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Supramolecular assemblies of stimuli-responsive amphiphilic molecules have been of utmost interest in targeted drug delivery applications, owing to their capability of sequestering drug molecules in one set of conditions and releasing them in another. To minimize undesired disassembly and stabilize noncovalently encapsulated drug molecules, the strategy of core or shell cross-linking has become a fascinating approach to constructing cross-linked polymeric or small molecule-based nanoassemblies. In this article, we discuss the design and synthetic strategies for cross-linked nanoassemblies from small molecule-based amphiphiles, with robust stability and enhanced drug encapsulation capability. We highlight their potential biomedical applications, particularly in drug or gene delivery, and cell imaging. This feature article offers a comprehensive overview of the recent developments in the application of small molecule-based covalently cross-linked nanocarriers for materials and biomedical applications, which may inspire the use of these materials as a potential drug delivery system for future chemotherapeutic applications. [ABSTRACT FROM AUTHOR]

Degradable polar hydrophobic ionic polyurethanes (D-PHI) are an emerging class of biomaterials with particular significance for blood-contacting applications due to their immunomodulatory effects and highly customizable block chemistry. In this manuscript, D-PHI polymer was formulated as a nanoparticle excipient for the first time by inverse emulsion polymerization. The nanoparticles were optimized with consideration of diameter, surface charge, size variability, and yield as a delivery vehicle for a custom vascular therapeutic peptide. A layer-by-layer (LBL) surface modification technique using poly-L-lysine was integrated within the nanoparticle design to optimize therapeutic loading efficiency. Solvent pH played a pivotal role in emulsion micelle formation, LBL polymer secondary structure, and the polymer functional group interactions critical for high therapeutic loading. The resulting nanoparticle platform met target size (200 ± 20 nm), polydispersity (<0.07), and storage stability standards, was nontoxic, and did not affect therapeutic peptide bioactivity in vitro. Surface-modified D-PHI nanoparticles can be reproducibly manufactured at low cost, generating a highly customizable excipient platform suitable for delivery of biomolecular therapeutics. These nanoparticles have potential applications in vascular drug delivery via localized infusion, drug eluting stents, and drug-coated angioplasty balloons. Nanoscale excipients have become critical in the delivery of many therapeutics to enhance drug stability and targeted biodistribution through careful design of nanoparticle composition, surface chemistry, and size. This manuscript describes the development of a nanoparticle excipient derived from an immunomodulatory degradable polar hydrophobic ionic polyurethane, in combination with a layer-by-layer surface modification approach utilizing poly-L-lysine, to transport a mimetic peptide targeting smooth muscle cell migration in vascular disease. The nanoparticle platform draws on the effect of pH to maximize drug loading and tailor particle properties. The low cost and easily reproducible system presents a highly customizable platform that can be adapted for therapeutic delivery across a wide range of clinical indications. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: This study developed and validated a simple, robust, and cost-effective RP-HPLC bioanalytical method for the determination of nebivolol hydrochloride (NBH) and amlodipine besylate (AMB) in human plasma. Briefly, NBH and AMB were extracted from plasma through protein precipitation using 5% formic acid and acetonitrile. Chromatographic separation was achieved using an Inertsil ODS-3 V column (150 mm × 4.6 mm, 5 μm) with a mobile phase composed of acetonitrile and buffer (40:60, v/v). The analysis was conducted using UV detection at 215 nm. Results: The bioanalytical method demonstrated linearity for NBH (4.50–180.12 μg/mL) and AMB (3.50–140.06 μg/mL). It exhibited good selectivity and sensitivity, with LLOQ responses within ≤ 20% of the analyte signal. Accuracy and precision were within acceptable limits. The extraction recovery from human plasma showed a CV (%) of 1.15% for NBH and 1.35% for AMB, indicating consistent recovery rates. Stability studies on drug-spiked human plasma at LQC and HQC levels confirmed the stability of the drugs under various conditions. Conclusion: The present bioanalytical method successfully quantified NBH and AMB simultaneously in plasma samples. It demonstrated suitability, supported by high recovery rates and low relative standard deviations. With its proven linearity, accuracy, and precision, this technique is well suited for drug identification in plasma samples. [ABSTRACT FROM AUTHOR]

PVA‐κcarrageenan (κCar) gel is widely used in the pharmaceutical field for transdermal drug delivery, enhancing drug stability and bioavailability. This study aims to modify PVA‐κCar gel by introducing tannic acid. Lidocaine was used as a model drug for incorporation into the novel gel. The PVA‐κCar matrix was mixed with tannic acid prior to freeze– thaw cycle to create a gel composite. The physicochemical features of this gel were evaluated using FTIR, XRD, thermal analysis, and SEM. The presence of tannic acid has reduced the thermal stability of PVA‐κCar from 84 to around 70 °C. The gel content of tannic acid‐modified PVA‐κCar was 34.6% (A) and 52.1% (B). The addition of tannic acid substantially increased gel viscosity. Cytotoxicity analysis showed that tannic acid‐modified PVA‐κCar gel did not affect the viability of HCT colon cancer cells. The encapsulation efficiency of lidocaine in tannic acid‐modified PVA‐κCar was 13 ± 0.2% (A) and 12 ± 0.5% (B), while the drug loading was 0.96 ± 0.01 (A) and 0.91 ± 0.02 (B). In vitro release of lidocaine from the modified PVA‐κCar exhibited a sustained release mechanism in phosphate‐buffered saline solution. These findings indicate that the gel possesses advantageous characteristics as a drug carrier. [ABSTRACT FROM AUTHOR]

Purpose: Fingolimod (FTY720; FT), a structural analog of sphingosine, has potential ocular applications. The goal of this study was to develop an FT-loaded nanoemulsion (NE; FT-NE) formulation for the efficient and prolonged delivery of FT to the posterior segment of the eye through the topical route. Methods: FT-NE formulations were prepared using homogenization followed by the probe sonication method. The lead FT-NE formulations (0.15% and 0.3% w/v loading), comprising soybean oil as oil and Tween® 80 and Poloxamer 188 as surfactants, were further evaluated for in vitro release, surface morphology, filtration sterilization, and stability at refrigerated temperature. Ocular bioavailability following topical application of FT-NE (0.3%) was examined in Sprague-Dawley rats. Results: The formulation, at both dose levels, showed desirable physicochemical characteristics, a nearly spherical shape with homogenous nanometric size distribution, and was stable for 180 days (last time point checked) at refrigerated temperature postfiltration through a polyethersulfone (0.22 µm) membrane. In vitro release studies showed prolonged release over 24 h, compared with the control FT solution (FT-S). In vivo studies revealed that effective concentrations of FT were achieved in the vitreous humor and retina following topical application of FT-NE. Conclusions: The results from these studies demonstrate that the FT-NE formulation can serve as a viable platform for the ocular delivery of FT through the topical route. [ABSTRACT FROM AUTHOR]

AbstractVesicular nanocarriers like niosomes and liposomes are widely researched for controlled drug delivery systems, with niosomes emerging as promising alternatives due to their higher stability and ease of manufacturing. This study aimed to develop and characterize a niosomal formulation for the encapsulation and sustained release of temozolomide (TMZ), a model lipophilic drug, and to compare the stability of niosomes and liposomes, with a particular focus on the behavior of their lipid bilayers. Niosomes were prepared using the thin-film hydration method, composed of Span 60 (Sorbitan monostearate), cholesterol, and soy lecithin in varying molar ratios. The study investigated critical properties such as drug loading capacity, release kinetics, and resistance to enzymatic degradation. The optimized formulation was analyzed for drug entrapment efficiency and stability against phospholipase A2 (PLA2) degradation. The optimized niosomal formulation, with a 4:2:1 molar ratio of Span 60: cholesterol, achieved a high TMZ entrapment efficiency of 73.23 ± 1.02% and demonstrated sustained drug release over 24 hours. In comparison, liposomes released their TMZ payload within 4 hours upon exposure to PLA2, while the niosomes maintained their release profile, indicating superior stability. Spectroscopic and thermal analysis confirmed successful drug encapsulation with no component incompatibilities. [ABSTRACT FROM AUTHOR]

