CN101904814A - 制备载药乳剂的方法 - Google Patents
制备载药乳剂的方法 Download PDFInfo
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- CN101904814A CN101904814A CN2009100525352A CN200910052535A CN101904814A CN 101904814 A CN101904814 A CN 101904814A CN 2009100525352 A CN2009100525352 A CN 2009100525352A CN 200910052535 A CN200910052535 A CN 200910052535A CN 101904814 A CN101904814 A CN 101904814A
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- oil
- emulsion
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- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 4
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- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
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- IYFATESGLOUGBX-YVNJGZBMSA-N Sorbitan monopalmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O IYFATESGLOUGBX-YVNJGZBMSA-N 0.000 claims description 2
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Abstract
本发明提供制备载药乳剂的方法,可减少药物在制备过程中的降解。该方法包括如下步骤:a.制备不含药物组分的空白乳剂;b.将治疗有效量的药物加入空白乳剂中制备载药乳剂。本工艺过程简单,避免使用有机溶剂,适合大规模工业化生产。
Description
技术领域
本发明涉及制备载药乳剂的方法,特别是将药物加入空白乳剂中制备载药乳剂的方法。
背景技术
乳剂的临床应用非常广泛,其中作为胃肠外给药的载体——脂肪乳的应用已有40多年历史,其特点包括:提高药物稳定性、降低毒副作用、使药物缓释、控释或具有靶向性。近年来在脂肪乳成熟的制备工艺基础上,载药乳剂的研究越来越受关注,载药后的产品既可以达到治疗效果,又可以为患者提供能量,更有利于患者恢复健康。
根据研制产品粒径大小,载药乳剂分为亚微乳和纳米乳。亚微乳(submicroemulsion)粒径在100~1000nm之间,外观不透明,呈浑浊或乳状,稳定性也不如纳米乳,虽可热压灭菌,但灭菌时间太长或重复灭菌,也会分层,属于热力学不稳定系统。纳米乳(nanoemulsion)是粒径为10~100nm的乳滴分散在另一种液体中形成的胶体分散系统,其乳滴多为球形,大小比较均匀,透明或半透明,经热压灭菌或离心也不能使之分层,通常属热力学稳定系统。
载药乳剂的一般制备工艺为:
第一步、油水两相的制备及混合;
第二步、初乳的制备;
第三步、终乳的制备。其中药物的加入都是在第一步或是第二步中,加入的方法有如下几种:1、药物若溶解于油相,可先将药物溶于油相再制成乳剂;2、若药物溶于水相,可先将药物溶于水后再制成乳剂;3、若药物不溶于油相也不溶于水相时,可先将药物、油相或/和乳化剂溶于适宜的有机溶剂中,除去有机溶剂后再制成乳剂。
