Statistically optimised ethosomes for transdermal delivery of tolterodine tartrate.

The aim of the current investigation is to optimize ethosomes statistically for enhancing transdermal potential of Tolterodine Tartrate (TT). Ethosomes bearing TT were prepared by cold method and characterized for various parameters like vesicle size, vesicle shape, surface morphology and % drug entrapment. Microscopic examinations suggest ethosomes as spherical unilamellar vesicles with a smooth surface. Optimized ethosomal vesicles were of 890±2.67nm size and showed 79.83±3.18% drug entrapment. Ex-vivo permeation studies across rat skin resulted in increased flux of 4.69±0.24µg/cm(2)/hr and decreased lag time of 0.13±0.05 hr when compared with drug solution (0.546±0.05µg/cm(2)/hr, 3±0.2 hr).This shows enhancement of transdermal delivery by 8.82 times. Anatomical changes in skin samples due to vesicle-skin interaction were observed on histological examination. Optimized formulation on storage at 4°C for 120 days showed insignificant growth in vesicular size revealing low aggregation of vesicles. The results collectively suggest ethosomes as carriers for accentuated transdermal delivery of TT.

Synergistic effect of iontophoresis and chemical enhancers on transdermal permeation of tolterodine tartrate for the treatment of overactive bladder.

PURPOSE: The objective of the study was to evaluate the synergistic transdermal permeation effect of chemical enhancers and iontophoresis technique on tolterodine tartrate (TT) transdermal gel and to evaluate its pharmacokinetic properties. MATERIALS AND METHODS: Taguchi robust design was used for optimization of formulations. Skin permeation rates were evaluated using the Keshary-chein type diffusion cells in order to optimize the gel formulation. In-vivo studies of the optimized formulation were performed in a rabbit model and histopathology studies of optimized formulation were performed on rats. RESULTS: Transdermal gels were formulated successfully using Taguchi robust design method. The type of penetration enhancer, concentration of penetration enhancer, current density and pulse on/off ratio were chosen as independent variables. Type of penetration enhancer was found to be the significant factor for all the responses. Permeation parameters were evaluated when maximum cumulative amount permeated in 24 hours (Q24) was 145.71 ± 2.00µg/cm² by CIT4 formulation over control (91.89 ± 2.30µg/cm²). Permeation was enhanced by 1.75 fold by CIT4 formulation. Formulation CIT4 containing nerolidol (5%) and iontophoretic variables applied (0.5mA/cm² and pulse on/off ratio 3:1) was optimized. In vivo studies with optimized formulation CIT4 showed increase in AUC and T1/2 when compared to oral suspension in rabbits. The histological studies showed changes in dermis indicating the effect of penetration enhancers and as iontophoresis was continued only for two cycles in periodic fashion so it did not cause any skin damage observed in the slides. CONCLUSION: Results indicated that iontophoresis in combination with chemical enhancers is an effective method for transdermal administration of TT in the treatment of overactive bladder.

Synergistic effect of iontophoresis and chemical enhancers on transdermal permeation of tolterodine tartrate for the treatment of overactive bladder

Purpose The objective of the study was to evaluate the synergistic transdermal permeation effect of chemical enhancers and iontophoresis technique on tolterodine tartrate (TT) transdermal gel and to evaluate its pharmacokinetic properties. Materials and Methods Taguchi robust design was used for optimization of formulations. Skin permeation rates were evaluated using the Keshary-chein type diffusion cells in order to optimize the gel formulation. In-vivo studies of the optimized formulation were performed in a rabbit model and histopathology studies of optimized formulation were performed on rats. Results Transdermal gels were formulated successfully using Taguchi robust design method. The type of penetration enhancer, concentration of penetration enhancer, current density and pulse on/off ratio were chosen as independent variables. Type of penetration enhancer was found to be the significant factor for all the responses. Permeation parameters were evaluated when maximum cumulative amount permeated in 24 hours (Q24) was 145.71 ± 2.00µg/cm2 by CIT4 formulation over control (91.89 ± 2.30µg/cm2). Permeation was enhanced by 1.75 fold by CIT4 formulation. Formulation CIT4 containing nerolidol (5%) and iontophoretic variables applied (0.5mA/cm2 and pulse on/off ratio 3:1) was optimized. In vivo studies with optimized formulation CIT4 showed increase in AUC and T1/2 when compared to oral suspension in rabbits. The histological studies showed changes in dermis indicating the effect of penetration enhancers and as iontophoresis was continued only for two cycles in periodic fashion so it did not cause any skin damage observed in the slides. Conclusion Results indicated that iontophoresis in combination with chemical enhancers is an effective method for transdermal administration of TT in the treatment of overactive bladder. .

