Iliopoulos Fotis, Caspers Peter J, Puppels Gerwin J, Lane Majella E
School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK.
RiverD International B.V., Marconistraat 16, 3029 AK Rotterdam, The Netherlands.
Pharmaceutics. 2020 Sep 18;12(9):887. doi: 10.3390/pharmaceutics12090887.
Previously, we reported the use of Confocal Raman Spectroscopy (CRS) to investigate the topical delivery of actives and excipients. We have also correlated the results from CRS with findings from in vitro diffusion studies in human skin. However, until now CRS has only been used as a semi-quantitative method of determining the skin uptake of molecules, with results expressed as arbitrary units of signal intensity. Clearly, this posed challenges for using CRS to determine skin delivery and to assess the drug bioavailability and bioequivalence of topical formulations. In the present work, the permeation of niacinamide (NIA) from various formulations in human skin was studied in vitro using conventional Franz cells and in vivo using a quantitative CRS method under finite dose conditions. The selection of NIA was based on its wide use in pharmaceutical and personal care formulations for many years. This is the first fully quantitative study to compare these methods. The vehicles investigated were neat Transcutol P (TC); binary combinations of propylene glycol (PG) with propylene glycol monolaurate (PGML); and ternary mixtures of PG, PGML, and isopropyl myristate (IPM). These solvents were selected to encompass a range of physicochemical properties. NIA permeation was evident from all formulations in vitro and in vivo. The vehicles PG:PGML and PG:PGML:IPM delivered comparable amounts across the skin in vitro at 24 h (100.3-106.7 µg/cm, > 0.05) that were significantly higher compared with those of TC (1.3 µg/cm, < 0.05). An excellent in vitro in vivo correlation (R = 0.98) was found following the linear regression of the cumulative amounts of NIA permeated in vitro and the amounts of NIA at 2 μm in the skin measured with CRS. A very good correlation between the cumulative permeation of NIA in vitro and the total amount of NIA that penetrated the stratum corneum (SC) per unit of surface area (μg/cm) in vivo was also observed, with a Pearson correlation coefficient (R) of 0.94. The findings support the use of CRS for the quantitative measurement of actives delivered to the skin in vivo. Future studies will focus on exploring the reproducibility and reliability of the method by investigating the delivery of different actives from a wider range of vehicles. Additionally, quantitative CRS will be evaluated further as a method for assessing the bioequivalence of topical formulations.
此前，我们报道了使用共焦拉曼光谱（CRS）来研究活性成分和辅料的局部递送。我们还将CRS的结果与人体皮肤体外扩散研究的结果进行了关联。然而，到目前为止，CRS仅被用作一种半定量方法来确定分子的皮肤摄取量，结果以信号强度的任意单位表示。显然，这给使用CRS来确定皮肤递送以及评估局部制剂的药物生物利用度和生物等效性带来了挑战。在本研究中，使用传统的Franz扩散池在体外研究了烟酰胺（NIA）从各种制剂在人体皮肤中的渗透情况，并在有限剂量条件下使用定量CRS方法在体内进行了研究。选择NIA是基于其在制药和个人护理制剂中多年的广泛应用。这是第一项比较这些方法的全面定量研究。所研究的载体包括纯的二乙二醇单乙醚（TC）；丙二醇（PG）与单月桂酸丙二醇酯（PGML）的二元组合；以及PG、PGML和肉豆蔻酸异丙酯（IPM）的三元混合物。选择这些溶剂是为了涵盖一系列物理化学性质。NIA在体外和体内从所有制剂中的渗透都是明显的。在24小时时，PG:PGML和PG:PGML:IPM载体在体外透过皮肤递送的量相当（100.3 - 106.7μg/cm², P > 0.05），与TC（1.3μg/cm², P < 0.05）相比显著更高。在对体外渗透的NIA累积量与用CRS测量的皮肤中2μm处的NIA量进行线性回归后发现了良好的体外 - 体内相关性（R = 0.98）。还观察到NIA在体外的累积渗透与体内每单位表面积（μg/cm²）穿透角质层（SC）的NIA总量之间具有非常好的相关性，皮尔逊相关系数（R）为0.94。这些发现支持使用CRS对体内递送至皮肤的活性成分进行定量测量。未来的研究将集中于通过研究更广泛载体中不同活性成分的递送情况来探索该方法的重现性和可靠性。此外，将进一步评估定量CRS作为评估局部制剂生物等效性方法的可行性。
