AAPS PharmSciTech最新文献

This study developed PEGylated liposomal gefitinib (GTL) to overcome clinical limitations of gefitinib therapy in NSCLC, including poor tumor targeting and suboptimal therapeutic outcomes. GTL was formulated using DPPC:cholesterol:mPEG-2000-DSPE (8:7:1) and comprehensively evaluated for tumor treatment efficacy. GTL achieved optimal physicochemical properties (87.7 ± 4.81 nm, EE 60.15%) with polymer relaxation-controlled release kinetics (Super Case II transport, n = 1.0789) providing sustained therapeutic exposure. The GTL demonstrated superior tumor treatment outcomes with threefold enhanced cytotoxicity (IC₅₀: 4.93 vs 15.03 μg/mL) and remarkable in vivo efficacy including 57% tumor volume reduction versus control and 32% superiority over free gefitinib. Comprehensive tumor treatment evaluation revealed enhanced apoptotic activity (68.35% caspase 3/7 activation), near-complete restoration of normal lung architecture, and significant tumor clearance confirmed by histopathological analysis. The controlled release mechanism enabled sustained therapeutic levels while minimizing systemic toxicity. GTL maintained stability for 12 months under ICH conditions, supporting clinical development. This work represents the comprehensive tumor treatment evaluation of gefitinib nanoformulation, demonstrating clinically relevant therapeutic superiority for improved NSCLC patient outcomes.

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Drug-drug co-amorphous systems (CAS) represent an emerging co-delivery strategy for combination therapy. Current research primarily explores combinations of poorly water-soluble drugs with water-soluble counterparts, while CAS comprising exclusively poorly water-soluble drugs remains underexplored. Such systems may exhibit unique dissolution behaviors due to the absence of hydrophilic components. In prior work, we developed a co-amorphous system of two poorly water-soluble drugs, baicalin (Bai) and imperatorin (Imp). However, this system demonstrated significant agglomeration during dissolution and limited dissolution enhancement. To address this, we incorporated trace hydroxypropyl methylcellulose (HPMC) into the Bai-Imp-CAS via spray drying. This study investigates HPMC’s impact on dissolution behavior and underlying mechanisms through comprehensive analyses of supersaturation dissolution, dispersion kinetics, agglomeration rate, contact angle, surface free energy, nucleation time, and crystal growth rate. Results indicate that trace HPMC significantly enhances dissolution performance by reducing contact angles and increasing surface free energy, thereby improving dispersibility and inhibiting recrystallization. Additionally, HPMC elevates the glass transition temperature (Tg), improving physical stability. These findings provide a novel theoretical framework for optimizing poorly soluble drug combinations and offer practical solutions for co-delivery system development.Finally, it is also important to note that the degree of improvement of HPMC on the dissolution of the two drugs in the difficult-to-dissolve drug combination is also related to the solubility of the drugs themselves, their crystallization properties and the ratio of the two drugs.

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This study investigates the influence of phospholipid saturation by comparing hydrogenated soy phosphatidylcholine (HSPC) and egg yolk phosphatidylcholine (EPC) on the physicochemical characteristics, colloidal stability, drug release behavior and antioxidant activity of quercetin-loaded ceramide-containing liposomes for topical delivery. Liposomes composed of EPC:Cer:Que and HSPC:Cer:Que were prepared by thin-film hydration followed by sonication. The nanosystems were studied for particle size, polydispersity index, ζ-potential, and entrapment efficiency. Colloidal stability was evaluated under mechanical stress, accelerated aging, and long-term storage, while in vitro drug release, drug retention, and antioxidant activity were assessed under simulated skin conditions. Incorporation of ceramides into EPC bilayer reduced stability issues associated with unsaturated phospholipids and maintained a fluid structure, promoting drug release. Both formulations exhibited enhanced colloidal stability with EPC-based liposomes maintaining their properties at all conditions, whereas HSPC-based liposomes showed increased particle size following mechanical stress. HSPC-based liposomes demonstrated higher quercetin entrapment efficiency (63 ± 5%), improved retention over time (75% at 90 days), and a more sustained release (45% at 480 min). EPC-based ceramide-containing liposomes exhibited faster release (50% at 240 min), resulting in greater antioxidant activity as indicated by DPPH assay (0.474 ascorbic acid equivalents), while FRAP assay results were comparable for both formulations (0.012 Fe²⁺ equivalents), indicating consistent ferric reducing potential after release. These findings highlight the significance of phospholipid composition in liposome behavior and provide insights into the design of stable and effective ceramide-containing nanosystems for topical delivery of poorly water-soluble compounds such as quercetin, with potential applications in managing photoaging, inflammation, and wound healing.

