Drug – bio-affecting and body treating compositions – Lymphokine
Reexamination Certificate
1996-01-30
2001-10-16
Schwartzman, Robert A. (Department: 1636)
Drug, bio-affecting and body treating compositions
Lymphokine
C514S008100, C514S012200
Reexamination Certificate
active
06303113
ABSTRACT:
The present invention is concerned with a process for the production of pharmaceutical preparations containing human protein or 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 including deletion, insertion and substitution variants 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; PCT/EP 91/00192; EP 169,566; WO 86/04506 (Chugai Seiyaku); EP 215,126 (Chugai Seiyaku); and WO 87/01132 (Kirin-Amgen) which are herein incorporated by reference into the present application. As used in the present invention, the term G-CSF-like activity means that the protein has the same biological activity as G-CSF.
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. As used in the present application, the term erythropoietin-like activity means that the protein has the same biological activity as erythropoietin. Such proteins have at least the primary structural conformation of human EPO which allows possession of the biological property of causing bone marrow cells to increase production of recticulocytes and red blood cells and to increase hemoglobin synthesis or iron uptake. Proteins with erythropoietin-like activity are described in EP 205,564, EP 0 411 678 and EP 148 605 which are herein incorporated by reference into the present application.
However, it has been ascertained that injection or infusion solutions containing human protein from different manufacturers were tolerated differently due to different compositions in the galenic formulation or due to small structural differences in the active substances with regard to the amino acid sequence or to the glycosylation pattern of the protein. Although the solutions known from the prior art were essentially isotonic solutions which themselves should be well-tolerated without major problems, unpleasant side effects were observed when they were administered. When for example injection solutions containing EPO were administered, patients often complained about pains at the point of injection which occurred during and after the administration. Depending on the particular galenic formulation used, burning pains frequently occurred in many patients especially when those injection solutions were used which contained human serum albumin and citrate buffer as additives for stabilization. In some cases, the patients developed a high temperature, high blood pressure, urticaria, back pain, nausea and also shock.
Furthermore it has been shown that injection solutions with a relatively low content of active substance cannot be adequately stabilized. Thus for example pharmaceutical formulations which contained EPO as the human protein in an amount of for example 500 to 20,000 U, are not sufficiently stable. It could be shown that some galenic formulations favored the undesired formation of aggregates or agglomerates of the human proteins especially when stored for longer periods. Consequently, immunological problems can arise when such preparations are used.
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° C. for 20 minutes and their structure is destroyed. It is also known that the usual preservatives used in pharmacy react with the active human protein ingredients and these are thereby inactivated. For this reason intravenous (i.v.) or subcutaneous (s.c.) preparations were previously produced as single-dose formulations under aseptic conditions without a preservative having been used in this case.
Thus, the problem existed of finding a process for the production of preserved pharmaceutical preparations containing human protein for injection or infusion purposes by means of which pharmaceutical preparations can be produced which do not have the above-mentioned disadvantages. It should be possible to administer these pharmaceutical preparations produced in this manner in a reproducible, well-tolerated manner. They should ensure an administration which is as pain-free as possible and should be germ-free. Furthermore multi-dose forms of administration (multi-dose containers) should be provided which are germ-free and can be administered with good tolerance.
This object is achieved in that in a process for the production of pharmaceutical preparations containing human protein for injection or infusion purposes, preservatives are added at a concentration of up to 2% (weight % to volume %, w/v; the conversion factor from w/v % to mg/ml is 10, i.e., 0.1%=1 mg/ml.) and especially 0.01 to 1% or 0.1 to 0.3% and, if desired, these are remove
Demmer Fritz
Gruber Werner
Markl Hans-Jorg
Winter Gerhard
Woog Heinrich
Arent Fox Kintner & Plotkin & Kahn, PLLC
Roche Diagnostics GmbH
Schwartzman Robert A.
LandOfFree
Process for the production of pharmaceutical preparations... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for the production of pharmaceutical preparations..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the production of pharmaceutical preparations... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2564798