Ahmed Elshafeey

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.

In this study an attempt to sustain the oral release of itopride hydrochloride (ITO), a highly water-soluble drug, by microencapsulation using different polymers was carried out. The prepared microcapsules were characterized according to: particle size, encapsulation efficiency, and in vitro drug release and in vivo study in healthy human volunteers. Results showed that the particle size of microcapsules ranged from 591 ± 2 to 886 ± 4 μm and the encapsulation efficiency of ITO inside microcapsules ranged from 63 ± 1 to 90 ± 1%. The optimum formulation had a particle size of 860 ± 11 μm and was able to entrap 90 ± 1% ITO. The in vitro release study showed that 88 ± 1% of ITO was released from the optimum formulation after 12 h using Eudragit RS-100. The pharmacokinetic parameters of the optimum formulation in human volunteers showed that the maximum plasma concentration was 1624 ± 168 ng/mL, AUC 0-∞ was 85835 ± 6116 ng .h/mL, AUC0-48 was 29728 ± 761 ng .h/mL, and the mean residence time was 108 ± 9 h. The relative bioavailability of ITO from the optimum formulation compared to commercial oral tablets Ganaton as a reference standard was 317.9%.

Objectives The purpose of this study was to develop an injectable depot liposphere delivery system with high loading capacity for controlled delivery of donepezil to decrease dosing frequency and increase patient compliance. Methods A 32 full factorial design was employed to study the effect of lipid type and drug-to-lipid ratio on the yield, encapsulation efficiency, mean diameter and the time required for 50% drug release (t50%). The pharmacokinetic behaviour of the lipospheres in rabbits was studied using tandem mass spectrometry. Key findings The yields of preparations were in the range of 66.22-90.90%, with high encapsulation efficiencies (89.68-97.55%) and mean particle size of 20.68-35.94 μm. Both lipid type and drug-to-lipid ratio significantly affected t50% (P < 0.0001), where the lipids can be arranged: glyceryl tripalmitate > compritol > cetyl alcohol, and the drug-to-lipid ratios can be arranged: 1: 40 > 1: 20 > 1: 10. The flow time of lipospheres through 19-gauge syringe needle was less than 6 s indicating good syringeability. The mean residence time of the subcutaneous and intramuscular lipospheres was significantly higher than the solution (almost 20 fold increase), with values of 11.04, 11.34 and 0.53 days, respectively (P < 0.01). Conclusion Subcutaneous and intramuscular delivery of donepezil glyceryl tripalmitate lipospheres achieves depot release, allowing less frequent dosing. © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.

One of the greatest challenges in in situ forming implant (ISFI) systems by polymer precipitation is the large burst release during the first 124 hours after implant injection. The aim of this study was to decrease the burst-release effect of a water-soluble model drug, donepezil HCl, with a molecular weight of 415.96Da, from in situ forming implants using a novel in situ implant containing lipospheres (ISILs). In situ implant suspensions were prepared by dispersing cetyl alcohol and glyceryl stearate lipospheres in a solution of poly-DL-lactide (PDL) or DL-lactide/glycolide copolymer (PDLG). Also, in situ implant solutions were prepared using different concentrations of PDL or PDLG solutions in N-methyl-2-pyrrolidone (NMP). Triacetin and Pluronic L121 were used to modify the release pattern of donepezil from the in situ implant solutions. In vitro release, rheological measurement, and injectability measurement were used to evaluate the prepared in situ implant formulae. It was found that ISIL decreased the burst effect as well as the rate and extent of drug release, compared to lipospheres, PDL, and PDLG in situ implant. The amount of drug released in the first day was 37.75, 34.99, 48.57, 76.3, and 84.82% for ISIL in 20% PDL (IL-1), ISIL in 20% PDLG (IL-2), lipospheres (L), 20% PDL ISFI (I5), and 20% PDLG ISFI (I8), respectively. The prepared systems showed Newtonian flow behavior. ISIL (IL-1 and IL-2) had a flow rate of 1.94 and 1.40mL/min, respectively. This study shows the potential of using in situ implants containing lipospheres in controlling the burst effect of ISFI. © 2012 Informa Healthcare USA, Inc.

The purpose of this study is to increase the lag time and prevent release of budesonide, a corticosteroid drug used in Crohn's disease for the first 5h and efficiently deliver it to the colon. Eudragit S100 spray-coated capsules and pulsatile systems using tablet plugs of cellulose acetate butyrate (CAB), HPMC K4M, guar gum, and pectin were prepared. Eudragit S100-coated capsules released 80.62% after 5h. In pulsatile systems, decreasing the ratio of the polymer significantly increased the rate and extent of drug release. Spray-coating with EUD S100 decreased the extent of drug release to 48.41%, 69.94%, 80.58%, and 45.23% in CAB, HPMC K4M, pectin, and guar gum, respectively; however, the entire amount was released in the target area. In the presence of bacterial enzymes, selected formulas showed nearly 100% release. X-ray imaging performed to monitor the capsules throughout the GIT in human volunteers of the capsules and spray-coated pulsatile systems with 25% guar gum in the plug showed bursting in the transverse and ascending colon, respectively. Both formulations showed marked reduction in induced rabbit colitis model. © 2011 Informa Healthcare USA, Inc.

The purpose of this study was to formulate budesonide (BUD) compression-coated tablets for colonic specific delivery. Pectin and guar gum were used as enzyme-dependent polymers. For comparison purposes, both pH- and time-dependent polymers were also tried. In vitro release studies were carried out at different pH (1.2, 6.8, and 7.4). Therapeutic efficacy of the prepared tablets compared to commercially available capsules and enema were evaluated in trinitrobenzenesulfonic acid-induced rabbit colitis model. In pH-dependent polymers, Eudragit (EUD) S100/EUD L100 (1:1) released 45.58% in the target area (colon). For time-dependent polymers, decreasing cellulose acetate butyrate (CAB) ratio increased the release in both pH 6.8 and 7.4 till it reached 40.58% and 93.65%, respectively, for 25% CAB. In enzyme-dependent polymers, increasing pectin ratio to 75% retarded the release (4.59% in pH 6.8 and 54.45% in pH 7.4) which was significantly enhanced to 99.31% using pectinolytic enzyme. Formula F14 coated with 75% pectin significantly reduced the inflammatory cells in the connective tissue core of the colon of the treated group and significantly decreased myeloperoxidase activity (3.90 U/g tissue weight). This study proved that BUD compression-coated with 75% pectin may be beneficial in the treatment of inflammatory bowel disease.