CN100479856C - 用于亲水性化合物非肠道给药的缓释药物组合物 - Google Patents
用于亲水性化合物非肠道给药的缓释药物组合物 Download PDFInfo
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- CN100479856C CN100479856C CNB018099254A CN01809925A CN100479856C CN 100479856 C CN100479856 C CN 100479856C CN B018099254 A CNB018099254 A CN B018099254A CN 01809925 A CN01809925 A CN 01809925A CN 100479856 C CN100479856 C CN 100479856C
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- microemulsion
- cosurfactant
- surfactant
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- water
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Abstract
本发明涉及稳定的、生物相容性的、以油包水(w/o型)微乳形式存在的药物组合物,其用于通过非肠道给药来持续释放亲水性或通过适当的衍生化制成亲水性的活性成分,本发明还涉及所述微乳的制备方法和用途。
Description
发明领域
本发明涉及以稳定的、生物相容性的且易于制备的油包水(w/o型)微乳形式存在的,用于活性成分非肠道给药的缓释药物组合物,该活性成分是亲水性的或者通过适当的衍生化而制成亲水性。更确切的说,对于需要防止生物体内水解酶的快速攻击并能在一定时间内持续释放从而避免反复给药的肽类活性成分或者生物学活性低聚糖或多糖而言,通过所述微乳来配制是将有利的。所述用于治疗用的制剂可注射给药而不会引起问题或显著的副作用,并且易于在工业上制备,因此该制剂具有显著的技术进步。
现有技术
微乳通常是指光学各向同性的体系,其在偏振光下观察不到双折射现象,它是透明的,热力学稳定的,液滴直径非常小,在5-200nm之间,它是通过分散混合两种不相混溶、但是在乳化剂存在下能稳定共存的液体而制备的,乳化剂可调整两种液体间分隔表面的化学-物理性质,并将界面张力基本上降低为零。油、水、表面活性剂及任选的辅助表面活性剂通常是形成微乳所必需的;形成油包水(w/o型)还是水包油(o/w)型微乳取决于共存的水相和油相的比例以及表面活性剂的性质。具体地讲,通过实验数据可得出包含水、疏水性化合物以及表面活性剂和辅助表面活性剂的混合物的三相图,在图上可标出w/o型和o/w型微乳稳定存在的区域。例如,Aboofazeli等人(Int.J.Pharm.111(1994)63-72)研究了各种具有辅助表面活性剂活性的化合物形成w/o型微乳的能力。作者所研究的体系由脂肪酸酯、1:1的卵磷脂-辅助表面活性剂和水的不同比例的混合物组成。用作辅助表面活性剂的化合物的效力等级为:伯胺>醇类>脂肪酸。此外,该效力被证实与醇类和脂肪酸烷基链的长短有关;即丁醇>戊醇>己醇>戊酸>己酸。在这些实验数据的基础上,醇类例如丁醇或戊醇以及相应的脂肪酸(次优选)似乎是最佳的备选物。使用上述化合物可制备出稳定的w/o型微乳,但是并不能保证所述制剂的可耐受性,尤其是当作为贮库使用时,因为此时该制剂与皮下或肌肉内的组织要接触数天甚至数周。
