Pharmaceutical formulations for sustained release

• US 20020176841A1
• Filed: 03/19/2002
• Published: 11/28/2002
• Est. Priority Date: 03/19/2001
• Status: Abandoned Application

• Current Assignee: GlaxoSmithKline LLC (GSK plc)
• Original Assignee: Praecis Pharmaceuticals, Inc. (GSK plc)
• Inventors: Barker, Nicholas, Wolfe, Janet L.
• Application Number:
  US10/102,530
• Publication Number:
  US 20020176841A1
• Time in Patent Office: Days
• US Class Current: 424/78.12
• CPC Class Codes: A61K 38/02 Peptides of undefined number of amino acids; Derivatives thereof
• CPC Class Codes: A61K 47/61 the organic macromolecular compound being a polysaccharide or a derivative thereof

Abstract

Sustained delivery pharmaceutical compositions comprising a solid ionic complex of a pharmaceutically active compound and an ionic macromolecule are provided by the present invention. The pharmaceutical compositions of the invention allow for loading of high concentrations of pharmaceutically active compounds and for delivery of a pharmaceutically active compound for prolonged periods of time, e.g., one month, after administration. Methods for preparing these pharmaceutical compositions, as well as methods of using them to treat a subject are also provided.

Claims

1. A pharmaceutical composition comprising a solid ionic complex, said complex comprising a pharmaceutically active compound and an ionic macromolecule.

2. The pharmaceutical composition of claim 1 wherein the pharmaceutically active compound has a net positive charge.

3. The pharmaceutical composition of claim 2, wherein the pharmaceutically active compound has at least one functional group selected from the group consisting of primary amino groups, secondary amino groups, tertiary amino groups, imino groups, quaternary ammonium groups, amidino groups, guanidino groups, phosphonium groups and sulfonium groups.

4. The pharmaceutical composition of claim 1, wherein the pharmaceutically active compound has a net negative charge.

5. The pharmaceutical composition of claim 4, wherein the pharmaceutically active compound has at least one functional group selected from the group consisting of carboxylate groups, sulfonate groups, phosphonate groups, sulfamate groups, sulfate ester groups, phosphate ester groups, sulfinate groups, phosphinate groups, carbonate groups, thiocarboxylate groups and carbamate groups.

6. The pharmaceutical composition of claim 2, wherein the pharmaceutically active compound contains at least one functional group selected from the group consisting of primary amino groups, secondary amino groups, tertiary amino groups, imino groups and quaternary ammonium groups.

7. The pharmaceutical composition of claim 2, wherein the pharmaceutically active compound has at least one functional group selected from the group consisting of carboxylate and sulfonate.

8. The pharmaceutical composition of claim 1, wherein the pharmaceutically active compound has a molecular weight of about 1000 amu or less.

9. The pharmaceutical composition of claim 1, wherein the pharmaceutically active compound has a molecular weight of about 750 amu or less.

10. The pharmaceutical composition of claim 1, wherein the pharmaceutically active compound has a molecular weight of about 500 amu or less.

11. The pharmaceutical composition of claim 2, wherein the pharmaceutically active compound has a net charge of at least +1.

12. The pharmaceutical composition of claim 2, wherein the pharmaceutically active compound has a net charge of at least +2.

13. The pharmaceutical composition of claim 4, wherein the pharmaceutically active compound has a net charge of at least −

1.

14. The pharmaceutical composition of claim 4, wherein the pharmaceutically active compound has a net charge of at least −

2.

15. The pharmaceutical composition of claim 1, wherein the ionic macromolecule comprises at least one functional group selected from the group consisting of carboxylic acid, sulfonic acid, sulfamic acid, primary amine, secondary amine, tertiary amine, quaternary ammonium, guanidino and amidino.

16. The pharmaceutical composition of claim 4, wherein the ionic macromolecule is a polypeptide or a polysaccharide.

17. The pharmaceutical composition of claim 1, wherein a single dose of the solid ionic complex provides sustained delivery of the pharmaceutically active compound to a subject for at least one week after the pharmaceutical composition is administered to the subject.

18. The pharmaceutical composition of claim 1, wherein a single dose of the solid ionic complex provides sustained delivery of the pharmaceutically active compound to a subject for at least two weeks after the pharmaceutical composition is administered to the subject.

