CN106361758B - A kind of compound ivermectin praziquantel two-arch tunnel emulsion and preparation method thereof - Google Patents
A kind of compound ivermectin praziquantel two-arch tunnel emulsion and preparation method thereof Download PDFInfo
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- CN106361758B CN106361758B CN201610773785.5A CN201610773785A CN106361758B CN 106361758 B CN106361758 B CN 106361758B CN 201610773785 A CN201610773785 A CN 201610773785A CN 106361758 B CN106361758 B CN 106361758B
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- praziquantel
- emulsion
- ivermectin
- arch tunnel
- emulsifier
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- FSVJFNAIGNNGKK-UHFFFAOYSA-N 2-[cyclohexyl(oxo)methyl]-3,6,7,11b-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4-one Chemical compound C1C(C2=CC=CC=C2CC2)N2C(=O)CN1C(=O)C1CCCCC1 FSVJFNAIGNNGKK-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 229960002957 praziquantel Drugs 0.000 title claims abstract description 38
- AZSNMRSAGSSBNP-UHFFFAOYSA-N 22,23-dihydroavermectin B1a Natural products C1CC(C)C(C(C)CC)OC21OC(CC=C(C)C(OC1OC(C)C(OC3OC(C)C(O)C(OC)C3)C(OC)C1)C(C)C=CC=C1C3(C(C(=O)O4)C=C(C)C(O)C3OC1)O)CC4C2 AZSNMRSAGSSBNP-UHFFFAOYSA-N 0.000 title claims abstract description 37
- SPBDXSGPUHCETR-JFUDTMANSA-N 8883yp2r6d Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O[C@@H]([C@@H](C)CC4)C(C)C)O3)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1C[C@H](C)[C@@H]([C@@H](C)CC)O[C@@]21O[C@H](C\C=C(C)\[C@@H](O[C@@H]1O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C1)[C@@H](C)\C=C\C=C/1[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\1)O)C[C@H]4C2 SPBDXSGPUHCETR-JFUDTMANSA-N 0.000 title claims abstract description 37
- 229960002418 ivermectin Drugs 0.000 title claims abstract description 37
- 239000000839 emulsion Substances 0.000 title claims abstract description 33
- 150000001875 compounds Chemical class 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000004945 emulsification Methods 0.000 title description 3
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000006184 cosolvent Substances 0.000 claims abstract description 13
- 239000008367 deionised water Substances 0.000 claims abstract description 12
- 229910021641 deionized water Inorganic materials 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 11
- RNIWSOXRCLEXPV-UHFFFAOYSA-N 2,2-dichlorotetradecanal Chemical compound CCCCCCCCCCCCC(Cl)(Cl)C=O RNIWSOXRCLEXPV-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims description 11
- 239000007924 injection Substances 0.000 claims description 10
- 238000002347 injection Methods 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000003921 oil Substances 0.000 claims description 4
- 239000004094 surface-active agent Substances 0.000 claims description 4
- -1 alkenyl urea Chemical compound 0.000 claims description 3
- 239000004202 carbamide Substances 0.000 claims description 3
- 239000012467 final product Substances 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 235000019198 oils Nutrition 0.000 claims description 3
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims description 2
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 claims description 2
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 claims description 2
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 2
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims description 2
- 229940093471 ethyl oleate Drugs 0.000 claims description 2
- 235000011187 glycerol Nutrition 0.000 claims description 2
- 229940113115 polyethylene glycol 200 Drugs 0.000 claims description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 2
- 229920000053 polysorbate 80 Polymers 0.000 claims description 2
- 235000012424 soybean oil Nutrition 0.000 claims description 2
- 239000003549 soybean oil Substances 0.000 claims description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims 2
- 229960005150 glycerol Drugs 0.000 claims 1
- 229960004063 propylene glycol Drugs 0.000 claims 1
- 239000003651 drinking water Substances 0.000 abstract description 5
- 235000020188 drinking water Nutrition 0.000 abstract description 5
- 238000001228 spectrum Methods 0.000 abstract description 5
- 241000607479 Yersinia pestis Species 0.000 abstract description 4
- 238000010790 dilution Methods 0.000 abstract description 4
- 239000012895 dilution Substances 0.000 abstract description 4
- 230000008569 process Effects 0.000 abstract description 3
- 238000006243 chemical reaction Methods 0.000 abstract description 2
- 239000003814 drug Substances 0.000 description 20
- 229940079593 drug Drugs 0.000 description 18
- 230000000694 effects Effects 0.000 description 11
- 244000000013 helminth Species 0.000 description 11
- 238000012360 testing method Methods 0.000 description 9
- 108010034145 Helminth Proteins Proteins 0.000 description 8
- 241000238631 Hexapoda Species 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 241000244206 Nematoda Species 0.000 description 6
- 238000010171 animal model Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 244000144972 livestock Species 0.000 description 6
