ABSTRACT
In the present study, pluronic lecithin organogel (PLO) of diltiazem hydrochloride (DZH) was developed by taking different ratios of organic phase to aqueous phase (1:3, 1:4, and 1:5) with varying concentration of soya lecithin (20, 30, and 40 % w/w) in organic phase (isopropyl myristate, IPM) and pluronic (20, 25, and 30 % w/w) in aqueous phase, respectively, and characterized for in vitro parameters and ex vivo permeation study. The results of in vitro parameters were found to be within permissible limit and all the PLOs were physically stable at refrigeration and ambient temperature. The influence of phase ratio and different concentrations of soya lecithin on DZH release from the PLOs was found to be significant (p < 0.05), whereas the influences of different concentrations of pluronic were insignificant. The effect of different solvents/penetration enhancers viz. IPM, propylene glycol (PG), dimethyl sulphoxide (DMSO), and D-limonene, in combination and alone, on the permeation of DZH across the dorsal skin of rat was studied. Among all, formulation containing IPM (PLO6) exhibited highest flux of 147.317 µg/cm(2)/h. Furthermore, histopathology section of treated skin sample illustrated that lipid bilayer disruption was the mechanism for the DZH permeation. The above results indicated that PLO6 may serve as a promising alternative delivery system for DZH in the effective treatment of hypertension.
Subject(s)
Diltiazem/pharmacokinetics , Gels/chemistry , Lecithins/chemistry , Poloxamer/chemistry , Skin Absorption , Administration, Cutaneous , Animals , Cyclohexenes/chemistry , Diltiazem/chemistry , Dimethyl Sulfoxide/chemistry , Drug Delivery Systems/methods , Drug Liberation , Drug Stability , Limonene , Myristates/chemistry , Propylene Glycol/chemistry , Rats , Terpenes/chemistryABSTRACT
The objective of the present investigation was to develop and optimize reservoir-type of transdermal drug delivery system of Simvastatin using response surface methodology. A total of 17 experimental runs were conducted according to three-factor, three-level Box-Behnken design employing Design expert®2 software to determine the effect of independent variables (simvastatin concentration, percentage of poloxamer 407, and concentration of D-limonene) on cumulative amount of simvastatin permeation through human cadaver skin in 48 h (dependent variable). The experimental data was fitted to different response surface models using multiple regression analysis and observed quadratic model was the best fit model with significant p-value (pê0.0003) and coefficient of determination value of 0.9949. The second-order polynomial equation and response surface plots indicated the significant influence of concentration of simvastatin and D-limonene on the simvastatin permeation in 48 h. The highest simvastatin permeation value of 76.94 µg/cm2 was observed in case of experimental number 10 with 1.5% (w/w) of simvastatin, 25% (w/w) of poloxamer 407, and 10% (w/w) of D-limonene. Using Derringer's desirability functional tool for optimization, the highest simvastatin permeation value of 78.7684 µg/cm2 in 48 h was predicted under optimum condition of; simvastatin concentration of 1.4893% (w/w), poloxamer 407 percentage of 22.43% (w/w), and D-limonene concentration of 9.8541% (w/w) with optimum desirability value. The in-vivo hypolipidemic study conducted for 14 days in hyperlipidemia induced Sprague-Dawley rats revealed that the optimized patch exhibited significant lowering of blood lipid profile. Finally, histology study was performed on skin sample used in permeation study of optimized formulation and compared with untreated skin sample. The treated skin sample showed a significant distortion in stratum corneum, which supported the ex-vivo permeation result. Thus, the patch may serve as an alternative therapy to oral dosage form of simvastatin with outmost patient compliance.
Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Hyperlipidemias/drug therapy , Models, Statistical , Simvastatin/administration & dosage , Technology, Pharmaceutical/methods , Administration, Cutaneous , Animals , Biomarkers/blood , Cyclohexenes/chemistry , Disease Models, Animal , Drug Compounding , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemistry , Hydroxymethylglutaryl-CoA Reductase Inhibitors/metabolism , Hyperlipidemias/blood , Hyperlipidemias/diagnosis , Limonene , Lipids/blood , Male , Middle Aged , Permeability , Poloxamer/chemistry , Rats, Sprague-Dawley , Simvastatin/chemistry , Simvastatin/metabolism , Skin/metabolism , Skin Absorption , Terpenes/chemistry , Time Factors , Transdermal PatchABSTRACT
Since the approval of first transdermal patch (Transderm Scop(®)) containing scopolamine in 1979, the improvement in systemic drug delivery through skin remains incremental. The traditional methods based on passive diffusion of drug molecules in to the skin are unable to deliver macromolecules, such as peptides, proteins, DNA and vaccines, due to the barrier properties of stratum corneum (SC). During the course of approximately 35 years, the focuses are not only to overcome the above barrier property of the skin but also the safety, accuracy and patient compliance aspect of the traditional methods. The former limitation can be overcome by altering the SC barrier function by different active methods such electrically assisted methods (sonophoresis, iontophoresis, electroporation, magnetophoresis, pressure waves, electron beam irradiation), SC abruption (microneedles, high-velocity jet) and SC removal (tape-stripping, suction, microdermabrasion, ablation). This review summarizes basic principles, mechanisms, advantages, limitations and recent development of above physical techniques along with skin anatomy and drug transport pathways across skin.
