CN108066767A - A kind of self-emulsification solid composition of the drug of class containing ivermectin of stabilization - Google Patents
A kind of self-emulsification solid composition of the drug of class containing ivermectin of stabilization Download PDFInfo
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Abstract
Present invention solves the technical problem that be improve ivermectin class drug water dissolvable and overcome ivermectin class drug in acid condition facile hydrolysis the defects of, the release of drug in vivo is improved to reach, while controls drug purpose that is not destroyed or being less destroyed in acidic gastric juice；The second is overcome medicament during preservation, the acid/base catalytic degradation of active ingredient and oxidative degradation problem, make medicament active principle degrade it is less.Currently preferred composition includes ivermectin class drug, Crodaret condensation product, Arabic gum or/and polyvinylpyrrolidone, Ergol or azone, 1,2 propylene glycol, maize cob meal；Other anti-parasite medicines can be also added in composition, preferred other anti-parasite medicines are cyromazine.
Description
Technical field
The invention belongs to veterinary drug preparation technologies of preparing, and in particular to a kind of preparation skill of the pharmaceutical composition of class containing ivermectin
Art, the composition prepared with the technology have high and more tolerant to acid/base catalytic degradation the characteristic of drug dissolution.
Background technology
Experiment and information：(1) ivermectin class drug does not almost dissolve in water.Such as it is only capable of dissolving in 1 liter of water
The ivermectin of 6-9 micrograms.Therefore, when preparing the oral solid formulation of the drug of class containing ivermectin, in order to ensure drug energy
It is more absorbed, the water solubility problems for improving drug are the sport technique segments that must take into consideration.(2) molecule of ivermectin class drug
There are 2 glycosidic bonds, it is easily catalyzed by acids hydrolysis and loses saccharide residue in structure.Such as ivermectin be easily catalyzed by acids hydrolysis and
Convert Viability relatively low monose ivermectin B1a(MS H2B1And H a)2B1aAglycone (is shown in Table 1).And the animals such as pig, chicken
Gastric juice is most in acidity, and acidity most can reach by force pH value 1 or so (acidity for being approximately equivalent to 0.1M hydrochloric acid).This prompts us：
By improving the acid resistance of preparation, to hinder hydrolysis of the acidic gastric juice to ivermectin class drug, this kind of medicine can be reduced
Loss of the object during oral, providing more can absorbed drug.(3) ivermectin class drug in alkaline conditions its
C2 positions in molecular structure easily occur epimerism and are converted into 2- epimers H2B1a(2-epimer H2B1a), its drive
Worm activity is only H2B1a1% or so of activity；The double bond of C3=C4 is easily shifted over, and is converted into the very low Δ of activity2,3H2B1a
(being shown in Table 3)；The lactone bond having in ivermectin molecular structure is equally easily by OH-It attacks and is destroyed.In fact, Yi Wei bacterium
, in addition to oxidative degradation, also there is acid/base catalytic degradation in degradation of the plain class drug during preservation.Open source information shows,
Such drug is more stable under the conditions of slant acidity, and suitable pH range is between 4-6.We are by using the system containing ivermectin
The experiment that agent carries out is shown, when forming the PH of carrier material of preparation more than 6.2, the impurity generated in the shelf-life is more
2- epimer ivermectins B1a；When the pH value of carrier material is less than 4.0, the impurity generated in the shelf-life is more
Monose ivermectin B1a.(4) ivermectin class drug is contacted with air, and oxidative degradation easily occurs, and prepares class containing ivermectin
During the solid pharmaceutical preparation of drug, solve the problems, such as the oxidative degradation of drug by adding in antioxidant in the formulation, be extremely difficult to pre-
The effect of phase.
In conclusion prepare the drug containing ivermectin preparation when, it is necessary to solve the problems, such as drug water-insoluble and gram
The oxidative degradation of medication object, acid/base catalytic degradation problem.
Surfactant can not only improve the water dissolvable of some hydrophobic drugs as solubilizer or cosolvent, and
The presence of specific surfactant can enhance the stabilization of preparation that some contain facile hydrolysis drug in acid or alkaline environment
Property, " this is because surfactant can form micella in the solution, that is, foring a kind of barrier ", this " glue for wrapping up in drug
Beam barrier " hinders H+、OH-Attack to facile hydrolysis drug.But if surfactant selection is improper, drug can be made more instead
Easily by acid/base catalytic degradation.Such as lauryl sodium sulfate (hereinafter referred to as SDS), it has the acid-catalyzed hydrolysis of ivermectin
There is significant humidification (being shown in Table 2).Therefore, the water soluble of hydrophobic drug is improved by the method for application surfactant
Property, while require preparation that there is the catalyzing hydrolysis effect of tolerance acid and improve stability of the preparation during preservation, surface-active
The selection of agent species is undoubtedly vital sport technique segment.
The content of the invention
The present invention solves the technical problem of the water dissolvable for improving ivermectin class drug and overcome ivermectin
Class drug in acid condition facile hydrolysis the defects of, improve drug dissolution rate in vivo to reach, while protect drug in acid
Property gastric juice in not destroyed or less destroyed purpose；Preparation is followed by overcome during preservation, the oxidation of active ingredient
Degradation and acid/base catalytic degradation problem, make medicament active principle degrade it is less.The present invention is preferably by surfactant and choosing
The auxiliary agent (Ergol or azone and Arabic gum etc.) selected is applied in combination, and is urged to prepare more resistant to oxidative degradation and acid/base
Change the composition of degradation, said composition can be used for preparing tablet, pulvis, pre-mixing agent.
Following each component is included in composition of the present invention：
A anti-parasite medicines, its content in every 1 kilogram of composition are 0.1-10 grams；The anti-parasitism
Worm drug include avermectin, emamection benaoate, Eprinomectin, ivermectin, doractin,
Moxidectin, department draw one kind in rhzomorph；
B includes 1.5-100 grams of solid dispersion medium, the solid dispersion medium bag in every 1 kilogram of composition
It includes more than one or both of Arabic gum, polyvinylpyrrolidone, acrylic resin；
C is more than or equal to 12 nonionic surfactant comprising hydrophilic lipophilic balance in the composition, is combining
Its content is 3-20 times of the anti-parasite medicine weight in object, is no more than the 20% of composition weight；
D in composition described in per kilogram is added without or adds in 0.2-5 grams of antioxidant, and the antioxidant includes dibutyl
It is more than one or both of hydroxy-methylbenzene, tertiary butyl-4-hydroxy anisole, propylgallate, vitamin C；Antioxidant
Addition can further reduce the tendentiousness that preparation is degraded due to oxidation.
E is added without or adds in 2-10 grams of 1,2-PD in composition described in per kilogram；1,2-PD is in composition system
The effect of solvent is primarily served during standby, plays the role of assistant for emulsifying agent during the self-emulsifying of preparation.
F in composition described in per kilogram is added without or adds in hydrophobic medium, and the hydrophobic medium includes benzene first
Acid benzyl ester, pungent/capric acid glyceryl ester, isopropyl myristate, azone, dipropylene glycol dibenzoate, diethylene glycol hexichol first
It is more than one or both of acid esters, ethyl oleate；The content of hydrophobic medium in the composition is the non-ionic surface
The 10-110% of activating agent weight；Hydrophobic medium can play the role of solvent in composition preparation process, be formed in emulsion droplet
Process plays the role of oil phase.The common feature of hydrophobic medium of the present invention is that have to ivermectin class drug relatively by force
Solvability, have very strong affinity with preferred surfactant, this is that they can form close " micella barrier ", with
Hinder H+、OH-With oxygen to the primary chemical basis of medicaments target.
G carrier materials add to 1 kilogram；The carrier material includes maize cob meal, zeolite powder, mountain flour, diatomite, stone
It is more than one or both of cream powder, starch, fish meal, powdered beef, pork liver powder, chicken liver meal, dried meat floss.
