CN111787802A - 抗细菌杀精润滑剂 - Google Patents
抗细菌杀精润滑剂 Download PDFInfo
- Publication number
- CN111787802A CN111787802A CN201980012288.5A CN201980012288A CN111787802A CN 111787802 A CN111787802 A CN 111787802A CN 201980012288 A CN201980012288 A CN 201980012288A CN 111787802 A CN111787802 A CN 111787802A
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- Prior art keywords
- guanidine
- composition
- polymeric
- composition according
- biocide
- 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.)
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Abstract
本发明涉及一种化学组合物,所述化学组合物包含至少一种聚合胍杀生物剂和至少一种烷基苯氧基聚乙氧基乙醇杀精剂的水溶液,以及至少一种增稠剂,所述化学组合物适于用作在性交中使用的杀生物剂和杀精剂。
Description
技术领域
本发明涉及稳定凝胶制剂中的杀精剂的亲密使用。
背景技术
已在文献中描述了含有杀精剂的亲密制剂。因此,US 5512289描述了一种含有烷基苯氧基聚乙氧基乙醇杀精剂(例如,常用杀精剂壬苯醇醚-9)和选自非离子型聚乙氧基化的化合物的增溶剂(主要为聚乙二醇(PEG)或聚山梨酯(吐温))的制剂。需要大量的这种增溶剂(主要是PEG),否则杀精剂会沉淀并形成乳白色糊状物。PEG和聚山梨酯是有害物质,因为其会降低皮肤的屏障功能。这特别不适于还应降低感染风险的亲密制剂。
烷基苯氧基聚乙氧基乙醇(特别是壬苯醇醚-9)本身就是较强的表面活性物质(US6028115),因此,如果制剂中发生了微相分离(例如,乳液),则不利于其作用,因为这会导致制剂的微观不均一性,从而形成具有不同活性(包括显著降低的活性)的区域。
本发明的一个目的为提供包含烷基苯氧基聚乙氧基乙醇杀精剂的替代制剂,其无需加入聚合化合物,例如PEG或聚山梨酯。另一个目的为向润滑剂提供杀生物物质,以降低感染性传播疾病的风险。
通过使用聚合胍作为杀生物物质来实现根据本发明的两个目的,此外,令人惊讶地是,其能够在润滑剂凝胶中形成稳定的增稠溶液。本文使用的“稳定的”意指不存在相分离,例如在US 5512289的对比实施例中观察到的相分离。
WO 2008/031105 Al描述了用于动物皮肤局部治疗的聚合胍杀菌剂。
UA 64406 A(摘要)描述了一种用于治疗坏死性溃疡性龈口炎的含有聚六亚甲基磷酸胍和各种油的软膏。
令人惊讶地,其已证明,当将少量的聚合胍类抗微生物物质加入制剂中时,可以省去PEG、聚山梨酯或选自非离子型聚乙氧基化的化合物的其它增溶剂。
发明内容
因此,本发明涉及一种化学组合物,所述化学组合物包含至少一种聚合胍杀生物剂和至少一种烷基苯氧基聚乙氧基乙醇杀精剂的水溶液,以及至少一种增稠剂。
所述组合物能够在性活动期间防止性传播疾病的传播,同时提供避孕作用而无需使用机械保护。凝胶制剂的使用提供了润滑剂凝胶的优点,从而能够实现无痛且更顺利的性交。其阻止了在没有润滑剂的性活动中发生的微损伤(造成额外的感染风险)的出现。在这方面,令人惊讶地,已经证明,根据本发明的组合物增强了聚合胍杀生物剂的杀生物作用。
“防止”或实际上“抑制”不应理解为意指绝对效果,即100%成功的防止,而是意指降低传播性传播疾病和/或受孕的风险或可能性。
