Development of Nanonized Nitrendipine and Its Transformation into Nanoparticulate Oral Fast Dissolving Drug Delivery System.

The present research focuses on the development of a nanoparticulate (nanocrystals-loaded) rapidly dissolving (orodispersible) tablet with improved solubility and bioavailability. The nanosuspension (NS) was prepared by antisolvent sonoprecipitation technique and the optimized NS was lyophilized to obtain nanocrystals (NCs), which were evaluated for various parameters. The nitrendipine (NIT) nanoparticulate orodispersible tablet (N-ODT) was prepared by direct compression method. The optimized N-ODT was evaluated for pre and post compression characteristics, in vivo pharmacokinetic and stability profile. The optimized NS showed a particle size of 505.74 ± 15.48 nm with a polydispersity index (PDI) of 0.083 ± 0.006. The % NIT content in the NCs was found to be 78.4 ± 2.3%. The saturation solubility of NIT was increased remarkably (26.14 times) in comparison to plain NIT, post NCs development. The DSC and p-XRD analysis of NCs revealed the perseverance of the integrity and crystallinity of NIT on lyophilization. The results of micromeritic studies revealed the good flow-ability and compressibility of NCs blend. All the post-compression properties of N-ODT were observed within the standard intended limit. The dispersion, wetting, and disintegration time of the optimized batch of N-ODT was found to be 39 ± 1.13 s, 44.66 ± 1.52 s, and 33.91 ± 0.94 s respectively. The in vitro dissolution study displayed 100.28 ± 2.64% and 100.61 ± 3.3% of NIT released from NCs (in 8 min) and N-ODT (in 6 min) respectively, while conventional NIT tablet took 30 min to release 99.94 ± 1.57% of NIT. The in vivo pharmacokinetic study in rabbits demonstrated significantly (p < 0.05) higher bioavailability of NIT on release from N-ODT than the conventional NIT tablet. Thus, N-ODT could be a promising tool for improving the solubility and bioavailability of NIT and to treat cardiovascular diseases effectively.

Validated LC-MS/MS method for the simultaneous determination of enalapril maleate, nitrendipine, hydrochlorothiazide, and their major metabolites in human plasma.

Hypertension is a major risk factor for atherosclerosis and ischemic heart disease. Most hypertensive patients need a combination of antihypertensive agents to achieve therapeutic goals. A rapid, sensitive, and selective liquid chromatography-tandem mass spectrometric method was developed and validated for simultaneous determination of enalapril maleate (ENA) and its major metabolite enalaprilat (ENAT), nitrendipine (NIT) and its major metabolite dehydronitrendipine (DNIT), and hydrochlorothiazide (HCT) in human plasma using felodipine as an internal standard (IS). The drugs were extracted from plasma using one-step protein precipitation. Chromatographic separation was performed on a Symmetry C18 column, with water and acetonitrile (10:90, v/v) as mobile phase. The detection was carried out using multiple reaction monitoring mode and coupled with electrospray ionization source. Multiple reaction monitoring transitions were m/z 377.1 → 234.1 for ENA, m/z 349.2 → 206.1 for ENAT, m/z 361.2 → 315.1 for NIT, m/z 359 → 331 for DNIT, m/z 295.9 → 205.1 for HCT, and m/z 384.1 → 338 for felodipine (IS). The method was linear over concentration ranges of 1-200, 20-500, 5-200, 2-100, and 5-200 ng/mL for ENA, ENAT, NIT, DNIT, and HCT, respectively, with r2 ≥ 0.99. Method validation was performed according to U.S. Food and Drug Administration guidelines. The validated method showed good sensitivity and selectivity and could be applied for therapeutic drug monitoring and bioequivalence studies.

Preparation of a Mesoporous Structure of SnO2 for Increasing the Oral Bioavailability and Dissolution Rate of Nitrendipine.

In this study, mesoporous SnO2 (MSn) with a three-dimensional mesoporous structure was prepared using MCM-48 as the template in order to increase the oral bioavailability and dissolution rate of insoluble drugs. The model drug, nitrendipine (NDP), was loaded into the MSn by the adsorption method. The structural features of MSn were characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), and N2 adsorption (desorption) analysis. NDP was existed in the pore channels of MSn in an amorphous state, which was characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR). MSn showed a good biocompatibility in the cell toxicity assay for Caco-2 cells. In vitro dissolution results suggested that MSn could significantly enhance the dissolution rate of NDP compared with commercial NDP tablets. Pharmacokinetic studies indicated that NDP-MSn tablets effectively enhanced the oral bioavailability of NDP. In conclusion, MSn was found to be a potential carrier for improving the solubility of insoluble drugs.

