Hesperidin (Hsd), a bioactive phytomedicine, experienced an antidiabetic activity versus both Type 1 and Type 2 Diabetes mellitus. However, its intrinsic poor solubility and bioavailability is a key challenging obstacle reflecting its oral delivery. From such perspective, the purpose of the current study was to prepare and evaluate Hsd-loaded sulfobutylether-β-cyclodextrin/chitosan nanoparticles (Hsd/CD/CS NPs) for improving the hypoglycemic activity of the orally administered Hsd. Hsd was first complexed with sulfobutylether-β-cyclodextrin (SBE-β-CD) and the complex (CX) was found to be formed with percent complexation efficiency and percent process efficiency of 50.53 ± 1.46 and 84.52 ± 3.16%, respectively. Also, solid state characterization of the complex ensured the inclusion of Hsd inside the cavity of SBE-β-CD. Then, Hsd/CD/CS NPs were prepared using the ionic gelation technique. The prepared NPs were fully characterized to select the most promising one (F1) with a homogenous particle size of 455.7 ± 9.04 nm, a positive zeta potential of + 32.28 ± 1.12 mV, and an entrapment efficiency of 77.46 ± 0.39%. The optimal formula (F1) was subjected to further investigation of in vitro release, ex vivo intestinal permeation, stability, cytotoxicity, and in vivo hypoglycemic activity. The results of the release and permeation studies of F1 manifested a modulated pattern between Hsd and CX. The preferential stability of F1 was observed at 4 ± 1 °C. Also, the biocompatibility of F1 with oral epithelial cell line (OEC) was retained up to a concentration of 100 µg/mL. After oral administration of F1, a noteworthy synergistic hypoglycemic effect was recorded with decreased blood glucose level until the end of the experiment. In conclusion, Hsd/CD/CS NPs could be regarded as a hopeful oral delivery system of Hsd with enhanced antidiabetic activity.

An alternative to oral administration for the delivery of therapeutic substances is the topical route, which frequently has comparable efficacy but may have a better tolerability profile. Gamma scintigraphy is a noninvasive technique that involves the application of radioactive substances to conduct biodistribution studies of therapeutic substances delivered through various routes. Nimesulide (NSD) was radiolabeled with technetium pertechnetate (Technetium99m [99mTc]) and this radiolabeled drug complex (99mTc-NSD) was used to prepare a topical gel formulation. The permeation of the radiolabeled drug from the topical gel was determined by gamma scintigraphy on human volunteers. The region of interest was calculated for the quantification of permeated radiolabeled drugs. This was observed that the mean percentage permeation of 99mTc-NSD was found to be 0.32 ± 0.22 to 36.37 ± 2.86 at 5 and 240 min. It was demonstrated that gamma scintigraphy may be a noninvasive and reliable technique for the determination of drug permeation through topical routes.

Permeation through biomembranes is ubiquitous for drugs to reach their active sites. Asymmetry of the cell plasma membrane (PM) has been described as having an important role in this process. Here we describe the interaction of a homologous series of 7-nitrobenz-2-oxa-1,3-diazol-4-yl (NBD)-labeled amphiphiles (NBD-Cn, n = 4 to 16) with lipid bilayers of different compositions (1-palmitoyl, 2-oleoyl-sn-glycero-3-phosphocholine (POPC):cholesterol (1:1) and palmitoylated sphingomyelin (SpM):cholesterol (6:4)), including an asymmetric bilayer. Both unrestrained and umbrella sampling (US) simulations (at varying distances to the bilayer center) were carried out. The free energy profile of NBD-Cn at different depths in the membrane was obtained from the US simulations. The behavior of the amphiphiles during the permeation process was described regarding their orientation, chain elongation, and H-bonding to lipid and water molecules. Permeability coefficients were also calculated for the different amphiphiles of the series, using the inhomogeneous solubility-diffusion model (ISDM). Quantitative agreement with values obtained from kinetic modeling of the permeation process could not be obtained. However, for the longer, and more hydrophobic amphiphiles, the variation trend along the homologous series was qualitatively better matched by the ISDM when the equilibrium location of each amphiphile was taken as reference (ΔG = 0), compared to the usual choice of bulk water.

