CN113662912B - Marbofloxacin controlled-release gel for livestock and preparation method thereof - Google Patents

Marbofloxacin controlled-release gel for livestock and preparation method thereof Download PDF

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CN113662912B
CN113662912B CN202110967342.0A CN202110967342A CN113662912B CN 113662912 B CN113662912 B CN 113662912B CN 202110967342 A CN202110967342 A CN 202110967342A CN 113662912 B CN113662912 B CN 113662912B
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marbofloxacin
controlled
release gel
gel
temperature
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CN113662912A (en
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魏培
钱淼
孙新堂
王成森
朱术会
朱瑞娟
杨文文
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Shandong Vocational Animal Science and Veterinary College
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Abstract

The invention provides marbofloxacin controlled release gel, which comprises a main drug marbofloxacin, a temperature sensitive matrix, a solubilizer, a preservative, a humectant and a pH regulator. The marbofloxacin controlled-release gel has the beneficial effects that the preparation process is simple, the stability is good, the irritation is small, and the pH value is suitable for the intrauterine pH environment of a female animal. The medicine is locally administrated through vagina or uterus, is adhered to vagina/uterus mucous membrane by means of temperature sensitive property, and has obvious endometritis treating effect and high biocompatibility and compliance.

Description

Marbofloxacin controlled-release gel for livestock and preparation method thereof
Technical Field
The invention belongs to the field of veterinary medicines, and particularly relates to a marbofloxacin controlled-release gel preparation.
Background
Marbofloxacin is a third generation of quinolone animal-specific antibacterial drug following enrofloxacin, darofloxacin, sarafloxacin, difloxacin, originally created by Swiss Roche, inc., vetoquinol further developed and marketed in the United kingdom for the first time in 1995, followed by subsequent marketing in France, the United states, and Europe. The structural formula is as follows:
Marbofloxacin is mainly used for resisting bacteria by inhibiting the activities of bacterial type II topoisomerase and type IV topoisomerase, and is not easy to generate cross drug resistance with other drugs because the action mechanism is different from other antibacterial drugs. Marbofloxacin has wide antibacterial spectrum, strong bactericidal capacity, strong activity on gram-positive bacteria and gram-negative bacteria, and even effect on certain mould and anaerobic bacteria. The medicine is widely distributed in animals, except central nervous system, the concentration of the medicine in all the investigated tissues is higher than that of blood plasma, such as liver, kidney, lung, breast, skin and other tissues, the medicine has strong penetrability, quick and complete in vivo absorption, long elimination half-life period, high bioavailability approaching 100%, wide safe dosage range and no obvious reproduction and genetic toxicity. These characteristics determine that marbofloxacin has great potential in preventing and treating respiratory system infection, urinary system infection, digestive system infection, superficial and deep skin tissue infection, eye and auditory canal infection and other aspects of livestock and poultry.
Marbofloxacin is widely used in the United states, european Union, new Zealand, japan and other countries at present, and is mainly used for treating female livestock mastitis-metritis-agalactia syndrome (MMA) and bacterial respiratory tract infection of cattle. Female animals have endometritis, a common disease of reproductive organs, mainly caused by bacteria entering the uterus and abnormally increasing and remaining therein during normal post-partum, abortion or oestrus, and the highest incidence after parturition or abortion. The traditional method for treating female animal endometritis is usually carried out by means of uterine drug lavage, intrauterine administration and the like, and has complicated operation and higher cost.
The main formulation of Marbofloxacin currently applied is injection or oral solution of lactate or hydrochloride, the injection or oral solution is absorbed by the whole body, and the drug is easy to generate drug resistance after long-term whole body absorption, firstly, the effective dosage reaching endometrium is less, the maintenance time is short, unlike local gel administration, and the Marbofloxacin is adhered to endometrium for long time to exert local treatment effect. Secondly, no topical preparation specially used for female animals endometritis is found.
Disclosure of Invention
The invention aims to provide a topical preparation of marbofloxacin, which is marbofloxacin controlled-release gel for female animal vaginal or uterine administration, has a large effective dosage reaching endometrium, and can adhere to the endometrium for a long time to exert a local treatment effect.
