Babasola Iyabo Oladunni, Zhang Wei, Amsden Brian G
Department of Chemical Engineering, Queen's University, Kingston, ON, Canada.
Eur J Pharm Biopharm. 2013 Nov;85(3 Pt A):765-72. doi: 10.1016/j.ejpb.2013.04.009. Epub 2013 May 9.
In this study, the potential of low molecular weight, viscous liquid polymers based on 5-ethylene ketal ε-caprolactone for localized delivery of proteins via an osmotic pressure release mechanism was investigated. Furthermore, the osmotic release mechanism from viscous liquid polymers was elucidated. 5-Ethylene ketal ε-caprolactone was homopolymerized or copolymerized with D,L-lactide (DLLA) by ring-opening polymerization. Polymer hydrophobicity was adjusted by choice of initiator; hydrophobic polymers were prepared by initiating with octan-1-ol, while more hydrophilic polymers were prepared by initiating with 350 g/mol methoxy poly(ethylene glycol) (PEG). Particles consisting of bovine serum albumin (BSA) as a model protein drug were co-lyophilized with trehalose at 50:50 and 10:90 (w/w) ratios and were mixed into the polymers at 1% and/or 5% (w/w) particle loading. The release and mechanism of release of BSA from the polymers were assessed in vitro. BSA was released in a sustained manner, with a near zero-order release profile and with minimal burst effect for 5-80 days depending on the polymer's hydrophilicity; the release was faster from the PEG initiated polymers than from the octan-1-ol initiated polymers. Increasing the particle loading from 1% to 5% (w/w) resulted in a more noticeable burst effect, but did not significantly increase the mass fraction release rate. This release behavior was determined to proceed as follows. Release from the polymer was triggered by the water activity gradient between the surrounding aqueous medium and the saturated solution, which forms when water is absorbed from the surrounding medium to dissolve a given particle. The generated pressure initiates swelling around the particle/polymer interface and creates a superhydrated polymer region through which the solute is transported by convection, at a rate determined by the osmotic pressure generated.
在本研究中，对基于5-乙烯缩酮ε-己内酯的低分子量粘性液体聚合物通过渗透压释放机制实现蛋白质局部递送的潜力进行了研究。此外，还阐明了粘性液体聚合物的渗透释放机制。5-乙烯缩酮ε-己内酯通过开环聚合进行均聚或与D,L-丙交酯（DLLA）共聚。通过选择引发剂来调节聚合物的疏水性；用1-辛醇引发制备疏水性聚合物，而用350 g/mol甲氧基聚（乙二醇）（PEG）引发制备亲水性更强的聚合物。以牛血清白蛋白（BSA）作为模型蛋白药物的颗粒与海藻糖按50:50和10:90（w/w）的比例共冻干，并以1%和/或5%（w/w）的颗粒载量混入聚合物中。在体外评估了BSA从聚合物中的释放及释放机制。BSA以持续方式释放，具有接近零级的释放曲线，且根据聚合物的亲水性，在5 - 80天内具有最小的突释效应；PEG引发的聚合物比1-辛醇引发的聚合物释放速度更快。将颗粒载量从1%增加到5%（w/w）会导致更明显的突释效应，但并未显著提高质量分数释放速率。这种释放行为被确定如下进行。聚合物的释放是由周围水性介质与饱和溶液之间的水活度梯度触发的，当水从周围介质被吸收以溶解给定颗粒时会形成饱和溶液。产生的压力引发颗粒/聚合物界面周围的溶胀，并形成一个超水合聚合物区域，溶质通过对流以由产生的渗透压决定的速率在该区域中传输。
