A study of hydrophobic domain formation of polymeric drug precipitation inhibitors in aqueous solution.

Despite the widespread use of polymers as precipitation inhibitors in supersaturating drug formulations, the current understanding of their mechanisms of action is still incomplete. Specifically, the role of hydrophobic drug interactions with polymers by considering possible supramolecular conformations in aqueous dispersion is an interesting topic. Accordingly, this study investigated the tendency of polymers to create hydrophobic domains, where lipophilic compounds may nest to support drug solubilisation and supersaturation. Fluorescence spectroscopy with the environment-sensitive probe pyrene was compared with atomistic molecular dynamics simulations of the model drug fenofibrate (FENO). Subsequently, kinetic drug supersaturation and thermodynamic solubility experiments were conducted. As a result, the different polymers showed hydrophobic domain formation to a varying degree and the molecular simulations supported interpretation of fluorescence spectroscopy data. Molecular insights were gained into the conformational structure of how the polymers interacted with FENO in solution phase, which apart from nucleation and crystal growth effects, determined drug concentrations in solution. Notable was that even at the lowest polymer concentration of 0.01 %, w/v, there were polymer-specific solubilisation effects of FENO observed and the resulting reduction in apparent drug supersaturation provided relevant knowledge both from a mechanistic and practical perspective.

Investigation of the solubility and thermodynamics of salicylic acid in 2-propanol and ethylene glycol/propylene glycol binary solvent mixtures at (293.15 to 313.15) K.

This study aimed to measure both the solubility and thermodynamics of salicylic acid in binary solvent mixtures of (2-propanol + ethylene glycol) and (2-propanol + propylene glycol) at different temperatures in the range of 293.2-313.2 K. The experimental solubility data were analyzed using various linear and nonlinear cosolvency models, such as the van'tt Hoff, Jouyban-Acree, Jouyban-Acree-van'tt Hoff, mixture response surface and modified Wilson models and to evaluate the models, the mean relative deviations of the back-calculated solubility data were compared with experimental values. Through this analysis, the apparent thermodynamic parameters, including Gibbs energy, enthalpy, and entropy were calculated using the van'tt Hoff and Gibbs equations for this system. Additionally, the density values for salicylic acid saturated mixtures were also measured and represent mathematically using the Jouyban-Acree model.

Electromagnetic drop-on-demand (DoD) technology as an innovative platform for amorphous solid dispersion production.

Production of amorphous solid dispersions (ASDs) is an effective strategy to promote the solubility and bioavailability of poorly water soluble medicinal substances. In general, ASD is manufactured using a variety of classic and modern techniques, most of which rely on either melting or solvent evaporation. This proof-of-concept study is the first ever to introduce electromagnetic drop-on-demand (DoD) technique as an alternative solvent evaporation-based method for producing ASDs. Herein 3D printing of ASDs for three drug-polymer combinations (efavirenz-Eudragit L100-55, lumefantrine-hydroxypropyl methylcellulose acetate succinate, and favipiravir-polyacrylic acid) was investigated to ascertain the reliability of this technique. Polarized light microscopy, differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and Fourier Transform  Infrared (FTIR) spectroscopy results supported the formation of ASDs for the three drugs by means of DoD 3D printing, which significantly increases the equilibrium solubility of efavirenz from 0.03 ± 0.04 µg/ml to 21.18 ± 4.20 µg/ml, and the equilibrium solubility of lumefantrine from 1.26 ± 1.60 µg/ml to 20.21 ± 6.91 µg/ml. Overall, the reported findings show how this new electromagnetic DoD technology can have a potential to become a cutting-edge 3D printing solvent-evaporation technique for on-demand and continuous manufacturing of ASDs for a variety of drugs.

Effect of polymerisation protocols on water sorption, solubility and hygroscopic expansion of fast-cure bulk-fill composite.

