Search

Sammar Fathy Elhabal,1 Nashwa Abdelaal,2 Saeed AS Al-Zuhairy,3 Mohamed Fathi Mohamed Elrefai,4,5 Mohamed Mansour Khalifa,6 Mohammad Ahmad Khasawneh,7 Ahmed Mohsen Elsaid Hamdan,8 Passant M Mohie,9 Rania A Gad,10 Soad L Kabil,11 Mohamed Kandeel El-Ashery,12,13 Bhaskara R Jasti,14 Nahla A Elzohairy,15,16 Nehal Elfar,17 Tayseer Elnawawy,18 Fatma E Hassan,19,20 Mohamed Ahmed El-Nabarawi21 1Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Mokattam, Cairo, Egypt; 2Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, USA; 3Department of Pharmacy, Kut University College, Kut, Wasit, Iraq; 4Department of Anatomy, Histology, Physiology, and Biochemistry, Faculty of Medicine, The Hashemite University, Zarqa, Jordan; 5Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 6Department of Human Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt; 7Department of Chemistry, College of Science, U.A.E. University, Al-Ain, United Arab Emirates; 8Department of Pharmacy Practice, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia; 9Department of Clinical Pharmacology, Faculty of Medicine, Alexandria University, Alexandria, Egypt; 10Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt; 11Department of Clinical Pharmacology, Faculty of Medicine, Zagazig University, Zagazig, Egypt; 12Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt; 13Medicinal Chemistry Department, Faculty of Pharmacy, King Salman International University, Ras-Sedr, South Sinai, Egypt; 14Department of Pharmaceutics and Medicinal Chemistry, Thomas J. Long School of Pharmacy & Health Sciences, University of the Pacific, Stockton, CA, USA; 15Air Force Specialized Hospital, Cairo, Egypt; 16Department of Microbiology and Immunology, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Mokattam, Cairo, Egypt; 17Department of Pharmaceutical Technology, Faculty of Pharmacy, Horus University, New Demiette, Egypt; 18Department of Pharmaceutics, Egyptian Drug Authority, Cairo, Egypt; 19Medical Physiology Department, Kasr Alainy, Faculty of Medicine, Cairo University, Giza, Egypt; 20General Medicine Practice Program, Department of Physiology, Batterjee Medical College, Jeddah, Saudi Arabia; 21Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, EgyptCorrespondence: Mohammad Ahmad Khasawneh, Email mohammad.khasawneh@uaeu.ac.aePurpose: Improving the treatment of psoriasis is a serious challenge today. Psoriasis is an immune-mediated skin condition affecting 125 million people worldwide. It is commonly treated with cyclosporine-A (CsA) and dithranol (DTH). CsA suppresses the activation of T-cells, immune cells involved in forming psoriatic lesions. Meanwhile, DTH is a potent anti-inflammatory and anti-proliferative drug that effectively reduces the severity of psoriasis symptoms such as redness, scaling, and skin thickness. CsA and DTH belong to BCS class II with limited oral bioavailability. We aim to develop a drug delivery system for topical co-delivery of CsA and DTH, exploring its therapeutic potential.Methods: Firstly, we developed a niosomal drug delivery system based on ceramide IIIB to form Cerosomes. Cerosomes were prepared from a mixture of Ceramide, hyaluronic acid, and edge activator using a thin-film hydration technique. To co-deliver CsA and DTH topically for the treatment of psoriasis. These two hydrophobic drugs encapsulated into our synthesized positively charged particle cerosomes.Results: Cerosomes had an average particle size of (222.36 nm± 0.36), polydispersity index of (0.415± 0.04), Entrapment Efficiency of (96.91%± 0.56), and zeta potential of (29.36± 0.38mV) for selected formula. In vitro, In silico, in vivo, permeation, and histopathology experiments have shown that cerosomes enhanced the skin penetration of both hydrophobic drugs by 66.7% compared to the CsA/DTH solution. Imiquimod (IMQ) induced psoriatic mice model was topically treated with our CsA/DTH cerosomes. We found that our formulation enhances the skin penetration of both drugs and reduces psoriasis area and severity index (PASI score) by 2.73 times and 42.85%, respectively, compared to the CsA/DTH solution. Moreover, it reduces the levels of proinflammatory cytokines, TNF-α, IL-10, and IL-6 compared to CsA/DTH solution administration.Conclusion: The Cerosomes nano-vesicle-containing CsA/DTH represents a more promising topical treatment for psoriasis, giving new hope to individuals with psoriasis, compared to commercial and other conventional alternatives. Keywords: biopharmaceutics classification system class II, BCS II, niosomes based on ceramide IIIB, cerosomes, psoriasis, psoriasis area and severity index, PASI score, imiquimod, IMQ, proinflammatory cytokines, niosomes

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

Rehab Abdelmonem,1 Raghda Rabe Hamed,1 Sally A Abdelhalim,2 Mohamed F ElMiligi,1,2 Mohamed A El-Nabarawi2 1Department of Industrial Pharmacy, College of Pharmaceutical Science and Drug Manufacturing, Misr University for Science and Technology, Cairo, Egypt; 2Department of Pharmaceutics, Faculty of Pharmacy, Cairo University, Cairo, EgyptCorrespondence: Rehab AbdelmonemDepartment of Industrial Pharmacy, College of Pharmaceutical Science and Drug Manufacturing, Misr University for Science and Technology, Al-Motameyez District, 6th October City, Giza, EgyptTel +20 1222127127Email drrahoba@yahoo.comIntroduction and Aim: Cinnarizine is indicated orally for treating vertigo associated with Ménière’s syndrome and has a local anesthetic effect as well. The present study aims to develop an aural Cinnarizine mucoadhesive transfersomal gel to overcome the first-pass metabolism.Methods: Eighteen Cinnarizine transfersomes were prepared by the thin-film hydration technique using different types of phosphatidylcholine and edge activators in different ratios. Formulae were tested for their appearance, entrapment efficiency, and in-vitro drug release after eight hours. F1, F4, F7, F9, F10, and F12 were selected to be examined for particle size, polydispersity index, and zeta potential. According to the previous parameters, F1 and F10 were incorporated into gels using different polymers according to factorial design 23. The eight gels were tested for appearance, pH, mucoadhesion, spreadability, drug content, in-vitro drug release after eight hours, and rheology. The transfersomal gel F1A was subjected to FTIR analysis and in-vivo pharmacokinetic study.Results: The transfersomal dispersion colors were ranging between the white and yellow. Their EE % ranged from 64.36± 1.985% to 94.09± 1.74%, and their in-vitro release percentages were between 61.82± 1.92% and 95.92± 1.18%. Also, the vesicles PS ranged from 212.3± 30.05nm to 2150± 35.35nm, DI from 0.238± 0.134 to 1± 0.00 and zeta potential from − 57.5± 2.54 to +4.73± 1.57 mV. The transfersomal gels showed pseudoplastic behavior, pH range of 5.5 to 8, a mucoadhesive force of 169.188± 1.26 to 321.212± 6.94 (dyne/cm2× 102), spreadability of 40 ± 7.03mm to 138 ± 3.77mm, and in-vitro drug release of 81.63± 1.128% to 97.78± 0.102%. The IR spectra of the (drug-excipients) physical mixture revealed that there were no shifts of incompatibility. The in-vivo pharmacokinetic study illustrated that [AUC]0– 24 of F1A was significantly higher than that of tablets at (P< 0.05), equivalent to 703.563± 26.470 and 494.256± 9.621ɲg.hr/mL respectively.Conclusion: The study revealed that Cinnarizine aural mucoadhesive targeted delivery provides an improved systemic bioavailability over the conventional oral route.Keywords: targeted transfersomes, aural gel, Cinnarizine

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

Rofida Albash,1 Mohamed A El-Nabarawi,2 Hanan Refai,1 Aly A Abdelbary2,31Department of Pharmaceutics, Faculty of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, Giza, Egypt; 2Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt; 3Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, October 6 University, Giza, EgyptIntroduction: The intention of this work was to load olmesartan medoxomil (OLM), a sparsely water soluble antihypertensive bioactive with low oral bioavailability (26%), into PEGylated bilosomes (PBs) for augmenting its transdermal delivery. PBs contain PEGylated single chain edge activator besides the components of traditional bilosomes (Span 60, cholesterol and bile salts). The PEG gives further resilience to vesicle membrane and is speculated to augment both permeability and bioavailability of OLM.Methods: A 24 factorial experiment was constructed to inspect the impact of diverse variables on vesicles’ features and sort out the optimal formula adopting Design Expert® software utilizing thin film hydration technique. Vesicles’ evaluation was done by finding out entrapment efficiency percent (EE%), particle size (PS), polydispersity index (PDI), zeta potential (ZP) and amount of drug released after 6 hrs (Q6h). The optimal formula was selected and characterized for further investigations.Results: The optimal formula (PB15) showed spherical vesicles with EE% of 72.49±0.38%, PS of 559.30±10.70 nm, PDI of 0.57±0.15, ZP of −38.35±0.65 mV and Q6h of 59.60±0.24%. PB15 showed higher deformability index (28.39±5.71 g) compared to traditional bilosomes (5.88±0.90 g) and transethosomes (14.94±0.63 g). Further, PB15 showed superior skin permeation from rat’s skin relative to the drug suspension. Moreover, confocal laser scanning microscopy examination revealed efficient penetration of the fluoro-labeled PB15 through skin. Histopathological study ensured the safety of PB15. In addition, in-vivo skin deposition studies showed higher OLM deposition in rat’s skin from PB15 compared to transethosomes and OLM suspension. Furthermore, pharmacodynamic and pharmacokinetic studies performed using male Wistar rats and male Albino rabbits, respectively, showed the superiority of PB15 over oral tablets. PB15 was found to have significantly higher AUC0–48 and AUC0–∞ relative to the oral tablets. As well, the relative bioavailability of PB15 was found to be 235.04%.Conclusion: Overall, the obtained results confirmed the creditable effect of PB15 for transdermal delivery.Keywords: bilosomes, confocal laser scanning microscopy, ex-vivo permeation, olmesartan medoxomil, pharmacodynamic study, pharmacokinetic study

