Despite the various therapeutic benefits and high tolerance of orally administered silybin, poor water-solubility can be the main restrictive physicochemical feature, which results in low oral bioavailability in the absorption. A milk thistle nanocrystal formulation (HM40) was prepared using a modified wet-milling method. Comprehensive characterization was performed to determine the physical morphology, crystallinity, and physicochemical properties. The long-term stability was evaluated over 24 months. In vitro silybin release was assessed at pH 1.2 for 2 h, followed by pH 6.8 for 4 h. Finally, in vivo pharmacokinetic studies were conducted in rats and healthy human volunteers. HM40 exhibited a nanocrystal structure maintaining crystallinity and enhanced the solubility and dissolution of silybin compared to that of the raw material. The stability over 24 months revealed consistent surface morphology, particle size, silybin content, and solubility. In vitro release profiles indicated a significant increase in the silybin release from HM40. In vivo pharmacokinetic studies demonstrated that HM40 showed 2.61- and 1.51-fold higher oral bioavailability in rats and humans, respectively, than that of the reference capsule. HM40 formulation presents a stable and promising approach for the oral delivery of poorly water-soluble silybin, with the potential for use in pharmaceutical formulations containing milk thistle.

Background/Objectives: Pharmaceutical cocrystallization offers a promising strategy to enhance drug properties while preserving molecular integrity. Ezetimibe, a BCS Class II hypolipidemic agent, faces therapeutic limitations due to poor aqueous solubility. This study aimed to systematically evaluate cocrystallization of ezetimibe with organic acid (benzoic, tartaric, or succinic acid) at varying stoichiometric ratios (1:0.5–1:2) to optimize physicochemical properties and oral bioavailability. Methods: Cocrystals were prepared via solvent evaporation (SEV) and solvent/anti-solvent (SAS) methods. Structural characterization included Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and powder/single-crystal X-ray diffraction (PXRD/SCXRD). Physicochemical performance was assessed through saturation solubility, in vitro dissolution, and in vivo pharmacokinetics in male Sprague Dawley rats (n = 4/group). Results: Benzoic acid cocrystals (1:2 ratio, SEV) showed O−H⋯N hydrogen bonding (FTIR band shifts: 2928 → 3264 cm⁻¹) and novel crystalline phases (12.4°, 16.7°, and 24.9°). SCXRD confirmed monoclinic P2₁/n symmetry (a = 5.42 Å, b = 5.05 Å) for benzoic acid cocrystals. Ezetimibe/benzoic acid cocrystals (1:2) achieved 64-fold solubility enhancement and 2× faster dissolution vs. pure ezetimibe. Pharmacokinetics revealed 3× higher Cmax (18.38 ng/mL) and 4× greater AUC (40.36 h·ng/mL) for optimized cocrystals. Tartaric and succinic acid cocrystals showed moderate improvements, with melting points intermediate between parent compounds. Conclusions: Both stoichiometry and preparation method strongly determined cocrystal performance. Benzoic acid at a 1:2 ratio via SEV demonstrated superior solubility, dissolution, and bioavailability, addressing ezetimibe’s formulation challenges. These findings underscore the potential of rational cocrystal design to overcome solubility barriers in oral dosage development, particularly for hydrophobic therapeutics.

