CN107157995B - A kind of compound imidacloprid transdermal composition preparation of pet broad-spectrum anti-parasite - Google Patents
A kind of compound imidacloprid transdermal composition preparation of pet broad-spectrum anti-parasite Download PDFInfo
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Abstract
The invention discloses compound imidacloprid transdermal composition preparations of a kind of pet broad-spectrum anti-parasite and preparation method thereof.The transdermal composition preparation is to be composed of the following mass fractions: 500,000-5,000,000 part of imidacloprid, 1,000-500,000 part of doractin, pyrethroid coumpound 100-20,000 part, solvent 2,000,000-8,000,000 part, penetration enhancer 100,000-2,000,000 part, 1-10 parts of antioxidant, adjuvant 500,000-5,000,000 part.The compound imidacloprid composition quality of the pharmaceutical preparations is stable, highly-safe, percutaneous absorbtion is good, good drug efficacy, irritation are small, using easy, environmental pollution is small, and there can be the longer sustained release phase, it can be used for killing epizoa in pet body, while having both the function of mosquito proof flea.
Description
Technical field
The present invention relates to a kind of compound imidacloprid transdermal composition preparation of pet broad-spectrum anti-parasite and its preparation sides
Method.Belong to field of veterinary.
Background technique
As the improvement of people's living standards, growing spiritual demand has caused pet craze.Pet not only gives the mankind
Flat life brings many enjoyment, also have many people using pet as a kind of emotion rely on mediate it is lonely with it is depressed, thin
Solve psychological pressure.But certain helminths are infected in contact of the pet with external environment unavoidably, and people are in the common life with pet
Again inevitably with pet close contact in work, a possibility that increasing infecting both domestic animals and human parasitic disease.Helminth can propagate a variety of diseases
Disease causes damages to the health of pet and the mankind, lethal can die when serious.
Imidacloprid (imidacloprid) is to push city in joint development in 1984 by Bayer Bitterfeld GmbH and Japanese pesticide company
The anabasine insecticide of field, also known as novel Nitromethylene insecticides are that insecticidal effect is relatively high in the insecticides
One of kind.Imidacloprid is the combination of Nitromethylene heterocycle structure and nicotine, acts on nAChR, is destroyed
The normal conduction of polypide central nervous system, causes the nerve of polypide to be destroyed, and is finally allowed to dead；More application is in agriculture at present
Medicine.Imidacloprid also has stronger neurotoxicity to helminth；But due to its more unique mechanism of action, imidacloprid is to majority
Lower toxicity is then presented in mammal, to people and pet safety with higher.
In compound imidacloprid composition prescription of the present invention, doractin (doramectin) prescription is contained.Doractin
It for the macrolides antiparasitic agent of new generation that the 1990s develops, is passed through using thiacyclohexane carboxylic acid as precursor
A kind of Avermectins antibiotic made of the Avid kyowamycin new strains fermentation of genetic recombination.The expelling parasite mechanism of doractin is
It is realized by the effect of reinforcing gamma -amino butyric acid, so that polypide nerve, which is difficult to stimulate, passes to muscle, prevents muscle from receiving
Contracting causes helminth to benumb and be purged.It is considered as one of classic anti-parasite medicine in current avermectin race, is
It is inside and outside it is simultaneous kill agent, have good repelling and killing efficacy to a variety of helminths.
Patent CN103003758A discloses a kind of compound percutaneous solution of Chinese and Western medicine and preparation method, transdermal solution composition
The weight ratio of ingredient and each constituent are as follows: doractin 0.1-5%, eucalyptus oil 10-50%, azone 2-3%, stabilizer 0.1-
2%, retarder thinner 40-85% can be used for treating pet psoriasis.But its medication needs daily each 1 time sooner or later, and compliance is poor.
Patent CN101401782A discloses a kind of Doractin dashing agent and preparation method thereof, and the dashing agent is by Doramectin
Element, propylene glycol, dehydrated alcohol, azone, Tween-80 and 2,6-di-tert-butyl p-cresol composition, are mainly used for killing the body of animal
Interior nematode and vermin.Its anti parasitic mechanism is single, and dosage form is also single, and application range is relatively narrow.
Patent CN102552304A discloses a kind of topical agent for treating pet mite infection, and the medicament is by doractin
0.005-0.01g, borneol 1-5g, propylene glycol 20-50mL, dehydrated alcohol 40-70mL composition, are mainly used for mite infection
Animal treated.But its medication needs 1 time a day, more time-consuming and laborious, and dosage form is single.
Patent CN104546885A, which is disclosed, a kind of treats dermopathic pharmaceutical composition and preparation method thereof, the composition
It is 1 part of doractin, 1-2 parts of Terbinafine.
In compound imidacloprid composition prescription of the present invention, pyrethroid insecticides prescription is contained.Pyrethroid
The mechanism of action of insecticides is the normal physiological of upset target polypide nerve, is allowed to dead by excited, spasm to paralysis.
Pyrethroid has the characteristics that high-efficiency low-toxicity, low-residual to mammal.Wherein, fenvalerate, chemical name alpha-cyano -3-
Phenoxy benzyl (R, S) -2- (4- chlorphenyl) -3 Methylbutanoic acid ester is the current maximum pyrethroid of China's application amount
Insecticide, the percutaneous LD of rat acute50>5000mg/kg；When concentration is higher, pyrethroid only has minimal irritation to rabbit skin,
Only has minimal irritation to eye.Thus, pyrethroid insecticides are in low concentration in application, being a kind of more excellent, safety
Animal press down the anti-flea mosquito repellent compound of lice, be suitable for pet body.
Patent CN1501773A, which is disclosed, a kind of can be applied to skin, liquid system for inhibiting helminth on animal body
Agent, composition and weight percentages of components are respectively as follows: permethrin 35-60%, imidacloprid or imidacloprid analog 2.5-
12.5%, N-Methyl pyrrolidone 27.5-62.5%, water 0-5%, phenol antioxidant 0-0.5% and organic acid 0-0.5%,
Also contain cosolvent 2.5-10%, for inhibiting tick and/or flea on the warm-blooded animal body including dog and cat.But prescription
In permethrin content it is very high, it is more obvious to the stimulation of eyes.
