CN1215331A - 以蓖麻油为基础的阿凡曼菌素和米尔倍霉素的注射制剂 - Google Patents
以蓖麻油为基础的阿凡曼菌素和米尔倍霉素的注射制剂 Download PDFInfo
- Publication number
- CN1215331A CN1215331A CN97193700A CN97193700A CN1215331A CN 1215331 A CN1215331 A CN 1215331A CN 97193700 A CN97193700 A CN 97193700A CN 97193700 A CN97193700 A CN 97193700A CN 1215331 A CN1215331 A CN 1215331A
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- CN
- China
- Prior art keywords
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- oleum ricini
- avermectins
- propylene glycol
- ivermectin
- 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.)
- Granted
Links
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- 239000000203 mixture Substances 0.000 title claims abstract description 11
- 239000007924 injection Substances 0.000 title abstract description 3
- 238000002347 injection Methods 0.000 title abstract description 3
- ZLBGSRMUSVULIE-GSMJGMFJSA-N milbemycin A3 Chemical class O1[C@H](C)[C@@H](C)CC[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 ZLBGSRMUSVULIE-GSMJGMFJSA-N 0.000 title abstract description 3
- 239000004359 castor oil Substances 0.000 title abstract 2
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- 238000009472 formulation Methods 0.000 title abstract 2
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- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 35
- 238000002360 preparation method Methods 0.000 claims description 33
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 claims description 30
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- 239000003381 stabilizer Substances 0.000 claims description 4
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- 150000005676 cyclic carbonates Chemical group 0.000 claims description 3
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 3
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- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 5
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- RCWUXKXEWJVOAO-CVBJKYQLSA-N 2,2-bis(hydroxymethyl)propane-1,3-diol;(z)-octadec-9-enoic acid Chemical compound OCC(CO)(CO)CO.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O RCWUXKXEWJVOAO-CVBJKYQLSA-N 0.000 description 1
- FKOKUHFZNIUSLW-UHFFFAOYSA-N 2-Hydroxypropyl stearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(C)O FKOKUHFZNIUSLW-UHFFFAOYSA-N 0.000 description 1
- WITKSCOBOCOGSC-UHFFFAOYSA-N 2-dodecanoyloxypropyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCC(C)OC(=O)CCCCCCCCCCC WITKSCOBOCOGSC-UHFFFAOYSA-N 0.000 description 1