现有技术中,中国专利CN1546016A“天然维生素E纳米制剂及其制备方法”、中国专利CN1634021A“一种新的静脉注射用紫杉醇乳剂及其制备方法”、中国专利CN1679576A“供静脉用长春花生物碱的稳定水包油乳剂及其制备方法”、中国专利CN1732936A“尼莫地平乳注射液及制备方法”、中国专利CN1947720A“克拉霉素的脂质微球注射液及其制备方法”、中国专利CN1399959A“依托咪酯脂肪乳注射剂的制备方法”、中国专利CN1861085A“鞘磷脂异丙酚脂肪乳剂及其制备方法”等都是在第一步油水两相的制备中加入药物。
中国专利CN17719954A“长春瑞滨脂质微球注射液及其制备方法”中是在第二步初乳制备时加入药物。
药物若溶解于水相或油相中一般需要的时间较长,对于化学性质不稳定的药物,在溶解过程中可能会生成降解产物;若采用有机溶剂,便会涉及有机溶剂残留问题。
发明内容
为了克服现有技术的不足,本发明将药物加入到空白乳剂中,而非加入到油相、水相或初乳中,本发明的空白乳剂相当于现有技术中的空白终乳,即本发明是在第三步终乳的制备中加入药物,从而可能减少药物在制备过程中的降解。
本文所用术语“空白乳剂”是指不含治疗有效量的药物的乳剂。
因此,本发明的目的是提供一种简单、可行的制备载药乳剂的新方法,可减少药物在制备过程中的降解。
本发明涉及一种新的制备载药乳剂的方法,首先制备不含药物组分的空白乳剂;再将药物加至空白乳剂中制备载药乳剂。
其中,空白乳剂的制备包括以下步骤:
(1)制备油相;
(2)制备水相;
(3)将油水两相混合,分散均匀后过高压均质机或微射流仪乳化。
所述药物可以粉末的形式,也可以药物溶液的形式加入到空白乳剂中,混合均匀,调节pH值,定容、过滤、分装、灭菌。灭菌的方式可以是热压灭菌也可以是过滤除菌。混合方式包括机械搅拌、高速剪切、超声波乳化、高压均质和微射流。
本发明所述药物可以是水溶性、脂溶性、微溶解或很难溶解在油相和水相中的药物。脂溶性的药物可以溶解的状态存在,被包裹于乳滴中,得到由非均相的分散乳滴形成的乳剂。水溶性的药物可以调节体系pH值,根据不同pH下药物脂溶性的变化将药物包裹于乳滴中。微溶解或很难溶解在油相和水相中的药物,可以一部分溶解于油相中,一部分以高度分散的纳米晶体形式存在于乳剂中,得到由非均相分散的乳滴和药物晶体共存乳剂。
本发明所述的载药乳剂含有药物、溶剂油、表面活性剂和水。根据药物不同的理化性质,载药乳剂中还可以有稳定剂、增溶剂、助溶剂、金属螯合剂、渗透压调节剂、抗氧剂或防腐剂中的一种或几种。
本发明所述的溶剂油包括矿物油、植物油、动物油、合成油中的一种或几种。
本发明所述的植物油选自大豆油、红花油、玉米油、椰子油、蓖麻油、鸦胆子油、棕榈油、中链脂肪酸甘油三酯、花生油、棉籽油或其混合物;所述的动物油选自鱼油、鲸蜡油或其混合物。
本发明所述的表面活性剂包括磷脂、非离子型表面活性剂或其混合物,表面活性剂可以溶解于油相,也可以分散于水相中。本发明所述的磷脂包括蛋黄卵磷脂、大豆磷脂、氢化蛋黄卵磷脂、氢化大豆卵磷脂或合成磷脂;非离子型表面活性剂包括吐温20、吐温40、吐温60、吐温80、吐温85、司盘20、司盘40、司盘60、司盘80、聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、聚氧乙烯硬脂酸酯、泊洛沙姆188、聚乙二醇硬脂酸酯15、聚乙二醇-维生素E琥珀酸酯或其混合物。
本发明所述的抗氧剂包括水溶性抗氧剂和油溶性抗氧剂,水溶性抗氧剂溶解于水相,油溶性抗氧剂溶解于油相,其中水溶性抗氧剂选自亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠、抗坏血酸、抗坏血酸钠、L-半胱氨酸或其混合物;油溶性抗氧剂选自α-生育酚、α-醋酸生育酚、α-生育酚琥珀酸酯、叔丁基对羟基茴香醚(BHA)、二叔丁基对甲酚(BHT)或其混合物;
