A PAMPA Assay as Fast Predictive Model of Passive Human Skin Permeability of New Synthesized Corticosteroid C-21 Esters

Bojan D Markovic,Sote M Vladimirov,Katarina D Karljikovic-Rajic,Jadranka V Odovic,Olivera A Cudina

doi:10.3390/molecules17010480

Abstract

The permeation properties of twenty newly synthesized α-alkoxyalkanoyl and α-aryloxyalkanoyl C-21 esters of standard corticosteroids: Fluocinolone acetonide, dexamethasone, triamcinolone acetonide and hydrocortisone were established using a PAMPA assay (70% silicone oil and 30% isopropyl myristate). The data were compared with parent corticosteroids with addition of mometasone furoate and hydrocortisone acetate. All newly synthesized corticosteroid C-21 esters have effective permeability coefficients higher then -6, mostly followed with high values of retention factors and low permeation. The examined compounds were grouped through relationship between obtained retention factors and permeation parameters (groups I–III). The classification confirmed group I (membrane retentions as well as permeation lower then 30%) for all corticosteroid standards except mometasone furoate, a potent topical corticosteroid which, with high membrane retention (81%) and low permeation (7.7%) fits into group III. The largest number of new synthesized corticosteroids C-21 esters, among them all fluocinolone acetonide C-21 esters, have high membrane retentions (32.4%–86.5%) and low permeations (1.3%–27.1%), fitting in group III. The classification was related to previously obtained anti-inflammatory activity data for the fluocinolone acetonide C-21 esters series. According to the PAMPA results the new synthesized esters could be considered as potential new prodrugs with useful benefit/risk ratio.

Highlights

Topical corticosteroids represent a significant group of drugs widely used in the therapy of skin disorders due to their anti-inflammatory and immunosuppressive actions
In this paper the permeability of six standard corticosteroids (FA, DEX, triamcinolone acetonide (TA), H, MF and H-21-Ac) as well as twenty newly synthesized C-21 α-alkoxyalkanoyl and α-aryloxyalkanoyl esters of fluocinolone acetonide (FA), DEX, TA and H were investigated with the Parallel Artificial Membrane Permeability Assay (PAMPA) test
Results in the PAMPA test confirmed that all investigated FA C-21 esters have high membrane retentions (R) and low permeation parameters [CA(t)/CD(0), Table 1] and fit in group

Summary

Introduction

Topical corticosteroids represent a significant group of drugs widely used in the therapy of skin disorders due to their anti-inflammatory and immunosuppressive actions. The applications of corticosteroids, especially to large areas, when the skin is injured, or under occlusive dressings may led to their absorption and systemic side-effects [1]. The local corticosteroids efficiency depends, at the first place, on their pharmacological potency and ability to be absorbed into the target epidermis and dermis cells [2,3,4]. It is consider that the low-potent formulations are more suitable for application in long-term therapy, while more potent formulation are reserved for short time treatments and for use at areas such as the hands or soles, where poorly potent corticosteroids are not effective [7]

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