El-Nesr, O. H. a, S. A. b Yahiya, and O. N. b El-Gazayerly, "Effect of formulation design and freeze-drying on properties of fluconazole multilamellar liposomes", Saudi Pharmaceutical Journal, vol. 18, no. 4, pp. 217-224, 2010. AbstractWebsite

Fluconazole-entrapped multilamellar liposomes were prepared using the thin-film hydration method. The effects of cholesterol molar ratio, charge-inducing agents, and α-tocopherol acetate on encapsulation efficiency values and in vitro drug release of multilamellar liposomes were studied. Freeze-dried liposomal products were prepared with or without cryoprotectants. Results showed that incorporation of stearylamine resulted in an increased entrapment of fluconazole, whereas incorporation of dicetyl phosphate decreased the drug entrapment efficiency. The incorporation of α-tocopherol acetate into fluconazole multilamellar liposomes resulted in the increase of entrapment efficiency of fluconazole liposomes. In vitro release studies revealed that incorporation of cholesterol into multilamellar liposomal formulations decreased drug permeability from formulations. Positively charged fluconazole multilamellar liposomes gave rise to a slow release rate compared to neutral liposomes whereas negatively charged fluconazole liposomes showed a rapid release rate. Physical stability studies showed that lyophilized cake of liposomes without cryoprotectants was compact and difficult to reconstitute compared to fluffy easily reconstituted cakes upon using cryoprotectants. Fluconazole retained in freeze-dried liposomes without cryoprotectants was 63.452% compared to 91.877% using three grams of trehalose as a cryoprotectant per gram lipid in positively charged multilamellar liposomes. Physical stability studies showed superior potentials of the lyophilized product after reconstitution in comparison with those of a solution product. © 2010.

Yehia, S. A. a, A. H. a Elshafeey, I. a Sayed, and A. H. b Shehata, "Optimization of budesonide compression-coated tablets for colonic delivery", AAPS PharmSciTech, vol. 10, no. 1, pp. 147-157, 2009. AbstractWebsite

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. © American Association of Pharmaceutical Scientists 2009.

b Elshafeey, A. H. a, Y. E. b Hamza, S. Y. b Amin, F. a Akhlaghi, and H. a Zia, "Enhanced bioavailability of fenoterol transdermal systems in rabbits", Journal of Bioequivalence and Bioavailability, vol. 3, no. 5, pp. 097-100, 2011. AbstractWebsite

The pharmacokinetic and bioavailability of fenoterol, a B2 adrenergic agonist were studied to determine the feasibility of enhanced transdermal delivery. Fenoterol has been widely used to treat asthmatic patients. Two fenoterol formulations were studied; the first was a liquid formulation of fenoterol in Transcutol: Oleic acid in a ratio 1:1(F1), while the second was a matrix system of fenoterol in Duro-tak® 87-2074 adhesive with 10% 1-dodecyl-2-pyrrolidinone as an enhancer (F2). For comparison, control matrix with fenoterol without any enhancer (F3) was also tested. The tested formulations were applied to the shaved back skin of rabbits using HILL TOP CHAMBER® in case of liquid formula. Blood samples were collected via auricle central vein for 24 hours and the plasma concentrations of fenoterol were determined by LC-MS/MS method. Pharmacokinetic parameters were calculated using the WinNonlin computer program. The results showed a maximum concentration of fenoterol in plasma of 514.8 ng/ml after application of the liquid formula while its AUC0-∞ amounted to be 485972(ng*min/ml) with a dose of 3mg/kg. The transdermal matrix prepared with 10% 1-dodecyl-2-pyrollidinone had a Cmax of 219 ng/ml and AUC0-∞ was 124636 (ng*min/ml) which is significantly higher than that obtained after application of the control patch without any enhancer. Therefore, the transdermal systems will offer an efficient drug delivery system for the treatment of bronchial asthma. © 2011 Elshafeey AH, et al.

b Elshafeey, A. H. a, Y. E. b Hamza, S. Y. b Amin, and H. a Zia, "In vitro transdermal permeation of fenoterol hydrobromide", Journal of Advanced Research, vol. 3, no. 2, pp. 125-132, 2012. AbstractWebsite

