Permeation Kinetics Research Articles

Optimization of hypobaric and ultrasonic processing of persimmon rhamnogalacturonan-I to enhance drug-digestion interactions.

The biological activity of polysaccharides used for nutraceuticals/drug excipients has been a neglected area of study. This work deals with the preparation, optimization, characterization, and evaluation of persimmon (Diospyros kaki Thunb.) fruit by-products and the study of the resultant dietary fiber (DF) interaction with other compounds, using acetaminophen as a model. Processing conditions for persimmon by-products were optimized to enhance antioxidant activity, with hypobaric, ultrasonic, and drying conditions tested at three levels of time and pH. The optimized DF was evaluated through in-vitro and ex-vivo release and permeation studies. Optimal conditions included three cycles of vacuum instantaneous expansion coupled with ultrasound waves (USEX), 42min of ultrasound assisted extraction (UAE), and a pH of 1.5. After treatments, the antioxidant capacity (AC) increased six-fold, and zeta potential (ζ) analysis indicated polysaccharide aggregation at the optimized pH. The optimized polysaccharides, mainly formed by rhamnogalacturonan-I, displayed nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent activity. In-vitro drug-DF interaction studies showed higher acetaminophen release during digestion. Permeation kinetics adhered to the Korsmeyer-Peppas model in both ex-vivo and in-vitro models, suggesting complex permeation mechanisms. Results suggest that the optimized DF enhances the bioavailability and controlled release of acetaminophen, indicating its potential for use in drug delivery systems and nutraceutical applications.

Moment Analysis of Solute Permeation Kinetics at the Interface of Spherical Molecular Aggregates by Using Partial Supplying High- Performance Liquid Chromatography

Moment Analysis of Solute Permeation Kinetics at the Interface of Spherical Molecular Aggregates by Using Partial Supplying High- Performance Liquid Chromatography

In vitro transdermal release of crocin from electrospun saffron and its comparison with in vitro digestion

Saffron extract (SE) was electrospun into pullulan-pectin (Pl-Pc), pullulan-pea protein-pectin (Pl-Pp-Pc), or zein nanofibers (NFs) for transdermal food supplement. The in vitro transdermal permeation mechanism and kinetics of SE from NFs were studied and compared with those of in vitro digestion. The ATR-FTIR spectra of NFs provided information on the interactions between SE and wall biopolymers. The release of SE from NFs was investigated in stimulated gastrointestinal media (SGF and SIF) using a dialysis bag, and transdermal permeation studies were performed via a membrane in a Franz diffusion cell. The wettability and swelling ratio of the NFs were determined. The Pl-Pc-SE sample, which has the lowest contact angle and the highest swelling index, resulted in the highest release of SE during digestion. The Ritger-Peppas and Higuchi models best represented the experimental release data from digestion and transdermal permeation. The release profile of SE from zein NFs in SGF was described using a non-Fickian mechanism. In contrast, the release mechanism for Pl-based NFs in SGF and all NFs during both release experiments was Fickian-controlled diffusion transport. The results indicate that NFs can be successfully used for the controlled delivery of SE and have the potential for transdermal applications as a dietary supplement.

Engineered PVA-tamarind gum-based biocomposite for sustained ophthalmic delivery of moxifloxacin: Effect of nanocellulose on physicochemical, mechanoelectrical and permeation kinetics

Widely used polysaccharide-based films in ophthalmic drug delivery have major limitations of inadequate mechanical strength, poor electrical conductivity, and insufficient ocular drug permeability. Moxifloxacin (MFX) biocomposite film of adequate mechanoelectrical properties was developed for sustained ophthalmic drug delivery. Nanocellulose (NC) incorporated (2.5, 5.0, 7.5, and 10.0 %) PVA-tamarind gum-based moxifloxacin composite was prepared using solvent casting method. The addition of NC improved the mechanical properties of the film, demonstrating its ability to strengthen the structure. Stress relaxation (SR) of the film has been augmented (64.67±7.55 to 73.15±0.34 %) due to increased content of NC (0 to 10 %) respectively. Film containing 5 % NC showed the critical edge of tensile strength (11.9±0.39 MPa), and also the threshold limit of electrical conductivity (4.5*107 Ω). The same film exhibited continued drug release as well as erosion-controlled sustained ocular permeation (pH 7.4) and revealed the highest antibacterial activity (ZOI of disc diffusion, cm) with Pseudomonas aeruginosa (4.63±0.15) and Staphylococcus aureus (4.30±0.26) of MFX (≈224 μg). Notably, incorporating NC produced non-irritating and safe for corneal delivery as confirmed by the Draize model test. Our findings suggested that the NC-containing PVA-tamarind gum-based composite film holds a promising approach for sustained ophthalmic delivery of MFX.