- OSCJHTSDLYVCQC-UHFFFAOYSA-N 2-ethylhexyl 4-[[4-[4-(tert-butylcarbamoyl)anilino]-6-[4-(2-ethylhexoxycarbonyl)anilino]-1,3,5-triazin-2-yl]amino]benzoate Chemical compound C1=CC(C(=O)OCC(CC)CCCC)=CC=C1NC1=NC(NC=2C=CC(=CC=2)C(=O)NC(C)(C)C)=NC(NC=2C=CC(=CC=2)C(=O)OCC(CC)CCCC)=N1 OSCJHTSDLYVCQC-UHFFFAOYSA-N 0.000 description 1
- BJRXGOFKVBOFCO-UHFFFAOYSA-N 2-hydroxypropyl 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCC(=O)OCC(C)O BJRXGOFKVBOFCO-UHFFFAOYSA-N 0.000 description 1
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- 239000002202 Polyethylene glycol Substances 0.000 description 1
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- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
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- STORWMDPIHOSMF-UHFFFAOYSA-N decanoic acid;octanoic acid;propane-1,2,3-triol Chemical compound OCC(O)CO.CCCCCCCC(O)=O.CCCCCCCCCC(O)=O STORWMDPIHOSMF-UHFFFAOYSA-N 0.000 description 1
- PWEOPMBMTXREGV-UHFFFAOYSA-N decanoic acid;octanoic acid;propane-1,2-diol Chemical compound CC(O)CO.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCCCC(O)=O.CCCCCCCCCC(O)=O PWEOPMBMTXREGV-UHFFFAOYSA-N 0.000 description 1
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- 229910052757 nitrogen Inorganic materials 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
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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
- A61K31/70—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
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Abstract
本发明公开了以蓖麻油为基础的阿凡曼菌素和米尔倍霉素的注射制剂。
Description
本发明涉及新的以蓖麻油为基础的动物用的阿凡曼菌素和米尔倍霉素的注射制剂。
EP-A 146414公开了异阿凡曼菌素的注射制剂。此制剂含有由丙二醇和甲醛缩甘油以60∶40的体积比组成的混合溶剂。已知丙二醇在一定浓度下会产生局部不可耐受性(参见：B.Kruss,ActaPharm.Technol.35(4)(1989)187-196)。也可造成水溶性的生物活性化合物异阿凡曼菌素沉淀在施药位置周围的组织上。因此在应用相应的制剂时可在注射位置观察到显著的肿胀和组织的不相容性。其中有部分在几周后才能恢复原状。
EP-A 393890公开了具体的阿凡曼菌素注射制剂。它们是以芝麻油和油酸乙酯体积比为90∶10为基础的油性制剂。此制剂是可耐受的，但其缺点是，在4℃冰箱中放置几天后就生成絮状沉淀。
EP-A 45655公开了阿凡曼菌素的其它注射制剂。所描述的制剂含有较高的乳化剂份额并在一些情况下是非常不可耐受的。
含有Triacetin(甘油三乙酸酯)的阿凡曼菌素的注射制剂在EP-A 413538中曾有描述。在EP-A 535734中描述了以甘油三乙酸酯和氢化的蓖麻油为基础的阿凡曼菌素注射制剂。
其它的用于米尔倍霉素和阿凡曼菌素的注射制剂在EP-A525307中曾有描述。制剂是这样配制的，在其中将甘油三硬脂酸酯与活性化合物熔化和与油状中性的甘油三酯混合和采用例如甲基纤维素和盐进行乳化。这样得到的微乳液的平均粒度在25μm和300μm之间。
本发明的主题是以蓖麻油为基础的阿凡曼菌素和米尔倍霉素的注射制剂。
制剂优选含有：
1．活性化合物0.1至10％(重量)
2．蓖麻油15至50％(重量)
3．由一元或多元醇的植物或合成的脂肪酸酯、脂肪族或芳香族醇、环状碳酸酯组成的系列的浓度为30至85％(重量)的一种或多种共溶剂。
4．必要时还有其它的助剂。
本发明的制剂对活性化合物具有突出的溶解性。
蓖麻油的高粘度可通过加入中等链长的甘油三酯或丙二醇辛酸酯/癸酸酯或油酸乙酯调节成所需的低值。此外可通过加入较小体积的疏水溶剂如苯甲醇，丙二醇或亚丙基碳酸酯在保持单相体系的情况下改进活性化合物的溶解度，进一步降低粘度和改进活性化合物的生物利用度。这新的制剂具有极好的高可耐受性和显示高的生物利用度。
