Solute-Vehicle-Skin Interactions and Their Contribution to Pharmacokinetics of Skin Delivery

Abstract

Human skin provides an effective route of delivery for selected drugs. Topical penetration of molecules is largely attributed to passive diffusion, and the degree of penetration can be represented by in silico, in vitro, and ex vivo models. Percutaneous absorption of pharmaceutical ingredients is a delicate balance between the molecular properties of the drug, the skin properties of the patients, and the formulation properties. Understanding this interplay can aid in the development of products applied to the skin. The kinetics of percutaneous absorption and an understanding of the rate-limiting steps involved can facilitate the optimization of these systems and enhance the degree to which skin drug delivery can be achieved. Solute-vehicle, vehicle-skin, and solute-skin interactions contribute notably to product release as well as the rate of absorption and diffusion across skin layers. These interactions alter the degree of permeation by interfering with the skin barrier or solubility and thermodynamic activity of the active pharmaceutical ingredient. This article aims to provide a concise understanding of some of the factors involved in the skin absorption of topical products, i.e., the pharmacokinetics of percutaneous absorption as well as the solute-vehicle-skin interactions that determine the rate of release of products and the degree of drug diffusion across the skin.

Keywords: in silico models; in-use conditions; metamorphosis of vehicle; partition coefficient; skin pharmacokinetics; skin–drug; skin–vehicle; topical delivery; vehicle–drug interactions.

Figure 1

A schematic representation of the kinetics of percutaneous absorption. (1) Drug release/partition from the applied topical formulation vehicle; (2, 3) partition into and diffusion of the drug within the SC (rate-limiting steps for most drugs); (4, 5) partition into and diffusion of drug within the viable epidermis (rate-limiting step for highly lipophilic drugs); and (6) absorption of the drug into the dermal blood supply before going into the systemic circulation for distribution and clearance from the body (Figure created with BioRender.com).

Figure 2

Drug permeation routes through the skin. The transepidermal route is divided into intercellular and intracellular/transcellular routes, with the transport of drugs occurring via the SC. The transappendageal route is divided into transglandular and transfollicular routes, transporting drugs via hair follicles and sweat ducts. Adapted and reproduced with permission from Ref [11]. Copyright 2023 Drug Discovery Today.

Figure 3

Typical permeation profile showing (a) infinite dosing initially at a non-steady state, followed by delayed drug absorption at a lag time before reaching steady-state diffusion; (b) finite dosing conditions with an increase in the flux of drug until reaching maximum value (J_max), followed by a decrease in flux until reaching a plateau. Adapted and reproduced with permission from Ref [75], licensed under the CC BY-NC-ND license (https://creativecommons.org/licenses/by/4.0/) access on 13 November 2023. Copyright 2022 MDPI.

Figure 4

In vitro cumulative amount permeated versus time of: (A) neat (pure) Methyl salicylate (MS) ester through human epidermal membranes under hydrated (closed symbols) and dehydrated (open symbols) conditions (mean ± SD, n = 4–5) [109]; (B) MS ester through human epidermal membranes from saturated aqueous solutions (hydrated; closed symbols) and in mineral oil (MO) with desiccant (dehydrated; open symbols) (mean ± SD, n = 4–5) [109]; (C) MS easter in Metsal™ Cream (a topical product) applied on human epidermal membranes (mean ± SEM, n = 3) [110].

Figure 5

Diagrammatic representation of lipid nanocarriers, including (1) liposomes, which release drugs upon the breakdown of their lipid bilayers; (2) transfersomes, incorporating edge activators that deform and pass through intercellular spaces across multiple skin layers to deliver drugs into the dermis; and (3) ethosomes, containing ethanol as a permeation enhancer, which disrupts lipid organization and facilitates deep penetration through the skin [115,121].

Figure 6

(A) Evaporation/time dependence of the zero-shear viscosity (η0) of O/W lidocaine cream F1. (B) Frequency sweep of O/W lidocaine cream F1 samples at 0 and 120 min (G: elastic modulus; G″: viscous modulus; η*: complex viscosity). In vitro permeation profiles of lidocaine in O/W lidocaine cream F1: (C) cumulative amount of lidocaine in F1 under unoccluded and occluded conditions, and (D) flux of lidocaine in F1 under unoccluded and occluded conditions [32].