Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
2001-06-28
2003-05-20
Borin, Michael (Department: 1631)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
Reexamination Certificate
active
06566504
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to inactivating viral contaminants of pharmaceutical preparations. More specifically, the present invention is directed to a process for inactivation of viral contaminants of lyophilized blood proteins, particularly Factor VIII, by heat.
BACKGROUND OF THE INVENTION
The primary therapeutic use of Factor VIII has been its intravenous administration to hemophilia A patients. In severe cases, relatively high concentrations of Factor VIII are required. These high concentrations are obtained by purification and concentration of Factor VIII. Factor VIII is commercially available as a lyophilized sterile dry powder which is reconstituted with sterile distilled water or sterile physiological saline for infusion into a hemophilia A patient.
Any viral contaminants in Factor VIII must be inactivated before the Factor VIII preparation can be clinically used so that the spread of HIV, hepatitis, etc., is prevented. There are a number of different approaches to inactivating viruses in Factor VIII. One approach is to heat the lyophilized product to at least 60° C. for at least 10 hours. Commonly, the lyophilized products are heated at 60° C. or even 80° C. for 72 hours. It has been found that a lyophilized, heat-treated Factor VIII product takes longer than desired to be reconstituted, and, additionally, the Factor VIII product can lose a substantial portion of its activity during the lyophilization and heating process. Accordingly, heating lyophilized Factor VIII for extended periods, e.g., 80° C. for 72 hours, to effect viral inactivation is not a preferred approach.
SUMMARY OF THE INVENTION
The present invention provides a process for stabilizing lyophilized blood proteins, particularly lyophilized Factor VIII, during viral inactivation by heat. The process comprises providing an aqueous solution of a blood protein. Cyclodextrin is added to the solution in an amount sufficient to form a complex with at least a portion of, and preferably all of the blood protein. The solution is then lyophilized to provide a dry blood protein/cyclodextrin complex.
The lyophilized blood protein/cyclodextrin complex is then heated to a temperature and for a time sufficient to inactivate any viral contaminants, preferably to a temperature of at least about 60° C. and more preferably to at least about 80° C. for a time of at least about 10 hours and preferably at least about 72 hours. The viral inactivated blood protein/cyclodextrin complex may be thereafter reconstituted to provide a solution of the blood protein administratable to a patient.
It has been discovered that the stabilization of blood protein with cyclodextrin prior to lyophilization results in a dramatic reduction of denaturation of the protein during dry heat viral inactivation. Additionally, the reconstitution time for the lyophilized blood protein stabilized in accordance with practice of the present invention is substantially reduced, with an attendant reduction of insoluble precipitates.
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Bhattacharya Prabir
Fedalizo Norman M.
Motokubota Toshiharu
Alpha Therapeutic Corporation
Borin Michael
Christie Parker & Hale LLP
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