AU2011257785A1

AU2011257785A1 - Injection of enrofloxacin and producing method thereof

Info

Publication number: AU2011257785A1
Application number: AU2011257785A
Authority: AU
Inventors: Huifeng Dong
Original assignee: S & E Animal Pharmaceutical Tianjin Co Ltd
Current assignee: S & E Animal Pharmaceutical (tianjin) Co Ltd
Priority date: 2010-05-22
Filing date: 2011-05-20
Publication date: 2012-08-30
Also published as: CN101810569A; KR20130080422A; WO2011147280A1; AU2011101749A4; CN101810569B

Abstract

An injection of enrofloxacin and the producing method thereof are disclosed. The injection comprises from 10 to 20 parts of enrofloxacin, from 0.1 to 0.5 part of antioxidant and from 0.1 to 0.5 part of chelating agent and has a neutral pH value. The antioxidant is sodium bisulfite or sodium thiosulfate. The chelating agent is EDTA. The injection is stable and not irritative. Its producing method comprises the steps of: (1) adding enrofloxacin to the aqueous solution of sodium hydroxide; (2) continuing adding the aqueous solution of sodium hydroxide to obtain a pH value of 9-13; (3) adding acidifying agent to obtain a neutral pH value; (4) adding the antioxidant; (5) adding the chelating agent; (6) adding water to obtain the final product. The acidifying agent in step (3) is one or two or three selected from the group of lactic acid, sodium butyrate and arginine.

