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Stabilized albumin-free recombinant factor VIII preparation having low sugar content

An albumin-stabilizing technology, applied in the field of albumin-free lyophilized preparations, which can solve problems such as destabilization effects

Inactive Publication Date: 2003-12-10
BAYER CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

During the development of this formulation, we discovered that histidine, introduced and used in the prior art as a buffer, actually had a destabilizing effect on the albumin-free lyophilized formulation

Method used

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  • Stabilized albumin-free recombinant factor VIII preparation having low sugar content
  • Stabilized albumin-free recombinant factor VIII preparation having low sugar content

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Experimental program
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Effect test

Embodiment 1

[0040] Contains 150mM NaCl, 2.5mM CaCl by titration 2 The effect of histidine on the stability of lyophilized rF VIII was studied by using different contents of histidine in rF VIII mixture with 165mM mannitol. The results are shown in Table 1 below.

[0041] Table 1

[0042] Histidine (mM)

[0043] It can be seen from the above data that increasing the amount of histidine leads to a decrease in the efficacy of replicating lyophilized rF VIII according to the dose-determining relationship. This result suggests that histidine does not play a role in stabilizing FVIII in the lyophilized state.

Embodiment 2

[0045] Stability of rF VIII in high-sugar and low-sugar formulations.

[0046] Recombinant coagulation factor VIII was prepared in two formulations. The instability was studied under accelerated storage conditions at 40°C.

[0047] Similar to the prior art formulations, the high sugar formulation is an amorphous formulation containing 50 mM sodium chloride, 2.5 mM calcium chloride, 5 mM histidine and 10% by weight maltose after reconstitution in water.

[0048] The low sugar-containing formulation of the present invention is a lens comprising an amorphous component of 1% sucrose (30 mM sucrose) for stabilizing the protein. After replication with WFI, the preparation contained 30 mM sodium chloride, 2.5 mM calcium chloride, 20 mM histidine, 290 mM glycine and approximately 200 IU / ml rF VIII. This formulation is compared with the prior art formulation in the accompanying drawings, where it can be seen that the low sugar rF VIII formulation of the present invention is more stab...

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Abstract

A stable albumin-free Recombinant Factor VIII (rFVIII) formulation in lyophilized form having both crystalline and amorphous components and comprising, when reconstituted with water, about 65 to 400 mM glycine, up to 50 mM histidine, 15 to 60 mM sucrose, up to 50 mM NaCl, up to 5 mM CaCl2 and 50 to 1500 IU / ml of rFVIII. A very preferred formulation comprises upon reconstitution with water about 290 mM glycine, 20 mM histidine, 30 mM sucrose, 30 mM NaCl, 2.5 mM CaCl2 and 50 to 1500 IU / ml of rFVIII. The residual water content of the lyophilized preparation is about 1 to 3% by weight, preferably about 1% by weight.

Description

technical field [0001] The present invention relates generally to pharmaceutical formulations of rF VIII, and more particularly to stable, albumin-free lyophilized formulations thereof. Background technique [0002] Coagulation factor VIII is a well-known plasma protein essential for the blood coagulation process. Although Factor VIII is generally available from human plasma, many efforts have been made in recent years to prepare Factor VIII (rF VIII) from recombinant sources in order to avoid possible contamination associated with blood products. In addition, a recombinant source of factor VIII can provide a virtually unlimited amount of the coagulation factor, thereby avoiding supply capacity limitations associated with the use of voluntary donated plasma as a starting material. [0003] Because one of the advantages of the rF VIII product is that it does not come from human plasma, thereby avoiding possible contamination caused by human plasma, the g...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K38/43A61K9/19A61K38/37A61K47/00A61K47/02A61K47/18A61K47/26C07K14/755
CPCA61K47/02A61K9/19A61K47/26A61K38/37A61K47/183A61P7/04
Inventor R·纳亚尔
Owner BAYER CORP
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