CN101484495B - 聚氨酯弹性体 - Google Patents

聚氨酯弹性体 Download PDF

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CN101484495B
CN101484495B CN2007800256285A CN200780025628A CN101484495B CN 101484495 B CN101484495 B CN 101484495B CN 2007800256285 A CN2007800256285 A CN 2007800256285A CN 200780025628 A CN200780025628 A CN 200780025628A CN 101484495 B CN101484495 B CN 101484495B
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尤卡·图奥米宁
阿马亚·祖鲁苏萨
马克·利文斯通
简纳·A·哈利代
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Abstract

本发明公开了一种线型聚合物，该线型聚合物通过将聚乙二醇或聚丙二醇；PEG-PPG-PEG或PPG-PEG-PPG嵌段共聚物；双官能胺或二醇和二异氰酸酯一起反应而得到。公开了一种可控释放组合物，其包含所述聚合物以及活性试剂。可以使用分子量为200至20,000的活性试剂。

Description

聚氨酯弹性体
本发明涉及亲水性热塑性聚氨酯弹性体聚合物，其适合于制备长时间周期释放药物活性试剂的可控释放组合物。它们的弹性体性质在例如子宫托、栓剂或阴道环的用途中提供更好的舒适性。 
从欧洲专利出版物EP0016652和EP0016654中已知道某些交联的聚氨酯水凝胶聚合物。这些专利说明书描述了这样的交联聚氨酯，所述交联聚氨酯通过使当量大于1500的聚环氧乙烷与反应性的多官能异氰酸酯和三官能化合物如烷烃三醇反应而形成。所得到的交联聚氨酯聚合物是可水溶胀而形成水凝胶的，但不是水溶性的，并且可以填充有水溶性的药物活性试剂。一种具体的聚氨酯聚合物是聚乙二醇8000、Desmodur(DMDI，即二环己基甲烷-4，4-二异氰酸酯)和1，2，6-己三醇的反应产物，并且该反应产物已经在商业上用于睾丸鞘膜的前列腺素递送。 
然而，这些聚氨酯聚合物具有许多实用上的缺点。尽管三醇交联剂的使用在提供相对可重复的溶胀特性的聚合物方面是有效的，但是溶胀百分比典型为200-300％(即，溶胀聚合物重量的增加量除以干燥聚合物的重量)。药物活性试剂通过这样填充：将该聚合物与药物活性试剂的水溶液接触，使得水溶液变成被吸收到聚合物中，从而形成水凝胶。然后将溶胀聚合物干燥回到所选择的用前含水量。使用常规的交联聚氨酯的后果是，溶胀度将可以被吸收到水凝胶结构中的药物活性试剂的分子量限制至低于约3000g/mol。另外的缺点在于仅仅可以使用水溶性的药物活性试剂。最后，由于常规的交联聚氨酯聚合物基本上是既不溶于水也不溶于有机溶剂的非热塑性聚合物(热固性的)，因此不可以将所形成的聚合物进一步加工成其它的固体形态，比如膜、单片装置、泡沫材料、晶片、复合材料、夹层结构、粒子、粒料、泡沫材料或涂层。另外，常规的交联聚氨酯聚合物的热固性属性排除了在不使用溶剂或水的情况下将药物与聚合物熔融混合以用适合的活性试剂填充该聚合物的可能性。 
