CN109453146A - Composition of resisting pathogenic microbes and its preparation method and application - Google Patents
Composition of resisting pathogenic microbes and its preparation method and application Download PDFInfo
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- CN109453146A CN109453146A CN201811614882.5A CN201811614882A CN109453146A CN 109453146 A CN109453146 A CN 109453146A CN 201811614882 A CN201811614882 A CN 201811614882A CN 109453146 A CN109453146 A CN 109453146A
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- thymol
- pathogenic microbes
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- solubilizer
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/74—Rubiaceae (Madder family)
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- A—HUMAN NECESSITIES
- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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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
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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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
- A61K9/08—Solutions
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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
- A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
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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
- A61P31/02—Local antiseptics
Abstract
The present invention relates to compositions of a kind of resisting pathogenic microbes and its preparation method and application, and wherein the composition of resisting pathogenic microbes is mainly prepared by Thymol, glycerol, solubilizer and water；The solubilizer is selected from least one of castor oil derivatives and polyglyceryl fatty acid ester composition.Thymol is dispersed in aqueous based systems under the action of above-mentioned solubilizer and glycerol in the drug, stability is good, pass through the synergistic function of Thymol and solubilizer, pathogenic microorganism can effectively be killed, prevent cause pathogeny imcrobe infection with, and accelerate cause pathogeny imcrobe infection inflammation disappear, can be used for the disinfection of animal local organization, teat cracked nipple can also be prevented, the prevention and treatment especially suitable for mastitis for milk cows.
Description
Technical field
The present invention relates to disinfectant technical fields, composition and its preparation side more particularly to a kind of resisting pathogenic microbes
Method and application.
Background technique
Mastitis for milk cows is caused by being infected as multiple pathogenic microorganisms, is the disease that milk cow is most common, endangers most serious
One of, it not only influences the output of milk, causes to lose through agent, and influence the quality of milk, jeopardizes human health.With Chinese milk cow
The high speed development of industry, high yield, stable yields are the basic goals of milk cow production, and the prevention and treatment of mastitis for milk cows becomes milk cow production
The most important thing.
The treatment method of mastitis for milk cows mainly has antibiotherapy and herbal treatment at present.Wherein antibiotherapy is ratio
It is more directly also most effective treatment method, common drug has tetracycline, streptomysin, penicillin, sulfa drugs etc., but
It is antibiotic to be used for a long time to be easy that pathogen is made to generate drug resistance, and antibiotic can remain in infected cattle body, pollute milk supply, medicine
Object residual bring food-safety problem has caused the extensive concern of people, and it is anti-that many countries have been distributed related regulation limit
Raw element uses on livestock and poultry.Chinese medicine derives from plant, animal, it is not easy to allow pathogenic bacteria to generate drug resistance, and in Contents in Cows
Metabolism is than that comparatively fast, will not remain in vivo, and then will not influence milk supply, still, treat the middle medication of mastitis for milk cows at present
The disadvantages of method mainly takes tank after decocting for Chinese herbal medicine, and there are complicated for operation, slow effect.
Thymol tool it is antibacterial, anti-oxidant and anti-inflammatory the effects of, have certain fragrance, Thymol remove as fragrance,
Outside food additives, Medicines are also used as, are used for sterilizing oral, it is also possible to handle wound, store dissec, also
It can be used as pest repellant and antioxidant.It is white crystal or semi-transparent clear crystal under Thymol room temperature, fusing point: 51.5 DEG C,
Boiling point: 233-235 DEG C, ethyl alcohol, ether, acetic acid, chloroform and benzene are highly soluble in.Field of medicaments is mainly used for bathing lotion, kills at present
Bacterium disinfectant, antioxidant etc. use, but generally can all be dissolved in progress preparation in ethyl alcohol and make and use.Due to milk
Cow teats are skin sensitivity position, and milk cow nipple medicated bath liquid can enter in milk, final edible by people, therefore general milk
Cow teats dip can all require non-stimulated, substantially nontoxic.
Summary of the invention
Based on this, a kind of composition of resisting pathogenic microbes is provided, can effectively kill pathogenic microorganism.
A kind of composition of resisting pathogenic microbes, by weight percentage, mainly by Thymol, glycerol, solubilizer and
Water is prepared；The solubilizer in castor oil derivatives and polyglyceryl fatty acid ester composition at least one
Kind.
