CN101247787B - 以包含药物、成膜聚硅氧烷和至少一种挥发性溶剂为基础的经皮药物的控制释放 - Google Patents
以包含药物、成膜聚硅氧烷和至少一种挥发性溶剂为基础的经皮药物的控制释放 Download PDFInfo
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Abstract
本发明涉及一种经皮药物的控制释放方法,该方法包括含有至少一种被增溶的药物、成膜聚硅氧烷和至少一种挥发性溶剂的组合物的局部给药。
Description
本发明涉及局部给药的药物制剂领域。
背景技术
药物进入皮肤的低渗透(和部分穿过角质层的渗透)通常会限制局部制剂的疗效。基本上,皮肤的渗透可通过以下方法得以提高:(i)增加药物在皮肤的扩散系数(ii)增加药物在皮肤的溶解度,和/或(iii)增加药物在制剂中的饱和度。然而,过饱和的制剂与传统制剂相比增加了药物的饱和度,其往往是不稳定的,这主要是因为药物的结晶作用。
发明概述
本发明提供一种经皮药物的控制释放方法,该方法包括含有至少一种被增溶的药物、成膜聚硅氧烷和至少一种挥发性溶剂的组合物的局部给药。
更特别的是,本发明提供一种方法,其中药物渗透作为贮库的皮肤上层,并在释放到真皮层以前聚集。
所述药物的例子可以是维生素D或维生素D类似物,例如骨化三醇或皮质甾醇例如氯倍他索或17-丙酸氯倍他索,单独或组合使用。
附图说明
发明内容
发明人发现,含有至少一种被增溶的药物、成膜聚硅氧烷和至少一种挥发性溶剂的局部用组合物,其允许经皮药物的控制释放,同时表现出良好的稳定性。药物的释放缓慢并且持久,从而使低剂量成为可能。因此,药物的给药剂量可以比包含同样药物但不含成膜聚硅氧烷和挥发性溶剂的组合物的剂量低。
药物根据特殊的零级动力学渗透到皮肤,这意味着药物浓度随时间呈直线变化,并且这种渗透是恒定而持续的。药物首先维持在皮肤的上层,也就是说皮肤层包括:
-角质层,
-透明层,
-粒状层,和
-生育层(包括棘层和基底层)。
药物到下层(即真皮和皮下组织)的释放通过药物的原位过饱和来控制。当组合物施用到皮肤上时,溶剂蒸发后达到过饱和。蒸发使药物在溶剂中浓缩,这有利于药物渗透到皮肤的上层并且形成贮库效应。同时,聚硅氧烷可控制溶剂的蒸发动力学和控制药物的结晶,这也有利于渗透。
这里描述的组合物包括至少一种药物,即一种药物活性成分。特别是其可包含两种药物。
有用的药物的例子是维生素D和维生素D类似物。
术语“维生素D”是指维生素D的多种形式,例如维生素D1、D2、D3或维生素D4。
术语“维生素D类似物”的意思是指表现出类似于维生素D生物学特性的化合物,特别是维生素D响应元素转活性性能(VDRE),例如维生素D受体的激动剂或拮抗剂活性。这些化合物优选包含侧链修饰的维生素D骨架和/或在该骨架中也包含修饰的合成化合物。这些类似物可包括结构类似的,特别是双芳香化合物。
维生素D类似物优选选自由骨化三醇、1,25-二羟维生素D3、度骨化醇、secalcitol、马沙骨化醇、西奥骨化醇、他卡西醇(他骨化醇)、帕立骨化醇、氟骨三醇、1α,24S-二羟基-维生素D2、1(S),3(R)-二羟基-20(R)-[((3-(2-羟基-2-丙基)-苯基)-甲氧基)-甲基)]-9,10-开环-孕甾-(Z),7(E),10(19)-三烯及其混合物组成的组。最优选骨化三醇。
进一步的例子包括那些在文献WO 02/34235、WO 00/64450、EP 1124779、EP1235824、EP1235777、WO 02/94754、WO 03/050067和WO 00/26167中描述的维生素D类似物。文献WO 00/26167中描述的化合物涉及维生素D的结构类似物,其对细胞增殖和分化表现出选择性活性,同时没有表现出任何高血钙活性。
有利的是,在组合物中溶解形式的维生素D或维生素D类似物的量从0.00001到5%w/w,优选从0.0001到3%w/w,以及更优选从0.0003到1%w/w。
另一种单独或组合维生素D或维生素D类似物使用的药物是皮质甾类。
术语“皮质甾类”的意思是I、II、III或IV组的局部类固醇(强或弱)。
更特别的是,其可选自由倍他米松、氯倍他索、氯倍他松、去羟米松、二氟可龙、二氟拉松、醋酸氟轻松、二氟美松、丙酮化氟新龙、氟地松、氟泼尼定、氯氟舒松、皮质醇、糠酸莫米松、去炎松、药学上可接受的酯或其丙酮化物组成的组。