 从专利出版物WO2004029125中已知道一些热塑性聚氨酯水凝胶聚合物。该专利说明书描述了线型热塑性聚氨酯，该线型热塑性聚氨酯通过使分子量大于4000g/mol的聚乙二醇与反应性的多官能异氰酸酯和双官能化合物比如烷烃二醇或二胺反应而形成。所得到的热塑性聚氨酯聚合物是可水溶胀而形成水凝胶的，但不是水溶性的，并且可以填充水溶性的药物活性试剂。一种具体的聚氨酯聚合物是聚乙二醇8000、Desmodur(DMDI，即二环己基甲烷-4，4-二异氰酸酯)和1，10-癸二醇的反应产物，并且该反应产物已经表现出600％至1700％乃至更高的溶胀百分比。这种类型的聚合物已经表现出对相对水溶性的药物例如磷酸克林霉素、缩宫素和米索前列醇的扩散填充和短期递送的适合性。 
然而，这种高溶胀性的热塑性聚氨酯聚合物具有许多实用上的缺点。由于PEG的高重量含量和嵌段长度，该聚合物仅仅适用于活性试剂的较短期的释放(即，10分钟至仅几小时的可控释放)，尤其在高度水溶性的药物的情况下。另外，低疏水含量，即，低量的疏水性化合物例如癸二醇(DD)或十二烷二醇(DDD)使得聚合物不适用于疏水性药物，因此限制了它的应用。亲水性和疏水性药物需要与这两相都具有相互作用以通过聚合物结构来控制它们的释放。此外，在疏水性和亲水性化合物之间的不平衡阻碍了微相分离，这样降低了处于干燥和潮湿这两种状态下的聚合物的机械强度。另外，由于聚合物的高结晶性和硬嵌段的形成，最终的聚合物是刚性的，并且加工温度较高。 
高溶胀性热塑性聚氨酯的溶胀百分比典型为200-1700％，并且取决于PEG含量和/或PEG嵌段的长度。通过使用与上述用于常规交联聚氨酯相同的方法以及药物和聚合物的熔融混合，可以填充药物活性试剂。然而，高溶胀和交联的聚氨酯聚合物所得到的释放时间和曲线(profile)是非常类似的。 
专利说明书WO94/22934公开了由聚环氧乙烷(数均分子量1000至12,000)、二胺和二异氰酸酯制备线型无规嵌段共聚物。Yu等在Biomaterials 12(1991)，3月，第2期，第119-120页公开了由聚乙二醇(数均分子量为5830)和低分子量聚丙二醇(分子量425)以及二异氰酸酯所形成的聚氨酯水凝胶的用途。专利说明书US4,202,880公开了由聚乙二醇(分子量400-20,000)、含2-6个碳原子的碱性二醇和二异氰酸酯制备聚氨酯。专 利说明书US 4,235,988是类似的公开，但是优选的PEG范围是600-6,000。 
本发明的目的是提供一种亲水性的热塑性聚氨酯弹性体，所述聚氨酯弹性体可以通过使用常规聚合物加工系统，例如熔融混合器、挤出机和注塑机，在低于活性试剂的降解温度的温度进行加工并且与活性试剂混合。本发明的另一个目的是提高熔体粘度，从而提高弹性并且降低聚合物的结晶性，以使用常规的熔融加工技术例如挤出和注塑，以及使用不同类型的溶剂，以形成任何所选择形状的药物填充弹性可控释放装置。 
本发明基于下列发现：通过使聚乙二醇或聚丙二醇与二醇或其它双官能化合物以及PPG-PEG-PPG或PEG-PPG-PEG嵌段共聚物和双官能异氰酸酯反应，可以得到在体温下具有适于药物填充的熔融加工性和弹性的热塑性聚氨酯弹性体。 
PEG代表聚乙二醇；而PPG代表聚丙二醇。 
具体地，本发明提供一种亲水性热塑性聚氨酯弹性体聚合物，该亲水性热塑性聚氨酯弹性体聚合物是通过将下列化合物一起反应而得到的： 
(a)聚乙二醇或聚丙二醇； 
(b)PEG-PPG-PEG或PPG-PEG-PPG嵌段共聚物； 
(c)双官能化合物；和 
(d)双官能异氰酸酯。 
根据所述四种组分(a)、(b)、(c)和(d)的比率，所制备的热塑性聚氨酯弹性体在水中可溶胀至特定的程度，例如1％至200％(例如20至100％)，从而更好地控制药物活性试剂从高溶胀性的PEG基线型聚氨酯中的释放。本发明的聚合物还适合溶解于某些有机溶剂，比如二氯甲烷、1-甲基-2-吡咯烷酮(NMP)和四氢呋喃，这些溶剂允许聚合物溶解并且流延成膜或涂层。它还允许将水溶解性差但是可溶解于有机溶剂的热不稳定性活性试剂填充在所述聚合物中。 
由于起始组分的独特组合，这些聚氨酯弹性体具有可以控制活性化合物释放几天至几个月的组成。 
