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
1996-09-17
1999-07-20
Patterson, Jr., Charles L.
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...
530384, 514 12, 424 9463, 424 943, 435212, 435 691, A61K 3514
Patent
active
059257393
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a pharmaceutical formulation for subcutaneous intramuscular or intradermal administration comprising coagulation factor VIII or factor IX and use thereof for manufacture of a medicament for treating haemophilia A or B. The formulation comprises coagulation factor VIII or factor IX with an activity of at least 200 IU/ml and an additive increasing the bioavailability of factor VIII or factor IX. Tests with factor VII gives a therapeutic level of active factor VIII in the blood stream for a surprisingly long period of time after subcutaneous, intramuscular or intradermal administration. The factor VIII is suitably a highly purified recombinant factor VIII, and preferably a deletion derivative thereof, which can be used for the manufacture of a medicament for subcutaneous administration.
BACKGROUND OF THE INVENTION
Haemophilia is an inherited disease which has been known for centuries but it is only within the last four decades that it has been possible to differentiate between the various forms; haemophilia A, haemophilia B and haemophilia C. Haemophilia A is the most frequent form. It affects only males with an incidence of one or two individuals per 10,000 live-born males. The disease is caused by strongly decreased level or absence of biologically active coagulation factor VIII (antihaemophilic factor), which is a protein normally present in plasma. The clinical manifestation of haemophilia A is a strong bleeding tendency and before treatment with factor VIII concentrates was introduced, the mean age of those patients was less than 20 years. Concentrates of factor VIII obtained from plasma have been available for about three decades. This has improved the situation for treatment of haemophilia patients considerably and given them possibility to live a normal life.
It is commonly recognized that the severity of haemophilia A and B, can be divided into three categories: severe, moderate and mild. In severe haemophilia A, the plasma level of factor VIII activity in the blood is less than 1% of the normal plasma level. In moderate haemophilia A, the plasma level of factor VIII activity in the blood is in the range of from 1 up to 4% of the normal plasma Level. In mild haemophilia A, the plasma level of factor VIII activity in the blood is in the range of from 5 up to 25% of the normal plasma level. The normal plasma level of factor VIII activity in the blood is defined as 1 IU/ml of blood Severe, moderate and mild haemophilia B, are defined by the same plasma levels as those given for factor VIII above. The normal plasma level of factor IX activity in the blood is defined as 1 IU/ml of blood Reference is here made to Inga Marie Nilsson in Hemophilia, Pharmacia Plasma Products, Stockholm, Sweden, p. 2-3, 1994.
A medicament with a very large and labile molecule, such as coagulation VIII with a molecular mass of 170 to 300 kDa, is normally given intravenously since these medicaments normally exhibit a very low bioavailability due to insufficient absorption and severe degradation, if given subcutaneously, intramuscularly or intradermally. Thus, a factor VIII concentrate dissolved in sodium citrate and injected intramuscularly yielded a maximum circulating level of only 1.4% of the normal plasma level (Pool et al, New England J. Medicine, vol. 275, no. 10, p. 547-548, 1966). The studies further revealed that there was no significant difference in the activity recovered in the circulation regardless of whether such citrate was added to the preparation. In a later study, a high-purity factor VIII was administered intramuscularly to haemophilic dogs and human volunteers (Johnson et al, Br. J. Hematology, vol. 21, p. 21-41, 1971). Although, the doses were much larger than used by Pool et al, neither the dogs nor the human volunteers showed a significant rise in plasma factor VIII levels. In fact, the plasma factor VIII concentration in the haemophilic human volunteers remained below 1% of the normal plasma level, i.e. the severe haemophilia A prevailed even af
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Mikaelsson Marianne
Osterberg Thomas
Sjostrom Brita
Spira Jack
Widlund Lars
Longton Enrique D.
Patterson Jr. Charles L.
Pharmacia & UpJohn AB
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