JP2787131B2 - Aqueous suspension - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to 5- (3-ethoxy-4-n-pentyloxyphenyl) thiazolidine useful for the prevention and treatment of cataracts, corneal disorders and iris / ciliary disorders caused by diabetes. The present invention relates to a stable aqueous suspension of 2,4-dione.

[0002]

2. Description of the Prior Art The main component of the aqueous suspension of the present invention is 5-
(3-Ethoxy-4-n-pentyloxyphenyl) thiazolidine-2,4-dione (hereinafter sometimes referred to simply as CT-112) is a known compound having an aldose reductase inhibitory action, Having an effect of preventing and treating chronic symptoms such as cataract, neurological disease and retinopathy caused by diabetes in animals (Japanese Patent Application Laid-Open No. 57-2807)
5) and having a therapeutic effect on iris / ciliary body disease (JP-A-61-43114). Also, an aqueous suspension of fine crystals of CT-112 used for treatment / prevention of the above-mentioned diseases is known, and PCT WO9
2/17174 includes aqueous polymer compounds and CT-
Aqueous suspensions containing 112 fine crystals have been described. Specific examples thereof include: (1) CT-112, an aqueous solution composed of hydroxypropyl methylcellulose, concentrated glycerin, sodium acetate, methyl parahydroxybenzoate, sodium hydroxide, hydrochloric acid and purified water; (2) CT-112
112, hydroxypropyl methylcellulose, polyvinyl alcohol, mannitol, benzalkonium chloride,
An aqueous solution comprising phosphoric acid and purified water, and (3) C
An aqueous solution comprising 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 prevention of decay of the drug and irritability and foreign body sensation when using the drug when actually applied to humans.

[0003]

Under such circumstances, the present inventors have conducted various studies to overcome the above-mentioned drawbacks,
It has been surprisingly found that a stable aqueous suspension free from the above-mentioned disadvantages can be obtained by combining a specific preservative with a buffering agent and a tonicity agent.

[0004]

That is, the present invention provides: Fine 5- (3-ethoxy-4-n-pentyloxyphenyl) thiazolidine containing water-soluble polymer compound, chlorobutanol and benzalkonium chloride and / or paraoxybenzoate
It is an aqueous suspension of 2,4-dione. 5- (3-ethoxy-4-n-) which is the active ingredient 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 a method analogous thereto. In the present invention, CT-112 used for preparing the aqueous suspension may be a free compound, but may be an alkali metal salt such as a sodium salt or a potassium salt. Fine crystals of CT-112 can be produced, for example, by the method described in PCT WO 92/17174. 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. It can be produced by adjusting the pH to 7 or less by adding an acid.
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), polyvinyl pyrrolidone (PVP),
Examples include hydroxypropylmethylcellulose (HPMC), methylcellulose (MC), hydroxyethylcellulose (HEC), polyethylene glycol, sodium carboxymethylcellulose (CMC-Na) and the like. Among them, HPMC is most preferable. The water-soluble polymer compound may be used in an appropriate combination of two or more kinds according to necessity and purpose.

[0005] 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 preservative first component and the second preservative are used as preservatives. Chlorobutanol is used as the preservative first component, and one or two of benzalkonium chloride and paraoxybenzoate are used as the preservative second component. Examples of the paraoxybenzoate include lower alkyl esters of paraoxybenzoic acid such as methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, and butyl paraoxybenzoate. As the preservative second component, a paraoxybenzoic acid ester is preferable. The concentration of chlorobutanol, which is the preservative first component, in the aqueous suspension of the present invention is generally 0.01 to 1.0 w / v%, preferably 0.1 to 1.0 w / v%.
1 to 0.5 w / v%. The concentration of benzalkonium chloride and / or p-hydroxybenzoate, which is the second preservative, in the aqueous suspension of the present invention is usually 0.001.
05 to 0.1 w / v%, preferably 0.001 to 0.0
5% w / v.

Next, a method for producing the aqueous suspension of the present invention will be described. First, an aqueous solution having a pH of 8 or more in which CT-112 and a water-soluble polymer compound are mixed or dissolved in water is prepared. In this case, both may be added to water and then the pH may be adjusted. One of the two may be added to water to adjust the pH, and then the other may be added and dissolved. The hydrophilic polymer compound may be dissolved. The addition of CT-112 and the water-soluble polymer compound to water may be simultaneous or separate, and either may be first. This dissolution process is preferably performed as quickly as possible to prevent decomposition of CT-112. Further, the water-soluble polymer compound may be used in advance dissolved in water,
By doing so, the dissolution time can be reduced. The pH of the aqueous solution is 8 or more, preferably 10-13. If the pH is too high, decomposition of CT-112 occurs, which is not preferable. In addition, when the pH is less than 8, the CT-
It takes a long time to dissolve 112, which is not preferable. In this case, the concentration of CT-112 is usually 0.5 w / v% or more,
Preferably, the concentration of the water-soluble polymer compound is from 0.01 to 10 w / v%, preferably from 0.01 to 10 w / v%, and preferably from 0.02 to 5 w / v%.
It is preferable to adjust to 5.0 w / v%. The pH is adjusted by adding an alkali compound. Examples of the alkali compound include salts such as borax, sodium carbonate, trisodium phosphate and trisodium citrate, which exhibit alkalinity when dissolved in water, in addition to bases such as sodium hydroxide and potassium hydroxide. Next, while stirring the aqueous solution thus obtained, acid is gradually added dropwise thereto to adjust the pH of the solution to 7 or less, preferably to about 4 to 6, to precipitate crystals of CT-112, Obtain a suspension. The stirring is preferably performed 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 those that exhibit acidity when dissolved in water, such as sodium dihydrogen phosphate and sodium dihydrogen citrate. Thus, the CT-112 having a uniform particle size of 10 μm or less is used.
An aqueous suspension of fine crystals of By adding chlorobutanol, benzalkonium chloride and / or paraoxybenzoate as a preservative and water as needed, the proportion of each component is adjusted to a predetermined concentration to obtain the aqueous suspension of the present invention. it can.