Rofida Albash,1 Aly A Abdelbary,2,3 Hanan Refai,1 Mohamed A El-Nabarawi2 1Department of Pharmaceutics, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, Giza, Egypt; 2Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt; 3Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, October 6 University, Giza, Egypt Introduction and aim: Olmesartan medoxomil (OLM) is an antihypertensive drug with low oral bioavailability due to extensive first-pass metabolism. This study aimed to prepare transetho­somes (TEs) for enhancing the transdermal delivery of OLM to avoid its oral problems. Methods: TE formulae were prepared utilizing 51.31 full factorial design using various surfactants (SAAs) and different phospholipid-to-SAA ratios. The formulae were characterized regarding their entrapment efficiency percentage (EE%), particle size (PS), polydispersity index (PDI), zeta potential (ZP), and the amount of drug released after 6 hours (Q6h). Design Expert® software was employed to select the optimum formula. Results: The optimum formula (TE14) had an EE% of 58.50%±1.30%, PS of 222.60±2.50 nm, PDI of 0.11±0.06, ZP of -20.80±0.30 mV, and Q6h of 67.40%±0.20%. In addition, TE14 was compared to transferosomes (TFs) in terms of elasticity and was found to show higher deformability index. Further, evaluation of ex vivo permeation using both rat and shed snake skin showed higher permeability of TE14 compared to TFs and OLM suspension. Confocal laser scanning microscopy confirmed the capability of the fluoro-labeled TE14 to penetrate deep within the skin, while the histopathological study confirmed its safety. TE14 successfully maintained normal blood pressure values of rats up to 24 hours. Moreover, TE14 showed superiority in dermatokinetic study when compared with drug suspension. Conclusion: Taken together, the obtained results confirmed the potential of employing TEs as a successful carrier for the transdermal delivery of OLM. Keywords: olmesartan medoxomil, transethosomes, factorial design, transdermal drug delivery, dermatokinetic study, confocal laser scanning microscopy, permeation

Noha M Badawi,1 Mahmoud H Teaima,2 Khalid M El-Say,3 Dalia A Attia,1 Mohamed A El-Nabarawi,2 Mohey M Elmazar4 1Department of Pharmaceutics, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; 2Department of Pharmaceutics and Industrial Pharmacy, Cairo University, Cairo, Egypt; 3Department of Pharmaceutics, King Abdulaziz University, Jeddah, Saudi Arabia; 4Department of Pharmacology, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt Background: Pomegranate extract (PE) is a natural product with potent antioxidant and anticancer activity because of its polyphenols content. The main purpose of this study was to maximize the PE chemotherapeutic efficacy by loading it in an optimized solid lipid nanoparticles (SLNs) formula.Materials and methods: The influence of independent variables, which were lipid concentration (X1), surfactant concentration (X2) and cosurfactant concentration (X3), on dependent ones, which were particle size (Y1), polydispersity index (Y2), zeta potential (Y3), entrapment efficiency (Y4) and cumulative % drug release (Y5), were studied and optimized using the Box–Behnken design. Fifteen formulations of PE-SLNs were prepared using hot homogenization followed by ultra-sonication technique. Response surface plots, Pareto charts and mathematical equations were produced to study the impact of independent variables on the dependent quality parameters. The anti-proliferative activity of the optimized formula was then evaluated in three different cancer cell lines, namely, MCF-7, PC-3 and HepG-2, in addition to one normal cell line, HFB-4.Results: The results demonstrated that the particle sizes ranged from 407.5 to 651.9 nm and the entrapment efficiencies ranged from 56.02 to 65.23%. Interestingly, the 50% inhibitory concentration of the optimized formula had more than a 40-fold improved effect on the cell growth inhibition in comparison with its free counterpart. Furthermore, it was more selective against cancer cells than normal cells particularly in MCF-7 breast cancer cells.Conclusion: These data proved that nanoencapsulation of PE enhanced its anticancer efficacy. Therefore, our results suggested that a PE-loaded SLNs optimized-formula could be a promising chemo­therapeutic agent. Keywords: pomegranate extract, solid lipid nanoparticles, Box–Behnken design, optimization, cancer cell lines

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

Sammar Fathy Elhabal,1 Nashwa Abdelaal,2 Saeed Abdul Kareem Saeed Al-Zuhairy,3 Mohamed Fathi Mohamed Elrefai,4,5 Ahmed Mohsen Elsaid Hamdan,6 Mohamed Mansour Khalifa,7 Sandra Hababeh,8 Mohammad Ahmad Khasawneh,9 Gehad M Khamis,10 Jakline Nelson,11 Passant M Mohie,10 Rania A Gad,12 Amira Rizk,13 Soad L Kabil,14 Mohamed Kandeel El-Ashery,15,16 Bhaskara R Jasti,17 Nahla A Elzohairy,18,19 Tayseer Elnawawy,20 Fatma E Hassan,21,22 Mohamed A El- Nabarawi23 1Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Mokattam, Cairo, Egypt; 2Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, USA; 3Department of Pharmacy, Kut University College, Kut, Wasit, Iraq; 4Department of Anatomy, Histology, Physiology and Biochemistry, Faculty of Medicine, The Hashemite University, Zarqa, Jordan; 5Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 6Department of Pharmacy Practice, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia; 7Department of Human Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt; 8Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; 9Department of Chemistry, College of Science U.A.E. University, Al-Ain, United Arab Emirates; 10Department of Clinical Pharmacology, Faculty of Medicine, Alexandria University, Alexandria, Egypt; 11Department of Microbiology and Immunology, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt; 12Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt; 13Food Science and Technology Department, Faculty of Agricultural, Tanta University, Tanta, Egypt; 14Department of Clinical Pharmacology, Faculty of Medicine, Zagazig University, Zagazig, Egypt; 15Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt; 16Medicinal Chemistry Department, Faculty of Pharmacy, King Salman International University, Ras-Sedr, South Sinai, Egypt; 17Department of Pharmaceutics and Medicinal Chemistry, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA, USA; 18Air Force Specialized Hospital, Cairo, Egypt; 19Department of Microbiology and Immunology, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Mokattam, Cairo, Egypt; 20Department of Pharmaceutics, Egyptian Drug Authority, Cairo, Egypt; 21Medical Physiology Department, Faculty of Medicine, Cairo University, Giza, Egypt; 22General Medicine Practice Program, Department of Physiology, Batterjee Medical College, Jeddah, Saudi Arabia; 23Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, EgyptCorrespondence: Sammar Fathy Elhabal, Email Sammar.Fathy@pharm.mti.edu.eg; sammar_fathy2007@yahoo.com; Mohamed A El- Nabarawi, Email mohamed.elnabarawi@pharm.cu.edu.egBackground: Diabetes Mellitus is a multisystem chronic pandemic, wound inflammation, and healing are still major issues for diabetic patients who may suffer from ulcers, gangrene, and other wounds from uncontrolled chronic hyperglycemia. Marshmallows or Althaea officinalis (A.O.) contain bioactive compounds such as flavonoids and phenolics that support wound healing via antioxidant, anti-inflammatory, and antibacterial properties. Our study aimed to develop a combination of eco-friendly formulations of green synthesis of ZnO-NPs by Althaea officinalis extract and further incorporate them into 2% chitosan (CS) gel.Method and Results: First, develop eco-friendly green Zinc Oxide Nanoparticles (ZnO-NPs) and incorporate them into a 2% chitosan (CS) gel. In-vitro study performed by UV-visible spectrum analysis showed a sharp peak at 390 nm, and Energy-dispersive X-ray (EDX) spectrometry showed a peak of zinc and oxygen. Besides, Fourier transforms infrared (FTIR) was used to qualitatively validate biosynthesized ZnO-NPs, and transmission electron microscope (TEM) showed spherical nanoparticles with mean sizes of 76 nm and Zeta potential +30mV. The antibacterial potential of A.O.-ZnO-NPs-Cs was examined by the diffusion agar method against Gram-positive (Staphylococcus aureus and Bacillus subtilis) and Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa). Based on the zone of inhibition and minimal inhibitory indices (MIC). In addition, an in-silico study investigated the binding affinity of A.O. major components to the expected biological targets that may aid wound healing. Althaea Officinalis, A.O-ZnO-NPs group showed reduced downregulation of IL-6, IL-1β, and TNF-α and increased IL-10 levels compared to the control group signaling pathway expression levels confirming the improved anti-inflammatory effect of the self-assembly method. In-vivo study and histopathological analysis revealed the superiority of the nanoparticles in reducing signs of inflammation and wound incision in rat models.Conclusion: These biocompatible green zinc oxide nanoparticles, by using Althaea Officinalis chitosan gel ensure an excellent new therapeutic approach for quickening diabetic wound healing. Keywords: wound healing, antimicrobial, antioxidant, Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, chitosan, wound concentration, wound incision

