CN1230890A - 阿凡曼菌素和米尔倍霉素的注射剂 - Google Patents
阿凡曼菌素和米尔倍霉素的注射剂 Download PDFInfo
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- CN1230890A CN1230890A CN97198028A CN97198028A CN1230890A CN 1230890 A CN1230890 A CN 1230890A CN 97198028 A CN97198028 A CN 97198028A CN 97198028 A CN97198028 A CN 97198028A CN 1230890 A CN1230890 A CN 1230890A
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- benzyl alcohol
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- 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 2
- 239000007972 injectable composition Substances 0.000 title 1
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- 229960002418 ivermectin Drugs 0.000 claims description 14
- 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 13
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 10
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 claims description 8
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims description 8
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- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 6
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- 150000002148 esters Chemical class 0.000 description 3
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- 239000003120 macrolide antibiotic agent Substances 0.000 description 3
- 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 3
- 235000010388 propyl gallate Nutrition 0.000 description 3
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 2
- 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 description 2
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- 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 2
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- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- UWHCKJMYHZGTIT-UHFFFAOYSA-N tetraethylene glycol Chemical compound OCCOCCOCCOCCO UWHCKJMYHZGTIT-UHFFFAOYSA-N 0.000 description 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 2
- GHHURQMJLARIDK-UHFFFAOYSA-N 2-hydroxypropyl octanoate Chemical compound CCCCCCCC(=O)OCC(C)O GHHURQMJLARIDK-UHFFFAOYSA-N 0.000 description 1
- 108010001394 Disaccharidases Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DBDJCJKVEBFXHG-UHFFFAOYSA-N L-Oleandrose Natural products COC1CC(O)OC(C)C1O DBDJCJKVEBFXHG-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- DBDJCJKVEBFXHG-BNHYGAARSA-N Oleandrose Natural products O(C)[C@H]1[C@H](O)[C@H](C)O[C@H](O)C1 DBDJCJKVEBFXHG-BNHYGAARSA-N 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 229910000831 Steel Inorganic materials 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
- 229940000188 cydectin Drugs 0.000 description 1
