CN107041872A - A kind of ivermectin class pharmaceutical preparation with high-dissolution in bile - Google Patents
A kind of ivermectin class pharmaceutical preparation with high-dissolution in bile Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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Abstract
Ivermectin class medicine is combined with solid dispersion medium, is coated in the state of dissolving or thawing on carrier material, after cured or drying, the solid pharmaceutical preparation of the medicine of class containing ivermectin is made.The ivermectin class medicine contained in preparation have in pig's bile/aqueous solution dissolution rate it is high, in water not dissolution (dissolving), the characteristics of (3 hours) are non-degradable in the 0.1 mole hydrochloride aqueous solution.Therefore, this agent can more effectively prevent the destruction of acidic gastric juice, and with enteron aisle, the characteristics of dissolution rate is high in the presence of bile.Solid dispersion medium specifically preferred according to the invention includes polyvinylpyrrolidone, solid polyethylene glycol, fusing point in 45 100 DEG C of hydrophobic solid decentralized medium, one in acrylic resin or more than one composition；Carrier material include maize cob meal, zeolite powder, stone flour, diatomite, land plaster, starch, fish meal, powdered beef, pork liver powder, chicken liver meal, chicken meal in one in or more than one composition.
Description
Technical field
The invention belongs to veterinary drug preparation technology of preparing, and in particular to a kind of preparation side of the pharmaceutical preparation of class containing ivermectin
Method, the preparation prepared with this method, which has, avoids characteristic of the hydrochloric acid in gastric juice to the acid-catalyzed hydrolysis of ivermectin class medicine, and in courage
The characteristics of there is high-dissolution under the emulsification of juice.
Background technology
Ivermectin class medicine is a kind of high-efficiency broad spectrum anti-parasite medicine, and it is to parasitic nematode in animal body and outer
Parasite have it is very strong kill effect, they are widely used in animal parasitosis and prevented and treated.Commercially available product for animals has
Parenteral solution, oral liquid, dashing agent, paste, granule, sustained release bolus, tablet, pulvis, pre-mixing agent etc..Wherein pre-mixing agent is main
It is used for the preventing and treating verminosis of pig and horse.There is 0.6% ivermectin pre-mixing agent of import commercially available prod (such as at this stage at home
Ivomec), domestic ivermectin/Albendazole's compound pre-mixing agent and pulvis, domestic oxide/ivermectin compound
Pulvis, it is also commercially available without domestic folk prescription pulvis or folk prescription pre-mixing agent.
Slightly solubility and on acid sensitiveness be influence insoluble drug oral administration biaavailability key factor.Experiment and money
Material display：(1) ivermectin class medicine is not almost dissolved in water.Such as it is only capable of dissolving the Yi Wei bacterium of 6-9 micrograms in 1 liter of water
Element.Therefore, when preparing the oral solid formulation of the medicine of class containing ivermectin, in order to ensure that medicine can more be absorbed, change
The dissolution in the gastrointestinal tract of kind medicine or dissolving are the sport technique segments for needing to consider.(2) molecular structure of ivermectin class medicine
In there are 2 glycosidic bonds, it is easily catalyzed by acids hydrolysis and loses saccharide residue.Such as ivermectin is easily catalyzed by acids hydrolysis and converted
Viability very low monose ivermectin B1a(MS H2B1And H a)2B1A aglycones (are shown in Table 1).And the gastric juice of the animal such as pig, chicken
Majority most can reach by force pH value 1 or so (acidity for being approximately equivalent to 0.1M hydrochloric acid) in acidity, its acidity.This points out us：Pass through
The acid resistance of preparation is improved, can be the mouth of this kind of medicine to hinder acidic gastric juice to the hydrolysis of ivermectin class medicine
Formulation can be provided safeguard by more absorb.We are detected to domestic commercially available prod, are as a result shown：Import
The special performance that 0.6% ivermectin pre-mixing agent (Ivomec) has the high and tolerable acid-catalyzed hydrolysis of drug dissolution (is shown in Table
2).And the dissolution rate of ivermectin is zero in nearly all domestic compounding powder and pre-mixing agent, even if ivermectin has a small amount of molten
The individual product gone out, the performance of its resistance to acid catalyzed degradation is also very poor；Bile in vitro emulsification test shows that domestic contains ivermectin
The compound solid preparation of class medicine ivermectin dissolution rate in 20% pig's bile/water is up to 38%.Clinical practice shows, just
For the effect for killing Sarcoptes suis and pig sucking louse, imported product determined curative effect.It is believed that except the guarantor of effective content in medicament
Ivermectin is in enteron aisle in the key elements such as the accuracy of card and dosage, the power and medicament of medicament tolerance acid-catalyzed hydrolysis effect
In dissolution rate equally be influence drug absorption key factor.Therefore, by dissolution rate of the product in water or in bile
Emulsifiable degree, and acid-catalyzed hydrolysis rate are of practical significance as the quality index for checking this similar drug quality, and this can
The quality of medicine is further monitored and reflected from another side, can enable that the control of this kind of drug quality is more scientific, standard
Really and comprehensively.
Experiment display, the C of ivermectin class medicine in the basic conditions in its molecular structure2Easily occur epimerism and turn
Turn to 2- epimers H2B1a(2-epimer H2B1A), its anthelmintic activity is only H2B11% or so of a activity；C3=C4
Double bond be easily shifted over, be converted into activity very low Δ2,3H2B1A (is shown in Table 3)；The lactone having in ivermectin molecular structure
Key is equally easily by OH-Attack and destroyed.In fact, degraded of the ivermectin class medicine during preserving, except oxidation drop
Solution is outer, also there are problems that acid/base catalytic degradation.Open source information shows that such medicine is more stable under the conditions of slant acidity, suitable
PH range is between 4-6.The experiment that we are carried out by using the preparation containing ivermectin is shown, when the carrier material of composition preparation
When the PH of material is more than 6.2, the impurity produced in the shelf-life is more 2- epimer ivermectins B1a；Work as carrier material
PH value when being less than 4.0, the impurity produced in the shelf-life is more monose ivermectin B1a.Experiment display, with present invention choosing
The oral formulations of the medicine of class containing ivermectin prepared by fixed carrier, its carrier material pH value is in 4.3-5.3, and stability is more preferable
(with the relative percentage content and increased MS H of the increased 2- epimers ivermectin of storage life2B1A percentage
Than technical indicator of the content as judgement).
It is visible in summary, when preparing the preparation of the medicine containing ivermectin, it is necessary to consider the water-insoluble problem of medicine
With oxidative degradation, the acid/base catalytic degradation problem for overcoming medicine.
