Pharmaceutics

Background: As a modulator of pre-mRNA splicing, the anti-cancer agent indisulam can induce aberrantly spliced neoantigens, enabling immunologic anti-tumor activity. Consequently, combining indisulam with immunotherapy is expected to be a promising novel approach in cancer therapy. However, a prerequisite for such a combination is that immune effector cells remain functional and unharmed by the chemical. Methods: To ensure the immunocompetence of human immune effector cells is maintained, we investigated the influence of indisulam on ex vivo-isolated T cells and monocyte-derived dendritic cells (moDCs) from healthy donors. We used indisulam concentrations from 0.625 µM to 160 µM and examined the impact on the following: (i) the activation of CD4+ and CD8+ T cells by CD3-crosslinking and via a high-affinity TCR, (ii) the cytotoxicity of CD8+ T cells, (iii) the maturation process of moDCs, and (iv) antigen-specific CD8+ T cell priming. Results: We observed dose-dependent inhibitory effects of indisulam, and substantial inhibition occurred at concentrations around 10 µM, but the various functions of the immune system exhibited different sensitivities. The weaker activation of T cells via CD3-crosslinking was more sensitive than the stronger activation via the high-affinity TCR. T cells remained capable of killing tumor cells after treatment with indisulam up to 40 µM, but T cell cytotoxicity was impaired at 160 µM indisulam. While moDC maturation was also rather resistant, T cell priming was almost completely abolished at a concentration of 10 µM. Conclusions: These effects should be considered in possible future combinations of immunotherapy with the mRNA splicing inhibitor indisulam.

Background: Photodynamic therapy (PDT) has evolved as a reliable therapeutic modality for cancer. However, the broad application of the technique is still limited because of poor bioavailability and the non-selective distribution of photosensitizers within host tissues. Herein, zein, a natural corn protein, was functionalized with glycyrrhetinic acid (GA) and polyethylene glycol (Z-PEG-GA) as a targeting platform for liver cancer cells. Parietin, as novel photosensitizer, was successfully encapsulated into zein via nanoprecipitation and used for the therapy of hepatocellular carcinoma. Methods: The in vitro phototoxicity of Z-PEG-GA nanoparticles and their non-functionalized control (Z-PEG) were assessed against hepatocellular carcinoma (HepG2 cells) and the In vivo biodistribution was determined in an adult male CD-1 Swiss albino mice model. Results: The formulated Z-PEG and Z-PEG-GA showed spherical shapes with average sizes of 82.8 and 94.7 nm for unloaded nanoparticles, respectively, and 109.7 and 111.5 nm for loaded nanoparticles carrying more than 70% of parietin, and Quantum yield measurements show that parietin’s photodynamic potential is conserved. Moreover, parietin-loaded Z-PEG-GA exhibited three-fold higher toxicity against liver cancer cells than its non-functionalized control and attained more than an eleven-fold enhancement in the generated intracellular reactive oxygen species (ROS) at a 9 J/cm2 radiant exposure. The generated intracellular ROS led to mitochondrial disruption and the release of cytochrome c. In vivo biodistribution studies revealed that fluorescence signals of Z-PEG-GA can persist in the excised animal liver for up to 24 h post-administration. Conclusions: Consequently, tailored zein can hold great potential for delivering several hydrophobic photosensitizers in anticancer PDT.

Background: Fluconazole (FLZ) is a broad-spectrum anti-fungal drug presenting poor flowability, mechanical properties, and limited aqueous solubility. These issues pose challenges for the handling and manufacturing of dosage forms of FLZ. The current research aimed to develop fluconazole co-crystal (CC) for improving its aqueous solubility, flowability, and mechanical properties. (2) Methods: The fluconazole benzoic acid (FLZ-BA) co-crystal was prepared using the solvent evaporation technique. The prepared co-crystal was characterized for drug content, solubility, anti-fungal activity, dissolution, and stability. DSC (Differential Scanning Calorimetry), PXRD (Powder X-Ray Diffraction), SEM (Scanning Electron Microscopy), and FTIR (Fourier Transmission Infrared) spectroscopy were carried out to confirm the co-crystal formation. The co-crystal was further evaluated for their flow characteristics and mechanical properties via CTC (compressibility, tabletability, and compactibility), Heckel, and Kawakita analysis. (3) Results: The CC showed 69.51% drug content and 13-fold greater aqueous solubility than pure FLZ. The DSC thermogram showed a sharp endothermic peak between the parent components, a distinct PXRD pattern was observed, and the SEM analysis revealed a different morphology, confirming the formation of co-crystal (new crystalline form). The CC showed immediate drug release and was found to more stable, and less hygroscopic than FLZ alone. The CC revealed better flowability, tabletability (tensile strength), compressibility, and compactibility. Moreover, Heckel and Kawakita analysis indicated the co-crystal to deform plastically, favoring improved compression. (4) Conclusions: The immediate drug release capabilities, improved hygroscopic stability, solubility, better antifungal activity, and flowability make FLZ-BA co-crystal a suitable candidate for the preparation of an immediate drug release dosage form. The study also revealed the application of co-crystal for improving the flowability and mechanical properties.