Nonionic surfactant of the hydrophilic lipophilic balance more than or equal to 12 includes Tweens, sells damp class, benzyl
Damp class, peregal, Crodaret condensation product, Emulsifier EL-60 condensation product, the condensation of polyethylene glycol vegetable oil
Object.
Nonionic surfactant of the hydrophilic lipophilic balance of selection more than or equal to 12 includes polyoxyethylene (35) castor-oil plant
Oil, polyoxyethylene (40) castor oil, polyoxyethylene (90) castor oil, polyoxyethylene (35) rilanit special, polyoxyethylene (40)
Rilanit special, polyoxyethylene (50) rilanit special, polyoxyethylene (60) rilanit special, polyethylene glycol (40) palm kernel
Oil, polyethylene glycol (60) corn oil, polyethylene glycol (60) corn oil glyceride, polyethylene glycol (60) apricot kernel oil, polyethylene glycol
(50) castor oil, hydrophilic lipophilic balance more than 12 Brij58, polyethylene glycol stearate SG-40, Brij-
More than one or both of 35.
It can also add in 1-100 grams of other anti-parasite medicine in the per kilogram composition, it is described other anti-to post
Infested drug include diclazuril, toltrazuril, albendazole, oxide, Phenbendasol, oxfendazole, febantel,
It is more than one or both of praziquantel, niclosamidum, Pyrantel, insect growth regulator, IGR；The insect
Growth regulator includes cyromazine, fenoxycarb, hydroprene, cloves are led to, methoprene, pyrrole phenylate, chlorfluazuron, diflubenzuron, fluorine
Mite urea, flufenoxuron, flubenzuron, lufenuron, tebufenozide, fluorobenzene urea, triflumuron.
The preparation method of composition includes but not limited to following several.
Preparation method one includes following operating procedure：
A. Arabic gum or/and polyvinylpyrrolidone are mixed with water, be prepared into Arabic gum containing 5-30% or/and
Aqueous povidone solution, it is spare；
B. the nonionic surfactant of ivermectin class drug and hydrophilic lipophilic balance more than or equal to 12 is mixed, added
Enter or be added without 1,2-PD, add in or be added without the hydrophobic medium, add in or be added without the antioxidant,
It is stirred under room temperature or heating condition, dissolves drug, the thick liquid of the drug of class containing ivermectin is made；
C. under agitation, the thick liquid of the drug of class containing ivermectin with the aqueous solution described in step a is mixed, filled
Divide stirring or handled with high-speed shearing machine, be prepared into sticky emulsion；
D. emulsion prepared by step c is uniformly mixed with the carrier material, it is dry to get the composition.
Preparation method two includes following operating procedure：
Polyvinylpyrrolidone or/and acrylic resin ethyl alcohol or 95% ethyl alcohol are dissolved, are prepared into polyvinyl pyrrole
The ethanol solution of alkanone or/and acrylic resin；It is added in into the ethanol solution of polyvinylpyrrolidone or/and acrylic resin
Ivermectin class drug, nonionic surfactant and 1,2-PD, add in or are not added with hydrophobic medium, add or are not added with antioxygen
Agent stirs under room temperature or heating condition, makes complete drug dissolution, and slightly sticky drug solution is made；Drug solution is existed
It is uniformly mixed under stirring condition with maize cob meal, through drying and removing ethyl alcohol, the composition is made.
Cyromazine 0.3-1% (weight/weight ratio) is included in the composition of selection.The composition of selection includes but unlimited
In following component (weight/weight ratio)：
A ivermectins 0.1-3% and cyromazine 0.3-1%；
B Arabic gums 3-10%；
C polyoxyethylene (40) rilanit special 1-8%；
D Ergols 0.3-3.5%；
E tertiary butyl-4-hydroxy anisoles 0.06-0.12%；
F propylgallates 0.018-0.036%；
G maize cob meals add to a hundred percent of composition weight.
The composition of selection, preparation comprise the following steps：
A mixes Arabic gum with water, is prepared into 5-30% Arabic gum aqueous solutions, spare；
B by ivermectin, polyoxyethylene (40) rilanit special, Ergol, tertiary butyl-4-hydroxy anisole, do not have
Propyl galate mixes, and under room temperature or heating condition, stirring dissolves drug, and the thick liquid containing ivermectin is made；
C by the thick liquid containing ivermectin under agitation with step a made from Arabic gum aqueous solution mix, stir
It mixes or is handled with high-speed shearing machine, be prepared into sticky emulsion；
The step c emulsion prepared is uniformly mixed by d with maize cob meal and cyromazine, dry, and the composition is made.
When moisture is evaporated completed under not intense agitation in the drying process prepared in above-mentioned composition
, in terms of microcosmic angle, the emulsion droplet that is dispersed in originally in the continuous phase being made of water and polyvinylpyrrolidone or Arabic gum
" micro-capsule " (" micella " that drug is formed by oil phase and nonionic surfactant coating) will be changed into, is scattered in not aqueous
The continuous phase being made of polyvinylpyrrolidone or Arabic gum in, so as to effectively hindering attack of the oxygen to drug, this
It is exactly the composition of the drug of class containing ivermectin prepared with this law, even if being added without antioxidant, drug is not easy to oxidative degradation
The reason for (see embodiment 9-16).In addition, the pH value for the continuous phase being made of Arabic gum in 4.2-4.7, is in Yi Wei bacterium
The most stable PH scopes of plain class drug (are not likely to produce 2- epimers H2B1The scope of a) so that composition stability is more
Good, the shelf-life is longer.Since the medium of embedding medicinal is Arabic gum or/and polyvinylpyrrolidone, the breast by good water solubility
Agent is formed, and determines that the release of this combination of traditional Chinese medicine object limits from " embedding medium ".Vitro release result of the test shows,
After composition is mixed with water made from above method, it is dissolved through vibrating drug, is present in the form of emulsion droplet in system
(forming lotion or submicron emulsion), release can reach more than 90%, and horizontal far above similar product (dissolution rate is left 60%
It is right).Vitro release result of the test shows said composition under body temperature, can promote after meeting body fluid in gastrointestinal motility
Under spontaneously form lotion, it is therefore contemplated that the composition prepared by the present invention is a kind of self-emulsifying drug delivery system (Jia Wei, Gao Wenyuan
Chief editor, Qiu Mingfeng associate editors, medicine controlled releasing novel form, Chemical Industry Press, April the 1st edition, the 71-83 pages in 2005).
Acid catalyzed hydrolysis experiment shows that the composition prepared as stated above is 0.09-0.11M's in concentration of hydrochloric acid
In solution, when heat preservation 2-3 is small under the conditions of 36-37 DEG C, detected with HPLC, monose Yi Wei in its chromatogram of particularly preferred preparation
Rhzomorph B1A peak areas and ivermectin B1A peak area ratios are less than 2% (embodiment 3 to embodiment 6).The commercial product ratio is more than
5%.Composition proposed by the present invention equally has stronger inhibitory action (table 7) to the catalytic degradation of alkali.
Pass through above【0038】Section and the【0039】The elaboration of section further illustrates the reality of the technology of the present invention
Matter feature and progress.
In addition, in our garbled surfactants, there are some surfactants because to ivermectin class drug
Acid catalyzed degradation shows apparent facilitation and is abandoned.Such as lauryl sodium sulfate surfactant, though they
So there is good solubilising/emulsification to ivermectin class drug, but due to having stronger promotion ivermectin simultaneously
Acid-catalyzed hydrolysis acts on (being shown in Table 2), and accordingly, there exist the tendentiousness increases destroyed by acidic gastric juice.
