AQUEOUS PREPARATION AND METHOD OF PREPARATION THEREOF

Abstract: This invention relates to an aqueous preparation com­ prising a compound (A) represented by the formula: and at least one of cyclodextrins selected from a α-­ cyclodextrin and dimethyl-β-cyclodextrin; and a method of preparation thereof. According to the aqueous preparation of this invention, coexistence with at least one medicament selected from α-­ cyclodextrin and dimethyl-β-cyclodextrin allows to enhance the solubility to water of compound (A) essential in this in­ vention to such a concentration that makes an expected cur­ ative effect available and to impart a desired stability to it. As a consequence, the aforesaid compound (A) can be utilized as a medicament for an aqueous preparation having anti-allergy action.

Description: This invention relates to an aqueous preparation containing a compound (A) represented by the formula: and α-cyclodextrin; and a method of preparation thereof. The aforesaid compound (A) is known to be a selective inhibitor for 5-riboxygenase which is one of important metabolism enzymes for arachidonic acid cascade and to inhibit the production of SRS-A or LTB₄, showing experimental allergic asthma which IgG and IgE in Guinea pigs or IgE in rats partake. In view of the strong anti-allergy action of compound (A), an attempt has been made to develop it as a medicament. EP-0 038 160 discloses a compound (A) as well as pharmaceutical compositions containing it. However, its solubility is too small to obtain an aqueous solution having a concentration sufficient to exhibit pharmacological effect and consequently, clinical application as an aqueous preparation such as oral drug, injection drug, nose drops (rhinenchysis drug) and eye drops is expected, but not yet realized in practice. In local administration of this compound as a liquid preparation such as a nose drops or eye drops, its concentration is generally required to be 0.1 to 3 mg/mℓ. The compound (A), however, has an extremely low solubility to water, for example, only showing a slight solubility on the order of less than 10 ng/mℓ at 25°C, so that its application as a liquid preparation was regarded as extremely difficult. FR-2 484 252 describes methods for producing aqueous solutions of active but insoluble or slightly soluble ingredients by using dimethyl-β-cyclodextrin. The present inventors have supposed that if an aqueous preparation which is a clinically applicable form is feasible with use of compound (A), application range of compound (A) will be remarkably enlarged and consequently, have attempted to make an aqueous preparation containing compound (A). The present inventors have intensively investigated into the possibility of preparing an aqueous preparation containing compound (A) with a view toward solving the problems above, and as a result, accomplished this invention on the basis of the finding that α-cyclodextrin enhances remarkably the solubility of compound (A) without impairing its stability. The present invention consists of an aqueous preparation containing compound (A) and α-cyclodextrin. According to another aspect, this invention provides a method of preparing an aqueous preparation comprising incorporating the compound (A) and α-cyclodextrin in an aqueous solvent to dissolve them. The aqueous preparation of this invention can be advantageously used for medicinal utility, for example, in the form of a nose drops, eye drops, embrocation, inhalant, oral drug or injection drug. As a medicament to be compounded in order to raise the solubility of compound (A) to water, α-cyclodextrin is used. An aqueous preparation is obtained by dissolving the aforesaid compound (A) and the aforesaid medicament in water, with compound (A) being contained in an amount of 0.001 to 0.5 W/V %, preferably 0.01 to 0.3 W/V % based on the totality of the aqueous preparation. Our experimental investigation has revealed that α-cyclodextrin shows a highly advantageous effect for the intended object whereas β-cyclodextrin and γ-cyclodextrin do not show any intended effect. Amount of α-cyclodextrin to be incorporated in an aqueous preparation of this invention is desired to be usually 0.1 to 15 W/V %, preferably, 1 to 10 W/V %. In the aqueous preparations of this invention, there may be incorporated conventional additives which are usually used for an aqueous preparation, for example, a buffer for pH adjustment (phosphoric acid buffer, boric acid buffer, citric acid buffer, tartaric acid buffer or acetic acid buffer; isotonic-rendering agent (sorbitol, glycerine, polyethylene glycol, propylene glycol, glucose or sodium chloride); antiseptic (benzalkonium chloride, paraoxybenzoic esters, benzyl alcohol, parachlorometaxylenol, chlorocresol, phenethyl alcohol, sorbic acid or its salts, thimerosal or chlorobutanol); chelating agent (sodium edetate, sodium citrate or sodium polyphosphate); thickener (polyvinyl pyrrolidone, methyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol or sodium polyacrylate) in a usual amount. Any medicinal ingredient other than compound (A) may also be incorporated in the aqueous preparation of this invention insofar as the intended object of this invention is not impaired. The pH of the aqueous