Pub Date : 2025-11-12DOI: 10.1016/j.ijpx.2025.100443
Pengkai Ma , Ziqi Jing , Xue Wang , Xiaoya Liu , Zirui Tan , Yujie Zhang , Zhijun Wang
Due to the intricate nature of tumors, developing multidrug delivery system to enhance synergistic therapy for tumors is urgently needed. Herein, we present a carrier-free nanocomplex (DHT NC@SF MPN), consisting of dihydrotanshinone-1 nanocrystals (DHT NC) combined with silybin-ferric metal-phenolic network coatings (SF MPN), for multidrug self-delivery and chemo/chemodynamic synergistic cancer therapy. The generated nanocomplex (DHT NC@SF MPN) was completely composed of three therapeutic ingredients: DHT (56.08 %), Sil (41.88 %), and Fe(III) (2.01 %) without incorporation of any nano-materials. It displayed spherical core-shell structure with particle size 262 nm and acid responding drug release. The nanocomplex could be efficiently uptaken by HGC-27 tumor cells through the lipid raft/caveolin mediated pathway. It exhibited stronger tumor cell proliferation inhibition, migration inhibition, cell apoptosis and ferroptosis compared with free drugs. On tumor bearing mice, it showed comparable anti-tumor efficacy with the commercial paclitaxel liposome while systemic toxicity was negligible. Therefore, the facile nanocarrier-free multidrug self-delivery nanoplatform shed light on developing advanced nanomedicine for tumor synergistic therapy.
{"title":"Carrier-free multi-components self-delivery nanocomplex for tumor synergistic therapy","authors":"Pengkai Ma , Ziqi Jing , Xue Wang , Xiaoya Liu , Zirui Tan , Yujie Zhang , Zhijun Wang","doi":"10.1016/j.ijpx.2025.100443","DOIUrl":"10.1016/j.ijpx.2025.100443","url":null,"abstract":"<div><div>Due to the intricate nature of tumors, developing multidrug delivery system to enhance synergistic therapy for tumors is urgently needed. Herein, we present a carrier-free nanocomplex (DHT NC@SF MPN), consisting of dihydrotanshinone-1 nanocrystals (DHT NC) combined with silybin-ferric metal-phenolic network coatings (SF MPN), for multidrug self-delivery and chemo/chemodynamic synergistic cancer therapy. The generated nanocomplex (DHT NC@SF MPN) was completely composed of three therapeutic ingredients: DHT (56.08 %), Sil (41.88 %), and Fe(III) (2.01 %) without incorporation of any nano-materials. It displayed spherical core-shell structure with particle size 262 nm and acid responding drug release. The nanocomplex could be efficiently uptaken by HGC-27 tumor cells through the lipid raft/caveolin mediated pathway. It exhibited stronger tumor cell proliferation inhibition, migration inhibition, cell apoptosis and ferroptosis compared with free drugs. On tumor bearing mice, it showed comparable anti-tumor efficacy with the commercial paclitaxel liposome while systemic toxicity was negligible. Therefore, the facile nanocarrier-free multidrug self-delivery nanoplatform shed light on developing advanced nanomedicine for tumor synergistic therapy.</div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"10 ","pages":"Article 100443"},"PeriodicalIF":6.4,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145516734","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}
Effective buccal drug delivery is limited by the barrier properties of the mucosa, necessitating innovative systems to enhance permeability without compromising tissue integrity. In this study, bilosomes composed of sodium glycodeoxycholate and phosphatidylcholine were evaluated as a nanoparticulate platform for buccal drug delivery. Their in vitro uptake was investigated using the TR146 buccal cell line. The bilosomes demonstrated stable physicochemical properties and no aggregation. Functional assays indicated that they transiently opened cell-cell junctions, promoting transport across the mucosal barrier while minimizing toxicity. Quartz crystal microbalance with dissipation monitoring confirmed specific interactions with barrier components, supported by observed modulation of desmosomal junctions and cellular uptake. Ex vivo studies using porcine buccal mucosa further showed concentration-dependent distribution. Collectively, these results suggest that bilosomes are a safe and effective platform for enhancing buccal drug absorption.