Background/Objectives: This study aimed to enhance the oral delivery and therapeutic synergy of atorvastatin (AT) and docetaxel (DT) through a metronomic schedule using a transporter-targeted nanoemulsion (NE), with the goal of improving antitumor efficacy and immune modulation. Methods: AT and DT were co-encapsulated in a NE system (AT/DT-NE#E) incorporating deoxycholic acid–DOTAP (D-TAP), biotin-conjugated phospholipid (Biotin-PE), and d-α-tocopherol polyethylene glycol succinate (TPGS) to exploit bile acid and multivitamin transport pathways and inhibit P-glycoprotein efflux. The optimized NE was characterized physicochemically and evaluated for permeability in artificial membranes and Caco-2/HT29-MTX-E12 monolayers. Pharmacokinetics, tumor suppression, and immune cell infiltration were assessed in vivo using rat and CT26.CL25 mouse models. Results: AT/DT-NE#E showed enhanced permeability of AT and DT by 45.7- and 43.1-fold, respectively, across intestinal cell models and improved oral bioavailability by 118% and 376% compared to free drugs. In vivo, oral metronomic AT/DT-NE#E reduced tumor volume by 65.2%, outperforming intravenous AT/DT. Combination with anti-PD1 therapy achieved a 942% increase in tumor suppression over the control, accompanied by marked increases in tumor-infiltrating CD45⁺, CD4⁺CD3⁺, and CD8⁺CD3⁺ T cells. Conclusions: Oral metronomic administration of AT/DT via a dual-transporter-targeted NE significantly improves drug absorption, tumor inhibition, and immune response. This strategy presents a safe and effective approach for colon cancer therapy, particularly when combined with immunotherapy.

Background: The limited aqueous solubility of basic drugs poses significant challenges for oral bioavailability, necessitating a different formulation approach. This study utilizes acidic or non-ionic polymers (its aqueous solution close to acidic-neutral pH) to stabilize a basic drug via drug-polymer interaction. Due to acid-base super solubilization effects, amorphous solid dispersions (ASDs) have good recrystallization inhibition, and improved dissolution and stability. Methods: To prepare nimodipine, a model drug, solid dispersion, spray–drying and melt–quenching techniques were used with carriers like HPC, HPMCAS, HPMCP, and PVP K25 polymers. Drug-polymer miscibility or interaction was carefully evaluated with different modeling to reduce processing temperature and inhibit recrystallization. Results: Based on preparation methods, there were two ASD types: one with a small particle size and low bulk density (spray–drying) and the other with big particle size and high bulk density, prepared at a low temperature to minimize degradation (melt–quenching). The solid–state analysis revealed a low glass transition temperature (Tg), suggesting amorphous forms. The surface morphology of nimodipine and its solid dispersions demonstrated a uniform and consistent system. Nimodipine with HPMCP via spray–drying (NIM.CP.SM) exhibited the highest drug release (89.51%) in phosphate buffer (pH 6.0) after 2 h without recrystallization. The in vivo pharmacokinetic profiles demonstrated a 33–fold increase in Cmax and a 15–fold increase in AUC0–∞ with NIM.CP.SM. Conclusions: These findings suggest that an HPMCP–based polymer combined with spray–drying technique produces a thermodynamically and physico-chemically stable ASD with enhanced in vitro and in vivo drug release.

Pharmaceutical cocrystals represent a promising strategy to enhance drug properties while preserving molecular integrity. This study investigates cocrystallization of a poorly soluble drug with different organic acids (benzoic acid, tartaric acid, succinic acid) at various ratios using solvent evaporation and anti-solvent precipitation methods. The resulting cocrystals had a lower melting peak, with formation of O-H···N hydrogen bonds (band shifts 2928®3264 cm−¹ and C=O vibration alterations at 1726 cm−¹), and novel crystalline phases at 12.4°, 16.7°, and 24.9°. Further study revealed that cocrystals formed with benzoic acid (1:2 ratio) had a monoclinic lattice (space group P2₁/n) and achieved 64-fold solubility enhancement and 2-fold dissolution rate. The pharmacokinetic study in animals showed a 3-fold maximum plasma drug concentration and 4-fold improvement in systemic exposure (AUClast), with a delayed time to peak concentration (Tmax), confirming a sustained release. These findings demonstrate that organic acid as a coformer in appropriate stoichiometric ratio, incorporated to a poorly soluble drug using a suitable preparation method, can drastically improve the physicochemical properties and bioavailability. Amongst the evaluated coformers, benzoic acid cocrystals have a potential to overcome the solubility barrier and promote the effective oral dosage form.