Nanovesicles of nitrendipine with lipid complex for transdermal delivery: pharmacokinetic and pharmacodynamic studies.

CONTEXT: Vesicular transdermal delivery can enhance the bioavailability of a drug especially affected by first-pass metabolism, e.g. nitrendipine. However effective transdermal delivery employs permeation enhancer, e.g oleic acid (OA) with ceramide 2, stearic acid, behenic acid, and cholesteryl sulfate lipid complex. OBJECTIVE: This study investigated the preparation, characterization of physicochemical properties, ex vivo permeation using human skin, pharmacokinetic parameters and antihypertensive potential in rats, of nitrendipine-loaded nanovesicles of ceramide 2, stearic acid, behenic acid and cholesteryl sulfate containing oleic acid gel (NOVG). MATERIALS AND METHODS: The nanovesicles were made using film hydration method and characterized for physicochemical properties, ex vivo permeation using human skin, pharmacokinetic parameters and antihypertensive potential. RESULTS: Nitrendipine-loaded nanovesicles of ceramide-2 containing oleic acid (NOV-5) have shown fluxes in the range of 4.88-24.72 µg/cm(2)/h nitrendipine oral suspension (NOS) at equal dose. NOVG-5 has shown almost 33% reduction in blood pressure in the first hour and a further decrease of 25% in the second hour to restore the normal pressure. DISCUSSION: The permeation increases with increase in OA content. OA gets integrated in vesicle wall and enhances its permeability, whereas ceramide content makes sure that skin does not become damaged even after permeation. CONCLUSION: NOVG-5 has shown the most favorable physicochemical properties and good permeation through skin providing good management of hypertension during crucial initial hours.

Preparation of starch macrocellular foam for increasing the dissolution rate of poorly water-soluble drugs.

Starch macrocellular foam (SMF), a novel natural bio-matrix material, was prepared by the hard template method in order to improve the dissolution rate and oral bioavailability of poorly water-soluble drugs. Nitrendipine (NDP) was chosen as a model drug and was loaded into SMF by the solvent evaporation method. SMF and the loaded SMF samples (NDP-SMF) were characterized by scanning electron microscopy, differential scanning calorimetry, X-ray powder diffraction and Fourier transform infrared spectroscopy. In vitro drug release studies showed that SMF significantly increased the dissolution rate of NDP. In vivo studies showed that the NDP-SMF tablets clearly increased the oral bioavailability of NDP in comparison with the reference commercial tablets. All the results obtained demonstrated that SMF was a promising carrier for the oral delivery of poor water-soluble drugs.

Effect of silibinin on the pharmacokinetics of nitrendipine in rabbits.

Silibinin, a major constituent of silymarin, is widely used for its hepatoprotective effects. This study investigated the effect of silibinin on the pharmacokinetics of oral nitrendipine in rabbits. In first set of experiment, male New Zealand rabbits were pretreated with silibinin (50 mg/kg, PO) for 7 days and on last day nitrendipine (10 mg/kg, PO) was administered. In second set, both silibinin and nitrendipine were coadministered to examine acute effect of silibinin on nitrendipine pharmacokinetics. The plasma concentration of nitrendipine was estimated by high performance liquid chromatography and different pharmacokinetic parameters were calculated using WinNonlin(®) software. Coadministration of silibinin had no significant effect on pharmacokinetics of nitrendipine when compared to control group. However, a 1.89-1.57-fold increase in area under the concentration-time curve and peak plasma concentration (C max), respectively, of nitrendipine was observed in silibinin pretreated group. The mean C max was 0.034 ± 0.005 µg/mL (nitrendipine alone) and 0.054 ± 0.006 µg/mL (nitrendipine after pretreatment with silibinin). The time to reach C max, elimination rate constant and elimination half-life of nitrendipine were not significantly different among control and silibinin treated groups. This study demonstrates that silibinin increase plasma concentration of nitrendipine. Henceforth, the pharmacodynamic influence of this interaction should be taken into consideration while prescribing nitrendipine to the patients already taking silymarin.

Is pomegranate juice a potential perpetrator of clinical drug-drug interactions? Review of the in vitro, preclinical and clinical evidence.

