JPH0789857A - Aqueous supension solution - Google Patents

Abstract

PURPOSE:To obtain a stable aqueous suspension solution containing 5-(3-ethoxy-4- n-pentyloxyphenyl) thiazolidine-2,4-dione useful as a therapeutic agent for corneal disorder as an active ingredient. CONSTITUTION:This aqueous suspension solution of fine crystal of 5-(3-ethoxy-4- n-pentyloxyphenyl)thiazolidine-2,4-dione contains a water-soluble polymer, chlorobutanol and benzalkonium chloride and/or p-oxybenzoic ester.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to 5- (3-ethoxy-4-n-pentyloxyphenyl) thiazolidine useful for the prevention / treatment of cataract, corneal disorder, iris / ciliary body disease and the like caused by diabetes. -2,4-dione stable aqueous suspension.

[0002]

BACKGROUND OF THE INVENTION The main component of the aqueous suspension of the present invention is 5-
(3-Ethoxy-4-n-pentyloxyphenyl) thiazolidine-2,4-dione (hereinafter sometimes simply referred to as CT-112) is a known compound having an aldose reductase inhibitory action and is a mammal including human. It has an effect of preventing / treating chronic symptoms such as cataracts, neurological diseases and retinopathy caused by diabetes in animals (JP-A-57-2807).
5) and that it has a therapeutic effect on iris / ciliary body disease (Japanese Patent Laid-Open No. 61-43114). Further, an aqueous suspension of fine crystals of CT-112 used for the treatment / prevention of the above-mentioned diseases is also known, and PCT WO9
2/17174, aqueous solution polymer compound and CT-
Aqueous suspensions containing 112 fine crystals are described. Specific examples thereof include (1) CT-112, hydroxypropylmethyl cellulose, concentrated glycerin, sodium acetate, methyl paraoxybenzoate, sodium hydroxide, hydrochloric acid and purified water; (2) CT-
112, hydroxypropyl methylcellulose, polyvinyl alcohol, mannite, benzalkonium chloride,
An aqueous liquid agent comprising phosphoric acid and purified water, and (3) C
An aqueous liquid formulation consisting of T-112, hydroxypropylmethylcellulose, concentrated glycerin, sodium acetate, sodium edetate, sodium hydroxide, hydrochloric acid and purified water is described. However, these prescriptions are not sufficiently satisfactory in terms of preventing the drug from decaying and feeling irritation when using the drug when actually applied to humans, feeling of foreign matter, and the like.

[0003]

Under these circumstances, the present inventors have made various studies to overcome the above-mentioned drawbacks,
It was surprisingly found that a stable aqueous suspension without the above-mentioned various drawbacks can be obtained by combining a buffering agent and a tonicity agent with a specific preservative.

[0004]

That is, the present invention is as follows. Fine 5- (3-ethoxy-4-n-pentyloxyphenyl) thiazolidine-containing water-soluble polymer compound, chlorobutanol and benzalkonium chloride and / or paraoxybenzoic acid ester
It is an aqueous suspension of 2,4-dione. 5- (3-ethoxy-4-n-, which is a medicinal component of the aqueous suspension of the present invention.
Pentyloxyphenyl) thiazolidine-2,4-dione (CT-112) can be produced by the method described in JP-A-57-28075 or in accordance therewith. In the present invention, CT-112 used in the preparation of the aqueous suspension may be a free compound, or may be an alkali metal salt such as sodium salt or potassium salt. Fine crystals of CT-112 can be produced, for example, by the method described in PCT WO92 / 17174. For example, an aqueous solution having a pH of 8 or more in which a water-soluble polymer compound and CT-112 are dissolved is prepared, and It can be produced by adding an acid to adjust the pH to 7 or less.
According to this method, fine crystals having a particle diameter of 10 μm or less can be obtained. CT-1 in the aqueous suspension of the present invention
The concentration of 12 is 0.01 to 5.0 w / v%, preferably 0.05 to 1.0 w / v%. Examples of the water-soluble polymer compound used in the present invention include polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP),
Examples thereof include hydroxypropylmethyl cellulose (HPMC), methyl cellulose (MC), hydroxyethyl cellulose (HEC), polyethylene glycol, sodium carboxymethyl cellulose (CMC-Na) and the like. Among them, HPMC is the most preferable. Two or more water-soluble polymer compounds may be appropriately combined and used depending on the need and purpose.