From described above as it can be seen that the present invention related is produced to commercially available being understood in depth to ivermectin physicochemical property
Product there are the problem of understanding on the basis of and propose.Therefore, feature of present invention is illustrated in order to clearer.It is necessary to right
The experiment of closely related main foundation is described by with the present invention.
1. hydrolysis experiment of the ivermectin in various concentration hydrochloric acid solution (using methanol/water as solvent).Test method is：
Test sample is when 36-37 DEG C of heat preservation placement 0-3 is small.The MS H in reaction solution are measured with HPLC methods2B1A and H2B1A hydrolyzes journey
Degree is with MS H2B1The peak area value of a account for 0 it is small when ivermectin B1a(H2B1A) peak area value (%) represents.Result of the test is shown in Table
1.
Hydrolysis of 1. ivermectin of table in various concentration hydrochloric acid solution (using methanol/water as solvent)
2.SDS is to the facilitation of the acid-catalyzed hydrolysis of ivermectin：Prepared by test specimen and test method is as follows.
(1) M-9 sample preparations and acid catalyzed hydrolysis：Take 0.8 gram of SDS, 50 microlitres of 1,2-PDs and 2.1 grams of lists
Sweet ester stirs 10 minutes in 50 milliliters of beakers at 80-85 DEG C, adds in the ethyl acetate solution 0.5 containing 0.060 gram of ivermectin
Milliliter, mixing add in 7 grams of maize cob meals, and mixing is down to room temperature to get M-9.1 gram of M-9 sample is taken in 25 milliliters of tool plug test tubes
In, 0.01M hydrochloric acid/20 milliliters of aqueous solution is added in, vibrates mixing, when 36-37 DEG C of reaction 3 is small.(2) preparation of microemulsion and acid
The hydrolysis of catalysis：Take 0.7 gram of SDS, 1 milliliter of 1,2-PD, the ethyl acetate solution 0.75 containing 0.150 gram of ivermectin
Milliliter, stirs and evenly mixs, adds water to 25 milliliters, is sufficiently stirred up to microemulsion；Take 1 milliliter of microemulsion plus 0.01M hydrochloric acid/aqueous solution
19 milliliters, when 36-37 DEG C of reaction 3 is small.(3) reference substance preparation and acid catalyzed hydrolysis：It takes containing 0.060 gram of ivermectin
0.5 milliliter of ethyl acetate solution, in 10 ml methanols, mixing adds in 10 milliliters of hydrochloric acid/aqueous solution that concentration is 0.02M, mixes
It is even, when 36-37 DEG C of reaction 3 is small.The MS H in above-mentioned reaction solution are detected with HPLC methods2B1a、H2B1a AG、H2B1A records peak face
Product value calculates H2B1A degradation rates (%), MS H2B1A and H2B1The ratio between peak area value of a (%), H2B1aAG(H2B1a glucosides is matched somebody with somebody
Base) and H2B1The ratio between peak area value of a (%) and H2B1A dissolution rates (%).Result of the test is shown in Table 2.As seen from Table 2, SDS is to her
The acid-catalyzed hydrolysis for tieing up rhzomorph has very strong facilitation.
Table 2.SDS is to the facilitation of the acid-catalyzed hydrolysis of ivermectin
3. ivermectin is in 0.1M NaOH solutions (methanol/water=1: the Degrading experiment in 1)：Take certain density Yi Wei
10 milliliters of rhzomorph/methanol solution is mixed with 10 milliliters of the sodium hydroxide solution of 0.2M, is placed 0-930 minutes at 21-24 DEG C.With
HPLC methods measure 2-epimer H in reaction solution2B1a、Δ2,3H2B1A and H2B1A calculates 2-epimer H2B1A and H2B1A peaks face
The ratio between product value (%), Δ2,3H2B1A and H2B1The ratio between a peak area values (%), H2B1A and 0 minute H2B1The ratio between a peak area values (%).
Result of the test is shown in Table 3.
In conclusion main points of the present invention and haveing an advantage that：(1) composition prepared with this technology, due to the surface of selection
Activating agent/Ergol or azone have the performance for forming " micella barrier " well so that ivermectin wherein included
Class drug is not easy by H+Attack, this reduces degree or the probability that drug is hydrolyzed by acidic gastric juice to a certain extent, thus gram
Taken because hydrochloric acid in gastric juice act on caused by drug loss the defects of.(2) composition prepared with technology proposed by the present invention, due to drug quilt
Medium embeds, so as to be provided with stronger barrier oxygen, H+、OH-The performance of attack.Therefore, the present invention preferably solves Yi Wei bacterium
The oxidative degradation of plain class pharmaceutical solid preparation and acid/base catalytic degradation problem so that preparation active ingredient during preservation is degraded
It is less, so as to improve product quality and the market competitiveness.
3. ivermectin of table is in 0.1M NaOH solutions (methanol/water=1: the degradation in 1)
Specific embodiment
Embodiment 1. carries out the screening of surfactant with the acid catalyzed degradation experiment of microemulsion
(1) microemulsion forms：Preparing the surfactant used in microemulsion includes polyethylene glycol (40) palm-kernel oil, poly- second
Glycol (60) corn oil, polyethylene glycol (60) corn oil glyceride, polyethylene glycol (60) apricot kernel oil, polyethylene glycol (50) castor-oil plant
Oil, Emulsifier EL-60 condensation product, Crodaret condensation product (including HEL-40, HEL-35, HEL-50,
HEL-60), nonylphenol polyoxyethylene ether (such as OP-10), brejs (Brij -35, Brij -58), polyethylene glycol stearate
(SG-40, SG-100, SG-12), polyoxyethylene lauryl alcohol ester (LAE-9), Cithrol 4ML, poloxamer
188th, lauryl sodium sulfate, Tween-80, active principle are ivermectin (0.6%), and the oil phase in microemulsion is acetic acid second
Ester, assistant for emulsifying agent are 1,2-PD, and water adds to 100% volume of microemulsion.
(2) acid catalyzed degradation test method：1 milliliter of microemulsion is taken, 19 milliliters of 0.1M hydrochloric acid solutions are added in, in 36-37 DEG C
React 1 it is small when, with being filtered after alkali tune PH, MS H in filtrate are detected with HPLC2B1A and H2B1A records chromatogram, calculates MS
H2B1A peak areas and H2B1The ratio between a peak areas (%).
(3) experimental result：With Crodaret condensation product, polyethylene glycol (40) palm-kernel oil, polyethylene glycol
(60) microemulsion prepared by corn oil, polyethylene glycol (60) corn oil glyceride, polyethylene glycol (60) apricot kernel oil, MS H2B1a
Peak area and H2B1The ratio between a peak areas are less than 1.8%；Its ratio of microemulsion prepared with PLURONICS F87 uses it less than 1.5%
Its peak area ratio of microemulsion or have interference more than 1.8% or to measure prepared by his surfactant；Lauryl sodium sulfate pair
Degradation of the ivermectin under acid catalysis has significant facilitation.
Composition and its acid catalyzed hydrolysis experiment of the embodiment 2. containing HEL-40 and different oiliness media
(1) basic recipe (weight ratio)：Ivermectin 0.6%, HEL-408%, 1,2-PD 1%, oil medium are fitted
Amount (being shown in Table 4), maize cob meal add to 100%.(2) acid-catalyzed hydrolysis is tested：1.00 grams of samples are taken in 25 milliliters of tool plug test tubes,
18 milliliters of water are added in, are vibrated 5 minutes, add in 2 milliliters of 1M hydrochloric acid solutions afterwards, mixing when 36-37 DEG C of heat preservation 2 is small, draws 5
Milliliter reaction solution, with sodium hydroxide solution tune PH, mixing adds in methanol constant volume to 10 milliliters, mixing, with 0.45um membrane filtrations,
Filtered solution is detected with HPLC, records peak area, calculates MS H2B1A peak areas and H2B1The ratio between a peak areas (%).Result of the test is shown in
Table 4.