The content of the invention
The present invention solves the technical problem of improve dissolution rate of the ivermectin class medicine in bile and overcome her
The defect of bacteriums medicines facile hydrolysis in acid condition is tieed up, to reach the dissolution rate for improving medicine in enteron aisle, is protected simultaneously
The purpose that medicine is not destroyed in acidic gastric juice；Next to that preparation is overcome during preserving, the oxidative degradation of its active ingredient
With acid/base catalytic degradation problem, make that the active principle of medicament degrades is less.Present invention selection solid dispersion technology is prepared in pig
Dissolution rate height and the oral solid formulation acted on more resistant to oxidative degradation and acid/base catalytic degradation, this is realized with this in bile
Subject invention.
Following each component is included in preparation of the present invention：
(1) anti-parasite medicine, its content in described every 1 kilogram of preparation is 0.1-15 grams；Described anti-parasitism
Worm medicine includes one in AVM, ivermectin, doractin, moxidectin, Eprinomectin, department's drawing rhzomorph
Kind.They belong to macrolides anti-parasite medicine.
(2) solid dispersion medium, it is in the anti-oxidant of preparation, the destruction of resistance hydrochloric acid in gastric juice and promotion medicine in bile/water
Dissolution serve extremely important effect；Its content in every 1 kilogram of preparation is 1-300 grams, its in the formulation suitable
Content is at least 3 times of the anti-parasite medicine weight；Solid dispersion medium content is higher in the formulation, and effective ingredient is more steady
Determine (being mainly not susceptible to oxidative degradation), but its upper content limit is restricted by the adsorption capacity of carrier material, when solid point
When the content of dispersion media in the formulation is more than 35%, it is inter-adhesive that in preparation process particle easily occurs for preparation, and preparation can become
Have viscosity；External bile emulsification test shows that the content of hydrophobic solid decentralized medium exceedes medicament contg in preparation
50 times when, reach the Amount of Bile increase that same dissolution rate needs.Therefore, for improving drug dissolution, if with thin
Aqueous solid decentralized medium prepares this agent, is not that solid dispersion medium content is The more the better.Described solid dispersion medium bag
Decentralized medium containing hydrophobic solid, polyethylene glycol, polyvinylpyrrolidone, acrylic resin under normal temperature for solid state；Institute
The hydrophobic solid decentralized medium stated includes monohydric alcohol stearic acid, glycerin monostearate, three stearic acid more than 15 carbon
One or more kinds of combinations in glyceride, behenic acid glyceride, behenic acids, hydrogenated vegetable oil, brazil wax, Arlacel-60
Thing.
(3) carrier material, adds to 1 kilogram.Described carrier material include maize cob meal, zeolite powder, stone flour, diatomite,
One or more kinds of compositions in land plaster, starch, fish meal, powdered beef, pork liver powder, chicken liver meal.
Hydrophobic solvent can be also added in the preparation, the hydrophobic solvent includes benzoate compounds, nitrogen
One or more kinds of composition in ketone, pungent/capric acid glyceryl ester, isopropyl myristate；The benzoates chemical combination
Thing includes but is not limited to Ergol, dipropylene glycol dibenzoate, diethylene glycol dibenzoate.In every 1 kilogram of preparation
In contained hydrophobic solvent be solid dispersion medium content 3-20%, weight ratio.Hydrophobic solvent was prepared in preparation
Cheng Zhongke plays a part of solvent, has facilitation to the bile emulsification of medicine when content is suitable, and have to the degraded of medicine
There is suppression to make.But when content exceedes the 30% of solid dispersion medium weight, preparation becomes sticky, mobility is deteriorated, bad stability.
0.2-5 grams of antioxidant is also included in described every 1 kilogram of preparation, the antioxidant includes butylated hydroxy-a
One or more kinds of compositions in benzene, tertiary butyl-4-hydroxy anisole, propylgallate, vitamin C.Antioxidant
Addition can further reduce the tendentiousness that preparation is degraded by oxidation.
2-10 grams of 1,2-PD can be also added in described every 1 kilogram of preparation.1,2-PD is prepared in preparation
During primarily serve the effect of solvent, the effect of assistant for emulsifying agent is served in the bile emulsion process of preparation.
Other anti-parasite medicines that percentage by weight is 1-10% can be also added in described preparation, described is other
Anti-parasite medicine includes one kind in albendazole, oxide, Phenbendasol, oxfendazole, insect growth regulator, IGR.
It is prepared by preparation selection following methods of the present invention.
Method one, polyvinylpyrrolidone or acrylic resin ethanol dissolved, be prepared into polyvinylpyrrolidone or
The ethanol solution of acrylic resin；Ivermectin class medicine and antioxidant are added to polyvinylpyrrolidone or acrylic acid tree
In the ethanol solution of fat, stirred under room temperature or heating condition, make complete drug dissolution, slightly sticky drug solution is made；Will
Drug solution is well mixed with carrier material under agitation, is dried, that is, described solid pharmaceutical preparation is made.
Method two, solid polyethylene glycol or described hydrophobic solid decentralized medium melted under the conditions of 65-90 DEG C, plus
Enter or be added without 1,2-PD, add or be added without hydrophobic solvent, add ivermectin class medicine and antioxidant, stirring makes
Medicine dissolves, and then is keeping adding described carrier material under conditions of 65-88 DEG C, is being sufficiently stirred for after mixing, in stirring bar
Less than 35 DEG C are cooled under part, solidifies material, is sieved, described solid pharmaceutical preparation is produced.
The preparation of the medicine of class containing ivermectin prepared as stated above, the dissolution rate in 0.1 molar hydrochloric acid solution is
Zero (by taking ivermectin as an example, detecting that the test limit of ivermectin is about 0.1 mcg/ml with HPLC methods), and it is molten in acid
Without acid catalyzed hydrolysate (such as MS H of detection in liquid2B1A etc.), this shows, technology proposed by the present invention solves acid stomach
Hydrolysis problem of the liquid to ivermectin class medicine；The external emulsification test of pig's bile carried out with the preparation containing ivermectin is shown：
(1) ivermectin in preparation can be emulsified by pig's bile, to be discharged into the form of emulsion droplet in pig's bile/aqueous solution；(2) by Yi Wei
Rhzomorph is combined with described solid dispersion medium, is prepared into solid dispersions, is then coated with corn cob granule surface, more favorably
In bile emulsification, ivermectin class drug dissolution is set to significantly improve (see embodiment 2).Acid catalyzed Degrading experiment and pig's bile
External emulsification test result points out us：(1) the ivermectin class medicine contained in preparation not dissolution (or dissolving) in gastric juice
And solution is changed into, acid catalyzed degradation reaction does not occur yet；(2) medicine that preparation contains can be by the breast of bile in enteron aisle
Change effect is dissolved, and then is absorbed by enteron aisle by epithelial tissue.As can be seen here, this agent is a kind of enteric coated preparations.This preparation is with entering
The ivermectin pre-mixing agent of mouth is different.The ivermectin pre-mixing agent of import is a kind of emulsifiable self-emulsifiable preparation of chance water, through inspection
Survey, import pre-mixing agent reacts 3 hours in 37 DEG C, 0.1 molar hydrochloric acid solution, ivermectin dissolution rate is 62% or so, HPLC
Chromatogram shows, MS H2B1A and H2B1A peak area ratio from the 0.2-0.4% of 0 hour by rising to more than 5.1%.