在消毒剂的专业领域中,聚合胍杀生物剂是已知的。其制造已在WO 01/85676Al和专利AT 408302 B和AT 411060 B中描述。聚合胍杀生物剂也被称为Akacid或X-Cid,并且已在Kratzer等人的Antibiotika Monitor(2006年2月1日)、Buxbaum等人的Journal ofAntimicrobial Chemotherapy(2006年,58,193-197)、US 2325586、GB 1095902A、WO 1999/054291 Al、WO 01/85676 Al、WO 2002/030877 Al、WO 2006/047800 Al、WO 2008/080184A2、WO 2009/092123 A2、EP 2520605 Al、WO 2013/064161 Al、WO 2014/113835 Al、WO2016/015081 Al(均通过参考并入本文)中描述。聚合胍杀生物剂还可以为复合物形式,例如与明胶或多糖的复合物(例如,如WO 2010/106007 Al中所述)。WO 2008/080184描述了聚合胍在非治疗应用中控制微生物的用途,例如,通过雾化以对空间进行消毒。在这方面提及的组合物为Akacid(聚-[2-(2-乙氧基)乙氧基乙基]氯化胍)和Akacid Plus(聚(六亚甲基氯化胍)和聚-[2-(2-乙氧基)乙氧基乙基]氯化胍以3:1的混合物)。
在这方面,术语“聚合胍”特别用于表示“基于亚烷基二胺和/或氧化亚烷基二胺的聚合胍衍生物”(WO 2009/009815 Al),特别是“基于在两个氨基之间包含烷基链或烷氧基链的二胺的杀生物的聚合胍衍生物,其中胍衍生物为胍酸加成盐与在两个氨基之间包含聚亚烷基链或聚氧化亚烷基链的二胺的缩聚产物”(EP 1280766 Bl,权利要求1)。聚(六亚甲基胍)盐和/或聚[2-(2-乙氧基)乙氧基乙基]胍盐是特别优选的。Akacid和Akacid Plus是优选的根据本发明的聚合胍杀生物剂。
根据本发明的组合物的优选实施方案的特征在于,提供了包含摩尔比在4:1和1:4之间的亚烷基二胺和氧化亚烷基二胺的聚合胍杀生物剂。亚烷基二胺和/或氧化亚烷基二胺的氨基优选位于末端,其中为了生产聚合胍杀生物剂,首先提供了作为亚烷基二胺的通式为NH2(CH2)nNH2的化合物,其中n为在2和10之间的整数,特别是6。为了生产聚合胍杀生物剂,提供了作为氧化亚烷基二胺的通式为NH2[(CH2)2O)]m(CH2)2NH2的化合物,其中n为在2和5之间的整数,特别是2。
优选的聚合胍杀生物剂可以选自聚(六亚甲基胍)、聚[2-(2-乙氧基)-乙氧基乙基]胍、聚三乙二醇胍、聚乙二醇胍、聚氧化亚丙基胍、聚氧化亚乙基胍。
特别优选地,聚合胍杀生物剂为聚亚烷基胍,特别是聚氧化亚烷基胍。“亚烷基”可以为C1-C8烷基,最优选C2-C6烷基,例如乙基、丙基、丁基、甲基丙基、戊基,其可以支化或不支化。在本文使用的术语“亚烷基”或“烷基”的所有情形中,其均是优选的。
在WO 2014/113835 Al和WO 2016/015081 Al中描述了极其适合本发明的更优选的聚合胍(均通过参考并入本文)。这种类型的聚合胍(也称为“聚胍”)可对应于下式(I)、(II)或(III):
其中,R1表示芳环体系,或表示乙烯,或具有通过闭环消去胍而获得的环状结构,所述芳环体系包含至少一个芳环,所述芳环任选地包含一个或多个选自O、N和S的杂原子并任选地被一个或多个乙烯基取代。R1的示例为苯(优选在对位或间位键合)、吡啶(优选键合至与N相邻的两个C原子)、二乙烯基苯、联苯(优选两个苯分别在对位键合)、1,3-双((E)-2-乙烯基)苯、呋喃、吡咯、噻吩、芴、乙烯(优选为顺式构型)。这种类型的聚合胍已在WO 2016/015081 Al中描述。
聚合胍还可以包含下式(IV)或其盐
其中
X选自-NH2、氨基胍基以及1,3-二氨基胍基;
Y选自-H和-R1-NH2;或X和Y共同表示产生环状结构的化学键;
R1选自包含2至20个碳原子的二价有机基团,其中,任选地,一个或多个碳原子被O或N替代;
a和b分别为0或1;
其中,当不存在1,3-二氨基胍单元时,a+b不等于2;
R2选自-H和-NH2;
其中,当a+b=0时,R2为-NH2;
当a+b=1时,R2为-H或-NH2;以及