聚醚型多元醇含有重复醚键-R-O-R-，并且具有两个以上的作为末端官能团的羟基。它们通过环氧化物对引发剂的催化加成(阴离子开环聚合)而制备。到目前为止最重要的环状醚是环氧乙烷和环氧丙烷。这些氧化物 与含活性氢的化合物(引发剂)比如水、二醇、多元醇和胺反应。可以使用或不使用催化剂。氢氧化钾或氢氧化钠是最通常使用的碱性催化剂。在达到所需的聚合度之后，将催化剂中和，通过过滤而除去，并且加入添加剂比如抗氧化剂。 
许多种在结构、链长和分子量上加以变化的组合物都是可以的。通过选择一种或多种氧化物、引发剂和反应条件以及催化剂，可以使范围从低分子量聚二醇至高分子量聚合物的一系列聚醚型多元醇聚合。因为这些聚合物含有重复的烯化氧单元，因此它们通常被称为聚亚烷基二醇或聚二醇。大多数聚醚型多元醇被制备用于聚氨酯用途。 
聚乙二醇(PEG)含有重复单元(-CH2CH2O-)，并且便利地通过将环氧乙烷加成到乙二醇上而制备，从而制备出双官能的聚乙二醇结构HO(CH2CH2O)nH，其中n是根据聚乙二醇的分子量而大小变化的整数。在本发明中采用的聚乙二醇通常是线型聚乙二醇，即，分子量为200至35,000g/mol(通常为400至2000)的二醇。 
聚丙二醇(PPG)是环氧丙烷的聚合物，因此含有重复单元(-CH2(CH3)CH2O-)。由于在聚合过程中伯羟基和仲羟基的共存和由于在聚合物上的多个甲基侧链，聚丙二醇具有独特的物理和化学性质。丙二醇的常规聚合导致无规立构聚合物。全同立构聚合物主要存在于实验室中。还可以产生无规立构和全同立构聚合物的混合物。PPG具有许多和聚乙二醇一样的性质。所有分子量的聚丙二醇都是具有低倾点的透明粘性液体，并且表现出相反的温度-溶解度关系，即随着分子量增加，水溶解度快速降低。末端羟基经历伯醇和仲醇的典型反应。聚丙二醇的仲羟基不像聚乙二醇中的伯羟基一样有反应性。PPG在许多用于聚氨酯的制剂中都有使用。在本发明中使用的聚丙二醇通常是线型的，并且分子量为200至4000g/mol(通常400至2000)。 
本发明还提供一种制备线型聚合物的方法，所述方法包括在真空下、于85℃至100℃的温度熔融并且干燥PEG或PPG，和所述嵌段共聚物以及双官能化合物；然后加入双官能异氰酸酯。 
基于环氧丙烷和环氧乙烷的嵌段共聚物(b)的制备可以由乙二醇、甘油、三羟甲基乙烷、三羟甲基丙烷、季戊四醇、山梨糖醇、蔗糖和几种其 它的化合物开始。还可以制备出混合和交替嵌段的共聚物。当PPG的仲羟基被环氧乙烷封端时，生成了具有末端伯羟基的PEG和PPG的嵌段共聚物。与仲羟基相比，伯羟基与异氰酸酯的反应性更高。在本发明中使用的PEG-PPG-PEG和PPG-PEG-PPG共聚物通常是线型的，并且分子量为200至14,000g/mol。嵌段共聚物表现出对本发明的聚合物的非晶弹性体性质有贡献。 
双官能化合物(c)与双官能异氰酸酯起反应，并且典型为双官能胺或二醇。在C5至C20、优选C8至C15的范围内的二醇是优选的。因此，发现癸二醇产生特别良好的结果。二醇可以是饱和或不饱和的二醇。可以使用支链的二醇，但是优选直链的二醇。两个羟基通常在末端碳原子上。优选的二醇包括1，6-己二醇、1，10-癸二醇、1，12-十二烷二醇和1，16-十六烷二醇。 
双官能异氰酸酯(d)通常是常规的二异氰酸酯中的一种，比如二环己基甲烷-4，4-二异氰酸酯、二苯基甲烷-4，4-二异氰酸酯、1，6-己二异氰酸酯等。 
组分(a)、(b)、(c)和(d)的当量比通常在分别是0.01-1∶0.01-1∶1∶1.02-3的范围内。当然，本领域技术人员通过合理的实验将确定组分的最佳比率以得到所需的性质。化合物(d)的量通常等于(a)、(b)和(c)的组合量以提供正确的化学计量。 