The mosquito-proof flea repellent object of the outstanding anti parasitic of above-mentioned three kinds of different role mechanism is formed compound, three association by the present invention
Together, so that invention formulation has the expelling parasite insecticidal action of more wide spectrum, while having to body ecto-and endoparasites significantly more efficient
Kill effect.
In conclusion currently on the market, antiparasitic agent used in most pets is tablet and injection, pet according to
It is bad from property；And external preparation or dosage form or application or anti parasitic mechanism are more single, using being limited to, are administered in addition
Number is more frequent, and compliance is bad.
Preparation capable of permeating skin can avoid the first pass effect of hepar of drug, make effective component as a kind of more novel drug delivery system
Bioavilability with higher；It is also avoided that the interaction of drug and gastrointestinal tract simultaneously, avoids drug to pet gastrointestinal tract
Damage；Meanwhile relatively steady and controllable blood concentration can be reached in pet body, the poison for significantly reducing drug is secondary
Effect.Be used as a solution simultaneously, in actual use, facilitate adjustment dosage and medicine-feeding part, it can be achieved that local emphasis to
Medicine.
Currently, still without a kind of simultaneously including imidacloprid, doractin and pyrethroid coumpound, and give prescription
Just, effective pet broad-spectrum anti-parasite preparation capable of permeating skin when long.
So far, in order to enrich pet medicine market, provide new selection for the clinical application of pet, present invention exploitation and openly
A kind of compound imidacloprid transdermal composition preparation of pet broad-spectrum anti-parasite and preparation method thereof.
Summary of the invention
Based on the above situation, the object of the present invention is to provide a kind of compound imidacloprid of pet broad-spectrum anti-parasite is transdermal
Composite preparation and preparation method thereof.
First technical problem to be solved by this invention is to provide a kind of compound pyrrole worm of pet broad-spectrum anti-parasite
Quinoline transdermal composition preparation.
Second technical problem to be solved by this invention is to provide a kind of compound pyrrole worm of pet broad-spectrum anti-parasite
The preparation method of quinoline transdermal composition preparation.
Third technical problem to be solved by this invention is that a kind of compound imidacloprid of pet broad-spectrum anti-parasite is saturating
Application of the peel composition preparation in pet anti parasitic.
In order to solve the first technical problem mentioned above, the technical solution provided by the present invention is:
The present invention provides a kind of compound imidacloprid transdermal composition preparation of pet broad-spectrum anti-parasite, feature exists
In comprising imidacloprid, doractin, pyrethroid coumpound, solvent, penetration enhancer, antioxidant and adjuvant.
The present invention provides a kind of compound imidacloprid transdermal composition preparation of pet broad-spectrum anti-parasite, feature exists
In it is made of following component, according to parts by weight: 500,000-5,000,000 part of imidacloprid, doractin 1,000-
500,000 parts, pyrethroid coumpound 100-20,000 part, 2,000,000-8,000,000 part of solvent, penetration enhancer
100,000-2,000,000 part, 1-10 parts of antioxidant, 500,000-5,000,000 part of adjuvant.
The mass percent of the pyrethroid coumpound is no more than 5%.
The pyrethroid coumpound be selected from one of Permethrin, decis, cypermethrin, fenvalerate or
Several combinations.
The solvent be selected from one of benzyl alcohol, propylene glycol, isopropanol, ethyl alcohol, acetone, n-butanol, ethyl acetate or
Several combinations.
The solvent is preferably benzyl alcohol.
The penetration enhancer is selected from azone (referred to as are as follows: Azone), dimethyl sulfoxide (referred to as are as follows: DMSO), dimethyl methyl
Amide (referred to as are as follows: DMF), dimethyl acetamide (referred to as are as follows: DMAc), decyl methyl sulfoxide (referred to as are as follows: DCMS), α-nitronaphthalene
(referred to as are as follows: referred to as α-NP), 1- methyl-α-pyrrolones (referred to as are as follows: 1-NMP), 1,5- dimethyl-α-pyrrolones (referred to as are as follows:
1,5-NMP), 1- ethyl-α-pyrrolones (referred to as are as follows: 1-NEP), 5- carboxyl-α-pyrrolones (referred to as are as follows: 5-NCP), 1- dodecane
One or more of base-α-pyrrolones (referred to as are as follows: 1-NDOP) combination.
The antioxidant is selected from 2,6- Butylated Hydroxytoluene, butylated hydroxy anisole, dibutyl hydroxy toluene, tert-butyl
The combination of one or more of hydroquinone, propylgallate.
The adjuvant is combined selected from one or more of ethyl alcohol, ethylene glycol, propylene glycol, glycerine, polyethylene glycol.
To solve above-mentioned second technical problem, the technical solution provided by the present invention is:
The present invention provides a kind of preparation sides of the compound imidacloprid transdermal composition preparation of pet broad-spectrum anti-parasite
Method specifically comprises the following steps: that the imidacloprid of recipe quantity is taken to be dissolved with appropriate solvent, solution A is made；Take the Doramectin of recipe quantity
Element is dissolved with appropriate solvent, and solution B is made；It takes the fenvalerate of recipe quantity to be dissolved with appropriate solvent, solution C is made；By solution
A, solution B and solution C mixing, supply the solvent of recipe quantity, the penetration enhancer and antioxidant of recipe quantity are added, fixed with adjuvant
Hold；The solution filtering with microporous membrane that will be obtained, the filling compound for a kind of pet broad-spectrum anti-parasite after clarity is qualified
Imidacloprid transdermal composition preparation.
