CN1177614C - 缓释组合物 - Google Patents

缓释组合物 Download PDF

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CN1177614C
CN1177614C CNB961116846A CN96111684A CN1177614C CN 1177614 C CN1177614 C CN 1177614C CN B961116846 A CNB961116846 A CN B961116846A CN 96111684 A CN96111684 A CN 96111684A CN 1177614 C CN1177614 C CN 1177614C
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太郎岩本
章夫木村
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竹彦大山
靖侑高桥
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Abstract

本发明提供一种缓释组合物，包括PLGA基质、生物活性剂和季铵表面活性剂，其中生物活性剂从PLGA基质的释放模式是由季铵表面活性剂的浓度控制。

Description

缓释组合物
本发明涉及用于持续释放生物活性剂的一种缓释的释放系统，尤其聚(乳酸/乙醇酸)(PLGA)释放系统。一方面，本发明提供一种包括PLGA基质，生物活性剂和季铵表面活性剂的缓释组合物，其中从PLGA基质释放生物活性剂的模式是由季铵表面活性剂的浓度控制。
聚(乳酸/乙醇酸)(PLGA)指乳酸(L)和乙醇酸(G)的共聚物，一般具有高达约50,000的分子量。优选地，L∶G比是100∶0-约25∶75。还可以存在附加的共聚单体和/或添加剂，如增塑剂和稳定剂，只要这一任意性可有可无的元素不会不利影响生物活性剂从PLGA基质的释放。
生物活性剂是合成的或天然的化合物，在被引入活的生物体内时体现生物效果。这类试剂包括诊断和治疗剂，同时包括用于治疗急性或慢性病症的大分子和小分子。对试剂的唯一限制是它在被引入PLGA基质之后对于预定的用途显示出足够的效力。
季铵表面活性剂是中心氮原子键接于四个有机基团的含氮阳离子和阴离子的盐，通式R4N+X-，它显示出表面活性性能。这类物质可以被分类为洗涤剂、润湿剂或乳化剂。在季铵表面活性剂中，一般至少一个R基是长链(大于6个碳原子)烷基或芳基。代表性的季铵表面活性剂包括，但不限于，烷基铵、苯甲烃铵和吡啶鎓家族的那些。更具体地说，季铵表面活性剂选自烷基三甲基铵盐，烷基二甲基苄基铵盐以及烷基吡啶鎓和咪唑鎓的盐。
持续(或受控)释放是指经过一定时间从PLGA基质逐渐释放生物活性剂。尽管可能由初期急剧释放阶段，但优选的是释放作用显示了相对线性的动力学，从而在释放时间内获得一种恒定的提供生物活性剂的作用。释放时间可以从几个小时到几个月，这取决于生物活性剂及其预定用途。需要的是，在治疗时间内生物活性剂从基质的累积释放量是较高的，以避免过多基质的装载和浪费未释放的生物活性剂。释放时间尤其可受如下因素控制：其中有，基质的质量和几何形状，活性剂的浓度，施用的部位，基质的分子量和摩尔组成，以及正如这里所说明的，释放模式改进剂的添加。
向PLGA基质引入生物活性剂和释放改进剂可以通过熟练药剂师已知的各种技术中的任何技术来实现。这类技术包括，但不限于，在US专利No.4,675,189和4,954,298描述的微囊包封技术，在其中作为例子举例的熔融挤出方法，和在J.Controlled Release，9：111-122(1989)描述的熔融压制方法。
基质的几何形状(例如圆柱形，微球形，纤维状)当然取决于制造技术并影响伴随释放动力学；然而，希望本发明是可操作的，而与基质的几何形状无关。
生物活性剂的浓度将依据试剂，其预定用途(即短期或长期)和制造方法来变化。在一个优选的实施方案中，活性剂浓度是约0.1wt％至约20wt％，更优选约1wt％至约10wt％，最优选约2wt％至约6wt％。季铵表面活性剂的浓度也将依据试剂，基质，所需要的释放模式等来变化。在一个优选的实施方案中，季铵表面活性剂浓度是约0.5wt％至约15wt％，更优选约2wt％至约8wt％。
