Pharmaceutical Research最新文献

Purpose: There are no preventive and few therapeutic options for melanoma, an aggressive skin cancer, especially in situations where N-Ras mutations are present. The new pan-Ras inhibitor ADT-007 has promise for treating melanoma. This study aimed to prepare a topical molecular targeted drug for prevention or treatment of early-stage melanoma using ultraflexible liposomes (UFLs) dispersed in a carbomer gel.

Methods: ADT-containing UFLs were evaluated for anticancer efficacy and selectivity in vitro using melanoma cell lines and normal keratinocytes. Comparisons were made between UFLs and traditional liposomes (TL) in terms of drug release, encapsulation efficiency, and skin permeation. Permeation tests were conducted using the skin-like Strat-M membrane. Stability of UFLs was assessed at 4°C.

Results: UFLs exhibited enhanced ADT-007 drug release and higher encapsulation efficiency compared to TL. ADT-007 from UFL carbomer gels penetrated more readily through the Strat-M membrane than that from TL or ADT-007 alone. UFLs were incredibly stable in regard to size and encapsulation efficiency, particularly at 4°C. This combination demonstrated low cytotoxicity against human keratinocytes but high toxicity against various human melanoma cancer cells, especially those harboring N-Ras mutations.

Conclusions: This study highlights the use of UFL-based gels as a promising strategy for prevention or targeted melanoma therapy by providing enhanced drug delivery, stability, and cancer cell selectivity.

Introduction: Sorafenib (SOR) is a low-dose multikinase inhibitor that suppresses angiogenesis by blocking vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors. The aim of the present study was to develop Sorafenib-loaded chitosan (CS) and hyaluronic acid (HA) polyelectrolyte complex nanoparticles (SCH-NP) for triple negative breast cancer (TNBC).

Methods: For TNBC therapy, SCH-NP were formulated and optimized using Central Composite Design (CCD). The prepared SCH-NP were characterized by particle size, zeta potential, Polydispersity index, Fourier Transform Infrared Spectroscopy (FTIR), entrapment efficiency, invitro drug release study, in-vitro and in vivo studies.

Results: SCH-NP were formulated and optimized using CCD. The developed SCH-NP showed particle size of 125 nm, zeta potential of -13.7 mV, PDI value 0.21 and entrapment efficiency of 82.07%. FTIR study confirmed no interaction between drug and polysaccharide. The cumulative release percentage of SOR from SCH-NP was 81.73%. SOR's IC50 value was much larger than, SCH-NP's in both MDA-MB 231 & 4T1 cell lines. After treatment for 18 days, the tumor volumes in mice increased to 447.4 mm³ (Phosphate buffer solution), 263.6 mm³ (pure SOR), treatment with SCH-NP results in a noteworthy decrease in the tumor volumes in mice by 66.1% (151.3 mm³).

Conclusions: The present study suggests that SCH-NP might be effective for the tumor-targeted delivery of Sorafenib and it might be a suitable nanocarrier for enhancing SOR cytotoxicity in vitro and may be useful for the tumor-targeted delivery of SOR.

Purpose: This study was aimed to develop reservoir-type extended-release (ER) formulations resistant to alcohol-induced dose dumping (ADD) using polyvinyl acetate (PVAc) and polyvinylpyrrolidone (PVP-90).

Methods: The ER formulations were developed utilizing water-soluble and water-insoluble core diluents and binders, along with various PVAc with PVP-90 (3:1 w/w) coating levels. In vitro risk mitigation studies were conducted to understand the impact of alcohol on the properties of polymer compositions and their films, including viscosity, swelling, elasticity, and breaking force. The PVAc with PVP-90 (3:1) film exhibited minimal swelling and maintained better integrity in the presence of alcohol.

Results: The ER tablets incorporating water-soluble L-PVP in the core did not exhibit burst release in alcoholic media but showed compromised ADD resistance at lower coating levels. Increasing the concentration of PVP-90 in the core resulted in a slower disintegration rate, with concentrations exceeding 15% preventing full disintegration of tablets within 2 h in 0.1N HCl with 40% alcohol. The optimized formulation, containing 25% PVP-90 in the core and PVAc with PVP-90 coating, minimized ADD risk and maintained an ER release profile even after exposure to accelerated storage conditions (40°C/75% RH) for 3 months.

Conclusion: The study highlights the importance of core and coating compositions in achieving ADD resistance. However, risk mitigation strategies including a new recommended dissolution method revealed that formulations meeting FDA guidelines could still exhibit dose dumping after just 2 h of alcohol exposure. This finding suggests the need to review regulatory standards for ADD resistance and harmonize requirements between agencies like EMA and US FDA to develop a relevant in vitro method for assessing ADD in modified release formulations.

