JPH05186348A - Preparation of aqueous suspension agent - Google Patents

Abstract

PURPOSE:To provide a process for producing a stable aqueous suspension agent containing 5-(3-ethoxy-4-n-pentyloxyphenyl)thiazolidine-2,4-dione useful as an agent for the treatment of corneal disorder, etc. CONSTITUTION:A fine aqueous suspension agent of 5-(3-ethoxy-4-n- pentyloxyphenyl thiazolidine-2,4-dione is produced by dissolving 5-(-ethoxy-4-n- pentyloxyphenyl) thiazolidine-2, 4-dione and one or more kinds of polymers selected from polyvinyl alcohol, polyvinyl pyrrolidone, hydroxypropylmethy cellulose, methyl ellulose and hydroxyethyl cellulose in water to obtain an aqueous solution having pH of >=8 and adjusting the pH of the solution to <=7 by adding an acid.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing a stable aqueous suspension. More specifically, it is useful for the prevention and treatment of diabetic cataracts, corneal disorders, iris and ciliary body disorders, etc. 5
-(3-Ethoxy-4-n-pentyloxyphenyl)
It relates to a method for producing a stable aqueous suspension of thiazolidine-2,4-dione.

[0002]

2. Description of the Related Art 5- (3-Ethoxy-4-n-pentyloxyphenyl) thiazolidine-2,4-dione (hereinafter simply referred to as CT-112) which is a main component of an aqueous suspension prepared by the method of the present invention. Is a known compound having an aldose reductase inhibitory action, and has a preventive / therapeutic effect on chronic conditions such as diabetic cataract, neurological disease and retinopathy in mammals including humans (Japanese Patent Laid-Open Publication No. Sho. 57-28075) and that it has a therapeutic effect on iris / ciliary body disease (Japanese Patent Laid-Open No. 61-43114). CT-112 for the treatment and prevention of the above diseases
When an aqueous solution such as an eye drop or an injectable solution containing PT is to be produced, CT-112 is extremely difficult to dissolve in water in a pH range suitable for use as an eye drop or an injectable solution. It is necessary to prepare a suspension. However, when preparing an aqueous suspension of CT-112, the conventional method such as dispersing the bulk powder of CT-112 as it is or dissolving it in an appropriate solvent to prepare an aqueous suspension is preferred. , CT-112 aggregated, incorporated into bubbles during manufacturing, adsorbed on containers, etc.
It was extremely difficult to prepare a stable aqueous suspension of CT-112, because of the decrease in the content and poor dispersibility.

[0003]

Under these circumstances, the present inventors have made various studies to overcome the above drawbacks,
It was surprisingly found that a stable aqueous suspension without the above-mentioned drawbacks can be obtained by changing pH in the presence of a specific water-soluble polymer compound from an aqueous solution in which pH-adjusted CT-112 is dissolved. It was

[0004]

That is, the present invention is as follows. One or more selected from the group of aqueous polymer compounds consisting of polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropylmethylcellulose, methylcellulose and hydroxyethylcellulose, and 5- (3-ethoxy-4-n-pentyloxyphenyl) thiazolidine-2,4- Of fine 5- (3-ethoxy-4-n-pentyloxyphenyl) thiazolidine-2,4-dione characterized by adjusting the pH to 7 or less by adding an acid to an aqueous solution of pH 8 or more in which dione is dissolved. 1. A method for producing an aqueous suspension, and Fine 5- (3-ethoxy-4-n-pentyloxyphenyl) thiazolidine-having a particle size of 10 μm or less
It is an aqueous eye drop obtained by suspending 2,4-dione.

5 which is a medicinal component of the aqueous suspension of the present invention
-(3-Ethoxy-4-n-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. The aqueous suspension preparation of the present invention is produced as follows. First, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyl methylcellulose,
An aqueous solution having a pH of 8 or more in which one or more kinds selected from the group consisting of methyl cellulose and hydroxyethyl cellulose (hereinafter sometimes simply referred to as a water-soluble polymer compound) and CT-112 is dissolved is prepared. This aqueous solution may be prepared by mixing or dissolving CT-112 and a water-soluble polymer compound in water and then adjusting the pH, or by adding either one to water and adjusting the pH, and then adding and dissolving the other. Alternatively, CT-112 and the water-soluble polymer compound may be dissolved in an aqueous solution whose pH has been adjusted in advance. CT-112
The water-soluble polymer compound 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 CT-
It is preferably done as quickly as possible to prevent decomposition of 112. Further, as the water-soluble polymer compound, those dissolved in water in advance may be used, and by doing so, the dissolution time can be shortened.