为了举例说明本发明，考察三种不同物理性能的生物活性剂：乙酸那法瑞林，中等分子量，水溶性肽(Mw＝1322)；萘普生，低分子量，水溶性化合物(Mw＝230)和酮咯酸氨丁三醇，低分子量，水溶性化合物(Mw＝376)。这些生物活性剂与以下两种代表性的季铵表面活性剂进行熔融共混：十四烷基二甲基苄基氯化铵(TDBAC)和十六烷基吡啶鎓氯化物(CPC)。氯化钠用来制备对比的、含生物活性剂的PLGA基质。
无须使用有机溶剂，通过熔融挤出方法从重均分子量4,500至18,000的PLGA制备包括浓度为4wt％的生物活性剂(药物)和各种浓度的表面活性剂的圆柱体。
从Taki Chemical Co.，Ltd.购得其中乳酸/乙醇酸的共聚比为50/50和重均分子量分别为4,500，10,000和18,000的三种PLGA(简写为PLGA-4,500，PLGA-10,000和PLGA-18,000)；十四烷基二甲基苄基氯化铵(TDBAC)，购自Nippon Oil&Fats Co.，Ltd.；和十六烷基吡啶鎓氯化物(CPC)，购自Wako Pure Chemical Ind.。其它化学品是试剂级的。
在岛津(Shimadzu)HPLC系统(6A)上测量PLGA的分子量，柱：Waters ultrastyragel 102，103和104A；运动相：THF；流速：1.0ml/min；波长：230nm；标准：聚苯乙烯(Supelco Inc.，分子量范围760-90,000)。
图1.乙酸那法瑞林乙酸盐从含有不同量的添加剂的PLGA-4,500圆柱体的释放模式：(A)TDBAC；(B)CPC；(C)NaCl。每一值表示平均值±SD(n＝3)。
图2.萘普生从含有不同量的添加剂的PLGA-10,000圆柱体的释放模式：(A)TDBAC；(B)NaCl。每一值表示平均值±SD(n＝3)。
图3.酮咯酸氨丁三醇从含有不同量的添加剂的PLGA-18,000圆柱体的释放模式：(A)TDBAC；(B)NaCl。每一值表示平均值±SD(n＝3)。
                             实施例1
这一实施例说明季铵盐能够改进水溶性的中等分子量肽药物从PLGA基质的释放模式。
按如下所述，制备在PLGA-4,500中含有4wt％的那乙酸法瑞林(Syntex，Palo Alto，CA)，无添加剂而有(按重量)2％TDBAC，4％TDBAC，2％CPC，4％CPC，2％NaCl，或20％NaCl的圆柱体。将药物与PLGA的混合物(200mg)和选择量的表面活性剂装入玻璃管中，在熔融温度75℃下加热熔化聚合物。熔体被均匀混合，装入聚丙烯注射器，并挤出。获得直径1.3mm的圆柱体，切成5mm的长度，按如下所述由高效液相色谱法(HPLC)测定药物含量和PLGA的分子量，以证实它们在制备过程中的稳定性。那法瑞林从圆柱体中的回收量是高于90％和PLGA的分子量保持不变。
在乙腈和磷酸钾水溶液(23∶77)的混合溶液中从PLGA圆柱体中抽提那法瑞林，并由HPLC分析，柱：Wakosil C8，4.6mm×25cm；运动相：0.1M NH4H2PO4-CH3CN(72∶25∶25)；流速：1.0ml/min；波长：225nm。
使用旋转瓶装置在37℃下研究药物释放性能。将圆柱体装入含有5ml的0.2M磷酸盐缓冲液(PH7.0)的玻璃瓶中。在指定的时间用新鲜的介质置换旧的介质，并在与以上所述相同的条件下由HPLC分析释放的药物。
图1示出了那法瑞林从含有不同添加剂的PLGA圆柱体(Mw＝4,500)的活体外释放模式；分别含(A)：TDBAC，(B)：CPC和(C)：氯化钠。那法瑞林从没有添加剂的PLGA圆柱体的释放明显地持续进行，并按照由Higuchi(1963)提出的基质释放机制进行，即所释放的那法瑞林的累积百分数与时间的平方根成正比(相关系数；r＝0.985)。在释放试验中的21天中，所释放的那法瑞林的总百分数被限制为42％。然而，那法瑞林从含有添加剂TDBAC或CPC的PLGA圆柱体的释放十分恒定，在整个试验时间内没有偏离，并根据所使用的添加剂的量而被加速。含有TDBAC(2％和4％)的圆柱体在14天内显示那法瑞林完全释放。另一方面，在21天内，那法瑞林从有CPC(2％)的圆柱体释放的百分数是大约75％。由于TDBAC和CPC的分子量类似(分别为368和340)，结果表明，就加速那法瑞林从PLGA基质中的释放而言，TDBAC胜于CPC。氯化钠向PLGA圆柱体中的添加(2％和20％)没有明显地改变那法瑞林的释放模式。
