CN101484493A - 亲水性聚氨酯组合物 - Google Patents

亲水性聚氨酯组合物 Download PDF

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CN101484493A
CN101484493A CNA2007800254415A CN200780025441A CN101484493A CN 101484493 A CN101484493 A CN 101484493A CN A2007800254415 A CNA2007800254415 A CN A2007800254415A CN 200780025441 A CN200780025441 A CN 200780025441A CN 101484493 A CN101484493 A CN 101484493A
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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

本发明公开了一种水溶胀性线型聚合物，该水溶胀性线型聚合物通过将数均分子量小于4000的聚环氧乙烷、脂族二醇和双官能异氰酸酯一起反应而制成。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。所述聚合物能够吸收分子量为200至20,000的药物活性试剂。

Description

亲水性聚氨酯组合物
本发明涉及亲水性线型聚氨酯聚合物，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。
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(PEG)8000、二环己基甲烷-4，4-二异氰酸酯(DMDI)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，这些交联的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。作为后果，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将水溶性的药物活性试剂用于填充。并且释放性能非常有限，原因是不能实现长期的释放；对于水溶性药物，可以达到体外24小时的最大释放时间。
除这些缺点以外，常规的交联聚氨酯聚合物基本上是非热塑性聚合物(热固性的)，因此既不溶于水也不溶于有机溶剂，从而使得不能有效地将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(PCT/GB2003/004208)中已知道某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的聚环氧乙烷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，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1，10-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还具有一些实用上的缺点。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(即，10分钟至仅几小时的可控释放)的释放，尤其在高度水溶性的药物的情况下。另外，低疏水含量，例如，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。此外，在疏水部位和亲水部位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的聚合物的机械强度。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控制它们的释放。
高溶胀的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的方法完全相同的方法，可以填充药物活性试剂，并且释放时间和曲线(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。本发明的某些实施方案的目的是提供一种上述类型的亲水性、低溶胀性的线型聚氨酯聚合物。本发明的另一个目的是提高该聚合物的可加工性，以在聚合物加工和药物填充步骤中允许使用常规的熔融加工技术，例如挤出、压模和注塑，以及使用不同类型的溶剂。
本发明是基于具有适合用于药物填充的熔融加工性能以及良好的药物释放性能的低溶胀性线型聚氨酯的合成，所述聚氨酯是通过使聚乙二醇与二醇或其它双官能化合物以及双官能异氰酸酯反应而制备的。
具体地，本发明提供一种水溶胀性线型聚合物，其是通过将下列化合物一起反应而得到的：
-数均分子量小于4000的聚环氧乙烷；
-脂族二醇；和
-双官能异氰酸酯。
根据这三种组分(a)、(b)和(c)的比率，所制备的线型低溶胀性聚合物在水中可溶胀至一定的程度，例如1％至200％(例如20至100％)，从而获得的药物活性试剂释放的控制比从已知的高溶胀性线型聚合物中获得的药物活性试剂释放的控制更好。本发明的聚合物还可以溶胀于其它溶剂(其中它们不溶解)，比如乙醇或异丙醇。本发明的线型聚合物还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。
聚环氧乙烷含有重复单元(-CH2CH2O-)并且便于通过将环氧乙烷逐步添加到含有活性氢原子的化合物中而制备。聚乙二醇通过将环氧乙烷加成到乙二醇上而制备，从而制备出双官能聚乙二醇结构HO(CH2CH2O)nH，其中n是根据聚乙二醇的分子量而改变大小的整数。在本发明中采用的聚环氧乙烷通常是线型聚乙二醇，即，当量为200至4000g/mol的二醇。
双官能脂族二醇与双官能异氰酸酯起反应，并且典型为至少C6或C8二醇。在C5至C20、优选C8至C15的范围内的二醇是优选的。因此，已经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。可以使用支链二醇，但是优选直链二醇。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)的比率(根据当量)通常在0.01-0.1：1：1.01-1.1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。组分(c)的量通常等于(a)和(b)的组合量以提供正确的化学计量。