This study aimed to synthesize and characterize chitosan-coated noisomal doxorubicin for the purpose of enhancing its medical application, particularly in the field of cancer treatment. Doxorubicin, a potent chemotherapeutic agent, was encapsulated within noisomes, which are lipid-based nanocarriers known for their ability to efficiently deliver drugs to target sites. Chitosan, a biocompatible and biodegradable polysaccharide, was used to coat the surface of the noisomes to improve their stability and enhance drug release properties. The synthesized chitosan-coated noisomal doxorubicin was subjected to various characterization techniques to evaluate its physicochemical properties. Transmission electron microscopy (TEM) revealed a spherical structure with a diameter of 500–550 ± 5.45 nm and zeta potential of +11 ± 0.13 mV with no aggregation or agglomeration. Chitosan-coated noisomes can loaded doxorubicin with entrapping efficacy 75.19 ± 1.45%. While scanning electron microscopy (SEM) revealed well-defined pores within a fibrous surface. It is observed that chitosan-coated niosomes loading doxorubicin have optimum roughness (22.88 ± 0.71 nm). UV spectroscopy was employed to assess the drug encapsulation efficiency and release profile. Differential scanning calorimetry (DSC) helped determine the thermal behavior, which indicated a broad endotherm peak at 52.4 °C, while X-ray diffraction (XRD) analysis provided information about the crystallinity of the formulation with an intense peak at 23.79°. Fourier-transform infrared spectroscopy (FTIR) indicated the formation of new bonds between the drug and the polymer. The findings from this study will contribute to the knowledge of the physical and chemical properties of the synthesized formulation, which is crucial for ensuring its stability, drug release kinetics, and biological activity. The enhanced chitosan-coated noisomal doxorubicin has the potential to improve the effectiveness and safety of doxorubicin in cancer treatment, offering a promising strategy for enhanced medical applications. [ABSTRACT FROM AUTHOR]

• More than 90 % of both patient groups, oMG and gMG were antibody-positive. • AChR antibody titer above 100 nmol/L seems to predict generalization. • oMG patients responded better to treatment, achieving quicker symptom satisfaction. • 1/3 (350) of all MG patients in Denmark was included in this chart review. • No difference in thymus pathology was found between oMG and gMG patients. The aim of this study was to evaluate clinical and serological differences between the ocular myasthenia gravis (oMG) and generalized MG (gMG). This study is a retrospective chart review, in which data was collected from patients fulfilling 2 of 3 diagnostic MG criteria (positive antibodies, evidence of neuromuscular transmission defect on neurophysiological examination, positive effect of pyridostigmine treatment). 350 patients were included and data concerning demographics and MG medical history were collected. Patients with oMG accounted for 15.7 % of the included patients. The two subgroups differed significantly in oMG having a later age at onset, lower AChR antibody-titers, longer doctor-to-diagnosis delay and less intensive MG treatment. Additionally, patients with oMG were faster at reaching a well-controlled disease state. Thymus pathology, number of antibody-positive (95.9 % of gMG and 94.5 % of oMG), sex, number of other autoimmune diseases and delay before drug stability did not differ between oMG and gMG. In conclusion, oMG is presumably a milder form of gMG characterized by lower AChR antibody-titers, a milder phenotype, and a quicker response to a less aggressive treatment. But otherwise, oMG and gMG show very similar characteristics, including the same frequency of positive AChR antibodies, which seems new compared to previous reports. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the physical compatibility between intravenous magnesium sulfate and potassium and sodium phosphate, a common electrolyte intravenous supplementation in pediatric intensive care units. Study design: Magnesium sulfate was mixed separately with potassium phosphate and sodium phosphate at ratios of 1:1, 1:4, and 4:1. Binary mixtures were prepared, in triplicate and under sterile conditions, by permuting the order of addition. The undiluted pure drugs were used as controls for possible sequence effects. Visual changes, turbidity, and pH were assessed immediately after mixing (baseline) and at 4 and 24 hours. Two observers performed visual changes by naked-eye visual inspection in order to search visible haze, particulate matter, gas formation, or color change. Turbidity was measured by nephelometry and incompatibility was defined as an increase of ≥0.5 nephelometric turbidity units (NTU) from baseline. pH was measured using a portable pH meter and incompatibility was defined as a variation of >1 pH unit during the observation period. Results: None of the admixtures exhibited visual changes or significant variations in turbidity (increases of ≥0.5 in nephelometric turbidity units) or pH (changes of >1 unit) during the observation period and neither compared with baseline. Conclusion: In this study, no visual changes were observed, and turbidity and pH evaluated by instrumental methods remained within acceptable limits and showed no significant variations from baseline, therefore no physical incompatibility between magnesium sulfate and potassium or sodium phosphate was found. [ABSTRACT FROM AUTHOR]

The aim of the study was to prepare nanostructured lipid carriers (NLCs) co-encapsulated with Quercetin and Morin and to compare the cytotoxicity of the NLCs with individual drugs as well as with their combination form. The Quercetin and Morin co-encapsulated NLCs were prepared by ultrasonication method. The size of the NLCs particles, the zeta potential value, % of drug entrapment efficiency (% EE), and % of cumulative drug release (% CDR) were estimated. The in vitro cytotoxicity study was carried out in MCF 7 cancer cell. The size of the NLCs particles ranged from 297.6 ± 14.1 to 456.4 ± 14.1 nm. The % EE of Quercetin and Morin in the optimized NLCs formulation (F6) were found to be 84.27 ± 2.1% and 87.11 ± 2.6%, respectively. However, the % CDR of Morin and Quercetin from the F6 formulation were 72.11 ± 3.4% and 81.56 ± 3.6%, respectively. The results of FTIR spectroscopy study indicated that the functional groups of Quercetin and Morin were remained intact in NLCs formulations. The TEM study result revealed that the prepared NLCs were spherical in shape. The in vitro cytotoxicity study result revealed that dual drug loaded NLCs showed higher cytotoxicity as compared to individual drug and their combinations. It was concluded that the Quercetin and Morin co-encapsulated NLCs formulation could be a promising candidate for combating the chemotherapy resistance in breast cancer. [ABSTRACT FROM AUTHOR]

The therapeutic potential of two important flavonoids, i.e. hesperidin and naringenin, remains unutilized due to pharmacokinetics issues, especially poor aqueous solubility. Hydrotropic solid dispersions with different agents like sodium salicylate, niacinamide, benzoic acid, and urea etc. can change the solubility profile of poorly soluble drugs. The current study investigated the potential of different hydrotropic agents in improving the solubility of both natural bioactives. The hydrotropic solid dispersion in 1:3 w/w drug: sodium salicylate ratio showed maximum solubility and dissolution amongst all the tested hydrotropes. This novel and economical approach could be explored for other poorly soluble pharmaceuticals. [ABSTRACT FROM AUTHOR]

Background: Currently, many natural gums are extensively utilized as suspending agents in the formulation of pharmaceutical suspensions. They are easily available, nontoxic, biodegradable, and cost‐effective to be used as pharmaceutical excipients. Objective: The present study was aimed at physicochemical characterization and evaluation of the suspending capacity of Boswellia papyrifera gum (BPG) in comparison with sodium carboxy methyl cellulose (SCMC) and tragacanth gum (TG). Methods: The extracted and powdered BPG was subjected to physicochemical properties such as micromeritics, solubility, swelling power, ash value, moisture content, conductivity, pH, and apparent viscosity using standard methods. Metronidazole benzoate suspensions were formulated using various concentrations of BPG, SCMC, and TG (1%–5% w/v). The apparent viscosity, flow rate, sedimentation volume, redispersibility number, pH, and drug content were studied as assessment parameters. Results: The micromeritic studies revealed that BPG exhibited good flow properties. There was also a significant increase in solubility and swelling power of the gum as a function of temperature. The gum had 2.78% ash value and 4.32% moisture content. Conductivity and apparent viscosity of the gum were found to be increased with concentration (p < 0.05). However, the apparent viscosity of BPG was decreased with shear rate (p < 0.05), rendering a pseudoplastic flow property of the gum, which is an ideal characteristic of suspending agents. The suspending capacity of the BPG was found to be comparable to SCMC, but higher than TG. Thus, it can be concluded that BPG could be used as the best alternative to natural and synthetic suspending agents. [ABSTRACT FROM AUTHOR]