- UYAAVKFHBMJOJZ-UHFFFAOYSA-N diimidazo[1,3-b:1',3'-e]pyrazine-5,10-dione Chemical compound O=C1C2=CN=CN2C(=O)C2=CN=CN12 UYAAVKFHBMJOJZ-UHFFFAOYSA-N 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
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- GOYBREOSJSERKM-ACZMJKKPSA-N oleandrose Chemical compound O=CC[C@H](OC)[C@@H](O)[C@H](C)O GOYBREOSJSERKM-ACZMJKKPSA-N 0.000 description 1
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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
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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
- A61K31/335—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
- 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
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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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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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
- A61K47/44—Oils, 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
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- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
本发明涉及基于含有芝麻油、中等链长甘油三酯、二醇酯或脂肪酸酯和一种其他选自单－或多羟基脂肪族或芳族醇和它们的衍生物(例如环状碳酸酯、乙酸酯、缩醛、缩酮)或蓖麻油的溶剂的溶剂混合物的阿凡曼菌素和米尔倍霉素的注射剂。
Description
本发明涉及新的基于含芝麻油的溶剂混合物的阿凡曼菌素和米尔倍霉素的注射剂。
异阿凡曼菌素的注射剂被揭示于EP-A-146414中。该制剂含有比率为60∶40v/v的丙二醇和环亚甲基甘油醚的溶剂混合物。人们已经知道，某些浓度的丙二醇可以引起局部无法忍受(参见综述：B.Kruss,Acta Pharm.Technol.35(4)(1989)187-196)。在给药部位附近的组织中也会发生水不溶性活性化合物异阿凡曼菌素的沉淀。因此，当使用相应的制剂时，在注射部位观察到明显肿胀和组织不相容，这种状况有时经过数周之后仍然存在。
具体的阿凡曼菌素注射剂被揭示于EP-A-393890中。它们是基于比率为90∶10v/v的芝麻油和油酸乙酯的油制剂。这些制剂是可以耐受的，但是它们有缺陷，即阿凡曼菌素/米尔倍霉素的溶解性不足使得通常不能够获得使用时需要的1％m/v或更高的浓度。通常，在高温条件下(T≥80℃)获得过饱和的1％m/v溶液，其在较低温度下又持续结晶出来。
阿凡曼菌素的其他注射剂公开在EP-A-45655中。该文献中描述的制剂含有较高量的乳化剂，并在某些情况下不能被很好地耐受。
含有三醋精(甘油三乙酸酯)的阿凡曼菌素注射剂描述在EP-A-413538中。在EP-A-535734中描述了基于三醋精和氢化蓖麻油的阿凡曼菌素注射剂。
米尔倍霉素和阿凡曼菌素的其他注射制剂描述在EP-A-525307中。该制剂通过熔化甘油三硬脂酸酯和活性化合物和与油性天然甘油三酯混合和使用例如甲基纤维素和盐乳化制备。由此得到的微乳液的平均颗粒大小是25-300微米。
本发明涉及基于含有芝麻油，中等链长甘油三酯或二醇酯或脂肪酸酯和一种其它溶剂的溶剂混合物的阿凡曼菌素和米尔倍霉素的注射剂。
该制剂优选含有：
1．活性化合物0.2-5％m/v；
2．芝麻油60-90％v/v；
3．中等链长甘油三酯或二醇酯或脂肪酸酯10-30％(体积)；
4．1-20％(体积)的苯甲醇或丙二醇或其他适合的脂肪族或芳族单-或多羟基醇和它们的衍生物(例如环状碳酸酯，乙酸酯，乙缩醛/缩酮)或蓖麻油；5．如果适当的话，其它辅助剂。
本发明的制剂具有明显的对活性化合物的溶解性。
通过加入中等链长甘油三酯或丙二醇辛酸酯/癸酸酯或尤其是油酸乙酯可以将芝麻油的高粘度调节至所需的低粘度。此外，通过加入较小体积的亲水性溶剂如苯甲醇，丙二醇或丙二醇碳酸酯并且保持单相系统，活性化合物的溶解性可以被改善，粘度可以被进一步降低，活性化合物的生物利用度可以被改善。蓖麻油是对涉及的活性化合物具有高溶解力的唯一的甘油三酯。
在本发明的制剂中使用的活性化合物是已知的。
阿凡曼菌素作为微生物的代谢产物从微生物--除虫链霉菌分离得到(US4310519)，并且基本上以A1a,A1b,A2a,A2b,B1a,B1b,B2a,和B2b的八种组分的混合物存在(I.Putter等，Experentia 37(1981)第963页，Birkhauser Verlag(Switzerland))。此外，人们对其合成衍生物，特别是22,23-二氢阿凡曼菌素B1(异阿凡曼菌素)也很有兴趣(US4199569)。米尔倍霉素B-41D从吸水链霉菌通过发酵分离得到(参见“米尔倍霉素：发现和开发”I.Junya等，Annu.Rep.Sankyo Res.Lab.45(1993)，第1-98页；日本专利8378549；GB1390336)。
