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Recombinant vwf formulations

a technology of vwf and vwf, which is applied in the direction of peptide/protein ingredients, inorganic non-active ingredients, extracellular fluid disorder, etc., can solve the problem of risk of blood-born pathogens, and achieve the effect of high stability in the pharmaceutical composition

Inactive Publication Date: 2009-07-30
BAXALTA GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009]The present invention provides formulations useful for compositions comprising recombinant VWF, resulting in a highly stable pharmaceutical composition. The stable pharmaceut

Problems solved by technology

However, in addition to quantity and purity issues with plasma-derived VWF, there is also a risk of blood-born pathogens (e.g., viruses and Variant Creutzfeldt-Jakob disease (vCJD).

Method used

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  • Recombinant vwf formulations
  • Recombinant vwf formulations
  • Recombinant vwf formulations

Examples

Experimental program
Comparison scheme
Effect test

example 1

Shaking Experiments

[0116]In order to determine the amount of precipitation of rVWF in various formulations, the percent recovery of rVWF following turbulent shaking was tested under a variety of conditions.

[0117]rVWF in Advate buffer (90 mM NaCl, 1.68 mM CaCl2, 10 mM L-histidine, 1 mM tris, 0.26 mM glutathione, 23.4 mM trehalose, 175.7 mM mannitol, and 0.1 g / L TWEEN-80, pH 7.0) or Advate 1:3 buffer (Advate buffer diluted 3-fold in water) was subjected to turbulent shaking on a shaker at room temperature (RT) for 0 min, 1 min, 2.5 hrs, or 4 days, and percent recovery of the rVWF was measured relative to the starting material prior to shaking. As shown in Table 1, losses of about 40-80% were observed in the Advate buffer while losses of about 20-30% were observed in the Advate 1:3 buffer. VWF antigen VWF:Ag corresponds to the amount of VWF which can be detected in an VWF-specific ELISA using polyclonal anti-VWF antibody, while VWF:RCo corresponds to the amount of VWF which causes aggl...

example 2

Stability of Recombinant VWF

[0121]The stability of rVWF was tested by assessing the activity level of rVWF present in a various formulations.

[0122]As shown in FIG. 1, rVWF is not stable in Advate buffer after 26 weeks due to the presence of 0.3 mM glutathione. As shown in FIG. 2, however, rVWF is more stable in Advate 1:3 buffer (e.g., for up 12 weeks at 4° C.)

[0123]As shown in FIG. 3, the stability of a citrate-based formulation (15 mM sodium citrate, 10 mM CaCl2, 100 mM NaCl, pH 7.0) is better than Advate 1:3 buffer formulation containing 0.1M glutathione.

[0124]Likewise, the concentration of rVWF was measured over time in various buffers. As shown in FIG. 4, FIG. 5 and FIG. 6, rVWF concentration is stable over time in Advate buffer, Advate 1:3 buffer, and citrate-based buffer, respectively.

example 4

Characterization of the Liquid Formulations

[0125]Differential scanning calorimetry (DSC) was used to assess the extent of protein (rVWF) unfolding in various buffers. As shown in Table 3, Advate buffer pH 7.0 is the optimum for stabilization.

[0126]DSC is a thermoanalytical technique in which the difference in the amount of heat required to increase the temperature of a sample and references are measured as a function of temperature. The result of a DSC experiment is a curve of heat flux versus temperature or versus time.

[0127]The Differential Scanning Calorimeter can scan through a range of temperatures while heating and cooling and it determines a phase transition, i.e. melting, crystallization, or glass transition, by measuring the amount of heat needed to reach a set temperature. The calorimeter was calibrated with a set of pure metals (zinc, indium, and tin) that have a known heat capacity, Cp and melting point, Tm. The respective reference buffer was placed into the reference c...

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Abstract

The present invention provides long-term stable pharmaceutical formulations of recombinant von-Willebrand Factor (rVWF) and methods for making and administering said formulations.

Description

[0001]This application claims priority of U.S. Provisional Application No. 61 / 017,418, filed Dec. 28, 2007, and U.S. Provisional Application No. 61 / 017,881 filed Dec. 31, 2007, each of which is incorporated by reference herein in its entirety.FIELD OF THE INVENTION[0002]Generally, the invention relates to formulations of recombinant VWF and methods for making a composition comprising recombinant VWF.BACKGROUND OF THE INVENTION[0003]Von Willebrand factor (VWF) is a glycoprotein circulating in plasma as a series of multimers ranging in size from about 500 to 20,000 kD. Multimeric forms of VWF are composed of 250 kD polypeptide subunits linked together by disulfide bonds. VWF mediates initial platelet adhesion to the sub-endothelium of the damaged vessel wall. Only the larger multimers exhibit hemostatic activity. It is assumed that endothelial cells secrete large polymeric forms of VWF and those forms of VWF which have a low molecular weight (low molecular weight VWF) arise from prote...

Claims

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Application Information

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IPC IPC(8): A61K38/16
CPCA61K9/0019A61K9/08A61K38/36A61K47/02A61K47/12A61K47/26A61K47/36A61P7/04A61K47/10A61K47/18A61K47/20A61K47/22A61K38/37A61K38/1709
Inventor MATTHIESSEN, PETERTURECEK, PETERSCHWARZ, HANS-PETERSCHNECKER, KURT
Owner BAXALTA GMBH
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