KR102647267B1 - Injectable preparation of tulathromycin and tolfenamic acid - Google Patents

Abstract

The present invention relates to a combination preparation (particularly an injection) of tulasromycin, which is widely used for respiratory diseases in cattle and pigs, and tolfenamic acid, which is used to treat acute inflammation related to respiratory diseases. The solubility of tulasromycin and tolfenamic acid is It relates to a pharmaceutical composition that ensures stability and a method of manufacturing the same.

Description

Injectable preparation of tulathromycin and tolfenamic acid}

The present invention relates to a pharmaceutical composition containing tulathromycin and tolfenamic acid, and specifically to a combination preparation or pharmaceutical composition that can effectively treat bacterial respiratory diseases in livestock.

Tulathromycin is administered to treat bacterial respiratory diseases such as glassy disease, pleuropneumonia, pasteurella pneumonia, and mycoplasma pneumonia in pigs. It treats the disease early by injecting all pigs living in the same household. It is a drug widely used to suppress enlargement, and is also effective against respiratory diseases in cattle.

Tolfenamic acid is a drug that inhibits COX (cyclooxygenase) and is effective as an antipyretic, analgesic, and anti-inflammatory agent. Since it is non-steroidal, it does not have steroid-like side effects like prednisolone.

When antibiotics and fever reducers are mixed and used in pig farms, they are used as prescribed by veterinarians, but if not, problems with mixing ratio and dosage, problems with change in properties after mixing, and safety and effectiveness when mixed use may arise. As this may be the case, ongoing interest and research on combination drugs are being conducted to improve this.

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

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

To solve this problem, select an appropriate solvent and solubilizing agent to prepare a highly stable tulathromycin and tolfenamic acid complex preparation or a combination of tulasromycin and tolfenamic acid with no change in the content of tulasromycin and tolfenamic acid and no change in color. The object is to provide a pharmaceutical composition containing the same and a method for producing the same.

Accordingly, the present inventors found that administration of a combination of tulathromycin and tolfenamic acid can secure ease of use, safety, and effectiveness compared to the combined administration of antibiotics and antipyretic analgesics, and that it is better for cattle and pigs than administering antibiotics or antipyretic analgesics as a single agent. It was judged that it could increase the effectiveness of treating acute inflammation related to respiratory diseases such as pleurisy and Pasteurella pneumonia.

In order to achieve the above object, the present invention is a complex preparation containing tulasromycin and tolfenamic acid, specifically a complex injection containing tulasromycin and tolfenamic acid, and the content of tulasromycin and tolfenamic acid during storage and distribution. Provided is a combination preparation or pharmaceutical composition with excellent stability without degradation or change in properties, and a method for manufacturing the same.

The combination preparation or pharmaceutical composition of the present invention contains tulathromycin and tolfenamic acid as active ingredients. The tulathromycin contains 50 mg to 200 mg by weight per ml, preferably 80 mg to 120 mg per ml. Additionally, tolfenamic acid contains 30 mg to 150 mg by weight per ml, preferably 60 mg to 100 mg by weight per ml. If tolathromycin and tolfenamic acid are contained below the above range, the effectiveness of preventing, improving or treating respiratory diseases is reduced, and if they exceed the above range, formulation is difficult.

The complex 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 is preferably in an injectable dosage form. The injectable formulation may be, for example, a liquid injectable formulation or a powder injectable formulation, but is not limited thereto.

In addition, the combination preparation or pharmaceutical composition may use polyvinylpyrrolidone or methylpyrrolidone, which can increase the solubility of the tulathromycin and tolfenamic acid complex injection, as a solubilizing agent. In this case, the solubilizing agent is based on weight per ml. It is used in an amount of 50 mg to 200 mg, preferably 50 mg to 150 mg by weight per ml. If the content is less than the above range, the solubility may decrease, and if the content is more than the above range, the viscosity may increase, making it difficult to administer by injection.

In addition, the complex preparation or pharmaceutical composition may use butylhydroxytoluene or butylhydroxyanisole as a stabilizer, wherein the stabilizer contains 0.1 mg to 3 mg per ml, preferably 0.5 mg to 2.5 mg per ml. and use it. If it is contained below the above range, its properties may change, and if it is contained above the above range, there is a problem that the normal usage amount that can be used in injections may be exceeded.

In addition to the above-mentioned ingredients, the combination preparation or pharmaceutical composition of the present invention may further include other conventional additives such as pharmaceutically acceptable carriers, antioxidants, buffers, and bacteriostatic agents commonly used in the art.

