CN1165478A - 微丸的形成 - Google Patents

微丸的形成 Download PDF

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CN1165478A
CN1165478A CN95196084A CN95196084A CN1165478A CN 1165478 A CN1165478 A CN 1165478A CN 95196084 A CN95196084 A CN 95196084A CN 95196084 A CN95196084 A CN 95196084A CN 1165478 A CN1165478 A CN 1165478A
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S·法兰克
J·E·洛夫罗施
L·博斯坦尼恩
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Abstract

本发明涉及通过沉淀溶在含聚合物/两亲物复合物的含水介质中的有机化合物形成该有机化合物微丸。该方法优选用来制备易溶的药用活性化合物。

Description

微丸的形成
本发明涉及有机化合物微丸的形成，即当将溶在水溶性溶剂中的该有机化合物溶液加到按形成聚合物/两亲物复合物的浓度含有聚合物和两亲化合物(表面活性剂或类脂)的含水介质中时形成沉淀。在该浓度下的含水介质体系是处于形成游离胶束的临界浓度以下的溶液。当加入该有机化合物后，化合物与聚合物/两亲物的复合物相互作用，因而增大其疏水性，并导致有机化合物/聚合物/两亲物聚集体沉淀。
按照本发明，微丸的粒径小于2微米。
本发明的目的是提供一种形成有机化合物尤其药用活性化合物微丸的方法，其中该法不包括乳化作用或水不溶性溶剂。
本法优选用来制备易溶的药用活性化合物。
从药学的观点出发，难溶药物的粒度越小，其溶解速度越大，且一般地说，其生物利用率越大〔J.H.Fincher，J.Pharm.Sci.57卷，1825页(1968年)〕。所以，微丸通常是通过机械细分大颗粒或通过小分子或离子聚集形成的(D.J.Shaw，“胶体和表面化学导论”，第三版，Butterworths，London，1980年，第一章)。
对含水介质中的聚合物/两亲物体系的研究已表明聚合物与带电两亲物的相互作用出现在不同阶段。离子型聚合物和带相反电荷的两亲物因静电相互作用而产生沉淀。另一方面，非离子型聚合物和两亲物间的相互作用在三种情况下出现。在非常稀的溶液中，存在非常小的物理粘合作用。当两亲物的浓度高于临界胶束浓度时，形成真胶束。但是在这两种浓度之间时，存在聚合物与两亲物的复合作用或粘合作用〔M.L.Fishman and F.R.Eirich，J.Phys.Chem，75卷，第20期，第3135-40页(1971年)〕。因而可形成小的聚合物/两亲物的聚集体或亚胶束。两亲物的存在使得不同聚合物分子间产生有效的吸引力，因而所形成的聚集体可包含一个以上的聚合物分子。该吸引力以及两亲物对聚合物的粘合力使得该聚合物的疏水性增强。如果该聚集体具有足够的疏水性，它将沉淀出来。将极性水溶性化合物(例如氯化钠)加到聚合物/两亲物体系中将进一步促进聚合物/两亲物聚集体的沉淀，这是因为在溶剂与聚合物/两亲物聚集体间的极性差异增大和因为极性化合物可减少用于聚合物/两亲物聚集体溶剂化的水分子数目的结果。当增加含聚合物例如纤维素衍生物体系的温度时也出现沉淀，因为其溶解度与温度成反比。已显示加入两亲物使羟丙甲基纤维素(HPMC)的浊点降低，在盐存在下该结果更明显〔J.E.Lofroth，L.Johansson，A.C.Norman，and K.Wettstrom，Progr.Colloid.Polym.Sci.84卷，73-77页(1991年)〕。
另一方面，如果加入疏水性化合物，它可以与聚合物/两亲物聚集体相互作用，因而增加该聚合物/两亲物的聚集体的疏水性并促进其沉淀。
已发现一种方法，该法惊人地包括形成微丸，而微丸生长受到在固体/液体界面上聚合物/两亲物聚集体的吸附作用和/或其浓度的限制。
所以，本发明涉及制备含有机化合物微丸的方法，该有机化合物在水溶性第一溶剂中的溶解度大于含水第二溶剂中的溶解度，该方法包含如下步骤：
(i)将该有机化合物溶解在水溶性第一溶剂中，
(ii)制备聚合物和两亲物在含水第二溶剂中的溶液，该有机化合物基本上不溶于第二溶剂，从而形成聚合物/两亲物的复合物，
(iii)混合步骤(i)和步骤(ii)的溶液，以便使含有机化合物和聚合物/两亲物的复合物的聚集体沉淀出来。
用于形成含有机化合物的微丸的新方法包括：
(1)将该化合物溶解在水溶性第一溶剂中，且该化合物是可溶的。