The influence that 4. oil medium of table acts on the acid-catalyzed hydrolysis of ivermectin
| Oil medium and content | MS H2B1a/H2B1The peak area % of a | H2B1A solubility % |
| Castor oil 2% | 3.18-3.43 | 66-72 |
| Rilanit special 2% | 2.99-3.56 | 63-69 |
| Soybean oil 3% | 2.97-3.14 | 67-73 |
| Sucrose stearate 5% | 3.34-4.25 | 66-75 |
| Glycerol stearate 3.3% | 3.05-4.18 | 62-69 |
| Glyceryl monostearate 3.3% | 2.98-3.56 | 69-74 |
| Glyceryl triacetate 3.3% | 2.97-3.28 | 72-77 |
| Ethyl oleate 9% | 1.63-1.95 | 74-80 |
| Isopropyl myristate 9% | 1.54-1.72 | 73-78 |
| Pungent/capric acid glyceryl ester 10% | 1.59-1.84 | 73-77 |
| Stearic acid 3.3% | 2.96-3.54 | 66-68 |
| Brazil wax 2% | 3.13-3.67 | 59-62 |
| Beeswax 2% | 3.33-3.89 | - |
| Hexadecanol 3.3% | 3.67-4.22 | 74-81 |
| Arlacel-80 3.3% | 1.89-2.59 | 77-85 |
| Ergol 2.6% | 0.97-1.26 | 68-74 |
| Dipropylene glycol dibenzoate 3% | 1.0-1.4 | - |
| Azone 3% | 1.12-1.41 | 63-72 |
| Diethylene glycol dibenzoate 3% | 1.1-1.4 | - |
As seen from Table 4, Ergol, azone, dipropylene glycol dibenzoate, diethylene glycol dibenzoate and HEL-
40 are applied in combination, followed by isopropyl myristate, pungent/capric acid three most strong to the resistance inhibitor action of the acid catalyzed degradation of ivermectin
Glyceride and ethyl oleate, other oil medium effects are weaker.
Embodiment 3. prepares the composition containing ivermectin 0.2% with HEL-40 and Ergol
(1) composition and preparation method：The active ingredient of composition is ivermectin described in table 5, and ivermectin is in group
It is 0.22-0.24 grams to close the content in object；Other ingredients are shown in Table 5.Maize cob meal grain size used is between 40-160 mesh sieves hole
Part.By above-mentioned【0018】Extremely【0022】The method of Duan Suoshu prepares NO.1-NO.7.
5. 0.2% ivermectin composition composition of table and content
(2) acid catalyzed degradation is tested
3.00 grams of samples are taken in 25 milliliters of tool plug test tubes, add in 18 milliliters of water, vibrates 5 minutes, adds in 1M hydrochloric acid afterwards
2 milliliters of solution, mixing in 36-37 DEG C of heat preservation to sample time, draw 4 milliliters of reaction solutions and add in 10% sodium hydroxide solution about
0.2 milliliter, mixing adds in 4 ml methanols, and mixing, with 0.45um membrane filtrations, filtered solution is detected with HPLC, records peak area, meter
Calculate MS H2B1A peak areas and H2B1The ratio between a peak areas (%).Result of the test is shown in Table 6.
The acid catalyzed degradation result of the test of 6. composition of table
By table 6 compared with table 1, hence it is evident that find out, using HEL-40 as solubilizer, can not only make the Yi Wei in composition
Rhzomorph has higher dissolution rate in water, and HEL-40 has significant inhibitory action to the acid catalyzed degradation of ivermectin.
Table 6 is also shown, does not contain the composition of Ergol, MS H2B1A and H2B1The peak area ratio (%) of a is containing benzoic acid
2-3 times of benzyl ester composition, it can be seen that, Ergol is used together with HEL-40, can more effectively inhibit acid to Yi Wei
The catalyzing hydrolysis effect of rhzomorph.
(3) base catalysis Degrading experiment
3.00 grams of samples are taken in 25 milliliters of tool plug test tubes, add in 18 milliliters of water, vibrates 5 minutes, adds in 1M hydrogen-oxygens afterwards
Change 2 milliliters of sodium solution, mixing when 20-23 DEG C of processing 2 is small, draws 4 milliliters of reaction solutions, add in 1M hydrochloric acid solutions about 0.4 immediately
Milliliter, mixing add in 4 ml methanols, and mixing, with 0.45um membrane filtrations, filtered solution is detected with HPLC, record peak area, calculate
2- epimers H2B1A peak areas and H2B1The ratio between a peak areas (%).Result of the test is shown in Table 7.
By table 7 as it can be seen that HEL-40 not only has ivermectin good solubilization and to Yi Wei compared with table 3
The acid catalyzed degradation of rhzomorph has significant inhibitory action, equally has to the base catalysis degradation of ivermectin and significantly inhibits to make
With.The detection data of table 7 are also shown, do not contain the composition of Ergol, 2-epimer H2B1A peak areas with
H2B1The ratio (%) of a peak areas is 3-4 times containing Ergol composition, it can be seen that, Ergol and HEL-40
Be applied in combination, can more effectively inhibit catalytic degradation of the alkali to ivermectin, this to extend ivermectin class drug shelf-life
Play important function.
The base catalysis Degrading experiment result of 7. preparation of table
(4) hot test
Composition in 60 DEG C of constant temperature is placed 14 days, is materialsed 3 grams, with 20 ml methanol mechanical shaking extraction 10 minutes, is used
0.22 μm of membrane filtration takes filtrate with HLPC detection MS H2B1a、2-epimer H2B1A (abbreviation 2-epimer in table 8) and H2B1A,
Peak area value is recorded, calculates MS H2B1A peak area values and H2B1A peak area values ratio (%), 2-epimer peak area values with
H2B1A peak area values ratio (%) and the H of 14 days2B1A peak area values and the H of 0 day2B1The ratio (%) of a peak area values.Result of the test
It is shown in Table 8.
8. hot test result of table
As seen from Table 8, sample is handled 14 days in 60 DEG C of constant temperature, the composition 2-epimer H containing Ergol2B1A's
Yield is significantly less than the composition without Ergol.And when Ergol is with HEL-40 ratio differences, 2-
epimer H2B1The yield of a has significant change.
Embodiment 4. prepares composition with HEL-40 and several hydrophobic mediums
Composition is shown in Table 9.Preparation method is by the【0018】Extremely【0022】It is prepared by section the method.Acid catalyzed degradation result of the test
It is shown in Table 10.
Table 9. preparation NO.8, NO.9, NO.10 and NO.11 are formed
| Preparation is numbered | NO.8 | NO.9 | NO.10 | NO.11 |
| Ivermectin g | 0.22 | 0.22 | 0.22 | 0.22 |
| P(40)HCO g | 2.2 | 2.2 | 2.2 | 2.2 |
| Arabic gum g | 3.3 | 3.3 | 3.3 | 3.3 |
| Pungent/capric acid glyceryl ester g | It does not contain | 0.81 | It does not contain | It does not contain |
| Isopropyl myristate g | It does not contain | It does not contain | 0.9 | It does not contain |
| Azone g | 1.1 | It does not contain | It does not contain | It does not contain |
| Soybean oil ml | It does not contain | It does not contain | It does not contain | 0.8 |
| 1,2-PD g | 0.35 | 0.35 | 0.35 | 0.35 |
| Maize cob meal g | 93 | 93.5 | 93 | 93 |
The acid catalyzed degradation result of the test of table 10. preparation NO.8, NO.9, NO.10 and NO.11
By table 10 as it can be seen that the composition containing azone or isopropyl myristate or pungent/capric acid glyceryl ester, MS H2B1a
Peak area and H2B1The ratio between a peak areas (%), much smaller than the composition (NO.11) containing soybean oil.
