Pharmaceutical Research最新文献

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.

Objective: Globally, a significant overlap exists between females affected by HIV and HSV-2 infections, and who have an unmet need for contraception. Intravaginal rings (IVRs) have become widely accepted by women worldwide for contraception and hormone replacement therapy and provide a promising platform as a multipurpose prevention technology (MPT).

Methods: Using state-of-the-art 3D printing process known as continuous liquid interface production (CLIP™), IVRs with an internal honeycomb (HC 2.53 mm) geometry were fabricated with a silicone-urethane resin. IVRs were loaded with a triple-drug combination of an anti-HIV drug (Dapivirine, DPV, 30 mg), an anti-herpes drug (Pritelivir, PTV, 20 mg) and a contraceptive hormone (Levonorgestrel, LNG, 2.0 mg) using a solvent swelling method in acetone.

Results: IVRs elicited zero-order release kinetics following an initial burst for all three APIs when formulated individually or in combination. Release rates were above benchmark therapeutic targets for DPV and LNG (200 µg/day DPV, 20 µg/day LNG). A series of accelerated stability studies demonstrated the physical integrity of IVRs after 6 months of storage at 40ºC/75%RH. DPV remained stable over 6 months, whereas PTV and LNG exhibited significant decrease in concentration after 3 months of storage with presence of degradation products detected by HPLC. Mouse size placebo rings (3 mm OD) elicited 100% cell viability in relevant cell lines and were well tolerated in vivo in mice.

Conclusions: Collectively, these results demonstrate that this first-in-line 3D printed MPT IVR has potential to expand preventative choices for young women and girls against HIV, HSV, and unplanned pregnancy.

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: 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.

Extracorporeal membrane oxygenation (ECMO) is a life-saving cardiopulmonary bypass technology for critically ill patients. Patients treated with ECMO receive multiple drugs to treat critical illnesses, prevent infections, and maintain sedation. However, inaccurate dosing information of some of the administered drugs is a significant cause of ECMO related mortality. Hydrophobic drugs tend to adsorb on the surface of ECMO circuit components leading to suboptimal dosing and therapeutic failure. Modifying the drugs can be exploited as a strategy to reduce drug adsorption in ECMO circuits. Propofol (Diprivan®) is a widely used anesthetic in ECMO patients that is known to substantially adsorb to ECMO circuit components due to its hydrophobicity. The objective of this work was to evaluate the PEGylation of propofol as a strategy to reduce its adsorption to the ECMO circuit. Poly(ethylene glycol) (PEG) was covalently conjugated to propofol with varying PEG lengths, i.e., 3 monomers of PEG (PEG₃), 5 monomers of PEG (PEG₅) and 2 kDa molecular weight PEG (PEG_2kDa). The conjugates were synthesized, characterized, and compared for their water solubility, ability to spontaneously form micelles, and in reducing adsorption to hydrophobic materials in an in vitro ECMO mimic assay. Further, the conjugates were tested for their anesthetic activity in a C57BL/6 mouse model. We demonstrated that PEG₅-Propofol and PEG_2kDa-Propofol had improved water solubility and significantly reduced the adsorption of propofol. PEG₅-Propofol also demonstrated a similar anesthetic activity (520 ± 109 secs) to free propofol (485 ± 103 secs). Our results demonstrate that PEG₅-Propofol is a promising anesthetic for administration to patients on ECMO.

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.

The peritoneal cavity presents both unique challenges and promising opportunities for targeted therapy in malignancies like ovarian, gastric, pancreatic, and colorectal cancers. Intraperitoneal drug delivery offers significant pharmacokinetic advantages over intravenous administration by achieving high local drug concentrations and tumor-specific delivery potential while minimizing systemic toxicity. Despite these theoretical advantages, the clinical implementation of intraperitoneal therapy is limited by several barriers, including restricted tissue penetration, incomplete peritoneal coverage, rapid drug clearance, catheter-related complications, posttreatment peritoneal adhesions, and ascites-induced permeability dysregulation. This review highlights three advanced strategies developed to overcome these obstacles: (1) particulate-based delivery systems, such as nanoparticles to enhance tumor specificity through passive accumulation, active targeting and on-demand drug release in response to internal or external stimuli; (2) Sustained drug release hydrogels and (3) pressurized intraperitoneal aerosol chemotherapy. Despite promising preclinical and clinical advancements, successful translation requires systematic optimization of multiple parameters, such as ascites dynamics, tumor heterogeneity, and multidrug resistance. The integration of advanced delivery technologies with a comprehensive understanding of peritoneal physiology remains crucial for achieving safe and effective clinical applications.