CN113662912A - Marbofloxacin controlled-release gel for livestock and preparation method thereof - Google Patents
Marbofloxacin controlled-release gel for livestock and preparation method thereof Download PDFInfo
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- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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 of simple preparation process, good stability, small irritation and adaptation of the pH value to the intrauterine pH environment of female animals. The medicine is locally administrated through vagina or uterus, is adhered to vagina/uterine mucosa by virtue of temperature-sensitive type temperature-sensitive property, prolongs the action time by utilizing the slow release of the medicine, and has remarkable treatment effect on endometritis and high biocompatibility and compliance of the preparation.
Description
Technical Field
The invention belongs to the field of veterinary medicines, and particularly relates to a marbofloxacin controlled-release gel preparation.
Background
Marbofloxacin, a third generation of quinolone animal-specific antibacterial drugs following enrofloxacin, danofloxacin, sarafloxacin, difloxacin, was first created by rotz, a company further developed by Vetoquinol, and was first marketed in the united kingdom in 1995, and subsequently in france, the united states and europe in succession. The structural formula is as follows:
marbofloxacin is antibacterial mainly by inhibiting the activity of bacteria 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 that of other antibacterial drugs. Marbofloxacin has wide antibacterial spectrum, strong bactericidal capability, strong activity to gram-positive bacteria and gram-negative bacteria, and even effective to some mould and anaerobic bacteria. The medicine has wide distribution in animal body, except central nervous system, the medicine concentration in all the studied tissues is higher than that in blood plasma, such as liver, kidney, lung, mammary gland, skin, etc., the medicine has strong penetrability, fast and complete absorption in body, long elimination half life, bioavailability near 100%, wide safe dosage range and no obvious reproduction and genetic toxicity. The characteristics all determine that marbofloxacin has great potential in the aspects of preventing and treating respiratory system infection, urinary system infection, digestive system infection, superficial and deep skin tissue infection, eye and ear canal infection and the like of livestock and poultry.
Marbofloxacin is widely used in the united states, european union, new zealand, japan and other countries, and is mainly used for treating female animal mastitis-metritis-agalactia syndrome (MMA) and bovine bacterial respiratory infection. Endometritis in dam is a common disease of reproductive organs, mainly caused by abnormal proliferation and retention of bacteria in uterus during normal post partum, abortion or estrus, with the highest incidence after parturition or abortion. The traditional method for treating female animal endometritis usually adopts uterine drug lavage, intrauterine drug administration and other modes, and has the disadvantages of complex operation and high cost.
The main dosage form of marbofloxacin applied at present is an injection or an oral solution of lactate or hydrochloride thereof, the injection and the oral solution are absorbed systemically, and the drug is easy to generate drug resistance after being absorbed systemically for a long time, and firstly, the effective dosage reaching endometrium is less, the maintaining time is short, the administration is not like local gel administration, and the marbofloxacin is adhered to the endometrium for a long time to play a local treatment role. Secondly, no special local preparation for the endometritis of the female animal is found.
Disclosure of Invention
The invention aims to provide a marbofloxacin local preparation, which is a marbofloxacin controlled-release gel applied to the vagina or the uterus of female animals, has more effective dosage reaching the endometrium, and is adhered to the endometrium for a longer time to play a local treatment role.
The technical scheme of the invention is as follows: the marbofloxacin controlled-release gel comprises a main drug marbofloxacin, 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, cellulose and chitosan. Preferably a poloxamer based matrix. In order to achieve better technical effect, the temperature-sensitive matrix is selected from one or more of poloxamer 407, poloxamer 188, methylcellulose, hydroxypropyl methylcellulose and chitosan-sodium glycerophosphate complex;
the solubilizer is selected from one or more of hydroxypropyl-beta-cyclodextrin, tween 20, tween 80 and sodium oleate.
The preservative is selected from one or more of ethyl hydroxybenzoate, methyl hydroxybenzoate, sodium benzoate, chlorhexidine acetate and chlorobutanol.
The humectant is selected from one or more of propylene glycol, glycerin and sorbitol.
The pH regulator is one or more of triethanolamine, sodium hydroxide and acetic acid-sodium acetate buffer salt.
