CN1147232C - 抗寄生虫制剂 - Google Patents
抗寄生虫制剂Info
- Publication number
- CN1147232C CN1147232C CNB998134554A CN99813455A CN1147232C CN 1147232 C CN1147232 C CN 1147232C CN B998134554 A CNB998134554 A CN B998134554A CN 99813455 A CN99813455 A CN 99813455A CN 1147232 C CN1147232 C CN 1147232C
- Authority
- CN
- China
- Prior art keywords
- preparation
- avermectins
- monose
- ether
- monomethyl ether
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 14
- 230000002141 anti-parasite Effects 0.000 title claims abstract description 9
- 239000003096 antiparasitic agent Substances 0.000 title claims abstract description 8
- 238000009472 formulation Methods 0.000 title claims abstract description 7
- 239000005660 Abamectin Substances 0.000 claims abstract description 45
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000002904 solvent Substances 0.000 claims abstract description 11
- 244000078703 ectoparasite Species 0.000 claims abstract description 10
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 9
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 9
- 230000000694 effects Effects 0.000 claims abstract description 6
- 238000002360 preparation method Methods 0.000 claims description 70
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 69
- QCAHUFWKIQLBNB-UHFFFAOYSA-N 3-(3-methoxypropoxy)propan-1-ol Chemical compound COCCCOCCCO QCAHUFWKIQLBNB-UHFFFAOYSA-N 0.000 claims description 32
- LPQOADBMXVRBNX-UHFFFAOYSA-N ac1ldcw0 Chemical compound Cl.C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3CCSC1=C32 LPQOADBMXVRBNX-UHFFFAOYSA-N 0.000 claims description 22
- SBASXUCJHJRPEV-UHFFFAOYSA-N 2-(2-methoxyethoxy)ethanol Chemical group COCCOCCO SBASXUCJHJRPEV-UHFFFAOYSA-N 0.000 claims description 16
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims description 14
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 14
- 238000011282 treatment Methods 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 235000010388 propyl gallate Nutrition 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- -1 isopropyl alcohols Chemical class 0.000 claims 1
- 239000007800 oxidant agent Substances 0.000 claims 1
- 230000001590 oxidative effect Effects 0.000 claims 1
- FXWHFKOXMBTCMP-WMEDONTMSA-N milbemycin Natural products COC1C2OCC3=C/C=C/C(C)CC(=CCC4CC(CC5(O4)OC(C)C(C)C(OC(=O)C(C)CC(C)C)C5O)OC(=O)C(C=C1C)C23O)C FXWHFKOXMBTCMP-WMEDONTMSA-N 0.000 abstract description 10