OBJECTIVE: This study examines the effect of two light-curing protocols from a LED polywave light curing unit (LCU) on water sorption, solubility, and hygroscopic expansion of fast and conventional bulk-fill resin-based composites (RBCs) aged in distilled water for 120 d. METHODS: Three bulk-fill RBCs materials were studied: Tetric PowerFill® (fast photo-polymerised composite) (TPF), Tetric EvoCeram bulk-fill (EVO), and GrandioSo x-tra bulk-fill (GSO) (conventional photo-polymerised composites). Specimens were prepared within a 3D-printed resin mold (8-mm diameter x 4-mm height) and light-cured from one side only with 2 modes of polywave LCU (Bluephase® PowerCure): 3 s mode and for 20 s in "Standard" mode. Water sorption and solubility were measured at fixed time intervals for 120 d of distilled water storage, then reconditioned to dry to measure desorption for 75 d, all at 37 ± 1 °C. Hygroscopic (volumetric) expansion was recorded at the same time intervals up to 120 d. Data were analysed through SPSS using Two-way ANOVA, One-way ANOVA, independent t-tests, and Tukey's post-hoc correction tests (p < 0.05). RESULTS: TPF, when irradiated for 3 s demonstrated minimal water sorption (0.83%), solubility (1.01 µg/mm3), and least volumetric expansion (1.64%) compared to EVO and GSO. While EVO showed the highest water sorption (1.03%) and solubility (1.95 µg/mm3) at 3 s. GSO had the lowest sorption (0.67%) and (0.56%) in 3 s and 20 s protocols, respectively. Nevertheless, all the sorption and solubility data were within the ISO 4049 limits. SIGNIFICANCE: For TPF, fast (3 s) polymerisation did not increase either water sorption or solubility, compared with 20 s irradiation. However, with the two comparative bulk-fill composites, fast cure increased water sorption by 15-25% and more than doubled solubility. These findings were consistent with the lesser volumetric expansions observed for Tetric PowerFill at both the fast and standard protocols, indicating its relative stability across polymerisation protocols.

Advances in Nanotechnology for Enhancing the Solubility and Bioavailability of Poorly Soluble Drugs.

This manuscript offers a comprehensive overview of nanotechnology's impact on the solubility and bioavailability of poorly soluble drugs, with a focus on BCS Class II and IV drugs. We explore various nanoscale drug delivery systems (NDDSs), including lipid-based, polymer-based, nanoemulsions, nanogels, and inorganic carriers. These systems offer improved drug efficacy, targeting, and reduced side effects. Emphasizing the crucial role of nanoparticle size and surface modifications, the review discusses the advancements in NDDSs for enhanced therapeutic outcomes. Challenges such as production cost and safety are acknowledged, yet the potential of NDDSs in transforming drug delivery methods is highlighted. This contribution underscores the importance of nanotechnology in pharmaceutical engineering, suggesting it as a significant advancement for medical applications and patient care.

Automated optimization of the solubility of a hyper-stable α-amylase.

Most successes in computational protein engineering to date have focused on enhancing one biophysical trait, while multi-trait optimization remains a challenge. Different biophysical properties are often conflicting, as mutations that improve one tend to worsen the others. In this study, we explored the potential of an automated computational design strategy, called CamSol Combination, to optimize solubility and stability of enzymes without affecting their activity. Specifically, we focus on Bacillus licheniformis α-amylase (BLA), a hyper-stable enzyme that finds diverse application in industry and biotechnology. We validate the computational predictions by producing 10 BLA variants, including the wild-type (WT) and three designed models harbouring between 6 and 8 mutations each. Our results show that all three models have substantially improved relative solubility over the WT, unaffected catalytic rate and retained hyper-stability, supporting the algorithm's capacity to optimize enzymes. High stability and solubility embody enzymes with superior resilience to chemical and physical stresses, enhance manufacturability and allow for high-concentration formulations characterized by extended shelf lives. This ability to readily optimize solubility and stability of enzymes will enable the rapid and reliable generation of highly robust and versatile reagents, poised to contribute to advancements in diverse scientific and industrial domains.

