CN103330679A - Film coating agent for treating pigeon ectozoa and preparation method thereof - Google Patents
Film coating agent for treating pigeon ectozoa and preparation method thereof Download PDFInfo
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- CN103330679A CN103330679A CN2013102752249A CN201310275224A CN103330679A CN 103330679 A CN103330679 A CN 103330679A CN 2013102752249 A CN2013102752249 A CN 2013102752249A CN 201310275224 A CN201310275224 A CN 201310275224A CN 103330679 A CN103330679 A CN 103330679A
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Abstract
The invention discloses a film coating agent for treating pigeon ectozoa and a preparation method thereof. The ectozoa is feather louse. The film coating agent is composed of the following materials: 8-12 g of ivermectin, 35-45 g of l-menthol, 13-18 g of polyvinyl alcohol-124, 38-42 mg of sodium carboxymethylcellulose, 55-65 ml of glycerin, 500 ml of water, and ethanol added to obtain the constant volume of 1000 ml. The invention also discloses the preparation method of the film coating agent. The film coating agent prepared by the invention has excellent film-forming property, and is capable of slowing releasing anthelmintics, persistent in curative effect, low in stress and safe to use. The formula and the preparation method of the film coating agent are unique and the treatment effect is obvious.
Description
Technical field
The present invention relates to a kind of liniment for the treatment of pigeon ectozoa (poultry louse) and preparation method thereof.Belong to the poultry field of pharmaceutical technology.
Background technology
Poultry louse is the common a kind of ectoparasite disease of poultry body surface, and this disease pathogen is Mallophaga (Mallophaga), is food with feather and the scurf of poultry, also sucks blood sometimes.The pigeon louse has the 1-2 millimetre long, and health can be separately, breast, and a chitinous ectoskeleton is arranged, and it can colonize on the feather of pigeon, so be called poultry louse again.But poultry louse is not suck blood, and poultry louse is to eat pigeon feather on one's body, the plumage powder, and outer skin, scurf, the dead cell fragment of skin etc. is made a living.The position of different types of poultry louse parasitism on the Columba livia body is also different, all live on one's body the pigeon all one's life, life cycle has several months, cause pigeon nervous, uneasy, can't can between the pigeon feather, touch by stable sleep poultry louse, can not sleep peacefully, feel blue, that appetite descends, feather drops fast, feather is grown up is bad, the hen pigeon laying rate descends or the not high other problem of rate of fertilization, naked eyes can observe directly.The method for the treatment of poultry louse generally is that ill Columba livia is carried out dipping or uses drug spray.He Wei's equality is formed compound recipe with the Radix Stemonae, FRUCTUS CARPESII, Omphalia, Rhizoma Osmundae the sick chicken of poultry louse is carried out dipping, has good curative effect.The author finds that to the main large-scale Columba livia field investigation of Nanjing periphery general dipping goes louse only can use in the Columba livia for matching to float, and the kind Columba livia of pairing also is not suitable for carrying out dipping.The Columba livia field is to use the insecticide of violating a ban to spray in dovecote for the main method for the treatment of control poultry louse now, these medicines stress be big to pigeon, the symptom of searching for food can appear stopping in the part pigeon in two days of spraying, even a small amount of pigeon death can appear, the use of forbidden drug also can work the mischief to human body, so the dipping to poultry is not desirable Therapeutic Method for intensive Columba livia field.
Chemical medicine class medicine ivermectin is novel wide spectrum, efficient, low toxicity antibiotics antiparasitic, and particularly nematicide and arthropod all have and well kill effect to endoparasite and ectoparasite.Use ivermectin dashing agents such as Ceng Wande are killed experiment effect to the external blood louse of pig and are shown, in 14 days for the treatment of sick pig on inspection its negative conversion rate be 100%, and not recurrence, effect is remarkable.As seen liniment is with its convenient drug administration, to animal stress be less etc. advantage become a kind of desirable administering mode that substitutes dipping and drug spray treatment poultry louse disease.But ivermectin does not appear in the newspapers as yet as liniment.
Summary of the invention
Technical problem to be solved by this invention provide a kind of easy to use, zest is little, curative effect is reliable, safe is used for the treatment of the ectozoal liniment of pigeon.
The technical problem that the present invention also will solve provides the preparation method of above-mentioned liniment.
For solving the problems of the technologies described above, the thinking that the present invention adopts is: be that raw material, left-handed menthol are that hold concurrently antiseptic, polyvinyl alcohol 124, sodium carboxymethyl cellulose of penetration enhancer is that filmogen, glycerol are cosolvent with the ivermectin, ethanol is solvent, is mixed with liniment with technology by a certain percentage.Because this dosage form is film forming voluntarily, protection internal layer medicine spreads to Intradermal, and can remove at any time, films at any time, uses easily.
Concrete technical scheme is as follows:
A kind of ectozoal liniment of pigeon that is used for the treatment of, described parasite is poultry louse, described liniment is made up of following material:
Ivermectin 8～12 grams, left-handed menthol 35～45 grams, polyvinyl alcohol-12413～18 gram, 38～42 milligrams of sodium carboxymethyl cellulose, 55～65 milliliters of glycerol, 500 milliliters in water, ethanol are settled to 1000 milliliters.
Described liniment preferably is made up of following material:
Ivermectin 10 grams, left-handed menthol 40 grams, polyvinyl alcohol-124 15 gram, 40 milligrams of sodium carboxymethyl cellulose, 60 milliliters of glycerol, 500 milliliters in water, ethanol are settled to 1000 milliliters.
