CN1070344A - 药物持续和受控释放的组合物以及制备该组合物的工艺 - Google Patents

药物持续和受控释放的组合物以及制备该组合物的工艺 Download PDF

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CN1070344A
CN1070344A CN92109509A CN92109509A CN1070344A CN 1070344 A CN1070344 A CN 1070344A CN 92109509 A CN92109509 A CN 92109509A CN 92109509 A CN92109509 A CN 92109509A CN 1070344 A CN1070344 A CN 1070344A
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P·奥索里尼
F·海姆加特诺
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Abstract

一种为使药用肽持续和受控释放而设计的组合 物，所述肽具有化学式(I)：
Ac-D-Nal-D-pclPhe-R3-Ser-Tyr-D-Cit- Leu-Arg-pro-D-Ala-NH2 其中R3代表D-Pal或D-Trp。获得的组合物呈生 物降解聚合物的微球体状态，其中掺入化学式为(I) 的肽水不溶性盐。

Description

一种为使药用肽持续和受控释放而设计的组合物，可呈生物降解聚合物微球体的状态，其中掺有所述药物。一种对其制备的方法。
为使药用肽持续和受控释放而设计的一种组合物，具有化学式（Ⅰ）
（Ⅰ）
其中R3是D-Pal，或D-Trp，呈生物降解聚合物微球体的状态，它包含化学式为（Ⅰ）的肽水不溶性盐。
制备上述组合物的方法，包括首先将水溶性肽盐转化为水不溶性肽盐，然后将这种肽盐悬浮于一种生物降解聚合物的溶液中，将所述悬浮液转化成水包油型乳状液，最后，在将水包油型乳状液转移到过量的水介质后，分离生物降解聚合物的微球体。
直到今天，人们提出多种方案以制备能够持续和受控释放药物的组合物，都是利用制造生物降解的植入体，微囊包封或制备各种尺寸的例如以微球体或微粒形式的生物降解多孔基体。在这方面，能提到采用水溶性药物相分离的微囊包封EP-A-0052510和制备植入体或生物降解多孔基体的EP-A-0058481和US-A-3976071，这些基体主要以聚交酯或共聚交酯-乙交酯为基础。这些技术利用作为载体的生物降解聚合物或共聚物在有机溶剂中的在先溶解，而且如果需要，还可利用药物本身的溶解。
其它技术，也能产生微胶囊或微球体的，则利用乳化方法，该方法最重要的步骤是从聚合物的有机溶液和该肽的水溶液获得（obtention）水包油型乳状液，在这方面可见US-A-4384975、3891570、4389330、3737337、4652441或WO-90/13361。然而，无论如何本技术领域的一般技术人员都必须利用复杂和困难的控制技术，为了尽可能地降低高水溶性活性肽的损失，例如双重乳化。
以一种利用形成水包油型乳状液随后将其转移到水介质中的方法，本发明出乎意料之外能很方便地克服至今已知技术的缺点。
实际上，首先采用将化学式（Ⅰ）的水溶性肽盐转化成水不溶性肽盐的程序，本发明就能使所属技术领域的技术人员获得一种新手段，它利用所使用的组分尤其是所用的溶剂和“非溶剂”的相对溶解度。
具有化学式（Ⅰ）的肽定义为LHRH类似物;可有效地用于治疗与荷尔蒙有关的病症。除非另有说明，否则定义的化学式（Ⅰ）的氨基酸具有L构型。D-Nal代表D-3-（2-萘基）-丙氨酸和D-Pal代表D-3-（3-吡啶基）-丙氨酸
本发明组合物呈生物降解聚合物的微球体的状态，含有化学式为（Ⅰ）的水不溶性肽盐。该组合物，包含如5%（重量）的水不溶性盐，在对人或动物非肠道使用后，所述肽能持续释放数日。
本发明还涉及制备上述定义的组合物方法。
尤其是，本发明的目的之一是具有下列特征的方法：
a.将化学式（Ⅰ）的水溶性肽盐转化成水不溶性肽盐;
b.所述水不溶性肽盐悬浮于含有溶解态的生物降解聚合物的有机介质中;
c.所述有机悬浮液分散于能使生成的乳状液形成连续相的水介质中;
d.所述乳状液被转移至过量的水介质中，最后，再将由此形成的微球体与液相分离。
本方法第一阶段包括用常规技术转化水溶性肽盐为水不溶性肽盐。所谓“水溶性的”是指肽盐在25℃时水溶解度超过或等于0.1mg/ml，最好超过或等于1.0mg/ml。
所谓“水不溶性的”是指肽盐在25℃时水溶解度低于或等于0.1mg/ml。肽盐如双羟萘酸盐、单宁酸盐、硬脂酸盐或棕榈酸盐皆满足此定义。
