Department of Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, China.
School of Life Science and Bio-Pharmaceutics, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, China.
J Control Release. 2017 Apr 28;252:83-94. doi: 10.1016/j.jconrel.2017.03.003. Epub 2017 Mar 6.
Though acrylic pressure sensitive adhesives (PSAs) are widely used in transdermal drug delivery system, molecular details of drug-PSA interactions, PSA molecular mobility variations and their influences on drug skin permeation are unclear. In this study, three classes of acrylic PSAs containing hydroxyl (AAOH), carboxyl (AACOOH) and non-functional group (AAnone) were synthesized. Their abilities of controlling drug release were evaluated using propranolol (PRO) and zaltoprofen (ZAL) in vitro and in vivo. Interaction details were identified by FT-IR, solid-state NMR and molecular modeling. Thermodynamic activity of drug and strength of drug-PSA interaction were characterized using miscibility study. PSA mobility was characterized using thermal analysis and rheology study. Thus, ionic interaction reduced the thermodynamic activity of PRO and mobility of AACOOH, which made PRO-AACOOH obtain a significant lower bioavailability (11.8±0.7%) than these of PRO-AAnone (40.7±2.5%) and PRO-AAOH (42.3±2.9%). Though thermodynamic activity of ZAL in AACOOH was lower than that in AAOH due to the hydrogen bonding, bioavailability of ZAL-AAOH (19.0±4.1%) exhibited no significant difference with ZAL-AACOOH (15.4±2.8%), mainly because AAOH mobility was decreased by ZAL. In conclusion, the strength, types and involved functional groups of drug-PSA interactions were identified. On this basis, it was found that different control patterns of drug release were not only caused by the thermodynamic or kinetic hindrance effects of drug-PSA interactions, but also influenced by the interactions introduced PSA mobility variations, which was an innovative mechanism of controlled release in transdermal patch. The conclusions extended our understanding about the mechanism of controlled drug release of drug-in-adhesive patch. In addition, they contributed to the design of TDDS and custom acrylic PSAs.
尽管丙烯酸压敏胶（PSA）在经皮给药系统中得到了广泛应用，但药物与 PSA 相互作用的分子细节、PSA 分子迁移率的变化及其对药物皮肤渗透的影响仍不清楚。在本研究中，合成了三类含羟基（AAOH）、羧基（AACOOH）和非功能基团（AAnone）的丙烯酸 PSA。通过体外和体内实验评估了它们控制普罗洛尔（PRO）和佐美洛芬（ZAL）释放的能力。通过傅里叶变换红外光谱（FT-IR）、固态核磁共振（NMR）和分子模拟确定了相互作用的细节。通过混溶性研究表征了药物的热力学活性和药物与 PSA 相互作用的强度。通过热分析和流变学研究表征了 PSA 的迁移率。因此，离子相互作用降低了 PRO 的热力学活性和 AACOOH 的迁移率，使得 PRO-AACOOH 的生物利用度（11.8±0.7%）显著低于 PRO-AAnone（40.7±2.5%）和 PRO-AAOH（42.3±2.9%）。尽管由于氢键的存在，ZAL 在 AACOOH 中的热力学活性低于 AAOH，但 ZAL-AAOH（19.0±4.1%）的生物利用度与 ZAL-AACOOH（15.4±2.8%）没有显著差异，主要是因为 ZAL 降低了 AAOH 的迁移率。总之，确定了药物与 PSA 相互作用的强度、类型和涉及的功能基团。在此基础上，发现不同的药物释放控制模式不仅是由于药物与 PSA 相互作用的热力学或动力学阻碍效应引起的，还受到相互作用引起的 PSA 迁移率变化的影响，这是经皮贴剂控释的一种创新机制。该结论扩展了我们对药物粘附贴剂控释机制的理解。此外，它们有助于 TDDS 和定制丙烯酸 PSA 的设计。