The marbofloxacin gel takes marbofloxacin as a main drug, the temperature of the gel is controlled by adopting a temperature sensitive matrix, the matrix is in a liquid state which is easy to flow in vitro or below the gelling temperature, the industrial production is facilitated, the matrix is converted into a semisolid gel when contacting the body temperature of an animal at the administration part, and the marbofloxacin gel has good gelling strength and adhesion capability, so that the action time of the drug is prolonged. Because marbofloxacin is sensitive to light and has poor solubility, the solubility of marbofloxacin can be greatly increased by adding the solubilizer, the drug absorption is promoted, the bioavailability is improved, and the stability of marbofloxacin can be improved by utilizing the inclusion effect of the solubilizer on marbofloxacin. The humectant is added, so that the antibacterial effect of the preservative can be improved while the water loss and the dryness of the gel during the storage process are prevented; the pH regulator is used to make the preparation conform to the weak acid environment in vagina and uterus, reduce the foreign property and irritation of the medicine to mucous membrane, promote the recovery of physiological internal environment of vagina and uterus, and obtain better effect in treating endometritis of female animals.
For better technical effect, the marbofloxacin gel comprises every 100 ml:
controlling each component in the formulation within the above dosage range provides a gel with improved safety and stability. In particular, the amount of temperature sensitive matrix affects the gelling temperature, and different matrices may affect the gelling temperature differently. For example, poloxamer 407 temperature sensitive matrix is selected, the gelling temperature is high when the dosage is less, and the gelling temperature is low when the dosage is more; the solubilizer mainly plays a role in dissolving the main drug, and the main drug is not completely dissolved due to too little dosage, so that the curative effect is influenced; too much preservative may not be dissolved or become irritating; the dosage of the humectant is less, so that the gel can be dehydrated and dried in the storage process, and the state of the gel can be influenced by excessive dosage; too much or too little pH regulator can make the pH of the gel not be maintained in the optimum range, and influence 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 a specific embodiment of the invention, the marbofloxacin controlled-release gel comprises, per 100 ml:
main drugs: 3.5-6.0g of marbofloxacin; temperature-sensitive substrate: 40715.0-19.0 g of poloxamer; solubilizer: 15.0-25.0g of hydroxypropyl-beta-cyclodextrin; preservative: 0.05-0.15g of ethylparaben; humectant: 2.5-7.5ml of propylene glycol; pH regulator: regulating pH to 4.0-6.0 with triethanolamine, and adding distilled water to 100 ml.
In a specific embodiment of the invention, the marbofloxacin controlled-release gel comprises, per 100 ml:
main drugs: 3.5-6.0g of marbofloxacin; matrix: 40715.0-19.0 g of poloxamer; 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: adjusting pH to 4.0-6.0 with sodium hydroxide, and adding distilled water to 100 ml.
In a specific embodiment of the invention, the marbofloxacin controlled-release gel comprises, per 100 ml:
main drugs: 3.5-6.0g of marbofloxacin; matrix: 40715.0-19.0 g of poloxamer; solubilizer: tween 2015.0-25.0 g; preservative: 0.05-0.15g of sodium benzoate; humectant: 2.5-7.5ml of propylene glycol; pH regulator: adjusting pH to 4.0-6.0 with acetic acid-sodium acetate buffer salt, and adding distilled water to 100 ml.
In a specific embodiment of the invention, the marbofloxacin controlled-release gel comprises, per 100 ml:
main drugs: 3.5-6.0g of marbofloxacin; matrix: 18815.0-19.0 g of poloxamer; solubilizer: 15.0-25.0g of hydroxypropyl-beta-cyclodextrin; preservative: 0.05-0.15g of ethylparaben; humectant: 2.5-7.5ml of propylene glycol; pH regulator: regulating pH to 4.0-6.0 with triethanolamine, and adding distilled water to 100 ml.
In a specific embodiment of the invention, the marbofloxacin controlled-release gel comprises, per 100 ml:
main drugs: 3.5-6.0g of marbofloxacin; matrix: 18815.0-19.0 g of poloxamer; 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 is adjusted to 4.0-6.0 by sodium hydroxide, and distilled water is added to 100 ml.
