Pub Date : 2025-11-20DOI: 10.1016/j.ejps.2025.107386
Michael T. Neary , Lianne M. Mulder , Ciaran O. Leime , Ronan MacLoughlin , Brunella Grassiri , Łukasz Baranowski , Piotr S. Kowalski , Abina M. Crean , Katie B. Ryan
Inhalation via nebulisation is a promising method to deliver high concentrations of siRNA to the lung epithelium in a direct and non-invasive manner for the treatment of numerous respiratory-related illnesses. However, nebulisation can be destructive towards siRNA nanocarriers leading to loss of siRNA and a diminished therapeutic outcome. Herein, we sought to explore how the nebulisation process, including adjustments in aerosol droplet size impacts the physicochemical properties of several lipid-based siRNA nanocarrier formulations. These included PEGylated and non-PEGylated cationic DOTAP-based lipoplexes (LPXs) and C12–200 based lipid nanoparticles (LNPs). Two Aerogen® Pro vibrating mesh nebuliser devices with capacities to generate aerosols of differing volumetric mean diameters (VMD) were utilised. The aerosol droplet sizes for the different siRNA formulations were 4.80 to 4.89 µm (High VMD device) and 3.56 to 3.59 µm (Low VMD device) demonstrating that the emitted droplet size distribution was consistent across multiple siRNA nanocarrier types. Further, the formulations exhibited mass median aerodynamic diameters (MMAD) of 4.03 – 4.84 µm (High VMD device) indicating their potential for targeting siRNA lung deposition. Aggregation in both lipoplex formulations and a significant reduction in LNPs’ siRNA encapsulation efficiency were observed. In vitro studies in Firefly luciferase (Fluc) expressing alveolar A549 cells demonstrated that cell viability and Fluc knockdown were generally unaffected by nebulisation. However, Fluc knockdown varied depending on formulation type and was highest for LNPs (93 %) and lowest for the PEGylated LPXs (max 30 %). Overall, this study shows that aerosols with consistent droplet size can be generated but the choice of nanocarrier impacts the stability and delivery efficacy and requires careful consideration for efficient nebulised siRNA delivery.
{"title":"Pulmonary delivery of siRNA lipoplexes and lipid nanoparticles using a vibrating mesh nebuliser","authors":"Michael T. Neary , Lianne M. Mulder , Ciaran O. Leime , Ronan MacLoughlin , Brunella Grassiri , Łukasz Baranowski , Piotr S. Kowalski , Abina M. Crean , Katie B. Ryan","doi":"10.1016/j.ejps.2025.107386","DOIUrl":"10.1016/j.ejps.2025.107386","url":null,"abstract":"<div><div>Inhalation via nebulisation is a promising method to deliver high concentrations of siRNA to the lung epithelium in a direct and non-invasive manner for the treatment of numerous respiratory-related illnesses. However, nebulisation can be destructive towards siRNA nanocarriers leading to loss of siRNA and a diminished therapeutic outcome. Herein, we sought to explore how the nebulisation process, including adjustments in aerosol droplet size impacts the physicochemical properties of several lipid-based siRNA nanocarrier formulations. These included PEGylated and non-PEGylated cationic DOTAP-based lipoplexes (LPXs) and C12–200 based lipid nanoparticles (LNPs). Two Aerogen® Pro vibrating mesh nebuliser devices with capacities to generate aerosols of differing volumetric mean diameters (VMD) were utilised. The aerosol droplet sizes for the different siRNA formulations were 4.80 to 4.89 µm (High VMD device) and 3.56 to 3.59 µm (Low VMD device) demonstrating that the emitted droplet size distribution was consistent across multiple siRNA nanocarrier types. Further, the formulations exhibited mass median aerodynamic diameters (MMAD) of 4.03 – 4.84 µm (High VMD device) indicating their potential for targeting siRNA lung deposition. Aggregation in both lipoplex formulations and a significant reduction in LNPs’ siRNA encapsulation efficiency were observed. <em>In vitro</em> studies in Firefly luciferase (Fluc) expressing alveolar A549 cells demonstrated that cell viability and Fluc knockdown were generally unaffected by nebulisation. However, Fluc knockdown varied depending on formulation type and was highest for LNPs (93 %) and lowest for the PEGylated LPXs (max 30 %). Overall, this study shows that aerosols with consistent droplet size can be generated but the choice of nanocarrier impacts the stability and delivery efficacy and requires careful consideration for efficient nebulised siRNA delivery.