在本发明的制剂中用的活性化合物是已知的。
阿凡曼菌素是从微生物Streptomyces avermitilis中作为微生物的代谢产物而分离出的(US-Pat.4 310 519)并可基本上以由8个组分A1a,A1b,A2a,A2b,B1a,B1b,B2a和B2b组成的混合物存在。(I.Putter et al.Experentia37(1981)S.963,Birkhuser Verlag(Schweiz))。此外合成的衍生物，尤其22,23二氢阿凡曼菌素B1(异阿凡曼菌素)也具有意义(US-Pat.4 199569)。米尔倍霉素B-41D是通过发酵从Streptomyceshygroscopicus分离出来(参见“Milbemycin:Discovery andDevelopment”I.Junya等人，Annu.Rep.Sankyo Res.Lab.45(1993),S.1-98,JP-Pat.8 378 549；GB1 390336)。
阿凡曼菌素，例如22,23二氢阿凡曼菌素B1(异阿凡曼菌素)和米尔倍霉素已知可作为杀内寄生虫剂并且是有许多专利申请及概述文章的主题(例如生物作用在：“Ivermectin and Abamectin”W.C.Campbell,Ed.,Springer Verlag,New York,N.Y.,1989；“Avermectins and Milbemycins Part Ⅱ”H.G.Davies etal.Chem.Soc.Rev.20(1991)S.271-339；ChemischeModifikationen in:G.Lukacs et al.(Eds.),SpringerVerlag,New York,(1990),Chapter3；Cydectin[Moxidectin und Derivate]:G.T.Carter et al.J.Chem.Soc.Chem.Commun.(1987),S.402-404)；EP423445-Al)“Doramectin:a potent novel endectozide”A.C.Goudie et al.Vet.Parasitol.49(1993),S.5-15)。
特别可强调的是下列式(Ⅰ)的阿凡曼菌素和其衍生物：
其中
基团R1至R4的意义列在下表1中和X是表示在C22-和C23-位之间(-C22R1-X-C23R2-)的单键或双键。
如是双键则在C22-和C23-位置无取代基(R1,R2)。
表1
| 大环状内酯 | -C22R1-X-C23R2- | R3 | R4 |
| 阿凡曼菌素A1a | -CH=CH- | -sec-Bu | -Me |
| 阿凡曼菌素A1b | -CH=CH- | -iso-Pr | -Me |
| 阿凡曼菌素A2a | -CH2-CHOH- | -sec-Bu | -Me |
| 阿凡曼菌素A2b | -CH2-CHOH- | -iso-Pr | -Me |
| 阿凡曼菌素B1a | -CH=CH- | -sec-Bu | -H |
| 阿凡曼菌素B1b | -CH=CH- | -iso-Pr | -H |
| 阿凡曼菌素B2a | -CH2-CHOH- | -sec-Bu | -H |
| 阿凡曼菌素B2b | -CH2-CHOH- | -iso-Pr | -H |
| 22,23-二氢阿凡曼菌素B1a | -CH2-CH2- | -sec-Bu | -H |
| 22,23-二氢阿凡曼菌素B1b | -CH2-CH2- | -iso-Pr | -H |
| Doramectin | -CH=CH- | -Chx | -H |
22,23-二氢阿凡曼菌素B1即为异阿凡曼菌素；sec-Bu=仲-丁基；iso-Pr=异丙基；Chx=环己基；-Me=甲基
通式(Ⅰ)的阿凡曼菌素和22,23-二氢阿凡曼菌素B1(异阿凡曼菌素)通常作为混合物应用。特别重要的是产品阿巴美丁(abamectin)，它基本上含有阿凡曼菌素B1，及其氢化产品，22,23-二氢阿凡曼菌素B1(异阿凡曼菌素)。
用“b”标志的在C25-位置有异丙基的大环内酯的化合物不必与C25-位置有仲-丁基的“a”化合物分离。一般是将由＞80％的仲-丁基衍生物(B1a)和＜20％的异-丙基衍生物(B1b)组成的两种物质的混合物分离出来和可按本发明应用。此外，在立体异构体中在C13-和C23-位置的取代基既可以α-位也可以β-位排列在环系统上，即该取代基可处于分子平面的上方或下方。在每种情况下，按本发明所有的立体异构体都考虑。
特别可以提及米尔倍霉素。米尔倍霉素与阿凡曼菌素或22,23-二氢阿凡曼菌素B1(异阿凡曼菌素)具有相同的大环内酯结构，但在13位不带有任何取代基(R5=氢)(即去掉了齐墩果糖二糖片段)。
作为大环内酯类的米尔倍霉素的实例可列举通式为(Ⅱ)的化合物
其中R1至R5基团的意义列于下面表2中。
表2
iso-Pr=异丙基
特别要强调的是以下活性物质
阿凡曼菌素B1a/B1b(阿巴美丁)，
22,23-二氢阿凡曼菌素B1a/B1b(异阿凡曼菌素)，
Doramectin,
Moxidectin。
活性物质在本发明的制剂中浓度为0.1至10％(重量)，优选为0.5-5％(重量)，特别优选为1-2％(重量)。
在本发明的制剂中采用的蓖麻油是已知的。其浓度为15至50％(重量)。
在本发明制剂中所采用的共溶剂是已知的。