Among the water-soluble polymer compounds, hydroxypropylmethyl cellulose is most preferable. Two or more water-soluble polymer compounds may be appropriately combined and used depending on the need and purpose. When used in combination of two or more, it is preferable to use hydroxypropylmethylcellulose and polyvinylpyrrolidone in combination, hydroxypropylmethylcellulose and polyvinyl alcohol in combination, and hydroxypropylmethylcellulose and hydroxyethylcellulose in combination. If necessary, the water-soluble polymer compound used in the present invention may be used in combination with another water-soluble polymer compound such as polyethylene glycol or sodium carboxymethyl cellulose.

The pH of the aqueous solution is 8 or more, preferably 10
It is 13. If the pH is too high, decomposition of CT-112 will occur, which is not preferable. If the pH is alkaline below 8, it takes time to dissolve CT-112, which is not preferable. The concentration of CT-112 is usually adjusted to 0.5 w / w% or more, preferably 2 to 5 w / w%. The concentration of the water-soluble polymer compound is usually adjusted to 0.1-10 w / w%, preferably 0.5-5 w / w%. 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 thus obtained aqueous solution, 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 obtain an aqueous suspension. In addition, stirring is CT-1
In order to avoid the incorporation of 12, it is preferable to avoid foaming as much as possible. Examples of the acid include acids such as hydrochloric acid, sulfuric acid, acetic acid, and phosphoric acid, as well as acids such as monosodium phosphate and monosodium citrate that exhibit acidity when dissolved in water. The aqueous suspension thus obtained is CT
Since the particle size of -112 is uniformly 10 µm or less, and the crystals thereof are hydrophilic and stable in water, an extremely stable aqueous suspension can be obtained. Also,
According to the production method of the present invention, since uniform fine particles can be easily prepared by changing the type and concentration of the water-soluble polymer compound, aseptic filtration becomes possible and stable without requiring aseptic raw material. It is also extremely advantageous in that an aqueous suspension can be obtained.

The aqueous suspension obtained by the production method of the present invention may be used as it is or by adding purified water to adjust the concentration of the components to be mixed, and if necessary, other additives may be blended and used as eye drops or injections. You can The concentration of CT-112 in the aqueous suspension varies depending on the type of target disease, the degree of its symptoms, the age / weight of the patient, the administration method, etc., but is usually 0.01 to 5 w / w%, preferably about 0. It is preferable to mix it in a ratio of about 05 to 1 w / w%.

The concentration of the water-soluble polymer compound in the aqueous suspension of the present invention varies depending on the concentration of CT-112 to be dispersed and the type and molecular weight of the water-soluble polymer compound, but it is usually about 0. 0.001 to 10 w / w%, preferably about 0.02 to 0.5 w / w%.

The aqueous suspension obtained by the production method of the present invention may further contain the same or different medicinal components in addition to CT-112 unless the purpose of the present invention is impaired. For example, in the case of eye drops, for example, a buffer which is usually added to conventional eye drops,
Isotonic agents [eg boric acid, salts (sodium chloride etc.), glycerin, sugars], preservatives (eg benzalkonium chloride, benzethonium chloride, cetylpiperidinium chloride, chlorobutanol, paraoxybenzoates, etc.) You may mix | blend. They may be used alone or in combination of two or more. The addition ratio of these in the eye drops is 0.05 to 2 w / w% for the buffer,
The isotonicity agent is usually about 5 w / w% or less, and the preservative is usually about 0.
It is preferable to mix them in an amount of about 001 to 0.5 w / w%.

