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In this study, Felodipine-loaded nanoparticles were prepared using the nanoprecipitation method, with quince seed mucilage serving as the polymer matrix and Tween 80 utilized as a stabilizing agent. The nanoparticles were thoroughly characterized using a range of analytical techniques, including dynamic light scattering (DLS), zeta potential measurement, Fourier-transform infrared spectroscopy (FTIR), thermal analysis, X-ray diffraction (XRD), and scanning electron microscopy (SEM). The Felodipine nanoparticles displayed an amorphous structure, with formulation FEL 4 achieving the highest entrapment efficiency of 67.68%. This formulation also had an average particle size of 675 ± 2.04 nm and a zeta potential of − 31.7 ± 1.34 mV. Saturation solubility tests revealed a significant enhancement in water solubility for the nanoparticles compared to pure Felodipine. Additionally, in vitro drug release studies demonstrated a sustained release profile over 24 h in phosphate buffer. Acute oral toxicity evaluations confirmed that the Felodipine nanoparticles did not exhibit any signs of toxicity. Overall, this study showed the successful fabrication of quince seed mucilage-based Felodipine-loaded nanoparticles as a promising approach to enhance solubility and achieve sustained drug release, with no evident toxicity. [ABSTRACT FROM AUTHOR]

Both triptolide (TP) and cyclopamine (CPA) exhibit strong anticancer effects in vitro with adverse reactions and low bioavailabilities because of their water insolubility and poor liposolubility. The preparation of functional polymer materials into micelles not only improved the apparent solubility of the drug, changed the release behavior of the drug, but also made the drug targeted. All-atom molecular dynamics (MD) methods were used to simulate the states of both TP and CPA in PLA-PEG block copolymer micelles. MD results showed that TP and CPA were concentrated in the core layer of micelles formed by PLA-PEG block copolymers. The polymers PLLA-PEG-COOH were synthesized using HO-PEG-COOH and PLA and characterized by FTIR, 1H NMR, 13 C NMR, and gel chromatography. The dual drug-loaded polymeric micelle ((TP + CPA)-PM) was prepared by solvent evaporation, and the encapsulation rates of TP and CPA were 65.44% and 78.16% using the HPLC method, respectively. The polymer micelles were nearly spherical and did not aggregate under transmission electron microscopy (TEM), and the particle size was about 75.32 ± 0.20 nm through dynamic light scattering (DLS). (TP + CPA)-PM showed similar inhibitory effects to free drugs on A2780, A549, HepG2, and SKOV3 cells, which was proved by the MTT proliferation inhibition experiment, Hoechst33258 fluorescence staining experiment, and flow cytometry experiment. These results appeared to support the assumption that polymeric micelles encapsulation did not affect drug activity. PLA-PEG block copolymer may be a promising drug delivery vehicle for loading TP and CPA in antitumor therapy. [ABSTRACT FROM AUTHOR]

Application of two coformers, l-tartaric acid (TA) and ascorbic acid (AA) was evaluated on the solubility of pioglitazone hydrochloride (PGZ.HCl). Solid dispersions were prepared using the solvent evaporation method. Drug solubility was evaluated in bio-relevant media and the results were compared to the physical mixtures (PM) of the drug + coformer, and the pure drug. Physicochemical characterisation of the developed products was characterised using Fourier transformation-infrared spectroscopy (FT-IR), Differential scanning calorimeter (DSC), and X-ray powder diffractometry (XPRD). Physical mixtures of PGZ-AA (PM) were able to enhance drug solubility to the same extent as the solvent evaporation method (PGZ-AA). This indicates that the preparation process has little effect on drug solubility. Up to 7-fold enhancement was observed for drug solubility in distilled water and buffer pH 1.2. Physical mixtures seem more feasible method to significantly enhance drug solubility without the need to use toxic solvents and time-consuming evaporation methods. [ABSTRACT FROM AUTHOR]

Background: Gastric fluid plays a key role in food digestion and drug dissolution, therefore, the amount of gastric fluid present in a fasted state may influence subsequent digestion and drug delivery. We aimed to describe intra‐ and interindividual variation in fasted gastric content volume (FGCV) and to determine the association with age, sex, and body size characteristics. Methods: Data from 24 MRI studies measuring FGCV in healthy, mostly young individuals after an overnight fast were pooled. The analysis included 366 participants who had up to 6 repeated measurements, with a total of 870 measurements. Linear mixed model analysis was performed to calculate intra‐ and interindividual variability and to assess the effects of age, sex, weight, height, weight*height as a proxy for body size, and body mass index (BMI). Results: FGCV ranged from 0 to 156 mL, with a mean (± SD) value of 33 ± 25 mL. The overall coefficient of variation within the study population was 75.6%, interindividual SD was 15 mL, and the intraindividual SD was 19 mL. Age, weight, height, weight*height, and BMI had no effect on FGCV. Women had lower volumes compared to men (MD: −6 mL), when corrected for the aforementioned factors. Conclusion: FGCV is highly variable, with higher intraindividual compared to interindividual variability, indicating that FGCV is subject to day‐to‐day and within‐day variation and is not a stable personal characteristic. This highlights the importance of considering FGCV when studying digestion and drug dissolution. Exact implications remain to be studied. [ABSTRACT FROM AUTHOR]

Drug solubility is an important parameter in the drug development process, yet it is often tedious and challenging to measure, especially for expensive drugs or those available in small quantities. To alleviate these challenges, machine learning (ML) has been applied to predict drug solubility as an alternative approach. However, the majority of existing ML research has focused on the predictions of aqueous solubility and/or solubility at specific temperatures, which restricts the model applicability in pharmaceutical development. To bridge this gap, we compiled a dataset of 27,000 solubility datapoints, including solubility of small molecules measured in a range of binary solvent mixtures under various temperatures. Next, a panel of ML models were trained on this dataset with their hyperparameters tuned using Bayesian optimization. The resulting top-performing models, both gradient boosted decision trees (light gradient boosting machine and extreme gradient boosting), achieved mean absolute errors (MAE) of 0.33 for LogS (S in g/100 g) on the holdout set. These models were further validated through a prospective study, wherein the solubility of four drug molecules were predicted by the models and then validated with in-house solubility experiments. This prospective study demonstrated that the models accurately predicted the solubility of solutes in specific binary solvent mixtures under different temperatures, especially for drugs whose features closely align within the solutes in the dataset (MAE < 0.5 for LogS). To support future research and facilitate advancements in the field, we have made the dataset and code openly available. Scientific contribution Our research advances the state-of-the-art in predicting solubility for small molecules by leveraging ML and a uniquely comprehensive dataset. Unlike existing ML studies that predominantly focus on solubility in aqueous solvents at fixed temperatures, our work enables prediction of drug solubility in a variety of binary solvent mixtures over a broad temperature range, providing practical insights on the modeling of solubility for realistic pharmaceutical applications. These advancements along with the open access dataset and code support significant steps in the drug development process including new molecule discovery, drug analysis and formulation. [ABSTRACT FROM AUTHOR]

Biological variability poses significant challenges in the development of effective therapeutics, particularly when it comes to drug solubility and bioavailability. Poor solubility across varying physiological conditions often leads to reduced absorption and inconsistent therapeutic outcomes. This review examines how nanotechnology, especially through the use of nanomaterials and magnetic nanoparticles, offers innovative solutions to enhance drug solubility and bioavailability. This comprehensive review focuses on recent advancements and approaches in nanotechnology. We highlight both the successes and remaining challenges in this field, emphasizing the role of continued innovation. Future research should prioritize developing universal therapeutic solutions, conducting interdisciplinary research, and leveraging personalized nanomedicine to address biological variability. [ABSTRACT FROM AUTHOR]

The combination of paclitaxel (PTX) with other chemotherapy drugs (e.g., gemcitabine, GEM) or genetic drugs (e.g., siRNA) has been shown to enhance therapeutic efficacy against tumors, reduce individual drug dosages, and prevent drug resistance associated with single-drug treatments. However, the varying solubility of chemotherapy drugs and genetic drugs presents a challenge in co-delivering these agents. In this study, nanoparticles loaded with PTX were prepared using the biodegradable polymer material poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx). These nanoparticles were surface-modified with target proteins (Affibody molecules) and RALA cationic peptides to create core-shell structured microspheres with targeted and cationic functionalization. A three-drug co-delivery system (PTX@PHBHHx-ARP/siRNAGEM) were developed by electrostatically adsorbing siRNA chains containing GEM onto the microsphere surface. The encapsulation efficiency of PTX in the nanodrug was found to be 81.02%, with a drug loading of 5.09%. The chemogene adsorption capacity of siRNAGEM was determined to be 97.3%. Morphological and size characterization of the nanodrug revealed that PTX@PHBHHx-ARP/siRNAGEM is a rough-surfaced microsphere with a particle size of approximately 150 nm. This nanodrug exhibited targeting capabilities toward BT474 cells with HER2 overexpression while showing limited targeting ability toward MCF-7 cells with low HER2 expression. Results from the MTT assay demonstrated that PTX@PHBHHx-ARP/siRNAGEM exhibits high cytotoxicity and excellent combination therapy efficacy compared to physically mixed PTX/GEM/siRNA. Additionally, Western blot analysis confirmed that siRNA-mediated reduction of Bcl-2 expression significantly enhanced cell apoptosis mediated by PTX or GEM in tumor cells, thereby increasing cell sensitivity to PTX and GEM. This study presents a novel targeted nanosystem for the co-delivery of chemotherapy drugs and genetic drugs. [ABSTRACT FROM AUTHOR]

