CN1035356C - 制备抗寄生虫制剂的方法 - Google Patents

制备抗寄生虫制剂的方法 Download PDF

Info

Publication number
CN1035356C
CN1035356C CN90102072A CN90102072A CN1035356C CN 1035356 C CN1035356 C CN 1035356C CN 90102072 A CN90102072 A CN 90102072A CN 90102072 A CN90102072 A CN 90102072A CN 1035356 C CN1035356 C CN 1035356C
Authority
CN
China
Prior art keywords
avermectins
injection
preparation
compound
ethyl oleate
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
Application number
CN90102072A
Other languages
English (en)
Other versions
CN1046282A (zh
Inventor
斯蒂芬·理查德·威克斯
爱德华·戴维逊
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Inc
Original Assignee
Pfizer Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from GB898908071A external-priority patent/GB8908071D0/en
Application filed by Pfizer Inc filed Critical Pfizer Inc
Publication of CN1046282A publication Critical patent/CN1046282A/zh
Application granted granted Critical
Publication of CN1035356C publication Critical patent/CN1035356C/zh
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/08Solutions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00Antiparasitic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00Antiparasitic agents
    • A61P33/10Anthelmintics

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Saccharide Compounds (AREA)

Abstract

一种抗寄生虫剂25-环己基阿凡曼菌素B1在含有50-95%芝麻油,剩余部分是油酸乙酯的溶剂中的溶液,它可有效地防治寄生虫,易于被动物耐受,并可利用标准的注射器注射。