- 244000045947 parasite Species 0.000 description 6
- 244000144977 poultry Species 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 241000283973 Oryctolagus cuniculus Species 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 241000242722 Cestoda Species 0.000 description 4
- 241000935974 Paralichthys dentatus Species 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- 235000006226 Areca catechu Nutrition 0.000 description 2
- 244000080767 Areca catechu Species 0.000 description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 2
- 108010062745 Chloride Channels Proteins 0.000 description 2
- 102000011045 Chloride Channels Human genes 0.000 description 2
- 208000003322 Coinfection Diseases 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- 206010021703 Indifference Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 208000030852 Parasitic disease Diseases 0.000 description 2
- 241001442514 Schistosomatidae Species 0.000 description 2
- 206010041415 Spastic paralysis Diseases 0.000 description 2
- 241000242541 Trematoda Species 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 238000009395 breeding Methods 0.000 description 2
- 230000001488 breeding effect Effects 0.000 description 2
- 229910001424 calcium ion Inorganic materials 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000010220 ion permeability Effects 0.000 description 2
- 230000002147 killing effect Effects 0.000 description 2
- 231100000518 lethal Toxicity 0.000 description 2
- 230000001665 lethal effect Effects 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- 230000035764 nutrition Effects 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 239000005660 Abamectin Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000034657 Convalescence Diseases 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- 241000283977 Oryctolagus Species 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 206010036590 Premature baby Diseases 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 206010039509 Scab Diseases 0.000 description 1
- 230000000507 anthelmentic effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000002242 deionisation method Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000000635 electron micrograph Methods 0.000 description 1
- 244000079386 endoparasite Species 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000033065 inborn errors of immunity Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000749 insecticidal effect Effects 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001069 nematicidal effect Effects 0.000 description 1
- 239000005645 nematicide Substances 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000000050 nutritive effect Effects 0.000 description 1
- 230000003071 parasitic effect Effects 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 208000028529 primary immunodeficiency disease Diseases 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000009781 safety test method Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
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- Health & Medical Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
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- Dispersion Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A kind of compound ivermectin praziquantel two-arch tunnel emulsion, the weight of every 100g emulsion forms are as follows: 0.1~2g of ivermectin, 0.1~25g of praziquantel, 0.01~3g of Arecoline hydrobromide, 1~10g of solvent naphtha, 0.1~5g of cosolvent, 20~30g of emulsifier, 10~20g of assistant for emulsifying agent, surplus are deionized water.Emulsion prepared by the present invention, pest-resistant spectrum is wide, significant in efficacy, can both be used with injecting after oil dilution when use, drinking water or injecting after can also being diluted with water uses, according to clinical concrete condition flexible choice.The present invention further discloses preparation method simultaneously, and process operability is strong, is conducive to conversion.
Description
Technical field
The invention belongs to veterinary medicine technical fields, and in particular to a kind of compound ivermectin praziquantel two-arch tunnel emulsion
And preparation method thereof.
Background technique
Animal parasitosis is common transmittable disease during livestock and poultry cultivation, and wherein nematode, tapeworm, fluke and insects are parasitic
Worm incidence rate almost accounts for 80% or more, is veterinary clinic common disease and frequently-occurring disease.After livestock and poultry infect helminth, polypide is in host
Breeding in vivo, development, absorb animal endotrophic, and the nutrition that animal eats is utilized by helminth, and appearance is thin, and nutrition is not
It is good, seriously affect Production of Livestock and Poultry level.Some insects helminths can also cause part other than causing raising poultry nutritive bad
It festers, bleeding, serious secondary infection, and other epidemic diseases can be broken out, seriously threaten livestock birds health.
