The method of preparation of the aqueous slurry and water ocular drug

 

(57) Abstract:

Stable aqueous suspension, which is especially suitable for eye drops in the treatment of keratopathy and other diseases, contains 5-(3-ethoxy-4-n-pentyloxide)thiazolidin-2,4-dione can be prepared by adding acid to the aqueous solution containing one or more compounds selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, oksipropilmetiltselljulozy, methylcellulose and acetylcellulose, and 5-(3-ethoxy-4-n-pentyloxide)thiazolidin-2,4-dione, and having a pH value of not less than 8, the purpose of regulation of this aqueous solution to a pH not higher than 7. 2 S. and 4 C.p. f-crystals, 5 PL.

The invention relates to pharmaceutical industry and relates to a method of making a stable aqueous suspension. More specifically, the invention relates to a method for producing a stable aqueous suspension of 5-(3-ethoxy-4-n-pentyloxide) thiazolidin-2,4-dione, which is used for the prevention and treatment among diabetic cataract, keratopathy and diseases of the iris and eyelashes.

The active ingredient of the aqueous suspension obtained by the method according to the invention, in particular, 5 the Association, having inhibitory activity to allocatedsize. It was shown that this compound has a preventive and therapeutic effects on chronic symptoms of diabetic cataracts, neuropathy and retinopathy in a mammal, including humans (Japanese patent application Kokai N 57-28075), and has therapeutic efficacy in diseases of the iris and cilia (Japanese patent application Kokai N 61-43114).

When you want to prepare an aqueous preparation of CT-112, such as eye drops or injection to treat or prevent the above diseases, requires suspending the compound in water, as ST-112 hardly soluble in water in the pH range which is acceptable for drugs topical application or injection.

However, if such an aqueous suspension is prepared by conventional pharmaceutical procedure, for example, by dispersing the powder mass CT-112 directly in water or by dissolving it in a suitable solvent and then transfer this solution into aqueous suspension, which is a consequence of this aggregation CT-112 or its capture by the foam during the manufacturing process or the adsorption is carried CT-112 on the wall of the container will result in a decrease in the content and protctive with this, the authors of the present invention have conducted research in this field of technology in order to overcome the above disadvantages and miraculously found stable suspension in water, is free from the above disadvantages can be successfully prepared, resulting in a gain aqueous solution of CT-112, pH of which had previously regulated to a certain value, and then adjust the pH of the specified aqueous solution in the presence of certain water-soluble macromolecular compound.

The object of the present invention is.

1. A method of obtaining a water suspension of finely powdered 5-(3-ethoxy-4-n-pentyloxide)-thiazolidin-2,4-dione, characterized by adding acid to the aqueous solution obtained by dissolving one or more elements selected from the group of water-soluble macromolecular compounds consisting of polyvinyl alcohol, polyvinylpyrrolidone, oksipropilmetiltselljulozy, methylcellulose and acetylcellulose and 5-(3-ethoxy-4-n-pentyloxide) thiazolidin-2,4-dione in water and having a pH value of not less than 8, in order to regulate the specified aqueous solution to a pH not higher than 7, and

2. Aqueous ophthalmic preparation for topical application, which is a suspension of the finely crushed 5-(3-ethoxy-4-n-pentyloxide) thiazolidin-2,4-dione, having a particle diameter of not more than 10 μm.

The obtaining of aqueous suspensions according to the present invention can be implemented as follows. First, prepare an aqueous solution having a pH of at least 8, one or more compounds selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, oksipropilmetiltselljulozy, methylcellulose and acetylcellulose (hereinafter sometimes collectively referred to as water-soluble macromolecular compound), and CT-112.