The Franz diffusion cell of percutaneous penetration application enhancements of the present invention carries out pigskin transdermal experiment.The results show that compound
The transdermal dashing agent of imidacloprid (contains imidacloprid 12.5%；Doractin 0.25%, fenvalerate 0.005%) for 24 hours departmental summary seep
Penetration, imidacloprid are 4473.32 μ g, and doractin is 82.21 μ g, and fenvalerate is 10.33 μ g；Unit in PBS acceptable solution
Infiltration rate constant (k), imidacloprid are 29.82 μ g/ (cm2H), doractin is 0.548 μ g/ (cm2H), fenvalerate is
0.768μg/(cm2h).Above-mentioned Vitro Experimental Results explanation, pours using a kind of compound imidacloprid is transdermal prepared by the present invention
Agent has good Transdermal absorption effect.Effective pest-resistant concentration of imidacloprid animal tissue is flat for 2.5 μ g/kg, 8kg weight animals
Tissue is total need to be administered 20 μ g, be administered 1mL (12.5mg), be coated with 1cm2, the imidacloprid penetrated per hour will be more than 20 μ g；And
Imidacloprid is in the intracorporal elimination long half time of the animals such as dog, cat, mouse, rabbit, pig in 8.7d (8.7-30.6d)；Thus drug enters
Intracorporal elimination amount is negligible with respect to Transdermal absorption, and imidacloprid 1h transit dose can reach pest-resistant effective dose.In addition,
It is administered by the above standard, drug is needed completely through skin more than 20d, and said preparation also has preferable slow release effect.Doramectin
Effective pest-resistant concentration of plain animal tissue, which is that 1 μ g/kg, 8kg weight animals average tissue is total, need to be administered 8 μ g；1mL is administered
(0.25mg) is coated with 15cm2, the doractin penetrated per hour will be more than 8 μ g, and doractin is in dog, cat, mouse, rabbit, pig etc.
The intracorporal elimination long half time of animal is in 3.3d (3.3-14.4d), thus drug enters intracorporal elimination amount with respect to Transdermal absorption
Negligible, doractin 1h transit dose can reach pest-resistant effective dose.The useful effect of fenvalerate animal tissue
Concentration is 9ng/kg, and 8kg weight animals average tissue is total need to be administered 72ng；It is administered 1mL (50 μ g), is coated with 15cm2, per hour
The fenvalerate of transmission will be more than 8 μ g, can reach pest-resistant effective dose.In conclusion said preparation percutaneous drug delivery can reach
The blood concentration for imitating expelling parasite, the transdermal composition preparation that can be used as animal expelling parasite are used for the treatment and prevention of pet anti parasitic.
Transdermal test in vitro comparative experiments is shown, when solvent is benzyl alcohol, a kind of prepared pet broad-spectrum anti-parasite
Compound imidacloprid transdermal composition has more significant Transdermal absorption.The results show that compound imidacloprid transdermal dashing agent (worm containing pyrrole
Quinoline 12.5%；Doractin 0.25%, fenvalerate 0.005%；Solvent is benzyl alcohol, and adjuvant is ethyl alcohol) for 24 hours departmental summary seep
Penetration, imidacloprid are 4473.32 μ g, and doractin is 82.21 μ g, and fenvalerate is 10.33 μ g；Unit in PBS acceptable solution
Infiltration rate constant (k), imidacloprid are 29.82 μ g/ (cm2H), doractin is 0.548 μ g/ (cm2H), fenvalerate is
0.768μg/(cm2h).And the transdermal dashing agent Comparative formulation 1 of compound imidacloprid (contains imidacloprid 12.5%；Doractin 0.25%,
Fenvalerate 0.005%；Solvent is propylene glycol, and adjuvant is ethyl alcohol) departmental summary infiltration capacity for 24 hours, imidacloprid is 2332.13 μ g,
Doractin is 37.86 μ g, and fenvalerate is 4.38 μ g；Unit permeation rate constant (k) in PBS acceptable solution, imidacloprid are
15.55μg/(cm2H), doractin is 0.252 μ g/ (cm2H), fenvalerate is 0.326 μ g/ (cm2h).Compound imidacloprid is saturating
Skin dashing agent Comparative formulation 2 (contains imidacloprid 12.5%；Doractin 0.25%, fenvalerate 0.005%；Solvent is isopropanol,
Adjuvant is ethyl alcohol) departmental summary infiltration capacity for 24 hours, imidacloprid is 2018.45 μ g, and doractin is 27.73 μ g, and fenvalerate is
3.37μg；Unit permeation rate constant (k) in PBS acceptable solution, imidacloprid are 13.46 μ g/ (cm2H), doractin is
0.186μg/(cm2H), fenvalerate is 0.251 μ g/ (cm2h).The transdermal dashing agent Comparative formulation 3 of compound imidacloprid (contains imidacloprid
12.5%；Doractin 0.25%, fenvalerate 0.005%；Solvent is n-butanol, and adjuvant is ethyl alcohol) departmental summary infiltration for 24 hours
Amount, imidacloprid are 3301.45 μ g, and doractin is 36.64 μ g, and fenvalerate is 6.01 μ g；Unit permeation in PBS acceptable solution
Rate constant (k), imidacloprid are 22.01 μ g/ (cm2H), doractin is 0.244 μ g/ (cm2H), fenvalerate is 0.447 μ g/
(cm2h)。
As it can be seen that the transdermal dashing agent of compound imidacloprid of preparation has better Transdermal absorption when solvent selects benzyl alcohol.
To solve above-mentioned third technical problem, compound pyrrole of the present invention to a kind of pet broad-spectrum anti-parasite
Worm quinoline transdermal composition preparation has carried out the anti parasitic experiment of dog.The Beagle dog of 30 infection worms, raising are selected in experiment
In the environment that mosquito flea nourishes, 5 groups are randomly divided into, the 1st, 2,3,4 group is pressed weight with 0.1,0.2,0.5,1mL/kg respectively
The compound imidacloprid transdermal composition preparation (containing imidacloprid 12.5%, doractin 0.25%, fenvalerate 0.005%) of dosage
It carries out the ear portion skin and embrocates administration, the 5th group is embrocated control group for physiological saline.The experimental results showed that 3d after medication, the 1st group
With the 2nd group in largely infect worm Beagle dog helminth symptom mitigate, crust partial exfoliation；Beagle dog goes out simultaneously
Now by mosquito flea bite the phenomenon that, visible flea activity in hair；Wherein the 2nd group of situation is slightly better than the 1st group；3rd group and the 4th
The symptom of group disappears substantially, and scytitis caused by helminth mitigates, and crust almost all falls off, and rarely seen flea is living in hair
It is dynamic, and rarely seen animal body and surrounding mosquito activity, animal mood are stablized, and column is no longer rubbed.7 days after medication, the 1st group still has part
Beagle dog has pruritis, flea activity is still seen in hair, microscopy is still with the presence of a small amount of worm living and worm's ovum；2nd group
The column phenomenon of rubbing of Beagle dog disappears substantially, and rarely seen flea activity, microscopy lose worm living but with the presence of worm's ovums in hair；3rd
Group and the 4th group of symptom completely disappear, and skin restores gloss and elasticity, rarely seen flea activity in hair, microscopy be not detected worm and
Worm's ovum；And the 5th group, the symptom of the Beagle dog in saline control group does not improve, and has exacerbation trend.The compound pyrrole worm
The cure rate of each dosage of the transdermal combination preparation of quinoline is respectively 50%, 83%, 100%, 100%, and therefore, which applies
When wiping administration, the effective mass dosage to Beagle dog is 0.5mL/kg weight.
