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CN1395491A - 作为生产生物复合材料的生物可降解基质的聚合物混合物 - Google Patents

作为生产生物复合材料的生物可降解基质的聚合物混合物 Download PDF

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CN1395491A
CN1395491A CN01803617A CN01803617A CN1395491A CN 1395491 A CN1395491 A CN 1395491A CN 01803617 A CN01803617 A CN 01803617A CN 01803617 A CN01803617 A CN 01803617A CN 1395491 A CN1395491 A CN 1395491A
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construction
pea
phage
polymer
wound
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CN1230206C (zh
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R·卡特萨瓦
Z·阿拉维茨
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Semodikesi Limited by Share Ltd
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Intralytix Inc
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Abstract

本发明提供用于控制生物活性材料的释放的可生物侵蚀构建物。在较佳方式中，该构建物可在接近生物表面的位置使用。该构建物以两种或多种聚(酯－酰胺)聚合物(PEA)为基础。使二元醇(D)、二元羧酸(C)和α－氨基酸(A)通过酯和酰胺键进行聚合，形成(DACA)n形式的这些聚合物。(DACA)n聚合物的一个例子由文中的式II表示。合适的氨基酸包括所有天然的或合成的α－氨基酸，优选中性氨基酸。

Description

作为生产生物复合材料的生物可 降解基质的聚合物混合物
                         发明背景
发明领域
本发明涉及用于控制生物学活性物质如杀死能引起疾病的细菌的治疗性噬菌体的释放的聚合基质。
相关领域的综述
引入杀菌物质的以生物可降解(或更确切地说是可生物侵蚀)聚合物为基质的生物活性复合材料可治疗表面受感染的伤口。一方面，杀菌物质除去伤口的细菌，给伤口愈合创造良好的条件，并防止细菌通过伤口覆盖物上用于分泌液排出的孔入侵；另一方面，能及时释放足够的降解产物(聚合碎片)的生物可降解聚合物可激活巨噬细胞，使其生产所需的生长因子，由此可加速伤口的愈合〔Pratt等人，1994，“二甲基二茂铁诱导的合成的生物可吸收聚酯的表面化学降解”，J.Polym.Sci.Part.，4：Polym.Chem.，32(5)：949；Greisler(1988)，“小直径脉管修补术：巨噬细胞-生物材料与生物可吸收的脉管修补物的相互作用”，Transactions ofASAIO，34：1051〕。
Mori等人在美国专利第3867520号中公开了一种治疗剂传递体系，该体系使用由聚氨基酸聚合物制成的膜，在膜中分散着油样或蜡样物质。治疗剂被溶解在载体中，当在内部或外部体表使用该膜时，该载体转移到该膜的表面，在那里制剂被释放。但是，这些膜在使用时不是生物可降解的。