{"title":"Boosting buccal drug absorption: Mechanistic insights into bilosome-mediated delivery","authors":"Eleftheria Pantazoglou , Scarlett Zeiringer , Matteo Tollemeto , Nazanin Zanjanizadeh Ezazi , Zhongyang Zhang , Leticia Hosta-Rigau , Jette Jacobsen , Ramona Jeitler , Eva Roblegg , Line Hagner Nielsen","doi":"10.1016/j.ijpx.2025.100444","DOIUrl":"10.1016/j.ijpx.2025.100444","url":null,"abstract":"<div><div>Effective buccal drug delivery is limited by the barrier properties of the mucosa, necessitating innovative systems to enhance permeability without compromising tissue integrity. In this study, bilosomes composed of sodium glycodeoxycholate and phosphatidylcholine were evaluated as a nanoparticulate platform for buccal drug delivery. Their in vitro uptake was investigated using the TR146 buccal cell line. The bilosomes demonstrated stable physicochemical properties and no aggregation. Functional assays indicated that they transiently opened cell-cell junctions, promoting transport across the mucosal barrier while minimizing toxicity. Quartz crystal microbalance with dissipation monitoring confirmed specific interactions with barrier components, supported by observed modulation of desmosomal junctions and cellular uptake. <em>Ex vivo</em> studies using porcine buccal mucosa further showed concentration-dependent distribution. Collectively, these results suggest that bilosomes are a safe and effective platform for enhancing buccal drug absorption.</div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"10 ","pages":"Article 100444"},"PeriodicalIF":6.4,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145516736","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}
Pub Date : 2025-11-11DOI: 10.1016/j.ijpx.2025.100445
Kun Yu , Sicheng Huang , Guochun Yang , Junze Tang , Xiaoyu Zhao , Rui Pan , Hailiang Zhang , Menghan Xu , Xiaofei Li , Xin Cheng , Anguo Hou
The study aimed to construct saikosaponin D (SSD)-based liposomes modified with phosphatidic acid (PA) and poloxamer 407 (P407) (termed P407-SSD-Lps), and to evaluate their tumor-targeting ability and antitumor efficacy through in vitro and in vivo experiments. The preparation process and formulation of the P407-SSD-Lps were optimized using single-factor and orthogonal experimental designs, followed by systematic characterization. Their antitumor activity and targeting specificity were assessed through in vitro experiments. Additionally, the tumor-targeting capability, therapeutic efficacy, and biocompatibility of the P407-SSD-Lps were investigated in murine orthotopic hepatocellular carcinoma transplantation models. The P407-SSD-Lps optimized through single-factor and orthogonal experiments exhibited ideal physicochemical properties. In vitro results demonstrated that the P407-SSD-Lps enhanced cell membrane permeability and promoted cellular uptake in the HepG2 cells. Additionally, they significantly inhibited the HepG2 cells proliferation and induced apoptosis. In murine orthotopic hepatocellular carcinoma transplantation models, the P407-SSD-Lps exhibited prolonged tumor accumulation and demonstrated potent antitumor efficacy with favorable biocompatibility. When delivering doxorubicin (DOX), the system not only retained high biocompatibility but also exhibited enhanced therapeutic efficacy. Employing the SSD as both a liposomal membrane stabilizer and a therapeutic agent constituted a novel expansion of “drug-excipient integration” material applications. Moreover, the SSD-based P407-SSD-Lps system functioned as a stable and efficient multifunctional liposomal delivery system, offering innovative therapeutic avenues for hepatocellular carcinoma treatment.