Description

Description Enrofloxacin Injection and Preparation Method thereof Technical Field The invention relates to an antibacterial for the prevention and control of aquatic diseases in poultry and livestock, more particularly to an enrofloxacin injection and a preparation method thereof. Background Enrofloxacin, having the chemical formula as follows: 1,4-dihydro- 1 -cyclopropyl-7-(4-ethyl- I -piperazinyl)-6-fluoro-4-oxo-3-quinoli, not only stands for a new generation of quinolone antibacterials, but is also a new drug special for the prevention and control of aquatic diseases in poultry and livestock. On the premise of keeping the characteristics of quinolone antibacterials such as broad spectrum, high efficiency, low toxicity, excellent absorption and convenient administration, enrofloxacin has significant curative effect against various infections caused by multiple bacteria, and particularly, it is obviously superior, in the aspect of killing a variety of mycoplasmas, to other quinolone antibacterials and various tylosin and tiamulin antibacterials that have been used for many years. However, enrofloxacin has quite low animal tolerance dosage when used in the form of oral liquid because of its extremely strong bitterness, therefore, enrofloxacin is generally administered in the form of injection during clinical application. Enrofloxacin is slightly soluble in water and soluble in basic solvent, so the injection used typically is the basic aqueous solution of enrofloxacin, which specifically is sodium hydroxide aqueous solution, however, the solubility of enrofloxacin in the basic aqueous solution is 10%, so the excess parts are precipitated out in the form of crystal. In addition, due to the subacidity of the biological environment in animal body, intensive irritation to animals would be brought after the basic aqueous solution, i.e. the enrofloxacin-containing sodium hydroxide aqueous solution, is injected into animal body via a syringe, as a result, animals will show distinct discomfort. Summary of the Invention The invention aims to overcome the shortages in the prior art and provide an enrofloxacin injection which is neutral in pH value and has no irritation to animal body. The content of the enrofloxacin in the injection is from 10% to 20% so that the curative effect of single administration is greatly improved, and simultaneously, the prepared enrofloxacin injection has stable properties, has no crystal separation after long-time storage, and is an injection with good curative effect and no irritation. The enrofloxacin injection is neutral in pH value and comprises 10 to 20 parts of enrofloxacin, 0.1 to 0.5 parts of antioxidant and 0.1 to 0.5 parts of chelating agent. The enrofloxacin accounts for 10 to 20% of the total weight of the injection. The antioxidant is sodium thiosulfate or sodium bisulfite. The chelating agent is EDTA. The invention further provides a preparation method of enrofloxacin injection, which comprises the steps of: (1) Adding enrofloxacin to sodium hydroxide aqueous solution; (2) Continuously adding the sodium hydroxide aqueous solution to adjust the pH value to be within a range from 9 to 13; (3) Adding an acidifying agent to adjust the pH value to be neutral; (4) Adding an antioxidant; (5) Adding a chelating agent; (6) Diluting with water to a constant volume to obtain the enrofloxacin injection. After the step (6) is finished, filtering sterilization by a 0.45-micron micropore filter membrane is performed. The concentration of the sodium hydroxide aqueous solution in the step (1) is 0.2 to 0.4 mol/I. The acidifying agent in the step (3) is one or two or three of lactic acid, sodium butyrate and arginine. The antioxidant in the step (4) is sodium thiosulfate or sodium bisulfite. The chelating agent in the step (5) is EDTA. The water in the step (6) is purified water. The invention has the advantages and positive effects as follows: The enrofloxacin injection prepared by the invention is added with one or two or three of lactic acid, sodium butyrate and arginine, finally leading to neutral pH value of the invention, in this way, no irritation is brought when the injection is injected into animals, furthermore, the content of the enrofloxacin is improved to 20% so that the curative effect of single administration is greatly improved, and simultaneously, the prepared enrofloxacin injection has stable properties, has no crystal separation after long-time storage, and is an injection with good curative effect and no irritation. Detailed Description of the Embodiments The invention will be further described below with reference to the embodiments that are regarded in an illustrative sense rather than a restrictive sense and accordingly could not limit the scope of the invention. The enrofloxacin injection in the invention is neutral in pH value, has no irritation to animal body and comprises 10 to 20 parts of enrofloxacin, 0.1 to 0.5 parts of antioxidant and 0.1 to 0.5 parts of chelating agent. The enrofloxacin accounts for 10 to 20% of the total weight of the injection. The antioxidant is sodium thiosulfate or sodium bisulfite. The chelating agent is EDTA (Ethylene Diamine Tetraacetic Acid). Embodiment I A preparation method of enrofloxacin injection comprises the following steps of: (1) Adding 20g enrofloxacin into 60ml sodium hydroxide aqueous solution with the concentration of 0.4mol/l, and stirring until the enrofloxacin is completed dissolved; (2) Continuously adding the sodium hydroxide aqueous solution with the concentration of 0.4mol/l to adjust the pH value to 12; (3) adding 20ml acidifying agent, i.e. lactic acid, wherein in the process of adding the acidifying agent, the enrofloxacin is separated out and crystallized at first, and then completely dissolved when the pH value becomes neutral along with the addition of the acidifying agent; (4) Adding 0.5g antioxidant, i.e. sodium thiosulfate, into the neutral solution; (5) Continuously adding 0.5g chelating agent, i.e. EDTA; (6) diluting with purified water to a constant volume of 100ml after the step (5) is finished, and performing filtering sterilization on the solution with constant volume by a 0.45-micron micropore filter membrane; (7) Separately packaging the injection after filtering sterilization to obtain finished products. In accordance with tests, the prepared enrofloxacin injection is neutral in pH value and the content of the effective ingredient, i.e. the enrofloxacin, in the injection is 20% based on the total weight of the injection. Embodiment 2 A preparation method of enrofloxacin injection comprises the following steps of: (1) Adding 1 5g enrofloxacin into 70ml sodium hydroxide aqueous solution with the concentration of 0.3mol/l, and stirring until a part of the enrofloxacin is dissolved and the remaining enrofloxacin exists in the form of precipitates; (2) Continuously adding the sodium hydroxide aqueous solution with the concentration of 0.3mol/l to adjust the pH value to 11, at this moment, the enrofloxacin is completely dissolved; (3) adding acidifying agents, i.e. 0.15g sodium butyrate and 1 Oml lactic acid, wherein in the process of adding the acidifying agents, the enrofloxacin is continuously separated out from the solution and crystallized, and then completely dissolved when the pH value becomes neutral along with the addition of the acidifying agents; (4) Adding O.4g antioxidant, i.e. sodium bisulfite, into the neutral solution; (5) Continuously adding 0.4g chelating agent, i.e. EDTA; (6) diluting with purified water to a constant volume of 100ml after the step (5) is finished, and performing filtering sterilization on the solution with constant volume by a 0.45-micron micropore filter membrane; (7) Separately packaging the injection after filtering sterilization to obtain finished products. In accordance with tests, the prepared enrofloxacin injection is neutral in pH value and the content of the effective ingredient, i.e. the enrofloxacin, in the injection is 15%. Embodiment 3 A preparation method of enrofloxacin injection comprises the following steps of: (1) Adding lOg enrofloxacin into 60ml sodium hydroxide aqueous solution with the concentration of 0.2mol/l, and stirring until a part of the enrofloxacin is dissolved and the remaining enrofloxacin exists in the form of precipitates; (2) Continuously adding the sodium hydroxide aqueous solution with the concentration of 0.5mol/l to adjust the pH value to 13, until the enrofloxacin is completely dissolved; (3) adding 15ml acidifying agent, i.e. lactic acid, wherein in the process of adding the acidifying agent, the enrofloxacin is continuously separated out from the solution and crystallized, and then completely dissolved when the pH value becomes neutral along with the addition of the acidifying agents; (4) Adding 0.1 g antioxidant, i.e. sodium thiosulfate, into the neutral solution; (5) Continuously adding 0.lg chelating agent, i.e. EDTA; (6) diluting with purified water to a constant volume of 100ml after the step (5) is finished, and performing filtering sterilization on the solution with constant volume by a 0.45-micron micropore filter membrane; (7) Separately packaging the injection after filtering sterilization to obtain finished products.

