Bioimplant formulation

• US 6,913,761 B1
• Filed: 07/20/1999
• Issued: 07/05/2005
• Est. Priority Date: 07/20/1998
• Status: Expired due to Term

• Current Assignee: Virbac Corporation (Virbac)
• Original Assignee: Peptech Limited (Teva Pharmaceutical Industries Limited)
• Inventors: Rathjen, Deborah Ann, Walsh, John Desmond, Trigg, Timothy Elliot
• Primary Examiner(s): Azpuru, Carlos A.
• Application Number:
  US09/743,059
• Time in Patent Office: 2,177 Days
• Field of Search: 424/423, 424/450, 514/12, 514/14, 514/15, 514/16, 514/17, 514/18, 514/19, 514/513, 514/514, 514/515, 530/328
• US Class Current: 424/423
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/70 Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug hollow drug-filled fibres A61K9/0092

Abstract

A pharmaceutical and/or veterinary formulation comprising about 2-30% (w/w) (on an active basis) of at least one active agent, about 0.5-20.0% (w/w) of a pore-foaming agent and the balance stearin. Such formulations provided release of the at least one active agent in humans and other animals for periods of 7 days up to about 2 years.

Claims

1. A pharmaceutical and/or veterinary formulation comprising about 2-30% (w/w) (on an active basis) of at least one active agent, about 0.5-20.0% (w/w) of a pore-forming agent and the balance stearin, with the proviso that where the at least one active agent is a gonadotropin-releasing hormone(GnRH) agonist(s) the pore-forming agent is not lecithin.

2. A formulation according to claim 1, wherein the formulation comprises about 5-10% (w/w) (on an active basis) of at least one active agent, about 1.0-10.0% (w/w) of a pore-forming agent and the balance stearin.

3. A formulation according to claim 1, wherein the formulation comprises about 5-10% (w/w) (on an active basis) of at least one active agent, about 2.0-5.0% (w/w) of a pore-forming agent and the balance stearin.

4. A formulation according to claim 1, wherein the at least one active agent is selected from peptides, polypeptides, proteins and nucleic acid compounds and derivatives.

5. A formulation according to claim 1, wherein the at least one active agent is selected from GnRH agonists.

6. A formulation according to claim 5, wherein the GnRH agonist(s) is selected from deslorelin, eulexin, goserelin, leuprolide, dioxalan derivatives, triptorelin, meterelin, buserelin, histrelin, nafarelin, lutrelin, leuprorelin and LHRH analogues.

7. A formulation according to claim 1, wherein the at least one active agent is selected from GnRH antagonists.

8. A formulation according to claim 7, wherein the GnRH anatgonist is selected from ramorelix, teverelix, cetrorelix, ganirelix, alanex and abarelix.

9. A formulation according to claim 1, wherein the at least one active agent is selected from somatostatin analogues.

10. A formulation according to claim 9, wherein the somatostatin analogue is selected from somatostatin-14, octreotide, laureotide and angiopeptin cyclopeptides.

11. A formulation according to claim 1, wherein the at least one active agent is selected from lipid lowering agents.

12. A formulation according to claim 11, wherein the lipid lowering agent is selected from cerevastatin, mevastatin, simvastatin, pravastatin and lovastatin.

13. A formulation according to claim 1, wherein the at least one active agent is selected from cyclosporins and cyclosporin analogues.

14. A formulation according to claim 13, wherein the cyclosporin or cyclosporin analogue is cyclosporin A.

15. A formulation according to claim 1, wherein the at least one active agent is selected from angiotensin converting enzyme inhibitors.

16. A formulation according to claim 15, wherein the angiotensin converting enzyme inhibitor is selected from captopril, enalapril, trandolaprilate, perindoprilate, quinaprilate, fasidotril, omapatrilate and lisinopril.

17. A formulation according to claim 1, wherein the at least one active agent is selected from calcitonins and calcitonin analogues.

18. A formulation according to claim 17, wherein the calcitonin is selected from human calcitonin, salmon calcitonin and porcine calcitonin.