Wherein, contain Borneolum Syntheticum 30～50 grams in per 1000 milliliters of liniment.
The above-mentioned preparation method that is used for the treatment of the ectozoal liniment of pigeon, it may further comprise the steps:
(1) polyvinyl alcohol-124 is soaked taking-up after 24 hours, it is standby to put into 60 ℃ of oven dryings;
(2) polyvinyl alcohol-124 after the step (1) that takes by weighing formula ratio is handled is put into stirred vessel, adds after 400 ml waters soak 2h, puts 85 ℃ of stirring in water bath dissolvings;
(3) add the slow stirring and evenly mixing of glycerol of formula ratio in the container of step (2);
(4) sodium carboxymethyl cellulose that continues to add formula ratio in the container of step (3) slowly stir, mixing, get blank liniment liquid, this liquid is maintained in the water-bath;
(5) to be dissolved in 400 ml volumes percentage compositions be in 75% the ethanol, to get the ivermectin alcoholic solution to the ivermectin that takes by weighing formula ratio, puts in the water-bath and preserve;
(6) take by weighing the left-handed menthol of formula ratio, slowly add in the ivermectin alcoholic solution, stirring and evenly mixing is put in the water-bath and is preserved;
(7) under the water bath condition, the alcoholic solution that is dissolved with ivermectin and left-handed menthol that step (6) is obtained slowly adds in the blank liniment liquid that step (4) obtains while hot, the limit edged stirs, and continues to add ethanol then and is settled to 1000 milliliters, and filtration makes.
In the step (4) (5) (5) (7), described water-bath, its temperature is 50～65 ℃; In the step (7), ethanol is heated to 50～65 ℃ in advance.
The application of above-mentioned liniment in preparation treatment pigeon ectozoa medicine, described parasite is poultry louse.
The present invention selects left-handed menthol to have originality as the penetration enhancer antiseptic of holding concurrently.Left-handed menthol has effects such as short saturating, antibiotic, antiinflammatory, and the menthol of other types does not then have this effect, and this specific character makes has brought into play this advantage well in the liniment preparation; Though the racemization menthol also has similar effect, preparation liniment consumption will double, and this just is unfavorable for the preparation of liniment.
This experimentation has compared the left-handed menthol of conventional Chinese medicine penetration enhancer to the short saturating effect of ivermectin, makes liniment with the short scheme of the best and suitable matrix formulations.Explore the Therapeutic Method of poultry parasite Chinese and Western combination by observing the anthelmintic therapeutic effect of this liniment in infecting poultry.
Beneficial effect: the present invention makes the dosage form of filming with ivermectin, and contains left-handed menthol in the liniment, is convenient to substitute injection and the oral epizoa infection that is used for the treatment of pigeon with applicator means.The liniment of preparation possesses good film property, can slowly discharge anthelmintic drug, curative effect is lasting, stress be little and use safety.Prescription of the present invention and manufacture method uniqueness, therapeutic effect is remarkable.
Description of drawings
(X ± S) (n=3) of the penetration enhancer infiltration coefficient of each concentration among table 1 embodiment 4;
Fig. 1 normal mouse epiderm skin structure (40 *);
Fig. 2 group of solvents 1h mouse skin epidermal structure (40 *);
Fig. 3 test group 1h mouse skin epidermal structure (40 *); Annotate: arrow indication place horny layer occurs separating with epidermis;
Fig. 4 group of solvents 3h mouse skin epidermal structure (40 *); Annotate: arrow indication place horny layer is arranged loose, occurs cavity between the horny layer;
Fig. 5 test group 3h mouse skin epidermal structure (40 *); Annotate: arrow indication place horny layer gauffer big cavity occurs with epidermis;
Fig. 6 group of solvents 6h mouse skin structure (40 *);
Fig. 7 test group 6h mouse skin epidermal structure (40 *); Annotate: arrow indication place horny layer cracking occurs and comes off;
Fig. 8 rabbit check plot epiderm skin structure (40 *);
Fig. 9 solvent district rabbit skin epidermal structure (40 *);
Figure 10 trial zone rabbit skin epidermal structure (40 *); Annotate: arrow indication place horny layer comes off fully.
The specific embodiment
According to following embodiment, the present invention may be better understood.Yet, those skilled in the art will readily understand that the described content of embodiment only is used for explanation the present invention, and should also can not limit the present invention described in detail in claims.
Embodiment 1:
Being used for the treatment of the ectozoal liniment of pigeon is made up of following material:
Ivermectin 10 grams, left-handed menthol 40 grams, polyvinyl alcohol-124 15 gram, 40 milligrams of sodium carboxymethyl cellulose, 60 milliliters of glycerol, 500 milliliters in water, ethanol are settled to 1000 milliliters.