P2X7 receptors are ATP-gated ion channels permeable to metal cations, such as Na+, K+, and Ca2+. They also exhibit permeability to various large molecular weight species, reaching up to 900 Da, in a process known as macropore formation, which is a unique functional hallmark across the P2X family. While well-documented in a range of different cell types, the molecular mechanism underlying this phenomenon is poorly understood, and has been clouded through the use of electrophysiological methodology prone to artifacts as a result of significant changes in ionic concentrations in asymmetric conditions. In this chapter, we discuss the permeation properties of P2X7, the related methodological challenges and the use of symmetrical organic cation solutions as a useful technique for probing P2X7 permeation.

The poor solubility and permeability of compounds beyond Lipinski\'s Rule of Five (bRo5) are major challenges for cell-based permeability assays. Due to their incompatibility with gastrointestinal components in biorelevant media, the exploration of important questions addressing food effects is limited. Thus, we established a robust mucin-protected Caco-2 assay to allow the assessment of drug permeation in complex biorelevant media. To do that, the assay conditions were first optimized with dependence of the concentration of porcine mucin added to the cells. Mucin-specific effects on drug permeability were evaluated by analyzing cell permeability values for 15 reference drugs (BCS class I-IV). Secondly, a sigmoidal relationship between mucin-dependent permeability and fraction absorbed in human (fa) was established. A case study with venetoclax (BCS class IV) was performed to investigate the impact of medium complexity and the prandial state on drug permeation. Luminal fluids obtained from the tiny-TIM system showed a higher solubilization capacity for venetoclax, and a better read-out for the drug permeability, as compared to FaSSIF or FeSSIF media. In conclusion, the mucin-protected Caco-2 assay combined with biorelevant media improves the mechanistic understanding of drug permeation and addresses complex biopharmaceutical questions, such as food effects on oral drug absorption.

Both exohedral and endohedral complexes of second row elements doped X12Y12 (X = B, Al and Y = P) nano-cages are evaluated for thermodynamic stabilities, electronic properties and kinetic barriers. Interaction energies are calculated to deeply perceive the stability of these complexes. Further, interconversion of exohedral and endohedral complexes is explored through an unprecedented approach, where 2nd row elements translate into nano-cages through boundary crossing. Subsequently, the kinetic barriers for encapsulation and decapsulation are also investigated through PES scanning of all elements by passing through hexagon of nano-cages. Systematic investigations revealed that due to larger diameter, AlP nanocage exhibits low encapsulation barriers in comparison to BP nano-cage. Such as; the encapsulation barrier of F@AlP (7.57 kcal mol-1) is lower than that of F@BP (129.78 kcal mol-1). Moreover, distortion of nano-cages due to translation of elements is also estimated by distortion energies. Large distortion energies of 113.81/118.39 kcal mol-1 are noticed for exo-B@AlP/exo-C@BP complexes. In addition, the electronic properties for all the complexes are probed and depicted that the endohedral doping have remarkable influence on the electronic properties of the nanocage in comparison to exohedral doping. NBO charge analysis shows that Be metal delivers charges of 0.08 |e|/0.03 |e| to the AlP/BP nanocage, causing the later more electron rich. Contrary to Be, all other doped atoms show negative charges.

Polymeric nanoparticles, which by virtue of their size (1-1000 nm) are able to penetrate even into cells, are attracting increasing interest in the emerging field of nanomedicine, as devices for, e.g., drugs or vaccines delivery. Because of the involved dimensional scale in the nanoparticle/cell membrane interactions, modeling approaches at molecular level are the natural choice in order to understand the impact of nanoparticle formulation on cellular uptake mechanisms. In this work, the passive permeation across cell membrane of oligomers made of two employed polymers in the biomedical field [poly-D,L-lactic acid (PDLA) and poly(3-hydroxydecanoate) (P3HD)] is investigated at fundamental atomic scale through molecular dynamics simulations. The free energy profile related to membrane crossing is computed adopting umbrella sampling. Passive permeation is also investigated using a coarse-grained model with MARTINI force field, adopting well-tempered metadynamics. Simulation results showed that P3HD permeation is favored with respect to PDLA by virtue of its higher hydrophobicity. The free energy profiles obtained at full atomistic and coarse-grained scale are in good agreement each for P3HD, while only a qualitative agreement was obtained for PDLA. Results suggest that a reparameterization of non-bonded interactions of the adopted MARTINI beads for the oligomer is needed in order to obtain a better agreement with more accurate simulations at atomic scale.