当a+b=2时,R2为-H;且n大于2。
这种类型的聚合胍已在WO 2014/113835 Al中描述。
在式(I)至(IV)中,例如,为了达到上述限定的聚合物的摩尔质量,n对应于倍数。作为示例,n可以为3至200。
WO 2014/113835 Al和WO 2016/015081 Al的实施例中的聚合胍是特别优选的(通过引用将两个出版物中的实施例并入本文)。在本发明的所有方面中,聚合胍聚间二甲苯胺氨基胍(PMAG)是特别优选的。
WO 2014/113835 Al和WO 2016/015081 Al的聚合胍(特别是PMAG)的优点在于,其可以使用少量的残余单体(例如,通常存在的HMDA-六亚甲基二胺)制造,因此毒性较低,这在本发明的上下文中特别有利。由凝胶形成剂(或另一种增稠剂)、壬苯醇醚(或另一种杀精剂)、PMAG(或另一种聚合胍,特别是WO 2014/113835 Al或WO 2016/015081 Al中的聚合胍)以及任选地利多卡因(或另一种局部麻醉剂)形成的组合物是特别优选的。
优选地,胍为胍盐,所述胍盐优选地选自卤化物(优选为氯化物)、磷酸盐(优选为磷酸二氢盐)、碳酸盐、硝酸盐、山梨酸盐、醋酸盐(优选为醋酸氢盐)、葡糖酸盐、柠檬酸盐、硅酸盐等。聚合胍也是如此。根据本发明的聚合胍可以为聚胍盐。例如,这些带有成盐离子(反离子)的化合物(例如,卤化物、磷酸盐等)已在AT 411060B中描述。
优选地,聚合胍杀生物剂的平均分子量为200Da至10000Da,优选为500Da至3000Da。作为示例,聚合胍杀生物剂可以设置有至少3个胍基团。可以通过膜的纳米过滤获得具有这些尺寸的聚合物。对于纳米过滤,使用具有适当孔径的过滤器,以使期望的摩尔质量通过。为了获得期望的聚合物,可以再循环滤液(用于除去较大的聚合物)或残余物(用于除去较小的聚合物)。期望并优选的聚合胍杀生物剂具有改善的毒理学。特别地,消除短链低聚物和单体以及消除合成产生的二胺基团是主要优点。否则这些物质可被阴道内膜吸收,并产生不希望的药理作用。本文的制剂的主要优点为局部应用和三重作用,而没有不希望的副作用。相应地,除去了单体起始材料(胍)和分子量为250Da或更低,或甚至400Da或更低的胍杀生物剂的低聚物或聚合物。
单体与分子量为250Da或更低的胍的短链低聚物(例如,HMDA)的比例优选小于组合物的0.1重量%,特别优选地小于组合物的0.05%,特别优选地小于0.01%,小于0.005%,小于0.001%或甚至小于0.0001%(全部为重量%)。特别优选地,组合物不含这些单体或短链低聚物,或如上所述,例如通过纳米过滤将其除去。
提供足够量或足够浓度的聚合胍杀生物剂,以抑制在性交期间出现的病原细菌(革兰氏阴性菌和/或革兰氏阳性菌)的生长。根据本发明被抑制的这种类型的细菌的示例为金黄色葡萄球菌、大肠杆菌、铜绿假单胞菌。
作为替选或组合,可以提供足够量或足够浓度的聚合胍杀生物剂,以抑制在性交期间出现的病原真菌的生长。根据本发明被抑制的这种类型的真菌的示例为白色念珠菌、酿酒酵母菌。
作为替选或组合,可以提供足够量或足够浓度的聚合胍杀生物剂,以抑制在性交期间出现的病毒对接受性伴侣的传播和感染。聚合胍杀生物剂的杀生物作用可抵抗这些病原体(主要是细菌)。尽可能地,聚合胍杀生物剂不应损害宿主或性伴侣(特别是人类)。人类是根据本发明的组合物将要治疗的优选使用者。
根据本发明的组合物可进一步包含烷基苯氧基聚乙氧基乙醇杀精剂,例如,壬基苯氧基聚(氧化亚乙基)乙醇(壬苯醇醚-9)。其特别优选地用作“液体避孕套”,即为液体、流体或使用时可流体化(即“液体”)的试剂,用于避孕,此外还用于预防疾病的传播。根据本发明可以使用的优选的杀精剂为壬苯醇醚-9、辛苯醇醚-9、十二烷基乙二醇单月桂酸酯、月桂醇聚醚10S以及甲氧基聚氧化乙二醇550月桂酸酯。
对于特定应用(即同性恋者使用),不需要这种杀精剂。而是在这种情况下使用局部麻醉剂(例如,利多卡因),以延迟性交时的过早性高潮(特别是男性之间)。也可以在异性性交中使用这种类型的局部麻醉剂,但是由于其对女性的影响而不太优选,因此该情况下可以省去局部麻醉剂。优选的其它局部麻醉剂可以包括苯佐卡因、地布卡因、苯甲醇、樟脑、间苯二酚、薄荷醇以及盐酸苯海拉明等,但不限于此。