Preparation method is as follows:
(1) polyvinyl alcohol-124 is soaked taking-up after 24 hours, it is standby to put into 60 ℃ of oven dryings;
(2) polyvinyl alcohol-124 after the step (1) that takes by weighing formula ratio is handled is put into stirred vessel, adds after 400 ml waters soak 2h, puts 85 ℃ of stirring in water bath dissolvings;
(3) add the slow stirring and evenly mixing of glycerol of formula ratio in the container of step (2);
(4) sodium carboxymethyl cellulose that continues to add formula ratio in the container of step (3) slowly stir, mixing, get blank liniment liquid, this liquid is maintained in 50～65 ℃ of water-baths;
(5) to be dissolved in 400 ml volumes percentage compositions be in 75% the ethanol, to get the ivermectin alcoholic solution to the ivermectin that takes by weighing formula ratio, puts in 50～65 ℃ of water-baths and preserve;
(6) take by weighing the left-handed menthol of formula ratio, slowly add in the ivermectin alcoholic solution, stirring and evenly mixing is put in 50～65 ℃ of water-baths and is preserved;
Under (7) 50～65 ℃ of water bath condition, the alcoholic solution that is dissolved with ivermectin and left-handed menthol that step (6) is obtained slowly adds in the blank liniment liquid that step (4) obtains while hot, the limit edged stirs, the continuation adding is preheated to 50～65 ℃ of ethanol and is settled to 1000 milliliters then, and filtration makes.
Embodiment 2:
Being used for the treatment of the ectozoal liniment of pigeon is made up of following material:
Ivermectin 8 grams, left-handed menthol 35 grams, Borneolum Syntheticum 40 grams, polyvinyl alcohol-124 13 gram, 38 milligrams of sodium carboxymethyl cellulose, 55 milliliters of glycerol, 500 milliliters in water, ethanol are settled to 1000 milliliters.
Preparation method is with embodiment 1, and difference is that in the step (6), Borneolum Syntheticum slowly adds in the ivermectin alcoholic solution with left-handed menthol.
Embodiment 3:
Being used for the treatment of the ectozoal liniment of pigeon is made up of following material:
Ivermectin 12 grams, left-handed menthol 45 grams, polyvinyl alcohol-124 18 gram, 42 milligrams of sodium carboxymethyl cellulose, 65 milliliters of glycerol, 500 milliliters in water, ethanol are settled to 1000 milliliters.
Preparation method is with embodiment 1.
Embodiment 4:
Present embodiment has compared conventional Chinese medicine penetration enhancer Borneolum Syntheticum, left-handed menthol to the short saturating effect of ivermectin, has determined the penetration enhancer concentration of suitable promotion ivermectin transdermal.
(1) foundation of analytical method
Wavelength is measured: it is an amount of to get ivermectin, is made into certain density solution with dehydrated alcohol, is blank with the dehydrated alcohol, gets ultra-violet absorption spectrum in the interscan of 200-800mm scope.The result shows that the ivermectin maximum absorption wavelength is at the 245nm place, and dehydrated alcohol does not have absorption value under this wavelength, is the absorbing wavelength of ivermectin assay so select 245nm.
(2) foundation of standard curve
Take by weighing a certain amount of ivermectin and make stock solution.Get respectively then stock solution with dehydrated alcohol be diluted to 1,10,20,30,40, the ivermectin solution of 50ug/ml Concentraton gradient, on ultraviolet spectrophotometer in measuring absorbance, be vertical coordinate (Y) with the absorbance, ivermectin content is that abscissa (X) returns, and the regression equation that obtains is:
y=0.0345x+0.0131(R
2=0.9983)
(3) precision test
Take by weighing a certain amount of ivermectin and make stock solution.Get respectively then stock solution with dehydrated alcohol be diluted to 5,10,25, the ivermectin solution of 50ug/ml Concentraton gradient, on ultraviolet spectrophotometer, in measuring absorbance, calculate withinday precision and day to day precision.RSD (%) shows that all below 5% withinday precision and day to day precision all meet the requirements.
(4) transdermal test
With ivermectin be made into the certain concentration solution solution add variable concentrations penetration enhancer (left-handed menthol concentration (mg/mL): 1%, 2%, 3%, 4%, 5%; 1%, 2%, 3%, 4%, 5% Borneolum Syntheticum concentration (mg/mL) :), as discharging liquid.Acceptable solution is blank solvent.
The skin that thaws under the room temperature carries out the transdermal test in vitro absorption test, and discharging the liquid consumption is 2ml, and reception liquid is 7ml, and experimental temperature is (37.0 ± 0.5) ℃, and vibration velocity is 150r/min.1,2,4,6,8,10, the 12h time point gets 5.0ml respectively, adds the reception liquid of equivalent simultaneously.Measure absorbance, and the substitution standard curve, calculate the accumulation penetrating concentration of each time point, and be calculated as follows accumulation infiltration capacity (Q).
Q=(VCn+∑n-1i=1CiVi)/A
In the formula: Q is unit interval accumulation infiltration capacity, and A is the transdermal diffusion area, and V is long-pending for accepting cell body, the concentration of acceptable solution when Cn is the n sub-sampling, C
iThe concentration of acceptable solution when being the i sub-sampling, Vi is sampling amount.The slope (K) that carries out linear regression gained equation with the time t of unit interval accumulation infiltration capacity Q is that ［ unit is μ g/ (cm to infiltration coefficient
2H) ］.
The pure and mild Borneolum Syntheticum of each concentration has short saturating effect to ivermectin, left-handed menthol is in the concentration range of 1%-4%, increase along with concentration, the accumulation transit dose increases, the short effect of 4% concentration is best, the accumulation transit dose of 12h is 646.5 ± 34.91 μ g, and descending appears in the left-handed menthol cumulant of 5% concentration.The similar quantity effect relationship does not then appear in the short effect of Borneolum Syntheticum group, wherein the short saturating effect of 2% Borneolum Syntheticum is minimum, and the short effect of 4% concentration is best, and the accumulation transit dose of 12h is 508.52 ± 35.17 μ g, other short effects of three groups are comparatively similar, do not have significant difference.The accumulation transit dose of 4% left-handed menthol 12h is higher than 4% Borneolum Syntheticum, significant difference.All time periods see through effect and all are significantly higher than blank group (namely not adding Borneolum Syntheticum or left-handed menthol).
