Table1_Nanostructured Lipid Carrier–Mediated Transdermal Delivery of Aceclofenac Hydrogel Present an Effective Therapeutic Approach for Inflammatory Diseases.docx

Aceclofenac (ACE), a cyclooxygenase-2 inhibitor, is the derivative of the diclofenac group that has been in use for the symptomatic treatment of systemic inflammatory autoimmune disease, rheumatoid arthritis (RA). Partial solubility, high lipophilic nature, and stability challenge its use in developing topical formulations. Hence, we developed and characterized nanostructured lipid carrier (NLC)–based ACE (ACE-NLC) hydrogel for an efficient transdermal delivery. NLC microemulsion was prepared using different lipids by various methods and was characterized with respect to particle size, zeta potential, surface morphology, and drug encapsulation efficiency. The optimized NLC formulation was incorporated into Carbopol® 940 gel, and this arrangement was characterized and compared with the existing marketed gel (Mkt-gel) formulation to assess in vitro drug release, rheology, texture profile, in vivo skin retention and permeation, and stability. Furthermore, prepared and characterized ACE-loaded NLC formulation was evaluated for skin integrity and fitted in a dermatokinetic model. The results of this study confirmed the spherical shape; smooth morphology and nanometric size attested by Zetasizer and scanning and transmission electron microcopy; and stability of the ACE-NLC formulation. The ACE-NLC-gel formulation showed good rheological and texture characteristics, and better skin distribution in the epidermis and dermis. Moreover, ACE-NLC permeated deeper in the skin layers and kept the skin integrity intact. Overall, NLC-based gel formulation of ACE might be a promising nanoscale lipid carrier for topical application when compared with the conventional Mkt-gel formulation.

醋氯芬酸（Aceclofenac, ACE）作为环氧合酶-2抑制剂（cyclooxygenase-2 inhibitor），属于双氯芬酸类衍生物，已被广泛用于全身性炎症性自身免疫性疾病（systemic inflammatory autoimmune disease）、类风湿关节炎（rheumatoid arthritis, RA）的对症治疗。然而，其溶解性有限、高脂溶性及稳定性缺陷，均为外用制剂的开发带来了挑战。为此，本研究开发并表征了基于纳米结构脂质载体（nanostructured lipid carrier, NLC）的醋氯芬酸水凝胶（ACE-NLC水凝胶），以实现高效透皮给药（transdermal delivery）。

本研究采用多种脂质与不同制备工艺制备了NLC微乳，并对其粒径、ζ电位（zeta potential）、表面形貌及药物包封率（drug encapsulation efficiency）进行了表征。将优化后的NLC制剂掺入卡波姆®940凝胶（Carbopol® 940 gel）基质中，随后对该复合制剂进行表征，并与市售凝胶（marketed gel, Mkt-gel）进行对比，以评估其体外药物释放（in vitro drug release）、流变学（rheology）特性、质地特性（texture profile）、体内皮肤滞留与渗透（in vivo skin retention and permeation）性能及稳定性。此外，本研究还对制备并表征的载醋氯芬酸NLC制剂开展了皮肤完整性评价，并将其拟合至皮肤动力学模型（dermatokinetic model）中。

本研究结果证实，ACE-NLC制剂呈球形、形貌光滑，粒径处于纳米级（经Zetasizer粒径分析仪、扫描及透射电子显微镜验证），且稳定性良好。ACE-NLC凝胶制剂展现出优异的流变学与质地特性，在表皮与真皮（epidermis and dermis）层中具有更优的皮肤分布。此外，ACE-NLC可在皮肤各层中实现更深层的渗透，且未破坏皮肤完整性。总体而言，与常规市售凝胶制剂相比，基于NLC的醋氯芬酸凝胶制剂有望成为一种极具应用前景的外用纳米级脂质载体（nanoscale lipid carrier）制剂。