Background/Objectives: Omeprazole is widely used for managing gastrointestinal disorders like GERD, ulcers, and H. pylori infections. However, its use in pediatrics presents challenges due to drug interactions (DDIs), metabolic variability, and safety concerns. Omeprazole’s pharmacokinetics (PK), primarily influenced by CYP2C19 metabolism, is affected by ontogenetic changes in enzyme expression, complicating dosing in children. Methods: This study aimed to develop and validate a physiologically based pharmacokinetic (PBPK) model for omeprazole and its metabolites to predict age-related variations in metabolism and response. Results: The PBPK model successfully predicted exposure to parent and metabolites in adults and pediatrics, incorporating competitive and mechanism-based inhibition of CYP2C19 and CYP3A4 by omeprazole and its metabolites. By accounting for age-dependent metabolic pathways, the model enabled priori predictions of omeprazole exposure in different age groups. Linking PK to the pharmacodynamics (PD) model, we described the impact of age-related physiological changes on intragastric pH, the primary outcome for proton pump inhibitors efficacy. Conclusions: The PBPK-PD model allowed for the virtual testing of dosing scenarios, providing an alternative to clinical studies in pediatrics where traditional DDI studies are challenging. This approach offers valuable insights for accurate dosing recommendations in pediatrics, accounting for age-dependent variability in metabolism, and underscores the potential of PBPK modeling in guiding pediatric drug development.

Background/Objectives: Infliximab, ipilimumab, and nivolumab are three monoclonal antibodies that have been associated with hepatotoxicity. Three separate physiologically based pharmacokinetic (PBPK) models were developed in GastroPlus® to simulate plasma and liver concentrations in patient populations after administration of either infliximab, ipilimumab, or nivolumab. Methods: The models include distribution and clearance mechanisms specific to large molecules, FcRn binding dynamics, and target-mediated drug disposition (TNF-α for infliximab, CTLA-4 for ipilimumab, and PD-1 for nivolumab). Results: The PBPK model for each large molecule was able to reproduce observed plasma concentration data in patient populations, including patients with rheumatoid arthritis and patients with solid tumors. Liver concentrations were predicted to be between 10% and 23% of the plasma concentrations for each of the three drugs, aligning with previously reported results. This lends further validity to the PBPK models and their ability to accurately predict hepatic concentrations in the absence of direct tissue measurements. Conclusions: These results can be used to drive liver toxicity predictions using the quantitative systems toxicology model, BIOLOGXsym™, which integrates hepatic interstitial concentrations with in vitro mechanistic toxicity data to predict the extent of liver toxicity for biologics.

Background: The prevalence of nontuberculous mycobacteria (NTM) infection is on the rise, surpassing that of pulmonary tuberculosis in Japan. Current standard therapy for NTM infection involves long-term treatment of at least 1.5 years, with low success rates and a high relapse rate. 99mTc-diethylenetriaminepentaacetic acid-galactosyl-human serum albumin (99mTc-GSA) is used for human liver imaging. In this study, we utilized 99mTc-GSA as a probe to detect Mycobacterium avium (M. avium), a major pathogen in NTM pulmonary diseases (NTM-PDs). Our aim was to investigate the non-invasive detection of M. avium using 99mTc-GSA on Single-Photon Emission Computed Tomography (SPECT). Methods: The accumulation of 99mTc-GSA in M. avium was investigated in vitro. In vivo, SPECT images were obtained after the administration of 99mTc-GSA to an M. avium thigh infection model. Subsequently, the contrast difference in accumulated 99mTc-GSA between infected and non-infected thighs was calculated using SPECT imaging. Furthermore, SPECT images were obtained for thighs infected with varying bacterial loads, and the accumulation was compared between them. Results: In vitro, we observed that 99mTc-GSA accumulates in M. avium. In vivo, SPECT images demonstrated the specific accumulation of 99mTc-GSA at the infection site, with this accumulation being correlated with the bacterial load. Conclusions: 99mTc-GSA specifically accumulates in M. avium, and SPECT can be used to monitor the distribution and quantity of M. avium in animals. By utilizing these measures, 99mTc-GSA can be targeted to the site of infection and used as a bacterial probe.