The combination preparation or pharmaceutical composition of the present invention may be used to prevent, improve, or treat respiratory diseases in animals. The animal is not limited, but is preferably a pig or cow.

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

Specific examples of the respiratory disease include swine Glasser's disease, swine enzootic pneumoniae, porcine reproductive & respiratory syndrome, pleural pneumonia, bronchial pneumonia, Pasteurella pneumonia, streptococcal infection, or porcine atrophy. It may be 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 tulathromycin and tolfenamic acid as active ingredients. Specifically, it is possible to provide a complex preparation or pharmaceutical composition of tulasromycin and tolfenamic acid that increases the solubility of tulasromycin and tolfenamic acid and suppresses the decrease in the content of tulasromycin and tolfenamic acid, and a method for manufacturing the same.

Figure 1 shows the overall manufacturing process of the preparation according to the present invention.
Figure 2 shows the solubility according to whether methylpyrrolidone is used in a combination injection of tulasromycin and tolfenamic acid.

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

However, the following examples and experimental examples only illustrate the present invention, and the content of the present invention is not limited to the following examples and experimental examples.

[Example]

Prescription and manufacturing method of tulathromycin and tolfenamic acid combination injection

<Prescription>

Raw material per 1ml 2L note Tulathromycin 100.0mg 200.0g Tolpenamic acid 80.0 mg 160.0g monothioglycerol 5.0 mg 10.0g Methylpyrrolidone 100.0mg 200.0g Can be replaced with polyvinylphyllolidone Butylhydroxytoluene 1.5mg 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 injectable solution

Dissolve methylpyrrolidone in 600g of dimethyl sulfoxide, add dimethylacetamide and monothioglycerol, dissolve butylhydroxytoluene, and add hydrochloric acid.

2. Dissolution of main ingredient

Tulathromycin and tolfenamic acid are dissolved in the prepared injection solution.

3. Pyoseon

The main ingredient was dissolved and then treated with distilled water for injection to prepare an injection.

[Comparative Example 1: Without use of methylpyrrolidone]

An injection was prepared according to the above production method by dissolving tulathromycin and tolfenamic acid in a solvent that did not use methylpyrrolidone.

[Comparative Example 2: Without using butylhydroxytoluene]

An injection was prepared according to the above production method by dissolving tulathromycin and tolfenamic acid in a solvent that did not use butylhydroxytoluene.

[Experimental Example 1]

1. Tulathromycin analysis method

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

- Test solution: The test solution was taken, diluted with a mobile phase mixed solvent to theoretically reach a final concentration of 1.0 mg/ml, and used as a test solution.

-HPLC experiment 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; 2.5 g of KH2PO4 was dissolved in 500 ml of purified water, and then 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 solution; The tolfenamic acid standard was precisely weighed and dissolved in the mobile phase solvent, then adjusted to a final concentration of 0.8 mg/ml and used as a standard solution.

- Test solution; The sample solution was taken and dissolved in a mobile phase solvent, then diluted to theoretically reach a final concentration of 0.8 mg/ml and used as the test solution.

- HPLC experimental conditions

1) Detector; UV detector

2) Column; 4.6x50mm, C18, 3um (octadecyl silylated silica filled column)

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

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

4) flow rate; 1.0ml/min

5) Wavelength; 280nm

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

2-1. Evaluation of properties depending on whether methylpyrrolidone is used or not

When prepared by the injection preparation method without using methylpyrrolidone and then treated with water for injection, a precipitate was formed and turned cloudy as shown in Figure 2. The injection prepared by the injection preparation method using methylpyrrolidone was transparent as shown in Figure 2. , when the combination injection of tulasromycin and tolfenamic acid was manufactured using the above injection manufacturing method, it was also suitable for the injection foreign body test. As shown in Figure 2, a mixed injection of tulasromycin and mefenamic acid was prepared as an injection solvent without using methylpyrrolidone, and when distilled water for injection was added, it was dissolved transparently when methylpyrrolidone was not used. When distilled water was added, a precipitate was easily formed immediately, but when manufactured using methylpyrrolidone, no precipitate was formed. It is also suitable for the foreign body test for injectables, so when preparing a mixed injection of tulathromycin and mefenamic acid, methylpyrrolidone or It was confirmed that the use of a solubilizing agent such as polyvinylpyrrolidone is preferable in the production of a complex injection of tulasromycin and tolfenamic acid.

