International Journal of Pharmaceutics: X最新文献

{"title":"Colistin and Oxyclozanide co-loaded PLGA nano-microspheres to reverse colistin resistance can effectively treat colistin-resistant Escherichia coli infections","authors":"Shuai-hua Li ,&nbsp;Meng-jing Feng ,&nbsp;Hao-tian Shao ,&nbsp;Jian-hua Liu,&nbsp;Hua Wu,&nbsp;Li Yuan,&nbsp;Xiao-yuan Ma,&nbsp;Gong-zheng Hu","doi":"10.1016/j.ijpx.2025.100402","DOIUrl":"10.1016/j.ijpx.2025.100402","url":null,"abstract":"<div><div>Colistin (COL) is widely recognized as the last line of defense for treating MDR-negative bacterial infections, but currently, bacteria have a very serious resistance to COL. The combination of antibacterial drugs and adjuvant drugs can reverse drug resistance, enhance antibacterial activity, and improve therapeutic effects. It is currently regarded as a new safe and effective strategy for controlling drug resistance. In this study, we found that the combination of Oxyclozanide (OXY) and colistin can effectively reverse colistin resistance. For multiple colistin resistant <em>Escherichia coli</em> (<em>E. coli</em>) strains, COL-OXY-PLGA @MS significantly reduced the MIC of COL monotherapy (8 &lt; MIC&lt;64) by 40–160 times. The prepared COL-OXY-PLGA@MS had particle sizes of 140–160 nm, PDI of 0.03–0.2, COL loading of 5.14 % and OXY loading of 2.93 %. The release rate of COL in COL-OXY-PLGA@MS at 72 h was 39.31 %, and there was no burst release. Cytotoxicity assay, hemolysis test and long-term injection tests in mice have proved that COL-OXY-PLGA@MS has good safety and biocompatibility. It was clearly observed by SEM that the COL-OXY-PLGA@MS group disrupted <em>E. coli 58</em> cells under 1 h of action with obvious exudation of contents, and large number of cells ruptured at 4 h and 12 h. COL-OXY-PLGA@MS significantly reduced mortality rate after <em>E. coli</em> infection in mice. This study successfully prepared COL-OXY-PLGA@MS with high safety and strong antibacterial effect, which has great potential in the treatment of infections caused by color-resistant Gram-negative bacteria and provides a new and important strategy for the clinical application of colistin.</div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"10 ","pages":"Article 100402"},"PeriodicalIF":6.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145216877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Construction and applications of exosome-microneedle integrated systems","authors":"Lijie Zheng ,&nbsp;Jiting Sun ,&nbsp;Lusheng Wang ,&nbsp;Zhixian Ding ,&nbsp;Yu Tang ,&nbsp;Mike Dai ,&nbsp;Heng Tang","doi":"10.1016/j.ijpx.2025.100360","DOIUrl":"10.1016/j.ijpx.2025.100360","url":null,"abstract":"<div><div>With the rapid advancement of drug delivery technologies, microneedles (MNs) have emerged as a novel transdermal delivery platform due to their ease of administration, minimally invasive nature, and high efficiency. MNs have demonstrated broad applicability for delivering diverse therapeutic agents, including small molecules, nucleic acids, peptides, and proteins. Exosomes (Exos), a class of extracellular vesicles with unique biological functions and significant clinical potential, have attracted increasing attention in recent years. However, their widespread application is limited by issues such as poor stability, low delivery efficiency, and potential safety and immune risks. The integration of Exos with MNs (Exos-MNs) systems offers a promising strategy to address these challenges. This review provides a comprehensive overview of recent advances in Exos-MNs delivery systems, including the technological advances of MNs, biological characteristics and engineering strategy of Exos, and the construction strategies of Exos-MNs. Additionally, we highlight recent developments in the application of Exos-MNs systems and discuss future perspectives and challenges for their clinical translation.</div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"10 ","pages":"Article 100360"},"PeriodicalIF":5.