School of Pharmaceutical Sciences, University of Geneva, CMU-1 rue Michel Servet, 1211 Genève 4, Switzerland; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, CMU-1 rue Michel Servet, 1211 Genève 4, Switzerland.
Geneva School of Economics and Management, University of Geneva, 40 Boulevard du Pont d'Arve, 1204 Genève, Switzerland.
Int J Pharm. 2021 Jul 15;604:120736. doi: 10.1016/j.ijpharm.2021.120736. Epub 2021 May 26.
Facial angiofibromas are benign tumors characteristic of tuberous sclerosis complex. The disease involves the mTOR pathway and the cutaneous manifestation responds to topical treatment with sirolimus (SIR). However, there are no approved topical SIR products and extemporaneous formulations have been sub-optimal. The aims of this study were (i) to develop aqueous formulations of SIR loaded in polymeric micelles prepared using D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and (ii) to use the cutaneous biodistribution method, in conjunction with a new statistical approach, to investigate the feasibility of SIR delivery to the viable epidermis. Optimized micelle solutions and hydrogels (0.2%) were developed and stable at 4 °C for at least 6 and 3 months, respectively. Cutaneous delivery experiments (infinite and finite dose) using porcine skin demonstrated that both formulations increased SIR cutaneous bioavailability as compared to the control (ointment 0.2%). Moreover, studies with the micellar hydrogel 0.2% demonstrated SIR deposition in the viable epidermis with no transdermal permeation. These encouraging results confirmed that polymeric micelles enabled development of aqueous SIR formulations capable of targeted epidermal delivery. Furthermore, the cutaneous biodistribution provided a detailed insight into drug bioavailability in the different skin compartments that could complement/explain clinical observations of formulation efficacy.
面部血管纤维瘤是结节性硬化症的特征性良性肿瘤。这种疾病涉及 mTOR 途径，皮肤表现对西罗莫司（SIR）的局部治疗有反应。然而，目前还没有批准的局部 SIR 产品，并且临时制剂效果不佳。本研究的目的是：(i) 开发使用 D-α-生育酚聚乙二醇 1000 琥珀酸酯（TPGS）制备的载有 SIR 的聚合物胶束的水性制剂；(ii) 使用皮肤生物分布方法，结合新的统计方法，研究 SIR 递送至有活力的表皮的可行性。优化了胶束溶液和水凝胶（0.2%），在 4°C 下至少稳定 6 和 3 个月。使用猪皮进行的皮肤给药实验（无限和有限剂量）表明，与对照（软膏 0.2%）相比，两种制剂均增加了 SIR 的皮肤生物利用度。此外，0.2%胶束水凝胶的研究表明 SIR 沉积在有活力的表皮中，没有透皮渗透。这些令人鼓舞的结果证实，聚合物胶束能够开发出能够靶向表皮递送的 SIR 水性制剂。此外，皮肤生物分布提供了对不同皮肤隔室中药物生物利用度的详细了解，这可以补充/解释制剂疗效的临床观察。
