Controlled release ACTH containing microspheres

• US 5,413,797 A
• Filed: 06/30/1994
• Issued: 05/09/1995
• Est. Priority Date: 03/12/1992
• Status: Expired due to Fees

• Current Assignee: Alkermes Controlled Therapeutics Inc. II (Alkermes plc)
• Original Assignee: Alkermes Controlled Therapeutics Inc. II (Alkermes plc)
• Inventors: Khan, M. Amin, Bernstein, Howard
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Spear, James M.
• Application Number:
  US08/268,715
• Time in Patent Office: 313 Days
• Field of Search: 424/422, 424/423, 424/424, 424/426, 424/486, 424/489, 424/434, 514/805
• US Class Current: 424/489
• CPC Class Codes: A61K 38/35 Corticotropin [ACTH]
• CPC Class Codes: A61K 9/1611 Inorganic compounds
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61K 9/7007 Drug-containing films, membranes or sheets A61K9/0041, A61K9/0043, A61K9/006, A61K9/0063 take precedence

Abstract

ACTH polymeric controlled release systems are described wherein the ACTH retains good biological activity and is released over an extended period of time following administration by injection. In the preferred embodiment, the ACTH polymeric microspheres are made using very cold temperatures to freeze the polymer-ACTH mixtures into polymeric microspheres with very high retention of biological activity and material. Sustained release of biologically active ACTH is achieved when the microspheres are tested in vitro, extending over a period of greater than one day to several months. Altered release can be achieved by inclusion of degradation modifiers, pore forming agents, and stabilizers of the ACTH.

Claims

1. A polymeric microsphere having a diameter of less than 1000 microns, formed of a biocompatible polymer selected from the group consisting of poly(lactide), poly(lactide-co-glycolide), poly(caprolactone), polycarbonates, polyamides, polyanhydrides, polyamino acids, polyortho esters, polyacetals, polycyanoacrylates, degradable polyurethanes, polyacrylates, polymers of ethylene-vinyl acetate and other acyl substituted cellulose acetates, polysaccharides, non-erodible polyurethanes, polystyrenes, polyvinyl chloride, polyvinyl fluoride, poly(vinyl imidazole), chlorosulphonated polyolefins, polyethylene oxide, copolymers and mixtures thereof and an excipient modulating polymer erosion rate selected from the group consisting of inorganic acids, organic acids, inorganic bases, organic bases, and surfactants in an amount between 0.1 and thirty percent (w/w, polymer), containing adrenocorticotropic hormone (ACTH) in a concentration of between 0.1% and 50% by weight, wherein the microspheres release the ACTH under physiological conditions over a period of time greater than one day by diffusion and degradation of the polymeric matrix.

2. The microspheres of claim 1 wherein the polymer is a polylactide.

3. The microspheres of claim 1 wherein the diameter is less than 180 microns.

4. The microspheres of claim 1 further comprising an excipient selected from the group consisting of excipients stabilizing ACTH potency, and excipients modifying the solubility of ACTH.

5. The microspheres of claim 4 wherein the erosion rate modulating agent is a pore forming agent added to the polymer in particulate form in a concentration of between one and thirty percent (w/w, polymer).

6. The microspheres of claim 4 wherein the stabilizers are selected from the group consisting of carbohydrates, amino acids, proteins, lipids, salts, fatty acids, and surfactants.

7. The microspheres of claim 4 wherein the excipients which modify the solubility of ACTH are present in a concentration of between 0.1 and thirty percent (w/w, polymer) and are selected from the group consisting of salts, complexing agents, inorganic acids, organic acids, inorganic bases, organic bases, and surfactants.

8. A method for administering ACTH comprising administering a biocompatible polymeric microsphere containing between 0.1 and 50% ACTH and an excipient modulating polymer erosion rate, and having a diameter of less than one hundred eighty microns into a patient in need of treatment with ACTH, wherein the polymeric microsphere is formed of a biocompatible polymer selected from the group consisting of poly(lactide), poly(lactide-co-glycolide), poly(caprolactone), polycarbonates, polyamides, polyanhydrides, polyamino acids, polyortho esters, polyacetals, polycyanoacrylates, degradable polyurethanes, polyacrylates, polymers of ethylene-vinyl acetate and other acyl substituted cellulose acetates, polysaccharides, non-erodible polyurethanes, polystyrenes, polyvinyl chloride, polyvinyl fluoride, poly(vinyl imidazole), chlorosulphonated polyolefins, polyethylene oxide, copolymers, and mixtures thereof and an excipient modulating polymer erosion rate selected from the group consisting of inorganic acids, organic acids, inorganic bases, organic bases, and surfactants in an amount between 0.1 and thirty percent (w/w, polymer), wherein the ACTH is released over a period of time in excess of one day by diffusion and degradation of the polymeric matrix.

9. The method of claim 8 wherein the microspheres are administered by application to a mucosal membrane.

10. The method of claim 8 wherein the polymer is a polylactide.

11. The method of claim 8 wherein the diameter of the microspheres is less than 70 microns.

12. The method of claim 8 wherein the microspheres are administered by injection intramuscularly, subcutaneously, intraperitoneally, or intradermally.