- 230000000699 topical effect Effects 0.000 abstract description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 abstract 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- RRZXIRBKKLTSOM-XPNPUAGNSA-N avermectin B1a Chemical compound C1=C[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 RRZXIRBKKLTSOM-XPNPUAGNSA-N 0.000 abstract 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 abstract 1
- 241000282472 Canis lupus familiaris Species 0.000 description 11
- 241001465754 Metazoa Species 0.000 description 8
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 5
- IBSREHMXUMOFBB-JFUDTMANSA-N 5u8924t11h 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(O3)C=C[C@H](C)[C@@H](C(C)C)O4)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.C1=C[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 IBSREHMXUMOFBB-JFUDTMANSA-N 0.000 description 4
- 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 description 4
- 241000258924 Ctenocephalides felis Species 0.000 description 4
- 241000282326 Felis catus Species 0.000 description 4
- 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 description 3
- 229950008167 abamectin Drugs 0.000 description 3
- QLFZZSKTJWDQOS-YDBLARSUSA-N doramectin 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(O3)C=C[C@H](C)[C@@H](C3CCCCC3)O4)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 QLFZZSKTJWDQOS-YDBLARSUSA-N 0.000 description 3
- 229960002418 ivermectin Drugs 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000273 veterinary drug Substances 0.000 description 3
- 241000002163 Mesapamea fractilinea Species 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000002537 cosmetic Substances 0.000 description 2
- 229960003997 doramectin Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- YZBLFMPOMVTDJY-CBYMMZEQSA-N moxidectin Chemical compound O1[C@H](C(\C)=C\C(C)C)[C@@H](C)C(=N/OC)\C[C@@]11O[C@H](C\C=C(C)\C[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 YZBLFMPOMVTDJY-CBYMMZEQSA-N 0.000 description 2
- 229960004816 moxidectin Drugs 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 244000045947 parasite Species 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- WGYZMNBUZFHYRX-UHFFFAOYSA-N 1-(1-methoxypropan-2-yloxy)propan-2-ol Chemical compound COCC(C)OCC(C)O WGYZMNBUZFHYRX-UHFFFAOYSA-N 0.000 description 1