将阿凡曼菌素类，例如22,23-二氢阿凡曼菌素B1(异阿凡曼菌素)和米尔倍霉素用作杀内寄生虫药早已为人所知，并且是许多专利申请和论文综述的主题(例如，有关生物学效果方面：“Ivermectinand Abamectin”W.C.Campbell,Ed.,Springer Verlag,New York,N.Y.,1989；“阿凡曼菌素和米尔倍霉素类，第Ⅱ部分”，H.G.Davieset al.Chem.Soc.Rev.20(1991)pp271-339；有关化学修饰方面：G.Lukacs et al.(Eds)。Springer-Verlag,New York,(1990)，第三章；Cydectin[Moxidectin and derivatives]:G.T.Carter et al.《英国化学会志》，化学通报，(1987),pp.402-404；EP423445A1)。“doramectin-一种新的强力杀内寄生虫药”A.C.Goudie etal.Vet.parasitol.49(1993),pp5-15)。
可以被特别强调的阿凡曼菌素类及其衍生物是那些具有通式(Ⅰ)的化合物：
如果有双键存在，在C22与C23位置没有取代基(R1,R2)。表1
22,23-二氢阿凡曼菌素B1是异阿凡曼菌素；sec-Bu=仲丁基；iso-Pr=异丙基；Chx=环己基；Me=甲基
| 大环内酯 | -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 |
通式(Ⅰ)的阿凡曼菌素类和22,23-二氢阿凡曼菌素B1(异阿凡曼菌素)通常作为混合物使用。其中特别有意义的是产物阿巴美丁，其含有阿凡曼菌素B1，和它们的氢化产物，22,23-二氢阿凡曼菌素B1(异阿凡曼菌素)。
不必将在C25位置上有一个异丙基团的标有“b”的大环内酯化合物从在C25位置上有仲丁基的“a”化合物中分离。一般是分离到这两种化合物的混合物，其中仲丁基衍生物(B1a)占80％以上，异丙基衍生物(B1b)不足20％，根据本发明可以使用该混合物。另外，在立体异物体情况下，C13和C23位置的取代基会在环上以α和β构型排列，即可能位于分子平面之上或之下。在每种情形下，所有立体异构体都在本发明考虑范围内。
米尔倍霉素类可以被特别地提到。米尔倍霉素类象阿凡曼菌素或22,23-二氢阿凡曼菌素B1(异阿凡曼菌素)那样具有相同的大环内酯环状结构，但在13位没有取代基(即丢失齐墩果糖的双糖片断)(R5=氢)。
作为来自大环内酯类的米尔倍霉素的实例，可以提及具有通式(Ⅱ)的化合物：
基团R1-R5具有下表2中给定的含义：表2
iso-Pr=异丙基
可以被特别强调的活性化合物是：
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
本发明制剂中存在的活性化合物的浓度是0.25％，优选0.5-2％，特别优选1％m/v。
本发明制剂中采用的芝麻油(60-90％v/v)是已知的。
本发明制剂中采用的粘度降低剂，尤其是油酸乙酯，是已知的。
可以用作注射制剂成分的其他良好溶剂尤其是苯甲醇，丙二醇，环亚甲基甘油醚，丙二醇碳酸酯，三醋精，Myvacete(Eastman的商标)，丙二醇二乙酸酯，聚乙二醇400，四甘醇和蓖麻油。特别优选苯甲醇(15％v/v)和蓖麻油(10-20％v/v)。
异阿凡曼菌素在苯甲醇中的溶解度大于40％(重量)，在蓖麻油中的溶解度是约4％(重量)．
用于本发明制剂的其他添加剂是稳定剂如丁基羟基茴香醚(BHA)，丁基羟基甲苯(BHT)或没食子酸丙酯，其总量最高达1000ppm。特别适合的稳定剂组合和浓度是，例如，100ppmBHA或100ppmBHA加150ppm没食子酸丙酯或200ppmBHA加100ppm没食子酸丙酯。
本发明制剂的粘度是20-60mPa.s(20℃)，优选25-55mPa.s(20℃)，特别优选30-51mPa.s(20℃)。
下面的实施例说明本发明．注释：
v/v=体积/体积相应于体积百分比
m/v=质量/体积
1％m/v表示，例如，10mg活性化合物在1ml溶液中。实施例1
芝麻油 足量100％v/v
油酸乙酯 10％v/v
苯甲醇 2％v/v
异阿凡曼菌素 1％m/v
丁基羟基茴香醚(BHA) 100ppm(Δ0.01％m/v)
密度： 0.922g/ml
粘度： 44mPa.s(20℃)
85mPa.s(5℃)
24mPa.s(39℃)实施例2
芝麻油 足量100％v/v
油酸乙酯 20％v/v
蓖麻油 10％v/v
异阿凡曼菌素 1％m/v
丁基羟基茴香醚(BHA) 100ppm(Δ0.01％m/v)
密度： 0.927g/ml
粘度： 38mPa.s(20℃)
83mPa.s(5℃)实施例1和2作为无菌注射液的一般制备方法：
将与100ppmBHA一起提供的芝麻油和油酸乙酯称量并且加入不锈钢容器中并且搅拌匀化。将溶于或部分溶于苯甲醇或蓖麻油的异阿凡曼菌素加入并且进一步搅拌。混合物温热至40-60℃以保证活性化合物迅速和完全地溶解(所有操作在氮气充气下进行)。然后将混合物在相同温度下通过0.22微米过滤器(通常预插入0.45微米或1微米过滤器)无菌过滤．然后无菌分散到棕色玻璃瓶中。
当用于家畜时这种方式制备的制剂是明显可忍耐的。此外，它们在60℃温度下贮存至少6周还是稳定的。
Claims (6)
1．基于含有芝麻油、中等链长甘油三酯、二醇酯或脂肪酸酯和一种其他选自单-或多羟基脂肪族或芳族醇和它们的衍生物(例如环状碳酸酯、乙酸酯、缩醛、缩酮)或蓖麻油的溶剂的溶剂混合物的阿凡曼菌素和米尔倍霉素的注射剂。
2．根据权利要求1的制剂，其特征在于，它们具有下列组成：
1．活性化合物0.2-5％m/v；
2．芝麻油60-90％v/v；
3．中等链长甘油三酯或二醇酯或脂肪酸酯10-30％(体积)；
4．1-20％的来自单-或多羟基脂肪族或芳族醇和它们的衍生物或蓖麻油的共溶剂；
5．如果适当的话，其他辅助剂。
3．根据权利要求1的制剂，其具有下列组成：
在溶剂混合物中的0.2-5％m/v的阿凡曼菌素或米尔倍霉素，该溶剂混合物的组成是60-90％v/v的芝麻油，和10-30％v/v的油酸乙酯或Miglyol812或Miglyol840和1-5％v/v苯甲醇或10-20％v/v的蓖麻油和任选地最多1000ppm的稳定剂。
4．根据权利要求1的制剂，其具有下列组成：
