JPH01294620A - Aqueous liquid preparation and production thereof - Google Patents

Abstract

PURPOSE:To obtain a clear aqueous solution preparation useful for allergic disease and having excellent stability by using tranilast as an active ingredient and polyvinyl pyrrolidone as a dissolving auxiliary. CONSTITUTION:N-(3,4-dimethoxycinnamoyl) anthranillic acid (general name: tranilast) or salt used as an active ingredient is dissolved in purified water, as necessary containing a basic substance (e.g., trisodium phosphate). Then polyvinyl pyrrolidone and further as necessary a buffer (e. g., acetic acid), preservative (e.g., phenol), stabilizing agent (e.g., edetate sodium), isotonicity (e.g., sodium chloride), etc., is added to the above-mentioned solution and the blend is prepared to provide the aimed product. The resultant preparation is useful as mixture for internal use and parenteral injection as well as a liquid medicine for external use such as a liquid medicine for eye, liquid medicine for nose and ear, external injection, aerosol, enhalent, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention provides N-(3
, 4-dimethoxycinnamoyl) anthranilic acid (common name: tranilast (hereinafter referred to as tranilast)) or a pharmacologically acceptable salt thereof as an active ingredient.

Conventional technology Tranilast has antiallergic effects and is effective against diseases caused by allergies, such as bronchial asthma, allergic rhinitis,
It is a useful compound as a therapeutic agent for atopic inflammation, hypersensitivity, etc. (Japanese Patent Publication No. 56-040710) Tranilast is an aromatic carboxylic acid derivative, but it is a compound that is extremely insoluble in water, and even as an alkali metal salt such as sodium salt or potassium salt, it is a compound that is hardly soluble in water.

For this reason, it has conventionally been difficult to produce an aqueous solution formulation containing tranilast as an active ingredient.

Problems to be Solved by the Invention In the treatment of hay fever, which has been on the rise in recent years, there is an increasing demand for symptomatic preparations such as eye drops and nasal drops.

It is desired to provide such a formulation for tranilast, which is useful as an anti-allergic agent, and therefore studies are being widely conducted to formulate a liquid formulation of poorly soluble tranilast.

An object of the present invention is to provide an aqueous solution formulation containing Tranist or a pharmacologically acceptable salt thereof as an active ingredient, which is useful as a liquid preparation such as eye drops and nasal drops for allergic diseases.

Means for Solving the Problems As a result of extensive research into producing an aqueous solution formulation of tranilast, which is extremely sparingly soluble in water, or a pharmacologically acceptable salt thereof, the present inventors decided to use a certain solubilizing agent. The present inventors have discovered that the object can be achieved by using the present invention.

That is, the present invention provides an aqueous solution formulation containing tranilast or a pharmacologically acceptable salt thereof useful as an anti-allergic agent as an active ingredient, and which is characterized by using polyvinylpyrrolidone and, if necessary, a basic substance. The present invention relates to a manufacturing method thereof.

As mentioned above, the aqueous solution formulation of the present invention is characterized by the use of polyvinylpyrrolidone as a solubilizing agent. This polyvinylpyrrolidone is used as a suspending agent in ordinary preparations, and there are almost no reports of its use as a solubilizing agent.

Furthermore, glycerin, propylene glycol, polyvinyl alcohol BG, which is generally used as a solubilizing agent,
-25, polyoxyethylene glycol 4000, etc., although tranilast dissolves within 24 hours, a crystalline white precipitate forms within 24 hours, making it impossible to obtain a clear and stable aqueous solution preparation.

It is surprising that a clear and stable aqueous solution preparation can be specifically prepared only when polyvinylpyrrolidone is used as a solubilizing agent.

The aqueous solution preparation of the present invention has tranilast clearly dissolved in water, and is a stable solution that does not produce floating matter or precipitates even when left standing, and can be used not only as an internal solution or an injection. It is extremely useful as an eye solution, an otorhinolaryngological solution such as a nasal solution, an injection, a spray, an inhaler, and other external solutions.

Furthermore, the aqueous solution formulation of the present invention may include lotions, ointments,
It can also be applied in the production of external preparations such as pasta preparations and liniment preparations.

The aqueous solution formulation of the present invention can be manufactured as follows. That is, tranilast or a pharmacologically acceptable salt thereof is heated and dissolved in purified water to which a basic substance has been added as necessary, then polyvinylpyrrolidone is added, and further buffers, preservatives, and stabilizers are added as necessary. , by adding isotonizing agents, etc.

When producing the aqueous preparation of the present invention, it is preferable to use the active ingredient tranilast in the form of a salt such as a sodium salt because of its high solubility; however, a basic substance may be added during dissolution. As such basic substances, bases such as borax, trisodium phosphate, sodium citrate, sodium hydroxide, potassium hydroxide, etc. or alkali metal salts of weak acids can be used.

The polyvinylpyrrolidone used as a solubilizing agent in the aqueous solution formulation of the present invention can be used regardless of its average molecular weight or type, but from the viewpoint of formulation, it is preferably one with a low viscosity and an average molecular weight of about 10,000 to 40,000. Among these, those with an average molecular weight of about 250,000 are most preferred. Further, the amount to be used may be about 4 times or more of the active ingredient tranilast, but it is most effective to use about 6 times the amount.

Buffers, preservatives, stabilizers, tonicity agents, etc. can be added to the aqueous preparation of the present invention, if necessary.

Examples of the buffer used in the present invention include acetic acid, phosphoric acid, or boric acid, or salts thereof, which are used in conventional pharmaceutical sciences.

Moreover, the basic substance used when dissolving tranilast can also be used.