而且,据报道,辅助表面活性剂和表面活性剂之间的比例非常重要;Aboofazeli等人报道的数据是两者之间的比例为1:1。Atwood等人(Int.J.Pharmacy 84 R5(1992))研究了卵磷脂/水/脂肪酸酯/丁醇混合物的特性,其中表面活性剂/辅助表面活性剂的比例为约1.7到3。作者证实,降低辅助表面活性剂相对于卵磷脂的量可以明显限制可观察到w/o型微乳存在的区域,即便使用的是非常有效的辅助表面活性剂例如丁醇。
表面活性剂通常根据经验等级进行分类,这些经验等级称为亲水亲油平衡值(HLB),其指定的数值范围在1到40之间。通常,w/o型微乳适宜的表面活性剂具有较低的HLB,而适合o/w型微乳的具有较高的HLB。当界面张力<2×10-2dyn/cm时,可形成稳定的微乳。任选存在的辅助表面活性剂可以增加界面流动性,因为辅助表面活性剂分子可以渗透到表面活性剂分子之间,由此产生一层非均相的界面膜层。辅助表面活性剂还能降低水相的亲水性,从而降低两相之间界面的张力。总的来说,使用辅助表面活性剂的优点在于其能在增加微乳稳定性的同时降低所需的表面活性剂的量;然而,正如上文已经提到的,最好能限制辅助表面活性剂的使用,因为其具有潜在的局部毒性,主要是在载体和皮下或肌内组织之间长时间接触的情况下。
人们已经了解了使用微乳作为活性成分载体的很多优点。
在成分之间比例的特定条件下,微乳可自发形成而不需要很高的能量来制备它;因此在工业规模上的制备非常容易。所述自发形成的微乳是热力学稳定的、均匀透明的,因此能用光谱技术进行监测。可以制得平均粒径<100nm的微乳,可通过用0.22微米薄膜商业过滤器过滤进行冷灭菌。微乳可实现低溶解度或低稳定性药物的给药。
此外,当存在额外的分散相或者温度发生改变时,所述体系会发生相转变:这一性质可影响活性成分的生物利用度,而其中的机理尚不清楚。
w/o型微乳可控制活性成分的释放或者通过防止水解酶破坏而延长其在生理液体中的稳定性。有大量关于微乳形成的综述,例如,“微乳的工业应用”,Marcel Dekker编1997,在“制药领域中的微乳:展望和应用”章节中涉及到了其在制药领域中的用途,而“微乳工艺手册”,Kumar Mittal编(1999),涉及它的化学物理方面。
w/o型微乳作为载体用以实现亲水性的或者通过适当衍生化变成亲水性的活性成分的控制释放的用途已报道于专利文献中。
具体地讲,对于生物可降解的分子,例如肽类,在一项研究中报道了含这些活性成分的非肠道给药的w/o型微乳[M.R.Gasco等人,Int.J.Pharm.62,119(1990)],其中,将LHRH激素类似物在一种由生物相容性成分组成的微乳中配制,活性成分含量为500μg/ml,微乳通过单次肌内注射以3mg/Kg的剂量向重约200g的成年雄性大鼠给药,其注射后所引起的睾酮血浆浓度下降能持续近30天;所述浓度要低于将活性成分溶于缓冲液中并以100μg/Kg的活性成分剂量对第二组小鼠进行反复注射(一天一次,共28天)所观察到的睾酮浓度。
必须注意的是:观察期间内睾酮浓度的下降是不均匀的,其在给药8天后才具有治疗效果。
该治疗效果的迟滞现象是非常不利的,尤其在治疗需要睾酮才能生长的前列腺肿瘤时,因此睾酮的正常产生终止的越快,治疗效果就越好。
上文提到的文献显示了由油酸乙酯(60.5%)、水(10.1%)、磷脂酰胆碱(18.9%)和己酸(10.5%)组成的、用于持续释放肽类的w/o型微乳的有效性。表面活性剂(磷脂酰胆碱)与辅助表面活性剂(己酸)的比例是1.8。作者认为所述微乳的组分,如果单独服用,是生物可相容的。然而既没有人提到过微乳作为一个整体的生物相容性,也没有人提到过与制剂接触的皮下组织的情况。