{"title":"Multifunctional saikosaponin D-liposomes for hepatocellular carcinoma: Formulation optimization, characterization, and in vitro/in vivo evaluation","authors":"Kun Yu , Sicheng Huang , Guochun Yang , Junze Tang , Xiaoyu Zhao , Rui Pan , Hailiang Zhang , Menghan Xu , Xiaofei Li , Xin Cheng , Anguo Hou","doi":"10.1016/j.ijpx.2025.100445","DOIUrl":"10.1016/j.ijpx.2025.100445","url":null,"abstract":"<div><div>The study aimed to construct saikosaponin D (SSD)-based liposomes modified with phosphatidic acid (PA) and poloxamer 407 (P407) (termed P407-SSD-Lps), and to evaluate their tumor-targeting ability and antitumor efficacy through in vitro and in vivo experiments. The preparation process and formulation of the P407-SSD-Lps were optimized using single-factor and orthogonal experimental designs, followed by systematic characterization. Their antitumor activity and targeting specificity were assessed through in vitro experiments. Additionally, the tumor-targeting capability, therapeutic efficacy, and biocompatibility of the P407-SSD-Lps were investigated in murine orthotopic hepatocellular carcinoma transplantation models. The P407-SSD-Lps optimized through single-factor and orthogonal experiments exhibited ideal physicochemical properties. In vitro results demonstrated that the P407-SSD-Lps enhanced cell membrane permeability and promoted cellular uptake in the HepG2 cells. Additionally, they significantly inhibited the HepG2 cells proliferation and induced apoptosis. In murine orthotopic hepatocellular carcinoma transplantation models, the P407-SSD-Lps exhibited prolonged tumor accumulation and demonstrated potent antitumor efficacy with favorable biocompatibility. When delivering doxorubicin (DOX), the system not only retained high biocompatibility but also exhibited enhanced therapeutic efficacy. Employing the SSD as both a liposomal membrane stabilizer and a therapeutic agent constituted a novel expansion of “drug-excipient integration” material applications. Moreover, the SSD-based P407-SSD-Lps system functioned as a stable and efficient multifunctional liposomal delivery system, offering innovative therapeutic avenues for hepatocellular carcinoma treatment.</div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"10 ","pages":"Article 100445"},"PeriodicalIF":6.4,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145516735","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}
Pub Date : 2025-11-09eCollection Date: 2025-12-01DOI: 10.1016/j.ijpx.2025.100433
Peter Roelants, Reza Ranjbar Choubeh, Nico Verbeeck, Rabindranath Andujar, Torsten Schultz-Fademrecht, Patrick Garidel, Viktor Gross
Polysorbate 20 (PS20) and polysorbate 80 (PS80) are essential surfactants used to stabilize biopharmaceutical products, yet their highly heterogeneous mixtures and susceptibility to oxidation and enzymatic hydrolysis complicate routine analysis. We developed a hierarchical generative model that reconstructs entire liquid chromatography-mass spectrometry (LC-MS) measurements to automatically interpret complex polysorbate datasets. By embedding domain knowledge of base structures, oxyethylene chain lengths, fatty acid esterification, and isotope patterns, the model resolves individual subspecies and provides molecular-level composition. Applied to PS20 and PS80, the approach distinguishes oxidative from hydrolytic degradation and yields pathway-specific fingerprints. Model outputs agree closely with manual integration while delivering greater depth and automation. This transforms polysorbate analysis from labor-intensive peak-by-peak workflows into an objective, comprehensive characterization tool suited for quality control, batch selection and degradation monitoring throughout development and manufacturing.
{"title":"Extraction of the polysorbate 20 and 80 fingerprint via generative modeling.","authors":"Peter Roelants, Reza Ranjbar Choubeh, Nico Verbeeck, Rabindranath Andujar, Torsten Schultz-Fademrecht, Patrick Garidel, Viktor Gross","doi":"10.1016/j.ijpx.2025.100433","DOIUrl":"10.1016/j.ijpx.2025.100433","url":null,"abstract":"<p><p>Polysorbate 20 (PS20) and polysorbate 80 (PS80) are essential surfactants used to stabilize biopharmaceutical products, yet their highly heterogeneous mixtures and susceptibility to oxidation and enzymatic hydrolysis complicate routine analysis. We developed a hierarchical generative model that reconstructs entire liquid chromatography-mass spectrometry (LC-MS) measurements to automatically interpret complex polysorbate datasets. By embedding domain knowledge of base structures, oxyethylene chain lengths, fatty acid esterification, and isotope patterns, the model resolves individual subspecies and provides molecular-level composition. Applied to PS20 and PS80, the approach distinguishes oxidative from hydrolytic degradation and yields pathway-specific fingerprints. Model outputs agree closely with manual integration while delivering greater depth and automation. This transforms polysorbate analysis from labor-intensive peak-by-peak workflows into an objective, comprehensive characterization tool suited for quality control, batch selection and degradation monitoring throughout development and manufacturing.</p>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"10 ","pages":"100433"},"PeriodicalIF":6.4,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12681885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145707699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-08DOI: 10.1016/j.ijpx.2025.100442