(3) hot test
Test method is identical with above-mentioned test method.Result of the test is shown in Table 11.
11. hot test result of table
Ivermectin composition containing Arabic gum and its dissolution rate and the acid-catalyzed hydrolysis experiment that embodiment 5. selects
(1) prepare：0.66 gram of ivermectin, 6 grams of HEL-40,2.3 grams of Ergols, 2.1 grams of 1,2-PDs are mixed
It closes, in 60-65 DEG C of stirring and dissolving, is cooled to about 40 DEG C, with 30 milliliters of abundant mixings of aqueous solution containing 20% Arabic gum, add in beautiful
83 grams of rice core powder, stirs and evenly mixs, dries to get M-113.M-113-1 is free of Ergol, other same M-113.
(2) test method：800 milliliters of the hydrochloric acid solution of 0.1M is added in into stripping rotor, is existed in dissolution medium temperature stabilization
At 36-37 DEG C, 40.00 grams of sample is added in, when reaction 3 is small under conditions of 36-37 DEG C, speed of agitator is 49-51r/min.1
Hour, 2 it is small when, 3 it is small when separately sampled 4 milliliters, after sodium hydroxide solution tune PH, add in 4 ml methanols, mixing, with 0.45 μ
M is filtered, and is taken 20 microlitres of filtered solution, is detected with HPLC, records chromatogram peak out, calculates MS H2B1A peak area values and the H of dissolution2B1a
The ratio (%) and H of peak area value2B1The dissolution rate (%) of a.Result of the test is shown in Table 12.
The acid catalyzed degradation result of the test of table 12.M-113 and M-113-1
Its dissolution rate of composition of the embodiment 6. containing different emulsifiers and acid-catalyzed hydrolysis experiment
Composition contains ivermectin 0.2%；1,2-PD 0.5%；Arabic gum 4%；Emulsifier 2%, species is shown in
Table 13；Benzyl Benzoate ester content is shown in Table 13；Maize cob meal of the grain size between 40-100 mesh sieves hole adds to 100 grams.
Emulsifier content and Benzyl Benzoate ester content in 13. composition of table
Dissolution rate and acid-catalyzed hydrolysis test method：The hydrochloric acid solution of 400 milliliters of 0.1M is added in into stripping rotor, is being dissolved out
Medium temperature stabilization adds in 60 grams of sample at 36-37 DEG C, is reacted under the conditions of 36-37 DEG C, speed of agitator is 49-51r/min
3 it is small when.When 1 is small, 2 it is small when, 3 it is small when separately sampled 4 milliliters, with adding in 4 ml methanols after sodium hydroxide solution tune PH, mix
It is even, with 0.45 μm of filtering, 20 microlitres of filtered solution is taken, is detected with HPLC, record chromatogram, calculate MS H2B1a peak areas and dissolution
The ratio (%) of H2B1a peak areas and the dissolution rate (%) of H2B1a.Result of the test is shown in Table 14.
The acid catalyzed degradation result of the test of 14. composition of table and the stripping quantity testing result of H2B1a
Testing result shown in table 14 further demonstrates that：Ergol and different surfaces activating agent combination application, all have
There is resistance inhibitor action of the significant enhancing to acid catalyzed degradation.
The difference of its stability of the composition of 7. material containing different carriers of embodiment
1. prepared by test specimen M-79：1.5 grams of Brijs -35,0.13 gram of monoglyceride, 0.16 gram of PEG-6000 are taken, in 80 DEG C
Melt, add in 0.3 milliliter of the ethyl acetate solution containing 0.061 gram of ivermectin, mixing adds 3 milliliters of water, stirs and evenly mixs, and adds in
PH value is 8.2 grams of the maize cob meal of 6.2-6.4, and abundant mixing, drying at room temperature obtains 10.39 grams of samples (M-79).
The preparation of M-88：It takes 0.8 gram of Brij -35, add in 0.3 milliliter of the ethyl acetate solution containing 0.061 gram of ivermectin,
Mixing adds in 2.7 milliliters of the aqueous solution containing 0.9 gram of Arabic gum, stirs and evenly mixs, and adds in the maize cob meal that pH value is 6.2-6.4
8.2 grams, abundant mixing, drying at room temperature obtains 10.35 grams of M-88.
2. hot test
Accurate to weigh each 3 parts of sample M-79, M-88, sample weighting amount is 1.0000 grams/part, in 25 milliliters of test tubes, after sealing
It is placed in 59-61 DEG C of chamber, constant temperature places 15 days, then with 20 ml methanol mechanical shaking extraction 10 minutes, with 0.22 μm of film mistake
Filter takes filtrate with HLPC detection MS H2B1a、2-epimer H2B1A and H2B1A records peak area, calculates MS H2B1A peak areas
With H2B1A peak area ratios (%), 2-epimer peak areas and H2B1A peak area ratios (%) and the H of 15 days2B1A peak areas and 0
It H2B1A peak area ratios (%).The result is shown in 15.
15. hot test result of table
The data from table 15 are as it can be seen that sample is handled 15 days in 60 DEG C of constant temperature, M-88 sample 2-epimer H2B1The generation of a
Amount, MS H2B1The yield and H of a2B1The degradation amount of a is below M-79.Display is measured, the pH value of M-88 samples is 4.32-
4.46 (results of Arabic gum effect).This result of the test shows that the pH value of carrier material has significantly the stability of preparation
It influences；Arabic gum is the excellent material for preparing this agent.
The preparation of 8. 0.6% ivermectin composition of embodiment and tablet
Take ivermectin, 0.9 gram of Ergol, 3 grams of HEL-35,0.45 gram of 1,2- that 0.66 gram of purity is 90% the third two
Alcohol, 0.03 gram of BHT, 0.005 gram of BHA in 500 milliliters of beakers, dissolve in 75-80 DEG C of stirred in water bath, are cooled to 40 DEG C of left sides
The right side adds in 18 grams of the aqueous solution containing 6 grams of Arabic gum, is sufficiently stirred mixing, then adds in 0.3 gram of vitamin C and 50 grams of corns
Core powder (grain size is between 100-200 mesh sieves hole) after being sufficiently stirred mixing, adds maize cob meal to 100 grams (about 36-37 grams),
It stirs and evenly mixs, it is dry to get 0.6% ivermectin composition that water content is 11-14%.Take said composition and 2 times of weight
Carrier (containing the mixtures such as 50% powdered beef and 50% adhesive, disintegrant, preservative) is uniformly mixed, wet granulation,
Every tablet of dog containing 0.8 milligram of ivermectin, cat anti parasitic tablet are pressed into after screening, drying.Dog, cat fasting state are to this
The active feeding rate of tablet is more than 90%.In vitro test, ivermectin dissolution rate is more than 88%, in 0.1 molar hydrochloric acid solution,
When 37 DEG C of reactions 2 are small, the ratio of MS H2B1a peak areas and H2B1a peak areas is less than 1.5%；40 DEG C are handled 6 months, 2-epimer
Degradation amount of the yield of H2B1a less than 0.3%, H2B1a is less than the 1.8% of primary quantity.