In accordance with tests, the prepared enrofloxacin injection is neutral in pH value and the content of the effective ingredient, i.e. the enrofloxacin, in the injection is 10%. Embodiment 4 A preparation method of enrofloxacin injection comprises the following steps of: (1) Adding 18g enrofloxacin into 60ml sodium hydroxide aqueous solution with the concentration of 0.4mol/l, and stirring until the enrofloxacin is completed dissolved; (2) Continuously adding the sodium hydroxide aqueous solution with the concentration of 0.4mol/1 to adjust the pH value to 12; (3) adding 16ml acidifying agent, i.e. lactic acid, wherein in the process of adding the acidifying agent, the enrofloxacin is separated out and crystallized at first, and then completely dissolved when the pH value becomes neutral along with the addition of the acidifying agent; (4) Adding 0.5g antioxidant, i.e. sodium thiosulfate, into the neutral solution; (5) Continuously adding 0.3g chelating agent, i.e. EDTA; (6) diluting with purified water to a constant volume of 100ml after the step (5) is finished, and performing filtering sterilization on the solution with constant volume by a 0.45-micron micropore filter membrane; (7) Separately packaging the injection after filtering sterilization to obtain finished products. In accordance with tests, the prepared enrofloxacin injection is neutral in pH value and the content of the effective ingredient, i.e. the enrofloxacin, in the injection is 20% based on the total weight of the injection. The results of analysis for the enrofloxacin injection prepared in Embodiments 1 to 4 are shown in Table 1, Table 2 or Table 3: Time I Month 3 Months 6 Months 12Months 18Months 24Months Type Embodiment Yellowish Yellowish Yellowish Yellowish Yellowish Yellowish solution without solution solution solution solution without solution crystal without crystal without crystal without crystal crystal without crystal separation separation separation separation separation separation Embodiment Yellowish Yellowish Yellowish Yellowish Yellowish Yellowish solution without solution solution solution solution without solution crystal without crystal without crystal without crystal crystal without crystal separation separation separation separation separation separation Embodiment Yellowish Yellowish Yellowish Yellowish Yellowish Yellowish solution without solution solution solution solution without solution 3 crystal without crystal without crystal without crystal crystal without crystal separation separation separation separation separation separation Embodiment Yellowish Yellowish Yellowish Yellowish Yellowish Yellowish solution without solution solution solution solution without solution 4 crystal without crystal without crystal without crystal crystal without crystal separation separation separation separation separation separation Table 1 Test on Enrofloxacin Injection's Stability It is apparent from Table I that, the enrofloxacin injection prepared by the invention has stable ingredients and no crystal separation after long-time storage. Embodiment I Embodiment 2 Embodiment 3 Embodiment 4 Chicken No adverse No adverse No adverse No adverse (2.5mg/kg) reaction reaction reaction reaction Duck No adverse No adverse No adverse No adverse reaction reaction reaction (2.5mg/kg) reaction Cow No adverse No adverse No adverse No adverse (2.5mg/kg) reaction reaction reaction reaction Pig No adverse No adverse No adverse No adverse (2.5mg/kg) reaction reaction reaction reaction Table 2 Adverse Reaction of Enrofloxacin Injection to Animals It is apparent from Table 2 that, the enrofloxacin injection prepared by the invention has no irritation to animals and causes no adverse reaction to animals after being injected. Control Group Embodiment Embodiment Embodiment Embodiment (No 1 2 3 4 Administration) Infection 100% 100% 100% 100% 100% Rate Mortality 94% 2% 6% 11% 3% Rate Cure Rate 98% 93% 89% 97% Table 3 Test on Curative Effect of Artificial Infected Chickens with Escherichia coli It is apparent from Table 3 that, the enrofloxacin injection prepared by the invention has good curative effect and high cure rate.

Claims

1. An enrofloxacin injection, characterized in that: the injection, which is neutral in pH value, comprises 10 to 20 parts of enrofloxacin, 0.1 to 0.5 parts of antioxidant and 0.1 to 0.5 parts of chelating agent.

2. The enrofloxacin injection according to claim 1, characterized in that: the enrofloxacin accounts for 10 to 20% of the total weight of the injection.

3. The enrofloxacin injection according to claim 1, characterized in that: the antioxidant is sodium thiosulfate or sodium bisulfite.

4. The enrofloxacin injection according to claim 1, characterized in that: the chelating agent is EDTA.

5. A preparation method of enrofloxacin injection, characterized in that: the method comprises the steps of: (1) Adding enrofloxacin to sodium hydroxide aqueous solution; (2) Continuously adding the sodium hydroxide aqueous solution to adjust the pH value to be within a range from 9 to 13; (3) Adding an acidifying agent to adjust the pH value to be neutral; (4) Adding an antioxidant; (5) Adding a chelating agent; (6) Diluting with water to a constant volume to obtain the enrofloxacin injection.

6. The preparation method of enrofloxacin injection according to claim 5, characterized in that: after the step (6) is finished, filtering sterilization by a 0.45-micron micropore filter membrane is performed.

7. The preparation method of enrofloxacin injection according to claim 5, characterized in that: the concentration of the sodium hydroxide aqueous solution in the step (1) is 0.2 to 0.4 mol/l.

8. The preparation method of enrofloxacin injection according to claim 5, characterized in that: the acidifying agent in the step (3) is one or two or three of lactic acid, sodium butyrate and arginine.

9. The preparation method of enrofloxacin injection according to claim 5, characterized in that: the antioxidant in the step (4) is sodium thiosulfate or sodium bisulfite.

10. The preparation method of enrofloxacin injection according to claim 5, characterized in that: the chelating agent in the step (5) is EDTA.