本发明所述的金属螯合剂选自乙二胺四乙酸、乙二胺四乙酸二钠盐、乙二胺四乙酸二钙盐或其混合物。
本发明所述的渗透压调节剂选自甘油、山梨醇、甘露醇、葡萄糖、氯化钠或其混合物。
本发明所述的稳定剂选自油酸、油酸钠、胆固醇、胆酸、胆酸钠、去氧胆酸、去氧胆酸钠或其混合物。
本发明所述的防腐剂选自丁香油、丙二醇、山梨醇、山梨酸甲酸、对羟基苯甲酸酯类、对羟基苯甲酸丁酯钙、对羟基苯甲酸甲酯钠、对羟基苯甲酸丙酯钠、苯甲醇、苯甲酸中的一种或几种。
本发明所述的助溶剂是油酸乙酯、苯甲酸苄酯、苯甲醇、乳酸乙酯、乙醇、1,2-丙二醇、聚乙二醇中的一种或几种。
本发明所述的药物为治疗人体或动物体的活性成分。药物选自抗肿瘤药、心血管药、抗感染药、抗真菌药、抗病毒药、抗过敏药、抗炎药、内分泌药、精神类药、抗生素类、免疫抑制剂、维生素或麻醉药。
本发明所述的药物可以是紫杉醇、多烯紫杉醇、长春瑞滨、长春新碱、羟基喜树碱、奥沙利铂、前列腺素E1、尼莫地平、环孢素、伊曲康唑、两性霉素、阿昔洛韦、地塞米松、地塞米松棕榈酸酯、吲哚美辛、地西泮、克拉霉素、平阳霉素、多柔比星、维生素A、维生素D2、维生素E、维生素K、布比卡因、丙泊酚、依托咪酯、氟比洛芬乙氧基α-乙酯。
本发明所述的载药乳剂可用作局部、口服和肠胃外给药,特别是静脉、皮内、皮下、肌肉和关节内或腹腔内给药,优选静脉给药。静脉给药时,载药乳剂中乳滴的平均粒径小于1000nm。
与现有技术相比,本发明有益效果为:
1、本发明避免了有机溶剂的使用,产品检验时不存在有机溶剂残留问题;
2、与普通制备工艺相比,药物加入方式的改变可能减小或避免制剂制备过程中药物的降解;
3、本发明工艺简便,利于大规模工业化生产。
因此可见,本发明方法不仅工艺简便,利于大规模工业化生产,而且改变了传统的加入药物方式,避免了由于工艺操作所引起的药物降解。
具体实施方式
以下通过实施进一步说明本发明,但不作为对本发明的限制。
实施例1
酒石酸长春瑞滨 0.05%
大豆油 5%
蛋黄卵磷脂 2%
注射用水 加至100%
在惰性气体保护下,称取大豆油50g预热至75℃;另将蛋黄卵磷脂20g加入适量注射用水中,搅拌均匀成水相,预热至75℃;在高速搅拌下,将水相加入油相中,混合均匀,并经高压均质机匀化制成空白乳剂,加入酒石酸长春瑞滨0.5g、调节pH值至8.0,定容至1000ml,机械搅拌至粒径在1000nm以下,0.22μm滤膜过滤除菌、灌装、充氮气、熔封。
实施例2
长春瑞滨 0.2%
大豆油 5%
蛋黄卵磷脂 2%
注射用水 加至100%
在惰性气体保护下,称取大豆油50g预热至75℃;另将蛋黄卵磷脂20g加入适量注射用水中,搅拌均匀成水相,预热至75℃;在高速搅拌下,将水相加入油相中,混合均匀,并经高压均质机匀化制成空白乳剂,加入长春瑞滨2g、调节pH值至8.0,定容至1000ml,机械搅拌至粒径在1000nm以下,0.22μm滤膜过滤除菌、灌装、充氮气、熔封。
实施例3
盐酸布比卡因 0.1%
蓖麻油 10%
大豆磷脂 2%
无水亚硫酸钠 0.2%
甘油 2.5%
注射用水加 至100%
在惰性气体保护下,称取蓖麻油100g预热至60℃;另将大豆磷脂20g、无水亚硫酸钠2g和甘油25g加入适量注射用水中,搅拌均匀成水相,预热至60℃;在高速搅拌下,将油相与水相混合均匀,并经高压均质机匀化制成空白乳剂,加入盐酸布比卡因0.1g、调节pH值至7.0,定容至1000ml,机械搅拌至粒径小于1000nm,0.22μm滤膜过滤除菌、灌装、充氮气、熔封。
实施例4
盐酸伊立替康 0.05%
大豆油 10%
蛋黄卵磷脂 2%
泊洛沙姆 2%
甘油 2.5%
注射用水 加至100%
在惰性气体保护下,称取大豆油100g作为油相,另将蛋黄卵磷脂20g、泊洛沙姆20g和甘油25g加入适量注射用水中,搅拌均匀成水相,在高速搅拌下,将油相与水相混合均匀,并经高压均质机匀化制成空白乳剂,加入盐酸伊立替康0.5g、调节pH值8.0,定容至1000ml,微射流仪中乳化至粒径小于1000nm,灌装、充氮气、熔封,旋转灭菌柜灭菌。
