Entecavir is a Biopharmaceutics Classification System class III antiviral agent with high solubility but low intestinal permeability, and its pronounced negative food effect requires administration on an empty stomach. An enteric-coated formulation containing a co-spray-dried powder of entecavir, a cationic polymer, and a mixture of permeation-enhancing excipients was therefore prepared and evaluated. Turbidimetric titration supported association between the cationic matrix-forming polymer and mucin, with a possible electrostatic contribution under the tested conditions. The permeation enhancer mixture did not increase passive permeation in a parallel artificial membrane permeability assay, but increased entecavir transport across Caco-2 monolayers by up to 3.8-fold, accompanied by concentration-dependent changes in monolayer resistance that substantially recovered after exposure, except at the highest concentration tested. In beagle dogs, the reference product's fed-to-fasted geometric mean ratios were 39.9% for the maximum plasma concentration (Cmax) and 91.2% for AUClast, indicating a food effect confined largely to the rate of absorption; enteric coating reduced fasted-state exposure in a separate study. Under fed conditions, exposure was generally greater at higher levels of the permeation enhancer mixture, whereas a control formulation in which entecavir was added after preparation of the drug-free carrier did not provide a comparable improvement. With the optimized formulation, the fed-to-fasted geometric mean ratios for AUClast and Cmax were 100.7% and 106.1%, respectively, with corresponding 90% confidence intervals entirely within 80.00–125.00%. These findings suggest limited food-related changes in exposure to the optimized formulation in beagle dogs under the tested liquid-meal conditions.
The goal of this work was to develop a chlorpromazine hydrochloride (CPZ)-containing dry powder inhaler (DPI) formulation with an extra-fine particle size and improved aerosolization performance for the adjuvant treatment of tuberculosis (TB). To optimize the product, Plackett–Burman and Box–Behnken experimental designs were applied to determine the parameters of nano spray drying. Pullulan and L-Leucine were used as excipients to achieve adequate aerodynamic properties. Physicochemical properties were characterized via laser diffraction, scanning electron microscopy, X-ray powder diffraction (XRPD), Fourier transform infrared spectroscopy (FT-IR), and thermal analysis(thermogravimetric analysis, differential scanning calorimetry), while in vitro performance was evaluated using the Andersen cascade impactor, the RespiCell™ dissolution apparatus, and the cytotoxicity assay using the A549 cell line. Furthermore, in vivo plasma and lung pharmacokinetics were quantified in Sprague–Dawley rats by UHPLC-MS/HRMS following intratracheal powder insufflation versus intravenous injection. The particle size of the product was under 2 μm (1.34 ± 0.03 μm) and showed a spherical form with a corrugated surface. The formulation is suitable for pulmonary delivery with adequate mass median aerodynamic diameter (MMAD 1.94 ± 0.03 μm) and high fine particle fraction (FPF) values (97.6 ± 0.36%). DPI had prolonged drug release. The DPI was non-toxic at concentrations of up to 10 μg/mL. The pharmacokinetic analyses revealed that intratracheal administration of the DPI prolonged the terminal half-life of CPZ in the plasma and demonstrated retention in the lungs. In conclusion, we developed a reproducible production process for CPZ-containing DPIs, achieving exceptional aerodynamic properties and potential sustained release. The results are promising for further investigations into the treatment of tuberculosis.
Fecal microbiota transplantation (FMT) is increasingly recognized as a promising therapeutic option for microbiota-related disorders. Its efficacy may be affected by factors related to both donor microbiota and the recipient’s intestinal barrier. Micro- and nanoplastics (MNPs), emerging environmental contaminants, have been recognized for their detrimental impacts on intestinal health. Existing studies have shown that MNPs can induce gut dysbiosis, impair intestinal barrier, and alter mucosal immune responses. These findings raise the possibility that MNPs may influence biological processes relevant to FMT, including donor microbiota characteristics and the recipient intestinal microenvironment. However, evidence of MNPs-induced intestinal toxicity does not establish impaired donor microbial engraftment or reduced therapeutic FMT efficacy, and the proposed relationship remains untested. Furthermore, although MNPs release from medical materials has been reported, whether FMT procedures contribute to measurable MNPs exposure remains unknown. This review summarizes current evidence on MNPs-associated intestinal health and proposes a potential mechanistic framework linking MNPs exposure to FMT outcomes, through alterations in gut microbiota, and intestinal barrier. Future studies are needed to validate this proposed framework by directly investigating the effects of MNPs exposure on donor microbial engraftment, microbial functional recovery, and clinical outcomes following FMT.
Lung cancer is a leading cause of death in the world and is highly heterogeneous with extensive molecular changes and often resistant to therapy. Despite significant advances in clinical management through surgery, chemotherapy, radiotherapy, and immunotherapy, some of these treatments are limited in effectiveness by late diagnosis, systemic toxicity, poor accumulation, molecular heterogeneity, and acquired resistance. This review provides a comprehensive overview of current and emerging therapeutic strategies for lung cancer, with particular emphasis on advanced drug delivery systems and nanomedicine-based approaches. Recent advances in lipid-based nanoparticles, polymeric nanoparticles and micelles, inorganic nanoparticles, and nanocrystals are highlighted for their ability to improve drug solubility, pharmacokinetics, tumor accumulation, cellular uptake, and controlled drug release. Active targeting and stimuli-responsive nanocarriers can improve tumor selectivity, intracellular drug delivery, and drug retention, potentially addressing selected resistance-associated mechanisms. Gene-delivery and genome-editing approaches offer additional opportunities to modulate resistance-related pathways, while photodynamic and photothermal therapies provide complementary strategies for localized tumor treatment. However, the extent to which these approaches reverse established drug resistance varies with the targeted mechanism and the experimental model employed. Distinguishing functional resistance reversal from improved drug delivery and general anticancer activity is therefore essential for assessing their translational potential.