Sidman在美国专利第4351337中公开了一种可移植的传递装置，它含有由聚α氨基酸成分形成的具有一种或多种药物和/或诊断用药自然地包含于其中的基质。该药物或诊断用药在移植了该移植物的宿主体内的酶对该聚合基质的作用下，通过扩散和/或生物降解而被释放。
Taniharal等人在美国专利第5770229号中公开了一种由交联多糖与药物制成的药学聚合物凝胶，该药物通过一种可被内源酶解离的连接与该多糖连接。这个体系中连接的药物以缓释形式从该聚合物上释放出来，但是其释放速率依个体内源酶的量的不同而有差异，而且，该聚合物虽然是生物可相容的，但它是生物不可降解的。
Kuroyangi及其合作者(1992，J.Appl.Biomater.，3：153-161)已开发了一种用于烧伤护理的伤口敷料，它是一种由细尼龙网丝支持的加了抗细菌药物烧伤宁的疏水的聚L-亮氨酸海绵状基质。这种伤口敷料抑制了细菌的生长，同时控制了流体的损失。但是，该敷料不可降解，它仍旧粘在伤口上，直到它自然地从愈合的皮肤上脱落。
格鲁吉亚专利第1090号描述了一种伤口敷料，它含有45-50wt.％的以天然α-氨基酸为基础的生物可降解聚(酯-酰胺)和50-55wt.％的干燥的噬菌体。该文中并没有详细描述该聚(酯-酰胺)的特征，但是，该敷料还含有0.05-0.15wt.％的表面固定不动的α-胰凝乳蛋白酶。加入的该聚(酯-酰胺)形成膜，该膜加速了表面伤口(包括烧伤)的愈合。
Tsitlanadze在Int.Symp.Biodegrad.Mater(October 7-9，1996，Hamburg，德国)的摘要中描述了通式I的规整聚(酯-酰胺)(PEA)的α-胰凝乳蛋白酶催化的水解：式中，k＝2、3、4或6
m＝4或8，和
R＝CH(CH3)2、CH2CH(CH3)2、CH(CH3)CH2CH3、(CH2)3CH3、CH2C6H5或(CH2)3SCH3。
据报道，α-胰凝乳蛋白酶被自然地固定在水溶液中的PEA的表面上，在生理条件下侵蚀该聚合物的表面，增加溶解了更多的疏水R基和疏水聚合物骨架。制备了以PEA聚合物为基础、含有噬菌体、抗生素或麻醉剂的生物复合材料，将其作为人造皮肤，用于研究烧伤和溃烂伤口的愈合。
                           发明内容
本发明提供用于控制生物活性材料的释放的可生物侵蚀构建物。在一个较佳方式中，该构建物可用在接近生物表面的地方。该构建物以两种或多种聚(酯-酰胺)聚合物(PEA)的混合物为基础。可由二元醇(D)、二元羧酸(C)和α-氨基酸(A)通过酯与酰胺键发生聚合，形成(DACA)n形式的这些聚合物。(DACA)n的一个例子显示在下面的式II中。合适的氨基酸包括所有天然或合成的α-氨基酸，较佳是中性氨基酸。
二元醇可以是所有的脂肪族二元醇，包括亚烷基二元醇如HO-(CH2)k-OH(即无支链)、支链二元醇(如丙二醇)、环状二元醇(如双无水己糖和环己二醇)或乙二醇基低聚二醇〔如二乙二醇、三乙二醇、四乙二醇或聚(乙二醇)〕。芳族二元醇(如双酚类)较少用于此目的，因为它们更具有毒性，并且以它们为基础的聚合物具有较少生物降解可能性的刚性链。
二羧酸可以是任何脂肪族二羧酸，如α，ω-二羧酸(即无支链)、支链二羧酸、环状二羧酸(如环己二羧酸)。芳族二元酸(如邻苯二甲酸等)较少用于此目的，因为它们更具有毒性，并且以它们为基础形成的聚合物具有刚性链结构、膜形成特性较差并具有较低的生物降解倾向。。
较佳的PEA聚合物具有下式II结构：
Figure A0180361700061
式中，k＝2-12，优选2、3、4或6，
m＝2-12，优选4或8，
R＝CH(CH3)2、CH2CH(CH3)2、CH(CH3)CH2CH3、(CH2)3CH3、CH2C6H5或(CH2)3SCH3。
该构建物可任意地含有生物活性内含物，这些内含物在该构建物降解(生物侵蚀)后释放。
在一个较佳实施例中，本发明提供生物可降解构建物，它们含有A是L-苯丙氨酸的第一PEA聚合物(Phe-PEA)和A是L-亮氨酸的第二PEA聚合物(Leu-PEA)。较佳的是，Phe-PEA与Leu-PEA的比例是10∶1到1∶1，更佳是5∶1到2.5∶1。可将该构建物制成可变形的片状，以使其与生物表面相适应。