Background: Oxiconazole nitrate is a broad spectrum imidazole antifungal agent. Poor solubility of this drug caused low bioavailability that limits the antifungal efficiency. Due to their low efficiency as drug delivery many conventional dosage form such as cream and ointment need high concentration of active ingredient for effective therapy, which may cause side effect. Materials and Methods: In this study nanosponge was prepared using hydroxyl ethyl cellulose and poly vinyl alcohol by emulsion solvent diffusion method. The entrapment efficiency of particle size has found in the range of 100nm-1µm and 55% - 88% respectively. Based on the characterization, nanosponge with least particle size and highest entrapment efficiency was selected for gel formulation. Results and Discussion: Four different formulations of gel were prepared by using carbopol 934 with varying the concentration of penetration enhancer and various evaluation studies were carried out. The in vitro release study showed that the nanosponge loaded gel formulation with higher concentration of penetration enhancer showed greater drug release. Conclusion: while compared with conventional gel. Based on the stability study carried out, it was concluded that formulation was stable at ambient conditions. [ABSTRACT FROM AUTHOR]

This article explores the emerging field of nanomedicine as a drug delivery system, aimed at enhancing the therapeutic efficacy of active pharmaceutical ingredients in medicinal plants. The traditional methods of applying medicinal plants present several limitations, such as low bioavailability, poor solubility, challenges in accurately controlling drug dosage, and inadequate targeting. Nanoformulations represent an innovative approach in drug preparation that employs nanotechnology to produce nanoscale particles or carriers, which are designed to overcome these limitations. Nanoformulations offer distinct advantages, significantly enhancing the solubility and bioavailability of drugs, particularly for the poorly soluble components of medicinal plants. These formulations effectively enhance solubility, thereby facilitating better absorption and utilization by the human body, which in turn improves drug efficacy. Furthermore, nanomedicine enables targeted drug delivery, ensuring precise administration to the lesion site and minimizing side effects on healthy tissues. Additionally, nanoformulations can regulate drug release rates, extend the duration of therapeutic action, and enhance the stability of treatment effects. However, nanoformulations present certain limitations and potential risks; their stability and safety require further investigation, particularly regarding the potential toxicity with long-term use. Nevertheless, nanomaterials demonstrate substantial potential in augmenting the efficacy of active pharmaceutical ingredients in medicinal plants, offering novel approaches and methodologies for their development and application. [ABSTRACT FROM AUTHOR]

6-thioguanine (6-TG) is an antimetabolite drug of purine structure, approved by the FDA for the treatment of acute myeloid lesukemia, and it is of interest in treating other diseases. The interaction of drugs with matrices is of interest to achieving a delayed, sustained, and local release. The interaction of 6-TG with an aluminum metal–organic framework (Al-MOF) DUT-4 is studied using a novel experimental approach, namely, mechano-chemistry by liquid-assisted grinding (LAG). The bonding of 6-TG to the DUT-4 matrix in the composite (6-TG)(DUT-4) was studied using ATR-FTIR spectroscopy and XRD. This interaction involves amino groups and C and N atoms of the heterocyclic ring of 6-TG, as well as the carboxylate COO− and (Al)O-H groups of the matrix, indicating the formation of the complex. Next, an in vitro delayed release of 6-TG was studied from composite powder versus pure 6-TG in phosphate buffered saline (PBS) at 37 °C. Herein, an automated drug dissolution apparatus with an autosampler was utilized, and the molar concentration of the released 6-TG was determined using an HPLC–UV analysis. Pure 6-TG shows a quick (<300 min) dissolution, while the composite gives the dissolution of non-bonded 6-TG, followed by a significantly (factor 6) slower release of the bonded drug. Each step of the release follows the kinetic pseudo-first-order rate law with distinct rate constants. Then, a pharmaceutical shaped body was prepared from the composite, and it yields a significantly delayed release of 6-TG for up to 10 days; a sustained release is observed with the 6-TG concentration being within the therapeutically relevant window. Finally, the composite shows a time-dependent (up to 9 days) stronger inhibition of leukemia MV-4-11 cell colonies than 6-TG. [ABSTRACT FROM AUTHOR]

Lopinavir (LPV) and ritonavir (RTV) are two of the essential antiretroviral active pharmaceutical ingredients (APIs) characterized by poor solubility. Hence, attempts have been made to improve both their solubility and dissolution rate. One of the most effective approaches used for this purpose is to prepare amorphous solid dispersions (ASDs). To our best knowledge, this is the first attempt aimed at developing ASDs via the electrospinning technique in the form of fibers containing LPV and RTV. In particular, the impact of the various polymeric carriers, i.e., Kollidon K30 (PVP), Kollidon VA64 (KVA), and Eudragit® E100 (E100), as well as the drug content as a result of the LPV and RTV amorphization were investigated. The characterization of the electrospun fibers included microscopic, DSC, and XRD analyses, the assessment of their wettability, and equilibrium solubility and dissolution studies. The application of the electrospinning process led to the full amorphization of both the APIs, regardless of the drug content and the type of polymer matrix used. The utilization of E100 as a polymeric carrier for LPV and KVA for RTV, despite the beads-on-string morphology, had a favorable impact on the equilibrium solubility and dissolution rate. The results showed that the electrospinning method can be successfully used to manufacture ASDs with poorly soluble APIs. [ABSTRACT FROM AUTHOR]

Chlortetracycline hydrochloride (CTC) is a broad-spectrum tetracycline antibiotic with a wide range of antibacterial activities. Due to low solubility, poor stability, and low bioavailability, clinical preparation development is limited. We sought to improve these solubility and dissolution rates by preparing solid dispersions. A hydrophilic polymer was selected as the carrier, and a solid dispersion was prepared using a medium grinding method, with samples characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), powder X-ray diffraction (PXRD), Fourier-transform infrared spectroscopy (FT-IR), and particle size distribution (PSD). To maximize CTC solubility and stability, different polymer types and optimal drug-to-polymer ratios were screened. The solubility of optimized povidone K30 (PVPK30) (1/0.75, w/w)-, hydroxypropyl-β-cyclodextrin (HP-β-CD) (1/2, w/w)-, and gelatin (1/1, w/w)-based solid dispersions was 6.25-, 7.7-, and 3.75-fold higher than that of pure CTC powder, respectively. Additionally, in vitro dissolution studies showed that the gelatin-based solid dispersion had a higher initial dissolution rate. SEM and PS analyses confirmed that this dispersion had smaller and more uniform particles than PVPK30 and HP-β-CD dispersions. Therefore, successful solid polymer dispersion preparations improved the CTC solubility, dissolution rates, and stability, which may have potential as drug delivery systems. [ABSTRACT FROM AUTHOR]

In this research paper, we explored the predictive capabilities of three different models of Polynomial Regression (PR), Extreme Gradient Boosting (XGB), and LASSO to estimate the density of supercritical carbon dioxide (SC-CO2) and the solubility of niflumic acid as functions of the input variables of temperature and pressure. The optimization of hyperparameters for these models is achieved using the innovative Barnacles Mating Optimizer (BMO) algorithm. For SC-CO2 density estimation, PR exhibits remarkable accuracy, showing an R-squared value of 0.99207 for data fitting. XGB performs admirably with an R2 of 0.92673, while LASSO model demonstrates good predictive ability, showing an R2 of 0.81917. Furthermore, we assess the models' performance in predicting the solubility of niflumic acid. PR exhibits excellent predictive capabilities with an R2 of 0.96949. XGB also delivers strong performance, yielding an R-squared score of 0.92961. LASSO performs well, achieving an R-squared score of 0.82094. The results indicated promising performance of machine learning models and optimizer in estimating drug solubility in supercritical CO2 as the solvent applicable for pharmaceutical industry. [ABSTRACT FROM AUTHOR]

