Device for the sustained release of aggregation-stabilized, biologically active agent

• US 6,514,533 B1
• Filed: 09/22/1997
• Issued: 02/04/2003
• Est. Priority Date: 06/11/1992
• Status: Expired due to Fees

• Current Assignee: Alkermes Controlled Therapeutics Inc. II (Alkermes plc)
• Original Assignee: Alkermes Controlled Therapeutics Inc. II (Alkermes plc)
• Inventors: Zale, Stephen E., Burke, Paul A., Auer, Henry E., Khan, M. Amin, Johnson, OluFunmi Lily, Bernstein, Howard, Tracy, Mark A.
• Primary Examiner(s): Webman, Edward J.
• Application Number:
  US08/934,830
• Time in Patent Office: 1,961 Days
• Field of Search: 424/486, 424/426, 424/428, 424/468, 424/457, 514/970
• US Class Current: 424/486
• CPC Class Codes: A61K 38/1816 Erythropoietin [EPO]
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61K 38/27 Growth hormone [GH], i.e. somatotropin
• 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: C07K 14/56 IFN-alpha

Abstract

A device for the sustained release in vivo of a water soluble, biologically active agent wherein the agent is susceptible to aggregation comprising a drug delivery device and aggregation-stabilized, biologically active agent wherein the aggregation-stabilized agent is disposed within the drug delivery device.

Claims

1. A sustained release device of a water soluble, biologically active protein or peptide wherein said protein or peptide is susceptible to aggregation, comprising:

a) a biocompatible polymeric matrix; and

b) particles of aggregation-stabilized, biologically active protein or peptide which include a biologically active protein or peptide and an aggregation stabilizer, wherein the aggregation-stabilizer is a multivalent metal cation from a metal cation component selected from the group consisting of metal salts, metal hydroxides and basic salts of weak acids having a metal cation, the biologically active protein or peptide and the metal cation are complexed and said particles are disposed within the biocompatible polymeric matrix.

2. A sustained release composition of claim 1 wherein the metal cation is a biocompatible multivalent cation selected from the group consisting of Zn⁺², Ca⁺², Cu⁺², Mg⁺² and combinations thereof.

3. A sustained release composition of claim 1 further comprising a second metal cation component, wherein the second metal cation component is dispersed within the biocompatible polymeric matrix.

4. A sustained release composition of claim 3 wherein the second metal cation component is selected from the group consisting of magnesium hydroxide, magnesium carbonate, calcium carbonate, zinc carbonate, magnesium acetate, zinc acetate, magnesium sulfate, zinc sulfate, magnesium chloride, zinc chloride, zinc citrate, magnesium citrate and combinations thereof.

5. A sustained release composition of claim 1 wherein the biocompatible polymeric matrix comprises poly(lactide-co-glycolide).

6. The sustained release device of claim 1 wherein the molar ratio of metal cation component to biologically active protein or peptide is from about 1:

2 to about 100;

1.

7. The sustained release device of claim 6 wherein the molar ratio of metal cation component to biologically active protein or peptide is from about 2:

1 to about 10;

1.

8. A sustained release device of a water soluble, biologically active protein or peptide wherein said protein or peptide is susceptible to aggregation, comprising:

a) a biodegradable polymeric matrix; and

b) particles of aggregation-stabilized, biologically active protein or peptide which include a biologically active protein or peptide and an aggregation stabilizer wherein the aggregation-stabilizer is a multivalent metal cation from a metal cation component selected from the group consisting of metal salts, metal hydroxides and basic salts of weak acids having a metal cation, the biologically active protein or peptide and the metal cation are complexed and said particles are disposed within the biodegradable polymeric matrix.