Moment analysis method for the determination of permeation kinetics of coumarin at lipid bilayers of liposomes by using capillary electrophoresis.

A method was developed for studying mass transfer kinetics at lipid bilayers of liposomes. Elution peaks of coumarin were measured by liposome electrokinetic chromatography (LEKC). Four types of phospholipids having different alkyl chains were used for preparing liposomes, which were used as pseudo-stationary phases in LEKC systems. Rate constants of permeation across lipid bilayers of liposomes or of adsorption at lipid membranes were determined by analyzing the first absolute and second central moments of the elution peaks measured by LEKC. The rate constants of permeation or adsorption tend to decrease with an increase in the carbon number of the alkyl chains of phospholipids. It was demonstrated that the moment analysis of elution peak profiles measured by LEKC is effective for determining lipid membrane permeability or adsorption kinetics. Compared with other conventional techniques, the method has some advantages for studying mass transfer kinetics at lipid bilayers. Solute permeation across or solute adsorption at real lipid bilayers of liposomes is analyzed. The principle of the method is the analysis of separation behavior in LEKC, which is different from that of the other ones. It is expected that the method contributes to the kinetic study of mass transfer at lipid bilayers from various perspectives.

Quantifying skin permeation of a novel metformin lotion using modified hydrophilic interaction liquid chromatography.

Aim: This study aimed to quantify the permeation of metformin (Met) lotion through pig ear skin using high-performance liquid chromatography, specifically hydrophilic interaction liquid chromatography (HILIC), to separate Met from biological contaminants and effectively measure its permeation through skin similar to human skin.Materials & methods: A Franz cell permeation assay was used to assess the permeation kinetics of 6% Met lotion through pig ear skin. Samples were collected at various time points and prepared for high-performance liquid chromatography analysis by removing large biological contaminants. The permeated Met was quantified by monitoring its retention time (RT) at 9min using HILIC, with an acidic, polar mobile phase and a normal-phase column.Results: A distinct Met peak with a RT of approximately 9min was observed in the 6% Met lotion, which was absent in the permeation samples from the 0% Met lotion. This peak (RT 9min) was distinct from the 'biological-contaminants' peaks at RT 2-3min and increased linearly over time, reaching 36.8% of the total applied Met at 24h.Conclusion: These findings demonstrate that the HILIC method effectively separates Met from biological components in pig ear skin, allowing accurate quantification of Met despite the presence of skin lipids and proteins.

An advanced in silico model of the oral mucosa reveals the impact of extracellular spaces on chemical permeation

Accurately predicting the permeation of chemicals through human epithelial tissues is crucial for pharmaceutical therapeutic design and toxicology. Current mathematical models of multi-layered stratified squamous epithelium such as those in the oral cavity use simplistic ‘bricks and mortar’ geometries that do not fully account for the complex cellular architecture that may affect chemical permeation in these tissues. Here we aimed to develop a new, advanced mechanistic mathematical model of the human epithelium that more accurately represents chemical tissue permeation. Using measurements of cell size and tortuosity from micrograph images of both human oral (buccal) and tissue-engineered buccal mucosa along with mechanistic mathematical modelling, we show that the convoluted geometry of the extracellular spaces within the epithelium significantly impacts chemical permeation. We next developed an advanced histologically and physiologically-relevant in silico model of buccal mucosal chemical permeation using partial differential equations, fitted to chemical permeation from in vitro assay data derived from tissue-engineered buccal mucosal models and chemicals with known physiochemical properties. Our novel in silico model can predict epithelial permeation kinetics for chemicals with different physicochemical properties in the absence or presence of permeability enhancers. This in vitro − in silico approach constitutes a step-change in the modelling of chemical tissue permeation and has the potential to expedite pharmaceutical innovation by improved and more rapid screening of chemical entities whilst reducing the need for in vivo animal experiments.

