Department of Pharmaceutical Sciences and Experimental Therapeutics, The University of Iowa, Iowa City, IA, 52242, USA.
The University of Iowa College of Pharmacy, 180 S. Grand Ave, Iowa City, IA, 52242, USA.
Pharm Res. 2022 Oct;39(10):2515-2527. doi: 10.1007/s11095-022-03356-1. Epub 2022 Aug 24.
PURPOSE: Treating chronic wounds is a significant clinical challenge, and a topical product would be ideal for pain management. Poloxamer 407, a thermosensitive polymer, would allow an analgesic drug to be topically applied to a wound as a liquid that transitions to a gel at physiologic temperature. Using diclofenac as a model analgesic drug, our goal was to determine effects of salt form on poloxamer gelation and drug delivery from poloxamer gels applied to excised skin with impaired barrier function. METHODS: Gelation properties of 17% and 20% poloxamer gels loaded with 0.4 to 1.7% diclofenac sodium, potassium, epolamine, or diethylamine were evaluated rheologically. Drug release and delivery were quantified using cellulose membranes, porcine skin, and tape-stripped porcine skin. RESULTS: Poloxamer gelation temperature increased with higher diclofenac concentration, regardless of salt form; the magnitude of increase varied in the following order: sodium>potassium>diethylamine>epolamine. Gelation temperature differences resulting from the various counterions generally matched previously observed trends of ion-specific effects on macromolecule solubility (the Hofmeister series). Despite changes in gelation behavior, we observed minimal corresponding effects on drug release or delivery. There were no significant differences in diclofenac released or delivered through intact porcine skin over 48 h. However, in studies with impaired (tape-stripped) skin, diclofenac delivery was slowest overall with the epolamine salt. CONCLUSION: Varying the salt form of a model analgesic drug can impact gelation and drug delivery characteristics of poloxamer systems. Further study of the mechanisms of these changes will be important for continued development of topical poloxamer products for clinical wound care.
目的:治疗慢性伤口是一项重大的临床挑战,局部用产品非常适合用于疼痛管理。泊洛沙姆 407 是一种温敏聚合物,可使镇痛药物作为液体涂于伤口,在生理温度下转变为凝胶。我们以双氯芬酸钠作为模型镇痛药物,旨在确定盐形式对泊洛沙姆凝胶形成和应用于屏障功能受损的离体皮肤的泊洛沙姆凝胶中药物释放和递送的影响。
方法:用流变学方法评估了载有 0.4%至 1.7%双氯芬酸钠、钾盐、依托孕胺或二乙胺的 17%和 20%泊洛沙姆凝胶的凝胶化特性。使用纤维素膜、猪皮和胶带剥离的猪皮定量测定药物释放和递送。
结果:无论盐形式如何,较高的双氯芬酸钠浓度都会增加泊洛沙姆的凝胶化温度;增加幅度的顺序如下:钠盐>钾盐>二乙胺>依托孕胺。各种抗衡离子引起的凝胶化温度差异通常与先前观察到的离子对大分子溶解度的特定效应(Hofmeister 系列)相符。尽管凝胶行为发生了变化,但我们观察到药物释放或递送几乎没有相应的变化。在 48 小时内,完整的猪皮对双氯芬酸钠的释放或递送没有明显差异。然而,在受损(胶带剥离)皮肤的研究中,依托孕胺盐的双氯芬酸钠递送总体上最慢。
结论:改变模型镇痛药物的盐形式会影响泊洛沙姆系统的凝胶化和药物递送特性。进一步研究这些变化的机制对于继续开发用于临床伤口护理的局部用泊洛沙姆产品非常重要。
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