根据所述文献的教导,人们制备了一种含有醋酸亮丙瑞林作为具有LHRH活性的活性成分的w/o型微乳,其由油酸乙酯(66.9%)、水(9.7%)、磷脂酰胆碱(19.4%)和己酸/丁酸以3/1混合的混合物(3.9%)组成。根据该文献,使用丁酸与己酸的混合物代替单独的己酸以降低表面活性剂与辅助表面活性剂的比例,即,从4.9下降至1.8。通过大鼠皮下注射对产品进行的体内测试证实了其有效性,但也意外的引起了人们对局部溃疡和顽固性皮下风湿性肉芽肿的警惕。尽管只使用了很少量的辅助表面活性剂,这些药理学上无法接受的结果仍然表明:当用于非肠道给药时,微乳单个组分的生物相容性并不足以保证组成微乳的混合物的生物相容性。
相似的,在各种专利例如WO 94/08610中公开和要求保护的混合物尽管提供了稳定的微乳并实现了活性成分在一定时间内可控的释放,却没有教导本领域技术人员如何实现亲水性活性成分的持续释放并同时避免上述副作用。实际上,所述微乳通常由水、油性组分、表面活性剂、辅助表面活性剂及可任选的电解质以各种比例组成。现有技术既没有对微乳“整体”的生物相容性进行评估,也没有指出为达到活性成分和微乳的稳定性以及制剂的生物相容性所需使用的混合物成分与活性成分的比例。
另一方面,所述专利没有明确的考虑与肌内(i.m)和皮下(s.c)给药有关的局部可耐受性问题,而此种给药方式是非肠道给药最适宜和简单的路径。
在大量的专利文献如US 3,976,071中还公开并要求保护了另一项已在工业规模上使用的用于肽类持续释放的技术,其中所述释放通过使用掺入了活性成分的生物可降解聚合物而实现。典型的生物可降解聚合物的例子是基于乙醇酸和乳酸的聚合物。所述技术的缺点是:其与上述乳液相比价格相对昂贵且麻烦费事,而且,其在制备过程中需要使用有机溶剂,尤其是含氯的有机溶剂,这将涉及破坏环境和药剂安全性方面的问题。
另一方面,所述制剂优选不会引起顽固性风湿性肉芽肿也不会导致局部溃疡。
发明内容
本发明目的在于提供一种稳定的w/o型微乳形式的缓释药物组合物,它制备简单,可对其进行消毒,且无显著的全身或局部的副作用,该组合物适于对亲水性的或者通过适当衍生化而变得亲水性的活性成分进行非肠道给药,优选肌内或皮下给药,因此,与现有技术相比,在技术上得到了显著的提高。
已发现了一种适于全面评估各种用于缓释给药的制剂其生物相容性的方法,该方法包括对用上文所述微乳进行治疗的动物做临床、验尸和组织学的检查。
根据该方法,如文献中所述(Protein Formulation and Delivery-E.J.McKelly 2000,第245-247页),当局部肿胀(其或多或少地显著依赖于给药剂量)是可逆的时,微乳被认为是可接受的;另一方面,对于被认为是生物可降解的材料也要观察其类似的组织应答,此应答对于影响药物在一定时间内的持续释放非常重要。不过,顽固性溃疡形式的局部不可耐受性被认为是不可接受的。
本发明的微乳由如下组分组成:最多20%的含活性成分的内层亲水性水相、30到98%的外层疏水相和最多50%的表面活性剂或表面活性剂与辅助表面活性剂的混合物。该微乳优选含有百分比≤35%的表面活性剂和辅助表面活性剂,其中表面活性剂/辅助表面活性剂的比值≥2,最优选≥3.5。
还可以使用其它不会影响微乳稳定性的生物相容性赋型剂。
适用于本发明微乳的表面活性剂选自天然或者合成的含C4-C20饱和或不饱和的羧酸残基的甘油磷脂,其磷酸酯部分含胆碱、乙醇胺、丝氨酸、甘油残基;胆固醇;糖例如山梨醇糖、半乳糖、葡萄糖、蔗糖等的C12-C20脂肪酸酯;C12-C20脂肪酸聚氧乙烯脱水山梨醇酯。
可任选使用的辅助表面活性剂选自C8-C20脂肪酸,C2-C14多羟基烷烃,优选丙二醇、己二醇和甘油,C2-C12醇,含C2-C8醇残基的乳酸酯。
疏水性连续相选自下列单独或混合形式的化合物:含C2-C8醇残基的C8-C20饱和或不饱和羧酸酯或者C8-C20脂肪酸的单甘油酯、二甘油酯和三甘油酯、或者适于非肠道给药的植物油,例如大豆油、花生油、芝麻油、棉籽油、葵花油。