To solve above-mentioned third technical problem, the present invention also carries out the compound imidacloprid transdermal composition preparation
The anti parasitic experiment of hamster.The gold hamster of 40 infection worms is selected in experiment, raises the environment bred in mosquito flea
In, be randomly divided into 4 groups, the 1st, 2,3 group press respectively weight with 2,5, the compound imidacloprid transdermal composition preparation of 10mL/kg dosage
(containing imidacloprid 12.5%, doractin 0.25%, fenvalerate 0.005%) carries out whole body and pours administration, and the 4th group is physiology salt
Water pours administration control group.The experimental results showed that 2d after medication, the helminth disease of the hamster of worm is largely infected in the 1st group
Shape mitigates, and still has apparent flea activity in hair, and periphery mosquito dances in the air, crust partial exfoliation, but has behavior of slightly fighting；The
2 groups and the 3rd group of symptom disappears substantially, and crust almost all falls off, rarely seen flea in hair, animal body and the rarely seen mosquito of surrounding
Activity, and animal mood is stablized.5 days after medication, the 1st group still has part hamster symptom not completely disappear, and microscopy still has a small amount of work
Worm and worm's ovum exist；2nd group and the 3rd group of symptom completely disappear, and skin restores gloss and worm and worm is not detected in elasticity, microscopy
Ovum；Meanwhile the 4th group, the symptom of the hamster in saline control group does not improve, and has exacerbation trend.The compound imidacloprid
The cure rate of transdermal each dosage of combination preparation is respectively 70%, 100%, 100%, and therefore, which pours administration
When, the effective mass dosage to gold hamster is 5mL/kg weight.
The transdermal combination preparation of compound imidacloprid prepared by the present invention (contains imidacloprid 12.5%, doractin 0.25%, cyanogen penta
Pyrethroids 0.005%) it is that can be absorbed into animal body to achieve the effect that kill epizoa in animal body by skin, drug warp
The process of the skin absorbed into serum sustainable long period, and without the destruction of liver " first pass effect " and gastrointestinal tract, it improves
The bioavilability of drug, while the side effect of oral administration of drugs is reduced, and can effectively extend the absorption process of drug
And action time, reduce administration frequency.
The transdermal combination preparation of compound imidacloprid prepared by the present invention (contains imidacloprid 12.5%, doractin 0.25%, cyanogen penta
Pyrethroids 0.005%), it is compared when being applied with single component in pharmaceutical composition, is remarkably improved the availability of drug；It can also be significant
Reduce toxic side effect when single component application in pharmaceutical composition.Drug combination preparation prepared by the present invention can overcome pyrrole
The reduction (numbness) of animal medicine-feeding part (such as at the basal part of the ear of Beagle dog) reaction sensitivity, can overcome more when worm quinoline is used alone
Draw rhzomorph when being used alone Transdermal absorption effect it is undesirable, can also overcome fenvalerate when being used alone since dosage is higher and
Caused apparent Ocular irritation effect.
It is of the invention to be advantageous in that:
1. providing a kind of compound imidacloprid transdermal composition system of pet broad-spectrum anti-parasite for the first time in field of veterinary
Agent.
2. providing a kind of compound imidacloprid transdermal composition system of pet broad-spectrum anti-parasite for the first time in field of veterinary
The preparation method of agent.
3. imidacloprid, doractin and pyrethroid coumpound are formed compound, anti parasitic for the first time by the present invention
Mosquito-proof drive flea mechanism is different, it can be achieved that the mosquito-proof drive flea effect of the anti parasitic of the multiple prevention and treatment of single administration.
4. imidacloprid, doractin and pyrethroid coumpound are formed compound for the first time by the present invention, can significantly reduce
The toxic side effect that one pack system is applied in each composition.
5. current many anti parasitic solutions only take into account the sprinkling of drug, and have ignored and certain preparation hand can be used
Section so that drug is achieved the purpose that Transdermal absorption, thus obtain deeper into anti parasitic effect.The present invention passes through the office to animal
Portion's administration, is absorbed by Cutaneous permeation, has good therapeutic effect to helminth.
6. the present invention by select be suitable for, suitable solvent, solve that imidacloprid solubility in solution is lower to ask
Topic.
7. it is lower to overcome imidacloprid solubility in solution with solvent by selecting suitable adjuvant jointly by the present invention
The problem of.
8. the present invention solves imidacloprid, doractin and pyrethroid by the way that suitable, suitable penetration enhancer is added
Ester type compound due to molecular weight greatly and fusing point is high and problem that bring percutaneous penetration is lower, transdermal experiment as the result is shown this
Transdermal combination preparation has good percutaneous absorbability.
9. the present invention is not limited to single administration mode, painting can be used, wiping, spray, drip, pour by being prepared as different dosage forms
A variety of form of medication such as bold and vigorous.
Specific embodiment
Embodiment 1-12
1. embodiment 1-12 prescription of table
Solution A is made the following steps are included: the imidacloprid of recipe quantity is taken to be dissolved with suitable solvent in preparation method；Take place
The doractin just measured is dissolved with suitable solvent, and solution B is made；The fenvalerate of recipe quantity is taken to be dissolved with suitable solvent,
Solution C is made；By solution A, solution B and solution C mix, supply the solvent of recipe quantity, be added recipe quantity penetration enhancer and
Antioxidant, with adjuvant constant volume；The filtering with microporous membrane for being 0.22 μm by obtained solution aperture fills after clarity is qualified
Dress.