In a specific embodiment of the invention, the marbofloxacin controlled-release gel comprises, per 100 ml:
main drugs: 3.5-6.0g of marbofloxacin; matrix: 18815.0-19.0 g of poloxamer; solubilizer: tween 2015.0-25.0 g; preservative: 0.05-0.15g of sodium benzoate; humectant: 2.5-7.5ml of propylene glycol; pH regulator: acetic acid-sodium acetate buffer salt sodium hydroxide is used for adjusting the pH value to 4.0-6.0, and distilled water is added to 100 ml.
The invention also provides marbofloxacin controlled-release gel for treating dam endometritis, and the formula of the marbofloxacin controlled-release gel is the same as that of the marbofloxacin 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 a proper amount of distilled water, magnetically stirring, and placing in a refrigerator to fully swell and uniformly disperse the temperature sensitive matrix to obtain a clear solution of the temperature sensitive matrix.
(2) And precisely weighing marbofloxacin and a solubilizer, placing the marbofloxacin and the solubilizer in the temperature sensitive matrix solution, performing ultrasonic treatment until the marbofloxacin and the solubilizer are dissolved, and performing magnetic 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 effect, the preparation method of the marbofloxacin controlled-release gel comprises the following steps:
(1) precisely weighing the temperature sensitive matrix, adding 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 the temperature sensitive matrix to obtain a clear solution of the temperature sensitive matrix.
(2) Precisely weighing marbofloxacin and a solubilizer, placing in the temperature sensitive matrix solution, performing ultrasonic treatment until the marbofloxacin and the solubilizer are dissolved, and magnetically stirring for 15-45 min.
(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 a specific embodiment of the invention, the marbofloxacin controlled-release gel,
in the embodiment, marbofloxacin is used as a main drug, poloxamer 407 is used as a temperature-sensitive gel matrix, the marbofloxacin is in a liquid state which is easy to flow in vitro or below the gelling temperature, the industrial production is facilitated, the marbofloxacin is in contact with the body temperature of an animal at the administration part and is converted into a semisolid gel, and the marbofloxacin has good gelling strength and adhesion capability, so that the action time of the drug is prolonged; because marbofloxacin is sensitive to light and has poor solubility, the addition of hydroxypropyl-beta-cyclodextrin can greatly increase the solubility of marbofloxacin, promote the absorption of medicaments and improve the bioavailability, and simultaneously, the inclusion effect of hydroxypropyl-beta-cyclodextrin on marbofloxacin can be utilized to improve the stability of marbofloxacin. Ethylparaben is used as a preservative; the propylene glycol is an ethylparaben solvent and a humectant, and can also increase the bacteriostatic effect of ethylparaben; triethanolamine is used as pH regulator to make the preparation conform to weak acid environment in vagina and uterus, reduce foreign property and irritation of medicine to mucous membrane, promote recovery of physiological internal environment in vagina and uterus, and obtain better effect in treating endometritis of female animal.
The marbofloxacin controlled-release gel prepared by the invention has the advantages of simple preparation process, good stability, small irritation and pH value adapted to the pH environment in the uterus of female animals. The medicine is locally administrated through vagina or uterus, is adhered to vagina and intrauterine mucosa by virtue of temperature-sensitive type temperature-sensitive property, prolongs the action time by utilizing the slow release of the medicine, and has remarkable treatment effect on endometritis and high biocompatibility and compliance of the preparation.
Drawings
FIG. 1 is the results of in vitro release test of examples 1-4 of the present invention.
Detailed Description
The present invention will be described in detail with reference to the following embodiments, but it should be understood that the scope of the present invention is not limited by these embodiments and the principle of the present invention, but is defined by the claims.
In the present invention, anything or matters not mentioned is directly applicable to those known in the art without any change except those explicitly described. Moreover, any embodiment described herein may be freely combined with one or more other embodiments described herein, and the technical solutions or ideas thus formed are considered 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 a person skilled in the art would consider such combination to be clearly unreasonable.
All features disclosed in this invention may be combined in any combination and such combinations are understood to be disclosed or described herein unless a person skilled in the art would consider such combinations to be clearly unreasonable.
The numerical points disclosed in the present specification include not only the numerical points specifically disclosed in the examples but also the endpoints of each numerical range in the specification, and ranges in which any combination of the numerical points is disclosed or recited should be considered as ranges of the present invention.
