JPS60224499A - Stable pharmaceutical preparation of uricase - Google Patents

Abstract

PURPOSE:In pharmaceutical preparation of uricase containing uricase in a stable state, to obtain pharmaceutical preparation for diagnosis having high reliability, by adding a nonionic surface active agent, serum albumin and/or a basic amino acid to uricase. CONSTITUTION:Uricase is dissolved in a proper buffer solution to give a uricase solution, which is blended with a stabilizer consisting of a nonionic surface active agent, serum albumin and/or a basic amino acid. They are stirred by a conventional procedure, and the mixed solution is dried by lyophilization, spray drying, etc. to give a product.

Description

[Detailed description of the invention] (Industrial application field) Misfire F! A relates to a uricase preparation containing uricase in a stable state.

[Comparison with conventional technology]

Uricase is applied to the measurement of uric acid in body fluids and is useful as a diagnostic enzyme agent. The principle of these measurement methods is based on the reaction formula below, and the hydrogen peroxide, carbon dioxide, and
7 by measuring the lantin or oxygen consumed.

Uric acid + 0. +2H,0')! Jh two! )797
) However, when uricase is converted into a solution and used, significant denaturation progresses during dissolution and storage, resulting in turbidity, which has a serious negative impact on measurement accuracy and is unstable. There are drawbacks that make it difficult to obtain uricase preparations.
Ta.

It has been known that by adding a nonionic surfactant to the uricase bath solution, the uricase solution is stabilized and no precipitate is formed (Japanese Patent Publication No. 1556, No. 1556).
. However, when this solution is redissolved after freeze-drying, some turbidity occurs.

(Objective of the Invention) As a result of intensive studies to solve these drawbacks, the inventors of the present invention found that an enzyme preparation having the composition described below can be used even when it is dissolved after freeze-drying or stored in a solution state. They found that no denaturation or turbidity occurs, leading to the completion of the present invention.

DETAILED DESCRIPTION OF THE INVENTION (i.e., a nonionic surfactant according to the invention, (ii) serum albumin and/or basic amino acids and
1) It is a patented uricase preparation characterized by containing uricase.

In addition to containing uricase as an essential component, the uricase preparation of the present invention also contains a nonionic surfactant, serum albumin, and/or basic amino moromi (hereinafter collectively referred to as a stabilizer). .

The uricase may be of any origin, such as animal origin, plant origin, microbial origin, etc., but yeast origin is preferred. The uricase preparation in the present invention includes:
It is not limited to those containing uricase alone as described above, but includes other substances such as enzymes and coenzymes necessary for quantifying uric acid, substrate 9 coloring agents, and stabilizers necessary for stabilizing these substances.

A general term for all products containing preservatives, etc. The uricase preparations include those provided in any form such as a solution or a dry powder.

Structural formula of the nonionic surfactant used in the present invention,
There are no other restrictions at all, and various types of surfactants can be used. Typical nonionic surfactants include polyoxyethylene alkyl ether type, polyoxyethylene alkyl phenol ether type, polyoxyethylene alkyl Examples include ester type.

The serum albumin may be derived from either animals or humans. Representative examples include bovine serum albumin, horse serum albumin, and human serum albumin. Basic amino acids include arginine, lysine, histidine, and salts thereof.

The mixing ratio of the above-mentioned stabilizers can be determined by taking into account the strength of the stabilizing effect, the chemical stability of the stabilizer itself, and the combination of the above-mentioned stabilizers. As a rough guideline, it is 0.0001 for a solution containing uricase.
A reliable effect can be obtained by selecting from the range of % to 10 inches.

In order to obtain a uricase preparation containing the above-mentioned stabilizer, uricase may be used alone or uricase may be combined with other enzymes, coenzymes, substrates, a color former, and a stabilizer.

A process of preparing m-liquid by blending concomitant agents such as preservatives.

The step of adding and mixing the above-mentioned stabilizer to the solution and, if necessary, the step of drying the solution are combined, but it is better to select an appropriate buffer when preparing the uricase solution mentioned at the beginning. Concentration 1-500mM, pH 6.0j 9.5
It is desirable that the M test solution Vc be dissolved at -1.

Next, when adding and mixing the stabilizer, add the stabilizer directly to the uricase solution, add 11 times while dispersing or dissolving the stabilizer in water or buffer solution, Mix the willow according to the usual method. Finally, when this mixed solution is dried to one seed, it is better to use conventional means such as freeze drying or spray drying.

(Effects of the Invention) Since the uricase preparation of the present invention is configured as described above, a stable uricase preparation can be obtained, and it can provide reliable uric acid measurement accuracy, making it an extremely useful enzyme drug for diagnosis. medicine was to be provided.

(Example) The present invention will be explained below with reference to examples.

Example 1 Using uricase obtained from yeast, it was dissolved in 0.1 fi/r borate buffer (pH 8,0) at a concentration of 10 units/m (l), and each compound in Table 1 was added to this solution. In addition, if necessary, the pH was readjusted to 8.0.The resulting enzyme layer solution was lyophilized as it was, lyophilized and redissolved at 7°C. leave it alone),
The 81!1 table shows the occurrence of turbidity.

The one with no additives produced less turbidity, but the one with no additives produced a significant amount of turbidity.

Example 2 A light purple formulation having the following composition was prepared.

Add the common compounds listed in Table 2, if necessary, and adjust the pH to 8.
The nine enzyme powder obtained by reconstitution to 0 and freeze-drying was dissolved in 10mj of the following solution. Its storage stability (25℃,
Table 2 shows the appearance of turbidity after leaving it for 5 days.

(Dissolution solution: 0.1M phosphate buffer (pH 7.0) Diethylaniline 10wII As is clear from Table 2, the solution containing nonionic surfactant, serum albumin, and basic bumino acid does not produce turbidity. Although the amount was small, the one without additives produced significant turbidity.

Table 2

Claims (1)

[Claims] (1) A stable uricase preparation characterized by containing a nonionic surfactant, (I11 serum albumin and/or basic amino acid and (1+1) uricase).