所述聚合物通常通过这样制备：在真空下以及在85℃至100℃的温度(例如95℃)，熔融并且干燥PEG或PPG和PEG-PPG-PEG或PPG-PEG-PPG嵌段共聚物，以及双官能化合物和典型的聚氨酯催化剂(如果使用的话)例如氯化铁、DABCO和/或辛酸锡(II)，以除去过量的水分；之后将二异氰酸酯，例如DMDI或HMDI加入其中。聚合在间歇式反应器或备选的连续反应器中进行；或者将反应混合物供给到模具中，并且反应特定的时间。在聚合之后，将聚合物冷却、造粒或者粒化，并且储存在冷冻装置中以进一步分析和处理。 
本发明的热塑性聚氨酯弹性体的弹性体性质应归于两个因素：硬嵌段和软嵌段的微相分离；和聚合物的半结晶性，该聚合物的非晶相具有低的玻璃化转变温度。硬嵌段由双官能化合物和二异氰酸酯形成。软嵌段是PEG、PPG或共聚物。弹性可以取决于硬嵌段与软嵌段的比率，并且可以由肖氏硬度的测量值表示。 
本发明的线型聚合物可溶于某些有机溶剂。这样允许聚合物被溶解，并且将所得到的溶液流延以形成膜。还可以将溶液用于包覆颗粒剂、片剂等，以改变聚合物释放性能。备选地，可以将溶液倒入到非溶剂中以沉淀出聚合物/活性微粒。另外，可以通过使用用于加工热塑性聚合物的常规技术将所述聚合物研磨、粉碎、造粒和熔融。 
因此，本发明还提供一种可控释放组合物，该组合物包含线型聚合物以及活性试剂。任何类型的塑料加工设备，例如挤出机、注塑机、压模设备和熔融混合器都可以被用于将聚合物和活性试剂混合在一起并且形成或者再成形为任何类型的药物负载装置，例如环、子宫托、片、棒、弹性物(spring)或锥形物。活性试剂可以是人或动物用的药物活性试剂。它还可以是需要持续释放性的任何其它试剂(例如灭藻剂、化肥等)。药物的固体剂型包括阴道用的栓剂、环和子宫托；口服用的口腔插入物；用于透皮给药的贴剂等。通常将这些剂型对病人给药，保持在适当的位置直至发生活性试剂的递送，然后除去废的聚合物。还可以将聚合物用于保持在体内的植入物；或者用于涂覆这样的植入物(例如支架)。 
本发明的聚合物是两亲性热塑性聚合物，因此适用于亲水性和疏水性的低和高分子量的药物活性试剂(至多以及超过3000的分子量，例如至多10,000，至多50,000，至多100,000，乃至至多200,000)的摄取。通常，活性试剂的分子量在200至20,000的范围内。因此可以结合多种水溶性的药物活性物质，如在EP0016652中所列举的那些。而且，本发明的线型聚合物可以填充水溶性差的药物活性的亲水和疏水试剂，条件是这些试剂可以与聚合物一起溶解于普通溶剂中。然后可以将所得到的溶液流延成任何所需的固体形状。另外，可以将本发明的线型聚合物与在聚合物加工温度是热稳定的药物活性试剂一起挤出填充或者熔融混合。 
对于有用活性试剂的基本上完全的释放，本发明的聚合物的释放时间可以超过12小时、24小时、5天、10天、20天、乃至80天。 
在本发明中使用的聚醚型多元醇共混物和共聚物是固有的(internal)和熔体的流变性、柔软性和释放率的调节剂。这些类型的低熔融两亲性的热塑性聚氨酯聚合物特别适于熔融填充药物活性试剂并且将所填充的聚合物熔融加工成药物装置。 
特别令人兴趣的药物活性试剂包括：蛋白质，例如干扰素α、β和γ，胰岛素，人生长激素，亮丙立德；苯二氮 类，例如咪达唑仑；抗偏头痛试剂，例如Triptophans、麦角胺及其衍生物；抗感染试剂，例如唑类、细菌性阴道病、念珠菌(Candida)；以及眼病试剂，例如拉坦前列素。 
活性试剂的具体名单包括H2受体拮抗药、抗毒蕈碱药(antimuscaririe)、前列腺素类似物、质子泵抑制剂、对氨水杨酸盐(aminosalycilate)、皮质类固醇激素、螯合剂、强心苷、磷酸二酯酶抑制药、噻嗪、利尿剂、碳酸酐酶抑制剂、抗高血压药、抗癌药、抗抑郁药、钙通道阻断剂、止痛剂、鸦片去痛剂、抗血小板药(antiplatel)、抗凝血剂、溶纤维蛋白药、他汀类药物(statin)、肾上腺素显效药、β阻断剂、抗组胺剂、呼吸兴奋剂、化痰药、祛痰药(expertorant)、苯并二氮 