The penetration enhancer ivermectin accumulative total transit dose data of different time points and variable concentrations see Table 1(table 1 and are the penetration enhancer infiltration coefficient (X ± S) (n=3)) of each concentration among the embodiment 4, and the infiltration coefficient of each concentration penetration enhancer 12h sees Table 2.
The penetration enhancer infiltration coefficient of each concentration of table 2 (X ± S) (n=3)
The infiltration coefficient of each concentration penetration enhancer 12h: the infiltration coefficient of left-handed menthol group is in the scope of 1-4%, along with concentration increases, infiltration coefficient increases, and wherein the infiltration coefficient of 4% concentration is significantly higher than other each groups, explanation is aspect the seepage velocity of ivermectin, left-handed menthol the best of 4%.Borneolum Syntheticum prescription face, the infiltration coefficient of the Borneolum Syntheticum of 4% concentration is the highest.
Embodiment 5: the film forming component proportioning test in the liniment.
The influence of PVA-124, glycerol, the transdermal agent of 1%CMC-Na is bigger, and therefore choosing PVA-124, glycerol and 1%CMC-Na is factor, establishes three kinds of levels, according to orthogonal table L
9(3
4) design 9 kinds of transdermal agents prepare scheme table 3.
Table 3 PVA-124, glycerol, 1%CMC-Na factor and horizontal allocative decision
Annotate: component ratio is by 1000 milliliters of liniment total amounts in this table.The consumption of CMC-Na is amounted to gained for the milliliter number that 1%CMC-Na solution multiply by use, and unit is milligram.
3 components determining film forming by orthogonal test are polyvinyl alcohol 124(PVA-124), the best proportioning ratio between glycerol and the sodium carboxymethyl cellulose (CMC-Na).Liniment finished product by experimental program is made carries out the comprehensive grading investigation from presentation quality and film formation time two aspects.Presentation quality: be uniformly dispersed, the color and luster unanimity, good toughness, good fluidity is 8 minutes; Be uniformly dispersed, the color and luster unanimity, poor toughness is 6 minutes; Disperse more evenly, slightly shade deviation is 4 minutes; Dispersion is poor, and shade deviation is evident as 2 fens; Having precipitation to separate out is 0 minute.Film formation time: get on the pigeon skin that liniment 2ml evenly is applied to 4cm * 4cm, per half a minute is investigated 1 time, observes also record film formation time; Comprehensive grading=(10-film formation time)+presentation quality.
The result: orthogonal experiments shows that PVA-124 is, and film formation time has the greatest impact, and the PVA-124 consumption is more few, and film formation time is more short, with the film formation time be the extreme difference R value of index as can be seen, three factors are A to the influence of film formation time〉B C.To transdermal agent appearance effects maximum be 1%CMC-Na, other two factors are close to the influence of outward appearance.Be index with presentation quality and film formation time comprehensive grading, the influence of 1%CMC-Na and PVA-124 is bigger, with the comprehensive grading be the extreme difference R value of index as can be seen, the primary and secondary of each factor act as: C〉A B.According to above-mentioned analysis, the best proportioning of liniment filmogen is: A2B1C3, and the factor of synopsis 3 and level, namely PVA-124 is 15g, glycerol 60ml, CMC-Na 40mg (being 1%CMC-Na 4ml).The results are shown in Table 4.Polyvinyl alcohol-124 13～18 gram, 38～42 milligrams of sodium carboxymethyl cellulose, 55～65 milliliters of glycerol
Be provided with the rational portfolio ratio scope of this liniment according to this result.
Table 4 orthogonal experiments (the liniment total amount is 1000 milliliters)
Embodiment 6: the safety of liniment and storage life test.
The safety testing of liniment: get 10 of healthy adult meat pigeons, male and female half-and-half, not having hair respectively under the chest of pigeon and wing goes out skin and carries out medication, and after the 30min after the medication, 1h, 6h and administration continuous three days observe the pigeon skins and symptoms such as erythema edema whether occur, and observe situations such as in the meantime the mental status of pigeon, drinking-water, feed.The result: ill symptoms does not all appear in meat pigeon skin in the pigeon of being tried, and all meat pigeon physiological activities all do not have any unusual performance, do not have death yet.
The storage life test of liniment: place room temperature to preserve 1 year for 25 ℃ 3 batches of laboratory products of this liniment, take out preparation observation outward appearance and do not find variations such as color, layering; Do the antibacterial cultivation and also do not see antibacterial; Be antibacterial bacteriostatic test people and have certain antibacterial effect.It is rotten to illustrate that this liniment does not take place, and still keeps curative effect.
Embodiment 7: liniment to percutaneous dosing after the constructed observation of keratodermatitis.
Mice is cut off the hair of abdominal part carefully with Shearing shears, recover naturally that the no any skin injury of inspection can use after 1 day.Drip a certain amount of liniment at mice depilation position, fix with the medical aseptic film of applying ointment or plaster.Blank group is then used with quadrat method with blank solvent and is handled, and matched group does not process.Respectively put to death a mice at 1h, 3h, 6h after the administration, take out skin samples at medicine-feeding part.