Growth Phase Contribution in Dictating Drug Transport and Subcellular Accumulation inside Escherichia coli.

Depending upon nutrient availability, bacteria transit to multiple growth phases. The transition from the active to nongrowing phase results in reduced drug efficacy and, in some cases, even multidrug resistance. However, due to multiple alterations in the cell envelope, probing the drug permeation kinetics during growth phases becomes perplexing, especially across the Gram-negative bacteria's complex dual membrane envelope. To advance the understanding of drug permeation during the life cycle of Gram-negative bacteria, we sought to address two underlying objectives: (a) how changes are occurring inside the bacterial envelope during growth and (b) how the drug permeation and accumulation vary across both the membranes and in subcellular compartments during growth. Both objectives are met with the help of nonlinear optical technique second-harmonic generation spectroscopy (SHG). Specifically, using SHG, we probed the transport kinetics and accumulation of a quaternary ammonium compound (QAC), malachite green, inside Escherichia coli in various growth phases. Further insight about another QAC molecule, propidium iodide, is accomplished using fluorescence microscopy. Results indicate that actively growing cells have faster drug transport and higher cytoplasmic accumulation than slow- or nongrowing cells. In this regard, the rpoS gene plays a crucial role in limiting drug transport across the saturation phase cultures. Moreover, within a particular growth phase, membrane permeability undergoes gradual changes much before the subsequent growth phase commences. These outcomes signify the importance of reporting the growth phase and rate in drug efficacy studies.

Skin deposition and permeation kinetics of cannabidiol and delta-9-tetrahydrocannabinol from cannabis extract containing gels

The study aimed to investigate the deposition and permeation characteristics of phytocannabinoids, namely delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), from cannabis extract containing gels. Cannabis extract with 26.3 % CBD and 28.4 % THC was used. The impact of permeation enhancers, namely propylene glycol, diethylene glycol monoethyl ether (DEGEE), ethanol (EtOH), and terpenes (eucalyptol and menthol), was examined. All cannabis extract gels had a pH range of 6.71–6.81 and a viscosity range of 456.6–4068.7 mPa⋅s. The phytocannabinoid release from the gels followed Zero-order kinetics with a rate of 14.5–25.7 μg⋅h−1 for CBD and 10.0−22.6 μg⋅h−1 for THC. A gel containing 12.5 % DEGEE and 12.5 % EtOH exhibited the highest release rate. The initial skin deposition followed Zero-order kinetics and reached a maximum level after 4 h. Permeation of phytocannabinoids closely followed Higuchi kinetics, with a rate of 0.14–54.21 μg⋅h−1/2 for CBD and 0.23−67.02 μg⋅h−1/2 for THC. A gel containing 25 % DEGEE and 25 % EtOH exhibited the highest apparent skin partition coefficient (K) value, resulting in the greatest phytocannabinoid deposition and permeation. Terpene introduction (5 %) significantly reduced the release rate, K value, and total skin absorption of phytocannabinoids. These findings offer useful insights into selecting the appropriate vehicle for cannabis extract topical products.

Characterization of The Permeation Properties of Membrane Filters and Sorption Properties of Sorbents Used for Polar Organic Chemical Integrative Samplers.

Polar organic chemical integrative samplers (POCIS) are promising devices for measuring the time-weighted average concentrations of hydrophilic compounds in aquatic environments. However, the mechanisms underlying compound uptake by POCIS remain unclear. We investigated the permeation kinetics of polyethersulfone and polytetrafluoroethylene membrane filters, and the sorption kinetics of Oasis HLB (Waters), Envi-Carb (Supelco), and Oasis WAX (Waters) sorbents. The log octanol-water partition coefficient (KOW) values of the 19 targeted compounds ranged from -0.55 to 6.0. The overall mass-transfer coefficients were negatively correlated with KOW, indicating that interactions between hydrophobic compounds and the membrane inhibit permeation. The sorption rate coefficient showed no correlation with KOW and depended on the type of sorbent used. These results imply that the uptake of highly hydrophilic compounds by POCIS is determined by both the membrane and the sorbent kinetics; however, membrane kinetics dominate the uptake of hydrophobic compounds. Environ Toxicol Chem 2024;43:2115-2121. © 2024 SETAC.

