Ahmed Elshafeey

Background: Favipiravir is an antiviral drug that was recently approved for the management of COVID-19 infection. Aim: This work aimed to develop a new method, using sugaring-out induced homogeneous liquid-liquid microextraction followed by HPLC/UV for the determination of favipiravir in human plasma. Materials & methods: The optimum extraction conditions were attained using 500 μl of tetrahydrofuran as an extractant and 1400 mg of fructose as a phase-separating agent. Results: The developed method was validated according to the US FDA bioanalytical guidelines and was found linear in the range of 25-80,000 ng/ml with a correlation coefficient of 0.999. Conclusion: These results showed that the developed method was simple, easy, valid and adequately sensitive for determination of favipiravir in plasma for bioequivalence studies. © 2022 Newlands Press.

Favipiravir is a potential antiviral medication that has been recently licensed for Covid-19 treatment. In this work, a gadolinium-based magnetic ionic liquid was prepared and used as an extractant in dispersive liquid–liquid microextraction (DLLME) of favipiravir in human plasma. The high enriching ability of DLLME allowed the determination of favipiravir in real samples using HPLC/UV with sufficient sensitivity. The effects of several variables on extraction efficiency were investigated, including type of extractant, amount of extractant, type of disperser and disperser volume. The maximum enrichment was attained using 50 mg of the Gd-magnetic ionic liquid (MIL) and 150 μl of tetrahydrofuran. The Gd-based MIL could form a supramolecular assembly in the presence of tetrahydrofuran, which enhanced the extraction efficiency of favipiravir. The developed method was validated according to US Food and Drug Administration bioanalytical method validation guidelines. The coefficient of determination was 0.9999, for a linear concentration range of 25 to 1.0 × 105 ng/ml. The percentage recovery (accuracy) varied from 99.83 to 104.2%, with RSD values (precision) ranging from 4.07 to 11.84%. The total extraction time was about 12 min and the HPLC analysis time was 5 min. The method was simple, selective and sensitive for the determination of favipiravir in real human plasma. © 2022 John Wiley & Sons, Ltd.

Bilosomes are innovative vesicular carriers containing bile salt with a non-ionic surfactant. Being highly flexible, bilosomes can squeeze themselves through the skin carrying the drug to the action site and improving its skin penetration. The objective of this research was to encapsulate niflumic acid (NA), a non-steroidal anti-inflammatory drug into Brij® integrated bilosomes (BIBs) for effective treatment of osteoarthritis through transdermal delivery. BIBs were formulated using 100 mg of Span 20 with different amounts of sodium cholate (NaC), sodium taurocholate (NaTC), or sodium glycocholate (NaGC) as bile salt, with the addition of 5 mg of Brij-93 or Brij-35. BIBs were prepared utilizing ethanol injection method with the application of (31 × 22) complete factorial design using Design-Expert® software. The optimal BIBs formulation determined was (B5) which contains 5 mg of NaTC used as bile salt and 5 mg of Brij-93. B5 exhibited entrapment efficiency% = 95.21 ± 0.00%, particle size = 373.05 ± 0.07 nm, polydispersity index = 0.27 ± 0.01, and zeta potential = –32.00 ± 0.00 mV. It also had a high elasticity with a spherical shape. B5 gel displayed a sustained release profile with a significantly 2.3 folds’ higher drug permeation percent across rat skin than that permeated from NA gel. Moreover, in vivo anti-osteoarthritic and histopathological studies assured the efficacy and safety of B5 gel and its superiority over NA gel. Generally, the outcomes confirmed the great efficacy of NA loaded BIBs for the topical treatment of osteoarthritis. © 2023 Elsevier B.V.

The consumption of non-steroidal anti-inflammatory drugs (NSAIDs) have increased lately around the world, as they are considered essential and popular drugs for effective reduction of pain and inflammation. They have analgesic, antipyretic, and anti-inflammatory activities; also, it was reported recently that they protect against various critical disorders like heart attacks and cancer. However, oral use of NSAIDs may cause several pulmonary, gastrointestinal, hepatic, cardiovascular, cerebral, and renal complications. Therefore, topical NSAIDs were recommended as a substitute to oral NSAIDs for the treatment of inflammation and pain. Still, the skin permeation of NSAIDs is considered a challenge, as the skin have an effective barrier function. Therefore, this review investigates various advanced vesicular nanocarriers and their applications through the skin, to augment the topical delivery of NSAIDs through stratum corneum over the conventional systems, enhance their effectiveness, and reduce the unwanted side effects. These innovative systems can manage bioavailability, solubility, stability, safety, and efficacy issues present in conventional systems. © 2023, The Author(s).