It is visible in summary, ivermectin class medicine preparation can be avoided into enteric coated preparations using solid dispersions technique
The destruction of hydrochloric acid in gastric juice, and can dissolution and absorption in enteron aisle by means of the emulsification of bile.
The more than【0018】Duan He【0019】The elaboration of section, further illustrates the essence of the technology of the present invention
Property feature and progress.
Formulations described above technology of preparing be to the research of ivermectin physicochemical property, related biological characteristic (such as
Emulsification of bile etc.) research, and on the basis of the understanding of problems of commercially available Related product and propose.Cause
This, in order to be able to the technical characteristic of the apparent explanation present invention, it is necessary to which related basic research is introduced.
1. hydrolysis experiment of the ivermectin in various concentrations hydrochloric acid solution (using methanol/water as solvent).Test method is：
Test sample is placed 0-3 hours in 36-37 DEG C of insulation.The MS H in reaction solution are determined with HPLC methods2B1A and H2B1A, hydrolyzes journey
Degree, with MS H2B1A peak area accounts for 0 hour ivermectin B1a(H2B1A) peak area (%) is represented.Result of the test is shown in Table 1.
Hydrolysis of the ivermectin of table 1. in various concentrations hydrochloric acid solution (using methanol/water as solvent)
2. the hydrolysis degree and dissolution determination of imported product ivermectin in various concentrations hydrochloric acid/aqueous solution.Experiment
Method is：1 gram of import sample is taken, is mixed with 20 milliliters of hydrochloric acid/aqueous solution, is reacted 3 hours at 36-37 DEG C, reaction solution is adjusted with alkali
After PH, filtering, filtrate is test liquid, test liquid is determined with HPLC methods, with MS H2B1A and H2B1The ratio between a chromatographic peak area
(%) represents the hydrolysis degree of ivermectin.Result of the test is shown in Table 2.Table 2 is compared with table 1, it can be seen that import she
Tie up the characteristics of rhzomorph pre-mixing agent has the destruction of obvious resistance acid.
The hydrolysis degree and dissolution rate of the imported product of table 2. ivermectin in various concentrations hydrochloric acid/aqueous solution
| Concentration of hydrochloric acid (M) | 0* | 0.01 | 0.05 | 0.10 |
| Hydrolysis degree (%) | 0.29-0.31 | 0.42-0.49 | 1.77-2.02 | 4.55-5.63 |
| Dissolution rate (%) | 59-67 | 59-67 | 59-67 | 59-67 |
| H2B1A degradation rates (%) | --- | 0.3 or so | 2.2 left and right | 3.7 left and right |
3. ivermectin is in 0.1M NaOH solutions (methanol/water=1: the Degrading experiment in 1).Take containing 0.6% Yi Wei bacterium
10 milliliters of element/methanol solution, is mixed with 0.2M 10 milliliters of sodium hydroxide solution, is placed 0-930 minutes at 21-24 DEG C.With
HPLC methods determine 2-epimer H in reaction solution2B1a、Δ2,3 H2B1A and H2B1A, calculates 2-epimer H2B1A chromatographic peak areas
With H2B1The ratio between a peak areas (%), Δ2,3 H2B1A and H2B1The ratio between a chromatographic peak area (%), the H for reacting different time2B1a
With 0 minute H2B1The ratio between a chromatographic peak areas (%).Result of the test is shown in Table 3.
The ivermectin of table 3. is in 0.1M NaOH solutions (methanol/water=1: the degraded in 1)
4. the pig's bile emulsification test of ivermectin.Mammal is respectively provided with the physiological property to intestinal secretion bile, from
And hydrophobic fats nutriment is emulsified and be easily absorbed by organisms by bile.For insoluble drug, it is
No to be emulsified to form emulsion droplet by bile, this is that it could be prepared into the important basis of enteric coated preparations.Therefore, We conducted pig
Bile emulsification test.Test method is：6 milligrams of ivermectin fine powder is taken, 10 milliliters is placed in and contains the water-soluble of 20% fresh pig's bile
In liquid, in 36-37 DEG C of oscillating reactions 60 minutes, the membrane filtration with 0.22 micron pore size is extracted reaction solution, filtrate is with methanol dilution 1
Analyzed, as a result shown with HPLC after times, filterable ivermectin amount is the 28-36% of primary quantity.Separately 6 milligrams are taken with batch
Ivermectin fine powder same treatment and measure in 10 milliliters of water, ivermectin is not detected in filtered solution, and (this law is detected
It is limited to 0.1 mcg/ml or so).Above result of the test shows that pig's bile has emulsification/solubilization to ivermectin.Yi Wei
The bile emulsification test of rhzomorph serves important enlightenment effect in our study, is follow-up solid dispersion medium screening
Lay a good foundation, and there is provided feasible research technique and scientific basis.
Embodiment
Embodiment 1. prepares the preparation containing ivermectin 0.2% with glycerin monostearate
(1) preparation of preparation：Preparation concrete composition is shown in Table 4.The active ingredient of preparation is ivermectin described in table 4,
The content of ivermectin in the formulation is 0.22-0.24 grams；Maize cob meal particle diameter used is 140-420 microns (equivalent to 40-
Part between 100 mesh sieve holes).By above-mentioned【0017】Duan Suoshu method prepares NO.1-NO.9 preparations.
(2) acid catalyzed degradation is tested
Each 3.00 grams of NO.1-NO.9 samples in table 4 are taken, are respectively placed in 25 milliliters of tool plug test tubes, 18 milliliters of water is added, shakes
Swing 5 minutes, 2 milliliters of 1M hydrochloric acid solutions are added afterwards, mix, 3 hours are incubated in 36-37 DEG C, with 1 micron of membrane filtration, draw 4 millis
Filtrate is risen, about 0.2 milliliter of 10% sodium hydroxide solution is added, mixed, 4 ml methanols are added, mixed, with 0.45 micron membranes mistake
Filter, filtered solution detects that 20 microlitres of sample introduction records chromatogram with HPLC.Result of the test is shown：In the reaction of NO.1-NO.9 samples
MS H are not detected in liquid2B1A and H2B1a.Imported product is measured in the same method, is as a result shown, import ivermectin pre-mixing agent exists
H in 0.1M hydrochloric acid solutions2B1A dissolution rates are 60-66%, the MS H of solution2B1A chromatographic peak areas and H2B1A chromatographic peak areas it
Than for 4.9-5.6%.