Before embarking on any experimental research endeavor, it is advisable to do a mathematical computation and thoroughly examine the methodology. Despite the use of polymeric nanocarriers, the regulation of bioavailability and drug release at the disease site remains insufficient. Several effective methods have been devised to address this issue, including the creation of polymeric nanocarriers that can react to stimuli such as redox potential, temperature, pH, and light. The present study has been utilized all-atom molecular dynamics (AA-MD) and coarse-grained molecular dynamics (CG-MD) methods and illustrated the drug release mechanism, which is influenced by pH, for Chitosan-Eudragit bioresponsive nanocarriers. The aim of current work is to study the molecular mechanism and atomistic interactions of PAX delivery using a Chitosan-Eudragit carrier. The ability of Eudragit polymers to dissolve in various organic solvents employed in the process of solvent evaporation is a crucial benefit in enhancing the solubility of pharmaceuticals. This study investigated the use of Chitosan-Eudragit nanocarriers for delivering an anti-tumor drug, namely Paclitaxel (PAX). Upon analyzing several significant factors affecting the stability of the drug and nanocarrier, it has been shown that the level of stability is more significant in the neutral state than the acidic state. Furthermore, the system exhibits higher stability in the neutral state. The used Chitosan-Eudragit nanocarriers exhibit a stable structure under alkaline conditions, but undergo deformation and release their payloads under acidic conditions. It was demonstrated that the in silico analysis of anti-tumor drugs and carriers' integration could be quantified and validated by experimental results (from previous works) at an acceptable level. [ABSTRACT FROM AUTHOR]

Introduction: Chlorogenic acid (CGA) has been identified to possess salient antiinflammatory, antioxidant, and anticancer attributes. However, its application is limited by its instability and low bioavailability. Liposomes have been considered effective pharmaceutical delivery vehicles due to their ability to continuously release loaded drugs, improve drug stability, and display good biocompatibility. They can be easily modified by other small molecules to acquire additional biological functions. In this study, we developed and characterized folic acid-TPGS-modified chlorogenic acid liposome (FTCLP) and evaluated its antiinflammatory activity. Methods: The successful encapsulation of CGA within FTCLP was confirmed through examination using electron microscopy, fourier-transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC). The in vitro release characteristics of FTCLP were evaluated using the dialysis bag membrane method. Meanwhile, a dextran sulfate sodium (DSS) -induced colitis model was employed to investigate the anti-inflammatory effect of FTCLP and its mechanism. Results: The FTCLP exhibited an encapsulation efficiency (EE) of 84.85 ± 1.20% and a drug loading (DL) of 11.67 ± 0.04%. The particle size of FTCLP was determined to be 150.63 ± 0.71 nm, with a polydispersity index (PDI) of 0.198 ± 0.02 and a zeta potential of 2.61 ± 0.38 mV. The in vitro release profile followed the Higuchi model, indicating sustained-release characteristics. The in vivo study demonstrated that FTCLP treatment was effective in improving the symptoms of DSS-induced inflammatory response, as evidenced by mitigation of weight loss, reduction in the disease activity index (DAI) score, restoration of colon length, and attenuation of colon tissue damage. Furthermore, the levels of pro-inflammatory cytokines, including interferon-gamma (INF-γ), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6), were markedly diminished in both the serum and colon tissue. FTCLP was also observed to suppress the expression of INF-γ, IL-1β, IL-6, tumor necrosis factor-alpha (TNF-α), and nuclear factor kappa B (NF-κB) p65, while concomitantly upregulating the expression of Janus kinase (JAK) and signal transducer and activator of transcription 3 (STAT3). Besides, the administration of FTCLP was found to result in an increase in the abundance of Lactobacillaceae and Peptostreptococcaceae, while decreasing the abundance of Bacteroidaceae, Rikenellaceae, and Helicobacteraceae. Conclusion: Following encapsulation of CGA within liposomes, FTCLP revealed favorable stability and sustained release properties, and enhanced the antiinflammatory effects by modulating multiple inflammation-related biomarkers. FTCLP has the potential to be a safe and effective drug for targeted therapy of colitis. [ABSTRACT FROM AUTHOR]

The global health concern of pharmacoresistant epilepsy necessitates innovative therapeutic strategies. Drug resistance often arises due to complex pharmacokinetic challenges. Beta-cyclodextrin, known for enhancing drug solubility and stability, offers a potential solution for improving the efficacy of antiseizure medications. This study aims to investigate the impact of beta-cyclodextrin-complexed rufinamide on seizure-like activity using an in vitro model of temporal lobe epilepsy. Seizure-like neuronal activity was induced using a low-magnesium model. Local field potentials were recorded from transverse rat hippocampal slices. Rufinamide was solubilized using beta-cyclodextrin and administered at 100 micromolar concentration. The impact on various seizure-like parameters and time-resolved phase-amplitude coupling was assessed. Rufinamide increased the duration of the preictal phase while reducing the duration of ictal and postictal phases. The frequency of seizure-like events was higher in rufinamide. No significant change was observed in the firing rate of the first 10 ictal spikes, but the firing frequency of the second set of 10 ictal spikes was higher during rufinamide perfusion. Time-resolved phase-amplitude coupling maximum analysis did not reveal significant differences between the control and rufinamide treatment. Beta-cyclodextrin-solubilized rufinamide significantly modulates seizure-like event dynamics, exhibiting both anticonvulsant and proconvulsant effects. While the compound shortened seizure-like activity, it increased the frequency of seizure-like events. Our observations suggest a need for further investigation into the solubilization method and its impact on rufinamide's bioavailability. Dose-dependent effects and underlying molecular mechanisms should also be explored to enhance the pharmacological properties of antiseizure medications. [ABSTRACT FROM AUTHOR]

Dry-route manufacturing technology development poses challenges to pharmaceutical technology research specialists, relying on active substance characteristics, excipient selection, and parameter optimization. Amongst various technological possibilities high shear mixing generally ensures dosage uniformity and tablet dissolution through influential shear forces, potentially enhancing dry powder blend processability. This study explores the processability of a placebo formulation within the quality by design framework to address some of the aforementioned challenges. A 24 full-factorial experimental design was used to assess the manufacturability of a placebo formulation via high shear mixing. The effect of impeller and chopper speed, high shear mixing time, and homogenization/lubrication times on powder blend rheology and compression properties was investigated. The findings of the present study showed that product critical quality attributes like resistance to crushing or disintegration time are mainly dependent on the mixing efficiency translated by the impeller speed and high shear mixing time. Software augmented process development enabled the attainment of the design space, ensuring the fulfilment of desired product performance criteria. Furthermore, the study has also shown that the careful selection of excipients is crucial in the case of dry-route manufacturing technologies, as sodium lauryl sulphate can noticeably influence the processability of powder blends due to its lubricant properties. Considering the advantages and challenges raised by high-shear mixing, software aided data analysis can further augment the formulation, scale-up and lifecycle management of products developed using this technological process. [ABSTRACT FROM AUTHOR]

Background/Objectives: Hydroxypropyl methylcellulose (HPMC) is one of the most commonly used hydrophilic polymers in formulations of matrix tablets for controlled release applications. However, HPMC attracts moisture and poses issues with drug stability in formulations containing moisture-sensitive drugs. Methods: Herein, the moisture sorption behavior of excipients and drug stability using aspirin as the model drug in matrix tablets were evaluated, using HPMC and the newly developed mannitol-coated HPMC, under accelerated stability conditions (40 °C, 75% relative humidity) with open and closed dishes. Results: Tablets prepared with mannitol-coated HPMC showed a slower drug degradation rate compared to tablets prepared with directly compressible HPMC. Initial moisture content and hygroscopicity were stronger predictors of drug stability compared to water activity when comparing samples without similar moisture content. In the early stage (day 0 to 30), the aspirin degradation rate was similar in both open and closed conditions, as moisture content is the main degradation contributor. In the later stage (day 30 to 90), aspirin degradation was faster under closed conditions than under open conditions, likely due to autocatalytic effects caused by the volatile acidic by-product entrapped in the closed environment. Conclusions: The findings from this study reinforced the importance of judicious excipient selection based on the understanding of excipient–moisture interactions to maximize the chemical stability of moisture-sensitive drugs. Mannitol-coated HPMC is a promising addition to the formulator's toolbox for the formulation of controlled release dosage forms by direct compression. [ABSTRACT FROM AUTHOR]