The technical scheme of the invention is as follows: the marbofloxacin controlled release gel comprises marbofloxacin as a main medicine, a temperature sensitive matrix, a solubilizer, a preservative, a humectant and a pH regulator.
The temperature sensitive matrix is selected from one or more of poloxamer, celluloses and chitosan. Preferably poloxamer based matrices. In order to obtain better technical effects, the temperature-sensitive matrix is one or more selected from poloxamer 407, poloxamer 188, methylcellulose, hydroxypropyl methylcellulose and chitosan-sodium glycerophosphate compound;
The solubilizer is selected from one or more of hydroxypropyl-beta-cyclodextrin, tween 20, tween 80 and sodium oleate.
The preservative is one or more selected from ethyl hydroxybenzoate, methyl hydroxybenzoate, sodium benzoate, chlorhexidine acetate and chlorobutanol.
The humectant is one or more selected from propylene glycol, glycerol and sorbitol.
The pH regulator is one or more of triethanolamine, sodium hydroxide and acetic acid-sodium acetate buffer salt.
The marbofloxacin is used as a main medicine, the temperature of the gel is controlled by adopting a temperature-sensitive matrix, and the matrix is in a flowable liquid state in vitro or below the gelation temperature, so that the marbofloxacin is convenient for industrial production, and is converted into a semisolid gel when being in contact with the body temperature of an animal at a medicine administration position, and has good gelation strength and adhesion capacity, so that the acting time of the medicine is prolonged. Because marbofloxacin is sensitive to light and has poor solubility, the solubility of the marbofloxacin can be greatly increased by adding the solubilizer, the medicine absorption is promoted, the bioavailability is improved, and meanwhile, the stability of the marbofloxacin can be improved by utilizing the inclusion effect of the solubilizer on the marbofloxacin. The humectant is added, so that the desiccation and dryness can be prevented in the storage process of the gel, and meanwhile, the antibacterial effect of the preservative can be improved; the pH regulator is used to make the preparation conform to the weak acidic environment in vagina and uterus, reduce the heterogenic property and irritation of the medicine to mucous membrane, promote the recovery of the physiological environment in vagina and uterus, and make the female livestock get better effect in the treatment of endometritis.
To achieve better technical effects, the marbofloxacin gel comprises per 100 ml:
Controlling each component in the prescription within the above dosage range is better in the safety and stability of the gel. Specifically, the amount of temperature sensitive matrix will affect the gelation temperature, and the different matrices will have different effects on the gelation temperature. For example, poloxamer 407 temperature sensitive matrix is selected, the dosage is less, the gelation temperature is high, and the dosage is more, the gelation temperature is low; the solubilizer mainly plays a role in dissolving the main medicine, and the insufficient dissolution of the main medicine can be caused by the small dosage, so that the curative effect is affected; too much preservative may not be dissolved or irritation may occur; the humectant is less in dosage, the gel can be dehydrated and dried in the storage process, and the gel state can be influenced by excessive dosage; too much or too little amount of the pH adjustor may cause the pH of the gel to be not maintained in an optimal range, affecting the stability of the main drug and the irritation of the gel.
The pH value of the marbofloxacin gel is preferably 4.5-5.0.
In one embodiment of the invention, the marbofloxacin controlled release gel comprises the following components per 100 ml:
Main medicine: 3.5-6.0g of marbofloxacin; a temperature sensitive matrix: poloxamer 407.0-19.0 g; solubilizer: 15.0-25.0g of hydroxypropyl-beta-cyclodextrin; preservative: 0.05-0.15g of ethylparaben; humectant: propylene glycol 2.5-7.5ml; pH regulator: triethanolamine is adjusted to pH 4.0-6.0, and distilled water is added to 100ml.
