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STABILIZATION OF IMMUNOGLOBULINS AND OTHER PROTEINS THROUGH AQUEOUS FORMULATIONS WITH SODIUM CHLORIDE AT WEAK ACIDIC TO NEUTRAL ph

a technology of sodium chloride and immunoglobulin, which is applied in the direction of antibody medical ingredients, inorganic non-active ingredients, extracellular fluid disorders, etc., to achieve the effects of stably formulating labile proteins, stably formulating labile therapeutic proteins, and simple self-administration

Inactive Publication Date: 2012-03-29
BAXTER INT INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a stable, aqueous composition of a labile therapeutic protein that can be formulated at mildly acidic to neutral pH with the addition of alkali metal salts. This allows for the production of therapeutic formulations that are simpler to self-administer and can be administered subcutaneously or intramuscularly without pain or tissue damage. The addition of alkali metal salts stabilizes the labile protein at pH values between 5.5 and 7.5. The concentration of the alkali metal salt should be between -75 mM and +200 mM, with the optimal concentration being -150 mM. The composition should also contain an amino acid, with the concentration ranging from -50 mM to -500 mM. The pH of the composition should be between 5.5 and 7.0. The invention also provides a method for stabilizing labile therapeutic proteins using alkali metal salts.

Problems solved by technology

However, the addition of greater than 75 mM of an alkali metal chloride salt (e.g., 100 mM or 150 mM sodium chloride) unexpectedly stabilizes these formulations.

Method used

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  • STABILIZATION OF IMMUNOGLOBULINS AND OTHER PROTEINS THROUGH AQUEOUS FORMULATIONS WITH SODIUM CHLORIDE AT WEAK ACIDIC TO NEUTRAL ph
  • STABILIZATION OF IMMUNOGLOBULINS AND OTHER PROTEINS THROUGH AQUEOUS FORMULATIONS WITH SODIUM CHLORIDE AT WEAK ACIDIC TO NEUTRAL ph
  • STABILIZATION OF IMMUNOGLOBULINS AND OTHER PROTEINS THROUGH AQUEOUS FORMULATIONS WITH SODIUM CHLORIDE AT WEAK ACIDIC TO NEUTRAL ph

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0642]To determine the role pH and salt concentration have on a plasma-derived 20% IgG composition, a two year stability study was conducted. This study revealed that the inclusion of sodium chloride and / or the formulation at neutral to mildly acid pH imparted a stabilizing effect on the 20% IgG composition.

[0643]Briefly, two IgG compositions prepared from pooled plasma according to the Gammagard SD process outlined in Teschner et al. (Vox Sang. 2007 January; 92(1):42-55) were concentrated to a final protein concentration of 20%. These preparations were then divided into several samples which were differentially formulated at pHs 6.5, 7.0, or 7.5 with and without 50 mM sodium chloride. The aqueous formulations were then stored at between 28° C. and 32° C. for 24 months. After the two year incubation period, the molecular size distributions of the IgG in the various formulations were investigated by high performance size exclusion chromatography (HP-SEC), the results of which are pro...

example 2

[0645]To further characterize the stabilizing effect that sodium chloride has on IgG compositions formulated at mildly acid to neutral pH, an accelerated stability study was performed. For the accelerated study, elevated temperatures (38° C. to 42° C.) were used to simulate longer time periods at room temperature (20° C. to 25° C.). Briefly, a 20% IgG composition, prepared as in Example 1, was divided into samples that were formulated with increasing salt concentrations (0 mM, 50 mM, 100 mM, and 150 mM) at mildly acid to neutral pHs (pH 5.5, 6.0, 6.5, 7.0, and 7.5). The aqueous formulations were then stored at between 38° C. and 42° C. for 6 months. After the 6 month incubation period, the molecular size distributions of the IgG in the various formulations were investigated by high performance size exclusion chromatography (HP-SEC). The percentage of IgG aggregates present in the various formulations is shown in FIG. 1.

[0646]As seen in FIG. 1, the stability of the immunoglobulin pre...

example 3

[0647]To evaluate the stabilizing effects of sodium chloride on other immunoglobulin preparations formulated at mildly acidic to neutral pH, preparations of Partobulin® NG (Baxter Biosciences) and Tetabulin® NG (Baxter Biosciences) were formulated accordingly and tested for stability, via aggregation formation, and activity, via anti-antigen potency, over a 6 month time frame. Partobulin® is a plasma-derived human anti-D antigen immunoglobulin preparation used for antenatal anti-D prophylaxis in Rh(D) negative pregnant women carrying Rh(D) positive fetuses, as well as for the treatment of Rh(D) negative persons after incompatible transfusions of Rh(D) positive blood or erythrocyte concentrate. Tetabulin® is a plasma-derived human tetanus immunoglobulin used for post-tetanus exposure prophylaxis and therapy of clinically manifest tetanus. Both Partobulin® and Tetabulin® are typically formulated at between 100 g / L and 170 g / L human protein (of which at least 90% are immunoglobulin G) ...

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Abstract

The present invention provides, among other aspects, storage stabile aqueous formulations of labile proteins at a mildly acidic to neutral pH. The present invention also provides methods for stabilizing a labile therapeutic protein composition at a mildly acidic to neutral pH. Advantageously, the methods and formulations provided herein allow stabile aqueous compositions of labile proteins at mildly acidic to neutral pH useful for parenteral administration.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS[0001]The present application claims the benefit of U.S. Provisional Application No. 61 / 384,209, filed Sep. 17, 2010, the content of which is expressly incorporated herein by reference in its entirety for all purposes.BACKGROUND OF THE INVENTION[0002]Biologics are medicinal products created by biological processes, including preparations isolated from natural sources (e.g., human plasma) and recombinant DNA technologies. Within the healthcare and pharmaceutical industries, biologics are becoming increasingly important for patient treatment and overall revenue growth (Goodman M. Nat Rev Drug Discov. (2009) November; 8(11):837). One important class of biologic drugs is therapeutic proteins, both isolated from natural sources and recombinantly produced. For example, plasma proteins are manufactured for therapeutic administration by isolation from pooled human plasma (e.g., GAMMAGARD LIQUID® [IVIG, Immune Globulin Intravenous (Human) 10%]; Baxter ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395A61K38/48A61K38/37A61K38/02A61K38/36
CPCA61K9/0019A61K39/39591A61K47/183A61K47/02
Inventor BUTTERWECK, HARALD ARNOBAUER, THERESA FRIEDERIKEHOFBAUER, LUCIATESCHNER, WOLFGANGZOECHLING, OLIVERSCHWARZ, HANS-PETERMAYER, CHRISTAHASSLACHER, MEINHARD
Owner BAXTER INT INC
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