烷基苯氧基聚乙氧基乙醇杀精剂(例如,壬苯醇醚-9)是已知的,并已在例如US5512289中描述。如在背景技术中所述,烷基苯氧基聚乙氧基乙醇杀精剂与水性聚合凝胶基质的组合会引起溶解问题,其中US 5512289提出了表面活性物质,例如聚山梨酯或大量的PEG。根据本发明,可以省去这些表面活性物质,因为,令人惊讶地,已经证明烷基苯氧基聚乙氧基乙醇和聚合胍杀生物剂具有互相增溶的作用,并且这种协同作用特别适合于用于性交的组合物。根据本发明,这两种物质(聚合胍杀生物剂和烷基苯氧基聚乙氧基乙醇)可以存在于溶液中或可以被溶解,并且由于这种化学作用,实际上完全没有相分离或不会形成浑浊乳液。
特别地,根据本发明的组合物为用于性交的润滑剂凝胶或润滑剂。
这些润滑剂凝胶或润滑剂具有通过增稠剂获得的增加的粘度。粘度可以为1Pa-s或更高,特别优选地为1Pa-s至900Pa-s,尤其优选地为7Pa-s至500Pa-s,特别优选地为35Pa-s至150Pa-s。在36℃下在大气压力(1巴)下测定粘度。
优选地,增稠剂为凝胶形成剂。例如,其可以选自羟烷基纤维素、纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素。栓剂中的增稠剂可以为栓剂基质,所述栓剂基质优选地选自硬化脂(Adeps Neutralis)、甘油-明胶混合物或可溶PEG(例如,PEG 400/4000),其中由于对膜的影响并增加了膜的渗透性,因此PEG不太优选,或不包含在根据本发明的组合物中。
增稠剂还可以具有成膜性质。因此,与增稠剂结合或独立于增稠剂,组合物可优选地包含一种或多种例如源自水溶性纤维素的成膜聚合物、树胶、壳聚糖等。优选地,这种源自纤维素的聚合物为羟烷基纤维素聚合物。更优选地,羟烷基纤维素聚合物选自:羟乙基纤维素、羧甲基纤维素、羟丙基纤维素以及羟丙基甲基纤维素等。最优选地,羟烷基纤维素聚合物为羟丙基纤维素。“烷基”可以为如上针对聚合物的定义(C1-C8烷基,包括优选的实施方案)。
优选地,组合物包含0.05重量%至1重量%的聚合胍杀生物剂,特别优选为0.1%至2%,尤其优选为0.4%至3%(全部为重量%)。
优选地,组合物包含0.05%至8%(重量)的烷基苯氧基聚乙氧基乙醇杀精剂,特别优选为0.1%至6%,尤其优选为0.3%至2%(全部为重量%)。
优选地,组合物包含1%至95%(重量)的增稠剂。在(粘性)液体和凝胶的情况下,组合物优选包含1%至30%的增稠剂(可以为凝胶形成剂)。优选地,所述范围为1.5%至20%,特别优选为2%至6%(全部为重量%)。在栓剂的情况下,增稠剂的量优选为50%至95%,特别优选为80%至93%。
组合物可以以单剂量形式提供,例如,以1mL至10mL,优选2mL至5mL的量提供。单剂量形式的示例为一次性移液管。一次性移液管可以为塑料移液管,在使用之前,将其头部拧开。
此外,组合物可以包含润湿剂,例如,丙二醇或甘油。润湿剂可以以1%至30%,优选3%至18%(全部为重量%)的浓度提供,特别是在液体组合物或凝胶组合物中。
优选地,组合物为均匀的组合物(没有不同相),其可以直接阴道施用。特别地,其不需要固体载体(例如,海绵),并在没有任何这种固体载体(在使用时仍然为固体)的情况下使用(与栓剂相反)。
此外,组合物可以包含其它酸化剂(例如,枸橼酸)或具有额外的抗氧化作用(例如,含有抗坏血酸)。
优选地,组合物的pH的范围为4.5至8,特别优选为5至7。pH可以使用常规酸和碱进行调节并且优选进行缓冲,即酸或碱应为弱酸或弱碱。优选地,酸选自碳酸、柠檬酸、磷酸、醋酸、苹果酸、盐酸、HEPES等。
优选地,仅使用本文列举的物质,并且特别不使用增强通过上皮层的通道的(其它)物质,例如PEG或聚山梨酯。还优选避免选自聚乙氧基化的非离子型化合物的增溶剂(其也包括聚乙二醇(PEG)或聚山梨酯(吐温))。为了不容易规避根据这些实施方案而保护的发明,这些不希望的物质可以以少量或不显著的量存在,例如,最大为1%或最大为0.5%(全部为重量%)。