[0012]

According to the method for producing an aqueous suspension of the present invention, CT-112 in the aqueous suspension has a particle size of 1 or less.
Since it is uniformly dispersed as particles having a particle size of 0 μm or less, it is possible to obtain an aqueous suspension agent which is stable for a long period of time and has no feeling of foreign matter. Therefore, the aqueous suspension of the present invention, diabetic cataract,
It can be advantageously used for the prevention and treatment of retinopathy, iris, ciliary body diseases and the like.

[0013]

EXAMPLES The present invention will be described in more detail below with reference to experimental examples and examples. [Experimental example 1] Examination of dispersant (1) Experimental method Sodium hydroxide 1 g and 5
-(3-Ethoxy-4-n-pentyloxyphenyl)
5 g of thiazolidine-2,4-dione was added and dissolved, and 500 ml of each dispersant having the concentration shown in Table 1 was added. While stirring this solution, 8N hydrochloric acid was added to adjust the pH to 5.5, and the solution was observed with a microscope.

[Table 1] (2) Results As a result, when polysorbate 80, HCO-60 and glycerin were used as dispersants, the crystal form of this compound was square and hydrophobic, whereas hydroxypurpyrumethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, hydroxy When ethyl cellulose and methyl cellulose were used as dispersants, the crystals were amorphous and hydrophilic. From the above results, it was confirmed that hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, hydroxyethylcellulose and methylcellulose as water-soluble polymer compounds are useful as dispersants.

[Experimental Example 2] Stability test Experimental method A 5 ml polypropylene container was filled with the formulation shown in Table 2 and 4 ° C, 15 ° C, 25 ° C, 30 ° C, 40 ° C and 50
It was left at ℃. After 2 months, the crystallinity and aggregates were observed and the particle size was measured. The above formulation was prepared as follows. HPMC, sodium hydroxide and this compound (CT-112) were completely dissolved in about 10 ml of purified water, and sterile filtration was performed. The pH of this solution was 12.2.
The pH was adjusted to 5.5 by gradually adding sterilized hydrochloric acid while stirring. To this solution was added 70 ml of an aqueous solution prepared by dissolving methyl paraoxybenzoate, sodium edetate, concentrated glycerin and sodium citrate and aseptically filtered, and sterilized purified water was added to make the total volume 100 ml.

[Table 2] Results The crystals of the compound (CT-112) had good dispersibility after 2 months at any temperature, and no aggregation was observed. From this result, it was confirmed that this formulation did not easily aggregate and was stable for a long period of time.

[Experimental Example 3] Stability by Additive The stability of the present compound by the additive was examined. First, a formulation was prepared by adding 10 ml of a double concentration of the formulation shown in Table 2 to 10 ml of a sterilized aqueous solution containing various additives shown below.

[Table 3] Experimental method The suspension aqueous solution of the above formulation was put in a 5 ml polypropylene container and subjected to a cycle test (5 ° C → 20 ° C → 40 ° C → 20 ° C.
Each 3 hours = 1 cycle) was performed. After 40 cycles, the crystal form and dispersion form of the present compound were observed and the particle size thereof was measured. As a result, it was found that all of them had no change in their crystal form and particle size and could be used as additives.

[Experimental Example 4] Experimental example 3 was added to the formulation shown in Table 2.
The same additives as in Example 1 were added, and the feeling of use of each eye drop was evaluated according to the following scores. The results were as follows.

[Table 4] From this result, it was found that none of the formulations had an irritating feeling.

Experimental Example 5 Purified water (Xm shown in Table 5)
l) Sodium hydroxide (0.5 g), hydroxypropyl methylcellulose (HPMC) (Y in Table 5
g) and CT-112 (1 g) were added and dissolved, and sterile filtration was performed. While stirring, 2N hydrochloric acid sterilized was gradually added dropwise to adjust the pH to 5.5. H in this liquid
PMC (Zg described in Table 5), methyl paraoxybenzoate (0.125 g) sodium edetate (0.05
g), concentrated glycerin (9.5 g) and sodium citrate (0.25 g) were dissolved and sterile filtered into an aqueous solution (8
0 ml), and then sterilized purified water to bring the total volume to 50
Formulations a, b and c were prepared as 0 ml. The feeling of use for each formulation was evaluated according to the criteria of Experimental Example 4. The results are as shown in Table 5.

[Table 5] From this result, CT-
It was found that when the concentration of 112 was 0.5 w / w% or more, an eye drop without irritation was obtained.