Experimental example 1:
The transdermal combination preparation of compound imidacloprid of embodiment 1 (contains imidacloprid 12.5%, doractin 0.25%, penta chrysanthemum of cyanogen
Ester 0.005%) percutaneous penetration
1. experimental method
1.1. reagent and instrument
The transdermal combination preparation of compound imidacloprid contains imidacloprid 12.5%, doractin for the preparation gained of embodiment 1
0.25%, fenvalerate 0.005%.
Franz diffusion cell (Sichuan University), BP211D electronic balance (Sartorius company, Germany), JA3003 electronics day
(it is public that Gongyi City gives magnificent instrument Limited Liability for flat (Shanghai analysis instrument factory), DF-101S heat collecting type constant-temperature heating magnetic stirring apparatus
Department), HL-2 type constant flow peristaltic pump (Qingpu Shanghai Hu Xi instrument plant), QZX-C type air bath oscillator (Harbin City Dongming medical treatment
Instrument plant).
1.2. percutaneous penetration method
1.2.1. the preparation of isolated skin: one piece of skin that a certain size is taken at experiment sucking pig (1 monthly age) neck back is taken
(2.5cm × 2.5cm), removes defeathering and subcutaneous fat, is cleaned with physiological saline and is used afterwards three times.
1.2.2. percutaneous penetration: isolated skin is fixed between diffuser casing and receiving chamber, and cuticula is towards diffusion
25mL receiving liquid (the 0.01MPBS solution containing 0.1% sodium Diacetate, pH 6.5) is added in room, receiving chamber and its system, opens
Constant flow pump drives away bubble, comes into full contact with receiving liquid with skin.System temperature is 37 ± 1 DEG C, and constant current flow rate pump is 2mL/min,
Receiving chamber is placed in magnetic stirring apparatus, and magnetic stirring apparatus revolving speed is 150rpm.After system stablizes 0.5h, compound is added in diffuser casing
The transdermal combination preparation 5mL of imidacloprid, after experiment starts, in 0.25,0.5,0.75,1,2,3,4,6,8,12,16,20, for 24 hours from connecing
It receives in liquid and samples 0.5mL, then fill into the fresh receiving liquid of equivalent.
1.3. drug detection
1.3.1. the assay of imidacloprid
Chromatographic condition: HPZORBAXXDBC18 chromatographic column (5 μm, 4.6mm × 150mm), mobile phase are 0.2% (v/v) second
Aqueous acid-acetonitrile (80:20, v/v), 25 DEG C of column temperature, flow velocity 2mL/min, 5 μ L of sample volume.UV detector wavelength is set as
270nm。
The preparation of standard solution: precision weighs imidacloprid standard items 10mg and is dissolved in 100mL volumetric flask, with acetonitrile constant volume, makees
For stock solution (100 μ g/mL), it is sealed in 4 DEG C.By stock solution with dilution in acetonitrile be series of concentrations be 0.1,0.2,0.5,1,
2, the standard solution of 5,10 μ g/mL.
The foundation of standard curve: taking 5 μ L sample introduction of above-mentioned standard solution, records peak area.It is x, pyrrole worm with imidacloprid concentration
Quinoline peak area is y, draws standard curve；Obtained equation of linear regression are as follows: y=400.34x+10.334, r2=0.9997.Line
Property range be 0.1-10 μ g/mL.Linear result is good, meets assay requirement.
1.3.2. the assay of doractin
Chromatographic condition: HPZORBAXXDBC18 chromatographic column (5 μm, 4.6mm × 150mm), mobile phase are acetonitrile-methanol-water
(45:45:20, v/v/v), 25 DEG C of column temperature, flow velocity 2mL/min, 5 μ L of sample volume.UV detector wavelength is set as 246nm.
The preparation of standard solution: precision weighs doractin standard items 10mg and is dissolved in 100mL volumetric flask, with methanol constant volume,
As stock solution (100 μ g/mL), it is sealed in 4 DEG C.By stock solution with methanol dilution be series of concentrations be 0.05,0.1,
0.2, the standard solution of 0.5,1,2,5 μ g/mL.
The foundation of standard curve: taking 5 μ L sample introduction of above-mentioned standard solution, records peak area.It is x with doractin concentration, it is more
Drawing rhzomorph peak area is y, draws standard curve；Obtained equation of linear regression are as follows: y=995.36x+33.479, r2=
0.9996.The range of linearity is 0.05-5 μ g/mL.Linear result is good, meets assay requirement.
1.3.3. the assay of fenvalerate
Chromatographic condition: HPZORBAXXDBC18 chromatographic column (5 μm, 4.6mm × 150mm), mobile phase be methanol-water (80:
20, v/v), 25 DEG C of column temperature, flow velocity 2mL/min, 5 μ L of sample volume.UV detector wavelength is set as 220nm.
The preparation of standard solution: precision weighs fenvalerate standard items 1mg and is dissolved in 100mL volumetric flask, with methanol constant volume, makees
For stock solution (10 μ g/mL), it is sealed in 4 DEG C.By stock solution with methanol dilution be series of concentrations be 0.02,0.05,0.1,
0.2, the standard solution of 0.5,1,2 μ g/mL.
The foundation of standard curve: taking 5 μ L sample introduction of above-mentioned standard solution, records peak area.It is x, cyanogen with fenvalerate concentration
Valerate peak area is y, draws standard curve；Obtained equation of linear regression are as follows: y=367.08x+66.883, r2=
0.9997.The range of linearity is 0.02-2 μ g/mL.Linear result is good, meets assay requirement.
1.4. data processing
Due to after every sub-sampling will fluid infusion, diluting effect is produced to the penetrating of drug, thus the accumulation of drug is penetrating
Measure TRcum(μ g/mL) can be corrected by following formula:
Wherein AnFor the measured value of the penetrating amount of n-th of sample；VsnFor the sampling volume of n-th of sample；VRFor reception tank
Volume.
Percutaneous rate can be calculated by following formula:
K=TRcum/tn
Wherein TRcum(μ g/mL) is the penetrating amount of accumulation of n-th sampling, tnIt (h) is n-th sample time.