The aim of this study was to determine if transdermal penetration of fenoterol, a β-agonist drug, could be enhanced and controlled by formulation modification and formulation of transdermal patches. Pre-formulation studies were performed to determine the feasibility of a transdermal dosage form of fenoterol. Penetration of fenoterol was determined using the hairless guinea pig skin with unjacketed Franz diffusion cell. Transdermal patches were formulated using drug in-adhesive technique. Several enhancers were investigated for fenoterol skin penetration. Transcutol-oleic acid co-solvent gives the highest drug flux among all tested liquid formulations. Pretreatment of the skin with oleic acid 2. h before patch application significantly increases drug diffusion. Cis-oleic acid gives best results compared to oleic acid. Azone derivative (1-dodecyl-2-pyrrolidinone) gives the highest drug diffusion amongst all tested enhancers. Results of this study show the feasibility of using fenoterol formulated in transdermal delivery system in the treatment of chronic asthma to improve patient compliance, bioavailability and reduce the inter-subject variability. © 2011 Cairo University.

Khalil, R. M. a, F. E. b Murad, S. A. c Yehia, M. S. a El-Ridy, and H. A. a Salama, "Free versus liposome-entrapped streptomycin sulfate in treatment of infections caused by Salmonella enteritidis", Pharmazie, vol. 51, no. 3, pp. 182-184, 1996. AbstractWebsite

Streptomycin sulfate liposomes were prepared by the vortex dispersion method. The liposomes were formulated from a mixture of L-α-dipalmitoyl phosphatidyl choline (DPPC), cholesterol with or without (neutral) a charge inducing agent. Two phospholipid molar ratios were considered, namely, DPPC/cholesterol 7:2 and 7:4. The amount of streptomycin sulfate entrapped was estimated, microbiologically, and found to range from 0.080 to 1.323% of the initial amount of drug used for preparation of liposomes, depending on the surface charge of the liposomal vesicles. Particle size analysis, measured by the coulter counter, showed a mean particle diameter ranging from 4.417-8.424 μm. Drug targeting experiments were done using Swiss mice as the experimental animals. The in-vivo results indicated that the streptomycin sulfate concentration targeted to the liver and spleen by the liposome encapsulated drug was 2-3 times that exhibited by the free drug. This effect occurred after one day of liposome injection, but it decreased over time from one to seven days. The amount of streptomycin sulfate targeted to the lung, by the liposome formulation 7:2:1 was more than that exhibited by the free drug. This is true only after 7 d from injection. On the other hand, the liposomes of molar ratio 7:4:1 showed much less effect even when compared to the free drug. The survival rate experiments indicated a definite protection against Salmonella enteritidis, exhibited by the liposome-encapsulated streptomycin compared to the free drug.

Yehia, S. A., O. N. El-Gazayerly, and E. B. Basalious, "Design and in vitro/in vivo evaluation of novel mucoadhesive buccal discs of an antifungal drug: Relationship between swelling, erosion, and drug release", AAPS PharmSciTech, vol. 9, no. 4, pp. 1207-1217, 2008. AbstractWebsite

Two groups of fluconazole mucoadhesive buccal discs were prepared: (a) Fluconazole buccal discs prepared by direct compression containing bioadhesive polymers, namely, Carbopol 974p (Cp), sodium carboxymethyl cellulose (SCMC), or sodium alginate (SALG) in combination with hydroxypropyl methylcellulose (HPMC) or hydroxyethyl cellulose (HEC). (b) Fluconazole buccal discs prepared by freeze drying containing different polymer combinations (SCMC/HPMC, Cp/HPMC, SALG/HPMC, and chitosan/SALG). The prepared discs were evaluated by investigating their release pattern, swelling capacity, mucoadhesion properties, and in vitro adhesion time. In vivo evaluation of the buccal disc and in vivo residence times were also performed. Fluconazole salivary concentration after application of fluconazole buccal systems to four healthy volunteers was determined using microbiological assay and high-performance liquid chromatography. SCMC/HPMC buccal disc prepared by direct compression could be considered comparatively superior mucoadhesive disc regarding its in vitro adhesion time, in vivo residence time, and in vitro/in vivo release rates of the drug. Determination of the amount of drug released in saliva after application of the selected fluconazole disc confirmed the ability of the disc to deliver the drug over a period of approximately 5 h and to reduce side effects and possibility of drug interaction encountered during systemic therapy of fluconazole, which would be beneficial in the case of oral candidiasis. © American Association of Pharmaceutical Scientists 2008.

