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A well-made chitosan-PVP block copolymer platform was equipped with highly ordered and uniform nano-channels. This highly adhesive block copolymer platform was designed to ensure the efficient co-delivery of two synergistic-acting hypoglycemic drugs. Linagliptin oral bioavailability is 30% due to poor permeability and intestinal degradation. Its pharmacokinetics shows a non-linear profile. Empagliflozin exhibited decreased permeability and decreased solubility in aqueous media between pH 1 and 7.5. Cubosomes were functionalized as a good microdomain to guest and improve the physicochemical characteristics of drug molecules with decreased permeability and solubility. Cubosomes loaded with linagliptin (linagliptin cubosomes (LCs)) and empagliflozin (empagliflozin cubosomes ECs) were separately prepared using the top-down method and optimized by applying 2 3 factorial design. Optimized cubosomal systems LCs (F3) and ECs (F4) were incorporated into a chitosan-PVP gel to obtain dual cubosome-loaded platforms (LECF) optimized through 2 2 factorial design. The permeation study from the optimized LECF (C1) ensured enhanced empagliflozin permeation alongside continued efflux for linagliptin, resolving potential risks due to its non-linear plasma profile. The in-vivo study revealed that AUC (0-∞) of linagliptin and empagliflozin was enhanced by 2- and threefold, respectively. Therefore, the chitosan-PVP block copolymer platform buccal application for the co-delivery of linagliptin and empagliflozin could contribute to enhanced clinical effectiveness in treating diabetes., (© 2023. The Author(s).)

Main Conclusion: The Na + /Ca 2+ ratio of 1/5 ameliorated the inhibitory action of NaCl and improved the germination and growth of Vicia faba. Addition of Rhizobium also enhanced nodulation and nitrogen fixation. Casting light upon the impact of salinity stress on growth and nitrogen fixation of Vicia faba supplemented with Rhizobium has been traced in this work. How Ca 2+ antagonizes Na + toxicity and osmotic stress of NaCl was also targeted in isosmotic combinations of NaCl and CaCl 2 having various Na + :Ca 2+ ratios. Growth of Vicia faba (cultivar Giza 3) was studied at two stages: germination and seedling. At both experiments, seeds or seedlings were exposed to successively increasing salinity levels (0, 50, 100, 150, and 200 mM NaCl) as well as isosmotic combinations of NaCl and CaCl 2 (Na + :Ca 2+ of 1:1, 1:5, 1:10, 1:15, 1:18, and 1: 20), equivalent to 150 mM NaCl. Inocula of the local nitrogen-fixing bacteria, Rhizobium leguminosarum (OP715892) were supplemented at both stages. NaCl salinity exerted a negative impact on growth and metabolism of Vicia faba; inhibition was proportional with increasing salinity level up to the highest level of 200 mM. Seed germination, shoot and root lengths, fresh and dry weights, chlorophyll content, and nodules (number, weight, leghemoglobin, respiration, and nitrogenase activity) were inhibited by salinity. Ca 2+ substitution for Na + , particularly at a Na/Ca ratio of 1:5, was stimulatory to almost all parameters at both stages. Statistical correlations between salinity levels and Na/Ca combinations proved one of the four levels (strong- or weak positive, strong- or weak negative) with most of the investigated parameters, depending on the parameter., (© 2024. The Author(s).)