Quantitative Study on Hydrogen Concentration–Hydrogen Embrittlement Sensitivity of X80 Pipeline Steel Based on Hydrogen Permeation Kinetics

Quantitative Study on Hydrogen Concentration–Hydrogen Embrittlement Sensitivity of X80 Pipeline Steel Based on Hydrogen Permeation Kinetics

Polycyclic aromatic hydrocarbon skin permeation efficiency in vitro is lower through human than pigskin and decreases with lipophilicity

Polycyclic aromatic hydrocarbons (PAH) are persistent environmental pollutants, which occasionally appear as contaminants in consumer products. Upon dermal contact, transfer of PAH into the stratum corneum (s.c.) and migration through the skin may occur, resulting in this class of highly toxic compounds to become bioavailable. In this study, dermal penetration through human and porcine skin of 24 PAH, comprising broad molar mass (M: 152–302 g/mol) and octanol-water partition coefficient (logP: 3.9–7.3) ranges, was evaluated via Franz diffusion cell in vitro assays. More lipophilic and potentially more toxic PAH had decreased permeation rates through the rather lipophilic s.c. into the more hydrophilic viable (epi-)dermis. Furthermore, human skin was less permeable than pigskin, a commonly used surrogate in skin penetration studies. In particular, the s.c. of human skin retains a greater share of PAH, an effect that is more pronounced for smaller PAH. Additionally, we compared the skin permeation kinetics of different PAH in pigskin. While small PAH (M < 230 g/mol, logP < 6) permeate the skin quickly and are detected in the receptor fluid after 2 h, large PAH (M > 252 g/mol, logP ≥ 6) do not fully permeate the skin up to 48 h. This indicates that highly lipophilic PAH do not become bioavailable as readily as their smaller congeners when transferred to the skin surface. Our data suggest that pigskin could be used as a surrogate for worst case scenario estimates of dermal PAH permeation through human skin.

Nanosuspension-Loaded Dissolving Microneedle Patches for Enhanced Transdermal Delivery of a Highly Lipophilic Cannabidiol.

Transdermal Drug Delivery System (TDDS) offers a promising alternative for delivering poorly soluble drugs, challenged by the stratum corneum's barrier effect, which restricts the pool of drug candidates suitable for TDDS. This study aims to establish a delivery platform specifically for highly lipophilic drugs requiring high doses (log P > 5, dose > 10 mg/kg/d), to improve their intradermal delivery and enhance solubility. Cannabidiol (CBD, log P = 5.91) served as the model drug. A CBD nanosuspension (CBD-NS) was prepared using a bottom-up method. The particle size, polydispersity index (PDI), zeta potential, and concentration of the CBD-NS were characterized. Subsequently, CBD-NS was incorporated into dissolving microneedles (DMNs) through a one-step manufacturing process. The intradermal dissolution abilities, physicochemical properties, mechanical strength, insertion depth, and release behavior of the DMNs were evaluated. Sprague-Dawley (SD) rats were utilized to assess the efficacy of the DMN patch in treating knee synovitis and to analyze its skin permeation kinetics and pharmacokinetic performance. The CBD-NS, stabilized with Tween 80, exhibited a particle size of 166.83 ± 3.33 nm, a PDI of 0.21 ± 0.07, and a concentration of 46.11 ± 0.52 mg/mL. The DMN loaded with CBD-NS demonstrated favorable intradermal dissolution and mechanical properties. It effectively increased the delivery of CBD into the skin, extended the action's duration in vivo, and enhanced bioavailability. CBD-NS DMN exhibited superior therapeutic efficacy and safety in a rat model of knee synovitis, significantly inhibiting TNF-α and IL-1β compared with the methotrexate subcutaneous injection method. NS technology effectively enhances the solubility of the poorly soluble drug CBD, while DMN facilitates penetration, extends the duration of action in vivo, and improves bioavailability. Furthermore, CBD has shown promising therapeutic outcomes in treating knee synovitis. This innovative drug delivery system is expected to offer a more efficient solution for the administration of highly lipophilic drugs akin to CBD, thereby facilitating high-dose administration.