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144653314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative green synthesis and molecular simulation of ibrutinib cocrystals for enhanced biopharmaceutical performance and in vivo pharmacokinetics","authors":"Divya Dhatri Kara,&nbsp;Pragathi Devanand Bangera,&nbsp;Mahesha Keerikkadu,&nbsp;Mahalaxmi Rathnanand","doi":"10.1016/j.ijpx.2025.100371","DOIUrl":"10.1016/j.ijpx.2025.100371","url":null,"abstract":"<div><div>Bruton's tyrosine kinase (BTK) inhibitor, Ibrutinib (IBR), belongs to class II of the Biopharmaceutics Classification System (BCS). CYP3A4 enzyme forces IBR to have a very limited oral bioavailability. This study employed hot-melt extrusion (HME) with carboxylic and carboxamide coformers, guided by computational screening, to prepare and characterize IBR cocrystals (IBR-CC). Several carboxylic acid and carboxyl amide coformers were chosen in accordance with computational evaluations and predictions for the solubility parameter to formulate IBR-CC. According to the computational results, the formulated IBR-CC systems had multiple hydrogen bonds and π-π-stacking interactions. The IBR-CC formulations were further evaluated for powder dissolution studies, flow properties, and in vitro release studies. Furthermore, IBR-CC formulations were correlated with better anticancer action in K562-CCL-243 cancer cells when compared with IBR. From the in vivo pharmacokinetic evaluation studies, it was proven that the IBR oral bioavailability in IBR-Nicotinamide-cocrystal formulation has shown a 4.58-fold improvement, IBR-Fumaric acid-cocrystal formulation has shown a 2.66-fold improvement, and IBR-3-Hydroxy benzoic acid has shown a 1.76-fold enhancement when compared with pure IBR suspension. Biodistribution studies showed greater drug release in the intestine and other lymphoid organs when administered with IBR-Nicotinamide-cocrystal formulation than pure IBR suspension. As a result, the IBR-CC formulations produced utilizing the HME approach serve as an effective method of drug delivery that increases IBR's solubility and oral bioavailability.</div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"10 ","pages":"Article 100371"},"PeriodicalIF":6.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144810422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spray drying: From a traditional technology to modern biotechnological applications","authors":"Andrea Milanesi ,&nbsp;Giada Diana ,&nbsp;Alessandro Candiani ,&nbsp;Alessandro Sodano ,&nbsp;Paolo Rassè ,&nbsp;Andrea Foglio Bonda ,&nbsp;Elia Bari ,&nbsp;Maria Luisa Torre ,&nbsp;Lorena Segale ,&nbsp;Lorella Giovannelli","doi":"10.1016/j.ijpx.2025.100449","DOIUrl":"10.1016/j.ijpx.2025.100449","url":null,"abstract":"<div><div>Spray drying, first patented in the late 19^th century, has evolved into a versatile technology for converting liquid feeds into stable, free-flowing powders. Its fundamental strength lies in the rapid atomization and solvent evaporation. It enables precise control over particle size, morphology, and moisture content, making it a consolidated tool across food, chemical, and pharmaceutical industries. In the pharmaceutical field, it has been successfully applied to inhalable powders, amorphous solid dispersions, and controlled-release systems. At the same time, innovations in equipment design and Quality by Design strategies have improved robustness and scalability. Emerging applications now highlight its potential to stabilize biopharmaceuticals and vaccines, where dry powder formulations can enhance shelf life and reduce reliance on the cold chain. Similarly, spray drying has become central in nanomedicine through “nano-into-micro” engineering strategies that transform nanoscale carriers into inhalable or targeted dry powders. A further frontier is aseptic spray drying, which addresses sterility requirements for parenteral formulations and vaccines, representing a key step toward industrial adoption. This review outlines the fundamental principles of spray drying, examines the impact of formulation components, and discusses challenges in scale-up and industrial implementation. It then explores the most recent advances in biopharmaceuticals, nanomedicine, and aseptic processing, offering an integrated perspective on how spray drying is transitioning from a traditional drying method into a platform technology for modern biotechnology and pharmaceutical applications.</div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"10 ","pages":"Article 100449"},"PeriodicalIF":6.