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

This study was designed to formulate a polymeric mixed micelle (PMM) formulation to sustainably release fexofenadine (FEX) to treat allergic conjunctivitis effectively. A 3 2 factorial design was employed where the studied factors were PL90G amount (X 1 ) and Pluronic (F127 and P123) mixture ratio (X 2 ), and the dependent variables were entrapment efficacy (EE, Y 1 , %), particle size (PS, Y 2 , nm), zeta potential (ZP, Y 3 , mV), and the percent of drug released after 6 h (Q6h, Y 4 , %). The optimized formula was blended with a hydrogel base to develop an FEX-PMM hydrogel, where the safety and efficiency of this hydrogel were evaluated using in vivo studies. The EE% of FEX-PMM ranged from 62.15 ± 2.75 to 90.25 ± 1.48%, the PS from 291.35 ± 6.43 to 467.95 ± 3.60 nm, the ZP from -5.41 ± 0.12 to -9.23 ± 0.23 mV, and the Q6h from 50.27 ± 1.11 to 95.38 ± 0.92%. The Draize test results confirmed the safety of the FEX-PMM hydrogel. Furthermore, the FEX-PMM hydrogel showed rapid recovery in animals with induced allergic conjunctivitis compared to the free drug hydrogel. These results assure PMM's capability to deliver FEX to the conjunctival surface in a sustained pattern, consequently achieving better therapeutic outcomes.

Obesity has been associated with the occurrence and prevalence of various chronic metabolic diseases. The management of obesity has evolved to focus not only on reducing weight, but also on preventing obesity-related complications. Studies have shown that bioactive components in natural products like white kidney bean extract (WKBE), propolis ethanolic extract (PEE), and chromium picolinate (CrPi 3 ) showed anti-obesity properties. However, no studies have examined the outcomes of combining any of these nutraceutical supplements. We compared the effects of HFD supplemented with WKBE, WKBE+PEE, or WKBE+PEE+CrPi 3 against control and obese groups using Sprague-Dawley rats fed a 45% high-fat diet as an in vivo model. Nutritional parameters, biochemical parameters, and biomarkers of cardiovascular disease, liver function, kidney function, and gut health were among the comparable effects. Our findings showed that combining the three nutraceutical supplements had a synergetic effect on reducing weight gain, food utilization rate, abdominal fat, serum lipids, arterial and hepatic lipids, risk of cardiovascular disease, and blood glucose level, in addition to improving renal function and gut microbiota. We attributed these effects to the α-amylase inhibitor action of WKBE, flavonoids, and polyphenol content of PEE, which were potentiated with CrPi 3 resulting in a further reduction or normalization of certain parameters.

The study aims to improve the ocular delivery of Nebivolol HCL (NBV) belonging to the Biopharmaceutics classification system (BCSII) by using spanlastic nanovesicles (SNVs) for ophthalmic delivery and incorporating them into hydroxypropyl methylcellulose gel with ketorolac tromethamine (KET) as an anti-inflammatory to improve glaucoma complications like Conjunctivitis. SNVs were prepared by ethanol injection technique using span (60) as a surfactant and labrasol as an edge activator (EA). The impact of formulation factors on SNVs properties was investigated using a Box-Behnken design. In vitro evaluations showed that the formulations (F1, F4, and F14), containing Span 60 and labrasol as EA (25%, 50%, and 25%), exhibited high EE% with low PS and high ZP and DI. Additionally, 61.72 ± 0.77%, 58.97 ± 1.44%, and 56.20 ± 2.32% of the NBV amount were released from F1, F4, and F14 after 5 h, compared to 93.94 ± 1.21% released from drug suspension. The selected formula (G1), containing F1 in combination with KET and 2% w /w HPMC, exhibited 76.36 ± 0.90% drug release after 12 h. Ex vivo Confocal laser scanning revealed a high penetration of NBV-SNVs gel that ascertained the results of the in-vitro study . In vivo studies showed a significant decrease in glaucoma compared to drug suspension, and histopathological studies showed improvement in glaucomatous eye retinal atrophy. G1 is considered a promising approach to improving ocular permeability, absorption, and anti-inflammatory activity, providing a safer alternative to current regimens., Competing Interests: The authors wish to declare no interest is involved in this publication., (© 2023 Published by Elsevier B.V.)

In our pursuit of enhancing acne treatment while minimizing side effects, we developed tailored Adapalene microsponges (MS) optimized using a Box-Behnken design 3 3 . The independent variables, Eudragit RS100 percentage in the polymer mixture, organic phase volume, and drug to polymer percentage, were explored. The optimized formulation exhibited remarkable characteristics, with a 98.3% ± 1.6 production yield, 97.3% ± 1.64 entrapment efficiency, and a particle size of 31.8 ± 1.1 µm. Notably, it achieved a 24 h cumulative drug release of 75.1% ± 1.4. To delve deeper into its efficacy, we evaluated the optimized microspongeal-gel in vitro, in vivo, and clinically. It demonstrated impressive retention in the pilosebaceous unit, a target for acne treatment. Comparative studies between our optimized Adapalene microspongeal gel and marketed Adapalene revealed superior performance. In vivo studies on Propionibacterium acnes-infected mice ears showed a remarkable 97% reduction in ear thickness, accompanied by a significant decrease in inflammatory signs and NF-κB levels, as confirmed by histopathological and histochemical examination. Moreover, in preliminary clinical evaluation, it demonstrated outstanding effectiveness in reducing comedonal lesions while causing fewer irritations. This not only indicates its potential for clinical application but also underscores its ability to enhance patient satisfaction, paving the way for future commercialization., (© 2024. The Author(s).)

l-carnitine is an essential dietary supplement of physiological importance. Handling and manufacture of l-carnitine is difficult due to its hygroscopic nature, resulting in impairing its flow properties, as well as solid dosage form stability. The study aimed at reducing l-carnitine hygroscopicity through its encapsulation within a hydrophobic, pH-insensitive polymer. A solid in oil in oil (s/o/o) emulsion solvent evaporation technique for microencapsulation was adopted to exclude the possibility of water uptake. The polymers used were two ethyl cellulose (EC) grades with different viscosities. The chosen solvent for the polymer was acetone, and liquid paraffin was the dispersion medium in which both the drug and polymer were insoluble. Sixteen formulations were developed, and evaluated to study the formulation parameters as anti-coalescent type, mixing speed, surfactant type and polymer ratio, and viscosity grade. A "One Factor at A Time" (OFAT) design of experiment, and a factorial design were utilized. Study results revealed that successful microencapsulation occurred by using Aerosil 200 (0.1 %) as anti-coalescent, a mixing speed of 1000 rpm, and Ethocel Std 20 at a 3:1 drug-to-polymer ratio. Microcapsule formulation containing l-carnitine base, successfully compressed into tablets, showed acceptable water content, disintegration time, hardness, and dissolution. Moreover, it showed acceptable stability upon storage at 40 °C at 75 % RH for six months compared to l-carnitine tablets prepared by wet granulation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

This study aimed to formulate and evaluate a floating raft system for the co-delivery of etoricoxib (ETO) and famotidine (FAM) using a combination of glucomannan with natural/semi-synthetic polysaccharides. Formulation variables affect gelation lag time (GLT), floating lag time (FLT), and release percentage of drugs after 1-8 h, Stability, and viscosity parameters were evaluated. In vivo X-ray studies, followed by the pharmacokinetic study, were performed on human volunteers. Formulations exhibited pseudoplastic behavior for ease of swallowing. The optimum raft system (ORS) comprised 1% Na alginate, 0.1% Low Methoxyl (LM) pectin, 0.8% Konjac glucomannan (KGL), 1% Precirol, and 1% CaCO 3 . ORS exhibited rapid GLT and FLT (around 42 and 8 sec respectively) in 0.1 N HCl as well as controlled release of ETO (15% in 1 h and 82% in 8 h) and FAM (29% in 1 h and 85% in 8 h). Formulation stability with the absence of any drug-excipient interactions was observed. The X-ray imaging showed a promising buoyancy ability for approximately 8 h. Compared with marketed products, ORS showed superior relative bioavailability for both drugs. These findings revealed the successful preparation of a promising raft system with improved dual drug delivery.

