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Hany SM Ali,1,2 Ahmed F Hanafy,3 Rawan Bafail,1 Hamad Alrbyawi,1 Marey Almaghrabi,1 Yaser M Alahmadi,4 Samar El Achy5 1Department of Pharmaceutics and Pharmaceutical Industries, College of Pharmacy, Taibah University, Madinah, Al-Madinah Al-Munawwarah, Saudi Arabia; 2Department of Pharmaceutics, Faculty of Pharmacy, Assiut University, Assiut, Egypt; 3Research and Development Department, Al Andalous Pharmaceutical Industries, Giza, Egypt; 4Department of Pharmacy Practice, College of Pharmacy, Taibah University, Madinah, Al-Madinah Al-Munawarah, 30001, Saudi Arabia; 5Department of Anatomical Pathology, Faculty of Medicine, University of Alexandria, Alexandria, EgyptCorrespondence: Hany SM Ali, Email hsali@taibahu.edu.sa, hafandy2000@yahoo.comBackground: Budesonide (BUD) is a BCS class II medication with poor water solubility and limited oral bioavailability. In this study, innovative solid self-microemulsifying drug delivery systems (BUD-SMEDDS) were developed for effective local management of distal ulcerative colitis (UC).Methods: Based on solubility and emulsification tests, the components of the self-microemulsifying drug delivery system (SMEDDS) were Capryol™ 90, Tween 80, and Transcutol HP. The impacts of BUD-SMEDDS ingredients (as inputs) on the average globule size (AGS), polydispersity index (PDI), and self-emulsification time (SET) as responses were investigated using the Box–Behnken design methodology. Solid rectal systems were then fabricated using the optimized values of SMEDDS components in Lutrol® bases. The developed systems were evaluated for in vitro characteristics and in vivo efficacy using a rat colitis model.Results: For all responses, the greatest impact was attributed to the oil content of SMEDDS. An optimized BUD-SMEDDS with AGS of 33 ± 2.9 nm, PDI of 0.29 ± 0.03 and SET of 25 ± 2.5 s) was selected for rectal formulations. The developed formulations demonstrated acceptable physical characteristics and mucoadhesive abilities. Differential scanning calorimetric (DSC) analysis revealed the absence of BUD crystallinity in the SMEDDS formulations. The drug release patterns could be regulated by selecting the grade and composition of the incorporated Lutrols. Clinical and histopathological assessments revealed considerable improvements in animals treated with BUD-SMEDDS formulations.Conclusion: Overall findings confirmed the superior capability of solid SMEDDS as BUD carriers to manage distal colitis in tested animals.Keywords: Budesonide, SMEDDS, Ulcerative colitis, Box Behnken design, efficacy

Hany SM Ali,1,2 Nader Namazi,1 Hossein M Elbadawy,3 Abdelaziz AA El-Sayed,4,5 Sameh A Ahmed,6,7 Rawan Bafail,1 Mohannad A Almikhlafi,3 Yaser M Alahmadi8 1Department of Pharmaceutics and Pharmaceutical Industries, College of Pharmacy, Taibah University, Madinah, Al-Madinah Al-Munawwarah, Saudi Arabia; 2Department of Pharmaceutics, Faculty of Pharmacy, Assiut University, Assiut, Egypt; 3Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Madinah, Al-Madinah Al-Munawarah, Saudi Arabia; 4Biology Department, Faculty of Science, Islamic University of Madinah, Madinah, Al-Madinah Al-Munawarah, Saudi Arabia; 5Zoology Department, Faculty of Science, Zagazig University, Zagazig, Al-Sharqiya, Egypt; 6Department of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Madinah, Al-Madinah Al-Munawarah, Saudi Arabia; 7Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Assiut University, Assiut, Egypt; 8Department of Pharmacy Practice, College of Pharmacy, Taibah University, Madinah, Al-Madinah Al-Munawarah, 30001 Saudi ArabiaCorrespondence: Hany SM Ali, Tel +966 50 286 4018, Fax +966 4 847 5027, Email hsali@taibahu.edu.sa; hafandy2000@yahoo.comBackground: Repaglinide (REP) is an antidiabetic drug with limited oral bioavailability attributable to its low solubility and considerable first-pass hepatic breakdown. This study aimed to develop a biodegradable chitosan-based system loaded with REP–solid lipid nanoparticles (REP-SLNs) for controlled release and bioavailability enhancement via transdermal delivery.Methods: REP-SLNs were fabricated by ultrasonic hot-melt emulsification. A Box–Behnken design (BBD) was employed to explore and optimize the impacts of processing variables (lipid content, surfactant concentration, and sonication amplitude) on