This is the preparation of an aqueous solution can be conducted by mixing or dissolving CT-112 and a water-soluble macromolecular compounds in water, and then by adjusting the pH of the solution or alternatively by adding one of these ingredients to the water, the regulation of the pH of the solution and then add and dissolve the other ingredients. So the pre-regulated to the desired level. Timing of the addition of CT-112 and the specified water-soluble macromolecular compound may be a choice of single or stepped, and in the latter case, any that may take place earlier. This process of dissolution is preferably performed as soon as possible to avoid decomposition of CT-112. Water-soluble macromolecular compound may be represented in the form of pre-dissolved in water, resulting in its dissolution may be reduced.

Of the above water-soluble macromolecular compounds the most preferred oksipropilmetiltselljulozy. Depending on the need and intended use of the above-mentioned water-soluble macromolecular compounds may be used in appropriate combination. When used in combination of two or more different water-soluble macromolecular compounds, preferred combinations, for example, oksipropilmetiltselljulozy-vinylpyrrolidone, oksipropilmetiltselljuloza-polyvinyl alcohol and oksipropilmetiltselljulozy-acetylcellulose. If necessary, these water-soluble macromolecular compounds according to the present invention can be COI is Col, sodium carboxymethyl cellulose, etc.

the pH of an aqueous solution of not less than 8 and preferably in the range from 10 to 13. Any pH value, excessive in relation to the specified range is undesirable because it can cause decomposition of CT-112. On the alkaline side, i.e. at a pH below 8, the dissolution of CT-112 is undesirable for a long time.

The concentration of CT-112 in the solution is usually not lower than 0.5 weight. and preferably from 2 to 5 weight.

The concentration of water-soluble macromolecular compound is usually from 0.1 to 10 weight. and preferably from 0.5 to 5 weight.

Regulation of pH is performed by adding alkaline compounds. The above-mentioned alkaline compound includes not only the base, such as caustic soda, caustic potash, etc. and salts, which dissolve in water to obtain alkaline solutions, such as pyramidically sodium, sodium carbonate, trisodium phosphate, trinatriytsitrat etc.

While stirring the thus obtained solution gradually add acid to regulate the solution to a pH not higher than 7, preferably from about 4 to about 6, resulting in ST-112 crystallization to obtain a water suspension. Mixing preferably the PTA includes not only a number of acids, such as hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid and so on, but such compounds that dissolve in water, giving acidic solutions, such as mononitrite, mononitriles etc.

Particles of CT-112 in the resulting suspension are uniform in size and not exceed 10 μm. In addition, the crystals are hydrophilic and stable in the water. Therefore, this suspension is very stable. In addition, as in the present invention can easily be obtained uniformly small particles by adjusting the type and/or concentration of the water-soluble macromolecular compound, the suspension may be sterilized by filtration, and because it means that it is not necessary to use sterile raw materials, stable aqueous suspension can be prepared with great advantage.

Aqueous suspension prepared by the method according to the present invention may be used either in the same form as it is received, or after adjusting the concentration of purified water and/or optionally adding other additives, such as ocular drug for topical application, injection, or other similar to the The proper concentration of CT-112 in aqueous suspensions depends on the type of disease, you want to be treated, on the severity of the clinical condition, the patient's age and body weight, route of administration, etc. but it is generally recommended to use CT-112 at a concentration of in General from 0.01 to 5 weight. and preferably from about 0.5 to 1 wt.

While the concentration of the specified water-soluble macromolecular compounds in aqueous suspensions depends on the concentration of CT-112, which is to be atomized, the type and molecular weight water-soluble macromolecular compounds, etc. it is recommended to use this connection in a concentration of generally from 0.001 to 1 weight. and preferably from 0.02 to 0.5 weight.

In aqueous suspensions obtained by the method according to the invention may be incorporated, if necessary, and without contradiction to the purposes of the invention other pharmacologically active compounds of the same type or of different types.

When the aqueous suspension should be used as an eye medicine for dropping, it can be incorporated various additives that are commonly used in ocular preparations for local application, such as buffers, isotherwise agents (for example, boric acid, salts (sodium chloride, and so on), glycerin, sugar is butanol, esters of para-hydroxy-benzoic acid and so on). Each of these additives can be used without additives or in combination with two or more types. The proportions of these additives in the final ocular drug can be from 0.05 to 2 weight. for buffers, usually not more than about 5 weight. for isotherwise agents, and from about 0.001 to 0.5 weight. for preservatives.