实施例5
多西他赛 0.05%
中链油 15%
蛋黄卵磷脂 2%
吐温-80 0.5%
油酸 0.4%
甘油 2.5%
VE 0.05%
注射用水 加至100%
在惰性气体保护下,将中链油150g、油酸4g、VE 0.5g、吐温-805g搅拌均匀成油相,预热至70℃;另将蛋黄卵磷脂20g和甘油25g加入适量注射用水中,预热至70℃;搅拌均匀成水相,在高速搅拌下,将油相与水相混合均匀,并经高压均质机匀化制成空白乳剂,加入多西他赛0.5g、调节pH值5.0,定容至1000ml,微射流仪中乳化至粒径小于1000nm,灌装、充氮气、熔封、旋转灭菌柜灭菌。
实施例6
两性霉素B 0.2%
鱼油 10%
蛋黄卵磷脂 2%
油酸钠 0.1%
甘油 2.5%
乙二胺四乙酸二钠 0.01%
注射用水 加至100%
在惰性气体保护下,称取鱼油100g预热至70℃;另将蛋黄卵磷脂20g、油酸钠1g、乙二胺四乙酸二钠0.1g、甘油25g加入适量注射用水中,预热至70℃;搅拌均匀成水相,在高速搅拌下,将油相与水相混合均匀,并经高压均质机匀化制成空白乳剂,加入两性霉素B 2g、调节pH值7.0,定容至1000ml,高压均质机内乳化至粒径小于1000nm,灌装、充氮气、熔封,旋转灭菌柜灭菌。
实施例7
前列腺素E1 10μg/ml
大豆油 10%
蛋黄卵磷脂 1.2%
油酸 0.1%
甘油 2.5%
注射用水 加至100%
在惰性气体保护下,将大豆油100g、油酸1g,搅拌均匀成油相;另将蛋黄卵磷脂12g、甘油25g加入适量注射用水中,搅拌均匀成水相;在高速搅拌下,将油相与水相混合均匀,并经高压均质机匀化制成空白乳剂,加入前列腺素E11mg、调节pH值5.0,定容至1000ml,高压均质机内乳化至粒径小于1000nm,灌装、充氮气、熔封,旋转灭菌柜灭菌。
实施例8
地西泮 0.1%
大豆油 10%
蛋黄卵磷脂 1.2%
油酸钠 0.05%
甘油 2.5%
注射用水 加至100%
在惰性气体保护下,称取大豆油100g作为油相;另将蛋黄卵磷脂12g、油酸钠0.5g、甘油25g加入适量注射用水中,搅拌均匀成水相;在高速搅拌下,将油相与水相混合均匀,并经高压均质机匀化制成空白乳剂,加入地西泮1g、调节pH值8.0,定容至1000ml,高压均质机内乳化至粒径小于1000nm,灌装、充氮气、熔封,旋转灭菌柜灭菌。
实施例9
依托咪酯 0.1%
大豆油 10%
蛋黄卵磷脂 1.2%
甘油 2.5%
注射用水 加至100%
在惰性气体保护下,称取大豆油100g预热至50℃;另将蛋黄卵磷脂12g、甘油25g加入适量注射用水中,搅拌均匀成水相,预热至50℃;在高速搅拌下,将油相与水相混合均匀,并经高压均质机匀化制成空白乳剂,加入依托咪酯1g、调节pH值5.0,定容至1000ml,高压均质机内乳化至粒径小于1000nm,灌装、充氮气、熔封,旋转灭菌柜灭菌。
实施例10
丙泊酚 0.1%
大豆油 5%
中链油 5%
蛋黄卵磷脂 1.2%
甘油 2.5%
注射用水 加至100%
在惰性气体保护下,将大豆油50g,中链油50g搅拌均匀成油相,预热至60℃;另将蛋黄卵磷脂12g、甘油25g加入适量注射用水中,搅拌均匀成水相,预热至60℃;在高速搅拌下,将油相与水相混合均匀,并经高压均质机匀化制成空白乳剂,加入丙泊酚1g、调节pH值8.0,定容至1000ml,高压均质机内乳化至粒径小于1000nm,灌装、充氮气、熔封,旋转灭菌柜灭菌。
实施例11
环孢素 0.1%
中链油 3%
聚氧乙烯蓖麻油 10%
PEG-400 5%
氯化钠 0.4%
注射用水 加至100%