适用的多元醇的植物-或合成的脂肪酸酯(油)是脂肪酸甘油三酯，优选是带有中等链长的脂肪酸甘油三酯。特别适用的是中性油，如中性植物油，和尤其是分馏的椰子油，例如众所周知的和在商业上可以得到的商品Miglyol。为此也参见助剂词典(助剂词典，第三版，第808至809页(1989)，作者Fiedler,(Lexikon der Hilfsstoffe,3,Auflage,Seiten 808至809,(1989)von Fiedler))。在此例如属于此类的是：Miglyol 810：它是一种分馏的椰子油，含有辛酸和癸酸的甘油三酯，分子量大约为520。其脂肪酸组成为C6最多占2％,C8约65-75％,C10约25-35％和C12最多2％，酸值大约为0.1,具有皂化值约340-360和碘值最大为1。Miglyol 812：它是一种分馏的椰子油，它含有辛酸和癸酸的甘油三酯和分子量约为520。其脂肪酸组成为C6最多为3％,C8约为50-65％,C10约30-45％和C12最多为5％，酸值约为0.1，皂化值约为330-345和碘值最多为1。Miglyol818：是辛酸、癸酸和亚麻酸的甘油三酯，分子量约为510。其脂肪酸组成为C6最多为3％,C8约为45-60％,C10约25-40％,C12约2-5％和C18约4-6,酸值约为0.2，皂化值约315-335和碘值最大为10。Captex 355(1)：辛酸和癸酸的甘油三酯。此甘油三酯的脂肪酸含量为己酸约2％，辛酸约55％，癸酸约42％。酸值最大为0.1，皂化值最大约为325-340和碘值最大为0.5。此外辛酸和癸酸的甘油三酯也是适用的，如已知商标为Myritol，在商业上也可获得的产品，为此参见助剂词典(Lexikon der Hilfsstoffe,3,Auflage,Seite 834(1989)von Fiedler)。属于这类产品的Myritol 813的酸值最大为1，皂化值约为340-350和碘值约为0.5。
其它适用的是：甘油单酯，甘油二酯和甘油单/二酯，尤其是辛酸或癸酸与甘油的酯化产品。优选的这类产品例如是含有辛酸/癸酸的甘油单酯和甘油二酯的产品或基本上或实际上由其组成的产品，这些产品在商业上以商标Imwitor可以得到，为此参考助剂词典(Lexikon derHilfsstoffe,3,Auflage,Seite645(1989)von Fiedler)。在此类产品中对在本发明组合物应用中特别适用的产品是Imwitor 742,它是一种由约60重量份(ppw)的辛酸和约40重量份(ppw)的癸酸的混合物与甘油的酯化产品。Imwiton 742通常是黄色结晶物质，它大约在26℃成液体。它的酸值最大为2，碘值最大为1，皂化值大约为235-275，含有大约40-50％的甘油单酯，含游离甘油最多为2％，熔点约为24-26℃，含不可皂化的组分最多为0.3％和过氧化物值最大为1。
不同的已知品种的脱水山梨糖醇脂肪酸酯，例如它以斯潘(Span)为商标在商业上可得到，例如归属于此类的有脱水山梨糖醇单月桂基酯，脱水山梨糖醇单棕榈基酯，脱水山梨糖醇单硬脂酰酯，脱水山梨糖醇硬脂酰三酯，脱水山梨糖醇单油酸酯和脱水山梨糖醇三油酸酯，这些例如参见助剂词典(Lexikon der Hilfsstoffe,3,Auflage,Seiten1139-1140(1989)von Fiedler)。
季戊四醇脂肪酸和聚亚烷基二醇醚，如季戊四醇二油酸酯，季戊四醇硬脂酸酯，季戊四醇单月桂酸酯，季戊四醇聚乙二醇醚和季戊四醇单硬脂酸酯和季戊四醇脂肪酸酯，这些参见助剂词典(Lexikon derHilfsstoffe,3,Auflage,Seiten 923-924(1989)vonFiedler)。
甘油单酯，如甘油单油酸酯，甘油单棕榈酸酯，甘油单硬脂酸酯，例如它们以Myvatex,Myvaplex和Myverol为商标是已知的和在商业上是可得到的。这些参见助剂词典(Lexikon der Hilfsstoffe,3,Auflage,Seiten 836(1989)von Fiedler)，和乙酰化的例如单乙酰化的和二乙酰化的甘油单酯，例如它以Myvacet为商标是已知的和在商业上是可得到的，这些参见助剂词典(Lexikon der Hilfsstoffe,3,Auflage,Seite835(1989)von Fiedler)。
丙二醇的单和二脂肪酸酯，如丙二醇二辛酸酯，丙二醇二月桂酸酯，丙二醇羟基硬脂酸酯，丙二醇异硬脂酸酯，丙二醇月桂酸酯，丙二醇蓖麻油酸酯，丙二醇硬脂酸酯等，这些参见助剂词典(Lexikon derHilfsstoffe,3,Auflage,Seiten 1013 ff.(1989)von Fiedler)。特别优选的是丙二醇的辛酸和癸酸的二酯，它以商标Miglyol 840为已知的和在商业上可得到的，为此参见助剂词典(Lexikon derHilfsstoffe,3,Auflage,Seite 809(1989)von Fiedler)。Migtyol 840的脂肪酸含量为C6最多约3％,C8约65-80％,C10约15-30％和C12最多为3％,和酸值最多为0.1，皂化值约为320340和碘值最多为1。此类中其它适用的产品是Capmul MCT(1),Captex 300(1),Captex 800(1),Neobee M5(2)和Mazol 1400(3)Imwitor(4)(1)=首都产品(Capital City Products),P.O.Box 569,Columbus,OH,USA(2)=Stepan,PVO Dept.,100West Hunter Ave.,Maywood,NJ 07607,USA(3)=Mazer Chemicals,3938Porett Drive,Gurnee,IL,USA(4)=Hüls AG,14370 Marl,Deutschland
其它共溶剂是苯甲醇，它同时作为防腐剂用，醇例如乙醇，乙二醇，甘油，环状碳酸酯，如亚丙基碳酸酯。共溶剂的浓度为30-85％(重量)。
其它添加剂是稳定剂如丁基羟基苯甲醚(BHA)，丁基羟基甲苯(BHT)或没食子酸丙酯总共至1000ppm。特适用的稳定剂组合和浓度是例如100ppm BHA或100ppm BHA加150ppm没食子酸丙酯或200ppm BHA加100ppm没食子酸丙酯。