How to describe the time-dependent dissolution of engineered nanomaterials?

Numerous processes such as solubility, agglomeration/aggregation, or protein corona formation may change over time and significantly affect engineered nanomaterial (ENM) structure, property, and availability, resulting in their reduced or increased toxicological activity. Therefore, understanding the dynamics of these processes is essential for assessing and managing the risks of ENMs during their lifecycle, ensuring safety by design. Of these processes, the importance of solubility (i.e., the ability to release ions from the surface) is undeniable. Thus, we propose a practical approach, the Kalapus equation (KEq), to determine ENMs' dissolution over time. As a proof-of-concept, the KEq was applied to determine the solubility of six commercially used metal and metal oxide nanoparticles over time. The KEq exhibited a higher coefficient of determination (R2 = 0.995-0.999) than the logarithmic equation (R2 = 0.835-0.986), and the pseudo-first-order equation (R2 = 0.915-0.994) over a range of experimental data. The newly introduced Kalapus equation outperformed the logarithmic and pseudo-first-order equations when extrapolating beyond the time range in which solubility was experimentally determined. The mean absolute error in solubility prediction for the KEq was 3.29 % and 4.28 % for the first and second data points, respectively, significantly lower than the 13.46 % and 18.05 % observed for the pseudo-first-order/first-order equation. The proposed equation can be used as a part of New Generation Risk Assessment (NGRA) methodology, especially new Integrated Approaches to Testing and Assessments (IATAs).

Nanosuspensions in ophthalmology: Overcoming challenges and enhancing drug delivery for eye diseases.

This review article provides a comprehensive overview of the advancements in using nanosuspensions for controlled drug delivery in ophthalmology. It highlights the significance of ophthalmic drug delivery due to the prevalence of eye diseases and delves into various aspects of this field. The article explores molecular mechanisms, drugs used, and physiological factors affecting drug absorption. It also addresses challenges in treating both anterior and posterior eye segments and investigates the role of mucus in obstructing micro- and nanosuspensions. Nanosuspensions are presented as a promising approach to enhance drug solubility and absorption, covering formulation, stability, properties, and functionalization. The review discusses the pros and cons of using nanosuspensions for ocular drug delivery and covers their structure, preparation, characterization, and applications. Several graphical representations illustrate their role in treating various eye conditions. Specific drug categories like anti-inflammatory drugs, antihistamines, glucocorticoids, and more are discussed in detail, with relevant studies. The article also addresses current challenges and future directions, emphasizing the need for improved nanosuspension stability and exploring potential technologies. In conclusion, nanosuspensions have substantial potential in advancing ophthalmic drug delivery by enhancing solubility and absorption. This article is a valuable resource for researchers, clinicians, and pharmaceutical professionals in this field, offering insights into recent developments, challenges, and future prospects in nanosuspension use for ocular drug delivery.

Choice of medium affects PBMC quantification, cell size, and downstream respiratory analysis.

High-resolution respirometry (HRR) can assess peripheral blood mononuclear cell (PBMC) bioenergetics, but no standardized medium for PBMC preparation and HRR analysis exist. Here, we study the effect of four different media (MiR05, PBS, RPMI, Plasmax) on the count, size, and HRR analysis (Oxygraph-O2k) of intact PBMCs. Remarkably, the cell count was 21 % higher when PBMCs were resuspended in MiR05 than in PBS or Plasmax, causing O2 flux underestimation during HRR due to inherent adjustments. Moreover, smaller cell size and cell aggregation was observed in MiR05. Based on our findings, we propose that Plasmax, PBS or RPMI is more suitable than MiR05 for HRR analysis of intact PBMCs. We provide oxygen solubility factors for Plasmax and PBS and encourage further optimization of a standardized HRR protocol for intact PBMCs.

Efficient production of human interleukin-3 from Escherichia coli using protein disulfide isomerase b'a' domain.