(3) pig's bile emulsification test
Each 3.00 grams of NO.1-NO.9 samples in table 4 are taken, are respectively placed in 50 milliliters of conical flask with stopper, 18 milliliters of water are added
With 2 milliliters of fresh pig's biles, 1 is incubated in 36-37 DEG C of vibration (136 revs/min, 1.5 centimetres of rotary shaker eccentric throw) small
When, with 1 micron of membrane filtration, 4 milliliters of filtrate is drawn, 4 ml methanols are added, mixed, with 0.45 micron of membrane filtration, filtered solution is used
HPLC detects (20 microlitres of sample introduction), records chromatogram, calculates H2B1A dissolution rate (%).Result of the test is shown in table 5.
The ivermectin pre-mixing agent composition of table 4. 0.2% and content
The preparation NO.1 to NO.9 of table 5. H in pig's bile/aqueous solution2B1A dissolution rate (%)
| Preparation is numbered | NO.1 | NO.2 | NO.3 | NO.4 | NO.5 | NO.6 | NO.7 | NO.8 | NO.9 |
| Dissolution rate % | 60.2 | 64.3 | 57.6 | 61.8 | 63.2 | 66.5 | 63.4 | 59.7 | 61.5 |
(4) NO.1-NO.9 samples deposit 3 months ivermectins and the changes of contents about material at 40 DEG C
Each 3.00 grams of NO.1-NO.9 samples in table 4 are taken, are placed in 25 milliliters of cillin bottles, are sealed, in 39-41 DEG C of incubator
Place 3 months, then to 20 ml methanols are added in every bottle, mechanical shaking extraction 15 minutes, extract solution is taken with 0.45 micron of membrane filtration
20 microlitres of filtrate, injects high pressure liquid chromatograph, carries out chromatography, records chromatogram, calculates H2B1A degradation rates (%), MS
H2B1A chromatographic peak areas and H2B1The ratio between a chromatographic peak areas (%), 2-epimer H2B1A chromatographic peak areas and H2B1A chromatographic peaks face
The ratio between product (%), is as a result shown in table 6.
The NO.1-NO.9 samples of table 6 are deposited 3 months at 40 DEG C, ivermectin and the changes of contents about material
| Preparation is numbered | NO.1 | NO.2 | NO.3 | NO.4 | NO.5 | NO.6 | NO.7 | NO.8 | NO.9 |
| MS/H2B1A % | 0.32 | 0.34 | 0.33 | 0.31 | 0.32 | 0.32 | 0.33 | 0.31 | 0.31 |
| 2-epi/H2B1A% | 0.07 | 0.13 | 0.02 | 0.23 | 0.11 | 0.22 | 0.21 | 0.12 | 0.09 |
| Degradation rate % | 0.62 | 0.78 | 0.36 | 0.58 | 2.56 | 2.83 | 2.79 | 0.55 | 0.61 |
Note：MS/H2B1a is represented the ratio between MS H2B1a chromatographic peak areas and H2B1a peak areas (%)；2-epi/H2B1a represents 2-
The ratio between epimer H2B1a chromatographic peak areas and H2B1a peak areas (%)；Degradation rate % represents H2B1a degradation rates (%).
This result of the test shows that the ivermectin that NO.1-NO.9 test samples contain does not dissolve (molten in an acidic solution
Go out)；The dissolution in the pig's bile aqueous solution；In the framework of the present definition, the ratio of dissolution rate and solid dispersion medium/ivermectin
Value is without obvious correlation；40 DEG C of stability test result shows, within the specific limits the oxidative degradation rate of ivermectin
There is close correlation with the ratio of solid dispersion medium/ivermectin, show that ratio is bigger, it is fewer that ivermectin is degraded
Trend, it is and far with antioxidant presence or absence.
Emulsification/solubilizing effect of the different drug concentration in bile of embodiment 2. to ivermectin in different formulations
This experiment have selected five groups of test samples, carry out the emulsification test of pig's bile, and the composition of five groups of test samples is shown in Table 7.
Emulsification test method is：Take 1 gram of test sample and 20 milliliters of various concentrations fresh pig's bile/aqueous solution (1: 19,2:
18th, 3: 17,4: 16) mix, in 37 DEG C of concussion reactions 1 hour, draw solution, filtering, filtrate was analyzed with HPLC；Separately take 1 gram of confession
Test product is mixed with 20 ml methanols, and concussion is extracted 15 minutes, filtering, and filtrate is tested liquid, is measured in the same method tested liquid, record
H2B1A chromatographic peak areas, using the area as reference, calculate test sample H in pig's bile/aqueous solution of various concentrations2B1A's is molten
Out-degree.Result of the test is shown in Table 8.
The composition of table 7, five groups of test samples
| Test sample is numbered | B-6-2 | B-7 | B-8 | B-9 | B-10 |
| Ivermectin (g) | 0.2023 | 0.2138 | 0.2156 | 0.225 | 0.224 |
| 1,2-PD (ml) | 0.6 | 0.6 | 0.6 | - | - |
| Monoglyceride (g) | - | 2.1 | 6.3 | - | - |
| PEG6000(g) | - | - | - | 0.66 | - |
| PVP(g) | - | - | - | - | 0.66 |
| Maize cob meal (g) | 29.25 | 27 | 23 | 29.1 | 29.19 |
Table 8, pig's bile emulsification test result
Interpretation of result：B-6-2 test samples be by ivermectin ethyl acetate (1.5 milliliters), 95% ethanol (3 milliliters) and
Directly mix, be made through drying with maize cob meal after 1,2-PD dissolving.B-7 and B-8 test samples are with melting by ivermectin
The monoglyceride and 1,2-PD of change maintain be well mixed under the temperature conditionss with maize cob meal afterwards in 75-85 DEG C of dissolving,
It is made through cooling solidification.B-9 and B-10 test samples are to dissolve ivermectin with 2 milliliters of ethyl acetate and 3 milliliter of 95% ethanol,
Then mixed with PVP or PEG6000, it is to be dissolved to be well mixed afterwards with maize cob meal, it is made after precipitation matchmaker.From preparation process
Visible with being formulated, the ivermectin contained in B-6-2 test samples is to be adsorbed with exposed state on maize cob meal；B-7 and B-8
The ivermectin contained in test sample is combined with monoglyceride, to be sticked in the form of solid dispersions on maize cob meal；B-9 and B-
The ivermectin contained in 10 test samples is combined with PVP or PEG6000, is also that corncob is sticked in the form of solid dispersions
On powder.Dissolution rate from table 8：(1) test sample (B-7, B-8, B-9 that ivermectin exists in solid dispersions form
And B-10), its dissolution rate of ivermectin contained in water is much larger than the dissolution rate of B-6-2 test samples.(2) drug concentration in bile is got over
Height, dissolution rate is higher.It these results suggest that ivermectin can be emulsified by bile；As drug concentration in bile increases, ivermectin it is molten
Out-degree increase；Ivermectin is prepared into after solid dispersions to can to significantly increase ivermectin molten in the pig's bile aqueous solution
Out-degree.Pig's bile emulsification test result points out us, even if not containing the ivermectin formulation of emulsification/solubilizer, is arrived in preparation
Up to after enteron aisle, ivermectin can still be present in bile emulsification/solubilising in enteron aisle, and intestinal juice is discharged into the form of emulsion droplet
In.
