Abu Hashim Irhan Ibrahim, Abo El-Magd Noha Fawzy, El-Sheakh Ahmed Ramadan, Hamed Mohammed Fawzy, Abd El-Gawad Abd El-Gawad Helmy
Department of Pharmaceutics, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
Int J Nanomedicine. 2018 Feb 20;13:1059-1079. doi: 10.2147/IJN.S156412. eCollection 2018.
The goal of the current study was to explore the potential benefits of Acitretin (Act) nanovesicular gel as a prospective antipsoriatic topical delivery system counteracting the drug challenges in terms of its extremely low aqueous solubility, instability, skin irritation, and serious systemic adverse effects. Act-loaded niosomes were successfully developed, entirely characterized, and optimized. Further evaluation of the optimized formula was conducted regarding its stability and ex vivo cytotoxicity on different cell lines. The optimized niosomal vesicles were then incorporated in gel base matrix and investigated by sequential ex vivo (skin permeation and deposition) and in vivo (skin irritation and antipsoriatic activity using mouse tail model) experiments. The optimized Act-loaded niosomes (span 60:cholesterol molar ratio 1:1) were spherical in shape and exhibited the highest entrapment efficiency (90.32±3.80%) with appropriate nanosize and zeta potential of 369.73±45.45 nm and -36.33±1.80 mV, respectively. Encapsulation of the drug in the nanovesicles was further emphasized by differential scanning calorimetric and powder X-ray diffraction studies. After 3 months storage at 4±1°C, the optimized formula preserved its stability. Act nano niosomal gel produced a remarkable enhanced ex vivo permeation profile up to 30 h and significant drug deposition in the viable epidermal-dermal layers compared with those of Act gel. The pronounced antipsoriatic activity of the medicated nano niosomes was proved ex vivo in HaCaT cells (a keratinocyte cell line). Topical application of Act nano niosomal gel to mouse tail model further established its distinct in vivo antipsoriatic superiority in terms of significantly higher orthokeratosis, drug activity, and reduction in epidermal thickness compared with the control and other gel formulations. Also, negligible skin irritation and better skin tolerability of Act nanovesicular gel were revealed by primary irritation index and histopathologic examination.
本研究的目的是探索阿维A（Act）纳米囊泡凝胶作为一种前瞻性的抗银屑病局部给药系统的潜在益处，以应对该药物因其极低的水溶性、不稳定性、皮肤刺激性和严重的全身不良反应所带来的挑战。成功制备了载有阿维A的脂质体，对其进行了全面表征和优化。对优化后的配方进行了稳定性和对不同细胞系的体外细胞毒性的进一步评估。然后将优化后的纳米囊泡脂质体掺入凝胶基质中，并通过连续的体外实验（皮肤渗透和沉积）和体内实验（使用小鼠尾巴模型的皮肤刺激性和抗银屑病活性）进行研究。优化后的载有阿维A的脂质体（司盘60：胆固醇摩尔比为1：1）呈球形，具有最高的包封率（90.32±3.80%），纳米尺寸合适，分别为369.73±45.45 nm，ζ电位为-36.33±1.80 mV。差示扫描量热法和粉末X射线衍射研究进一步证实了药物被包裹在纳米囊泡中。在4±1°C下储存3个月后，优化后的配方保持了其稳定性。与阿维A凝胶相比，阿维A纳米脂质体凝胶在长达30小时的时间内显著增强了体外渗透特性，并在有活力的表皮-真皮层中有显著的药物沉积。在HaCaT细胞（一种角质形成细胞系）中进行的体外实验证明了含药纳米脂质体具有显著的抗银屑病活性。将阿维A纳米脂质体凝胶局部应用于小鼠尾巴模型，与对照组和其他凝胶制剂相比，在显著更高的正角化、药物活性和表皮厚度降低方面进一步确立了其独特的体内抗银屑病优势。此外，通过初级刺激指数和组织病理学检查发现，阿维A纳米囊泡凝胶的皮肤刺激性可忽略不计，皮肤耐受性更好。