在另一实施例中，本发明提供了含有PEA聚合物且还含有生物活性制剂的可生物侵蚀构建物，生物活性制剂可选自防腐剂、抗感染剂(如噬菌体、抗生素、抗细菌剂、抗原虫剂和抗病毒剂)、止痛剂、消炎药(包括类固醇和非类固醇类消炎药，包括COX-2抑制剂)、抗肿瘤制剂、避孕药、CNS活性药物、激素和疫苗。
在又一实施例中，本发明的可生物侵蚀构建物含有能水解解离该PEA聚合物的酶，如α-胰凝乳蛋白酶。在一个较佳实施方式中，该酶被吸附在该构建物的表面上。在一个特别优选的实施方式中，该构建物含有通过酶的作用而释放的噬菌体。
本发明还提供一种治疗具有溃烂伤口的患者的方法，它包括将权利要求1的可生物侵蚀构建物插入该伤口中，或者包扎该伤口，其中，该可生物侵蚀构建物含有生物活性制剂，这种制剂可以是噬菌体、抗生素、防腐剂或止痛剂。用本发明构建物处理的伤口可以是敞开的或受感染的，该构建物可以成可变形片状的形式。在一个较佳实施方式中，用于治疗伤口的该构建物含有对在该伤口中发现的细菌具有特异性的噬菌体。该构建物还可含有能水解解离该PEA聚合物的酶。
目前还没有获得完全由天然的和无毒性且具有高可塑性(如当水合时具有柔韧性)与高的酶催化生物降解速率、在普通溶剂如氯仿中溶解、并适合加入或自然地固定(吸附)在酶如胰蛋白酶、α-胰凝乳蛋白酶和脂酶的表面上的构件制成的生物可降解的聚合物或聚合物混合物。本发明的聚合物混合物具有上述所有特性，使得它们可用作具有塑性、并起到以持续/受控的方式释放生物活性物质的伤口敷料/愈合装置的基质。
                      附图的简短描述
图中显示长达6个月以上时间脂酶体内催化的聚合物的生物降解。
                      实施例的详细描述
噬菌体裂解物治疗发炎或感染的化脓病灶所需的药物的量大，且需频繁使用(每天3-5次)，这样就增加了噬菌体制品和该伤口敷料的消耗。从这一角度看，应用噬菌体储存器提供受控释放与长时间作用的药物是优良的。
生物可吸收的(或可生物侵蚀的)聚合物是制备噬菌体和/或其它生物活性化合物的储存器最适当的基质。以可生物侵蚀的聚合物为基础的生物活性复合材料，在控制药物的释放以给周围组织提供所需浓度的生物活性物质方面是已知的。由于由可生物侵蚀聚合物制成的复合材料中的物质被周围生物环境所降解或溶解，所以该复合材料会随着时间而逐渐消失。催化聚合物中的共价键的酶可促进这种降解。(这些酶可存在于生物环境中，或者由外源加入，可以成该构建物的一部分或者其它形式)。生物学活性物质从可生物侵蚀构建物中的受控释放或持续释放是指该物质迁延从它注入的地方简单地扩散到生物体环境中。受控释放一般是由于一些干扰该物质的正常扩散的因素所造成，如该扩散物质的扩散障碍或有限的溶解度而使释放受到控制。本发明的可生物侵蚀构建物便是提供随着该聚合物的降解而逐步被除去的扩散障碍。
最近，人们还已发展了聚合物降解产物以足够的量快速释放到周围组织中，以激活噬菌体生产加速伤口愈合的生长因子的技术。聚合物降解产物是正常的代谢组分或易于被细胞消化的组分是有益的。用作基质的聚合物应具有足够的弹性，以紧紧地覆盖伤口。还非常需要的是，该聚合物基质能通过简单的方法使酶(如胰蛋白酶、α-胰凝乳蛋白酶、脂酶等)固定在表面上，或者将酶加到大块的基质中。这些酶可参与伤口愈合过程，还可以恒定的和所需的速率侵蚀聚合物(如催化聚合物骨架中酯键的水解)，使杀菌化合物以及足量的基质降解纤维释放到周围组织中，以刺激巨噬细胞。