其它不希望的物质为氧化性物质,例如聚维酮碘;这些物质完全不存在或仅以较少的量存在,例如,最大为0.5%或最大为0.1%(全部为重量%)。
相似地,表面活性物质(例如,苯扎氯铵)被认为是不希望的物质,因为其可以增加阴道内膜对病原体的渗透性。这些物质优选以最大1%,特别优选最大0.1%(全部为重量%)的量存在。仅出于说明的目的,所包含的根据本发明的物质(例如,聚合胍杀生物剂、杀精剂或局部麻醉剂)不是不希望的物质。
组合物还可以包含药物载体物质、粘合剂(优选为聚合粘合剂)和/或添加剂。术语“载体物质”表示可以与组合物一起施用的增稠剂,例如,水、生理盐水、粘合剂或介质。对于固体或液体组合物,药物组合物中的载体物质或添加剂可以为SiO2、TiO2、粘合剂(例如,微晶纤维素、聚乙烯吡咯烷酮(聚维酮)、黄芪胶、明胶、淀粉、乳糖或单水乳糖、藻酸、玉米淀粉等)、润滑剂或表面活性剂(例如,硬脂酸镁或十二烷基硫酸钠)、流动调节剂(例如,胶体二氧化硅)。
根据本发明的特别优选的组合物包含以下物质:
全部为重量%。
组合物可进一步包含:
全部为重量%。
代替氢氧化钠或柠檬酸或者除了氢氧化钠或柠檬酸之外,组合物还可以包含如上所述的缓冲剂组分,特别是为了调节如上所述的pH。
此外,本发明涉及根据本发明的任一实施方案的组合物在阴道抗细菌、抗真菌和/或抗病毒消毒中的用途。本发明还涉及其在性活动期间作为润滑剂的用途,以及两种功能的组合。由于壬苯醇醚是任选的(例如,作为无避孕作用的纯润滑剂),因此本发明还涉及包含至少一种聚合胍杀生物剂水溶液和至少一种增稠剂的化学组合物在性活动期间用于阴道抗细菌、抗真菌和/或抗病毒消毒的用途,或通过将包含至少一种聚合胍杀生物剂水溶液和至少一种增稠剂的组合物引入参与性活动的性器官中(特别是人体通道)以在性活动期间阻止性传播疾病传播的方法。优选地,组合物或其组分之一或用途如上文和下文所定义。
此外,本发明涉及防止感染性传播疾病或在性活动期间避孕的方法,其包括将根据本发明的任一实施方案的组合物引入进行性活动的阴道腔中。
不需要由阴道内的固体物质(例如,海绵或屏障)提供的机械保护,因此在根据本发明的用途中可以将其省去。
根据本发明的组合物优选为在溶解有活性物质的粘性液体中的润滑剂凝胶。润滑剂凝胶的优点为无痛且更顺利的性交。制剂的凝胶性质缓解了主要发生在绝经后妇女中的阴道内膜的干燥,因此在性活动期间不会出现疼痛,或降低其风险。
此外,可以使用如上所述的局部麻醉剂以缓解男性早泄。
根据本发明的组合物既可用于异性恋者,也可用于男性同性恋者。除了防止在阴道内传播病原体之外,还可以在其它身体通道(例如,肛门)的情况下防止这种传播。在同性性交的情况下,优点在于凝胶性质的施用形式,其使得性交更顺利,并阻止性传播疾病的传播。组合物的凝胶性质意味着肛门内膜的微损伤(使用传统避孕套时经常发生的问题,避孕套随后可能会破裂)显著降低。通过防止内膜的微损伤,显著降低了感染病原体的风险。
可以使用根据本发明的组合物(或可以提供根据本发明的组合物的一种用途)以减少病原体的任何传播。这种类型的病原体可以为细菌、真菌或病毒。根据本发明被抑制传播的细菌的示例为金黄色葡萄球菌、大肠杆菌、铜绿假单胞菌。根据本发明被抑制传播的真菌的示例为白色念珠菌、酿酒酵母菌。聚合胍和双胍的抗病毒作用经常在文献中描述(例如,Klein等人,Journal of General Virology(2000年),81,895-901)。
聚合胍具有较强的杀病毒活性(特别是对裸病毒)。已在文献中描述了其对在性交期间传播且应加以防护的常规病毒的抗病毒活性,部分地通过使用结构相似的聚合胍衍生物聚六亚甲基双胍(PHMB)进行的试验,参见Romanowski等人(JAMA Ophthalmol,2013年4月,131(4):495-8)、Gentile等人(BMC Clinical Pathology,2012年12月:17)、Valluri等人(Cornea,1997年,16(5):556-559)、Passic等人(Biomed Pharmacother,2010年,64(10):723-732)。根据本发明的组合物可以通过活性物质和凝胶/酸/聚合物混合物来降低或防止病毒从病毒携带者传播到接触者的细胞。减少或防止传播的病毒的示例为HPV(人乳头状瘤病毒)、HSV(单纯疱疹病毒)或HIV(人类免疫缺陷病毒)。