(2)制备聚合物和两亲物在含水第二溶剂中的溶液，要求形成微丸的化合物或多或少地不溶解在该溶剂中，优选将体系浓度处于开始形成游离胶束的临界浓度以下。该聚合物和两亲物的浓度利于它们相互作用，但未达到两亲物的临界胶束浓度。所以，将聚合物的疏水性增大到所需程度即无沉淀出现的程度。在许多情况下，通过控制温度也可以防止该聚合物沉淀，因为聚合物的溶解度与温度有关。
(3)在搅拌下，混合步骤(1)和步骤(2)的溶液。该有机化合物与该聚合物/两亲物的复合物相互作用，从而增大了其疏水性，出现药物/聚合物/两亲物聚集体沉淀。
(4)然后优选用絮凝方法分离所形成的微丸并且用适当方法收集。
本发明方法中所用的有机化合物是其溶解度从一种溶剂到另一种溶剂要下降的任何有机化学实体。该有机化合物可以是来自不同类别的药用活性化合物例如抗高脂血症剂(antihyperlipidemics)、抗菌剂例如磺胺嘧啶，非甾体抗炎药例如消炎痛，抗高胆固醇血症剂例如普罗布考(probucol)，和甾体化合物例如地塞米松，但不限于此。或者这类有机化合物可用作药用制剂和化妆品中的辅助剂或赋形剂，例如防腐剂如对羟基苯甲酸丙酯，但不限于此。
按照本发明的第一溶剂是一种溶剂或多种溶剂的混合物，它对所述有机化合物可相对溶解，对第二溶剂是可混溶的。常见的这类溶剂包括：甲醇、乙醇、异丙醇、丙酮、N，N-二甲基甲酰胺和乙腈，但不限于此。
按照本发明的第二溶剂是水或含如下一种或多种不同的添加剂的水溶液，例如(但不限于此)：
1.聚合物类，例如：葡聚糖、聚乙二醇、聚乙烯吡咯烷酮，纤维素的衍生物如甲基纤维素和羟丙甲基纤维素，明胶和角叉菜胶。
2.盐类，例如：一价离子如氯化钠，二价离子如硫酸钠和氯化钙，和三价离子如三氯化铝。
3.表面活性剂类，例如：非离子如脱水山梨醇脂肪酸酯和其聚氧乙烯衍生物，阴离子如十二烷基磺酸钠，和阳离子如十六烷基三甲基溴化铵。
4.增稠剂例如：亲水性胶体如明胶、阿拉伯胶和黄蓍胶。
5.助溶剂例如：甘油、丙二醇、甲醇、乙醇和异丙醇。
按照本发明的聚合物，其溶液在第二溶剂中制备，是指具有较高分子量的各种有机化学实体，例如(但不限于此)：
1.乙烯基衍生物例如：聚乙烯吡咯烷酮。
2.纤维素衍生物例如甲基纤维素和羟丙基甲基纤维素。
3.聚乙二醇例如聚乙二醇6,000和聚乙二醇10,000。
按照本发明的两亲物是这样一种化合物：其分子由两部分组成，从性质上一部分是亲水的，而另一部分是疏水的。这类化合物包括(但不限于此)：
1.非离子类例如：胆固醇、卵磷脂、脱水山梨醇脂肪酸酯及其聚氧乙烯衍生物。
2.阴离子类例如：烷基磺酸盐如十二烷基磺酸钠和胆汁酸盐类如胆酸钠和牛磺胆酸钠。
3.阳离子类例如：溴化十六烷基三甲基铵和氯化苄烷铵。
该有机化合物在第一溶剂中的浓度可以低到0.01％(重量)的浓度，高到其在第一溶剂中的饱和浓度(但不限于此)，包括在温度直到第一溶剂沸点的范围内形成过饱和溶液的浓度。
聚合物在第二溶剂中的浓度可以为0.01-50％(重量)，优选0.01-10％(重量)。
两亲物在第二溶剂中的浓度可以为0.001-50％(重量)，优选0.001-5％(重量)。
可以通过不同方式达到絮凝作用，例如：
1.加入电解质例如硫酸钠、磷酸钠和磷酸钾，但不限于此。
2.改变温度。
3.加入高分子量的聚合物(桥连絮凝)。
可以采用不同的方法收集微丸，例如(但不限于此)：
1.离心和超速离心。
2.过滤。
3.反渗透后蒸发。
4.通过加热和/或减压蒸除溶剂。
5.冷冻干燥。
6.喷雾干燥。
7.流化床干燥。
8.任意结合使用上述方法。
按照本发明的一个实施例，本法包括如下步骤：
1)将一种药用活性化合物例如抗高脂血症剂溶解在水溶性第一溶剂中；
2)将聚乙烯吡咯烷酮和十二烷基磺酸钠溶解在第二溶剂中，该溶剂是含水的溶剂，例如水，而该活性化合物在其中多少有些不溶。在聚乙烯吡咯烷酮和十二烷基磺酸钠此刻浓度下的体系处于形成游离胶束的临界浓度以下，未出现聚合物/两亲物复合物的沉淀。
3)在保持连续搅拌的情况下，将从步骤(1)得到的溶液加到步骤(2)所制备的溶液中。出现沉淀，形成药物/聚合物/两亲物的微丸的混悬液。
4)通过加入电解质如磷酸钾的水溶液，使得到的微丸絮凝。
5)将该混悬液离心，用水洗两遍，离心，再分散在水中，然后冷冻干燥。
通过下列实施例说明按照本发明的形成微丸的方法。
实施例
将含1克的普罗布考(降血脂药)和12毫升的无水乙醇的溶液在1200转数/分的电磁搅拌下，加入到含2克聚乙烯吡咯烷酮(分子量为360,000)、0.1克十二烷基磺酸钠和50毫升水的溶液中。该过程产生含普罗布考微丸的白色混悬液。然后加入磷酸钾溶液使微丸絮凝。通过离心，分离絮凝后的微丸，用水洗两遍，用声处理再分散，然后冷冻干燥。通过在光学显微镜下观察样品来监控该过程。用电子显微镜来观察冷冻干燥后的成品，可看到小于2微米的微丸的聚集体。