The composition low toxicity of the above-mentioned resisting pathogenic microbes of the present invention, irritation are small, no pollution to the environment, and to humans and animals
Safety, plays good solubilization by certain types of solubilizer and glycerol p-Thymol, enables Thymol
Uniform and stable is scattered in composition system, meanwhile, the bactericidal effect of the specific solubility enhancers p-Thymol also has synergy
Effect, enables composition effectively to kill pathogenic microorganism.Wherein, the effects of Thymol tool is antibacterial, anti-oxidant and anti-inflammatory,
Since Thymol has lipophilicity, it is able to enter cell membrane and causes phospholipid bilayer structure disturbance, influence the table of protein
It can inhibit to cause thallus dead such as Escherichia coli, staphylococcus aureus, Salmonella up to Metabolism of Citric Acid access
The major part pathogenic microorganism such as bacterium, Pseudomonas fluorescens, thermal necrosis silk bacterium；With castor oil derivatives or/and gather sweet
Oil and fat acid ester composite is the dissolution that solubilizer can promote Thymol, enhances its lipophilicity, promotes it to pathogen
Killing effect；On the one hand glycerol can be used as the solvent of dissolution Thymol, furthermore it has the function of good skin care,
It can prevent mammilla of milk cattle from chapping.
In one of the embodiments, in the composition, by weight percentage, the content of the Thymol is
0.01%~10%, the content of the glycerol is 0.1%~20%, and the content of the solubilizer is 0.1%~10%.
Further, the mass ratio of the glycerol and the Thymol is (5~20): 1；The solubilizer and described hundred
In the mass ratio of fragrant phenol be (3~10): 1.
In one of the embodiments, the castor oil derivatives be selected from 35 rilanit special of polyoxyethylene,
At least one of polyoxyl 40 hydrogenated castor oil and Cremophor RH60；The polyglyceryl fatty acid ester combination
Object is selected from least one of -6 caprylate of polyglycereol, -4 certain herbaceous plants with big flowers acid esters of polyglycereol and -3 cocounut oil acid esters of polyglycereol.
More preferably, the solubilizer is Cremophor RH60.
Polyethylene glycol hydrogenated 60 castor oil can be such that Thymol is dissolved in water well, to form transparent liquid
Preparation；But the irritation of composition can be reduced to avoid ethyl alcohol is used, when use can also promote the absorption of Thymol, mention
High-drug-effect.
The raw material for preparing of the composition further includes Lignum et Radix Naucleae extract in one of the embodiments, in the composition
In, by weight percentage, the content of the Thymol is 0.5%~5%, the content of the Lignum et Radix Naucleae extract is 0.5%
~5%, the content of the glycerol is 3%~20%, the content of the solubilizer is 0.1%~5%.
It should be understood that the composition prepare raw material can also include in addition to Lignum et Radix Naucleae extract other have disappear
The plant extracts of scorching effect, more preferably, such as Lignum et Radix Naucleae extract.
Lignum et Radix Naucleae extract has the effect of clearing heat and detoxicating, anti-inflammatory, swelling and pain relieving, and the sterilization of Thymol can be promoted to make
With, play prevention the inflammation as caused by cause pathogeny imcrobe infection, and accelerate the inflammation as caused by cause pathogeny imcrobe infection disappear.
The mass flow ratio of the Thymol and the Lignum et Radix Naucleae extract is (1~3) in one of the embodiments: 1.
In one of the embodiments, in the composition, by weight percentage, the content of the Thymol is
1%~5%, the content of the Lignum et Radix Naucleae extract is 0.5%~1%, the content of the glycerol is 5%~15%, the solubilising
The content of agent is 1%~5%.
The composition of the above-mentioned resisting pathogenic microbes of the present invention, functional component Thymol and Lignum et Radix Naucleae extract in glycerol and
It is evenly dispersed and be dissolved in water under the solubilization of solubilizer, formed stablize, the liquid preparation of homogeneous transparent；Thymol and
Lignum et Radix Naucleae extract is dispersed in aqueous based systems, can further be played the role of synergistic sterilizing, be obtained bactericidal effect
To raising, pathogenic microorganism can be effectively killed, plays prevention inflammation as caused by cause pathogeny imcrobe infection, and accelerate cause of disease
The inflammation of microorganism infection disappears.Meanwhile Thymol and Lignum et Radix Naucleae extract can be good at dissolving under the action of solubilizer
In water, medicine irritation can be reduced to avoid the organic solvents such as ethyl alcohol are used；There are also good moist works to skin for glycerol
With can prevent mammilla of milk cattle from chapping.
Another object of the present invention is to provide a kind of preparation method of the composition of the composition of above-mentioned resisting pathogenic microbes,
The following steps are included:
According to the raw material composition of the composition of the resisting pathogenic microbes, by the Thymol and the glycerol, described
Solubilizer is uniformly mixed, and obtains the first mixture；
The Lignum et Radix Naucleae extract and/or the water are added in first mixture, stirred and evenly mixed.
Further, it during preparing the first mixture, can heat, heating temperature is accelerated at 10 DEG C~60 DEG C with this
Or promote dissolution.