优选地，亲水性PEG单元的量小于50重量％，优选小于40重量％，并且通常小于30重量％。同样，疏水性二醇的量超过20重量％、30重量％或40重量％。二异氰酸酯通常为聚合物的20-50重量％。
本发明还提供一种制备所述聚合物的方法，所述方法包括在真空下、于85℃至100℃的温度将聚环氧乙烷与脂族二醇一起熔融并且干燥；然后加入双官能异氰酸酯。
所述聚合物通常通过这样制备：在85℃至100℃的温度(例如95℃)以及在真空下，将聚乙二醇与双官能化合物和典型的聚氨酯催化剂例如氯化铁、三亚乙基二胺(DABCO)和/或辛酸锡(II)一起熔融并且干燥，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。然后将反应混合物倒入到模具中，并且反应特定的时间。因此，首先以固体的形式形成聚合物。然而，本发明的线型聚合物可溶于某些有机溶剂，比如在表2中提供的那些(但是并不是所有的聚合物都可溶于所有溶剂中)。这允许聚合物溶解，并且将所得到的溶液流延成膜。还可以将溶液用于包覆颗粒剂、片剂等，以改变它们的释放性能。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用于将聚合物和药物混合在一起，并且将它们形成或者再成形为任何类型的药物填充形式。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(例如灭藻剂、化肥等)的任何其它试剂。药物的固体剂型包括阴道用的栓剂、环和阴道栓剂，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)。
本发明的线型聚合物是两亲性的热塑性聚合物，因此适用于亲水性、疏水性、低和高分子量药物活性试剂(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)的吸收。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，如在专利说明书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200、400、800、1200分钟，乃至更长。
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
Figure A200780025441D0008114548QIETU
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 A200780025441D0008114548QIETU
、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、局部抗菌药、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聚乙二醇、二醇和二异氰酸酯的种类和比率对聚合物的性能的影响。
在附图中，图1显示了聚合物A的分子量随聚合时间的变化；并且图2是各种聚合物的释放曲线的比较。
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、二醇和二异氰酸酯，以证明它们对所制备的亲水性线型聚氨酯聚合物的性质的影响。PEG400、PEG600、PEG1000、PEG 1200、PEG2000和PEG4000分别是分子量为400、600、1000、1200、2000和4000g/mol的聚乙二醇；DD是1，10-癸二醇，并且DDD是1，12-十二烷二醇；DMDI是二环己基甲烷-4，4-二异氰酸酯并且HMDI是1，6-己二异氰酸酯；FeCl3是氯化铁，DABCO是三亚乙基二胺，并且SnOct2是辛酸亚锡。
聚合物是使用在专利出版物WO2004029125中的聚合方法制备的。在加入二异氰酸酯之前，在旋转蒸发器中，将PEG与二醇和催化剂一起在95℃熔融并且真空干燥。表1显示了所制备的聚合物。
Figure A200780025441D00101
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)研究聚合时间对所制备的聚合物的影响。对聚合物A进行以聚合时间的函数形式的分子量测定，并且示出在图1中。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P，用DABCO和SnOct2代替氯化铁(表1)；而对于聚合物O，只使用DABCO(表1)。聚合物D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
对于表1中的聚合物C、D、F、H、I、J、K、L、M、O和P，除用HMDI代替DMDI以外，与在实施例1中一样进行聚合。
实施例5.两步聚合方法
将两步聚合方法用于制备表1中的聚合物H。在聚合反应之前，将PEG-催化剂混合物在旋转蒸发器中干燥。首先将二异氰酸酯(HMDI)供给到加热的(95℃)搅拌罐式反应器中，随后添加熔融的PEG-催化剂混合物，该混合物是采用恒定混合(60rpm)在12分钟内添加的。继续进一步反应28分钟，此时将二醇(DDD)供给到该反应器中。将反应混合物进一步搅拌7分钟。此时停止混合，并且将聚合物在95℃进一步固化10小时，之后将其冷却至室温。
实施例6.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)或高温下进行24小时的溶解度测试。所选择的聚合物的溶解度结果示于表2中。
表2.聚合物在所选择的溶剂中和不同温度下的溶解性。
Figure A200780025441D00121
DCM二氯甲烷
HFIP       六氟异丙醇
CHCl3      三氯甲烷
THF        四氢呋喃
DMAC       二甲基乙酰胺
DMSO       二甲基亚砜
NMP        1-甲基-2-吡咯烷酮
LiBr       溴化锂
实施例7.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5-10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：
Figure A200780025441D00122
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％
 