In one embodiment of the invention, the marbofloxacin controlled release gel comprises the following components per 100 ml:
main medicine: 3.5-6.0g of marbofloxacin; a substrate: poloxamer 407.0-19.0 g; solubilizer: 15.0-25.0g of hydroxypropyl-beta-cyclodextrin; preservative: 0.05-0.15g of ethylparaben; humectant: 2.5-7.5ml of glycerol; pH regulator: the pH value of sodium hydroxide is regulated to 4.0-6.0, and distilled water is added to 100ml.
In one embodiment of the invention, the marbofloxacin controlled release gel comprises the following components per 100 ml:
Main medicine: 3.5-6.0g of marbofloxacin; a substrate: poloxamer 407.0-19.0 g; solubilizer: tween 20.0-25.0 g; preservative: 0.05-0.15g of sodium benzoate; humectant: propylene glycol 2.5-7.5ml; pH regulator: the pH value of the acetic acid-sodium acetate buffer salt is adjusted to 4.0-6.0, and distilled water is added to 100ml.
In one embodiment of the invention, the marbofloxacin controlled release gel comprises the following components per 100 ml:
Main medicine: 3.5-6.0g of marbofloxacin; a substrate: poloxamer 188 15.0-19.0g; solubilizer: 15.0-25.0g of hydroxypropyl-beta-cyclodextrin; preservative: 0.05-0.15g of ethylparaben; humectant: propylene glycol 2.5-7.5ml; pH regulator: triethanolamine is adjusted to pH 4.0-6.0, and distilled water is added to 100ml.
In one embodiment of the invention, the marbofloxacin controlled release gel comprises the following components per 100 ml:
Main medicine: 3.5-6.0g of marbofloxacin; a substrate: poloxamer 188 15.0-19.0g; solubilizer: 15.0-25.0g of hydroxypropyl-beta-cyclodextrin; preservative: 0.05-0.15g of ethylparaben; humectant: 2.5-7.5ml of glycerol; pH regulator: the pH value of sodium hydroxide is regulated to 4.0-6.0, and distilled water is added to 100ml.
In one embodiment of the invention, the marbofloxacin controlled release gel comprises the following components per 100 ml:
Main medicine: 3.5-6.0g of marbofloxacin; a substrate: poloxamer 188 15.0-19.0g; solubilizer: tween 20.0-25.0 g; preservative: 0.05-0.15g of sodium benzoate; humectant: propylene glycol 2.5-7.5ml; pH regulator: the pH value of the acetic acid-sodium acetate buffer salt sodium hydroxide is adjusted to 4.0-6.0, and distilled water is added to 100ml.
The invention also provides marbofloxacin controlled-release gel for treating female animal endometritis, and the prescription of the marbofloxacin controlled-release gel is the same as the bofloxacin controlled-release gel.
In the invention, the marbofloxacin controlled release gel is a controlled release gel for vaginal or uterine administration.
The invention also provides a preparation method of the marbofloxacin controlled-release gel,
(1) Precisely weighing the temperature-sensitive matrix, adding into a proper amount of distilled water, magnetically stirring, and placing in a refrigerator to make the matrix fully swelled and uniformly dispersed to obtain a clear solution of the temperature-sensitive matrix.
(2) And precisely weighing marbofloxacin and a solubilizer, placing the marbofloxacin and the solubilizer into the temperature-sensitive matrix solution, and performing ultrasonic treatment until the marbofloxacin and the solubilizer are dissolved and magnetically stirring.
(3) Dissolving antiseptic in humectant, adding into the above solution, stirring, adding distilled water, and adjusting pH to 4.0-6.0 with pH regulator to obtain Marbofloxacin controlled release gel.
In order to obtain better technical effects, the preparation method of the marbofloxacin controlled release gel comprises the following steps:
(1) Precisely weighing the temperature sensitive matrix, adding into appropriate amount of distilled water, magnetically stirring for 15-45min, and standing in a refrigerator at 4deg.C overnight to allow it to fully swell and disperse uniformly to obtain clear solution of the temperature sensitive matrix.
(2) Accurately weighing marbofloxacin and solubilizer, placing in the temperature-sensitive matrix solution, and magnetically stirring for 15-45min after ultrasonic treatment until the marbofloxacin and the solubilizer are dissolved.