本发明制剂的粘度在25至60mPa.s(20℃)之间，优选在30至55mPa.s(20℃)之间，特别优选在35和51mPa.s(20℃)之间。
下面实例解释本发明
注释：
1％M/V即是在1ml溶液中有10mg活性化合物。实例1a)Miglyol812q.s.100％V/Vb)Miglyol812q.s.100％V/V
蓖麻油 20％V/V 蓖麻油 20％V/V
苯甲醇 2％V/V 苯甲醇 2％V/V
异阿凡曼菌素 1％M/V 异阿凡曼菌素 2％M/V
密度： 0.954g/ml 密度： 0.956g/ml
粘度：在20℃为48mPa.s 粘度：在20℃为48mPa.s
在5℃为95mPa.s 在5℃为105mPa.s实例2a)Miglyol812q.s.100％V/V b)Miglyol812q.s.100％V/V
蓖麻油 20％V/V 蓖麻油 20％V/V
亚丙基碳酸酯 3％V/V 亚丙基碳酸酯 3％V/V
苯甲醇 2％V/V 苯甲醇 2％V/V
异阿凡曼菌素 1％M/V 异阿凡曼菌素 2％M/V
密度： 0.962g/ml 密度： 0.964g/ml
粘度：在20℃为42mPa.s 粘度：在20℃为44mPa.s
在5℃为91mPa.s 在5℃为97mPa.s实例3a)Miglyol812q.s.100％V/V b)Miglyol812q.s.100％V/V
蓖麻油 20％V/V 蓖麻油 20％V/V
异阿凡曼菌素 1％M/V 异阿凡曼菌素 2％M/V
密度： 0.952g/ml 密度： 0.954g/ml
粘度：在20℃为51mPa.s 粘度：在20℃为51mPa.s
在5℃为105mPa.s 在5℃为117mPa.s实例4a)Miglyol812q.s.100％V/V b)Miglyol812q.s.100％V/V
蓖麻油 35％V/V 蓖麻油 35％V/V
异阿凡曼菌素 1％M/V 异阿凡曼菌素 2％M/V
密度： 0.939g/ml 密度： 0.941g/ml
粘度：在20℃为38mPa.s 粘度：在20℃为42mPa.s
在5℃为75mPa.s 在5℃为76mPa.s实例5a)油酸乙酯q.s.100％V/V b)油酸乙酯q.s.100％V/V
蓖麻油 45％V/V 蓖麻油 45％V/V
异阿凡曼菌素 1％M/V 异阿凡曼菌素 2％M/V
密度： 0.916g/ml 密度： 0.918g/ml
粘度：在20℃为40mPa.s 粘度：在20℃为49mPa.s
在5℃为91mPa.s 在5℃为98mPa.s实例6a)Miglyol840q.s.100％V/V b)Miglyol840q.s.100％V/V
蓖麻油 35％V/V 蓖麻油 35％V/V
丙二醇 5％V/V 丙二醇 5％V/V
苯甲醇 5％V/V 苯甲醇 5％V/V
异阿凡曼菌素 1％M/V 异阿凡曼菌素 2％M/V
密度：0.952g/ml 密度： 0.954g/ml
粘度：在20℃为36mPa.s 粘度：在20℃为38mPa.s
在5℃为76mPa.s 在5℃为81mPa.s实例7a)油酸乙酯q.s.100％V/V
蓖麻油 40％V/V
丙二醇 5％V/V
苯甲醇 5％V/V
异阿凡曼菌素 1％M/V
密度： 0.926g/ml
粘度： 在20℃为34mPa.s， 在5℃为70mPa.s实例8a)Miglyol840q.s.100％V/V
蓖麻油 35％V/V
苯甲醇 20％V/V
异阿凡曼菌素 1％M/V
密度： 0.965g/ml
粘度：在20℃为28mPa.s
在5℃为56mPa.s实例9a)Miglyol840q.s.100％V/V
蓖麻油 35％V/V
亚丙基碳酸酯 10％V/V
苯甲醇 5％V/V
异阿凡曼菌素 1％M/V
密度： 0.975g/ml
粘度：在20℃为27mPa.s
在5℃为53mPa.s实例10a)Imwitor408q.s.100％V/V
蓖麻油 30％V/V
异阿凡曼菌素 1％M/V
密度： 0.953g/ml
粘度：在20℃为30mPa.ms
在5℃为66mPa.s
Imwitor是Hüls公司的商品名，Imwitor408是1,2-丙二醇单-二辛酯(INCI(CTFA)-标志)。按照目前的产品信息Imwitor大约含10％的游离丙二醇和约50％甘油单酯。对异阿凡曼菌素显示高溶解性能(＞20％M/V)。实例1至10用于注射的无菌溶液的一般制造规程
将制剂的助剂称量加入到一不锈钢容器中和搅拌均化。在继续搅拌下加入异阿凡曼菌素。将混合物温热至40至50℃，以加速活性化合物的溶解(尽可能在氮气保护下)。在完全溶解后在同样温度用0.22μm滤器进行无菌过滤(通常在前面放有0.45μm或1μm滤器)。将溶液无菌装填在褐色玻璃瓶中。
这样制备的制剂特别适用于牛。此外它在4℃和60℃之间的温度贮存超过至少6个星期都是稳定的。
Claims (6)
1．以蓖麻油为基础的阿凡曼菌素和米尔倍霉素的注射制剂。
2．按权利要求1的制剂，其特征在于，它们有以下的组成：
1．活性化合物0.1至10％(重量)
2．蓖麻油15至50％(重量)
3．来自由一元或多元醇的植物或合成的脂肪酸酯、脂肪族或芳香族醇、环状碳酸酯组成的系列的一种或多种共溶剂，浓度为30至85％(重量)
4．必要时其它的助剂。
3．按权利要求1的制剂，组成如下：0.1至10％M/V的阿凡曼菌素或米尔倍霉素在由15-50％V/V蓖麻油，及30至85％V/V的中等链长的甘油三酯和/或丙二醇辛酸酯/癸酸酯和/或油酸乙酯组成的溶剂混合物中和0至30％V/V由苯甲醇，丙二醇或亚丙基碳酸酯溶剂组成的混合物以及任选地最多1000ppm的稳定剂。
4．按权利要求1的制剂，组成如下：20至45％V/V蓖麻油，45-80％V/V中等链长的甘油三酯或丙二醇辛酸酯/癸酸酯或油酸乙酯和0-20％V/V苯甲醇，0-10％V/V丙二醇或亚丙基碳酸酯及任选地最多500ppm的稳定剂。
5．按权利要求1制剂的制备方法，其特征在于，将活性化合物与蓖麻油混合和加入共溶剂或将活性化合物溶解在蓖麻油和共溶剂的混合物中。