酯或丙酮化物的例子包括17-戊酸酯、17-丙酸酯、17,21-二丙酸酯,丙酮化物、丙酮化物-21-N-苯甲酰基-2-甲基-β-丙氨酸酯、丙酮化物-21-(3,3-二甲基丁酸酯)和17-丁酸酯。
最优选的是,皮质甾类是氯倍他索或17-丙酸氯倍他索。
有利的是,在组合物中溶解形式的皮质甾类的量为0.0001到1%w/w,优选从0.0005到3%w/w,以及更优选为0.001到0.1%w/w。
在一个优选的实施方式案,活性成分溶解在相同溶剂或几种溶剂中。
溶剂选自药学上可接受的化合物,即适用于局部给药的化合物。
优选的挥发性溶剂包括链烷醇类、烷基二醇类、烷基酮类,和/或包含1到6个碳原子,特别是1到4个碳原子的烷基部分的烷基酯类,例如乙醇、异丙醇、正丁醇、乙酸乙酯、丙酮及其混合物。
特别是当药物是骨化三醇和17-丙酸氯倍他索时,优选的挥发溶剂为乙醇。
有利的是,组合物中溶剂的量是1到50%w/w(基于组合物总重量),优选2到40%w/w,以及更优选5到20%w/w。
本发明使用的成膜聚硅氧烷包括至少一种聚硅氧烷弹性体。
术语“聚硅氧烷弹性体”在这里是指任何的显示出化学交联并具有粘弹性质的硅氧烷聚合物。
根据本发明,合适的聚硅氧烷弹性体是在专利US4,980,167和US4,742,142中描述的那些。使用的聚硅氧烷特别可以是硅氢化的加成产物(加合物),和/或由(i)具有不饱和基团,例如乙烯基或烯丙基的聚硅氧烷,例如链接至少一个原子,和(ii)可参与加成反应的另一种硅产品,例如有机氢化聚合硅氧烷,加成得到的聚合产物。
根据一个特殊的实施方案,聚硅氧烷弹性体可以至少一种挥发性硅油的形式存在,即具有2到10个硅原子的直链或环状的聚硅氧烷油。
术语“聚硅氧烷油”在这里是指与皮肤、粘膜或角蛋白纤维接触后能蒸发的任何硅油,优选在常温和常压下蒸发过程小于1小时。
在本发明中使用的聚硅氧烷油,例如是具有2到10个硅原子的直链或环状聚硅氧烷,任选包括具有1到22个碳原子的烷基或烷氧基。本发明中使用的硅油有利的是表现出至多6×10-6m2/s(6厘沲)的粘度。
合适的挥发性硅油特别包括低分子量的环甲硅油和/或聚二甲基硅氧烷。在该范围内,环状的聚硅氧烷,特别是环状甲氧基的聚硅氧烷,具有4到12个的硅氧烷环,例如八甲基环四硅氧烷和十甲基环五硅氧烷。其他合适的挥发性硅油是十二甲基环六硅氧烷、七甲基己基三硅氧烷、七甲基辛基三硅氧烷、六甲基二硅氧烷、八甲基三硅氧烷、十甲基四硅氧烷、十二甲基五硅氧烷及其混合物。
根据一个特别的实施方案,本发明方法中使用的成膜聚硅氧烷是通过下列物质在催化剂存在下交联获得的聚硅氧烷产物:
(A)具有≡SIH基团的聚硅氧烷;
(B)α,ω-二烯;
(C)具有低分子量的聚硅氧烷。
在该范围内,聚硅氧烷(A)有利的包括一种或多种具有如下分子式(A1)、(A2-1)和(A2-2)之一的化合物:
R3 14SiO(R15 2SiO)a(R16HSiO)bSiR3 14 (A1)
HR2 14SiO(R15 2SiO)a(R16HSiO)bSiR2 14H (A2-1),
HR2 14SiO(R15 2SiO)cSiR2 14H (A2-2)
其中:
-R14、R15和R16是相同或不同的,并且每一个代表具有1到6个碳原子的烷基;
-a是0到250的整数,
-b是1到250的整数;并且
-c是0到250的整数。
-优选地,聚硅氧烷(A)包含具有上述分子式(A2-1)和/或(A2-2)的化合物,优选与具有分子式(A1)的化合物一起,摩尔比(A2-1+A2-2):(A1)优选为0到20之间,特别是0到5。
α,ω-二烯(B)为式CH2=CH(CH2)dCH=CH2的化合物,其中d是1到20的整数。
合适的α,ω-二烯的代表性例子特别是1,4-戊二烯、1,5-己二烯、1,6-庚二烯、1,7-辛二烯、1,8-壬二烯、1,9-癸二烯、1,11-十二碳二烯、1,13-十四碳二烯和1,19-二十碳二烯。
聚硅氧烷(C)可特别的包括下列物质的一种或其组合:
(C1)直链、支链或环状的挥发性甲基硅氧烷,例如:
-选自六甲基二硅氧烷、八甲基三硅氧烷、十甲基四硅氧烷、十二甲基五硅氧烷、十四甲基六硅氧烷、和/或十六甲基七硅氧烷的挥发性甲氧基硅氧烷。
