Pharmaceutical Research最新文献

Purpose: Conventional nanoparticle manufacturing techniques remain costly, labor-intensive, and difficult to scale, while also being subject to batch-to-batch variability. These limitations hinder their clinical translation, particularly in first-in-human trials. Emerging transformative technologies such as microfluidics and three-dimensional (3D) printing offer opportunities to develop agile, continuous, and scalable manufacturing processes. This study aims to demonstrate the feasibility of continuous microfluidic production of nanoparticles using customizable 3D-printed chips, integrated with atomization technologies, to generate solid nano-enabled controlled release therapies.

Methods: 3D-printed microfluidic chips were designed using computational fluid dynamics (CFD) to optimize flow characteristics. Nifedipine (NFD)-loaded nanoparticles were continuously manufactured with Eudragit L-100 and subsequently embedded into pullulan microparticles by spray-drying, yielding nano-in-microparticles (NIM). Particle size, encapsulation efficiency, solid-state properties, permeability, and release kinetics were assessed in ex vivo Franz cell studies across porcine intestinal membranes.

Results: Continuous microfluidic processing produced NFD-loaded nanoparticles with 95% encapsulation efficiency. Spray-drying yielded spherical pullulan-based NIMs of ~ 10 µm, which, upon rehydration, released NFD nanoparticles of ~ 100 nm. The nanoparticles retained their amorphous state and displayed a three-fold increase in intestinal permeability compared to free drug, accompanied by a three-fold reduction in lag time. Release studies demonstrated reduced burst release and a sustained zero-order release profile over 24 h, favorable for blood pressure maintenance therapy.

Conclusions: The integration of 3D-printed microfluidic chip design with continuous manufacturing and spray-drying enables scalable production of solid nano-enabled therapies. The NFD-loaded NIMs demonstrated enhanced permeability and controlled release, supporting the potential of this platform for the clinical translation of nanomedicines.

Background: Post-approval changes (PACs) in formulations requires a risk assessment of safety and efficacy for extending the product lifecycle. While BCS class I and III are candidates for biowaivers, standard bioequivalence trials are recommended for compounds with controversial classification (i.e., azithromycin). Surrogate techniques, including predictive in vitro dissolution and modeling, have shown their potential in biopharmaceutic assessment of formulations. In this paper, we aimed to assess the risk associated with PACs in azithromycin immediate-release (IR) tablets using a model-informed approach.

Methods: Two bioequivalent bio-batches (test and reference) were compared to a new test formulation. Dissolution was studied in the gastric and predictive in vitro surrogate media. This latter was tailored to azithromycin IR formulations using the reversible non-equilibrium and Mooney's models to calculate surface pH and equivalent phosphate molarities, respectively. A virtual population that matched the bioequivalence study was created using dissolution input and individual pharmacokinetic data. With these, contributions of dissolution and permeation were estimated using a series resistance model, and virtual bioequivalence was tested.

Results: The new formulation dissolved noticeable faster in gastric media, although dissolution was comparable in surrogate media across formulations. Nonetheless, the series resistance model revealed that dissolution was much faster than transepithelial absorption, indicating absorption is rate-limited by permeability. Bioequivalence simulations supported this result.

Conclusions: The potential of integrating predictive dissolution in a model-informed PACs (MIPACs) approach was demonstrated. However, a waiver of bioequivalence studies for azithromycin may not be justified before evaluating the potential effect of excipient on azithromycin permeability.

Aims: Volagidemab, a fully human IgG2 monoclonal antibody, is a competitive glucagon receptor (GCGR) inhibitor that blocks endogenous glucagon (GCG) activity. This study developed a population pharmacokinetics/pharmacodynamics (PopPK/PD) model and established the exposure-response (E-R) relationship for Volagidemab.

Methods: Data from healthy Chinese and US subjects administered a single subcutaneous (SC) dose of Volagidemab were analyzed. A PopPK/PD model characterized drug disposition and effect. E-R analyses evaluated the relationship between plasma GCG concentrations and fasting plasma glucose (FPG).

Results: Volagidemab exhibited dose-dependent PK, characterized by a nonlinear distribution and linear elimination model incorporating a single transit absorption compartment. The PD response, defined as the log-transformed fold change in GCG, was well described by an E_max model. Body mass index (BMI) was identified as a significant covariate for apparent central volume of distribution (V_c). Empirical Bayes (EBE) estimates indicated no clinically meaningful differences in PopPK/PD parameters between Chinese and US subjects. E-R analysis demonstrated a linear relationship between GCG fold change and FPG. Baseline FPG was identified as a significant covariate influencing the slope, suggesting greater glucose reduction in individuals with higher baseline FPG. Simulations showed a distinct plateau in the E-R relationship, with minimal additional therapeutic effect observed between 35 and 42 mg.

Conclusions: This analysis confirms minimal ethnic differences in the PK/PD of Volagidemab between healthy Chinese and US subjects. The limited impact of covariates supports dose bridging, facilitating clinical development in China.