2. results and discussion
The results show that used compound imidacloprid transdermal composition preparation (contains imidacloprid 12.5%, doractin
0.25%) it is 4473.32 μ g that unit permeation amount, which is imidacloprid, for 24 hours, and doractin is 82.21 μ g, and fenvalerate is 10.33 μ g；
Unit permeation rate constant (k) in PBS acceptable solution, imidacloprid are 29.82 μ g/ (cm2H), doractin is 0.548 μ g/
(cm2H), fenvalerate is 0.768 μ g/ (cm2H), illustrate that the transdermal combination preparation has good Transdermal absorption effect.Pyrrole worm
Effective pest-resistant concentration of quinoline animal tissue, which is that 2.5 μ g/kg, 8kg weight animals average tissues are total, need to be administered 20 μ g, and 1mL is administered
(12.5mg) is coated with 1cm2, the imidacloprid penetrated per hour will be more than 20 μ g；And imidacloprid is in animals such as dog, cat, mouse, rabbit, pigs
Intracorporal elimination long half time is in 8.7d (8.7-30.6d)；Thus drug enters intracorporal elimination amount and can neglect with respect to Transdermal absorption
Slightly disregard, doractin 1h transit dose can reach pest-resistant effective dose.In addition, being administered by the above standard, drug is completely saturating
It crosses skin to need more than 20d, said preparation also has preferable slow release effect.Effective pest-resistant concentration of doractin animal tissue is
1 μ g/kg, 8kg weight animals average tissue is total need to be administered 8 μ g；It is administered 1mL (0.25mg), is coated with 15cm2, penetrate per hour
Doractin will be more than 8 μ g, and doractin in the intracorporal elimination long half time of the animals such as dog, cat, mouse, rabbit, pig in 3.3d
(3.3-14.4d), thus drug enters intracorporal elimination amount and can be neglected with respect to Transdermal absorption, doractin 1h transit dose is
It can reach pest-resistant effective dose.The useful effect concentration of fenvalerate animal tissue is 9ng/kg, 8kg weight animals averagely group
It knits to amount to and 72ng need to be administered；It is administered 1mL (50 μ g), is coated with 15cm2, the fenvalerate penetrated per hour will be more than 8 μ g, can reach
Pest-resistant effective dose.In conclusion said preparation percutaneous drug delivery can reach the blood concentration of effective expelling parasite, animal expelling parasite can be used as
Transdermal composition preparation be used for pet anti parasitic treatment and prevention.
Experimental example 2
The transdermal superiority of the transdermal combination preparation of compound imidacloprid compares
1. experimental method
1.1. reagent and instrument
The transdermal combination preparation 1 of compound imidacloprid contains imidacloprid 12.5%, doractin for the preparation gained of embodiment 1
0.25%, fenvalerate 0.005%；Solvent is benzyl alcohol, and adjuvant is ethyl alcohol.The transdermal combination preparation Comparative formulation of compound imidacloprid
1, Comparative formulation 2 and Comparative formulation 3, respectively comparative example 1, comparative example 2 and the preparation gained of comparative example 3, solvent is respectively the third two
Alcohol, isopropanol and n-butanol, adjuvant are ethyl alcohol.
Instrument is the same as 1.1 in embodiment 13.
1.2. percutaneous penetration method
With 1.2 in embodiment 13.
1.3. drug detection
With 1.3 in embodiment 13.
1.4. data processing
With 1.4 in embodiment 13.
2. results and discussion
The results show that departmental summary infiltration capacity, imidacloprid are the transdermal dashing agent of compound imidacloprid (solvent is benzyl alcohol) for 24 hours
4473.32 μ g, doractin are 82.21 μ g, and fenvalerate is 10.33 μ g；Unit permeation rate constant in PBS acceptable solution
(k), imidacloprid is 29.82 μ g/ (cm2H), doractin is 0.548 μ g/ (cm2H), fenvalerate is 0.768 μ g/ (cm2h)。
And departmental summary infiltration capacity, imidacloprid are the transdermal dashing agent Comparative formulation 1 (solvent is propylene glycol) of compound imidacloprid for 24 hours
2332.13 μ g, doractin are 37.86 μ g, and fenvalerate is 4.38 μ g；Unit permeation rate constant in PBS acceptable solution
(k), imidacloprid is 15.55 μ g/ (cm2H), doractin is 0.252 μ g/ (cm2H), fenvalerate is 0.326 μ g/ (cm2h)。
Departmental summary infiltration capacity, imidacloprid are 2018.45 μ to the transdermal dashing agent Comparative formulation 2 (solvent is isopropanol) of compound imidacloprid for 24 hours
G, doractin are 27.73 μ g, and fenvalerate is 3.37 μ g；Unit permeation rate constant (k) in PBS acceptable solution, imidacloprid
For 13.46 μ g/ (cm2H), doractin is 0.186 μ g/ (cm2H), fenvalerate is 0.251 μ g/ (cm2h).Compound imidacloprid
Departmental summary infiltration capacity, imidacloprid are 3301.45 μ g, doractin to transdermal dashing agent Comparative formulation 3 (solvent is n-butanol) for 24 hours
For 36.64 μ g, fenvalerate is 6.01 μ g；Unit permeation rate constant (k) in PBS acceptable solution, imidacloprid are 22.01 μ g/
(cm2H), doractin is 0.244 μ g/ (cm2H), fenvalerate is 0.447 μ g/ (cm2h).In conclusion solvent selects benzene first
When alcohol, the transdermal dashing agent of compound imidacloprid of preparation has better Transdermal absorption.
Experimental example 3
Compound imidacloprid transdermal composition preparation (contains imidacloprid 12.5%, doractin 0.25%, fenvalerate
0.005%) dog anti parasitic experiment
1. experimental method
1.1. drug
The transdermal combination preparation of compound imidacloprid contains imidacloprid 12.5%, doractin for the preparation gained of embodiment 1
0.25%, fenvalerate 0.005%.