- 241000490513 Ctenocephalides canis Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229940091906 dectomax Drugs 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 244000079386 endoparasite Species 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229940007210 ivomec Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- AFJYYKSVHJGXSN-KAJWKRCWSA-N selamectin Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1C(/C)=C/C[C@@H](O[C@]2(O[C@@H]([C@@H](C)CC2)C2CCCCC2)C2)C[C@@H]2OC(=O)[C@@H]([C@]23O)C=C(C)C(=N\O)/[C@H]3OC\C2=C/C=C/[C@@H]1C AFJYYKSVHJGXSN-KAJWKRCWSA-N 0.000 description 1
- 229960002245 selamectin Drugs 0.000 description 1
- 239000002453 shampoo Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000004544 spot-on Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
Classifications
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
- A61K9/0017—Non-human animal skin, e.g. pour-on, spot-on
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
-
- 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
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/14—Ectoparasiticides, e.g. scabicides
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Zoology (AREA)
- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Dentistry (AREA)
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- Agronomy & Crop Science (AREA)
- Pest Control & Pesticides (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Agricultural Chemicals And Associated Chemicals (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Saccharide Compounds (AREA)
Abstract
适于局部应用的长效抗寄生虫制剂，其含有：(a)0.1-50%w/v的具有抗内和/或外寄生物活性的阿凡曼菌素或米尔倍霉素；(b)1-50%v/v的二(C2-4二醇)单(C1-4烷基)醚；(c)选择性的抗氧剂；和(d)选择性的皮肤可接受的挥发性溶剂适量v/v。
Description
本发明涉及抗寄生虫制剂，特别是适于向哺乳动物、包括人和家养动物例如猫和狗进行局部应用的含有阿凡曼菌素或米尔倍霉素、包括其衍生物的抗寄生虫制剂，该制剂可用于治疗由内寄生物和/或外寄生物引起的病症。特别令人感兴趣的是对跳蚤和/或犬恶丝虫有活性之物质的制剂。
抗寄生虫的阿凡曼菌素、米尔倍霉素及其衍生物记载于大量的出版物中，参见，例如欧洲专利申请公开号0214731、0284176、0317148、0308145、0340832、0335541、0350187、0170006、0254583、0334484、0410615，英国专利申请号1573955、1390336，国际专利申请公开号WO 94/15944和WO 95/22552，“伊维菌素和阿巴美丁”，WC Campbell，Springer Verlag，New York(1989)和“多拉克汀-一种有效的新型杀内寄生物剂”，AC Goudie等，《兽类寄生虫学》(Vet.Parasitol.)49(1993)5。
有许多种这样的物质已被商业化，例如伊维菌素(IvomecTM)、多拉克汀(DectomaxTM)、莫昔克汀和阿巴美丁(AvomecTM)。
国际专利申请公开号WO 94/15944(其教导的内容引入本文作为参考)描述了一组具有治疗多种由内和/或外寄生物引起的疾病之活性的阿凡曼菌素13-单糖的5-肟基衍生物，包括5-肟基-22，23-二氢-25-环己基阿凡曼菌素B1单糖(西拉克汀(selamectin)，实施例5)。
本发明描述了适于局部应用的长效制剂，该制剂可以传递具有抗内和/或外寄生物活性的阿凡曼菌素和米尔倍霉素。这些制剂具有良好的化妆品性能、存放时的稳定性、皮肤耐受性和经皮传递特性。