[0007] The aqueous suspension of the present invention may further contain CT-11 unless the object of the present invention is impaired.
In addition to 2, the same or different medicinal ingredients may be contained, and if necessary, other additives may be blended to provide, for example, eye drops. In the case of eye drops, in addition to the above-mentioned components, additives usually blended with 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 regulators (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 alone 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 do not limit the scope of the present invention.

[0008]

EXAMPLE 1 Sodium hydroxide (1.4%) was added to about 200 ml of sterilized purified water.
g) and sodium acetate (2 g) were completely dissolved, and CT-112 (10 g) was added thereto to completely dissolve. 200 ml of a solution in which HPMC (2 g) was dissolved was added to this solution, and the solution was sterilized by filtration. The pH of this solution was 11.7.
To this solution, sterilized 0.5N hydrochloric acid was gradually added dropwise while stirring to adjust the pH to 5.5. To this solution were added separately prepared concentrated glycerin (88 g), methyl paraoxybenzoate (1 g), HPMC (2 g), and chlorobutanol (1 g).
2 g), sodium edetate (0.8 g) and sodium acetate (2 g) were dissolved and sterilized by filtration.
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 About 10 ml of sterilized purified water was treated with sodium hydroxide (0.07
g) and sodium acetate (0.1 g) were completely dissolved, and CT-112 (0.5 g) was added thereto to completely dissolve. A solution of HPMC (0.1 g) dissolved in this solution 10 m
and sterilized by filtration. The pH of this solution is 11.7
Met. To this solution, sterilized 0.5N hydrochloric acid was gradually added dropwise while stirring to adjust the pH to 5.5. To this solution, separately prepared concentrated glycerin (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 dissolved, and 350 ml of an aqueous solution sterilized by filtration was added.
Was adjusted to 5.5, and sterile purified water was added thereto to make a total volume of 500 ml.
And

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

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

Example 5 In about 20 ml of sterilized purified water, sodium hydroxide (0.14
g) and sodium acetate (0.2 g) were completely dissolved, and CT-112 (1 g) was added thereto to completely dissolve. To this solution, 20 ml of a solution in which HPMC (0.2 g) and HEC (0.05 g) were dissolved was added and sterilized by filtration. The pH of this solution was 11.7. To this solution, sterilized 0.5N hydrochloric acid was gradually added dropwise while stirring to adjust the pH to 4.0. To this solution was added sodium chloride (3
g), benzalkonium chloride (0.02 g), chlorobutanol (0.6 g), sodium edetate (0.08 g)
g) and sodium acetate (0.2 g) were dissolved, 250 ml of an aqueous solution 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 Examples] The irritation and foreign body sensation when the aqueous suspensions of Examples 1, 2, and 3 were 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 chlorobutanol was not used was used. Table 1 shows the results.

[Table 1]

When the control was instilled, individual differences were observed in irritation and foreign body sensation. However, when the aqueous suspensions of Examples 1, 2 and 3 were instilled, almost all humans suffered from irritation and foreign body sensation. I did not admit. This suggests that the irritation and the like of the eye drops at the time of instillation may cause individual differences in humans because subjective factors such as feeling of use are also taken into account.
It was found that irritation and foreign body sensation could be eliminated by adding chlorobutanol to the aqueous suspension of CT-112.

[0015]

According to 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.
Moreover, it is painless when administered as eye drops. Therefore, the aqueous suspension of the present invention can be advantageously used for the prevention and treatment of cataract, retinopathy, iris and ciliary disease caused by diabetes.

────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Katsuhiro Inada 1-35 Kita-Ochiai, Suma-ku, Kobe-shi, Hyogo Maison-Akiya 102 (56) References JP-A-5-186348 (JP, A) Kaihei 2-121920 (JP, A) (58) Field surveyed (Int. Cl. ⁶ , DB name) A61K 31/425 A61K 9/107 A61K 47/10 A61K 47/14

Claims (6)

(57) [Claims] (1) hydroxypropyl methylcellulose ,
Chlorobutanol and parahydroxybenzoate
Comprising a Le 5- (3-ethoxy -4-n-pentyloxyphenyl) aqueous ophthalmic suspension of fine crystals of thiazolidine-2,4-dione. 2. The aqueous ophthalmic suspension 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 content ratio of hydroxypropylmethylcellulose and 5- (3-ethoxy-4-n-pentyloxyphenyl) thiazolidine-2,4-dione is 0.001 to 5.0 w / respectively. v% and 0.01-5.0
The aqueous suspension ophthalmic solution according to claim 1, which is w / v%. 4. A chlorobutanol content of from 0.01 to 0.01.
The aqueous suspension ophthalmic solution according to claim 1, which is 1.0 w / v%. 5. The method according to claim 1, wherein the content of the paraoxybenzoic acid ester is
The aqueous ophthalmic suspension according to claim 1, which is 0.001 to 0.05 w / v%. 6. The aqueous suspension ophthalmic preparation according to claim 1, which is a hypoallergenic ophthalmic preparation for preventing and treating corneal disorders caused by diabetes.