Pharmaceutical Research最新文献

Intravenous (IV) administration of therapeutic antibodies requires multiple in-use steps to ensure safety, purity and potency before patient administration. This review systematically examines 93 FDA-approved therapeutic antibodies administered via IV infusion, focusing on critical clinical in-use parameters reported in their prescribing information. Key parameters analyzed include storage conditions, drug concentrations, dosing regimens, dilution and diluents, infusion rates, priming and flushing procedures, needle and syringe specifications, IV bag and line materials, infusion filters, pumps, and venous access devices. The statistical analysis of these parameters highlights the most commonly used industry practices, providing a comprehensive reference for formulation scientists designing clinical in-use studies or drafting pharmacy manuals for antibody-based products. Our findings show that saline is the most frequently recommended diluent, though some antibodies recommend alternative diluents such as dextrose solutions or lactated Ringer's solution. Similarly, filters are recommended for 65% of the analyzed drug products, yet variations exist in pore size and material recommendations. Additionally, oncology-related antibodies often require graduated infusion rates to mitigate infusion-related reactions, and 31% of antibodies suggest adjusting infusion rates based on patient tolerance. These findings highlight the need for systematic in-use studies covering various scenarios and clinical settings to establish evidence-based recommendations. Well-designed clinical in-use studies, coupled with well-structured pharmacy manuals that clearly outline in-use preparation steps, enhance clarity, reduce preparation errors, and improve workflow efficiency to ultimately ensure safe and effective IV administration of therapeutic antibodies.

Purpose: Ursodeoxycholic acid (UDCA) has low toxicity and restores biochemical parameters in cholestatic preschoolers and children. The edible film is a new dosage form included in USP-NF 2023. The objective was to design edible UDCA films (25 and 50 mg of UDCA/film) for chronic oral administration to pediatric patients.

Methods: Films were developed with mannuronic acid-rich alginate by casting. They were evaluated for 18 months-storage at 25 °C and 33.3% relative humidity (RH).

Results: UDCA powder crystallinity decreased from 75% to 28-32% in UDCA films. Film water content decreased with increasing UDCA dose. Glass transition temperature (T_g) increased from ‒129.15ºC (UDCA powder) to ≈ ‒80ºC for UDCA films (33.3% RH), while 0% RH UDCA powder (80% crystallinity) had not T_g. Film-FTIR spectra demonstrated that UDCA particles were buried or coated by the alginate film network. Films showed homogeneous UDCA distribution, adequate tensile strength, rapid swelling and disintegration (43-58 s), and UDCA content within USP specifications for 18 months.

Conclusions: Amorphous systems like these films can improve solubility and oral bioavailability of poorly water-soluble UDCA. Moreover, flexible alginate films ensure not only UDCA stability but also treatment adherence for pediatric oral simple administration given also the alginate taste-masking properties.

Evaluation of drug delivery for locally acting orally inhaled drug products (OIDPs) is challenging because there are no routinely conducted studies that directly quantify drug concentration in specific regions of the human lungs. In vivo regional deposition studies are helpful for understanding region-specific drug delivery to the lungs but are limited by a variety of factors including small population samples, long study duration, and representation of results in two-dimensional rather than three-dimensional frameworks. Lung regional deposition modeling (RDM) can provide useful insights on region-specific drug delivery to the lungs for locally acting OIDPS because it can be used to understand many of the underlying physical processes that influence drug delivery, and it can be used to develop in vitro in vivo correlations. When RDM is combined with in vitro and/or in vivo data that serve as model validation comparators as well as sources for model parameter inputs, and model credibility is established, it may be considered model-integrated evidence (MIE) when it is used to facilitate generic locally acting OIDP development and approval and thereby improve accessibility of OIDPs.

Objectives: To develop and optimize myricetin-loaded inhalable microspheres using ionotropic gelation technique for sustained pulmonary delivery in Chronic Obstructive Pulmonary Disease (COPD) treatment.

Methods: Myricetin-loaded microspheres were prepared using varying concentrations of gellan gum and sodium alginate through a 3² full factorial design. Formulations were characterized for physicochemical properties, in vitro release, aerodynamic performance using twin impinger, and stability. The optimized formulation was evaluated for bronchodilatory activity using histamine-induced contraction of goat tracheal chain model and compared with theophylline anhydrous.

Results: The optimized formulation (DF4) exhibited spherical morphology with ideal particle size for pulmonary delivery (7.72 μm), high entrapment efficiency (72.84%), and negative zeta potential ensuring colloidal stability. This formulation demonstrated excellent aerodynamic properties (FPF 31.71%), sustained drug release over 12 h, and remarkable stability over 6 months under both accelerated and real-time storage conditions. The formulation showed significant bronchodilatory activity with 63.47% relaxation at 25 μg/ml, achieving approximately 80.8% efficacy compared to theophylline anhydrous.