For the generation of prevention and control parasitic disease, need periodically to carry out expelling parasite to animal in production, health expelling parasite needs wide
The anthelmintic of spectrum, but the drug that few all types helminths are all killed at present.Therefore, generally mostly cooperated using several drugs
Use, such as drive nematode, the ivermectin of insect and the praziquantel of expelling tenia, fluke are used cooperatively, curative effect highly significant and when
Under a kind of popular expelling parasite scheme.
Ivermectin belongs to Avermectins nematocide, mainly enhancing invertebrate nerve synapse caudacoria to chlorine from
The permeability of son finally makes the neural paralysis of polypide and lethal so that block nerves signal transmits.Insecticidal action mainly passes through two
Different approach is planted to enhance neu to chloride ion permeability, one is inhibiting by enhancing invertebrate peripheral nerve
The release of neurotransmitter GABA；The second is causing the chloride channel controlled by glutamic acid open.Since mammal does not have
The chloride channel of glutamic acid control, therefore mammal is used comparatively safe.Ivermectin is to nematode, insects helminth
With efficiently killing effect, and dosage is seldom, and per kilogram of body weight about 2~3mg can reach ideal effect.
Praziquantel is clinically common expelling tenia, Trematoda drug, and appearance is white or off-white powder, and bitter, which has, to be drawn
It is moist.After taking, blood fluke in host can be made to generate spastic paralysis and fall off, and migrate to liver.To most of tapeworms
Adult and prematurity polypide are effective, in addition minimum to animal toxicity, are highly desirable drugs.Its pest-resistant mechanism is to blood fluke
There is the effect of 5-TH sample, causes polypide spastic paralysis；Polypide sarcoplasm film can be influenced to calcium ion permeability simultaneously, be calcium ion
Interior stream increases, and keeps polypide dead.Praziquantel toxicity is also very low, and application is safe.
Currently, praziquantel dosage form is concentrated mainly on tablet, pulvis, liquid preparation is fewer, has in document to liquid dosage form
The report of research, but universal drugloading rate is not high, and clinically the compound praziquantel liquid preparation of high-content is in great demand, Yi Wei
Though rhzomorph has liquid preparation, single use is only effective to nematode and insects helminth, if being able to cooperate anti-tapeworm and fluke
Praziquantel use, a drug, a variety of polypides all kill, certainly will have a wide range of applications.
For above situation, need one kind that can compound ivermectin praziquantel together in the market, and stability is strong,
Drugloading rate high liquid preparation is covered the shortage.
Summary of the invention
The purpose of the present invention is to provide a kind of compound ivermectin praziquantel two-arch tunnel emulsions, while providing its preparation
Method is another goal of the invention of the invention.
Based on above-mentioned purpose, the present invention is adopted the following technical scheme that: a kind of compound ivermectin praziquantel two-arch tunnel cream
Agent, the weight composition of every 100g emulsion are as follows: 0.1~2g of ivermectin, 0.1~25g of praziquantel, Arecoline hydrobromide 0.01~
3g, 1.0~10g of solvent naphtha, 0.1~5g of cosolvent, 20~30g of emulsifier, 10~20g of assistant for emulsifying agent, surplus are deionized water.
Preferably, the weight composition of every 100g emulsion are as follows: 0.5~1g of ivermectin, 5~20g of praziquantel, hydrobromic acid betel nut
1.0~2g of alkali, 3~8g of solvent naphtha, 2~4g of cosolvent, 23~28g of emulsifier, 12~18g of assistant for emulsifying agent, surplus are deionization
Water.
Preferably, the weight composition of every 100g emulsion are as follows: ivermectin 1g, praziquantel 15g, Arecoline hydrobromide 1.5g,
Solvent naphtha 6g, cosolvent 3g, emulsifier 25g, assistant for emulsifying agent 15g, surplus are deionized water.
Preferably, the solvent naphtha is ethyl acetate, in isopropyl myristate, injection soybean oil, ethyl oleate
One or two kinds of mixtures.
Preferably, the cosolvent is N, N- dimethyl propylene alkenyl urea.
Preferably, the emulsifier be one of Tween-81, Tween-40, Tween-80 in Arlacel-80, Arlacel-85
A kind of compounding after mixed surfactant.