{Purpose: The aim of this study was to encapsulate clotrimazole (CLT), an antifungal drug with poor water solubility characteristics, into spanlastics (SPs) to provide a controlled ocular delivery of the drug. Methods: Span 60 was used in the formulation of SPs with Tween 80, Pluronic F127, or Kolliphor RH40 as an edge activator (EA). The presence of EA offers more elasticity to the membrane of the vesicles which is expected to increase the corneal permeation of CLT. SPs were prepared using ethanol injection method applying 32 complete factorial design to study the effect of formulation variables (ratio of Span 60: EA (w/w) and type of EA) on SPs characteristics (encapsulation efficiency percent (EE%), average vesicle size (VS), polydis-persity index (PDI) and zeta potential (ZP)). Design-Expert software was used to determine the optimum formulation for further investigations. Results: The optimum formulation determined was S1, which contains 20 mg of Tween 80 used as an EA and 80 mg of Span 60. S1 exhibited EE% = 66.54 ± 7.57%

Famotidine HCl has low bioavailability (40-45%) due to its narrow absorption window and low solubility in intestinal pH. Lipids were utilized in the formulation of novel gastroretentive dosage forms to increase the availability of famotidine HCl at its absorption site. Novel non-swellable gastroretentive lipid disks (D) and swellable compression coated tablets with a lipid core (T) were prepared. Formulae were characterized by friability testing, in-vitro buoyancy, in-vitro drug release and scanning electron microscopy (SEM). Factorial designs of 22× 31 and 32 were planned for the optimization of disks and tablets, respectively, using Design-Expert® software. X-ray imaging was used for the in-vivo visualization of the selected formula in human gastrointestinal tract (GIT). Moreover, a bioavailability study was performed in healthy human volunteers using the optimized disk formula (D10). Results showed that formulae D10 (containing stearyl alcohol and polyethylene glycol in a ratio of 9:1 w/w) and T7 (containing polyethylene oxide only) had highest desirability values (0.684 and 0.842, respectively). Lipids achieved instantaneous floating and sustained the release of famotidine HCl over a prolonged period of time with significant bioavailability enhancement.

Famotidine is a potent H2-receptor antagonist most commonly used by elderly patients. Orodispersible tablets (ODT) are gaining popularity over conventional tablets due to their convenience and suitability for patients having dysphagia. The purpose of this study is to prepare famotidine ODT using the economic direct-compression method. A 32 full factorial design was used to evaluate the influence of different excipients on the properties and in vitro dissolution of famotidine ODT. Two factors were studied for their qualitative effects, namely, disintegrants and diluents. Disintegrants were studied in three levels viz. Ac-Di-Sol, sodium starch glycolate (Primojel) and low-substituted hydroxypropyl cellulose (L-HPC). Fillers were studied in three levels viz. mannitol, spray dried lactose and Avicel PH 101. The ODTs were prepared by direct compression and were evaluated for hardness, drug content, uniformity of weight, in vitro disintegration time, oral disintegration time, wetting time and in vitro dissolution. Maximum dissolution and minimum oral disintegration time (11.4 s) were observed in F7 prepared using L-HPC and mannitol. Furthermore, in human volunteers it showed significant increase in bioavailability compared to Servipep® with mean AUC(0-∞) 117.1 ng/ml and 82.71 ng/ml, respectively, and its relative bioavailability was 141.57%. Hence, ODT (F7) could possibly be used to overcome the drawbacks of conventional famotidine tablets in elderly patients with significant increase in oral bioavailability. © 2009 Elsevier Ltd. All rights reserved.

The aim of this study was to evaluate the bioavailability of two aripiprazole tablets, coprecipitate (CP) and nanoparticles (NP) when compared to the market tablets. A single-dose, randomized, three period crossover design under fasting conditions in healthy human volunteers was studied. The dissolution rate of the CP, NP and market tablets was determined. In order to investigate the feasibility of in vitro data as a tool for predicting in vivo results, two types of in vitro-in vivo correlation (IVIVC), level C and multiple level C, were studied. Almost 75% of aripiprazole was dissolved from the nanoparticles tablets within 10 minutes compared with 20% and 46% for coprecipitate and market tablets, respectively. The mean AUC 0-72 value of aripiprazole from the NP tablets (6136.35 ± 421.29 ng.hr/mL) was significantly higher than both CP tablets (3216.12 ± 525.02 ng.hr/mL) and market tablets (5215.57 ± 457.28 ng.hr/mL) (p d" 0.05). The relative bioavailability of aripiprazole after oral administration of the CP and NP tablets was 61.66% and 117.65%, respectively. The higher dissolution rate of NP tablets resulted in rapid absorption of aripiprazole and consequently higher bioavailability. Multiple level C IVIVC showed the bioequivalence of NP and bioinequivalence of the CP tablets in comparison to market tablets.

