Badr-Eldin, S. M., S. A. Elkheshen, and M. M. Ghorab, "Improving tadalafil dissolution via surfactant-enriched tablets approach: Statistical optimization, characterization, and pharmacokinetic assessment", Journal of Drug delivery Science and Technology, vol. 41, pp. 197-205, 2017. AbstractWebsite

Tadalafil suffers from poor aqueous solubility that could lead to fluctuating blood levels and unreproducible effect. Thus, this work aimed at improving tadalafil dissolution utilizing the approach of surfactant-enriched tablets. The feasibility of minimizing various surfactants quantities was investigated by establishing the ratio of the surfactant to drug that is required for drug solubilization in micellar solutions. Based on the computed ratios, Tween was precluded from formulation studies due to its poor solubilizing capacity towards the drug. 23 factorial design was employed to assess the impact of formulation attributes on tablets' characteristics. Based on the statistical analysis and the desirability function approach, tablet formulation F6 prepared using CTAB, Avicel PH 102, and 5% Ac-Di-Sol was selected as the optimum formulation. The selected formulation showed adequate stability after storage at 40 °C and 75% R.H. for twelve weeks. Pharmacokinetic study revealed that the selected surfactant-enriched tablet formulation F6 showed enhanced bioavailability compared to the market product Cialis®.

Ahmed, O. A. A., K. M. El-Say, B. M. Aljaeid, S. M. Badr-Eldin, and T. A. Ahmed, "Optimized vinpocetine-loaded vitamin E D-α-tocopherol polyethylene glycol 1000 succinate-alpha lipoic acid micelles as a potential transdermal drug delivery system: in vitro and ex vivo studies.", International journal of nanomedicine, vol. 14, pp. 33-43, 2019. AbstractWebsite

Background: Vinpocetine (VNP), a semisynthetic natural product, is used as a vasodilator for cerebrovascular and age-related memory disorders. VNP suffers from low oral bioavailability owing to its low water solubility and extensive first-pass metabolism. This work aimed at utilizing D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and alpha lipoic acid (ALA) to develop efficient micellar system for transdermal delivery of VNP.

Materials and methods: VNP-TPGS-ALA micelles were prepared, characterized for particle size using particle size analyzer, and investigated for structure using transmission electron microscope. Optimization of VNP-TPGS-ALA micelles-loaded transdermal films was performed using Box-Behnken experimental design. The investigated factors were percentage of ALA in TPGS (X), citral concentration (X), and propylene glycol concentration (X). Elongation percent (Y), initial permeation after 2 hours (Y), and cumulative permeation after 24 hours (Y) were studied as responses.

Results: Statistical analysis revealed optimum levels of 16.62%, 3%, and 2.18% for X, X, and X, respectively. Fluorescent laser microscopic visualization of skin penetration of the optimized transdermal film revealed marked widespread fluorescence intensity in skin tissue after 0.5, 2, and 4 hours compared with raw VNP transdermal film formulation, which indicated enhancement of VNP skin penetration.

Conclusion: The obtained results highlighted the potentiality of VNP nanostructure-based films for controlling the transdermal permeation of the drug and improving its effectiveness.

Ahmed, T. A., S. M. Badr-Eldin, O. A. A. Ahmed, and H. Aldawsari, "Intranasal optimized solid lipid nanoparticles loaded in situ gel for enhancing trans-mucosal delivery of simvastatin", Journal of Drug Delivery Science and Technology , vol. 48, pp. 499-508, 2018. AbstractWebsite

The aim of this study was to develop optimized simvastatin (SMV) solid lipid nanoparticles (SLNs) with subsequent loading into a thermosensitive in situ gel (ISG) to enhance and control intranasal drug permeation. Three formulation factors were optimized for their effect on particle size and entrapment efficiency (EE). SLNs components were studied thru solid-state characterization. The optimized formulation was morphologically characterized and loaded into poloxamer ISG formulations of different concentrations. Evaluations were done for gelation temperature, viscosity, muco-adhesion strength, and in vitro and ex vivo permeations. Transport across nasal mucosal layers was characterized using a fluorescence laser microscope. The studied factors significantly affected particle size and EE. The drug was successfully encapsulated and homogenously dispersed in the lipid matrix and changed from a crystalline to amorphous state in the optimized SLNs. Transmission electron microscope illustrated the presence of nanoparticles, while scanning electron microscope observations indicated fusion of the particles. An ISG formulation containing 22% poloxamer loaded with optimized SLNs exhibited better mucoadhesion and ex vivo drug permeation, and was able to penetrate deeper into the nasal tissue when compared to the same formulation loaded with pure drug. No signs of inflammation or necrosis were observed upon histopathological study. In summary, this thermosensitive ISG formulation containing SMV SLNs can be considered as an alternative to currently available oral drug formulations, however, further pre/clinical studies are needed.

