Radwan, S. A. A., W. H. El-Maadawy, C. Yousry, A. N. ElMeshad, and R. A. Shoukri, "Zein/Phospholipid Composite Nanoparticles for Successful Delivery of Gallic Acid into aHSCs: Influence of Size, Surface Charge, and Vitamin A Coupling", International Journal of Nanomedicine, vol. 15, pp. 7995-8018, 2020.
Radwan, S. A. A., W. H. El-Maadawy, A. N. ElMeshad, R. A. Shoukri, and C. Yousry, "Impact of Reverse Micelle Loaded Lipid Nanocapsules on the Delivery of Gallic Acid into Activated Hepatic Stellate Cells: A Promising Therapeutic Approach for Hepatic Fibrosis.", Pharmaceutical research, vol. 37, issue 9, pp. 180, 2020. Abstractimpact_of_reverse_micelle_loaded_lipid_nanocapsules_on_the_delivery_of_gallic_acid_into_activated_hepatic_stellate_cells_a_promising_therapeutic_approach_for_hepatic_fibrosis.pdf

PURPOSE: Gallic acid (GA) is a polyphenolic compound with proven efficacy against hepatic fibrosis in experimental animals. However, it suffers from poor bioavailability and rapid clearance that hinders its clinical investigation. Accordingly, we designed and optimized reverse micelle-loaded lipid nanocapsules (RMLNC) using Box-Behnken design that can deliver GA directly into activated-hepatic stellate cells (aHSCs) aiming to suppress hepatic fibrosis progression.

METHODS: GA-RMLNC was prepared using soft energy, solvent free phase inversion temperature method. Effects of formulation variables on particle size, zeta potential, entrapment efficiency (EE%) and GA release were studied. In-vivo biodistribution of GA-RMLNC in rats and in-vitro activities on aHSCs were also explored.

RESULTS: Nano-sized GA-RMLNCs (30.35 ± 2.34 nm) were formulated with high GA-EE% (63.95 ± 2.98% w/w) and physical stability (9 months). The formulated system showed burst GA release in the first 2 h followed by sustained release profile. In-vivo biodistribution imaging revealed that RMLNC-loaded with rhodamine-B accumulated mainly in rats' livers. Relative to GA; GA-RMLNC displayed higher anti-proliferative activities, effective internalization into aHSCs, marked down-regulation in pro-fibrogenic biomarkers' expressions and elevated HSCs' apoptosis.

CONCLUSIONS: These findings emphasize the promising application of RMLNC as a delivery system in hepatic fibrosis treatment, where successful delivery of GA into aHSCs was ensured via increased cellular uptake and antifibrotic activities.

Yousry, C., P. M. Zikry, E. B. Basalious, and O. N. El-Gazayerly, "Self-nanoemulsifying System Optimization for Higher Terconazole Solubilization and Non-Irritant Ocular Administration.", Advanced pharmaceutical bulletin, vol. 10, issue 3, pp. 389-398, 2020. Abstractsnes.pdf

Eye drops' formulations of poorly water-soluble drugs, offer the advantage of crossing the lipophilic cornea, but their limited aqueous solubility may lead to low ocular bioavailability limiting their therapeutic uses. Terconazole (TZ) is an antifungal drug with low aqueous solubility, restricting its application in ocular fungal infection. Thus, the aim of the work in this study is to enhance TZ solubilization, permitting better ocular permeation and higher bioavailability. To achieve this goal, different self-nanoemulsifying systems (SNESs) were prepared using different oils, surfactants and co-surfactants. Ternary phase diagrams were constructed to identify self nano-emulsification regions for each oil system examined; either Labrafil M2125CS or Capryol 90. TZ saturated solubility in the different formulated systems were measured and systems showing highest potential for TZ solubilization were selected. The optimized systems were chosen based on their globule size, polydispersity index, self-emulsification characteristics. Finally, TZ release as well as the irritation effect via Hen's Egg test-chorioallantoic membrane (HET-CAM test) of the optimized system was observed in vitro. The optimized system was formulated using 20% w/w Labrafil M2125 CS, 50% w/w Tween 80 and 30% w/w Transcutol HP. Oil globules showed size range of 15.13 nm and self-emulsification time of 12.80 seconds. The system released 100% of the drug within half an hour compared to 2 hours in case of TZ-suspension. Finally, HET-CAM test showed non-irritating response and normal vascularization of the chorioallantoic membrane. The formulated SNES could be a promising approach to enhance ocular efficacy of TZ.

