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Rania M Yehia,1 Dalia A Attia,1 Mohamed M Elmazar,2 Mohamed A El-Nabarawi,3 Mahmoud H Teaima3 1Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, The British University in Egypt (BUE), Cairo, Egypt; 2Department of Pharmacology and Toxicology, Faculty of Pharmacy, The British University in Egypt (BUE), Cairo, Egypt; 3Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, EgyptCorrespondence: Dalia A Attia, Suez Desert Road, El Sherouk City, Cairo, 1183, Egypt, Tel +2 1111414144 ; +2 02 268 90000, Ext. 1831, Fax +20226300010/20, Email dalia.rhman@bue.edu.egPurpose: The objective of the present study was to scrutinize the microsponges (MS) as a carrier system using Adapalene (ADA) as a model drug.Methods: Data modelling was implemented using Plackett-Burman design to identify the main variables affecting the formulation of ADA-MS. The adopted method of preparation for MS was quasi-emulsion solvent diffusion method. The nominated independent variables were volume of organic phase, sonication time, stirring speed, drug percent, polymer type, emulsifier concentration, and method of organic phase addition. As for the dependent variables, they included entrapment efficiency (E.E.%), production yield (P.Y.%), particle size (P.S.) and morphology. Furthermore, selected ADA loaded microsponges (ADA-MS) were in vitro assayed for their biological activities via cytotoxicity, UVA irradiation and cell viability, and antimicrobial activity.Results: The study indicated that the drug percent, polymer type and surfactant concentration have the key significant effect on E.E.% and P.Y.%, while, the drug percent, stirring speed and volume of organic phase have had a significant effect on P.S. and their morphology. Furthermore, ADA-MS had a momentous cytotoxic effect on A431 and M10 cell-lines with exceptional enrichment when the polymer Eudragit RS100 was used. Also, the ADA-MS increased the cell viability after UVA irradiation on HFB-4 cell-line by 14% to 43%, especially when using Ethyl Cellulose as a polymer. Lastly, the antimicrobial activity of ADA against Propionibacterium acnes was boosted when incorporated into MS.Conclusion: The Plackett−Burman design proved its impact in discerning preparation variables affecting the quality of ADA-MS formulation, with heightening of the in vitro biological activities of ADA. Thus, MS was presumed to be an auspicious carrier system for ADA.Graphical Abstract: Keywords: Plackett-Burman, anticancer, antibacterial, UVA irradiation

Mahmoud Teaima,1 Rehab Abdelmonem,2 Yomna A Adel,3 Mohamed A El-Nabarawi,1 Tayseer M El-Nawawy3 1Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt; 2Department of Industrial Pharmacy, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology (MUST), 6th of October City, Giza, 12566, Egypt; 3Department of Pharmaceutics, Egyptian Drug Authority, Cairo, EgyptCorrespondence: Mahmoud TeaimaDepartment of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, 11562, EgyptEmail mahmoud.teaima@pharma.cu.edu.egPurpose: The purpose of this study was to prepare telmisartan transethosomes, incorporate them into a gel, evaluate them for in vitro drug release and in vivo permeation using iontophoresis to enhance their transdermal delivery.Materials and Methods: TE formulae were prepared using various surfactants (SAAs), different ethanol concentrations, and different phospholipid-to-SAA ratios with different cholesterol ratios, characterized according to their entrapment efficiency percentage (EE%), zeta potential (ZP), particle size (PS), and polydispersity index (PDI). The optimum three formulae were incorporated into a gel, evaluated physically, in vitro dissolution, and ex vivo drug permeation using rat skin and Iontophoresis was performed on the best formula.Results: The optimum three formulae (F29, F31, F32) had an EE% of 97± 0.26%, 89± 0.25% and 88± 0.17%, PS of 244± 5.88 nm, 337± 4.6 nm and 382.2± 3.06 nm, PDI of 0.57± 1.9, 0.5± 1.4 and 0.63± 2.2 and ZP of − 31.6± 1.59 mV, − 28.3± 3.79 mV and − 31± 5.65, respectively. Selecting F29 for in vivo study by iontophoretic enhancement, Cmax was increased by 1.85 folds compared to the commercial oral tablet and by 1.5 folds compared to transdermal gel. Tmax decreased by half using iontophoresis compared to commercial tablets and transdermal gel.Conclusion: The transethosomal formulation of telmisartan enhanced its transdermal absorption and increased its bioavailability as well. Iontophoresis was used to increase maximum plasma concentration and reduce Tmax by half.Keywords: telmisartan, TEL, entrapment efficiency, EE, transethosomes, iontophoresis

