Patel Avnish, Iliopoulos Fotis, Caspers Peter J, Puppels Gerwin J, Lane Majella E
Department of Pharmaceutics, UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK.
RiverD International B.V., Marconistraat 16, 3029 AK Rotterdam, The Netherlands.
Pharmaceutics. 2021 Apr 13;13(4):542. doi: 10.3390/pharmaceutics13040542.
The composition of topical and transdermal formulations is known to determine the rate and the extent of drug delivery to and through the skin. However, to date, the role of excipients in these formulations on skin delivery of actives has received little attention from scientists in the field. Monitoring skin absorption of both drug and vehicle may provide insights into the mechanism by which excipients promote permeation and may facilitate the design of effective and safer products. Previously, we have investigated the use of quantitative Confocal Raman Spectroscopy (CRS) to investigate the delivery of an active to the skin, and we also reported the first fully quantitative study that compared this method with the well-established in vitro permeation test (IVPT) model. To further explore the potential of quantitative CRS in assessing topical delivery, the present work investigated the effects of commonly used excipients on the percutaneous absorption of a model drug, ibuprofen (IBU). Permeation of IBU and selected solvents following finite dose applications to human skin was determined in vitro and in vivo by Franz diffusion studies and quantitative CRS, respectively. The solvents used were propylene glycol (PG), dipropylene glycol (DPG), tripropylene glycol (TPG), and polyethylene glycol 300 (PEG 300). Overall, the cumulative amounts of IBU that permeated at 24 h in vitro were similar for PG, DPG, and TPG ( > 0.05). These three vehicles outperformed PEG 300 ( < 0.05) in terms of drug delivery. Concerning the vehicles, the rank order for in vitro skin permeation was DPG ≥ PG > TPG, while PEG 300 did not permeate the skin. A linear relationship between maximum vehicle and IBU flux in vitro was found, with a correlation coefficient (R) of 0.95. When comparing in vitro with in vivo data, a positive in vitro-in vivo (IVIV) correlation between the cumulative permeation of IBU in vitro and the total amount of IBU that penetrated the stratum corneum (SC) in vivo was observed, with a Pearson correlation coefficient (R) of 0.90. A strong IVIV correlation, R = 0.82, was found following the linear regression of the cumulative number of solvents permeated in vitro and the corresponding skin uptake in vivo measured with CRS. This is the first study to correlate in vivo permeation of solvents measured by CRS with data obtained by in vitro diffusion studies. The IVIV correlations suggest that CRS is a powerful tool for profiling drug and vehicle delivery from dermal formulations. Future studies will examine additional excipients with varying physicochemical properties. Ultimately, these findings are expected to lead to new approaches for the design, evaluation, and optimization of formulations that target actives to and through the skin.
众所周知，局部和透皮制剂的组成决定了药物递送至皮肤并透过皮肤的速率和程度。然而，迄今为止，这些制剂中的辅料对活性成分经皮递送的作用在该领域的科学家中很少受到关注。监测药物和载体在皮肤中的吸收情况，可能有助于深入了解辅料促进渗透的机制，并有助于设计出更有效、更安全的产品。此前，我们已经研究了使用定量共聚焦拉曼光谱（CRS）来研究活性成分向皮肤的递送情况，并且我们还报告了第一项将该方法与成熟的体外渗透试验（IVPT）模型进行比较的完全定量研究。为了进一步探索定量CRS在评估局部递送方面的潜力，本研究调查了常用辅料对模型药物布洛芬（IBU）经皮吸收的影响。分别通过Franz扩散研究和定量CRS在体外和体内测定了有限剂量应用于人体皮肤后IBU和选定溶剂（丙二醇（PG）、二丙二醇（DPG）、三丙二醇（TPG）和聚乙二醇300（PEG 300））透过皮肤的情况。总体而言，PG、DPG和TPG在体外24小时时渗透的IBU累积量相似（P>0.05）。在药物递送方面，这三种载体的表现优于PEG 300（P<0.05）。关于载体，体外皮肤渗透的排序为DPG≥PG>TPG，而PEG 300未渗透皮肤。发现体外最大载体通量与IBU通量之间存在线性关系，相关系数（R）为0.95。当比较体外和体内数据时，观察到体外IBU的累积渗透量与体内穿透角质层（SC）的IBU总量之间存在正的体外-体内（IVIV）相关性，Pearson相关系数（R）为0.90。在对体外渗透的溶剂累积量与用CRS测量的体内相应皮肤摄取量进行线性回归后，发现了很强的IVIV相关性，R = 0.82。这是第一项将通过CRS测量的溶剂在体内的渗透情况与通过体外扩散研究获得的数据相关联的研究。IVIV相关性表明CRS是分析皮肤制剂中药物和载体递送情况的有力工具。未来的研究将考察具有不同物理化学性质的其他辅料。最终，这些发现有望为将活性成分靶向递送至皮肤并透过皮肤的制剂的设计、评估和优化带来新方法。
