Shahira F. El-Menshawe

Nanotransfersomes of carvedilol for intranasal delivery: formulation, characterization and in vivo evaluation

Abstract Context: Development of carvedilol-loaded transfersomes for intranasal administration to overcome poor nasal permeability and hepatic first pass effect so as to enhance its bioavailability. Objective: The purpose of this study was to develop carvedilol-loaded transfersomes containing different edge activators (EAs) then evaluating the in vivo behavior of the optimized formula in rabbits. Methods: The vesicles were prepared by incorporating different EAs including Span 20, Span 60, Tween 20, Tween 80, and sodium deoxycholate (SDC) in the lipid bilayer and each EA was used in three different ratios with respect to phosphatidylcholine (PC) including 95:5%, 85:15%, and 75:25% w/w (PC:EA). Evaluation of transfersomes was carried out in terms of shape, size, entrapment efficiency (EE), in vitro release, ex vivo permeation, confocal laser scanning microscopy (CLSM), and stability studies. The pharmacokinetic study of the optimized formula was conducted in rabbits. Results: The mean diameter of the vesicles was in the range of 295–443 nm. Transfersomes prepared with 95:5% (w/w) (PC:EA) ratio showed highest EE% where Span 60 gave the highest values. Whereas those prepared using 85:15% w/w ratio showed highest percentages of drug release where SDC was superior to other EAs. The developed transfersomes exhibited significantly higher amounts of carvedilol permeated through nasal mucosa. CLSM of formula T14 containing SDC with 85:15% (w/w) (PC:EA) ratio revealed high permeation across the nasal mucosa. Conclusion: The nanotransfersomal vesicles were significantly more efficient in nasal delivery of carvedilol with absolute bioavailability of 63.4%.

Topical ketoprofen nanogel: artificial neural network optimization, clustered bootstrap validation, and in vivo activity evaluation based on longitudinal dose response modeling

Abstract Objectives: This work aimed at investigating the potential of solid lipid nanoparticles (SLN) as carriers for topical delivery of Ketoprofen (KP); evaluating a novel technique incorporating Artificial Neural Network (ANN) and clustered bootstrap for optimization of KP-loaded SLN (KP-SLN); and demonstrating a longitudinal dose response (LDR) modeling-based approach to compare the activity of topical non-steroidal anti-inflammatory drug formulations. Methods: KP-SLN was fabricated by a modified emulsion/solvent evaporation method. Box–Behnken design was implemented to study the influence of glycerylpalmitostearate-to-KP ratio, Tween 80, and lecithin concentrations on particle size, entrapment efficiency, and amount of drug permeated through rat skin in 24 hours. Following clustered bootstrap ANN optimization, the optimized KP-SLN was incorporated into an aqueous gel and evaluated for rheology, in vitro release, permeability, skin irritation and in vivo activity using carrageenan-induced rat paw edema model and LDR mathematical model to analyze the time course of anti-inflammatory effect at various application durations. Results: Lipid-to-drug ratio of 7.85 [bootstrap 95%CI: 7.63–8.51], Tween 80 of 1.27% [bootstrap 95%CI: 0.601–2.40%], and Lecithin of 0.263% [bootstrap 95%CI: 0.263–0.328%] were predicted to produce optimal characteristics. Compared with profenid® gel, the optimized KP-SLN gel exhibited slower release, faster permeability, better texture properties, greater efficacy, and similar potency. Conclusions: SLNs are safe and effective permeation enhancers. ANN coupled with clustered bootstrap is a useful method for finding optimal solutions and estimating uncertainty associated with them. LDR models allow mechanistic understanding of comparative in vivo performances of different topical formulations, and help design efficient dermatological bioequivalence assessment methods.

Nanosized soy phytosome-based thermogel as topical anti-obesity formulation: an approach for acceptable level of evidence of an effective novel herbal weight loss product