Above-mentioned preparation method, easy to operate, safety, required equipment is simple, and products obtained therefrom quality is stablized, and is easy to industry
Metaplasia produces.
Yet another object of that present invention is to a kind of applications for the composition for providing above-mentioned resisting pathogenic microbes, which is characterized in that
Pathogenic microorganism is killed for non-therapeutic destination.
Above-mentioned resisting pathogenic microbes composition can effectively kill pathogenic microorganism, therefore, can be used for preparing killing disease
The drug of pathogenic microorganism plays the role of preventing cause pathogeny imcrobe infection.
Specific embodiment
To facilitate the understanding of the present invention, below will to invention is more fully described, and give it is of the invention compared with
Good embodiment.But the invention can be realized in many different forms, however it is not limited to embodiment described herein.Phase
Instead, purpose of providing these embodiments is makes the disclosure of the present invention more thorough and comprehensive.
Unless otherwise defined, all technical and scientific terms used herein and belong to technical field of the invention
The normally understood meaning of technical staff is identical.Term as used herein in the specification of the present invention is intended merely to description tool
The purpose of the embodiment of body, it is not intended that in the limitation present invention.Term as used herein "and/or" includes one or more phases
Any and all combinations of the listed item of pass.
The composition of a kind of resisting pathogenic microbes of an embodiment of the present invention, by weight percentage, mainly by following
Raw material is made: 0.01%~10% Thymol, 0.1%~20% glycerol, 0.1%~10% solubilizer and excess water；Its
In, solubilizer is selected from least one of castor oil derivatives and polyglyceryl fatty acid ester composition.
In one embodiment, castor oil derivatives are selected from 35 rilanit special of polyoxyethylene, polyoxyethylene 40
At least one of rilanit special and Cremophor RH60；Polyglyceryl fatty acid ester composition is selected from polyglycereol -6
At least one of caprylate, -4 certain herbaceous plants with big flowers acid esters of polyglycereol and -3 cocounut oil acid esters of polyglycereol.
More preferably, solubilizer is Cremophor RH60.Cremophor RH60 can make thyme
Extract (i.e. Thymol) is extraordinary to be dissolved in water-based, and the stability of gained mixed system is high；Polyoxy second simultaneously
Alkene rilanit special can also increase said medicine to the control efficiency of cause pathogeny imcrobe infection.
In one embodiment, the mass ratio of the glycerol and the Thymol is (5~20): 1, solubilizer and described hundred
In the mass ratio of fragrant phenol be (3~10): 1.
In one embodiment, Lignum et Radix Naucleae extract is the water or ethanol extract of nauclea officinalis.
Specifically, Lignum et Radix Naucleae extract is the xeraphium of nauclea officinalis leaf, branch, dry, skin and/or root after water or ethanol solution extraction
Agent.
More preferably, Lignum et Radix Naucleae extract is the dry pulvis of water extract of nauclea officinalis leaf.
Specifically the preparation method comprises the following steps: taking nauclea officinalis leaf, it is ground into coarse powder after chopping, adds water to cook, filter, subtracted after filtrate concentration
It press dry dry.
In one embodiment, the Thymol in thyme essential oil, Herba Origani Vulgaris quintessence oil and basil oil at least
It is a kind of.
It is appreciated that Thymol can be added in said medicine with purified form；Alternatively, can will include thyme
The thyme linaloe oil of phenol or thyme extract etc. include that the active matter of Thymol is added in said medicine, while ensuring hundred
In fragrant phenol in required effective concentration drug existing in this application.Thyme linaloe oil or thyme extract are obtained from thyme, ox
To and the plants such as clore basil.
More preferably, Thymol is added in the form of thyme plant extract.
In one embodiment, the raw material for preparing of the composition of resisting pathogenic microbes further includes Lignum et Radix Naucleae extract, and by weight hundred
Point than meter, composition is mainly prepared from the following raw materials: 0.5%~5% Thymol, 0.5%~5% Lignum et Radix Naucleae extract,
3%~20% glycerol, 0.1%~5% solubilizer and excess water.
In one embodiment, the mass ratio of Thymol and the Lignum et Radix Naucleae extract is (1~3): 1.
Further, the mass ratio of Thymol and Lignum et Radix Naucleae extract is (2~3): 1.
In one embodiment, by weight percentage, the composition of resisting pathogenic microbes is mainly prepared from the following raw materials:
1%~5% Thymol, 0.5%~1% Lignum et Radix Naucleae extract, 5%~15% glycerol, 1%~5% solubilizer and remaining
Measure water.