Further determine stability of B-7, B-8, B-9 and B-10 test sample in the 0.1 mole hydrochloride aqueous solution.Experiment
Method is：Each 1.00 grams of B-7, B-8, B-9 and B-10 test sample in table 7 are taken, are respectively placed in 25 milliliters of tool plug test tubes, are added
20 milliliters of 0.1M hydrochloric acid solutions, are mixed, and 3 hours are incubated in 36-37 DEG C, with 1 micron of membrane filtration, are drawn 5 milliliters of filtrates, are added
About 0.25 milliliter of 10% sodium hydroxide solution, is mixed, and is added methanol to 10 milliliters, is mixed, and uses 0.22um membrane filtrations, and filtered solution is used
HPLC detects that 20 microlitres of sample introduction records chromatogram.Result of the test is shown：In the acid catalysis of B-7, B-8, B-9 and B-10 test sample
MS H are not detected in hydrolysis liquid2B1A and H2B1A (detection of this assay method is limited to 0.1 mcg/ml or so).
This result of the test shows that the ivermectin that B-7, B-8, B-9 and B-10 test sample contain does not dissolve in an acidic solution
(dissolution).
Above test result analysis show, ivermectin is combined with solid dispersion medium be prepared into it is adsorbable in corncob
On solid dispersions, effectively avoid the destruction of hydrochloric acid in gastric juice, and there is in the presence of pig's bile fine dissolution rate,
This means this product is a kind of good enteric coated preparations.
Embodiment 3. prepares the preparation containing AVM 0.1% with glycerin monostearate
(1) preparation of preparation：Preparation concrete composition is shown in Table 9.The active ingredient of preparation is AVM described in table 9,
The content of AVM in the formulation is 0.11-0.13 grams；Maize cob meal used is the part between 40-160 mesh sieves hole.Press
Above-mentioned【0017】Duan Suoshu method prepares NO.10-NO.14 preparations.
(2) acid catalyzed degradation is tested
Each 3.00 grams of NO.10-NO.14 samples in table 9 are taken, are respectively placed in 25 milliliters of tool plug test tubes, 18 milliliters of water are added,
Vibration 5 minutes, adds 2 milliliters of 1M hydrochloric acid solutions afterwards, mixes, and 3 hours are incubated in 36-37 DEG C, with 1 micron of membrane filtration, draws 4
Milliliter filtrate, adds about 0.2 milliliter of 10% sodium hydroxide solution, mixes, and adds 4 ml methanols, mixes, with 0.22 micron membranes mistake
Filter, filtered solution detects that 20 microlitres of sample introduction records chromatogram with HPLC.Result of the test is shown：In the acid of NO.10-NO.14 samples
Monose AVM B is not detected in the hydrolysis liquid of catalysis1A and AVM B1a。
(3) pig's bile emulsification test
Each 3.00 grams of NO.10-NO.14 samples in table 9 are taken, are respectively placed in 50 milliliters of conical flask with stopper, 18 milliliters are added
Water and 2 milliliters of fresh pig's biles, in 36-37 DEG C of vibration (136 revs/min, 1.5 centimetres of rotary shaker eccentric throw) insulation 1
Hour, with 1 micron of membrane filtration, 4 milliliters of filtrate is drawn, 4 ml methanols are added, mixed, with 0.45 micron of membrane filtration, filtered solution is used
HPLC detects (20 microlitres of sample introduction), records chromatogram, calculates AVM B1A dissolution rate (%).Result of the test is shown in table 10.
The AVM pre-mixing agent composition of table 9. 0.1% and content
The preparation NO.10 to NO.14 of table 10. B in pig's bile/aqueous solution1A dissolution rate (%)
| Preparation is numbered | NO.10 | NO.11 | NO.12 | NO.13 | NO.14 |
| Dissolution rate % | 61-65 | 56-59 | 57-58 | 69-71 | 67-70 |
(4) NO.10-NO.14 samples are deposited 3 months at 40 DEG C, AVM and the changes of contents about material
Each 5.00 grams of NO.10-NO.14 samples in table 9 are taken, are placed in 25 milliliters of cillin bottles, are sealed, in 39-41 DEG C of incubator
It is middle to place 3 months, then to adding 20 ml methanols in every bottle, mechanical shaking extraction 15 minutes, extract solution with 0.22 micron of membrane filtration,
20 microlitres of filtrate is taken, high pressure liquid chromatograph is injected, chromatography is carried out, chromatogram is recorded, AVM B is calculated1A degradation rates
(%), monose AVM B1A chromatographic peak areas and AVM B1The ratio between a chromatographic peak areas (%), 2-epimer AVMs
B1A chromatographic peak areas and AVM B1The ratio between a chromatographic peak areas (%), are as a result shown in table 11.
Table 11.NO.10-NO.14 samples are deposited 3 months at 40 DEG C, AVM and the changes of contents about material
| Preparation is numbered | NO.10 | NO.11 | NO.12 | NO.13 | NO.14 |
| MS/B1A % | 0.36 | 0.34 | 0.33 | 0.31 | 0.32 |
| 2-epi/B1A% | 0.21 | 0.17 | 0.64 | 0.45 | 0.91 |
| Degradation rate % | 2.3-2.8 | 0.7-1.1 | 1.3-1.6 | 3.2-3.5 | 3.5-4.1 |
Note：MS/B1a is represented the ratio between avermectin B1 monosaccharide a chromatographic peak areas and Avermectin B1a peak area (%)；2-epi/
B1a is represented the ratio between 2-epimer Avermectin B1as chromatographic peak area and Avermectin B1a peak area (%)；Degradation rate % is represented
Avermectin B1a degradation rate (%).
This result of the test shows that the AVM that NO.10-NO.14 test samples contain does not dissolve in an acidic solution
(dissolution)；The dissolution in the pig's bile aqueous solution；In the framework of the present definition, dissolution rate and solid dispersion medium/ivermectin
Ratio have certain correlation；40 DEG C of stability test result shows that oxidative degradation rate and the solid of AVM disperse
The ratio of medium/ivermectin has close correlation, shows that ratio is bigger, fewer trend of AVM degraded；2-
The yield of epimer Avermectin B1as is relevant with stearic acid presence or absence.
Embodiment 4. prepares the solid pharmaceutical preparation containing ivermectin with Arlacel-60 and Ergol
(1) preparation of preparation：Preparation composition is shown in Table 12.The active ingredient of preparation is ivermectin described in table 12, she
It is 0.2-1.40 grams to tie up the content of rhzomorph in the formulation；Maize cob meal used is all by crossing 60 mesh sieves.By above-mentioned【0017】
Duan Suoshu method preparation of preparation 15- preparations 23.