Toni Wildgrube, Stefan Senekowitsch, Robin Krüger, Fabian Winter, Michael Grimm, Werner Weitschies, Philipp Schick
Gastric emptying is a critical determinant of the pharmacokinetics of orally administered drugs. A key limitation in studies using caffeine as a marker for gastric emptying is the requirement for prior caffeine abstinence, which can complicate study design and participant recruitment. The present study was conducted with the objective of evaluating the potential use of the methylurates methylliberine and theacrine as novel salivary markers for the assessment of gastric emptying of non-caloric liquids, in comparison to the established marker caffeine. A Salivary Tracer Technique (STT) was employed in a crossover study that involved twelve healthy volunteers. The subjects participating in the study were under fasted state conditions according to the guidelines of the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) when they received ice capsules containing either caffeine, methylliberine, theacrine, or a combination of these three substances. Salivary samples were collected at predetermined intervals over 24 h in order to analyse their pharmacokinetic profiles. The results demonstrated a rapid absorption, with maximum salivary concentrations (cmax) reached within 30 min for all markers. It is noteworthy that methylliberine and theacrine exhibited strong correlations with caffeine in their absorption profiles, with Pearson correlation coefficients of r = 0.9973 and r = 0.9865, respectively, during the initial 40 min post-administration. Furthermore, the elimination half-lives (t1/2) of methylliberine and theacrine were found to differ significantly, with methylliberine exhibiting a rapid elimination profile (t1/2 = 1.15 ± 0.12 h) in comparison to theacrine (t1/2 = 21.00 ± 7.55 h). These results support methylliberine and theacrine as promising non-invasive markers of gastric emptying, offering viable alternatives to caffeine that may eliminate the need for abstinence and may allow for more efficient multi-tracer pharmacokinetic studies.
{"title":"A comparison of theacrine and methylliberine with caffeine as salivary markers for determining gastric emptying","authors":"Toni Wildgrube, Stefan Senekowitsch, Robin Krüger, Fabian Winter, Michael Grimm, Werner Weitschies, Philipp Schick","doi":"10.1016/j.ijpx.2025.100442","DOIUrl":"10.1016/j.ijpx.2025.100442","url":null,"abstract":"<div><div>Gastric emptying is a critical determinant of the pharmacokinetics of orally administered drugs. A key limitation in studies using caffeine as a marker for gastric emptying is the requirement for prior caffeine abstinence, which can complicate study design and participant recruitment. The present study was conducted with the objective of evaluating the potential use of the methylurates methylliberine and theacrine as novel salivary markers for the assessment of gastric emptying of non-caloric liquids, in comparison to the established marker caffeine. A Salivary Tracer Technique (STT) was employed in a crossover study that involved twelve healthy volunteers. The subjects participating in the study were under fasted state conditions according to the guidelines of the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) when they received ice capsules containing either caffeine, methylliberine, theacrine, or a combination of these three substances. Salivary samples were collected at predetermined intervals over 24 h in order to analyse their pharmacokinetic profiles. The results demonstrated a rapid absorption, with maximum salivary concentrations (c<sub>max</sub>) reached within 30 min for all markers. It is noteworthy that methylliberine and theacrine exhibited strong correlations with caffeine in their absorption profiles, with Pearson correlation coefficients of <em>r</em> = 0.9973 and <em>r</em> = 0.9865, respectively, during the initial 40 min post-administration. Furthermore, the elimination half-lives (t<sub>1/2</sub>) of methylliberine and theacrine were found to differ significantly, with methylliberine exhibiting a rapid elimination profile (t<sub>1/2</sub> = 1.15 ± 0.12 h) in comparison to theacrine (t<sub>1/2</sub> = 21.00 ± 7.55 h). These results support methylliberine and theacrine as promising non-invasive markers of gastric emptying, offering viable alternatives to caffeine that may eliminate the need for abstinence and may allow for more efficient multi-tracer pharmacokinetic studies.</div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"10 ","pages":"Article 100442"},"PeriodicalIF":6.4,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145516729","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}
Pub Date : 2025-11-07DOI: 10.1016/j.ijpx.2025.100441
Ivana Ruseska , Amina Tucak-Smajić , Ivan Vidaković , Karin Kornmüller , Edina Vranić , Andreas Zimmer