本发明微乳进一步的特征为其pH在4.5-7.5之间,优选为5-7,当乳液组合物本身达不到所述pH值时,优选向微乳中加入适量天然氨基酸来达到该pH值,同时还不会影响乳液的稳定性和液滴平均粒径。
本发明w/o型微乳特别适合作为肽类的载体,特别是LHRH类似物,例如醋酸亮丙瑞林、戈舍瑞林、曲普瑞林、醋酸那法瑞林、组氨瑞林、西曲瑞克或相应的醋酸盐;或者如促生长素抑制素或其类似物,例如醋酸奥曲肽及醋酸兰瑞肽等肽类。
此外,本发明的微乳特别适用于作为多糖、尤其是未分离的肝素或者低分子量肝素的载体。
本发明的微乳可用于制备可缓释亲水性活性成分的制剂。本发明进一步的发明目的是提供所述缓释制剂,该制剂不会引起局部溃疡和产生顽固性风湿性肉芽肿,能在药物有效的时间内被吸收。在使用LHRH-型肽类,尤其是亮丙瑞林、戈舍瑞林、曲普瑞林、醋酸那法瑞林、组氨瑞林、西曲瑞克及其相应的盐的情况下,可实现至少30天的持续释放。在使用促生长素抑制素、奥曲肽和兰瑞肽时,可实现至少8天的持续释放。
本发明进一步的涉及含亮丙瑞林、戈舍瑞林、曲普瑞林、醋酸那法瑞林、组氨瑞林、西曲瑞克或相应的醋酸盐的本发明的微乳在制备抑制睾酮生成的药物上的应用,该药物在单次给药后至少能起效30天,且给予该药物48小时后睾酮浓度就已降低。
本发明还涉及含奥曲肽或其类似物的微乳在制备用于抑制生长激素产生的药物上的应用,该药物至少能作用8天。
本发明进一步的目的是含未分离的肝素或低分子量肝素的微乳在制备在单次给药后能持续释放的药物上的应用。
以下实施例将进一步的阐述本发明。
实施例1-含醋酸亮丙瑞林的w/o型微乳的制备
a)水相的制备
将350mg醋酸亮丙瑞林溶于加入了200mg赖氨酸的10ml注射用水中。
b)油相的制备
在一适宜的恒温在60-70℃的容器内,在搅拌的情况下将60g油酸乙酯、25g大豆卵磷脂(纯度>95%)和5g辛酸混合。将所得透明均匀的溶液冷却至室温。
c)微乳的制备
在搅拌的条件下将水相(溶液a)加入到油相(溶液b)中,得到透明均匀的微乳。根据所使用的溶于水相的赖氨酸和辛酸的量可估算出pH值约为6。
所述微乳通过用适宜的0.22μm膜过滤灭菌。
所述微乳中醋酸亮丙瑞林的含量用HPLC分析法在下述条件下检测:
固定相: Vydac C18 5μ柱(250 x 4mm)
流动相A: H2O+0.1% TFA
B: CH3OH+0.1% TFA
洗脱梯度: 20′100% A到100% B
流速: 0.8ml/分钟
检测器: UV 214nm
醋酸亮丙瑞林含量为3mg/ml。
实施例2-含醋酸亮丙瑞林的w/o型微乳的制备
按照实施例1的操作方法,只是在10ml水中溶解600mg的醋酸亮丙瑞林。
实施例3-含醋酸亮丙瑞林的w/o型微乳的制备
按照实施例1的操作方法,但是不加入200mg赖氨酸。计算得pH值约为3。
实施例4-含醋酸亮丙瑞林的w/o型微乳的制备
按照实施例1的操作方法,只是在10ml水中溶解900mg醋酸亮丙瑞林。
实施例5-含醋酸亮丙瑞林的w/o型微乳的制备
按照实施例1的操作方法,但是要将表面活性剂和辅助表面活性剂的量分别改变成15g大豆卵磷脂和3g辛酸。用这种方法制备,虽然表面活性剂和辅助表面活性剂之间的比例仍然没有改变(5:1),但是两种成分混合物的总量已从30%变化至18%。
实施例6-含奥曲肽的w/o型微乳的制备
按照实施例1的操作方法,但是在10ml水中溶入3g奥曲肽,替代在10ml水中溶入350mg醋酸亮丙瑞林的操作。
实施例7-含肝素的w/o型微乳的制备
按照实施例1的操作方法,但是向10ml水中溶入50mg钙盐或钠盐形式的未分离的肝素而不是350mg醋酸亮丙瑞林。
实施例8-含醋酸亮丙瑞林的w/o型微乳的制备
按照实施例1的操作方法,但是需要将油相质量和数量的组成改变为:油酸乙酯(66.9%)、磷脂酰胆碱(19.4%)及3:1的己酸-丁酸混合物(总共3.9%)。