本发明可以例如在性伴侣确诊之后对感染这些病原体的传播提供特异性预防,或预防性使用,从而防止可能的传播。
附图说明
现将通过以下附图和实施例的说明更详细地描述本发明。
附图显示了根据本发明的组合物和纯Akacid在不同活性物质浓度下对各种病原体的抑制作用,即MRSA1(图1)、EK4(图2)、Strepto8(图3)、E.Coli 13(图4)、KL 37(图5)、PS23(图6)、Asp.Fum.45(图7)、Asp.Faec.46(图8)、C.albicans(图9)、C.krusei(图10),在每种情况下使用共同的阳性对照(PC)和阴性对照(NC)。
具体实施方式
实施例1:聚胍制剂的生产
基本制剂为采用各种配方的聚胍类杀生物物质(Akacid,描述于Kratzer等人的Antibiotika Monitor(2006年2月1日)、Buxbaum等人的Journal of AntimicrobialChemotherapy(2006年,58,193-197)、WO 01/85676 Al、WO 2006/047800 Al、WO 2008/080184 A2、WO 2013/064161 Al),例如Akacid Plus(聚六亚甲基氯化胍与聚-[2-(乙氧基)乙氧基乙基]氯化胍以3:1的混合物)。这些杀生物聚合胍化合物具有优异的抗微生物特性,此外还能够与在不存在选自聚乙氧基化的非离子型化合物的增溶剂的情况下难以混合的物质配制稳定的制剂。
使用改进的方法生产Akacid,其中,在一步合成中使起始物质三乙二醇与六亚甲基二胺和盐酸胍反应,然后通过三个NF膜过滤以除去较低分子量的单体和较高分子量的单体,从而生产出具有更好药理性质的单体纯化的Akacid Plus组分。这种Akacid Plus(或“X-Cid”)的重均分子量约为1000道尔顿(主要为500至3000道尔顿)。组合物以水溶液的形式制备以用于进一步配制。
物质的量以克或%给出。除非另有说明,否则所有的百分数均以重量%给出。
实施例2:“女用液体避孕套”制剂
“女用液体避孕套”制剂由包含羟乙基纤维素的凝胶组成。用纯化水使羟乙基纤维素膨胀5分钟,直到获得粘度较低的凝胶。
将柠檬酸溶液加入该凝胶基质中;在混合所有其它物质之后,通过氢氧化钠溶液将pH调节至5.5-6.2。
将两种活性物质Akacid Plus 1000(浓度为0.2-1%)和杀精物质9-壬苯醇醚(浓度为5%)或促进避孕的其它物质(例如,乳酸、柠檬酸、奎宁、石榴籽提取物、蜂蜜或金合欢碎芽)加入制备的凝胶基质中。使用1.8mL的一次性塑料移液管进行凝胶施用,在使用之前将其头部拧开。必须至少在性交前1-3分钟将总量插入阴道内。随后通过性活动本身使凝胶分布。
制剂I,“女用液体避孕套”:
实施例3:“男用液体避孕套”制剂
“男用液体避孕套”制剂为包含羟乙基纤维素的凝胶。用纯化水使羟乙基纤维素膨胀5分钟,直到通过剪切获得粘度较低的凝胶。将两种活性物质Akacid Plus 1000(例如,浓度为0.2%)和局部麻醉剂盐酸利多卡因(浓度为0.4%)加入已生产的软膏基质中。加入局部麻醉剂的目的为脱敏,以缓解早泄。此处pH为中性或略碱性。制剂不具有避孕作用,主要用于防止男性由于没有保护的性交而造成的感染。
制剂II“男用液体避孕套”:
实施例4:“液体避孕套栓剂”制剂
将称量的Akacid Plus 1000和壬苯醇醚-9共同加入熔融的Adeps Neutralis溶液中,在冷却至约40-45℃之后,将其倒入2g的栓剂模具中,使其冷却并固化。
制剂III“液体避孕套栓剂1%”,10片:
实施例5:“液体避孕套”与纯Akacid的抗细菌效果的比较
通过互相比较试验了以下组合物,其中仅改变各种稀释液中Akacid的浓度(如实施例1中所述的Akacid Plus)。
组合物1:如实施例2中所述的含有壬苯醇醚-9的“液体避孕套”(“女用液体避孕套”)
