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...
Patent
1984-10-30
1987-03-17
Schain, Howard E.
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...
424101, 530384, 530830, A61K 3514, A61K 3516, C07K 328, C07K 1500
Patent
active
046508589
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a concentrate of the antihemophilic Factor VIII, called AHF, and a process for producing such a concentrate.
It is known that the ability of the blood to coagualate is controlled by a system of coagulation proteins, of which AHF or Factor VIII is an important component.
Hemophilia A patients have completely or partly lost the ability to produce AHF. AHF-containing preparations are injected to treat this disease, and it is therefore important to have preparations containing suitably high concentrations of AHF and with as low a content of other proteins as possible, such as fibrinogen and immunoglobulins.
In particular in the treatment of inhibitor patients--i.e. patients who produce antibodies against AHF and who therefore need administration of the preparation in excess--with high doses of AHF, it is important that the specific activity (units AHF/mg protein) is high since supply of "other proteins" in large amounts may cause undesirable side effects. Side effects in AHF treatment caused by immunoglobulins is described e.g. by Tilsner et al., Munch. Med. Wschr. 124 (1982) No. 22, p. 553-557.
AHF is normally recovered from the so-called cryoprecipitate, which mainly consists of fibrinogen, albumin, IgG and IgM, while AHF constitutes less than 1% of the total protein amount. The specific activity of a cryoprecipitate is typically 0.1 to 0.3 unit AHF/mg protein.
It is known that part of the unnecessary protein can be removed by precipitation with glycine or polyethylene glycol (PEG). Precipitation can optionally be accomplished several times, first with one precipitant and then with the other.
Thus, it has been kown for a long time to precipitate AHF with about 2M glycine at a low temperature, cf. Webster et al., Amer. J. Med. Sc. 250, No. 6, p. 643-650 (1965). Webster used a cryoprecipitate which was dissolved in water and fractionated at a low temperature (<10.degree. C.) with increasing concentrations of glycine until 2.3 molar. This type of precipitation relies upon the fact that AHF is precipitated in the cold together with fibrinogen by addition of glycine. This results in a specific activity of 0.3 to 0.5 unit AHF/mg protein.
It is known from the EP Patent Specification No. 32,655, cf. the DK Patent Application No. 1762/80, that when redissolved cryoprecipitate is fractionated with 2M glycine as a precipitant at higher temperatures such as 30.degree. to 45.degree. C., a large proportion of the other proteins, such as fibrinogen, is precipitated first so that AHF remains in the supernatant from which it can be recovered.
When PEG is used as a precipitant, fractionated PEG precipitation is frequently accomplished where most of the fibrinogen and some IgM are removed by precipitation with a low PEG concentration (2 to 6%), and then AHF is precipitated from the albumin-containing supernatant with a high PEG concentration (5 to 15%). Such PEG/PEG precipitations are described by e.g. Newman et al., Brit. J. Haematology 21, 1971, p. 1; the U.S. Pat. No. 3,652,530; the DK Patent Application No. 364/77; the FR Patent Specification No. 2,460,305; the DK Patent Application No. 3602/81. These methods provide an AHF concentrate with a specific activity of 1 to 3 units/mg protein.
Processes comprising multi-step precipitations where more than one precipitant is used are likewise known. Glycine precipitation at a low temperature, e.g., can be carried out before or after PEG/PEG precipitations, and glycine precipitations can optionally be carried out both before and after the PEG/PEG precipitations. This is described in the U.S. Pat. No. 3,682,881 and the U.S. Pat. No. 3,631,018. Generally, this results in preparations with a specific activity of 1 to 3 units/mg protein.
When in this context precipitation with glycine is accomplished at a low temperature, the AHF-containing precipitate is utilized, i.e. in subsequent PEG precipitations on a redissolved AHF-containing precipitate there is only a low concentration of glycine in the solution.
If glycine is used at a high temperature in
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Nordfang Ole
Rasmussen Mirella E.
Nordisk Gentofte A/S
Schain Howard E.
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