KR20040085694A - A process for the preparation of a liquid formulation comprising amprolium, sulfaquinoxaline, and ethopabate - Google Patents

Abstract

PURPOSE: Provided is a process for the preparation of a liquid formulation comprising amprolium, sulfaquinoxaline, and ethopabate, without the generation of precipitates or floats. The prepared formulation keeps its won efficacy and stability even orally administered into livestock. CONSTITUTION: The process for the preparation of a liquid formulation containing amprolium, sulfaquinoxaline, and ethopabate comprises the steps of: (a) adding sodium hydroxide or potassium hydroxide to sodium sulfaquinoxaline; (b) adding N-methylpyrrolidone or dimethylsulfoxide to the solution obtained in the step(a), followed by dissolution; (c) adding amprolium hydrochloride to the solution obtained in the step(b), followed by dissolution; and (d) dissolving ethopabate in N-methylpyrrolidone or dimethylsulfoxide, followed by addition to the solution obtained in the step(c).

Description

A process for the preparation of a liquid formulation comprising amprolium, sulfaquinoxaline, and ethopabate}

The present invention relates to a process for the preparation of liquid formulations containing ampprolium, sulfaquinoxaline, and etopabate.

Amprolium hydrochloride, sodium sulfaquinoxaline, and ethopabate are useful as coccidiostats in animal medicines such as livestock.

In order to effectively suppress livestock coccidiosis, it is generally known that the combination of amprolium hydrochloric acid and sodium sulfaquinoxaline is used as two kinds of mixed drugs, and it is also preferable to use 3 of amplolium, sulfaquinoxaline, and etopabate. The use of a combination of species may result in a greater synergistic effect at lower doses than the two combinations of amprolium and sulfaquinoxaline, as well as to reduce the side effects and toxicity of sulfaquinoxaline (causing new stones). It is known that there is. At present, a mixed powder formulation of amprolium hydrochloric acid and sulfaquinoxaline sodium or a mixed powder formulation of amprolium hydrochloric acid, sulfaquinoxaline sodium and etopabate is commercially available.

On the other hand, in the case of using the two or three kinds of mixed powder formulations, the preparation is dissolved by stirring in a small amount of water, and then used to prepare a desired concentration by adding water or livestock drinking water secondarily. Therefore, the use thereof is inconvenient, and there is a problem that precipitation or entanglement occurs by not completely dissolving the powder formulation.

In order to overcome the problems of the mixed powder formulation, Korean Patent Laid-Open Publication No. 2001-53872 discloses a liquid formulation containing amprolium hydrochloric acid and sulfaquinoxaline sodium. According to the prior art, the pH is adjusted to neutral (about pH 7) by dissolving amprolium hydrochloric acid in purified water and then adding sodium or potassium hydroxide, and dissolving sodium sulfaquinoxaline therein, followed by polysorbate, glycerol After adding a dissolution aid and the like, purified water is added to adjust the pH to 9 to 11 to prepare a liquid formulation.

However, when preparing a liquid formulation according to the prior art, when sodium hydroxide or potassium hydroxide is added to an aqueous solution of amprolium hydrochloric acid to adjust to neutral pH, the amprolium precipitates immediately and becomes turbid, and sulfaquinoxaline sodium is added thereto. Precipitation is then accelerated, resulting in the entire solution turning into a paste. In addition, even if a dissolution aid such as polysorbate is added thereto and water is added again, a problem that cannot be produced as a liquid formulation occurs.

Furthermore, when preparing three mixed liquid formulations of amprolium, sulfaquinoxaline, and etopabate, etopabate is a poorly water-soluble drug, unlike amprolium hydrochloric acid and sulfaquinoxaline sodium, which have high solubility in water. Therefore, it cannot be dissolved in an aqueous solution containing ampprolium and sulfaquinoxaline and thus cannot be prepared as a liquid formulation. In addition, even if the etopabate is dissolved in a solvent such as methanol, ethanol, acetone, acetonitrile, and added to an aqueous solution containing amprolium and sulfaquinoxaline to prepare a liquid phase, the etopabate is diluted when water is added for final use. Problem occurs that precipitates again or floats are generated.