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145568587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of an efficient approach to boost fused deposition modeling (FDM) printing of felodipine-HPMC tablets for enhanced physical stability","authors":"Haixia Ren ,&nbsp;Charles A. Laughton ,&nbsp;Clive J. Roberts ,&nbsp;Kam Loon Fow","doi":"10.1016/j.ijpx.2025.100394","DOIUrl":"10.1016/j.ijpx.2025.100394","url":null,"abstract":"<div><div>Fused deposition modeling (FDM) is a widely investigated 3D printing technology for pharmaceutical applications because of its advantages, including easy access of equipment and cost-effectiveness. Despite its versatility, the FDM 3D printing process is multi-step, time-consuming and resource intensive, and requires a holistic selection of material and formulation design to achieve successful printing. The aim of this work is to develop an efficient approach to streamline FDM 3D tablet-printing processes, as well as to explore the factors that may influence the physical stability of the tablets produced. For this purpose, the polymer Affinisol™ HPMC HME 15LV and the model drug felodipine were selected for printing process evaluation, and the produced drug-polymer tablets were investigated for printing quality and physical stability. The approach began with a material-based rheological study to predict the processing temperature range for the hot melt extrusion process which was used to produce the required filament feedstock for FDM 3D printing. Flory-Huggins (F-H) theory and phase diagram were applied to guide the expected drug-polymer system physical stability with various ratios under different temperatures, suggesting that the system would be unstable when the weight fraction of felodipine is greater than 0.3. Based on these analyses, FDM 3D printed tablets with varying drug loads, printing temperatures, and infill densities were produced, and the long-term physical stability of the printed tablets under different conditions was monitored using XRD, DSC and polarized light microscopy. The results of the extrusion and printing process, as well as the observed long-term physical stability, were consistent with the findings from the predictions from the rheological study and theoretical evaluations. This suggests that an approach which combines rheological studies, theoretical evaluations and phase diagram construction could be applied as a pre-screen and optimization strategy, removing the need for full material characterization prior to FDM 3D printing of medicine. Such an approach significantly minimizes the amount of drug required, accelerates excipient selection, and optimizes the process for pharmaceutical manufacturing using FDM 3D printing. Furthermore, this methodology holds promise for broader application in other material-based FDM printing processes, offering a versatile framework for optimizing printing quality and stability across diverse systems.</div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"10 ","pages":"Article 100394"},"PeriodicalIF":6.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145265805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Self-healing hydrogel loaded with M2pep-modified recombinant apoferritin enhanced chemotherapy in hepatocellular carcinoma via reprogramming tumor-associated macrophage","authors":"Jiayi Qin ,&nbsp;Pei Chen ,&nbsp;Xin Li ,&nbsp;Qingsong Tang ,&nbsp;Qingwei Zhao ,&nbsp;Haiqin Huang ,&nbsp;Yangbo Zhu","doi":"10.1016/j.ijpx.2025.100414","DOIUrl":"10.1016/j.ijpx.2025.100414","url":null,"abstract":"<div><div>Chemotherapy plays an important role in the clinical systemic management of advanced hepatocellular carcinoma (HCC). However, the efficacy of chemotherapy is remarkably suppressed by the tumor microenvironment. After observing the prevalent M2-tumor associated macrophages (TAMs) in clinical HCC specimen, we developed a dual protein drug delivery system, namely, genetically engineered M2 macrophage targeting peptide (M2pep) modified recombinant apoferritin (HFn) for the delivery of \"old drug\" chloroquine (CQ), and bovine serum albumin (BSA) for the delivery of PTX for the synergistic treatment of HCC. To avoid additional efficacy limitations caused by systemic exposure, BSA@PTX and M2-HFn@CQ were incorporated into a self-healing hydrogel (COT@BP/M2HC) composed of carboxymethyl chitosan, oxidized sodium alginate and tannic acid. The experimental results demonstrated this COT@BP/M2HC hydrogel had good biocompatibility and biodegradability, adhesion, injectability and self-healing properties. It was further confirmed that a single peritumoral injection of COT@BP/M2HC successfully promoted the polarization of M2 TAMs to M1 TAMs, and the M1/M2 ratio increased by 4.63 times compared with the BSA@PTX group, thereby achieving 74.7 % tumor growth inhibition in HCC tumor-bearing mouse models. These findings revealed a potential TAM polarizing effect of CQ and provided a reliable combination strategy for improving HCC chemotherapy efficacy.