The concentration of the water-soluble polymer compound in the aqueous suspension of the present invention is usually 0.001 to 5.0 w / v%, preferably 0.02 to 1.0 w / v%. In the aqueous suspension of the present invention, both the first and second antiseptic components are used as antiseptics. Chlorobutanol is used as the first antiseptic component, and one or two of benzalkonium chloride and paraoxybenzoic acid ester is used as the second antiseptic component. Examples of the paraoxybenzoic acid ester include lower alkyl esters of paraoxybenzoic acid such as methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate and butyl paraoxybenzoate. As the second antiseptic component, paraoxybenzoic acid ester is preferable. The concentration of chlorobutanol, which is the first antiseptic component, in the aqueous suspension of the present invention is usually 0.01 to 1.0 w / v%, preferably 0.
It is 1 to 0.5 w / v%. The concentration of benzalkonium chloride and / or paraoxybenzoic acid ester which is the second antiseptic component in the aqueous suspension of the present invention is usually 0.00
05-0.1 w / v%, preferably 0.001-0.0
It is 5 w / v%.

Next, a method for producing the aqueous suspension of the present invention will be described. First, CT-112 and a water-soluble polymer compound are mixed or dissolved in water to prepare an aqueous solution having a pH of 8 or more. In this case, both may be added to water and then the pH may be adjusted, or one of them may be added to water to adjust the pH and then the other may be added and dissolved, or CT-112 and water-soluble solution may be added to an aqueous solution whose pH has been adjusted in advance. The high molecular compound may be dissolved. The CT-112 and the water-soluble polymer compound may be added to water at the same time or separately, and either one may be added first. This dissolution process is preferably performed as quickly as possible to prevent decomposition of CT-112. Further, as the water-soluble polymer compound, those previously dissolved in water may be used,
By doing so, the dissolution time can be shortened. The pH of the aqueous solution is 8 or more, preferably 10 to 13. If the pH is too high, decomposition of CT-112 will occur, which is not preferable. If the pH is alkaline below 8, CT-
It takes time to dissolve 112, which is not preferable. The concentration of CT-112 in this case is usually 0.5 w / v% or more,
Preferably 1 to 5 w / v%, the concentration of the water-soluble polymer compound is usually 0.01 to 10 w / v%, preferably 0.02 to
It is better to adjust it to 5.0 w / v%. The pH is adjusted by adding an alkaline compound. Examples of the alkaline compound include bases such as sodium hydroxide and potassium hydroxide, and salts such as borax, sodium carbonate, trisodium phosphate, and trisodium citrate which exhibit alkalinity when dissolved in water. Next, while stirring the aqueous solution thus obtained, an acid is gradually added dropwise to the solution to adjust the pH of the solution to 7 or less, preferably about 4 to 6, to precipitate crystals of CT-112 to form an aqueous solution. A suspension is obtained. In addition, it is preferable to stir so as not to foam as much as possible in order to avoid taking in CT-112. Examples of the acid include acids such as hydrochloric acid, sulfuric acid, acetic acid, and phosphoric acid, as well as acids such as sodium dihydrogen phosphate and sodium dihydrogen citrate that exhibit acidity when dissolved in water. In this way, CT-112 having a uniform particle size of 10 μm or less
An aqueous suspension of fine crystals of can be obtained. Chlorobutanol, benzalkonium chloride and / or paraoxybenzoic acid ester as a preservative, and optionally water are added thereto to adjust the proportion of each component to a predetermined concentration to give the aqueous suspension of the present invention. it can.