Technical and scientific terms used herein are to be defined only in accordance with their definitions, and are to be understood as having ordinary meanings in the art without any definitions.
In the examples, marbofloxacin, poloxamer 407, hydroxypropyl-beta-cyclodextrin, tween 20, polyethylene glycol 400, ethylparaben, sodium benzoate, propylene glycol, glycerol and triethanolamine are all commercially available medicinal grade substances.
Example 1
Precisely weighing 40715.0 g of poloxamer, adding an appropriate amount of distilled water, magnetically stirring for 15-45min, and placing in a refrigerator at 4 ℃ overnight to fully swell and uniformly disperse the poloxamer to obtain a clear solution of poloxamer 407. And precisely weighing 3.5g of marbofloxacin and 15.0g of hydroxypropyl-beta-cyclodextrin, placing the marbofloxacin and the 15.0g of hydroxypropyl-beta-cyclodextrin into the poloxamer 407 solution, carrying out ultrasonic treatment until the marbofloxacin and the 15.0g of hydroxypropyl-beta-cyclodextrin are dissolved, and carrying out magnetic stirring for 15-45 min. Dissolving 0.05g of ethylparaben in 6.5ml of propylene glycol, adding the solution into the solution, stirring uniformly, adding distilled water to 100ml, and adjusting the ph to 4.5-5.0 by using triethanolamine to obtain the marbofloxacin controlled-release gel.
2. Example 2
Precisely weighing 40716.0 g of poloxamer, adding an appropriate amount of distilled water, magnetically stirring for 15-45min, and placing in a refrigerator at 4 ℃ overnight to fully swell and uniformly disperse the poloxamer to obtain a clear solution of poloxamer 407. And precisely weighing 4.5g of marbofloxacin and 20.0g of hydroxypropyl-beta-cyclodextrin, placing the marbofloxacin and the 20.0g of hydroxypropyl-beta-cyclodextrin into the poloxamer 407 solution, performing ultrasonic treatment until the marbofloxacin and the hydroxypropyl-beta-cyclodextrin are dissolved, and performing magnetic stirring for 15-45 min. Dissolving 0.08g of ethylparaben in 4.5ml of propylene glycol, adding into the solution, stirring uniformly, adding distilled water to 100ml, and adjusting pH to 4.5-5.0 with triethanolamine to obtain the marbofloxacin controlled-release gel.
3. Example 3
Precisely weighing 40719.0 g of poloxamer, adding an appropriate amount of distilled water, magnetically stirring for 15-45min, and placing in a refrigerator at 4 ℃ overnight to fully swell and uniformly disperse the poloxamer to obtain a clear solution of poloxamer 407. And precisely weighing 5.5g of marbofloxacin and 2025.0 g of tween into the poloxamer 407 solution, performing ultrasonic treatment until the marbofloxacin and the tween are dissolved, and performing magnetic stirring for 15-45 min. Dissolving 0.12g of sodium benzoate in 2.5ml of glycerol, adding the solution into the solution, stirring uniformly, adding distilled water to 100ml, and adjusting the ph to 4.5-5.0 by using triethanolamine to obtain the marbofloxacin controlled-release gel.
4. Example 4 (comparative example)
Precisely weighing 40716.0 g of poloxamer, adding an appropriate amount of distilled water, magnetically stirring for 15-45min, and placing in a refrigerator at 4 ℃ overnight to fully swell and uniformly disperse the poloxamer to obtain a clear solution of poloxamer 407. And precisely weighing 4.5g of marbofloxacin and 40020.0 g of polyethylene glycol, placing the marbofloxacin and the 40020.0 g of polyethylene glycol into the poloxamer 407 solution, performing ultrasonic treatment until the marbofloxacin and the 40020.0 g of polyethylene glycol are dissolved, and performing magnetic stirring for 15-45 min. Dissolving 0.08g of ethylparaben in 4.5ml of propylene glycol, adding into the solution, stirring uniformly, adding distilled water to 100ml, and adjusting pH to 4.5-5.0 with triethanolamine to obtain the marbofloxacin controlled-release gel.