实施例9-含醋酸亮丙瑞林的w/o型微乳的制备
a)水相的制备
将60mg醋酸亮丙瑞林溶于加入了8mg赖氨酸的0.6ml注射用水中。
b)油相的制备
将2.1g油酸乙酯、215mg单油酸聚氧乙烯脱水山梨醇酯和1g大豆卵磷脂在一适宜容器中混合,在搅拌的情况下加热到50℃。然后将所得透明均匀的混合物冷却至室温。
将水溶液在搅拌的情况下缓慢地分批加入到油性混合物中,得到含1.5%醋酸亮丙瑞林的透明微乳。
实施例10-含醋酸亮丙瑞林的w/o型微乳的制备
a)水相的制备
将60mg醋酸亮丙瑞林溶于加入了4.1mg赖氨酸的0.2ml注射用水中。
b)油相的制备
将1.2g油酸乙酯、0.5g单油酸聚氧乙烯脱水山梨醇酯和0.1g辛酸在一适宜容器中混合,在搅拌的情况下加热到50℃。然后将所得透明均匀的混合物冷却至室温。
将水溶液在搅拌的情况下缓慢地分批加入到油性混合物中,得到含3mg/ml的醋酸亮丙瑞林的透明微乳。
实施例11-含醋酸奥曲肽的w/o型微乳的制备
a)水相的制备
将20mg醋酸奥曲肽溶于含0.2g丙二醇和4mg赖氨酸的0.2ml注射用水中。
b)油相的制备
将0.98g油酸乙酯、0.5g大豆卵磷脂和0.1g辛酸在一适宜容器中混合,在搅拌情况下加热至50℃。然后将所得透明均匀的混合物冷却至室温。
将水溶液在搅拌的情况下缓慢地分批加入到油性混合物中,得到含10mg/ml的醋酸奥曲肽的透明微乳。
实施例12-含醋酸奥曲肽的w/o型微乳的制备
a)水相的制备
将10mg醋酸奥曲肽溶于加入了2mg赖氨酸的0.1ml注射用水中。
b)油相的制备
将0.59g油酸乙酯、0.25g大豆卵磷脂和0.05g辛酸在一适宜的容器中混合,在搅拌情况下加热至50℃。然后将所得透明均匀的混合物冷却至室温。
将水溶液在搅拌的情况下缓慢地分批加入到油性混合物中,得到含1%醋酸奥曲肽的透明微乳。
实施例13-含醋酸奥曲肽的w/o型微乳的制备
将0.59g油酸乙酯、0.25g大豆卵磷脂和0.05g辛酸在一适宜容器中混合,在搅拌情况下加热到50℃。然后将所得透明均匀的混合物冷却至室温。将含有2mg赖氨酸的0.1g注射用水在搅拌下缓慢的加入到油溶液中。将10mg醋酸奥曲肽在搅拌的情况下加入到所形成的透明微乳中。几秒钟内活性成分便被包埋在了所述微乳中。将微乳用0.22mcm聚砜滤器过滤。所得透明微乳用HPLC分析显示醋酸奥曲肽的含量为6.35mg/ml。
实施例14-含肌红蛋白的w/o型微乳的制备
a)水相的制备
将5.5mg肌红蛋白溶于加入了10mg赖氨酸的1.5ml注射用水中。
b)油相的制备
将2g油酸乙酯、1.2g大豆卵磷脂和0.25g辛酸在一适宜容器中混合加热至50℃。将所得透明均匀的混合物冷却至室温。
将水溶液在搅拌的情况下缓慢地分批加入到油性混合物中。所得透明的微乳中含有1.3mg/ml肌红蛋白。
实施例15-按实施例1和实施例2所述制备的含醋酸亮丙瑞林的微乳其有效性的体内评价
将三组Sprague Dawley雄性大鼠(每组10只)在试验前圈养5天,可随意接近水和食物。
将按照实施例1和实施例2所述制备的,区别在于醋酸亮丙瑞林浓度不同的两种微乳,即3mg/ml(实施例1)和6mg/ml(实施例2)的微乳,以单剂量形式给予各组的大鼠,活性剂量相当于0.750mg/kg。
对照动物(每组3只)给予盐水溶液。
在第1、2、3、4、7、14、21、28、42和56天取血样评估睾酮血浆浓度。血样经离心后,用EIA试剂盒测定血清睾酮。
在给药60天后才对血清睾酮浓度进行评估。
结果示于图1中。
下文表1总结了试验动物被考察器官的重量的数据。
本发明的制剂,无论微乳中活性成分的浓度是多少,均没有显著的全身性或者局部副作用,且在注射后48小时即可产生治疗效果并在至少30天的时间内持续释放活性成分。