本发明者已合成了新的生物可降解聚(酯-酰胺)(PEA)，它由天然的α-氨基酸(包括必需氨基酸如L-苯丙氨酸和L-亮氨酸)和无毒性的化合物(如脂肪族和二元羧酸)制成。Arabuli等人(1994)在“以天然氨基酸为基础的杂链聚合物，以二-(L-苯丙氨酸)α，ω-亚烷基二酯和己二酸为基础的规整聚)(酯-酰胺)的合成和酶水解”〔Macromol.Chem.Phys.，195(6)：2279〕和Katsarava等人(1999)在“氨基酸基生物类似物聚合物，以二-(α-氨基酸)α，ω-亚烷基二酯和脂肪族二元羧酸为基础的规整聚(酯-酰胺)的合成和研究”〔J.Polym.Sci.Part A：Chemistry，37：391-407〕中报道了合适的合成方法，本文纳入这两篇文献的全部内容作为参考。可用这些快速地可生物侵蚀、生物相容的聚(酯-酰胺)形成可生物侵蚀的聚合物基质。
本发明的聚(酯-酰胺)不含有任何毒性成分。α-氨基酸如必需氨基酸L-苯丙氨酸和L-亮氨酸都是天然产物。这些正常的代谢组分在通过生物降解释放后被细胞消化。脂肪酸和二元醇是已知的常在食品工业中使用的无毒性产品。它们还被用作其它类生物可降解聚合物如被美国食品和药物管理局(FDA)批准用于临床实验和其它实际用途的聚酐和聚-(原酸酯)的构件。
非常重要的是，本发明使用的聚(酯-酰胺)可溶解在不使生物活性物质如噬菌体灭活的有机溶剂中。这些聚合物在氯仿中是可溶的，在此溶剂中，酶如胰蛋白酶、α-胰凝乳蛋白酶、脂酶的活性能保持足够稳定，以在制备含有酶的聚合物构建物过程中能生存。
可将酶加到聚合物的氯仿溶液中，以在将该溶液浇洒在玻璃板上和使该溶剂蒸发时形成含有酶的聚合物基质。对于根据本发明加了酶的聚合物膜，这些酶可催化PEA的水解(侵蚀)，这对于生物活性物质释放到周围组织中是重要的。PEA的生物降解速率可在一个宽的范围内变化，如跨越101-103mg/cm2·h。该降解速率是该复合材料中酶的活性的函数。可将这些聚合物设计成随着时间释放足量的基质降解产物(聚合物碎片)，以激活巨噬细胞。
可通过将该聚合物膜浸入酶的水溶液中不同的时间，使酶自发地固定到以L-苯丙氨酸为基础的PEA表面上。(如一般浸入15-20分钟)。以L-亮氨酸为基础的PEA采用这种简单的方法不能容易地吸附酶，因而，以L-苯丙氨酸为基础的PEA更适合用来制备具有固定于表面的酶的生物可降解基质。但是，以L-苯丙氨酸为基础的PEA在用作伤口敷料时不具备足够的弹性。由L-亮氨酸组成的PEA在水合时(即水作为增塑剂)具有可塑性，更适合用于生物学应用如伤口覆盖物(敷料)；但是，由L-亮氨酸PEA制得的膜非常粘，沾上它们时将不方便操作。此外，L-亮氨酸基的PEA对酶的固定很差。
本发明者已发现，将各类PEA混合起来可克服它们固有的不利特征。由大约70％的L-苯丙氨酸基PEA和30％的L-亮氨酸基PEA制得的聚合物混合物具有如下特性：
·良好的可塑性(紧紧覆盖伤口所需)
·没有自我粘结
·能固定酶
如本发明所考虑的，本发明的基础即聚合物混合物具有足够的可塑性，使得由其制得的膜可被人工操作而变形，从而可紧紧与不规则的生物表面(如凹的伤口表面)相吻合。此外，稍微使点力就可容易地将由此聚合物混合物制得的膜分离下来，使各片膜在分离后保持完整。最后，由本发明的聚合物混合物制得的物件的表面将吸附蛋白质，这样可被检测到的可测量酶活性的酶在该物件浸渍到该酶溶液中后粘附到该物件的表面上。
本发明提供了含有至少两种式II的PEA的聚合物混合物。较佳的是，该混合物含有一种其R对应于苯丙氨酸的侧链的PEA(Phe-PEA)和一种其R对应于亮氨酸的侧链的PEA(Leu-PEA)。Phe-PEA和Leu-PEA的比为10∶1到1∶1，但较佳为5∶1到2.5∶1。该混合物可含有其他PEA(事实上是其它聚合物)，只要所得的混合物仍具有上述所需的特性。该混合物中的其它聚合物当然也能溶解于该混合物分散于其中以制备本发明构建物的溶剂中。Leu-PEA和Phe-PEA都能溶解于极性溶剂或者中性溶剂中，前者包括二甲基甲酰胺(DMF)、二甲基乙酰胺、二甲基亚砜(DMSO)、三氟乙醇、六氟异丙醇等，后者包括氯仿等。较佳使用氯仿和类似的溶剂制备含有生物活性组分的可生物侵蚀膜，因为他们的挥发性较大(这对膜的制备是重要的)以及对酶(如胰凝乳蛋白酶或脂酶)、噬菌体或其它生物活性组分的灭活作用减小。