1％m/v的异阿凡曼菌素，65-90％v/v的芝麻油，10-20％v/v的油酸乙酯和1-3％v/v苯甲醇或10％v/v的蓖麻油和任选地最多500ppm的稳定剂。
5．制备权利要求1的制剂的方法，其特征在于，将活性化合物(部分)溶解于蓖麻油或苯甲醇中并且加入剩余的溶剂，或者将活性化合物溶解于所有三种溶剂的混合物中。
6．蓖麻油或苯甲醇作为增溶剂在权利要求1的制剂中的用途。
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103417478A (zh) * | 2012-05-18 | 2013-12-04 | 中国农业科学院兰州畜牧与兽药研究所 | 一种以水为基质的伊维菌素o/w型注射液及其制备方法 |
| 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 |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6458373B1 (en) | 1997-01-07 | 2002-10-01 | Sonus Pharmaceuticals, Inc. | Emulsion vehicle for poorly soluble drugs |
| US7030155B2 (en) | 1998-06-05 | 2006-04-18 | Sonus Pharmaceuticals, Inc. | Emulsion vehicle for poorly soluble drugs |
| KR20000025762A (ko) * | 1998-10-14 | 2000-05-06 | 유충식 | 이버멕틴류의 가용화 조성물 |
| 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 |
| US6872708B2 (en) * | 2001-09-10 | 2005-03-29 | Mitsukazu Matsumoto | Local injection prescription |
| US7396819B2 (en) * | 2003-08-08 | 2008-07-08 | Virbac Corporation | Anthelmintic formulations |
| WO2005094210A2 (en) | 2004-03-12 | 2005-10-13 | The Hartz Mountain Corporation | Multi-action anthelmintic formulations |
| WO2010008891A2 (en) * | 2008-06-24 | 2010-01-21 | Merial Limited | Anthelminthic formulations |
| CN102316876B (zh) * | 2009-02-16 | 2013-07-17 | 佐蒂斯有限责任公司 | 高剂量多拉菌素制剂 |
| CN103096934A (zh) * | 2010-03-09 | 2013-05-08 | 詹森生物科技公司 | 非水性高浓度低粘度混悬剂 |
| US9072668B2 (en) | 2010-03-09 | 2015-07-07 | Janssen Biotech, Inc. | Non-aqueous high concentration reduced viscosity suspension formulations of antibodies |
| US20110223208A1 (en) * | 2010-03-09 | 2011-09-15 | Beth Hill | Non-Aqueous High Concentration Reduced Viscosity Suspension Formulations |
| KR20140136005A (ko) | 2012-03-13 | 2014-11-27 | 바이엘 뉴질랜드 리미티드 | 지속성 조성물 |
| WO2017119928A1 (en) * | 2016-01-08 | 2017-07-13 | Abon Pharmaceuticals, Llc | Long acting injectable formulations |
| US20210137960A1 (en) | 2018-02-01 | 2021-05-13 | Yale University | Compositions and methods for inhibition of nuclear-penetrating antibodies |
| CN114107097B (zh) * | 2021-11-10 | 2024-03-05 | 河北兴柏农业科技股份有限公司 | 一种阿佛曼链霉菌活性孢子的固体发酵工艺 |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ197796A (en) * | 1980-08-04 | 1984-11-09 | Merck & Co Inc | Stabilised aqueous formulations containing ivermectin |
| NZ210505A (en) * | 1983-12-22 | 1988-06-30 | Merck & Co Inc | Parasiticidal compositions containing avermectin or milbemycin derivatives |
| US6001822A (en) * | 1989-04-11 | 1999-12-14 | Pfizer Inc. | Antiparasitic formulations |
| DK0393890T3 (da) * | 1989-04-11 | 1992-09-28 | Pfizer | Injicerbart præparat indeholdende 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 |
