KR20230001677A - Injectable preparation of tulathromycin and tolfenamic acid - Google Patents

Abstract

The present invention relates to a combination formulation (particularly, an injection) of tulasthromycin, which is widely used for respiratory diseases in cattle and pigs, and tolfenamic acid, which is used for the treatment of acute inflammation related to respiratory diseases. More specifically, the present invention relates to a pharmaceutical composition ensuring the solubility and stability of tulasromycin and tolfenamic acid, and a manufacturing method thereof.

Description

Complex injectable preparation of tulathromycin and tolfenamic acid {Injectable preparation of tulathromycin and tolfenamic acid}

The present invention relates to a pharmaceutical composition containing tulasthromycin and tolfenamic acid, and specifically, to a combined preparation or pharmaceutical composition capable of effectively treating bacterial respiratory diseases of livestock.

Tulathromycin is administered in the case of bacterial respiratory diseases such as Glasser's disease, pleural pneumonia, pasteurella pneumonia, and mycoplasma pneumonia in pigs to treat the disease and to treat the disease by injection to all pigs living together in the early stage. It is a drug that is widely used to suppress enlargement, and is also an excellent drug for respiratory diseases in cattle.

Tolfenamic acid is a drug that inhibits cyclooxygenase (COX) and is effective as an antipyretic and analgesic anti-inflammatory drug.

When antibiotics and antipyretics are mixed and used in pig farms, they are sometimes used as prescribed by veterinarians, but otherwise, problems with the mixing ratio and amount used, problems with changes in properties after mixing, and problems with safety and effectiveness when mixed use may occur. In order to improve this, continuous interest and research on combination drugs are being conducted.

Tulasromycin is well soluble in organic solvents such as methanol, acetone and ethyl acetate, but insoluble in water, well soluble in N,N-dimethylformamide, slightly soluble in ethanol and dichloromethane, and almost insoluble in water. In order to prepare an injection by dissolving tulasthromycin and tolfenamic acid, which are drugs with low solubility, it is very important to select a solvent and a solubilizing agent. In addition, even if tulasromycin and tolfenamic acid are dissolved, there is a problem in that the color changes or the content decreases after time.

Registered Patent Publication No. 10-1776274 Registered Patent Publication No. 10-2086462

In order to solve these problems, by selecting appropriate solvents and solubilizers, there is no change in the content of tulasthromycin and tolfenamic acid, and no change in color. It is intended to provide a pharmaceutical composition comprising the same and a method for preparing the same.

Accordingly, the inventors of the present invention found that when administered as a combination of tulasromycin and tolfenamic acid, convenience in use, safety and effectiveness can be secured compared to the case of combined administration of antibiotics and antipyretic analgesics and antipyretic analgesics. It was judged that the effect of acute inflammatory treatment related to respiratory diseases such as pleural pneumonia and Pasteurella pneumonia, which are respiratory diseases, could be increased.

In order to achieve the above object, the present invention is a combination preparation containing tulathromycin and tolfenamic acid, specifically, a combination injection containing tulasthromycin and tolfenamic acid. Provided is a combined preparation or pharmaceutical composition with excellent stability without degradation or change in properties and a method for preparing the same.

The combined preparation or pharmaceutical composition in the present invention contains tulasthromycin and tolfenamic acid as active ingredients. The tulasthromycin comprises 50 mg to 200 mg per ml by weight, preferably 80 mg to 120 mg per ml. In addition, tolfenamic acid is included in an amount of 30 mg to 150 mg per ml on a weight basis, preferably 60 mg to 100 mg per ml on a weight basis. When tolasromycin and tolfenamic acid are included below the above range, the effect of preventing, improving or treating respiratory diseases is reduced, and when the above range is exceeded, formulation is difficult.

The combination preparation or pharmaceutical composition may be prepared in dosage forms such as tablets, capsules, sustained-release preparations, elixirs, suspensions, syrups, wafers, injections, suspensions, etc., but preferably injectable preparations. The injection formulation may be, for example, a liquid injection formulation or a powder injection formulation, but is not limited thereto.

