Usama A. Fahmy

Transdermal glimepiride delivery system based on optimized ethosomal nano-vesicles: Preparation, characterization, in vitro, ex vivo and clinical evaluation.

This work aimed to develop an optimized ethosomal formulation of glimepiride then loading into transdermal films to offer lower drug side effect, extended release behavior and avoid first pass effect. Four formulation factors were optimized for their effects on vesicle size (Y1), entrapment efficiency (Y2) and vesicle flexibility (Y3). Optimum desirability was identified and, an optimized formulation was prepared, characterized and loaded into transdermal films. Ex-vivo permeation study for the prepared films was conducted and, the permeation parameters and drug permeation mechanism were identified. Penetration through rat skin was studied using confocal laser microscope. In-vivo study was performed following transdermal application on human volunteers. The percent of alcohol was significantly affecting all the studied responses while the other factors and their interaction effects were varied on their effects on each response. The optimized ethosomal formulation showed observed values for Y1, Y2 and Y3 of 61 nm, 97.12% and 54.03, respectively. Ex-vivo permeation of films loaded with optimized ethosomal formulation was superior to that of the corresponding pure drug transdermal films and this finding was also confirmed after confocal laser microscope study. Permeation of glimepiride from the prepared films was in favor of Higushi-diffusion model and exhibited non-Fickian or anomalous release mechanism. In-vivo study revealed extended drug release behavior and lower maximum drug plasma level from transdermal films loaded with drug ethosomal formulation. So, the ethosomal formulation could be considered a suitable drug delivery system especially when loaded into transdermal vehicle with possible reduction in side effects and controlling the drug release.

Enhanced permeation parameters of optimized nanostructured simvastatin transdermal films: ex vivo and in vivo evaluation.

Abstract Objective: Detailed optimization process was carried out to enhance permeation parameters, and hence bioavailability, of simvastatin (SMV) transdermal films. Methods: SMV solubility was investigated in various oils, surfactants and co-surfactants/co-solvents. Mixtures of the selected components were prepared to identify zone of nanoemulsion formation that was utilized in Extreme Vertices mixture design to develop SMV self-nanoemulsifying drug delivery systems (SNEDDS) with minimum globule size. Optimized SMV-SNEDDS were included in the preparation of transdermal films. A fractional factorial design was implemented to evaluate effects of the factors on the amount of SMV permeated. The optimized film was investigated for ex vivo skin permeation and in vivo pharmacokinetic parameters. Results: The optimum SNEDDS formula was 0.09, 0.8 and 0.11 for Sefsol 218, tween 80 and PEG 200, respectively. Fractional factorial design depicted the optimized SMV transdermal film with 2% HPMC and 2% DMSO as permeation enhancer that showed 1.82-fold improvements in skin flux. The pharmacokinetic data showed higher Cmax and almost doubled AUC compared with raw SMV-loaded films. Conclusion: The two-step optimization implemented to optimize and control the experimental conditions for the preparation of SMV-SNEDDS-transdermal film with improved ex vivo skin permeation and enhanced in vivo parameters.

Optimization of caseinate-coated simvastatin-zein nanoparticles: improved bioavailability and modified release characteristics

The current study focuses on utilization of the natural biocompatible polymer zein to formulate simvastatin (SMV) nanoparticles coated with caseinate, to improve solubility and hence bioavailability, and in addition, to modify SMV-release characteristics. This formulation can be utilized for oral or possible depot parenteral applications. Fifteen formulations were prepared by liquid–liquid phase separation method, according to the Box–Behnken design, to optimize formulation variables. Sodium caseinate was used as an electrosteric stabilizer. The factors studied were: percentage of SMV in the SMV-zein mixture (X1), ethanol concentration (X2), and caseinate concentration (X3). The selected dependent variables were mean particle size (Y1), SMV encapsulation efficiency (Y2), and cumulative percentage of drug permeated after 1 hour (Y3). The diffusion of SMV from the prepared nanoparticles specified by the design was carried out using an automated Franz diffusion cell apparatus. The optimized SMV-zein formula was investigated for in vivo pharmacokinetic parameters compared with an oral SMV suspension. The optimized nanosized SMV-zein formula showed a 131 nm mean particle size and 89% encapsulation efficiency. In vitro permeation studies displayed delayed permeation characteristics, with about 42% and 85% of SMV cumulative amount released after 12 and 48 hours, respectively. Bioavailability estimation in rats revealed an augmentation in SMV bioavailability from the optimized SMV-zein formulation, by fourfold relative to SMV suspension. Formulation of caseinate-coated SMV-zein nanoparticles improves the pharmacokinetic profile and bioavailability of SMV. Accordingly, improved hypolipidemic activities for longer duration could be achieved. In addition, the reduced dosage rate of SMV-zein nanoparticles improves patient tolerability and compliance.