Description

制备抗寄生虫制剂的方法
本发明涉及结构为式(I)化合物的肠胃外制剂的制备,此化合物称为25-环己基阿凡曼菌素B1。
此化合物是阿凡曼菌素家族的一员,欧洲专利公开0214713对此有记载并要求了专利保护。阿凡曼菌素类是高度活性的抗寄生虫剂,尤其可用作驱蠕虫剂、杀外寄生虫剂、杀虫剂和杀螨剂。
抗寄生虫剂对于动物最为常用的施用制剂是非肠胃的、皮下或肌肉制剂。通常,水是一种方便的用于注射的液体,但阿凡曼菌素类在水中的溶解度太低,简单的水溶液浓度低到无法使用。如4389397号美国专利所述,用表面活性剂作为促溶剂和使用合适的有机共溶剂形成胶团溶液,可使某些阿凡曼菌素在水中溶解。然而,这些制剂所提供的活性化合物的剂量不足以令人满意地除去动物体内外的寄生虫。
欧洲专利公开146414记载了阿凡曼菌素的共溶剂溶液,即含有少量水的甘油甲醛和丙二醇的混合液或丙二醇,供肠胃外使用。但是,已知丙二醇在皮下或肌肉注射中引起刺激作用。此外,这些制剂中的少量水会导致阿凡曼菌素的水解作用。
这种含有可与水混溶的有机溶剂的阿凡曼菌素制剂,倾向于在注射部位使阿凡曼菌素产生不期望的局部沉淀。这可能在注射部位导致刺激和肿胀,并使抗寄生虫效果降低和不一致。
确实,市售抗寄生虫剂“可用于家畜注射的Ivomec”(一种称为异阿凡曼菌素的共溶剂阿凡曼菌素制剂)仅适用皮下注射,并可能在注射部位导致刺激和肿胀。
另一种提供阿凡曼菌素注射液的方法是,将阿凡曼菌素溶于药用油中。英国专利公开2166436中公开了用花生油、棉籽油以及油酸乙酯作为某些阿凡曼菌素的溶剂。然而,花生油和棉籽油提供的溶液不能使化合物I的浓度至少达到1%w/v,而这正是一般的兽医药品所要求的。兽医制剂通常都是在农场于低温下使用或贮存,温度低至4℃甚至更低,因此,即使阿凡曼菌素于正常室温下在油中的溶解度足够高,它也可能在暴露于低温条件时沉淀或形成过饱和溶液,从而变得不能使用。纯的油酸乙酯以及含有大量油酸乙酯的油类混合物侵蚀常用兽医注射器的某些塑料或橡胶组分,使它们变得不能使用。
欧洲专利公开285561记载了用纯的芝麻油作为另一组化合物米尔倍霉素(milbemycins)的可能溶剂。在比较粘度和可注射性的研究中发现,纯芝麻油的粘度太高,在用常规的兽医注射器时,不能用它作为溶剂进行注射。由于此原因,在实际的野外条件下,不能用纯芝麻油作注射用溶剂。
本发明旨在提供化合物(I)的肠胃外制剂,它能有效地防治体内和体外的寄生虫,它在对家畜作皮下和肌肉注射时易于被家畜耐受,并可用常规的注射器进行注射。
本发明提供了25-环己基阿凡曼菌素B1即化合物(I)的一种溶液,其溶剂含有50-95%体积的芝麻油,剩余部分是油酸乙酯。
优选的溶剂混合物含有75-90%体积的芝麻油,剩余部分是油酸乙酯。
对于皮下或肌肉注射来说,优选的阿凡曼菌素含量为1-30mg/ml,最优选为大约10mg/ml。
本发明的制剂是单相溶液,它可有效地治疗由内寄生虫引起的多种疾病,其中尤其包括蠕虫病,这是最经常由称为线虫的一类寄生蠕虫引起的疾病,它能给猪、羊、马和牛饲养业带来严重的经济损失,并能影响家养动物和禽类。这些化合物还能有效地防治影响各种动物的其他线虫,包括例如狗中的恶丝虫属,以及能够感染人体的各种寄生虫,包括肠胃寄生虫如钩虫属、板口线虫属、蛔虫属、类圆线虫属、毛线虫属、毛细线虫属、鞭虫属、蛲虫属,以及存在于血液或其他组织和器官中的寄生虫如线状蠕虫(fillarlal worm)和肠外阶段的类圆线虫属和毛线虫属。
本发明的制剂还可有效地治疗外寄生虫感染,尤其包括家畜和家禽的节肢动物外寄生虫如蜱、虱、螨、蚤、丽蝇、叮咬昆虫及能影响牛和马的迁移性双翅目幼虫。
已经意外地发现,本发明制剂的性质优于上述现有技术制剂,即用它们对家畜进行皮下或肌肉注射时对注射部位无刺激或几乎无刺激,适合用于常用的标准注射器,并能产生一致的抗寄生虫效果。
本发明溶液的进一步的优点是,制剂载体中含有不饱和酸的酯类,因此在长时间贮存时不使阿凡曼菌素受空气氧化。
本发明的溶液可如下简单地配制:将化合物(I)溶于芝麻油油酸乙酯混合物中,然后消毒和包装,用于常规方式的注射。
下面的实例通过举例描述了本发明的制剂。
                       实例
通过下述方法制备并测试25-环己基阿凡曼菌素Bl在油制剂中的溶液。
                       实例1
用下述成分配制注射液,该注射液在1ml芝麻油和油酸乙酯的公称90/10混合物中含有10mg化合物I:化合物I              10mg油酸乙酯             0.1ml芝麻油             加至1.0ml
将油酸乙酯和芝麻油混合并加热至80℃,同时用氮吹扫。然后将化合物I加至热油中直至溶解,使得到的溶液迅速冷却,如果需要,用芝麻油调整体积至1ml。通过膜过滤使此最终溶液消毒并无菌包装。
                     实例2
采用实例1的方法,用下列成分配制注射液,该注射液在1ml芝麻油和油酸乙酯的公称50/50混合物中含有10mg化合物I:化合物I               10mg油酸乙酯              0.5ml芝麻油              加至1.0ml
                       实例3
采用实例1的方法,用下列成分配制注射液,该注射液在1ml芝麻油和油酸乙酯的公称75/25混合物中含有10mg化合物I:化合物I               10mg油酸乙酯              0.25ml芝麻油               加至1.0ml
                       实例4
采用L.G.Cramer等的方法(Vet.Record122:611-612,1988)加以修改,测定化合物I对外寄生虫的效果。
通过皮下注射在第0天以200ug/kg的剂量给两组牛施用化合物I。A组施用的化合物I是根据美国专利4389397的含水胶团制剂,在每毫升制剂中含有2.5mg化合物I、120mg Tween80(注册商标)、200mg甘油甲醛、大约10mg苄醇,剩余部分为水。处理B组的化合物I是实例1的制剂。然后,在第0、2和4天对处理组及各种处理的对照组接种微小牛蜱(Boophilus microplus)幼虫,使蜱发育成成虫。第21和32天之间收集产生的吸血的雌性蜱成虫,记录日平均计数示于表1中。
表1 收集的雌性微小牛蜱的日平均计数
天    胶团制剂  未处理对照  实例1制剂  未处理对照
21       0           287       0            0
22       0           651       0           324
23       0           879       0           996
24       0           753       0           1507
25       16          554       0           663
26       76          267       0           852
27       85          48        0           329
28       36          10        8           35
29       28          5         15          19
30       16          0         3           1
31       0           0         3           1
32       0           0         1           0
总计     257         3454      30          4727
用实例1制剂处理不仅延迟了雌性蜱成虫的产生,而且使收集到的蜱减少。
                       实例5
在牛的半膜肌内注射阿凡曼菌素制剂后,评价其耐受性。在处理后第7和14天无痛处死牛,然后摘取注射部位及其周围的组织。检查组织的宏观病理学,利用下述分级系统评价注射部位的损伤。
0=正常,无可见损伤
1=轻度伤疤
2=重度伤疤
3=包囊碎片<1.0cm3
4=包囊碎片>1.0<2.5cm3
5=包囊碎片>2.5cm3
等级0、1和2被认为是可接受的。大于2的等级具有包囊碎片。实例1和2的化合物I制剂以200ug/kg的剂量对牛进行肌肉注射。将注射部位的耐受性与以同样剂量和途径施用的抗寄生虫剂异阿凡曼菌素(商标;用于牛的Ivomec)的共溶剂制剂作比较。
表2  肌肉注射部位耐受性等级的比较处理           天         家畜数     平均等级实例1制剂      7           5           0.4
           14          10          0.0实例2制剂      7           5           0.4
           14          10          0.0Ivomec         7           4           3.75
           14          8           2.75
实例1和2制剂中的化合物I易于被耐受,只在注射7天后有少量小损伤;14天后完全消失。相反,肌肉注射的Ivomec的耐受性在第7天很差,在注射后14天仍可见到包囊碎片。