Chronic wounds pose a significant healthcare challenge, impacting millions of patients worldwide and burdening healthcare systems substantially. These wounds often occur as comorbidities and are prone to infections. Such infections hinder the healing process, complicating clinical management and proving recalcitrant to therapy. The environment within the wound itself poses challenges such as lack of oxygen, restricted blood flow, oxidative stress, ongoing inflammation, and bacterial presence. Traditional systemic treatment for such chronic peripheral wounds may not be effective due to inadequate blood supply, resulting in unintended side effects. Furthermore, topical applications are often impervious to persistent biofilm infections. A growing clinical concern is the lack of effective therapeutic modalities for treating chronic wounds. Additionally, the chemically harsh wound microenvironment can reduce the effectiveness of treatments, highlighting the need for drug delivery systems that can deliver therapies precisely where needed with optimal dosages. Compared to cell-based therapies, exosome-based therapies offer distinct advantages as a cell-free approach for chronic wound treatment. Exosomes are of endosomal origin and enable cell-to-cell communications, and they possess benefits, including biocompatibility and decreased immunogenicity, making them ideal vehicles for efficient targeting and minimizing off-target damage. However, exosomes are rapidly cleared from the body, making it difficult to maintain optimal therapeutic concentrations at wound sites. The hydrogel-based approach and development of biocompatible scaffolds for exosome-based therapies can be beneficial for sustained release and prolong the presence of these therapeutic exosomes at chronic wound sites. Engineered exosomes have been shown to possess stability and effectiveness in promoting wound healing compared to their unmodified counterparts. Significant progress has been made in this field, but further research is essential to unlock their clinical potential. This review seeks to explore the benefits and opportunities of exosome-based therapies in chronic wounds, ensuring sustained efficacy and precise delivery despite the obstacles posed by the wound environment.

Background/Objectives: Parkinson’s disease (PD) is a rapidly growing neurological disorder in the developed world, affecting millions over the age of 60. The decline in motor functions occurs due to a progressive loss of midbrain dopaminergic neurons, resulting in lowered dopamine levels and impaired muscle function. Studies show defective mitochondrial autophagy (or “mitophagy”) links to PD. Rho-associated coiled-coil containing protein kinases (ROCK) 1 and ROCK2 are serine/threonine kinases, and their inhibition can enhance neuroprotection in PD by promoting mitophagy. Methods: We examine the effects of ROCK inhibitor SR3677, delivered via macrophage-derived small extracellular vesicles (sEVs) to Parkin Q311X(A) PD mouse models. sEVs with SR3677, administered intranasally, increased mitophagy gene expression, reduced inflammatory factors, and elevated dopamine levels in brain tissues. Results: ROCK2 expression decreased, showing the drug’s inhibitory effect. sEV-SR3677 treatment was more effective than treatment with the drug alone, although sham EVs showed lower effects. This suggests that EV-SR3677 not only activates mitochondrial processes but also promotes the degradation of damaged mitochondria through autophagy. Mitochondrial functional assays and oxygen consumption in ex vivo glial cultures revealed that sEV-SR3677 significantly improved mitochondrial respiration compared to that in untreated or SR3677-only treated cells. Conclusion: We demonstrated the efficacy of ROCK2 inhibition on mitochondrial function via sEV-SR3677 in the PD mouse model, necessitating further studies to explore design challenges and mechanisms of sEV-SR3677 as mitochondria-targeted therapy for PD

Background/Objectives: The pharmaceutical industry demands stringent regulation of product characteristics and strives to ensure the reproducibility of granules manufactured via the wet granulation process. A systematic model employing the discrete element method (DEM) was developed herein to gain insights into and better control this process. Methods: The model comprehensively simulates particle behavior during granulation by considering the intrinsic properties of the powder material, the specific geometry of the granulation equipment, and various operational conditions, including impeller speed and chopper use. Notably, this approach can simulate dynamic interactions among particles and integrate complex phenomena, such as cohesion, which is crucial for predicting the formation and quality of granules. Results: To further support process optimization, an EDEMpy artificial intelligence (AI) tool was developed as a posttreatment routine to monitor and analyze agglomerate size distributions, proving essential for assessing the efficiency of the granulation process and the quality of resulting granules. The DEM model was evaluated by comparing its output with experimental data collected from a 0.5 L high-shear granulator. The model reproduced the granule growth kinetics observed experimentally, confirming the agreement between the experimental and numerical analyses. Conclusions: This underscores the model’s potential in predicting and controlling granule quality in wet granulation processes, enhancing the precision and efficiency of pharmaceutical manufacturing.