Statistical optimization of controlled release microspheres containing cetirizine hydrochloride as a model for water soluble drugs

Abstract The purpose was to improve the encapsulation efficiency of cetirizine hydrochloride (CTZ) microspheres as a model for water soluble drugs and control its release by applying response surface methodology. A 33 Box–Behnken design was used to determine the effect of drug/polymer ratio (X1), surfactant concentration (X2) and stirring speed (X3), on the mean particle size (Y1), percentage encapsulation efficiency (Y2) and cumulative percent drug released for 12 h (Y3). Emulsion solvent evaporation (ESE) technique was applied utilizing Eudragit RS100 as coating polymer and span 80 as surfactant. All formulations were evaluated for micromeritic properties and morphologically characterized by scanning electron microscopy (SEM). The relative bioavailability of the optimized microspheres was compared with CTZ marketed product after oral administration on healthy human volunteers using a double blind, randomized, cross-over design. The results revealed that the mean particle sizes of the microspheres ranged from 62 to 348 µm and the efficiency of entrapment ranged from 36.3% to 70.1%. The optimized CTZ microspheres exhibited a slow and controlled release over 12 h. The pharmacokinetic data of optimized CTZ microspheres showed prolonged tmax, decreased Cmax and AUC0–∞ value of 3309 ± 211 ng h/ml indicating improved relative bioavailability by 169.4% compared with marketed tablets.

Solid lipid nanoparticles for transdermal delivery of avanafil: optimization, formulation, in-vitro and ex-vivo studies

Abstract Context: Avanafil (AVA) is used in the treatment of erectile dysfunction, but is reported for its poor aqueous solubility. Solid lipid nanoparticles (SLNs) are lipid carriers that can greatly enhance drug solubility and bioavailability. Objective: This work was aimed to formulate and optimize AVA SLNs with subsequent loading into hydrogel films for AVA transdermal delivery. Materials and methods: AVA SLNs were prepared utilizing homogenization followed by ultra-sonication technique. The prepared SLNs were characterized for particle size, charge, surface morphology and drug content. The optimized SLNs formulation was incorporated into transdermal films prepared using HPMC and chitosan. Hydrogel films were evaluated for ex-vivo rat skin permeation using automated Franz diffusion cells. The permeation parameters and the release mechanism were evaluated. The transdermal permeation of the prepared AVA SLNs through the skin layers was studied using confocal laser scanning microscope. Results: Lipid concentration and % of oil in lipid had a pronounced effect on particle size while, entrapment efficiency was significantly affected by lipid concentration and % of cholesterol. The optimized AVA SLNs showed particle size and entrapment efficiency of 86 nm and 85.01%, respectively. TEM images revealed spherecity of the particles. High permeation parameters were observed from HPMC films loaded with AVA SLNs. The release data were in favor of Higuchi diffusion model. The prepared AVA SLNs were able to penetrate deeper in skin layers. Conclusion: HPMC transdermal film-loaded AVA SLNs is an effective and alternative to per-oral drug administration.

Improvement of fluvastatin bioavailability by loading on nanostructured lipid carriers.

The aim of this study is to prepare fluvastatin nanostructured lipid carriers (FLV-NLCs) in order to find an innovative way to alleviate FLV-associated disadvantages. The limitations include poor solubility and extensive first-pass metabolism, resulting in low (30%) bioavailability and short elimination half-life (1–3 hours). FLV-NLCs were prepared by hot emulsification–ultrasonication method. Ten runs were created by three-level factorial design (32) to optimize FLV-NLCs formulation process. In this study, two factors, four responses, and three-level factorial design were endorsed. The studied variables were lipid:oil ratio (X1) and sonication time (X2). However, the responses parameter determined the particle size (Y1, nm), entrapment efficiency percent (EE%, Y2), particles zeta potential (Y3), and 80% of the drug release after 24 hours (X4). Furthermore, stability and in vivo pharmacokinetics were studied in rats. The optimized consisted formula had an average particle size of 165 nm with 75.32% entrapment efficiency and 85.32% of drug released after 24 hours, demonstrating a sustaining drug release over 24 hours. An in vivo pharmacokinetic study revealed enhanced bioavailability by >2.64-fold, and the mean residence time was longer than that of FLV. We concluded that NLCs could be promising carriers for sustained/prolonged FLV release with enhanced oral bioavailability.