一方面，本发明提供了适于局部应用的长效抗寄生虫制剂，其含有：
(a)约0.1-50％w/v的具有抗内和/或外寄生物活性的阿凡曼菌素或米尔倍霉素；
(b)约1-50％v/v的二(C2-4二醇)单(C1-4烷基)醚；
(c)选择性的抗氧剂；和
(d)选择性的皮肤可接受的挥发性溶剂适量v/v。
[“w/v是指重量/体积，即“ 1％w/v”表示每100ml制剂中有1g。]
本发明的制剂具有良好的化妆品性能。例如，当局部涂抹于家养动物例如猫或狗的毛皮上时，它们可以很好地散开，在很宽的温度范围内与皮肤产生良好的接触。它们不会象某些市售的阿凡曼菌素或米尔倍霉素在含脂肪赋形剂中的制剂那样留下难看的油斑。
某些本发明的制剂具有足够的效力，从而使治疗的间隔期可以很长，例如数周或一个月。
优选活性化合物同时具有抗内和外寄生物的活性。
优选活性化合物选自伊维菌素、多拉克汀、阿巴美丁、莫昔克汀以及国际专利申请公开号WO 94/15944中概括性和具体公开的阿凡曼菌素13-单糖5-肟类化合物。
首选的活性化合物是5-肟基-22，23-二氢-25-环己基阿凡曼菌素B1单糖(西拉克汀)。
优选的二(C2-4二醇)单(C1-4烷基)醚是二乙二醇单甲醚(DEGMME)或二丙二醇单甲醚(DPGMME)。
更优选的二醇单甲醚是DPGMME。
可以使用任何来源的药物/兽药品质的二(C2-4二醇)单(C1-4烷基)醚。例如，可接受的DPGMME的商业来源是Dow Corning，其产品“Dowanol DPMTM”具有如下性质：沸点74.6℃(13mbar)；冰点-83℃；密度0.948g/cm3(25℃)；粘度3.72mPas(25℃)；反射指数1.421(25℃)。
优选二(C2-4二醇)单(C1-4烷基)醚在制剂中的含量为最多约20％v/v，仍更优选在约2-16％v/v的范围内，更优选在约4-12％v/v的范围内，首选在约6-12％v/v的范围内。
优选含有皮肤可接受的挥发性溶剂并且所述溶剂是乙醇或异丙醇(IPA)。
更优选皮肤可接受的溶剂是IPA。
优选活性化合物与二醇单甲醚的w/v与v/v的比值在约(0.5至2)比1的范围内。
更优选活性化合物与二醇单甲醚的w/v与v/v的比值为约(0.7至1.4)比1。
仍更优选活性化合物与二醇单甲醚的w/v与v/v的比值为约(0.9至1.1)比1。
首选活性化合物与二醇单甲醚的w/v比v/v的比值为约1∶1。
优选活性成分阿凡曼菌素或米尔倍霉素在整个制剂中的含量在约1％至约16％w/v的范围内，更优选约4％至约12％w/v，仍更优选约6％至约12％w/v。
制剂还可以选择性地含有抗氧剂，例如没食子酸丙酯、BHA(2-叔丁基-4-甲氧基苯酚)或BHT(2，6-二叔丁基-4-甲基苯酚)。如果存在抗氧剂的话，优选是BHT。
如果存在抗氧剂的话，优选其含量低于0.2％w/v，更优选低于0.1％w/v。
优选由如下成分组成的制剂：
(a)5-肟基-22，23-二氢-25-环己基阿凡曼菌素B1单糖(西拉克汀，含量为1％至16％w/v)；
(b)含量为1％至16％v/v的DEGMME或DPGMME，活性化合物与DEGMME/DPGMME的w/v与v/v的比值为约1∶1；
(c)异丙醇适量至100％v/v；
和选择性的(d)BHT(低于0.1％w/v)。
更优选由如下成分组成的制剂：
(a)5-肟基-22，23-二氢-25-环己基阿凡曼菌素B1单糖(西拉克汀，含量为6％至12％w/v)；
(b)6％至12％v/v的DEGMME或DPGMME，活性化合物与DEGMME/DPGMME的w/v与v/v的比值为约1∶1；
(c)异丙醇适量至100％v/v；
和选择性的(d)BHT(低于0.1％w/v)。
一组优选的制剂由如下实施例中所述的制剂组成。
本发明的另一方面是通过施用有效量本发明的制剂来治疗由内或外寄生物所引起的病症的方法。
本发明的另一方面是本发明的制剂用于药物。
本发明的另一方面是本发明的制剂在生产用于治疗由内或外寄生物所引起之病症的药物中的用途。
本发明的制剂可以通过常规方法进行制备，例如将阿凡曼菌素和/或米尔倍霉素以及选择性的抗氧剂按照常规的药物或兽药实践溶于溶剂或溶剂混合物中，例如将各成分的混合物进行搅拌，如需要，同时进行加热。
通过如下实施例来说明本发明，其中
(i)将BHT抗氧剂(如果存在的话)溶于DPGMME或DEGMME和IPA的混合物中，
(ii)加入药物，然后将混合物搅拌直至溶解，
(iii)滤除残余物，然后装到适合的容器中。
实施例1
由如下成分组成的制剂：
(a)5-肟基-22，23-二氢-25-环己基阿凡曼菌素B1单糖6％w/v
(b)DPGMME 6％v/v
(c)BHT 0.08％w/v
(d)IPA适量至100％v/v。
实施例2
由如下成分组成的制剂：
(a)5-肟基-22，23-二氢-25-环己基阿凡曼菌素B1单糖6％w/v
(b)DPGMME 6％v/v
(c)IPA适量至100％v/v。
实施例3
由如下成分组成的制剂：
(a)5-肟基-22，23-二氢-25-环己基阿凡曼菌素B1单糖8％w/v
(b)DPGMME 16％v/v
(c)BHA 0.1％w/v
(d)IPA适量至100％v/v。
实施例4
由如下成分组成的制剂：
(a)5-肟基-22，23-二氢-25-环己基阿凡曼菌素B1单糖12％w/v
(b)DPGMME 12％v/v
(c)BHT 0.08％w/v
(d)IPA适量至100％v/v。
实施例5
由如下成分组成的制剂：
(a)5-肟基-22，23-二氢-25-环己基阿凡曼菌素B1单糖12％w/v
(b)DPGMME 12％v/v
(c)IPA适量至100％v/v。