在一个较佳方式中，本发明的聚合物混合物被制成可生物侵蚀膜。本发明的膜可以是单层或多层，如具有一PEA混合物层和一邻近的聚(硅氧烷合成橡胶)层的双层膜。但是，使用该聚合物混合物的其它可生物侵蚀的构建物易于被本领域的熟练技术人员所理解，并且在本发明的考虑之内。例如，可将聚合物混合物施加到可被生物降解或者不可被生物降解的支持材料如纤维或非纤维三维构建物或编织支持物上，形成可生物侵蚀的包衣。本发明该三维构建物的合适形式是泡沫，这种泡沫可采用常规的方法形成。例如，可如下将Phe-PEA/Leu-PEA混合物制成泡沫：将噬菌体和其它生物活性物质(约1g)在Phe-PEA/Leu-PEA(1g)的氯仿(10mL)中的悬浮液涂布到疏水性表面上，然后是90-99％的氯仿在室温下在大气压中蒸发掉。之后可在室温下使用减压将剩余的氯仿除去，然后在减压条件下干燥所得的泡沫膜12小时。根据另一方法，可将(占氯仿体积的)1-10％的正戊烷加到上述悬浮液中。将该混合物涂布到疏水性表面上，然后使其在室温下干燥24小时，然后可将该泡沫膜在减压下进行最后的干燥处理12小时。也可使用超声衰变技术获得泡沫膜。
由本发明的聚合物制得的构建物可以是包括被用作如伤口绷带或烧伤敷料的支持材料的装置的一部分。当然，在编织支持物上形成包衣的混合物较佳保留了用于膜形成的混合物的柔韧性和/或弹性，但用于将刚性、三维构建物包衣的混合物的弹性可少些。这种混合无可具有较高含量的Phe-PEA，用于这些用途的其PEA聚合物仅有Phe-PEA的包衣也在本发明的考虑之中。
在另一方式中，本发明考虑到了由本发明全部或部分混合物组成的可用于外科移植的构建物。本发明的构建物也可制成用于伤口包扎的装置(如凝胶泡沫)，或者用作外科器械中的组件，如Penrose引流管、留置导管、腹膜透析用导管和任何其它与体腔、血液循环或淋巴循环接触的器械，并且，本发明的构建物也可用于预防潜在的传染或被感染的风险。本发明还考虑到用于口腔卫生的器械，包括齿龈移植物(如牙齿周围的疾病或齿龋)。这些构建物较佳含有在其被侵蚀后以受控的方式释放的生物活性材料。从想注入的位置考虑，具体的生物活性内含物的合适选择对本领域的熟练的技术人员将是显而易见的。例如，可将含有杀菌剂如噬菌体的复合材料注入体内，以治疗ostcomyclitis等。或者，可将本发明的可生物侵蚀的复合材料加到目标位置，用作持续/受控释放的抗癌和/或其他药物。通过从该构建物中的扩散、或者通过该构建物的降解、或通过这些方法的组合使用，使生物活性材料以受控释放的方式释放出来。
生物活性和/或非活性生物相容材料可以最多60重量％或以上的量存在与该可侵蚀的构建物中，只要他们的加入没有破坏本发明的膜的所需的特性即可。考虑加到本发明构建物中的生物活性材料包括但不限于防腐剂、抗感染剂(如噬菌体、抗生素、抗细菌剂、抗原虫剂和抗病毒剂)、止痛剂、消炎药(包括类固醇和非类固醇类消炎药，包括COX-2抑制剂)、抗肿瘤药物、避孕药、CNS活性药物、激素和疫苗。具体而言，构建物可包括一种或多种葡萄糖酸钙和其它的噬菌体稳定用添加剂、透明质酸酶、纤维蛋白裂解酶、和其它纤维蛋白水解酶、甲基月桂基(methylluracyl)和其它刺激代谢过程的制剂、碳酸氢钠、L-精氨酸和其它血管扩张剂、苯坐卡因和其它止痛药、单糖和二糖、多糖和黏多糖、灭滴灵和其它抗原虫剂、Clotrimazolum和其它抗真菌药物、凝血酶和其它止血剂、维生素、Prednizolone和其它抗炎症类固醇、和Voltaren(环氟拉嗪钠)和其它抗炎症非类固醇类药物。当然，本领域熟练的技术人员将在任何情况下都能确认具体的构建物制剂保留了本文上面所述的所需特性，不具有任何一种这些特性的构建物不在本发明的范围之内。