至于所述生物降解聚合物，使用最为普通的是聚合物，如聚交酯、聚乙交酯或乳酸和乙醇酸共聚物。
在优选的聚合物当中，值得指出的是乳酸和乙醇酸的共聚物（PLGA），尤其是含45-90（摩尔）乳酸单元的L-或D，L-乳酸和相应各为55-10%（摩尔）的乙醇酸单元的共聚物。
至于为聚合物所选择的溶剂，可使用有机溶剂例如二氯甲烷，然而在任何情况下，该溶剂对于所选用的肽或肽盐都必须是“非溶剂”。
根据本发明，一旦所述肽或盐被悬浮于聚合物的有机溶液后，应将该溶液掺入予定量的水介质中，最为普通的是用适当的表面活性剂补充的水中，目的是快速生成均匀的水包油型乳状液，所述水介质的作用在于维持连续相。在制备这样的乳状液时应考虑各种因素，这些因素同样也影响由本方法产生的微球体大小或结构。必须加以考虑的因素之一是有机溶液加到水介质中的速率;另一个因素是温度或进一步的搅拌速度或分散能（超声处理），上述最后一个参数尤其影响最终微球体的大小。为了达到予定的目的，选择乳化的方法和条件是在所属技术领域的一般技术人员能力范围之内的。
在制备所述乳状液中，还能证实改变接触相的体积比，尤其是减小相对于水相的有机相起始体积是有益的。在某些情况下，由于所使用的有机溶剂例如二氯甲烷的挥发性，在搅拌过程中自发地出现蒸发已证实是充分的;在其它情况下，这种希望的现象可通过减压部分蒸发法得到加速。
有机-水乳状液稳定后，将其转移至过量的水介质中，最为普通的是水。该操作的目的是增强乳状液中初期形成的微球体硬度，此时提取仍然留在所述微球体内部的有机溶剂。这样做的另一目的在于同时除去在最后的硬化过程中残留在聚合物体内的微量表面活性剂。值得注意的是水对于生物降解的聚合物如PLGA和载留在所述微球体内部的肽盐都是“非溶剂”。这种情况对于必需提取残留聚合物溶剂（如CH2Cl2）是特别有利的。
将所述乳状液转移至过量含水介质中后，采用常规技术例如离心、过滤或重力沉降收集硬化的微球体。然后对其洗涤、提纯和干燥。
本发明方法优点之一是有可能获得大小精确控制的微球体，这种控制主要在乳状液制备过程中（例如搅拌速度）发生，另一个优点是能使肽达到特别高的填充量，5、10或20%（重量），或更高，这取决于条件。另外，肽或肽盐掺入的效率特别高;这主要是由于先前将所选择的肽由水溶性盐转化成水不溶性盐。
按本发明方法由上述成分制得的微球体，在经过适当的灭菌后，可用于制备非肠道用的悬浮液，例如肌肉或皮下注射。
本发明将通过下列实例予以说明，用于这些实例的操作条件对本发明没有任何限制。
例1
将3克化学式为
的LHRH类似物的乙酸盐，用常规技术转化成相应的双羟萘酸盐并用这样的方式处理以便获得平均粒度接近10微米的颗粒。
然后将所述0.317克的双羟萘酸盐悬浮于20ml的CH2Cl2中，再将所述悬浮液加入20ml含1.683克溶解的D，L-乳酸和乙醇酸（PLGA）75∶25（摩尔%/在HFIP中比浓对数粘度0.82）共聚物的CH2Cl2中。该混合物在搅拌条件下于室温下制备，以获得完全均匀的悬浮液。
将所得到的部分悬浮液倒入含0.075%溶解的甲氧基纤维素的50ml水中，再于室温下连续搅拌（搅拌速度：900rpm）混合物约90分钟。按平均30分钟的规定时间间隔监测乳状液的形成，同时取样并用显微镜检查所获得的微球体。
搅拌结束后（微球体大小降低稳定），所述悬浮液的一部分被转移至2升保温于大约10℃的水中，同时搅拌混合物直至均化。
从反应混合物中分离PLGA微球体并用连续离心法交替地用水洗涤将其提纯，最后过滤并减压干燥。由此收集到1.61克PLGA微球体（产率：80%），其中有94%以上的颗粒具有低于100微米的直径（最大为55-83微米）。
分析（溶解固体PLGA，提取并用HPLC测定肽）表明微球体的双羟萘酸盐填充量为9.05%（重量）（理论量：10%）。
将由此获得的微球体随后用γ-射线进行灭菌并悬浮于适当的无菌载体中。体内检验（测量雄鼠的血睾酮水平）证实活性物质的正常释放。
例2
使用与例1完全相同的程序，对于1.366克的PLGA75∶25，使用0.634克的LHRH类似物的双羟萘酸盐。
PLGA微球体：1.70克（产率：85%）
填充量水平：18.3%（理论量：20%）
由此获得的微球体随后经γ-射线灭菌后悬浮于合适的无菌载体中。体内检验（测量雄鼠的类似物血清水平）证实在至少24天内生物有效量的活性物质正常释放。
时间（天） 肽测量值（ng/ml)
0+3小时123681014162024 47.148.952.246.950.440.142.129.833.533.025.6
这些结果通过以D30使试验对象致死完成的分析进一步得到证实：至少80%的睾丸重量损失，至少90%的精液囊的重量损失。
例3
所用程序与例1完全相同，但使用肽的化学式为：
通过将其乙酸盐转化成相应的双羟萘酸盐并对后者进行相同的后续处理，可获得类似的结果。