Claims (4)

1、一种制备25-环己基阿凡曼菌素B1溶液的方法,包括将25-环己基阿凡曼菌素B1溶于一种溶剂中,该溶剂含有50-95%体积的芝麻油,剩余部分是油酸乙酯。
2、根据权利要求1的方法,其特征在于,其中的溶剂含有75-90%体积的芝麻油,剩余部分是油酸乙酯。
3、根据权利要求1或2的方法,其特征在于,所形成的溶液含有1-30mg/ml 25-环己基阿凡曼菌素B1。
4、根据权利要求3的方法,其特征在于,所形成的溶液含有大约10mg/ml 25-环己基阿凡曼菌素B1。
CN90102072A 1989-04-11 1990-04-11 制备抗寄生虫制剂的方法 Expired - Lifetime CN1035356C (zh)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB898908071A GB8908071D0 (en) 1989-04-11 1989-04-11 Antiparasitic formulations
GB8908071.7 1989-04-11
SG27894A SG27894G (en) 1989-04-11 1994-02-22 Injectable compositions containing 25-cyclohexyl-avermectin B1

Publications (2)

Publication Number Publication Date
CN1046282A CN1046282A (zh) 1990-10-24
CN1035356C true CN1035356C (zh) 1997-07-09

Family

ID=26295191

Family Applications (1)

Application Number Title Priority Date Filing Date
CN90102072A Expired - Lifetime CN1035356C (zh) 1989-04-11 1990-04-11 制备抗寄生虫制剂的方法

Country Status (16)