在一个较佳方式中，本发明提供了一种处理愈合差和伤口血管化差(可能包括的糖尿病患者足部溃疡、活动减少的患者的压力性溃疡和其它溃疡以及敞开的皮肤病区)的方法。在医学中，伤口愈合差的情况(如足部溃疡的糖尿病患者和患有褥疮的卧床不起患者)代表了一种主要的和非常昂贵的治疗问题。在这种情况下使用抗生素一般不凑效。由于血管化差的缘故，抗生素很少能达到在感染区域充分根除感染的治疗水平。而且，由于这些患者常常重复使用抗生素，使得引起感染的细菌病原体常产生抗生素抗性。在此方式以及其它治疗伤口的实施方式中，本发明聚合物构建物的受控释放特征避免了持续重复使用杀菌材料的必要性，以及无需换用其它相关的敷料。
已证明介导适当的治疗剂的持续/受控释放的生物复合材料对使感染伤口和腔愈合尤其有效。由这些生物复合材料制得的称为“人造皮肤”的膜材料具有以下重要的治疗效果：
·当将聚合物材料施加到这些伤口的表面上时，它们起到阻止对外部机械作用和细菌入侵的保护者的作用，它们还防止热和水分的损失，水分从伤口表面不受控制地蒸发常常会产生这样的损失；
·可使用生物学活性化合物的缓释特性来促进抗细菌制剂在感染位置的适当且稳定的释放。
使用生物复合材料“人造皮肤”的患者不需要固定不动，从而有利于患者回到正常的日常生活中，这是这类患者的一个重要的考虑。
治疗长期感染的伤口的一个关键要素是抑制致病细菌菌群。使用生物复合材料，可将杀菌物质加到该生物复合材料结构中，从而实现这种抑制作用。在这种装置中也可使用抗生素，但它们的药效由于抗生素抗性的发展而逐渐受到限制。最近，人们对将杀菌物质如磺胺嘧啶银(和磺胺的相关二嗪衍生物)、furagin(和它的药用盐)和氯己啶(chlorohexydine)(和它的药用盐)加到生物复合材料中感兴趣。但是，这些化合物的使用可能受到它们的固有的毒性所限制，尤其是对于患有潜在的肾或肝疾病的患者。
将噬菌体加到这种生物复合材料中的做法提供了另一方法。噬菌体是杀死特殊的细菌的病毒。在二十世纪初发现了病毒引起的微生物的溶菌作用。任何一种噬菌体都倾向于对某种细菌高度特异，这就要求进行治疗时得仔细确定目标(即，没有可“杀死一切”的广谱抗生素的类似物)。但是，这也意味着可采用噬菌体治疗方法杀死特殊的病原体，而不会干扰正常的细菌菌群。
已报道，噬菌体可有效治疗由假单胞菌属(Pseudomonas)、葡萄球菌属(Staphylococcus)、克雷伯杆菌属(Klebsiella)、变形杆菌属(Proteus)、大肠杆菌和其它致病菌种引起的皮肤传染病；这些研究中获得的成功比例为75-100％，视不同的病菌而定。但是，在这些研究中将噬菌体加到水溶液制品、气溶胶和膏状物等各种载体中。
已成功地使用由L-苯丙氨酸、L-亮氨酸、脂肪酸和1，4-丁二醇组成的聚合物混合物制备含有杀菌物质的生物活性复合材料。以这种生物复合材料为基础的伤口敷料具有高的伤口愈合特性。
可以看出，由上述材料开始制备、以生物可吸收(可生物侵蚀)的聚合物为基础、含有噬菌体的复合物作为杀菌物质的生物活性复合材料将是具有加速伤口愈合能力的有效的敷料。2000年1月11日提交的题为“对抗万古霉素抗性肠球菌(VRE)特异的噬菌体”的美国临时申请第60/175415号和2000年5月19日提交的题为“使用噬菌体的方法和卫生设备”的美国临时申请第60/205240号中描述了合适的噬菌体，本文将这两篇申请的公开内容纳入作为参考。
                            实施例
制备效价为2×106-2×107噬斑形成单位的葡萄球加菌属(Staphylococcus)、链球菌属(Streptococcus)、大肠杆菌、变形杆菌属(Proteus)和绿脓假单胞菌(Pseudomonas aeruginosa)的多价噬菌体混合物，并将其用作此研究的生物活性物质。如下将噬菌体制备成冻干的粉末：将悬浮在蔗糖-明胶混合物水溶液中的噬菌体冻干，得到干燥的块状物，将此块状物研磨成细粉末。在此过程中，50mg干制品对应于1ml液体噬菌体，其效价为2×106-2×107。生物活性复合材料中的任一组分(聚合物、有机溶剂、α-胰凝乳蛋白酶、脂酶)都没有影响噬菌体的活性——在所有的情况中都维持了100％的原始活性。