With Shearing shears cut off tame rabbit back the hair, naturally the recovery 1 day, the rabbit skin of back is divided into 3 zones: check plot, solvent district, menthol district.Each zone drips a certain amount of liniment respectively, with the airtight fixing 10h that continues of the aseptic film of applying ointment or plaster.Does not handle the check plot.After experiment finishes, put to death rabbit, take out skin samples at medicine-feeding part.
Skin treatment: skin is cut into the fritter that is approximately 1cm * 0.5cm, and clean with the normal saline rinsing, the filter paper drying places fixedly 24h of 10% neutral formalin solution.Fixing, dehydration according to a conventional method, embedding, section, dewaxing, rehydration, hematoxylin-eosin staining are observed under 40 times of light microscopics.
Mouse skin om observation result:
Thinner from the visible mouse skin horny layer of control group mice epiderm skin structure, be attached to the skin outermost layer, be the first road barrier (Fig. 1) of skin opposing external substance intrusion.1h is carried out in test, and in the group of solvents mouse skin epidermal structure, horny layer changes and be not obvious, and loose (Fig. 2) appears in the part horny layer.The mouse skin horny layer changes not obviously in the test group, occurs horny layer perk and epidermis and occurs separating and form cavity (Fig. 3).3h is carried out in test, and group of solvents mouse skin horny layer is arranged loose, occurs cavity (Fig. 4) between the corneocyte.Obscission appears in test group mouse skin cutin, and horny layer is mobile to be increased and fold occurs and separate with epidermis and cavity (Fig. 5) occurs.6h is carried out in test, and group of solvents mouse skin structure is similar to mice epidermal structure in the 3h group of solvents, and horny layer is banded to be arranged, and more variation (Fig. 6) do not occur.Test group mouse skin horny layer cracking comes off, and more cavity (Fig. 7) appears in skin inner layer.
Menthol acts on keratodermatitis in the experimental result explanation liniment, increase along with the time, keratodermatitis is arranged loose disorderly, the attenuation that comes off appears in last horny layer, thereby make medicine see through horny layer fast and enter skin corium, cavity appears in skin inner layer among the 6h simultaneously, shows that cutaneous permeability increases, and is conducive to the absorption of drug molecule.The group of solvents mesocuticle is in 6h, keratodermatitis occurs loose disorderly, can increase the transmission rates of medicine to a certain extent, but obscission does not appear in horny layer in this process, in the group of solvents of 6h, horny layer is banded to be arranged, and more variation do not occur, illustrates that the loose phenomenon of group of solvents mesocuticle stops.
Matched group rabbit keratodermatitis is band shape and is evenly distributed on the epidermis, arranges comparatively closely, and anoderm comes off or be free, and cutin forms thin arrangement closely (Fig. 8); Skin keratin forms that the space becomes big between the cell in the solvent district, and horny layer is arranged loose and epiderm skin subregion composition from state (Fig. 9); Seriously coming off appears in keratodermatitis in the trial zone, and the part horny layer comes off fully, the separated attitude of horny layer and epiderm skin, and the space becomes big between the horny layer, and skin inner layer granule occurs and enriches phenomenon (Figure 10).
This result of the test illustrates that equally left-handed menthol plays disorderly destruction to keratodermatitis in the liniment, because experimental period reaches 10h, coming off fully appears in keratodermatitis, this moment, medicine can not be subjected to the horny layer obstruction, touch the abundant skin corium of blood capillary very soon, thereby accelerate the absorption of effective ingredient.The skin endoparticle enriches phenomenon and whether absorbs the relevant further research that remains with drug transdermal.Loosening appears in keratodermatitis in the group of solvents, but does not occur coming off, and still there is inhibition in drug molecule, but can increases the Transdermal absorption of medicine to a certain extent.
Embodiment 8: the pharmacokinetics of ivermectin in the meat pigeon body in the liniment.
(1) meat pigeon and sample: choose 6 monthly ages, 3 of healthy meat pigeons, body weight 0.48 ± 0.06kg, water 12h is can't help in fasting before the experiment.During experiment, laboratory animal is equivalent to every 40mg ivermectin by cervical region crop place's administration 2ml.And the accurate recording time.Respectively at before the administration and administration after 2h, 4h, 6h, 8h, 10h, 12h, 18h, 24h, 36h, the about 1mL of 48h wing venous blood collection, place oneself to number and be added with the centrifuge tube of heparin sodium aqua, mixing gently, with the centrifugal 15min of 3000r/min, separated plasma is put in-20 ℃ of refrigerators and is saved to mensuration.
Blood sample thaws naturally, shakes up, the accurate blood plasma 25 μ L that absorb each time point collection, place the EP pipe of clean 1.5mL, add stable (interior mark, concentration 100ng/mL) acetonitrile solution of 200 μ L (adding 200 μ L acetonitriles in the blank plasma sample), vortex (2500rpm, 3min), centrifugal (12000rpm, 3min), getting 180 μ L upper organic phase is transferred in the 96 hole depth orifice plates, add 100 μ L ultra-pure waters, (500rpm 5min) carries out LC-MS/MS and analyzes behind the mixing in vibration.