In addition, the combined preparation or pharmaceutical composition may use polyvinylpyrrolidone or methylpyrrolidone, which can increase the solubility of the tulasromycin and tolfenamic acid complex injection, as a solubilizer, wherein the solubilizer is based on weight per ml. 50 mg to 200 mg, preferably including 50 mg to 150 mg per ml by weight. When included in less than the above range, solubility is reduced, and when included in addition to the above range, viscosity increases, which may cause difficulty in administering injections.

In addition, the combined preparation or pharmaceutical composition may use butylhydroxytoluene or butylhydroxyanisole as a stabilizer, wherein the stabilizer includes 0.1 mg to 3 mg per ml, preferably 0.5 mg to 2.5 mg per ml. and use it When included in less than the above range, the properties may change, and when included in excess of the above range, there is a problem that the normal amount that can be used in injections may be exceeded.

The combined preparation or pharmaceutical composition of the present invention may additionally include other conventional additives such as pharmaceutically acceptable carriers, antioxidants, buffers, and bacteriostatic agents commonly used in the art in addition to the above components.

The combined preparation or pharmaceutical composition of the present invention may be used for preventing, improving or treating respiratory diseases in animals. The animal may be, but is not limited to, preferably a pig or a cow.

Persistent respiratory diseases may refer to respiratory diseases caused by infection with infectious agents such as mycoplasma, bacteria, and viruses. Such respiratory diseases can lead to problems such as stunted growth and reduced feed efficiency.

Specific examples of the respiratory disease include Glasser's disease in swine, swine epidemic pneumonia (Swine enzootic pneumoniae), porcine reproductive & respiratory syndrome (Porcine Reproductive & Respiratory Syndrome), pleural pneumonia, bronchopneumonia, Pasteurella pneumonia, streptococcal infection or swine atrophic It may be any one or more selected from the group consisting of rhinitis, but is not limited thereto.

The present invention relates to a combination preparation or pharmaceutical composition containing tulasthromycin and tolfenamic acid as active ingredients. Specifically, it is possible to provide a combination preparation or pharmaceutical composition of tulasthromycin and tolfenamic acid that increases the solubility of tulasthromycin and tolfenamic acid and suppresses a decrease in the content of tulasthromycin and tolfenamic acid, and a method for preparing the same.

Figure 1 shows the overall manufacturing process of the formulation according to the present invention.
Figure 2 shows the dissolution properties according to the use of methylpyrrolidone in the tulasromycin and tolfenamic acid complex injection.

Hereinafter, the present invention will be described in detail by examples and experimental examples.

However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the contents of the present invention are not limited to the following Examples and Experimental Examples.

[Example]

Prescription and manufacturing method of tulasromycin and tolfenamic acid complex injection

<prescription>

Raw material per 1ml 2L note Tulasthromycin 100.0mg 200.0g tolfenamic acid 80.0mg 160.0g monothioglycerol 5.0mg 10.0g Methylpyrrolidone 100.0mg 200.0g Substitutable with polyvinylpyrrolidone Butylhydroxytoluene 1.5 mg 3.0g Can be replaced with butylhydroxyanisole Dimethylacetamide 340.0mg 680.0g dimethyl sulfoxide 300.0mg 600.0g Hydrochloric acid 19.0mg 38.0g water for injection Appropriate amount

<Manufacturing method>

1. Preparation of solvents for injections

Methylpyrrolidone was dissolved in 600 g of dimethyl sulfoxide, dimethylacetamide and monothioglycerol were added, butylhydroxytoluene was dissolved, and hydrochloric acid was added.

2. Dissolution of the main component

Dissolve tulasthromycin and tolfenamic acid in the prepared solvent for injection.

3. Pyoseon

After dissolving the main component, it was marked with distilled water for injection to prepare an injection.

[Comparative Example 1: Without methylpyrrolidone]

An injection was prepared according to the above preparation method by dissolving tulasthromycin and tolfenamic acid in a solvent not using methylpyrrolidone.

[Comparative Example 2: Without butylhydroxytoluene]

An injection was prepared according to the above preparation method by dissolving tulasthromycin and tolfenamic acid in a solvent not using butylhydroxytoluene.

[Experimental Example 1]

1. Tulasthromycin assay method

-Standard solution preparation: Tulasthromycin standard was precisely weighed and dissolved in a mobile phase mixed solvent, and then adjusted to a final concentration of 1.0 mg/ml to be used as a standard solution.