Property and effect experiment of marbofloxacin controlled release gel:
1. determination of the gelation temperature
Approximately 10mL of marbofloxacin controlled release gel (example 1, example 2, example 3, example 4) and a magnetic stir bar were placed in a water bath. The middle of a rubber plug in the penicillin bottle is perforated and a thermometer is inserted, and the lower end of the thermometer is completely immersed in the solution. And starting the electromagnetic stirrer, and keeping the water bath heating rate to rise by 1 ℃ about 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 in parallel 3 times, and the average value was taken.
| Sample numbering | T1 | T2 | | 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 | Poor gel properties | Poor gel properties | Poor gel properties | Poor gel properties |
2. In vitro release test
Precisely measuring 3mL of marbofloxacin controlled-release gel (example 1, example 2, example 3 and example 4), placing the marbofloxacin controlled-release gel into a dialysis bag with the molecular weight cutoff of 8000-12000, fastening two ends, placing the marbofloxacin controlled-release gel into a rotary basket of a dissolution instrument, containing 900mL of degassing release medium in the 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 in 1, 2, 6, 10, 12, 24 and 36h, supplementing the release medium with equal temperature and equal amount, filtering with a 0.45 mu m microporous membrane to obtain a 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, and the cumulative release rate (%) (mass of released drug/total mass of drug administered) was plotted with time as abscissa and the cumulative release rate as ordinate. The results are shown in FIG. 1.
3. Stability survey
In order to examine the stability of the prepared marbofloxacin controlled-release gel (example 1, example 2, example 3 and example 4), the stability of the preparation is examined by 6-month accelerated test, 12-month long-term test (room-temperature sample retention test) and centrifugal test according to the technical guide principle of veterinary chemical drug stability research in the technical guide principle compilation of veterinary drug research.
3.1 accelerated test in each example, 20g of each of 3 batches of samples are placed in a thermostat with the temperature of 30 +/-2 ℃ and the relative humidity of 65 +/-5% for 6 months to carry out accelerated test, and the samples are sampled at 0, 1, 2, 3 and 6 months respectively to examine the quality indexes of the samples, such as properties, uniformity, pH, content and the like. The results show that examples 1 to 3 are all semi-solid gel-like with faint yellow, transparency and uniform texture, no delamination occurs, example 4 is viscous liquid with faint yellow, turbidity and nonuniform texture, delamination occurs, and the pH value and content are shown in the following table.
3.2 Long-term test 3 batches of samples of each example were taken 20g each and placed at 25 ℃. + -. 2 ℃ and 60%. + -. 10% relative humidity for 12 months under dark conditions, and sampled at 0, 3, 6, 9 and 12 months, respectively, to observe and examine quality indexes such as sample property, uniformity, pH and content. The results show that examples 1 to 3 are all semi-solid gel-like with faint yellow, transparency and uniform texture, no delamination occurs, example 4 is viscous liquid with faint yellow, turbidity and nonuniform texture, delamination occurs, and the pH value and content are shown in the following table.
3.3 centrifugation test in each example, 10g of each of 3 batches of samples were taken, placed in a 50ml centrifuge tube, centrifuged at 3000r/min for 30min, and the gel was observed for delamination. The result shows that the marbofloxacin controlled-release gels in the examples 1 to 3 are fine and sticky light yellow liquid after centrifugation, and the layering phenomenon does not occur, and the example 4 is thinner light yellow liquid, and the layering phenomenon occurs, so that the stability is poor.
4. Irritation test
The mucosa irritation of the prepared marbofloxacin controlled-release gel (example 1, example 2, example 3 and example 4) is evaluated by adopting a rabbit consubstantial left and right eye self-control method. Selecting 6 healthy rabbits without pathological changes or inflammatory symptoms of cornea, iris and conjunctiva, dripping 1 drop of marbofloxacin controlled-release gel into the left eye of the rabbit during the test, dripping 1 drop of normal saline into the right eye of the rabbit as a control, closing the eyes for about 7-10 seconds, and observing the reaction conditions of the eye mucous membranes of the rabbits at 1, 6, 12, 24, 48 and 72 hours after the medicine dripping.