如下制备生物活性膜：将干噬菌体在含有适当溶剂的聚合物溶液中的精制悬浮液浇洒到玻璃表面上，然后使其干燥至恒重。获得成膜形式的复合材料，它具有下述特征：重1g，膜面积为60-65cm2，厚度为0.2-0.3mm。之后，将α-胰凝乳蛋白酶固定在该膜的表面上。视需要可将该膜打孔。对于具体的应用，也可将止痛剂和/或抗生素加到该复合材料中。
使用固体培养基上的细菌菌落进行体外实验，测定所获得的膜的活性。通过测量溶菌区域的宽度来评价活性。该膜的活性与所使用的干噬菌体的活性相同，纯的聚合物膜没有显示出任何杀菌活性。
在生理条件下，在磷酸盐缓冲液中研究噬菌体从9cm圆盘状膜上释放的动力学(表1)。可以看到，在第一个24小时内，噬菌体从固定了α-胰凝乳蛋白酶的膜和没有固定该酶的膜上的释放是可比的；固定了酶的膜的释放速率仅高1.5-2倍。这可由噬菌体从没有酶的膜的表面区域大量脱附来解释。但是，当这些膜在第24小时和第120小时被转移到新鲜的缓冲液中后，在这两个阶段，酶催化的侵蚀机制对于噬菌体从膜上的释放变得重要，它们的释放速率差异超过一个数量级。这个结果清楚表明，α-胰凝乳蛋白酶促进噬菌体从生物活性复合材料释放。
                                 表    1
        噬菌体和抗生素从含药的伤口敷料膜中的持续释放
噬菌体从直径为9cm的圆盘状Phe-PEA膜上释放到10mL磷酸盐缓冲液(0.2M、pH7.4、T＝37℃)。9cm的圆盘状Phe-PEA/噬菌体膜大约含有1800×104个噬菌体。
    1mL溶液中噬菌体的效价
时间(小时) 具有α-胰凝乳蛋白酶的复合材料噬菌体/Phe-PEA膜 没有固定α-胰凝乳蛋白酶的复合材料噬菌体/Phe-PEA膜
    1     2.0×104     1.3×104
    3     5.0×104     3.0×104
    24     8.0×104     4.0×104
    24小时后，转移到新的10mL缓冲液中后
    1     3.2×104     1.3×104
    3     9.0×104     3.1×104
    96     200.0×104     90.0×104
                  120小时后，转移到新的10mL缓冲液后
时间(小时) 具有α-胰凝乳蛋白酶的复合材料噬菌体/Phe-PEA膜 没有固定α-胰凝乳蛋白酶的复合材料噬菌体/Phe-PEA膜
    1     2.5×104     0.06×104
    4     5.0×104     0.20×104
应注意的是，固定了α-胰凝乳蛋白酶的表面可起到额外的作用，即它可分解肽和变性蛋白质。如可从文献中知道的，这种酶促清创法使伤口变得卫生，并加速了愈合。
用了1.5年的时间定时检测了本发明的膜抗预先存在的实验室用菌株和新接受菌株的活性，结果是该膜在此时期中保持了它的活性。固定了酶的表面在此时期中也是活跃的。附图显示了脂酶在六个月的时间里体内催化聚合物的降解的情况。该体内实验数据归纳在表2中。
                   表2.生物复合材料的体内降解
样品   大鼠数量   每只大鼠使用的膜的数量 持续时间(天) 结  果
4-L-Phe-4 2 2 109 膜被完全吸收，在一例中观察到痕量的结缔组织包囊
4-L-Phe-4 2 2 123 膜被完全吸收，没有观察到痕量的组织反应
4-L-Phe-4 2 2 175 膜被完全吸收，没有观察到痕量的组织反应
4-L-Phe-4-Lip 3 2 39  2只大鼠中的膜被完全吸收，一只大鼠两张膜都形成囊状物
4-L-Phe-4-Lip 1 2 42 膜被完全吸收，没有观察到痕量的组织反应
4-L-Phe-4-Lip 4 4 44 膜被完全吸收，没有观察到痕量的组织反应
   4-L-Phe-4-Lip     1     2     45 两张膜都形成囊状物
