Abstract
The purpose of this study was to evaluate the influence of piperine on permeation of repaglinide (RGE) across rat epidermis. In addition, the role of chitosan (CTN) and its combination with piperine was investigated for exploring the possibility of further enhancing the permeation of RGE. The permeation of RGE across excised rat epidermis was, respectively, ~4-fold, ~5-fold and ~6- fold higher when piperine (0.008% w/v), CTN (1% w/v), or piperine – CTN mixture was used as donor vehicle as compared to propylene glycol: ethanol (PG: EtOH) (7:3) mixture. The merger of T2 and T3 (lipid-specific) and obliteration of T4 (protein-specific) endothermic transitions in the thermograms of excised rat epidermis suggested overwhelming influence of these treatments on skin lipids and proteins. Further, the observed increase in intercellular space, disordering of lipid structure and corneocyte detachment indicated considerable effect on the ultrastructure of rat epidermis. The enhancement in permeation of RGE across rat epidermis excised after various treatments for different periods was correlated with the transepidermal water loss of similarly treated viable rat skin. The treatment of HaCaT cell line with piperine influenced the TJ plaque protein zonula occludens (ZO-1) as evidenced by reduced immunofluorescence of anti-TJP1 (ZO-1) antibody in confocal laser scanning microscopic studies. Treatment of HaCaT cells with CTN decreased the intensity of fluorescence on the cell walls only marginally. However, remarkable decrease in the immunofluorescence of anti-TJP1 (ZO-1) antibody was observed after treatment of HaCaT cells with mixture of piperine and CTN. The systemic delivery of RGE in rats was enhanced by 8-fold and 9.5-fold from transdermal formulations containing, respectively, piperine (0.008 % w/v) or piperine (0.008 % w/v)–CTN (1% w/v) mixture as enhancer. Overall, the observations suggested overwhelming influence of piperine and CTN on ZO-1 protein to be responsible for enhancing the percutaneous permeation of RGE.
Highlights
It was evident from the Scanning electron microscopic (SEM) / transmission electron microscopic (TEM) studies that piperine– CTN mixture was more effective than piperine in altering the ultrastructural features of rat epidermis and this was manifested in the Transepidermal water loss (TEWL)
The immunofluorescence of HaCaT cells treated with piperine–CTN mixture indicated greater effect on ZO-1 protein as compared to treatment with piperine alone
The magnitude of the effect of piperine–CTN mixture observed in these studies was not reflected in the in vitro permeation enhancement of RGE across excised rat epidermis
Summary
The literature does not reveal any transdermal patch of RGE approved for human use This may be due to the excellent impervious nature of skin, which is the major impediment in the successful transcutaneous passage of almost all drugs. Most of the synthetic chemicals used for this purpose do not allow the skin to return to normal condition for very long duration [2] and often get transported into the systemic circulation [3]. It is for these reasons that the quest for safe and effective percutaneous permeation enhancers continues. Herbal enhancers are comparatively safer and possess great potential for use in transdermal formulation
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