(3) Dissolving antiseptic in humectant, adding into the above solution, stirring, adding distilled water to 100ml, and adjusting pH to 4.5-5.0 with pH regulator to obtain Marbofloxacin controlled release gel.
In one embodiment of the invention, marbofloxacin controlled release gel,
In the embodiment, marbofloxacin is taken as a main drug, poloxamer 407 is taken as a temperature-sensitive gel matrix, and the marbofloxacin is in a flowable liquid state in vitro or below a gelation temperature, so that the marbofloxacin is convenient for industrial production, and is converted into a semisolid gel when being in contact with the body temperature of an animal at a drug administration part, and has good gelation strength and adhesion capacity, so that the action time of the drug is prolonged; because marbofloxacin is sensitive to light and has poor solubility, the solubility of the marbofloxacin can be greatly increased by adding the hydroxypropyl-beta-cyclodextrin, the drug absorption is promoted, the bioavailability is improved, and meanwhile, the stability of the marbofloxacin can be improved by utilizing the inclusion effect of the hydroxypropyl-beta-cyclodextrin on the marbofloxacin. The ethylparaben is used as a preservative; propylene glycol is a ethylparaben solvent and a humectant, and meanwhile, the antibacterial effect of ethylparaben can be improved; the triethanolamine is used as a pH regulator, so that the preparation accords with the weak acidic environment in the vagina and uterus, reduces the heterogenic property and the irritation of the medicine to mucous membranes, promotes the recovery of the physiological environment in the vagina and uterus, and ensures that the female livestock have better effect in the treatment of endometritis.
The marbofloxacin controlled-release gel prepared by the invention has the advantages of simple preparation process, good stability, small irritation and pH value adaptation to the intrauterine pH environment of female animals. The medicine is locally administrated through vagina or uterus, is adhered to vagina and endometrium by means of temperature sensitive property, and has obvious endometritis treating effect and high biocompatibility and compliance.
Drawings
FIG. 1 shows the results of in vitro release test of examples 1 to 4 according to the present invention.
Detailed Description
The invention is described in detail below in connection with the embodiments, but it should be noted that the scope of the invention is not limited by these embodiments and the principle explanation, but is defined by the claims.
In the present invention, any matters or matters not mentioned are directly applicable to those known in the art without modification except for those explicitly stated. Moreover, any embodiment described herein can be freely combined with one or more other embodiments described herein, and the technical solutions or ideas thus formed are all considered as part of the original disclosure or original description of the present invention, and should not be considered as new matters not disclosed or contemplated herein unless such combination would obviously be unreasonable to one skilled in the art.
All of the features disclosed in this invention may be combined in any combination which is understood to be disclosed or described in this invention unless the combination is obviously unreasonable by those skilled in the art.
The numerical points disclosed in the present specification include not only the numerical points specifically disclosed in the embodiments but also the end points of each numerical range in the specification, and any combination of these numerical points should be considered as a disclosed or described range of the present invention.
Technical and scientific terms used in the present invention are defined to have their meanings, and are not defined to have their ordinary meanings in the art.
In the examples, marbofloxacin, poloxamer 407, hydroxypropyl-beta-cyclodextrin, tween 20, polyethylene glycol 400, ethyl hydroxybenzoate, sodium benzoate, propylene glycol, glycerol and triethanolamine are all commercially available pharmaceutical grade substances.
Example 1
Precisely weighing poloxamer 407.0 g, adding into a proper amount of distilled water, magnetically stirring for 15-45min, and then placing in a refrigerator at 4 ℃ for overnight, so that the poloxamer 407 is fully swelled and uniformly dispersed to obtain a clear solution of poloxamer 407. Then accurately weighing 3.5g of marbofloxacin and 15.0g of hydroxypropyl-beta-cyclodextrin, placing into the poloxamer 407 solution, carrying out ultrasonic treatment until the marbofloxacin and the hydroxypropyl-beta-cyclodextrin are dissolved, and magnetically stirring for 15-45min. Dissolving 0.05g of ethylparaben in 6.5ml of propylene glycol, adding into the above solution, stirring, adding distilled water to 100ml, and regulating pH to 4.5-5.0 with triethanolamine to obtain Marbofloxacin controlled-release gel.