Purpose: In vitro respiratory models such as the Next Generation Impactor (NGI), remain the gold standard for aerodynamic particle size distribution (APSD) testing, however, they lack the anatomical complexity, limiting their ability to replicate in vivo deposition. To address this limitation, the Advanced Integrated Respiratory (AIR) model, a physiologically relevant benchtop system incorporating anatomically accurate silicone casts of the upper and lower airways, was used to assess deposition of salbutamol sulphate delivered via three clinically relevant platforms.

Methods: Salbutamol sulphate was delivered using a pressurised metered-dose inhaler (pMDI), a dry powder inhaler (DPI), and a jet nebuliser. Deposition profiles obtained in the AIR model were benchmarked against the NGI.

Results: Both systems showed consistent patterns for DPI and nebuliser aerosols, with highest deposition in the oropharyngeal and intrathoracic regions, respectively. In contrast, pMDI testing revealed important differences: the AIR model predicted markedly higher oropharyngeal retention and reduced intrathoracic delivery, aligning more closely with published in vivo scintigraphy studies than the NGI.

Conclusion: These findings demonstrate that anatomically realistic models provide critical insights into deposition behaviour, particularly for propellant driven inhalers and underscore the value of integrating physiologically relevant platforms alongside conventional impactors in aerosol characterisation.

Introduction: Lyophilization is a promising strategy to enhance the long-term stability of messenger RNA lipid nanoparticles (mRNA-LNPs). However, lyophilization-induced stresses can impact product quality and the underlying mechanisms remain poorly understood. In this study, we systematically investigated stresses that arise during the freezing step, during the initial stage of the lyophilization process.

Methods: We examined the impact of different freezing protocols (freezing at 0.1, 0.5, and 1.5 K/min, plus controlled nucleation at -10°C) on mRNA-LNP stability. We also explored formulation strategies to mitigate freezing stress: (A) increasing mRNA-LNP concentration or adding empty LNPs to induce colloidal crowding, (B) adding Poloxamer 188 to reduce interfacial stress, (C) incorporating sucrose within LNPs to protect mRNA and reduce osmotic stress, and (D) adding NaCl or L-Methionine to modulate mRNA-lipid interactions. We evaluated particle size, polydispersity index, encapsulation efficiency (EE), mRNA integrity, and eGFP expression in HeLa cells.

Results: Faster freezing minimized LNPS particle size increase by trend but reduced EE. Controlled nucleation improved EE but increased LNP particle size. However, eGFP expression was more influenced by particle size than EE.

Conclusion: These findings provide a mechanistic understanding of how freezing-induced stresses affect mRNA-LNP quality. We hypothesize that cryo-concentration caused by slow freezing leads to increasing size of LNP particles, while higher ice-liquid interfacial stress caused by fast freezing reduces EE. As these effects follow opposing trends, optimizing freezing conditions is crucial. Understanding these mechanisms will guide rational formulation and lyophilization process design for mRNA-LNPs.

Background: Ovarian cancer remains a challenging oncology concern owing to its late diagnosis, high risk of recurrence, and predisposition for developing chemoresistance. Despite their initial effectiveness, traditional chemotherapy regimens frequently trigger multidrug resistance through multiple mechanisms. By improving drug solubility, stability, tumor-specific accumulation, and overcoming resistance pathways, nanotechnology offers revolutionary potential in addressing these limitations.

Objective: With an emphasis on nanotechnology-based drug delivery methods as a potential means to combat chemoresistance in ovarian cancer, this review aims to address the urgent need for innovative approaches that can overcome these treatment barriers.

Methods: In view of their ability to alter cancerous pathways as well as enhance chemosensitivity, novel approaches such as siRNA, miRNA, exosomebased treatments, ligand-functionalized nanoparticles, and antibody-drug conjugates are mentioned. Notably, exosomes and liganddecorated carriers enhance biocompatibility and selective cellular uptake, whereas siRNA and miRNA delivery systems are designed to silence genes associated with drug resistance. A comprehensive evaluation of preclinical and clinical studies was mentioned, focused on nanotechnology-enabled approaches.

Results: Clinically, several nanoformulations have gone through trials or been approved, showing potential for translation. Preclinical results are encouraging, but there are still challenges with immune responses, tumor heterogeneity, and scalable production. Optimizing therapy outcomes requires combining patient-specific targeting, novel carrier designs, and molecular diagnostics.

Conclusion: This review emphasizes the significance of ongoing interdisciplinary efforts to close the gap between clinical adoption and experimental success, as well as the paradigm change toward precision nanomedicine in ovarian cancer. Nanotechnology-driven therapeutics represent a promising frontier in overcoming chemoresistance in ovarian cancer.

Objective: The actuator orifice diameter (OD) of pressurized metered dose inhalers (pMDIs) is known to influence the plume geometry and spray pattern exiting the orifice. Actuator OD has previously been found to influence in vitro regional deposition in an adult extrathoracic airway model for a suspension epinephrine formulation, with smaller OD reducing oral cavity deposition. Whether this effect persists in the smaller extrathoracic airways of school-aged children is unknown.

