Dalia Mahmoud Ghorab

Despite the effectiveness and high tolerability of vilazodone (VLZ) as an antidepressant, its use is still limited due to its poor solubility and food dependent absorption. This study aims to load VLZ-phospholipid complex into self-assembled micelles forming VLZ-PL mixed micelles (VLZ-PL-MM), that can enhance VLZ solubility, improve its bioavailability and reduce the pharmacokinetic variability between the fed and fasting conditions. The effect of surfactant type and concentration was assessed using four different non-ionic surfactants (Brij 58, Tween 80, Labrasol and Pluronic F127) in four different weight ratios between the drug-complex and surfactant (1:0.5, 1:1, 1:2 and 1:3 w/w). Two VLZ-PL-MM formulae prepared using Brij 58 and Labrasol in 1:3 w/w ratio were selected as optimised ones since they have the highest encapsulation efficiency (100.83 and 93.87%, respectively), a particle size below 250 nm (206.73 and 221.33 nm, respectively) and negative zeta potential values (-29.63, -17.20 mV, respectively). Lyophilisation of these formulations using 3% sucrose was successful with no statistical changes in particle size and zeta potential upon rehydration. Both formulations elicited faster and higher in-vitro drug release profiles compared to the pure drug and the marketed tablet. In addition, both selected formulae improved ex-vivo permeation across rabbit intestinal membrane compared to the pure drug and the marketed tablet, with marked superiority of the one prepared using Brij 58. The results of the in-vivo study in male albino rabbits revealed similar AUC values after the oral administration of the best achieved VLZ-PL-MM system under fed and fasted conditions (769.89 and 741.55 ng.h mL, respectively). On the other hand, the marketed product showed significantly lower values of the AUC relative to the VLZ-PL-MM system and there was a marked enhancement of absorption of drug from the marketed product in presence of food (244.24 and 174.96 ng.h mL under fed and fasted conditions, respectively). In addition, VLZ concentrations in the brain after 24 h obtained from the selected VLZ-PL-MM were significantly higher than those obtained from marketed tablet under fed and fasted conditions. Thus, the phospholipid mixed micelles formulation enhances the oral bioavailability of the poorly soluble drug and reduces the pharmacokinetic variability between fasting and fed conditions.

Up to date, there were no approved drugs against coronavirus (COVID-19) disease that dangerously affects global health and the economy. Repurposing the existing drugs would be a promising approach for COVID-19 management. The antidepressant drugs, selective serotonin reuptake inhibitors (SSRIs) class, have antiviral, anti-inflammatory, and anticoagulant effects, which makes them auspicious drugs for COVID 19 treatment. Therefore, this study aimed to predict the possible therapeutic activity of SSRIs against COVID-19. Firstly, molecular docking studies were performed to hypothesize the possible interaction of SSRIs to the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-COV-2) main protease. Secondly, the candidate drug was loaded in lipid polymer hybrid (LPH) nanoparticles to enhance its activity. The studied SSRIs were Fluoxetine hydrochloride (FH), Atomoxteine, Paroxetine, Nisoxteine, Repoxteine RR, and Repoxteine SS. Interestingly, FH could effectively bind with SARS-COV-2 main protease via hydrogen bond formation with low binding energy (-6.7 kcal/mol). Moreover, the optimization of FH-LPH formulation achieved 65.1 ± 2.7% encapsulation efficiency, 10.3 ± 0.4% loading efficiency, 98.5 ± 3.5 nm particle size, and -10.5 ± 0.45 mV zeta potential. Additionally, it improved cellular internalization in a time-dependent manner with good biocompatibility on Human lung fibroblast (CCD-19Lu) cells. Therefore, the study suggested the potential activity of FH-LPH nanoparticles against the COVID-19 pandemic.