Purpose: Colorectal cancer (CRC) is a leading cause of cancer mortality with current chemotherapeutic strategies often limited by systemic side effects and suboptimal tumor targeting. This study aimed to enhance the delivery and efficacy of paclitaxel (PTX) for CRC therapy by engineering nanoparticles (NPs) actively targeted to the folate receptor-α (FRα) using pemetrexed, an FDA-approved antifolate with high FRα affinity.

Methods: A novel FRα-targeted polymer (PLGA-PEG-pemetrexed) was synthesized by ring-opening polymerization and used to prepare tumor-targeted nanoparticles (TTNPs). The physical characteristics of TTNPs and non-targeted NPs (NTNPs) were evaluated by dynamic light scattering and TEM. Cellular uptake was assessed in FRα-expressing CT26 colorectal cancer cells by flow cytometry and confocal imaging. Cytotoxicity was evaluated using PrestoBlue™ assays. In vivo tumor targeting and therapeutic efficacy were assessed in a syngeneic CT26 tumor-bearing BALB/c mouse model using IVIS imaging, tumor accumulation and growth measurements.

Results: The synthesized PLGA-PEG-pemetrexed formed uniform, negatively charged NPs with a hydrodynamic diameter of 140-170 nm. TTNPs demonstrated significantly enhanced uptake in FRα-expressing CT26 cells compared to NTNPs, which was abrogated by folic acid pre-treatment. In vitro, PTX-loaded TTNPs exhibited greater cytotoxicity against CT26 cells than free PTX. In vivo, TTNPs showed superior tumor accumulation compared to NTNPs, resulting in significantly greater tumor growth inhibition and increased intratumoral PTX concentrations. All treatments were well tolerated.

Conclusion: Our results demonstrate that active targeting of chemotherapy-loaded NPs with a FRα ligand, pemetrexed, enhances tumor targeting and antitumor efficacy in a CRC model.

Cardiac amyloidosis caused by amyloid light chain proteins is a life-threatening manifestation of systemic amyloid light chain amyloidosis, yet it remains underrecognized. This review explores the pathogenic mechanisms underlying cardiac involvement in amyloid light chain amyloidosis, focusing on two key pathways: the physical disruption from extracellular amyloid deposition and direct cardiotoxicity from circulating light chains, which induce oxidative stress, mitochondrial dysfunction, and apoptosis. Emerging therapies, including cellular immunotherapies such as chimeric antigen receptor T cells and bispecific antibodies, plasma cell-directed agents, and strategies that promote amyloid fibril removal or restore cardiomyocyte function are also evaluated. Despite advances, challenges persist in managing toxicities, accelerating amyloid clearance, and validating treatments in broader populations. Future efforts should prioritize early diagnosis, optimized combination therapies, mass spectrometry-driven drug discovery, and the development of reliable human in vitro and animal models to better recapitulate disease mechanisms and facilitate therapeutic development.

Purpose: Intranasal delivery of monoclonal antibodies (mAb) offers an attractive approach for preventing or treating respiratory viral infections. Previously, we showed that thin-film freeze-dried powder (TFFD powder) of AUG-3387, an anti-SARS-CoV-2 spike protein mAb, could be sprayed into the posterior nasal cavity region of a nasal cast model using Aptar's unidose powder (UDSp) nasal spray system. This work investigated the feasibility of filling TFFD mAb powders into the UDSp system using drum filling.

Methods: New TFFD AUG-3387 powders were prepared by including magnesium stearate and/or hydroxypropyl methylcellulose in them. The powders were comminuted and their flow properties measured. A selected powder was filled into UDSp systems using a Harro Höfliger Drum TT benchtop filler or a Quantos hand-held powder dispenser at target fill weights of 0.5 and 1.0 mg, and the performance of the filled systems was evaluated.

Results: The F8 TFFD AUG-3387 powder was selected for drum filling due to its 'passable' to 'excellent' flowability and its minimal sensitivity to controlled moisture exposure. Drum filling succeeded at both target fill weights, consistently compacting the powder into pucks without ejection failures. The average fill weight was 0.54 ± 0.09 mg for the 0.5 mg target and 1.11 ± 0.08 mg for the 1.0 mg target. The drum-filled UDSp systems performed similarly to the Quantos-filled systems in shot weight uniformity, emitted particle size, and deposition in a nasal cast, although differences were observed in certain spray characteristics.