Nanosponges are porous solid nanoparticles composed of hyper-cross-linked polymers that serve as specific micro-domains designed for the co-encapsulation of two drugs with different chemical structures. Our goal was to engineer a novel assembly of multilayer nanosponges (MLNS) based on a layer-by-layer approach. This MLNS was engineered to incorporate two drugs (linagliptin and empagliflozin) in a new drug delivery route. Linagliptin has a low oral bioavailability due to intestinal degradation and low permeability. Its pharmacokinetics shows a non-linear profile which leads to a disproportionate increase in its effectiveness with increasing the dose frequency. Empagliflozin has a low permeability and is very slightly soluble in aqueous media between pH 1-7.5. MLNS could improve their bioavailability along with resolving possible risks due to the non-linear pharmacokinetics of linagliptin and maximizing its dose efficiency. 2 3 factorial design was used to optimize the novel systems. MLNS (F4) was chosen as the optimal system with an average diameter of 40 nm and the highest entrapment efficiency which accounts for 92.93 % ± 2.27 and 100.94 % ± 0.55 for linagliptin and empagliflozin respectively. Förster resonance energy transfer confirmed the formation of a multilayer structure in MLNS. The optimized system was incorporated within chitosan mucoadhesive buccal films which were optimized through 2 2 factorial design. The permeation study from optimized MLNS-film (B4) ensured an improved empagliflozin permeation along with a controlled efflux for linagliptin, resolving possible risks due to the nonlinear plasma profile. The in-vivo study of MLNS-film (B4) revealed that AUC (0-∞) of linagliptin and empagliflozin was enhanced by two-fold and ten-fold, respectively. Therefore, the nano-buccal formulation for the co-delivered hypoglycemic drugs could contribute to improved clinical efficacy in the treatment of diabetes., Competing Interests: Conflict of interest The authors report no conflicts of interest. The authors only are responsible for the content and writing of the article., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Carvedilol (CRV) is a non-selective third generation beta-blocker used to treat hypertension, congestive heart failure and angina pectoris. Oral administration of CRV showed poor bioavailability (25%), which might be ascribed to its extensive first-pass metabolism. Buccal delivery is known to boost drugs bioavailability. The aim of this study is to investigate the efficacy of bilosomes-based mucoadhesive carvedilol nanosponge for enhancing the oral bioavailability of CRV. The bilosomes were prepared, optimized and characterized for particle size, surface morphology, encapsulation efficiency and ex-vivo permeation studies. Then, the optimized formula was incorporated into a carboxymethyl cellulose/hydroxypropyl cellulose (CMC/HPC) composite mixture to obtain buccal nanosponge enriched with CRV bilosomes. The optimized bilosome formula (BLS9), showing minimum vesicle size, maximum entrapment, and highest cumulative in vitro release, exhibited a spherical shape with 217.2 nm in diameter, 87.13% entrapment efficiency, and sustained drug release for up to 24 h. In addition, ex-vivo drug permeation across sheep buccal mucosa revealed enhanced drug permeation with bilosomal formulations, compared to aqueous drug suspension. Consecutively, BLS9 was incorporated in a CMC/HPC gel and lyophilized for 24 h to obtain bilosomal nanosponge to enhance CRV buccal delivery. Morphological analysis of the prepared nanosponge revealed improved swelling with a porosity of 67.58%. The in vivo assessment of rats indicated that CRV-loaded nanosponge efficiently enhanced systolic/diastolic blood pressure, decreased elevated oxidative stress, improved lipid profile and exhibited a potent cardio-protective effect. Collectively, bilosomal nanosponge might represent a plausible nanovehicle for buccal delivery of CRV for effective management of hypertension.

Mosapride belongs to class IV in Biopharmaceutics Classification System and is used in the treatment of reflux esophagitis. It exhibits poor bioavailability due to limited permeability, solubility and extensive first-pass metabolism. In this study, intranasal mosapride-loaded cross-linked xyloglucan Pluronic micelles (MOS-XPMs) was formulated and optimized to improve the low solubility & bioavailability of MOS. The solid dispersion technique using 2 3 full factorial design was applied. (MOS-XPMs) (F4) had the highest desirability value (0.952) and, therefore, it was selected as an optimal system. Xyloglucan cross-linked in the shell of Pluronic micelles offered improved stability and mucoadhesiveness to MOS-XPMs. 1 H NMR spectra ensured the cross-linking of xyloglucan with Pluronic micelle shell and micelle stabilization. A Pharmacodynamic study revealed that MOS-XPMs showed 1.5-fold increase in duodenal and cecal motility compared to MOS suspension and 1.7-fold increase compared to the oral marketed product. The new MOS-XPMs were shown to be successful at improving the therapeutic efficacy of mosapride., 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., (© 2020 THE AUTHORS. Published by Elsevier BV on behalf of Cairo University.)