2. Example 2
Precisely weighing poloxamer 407.0 g, adding into a proper amount of distilled water, magnetically stirring for 15-45min, and then placing in a refrigerator at 4 ℃ for overnight, so that the poloxamer 407 is fully swelled and uniformly dispersed to obtain a clear solution of poloxamer 407. Then accurately weighing 4.5g of marbofloxacin and 20.0g of hydroxypropyl-beta-cyclodextrin, placing into the poloxamer 407 solution, carrying out ultrasonic treatment until the marbofloxacin and the hydroxypropyl-beta-cyclodextrin are dissolved, and magnetically stirring for 15-45min. Dissolving 0.08g of ethylparaben in 4.5ml of propylene glycol, adding into the above solution, stirring, adding distilled water to 100ml, and regulating pH to 4.5-5.0 with triethanolamine to obtain Marbofloxacin controlled-release gel.
3. Example 3
Precisely weighing poloxamer 407 19.0g, adding into a proper amount of distilled water, magnetically stirring for 15-45min, and placing in a refrigerator at 4 ℃ overnight to fully swell and uniformly disperse to obtain a clear solution of poloxamer 407. Then precisely weighing 5.5g of marbofloxacin and 25.0g of tween 20, placing the marbofloxacin and the tween 20 into the poloxamer 407 solution, carrying out ultrasonic treatment until the marbofloxacin and the tween are dissolved, and magnetically stirring for 15-45min. Dissolving 0.12g sodium benzoate in 2.5ml glycerin, adding into the above solution, stirring, adding distilled water to 100ml, and regulating pH with triethanolamine to 4.5-5.0 to obtain Marbofloxacin controlled release gel.
4. Example 4 (comparative example)
Precisely weighing poloxamer 407.0 g, adding into a proper amount of distilled water, magnetically stirring for 15-45min, and then placing in a refrigerator at 4 ℃ for overnight, so that the poloxamer 407 is fully swelled and uniformly dispersed to obtain a clear solution of poloxamer 407. Then accurately weighing 4.5g of marbofloxacin and 400.0 g of polyethylene glycol, placing the marbofloxacin and the polyethylene glycol into the poloxamer 407 solution, carrying out ultrasonic treatment until the marbofloxacin and the polyethylene glycol are dissolved, and magnetically stirring for 15-45min. Dissolving 0.08g of ethylparaben in 4.5ml of propylene glycol, adding into the above solution, stirring, adding distilled water to 100ml, and regulating pH to 4.5-5.0 with triethanolamine to obtain Marbofloxacin controlled-release gel.
Property and effect experiments of marbofloxacin controlled release gel:
1. Gel temperature determination
Penicillin bottles containing about 10mL of marbofloxacin controlled release gel (example 1, example 2, example 3, example 4) and magnetic stirrer were placed in a water bath. The middle of the rubber stopper in the penicillin bottle is perforated and inserted into a thermometer, and the lower end of the thermometer is completely immersed into the solution. The electromagnetic stirrer is started, and the temperature rise rate of the water bath is kept to be increased by 1 ℃ every 1-2 min. The temperature at which the magnetic stirrer completely stopped rotating was defined as the gelation temperature (T in degrees Celsius), and each sample was measured 3 times in parallel and the average value was taken.