Enabling drug formulations are often required to ensure sufficient absorption after oral administration of poorly soluble drugs. While these formulations typically increase the apparent solubility of the drug, it is widely acknowledged that only molecularly dissolved, i.e., free fraction of the drug, is prone for direct absorption, while colloid-associated drug does not permeate to the same extent. In the present study, we aimed at comparing the effect of molecularly and apparently (i.e., the sum of molecularly and colloid-associated drug) dissolved drug concentrations on the oral absorption of a poorly water-soluble drug compound, Alectinib. Mixtures of Alectinib and respectively 50 %, 25 %, 12.5 %, and 3 % sodium lauryl sulfate (SLS) relative to the dose were prepared and small-scale dissolution tests were performed under simulated fed and fasted state conditions. Both the molecularly and apparently dissolved drug concentrations were assessed in parallel using microdialysis and centrifugation/filtration sampling, respectively. The data served as the basis for an in vitro-in vivo correlation (IVIVC) and as input for a GastroPlusTM physiologically-based biopharmaceutics model (PBBM). It was shown that with increasing the content of SLS the apparently dissolved drug in FeSSIF and FaSSIF increased to a linear extent and thus, the predicted in vivo performance of the 50 % SLS formulation, based on apparently dissolved drug, would outperform all other formulations. Against common expectation, however, the free (molecularly dissolved) drug concentrations were found to vary with SLS concentrations as well, yet to a minor extent. A systematic comparison of solubilized and free drug dissolution patterns at different SLS contents of the formulations and prandial states allowed for interesting insights into the complex dissolution-/supersaturation-, micellization-, and precipitation-behavior of the formulations. When comparing the in vitro datasets with human pharmacokinetic data from a bioequivalence study, it was shown that the use of molecularly dissolved drug resulted in an improved IVIVC. By incorporating the in vitro dissolution datasets into the GastroPlusTM PBBM, the apparently dissolved drug concentrations resulted in both, a remarkable overprediction of plasma concentrations as well as a misprediction of the influence of SLS on systemic exposure. In contrast, by using the molecularly dissolved drug (i.e., free fraction) as the model input, the predicted plasma concentration-time profiles were in excellent agreement with observed data for all formulations under both fed and fasted conditions. By combining an advanced in vitro assessment with PBBM, the present study confirmed that only the molecularly dissolved drug, and not the colloid-associated drug, is available for direct absorption. [Display omitted] [ABSTRACT FROM AUTHOR]

This study presents the self-assembly of polyethylene oxide (PEO)-block-polypropylene oxide (PPO)-block-polyethylene oxide (PEO)-based block copolymer (BCP) commercially known as Pluronic® P123 in water and in the presence of different copolymeric surfactants (L61, L62, L64, and F68) with varying degree of hydrophilicity, i.e., %EO content. The clouding behavior demonstrates the varied phase transition ranging from solution, blue point (BP), and cloud point (CP). The characteristics of the micelles in the single and mix system are characterized utilizing dynamic light scattering (DLS) and small-angle neutron scattering (SANS) techniques at different temperatures. These scattering approaches provide an insightful information on the micelle size and shape. The size variations in self-assembled micelles designated the micelles to undergo growth/transition in shape from spherical to elongated ellipsoidal as function of temperature. Additionally, the application of these nanoscale micellar aggregates as carriers for delivering the anticancer drug Quercetin (QCT) was undertaken by a thorough quantitative and qualitative analysis to gain valuable insights into the effectiveness of the mix-micellar system as an ideal platform for drug delivery. A comprehensive investigation of drug release kinetics is presented using various kinetic models. The MTT (cytotoxicity assay) assay is used to gauge the effectiveness of the QCT-loaded copolymeric micelles. Micellar transition of 5% w/v P123 in water and in the presence of copolymeric surfactants as additives at 0.2% weight fraction (fix) at different temperatures [ABSTRACT FROM AUTHOR]

Lurasidone hydrochloride (LRS HCl), an antipsychotic drug with low aqueous solubility, was dispersed in a matrix of polyethylene glycol (PEG) using the green solvent evaporation method. The green solvents used were water and ethanol. Solid dispersions and physical mixtures were prepared at various drug-to-polymer ratios, characterized by XRPD, FTIR, and DSC analyzes, and then used for the preparation of fast disintegrating tablets (FDTs). The tablets were analyzed for hardness, disintegration, and in vitro dissolution of LRS HCl. In vitro release profiles showed a significant improvement in the release rate of LRS HCl from tablets prepared with solid dispersions compared to those containing untreated LRS HCl or the physical mixture. The presented results confirm that the use of solid dispersions prepared by the green solvent evaporation method is a promising approach to enhance the in vitro dissolution of poorly soluble drugs such as LRS HCl. The applicability of mathematical models was tested to describe the release profiles of LRS HCl from FDTs. The diffusion process, following Fick's law for drug release, appears to be the predominant release mechanism for this specific drug in FDTs. [ABSTRACT FROM AUTHOR]

Bedaquiline (BDQ) is an orally administered diarylquinoline class anti-tuberculosis drug used in the combination therapy of MDR-TB. Currently, it is marketed as bedaquiline fumarate (BDQ--FA). However, due to its poor water solubility, BDQ--FA must be taken with food to enhance bioavailability. Concurrent administration reduces patient compliance and may increase the risk of inconsistent serum levels due to differences in dietary habits. This study designed and synthesized the saccharin salt of bedaquiline (BDQ--SA). Compared to the marketed fumarate salt, BDQ--SA exhibits better solubility and absorption. The food effect of commercially available BDQ--FA in beagle dogs was 7.2 times, while that of BDQ--SA was 3.2 times. This study provides a good example of using a new salt form to improve drug solubility and mitigate the food effect of the drug. [ABSTRACT FROM AUTHOR]

Liposils, synthesized via the liposome templating method, offer a promising strategy for enhancing liposome stability by employing a silica coating. This study focuses on the development of nanocarriers utilizing silica-coated nanoliposomes for encapsulating the poorly water-soluble drug, ibrutinib. Ibrutinib-loaded nanoliposomes were meticulously formulated using the reverse-phase evaporation technique, serving as templates for silica coating, resulting in spherical liposils with an average size of approximately 240 nanometers. Comprehensive characterization of the liposil's physical and chemical properties was conducted using various analytical methods, including dynamic light scattering, transmission electron microscopy, Fourier-transform infrared spectroscopy, and X-ray diffraction analysis. Liposils demonstrated superior performance compared to ibrutinib-loaded nanoliposomes, showing sustained drug release profiles in simulated intestinal fluids and resistance to simulated gastric fluid, as confirmed by dissolution studies. Moreover, ibrutinib liposils exhibited a significant increase in half-life (4.08-fold) and notable improvement in bioavailability (3.12-fold) compared to ibrutinib suspensions, as determined by pharmacokinetic studies in rats. These findings underscore the potential of liposils as nanocarriers for orally delivering poorly water-soluble drugs, offering enhanced stability and controlled release profiles, thereby improving bioavailability prospects and therapeutic efficacy. This approach holds promise for addressing challenges associated with the oral administration of drugs with limited solubility, thereby advancing drug delivery technologies and clinical outcomes in pharmaceutical research and development. [ABSTRACT FROM AUTHOR]

Additive manufacturing of pharmaceutical formulations offers advanced micro-structure control of oral solid dose (OSD) forms targeting not only customised dosing of an active pharmaceutical ingredient (API) but also custom-made drug release profiles. Traditionally, material extrusion 3D printing manufacturing was performed in a two-step manufacturing process via an intermediate feedstock filament. This process was often limited in the material space due to unsuitable (brittle) material properties, which required additional time to develop complex formulations to overcome. The objective of this study was to develop an additive manufacturing MicroFactory process to produce an immediate release (IR) OSD form containing 250 mg of mefenamic acid (MFA) with consistent drug release. In this study, we present a single-step additive manufacturing process employing a novel, filament-free melt extrusion 3D printer, the MicroFactory, to successfully print a previously 'non-printable' brittle Soluplus®-based formulation of MFA, resulting in targeted IR dissolution profiles. The physico-chemical properties of 3D printed MFA-Soluplus®-D-sorbitol formulation was characterised by thermal analysis, Fourier Transform Infrared spectroscopy (FTIR), and X-ray Diffraction Powder (XRPD) analysis, confirming the crystalline state of mefenamic acid as polymorphic form I. Oscillatory temperature and frequency rheology sweeps were related to the processability of the formulation in the MicroFactory. 3D printed, micro-structure controlled, OSDs showed good uniformity of mass and content and exhibited an IR profile with good consistency. Fitting a mathematical model to the dissolution data correlated rate parameters and release exponents with tablet porosity. This study illustrates how additive manufacturing via melt extrusion using this MicroFactory not only streamlines the manufacturing process (one-step vs. two-step) but also enables the processing of (brittle) pharmaceutical immediate-release polymers/polymer formulations, improving and facilitating targeted in vitro drug dissolution profiles. [ABSTRACT FROM AUTHOR]