particle size (PS), and entrapment efficiency (EE). The optimized REP-SLN formulation was then incorporated within a chitosan solution to develop a transdermal delivery system (REP-SLN-TDDS) and evaluated for physicochemical properties, drug release, and ex vivo permeation profiles. Pharmacokinetic and pharmacodynamic characteristics were assessed using experimental rats.Results: The optimized REP-SLNs had a PS of 249± 9.8 nm and EE of 78%± 2.3%. The developed REP-SLN-TDDS demonstrated acceptable characteristics without significant aggregation of REP-SLNs throughout the casting and drying processes. The REP-SLN-TDDS exhibited a biphasic release pattern, where around 36% of the drug load was released during the first 2 h, then the drug release was sustained at around 80% at 24 h. The computed flux across rat skin for the REP-SLN-TDDS was 2.481± 0.22 μg/cm2/h in comparison to 0.696± 0.07 μg/cm2/h for the unprocessed REP, with an enhancement ratio of 3.56. The REP-SLN-TDDS was capable of sustaining greater REP plasma levels over a 24 h period (p< 0.05). The REP-SLN-TDDS also reduced blood glucose levels compared to unprocessed REP and commercial tablets (p< 0.05) in experimental rats.Conclusion: Our REP-SLN-TDDS can be considered an efficient therapeutic option for REP administration.Keywords: repaglinide, chitosan, solid-lipid nanoparticles, Box–Behnken design, transdermal, bioavailability

This study aimed to formulate and statistically optimize spanlastics loaded spongy insert (SPLs-SI) of prednisolone Na phosphate (PRED) to enhance and sustain its anti-inflammatory effect in a controlled manner. An I-optimal optimization was employed using Design-Expert® software. The formulation variables were sonication time, the Span 60: EA ratio and type of edge activator (Tween 80 or PVA) while Entrapment efficiency (EE%), Vesicles' size (VS) and Zeta potential (ZP) were set as the dependent responses. This resulted in an optimum spanlastics (SPLs) formulation with a desirability of 0.919. It had a Span60:Tween80 ratio of 6:1 with a sonication time of 9.5 min. It was evaluated in terms of its EE%, VS, ZP, release behavior in comparison to drug solution in addition to the effect of aging on its characteristics. It had EE% of 87.56, VS of 152.2 nm and ZP of -37.38 Mv. It showed sustained release behavior of PRED in comparison to drug solution with good stability for thirty days. TEM images of the optimized PRED SPLs formulation showed spherical non-aggregated nanovesicles. Then it was loaded into chitosan spongy insert and evaluated in terms of its visual appearance, pH and mucoadhesion properties. It showed good mucoadhesive properties and pH in the safe ocular region. The FTIR, DSC and XRD spectra showed that PRED was successfully entrapped inside the SPLs vesicles. It was then exposed to an in-vivo studies where it was capable of enhancing the anti-inflammatory effect of PRED in a sustained manner with once daily application compared to commercial PRED solution. The spongy insert has the potential to be a promising carrier for the ocular delivery of PRED., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Randa Mohammed Zaki reports financial support was provided by 10.13039/100009392Prince Sattam bin Abdulaziz University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Tropomyosin-receptor kinase A (TrkA) is the primary isoform among the tropomyosin-receptor kinases that have been associated with human cancer development, contributing to approximately 7.4% of all cancer cases. TrkA represents an attractive target for cancer treatment; however, currently available TrkA inhibitors face limitations in terms of resistance development and potential toxicity. Hence, the objective of this study was to identify new allosteric-approved inhibitors of TrkA that can overcome these challenges and be employed in cancer therapy. To achieve this goal, a screening of 9,923 drugs from the ChEMBL database was conducted to assess their repurposing potential using molecular docking. The top 49 drug candidates, exhibiting the highest docking scores (-11.569 to -7.962 kcal/mol), underwent MM-GBSA calculations to evaluate their binding energies. Delanzomib and tibalosin, the top two drugs with docking scores of -10.643 and -10.184 kcal/mol, respectively, along with MM-GBSA dG bind values of -67.96 and -50.54 kcal/mol, were