实施例6
由如下成分组成的制剂：
(a)5-肟基-22，23-二氢-25-环己基阿凡曼菌素B1单糖16％w/v
(b)DPGMME 16％v/v
(c)BHA 0.1％w/v
(d)IPA适量至100％v/v。
实施例7
由如下成分组成的制剂：
(a)5-肟基-22，23-二氢-25-环己基阿凡曼菌素B1单糖16％w/v
(b)DEGMME 16％v/v
(c)IPA适量至100％v/v。
实施例8
由如下成分组成的制剂：
(a)5-肟基-22，23-二氢-25-环己基阿凡曼菌素B1单糖16％w/v
(b)DPGMME 8％v/v
(c)IPA适量至100％v/v。
实施例9
由如下成分组成的制剂：
(a)5-肟基-22，23-二氢-25-环己基阿凡曼菌素B1单糖16％w/v
(b)DPGMME 16％v/v
(c)IPA适量至100％v/v。
实施例10
由如下成分组成的制剂：
(a)5-肟基-22，23-二氢-25-环己基阿凡曼菌素B1单糖16％w/v
(b)DEGMME 8％v/v
(c)IPA适量至100％v/v。
实施例11
含有如下成分的制剂(mg/ml)：
(a)5-肟基-22，23-二氢-25-环己基阿凡曼菌素B1单糖(60)；
(b)DPGMME(56.28)；
(c)BHT(0.8)；和
(d)IPA(697.92)。
实施例12
含有如下成分的制剂(mg/ml)：
(a)5-肟基-22，23-二氢-25-环己基阿凡曼菌素B1单糖(120)；
(b)DPGMME(112.56)；
(c)BHT(0.8)；和
(d)IPA(613.64)。
当然，单位剂量制剂中抗寄生物的阿凡曼菌素/米尔倍霉素的含量可以随着阿凡曼菌素/米尔倍霉素在治疗具体病症时的效力、所需的应用频率等根据常规的兽医和药物实践来改变。
本发明的制剂可以根据常规的药物和兽药实践以适于所面临的具体应用、所治疗的宿主动物的具体物种和体重、所涉及的一种或多种寄生物、感染的程度等的方式来给药。
例如，对于狗和猫，将剂量为4mg/kg至12mg/kg，优选约9mg/kg宿主动物体重的5-肟基-22，23-二氢-25-环己基阿凡曼菌素B1单糖(西拉克汀)以单剂量的形式每月一次给药将足以控制跳蚤和预防犬恶丝虫，当然，在某些情况下可能需要更高或更低的剂量范围，这些剂量范围也包括在本发明的范围内。对于家养动物例如典型的家养猫或狗，6mg/kg剂量的典型剂量方案为每月一次0.25ml至2ml实施例1的制剂。
本发明的制剂特别适于局部给药。对于局部应用，可以采用浸、喷雾、倾倒、点滴(spot-on)、喷射液体、香波、颈圈、标签、马具等。特别优选点滴制剂。
应当理解，术语“治疗”包括预防、减轻或治愈由一种或多种寄生物引起的一种或多种病症。
以下将说明本发明制剂的效力。将三种西拉克汀制剂以8mg/kg的单一局部剂量给药，然后评估在一段时间内对诱发的狗跳蚤(猫栉头蚤)感染的作用。三种制剂均含有160mg/mL的西拉克汀并分别含有16％w/v二乙二醇单甲醚(DEGMME)、8％w/v二丙二醇单甲醚(DPGMME)或16％w/v DPGMME，用异丙醇调整体积。将36只(16只雄性，20只雌性)预先用100只未喂食的活的成熟跳蚤感染的狗通过跳蚤计数随机分成4组，随后这4组分别接受盐水(阴性对照，T1)、西拉克汀/16％w/vDEGMME(T2)、西拉克汀/8％w/v DPGMME(T3)和西拉克汀/16％w/vDPGMME(T4)。于第0天在肩胛骨前方脖子的根部进行局部给药。通过用梳子计数每只狗上存在的活跳蚤数来评估效力。将每只狗用约100只未喂食的活的成熟猫栉头蚤在第1、4、11、18、23、27、32和39天感染，然后在每次感染约72小时后在第4、7、14、21、26、30、35和42天用梳子进行计数。在研究过程中未出现不利的药物反应并且没有发生死亡。在每次治疗后对跳蚤进行计数的那天，三种西拉克汀制剂的几何平均跳蚤梳子计数均显著低于(P≤0.05)盐水对照。对于T2、T3和T4，在第30天的效力(几何平均跳蚤梳子计数减少的百分比)分别为98.6％、98.2％和99.4％。在第35天，T2、T3和T4的效力分别为93.5％、95.9％和97.7％。在第42天，T2、T3和T4的效力分别为67.3％、82.3％和88.1％。
以3mg/kg、6mg/kg和9mg/kg的剂量局部给药来评估西拉克汀制剂对诱发的狗猫栉头蚤感染的效力，以便确定适宜的剂量。制剂在异丙醇中含有12％(120mg/mL)西拉克汀和11.26％w/v二丙二醇单甲醚(DPGMME)。将48只狗(24只雄性，24只雌性)通过跳蚤计数按性别随机分成4组：安慰剂(阴性对照，T1)或3mg/kg(T2)、6mg/kg(T3)和9mg/kg(T4)的西拉克汀。于第0天在动物肩胛骨前方脖子根的背部进行局部给药。通过用梳子计数每只狗上存在的活跳蚤数来评估效力。将每只狗用约100只未喂食的活的成熟猫栉头蚤在第4、11、18和27天感染，然后在每次感染约72小时后在第7、14、21和30天用梳子进行计数。在研究过程中未出现不利的药物反应并且没有动物死亡。在第7、14和21天，三组西拉克汀治疗的几何平均跳蚤梳子计数的减少百分比范围从94.6％至100％。在第30天，T2、T3和T4的减少百分比分别为81.5％、94.7％和90.8％。方差分析表明治疗组(T2、T3和T4合并)第30天的跳蚤梳子计数显著低于(P≤0.05)安慰剂(T1)，用3mg/kg治疗(T2)的计数显著高于(P≤0.05)用6mg/kg和9mg/kg治疗(T3和T4合并)的计数，T3和T4之间没有统计学差异(P＞0.10)。
