JPS62153224A - Plasminogen preparation - Google Patents

Abstract

PURPOSE:The title preparation that is obtained by adding effective amounts of saccharides and aminoacids to a dried powder of plasminogen, as solubilizers to inhibit the development of turbidity and fibrous substances on redissolution. CONSTITUTION:A dried powder of plasminogen (obtained from serum, plasm, ascites, placenta extrat of human or animals) is combined with a solubilizer at least one selected from sugar alcohol such as mannitol or sorbitol and basic aminoacids such as arginine in a amount of 0.5-10 W/V%, preferably 0.5-5 W/V% based on 100-500 CU/ml to give the objective plasminogen preparation which can be expected to be practically used as a remedy for a variety of thromboses. The combination of a sugar alcohol (A) and (B) a basic aminoacid is preferred as the solubilizer and the weight ratio of A/B is 0.1-3, optimally 1. The dose is intravenously 100-3,000 CU/injection.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to improvements in plasminogen preparations, and more particularly, to preparations with improved solubility upon redissolution.

[Prior art]

Plasminogen is activated by urokinase and the like to become plasminogen, which decomposes fibrin and causes fibrinolysis.

Plasmin is used to study fibrinolytic phenomena, and
In recent years, it has also been clinically applied as a fibrinolytic therapeutic agent (thrombus therapeutic agent).

In plasmin preparations, plasminogen itself is a precursor enzyme and is a stable substance, and is stable as long as the preparation does not contain plasmin or the like as a contaminant. However, when plasminogen is prepared as a dry preparation, its solubility and solubility in water deteriorates when it is redissolved.

[Problem that the invention seeks to solve]

An object of the present invention is to provide a plasminogen preparation that improves the solubility and solubility of dry powdered plasminogen in water.

[Means for solving problems]

The present invention consists of a plasminogen preparation characterized in that sugar or amino acid is added to a dry powder of plasminogen in an effective amount as a solubilizing agent to suppress the generation of cloudy and filamentous substances during redissolution.

The plasminogen solution used in the present invention is not particularly limited, and may include human, animal serum, plasma, ascites, Taipan extract, Taipan tissue extract, plasma fibrinogen, T-globulin, and albumin. Fraction II of Cohn's low-temperature alcohol fractionation method in plasma protein fractionation, which is commonly used in the production of important biological drugs such as plasminogen, is purified by a widely known method. is,
Further, examples of the dry powder of plasminogen include the dry powder of the above-mentioned aqueous solution, especially the freeze-dried powder.

Examples of plasminogen purification methods include the previously pending method of the present inventors (Japanese Unexamined Patent Publication No. 55-1-3592), and the purification method using lysine-Sepharose (Science, 170°1095.19).
1970) can be exemplified as a typical method.

The solubilizing agent used in the present invention is preferably at least one selected from sugar alcohols such as mannitol and sorbitol, and basic amino acids such as arginine. In addition, a more preferred embodiment of the present invention is a combination of a sugar alcohol and a basic amino acid.

The amount of solubilizer used is 100-500C of plasminogen.
0.5% (W/V) to 10% (W/V) to U/m1
V). More preferably 0.5 to 5% (W/
V). Within this range of addition amount, the balance between stability, water solubility, solubility, and formulation of the formulation is best. When sugar alcohol (A) and basic amino acid (B) are used together, the weight ratio of B/A can be used in a range of 0.1 to 3, but is optimally 1.

Plasminogen is usually used as a freeze-dried product, but a solubilizer is preferably added before drying.

The thus prepared plasminogen preparation is dissolved in distilled water for physiological saline injection and used for treatment. For treatment, intravenous administration is generally performed, and 100 to 3000 CtJ is administered each time.

In addition, an effective amount of excipients may be added to the formulation of the present invention according to the usual techniques for manufacturing pharmaceuticals.

〔effect〕

The preparation of the present invention suppresses the generation of cloudy and filamentous substances when redissolved, so it is safer and more suitable for practical use as a medical preparation.

This preparation is expected to be applied to the treatment of various thromboses.

[Example/Experiment example]

EXAMPLES The present invention will be explained below with reference to Examples and Experimental Examples, but the present invention is not limited by these in any way. The CU unit used in the explanation is casein unit: Vox
Sanguinis 5°357~376 (1
960).

Example 1 Add 300 CU/mβ of plasminogen solution derived from human serum to
After adding 1% (W/V) of D-mannitol and 1% (W/V) of L-arginine and correcting the pH to 7.2, freeze-drying was performed. As a result of testing the plasminogen activity and solubility of this product after drying, there was no decrease in activity (,
Both solubility and solubility were good.

Experimental example 1 Plasminogen solution derived from human serum 150CU/ml, 5
Various lysing agents were added to 0 mfi phosphate buffer pH 7.2, followed by freeze-drying. After storage at room temperature for one month, the residual potency of plasminogen specific activity and solubility and solubility of each preparation were examined. The results are shown in Table 1. In the table, O indicates easily soluble, Δ indicates slightly insoluble matter, and × indicates insoluble matter.

Claims (5)

[Claims] (1) A plasminogen preparation comprising a dry powder of plasminogen to which an effective amount of sugar or amino acid is added as a solubilizer to suppress the generation of cloudiness and filamentous substances during redissolution. (2) Claim No. 1 in which the sugar is a sugar alcohol
). (3) The preparation according to claim (1), wherein the amino acid is a basic amino acid. (4) The amount of solubilizer added is 100 to 5 of plasminogen.
0.5% (W/V) to 10% for 00CU/ml
(W/V) The formulation according to claim (1). (5) The preparation according to claim (1), which comprises using a sugar alcohol and a basic amino acid together as a solubilizing agent.