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Last Updated: March 29, 2024

Claims for Patent: 5,968,895


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Summary for Patent: 5,968,895
Title: Pharmaceutical formulations for sustained drug delivery
Abstract:Sustained delivery formulations comprising a water-insoluble complex of a peptide and a carrier macromolecule are disclosed. The formulations of the invention allow for loading of high concentrations of peptide in a small volume and for delivery of a pharmaceutically active peptide 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 peptide 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)
Application Number:08/762,747
Patent Claims:1. A pharmaceutical composition comprising a solid ionic complex of an LHRH analogue and a carrier macromolecule, wherein the carrier and analogue used to form the complex are combined at a weight ratio of carrier:analogue of 0.5:1 to 0.1:1 and wherein said complex is not a microcapsule.

2. The pharmaceutical composition of claim 1, 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.

3. The pharmaceutical composition of claim 1, 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.

4. The pharmaceutical composition of claim 1, 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.

5. The pharmaceutical composition of claim 1, 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.

6. The pharmaceutical composition of claim 1, wherein the LHRH analogue is a multivalent cationic or anionic peptide.

7. The pharmaceutical composition of claim 1, wherein the LHRH analogue is 5 to 20 amino acids in length.

8. The pharmaceutical composition of claim 1, wherein the LHRH analogue is 8 to 15 amino acids in length.

9. The pharmaceutical composition of claim 1, wherein the LHRH analogue is 8 to 12 amino acids in length.

10. A pharmaceutical composition consisting essentially of a solid ionic complex of a pharmaceutically active peptide and a carrier macromolecule, wherein the carrier and peptide used to form the complex are combined at a weight ratio of carier:peptide of 0.5:1 to 0.1:1 and wherein said complex is not a microcapsule.

11. The pharmaceutical composition of claim 10, wherein The pharmaceutically active peptide is cationic and the carrier macromolecule is anionic.

12. The pharmaceutical composition of claim 10, 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.

13. The pharmaceutical composition of claim 10, 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.

14. The pharmaceutical composition of claim 10, 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.

15. The pharmaceutical composition of claim 10, 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.

16. The pharmaceutical composition of claim 10, wherein the pharmaceutically active peptide is a multivalent cationic or anionic peptide.

17. The pharmaceutical composition of claim 10, wherein the peptide is 5 to 20 amino acids in length.

18. The pharmaceutical composition of claim 10, wherein the peptide is 8 to 15 amino acids in length.

19. The pharmaceutical composition of claim 10, wherein the peptide is 8 to 12 amino acids in length.

20. The pharmaceutical composition of any one of claims 1 or 10, wherein the carrier macromolecule is an anionic polymer.

21. The pharmaceutical composition of any one of claims 1 or 10, wherein the carrier macromolecule is an anionic polyalcohol derivative, or fragment thereof.

22. The pharmaceutical composition of any one of claims 1 or 10, wherein the carrier macromolecule is an anionic polysaccharide derivative, or fragment thereof.

23. The pharmaceutical composition of any one of claims 1 or 10, wherein the carrier macromolecule is carboxymethylcellulose, or a fragment or derivative thereof.

24. The pharmaceutical composition of any one of claims 1 or 10, wherein the carrier macromolecule is selected from the group consisting of algin, 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.

25. The pharmaceutical composition of any one of claims 1 on 10, which is a lyophilized solid.

26. The pharmaceutical composition of any one of claims 1 or 10, wherein said solid ionic complex is suspended as a liquid suspension or dispersed as a semi-solid dispersion.

27. A pharmaceutical composition of claim 10, wherein said pharmaceutically active peptide is an LHRH analogue.

28. The pharmaceutical composition of claim 27 wherein said pharmaceutically active peptide is an LHRH antagonist.

29. The pharmaceutical composition of claim 27 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.

30. The pharmaceutical composition of claim 27 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.

31. The pharmaceutical composition of any one of claims 1 or 27, wherein the LHRH analogue is an LHRH antagonist having the following structure: Ac-D-Nal-4-Cl-D-Phe-D-Pal-Ser-N-Me-Tyr-D-Asn-Leu-Lys(iPr)-Pro-D-Ala.

32. The pharmaceutical composition of claim 10, wherein said pharmaceutically active peptide is selected from the group consisting of bradykinin analogues, parathyroid hormone, adenocorticotrophic hormone, calcitonin, and vasopressin analogues.

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