The result shows that the left eye cornea of the rabbit is transparent and has no turbidity, the iris texture is clear, and the rabbit has no congestion and swelling, and has no obvious difference with the right eye. The left eye of the rabbit dropping the marbofloxacin controlled-release gel only observes a small amount of secretion after 1 hour and 6 hours, the rest of the marbofloxacin controlled-release gel 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 lapse and the metabolism of the medicine, and the marbofloxacin controlled-release gel gradually recovers to be normal after 12 hours, which shows that the marbofloxacin controlled-release gel has no obvious stimulation on the eye mucosa of the rabbit and meets the requirement of the mucosa medicinal preparation in 2020 edition of veterinary pharmacopoeia.
5. Observation of curative effect of endometritis of sow
The treatment effect of the marbofloxacin controlled-release gel (example 1, example 2, example 3 and example 4) on the endometritis is researched by taking a sow as a model animal. Grouping according to the disease degree of the sow endometritis, setting the florfenicol uterine injectant as a positive control, and inspecting the cure rate and the effective rate of the sow endometritis.
200 sick sows are divided into three groups of mild (100) sow groups, moderate (60) sow groups and severe (40) sow groups according to the disease conditions. Mild component 80 heads were used for treatment with marbofloxacin controlled release gel (20 heads per example) and 20 heads for treatment with florfenicol uterine injectate; the medium group is randomly divided into 48 heads for the treatment of marbofloxacin controlled-release gel (12 heads for each example), and 12 heads for the treatment of florfenicol uterine injectate; the heavy group was randomized 32 heads for treatment with marbofloxacin controlled release gel (8 heads for each example) and 8 heads for treatment with florfenicol uterine injectate. The therapeutic dose of marbofloxacin controlled-release gel (40ml:2g) is 40ml, and the marbofloxacin controlled-release gel is locally administrated in uterus for 1 time in 1 day and 1 time every 1 day; the therapeutic dose of florfenicol uterine injectant (25ml:2g) was 25ml, administered by uterine perfusion 1 time for 1 day and 1 more time every 1 day. After the medicine is used, the treatment condition of the sick sow is observed, the treatment effect is divided into three grades of cure, effective and ineffective, the cure rate (%) and the effective rate (%) are calculated, and the test data are processed by t test.
The cure rate (%) < cure number/total number of cases x 100%
Effective rate (%) - (cured amount + effective amount)/total number of cases × 100%
The results show that the cure rates of the marbofloxacin controlled-release gel (example 1, example 2, example 3 and example 4) are 67.5%, 82.5%, 77.5% and 45.0% respectively, and the effective rates are 87.5%, 95.0%, 92.5% and 72.5% respectively; the curative ratio of the florfenicol uterus injectant is 52.5 percent, and the effective rate is 77.5 percent. Compared with the florfenicol uterus injectant positive control group, the marbofloxacin controlled-release gel group (examples 1-3) has obvious difference in cure rate (P < 0.05), obvious difference in effective rate (P < 0.05) and no obvious difference in example 4. The formula of example 4 has poor solubilization effect and low drug effect, and polyethylene glycol 400 and ethylparaben in the formula are subjected to complexation reaction to influence the preservative effect.
While one embodiment of the present invention has been described in detail, the description is only a preferred embodiment of the present invention and should not be taken as limiting the scope of the invention. All equivalent changes and modifications made within the scope of the present invention shall fall within the scope of the present invention.
Claims (10)
1. The marbofloxacin controlled-release gel is characterized by comprising a main drug marbofloxacin, a temperature sensitive matrix, a solubilizer, a preservative, a humectant and a pH regulator.
2. The controlled release marbofloxacin gel of claim 1, wherein: the temperature-sensitive matrix is selected from one or more of poloxamer, cellulose and chitosan;
preferably, the temperature-sensitive matrix is selected from one or more of poloxamer 407, poloxamer 188, methylcellulose, hydroxypropyl methylcellulose, chitosan-sodium glycerophosphate complex.
3. The controlled release marbofloxacin gel of claim 1, wherein: the solubilizer is selected from one or more of hydroxypropyl-beta-cyclodextrin, tween 20, tween 80 and sodium oleate.