在惰性气体保护下,称取中链油30g预热至60℃;另将聚氧乙烯蓖麻油100g、PEG-40050g、氯化钠4g加入适量注射用水中,搅拌均匀成水相,预热至60℃;在高速搅拌下,将油相与水相混合均匀,并经高压均质机匀化制成空白乳剂,加入环孢素1g、调节pH值7.4,定容至1000ml,高速剪切乳化至粒径小于100nm,0.22μm滤膜过滤除菌、灌装、充氮气、熔封。
实施例12
尼莫地平 0.1%
大豆油 15%
大豆磷脂 1.2%
油酸钠 0.05%
甘油 2.25%
注射用水 加至100%
在惰性气体保护下,将大豆油150g,大豆磷脂12g搅拌均匀成油相,预热至60℃;另将甘油22.5g、油酸钠0.5g加入适量注射用水中,搅拌均匀成水相,预热至60℃;在高速搅拌下,将油相与水相混合均匀,并经高压均质机匀化制成空白乳剂,加入尼莫地平1g、调节pH值8.0,定容至1000ml,高压均质机内乳化至粒径小于1000nm,灌装、充氮气、熔封,旋转灭菌柜灭菌。
实施例13
维生素D2 0.5%
大豆油 5%
大豆磷脂 1.5%
甘油 2.25%
注射用水 加至100%
在惰性气体保护下,将大豆油50g,大豆磷脂15g搅拌均匀成油相,预热至70℃;另将甘油22.5g加入适量注射用水中,搅拌均匀成水相,预热至70℃;在高速搅拌下,将油相与水相混合均匀,并经高压均质机匀化制成空白乳剂,加入维生素D25g、调节pH值8.0,定容至1000ml,高压均质机内乳化至粒径小于1000nm,灌装、充氮气、熔封,旋转灭菌柜灭菌。
实施例14
阿昔洛韦 0.5%
大豆油 10%
大豆磷脂 2%
油酸钠 0.05%
甘油 2.25%
注射用水 加至100%
在惰性气体保护下,将大豆油100g预热至70℃;另将大豆磷脂20g、甘油22.5g、油酸钠0.5g加入适量注射用水中,搅拌均匀成水相,预热至70℃;在高速搅拌下,将油相与水相混合均匀,并经高压均质机匀化制成空白乳剂,加入阿昔洛韦5g、调节pH值8.0,定容至1000ml,高压均质机内乳化至粒径小于1000nm,灌装、充氮气、熔封,旋转灭菌柜灭菌。
实施例15
制备方法同实施例14,不同之处在于药物为克拉霉素,其处方用量为0.1%。
实施例16
制备方法同实施例14,不同之处在于药物为地塞米松,其处方用量为0.1%。
实施例17
制备方法同实施例14,不同之处在于药物为多柔比星,其处方用量为0.1%。
Claims (22)
1.一种制备载药乳剂的方法,其特征在于该方法包括以下步骤:
制备不含药物组分的空白乳剂;
将治疗有效量的药物加入所述的空白乳剂中制备载药乳剂。
2.根据权利要求1所述的方法,其特征在于所述药物以溶解的状态存在,被包裹于乳滴中,得到由非均相的分散乳滴形成的乳剂。
3.根据权利要求1所述的方法,其特征在于所述药物以高度分散的纳米晶体形式存在于乳剂中,得到由非均相分散的乳滴和药物晶体共同存在形成的乳剂。
4.根据权利要求1~3任一项所述的方法,其特征在于所述空白乳剂的制备包括以下步骤:
制备油相;
制备水相;
将油水两相混合,分散均匀后经高压均质或微射流乳化。
5.根据权利要求1~4任一项所述的方法,其特征在于所述药物以粉末的形式或以药物溶液的形式加入到空白乳剂中,混合均匀,调节pH值,定容、过滤、分装、灭菌。
6.根据权利要求1~5任一项所述的方法,其特征在于所述的混合包括机械搅拌、高速剪切、超声波乳化、高压均质和微射流。
7.根据权利要求1~6任一项所述的方法,其特征在于所述的载药乳剂中含有药物、溶剂油、表面活性剂和水。
8.根据权利要求7所述的方法,其特征在于所述的溶剂油选自矿物油、植物油、动物油、合成油中的一种或几种。
9.根据权利要求8所述的方法,其特征在于所述的植物油选自大豆油、红花油、玉米油、椰子油、蓖麻油、鸦胆子油、棕榈油、中链脂肪酸甘油三酯、花生油、棉籽油或其混合物;所述的动物油选自鱼油、鲸蜡油或其混合物。
10.根据权利要求7所述的方法,其特征在于所述的表面活性剂选自磷脂、非离子型表面活性剂或其混合物,所述的表面活性剂溶解于油相或分散于水相中。
