CN1330921A - 由复乳法制造缓释性微球的方法 - Google Patents
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- CN1330921A CN1330921A CN00128884A CN00128884A CN1330921A CN 1330921 A CN1330921 A CN 1330921A CN 00128884 A CN00128884 A CN 00128884A CN 00128884 A CN00128884 A CN 00128884A CN 1330921 A CN1330921 A CN 1330921A
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Abstract
本发明提供一种经复乳法制造缓释性微球的方法,其是将药物包封入由可生物降解性高分子组成的担体中,能够持续性地调节药物的释放。将药物分别溶解或者分散在溶解了可生物降解性高分子的2种以上的乳相中,制造出2种以上的1次乳相或乳剂,制造出的2种以上的1次乳相或乳剂同时或者连续地分散在1种水相中,从分散有药物的微球中除去有机溶剂,制造包封入药物的微粒。
Description
本发明是关于将药物包封入由可生物降解性高分子组成的担体中,能够持续性地调节药物的释放的微球的制造方法。
作为以前的缓释型药物传送***(DDS;Drug Delivery System)制剂的通常的制造方法来说,已知的有经凝聚法(coacervation)、乳浊液相分离法或者喷雾干燥法所至的微囊化以及有机或水相中的溶剂蒸发法等。在这些方法中,使用最多的是水相中溶剂蒸发法,它分为多重乳化蒸发法(W/O/W;Water/Oil/Water)和单次乳化蒸发法(O/W;Oil/Water)。
一般地,象肽类以及蛋白质这样的水溶性药物的包封,主要使用W/O/W法,该方法是:将药物溶解在水溶液中,将得到的含有药物的水溶液分散在含有可生物降解性高分子的有机溶剂中,形成1次乳剂(waterin oil)之后,再将其分散在水相中。另外,脂溶性药物的包封主要使用O/W法,该方法是:药物和可生物降解性高分子一起溶解(oil)在有机溶剂或有机溶剂的混合物中之后,再将其分散在水相中。两种方法均有将有机溶剂相中的高分子分散在水相中的过程,有机溶剂在通过提取或蒸发等法除去的过程中,高分子的溶解度降低,使其固化,此过程的结果即可以形成微球。一般地,经W/O/W法制造出的微球,与经O/W法制造出的微球相比,因为多孔性增加、表面积增大,所以有着药物的初期释放速度相对地较高这样地特征。
决定持续性地释放药物的时间长短的代表性地因素,是由高分子的化学组成、分子量、亲水性、有机溶剂的组成、乳化剂或添加剂的种类以及浓度决定的。在这其中最重要的因素,是高分子的化学组成、分子量以及亲水性等。例如,对于丙交酯和乙交酯以不同的摩尔比构成的共聚物的聚丙交酯-乙交酯(polylactide-co-glycolides,PLGA)高分子的情况,随着丙交酯的摩尔比和它的分子量越增加,其分解速度越缓慢。因此,为了制造能够更长时间持续性地释放药物的微球,可以使用丙交酯的含量相对地增多、分子量也更大的高分子。可是,可以在更长时间内缓慢分解的高分子,却存在有在初期或者中期的任一部分释放几乎不进行等的问题。因此仅仅对于1种的高分子来说,制造出要在希望的时间内(例如1个月、2个月、3个月、6个月等)能够持续性地释放药物的缓释性微粒,需要付出大量的努力和时间。因此以前的制造方法,对将降解速度快的高分子和降解速度慢的高分子进行混合,然后把药物包封入此种混合物的方法进行了研究,但从由此方法制造出来的微球中,不能从被包封在混合后的每个高分子微球中释放出的药物量正确地预测药物的释放速度。作为此种情况的理由来说,不同特性的2种以上的高分子存在于1个微球上,受到来自在生物体内降解速度快的高分子产生的降解产物的影响,降解速度慢的高分子的降解,比其单独存在时有速度加快的倾向。其结果,药物在生物体内释放速度也受到降解速度快的高分子的影响,致使包封在不同的高分子中的药物的释放速度的平均值结果不一致。
为了克服象这个样的缺点,有一种方法是:将药物分别包封到降解速度不同的2种以上的高分子中,再将得到的微球以适当的比例进行混合,则可得到在所希望的时间内药物能够持续地被释放的微球(美国专利第4,897,268号),但对于象这样的方法,为了达到1种剂型的商品化,在制造2种以上的微球的工艺上有困难,在经济方面也有着效率低的缺点。
本发明的目的在于,将药物分别溶解或分散在降解速度不同的2种以上的可生物降解性高分子的乳相中,制造2个以上的1次乳相或乳剂,通过将它同时地或者连续地分散在1种水相中,制造出各自的释放特性保持不变的微球的混合物,得到在一定的时间内,能够持续性地释放药物的缓释性制剂。因此它与通过高分子混合法制造的方法相比,释放时间的预测较容易,通过在1次乳相或乳剂的阶段,对适当的高分子组成、分子量或溶剂的组成及浓度、添加剂等分别进行各种调节,经1步工艺,能够制造在所希望期间、持续性地释放的缓释性制剂。