Background/Objectives: The phytochemicals ferulic acid (Fer) and eugenol display neuroprotective effects for their anti-oxidative properties; moreover, eugenol can induce dopamine (DA) release from dopaminergic neuronal cells. However, poor bioavailability and/or fast elimination rate limit their clinical benefits. We therefore propose a new nasal formulation based on a nanoemulsion (NE) for the jointed brain-targeting of eugenol and methyl ferulate (Fer-Me, i.e., a Fer-lipidized derivative maintaining the parent compound anti-oxidative properties). NE was obtained using chitosan oleate, a surfactant combining mucoadhesive and absorption-enhancing properties with stabilizing effects on the dispersion of eugenol, used as a Fer-Me vehicle. Methods: The nasal formulation was obtained by spontaneous emulsification processes; cell viability and uptake studies were performed on an in vitro model of respiratory mucosa (RPMI 2650 cells). After intravenous and nasal administrations, the pharmacokinetic profiles of eugenol and Fer-Me in rats’ bloodstreams and cerebrospinal fluid (CSF) were analyzed via HPLC-UV analysis. Results: The NE dispersed-phase mean diameter was 249.22 ± 32.78 nm; Fer-Me and eugenol loading in NE was about 1 and 2 mg/mL, respectively. NE increased the uptake of loaded compounds by mucosal cells. Following intravenous administration, the Fer-Me plasma half-life was 10.08 ± 0.37 min, and a negligible ability of the compound to permeate in the CSF, compared to eugenol, was observed. NE nasal administration allowed us to sensibly increase the Fer-Me brain-targeting and prolong the eugenol permanence in the CSF. Conclusions: This nasal formulation appears promising to overcome Fer and eugenol pharmacokinetic issues. The possible translational relevance of the present findings is discussed.

Background/Objectives: Carvacrol, a monoterpenoid phenol found in essential oils, exhibits many biological activities, including anticancer properties through mechanisms such as induction of apoptosis. These properties can be enhanced if encapsulated within nanoparticles. This study focuses on producing functionalized carvacrol-loaded nanostructured lipid carriers (NLCs) applied to the treatment of breast cancer. Methods: NLCs were produced by hot emulsification with the sonication method and optimized by the Box–Behnken design, considering Precirol® (1, 4, 7%), carvacrol (1, 5, 9%), and Tween® (0.1, 0.5, 0.9%) as independent variables. Results: The optimized NLC containing 2% carvacrol had a particle size of 111 ± 2 nm, PdI of 0.26 ± 0.01, and zeta potential of −24 ± 0.8 mV. The solid lipid (Precirol®) was the variable that most influenced particle size. NLCs were functionalized with Pluronic® F68, cholesterol, chitosan, and polyethylene glycol (0.05–0.2%), with oNLC-Chol presenting the most promising results, with no significant increase in particle size (±12 nm) and high encapsulation efficiency (98%). Infrared spectra confirm effective carvacrol encapsulation, and stability tests showed no significant physicochemical changes for 120 days of storage at 4 °C. When incubated with albumin (5 mg/mL), NLCs showed overall good stability over 24 h, except for oNLC-Chol, which increased slightly in size after 24 h. In addition, oNLC increased the cytotoxic effect of carvacrol by 12-fold, resulting in an IC50 of 7 ± 1 μg/mL. Conclusions: Therefore, it was possible to produce stable, homogeneous NLCs with nanometric sizes containing 2% carvacrol that displayed improved anticancer efficacy, indicating their potential as a delivery system.

Background: Melanoma is one of the most common malignancies, posing a significant health threat to patients, particularly in advanced stages due to its high aggressiveness. Chemotherapy agents with biocompatibility and low susceptibility to induce resistance are required for systematic management. Methods: Dendrimer-derived mimics (DMs) of host defense peptides (HDPs), which were constructed by a dendrimer core and optimized ratios of the hydrophobic arm, were used to treat A375 cells and HaCaT cells as the control. Live/dead staining, flow cytometry, and scanning electron microscopy (SEM) were conducted to analyze the anticancer mechanism. Mice with subcutaneous tumors were used to test the antitumor activity and toxicity in vivo. Results: DMs exhibited enhanced activity against A375 cells with remarkable selectivity, which mimics the action of natural HDPs and can cause damage to cell membranes. DMs can effectively inhibit solid tumor growth with minimal systemic toxicity and no adverse effects on healthy tissues. Conclusion: All the findings highlight DMs as promising anticancer candidates with significant potential for systemic melanoma therapy.