The area of fruit juice-drug interaction has received wide attention with numerous scientific and clinical investigations performed and reported for scores of drugs metabolized by CYP3A4/CYP2C9. While grapefruit juice has been extensively studied with respect to its drug-drug interaction potential, numerous other fruit juices such as cranberry juice, orange juice, grape juice, pineapple juice and pomegranate juice have also been investigated for its potential to show drug-drug interaction of any clinical relevance. This review focuses on establishing any relevance for clinical drug-drug interaction potential with pomegranate juice, which has been shown to produce therapeutic benefits over a wide range of disease areas. The review collates and evaluates relevant published in vitro, preclinical and clinical evidence of the potential of pomegranate juice to be a perpetrator in drug-drug interactions mediated by CYP3A4 and CYP2C9. In vitro and animal pharmacokinetic data support the possibility of CYP3A4/CYP2C9 inhibition by pomegranate juice; however, the human relevance for drug-drug interaction was not established based on the limited case studies.

In vitro to in vivo extrapolation and physiologically based modeling of cytochrome P450 mediated metabolism in beagle dog gut wall and liver.

The beagle dog is a widely used in vivo model to guide clinical formulation development and to explore the potential for food effects. However, the results in dogs are often not directly translatable to humans. Consequently, a physiologically based modeling strategy has been proposed, using the dog as a validation step to verify model assumptions before making predictions in humans. One current weakness in this strategy is the lack of validated tools to incorporate gut wall metabolism into the dog model. In this study, in vitro to in vivo extrapolation factors for CYP2B11 and CYP3A12 mediated metabolism were established based on tissue enzyme abundance data reported earlier. Thereafter, physiologically based modeling of intestinal absorption in beagle dog was conducted in GastroPlus using V(max) and K(m) determined in recombinant enzymes as inputs for metabolic turnover. The predicted fraction of absorbed dose escaping the gut wall metabolism (F(g)) of all five reference compounds studied (domperidone, felodipine, nitrendipine, quinidine, and sildenafil) were within a two-fold range of the value estimated from in vivo data at single dose levels. However, further in vivo studies and analysis of the dose-dependent pharmacokinetics of felodipine and nitrendipine showed that more work is required for robust forecasting of nonlinearities. In conclusion, this study demonstrates an approach for prediction of the gut wall extraction of CYP substrates in the beagle dog, thus enhancing the value of dog studies as a component in a strategy for the prediction of human pharmacokinetics.

The development of a novel dry powder inhaler.

A novel active and multi-dose dry powder inhaler (DPI) was developed and evaluated to deliver a small quantity (100-500 µg) of pure drug without any excipient. This dry powder inhaler utilized two compressed air flows to dispense and deliver drug powder: the primary flow aerosolizes the drug powder from its pocket and the secondary flow further disperses the aerosol. In vitro tests by Anderson Cascade Impactor (ACI) indicated that the fine particle fraction (FPF) (<4.7 µm) of drug delivery could reach over a range of 50-70% (w/w). Emitted dose tests showed that delivery efficiency was above 85% and its relative standard deviation (RSD) was under 10%. Confocal microscopy was used to confirm the deposition of fluorescently labeled spray-dried powder in rabbit lungs. Also, a chromatographic method was used to quantify drug deposition. The results of animal tests showed that 57% of aerosol deposited in the rabbit lung and 24% deposited in its trachea. All the results implied that this novel active dry powder inhaler could efficiently deliver a small quantity of fine drug particles into the lung with quite high fine particle fraction.

A novel surface modified nitrendipine nanocrystals with enhancement of bioavailability and stability.

In this study, chitosan, a cationic polymer with positive charge, was introduced to modify the nanocrystals of nitrendipine with negative charge. The nanocrystals were prepared via precipitation-high pressure homogenization method. Then the nanocrystals were dispersed into chitosan solution, and the free chitosan was removed by centrifugation to obtain the chitosan modified nanocrystals, which remained the same particle size. However, the zeta-potential changed to positive after modification. The physical stability of the chitosan modified nanocrystals was remarkably improved under ambient conditions. During the in vitro dissolution test, the modified nanocrystals showed a certain degree of slow-release property. In the in vivo study, the C(max) of nitrendipine remained the same, however, the T(max) delayed from 0.75 h to 1.5 h with the chitosan modified nanocrystals. The surface modification by chitosan improved the bioavailability compared with the initial nanocrystals, which had demonstrated significant improvement of bioavailability compared to the traditional coarse powder form. Based on the experimental results, modification of the nanocrystals with certain polymer was supposed to be a good method to control the in vitro and in vivo behaviors of the nanocrystals, which could further increase the bioavailability of the water insoluble drug.