In recent decades, unfavorable solubility of novel therapeutic agents is considered as an important challenge in pharmaceutical industry. Supercritical carbon dioxide (SCCO2) is known as a green, cost-effective, high-performance, and promising solvent to develop the low solubility of drugs with the aim of enhancing their therapeutic effects. The prominent objective of this study is to improve and modify disparate predictive models through artificial intelligence (AI) to estimate the optimized value of the Oxaprozin solubility in SCCO2 system. In this paper, three different models were selected to develop models on a solubility dataset. Pressure (bar) and temperature (K) are the two inputs for each vector, and each vector has one output (solubility). Selected models include NU-SVM, Linear-SVM, and Decision Tree (DT). Models were optimized through hyper-parameters and assessed applying standard metrics. Considering R-squared metric, NU-SVM, Linear-SVM, and DT have scores of 0.994, 0.854, and 0.950, respectively. Also, they have RMSE error rates of 3.0982E-05, 1.5024E-04, and 1.1680E-04, respectively. Based on the evaluations made, NU-SVM was considered as the most precise method, and optimal values can be summarized as (T = 336.05 K, P = 400.0 bar, solubility = 0.00127) employing this model. Fig 4 [ABSTRACT FROM AUTHOR]

Drug Delivery Systems (DDSs) of known drugs are prominent candidates for new and more effective treatments of various diseases, as they may increase drug solubility, dissolution velocity, and bioavailability. Mitotane (o,p′-dichlorodimethyl dichloroethane [o,p′-DDD]) is used for the treatment of adrenocortical cancer and, occasionally, Cushing's syndrome. However, the efficacy of mitotane is limited by its low oral bioavailability, caused by its extremely poor aqueous solubility. This research explores the development of a new powder self-emulsifying drug delivery system (P-SEDDS) for mitotane to improve its oral bioavailability. The study focuses on the new concept of a mitotane-loaded P-SEDDS to overcome the challenges associated with its limited solubility and high logP, thereby improving its therapeutic efficacy, reducing off-target toxicity, and avoiding first-pass metabolism. The P-SEDDS formulations were meticulously designed using only α-cyclodextrin and oil, with the goal of achieving a stable and efficient P-SEDDS. The optimized formulation was characterized for pharmaceutical properties, and its pharmacokinetic behavior was examined in rats. The results demonstrated a significant enhancement in the bioavailability of mitotane when delivered through the P-SEDDS, attributed to the increased dissolution velocity and improved absorption of the poorly water-soluble drug. The results suggest that a mitotane-loaded P-SEDDS has distinctly enhanced in vitro and in vivo performance compared with conventional mitotane formulations (Lysodren®), which leads to the conclusion that the P-SEDDS formulation could be a viable and effective strategy for improving the dissolution rate and bioavailability of poorly aqueous-soluble ingredients. [ABSTRACT FROM AUTHOR]

Although niflumic acid (NA) is one of the most used non-steroidal anti-inflammatory drugs, it suffers from poor solubility, low bioavailability, and significant adverse effects. To address these limitations, the complexation of NA with cyclodextrins (CDs) is a promising strategy. However, complexing CDs with low molecular weight drugs like NA can lead to low CE. This study explores the development of inclusion complexes of NA with 2-hydroxypropyl-β-cyclodextrin (2HP-β-CD), including the effect of converting NA to its sodium salt (NAs) and adding hydroxypropyl methylcellulose (HPMC) on complex formation. Inclusion complexes were prepared using co-evaporation solvent and freeze-drying methods, and their CE and Ks were determined through a phase solubility study. The complexes were characterized using physicochemical analyses, including FT-IR, DSC, SEM, XRD, DLS, UV-Vis, 1H-NMR, and 1H-ROESY. The dissolution profiles of the complexes were also evaluated. The analyses confirmed complex formation for all systems, demonstrating drug–cyclodextrin interactions, amorphous drug states, morphological changes, and improved solubility and dissolution profiles. The NAs-2HP-β-CD-HPMC complex exhibited the highest CE and Ks values, a 1:1 host-guest molar ratio, and the best dissolution profile. The results indicate that the NAs-2HP-β-CD-HPMC complex has potential for delivering NA, which might enhance its therapeutic effectiveness and minimize side effects. [ABSTRACT FROM AUTHOR]

Despite the safety and convenience of oral administration, poorly water-soluble drugs compromise absorption and bioavailability. These drugs can exhibit low dissolution rates, variability between fed and fasted states, difficulty permeating the mucus layer, and P-glycoprotein efflux. Drug nanocrystals offer a promising strategy to address these challenges. This review focuses on the opportunities to develop orally administered nanocrystals based on pharmacokinetic outcomes. The impacts of the drug particle size, morphology, dissolution rate, crystalline state on oral bioavailability are discussed. The potential of the improved dissolution rate to eliminate food effects during absorption is also addressed. This review also explores whether permeation or dissolution drives nanocrystal absorption. Additionally, it addresses the functional roles of stabilizers. Drug nanocrystals may result in prolonged concentrations in the bloodstream in some cases. Therefore, nanocrystals represent a promising strategy to overcome the challenges of poorly water-soluble drugs, thus encouraging further investigation into unclear mechanisms during oral administration. [ABSTRACT FROM AUTHOR]

A novel ophthalmic delivery system utilizing levofloxacin-loaded, preservative-free, nanofiber-based inserts was investigated. Polyvinyl alcohol (PVA) and Poloxamer 407 (Polox)were employed as matrix materials, while hydroxypropyl-beta-cyclodextrin (HP-β-CD) was a solubilizer. The formulations were prepared via electrospinning and characterized for fiber morphology, drug dissolution, cytotoxicity, and antimicrobial activity. Scanning electron microscopy confirmed uniform fibrous structures. Fourier Transform Infrared spectroscopy and X-ray diffraction analyses demonstrated the amorphous state of levofloxacin within the fibers. In vitro dissolution studies revealed a rapid (within 2 min) and complete drug release, with higher HP-β-CD levels slightly delaying the release. Cytotoxicity tests showed increased HP-β-CD concentrations induced irritation, that was mitigated by sodium hyaluronate. The antimicrobial efficacy of the nanofibers was comparable to conventional eye drops, with lower minimum inhibitory concentrations for most tested strains. The nanofibrous formulation prepared from a PVA–Polox-based viscous solution of the drug:CD 1:1 mol ratio, containing 0.4% (w/w) sodium hyaluronate) was identified as a particularly promising alternative formulation due to its rapid and complete dissolution, good biocompatibility, and effective antimicrobial properties. Its gelling properties indicate that the residence time on the eye surface can be increased, potentially reducing discomfort and enhancing therapeutic outcomes. The nanofibrous formulations enhanced antimicrobial efficacy, providing a preservative-free alternative that minimizes the potential eye irritation that might occur because of the preservative agent and reduces the administrated dose frequency by extending the drug's retention time on the eye's surface. Subsequently, it improves patients' adherence, which would reflect positively on the bioavailability. The levofloxacin-HP-β-CD nanofibers demonstrate promise as an alternative to traditional eye drops, offering advantages in solubility, stability, and patient compliance for ocular infection treatment. [ABSTRACT FROM AUTHOR]

Drug resistance remains a critical barrier in cancer therapy, diminishing the effectiveness of chemotherapeutic, targeted, and immunotherapeutic agents. Overexpression of proteins such as B-cell lymphoma 2 (Bcl-2), inhibitor of apoptosis proteins (IAPs), protein kinase B (Akt), and P-glycoprotein (P-gp) in various cancers leads to resistance by inhibiting apoptosis, enhancing cell survival, and expelling drugs. Although several inhibitors targeting these proteins have been developed, their clinical use is often hampered by systemic toxicity, poor bioavailability, and resistance development. Nanoparticle-based drug delivery systems present a promising solution by improving drug solubility, stability, and targeted delivery. These systems leverage the Enhanced Permeation and Retention (EPR) effect to accumulate in tumor tissues, reducing off-target toxicity and increasing therapeutic efficacy. Co-encapsulation strategies involving anticancer drugs and resistance inhibitors within nanoparticles have shown potential in achieving coordinated pharmacokinetic and pharmacodynamic profiles. This review discusses the mechanisms of drug resistance, the limitations of current inhibitors, and the advantages of nanoparticle delivery systems in overcoming these challenges. By advancing these technologies, we can enhance treatment outcomes and move towards more effective cancer therapies. [ABSTRACT FROM AUTHOR]