Country Link
EP (1) EP0393890B1 (zh)
JP (1) JPH0647548B2 (zh)
CN (1) CN1035356C (zh)
AP (1) AP133A (zh)
AU (1) AU609660B2 (zh)
CY (1) CY1777A (zh)
DK (1) DK0393890T3 (zh)
EG (1) EG18956A (zh)
ES (1) ES2052173T3 (zh)
FI (1) FI92015C (zh)
GR (1) GR3005794T3 (zh)
HK (1) HK39294A (zh)
NO (1) NO175882C (zh)
OA (1) OA09203A (zh)
RU (1) RU1836084C (zh)
SG (1) SG27894G (zh)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19613972A1 (de) * 1996-04-09 1997-10-16 Bayer Ag Injektionsformulierungen von Avermectinen und Milbemycinen auf Basis von Rizinusöl
EP0928136B1 (en) * 1996-06-05 2003-10-22 Ashmont Holdings Limited Injectable compositions
DE19638045A1 (de) * 1996-09-18 1998-03-19 Bayer Ag Injektionsformulierungen von Avermectinen und Milbemycinen
KR20000025762A (ko) * 1998-10-14 2000-05-06 유충식 이버멕틴류의 가용화 조성물
GB9827727D0 (en) 1998-12-16 1999-02-10 Pfizer Ltd Antiparasitic formulations
NZ590141A (en) * 2008-06-24 2012-05-25 Merial Ltd Anthelminthic formulations including castor oil and another vegetable oil
CA2750626C (en) * 2009-02-16 2013-10-01 Pfizer Inc. High dosage doramectin formulation
WO2011043962A2 (en) * 2009-10-07 2011-04-14 Wyeth Llc Compositions comprising adjuvant, macrolide and proteinaceous antigen and methods of use thereof

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1182857B (it) * 1984-09-14 1987-10-05 Glaxo Group Ltd Composti antibiotici, composizioni antiparassitarie che li contengono e procedimento per prepararli ed applicarli
ES8802229A1 (es) * 1985-04-30 1988-04-16 Glaxo Group Ltd Un procedimiento para preparar nuevos derivados lactonicos macrociclicos.
US4707470A (en) * 1985-05-17 1987-11-17 Smithkline Beckman Corporation Polyene antibiotic emulsion formulation
EP0285561A3 (de) * 1987-03-27 1989-10-25 Ciba-Geigy Ag Parasitizide und insektizide Milbemycin-Derivate
ATE87926T1 (de) * 1987-11-09 1993-04-15 Pfizer Ethylierte avermectine.

Also Published As

Publication number Publication date
FI92015C (fi) 1994-09-26
RU1836084C (ru) 1993-08-23
FI901816A0 (fi) 1990-04-10
SG27894G (en) 1995-03-17
FI92015B (fi) 1994-06-15
NO175882C (no) 1994-12-28
CY1777A (en) 1995-10-20
NO175882B (no) 1994-09-19
DK0393890T3 (da) 1992-09-28
EP0393890A1 (en) 1990-10-24
AU5311990A (en) 1990-11-08
AP9000174A0 (en) 1990-04-30
ES2052173T3 (es) 1994-07-01
JPH02290820A (ja) 1990-11-30
JPH0647548B2 (ja) 1994-06-22
AP133A (en) 1991-06-05
OA09203A (fr) 1992-06-30
GR3005794T3 (zh) 1993-06-07
NO901637D0 (no) 1990-04-10
HK39294A (en) 1994-05-06
CN1046282A (zh) 1990-10-24
EG18956A (en) 1994-04-30
EP0393890B1 (en) 1992-08-12
NO901637L (no) 1990-10-12
AU609660B2 (en) 1991-05-02

Similar Documents

Publication Publication Date Title
EP1136081B1 (en) Sustained-release compositions for the parenteral administration of macrolides
EP0535734B1 (en) Long acting injectable formulations containing hydrogenated castor oil
CN1035356C (zh) 制备抗寄生虫制剂的方法
US6699847B2 (en) Antiparasitic formulation
US6001822A (en) Antiparasitic formulations
JP2012517994A (ja) 高投与量ドラメクチン製剤
AU2001235489A1 (en) Veterinary compositions for the treatment of parasitic diseases
EP1259244A1 (en) Veterinary compositions for the treatment of parasitic diseases
CA2014157C (en) Antiparasitic formulation containing 25-cyclohexyl-avermectin b1
RU2140737C1 (ru) Средство для профилактики и лечения паразитарных заболеваний животных
KR920006913B1 (ko) 구충제 제형
CN116196271A (zh) 宠物用赛拉菌素外用滴剂及其制备方法
Ferguson Anthelmintic activity of ivermectin against Ascaris, Trichuris and Metastrongylus infection in swine

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C14 Grant of patent or utility model
GR01 Patent grant
C15 Extension of patent right duration from 15 to 20 years for appl. with date before 31.12.1992 and still valid on 11.12.2001 (patent law change 1993)
OR01 Other related matters