Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1994-12-05
1996-12-31
Rose, Shep K.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
424530, 424531, 514 21, 514802, 530383, 530393, A61K 3516, A61K 3718, A61K 3764, A61K 39395
Patent
active
055895166
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a liquid preparation of antithrombin-III, which is stable during a long-term storage, and a method for stabilizing the liquid preparation of antithrombin-III.
BACKGROUND ART
An antithrombin-III (hereinafter referred to as AT-III) is a kind of sugar protein belonging to .alpha..sub.2 globulin present in plasma and has a molecular weight of 65,000-68,000. An AT-III has a protease inhibitory activity and shows a strong inhibitory action on coagulation activity of thrombin, as well as an inhibitory action on other blood coagulation factors, activated X factor, activated IX factor and the like. It has been reported that AT-III also shows an inhibitory action on plasmin and trypsin. These inhibitory actions are known to generally proceed faster in the presence of heparin.
An AT-III having such pharmacological actions is used for the correction of abnormally enhanced coagulation, specifically for the treatment of disseminated intravascular coagulation (DIC). AT-III shows poor stability when dissolved and causes side effects in intravenous administration by polymerizing. Accordingly, AT-III has been formulated into lyophilized preparations.
Incidentally, liquid preparations are more advantageous than lyophilized preparations in that they do not require dissolution in injectable distilled water when in use, thus making administration easy, and are produced economically with no need for a freeze-dry step in the production thereof. However, practical formulation of AT-III into liquid preparations has gotten behind due to the poor stability of AT-III in a solution state. There has been only one report in the field of reagent that confirms possible 7 day storage of AT-III in a solution state at 4.degree. C. in the presence of heparin (Japanese Patent Unexamined Publication No. 103463/1980).
DISCLOSURE OF THE INVENTION
An object of the present invention is to improve the stability of AT-III in a solution state and provide a liquid preparation of AT-III, which permits a long-term storage, stability during a long-term storage, particularly at a temperature ranging from 4.degree. C. to room temperature, and easy administration thereof. Another object of the present invention is to provide a method for improving the stability of a liquid AT-III preparation during storage.
With the aim of solving the aforementioned problems in the prior art, the present inventors have conducted a wide range of studies regarding stabilization of AT-III in a solution state, and found that the use of an organic acid, a salt thereof, a sugar sulfate or a surfactant as a stabilizer results in a markedly improved stability of AT-III in a solution state, permitting AT-III to stay stable during a long-term storage. The present inventors have also found that AT-III is extremely stable without a stabilizer in a solution having a pH of 9-10. The present inventors have further found that a liquid AT-III preparation thus prepared poses no clinical problems in terms of pharmacological effect and safety, which resulted in the completion of the invention. It is specifically noted that, while AT-III shows poor stability in a solution of pH 7-8, which is a preferable pH range for injections, the stability thereof in the pH range of 7-8 is remarkably improved by adding the aforementioned compounds as stabilizers.
That is, the present invention relates to: acid or a salt thereof; sulfate and has a pH of 7-10; comprising adding an organic acid or a salt thereof as a stabilizer to a liquid preparation of AT-III; comprising adding a sugar sulfate as a stabilizer to a liquid preparation of AT-III and adjusting its pH to 7-10; comprising adjusting its pH to 9-10; and comprising adding a surfactant to the preparation.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is a graph showing the results of Experimental Example 3, wherein the stability of AT-III in an aqueous solution prepared by dissolving a lyophilized preparation of AT-III, and the stability of AT-III in a liquid preparation of the present invention were c
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Fukuyama Hajime
Ohmizu Akimasa
Takechi Kazuo
Uriyu Katsuhiro
Yokoyama Kazumasa
Rose Shep K.
The Green Cross Corporation
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