Pharmaceutical composition for interleukin-2 containing physiologically compatible stabilizers

• US 5,078,997 A
• Filed: 04/18/1989
• Issued: 01/07/1992
• Est. Priority Date: 07/13/1988
• Status: Expired due to Term

• Current Assignee: Chiron Corporation (Bayer AG)
• Original Assignee: Cetus Corporation (Bayer AG)
• Inventors: Hora, Maninder S., Laderman, Kenneth A., Katre, Nandini
• Primary Examiner(s): Draper, Garnette D.
• Application Number:
  US07/339,971
• Time in Patent Office: 994 Days
• Field of Search: 424/85.1, 424/85.2, 514/970
• US Class Current: 424/85.2
• CPC Class Codes: A61K 38/2013 IL-2
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 47/186 Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00

Abstract

The present invention is a pharmaceutical composition for proteins which are not stably soluble. The preferred protein is IL-2 and the preferred composition includes amino acids, vitamins, polymers, fatty acids or low molecular weight acids.

Claims

1. A pharmaceutical composition that is stable, sterile, and soluble in an aqueous medium, which can be lyophilized and reconstituted without losing its solubility, comprising IL-2 and a stabilizer, wherein the stabilizer is selected from the group consisting of:

an arginine/carnitine mixture;

carnitine;

betaine;

pyridoxine polyvinylpyrrolidone;

salts of capric acid;

or mixtures thereof.

2. A pharmaceutical composition in accordance with claim 1, wherein the stabilizer is selected from the group consisting of:

an arginine/carnitine mixture;

carnitine;

or betaine.

3. A pharmaceutical composition in accordance with claim 1, wherein the stabilizer an is arginine/carnitine mixture.

4. A pharmaceutical composition in accordance with claim 1, wherein the stabilizer comprises betaine.

5. A pharmaceutical composition in accordance with claim 1, wherein the stabilizer comprises carnitine and the composition further comprises serum albumin.

6. A pharmaceutical composition in accordance with claim 1, wherein the concentration of IL-2 is between 0.1 and 2.0 mg/ml IL-2.

7. A pharmaceutical composition in accordance with claim 1, further comprising a sugar or sugar alcohol and a buffer.

8. A pharmaceutical composition in accordance with claim 7, wherein the sugar is sucrose and the buffer is citrate.

9. A pharmaceutical composition in accordance with claim 8, wherein the IL-2 is added to the composition after the sucrose, citrate, and stabilizer have been added and the pH adjusted to between 5 and 8.5.

14. A process for making a pharmaceutical IL-2 composition, comprising, admixing at least one of the stabilizers claimed in claim 1, a buffer, and a sugar or a sugar alcohol;

ensuring that the pH of the solution containing the stabilizer, buffer, and sugar or sugar alcohol is between 6 and 8; and

then adding IL-2 to the admixture.

10. A pharmaceutical composition that is stable, sterile and soluble in an aqueous medium even after lyophilization and reconstitution, comprising:

IL-2;

a stabilizer comprising between 0.2 and 3.0 w/v % arginine and between 0.2 and 3.0 w/v % carnitine;

between 2 and 6 w/v % sucrose;

0.01 and 0.3M citrate, so that the resulting composition has a pH between 6 and 7.5.

11. A pharmaceutical composition in accordance with claim 10, wherein the concentration of IL-2 is between 0.1 and 2.0 mg/ml IL-2.

12. A pharmaceutical composition in accordance with claim 10, wherein the composition is in the lyophilized form.

13. A pharmaceutical composition in accordance with claim 10, wherein the composition is in liquid form.