Sample numbering T1 T2 T3 T average
1 38.4 38.2 38.5 38.37
2 35.0 34.7 34.5 34.73
3 26.4 26.7 26.5 26.57
4 Gel property difference Gel property difference Gel property difference Gel property difference
2. In vitro Release test
Precisely measuring 3mL of marbofloxacin controlled-release gel (example 1, example 2, example 3 and example 4), placing into a dialysis bag with a molecular weight cut-off of 8000-12000, fastening two ends, placing into a rotary basket of a dissolution instrument, holding 900mL of degassing release medium in a dissolution cup, starting the dissolution instrument, adjusting the rotation speed of the dissolution instrument and the temperature of the dissolution medium to required values, sampling 5mL at 1, 2, 6, 10, 12, 24 and 36h, supplementing release medium with equal temperature and equal amount, filtering with a 0.45 μm microporous filter membrane to obtain subsequent filtrate, and measuring the concentration of the drug by adopting a High Performance Liquid Chromatography (HPLC) method. The cumulative release rate (Q) of marbofloxacin was calculated from the standard curve, the cumulative release rate (%) = mass of released drug/total mass of drug administered, the cumulative release rate was plotted on the abscissa with time as the ordinate. The results are shown in FIG. 1.
3. Stability investigation
To examine the stability of the prepared marbofloxacin controlled release gels (example 1, example 2, example 3, example 4), the stability of the formulations was examined by a 6-month acceleration test, a 12-month long-term test (room temperature leave-on test) and a centrifugal test, respectively, according to the veterinary chemical drug stability study technical guidelines in the veterinary drug study technical guidelines compilation.
3.1 Accelerated test in each example, 20g of each sample of 3 batches was placed in an incubator with a temperature of 30.+ -. 2 ℃ and a relative humidity of 65%.+ -. 5% for 6 months to conduct an accelerated test, and samples were taken at the time of 0 th month, 1 th month, 2 th month, 3 th month and 6 th month, and quality indexes such as properties, uniformity, pH and content of the samples were examined. The results show that examples 1-3 are all pale yellow, transparent, semi-solid gels with uniform texture, no delamination, and example 4 is a pale yellow, turbid, non-uniform viscous liquid with delamination, pH and content as shown in the table below.
3.2 Long-term test Each example takes 20g of 3 batches of samples, and places the samples at 25+/-2 ℃ and 60+/-10% relative humidity for 12 months under the dark condition, and samples are taken at the time of 0, 3, 6, 9 and 12 months respectively, so that quality indexes such as properties, uniformity, pH, content and the like of the samples are inspected. The results show that examples 1-3 are all pale yellow, transparent, semi-solid gels with uniform texture, no delamination, and example 4 is a pale yellow, turbid, non-uniform viscous liquid with delamination, pH and content as shown in the table below.
3.3 Centrifugation experiments 3 batches of samples were taken, 10g each, placed in 50ml centrifuge tubes, centrifuged at 3000r/min for 30min and observed for gel delamination. The results show that the marbofloxacin controlled-release gels in examples 1-3 are fine and sticky pale yellow liquid after centrifugation, and have no layering phenomenon, the marbofloxacin controlled-release gel in example 4 is thinner pale yellow liquid, and have layering phenomenon and poor stability.
4. Irritation test
The mucosa irritation of the prepared marbofloxacin controlled-release gel (example 1, example 2, example 3 and example 4) was evaluated by a rabbit homozygote left and right eye self-contrast method. Selecting 6 healthy rabbits, dripping 1 drop of marbofloxacin controlled-release gel into the left eye of the rabbits during test, dripping 1 drop of physiological saline into the right eye as a control, closing the eyes for about 7-10 seconds, and observing the reaction conditions of the eye mucosa of the rabbits 1, 6, 12, 24, 48 and 72 hours after the dripping.
The results show that the left eye of the rabbit has transparent cornea, no turbidity, clear iris texture, no congestion and swelling, and no obvious difference from the right eye in the observation time. The left eye of the rabbit dropping the marbofloxacin controlled-release gel only observes a small amount of secretion after 1h and 6h, the rest is the same as the right eye dropping the normal saline, the local stimulation effect of the gel on the eye mucosa is weakened along with the time and the metabolism of the medicine, and the normal state is gradually recovered after 12h, which shows that the marbofloxacin controlled-release gel has no obvious stimulation on the eye mucosa of the rabbit and meets the requirements of the mucous membrane drug preparation of the animal pharmacopoeia 2020 edition.