{Transnasal brain drug targeting could ensure better drug delivery to the brain through the olfactory pathway. Risperidone bioavailability is 66% in extensive metabolizers and 82% in slow metabolizers. The aim of this study is to investigate the ability of the nanovesicular spanlastics to effectively deliver risperidone through the nasal route to the brain and increase its bioavailability. Spanlastics formulae, composed of span and polyvinyl alcohol, were designed based on central composite statistical design. The planned formulae were prepared using ethanol injection method. The prepared formulae were characterized by testing their particle size, polydispersity index, zeta potential and encapsulation efficiency. The optimized formula having the lowest particle size, polydispersity index, the highest zeta potential and encapsulation efficiency was subjected to further investigations including characterization of its rheological properties, elasticity, transmission electron microscopy, in vitro diffusion, ex vivo permeation, histopathology and in vivo biodistribution. The optimized formula was composed of 5 mg/mL span and 30 mg/mL polyvinyl alcohol. It showed significantly higher transnasal permeation and better distribution to the brain, when compared to the used control regarding the brain targeting efficiency and the drug transport percentage (2.16 and 1.43 folds increase, respectively). The study introduced a successful and promising formula to directly and effectively carry the drug from nose to brain. (C) 2017 Elsevier B.V. All rights reserved.}

In this chapter three marine polysaccharides have been reviewed: chitosan, alginate and carrageenan. Their origins, structures, blending with each other and with other polymers and structure modifications were discussed, with special emphasis on their applications in various pharmaceutical fields, biotechnology, tissue engineering and gene delivery if ever used. © 2010 by Nova Science Publishers, Inc. All rights reserved.

Carvedilol (CV), a β-blocker essential for treating cardiovascular diseases, faces bioavailability challenges due to poor water solubility and first-pass metabolism. This study developed and optimized chitosan (CS)-coated niosomes loaded with CV (CS/CV-NS) for intranasal (IN) delivery, aiming to enhance systemic bioavailability. Utilizing a Quality-by-Design (QbD) approach, the study investigated the effects of formulation variables, such as surfactant type, surfactant-to-cholesterol (CHOL) ratio, and CS concentration, on CS/CV-NS properties. The focus was to optimize specific characteristics including particle size (PS), polydispersity index (PDI), zeta potential (ZP), entrapment efficiency (EE%), and mucin binding efficiency (MBE%). The optimal formulation (Opt CS/CV-NS), achieved with a surfactant: CHOL ratio of 0.918 and a CS concentration of 0.062 g/100 mL, using Span 60 as the surfactant, exhibited a PS of 305 nm, PDI of 0.36, ZP of + 33 mV, EE% of 63 %, and MBE% of 57 %. Opt CS/CV-NS was characterized for its morphological and physicochemical properties, evaluated for stability under different storage conditions, and assessed for in vitro drug release profile. Opt CS/CV-NS demonstrated a 1.7-fold and 4.8-fold increase in in vitro CV release after 24 h, compared to uncoated CV-loaded niosomes (Opt CV-NS) and free CV, respectively. In vivo pharmacokinetic (PK) study, using a rat model, demonstrated that Opt CS/CV-NS achieved faster Tmax and higher Cmax compared to free CV suspension indicating enhanced absorption rate. Additionally, Opt CV-NS showed a 1.68-fold higher bioavailability compared to the control. These results underscore the potential of niosomal formulations in enhancing IN delivery of CV, offering an effective strategy for improving drug bioavailability and therapeutic efficacy. © 2024 Elsevier B.V.