Inhalable formulations with cyclodextrins (CDs) as solubility and absorption enhancers show promise for pulmonary delivery. Thiolated hydroxypropyl-β-cyclodextrin (HP-β-CD-SH) has mucoadhesive properties, enhancing drug absorption. Moreover, it has self-aggregation capability, which could further improve absorption and drug stability, as well as reduce irritation. This study aims to stabilize CD nanoaggregates using bifunctional cross-linkers and evaluate their benefits for lung drug delivery compared to pristine HP-β-CD-SH. Methods: The effectiveness of cross-linked HP-β-CD-SH nanoparticles (HP-β-CD-SH-NP) was compared to transient nanoaggregates in enhancing the activity of dexamethasone (DMS) and olive leaf extracts (OLE). DMS, a poorly soluble drug commonly used in lung treatments, and OLE, known for its antioxidant properties, were chosen. Drug-loaded HP-β-CD-SH-NP were prepared and nebulized onto a lung epithelial Air–Liquid Interface (ALI) model, assessing drug permeation and activity. Results: HP-β-CD-SH with 25% thiolation was synthesized via microwave reaction, forming 150 nm nanoaggregates and stabilized 400 nm HP-β-CD-SH-NP. All carriers showed good complexing ability with DMS and OLE and were biocompatible in the lung ALI model. HP-β-CD-SH promoted DMS absorption, while stabilized HP-β-CD-SH-NP protected against oxidative stress. Conclusion: HP-β-CD-SH is promising for lung delivery, especially as stabilized nanoaggregates, offering versatile administration for labile molecules like natural extracts. [ABSTRACT FROM AUTHOR]

A targeted micellar formation of doxorubicin (Dox) and curcumin (Cur) was evaluated to enhance the efficacy and reduce the toxicity of these drugs in KG1a leukemic stem cells (LSCs) compared to EoL-1 leukemic cells. Dox-Cur-micelle (DCM) was developed to improve the cell uptake of both compounds in LSCs. Cur-micelle (CM) was produced to compare with DCM. DCM and CM were conjugated with two FLT3 (FMS-like tyrosine kinase)-specific peptides (CKR; C and EVQ; E) to increase drug delivery to KG1a via the FLT3 receptor (AML marker). They were formulated using a film-hydration technique together with a pH-induced self-assembly method. The optimal drug-to-polymer weight ratios for the DCM and CM formulations were 1:40. The weight ratio of Dox and Cur in DCM was 1:9. DCM and CM exhibited a particle size of 20–25 nm with neutral charge and a high %EE. Each micelle exhibited colloidal stability and prolonged drug release. Poloxamer 407 (P407) was modified with terminal azides and conjugated to FLT3-targeting peptides with terminal alkynes. DCM and CM coupled with peptides C, E, and C + E exhibited a higher particle size. Moreover, DCM-C + E and CM-C + E showed the highest toxicity in KG-1a and EoL-1 cells. Using two peptides likely improves the probability of micelles binding to the FLT3 receptor and induces cytotoxicity in leukemic stem cells. [ABSTRACT FROM AUTHOR]

While bioactivity and a favorable safety profile for biotherapeutics is of utmost importance, manufacturability is also worth of consideration to ease the manufacturing process. Manufacturability in the scientific literature is mostly related to stability of formulated drug substances, with limited focus on downstream process‐related manufacturability, that is, how easily can a protein be purified. Process‐related impurities or biological impurities like viruses and host cell proteins (HCP) are present in the harvest which have mostly acid isoelectric points and need to be removed to ensure patient safety. Therefore, during molecule design, the surface charge of the target molecule should preferably differ sufficiently from the surface charge of the impurities to enable an efficient purification strategy. In this feasibility study, we evaluated the possibility of improving manufacturability by adapting the surface charge of the target protein. We generated several variants of a GLP1‐receptor‐agonist‐Fc‐domain‐FGF21‐fusion protein and demonstrated proof of concept exemplarily for an anion exchange chromatography step which then can be operated at high pH values with maximal product recovery allowing removal of HCP and viruses. Altering the surface charge distribution of biotherapeutic proteins can thus be useful allowing for an efficient manufacturing process for removing HCP and viruses, thereby reducing manufacturing costs. [ABSTRACT FROM AUTHOR]

There are many factors to consider when selecting a container closure system for parenteral drug products to maintain their quality, efficacy, and safety. One aspect to consider for products stored in glass vials is the glass type. Although the glass vials in which most parenteral products are stored are classified as Type I by the United States Pharmacopoeia, Chapter <660>, not all glass vials that meet the glass performance characteristics of Type I are equivalent. In the study presented here, Type I glass vials from three suppliers of three different Type I glass vials (standard, delamination control, and coated) were investigated to evaluate the impact that each Type I glass vial had on the stability of a drug product under development. To evaluate this impact, a three-phase study was conducted in which the compatibility between the drug product and each vial was assessed through the measurement of the critical quality attributes of the product, extractable and leachable inorganic elements were analyzed for each vial, and finally a stability study under accelerated conditions was conducted for the drug product in the most compatible vial based on the aforementioned experiments. Results from this study demonstrated that there are, in fact, significant differences in glass vials regardless of their classification as Type I. In the study conducted here, delamination control Type I glass vials were found to be superior to both Standard Type I and coated Type I vials for the drug product under investigation. [ABSTRACT FROM AUTHOR]

Brain can be a useful specimen for toxicology testing as it is a protected and isolated organ with lower metabolic activity than other tissues, but there is currently no published data supporting the stability of stimulant drugs in prepared brain homogenates. Brain homogenates were evaluated to determine the stability of the following stimulant drugs: amphetamine, benzoylecgonine, bupropion, cocaethylene, cocaine, ephedrine, methylenedioxyamphetamine, methylenedioxymethamphetamine, methamphetamine, and phentermine. Four different homogenates were prepared at a 1:4 dilution with deionized water and fortified at 500 ng/mL of: cocaine without sodium fluoride, cocaine with 1% sodium fluoride, stimulant drugs other than cocaine without sodium fluoride, and stimulant drugs other than cocaine with 1% sodium fluoride. The fortified homogenates were aliquoted into 13 × 100-mm screw cap tubes and stored at room temperature (∼20°C), refrigerated (2–8°C), or frozen (<−5°C) and analyzed in triplicate on Days 0, 1, 3, 7, 14, 30, 60, and 90. Analytes were considered stable as long as the difference in analyte/internal standard response ratio from Day 0 was less than 20% and the peaks met qualitative acceptance criteria. All analytes were stable for up to 90 days when stored frozen with or without sodium fluoride and had variable stability at all other evaluated conditions. [ABSTRACT FROM AUTHOR]

Recently, polymeric multi-layer capsules have gained a great deal of attention from the life science community. Furthermore, myriad interesting systems have appeared in the literature with biodegradable components and biospecific functionalities. In the present work, we presented a mathematical model of drug release from a multi-layer capsule into a target tissue. The diffusion problem was described by a system of coupled partial differential equations, Fickian and non-Fickian, which we solved numerically via nonuniform finite differences method. Energy estimates were further established for the coupled system and also, the convergence properties of the proposed numerical method were justified. We ultimately demonstrated the qualitative behavior of the system. [ABSTRACT FROM AUTHOR]

Wounds in diabetes is a complex problem that requires effective treatment at a high cost. Adjuvant therapy from natural bioactive elements can be an alternative to overcome problems in diabetic wound healing disorders. Allicin and quercetin are natural bioactive substances contained in several fruit or vegetable plants that have various pharmacological effects. The purpose of this study was to determine the effect of allicin and quercetin in emulsion form as wound medicine in helping the wound healing process. Diabetic wistar rats with wounds on their backs measuring 1 × 1 cm were divided into four treatment groups which were given wound medicine once a day for seven days according to their distribution. The wound healing process was evaluated on the third and seventh day. Data were observed and analyzed using appropriate statistical tools. Measurement of wound healing indicators was carried out by examining wound contraction and histopathological examination showing that the treatment group given the allicin and quercetin formula experienced an improvement compared to the treatment group without allicin and quercetin. Allicin and quercetin increase the percentage of wound contraction, increase the density of blood vessels and the epithelialization process in the wound so that the wound healing process becomes faster. In conclusion, allicin and quercetin can be effective adjuvant therapies in helping wound healing in diabetes. Wound medication in the form of an emulsion is an effective choice, because it can maintain the stability of the allicin and quercetin content and can make the wound environment moist. [ABSTRACT FROM AUTHOR]

Imatinib, a small molecule kinase inhibitor, is used as a cancer growth blocker. However, one of its most serious side effects is congestive cardiac failure. Reducing drug toxicity may be achieved through the use of drug delivery systems. Biocompatible metal-organic framework (MOF) materials, namely FeMIL-100 and FeMIL-101-NH2, were employed as potential imatinib carriers. They efficiently delivered the drug as an anticancer agent while minimizing cardiotoxicity. Notably, the release of imatinib from FeMIL-100 was rapid in acidic conditions and slower in pH-neutral environments, allowing targeted delivery to cancer cells. The carrier's pH-dependent stability governed the drug release mechanism. Two release models—Korsmeyer–Peppas and Weibull—were fitted to the experimental data and discussed in terms of drug release from a rigid microporous matrix. Cytotoxicity tests were conducted on two cell lines: HL60 (a model cell line for acute myeloid leukemia) and H9c2 (a cell line for cardiomyocytes). Overall, the metal-organic framework (MOF) carriers mitigated imatinib's adverse effects without compromising its effectiveness. [ABSTRACT FROM AUTHOR]