                         实施例2
这一实施例说明季铵盐能够改进低分子量、水不溶性药物从PLGA基质的释放模式。
按如下所述，制备在PLGA-10,000中含有4wt％的萘普生(Syntex，Palo Alto，CA)、无添加剂和有(按重量)2％TDBAC，4％TDBAC，4％NaCl，或8％NaCl的圆柱体。将药物与PLGA的混合物(200mg)和选择量的表面活性剂装入玻璃管中，在熔融温度80℃下加热熔化聚合物。熔体被均匀混合，装入聚丙烯注射器，并挤出。获得直径1.3mm的圆柱体，切成5mm的长度，按如下所述由高效液相色谱法(HPLC)测定药物含量和PLGA的分子量，以证实它们在制备过程中的稳定性。萘普生从圆柱体中的回收量是高于90％且PLGA的分子量保持不变。
在乙腈和磷酸钾水溶液(23∶77)的混合溶液中从PLGA圆柱体中抽提萘普生，并由HPLC分析，柱：Sphersorb C18，4.6mm×25cm；流动相：CH3OH-H2O-CH3COOH(55∶44∶1)；流速：0.8ml/min；波长：254nm。
使用旋转瓶装置在37℃下研究药物释放性能。将圆柱体装入含有5ml的0.2M磷酸盐缓冲液(PH7.0)的玻璃瓶中。在指定的时间用新鲜的介质置换旧的介质，并在与以上所述相同的条件下由HPLC分析释放的药物。
图2(A)和(B)分别示出了萘普生从含有TDBAC和氯化钠的PLGA圆柱体(Mw＝10,000)的释放模式。在7天内观察到萘普生从图2中所说明的每一种圆柱体的释放量超过90％。然而，萘普生释放模式没有受到所使用的添加剂的影响。尽管对于没有添加剂的PLGA圆柱体观察到了初期急剧释放64％的萘普生，但通过以2％和4％量添加TDBAC，PLGA圆柱体显示出萘普生完全的和恒定的释放，而与TDBAC含量无关。尽管对于含有氯化钠(4％和8％)PLGA圆柱体也观察到了萘普生的初期急剧释放，但随后的释放也被加速，在4天内萘普生释放的总百分数是约90％。据信，氯化钠的添加，通过为低分子量化合物形成含水孔隙而提高PLGA基质的渗透性。
                        实施例3
这一实施例说明季铵表面活性剂能够改进低分子量的、水溶性的药物从PLGA基质的释放模式。
按如下所述，制备在PLGA-18,000中含有4wt％的酮咯酸氨丁三醇(Syntex，Palo ALto，CA)、无添加剂和有(按重量)2％TDBAC，4％TDBAC，4％NaCL，或8％NaCL的圆柱体。将药物与PLGA的混合物(200mg)和选择量的表面活性剂装入玻璃管中，在熔融温度95℃下加热熔化聚合物。熔体被均匀混合，装入聚丙烯注射器，并挤出。获得直径1.3mm的圆柱体，切成5mm的长度，按如下所述由高效液相色谱法(HPLC)测定药物含量和PLGA的分子量，以证实它们在制备过程中的稳定性。酮咯酸从圆柱体中的回收量是高于90％且PLGA的分子量保持不变。
在乙腈和磷酸钾水溶液(23∶77)的混合溶液中从PLGA圆柱体中抽提酮咯酸，并由HPLC分析，柱：Spherisorb C18，4.6mm×25cm；流动相：CH3OH-H2O-CH3COOH(55∶44∶1)；流速：0.8mL/min；波长：254nm。
使用旋转瓶装置在37℃下研究药物释放性能。将圆柱体装入含有5ml的0.2M磷酸盐缓冲液(PH7.0)的玻璃瓶中。在指定的时间用新鲜的介质置换旧的介质，并在与以上所述相同的条件下由HPLC分析释放的药物。
图3示出了酮咯酸从含有TDBAC和氯化钠的PLGA圆柱体(Mw＝18,000)的释放模式；分别含(A)：TDBAC，(B)：氯化钠。尽管低分子量和高的水溶性，对于没有添加剂的PLGA圆柱体显示了有小量药物释放的滞后时间。在7天的滞后时间之后，在随后的7天当中观察到酮咯酸的快速释放并达到约70％。在有添加剂的圆柱体中，尽管显示氯化钠对酮咯酸释放没有影响，随着TDBAC的量的增加，在释放模式中的滞后时间减少，和释放速度变得恒定，一直到完全释放为止。结果表明，高分子量(18,000)的PLGA太致密，以致于无法使水充分渗透，但它的渗透性可通过添加TDBAC得以改进。
上面的实施例仅仅是为了说明本发明，无论如何不应认为限制了本发明。