本发明,将象LHRH那样的同类型的药物包封入由可降解性脂肪族聚酯类高分子组成的担体中,能够制造可以持续性地释放药物的缓释性制剂。
即本发明包括:将药物分别溶解或者分散在溶解了可生物降解性高分子的2种以上的乳相中,制造出2种以上的1次乳相或乳剂的阶段、将制造出的2种以上的1次乳相或乳剂同时或者连续地分散在1种水相中的阶段、从分散有药物的微球中除去有机溶剂制造包封入药物的微球的阶段。
本发明是:制造多个的1次乳相或乳剂,将它们同时地或连续地分散在1种水相中,通过制造出分别保持有各自的释放特性的微球的混合物,得到在一定期间持续性地释放药物的缓释性制剂的制造方法;与以前通过高分子混合法制造的方法相比,可以较容易地调节释放时间,特别是不改变整个的释放期间,而能够调节初期的释放量。本发明,是在1次乳相或乳剂的阶段,通过对适当的高分子组成、分子量或溶剂的组成及浓度、添加剂等分别进行各种调节,经1步工艺,制造缓释性制剂的方法,其制造过程可以分成下面的3个阶段。
(第1阶段)药物以及可生物降解性高分子的种类、组成或浓度当中,制造2种以上的物理方面或者化学方面性质不同的1次乳相或乳剂(oil或者water in oil)。
(第2阶段)将制得的2种以上的1次乳相或乳剂分散在1种水相中。
(第3阶段)从分散了的微球中除去有机溶剂得到微粒。
在上述第2阶段中,更具体地说明将2种以上的1次乳相或乳剂分散在1种水相中的方法时,可以是将2种以上的1次乳相或乳剂同时或连续地分散在1种水相中;也可以是将第1种1次乳剂分散在水相中之后,使水相的物理方面或化学方面的因素发生变化后,再将第2种的1次乳剂分散进去。在此,“水相的物理方面或化学方面因素的变化”是指搅拌机的速度或者水相的量、包含在水相中的乳化剂、添加剂的浓度、温度等。
作为可以在本发明中使用的可生物降解性高分子化合物,有醋酸纤维素、醋酸纤维素丙酸酯、纤维素丁酸酯、纤维素丙酸酯、纤维素戊酸酯、香豆酮-茚聚合物、二丁基氨基羟丙醚、乙基纤维素、乙烯-乙酸乙烯酯共聚物、甘油二硬脂酸酯、羟丙基甲基纤维素邻苯二甲酸酯、2-甲基-5-乙烯基吡啶甲基丙烯酸酯-甲基丙烯酸共聚物、聚氨基酸、聚酸酐、聚己内酯、聚碳酸酯、聚丁二烯、聚酯、聚羟基丁酸、聚甲基丙烯酸甲酯、聚甲基丙烯酸酯、聚原酸酯、聚丙烯、多糖类(藻蛋白酸、甲壳质、聚乙酰壳多糖、软骨素、糊精、葡聚糖、透明质酸、肝素、硫酸角蛋白、淀粉)、聚苯乙烯、聚乙烯(基)乙缩醛二乙基氨基乙酸酯、聚醋酸乙烯酯、聚乙烯醇、聚乙烯醇缩丁醛、聚乙烯醇缩甲醛、蛋白质(白蛋白、酪蛋白、胶原蛋白、纤维、纤维蛋白原、明胶、血红蛋白、转铁蛋白(transfferin)、玉米蛋白)、氯乙烯-丙烯-醋酸乙烯酯共聚物、氯乙烯-醋酸乙烯酯共聚物、蜡类(牛脂、鲸蜡、蜂蜡、石蜡、蓖麻蜡)、高分子脂肪酸类(肉豆蔻酸、棕榈酸、硬脂酸、山愈酸)等。在上述高分子中,最优选的是使用聚丙交酯、聚乙交酯、为它们的共聚物的聚丙交酯-共一乙交酯(PLGA)等的脂肪族聚酯类。
上述可生物降解性高分子当中,以PLGA为例更详细地说明本发明。已知PLGA在生物体内最终被降解为乳酸和羟基乙酸的单体,所以认为是无害的有生物适应性的物质,是经美国FDA许可的物质,即作为***癌的治疗药被使用的LHRH同类物,和作为给予小儿矮小症患者的人体生长激素的缓释性药物释放剂型中被使用。PLGA根据其单体的乳酸和羟基乙酸的比例、分子量、亲水性等的物理方面的特性,存在着多样的种类,它们在生物体内分别具有从短的2周一直到长的几个月的期间内被降解的特性。
经本发明制造微球的方法中,在第1阶段,作为制造2种以上的1次乳相或乳剂的例子,第1种的1次乳相,是通过将药物和生物体内降解速度比较快的PLGA,就是说单体比为50∶50、或者亲水性大的PLGA(例如末端含有羧基残基的PLGA:RG502H,RG503H等)、或者分子量小的PLGA,溶解在有机溶剂中制造的;第2种的1次乳相,是通过将药物和生物体内降解速度比较慢的PLGA,就是说单体比为75∶25、或者亲水性小的PLGA(例如末端羧基用十二烷基等取代了的PLGA:RG502,RG503等)、或者分子量大的PLGA,溶解在有机溶剂中制造的。当药物是水溶性的场合,在上述各项中,将药物溶解在水溶液中,在溶解了各高分子的乳相中分散成乳剂状态,由此可以制造2种以上的一次乳剂。