19. A formulation according to claim 1, wherein the at least one active agent is selected from substance P antagonists.

20. A formulation according to claim 19, wherein the substance P antagonist is selected from Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH₂, Gln-Gln-Phe-Phe-Gly-Leu-Met-NH₂, Gln-Phe-Phe-Gly-Lou-Met-NH₂. Phe-Phe-Gly-Leu-Met-NH₂, Phe-Gly-Leu-Met-NH₂ and Gly-Leu-Met-NH₂.

21. A formulation according to claim 1, wherein the at least one active agent is selected from pain killing agents.

22. A formulation according to claim 21, wherein the painkilling agent is selected from morphine, levorphanol, meperidine, bupivacaine, lidocaine, etidocaine and mepivacaine.

23. A formulation according to claim 1, wherein the at least one active agent is selected from opioid antagonists.

24. A formulation according to claim 23, wherein the opioid antagonist is selected from naltrexone, naloxone and methadone.

25. A formulation according to claim 1, wherein the at least one active agent is selected from anti-depressant agents.

26. A formulation according to claim 25, wherein the anti-depressant agent is selected from venlafaxine, triflupromazine, methotrimeprazine, promethazine, buspirone, gepirone and fluoxetine.

27. A formulation according to claim 1, wherein the at least one active agent is selected from non-steroidal anti-inflammatory agents.

28. A formulation according to claim 27, wherein the at least one active agent is naproxen sodium indomethacin, sulindac, tolmelin, acemetacin, zomepirac, mefenamic acid, fenoprofen, flufenamic acid, phenylbutazone, flurbiprofen, ketoprofen and axsain.

29. A formulation according to claim 1, wherein the at least one active agent is selected from paroxetine, galanin antagonists, activin, inhibin fragments, adrenocorticotropic hormone (ACTH) and variants and fragments thereof, growth hormone and growth hormone analogues, erythropoietin (EPO) and erythropoietin analogues, endothelin antagonists, leptin and leptin analogues, thyrotropin releasing hormone (TRH) and TRH analogues, theophylline and theophylline analogues.

30. A formulation according to claim 1, wherein the at least one active agent is selected from vaccine antigens and DNA encoding vaccine antigens.

31. A formulation according to claim 1, wherein the at least one active agent has a log octanol/water partition coefficient (log P) in the range of 5.0 to −

3.0.

32. A formulation according to claim 31, wherein the at least one active agent has a log octanol/water partition coefficient (log P) in the range of 3.0 to −

3.0.

33. A formulation according to claim 31, wherein the at least one active agent has a log octanol/water partition coefficient (log P) in the range 1.0 to −

3.0.

34. A formulation according to claim 1, wherein the pore-forming agent is selected from inorganic salts, organic salts, sugars, amino sugars, amino acids, peptides, water-soluble proteins, water-soluble vitamins and combinations thereof.

35. A formulation according to claim 34, wherein the pore-forming agent is selected from lecithin, lysine, sodium sulphate, sodium acetate, glucose and hydroxy propyl methylcellulose (HPMC).

36. A formulation according to claim 1, wherein at least one active agent, is released in vitro into phosphate buffered saline, as herein before described, at 37°

C. at a rate of about 2 ug-1.5 mg/day for at least 7 days.

37. A formulation according to claim 1, wherein the formulation is in the form of free flowing beads or rods.

38. A formulation according to claim 1, wherein the at least one active agent has been pre-treated with a process comprising at least two freeze drying steps.

39. A formulation according to claim 38, wherein the pre-treatment process comprises the steps of;

(i) forming a 5-50% (w/w) solution of the active agent(s),

(ii) freeze drying said solution of step (i),

(iii) forming a 25-75% (w/w) solution or homogenate from said freeze dried active agent(s), and

(iv) freeze drying said solution or homogenate of step (iii).

40. A method of treating a disease or condition is a human or other animal, the method comprising administering to the human or other animal a formulation according to claim 1.