Human interleukin-3 (IL3) is a multifunctional cytokine essential for both clinical and biomedical research endeavors. However, its production in Escherichia coli has historically been challenging due to its aggregation into inclusion bodies, requiring intricate solubilization and refolding procedures. This study introduces an innovative approach employing two chaperone proteins, maltose binding protein (MBP) and protein disulfide isomerase b'a' domain (PDIb'a'), as N-terminal fusion tags. Histidine tag (H) was added at the beginning of each chaperone protein gene for easy purification. This fusion of chaperone proteins significantly improved IL3 solubility across various E. coli strains and temperature conditions, eliminating the need for laborious refolding procedures. Following expression optimization, H-PDIb'a'-IL3 was purified using two chromatographic methods, and the subsequent removal of the H-PDIb'a' tag yielded high-purity IL3. The identity of the purified protein was confirmed through liquid chromatography coupled with tandem mass spectrometry analysis. Biological activity assays using human erythroleukemia TF-1 cells revealed a unique two-step stimulation pattern for both purified IL3 and the H-PDIb'a'-IL3 fusion protein, underscoring the protein's functional integrity and revealing novel insights into its cellular interactions. This study advances the understanding of IL3 expression and activity while introducing novel considerations for protein fusion strategies.

Enhancement of Mechanical Properties of High-Thermal-Conductivity Composites Comprising Boron Nitride and Poly(methyl methacrylate) Resin through Material Design Utilizing Hansen Solubility Parameters.

Materials for heat sinks in automotive heat dissipation systems must demonstrate both high thermal conductivity and stress resistance during assembly. This research proposes a composite material, comprised of thermally conductive ceramic fillers and matrix resins, as a suitable option for such application. The strategy for designing this material interface is directed with Hansen solubility parameters (HSP). A composite material featuring a honeycomb-like structure made of poly(methyl methacrylate) (PMMA) and boron nitride (BN) particles was successfully fabricated through press molding. This yielded a continuous BN network exhibiting high thermal conductivity and moderate mechanical strength. The HSP evaluation led to the suggestion of introducing highly polar functional groups into the matrix resin to enhance the affinity between PMMA resin and BN fillers. In line with this recommendation, a nitrile (CN) group─a highly polar group─was introduced to PMMA (CN-PMMA), significantly enhancing the composite's maximum bending stress without noticeably degrading other properties. Surface HSP evaluation through contact angle measurements revealed an "interface enrichment effect", with the CN groups concentrating at the resin-filler interface and effectively interacting with the surface functional groups on the BN particles, which resulted in an increase in the maximum bending stress. These findings emphasize the advantage of employing HSP methodologies in designing high-performance composite materials.

Plant polysaccharide-derived edible film packaging for instant food: Rapid dissolution in hot water coupled with exceptional mechanical and barrier characteristics.

A comprehensive multiscale analysis was conducted to explore the effects of different ratios of these materials on its properties. The results show that KC played a crucial role in controlling solution viscosity and gel and sol temperatures. The dissolution time at high water temperatures primarily decreased with an increase in SA content. Higher KC and CS content increased tensile strength (TS) and elongation at break (ε), while also exhibiting better thermal stability. Water vapor transmission (WVT) and permeability (PV) initially decreased, then increased with the increase of SA and CS contents. Finally, an SA:KC:CS ratio of 1:3:2 showed optimal comprehensive properties, with a dissolution time of about 60.0 ± 3.8 s, TS of 23.80 ± 0.29 MPa, ε of 18.61 ± 0.34 %, WVT of 21.74 ± 0.62 g/m2·24h, and PV of 5.39 ± 0.17 meq/kg. Meanwhile, the SA:KC:CS edible food packaging only introduced minimal effects on food after dissolution, and the total bacterial count met regulatory standards.

Ultraviolet spectrophotometry as method to determine the concentration of ß-myrcene released from chitosan in aqueous medium.