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Cancer remains one of the most significant global health challenges, with its burden continuing to rise. The limitations of conventional anticancer therapies caused by the lack of tissue selectivity, demands urgent development of safer and more selective therapies to target tumors. Identifying the fundamental cancer hallmarks provided a comprehensive understanding of cancer biology for effective tumor targeting, encompassing tumor-promoting inflammation, metabolic reprogramming, immune evasion, genomic instability, phenotypic plasticity, epigenetic reprogramming, and polymorphic microbiomes. Moreover, drug repurposing is a cost-effective and time-saving method for cancer therapy that accelerates the drug discovery process by reusing drugs for new indications. Current research is focusing on combining drug repurposing with nanocarriers that enhance tumor targeting, reduce the side effects, and improve the bioavailability of the drug in a single nanoformulation. This article analyzes various types of nanoparticles encapsulating different classes of drugs, such as phenelzine, fexofenadine, telmisartan, losartan, metformin, canagliflozin, atorvastatin, and fenbendazole, highlighting their anticancer effects and the influence of nanocarriers on the drug’s therapeutic effect. Results revealed that drug-encapsulated nanoparticles enhanced antitumor effects compared to the free drug solutions. This is attributed to the synergism from the nanocarrier’s functionalization, sustained drug release, and improved cellular uptake within tumors that leads to targeting multiple cancer hallmarks. Additionally, this review highlights the present challenges in the clinical translation of nanoformulation and demonstrates how artificial intelligence may facilitate drug screening and identification, therapeutic optimization, and large-scale manufacture. Finally, using these technologies in combination with drug repurposing presents a promising direction for advancing cancer treatment.

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The objective of the work was to design a novel felbinac transdermal patch to improve its transdermal delivery efficiency by adding chemical penetration enhancers. The adhesion properties and in vitro transdermal release performance were first evaluated. The transdermal stability and skin irritation were then evaluated. Moreover, in vivo tissue distribution was also examined. The novel felbinac transdermal patch with high adhesion was prepared by calendar coating method. Different types of chemical enhancers and their amount on in vitro transdermal delivery efficiency were systematically screened. In vitro transdermal release experiments showed that by adding 1% propylene glycol (PG) as penetration enhancers, the cumulative transdermal amount of the transdermal patch within 12 h was 189.03 μg/cm², which was twice that of commercial product SELTOUCH® (94.44 μg/cm²). In addition, the transdermal patch still maintained stable permeability after being stored at room temperature for 4 months and also had good safety. Further, in vivo experiments confirmed that the concentration of felbinac in plasma, skin, and muscle tissues was significantly increased following administration of the self-made transdermal patch compared to SELTOUCH®. In conclusion, the felbinac transdermal patch developed in this study demonstrated high adhesion, excellent transdermal delivery efficiency and good stability, representing a transdermal drug delivery system with great clinical application potential.

