Repaglinide-Solid Lipid Nanoparticles in Chitosan Patches for Transdermal Application: Box-Behnken Design, Characterization, and In Vivo Evaluation.

Background: 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.

Unlocking the potential of approved drugs for the allosteric inhibition of tropomyosin-receptor kinase A using molecular docking and molecular dynamics studies.

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.

Design of Novel Letrozole Analogues Targeting Aromatase for Breast Cancer: Molecular Docking, Molecular Dynamics, and Theoretical Studies on Gold Nanoparticles.

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.

Acute paracetamol toxicity-induced inflammatory and oxidative effects are relieved by Aleppo galls: a novel experimental study.

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.

Aleppo galls alleviate paracetamol-induced hepatotoxicity and tissue damage: an experimental study.

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.

Assessment of epinephrine sublingual stability and permeability pathways to enhance its permeability for the treatment of anaphylaxis.

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.

Modulation of the sublingual microenvironment and pH-dependent transport pathways to enhance atropine sulfate permeability for the treatment of organophosphates poisoning.

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.

Effect of the filler grade on the characteristics and the sublingual permeability of atropine sulfate fast disintegrating sublingual tablets.

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.

Effect of Fast-Disintegrating Tablets' Characteristics on the Sublingual Permeability of Atropine Sulfate for the Potential Treatment of Organophosphates Toxicity.

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 (JAUC0-15) compared to group A FDSTs. Also, the cumulative AS (JAUC0-90) 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.

Formulation and Evaluation of Fast-Disintegrating Sublingual Tablets of Atropine Sulfate: the Effect of Tablet Dimensions and Drug Load on Tablet Characteristics.

In this study, we formulated and evaluated the effects of tablet dimensions and drug load on the characteristics of atropine sulfate (AS) fast-disintegrating sublingual tablets (FDSTs). We aim to develop AS FDSTs as an alternative non-invasive and portable dosage form for the emergency treatment of organophosphate (OP) toxicity. AS autoinjector, AtroPen®, is the only self-administered dosage form available as an antidote for-out-of-hospital emergency use, but it is associated with several limitations and drawbacks. Seven FDST formulations of two tablet sizes, 150 mg (A) and 50 mg (B), and of several AS loads, 0 mg (A1, B1), 2 mg (A2, B2), 4 mg (B3), and 8 mg (B4a, B4b), were formulated and manufactured by direct compression. AS FDST characteristics were evaluated using USP and non-USP tests. Results were statistically compared at p < 0.05. All FDSTs passed the USP content uniformity and friability tests, disintegrated and released AS in ≤30 and 60 s. B1 and B2 were significantly harder than A1 and A2. Water uptake of A1 was significantly the highest. However, B1 and B2 had shorter disintegration and wetting times and higher amounts of AS dissolved than did A1 and A2 (p < 0.05). Increasing AS negatively affected FDST tensile strength (p < 0.05 for B4a) and water uptake (p < 0.05 for B3, B4a and B4b), however, without affecting AS dissolution. Formulation of AS up to 16% into smaller FDSTs was successful. Smaller FDSTs were harder and disintegrated more quickly. These AS FDSTS have the potential for further in vivo testing to evaluate their OP antidote potential.