In this monograph, the potential use of methods based on the Biopharmaceutics Classification System (BCS) framework to evaluate the bioequivalence of solid immediate-release (IR) oral dosage forms containing fexofenadine hydrochloride as a substitute for a pharmacokinetic study in human volunteers is investigated. We assessed the solubility, permeability, dissolution, pharmacokinetics, pharmacodynamics, therapeutic index, bioavailability, drug-excipient interaction, and other properties using BCS recommendations from the ICH, FDA and EMA. The findings unequivocally support fexofenadine's classification to BCS Class IV as it is neither highly soluble nor highly permeable. Further impeding the approval of generic equivalents through the BCS-biowaiver pathway is the reference product's inability to release ≥ 85 % of the drug substance within 30 min in pH 1.2 and pH 4.5 media. According to ICH rules, BCS class IV drugs do not qualify for waiving clinical bioequivalence studies based on the BCS, even though fexofenadine has behaved more like a BCS class I/III than a class IV molecule in pharmacokinetic studies to date and has a wide therapeutic index. [ABSTRACT FROM AUTHOR]

Amorphous drugs represent an intriguing option to bypass the low solubility of many crystalline formulations of pharmaceuticals. The physical stability of the amorphous phase with respect to the crystal is crucial to bring amorphous formulations into the market—however, predicting the timescale involved with the onset of crystallization a priori is a formidably challenging task. Machine learning can help in this context by crafting models capable of predicting the physical stability of any given amorphous drug. In this work, we leverage the outcomes of molecular dynamics simulations to further the state-of-the-art. In particular, we devise, compute, and use "solid state" descriptors that capture the dynamical properties of the amorphous phases, thus complementing the picture offered by the "traditional," "one-molecule" descriptors used in most quantitative structure–activity relationship models. The results in terms of accuracy are very encouraging and demonstrate the added value of using molecular simulations as a tool to enrich the traditional machine learning paradigm for drug design and discovery. [ABSTRACT FROM AUTHOR]

Schematic representation of co-delivery liposomes for the treatment of malignant tumors. [Display omitted] • Efficient co-loading of PROTAC and siRNA into novel liposomes. • Enhancement of PROTAC drug solubility and endocytosis via a novel lipid nanodelivery system. • Synergistic action of PROTAC and siRNA for enhanced degradation of BCL-xL target protein. • Augmented tumor therapeutic effects through synergistic interaction of PROTAC and siRNA. Targeted elimination of damaged or overexpressed proteins within the tumor serves a pivotal role in regulating cellular function and restraining tumor cell growth. Researchers have been striving to identify safer and more effective methods for protein removal. Here, we propose the synergistic employment of a small molecule degrading agent (PROTAC) and siRNA to attain enhanced protein clearance efficiency and tumor therapeutic effects. Co-delivery liposomes were prepared to facilitate the efficient encapsulation of PROTAC and siRNA. Specifically, the cationic liposome significantly improved the solubility of the insoluble PROTAC (DT2216). The cationic polymer (F-PEI) achieved efficient encapsulation of the nucleic acid drug, thereby promoting endocytosis and enhancing the therapeutic impact of the drug. Both in vivo and in vitro experiments demonstrated remarkable degradation of target proteins and inhibition of tumor cells by the co-delivery system. In conclusion, the co-delivery liposomes furnished a nano-delivery system proficient in effectively encapsulating both hydrophilic and hydrophobic drugs, thereby presenting a novel strategy for targeted combination therapy in treating tumors. [ABSTRACT FROM AUTHOR]

In the tumor treatment by Fenton reaction‒based nanocatalytic medicines, the gradual consumption of Fe(II) ions greatly reduces the production of hydroxyl radicals, one of the most active reactive oxygen species (ROS), leading to much deteriorated therapeutic efficacy. Meanwhile, the ROS consumption caused by the highly expressed reduced glutathione (GSH) in the tumor microenvironment further prevents tumor apoptosis. Therefore, using the highly expressed GSH in tumor tissue to promote the Fe(III) reduction to Fe(II) can not only weaken the resistance of tumor to ROS attack, but also generate enough Fe(II) to accelerate the Fenton reaction. In view of this, an allicin‒modified FeO1‐xOH nanocatalyst possessing varied valence states (II, III) has been designed and synthesized. The coexistence of Fe(II)/Fe(III) enables the simultaneous occurrence of Fenton reaction and GSH oxidation, and the Fe(III) reduction by GSH oxidation results in the promoted cyclic conversion of Fe ions in tumor and positive catalytic therapeutic effects. Moreover, allicin capable of regulating cell cycle and suppressing tumor growth is loaded on FeO1‐xOH nanosheets to activate immune response against tumors and inhibit tumor recurrence, finally achieving the tumor regression efficiently and sustainably. This therapeutic strategy provides an innovative approach to formulate efficient antitumor nanomedicine for enhanced tumor treatment. [ABSTRACT FROM AUTHOR]

The aim of this study was to synthesize and evaluate nanostructured lipid carriers (NLCs) loaded with Remdesivir (RDV) to control its side effects in COVID-19 patients. Due to the low solubility and short half-life of RDV in the blood, an injectable formulation was prepared using sulphobutylether-beta-cyclodextrin. However, it can accumulate in the kidney and cause renal impairment. NLCs improve the parenteral delivery of hydrophobic drugs such as RDV by increasing drug solubility and bioavailability. For the synthesis of RDV-NLCs, the aqueous phase containing Tween 80 was injected into the lipid phase under rapid stirring and was sonicated. The experimental conditions were optimized using Box-Behnken design and Design Expert software. The optimum formulation contained a total lipid of 2.13%, a total surfactant of 1%, and a hot bath time of 71 min. The optimum formulation showed particle size, polydispersity index, zeta potential, and entrapment efficiency values of 151.0 ± 1.7 nm (from 149.1 to 152.1), 0.4 ± 0.1 (from 0.3 to 0.5), −43.8 ± 1.2 mV (from −42.4 to −44.7), and 81.34 ± 1.57% (from 79.52 to 82.33%), respectively. RDV-NLCs showed acceptable stability for 30 days at 25 ℃ and were compatible with commonly used intravenous infusion fluids for 48 h. FE-SEM images of RDV-NLC showed spherical particles with a mean diameter of 207 nm. The NLC-RDV formulation showed a sustained release of RDV with a low risk of dose-dumping, minimizing potential side effects. In addition, RDV in the form of RDV-NLC causes less cytotoxicity to healthy normal kidney cells, which is expected to reduce renal impairment in COVID-19 patients. [ABSTRACT FROM AUTHOR]

Poor water solubility of drugs is a limiting factor for their bioavailability and pharmacological activity. Many approaches are known to improve drug solubility, and among them, the physical method, solid dispersions (SDs), is applied. SDs are physical mixtures of a drug and a carrier, sometimes with the addition of a surfactant, which can be obtained by milling, cryomilling, spray-drying, or lyophilization processes. In this study, solid dispersions with etodolac (ETD-SDs) were prepared by the milling method using different carriers, such as hypromellose, polyvinylpyrrolidone, copovidone, urea, and mannitol. Solubility studies, dissolution tests, morphological assessment, thermal analysis, and FTIR imaging were applied to evaluate the SD properties. It was shown that the ball-milling process can be applied to obtain SDs with ETD. All designed ETD-SDs were characterized by higher water solubility and a faster dissolution rate compared to unprocessed ETD. SDs with amorphous carriers (HPMC, PVP, and PVP/VA) provided greater ETD solubility than dispersions with crystalline features (urea and mannitol). FTIR spectra confirmed the compatibility of ETD with tested carriers. [ABSTRACT FROM AUTHOR]

In this study, a novel oral formulation of berberine hydrochloride (BBH) hydrogel was successfully synthesized through physical cross-linking using chitosan (CS) and carboxymethyl-β-cyclodextrin (CMCD). The characterization results confirmed the successful synthesis of the CS/CMCD hydrogel and the subsequent loading of BBH into this composite (CS/CMCD/BBH) was effectively accomplished. The BBH was used as a model drug and the resulting hydrogel demonstrated a sustained drug release profile. In addition to its improved solubility and sustained release characteristics, the hydrogel exhibited excellent antibacterial activity against common pathogens such as Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), and Candida albicans (C. albicans). Additionally, in vitro studies indicated that the hydrogel was not cytotoxic to NIH3T3 and HaCaT cells, suggesting its safety for biomedical applications. This lack of cytotoxic effects, combined with the mechanical strength, solubility improvements, and antibacterial properties of the hydrogel, positions the CS/CMCD/BBH hydrogel as a promising candidate for the effective oral delivery of BBH. By addressing the solubility and delivery challenges of BBH, this hydrogel offers a viable solution for the oral administration of BBH, with potential applications in various biomedical fields. [ABSTRACT FROM AUTHOR]