组合物2:如实施例2中所述的不含有壬苯醇醚-9(而是含有水)的“液体避孕套”(“女用液体避孕套”)
组合物3:Akacid Plus,剩余部分:水
所试验的病原体:
·MRSA 1-金黄色葡萄球菌(Staphylococcus aureus)
·EK 4-屎肠球菌(Enterococcus faecium)
·Strepto 8-肺炎链球菌(Streptococcus pneumoniae)
·E.coli 13-大肠杆菌(Escherichia coli)
·KL 37-肺炎克雷伯菌(Klebsiella pneumonia)
·PS 23-铜绿假单胞菌(Pseudomonas aeruginosa)
·Asp.Fum.45-烟曲霉菌(Aspergillus fumigatus)
·Asp.Faec.46-烟曲霉菌(Aspergillus fumigatus)
·C.Alb.-白色念珠菌(Candida albicans)
·C.Krusei 26-克柔假丝酵母菌(Candida krusei)
培养基:
细菌:Müller Hinton肉汤
真菌:Sabouraud肉汤
分析:
除对照孔外(每孔中加入100μL的培养基),在96孔培养皿的所有孔中加入50μL的各自的培养基。制备样品,并将100μL的样品加入孔中。
将50μL的试验组合物加入孔中,其中试验组合物具有不同的X-cid浓度,从0.6%开始,并用组合物的剩余组分分别进行1:1稀释,即0.6%、0.3%、0.15%、0.075%、0.0375%、0.0188%、0.00938%、0.00469%、0.00234%、0.00117%(四舍五入,所有百分比均为重量%)。
解冻病原体样品,并在各自的培养基中稀释。将50μL的病原体样品加入所有孔中(除了阴性对照之外)。在35℃下孵育过夜。第二天,使用SpectraMax 190酶标仪对培养皿进行视觉评估和测量。
SpectraMax 190酶标仪的测量结果显示在图1-图10中。
显然,对于MRSA,在所有浓度下均具有“液体避孕套”活性。个别异常值被认为是可能由于使用移液管运输材料的量不相等。这是可能的,因为该物质本身非常粘,因此有时难以吸取精确的量。
含有壬苯醇醚的“液体避孕套”也是如此。
对于Akacid 7(=X-Cid试验物质),直到0.009375%的浓度都可以观察到活性。在这之后,不再产生抑制作用。
对于EK 4,直到0.08175%的浓度都可以观察到“液体避孕套”活性,而当结合壬苯醇醚时,直到0.009375%的浓度都可以观察到“液体避孕套”活性。
Akacid 7直到0.0375%的浓度都具有活性。令人惊讶地,这意味着,在相同的Akacid浓度下,“液体避孕套”比纯Akacid更有效。只能假设这是由于组合物的协同作用。
对于链球菌8,活性的可见性再次出现变化,因此,仅在前两个浓度中获得了真正的抑制作用。
对于Akacid 7,直到0.0046875%的浓度都可以观察到对链球菌8的活性。
对于E.coli 13,再次观察到“液体避孕套”和结合有壬苯醇醚的“液体避孕套”的活性变化。对于Akacid 7,直到0.01875%的浓度都具有活性。
对于KL 37,直到0.009375%的浓度都可以观察到“液体避孕套”的活性,而当结合壬苯醇醚时,直到0.0046875%的浓度都可以观察到“液体避孕套”的活性。对于Akacid 7,直到0.0375%的浓度都可以观察到活性。
对于PS 23,Akacid 7直到0.0375%的浓度都具有活性。对于“液体避孕套”和“液体避孕套”与壬苯醇醚的组合,直到0.01875%的浓度都可以观察到抑制作用。
对于烟曲霉菌45,几乎在所有浓度下(直至0.00118%(最小试验浓度))均观察到了“液体避孕套”和“液体避孕套”与壬苯醇醚的组合的活性。对于Akacid 7,仅在直到0.009%时获得了活性。对于烟曲霉菌46,“液体避孕套”和“液体避孕套”与壬苯醇醚的组合在0.6%下具有活性。对于Akacid 7,在0.15%的浓度下观察到了活性。对于白色念珠菌,“液体避孕套”和结合有壬苯醇醚的“液体避孕套”直到0.3%都具有活性。对于Akacid 7,直到0.075%的浓度都可见抑制作用。