Figure G2007800256285D00072
、巴比妥酸盐、抗焦虑药、安定药、三环抗抑郁药、5HT1拮抗药、麻醉剂、5HT、激动剂、止吐药、抗癫痫病药、多巴胺能药、抗生素、抗真菌药、驱肠虫药、抗病毒药、抗原虫药、抗糖尿病药、胰岛素、甲状腺毒素、雌性激素(femal sex hormone)、雄性激素、抗雌性激素药、下丘脑药(hypothalamic)、垂体激素、垂体后叶激素拮抗药、抗利尿激素拮抗药、二膦酸盐、多巴胺受体兴奋剂、雄激素、非甾族抗炎药、免疫抑制剂局部麻醉药、镇静剂、抗银屑病药、银盐、局部抗菌疫苗。 
现在，在下面通过实施例描述本发明的实施方案。在下面的表、实施例和图中可以看到PEG或PPG、PEG-PPG-PEG或PPG-PEG-PPG共聚物、二醇和二异氰酸酯的种类和比率对聚合物的性能的影响。 
图1显示了某些聚合物的分子量与聚合时间的函数关系；和 
图2至5显示了各种活性试剂的释放曲线。 
实施例1.聚合物制备 
使用在化学计量比的范围内的各种聚乙二醇、聚丙二醇、PEG-PPG-PEG、PPG-PEG-PPG、二醇和二异氰酸酯以证明它们对亲水性线型聚氨酯弹性体聚合物的性质的影响。PEG400、PEG900、PEG1000和PEG2000分别是分子量为400、900、1000和2000g/mol的聚乙二醇；PPG1000和PPG2000是分子量为1000和2000g/mol的聚丙二醇；PEG-PPG-PEG1100和PEG-PPG-PEG4400是分子量为1100和4400g/mol的嵌段共聚物； PPG-PEG-PEG2000是分子量为2000g/mol的嵌段共聚物；DD是1，10-癸二醇，而DDD是1，12-十二烷二醇；DMDI是二环己基甲烷-4，4-二异氰酸酯，而HMDI是1，6-己二异氰酸酯；FeCl3是氯化铁，DABCO是三亚乙基二胺，而SnOct2是辛酸亚锡。 
聚合物通过使用在WO专利出版物WO2004029125中描述的聚合方法制备。在旋转蒸发器中，将PEG、PPG、PEG-PPG-PEG和/或PPG-PEG-PPG与二醇和催化剂(如果使用的话)一起在95℃、低于1mbar的压力下熔融并且真空干燥1小时。在这种情况下，将干燥的混合物供给到反应器中，然后加入二异氰酸酯。所制备的聚合物示于表1中。 
实施例2.作为时间函数的聚合反应 
使用三级检测尺寸排阻色谱(SEC)研究了聚合时间对所制备的聚合物的影响。对聚合物B和C进行以聚合时间的函数形式的分子量测定，参见下图1。聚合物的分子量确定聚合物的流变性、熔体流动性和机械性能。因此，测定分子量值的重要是明显的。 
实施例3.催化剂对聚合反应的影响 
与在实施例1中一样进行聚合，但是对于聚合物N，用DABCO和SnOct2代替氯化铁(表1)；而对于聚合物M，只使用DABCO(表1)。聚合物H是在不存在催化剂的情况下制备的(表1)。 
实施例4.不同二异氰酸酯的使用 
对于聚合物F、G、H、I、K、L、M、N、O、P、Q和R，除如表1中用HMDI代替DMDI以外，与在实施例1中一样进行聚合。 
实施例5.聚合物在不同溶剂中的溶解度 
将表1中的多种聚合物溶解在不同溶剂中以找到适合的溶剂。在室温(RT)下进行24小时溶解度测试。所选择的聚合物的溶解度结果示于表2中。 
表2.在所选择的溶剂中的聚合物溶解性。 
Figure G2007800256285D00101
DCM    二氯甲烷 
THF    四氢呋喃 
TEA    三乙胺 
实施例6.聚合物在不同溶剂中的溶胀能力 
对多种所选择的聚合物进行在水、乙醇、异丙醇(IPA)和IPA/水的50％混合物中的溶胀测定，以测量被聚合物吸收的溶剂的量。基于10个样品的平均溶胀计算结果，并且将该结果显示于表3中。下面显示了用于计算的公式： 