The aqueous suspension of the present invention further comprises CT-11 unless the purpose of the present invention is impaired.
In addition to 2, the same or different medicinal components may be contained, and if necessary, other additives may be blended to provide eye drops, for example. In the case of eye drops, in addition to the above components, additives usually added to conventional eye drops such as buffers (phosphate, acetate, boric acid, citrate, etc.), isotonic agents (sodium chloride). , Sorbitol, glycerin, etc.), chelating agents (sodium edetate, sodium citrate, etc.), pH adjusters (hydrochloric acid, acetic acid, sodium hydroxide, etc.), and surfactants (polysorbate 80, etc.) may be added as appropriate. Glycerin is preferred as the tonicity agent. They may be used either individually or in combination of two or more. Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples to clarify the effects of the present invention.
These are merely examples, and these do not limit the scope of the present invention.

[0008]

【Example】

Example 1 Sodium hydroxide (1.4
g) and sodium acetate (2 g) were completely dissolved, and CT-112 (10 g) was added thereto and completely dissolved. 200 ml of a solution in which HPMC (2 g) was dissolved was added to this solution and sterilized by filtration. The pH of this liquid was 11.7.
0.5N hydrochloric acid sterilized while stirring was gradually added dropwise to this solution to adjust the pH to 5.5. To this solution, separately prepared concentrated griserine (88 g), methyl paraoxybenzoate (1 g), HPMC (2 g), chlorobutanol (1
2 g), sodium edetate (0.8 g) and sodium acetate (2 g) dissolved and sterilized by filtration 250
0 ml was added to adjust the pH to 5.5, and sterile purified water was added to make the total volume 4000 ml.

Example 2 Sodium hydroxide (0.07 ml) was added to about 10 ml of sterile purified water.
g) and sodium acetate (0.1 g) were completely dissolved, and CT-112 (0.5 g) was added thereto and completely dissolved. A solution of HPMC (0.1 g) dissolved in this solution 10 m
1 was added and sterilization by filtration was performed. The pH of this solution is 11.7.
Met. 0.5N hydrochloric acid sterilized while stirring was gradually added dropwise to this solution to adjust the pH to 5.5. Separately prepared concentrated griserine (12.5 g), methyl paraoxybenzoate (0.125 g) and HPMC (0.
4 g), chlorobutanol (1.5 g), sodium edetate (0.1 g) and sodium acetate (0.4 g)
Was added, and 350 ml of an aqueous solution sterilized by filtration was added to
Was adjusted to 5.5, and sterilized purified water was added to bring the total volume to 500 ml.
And

Example 3 Sodium hydroxide (0.7%) was added to about 100 ml of sterile purified water.
g) and sodium acetate (1 g) were completely dissolved, and CT-112 (5 g) was added thereto and completely dissolved. 200 ml of a solution in which HPMC (1 g) was dissolved was added to this solution and sterilized by filtration. The pH of this liquid was 11.7. 0.5N hydrochloric acid sterilized while stirring was gradually added dropwise to this solution to adjust the pH to 5.5. Separately prepared concentrated griseline (125 g), benzalkonium chloride (0.25 g), HPMC (4 g), chlorobutanol (15 g), sodium edetate (1 g) and sodium acetate (4 g) were dissolved in this solution, Filter-sterilized aqueous solution 350
0 ml was added to adjust the pH to 5.5, and sterile purified water was added to make the total volume 5000 ml.

Example 4 Sodium hydroxide (0.07 ml) was added to about 10 ml of sterile purified water.
g) and sodium acetate (0.1 g) were completely dissolved, and CT-112 (0.5 g) was added thereto and completely dissolved. 10m of liquid in which PVA (0.05g) is dissolved in this liquid
1 was added and sterilization by filtration was performed. The pH of this solution is 11.7.
Met. 0.5N hydrochloric acid sterilized while stirring was gradually added dropwise to this solution to adjust the pH to 5.5. Separately prepared concentrated griserine (11 g), methyl paraoxybenzoate (0.05 g), chlorobutanol (0.6 g), sodium edetate (0.04 g) and sodium acetate (0.1 g) were dissolved in this solution. Then, 250 ml of an aqueous solution sterilized by filtration was added to adjust the pH to 5.5, and sterile purified water was added to make a total volume of 500 ml.