(2) mass spectrum condition: electric spray ion source (ESI), cation scanning, multiple-reaction monitoring (MRM).High pure nitrogen is carrier gas, collision gas and gas curtain gas, electron spray voltage (IS)+5500V, remove a bunch voltage (DP) 96V, atomization gas pressure (GAS1) 75kPa, secondary air speed (GS2) is 60L/min, gas curtain atmospheric pressure (CUR) 25kPa, assist gas pressure power (GAS2) 275.8kPa, 400 ℃ of ion source temperatures (TEM), collision cell pressure (CAD) 6kPa.
(3) specificity of method: get the plasma sample of collecting after blank plasma, dosing blood plasma and the administration respectively, press the operation of plasma sample processing method, sample introduction carries out LC-MS/MS and analyzes, the record chromatogram.Whether investigation has endogenic material to influence measurement result is carried out analysis and judgement, confirms the specificity of this method.
Under this experimental condition, the endogenous material in the blank plasma is not disturbed the mensuration of this product, and the component of other in ivermectin and the medicine has obtained separating preferably.The retention time of ivermectin is consistent with the appearance time of standard substance in the meat pigeon blood sample, and its retention time is 2.73min, and the stable retention time of interior mark is 1.99min, and this law specificity good (Fig. 9) is described.
(4) preparation of standard curve: get a certain amount of blank plasma and quantitatively add ivermectin series standard solution respectively and make it contain ivermectin to be respectively: 5000ng/mL, 2500ng/mL, 1000ng/mL, 500ng/mL, 100ng/mL, 50ng/mL, 1ng/mL, press plasma sample and handle operational approach, carrying out LC-MS/MS analyzes, the record chromatogram, calculate ivermectin area A s respectively with the ratio f(f=As/Ai of interior mark peak area Ai), be abscissa with blood drug level x, peak area ratio f is vertical coordinate, carry out the rectilinear regression computing with weighting (W=1/x2) method of least square, try to achieve the equation of linear regression f=ax+b of standard curve.Lower limit of quantitation is the minimum point of the standard curve range of linearity.
Record in 1～5000ng/mL concentration range, drug level and medicine/interior mark peak area ratio meets equation of linear regression.The minimum lower limit of quantitation that this experiment is determined is 1ng/mL.Curvilinear equation: y=0.00491x+0.0171 (R=0.9973)
(5) ivermectin accuracy and precision are investigated: precision with batch in 6 times and batch between 3 relative standard deviations of measuring represent that accuracy is represented (%) with the degree of closeness of measured value and actual value.In 1～5000ng/mL concentration range, the withinrun precision scope of measuring ivermectin is respectively 2.3%～12.2%, and accuracy range is 91.5%～112% in batch, the results are shown in Table 5～table 7.
Table 5 LC-MS/MS method is measured withinrun precision and the accuracy (first) of ivermectin in the plasma sample
Table 6 LC-MS/MS method is measured withinrun precision and the accuracy (second batch) of ivermectin in the plasma sample
Table 7 LC-MS/MS method is measured withinrun precision and the accuracy (the 3rd batch) of ivermectin in the plasma sample
Betweenrun precision and accuracy determination result are as follows, and the result shows that the betweenrun precision scope is 2.1%～9.2%, and accuracy range is respectively 91.1%～108% between batch, the results are shown in Table 8.
Table 8 LC-MS/MS method is measured betweenrun precision and the accuracy (n=3) of ivermectin in the plasma sample
(6) haemoconcentration of ivermectin in the meat pigeon blood plasma: detect smear gather behind the self-control liniment 2,4,6,8,10,12,18,24,36, ivermectin concentrations in the blood plasma of 48h, the ivermectin measured value in the meat pigeon blood plasma sees Table 9.
Plasma drug level (n=3) behind the table 9 meat pigeon transdermal administration
(7) pharmacokinetic parameter result of calculation: after pigeon gave 40mg/ ivermectin, estimation gained pharmacokinetic parameters saw Table 10.
Table 10 pigeon gives pharmacokinetic parameter behind 40mg/ the ivermectin
Annotate: T1/2 is terminal to be eliminated the half-life, the Tmax peak time, and Cmax. reaches peak concentration, area under AUC. blood drug level-time graph, MRT. average residence time, Vz/F. apparent volume of distribution, Cl/F. clearance rate.
The result: 2 drug level peaks appear in blood drug level behind transdermal administration-time curve, be referred to as " bimodal " phenomenon, about drug absorption occur bimodal or multimodal phenomenon and Study on Mechanism thereof at the existing report of other animals such as rabbit, Mus, produce multimodal factor reason it is generally acknowledged following some: (1) oral administration, the a medicine arrives small intestinal at twice in the gastric emptying stage, occurs drug absorption twice; The b medicine absorbs at two positions of harmonization of the stomach small intestinal; The liver sausage Circulation of c medicine; (2) the preparation factor of medicine; (3) after fat-soluble medicine absorbs, be distributed to rapidly in the tissue, after the metabolism of blood Chinese medicine is arrived to a certain degree, occur secondary again and be released into blood.Jiang Xiaowen etc. have measured the pharmacokinetics of compound ivermectin emulsion in the goat body, and bimodal phenomenon appearred in curve when the result showed the medicine of ivermectin, and peak time is at 4h and 16h; During this experimental drug curve occur bimodal phenomenon probably with transdermal administration fat-soluble relevant with the ivermectin height.Ivermectin can extensively be distributed to each organ of body, and wherein fatty ivermectin carries out one of main place of biotransformation, and fatty Chinese medicine elimination speed is very slow, and the secondary that medicine may occur discharges; Liniment also may be that bimodal reason appears in curve when causing medicine to the slow releasing function of medicine.The appearance at medicine drug-time curve second peak certainly will influence drug potency and elimination process." bimodal " phenomenon has increased area under the drug-time curve (AUC) really under study for action, has also prolonged the elimination half-life simultaneously, and this provides the foundation of science for formulating the clinical administration scheme.