表3.所选择的聚合物在不同的溶胀介质(水、乙醇、IPA和50％IPA/水)中的溶胀％ 
Figure G2007800256285D00112
实施例7.肖氏硬度测试(弹性测量) 
使用硬度计A和D测试所制备的聚合物的肖氏硬度。硬度计A和D通常分别用于测量柔软和硬质的橡胶的弹性。这些测量对于本领域技术人员是熟知的。结果表示为四个测量值的平均值并且显示在表4中。 
表4.对制备的聚合物测定的肖氏硬度值 
Figure DEST_PATH_GSB00000520544200031
实验条件： 
温度          21℃ 
相对湿度％RH  39 
实施例8.通过压模制备的聚合物膜 
在加工之前，将多种从表1中选出的聚合物在真空下通宵干燥。将压模机的上板和下板温度设定在目标加工温度。将两个Teflon板放置在模具和热板之间。熔融时间为3-5分钟，然后在压力(170-200巴)下保持30-120秒。使用预定量的聚合物填充模具。在冷却至室温之后，将样品(尺寸为30mm×10mm×1mm的子宫托装置)进行机械冲压，并且保持在冷冻机中以进一步分析。膜加工条件显示于表5中。 
表5.采用压模热加工所制备的聚合物。 
  聚合物   温度(℃)   料筒压力  (巴)   熔融时间  (s)   加压时间  (s)   模塑厚度  (mm)
  聚合物A*   160   200   240   120   1.0
  聚合物A*   160   200   210   120   1.0
  聚合物A   150   200   120   60   0.25
  聚合物C   130   200   180   60   0.4
实施例9.药物填充-挤出 
使用两种不同活性的化合物氟康唑和奥昔布宁填充所选择的聚合物。使用16mm共旋转双螺杆实验室挤出机填充聚合物。表6显示了药物填充条件。 
表6.用于氟康唑填充装置的挤出填充条件。 
  聚合物名  称   药物   药物(重量  ％)   螺杆速度  (rpm)   从进料至模头的温度  曲线(℃)
  聚合物A*   氟康唑   20   40   55-95-120-120-120
  聚合物A*   氟康唑   50   40   55-95-115-115-115
  聚合物A   氟康唑   20   60   80-110-110-110-110
  聚合物A   氟康唑   50   60   103-113-115-115-115
  聚合物A   奥昔布宁   5   60   80-115-115-115-115
  聚合物A   奥昔布宁   10   40   90-110-110-110-110
  聚合物A   奥昔布宁   15   60   80-110-110-110-110
  聚合物B   奥昔布宁   5   50   132-132-132-132-132
  聚合物B   奥昔布宁   10   40   133-133-133-133-136
  聚合物C   氟康唑   20   60   95-115-115-115-115
  聚合物C   奥昔布宁   5   60   85-100-105-105-105
  聚合物C   奥昔布宁   10   50   80-100-105-105-105
  聚合物C   奥昔布宁   15   40   80-100-110-110-110
使用氟康唑以两种不同的药物量填充两种不同批次的相同聚合物组合物(聚合物A和A*)，以证明聚合过程的可重复性。发现释放结果是可重复的。 
填充到聚合物中的活性化合物的量基于所需的治疗剂量。 
实施例10.药物释放研究-聚合物的影响 