Yousry, C., P. M. Zikry, H. M. Salem, E. B. Basalious, and O. N. El-Gazayerly, "Integrated nanovesicular/self-nanoemulsifying system (INV/SNES) for enhanced dual ocular drug delivery: statistical optimization, in vitro and in vivo evaluation.", Drug delivery and translational research, 2020. Abstractyousry2020_article_integratednanovesicularself-na.pdf

Ocular drug administration is usually problematic and suffers low bioavailability due to several physiological and biological factors that hinder their effective treatment. Terconazole (TZ) is considered as one of the effective ocular antifungal agents that is usually administrated intravitreally for higher efficacy. The aim of the work in this study is to formulate a TZ-loaded ocular drug delivery system with high efficiency and good tolerability. First, TZ-loaded bile-based nanovesicles (BBNV) were prepared and the formulation variables (namely, Span 60, cholesterol, and sodium deoxycholate levels) were optimized based on the results of the entrapment efficiency (EE%), particle size (PS), and zeta potential (ZP) using Box-Behnken statistical design. The optimized system was formulated using 73.59 mg Span 60, 1.28 mg cholesterol, and 3.11 mg sodium deoxycholate. The formulated system showed vesicles with PS of 526 nm, - 42.2 mV ZP, and 93.86% EE%. TZ release, cellular uptake, and cytotoxicity of the optimized system were evaluated in vitro. In addition, in vivo assessment of its safety was conducted histopathologically and via ocular irritation test to ensure the ocular tolerance of the system. Afterwards, the optimized TZ-loaded BBNV was integrated into a self-nanoemulsifying system (SNES) to allow faster TZ release for immediate antifungal effect, enhanced ocular residence, and improved ocular permeation. TZ release study revealed more than 2 folds increment in drug release rate from the integrated system compared to BBNV alone. Finally, this integrated system was assessed for its antifungal activity in vivo where it demonstrated higher antifungal activity against induced Candida albicans infection. Graphical abstract.

Yousry, C., I. S. Ahmed, M. M. Amin, and O. N. Elgazayerly, "Superhydrophobic Substrates for Ultrahigh Encapsulation of Hydrophilic Drug into Controlled-Release Polyelectrolyte Complex Beads: Statistical Optimization and In Vivo Evaluation.", Pharmaceutics, vol. 11, issue 6, 2019. Abstractpharmaceutics-11-00257.pdf

In this work, ultrahigh drug-loaded chitosan (Ch)/K-carrageenan (Kc) polyelectrolyte complex (PEC) beads were formed in situ by cross-linking in a glutaraldehyde-saturated atmosphere and were prepared on superhydrophobic substrates fabricated by spraying glass surfaces with ready-made spray for domestic use (NeverWet). Verapamil hydrochloride (VP), a highly hydrophilic drug with a short biological half-life, was incorporated into a series of Ch-based and/or Ch/Kc-PEC-based beads to control its release profile in vivo. The formulation of VP-loaded beads was optimized using stepwise statistical designs based on a prespecified criterion. Several characteristics of the prepared beads, such as entrapment efficiency (EE%), in vitro drug release, swelling ratio, size and surface microstructure as well as molecular interactions between the drug and formulation ingredients, were investigated. In vivo pharmacokinetic (PK) studies were carried out using the rabbit model to study the ability of the optimized VP-loaded beads to control the absorption rate of VP. Results revealed that the prepared superhydrophobic substrates were able to fabricate VP-loaded beads with extremely high EE exceeding 90% / compared to only 27.80% when using conventional ionotropic gelation technique. PK results showed that the rate of VP absorption was well controlled following oral administration of the optimized beads to six rabbits compared to a marketed VP immediate release (IR) tablet, as evidenced by a 2.2-fold increase in mean residence time (MRT) and 5.24-fold extension in half value duration (HVD) over the marketed product without any observed reduction in the relative oral bioavailability.

Yousry, C., M. M. Amin, A. H. Elshafeey, and O. N. Elgazayerly, "Ultrahigh verapamil-loaded controlled release polymeric beads using superamphiphobic substrate: D-optimal statistical design, in vitro and in vivo performance.", Drug delivery, vol. 25, issue 1, pp. 1448-1460, 2018 Nov. Abstractultrahigh verapamil loaded controlled release polymeric beads using superamphiphobic substrate

