JPH0449233A - Preparation for medical care - Google Patents

Abstract

PURPOSE:To provide a preparation containing albumin and 2-(2'- methoxyphenylazo)-1H-imidazole derivative as active ingredients, improved in the water solubility of the derivative due to the physical adsorption thereof to the albumin without a special preliminary treatment and having good stability for a long period. CONSTITUTION:The preparation contains albumin and 2-(2'-methoxyphenylazo)-1 H-imidazole derivative as active ingredients. The content of the albumin is ordinarily selected from a range of 1-30wt.%. The 2-(2'-methoxyphenylazo)-1H- imidazole derivative is a compound of the formula (X is H, halogen) including 2-(2'-methoxyphenylazo)-1H-imidazole and exhibits pharmacological actions such as oxytocic action and arterial hypertension-treating action. The preparation is prepared, e.g. by a method wherein the compound of the formula is added to an albumin aqueous solution in a concentration less than the saturated concentration of the compound.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention provides novel medical preparations, more specifically, 2-(2'-methoxyphenylazo)-
The present invention relates to a medical preparation containing a 1H-imidazole derivative as an active ingredient and suitable as an injection, a drip, or an oral preparation.

BACKGROUND OF THE INVENTION It has been known that 2-(2'-methoxyphenylazo)-1H-imidazole derivatives have various pharmacological effects, such as medical compositions containing uterine contractions containing these imidazole derivatives as a main component. Monoya (Unexamined Japanese Patent Publication No. 57-15
No. 4130) and agents for treating edema, hypotension, heart failure and mucosal hyperemia (Japanese Patent Publication No. 56123/1983).

Thus, 2-(2'-methoxyphenylazo)-1
Although H-imidazole derivatives have various pharmacological actions and are useful for medical purposes, they have the disadvantage of low solubility in water. Therefore, it was desired to make it water-soluble.

In the medical formulation field, in order to make such water-insoluble substances water-soluble, increase their usefulness, and facilitate preparation, they are usually solubilized into surfactant micelles, liposomes, and lipid bimolecules. Measures such as embedding in membranes, inclusion in cyclodextrins, chemical bonding with synthetic polymers or biodegradable polymers, and embedding in matrices have been taken, but the 2-(2' -methquinphenylazo)-1
Regarding H-imidazole derivatives, the above-mentioned methods are not necessarily fully satisfactory in terms of their stability and solubilization efficiency.

On the other hand, it has been reported that serum albumin generally transports 12 molecules of higher fatty acids per molecule bound to a lipophilic pocket-like moiety [The Plasma Proteins Jg.
Page 179, Academic Press New York (
(1960)], it can be easily inferred that the hydrophobic groups of higher fatty acids and other surface-active substances bind to the lipophilic pocket-like portion.

Furthermore, after denaturing serum albumin, fluorescein is added to it and the solution is rapidly diluted. It has been reported that a similar phenomenon is observed even if the product is replaced with [Biochim, Biophys, Acta].
, Vol. 278, p. 193 (1972)]. Furthermore, when serum albumin is denatured with 2-chloroethanol containing bebenzobire and the solvent is removed by freeze-drying, serum albumin contains 10 molecules of benzopyrene per molecule. It has also been found that biophysics can be incorporated into molecules.
Him.

Biophys, Acta) J, Vol. 365, No. 181
Page (1974)].

In this way, alumino has the property of binding surface-active substances such as higher fatty acids and improving their water solubility, as well as their ability to absorb heat and plating.
H1 By denaturing with organic solvents, surfactants, etc., even substances that do not have surface activity can be incorporated into the molecule.
Albumin has the property of improving water solubility, and attempts are being made to utilize this property to use albumin in medical preparations as a solubilizing agent to solubilize drugs that are insoluble or poorly soluble in water. Various things have been done.

For example, (1) In order to use a poorly water-soluble drug as an injectable preparation, research is being conducted to make the drug soluble in water by chemically bonding the drug to albumin via a third substance such as an amino acid. Molecular Pharmacology (Mo1
．． Pharmacol) J, Volume 13, No. 8088(1)
977), [Procedure of the National Academy of Sciences (Proc. Natl.

(2) Formation of albumin microspheres by taking advantage of the fact that albumin is susceptible to thermal denaturation. Research to embed drugs in this to make them water-soluble [Chem, Pharm, Bu
ll,) J, Vol. 29, pp. 1433-1438 (1981)], and (3) a complex of albumin with brostanic acid or a fatty acid having a brostanic acid-like skeleton, and albumin. Kaisho 48-3
(4) Medical kallikrein preparation containing albumin (Japanese Unexamined Patent Publication No. 115723/1983)
etc. are disclosed.