Fluorinated cyclopropanes are highly desired pharmacophores in drug discovery owing to the rigid nature of the cyclopropane ring and the beneficial effects of C−F bonds on the pharmacokinetic properties, cell permeability, and metabolic stability of drug molecules. Herein a biocatalytic strategy for the stereoselective synthesis of mono‐fluorinated and gem‐difluoro cyclopropanes is reported though the use of engineered myoglobin‐based catalysts. In particular, this system allows for a broad range of gem‐difluoro alkenes to be cyclopropanated in the presence of diazoacetonitrile with excellent diastereo and enantiocontrol (up to 99 : 1 d.r. and 99 % e.e.), thereby enabling a transformation not currently accessible with chemocatalytic methods. The synthetic utility of the present approach is further exemplified through the gram‐scale synthesis of a key gem‐difluorinated cyclopropane intermediate useful for the preparation of fluorinated bioactive molecules. [ABSTRACT FROM AUTHOR]

The objective of the present investigation is to improve the solubility of valsartan and prepare immediate release tablets. To increase the solubility and bioavailability of valsartan, a low-soluble antihypertensive drug, immediate release dosage forms were formulated by a direct compression method using a solid dispersion technique with three different carriers (β-cyclodextrin, polyvinyl pyrrolidone K30 and poloxamer 188) at three different ratios (1:3, 1:4 and 1:5). Nine physical mixtures (PM1–PM9) were prepared and various physical parameters were characterised in in vitro release studies. Out of the prepared physical mixtures, PM8 showed the best results, with 94.2% of the drug dissolving within 30 min. Formulation PM8 solid dispersion further used for the preparation of valsartan immediate release tablets by using sodium starch glycolate superdisintegrant, at different concentrations (3%, 4% and 5%; i.e., IF1, IF2 and IF3 formulations, respectively). The optimised formulation showed friability and disintegration values of 0.456±0.9 and 6.2±0.4 min. Among the three immediate release formulations, IF2, which contains 4% sodium starch glycolate, demonstrated an 84.46% drug release in 30 min and a 99.69% drug release in 1 hr, indicating increased drug solubility. When compared with a valsartan pure drug, the solubility of the solid dispersion increased by 135.06-fold. The results show that the optimised IF2 formulation demonstrated enhanced drug solubility by 135.06-fold, using a solid dispersion technique with poloxamer 188. This can be explained by the conversion of crystalline to an amorphous form of drug, leading to a reduction in the contact angle between the drug and the gastric medium. It can be concluded that poloxamer 188 is a suitable carrier and that use of a physical mixture technique is an applicable method to improve the solubility of valsartan. [ABSTRACT FROM AUTHOR]

This article evaluates the current gaps around the impact of post-manufacturing processes on the product qualities of protein-based biologics, with a focus on user centricity. It includes the evaluation of the regulatory guidance available, describes a collection of scientific literature and case studies to showcase the impact of post-manufacturing stresses on product and dosing solution quality. It also outlines the complexity of clinical handling and the need for communication, and alignment between drug providers, healthcare professionals, users, and patients. Regulatory agencies provide clear expectations for drug manufacturing processes, however, guidance supporting post-product manufacturing handling is less defined and often misaligned. This is problematic as the pharmaceutical products experience numerous stresses and processes which can potentially impact drug quality, safety and efficacy. This article aims to stimulate discussion amongst pharmaceutical developers, health care providers, device manufacturers, and public researchers to improve these processes. Patients and caregivers' awareness can be achieved by providing relevant educational material on pharmaceutical product handling. [Display omitted] • After drug product manufacturing and release, drugs may experience additional stresses during transport and clinical handling that may potentially impact product quality, safety and efficacy. • This review highlights some of these complex post-manufacturing processes, from transport, pharmacy compounding and administration to patients. The controls of these processes can be governed by different national, states and local regulatory guideline, and sometimes follow non-harmonized practices, which lack the rigor of good manufacturing practices (GMP). • Many academic studies have been published to study drug stability, but they often lack the scientific rigors of GMP characterization due to the absence of validated analytical methods, well-characterized material, and risk-based experimental designs. In isolation, these observations provide an incomplete profile product stability profile and conflicts with recommendation from regulators and drug manufacturers. • The key to bridge these differences can be achieved through collaboration between industries, academics and regulators to better understanding product development and risks. RealHOPE project fosters data driven scientific research by bringing in industry expertise and resources to help academics improve on patient outcome and to help provide educational material for better understanding of drug product handling for all stakeholders including health care providers. [ABSTRACT FROM AUTHOR]

Nanoparticles composed of Levan and Dolutegravir (DTG) have been successfully synthesized using a spray drying procedure specifically designed for milk/food admixture applications. Levan, obtained from the microorganism Bacillus subtilis, was thoroughly characterized using MALDI-TOF and solid-state NMR technique to confirm its properties. In the present study, this isolated Levan was utilized as a carrier for drug delivery applications. The optimized spray-dried nanoparticles exhibited a smooth surface morphology with particle sizes ranging from 195 to 329 nm. In the in-vitro drug release experiments conducted in water media, the spray-dried nanoparticles showed 100 % release, whereas the unprocessed drug exhibited only 50 % release at the end of 24 h. Notably, the drug release in milk was comparable to that in plain media, indicating the compatibility. The improved dissolution rate observed for the nanoparticles could be attributed to the solid-state conversion (confirmed by XRD analysis) of DTG from its crystalline to amorphous state. The stability of the drug was verified using Fourier Transform Infra-Red Spectroscopy and Thermogravimetry-Differential Scanning Calorimetry analysis. To evaluate the in-vitro cellular toxicity, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was conducted, which revealed the CC 50 value of 88.88 ± 5.10 µg/mL for unprocessed DTG and 101.08 ± 37.37 µg/mL for DTG nanoparticles. These results indicated that the toxicity of the nanoparticles was comparable to the unprocessed drug. Furthermore, the anti-HIV activity of the nanoparticles in human cell lines was found to be similar to that of the pure drug, emphasizing the therapeutic efficacy of DTG in combating HIV. [Display omitted] [ABSTRACT FROM AUTHOR]

Freezing is essential for the stability of biological drug substances and products, particularly in frozen solution formulations and during the primary drying of lyophilized preparations. However, the unfrozen segment within the frozen matrix can alter solute concentration, ionic strength, and stabilizer crystallization, posing risks of increased biophysical instability and faster chemical degradation. While quantifying the unfrozen water content is important for designing stable biopharmaceuticals, there is a lack of analytical techniques for in situ quantitative measurements. In this study, we introduce a 1H magic angle spinning NMR technique to identify the freezing point (T ice) and quantify mobile water content in frozen biologics, applying this method to analyze the freezing of a commercial high-concentration drug product, Dupixent®. Our results demonstrate that water freezing is influenced by buffer salt properties and formulation composition, including the presence of sugar cryoprotectants and protein concentration. Additionally, the 1H chemical shift can probe pH in the unfrozen phase, potentially predicting the microenvironmental acidity in the frozen state. Our proposed methodology provides fresh insights into the analysis of freeze-concentrated solutions, enhancing our understanding of the stability of frozen and lyophilized biopharmaceuticals. [Display omitted] [ABSTRACT FROM AUTHOR]

Transport of biopharmaceuticals from a hospital to a patient's home is scarcely researched but it is essential to investigate the effects of such transport on the stability of the drug, before home-based care can take place. In this study, transport of biopharmaceuticals in vials that are marketed as ready-to-administer from a hospital pharmacy to patients' homes was investigated. Immunoglobulin packages were tracked with 10 G and 25 G shock indicators and temperature data loggers. In the control group, immunoglobulins were transported from the hospital pharmacy to the outpatient daycare unit. During the transport process to patients' homes (n = 39), almost half of the packages were shocked with 25 G and more than half of all packages exceeded the required temperature range. Fortunately, the results found do not affect the stability of the ready-to-administer vials with immunoglobulins. However, these results indicate that the transport of biopharmaceuticals should be better controlled as not all biopharmaceuticals or formulations are so stable. Therefore, results of this pilot study provide a basis for recommendations for home-based therapy. [ABSTRACT FROM AUTHOR]