Energetics and Kinetics of Membrane Permeation of Photoresists for Bioprinting

Abstract3D bioprinting is a promising technology which typically uses bioinks to pattern cells and their scaffolds. The selection of cytocompatible inks is critical for the printing success. In laser‐based 3D bioprinting, photoresist molecules are used as bioinks. However, the interaction of photoresists with lipid membranes and their permeation into the cell remains poorly understood. Here, molecular dynamics simulations and in vitro assays address this issue, retrieving partition coefficients, free energies, and permeabilities for twelve commonly used photoresists in model lipid bilayers. Crossing the hydrophobic center of the membrane constitutes the rate limiting step during permeation. In addition, three photoresists feature a preferential localization site at the acyl chain head group interface. Photoresist permeabilities range over ten orders of magnitude, with some molecules being membrane‐permeable on bioprinting timescales. Moreover, permeation correlates well with the oil–water partition coefficients and is severely hampered by the lipid ordering imposed by the lipid saturation. Overall, the mechanism of interaction of photoresists with model lipid bilayers is provided here, helping to classify them according to their residence in the membrane and permeation through it. This is useful information which will help guide the selection of cytocompatible photoresists for 3D bioprinting.

Controlled delivery of mupirocin using chitosan films with silver nanoparticles

Wound healing remains a challenge due to the proliferation of resistant microorganisms caused by burns, chronic illnesses, trauma, and post-surgery wounds. One treatment option is the use of topical antibiotics, such as mupirocin. To this end, we developed polymeric hydrogel films composed of chitosan cross-linked with epichlorohydrin and containing silver nanoparticles. These films serve as a matrix for the controlled delivery of mupirocin. The obtained results indicate that the films are promising for the development of controlled delivery systems for mupirocin. They exhibited favorable permeation kinetics, swelling capacity, uniformity, and antibacterial activity. However, of the films studied, the one containing silver nanoparticles obtained using sodium borohydride showed the best results in terms of antibacterial activity. Therefore, it has greater clinical potential for wound healing.

Brain Targeted Drug Delivery System of Carmustine: Design, Development, Characterization, in vitro, ex vivo Evaluation and in vivo Pharmacokinetic Study

The treatment of gliomas remains difficult task. Carmustine is a drug that is used in the treatment of gliomas. Flexible liposomes embedded in situ thermoreversible nasal gel preparations of Carmustine were studied for in vitro carmustine release, ex vivo carmustine permeation and carmustine release kinetics. The epithelial layers of nasal tissue were found to be intact and undamaged during histological analysis. Intranasal administration of optimized flexible liposomes embedded in a nasal gel showed higher Cmax (Approximately two-fold), AUC0→t (Approximately three-fold), AUC0→∞ (Approximately six-fold), and lower Tmax (1 h) in the brain, compared to intravenous injection of carmustine. The present study demonstrates that the flexible liposome embedded thermoreversible in situ intranasal gel of carmustine improved the targeted uptake of carmustine in the brain through the nasal delivery system and could be a reliable and effective delivery system for carmustine in the treatment of gliomas.

Interaction of anionic Fe3O4 nanoparticles with lipid vesicles: a review on deformation and poration under various conditions.

This review focuses on the deformation and poration of lipid vesicles caused by the interaction of anionic magnetite nanoparticles (MNPs). Effects of various factors, such as surface charge density, salt and sugar concentrations in buffer, membrane cholesterol content, polymer-grafted phospholipid, and membrane potential have been discussed for the interaction of MNPs with lipid vesicles. To quantify these effects on the vesicles, compactness, fraction of deformation and poration, dynamics of membrane permeation, and kinetics of membrane permeation have been critically evaluated. The review explores the potential advancements as well as future directions of the research field in the biomedical application of MNPs.

Theoretical analysis of secondary shelf life: Interactive relationship with package opening time and food quality degradation rate shift

Simple dimensionless formula was mathematically derived to relate secondary shelf life (SSL) of packaged foods to package opening time (POT) and food quality deterioration rate shift (k2/k1) thereafter. Their primary shelf life (PSL) was assumed to be time period to reach a critical limit of acceptability in the intact packaged state. A formula universally applicable for first order, zero order, exponential autoxidation and moisture permeation kinetics could be formulated: SSL/PSL=(1-POT/PSL)/(k2/k1). The model formula was verified by mathematical simulation for typical conditions of kinetic parameters and quality limits. Its implication and limitation were discussed in perspective of practical applicability keeping in mind the supposed hypotheses. Overview on the nature of SSL as function of POT and k2/k1 shows that the latter influences SSL dominantly, and keeping it low after package opening, desirably below 5, is essential to ensure substantially long SSL. The formulated model can be useful to provide guideline of package opening and SSL in shelf life management including marketing and consumer use of the packaged foods.