Purpose Herbal supplements are currently available as a safer alternative to manage obesity, which has become a rising problem over the recent years. Many chemical drugs on the market are designed to prevent or manage obesity but high cost, low efficacy, and multiple side effects limit its use. Nano lipo-vesicles phytosomal thermogel of Soybean, Glycine max (L.) Merrill, was formulated and evaluated in an attempt to investigate its anti-obesity action on body weight gain, adipose tissue size, and lipid profile data. Methods Three different techniques were used to prepare phytosome formulations including solvent evaporation, cosolvency, and salting out. The optimized phytosome formulation was then selected using Design Expert® (version 7.0.0) depending on the highest entrapment efficiency, minimum particle size (PS), and maximum drug release within 2 hours as responses for further evaluation. The successful phytosome complex formation was investigated by means of Fourier-transform infrared spec troscopy and determination of PS and zeta potential. Phytosome vesicles’ shape was evaluated using transmission electron microscope to ensure its spherical shape. After characterization of the optimized phytosome formulation, it was incorporated into a thermogel formulation. The obtained phytosomal thermogel formulation was evaluated for its clarity, homogeneity, pH, and gel transformation temperature besides rheology behavior and permeation study. An in vivo study was done to investigate the anti-weight-gain effect of soy phytosomal ther mogel. Results EE was found to be >99% for all formulations, PS ranging from 51.66–650.67 while drug release was found to be (77.61–99.78) in range. FTIR and TEM results confirmed the formation of phytosome complex. In vivo study showed a marked reduction in body weight, adipose tissue weight and lipid profile. Conclusion Concisely, soy phytosomal thermogel was found to have a local anti-obesity effect on the abdomen of experimental male albino rats with a slight systemic effect on the lipid profile data.

Preparation and Optimization of Buccal Propranolol HydrochlorideNanoethosomal Gel: A Novel Approach for Enhancement of Bioavailability

Propranolol hydrochloride is widely used in the treatment of hypertension and other cardiac conditions. However, the drug is extensively metabolized in the liver. The purpose of this research was to formulate and optimize a nanoethosomal buccal gel of propranolol hydrochloride in an attempt to improve its bioavailability. The ethosomes were prepared using cold method whereas a 23 full-factorial design was employed to investigate the effect of phosphatidylcholine (PC), propylene glycol (PG), and ethanol concentration on entrapment efficiency, particle size and % of drug released. The adjusted and predicted coefficients of determination as well as the CV% were used to assess the fitness of the experimental model. The optimized formulation F5 containing (1% PC, 10% PG and 50% ethanol) was incorporated in 1% Carbopol 934 gel base. The buccal gel was evaluated by assessment of the ex vivo drug permeation and in vivo bioavailability. It was noted from regression equations, contour plots and 3D-response surface plots that the three dependent variables had a direct relationship with PC concentration and an inverse relationship with PG and ethanol concentrations. The viscosity of both the ethosomal and control gel which contains the free drug powder was 20745 cp and 12411 cp respectively. Both gel preparations were homogenous with a pH value of 6.8. The ethosomal gel exhibited a high flux across a freshly dissected chicken buccal mucosa with an enhancement ratio of 1.314. The mean AUC0-24 for oral tablets, control gel and ethosomal gel were 426.17 ± 51.78 ng.hr/mL, 579.102 ± 66.19 ng.hr/mL and 810.39 ± 92.33 ng.hr/mL respectively. The relative bioavailability was dramatically enhanced from 135.885% after using the control gel to 190.157% with the ethosomal system when compared to the marketed product Inderal® tablet (40 mg). The choice of the buccal route together with the use of ethosomes was an appropriate approach to improve the propranolol bioavailability.

A novel transdermal nanoethosomal gel of betahistine dihydrochloride for weight gain control: in-vitro and in-vivo characterization

Background Betahistine dihydrochloride (BDH) is a histamine analog used to control weight gain, with short elimination half-life and gastric irritation as side effects. Objective The aim of the current investigation is to formulate and optimize a topical BDH ethosomal gel for weight gain control. Materials and methods Box–Behnken design was applied to study the effect of independent variables: phosphatidylcholine (PC), propylene glycol (PG), and ethanol on vesicle size; entrapment efficiency; % drug release; and flux. The morphology and zeta potential of the optimized formulation were evaluated. The % drug release, flux, and pharmacodynamics of the optimized formulation gel were studied. Results The size and entrapment efficiency percent had a direct positive relationship with the concentration of PC and negative relationship with ethanol and PG. The % drug release and flux decreased with increasing PC and PG, while ethanol enhanced both responses. Regression modeling indicated a good correlation between dependent and independent variables, where F16 was chosen as the optimized formulation. F16 showed well-defined spherical vesicles and zeta potential of −24 mV, and % release from the gel exceeded 99.5% over 16 h with the flux of 0.28 mg/cm2/h. Food intake and weight gain of rats were significantly decreased after transdermal application of the BDH ethosomal gel when compared with control, placebo, and BDH gel. The histopathological findings proved the absence of inflammation and decrease in adipose tissue. Conclusion Results obtained showed a significant, sustained transdermal absorption of BDH ethosomal gel and, consequently, a decrease in food intake and weight gain.