The oral pathway is the preferred drug administration route in pharmaceutical sciences, however, the most employed 'highly active' drug candidates suffer from poor water solubility. The aim of this study was to develop repaglinide (RL)-loaded chitosan-grafted mesoporous silica material (MSM) to enhance drug dissolution. Such enhanced dissolution was investigated in in vitro and in vivo conditions. Our results showed successful grafting of chitosan (CN) on the surface of the MSM and the loading of RL into the mesopores of the silica host. Furthermore, the obtained drug dissolution profiles were fitted to mathematical models to characterize and compare drug dissolution profiles. Cytotoxicity evaluation against the human colorectal adenocarcinoma (Caco-2) cell line showed concentration-dependent toxicity for the MSN-based particles. Various liver and kidney mitochondrial functional parameters including lipid peroxidation assay, complex II activity, mitochondrial glutathione (GSH) level assay, ferric reducing antioxidant power (FRAP) assay, protein carbonyl level, and reactive oxygen species (ROS) formation, were used to investigate the biosafety of the silica-based dissolution enhancer. A significant reduction in blood glucose was observed after oral administration of the biocomposites for 24 h. The histopathological studies of the kidney and liver indicated no MSM-related adverse effects. We believed that our achievements can help the use of the hybrid organic–inorganic MSMs in improving the bioavailability of PWSDs in the one hand and, on the other hand, open a novel avenue to develop biocompatible and nontoxic MSMs in oral bioavailability of PWSDs. [ABSTRACT FROM AUTHOR]

Amphotericin B (AmB) is the gold standard for antifungal therapy; however, its poor solubility limits its administration via intravenous infusion. A promising formulation strategy to achieve an oral formulation is the development of amorphous solid dispersions (ASDs) via spray-drying. Inclusion of surfactants into ASDs is a newer concept, yet it offers increased dissolution opportunities when combined with a polymer (HPMCAS 912). We developed both binary ASDs (AmB:HPMCAS 912 or AmB:surfactant) and ternary ASDs (AmB:HPMCAS 912:surfactant) using a variety of surfactants to determine the optimal surfactant carbon chain length and functional group for achieving maximal AmB concentration during in vitro dissolution. The ternary ASDs containing surfactants with a carbon chain length of 14 ± 2 carbons and a sulfate functional group increased the dissolution of AmB by 90-fold compared to crystalline AmB. These same surfactants, when added to a binary ASD, however, were only able to achieve up to a 40-fold increase, alluding to a potential interaction occurring between excipients or excipient and drug. This potential interaction was supported by dynamic light scattering data, in which the ternary formulation produced a single peak at 895.2 dnm. The absence of more than one peak insinuates that all three components are interacting in some way to form a single structure, which may be preventing AmB self-aggregation, thus improving the dissolution concentration of AmB. [ABSTRACT FROM AUTHOR]

Neratinib maleate (NM), a tyrosine kinase inhibitor, is used in the treatment of breast cancer. NM is orally administered at a high dose of 290 mg due to its low solubility and poor dissolution rate at pH > 3, as well as gut-wall metabolism limiting its bioavailability. Self-emulsifying drug delivery systems (SEDDSs) of NM were developed in the current study to improve its oral bioavailability. The oily vehicle (clove oil) was selected based on the solubility of NM, while the surfactant and the cosurfactant were selected based on the turbidimetric analysis. Three different sets were screened for surfactant selection in the preparation of SEDDS formulations, the first set containing Cremophor® EL alone as the surfactant, the second set containing a mixture of Cremophor® EL (surfactant) and Caproyl® PGMC (cosurfactant), and the third set containing a mixture of Cremophor® EL (surfactant) and Capmul® MCM C8 (cosurfactant). Propylene glycol was used as the cosolubilizer in the preparation of SEDDSs. A series of studies, including the construction of ternary phase diagrams to determine the zone of emulsification, thermodynamic stability studies (involving dilution studies, freeze-thaw, and heating–cooling studies), turbidimetric analysis, and physicochemical characterization studies were conducted to identify the two most stable combinations of SEDDSs. The two optimized SEDDS formulations, TP16 and TP25, consisted of clove oil (45% w/w) and propylene glycol (5% w/w) in common but differed with respect to the surfactant or surfactant mixture in the formulations. TP16 was prepared using a mixture of Cremophor® EL (surfactant) and Caproyl® PGMC (cosurfactant) in a 4:1 ratio (50% w/w), while TP25 contained only Cremophor® EL (50% w/w). The mean globule sizes were 239.8 ± 77.8 nm and 204.8 ± 2.4 nm for TP16 and TP25, respectively, with an emulsification time of <12 s for both formulations. In vitro drug dissolution studies performed at different pH conditions (3.0, 4.5, 6.8) have confirmed the increase in solubility and dissolution rate of the drug by TP16 and TP25 at all pH conditions compared to plain NM. An oral pharmacokinetic study in female Wistar rats showed that the relative bioavailability (Frel) values of TP16 and TP25 over the plain NM were 2.18 (p < 0.05) and 2.24 (p < 0.01), respectively. [ABSTRACT FROM AUTHOR]

Topical ocular drug delivery faces several challenges due to the eye's unique anatomy and physiology. Physiological barriers, tear turnover, and blinking hinder the penetration of drugs through the ocular mucosa. In this context, nanoparticles offer several advantages over traditional eye drops. Notably, they can improve drug solubility and bioavailability, allow for controlled and sustained drug release, and can be designed to specifically target ocular tissues, thus minimizing systemic exposure. This study successfully designed and optimized PLGA and PCL nanoparticles for delivering baricitinib (BTB) to the eye using a factorial design, specifically a three-factor at five-levels central rotatable composite 23+ star design. The nanoparticles were small in size so that they would not cause discomfort when applied to the eye. They exhibited low polydispersity, had a negative surface charge, and showed high entrapment efficiency in most of the optimized formulations. The Challenge Test assessed the microbiological safety of the nanoparticle formulations. An ex vivo permeation study through porcine cornea demonstrated that the nanoparticles enhanced the permeability coefficient of the drug more than 15-fold compared to a plain solution, resulting in drug retention in the tissue and providing a depot effect. Finally, the in vitro ocular tolerance studies showed no signs of irritancy, which was further confirmed by HET-CAM testing. [ABSTRACT FROM AUTHOR]

The objective of the conducted research was to design 2 mm orodispersible minitablets of pediatric doses of hydrocortisone (0.5 mg; 1.0 mg) with desirable pharmaceutical properties and eliminate the sensation of a bitter taste using preparation of solid dispersion by ball mill. Hydrocortisone was selected as the model substance, as it is widely utilized in the pediatric population. ODMTs were prepared by compression (preceded by granulation) in a traditional single-punch tablet machine and evaluated using pharmacopoeial tests, DSC, and FTIR analysis. The methods used to evaluate the effectiveness of the taste-masking effect included in vivo participation of healthy volunteers, in vitro drug dissolution and utilization of an analytical device—"electronic tongue". The research employed a preclinical animal model to preliminary investigate the bioequivalence of the designed drug dosage form in comparison to reference products. The study confirmed the possibility of manufacturing good-quality hydrocortisone ODMTs with a taste-masking effect owing to the incorporation of a solid dispersion in the tablet mass. [ABSTRACT FROM AUTHOR]

The present study investigated the effect of different polymers and manufacturing methods (hot melt extrusion, HME, and spray drying, SD) on the solid state, stability and pharmaceutical performance of amorphous solid dispersions. In the present manuscript, a combination of different binary amorphous solid dispersions containing 20% and 30% of drug loadings were prepared using SD and HME. The developed solid-state properties of the dispersions were evaluated using small- and wide-angle X-ray scattering (WAXS) and modulated differential scanning calorimetry (mDSC). The molecular interaction between the active pharmaceutical ingredients (APIs) and polymers were investigated via infrared (IR) and Raman spectroscopy. The in vitro release profile of the solid dispersions was also evaluated to compare the rate and extend of drug dissolution as a function of method of preparation. Thereafter, the effect of accelerated stability conditions on the physicochemical properties of the solid dispersions were also evaluated. The results demonstrated higher stability of Soluplus® (SOL) polymer-based solid dispersions as compared to hydroxypropyl methylcellulose (HPMC)-based solid dispersions. Moreover, the stability of the solid dispersions was found to be higher in the case of API having high glass transition temperature (Tg) and demonstrated higher interaction with the polymeric groups. Interestingly, the stability of the melt-extruded dispersions was found to be slightly higher as compared to the SD formulations. However, the down-processing of melt-extruded strands plays critical role in inducing the API crystal nuclei formation. In summary, the findings strongly indicate that the particulate properties significantly influence the performance of the product. [ABSTRACT FROM AUTHOR]