The pre-mixing agent composition of table 12. and content
(2) acid catalyzed degradation is tested
Hs of the preparation 15-23 in 0.1M hydrochloric acid solutions is determined by method described in embodiment 12B1A dissolution rates and MS
H2B1A, result of the test is shown：MS H are not all detected in the reaction solution of preparation 15- preparations 232B1A and H2B1a。
(3) pig's bile emulsification test
Take preparation 15-23 described in table 12 appropriate (equivalent to containing 6 milligrams of ivermectins) respectively, be respectively placed in 50 milliliters of tools
Fill in triangular flask, add 18 milliliters of water and 2 milliliters of fresh pig's biles, (136 revs/min, rotatably shake in 36-37 DEG C of vibration
1.5 centimetres of eccentric throw of bed) 1 hour is incubated, with 1 micron of membrane filtration, 4 milliliters of filtrate is drawn, 4 ml methanols are added, mixed, is used
0.22 micron of membrane filtration, filtered solution is detected (20 microlitres of sample introduction) with HPLC, records chromatogram, calculates H2B1A dissolution rate (%).
Result of the test is shown in table 13.
The preparation 15 to 23 of table 13. H in pig's bile/aqueous solution2B1A dissolution rate (%)
| Preparation is numbered | 15 | 16 | 17 | 18 | 19 | 20 | 21 | 22 | 23 |
| Dissolution rate % | 55 | 62 | 66 | 61.8 | 63.2 | 68 | 59 | 68 | 66 |
(4) sample of preparation 15- preparations 23 is deposited into 3 months ivermectins and the changes of contents about material at 40 DEG C
Preparation 15-23 appropriate (equivalent to 6 milligrams of ivermectin) is taken in table 12, is placed in 25 milliliters of cillin bottles, seals,
Place 3 months in 39-41 DEG C of incubator, then to adding 20 ml methanols in every bottle, mechanical shaking extraction 15 minutes, extract solution uses 0.22
Micron membrane filtration, takes 20 microlitres of filtrate, injects high pressure liquid chromatograph, carries out chromatography, records chromatogram, calculates H2B1A drops
Solution rate (%), MS H2B1A chromatographic peak areas and H2B1The ratio between a chromatographic peak areas (%), 2-epimer H2B1A chromatographic peak areas with
H2B1The ratio between a chromatographic peak areas (%), are as a result shown in table 14.
The preparation 15-23 samples of table 14 deposit 3 months ivermectins and the changes of contents about material at 40 DEG C
| Preparation is numbered | 15 | 16 | 17 | 18 | 19 | 20 | 21 | 22 | 23 |
| MS/H2B1A % | 0.38 | 0.35 | 0.35 | 0.32 | 0.36 | 0.37 | 0.36 | 0.33 | 0.33 |
| 2-epi/H2B1A% | 0.35 | 0.42 | 0.37 | 0.53 | 0.18 | 0.22 | 0.63 | 0.44 | 0.36 |
| Degradation rate % | 0.47 | 1.62 | 1.87 | 0.98 | 1.13 | 2.04 | 2.99 | 1.20 | 1.04 |
Note：MS/H2B1a is represented the ratio between MS H2B1a chromatographic peak areas and H2B1a peak areas (%)；2-epi/H2B1a represents 2-
The ratio between epimer H2B1a chromatographic peak areas and H2B1a peak areas (%)；Degradation rate % represents H2B1a degradation rates (%).
This result of the test shows that the ivermectin that preparation 15-23 contains does not dissolve (dissolution) in an acidic solution；
Dissolution in the pig's bile aqueous solution；In the framework of the present definition, dissolution rate is related to the ratio of solid dispersion medium/ivermectin
Property is not notable；40 DEG C of stability test result shows that the oxidative degradation rate of ivermectin is disperseed with solid within the specific limits
The ratio of medium/ivermectin has close correlation, shows that ratio is bigger, fewer trend of ivermectin degraded.
The rilanit special of embodiment 5., brazil wax, solid polyethylene glycol, glyceryl tristearate, behenic acids glyceride,
Octadecyl alcolol prepares the solid pharmaceutical preparation containing ivermectin
(1) preparation of preparation：Preparation composition is shown in Table 15.The active ingredient of preparation is ivermectin described in table 15, she
It is 0.3-0.33 grams to tie up the content of rhzomorph in the formulation；0.6 gram of Ergol, solid dispersion medium content is shown in Table 15, corn
Core powder adds to 100 grams, and maize cob meal used is all by crossing 40 mesh sieves.By above-mentioned【0017】Duan Suoshu method preparation of preparation
24- preparations 30.Reference substance does not contain solid dispersion medium, and preparation method is direct after ivermectin is dissolved with 10 milliliters of ethanol
It is well mixed, dries with maize cob meal, removes ethanol and produce reference substance.
The pre-mixing agent composition of table 15. and content
| Preparation is numbered | 24 | 25 | 26 | 27 | 28 | 29 | 30 | Reference substance |
| Rilanit special | 6 | - | ||||||
| Brazil wax | 6 | - | ||||||
| Macrogol 6000 | 9 | - | ||||||
| Glyceryl tristearate | 8 | - | ||||||
| Behenic acid glyceride | 8 | - | ||||||
| Octadecyl alcolol | 6 | - | ||||||
| PEG20000 | 12 | - |
(2) acid catalyzed degradation is tested
Hs of the preparation 24-30 in 0.1M hydrochloric acid solutions is determined by method described in embodiment 12B1A and MS H2B1A, experiment
As a result show：MS H are not all detected in the reaction solution of preparation 24 to preparation 302B1A and H2B1a。
(3) pig's bile emulsification test
Preparation 24-30 and appropriate reference substance (equivalent to containing 6 milligrams of ivermectins) are taken respectively, are respectively placed in 50 milliliters of tool plugs
In triangular flask, 18 milliliters of water and 2 milliliters of fresh pig's biles are added, (136 revs/min, rotary shaker are vibrated in 36-37 DEG C
1.5 centimetres of eccentric throw) 1 hour is incubated, with 1 micron of membrane filtration, 4 milliliters of filtrate is drawn, 4 ml methanols are added, mixed, with 0.45
Micron membrane filtration, filtered solution is detected (20 microlitres of sample introduction) with HPLC, records chromatogram, calculates H2B1A dissolution rate (%).Experiment
As a result it is shown in table 16.
The preparation 24-30 of table 16. and the reference substance H in pig's bile/aqueous solution2B1A dissolution rate (%)
| Preparation is numbered | 24 | 25 | 26 | 27 | 28 | 29 | 30 | Reference substance |
| Dissolution rate % | 55-63 | 53-56 | 84-88 | 61.8 | 63.2 | 72-76 | 87-90 | 48-51 |
This result of the test shows that the ivermectin that preparation 24-30 contains does not dissolve (dissolution) in an acidic solution,
Dissolution in the pig's bile aqueous solution；Preparation its ivermectin dissolution rate that ivermectin is present in solid dispersions form is big, containing poly-
The preparation dissolution rate of ethylene glycol is maximum.The ivermectin dissolution rate of reference substance is relatively low.
