Composition for sustained release of non-aggregated erythropoietin

• US 5,716,644 A
• Filed: 06/07/1995
• Issued: 02/10/1998
• Est. Priority Date: 06/11/1992
• Status: Expired due to Fees

• Current Assignee: Alkermes Controlled Therapeutics Inc. II (Alkermes plc)
• Original Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Inventors: Brickner, Avram, Bernstein, Howard, Zale, Stephen E., Burke, Paul A.
• Primary Examiner(s): Lovering, Richard D.
• Application Number:
  US08/478,502
• Time in Patent Office: 979 Days
• Field of Search: 264/4.6, 428/402.2, 428/402.21, 424/460, 424/462, 424/491, 424/497, 514/8, 514/963, 514/965, 530/395, 530/397
• US Class Current: 424/497
• CPC Class Codes: A61K 38/1816 Erythropoietin [EPO]
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• 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 9/1658 Proteins, e.g. albumin, gelatin
• 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 9/5031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5052 Proteins, e.g. albumin
• CPC Class Codes: A61K 9/5153 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5169 Proteins, e.g. albumin, gelatin
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

A composition, and methods of forming and using said composition, for the sustained release of non-aggregated, biologically active, erythropoietin (EPO). The sustained release composition of this invention comprises a polymeric matrix of a biocompatible polymer and particles of biologically active, aggregation-stabilized EPO, wherein said particles are dispersed within the biocompatible polymer.

The method of the invention for producing a composition for the sustained release of biologically active EPO, includes dissolving a biocompatible polymer in a polymer solvent to form a polymer solution, dispersing particles of biologically active, aggregation-stabilized EPO in the polymer solution, and then solidifying the polymer to form a polymeric matrix containing a dispersion of said EPO particles.

The method for using a composition of the invention is a method for providing a therapeutically effective blood level of biologically active, non-aggregated erythropoietin in a subject for a sustained period. In this method, a subject is administered an effective dose of the sustained release composition of the present invention.

Claims

1. Biologically active, aggregation-stabilized erythropoietin, comprising a lyophilized solution containing:

a) biologically active erythropoietin;

b) ammonium sulfate; and

c) a buffer with a pH between 5 and 7.

2. A method for forming particles of biologically active, aggregation-stabilized erythropoietin, comprising the steps of:

a) mixing ammonium sulfate with a solution of isolated biologically active erythropoietin to form an aggregation stabilizing mixture;

b) forming particles from said mixture, wherein said particles contain isolated biologically active erythropoietin and ammonium sulfate.

3. A method for providing a therapeutically effective blood level of biologically active, non-aggregated erythropoietin in a subject for a sustained period, comprising administering to the subject a dose of a composition for the sustained release of biologically active, non-aggregated erythropoietin from a polymeric matrix, comprising:

a) a biodegradable polymer; and

b) particles of biologically active, aggregation-stabilized erythropoietin, wherein said particles include erythropoietin in contact with ammonium sulfate and wherein said erythropoietin particles are dispersed within the polymeric matrix.

4. A method for providing a therapeutically effective blood level of biologically active, non-aggregated erythropoietin in a subject for a sustained period, comprising administering to the subject a dose of a composition for the sustained release of biologically active, non-aggregated erythropoietin from a polymeric matrix, comprising:

a) a biodegradable polymer; and

b) particles of biologically active, aggregation-stabilized erythropoietin, wherein said particles include erythropoietin in contact with ammonium sulfate and are formed by lyophilizing a mixture containing;

a) biologically active erythropoietin;

b) ammonium sulfate; and

c) a buffer with a pH between about 4 and about 8;

and wherein said erythropoietin particles are dispersed within the polymeric matrix.