Mahmoud H Teaima,1 Khaled M Abdel-Haleem,2 Rewan Osama,2 Mohamed A El-Nabarawi,1 Osama S Elnahas2 1Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt; 2Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, October 6 University, Giza, EgyptCorrespondence: Mahmoud H TeaimaDepartment of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, 11562, EgyptTel +201005840264Email mahmoud.teaima@pharma.cu.edu.egSignificance: Statins are an important class of drugs that help to control hyperlipidemia, and one of these statins recently used is pitavastatin calcium (PITA). Nevertheless, the most reported adverse effect of statins is myopathy. Therefore, combining statins with non-steroidal anti-inflammatory drugs (NSAIDs) as Lornoxicam (LORNO) can help in the management of statin-induced myopathy.Purpose: This study aimed to formulate and evaluate different oral disintegrating tablets (ODTs) containing PITA using different co-processed excipients. The best PITA-ODT was selected and reformulated with the addition of LORNO, forming a single ODT comprising both drugs. The pharmacokinetic parameters of PITA and LORNO in a single ODT were compared to those of the marketed products (Lipidalon® and Lornoxicam®).Methods: Eight PITA-ODTs were prepared via direct compression. The prepared PITA-ODTs were evaluated for their weight variation, thickness, breaking force, friability, drug content, and wetting time (WT). In-vitro disintegration time (DT) and dissolution were also evaluated and taken as parameters for selection of the best formula based on the criteria of scoring the fastest DT and highest Q10 min. LORNO was added to the selected PITA-ODT, forming a single ODT (M1) comprising both drugs, which was subjected to an in-vivo pharmacokinetic study using rats as an animal model and liquid chromatography-mass spectrometry (LC-MS/MS) for analysis of both drugs in rat plasma.Results: Results showed that all PITA-ODTs had acceptable physical properties in accordance with pharmacospecial standards. PITA-ODT prepared with Pharmaburst® (F2) had significantly (p< 0.05) the fastest DT (6.66± 1.52 s) and highest Q10 min (79.07± 2.02%) and was chosen as the best formula. The in-vivo pharmacokinetic study of M1 formula showed higher percent relative bioavailability (%RB) of 286.7% and 169.73% for PITA and LORNO, respectively, compared with the marketed products.Conclusion: The single ODT comprising PITA and LORNO was promising for instant co-delivery of both drugs with higher %RB when compared with the marketed products.Keywords: oral disintegrating tablets, co-processed excipients, pitavastatin calcium, Lornoxicam, in-vivo pharmacokinetic study, liquid chromatography-mass spectrometry

Rehab Abdelmonem,1 Menna M Abdellatif,1 Inas Essam Ibrahim Al-Samadi,1 Mohamed A El-Nabarawi2 1Department of Industrial Pharmacy, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology (MUST), 6th of October, Giza, 12566, Egypt; 2Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Giza, EgyptCorrespondence: Menna M Abdellatif Tel +20 1005647945Email menna.abdallatif@must.edu.egPurpose: This study aimed to formulate an orally disintegrating tablet (ODT) containing both baclofen and meloxicam together for treating osteoarthritis.Methods: Direct compression method was used to prepare ODTs using three types of co-processed excipients (Prosolv ODT G2®, F-melt®, and Pharmaburst® 500). ODTs were evaluated according to weight variation, thickness, friability, hardness, drug content, wetting time, in-vitro disintegration time, in-vitro dissolution test, and palatability. To enhance the in-vitro dissolution of meloxicam and palatability of ODT, a six sigma methodology was used, and an improvement phase was established where ODTs were prepared using