Abstract
In the present study, we designed and developed novel lipids that include (Z)-1-(Octadec-9-en-1-yl)-pyrrolidine (Cy5T), 1, 1-Di-((Z)-octadec-9-en-1-yl)pyrrolidin-1-ium iodide (Cy5), (Z)-1-(Octadec-9-en-1-yl)-piperidine (Cy6T), and 1, 1-Di-((Z)-octadec-9-en-1-yl) piperidin-1-ium iodide (Cy6) to enhance the transdermal permeation of some selected drugs. Firstly, we evaluated the transdermal permeation efficacies of these lipids as chemical permeation enhancers in vehicle formulations for melatonin, ß-estradiol, caffeine, α-MSH, and spantide using franz diffusion cells. Among them Cy5 lipid was determined to be the most efficient by increasing the transdermal permeation of melatonin, ß-estradiol, caffeine, α-MSH, and spantide by 1.5 to 3.26-fold more at the epidermal layer and 1.3 to 2.5-fold more at the dermal layer, in comparison to either NMP or OA. Hence we developed a nanoparticle system (cy5 lipid ethanol drug nanoparticles) to evaluate any further improvement in the drug penetration. Cy5 lipid formed uniformly sized nanoparticles ranging from 150–200 nm depending on the type of drug. Further, Cy5 based nanoparticle system significantly (p<0.05) increased the permeation of all the drugs in comparison to the lipid solution and standard permeation enhancers. There were about 1.54 to 22-fold more of drug retained in the dermis for the Cy5 based nanoparticles compared to OA/NMP standard enhancers and 3.87 to 66.67-fold more than lipid solution. In addition, epifluorescent microscopic analysis in rhodamine-PE permeation studies confirmed the superior permeation enhancement of LEDs (detection of fluorescence up to skin depth of 340 μm) more than lipid solution, which revealed fluorescence up to skin depth of only 260 μm. In summary the present findings demonstrate that i) cationic lipid with 5 membered amine heterocyclic ring has higher permeating efficacy than the 6 membered amine hertocyclic ring. ii) The nanoparticle system prepared with Cy5 showed significant (p<0.05) increase in the permeation of the drugs than the control penetration enhancers, oleic acid and NMP.
Highlights
Transdermal drug delivery offers several advantages over the conventional methods of drug administration such as avoiding the first pass metabolism, reducing systemic side effects and providing sustained release of drugs [1]
Lipid 1 was synthesized by coupling oleyl iodide with pyrrolidine
There is limitation to the extent of transdermal permeation of relatively large drugs such as peptides, which represent a large majority of active agents for therapeutic applications, across the stratum corneum [18]
Summary
Transdermal drug delivery offers several advantages over the conventional methods of drug administration such as avoiding the first pass metabolism, reducing systemic side effects and providing sustained release of drugs [1]. Among the transdermal permeation enhancing approaches, the use of chemical penetration enhancers is the most suitable option owing to the low cost and ease of application [9,10,11] These chemicals interact with constituents of the major skin barrier, stratum corneum, to promote drug flux. Despite the fact that several compounds have been evaluated as permeation enhancers, their low permeabilities and skin irritation properties have limited their application in transdermal systems Amphiphilic compounds such as azone, seven alkyl-6-(2,5dioxopyrrolidin-1- yl) hexanoates and seven alkyl-6-(2,5dioxopyrrolidin-1-yl)-2-(2-oxoazepan-1-yl)hexanoates, each containing a polar head and a lipophilic chain, are notable examples in this class of permeation enhancers. They each possess high activity coupled with low toxicity. These molecules are capable of inserting themselves into the stratum corneum, ceramide-rich lipid lamellae and disrupting their tight packing [12,13]
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