Al-Tikriti Yassir, Hansson Per
Department of Pharmacy, Uppsala University, Box 580, 751 23 Uppsala, Sweden.
J Phys Chem B. 2020 Mar 19;124(11):2289-2304. doi: 10.1021/acs.jpcb.0c00030. Epub 2020 Mar 10.
We investigated the loading of an amphiphilic drug, amitriptyline hydrochloride (AMT), onto sodium polyacrylate hydrogels at low ionic strength and its release at high ionic strength. The purpose was to show how the self-assembling properties of the drug and the swelling of the gel network influenced the loading/release mechanisms and kinetics, important for the development of improved controlled-release systems for parenteral administration of amphiphilic drugs. Equilibrium studies showed that single microgels (∼100 μm) in a large solution volume underwent a discrete transition between swollen and dense states at a critical drug concentration in the solution. For single macrogels in a small solution volume, the transition progressed gradually with increasing amount of added drug, with swollen and dense phases coexisting in the same gel; in a suspension of microgels, swollen and collapsed particles coexisted. Time-resolved micropipette-assisted microscopy studies showed that drug self-assemblies accumulated in a dense shell enclosing the swollen core during loading and that a dense core was surrounded by a swollen shell during release. The time evolution of the radius of single microgels was determined as functions of liquid flow rate, network size, and AMT concentration in the solution. Mass transport of AMT in the surrounding liquid, and in the dense shell, influenced the deswelling rate during loading. Mass transport in the swollen shell controlled the swelling rate during release. A steady-state kinetic model taking into account drug self-assembly, core-shell phase separation, and microgel volume changes was developed and found to be in semiquantitative agreement with the experimental loading and release data.
我们研究了在低离子强度下将两亲性药物盐酸阿米替林（AMT）负载到聚丙烯酸钠水凝胶上以及在高离子强度下其释放情况。目的是展示药物的自组装特性和凝胶网络的溶胀如何影响负载/释放机制及动力学，这对于开发改进的两亲性药物肠胃外给药控释系统很重要。平衡研究表明，在大溶液体积中的单个微凝胶（约100μm）在溶液中的临界药物浓度下会在溶胀态和致密态之间发生离散转变。对于小溶液体积中的单个大凝胶，随着添加药物量的增加，转变逐渐进行，同一凝胶中溶胀相和致密相共存；在微凝胶悬浮液中，溶胀和塌陷的颗粒共存。时间分辨微量移液器辅助显微镜研究表明，在负载过程中药物自组装体聚集在包围溶胀核心的致密壳层中，而在释放过程中致密核心被溶胀壳层包围。确定了单个微凝胶半径随液体流速、网络尺寸和溶液中AMT浓度的时间演变。AMT在周围液体和致密壳层中的质量传输影响了负载过程中的消肿速率。溶胀壳层中的质量传输控制了释放过程中的溶胀速率。开发了一个考虑药物自组装、核壳相分离和微凝胶体积变化的稳态动力学模型，发现该模型与实验负载和释放数据半定量一致。