A PEGylated Tween 80-functionalized chitosan-lipidic (PEG-T-Chito-Lip) nano-vesicular hybrid was developed for intranasal administration as an alternative delivery route to help improve the poor oral bioavailability of BCS class-III model/antiemetic (metoclopramide hydrochloride; MTC). The influence of varying levels of chitosan, cholesterol, PEG 600, and Tween 80 on the stability/release parameters of the formulated nanovesicles was optimized using Draper-Lin Design. Two optimized formulations (Opti-Max and Opti-Min) with both maximized and minimized MTC-release goals, were predicted, characterized, and proved their vesicular outline via light/electron microscopy, along with the mutual prompt/extended in-vitro release patterns. The dual-optimized MTC-loaded PEG-T-Chito-Lip nanovesicles were loaded in intranasal in-situ gel (ISG) and further underwent in-vivo pharmacokinetics/nose-to-brain delivery valuation on Sprague-Dawley rats. The absorption profiles in plasma (plasma-AUC 0-∞ ) of the intranasal dual-optimized MTC-loaded nano-vesicular ISG formulation in pretreated rats were 2.95-fold and 1.64-fold more than rats pretreated with orally administered MTC and intranasally administered raw MTC-loaded ISG formulation, respectively. Interestingly, the brain-AUC 0-∞ of the intranasal dual-optimized MTC-loaded ISG was 10 and 3 times more than brain-AUC 0-∞ of the MTC-oral tablet and the intranasal raw MTC-loaded ISG, respectively. It was also revealed that the intranasal dual-optimized ISG significantly had the lowest liver-AUC 0-∞ (862.19 ng.g -1 .h -1 ) versus the MTC-oral tablet (5732.17 ng.g -1 .h -1 ) and the intranasal raw MTC-loaded ISG (1799.69 ng.g -1 .h -1 ). The brain/blood ratio profile for the intranasal dual-optimized ISG was significantly enhanced over all other MTC formulations (P < 0.05). Moreover, the 198.55% drug targeting efficiency, 75.26% nose-to-brain direct transport percentage, and 4.06 drug targeting index of the dual-optimized formulation were significantly higher than those of the raw MTC-loaded ISG formulation. The performance of the dual-optimized PEG-T-Chito-Lip nano-vesicular hybrids for intranasal administration evidenced MTC-improved bioavailability, circumvented hepatic metabolism, and enhanced brain targetability, with increased potentiality in heightening the convenience and compliance for patients.

Repaglinide (RPG), a monotherapy insulin secretagogue used to treat diabetes mellitus-type II yet, it suffers from poor water solubility and variable bioavailability (∼ 50%) due to hepatic first pass metabolism. In this study, 2FI I-Optimal statistical design was employed to encapsulate RPG into niosomal formulations using cholesterol,span 60 and peceol TM . The optimized niosomal formulation (ONF) showed particle size 306.60 ± 84.00 nm, zeta potential -38.60 ± 1.20 mV, polydispersity index 0.48 ± 0.05 and entrapment efficiency 92.00 ± 2.60%. ONF showed > 65% RPG release that lasted for 3.5 h, and significantly higher sustained release compared to Novonorm® tablets after 6 h ( p  < 0.0001). TEM for ONF showed spherical vesicles with dark core and light-colored lipid bilayer membrane. RPG peaks disappeared in FTIR confirming successful RPG entrapment. To eliminate dysphagia associating conventional oral tablets, chewable tablets loaded with ONF were prepared using coprocessed excipients; Pharmaburst ® 500, F-melt ® and Prosolv ® ODT. Tablets showed friability <1%, hardness 3.9 ± 0.423-4.7 ± 0.410 Kg, thickness 4.1 ± 0.045-4.4 ± 0.017 mm and acceptable weight.All tablets showed robust RPG release at 30 min compared to Novonorm ® tablets. At 6h, chewable tablets containing only Pharmaburst ® 500 and F-melt ® showed sustained and significantly increased RPG release compared to Novonorm ® tablets ( p  < 0.05). Pharmaburst ® 500 and F-melt ® tablets showed rapid in vivo hypoglycemic effect with 5 and 3.5 fold significant reduction in blood glucose compared to Novonorm ® tablets ( p  < 0.05) at 30 min. Also, at 6h the same tablets showed 1.5 and 1.3 fold significant extended reduction in blood glucose compared to the same market product ( p  < 0.05). It could be concluded that chewable tablets loaded with RPG ONF represent promising novel oral drug delivery systems for diabetic patients suffering from dysphagia.

Canagliflozin (CFZ) is a sodium-glucose cotransporter-2 inhibitor (SGLT2) that lowers albuminuria in type-2 diabetic patients, cardiovascular, kidney, and liver disease. CFZ is classified as class IV in the Biopharmaceutical Classification System (BCS) and is characterized by low permeability, solubility, and bioavailability, most likely attributed to hepatic first-pass metabolism. Nanocrystal-based sublingual formulations were developed in the presence of sodium caprate, as a wetting agent, and as a permeability enhancer. This formulation is suitable for children and adults and could enhance solubility, permeability, and avoid enterohepatic circulation due to absorption through the sublingual mucosa. In the present study, formulations containing various surfactants (P237, P338, PVA, and PVP K30) were prepared by the Sono-homo-assisted precipitation ion technique. The optimized formula prepared with PVP-K30 showed the smallest particle size (157 ± 0.32 nm), Zeta-potential (-18 ± 0.01), and morphology by TEM analysis. The optimized formula was subsequently formulated into a sublingual tablet containing Pharma burst-V® with a shorter disintegration time (51s) for the in-vivo study. The selected sublingual tablet improved histological and biochemical markers (blood glucose, liver, and kidney function), AMP-activated protein kinase (AMPK), and protein kinase B (AKT) pathway compared to the market formula, increased CFZ's antidiabetic potency in diabetic rabbits, boosted bioavailability by five-fold, and produced faster onset of action. These findings suggest successful treatment of diabetes with CFZ nanocrystal-sublingual tablets.

To design and evaluate hyaluronan-based cubosomes loaded with bromfenac sodium (BS) for ocular application to enhance the corneal permeation and retention in pterygium and cataract treatment. BS-loaded cubosomes were prepared by the emulsification method, employing 2 3 full factorial design using Design-Expert® software. Glycerol monoolein (GMO) and poloxamer 407 (P407) as lipid phase and polyvinyl alcohol (PVA) as stabilizer were the used ingredients. The optimized formulation (OBC; containing GMO (7% w/w), P407 (0.7% w/w) and PVA (2.5% w/w)) was further evaluated. OBC had an entrapment efficiency of 61.66 ± 1.01%, a zeta potential of -30.80 ± 0.61 mV, a mean particle size of 149.30 ± 15.24 nm and a polydispersity index of 0.21 ± 0.02. Transmission electron microscopy confirmed its cubic shape and excellent dispersibility. OBC exhibited high stability and no ocular irritation that was ensured by histopathology. Ex vivo permeation study showed a significant increase in drug deposition and permeability parameters through goat cornea, besides, confocal laser microscopy established the superior permeation capability of OBC, as compared to drug solution. In vivo pharmacokinetics in aqueous humor indicated higher AUC 0-tlast (18.88 µg.h/mL) and mean residence time (3.16 h) of OBC when compared to the marketed eye drops (7.93 µg.h/mL and 1.97 h, respectively). Accordingly, hyaluronan-enriched cubosomes can be regarded as a promising carrier for safe and effective topical ocular delivery.

Etoricoxib, as a model drug, has a poor solubility and dissolution rate. Cyclodextrin derivatives can be used to solve such a problem. A comparative study was run on three cyclodextrin derivatives, namely β-CD, HP β-CD, and SBE β-CD, to solve the drug problem through the formulation of solid dispersions and their preparation into fast-dissolving tablets. Preparations utilized different (1:1, 1:2, and 1:4) drug:carrier ratios. Nine fast-dissolving tablets (containing 1:4 drug: carrier) were formulated using Prosolv ODT ® and/or F-melt ® type C as super-disintegrants. Optimized formulation was chosen based on a 3 2 factorial design. The responses chosen were the outcomes of the in vitro evaluation tests. The optimized formulation that had the highest desirability (0.86) was found to be SD-HP3, which was prepared from etoricoxib: HP β-CD at a 1:4 ratio using equal amounts of Prosolv ODT ® and F-melt ® type C. An in vivo evaluation of SD-HP3 on a rabbit model revealed its superiority over the marketed product Arcoxia ® . SD-HP3 showed a significantly lower Tmax (13.3 min) and a significantly higher Cmax (9122.156 μg/mL), as well as a significantly higher AUC, than Arcoxia ® . Thus, the solubility, dissolution, and bioavailability of etoricoxib were significantly enhanced.

This study aims to formulate a buccal mucoadhesive gel containing prednisolone sodium metazoate-loaded quatsomes for efficient localized therapy of recurrent aphthous ulcers. Quatsomes were prepared using a varied concentration of quaternary ammonium surfactants (QAS) and cholesterol (CHO). A 2 3 factorial design was conducted to address the impact of independent variables QAS type (X 1 ), QAS to CHO molar ratio (X 2 ), and sonication time (X 3 ). The dependent variables were particle size (PS; Y 1 ), polydispersity index (PDI; Y 2 ), zeta potential (ZP; Y 3 ), entrapment efficiency percent (EE%; Y 4 ) and percent of drug released after 6 h (Q6%: Y 5 ). Then, the selected quatsomes formula was incorporated into different gel bases to prepare an optimized mucoadhesive gel to be evaluated via in vivo study. The PS of the developed quatsomes ranged from 69.47 ± 0.41 to 113.28 ± 0.79 nm, the PDI from 0.207 ± 0.004 to 0.328 ± 0.004, ZP from 45.15 ± 0.19 to 68.1 ± 0.54 mV, EE% from 79.62 ± 1.44 to 98.60% ± 1.22 and Q6% from 58.39 ± 1.75 to 94.42% ± 2.15. The quatsomal mucoadhesive gel showed rapid recovery of ulcers, which was confirmed by the histological study and the evaluation of inflammatory biomarkers. These results assured the capability of the developed quatsomal mucoadhesive gel to be a promising formulation for treating buccal diseases.