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"216 ","pages":"Article 107386"},"PeriodicalIF":4.7,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This study aimed to evaluate the impact of incorporating yeast cell wall (YCW) into alginate/whey protein (ALG/WP) particles as a strategy to improve oral insulin delivery. Insulin-loaded particles were produced by an extrusion–gelation process with or without YCW, and their physicochemical, mucoadhesive, and permeability properties were assessed in vitro, ex vivo, and in vivo. The inclusion of YCW increased the viscosity of the polymeric solution, resulting in more cohesive particles and a significant reduction in insulin loss during coating. Encapsulation efficiencies ranged from 65 to 99%. However, YCW did not significantly affect particle size or the release mechanism, which remained diffusion-controlled. Although YCW-containing beads exhibited enzyme inhibitory and mucoadhesive properties, insulin protection against enzymatic degradation was similar to that of control beads. YCW moderately enhanced insulin permeability in Caco-2 cell monolayers without cytotoxicity, consistent with a reversible reduction of transepithelial electrical resistance. This effect did not translate into a measurable increase in insulin absorption in ex vivo duodenum or in vivo duodenal administration, indicating that its contribution as an absorption enhancer is limited under physiologically complex conditions.
{"title":"Impact of yeast cell wall incorporation on the mucoadhesion, stability, oral permeability and release profile of alginate/whey protein beads loaded with insulin","authors":"Emmanuelle Lainé , Valerie Hoffart , Imen Dhifallah , Ghislain Garrait , Eric Beyssac","doi":"10.1016/j.ejps.2025.107385","DOIUrl":"10.1016/j.ejps.2025.107385","url":null,"abstract":"<div><div>This study aimed to evaluate the impact of incorporating yeast cell wall (YCW) into alginate/whey protein (ALG/WP) particles as a strategy to improve oral insulin delivery. Insulin-loaded particles were produced by an extrusion–gelation process with or without YCW, and their physicochemical, mucoadhesive, and permeability properties were assessed <em>in vitro, ex vivo</em>, and <em>in vivo</em>. The inclusion of YCW increased the viscosity of the polymeric solution, resulting in more cohesive particles and a significant reduction in insulin loss during coating. Encapsulation efficiencies ranged from 65 to 99%. However, YCW did not significantly affect particle size or the release mechanism, which remained diffusion-controlled. Although YCW-containing beads exhibited enzyme inhibitory and mucoadhesive properties, insulin protection against enzymatic degradation was similar to that of control beads. YCW moderately enhanced insulin permeability in Caco-2 cell monolayers without cytotoxicity, consistent with a reversible reduction of transepithelial electrical resistance. This effect did not translate into a measurable increase in insulin absorption in ex vivo duodenum or <em>in vivo</em> duodenal administration, indicating that its contribution as an absorption enhancer is limited under physiologically complex conditions.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"216 ","pages":"Article 107385"},"PeriodicalIF":4.7,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-19DOI: 10.1016/j.ejps.2025.107383
Katrin F. Wiebe , Stefan C. Schneid , Werner Hoheisel , Wolfgang Frieß , Olivia M. Merkel
During the pandemic, lipid nanoparticles (LNPs) became widely established as RNA nanocarriers, and hold the promise of future targeting of a broad variety of previously untreatable diseases. LNPs are mostly administered invasively via intramuscular or intravenous injections. Given the lung’s large surface, high vascularization and low nuclease abundance, inhalation offers a promising alternative for both local and systemic delivery of LNPs. Vibrating mesh nebulizers present a patient-friendly, high-dose delivery platform. However, the nebulization process imposes thermal and mechanical stress on the LNP formulation. This study contributes to a better understanding of how nebulization affects the physicochemical properties and biological activity of LNPs, depending on formulation and process parameters. We investigated the impact of formulation and process variables such as temperature, concentration, buffer type, and RNA modality on LNP properties including particle size distribution, zeta potential, in vitro activity, and RNA integrity. While aggregating, siRNA LNPs protected the encapsulated RNA from degradation, and preserved biological function. In contrast, after the nebulization of mRNA LNPs the cargo was degraded and the biological function diminished. This observation can possibly be attributed both to the higher sensitivity of mRNA toward physical and chemical degradation, and the cargo-dependent morphology of LNPs. While demonstrating that siRNA LNPs preserved their most important characteristics, namely RNA integrity and biological function, our findings emphasize the need for route-specific optimization of LNPs, which need to meet different critical quality criteria when used for inhalation rather than injection.