作为其它的例子,制造各自的1次乳相或1次乳剂时,可生物降解性高分子使用同一种物质,但药物的种类可以不同。具体地说,将LHRH(Leutenizing Hormone Releasing Hormone-生长激素释放激素)的同类物,例如通过在第1种的1次乳相当中,溶解属于LHRH同类物中拮抗物质(antagonist)的1种;在第2种的1次乳相当中,溶解属于LHRH同类物中作用物质(agonist)的1种,可以制造2种不同的1次乳相。另外,不可以使用高分子的种类或药物的种类相互不同的2种物质,但通过1种的药物和1种的高分子可以制造物理方面或者化学方面的性质不同的2种1次乳相或乳剂。例如,对于2种的1次乳相或乳剂,通过调节不同的药物或高分子的重量比、药物或高分子占有机溶剂的重量比、被使用的有机溶剂的比(使用有机溶剂的混合物时)、水溶液和有机溶剂的比(水溶性药物的时候,即W/O/W法)等,可以实现。通过象这样的媒介参数的差别制造出的微球在构造形态学上具有互相不同的特性,一般地,药物的释放速度也相互地不同。例如,通常高分子占有机溶剂的重量比增加的时候,1次乳相或乳剂的黏度增加,药物的包封率增加,微球的大小也相应地增大。另外作为其它的例子,通常药物为水溶性的场合,药物的含有率增大时显示出生物体内的释放速度增加的倾向;而脂溶性药物的场合,药物的含有率增大时显示出释放速度减小的倾向。在使用有机溶剂的混合物时,根据各种有机溶剂在水中的溶解度或沸点的差别,由于分散在2次水相中的乳剂的有机溶剂的提取或蒸发速度相互不同,其结果微球的特性发生变化,致使药物的释放速度也受到影响。
在按照本发明的微球制造方法中,将在第2阶段制造的2种以上的1次乳相或乳剂分散在1种水相中的方法的具体的例子可列举如下。作为最简单的例子,是在1种的水相中,使2种以上的1次乳相或乳剂同时分散的方法;或者是将第1种1次乳相或乳剂分散,再立即将第2种的1次乳相或乳剂分散的方法。通常对于象这样的方法,通过充分地使用水相的量,应该能够将存在于全部的1次乳相或乳剂中的有机溶剂充分地提取或蒸发除去。与此不同,也可以使用将第1种的1次乳相或乳剂分散在水相中之后,让“水相的物理化学方面的要素”发生变化后,再将第2种的1次乳相或乳剂分散在水相中的方法。所谓“水相的物理化学方面的要素”,如上所述,是指搅拌机的速度或者水相的量、包含在水相中的乳化剂、添加剂的浓度、温度等,故通过它们的变化可以引起微球的特性发生如下说明那样的变化。一般地,随着搅拌机的速度增加乳剂的微粒大小减小,由此微球的大小也变小。水相的量增加的话,从乳剂中的有机溶剂的抽出速度也加快,可生物降解性高分子的固化提前发生,微球的大小也增大。水相的温度因为对有机溶剂的蒸发速度有影响,随着温度提高蒸发速度加快。通过可生物降解性高分子的固化速度、微粒的大小等变化,最终使药物的释放速度也受到影响。因此,将第1种的1次乳相或乳剂分散后,增加水相的量、提高温度、何种程度除有机溶剂时,均对存在在第2种1次乳相或乳剂中的有机溶剂能否充分地提取除去产生影响。因此,将2种以上的1次乳相或乳剂分散在1种水相中的时候,应考虑存在于各1次乳相或乳剂中的有机溶剂的种类、量等,并且水相的量或温度等也应考虑即可制造出微球。
作为能够提供到本发明中的药物,包括生理活性肽以及蛋白质、抗癌药、抗生素、解热药、镇痛药、抗炎药、去痰药、镇静剂、肌肉松弛药、治疗癫痫药、抗溃疡药、抗抑郁药、抗***反应药、强心剂、抗心率失常药、血管扩张药、降压性利尿药、糖尿病治疗药、高血脂症治疗药、抗凝药、促凝血药、抗结核药、激素、麻醉拮抗剂、骨吸收抑制药、骨形成促进药以及血管形成抑制药。
生理活性肽和蛋白质是2种以上的氨基酸组成的、分子量约200~100,000,作为这样的肽及蛋白质药物的例子,包括:人生长激素、生长激素释放激素、生长激素释放肽、干扰素、群体刺激因子、色甘酸钠、巨噬细胞活性因子、巨噬细胞肽、B细胞因子、T细胞因子、蛋白质A、***反应抑制因子、细胞死因不明糖蛋白质、免疫毒素、淋巴毒素、肿瘤抑制因子、转移生长因子、α-1抗胰蛋白酶、白蛋白和它的多肽片断、转脂蛋白-E、红细胞生成素、因子VII、因子VIII、因子IX、纤维蛋白溶酶原活性因子、尿激酶、链激酶、蛋白质C、C-反应性蛋白质、肾素抑制剂、胶原酶抑制剂、超氧化歧化酶、来源于血小板的生长因子、表皮生长因子、角质生长(カチリジ)诱导因子、结合组织活性因子、滤胞刺激激素、黄体形成激素、黄体形成激素释放激素、神经生长因子、甲状旁腺激素、松弛素、细胞周期蛋白(シクレチン)、促生长因子、胰岛素类似生长因子、促肾上腺皮质激素、胰高血糖素、胰激素(コロシストキニン)、胰脏多肽、促胃泌素释放肽、促肾上腺皮质激素释放因子、甲状腺刺激激素、对各种病毒、细菌、毒素等的单克隆性或者多克隆性抗体、来源于各种病毒的疫苗抗原等。
作为抗癌药的例子,有博来霉素、甲氨蝶呤、放线菌素D、丝裂霉素C、硫酸长春新碱、硫酸长春花碱、柔红霉素、多柔比星、新制癌菌素、盐酸阿糖胞苷、氟尿嘧啶、四氢糠偶酰-5-氟尿嘧啶、云芝多糖、溶血链球菌、蘑菇多糖、左旋咪唑、贝他定、阿齐美克、甘草甜素、多聚类(多聚I:C,多聚A:U,多聚ICLC)等。
作为抗生素的例子,有庆大霉素、地贝卡星、卡那霉素、利维霉素、妥布霉素、阿米卡星、费氏霉素、西素米星、盐酸四环素、盐酸土霉素、罗利环素、盐酸多西环素、氨苄西林、哌拉西林、替卡西林、头孢噻吩、头孢噻啶、头孢替安、头孢磺啶、头孢甲肟、头孢美唑、头孢唑啉、头孢噻肟、头孢哌酮、头孢唑肟、羟羧氧酰胺菌素(mochisalactam)、沙钠霉素、磺胺甾星以及氨曲南等。