Solid pharmaceutical preparation of the embodiment 6. containing polyvinylpyrrolidone and ivermectin
8 grams of polyvinylpyrrolidones are dissolved with 20 milliliters of ethanol, polyvinylpyrrolidonesolution solution is prepared into；By 0.33 gram
Ivermectin and antioxidant are added in the ethanol solution containing polyvinylpyrrolidone, are stirred at ambient temperature, make medicine
It is completely dissolved, the slightly sticky ethanol solution containing ivermectin and polyvinylpyrrolidone is made；Ivermectin and poly- second will be contained
The ethanol solution of alkene pyrrolidone is mixed with 91 grams of maize cob meals, is stirred, and is dried, that is, is made and is contained ivermectin/polyethylene
The solid pharmaceutical preparation of pyrrolidones solid dispersions.This agent dissolution rate of ivermectin in the 20% pig's bile aqueous solution can reach
More than 80%, than the high 31-38.6% of conventional formulation dissolution rate without polyvinylpyrrolidone.
Solid pharmaceutical preparation of the embodiment 7. containing polyvinylpyrrolidone and Si La rhzomorphs
4 grams of polyvinylpyrrolidones are dissolved with 15 milliliters of ethanol, polyvinylpyrrolidonesolution solution is prepared into；By 0.11 gram
Department draws rhzomorph and antioxidant to be added in the ethanol solution containing polyvinylpyrrolidone, stirs at ambient temperature, makes medicine
It is completely dissolved, the ethanol solution that rhzomorph and polyvinylpyrrolidone are drawn containing department is made；Department will be contained and draw rhzomorph and polyvinylpyrrolidine
The ethanol solution of ketone is mixed with the maize cob meal of 30 grams of mesh sieves of mistake 60, is stirred, and is dried, is then mixed with 66 grams of pork liver powders
It is even, that is, the solid pharmaceutical preparation that rhzomorph/polyvinylpyrrolidone solid dispersions are drawn containing department is made.This agent is in the 20% pig's bile aqueous solution
Middle department draws the dissolution rate of rhzomorph to can reach more than 93%, higher by more than 40% than the preparation dissolution rate without polyvinylpyrrolidone.
This agent room temperature is deposited 3 years, and the degradation rate of active principle is only the 0.35-0.62% of labelled amount.This agent is used for dog, cat parasitic disease
Preventing and treating, takes food rate more than 95%, takes food 0.3 gram of this product by dog, cat per kilogram of body weight, the drive to nematode and epizoa is net automatically
Rate is more than 98%, single administration sustainable 30 days of phase of preventing and treating.
Solid pharmaceutical preparation of the embodiment 8. containing acrylic resin and ivermectin
6 grams of No. 2 acrylic resins are dissolved with 15 milliliter of 95% ethanol, solution is made；By 0.22 gram of ivermectin and anti-
Oxidant is added in the ethanol solution containing acrylic resin, is stirred at ambient temperature, makes complete drug dissolution, is made and is contained her
Tie up the ethanol solution of rhzomorph and acrylic resin；Ethanol solution containing ivermectin and acrylic resin is mixed with 94 grams of powdered beefs
Close uniform, dry, that is, the solid pharmaceutical preparation containing ivermectin/acrylic resin solid dispersions is made.This agent is in 20% pig's bile
The dissolution rate of ivermectin can reach more than 88% in the aqueous solution.This agent room temperature is deposited 2 years, and the degradation rate of active principle is only mark
The 0.61-0.86% for the amount of showing.This agent is used for dog, cat preventing and treating verminosis, rate is taken food automatically more than 93%, by dog, cat per kilogram
Body weight takes food 0.15 gram of this product, and the net rate of drive to nematode and epizoa is more than 98%, and single administration prevented and treated the phase up to 30 days.
Solid pharmaceutical preparation of the embodiment 9. containing acrylic resin, polyvinylpyrrolidone and ivermectin
By 2 grams of No. 2 acrylic resins, 6 grams of polyvinylpyrrolidones, dissolved with 25 milliliter of 95% ethanol, solution is made；Will
0.22 gram of ivermectin and antioxidant are added in the ethanol solution containing acrylic resin and polyvinylpyrrolidone, in room temperature
Under the conditions of stir, make complete drug dissolution, be made containing ivermectin, acrylic resin, polyvinylpyrrolidone ethanol solution；
It will be well mixed containing ivermectin, acrylic resin, the ethanol solution of polyvinylpyrrolidone with 32 grams of maize cob meals, Ran Houyu
60 grams of land plasters are well mixed, and are dried, that is, are made and are contained ivermectin/acrylic resin, polyvinylpyrrolidone solid dispersions
Solid pharmaceutical preparation.This agent dissolution rate of ivermectin in the 20% pig's bile aqueous solution can reach more than 90%.This agent room temperature is deposited
Put 2 years, the degradation rate of active principle is only the 0.35-0.61% of labelled amount.This agent is used for pig preventing and treating verminosis, at every 1 ton
1 kilogram is added in feed, continuous feeding 5-7 days, the net rate of drive to nematode and epizoa is more than 98%.
Solid pharmaceutical preparation of the embodiment 10. containing polyvinylpyrrolidone and moxidectin
By 6 grams of polyvinylpyrrolidones, dissolved with 20 milliliter of 95% ethanol, solution is made；By 0.22 gram of moxidectin and
Antioxidant is added in the ethanol solution containing polyvinylpyrrolidone, is stirred at ambient temperature, makes complete drug dissolution, system
The ethanol solution of ivermectin, polyvinylpyrrolidone must be contained；By containing ivermectin, the ethanol solution of polyvinylpyrrolidone with
The maize cob meals of 30 grams of mesh sieves of mistake 120 is well mixed, and then be well mixed with 64 grams of starch, is dried, that is, be made contain moxidectin/
The solid pharmaceutical preparation of polyvinylpyrrolidone solid dispersions.The dissolution rate of ivermectin can in the 20% pig's bile aqueous solution for this agent
Reach more than 92%.This agent room temperature is deposited 2 years, and the degradation rate of active principle is only the 0.52-0.83% of labelled amount.This agent is used for
Pig preventing and treating verminosis, adds 1 kilogram, continuous feeding 5-7 days, to the net rate of drive of nematode and epizoa in every 1 ton of feed
More than 98%.
