Ruiz Victor H, Encinas-Basurto David, Sun Bo, Eedara Basanth Babu, Dickinson Sally E, Wondrak Georg T, Chow H -H Sherry, Curiel-Lewandrowski Clara, Mansour Heidi M
Department of Pharmacology and Toxicology, The University of Arizona College of Pharmacy, Tucson, AZ 85721, USA.
Center for Translational Science, Florida Interational University, Port St. Lucie, FL 34987, USA.
Pharmaceutics. 2022 Mar 24;14(4):700. doi: 10.3390/pharmaceutics14040700.
Nonmelanoma skin cancers (NMSCs) are the most common malignancies worldwide and affect more than 5 million people in the United States every year. NMSC is directly linked to the excessive exposure of the skin to solar ultraviolet (UV) rays. The toll-like receptor 4 (TLR4) antagonist, resatorvid (TAK-242), is a novel prototype chemo preventive agent that suppresses the production of inflammation mediators induced by UV exposure. This study aimed to design and develop TAK-242 into topical formulations using FDA-approved excipients, including DermaBase, PENcream, polyethylene glycol (PEG)-400, propylene glycol (PG), carbomer gel, hyaluronic acid (HA) gel, and Pluronic F-127 poloxamer triblock copolymer gel for the prevention of skin cancer. The physicochemical properties of raw TAK-242, which influence the compatibility and solubility in the selected base materials, were confirmed using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), hot-stage microscopy (HSM), Raman spectroscopy, and attenuated total reflectance Fourier-transform infrared (ATR-FTIR) spectroscopic analysis. The permeation behavior of TAK-242 from the prepared formulations was determined using Strat-M transdermal diffusion membranes, and 3D cultured primary human-derived epidermal keratinocytes (EpiDerm). Despite TAK-242's high molecular weight and hydrophobicity, it can permeate through reconstructed human epidermis from all formulations. The findings, reported for the first time in this study, emphasize the capabilities of the topical application of TAK-242 via these multiple innovative topical drug delivery formulation platforms.
非黑素瘤皮肤癌（NMSCs）是全球最常见的恶性肿瘤，在美国每年影响超过500万人。NMSC与皮肤过度暴露于太阳紫外线（UV）直接相关。Toll样受体4（TLR4）拮抗剂瑞斯托维德（TAK - 242）是一种新型的化学预防剂原型，可抑制紫外线暴露诱导的炎症介质产生。本研究旨在使用美国食品药品监督管理局（FDA）批准的辅料，包括DermaBase、PENcream、聚乙二醇（PEG）- 400、丙二醇（PG）、卡波姆凝胶、透明质酸（HA）凝胶和普朗尼克F - 127泊洛沙姆三嵌段共聚物凝胶，将TAK - 242设计并开发成局部用制剂，用于预防皮肤癌。使用X射线粉末衍射（XRPD）、差示扫描量热法（DSC）、热台显微镜（HSM）、拉曼光谱和衰减全反射傅里叶变换红外（ATR - FTIR）光谱分析，确定了影响TAK - 242在所选基质材料中相容性和溶解性的物理化学性质。使用Strat - M透皮扩散膜和3D培养的原代人源表皮角质形成细胞（EpiDerm），测定了TAK - 242从制备的制剂中的渗透行为。尽管TAK - 242分子量高且具有疏水性，但它可以从所有制剂中渗透过重建的人表皮。本研究首次报道的这些发现强调了通过这些多种创新的局部药物递送制剂平台局部应用TAK - 242的能力。
