Transdermal drug delivery of imipramine hydrochloride.: I. Effect of terpenes

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Abstract

The objective of this investigation was to study the effect of different terpenes on IMH permeation in EtOH:W (2:1) system. Permeation studies of IMH were carried out with unjacketed Franz diffusion cells through rat skin. The flux of IMH with terpenes was found to be significantly higher than that in control (EtOH:W, 2:1) (P<0.05). Amongst all studied terpenes, menthol, terpineol, cineole and menthone were found to be effective permeation enhancers for IMH. It was found that the contribution of diffusivity in enhanced permeation of IMH was much higher in comparison to partitioning of IMH in skin with terpene treatment. Results of this study were explained with the help of H-bond breaking potential and self-association of terpenes. In order to elucidate the effect of terpenes on stratum corneum barrier FT-IR was used.

Introduction

TCAs are widely used in treatment of unipolar and bipolar depression, which is characterized by extreme sadness, despair and anhedonia. The problem of high first-pass metabolism, variation in gastrointestinal absorption [1] and patient non-compliance with conventional per oral delivery can be overcome with transdermal delivery of TCAs. As transdermal delivery offer inherent advantages such as: (a) by-passes first pass metabolism; (b) enables control of input; (c) avoids problems of stomach emptying, pH effects and enzymatic deactivation associated with gastrointestinal tract passage [2]. However, their poor permeability and high dose are the major hurdles in delivery across the skin. Panchagnula [3] and Stott et al. [4] have suggested the use of solvent, e.g., dimethylsulfoxide, dimethylacetamide and complex coacervation technique, respectively, for enhancement of TCAs permeation through skin [3], [4]. With these approaches flux of IMH was not high enough to achieve the desired plasma level. Therefore, in this investigation terpenes were selected as permeation enhancers to study their effect on IMH in vitro permeation across the rat skin. Terpenes are non-toxic and non-irritant [5] to skin and are extensively used in transdermal delivery as permeation enhancers with hydrophilic (5-fluorouracil [6], propanolol hydrochloride [7]) and lipophilic (indomethacin and ketoprofen [8], estradiol [9]) drugs. In addition, FT-IR was used to elucidate the mechanism of action of terpenes effect on lipid bilayer of SC.

Section snippets

Materials

IMH and cineole were procured from Sigma (St. Louis, MO, USA). [3H]IMH (specific activity, 48.00 Ci/mmol) was obtained from Du Pont (Wilmington, DE). Pulegone, α-terpineol, menthol, ethanol, carvone and menthone were purchased either from Merck, (Germany) or Fluka Chem (Germany). Tissue solubilizer (NCS II) and scintillation cocktail (BCS 104) were purchased from Amersham (UK). All other chemicals used were of reagent grade.

Preparation of full thickness skin

The skin samples were harvested from the dorsal surface of the Sprague–Dawley rats. Hair on dorsal skin of animal was removed with animal hair clipper (Aesculp, Germany), subcutaneous tissue was surgically removed and dermis side was wiped with isopropyl alcohol to remove residual adhering fat. The skin was washed with distilled water, wrapped in aluminium foil and stored in a freezer at −20°C till further use. The protocol for this study was approved by NIPER’s Institutional Animal Ethics

Results and discussion

Permeation profile of IMH with and without the treatment of terpenes is shown in Fig. 1. Flux values of IMH, with and without terpene treatment are given in Table 1, in decreasing order is as follows; menthol≥cineole>terpineol>menthone>pulegone>carvone>control (EtOH:W, 2:1). Flux of IMH in terpenes was significantly different from control (EtOH:W, 2:1) (P<0.05). However, among the terpenes, flux of IMH with menthol, cineole and terpineol was significantly different from pulegone and carvone (P

Conclusions

Amongst all the terpenes, menthol was found to be an effective permeation enhancer for IMH. In general, it was observed that terpenes with minimum degree of unsaturation, like menthol, cineole, menthone, are good permeation enhancers for polar and water-soluble drugs, such as IMH. The disruption of the hydrogen bond network at the head of ceramides by terpenes is a probable mechanism for enhanced permeation of IMH, as supported by the FT-IR results of this study and literature reports on DSC

Acknowledgements

One of the authors (AKJ) is thankful to Council of Scientific and Industrial Research, India (CSIR, Grant sanction no. 01(1460)/97/EMRII) for financial support.

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