</div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"10 ","pages":"Article 100414"},"PeriodicalIF":6.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145265806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structured engineering of self-emulsifying drug delivery systems (SEDDS) via 3D printing: Comprehensive review","authors":"Induja Govindan,&nbsp;Anjana A. Kailas,&nbsp;K.A. Abutwaibe,&nbsp;Thamizharasan Annadurai,&nbsp;Ujwala Achar,&nbsp;Anup Naha,&nbsp;Srinivas Hebbar","doi":"10.1016/j.ijpx.2025.100416","DOIUrl":"10.1016/j.ijpx.2025.100416","url":null,"abstract":"<div><div>The combination of self-emulsifying drug delivery systems (SEDDS) with three-dimensional printing (3DP) technologies represents an innovative and promising strategy for developing personalised dosage forms. Through precise control over dosage form architecture, controlled drug release kinetics, and individualised therapeutic customisation, 3DP offers distinct and transformative advantages over conventional pharmaceutical formulation approaches. This review focuses on the application of modern 3DP techniques, specifically fused deposition modelling (FDM), semi-solid extrusion (SSE), and drop-on-demand (DoD), in the formulation and production of SEDDS. Each technique is critically evaluated in terms of formulation compatibility, operational mechanisms, and its potential to address the current manufacturing challenges associated with SEDDS. 3DP technologies offer several benefits, including enhanced flexibility in production, the ability to fabricate on demand, and the potential to accommodate complex and personalised therapeutic regimens. However, these methods also face notable limitations, such as material constraints, variability in print quality, mechanical and safety issues, and a lack of clear regulatory guidance. Despite their potential, the use of 3DP in SEDDS development remains relatively unexplored. This review aims to provide a comprehensive overview of the current research landscape, identify existing technological and regulatory barriers, and discuss future prospects for integrating 3DP into next-generation SEDDS formulations.</div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"10 ","pages":"Article 100416"},"PeriodicalIF":6.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145323273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polymeric particle-based antigen delivery system: From immunological engineering to clinical translation","authors":"Yanlun Shi,&nbsp;Lin Zhu,&nbsp;Zhiwei Qiao,&nbsp;Yanan Zhai,&nbsp;Jinwei Di,&nbsp;Shan Wang,&nbsp;Jingyu Cui,&nbsp;Ying Wang,&nbsp;Yuhua Ran,&nbsp;Jing Gao","doi":"10.1016/j.ijpx.2025.100466","DOIUrl":"10.1016/j.ijpx.2025.100466","url":null,"abstract":"<div><div>Recombinant subunit vaccines and nucleic acid vaccines have attracted considerable research interest due to their superior safety and scalability for industrial production. However, these platforms often require advanced delivery strategies to elicit robust immune responses. Polymeric particles, with their unique ability to maintain antigen stability, enhance immunogenicity, and enable controlled release along with inherent biocompatibility and biodegradability, have emerged as a versatile platform for vaccine delivery and adjuvant applications. This review outlines the key physicochemical properties, immunological mechanisms, and release kinetics of polymer-based carriers, and critically evaluates recent progress in polymer vaccine formulations designed for the co-delivery of antigens and immunostimulatory agents. Future development will likely focus on integrating computational material design with immune profiling to create intelligent systems capable of mimicking pathogenic invasion and enabling single-dose, cold-chain-independent vaccination. Collectively, these insights provide a foundation for engineering next-generation polymer-particle vaccines.</div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"10 ","pages":"Article 100466"},"PeriodicalIF":6.