The composition low toxicity of the above-mentioned resisting pathogenic microbes of the present invention, irritation are small, no pollution to the environment, and to humans and animals
Safety, wherein Thymol and Lignum et Radix Naucleae extract form uniform mixed system under the solubilization of solubilizer and glycerol, and
It is acted synergistically by Thymol and Lignum et Radix Naucleae extract, can effectively kill pathogenic microorganism.Wherein, Thymol tool suppression
Bacterium, it is anti-oxidant and anti-inflammatory the effects of, due to Thymol have lipophilicity, be able to enter cell membrane and cause phospholipid bilayer knot
Structure disorder, influences expression and the Metabolism of Citric Acid access of protein, to cause thallus dead, can inhibit as Escherichia coli,
The major part pathogenic microorganism such as staphylococcus aureus, salmonella, Pseudomonas fluorescens, thermal necrosis silk bacterium；Lignum et Radix Naucleae extract
With clearing heat and detoxicating, the effect of anti-inflammatory, swelling and pain relieving, the bactericidal effect of Thymol can be promoted, it is micro- by cause of disease to play prevention
Inflammation caused by biological infection accelerates the inflammation as caused by cause pathogeny imcrobe infection to disappear.
Another object of the present invention is to provide a kind of preparation method of the composition of the composition of above-mentioned resisting pathogenic microbes,
The following steps are included:
According to the raw material proportioning of the composition of above-mentioned resisting pathogenic microbes, Thymol, glycerol and solubilizer are mixed equal
It is even, obtain the first mixture；
Lignum et Radix Naucleae extract and/or water are added in the first mixture, stirred and evenly mixed.
Above-mentioned preparation method passes through the order by merging of strict control each component, and each component is made sufficiently to dissolve and be uniformly mixed,
It avoids causing certain components especially Thymol that cannot be dissolved in water-based well because mixing is improper, to influence drug effect
And stability.And the above method is easy to operate, safety, and required equipment is simple, and products obtained therefrom quality is stablized, and is easy to industry
Metaplasia produces.
Specifically, at room temperature, Thymol is uniformly mixed with glycerol, solubilizer, obtains the first mixture；
Then Lignum et Radix Naucleae extract is added in the first mixture, it is stirring while adding, after mixing, water, stirring is added
It is completely dissolved to Lignum et Radix Naucleae extract.
Further, it during preparing the first mixture, can heat, heating temperature is accelerated at 10 DEG C~60 DEG C with this
Or promote dissolution.
A further embodiment of this invention is to provide a kind of application of the composition of above-mentioned resisting pathogenic microbes, above-mentioned will resist
The composition of pathogenic microorganism is used to prepare the drug for killing pathogenic microorganism.
The composition of above-mentioned resisting pathogenic microbes can effectively kill pathogenic microorganism, therefore, can be used for preparing killing
The drug of pathogenic microorganism plays the role of preventing cause pathogeny imcrobe infection.
In one embodiment, the composition of above-mentioned resisting pathogenic microbes is used to prepare to the medicine for killing pathogenic microorganism
Object can be used for the disinfection of animal local organization.In this way, the pathogenic microorganism on animal local organization surface can be killed, pre- diseases prevention
Pathogenic microorganism infection.
Specifically, animal local organization includes but is not limited to the local group such as breast, oral cavity, vagina, uterus, ear canal, four limbs
It knits.It is appreciated that so-called animal further includes people, so-called disinfection can for the cleaning of animal local organization, dipping, smearing,
The disinfection of the modes such as spraying prevents cause pathogeny imcrobe infection animal to kill the pathogenic microorganism on animal local organization surface.
More preferably, the composition and drug of above-mentioned resisting pathogenic microbes be particularly suitable for cow breast, the cleaning and sterilizing of nipple,
To prevent the generation of mammitis.
In one embodiment, the composition of above-mentioned resisting pathogenic microbes can also be used in the cleaning-sterilizing of pet and hatching egg disappears
Poison etc..
In one embodiment, the concrete operation method of disinfection can be surface clean, spraying, instillation, smearing and dipping
Deng.
The following are specific embodiments
Embodiment 1
The formula of the composition of resisting pathogenic microbes are as follows: Thymol 1wt%, glycerol 5wt%, efficient solubilizing agents 115C
(Cremophor RH60) 5wt% and excess water.
(1) each raw material component is accurately weighed, wherein thyme plant extract is purchased from symris company, Thymol
Content is 99%.
(2) at normal temperatures and pressures, the Thymol of formula ratio and glycerol, efficient solubilizing agents 115C are uniformly mixed, are obtained mixed
Close object.
(3) water of formula ratio is slowly added in the mixture prepared to step (2), it is stirring while adding, until being completely dissolved
?.
Embodiment 2
The formula of the composition of resisting pathogenic microbes are as follows: Thymol 3wt%, glycerol 10wt%, nauclea officinalis leaf water extract
1wt%, efficient solubilizing agents 115C (Cremophor RH60) 3wt% and excess water.