6．蓖麻油用于制备权利要求1制剂的应用。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19613972A DE19613972A1 (de) | 1996-04-09 | 1996-04-09 | Injektionsformulierungen von Avermectinen und Milbemycinen auf Basis von Rizinusöl |
| DE19613972.4 | 1996-04-09 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1215331A true CN1215331A (zh) | 1999-04-28 |
| CN1095662C CN1095662C (zh) | 2002-12-11 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97193700A Expired - Lifetime CN1095662C (zh) | 1996-04-09 | 1997-03-27 | 以蓖麻油为基础的阿凡曼菌素或米尔倍霉素的注射制剂、其制备以及蓖麻油的相关应用 |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US6063394A (zh) |
| EP (1) | EP0896534B1 (zh) |
| JP (1) | JP4257870B2 (zh) |
| CN (1) | CN1095662C (zh) |
| AT (1) | ATE285233T1 (zh) |
| AU (1) | AU718807B2 (zh) |
| BR (1) | BR9708540B1 (zh) |
| CA (1) | CA2251087C (zh) |
| DE (2) | DE19613972A1 (zh) |
| ES (1) | ES2235230T3 (zh) |
| HK (1) | HK1019404A1 (zh) |
| NZ (1) | NZ332224A (zh) |
| PT (1) | PT896534E (zh) |
| WO (1) | WO1997037653A1 (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003101419A1 (fr) * | 2002-05-31 | 2003-12-11 | Eco Animal Health Ltd | Produit d'injection a liberation soutenue contenant des substances anti-parasites |
| CN101773467B (zh) * | 2010-01-20 | 2015-09-09 | 北京大北农动物保健科技有限责任公司 | 一种美贝霉素或美贝霉素肟的兽用缓释注射液及制备方法 |
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|---|---|---|---|---|
| DE19638045A1 (de) * | 1996-09-18 | 1998-03-19 | Bayer Ag | Injektionsformulierungen von Avermectinen und Milbemycinen |
| EA002497B1 (ru) * | 1997-12-03 | 2002-06-27 | Мерк Энд Ко., Инк. | Инъекционные композиции пролонгированного действия, содержащие гидрогенизированное касторовое масло |
| US6174540B1 (en) | 1998-09-14 | 2001-01-16 | Merck & Co., Inc. | Long acting injectable formulations containing hydrogenated caster oil |
| GB9827727D0 (en) * | 1998-12-16 | 1999-02-10 | Pfizer Ltd | Antiparasitic formulations |
| GB0000313D0 (en) | 2000-01-10 | 2000-03-01 | Astrazeneca Uk Ltd | Formulation |
| AU781682B2 (en) * | 2000-03-20 | 2005-06-09 | Zoetis Services Llc | Sustained-release compositions for parenteral administration |
| US20050009762A1 (en) * | 2003-06-06 | 2005-01-13 | Strobel Michael Albert | Application of water and organic solvent soluble ivermectin for topical and oral use |
| US7262214B2 (en) | 2003-02-26 | 2007-08-28 | Merial Limited | 1-N-arylpyrazole derivatives in prevention of arthropod-borne and mosquito-borne diseases |