Preferably, the assistant for emulsifying agent be dehydrated alcohol, 1,2-PD, polyethylene glycol 200 or glycerine one kind or
Two kinds of mixtures.
Preferably, the deionized water is sterile deionized water.
The preparation method of the compound ivermectin praziquantel two-arch tunnel emulsion, comprising the following steps: (a) is first by her
Dimension rhzomorph, praziquantel are mixed with solvent naphtha, sequentially add cosolvent, emulsifier mixes to obtain system 1；(b) by Arecoline hydrobromide
It is dissolved in deionized water, assistant for emulsifying agent mixing is added, obtains system 2；(c) system 1 is heated to 60~80 DEG C, delayed at this temperature
Slow that system 2 is added, stirring while adding, system is by dilute retrogradation, after system 2 is added completely into, continue to stir and maintain temperature 60~
80 DEG C of at least 30min, stop stirring later, and standing is cooled to room temperature to obtain the final product.
Reasonable recipe of the present invention has pest-resistant spectrum width, Nemata, tapeworms, suction for livestock and poultry inside and outside parasitic treatments
Insects and insects helminth kill effect, and use is safe, curative for effect.
The non-oil-in-water type of emulsion feature prepared by the present invention nor water-in-oil type, but the bicontinuous that grease dissolves each other, face
Bed in use, can with oil dilution after injection, after can also being diluted with water drinking-water or injection, can according to clinic need with
Machine strain.
In prescription of the present invention, each component is in the effect wherein played are as follows:
1) ivermectin, praziquantel and the Arecoline hydrobromide selected are directed to Nemata as pharmaceutical composition, ivermectin
It is very strong that effect is killed with insects helminth, and praziquantel kills effect ideal, hydrobromic acid betel nut to tapeworms and Trematoda
Alkali can assist killing helminth, and prescription expelling parasite spectrum is wide, and especially to the regular expelling parasite health care of livestock and poultry, clinical effectiveness is significant；
2) present invention selection Tweens and spans surfactant are used cooperatively, and are because both surfactants are matched
Under conjunction, it is especially advantageous for forming stable two-arch tunnel emulsion；
3) N that the present invention selects, N- dimethyl propylene alkenyl urea are cosolvent, can increase drug solubility, prevent high load medicine
There is drug precipitation phenomenon in later period placement process in the praziquantel of amount, and the selection of cosolvent is also prescription wound of the invention
New point.
Other than prescription advantage, simple process of the invention does not need to introduce complicated equipment, general veterinary drug enterprises
The workshop GMP can produce, therefore production cost is low, be conducive to a wide range of popularization of drug.
Compared with prior art, the present invention passing through the improvement of prescription and technique, the technical effect reached are as follows: firstly, this hair
Bright emulsion pest-resistant spectrum is wide, and use is safe, and property is stablized, significant in efficacy；Secondly, emulsion prepared by the present invention is two-arch tunnel,
, can be with injection after oil dilution when clinical use, drinking-water or injection after can also being diluted with water can be according to clinical needs
It adjusts to changed conditions, it is easy to use.Furthermore preparation process strong operability of the invention, utilizes conversion.
Detailed description of the invention
Fig. 1 is the electron micrograph of two-arch tunnel emulsion made from the embodiment of the present invention 1；(HV=80.0kv,
Direct Mag:5000x).
Specific embodiment
The present invention will be illustrated by embodiment below, but these specific embodiments do not limit this hair in any way
Bright protection scope.
Embodiment 1-10
To keep specification succinct, it is double to provide compound ivermectin praziquantel described in embodiment 1-10 in the form of a table below
The weight of continuous phase emulsion forms, and is specifically shown in Table 1.
The preparation method of compound ivermectin praziquantel two-arch tunnel emulsion described in embodiment 1-10, including following step
It is rapid:
(a) ivermectin, praziquantel and solvent naphtha are uniformly mixed, cosolvent is added and stirs evenly, adds emulsifier
It stirs evenly, obtains system 1；
(b) Arecoline hydrobromide is dissolved in deionized water, adds assistant for emulsifying agent, stirred evenly, obtain system 2；
(c) system 1 is heated to 70 DEG C, and maintains constant temperature, be slowly added to system 2 at this time, stirring while adding, system is by dilute
Retrogradation continues to stir and maintains temperature 70 C 40min after being added to system 2, stops stirring later, and standing is cooled to room
Temperature to obtain the final product.