Effect of pomegranate juice on intestinal transport and pharmacokinetics of nitrendipine in rats.

Pomegranate juice (PJ) is known to be a potent inhibitor of human cytochromes (CYP), particularly CYP2C9 and CYP3A4. The purpose of this study was to investigate the effect of oral PJ on the pharmacokinetics of nitrendipine (10 mg/kg) in rats. The effect of PJ was also investigated on the absorption kinetics of nitrendipine in rats using a single-pass intestinal perfusion model. There was a significant increase in effective permeability, absorption rate constant and fraction of drug absorbed in the pretreated group when compared with the control group, probably due to inhibition of the P-glycoprotein-mediated efflux of the drug by PJ. In comparison with control, PJ treatment significantly increased the area under the concentration-time curve of oral nitrendipine. The peak plasma concentration of nitrendipine was also significantly increased by PJ. However, elimination half-life of nitrendipine was not altered significantly in both PJ co-administered and pretreated groups. These results suggest that PJ inhibits the intestinal metabolism of nitrendipine without inhibiting the hepatic metabolism in rats. Therefore, the concomitant use of PJ, as food supplement, and nitrendipine should be avoided, although further clinical studies need to be undertaken in order to confirm this finding.

Effect of pomegranate juice on the pharmacokinetics of nitrendipine in rabbits.

Pomegranate juice (PJ) is known to be a potent inhibitor of human cytochrome enzymes. The purpose of this study was to investigate the effect of acute and chronic PJ on the pharmacokinetics of oral nitrendipine (10 mg/kg) in rabbits. Male New Zealand rabbits were pretreated with PJ for 1 week and on the last day, a single dose of nitrendipine was given orally. In another group, both PJ and nitrendipine were co-administered to evaluate the acute effect of PJ on nitrendipine pharmacokinetics. The control group received oral distilled water for 1 week and administered with nitrendipine on the last day. Blood samples were collected at different time points and nitrendipine concentration was estimated by high-performance liquid chromatography. Relative to control, the area under the concentration-time curve and peak plasma concentration of nitrendipine were 2.03- and 2-fold, respectively, greater in the PJ-pretreated group. However, co-administration of PJ had no significant effect on these parameters. Further, there was no significant change in the elimination rate constant and elimination half-life of nitrendipine in both PJ co-administered and pretreated groups in comparison with control. These results suggest that PJ inhibits the intestinal metabolism of nitrendipine without affecting hepatic metabolism in rabbits. Although this potential interaction needs to be explored further, the concomitant use of PJ and nitrendipine should be avoided.

Simultaneous determination of nitrendipine and hydrochlorothiazide in spontaneously hypertensive rat plasma using HPLC with on-line solid-phase extraction.

A HPLC method with on-line solid phase extraction (SPE) and DAD detection was developed for the simultaneous determination of nitrendipine and hydrochlorothiazide in spontaneously hypertensive rat (SHR) plasma. Plasma samples (100 µL) were injected directly onto a CAPCELL MF C(8) SPE column. High-abundance proteins and most matrixes in plasma were removed by on-line SPE technology, while nitrendipine and hydrochlorothiazide trapped on the SPE column were effectively separated on a C(18) analytical column. The column temperature was maintained at 20°C. The optimal detection wavelength was 237 nm for NTDP and 271 nm for HCTZ. The total analytical run time was 34 min. The proposed method was linear over the range 5-500 ng mL(-1) for nitrendipine and 10-1000 ng mL(-1) for hydrochlorothiazide. The lower limit of detection (LLOD) was 0.5 and 0.6 ng mL(-1) for nitrendipine and hydrochlorothiazide, respectively. The sensitivity and precision of the method were within acceptable limits during validation period. The method was successfully used to investigate the pharmacokinetic characteristics of nitrendipine and hydrochlorothiazide in spontaneously hypertensive rats.

Nitrendipine nanocrystals: its preparation, characterization, and in vitro-in vivo evaluation.