lyophilization and levigation techniques. Finally, a pharmacokinetic study of the improved ODT was accomplished in comparison to the conventional oral tablet.Results: Pharmaburst-based formula (F4) showed the shortest wetting time and, consequently, the shortest disintegration time and the highest percentage of drug dissolved within 3 min compared to the other formulae. All the improved ODTs had a bitterness taste score vary from (0) palatable and (+1) tasteless. The current sigma level was 3.628 σ and 3.33 σ for palatability and solubility of ODT, respectively, which indicated the process was successfully improved compared with the previous sigma level of 2.342 σ of both processes. Pharmacokinetic study of the improved ODTs showed a significant decrease of Tmax to 120 and 30 min instead of 180 and 120 min for meloxicam and baclofen, respectively.Conclusion: ODTs were successfully improved using the six sigma methodology, the pharmacokinetic parameters of both drugs were enhanced due to rapid absorption through the oral mucosa.Keywords: baclofen, meloxicam, co-processed excipients, orally disintegrating tablet, six sigma methodology

Rana M Gebreel,1 Noha A Edris,2 Hala M Elmofty,2 Mina I Tadros,3,4 Mohamed A El-Nabarawi,3 Doaa H Hassan1 1Department of Pharmaceutics, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, Giza, Egypt; 2Department of Ophthalmology, Faculty of Medicine, Cairo University, Cairo, Egypt; 3Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt; 4Department of Pharmaceutics, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Cairo, EgyptCorrespondence: Mina I Tadros Tel +20 1223620458Fax +20 223628246Email mina.tadros@pharma.cu.edu.egAim: Norfloxacin (NFX) has low ocular bioavailability. The current work aimed to develop NFX-loaded nanoparticle (NP)-laden hydrogels to improve the ocular potential of NFX, minimize the need for frequent instillations and lower undesirable side effects.Methods: NFX-loaded NPs were developed via the double-emulsion/solvent evaporation technique, according to 21 .41 full factorial design, using two types of polylactic-co-glycolic acid (PLGA) polymer and four (drug: polymer) ratios. NPs were evaluated for particle size (PS), polydispersity index (PDI), zeta potential (ZP), drug entrapment efficiency percentage (EE%), drug percentage released after 30 min (Q30min) and 12 hours (Q12h), drug percentage permeated through goat corneas after 30 min (P30min) and 12 hours (P12h) and morphology. Two formulae were statistically selected and incorporated into hydroxypropyl methylcellulose (HPMC)-based hydrogels; G1 – G4. The latter systems were evaluated for appearance, clarity, pH, spreadability, rheology, drug percentages released, drug percentages permeated, antimicrobial activity against Pseudomonas aeruginosa, and histopathological changes.Results: The selected NPs (NP2 and NP6) were spherical in shape and possessed suitable PS (392.02 nm and 190.51 nm) and PDI (0.17 and 0.18), high magnitude of ZP (− 30.43 mV and − 33.62 mV), high EE% (79.24% and 91.72%), low Q30min (10.96% and 16.65%) and P30min (17.39% and 21.05%) and promising Q12h (58.23% and 71.20%) and P12h (53.31% and 65.01%), respectively. Clear, spreadable, tolerable, pseudoplastic, and thixotropic HPMC-based hydrogels were developed. They showed more prolonged drug release and drug permeation profiles. NP2- and NP6-laden hydrogels (G3 and G4 systems, respectively) had promising antibacterial activity, and reasonable histopathological safety.Conclusion: G3 and G4 are potential ocular delivery systems for NFX.Keywords: norfloxacin, nanoparticles, PLGA, ocular delivery, Pseudomonas keratitis