-Test solution: The sample solution was diluted to a theoretical final concentration of 1.0 mg/ml by adding a mobile phase mixed solvent, and used as the test solution.

-HPLC test conditions:

1) detector; UV detector

2) column; 4.6x50mm, C18, 3um (octadecylsilylated silica packed column)

3) mobile phase; KH2PO4 buffer : methanol : acetonitrile = 150 : 225 : 125

KH2PO4 buffer solution; After dissolving 2.5 g of KH2PO4 in 500 ml of purified water, 8N KOH solution was added to adjust the pH to 7.0.

4) flow rate; 1.0ml/min

5) wavelength; 205 nm

2. Tolfenamic acid analysis method

- preparation of standard solutions; Tolfenamic acid standards were precisely weighed and dissolved in a mobile phase solvent, and then adjusted to a final concentration of 0.8 mg/ml, which was used as a standard solution.

- sample solution; After taking the sample solution and dissolving it in a mobile phase solvent, the final concentration was theoretically diluted to 0.8 mg/ml and used as the test solution.

- HPLC test conditions

1) detector; UV detector

2) column; 4.6x50mm, C18, 3um (octadecylsilylated silica packed column)

3) mobile phase; KH2PO4 buffer : methanol : acetonitrile = 150 : 225 : 125

KH2PO4 buffer solution; After dissolving 2.5 g of KH2PO4 in 500 ml of purified water, the pH was adjusted to 7.0 with 8N KOH solution.

4) flow rate; 1.0ml/min

5) wavelength; 280 nm

[Experimental Example 2] Foreign body test of tulasthromycin and tolfenamic acid complex injection

2-1. Evaluation of properties according to the use of methylpyrrolidone

When prepared by the injection manufacturing method without using methylpyrrolidone and then marked with water for injection, a precipitate was formed and turned cloudy as shown in FIG. 1, and the injection prepared by the injection manufacturing method using methylpyrrolidone was transparent as shown in FIG. , When the tulasromycin and tolfenamic acid complex injection was prepared by the above injection preparation method, it was also suitable for the foreign body test of the injection. As shown in FIG. 1, when a mixed injection of tulasromycin and mefenamic acid was prepared as an injection solvent without using methylpyrrolidone and distilled water for injection was added, it was transparently dissolved when methylpyrrolidone was not used. When distilled water was added, a precipitate was easily formed, but when prepared using methylpyrrolidone, no precipitate was formed. It was confirmed that the use of a solubilizing agent such as polyvinylpyrrolidone is preferable for the preparation of a complex injection of tulasthromycin and tolfenamic acid.

2-2. Evaluation of properties of complex injections according to the use of butylhydroxytoluene

According to the above exemplified injection prescription and manufacturing method, a composite injection of tulasthromycin and tolfenamic acid was prepared using butylhydroxytoluene, and the content change of tulasthromycin and tolfenamic acid for 3 months at refrigeration, room temperature (25 ℃), 40 ℃ The results of testing the change in appearance are shown in Table 2 below.

Stability test results of complex injections using butyl hydroxytoluene keep
condition chief ingredient 0 months 1 month 2 months 3 months content appearance content appearance content appearance content appearance 40℃ Tulasthromycin pale yellow 104.2 pale yellow 103.6 pale yellow 103.2 pale yellow tolfenamic acid 103.6 103.8 103.1 25℃ Tulasthromycin pale yellow 104.0 pale yellow 104.1 pale yellow 104.3 pale yellow tolfenamic acid 104.3 103.9 103.7

As shown in Table 2, when a composite injection of tulathromycin and tolfenamic acid was prepared using butylhydroxytoluene and the stability test was evaluated for 3 months at 25 ° C and 40 ° C, there was no change in the properties of the formulation, and tulasromycin and tolfe There was no change in the name of Namsan Mountain. This is judged to be the effect of butylhydroxytoluene.

2-3. Evaluation of properties of complex injections without butylhydroxytoluene

According to the above-mentioned injection prescription and manufacturing method, tulasthromycin and tolfenamic acid complex injections were prepared without using butylhydroxytoluene, and refrigeration, room temperature (25 ℃) and 40 ℃ Table 3 shows the results of testing the change in properties.