However, in the research in (1) and (2) above, the water solubility of the drug was improved by chemically bonding albumin and the drug via a third substance or by thermally denaturing albumin. , and 2−(2'
-methoxyphenylazo) -1H-imidazole derivatives are not considered at all. In addition, (3) above
In the complex with albumin, the water solubility of the drug is improved by forming a complex between the drug and albumin using some binding force, and in order to form this complex, the drug must be In addition to requiring complicated operations such as pretreatment to degrease, dialysis equilibrium method, and finally freeze-drying, the chemicals used contain cyclopentane in the middle of the hydrocarbon chain of the long-chain fatty acid. Limited to ring-bearing brostanoic acid and its analogs.

On the other hand, regarding (4) pharmaceutical kallikrein preparations, although it mentions the improvement of solubility (restorability) during freeze-drying, it does not mention at all the improvement of the solubility of the drug itself; There is no mention of whether or not the improvement in solubility during treatment is due to albumin.

Furthermore, a solubilizing agent consisting of human serum albumin has been proposed (Japanese Patent Laid-Open No. 58-216126).

In this solubilizing agent, long-chain carboxylic acids having an aromatic functional group with a large steric hindrance, non-long-chain carboxylic acids having an aromatic functional group with a large steric hindrance, and drugs without a carboxylic acid group are used. It has been shown that drugs without carboxylic acids include steroid hormones such as progesterone, testosterone, and estradiol, barbital compounds such as amobarbital and phenobarbital, and 2-(3-(5 −
Methyl-13,14-oxadiazol-2-yl)-
3,3-diphenylpropylcouazabicyclo(2,2
, 2) Octane, etc. are exemplified. however,
The 2-(2'methoxyphenylazo)-1H-imidazole derivative is a drug that does not have a carboxylic acid in its molecule, but it has a completely different molecular structure from the drug that does not have a carboxylic acid. .

In this way, the 2-(2'-methoxyphenylazo)-1H-imidazole derivative, which is not a surfactant such as a higher fatty acid and does not have a carboxylic acid, can be water-solubilized using albumin. was completely unknown until now.

Problems to be Solved by the Invention The present invention provides an injection that efficiently solubilizes 2-(2'-methoxyphenylazo)-1H-imidazole derivatives having various pharmacological actions in water and contains this derivative as an active ingredient. The purpose of this work is to provide pharmaceutical preparations with excellent stability suitable for use as infusions, oral preparations, and the like.

Means for Solving the Problems The present inventors have made extensive efforts to water-solubilize 2-(2'-methoxyphenylazo)-1H-imidazole derivatives in order to develop pharmaceutical preparations having the above-mentioned desirable properties. As a result of repeated research, albumin can efficiently solubilize imidazole derivatives in water without being denatured by heat, 1) Hx organic solvents, surfactants, etc., and formulations containing albumin are stable. It was also found that the present invention was completed based on this knowledge.

That is, the present invention provides a pharmaceutical preparation containing albumin and a 2-(2'-methoxyphenylazo)-1H-imidazole derivative.

The present invention will be explained in detail below.

The 2-(2'-methoxyphenylazo)-1H-imidazole derivative as the active ingredient in the preparation of the present invention is an azo compound represented by the general formula (wherein X is a hydrogen atom or a halogen atom) or a salt thereof. used.

As the compound represented by the general formula (I), 2-(
2'-methoxyphenylazo)-1H-imidazole,
2-(5'-fluoro-2'-methoxyphenylazo)
-1H-imidazole, 2-(5'-chloro-2'-methoxyphenylazo)-1H-imidazole, 2-(5
Examples include '-bromo-2'-methoxyphenylazo)-1H-imidazole and 2-(5''iodo-2'-methoxyphenylazo)-1H-imidazole.Salts of these compounds include pharmacologically acceptable salts. With salts that can Examples of these imidazole derivatives include acid addition salts.These imidazole derivatives have effective pharmacological effects in the treatment of uterine contractions, edema, hypotension, heart failure, mucosal hyperemia, etc. In the preparation of the present invention, 1 A species may be used, or two or more species may be used in combination.

On the other hand, there are no particular restrictions on the albumin used in the preparation of the present invention, but when the preparation is used in humans, it must be derived from healthy human plasma, negative for HBs antigen and anti-old V antibody, and It is desirable that hepatitis virus is inactive. Further, serum proteins obtained by removing fibrinogen from human plasma proteins, human serum albumin containing only the albumin fraction, etc. can be used, but albumin purity of 80% by weight or more is preferable.

Such human-derived albumin can be obtained by, for example, ethanol fractionation method (Japanese Patent Publication No. 47-2869, Japanese Patent Publication No. 35529
However, in the present invention, products that have undergone pretreatment such as degreasing may be used, or products commercially available as special blood products may be used as they are.