-环状挥发性甲基硅氧烷,例如六甲基化环三硅氧烷、八甲基化环四硅氧烷、十甲基化环五硅氧烷、和/或十二甲基化环六硅氧烷。
-支链挥发性甲基硅氧烷,例如七甲基-3-[(三甲基甲硅烷)氧基]-三硅氧烷、六甲基-3,3-双[(三甲基甲硅烷)氧基]-三硅氧烷、和/或五甲基[(三甲基甲硅烷)氧基]-环三硅氧烷;
(C2)烷基和/或芳基硅氧烷,其是直链或环状的,和挥发性或非挥发性的,
特别是低分子量非挥发性粘度在100到1000mm2/s(厘沲)的化合物,特别是那些如下通式描述的化合物:
其中:
-e值优选80到375,
-R17和R18为具有1到20个碳原子的烷基,或例如苯基的芳基,例如聚二甲基硅氧烷、聚二乙基硅氧烷、聚甲基乙基硅氧烷、聚甲基苯基硅氧烷和/或聚二苯基硅氧烷;
(C3)官能化硅氧烷,其为直链或环状,特别是液体硅氧烷,例如用选自丙烯酰胺、丙烯酸酯、酰胺、氨基、甲醇、羧基、氯化烷基(chloroalkyles)、环氧 基、二醇、长春胺、巯基、甲酯、全氟和硅醇的基团官能化的。
优选地,聚硅氧烷(C)为选自挥发性聚甲基硅烷的低分子硅油,其为直链或环状。
根据本发明,适宜用作成膜聚硅氧烷其他聚硅氧烷为平均分子量至少为10000(例如从10000到10000000)的硅聚合物。这类聚硅氧烷的例子包括交联硅氧烷的共聚物,特别是聚二甲基硅氧烷或聚二甲基硅氧烷衍生物的共聚物,例如硬脂酰基甲基-二甲基硅氧烷共聚物(例如Grant Industries的《GransilSR-CYC》)、《Polysilicone-11》类型的共聚物(在环甲基硅氧烷的存在下,通过乙烯基端接的硅氧烷与甲基氢化聚二甲基硅氧烷反应生成的交联硅氧烷弹性体)、交联的鲸脂基聚二甲基硅氧烷/乙烯聚二甲基硅氧烷共聚物(即与乙烯基二甲基聚硅氧烷交联的鲸脂基聚二甲基硅氧烷共聚物)、交联的聚二甲基硅氧烷/苯基乙烯基聚二甲基硅氧烷共聚物(即与苯基乙烯基聚二甲基硅氧烷交联的二甲基聚硅氧烷共聚物)和交联的聚二甲基硅氧烷/乙烯基聚二甲基硅氧烷共聚物(即与乙烯基聚二甲基硅氧烷交联的二甲基聚硅氧烷共聚物)。
特别是得自Grant Industries的由硅氧烷制成的凝胶。这些凝胶的例子特别包括:
-聚硅氧烷-11和异十二烷的混合物,例如商品《Gransil IDS》,
其他的例子是环五硅氧烷和聚二甲基硅氧烷/乙烯基聚二甲基硅氧烷交联聚合物的凝胶,例如General Electric Company的《SPE839》。其他的还有那些市场上购自Shin-Etsu Company的以下标号:KSG-15、KSG-16和KSG-17的硅氧烷凝胶。
根据一个特别的实施方案,在本发明方法使用的组合物不含具有烷基基团 的聚硅氧烷。
不论其实际性质如何,本发明方法中成膜聚硅氧烷在组合物中有利的浓度为占组合物总重量的20到90%重量,优选30到80%之间。
这里描述的组合物可进一步地包括油性添加剂,例如棕榈酸异丙酯、二辛醚、聚二甲基硅氧烷或其混合物。
这里描述的组合物还可包括香味加强剂、防腐剂,例如对羟基苯甲酸酯、稳定剂、水分调节剂、pH调节剂、渗透压调节剂、乳化剂、UV-A和UV-B防晒剂、和抗氧化剂,例如α-生育酚、丁基羟基茴香醚或丁基羟基甲苯、超氧化物歧化酶、泛醇,或某些螯合剂。
优选地,组合物的形式是霜剂、凝胶剂、软膏剂或发膏剂。
优选地,组合物基本上不含水,即包含少于5%的水,优选少于3%,更优选0%的水。
优选的组合物包括:
-棕榈酸异丙酯
-环五硅氧烷
-环状聚二甲基硅氧烷5/聚二甲基硅氧烷交联聚合物
-骨化三醇
-17-丙酸氯倍他索
-乙醇。
在一个优选的实施方案中,组合物包括:
-棕榈酸异丙酯0.5-2%
-环五硅氧烷10-20%
-环状聚二甲基硅氧烷5/聚二甲基硅氧烷交联聚合物70-80%
-骨化三醇0.0001-0.0005%
-17-丙酸氯倍他索0.01-0.05%
-乙醇5-10%。
实施例:
实施例1:控释制剂的制备
下面描述的步骤是包含一种维生素D类似物和一种皮质甾类的硅氧烷软膏剂的一般制造方法。所述步骤在室温20℃到25℃之间进行。
第一步:包含硅氧烷的相(相I)的制备:
第二步:包含活性成分的相(相II)的制备:
在适当的溶剂和抗氧化剂中,制备包含维生素D类似物的母液。搅拌溶液直至活性物质溶解。
将皮质甾类称量并放入溶剂中。搅拌溶液直到活性物质溶解。
在搅拌下,将两种活性相并入到相I中。混合物均质化。