(1) each raw material component is accurately weighed, wherein thyme plant extract is purchased from symris company, Thymol
Content is 99%, and nauclea officinalis water extract is purchased from Xi'an Bioisystech Co., Ltd, Tianrui, with rutin (C27H30O16) meter >=
3.82%) following embodiment is identical.
(2) at normal temperatures and pressures, the Thymol of formula ratio and glycerol, efficient solubilizing agents 115C are uniformly mixed, are obtained mixed
Close object.
(3) the nauclea officinalis water extract of formula ratio is added in the mixture of step (2).
(4) water of formula ratio is slowly added in the mixture prepared to step (3), it is stirring while adding, until being completely dissolved
?.
Embodiment 3
The formula of the composition of resisting pathogenic microbes are as follows: Thymol 1wt%, nauclea officinalis leaf water extract 0.5wt%, glycerol
5wt%, efficient solubilizing agents 115C (Cremophor RH60) 1wt% and excess water.
(1) each raw material component is accurately weighed.
(2) at normal temperatures and pressures, the Thymol of formula ratio and glycerol, efficient solubilizing agents 115C are uniformly mixed, are obtained mixed
Close object；
(3) the nauclea officinalis water extract of formula ratio is added in the mixture of step 2)；
(4) water of formula ratio is slowly added in the mixture prepared to step 3), it is stirring while adding, until being completely dissolved i.e.
It can.
Embodiment 4
Embodiment 3 is substantially the same manner as Example 1, the difference is that, the formula of the drug of embodiment 3 are as follows: Thymol
5wt%, nauclea officinalis leaf water extract 1wt%, glycerol 15wt%, efficient solubilizing agents 115C (Cremophor RH60)
5wt% and excess water.
Comparative example 1
Comparative example 1 is substantially the same manner as Example 1, the difference is that, comparative example 1 replaces efficiently increasing with sodium alkyl benzene sulfonate
Solvent 115C.
Comparative example 2
Comparative example 2 is substantially the same manner as Example 1, the difference is that, the formula of comparative example 2 are as follows: 1wt% thyme
Phenol, 5wt% glycerol and excess water.It is found in preparation process, the dissolution of gained pharmaceutical preparation is incomplete.
Comparative example 3
Comparative example 3 is substantially the same manner as Example 2, the difference is that, the formula of comparative example 3 are as follows: 3wt% Thymol,
1wt% Lignum et Radix Naucleae extract, 0.5wt% efficient solubilizing agents 115C and excess water.Preparation gained pharmaceutical preparation is in muddy shape.
Embodiment 5
Embodiment 5 is substantially the same manner as Example 2, the difference is that, the formula of the drug of embodiment 4 are as follows: Thymol
3wt%, glycerol 10wt%, Lignum et Radix Naucleae extract 1wt%, 35 rilanit special 3wt% of polyoxyethylene and excess water.
Embodiment 6
Embodiment 6 is substantially the same manner as Example 2, the difference is that, the formula of the drug of embodiment 5 are as follows: Thymol
3wt%, glycerol 10wt%, Lignum et Radix Naucleae extract 1wt%, -4 certain herbaceous plants with big flowers acid esters 3wt% of polyglycereol and excess water.
Embodiment 7
Embodiment 7 is substantially the same manner as Example 2, the difference is that, the formula of the drug of embodiment 6 are as follows: Thymol
0.5wt%, glycerol 3wt%, Lignum et Radix Naucleae extract 0.5wt%, polyethylene glycol hydrogenated 60 castor oil 0.2wt% and excess water.
Effect proof property test
One, stability test
1, test specimen: the composition of the resisting pathogenic microbes of embodiment and comparative example preparation.
2, testing program: referring to " Republic of China Veterinary Pharmacopoeia (version in 2015) " (one) annex 9001 --- raw material
Drug and preparation stability test direction principle carry out influence factor test, accelerated test.Specific testing program and result are as follows:
1) influence factor testing program and result:
Take test specimen, by commercially available back, be respectively placed in two conditions of high temperature (60 DEG C) He Qiangguang (4500 ± 500Lx) into
Row high temperature and strong shadow rang factorial experiments, place 10 days, respectively at 0 day, 5 days, 10 days progress Thymol content detections and molten
Liquid character observation, the stability of test specimen is investigated as index, and testing result see the table below 1.
1 influence factor test result of table
2) accelerated test scheme and result:
Test specimen is taken, by commercially available back, is placed 6 months under conditions of 40 DEG C ± 2 DEG C, relative humidity 75% ± 5%.