聚合物名称       在水中的溶胀％       在乙醇中的溶胀％         在IPA中的溶胀％        在50％IPA/水中的溶胀％        
聚合物A 81 190 15 300
聚合物E 41 80 18 115
聚合物J 10 - - -
聚合物K 5.6 - - -
聚合物P*3    1.5 - - -
实施例8.肖氏硬度测试
使用硬度计A和D测试所制备的聚合物的肖氏硬度。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.对所制备的聚合物测定的肖氏硬度值
Figure A200780025441D00131
Figure A200780025441D00141
实验条件：
温度            21℃
相对湿度％RH    39
实施例9.通过压模制备的聚合物膜
在加工之前，将从表1中选出的多种聚合物和药物填充聚合物制剂在真空下通宵干燥。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的阴道栓剂装置)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 氟康唑(重量％) 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 - 150 200 180 60 0.4
聚合物B - 160 170 180 30 1.0
聚合物B - 160 200 240 120 1.0
聚合物C - 190 200 180 20 0.4
聚合物C - 200 200 180 60 0.4
聚合物D - 180 200 300 60 0.4
聚合物D - 200 200 180 50 0.4
聚合物E - 165 200 270 60 0.4
聚合物E 20 160 200 270 60 1.0
聚合物E - 170 200 210 60 0.4
聚合物H - 160 170 180 30 1.0
聚合物P - 200 200 180 50 04
实施例10.药物填充-挤出
使用范例(model)药物氟康唑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 30 96-150-150-150-155
聚合物E 氟康唑 20 30 95-135-135-135-135
实施例11.药物释放研究
通过基于USP搅拌桨方法的溶解方法研究由挤出填充的聚合物释放的氟康唑的量。该技术包括自动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 UV500分光光度计上。系统使用Dsolve软件进行操作。
实验条件：
温度      37℃
溶解介质  500ml的脱气去离子水
将挤出填充的聚合物与扩散填充的交联和线型高溶胀性聚合物的体外药物释放性能进行比较，参见图2。将挤出填充的聚合物A和E与来自专利WO2004029125的另一种挤出填充的线型高溶胀性聚合物(高溶胀％、20重量％的氟康唑)绘图。在下图中也示出了来自专利EP0016652/EP0016654的扩散填充的交联聚合物(交联、17重量％的氟康唑)以及来自专利WO2004029125的另一种线型扩散填充的高溶胀性聚合物(高溶胀％、17重量％的氟康唑)。

Claims (16)

1.一种水溶胀性线型聚合物，所述水溶胀性线型聚合物是可通过将下列化合物一起反应而得到的：
(a)数均分子量小于4000的聚环氧乙烷；
(b)脂族二醇；和
(c)双官能异氰酸酯。
2.根据权利要求1所述的线型聚合物，其中所述聚环氧乙烷是当量为200至4000g/mol的二醇。
3.根据任一项权利要求所述的线型聚合物，其中所述脂族二醇为C5至C20二醇。
4.根据权利要求3所述的线型聚合物，其中所述脂族二醇为C8至C15二醇。
5.根据权利要求4所述的线型聚合物，其中所述脂族二醇是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。
6.根据任一项前述权利要求所述的线型聚合物，其中所述双官能异氰酸酯是二环己基甲烷-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。
7.根据任一项前述权利要求所述的线型聚合物，其中以当量计，组分(a)：(b)：(c)的比率在0.01-1：1：1.01-1.1的范围内。
8.根据任一项前述权利要求所述的线型聚合物，其中亲水性PEG单元的量小于所述聚合物的50重量％。
9.根据任一项前述权利要求所述的线型聚合物，其中疏水性二醇的量超过所述聚合物的20重量％。
10.根据任一项前述权利要求所述的线型聚合物，其中所述二异氰酸酯的量为所述聚合物的20-50重量％。
11.一种制备根据任一项前述权利要求所述的水溶胀性线型聚合物的方法，所述方法包括：在真空下、于85℃至100℃的温度，将聚环氧乙烷与所述脂族二醇一起进行熔融并且干燥；然后加入所述双官能异氰酸酯。
12.一种可控释放组合物，所述可控释放组合物包含权利要求1至10中任一项所述的线型聚合物以及活性试剂。
13.根据权利要求12所述的组合物，所述组合物被加工成固体剂型。
14.根据权利要求13所述的组合物，其中所述剂型为栓剂、阴道环或阴道栓剂；口腔插入物或透皮贴剂。
15.根据权利要求13所述的组合物，其中所述剂型为植入物。
16.根据权利要求12至15中任一项所述的组合物，其中所述活性试剂是分子量在200至20,000的范围内的药物活性试剂。
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