Claims (8)

1.制备含有机化合物微丸的方法，该有机化合物在水溶性第一溶剂中的溶解度大于它在含水第二溶剂中的溶解度，该方法包括如下步骤：
(i)将所述有机化合物溶解在水溶性第一溶剂中，
(ii)制备聚合物和两亲物在含水第二溶剂中的溶液，该有机化合物基本上不溶于第二溶剂，从而形成聚合物/两亲物复合物，
(iii)混合步骤(i)和步骤(ii)的溶液，以便使含有机化合物和聚合物/两亲物复合物的聚集体沉淀出来。
2.按照权利要求1的方法，其中在根据步骤(ii)制备的溶液中的聚合物和两亲物的浓度低于开始形成游离胶束的临界浓度。
3.按照权利要求1的方法，其中通过加入电解质使得沉淀出的聚集体絮凝，此后，用离心的方法分离该聚集体，以便分得粒径小于2微米的聚集体。
4.按照前面权利要求中任一权项的方法，其中，将该聚合物和两亲物在溶液中混合，使其相互作用并通过加入疏水性有机化合物使其沉淀。
5.按照前面权利要求中任一项的方法，其中，该化合物是药用活性化合物。
6.按照权利要求5的方法，其中，该药用活性化合物是抗高脂血症剂。
7.按照前面权利要求中任一项的方法，其中，该聚合物是药学上可接受的辅助剂。
8.按照权利要求1至7中任一权项要求的方法制备的含药用活性化合物和药用辅助剂的微丸在制备药用制剂中的用途。
CN95196084A 1994-11-09 1995-11-03 微丸的形成 Pending CN1165478A (zh)

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SE9403846A SE9403846D0 (sv) 1994-11-09 1994-11-09 Small particle formation
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EP0788350A1 (en) 1997-08-13
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DE69525639D1 (de) 2002-04-04
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IS4467A (is) 1997-04-21
NO971986L (no) 1997-04-29
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DK0788350T3 (da) 2002-04-29
CZ129597A3 (en) 1997-12-17
EE9700214A (et) 1998-04-15
SK55997A3 (en) 1998-01-14
ATE213625T1 (de) 2002-03-15
NZ295497A (en) 1998-05-27
KR970706799A (ko) 1997-12-01
WO1996014833A1 (en) 1996-05-23
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IL115878A0 (en) 1996-01-31
SE9403846D0 (sv) 1994-11-09

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