作为解热药的例子,有含有止疼剂和水杨酸的抗炎药(anti-inflammatory agents include水扬酸)、安乃近、氟芬那酸、双氯芬酸、吲哚美辛、***、盐酸哌替啶、酒石酸左啡诺以及羟***酮等。
作为镇痛药,有盐酸麻黄碱、盐酸甲基麻黄碱、盐酸那可丁、磷酸可待因、二氢磷酸可待因、盐酸阿洛拉胺、盐酸氯苯达诺、盐酸哌吡苯胺、氯苯哌醚、盐酸普罗托醇、盐酸异丙肾上腺素、硫酸磺丁醇酯(Sulbutamol Sulfate)以及硫酸特布他林等。
作为镇静药的例子,有氯丙嗪、丙氯拉嗪、三氟培那嗪、硫酸阿托品以及甲基东莨菪碱等。
作为肌肉松弛药的例子,有普立地诺甲烷磺酸盐、氯筒箭毒碱、泮库溴胺等。
作为抗癫痫药的例子有:含有苯妥因钠的抗癫痫药(antiepilepticsinclude phenytoin)、乙琥胺、氯氮乙酰唑胺钠等。
作为抗溃疡药的例子有甲氧氯普胺、盐酸组胺等。
作为抗抑郁症药的例子有丙米嗪、氯米帕明、诺昔替林以及硫酸苯乙利定等。
作为抗***反应药的例子有盐酸苯海拉明、马来酸安索氯芬铵、***吡那敏、盐酸甲地嗪、盐酸克立咪唑、盐酸二苯拉林以盐酸甲氧那明等。
作为强心药的例子有反-π-樟脑醛、茶碱醋酸钠、氨茶碱和盐酸依替福林等。
作为抗心律不齐药物的例子有心得安、心得舒、丁呋心安及心得平等。
作为血管扩张剂的例子有盐酸奥昔非君、地尔硫、盐酸妥拉苏啉、克冠二胺以及硫酸丁酚胺等。
作为降压利尿剂的例子有溴化六烃季胺、戊双吡铵、盐酸美加明、盐酸乙肼苯哒嗪、可乐宁等。
作为抗糖尿病药的例子有格列嘧啶钠、格列吡嗪、盐酸苯乙双胍、盐酸丁福明以及二甲双胍等。
作为降血脂药的例子有普伐他汀钠、辛伐他汀、克利贝特、安妥明、降酯丙二醇酯以及苯扎贝特等。
作为抗凝血剂的例子有肝素钠、作为促凝血剂的例子有促凝血酶原激酶、凝血酶、甲萘氢醌硫酸钠、乙酰甲萘醌、凝血酸、硫酸肾上腺素缩氨脲钠以及甲磺酰肾上腺素氨基胍等。
作为抗结核药的例子,有异烟肼、乙胺丁醇以及对氨基水杨酸等。
作为激素类的例子,有强的松龙及盐(强地松龙,强地松龙磷酸钠-Predonizolone,Predonizolone Sodium Phosphate)、地噻米松硫酸盐(***硫酸钠-dexamethasone sodium sulfate)、倍他米松磷酸盐(倍他米松磷酸钠-betamethasone sodium phosphate)、磷酸己雌酚盐、醋酸己雌酚盐以及甲硫咪唑。
作为麻醉拮抗剂的例子,有酒石酸烯丙左吗喃、盐酸烯丙***以及盐酸纳洛酮;作为骨吸收抑制剂的例子,有依普黄酮等;作为骨形成促进剂的例子,有多肽类(例如BMP,PTH,TGF-beta及IGF-1)等。
作为血管形成抑制剂的例子,有甾类化合物、夫马洁林以及fumagillol衍生物等。
生理活性药物也可以由在药理学上能够适用的盐的形式组成(例如,生理活性药物具有象氨基那样的碱性基团时,可以同盐酸、硫酸、硝酸那样的无机酸成盐以及同碳酸、琥珀酸成为有机酸盐;生理活性药物具有象羧基那样的酸性基团时,可以同钠、钾形成无机盐,也可以同三乙基胺、精氨酸那样的碱性基团形成有机化合物盐)。
通过以下的实施例更详细地说明本发明,但本发明的技术性范围并不局限在这些实施例。
(实施例1)由复乳法制造含有亮兰的微球/含有若丹明的微球(1∶1)的混合物
将0.1g亮兰溶解于1.5g甲醇中之后,再分散在于2.0g二氯甲烷中溶解了0.5gRG502H(Boehringer Ingelheim制造)的高分子溶液中,制成1次乳剂(DP1)。将0.1g若丹明溶解于1.5g甲醇中之后,再分散在于2.0g二氯甲烷中溶解了0.5gRG502H的高分子溶液中,制成1次乳剂(DP2)。将制成的1次乳剂(DP1)和1次乳剂(DP2)依次加入到预先调节至25℃的、含有0.5%聚乙烯醇的250ml蒸馏水溶液中,用3,500rpm的乳匀机使其分散。乳匀机的速度调节至3,000rpm、运转15分钟形成乳剂后,将温度升至40℃,蒸发1小时除去有机溶剂,使其固化制造出微球。图1a是此微球的光学显微镜照片。
(比较例1)
A:含有亮兰微球的制造
将0.2g亮兰溶解于3g甲醇中之后,再分散在于2.0g二氯甲烷中溶解了1gRG502H的高分子溶液中,制成1次乳剂。将制成的1次乳剂加入到预先调节至25℃的、含有0.5%聚乙烯醇的250ml蒸馏水溶液中,用3,500rpm的乳匀机使其分散。乳匀机的速度调节至3,000rpm、运转15分钟形成乳剂后,将温度升至40℃,蒸发1小时除去有机溶剂,使其固化制造出微球。图1b是此微球的光学显微镜照片。
B:含有若丹明微球的制造