{"title":"Impact of formulation and process parameters on the stability and bioactivity of RNA-loaded lipid nanoparticles during nebulization","authors":"Katrin F. Wiebe , Stefan C. Schneid , Werner Hoheisel , Wolfgang Frieß , Olivia M. Merkel","doi":"10.1016/j.ejps.2025.107383","DOIUrl":"10.1016/j.ejps.2025.107383","url":null,"abstract":"<div><div>During the pandemic, lipid nanoparticles (LNPs) became widely established as RNA nanocarriers, and hold the promise of future targeting of a broad variety of previously untreatable diseases. LNPs are mostly administered invasively via intramuscular or intravenous injections. Given the lung’s large surface, high vascularization and low nuclease abundance, inhalation offers a promising alternative for both local and systemic delivery of LNPs. Vibrating mesh nebulizers present a patient-friendly, high-dose delivery platform. However, the nebulization process imposes thermal and mechanical stress on the LNP formulation. This study contributes to a better understanding of how nebulization affects the physicochemical properties and biological activity of LNPs, depending on formulation and process parameters. We investigated the impact of formulation and process variables such as temperature, concentration, buffer type, and RNA modality on LNP properties including particle size distribution, zeta potential, <em>in vitro</em> activity, and RNA integrity. While aggregating, siRNA LNPs protected the encapsulated RNA from degradation, and preserved biological function. In contrast, after the nebulization of mRNA LNPs the cargo was degraded and the biological function diminished. This observation can possibly be attributed both to the higher sensitivity of mRNA toward physical and chemical degradation, and the cargo-dependent morphology of LNPs. While demonstrating that siRNA LNPs preserved their most important characteristics, namely RNA integrity and biological function, our findings emphasize the need for route-specific optimization of LNPs, which need to meet different critical quality criteria when used for inhalation rather than injection.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"216 ","pages":"Article 107383"},"PeriodicalIF":4.7,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145563047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This study aimed to evaluate the risk of developing ocular outcomes, including diabetic retinopathy (DR), open-angle glaucoma (OAG), and visual loss, in patients with type 2 diabetes mellitus (T2DM) treated with dapagliflozin, a sodium glucose cotransporter 2 inhibitor (SGLT2i), compared to those receiving other hypoglycemic agents.
Methods
This was an observational, retrospective, multi-center cohort study using data from the Taipei Medical University Clinical Research Database (2016–2020). Participants included 18,854 newly diagnosed T2DM patients with an estimated glomerular filtration rate above 45 ml/min/m². After excluding those with a history of DR, OAG, or visual loss, 1400 dapagliflozin users and 1400 non-SGLT2i users were matched using 1:1 propensity score matching. The primary outcome was the composite incidence of DR, OAG, or visual loss.
Results
After 1-year follow-up, dapagliflozin users had a significantly lower incidence of DR, OAG, or visual loss (2.78 % vs. 5.35 %; adjusted hazard ratio [aHR], 0.53; 95 % CI, 0.36–0.79, p = 0.002). At the 2-year follow-up, the incidence was 3.85 % in dapagliflozin users compared to 6.35 % in non-SGLT2i users (aHR, 0.63; 95 % CI, 0.44–0.88, p = 0.007).
Conclusions
Dapagliflozin was associated with a significantly lower incidence of DR, OAG, or visual loss in newly diagnosed T2DM patients within five years, suggesting its potential benefit in preventing ocular complications.