Darwesh, B., H. M. Aldawsari, and S. M. Badr-Eldin, "Optimized Chitosan/Anion Polyelectrolyte Complex Based Inserts for Vaginal Delivery of Fluconazole: In Vitro/In Vivo Evaluation.", Pharmaceutics, vol. 10, issue 4, 2018 Nov 12. AbstractWebsite

(1) Background: Fluconazole, used orally for vaginal candidiasis, has reported gastrointestinal side effects. Therefore, researchers directed towards the drug vaginal delivery. However, vaginal delivery is limited by poor retention and leakage. Thus, this work aimed at exploring chitosan/anion polyelectrolyte complex (PEC) for the formulation of fluconazole vaginal inserts with controlled release and appreciable mucoadhesion. (2) Methods: PECs were prepared and assessed for interactions. Fluconazole PEC based vaginal inserts were prepared by lyophilization using mannitol. 3¹5¹ factorial design was applied to investigate the effect of the anion type and Chitosan/anion ratio on the inserts mucoadhesion and release properties. The optimized insert [based on 5:5 chitosan: anionic polymer (sodium alginate)] release was modulated by the release retardant; Compritol 888. The selected formulation was subjected to microbiological and histological evaluation. (3) Results: Fluconazole inserts showed satisfactory drug content, acceptable friability percentages and highest swelling indices at six hours. Statistical analysis showed significant effect of the studied factors on detachment force and release properties. Microbiological assays revealed significantly higher antifungal activity of inserts compared to fluconazole solution. Reduced inflammatory cells were confirmed by histological evaluation. (4) Conclusion: CH/Alg based vaginal insert could be a promising platform for vaginal delivery of antifungal drugs used for vaginal candidiasis treatment.

Ahmed, O. A. A., and S. M. Badr-Eldin, "In situ misemgel as a multifunctional dual-absorption platform for nasal delivery of raloxifene hydrochloride: formulation, characterization, and in vivo performance.", International journal of nanomedicine, vol. 13, pp. 6325-6335, 2018. AbstractWebsite

Background: Raloxifene hydrochloride (RLX) is approved by the US Food and Drug Administration for the treatment and prevention of osteoporosis, in addition to reducing the risk of breast cancer in postmenopausal women. RLX has the disadvantages of low aqueous solubility, extensive presystemic intestinal glucuronidation, and first-pass metabolism, resulting in a limited bio-availability of only 2%. The aim of this work was to enhance the bioavailability of RLX via the formulation of an in situ nasal matrix (misemgel) comprising micelles made of vitamin E and D-α-tocopheryl polyethylene glycol 1000 succinate and nanosized self-emulsifying systems (NSEMS).

Materials and methods: Optimization of the RLX-loaded NSEMS was performed using a mixture design. The formulations were characterized by particle size and then incorporated into an in situ nasal gel. Transmission electron microscopy, bovine nasal mucosa ex vivo permeation, and visualization using a fluorescence laser microscope were carried out on the RLX in situ misemgel comparing with raw RLX in situ gel. In addition, the in vivo performance was studied in rats.

Results: The results revealed improved permeation parameters for RLX misemgel compared with control gel, with an enhancement factor of 2.4. In vivo studies revealed a 4.79- and 13.42-fold increased bioavailability for RLX in situ misemgel compared with control RLX in situ gel and commercially available tablets, respectively. The obtained results highlighted the efficacy of combining two different formulations to enhance drug delivery and the benefits of utilizing different possible paths for drug absorption.

Conclusion: The developed in situ misemgel matrix could be considered as a promising multifunctional platform for nasal delivery which works based on a dual-absorption mechanism.