Stability test results of complex injections without butyl hydroxytoluene keep
condition chief ingredient 0 months 1 month 2 months 3 months content appearance content appearance content appearance content appearance 40℃ Tulasthromycin pale yellow 102.1 dark yellow 100.6 thick
yellow 98.2 thick
yellow tolfenamic acid 103.5 100.5 98.3 25℃ Tulasthromycin pale yellow 103.1 pale
dark yellow 101.1 thick
yellow 99.1 thick
yellow tolfenamic acid 103.5 100.6 98.1

As shown in Table 3, when tulasromycin and tolfenamic acid complex injections were prepared without using butylhydroxytoluene and tested for stability at 25 ° C and 40 ° C for 3 months, the color changed to dark yellow even after 1 month at 40 ° C. The content of tulathromycin and tolfenamic acid decreased, and the properties began to change after 1 month at 25 ° C., and the content of tulathromycin and tolfenamic acid also decreased after 2 months. This is considered to indicate that it is difficult to secure the stability of the tulathromycin and tolfenamic acid complex injection unless butylhydroxytoluene or butylhydroxyanisole is used to secure the stability of the tulathromycin and tolfenamic acid complex injection.

[Experimental Example 3] Evaluation of long-term stability of the injection according to the present invention

After preparing the complex injection of tulasromycin and tolfenamic acid by the method exemplified above, the results of the experiment at room temperature (25 ° C.) at 3-month intervals according to the 12-month injection test items are shown in Table 4.

Results of long-term stability test of tulasromycin and tolfenamic acid complex injection Test Items standard duration (months) 0 3 6 9 12 appearance yellow transparent liquid Pale yellow transparent liquid Pale yellow transparent liquid Pale yellow transparent liquid Pale yellow transparent liquid Pale yellow transparent liquid pH 5.5 to 7.5 6.40 6.41 6.41 6.43 6.55 content test It should contain tulasthromycin corresponding to 90~120% of the indicated amount. 102.8% 102.6% 102.5% 102.3% 101.8% It should contain tolfenamic acid equivalent to 90~120% of the indicated amount. 101.3% 101.3% 101.2% 101.2% 100.4% sterility test Must be sterile. sterile sterile sterile sterile sterile endotoxin
(EU/mL) Less than 20 EU/mL < 20 < 20 < 20 < 20 < 20 insoluble
alien substance When observed with the naked eye, it should be clear and free of easily detectable insoluble foreign matter. clear and easy
detected
no foreign matter clear and easy
detected
no foreign matter clear and easy
detected
no foreign matter clear and easy
detected
no foreign matter clear and easy
detected
no foreign matter insoluble
particulate 10 ㎛ or more: 6,000 or less
25 ㎛ or more: 600 or less 236/5 211/4 237/1 180/1 192/2

As shown in Table 4 above, when the injections were prepared with the optimal prescription of tulasromycin and tolfenamic acid and the injections were tested at 25 ° C at 3-month intervals for 12 months, all test items showed changes in properties or content for 12 months, as well as It was confirmed that the formulation had excellent stability without generation of insoluble particulates.

This is the result of confirming that the present inventors established by studying the pharmaceutical composition and manufacturing method of the complex injection of tulasthromycin and tolfenamic acid are formulations with excellent stability.

Claims (6)

A combined preparation containing tulasromycin and tolfenamic acid,
A combination formulation comprising 80 mg to 120 mg of tulasromycin by weight per ml and 60 mg to 100 mg of tolfenamic acid by weight per ml. The combination preparation according to claim 1, wherein the combination preparation is a liquid injection formulation. The combination preparation according to claim 1, wherein the combination preparation contains 50 mg to 150 mg based on weight per ml of polyvinylpyrrolidone or methylpyrrolidone as a solubilizing agent. The combination formulation according to claim 1, wherein the combination formulation contains 0.5 mg to 2.5 mg per ml of butylhydroxytoluene or butylhydroxyanisole as a stabilizer. The combination preparation according to any one of claims 1 to 4, which is for preventing, improving or treating respiratory diseases in animals. The method of claim 5, wherein the respiratory disease is at least one selected from the group consisting of porcine Glasser disease, porcine epidemic pneumonia, porcine reproductive and respiratory syndrome, pleural pneumonia, bronchopneumonia, pasteurella pneumonia, streptococcal infection, or swine atrophic rhinitis. Characterized by a combination formulation.

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