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revolutionary hyaluronic acid-modified edge-activated spanlastics as a novel approach to boost Hepatoprotective activity of Curcumin: Optimization, biochemical analysis and in-vivo assessment","authors":"Sadek Ahmed ,&nbsp;Osama Saher ,&nbsp;Rana M. ElBishbishy ,&nbsp;Mennatullah M. Ibrahim","doi":"10.1016/j.ijpx.2025.100430","DOIUrl":"10.1016/j.ijpx.2025.100430","url":null,"abstract":"<div><div>Drug-induced liver injury (DILI) represents a critical clinical problem that often necessitates lowering the therapeutic dose or even complete drug withdrawal, ultimately resulting in treatment failure. Curcumin (Cur), a natural polyphenolic compound, demonstrates strong hepatoprotective and antioxidant activity; however, its poor solubility and limited bioavailability hinder its therapeutic use. To overcome these limitations, the present study aimed to develop and optimize curcumin-loaded hyaluronic acid-modified edge-activated spanlastics (Cur-HES) as an efficient delivery system for enhancing the hepatoprotective efficacy of curcumin against carbon tetrachloride (CCl₄)-induced liver damage. Cur-HES were prepared using the ethanol injection method and systematically optimized <em>via</em> a 23 full factorial design, where the independent variables included hyaluronic acid-to-surfactant ratio (X1), edge activator-to-drug ratio (X2), and Span 80 % contribution (X3). Formulations were assessed for entrapment efficiency (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP). The optimized formulation achieved a desirability value of 0.982, with EE% of 88.4 %, PS of 105.2 nm, PDI of 0.19, and ZP of −20.9 mV. Transmission electron microscopy revealed spherical vesicles. <em>In-vitro</em> release exhibited biphasic Higuchi diffusion kinetics, while stability testing confirmed preservation of physicochemical properties for three months. <em>In-vivo</em> evaluation demonstrated that Cur-HES provided significantly greater hepatoprotection than free Cur in the CCl₄-induced hepatotoxicity model, as evidenced by marked reductions in serum ALT and AST levels. Histopathological examination supported these findings, showing preserved liver architecture in treated groups. Overall, Cur-HES represents a promising nanocarrier platform to boost the hepatoprotective activity of Cur, offering a safe and effective therapeutic strategy against DILI.</div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"10 ","pages":"Article 100430"},"PeriodicalIF":6.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145415928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tailored transethosomal systems for tadalafil transdermal delivery: Impact of Phosal and edge activators on skin permeation and cellular uptake","authors":"Turky Omar Asar ,&nbsp;Hossam S. El-Sawy ,&nbsp;Ahmed M. Reda ,&nbsp;Mohamed Ashraf ,&nbsp;Amer H. Asseri ,&nbsp;Abdelsattar M. Omar ,&nbsp;Tarek A. Ahmed ,&nbsp;Khalid M. El-Say","doi":"10.1016/j.ijpx.2025.100376","DOIUrl":"10.1016/j.ijpx.2025.100376","url":null,"abstract":"<div><div>Tadalafil (TDLF), a Biopharmaceutics Classification System (BCS) Class II drug, exhibits poor aqueous solubility and extensive first-pass metabolism, which limits its therapeutic efficacy. We developed Phosal-based transethosomes (TrEthOs) to overcome these challenges, thereby enhancing transdermal delivery. A Box-Behnken design was employed to optimize the formulation by evaluating the effects of Phosal type, polyethylene glycol (PEG) 400 concentration, and cholesterol content. The optimized TrEthOs exhibited a mean vesicle size of 129.74 nm and an entrapment efficiency of 67.3%, ensuring efficient encapsulation of the drug. <em>Ex vivo</em> permeation studies demonstrated a cumulative TDLF permeation of 70.24% over 6 hours, with a steady-state flux of 19.49 × 10^-4 mg/cm²·min. Confocal laser scanning microscopy confirmed deep skin penetration, while <em>in vitro</em> studies revealed significantly enhanced cellular uptake (P &lt; 0.0001) and reduced cytotoxicity (IC₅₀ = 67.61 μg/mL) compared to pure TDLF (IC₅₀ = 34.85 μg/mL). The novel Phosal-based TrEthOs system presents a promising transdermal drug delivery strategy, potentially reducing dosing frequency and improving patient compliance. These outcomes emphasize the potential of advanced nanocarrier systems to optimize systemic bioavailability while minimizing adverse effects.</div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"10 ","pages":"Article 100376"},"PeriodicalIF":6.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144866522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}