Yehia, S. A., O. N. El-Gazayerly, and E. B. Basalious, "Fluconazole mucoadhesive buccal films: In vitro/in vivo performance", Current Drug Delivery, vol. 6, no. 1, pp. 17-27, 2009. AbstractWebsite

Fluconazole mucoadhesive buccal films were prepared using film forming polymers namely; hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (HEC), chitosan, Eudragit and sodium alginate (SALG) either alone or in combination with bioadhesive polymers. The bioadhesive polymers studied were sodium carboxymethyl cellulose (SCMC), Carbopol 974P, and polycarbophil (AA-A). The prepared films were characterized by means of film thickness, surface pH, swelling capacity, in vitro adhesion, in vivo residence time, in vitro drug release and in vivo drug release to determine the amount of drug release from selected film formulae using microbiological assay and HPLC. Optimum release behavior, convenient bioadhesion, acceptable elasticity were exhibited by film containing 2% HPMC and 1% SCMC (fresh or stored for 6 months). Determination of the amount of drug released in saliva after application of the selected fluconazole films confirmed the ability of the film to deliver the drug over a period of approximately 300 minutes and to reduce side effects and possibility of drug interaction encountered during systemic therapy of fluconazole, which would be beneficial in the case of oral candidiasis. © 2009 Bentham Science Publishers Ltd.

Yehia, S. A. a, A. H. a Elshafeey, I. a Sayed, and A. H. b Shehata, "Optimization of budesonide compression-coated tablets for colonic delivery", AAPS PharmSciTech, vol. 10, no. 1, pp. 147-157, 2009. AbstractWebsite

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. © American Association of Pharmaceutical Scientists 2009.

Yehia, S. A., A. H. Elshafeey, and I. Elsayed, "Pulsatile systems for colon targeting of budesonide: In vitro and in vivo evaluation", Drug Delivery, vol. 18, no. 8, pp. 620-630, 2011. AbstractWebsite

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.

Yehia, S. A., A. H. Elshafeey, A. El Meshad, and H. A. Al-Bialey, "A pharmaceutical study on different approaches for itopride hydrochloride sustainment: In-vitro and in-vivo evaluation", Journal of Chemical and Pharmaceutical Research, vol. 4, no. 2, pp. 1398-1412, 2012. AbstractWebsite

Recent trends indicate that dosage form drug delivery systems are especially suitable for achieving sustained or delayed release oral formulations with low risk of dose dumping, flexibility of blending to attain different release patterns as well as reproducibility. One of the approaches toward this goal was to develop and formulate extended release matrix oral tablets of itopride hydrochloride (ITO) as a highly water soluble drug and to increase its gastric retention time. Matrix tablets of (ITO) were developed using different methods such as: (wetting granulation, direct compression, and coating compression), by using different types of polymers (hydroxypropyl methyl cellulose (HPMC) K15M, hydroxypropyl cellulose (HPC) low viscosity, Eudragit ® RL100, and Carnauba wax). The prepared tablets were evaluated according to various physicochemical characteristics such as: weight and thickness variation, drug content, hardness, friability, and in vitro drug release. Tablet weight variation ranged from 395 ± 0.34 to 409 ± 1.78 mg, thickness ranged from 3.16 ± 1.37 to 3.74 mm, drug content ranged from 94.5 ± 1.01% to 106.2 ± 0.08%, friability ranged from 0.04 ± 0.69 to 0.84 ± 0.45, and hardness ranged from 5.25 ± 0.25 to 8.80 ± 0.4 Kg/cm 2. Results indicated that drug release depended upon method of preparation and polymer type. Furthermore, in vivo testing of the optimum sustained release tablet formulation (F23) using coating compression by HPMC as coat was performed in human subjects, and determined and compared to that of a commercial oral tablet (Ganaton ®) as a reference formulation. The obtained the maximum plasma concentration (C max) and the area under the curve from zero to infinity (AUC ( 0-∞) values were higher following formulated tablet administration than after Ganaton ® administration. The percentage relative bioavailability of ITO from the selected formula in human volunteers was found to be 243% compared to Ganaton ®.