Pharmaceutical Research最新文献

Objective: Bicyclol, a hepatoprotective agent, is often used in combination with other drugs for liver diseases, including drug-induced liver injury (DILI), raising concerns about potential drug-drug interactions (DDIs). This study investigates the interaction between bicyclol and key transporters (OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, MATE2-K, P-gp, BCRP, BSEP) to predict transporter-related DDI risks.

Methods: Transporter interaction studies were conducted using cell lines or membrane vesicles overexpressing human uptake and efflux transporters. The substrate and inhibitory potential of bicyclol were systematically evaluated through transport and inhibition assays. The static model and criteria were applied to assess the risk of transporter-related DDIs in vivo.

Results: Bicyclol was not a substrate of above-mentioned transporters. Regarding inhibition, it was not an inhibitor of OATP1B1, OATP1B3, OAT1, OAT3, MATE1, MATE2-K, or BSEP (IC₅₀s > 100 μM). However, it was a marginal inhibitor of OCT2 (IC₅₀ = 76.2 μM), a weak inhibitor of P-gp (IC₅₀ = 123 μM), and a strong inhibitor of BCRP (IC₅₀ = 8.5 μM). The static model predicted that only BCRP would be inhibited in vivo by bicyclol, suggesting dose optimization might be required for BCRP substrates.

Conclusions: Here, we systematically elucidated the substrate and inhibition potential of bicyclol on major human drug transporters for the first time, which may provide the basis for rational co-administration of bicyclol, potentially broadening its clinical application.

Objective: The development of protein formulations is grappled by the complexity of maintaining protein integrity during the arduous formulation process. While several excipients have been employed for the stabilization of proteins, including the recombinant human growth hormone (rhGH), a precise process control is still paramount. This study aims to investigate the effect of mannitol polymorphism on the structural stability of rhGH in its spray-dried formulations.

Methods: rhGH was co-spray dried with mannitol at protein:mannitol ratios (1:0.5 to 1:6, w/w). Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) characterized mannitol crystallinity. Furthermore, circular dichroism (CD) spectroscopy measured secondary structure pre- and post-accelerated storage (40°C/75% RH, 4 weeks), and SDS-PAGE was leveraged to evaluate protein aggregation.

Results: Spray-dried powders exhibited spherical particles (1-5 µm) with surface indentations. PXRD reported high levels of mannitol crystallization with ratios of 1:0.5, 1:1.5, and 1:6, which was corroborated by the change in crystallization index using DSC. Parallelly, it corresponded to reductions in α-helix content ranging from 21.8 to 25%, after storage. In contrast, the 1:4 ratio predominantly demonstrated an 8.4% increase in α-helix content, indicating enhanced stability. SDS-PAGE confirmed greater aggregation in samples with higher mannitol crystallization, whereas the 1:4 formulation minimized aggregation.

Conclusion: Mannitol crystallization strongly influences rhGH stability in spray-dried powders. An optimal protein:mannitol ratio of 1:4 helped maintain mannitol in the amorphous state, preserved secondary structure, and reduced aggregation during storage. These findings underscore excipient crystallization as a key determinant of protein stability and identify a stabilizing composition for spray-dried rhGH.

Purpose: This review aims to examine the impact of three-dimensional (3D) printing technologies on enhancing psychiatric pharmacotherapy through facilitating personalized and patient-centered drug delivery. This research specifically addresses problems such as poor medication compliance, polypharmacy, and palatability issues, especially in pediatric and elderly populations.

Methods: A thorough review of the literature was conducted, focusing on novel advances in 3D printing techniques, including fused deposition modeling (FDM), semisolid extrusion (SSE), stereolithography, inkjet printing, binder jetting, and selective laser sintering (SLS). Selected research highlighted the application of such technologies in developing customized oral drug dosage forms. Emphasis was placed on the exploitation of polymers like Eudragit® E PO, flavor-masking excipients, and their combination with biosensor and artificial intelligence (AI) systems. Case studies were assessed to ascertain their relevance and innovation in the development of psychiatric medications.

