Patent EA-002754-B1 (EA)
Title: Stable liquid interferon formulations
Inventor: DIBIASI MARY D
IPC: A61P43/00
Filed: 1997-12-23
Abstract: 1. A liquid composition comprising an interferon and a stabilizing agent selected from the group consisting of acidic amino acids, arginine or glycine and arginine-HCl, wherein the stabilizing agent at between about 0.3% and 5% by weight and a liquid composition has not been reconstituted from lyophilized interferon and wherein the liquid composition is not further lyophilized. 2. The liquid composition of claim 1, wherein the interferon is a interferonbeta, or a recombinantly produced interferon. 3. The liquid composition of claim 1 having a pH between about 4.0 and about 7.2. 4. The liquid composition of claim 3, having a pH of 4.8 to 5.2. 5. The liquid composition of claim 4, having a pH of 5.0. 6. The liquid composition of claim 4 wherein the acidic amino acid is glutamic acid. 7. The liquid composition of claim 1, wherein stabilizying agent is arginine-HC1. 8. The liquid composition of claim 1 having an interferon concentration between about 6 IMU/ml and 50 IMU/ml. 9. A liquid composition, comprising a 20 mM acetate buffer at pH between 4.5 and 5.5, intferferon beta and a stabilizying agent selected from the group consisting of: (a) about 2.6% by weight of arginine, (b) 100 mM sodium chloride and about 0.5% by weight of glycine, (c) about 2.6% by weight of arginine and 15 mg/ml human serum albumin, (d) about 2.6% by weight of argenine and a surfactant, (e) 140 mM sodium chloride, (f) 140 mM sodium chloride and 15 mg/ml ml human serum albumin, (g) 140 mM sodium chloride and a surfactant, (h) about 3.2 % by weight of arginine-HCl, (i) about 3.2% by weight of arginine and 15 mg/ml human serum albumin, (j) about 3.2 % by weight of arginine-HCl, and a surfactant, wherein liquid composition has not been reconstituted from lyophilized interferon and wherein the liquid composition is not further lyophilized. 10. The liquid composition of claim 9, wherein the surfactant is 0.1 % (w/v) Pluronic F. 11. The liquid composition of claim 9, wherein the stabilizying agent is the arginine-HCl in an amount of about 3.2% by weight. 12. The liquid composition at pH 5.0 that comprises interferon-beta and 170 mM L-glutamic acid in an amount of 2.5% by weight, wherein liquid composition has not been reconstituted from lyophilized interferon and wherein the liquid composition is not further lyophilized. 13. The liquid composition of claim 1, comprising the glycine and further comprising a salt. 14. The liquid composition of claim 12, further including ingredients selected from the group consisting of 15 mg/ml human serum albumin and 0.1 % (w/v) Pluronic F-68. 15. A liquid composition comprising a 20 mM phosphate buffer at pH 7.2 including interferon-beta plus a stabilizing agent selected from the group consisting of: (a) 2.4% by weight of arginine; and (b) 100 mM sodium chloride combined with 0.5% by weight of glycine, wherein liquid composition has not been reconstituted from lyophilized interferon and wherein the liquid composition is not further lyophilized. 16. A liquid pharmaceutical composition contained within a storage vessel, the liquid suitable for parenteral administration to mammals and comprising (a) an effective amount of interferon-beta, (b) a buffer maintaining the pH within the range of 4.0 to 6.0, and (c) an amino acid stabilizing agent selected from the group consisting of acidic amino acids, arginine or glycine and arginine-HC1, wherein the stabilizying agent is in amount of about 0.3-5% by weight, and the interferon beta has not been reconstituted from lyophilized interferon and wherein the liquid composition is not further lyophilized. 17. The liquid composition of claim 16, wherein the interferon-beta essentially retains its anti-viral activity during storage at a temperature of between about 2 degree C and about 25 degree C. for a period of at least 2 months. 18. The liquid composition of claim 16, wherein the interferon-beta has not been subjected to prior cavitation. 19. The liquid composition of claim 16 wherein the buffer is an organic acid buffer selected from the group consisting of citrate, succinate, tartrate, fumarate, gluconate, oxalate, lactate and acetate buffer. 20. The liquid composition of claim 16, wherein the pH of the liquid composition is in the range of 4.5 to 5.5. 21. The liquid composition of claim 20, wherein the pH of the liquid composition is 5.0. 22. The liquid composition of claim 16, which is sterile. 23. The liquid composition of claim 16, which is isotonic to blood. 24. The liquid composition of claim 16, wherein the interferon-beta is human recombinant interferon-beta. 25. The liquid composition of claim 24 wherein the activity of the human recombinant interferon-beta is in the range of 6 to 50 IMU/ml protein. 26. A frozen liquid composition comprising an interferon and a stabilizing agent at between about 0.3 % and 3.13 % by weight which is an amino acid selected from the group consisting of acidic amino acids, arginine and glycine, wherein the frozen composition has not been reconstituted from lyophilized interferon and wherein the frozen liquid composition is not further lyophilized. 27. A kit for parenteral administration of a liquid interferon formulation, wherein the kit comprises: a) a vessel containing a liquid formulation at a pH of between 4 and 6, the liquid comprising a pharmaceutically effective amount of interferon-beta that has not been previously lyophilized and a amino acid stabilizing agent at less than about 3.1 % by weight; and b) instructions for use thereof. 28. The kit of claim 27, further comprising: c) an alcohol swab; d) a needle; and at least one adhesive bandage. 29. The kit of claim 27, wherein the vessel is a syringe having at least one surface in contact with the liquid formulation, the surface coated with a material selected from the group consisting of silicone and polytetrafluoroethylene. 30. The kit of claim 27, wherein the vessel is a syringe and the liquid formulation contained with the syringe lacks an oxygen-containing/liquid interface.