The content of albumin in the preparation of the present invention is appropriately selected depending on the purpose of use, and is usually selected within the range of 1 to 30% by weight.

To prepare the preparation of the present invention, 2-(2'-methoxyphenylazo)-1H
- It may be prepared by adding the imidazole derivative to a concentration below the saturation solubilization amount, or by adding the imidazole derivative in an amount above the saturation solubilization amount and then removing insoluble matter by filtration. You may. Further, at this time, electrolytes of a pharmacologically acceptable type and amount may be added.

Furthermore, the albumin prepared in this way and 2-(2
'-methoxyphenylazo)-1H-imidazole derivative may be stored as a dry powder and dissolved in purified water at the time of use, or human plasma protein, human serum protein, human serum albumin. An aqueous solution in which the 2-(2'-methoxyphenylazo) 1-former imidazoyl derivative is stored separately and the imidazole derivative may be dissolved in the aqueous solution at the time of use.

At this time, in order to improve the dissolution rate, pharmacologically acceptable electrolytes and sugars may be added in advance. Examples of the electrolyte include sodium chloride and sodium caprylate, and examples of the sugar include glucose and maltose, but the electrolyte should be at a concentration of 4 mg/mQ or less, and the sugar should be at a concentration of 300 mg/mQ or less. It is desirable to use it so that

The medical preparation containing albumin and a 2-(2'-methoxyphenylazo)-1H-imidazole derivative of the present invention can be obtained by combining the imidazole derivative, which is not an interfacial substance, with the albumin without denaturing the albumin. , water solubilized, for example 2-(
5'-chloro-2'-methoxyphenylazo)-1H-
When polyacrylamide gel electrophoresis is performed on an aqueous solution of human serum albumin in which imidazole has been dissolved, yellow 2-(5'-chloro-2'-
Migration of methoxyphenylazo)-1H-imidazole is observed.

Effects of the Invention According to the present invention, albumin can be processed without any special pretreatment such as defatting albumin, or without denaturing albumin with heat, pH 1 organic solvent, surfactant, etc.
The -(2'-methquinphenylazo)-1H-imidazole derivative can be physically adsorbed onto the albumin to make it water-soluble.

The medical preparations of the present invention have excellent long-term storage stability, and include injections,
It is suitably used as a drip solution or an oral preparation.

Examples Next, the present invention will be explained in more detail with reference to examples.
The present invention is not limited in any way by these examples.

Example 1 An excess of 2-(5'-chloro-2'-methoxyphenylazo)-18-imidazole was added to a 5% by weight aqueous solution of human serum albumin (manufactured by Nguma, A-1887).
After shaking gently for about 5 minutes at room temperature,
An aqueous solution was prepared by filtration through a filter.

The 2-(5'-chloro-2'
-methquinphenylazo)-1H-imidazole, the solubilized amount immediately after preparation and after storage at room temperature for 3 months was quantitatively analyzed by HPLC. The results are shown in Table 1.

Examples 2 to 5, Comparative Example The same procedure as in Example 1 was carried out except that the concentration of the human serum albumin aqueous solution was changed as shown in Table 1. The results are shown in Table 1.

Table 1 As is clear from Table 1, it can be seen that the solubilized amount of the imidazole is increased in the Examples and that the preparations are stable.

Examples 6-10 2-(5'-chloro-2'-methoxyphenylazo)
-1H-imidazole was replaced with 2-(5'-promo-2'-methoxyphenylazo)-1H-imidazole and an aqueous human serum albumin solution with the concentration shown in Table 2 was used, but the procedure was carried out in the same manner as in Example 1. It was carried out. The results are shown in Table 2.

Examples 11-15 The experiment was carried out in the same manner as in Example 1, using the stock solution and diluted solution of albumin 25%-alpha (manufactured by Midori Juji Co., Ltd.) as human serum albumin aqueous solutions.

Note that purified water was used to dilute albumin 25%-alpha. The results are shown in Table 3.

Table 3 Table 2 Examples 16 to 20 Albumin (25%) as human serum albumin aqueous solution
- It was carried out in the same manner as in Example 1 using the stock solution and diluted solution of Cutter (manufactured by Bayer Yakuhin). Note that purified water was used to dilute albumin (25%), strength, and jitter. The results are shown in Table 4.

Table 4 Procedural Amendment July 13, 1990 Director General of the Patent Office Toshi Uematsu 1, Indication of the Case 1990 Patent Application No. 155276 2, Title of Invention Medical Preparation 3, Person Making Amendment Case Relationship with Patent applicant Lion Co., Ltd. 3-7 Honjo-chome, Sumida-ku, Tokyo Company representative Atsushi Kobayashi 4, agent

Claims (1)

[Claims] 1 Albumin and 2-(2'-methoxyphenylazo)
-1H-imidazole derivative.