Claims (13)

1、缓释组合物，包括聚(乳酸/乙醇酸)共聚物，生物活性剂和季铵表面活性剂。
2、权利要求1的组合物，其中该表面活性剂的季铵离子选自烷基铵、苯甲烃铵、吡啶鎓离子和烷基咪唑鎓离子。
3、权利要求2的组合物，其中季铵离子选自烷基三甲基铵，烷基二甲基苄基铵以及烷基吡啶鎓和烷基咪唑鎓离子。
4、权利要求3的组合物，其中季铵离子选自十四烷基二甲基苄基铵和十六烷基吡啶鎓。
5、权利要求1-4中任何一项的组合物，其中在该聚(乳酸/乙醇酸)共聚物中乳酸/乙醇酸的摩尔比至少是25∶75。
6、权利要求1-4中任何一项的组合物，其中该聚(乳酸/乙醇酸)共聚物具有重均分子量4,500至50,000。
7、权利要求1-4中任何一项的组合物，其中该聚(乳酸/乙醇酸)共聚物具有重均分子量4,500至18,000。
8、权利要求1-4中任何一项的组合物，其中该季铵表面活性剂占组合物的0.5wt％至15wt％。
9、权利要求1-4中任何一项的组合物，其中该季铵表面活性剂占组合物的2wt％至8wt％。
10、权利要求1-4中任何一项的组合物，其中该生物活性剂占组合物的0.1wt％至20wt％。
11、权利要求1-4中任何一项的组合物，其中该生物活性剂占组合物的1wt％至10wt％。
12、权利要求1-4中任何一项的组合物，其中该生物活性剂占组合物的2wt％至6wt％。
13、权利要求1-4中任何一项的组合物，其中该生物活性剂选自那法瑞林、萘普生和酮咯酸。
CNB961116846A 1995-08-30 1996-08-29 缓释组合物 Expired - Lifetime CN1177614C (zh)

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US08/560,081 US5759583A (en) 1995-08-30 1995-11-17 Sustained release poly (lactic/glycolic) matrices

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CA2183620A1 (en) 1997-03-01
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CN1152468A (zh) 1997-06-25
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US5759583A (en) 1998-06-02
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TR199600695A2 (tr) 1997-03-21
BR9603619A (pt) 1998-05-19
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