Conclusions: It is feasible to drum fill TFFD mAb powder at low fill weights.

Purpose: U.S. Food and Drug Administration (FDA) recommends reference scaled limits and variability comparison for bioequivalence (BE) demonstration of narrow therapeutic (NTI) drugs while most other regulatory agencies apply direct tightening of BE limits. This study evaluates strengths and limitations of different BE criteria using abbreviated new drug application (ANDA) data received by FDA to support harmonization of NTI drug BE criteria.

Methods: We analyzed four-way fully-replicated crossover BE study data in NTI ANDAs, applying BE criteria from different agencies and alternative criteria (e.g., Paixão's criteria, modified Paixão's and FDA criteria) to compare passing rates.

Results: Current EMA and FDA criteria seem stringent with NTI drugs having moderate and low within-subject variability (e.g., S_WR), respectively. Capping BE limits at 90.00-111.11% when σ_WR ≤ 0.10 in alternative FDA criteria improved passing rates and better aligns with NTI quality standards. An additional point estimate constraint of 90.00-111.11% enforced geometric mean ratio closer to 1 but reduced passing rates when S_WR was moderate to high. FDA's regulatory constant resulted in slightly less stringent scaled BE limits than Paixão's, but may better align with observed S_WR ranges for NTI drugs. Alpha adjustment reduced Type I error but slightly decreased study passing rates.

Conclusion: Alternative FDA criteria with capping at 90.00-111.11% when σ_WR ≤ 0.10 and applying alpha adjustment provides reasonably stringent standards for BE demonstration of NTI drugs. This in-depth analysis of ANDA BE data will help ICH M13C Expert Working Group make informed decisions about harmonization options for BE demonstration of NTI drugs.

Ocular inflammation is a major contributor to vision-threatening disorders, with phosphodiesterase 4 (PDE4), a key regulator of cAMP playing a central role in pro-inflammatory signaling. Although investigational PDE4 inhibitors like Rolipram (RP) show therapeutic promise, their systemic toxicity limits clinical application, underscoring the need for safer, targeted alternatives. Urolithin A (UA), a gut-derived metabolite of ellagic acid with emerging anti-inflammatory properties, was evaluated as a novel PDE4 inhibitor. Molecular docking revealed that UA binds with high affinity to the A-chain of PDE4A (-8.79 kcal/mol), forming unique π-π stacking and multiple hydrogen bonds. In contrast, RP binds preferentially to the B-chain with slightly lower affinity (-8.42 kcal/mol) and fewer stabilizing interactions. While both ligands engage similar catalytic residues, UA exhibited a more extensive binding profile, suggesting enhanced stability and specificity. In lipopolysaccharide (LPS)-stimulated human retinal pigment epithelial cells (ARPE-19), UA significantly inhibited PDE4A activity, elevated intracellular cAMP, and reduced key inflammatory mediators (NF-κB, IL-6, TNF-α), as demonstrated by immunofluorescence, ELISA, and gene expression analysis. These findings support UA's function as an anti-inflammatory agent by inhibiting PDE4A, highlighting its potential as a safer systemic or localized therapy for ocular inflammatory diseases.

Objective: Orodispersible films (ODF) blend the dose accuracy of solid dosage forms and the ease of administration of liquid dosage forms, hence offer many advantages. This study investigated the feasibility of two extrusion-based 3D printing techniques (pneumatic and syringe) to fabricate ODFs in a benchtop setting.

Methods: We fabricated fast-dissolving ODFs using pneumatic and syringe print heads and compared the variations in the process parameters, ease of fabrication, and characterized the properties of the final dosage forms. The variation in the printing parameters, drying time, drying temperature, and needle/nozzle types on the reproducibility and uniformity of the ODFs prepared from, these two printheads were studied. Feed materials for extrusion were selected based on rheological properties, printability, and reproducibility. An optimized ODF formulation composition was kept common and utilized for comparison.

Results: The ODFs from pneumatic and syringe-based extrusion printheads consistently created bulk batches with little to no significant variation. Syringe-based extrusion showed high precision with identical dimensions, whereas pneumatic extrusion showed quick fabrication. The ODFs produced by both methods were highly reproducible and showed excellent film properties such as mechanical strength, disintegration, and dissolution. The ODFs showed adequate mechanical strength (>0.72 N/mm²) for packaging and transport. The disintegration time was less than a minute, and quicker dissolution within 20 min.

Conclusion: Both pneumatic and syringe-based 3D printing technologies are deemed to be potentially viable alternatives for the fabrication of personalized dosage forms such as ODFs in pharmacy and clinical settings.