| US5030650A (en) | 1989-09-11 | 1991-07-09 | American Cyanamid Company | 13-halo-23-imino derivatives of LL-F28249 compounds and their use as endo- and ectoparasiticidal, insecticidal, acaricidal and nematocidal agents |
| US5055486A (en) | 1989-12-22 | 1991-10-08 | American Cyanamid Company | 13-alkyl-23-imino derivative of LL-F28249 compounds and their use as endo- and ectoparasiticidal, insecticidal, acaricidal and nematocidal agents |
| DK0525307T3 (da) * | 1991-07-23 | 1996-04-01 | American Cyanamid Co | Stabile præparater til parenteral indgivelse og deres anvendelse |
| DK0535734T3 (da) * | 1991-09-30 | 1999-08-09 | Merck & Co Inc | Langtidsvirkende injicerbare formuleringer indeholdende hydrogeneret castorolie |
| GB2275193A (en) * | 1993-02-17 | 1994-08-24 | Merck & Co Inc | Formulations for the topical delivery of avermectins |
| DE4443888A1 (de) * | 1994-12-09 | 1996-06-13 | Bayer Ag | Dermal applizierbare Formulierungen von Parasitiziden |
| EP0873127B1 (en) * | 1995-09-25 | 2006-11-15 | Ashmont Holdings Limited | Anthelmintic macrocyclic lactone compositions |
| DE19613972A1 (de) * | 1996-04-09 | 1997-10-16 | Bayer Ag | Injektionsformulierungen von Avermectinen und Milbemycinen auf Basis von Rizinusöl |
| RU2140737C1 (ru) * | 1998-09-22 | 1999-11-10 | Мосин Владимир Александрович | Средство для профилактики и лечения паразитарных заболеваний животных |
| CN1219393A (zh) * | 1998-11-13 | 1999-06-16 | 王玉万 | 一种含阿维菌素或伊维菌素的兽用抗寄生虫油剂口服液及其制备方法 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| CN103417478A (zh) * | 2012-05-18 | 2013-12-04 | 中国农业科学院兰州畜牧与兽药研究所 | 一种以水为基质的伊维菌素o/w型注射液及其制备方法 |
| CN103417478B (zh) * | 2012-05-18 | 2014-09-10 | 中国农业科学院兰州畜牧与兽药研究所 | 一种以水为基质的伊维菌素o/w型注射液及其制备方法 |
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| DE59708905D1 (de) | 2003-01-16 |
| US20020160967A1 (en) | 2002-10-31 |
| BR9712058B1 (pt) | 2009-05-05 |
| BR9715298B1 (pt) | 2014-10-14 |
| ZA978352B (en) | 1998-03-24 |
| WO1998011902A1 (de) | 1998-03-26 |
| AU4621597A (en) | 1998-04-14 |
| EP0939638B1 (de) | 2002-12-04 |
| AU750874B2 (en) | 2002-08-01 |
| AR008844A1 (es) | 2000-02-23 |
| CN1130203C (zh) | 2003-12-10 |
| PL332137A1 (en) | 1999-08-30 |
| CA2265952C (en) | 2009-11-17 |
| DK0939638T3 (da) | 2003-03-24 |
| BRPI9715298B8 (pt) | 2016-04-26 |
| ES2184135T3 (es) | 2003-04-01 |
| BR9712058A (pt) | 1999-08-24 |
| HK1022845A1 (en) | 2000-08-25 |
| KR20000035978A (ko) | 2000-06-26 |
| JP4822196B2 (ja) | 2011-11-24 |
| ATE228845T1 (de) | 2002-12-15 |
| CA2265952A1 (en) | 1998-03-26 |
| JP2001503029A (ja) | 2001-03-06 |
| EP0939638A1 (de) | 1999-09-08 |
| DE19638045A1 (de) | 1998-03-19 |
| NZ334673A (en) | 2000-10-27 |
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