Drug – bio-affecting and body treating compositions – Lymphokine
Patent
1994-02-15
1996-04-02
Chan, Christina Y.
Drug, bio-affecting and body treating compositions
Lymphokine
514 8, 514 12, 514 21, 530351, 530380, 530395, 530397, 530399, 530829, A61K 3514, A61K 3816, C07K 14505, C07K 14535
Patent
active
055038271
DESCRIPTION:
BRIEF SUMMARY
The present invention is concerned with a process for the production of pharmaceutical preparations containing human protein for use as an infusion or injection solution in a well-tolerated form.
In the meaning of the present invention, human proteins are endogenous proteins occurring in only small amounts which are used for therapeutic purposes such as e.g. t-PA (tissue plasminogen activator), G-CSF (granulocyte colony stimulating factor), streptokinase, urokinase, interferon or EPO (erythropoietin) and their recombinantly-produced derivatives which on the whole have similar or comparable pharmacological properties.
Pharmaceutical preparations containing human protein are described in the European Patent Application EP 0 430 200 for subcutaneous or intramuscular administration which, by means of the addition of amino acids, have a better bioavailability and are better tolerated in comparison with known forms of administration.
Stabilized pharmaceutical preparations containing human protein which contain inter alia, urea and various amino acids, are known from EP 0 306 824, in which EPO and G-CSF in particular are mentioned by way of example as human proteins.
Furthermore in EP 0 456 153 galenic aqueous formulations of EPO are described for the production of injection preparations for subcutaneous or intramuscular administration which have a pH value of 6-8 and solely contain an alkali metal phosphate or alkali metal halide for stabilization.
The production of the above-mentioned human proteins by genetic engineering is known for example from the following Patent Applications: processes are described in the PCT applications WO 85/02610 and WO 86/03520 for the production of rh-EPO (recombinant human erythropoietin) by genetic engineering. Furthermore, the production of polypeptides with erythropoietin-like action is described in EP 0 409 113; EP 0 357 804; WO 86/02100 and WO 91/05867. Furthermore, processes are known from the prior art for the production of other recombinant proteins, for example of polypeptides with plasminogen activator-like action from WO 90/09437; EP 0 227 462; EP 0 400 545 or EP 0 440 763. The production of polypeptides with G-CSF-like action is known for example from EP 91 107 429.2 and PCT/EP 91/00192.
EPO is a glycoprotein which stimulates the formation of haemoglobin and erythrocytes in the bone marrow. This lipoprotein is mainly formed in the kidney, is present in a very small amount in the serum and is excreted under physiological conditions in the urine.
The previous pharmaceutical preparations known from the prior art which contain human proteins are formulations which as a rule do not contain preservatives since they are generally used for a single administration in the form of a so-called single-dose formulation or single-dose container. In contrast, so-called multi-dose units or multi-dose containers are suitable for a multiple administration in any desired partial amounts of the active substance. Special demands are thereby made on the stability and storability of such forms of administration, especially with regard to the sterility of the solutions. For this reason such solutions are provided with preservatives in order to prevent the growth of micro-organisms in the prepared injection or infusion solution ready for administration.
However, the production of preserved pharmaceutical preparations containing human protein has proven to be difficult. When preservatives are used it has been shown that these give rise to stability problems if the pharmaceutical preparations are stored for longer periods. In this process the human proteins are inactivated and agglomerates are formed which may be the cause of the observed intolerance to the injection solutions. The usual processes for the production of preserved pharmaceutical formulations for infusion or injection purposes cannot be used in the case of active human protein ingredients since the active substances are inactivated under the sterilization conditions in autoclaves at 121.degree. C. for 20 minutes and their structure
REFERENCES:
patent: 4992419 (1991-02-01), Woog et al.
Demmer Fritz
Gruber Werner
Markl Hans-Jorg
Winter Gerhard
Woog Heinrich
Boehringer Mannheim GmbH
Chan Christina Y.
Degen Nancy J.
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