Immunotolerant prothrombin complex preparation

Details Immunotolerant prothrombin complex preparation Immunotolerant prothrombin complex preparation

2000-01-28

2002-03-19

Witz, Jean C. (Department: 1651)

Drug, bio-affecting and body treating compositions

Extract, body fluid, or cellular material of undetermined...

Blood

C424S530000, C424S094200, C435S002000, C435S003000

Reexamination Certificate

active

06358534

ABSTRACT:

The invention relates to a pharmaceutical composition for treating blood coagulation disorders, in particular for treating factor VIII inhibitor patients. The invention furthermore relates to a method for preparing such a composition as well as the use thereof.
Blood coagulation is triggered by a series of consecutive reactions of different proteins and enzymes, respectively. By a deficiency of blood coagulation factors, the formation of fibrin from fibrinogen and, thus, wound closure, is prohibited; the consequence are hemorrhages. Such is the case with hemophilia A. This is the most wide-spread bleeding disease and is caused by a deficiency of factor VIII. For a substitution treatment of hemophilia A, preparations are used which contain factor VIII. Treatment with these preparations in most instances leads to a rapid hemostasis.
There are, however, also patients who do not only suffer from a factor VIII deficiency, but who have also developed an inhibitor directed against factor VIII. A further collective of patients has factor VIII inhibitors without suffering from hemophilia A Depending on the amount of factor VIII inhibitors present, the effect of factor VIII supplied is inhibited by neutralization of the latter.
At present, preparations on the basis of a plasma fraction which contains a mixture of coagulation factors are offered for a treatment of factor VIII inhibitor patients. This plasma fraction may, e.g., comprise the factors of the prothrombin complex (factors II, VII, IX and X). A blood coagulation-promoting preparation having factor VIII inhibitor bypass activity (FEIBA® TIM 4, from BAXTER AG) is, e.g., obtained according to AT-B 0 368 883 by treating cryosupernatant. This preparation also comprises the coagulation factors II, VII, IX and X.
The action of a FEIBA preparation is manifold due to its complex composition. Mariani et al. (Thrombosis Res. 31, 475-488 (1983)) mentions factor VII in its activated form as an active principle. It has been found that after infusion of a FEIBA preparation there occurs an increased content of factor VIIa in the plasma of hemophiliacs.
Likewise, Teitel (Thrombosis and Haemostasis 66 (5) 559-564 (1991)) discusses the role of factor VIIa in prothrombin complex concentrates with a factor VIII bypassing activity. At the same time also the active principle of factor Xa in such preparations is discussed. The prothrombin complex concentrates assayed contained factor VIIa, expressed by the ratio of factor VII activity to factor VII antigen, of 2.1 and 2.5.
The prothrombin-containing therapeutic composition prepared according to EP 0 044 343-B1 is suitable for the treatment of coagulation factor inhibitors and comprises an activated prothrombin complex in which the factors partially are activated The content of factor VIIa is from 8-80 units/ml The factor IX concentration ranges from 15 to 112 units/ml. Accordingly, the content of factor VIIa, based on factor IX, is 0.07-5.3 U of factor VIIa/U of factor IX. Vinazzer (Thromb. Res. 26:21-29 (1982)) shows the difference of the preparations AUTOPLEX, prepared according to EP 0 044 343, and FEIBA. As shown there, AUTOPLEX is characterized by the higher content of thrombin (factor IIa), measured in NIH units, as compared to FEIBA (cf. table 1, page 24).
Yet also highly purified factor VIIa preparations have been suggested for the therapy of coagulation inhibitor conditions (e.g. EP 0 082 182-B1) and Hedner et al. (Haemostasis 19, 335-343 (1989)).
An advantage of factor VIIa preparations is their freedom from factor VIII. The content of factor VIII in prothrombin complex preparations or in activated prothrombin complex preparations such as, e.g., FEIBA, has the effect in patients with functional factor VIII inhibitors that these inhibiting antibodies are boosted by a renewed administration of factor VIII with the consequence that the condition of the inhibitor hemophilia even deteriorates temporarily.
It has, however, been found that for an effective hemostasis in factor VIII inhibitor hemophilia, the action of factor VIIa preparations is interior to that of prothrombin complex factor preparations (Turecek P. et al., Thrombosis & Haemostasis, 1997, p.222).
It is thus an object of the present invention to provide a preparation which has the effectiveness or efficiency of prothrombin complex factor preparations, without, however, leading to the undesired immunological side reactions of such preparations.
The afore-mentioned object is achieved in that according to the present invention, an immunotolerant pharmaceutical prothrombin complex preparation comprising factors II, IX, X and, optionally, VII with a low factor VIII antigen content is provided.
The factor VIII antigen content of the preparation according to the invention preferably is less than 10%, in particular less than 5%. The factor VIII content preferably is less than 0.1 factor VIII:C antigen/U FEIBA. In a particularly preferred embodiment, the factor VIII antigen content is even below 0.03/U FEIBA, more preferred below 0.02/U FEIBA, and most preferred below the detection limit.
The finding that particularly in case of a further purification of the prothrombin complex factors from plasma or from a plasma fraction, the factor VIII content and, optionally, also the phospholipid content can be reduced so much while the activity of the prothrombin complex factors is largely retained must be considered to be surprising.
In particular, the pharmaceutical preparation according to the invention contains at least the factors IXa, Xa and VIIa and has FEIB activity, i.e. it shortens the coagulation time of a factor VIII-deficient plasma with a functional inhibitor (in this context, cf., e.g., AT-B 350 726).
The preparation according to the invention can be prepared from plasma or from a plasma fraction. The plasma fraction may be prepared from plasma, in particular plasma of human origin, by a chromatographic treatment, precipitation or centrifugation, or the supernatant of the cryoprecipitate is used.
The plasma fraction comprises vitamin K-dependent factors, such as factors of the prothrombin complex, yet also proteins S, C and/or Z are preferably contained therein.
In a particularly preferred embodiment, the preparation is free from phospholipids. Preferably, the upper limit of phospholipids contained is 0.1 nmol/U of FEIBA (for a determination, cf. the Examples).
Because of this freedom from phospholipids, the formation of undesired antibodies to factor VIII can be reduced or prevented, respectively.
According to the present invention, also a method or producing this preparation is provided. This method comprises the following steps:
a) Providing plasma or a plasma fraction comprising factors II, IX, X and, optionally, factor VII,
b) contacting the plasma or the plasma traction with a carrier material, optionally in the presence of a detergent, so that factor VIII and, optionally, phospholipids are separated from factors II, IX, X and, optionally, factor VII,
c) purifying the plasma or the plasma fraction, and
d) recovering a fraction comprising factors II, IX, X and, optionally, factor VII.
In a preferred variant, steps b and c or b, c and d, respectively, are carried out as one method step.
The plasma fraction used preferably is one having at least an intermediary purity.
By a “preparation having an intermediary purity”, a plasma fraction is to be understood which is analogous to the definition of the intermediary purity of factor VIII preparations (in this context, cf., e.g., Wood Clive (ed.) Factor VIII: Purity and prophylaxis, Royal Society of Medicine).
Accompanying proteins which are not removed by a chromatographic purification thus may still be present in a preparation of intermediary purity.
As the Starting material, a conventional commercially available prothrombin complex factor preparation may be used, such as, e.g., FEIBA S-TIM 4, from BAXTER, or activated prothrombin complex.
As respective purification treatments, the methods known from the prior art are employed, preferably a chromatographic treatment, precipitation or cen

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