Predicting nanocarrier permeation across the human intestine in vitro: model matters.

For clinical translation of oral nanocarriers, simulation of the intestinal microenvironment during in vitro testing is crucial to evaluate interactions with the intestinal mucosa. However, studies are often conducted using simplistic cell culture models, overlooking key physiological factors, and potentially leading to an overestimation of nanocarrier permeation. In this study, we systematically investigate different tissue models of the human intestine under static cultivation and dynamic flow conditions and analyze the impact of altered tissue characteristics on nanocarrier permeation. Our results reveal that the selection of cell types as well as the respective culture condition have a notable impact on the physiological characteristics of the resulting tissues. Tissue layer thickness, mucus secretion, and barrier impairment, all increase with increasing amounts of goblet cells and the application of dynamic flow conditions. Permeation studies with poly(lactic-co-glycolic acid) (PLGA) nanocarriers with and without polyethylene glycol (PEG) coating elucidate that the amount of mucus present in the respective model is the limiting factor for the permeation of PLGA nanocarriers, while tissue topography presents the key factor influencing PEG-PLGA nanocarrier permeation. Furthermore, both nanocarriers exhibit diametrically opposite permeation kinetics compared to soluble compounds. In summary, these findings reveal the critical role of the implemented test systems on permeation assessment and emphasize that, in the context of preclinical nanocarrier testing, the choice of in vitro model matters.

Evaluation of the passive permeability of antidepressants through pore-suspended lipid bilayer

HypothesisThe antidepressant drug imipramine, and its metabolite desipramine show different extents of interaction with, and passive permeation through, cellular membrane models, with the effects depending on the membrane composition. Through multimodal interrogation, we can observe that the drugs have a direct impact on the physicochemical properties of the membrane, that may play a role in their pharmacokinetics. ExperimentsMicrocavity pore-suspended lipid bilayers (MSLBs) of four different compositions, each with a different headgroup charge namely; zwitterionic dioleoylphosphatidylcholine (DOPC), mixed DOPC and negatively charged dioleoylphosphatidylglycerol (DOPG) (3:1), mixed DOPC and positively charged dioleoyltrimethylammoniumpropane (DOTAP) (3:1), and with increasing complex composition mimicking blood-brain-barrier (BBB) were prepared on gold and polydimethylsiloxane (PDMS) substrates using a Langmuir-Blodgett-vesicle fusion method. The molecular interaction and permeation of antidepressants, imipramine, and its metabolite desipramine with the lipid bilayers were evaluated using highly sensitive label-free electrochemical impedance spectroscopy (EIS) and surface-enhanced Raman spectroscopy (SERS). Drug-induced membrane packing/fluidity alterations were assessed using fluorescence lifetime imaging (FLIM) and fluorescence lifetime correlation spectroscopy (FLCS) of MSLB over microfluidic PDMS array. FindingsUsing EIS to evaluate in real-time membrane admittance changes, we found that imipramine greatly increases the ion permeability of negatively charged DOPC:DOPG (3:1) membranes. The effect was observed also at neutral (DOPC) and to a lesser extent at positively charged DOPC:DOTAP(3:1) membranes. In contrast, desipramine had a much weaker impact on ion permeability across all bilayer compositions. Temporal capacitance data show that desipramine intercalates at negatively charged membrane thereby increasing the thickness of the membrane. The overall kinetics of the imipramine permeation is higher than that of desipramine. This was confirmed using SERS, which also provides an evaluation of drug passive permeation based on arrival time across the membrane. Using FLCS, we found that imipramine increases the lipid membrane fluidity, whereas desipramine lowers it, with the exception of the negatively charged membrane. A translocation rate pharmacokinetics model was established for the first time at the MSLB platform by real-time monitoring of the variation in membrane resistance of pristine DOPC and blood-brain-barrier (BBB) membrane.