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

A complex injection of tulasromycin and tolfenamic acid was prepared using butylhydroxytoluene using the above-described injection prescription and manufacturing method, and was refrigerated at room temperature (25°C) and 40°C for 3 months to determine the content changes of tulasromycin and tolfenamic acid. The results of the property change experiment are shown in Table 2 below.

Stability test results of complex injection using butylhydroxytoluene keep
condition chief ingredient 0 months 1 month 2 months 3 months content Appearance content Appearance content Appearance content Appearance 40℃ Tulathromycin light yellow 104.2 light yellow 103.6 light yellow 103.2 light yellow Tolpenamic acid 103.6 103.8 103.1 25℃ Tulathromycin light yellow 104.0 light yellow 104.1 light yellow 104.3 light yellow Tolpenamic acid 104.3 103.9 103.7

As shown in Table 2, when a complex injection of tulasromycin and tolfenamic acid was prepared using butylhydroxytoluene and a stability test was performed for 3 months at 25°C and 40°C, there was no change in the properties of the formulation, and there was no change in the properties of the formulation. There was no change in the content of Namsan. This is believed to be the effect of butylhydroxytoluene.

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

Using the injection prescription and manufacturing method exemplified above, a complex injection of tulasromycin and tolfenamic acid was prepared without using butylhydroxytoluene, and was refrigerated at room temperature (25°C) and 40°C to determine the content changes of tulasromycin and tolfenamic acid. The results of the experiment on change in properties are shown in Table 3.

Stability test results of complex injection without butylhydroxytoluene keep
condition chief ingredient 0 months 1 month 2 months 3 months content Appearance content Appearance content Appearance content Appearance 40℃ Tulathromycin light yellow 102.1 dark yellow 100.6 thick
yellow 98.2 thick
yellow Tolpenamic acid 103.5 100.5 98.3 25℃ Tulathromycin light yellow 103.1 pale
dark yellow 101.1 thick
yellow 99.1 thick
yellow Tolpenamic acid 103.5 100.6 98.1

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

[Experimental Example 3] Long-term stability evaluation of the injection according to the present invention

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

Long-term stability test results of tulathromycin and tolfenamic acid combination injection Test Items standard period (months) 0 3 6 9 12 Appearance yellow transparent liquid It is a light yellow transparent liquid. It is a light yellow transparent liquid. It is a light yellow transparent liquid. It is a light yellow transparent liquid. It is a light yellow transparent liquid. pH 5.5~7.5 6.40 6.41 6.41 6.43 6.55 Content test It must contain tulathromycin equivalent to 90-120% of the labeled amount. 102.8% 102.6% 102.5% 102.3% 101.8% It must contain tolfenamic acid equivalent to 90-120% of the labeled amount. 101.3% 101.3% 101.2% 101.2% 100.4% Sterility test It 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 must be clear and free of easily detectable insoluble foreign substances. 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 larger: 6,000 or less
Over 25 ㎛: 600 or less 236/5 211/4 237/1 180/1 192/2

As shown in Table 4 above, when an injectable drug was manufactured with the optimal prescription of tulasromycin and tolfenamic acid and the injectable drug test items were tested at 25°C at 3-month intervals for 12 months, there was no change in appearance or content for 12 months in all test items. It was confirmed that it was a highly stable formulation without generating insoluble particulates.

This is the result of confirming that the present inventors studied the pharmaceutical composition and manufacturing method of the combined injection of tulasromycin and tolfenamic acid and established it as a preparation with excellent stability.

Claims (6)

A combination preparation containing tulathromycin and tolfenamic acid,
Methylpyrrolidone was dissolved in dimethyl sulfoxide, dimethylacetamide and monothioglycerol were added, butylhydroxytoluene was dissolved, and hydrochloric acid was added. It contains 80 mg to 120 mg of the tulasromycin based on the weight per ml of the solvent. , a complex preparation containing 60 mg to 100 mg of tolfenamic acid based on weight per ml of the solvent. The combination preparation according to claim 1, wherein the combination preparation is a liquid injectable formulation. The combination preparation according to claim 1, wherein the solvent contains 50 mg to 150 mg of methylpyrrolidone as a solubilizing agent based on weight per ml. The composite preparation according to claim 1, wherein the solvent contains 0.5 mg to 2.5 mg per ml of butylhydroxytoluene as a stabilizer. The combination preparation according to any one of claims 1 to 4, wherein the combination preparation 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's disease, porcine epidemic pneumonia, porcine reproductive and respiratory syndrome, pleuritic pneumonia, bronchial pneumonia, Pasteurella pneumonia, streptococcal infection, or porcine atrophic rhinitis. Characterized complex preparation.