| US20050271459A1 (en) * | 2004-06-03 | 2005-12-08 | World Wide Stationery Mfg. Co., Ltd. | Interlocking ring tip formations for paired ring members of a ring binder mechanism |
| NZ534939A (en) * | 2004-08-26 | 2007-04-27 | Bomac Research Ltd | Injectable formulation comprising an anthelmintic compound with complexing compound for improved solubility |
| DE102004053964A1 (de) * | 2004-11-09 | 2006-05-11 | Bayer Healthcare Ag | Mittel gegen Demodikose |
| WO2009027697A2 (en) * | 2007-08-31 | 2009-03-05 | Archimedes Development Limited | Non-aqueous pharmaceutical compositions |
| 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 |
| KR101805087B1 (ko) * | 2010-09-16 | 2017-12-05 | 주식회사 엘지화학 | 높은 방부력을 제공하는 오일 주사 제형 |
| CA2867079A1 (en) | 2012-03-13 | 2013-09-19 | Bayer New Zealand Limited | Long acting compositions |
| SI3723739T1 (sl) | 2017-12-15 | 2024-08-30 | Tarsus Pharmaceuticals, Inc. | Paraziticidni pripravki na osnovi izoksazolina in njihova uporaba za zdravljenje blefaritisa |
| CN113507922A (zh) * | 2019-03-01 | 2021-10-15 | 勃林格殷格翰动物保健美国公司 | 可注射的氯舒隆组合物、其方法和用途 |
| US11638714B2 (en) | 2020-11-10 | 2023-05-02 | Mountain Valley Md Inc | Water dissolvable macrocyclic lactone cyclodextrin complexes |
| US11077134B1 (en) | 2020-11-10 | 2021-08-03 | Mountain Valley Md Inc | Water dissolvable macrocyclic lactone cyclodextrin complexes |
| CN114642632A (zh) * | 2022-02-25 | 2022-06-21 | 河北科技大学 | 一种莫西克汀注射液及其制备方法 |
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| US4199569A (en) * | 1977-10-03 | 1980-04-22 | Merck & Co., Inc. | Selective hydrogenation products of C-076 compounds and derivatives thereof |
| OA06863A (fr) * | 1980-08-04 | 1983-02-28 | Merck & Co Inc | Solubilisation de l'invermectine dans l'eau. |
| NZ210505A (en) * | 1983-12-22 | 1988-06-30 | Merck & Co Inc | Parasiticidal compositions containing avermectin or milbemycin derivatives |
| DE3727648A1 (de) * | 1987-08-19 | 1989-03-02 | Bayer Ag | Neue avermectin derivate, verfahren zu ihrer herstellung und ihre verwendung |
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| EP0393890B1 (en) * | 1989-04-11 | 1992-08-12 | Pfizer Limited | Injectable compositions containing 25-cyclohexyl-avermectin b1 |
| NZ234802A (en) * | 1989-08-14 | 1992-11-25 | Merck & Co Inc | Long acting injectable formulations comprising an avermectin compound and triacetin. treatment for internal and external parasites of animals |
| DE69208765T2 (de) * | 1991-07-23 | 1996-09-26 | American Cyanamid Co | Stabile Zusammensetzungen für parenterale Verabrechung und ihre Verwendung |