Accordingly, the present inventors have conducted research to develop an improved method for preparing a liquid formulation containing ampprolium, sulfaquinoxaline, and etopabate. Thus, an aqueous sulfaquinoxaline aqueous alkali solution is prepared first, and then N- as a stabilizer. After adding methylpyrrolidone or dimethyl sulfoxide, an aqueous solution of amprolium hydrochloric acid is added, and then dissolving etopabate in the stabilizer to find that a transparent and stable liquid formulation can be prepared to complete the present invention. It became.

Accordingly, an object of the present invention is to provide a method for producing a liquid formulation containing ampprolium, sulfaquinoxaline, and etopabate.

In order to achieve the above object, the present invention comprises the steps of (a) adding sodium hydroxide or potassium hydroxide to an aqueous sulfaquinoxaline sodium solution; (b) adding N-methylpyrrolidone or dimethyl sulfoxide to the solution obtained in step (a) to dissolve it; (c) adding an aqueous solution of amprolium hydrochloric acid to the solution obtained in step (b) to dissolve it; And (d) dissolving etofabate in N-methylpyrrolidone or dimethylsulfoxide, and adding the solution to the solution obtained in step (c) to dissolve it, including amprolium, sulfaquinoxaline, and etopabate. It provides a method for producing a liquid formulation.

In addition, the present invention comprises the steps of (a) adding sodium hydroxide or potassium hydroxide to an aqueous sulfaquinoxaline sodium solution; (b) dissolving etofabate in N-methylpyrrolidone or dimethylsulfoxide and adding it to the solution obtained in step (a); And (c) adding an aqueous solution of amprolium hydrochloric acid to the solution obtained in step (b) to dissolve it, thereby providing a method for preparing a liquid formulation containing ampprolium, sulfaquinoxaline, and etopabate.

In addition, the production method of the present invention may further comprise the step of adding ascorbic acid (ascorbic acid), preferably ascorbic acid in the last step, the amount of ascorbic acid is used in the liquid formulation 1 to 5% by weight relative to the total weight is preferred.

In the preparation method of the present invention, the amount of sodium hydroxide or potassium hydroxide is preferably 1 to 5% by weight based on the total weight of the liquid formulation, and the amount of N-methylpyrrolidone or dimethyl sulfoxide is 20 to the total weight of the liquid formulation. 45 weight% is preferable. In addition, the total amount of amprolium hydrochloric acid, sulfaquinoxaline sodium, and etopabate is preferably 5 to 45% by weight based on the total weight of the liquid formulation, and the amount of sulfaquinoxaline sodium and etopabate is 100 parts by weight of amprolium hydrochloride. 25-100 weight part and 1-10 weight part are preferable, respectively.

Hereinafter, the present invention will be described in more detail.

In step (a), sulfaquinoxaline sodium has a high solubility in water, so that an aqueous solution can be easily prepared, and the pH of the solution is weakly alkaline. When a strong alkaline substance such as sodium hydroxide or potassium hydroxide is added thereto, the pH of the solution ranges from about 8 to 12. In the production method of the present invention, the amount of sodium hydroxide or potassium hydroxide is preferably 1 to 5% by weight based on the total weight of the liquid formulation.

When N-methylpyrrolidone or dimethyl sulfoxide is added to the alkaline aqueous solution of sulfaquinoxaline, it is easily dissolved to obtain a transparent solution. Here, N-methylpyrrolidone or dimethyl sulfoxide can be effectively mixed with water under alkaline conditions, and sulfaquinoxaline sodium or even if diluted to a predetermined concentration when using a liquid preparation prepared according to the preparation method of the present invention. In addition, since the mixed Amprolium hydrochloric acid or etopabate does not precipitate, it is possible to maintain the stability of the liquid formulation. In the production method of the present invention, the amount of N-methylpyrrolidone or dimethyl sulfoxide is preferably 20 to 45% by weight based on the total weight of the liquid preparation.