Badr-Eldin, S. M., and O. A. Ahmed, "Optimized nano-transfersomal films for enhanced sildenafil citrate transdermal delivery: ex vivo and in vivo evaluation.", Drug design, development and therapy, vol. 10, pp. 1323-33, 2016. AbstractWebsite

Sildenafil citrate (SLD) is a selective cyclic guanosine monophosphate-specific phosphodiesterase type 5 inhibitor used for the oral treatment of erectile dysfunction and, more recently, for other indications, including pulmonary hypertension. The challenges facing the oral administration of the drug include poor bioavailability and short duration of action that requires frequent administration. Thus, the objective of this work is to formulate optimized SLD nano-transfersomal transdermal films with enhanced and controlled permeation aiming at surmounting the previously mentioned challenges and hence improving the drug bioavailability. SLD nano-transfersomes were prepared using modified lipid hydration technique. Central composite design was applied for the optimization of SLD nano-transfersomes with minimized vesicular size. The independent variables studied were drug-to-phospholipid molar ratio, surfactant hydrophilic lipophilic balance, and hydration medium pH. The optimized SLD nano-transfersomes were developed and evaluated for vesicular size and morphology and then incorporated into hydroxypropyl methyl cellulose transdermal films. The optimized transfersomes were unilamellar and spherical in shape with vesicular size of 130 nm. The optimized SLD nano-transfersomal films exhibited enhanced ex vivo permeation parameters with controlled profile compared to SLD control films. Furthermore, enhanced bioavailability and extended absorption were demonstrated by SLD nano-transfersomal films as reflected by their significantly higher maximum plasma concentration (C max) and area under the curve and longer time to maxi mum plasma concentration (T max) compared to control films. These results highlighted the potentiality of optimized SLD nano-transfersomal films to enhance the transdermal permeation and the bioavailability of the drug with the possible consequence of reducing the dose and administration frequency.

Aldawsari, H. M., S. M. Badr-Eldin, G. S. Labib, and A. H. El-Kamel, "Design and formulation of a topical hydrogel integrating lemongrass-loaded nanosponges with an enhanced antifungal effect: in vitro/in vivo evaluation.", International journal of nanomedicine, vol. 10, pp. 893-902, 2015. AbstractWebsite

Lemongrass oil (LGO) is a volatile oil extracted from the leaves of Cymbopogon citratus that has become one of the most important natural oils in the pharmaceutical industry because of its diverse pharmacologic and clinical effects. However, LGO suffers from low aqueous solubility, which could lead to a reduced effect. Moreover, the instability of its major active constituent, citral, could lead to volatilization, reaction with other formulation ingredients, and consequently, skin irritation. To surmount these problems, this research aims to formulate lemongrass-loaded ethyl cellulose nanosponges with a topical hydrogel with an enhanced antifungal effect and decreased irritation. The minimal inhibitory concentration and minimal fungicidal concentration of LGO against Candida albicans strain ATC 100231, determined using the broth macrodilution method, were found to be 2 and 8 μL/mL, respectively. The emulsion solvent evaporation technique was used for the preparation of the nanosponges. The nanosponge dispersions were then integrated into carbopol hydrogels (0.4%). Nine formulations were prepared based on a 32 full factorial design employing the ethyl cellulose:polyvinyl alcohol ratio and stirring rate as independent variables. The prepared formulations were evaluated for particle size, citral content, and in vitro release. Results revealed that all the nanosponge dispersions were nanosized, with satisfactory citral content and sustained release profiles. Statistical analysis revealed that both ethyl cellulose:polyvinyl alcohol ratio and stirring rate have significant effects on particle size and percentage released after 6 hours; however, the effect of the stirring rate was more prominent on both responses. The selected hydrogel formulation, F9, was subjected to surface morphological investigations, using scanning and transmission electron microscopy, where results showed that the nanosponges possess a spherical uniform shape with a spongy structure, the integrity of which was not affected by integration into the hydrogel. Furthermore, the selected formulation, F9, was tested for skin irritation and antifungal activity against C. albicans, where results confirmed the nonirritancy and the effective antifungal activity of the prepared hydrogel.

Abduljabbar, H., S. M. Badr-Eldin, and H. Aldawsari, "Gastroretentive Ranitidine Hydrochloride Tablets with Combined Floating and Bioadhesive Properties: Factorial Design Analysis, In Vitro Evaluation and In Vivo Abdominal X-Ray Imaging", Current drug delivery, vol. 12, issue 5, pp. 578-590, 2015. AbstractWebsite