The preparation of rhzomorph composition and tablet is drawn by the department of embodiment 9. 0.4%
0.44 gram 90% of department is taken to draw rhzomorph, 1.7 grams of azones, 4 grams of HEL-40, in 500 milliliters of beakers, at 75-80 DEG C
Stirred in water bath dissolves, and is cooled to 40 DEG C or so, adds in 30 grams of the aqueous solution containing 8 grams of Arabic gum, is sufficiently stirred mixing, then
Add 50 grams of maize cob meal (between 100-200 mesh sieves hole), stir and evenly mix, add in digested tankage pine (grain size 30-80 mesh sieves hole it
Between) 36 grams, it is sufficiently stirred dry after mixing, obtains the department that water content is 10-12% and draw rhzomorph composition.Said composition is taken with waiting weight
The carrier (containing the mixtures such as 50% digested tankage pine and 50% adhesive, disintegrant, preservative) of amount is uniformly mixed, wet method system
Grain is pressed into every and draws the dog of rhzomorph, cat anti parasitic tablet containing 0.8 milligram of department after screening, drying.Dog, cat fasting state
90% is more than to the active feeding rate of the tablet.In vitro test, department draw rhzomorph dissolution rate to be more than 79%, and 40 DEG C are handled 6 months, drop
Solution amount is less than the 1.2% of primary quantity.This product is disposably fed, per kilogram of body weight takes this product 1/ for dog, cat preventing and treating verminosis
2-1 pieces, monthly.
The preparation of 10. 0.4% emamection benaoate pulvis of embodiment and tablet
Take the emamection benaoate, 0.8 gram of azone, 2.2 grams of HEL-40,0.2 that 0.44 gram of purity is 90%
Gram 1,2-PD in 500 milliliters of beakers, is dissolved in 70-80 DEG C of stirred in water bath, when being cooled to 35-40 DEG C, add in containing Ah
Primary 2 grams of glue, 30 grams of the aqueous solution of 6 grams of polyvinylpyrrolidone are drawn, is sufficiently stirred into emulsion, adds in 88 grams of maize cob meal (grains
Footpath is between 100-200 mesh sieves hole), abundant mixing in 25-35 DEG C of drying, obtains emamection benaoate/corncob
Powder drug-carried fine particle.60 grams of powdered beef is taken, with drug-carried fine particle mixing to get emamection benaoate pulvis.This agent is used
In dog, cat preventing and treating verminosis, per kilogram of body weight feeds 0.1-0.2 grams of this product, monthly feeds once, and active feeding rate is almost
100%, control effect is outstanding.This product is taken by equivalent and containing 50% powdered beef and 50% adhesive, disintegrant, preservative
Mixture be uniformly mixed, pelletize, screening, it is dry after be pressed into tablet.Dog, cat fasting state are big to the active feeding rate of the tablet
In 96%.In vitro test, dissolution rate are more than 83%, and 40 DEG C are handled 6 months, and degradation amount is less than the 2.4% of primary quantity.
It is prepared by 11. 0.3% doractin composition of embodiment and tablet
Take doractin, 2 grams of Ergols, 2.4 grams of HEL-60,0.35 gram of 1,2- that 0.33 gram of purity is 90% the third two
Alcohol in 500 milliliters of beakers, is dissolved in 70-80 DEG C of stirred in water bath, when being cooled to 35-40 DEG C, is added in containing Arabic gum 3.3
Gram, 13 grams of the aqueous solution of 3 grams of polyvinylpyrrolidone, be sufficiently stirred into emulsion, adding in 50 grams of maize cob meals, (grain size is in 40-
Between 160 mesh sieve holes), then abundant mixing adds maize cob meal to 100%, dry to get 0.3% doractin composition.
This composition is used for pig preventing and treating verminosis, and feed per ton adds 0.66 kilogram of this product, even feeds 7 days, is monthly fed once to pig,
100% is almost to the net rate of the drive of Sarcoptes suis and nematode.Although this product does not add in antioxidant, room temperature stores 2 years, effectively
The degradation rate of component is only the 0.86-1.24% of labelled amount, much smaller than commercial product.
It is prepared by 12. 0.25% ivermectin of embodiment, 10% Albendazole's composition and tablet
Take the ivermectin, 1.7 grams of Ergols, 3.25 grams of HEL-40,0.35 gram 1,2- that 0.27 gram of purity is 90%
Propylene glycol, in 500 milliliters of beakers, in 80-85 DEG C of water-bath, stirring and dissolving when being cooled to 35-50 DEG C, is added in containing Arab
30 grams of the aqueous solution that 8 grams of glue, is stirred well into emulsus, and 60 grams of maize cob meals are added in into lotion, and (grain size is in 80-160 mesh sieves
Between hole) and 10 grams of Albendazoles, mixing is sufficiently stirred, adds in maize cob meal (grain size is between 100-200 mesh sieves hole) to 100
Gram, it is dry to get 0.25% ivermectin, 10% Albendazole's composition.The carrier of said composition and 2 times of weight is taken (to contain
The mixtures such as 60% hepar siccatum and 40% adhesive, disintegrant, preservative) it is uniformly mixed, granulation, it is suppressed after screening, drying
In flakes.Dog, cat fasting state are more than 88% to the active feeding rate of the tablet.In vitro test, ivermectin dissolution rate are more than
90%, 40 DEG C are handled 6 months, and ivermectin degradation amount is less than the 0.89% of primary quantity.
It is prepared by 13. 0.2% ivermectin of embodiment, 5% albendazole oxide composition and tablet
Take ivermectin, 1.3 grams of Ergols, 4 grams of HEL-40,0.4 gram of 1,2- that 0.22 gram of purity is 90% the third two
Alcohol in 500 milliliters of beakers, is dissolved in 80-85 DEG C of stirred in water bath, when being cooled to 35-50 DEG C, is added in containing 4 grams of Arabic gum
16 grams of aqueous solution, be stirred well into emulsion, added in into lotion 50 grams of maize cob meals (grain size 60-160 mesh sieves hole it
Between) and 5 grams of albendazole oxides, mixing is sufficiently stirred, adds in maize cob meal (grain size is between 100-200 mesh sieves hole) to 100 grams,
Drying is to get 0.2% ivermectin, 5% albendazole oxide composition.Take said composition with etc. the carriers of weight (contain 60%
Hepar siccatum and the mixtures such as 50% adhesive, disintegrant, preservative) be uniformly mixed, granulation, screening, it is dry after it is tabletted.
Dog, cat fasting state are more than 92% to the active feeding rate of the tablet.In vitro test, ivermectin dissolution rate are more than 88%, 40
DEG C processing 6 months, ivermectin degradation amount be less than primary quantity 1.1%.
Embodiment 14. prepares 0.2% abamectin composition
Take the avermectin, 1.4 grams of Ergols, 2.2 grams of HEL-40,0.35 gram of 1,2- third that 0.22 gram of purity is 90%
Glycol in 500 milliliters of beakers, is dissolved in 70-80 DEG C of stirred in water bath, when being cooled to 35-50 DEG C, is added in containing Arabic gum 4
Gram, 13 grams of the aqueous solution of 1 gram of polyvinylpyrrolidone, be sufficiently stirred into emulsion, adding in 50 grams of maize cob meals, (grain size is in 40-
Between 160 mesh sieve holes), then abundant mixing adds maize cob meal to 100%, dry to get 0.2% abamectin composition.
Although this composition does not add in antioxidant, room temperature is stored 2 years, and the degradation rate of active principle is only the 1.82- of labelled amount
2.42%.Commercially available 1% avermectin powder is placed 1 year in similarity condition, and the degradation rate of avermectin has reached labelled amount
11-14% has not met the requirement of quality standard.Avermectin bulk pharmaceutical chemicals are placed at room temperature for 1 year its degradation rate and have also exceeded 10%,
And the thinner degradation of particle is more.
