AAPS PharmSciTech最新文献

Antibody-drug conjugates (ADCs) have gained significant successes in the cancer treatment and are expanding rapidly into other therapeutic areas. This review outlines the integration of the analytical development and process development based on the technical challenges and control strategy of different process stages from the antibody intermediate, drug-linker intermediate, ADC drug substance (DS) to drug product (DP). The priority of analytical method development should be tailored to support the cascades of process development decision-making at early-stage, while additional analytical development for process characterization and product understanding should be planned to deliver a comprehensive analytical control strategy at late-stage for licensure. The development strategy of a few unique ADC methods including drug-antibody ratio (DAR), residual free drug quantitation, and cytotoxicity assay (bioassay) are discussed. Furthermore, the QC testing network should be strategized to allow fast speed to IND and clinical trial; the approaches including consolidated QC testing, central QC lab, one-stop shop, and conditional release may be considered and adjusted from early to late-stage product development.

Finger fractures are among the most common musculoskeletal injuries, yet conventional splints for finger are often poorly fitted, uncomfortable, and incapable of providing localized therapeutic support, which can delay healing and increase complications. This study presents a computed tomography (CT)-guided, patient-specific 3D-printed finger splint incorporating a bilayer electrospun nanofiber coating mat for localized dual delivery of hydrocortisone (HCT) and ibuprofen (IBU), providing concurrent anti-inflammatory and analgesic therapy through two distinct mechanisms. CT data were segmented to generate customized splint geometries, which were fabricated using fused deposition modeling (FDM) to produce a rigid polylactic acid outer shell and stereolithography (SLA) to create a flexible inner layer. The inner surface was sequentially coated with IBU-loaded polycaprolactone nanofibers then HCT-loaded pullulan. Comprehensive characterization by SEM, FTIR, DSC, and XRD confirmed smooth, bead-free PCL nanofibers, strong adhesion to the microtextured SLA surface, and amorphous dispersion of both drugs with entrapment efficiencies above 90%. In vitro release studies demonstrated rapid HCT liberation of 79.68 ± 0.17% within 2 h, and IBU release of 51.75 ± 4.35% within 24 h. Ex vivo porcine skin permeation studies showed significantly enhanced drug delivery compared with pure drug controls, with cumulative permeation values of 155.52 ± 19.97 µg/cm² for ibuprofen and 74.38 ± 2.18 µg/cm² for hydrocortisone at 24 h. These findings demonstrate the feasibility of CT-based personalized finger splints that integrate structural support with localized multidrug delivery, highlighting a promising platform for next generation, patient-tailored fracture management.

Glaucoma therapy is often limited by poor ocular bioavailability and the short residence time of conventional eye drops, highlighting the need for sustained-release delivery systems. This study presents the development of a thermosensitive in situ hydrogel incorporating cation-exchange resin (CER) for sustained delivery of betaxolol hydrochloride (BH) in glaucoma therapy. CER microspheres were prepared using a seed swelling method, and drug loading was achieved through an ion-exchange interaction to obtain BH@CER, which was characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and scanning electron microscopy (SEM). A thermosensitive hydrogel-microspheres composite (BH@CER@P407) was formulated using optimized concentrations of poloxamer 407 (P407), exhibiting a sol-to-gel transition at approximately 34°C for easy administration and prolonged ocular retention. In vitro release studies indicated that BH@CER@P407 achieved sustained release (85% over 12 h), in contrast to the pronounced burst release of commercial BH eye drops (Betoptic® S, 90% within 2 h). In vivo evaluations in New Zealand rabbits revealed strong ocular adhesion and retention for up to 8 h, correlating with sustained intraocular pressure (IOP) reduction. Ocular irritation studies confirmed excellent biocompatibility. Compared to Betoptic® S, the BH@CER@P407 offers enhanced ocular residence and prolonged therapeutic efficacy, presenting a promising strategy for improving glaucoma treatment.

Liquid-liquid phase separation (LLPS) is a metastable state in which a highly supersaturated solution phase separates into a drug-rich nanoaggregate phase dispersed in a drug-lean phase. LLPS-driven formation of drug-rich nanoaggregates has emerged as a key determinant of oral drug absorption. Despite this growing recognition, the influence of LLPS on ocular delivery remains unexplored. In this study, we investigated whether the nanoaggregate phase generated by LLPS modulates transcorneal permeation and compared the resulting drug flux with that of a dialysis membrane. Ketoconazole (KTZ) undergoes LLPS by gradual addition of a DMSO solution in simulated tear fluid (STF), pH 7.4, in the presence and absence of a polymer (HPMC-E15). The LLPS onset concentration and its stability were characterized by turbidity at 500 nm and count rate (kcps) using dynamic light scattering (DLS). Permeability studies were conducted using a diffusion experiment, and fluorescence microscopy was performed to investigate the uptake of a lipophilic dye Nile Red in the corneal membrane. Our findings demonstrate that polymer-stabilized nanoaggregates formed via LLPS significantly enhance flux across porcine cornea (p < 0.05). Diffusion assays combined with fluorescence microscopy suggest that this enhancement could be due to direct uptake of nanoaggregate phase or rapid partitioning of free drug into the corneal epithelium, facilitating transcorneal permeation. Strikingly, this effect was absent in the dialysis membrane, underscoring the role of biological tissue architecture in governing drug diffusion. The corneal permeation assay is not only a biorelevant model but also a discriminatory platform for evaluating LLPS-derived nanoaggregates.