preparation of this invention is usually within the range of 3 to 10, preferably, 4 to 8. The aqueous preparation of this invention is usually prepared by incorporating and dissolving compound (A) and α-cyclodextrin in an aqueous solvent. Particularly, it is preferred, after dissolution, to subject the resulting solution to pH adjustment and further to sterilization treatment. In preparing a nose drops or eye drops, it is desirable that after an antiseptic is dissolved in an aqueous solvent, α-cyclodextrin is incorporated, and compound (A) is incorporated, if necessary, together with a buffer, isotonic-rendering agent, chelating agent and thickener, to completely dissolve it. The sterilization treatment includes, for example, heat treatment and filtration. In compounding other medicinal ingredient than compound (A), it may be added at any stage insofar as the object of this invention is not changed, but desirably, it is added after compound (A) is dissolved. The invention will be hereinbelow described in more detail with reference to experimental examples and working examples. Experimental Example 1 Examination of Solubility: In order to demonstrate the effect of increase in solubility of compound (A) when α-cyclodextrin is compounded with it, comparative solubility test was effected between α-cyclodextrin and various kinds of dissolution-assisting agents as a control. The dissolution-assisting agents used as a control are dimethyl-β-cyclodextrin β-cyclodextrin, γ-cyclodextrin, polyvinyl pyrrolidone (hereinbelow abbreviated as PVP), polyoxyethylene monostearate (hereinbelow abbreviated as MYS-40), polyoxyethylene sorbitan monooleate (hereinbelow abbreviated as TO-80), and polyoxyethylene cured castor oil (hereinbelow abbreviated as HCO-40, HCO-60). As a result, prominent enhancement of solubility was observed with α-cyclodextrin and dimethyl-β-cyclodextrin whereas such effect was hardly observed with other control dissolution-assisting agents. Solubility was determined by dissolving the respective dissolution-assisting agents into 0.2 mole of phosphoric acid buffer solution (Na₂HPO₄NaH₂PO₄, pH 6.0), then adding excessive amount of compound (A) and shaking the mixed solution at room temperature (15°C to 20°C) for 5 days, centrifuging the solution, filtering the supernatant by use of cotton stoppers, and subsequently measuring the concentration of compound (A) contained in the filtrate with a high-speed liquid chromatography. Results are shown in Table 1. As will be apparent from these results, it was unexpected that α-cyclodextrin exhibits a conspicuous solubility-enhancing effect of 1000 times as high as that of phosphoric acid buffer having pH 6. The same effect only showed dimethyl-β-cyclodextrin β-Cyclodextrin or γ-cyclodextrin can hardly enhance the solubility. The other dissolution-assisting agents showed little increase in solubility to the degree that is practically available, either. Experimental Example 2 Stability test of compound (A) was performed in the following formula at varying pHs: Formula Compound (A) 0.05 g α-Cyclodextrin 5.0 g Na₂HPO₄·H₂O 0.5 g H₃PO₄ proper amount Purified Water amount totaling 1000 mℓ Results are shown in Table 2. As a result, it has become apparent that the aqueous preparation of this invention is stable in the pH range of 4 to 6. Further stability test at 60°C with a high-speed liquid chromatography was effected in accordance with the formulae given below containing, as a dissolution-assisting agent, TO-80 and α-cyclodextrin, respectively. Results obtained are given in Table 3. It was proved that the formula containing α-cyclodextrin is more stable than the formula containing TO-80. Pharmaceutical Example 1 (Nose drops) In 800 mℓ of purified water being heated, methyl p-oxybenzoate and propyl p-oxybenzoate were dissolved, and disodium phosphate, monosodium phosphate, α-cyclodextrin and concentrated glycerine were added in sequence and heated, and then, compound (A) was dissolved. After cooling, benzyl alcohol was added and dissolved, and the solution obtained was adjusted to pH 6.0 with sodium hydroxide and totaled to 1.0 ℓ by the addition of purified water. The solution was filtered through a 0.45 µ membrane filter, and filled in a predetermined container to produce a liquid preparation for nose drops. According to the aqueous preparation of this invention, coexistence with α-cyclodextrin allows to enhance the solubility to water of compound (A) essential in this invention to such a concentration that makes an expected curative effect available and to impart a desired stability to it. As a consequence, the aforesaid compound (A) can be utilized as a medicament for an aqueous preparation having anti-allergy action.

Claims: An aqueous preparation containing the compound (A) represented by the formula: and α-cyclodextrin. A method of preparing an aqueous preparation comprising incorporating the compound (A) represented by the formula: and α-cyclodextrin in an aqueous solvent to dissolve them.

Inventors: MORITA, YASUSHI, TERAYAMA, HIDEO, YAMAMOTO, YUJIRO
Applicants: SENJU PHARMACEUTICAL CO., LTD.
Application year: 1987
Main classification: A61K31
IPC codes: C07C50, A61K47, A61K9, A61P37, A61P27, A61P43, A61K31, A61P11