Myrcene (ß-myrcene), found in essential oils from plant species such as hops and cannabis, has many advantageous properties, but its use is limited due to volatility and low solubility in water. One way to circumvent these limitations is to encapsulate the essential oils in a polymer matrix. However, these hydrophobic molecules are difficult to quantify when dispersed in water. Seeking to study the release of this terpene in drug release tests from polymeric matrices, this work aimed to develop an easy and cheap UV spectrophotometric method for the quantification of ß-myrcene in aqueous medium. To achieves this goal, samples were prepared in 0.05% (w/v) polysorbate 80 solution, with concentrations of ß-myrcene ranging from 0.01% to 0.1% (v/v), and were analyzed at 226 nm. Each sample was analyzed in triplicate and repeated on three different days, to evaluate the repeatability of the results. The results were subjected to Q, F and Student's t-tests. The regression parameters obtained for ß-myrcene were above 0.99 and through statistical analysis, it was possible to confirm the repeatability for the results. The values of the limits of detection and quantification indicated that the method is not affected by intrinsic factors of the equipment. The results of accuracy, robustness and selectivity showed recovery rates within acceptable limits. This demonstrates that the quantification of ß-myrcene in aqueous medium by UV spectrophotometry is feasible.

Combination of co-amorphization with SNEDDS outperforms Ofev® in the oral absorption of nintedanib.

Nintedanib (NTD), approved for the treatment of idiopathic pulmonary fibrosis and advanced non-small cell lung cancer, is one of brick dusts with high melting point. Although NTD has been marketed as Ofev®, a soft capsule of NTD ethanesulfonate (NTD-ESA) suspended in oil components, the oral bioavailability is quite low and highly variable. To improve the oral absorption behavior of NTD, we prepared SNEDDS formulation containing NTD-(+)-10-camphorsulfonic acid (CSA) complex with 2% HPMCP-50. CSA disrupted the high crystallinity of NTD-ESA and the formed complex, NTD-CSA, was found to be amorphous by DSC and XRPD. NTD-CSA provided solubilities in various vehicles much higher than NTD-ESA. Under the gastric luminal condition, NTD-CSA SNEDDS with or without 2% HPMCP-50 and NTD-CSA powder indicated very good dissolution of NTD from early time periods, while NTD was gradually dissolved until around 60 min from NTD-ESA and Ofev®. Under the small intestinal luminal condition, in contrast, both NTD-CSA SNEDDS formulations almost completely dissolved NTD throughout the experiments, while Ofev®, NTD-CSA, and NTD-ESA exhibited a very poor dissolution of NTD. In the in vivo absorption study, NTD-CSA SNEDDS with 2% HPMCP-50 significantly improved NTD absorption and reduced the inter-individual variation in oral absorption behavior compared with Ofev®.

Evaluation of digestibility, solubility, and surface properties of trehalose-conjugated quinoa proteins prepared via pH shifting technique.

Soluble trehalose-conjugated quinoa proteins (T-QPs) were effectively prepared using the pH-shifting mechanism. The structural properties of the T-QPs were evaluated using a comparative evaluation, which included analyzing the amide I, surface charge and hydrophobicity, protein conformation, thermal stability, and protein structures. The results suggested that the development of the T-QPs was influenced mainly by no-covalent bonds. These interactions significantly influenced (P < 0.05) the quinoa proteins' conformation and higher-protein structure. T-QP had significant (P < 0.05) surface properties. Furthermore, the T-QPs exhibited improved solubility (79.7 to 88.4%) and digestibility (79.8 to 85.1%). Therefore, quinoa protein proved an excellent plant-based protein for conjugation with disaccharides. These findings provide significant insight into the potential development of modified proteins with enhanced solubility and digestibility by creating trehalose-conjugated plant-based proteins.

HSPiP, Computational, and Thermodynamic Model-Based Optimized Solvents for Subcutaneous Delivery of Tolterodine Tartrate and GastroPlus-Based In Vivo Prediction in Humans: Part I.