Embodiment 9: therapeutic effect is observed behind the meat pigeon artificial challenge poultry louse.
Select 90 healthy no poultry louse infection white plumage Wang Ge of 3-5 monthly age, wherein 30 isolated rearings, other gets 60 every pigeons and inserts the poultry louse that lives more than 100 at position skins such as its wing inboard, abdominal part, neck weeks, raised together with 2 months, under the wing of every pigeon of examine, when comparatively intensive poultry louse (each visual field〉10) all appears in shank, cervical region, back, pigeon is divided into 2 groups, every group 30, first group as medication treatment group, second group is not medication matched group, the negative matched group of the pigeon of 30 isolated rearings.Medication group pigeon is pressed the 2ml dosed administration for every at crop place percutaneous drug delivery, and blank group is left intact.The poultry louse infection conditions is observed the statistics result of infection under 24h after the administration, 48h, the blank group of the medication combination of the 72h meat pigeon wing.Criterion: every pigeon selects under the bilateral wing, back, abdominal part, shank, 5 positions of cervical region, lifts up feather, occurs 10 above poultry louse in average each visual field, all 5 positions and is judged to invalidly, is judged to below 5 effectively, does not see that poultry louse is judged to healing.
The results are shown in Table 11.
Therapeutic effect is observed behind the table 11 meat pigeon artificial challenge poultry louse
As can be seen from Table 11, after the medication 24 hours existing greater than 95% effective percentage, effective percentage reaches 100% after 48 hours; 73.3% cure rate was arranged in 24 hours, and cure rate reaches more than 96% after 48 hours, and not treatment group does not have any improvement.The result shows after using product treatment of the present invention better curative effect.
Embodiment 10: liniment is to infecting the therapeutic effect of poultry louse meat pigeon.
Each 500 of the adult meat pigeons of selecting Xixia District Columba livia field and Liuhe District to culture to suffer from poultry louse in Columba livia field, Donggou, Nanjing, residential quarter.100 ill meat pigeons are divided into blank group and medication group, 50 every group at random.Other learn from else's experience check no any epizoa infection 50 of pigeons in contrast.Medication group pigeon is pressed the 2ml dosed administration for every at crop place percutaneous drug delivery, and blank group is left intact.The poultry louse infection conditions is observed under 24h after the administration, 48h, the blank group of the medication combination of the 72h meat pigeon wing.During treating, untoward reaction does not all take place in the medication meat pigeon, and meat pigeon drinking-water is searched for food normal, does not occur unusual.
Therapeutic effect:
Medication group poultry louse under the 24h meat pigeon wing after the administration obviously reduces, the lighter meat pigeon anthelmintic fully of most of infection, and cure rate reaches 72% (72/100); 48h after the administration, the infected situation of meat pigeon is clearly better, and cure rate reaches 91% (91/100), and poultry louse does not obviously reduce yet under the meat pigeon wing of Zhi Yuing.Treat to 72h, medication group cure rate reaches 94% (94/100).Blank group meat pigeon infects still and exists, and increasing appears in poultry louse under most of meat pigeon wing.See table 12 for details.
Table 12 self-control liniment is to infecting the clinical therapeutic efficacy of poultry louse
Annotate: 1, test group 1 Columba livia is taken from Xixia District Columba livia field; Test group 2 Columba livias are taken from Liuhe District and culture the residential quarter
2, criterion: every pigeon selects under the bilateral wing, back, abdominal part, shank, 5 positions of cervical region, lifts up feather, occurs 10 above poultry louse in average each visual field, all 5 positions and is judged to invalidly, is judged to below 5 effectively, does not see that poultry louse is judged to healing.
The result shows, the self-control liniment has been carried out the evaluation of anthelminthic effect to the meat pigeon that infects poultry louse, and poultry louse reduces under the administration 24h postoperative infection meat pigeon wing, can fully recover after infecting lighter meat pigeon 24h, and cure rate reaches 72%.The cure rate of 48h after administration reaches 91%, does not cure that poultry louse obviously reduces under the meat pigeon wing; The most of meat pigeon of administration 72h recovers normal, and cure rate reaches 94%; Comparatively serious for the poultry louse infection, the meat pigeon suggestion of curing after the administration can rechallenge.Because this self-control liniment adopts left-handed menthol as penetration enhancer, medication is not infected comparatively seriously that tickling usually appears in meat pigeon, is closed one's eyes, feather is loose, the symptom of standing transfixed to the ground and stop to search for food, and becoming thin appears in build.Test and medication group meat pigeon paid a return visit in back one month, recurrence all appears in medication group meat pigeon.This therapeutic effect shows that the self-control liniment has good anthelminthic effect to the meat pigeon poultry louse.