AbstractThis study aimed to formulate and evaluate lyophilized, long acting, levofloxacin hemihydrate ocular semi-sponges that would fit cul-de-sac shape for bacterial conjunctivitis treatment. Formulae were prepared using casting/freeze drying technique employing a (41 × 31) full factorial design to examine the effects of polymer type (Gelrite, chitosan (low and high molecular weight), and sodium carboxymethylcellulose), and concentration (1%, 1.5%, 2%) on viscosity of the formed solutions, quantity of drug released after 12 h (Q12h) and time for 50% of the drug to be released (T50%). Formulae were evaluated for weight and content uniformity, surface pH, water uptake, and in vitro drug release with its kinetic analysis. The optimal formula was chosen using Design-Expert® software and subjected to scanning electron microscope imaging, γ-sterilization and in-vivo evaluation. Results showed that formula G 2 (2% w/w Gelrite) had the highest desirability (0.894), a zero order drug release profile, and stability after γ-sterilization. Formula G 2 showed longer residence time (12 h) in rabbits' eye fluids compared to the commercial Levoxin® eye drops (4 h) with good correlations between in vitro and in vivo results. Conclusively, Gelrite ocular levofloxacin hemihydrate semi-sponges are promising drug delivery systems that would improve both patient compliance and treatment efficacy.

The present study was designed to improve the ocular availability of ketorolac tromethamine and to prolong its precorneal residence time for the treatment of postoperative ocular inflammation. Ketorolac tromethamine nanodispersions were successfully prepared by nanoprecipitation method using Eudragit(®) RL100. These nanodispersions were characterized in terms of particle size, zeta potential, entrapment efficiency and in vitro release. Consequently, the optimum nanodispersion was incorporated into thermosensitive in situ gel. The optimum gelling capacity was obtained by 20% Pluronic(®) F-127 and 14% Pluronic(®) F-127/1.5% HPMC K4m. The gelling temperature and gelation time of the in situ gels increased by decreasing the concentration of Pluronic(®) F-127. The mucoadhesive strength was significantly improved by the addition of HPMC. Incorporation of ketorolac tromethamine loaded nanodispersions into in situ gel bases sustained the release of ketorolac tromethamine, improved its ocular availability and prolonged its residence time without causing irritation to eye.

The study aimed to formulate and evaluate levofloxacin hemihydrate ocular in situ gels along with freshly prepared disappearing preservative reported to be safer to human eyes. Formulae were prepared using thermosensitive (PF127 and PF68) or ion-activated (Gelrite) polymers. They were evaluated for gelation temperature (GT), capacity, content uniformity, pH, rheological behavior, in vitro drug release with kinetic analysis. Best formulae were exposed to storage effect to select the optimum formula that was subjected to different sterilization methods and in vivo evaluation. The prepared disappearing preservative (sodium perborate monohydrate) proved to be active oxidative preservative and compatible with our formulae. F9 (24% PF127, 15% PF 68, 0.5% levofloxacin hemihydrate, and 0.0025% sodium perborate monohydrate) showed prolonged drug release (12 h), acceptable GT, viscosity, and pH. It remained stable over 3 months at two temperatures and was best sterilized by filtration. It showed longer residence time (12 h) in rabbits' eye fluids compared with the Levoxin® eye drops (4 h). This successful attempt of using thermo-gelling system along with a disappearing type of preservatives would allow the use of these systems to achieve sustained release of antimicrobial drugs with minimum risk of eye damage improving patient compliance and treatment efficacy.

This study aims at formulating solid lipid nanoparticles (SLNs) of Vinpocetine (VIN) to be used as a brain targeted sustained drug-delivery system. VIN is a derivative of vincamine alkaloid, used for chronic cerebral vascular ischemia. However, it suffers from low bioavailability and short half-life. Its oral bioavailability is recorded to be between 7 and 55%. Its elimination half-life is 1-2 h so it would be a good candidate for a sustained drug-delivery system. VIN SLNs were prepared using modified high shear homogenization followed by ultrasonication technique. The effect of incorporating different lipids at different concentrations of various surfactants was investigated. The VIN SLNs were characterized by entrapment efficiency percent (EE%), particle size distribution, zeta-potential, and cumulative released percent after 96 h. The EE% ranged between 83.34% ± 0.95-94.56% ± 0.11 due to the lipophilic character of VIN. The mean particle size measured ranged from 123 nm-464 nm. The cumulative released percent after 96 h ranged from 23.55% to 75.67% showing a controlled release profile. Formula (F32) composed of 5% glyceryl monostearate (GMS) and stabilized by 2% surfactant mixture [Tween 80, Pluronic F 68 (1:1)] was the most appropriate formula for brain delivery having EE% of 89.09% ± 1.49, zero-order release kinetics with cumulative released percent of 72.12% after 96 h, zeta-potential of -11.3 ± 0.97 mV. It showed a unimodal size distribution with particle size ≈ 90 nm and polydispersity index of 0.121. The formula of choice in this study exhibited a zero-order sustained release profile and met the requirement for a brain targeted SLN so it could be a promising formula to deliver VIN to the brain.