subjected to 200 ns molecular dynamic simulations, confirming their stable interactions with TrkA. Based on these findings, we recommend further experimental evaluation of delanzomib and tibalosin to determine their potential as allosteric inhibitors of TrkA. These drugs have the potential to provide more effective and less toxic therapeutic alternatives. The approach employed in this study, which involves repurposing drugs through molecular docking and molecular dynamics, serves as a valuable tool for identifying novel drug candidates with distinct therapeutic uses. This methodology can contribute to reducing the attrition rate and expediting the process of drug discovery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mukhtar, Abdelmoniem, Elrufaie, Edris, Ghaboosh, Mahgoub, Garelnabi, Osman, Sherif, Ashour, Ghazawi, Samman, Alhaddad, Bafail, Ibrahim, Mohamed and Alzain.)

The use of aromatase inhibitors is an established therapy for estrogen-dependent breast cancer in postmenopausal women. However, the only commercially available aromatase inhibitor, letrozole, is not highly selective; in addition to aromatase, it has an affinity for binding to desmolase, an enzyme involved in steroidogenesis, which explains the main side effects. Therefore, we designed new compounds based on the structure of letrozole. More than five thousand compounds were constructed based on the letrozole structure. Then, these compounds were screened for their binding ability toward the target protein, aromatase. Quantum docking, Glide docking, and ADME studies showed 14 new molecules with docking scores of ≤-7 kcal/mol, compared to the docking score of -4.109 kcal/mol of the reference, letrozole. Moreover, molecular dynamics (MD) and post-MD MM-GBSA calculations were calculated for the top three compounds, and the results supported in their interaction's stability. Finally, the density-functional theory (DFT) study applied to the top compound to study the interaction with gold nanoparticles revealed the most stable position for the interaction with the gold nanoparticles. The results of this study confirmed that these newly designed compounds could be useful starting points for lead optimization. Further in vitro and in vivo studies are recommended for these compounds to verify these promising results experimentally.

Background: Paracetamol (acetaminophen) is an over-the-counter non-steroidal anti-inflammatory drug that may cause acute toxic overdosage particularly in neuropsychiatric patients. Paracetamol is also very commonly prescribed as an analgesic and antipyretic agent. Paracetamol toxicity causes decreased reduced glutathione and oxidative tissue damage. Aleppo galls is a promising natural remedy exerting antioxidant and tissue-protective effects that may combat acetaminophen-induced oxidative tissue damage., Methodology: Biochemical and toxicological effects of a toxic dose of paracetamol (250 mg/kg) were investigated for three consecutive days versus the tissue-protective effects of Aleppo galls. Eighteen white albino mice were randomly allocated in this study and divided into three experimental groups (six mice per group): negative control (received intraperitoneal sterile water injection), paracetamol toxicity group (received intraperitoneal paracetamol injection) and the third group (received paracetamol injection at 250 mg/kg/day together with oral Aleppo galls treatment at 250 mg/kg/day for 3 consecutive days). All mice were sacrificed by the end of the study., Results: Our data revealed that paracetamol toxicity exerted significant oxidative stress damaging effects (high serum malondialdehyde, decreased serum catalase and decreased total antioxidant capacity), and significant inflammatory effects (high serum IL-6) and significant tissue-damaging effects (high serum LDH). Aleppo galls treatment significantly protected against acetaminophen toxicity-induced oxidative stress effects (P<0.001), inflammatory effects (P<0.001) and tissue-damaging effects (P<0.001)., Conclusion: Aleppo galls are promising for future drug therapeutics and for the synthesis of natural remedies for treating paracetamol toxicity. We recommend formulating Aleppo galls extract as a pharmaceutical nutrition and to be given to those who need to take large doses of paracetamol., Competing Interests: None., (IJPPP Copyright © 2023.)

