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
1997-11-26
1999-07-06
Tsang, Cecilia J.
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...
530380, 530384, 530414, 530417, 530427, 530829, 530830, 514 12, 514 21, 514 53, 514834, A61K 3514, A61K 3800
Patent
active
059199083
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a final drug product of a plasma protein selected from the group consisting of coagulation factor VIII and factor IX, in an aqueous solution, wherein the concentration of oxygen in the solution is reduced and/or the solution contains an antioxidant, and wherein the solution further contains a carbohydrate in a concentration of at least 350 mg/ml. In this way, the protein activity can be essentially retained after storage for at least 6 months. The present invention also relates to a process for preparing the final drug product, and a method for improving the long-term stability of coagulation factor VIII and factor IX in an aqueous solution, wherein the solution contains a carbohydrate in a concentration of at least 350 mg/ml, and wherein the solution is stored in its final container under an oxygen-reduced atmosphere.
BACKGROUND OF THE INVENTION
The stability of proteins is generally a problem in pharmaceutical industry. It has often been solved by drying the protein in various drying processes, such as freeze-drying. The protein has thereafter been distributed and stored in dried form. The solution before drying or freeze-drying, the dried material and the re-constituted product should all be stable, to avoid a substantial loss of activity in the drying process, as well as during storage or handling. The freeze-drying process is a costly and time consuming process step, which reduces the yield of the product. It would therefore be a great advantage if this step could be avoided when preparing a commercial product. Furthermore, the patient necessarily has to reconstitute the dried protein in a solvent before use, which could be inconvenient for the patient.
Hemophilia 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; hemophilia A and hemophilia B. Hemophilia 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 (antihemophilic factor), which is a protein normally present in plasma. The clinical manifestation of hemophilia A is a strong bleeding tendency and before treatment with factor VIII concentrates was introduced, the mean age of the patients concerned 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 hemophilia patients considerably and offered them possibility of living a normal life.
A formulation with a low concentration of a protein such as factor VIII, will generally loose activity during purification, sterile manufacturing, in the package and during administration. This problem is usually solved by the addition of human serum albumin (HSA) which reduces the loss of the active protein considerably. HSA functions as a general stabilizer during purification, sterile manufacturing and freeze-drying (see review by Wang et al., J. of Parenteral Sci. and Tech. Vol 42, Number 2S, supplement. 1988). The use of HSA for stabilization of factor VIII is known and is currently used in all highly purified factor VIII products on the market. However, use of HSA is costly and it is desirable to avoid addition of HSA to a therapeutic protein manufactured by recombinant DNA technology. In addition, the use of HSA as a formulation excipient often limits the use of many of the most powerful and sensitive analytical methods for protein characterization.
Several solutions have been proposed for stabilizing various proteins without using HSA. For example, WO-A-94/26286 to Pharmacia proposes reducing the oxygen concentration as a means to improve the stability of factor VIII solutions ready for use. Furthermore, carbohydrates such as disaccharides or sugar alcohols, have been used previously for stabilizing solutions containing conventional factor VI
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Fatouros Angelica
Osterberg Thomas
Mohamed Abdel A.
Pharmacia & UpJohn AB
Tsang Cecilia J.
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