当两种活性成分的溶剂相同时,在维生素D类似物的母液中加入皮质甾类。
表1:
2Mirasil CM5
实施例2:药物的持续释放
本研究的目的是比较固定组成的骨化三醇3μg/g和丙酸氯倍他索250μg/g(实施例1的组合物),其通过对三种已上市的皮质甾类制剂的漂白能力进行评估:
-Diprolene乳膏(二丙酸倍他米松500μg/g)
方法学:
本研究作为单中心、研究者设盲、主动控制、个体内比较。
试验产品随机分配到预标记的2.2cm直径大小的前臂上。该方法由受过训练的实验员在漂白评估者看不见的情况下进行。试验产品作为六小时非闭合应用进行给药。
用目测和薄层色谱法在应用所述产品前30分钟内,以及清除多余物(应用研究产品6小时后开始清除)后10分钟、2小时、4小时、6小时、18小时和22小时对血管收缩进行评估。漂白目测评分(初期的药效动力学变量)由两个不同的受过训练的评估者使用5分制(0:无漂白到4:最大漂白)进行判断。薄层色谱的评估(第二个药效学变量)是基于使用ChromaMeter Minolta CR 300得到的薄层参数(a*和L*值)。
在本研究中,每次观察后均对所有主体进行安全评价。用于安全测量的第一参数被记录为不良反应。
目测评分由两个熟练的评估者使用下列的5分制各自进行:
0皮肤颜色没有改变
1轻微漂白(基本看不见)
2明显漂白
3强烈漂白
4被认为的最大漂白
对于目测评分,分析变量是两个评估者在每个部位的评分的平均值。曲线下面积通过主体和治疗T0(在施用前)到T28小时(产品移开后22小时)来计算。薄层色谱变量a*和L*根据它们在应用前的基线值Δa*和ΔL*来调节。曲线下面积通过主体和从T0(在施用前)到T28小时(产品移开后22小时)的治疗来计算。曲线下面积通过参数来分析模型中包括主体、区域和治疗在内的因素。
这种治疗通过Tukey多重比较测试来进行比较和分类,其在5%两面显著性水平下进行。
结果:
本研究招募了24人(2个男性和22个女性健康主体,年龄在20.4到42.3岁)。24个主体根据协议完成了该研究。没有任何人从分析中排除。
关于漂白目测评分(基于5分制)的评估,分析变量是两个评估者对每个部位评分的平均值的曲线下面积(AUC)。AUC通过主体和从T0(在施用前)到T28小时(产品清除后22小时)的治疗来计算。这些数据概括于下表2:
根据漂白目测评分(初期药动学变量),将考察的产品分成收缩活性显著不同的两组,如下:
然而,我们发现得到了一种非常特殊的收缩活性曲线,其中硅氧烷软膏的释放十分缓慢。在产品使用T0+22小时后,即28小时后仍没有达到最大效果。因此,产品的AUC不完整,并且不能适当地与其他可计算全部AUC的产品进行比较。
薄层色谱参数L*和a*证实了由目测评分得到的结果。
以安全方式进行分析时,既没有与治疗有关的不良反应,也没有严重的不良反应报道。在研究过程中,仅仅有一个不相关的不良反应(普通感冒)报道。因此,所有的测试产品被认为是可被良好耐受的。
结论:
硅软膏中的氯倍他索持续增加地释放,并且到28小时后仍没有到达血管收缩的最大效果。
实施例三:药物的分布
[根据实验记录和结果的解释对实施例进行更具体的描述]
当17-丙酸氯倍他索应用于人类皮肤(Franz’cell)16小时后,发现其在角 质层累积。
表3:
Claims (16)
1.组合物用于制备药剂的用途,所述药剂用于药物的经皮控制释放,所述控制释放包括含有至少一种增溶的药物、成膜聚硅氧烷和至少一种挥发性溶剂的所述组合物的局部给药,其中该组合物包含一种增溶的皮质甾类,且该皮质甾类是17-丙酸氯倍他索。
2.根据权利要求1的用途,其中该药物的给药剂量比包含相同药物但不含成膜聚硅氧烷和挥发性溶剂的组合物所用的剂量低。
3.根据权利要求1的用途,其中组合物包括两种药物。
4.根据权利要求1的用途,其中组合物包含增溶的维生素D或维生素D类似物。
5.根据权利要求4的用途,其中维生素D类似物选自由骨化三醇、1,25-二羟维生素D3、度骨化醇、马沙骨化醇、西奥骨化醇、他卡西醇、帕立骨化醇、氟骨三醇、1α,24S-二羟基-维生素D2、1(S),3(R)-二羟基-20(R)-[((3-(2-羟基-2-丙基)-苯基)-甲氧基)-甲基)]-9,10-开环-孕甾-(Z),7(E),10(19)-三烯及其混合物组成的组。
6.根据权利要求5的用途,其中维生素D类似物是骨化三醇。