{"title":"The influence of dapagliflozin on diabetic ocular complications: An observational cohort study","authors":"Jo-Hsin Chen , Fei-Hung Hung , Yu-Ting Wang , Jin-Hua Chen , Shu-Fen Liao , Chun-Mei Hsueh , Jong-Shiuan Yeh , Gregory Y.H. Lip","doi":"10.1016/j.ejps.2025.107382","DOIUrl":"10.1016/j.ejps.2025.107382","url":null,"abstract":"<div><h3>Background</h3><div>This study aimed to evaluate the risk of developing ocular outcomes, including diabetic retinopathy (DR), open-angle glaucoma (OAG), and visual loss, in patients with type 2 diabetes mellitus (T2DM) treated with dapagliflozin, a sodium glucose cotransporter 2 inhibitor (SGLT2i), compared to those receiving other hypoglycemic agents.</div></div><div><h3>Methods</h3><div>This was an observational, retrospective, multi-center cohort study using data from the Taipei Medical University Clinical Research Database (2016–2020). Participants included 18,854 newly diagnosed T2DM patients with an estimated glomerular filtration rate above 45 ml/min/m². After excluding those with a history of DR, OAG, or visual loss, 1400 dapagliflozin users and 1400 non-SGLT2i users were matched using 1:1 propensity score matching. The primary outcome was the composite incidence of DR, OAG, or visual loss.</div></div><div><h3>Results</h3><div>After 1-year follow-up, dapagliflozin users had a significantly lower incidence of DR, OAG, or visual loss (2.78 % vs. 5.35 %; adjusted hazard ratio [aHR], 0.53; 95 % CI, 0.36–0.79, <em>p</em> = 0.002). At the 2-year follow-up, the incidence was 3.85 % in dapagliflozin users compared to 6.35 % in non-SGLT2i users (aHR, 0.63; 95 % CI, 0.44–0.88, <em>p</em> = 0.007).</div></div><div><h3>Conclusions</h3><div>Dapagliflozin was associated with a significantly lower incidence of DR, OAG, or visual loss in newly diagnosed T2DM patients within five years, suggesting its potential benefit in preventing ocular complications.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"216 ","pages":"Article 107382"},"PeriodicalIF":4.7,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145556523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-13DOI: 10.1016/j.ejps.2025.107379
Roman Groß, Michael Uwe Hartig, Kai Berkenfeld, Alf Lamprecht
Dry powder inhalers (DPIs) provide important therapy options for the treatment of airway diseases. It is widely reported that the success of an inhalation maneuver depends not only on the properties of the formulation and the device, but also on the patients’ ability to apply the inhaler as intended. An insufficient duration of the inhalation maneuver or an insufficient inspiration force might lead to an unfavorable therapeutic outcome. To counteract this problem, the study demonstrates feasibility of a new feedback system for RS01-type DPI devices aiding to assess the quality of the inhalation maneuver. Capsules have been modified to hold a neodymium magnet permitting to induce electric currents into an adjacently placed coil when rotating. The voltage induced was recorded and profiles obtained were shown to contain information about the duration flow rate applied during the actuation. Number of capsule revolutions and the overall volume (R2 = 0.9991), as well as the applied flow rate and the frequency for the Cyclocaps® formulation (R2 = 0.9893) were positively correlated when investigated under in vitro conditions using linear flow profiles. Through adequately characterizing a formulation with the new system and then linking the obtained fraction of the emitted mass with an aerodynamic diameter < 5 µm to the mentioned feedback variables, predictions can be made about the inhalation quality as well as the amount of respirable particles inhaled.