The method of preparation of the aqueous slurry according to the present invention results in aqueous suspension, in which CT-112 uniformly dispersed in the form of fine particles less than 10 microns, and which remains stable over a long period of time, without giving you the feeling of a third-party body. Thus, the aqueous suspension according to the present invention can be used with great benefit in the prevention and treatment among diabetic cataracts, retinopathy and diseases of the iris and eyelashes.

The best variant embodiment of the invention.

The following experimental and working examples additionally illustrate the present invention.

Experimental example 1.

The study of the dispersant.

(1) Method.

In 100 ml of sterile is m by adding 500 ml of one of the dispersant, shown in the table.1. With stirring, this solution was added dropwise hydrochloric acid 8H to regulate the pH of the solution to 5.5.

This solution was analyzed under the microscope.

(2) the Results.

It was found that while the dispersed crystals of the active compound was in the form of a square and were hydrophobic in the case of the use of Polysorbate 80, HCO-60 or glycerol as a dispersant, they were amorphous and hydrophilic, when the dispersant was oksipropilmetiltselljuloza polyvinylpyrrolidone, polyvinyl alcohol, acetylcellulose or methylcellulose. The above results show that water-soluble macromolecular compounds, in particular oksipropilmetiltselljulozy, polyvinylpyrrolidone, polyvinyl alcohol, acetylcellulose and methylcellulose are useful dispersing agents according to the invention.

Experimental example 2.

The test of stability.

(1) Method.

The composition is shown in table.2, was injected in polypropylene vessels with a capacity of 5 ml and allowed to stand at 4,15,25,30,40 and 50oC. After 2 months these samples were analyzed for crystallinity and aggregation and changed the diameters of participation (CT-112) was carefully dissolved in about 10 ml of purified water and the solution was filtered through a bacterial filter. the pH of this solution was to 12.2. While stirring this solution dropwise slowly added hydrochloric acid to adjust the pH to 5.5. To this solution was added 70 ml of a solution obtained dissolved methyl pair of oxybenzoates, edetate sodium, concentrated glycerin and sodium citrate in water and filtering the solution through a bacterial filter. This mixture was further diluted with purified water to obtain the 100 ml.

(2) the Results.

If any of the above temperatures active connection remained uniformly dispersed, without exposure of adhesion, even after 2 months. In the result, it was found that the above composition is not easy undergoes aggregation and remains stable for an extended period of time.

Experimental example 3.

Stability depending on the additions.

The stabilizing effects of various additives on the active connection was rejected. First, the composition prepared by adding 10 ml of purified water containing one of the following additives, and 10 ml of double concentrate composition is shown in table.2.

Additives and concentrations of compounds pretty vessel with a capacity of 5 ml and subjected to cyclic testing (5 - 20 - 40 30oC, 3 h in each case on the cycle). After 40 cycles were analyzed crystalline form and dispersed state of the active connection, and also measured the diameter of the particles.

(2) the Results.

None of the suspensions showed no form of crystals or particles, which indicates the possibility of applying the above-mentioned additives.

Experimental example 4.

The portions of the structure of the table.2 added the same additives which were used in the experimental example 3, respectively, and summed up the feeling from the application of the obtained ocular preparations according to the evaluation criteria below.

The results are presented in table.4.

The above results showed that none of the drugs showed irritation.

Experimental example 5.