7.根据权利要求1的用途,其中挥发性溶剂选自由链烷醇类、烷基二醇类、烷基酮类、和/或烷基酯组成的组,其中烷基部分包含1到6个碳原子。
8.据权利要求7的用途,其中挥发性溶剂是乙醇。
9.根据权利要求1的用途,其中成膜聚硅氧烷包括至少一种聚有机硅氧烷弹性体。
10.根据权利要求9的用途,其中聚有机硅氧烷弹性体以至少一种挥发性硅油的形式存在,其是具有2到10个硅原子的直链或环状聚有机硅氧烷油。
11.根据权利要求1的用途,其中硅氧烷的含量为组合物总重量的20到90%重量。
12.根据权利要求1的用途,其中溶剂的含量为组合物总重量的1到50%重量。
13.根据权利要求1的用途,其中组合物为乳膏、凝胶或软膏形式。
14.根据权利要求1的用途,其中组合物基本上不含水。
15.根据权利要求1的用途,其中组合物包含:
-棕榈酸异丙酯
-环五硅氧烷
-环状聚二甲基硅氧烷5/聚二甲基硅氧烷交联聚合物
-骨化三醇
-17-丙酸氯倍他索
-乙醇。
16.根据权利要求15的用途,其中组合物包含占组合物重量的重量比为:
-棕榈酸异丙酯 0.5-2%
-环五硅氧烷 10-20%
-环状聚二甲基硅氧烷5/聚二甲基硅氧烷交联聚合物 70-80%
-骨化三醇 0.0001-0.0005%
-17-丙酸氯倍他索 0.01-0.05%
-乙醇 5-10%。
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CN103480026A (zh) * | 2007-03-08 | 2014-01-01 | 莫科治疗有限公司 | 一种疤痕敷料制剂 |
WO2009009135A1 (en) | 2007-07-11 | 2009-01-15 | Dow Corning Corporation | Compositions for delivering a drug |
EP2451280A4 (en) * | 2009-07-09 | 2012-12-26 | Crescendo Therapeutics Llc | METHOD FOR WOUND HEALING AND SCALING MODULATION |
CA2785249A1 (en) * | 2009-12-22 | 2011-06-30 | Leo Pharma A/S | Pharmaceutical composition comprising vitamin d analogue and cosolvent-surfactant mixture |
US9254296B2 (en) | 2009-12-22 | 2016-02-09 | Leo Pharma A/S | Pharmaceutical composition comprising vitamin D analogue and cosolvent-surfactant mixture |
US20160095876A1 (en) | 2014-10-01 | 2016-04-07 | Rochal Industries, Llp | Composition and kits for inhibition of pathogenic microbial infection and methods of using the same |
TW201636025A (zh) * | 2015-04-15 | 2016-10-16 | Maruho Kk | 皮膚用之醫藥組成物 |
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- 2006-05-22 JP JP2008515155A patent/JP2008542423A/ja active Pending
- 2006-05-22 EP EP06754427A patent/EP1901709A2/en not_active Withdrawn
- 2006-05-22 KR KR1020077028565A patent/KR20080016612A/ko not_active Application Discontinuation
- 2006-05-22 MX MX2007015672A patent/MX2007015672A/es not_active Application Discontinuation