Claims (24)
1.抗寄生虫制剂，其含有：
(a)0.1-50％w/v的阿凡曼菌素13-单糖5-肟；
(b)1-50％v/v的二(C2-4二醇)单(C1-4烷基)醚。
2.权利要求1的制剂，其中还含有氧化剂。
3.权利要求1或2的制剂，其中还含有适量的皮肤可接受的挥发性溶剂。
4.权利要求1或2所述的制剂，其中二(C2-4二醇)单(C1-4烷基)醚的含量为1-20％v/v。
5.权利要求1或2所述的制剂，其中的阿凡曼菌素13-单糖5-肟具有抗内和外寄生物的活性。
6.权利要求1或2所述的制剂，其中的阿凡曼菌素13-单糖5-肟是5-肟基-22，23-二氢-25-环己基阿凡曼菌素B1单糖。
7.权利要求1或2所述的制剂，其中的二(C2-4二醇)单(C1-4烷基)醚是二乙二醇单甲醚或二丙二醇单甲醚。
8.权利要求7所述的制剂，其中的二(C2-4二醇)单(C1-4烷基)醚是二丙二醇单甲醚。
9.权利要求3所述的制剂，其中含有皮肤可接受的溶剂并且所述溶剂是乙醇或异丙醇。
10.权利要求9所述的制剂，其中皮肤可接受的溶剂并且所述溶剂是异丙醇。
11.权利要求1或2所述的制剂，其中阿凡曼菌素13-单糖5-肟与二(C2-4二醇)单(C1-4烷基)醚的w/v与v/v的比值在0.5至2∶1的范围内。
12.权利要求11所述的制剂，其中阿凡曼菌素13-单糖5-肟与二(C2-4二醇)单(C1-4烷基)醚的w/v与v/v的比值为0.7至1.4∶1。
13.权利要求12所述的制剂，其中阿凡曼菌素1 3-单糖5-肟与二(C2-4二醇)单(C1-4烷基)醚的w/v与v/v的比值为0.9至1.1∶1。
14.权利要求13所述的制剂，其中阿凡曼菌素13-单糖5-肟与二(C2-4二醇)单(C1-4烷基)醚的w/v与v/v的比值为1∶1。
15.权利要求1或2所述的制剂，其中阿凡曼菌素13-单糖5-肟在整个制剂中的含量在1％至16％的范围内。
16.权利要求15所述的制剂，其中阿凡曼菌素13-单糖5-肟在整个制剂中的含量在4％至12％的范围内。
17.权利要求16所述的制剂，其中阿凡曼菌素13-单糖5-肟在整个制剂中的含量在6％至12％的范围内。
18.权利要求2所述的制剂，其中含有的抗氧剂选自没食子酸丙酯、2-叔丁基-4-甲氧基苯酚和2，6-二叔丁基-4-甲基苯酚。
19.权利要求18所述的制剂，其中含有的抗氧剂是2，6-二叔丁基-4-甲基苯酚。
20.权利要求1的制剂，其中，所述制剂含有如下成分：
(a)5-肟基-22，23-二氢-25-环己基阿凡曼菌素B1单糖，含量为1％至16％w/v；
(b)含量为1％至16％v/v的二乙二醇单甲醚或二丙二醇单甲醚，并且活性成分与二乙二醇单甲醚/二丙二醇单甲醚的w/v与v/v的比值为1∶1；
(c)异丙醇适量。
21.权利要求20的制剂，其中还含有(d)2，6-二叔丁基-4-甲基苯酚。
22.权利要求20的制剂，其含有如下成分：
(a)5-肟基-22，23-二氢-25-环己基阿凡曼菌素B1单糖，含量为6％至12％w/v；
(b)6％至12％v/v的二乙二醇单甲醚或二丙二醇单甲醚，并且活性化合物与二乙二醇单甲醚/二丙二醇单甲醚的w/v与v/v的比值为1∶1；
(c)异丙醇适量。
23.权利要求22的制剂，其中还含有(d)2，6-二叔丁基-4-甲基苯酚。
24.权利要求1至23中任意-项所述的制剂在生产用于治疗由内或外寄生物所引起之病症的药物中的用途。
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| GBGB9825402.2A GB9825402D0 (en) | 1998-11-19 | 1998-11-19 | Antiparasitic formulations |
| GB9825402.2 | 1998-11-19 | ||
| PCT/IB1999/001715 WO2000030449A1 (en) | 1998-11-19 | 1999-10-20 | Antiparasitic formulations |
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| CN1147232C true CN1147232C (zh) | 2004-04-28 |
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| BR112014024606B1 (pt) * | 2012-04-04 | 2022-11-16 | Syngenta Participations Ag | Composição de macrólido pesticida não aquosa |
| AR094882A1 (es) | 2013-02-26 | 2015-09-02 | Zoetis Llc | Selamectina para el tratamiento de las infestaciones por piojos de mar, composición |
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| PL3595441T3 (pl) | 2017-03-17 | 2023-12-04 | Krka, D.D., Novo Mesto | Stabilna kompozycja weterynaryjna do stosowania miejscowego |
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