将0.2g若丹明溶解于3g甲醇中之后,再分散在于2.0g二氯甲烷中溶解了1gRG502H形成的高分子溶液中,制成1次乳剂。将制成的1次乳剂加入到预先调节至25℃的、含有0.5%聚乙烯醇的250ml蒸馏水溶液中,用3,500rpm的乳匀机使其分散。乳匀机的速度调节至3,000rpm、运转15分钟形成乳剂后,将温度升至40℃,蒸发1小时除去有机溶剂,使其固化制造出微球。图1c是此微球的光学显微镜照片。
C:由高分子混合法制造含有亮兰/若丹明(1∶1)的微球
将0.1g亮兰和0.1g若丹明溶解于3g甲醇中之后,分散在于2.0g二氯甲烷中溶解了1gRG502H形成的高分子溶液中,制成1次乳剂。将制成的1次乳剂加入到预先调节至25℃的、含有0.5%聚乙烯醇的250ml蒸馏水溶液中,用3,500rpm的乳匀机使其分散。乳匀机的速度调节至3,000rpm、运转15分钟形成乳剂后,将温度升至40℃,蒸发1小时除去有机溶剂,使其固化制造出微球。图1d是此微球的光学显微镜照片。
通过实施例1、比较例1A、比较例1B以及比较例1C制造出的微粒的光学显微镜照片,分别表示在图1a、图1b、图1c、图1d。由实施例1制造出的微球,已知是采取由比较例1的A和B制造出的微球以1∶1进行混合的形式;另一方面由比较例1C的高分子混合法制造出的微球的场合,采取的是2种颜色被混合在一起的形式。
(实施例2)制造至少能够在28天持续性地释放的含有醋酸亮丙瑞林的可生物降解性微球
A型:将62.5mg醋酸亮丙瑞林(leuprolelin acetate)溶解于0.28g甲醇后,再分散在于1.125g二氯甲烷中溶解了丙交酯和乙交酯以50∶50,平均分子量为8,600的0.438gPLGA(RG502H,BoehringerIngelheim)的高分子溶液中,制成1次乳剂(DP1)。62.5mg醋酸亮丙瑞林溶解于0.37g甲醇后,再分散在于1.313g二氯甲烷中溶解了丙交酯和乙交酯以50∶50、平均分子量为33,000的0.438gPLGA(RG503H,Boehringer Ingelheim)的高分子溶液中,制成1次乳剂(DP2)。将制成的1次乳剂(DP1)和1次乳剂(DP2)依次加入到预先调节至25℃的、含有0.3%聚乙烯醇的250ml蒸馏水溶液中,用3,500rpm的乳匀机使其分散。乳匀机的速度调节至3,000rpm、运转15分钟形成乳剂后,将温度升至40℃,蒸发2小时除去有机溶剂,使其固化制造出微球。
由本发明制造出的微球的扫描电子显微镜照片显示于图2a(放大100倍)以及图2b(放大800倍)。可以见到在图2b的被放大照片的右侧的微球,是具有多孔性的微球,其原因是DP1来源于502H高分子;左侧是具有非多孔性的微球,其原因是DP2来源于503H高分子,两者能够明确地区分开。
B型:将75mg醋酸亮丙瑞林溶解于0.27g甲醇后,再分散在于1.903g二氯甲烷中溶解了0.425gRG502H的高分子溶液中,制成1次乳剂(DP1)。将75mg醋酸亮丙瑞林溶解于0.36g甲醇后,再分散在于1.275g二氯甲烷中溶解了0.425gRG503H的高分子溶液中,制成1次乳剂(DP2)。以下,与实施例2的A型同样地进行,制造出微球。
(比较例2)
A:含有醋酸亮丙瑞林的RG502H微球的制造
62.5mg醋酸亮丙瑞林溶解于0.28g甲醇后,再分散在于1.125g二氯甲烷中溶解了0.438gRG502H的高分子溶液中,制成1次乳剂。将制成的1次乳剂加入到预先调节至25℃的、含有0.3%聚乙烯醇的125ml蒸馏水溶液中,用3,500rpm的乳匀机使其分散。以下,与实施例2的A型同样地进行,制造出微球。
B:含有醋酸亮丙瑞林的RG503H微球的制造
62.5mg醋酸亮丙瑞林溶解于0.37g甲醇后,再分散在于1.313g二氯甲烷中溶解了0.438gRG503H的高分子溶液中,制成1次乳剂。将制成的1次乳剂加入到预先调节至25℃的、含有0.3%聚乙烯醇的125ml蒸馏水溶液中,用3,500rpm的乳匀机使其分散。以下,与实施例2的A型同样地进行,制造出微球。
C:含有醋酸亮丙瑞林的RG502H/RG503H(1∶1)微球的制造
125mg醋酸亮丙瑞林溶解于0.65g甲醇后,再分散在于2.438g二氯甲烷中溶解了0.438gRG502H和0.438gRG503H的高分子溶液中,制成1次乳剂。将制成的1次乳剂加入到预先调节至25℃的、含有0.3%聚乙烯醇的250ml蒸馏水溶液中,用3,500rpm的乳匀机使其分散。以下,与实施例2的A型同样地进行,制造出微球。
(试验例1)体外药物释放试验
用在本发明的实施例2和比较例2制成的微球,同以市售的Leuplin(日本タケダ公司制造)作为对照药进行体外释放试验的对比,具体过程如下。分别称取5mg的经冷冻干燥得到的微球,分别加入到有0.033M磷酸盐缓冲液(pH7.0)的35个试验管中,使其分散后,在37℃进行释放。试验天数为0.25、1、4、7、14、21、28天,在各试验日从5个试管中取试样,离心分离,得到的微球用二氯甲烷/乙酸酯缓冲液(1∶1,v/v)提取,转移到乙酸酯层的ロイプロリド的量使用HPLC法进行测定。此HPLC的分析条件:以含有0.1%三氟乙酸的28%乙腈水溶液为流动相,检测波长为280nm,流速为1.0ml/min,结果见图3。