4. The controlled release marbofloxacin gel of claim 1, wherein: the preservative is selected from one or more of ethyl hydroxybenzoate, methyl hydroxybenzoate, sodium benzoate, chlorhexidine acetate and chlorobutanol.
5. The controlled release marbofloxacin gel of claim 1, wherein: the humectant is selected from one or more of propylene glycol, glycerin and sorbitol;
the pH regulator is one or more of triethanolamine, sodium hydroxide and acetic acid-sodium acetate buffer salt.
6. The controlled release marbofloxacin gel of claim 1, wherein: the marbofloxacin gel comprises, per 100 ml:
preferably, the pH value of the marbofloxacin gel is 4.5-5.0.
7. The controlled release marbofloxacin gel of claim 1, wherein:
the marbofloxacin controlled-release gel comprises, per 100 ml:
main drugs: 3.5-6.0g of marbofloxacin; temperature-sensitive substrate: 40715.0-19.0 g of poloxamer; solubilizer: 15.0-25.0g of hydroxypropyl-beta-cyclodextrin; preservative: 0.05-0.15g of ethylparaben; humectant: 2.5-7.5ml of propylene glycol; pH regulator: regulating pH value to 4.0-6.0 with triethanolamine, and adding distilled water to 100 ml;
the marbofloxacin controlled-release gel comprises, per 100 ml:
main drugs: 3.5-6.0g of marbofloxacin; matrix: 40715.0-19.0 g of poloxamer; 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: adjusting pH to 4.0-6.0 with sodium hydroxide, and adding distilled water to 100 ml;
the marbofloxacin controlled-release gel comprises, per 100 ml:
main drugs: 3.5-6.0g of marbofloxacin; matrix: 40715.0-19.0 g of poloxamer; solubilizer: tween 2015.0-25.0 g; preservative: 0.05-0.15g of sodium benzoate; humectant: 2.5-7.5ml of propylene glycol; pH regulator: adjusting pH to 4.0-6.0 with acetic acid-sodium acetate buffer salt, and adding distilled water to 100 ml;
the marbofloxacin controlled-release gel comprises, per 100 ml:
main drugs: 3.5-6.0g of marbofloxacin; matrix: 18815.0-19.0 g of poloxamer; solubilizer: 15.0-25.0g of hydroxypropyl-beta-cyclodextrin; preservative: 0.05-0.15g of ethylparaben; humectant: 2.5-7.5ml of propylene glycol; pH regulator: regulating pH value to 4.0-6.0 with triethanolamine, and adding distilled water to 100 ml;
the marbofloxacin controlled-release gel comprises, per 100 ml:
main drugs: 3.5-6.0g of marbofloxacin; matrix: 18815.0-19.0 g of poloxamer; 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 is adjusted to 4.0-6.0 by sodium hydroxide, and distilled water is added to 100 ml.
The marbofloxacin controlled-release gel comprises, per 100 ml:
main drugs: 3.5-6.0g of marbofloxacin; matrix: 18815.0-19.0 g of poloxamer; solubilizer: tween 2015.0-25.0 g; preservative: 0.05-0.15g of sodium benzoate; humectant: 2.5-7.5ml of propylene glycol; pH regulator: acetic acid-sodium acetate buffer salt sodium hydroxide is used for adjusting the pH value to 4.0-6.0, and distilled water is added to 100 ml.
8. The controlled release marbofloxacin gel of claim 1, wherein: the marbofloxacin controlled-release gel preparation,
9. a marbofloxacin controlled-release gel for treating dam endometritis is characterized in that: the marbofloxacin controlled-release gel is the marbofloxacin controlled-release gel in any one of claims 1 to 8.
10. A preparation method of marbofloxacin controlled-release gel is characterized by comprising the following steps: the method comprises the following steps of (1) precisely weighing a temperature-sensitive matrix, adding a proper amount of distilled water, magnetically stirring, and placing in a refrigerator to fully swell and uniformly disperse the temperature-sensitive matrix to obtain a clear solution of the temperature-sensitive matrix;
(2) precisely weighing marbofloxacin and a solubilizer, placing the marbofloxacin and the solubilizer in the temperature-sensitive matrix solution, performing ultrasonic treatment until the marbofloxacin and the solubilizer are dissolved, and performing magnetic 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.
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