Results: 3D printing allows the manufacture of tailored psychiatric drugs with greater dosing versatility, taste masking, and the ability to merge several active drug ingredients into a single pharmaceutical form. Patient-friendly dosage forms such as chew gummies and chocolate tablets demonstrated enhanced acceptability. Also, forthcoming technologies such as 4D printing and AI-driven biosensors yield intelligent, interactive drug release systems that are specific to individual physiological or behavioral inputs.

Conclusions: 3D printing represents a paradigm-shifting advance in psychiatric care, offering solutions to long-standing treatment compliance and fixed-dose challenges. Although regulatory and scalability challenges persist, the intersection of pharmaceutical engineering, material science, and artificial intelligence creates an encouraging platform for the future of precision mental care therapies.

Exosomes (EXM), cell-secreted nanoscale vesicles, are now used as promising tools for therapeutic protein, nucleic acid, and small molecule delivery. However, various challenges, such as rapid immune system clearance, ineffective cargo loading, and reduced targeting specificity, hold them back from being clinically translated. Recent breakthroughs in EXM engineering have made them excellent biomolecule delivery tools. This review critically explores state-of-the-art strategies to maximize cargo incorporation, reengineer EXM surfaces, and create synthetic EXM mimetics. We present important engineering methods, such as genetic manipulation to increase cargo encapsulation, functionalization with targeting ligands, and designing synthetic vesicle structures. We further discuss the therapeutic uses of engineered EXM for different applications, such as cancer treatment, gene therapy, and regenerative medicine, highlighting their potential to evade biological barriers like the blood-brain barrier. Challenges in manufacturing, quality control, and regulatory concerns of translating engineered EXM into clinical therapies are also discussed. We emphasized the upcoming trends that would facilitate improving EXM-based delivery platforms, such as the creation of multifunctional engineered EXM and the incorporation of artificial intelligence for tailored drug delivery. This review stresses the revolutionary value of EXM engineering in establishing next-generation targeted therapeutics, unveiling new fronts for precision medicine and personalized health.

PURPOSE OR OBJECTIVE: Each Easyhaler^® Salbutamol 100 μg dry powder inhaler (DPI) uniquely requires pre-actuation shaking, unlike most commercial DPIs. This study aimed to investigate the aerodynamic and functional implications of pre-actuation shaking to determine its effect on drug delivery performance.

Methods: Device actuation was performed following 0 to 5 pre-actuation shakes. Performance was assessed using a multi-technique approach: cascade impaction, dose uniformity testing (DUSA), laser diffraction (SprayTec), optical microscopy, and scanning electron microscopy (SEM). Key parameters measured included emitted dose (ED), delivered dose (DD), fine particle dose (FPD), fine particle fraction (FPF), mass median aerodynamic diameter (MMAD), and throat deposition.

Results: Delivered dose remained relatively constant regardless of shaking. However, FPD and FPF significantly improved with increased shaking, particularly at three to five shakes. Cascade impaction demonstrated reduced throat deposition and greater deposition in stages 3-4 (< 5 µm respirable fraction) under these conditions. An inverse correlation between throat deposition and FPF was identified. SEM and microscopy confirmed consistent particle morphology and blend uniformity, while laser diffraction showed a predominance of larger carrier particles under 0-shake conditions.

Conclusions: Pre-actuation shaking substantially influences the aerosolization performance of Easyhaler^® Salbutamol. At least three vertical shakes are required to achieve optimal fine particle delivery and reduce throat deposition. These findings highlight the importance of proper patient instruction on device handling. Further studies should assess whether similar effects occur with other Easyhaler^® formulations.

Objective: Histone deacetylase (HDAC) inhibitors have emerged as promising cancer therapeutics by regulating gene expression, halting cell cycle progression, and inducing apoptosis. This study explores the structure-activity relationship of 2-mercaptoquinazolin-4(3H)-one derivatives as potential anticancer agents and HDAC inhibitors.

Methods: The library compounds were prepared via a three-step pathway by incorporating 2-mercaptoquinazoline and a hydroxamic acid moiety. The cytotoxicity of 27 synthesized hydroxamic acid derivatives was evaluated against SW620 (colon cancer), MDA-MB-231 (breast cancer), and MRC-5 (normal lung fibroblast) cell lines. Molecular docking studies on HDAC-isoforms for the 4a-i were also performed to identify the essential structural features that contribute to the biological activities.