Green coffee bean extract (GCBE) provides diversified health benefits. However, its reported low bioavailability impeded its utilization in various applications. In this study, GCBE-loaded solid lipid nanoparticles (SLNs) were prepared to improve the bioavailability through enhanced intestinal absorption of GCBE. During the preparation of promising GCBE-loaded SLNs, the lipid concentration, surfactant concentration, and co-surfactant amount are crucial that were optimized using the Box-Behnken design, while particle size, polydispersity index (PDI), ζ-potential, entrapment efficiency, and cumulative drug release were the measured responses. GCBE-SLNs were successfully developed by a high shear homogenization technique using geleol as a solid lipid, tween 80 as a surfactant, and propylene glycol as Co-SAA. The optimized SLNs contained 5.8% geleol, 5.9% tween 80, and 80.4 mg PG resulting in a small particle size of 235.7 ± 12.5 nm, reasonably acceptable PDI of 0.417 ± 0.023, and ζ-potential of -15 ± 0.14 mV, with a high entrapment efficiency of 58.3 ± 0.85% and cumulative release of 7575 ± 0.78%. Furthermore, the performance of the optimized GCBE-SLN was evaluated using an ex vivo everted sac model where the intestinal permeation of GCBE was improved due to nanoencapsulation using SLN. Consequently, the results enlightened the auspicious potential of exploiting oral GCBE-SLNs for boosting intestinal absorption of chlorogenic acid., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

The study aims to investigate the ability of lyophilized nasal inserts of nanosized atomoxetine HCl solid lipid nanoparticles (ATM-SLNs) to transport atomoxetine (ATM) directly to the brain and overcome the first-pass metabolism. In this case, 16 formulae of (ATM-SLNs) were prepared using hot melt emulsification, stirring and ultrasonication method technique. A full factorial design was established with 2 4 trials by optimization of four variables; lipid type (Compritol 888 ATO or stearic acid) (X1), lipid to drug ratio [(1:2) or (2:1)] (X2), span 60: Pluronic f127 ratio [(1:3) or (3:1)] (X3) and probe sonication time (five or ten minutes) (X4). The prepared SLNs were characterized for entrapment efficiency (EE%), in-vitro drug release after 30 min (Q30min), particle size (PS), zeta potential (ZP) and polydispersity index (PDI). Design Expert ® software was used to select the optimum two formulae. The morphological examination for the optimum two formulae was carried out using a transmission electron microscope (TEM). Furthermore, eight lyophilized nasal inserts were prepared by using a 2 3 full factorial design by optimization of three variables: type of (ATM-SLNs) formula (X1), type of polymer (NOVEON AA1 or HPMC K100m) (X2) and concentration of polymer (X3). They were evaluated for nasal inserts' physicochemical properties. The two optimum inserts were selected by Design Expert ® software. The two optimum insets with the highest desirability values were (S4 and S8). They were subjected to DSC thermal stability study and in-vivo study on rats. They were compared with atomoxetine oral solution, atomoxetine (3 mg/kg, intraperitoneal injection) and the pure atomoxetine solution loaded in lyophilized insert. (ATM-SLNs) showed EE% range of (41.14 mg ± 1.8% to 90.6 mg ± 2.8%), (Q30min%) of (27.11 ± 5.9% to 91.08 ± 0.15%), ZP of (-8.52 ± 0.75 to -28.4 ± 0.212% mV), PS of (320.9 ± 110.81% nm to 936.7 ± 229.6% nm) and PDI of (0.222 ± 0.132% to 0.658 ± 0.03%). Additionally, the two optimum (ATM-SLNs) formulae chosen, i.e., F7 and F9 showed spherical morphology. Nasal inserts had assay of drug content of (82.5 ± 2.5% to 103.94 ± 3.94%), Q15min% of (89.9 ± 6.4% to 100%) and Muco-adhesion strength of (3510.5 ± 140.21 to 9319.5 ± 39.425). DSC results of S4 and S8 showed compatibility of (ATM) with the other excipients. S8 and S4 also showed higher trans-nasal permeation to the brain with brain targeting efficiency of (211.3% and 177.42%, respectively) and drug transport percentages of (52.7% and 43.64%, respectively). To conclude, lyophilized nasal inserts of (ATM-SLNs) enhanced (ATM) trans-nasal drug targeting permeation and brain targeting efficiency.

It was found that propranolol hydrochloride (PNL), which is a beta-blocker used for hypertension treatment, has a potent spermicidal activity through local anesthetic activity or beta-blocking effect on sperm cells subsequently it could be used as a contraceptive remedy. This study aimed to entrap PNL into invasomes (INVs) and then formulate it as a locally acting contraceptive gel. PNL-loaded mucoadhesive INVs were prepared via the thin-film hydration technique. The D-optimal design was utilized to fabricate INVs employing lipid concentration (X 1 ), terpenes concentration (X 2 ), terpenes type (X 3 ), and chitosan concentration (X 4 ) as independent variables, while their impact was observed for entrapment efficiency percent (Y 1 ; EE%), particle size (Y 2 ; PS), zeta potential (Y 3 ; ZP), and amount of drug released after 6 h (Y 4 ; Q6h). Design Expert® was bestowed to nominate the desired formula. The selected INV was subjected to further studies and formulated into a mucoadhesive gel for ex-vivo and in-vivo investigations. The optimum INV showed a spherical shape with EE% of 65.01 ± 1.24%, PS of 243.75 ± 8.13 nm, PDI of 0.203 ± 0.01, ZP of 49.80 ± 0.42 mV, and Q6h of 53.16 ± 0.73%. Differential scanning calorimetry study asserted the capability of INVs to entrap PNL. Permeation studies confirmed the desired sustained effect of PNL-loaded INVs-gel compared to PNL-gel, INVs, and PNL solution. Sperm motility assay proved the potency of INVs-gel to inhibit sperm motility. Besides, the histopathological investigation verified the tolerability of the prepared INVs-gel. Taken together, the gained data justified the efficacy of PNL-loaded INVs-gel as a potential locally acting contraceptive.

Loratadine (LORA), is a topical antihistamine utilized in the treatment of ocular symptoms of COVID-19. The study aimed to develop a Loratadine Nanostructured Lipid Carriers Ocugel (LORA-NLCs Ocugel), enhance its solubility, trans-corneal penetrability, and bioavailability. full-factorial design was established with 2 4 trials to investigate the impact of several variables upon NLCs properties. LORA-NLCs were fabricated by using hot melt emulsification combined with high-speed stirring and ultrasonication methods. All obtained formulae were assessed in terms of percent of entrapment efficiency (EE%), size of the particle (PS), zeta potential (ZP), as well as in-vitro release. Via using Design Expert® software the optimum formula was selected, characterized using FTIR, Raman spectroscopy, and stability studies. Gel-based of optimized LORA-NLCs was prepared using 4% HPMC k100m which was further evaluated in terms of physicochemical properties, Ex-vivo, and In-vivo studies. The optimized LORA-NLCs, comprising Compritol 888 ATO ® , Labrasol ® , and Span ® 60 showed EE% of 95.78 ± 0.67%, PS of 156.11 ± 0.54 nm, ZP of -40.10 ± 0.55 Mv, and Qh6% of 99.67 ± 1.09%, respectively. Additionally, it illustrated a spherical morphology and compatibility of LORA with other excipients. Consequently, gel-based on optimized LORA-NLCs showed pH (7.11 ± 0.52), drug content (98.62%± 1.31%), viscosity 2736 cp, and Q12% (90.49 ± 1.32%). LORA-NLCs and LORA-NLCs Ocugel exhibited higher ex-vivo trans-corneal penetrability compared with the aqueous drug dispersion. Confocal laser scanning showed valuable penetration of fluoro-labeled optimized formula and LORA-NLCs Ocugel through corneal. The optimized formula was subjected to an ocular irritation test (Draize Test) that showed the absence of any signs of inflammation in rabbits, and histological analysis showed no effect or damage to rabbit eyeballs. C max and the AUC 0-24 were higher in LORA-NLCs Ocugel compared with pure Lora dispersion-loaded gel The research findings confirmed that NLCs could enhance solubility, trans-corneal penetrability, and the bioavailability of LORA.