Controlled-release multiparticulate systems of hydrophilic drugs usually suffer from poor encapsulation and rapid-release rate. In the present study, ultra-high loaded controlled release polymeric beads containing verapamil hydrochloride (VP) as hydrophilic model drug were efficiently prepared using superamphiphobic substrates aiming to improve patient compliance by reducing dosing frequency. Superamphiphobic substrates were fabricated using clean aluminum sheets etched with ammonia solution and were treated with 1.5% (w/v) perfluorodecyltriethoxysilane (PFDTS) alcoholic solution. The effect of the main polymer type (lactide/glycolide (PLGA) 5004A, PLGA 5010, and polycaprolactone (PCL)), copolymer (Eudragit RS100) content together with the effect of drug load on encapsulation efficiency (EE%) and in vitro drug release was statistically studied and optimized via D-optimal statistical design. In vivo pharmacokinetic study was carried out to compare the optimized system relative to the market product (Isoptin). Results revealed that superamphiphobic substrates were successfully prepared showing a rough micro-sized hierarchical structured surface upon observing with scanning electron microscope and were confirmed by high contact angles of 151.60 ± 2.42 and 142.80°±05.23° for water and olive oil, respectively. The fabricated VP-loaded beads showed extremely high encapsulation efficiency exceeding 92.31% w/w. All the prepared systems exhibited a controlled release behavior with Q12 h ranging between 5.46 and 95.90%w/w. The optimized VP-loaded system composed of 150 mg (1.5% w/v) PCL without Eudragit RS100 together with 160 mg VP showed 2.7-folds mean residence time compared to the market product allowing once daily administration instead of three times per day.

Yousry, C., S. A. Elkheshen, H. M. El-Laithy, T. Essam, and R. H. Fahmy, "Studying the influence of formulation and process variables on Vancomycin-loaded polymeric nanoparticles as potential carrier for enhanced ophthalmic delivery.", European journal of pharmaceutical sciences , vol. 100, pp. 142-154, 2017 Jan 13. Abstract

Ocular topically applied Vancomycin (VCM) suffers poor bioavailability due to its high molecular weight and hydrophilicity. In the present investigation, VCM-loaded polymeric nanoparticles (PNPs) were developed aiming to enhance its ocular bioavailability through prolonging its release pattern and ophthalmic residence. PNPs were prepared utilizing double emulsion (W/O/O), solvent evaporation technique. 2(3)×4(1) full factorial design was applied to evaluate individual and combined influences of polymer type, Eudragit® RS100, sonication time, and Span®80 concentration on PNPs particle size, encapsulation efficiency, and zeta potential. Further, the optimized formulae were incorporated in 1% Carbopol®-based gel. In-vivo evaluation of the optimized formulae was performed via Draize test followed by microbiological susceptibility testing on albino rabbits. Results revealed successful formulation of VCM-loaded PNPs was achieved with particle sizes reaching 155nm and up to 88% encapsulation. Draize test confirmed the optimized formulae as non-irritating and safe for ophthalmic administration. Microbiological susceptibility testing confirmed prolonged residence, higher Cmax. with more than two folds increment in the AUC(0.25-24) of VCM-PNPs over control groups. Thus, VCM-loaded PNPs represent promising carriers with superior achievements for enhanced Vancomycin ophthalmic delivery over the traditional use of commercially available VCM parenteral powder after constitution into a solution by the ophthalmologists.

Yousry, C., R. H. Fahmy, T. Essam, H. M. El-Laithy, and S. A. Elkheshen, "Nanoparticles as tool for enhanced ophthalmic delivery of vancomycin: a multidistrict-based microbiological study, solid lipid nanoparticles formulation and evaluation.", Drug development and industrial pharmacy, vol. 42, issue 11, pp. 1752-1762, 2016 Apr 19. Abstract

CONTEXT: A microbiological multidistrict-based survey from different Egyptian governorates was conducted to determine the most prevalent causative agents of ocular infections in the Egyptian population. Antibiotic sensitivity testing was then performed to identify the most potent antimicrobial agent. Vancomycin (VCM) proved the highest activity against gram-positive Staphylococcus bacteria, which are the most commonly isolated causative agents of ocular infection. However, topically applied VCM suffers from poor ocular bioavailability because of its high molecular weight and hydrophilicity.

OBJECTIVE: The aim of the present study was to develop VCM-loaded solid lipid nanoparticles (SLNs) using water-in-oil-in-water (W/O/W) double emulsion, solvent evaporation technique to enhance ocular penetration and prolong ophthalmic residence of VCM.

METHOD: Two consecutive full factorial designs (2(4) followed by 3(2)) were adopted to study the effect of different formulation and process parameters on SLN formulation. The lipid type and structure, polyvinyl alcohol (PVA) molecular weight and concentration, sonication time, as well as lipid:drug ratio were studied as independent variables. The formulated SLN formulae were evaluated for encapsulation efficiency (EE%), particle size (PS), and zeta potential as dependent variables.

RESULTS: The statistically-optimized SLN formula (1:1 ratio of glyceryltripalmitate:VCM with 1% low molecular weight PVA and 1 min sonication time) had average PS of 277.25 nm, zeta potential of -20.45, and 19.99% drug encapsulation. Scanning and transmission electron micrographs showed well-defined, spherical, homogenously distributed particles.

CONCLUSION: The present study suggests that VCM incorporation into SLNs is successfully achievable; however, further studies with different nanoencapsulation materials and techniques would be valuable for improving VCM encapsulation.