In sterile purified water (X ml in the table.5) dissolved sodium hydroxide (0.5 g), oxytropidoceras (OPMC) (Y g in the table.5) and CT-112 (1 g), and the solution was filtered through a bacterial filter. Under stirring solution dropwise slowly added 2N hydrochloric acid to adjust the pH to 5.5. To this solution was added an aqueous solution (80 ml), prepared by solution and sodium citrate (0.25 g) and filtering the solution through a bacterial filter. This mixture was further diluted with sterile purified water to obtain 500 ml of Thus obtained preparations a,b and C. the Feeling from the use of these drugs was evaluated according to the same evaluation criteria as that used in experimental example 4.

The results are shown in table.5.

Thus, it was shown that when the concentration of CT-112 before adding acid is not less than 0.5 weight. the obtained ocular drug is not irritating.

Example 1.In about 200 ml of purified water was carefully dissolved 0.8 g sodium hydroxide and 1 g of sodium acetate. Then added 5 g of 5-(3-ethoxy-4-n-pentyloxide) thiazolidin-2,4-dione and thoroughly dissolved in the above solution. After this was added 200 μl of 2.5% (weight/weight) aqueous solution of oksipropilmetiltselljulozy and the mixture was filtered through a bacterial filter. the pH of this solution was 11.7. While stirring this solution dropwise slowly added hydrochloric acid 1H to regulate the pH to 5. To this solution was added 700 ml of an aqueous solution prepared by dissolving 20 g of concentrated glycerin and 0.3 g methyl para-hydroxy-benzoate and filtering the resulting solution through a bacterial filter, with posledeistvii 2 ml of sodium hydroxide 1H and 0.25 g of 5-(3-ethoxy-4-n-pentyloxide)-thiazolidin-2,4-dione. Then add 10 ml of 10% (weight/weight) of polyvinyl alcohol and the mixture was filtered through a bacterial filter. the pH of the solution was 11.8. With stirring, this solution was added dropwise 1 weight. phosphoric acid to regulate the pH of the solution to 5.5. To this solution was added 70 ml of an aqueous solution, prepared by dissolving 4 g of mannitol and 0.005 g of benzalkonium chloride in water and filtering the resulting solution through a bacterial filter, followed by the addition of purified water to make 100 ml.

Example 3.To a homogeneous solution consisting of 220 ál of sodium hydroxide of 0.2 H, 5 mg of sodium acetate and 12.5 mg of 5-(3-ethoxy-4-n-pentyloxide) thiazolidin-2,4-dione, was added 200 μl of 25% (weight/weight) aqueous solution of oksipropilmetiltselljulozy, and the mixture was filtered through a bacterial filter. the pH of this solution was 11.8. While stirring this solution by drops gradually added hydrochloric acid for 0.5 H to regulate the pH to 5.5. To this solution was added 3.5 ml of an aqueous solution prepared by adding 1 mg of sodium acetate and filtering the resulting solution through a bacterial filter, followed by the addition of purified water to obtain 5 ml

1. Method of preparation of the aqueous spilota added to aqueous solution of micronized 5-(3-ethoxy-4-n-pentyloxide)thiazolidin-2,4-dione, having a pH value of not lower than 8, to bring the pH to a value not higher than 7, in the presence of one or more water-soluble macromolecular compounds selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropylmethylcellulose, methyl cellulose and hydroxyethyl cellulose.

2. The method according to p. 1, wherein the water-soluble macromolecular compound is in a state of aqueous solution.

3. The method according to p. 1, characterized in that the concentration of 5-(3-ethoxy-4-n-pentyloxide)thiazolidin-2,4-dione is not less than 0.5 wt.

4. The method according to p. 2, characterized in that the concentration vodorastvorimogo macromolecular compounds is 0.1 to 10.0 wt.

5. The method according to p. 1, wherein the water-soluble macromolecular compound is a hypromellose, a mixture of polyvinylpyrrolidone and hydroxypropylmethylcellulose, a mixture of polyvinyl alcohol and hydroxypropylmethylcellulose or a mixture of hydroxyethyl cellulose and hydroxypropylmethylcellulose.

6. Aqueous ophthalmic preparation for topical application, characterized in that it is a suspension containing 0.5 wt. thin

 

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