Food can change various physiological parameters along the gastrointestinal tract, potentially impacting postprandial drug absorption. It is thus important to consider different in vivo conditions during in vitro studies. Therefore, a novel dissolution medium simulating variable postprandial pH values and lipid concentrations was developed and used in this study. Additionally, by establishing and validating a suitable analytical method, the effects of these parameters on the dissolution of a model drug, cinnarizine, and on its distribution between the lipid and aqueous phases of the medium were studied. Both parameters, pH value and lipid concentration, were shown to influence cinnarizine behavior in the in vitro dissolution studies. The amount of dissolved drug decreased with increasing pH due to cinnarizine's decreasing solubility. At pH values 5 and 7, the higher concentration of lipids in the medium increased drug dissolution, and most of the dissolved drug was distributed in the lipid phase. In all media with a lower pH of 3, dissolution was fast and complete, with a significant amount of drug distributed in the lipid phase. These results are in accordance with the in vivo observed positive food effect on cinnarizine bioavailability described in the literature. The developed medium, with its ability to easily adjust the pH level and lipid concentration, thus offers a promising tool for assessing the effect of co-ingested food on the dissolution kinetics of poorly soluble drugs. [ABSTRACT FROM AUTHOR]

The deposition, residence time, and dissolution profile of nasal suspensions containing corticosteroids play a key role in their in vivo efficacy after administration. However, the conventional methods available to characterize nasal products appear to be unsuitable to exhaustively cover these aspects. The work aims to investigate technological aspects of Ryaltris (mometasone furoate and olopatadine hydrochloride nasal spray) compared to other commercial anti-allergic nasal products, namely, Dymista (azelastine hydrochloride and fluticasone propionate), Nasonex (mometasone furoate), and Avamys (fluticasone furoate). Innovative characterization methods were combined with more traditional approaches to investigate the anti-allergic nasal sprays. These methods applied together allowed to differentiate between the different products and provided a clear picture of the nasal product behavior in terms of drug dissolution and deposition. In particular, the dissolution tests were performed exploiting the Respicell® apparatus, an innovative technique that allows for the investigation of inhalation products. Then, formulation viscosities were considered along with a formulation flow test on an inclined plane. Finally, the intranasal deposition profile of the commercial formulations was determined using a silicon nasal cast. The results highlight in vitro significant differences in terms of viscosity as well as dissolution rate of the nasal products, with Ryaltris showing a higher viscosity and lower flow compared to other products, which, along with a corticosteroid faster dissolution rate than Dymista, suggest a potential advantage in terms of clinical behavior. [ABSTRACT FROM AUTHOR]

Indomethacin (IND) as a non-selective cyclooxygenase 1 and 2 inhibitor administered orally causes numerous adverse effects, mostly related to the gastrointestinal tract. Moreover, when applied exogenously in topical preparations, there are obstacles to its permeation through the stratum corneum due to its low water solubility and susceptibility to photodegradation. In this work, solid dispersions (SDs) of IND with low-substituted hydroxypropyl cellulose (LHPC) were developed. The IND—SDs were incorporated into a hydroxypropyl guar (HPG) hydrogel to enhance drug solubility on the skin. The hydrogels were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), powder X-ray diffraction (XRPD), Fourier-transform infrared spectroscopy (FTIR), viscosity, drug release, and unspecific cytotoxicity in mammalian cells. SEM showed a highly porous structure for SD hydrogels. DSC and XRPD studies showed that amorphous IND species were formed; therefore, these hydrogels exhibited superior drug release in comparison with IND raw material hydrogels. FTIR evidenced the presence of the hydrogen bond in the SD hydrogel. The rheology parameter viscosity increased across gels formulated with SDs in comparison with hydrogels with pure IND. In addition, IND—SD hydrogels combine the advantages of a suitable viscosity for dermal use and no potentially hazardous skin irritation. This study suggests that the formulated IND—SD hydrogels represent a suitable candidate for topical administration. [ABSTRACT FROM AUTHOR]

Sulfated polysaccharides have a variety of important biologically active properties, such as anticoagulant, hypolipidemic, antiviral activity, the ability to be a means of targeted drug delivery and to improve the water solubility of certain drugs. Initial and sulfated polysaccharides' biological activity depends on the method of their preparation, composition and structure. Currently, there is an extensive body of literature data on methods for the sulfation of various natural polysaccharides. However, modern reviews on this topic mainly focus on the biological activity and application of sulfated polymers, rather than on synthesis methods. The latest comprehensive review on methods for the synthesis of sulfated polysaccharides was performed by Caputo in 2019. To further study this area, you need to know the latest trends in this topic. Based on this, we decided to create a new, up-to-date review covering most of the existing methods for the synthesis of sulfated polysaccharides. This work examined methods for the synthesis of biologically active polysaccharide sulfates and their effect on polymer characteristics, as well as the advantages and disadvantages of each method. Traditional methods for sulfating polysaccharides were reviewed such as using a complex of sulfur trioxide with pyridine, and new methods based on the use of toxic free and corrosive free reagents. Some data on the biological activity of the obtained polysaccharides are considered. [ABSTRACT FROM AUTHOR]

[Display omitted] • Presenting a universal carrier designed to address issues like inadequate solubility, limited targeting, and complex preparation processes for a variety of anticancer drugs. • The as-prepared SN38-GY-CCYRGD nanoparticles exhibit greatly improved solubility, targeting efficacy and enhanced anticancer effectiveness. • Pioneering an innovative delivery method, seamlessly integrating efficient and secure techniques into a unified carrier system, custom-designed for hydrophobic anticancer drugs. The current state of drug delivery systems allows for the resolution of specific issues like inadequate solubility, limited targeting capabilities, and complex preparation processes, requiring tailored designs for different drugs. Yet, the major challenge in clinical application lies in surmounting these obstacles with a universal carrier that is effective for a variety of anticancer drugs. Herein, with the help of computer simulation, we rationally design ultrashort peptides GY and CCYRGD, which can co-assemble with hydrophobic anticancer drugs into nanoparticles with enhanced solubility, targeting ability and anticancer efficacy. Taking 7-ethyl-10-hydroxy camptothecin (SN38) as a model anticancer drug, the co-assembled SN38-GY-CCYRGD nanoparticles significantly enhance the water solubility of SN38 by more than three orders of magnitude. The as-prepared nanoparticles can effectively kill cancer cells, e.g., human small cell lung cancer (A549) cells with a notable cell mortality rate of 71%. Mice experimental results demonstrate the nanoparticles' efficient targeting capability, marked reducing the toxicity to normal tissues while improving antitumor efficacy. This work presents a novel drug delivery method, integrating effective, targeted, and safe strategies into a comprehensive carrier system, designed for the administration of hydrophobic anticancer drugs. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD), affecting about ten million people globally, presents a significant health challenge. Rotigotine (RTG), a dopamine agonist, is currently administered as a transdermal patch (Neupro®) for PD treatment, but the daily application can be burdensome and cause skin irritation. This study introduces a combinatorial approach of dissolving microarray patch (MAP) and nanosuspension (NS) for the transdermal delivery of RTG, offering an alternative to Neupro®. The RTG-NS was formulated using a miniaturized media milling method, resulting in a nano-formulation with a mean particle size of 274.09 ± 7.43 nm, a PDI of 0.17 ± 0.04 and a zeta potential of −15.24 ± 2.86 mV. The in vitro dissolution study revealed an enhanced dissolution rate of the RTG-NS in comparison to the coarse RTG powder, under sink condition. The RTG-NS MAPs, containing a drug layer and a 'drug-free' supporting baseplate, have a drug content of 3.06 ± 0.15 mg/0.5 cm2 and demonstrated greater amount of drug delivered per unit area (∼0.52 mg/0.5 cm2) than Neupro® (∼0.20 mg/1 cm2) in an ex vivo Franz cell study using full-thickness neonatal porcine skin. The in vivo pharmacokinetic studies demonstrated that RTG-NS MAPs, though smaller (2 cm2 for dissolving MAPs and 6 cm2 for Neupro®), delivered drug levels comparable to Neupro®, indicating higher efficiency per unit area. This could potentially avoid unnecessarily high plasma levels after the next dose at 24 h, highlighting the benefits of dissolving MAPs over conventional transdermal patches in PD treatment. [Display omitted] • An alternative approach to deliver rotigotine via microarray patch was introduced. • Dose per unit area can be improved by using such approach in comparison to Neupro®. • A single 24 h application can provide therapeutic rotigotine levels to at least 2 days. • Unnecessarily high rotigotine plasma level may be avoided by using such approach. [ABSTRACT FROM AUTHOR]

