Department of Mechanical Engineering and Materials Science, Yale University, New Haven, CT 06520-8286, USA.
J Control Release. 2011 Sep 5;154(2):203-10. doi: 10.1016/j.jconrel.2011.05.018. Epub 2011 May 26.
While conventional methods for biodegradable particle production rely predominately on batch, emulsion preparation methods, an alternative process based on multiplexed electrospray (ES) can offer distinct advantages. These include enhanced encapsulation efficiency of hydrophilic and hydrophobic agents, scale-up potential, tight control over particle size and excellent particulate reproducibility. Here we developed a well-controlled ES process to synthesize coated biodegradable polymer particles. We demonstrate this process with the Poly(DL-lactic-co-glycolic acid) system encapsulating amphiphilic agents such as doxorubicin (DOX), Rhodamine B (RHO(B)) and Rhodamine B octadecyl ester perchlorate (RHO(BOEP)). We show that in a single-step flow process particles can be made encapsulating the agent with high efficiency and coated either with emulsifiers that stabilize them in solution or that may facilitate further functionalization for targeted drug delivery. The coating process allows for the surface modification of the particles without further changes in particle size or morphology, and with minimal loss of drug (>94% encapsulation efficiency). This synthesis technique is well suited for massive scale-up using microfabricated, multiplexed arrays consisting of multiple electrospray nozzles operating in parallel. A simple analytical model of the diffusion of the encapsulated agent within the polymer reveals two distinct phases in the cumulative release profile: a first phase in which the release is dominated by diffusion and a second phase with a slower release related to the erosion of the polymer matrix. The first, diffusion-driven stage is highly affected by particle agglomeration properties, whereas the second one shows a much less pronounced dependence on particle size. Modeling suggests that the size of the particles will substantially influence the initial burst in both the percentage of drug released and the rate at which it is released. It will also affect to a smaller extent the secondary slow and sustained release. Our study highlights the importance of tight control over particle size and morphology and the avoidance of particle aggregation for control over the release kinetics and formulation repeatability.
虽然传统的可生物降解颗粒生产方法主要依赖于批量和乳液制备方法，但基于复用电喷雾（ES）的替代工艺具有明显的优势。这些优势包括提高亲水性和疏水性试剂的包封效率、扩大规模的潜力、对粒径的紧密控制以及出色的颗粒重现性。在这里，我们开发了一种可控制的 ES 工艺来合成包封的可生物降解聚合物颗粒。我们使用聚（DL-丙交酯-共-乙交酯）系统来演示此过程，该系统可以包封阿霉素（DOX）、罗丹明 B（RHO（B））和罗丹明 B 十八烷基酯高氯酸盐（RHO（BOEP））等两亲性试剂。我们表明，在单步流过程中，可以以高效率制备封装有试剂的颗粒，并且可以用乳化剂进行涂层，该乳化剂可以稳定它们在溶液中，或者可以促进进一步的功能化以进行靶向药物输送。该涂层工艺可以在不改变颗粒尺寸或形态的情况下对颗粒进行表面改性，并且药物损失最小（>94%的包封效率）。这种合成技术非常适合使用由多个平行运行的电喷雾喷嘴组成的微制造、复用阵列进行大规模扩大。被包封的试剂在聚合物内扩散的简单分析模型揭示了累积释放曲线中的两个不同阶段：第一个阶段，释放主要由扩散控制；第二个阶段，释放速度较慢，与聚合物基质的侵蚀有关。第一个阶段，扩散驱动阶段受颗粒聚集性质的强烈影响，而第二个阶段则对颗粒尺寸的依赖性较小。模型表明，颗粒尺寸将极大地影响药物释放百分比和释放速度的初始爆发。它还将在较小程度上影响次要的缓慢和持续释放。我们的研究强调了对颗粒尺寸和形态的严格控制以及避免颗粒聚集以控制释放动力学和配方重现性的重要性。