Example 5 Sodium hydroxide (0.14 ml) was added to about 20 ml of sterile purified water.
g) and sodium acetate (0.2 g) were completely dissolved, and CT-112 (1 g) was added thereto and completely dissolved. 20 ml of a solution in which HPMC (0.2 g) and HEC (0.05 g) were dissolved was added to this solution and sterilized by filtration. The pH of this liquid was 11.7. 0.5N hydrochloric acid sterilized while stirring was gradually added dropwise to this solution to adjust the pH to 4.0. Separately prepared sodium chloride (3
g), benzalkonium chloride (0.02 g), chlorobutanol (0.6 g), sodium edetate (0.08)
g) and sodium acetate (0.2 g) were dissolved, 250 ml of an aqueous solution which had been sterilized by filtration was added to adjust the pH to 4.0, and sterile purified water was added to make a total volume of 400 ml.

[0013]

[Experimental Example] The irritation and foreign-body sensation of each of the aqueous suspensions of Examples 1, 2, and 3 when applied to humans (A, B, C, D, and E) were examined. As a control, an aqueous suspension having the same formulation as in Example 1 except that it did not contain chlorobutanol was used. The results are shown in Table 1.

[Table 1]

When the control was instilled, there were individual differences in irritation and foreign body sensation. However, when the aqueous suspension preparations of Examples 1, 2 and 3 were instilled, most humans experienced irritation and foreign body sensation. I did not admit. This suggests that the irritation and the like of the eye drops when applied to the eye may cause individual differences due to the addition of subjective factors such as feeling of use in humans.
It was found that by adding chlorobutanol to the CT-112 aqueous suspension, the irritation and foreign body sensation can be eliminated.

[0015]

INDUSTRIAL APPLICABILITY In the aqueous suspension of the present invention, CT-112 in the aqueous suspension is uniformly dispersed as particles having a particle diameter of 10 μm or less, which is stable for a long period of time and has no foreign substance sensation.
Moreover, it is painless when administered as eye drops. Therefore, the aqueous suspension of the present invention can be advantageously used for the prevention / treatment of cataract, retinopathy, iris / ciliary body disease and the like caused by diabetes.

Front page continuation (72) Inventor Katsuhiro Inada 1-3-5 Suma-ku, Kobe-shi, Hyogo Prefecture Maison 102 No. 102

Claims (7)

[Claims] 1. 5- (3-Ethoxy-4-n-pentyloxyphenyl) thiazolidine-containing a water-soluble polymer compound, chlorobutanol and benzalkonium chloride and / or paraoxybenzoic acid ester.
Aqueous suspension of fine crystals of 2,4-dione. 2. The aqueous suspension agent according to claim 1, wherein the fine crystals of 5- (3-ethoxy-4-n-pentyloxyphenyl) thiazolidine-2,4-dione have a particle size of 10 μm or less. 3. The aqueous suspension agent according to claim 1, wherein the water-soluble polymer compound is hydroxypropylmethyl cellulose. 4. The aqueous suspension according to claim 1, wherein the benzalkonium chloride and / or the paraoxybenzoic acid ester is a paraoxybenzoic acid ester. 5. The content ratio of the water-soluble polymer compound and 5- (3-ethoxy-4-n-pentyloxyphenyl) thiazolidine-2,4-dione is from 0.001 to 0.001, respectively.
The aqueous suspension according to claim 1, which is 5.0 w / v% and 0.01 to 5.0 w / v%. 6. The content ratio of chlorobutanol is 0.01 to.
The aqueous suspension according to claim 1, which is 1.0 w / v%. 7. The content ratio of benzalkonium chloride and / or paraoxybenzoic acid ester is 0.0005.
The aqueous suspension according to claim 1, which is 0.1 w / v%.