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