Mahmoud Teaima,1 Magdi M. Abdel Hamid,2 Nabil A. Shoman,2 Bhaskara R. Jasti,3 Mohamed A. El-Nabarawi1 1Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt; 2Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt; 3Department of Pharmaceutics and Medicinal Chemistry, Thomas J. Long School of Pharmacy & Health Sciences, University of the Pacific, Stockton, California, USACorrespondence: Mahmoud TeaimaDepartment of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, EgyptEmail mahmoud.teaima@pharma.cu.edu.egPurpose: Bupropion is an antidepressant drug that facilitates weight loss. It is a highly water-soluble drug that needs multiple dosing, so it is considered a potential candidate for oral controlled-release dosage form. The aim of this research was to formulate and evaluate satiety-inducing swellable floating bupropion tablets by direct compression targeting depression associated with eating disorders. Various combinations of natural and semi-synthetic hydrogels were selected to achieve maximum swelling and remaining buoyant in the stomach. This synergistically enhances weight loss by increasing satiety.Methods: An I-optimal mixture design was conducted to establish the optimal quantitative composition of tablets. Friability, floating lag time, swelling index after 4 and 8 hours, along with the percent of bupropion released at 1 and 8 hours were selected as dependent variables. The optimized formulation was characterized by physicochemical properties, thermal stability, and chemical interaction. In vivo radiographic evaluation of gastric residence besides, the oral bioavailability relative to marketed Wellbutrin® sustained-release tablets were investigated using human volunteers.Results: The optimized formulation (73.3 mg xanthan, 120 mg glucomannan, 8.4 mg tamarind kernel powder, 78.3 mg HPMC K15M) was achieved with the overall desirability equals 0.782. In vivo radiographic study showed that formulation was retained for > 8 hours in the stomach. Compared with the marketed BUP tablets, the Cmax was almost the same with a significant increase (p =0.004) for Tmax.Conclusion: Using combinations of these hydrogels would be promising gastroretentive delivery systems in the control of bupropion rate release with enhanced floating and swelling features.Keywords: gastroretentive drug delivery, natural hydrogels, HPMC, depression, eating disorder

Mahmoud Hasan Teaima,1 Mohamed Yasser,2,3 Mohamed Ahmed El-Nabarawi,1 Doaa Ahmed Helal4 1Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt; 2Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Horus University, New Damietta, Egypt; 3Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Sinai University, North Sinai, Egypt; 4Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Fayoum University, Fayoum, EgyptCorrespondence: Mahmoud Hasan TeaimaDepartment of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, EgyptTel +20 1005840264Email mahmoud.teaima@pharma.cu.edu.egObjective: The purpose of this study was to prepare proniosomal vesicles of Telmisartan (TEL) to be compressed into tablets which will be further evaluated in vitro and in vivo.Materials and Methods: An experimental design was adopted using surfactants of different HLB values (span 40-brij 35), different cholesterol ratios (20– 50%) and different phospholipid types (egg yolk-soyabean). Different responses were measured followed by tablet manufacturing. The highest EE was shown in F3 (85%) while the lowest value was obtained in F7 (8.4%). Finally, zeta potential results were in the range of − 0.67 to − 27.6 mv. Compressibility percent revealed that F5 showed an excellent flowability characteristic with a value of 9.74± 1.61 while F3 and F6 showed good flowability characteristics. By the end of the release, F6 showed approximately 90% drug release.Results: F6 was selected for the in vivo study; Cmax was increased by 1.5-fold while AUC0-∞ also increased significantly by 3-fold when compared with commercial tablet and finally, tmax was increased by 3-fold indicating sustained release pattern. The relative bioavailability was also increased by 3.2-fold.Conclusion: The results of this study suggested that the formulation of compressed tablets containing more stable proniosomal powder extended the release of TEL and increased its bioavailability as well.Keywords: telmisartan, TEL, proniosomal-derived niosomes, entrapment efficiency, EE, sustained-release tablet, bioavailability, multifactorial design