Tolterodine tartrate (TOTA) is associated with adverse effect, high hepatic access, varied bioavailability, slight aqueous solubility, and short half-life after oral delivery. Hansen solubility parameters (HSP, HSPiP program), experimental solubility (T = 298.2 to 318.2 K and p = 0.1 MPa), computational (van't Hoff and Apelblat models), and thermodynamic models were used to the select solvent(s). HSPiP predicted PEG400 as the most suitable co-solvent based on HSP values (δd = 17.88, δp = 4.0, and δh = 8.8 of PEG400) and comparable to the drug (δd = 17.6, δp = 2.4, and δh = 4.6 of TOTA). The experimental mole fraction solubility of TOTA was maximum (xe = 0.0852) in PEG400 confirming the best fit of the prediction. The observed highest solubility was attributed to the δp and δh interacting forces. The activity coefficient (ϒi) was found to be increased with temperature. The higher values of r2 (linear regression coefficient) and low RMSD (root mean square deviation) indicated a good correlation between the generated "xe" data for crystalline TOTA and the explored models (modified Apelblat and van't Hoff models). TOTA solubility in "PEG400 + water mixture" was endothermic and entropy-driven. IR (immediate release product) formulation can be tailored using 60% PEG400 in buffer solution for 2 mg of TOTA in 0.25 mL (dosing volume). The isotonic binary solution was associated with a pH of 7.2 suitable for sub-Q delivery. The approach would be a promising alternative with ease of delivery to children and aged patients.

Temperature effects and molecular insights towards the optimization of polyvinyl alcohol as adsorbent of organic pollutants from aqueous solution.

One of the easier methods of wastewater treatment is adsorption due to its simplicity in implementation, environmental friendliness, and economic feasibility. Polyvinyl alcohol (PVA) looks promising as an adsorbent due to its biocompatible, non-toxic, water-soluble and eco-friendly nature. The investigation of PVA for its potential in the adsorption of pollutants has been reported in many studies but the mechanistic understanding of the adsorption is poor. The present study used a theoretical approach through density functional theory and Monte Carlo with molecular dynamics simulations to investigate the adsorption mechanism behaviors of model organic molecules (bromothymol blue (BTB), methylene blue (MB), metronidazole (MNZ) and tetracycline (TC)) on PVA surface. The quantum chemical calculations result showed that with the increase in PVA chains (2, 4, 8, 16, and 32 units), the zero-point energy decreases (from -308.79 to -4922.93 kcal/mol) while the dipole moment increases (from 4.37 to 87.52 Debye). Temperature effect on the PVA chain structures showed the same trends for all the chain units and with the increase in temperature (50-600 K), there are no appreciable changes in zero-point energy, enthalpy energy increases while Gibbs free energy decreases. Considering PVA-pollutant complexes, the effects of temperature on the structures showed that there are no appreciable changes in the zero-point energy, Gibbs free and thermal energies increase with an increase in temperature while the kinetic rate of reactions decreases with an increase in temperature. The enthalpy of the reaction showed different trends with antibiotic and dye complexes. In all the thermodynamic properties investigated and the rate of reaction, the order of affinity of the pollutants with PVA followed TC > MNZ > MB > BTB. Monte Carlo simulation was used to investigate the adsorption behavior of the pollutants on the surface of PVA. The negative adsorption energies (-366.56 to -2266.81 kcal/mol) in terms of affinity towards the pollutants on the surface of PVA followed the sequence TC > MNZ > BTB > MB and the molecular dynamic simulation results followed the same order. The obtained results give valuable insights into the mechanism and performance of PVA as an adsorbent. Most of these computational observations are in good agreement with the available experimental results.

Modification of microenvironmental pH of nanoparticles for enhanced solubility and oral bioavailability of poorly water-soluble celecoxib.