In the preparation method of the present invention, etopabate is added by dissolving in N-methylpyrrolidone or dimethyl sulfoxide, and some N-methylpyrrolidone or dimethyl sulfoxide is added in advance to add amprolium hydrochloric acid and sulfaquinoxaline sodium. To prepare a liquid formulation containing a solution prepared by adding N-methylpyrrolidone or dimethyl sulfoxide solution of etopabate, or N-methylpyrrolidone or dimethyl of etopabate in aqueous solution of sulfaquinoxaline A sulfoxide solution may be added followed by an aqueous solution of amprolium hydrochloric acid to prepare a liquid formulation. When some N-methylpyrrolidone or dimethyl sulfoxide is previously added, the amount is preferably 10 to 30% by weight based on the total weight of N-methylpyrrolidone or dimethyl sulfoxide added to the liquid formulation.

Therefore, N-methylpyrrolidone or dimethyl sulfoxide used in the preparation method of the present invention not only serves as a solvent for effectively dissolving etopabate, but also when diluted with water, amprolium hydrochloric acid and etopabate Since it does not precipitate, it also serves as a stabilizer to maintain the stability of the liquid formulation.

Amprolium hydrochloric acid aqueous solution can be prepared by easily dissolving in water because the aqueous solution of amprolium hydrochloric acid is high.

In the production method of the present invention, it is preferable that the amount of amprolium hydrochloric acid, sulfaquinoxaline sodium, and etopabate is 5 to 45% by weight based on the total weight of the liquid formulation, and the amount of sulfaquinoxaline sodium and etopabate is used. 25-100 weight part and 1-10 weight part are preferable with respect to 100 weight part of amprolium hydrochloric acid, respectively.

In addition, the production method of the present invention may include the step of adding ascorbic acid (ascorbic acid). The ascorbic acid may not only provide an immune enhancing effect and nourish the animal by itself, but also exhibit an unexpected effect of enhancing the stability of the liquid preparation according to the present invention.

In the preparation method of the present invention, the step of adding ascorbic acid may be preferably performed at any stage of the preparation step, but considering the stability of ascorbic acid, it is preferable to add ascorbic acid after performing the final step. Although the amount of ascorbic acid used is not particularly limited, in order to effectively increase the stability of the liquid preparation prepared according to the preparation method of the present invention, at least 1% by weight based on the total weight of the liquid preparation, and preferably the total weight of the liquid preparation. It is preferable that it is 1 to 5 weight% with respect to.

The liquid preparation prepared by the preparation method may add a preservative such as methyl-4-hydroxybenzoate or propyl 4-hydroxybenzoate, and may be diluted to a predetermined concentration by adding water if necessary.

When preparing a liquid formulation according to the production method of the present invention, it is possible to prepare a stable liquid formulation without precipitation or the formation of suspended solids, it is possible to maintain the effectiveness and stability even when administered in the form of oral negative to livestock.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the present invention is not limited by the examples.

Example 1.

200 L of purified water was added to a 1,000 L reactor, 200 kg of sulfaquinoxaline sodium was added with stirring, and stirred for 30 minutes. Then, 40 kg of sodium hydroxide was added to dissolve it. While stirring the obtained solution, the solution which melt | dissolved 10 kg of etopatate was added to 200 L of N-methylpyrrolidone, and the solution which melt | dissolved 200 kg of amprolium hydrochloric acid # 200kg in purified water was gradually added. Purified water was added to the resulting solution so that the final volume was 1,000L.

Example 2.

200 L of purified water was added to a 1,000 L reactor, 200 kg of sulfaquinoxaline sodium was added with stirring, and stirred for 30 minutes. Then, 40 kg of sodium hydroxide was added to dissolve it. While stirring the obtained solution, 180 L of N-methylpyrrolidone was added, and the solution which melt | dissolved 200 kg of Amprolium hydrochloric acid # 200kg in 200L of purified water was added gradually. A solution of 10 kg of etopabate was added to 20 L of N-methylpyrrolidone, and then purified water was added so that the final volume was 1,000 L.

Examples 3-9.

Next to prepare a liquid formulation in the same manner as in Example 2 in the content of Table 1, all the prepared liquid formulations represented a transparent liquid.