Poultry louse is the common parasitic infection in Columba livia field, cultures because of meat pigeon to be intensive, and touch opportunity is many, epizoa infection rate almost 100%.Ivermectin has good anthelminthic effect to poultry louse, and for a long time, people get used to considering therapeutic scheme from angle oral and injection.Because ivermectin is water insoluble, the drinking-water administration is not desirable administering mode.The breed of meat pigeon all is that raw grain is fed, and the administration of ivermectin spice is often inhomogeneous because of administration, so can not play good administering effect.Though injection for curing can be obtained satisfactory effect, the injection meeting to animal bring more greatly stress, if do not note health, also can cause animal wound infection to occur during the injection, particularly because being difficult to accomplish a Columba livia one pin, be easy to cause cross infection.The Columba livia field is to use the insecticide of violating a ban to spray in dovecote for the main method for the treatment of control poultry louse now, and these medicines stress be bigger to pigeon, and the symptom of searching for food can appear stopping in the part pigeon, even a small amount of virgin Columba livia death can occur.Ivermectin is made liniment, then can overcome the problems referred to above from percutaneous drug delivery.Ivermectin is short down saturating left-handed menthol, sees through skin and enters blood, thereby reach therapeutic effect.From the therapeutic outcome of experiment, transdermal administration is practical, for the treatment of meat pigeon poultry louse provides a kind of new preparation.
Claims (6)
1. one kind is used for the treatment of the ectozoal liniment of pigeon, and described parasite is poultry louse, it is characterized in that, described liniment is made up of following material:
Ivermectin 8～12 grams, left-handed menthol 35～45 grams, polyvinyl alcohol-124 13～18 gram, 38～42 milligrams of sodium carboxymethyl cellulose, 55～65 milliliters of glycerol, 500 milliliters in water, ethanol are settled to 1000 milliliters.
2. the ectozoal liniment of pigeon that is used for the treatment of according to claim 1 is characterized in that described liniment is made up of following material:
Ivermectin 10 grams, left-handed menthol 40 grams, polyvinyl alcohol-124 15 gram, 40 milligrams of sodium carboxymethyl cellulose, 60 milliliters of glycerol, 500 milliliters in water, ethanol are settled to 1000 milliliters.
3. the ectozoal liniment of pigeon that is used for the treatment of according to claim 1 is characterized in that, contains Borneolum Syntheticum 30～50 grams in per 1000 milliliters of liniment.
4. the described preparation method that is used for the treatment of the ectozoal liniment of pigeon of claim 1 is characterized in that it may further comprise the steps:
(1) polyvinyl alcohol-124 is soaked taking-up after 24 hours, it is standby to put into 60 ℃ of oven dryings;
(2) polyvinyl alcohol-124 after the step (1) that takes by weighing formula ratio is handled is put into stirred vessel, adds after 400 ml waters soak 2h, puts 85 ℃ of stirring in water bath dissolvings;
(3) add the slow stirring and evenly mixing of glycerol of formula ratio in the container of step (2);
(4) sodium carboxymethyl cellulose that continues to add formula ratio in the container of step (3) slowly stir, mixing, get blank liniment liquid, this liquid is maintained in the water-bath;
(5) to be dissolved in 400 ml volumes percentage compositions be in 75% the ethanol, to get the ivermectin alcoholic solution to the ivermectin that takes by weighing formula ratio, puts in the water-bath and preserve;
(6) take by weighing the left-handed menthol of formula ratio, slowly add in the ivermectin alcoholic solution, stirring and evenly mixing is put in the water-bath and is preserved;
(7) under the water bath condition, the alcoholic solution that is dissolved with ivermectin and left-handed menthol that step (6) is obtained slowly adds in the blank liniment liquid that step (4) obtains while hot, the limit edged stirs, and continues to add ethanol then and is settled to 1000 milliliters, and filtration makes.
5. the preparation method that is used for the treatment of the ectozoal liniment of pigeon according to claim 4 is characterized in that in the step (4) (5) (5) (7), described water-bath, and its temperature is 50～65 ℃; In the step (7), ethanol is heated to 50～65 ℃ in advance.
6. the application of the described liniment of claim 1 in preparation treatment pigeon ectozoa medicine, described parasite is poultry louse.
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| CN102258455A (en) * | 2010-05-28 | 2011-11-30 | 上海市计划生育科学研究所 | Film coating agent containing steroid hormone and its preparation method |
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| CN111568886A (en) * | 2020-06-16 | 2020-08-25 | 福建师范大学福清分校 | Chinese and western medicine compound film coating agent for treating bovine acariasis and preparation method thereof |
| CN111568886B (en) * | 2020-06-16 | 2022-09-13 | 福建师范大学福清分校 | Chinese and western medicine compound film coating agent for treating bovine acariasis and preparation method thereof |
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Address after: Qixia Xiaozhuang Village Center District of Nanjing City, Jiangsu province 210000 No. 130 Applicant after: Jinling Institute of Technology Applicant after: Jiangsu Oak Animal Medicine Co., Ltd. Address before: No. 99 Jiangning Road, Nanjing District hirokage 210000 cities in Jiangsu Province Applicant before: Jinling Institute of Technology Applicant before: Jiangsu Oak Animal Medicine Co., Ltd. |
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Effective date of registration: 20220113 Address after: 224200 No. 97, Fangong North Road, Dongtai town, Dongtai City, Yancheng City, Jiangsu Province Patentee after: JIANGSU OAK ANIMAL MEDICINE Co.,Ltd. Address before: No.130, Xiaozhuang central village, Qixia District, Nanjing, Jiangsu Province, 210000 Patentee before: JINLING INSTITUTE OF TECHNOLOGY Patentee before: Jiangsu Ouke Animal Pharmaceutical Co., Ltd; |