Effect of chemical enhancers in transdermal permeation of alfuzosin hydrochloride.

The objective of the present study is to explore the efficient chemical penetration enhancer among the various enhancers available in overcoming the stratum corneum barrier in transdermal delivery of Alfuzosin hydrochloride (AH). The different enhancers were incorporated in 2% Carbopol gel which was selected as a control and evaluated by in vitro diffusion studies through dialysis membrane and permeation through the rat abdominal skin using Keshary-Chien diffusion cells. All the enhancers increased the release rate through the dialysis membrane when compared with control except oleic acid which decreased the release rate but showed maximum solubility of the drug. Among the various enhancers Transcutol 20% and tween-20 (2%) showed the highest cumulative amount (Q(24)) of 702.28 ± 6.97 µg/cm(2) and 702.74 ± 7.49 µg/cm(2), respectively. A flux rate of 31.08 ± 0.21 µg/cm(2)/hr by Transcutol 20% and 30.38 ± 0.18 µg/cm(2)/hr by tween-20 (2%) was obtained. Transcutol 20% showed decreased lag time of 0.13 ± 0.05 hr. The lowest skin content of 342.33 ± 5.30 µg/gm was seen with oleic acid 2.5%. Maximum enhancement of flux by 3.94-fold was obtained with transcutol 20%. Primary skin irritation studies were performed with rabbit. Histopathological studies of transcutol 20% showed marked changes such as degeneration and infiltration of mononuclear cells in dermis indicating the effect of transcutol on the skin. Among the different enhancers transcutol is efficient in enhancing transdermal delivery of AH.

Terpenes: Effect of lipophilicity in enhancing transdermal delivery of alfuzosin hydrochloride.

Transdermal drug delivery has attracted much attention as an alternative to intravenous and oral methods of delivery. But the main barrier is stratum corneum. Terpenes classes of chemical enhancers are used in transdermal formulations for facilitating penetration of drugs. The aim of the study is to evaluate terpenes as skin penetration enhancers and correlate its relationship with permeation and lipophilicity. In this study, alfuzosin hydrochloride (AH) hydrogels were prepared with terpenes using Taguchi orthogonal array experimental design. The formulations contained one of eight terpenes, based on their lipophilicity (log P 2.13-5.36). The percutaneous permeation was studied in rat skin using diffusion cell technique. Flux, cumulative amount, lag time and skin content of AH were measured over 24 hours and compared with control gels. Nerolidol with highest lipophilicity (log P 5.36 ± 0.38) showed highest cumulative amount (Q(24)) of 647.29 ± 18.76 µg/cm(2) and fluxrateof 28.16 ± 0.64 µg/cm(2)/hour. It showed decreased lag time of 0.76 ± 0.15 hours. Fenchone (2.5%) (log P 2.13 ± 0.30) produced the longest lag time 4.8 ± 0.20 hours. The rank order of enhancement effect was shown as nerolidol > farnesol > limonene > linalool > geraniol > carvone > fenchone > menthol. Lowest skin content was seen with carvone. Increase in lipophilicity of terpenes showed increase in flux, cumulative amount (Q(24)), and enhancement ratio which was significant with P < 0.000. But lag time was decreased and no correlation was found between lipophilicity and skin content. Histological studies showed changes in dermis which can be attributed to disruption of lipid packing of stratum corneum due to effect of nerolidol within lipid lamellae. It was found that small alcoholic terpenes with high degree of unsaturation enhance permeation of hydrophilic drugs, liquid terpenes enhance better than solid terpenes and terpenes with high lipophilicity are good penetration enhancers.