Embodiment 11. is containing polyvinylpyrrolidone and ivermectin, the solid pharmaceutical preparation of Phenbendasol
8 grams of polyvinylpyrrolidones are dissolved with 20 milliliters of ethanol, polyvinylpyrrolidonesolution solution is prepared into；By 0.22 gram
Ivermectin and antioxidant are added in the ethanol solution containing polyvinylpyrrolidone, are stirred at ambient temperature, make medicine
It is completely dissolved, the slightly sticky ethanol solution containing ivermectin and polyvinylpyrrolidone is made；Ivermectin and poly- second will be contained
The ethanol solution of alkene pyrrolidone is mixed with the maize cob meal of 44 grams of mesh sieves of mistake 60, is stirred, and is then added 6 grams of fragrant benzene and is rattled away
Azoles, adds 42 grams of land plaster after mixing, be well mixed, and dries, and is made and contains ivermectin/polyvinylpyrrolidone solid dispersions
With the solid pharmaceutical preparation of Phenbendasol.This agent dissolution rate of ivermectin in the 20% pig's bile aqueous solution can reach more than 85%.
Embodiment 12. is containing polyvinylpyrrolidone and Si La rhzomorphs, the solid pharmaceutical preparation of oxfendazole
4 grams of polyvinylpyrrolidones are dissolved with 15 milliliters of ethanol, polyvinylpyrrolidonesolution solution is prepared into；By 0.11 gram
Department draws rhzomorph and antioxidant to be added in the ethanol solution containing polyvinylpyrrolidone, stirs at ambient temperature, makes medicine
It is completely dissolved, the ethanol solution that rhzomorph and polyvinylpyrrolidone are drawn containing department is made；Department will be contained and draw rhzomorph and polyvinylpyrrolidine
The ethanol solution of ketone is mixed with the maize cob meal of 30 grams of mesh sieves of mistake 60, is stirred, and then adds 2.5 grams of oxfendazole, mixing
After uniform, further it is well mixed, dries with 60 grams of pork liver powders and 6 grams of butter, remove ethanol, is made and draws rhzomorph/poly- second containing department
The solid pharmaceutical preparation of alkene pyrrolidone solid dispersions and oxfendazole.This agent is taken charge of in the 20% pig's bile aqueous solution draws the molten of rhzomorph
Out-degree can reach more than 83%.This agent room temperature is deposited 3 years, and the degradation rate of active principle is only the 0.35-0.62% of labelled amount.This
Agent is used for dog, cat preventing and treating verminosis, rate is taken food automatically more than 92%, dog, cat take food 0.3 gram of this product by per kilogram of body weight, right
The net rate of drive of nematode and epizoa is more than 98%, single administration sustainable 30 days of phase of preventing and treating.
Claims (5)
1. a kind of oral solid formulation containing anti-parasite medicine, it is characterised in that the solid pharmaceutical preparation includes following each component：
A, in every 1 kilogram of oral solid formulation include 0.1-15 grams of anti-parasite medicine；Described anti-parasite medicine includes
One kind in AVM, ivermectin, doractin, moxidectin, Eprinomectin, department's drawing rhzomorph；
B, 10-300 grams of solid dispersion medium is included in every 1 kilogram of solid pharmaceutical preparation, described solid dispersion medium is comprising hydrophobic
Property solid dispersion medium, under normal temperature be the polyethylene glycol of solid state, polyvinylpyrrolidone, one kind in acrylic resin or
More than one composition；The hydrophobic solid decentralized medium includes monohydric alcohol, stearic acid, single tristearin more than 15 carbon
Acid glyceride, glyceryl tristearate, behenic acid glyceride, behenic acids, hydrogenated vegetable oil, brazil wax, Arlacel-60；
C, carrier material, add to 1 kilogram；Described carrier material includes maize cob meal, zeolite powder, stone flour, diatomite, gypsum
One or more kinds of compositions in powder, starch, fish meal, powdered beef, pork liver powder, chicken liver meal.
2. the oral solid formulation as described in claim 1, it is characterised in that hydrophobicity is included in the oral solid formulation
Solvent, described hydrophobic solvent includes Ergol, pungent/capric acid glyceryl ester, isopropyl myristate, azone or oleic acid
One or more kinds of compositions in ethyl ester；The content of hydrophobic solvent in the formulation is the solid dispersion medium content
3-20%.
3. the oral solid formulation as described in claim 1, it is characterised in that wrapped in described per kilogram oral solid formulation
Containing 0.2-5 grams of antioxidant, the antioxidant includes dibutyl hydroxy toluene, tertiary butyl-4-hydroxy anisole, gallic acid third
One or more kinds of compositions in ester, vitamin C.
4. the oral solid formulation as described in claim 1, it is characterised in that wrapped in described every 1 kilogram of oral solid formulation
Containing 10-100 grams of other anti-parasite medicine, described other anti-parasite medicines include albendazole, oxide, fragrant benzene
The one kind rattled away in azoles, oxfendazole, insect growth regulator, IGR.
5. the oral solid formulation as described in claim 1-3 any one, it is characterised in that the oral solid formulation selection
It is prepared by following methods：
Method one：Polyvinylpyrrolidone or acrylic resin ethanol are dissolved, polyvinylpyrrolidone or propylene is prepared into
The ethanol solution of acid resin；Ivermectin class medicine and antioxidant are added to polyvinylpyrrolidone or acrylic resin
In ethanol solution, stirred under room temperature or heating condition, make complete drug dissolution, slightly sticky drug solution is made；By medicine
Solution is well mixed with described carrier material under agitation, is dried, that is, described oral solid formulation is made；
Method two：Solid polyethylene glycol or described hydrophobic solid decentralized medium are melted under the conditions of 65-90 DEG C, add or
Hydrophobic solvent is added without, ivermectin class medicine and antioxidant is added, stirring dissolves medicine, is then being kept for 65-88 DEG C
Under conditions of add the carrier material, be sufficiently stirred for, it is well mixed after cool to less than 35 DEG C under agitation, make material
Solidification, sieving produces described this agent of oral administration solid.
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| CN201710033272.5A Pending CN107041872A (en) | 2017-01-18 | 2017-01-18 | A kind of ivermectin class pharmaceutical preparation with high-dissolution in bile |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1522706A (en) * | 2003-02-19 | 2004-08-25 | 王玉万 | Preparation of solid dispersoid containing large ring lactone parasite medicine |
| CN101919804A (en) * | 2010-08-05 | 2010-12-22 | 洛阳惠中兽药有限公司 | Application of solid dispersion to preparation of veterinary drugs |
| CN102908316A (en) * | 2012-11-12 | 2013-02-06 | 西南大学 | Ivermectin water-soluble solid dispersion and preparation method thereof |
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2017
- 2017-01-18 CN CN201710033272.5A patent/CN107041872A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1522706A (en) * | 2003-02-19 | 2004-08-25 | 王玉万 | Preparation of solid dispersoid containing large ring lactone parasite medicine |
| CN101919804A (en) * | 2010-08-05 | 2010-12-22 | 洛阳惠中兽药有限公司 | Application of solid dispersion to preparation of veterinary drugs |
| CN102908316A (en) * | 2012-11-12 | 2013-02-06 | 西南大学 | Ivermectin water-soluble solid dispersion and preparation method thereof |
Non-Patent Citations (1)
| Title |
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| 李桂杰: "《饲料营养与配制技术》", 30 April 2013, 辽宁大学出版社 * |
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