AbstractThe growing co-consumption of botanical natural products with conventional medications has intensified the need to understand potential effects on drug safety and efficacy. This review delves into the intricacies of intestinal pharmacokinetic interactions between botanical natural products and drugs, such as alterations in drug solubility, permeability, transporter activity, and enzyme-mediated metabolism. It emphasizes the importance of understanding how drug solubility, dissolution, and osmolality interplay with botanical constituents in the gastrointestinal tract, potentially altering drug absorption and systemic exposure. Unlike reviews that focus primarily on enzyme and transporter mechanisms, this article highlights the lesser known but equally important mechanisms of interaction. Applying the Biopharmaceutics Drug Disposition Classification System (BDDCS) can serve as a framework for predicting and understanding these interactions. Through a comprehensive examination of specific botanical natural products such as byakkokaninjinto, green tea catechins, goldenseal, spinach extract, and quercetin, we illustrate the diversity of these interactions and their dependence on the physicochemical properties of the drug and the botanical constituents involved. This understanding is vital for healthcare professionals to effectively anticipate and manage potential natural product-drug interactions, ensuring optimal patient therapeutic outcomes. By exploring these emerging mechanisms, we aim to broaden the scope of natural product-drug interaction research and encourage comprehensive studies to better elucidate complex mechanisms. [ABSTRACT FROM AUTHOR]

Ensifentrine (ENSE) is a bifunctional dual phosphodiesterase 3/4 inhibitor that has both anti-inflammatory and bronchodilatory activities and is considered a new option for the therapy of chronic obstructive pulmonary disease (COPD) and various other respiratory inflammatory diseases for which it is currently undergoing clinical trials. This study presents a groundbreaking effort to evaluate the impact of ENSE polymorphs (forms I, II, and III) on ENSE solubility and chemical stability—both of which are critical factors for drug formulation. Different procedures for the induced crystallisation of ENSE were adopted, and the obtained polymorphic forms were investigated. All the newly obtained solid forms were characterized via single-crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), field emission scanning electron microscopy (FE-SEM), nuclear magnetic resonance (1H & 13C NMR), solid-state UV-visible spectroscopy, Fourier-transform infrared (FT-IR) spectroscopy, thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC)). Interestingly, altering various crystallisation processes with varied solvent polarity in the solution affects the crystal structure and polymorphic forms. Form I (parent form) was converted into forms II and III using the reactive crystallization method with combinations of formic acid : H2O (1 : 1) and formic acid : ethyl acetate (1 : 1), respectively. The reverse transformation was accomplished through gradual evaporation using different solvents. Similarly, variable-temperature PXRD (VT-PXRD) experiments revealed that form II converted into form I at 204 °C, whereas form III remained unaltered. In addition, the physicochemical properties of these three polymorphs were thoroughly discussed, and their solubility was tested in pH 1.2 and pH 7 media. A comprehensive examination of the residue that was recovered after solubility tests verified that form II and form III were converted into form I at both pH levels and that form I did not exhibit any phase change or dissociation at pH 7, whereas at pH 1.2, form I was converted into a new stable form and a thorough analysis verified that it was transformed into ENSE.Cl salt. To the best of our knowledge, this is the first study on the investigation of multiple forms of ENSE with varying physicochemical properties, and we hope that the current data will offer some valuable perspective prior to the development of ENSE as a medication. [ABSTRACT FROM AUTHOR]

Monoanionic gold bis(dithiolene) complexes were recently shown to display activity against ovarian cancer cells, Gram-positive bacteria, Candida strains and the rodent malaria parasite, P. berghei. To date, only monoanionic gold(III) bis(dithiolene) complexes with a thiazoline backbone substituted with small alkyl chains have been evaluated for biomedical applications. We now analyzed the influence of the length and the hydrophobicity vs. hydrophilicity of these complexes' alkyl chain on their anticancer and antiplasmodial properties. Isomer analogues of these monoanionic gold(III) bis(dithiolene) complexes, this time with a thiazole backbone, were also investigated in order to assess the influence of the nature of the heterocyclic ligand on their overall chemical and biological properties. In this report we present the total synthesis of four novel monoanionic gold(III) bis(dithiolene) complexes with a long alkyl chain and a polyoxygenated (PEG) chain aiming to improve their solubility and biological properties. Our results showed that the complexes with a PEG chain showed promising anticancer and antiplasmodial activities beside improved solubility, a key parameter in drug discovery and development. [ABSTRACT FROM AUTHOR]

Absolute qualifications with the application of protic ionic liquids (PILs) and a recognition of the numerous thermophysical features of these materials are required in various processes. Due to the wonderful applications of these compounds and their high potential in the chemical and pharmaceutical industries, there is a particular eagerness to utilize these PILs in drug solubility and delivery area. The aim of this investigation was to explore the solubility of the acetaminophen (ACP) in three PILs base on ethanolamine laurate [(2-hydroxyethylammonium laurate [MEA]La), (bis(2-hydroxyethyl)ammonium laurate [DEA]La), and (tris(2-hydroxyethyl)ammonium laurate [TEA]La)]. The shake flask method has been employed in this study, and the conditions were set at T = (298.15–313.15) K and atmospheric pressure. Moreover, the experimental solubility data was correlated using a variety of empirical and thermodynamic models, encompassing e-NRTL and Wilson activity coefficient models and the empirical models such as Van't Hoff-Jouyban-Acree and Modified Apelblat-Jouyban-Acree. Their performance for the system containing [MEA]La follow the trend for activity coefficient models and empirical respectively: the Wilson > e-NRTL and Modified Apelblat–Jouyban–Acree > Van't Hoff–Jouyban–Acree. On the other hand, [DEA]La and [TEA]La PILs followed slightly different trend for activity coefficient models and empirical respectively: the Wilson > e-NRTL and Van't Hoff–uyban–Acree > Modified Apelblat–Jouyban–Acree. The Van't Hoff and Gibbs equations were used to determine the thermodynamic properties of dissolution in the studied systems. [ABSTRACT FROM AUTHOR]

Efficient drug delivery is crucial for the creation of effective pharmaceutical treatments, and polyethylene glycol (PEG) carriers have been emerged as promising candidates for this purpose due to their bio-compatibility, enhancement of drug solubility, and stability. In this study, we utilized molecular simulations to examine the interactions between PEG carriers and selected drug molecules extracted from Celastrus hindsii: Hindsiilactone A, Hindsiiquinoflavan B, Maytenfolone A, and Celasdin B. The simulations provided detailed insights into the binding affinity, stability, and structural properties of these drug molecules when complexed with PEG carriers. A multi-scale approach combining density functional theory (DFT), extended tight-binding (xTB), and molecular dynamics (MD) simulations was conducted to investigate both unbound and bound states of PEG/drug systems. The results from DFT and xTB calculations revealed that the unbound complex has an unfavorable binding free energy, primarily due to negative contributions of delta solvation free energy and entropy. The MD simulations provided more detailed insights into the interactions between PEG and drug molecules in water solutions. By integrating the findings from the multi-scale simulations, a comprehensive picture of the unbound and bound states of PEG and drug systems were obtained. This information is valuable for understanding the molecular mechanisms governing the binding of drugs in PEG-based delivery platforms, and it contributes to the rational design and optimization of these systems. [ABSTRACT FROM AUTHOR]

ABSTRACT:The partial water solubility of ambrisentan poses a challenge to its oral administration despite being the second oral endothelin A-receptor antagonist approved in the United States. In this study, we aimed to improve ambrisentan’s solubility and bioavailability using an amphiphilic phospholipid carrier. Phospholipids, with their glycerol-bound, phosphorus-containing amphiphilic nature, are known to prolong drug lifespan by facilitating drug penetration across cell membranes through hydrogen bonds or van der Waals interactions. Moreover, phospholipid compounds have been shown to significantly enhance drug solubility, permeability, and bioavailability in various studies. We optimized the ratios of ambrisentan and phospholipid carriers (1:1, 1:3, and 1:5) based on saturation and phase solubility experiments. Solid dispersion was prepared using the solvent evaporation technique. Differential scanning calorimetry (DSC), X-ray diffraction (XRD), and scanning electron microscopy (SEM) analyses confirmed the conversion of ambrisentan from a crystalline to an amorphous form in the solid dispersion. The solubility of ambrisentan in the solid dispersion increased by 13-fold with a 1:5 ratio of ambrisentan to phospholipid carrier. The release profile indicated rapid release of the active substance within the first 15 min, corresponding to the peak phospholipid concentration. Pharmacokinetic studies demonstrated higher bioavailability of the medicine compared to the pure drug. This study suggests that phospholipids can effectively enhance drug solubility and bioavailability in solid dispersion systems. [ABSTRACT FROM AUTHOR]