Methods: Regional extrathoracic deposition of epinephrine from pMDIs was investigated using an idealized child mouth-throat geometry. A sectioned version of the Alberta Idealized Child Throat (AICT), divided into analogues of the oral cavity, the pharynx/larynx, and the upper trachea, was used to test pMDIs with small and large ODs (0.22 and 0.44 mm) across a range of inhalation flowrates (10, 30, 60, and 100 L/min), with two inhaler insertion angles (transverse and coaxial). In addition, the effect of increasing ambient humidity on regional extrathoracic deposition was explored with both actuator ODs.

Results: Actuator OD strongly influenced in vitro regional extrathoracic deposition in the child model, with the smaller OD decreasing oral cavity deposition, and increasing delivery to the laryngeal region and lungs. While increased ambient humidity influenced in vitro regional extrathoracic deposition, the influence of environmental changes was minor when compared with changes associated with actuator OD.

Conclusion: Overall, for the suspension epinephrine formulation tested, the reduction in oral cavity deposition observed for the smaller OD actuator was maintained despite varying extrathoracic airway size (child vs. adult) and varying ambient humidity.

Purpose: This study aimed to evaluate the capacity of low-field nuclear magnetic resonance (LF NMR) as a standalone or orthogonal method for monitoring key parameters of interest for upstream cell culture fermentation in vaccine manufacturing.

Methods: Off-line near-infrared (NIR) and NMR measurements of fermentation samples from cells were acquired using the Matrix-F spectrometer with an Excalibur XP25 probe and the Fourier 80 LF NMR spectrometer respectively. Comparative analyses and multivariate modeling were employed against off-line reference and NIR models to characterize the process parameters of glucose, lactate and pH. Additional metabolites were identified and quantified using LF NMR signals. Indirect hard modeling was applied using LF NMR data to achieve relative quantification and visualization of metabolite concentrations.

Results: LF NMR was applied to quantify lactate, glucose and pH in the cell upstream fermentation media, showing good agreement and comparable measurements to off-line and NIR methods. Further analysis of the LF NMR spectra allowed identification and quantification of additional metabolites. The results demonstrate that LF NMR can provide complementary information to NIR and expand process understanding by revealing dynamic changes in parameters of interest during fermentation.

Conclusions: This study demonstrates that LF NMR is a feasible and effective analytical tool for monitoring cell fermentation process during vaccine manufacturing. As a standalone or orthogonal method to NIR, LF NMR provides valuable insights to support real-time measurements for process control in vaccine manufacturing.

Purpose and objective: Microneedles have emerged as a promising platform for transdermal drug delivery, offering high patient compliance, ease of use, and minimal invasiveness. Despite extensive research on microneedle design and fabrication, the influence of intrinsic drug properties on delivery performance remains insufficiently understood. This study is aimed to determine the individual effects of key transport properties of the loaded drug on delivery outcomes across different skin layers and the systemic circulation.

Methods: A multiphysics model is employed to characterise transdermal drug delivery via microneedles, based on a multilayer skin model that incorporates realistic anatomical structures and dimensions. Nine key drug-related parameters are investigated, including drug diffusivity in the microneedle and skin tissues, partition coefficients between the tissue and microneedle, between the cell membrane and interstitial space, and between the cell interior and interstitial space, as well as the protein binding coefficient, transvascular permeability, elimination rate in the skin tissue, and plasma clearance.

Results: The simulations reveal distinct responses of drug delivery performance in each skin layer and in the blood circulation to variations in each property, with optimal values existing depending on the location of the therapeutic target within the skin.

Conclusions: The findings provide mechanistic insights into the interplay between drug physicochemical characteristics and transdermal transport dynamics, offering valuable guidance for rational drug selection, formulation design, and the development of microneedle-based therapeutics.

Purpose: Accurate prediction of aerosol deposition in the extrathoracic airway is critical for designing inhaled therapies, yet many experimental and computational studies rely on geometries that are either simplified or subject-specific but not necessarily physiologically consistent with oral inhalation. This inconsistency can lead to varying estimates of drug delivery efficiency, particularly in the mouth-throat region where flow behavior and particle deposition are highly sensitive to physiological detail.

Methods: This study investigated the influence of airway geometry on aerosol drug delivery by quantifying the deposition of salbutamol sulfate across simplified and subject-specific extrathoracic models. An artificially opened mouth, derived from a closed mouth CT scan and a realistic oral inhalation geometry, were compared to a simplified airway model and the pharmaceutical standard model. All experiments were performed at an inhalation flow rate of 30 l min $_{}^{-1}$ using a metered dose inhaler (Ventolin $_{}^{\circledR }$ ).

Results: Each airway was segmented into 10 regions, from the device mouthpiece through the mouth-throat, larynx, and trachea, to the eight stages representing the lower airway. The artificial open mouth geometry produced the lowest ling deposition only 9% , while the realistic oral inhalation had lung deposition of 45%, more consistent with the simplified models.

Conclusions: Subject-specific airway models are not inherently more realistic than simplified models. When physiological features of oral inhalation-specifically soft palate elevation and a smaller mouth opening than a fully opened mouth-are not captured in the model geometry, simplified geometries based on oral inhalation conditions may more accurately represent true deposition patterns than subject-specific models derived from restful breathing CT scans.