Conclusion: The optimized myricetin-loaded inhalable microspheres represent a promising pulmonary delivery system for COPD management, offering advantages of sustained drug release, improved lung deposition, and significant bronchodilatory effect. This formulation holds potential for reducing dosing frequency, enhancing patient compliance, and improving therapeutic outcomes in COPD patients, warranting further in vivo studies before clinical translation.

Purpose: The objective of this research was to explore the application of controlled ice nucleation (CN) technology to enhance the critical quality attributes (CQAs) and manufacturing efficiency of freeze-dried monoclonal antibody (mAb) drug products. The study aimed to address challenges associated with conventional freeze-drying process, such as low supercooling temperatures and inhomogeneous ice nucleation temperatures, and to evaluate whether CN could improve product quality, and the overall efficiency of the lyophilization process.

Methods: Various mAb drug products were manufactured using three different lyophilization methods during the freezing step, including conventional, annealing, and CN. The CQAs of the drug products were assessed, including residual moisture content, reconstitution time, product appearance, microscopic morphology, specific surface area, protein purity, charge variance, and sub-visible particulates. Comparative analyses were conducted to evaluate the impact of the CN on product quality and process efficiency.

Results: CN demonstrated significant improvements in product appearance, uniformity, reconstitution properties, and stability. It notably reduced the primary drying time, enhancing the overall efficiency of the freeze-drying process. Furthermore, the CN method produced lyophilized drug products with consistent cake appearance, improved quality, and enhanced stability, ensuring therapeutic efficacy and patient safety.

Conclusions: CN technology represents a major advancement in pharmaceutical manufacturing. The implementation of CN has the potential to improve the CQAs of drug products, optimize the lyophilization process, reduce operational costs, and increase production throughput. These findings underscore the importance of adopting innovative technologies like CN to meet the growing demand for high-quality and efficient biopharmaceutical production.

Objective: Microneedle technologies have emerged as a promising approach to improve intradermal drug delivery. This study presents a comprehensive workflow for fabricating polymeric microneedle arrays utilising ultrahigh-resolution 3-dimensional (3D) printing and silicone mould fabrication.

Methods: In this work, an extensive toolbox with over 75 distinct microneedle designs was created and sequentially fabricated from acryl using our workflow based on ultrahigh-resolution 3D printing.

Results: The microneedle design parameters included obelisk and cone-like shapes, various lengths, base and tip diameters, and different densities. We systematically assessed the optimal design parameters for effective penetration of ex vivo human skin explants.

Conclusion: Our workflow, combined with application in an ex vivo human skin model, allows systematic comparison of multiple microneedle design parameters for efficacy. This work demonstrates the potential of this systematic modelling and ultrahigh-resolution 3D printing approach to optimize microneedles for intradermal biomedical applications, including therapeutic cancer vaccination.

Objective: This work aims to develop an electrochemical biosensor for the analysis of zidovudine (ZDV) in commercial tablets.

Method: The biosensor utilised silver nanoclay composites (AgNCs) together with drop-coated Human Serum Albumin (HSA) on a glassy carbon electrode (GCE/AgNCs/HSA). The electrochemical properties of the GCE/AgNCs/HSA were studied using cyclic voltammetry (CV) and analysed using the Randles-Sevcik equation. Procedurally, optimised differential pulse voltammetry (DPV) technique in 1 M PBS, pH 7.04, was used to determine analytical parameters of the methods, validation, and study of commercial tablets.

Results: The optimum procedural conditions used were -0.4 V to -1 V potential range, 0.0405 V step potential, 0.075 V modulation amplitude, 0.01 s modulation time, and 0.25 s interval time. GCE/AgNCs/HSA film's electrochemical properties obtained were a diffusion coefficient (D) of 1.55 × 10-11 cm2.s-1, a heterogeneous rate constant (Ks) of 3.40 × 10-6 cm.s-1, with two electrons. The calibration graph linear range was from 0.12 to 6.98 μM with a low limit of detection (LOD) of 0.3 μM, and 1.0 μM limit of quantification (LOQ). Method validation showed an acceptable %RSD for reproducibility and repeatability. The sensor was stable over 10 days and remained unaffected by the presence of the interferences studied. The commercial study of 300 mg commercial tablets was found to be 301.3 mg with 1.9% RSD, which is in agreement with the tablet's stated amount.

Conclusion: The development of the GCE/AgNCs/HSA biosensor was successful and efficiently used to quantify ZDV in tablets.

Introduction: A common approach to scaling clearance from adults to children is to apply a maturation function for the dominant elimination pathway in adults. We investigate for drugs mainly cleared through hepatic metabolism, how the fraction metabolized changes and whether this pathway remains dominant in young children.