Preservatives include phenolic substances such as phenol, cresol, chlorocresol, and hydroxybenzoic acid esters, alcohols such as chlorobutanol and propylene glycol, and acidic substances such as benzoic acid, dehydroacetic acid, and sulfite. Mention may be made of the substance and its salts, such as quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride, etc. and thimerosal.

Examples of the stabilizer include sodium edetate, sodium sulfite, sodium bisulfite, sodium thiosulfate, Rongalite, and ascorbic acid, which are commonly used as stabilizers for aqueous solutions.

Isotonic agents include salts such as sodium chloride, potassium chloride, calcium chloride, etc., and glycerin.

When a quaternary ammonium salt such as benzalkonium chloride or benzethonium chloride is used as a preservative in the production method of the present invention, an insoluble salt is formed with tranilast and cloudiness occurs, but nonionic surfactants or amphoteric surfactants Alternatively, a clear solution state can be maintained by adding a mixture of both.

As such a nonionic surfactant) ILB is 1
0 to 16 is preferable, and examples thereof include polyoxyethylene hydrogenated castor oils and polyoxyethylene sorbitan monoesters such as polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monopalmitate, and polyoxyethylene sorbitan monolaurate. I can play Toka.

Examples of the amphoteric surfactant include lauryldimethylaminoacetic acid betaine, lauryldimethylamine oxide, and laurylcarboxymethylhydroxyethylimidazolinium betaine.

The aqueous formulation of the present invention is extremely stable, with 70-12
Even when heated at 0℃ for 30 minutes, the active ingredient tranilast does not decompose at all, so even when dissolving and preparing a large amount of tranilast, it is possible to freely set the most preferable heating temperature in terms of thermal efficiency, workability, etc. can.

The aqueous preparation of the present invention contains about 0.0% of the active ingredient tranilast.
However, as mentioned above, the active ingredient tranilast hardly decomposes even when heated at 70-120°C for about 30 minutes, and even when stored at room temperature and protected from light for about 4 weeks. No change in content was observed.

In addition, the aqueous solution itself is extremely stable, with no differences observed in pH and osmotic pressure immediately after preparation and after storage at room temperature for 1 week in the dark, and even after storage at 11° at room temperature for 2 months in the dark for liquid observation. No floating matter, precipitates, crystals, etc. were observed.

As described above, the aqueous solution preparation of the present invention is an extremely stable and clear liquid preparation, and is useful as an internal solution, an external solution, an injection, and the like.

EXAMPLES The content of the present invention will be explained in more detail with reference to the following examples.

Example 1 Nasal solution formulation Tranilast 0.5% Trisodium phosphate 0.5% Polyvinylpyrrolidone 3.0% Sodium edetate 0.01% Chlorobutanol 0.3% Sterile purified water Appropriate amount of Tranilast 0.5g and phosphoric acid Trisodium 0.5
Add 20 g of sterile purified water with stirring and heat to 60-80°C.
0.6g of polyvinylpyrrolidone was added to the solution, and then 0.01g of sodium edetate was added.

After adding 0.3 g of chlorobutanol, add sterilized purified water to make the total volume 100 g, pH near, 4, osmotic pressure ratio:
A 0.5% aqueous solution of about 1.0 tranillas) was obtained.

Example 2 Eye drop formulation Tranilast 0.5% borax
0.35% polyvinylpyrrolidone
3% Methyl paraoxybenzoate 0.026% Propyl paraoxybenzoate 0.014% Sodium edetate
0.01% Glycerin 2% Sterile Purified Water Appropriate amount Tranilas hO, 5 g and Borax 0.35 g were added to 50 mff1 of sterile purified water with stirring, heated and dissolved at 60-80°C, and this solution was added with 3 g of polyvinylpyrrolidone and rose oxybenzoin. 0.026 g of methyl acid, 0.014 g of propyl oxybenzoate, 0.014 g of sodium edetate.
After adding and dissolving 01 g of glycerin and 2 g of glycerin, sterilized purified water was added to bring the total amount to 100 d to obtain a 0.5% aqueous solution of tranilast with a pH of near 4 and an osmotic pressure ratio of 1.0.

Example 3 Eye drop formulation Tranilast 1% trisodium phosphate 1% polyvinylpyrrolidone 6% sodium edetate 0.01% benzalkonium chloride 0.005% purified water
Appropriate amount of 1 g of tranilast and 1 g of trisodium phosphate at 0.
1% polyoxyethylene sorbicun monooleate) 50
ml with stirring, and heat-dissolved at 60-80°C, and to this solution were added 6 g of polyvinylpyrrolidone, 0.01 g of sodium edetate, and 0.25 g of penzalkonium chloride for injection. % Polyvinylpyrrolidone 1.5% Purified water Appropriate amount Tranilast 0.25g and trisodium phosphate 0.
25g of purified water 20m/! 60~ while stirring.
After heating and dissolving at 80°C, add 1.5 g of polyvinylpyrrolidone to this solution and dissolve it, add purified water to make the total amount 100-. A 0.25% aqueous solution was obtained.

Claims (3)

[Claims] (1) An aqueous solution formulation containing N-(3,4-dimethoxycinnamoyl)anthranilic acid or a pharmacologically acceptable salt thereof as an active ingredient, characterized by using polyvinylpyrrolidone and, if necessary, a basic substance. Aqueous formulation (2) Aqueous solution formulation according to claim 1, characterized in that polyvinylpyrrolidone having an average molecular weight of about 25,000 is used. (3) N-(3,4-dimethoxycinnamoyl)anthranilic acid or a pharmacologically acceptable salt thereof is heated and dissolved in purified water to which polyvinylpyrrolidone and a basic substance is added as necessary. A method for producing an aqueous solution formulation, characterized by adding a buffer, a preservative, a stabilizer, a tonicity agent, etc.