Investigation of Permeation of Theophylline through Skin Using Selected Piperazine-2,5-Diones

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 Withdrawn samples were analyzed by RP-HPLC for determination of the permeated amount of theophylline.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.

Heterocycles in Medicinal Chemistry

“…Sulekova et al published a study evaluating the release of 5-fluorouracil from unmodified and modified mesoporous silica matrices [5]. A complex synthesis–analytical–galenical study described the synthesis of several piperazine-2,5-dione derivatives and their transdermal enhancement activity using theophylline as a model drug, and the prepared compounds can be potentially used as excipients in semi-solid drug formulations or transdermal therapeutic systems [6].…”

Nanofibrous Scaffolds for Skin Tissue Engineering and Wound Healing Based on Synthetic Polymers

“…Alaptide is a spirocyclic dipeptide, which was designed as an analogue of melanocyte-stimulating hormone release-inhibiting factor (MIF) and synthesized by Kasafirek et al at the Research Institute for Pharmacy and Biochemistry in Prague, Czechoslovakia, in the 1980s of the twentieth century [68]. Alaptide showed a great potential for regeneration of the injured skin and also for enhanced transdermal penetration of drugs [69,70]. Arginine is amino acid which is a precursor of nitric oxide, implicated in wound healing.…”

Applications of Nanobiotechnology

“…The NPs with an average diameter of 2 nm and height of six atomic monolayers showed optimum catalytic activity [69]. The Au NPs on amorphous silica support produced by Mukherjee et al were able DOI: http://dx.doi.org /10.5772/intechopen.87973 to catalyze hydrogenation of cyclohexene [70]. The Ag NPs produced by lychee (L. chinensis) extract showed significant photocatalytic activity even after three times of reusing [71].…”