Background: Acute paracetamol toxicity is a common and potentially life-threatening emergency causing liver failure that may necessitate liver transplantation. Unfortunately, current therapies are still defective., Objectives: To investigate the protective effects exerted by Aleppo galls (Quercus infectoria Olivier) extract against acute paracetamol toxicity in mice., Methodology: Eighteen mice were divided into three experimental groups, each included six mice in each group. The groups included: negative control group, paracetamol toxicity group that received an acute toxic intraperitoneal dose of paracetamol (250 mg/kg) for four consecutive days, and treatment group (received 250 mg/kg paracetamol followed few hours later by Aleppo galls extract for the same duration). Animals were anaesthetized using ether anaesthesia. Animals were sacrificed by decapitation and blood samples were drawn. Paracetamol toxicity effects versus Aleppo galls protection were evaluated on liver function tests, liver histology, serum cholesterol and serum triglycerides., Results: Acute paracetamol toxicity caused significantly elevated serum transaminases (ALT and AST), decreased serum albumin, and increased serum cholesterol and triglycerides. Aleppo galls extract exerted significant protective effects and restored near normal serum levels of the previously-mentioned parameters. Upon histopathological evaluation, mice in the control group showed normal hepatic architecture with preserved hepatic cords and sinuses. Acute paracetamol toxicity induced peripheral zonal degeneration with focal necrosis of the hepatic tissue. The hepatocytes showed cytoplasmic vacuolation with indistinct cell borders. Central hepatic venules were congested. Administration of Aleppo galls extract reduced the tissue damaging effects induced by paracetamol toxicity with only minimal residual degenerative changes that were observed with absent necrosis., Conclusion: Quercus infectoria Olivier (Aleppo galls) is a promising source of phytochemicals and future therapeutics., Competing Interests: None., (IJBMB Copyright © 2023.)

Prompt epinephrine (Epi) injection using auto-injectors is the initial life-saving out-of-hospital treatment for anaphylaxis. However, patients and healthcare providers are eagerly awaiting a more convenient alternative dosage form that would overcome auto-injectors drawbacks. Previously, we extensively evaluated multiple alternative fast-disintegrating sublingual Epi tablet (FDSTs) formulations. However, the sublingual stability of Epi and effect of modifying the sublingual microenvironment pH on its stability and transport pathways were not yet fully investigated. Results depicted that Epi remained sufficiently stable at various pHs in human saliva and porcine sublingual tissue's extract. Epi permeability (EP) through excised porcine sublingual membrane was greatest at pH 8.0 (p < 0.05), 11-fold higher than the negative control (Epi at pH 6.8). Sodium carbonate (Na Carb) 0.75% was the most efficient buffer to modify Epi solution pH to 8.0. Both sodium dodecyl sulfate (SDS) 0.075% and palmitoyl-DL-carnitine chloride (PCC) 1.2% increased paracellular EP 10-fold and 3-fold, respectively; however, both demonstrated a delayed enhancement (>5 min). Meanwhile, Na Carb and SDS combination increased EP 23-fold without a delay. It is evident that pH-modifiers or their SDS combination showed promising potential to enhance Epi sublingual permeability and further reduce the required Epi dose using FDSTs as a feasible alternative to Epi auto-injectors., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Atropine sulfate (AS) auto-injectors are the only approved antidote for out-of-hospital emergency treatment of organophosphates (OP) toxicity. However, they are only available for military use and require the administration of multiple auto-injectors. Therefore, an alternative, patient-friendly and more affordable fast-disintegrating sublingual tablets (FDSTs) of AS were previously developed. In this article, the effect of modifying the microenvironment's pH and/or using penetration enhancers on AS sublingual transport pathways were evaluated in an attempt to further enhance AS sublingual permeability. Ten different