Physical Medicine and Rehabilitation Research Center, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
Exp Dermatol. 2023 Sep;32(9):1459-1467. doi: 10.1111/exd.14850. Epub 2023 Jun 7.
Opioid and local anaesthetic receptors are abundantly concentrated in different layers of the skin. Therefore, simultaneous targeting of these receptors can produce more potent dermal anaesthesia. Herein, we developed lipid-based nanovesicles for the co-delivery of buprenorphine and bupivacaine to efficiently target skin-concentrated pain receptors. Invasomes incorporating two drugs were prepared by ethanol injection method. Subsequently, the size, zeta potential, encapsulation efficiency, morphology, and in-vitro drug release of vesicles were characterized. Ex-vivo penetration features of vesicles were then investigated by the franz diffusion cell on the full-thickness human skin. Wherein, it was demonstrated that invasomes penetrated the skin deeper and delivered bupivacaine more effectively than buprenorphine to the target site. The superiority of invasome penetration was further evidenced by the results of ex-vivo fluorescent dye tracking. Estimation of in-vivo pain responses by the tail-flick test revealed that compared with the liposomal group, the group receiving invasomal formulation and drug-free invasomal formulation (only containing menthol) displayed increased analgesia in the initial times of 5 and 10 min. Also, no signs of oedema or erythema were observed in the Daze test in any of the rats receiving the invasome formulation. Finally, ex-vivo and in-vivo assays demonstrated efficiency in delivering both drugs into deeper layers of skin and exposing them to the located pain receptors, which improves the time of onset and the analgesic effects. Hence, this formulation appears to be a promising candidate for tremendous development in the clinical setting.
阿片类药物和局部麻醉药受体在皮肤的不同层中高度集中。因此，同时针对这些受体可以产生更有效的皮肤麻醉效果。在此，我们开发了基于脂质的纳米囊泡，用于同时递送丁丙诺啡和布比卡因，以有效地针对皮肤集中的疼痛受体。通过乙醇注入法制备了包含两种药物的侵入体。随后，对囊泡的粒径、Zeta 电位、包封效率、形态和体外药物释放进行了表征。然后通过Franz 扩散细胞在全厚人皮肤上研究了囊泡的体外渗透特征。结果表明，与丁丙诺啡相比，侵入体更深入地穿透皮肤，并更有效地将布比卡因递送至靶位。通过体外荧光染料追踪实验进一步证明了侵入体渗透的优越性。通过尾巴闪烁试验估计体内疼痛反应，与脂质体组相比，接受侵入体制剂和无药物侵入体制剂（仅含薄荷醇）的组在 5 分钟和 10 分钟的初始时间显示出更强的镇痛作用。在任何接受侵入体制剂的大鼠中，在 Daze 试验中均未观察到水肿或红斑的迹象。最后，体外和体内试验均证明了将两种药物递送至皮肤更深层并将其暴露于定位疼痛受体的效率，从而提高了起效时间和镇痛效果。因此，该制剂似乎是在临床环境中进行大量开发的有前途的候选物。