0th month during test, 1 month, 2 months, 3 months, 6 the end of month it is separately sampled primary, carry out Thymol content detection
With solution character observation, the stability of test specimen is investigated as index, testing result see the table below 2.
2 accelerated test result of table
Two, irritation test
1, test specimen:
The composition of the resisting pathogenic microbes of embodiment 1 and embodiment 2, by the limited public affairs of Foshan City South Sea east Australia dragon pharmacy
Department develops；0.9% sodium chloride injection, specification: 500mL, lot number A10082202, by Guizhou world medicine company Co., Ltd
Production.
2, experimental animal:
New zealand rabbit, 32, regular grade, weight about 2kg, 24 females, 8 males, by Guangdong Province medical experiment animal
The heart provides.Animal buys rear environment back and adapts to raising 3d, using natural lighting, feeds full price rabbit material during test, and drinking-water is sufficient, no
It is restricted, at 26 DEG C, relative humidity is 40%~70% for room temperature control.
3, experimental design
1), skin irritation test
16 new zealand rabbits are randomly divided into intact skin group (I group) and damaged skin group (II group), every group 4, male and female
Animal experiment that is fifty-fifty, then respectively taking half animal to carry out embodiment 1 and embodiment 2 at random.For 24 hours by animal before I group of on-test
It is 3cm × 3cm without hair-fields that vertebra two sides antimere, which respectively shaves out area with shaver, checks after skin depilatory and goes to hair-fields
It is whether injured due to unhairing, the irritation test without intact skin of skin damage.The production of II group of damaged skin is to adopt
Unhairing disinfection skin is scratched into skin epidermis by " # " font (interval 1cm) with No. 7 syringe needles of disposable sterilization, is degree with oozing of blood,
The damaged degree of left and right sides skin is almost the same.Left side is 1 medication area of embodiment, takes 0.5m L to be directly coated at left side and goes
On the skin of hair, then with two layers of gauze (2.5cm × 2.5cm) and one layer of glassine paper or the like covering, then with nonirritant
Adhesive plaster and bandage are fixed, and right side is saline control area.Application time at least 4h after sticking, removes tested material
And medicine-feeding part is cleaned with warm water or nonirritant solvent.Successive administration 3d, every time removal drug after 1h and again stick before,
Observation, record erythema and oedema, coating part whether have pigmentation, blutpunkte, pachylosis or epidermatic atrophy situation and its
Time of origin and regression time, and score referring to the following table 3 skin irritation reaction standards of grading, using consubstantiality right side itself
Comparison.After last coating, 30~60min after removing drug, for 24 hours, 48h and 72h visually observe and record coating part whether there is or not
Situations such as erythema and oedema.To the skin irritation test of multiple dosing, each group integral of each observing time point is calculated first
Then mean value calculates daily every animal integral mean value, according to the form below 4 in the observation time limit and carries out stimulus intensity evaluation.
3 skin wound repair standards of grading of table
4 skin irritatin intensity evaluation standard of table
| Score value | Evaluation |
| 0~0.49 | It is nonirritant |
| 0.5~2.99 | Slight stimulation |
| 3.0~5.99 | Moderate irritation |
| 6.0~8.0 | Strong and stimulating |
2), vaginal mucosa irritation test
Female New Zealand rabbit 12 are taken, is divided into 1 group of contamination, contaminate 2 groups and control group, every group 4.Contaminate 1 group and contamination 2
The resisting pathogenic microbes composition 2mL of group difference vagina perfusion embodiment 1 and embodiment 2, control animals are made of physiological saline
Same processing.After contamination for 24 hours, it using air embolism method euthanasia animal, cuts open the belly and takes out complete vagina, longitudinally split, meat
Eye has seen whether that hyperemia, oedema etc. show.There is the vagina of the performances such as hyperemia, oedema to be put into 10% formalin solution fixed
More than for 24 hours, the tissue film-making for choosing the both ends and central 3 positions of vagina carries out histopathological examination after HE dyeing.It presses
The following table 5 mucosa irritation reaction standards of grading score, and the mucosa irritation of each observing time each animal is reacted score value
It is added to obtain total mark, by one group of integral summation divided by number of animals to get last score value.6 mucosa irritation strength grading of according to the form below
Standard carries out stimulus intensity classification, to judge its stimulation degree.