The current study aims to develop niosomal nanocarriers for intranasal delivery of dronedarone hydrochloride to ameliorate its limited bioavailability. Niosomes were prepared by ethanol injection method and optimized using 3² full factorial experimental design. Both Span ® type (X1) and Span ® : cholesterol ratio (X2) were set as independent variables. Vesicle size (Y1), polydispersity index (Y2), zeta potential (Y3), and entrapment efficiency (Y4) were set as responses. The optimal formula was further incorporated into an ion-sensitive in situ gelling polymer for intranasal delivery. Optimal formula (N7), which is composed of Span ® 80: cholesterol (1:1), was of the least vesicle size (121.27 ± 13.31 nm), least polydispersity index (0.43 ± 0.073), highest zeta potential (-22.23 ± 2.84 mV) and highest entrapment efficiency (73.44 ± 2.8%). About 75.86% and 60.29% of dronedarone hydrochloride were released from N7 dispersion and in situ gel, respectively, within 12 h, compared to only 13.3% released from a drug-free suspension. In vivo pharmacokinetic study on male New Zealand rabbits resulted in significantly higher C max , AUC 0-72, and AUC 0-∞ of intranasal niosomal in situ gel compared to oral suspension. Almost twofold amplification of relative bioavailability was obtained after intranasal administration of niosomal in situ gel (195.7%) compared to oral suspension.

This study aims to develop efficient topical therapy for keratomycosis using sertaconazolenitrate (STZN)-loaded leciplex (LP). The D-optimal design was used to optimize STZN-loaded LP by utilizing soy phosphatidylcholine (SPC) molar ratio (X 1 ), cationic surfactant molar ratio (X 2 ), and cationic surfactant type (X 3 ) as the independent variables, whereas their impact was studied for entrapment efficiency percent (EE; Y 1 ), particle size (PS; Y 2 ), polydispersity index (PDI; Y 3 ), zeta potential (ZP; Y 4 ), and permeability coefficient (Kp; Y 5 ). The optimized formula was evaluated regarding morphology, ex vivo permeation, mucoadhesion, stability, and in vivo studies. The optimized formula was spherical and showed EE of 84.87 ± 1.71%, PS of 39.70 ± 1.35 nm, PDI of 0.242 ± 0.006, ZP of +54.60 ± 0.24 mV, and Kp of 0.0577 ± 0.0001 cm/h. The ex vivo permeation study revealed that the optimized formula enhanced the Kp and corneal deposition by 2.78 and 12.49 folds, respectively, compared to the aqueous drug dispersion. Furthermore, the optimized formula was stable and revealed promising mucoadhesion properties. Finally, the in vivo studies showed that the optimized formula was superior to the drug dispersion in treating rats with induced keratomycosis. These results confirmed the capabilities of LP as a promising nanocarrier for treating ocular diseases topically.

Objective: Clonazepam (CP) is a potent long-acting nitrobenzodiazepine derivative that could be used for targeting peripheral benzodiazepine receptors. Phospholipid magnesome is a new vesicular nanosystem recently developed for brain targeting. Improving the uptake of 131 I-CP to the brain might be effective for the diagnosis and/or radiotherapy of certain brain diseases and/or tumors., Methods: CP was radiolabeled with 131 I using direct electrophilic substitution reaction. Quality control of 131 I-CP was performed using different techniques. Different formulas of 131 I-CP were prepared and characterized according to particle size and polydispersity index. The structural features of the optimized formula were then interpreted using transmission electron microscopy and scanning electron microscopy, whereas pharmacokinetic and in vivo behaviors were estimated using the intravenous and intranasal delivery routes., Results: The heart and blood demonstrated lower uptake of 131 I-CP, which inevitably decreased the nontarget effects of radioiodine. Intranasally administered 131 I-CP-loaded magnesomes (INMg) had noticeably higher brain uptake (7.1 ± 0.09%ID/g) with rapid onset of action within 5 min and effective pharmacokinetic behavior. INMg had a drug targeting efficiency and nose-to-brain direct transport percentage of 121.1% and 94.6%, respectively as well as a relative bioavailability of 441.04 ± 75.5%., Conclusion: The present study showed that 131 I-CP-loaded magnesomes can be a beneficial brain-targeting approach for improving the diagnosis and/or radiotherapy of certain brain diseases., (Copyright © 2021. Published by Elsevier B.V.)

Background: There are limited studies on the role of efficient regulatory mechanisms in facilitating greater access to Hepatitis C virus (HCV) treatment. Evidence to support the importance of effective pharmaceutical policies and regulations in improving access to oral viral drugs towards the elimination of HCV is needed. This study aims to explore the adequacy of the implemented pharmaceutical policies and regulations in Egypt and their role to improve the availability and affordability of direct-acting antivirals (DAAs) to achieve universal access to the treatment of HCV., Methods: The study adopts a qualitative methodology using desk review of regulatory and legislative information, literature review, and semi-structured interviews with key experts from the concerned governmental regulatory agencies, pharmaceutical industries, academic organizations, professional associations, civil society organizations, and clinicians who are working in researching treatments for hepatitis C., Findings: The common DAAs available in the market are Daclatasvir, Sofosbuvir, and Sofosbuvir-based direct-acting antiviral combinations. Fast-track medicines registration pathway for marketing authorization of DAAs is used to reduce market access time frames. The pricing policies are supplemented using price negotiation to set up affordable prices that led to a reasonable price for DAAs. Using Trade-Related Aspects of Intellectual Property Rights (TRIPs) flexibility and local production of quality generics DAAs at lower prices. In addition, political will and collaboration between the government, civil society, and pharmaceutical companies improved patients' access to affordable DAAs and succeeding hepatitis C treatment in Egypt., Conclusions: The study findings indicated that the implemented pharmaceutical policies and regulations have an immense role in enhancing access to medicines towards the elimination of hepatitis C in Egypt., (© 2021. The Author(s).)

Bisoprolol hemifumarate (BH) is an antihypertensive drug that is used as first-line treatment for chronic hypertension and angina pectoris. Our study was performed to enhance the transdermal delivery of BH, a hydrophilic drug active with high molecular weight, through differently prepared hydrogels. The synergistic effect of permeation enhancers and iontophoresis was investigated via both ex vivo and in vivo permeation studies. Ex vivo iontophoretic permeation studies were performed by using male albino Wistar rat skin. Cellosolve ® hydrogel (F7) showed a 1.5-fold increase in Q 180 , Jss, and FER compared to F5 (lacking permeation enhancer). BH pharmacokinetic data were studied in human volunteers, following transdermal delivery of F7, using Phoresor ® Unit II iontophoresis device, compared to conventional oral tablets. F7 showed 1.9- and 2-fold higher values of C max and AUC 0-40 , respectively compared to Concor ® tablets, as well as a smaller T max (2.00 ± 2.00 h). The relative bioavailability of F7 was found to be 201.44%, relative to Concor ® tablets, demonstrating the significantly enhanced transdermal permeation of BH from the selected hydrogel by iontophoresis, in human volunteers. Finally, results showed the successful utility of permeation enhancers combined with iontophoresis in significantly enhanced transdermal permeation of BH, despite its large molecular weight and hydrophilic nature. Therefore, this strategy could be employed as a successful alternative route of administration to conventional oral tablets.

Acetazolamide (ACZ) is a diuretic used in glaucoma treatment; it has many side effects. Carvedilol (CAR) is a non-cardioselective beta-blocker used in the treatment of elevated intraocular pressure; it is subjected to the first-pass metabolism and causes fluids accumulation leading to edema. This study focuses on overcoming previous side effects by using a topical formula of a combination of the two previous drugs. Sixty formulations of niosomes containing Span 20, Span 60, Tween 20, and Tween 60 with two different ratios were prepared and characterized. Formulation with the lowest particle size (416.30 ± 0.23), the highest zeta potential (72.04 ± 0.43 mv), and the highest apparent coefficient of corneal permeability (0.02 ± 0.29 cm/h) were selected. The selected formula was incorporated into the gel using factorial design 2 3 . Niosomes (acetazolamide/carvedilol) consisting of Span 60 and cholesterol in the molar ratio (7:6), HMPC, and carbopol with two different ratios were used. The selected formula was subjected to an in vivo study of intraocular pressure in ocular hypertensive rabbits for 60 h. The sustained gel formula of the combination decreased (IOP) to normal after 1 h and sustained efficacy for 4 days. Histological analysis of rabbit eyeballs treated with the selected formula showed improvement in glaucomatous eye retinal atrophy.

Diacerein (DCN), a BCS II compound, suffers from poor aqueous solubility and limited bioavailability. Solid dispersion systems (SD) of DCN were prepared by solvent evaporation, using hydrophilic polymers. In-vitro dissolution studies were performed and dissolution parameters were evaluated. I-Optimal factorial design was employed to study the effect of formulation variables (drug:polymer ratio and polymer type) on the measured responses including; drug content (DC) (%), dissolution efficiency at 15 min (DE (15 min)%) and 60 min (DE (60 min)%) and mean dissolution time (MDT) (min). The optimized SD was selected, prepared and evaluated, allowing 10.83 and 3.42 fold increase in DE (15 min)%, DE (60 min)%, respectively and 6.07 decrease in MDT, compared to plain drug. DSC, XRD analysis and SEM micrographs confirmed complete amorphization of DCN within the optimized SD. Physiologically based pharmacokinetic (PBPK) modeling was employed to predict PK parameters of DCN in middle aged healthy adults and geriatrics. Simcyp® software established in-vivo plasma concentration time curves of the optimized SD, compared to plain DCN. Relative bioavailability of the optimized SD compared to plain drug was 229.52% and 262.02% in healthy adults and geriatrics, respectively. Our study reports the utility of PBPK modeling for formulation development of BCS II APIs, via predicting their oral bio-performance., Competing Interests: The authors have declared that no competing interests exist.