对于克柔假丝酵母菌26,与“液体避孕套”和“液体避孕套”与壬苯醇醚的组合相比,Akacid的抑制作用最高,实际上,直到0.08175%的浓度都具有抑制作用。对于“液体避孕套”,直到0.075%的浓度都可见抑制作用。对于结合有壬苯醇醚的“液体避孕套”,直到0.0375%的浓度都可以观察到抑制作用。
总而言之,在单独的“液体避孕套”和含有壬苯醇醚的“液体避孕套”之间几乎没有差异,或仅存在极小的差异。然而,在大多数情况下,与两种“液体避孕套”组合物相比,Akacid 7的抑制作用较小。
Claims (15)
1.一种化学组合物,所述化学组合物包含至少一种聚合胍杀生物剂和至少一种烷基苯氧基聚乙氧基乙醇杀精剂或局部麻醉剂的水溶液,以及至少一种增稠剂。
2.根据权利要求1所述的组合物,其特征在于,所述聚合胍杀生物剂为聚亚烷基胍,优选为聚氧化亚烷基胍。
3.根据权利要求2所述的组合物,其特征在于,所述聚合胍杀生物剂选自聚六亚甲基胍、聚[2-(2-乙氧基)-乙氧基乙基]胍、聚三乙二醇胍、聚乙二醇胍、聚氧化亚丙基胍、聚氧化亚乙基胍。
4.根据权利要求1至3中任一项所述的组合物,其特征在于,所述胍为胍盐,所述胍盐优选地选自卤化物、磷酸盐、碳酸盐、硝酸盐、山梨酸盐、醋酸盐、葡糖酸盐、柠檬酸盐、硅酸盐,所述卤化物优选为氯化物,所述磷酸盐优选为磷酸二氢盐,所述醋酸盐优选为醋酸氢盐。
5.根据权利要求1至4中任一项所述的组合物,其特征在于,所述聚合胍杀生物剂的平均分子量为200Da至10000Da,优选为500Da至3000Da。
6.根据权利要求1至5中任一项所述的组合物,其特征在于,所述烷基苯氧基聚乙氧基乙醇杀精剂为壬基苯氧基聚(氧化亚乙基)乙醇(壬苯醇醚-9)。
7.根据权利要求1至6中任一项所述的组合物,其特征在于,所述增稠剂为凝胶形成剂或栓剂基质,所述凝胶形成剂优选地选自羟烷基纤维素、纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素,所述栓剂基质优选地选自硬化脂、甘油-明胶混合物或可溶PEG,例如PEG 400/4000。
8.根据权利要求1至7中任一项所述的组合物,其特征在于,所述组合物包括0.05%至10%(重量)的聚合胍杀生物剂。
9.根据权利要求1至8中任一项所述的组合物,其特征在于,所述组合物包括0.05%至8%(重量)的烷基苯氧基聚乙氧基乙醇杀精剂。
10.根据权利要求1至9中任一项所述的组合物,其特征在于,所述组合物包括1%至95%(重量)的增稠剂。
11.根据权利要求1至10中任一项所述的组合物,其特征在于,所述组合物为1mL至5mL的量的单剂量形式,优选使用一次性移液管。
12.根据权利要求1至11中任一项所述的组合物,其特征在于,所述组合物包含润湿剂,优选为丙二醇。
14.包含至少一种聚合胍杀生物剂水溶液和至少一种增稠剂的化学组合物在性活动期间用于阴道抗细菌、抗真菌和/或抗病毒消毒的用途。
15.一种防止感染性传播疾病或在性活动期间避孕的方法,所述方法包括将如权利要求1至13中任一项所述的组合物引入进行性活动的阴道腔中。
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JP2021513569A (ja) | 2021-05-27 |
MX2020008140A (es) | 2020-10-12 |
US20210038637A1 (en) | 2021-02-11 |
EP3749095A1 (de) | 2020-12-16 |
EP3524055A1 (de) | 2019-08-14 |
BR112020015955A2 (pt) | 2020-12-15 |
WO2019154983A1 (de) | 2019-08-15 |
RU2020129407A (ru) | 2022-03-09 |
KR20200119829A (ko) | 2020-10-20 |
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