5 vaginal mucosa irritation of table reacts standards of grading
6 vaginal mucosa stimulus intensity evaluation criterion of table
| Average value | Evaluation |
| 0~0.4 | It is nonirritant |
| 0.5~1.5 | Slight stimulation |
| 1.51~2.5 | Moderate irritation |
| > 2.5 | Severe irritation |
4, test result
1), skin irritation test result new zealand rabbit observes skin after phase and administration is administered in 3d in 3d daily
Medicine-feeding part.The results show that the 2 medicine-feeding part skin (left side) of embodiment 1 and embodiment of intact skin group and damaged skin group
Erythema is found no with saline control position (right side) and oedema is formed, and is 0 point by regulation standards of grading；Also it does not find
The abnormal responses such as pigmentation, drug induccd bleeding and pachylosis.The activity of animal subject, feeding, drinking-water, defecation, urination, body
Weight and appearance etc. also do not occur exception.According to the related skin irritation test dermoreaction scoring of country and response intensity evaluation mark
Standard, embodiment 1 is to new zealand rabbit intact skin and the nonirritant reaction of damaged skin, and concrete outcome is referring to the following table 7.
Evaluation of 7 embodiment 2 of table to new zealand rabbit skin irritation
2), during the medication of vaginal mucosa irritation test result, 1 group of contamination, contamination 2 groups and control group new zealand rabbit whole body
Situation is showed no exception, and introitus also has no obvious congested, red and swollen and abnormal secretion outflow.Visually observe the vagina group of taking-up
It knits, each group is showed no congested vaginal mucosa, oedema and blutpunkte, and vaginal mucosa stimulation is equally divided into 0, according to the related vagina of country
Mucosa irritation reaction scoring and response intensity evaluation criterion, embodiment 1, embodiment 2 resisting pathogenic microbes composition to new west
Blue rabbit disposable vaginal mucosa irritation intensity be it is nonirritant, concrete outcome is referring to the following table 8.Vaginal mucosa histopathological examination
It is without exception.
8 embodiment 1 of table visually observes stimulate the reaction intensity to new zealand rabbit vaginal mucosa
The result shows that the composition of the resisting pathogenic microbes of embodiment 1 and embodiment 2 is stingless to skin and vaginal mucosa
Swash property, prompt application security of the invention good, clinical use safety meets breast injection medication requirements, is worth clinically
Further genralrlization application.
Three, clinical effect trial
1, test specimen: the composition of the resisting pathogenic microbes of Examples 1 to 7 and comparative example 1~3.
2, experimental animal:
It is 120 total to choose the large-scale milk cattle cultivating factory's clinic mastitis natural occurrence case in Hebei.Body temperature, whole body disease
Shape is obvious, and appetite is poor；Newborn area is rubescent, swelling, and has lump；Palpation has heat, pain reaction；There are flocculus, grumeleuse in cream, or is in water
Sample；SCC (body cell) ﹥ 200,000/mL, CMT (California mammitis detection method) test strong positive in milk mixture；Milk yield is reduced
Equal clinic mastitis symptom.
3, test method
1) medication: being divided into 12 groups, and 1~10 group is test group, to suffering from after ox is early, evening has squeezed milk, cleans newborn area, makes
Nipple dipping disinfection is carried out with the embodiment of the present invention 1, each pathogenetic breast of trial drug group is corresponding every 12h perfusion 100mL
Trial drug embodiment, successive administration 7 days；11 groups are prevention control group, to suffering from after ox is early, evening has squeezed milk, clean newborn area,
Nipple dipping disinfection is carried out using the embodiment of the present invention 1, each pathogenetic breast of trial drug group is opposite every 12h perfusion 100mL
The trial drug embodiment 1 answered does not continue to use embodiment 1 and carries out nipple dipping disinfection after continuous use 7 days, 7 days；12 groups are
Control group, not administration group.
2), index of assessment of curative effect
A, cure: constitutional symptom disappears, and appetite restores normal；The symptoms such as red, swollen, the hot, pain of ill breast district completely disappear, cream
Juice appearance restores normal, lactation amount rebound significantly；200,000/mL of SCC ﹤ in cream；Pathogenic bacteria are not detected in newborn area's milk sample.
B, effectively: constitutional symptom disappears substantially, and appetite restores normal；The symptoms such as red, swollen, the hot, pain of ill breast district obviously change
Kind or mitigation；Milk outward appearance is normal, and lactation amount has to be restored to a certain degree；SCC is reduced to a certain degree in cream；In newborn area's milk sample
Pathogenic bacteria ﹤ 1000cfu/mL.
C, invalid: constitutional symptom, which does not disappear, even to be aggravated；Ill breast district symptom, which is not improved, even to be aggravated；Milk outward appearance
More abnormal, milk yield does not restore even lactation and stops；Or recurrence in two weeks after being discontinued；SCC is substantially unchanged in cream in cream；
Pathogenic bacteria quantity ﹥ 1000cfu/mL in newborn area's milk sample.
3), recurrence rate monitors
1 area Zhou Neiru clinical symptoms and the monitoring of milk sample pathogenic bacteria after being discontinued to the milk cow after healing.