AbstractA new class of diphenylurea was identified as a novel antibacterial scaffold with an antibacterial spectrum that includes highly resistant staphylococcal isolates, namely methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA & VRSA). Starting with a lead compound 3 that carries an aminoguanidine functionality from one side and a n-butyl moiety on the other ring, several analogues were prepared. Considering the pharmacokinetic parameters as a key factor in structural optimization, the structure-activity-relationships (SARs) at the lipophilic side chain were rigorously examined leading to the discovery of the cycloheptyloxyl analogue 21n as a potential drug-candidate. This compound has several notable advantages over vancomycin and linezolid including rapid killing kinetics against MRSA and the ability to target and reduce the burden of MRSA harboring inside immune cells (macrophages). Furthermore, the potent anti-MRSA activity of 21n was confirmed in vivo using a Caenorhabditis elegans animal model. The present study provides a foundation for further development of diphenylurea compounds as potential therapeutic agents to address the burgeoning challenge of bacterial resistance to antibiotics.

Pluronic-based nanostructured gels were developed and optimized to increase the permeability of vinpocetine through the skin and the mucous layer of the nasal cavity. A modified thin-film hydration technique was utilized to prepare the nanostructured gel formulae containing different concentrations of Pluronic F127, Pluronic F68 and oleic acid. The formed nanodispersions were tested for their pH, particle size, zeta potential, polydispersity index, entrapment efficiency and gelation temperature. Box-Behnken statistical design was used to choose the optimized nasal and transdermal nanostructured gel formulae utilizing Design-Expert® software. The nasal optimized formula consisted of 2.4% oleic acid, 23.46% total surfactants and 27.13% Pluronic F68, had a gelation temperature of 35 °C which could be suitable to form in situ gel upon application into the nasal cavity. On the other hand, the transdermal optimized formula, composed of 1.77% oleic acid, 22.46% total surfactants and 11.54% Pluronic F68, formed gel at room temperature that could be suitable to be applied onto the skin. The optimized gel formulae were investigated for their in vitro drug release, rheology, morphology, histopathology and ex vivo permeation. The extent of drug permeated from the optimized formula through both nasal and skin membranes was significantly increased by 3.39 and 4.7 folds when compared to the drug suspension. Finally, the obtained findings ensured the creditable impact of the nanostructured gels as promising nanocarriers for enhancing transmucosal and transdermal vinpocetine permeation.

The aim of this study was to increase the in vivo mean residence time of vinpocetine after IV injection utilizing long circulating mixed micellar systems. Mixed micelles were prepared using Pluronics L121, P123 and F127. The systems were characterized by testing their entrapment efficiency, particle size, polydispersity index, zeta potential, transmission electron microscopy and in vitro drug release. Simple lattice mixture design was planned for the optimization using Design-Expert® software. The optimized formula was lyophilized, sterilized and imaged by scanning electron microscope. Moreover, the in vivo behavior of the optimized formula was evaluated after IV injection in rabbits. The optimized formula, containing 68% w/w Pluronic L121 and 32% w/w Pluronic F127, had the highest desirability value (0.621). Entrapment efficiency, particle size, polydispersity index and zeta potential of the optimized formula were 50.74 ± 3.26%, 161.50 ± 7.39 nm, 0.21 ± 0.03 and -22.42 ± 1.72 mV, respectively. Lyophilization and sterilization did not affect the characteristics of the optimized formula. Upon in vivo investigation in rabbits, the optimized formula showed a significantly higher elimination half-life and mean residence time than the market product. Finally, mixed micelles could be considered as a promising long circulating nanocarrier for lipophilic drugs.

The objective of this work was to design a diclofenac epolamine (DE) flash tablets (FTs) intended to dissolve in the mouth saliva, thereby improving the DE bioavailability and reducing its first-pass liver metabolism. Design-Expert software was used to build a 31.22 full factorial design (12 runs). FTs were fabricated using lyophilization process. The dissolution response was selected to pick the optimized run. The results indicate that the optimized run (R1) showed the fastest drug dissolution (total dissolution in 12 min). The predicted run (Rp) showed a desirability of about 0.93. Differential scanning calorimetry(DSC) analysis results showed a decrease in the drug melting point of the R1 formulation. Fourier–transform infrared spectroscopy (FTIR) showed the compatibility of the drug with other components of formulation, X-ray powder diffraction (XRPD) analysis showed the evolution of the drug physical state from a crystalline to an amorphous form and scanning electron microscopy(SEM) divugled the disappearance of drug crystals in gelatin strands. The results of the pharmacokinetic study performed in 6 human volunteers evidenced an increase in the maximum DE concentration in plasma and, consequently, an increased bioavailability of the FT formulation as compared with a reference formulation(Fr). Concisely, the developed FTs (R1) showed promising results which could be able to enhance oral bioavailability, reduce the therapeutic dose of the drug, and abate of the complications accompanied with conventional dosage forms.