In this work chitosan-hyaluronic acid composite sponge scaffold enriched with Andrographolide (AND) lipid nanocarriers was developed. Nanocarriers were prepared using solvent diffusion method by applying 2 3 factorial design. NLC4 had the highest desirability value (0.882) and therefore, it was chosen as an optimal nanocarrier. Itexhibited spherical shape with 253nm, 83.04% entrapment efficiency and a prolonged release of AND up to 48-h. Consecutively, NLC4 was incorporated in a chitosan-hyaluronic acid gel and lyophilized for 24h to obtain chitosan-hyaluronic acid/NLC4 nanocomposite sponge to enhance AND delivery to wound sites. The morphology of sponge was characterized by scanning electron microscopy. Nanocomposites showed a porosity of 56.22% with enhanced swelling. The in vivo evaluation in rats reveals that the chitosan-hyaluronic acid/NLC4 sponge enhances the wound healing with no scar and improved tissue quality. These results strongly support the possibility of using this novel chitosan-hyaluronic acid/NLC4 sponge for wound care application., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Salbutamol sulphate (SS) is a model short-acting β2-adrenergic receptor agonist used for the relief of bronchospasm having poor bioavailability (50%) due to its extensive first-pass effect., Objective: Formulation of SS as fast dissolving sublingual films (FDSFs) using a biocompatible and biodegradable Pullulan polymer to bypass its metabolism in liver and offers a fast relieve of asthma., Method: Films were prepared by solvent casting technique adopting 32 factorial design to study the effect of two independent variables namely; polymer type (HPMC E5, Pullulan, and L-HPC) and polymer to Maltodextrin ratio (3:0, 3:1 or 5:1). Films physicomechanical properties, disintegration time and in-vitro dissolution of the prepared formulations were evaluated., Results: Formula F3 containing Pullulan with Maltodextrin in a ratio 3:1 has the least disintegration time (26±2.6 seconds) and the highest dissolution rate (100%±0.5%) after four minutes. Pharmacokinetic study of the optimum formula F3 in healthy human volunteers revealed a shorter tmax (0.75±0.25 hour) compared to Ventolin® tablet 2 mg (2.1±0.37 hour). Clinical evaluation of F3 in 14 male asthmatic patients using ZAN Spirometry showed clinical improvement in lung function parameters when compared with Ventolin® tablets., Conclusion: FDSFs significantly improved the bioavailability of SS and resulted in dramatic improvement in its clinical efficacy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Context: Garlic oil and Eruca oil have been reported to have excellent antimicrobial activity. However, the exact knowledge of their required hydrophilic-lipophilic balance (rHLB) values to facilitate their emulsification are still not reported in the literature., Objective: The objective of this study is to determine rHLB values of Garlic and Eruca oils to formulate an elegant stable cream formulation enriched with both oils., Materials and Methods: Emulsions of both oils were prepared by the bottle method using water, Tween 80 and Span 80. Formulated emulsions were evaluated for creaming index (CI), droplet size, and turbidity to determine rHLB. Utilizing determined rHLB, creams were formulated using a combination of two surfactants, Span 60:Brij 58 (1:2.333) at three different concentrations (2, 4, and 6%)., Results: rHLB of Garlic oil and Eruca oil was determined to be 7.92 ± 0.27 and 9.76 ± 0.32, respectively. Stable cream (F1) developed with 2% surfactant blend showed elegant rheological properties, the best antimicrobial activity against Staphyococcus aureus ATCC29737, Escherichia coli ATCC25299 S. aureus (MRSA), Malassezia fufur AUMC No. 5173 with no skin irritation. In addition, its texture parameters and pH were found to be consistent over 12 months at 25 ± 1 °C and 60% relative humidity., Discussion: The lowest CI, smallest droplet size, and highest turbidity were obtained at the optimum surfactant concentration in the prepared emulsions. Increasing surfactant blend concentration in cream formulations leads to increasing viscosity and consequently decreasing antimicrobial activity., Conclusion: Determination of the rHLB of Garlic and Eruca oils allows the ease of preparation of stable, consistent, and non-irritant cream.

The main objective of this work is to find out whether aluminum (Al) toxicity and Ca depletion cause cell death of tobacco cells via similar sequence of events. Tobacco cell suspension culture exhibited maximum fresh weight in the presence of a wide range of Ca concentrations between 0.1-1.0 mM whereas higher concentrations (>1.0-5.0 mM) gradually lowered cell fresh weight. However, this decrease in fresh weight does not imply a negative impact on cell viability since cell growth recommenced in fresh MS medium with rates mostly higher than those of low Ca. In addition, high Ca seems to be crucial for survival of Al-treated cells. On the other side, tobacco cells exhibited extreme sensitivity to complete deprivation of Ca. Without Ca, cells could not survive for 18 h and substantially lost their growth capability. Evans blue uptake proved membrane damage of Ca-depleted same as Al-treated cells; relative to maintained membrane intactness of calcium-supplemented (control) ones. Percentage of membrane damage and the growth capability (survival) of tobacco cells exhibited a clear negative correlation.Alterations in growth (fresh weight per aliquot) could not be ascribed neither to cell number nor to decreased dry matter allocation (dry weight/fresh weight percentage) but was mainly due to decreased cellular water content. In this context, Ca-depleted cells lost about half their original water content while 100 microM Al-treated ones retained most of it (ca 87%). This represented the single difference between the two treatments (discussed in the text). Nevertheless, such high water content of the Al-treated cells seems physiologically useless since it did not result in improved viability. Similarities, however, included negligible levels of growth capability, maximum levels of membrane damage, and comparable amounts of NO(3) (-) efflux. As well, both types of treatments led to a sharp decline in osmotic potential that is, in turn, needed for water influx. The above-mentioned sequence of events, induced by Al application looks, to a great extent, similar to Ca depletion syndrome leading finally to cell death of tobacco cells.