In other embodiments, it as long as the temperature of system meets between 60~80 DEG C in step (c), is added to system 2
After continue to time at least 30min effect of the invention can be achieved.
The weight of 1 embodiment 1-10 of table forms (total 100g)
。
Test example
The product property of 1 product of the present invention of test example and stability test
Electronic Speculum observation is scanned to the product of embodiment 1-10 preparation, as shown in Figure 1, it will be seen from figure 1 that the present invention
Emulsion obtained is in water phase and oily phase two-arch tunnel distribution.
The appearance for the product that the present invention obtains is the uniform faint yellow or yellow liquid of quality, to the embodiment of the present invention 1-
10 are sampled, and carry out room temperature respectively to each embodiment, 40 DEG C of high temperature and humidity are placed, 4 DEG C of low temperature are placed and -20 DEG C cold
Freeze and place, and separately sampled observation character when 0d, 15d, 30d, 90d and 180d, as a result, it has been found that, the product that each embodiment obtains
Situation is precipitated without layering and drug, there is preferable stability.
The safety testing of 2 product of the present invention of test example
The safety used below by way of clinical trial verifying drug.
Kun Ming mice 80 for choosing 20g or so, points 4 groups, every group 20, first group is control group, the 2nd, 3,4 group
For high, medium and low dosage group of the invention.By taking embodiment 1 as an example, respectively to every stomach-filling stoste of the 2nd, 3,4 group of mouse, 2 times it is dilute
Liquid and 4 times of dilution 0.5ml are released, control group stomach-filling the same dose of physiological saline are observed continuously one week after application, and record each
Drinking-water, the diet, death, clinical manifestation of mouse are organized, dissect is carried out within the 8h if having dead mouse after death, if without dead
It dies, randomly selects 2 for every group after experiment, dissect after cervical dislocation is lethal is observed the lesion situation of each organ and is damaged
Situation simultaneously records.
Experimental result:
1. each group mouse drinking-water, diet are all normal, indifference；
2. each group mouse does not occur death；
3. each group mouse is without poisoning clinical manifestation；
4. three groups of mouse dissects are normal, each organ is not damaged and other fouling characteristics；
The result shows that: two-arch tunnel ivermectin praziquantel emulsion good security of the invention.
3 pharmacodynamic test of test example
Somewhere morbidity warren, 3 monthly age New Zealand rabbits play expelling parasite needle since breeding environment is poor not in time after wean, then
In addition ambient humidity is big, temperature is high, causes in rabbit group that acarid disease is high-incidence, and main physical signs show as having bulk incrustation inside auricle,
Some are serious to be immediately seen from the outside even without breaking auricle into two with one's hands.Due to itching, rabbit frequently grabs ear with foot, causes to fester, pole
Easy secondary infection, and due to hypoimmunity, environmental condition is poor, and also suspecting has the mixed sense of other kinds of helminth.Choose the state of an illness
Similar rabbit 60, random point 3 groups, every group 20.First group is control group, and 1ml physiological saline is subcutaneously injected in every neck,
Second group is common ivermectin injection drug control group, and every is injected ivermectin injection by 3mg/kg, and third group is
Medicine group of the invention, two-arch tunnel emulsion of the present invention prepared by embodiment 1, with the calculating of ivermectin amount, the agent of 3mg/kg
Amount, neck subcutaneous injection.After a week, it is primary to repeat medication.After treatment, the daily performance for observing rabbit and acarid incrustation fall off
Situation, and record, it the results are shown in Table shown in 2.
Evaluation criterion:
Dead: experimental animal occurs dead during finger to finger test, and -1 point；
Invalid: after referring to medication, though experimental animal does not occur death, Symptoms and sign do not have improvement sign, and 0 point；
Lapse to: after referring to medication, experimental animal Symptoms and sign are obviously improved, and rabbit no longer acutely grabs auricle, auricle
Inside incrustation obviously becomes smaller, but does not completely disappear also, in convalescence, 1 point；
Recovery from illness: after referring to medication, experimental animal fully recovers, and all behaviors and sign indifference before the onset, in auricle
It forms a scab and completely falls off disappearance, 2 points；
Total effective rate: the ratio of the experimental animal number and this group of experimental animal sum that lapse to and fully recover after referring to medication ×
100%；
2 pharmacodynamic test result of table
。
Test result: control group does not have to any drug, and in the case where leaning on animal itself resistance completely, endoparasite is cured
Hair is serious；Common ivermectin injection group, lapses to rate 40%, cure rate 45%, total effective rate 85%, and emulsion group of the present invention lapses to
Rate 20%, cure rate 75%, total effective rate 95%, hence it is evident that be better than common ivermectin injection group.