Results: The results demonstrated that substituents at the N-3 position significantly influenced anticancer activity, with methyl-substituted derivatives (4a-i) exhibiting the highest cytotoxicity, followed by phenyl-substituted (7a-i) and benzyl-substituted (10a-i) compounds. Among the tested compounds, 4a (-H) and 4c (7-CH₃) showed as the most potent active compounds, with IC₅₀ values of 4.24 ± 1.16 µM and 3.61 ± 0.32 µM against SW620 cells, and 2.93 ± 0.68 µM and 3.34 ± 0.32 µM against MDA-MB-231 cells, respectively. HDAC inhibition assays revealed that 4a-d and 4 g exhibited superior inhibitory activity compared to SAHA. Further investigation of 4a and 4c in SW620 cells showed that both compounds induced G2/M phase cell cycle arrest and promoted apoptosis, supporting their potential as promising HDAC inhibitors with anticancer properties.

Conclusions: Among the most active compounds, 4a and 4c may serve as promising leads for the development of novel HDAC-targeted anticancer therapies.

Purpose: Intravitreal injection is an administration route for ocular therapeutics of different molecular sizes, including antibodies, antisense oligonucleotides, and adeno-associated viruses. The purpose of this study was to identify the effect of molecular size on ocular drug distribution after intravitreal injection by computed tomography (CT) and to construct a mathematical model for clinical dosage and regimen optimization.

Methods: Contrast agents of different molecular sizes (ca. 1-110 nm) were intravitreally injected into rabbits and their distributions were visualized using CT. Subsequently, a computational spatial model of the rabbit eyeball with an intravitreal diffusion coefficient was constructed from CT images using the finite element method. The model was then extended to the human eyeball.

Results: CT images indicated that: 1) all contrast agents moved in the direction of gravity according to body position, and 2) intravitreal diffusivity decreased with increasing molecular size. The computational rabbit eyeball model successfully reproduced the CT images, and the intravitreal diffusion coefficient of each contrast agent was determined. Furthermore, simulation results with the human eyeball model suggested that maintaining the supine position after intravitreal injection provides better exposure at the macula, particularly for therapeutics with larger molecular size.

Conclusions: Using computational spatial modeling based on CT images, we identified the effect of molecular size on ocular drug distribution after intravitreal injection in humans. These findings are expected to aid the establishment of appropriate times to maintain the supine position to ensure targeted exposure in accordance with modality size, as well as the estimation of optimal clinical doses.

Objective: The therapeutic potential of STING agonists in cancer immunotherapy is hindered by poor tumor selectivity, resulting in systemic inflammation. Conventional targeted delivery strategies rely on cell-surface markers, which inadequately distinguish tumor from normal cells. Here, we propose an intracellular-protein-guided approach to achieve tumor selective STING activation.

Methods: Leveraging the elevated phosphorylated AKT (p-AKT) levels characteristic of tumor cells, we engineered a synergistic co-delivery liposomal platform to selectively enhance STING agonist activity within tumors. Hydroxypropyl-β-cyclodextrin (HPβCD) liposomes were used to co-encapsulate resveratrol (Res), a mild, natural STING agonist, and curcumin (Cur), an AKT inhibitor, enabling simultaneous tumor targeting and AKT inhibition-mediated amplification of STING signaling.

Results: The co-loaded HPβCD liposomes achieved potent, tumor-selective STING activation enhanced by AKT inhibition. In vitro, this system reduced tumor cell proliferation by > 60% compared to controls. In vivo, Cur pretreatment markedly amplified Res-induced STING signaling, eliciting robust adaptive immune responses, suppressing metastatic recurrence, and extending median survival from 35 to 85 days (p < 0.05) relative to monotherapy groups.

Conclusions: This study demonstrates that combining AKT pathway inhibition with STING activation offers a powerful, tumor-selective immunotherapy approach. By leveraging intracellular biomarkers rather than surface antigens, the co-delivery liposomal system achieves potent immunomodulation with minimal off-target effects, highlighting its potential as a next-generation strategy for precision cancer immunotherapy.

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.