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Poor oral bioavailability in most modern pharmaceuticals is primarily caused by poor aqueous solubility. Most NCEs (New Chemical Entities) and nearly 40% of drugs on the market fall into either Biopharmaceutical Classification System (BCS) class II or IV, both characterized by very poor aqueous solubility. This leads to a higher demand for techniques that improve solubility in water-based media. This study aims to compile and present a comprehensive and detailed assessment of cocrystals and nano-cocrystals. It emphasizes the importance of in-depth research into nano-cocrystals to gather more raw data, which will support the eventual translation of nano-cocrystals into clinical use and market approval. Cocrystal technology has been used to enhance various physicochemical parameters, including stability, solubility, and bioavailability. Nano-cocrystallization is a new emerging technique that combines the benefits of cocrystallization with nanosizing, resulting in cocrystals with improved physicochemical properties and increased surface area due to nanoscale particles. These methods not only enhance aqueous solubility but have also been shown to directly increase the dissolution rate and improve the dissolution profile of drug substances. A literature review was conducted using PubMed, Scopus, and patent databases. Cocrystals and multicomponent systems are discussed with an emphasis on their crystal structure, types and nature of bonds formed, and any significant variations or special characteristics are highlighted. This thorough review offers an overview of cocrystals and nano-cocrystals, outlining the cocrystallization process and various methods for formulation and characterization. It also covers the selection process for coformers, including new computational, AI, and machine learning techniques for screening. The review introduces nano-cocrystals, describing their synthesis methods and benefits. It discusses polymorphism in both cocrystals and nano-cocrystals, and compares cocrystals as a way to improve solubility. Additionally, it evaluates their different applications and clinical outcomes. The discussion points out that the limited research on nano-cocrystals hinders their translation into industrial and clinical use. In contrast, cocrystals, despite some barriers, have achieved notable commercial success.

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Acute lung injury (ALI) is the major cause of respiratory failure, often triggered by inflammatory responses resulting in disruption of the pulmonary gas-blood barrier. Existing treatments are limited by the poor bioavailability via systemic administration, whereas volatile oils are unsuitable for developing into inhalable formulations. In this study, we developed an inhalable cocrystal of Exocarpium Citri Grandis volatile oil (EVO) using crystallization technology with β-cyclodextrin (EVO-βCD), aiming to improve the drug’s bioavailability and enhance its therapeutic efficacy for ALI. In vitro studies revealed that EVO-βCD exhibited no significant cytotoxicity at concentrations of 7.5–120.0 µg/mL and did not cause hemolysis at concentrations between 3.75–60.0 µg/mL, suggesting favorable safety profiles. Additionally, EVO and EVO-βCD significantly reduced the ROS production in LPS pretreated 16HBE cells, highlighting their antioxidant potential. In vivo experiments demonstrated that EVO-βCD cocrystals were more effective than free EVO in reducing inflammatory cytokines (TNF-α, IL-1β, IL-6) and improving pulmonary edema in LPS-induced acute lung injury in mice. The cocrystal formulation enhanced the release rate of the drug, addressing the challenges of conventional powder inhalants. These findings suggest that EVO-βCD cocrystals hold promise as a novel therapeutic approach for ALI treatment with enhanced safety and efficacy.

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The study presents a novel approach for treating acute lung injury (ALI) using a cocrystal formulation of volatile oil from Exocarpium Citri Grandis (EVO) encapsulated by β-cyclodextrin (EVO-βCD).

