Abstract
Transdermal administration of drugs that penetrate, in this case directly into the blood circulation, has many advantages and is promising for many drugs thanks to its easy application and good patient compliance. (S)-8-Methyl-6,9-diazaspiro[4.5]decan-7,10-dione (alaptide), has been studied as a potential chemical permeation enhancer. Based on its structure, four selected piperazine-2,5-diones were synthesized by means of multi-step synthetic pathways. All the compounds were investigated on their ability to enhance the permeation of the model drug theophylline from the hydrophilic medium propylene glycol:water (1:1). In vitro experiments were performed using vertical Franz diffusion cells at constant temperature 34 ± 0.5 °C and using full-thickness pig (Sus scrofa f. domestica) ear skin. Withdrawn samples were analyzed by RP-HPLC for determination of the permeated amount of theophylline. All the compounds were applied in ratio 1:10 (w/w) relative to the amount of theophylline. One hour after application, the permeated amount of theophylline from formulations with alaptide and (3S,6S)-3,6-dimethylpiperazine-2,5-dione, was ca. 15- and 12-fold higher, respectively, than from the formulation without the tested compounds. Despite the enhancement ratio of both enhancers in a steady state was ca. 2.3, the pseudo-enhancement ratio in the time range from 1 to 3 h was 4.4. These enhancement ratios indicate that the compounds are able to enhance the permeation of agents through the skin; however, the short-term application of both compound formulations seems to be more advantageous. In addition, the screening of the cytotoxicity of all the prepared compounds was performed using three cell lines, and the compounds did not show any significant toxic effect.
Highlights
Pharmaceutics can be administered in different ways depending on their physicochemical properties and pharmacokinetic profile [1]
The ability of all the compounds to enhance the permeation of the model drug theophylline from the medium of propylene glycol:water (1:1) was investigated using vertical Franz diffusion cells and a full-thickness pig (Sus scrofa f. domestica) ear skin
All the compounds were tested on their cytotoxic effect using human foreskin fibroblasts and two cancer cell lines, and none of the compounds expressed any toxic effect
Summary
Pharmaceutics can be administered in different ways depending on their physicochemical properties and pharmacokinetic profile (in general, based on their ADME profile) [1]. Molecules 2019, 24, 566 of skin for the transdermal administration of drugs that can penetrate directly into the system circulation has many advantages, and it is a promising way for administration of many drugs. Transdermal drug delivery frequently encounters the problem of limited penetration of active pharmaceutical ingredients through the skin [2,3]. Many different approaches to overcome the skin barrier can be found; from chemical and/or physical modifications of drugs [5] to the specific composition of final drug formulations or application of electrically assisted methods [3,6,7]. The use of chemical permeation enhancers (CPEs), specific pharmaceutical excipients, is one of the possibilities to facilitate drug delivery through the skin
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