| ES2131515T3 (es) * | 1991-09-30 | 1999-08-01 | Merck & Co Inc | Formulados inyectables de accion prolongada que contienen aceite de ricino hidrogenado. |
| WO1994008566A1 (en) * | 1992-10-21 | 1994-04-28 | Micro Vesicular Systems, Inc. | Entrapment vehicle and method |
-
1996
- 1996-04-09 DE DE19613972A patent/DE19613972A1/de not_active Withdrawn
-
1997
- 1997-03-27 CA CA002251087A patent/CA2251087C/en not_active Expired - Lifetime
- 1997-03-27 CN CN97193700A patent/CN1095662C/zh not_active Expired - Lifetime
- 1997-03-27 AU AU25066/97A patent/AU718807B2/en not_active Expired
- 1997-03-27 AT AT97916406T patent/ATE285233T1/de active
- 1997-03-27 ES ES97916406T patent/ES2235230T3/es not_active Expired - Lifetime
- 1997-03-27 EP EP97916406A patent/EP0896534B1/de not_active Expired - Lifetime
- 1997-03-27 WO PCT/EP1997/001569 patent/WO1997037653A1/de active IP Right Grant
- 1997-03-27 JP JP53579597A patent/JP4257870B2/ja not_active Expired - Fee Related
- 1997-03-27 PT PT97916406T patent/PT896534E/pt unknown
- 1997-03-27 US US09/155,836 patent/US6063394A/en not_active Expired - Lifetime
- 1997-03-27 NZ NZ332224A patent/NZ332224A/en not_active IP Right Cessation
- 1997-03-27 DE DE59712134T patent/DE59712134D1/de not_active Expired - Lifetime
- 1997-03-27 BR BRPI9708540-5A patent/BR9708540B1/pt active IP Right Grant
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1999
- 1999-10-14 HK HK99104544A patent/HK1019404A1/xx not_active IP Right Cessation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003101419A1 (fr) * | 2002-05-31 | 2003-12-11 | Eco Animal Health Ltd | Produit d'injection a liberation soutenue contenant des substances anti-parasites |
| CN101773467B (zh) * | 2010-01-20 | 2015-09-09 | 北京大北农动物保健科技有限责任公司 | 一种美贝霉素或美贝霉素肟的兽用缓释注射液及制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| ES2235230T3 (es) | 2005-07-01 |
| AU2506697A (en) | 1997-10-29 |
| EP0896534A1 (de) | 1999-02-17 |
| HK1019404A1 (en) | 2000-02-11 |
| PT896534E (pt) | 2005-04-29 |
| CA2251087C (en) | 2008-01-15 |
| NZ332224A (en) | 2000-06-23 |
| CA2251087A1 (en) | 1997-10-16 |
| BR9708540B1 (pt) | 2010-07-27 |
| JP2000508301A (ja) | 2000-07-04 |
| WO1997037653A1 (de) | 1997-10-16 |
| BR9708540A (pt) | 1999-08-03 |
| AU718807B2 (en) | 2000-04-20 |
| CN1095662C (zh) | 2002-12-11 |
| US6063394A (en) | 2000-05-16 |
| EP0896534B1 (de) | 2004-12-22 |
| DE59712134D1 (de) | 2005-01-27 |
| JP4257870B2 (ja) | 2009-04-22 |
| DE19613972A1 (de) | 1997-10-16 |
| ATE285233T1 (de) | 2005-01-15 |
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