1.2. experimental animal
The Beagle dog of 30 infection worms is selected, half male and half female, at about 1 age, weight 7-9kg, clinical manifestation is itch,
It raises in the environment that flea mosquito breeds.Infect the Beagle of worm in feeding environment accessible various objects (such as
Fixed device of iron cage, feed trough, kettle etc.) and ground on constantly rub and itch, firmly rub.In the head of the Beagle dog of infection worm
There is scytitis in portion, cheek, ear, neck, shoulder back, abdomen, trunk two sides agent four limbs, show as coat fall off, scurf,
Flush, or even have the leaching of inflammatory liquid, bleeding, nodule scab；Cortical thickening, it is coarse be hardened, or even chap.Microscopy it is visible or
Worm and worm's ovum.Visible flea activity, animal body mosquito surround in animal hair.
1.3. the grouping and treatment of worm Beagle dog are infected
1.3.1. experimental group and administration: the Beagle dog of 30 natural infection worms is selected in experiment, and half male and half female is random
Be divided into 5 groups, the 1st, 2,3,4 group press respectively weight with 0.1,0.2,0.5, the transdermal combination preparation of compound imidacloprid of 1mL/kg dosage
(contain imidacloprid 12.5%；Doractin 0.25%, fenvalerate 0.005%) carry out the ear portion skin embrocate administration, the 5th group is
Physiological saline embrocates control group.When administration, medical fluid is drawn with 10mL syringe, preparation is embrocated in Beagle dog auris dextra basal part of the ear skin
Place, medical fluid of being subject to are not lost.Situation is grouped referring to table 1.
2. experimental infection worm Beagle dog of table is grouped agent administration
1.3.2. Symptom Observation and judgement: pruritus is checked in the clinical manifestation of the Beagle dog of the worm of observation infection daily
Whether shape and cutaneous lesions improve and restore；Check the activity condition of flea and mosquito in animal hair.After 7d, lesion is scraped
The skin histology of position and healthy skin intersection, sets in culture dish, checks worm and worm's ovum situation using humidification method.
2. results and discussion
Timing daily is observed and the associated clinical symptoms of record experiment Beagle dog.3d after medication, in the 1st group and the 2nd group
The symptom of the Beagle dog of most of infection worm mitigates, and crust partial exfoliation, Beagle dog occurs being stung by mosquito flea simultaneously
The phenomenon that stinging, visible flea activity in hair；Wherein the 2nd group of situation is slightly better than the 1st group；3rd group and the 4th group of symptom disappears substantially
It loses, scytitis caused by helminth mitigates, and crust almost all falls off, rarely seen flea activity in hair, and rarely seen animal
Body and surrounding mosquito activity, animal mood are stablized, and column is no longer rubbed.7 days after medication, the 1st group still has part Beagle dog to have itch
Symptom is still shown in flea activity in hair, and microscopy is still with the presence of a small amount of work worm and worm's ovum；2nd group of Beagle dog rubs column phenomenon
It disappears, rarely seen flea activity, microscopy lose worm living but with the presence of worm's ovums in hair；3rd group and the 4th group of symptom completely disappear,
Skin restores gloss and elasticity, rarely seen flea activity in hair, and worm and worm's ovum is not detected in microscopy；And the 5th group, physiological saline pair
Do not improve according to the symptom of the Beagle dog in group, and has exacerbation trend.Specific experiment result is referring to table 2.
Clinical efficacy of the 3. compound imidacloprid transdermal composition preparation of table to Beagle dog worm
As shown in Table 2, the cure rate of each dosage of the transdermal combination preparation of the compound imidacloprid be respectively 50%, 83%,
100%, 100%, therefore, which is 0.5mL/kg weight to the effective mass dosage of Beagle dog.
3. brief summary
During the experiment, administration each group has no apparent adverse drug reaction, and diet is normal, excretion is normal.From healing
From the point of view of rate, the cure rate of dosage 0.5mL/kg and 1mL/kg group is 100%, 0.1mL/kg and 0.2mL/kg dosage group
In, the anthelminthic effect of individual Beagle dogs is undesirable, and reason may is that underdosage.
Experimental example 4
Compound imidacloprid transdermal composition preparation (contains imidacloprid 12.5%, doractin 0.25%, fenvalerate
0.005%) mouse anti parasitic experiment
1. experimental method
1.1. drug
The transdermal combination preparation of compound imidacloprid contains imidacloprid 12.5%, doractin for the preparation gained of embodiment 1
0.25%, fenvalerate 0.005%.
1.2. experimental animal
The gold hamsters of 40 infection worms are selected, half male and half female, at the 5-12 monthly age, weight 220-300g, clinical manifestation is
Itch is raised in the environment that flea mosquito breeds.The hamster disposition for infecting worm is more irascible, constantly turns in feeding environment
Rolling firmly rubs.Head, cheek, ear, neck, shoulder back, abdomen, trunk two sides agent four limbs in the hamster of infection worm
There is scytitis, show as coat fall off, scurf, flush, or even have the leaching of inflammatory liquid, bleeding, nodule scab；Cortex
Thicken, it is coarse be hardened, or even chap.Microscopy is visible or worm and worm's ovum.Visible flea activity, animal body mosquito in animal hair
It surrounds.
1.3. the grouping and treatment of worm hamster are infected
1.3.1. experimental group and administration: the hamster of 40 natural infection worms is selected in experiment, and half male and half female is randomly divided into 4
Group, the 1st, 2,3 group press respectively weight with 2,5, the transdermal combination preparation agent of compound imidacloprid of 10mL/kg dosage is (containing imidacloprid
12.5%, doractin 0.25%, fenvalerate 0.005%) it carries out whole body and pours administration, the 4th group is that physiological saline pours pair
According to group.When administration, medical fluid is drawn with 5mL syringe, hamster is placed on porcelain pallet, and preparation whole body is poured in hamster body.Point
Group situation is referring to table 3.
4. experimental infection worm gold hamster of table is grouped agent administration
1.3.2. Symptom Observation and judgement: daily observation infection worm hamster clinical manifestation, check pruritis and
Whether cutaneous lesions improve and restore；Check the activity condition of flea and mosquito in animal hair.After 5d, diseased region is scraped
It with the skin histology of healthy skin intersection, sets in culture dish, worm and worm's ovum situation is checked using humidification method.