(试验例2)亮丙瑞林的血中浓度试验
在实施例2中制成的微球同以市售的ロイプリン(Leuplin)(日本タケダ公司制造)作为对照样品进行比较试验,给予大白鼠后,测定血中药物浓度的经时变化。试验中使用的动物,为10只SD种雄性白色大鼠。将实施例2的微球和ロイプリン经肌肉注射分别给予5只大白鼠。给药量每只大鼠相当于0.9mg,给药后,于1、3、7、14、21、28、35天由尾静脉取血测定血中药物浓度,结果见图4。
(试验例3)***的血中浓度试验
在实施例2中制成的微球同以市售的ロイプリン(日本タケダ公司制造)作为对照样品进行比较试验,给予大白鼠后,测定血中药物浓度的经时变化。试验中使用的动物,为10只SD种雄性白色大鼠。将实施例2的微球和ロイプリン经肌肉注射分别给予5只大白鼠。给药量以每kg体重相当于3mg,给药后,于0.25、1、3、7、14、21、28、35天由尾静脉取血测定血中药物浓度,结果见图4。
(实施例3)至少可2个月持续性地释放的含有阿霉素的可生物降解性微球的制造
将20mg阿霉素溶解于0.563g甲醇后,再分散在于2.253g二氯甲烷中溶解了0.875gRG502H的高分子溶液中,制成1次乳剂(DP1)。将15mg阿霉素溶解于0.735g甲醇后,再分散在于2.624g二氯甲烷中溶解了丙交酯和乙交酯以50∶50的摩尔比、平均分子量为14,500的0.875gPLGA(RG502,Boehringer Ingelheim)的高分子溶液中,制成1次乳剂(DP2)。
将制成的1次乳剂DP1和DP2同时加入到预先调节至25℃的、含有0.3%聚乙烯醇的500ml蒸馏水溶液中,用3,500rpm的乳匀机使其分散。以下按实施例2的A型同样地进行,制造出微球。
(实施例4)制造至少能够在3个月持续性地释放、含有醋酸亮丙瑞林的可生物降解性微球
A型:将62.5mg醋酸亮丙瑞林溶解于0.282g甲醇后,再分散在于1.217g二氯甲烷中溶解了0.438gRG502H的高分子溶液中,制成1次乳剂(DP1)。将187.5mg醋酸亮丙瑞林溶解于0.492g甲醇后,再分散在于1.97g二氯甲烷中溶解了平均分子量为15,000的1.3g聚丙交酯(PLA0015,日本Wako公司制造)的高分子溶液中,制成1次乳剂(DP2)。将制成的1次乳剂DP1和DP2依次加入到预先调节至25℃的、含有0.3%聚乙烯醇的500ml蒸馏水溶液中,用3,500rpm的乳匀机使其分散。以下按实施例2的A型同样地进行,制造出微球。
B型:将125mg醋酸亮丙瑞林溶解于0.328g甲醇后,再分散在于1.3g二氯甲烷中溶解了0.875gPLA0015的高分子溶液中,制成1次乳剂。制成的1次乳剂分取1/2,加入到预先调节至10℃的、含有0.1%聚乙烯醇的125ml蒸馏水溶液中,用3,500rpm的乳匀机使其分散。将含有0.3%聚乙烯醇的125ml蒸馏水溶液慢慢地加入之后,将温度调节至25℃,将残留的1次乳剂分散进去。以下,与实施例2的A型同样地进行,制造出微球。
(实施例5)制造至少能够在4个月持续性地释放、含有醋酸亮丙瑞林的可生物降解性微球
将62.5mg醋酸亮丙瑞林溶解于0.282g甲醇后,再分散在于1.127g二氯甲烷中溶解了0.438gRG502H的高分子溶液中,制成1次乳剂(DP1)。将187.5mg醋酸亮丙瑞林溶解于0.492g甲醇后,再分散在于1.97g二氯甲烷中溶解了丙交酯和乙交酯以50∶50的摩尔比、平均分子量为14,500的1.3gPLGA(RG502,Boehringer Ingelheim)的高分子溶液中,制成1次乳剂(DP2)。将制成的1次乳剂DP1和DP2依次加入到预先调节至25℃的、含有0.3%聚乙烯醇的500ml蒸馏水溶液中,用3,500rpm的乳匀机使其分散。以下,与实施例2的A型同样地进行,制造出微球。
(实施例6)制造至少可6个月持续性地释放的、含有醋酸亮丙瑞林的可生物降解性微球
将125mg醋酸亮丙瑞林溶解于0.328g甲醇后,再分散在于1.313g二氯甲烷中溶解了0.875Gpla0015的高分子溶液中,制成1次乳剂(DP1)。将125mg醋酸亮丙瑞林溶解于0.735g甲醇后,再分散在于2.624g二氯甲烷中溶解了丙交酯和乙交酯以85∶15的摩尔比、分子量为220,000的0.875gPLGA(RG858,Boehringer Ingelheim)的高分子溶液中,制成1次乳剂(DP2)。将制成的1次乳剂DP1和DP2依次加入到预先调节至25℃的、含有0.3%聚乙烯醇的500ml蒸馏水溶液中,用3,500rpm的乳匀机使其分散。以下按实施例2的A型同样地进行,制造出微球。
(实施例7)制造不同种类高分子的可生物降解性微球
按实施例2A,象下面那样,替换可生物降解性高分子,形成1次乳剂,制造出微球。
