JPH0789858A - Aqueous solution composition - Google Patents

Abstract

PURPOSE:To obtain an aqueous solution composition having a dissolved pharmacodynamically effective component in a high concentration. CONSTITUTION:This composition contains 6-[3-(3,4-dimethoxybenzyl)amino-2- hydroxypropoxy)carbostyri] or its salt as an active ingredient and DL-lactic acid as a dissolution auxiliary.

Description

Detailed Description of the Invention

[0001]

This invention relates to aqueous solution compositions.

[0002]

BACKGROUND OF THE INVENTION 6- [3- (3,4-dimethoxybenzyl) amino-2-hydroxypropoxy] carbostyril (hereinafter referred to as "active compound") or its salt has a positive inotropic effect on the heart. Drug that enhances the contractile force of
More specifically, it is a well known fact that it is a compound which is suitably used as a cardiotonic drug, a therapeutic agent for heart failure, and the like, and which has an antihistamine effect and is suitably used (for example, JP-A-56-8319) JP-A-5-5900
No. 5).

The above compounds are weakly basic compounds which are difficult to dissolve in water. In order to dissolve such a weakly basic compound in water, it is common to employ a method of dissociating and dissolving the weakly basic compound by allowing an acidic compound to coexist and maintaining the pH in the acidic region. .

However, the above compounds are easily prepared into an aqueous solution having a concentration capable of easily forming a poorly soluble salt with an acidic compound coexisting to make the pH acidic, and as a result exhibiting a therapeutically sufficient pharmacological action. Therefore, it is difficult to formulate a drug such as an injection or an oral preparation containing the above compound, and the present situation is that the dosage unit form of the drug is limited.

[0005]

The present inventors have conducted various studies on the physical properties and dissolution behavior of active compounds and salts thereof, and as a result, the active compounds were found to have other pharmaceutically acceptable acids and optical properties. To form a low-solubility salt in optically active L-lactic acid, but does not form a salt in optically inactive DL-lactic acid.
It was found that the coexistence of L-lactic acid significantly improves the solubility of the active compound or its salt in water. The present invention has been completed based on such knowledge.

That is, the present invention relates to an aqueous solution composition characterized by containing an active compound or a salt thereof as an active ingredient and further containing DL-lactic acid as a solubilizing agent.

The aqueous solution composition of the present invention contains an active compound or a salt thereof and DL-lactic acid. The salt of the active compound is not particularly limited, and succinate, tartrate, mesylate, maleate, hydrochloride,
Examples thereof include sulfate. Among the active compounds and salts thereof, the active compounds are most preferable, and then the active compounds such as the disuccinate and the tartarate are preferable. The amount of the active compound or its salt contained in the aqueous solution composition of the present invention can be appropriately selected from a wide range depending on the purpose of use. For example, when used as an aqueous solution for pharmaceutical formulations, the aqueous composition should contain a substantial amount of active compound or salt thereof to provide the desired therapeutic effect, usually 0.01-70 based on the total weight of the aqueous composition. It is good to contain about%.

The compounding ratio of the active compound or its salt and DL-lactic acid to be contained in the aqueous solution composition of the present invention is not particularly limited and can be appropriately selected from a wide range, but the former 100 parts by weight. 1-2 for the latter
000 parts by weight, usually 10 to 200 parts by weight, preferably 20 to 80 parts by weight, more preferably 30 to
About 60 parts by weight is preferable. When the blending ratio of DL-lactic acid decreases, it becomes difficult to achieve the intended purpose of the present invention. On the contrary, if the blending ratio of DL-lactic acid is increased, the drug obtained by using the aqueous solution composition of the present invention tends to have irritation, which is not preferable. The aqueous solution composition usually has a pH value of about 1 to 8, preferably a pH value of 2
It should be about 7.

If necessary, the aqueous solution composition of the present invention may further contain a buffering agent, an antioxidant, a preservative, an isotonicity agent, a pH adjusting agent and the like. Examples of the buffer include sodium phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, boric acid, sodium borate, citric acid, sodium citrate, tartaric acid, sodium tartrate, acetic acid, sodium acetate, epsilon aminocaproic acid, sodium glutamate and the like. Can be mentioned. Examples of the antioxidant include sodium sulfite, sodium pyrosulfite, sodium bisulfite, sodium thiosulfite, and ascorbic acid. Examples of the preservative include chlorobutanol, benzalkonium chloride, benzethonium chloride, phenylmercury salt, thimerosal, phenethyl alcohol, methylparaben, propylparaben and the like. As the isotonicity agent, a non-electrolyte is preferable, and more specifically, saccharides such as mannitol, sorbitol, fructose, xylitol and dextrose, and polyhydric alcohols such as glycerin are preferable. Examples of more preferable tonicity agents include non-reducing sugars such as D-sorbitol and D-mannitol. Examples of the pH adjusting agent include sodium hydroxide and hydrochloric acid. Further, in the present invention, DL-
It is also possible to use other solubilizing agents together with lactic acid. Examples of such solubilizing agents include polyoxyethylene lauryl ether, polyoxyethylene glycol ethers such as polyoxyethylene oleyl ether, polyethylene glycol monolaurate, polyethylene glycol higher fatty acid ester salts such as polyethylene glycol monooleate, and polyoxyethylene glycol monooleate. Examples thereof include oxyethylene sorbitan monolaurate and polyoxyethylene fatty acid ester.

The aqueous solution composition of the present invention is, for example, an injection,
It can be suitably used for preparation of eye drops, transmucosal administration preparation, oral administration preparation and the like. When preparing these various preparations, in addition to the above buffers, antioxidants, preservatives, isotonic agents, pH adjusting agents, etc., conventional stabilizers, thickeners, semisolid groups Additives such as agents, solid bases, excipients, disintegrants, and corrigents can also be used as necessary.

[0011]

INDUSTRIAL APPLICABILITY According to the present invention, an aqueous solution composition in which an active compound is dissolved at a high concentration is provided.

[0012]

EXAMPLES The present invention will be further clarified with reference to Examples and Formulation Examples below.

Example 1 A mixture of 100 parts by weight of the active compound and 30 parts by weight of DL-lactic acid was dissolved in water and the solubility of the active compound was examined. The result was 70 w / v% or more. For comparison, the solubility of the active compound or its salt is also shown in Table 1.

[0014]

[Table 1]

Formulation Example 1 The above raw materials are dissolved in heated water for injection, filtered through a 0.2 μm membrane filter, filled and sealed in ampoules or vials, and steam sterilized at 121 ° C. for 20 minutes,
It was an injection.

Formulation Example 2 The above raw materials were dissolved in sterilized purified water, and aseptically filtered with a 0.2 μm membrane filter, then filled and sealed in an eye drop container to obtain an eye drop.

Formulation Example 3 The active compound is dissolved in purified water containing DL-lactic acid. This was added to the heated and dissolved Macrogol base, and the mixture was stirred until it became uniform, then filled in a container and cooled to form a suppository.

Formulation Example 4 The above raw materials were dissolved to obtain a syrup.

Formulation Example 5 An injection was prepared in the same manner as in Formulation Example 1.

Formulation Example 6 An injection was prepared in the same manner as in Formulation Example 1.

Formulation Example 7 An eye drop was prepared in the same manner as in Preparation Example 7.

Claims (1)

[Claims] 1. A method comprising 6- [3- (3,4-dimethoxybenzyl) amino-2-hydroxypropoxy] carbostyril or a salt thereof as an active ingredient, and DL-lactic acid as a solubilizing agent. A characteristic aqueous solution composition.