Diacerein (DCN), a potent anti-inflammatory API used to treat osteoarthritis yet, it suffers from poor water solubility which affects its oral absorption. Unabsorbed colonic DCN is converted into rhein, which is responsible for laxation as a main side effect of DCN treatment. Therefore, in this study orally disintegrating tablets (ODTs) loaded with optimized DCN solid dispersion system were prepared using different co-processed excipients (Prosolv® ODT, Pharmaburst® 500 and F-melt®), aiming to achieve improved solubility, rapid absorption and consequently limited amount of rhein reaching the colon. Prepared ODTs were evaluated for physical characteristics, in-vitro drug release, disintegration and wetting times. Dissolution parameters; dissolution efficiency percent at 10 (DE (10 min)%) and 30 (DE (30 min)%) min and mean dissolution time (MDT) were determined. The optimized ODT showed 1.50 and 1.12 fold increase in DE (10 min)% and DE (30 min)%, respectively and 2 fold decrease in MDT, compared to Diacerein® capsules. In-vivo anti-inflammatory effect of optimized ODT, using rat paw edema revealed significant increase in edema inhibition (p < 0.0465) and promoted onset of action compared to Diacerein® capsules at 0.5 hr. It could be concluded that optimized ODT could be promising for enhanced dissolution and rapid absorption of DCN from the oral cavity., Competing Interests: No authors have competing interests.

Biopolymeric chitosan structure (Cs) is rationally investigated owing to its potentiality in pharmaceutical applications. The synthetic routes of biomimetic Cs-based blend electrospun nanofibers were studied. Herein, biocompatible crosslinked electrospun polyvinyl alcohol (PVA)/Cs-reduced gold nanoparticles (Cs(Rg))/β-CD (beta-cyclodextrin) in pure water were fabricated. To this end, supportive PVA as a carrier, Cs bio modifier, and gold reductant and β-CD as smoother, inclusion guest molecule, and capping agent exhibit efficient entrapment of moxifloxacin (Mox) and consequently accelerate release. Besides, PVA/Cs(Rg)/β-CD paves towards controlled drug encapsulation-release affinity, antimicrobial, and for wound dressing. Without losing the nanofiber structure, the webs prolonged stability for particle size and release content up to 96.4%. The synergistic effect of the nanoformulation PVA/Cs(Rg)/β-CD against pathogenic bacteria, fungus, and yeast, including Staphylococcus aureus , Escherichia coli , Candida albicans , and Aspergillus niger , posed clear zones up to 53 φmm. Furthermore, a certain combination of PVA/Cs (Rg)/β-CD showed a total antioxidant capacity of 311.10 ± 2.86 mg AAE/g sample. In vitro cytotoxicity assay of HePG2 and MCF-7 NF6 can eradicate 34.8 and 29.3 µg/mL against selected cells.

To obtain a healthy human being with beneficial microflora against different pathogenic infections, classical antibiotics with nanosized biomaterials were used to inhibit the growth of bacterium by their potent synergistic effect. Hence, this study planned to load an oxazolidinone antibiotic named linezolid (LD) onto functionalized chitosan (CN) with 3, 5- dinitrosalyslic acid (DA) via microwave synthesis without harsh condition. The exploring synergistic effect of linezolid (LD) with CN/DA controllable nanostructure was compact efflux-mediated methicillin-resistant Staphylococcus aureus (MRSA) burden and other selected bactericide Gram-positive ( (S. aureus), Gram-negative ( E. coli ), Fungi (C. albicans), Yeast (A. niger), and E. faecalis . The obtained results showed that LD was incorporated into both the internal and external surface of the aggregated CN/DA nanosystem with an average diameter of 150 nm ± 4 hints of the drug loading. Owing to the nature of functionalized CN, the release efficiency attains 98.4% within 100 min. The designed LD@CN/DA exhibited inhibition zone 54 mm, 59 mm, 69 mm, 54 mm, 57 mm, and 24 mm against the tested microbes respectively rather than individual LD. The major target of the current research is achieved by using LD@CN/DA as a nanoantibiotic system that has exceptional consistently active against multi-resistant pathogens, in between MRSA which resist LD. Also, cell viability was performed even after three days of direct cell culture on the surface of the designed nanoantibiotic. The mechanism of microbial inhibition was correlated and rationalized to different charges and the presence of oxygen species against microbial infections. Our findings provide a deep explanation about nanostructured antibiotics design with enhanced potentially pathogen-specific activity., Competing Interests: The authors declare that there is no conflict of interest., (© 2020 Published by Elsevier B.V. on behalf of King Saud University.)

Solid lipid nanoparticles (SLNs) are very potential formulations for topical delivery of antifungal drugs. Hence, the purpose of this research was to formulate the well-known antifungal agent Fluconazole (FLZ)-loaded SLNs topical gel to improve its efficiency for treatment of Pityriasis Versicolor (PV). FLZ-SLNs were prepared by modified high shear homogenization and ultrasonication method using different concentration of solid lipid (Compritol 888 ATO, Precirol ATO5) and surfactant (Cremophor RH40, Poloxamer 407). The physicochemical properties and the in vitro release study for all FLZ-SLNs were investigated. Furthermore, the optimized FLZ-SLN formula was incorporated into gel using Carpobol 934. A randomized controlled clinical trial (RCT) of potential batches was carried out on 30 well diagnosed PV patients comparing to market product Candistan ® 1% cream. Follow up was done for 4 weeks by clinical and KOH examinations. The results showed that FlZ-SLNs were almost spherical shape having colloidal sizes with no aggregation. The drug entrapment efficiency ranged from 55.49% to 83.04%. The zeta potential values lie between -21 and -33 mV presenting good stability. FLZ showed prolonged in vitro release from SLNs dispersion and its Carbapol gel following Higuchi order equation. Clinical studies registered significant improvement (p < .05) in therapeutic response (1.4-fold; healing%, 4-fold; complete eradication) in terms of clinical cure and mycological cure rate from PV against marketed cream. Findings of the study suggest that the developed FLZ loaded SLNs topical gels have superior significant fast therapeutic index in treatment of PV over commercially available Candistan ® cream.

Being one of the highly effective drugs in treatment of Alzheimer's disease, Rivastigmine brain targeting is highly demandable, therefore liposomal dispersion of Rivastigmine was prepared containing 2 mol% PEG-DSPE added to Lecithin, Didecyldimethyl ammonium bromide (DDAB), Tween 80 in 1:0.02:0.25 molar ratio. A major challenge during the preparation of liposomes is maintaining a stable formulation, therefore the aim of our study was to increase liposomal stability by addition of DDAB to give an electrostatic stability and PEG-DSPE to increase stability by steric hindrance, yielding what we called an electrosteric stealth (ESS) liposomes. A medium nano-sized liposome (478 ± 4.94 nm) with a nearly neutral zeta potential (ZP, -8 ± 0.2 mV) and an entrapment efficiency percentage of 48 ± 6.22 was prepared. Stability studies showed no major alteration after three months storage period concerning particle size, polydispersity index, ZP, entrapment efficiency and in vitro release study confirming the successful formation of a stable liposomes. No histopathological alteration was recorded for ESS liposomes of the sheep nasal mucosa. While ESS liposomes showed higher % of drug permeating through the sheep nasal mucosa (48.6%) than the drug solution (28.7%). On completing the in vivo pharmacokinetic studies of 36 rabbits showed 424.2% relative bioavailability of the mean plasma levels of the formula ESS compared to that of RHT intranasal solution and 486% relative bioavailability of the mean brain levels.

SBA-15 is used to enhance the bioavailability of poorly soluble ketoprofen (KP) through stabilization of its amorphous state. Additionally, the current work provides a complete in vitro and in vivo study on preformulated KP-SBA-15 sample and formulated KP-SBA-15 in hard gelatin capsule. Loading of KP was done by a novel method called immersion-rotavapor method. KP was quantified by extraction and thermal gravimetric analysis (TGA). Characterization of the loaded SBA-15 sample was done by high resolution transmission electron microscopy (HRTEM), small angle X-ray diffraction (SAXRD), nitrogen adsorption/desorption isotherms, differential scanning calorimetry (DSC), Fourier transform infrared (FT-IR) spectroscopy and dissolution profiles. The loaded sample was formulated in hard gelatin capsule. The anti-inflammatory and analgesic studies were carried out on 24 adult male albino rats. TGA and extraction results showed 54.4 wt% of drug incorporated. Characterization of KP-SBA-15 sample confirmed the successful encapsulation of KP into the carrier pores in a molecular amorphous state. Additionally, loading of KP did not affect the mesoporous internal structure. During the first 5 min, the dissolution study showed very high release rates; nearly 50% of KP was released. These results were reflected on the in vivo study resulting in 82% inhibition in edema after 1 h and maximum analgesia after 30 min from the administration of the formulated sample. SBA-15 mesoporous silica nanoparticle proved to be a very promising drug delivery carrier that can be used as a facile way to enhance the bioavailability of poorly soluble drugs.