Assessment of simvastatin niosomes for pediatric transdermal drug delivery

Abstract The prevalence of childhood dyslipidemia increases and is considered as an important risk factor for the incidence of cardiovascular disease in the adulthood. To improve dosing accuracy and facilitate the determination of dosing regimens in function of the body weight, the proposed study aims at preparing transdermal niosomal gels of simvastatin as possible transdermal drug delivery system for pediatric applications. Twelve formulations were prepared to screen the influence of formulation and processing variables on critical niosomal characteristics. Nano-sized niosomes with 0.31 μm number-weighted size displayed highest simvastatin release rate with 8.5% entrapment capacity. The niosomal surface coverage by negative charges was calculated according to Langmuir isotherm with n = 0.42 to suggest that the surface association was site-independent, probably producing surface rearrangements. Hypolipidemic activities after transdermal administration of niosomal gels to rats showed significant reduction in cholesterol and triglyceride levels while increasing plasma high-density lipoproteins concentration. Bioavailability estimation in rats revealed an augmentation in simvastatin bioavailability by 3.35 and 2.9 folds from formulation F3 and F10, respectively, compared with oral drug suspension. Hence, this transdermal simvastatin niosomes not only exhibited remarkable potential to enhance its bioavailability and hypolipidemic activity but also considered a promising pediatric antihyperlipidemic formulation.

Finasteride-loaded biodegradable nanoparticles: Near-infrared quantification of plasma and prostate levels

Finasteride is an orally active testosterone 5-alpha-reductase inhibitor that is used for the treatment of benign prostatic hyperplasia as a surgical alternative. The aim of this work was to improve finasteride levels in plasma and prostate through the formulation of biodegradable finasteride nanoparticles and to quantify finasteride levels using near-infrared application. Finasteride nanoparticles were prepared by emulsion solvent evaporation method utilizing the biodegradable polymers poly(lactic-co-glycolic acid) and poly-ϵ-caprolactone. The prepared nanoparticles were characterized by particle size, zeta potential, and encapsulation efficiency. The selected finasteride-biodegradable formula was examined in vivo, and both plasma and prostate levels of finasteride were quantified utilizing near-infrared technique. Results revealed that the prepared finasteride nanoparticles size range was from 231 ± 78 to 956 ± 224 nm with finasteride–poly-ϵ-caprolactone nanoparticles showing larger particle sizes compared with finasteride–poly(lactic-co-glycolic acid) nanoparticles. The encapsulation efficiency ranged from 68.89% ± 2.99% to 99.15% ± 4.32%. The selected formula of finasteride nanoparticles showed improved levels of finasteride in both plasma and prostate of the investigated rats. The realization of sustained release of biodegradable finasteride nanoparticles for possible oral or parenteral application could improve the activity of the drug for sustaining release time with lower dosing recurrence that improves patient compliance.

Quantification of simvastatin in mice plasma by near-infrared and chemometric analysis of spectral data.

Time and cost saving is an essential requirement in pharmacokinetics and bioequivalence studies. The aim of this study is to use a simple, fast, and nondestructive near-infrared transmission spectroscopic method to quantify simvastatin (SMV) concentrations in mice plasma and also to improve SMV bioavailability by using alpha-lipoic acid as a carrier. Calibration curve was built at a concentration range of 10–250 ng/mL, and HPLC method was considered as a reference method. A partial least squares regression analysis model was used for method development, which gave less root mean square error cross-validation. Comparison of SMV concentrations obtained from both instruments showed no statistically significant differences between all the data. Near-infrared spectroscopy was utilized as a rapid, simple accurate method to quantify drug–plasma concentrations without need for any extraction protocols, and the significant effect of alpha-lipoic acid as a novel carrier to enhance SMV bioavailability is also addressed.

Combined strategy for suppressing breast carcinoma MCF-7 cell lines by loading simvastatin on alpha lipoic acid nanoparticles.

ABSTRACT Background: Augmentation of simvastatin (SMV) cytotoxicity in breast carcinoma cell lines MCF-7, by: improvement of cellular uptake and loading on alpha lipoic acid (ALA). Methods: In this study, SMV was loaded on ALA nanoparticles and characterized for surface morphology, SMV entrapment efficiency percent (%EE), zeta potential and release profile. Cellular viability, morphology and uptake and DNA fragmentations were analyzed as a hallmark of cellular apoptosis. Results: TEM images demonstrated spherical nanoparticles with particle size 104.7 ± 5.5 nm, SMV %EE was 95.8 ± 2.1% with a zeta potential – 23.6 ± 5.4 mV, and release properties were significantly enhanced. IC50 was decreased to 22.2 ± 2.4 µM while raw SMV was 49.3 ± 6.6 µM. Cellular uptake of SMV-ALA nanoparticles was increased by about 3- and 2-folds after 2 and 4 h, respectively. DNA fragments confirmed the apoptosis property of ALA, which is associated with SMV cytotoxicity. Conclusion: This study suggests evidence that SMV loaded on ALA nanoparticles increases the MCF-7 cellular uptake and cytotoxic effects induced by SMV as revealed by significantly enhanced cell death rates in MCF-7 cells. These findings demonstrate that ALA induces cell death, which makes the combination a candidate for tumor therapy.