Sustained and controlled release of water insoluble polypeptides

• US 5,192,741 A
• Filed: 09/20/1988
• Issued: 03/09/1993
• Est. Priority Date: 09/21/1987
• Status: Expired due to Term

• Current Assignee: Debio Recherche Pharmaceutique SA
• Original Assignee: Debiopharm SA (Debiopharm)
• Inventors: Mauvernay, Rolland-Yves, Deghenghi, Romano, Orsolini, Piero
• Primary Examiner(s): GRIFFIN, RONALD
• Application Number:
  US07/247,060
• Time in Patent Office: 1,631 Days
• Field of Search: 514/12, 514/13, 514/14, 514/15, 514/16, 514/3, 514/4, 514/16, 530/303, 530/304
• US Class Current: 424/422
• CPC Class Codes: A61K 38/04 Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof enzyme inhibitors A61K38/005; gastrins A61K38/2207, somatostatins A61K38/31, melanotropins A61K38/34 ; protease inhibitors A61K38/55
• CPC Class Codes: A61K 38/09 Luteinising hormone-releasing hormone [LHRH] , i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
• 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 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)

Abstract

There is disclosed a pharaceutical composition for sustained and controlled release of drug over an extended period of time comprising a polylactide, a copolymer of lactic and glycolic acid, a mixture of such polymers and a water-insoluble peptide which, when placed in an aqueous physiologically-type environment releases the peptide in continuous manner for a period of at least one week, and with an initial release for the first twenty-four hours of not more than 30% of the total amount released. There is thus provided the control of the release pattern and in general a decrease of the initial burst effect.

Claims

1. A process for preparing a pharmaceutical composition designed for sustained and controlled release of a peptide, said process comprising selecting a water-insoluble peptide salt;

dispersing the water-insoluble peptide salt into a solution of a polylactide polymer, a polyglycolide polymer, a copolymer of lactic and glycolic acids, or a mixture of said polymers and a solvent;

removing the solvent of the solution to form a residue; and

shaping the residue into solid particles of said pharmaceutical composition suitable for administration by parenteral injection or as a subcutaneous implant.

3. A process as claimed in claim 1 or 2 which further comprises selecting said water-insoluble peptide from pharmaceutically acceptable salts of LHRH and synthetically prepared analogues thereof.

4. A process as claimed in claim 3 wherein the pharmaceutically acceptable salt is selected from the group consisting of pamoate, tannate and stearate salts.

5. A process as claimed in claim 1 or 2 which further comprises selecting said water-insoluble peptide from pharmaceutically acceptable salts of oxytocin, vasopressin, ACTH, calcitonin, epidermal growth factor, prolactin, inhibin, interferon, somatstatin insulin, glucagon, atrial natriuretic factor, endorphin, a peptide renin inhibitor, growth hormone releasing factor, peptide T and synthetic analogues thereof.

6. A process as claimed in claim 1 or 2 wherein said water-insoluble peptide salt is dispersed within said solution by high shear mixing.

7. A process as claimed in claim 1 or 2 which further comprises sterlizing said composition by exposure to gamma radiation at between 2.5 and 2.8 Mrad.

8. The process of claim 1 wherein said peptide, polymer or copolymer is selected so as to provide a continuous release of said peptide when placed in a physiological environment.

9. The process of claim 1 further comprising selecting a water-insoluble peptide and polylactide polyglycolide polymer or copolymer molar ratio, and dosing said polymer or copolymer with said peptide salt so that said subcutaneous implant provides a continuous release of peptide when placed in a physiological environment.

2. A process for preparing a pharmaceutical composition designed for sustained and controlled release of a peptide, said process comprising selecting a water insoluble peptide salt;

dispersing a water-insoluble peptide salt into a solution of a polylactide polymer, a polyglycolide polymer, a copolymer of lactic and glycolic acids or a mixture of said polymers;

adding a coacervation agent to the solution to form microcapsules of the peptide salt and polymer(s);

pouring the resulting microcapsules into a pharmaceutically acceptable hardening liquid; and

collecting the microcapsules for use as a pharmaceutical composition suitable for administration by parenteral injection or as a subcutaneous implant.

10. The process of claim 2 further comprising selecting a water-insoluble peptide and polylactide polyglycolide polymer or copolymer molar ratio, and dosing said polymer or copolymer with said peptide salt so that said microspheres provide a continuous release of peptide when placed in a physiological environment.

11. A process for preparing a pharmaceutical composition for sustained and controlled release of a peptide, said process comprising:

forming a water-insoluble salt of LHRH or a synthetic analog thereof;

dispersing the water-insoluble peptide salt with mixing into a solution of a polylactide polymer, a polyglycolide polymer, a copolymer of lactic and glycolic acids or a mixture of said polymers and a solvent;

forming microparticles of the peptide salt and polymer(s) by evaporating the solvent;

drying the microparticles;

extruding the microparticles into rods;

grinding the rods into granular material;

sieving the granular materials; and

collecting a fraction and sterlizing the fraction for use as the pharmaceutical composition.

14. The process of claim 11 wherein the rods are ground cryogenically into the granular material.

12. A process for preparing a pharmaceutical composition designed for sustained and controlled release of a peptide, said process comprising forming a water insoluble peptide salt from a water-soluble peptide;

dispersing said water-insoluble peptide salt into a solution of a polylactide polymer, a polyglycolide polymer, a copolymer of lactic and glycolic acids or a mixture of said polymers;

adding a coacervation agent to the solution to form microcapsules of the peptide salt and polymer(s);

pouring the resulting microcapsules into a pharmaceutically acceptable hardening liquid; and

collecting the microcapsules for use as a pharmaceutical composition suitable for administration by parenteral injection or as a subcutaneous implant.

13. The process of claim 12, further comprising selecting said peptide from the group consisting of pamoate, tannate and stearate salts of D-Trp⁶ -LHRH and selecting a mixture of D,L-lactide and glycolide as said polymer.