Lipotomes were designed to enhance lacidipine's oral bioavailability by improving its solubility and enhancing the oral lymphatic uptake. Lipotomes were prepared using cetyl alcohol and Tween® 80 using a thin film hydration technique. Cetyl alcohol was chosen for imparting a lipophilic environment that would enforce the lymphatic uptake while Tween® 80 would improve drug solubility within the lipotomes. Lipotomes were characterized by analyzing their particle size, solubilization efficiency and in-vitro drug release. Central composite design was applied to statistically optimize the formulations using Design-Expert® software. The optimum formula (OLT) was made up of excipients:drug ratio of 36.59:1 w/w and Tween® 80:cetyl alcohol ratio of 4:1 w/w. OLT was lyophilized and filled into Eudragit® L100 enteric coated capsules. Mannitol (10% w/v) was the ideal cryoprotectant to retain the physicochemical characteristics of the OLT formulation after lyophilization. In conclusion, the selected lyophilized formula (L3) succeeded in enhancing drug's oral bioavailability in human volunteers compared to the commercial product confirming the success of lipotomes as a novel oral nanocarrier for insoluble drugs having extensive first pass metabolism. © 2014 Elsevier B.V.

Context: Diacerein (DCN) has low aqueous solubility (3.197 mg/L) and, consequently, low oral bioavailability (35%-56%). To increase both the solubility and dissolution rate of DCN while maintaining its crystalline nature, high pressure homogenization was used but with only a few homogenization cycles preceded by a simple bottom-up technique. Methods: The nanosuspensions of DCN were prepared using a combined bottom-up/top-down technique. Different surfactants-polyvinyl alcohol, sodium deoxycholate, and sodium dodecyl sulfate-with different concentrations were used for the stabilization of the nanosuspensions. Full factorial experimental design was employed to investigate the influence of formulation variables on nanosuspension characteristics using Design-Expert® Software. Particle size (PS), zeta potential, saturation solubility, in vitro dissolution, and drug crystallinity were studied. Moreover, the in vivo performance of the optimized formula was assessed by bioavailability determination in healthy human volunteers. Results: The concentration of surfactant had a significant effect on both the PS and polydispersity index values. The 1% surfactant concentration showed the lowest PS and polydispersity index values compared with other concentrations. Both type and concentration of surfactant had significant effects on the zeta potential. Formula F8 (containing 1% sodium deoxycholate) and Formula F12 (containing 1% sodium dodecyl sulfate) had the highest desirability values (0.952 and 0.927, respectively). Hence, they were selected for further characterization. The saturated solubility and mean dissolution time, in the case of F8 and F12, were significantly higher than the coarse drug powder. Techniques utilized in the nanocrystals' preparation had no effect on DCN crystalline state. The selected formula (F12) showed a higher bioavailability compared to the reference market product with relative bioavailability of 131.4%. Conclusion: The saturation solubility, in vitro dissolution rate and relative bioavailability of DCN were significantly increased after nanocrystallization. Less time and power consumption were applied by the combination of bottom-up and top-down techniques. © 2014 Elsayed et al.

Statins are mainly used for the treatment of hyperlipidemia, but recently, their anticancer role was extremely investigated. The goal of this study was to statistically optimize novel elastic nanovesicles containing rosuvastatin calcium to improve its transdermal permeability, bioavailability, and anticancer effect. The elastic nanovesicles were composed of Tween® 80, cetyl alcohol, and clove oil. The nanodispersions were investigated for their entrapment efficiency, particle size, zeta potential, polydispersity index, and elasticity. The optimized elastic nanovesicular dispersion is composed of 20% cetyl alcohol, 53.47% Tween 80, and 26.53% clove oil. Carboxy methylcellulose was utilized to convert the optimized elastic nanovesicular dispersion into elastic nanovesicular gels. Both the optimized dispersion and the optimized gel (containing 2% w/v carboxymethylcellulose) were subjected to in vitro release study, scanning and transmission electron microscopy, histopathological evaluation, and ex vivo permeation. The cell viability assay of the optimized gel on MCF-7 and Hela cell lines showed significant antiproliferative and potent cytotoxic effects when compared to the drug gel. Moreover, the optimized gel accomplished a significant increase in rosuvastatin bioavailability upon comparison with the drug gel. The optimized gel could be considered as a promising nanocarrier for statins transdermal delivery to increase their systemic bioavailability and anticancer effect.

