Purdue University, Weldon School of Biomedical Engineering, West Lafayette, IN 47907, USA.
Purdue University, Weldon School of Biomedical Engineering, West Lafayette, IN 47907, USA; Chong Kun Dang Research (CKD) Institute, Gyeonggi-do 16995, South Korea.
J Control Release. 2020 Sep 10;325:347-358. doi: 10.1016/j.jconrel.2020.06.023. Epub 2020 Jul 7.
Injectable, long-acting drug delivery systems provide effective drug concentrations in the blood for up to 6 months. Naltrexone-loaded poly(lactide-co-glycolide) (PLGA) microparticles were prepared using an in-line homogenization method. It allows the transition from a laboratory scale to scale-up production. This research was designed to understand how the processing parameters affect the properties of the microparticles, such as microparticle size distributions, surface and internal morphologies, drug loadings, and drug release kinetics, and thus, to control them. The in-line homogenization system was used at high flow rates for the oil- and water-phases, e.g., 100 mL/min and 400 mL/min, respectively, to continuously generate microparticles. A high molecular weight (148 kDa) PLGA at various concentrations was used to generate oil-phases with a range of viscosities and also to compare with a 64 and 79 kDa at a single, high concentration. The uniformity of the microparticles was found to be related to the viscosity of the oil-phase. As the viscosity of the oil-phase increased from 52.6 mPa∙s to 4046 mPa∙s, the span value (a measure of uniformity) increased from 1.24 to 3.1 for the microparticles generated at the homogenization speed of 2000 RPM. Increasing the PLGA concentration from 5.58% to 16.85% showed a corresponding rise in the encapsulation efficiency from 74.0% to 85.8% and drug loading (DL) from 27.4% to 31.7% for the microparticles made with the homogenization speed of 2000 RPM. These increases may be due to a faster shell formulation, enabling PLGA microparticles to entrap more naltrexone into the structure. A higher DL, however, shortened the drug release duration from 56 to 42 days. The changes in morphology of the microparticles during different phases of the in vitro release study were also studied for three types of microparticles made with different PLGA concentrations and molecular weights. As PLGA microparticles went through structural changes, the surface showed raisin-like wrinkled morphologies within the first 10 days. Then, the microparticles swelled to form smooth surfaces. The in-line approach produced PLGA microparticles with a highly reproducible size distribution, DL, and naltrexone release rate.
可注射、长效药物输送系统可在血液中提供长达 6 个月的有效药物浓度。载有纳曲酮的聚（乳酸-共-乙醇酸）（PLGA）微球采用在线匀化法制备。它允许从实验室规模过渡到放大生产。本研究旨在了解加工参数如何影响微球的性质，例如微球粒径分布、表面和内部形态、载药量和药物释放动力学，从而控制这些性质。在线匀化系统用于高流速的油相和水相，例如，分别为 100 毫升/分钟和 400 毫升/分钟，以连续生成微球。使用各种浓度的高分子量（148 kDa）PLGA 生成具有不同粘度范围的油相，并与单一、高浓度的 64 和 79 kDa 进行比较。发现微球的均匀性与油相的粘度有关。随着油相粘度从 52.6 mPa·s 增加到 4046 mPa·s，在匀化速度为 2000 RPM 下生成的微球的跨度值（衡量均匀性的指标）从 1.24 增加到 3.1。将 PLGA 浓度从 5.58%增加到 16.85%，在匀化速度为 2000 RPM 下生成的微球的包封效率从 74.0%增加到 85.8%，载药量（DL）从 27.4%增加到 31.7%。这些增加可能是由于更快的壳形成，使 PLGA 微球能够将更多的纳曲酮包裹到结构中。然而，更高的 DL 缩短了药物释放时间，从 56 天缩短到 42 天。还研究了不同 PLGA 浓度和分子量的三种微球在体外释放研究的不同阶段的微球形态变化。随着 PLGA 微球经历结构变化，表面在最初的 10 天内呈现出葡萄干状的褶皱形态。然后，微球膨胀形成光滑的表面。在线方法生产的 PLGA 微球具有高度可重现的粒径分布、DL 和纳曲酮释放率。