Embodiment 15. prepares 0.2% moxidectin composition
By 0.22 gram of moxidectin, 1.1 grams of Ergols, 2.2 grams of HEL-40,0.35 gram of 1,2-PD, in 500 millis
It rises in beaker, is dissolved in 70-80 DEG C of stirred in water bath, when being cooled to 35-50 DEG C, added in containing 4 grams of Arabic gum, polyvinyl pyrrole
13 grams of the aqueous solution that 1 gram of alkanone, is sufficiently stirred into emulsion, add in 50 grams of maize cob meals (grain size 40-160 mesh sieves hole it
Between), then abundant mixing adds maize cob meal to 100%, dry to get 0.2% moxidectin composition.Though this composition
So without adding in antioxidant, but room temperature is stored 2 years, and the degradation rate of active principle is only the 1.35-1.68% of labelled amount.This group
Closing object can be used as pulvis or pre-mixing agent directly to use, and also can prepare piece agent or other dosage forms with auxiliary material combination.
Embodiment 16. prepares 0.02% ivermectin composition
The ivermectin, 0.4 gram of azone, 0.44 gram of HEL-40,0.2 gram of 1,2-PD that 0.022 gram of purity is 90% are taken,
It in 500 milliliters of beakers, is dissolved in 70-80 DEG C of stirred in water bath, when being cooled to 35-40 DEG C, adds in containing 1 gram of Arabic gum, gathers
4 grams of the aqueous solution that 0.5 gram of vinylpyrrolidone is sufficiently stirred into emulsion, and adding in 20 grams of maize cob meals, (grain size is in 100-200
Between mesh sieve hole), abundant mixing in 25-40 DEG C of drying, obtains ivermectin/maize cob meal drug-carried fine particle.Weigh powdered beef 77
Gram, with drug-carried fine particle mixing to get 0.02% ivermectin powder.This agent is fed for dog, cat preventing and treating verminosis, per kilogram of body weight
1 gram of this product is taken, is monthly fed once, active feeding rate is almost 100%, and control effect is outstanding.Although this product does not add in anti-
Oxidant, but room temperature is stored 2 years, the degradation rate of active principle are only the 1.13-1.28% of labelled amount, 2-epimer H2B1a with
The ratio that the ratio of H2B1a is less than 0.2%, MS H2B1a and H2B1a is less than 0.6%, much smaller than commercial product.
It is prepared by 17. 0.4% ivermectin composition of embodiment
Take 0.44 gram 90% ivermectin, 2 grams of azones, 4.4 grams of HEL-40,0.62 gram of citric acid, 5 grams of poly- second two
Alcohol -10000,5 grams of polyvinylpyrrolidones and 10 milliliters of ethyl alcohol in 500ml beakers, are dissolved in 70-75 DEG C of stirred in water bath,
50 grams of maize cob meals (grain size is between 30-100 mesh sieves hole) are added in, stirs and evenly mixs, dries and removes ethyl alcohol, add maize cob meal extremely
100 grams, mixing obtains ivermectin composition.
Embodiment 18. prepares 0.2% ivermectin and 0.6% cyromazine composition
Composition：2.2 grams of ivermectin, 6.6 grams of cyromazine, 68 grams of Arabic gum, (40) 28 grams of HEL-, Ergol
8 grams, 1 gram of BHA, 0.36 gram of PG, maize cob meal adds to 1 kilogram.
Preparation method：A. Arabic gum with water is mixed, is prepared into the aqueous solution of 30% Arabic gum, it is spare；B. by her
Rhzomorph, HEL- (40), Ergol, BHA, PG mixing are tieed up, is stirred under the conditions of 60-75 DEG C, dissolves drug, be made containing her
Tie up the liquid of rhzomorph；C. by the liquid containing ivermectin under agitation with step a made from contain 30% Arabic gum water
Solution mixes, and is sufficiently stirred, is prepared into slightly sticky emulsion；D. the emulsion prepared by step c and maize cob meal and ring third
Ammonia piperazine mixes, and stirs evenly, and in 40-60 DEG C of drying, crosses 30 mesh sieves, the composition is made.
19. 0.2% ivermectin of embodiment and 0.6% cyromazine composition
Composition：2.2 grams of ivermectin, 6.6 grams of cyromazine, 44 grams of Arabic gum, (40) 26 grams of HEL-, Ergol
15 grams, 80 grams of glycerin monostearate, 1 gram of BHA, 0.36 gram of PG, maize cob meal adds to 1 kilogram.
Preparation method：A. Arabic gum with water is mixed, is prepared into the aqueous solution of 20% Arabic gum, it is spare.B. by her
Rhzomorph, HEL- (40), Ergol mixing are tieed up, is stirred under the conditions of 60-75 DEG C, dissolves drug, be made containing ivermectin
Liquid.C. by the liquid containing ivermectin under agitation with step a made from mix containing the aqueous solution of 20% Arabic gum
It closes, is sufficiently stirred, is prepared into sticky emulsion；D. the step c emulsion prepared with maize cob meal is mixed, stirred evenly,
It is dry, 30 mesh sieves are crossed, is made and carries medicine particle；E., glycerin monostearate stirs to thawing under the conditions of 60-75 DEG C, add in BHA,
PG, medicine particle and cyromazine are carried, is stirred and evenly mixed under the conditions of 60-75 DEG C, cooled down, obtain the composition.
20. 0.2% ivermectin of embodiment and 0.6% cyromazine composition
Composition：2.2 grams of ivermectins, 6.6 grams of cyromazines, 44 grams of Arabic gums, 26 grams of HEL- (40), 15 grams of azones,
80 grams of PEG-6000,1 gram of BHA, 0.36 gram of PG, maize cob meal add to 1 kilogram.
Preparation method：A. Arabic gum with water is mixed, is prepared into the aqueous solution of 20% Arabic gum, it is spare.B. by her
Rhzomorph, HEL- (40), Ergol, PEG-6000, BHA, PG mixing are tieed up, is stirred under the conditions of 65-80 DEG C, makes drug molten
The liquid containing ivermectin is made in solution.C. the liquid containing ivermectin is made under 70-75 DEG C and stirring condition with step a
Containing 20% Arabic gum aqueous solution mixing, be sufficiently stirred, be prepared into sticky emulsion；D. the emulsus prepared by step c
Liquid is stirred evenly with maize cob meal and cyromazine under the conditions of 65-80 DEG C, is down to room temperature, dry, crosses 30 mesh sieves, is made described
Composition.
21 embodiment 18 of embodiment, embodiment 19, the dissolution rate of embodiment 20 and stability test
(1) Dissolution Rate Testing：Each 3 grams of the composition of Example 18,19,20 is mixed with 20 milliliters of water respectively, in 36-37
DEG C vibration extraction 25 minutes, with 0.45 micron of membrane filtration, takes filtrate to be measured with HPLC, is measured in the same method reference substance solution, record color
Spectrogram calculates the dissolution rate of ivermectin with external standard method.The results show：The dissolution rate of embodiment 18,19,20 is respectively 87-
92%th, 78-83%, 92-94%.
(2) stability test one：Respectively each 3 grams of the composition of Example 18,19,20 and 20 milliliter of 0.1 mole hydrochloride/
Aqueous solution mixes, and when 36-37 DEG C of oscillating reactions 3 is small, with 0.45 micron of membrane filtration after tune PH, filtrate is taken to be measured with HPLC, remembered
Chromatogram is recorded, calculates MS H2B1A peak area values and H2B1The ratio (%) of a peak area values.The results show：Embodiment 18,19,20
Ratio be respectively 1.78-2.01%, 1.51-1.85%, 1.56-1.95%.
(3) stability test two：It is measured after the composition of embodiment 18,19,20 is handled 6 months in 40 DEG C with HPLC,
Chromatogram is recorded, calculates 2-epimer H2B1A peak areas and H2B1The ratio (%) and H of a peak areas2B1Degradation rate (the degradation of a
Amount accounts for the percentage of primary quantity).The results show：The ratio of embodiment 18,19,20 is respectively 0.08-0.17%, 0.11-
0.24%th, 0.13-0.32%；Ivermectin degradation rate is respectively 0.29-0.42%, 0.22-0.38%, 0.31-0.36%.