The study aimed to develop stable single-walled carbon nanotube (SWCNT) dispersions in water that exhibit low protein adsorption in biological media, entrap Memantine, and release the drug in a controlled manner. Specifically, SWCNTs were functionalized, initially oxidized, and then non-covalently conjugated with pyrene methoxy polyethylene glycols (PEG). Dynamic light scattering, Raman spectroscopy, and Fourier-transform infrared spectroscopy were used to evaluate various physicochemical properties of PEG functionalized SWCNTs (PEGSWCNTs). A D-optimal design, utilizing JMP Pro 16, was employed to design the experiment and investigate the effects of oxidation time and PEG concentration on the physicochemical properties of SWCNT dispersions. The optimal dispersions exhibited hydrodynamic particle sizes, polydispersity indices, and zeta potentials ranging from 157.5 to 204.4 nm, 0.231 to 0.255, and -27.8 to -18.8 mV, respectively. The interaction between serum proteins and PEGSWCNTs was evaluated using dynamic light scattering, bicinchoninic acid, and sodium dodecyl sulfate–polyacrylamide gel electrophoresis. The serum protein–SWCNT interaction was significantly reduced due to the presence of PEGs, depending on PEG concentrations, the ratio of long-chain PEG molecules to short-chain PEG molecules, and the physicochemical properties of PEGSWCNT dispersions. Finally, Memantine was incorporated into the optimal PEGSWCNT dispersions. The entrapment efficiency, drug loading, and drug release from the dispersions were evaluated using gas chromatography with flame ionization detection (GC/FID). The results indicated that PEGSWCNT particles could entrap Memantine. The in vitro drug release profile exhibited an extended release over 3 to 7 h, with a significant burst release occurring in the first hour (more than 50%). Higher PEG density and a higher PEG20K/2K ratio exhibited slower drug release rates. The release profiles of the formulations using 40% PEG were fitted to the Weibull model, indicating that Memantine release from the SWCNT dispersions followed a Fickian diffusion mechanism.

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The development of dry powder inhalers (DPIs) for pulmonary drug delivery is complex, requiring optimization of variable factors to ensure effective lung deposition. This study investigates the factors influencing the dispersibility of glycopyrronium bromide (GLP) and indacaterol maleate (IND) in adhesive mixtures using both in vitro and in silico approaches. The formulation was designed to match the reference listed drug (RLD), using lactose and magnesium stearate as excipients. Key variables examined included mixing energy, carrier particle size distribution (PSD), and active pharmaceutical ingredient (API) particle size characteristics across multiple suppliers.

A Next Generation Impactor (NGI) was employed to assess the aerodynamic particle size distribution (APSD) of 67 formulations. The collected impactor data were analyzed using machine learning (ML) models, leveraging the h2o AutoML framework. Stacked ensemble models demonstrated high predictive accuracy (R²: 0.940 for GLP, 0.969 for IND), identifying key formulation parameters affecting dispersibility. SHAP analysis revealed that GLP dispersibility was influenced primarily by GLP PSD (d90, d50, SPAN), lactose d10, and mixing energy, while IND was more dependent on lactose PSD and its own particle size.

The findings confirm that both APIs interact with each other within the formulation, significantly impacting their reciprocal deposition profiles. These insights highlight the challenge of developing bioequivalent DPI formulations and emphasize the importance of PSD control, mixing energy optimization, and advanced ML modeling in predicting therapeutic equivalence. The study provides a predictive framework to support the development of generic inhalation products, improving regulatory approval pathways and ensuring effective pulmonary drug delivery.

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The multi-stage cascade impactor (CI) is the recognized apparatus for the characterization of the aerodynamic particle size distribution (APSD) of aerosols emitted from all classes of orally inhaled products. There is presently a mixed level of understanding in the community of those evaluating inhaler performance about the fundamentals of how these apparatuses accomplish their particle size fractionation and therefore how to analyze their data in a technically correct and meaningful manner. The purpose of this article, therefore, is first to set out how the CI functions from the standpoint of the underlying physical processes associated with inertial size fractionation. The explanation of these size fractionation processes describes the relationship of the mass of active pharmaceutical ingredient to particle aerodynamic size. Second, based on these fundamentals, a detailed analysis is provided in support of calculating in a technically correct manner the cascade impactor-derived estimation of metrics describing the APSD. In a comprehensive Supplemental Information packet, the underlying mathematical principles are explained that govern both arithmetic and geometric forms of the traditional assumed shapes that the APSD may take when deriving measures in support of inhaler performance assessments.

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