Conclusion (of pressure testing): the treatment of compound ivermectin praziquantel two-arch tunnel emulsion of the invention to animal epizoon
With significant curative effect.
Claims (7)
1. a kind of compound ivermectin praziquantel two-arch tunnel emulsion, which is characterized in that the weight of every 100g emulsion forms are as follows: she
Tie up 0.1~2g of rhzomorph, 0.1~25g of praziquantel, 0.01~3g of Arecoline hydrobromide, 1.0~10g of solvent naphtha, cosolvent 0.1~
5g, 20~30g of emulsifier, 10~20g of assistant for emulsifying agent, surplus are deionized water；The emulsifier be Tween-81, Tween-40,
One of Tween-80 compounded with one of Arlacel-80, Arlacel-85 after mixed surfactant；The cosolvent is N,
N- dimethyl propylene alkenyl urea.
2. compound ivermectin praziquantel two-arch tunnel emulsion as described in claim 1, which is characterized in that every 100g emulsion
Weight composition are as follows: 0.5~1g of ivermectin, 5~20g of praziquantel, 1.0~2g of Arecoline hydrobromide, 3~8g of solvent naphtha, hydrotropy
2~4g of agent, 23~28g of emulsifier, 12~18g of assistant for emulsifying agent, surplus are deionized water.
3. compound ivermectin praziquantel two-arch tunnel emulsion as claimed in claim 2, which is characterized in that every 100g emulsion
Weight composition are as follows: ivermectin 1g, praziquantel 15g, Arecoline hydrobromide 1.5g, solvent naphtha 6g, cosolvent 3g, emulsifier 25g,
Assistant for emulsifying agent 15g, surplus are deionized water.
4. compound ivermectin praziquantel two-arch tunnel emulsion a method according to any one of claims 1-3, which is characterized in that described molten
Agent oil is the mixture of one or both of ethyl acetate, isopropyl myristate, injection soybean oil, ethyl oleate.
5. compound ivermectin praziquantel two-arch tunnel emulsion a method according to any one of claims 1-3, which is characterized in that described to help
Emulsifier is one or two kinds of mixtures of dehydrated alcohol, 1,2- propylene glycol, polyethylene glycol 200 or glycerine.
6. compound ivermectin praziquantel two-arch tunnel emulsion a method according to any one of claims 1-3, which is characterized in that described to go
Ionized water is sterile deionized water.
7. the preparation method of any compound ivermectin praziquantel two-arch tunnel emulsion of claim 1-3, feature exist
In, comprising the following steps: (a) first mixes ivermectin, praziquantel and solvent naphtha, sequentially adds cosolvent, emulsifier mixing
Obtain system 1；(b) Arecoline hydrobromide is dissolved in deionized water, assistant for emulsifying agent mixing is added, obtains system 2；(c) system 1 is added
Heat is to 60~80 DEG C, at this temperature, is slowly added to system 2, and stirring while adding, system is added completely by dilute retrogradation to system 2
Afterwards, continue to stir and maintain 60~80 DEG C of at least 30min of temperature, stop stirring later, standing is cooled to room temperature to obtain the final product.
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Non-Patent Citations (4)
| Title |
|---|
| 关于驱虫药药效的对比试验;哈得力·阿扎太等;《当代畜牧》;20141031;第90-91页 |
| 复方伊维菌素和吡喹酮纳米乳的制备与质量评价;汤佳莘等;《西北农林科技大学学报（ 自然科学版）》;20140228;第42卷(第2期);第35-40页 |
| 微乳及微乳制剂的研究;史同瑞等;《上海畜牧兽医通讯》;20051231(第5期);第10-11页 |
| 难溶性药物给药策略的研究;何洪等;《中医临床研究》;20111231;第3卷(第2期);第17-18页 |
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