Background/Objectives: This study aimed to develop and evaluate an anti-pollution film-forming spray (FFS) containing coffee cherry pulp extract (FFS-CCS). The formulation was designed to create a protective skin barrier, improving skin health while defending against environmental pollutants. Its physical properties, dust resistance, stability, skin penetration, and clinical effectiveness were assessed to ensure optimal performance and safety. Methods: Various polymers and a ternary solvent system were used to enhance the stability and solubility of bioactive compounds from the coffee cherry pulp extract. The formulations were characterized based on appearance, film formation, viscosity, pH, spray uniformity, spray pattern, angle, film thickness, and particle adhesion. Stability testing was conducted under different storage conditions. Skin penetration was assessed using Franz diffusion cells with Strat-M® membranes to simulate human skin. A single-blind, placebo-controlled trial with 42 participants was conducted over 60 days to evaluate the effects of FFS-CCS on skin hydration, tone, and wrinkle reduction. Clinical assessments were performed using a Corneometer, Mexameter, and Skin Visioscan. Results: The FFS1-CCS formulation, incorporating PVP K90 and a ternary solvent system, significantly improved the solubility, stability, and bioavailability of key bioactive compounds (chlorogenic acid, caffeine, and theophylline). Physical characterization confirmed uniform, transparent films with optimal viscosity and sprayability. Stability testing showed minimal degradation. Skin penetration and retention studies revealed enhanced retention of bioactive compounds with minimal systemic absorption. PVP K90, along with ethanol and propylene glycol, extended the compounds’ residence time on the skin, ensuring localized delivery. Clinically, FFS1-CCS significantly improved skin hydration, reduced roughness, lightened skin tone, and decreased erythema. Conclusions: The FFS1-CCS formulation utilizing PVP K90 significantly enhanced the stability, bioavailability, and skin retention of coffee cherry pulp extract, resulting in improved skin hydration, wrinkle reduction, and skin tone enhancement. These findings highlight the potential of coffee cherry pulp extract as a multifunctional, sustainable cosmeceutical ingredient, offering both anti-aging and environmental protection benefits, making it a promising solution for skincare applications.

Pulmonary drug delivery is governed by three main categories of forces: interparticle forces in the powder formulation, the dispersion forces during inhalation by the device, and deposition forces in the lungs. The interaction between fine inhalable powder particles of the active ingredient is governed by various types of forces, such as capillary forces, electrostatic forces, and van der Waals forces. The different types of inter-particle interactions influence the balance between powder dispersibility and agglomerate stability. The high level of cohesion forces arising from high surface energy of very fine powder hinders powder flowability, leading to issues of agglomeration. Therefore, there is a critical need for advanced manufacturing techniques to overcome the challenges of handling and manufacture of fine cohesive particles, particularly high-dose powders for inhalation. This review will focus on the challenges facing the formulation process of very fine inhalable powder, the various types of existing particle engineering techniques for high-dose powder inhalers, and the characterization techniques employed to analyse the powder characteristics required to meet the acceptance criteria of inhalable preparations.

Background: Natural biopolymeric matrices for developing dressings have been extensively studied, as they may exhibit beneficial properties for wound healing. Gelatin possesses promising structural and physicochemical properties for incorporating active compounds (ACs). O/W emulsions are an alternative delivery system for AC with different properties and solubilities, promoting wound healing. Objective: This study aimed to develop gelatin films by adding silver nanoparticles and healing agents encapsulated in an O/W emulsion to treat skin wounds. Methods: A film-forming dispersion was prepared using gelatin and glycerol as a plasticizer, and films were obtained using the casting technique. Emulsions with ACs (EAs) and without ACs (ECs) were incorporated into the films. The formulations were analyzed by FESEM and characterized for their mechanical, thermal, and swelling properties, as well as their water vapor permeability. Results: The results showed that films with a higher amount of emulsion exhibited greater structural rigidity and lower permeability, while films with lower amounts of emulsion demonstrated more elasticity and higher permeability. General and organ-specific toxicity were evaluated in zebrafish larvae. The films showed no lethal or sub-lethal effects on the morphology or activity of the brain, heart, and liver. Conclusions: The active films developed could provide stable support and a safe delivery system for active compounds to treat skin lesions, minimizing the risk of infection and the need to heal a wound.

