Comparison of Membrane Depth Determination Techniques for Active Ingredient Skin Penetration Studies Using Microdialysis

Abstract

<b><i>Introduction:</i></b> The skin is a major physical barrier to the environment, and thus, percutaneous delivery of active ingredients to the dermal target site faces a unique set of hurdles. The efficacy of these active ingredients is governed by their release into the underlying epidermal and dermal tissue, especially when administered topically. <b><i>Objective:</i></b> The aim of this study was to understand if different physicochemical properties influence the skin penetration of active ingredients and the depth to which they penetrate into the dermis. <b><i>Methods:</i></b> A microdialysis (MD) setup was used to compare the percutaneous penetration in superficial and deep implanted MD membranes in porcine skin. The precise MD membrane depth was determined using histological sectioning paired with microscopy, ultrasound, and a novel computed tomographic approach. <b><i>Results:</i></b> In study A, the measured depth of the superficial and deep implanted MD membranes was compared using histological sectioning, ultrasound, and computed tomography. Experimental determination of the depth up to which penetration occurs was found to be crucial to percutaneous penetration studies. In study B, the lipophilic differences of the active ingredients and its influences on the penetration was tested using hydrophilic caffeine and lipophilic LIP1 as model compounds, which have an identical molecular weight with different lipophilic characteristics. It is assumed that the lipophilic characteristics of active ingredients influence their penetration and thus governs the concentration of these molecules reaching their target site. <b><i>Conclusion:</i></b> The transdermal penetration of caffeine was found to exceed that of LIP1 through the hydrophilic environment of the dermis. Thus, the findings of this study show that the precise MD dermis localization and the physicochemical properties, such as lipophilicity, influence the penetration rate of active ingredients and lay the foundation for creating optimized transdermal delivery systems.

Lateral Dermal Penetration Is Dependent on the Lipophilicity of Active Ingredients

“…The in vitro and ex vivo recovery of caffeine and LIP1 were determined and compared [23]. The in vitro recovery is higher than the ex vivo recovery with a higher caffeine penetration concentration compared with LIP1.…”

“…The in vitro recovery is higher than the ex vivo recovery with a higher caffeine penetration concentration compared with LIP1. The MD membrane depth inside the skin was determined via US and superficial and deep-implanted MD membranes were positioned on average 337 ± 43 and 1,082 ± 116 μm underneath the skin surface, respectively [23].…”

“…The in vitro recovery of caffeine and LIP1 was found to be higher than the concentration recovered ex vivo. Comparing the active ingredients, caffeine was taken up into the MD membrane at an in vitro setup with 1.3-fold higher concentration and for the ex vivo setup 1.6-fold higher concentration, compared to LIP1 [23]. To generate further insight into the diffusion process, a novel lateral MD penetration setup was developed.…”

“…The active ingredient, which penetrates the skin, is received inside the membrane, and is eventually flushed out enabling sampling. While performing the MD experiments the localization of the membrane inside the skin is important, the membrane is placed in a defined depth, which enables the determination of the penetration depth for each respective substance [23]. The depth is controlled via methods like ultrasound (US) measurement or via tissue sectioning [12, 24, 25].…”

Pharmacokinetics of tilmicosin in chicken joints based on a novel microdialysis sampling method

“…Microdialysis is an emerging biological sampling technology that has the advantage of live, real-time and continuous sampling from the tissue target and free drug concentrations can be determined directly using HPLC-MS/MS without extraction or other pretreatment. Hence, microdialysis is a novel method to study drug PK characteristics in target sites and has been applied to brain (Kim et al, 2021), kidney (Lubda et al, 2021), liver (Li et al, 2014) and lung (Lanni et al, 2021). However, microdialysis employed in the chicken joint has not been reported.…”