Glimepiride (GLM), an essential sulfonylurea for type 2 diabetes management, suffers from poor solubility, variable absorption, and a narrow upper-GI absorption window, resulting in inconsistent therapeutic outcomes. To overcome these limitations, floating-mucoadhesive (FM) gastro-retentive tablets were developed using HPMC K15M, Carbopol 940P, and sodium bicarbonate to achieve prolonged gastric retention and controlled intragastric drug release. A 3² factorial design was employed to optimize polymer composition and effervescent loading, yielding an optimized formulation with rapid buoyancy and uninterrupted flotation for more than 24 h. Physicochemical evaluation (FTIR, DSC) confirmed drug-excipient compatibility, while pre and post-compression analyses verified acceptable mechanical and micromeritic characteristics. In-vitro studies demonstrated sustained GLM release for 6 h, following Higuchi kinetics with Fickian diffusion, supported by stable swelling dynamics and moderate mucoadhesive strength. Scanning electron microscopy further elucidated the release mechanism by revealing time-dependent matrix swelling, pore formation, and internal structural evolution during dissolution, corroborating diffusion-controlled drug transport. The optimized system exhibited in-vitro attributes indicative of prolonged gastric retention and controlled drug release, suggesting its potential to improve the oral bioavailability of GLM. This formulation approach may be extended to other drugs requiring localized gastric retention and diffusion-modulated release.

Pazopanib, a multitargeted tyrosine kinase inhibitor faces challenges at the formulation forefront due to high melting point, pH-dependent low aqueous solubility, in-vivo precipitation, low dissolution kinetics and, P-gp mediated drug efflux. To address these limitations an amorphous nanosuspension of Pazopanib (PZB-NS) was developed using an antisolvent precipitation approach with a dual stabilizer system comprising polyvinylpyrrolidone K-30 (PVP K-30) and Soluplus®. Formulation optimization was conducted using a Box-Behnken design (BBD) investigating critical process parameters such as polymer and surfactant concentrations, and solvent-to-antisolvent addition rate. The optimized nanosuspension exhibited a particle size of 123.9 ± 3.36 nm with 0.121 ± 0.002 PDI. The nano-formulation was further subjected to morphological characterization through PLM, SEM and PXRD that demonstrated amorphous transition of highly crystalline PZB. The FT-IR spectra revealed stabilizer-mediated hydrogen bonding and hydrophobic interactions while TEM micrographs depicted the formation of micelle-like assemblies that conferred colloidal stability and facilitated drug encapsulation. PZB-NS demonstrated 23-fold increase in kinetic solubility and accelerated dissolution achieving nearly complete drug release under both acidic (pH 1.2) and neutral (pH 6.8) conditions. Further, in-vivo pharmacokinetic evaluation was conducted in male Wistar rats and demonstrated a five-fold enhancement in systemic exposure as compared to crystalline PZB with no crystallization events. Taken together this is the first report describing a polymer-surfactant stabilized amorphous nanosuspension of PZB that offers a synergistic platform integrating solid-state pharmaceutics and nanotechnology so as to overcome biopharmaceutical barriers of challenging molecules.

Chronic Pseudomonas aeruginosa (PA)-induced pulmonary infection poses a severe global health threat due to limited therapeutic efficacy of conventional systemic administration and rising drug resistance. Inhalation therapy offers targeted pulmonary drug delivery but is hindered by suboptimal formulations and inefficient nebulizers. Herein, we developed a novel levofloxacin inhalation solution (LIS) and a custom-engineered vibrating-mesh nebulizer (PJ-102) as a synergistic drug-device combination for the treatment of chronic pulmonary infection. LIS exhibited excellent aerosolization performance with a 1.81-fold fine particle fraction of that of commercial jet nebulizer. And the superiority in treating chronic pulmonary infection was also proved by in vivo experiments. Additionally, LIS avoided the hepatotoxicity associated with systemic levofloxacin exposure, as evidenced by stable liver enzyme levels and normal hepatic pathology. This established LIS offered a promising therapeutic candidate for refractory PA-induced pulmonary infections and a valuable framework for advanced antimicrobial inhalation therapy development.

Acne vulgaris is highly prevalent and burdensome, yet conventional topical therapies are limited by poor stratum corneum penetration, follicular obstruction, low drug deposition at pilosebaceous targets, drug instability, local irritation/side effects, and variable patient adherence. This review synthesizes recent nanoformulation advances in the context of acne pathophysiology and the specific delivery barriers it creates. Lipid-based carriers (solid lipid nanocarriers (SLNs), nanostructured lipid carriers (NLCs), nanoemulsions (NEs)) and vesicular systems (liposomes, niosomes, transfersomes) can protect labile actives, enhance appendageal/follicular access, and modulate release to limit irritation, while polymeric platforms (micelles, microsponges, nanoparticles) further improve residence time and controlled delivery. Early clinical studies suggest improved lesion reduction and tolerability versus conventional vehicles; however, broader translation remains constrained by manufacturing reproducibility, scale-up, regulatory clarity, long-term safety evaluation, and cost-effectiveness. As forward-looking avenues, multifunctional co-delivery (e.g., retinoid with antibiotic/anti-inflammatory), energy-responsive adjuncts (photothermal or precision cryo as non-drug complements), and green, biodegradable materials are being explored to better tackle biological challenges such as hyperkeratinisation-related obstruction, biofilms, and irritation, while aligning with sustainability goals. Overall, nanoformulations offer a credible path to more effective, patient-centered topical acne therapy; realizing this potential will require rigorous, adequately powered clinical trials, standardized dermatopharmacokinetic endpoints, and quality-by-design scale-up to bridge laboratory promise to practice.