Fabrication of gastro-floating sustained-release etoricoxib and famotidine tablets: design, optimization, in-vitro, and in-vivo evaluation.

In this study, a new gastro-floating sustained-release tablet (GFT) with a combination of Etoricoxib (ET) and Famotidine (FM) was successfully developed. GFTs were prepared by using a combination of hydrophilic swellable natural/semi-synthetic polymers as a controlled-release layer. Through a 24 full factorial statistical experimental design, the effects of formulation factors on the release of GFTs were conducted. The ideal floating tablet (FT) comprised konjac-gum (150 mg), guar-gum (26.57 mg), xanthan-gum (54.17 mg), and HPMC-K15-M (69.25 mg). The ideal FT exhibited a high swelling index (SI) (297.7%) and rapid FLT (around 50 s) in 0.1 N HCl as well as controlled release of ET (22.43% in 1 h and 77.47% in 8 h) and FM (24.89% in 1 h and 93.82% in 8 h) with the absence of any drug-excipient interactions. The AUC0∼72 (ng h/mL) of ET and FM in the GFTs were approximately double-fold of the market, respectively. The relative bioavailability was (207.48 ± 12.02% and 208.51 ± 13.11%) compared with commercial tablets. The X-ray imaging showed a promising buoyancy ability for approximately 8 h. These findings revealed the successful preparation of the sustained-release floating tablet with improved dual drug delivery.

Quinazolines and thiazolidine-2,4-dions as SARS-CoV-2 inhibitors: repurposing, in silico molecular docking and dynamics simulation.

This paper presents an extensive analysis of COVID-19 with a specific focus on VEGFR-2 inhibitors as potential treatments. The investigation includes an overview of computational methodologies employed in drug repurposing and highlights in silico research aimed at developing treatments for SARS-CoV-2. The study explores the possible effects of twenty-eight established VEGFR-2 inhibitors, which include amide and urea linkers, against SARS-CoV-2. Among these, nine inhibitors exhibit highly promising in silico outcomes (designated as 3-6, 11, 24, 26, 27, and sorafenib) and are subjected to extensive molecular dynamics (MD) simulations to evaluate the binding modes and affinities of these inhibitors to the SARS-CoV-2 Mpro across a 100 ns timeframe. Additionally, MD simulations are conducted to ascertain the binding free energy of the most compelling ligand-pocket complexes identified through docking studies. The findings provide valuable understanding regarding the dynamic and thermodynamic properties of the interactions between ligands and pockets, reinforcing the outcomes of the docking studies and presenting promising prospects for the creation of therapeutic treatments targeting COVID-19.

PEGylated Tween 80-functionalized chitosan-lipidic nano-vesicular hybrids for heightening nose-to-brain delivery and bioavailability of metoclopramide.

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-AUC0-∞) 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-AUC0-∞ of the intranasal dual-optimized MTC-loaded ISG was 10 and 3 times more than brain-AUC0-∞ 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-AUC0-∞ (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.

Merging konjac glucomannan with other copolymeric hydrogels as a cutting-edge liquid raft system for dual delivery of etoricoxib and famotidine.

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% CaCO3. 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.

Optimization of hyaluronan-enriched cubosomes for bromfenac delivery enhancing corneal permeation: characterization, ex vivo, and in vivo evaluation.

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 23 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 AUC0-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.

Formulation, Characterization and Comparative Pharmacokinetic Study of Bupropion Floating Raft System as a Promising Approach for Treating Depression.

The aim of this study was to formulate, evaluate, and compare satiety-enhancing floating raft system (FRS) of bupropion as gastroretentive drug delivery systems (GRDDS) using in-situ gelling pectin and alginate. Bupropion was considered as a good candidate for such systems due to high water solubility that requires frequent dosing. Pectin and alginate could prolong satiety sensation augmenting weight loss of bupropion. A 24 full factorial design was tailored to inspect the effect of the response variables (gel-forming polymer type, calcium carbonate percentage, glyceride lipid type and percentage). Gelation lag time, floating lag time, as well as drug released percent after 1 and 8 h were selected as dependent variables. The optimal system was investigated for compatibility and bioavailability study in healthy human volunteers relative to marketed Wellbutrin® sustained release tablets. The optimal FRS (3% alginate, 2% precirol®, and 2% CaCO3) was selected. This system had an optimum viscosity that will allow a rapid sol-gel transformation in the stomach, excellent floating behavior, and controlled release profile with a comparable bioavailability. The optimal FRS would be a novel liquid GRDDS in controlling bupropion rate release especially for depression associated with eating disorders or dysphagia improving patient compliance and drug efficacy.

Promising Swellable Floating Bupropion Tablets: Formulation, in vitro/in vivo Evaluation and Comparative Pharmacokinetic Study in Human Volunteers.

PURPOSE: 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.