Example Amprolium hydrochloride (kg) Sulfaquinoxaline Sodium (kg) Etopabate (kg) Alkalizing agent (kg) Stabilizer (L) Total amount (L) 3 200 150 10 Sodium Hydroxide (40) N-methylpyrrolidone (200) 1000 4 200 100 10 Sodium Hydroxide (40) N-methylpyrrolidone (200) 1000 5 200 50 10 Sodium Hydroxide (40) N-methylpyrrolidone (200) 1000 6 200 200 10 Potassium Hydroxide (40) N-methylpyrrolidone (200) 1000 7 200 150 10 Potassium Hydroxide (40) N-methylpyrrolidone (200) 1000 8 200 100 10 Potassium Hydroxide (40) N-methylpyrrolidone (200) 1000 9 200 50 10 Potassium Hydroxide (40) N-methylpyrrolidone (200) 1000

Examples 10 to 17.

Next, the liquid formulation was prepared in the same manner as in Example 2 with the content of Table 2, and all of the prepared liquid formulations exhibited transparent liquid phases.

Example Amprolium hydrochloride (kg) Sulfaquinoxaline Sodium (kg) Etopabate (kg) Alkalizing agent (kg) Stabilizer (L) Total amount (L) 10 200 200 10 Sodium Hydroxide (50) N-methylpyrrolidone (200) 1000 11 200 150 10 Sodium Hydroxide (30) N-methylpyrrolidone (300) 1000 12 200 100 10 Sodium Hydroxide (20) N-methylpyrrolidone (400) 1000 13 200 50 10 Sodium Hydroxide (10) N-methylpyrrolidone (450) 1000 14 200 200 10 Potassium Hydroxide (50) N-methylpyrrolidone (200) 1000 15 200 150 10 Potassium Hydroxide (30) N-methylpyrrolidone (300) 1000 16 200 100 10 Potassium Hydroxide (20) N-methylpyrrolidone (400) 1000 17 200 50 10 Potassium Hydroxide (10) N-methylpyrrolidone (450) 1000

Examples 18-25.

Next, a liquid formulation was prepared in the same manner as in Example 2, the content of Table 3, and all of the prepared liquid formulations showed a transparent liquid phase.

Example Amprolium hydrochloride (kg) Sulfaquinoxaline Sodium (kg) Etopabate (kg) Alkalizing agent (kg) Stabilizer (L) Total amount (L) 18 200 200 10 Sodium Hydroxide (50) Dimethyl sulfoxide (200) 1000 19 200 150 10 Sodium Hydroxide (30) Dimethyl sulfoxide (300) 1000 20 200 100 10 Sodium Hydroxide (20) Dimethyl sulfoxide (400) 1000 21 200 50 10 Sodium Hydroxide (10) Dimethyl sulfoxide (450) 1000 22 200 200 10 Potassium Hydroxide (50) Dimethyl sulfoxide (200) 1000 23 200 150 10 Potassium Hydroxide (30) Dimethyl sulfoxide (300) 1000 24 200 100 10 Potassium Hydroxide (20) Dimethyl sulfoxide (400) 1000 25 200 50 10 Potassium Hydroxide (10) Dimethyl sulfoxide (450) 1000

Examples 26-33.

Except for adding ascorbic acid before adjusting the final volume by adding purified water, the liquid formulation was prepared in the same manner as in Example 2, the content of the following Table 4, all the prepared liquid formulations represented a transparent liquid.

Example Amprolium hydrochloride (kg) Sulfaquinoxaline Sodium (kg) Etopabate (kg) Ascorbic acid (kg) Alkalizing agent (kg) Stabilizer (L) Total amount (L) 26 200 200 10 50 Sodium Hydroxide (50) N-methylpyrrolidone (200) 1000 27 200 150 10 30 Sodium Hydroxide (30) N-methylpyrrolidone (300) 1000 28 200 100 10 20 Sodium Hydroxide (20) N-methylpyrrolidone (400) 1000 29 200 50 10 10 Sodium Hydroxide (10) N-methylpyrrolidone (450) 1000 30 200 200 10 50 Potassium Hydroxide (50) N-methylpyrrolidone (200) 1000 31 200 150 10 30 Potassium Hydroxide (30) N-methylpyrrolidone (300) 1000 32 200 100 10 20 Potassium Hydroxide (20) N-methylpyrrolidone (400) 1000 33 200 50 10 10 Potassium Hydroxide (10) N-methylpyrrolidone (450) 1000

