Method for preparing a pharmaceutical composition in the form of microparticles

• US 5,134,122 A
• Filed: 07/20/1990
• Issued: 07/28/1992
• Est. Priority Date: 07/28/1989
• Status: Expired due to Term

• Current Assignee: Debio Recherche Pharmaceutique SA
• Original Assignee: Debiopharm SA (Debiopharm)
• Inventors: Orsolini, Piero
• Primary Examiner(s): LEE, LESTER
• Application Number:
  US07/555,973
• Time in Patent Office: 739 Days
• Field of Search: 424/489, 514/12-18
• US Class Current: 424/497
• CPC Class Codes: A61K 38/09 Luteinising hormone-releasing hormone [LHRH] , i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
• CPC Class Codes: A61K 38/23 Calcitonins
• CPC Class Codes: A61K 38/25 Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
• CPC Class Codes: A61K 38/31 Somatostatins
• 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

A method for preparing a pharmaceutical composition in the form of microparticles, the composition thus obtained and its use for preparing injectable suspensions.

Claims

1. A method for preparing a pharmaceutical composition which is aimed at providing a prolonged and a controlled release of medicamentous substance, which is obtained in the form of microparticles of a copolymer of lactic and glycolic acids, and which incorporates, as the active substance, the pamoate, tannate, stearate or palmitate salt of a natural or of a synthetic peptide, characterized in that:

a) the selected copolymer and active substance, both present in the form of microparticles whose average grain size is below approximately 200 microns, are dry-mixed in relative amounts such that the active substance is present in a proportion of about 0.1-15% by weight;

b) the powdered mixture thus obtained is compressed and is heated up to approximately 80°

C.;

c) the precompressed and preheated mixture is subjected to an extrusion at a temperature of between approximately 80° and

100°

C.; and

d) the product resulting from the extrusion is pulverized at low temperature and then, the microparticles having a grain size below approximately 200 microns are selected and finally collected.

2. A method according to claim 1, characterized in that the microparticles of copolymer have an average grain size below or equal to 180 microns.

3. A method according to claim 2, characterized in that the precompression and the preheating of the mixture are carried out simultaneously by means of an endless screw.

4. A method according to claim 3, characterized in that the extrusion is carried out at a pressure in the range from 50 to 500 kg/cm².

5. A method according to claim 4, characterized in that the pulverization of the product resulting from the extrusion is a cryogenic pulverization.

6. A method according to claim 5, characterized in that the selection of the microparticles resulting from the pulverization is carried out by sieving.

7. A method according to claim 6, characterized in that the copolymer of lactic and glycolic acids is a copolymer of L- or D,L-lactic acid containing respectively 45 to 90% (moles) of lactic acid units and 55 to 10% (moles) of glycolic acid units.

8. A method according to claim 7, characterized in that the active substance is the pamoate, tannate, stearate or palmitate of a natural or of a synthetic peptide comprising 3 to 45 amino acids, and including LH-RH, somatostatin, GH-RH, calcitonin or one of their synthetic analogues or homologues.

9. A method according to claim 8, characterized in that the active substance is a pamoate of LH-RH, of somatostatin or of one of their analogues or homologues selected from ##STR7## (R¹ =lower alkyl).

20. The method of claim 1 wherein additional heat and pressure are simultaneously applied in slowly increasing amounts to the powdered mixture of the selected copolymer and active substance.

21. The method of claim 20 wherein additional heat and pressure are simultaneously applied in slowly increasing amounts to the powdered mixture of the selected copolymer and active substance as the mixture is transported in an endless screw.

10. A method for preparing a pharmaceutical composition which provides a prolonged and controlled release of an active substance, which comprises:

a) mixing microparticles of a copolymer of lactic and glycolic acids with microparticles of an active substance of an insoluble salt of a natural or synthetic peptide comprising 3 to 45 amino acids for a sufficient time to form a homogenous mixture containing about 0.1 to 15% by weight of the active substance, each of said microparticles having an average grain size of below approximately 200 microns; and

b) precompressing and preheating the mixture prior to extruding the precompressed and preheated mixture at a temperature of between approximately 80° and

100°

C. to form a product for use as said pharmaceutical composition.

11. A method according to claim 10 which further comprises:

c) pulverizing the extruded product at low temperature; and

d) selecting the microparticles which have a grain size of below about 200 microns for use as said pharmaceutical composition.

12. A method according to claim 11 which further comprises selecting the microparticles of the copolymer to have an average grain size of 180 microns or less.

13. A method according to claim 11 wherein the precompressing and preheating of the mixture are carried out simultaneously by passing the mixture through an endless screw.

14. A method according to claim 11 wherein the extrusion is carried out at a pressure in the range of about 50 to 500 kg/cm².

15. A method according to claim 11 which further comprises pulverizing the extruded product at cryogenic temperatures.

16. A method according to claim 11 wherein the selection of the microparticles for use as the pharmaceutical composition is obtained by sieving the desired grain size of the pulverized product.

17. A method according to claim 11 which further comprises selecting the copolymer of lactic and glycolic acids to be a copolymer of L- or D,L-lactic acid containing 45 to 90% (moles) of lactic acid units and 55 to 10% (moles) of glycolic acid units.

18. A method according to claim 11 which further comprises selecting the active substance to be a pamoate, tannate, stearate or palmitate salt of LH-RH, somatostatin, GH-RH, calcitonin or a synthetic analogue or homologue thereof.

19. A method according to claim 11 which further comprises selecting the active substance to be a pamoate salt of LH-RH, somatostatin or an analogue or homologue thereof selected from the group consisting of:

##STR8## where R¹ =a lower alkyl group.

22. The method of claim 10 wherein additional heat and pressure are simultaneously applied in slowly increasing amounts to the powdered mixture of the selected copolymer and active substance.

23. The method of claim 22 wherein additional heat and pressure are simultaneously applied in slowly increasing amounts to the powdered mixture of the selected copolymer and active substance as the mixture is transported in an endless screw.