- 2006-05-22 RU RU2008100037/14A patent/RU2008100037A/ru unknown
- 2006-05-22 BR BRPI0613230-8A patent/BRPI0613230A2/pt not_active IP Right Cessation
- 2006-05-22 CN CN2006800204905A patent/CN101247787B/zh not_active Expired - Fee Related
- 2006-05-22 AU AU2006256860A patent/AU2006256860B2/en not_active Expired - Fee Related
- 2006-05-22 WO PCT/EP2006/005831 patent/WO2006131401A2/en active Application Filing
- 2006-05-22 CA CA002610755A patent/CA2610755A1/en not_active Abandoned
- 2006-06-08 AR ARP060102384A patent/AR054381A1/es unknown
Patent Citations (5)
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CN1048322A (zh) * | 1989-06-27 | 1991-01-09 | 美国氰胺公司 | 表面凝胶配方和粉刺的治疗方法 |
WO2000072817A1 (en) * | 1999-05-28 | 2000-12-07 | Neutrogena Corporation | Water-in-oil emulsion comprising a silicone gel containing vitamin c |
CN1353735A (zh) * | 1999-05-28 | 2002-06-12 | 纽创基纳有限公司 | 含水杨酸硅氧烷凝胶 |
US6365670B1 (en) * | 2000-03-10 | 2002-04-02 | Wacker Silicones Corporation | Organopolysiloxane gels for use in cosmetics |
US6410038B1 (en) * | 2000-06-14 | 2002-06-25 | Dow Corning Corporation | Water-in-oil-in-polar solvent emulsions |
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Title |
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Also Published As
Publication number | Publication date |
---|---|
BRPI0613230A2 (pt) | 2011-01-04 |
JP2008542423A (ja) | 2008-11-27 |
WO2006131401A2 (en) | 2006-12-14 |
CN101247787A (zh) | 2008-08-20 |
EP1901709A2 (en) | 2008-03-26 |
RU2008100037A (ru) | 2009-07-20 |
AU2006256860A1 (en) | 2006-12-14 |
AR054381A1 (es) | 2007-06-20 |
CA2610755A1 (en) | 2006-12-14 |
WO2006131401A3 (en) | 2007-03-15 |
AU2006256860B2 (en) | 2012-04-19 |
MX2007015672A (es) | 2008-02-20 |
KR20080016612A (ko) | 2008-02-21 |
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