microRNA-27a is a promising candidate for miRNA mimic therapy to combat obesity, but its clinical application is hindered by enzymatic degradation and low membrane permeability. To address these challenges, we developed cationic nanostructured lipid carriers (cNLCs) via high-pressure homogenization as non-viral carriers for miRNA-27a. However, the formation of a protein corona in biologically-relevant media altered the particle size and surface charge, significantly reducing cellular uptake. To mitigate this issue, we hypothesized that coating miRNA/cNLC complexes with human serum albumin (HSA) will prevent protein corona formation and enhance cellular uptake. The HSA-coated miRNA/cNLC complexes, termed albuplexes, were characterized for particle size, zeta potential, morphology, and stability in various media. The integrity of the HSA coat was assessed using circular dichroism and UV/Vis spectroscopy. We also evaluated the biocompatibility and cellular uptake of albuplexes in 3T3-L1 cells. The biological effects of miRNA-27a on adipocyte development were analyzed through light microscopy and absorbance measurements of Oil-red-O dye in lipid droplets. Results indicated that albuplexes possess favourable physicochemical properties and enhanced stability in serum. Notably, albuplexes were rapidly taken up by 3T3-L cells via endocytosis, although 20 % HSA in the culture medium completely inhibited uptake. Furthermore, albuplexes exhibited an anti-adipogenic effect by reducing the lipid droplet accumulation, suggesting their potential as a therapeutic strategy for miRNA replacement in obesity treatment.
{"title":"Optimizing microRNA delivery via albumin-decorated nanostructured lipid carriers","authors":"Ivana Ruseska , Amina Tucak-Smajić , Ivan Vidaković , Karin Kornmüller , Edina Vranić , Andreas Zimmer","doi":"10.1016/j.ijpx.2025.100441","DOIUrl":"10.1016/j.ijpx.2025.100441","url":null,"abstract":"<div><div>microRNA-27a is a promising candidate for miRNA mimic therapy to combat obesity, but its clinical application is hindered by enzymatic degradation and low membrane permeability. To address these challenges, we developed cationic nanostructured lipid carriers (cNLCs) via high-pressure homogenization as non-viral carriers for miRNA-27a. However, the formation of a protein corona in biologically-relevant media altered the particle size and surface charge, significantly reducing cellular uptake. To mitigate this issue, we hypothesized that coating miRNA/cNLC complexes with human serum albumin (HSA) will prevent protein corona formation and enhance cellular uptake. The HSA-coated miRNA/cNLC complexes, termed albuplexes, were characterized for particle size, zeta potential, morphology, and stability in various media. The integrity of the HSA coat was assessed using circular dichroism and UV/Vis spectroscopy. We also evaluated the biocompatibility and cellular uptake of albuplexes in 3T3-L1 cells. The biological effects of miRNA-27a on adipocyte development were analyzed through light microscopy and absorbance measurements of Oil-red-O dye in lipid droplets. Results indicated that albuplexes possess favourable physicochemical properties and enhanced stability in serum. Notably, albuplexes were rapidly taken up by 3T3-L cells via endocytosis, although 20 % HSA in the culture medium completely inhibited uptake. Furthermore, albuplexes exhibited an anti-adipogenic effect by reducing the lipid droplet accumulation, suggesting their potential as a therapeutic strategy for miRNA replacement in obesity treatment.</div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"10 ","pages":"Article 100441"},"PeriodicalIF":6.4,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145516616","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}
Pub Date : 2025-11-07DOI: 10.1016/j.ijpx.2025.100440
J. Siepmann, F. Siepmann
Poly(lactic-co-glycolic acid) (PLGA)-based microparticles and implants are of continuously increasing importance as parenteral controlled drug delivery systems. However, the underlying drug release mechanisms are often not understood, rendering product optimization difficult: The effects of formulation and processing parameters on drug release can be surprising. Also, upscaling and troubleshooting during production at industrial scale can be highly cumbersome. This can be attributed to the complexity of the physicochemical processes, which can be involved in the control of drug release. Generally, tri-phasic drug release patterns are observed: An initial burst release is followed by a zero order release phase and a final, again, rapid release phase. The relative importance of the different phases can strongly depend on the: (i) composition (e.g., type & amount of drug and polymer), geometry and dimensions of the system, (ii) manufacturing procedure, and (iii) conditions in the surrounding environment (e.g., bulk fluid versus human tissue). Water penetration into the system, drug dissolution, limited solubility effects, drug diffusion through an “intact polymeric matrix” (polymer phase) and/or through water filled pores, pore closure due to local PLGA swelling, osmotic effects, polymer degradation, local drops in micro-pH, autocatalytic effects, substantial swelling of the entire system as well as other phenomena can be of importance. This article aims at giving an overview on the current knowledge in this field. Please note that it is hypotheses-driven, thus, general conclusions should be seen with caution. Also, each drug delivery system should be considered on a case-by-case basis. This article also aims at raising awareness on two aspects, which are often neglected: (i) Substantial system swelling is likely the root cause for the onset of the third drug release phase in many systems. (ii) In the case of microparticles, only looking at drug release from ensembles (hundreds of thousands/millions) of particles can be misleading.