Example 34. Stability Test

The liquid preparations prepared in Examples 1 and 26 were divided into three groups (n = 3), and the liquid preparations of each group were stored in airtight containers for 6 months at room temperature and 40 ° C, respectively. , And contents were measured at 2, 4, and 6 months, and the results are shown in Tables 5, 6, 7, and 8 below.

group Archive Characteristics over time Early 2 months later 4 months later 6 months later First group Room temperature Example 1 partridge fitness fitness fitness Example 26 partridge fitness fitness fitness 40 ℃ Example 1 partridge fitness fitness fitness Example 26 partridge fitness fitness fitness 2nd group Room temperature Example 1 partridge fitness fitness fitness Example 26 partridge fitness fitness fitness 40 ℃ Example 1 partridge fitness fitness fitness Example 26 partridge fitness fitness fitness Third group Room temperature Example 1 partridge fitness fitness fitness Example 26 partridge fitness fitness fitness 40 ℃ Example 1 partridge fitness fitness fitness Example 26 partridge fitness fitness fitness

group Archive Share according to elapsed period Early 2 months later 4 months later 6 months later First group Room temperature Example 1 1.05 1.04 1.04 1.05 Example 26 1.05 1.05 1.05 1.05 40 ℃ Example 1 1.05 1.05 1.04 1.05 Example 26 1.05 1.05 1.05 1.05 2nd group Room temperature Example 1 1.05 1.05 1.05 1.04 Example 26 1.05 1.05 1.05 1.05 40 ℃ Example 1 1.05 1.05 1.05 1.05 Example 26 1.05 1.05 1.05 1.05 Third group Room temperature Example 1 1.05 1.05 1.05 1.04 Example 26 1.05 1.05 1.05 1.05 40 ℃ Example 1 1.05 1.05 1.05 1.05 Example 26 1.05 1.05 1.05 1.05

group Archive PH over time Early 2 months later 4 months later 6 months later First group Room temperature Example 1 9.45 9.25 9.23 9.15 Example 26 9.47 9.43 9.45 9.44 40 ℃ Example 1 9.36 9.26 9.34 9.36 Example 26 9.35 9.34 9.37 9.35 2nd group Room temperature Example 1 9.25 9.22 9.24 9.23 Example 26 9.23 9.25 9.25 9.22 40 ℃ Example 1 9.28 9.26 9.27 9.31 Example 26 9.27 9.26 9.27 9.25 Third group Room temperature Example 1 9.52 9.43 9.45 9.31 Example 26 9.48 9.45 9.46 9.44 40 ℃ Example 1 9.47 9.42 9.33 9.29 Example 26 9.45 9.46 9.43 9.42

First group Archive Content over time Early 2 months later 4 months later 6 months later Amprolium hydrochloric acid Room temperature Example 1 104.3 103.2 102.7 100.7 Example 26 104.5 104.3 103.6 103.2 40 ℃ Example 1 103.2 102.8 101.2 99.8 Example 26 103.3 103.0 102.5 102.1 Sulfaquinoxaline sodium Room temperature Example 1 103.8 102.7 101.8 99.2 Example 26 103.7 103.3 102.7 102.5 40 ℃ Example 1 103.7 101.8 99.4 98.8 Example 26 103.5 102.7 102.6 101.7 Etopabate Room temperature Example 1 108.4 106.8 104.5 103.6 Example 26 108.4 107.5 106.4 106.0 40 ℃ Example 1 107.2 105.5 104.9 103.8 Example 26 106.9 106.1 105.4 104.8