19. The pharmaceutical composition of claim 1, wherein a single dose of the solid ionic complex provides sustained delivery of the pharmaceutically active compound to a subject for at least three weeks after the pharmaceutical composition is administered to the subject.

20. The pharmaceutical composition of claim 1, wherein a single dose of the water-insoluble 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.

21. The pharmaceutical composition of claim 1, wherein said solid ionic complex is a lyophilized solid.

22. The pharmaceutical composition of claim 1, wherein said solid ionic complex is suspended as a liquid suspension or dispersed as a semi-solid dispersion.

23. The pharmaceutical composition of claim 1, wherein the pharmaceutically active compound content of the solid ionic complex is at least 50% by weight.

24. The pharmaceutical composition of claim 1, wherein the pharmaceutically active compound content of the solid ionic complex is at least 60% by weight.

25. The pharmaceutical composition of claim 1, wherein the pharmaceutically active compound content of the solid ionic complex is at least 70% by weight.

26. The pharmaceutical composition of claim 1, wherein the pharmaceutically active compound content of the solid ionic complex is 50% to 90% by weight.

27. The pharmaceutical composition of claim 1, wherein the pharmaceutically active compound and the ionic macromolecule used to form the solid ionic complex are combined at a weight ratio of ionic macromolecule:

pharmaceutically active compound of 0.5;

1 to 0.1;

1

28. The pharmaceutical composition of claim 1, wherein the pharmaceutically active compound and the ionic macromolecule used to form the solid ionic complex are combined at a weight ratio of ionic macromolecule:

pharmaceutically active compound of 1;

1 to 0.1;

1

29. The pharmaceutical composition of claim 1, wherein the solid ionic complex is not a microcapsule.

30. A packaged formulation for treating a subject for a condition treatable with a pharmaceutically active compound, comprising the pharmaceutical composition of claim 1 packaged with instructions for using the composition for treating a subject having a condition treatable with a pharmaceutically active compound.

31. A method for treating a subject for a condition treatable with a pharmaceutically active compound, comprising administering to the subject the pharmaceutical composition of claim 1.

32. A method for preparing a pharmaceutical formulation, comprising:

providing a pharmaceutically active compound and an ionic macromolecule;

combining the pharmaceutically active compound and the ionic macromolecule under conditions such that a solid ionic complex of the pharmaceutically active compound and the ionic macromolecule forms; and

preparing a pharmaceutical formulation comprising the solid ionic complex.

33. The method of claim 32, wherein a solution of the pharmaceutically active compound and a solution of the ionic macromolecule are combined until a water-insoluble complex of the pharmaceutically active compound and the ionic macromolecule precipitates.

34. The method of claim 33, wherein the solution of the pharmaceutically active compound and the solution of the ionic macromolecule are aqueous solutions.

35. The method of claim 33, wherein the solution of the pharmaceutically active compound and the solution of the ionic macromolecule are combined and heated until a water-insoluble complex of the pharmaceutically active compound and the ionic macromolecule precipitates.

36. The method of claim 33, further comprising sterilizing the water-insoluble complex by gamma irradiation or electron beam irradiation.

37. The method of claim 33, wherein the water-insoluble complex is formed using aseptic procedures.

38. A method for identifying a pharmaceutically active compound which can form an insoluble complex with an ionic polymer, the method comprising:

(1) providing a multiplicity of solutions, each of said solutions comprising a pharmaceutically active compound;

(2) contacting the solutions of step (1) with an ionic polymer to produce a mixture comprising a pharmaceutically active compound and an ionic polymer; and

(3) determining the turbidity of the mixture of step (2), thereby identifying a pharmaceutically active compound which can form an insoluble complex with an ionic polymer.

39. A method for selecting an ionic polymer capable of forming an insoluble complex with a pharmaceutically active compound, the method comprising:

(1) providing a solution comprising the pharmaceutically active compound;

(2) providing n distinct solutions, where n is an integer of two or greater, each of said n distinct solutions comprising an ionic polymer;

(3) contacting each of n aliquots of the solution comprising the pharmaceutically active compound with one of the solutions comprising an ionic polymer, thereby forming n mixtures comprising a pharmaceutically active compound and an ionic polymer; and

(4) determining the turbidity of each mixture of step (3), thereby selecting an ionic polymer capable of forming an insoluble complex with a pharmaceutically active compound.