Objectives: This study highlighted the key role played by high-pressure (HP) dielectric spectroscopic measurements of amorphous CBD to probe the molecular dynamics in order to examine the physical stability of the drug. The pharmacological properties of CBD assure that this can be a promising drug for the pharmaceutical industry. Hence, it is important to check the physical stability under elevated temperature and pressure conditions to understand the behavior of the drug under manufacturing conditions. Methods: This research investigated the molecular dynamics at various temperatures and pressures. We utilized the HP dielectric studies which are considered as an advanced and sensitive tool to determine both the molecular dynamics and the phase transformations. Results: This paper discusses the physical stability by analyzing the behavior of structural relaxation and crystallization tendencies of the amorphous drug under ambient and elevated pressure conditions. This study verified that amorphous CBD is highly physically stable at storage and elevated temperature conditions under ambient pressure. Conclusions: Accordingly, we examined the physical stability under elevated pressures at storage temperature, and we observed that the compression induced the crystallization of amorphous CBD. The breaking of weak hydrogen bonds present in the CBD might be the reason for this destabilization at elevated pressures. The least physical stability at high-pressure conditions was also confirmed by the broadening of the α-relaxation peak at high pressures.

Background/Objectives: GL-II-73 is a positive allosteric modulator that is selective for α5GABAA receptors and has physicochemical properties that favor nanocarrier formulations when parenteral delivery to the central nervous system is desired. Our aim was to develop an optimized nanoemulsion containing GL-II-73 and subsequently test whether this would improve permeation across the blood–brain barrier (BBB) and availability in the brain. Methods: The nanoemulsions were formulated and subjected to detailed physiochemical characterization. The optimized formulation was tested in comparison to a solution of GL-II-73 in the appropriate solvent in an in vitro model of the blood–brain barrier based on human induced pluripotent stem cell-derived microvascular endothelial cells, astrocytes, and pericytes. Plasma and brain exposure to GL-II-73 and its metabolite MP-III-022 was investigated in an in vivo neuropharmacokinetic study in rats exposed to the selected nanoemulsion and the conventional solution formulation. Results: The selected biocompatible nanoemulsion exhibited satisfactory physicochemical properties for parenteral administration, with a Z-ave of 122.0 ± 1.5, PDI of 0.123 ± 0.009 and zeta potential of −40.7 ± 1.5, pH of 5.16 ± 0.04, and adequate stability after one year of storage, and allowed the localization of GL-II-73 in the stabilization layer. The permeability of GL-II-73 through the BBB was twice as high with the selected nanoemulsion as with the solution. The availability of GL-II-73 and MP-III-022 (also a positive allosteric modulator selective for α5GABAA receptors) in the brain was 24% and 61% higher, respectively, after intraperitoneal administration of the nanoemulsion compared to the solution; the former increase was statistically significant. Conclusions: The increased permeability in vitro proved to be a good predictor for the improved availability of GL-II-73 in brain tissue in vivo from the formulation obtained by encapsulation in a nanoemulsion. The putative additive effect of the parent molecule and its metabolite MP-III-022 could lead to enhanced and/or prolonged modulation of α5GABAA receptors in the brain.

Background/Objectives: Hyperlipidemia is a silent threat lurking in the bloodstream of millions worldwide. The nano-based platform has emerged as a promising drug delivery technology. Repaglinide, an anti-diabetic drug, was investigated recently as an antihyperlipidemic candidate that could supersede the available antihyperlipidemic drugs. Our goal was to optimize albumin-based nanoparticles loaded with Repaglinide for parenteral delivery and conduct in silico and in vivo studies to explore the efficacy of Repaglinide for the management of hyperlipidemia along with its anti-diabetic effect. Methods: The impact of three independent factors, the albumin%, acetone volume, and glutaraldehyde/albumin, on the particle size, zeta potential, and entrapment efficiency was investigated. Results: The optimized formulation was spherical, homogenous of an average diameter (~181.86 nm) with a narrow size distribution, a zeta potential of −24.26 mV, and 76.37% as the EE%. The in vitro release of Repaglinide from nanoparticles showed a sustained release pattern for 168 h, with an initial burst release after 24 h, and was fitted to the Fickian diffusion mechanism. A molecular docking simulation showed a strong affinity to several protein targets, and the results were very promising, where Repaglinide gave a score of −7.70 Kcal/mol compared to Mevastatin (−6.71 Kcal/mol) and Atorvastatin (−8.36 Kcal/mol). On conducting in vivo studies on animal models, the optimized formula recorded a statistically significant decrease in the serum levels of total cholesterol, triglyceride, and low-density lipoproteins, with an increased high-density lipoprotein. Conclusions: This study suggested albumin nanoparticles as potential nanocarriers for the parenteral delivery of Repaglinide to ameliorate its antihyperlipidemic benefits, especially in diabetic patients.