This research work dives into the complexity of hot-melt extrusion (HME) and its influence on drug stability, focusing on solid dispersions containing 30% of glibenclamide and three 50:50 polymer blends. The polymers used in the study are Ethocel Standard 10 Premium, Kollidon SR and Affinisol HPMC HME 4M. Glibenclamide solid dispersions are characterized using thermal analyses (thermogravimetric analysis (TGA) and differential scanning calorimetry), X-ray diffraction and scanning electron microscopy. This study reveals the transformation of glibenclamide into impurity A during the HME process using mass spectrometry and TGA. Thus, it enables the quantification of the extent of degradation. Furthermore, this work shows how polymer–polymer blend matrices exert an impact on process parameters, the active pharmaceutical ingredient's physical state, and drug release behavior. In vitro dissolution studies show that the polymeric matrices investigated provide extended drug release (over 24 h), mainly dictated by the polymer's chemical nature. This paper highlights how glibenclamide is degraded during HME and how polymer selection crucially affects the sustained release dynamics. [ABSTRACT FROM AUTHOR]

This study investigates the use of camel milk-derived exosomes (CMEs) as carriers for ARV-825, an anticancer agent targeting bromodomain-containing protein 4 (BRD4), in oral chemotherapy. CMEs were isolated and characterized, and ARV-825-loaded CME formulations were prepared and evaluated through various in vitro and in vivo tests. The ARV-825-CME formulation exhibited an entrapment efficiency of 42.75 ± 5.05%, a particle size of 136.8 ± 1.94 nm, and a zeta potential of −32.75 ± 0.70 mV, ensuring stability and sustained drug release. In vitro studies showed a 5.4-fold enhancement in drug release kinetics compared to the free ARV-825 solution. Permeability studies indicated a 3.2-fold increase in apparent permeability, suggesting improved cellular uptake. Cytotoxicity assays demonstrated potent anticancer activity, with IC50 values decreasing by 1.5 to 2-fold in cancer cell lines SF8628 DIPG and H1975R (resistant to Osimertinib). In vivo pharmacokinetic studies in Sprague-Dawley rats revealed superior systemic absorption and bioavailability of ARV-825 from CMEs, with a 2.55-fold increase in plasma concentration and a 5.56-fold increase in AUC. Distribution studies confirmed absorption through the ileum. This research highlights the potential of CMEs as a promising delivery platform for ARV-825, enhancing its therapeutic efficacy and offering a novel approach to cancer treatment. [ABSTRACT FROM AUTHOR]

Glycopyrrolate is a competitive muscarinic receptor antagonist used in the treatment of sialorrhea, especially in pediatrics. Degradation research was conducted to better understand the stability of the active pharmaceutical ingredient (API). Using an HPLC-UV method, we evaluated the chemical stability of the oral solution of the galenic compound glycopyrrolate 0.5 mg/mL under different storage conditions. Method validation was performed according to the International Council for Harmonization (ICH) Q2(R2) guidelines. The results of the stability study of the galenic compound in different storage conditions, with the exception of those stored in glass containers at 45 °C for more than 3 months, were stable (100 ± 10% of the nominal concentration). The aim of this work was to study the stability of the galenic compound glycopyrrolate in two different types of containers and at three different storage temperatures. Glycopyrrolate showed degradation beyond the limits only in glass at 45 °C and after 2 months of storage. The results indicate that oral liquid dosage forms of glycopyrrolate are stable for at least 210 days when stored at room temperature or at 4 °C, in glass or PET, for at least 7 months, maintaining product quality according to the standards established by the European Pharmacopoeia, ensuring long-term coverage for pediatric patient therapies. [ABSTRACT FROM AUTHOR]

Bacterial respiratory tract infections (e.g., in patients with cystic fibrosis) may be treated with the intravenous infusion of a piperacillin/tazobactam (P/T) solution through an elastomeric device. In the present work, we combined a 24-h drug stability study with an assessment of the drug solution flow rate during an in vitro simulated infusion. Experiments were performed in triplicate with two excipient-free generic P/T solutions and an excipient-containing proprietary P/T solution in saline (all 50/6.25 mg/mL) released from an elastomeric infusion device at 32 °C. The P/T solutions' stability was assessed by an HPLC-UV assay, pH and osmolality measurements, a visual assessment, and particle counting. Before these analyses, a forced degradation study was performed. To assess the flow rate, a precision scale was used to weigh the solution collected at the infusion line outlet. The stability criteria were <10% degradation and a flow rate within ± 15% of the nominal value over the 24-h infusion period: all three P/T solutions were found to be stable. The actual flow rate was lower than the expected flow rate; this difference was probably due to the drug solution's high viscosity and must be taken into account in clinical use. [ABSTRACT FROM AUTHOR]

Background: Flucytosine is an antifungal agent used in combination with other medicines for the treatment of fungal infections. It was available as intravenous (IV), oral tablet, and capsule formulations up until October 2021, when the IV product, Ancotil, was discontinued with no alternative brands available. Aim: This study aimed to formulate a suitable formulation with appropriate stability data for medium to long‐term nasogastric (NG) administration use. Method: Flucytosine 500 mg tablets (Ancotil) were crushed and suspended in (1) Ora‐Plus (OP) + Ora‐Sweet (OS) and (2) Ora‐Blend (OB) to produce 100 mg/mL suspensions (n = 3 for each suspending base) that were stored at 2–8°C in amber glass bottles until assayed. Appearance, odour and pH, and the concentrations of flucytosine in the suspensions were determined by high‐performance liquid chromatography on days 1, 8, and 15. A subjective assessment of the ease of suspension for NG administration via a size 10fr nasogastric tube (NGT) was also tested. Ethics approval was not required for this research article as it was a stability study and did not contain human participants or human data. Results: One of the three OB suspension bottles demonstrated significant suspension clumping resulting in all OB suspensions being excluded from further analysis. There was no change in appearance, odour or pH with the OP + OS based flucytosine suspensions and they extruded easily through a size 10fr NGT with minimal force. The three OP + OS bottles of flucytosine suspension were stable (>98% at all timepoints assessed) for 15 days at 2–8°C when stored in amber glass bottles. Conclusions: The OP + OS suspensions showed chemical stability for up to 15 days when stored under refrigerated conditions and protected from light, making this a suitable multidose enteral alternative to IV flucytosine. [ABSTRACT FROM AUTHOR]

Simple Summary: Antibody–drug conjugates (ADCs) have emerged as a potent cancer therapy by selectively delivering cytotoxic payloads to tumors. However, they face limitations due to acquired resistance and adverse effects. New ADC formats, such as bispecific ADCs and probody–drug conjugates, offer potential solutions. Nevertheless, single-domain antibodies (VHHs), also known as nanobodies, present a promising alternative. VHHs possess unique characteristics over ADCs, including a smaller size, enhanced tissue penetration, and rapid clearance. Their stability, solubility, and manufacturability surpass those of conventional antibodies, enabling cost-effective production and expanding the range of targetable antigens. Therefore, VHHs can mitigate some of the risks associated with conventional ADCs, representing an exciting prospect for next-generation ADCs. Background: Antibody–drug conjugates (ADCs) represent potent cancer therapies that deliver highly toxic drugs to tumor cells precisely, thus allowing for targeted treatment and significantly reducing off-target effects. Despite their effectiveness, ADCs can face limitations due to acquired resistance and potential side effects. Objectives: This study focuses on advances in various ADC components to improve both the efficacy and safety of these agents, and includes the analysis of several novel ADC formats. This work assesses whether the unique features of VHHs—such as their small size, enhanced tissue penetration, stability, and cost-effectiveness—make them a viable alternative to conventional antibodies for ADCs and reviews their current status in ADC development. Methods: Following PRISMA guidelines, this study focused on VHHs as components of ADCs, examining advancements and prospects from 1 January 2014 to 30 June 2024. Searches were conducted in PubMed, Cochrane Library, ScienceDirect and LILACS using specific terms related to ADCs and single-domain antibodies. Retrieved articles were rigorously evaluated, excluding duplicates and non-qualifying studies. The selected peer-reviewed articles were analyzed for quality and synthesized to highlight advancements, methods, payloads, and future directions in ADC research. Results: VHHs offer significant advantages for drug conjugation over conventional antibodies due to their smaller size and structure, which enhance tissue penetration and enable access to previously inaccessible epitopes. Their superior stability, solubility, and manufacturability facilitate cost-effective production and expand the range of targetable antigens. Additionally, some VHHs can naturally cross the blood–brain barrier or be easily modified to favor their penetration, making them promising for targeting brain tumors and metastases. Although no VHH–drug conjugates (nADC or nanoADC) are currently in the clinical arena, preclinical studies have explored various conjugation methods and linkers. Conclusions: While ADCs are transforming cancer treatment, their unique mechanisms and associated toxicities challenge traditional views on bioavailability and vary with different tumor types. Severe toxicities, often linked to compound instability, off-target effects, and nonspecific blood cell interactions, highlight the need for better understanding. Conversely, the rapid distribution, tumor penetration, and clearance of VHHs could be advantageous, potentially reducing toxicity by minimizing prolonged exposure. These attributes make single-domain antibodies strong candidates for the next generation of ADCs, potentially enhancing both efficacy and safety. [ABSTRACT FROM AUTHOR]