AS FDST formulations with or without the incorporation of alkalizer and various penetration enhancers were manufactured and characterized. AS permeability was investigated through excised porcine sublingual membrane using Franz cells. Results showed that the incorporation of either a transcellular enhancer or alkalizer achieved a significantly higher AS permeability enhancement (twofold). Combining sodium bicarbonate (Na Bicarb) 2% as alkalizer with sodium dodecyl sulfate (SDS) 1% as a transcellular enhancer resulted in the greatest synergistic enhancement in AS sublingual permeability (up to twelvefold). In conclusion, the modified AS FDST developed in this work has the potential to improve the pharmacokinetic parameters of AS following sublingual administration for the first-aid treatment of OP toxicity in future animal bioequivalency studies., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Context: AS FDSTs will provide an accessible alternative for AS autoinjector (ATROPEN ® ), and a noninvasive first-aid antidote for the treatment of organophosphate (OP) poisoning and reduce the number of fatalities due to nerve gas attacks or OP pesticide poisoning. Objective: The effects of changing the filler grade on the characteristics of atropine sulfate (AS) fast disintegrating sublingual tablets (FDSTs) and AS sublingual permeability were investigated in order to optimize the formulation of AS FDSTs and, therefore, AS sublingual permeability. Methods: Two batches of AS FDSTs containing AS 8 mg were formulated and manufactured using two different filler grades: microcrystalline cellulose (MCC) UF-702 (formulation A) and MCC PH-301 (formulation B). Several United States Pharmacopeia (USP) and non-USP physical tests were performed to evaluate the AS FDSTs' characteristics. The AS permeability from the two AS FDST batches were evaluated using Franz cells through excised porcine sublingual membranes. Results were statistically compared at p  < .05. Results: Both batches passed the content uniformity and friability tests. Formulation A tablets were significantly different from formulation A tablets and resulted in better powder flowability, higher breaking force, faster disintegration, faster dissolution rate, higher water uptake, and higher AS permeability. Conclusion: The selection of the filler grade to be used in the formulation of AS FDSTs can significantly impact their characteristics and significantly affect AS sublingual permeability, which can be used to improve the sublingual delivery of AS and the potential of using AS FDSTs as an alternative dosage form for the first-aid treatment of OP poisoning.

Atropine sulfate (AS) fast-disintegrating sublingual tablets (FDSTs) were tested for AS sublingual permeation's feasibility as a potential alternative dosage form to treat organophosphates (OP) toxicity. More than 12,000 OP pesticide toxicity cases were reported in the USA from 2011 to 2014. AS is the recommended antidote for OP toxicity; however, it is only available as an ATROPEN® auto-injector, an IM injection, for self-administration, which is associated with several drawbacks and limitations. Six AS FDST batches were formulated and characterized. Two tablet sizes, group A weighing 150 mg and group B weighing 50 mg, were formulated with three different AS doses: 2 mg (A1 and B1), 4 mg (A2 and B2), and 8 mg (A3 and B3). AS in vitro diffusion and sublingual permeation were investigated in Franz cells using a cellulose membrane and an excised porcine sublingual membrane. The effect of AS load and tablet size on sublingual permeation was also evaluated. All batches passed quality control tests. AS FDSTs' size and AS load had a significant effect on tablet disintegration time and drug dissolution, which significantly impacted AS concentration gradient across the diffusional membrane. Group B FDSTs (smaller tablets) resulted in a significantly higher initial permeation (JAUC 0-15 ) compared to group A FDSTs. Also, the cumulative AS (JAUC 0-90 ) and AS influx (J) increased linearly with increasing AS dose. These AS FDSTs have the potential to be explored in vivo to determine the required bioequivalent sublingual AS dose as an alternative dosage form for the treatment of OP toxicity.