{"title":"Release mechanisms of PLGA-based drug delivery systems: A review","authors":"J. Siepmann, F. Siepmann","doi":"10.1016/j.ijpx.2025.100440","DOIUrl":"10.1016/j.ijpx.2025.100440","url":null,"abstract":"<div><div>Poly(lactic-<em>co</em>-glycolic acid) (PLGA)-based microparticles and implants are of continuously increasing importance as parenteral controlled drug delivery systems. However, the underlying drug release mechanisms are often not understood, rendering product optimization difficult: The effects of formulation and processing parameters on drug release can be surprising. Also, upscaling and troubleshooting during production at industrial scale can be highly cumbersome. This can be attributed to the complexity of the physicochemical processes, which can be involved in the control of drug release. Generally, tri-phasic drug release patterns are observed: An initial burst release is followed by a zero order release phase and a final, again, rapid release phase. The relative importance of the different phases can strongly depend on the: (i) composition (e.g., type & amount of drug and polymer), geometry and dimensions of the system, (ii) manufacturing procedure, and (iii) conditions in the surrounding environment (e.g., bulk fluid versus human tissue). Water penetration into the system, drug dissolution, limited solubility effects, drug diffusion through an “intact polymeric matrix” (polymer phase) and/or through water filled pores, pore closure due to local PLGA swelling, osmotic effects, polymer degradation, local drops in micro-pH, autocatalytic effects, substantial swelling of the entire system as well as other phenomena can be of importance. This article aims at giving an overview on the current knowledge in this field. Please note that it is <em>hypotheses-driven</em>, thus, general conclusions should be seen with caution. Also, each drug delivery system should be considered on a <em>case-by-case basis</em>. This article also aims at raising awareness on two aspects, which are often neglected: (i) Substantial system swelling is likely the root cause for the onset of the <em>third</em> drug release phase in many systems. (ii) In the case of <em>microparticles</em>, only looking at drug release from <em>ensembles</em> (hundreds of thousands/millions) of particles can be misleading.</div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"10 ","pages":"Article 100440"},"PeriodicalIF":6.4,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145516737","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}
Pub Date : 2025-11-06DOI: 10.1016/j.ijpx.2025.100439
Alžběta Turnovská, Tomáš Etrych
Photodynamic therapy (PDT) is widely studied and complex method useful as a minimally invasive cancer treatment strategy, relying on photosensitizers (PSs), light, and oxygen to induce cytotoxicity. Indeed, the controlled delivery of conventional PSs is the key factor in achieving effective treatment outcome. Among many drug delivery systems, the polymeric micelles represent a promising platform to address the solubility, stability, and delivery challenges associated with PSs. The design of micelles, constructed from hydrophilic and hydrophobic polymeric blocks in diverse structures, enables precise tailoring of carrier properties to optimize PS delivery. This paper focuses on the potential applications and limitations of polymer micelles for the controlled delivery of PSs in the field anticancer therapy. Various methods of synthesis, incorporation of PSs as well as their release and activation are described in detail. The effect of micellar system employment on circulation time, off-target effects, and both passive and active targeting are thoroughly depicted. Despite the clinical promise, the limitations of PDT including shallow tissue penetration and restricted applicability to superficial or endoscope-accessible tumors are discussed, as well as the future prospects consisting in red-shifted or two-photon absorption systems.