Context: Pravastatin sodium (PVS) is a freely water-soluble HMG-CoA inhibitor that suffers from instability at gastric pH, extensive first pass metabolism, short elimination half-life (1-3 h) and low oral bioavailability (18%)., Objective: To overpower these drawbacks and to maximize drug absorption at its main site of absorption at the duodenum, enteric surface-coated PVS-loaded nanocubosomal dispersions were presented., Materials and Methods: Glyceryl monooleate (GMO)-based dispersions were developed by the fragmentation or the liquid precursor methods using Pluronic® F127 or Cremophor® EL as surfactants. As a challenging enteric-coating approach, the promising dispersions were surface-coated via lyophilization with Eudragit® L100-55; a duodenum-targeting polymer. The drug content, particle size, zeta potential, morphology and release studies of PVS-loaded dispersions were evaluated before and after surface-coating. Compared to an aqueous PVS solution, the pharmacokinetics of the best achieved system (E-F8) was evaluated (UPLC-MS/MS) in rats., Results: The enteric surface-coated nanocubosomal dispersions were more or less spherical in shape and showed high drug-loading, negative zeta potential values and fine-tuned biphasic drug-release patterns characterized by retarded (2 h) and sustained (10 h) phases in pH 1.2 and pH 6.8, respectively. E-F8 system showed significantly (p< 0.05) higher oral bioavailability, delayed T max and prolonged MRT 0-∞ following oral administration in rats., Conclusions: The duodenum-triggering potential and the controlled-release characteristics of the best achieved system for smart PVS delivery were revealed.

Context: Muscle spasm needs prompt relief of symptoms. Chlorzoxazone is a centrally muscle relaxant., Objectives: The aim of this study was to prepare chlorzoxazone orodispersible tablets (ODTs) allowing the drug to directly enter the systemic circulation and bypassing the first-pass metabolism for both enhancing its bioavailability and exerting a rapid relief of muscular spasm., Materials and Methods: ODTs were prepared by direct compression method using Pharmaburst®500, Starlac®, Pearlitol flash®, Prosolv® odt and F-melt® as co-processed excipients. Three ratios of the drug to the other excipients were used (0.5:1, 1:1 and 2:1)., Results and Discussion: All ODTs were within the pharmacopeial limits for weight and content. ODTs containing Pharmaburst®500 showed the shortest wetting time (∼45.33 s), disintegration time (DT) (∼43.33 s) and dissolution (Q 15min 100.63%). By increasing the ratio of CLZ: Pharmaburst®500 from 0.5:1 to 1:1 and 2:1, the DT increased from 26.43 to 28.0 and 43.33 s, respectively. By using Prosolv® odt, ODTs failed to disintegrate in an acceptable time >180 s. DT of ODTs using different co-processed excipients can be arranged as follows: Pharmaburst® 500 < F-melt® max (0.333 h) compared with Myofen® capsules (250 mg CLZ) (1.083 h) which is considered a promising treatment, especially for the rapid relief of muscle spasm., Conclusion: It could be concluded that orodispersible tablets are a promising carrier for CLZ designed for management of muscle spasm due to the enhanced dissolution and rapid absorption of the drug through the oral mucosa.

Meloxicam (Mel) is a non-steroidal potent anti-inflammatory drug with effective analgesic effect for various situations; e.g. postoperative pain. The early systemic exposure to Mel and hence the rapid onset of pharmacological action is limited by its poor water solubility; a situation which may be more pronounced during acute pain episode because of reduced gastric motility that affects disintegration and dissolution of solid dosage forms. To overcome delayed absorption of Mel, improvement in the dissolution behavior of Mel is essential. Firstly, Mel spherical crystalline agglomerates (SCA) were prepared. Secondly, selected Mel SCA were integrated into intraoral fast disintegrating (OF) and edible (EF) films, they possess larger surface area that leads to rapid disintegration and release of the drug into the oral cavity within seconds and hence a rapid onset of action could be achieved. Stability study of formulations resulting in faster and higher extent of dissolution and suitable mechanical properties (G3 and G12) revealed their physical and chemical stability after three months of storage under different conditions. Both G3 and G12 successfully offered rapid absorption rate and accordingly an earlier systemic exposure to Mel compared to Mobic tablets as revealed by significantly earlier T max and higher AUC 0-0.5h and AUC 0-4h . T max following G3 fast disintegrating film administration was comparable to that reported following Mel parenteral administration but avoiding patient inconvenience. Both films may be suitable alternative to conventional oral and intramuscular Mel especially when earlier onset of action is required (in acute conditions).

Objective. To formulate and evaluate slow release ketoconazole and ketorolac to treat fungal keratitis and associated inflammation. Methods. Experimental study with the following outcome measures. Pharmaceutical Evaluation. Mucoadhesive gels containing ketoconazole and ketorolac were used. Microbiological in vitro evaluation was performed using cup method. In vivo evaluation was performed on 24 rabbits divided into 2 groups, 12 rabbits each, group A (fast release formula; 6 times daily) and group B (slow release formula; 3 times daily). Each group was divided into two subgroups (6 rabbits each). Both eyes of rabbits were inoculated with Candida albicans. The left eye of all rabbits received the combination formulae. The right eye for one subgroup received ketoconazole as control 1 while the other subgroup received placebo as control 2. Clinical follow-up was done and, finally, the corneas were used for microbiological and pathological evaluation. Results. Gels containing high polymer concentration showed both high viscosity and mucoadhesion properties with slower drug release. The infected eyes treated with slow release formula containing both drugs showed better curing of the cornea and pathologically less inflammation than eyes treated with fast release formula. Conclusion. Slow release formula containing ketoconazole and ketorolac showed higher activity than fast release formula against fungal keratitis and associated inflammation.

Objective: A stress induced rise in the blood pressure. Some believe that patients with hypertension are characterized by a generalized state of increased anxiety., Aim: The purpose of this study is to prepare a fixed dose bi therapy using bisoprolol hemifumarate (BH) as antihypertensive drug and buspirone hydrochloride (BuHCl) as anxiolytic drug, which can be used to treat both diseases concomitantly. Using sublingual tablets is hopeful to improve the BuHCl poor oral bioavailability and to facilitate administration to patients experiencing problems with swallowing., Materials and Methods: A total of 5mg BH and 10mg BuHCl were selected based on compatibility study. A 3×22 full factorial design was adopted for the optimization of the tablets prepared by direct compression method. The effects of the filler type, the binder molecular weight, and the binder type were studied. The prepared formulae were evaluated according to their physical characters as hardness, friability, disintegration time (new modified method and in vivo disintegration time) and wetting properties. In vitro drugs dissolute, permeation through the buccal mucosa and the effect of storage were analyzed by a new valid high pressure liquid chromatography (HPLC) method. Bioavailability study of the selected formula study was carried out and followed by the clinical., Results: The optimized tablet formulation showed accepted average weight, hardness, wetting time, friability, content uniformity, disintegration time (less than 3 min). Maximum drug release could be achieved with in 10 min. In addition enhancing drug permeation through the buccal mucosa and, the maximum concentration of the drug that reached the blood was in the first 10 min which means a rapid onset of action and improved the extent of both drug's absorption., Conclusion: The results revealed that sublingual (F6) tablets containing both drugs would maintain rapid onset of action, and increase bioavailability. BuHCl with BH can be attributed to the marked decline in DBP and SBP. That led to a reduction in the MAP.

Frequent instillation of terbinafine hydrochloride (T HCl) eye drops (0.25%, w/v) is necessary to maintain effective aqueous humor concentrations for treatment of fungal keratitis. The current approach aimed at developing potential positively charged controlled-release polymeric nanoparticles (NPs) of T HCl. The estimation of the drug pharmacokinetics in the aqueous humor following ocular instillation of the best-achieved NPs in rabbits was another goal. Eighteen drug-loaded (0.50%, w/v) formulae were fabricated by the nanopreciptation method using Eudragit® RS100 and chitosan (0.25%, 0.5%, and 1%, w/v). Soybean lecithin (1%, w/v) and Pluronic® F68 (0.5%, 1%, and 1.5%, w/v) were incorporated in the alcoholic and aqueous phases, respectively. The NPs were evaluated for particle size, zeta potential, entrapment efficiency percentage (EE%), morphological examination, drug release in simulated tear fluid (pH 7.4), Fourier-transform IR (FT-IR), X-ray diffraction (XRD), physical stability (2 months, 4°C and 25°C), and drug pharmacokinetics in the rabbit aqueous humor relative to an oily drug solution. Spherical, discrete NPs were successfully developed with mean particle size and zeta potential ranging from 73.29 to 320.15 nm and +20.51 to +40.32 mV, respectively. Higher EE% were achieved with Eudragit® RS100-based NPs. The duration of drug release was extended to more than 8 h. FT-IR and XRD revealed compatibility between inactive formulation ingredients and T HCl and permanence of the latter's crystallinity, respectively. The NPs were physically stable, for at least 2 months, when refrigerated. F5-NP suspension significantly (P<0.05) increased drug mean residence time and improved its ocular bioavailability; 1.657-fold.