This study aimed to develop a novel pH-modified nanoparticle with improved solubility and oral bioavailability of poorly water-soluble celecoxib by modifying the microenvironmental pH. After assessing the impact of hydrophilic polymers, surfactants and alkaline pH modifiers on the drug solubility, copovidone, sodium lauryl sulfate (SLS) and meglumine were chosen. The optimal formulation of solvent-evaporated, surface-attached and pH-modified nanoparticles composed of celecoxib/copovidone/SLS/meglumine at weight ratios of 1:1:0.2:0, 1:0.375:1.125:0 and 1:1:1:0.2:0.02, respectively, were manufactured using spray drying technique. Their physicochemical characteristics, solubility, dissolution and pharmacokinetics in rats were evaluated compared to the celecoxib powder. The solvent-evaporated and pH-modified nanoparticles converted a crystalline to an amorphous drug, resulting in a spherical shape with a reduced particle size compared to celecoxib powder. However, the surface-attached nanoparticles with insignificant particle size exhibited the unchangeable crystalline drug. All of them gave significantly higher solubility, dissolution, and oral bioavailability than celecoxib powder. Among them, the pH-modified nanoparticles demonstrated the most significant improvement in solubility (approximately 1600-fold) and oral bioavailability (approximately 4-fold) compared to the drug powder owing to the alkaline microenvironment formation effect of meglumine and the conversion to the amorphous drug. Thus, the pH-modified nanoparticle system would be a promising strategy for improving the solubility and oral bioavailability of poorly water-soluble and weakly acidic celecoxib.

[Evaluation of Solubility and Membrane Permeability of Middle-Molecule Compounds Using Artificial Membranes and Living Cells].

In contrast to small molecules, middle molecules present a promising therapeutic modality owing to their elevated specificity, minimal adverse effects, capacity to target protein-protein interactions, and, unlike antibody-based drugs, their suitability for oral administration and intracellular target engagement. Post-oral administration, the paramount considerations encompass solubility and membrane permeability during the initial phase until the drug attains systemic circulation. Furthermore, penetration of the cell membrane is essential to accessing intracellular targets. We evaluated the solubility and membrane permeability of 965 compounds sourced from middle molecule libraries affiliated with Hokkaido University, Kitasato University, and the University of Tokyo. To gauge membrane permeability, we employed both the parallel artificial membrane permeability assay (PAMPA) and Caco-2 cell monolayers. Notably, while membrane permeability in Caco-2 cells exhibited an approximate threefold increase in comparison to PAMPA measurements, certain compounds demonstrated permeability levels less than one-third of those observed in Caco-2 cells. Recognizing the potential involvement of efflux transporters expressed in Caco-2 cells in these variations, we conducted additional assessments involving directional transport in the presence of a transporter inhibitor. Our findings suggest that nearly 80% of these compounds serve as substrates for efflux transporters. Considering the relevance of intracellular targets, we shifted our focus from membrane permeation to intracellular uptake, conducting simulations tailored to assess cellular uptake.

Pharmaceutical applications of therapeutic deep eutectic systems (THEDES) in maximising drug delivery.

The issue of poor solubility of active pharmaceutical ingredients (APIs) has been a salient area of investigation and novel drug delivery systems are being developed to improve the solubility of drugs, enhance their permeability and thereby their efficacy. Several techniques for solubilization enhancement of poorly soluble drugs are often employed at various stages of pharmaceutical drug product development. One such delivery system is the therapeutic deep eutectic system (THEDES), which showed great potential in the enhancement of solubility and permeability of drugs and ultimately augmenting their bioavailability. THEDES are made by mixing drugs with deep eutectic solvents (DESs) in a definite molar ratio by the hit and trial method. The DESs are a new class of green solvents which are non-toxic, cheap, easy to prepare, biodegradable and have multiple applications in the pharmaceutical industry. The terminologies such as ionic liquids (ILs), DES, THEDES, and therapeutic liquid eutectic systems (THELES) have been very much in use recently, and it is important to highlight the pharmaceutical applications of these unexplored reservoirs in drug solubilization enhancement, drug delivery routes, and in the management of various diseases. This review is aimed at discussing the components, formulation strategies, and routes of administration of THEDES that are used in developing the formulation. Also, the major pharmaceutical applications of THEDES in the treatment of various metabolic and non-metabolic diseases are reviewed.