CONTEXT: Celecoxib suffers from low and variable bioavailability following oral administration of solutions or capsules. Recent studies proved that chemoprevention of colorectal cancer is possible with celecoxib.

OBJECTIVE: This work aimed to tailor colon-targeted celecoxib-loaded microparticles using time-dependant and pH-dependant coats. Estimation of drug pharmacokinetics following oral administration to fasted rats was another goal.

METHODS: A 2³ factorial design was adopted to develop poly-ε-caprolactone (PCL) celecoxib-loaded microparticles (F1-F8). To minimize drug-percentages released before colon, another coat of Eudragit® S100 was applied. In vitro characterization of microparticles involved topography, determination of particle size and entrapment efficiency (EE %). Time for 50% drug release (t(₅₀%)) and drug-percentages released after 2 hours (Q(2h)) and 4 hours (Q(4h)) were statistically compared. Estimation of drug pharmacokinetics following oral administration of double-coat microparticles (F10) was studied in rats.

RESULTS: PCL-single-coat microparticles were spherical, discrete with a size range of 60.66 ± 4.21-277.20 ± 6.10 μm. Direct correlations were observed between surfactant concentration and EE%, Q(2h) and Q(4h). The PCL M.wt. and drug: PCL ratio had positive influences on EE% and negative impacts on Q(2h) and Q(4h). When compared to the best achieved PCL-single-coat microparticles (F2), the double-coat microparticles (F10) showed satisfactory drug protection; Q(2h) and Q(4h) were significantly (P < 0.01) decreased from 31.84 ± 1.98% and 54.72 ± 2.10% to 15.92 ± 1.78% and 26.93 ± 2.76%, respectively. When compared to celecoxib powder, F10 microparticles enhanced the bioavailability and extended the duration of drug-plasma concentration in rats.

CONCLUSION: The developed double-coat microparticles could be considered as a promising celecoxib extended-release colon-targeting system.

Nicardipine hydrochloride, a calcium channel blocker with significant vasodilating and antihypertensive activities, was formulated in this work as sustained release floating capsules. A hydrocolloid of high viscosity grade was used for the floating systems. The inclusion of sodium bicarbonate to allow evolution of CO2 to aid buoyancy was studied. Polymers that retard drug release were included as coprecipitates with the drug and/or as additives in the formulated capsules. Both simple powder mixing of the ingredients and granule preparation via wet granulation were used. Seven capsule formulae were prepared. The prepared capsules were evaluated in vitro by testing drug dissolution, floating time and the kinetics of drug release. In vitro evaluation of a commercially available conventional 20 mg capsule of nicardipine hydrochloride, "Micard", was carried out for comparison. The hydrocolloid used succeeded in effecting capsule buoyancy. Floating time increased with increasing the proportion of the hydrocolloid. Inclusion of sodium bicarbonate increased buoyancy. All of the seven floating capsule formulae prepared proved efficient in controlling drug release. The sustained release floating capsule formulation of choice was evaluated in vivo in comparison to "Micard" capsules using rabbits. Reversed phase HPLC with UV detection was used for drug determination in rabbit plasma. Plasma concentration time curves revealed a longer drug duration for administration in the sustained release formula than the conventional "Micard" capsule being 16 h in the former versus 8 h for the latter.