength, solvent, pressure, stress, light intensity, electric field, magnetic field and gelating agents.

6. The composition according to claim 5 wherein said continuous gel phase is formed from block copolymers comprising an effective amount of biodegradable hydrophobic polyester A polymer blocks and polyethylene glycol B polymer blocks.

7. The composition according to claim 6 wherein the effective amount of biodegradable hydrophobic polyester A polymer blocks is 10-83% by weight of said block copolymer.

8. The composition according to claim 5 wherein said continuous gel phase is formed from a reverse thermal gelation (RTG) system comprising an effective amount of block copolymers comprising biodegradable hydrophobic polyester A polymer blocks and polyethylene glycol B polymer blocks.

9. The composition according to claim 8 wherein said RTG system is a mixture of two or more said block copolymers having different gelation properties.

10. The composition according to claim 9 wherein said RTG system comprises tri-block copolymers.

11. The composition according to claim 10 wherein said tri-block polymer comprises about 51 to 83% by weight of said biodegradable hydrophobic polyester, and about 17 to 49% by weight of polyethylene glycol(PEG).

12. The composition according to claim 8 wherein the biodegradable hydrophobic polyester is synthesized from monomers selected from the group consisting of D,L-lactide, D-lactide, L-lactide, D,L-lactic acid, D-lactic acid, L-lactic acid, glycolide, glycolic acid, ε

-caprolactone, ε

-hydroxy hexanoic acid, and copolymers thereof.

13. The composition according to claim 12 wherein the biodegradable hydrophobic polyester is synthesized from monomers selected from the group consisting of D,L-lactide, D-lactide, L-lactide, D,L-lactic acid, D-lactic acid, L-lactic acid, glycolide, glycolic acid, and copolymers thereof.

14. The composition according to claim 8 wherein the biodegradable hydrophobic polyester comprises between about 20 to 100 mole percent lactide and between about 0 to 80 mole percent glycolide.

15. The composition according to claim 10 wherein, in the triblock copolymer, each biodegradable block has an average molecular weight of between about 270 and 3000.

16. The composition according to claim 1 wherein said microparticle is in the form of a member selected from the group consisting of microcapsules, microspheres, and nanospheres.

17. The composition according to claim 16 wherein said microparticle is in the form of a member selected from the group consisting of microcapsules and microspheres.

18. The composition according to claim 1 wherein said microparticle is biodegradable.

19. The composition according to claim 18 wherein said agent is a bioactive agent, a drug, or any agent which can be loaded to the microparticle.

20. The composition according to claim 19 wherein said drug is a polypeptide or protein, oligonucleotide or gene, hormone, anti-cancer or anti-cell proliferation agent.

21. The composition according to claim 20 wherein said drug is a polypeptide or protein and is a member selected from the group consisting of oxytocin, vasopressin, adrenocorticotropic hormone, epidermal growth factor, platelet-derived growth factor (PDGF), prolactin, luliberin, luteinizing hormone releasing hormone (LHRH), LHRH agonists, LHRH antagonists, growth hormone (human, porcine, bovine, etc.), growth hormone releasing factor, insulin, erythropoietin, somatostatin, glucagon, interleukin-2 (IL-2), interferon-α

, β

, or γ

, gastrin, tetragastrin, pentagastrin, urogastrone, secretin, calcitonin, enkephalins, endorphins, angiotensins, thyrotropin releasing hormone (TRH), tumor necrosis factor (TNF), nerve growth factor (NGF), granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), macrophage-colony stimulating factor (M-CSF), heparinase, bone morphogenic protein (BMP), HANP, glucagon-like peptide (GLP-1), interleukin-11 (IL-11), interleukin-12 (IL-12), VEG-F, recombinant hepatitis B surface antigen (rHBsAg), renin, bradykinin, bacitracins, polymyxins, colistins, tyrocidine, gramicidins, cyclosporins and synthetic analogues, modifications and pharmacologically active fragments thereof, enzymes, cytokines, antibodies and vaccines.

22. The composition according to claim 1 wherein the microparticle content of said composition is between about 0.0001 and 30% by weight.

23. The composition according to claim 1 wherein the drug content of said microparticle is between about 0.001 and 30% by weight.

24. The composition according to claim 21 wherein said polypeptide or protein is a member selected from the group consisting of erythropoietin, luteinizing hormone releasing hormone (LHRH), LHRH agonists, LHRH antagonists, growth hormones (human, porcine, bovine, etc.), tumor necrosis factor (TNF), nerve growth factor (NGF), granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), macrophage-colony stimulating factor (M-CSF), glucagon-like peptide (GLP-1), interleukin-11 (IL-11), interleukin-12 (IL-12), VEG-F, recombinant hepatitis B surface antigen(rHBsAg), cyclosporins and synthetic analogues, modifications and pharmacologically active fragments thereof.

25. The composition according to claim 24 wherein said polypetide or protein is a human growth hormone, or synthetic analogue, modification and pharmacologically active fragment thereof.

26. The composition according to claim 19 wherein said drug is a member selected from the group consisting of testosterone, estradiol, progesterone, prostaglandins, leuprolide acetate, and synthetic analogues, modifications and pharmaceutically equivalents thereof.

27. The composition according to claim 19 wherein said drug is an anti-cancer agent selected from the group consisting of mitomycin, bleomycin, BCNU, carboplatin, doxorubicin, daunorubicin, methotrexate, paclitaxel, taxotere, actinomycin D, camptothecin, and synthetic analogues, modifications and pharmaceutically equivalents thereof.

28. The composition according to claim 1 further comprising a second agent.

29. The composition according to claim 28 wherein the second agent is a bioactive agent or a drug.

30. The composition according to claim 29 wherein some microparticles contain the first agent and other microparticles contain the second agent.

31. The composition according to claim 29 wherein the gel matrix contains both the first and the second agent.

32. The composition according to claim 28 wherein the second agent is an agent regulating the release profile of the microparticle.

33. A method for delivering an agent to a biological environment in a controlled manner for a prolonged period of time, comprising the steps of:

(1) providing a dual phase polymeric delivery composition according to claim 1,

(2) maintaining said composition as a liquid; and

(3) administering said composition as a liquid to the biological environment, with subsequent gel formation in the biological environment in response to a stimuli.

34. The method according to claim 33 wherein said administration is via parenteral, ocular, topical, inhalation, transdermal, vaginal, buccal, transmucosal, transurethral, rectal, nasal, oral, pulmonary or aural routes.

35. The method according to claim 33 wherein the biological environment is a warm blooded animal.

36. A method for delivering an agent to a biological environment in a controlled manner for a prolonged period of time, comprising the steps of:

(1) providing a dual phase polymeric delivery composition according to claim 1,

(2) gelling said composition; and

(3) administering said composition as a gel to the biological environment.

37. The method according to claim 36 wherein said administration is via parenteral, ocular, topical, inhalation, transdermal, vaginal, buccal, transmucosal, transurethral, rectal, nasal, oral, pulmonary or aural routes.

38. The method according to claim 37 wherein the biological environment is a warm blooded animal.

39. A method for enhancing the stability of a drug during the release from a microparticle delivery system process by providing a dual phase biodegradable polymeric delivery composition according to claim 1.