Background: Olanzapine is a psychotropic agent that belongs to the thienobenzodiazepine class. Objective: The aim of this study was to assess the bioequivalence of 2 commercial 10-mg tablet formulations of olanzapine by statistical analysis of the pharmacokinetic parameters Cmax, AUC from 0 to 72 hours after dosing (AUC0-72), and AUC0-∞ as required by the Egyptian health authority for the marketing of a generic product. Methods: This bioequivalence study was carried out in healthy male volunteers using a single-dose, randomized, 2-way crossover design under fasting conditions. Statistical analysis of the pharmacokinetic parameters Cmax, AUC0-72, and AUC0-∞ was conducted to determine bioequivalence (after log-transformation of data using analysis of variance and 90% CIs) and to gain marketing approval in Egypt. The formulations were considered to be bioequivalent if the log-transformed ratios of the 3 pharmacokinetic parameters were within the predetermined bioequivalence range (ie, 80%-125%), as established by the US Food and Drug Administration (FDA). Both the test product (Trademark: Integrol® [Global Napi Pharmaceuticals, Cairo, Egypt]) and the reference product (Trademark: Zyprexa® [Eli Lilly and Company, Basingstoke, Hampshire, United Kingdom]) were administered as 10-mg tablets with 240 mL of water after an overnight fast on 2 treatment days, separated by a 2-week washout period. After dosing, serial blood samples were collected for 72 hours. Plasma samples were analyzed using a sensitive, reproducible, and accurate liquid chromatography-tandem mass spectrometry method capable of quantitating olanzapine in the range of 0.167 to 16.7 ng/mL, with a lower limit of quantitation of 0.167 ng/mL. Adverse events were reported by the volunteers as instructed or observed by the resident physician, and were recorded, tabulated, and evaluated. Results: Twenty-four healthy adult male volunteers participated in this study. Their mean (SD) age was 24.7 (6.2) years (range, 19-41 years), mean weight was 73.4 (6.7) kg (range, 64-89 kg), and mean height was 174.25 (4.6) cm (range, 168-186 cm). Values for Cmax, AUC0-72, AUC0-∞, Tmax, t1/2, and the terminal disposition rate constant were found to be in agreement with previously reported values. The differences between the 2 products did not reach statistical significance at P ≤ 0.05 (90% CIs: Cmax, 101.82-124.79; AUC0-72, 93.36-102.04; and AUC0-∞, 88.57-101.77). The test/reference ratio of these parameters was within the acceptance range of the FDA criterion for bioequivalence. Both formulations were apparently well absorbed from the gastrointestinal tract (ie, no specific gastrointestinal tract-related adverse events were reported). Conclusions: In this small study in healthy male volunteers, there were no statistically significant differences in any of the calculated pharmacokinetic parameters between the 10-mg test and reference tablets of olanzapine. The 90% CIs for the ratios of mean Cmax, AUC0-72, and AUC0-∞ were within the range of 80% to 125% (using log-transformed data), meeting the FDA regulatory criterion for bioequivalence. Both formulations were well tolerated. © 2009 Excerpta Medica Inc. All rights reserved.

Purpose: The aim of this work was to investigate the feasibility of using nanosized microemulsion for transdermal delivery of tolterodine tartrate. Methods: The effect of three microemulsions formed by Labrasol: Plurol (3:1), isopropyl myristate and water on the permeation of tolterodine through miniature pig skin was studied in vitro using Franz diffusion cell. For comparison purpose, the effect of different vehicles on the permeation was also studied. Drug pharmacokinetics was studied after transdermal application to human volunteers compared to the commercial oral dosage form using a newly developed LC-MS/MS assay. Results: The vehicle PEG 400:Phosphate buffer pH 7.4 in the ratio of 1:1 significantly enhanced tolterodine permeation across pig skin. The microemulsion system (ME3) containing the highest amount of water (50%) significantly enhanced permeation with Q24 of 0.746 mg.cm -2. In contrast to oral delivery, a sustained activity was observed over a period of 72 h after transdermal application of this microemulsion to human volunteers with significant lower Cmax (1.06 ng/ml), delayed Tmax (3.17 h) and higher MRT value (147.82 h) (p<0.05). Conclusion: This sustained activity was due to the controlled release of drug into the systemic circulation with expected increase in the patient compliance and prevention of nocturnal enuresis. © 2009 Springer Science+Business Media, LLC.