{"title":"Polymeric micelles in advanced photodynamic therapy: Design, delivery and translational prospects","authors":"Alžběta Turnovská, Tomáš Etrych","doi":"10.1016/j.ijpx.2025.100439","DOIUrl":"10.1016/j.ijpx.2025.100439","url":null,"abstract":"<div><div>Photodynamic therapy (PDT) is widely studied and complex method useful as a minimally invasive cancer treatment strategy, relying on photosensitizers (PSs), light, and oxygen to induce cytotoxicity. Indeed, the controlled delivery of conventional PSs is the key factor in achieving effective treatment outcome. Among many drug delivery systems, the polymeric micelles represent a promising platform to address the solubility, stability, and delivery challenges associated with PSs. The design of micelles, constructed from hydrophilic and hydrophobic polymeric blocks in diverse structures, enables precise tailoring of carrier properties to optimize PS delivery. This paper focuses on the potential applications and limitations of polymer micelles for the controlled delivery of PSs in the field anticancer therapy. Various methods of synthesis, incorporation of PSs as well as their release and activation are described in detail. The effect of micellar system employment on circulation time, off-target effects, and both passive and active targeting are thoroughly depicted. Despite the clinical promise, the limitations of PDT including shallow tissue penetration and restricted applicability to superficial or endoscope-accessible tumors are discussed, as well as the future prospects consisting in red-shifted or two-photon absorption systems.</div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"10 ","pages":"Article 100439"},"PeriodicalIF":6.4,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145516733","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}
Pub Date : 2025-11-05DOI: 10.1016/j.ijpx.2025.100436
Meiru Liu , Yinru Jiang , Penghui Yuan , Shuang Li , Baoxi Zhang , Xia Zhou , Bin Su , Yifei Xie , Dezhi Yang , Linglei Kong , Li Zhang , Yang Lv , Guanhua Du
Emodin (EMO) shows therapeutic promise for ulcerative colitis (UC), yet its clinical utility is hampered by low bioavailability. To rationally overcome this limitation, this study employed cocrystal engineering, strategically selecting tetramethylpyrazine (TMP)—a natural compound from traditional Chinese medicine—as the cocrystal coformer (CCF). The selection of TMP was guided by a systematic CCF screening strategy, incorporating extensive literature analysis of natural compound CCF candidates, computational chemistry methods to predict favorable hydrogen-bonding interactions and interaction sites with EMO, and machine learning assessment of cocrystallization propensity. Utilizing this rational design approach, we successfully synthesized and characterized a novel EMO-TMP cocrystal through comprehensive solid-state characterization techniques. The resulting cocrystal significantly enhanced the aqueous solubility of EMO while preserving its intrinsic bioactivity. Pharmacokinetic studies confirmed that the cocrystal formulation markedly improved the oral bioavailability of EMO. In a dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) model, the EMO-TMP cocrystal demonstrated superior efficacy compared to EMO alone, effectively alleviating colitis symptoms and associated pathological markers. This enhanced in vivo efficacy is attributed to the significantly improved systemic exposure achieved through the rationally designed cocrystal. Our findings establish the EMO-TMP cocrystal as a highly promising strategy to surmount the physicochemical barriers of EMO, unlocking its full clinical potential for UC treatment. Critically, this work not only validates TMP as an efficient and safe CCF specifically suited for active pharmaceutical ingredients (APIs) rich in hydrogen-bond donors, but also exemplifies the value of leveraging formulation principles and compatible components inherent in traditional Chinese medicine through advanced crystal engineering approaches.