A drug is any substance capable of altering the functioning of a person's body and mind. In this paper, a deterministic nonlinear model was adapted to investigate the behavior of drug abuse and addiction that incorporates intervention in the form of awareness and rehabilitation. In the mathematical analysis part, the positivity and boundedness of the solution and the existence of drug equilibria have been ascertained, which shows that the model consists of two equilibria: a drug-free equilibrium and a drug endemic equilibrium point. The drug-free equilibrium was found to be both globally and locally asymptotically stable if the effective reproduction number is less than or equal to one ( R c ≤ 1). Furthermore, we were able to show the existence of a unique drug endemic equilibrium whenever R c > 1. Global asymptotic stability of a drug endemic equilibrium point has been ascertained using a nonlinear Lyapunov function of Go–Volterra type, which reveals that the drug endemic equilibrium point is globally asymptotically stable if an effective reproduction number is greater than unity and if there is an absence of a reversion rate of mended individuals (i.e., ω = 0). In addition, an optimal control problem was formulated to investigate the optimal strategy for curtailing the spread of the behavior using control variables. The control variables are massive awareness and rehabilitation intervention of both public and secret addicted individuals. The optimal control simulation shows that massive awareness control is the best to control drug addiction in a society. In sensitivity analysis section, the proportion of those who are exposed publicly shows to be a must sensitive parameter that can reduce the reproduction number, and the effective contact rate shows to be a must sensitive parameter to increase the reproduction number. Numerical simulations reveal that the awareness rate of exposed publicly and the rehabilitation rate of addicted publicly are very important parameters to control drug addiction in a society. [ABSTRACT FROM AUTHOR]

Purpose: Generic lorazepam oral solution is supplied in a 30 mL multi-dose bottle requiring protection from light and refrigeration, with a beyond use date of 90 days once the bottle is opened. The repackaging of 1 mL doses of lorazepam oral solution into oral syringes allows for facilitated dispensing, yet no available data supports repackaging and storing lorazepam oral solution in syringes. The validation and application of a stability-indicating high-performance liquid chromatography with ultraviolet detection (HPLC-UV) method for the quantification of lorazepam allowed for the determination of the stability of lorazepam oral solution when stored in oral syringes. Methods: A stability-indicating HPLC-UV method was developed for the quantification of lorazepam in oral solution. The method was validated using guidance from USP < 1225 >. For the stability investigation, 2 mg/mL lorazepam oral solution was aliquoted into clear plastic oral syringes in 1 mLmilliliter doses from 2 multi-dose stock bottles and randomly allocated for storage in room temperature or refrigerated environment. Baseline lorazepam concentrations were measured on the day the study was initiated and designated as 100% initial concentration samples. Subsequent samples were analyzed in triplicate at time points of 24, 48, and 96 hours and 7, 10, 14, 21, 30, and 60 days. Results: The calibration curves on three non-consecutive days met the linearity criteria of R 2 > 0.99. Inter- day and intra-day precision and accuracy (percent relative standard deviation and percent error) were ≤2% over three days. During the stability investigation, percent initial concentration of lorazepam from room and refrigerated syringes remained above 90% for the duration of the study. Conclusion: The stability-indicating HPLC-UV method was successfully applied to the investigation of lorazepam oral solution stability when stored in syringes at room and refrigerated temperatures. The emergent need for use of lorazepam concentrate for inpatients and the restrictions of how the medication is supplied necessitated a need for the evaluation of repackaging into unit dose syringes for immediate availability from automated dispensing cabinets. Lorazepam oral solution stored in clear plastic syringes maintained greater than 90% initial concentration at both room and refrigerated temperatures for 60 days. [ABSTRACT FROM AUTHOR]

Retinal diseases are the leading cause of blindness, resulting in irreversible degeneration and death of retinal neurons. One such cell type, the retinal ganglion cell (RGC), is responsible for connecting the retina to the rest of the brain through its axons that make up the optic nerve and is the primary cell lost in glaucoma and traumatic optic neuropathy. To date, different therapeutic strategies have been investigated to protect RGCs from death and preserve vision, yet currently available strategies are restricted to treating neuron loss by reducing intraocular pressure. A major barrier identified by these studies is drug delivery to RGCs, which is in large part due to drug stability, short duration time at target, low delivery efficiency, and undesired off-target effects. Therefore, a delivery system to deal with these problems is needed to ensure maximum benefit from the candidate therapeutic material. Extracellular vesicles (EV), nanocarriers released by all cells, are lipid membranes encapsulating RNAs, proteins, and lipids. As they naturally shuttle these encapsulated compounds between cells for communicative purposes, they may be exploitable and offer opportunities to overcome hurdles in retinal drug delivery, including drug stability, drug molecular weight, barriers in the retina, and drug adverse effects. Here, we summarize the potential of an EV drug delivery system, discussing their superiorities and potential application to target RGCs. [Display omitted] [ABSTRACT FROM AUTHOR]

This narrative review aims to summarise the information available on the use of subcutaneous (SC) levetiracetam (LEV) in the adult palliative care setting using clinical texts, databases, journals, and grey literature. A search strategy utilising Embase, Medline CINALH and Cochrane databases, as well as Google Scholar, was conducted with the mapped search terms "levetiracetam", "subcutaneous" and "palliative". LEV intravenous (IV) proprietary products are used subcutaneously, including as continuous subcutaneous infusions (CSCIs), in the adult palliative care setting. The total LEV daily dose ranged from 250 mg to 5000 mg and LEV was administered with various diluents at varying volumes. The data identified a clinical desire to mix LEV with other medications; however, the current evidence on combination compatibility is observational only and drug stability in combinations is lacking. The majority of information in the literature on SC LEV use is based on case reports and retrospective audits. Case reports, whilst at times offering more clinical detail, represent specific circumstances not necessarily applicable to a larger patient cohort. The findings of retrospective audits are limited by the documentation and detail reported at the time of patient care that may not be designed for data collection. [ABSTRACT FROM AUTHOR]

The vascular system maintains cellular homeostasis by transporting oxygen, nutrients, and metabolic waste products. The vascular system is involved in a variety of fundamental physiological phenomena and is closely associated with human vascular diseases. Additionally, the stability of drugs in the vasculature affects their efficacy. Therefore, researchers have used vascular models to study vascular diseases, assess drug stability, and screen drugs. However, there are many shortcomings in the animal models and in vitro two-dimensional vascular models that have been extensively developed. In this paper, we specifically review the construction methods of in vitro vascular models and classify the specific methods into photolithography, soft lithography, self-assembly, template, 3D bioprinting, and laser degradation/cavitation. The first two are microfluidics-based methods and the last three are non-microfluidics-based methods. The vascular model construction methods reviewed in this paper overcome the shortcomings of traditional models—which cannot accurately reproduce the human vascular microenvironment—and can assist in the construction of in vitro 3D vascular models and tissue engineering vascularization. These models can be reused by perfusion devices, and the cells within the channels reside on biocompatible materials that are used to simulate the microenvironment and 3D cellular organization of the vasculature in vivo. In addition, these models are reproducible in shape and length, allowing experiments to be repeated, which is difficult to do with natural vessels. In vitro vascular models are widely used in research and drug screening for diseases associated with endothelial dysfunction, cancer, and other vascular abnormalities. [ABSTRACT FROM AUTHOR]

