Details for Patent: 6,180,608

Title:	Pharmaceutical formulations for sustained drug delivery
Abstract:	Sustained delivery formulations comprising a water-insoluble complex of a peptidic compound (e.g., a peptide, polypeptide, protein, peptidomimetic or the like) and a carrier macromolecule are disclosed. The formulations of the invention allow for loading of high concentrations of peptidic compound in a small volume and for delivery of a pharmaceutically active peptidic compound for prolonged periods, e.g., one month, after administration of the complex. The complexes of the invention can be milled or crushed to a fine powder. In powdered form, the complexes form stable aqueous suspensions and dispersions, suitable for injection. In a preferred embodiment, the peptidic compound of the complex is an LHRH analogue, preferably an LHRH antagonist, and the carrier macromolecule is an anionic polymer, preferably carboxymethylcellulose. Methods of making the complexes of the invention, and methods of using LHRH-analogue-containing complexes to treat conditions treatable with an LHRH analogue, are also disclosed.
Inventor(s):	Gefter; Malcolm L. (Lincoln, MA), Barker; Nicholas (Southborough, MA), Musso; Gary (Hopkinton, MA), Molineaux; Christopher J. (Brookline, MA)
Assignee:	Praecis Pharmaceuticals, Inc. (Cambridge, MA)
Filing Date:	Dec 11, 1997
Application Number:	08/988,851
Claims:	1. A packaged formulation for treating a subject for a condition treatable with an LHRH analogue, comprising: a solid ionic complex of an LHRH angalogue and a carrier macromolecule packaged with instructions for fusing the complex for treating a subject having a condition treatable with an LHRH analogue, wherein the peptide content of said complex is 57% to 80% by weight. 2. The packaged formulation of claim 1, wherein the LHRH analogue has the following structure: Ac-D-Nal.sup.1, 4-Cl-D-Phe.sup.2, D-Pal.sup.3, N-Me-Tyr.sup.5, D-Asn.sup.6, Lys(iPr).sup.8, D-Ala.sup.10 -LHRH, and the carrier macromolecule is carboxymethylcellulose, or a pharmaceutically acceptable salt thereof. 3. In a syringe having a lumen, the improvement comprises, inclusion of a liquid suspension of a solid ionic complex of an LHRH analogue and a carrier macromolecule in the lumen, wherein the peptide content of said complex is 57% to 80% by weight. 4. The syringe of claim 3, wherein the LHRH analogue has the following structure: Ac-D-Nal.sup.1, 4-Cl-D-Phe.sup.2, D-Pal.sup.3, N-Me-Tyr.sup.5, D-Asn.sup.6, Lys(iPr).sup.8, D-Ala.sup.10 -LHRH, and the carrier macromolecule is carboxymethylcellulose, or a pharmaceutically acceptable salt thereof. 5. A method for treating a subject for a condition treatable with an LHRH analogue, comprising administering to the subject a pharmaceutical formulation comprising a solid ionic complex of an LHRH analogue and a carrier macromolecule, wherein the peptide content of said complex is 57% to 80% by weight. 6. The method of claim 5, wherein the complex provides sustained delivery of the LHRH analogue to a subject for at least one week after the pharmaceutical composition is administered to the subject. 7. The method of claim 5, wherein the complex provides sustained delivery of the LHRH analogue to a subject for at least two weeks after the pharmaceutical composition is administered to the subject. 8. The method of claim 5, wherein the complex provides sustained delivery of the LHRH analogue to a subject for at least three weeks after the pharmaceutical composition is administered to the subject. 9. The method of claim 5, wherein the complex provides sustained delivery of the LHRH analogue to a subject for at least four weeks after the pharmaceutical composition is administered to the subject. 10. The method of claim 5, wherein the LHRH analogue is an LHRH antagonist. 11. The method of claim 10, wherein the LHRH antagonist has the following structure: Ac-D-Nal.sup.1, 4-Cl-D-Phe.sup.2, D-Pal.sup.3, N-Me-Tyr.sup.5, D-Asn.sup.6, Lys(iPr).sup.8, D-Ala.sup.10 -LHRH. 12. The method of claim 5, wherein the carrier macromolecule is an anionic polymer. 13. The method of claim 5, wherein the carrier macromolecule is an anionic polyalcohol derivative, or fragment thereof, or a pharmaceutically acceptable salt thereof. 14. The method of claim 5, wherein the carrier macromolecule is an anionic polysaccharide derivative, or fragment thereof, or a pharmaceutically acceptable salt thereof. 15. The method of claim 5, wherein the carrier macromolecule is carboxymethylcellulose, or a pharmaceutically acceptable salt thereof. 16. The method of claim 5, wherein the carrier macromolecule is selected from the group consisting of align, alginate, anionic acetate polymers, anionic acrylic polymers, xantham gums, anionic carageenan derivatives, anionic polygalacturonic acid derivatives, sodium starch glycolate, and fragments, derivatives and pharmaceutically acceptable salts thereof. 17. The method of claim 5, wherein the pharmaceutical formulation is administered to the subject by a parenteral route. 18. The method of claim 5, wherein the pharmaceutical formulation is administered to the subject orally. 19. The method of claim 5, wherein the pharmaceutical formulation is administered by intramuscular injection or subcutaneous/intradermal injection. 20. The method of claim 5, wherein the condition treatable with an LHRH analogue is a hormone dependent cancer. 21. The method of claim 20, wherein the hormone dependent cancer is prostate cancer. 22. The method of claim 5, wherein the condition treatable with an LHRH analogue is selected from the group consisting of benign prostatic hypertrophy, precocious puberty, endometriosis and uterine fibroids. 