Ranitidine HCl is an H2-antagonist that suffers from low oral bioavailability of 50%. The site-specific absorption from the upper part of the small intestine and the colonic metabolism of the drug could partially contribute to its reduced bioavailability. To surmount these drawbacks, this work aimed at the formulation of Ranitidine HCl gastroretentive floating-biaodhesive tablets. A 3(2) factorial design was applied to assess the effects of matrix former (HPMC K100M): drug ratio, and the release retardant (Carbopol 971) amount on the characteristics of the tablets prepared using direct compression technique. The prepared tablets were thoroughly evaluated for physical properties, floating, swelling, bioadhesive and in vitro release behaviors. Statistical analysis of the results revealed significant effects for both formulation variables on the swelling index, maximum detachment force and cumulative percent drug released after 6 hours. In addition, the matrix- former: drug ratio showed a statistically significant effect on the floating lag time. Kinetic analysis of the release data indicated Higuchi diffusion kinetics and anomalous transport mechanism for all formulations. Scanning electron micrographs of the selected tablet formulation; F8, revealed intact surface without any perforations or channels in the dry state, while polymer expansion (relaxation) with some perforated areas were observed on the surface of the tablets after 12 hours dissolution in 0.1 N HCl. Furthermore, in vivo abdominal x-ray imaging showed good floating behavior of the selected formulation; F8, for up to 6 hours with appropriate bioadhesive property. In conclusion, the selected ranitidine HCl floating-bioadhesive tablets could be regarded as a promising gastroretentive drug delivery system that could deliver the drug at a controlled rate.

El-Say, K. M., T. A. Ahmed, S. M. Badr-Eldin, H. M. Aldawsari, U. A. Fahmy, and O. A. A. Ahmed, "Enhanced permeation parameters of optimized nanostructured simvastatin transdermal films: ex vivo and in vivo evaluation.", Pharm. Dev. Technol., vol. 20, issue 8, pp. 919-926, 2015. AbstractWebsite

Objective: Detailed optimization process was carried out to enhance permeation parameters, and hence bioavailability, of simvastatin (SMV) transdermal films. Methods: SMV solubility was investigated in various oils, surfactants and co-surfactants/co-solvents. Mixtures of the selected components were prepared to identify zone of nanoemulsion formation that was utilized in Extreme Vertices mixture design to develop SMV self-nanoemulsifying drug delivery systems (SNEDDS) with minimum globule size. Optimized SMV-SNEDDS were included in the preparation of transdermal films. A fractional factorial design was implemented to evaluate effects of the factors on the amount of SMV permeated. The optimized film was investigated for ex vivo skin permeation and in vivo pharmacokinetic parameters. Results: The optimum SNEDDS formula was 0.09, 0.8 and 0.11 for Sefsol 218, tween 80 and PEG 200, respectively. Fractional factorial design depicted the optimized SMV transdermal film with 2% HPMC and 2% DMSO as permeation enhancer that showed 1.82-fold improvements in skin flux. The pharmacokinetic data showed higher Cmax and almost doubled AUC compared with raw SMV-loaded films. Conclusion: The two-step optimization implemented to optimize and control the experimental conditions for the preparation of SMV-SNEDDS-transdermal film with improved ex vivo skin permeation and enhanced in vivo parameters.

Aburahma, M. H., and S. M. Badr-Eldin, "Compritol 888 ATO: a multifunctional lipid excipient in drug delivery systems and nanopharmaceuticals.", Expert opin. Drug Del., vol. 11, issue 12, pp. 1865-1883, 2014. Abstractcompritol.pdfWebsite

Compritol® 888 ATO is a lipid excipient that is generally used in cosmetic industry as a surfactant, emulsifying agent and viscosity-inducing agent in emulsions or creams. Based on its chemical composition, Compritol 888 ATO is a blend of different esters of behenic acid with glycerol. Areas covered: Recently, there has been great interest in the multiple roles that Compritol 888 ATO plays in various pharmaceutical delivery systems. Accordingly, this review aimed at summarizing the current and potential applications of Compritol 888 ATO in various drug delivery areas. Expert opinion: Different researches have highlighted the feasibility of using Compritol 888 ATO as a lubricant or coating agent for oral solid dosage formulations. It has also been explored as a matrix-forming agent for controlling drug release. At present, the most common pharmaceutical application of Compritol 888 ATO is in lipid-based colloidal drug delivery system such as solid lipid microparticles, solid lipid nanoparticles and nanostructured lipid carriers. Although, Compritol 888 ATO has acceptable regulatory and safety profiles and although the number of articles that emphasize on its applicability as an innovative excipient in pharmaceutical technology is continuously increasing, it is not widely used in the pharmaceutical market products and its use is limited to its sustain release ability in extended release tablets.

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