{"title":"Crystal engineering optimizes emodin-tetramethylpyrazine combination: From cocrystal design to in vivo anti-colitis efficacy assessment","authors":"Meiru Liu , Yinru Jiang , Penghui Yuan , Shuang Li , Baoxi Zhang , Xia Zhou , Bin Su , Yifei Xie , Dezhi Yang , Linglei Kong , Li Zhang , Yang Lv , Guanhua Du","doi":"10.1016/j.ijpx.2025.100436","DOIUrl":"10.1016/j.ijpx.2025.100436","url":null,"abstract":"<div><div>Emodin (EMO) shows therapeutic promise for ulcerative colitis (UC), yet its clinical utility is hampered by low bioavailability. To rationally overcome this limitation, this study employed cocrystal engineering, strategically selecting tetramethylpyrazine (TMP)—a natural compound from traditional Chinese medicine—as the cocrystal coformer (CCF). The selection of TMP was guided by a systematic CCF screening strategy, incorporating extensive literature analysis of natural compound CCF candidates, computational chemistry methods to predict favorable hydrogen-bonding interactions and interaction sites with EMO, and machine learning assessment of cocrystallization propensity. Utilizing this rational design approach, we successfully synthesized and characterized a novel EMO-TMP cocrystal through comprehensive solid-state characterization techniques. The resulting cocrystal significantly enhanced the aqueous solubility of EMO while preserving its intrinsic bioactivity. Pharmacokinetic studies confirmed that the cocrystal formulation markedly improved the oral bioavailability of EMO. In a dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) model, the EMO-TMP cocrystal demonstrated superior efficacy compared to EMO alone, effectively alleviating colitis symptoms and associated pathological markers. This enhanced <em>in vivo</em> efficacy is attributed to the significantly improved systemic exposure achieved through the rationally designed cocrystal. Our findings establish the EMO-TMP cocrystal as a highly promising strategy to surmount the physicochemical barriers of EMO, unlocking its full clinical potential for UC treatment. Critically, this work not only validates TMP as an efficient and safe CCF specifically suited for active pharmaceutical ingredients (APIs) rich in hydrogen-bond donors, but also exemplifies the value of leveraging formulation principles and compatible components inherent in traditional Chinese medicine through advanced crystal engineering approaches.</div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"10 ","pages":"Article 100436"},"PeriodicalIF":6.4,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145516742","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}
Pub Date : 2025-11-01DOI: 10.1016/j.ijpx.2025.100434
Sahar Marefat , Ali Shayanfar , Farnaz Monajjemzadeh
The evaluation of color in pharmaceutical materials and products serves as an essential method for assessing physical appearance, stability, and overall quality control. Any recognizable color change in pharmaceuticals may lead to failure in meeting quality objectives. Traditional visual examinations, while commonly used, are subjective and prone to inconsistency, making them inadequate for precise assessment. As a result, advanced instrumental techniques have gained prominence, with CIE (Commission Internationale de l'Eclairage) Lab color space being widely recognized for its accuracy and applicability. Developed by the International Commission on Illumination, the CIELab system characterizes color using three components: L (lightness), a⁎ (red-green axis), and b⁎ (yellow-blue axis), providing a quantitative, standardized approach for color measurement. This method has been extensively utilized in pharmaceutical research and industry for diverse applications, such as quality control, stability studies, and batch-to-batch consistency evaluations. The present review aims to discuss studies that have employed this method in pharmaceutical color assessment, and related quality control issues.
{"title":"Developments in image-based colorimetric analysis methods and applications of CIElab color space in pharmaceutical sciences: A narrative review","authors":"Sahar Marefat , Ali Shayanfar , Farnaz Monajjemzadeh","doi":"10.1016/j.ijpx.2025.100434","DOIUrl":"10.1016/j.ijpx.2025.100434","url":null,"abstract":"<div><div>The evaluation of color in pharmaceutical materials and products serves as an essential method for assessing physical appearance, stability, and overall quality control. Any recognizable color change in pharmaceuticals may lead to failure in meeting quality objectives. Traditional visual examinations, while commonly used, are subjective and prone to inconsistency, making them inadequate for precise assessment. As a result, advanced instrumental techniques have gained prominence, with CIE (Commission Internationale de l'Eclairage) Lab color space being widely recognized for its accuracy and applicability. Developed by the International Commission on Illumination, the CIELab system characterizes color using three components: L (lightness), a<sup>⁎</sup> (red-green axis), and b<sup>⁎</sup> (yellow-blue axis), providing a quantitative, standardized approach for color measurement. This method has been extensively utilized in pharmaceutical research and industry for diverse applications, such as quality control, stability studies, and batch-to-batch consistency evaluations. The present review aims to discuss studies that have employed this method in pharmaceutical color assessment, and related quality control issues.</div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"10 ","pages":"Article 100434"},"PeriodicalIF":6.4,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145462890","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}
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