Background: Paullinia cupana Kunth, popularly known as guarana, a native Amazonian shrub cultivated by the Sateré-Mawé ethnic group, has been used in traditional medicine for various purposes, including stimulant and therapeutic actions, due to its chemical composition, which is rich in bioactive compounds. This study explored the reductive potential of guarana with nanobiotechnology and aimed to synthesize silver nanoparticles (AgNPs) using the aqueous extract of leaves collected during the dry and rainy seasons, assessing their biological and catalytic activities. Methods: The AgNPs were synthesized in a water bath at 70 °C for three hours and then characterized using techniques such as UV-Vis spectroscopy, DLS, zeta potential, MET, NTA, and EDX and had their effects on various biological systems assessed in vitro, as well as in catalytic tests aimed at indicating the probable influence of the time when the plant material was collected on the properties of the nanostructures. Results: The AgNPs had an average diameter between 39.33 and 126.2 nm, spherical morphology, absorption bands between 410 and 450 nm, and high colloidal stability over two years. The biological results showed antibacterial activity against all the species tested, as well as remarkable antioxidant action against DPPH and ABTS free radicals, in the same way as the aqueous leaf extracts of P. cupana, in addition to cytotoxic properties against cancerous (A431 and A549) and non-cancerous (HaCaT and HNTMC) cells. The AgNPs were active against promastigote forms of Leishmania (Leishmania) amazonensis while not affecting the viability of macrophages, and from the LC50 and LC90 values, the AgNPs were more effective than the metal salt solution in controlling Aedes aegypti larvae and pupae. We also reported that the catalytic degradation of the organic dyes methylene blue (MB) and methyl orange (MO) by AgNPs was over 90% after 40 or 14 min, respectively. Conclusions: Thus, our results support the potential of seasonal extracts of guarana leaves to produce AgNPs with diverse application possibilities for the health, industrial, and environmental sectors.

Cyclodextrin (CD)-based drug delivery systems have emerged as a promising strategy to overcome limitations commonly encountered in antidepressant therapy, including low bioavailability, poor solubility, and suboptimal penetration of the blood–brain barrier. This review synthesizes current evidence demonstrating that complexing various classes of antidepressants—such as tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and atypical antidepressants—with β-CD or its derivatives significantly enhances drug solubility and stability. In addition, encapsulation with CDs can diminish systemic toxicity and improve pharmacokinetics, thereby helping to optimize dosage regimens and reduce adverse effects. Analysis of published in vitro and in vivo studies indicates that CD formulations not only boost therapeutic efficacy but also enable sustained or targeted release, which is critical for drugs requiring precise plasma and tissue concentrations. When compared to other carriers (e.g., liposomes, polymeric nanoparticles, dendrimers), CD-based systems often stand out for their ease of formulation, biocompatibility, and cost-effectiveness, although limited drug-loading capacity can be a drawback. We recommend expanding in vivo trials to substantiate the clinical benefits of CD–antidepressant complexes, particularly for treatment-resistant cases or specific subpopulations (e.g., elderly and pediatric patients). Additional investigations should also explore hybrid systems—combining CDs with advanced nano- or macroparticles—to amplify their advantages and address any limitations. Ultimately, integrating CDs into antidepressant regimens holds substantial potential to refine therapy outcomes, reduce adverse events, and pave the way for more personalized, effective interventions for depression.

Background/Objective: Hot-melt extrusion has been established as a formulation strategy for various pharmaceutical applications. However, tailoring the screw configuration is a major challenge where 1D modeling is utilized. This usually requires specific screw parameters, which are rarely noted in the literature, especially when dealing with shear-thinning formulations. Methods: Therefore, a custom-made test rig was used to assess the behavior of various conveying and kneading elements using Newtonian silicon oil and shear-thinning silicon rubber. The pressure and the power were measured as a function of volume flow. A model was proposed characterizing the screw element behavior by six individual parameters . Results: The experimental results regarding the behavior with respect to Newtonian fluids were in good agreement with the literature and were modeled in accordance with the Pawlowski approach. In terms of shear-thinning fluids, the influence of screw speed on pressure and power was quantified. An evaluation framework was proposed to assess this effect using two additional parameters. Based on a high number of repetitive measurements, a confidence interval for the individual screw parameters was determined that is suitable to highlight the differences between element types. Conclusions: Finally, geometrical screw parameters for Newtonian and shear-thinning flow were assessed and modeled, with three conveying and three kneading elements characterized.