11.根据权利要求10所述的方法,其特征在于所述的磷脂选自蛋黄卵磷脂、大豆磷脂、氢化蛋黄卵磷脂、氢化大豆卵磷脂或合成磷脂;非离子型表面活性剂选自吐温20、吐温40、吐温60、吐温80、吐温85、司盘20、司盘40、司盘60、司盘80、聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、聚氧乙烯硬脂酸酯、泊洛沙姆188、聚乙二醇硬脂酸酯15、聚乙二醇-维生素E琥珀酸酯或其混合物。
12.根据权利要求1~11任一项所述的方法,其特征在于所述的载药乳剂中进一步含有稳定剂、增溶剂、助溶剂、金属螯合剂、渗透压调节剂、抗氧剂或防腐剂中的一种或几种。
13.根据权利要求12所述的方法,其特征在于所述的抗氧剂选自水溶性抗氧剂或油溶性抗氧剂,所述的水溶性抗氧剂溶解于水相,所述的油溶性抗氧剂溶解于油相,其中所述的水溶性抗氧剂选自亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠、抗坏血酸、抗坏血酸钠、L-半胱氨酸或其混合物;所述的油溶性抗氧剂选自α-生育酚、α-醋酸生育酚、α-生育酚琥珀酸酯或其混合物、叔丁基对羟基茴香醚或二叔丁基对甲酚。
14.根据权利要求12所述的方法,其特征在于所述的金属螯合剂选自乙二胺四乙酸、乙二胺四乙酸二钠盐、乙二胺四乙酸二钙盐或其混合物。
15.根据权利要求12所述的方法,其特征在于所述的渗透压调节剂选自甘油、山梨醇、甘露醇、葡萄糖、氯化钠或其混合物。
16.根据权利要求12所述的方法,其特征在于所述的稳定剂选自油酸、油酸钠、胆固醇、胆酸、胆酸钠、去氧胆酸、去氧胆酸钠或其混合物。
17.根据权利要求12所述的方法,其特征在于所述的防腐剂选自丁香油、丙二醇、山梨醇、山梨酸甲酸、对羟基苯甲酸丁酯钙、对羟基苯甲酸甲酯钠、对羟基苯甲酸丙酯钠、苯甲醇、苯甲酸中的一种或几种。
18.根据权利要求12所述的方法,其特征在于所述的助溶剂选自油酸乙酯、苯甲酸苄酯、苯甲醇、乳酸乙酯、乙醇、1,2-丙二醇、聚乙二醇中的一种或几种。
19.根据上述权利要求1~18任一项所述的方法,其特征在于所述药物为治疗人体或动物体的活性成分。
20.根据上述权利要求1~19任一项所述的方法,其特征在于所述药物选自抗肿瘤药、心血管药、抗感染药、抗真菌药、抗病毒药、抗过敏药、抗炎药、内分泌药、精神类药、抗生素类、免疫抑制剂、维生素或麻醉药。
21.根据上述权利要求1~20任一项所述的方法,其特征在于所述载药乳剂为局部、口服和肠胃外给药剂型,特别是为静脉、皮内、皮下、肌肉和关节内或腹腔内给药剂型,优选为静脉给药剂型。
22.根据权利要求21所述的方法,其特征在于所述载药乳剂静脉给药时,乳剂中乳滴的平均粒径小于1000nm。
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KR20120027298A (ko) | 2012-03-21 |
WO2010139278A1 (zh) | 2010-12-09 |
HK1154502A1 (zh) | 2012-04-27 |
CN102159188B (zh) | 2014-07-09 |
MX2011012884A (es) | 2012-01-12 |
AU2010256130A1 (en) | 2012-01-19 |
CN102159188A (zh) | 2011-08-17 |
CA2762918A1 (en) | 2010-12-09 |
JP2012528804A (ja) | 2012-11-15 |
EP2438909A1 (en) | 2012-04-11 |
BRPI1010950A2 (pt) | 2018-03-06 |
US20120177699A1 (en) | 2012-07-12 |
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