Methods: A physiologically-based pharmacokinetic workflow was developed investigating 460 hypothetical drugs that were for 90% or 70% cleared through hepatic metabolism in adults with remaining clearance through glomerular filtration. Their unbound drug fractions were between 1 and 99% and they were metabolized by isoenzymes with different maturation patterns. Absolute and relative clearance through hepatic metabolism was calculated in a typical adult and seven typical pediatric individuals younger than 4 years.

Results: When hepatic metabolism comprises 90% of total plasma clearance in adults, it tends to remain the dominant elimination route throughout childhood for substrates of all isoenzymes, except for substrates of CYP2A6, UGT1A1, and UGT2B7. However, when hepatic metabolism comprises 70% of the total plasma clearance in adults, hepatic metabolism will not remain dominant for at least part of the pediatric age-range for substrates of many enzymes, except for substrates of CYP2C8, CYP2C9, and SULT1A1.

Conclusion: This study identified scenarios in which hepatic metabolism cannot be assumed to remain dominant in children younger than 4 years, when it is the dominant elimination route in adults. In these scenarios, scaling for the dominant clearance route in adults will yield underprediction of total plasma clearance and the contribution of alternative routes needs to be considered.

Purpose: This work aims to accelerate and enhance pharmaceutical drug dissolution prediction by integrating advanced Large Language Models (LLMs) and AI-diffusion models to reduce reliance on time-consuming, costly empirical experiments. The framework sets a foundation for broader adoption of generative AI in drug development.

Methods: This work introduces a DeepSeek based LLM framework augmented by prompt engineering (zero-shot, few-shot, chain-of-thought) and adaptive weighted retrieval-augmented generation (RAG) to systematize dissolution profile from basic physical properties. Moreover, a diffusion model synthesizes SEM-derived morphological parameters (e.g., particle size, surface area), circumventing error accumulation from multi-instrument characterization workflows. These parameters feed the RAG database, enabling LLM predictions grounded in structure-performance relationships rather than idealized assumptions.

Results: Overall, the LLM generated dissolution profile (few-shot chain-of-thought with RAG) provides a good agreement between experimental and the prediction result among others. Sensitivity analysis is investigated to quantify the reliability and stability of the prompt content. Additionally, diffusion-generated structural data from SEM images combined with the LLM's predictive capabilities are tested to connect macro-scale physical properties with microstructural characteristics, achieving a close profile trend with acceptable RMSE and PCC.

Conclusions: This study demonstrates the potential of the DeepSeek-based LLM framework to describe the dissolution of drug powders. Among the different system prompt strategies, few-shot chain-of-thought with RAG performs the best dissolution profile among others. While it may overcomplicate straightforward tasks in certain scenarios. The combination of diffusion models successfully bridges AI-driven insights (e.g., dissolution predictions) with physical and structural drug properties (e.g., particle geometry from SEM images).

Background: VGB-R04, an investigational gene therapy employs an engineered AAV8 capsid-based vector to deliver a liver-specific expression cassette encoding the high-activity FIX Padua variant (R338L) of human coagulation factor IX for Hemophilia B. The pharmacodynamics, Pharmacokinetic, immunogenicity and safety of VGB-R04 needs to be evaluated for non-clinical research.

Methods: The pharmacodynamics, Pharmacokinetic, immunogenicity and safety study of VGB-R04 via intravenous injection in mice and cynomolgus monkeys were conducted to support an investigational new drug (IND) application. The endpoints included pharmacodynamic biomarkers, in-life measurements. Anti-AAV8 neutralizing antibodies and anti-hFIX Padua protein antibody test, viral shedding, and tissue bio-distribution were analyzed.

Results: The peak concentration was noted one hour after injection, subsequently exhibiting a distinct decline over time. The elimination rate of target genes in mouse blood exceeded that in cynomolgus monkeys. The concentration in liver tissues was indicating distinct liver tissue tropism. The elimination rate of target genes in mouse liver exceeded that in cynomolgus monkeys. The plasma concentration of hFIX Padua protein exhibited a dose-dependent elevation in mice. Cynomolgus monkeys exhibited significant elevation in plasma concentrations of hFIX Padua protein at 4 × 10¹³ vg/kg. Anti-AAV8 neutralizing antibodies can be detected in both species, but no antibodies against anti-hFIX Padua were seen in mice. The NOAEL were 8 × 10¹² vg/kg in mice and 4 × 10¹³ vg/kg in monkeys.

Conclusion: The studies demonstrated the pharmacodynamic advantages, pharmacokinetic profile with target distribution and potential safety of VGB-R04 in mice and cynomolgus monkeys after a single administration. The results support the gene therapy for future clinical studies.