The present investigation was undertaken with the objective of developing a solid formulation containing nitrendipine nanocrystals for oral delivery. Nitrendipine nanocrystals were prepared using a tandem precipitation-homogenization process. Then, spray drying, a cost-effective method very popular in industrial situations, was employed to convert the nanocrystals into a solid form. The parameters of the preparation process were investigated and optimized. The optimal process was as follows: firstly, nitrendipine/acetone solution (100 mg/ml) was added to a polyvinyl alcohol solution (1 mg/ml) at 10°C, then the pre-suspension was homogenized for 20 cycles at 1,000 bar. Both differential scanning calorimetry and X-ray diffraction analysis indicated that nitrendipine was present in crystalline form. The in vitro dissolution rate of the nanocrystals was significantly increased compared with the physical mixture and commercial tablet. The in vivo testing demonstrated that the C(max) of the nanocrystals was approximately 15-fold and 10-fold greater than that of physical mixture and commercial tablet, respectively. In addition, the AUC(0→24) of the nanocrystals was approximately 41-fold and 10-fold greater than that of physical mixture and commercial tablet, respectively.

Development of a LC-ESI-MS3 method for determination of nitrendipine in human plasma.

A novel and sensitive method utilizing high performance liquid chromatography coupled with electrospray ionization source tandem mass spectrometry (LC-ESI-MS(3)) was developed for the first time in order to analyze nitrendipine in human plasma samples. Human plasma samples were prepared by protein precipitation with acetonitrile and well resolved on a 100 mm reversed-phase column in gradient elution with 0.05% (v/v) formic acid in acetonitrile as the mobile phase. Determination was performed in MS(3) scan mode for nitrendipine and in the multiple reaction monitoring (MRM) mode for nimodipine (internal standard). This method, having a lower limit of quantification (LLOQ) of 0.05 ng/mL when using a 100 µL sample aliquot (5 pg/sample), is acceptable for calibration of the linearity and repeatability and is of better sensitivity than the reported methods (>0.25 ng/mL). The major advantages of the method are that small sample volume (100 µL) is required, simple sample processing technique, high sensitivity and excellent selectivity is guaranteed by the MS(3) detection. The proposed validated method has been successfully applied to a clinical study on nitrendipine.

Ultra-performance liquid chromatography-tandem mass spectrometry method for the determination of nitrendipine in dog plasma and its application to a pharmacokinetic study of a solid self-emulsifying pellet formulation.

A rapid, sensitive and selective ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the quantitative determination of nitrendipine (NTD, CAS 39562-70-4) in dog plasma. Using propranolol hydrochloride (CAS 318-98-9) as an internal standard (IS), plasma samples pretreatment adopted a simple liquid-liquid extraction process with diethyl ether. Separation was carried out by a gradient elution on an Acquity UPLC BEH C18 column with a mobile phase consisting of water (containing 0.1% formic acid) and acetonitrile. Detection was performed by a triple-quadrupole mass spectrometry with positive electrospray ionization (ESI) as source ionization in multiple-reaction monitoring (MRM) mode at m/z 361.0 --> 315.0 for NTD and m/z 260.2 --> 116.0 for IS. The method demonstrated good linearity at the concentrations ranged from 0.1-200 ng/mL and the lower limit of quantification (LLOQ) of NTD was 0.1 ng/mL. The intra- and inter-day relative standard deviations (RSD) were less than 10%. The mean extraction recoveries of NTD and IS were 90.2% and 82.4%, respectively. Finally, the method was successfully applied to a pharmacokinetic study of home-made solid self-emulsifying pellets and conventional NTD tablets in beagle dogs following a single oral administration.

Effect of crystal size on the in vitro dissolution and oral absorption of nitrendipine in rats.

PURPOSE: To investigate the effect of crystal size on the dissolution and oral absorption of nitrendipine, a poorly soluble drug, in rats. METHODS: Five types of nitrendipine crystal suspensions with different particle sizes (200 nm, 620 nm, 2.7 microm, 4.1 microm, 20.2 microm) were prepared either by the precipitation-ultrasonication or the anti-solvent precipitation method. The simulated intestinal fluid in the fasted state (FaSSIF) was selected as the dissolution medium, and the dissolution behaviors of different nitrendipine crystals were simulated based on a Noyes-Whitney type equation. The in vivo absorption and the absolute bioavailability of the different nitrendipine crystals were evaluated in Wistar rats. RESULTS: The dissolution rate of nitrendipine was significantly increased by a reduction in particle size. The dissolution test in FaSSIF could discriminate between the differences in the dissolution rates of the different particle sizes, and the simulated results were in agreement with the observed dissolution curves. From the simulated T(50%) values (50% dissolution time), the dissolution rates of crystals with particle sizes of 200 nm, 620 nm, 2.7 microm, 4.1 microm and 20.2 microm were calculated to be 5.1 x 10(4), 1.0 x 10(4), 237, 64 and 11-fold greater than that of the raw crystals and resulted in absolute bioavailability of 61.4% 51.5%, 29.4%, 26.7%, 24.7%, respectively. The reduction in the drug particle size correlated well with incremental improvements in oral absorption. A good linear relationship was observed between the Log (T(50%)) and the absolute bioavailability of nitrendipine. CONCLUSIONS: The dissolution rate and the oral bioavailability of nitrendipine were significantly affected by the crystal size, and the oral bioavailability could be improved significantly by preparing it as nanocrystals. FaSSIF can be used to predict differences in oral absorption of crystals with different particle sizes.