The increase in the variety of nano-based tools offers new possibilities to approach the therapy of poorly treatable tumors, which includes glioblastoma multiforme (GBM; a primary brain tumor). The available nanocomplexes exhibit great potential as vehicles for the targeted delivery of anti-GBM compounds, including chemotherapeutics, nucleic acids, and inhibitors. The main advantages of nanoparticles (NPs) include improved drug stability, increased penetration of the blood–brain barrier, and better precision of tumor targeting. Importantly, alongside their drug-delivery ability, NPs may also present theranostic properties, including applications for targeted imaging or photothermal therapy of malignant brain cells. The available NPs can be classified into two categories according to their core, which can be metal or non-metal based. Among non-metal NPs, the most studied in regard to GBM treatment are exosomes, liposomes, cubosomes, polymeric NPs, micelles, dendrimers, nanogels, carbon nanotubes, and silica- and selenium-based NPs. They are characterized by satisfactory stability and biocompatibility, limited toxicity, and high accumulation in the targeted tumor tissue. Moreover, they can be easily functionalized for the improved delivery of their cargo to GBM cells. Therefore, the non-metal NPs discussed here, offer a promising approach to improving the treatment outcomes of aggressive GBM tumors. [ABSTRACT FROM AUTHOR]

A peptide-based hydrogel sequence was computationally predicted from the Ala-rich cross-linked domains of elastin. Three candidate peptides were subsequently synthesised and characterised as potential drug delivery vehicles. The elastin-derived peptides are Fmoc-FFAAAAKAA-NH2, Fmoc-FFAAAKAA-NH2, and Fmoc-FFAAAKAAA-NH2. All three peptide sequences were able to self-assemble into nanofibers. However, only the first two could form hydrogels, which are preferred as delivery systems compared to solutions. Both of these peptides also exhibited favourable nanofiber lengths of at least 1.86 and 4.57 µm, respectively, which are beneficial for the successful delivery and stability of drugs. The shorter fibre lengths of the third peptide (maximum 0.649 µm) could have inhibited their self-assembly into the three-dimensional networks crucial to hydrogel formation. [ABSTRACT FROM AUTHOR]

Vinpocetine (VP) is distributed after oral and intravenous administration, and its uptake in the thalamus, basal ganglia, and visual cortex. Due to poor bioavailability (~7%) and marked first-pass effect (~75%), including a short half-life (2–3 h), oral administration of VP is limited. It requires frequent administration of the drug to obtain a therapeutic effect. Attempts to overcome these difficulties include the use of new drug delivery systems and/or alternative routes of drug administration. One possibility is the common administration of lipid emulsion and drug using the same catheter. However, this procedure is not recommended due to potential interaction and lack of safety data. For this purpose, we checked the compatibility of VP solutions with eight commercially available parenteral nutrition admixtures, i.e., Lipoflex special, Omegaflex special, Lipoflex peri, Omegaflex peri, Kabiven, SmofKabiven, Kabiven Peripheral, and Olimel Peri N4E. Coadministration is only possible if the stability of the drug and the lipid emulsion is confirmed. The available data are scarce and only concern the incompatibility of VP with ibuprofen. Compatibility tests were carried out in simulated administration through a Y-site connector using clinical flow rates. The stability of the drug and lipid emulsion was assessed by visual inspection and measurement of pH, osmolality, particle size as mean droplet diameter (MDD) and percentage of lipids residing in globules larger than 5 µm (PFAT5), zeta potential, polydispersity index, and lipid-free parenteral nutrition admixture(PNA) turbidity. The results of the compatibility of VP with eight commercial PN admixtures showed that all lipid emulsions show different signs of destabilization. In the studied samples, particles larger than 1000 nm, a significant increase in MDD, zeta potential, and loss of homogeneity visible as an increase in the polydispersity index were observed. Most of the samples had PFAT5 above the USP limit (0.05%). Taking into account the obtained data, VP should not be administered with the studied lipid emulsions for parenteral nutrition. [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]

Erastin, a ferroptosis-inducing system x c − inhibitor, faces clinical challenges due to suboptimal physicochemical and pharmacokinetic properties, as well as relatively low potency and off-target toxicity. Addressing these, we developed ECINs, a novel laser-responsive erastin-loaded nanomedicine utilizing indocyanine green (ICG)-grafted chondroitin sulfate A (CSA) derivatives. Our aim was to improve erastin's tumor targeting via CSA–CD44 interactions and enhance its antitumor efficacy through ICG's photothermal and photodynamic effects in the laser-on state while minimizing off-target effects in the laser-off state. ECINs, with their nanoscale size of 186.7 ± 1.1 nm and high erastin encapsulation efficiency of 93.0 ± 0.8%, showed excellent colloidal stability and sustained drug release up to 120 h. In vitro , ECINs demonstrated a mechanism of cancer cell inhibition via G1-phase cell cycle arrest, indicating a non-ferroptotic action. In vivo biodistribution studies in SK-HEP-1 xenograft mice revealed that ECINs significantly enhanced tumor distribution of erastin (1.9-fold greater than free erastin) while substantially reducing off-target accumulation in the lungs and spleen by 203-fold and 19.1-fold, respectively. Combined with laser irradiation, ECINs significantly decreased tumor size (2.6-fold, compared to free erastin; 2.4-fold, compared to ECINs without laser irradiation) with minimal systemic toxicity. This study highlights ECINs as a dual-modality approach for liver cancer treatment, demonstrating significant efficacy against tumors overexpressing CD44 and system x c −. Erastin-loaded chondroitin sulfate-propanesultone indocyanine green nanoparticles (ECINs) target CD44 and system x c − overexpressing hepatocellular carcinoma. Near-infrared laser irradiation at the tumor site triggers non-ferroptotic anticancer activity, further enhanced by phototherapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: The Target Product Profile (TPP) is a tool used in industry to guide development strategies by addressing user needs and fostering effective communication among stakeholders. However, they are not frequently used in academic research, where they may be equally useful. This systematic review aims to extract the features of accessible TPPs, to identify commonalities and facilitate their integration in academic research methodology. Methods: We searched peer-reviewed papers published in English developing TPPs for different products and health conditions in four biomedical databases. Interrater agreement, computed on random abstract and paper sets (Cohen's Kappa; percentage agreement with zero tolerance) was > 0.91. We interviewed experts from industry contexts to gain insight on the process of TPP development, and extracted general and specific features on TPP use and structure. Results: 138 papers were eligible for data extraction. Of them, 92% (n = 128) developed a new TPP, with 41.3% (n = 57) focusing on therapeutics. The addressed disease categories were diverse; the largest (47.1%, n = 65) was infectious diseases. Only one TPP was identified for several fields, including global priorities like dementia. Our analyses found that 56.5% of papers (n = 78) was authored by academics, and 57.8% of TPPs (n = 80) featured one threshold level of product performance. The number of TPP features varied widely across and within product types (n = 3–44). Common features included purpose/context of use, shelf life for drug stability and validation aspects. Most papers did not describe the methods used to develop the TPP. We identified aspects to be taken into account to build and report TPPs, as a starting point for more focused initiatives guiding use by academics. Discussion: TPPs are used in academic research mostly for infectious diseases and have heterogeneous features. Our extraction of key features and common structures helps to understand the tool and widen its use in academia. This is of particular relevance for areas of notable unmet needs, like dementia. Collaboration between stakeholders is key for innovation. Tools to streamline communication such as TPPs would support the development of products and services in academia as well as industry. [ABSTRACT FROM AUTHOR]

The limited number of available antifungal drugs and the increasing number of fungal isolates that show drug or multidrug resistance pose a serious medical threat. Several yeast pathogens, such as Nakaseomyces glabratus (Candida glabrata), show a remarkable ability to develop drug resistance during treatment through the acquisition of genetic mutations. However, how stable this resistance and the underlying mutations are in non-selective conditions remains poorly characterized. The stability of acquired drug resistance has fundamental implications for our understanding of the appearance and spread of drug-resistant outbreaks and for defining efficient strategies to combat them. Here, we used an in vitro evolution approach to assess the stability under optimal growth conditions of resistance phenotypes and resistance-associated mutations that were previously acquired under exposure to antifungals. Our results reveal a remarkable stability of the resistant phenotype and the underlying mutations in a significant number of evolved populations, which conserved their phenotype for at least two months in the absence of drug-selective pressure. We observed a higher stability of anidulafungin resistance over fluconazole resistance, and of resistance-conferring point mutations as compared with aneuploidies. In addition, we detected accumulation of novel mutations in previously altered resistance-associated genes in non-selective conditions, which suggest a possible compensatory role. We conclude that acquired resistance, particularly to anidulafungin, is a long-lasting phenotype, which has important implications for the persistence and propagation of drug-resistant clinical outbreaks. [ABSTRACT FROM AUTHOR]