23. The method of claim 5, wherein the LHRH analogue is administered for in vitro fertilization or contraceptive purposes. 24. A pharmaceutical composition comprising a solid ionic complex of a pharmaceutically active peptide and a carrier macromolecule, wherein the peptide content of said complex is 57% to 80% by weight. 25. A pharmaceutical composition consisting essentially of a solid ionic complex of a pharmaceutically active peptide and a carrier macromolecule, wherein the peptide content of said complex is 57% to 80% by weight. 26. The pharmaceutical composition of any one of claim 24 or 25, wherein the pharmaceutically active peptide is cationic and the carrier macromolecule is anionic. 27. The pharmaceutical composition of any one of claim 24 or 25, wherein the pharmaceutically active peptidic compound is aniotic and the currier macromolecule is cationic. 28. The pharmaceutical composition of any one of claim 24 or 25, wherein the complex provides sustained delivery of the pharmaceutically active peptide to a subject for at least one week after the pharmaceutical composition is administered to the subject. 29. The pharmaceutical composition of any one of claim 24 or 25, wherein the complex provides sustained delivery of the pharmaceutically active peptide to a subject for at least two weeks after the pharmaceutical composition is administered to the subject. 30. The pharmaceutical composition of any one of claim 24 or 25, wherein the complex provides sustained delivery of the pharmaceutically active peptide to a subject for at least three weeks after the pharmaceutical composition is administered to the subject. 31. The pharmaceutical composition of any one of claim 24 or 25, wherein the complex provides sustained delivery of the pharmaceutically active peptide to a subject for at least four weeks after the pharmaceutical composition is administered to the subject. 32. The pharmaceutical composition of any one of claim 24 or 25, wherein the pharmaceutically active peptide is a multivalent cationic or anionic peptide. 33. The pharmaceutical composition of any one of claim 24 or 25, wherein the peptide is 5 to 20 amino acids in length. 34. The pharmaceutical composition of any one of claim 24 or 25, wherein the peptide is 1 to 15 amino acids in length. 35. The pharmaceutical composition of any one of claim 24 or 25, wherein the peptide is 8 to 12 amino acids in length. 36. The pharmaceutical composition of any one of claim 24 or 25, wherein the carrier macromolecule is an anionic polymer. 37. The pharmaceutical composition of any one of claim 24 or 25, wherein the carrier macromolecule is an anionic polyalcohol derivative, or fragment thereof. 38. The pharmaceutical composition of any one of claim 24 or 25, wherein the carrier macromolecule is an anionic polysaccharide derivative, or fragment thereof. 39. The pharmaceutical composition of any one of claim 24 or 25, wherein the carrier macromolecule is carboxymethylcellulose, or a fragment or derivative thereof. 40. The pharmaceutical composition of any one of claim 24 or 25, wherein the carrier macromolecule is selected from the group consisting of align, alginate, anionic acetate polymers, anonic acrylic polymers, xantham gums, anionic carageenan derivatives, anionic polygalacturonic acid derivatives, sodium starch glycolate, and fragments, derivatives and pharmaceutically acceptable salts thereof. 41. The pharmaceutical composition of any one of claim 24 or 25, which is a lyophilized solid. 42. The pharmaceutical composition of any one of claim 24 or 25, wherein said solid ionic complex is suspended as a liquid suspension or dispersed as a semi-solid dispersion. 43. The pharmaceutical composition of any one of claim 24 or 25, wherein said pharmaceutically active peptide is an LHRH analogue. 44. The pharmaceutical composition of claim 43 wherein the LHRH analogue is an LHRH antagonist comprising a peptide compound, wherein a residue of the peptide compound corresponding to the amino acid at position 6 of natural mammalian LHRH comprises a D-asparagine structure. 45. The pharmaceutical composition of claim 43 wherein the LHRH analogue is an LHRH antagonist comprising a peptide compound comprising a structure: A-B-C-D-E-F-G-H-I-J wherein A is pyro-Glu, Ac-D-Nal , Ac-D-Qal, Ac-Sar, or Ac-D-Pal B is His or 4-Cl-D-Phe C is Trp, D-Pal, D-Nal, L-Nal, D-Pal(N-O), or D-Trp D is Ser E is N-Me-Ala, Tyr, N-Me-Tyr, Ser, Lys(iPr), 4-Cl-Phe, His, Asn, Met, Ala, Arg or Ile; F is D-Asn, D-Gln, or D-Thr; G is Leu or Trp; H is Lys(iPr), Gln, Met, or Arg I is Pro; and J is Gly-NH.sub.2 or D-Ala-NH.sub.2 ; or a pharmaceutically acceptable salt thereof. 46. The pharmaceutical composition of claim 43, wherein the LHRH analogue is an LHRH antagonist having the following structure: Ac-D-Nal.sup.1, 4-Cl-D-Phe.sup.2, D-Pal.sup.3, N-Me-Tyr.sup.5, D-Asn.sup.6, Lys(iPr).sup.8, D-Ala.sup.10 -LHRH. 47. The pharmaceutical composition of claim 43 wherein said pharmaceutically active peptide is an LHRH antagonist. 48. The pharmaceutical composition of claim 43, wherein the LHRH analogue is the LHRH agonist Leuprolide having the structure pGlu-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro(ethylamide)-Gly. 49. The pharmaceutical composition of claim 43, wherein the LHRH analogue is the LHRH antagonist Cetrorelix having the structure Ac-D-Nal-4-Cl-D-Phe-D-Pal-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala. 50. The pharmaceutical composition of any one of claim 24 or 25, wherein said pharmaceutically active peptide is selected from the group consisting of bradykinin analogues, parathyroid hormone, adenocorticotrophic hormone, calcitonin, and vasopressin analogues.