Preparation of stable nitrendipine nanosuspensions using the precipitation-ultrasonication method for enhancement of dissolution and oral bioavailability.

The aim of this study was to prepare and characterize nitrendipine nanosuspensions to enhance the dissolution rate and oral bioavailability of this drug. Nanosuspensions were prepared by the precipitation-ultrasonication method. The effects of five important process parameters, i.e. the concentration of PVA in the anti-solvent, the concentration of nitrendipine in the organic phase, the precipitation temperature, the power input and the time length of ultrasonication on the particle size of nanosuspensions were investigated systematically, and the optimal values were 0.15%, 30 mg/ml, below 3 degrees C, 400 W and 15 min, respectively. The particle size and zeta potential of nanocrystals were 209 nm (+/- 9 nm) and -13.9 mV (+/-1.9 mV), respectively. The morphology of nanocrystals was found to be flaky in shape by scanning electron microscopy (SEM) observation. The X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) analysis indicated that there was no substantial crystalline change in the nanocrystals compared with raw crystals. The in vitro dissolution rate of nitrendipine was significantly increased by reducing the particle size. The in vivo test demonstrated that the C(max) and AUC(0-->12) values of nanosuspension in rats were approximately 6.1-fold and 5.0-fold greater than that of commercial tablets, respectively.

Formulation and evaluation of monolithic matrix polymer films for transdermal delivery of nitrendipine.

The objective of the present work was to develop a suitable transdermal drug delivery system for nitrendipine. Polymeric films of nitrendipine were prepared by the film casting technique (glass ring) on mercury substrate. They were evaluated for physicochemical parameters, in vitro release and ex vivo permeation (heat separated human epidermis). Release of the drug from the films followed anomalous transport (0.5 < n < 1).Polymeric combination containing Eudragit RL 100:PVP K 30 in a 4:6 ratio showed the best results. Maximum drug release and skin permeability coefficient in 48 h were 85.8% and 0.0142 cm h(-1), respectively, in formulation C3 (Eudragit RL 100/Plasdone S 630; 4:6) and 88.0% and 0.0155 cm h(-1), respectively, in formulation, D3 (Eudragit RL 100/PVP K 30; 4:6). FTIR and TLC studies indicated no drug and polymer interaction.

Design, development, physicochemical, in vitro and in vivo evaluation of monolithic matrix type transdermal patches containing nitrendipine.

The matrix type transdermal drug delivery systems (patches) of Nitrendipine were prepared by film casting technique. The patches were characterized for physical, in vitro release studies and ex-vivo permeation studies (human cadaver skin). On the basis of in vitro drug release and skin permeation performance, formulation B3 was found to be better than the other formulations and it was selected as the optimized formulation. The final optimized formulation (B3) was subjected to skin irritation, pharmacokinetic, pharmacodynamic and stability studies. The maximum percentage drug release in 48 hours was 94.67 +/- 3.25 for B3 and 91.43 +/- 2.106 for A2 formulation. Again formulation B3 (0.0627 mg/cm2/h) and A2 (0.0566 mg/cm2/h) showed maximum skin flux in the respective series. Patches prepared with Plasdone S-630 were more flexible as compared to PVP K 30 containing patches. Patches prepared with PVP K 30 showed drug release and skin permeation at higher percentage as compared to those containing Plasdone S-630. The interaction studies carried out by comparing the results of ultraviolet, infrared, TLC and DSC analyses for the pure drug, medicated and placebo formulations indicated no chemical interaction between the drug and excipients. The TDDS was found to be free of any skin irritation as suggested by skin irritation score of 1.16 (< 2.00) under Draize score test.