Example 1 0.8 g of sodium hydroxide and 1 g of sodium acetate were completely dissolved in about 200 ml of purified water, and 5- (3-ethoxy-4-n-pentyloxyphenyl) thiazolidine-2 was dissolved therein. , 4, -dione (5 g) was completely dissolved, 200 μl of 2.5 w / w% hydroxypropylmethylcellulose aqueous solution was added, and filter sterilization was performed. The pH of this solution was 11.7. Gradually add 1N hydrochloric acid sterilized while stirring to p
Adjusted to H5. To this solution, 20 g of concentrated glycerin and 0.3 g of methyl paraoxybenzoate were dissolved, and 700 ml of an aqueous solution obtained by aseptic filtration were added, and sterile purified water was further added to make a total volume of 1000 ml.

Example 2 2 ml of 1N sodium hydroxide and 5- (3-ethoxy-) were added to about 10 ml of purified water.
4-n-pentyloxyphenyl) thiazolidine-2,
After completely dissolving 0.25 g of 4, -dione and adding 10 ml of 10 w / w% polyvinyl alcohol, aseptic filtration was performed. The pH of this solution was 11.8. While stirring, 1 w / w% phosphoric acid sterilized was gradually added dropwise to adjust the pH to 5.5. To this solution, 4 g of mannitol and 0.005 g of benzalkonium chloride were dissolved, and 70 ml of an aqueous solution obtained by aseptic filtration was added, and sterile purified water was further added to make a total volume of 100 ml.

Example 3 220 μl of 0.2 N sodium hydroxide, 5 mg of sodium acetate and 5- (3-
Completely dissolve 12.5 mg of ethoxy-4-n-pentyloxyphenyl) thiazolidine-2,4, -dione
200 μl of 5 w / w% hydroxypropylmethyl cellulose aqueous solution was added, and sterile filtration was performed. The pH of this solution was 11.8. 0.5 N hydrochloric acid that had been sterilized while stirring was gradually added to this to adjust the pH to 5.5. Sodium edetate (1 mg) was dissolved in this solution, and sterile filtered aqueous solution (3.5 ml) was added, and sterile purified water was further added to make a total volume of 5 ml.

Claims (9)

[Claims] 1. One or more selected from the group of water-soluble polymer compounds consisting of polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropylmethylcellulose, methylcellulose and hydroxyethylcellulose, and 5-
A fine 5- (3) characterized in that the pH is adjusted to 7 or lower by adding an acid to an aqueous solution of (3-ethoxy-4-n-pentyloxyphenyl) thiazolidine-2,4-dione dissolved therein and having a pH of 8 or higher. A process for producing an aqueous suspension of -ethoxy-4-n-pentyloxyphenyl) thiazolidine-2,4-dione. 2. A water-soluble polymer compound in an aqueous solution and 5-
The content ratio of (3-ethoxy-4-n-pentyloxyphenyl) thiazolidine-2,4-dione was 0.
The method for producing an aqueous suspension according to claim 1, wherein the amount is 1 to 10 w / w% and 0.5 w / w% or more. 3. The method for producing an aqueous suspension according to claim 1, wherein the selected water-soluble polymer compound is hydroxypropylmethyl cellulose. 4. The method for producing an aqueous suspension according to claim 1, wherein the selected water-soluble polymer compounds are hydroxypropylmethylcellulose and polyvinylpyrrolidone. 5. The method for producing an aqueous suspension according to claim 1, wherein the selected water-soluble polymer compound is hydroxypropylmethyl cellulose and polyvinyl alcohol. 6. The method for producing an aqueous suspension according to claim 1, wherein the selected water-soluble polymer compounds are hydroxypropylmethyl cellulose and hydroxyethyl cellulose. 7. The pH of the aqueous solution is 10 to 13.
A method for producing the aqueous suspension described. 8. The method for producing an aqueous suspension according to claim 1, wherein the pH is adjusted to 4 to 6 by adding an acid. 9. A fine 5- (3-) having a particle diameter of 10 μm or less.
Aqueous eye drops prepared by suspending ethoxy-4-n-pentyloxyphenyl) thiazolidine-2,4-dione