Lot No. | 高分子(重量平均分子量) | |
DP1 | DP2 | |
DKLP134 | 聚丁二烯(8000) | 聚丙交酯(10000) |
DKLP141 | 聚羟基丁烯(9000) | 聚醋酸乙烯酯(12000) |
DKLP146 | 聚丙烯(6000) | 聚丁二烯(15000) |
DKLP153 | 聚醋酸乙烯酯(9000) | 聚丙烯(18000) |
DKLP155 | 聚己内酯(8500) | 聚丁二烯(13000) |
DKLP162 | 聚乙烯醇缩丁醛(7000) | 聚苯乙烯(9000) |
DKLP167 | 聚苯乙烯(6000) | 聚羟基丁烯(11000) |
通过以上的实施例、试验例、适用例,说明本发明能够制造象下面的表中所示那样、将物理方面或者化学方面的因素不同的2种以上的1次乳剂,以一定的比例进行组合,得到在所希望的时间能够持续性地释放的微球。下面的表将由高分子(分子量、亲水性、高分子/有机溶剂、共聚物)、药物、添加剂单独地制造出的乳剂,与理论上进行组合时的特点进行整理比较。
由于物理方面的、化学方面的因素的变化产生的影响 | 单独制造乳剂时 | 理论上组合 | ||
乳剂1 | 乳剂2 | 全部长时间持续性地释放 | ||
释放速度快 | 长时间释放、初期释放慢 | |||
高分子 | 分子量 | 小 | 大 | |
亲水性 | 高 | 低 | ||
高分子/有机溶剂 | 少 | 多 | ||
丙交酯/乙交酯1) | 少 | 多 | ||
药物 | 药物/高分子 | 多 | 少 | |
添加剂2) | 含量 | 多 | 少(或没有) |
1)丙交酯-乙交酯共聚物的情况
2)是Na+及Ca++等的盐、柠檬酸、酒石酸等的酸类以及氨基酸。
如上所述,组合可以多样化地进行,例如,由分子量大的物质、分子量小的物质、改变高分子和有机溶剂的比例的物质,加入了添加剂的物质可以制造4种的1次乳剂,经在水相中同时或者依次进行分散,均能够制造出适当释放时间的缓释性微球。
[发明的效果]
象以上说明的那样,本发明,通过经单一工艺能够制造具有多样性的药物释放特性的微球的混合物,各自的释放特性可以维持不变。因此,由经各工序制出的微粒的药物释放特性通过理论上的组合,可以提供一种在一定时间内有效地诱导持续性释放的微球制剂。
下面对附图作简要地说明。
[图1a]
是在本发明的实施例1中制造出的微球的光学显微镜照片。
[图1b]
是在比较例1A中制造出的微球的光学显微镜照片。
[图1c]
是在比较例1B中制造出的微球的光学显微镜照片。
[图1d]
是在比较例1C中制造出的微球的光学显微镜照片。
[图2a]
是在本发明的实施例2A中制造出的微球放大100倍的电子显微镜照片。
[图2b]
是在本发明的实施例2A中制造出的微球放大800倍的电子显微镜照片。
[图3]
是显示在本发明的实施例2和比较例2中制造出的微球以及ロイプリン制品的体外释放试验结果的图表(-□-:ロイプリン、-△-:比较例2A、-○-:实施例2A、--:比较例2B、-◇-:实施例2B)
[图4]
是显示在本发明的实施例2中制造出的微球以及ロイプリン制品的体内释放试验结果的图表(-□-:ロイプリ ン、-△-:比较例2B、-○-:
实施例2A)
[图5]
是显示由在本发明的实施例2中制造出的微球以及由ロイプリン制品引起的体内***抑制结果的图表(-○-:对照组、-□-:ロイプリン、-△-:实施例2A、--:实施例2B)
Claims (11)
1.一种由复乳法制造缓释性微球的方法。其特征在于,该方法包括:将药物分别溶解或者分散在溶解了可生物降解性高分子的2种以上的乳相中,制造出2种以上的1次乳相或乳剂的阶段、和将制造出的2种以上的1次乳相或乳剂同时或者连续地分散在1种水相中的阶段、以及从分散有药物的微球中除去有机溶剂,制得包封入药物的微粒的阶段。
2.按照权利要求1记载的由复乳法制造缓释性微球的方法,其特征在于,将1次乳相或乳剂分散在1种水相中的方法,是将2种以上的1次乳相或乳剂同时或者连续地分散在1种水相中;或者是将1次乳剂(DP1)分散在水相中之后,使水相的物理方面或化学方面的要素发生变化后,接着将另外的1次乳剂(DP2)分散到水相中。
3.按照权利要求2记载的由复乳法制造缓释性微球的方法,其特征在于,作为使水相的物理方面或化学方面的要素发生变化的方法,是调节搅拌机的速度到100~5,000rpm、水相的量为1次乳剂或乳相的20倍~1,000倍、包含在水相中的乳化剂为1%~10%的聚山梨醇酯或者聚乙烯醇、添加剂为0.1%~5%的明胶、羧甲基纤维素或钙、温度为5℃~40℃,并使之分散。
4.按照权利要求1记载的由复乳法制造缓释性微球的方法,其特征在于,作为制造1次乳相或乳剂的方法,是采用将在水溶液中溶解了药物的含药水溶液,分散在含有可生物降解性高分子的有机溶剂中,形成了1次乳剂后,将此乳剂分散在水相中的二重乳化蒸发法(W/O/W);或者采用将药物和可生物降解性高分子一起溶解在有机溶剂或有机溶剂的混合物中之后,将此液分散在水相中的单一乳化蒸发法(O/W)。