通过溶解研究测定挤出填充的聚合物的体外药物释放性能。通过使用基于用于短时间释放的USP搅拌桨方法和用于长时间释放的带有Erlenmeyer锥形瓶的恒温箱振荡器方法的溶解方法，研究由挤出填充的聚合物所释放的氟康唑和奥昔布宁的量。USP搅拌桨技术包括自动UV溶解系统，其中将Distek(2100C型号)溶解搅拌桨(速度50rpm)通过Icalis蠕动泵连接到Unicam UV 500分光光度计上。系统使用Dsolve软件进行操作。在恒温箱振荡器方法中，手动取得样品，并且使用Unicam UV 500分光光度计分析样品。 
实验条件： 
温度        37℃ 
溶解介质    500ml的脱气的去离子水 
在该实施例中，研究了聚合物结构对氟康唑的释放的影响。使用挤出技术，用20重量％的氟康唑填充聚合物A和C，并且用5％奥昔布宁填充聚合物A、B和C。氟康唑和奥昔布宁的释放根据聚合物基体而变化，参见图2a和2b。 
实施例11.药物释放研究-药物的影响 
当改变药物种类时，获得了不同的释放曲线。将氟康唑和奥昔布宁填充在聚合物A中。归一化的溶解曲线显示在图3中。使用与实施例10中相同的溶解方法测定释放曲线。 
实施例12.药物释放研究-药物量的影响 
通过溶解研究，研究了增加的填充含量的影响。研究了不同的药物含量对聚合物A的释放性能的影响，并且将其显示在图4中。将氟康唑填充量从20重量％增加至50重量％。使用与实施例10中相同的溶解方法测定释放曲线。 
实施例13.药物释放研究-与高溶胀性聚合物比较 
将聚合物A和聚合物C所得到的氟康唑释放曲线与交联和线型的高 溶胀性聚氨酯聚合物所得到的释放曲线进行比较，参见图5。扩散填充的交联聚合物(交联的17重量％氟康唑)来自专利EP0016652/EP0016654。而线型高溶胀性聚合物来自专利WO2004029125，并且使用扩散(高溶胀％、17重量％的氟康唑)以及挤出技术(高溶胀％、20重量％的氟康唑)进行填充。使用与实施例10中相同的溶解方法测定释放曲线。这些新的聚合物可以提供对药物释放的优异控制，参见图5。 

Claims (13)

1.一种可控释放组合物，所述可控释放组合物包含可通过将下列化合物一起反应而得到的线型聚合物以及活性试剂：
(a)聚乙二醇或聚丙二醇；
(b)PEG-PPG-PEG或PPG-PEG-PPG嵌段共聚物；
(c)双官能化合物；和
(d)双官能异氰酸酯，
其中所述双官能化合物与所述双官能异氰酸酯起反应。
2.根据权利要求1所述的组合物，其中所述聚乙二醇是分子量为400至2000的线型聚乙二醇。
3.根据权利要求1所述的组合物，其中所述聚丙二醇是分子量为400至2000的线型聚丙二醇。
4.根据权利要求1所述的组合物，其中所述嵌段共聚物的分子量为200至14,000。
5.根据权利要求1所述的组合物，其中所述双官能化合物(c)是二醇。
6.根据权利要求5所述的组合物，其中所述二醇是C5至C20二醇。
7.根据权利要求6所述的组合物，其中所述二醇是C8至C15二醇。
8.根据权利要求6所述的组合物，其中所述二醇是1，6-己二醇、1，10-癸二醇、1，12-十二烷二醇或1，16-十六烷二醇。
9.根据权利要求1所述的组合物，其中所述双官能异氰酸酯(d)是二环己基甲烷-4，4-二异氰酸酯、二苯基甲烷-4，4-二异氰酸酯或1，6-己二异氰酸酯。
10.根据权利要求1所述的组合物，其中所述组分(a)、(b)、(c)和(d)的当量比在0.01-1∶0.01-1∶1∶1.02-3的范围内。
11.根据权利要求1所述的组合物，所述组合物被加工成固体剂型。
12.根据权利要求11的组合物，所述组合物处于阴道用的栓剂、环或子宫托，口腔插入物或透皮贴剂的形式。
13.根据权利要求11的组合物，所述组合物处于植入物的形式。
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