Claims (11)

1、一种组合物，用于药用肽的持续和受控释放，所述肽具有化学式(Ⅰ)：
其中R3代表D-Pal或D-Trp，其特征在于它呈生物降解聚合物的微球体状态，其中含有化学式(Ⅰ)的肽水不溶性盐。
2、按照权利要求1所述组合物，其中水不溶性肽是双羟萘酸盐、单宁酸盐、硬脂酸盐或棕榈酸盐。
3、按照权利要求1或2所述组合物，其中生物降解聚合物是聚交酯，聚乙交酯或乳酸和乙醇酸的共聚物。
4、按照权利要求3所述组合物，其中乳酸和乙醇酸的共聚物是含45-90%（摩尔）的乳酸单元的L-或D、L-乳酸和相应55-10%（摩尔）的乙醇酸单元的共聚物。
5、按照权利要求1-4中的一项所述组合物，呈乳酸和乙醇酸75∶25（摩尔%）共聚物的微球体状态，包含至少5%（重量）肽化学式为（Ⅰ）的双羟萘酸盐。
6、按照权利要求1所述组合物可用于非肠道用的一种药物制剂中。
7、按照权利要求1所述组合物的制备方法，其特征在于：
a）化学式（Ⅰ）的水溶性肽盐转化成水不溶性肽盐;
b）所述水不溶性肽盐悬浮于一种含溶解态生物降解聚合物的有机介质中;
c）所述有机悬浮液分散于水介质中，使得到的乳状液形成连续相;
d）所述乳状液转移至过量的水介质中，最后将由此获得的微球体与液相分离。
8、按照权利要求7所述方法，其特征在于将水包油型乳状液转移至过量水介质之前，部分蒸发有机溶剂以形成油相。
9、按照权利要求7所述方法，其特征在于水不溶性肽盐是双羟萘酸盐、单宁酸盐、硬脂酸盐或棕榈酸盐。
10、按照权利要求7-9的一项所述方法，其特征在于生物降解聚合物是聚交酯、聚乙交酯、或乳酸和乙醇酸的共聚物。
11、按照权利要求10所述方法，其特征在于乳酸和乙醇酸共聚物是一种含45-90%（摩尔）乳酸单元的L-或D，L-乳酸和相应55-10%（摩尔）的乙醇酸单元的共聚物。
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