The aim of this study was to prepare and evaluate simvastatin (SIM) loaded elastic provesicular systems for effective topical wound management. SIM provesicles were prepared using the non-ionic surfactant Span 40, cholesterol and three edge activators i.e. Span 80, Tween 80 and sodium cholate. The vesicles revealed high SIM encapsulation efficiency ranging from 87.25 to 98.15%, whereas vesicle sizes ranged from 462.3 to 801.5 nm. Vesicle sizes decreased with increasing the concentration of the edge activator. High negative zeta potential values were observed, revealing good stability of the vesicular formulations. The release of SIM from hydrated provesicular carriers was biphasic in nature. The selected SIM provesicular elastic carrier exerted approximately two-fold increase in the amount of SIM permeated through rat skin, compared to the free drug. Evaluation of wound healing activity of the selected provesicular formulation revealed significant reduction in wound size in rats, fourteen days post-wounding. These results were further confirmed by a significant increase in expression of vascular endothelial growth factor and collagen type I compared to the free drug. These results indicate that provesicular carriers could be a promising drug delivery system for encapsulating SIM and enhancing its wound healing efficacy.

This study investigated the effects of drug recrystallization on the in vitro performance of testosterone drug-in-adhesive transdermal delivery system (TDS). Six formulations were prepared with a range of dry drug loading in the adhesive matrix from 1% to 10% w/w with the aim of generating TDS with various levels of drug crystals. We visually quantified the amount of crystals in TDS by polarized light microscopy. The effect of drug recrystallization on adhesion, tackiness, cohesive strength, viscoelasticity, drug release, and drug permeation through human cadaver skin were evaluated for these TDS samples. The Optical images showed no crystals in 1% and 2% testosterone TDSs; however, the amount of crystals increased by increasing testosterone loading from 4 to 10%. A proportional and significant decrease (p < 0.05) in tack, peel, and shear strength of the adhesive matrix with increasing amount of crystals in TDS was observed. The drug crystals resulted in a proportional deterioration of the viscoelastic properties of the adhesive matrix. The 2% testosterone TDS showed faster drug release rate when compared to 1% testosterone TDS. The increase in drug loading from 2% to 4% w/w slightly increased the cumulative amount of testosterone released. Further increase in drug loading in TDS to 6, 8, and 10% was nonsignificant (p > 0.05) to affect the drug release and permeation. In conclusion, this study demonstrated that the extent of drug recrystallization can be quantitatively correlated with the deterioration of performance characteristics of TDS products.

Advanced drug delivery systems (ADDS) are widely explored to overcome poor aqueous solubility of orally administered drugs. However, the prediction of their in vivo performance is challenging, as in vitro models typically do not capture the interplay between processes occurring in the gut. In additions, different models are used to evaluate the different systems. We therefore present a method that allows monitoring of luminal processing (dissolution, digestion) and its interplay with permeation to better inform on the absorption of felodipine formulated as ADDS. Experiments were performed in a µFLUX-apparatus, consisting of two chambers, representing the intestinal and serosal compartment, separated by Caco-2 monolayers. During dissolution-digestion-permeation experiments, ADDS were added to the donor compartment containing simulated intestinal fluid and immobilized lipase. Dissolution and permeation in both compartments were monitored using in situ UV-probes or, when turbidity interfered the measurements, with HPLC analysis. The method showed that all ADDS increased donor and receiver concentrations compared to the condition using crystalline felodipine. A poor correlation between the compartments indicated the need for an serosal compartment to evaluate drug absorption from ADDS. The method enables medium-throughput assessment of: (i) dynamic processes occurring in the small intestine, and (ii) drug concentrations in real-time.