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High concentration factor vii polypeptide formulations comprising an aromatic preservative and an antioxidant

A technology of aromatic preservatives and antioxidants, applied in medical preparations with non-active ingredients, medical preparations containing active ingredients, peptidases, etc., can solve problems such as harmful protein stability

Inactive Publication Date: 2010-03-17
NOVO NORDISK HEALTH CARE AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Surprisingly, these authors found that about 30% of the protein molecules were oxidized after 4 weeks of incubation at 25°C in the presence of m-cresol, indicating that preservative-containing formulations are very detrimental to protein stability.

Method used

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  • High concentration factor vii polypeptide formulations comprising an aromatic preservative and an antioxidant
  • High concentration factor vii polypeptide formulations comprising an aromatic preservative and an antioxidant
  • High concentration factor vii polypeptide formulations comprising an aromatic preservative and an antioxidant

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Experimental program
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Embodiment approach

[0113] The inventors have now determined that the following embodiments are particularly beneficial, namely a liquid, aqueous pharmaceutical composition as defined herein, comprising:

[0114] Factor VII polypeptide (i) at 10-90 mg / mL;

[0115] a buffer (ii) suitable for maintaining a pH in the range of about 5.0 to about 9.0;

[0116] at least one aromatic preservative (iii) at a concentration of 0.1-20 mg / mL; and

[0117] at least one antioxidant (iv) at a concentration of 0.1-5.0 mg / mL;

[0118] stability

[0119] The compositions of the invention are useful as stable ready-to-use compositions of Factor VII polypeptides. The compositions will generally be stable for at least 6 months, preferably up to 36 months when stored at a temperature in the range of 2°C to 8°C.

[0120] The term "stable" is intended to mean that (i) the composition retains at least 50% of its original biological activity as measured by a one-stage coagulation assay (Assay 4) after storage at 2°C t...

Embodiment 1

[0182] As above, under the following conditions: 3 μM activated factor VII, 50 mM imidazole, pH 6.5, 20 mM CaCl 2 , 50 mM NaCl, 0.5 mg / mL bovine serum albumin, 1 mM S-2288, the amidolytic activity of activated Factor VII was measured by degradation of D-ILE-PRO-ARG-P-nitroanilide. Activity was measured in a number of different concentrations of m-cresol and phenol. All experiments were performed in duplicate. figure 1 Shows the amidolytic activity at different preservative concentrations, in arbitrary units. Surprisingly, a decrease in activity was observed with increasing preservative concentration.

Embodiment 2

[0184] Under the following conditions: 15 mg / mL activated factor VII, 10 mM histidine, pH 6.0, 20 mM CaCl 2 , 8% sucrose, and activated factor VII were mixed with different concentrations of m-cresol or phenol. Samples in a total volume of 100 μl were dispensed into quartz microtiter plates (Hellma) and turbidity was assessed by measuring the absorbance at 400 nm on a plate reader. Turbidity is indicative of precipitation in the sample. Significant precipitation was observed in the samples at the highest preservative concentration studied. This phenomenon may limit the use of m-cresol and phenol without the addition of other excipients to remedy the precipitation.

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Abstract

The present invention relates to pharmaceutical compositions comprising at least 10 mg / mL of a Factor VII polypeptide (i); a buffering agent (ii) suitable for keeping pH in the range of from about 5.0to about 9.0; at least one aromatic preservative (iii) in a concentration of at least 0.1 mg / mL; and at least one antioxidant (iv) in a concentration of at least 0.1 mg / mL; the composition optionallycomprising further components, with the proviso that none of such further components are Factor VII polypeptide stabilizing agents selected from (a) metal-containing agents, wherein said metal is selected from the group consisting of first transition series metals of oxidation state +II, except zinc; and (b) stabilising agent comprising a -C(=N-Z1-R1)-NH-Z2-R2 motif.

Description

field of invention [0001] The present invention relates to novel ready-to-use formulations of Factor VII polypeptides (hereinafter: liquid aqueous pharmaceutical compositions), comprising high concentrations of Factor VII polypeptides, buffers and combinations of at least one aromatic preservative and at least one antioxidant. Background of the invention [0002] Factor VII, involved in the coagulation cascade, has proven to be an effective therapeutic agent for the treatment of various pathological conditions. Accordingly, there is an increasing need for formulations comprising activating Factor VII polypeptides that are pharmaceutically acceptable and exhibit consistent and predetermined clinical efficacy. [0003] Recombinantly produced Factor VII polypeptide compositions now commercially available (Novo Nordisk A / S, Denmark) is, for example, presented as a vial (approximately 3.0 mL volume) containing 1.2 mg recombinant human Factor VIIa, 5.84 mg NaCl, 2.94 mg CaCl 2 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/00A61K47/18A61K9/08A61K47/10A61K38/37A61P7/04A61K38/48C12N9/64
CPCA61K9/0019A61K47/183A61K38/4846C12N9/6437C12Y304/21021A61K9/08A61K47/10A61K47/20A61P7/04A61P43/00
Inventor C·里谢尔M·B·詹森A·D·尼尔森
Owner NOVO NORDISK HEALTH CARE AG
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