More than result of the test shows that the composition dissolution rate of embodiment 18,19,20 is high and stability is good.
Claims (9)
1. a kind of Orally-administered solid composition containing anti-parasite medicine of stabilization, the composition includes following each component：
A includes 0.1-10 grams of anti-parasite medicine in every 1 kilogram of composition；The anti-parasite medicine includes AVM hereinafter
Rhzomorph, emamection benaoate, Eprinomectin, ivermectin, doractin, moxidectin, department draw
One kind in rhzomorph；
B in every 1 kilogram of composition comprising 1.5-100 grams of solid dispersion medium, the solid dispersion medium include Ah
Draw primary glue or polyvinylpyrrolidone or Arabic gum and one or both of polyvinylpyrrolidone or acrylic resin with
On；
C is more than or equal to 12 nonionic surfactant comprising hydrophilic lipophilic balance in the composition, in the composition
Its content is 3-20 times of the anti-parasite medicine weight, and content is no more than the 20% of composition weight；
D in composition described in per kilogram is added without or adds in 0.2-5 grams of antioxidant, and the antioxidant includes dibutyl hydroxy
It is more than one or both of toluene, tertiary butyl-4-hydroxy anisole, propylgallate, vitamin C；
E is added without or adds in 2-10 grams of 1,2-PD in composition described in per kilogram；
F in composition described in per kilogram is added without or adds in hydrophobic medium, and the hydrophobic medium includes Benzyl Benzoate
Ester, pungent/capric acid glyceryl ester, isopropyl myristate, azone, dipropylene glycol dibenzoate, diethylene glycol dibenzoate,
It is more than one or both of ethyl oleate；The content of hydrophobic medium in the composition is the nonionic surfactant
The 10-110% of weight；
G carrier materials add to 1 kilogram；The carrier material include maize cob meal, zeolite powder, mountain flour, diatomite, land plaster,
It is more than one or both of starch, fish meal, powdered beef, pork liver powder, chicken liver meal, dried meat floss.
2. by composition described in claim 1, it is characterised in that the hydrophilic lipophilic balance more than or equal to 12 it is non-from
Sub- surfactant includes Tweens, sells damp class, brejs, peregal, Crodaret condensation product, polyoxyethylene
Castor oil condensation product, polyethylene glycol vegetable oil condensation product.
3. by composition described in claim 1, it is characterised in that the hydrophilic lipophilic balance more than or equal to 12 it is non-from
Sub- surfactant includes polyoxyethylene (35) castor oil, polyoxyethylene (40) castor oil, polyoxyethylene (90) castor oil, polyoxy
Ethylene (35) rilanit special, polyoxyethylene (40) rilanit special, polyoxyethylene (50) rilanit special, polyoxyethylene (60)
Rilanit special, polyethylene glycol (40) palm-kernel oil, polyethylene glycol (60) corn oil, polyethylene glycol (60) corn oil glyceride,
The Brij58 of polyethylene glycol (60) apricot kernel oil, polyethylene glycol (50) castor oil, hydrophilic lipophilic balance more than 12,
It is more than one or both of polyethylene glycol stearate SG-40, SG-100, Brij -35.
4. by composition described in claim 1, it is characterised in that other comprising 1-100 grams in the per kilogram composition
Anti-parasite medicine, other anti-parasite medicines include diclazuril, toltrazuril, albendazole, oxide,
In Phenbendasol, oxfendazole, febantel, praziquantel, niclosamidum, Pyrantel, insect growth regulator, IGR
One or more；The insect growth regulator, IGR includes cyromazine, fenoxycarb, hydroprene, cloves are led to, alkene worm
Ester, pyrrole phenylate, chlorfluazuron, diflubenzuron, flucycloxuron, flufenoxuron, flubenzuron, lufenuron, tebufenozide, fluorobenzene urea, triflumuron.
5. by composition described in claim 1, it is characterised in that the composition preparation comprises the following steps：
A. Arabic gum or/and polyvinylpyrrolidone with water are mixed, is prepared into the Arabic gum containing 5-30% or/and poly- second
Alkene pyrrolidone aqueous solution, it is spare；
B. the nonionic surfactant of ivermectin class drug and hydrophilic lipophilic balance more than or equal to 12 is mixed, add in or
1,2-PD is added without, adds in or be added without the hydrophobic medium, the antioxidant is added in or be added without, in room
It is stirred under temperature or heating condition, dissolves drug, the thick liquid of the drug of class containing ivermectin is made；
C. under agitation, the thick liquid of the drug of class containing ivermectin with the aqueous solution described in step a is mixed, fully stirred
It mixes or is handled with high-speed shearing machine, be prepared into sticky emulsion；
D. emulsion prepared by step c is uniformly mixed with the carrier material, it is dry to get the composition.
6. by composition described in claim 1, it is characterised in that the composition includes following preparation process：
Polyvinylpyrrolidone or/and acrylic resin ethyl alcohol or 95% ethyl alcohol are dissolved, are prepared into polyvinylpyrrolidone
Or/and the ethanol solution of acrylic resin；Yi Wei is added in into the ethanol solution of polyvinylpyrrolidone or/and acrylic resin
Bacteriums drug, nonionic surfactant and 1,2-PD add in or are not added with hydrophobic medium, add or are not added with anti-oxidant
Agent stirs under room temperature or heating condition, makes complete drug dissolution, and slightly sticky drug solution is made；Drug solution is being stirred
It is uniformly mixed under the conditions of mixing with maize cob meal, through drying and removing ethyl alcohol, the composition is made.
7. by composition described in claim 1, it is characterised in that include 3-10 grams of cyromazine in per kilogram composition.
8. the composition as described in claim 7, it is characterised in that following each component is included in per kilogram composition：
3-10 grams of 1-3 grams of a ivermectins and cyromazine；
30-100 grams of b Arabic gums；
10-80 grams of c polyoxyethylene (40) rilanit special；
3-35 grams of d Ergols；
0.6-1.2 grams of e tertiary butyl-4-hydroxies anisole；
0.18-0.36 grams of f propylgallates；
G maize cob meals add to 1 kilogram.
9. the composition as described in claim 8, it is characterised in that the preparation of the composition comprises the following steps：
A mixes Arabic gum with water, is prepared into 5-30% Arabic gum aqueous solutions, spare；
B is by ivermectin, polyoxyethylene (40) rilanit special, Ergol, tertiary butyl-4-hydroxy anisole, nutgall
Propyl propionate mixes, and under room temperature or heating condition, stirring dissolves drug, and the thick liquid containing ivermectin is made；
C by the thick liquid containing ivermectin under agitation with step a made from Arabic gum aqueous solution mix, stirring or
It is handled with high-speed shearing machine, is prepared into sticky emulsion；
The step c emulsion prepared is uniformly mixed by d with maize cob meal and cyromazine, dry, and the composition is made.
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| CN2016110107396 | 2016-11-17 | ||
| CN201611010739 | 2016-11-17 |
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| CN107028892A (en) * | 2017-04-25 | 2017-08-11 | 北京中农华威生物医药研究院 | A kind of composition of the medicine of class containing ivermectin of stabilization |
| CN108552196A (en) * | 2018-06-01 | 2018-09-21 | 广东中迅农科股份有限公司 | A kind of Pesticidal combination containing Ivermectin HCL and cyromazine |
| EP3578181A1 (en) * | 2018-06-05 | 2019-12-11 | Bayer Animal Health GmbH | Formulation for use in the simultaneous treatment of coccidial infections and iron deficiencies |
| RU2828711C2 (en) * | 2018-06-05 | 2024-10-16 | Байер Энимал Хелс Гмбх | Composition for use for simultaneous treatment of coccidial infections and iron deficiency anemias |
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