5. Observation of curative effect of endometritis of sow
The therapeutic effect of marbofloxacin controlled-release gel (example 1, example 2, example 3, example 4) on endometritis was studied using sow as a model animal. Grouping according to the degree of endometritis of the sow, and setting the florfenicol uterus injectant as a positive control to examine the cure rate and the effective rate of the endometritis of the sow.
200 Sows were divided into three groups of mild (100) moderate (60) and severe (40) according to disease condition. A mild group of 80 random fractions for treatment of marbofloxacin controlled-release gels (20 for each example) and 20 for treatment of florfenicol uterine infusion; the medium group is divided into 48 groups for the treatment of marbofloxacin controlled-release gel (12 groups for each example) and 12 groups for the treatment of florfenicol uterus injectant; severe group random 32 split was used for treatment of marbofloxacin controlled release gels (8 for each example) and 8 for treatment of florfenicol uterine infusion. Marbofloxacin controlled-release gel (40 ml:2 g) with therapeutic dose of 40ml is administered topically in uterus, 1 time every 1 day, and 1 time every 1 day; the therapeutic dose of florfenicol uterine infusion (25 ml:2 g) was 25ml, administered by uterine infusion 1 time a day and 1 time a further 1 time a day apart. After administration, the treatment condition of the sick sow is observed, the treatment effect is divided into three grades of cure, effectiveness and ineffectiveness, the cure rate (%) and the effective rate (%) are calculated, and the test data are processed by t-test.
Cure rate (%) = number of cures/total number of cases x 100%
Effective rate (%) = (cure number + effective number)/total case number x 100%
The results show that the cure rates of marbofloxacin controlled-release gel (example 1, example 2, example 3 and example 4) are 67.5%, 82.5%, 77.5% and 45.0%, and the effective rates are 87.5%, 95.0%, 92.5% and 72.5%, respectively; the cure rate of the florfenicol uterus injectant is 52.5%, and the effective rate is 77.5%. Compared with the florfenicol uterus injectant positive control group, the marbofloxacin controlled-release gel group (examples 1-3) has obvious cure rate average difference (P < 0.05), obvious effective rate difference (P < 0.05) and no obvious difference in example 4. The formulation of example 4 has poor solubilization effect and low drug effect, and polyethylene glycol 400 and ethyl hydroxybenzoate in the prescription undergo complex reaction to affect the antiseptic effect.
The foregoing describes one embodiment of the present invention in detail, but the description is only a preferred embodiment of the present invention and should not be construed as limiting the scope of the invention. All equivalent changes and modifications within the scope of the present invention are intended to be covered by the present invention.

Claims (3)

1. A marbofloxacin controlled-release gel, characterized in that every 100ml of the marbofloxacin gel comprises:
the temperature sensitive matrix is selected from poloxamer 407; the solubilizer is selected from hydroxypropyl-beta-cyclodextrin; the preservative is selected from ethyl hydroxy benzoate; the humectant is selected from propylene glycol; the pH regulator is triethanolamine;
the preparation method of the marbofloxacin controlled-release gel comprises the following steps:
(1) Precisely weighing a temperature-sensitive matrix, adding the temperature-sensitive matrix into a proper amount of distilled water, magnetically stirring, and then placing the mixture in a refrigerator to fully swell and uniformly disperse the mixture to obtain a clear solution of the temperature-sensitive matrix;
(2) Then accurately weighing marbofloxacin and a solubilizer, placing the marbofloxacin and the solubilizer into the temperature-sensitive matrix solution, carrying out ultrasonic treatment until the marbofloxacin and the solubilizer are dissolved, and magnetically stirring;
(3) Dissolving antiseptic in humectant, adding into the above solution, stirring, adding distilled water, and adjusting pH to 4.0-6.0 with pH regulator to obtain Marbofloxacin controlled release gel.
2. The marbofloxacin controlled-release gel of claim 1, wherein: the marbofloxacin controlled-release gel agent,
3. A marbofloxacin controlled-release gel for treating female animal endometritis, which is characterized in that: the marbofloxacin controlled-release gel is the marbofloxacin controlled-release gel of claim 1 or 2.
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