2nd group Archive Content over time Early 2 months later 4 months later 6 months later Amprolium hydrochloric acid Room temperature Example 1 103.8 102.2 100.5 99.8 Example 26 103.5 102.9 102.4 101.6 40 ℃ Example 1 102.3 101.7 100.1 98.5 Example 26 102.2 101.5 100.8 100.7 Sulfaquinoxaline sodium Room temperature Example 1 103.5 102.8 100.8 99.2 Example 26 103.4 103.2 102.5 101.4 40 ℃ Example 1 103.4 102.1 99.8 98.7 Example 26 103.6 102.8 102.0 101.3 Etopabate Room temperature Example 1 106.4 104.7 103.5 102.6 Example 26 105.8 105.1 104.6 103.9 40 ℃ Example 1 105.2 104.2 103.7 101.7 Example 26 105.5 104.9 104.2 103.8

Third group Archive Content over time Early 2 months later 4 months later 6 months later Amprolium hydrochloric acid Room temperature Example 1 104.4 103.5 102.8 100.8 Example 26 104.5 103.8 103.3 102.6 40 ℃ Example 1 104.3 103.4 102.3 100.2 Example 26 104.7 104.3 103.5 102.4 Sulfaquinoxaline sodium Room temperature Example 1 103.5 102.8 101.9 99.4 Example 26 103.2 102.5 102.3 101.5 40 ℃ Example 1 103.6 102.6 101.3 99.2 Example 26 103.4 103.0 102.5 101.6 Etopabate Room temperature Example 1 105.7 105.5 103.4 102.8 Example 26 105.4 104.6 104.1 103.5 40 ℃ Example 1 105.2 104.6 102.1 101.7 Example 26 104.8 104.2 103.8 103.1

As can be seen from the stability test results, the liquid formulation according to the present invention maintains a high stability, especially when ascorbic acid is added it can be seen that the stability is higher.

According to the present invention, a method for preparing a liquid formulation containing amprolium, sulfaquinoxaline, and etopabate can be used to prepare a stable liquid formulation without precipitation or formation of suspended solids. Effectiveness and stability can be maintained.

Claims (11)

(a) adding sodium hydroxide or potassium hydroxide to an aqueous sulfaquinoxaline sodium solution; (b) adding N-methylpyrrolidone or dimethyl sulfoxide to the solution obtained in step (a) to dissolve it; (c) adding an aqueous solution of amprolium hydrochloric acid to the solution obtained in step (b) to dissolve it; And (d) a liquid containing amprolium, sulfaquinoxaline, and etopabate, which comprises dissolving etopabate in N-methylpyrrolidone or dimethylsulfoxide and adding it to the solution obtained in step (c). Method of Preparation of the Formulation. (a) adding sodium hydroxide or potassium hydroxide to an aqueous sulfaquinoxaline sodium solution; (b) dissolving etofabate in N-methylpyrrolidone or dimethylsulfoxide and adding it to the solution obtained in step (a); And (c) A method for producing a liquid formulation containing ampulolium, sulfaquinoxaline, and etopabate, comprising adding and dissolving an aqueous solution of amprolium hydrochloride to the solution obtained in step (b). The method of claim 1 comprising the step of adding ascorbic acid. The method of claim 2 comprising the step of adding ascorbic acid. The process according to claim 3 or 4, wherein ascorbic acid is added after carrying out the final step. The method according to claim 5, wherein the amount of ascorbic acid used is 1 to 5% by weight based on the total weight of the liquid formulation. The production method according to any one of claims 1 to 4, wherein the amount of sodium hydroxide or potassium hydroxide is 1 to 5% by weight based on the total weight of the liquid formulation. The production method according to any one of claims 1 to 4, wherein the amount of N-methylpyrrolidone or dimethyl sulfoxide is 20 to 45% by weight based on the total weight of the liquid formulation. The production method according to any one of claims 1 to 4, wherein the total amount of amprolium hydrochloric acid, sulfaquinoxaline sodium, and etopabate is 5 to 45% by weight based on the total weight of the liquid formulation. The preparation according to any one of claims 1 to 4, wherein the amount of sulfaquinoxaline sodium and etopabate is 25 to 100 parts by weight and 1 to 10 parts by weight, respectively, based on 100 parts by weight of amprolium hydrochloric acid. Way. A liquid preparation containing 25 to 100 parts by weight of sulfaquinoxaline sodium and 1 to 10 parts by weight of etopabate, and 1 to 5% by weight, based on 100 parts by weight of amprolium hydrochloric acid, based on the total weight.