4, test result:
1), therapeutic evaluation result
2), recurrence rate monitoring result
It is observed in 1 week after drug withdrawal, in 2 groups (embodiments 2) and 4 groups of (embodiment 4) test groups, 9 of the healing of 10 cow heads
Without recurrence, another 1 recurs, and the milk cow after embodiment 1 and 3 is cured has 2 recurrences, the milk cow after the healing of embodiment 5 and 6
Milk cow after having 3 recurrences, embodiment 7 to cure has 4 recurrences；Milk cow after comparative example 1 and 2 is cured is recurred, and cure rate is
0, the milk cow after comparative example 3 is cured only is not recurred for 1.11st group (prevention control group) is discontinued in latter week in the above drug,
Example 1 drug is not continued to use and carries out nipple dipping disinfection, and the recurrence for milk cow after curing occur is 5；12nd group of (blank pair
According to group) after the above test is discontinued in 1 week, medication treatment is carried out to it, uses the resisting pathogenic microbes group of the embodiment of the present invention 1
Object is closed, after being used 1 week, mammitis clinical symptoms are obviously improved, and effective percentage reaches 80% or more.
Each technical characteristic of embodiment described above can be combined arbitrarily, for simplicity of description, not to above-mentioned reality
It applies all possible combination of each technical characteristic in example to be all described, as long as however, the combination of these technical characteristics is not deposited
In contradiction, all should be considered as described in this specification.
The embodiments described above only express several embodiments of the present invention, and the description thereof is more specific and detailed, but simultaneously
It cannot therefore be construed as limiting the scope of the patent.It should be pointed out that coming for those of ordinary skill in the art
It says, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to protection of the invention
Range.Therefore, the scope of protection of the patent of the invention shall be subject to the appended claims.
Claims (10)
1. a kind of composition of resisting pathogenic microbes, which is characterized in that mainly prepared by Thymol, glycerol, solubilizer and water
It forms；
The solubilizer is selected from least one of castor oil derivatives and polyglyceryl fatty acid ester composition.
2. the composition of resisting pathogenic microbes according to claim 1, which is characterized in that in the composition, by weight
Percentages are measured, the content of the Thymol is 0.01%~10%, and the content of the glycerol is 0.1%~20%, described
The content of solubilizer is 0.1%~10%.
3. the composition of resisting pathogenic microbes according to claim 2, which is characterized in that the glycerol and the thyme
The mass ratio of phenol is (5~20): 1；The mass ratio of the solubilizer and the Thymol is (3~10): 1.
4. the composition of resisting pathogenic microbes according to claim 1, which is characterized in that the Emulsifier EL-60 spreads out
Biology in 35 rilanit special of polyoxyethylene, polyoxyl 40 hydrogenated castor oil and Cremophor RH60 extremely
Few one kind；The polyglyceryl fatty acid ester composition is selected from -6 caprylate of polyglycereol, -4 certain herbaceous plants with big flowers acid esters of polyglycereol and -3 coconut palm of polyglycereol
At least one of oleate.
5. the composition of resisting pathogenic microbes according to claim 4, which is characterized in that the solubilizer is polyoxyethylene
60 rilanit specials.
6. the composition of described in any item resisting pathogenic microbes according to claim 1~5, which is characterized in that the composition
The raw material for preparing further include Lignum et Radix Naucleae extract；In the composition, by weight percentage, the content of the Thymol is
0.5%~5%, the content of the Lignum et Radix Naucleae extract is 0.5%~5%, the content of the glycerol is 3%~20%, the increasing
The content of solvent is 0.1%~5%.
7. the composition of resisting pathogenic microbes according to claim 6, which is characterized in that the Thymol and the gallbladder
The mass ratio of the wooden extract is (1~3): 1.
8. the composition of resisting pathogenic microbes according to claim 6, which is characterized in that in the composition, by weight
Percentages are measured, the content of the Thymol is 1%~5%, the content of the Lignum et Radix Naucleae extract is 0.5%~1%, described
The content of glycerol is 5%~15%, the content of the solubilizer is 1%~5%.
9. the preparation method of the composition of resisting pathogenic microbes according to any one of claims 1 to 8, which is characterized in that including
Following steps:
According to the raw material composition of the composition of the resisting pathogenic microbes, by the Thymol and the glycerol, the solubilising
Agent is uniformly mixed, and obtains the first mixture；
The Lignum et Radix Naucleae extract and/or the water are added in first mixture, stirred and evenly mixed.
10. the application of the composition of any resisting pathogenic microbes of claim 1~8, which is characterized in that be used to prepare and kill
Go out the drug of pathogenic microorganism.
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| CN110464738A (en) * | 2019-09-26 | 2019-11-19 | 成都科宏达科技有限公司 | A kind of compound disinfectant preventing cow breast disease |
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