2. results and discussion
Timing daily is observed and the associated clinical symptoms of record experiment hamster.2d after medication largely infects in the 1st group compacted
The symptom of the hamster of worm mitigates, and still apparent flea activity, periphery mosquito dance in the air in hair, crust partial exfoliation, but have slight
It fights behavior；2nd group and the 3rd group of symptom disappears substantially, and crust almost all falls off, rarely seen flea in hair, animal body and
The rarely seen mosquito activity of surrounding, and animal mood is stablized.5 days after medication, the 1st group still has part hamster symptom not completely disappear, mirror
Inspection is still with the presence of a small amount of worm living and worm's ovum；2nd group and the 3rd group of symptom completely disappear, and skin restores gloss and elasticity, and microscopy is not
Detect worm and worm's ovum；Meanwhile the 5th group, the symptom of the hamster in saline control group does not improve, and has exacerbation trend.
Specific experiment result is referring to table 4.
Clinical efficacy of the 5. compound imidacloprid transdermal composition preparation of table to gold hamster worm
As shown in Table 4, the cure rate of each dosage of the transdermal combination preparation of the compound imidacloprid be respectively 70%, 100%,
100%, therefore, which is 5mL/kg weight to the effective mass dosage of hamster.
3. brief summary
During the experiment, administration each group has no apparent adverse drug reaction, and diet is normal, excretion is normal.From healing
From the point of view of rate, the cure rate of dosage 5mL/kg and 10mL/kg group is drive of 100%, the 2mL/kg dosage group to individual hamsters
Worm effect is undesirable, and reason may is that underdosage.
Embodiment 17
Compound imidacloprid transdermal composition preparation (contains imidacloprid 12.5%, doractin 0.25%, fenvalerate
0.005%) Beagle dog medicine-feeding part sensitivity experiment
1. experimental method
1.1. drug
The transdermal combination preparation of compound imidacloprid contains imidacloprid 12.5%, doractin for the preparation gained of embodiment 1
0.25%, fenvalerate 0.005%.Imidacloprid folk prescription solution is free of doractin and fenvalerate, remaining is the same as embodiment 1
It is obtained, contain imidacloprid 12.5%.
1.2. experimental method
18 health Beagle dogs are selected, half male and half female, at about 1 age, weight 8-9kg is randomly divided into two groups.(A) group in
It is coated with physiological saline by 0.5mL/kg at the basal part of the ear, (B) group is coated with compound imidacloprid composition preparation by 0.5mL/kg at the basal part of the ear,
(C) group is coated with imidacloprid folk prescription solution by 0.5mL/kg at the basal part of the ear；After solution comes into full contact with basal part of the ear skin 2-3min, use is small
Rod stimulates Beagle dog the ear portion skin, observes reaction of animals.
2. experimental result
(A) group Beagle dog the ear portion is had stronger reaction by after the stimulation of small rod, shows as getting rid of ear, head is quickly returned
Turn, open one's mouth to bark and demonstrate；(B) it after group Beagle dog is stimulated, all shows to get rid of ear and turn one's head, momentum of barking is slightly weak；And
(C) after group Beagle dog is stimulated, almost without reaction, occasionally have later.
3. brief summary
This part the experimental results showed that, after imidacloprid and doractin and fenvalerate composition pharmaceutical composition, can gram
Take the side effect of medicine-feeding part caused when imidacloprid is used alone (numbness) slow in reacting.
The above embodiment of the present invention is not to this hair merely to the citing for clearly illustrating the present invention and making
The restriction of bright embodiment.For those skilled in the relevant art, it can also be done on the basis of above description and citing
Other various forms of adjustment and variation out.This specification can not be exhaustive all embodiments.It is all to belong to this hair
The obvious adjustment and variation that bright technical solution is extended out are still in the scope of protection of the present invention.
Claims (4)
1. a kind of compound imidacloprid transdermal composition preparation of pet broad-spectrum anti-parasite, which is characterized in that by following proportion
Each group be grouped as: imidacloprid 12.5g, doractin 0.25g, fenvalerate 0.005g, benzyl alcohol 60g, azone 6g, 2,6 uncles
Butyl paracresol 0.015mg, ethyl alcohol to 100ml.
2. a kind of a kind of system of the compound imidacloprid transdermal composition preparation of pet broad-spectrum anti-parasite described in claim 1
Preparation Method, which is characterized in that specifically comprise the following steps: that the imidacloprid of recipe quantity is taken to be dissolved with appropriate benzyl alcohol, solution is made
A；It takes the doractin of recipe quantity to be dissolved with appropriate benzyl alcohol, solution B is made；Take the fenvalerate of recipe quantity with appropriate benzyl alcohol
Dissolution, is made solution C；By solution A, solution B and solution C mix, supply the benzyl alcohol of recipe quantity, be added recipe quantity azone,
2,6 Butylated Hydroxytoluenes, with ethyl alcohol constant volume；The solution filtering with microporous membrane that will be obtained, it is filling for one kind after clarity is qualified
The compound imidacloprid transdermal composition preparation of pet broad-spectrum anti-parasite.
3. a kind of system of the compound imidacloprid transdermal composition preparation of pet broad-spectrum anti-parasite according to claim 2
Preparation Method, it is characterised in that: the miillpore filter pore size is 0.22 μm.
4. a kind of compound imidacloprid transdermal composition preparation of pet broad-spectrum anti-parasite according to claim 1,
It is characterized by: the solution compound imidacloprid transdermal composition preparation is dashing agent, spray, liniment, drops or puts on the skin
Agent.
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| CN1386420A (en) * | 2001-05-22 | 2002-12-25 | 王玉万 | Antiparasitic medicine containing imidacloprid for pet |
| CN1561163A (en) * | 2000-11-30 | 2005-01-05 | 拜尔健康护理有限责任公司 | Compositions for enhanced acaricidal activity |
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| CN1561163A (en) * | 2000-11-30 | 2005-01-05 | 拜尔健康护理有限责任公司 | Compositions for enhanced acaricidal activity |
| CN1386420A (en) * | 2001-05-22 | 2002-12-25 | 王玉万 | Antiparasitic medicine containing imidacloprid for pet |
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