Mohamed A El-Nabarawi,1 Adel A Ali,2 Heba M Aboud,2 Amira H Hassan,2 Amany H Godah2 1Department of Pharmaceutics, Faculty of Pharmacy, Cairo University, Cairo, 2Department of Pharmaceutics, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt Objective: Betahistine dihydrochloride (BH.2HCl), an anti-vertigo histamine analog used in the treatment of Ménière’s disease, undergoes extensive first-pass metabolism and suffers from short biological half-life. The aim of the present work was to develop and estimate controlled release mucoadhesive buccal tablets of BH.2HCl with a unidirectional drug flow to overcome this encumbrance. Methods: A direct compression method was adopted for preparation of the tablets using mucoadhesive polymers like guar gum, hydroxypropyl methyl cellulose K4M, sodium carboxymethyl cellulose and their combinations. The tablets were coated from all surfaces except one surface with a solution of 5% (w/v) cellulose acetate and 1% (w/v) dibutyl phthalate. Different permeation enhancers like 2% sodium deoxycholate, 2% sodium cholate hydrate (SCH) and 5% menthol were tested. Swelling index, ex vivo residence time, mucoadhesion strength, in vivo testing of mucoadhesion time, in vitro dissolution and ex vivo permeation were carried out. Furthermore, compatibility and accelerated stability studies were performed for the drug excipients. Finally, drug bioavailability of the BH.2HCl-optimized buccal mucoadhesive formulation was compared with that of the orally administered Betaserc® 24 mg tablet in six healthy male volunteers. Results: Formulation F10, which contained a combination of 35% guar gum and 5% sodium carboxymethyl cellulose, exhibited long adhesion time, high adhesion strength and diminished irritation to volunteers and showed zero-order release kinetics. SCH produced a significant enhancement in permeation of BH.2HCl across buccal mucosa. BH.2HCl-optimized buccal mucoadhesive formulation showed percentage relative bioavailability of 177%. Conclusion: The developed mucoadhesive tablets represent a promising alternative for the buccal delivery of BH.2HCl. Keywords: betahistine dihydrochloride, transbuccal delivery, unidirectional drug flow, permeation enhancer, relative bioavailability

Mohamed A El Nabarawi,1 Mahmoud H Teaima,1 Rehab A Abd El-Monem,2 Nagla A El Nabarawy,3 Dalia A Gaber4 1Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt; 2Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Misr University for Science and Technology, 6th of October, Egypt; 3National Egyptian Center of Environment and Toxicological Research (NECTER), Faculty of Medicine, Cairo University, Cairo, Egypt; 4Department of Quality Control, Holding Company for Biological Products and Vaccines, Cairo, Egypt Abstract: To prolong the residence time of dosage forms within the gastrointestinal tract until all drug is released at the desired rate is one of the real challenges for oral controlled-release drug delivery systems. This study was designed to develop a controlled-release floating matrix tablet and floating raft system of Mebeverine HCl (MbH) and evaluate different excipients for their floating behavior and in vitro controlled-release profiles. Oral pharmacokinetics of the optimum matrix tablet, raft system formula, and marketed Duspatalin® 200 mg retard as reference were studied in beagle dogs. The optimized tablet formula (FT-10) and raft system formula (FRS-11) were found to float within 34±5 sec and 15±7 sec, respectively, and both remain buoyant over a period of 12 h in simulated gastric fluid. FT-10 (Compritol/HPMC K,100M 1:1) showed the slowest drug release among all prepared tablet formulations, releasing about 80.2% of MbH over 8 h. In contrast, FRS-11 (Sodium alginate 3%/HPMC K,100M 1%/Precirol 2%) had the greatest retardation, providing sustained release of 82.1% within 8 h. Compared with the marketed MbH product, the Cmax of FT-10 was almost the same, while FRS-11 maximum concentration was higher. The tmax was 3.33, 2.167, and 3.0 h for marketed MbH product, FT-10, and FRS-11, respectively. In addition, the oral bioavailability experiment showed that the relative bioavailability of the MbH was 104.76 and 116.01% after oral administration of FT-10 and FRS-11, respectively, compared to marketed product. These results demonstrated that both controlled-released floating matrix tablet and raft system would be promising gastroretentive delivery systems for prolonging drug action. Keywords: GRDDS, Precirol®, Compritol®, HPMC, Na alginate