4-L-Phe-4-Lip 5 3 77  14张膜被完全吸收，仅有1张膜是形成囊状物
4-L-Phe-4-Lip 2 2 145 膜被完全吸收，没有观察到痕量的组织反应
在这些例子中，发现脂酶被灭活，即它没有催化聚(酯酰胺)的水解。
总计57张膜(每张重20-25mg)经皮下植入大鼠，52张完全被吸收，仅有5张4-L-Phe-4-Lip系列由于酶灭活的缘故形成囊状物。
4-L-Phe-4-PEA基于L-苯丙氨酸、脂肪酸和1，4-丁二醇，4-L-Phe-4-Lip也相同，加了脂酶(每1g PEA加10mg脂酶)。

Claims (17)

1.一种用于控制生物活性材料释放的可生物侵蚀的构建物，它含有两种或多种使二元醇(D)、二元羧酸(C)和α-氨基酸(A)通过酯和酰胺键进行聚合而制得的成(DACA)n形式的聚(酯-酰胺)聚合物(PEA)的混合物，其中，该PEA聚合物具有下式结构：式中，k＝2-12，优选2、3、4或6，
m＝2-12，优选4或8，
R＝CH(CH3)2、CH2CH(CH3)2、CH(CH3)CH2CH3、(CH2)3CH3、CH2C6H5或(CH2)3SCH3。
2.如权利要求1所述的构建物，其特征在于，k＝2、3、4或6，m＝4或8。
3.如权利要求1所述的构建物，其特征在于，所述混合物含有A是L-苯丙氨酸的第一PEA(Phe-PEA)和A是L-亮氨酸的第二PEA(Leu-PEA)。
4.如权利要求3所述的构建物，其特征在于，所述Phe-PEA与Leu-PEA的比例是10∶1到1∶1。
5.如权利要求3所述的构建物，其特征在于，所述Phe-PEA与Leu-PEA的比例是5∶1到2.5∶1。
6.如前述权利要求中任一项所述的构建物，其特征在于，所述构建物是与生物表面适配的可变形的片状物。
7.如前述权利要求中任一项所述的构建物，其特征在于，该构建物还含有生物活性制剂。
8.如权利要求7所述的构建物，其特征在于，该生物活性制剂选自防腐剂；抗感染剂，如噬菌体、抗生素、抗细菌剂、抗原虫剂和抗病毒剂；止痛剂；消炎药，包括类固醇和非类固醇类消炎药，包括COX-2抑制剂；抗肿瘤制剂；避孕药；CNS活性药物；激素和疫苗。
9.如前述权利要求中任一项所述的构建物，其特征在于，所述构建物含有能水解解离该PEA聚合物的酶。
10.如权利要求9所述的构建物，其特征在于，所述酶是α-胰凝乳蛋白酶。
11.如权利要求9所述的构建物，其特征在于，所述酶被吸附在该构建物的表面上。
12.如权利要求9所述的构建物，其特征在于，所述构建物含有会因所述酶的作用而释放的噬菌体。
13.一种治疗具有溃烂伤口的患者的方法，它包括将权利要求1所述的可生物侵蚀的构建物插入该伤口中，或者覆盖该伤口，其中，该可生物侵蚀的构建物是含有生物活性制剂的可变形的片状物。
14.如权利要求13所述的方法，其特征在于，所述生物活性制剂是噬菌体、抗生素、防腐剂或止痛剂。
15.如权利要求13所述的方法，其特征在于，所述伤口是敞开的或受感染的。
16.如权利要求14所述的方法，其特征在于，所述噬菌体对该伤口中发现的细菌具有特异性。
17.如前述权利要求中任一项所述的方法，其特征在于，所述构建物还含有能水解解离该PEA聚合物的酶。
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CN110709112A (zh) * 2017-04-26 2020-01-17 菲吉乐科(加拿大)有限公司 噬菌体的等离子体固定及其应用

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US6699701B1 (en) 2004-03-02
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US7459272B2 (en) 2008-12-02
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