Background: Activated hepatic stellate cells (aHSCs) play a significant role during the onset of hepatic fibrosis, ultimately leading to excessive deposition of extracellular matrix (ECM) and other typical pathological features, and thus have become a popular target for the treatment of hepatic fibrosis. However, current aHSC-centric therapy strategies achieve unsatisfactory results, mainly due to the lack of approved anti-fibrosis drugs and sufficiently efficient aHSC-targeted delivery systems. In this study, our aim was to develop an Imatinib-loaded nanoparticle delivery system based on a chondroitin sulfate derivative to enhance aHSC targeting efficiency, improve the therapeutic effect for hepatic fibrosis, and investigate the underlying mechanism. Methods: The carboxyl group of chondroitin sulfate and the amino group of 1-hexadecylamine were linked by an amide bond in this study to produce the amphiphilic carrier CS-HDA. Then, the Imatinib-loaded nanoparticles (IM-CS NPs) were designed to efficiently target aHSCs through CD44-mediated endocytosis and effectively inhibit HSC overactivation via PDGF and TGF-β signaling pathways. Results: Both in vitro cellular uptake experiments and in vivo distribution experiments demonstrated that CS-HDA-modified nanoparticles (IM-CS NPs) exhibited a better targeting ability for aHSCs, which were subsequently utilized to treat carbon tetrachloride-induced hepatic fibrosis mouse models. Finally, significant fibrosis resolution was observed in the carbon tetrachloride-induced hepatic fibrosis mouse models after tail vein injection of the IM-CS NPs, along with their outstanding biocompatibility and biological safety. Conclusions: IM-loaded NPs based on an amphiphilic CS derivative have remarkable antifibrotic effects, providing a promising avenue for the clinical treatment of advanced hepatic fibrosis.

Pharmaceutical 3D printing, combined with nanomaterials and nanodevices, presents a transformative approach to precision medicine for treating neurological diseases. This technology enables the creation of tailored dosage forms with controlled release profiles, enhancing drug delivery across the blood−brain barrier (BBB). The integration of nanoparticles, such as poly lactic-co-glycolic acid (PLGA), chitosan, and metallic nanomaterials, into 3D-printed scaffolds improves treatment efficacy by providing targeted and prolonged drug release. Recent advances have demonstrated the potential of these systems in treating conditions like Parkinson’s disease, epilepsy, and brain tumors. Moreover, 3D printing allows for multi-drug combinations and personalized formulations that adapt to individual patient needs. Novel drug delivery approaches, including stimuli-responsive systems, on-demand dosing, and theragnostics, provide new possibilities for the real-time monitoring and treatment of neurological disorders. Despite these innovations, challenges remain in terms of scalability, regulatory approval, and long-term safety. The future perspectives of this technology suggest its potential to revolutionize neurological treatments by offering patient-specific therapies, improved drug penetration, and enhanced treatment outcomes. This review discusses the current state, applications, and transformative potential of 3D printing and nanotechnology in neurological treatment, highlighting the need for further research to overcome the existing challenges.

This study focuses on analyzing the in vitro release characteristics, as well as improving the penetration rate and stability of hydrocortisone acetate and pramoxine. This medication combination (hydrocortisone and pramoxine) is the first generic drug product utilized to alleviate minor pain, itching, swelling, and discomfort associated with anorectal conditions such as hemorrhoids. Background/Objectives: The developed novel formulations contain hydrocortisone acetate and pramoxine HCl as active ingredients, at least one solvent, at least one penetrating agent, at least one emulsifying agent, at least one surfactant, and at least one antimicrobial preservative, and pH values between 3.0 and 5.0, preferably between 3.5 and 4.5. Methods: Typical semi-solid dosage form quality control tests included appearance, identification, content homogeneity, pH, viscosity, assay, compounds of interest, microbiological testing, and in vitro release testing. In in vitro release testing, a series of formulations containing hydrocortisone acetate and pramoxine were tested for in vitro release across the Strat-M membrane using Franz diffusion cells methodology in comparison to a reference product (Pramosone Cream 2.5%). Results: Quantitative content of the release tests of the active ingredients in the cream, assay tests, antimicrobial preservative efficacy, and stability tests were carried out by high-sensitivity liquid chromatography. Conclusions: In conclusion, the cream formulations developed in this study have the potential to offer more effective treatment compared to reference products in terms of both in vitro release rates, and their reliability and validity were confirmed through validation studies.