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Method for stabilizing polypeptides lacking methionine

Inactive Publication Date: 2007-08-16
DOW PHARMA SCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011] In accordance with the method of the invention, it has been found that a higher level of protection of a polypeptide against oxidative degradation is obtained by increasing the relative proportion of methionine to the polypeptide in a composition. Thus, if only minimal protection against oxidative degradation is desired, a very low ratio of methionine:polypeptide may be utilized. Higher relative concentrations of methionine:polypeptide provide a higher degree of protection.

Problems solved by technology

Liquid or semi-solid formulations containing one or more polypeptides are typically subject to degradation during storage, such as due to oxidation.
It has been found to be difficult or even impossible to prepare and package a peptide-containing formulation so as to guarantee that oxidants, atmospheric oxygen and formulation excipients bearing residual oxidants, will be excluded.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

DEGRADATION OF P-113

[0016] Three groups of identical aqueous compositions containing 0.01% w / w (0.064 mM) P-113 polypeptide were made. The first and second groups contained either 3% w / w (882 mM) or 5% w / w (1,470 mM) hydrogen peroxide (H2O2), a powerful oxidizing agent. The third group of compositions was a control group and contained no hydrogen peroxide. The compositions were stored at room temperature and were tested at varying intervals to determine the degree of oxidative degeneration of the polypeptide. The results are shown in Table 1.

TABLE 1P-113 Recovery from Hydrogen Peroxide Aqueous SolutionsP-113 Recovery %Time in HoursControl3% H2O25% H2O20100——2199.367.660.52499.660.851.44899.555.838.660100.251.930.6

[0017] As shown in Table 1, the degradation of the polypeptide was proportional to the concentration of H2O2. After 72 hours, the P-113 was degraded about 50% in the 3% H2O2 composition and about 70% in the 5% H2O2 composition. In the control composition containing no H2O...

example 2

DEGRADATION OF P-113 IN THE PRESENCE OF METHIONINE

[0018] Compositions similar to the compositions of Groups 1 and 2 of Example 1 were made but with varying concentrations of added methionine. Because the majority of the degradation of P-113 when exposed to H2O2 occurred within 24 hours, this time period was evaluated to determine the protective capability of methionine. Additionally, the degradation of P-113 when exposed to 3% H2O2 for 48 hours was also evaluated. Data is shown in Table 2.

TABLE 2P-113 Recovery from Hydrogen Peroxide AqueousSolutions Containing MethionineTime inMethionineMethioninemM Met / P-113 Recovery %Hours% w / wmMmM P-1133% H2O25% H2O2240.16.71104.879.270.90.213.42209.780.880.90.320.13314.581.378.70.426.84419.481.180.10.533.55524.281.879.3480.213.42209.776.60.320.13314.576.80.426.84419.477.2

[0019] As shown in Table 2, the optimum concentration of methionine to protect a 0.01% (0.064 mM) P-113 composition is about 0.2% w / w (13.42 mM) or higher. When a 0.1% w / w (6....

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Abstract

Methionine is an effective antioxidant for polypeptides having an amino acid sequence lacking methionine. Compositions containing polypeptides having an amino acid sequence that is free of methionine residues are stabilized from oxidative degradation by combining methionine in the composition in an amount effective to inhibit oxidation of the polypeptide.

Description

FIELD OF THE INVENTION [0001] The invention pertains to the field of stabilizing, such as by inhibiting the oxidation of, a polypeptide in a liquid or semi-solid medium. BACKGROUND OF THE INVENTION [0002] Liquid or semi-solid formulations containing one or more polypeptides are typically subject to degradation during storage, such as due to oxidation. It has been found to be difficult or even impossible to prepare and package a peptide-containing formulation so as to guarantee that oxidants, atmospheric oxygen and formulation excipients bearing residual oxidants, will be excluded. Oxygen and residual oxidants cause rapid oxidation of many of the amino acid residues in a polypeptide. [0003] Methionine is an amino acid residue that is vulnerable to oxidation. In the presence of oxidants, methionine is rapidly oxidized to methionine sulfoxide. Takruri, U.S. Pat. No. 5,272,135 discloses that adding methionine to a liquid or semi-solid medium containing a methionine-containing polypeptid...

Claims

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Application Information

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IPC IPC(8): A61K38/16C07K14/00
CPCC07K14/00A61K38/00
Inventor MAYHEW, JAMESWAGNER, HALI
Owner DOW PHARMA SCI INC
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