5.按照权利要求1记载的由复乳法制造缓释性微球的方法,其特征在于,可生物降解性高分子包括聚丙交酯高分子、聚乙交酯高分子、丙交酯和乙交酯的高分子共聚合物、或者它们的混合物。
6.按照权利要求1记载的由复乳法制造缓释性微球的方法,其特征在于,可生物降解性高分子包括:从醋酸纤维素、醋酸纤维素丙酸酯、纤维素丁酸酯、纤维素丙酸酯、纤维素戊酸酯、香豆酮-茚聚合物、二丁基氨基羟丙醚、乙基纤维素、乙烯-乙酸乙烯酯共聚物、甘油二硬脂酸酯、羟丙基甲基纤维素邻苯二甲酸酯、2-甲基-5-乙烯基-吡啶甲基丙烯酸酯-甲基丙烯酸共聚物、聚氨基酸、聚酸酐、聚己内酯、聚碳酸酯、聚丁二烯、聚酯、聚羟基甘油三丁酸酯、聚甲基丙烯酸甲酯、聚甲基丙烯酸酯、聚原酸酯、聚丙烯、多糖类、聚苯乙烯、聚乙烯(基)乙缩醛二乙基氨基乙酸酯、聚醋酸乙烯酯、聚乙烯醇、聚乙烯醇缩丁醛、聚乙烯醇缩甲醇、蛋白质、氯乙烯-丙烯-醋酸乙烯共聚物、氯乙烯-醋酸乙烯共聚物、蜡类、高分子脂肪酸类中选择出的1种以上物质。
7.按照权利要求1记载的由复乳法制造缓释性微球的方法,其特征在于,药物包括:生理活性肽以及蛋白质、抗癌药、抗生素、解热药、镇痛药、消炎药、去痰药、镇静剂、肌肉松弛药、治癫痫药、抗溃疡药、抗抑郁症药、抗***反应药、强心剂、抗心率失常药、血管扩张药、低血压性利尿药、糖尿病治疗药、高血脂症治疗药、抗凝药、促凝血药、抗结核药、激素、麻醉拮抗剂、骨吸收抑制药、骨形成促进药以及血管形成抑制药的药物,这些药物形成的盐的形式也包括在内。
8.按照权利要求1记载的由复乳法制造缓释性微球的方法,其特征在于,在1次乳相中,药物的含量是1%~50%,高分子的浓度是5%~50%。
9.按照权利要求1至7任何一项记载的由复乳法制造缓释性微球的方法,其特征在于,药物包括醋酸戈舍瑞林、醋酸那法瑞林、醋酸布舍瑞林以及醋酸亮丙瑞林。
10.按照权利要求1至5任何一项记载的由复乳法制造缓释性微球的方法,其特征在于,可生物降解性高分子是丙交酯与乙交酯的摩尔比为45∶55~55∶45,重量平均分子量为6,000~10,000以及25,000~35,000的高分子,通过将此种高分子同时或者依次地分散到水相中,得到可以长时间持续性地释放药物的微球。
11.由权利要求1的复乳法制造出的长期缓释性微球。
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Also Published As
Publication number | Publication date |
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FR2810885B1 (fr) | 2003-10-17 |
ITTO20000963A1 (it) | 2002-04-13 |
BR0005287A (pt) | 2002-02-13 |
TR200003123A2 (tr) | 2002-01-21 |
JP3641418B2 (ja) | 2005-04-20 |
ZA200004485B (en) | 2001-02-28 |
MXPA00009408A (es) | 2002-03-15 |
IN189017B (zh) | 2002-12-07 |
BRPI0005287B1 (pt) | 2019-01-22 |
ES2185460B1 (es) | 2004-06-16 |
IT1320273B1 (it) | 2003-11-26 |
ES2185460A1 (es) | 2003-04-16 |
DE10045374B4 (de) | 2007-08-30 |
JP2002020269A (ja) | 2002-01-23 |
KR100392501B1 (ko) | 2003-07-22 |
DE10045374A1 (de) | 2002-01-24 |
ITTO20000963A0 (it) | 2000-10-13 |
GB2363986A (en) | 2002-01-16 |
KR20020000698A (ko) | 2002-01-05 |
US6506410B1 (en) | 2003-01-14 |
GB0020992D0 (en) | 2000-10-11 |
CA2317769A1 (en) | 2001-12-28 |
GB2363986B (en) | 2002-12-11 |
PL348343A1 (en) | 2002-01-02 |
FR2810885A1 (fr) | 2002-01-04 |
CA2317769C (en) | 2005-03-15 |
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