该效果与使用以生物可降解聚合物为基础的市售制储库剂“Enantone”所达到的效果相当。
实施例16-微乳皮下可受耐性的评价
通过向至少含9只大鼠的试验组单次注射给药下表2所示的微乳来进行评价皮下可耐受性的试验。
在给药后第48小时、第7天和第14天时进行临床上、验尸、组织学的检查。
表2
(1)按照实施例1的方法制备的微乳。
(2)按照实施例8的方法制备的微乳。
*分值含义:1轻微;2中度;3严重。
该试验显示该制剂具有生物相容性,它不产生顽固性的局部溃疡,而其产生的肿胀是产物注射量和皮下组织中油酸乙酯的清除速率的函数(参见Howard等,Int.J.Pharm.16(1983)31-39中的描述)。
实施例17-含醋酸奥曲肽微乳的有效性的体内评价
将按照实施例11的描述制备的含奥曲肽的微乳以相当于6mg/大鼠的剂量向6只体重约175-200g的雄性大鼠给药。在给药前、给药后第0.5小时、第24小时、第4天、第6天和第8天抽取血浆样品。
从血浆中提取奥曲肽并用LC-MS-MS仪器参照校准曲线进行分析。血浆浓度示于下文的表3中:
表3
取样时间 | 0.5小时 | 24小时 | 4天 | 6天 | 8天 |
奥曲肽(ng/ml) | 539 | 40.2 | 62.5 | 4.5 | 7.6 |
给药后第8天仍能发现明显的奥曲肽血浆浓度。
实施例18-含醋酸亮丙瑞林微乳的剂量/效力比的评价
将按照实施例2的描述制备的含醋酸亮丙瑞林的制剂以2.25mg/kg的单剂量向大鼠给药(实施例组)。对照动物接受相应剂量的盐水溶液(对照)。
在第0、1、2、3、5、7、14、21、28、42和56天对血液样品中的睾酮血浆浓度进行评估。血样离心后将血清睾酮用Elisa试剂盒进行测定。
结果示于图2中。
给药动物的有关器官重量的数据概括于下表4中。
表4:醋酸亮丙瑞林微乳或盐水溶液对大鼠体重和生殖器官重量的影响(实施例组和对照组)。
给予微乳56天后清楚的证实了睾酮血浆浓度和生殖器官重量的降低。
Claims (6)
1.一种稳定的、生物相容性的、可耐受性很好的w/o型微乳,其适用于亲水性的或者通过适当的衍生化制成亲水性的生物活性化合物的非肠道给药,且能提供所含活性化合物的持续释放,所述微乳由:
a)最多20%的含治疗活性亲水性化合物的内层亲水性水相;
b)30到98%的外层疏水性相,选自含C2-C8醇残基的C8-C20饱和或不饱和羧酸酯或者C8-C20脂肪酸的单甘油酯、二甘油酯和三甘油酯;
c)最多50%的与辅助表面活性剂混合使用的表面活性剂组成,
所述表面活性剂选自含C4-C20饱和或不饱和的羧酸残基的天然或合成的甘油磷脂,其包含胆碱、乙醇胺、丝氨酸、甘油残基作为其磷脂部分,所述辅助表面活性剂选自C8-C20脂肪酸和C2-C12醇,并且其中表面活性剂/辅助表面活性剂的比值≥2,
所述活性化合物是醋酸亮丙瑞林、戈舍瑞林、曲普瑞林、那法瑞林、组氨瑞林、奥曲肽、兰瑞肽、未分离的肝素或者低分子量肝素。
2.权利要求1的微乳,其中含生物活性化合物的水相的pH值在4.5到7.5之间。
3.权利要求2的微乳,其中含生物活性化合物的水相的pH值在5到7之间。
4.权利要求2的微乳,其中的pH通过加入天然氨基酸来调节。
5.权利要求1-3中任何一项的微乳,其中表面活性剂/辅助表面活性剂的比值≥3.5。
6.权利要求1-3中任何一项的微乳,其中表面活性剂和辅助表面活性剂的含量低于35%。
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CN105392470A (zh) * | 2013-07-09 | 2016-03-09 | 益普生药业公司 | 用于使兰瑞肽缓释的药物组合物 |
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