{"title":"A magnet-based capsule rotation tracking for assessing inhalation success in dry powder inhalers","authors":"Roman Groß, Michael Uwe Hartig, Kai Berkenfeld, Alf Lamprecht","doi":"10.1016/j.ejps.2025.107379","DOIUrl":"10.1016/j.ejps.2025.107379","url":null,"abstract":"<div><div>Dry powder inhalers (DPIs) provide important therapy options for the treatment of airway diseases. It is widely reported that the success of an inhalation maneuver depends not only on the properties of the formulation and the device, but also on the patients’ ability to apply the inhaler as intended. An insufficient duration of the inhalation maneuver or an insufficient inspiration force might lead to an unfavorable therapeutic outcome. To counteract this problem, the study demonstrates feasibility of a new feedback system for RS01-type DPI devices aiding to assess the quality of the inhalation maneuver. Capsules have been modified to hold a neodymium magnet permitting to induce electric currents into an adjacently placed coil when rotating. The voltage induced was recorded and profiles obtained were shown to contain information about the duration flow rate applied during the actuation. Number of capsule revolutions and the overall volume (R<sup>2</sup> = 0.9991), as well as the applied flow rate and the frequency for the Cyclocaps® formulation (R<sup>2</sup> = 0.9893) were positively correlated when investigated under in vitro conditions using linear flow profiles. Through adequately characterizing a formulation with the new system and then linking the obtained fraction of the emitted mass with an aerodynamic diameter < 5 µm to the mentioned feedback variables, predictions can be made about the inhalation quality as well as the amount of respirable particles inhaled.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"216 ","pages":"Article 107379"},"PeriodicalIF":4.7,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-13DOI: 10.1016/j.ejps.2025.107380
Lee Roy Oldfield , Björn Fischer , Tobias Auel , Anne Seidlitz
This study presents the development and characterisation of dual extrusion 3D printed multiple unit particle system (MUPS) tablets incorporating metoprolol succinate. Pharmaceutical-grade filaments were prepared via hot-melt extrusion, comprising a drug loaded sustained release formulation of Eudragit® RL PO, and a rapidly disintegrating tablet shell formulation based on Kollicoat® IR. The use of fused filament fabrication enabled the integration of drug-loaded cylindrical particles within the tablet shell. Comprehensive morphological and structural analyses, including scanning electron microscopy, X-ray micro-computed tomography, and digital microscopy, confirmed uniform particle geometry and distribution. The manufactured tablets met European Pharmacopoeia (Ph. Eur.) specifications for mass uniformity. Disintegration testing demonstrated complete disintegration of the tablet shell within 15 min. X-ray powder diffraction indicated the active pharmaceutical ingredient (API) was present in an amorphous state post-processing. High-performance liquid chromatography analysis revealed thermal degradation during 3D printing, with a reduction in API content from 97.8 % in the extruded filament to 65.9 % in the printed MUPS tablets. A linear correlation between the number of printed particle layers and the final drug content was shown, supporting the concept of dose individualisation. In vitro dissolution testing showed that 80 % of the incorporated API was released within 105 to 150 min. The findings confirm the feasibility of producing API-3D-MUPS tablets using pharmaceutical-grade materials, while also identifying critical product defects, formulation and process parameters such as thermal instability of the API or particle agglomeration - that require further optimisation of formulation and process parameters to enable broader application in personalised drug delivery.
本研究介绍了双挤出3D打印多单位颗粒系统（MUPS）片的发展和特征，其中含有琥珀酸美托洛尔。通过热熔挤压法制备药物级长丝，包括Eudragit®RL PO的载药缓释制剂和基于Kollicoat®IR的快速崩解片壳制剂。熔融丝制造的使用使载药的圆柱形颗粒集成在片剂外壳内。全面的形态和结构分析，包括扫描电子显微镜、x射线微计算机断层扫描和数字显微镜，证实了均匀的颗粒几何形状和分布。所制片剂质量均匀性符合欧洲药典标准。崩解试验表明，片壳在15分钟内完全崩解。x射线粉末衍射表明原料药经后处理后呈无定形存在。高效液相色谱分析显示，在3D打印过程中，API含量从挤压长丝的97.8%降低到打印的MUPS片剂的65.9%。打印颗粒层的数量和最终药物含量之间的线性相关性显示，支持剂量个性化的概念。体外溶出度试验表明，掺入的原料药80%在105 ~ 150 min内释放。研究结果证实了使用医药级材料生产API- 3d - mups片剂的可行性，同时也确定了关键的产品缺陷、配方和工艺参数，如API的热不稳定性或颗粒团聚——这些都需要进一步优化配方和工艺参数，以便在个性化药物输送中得到更广泛的应用。
{"title":"Development of a 3D printed multiple unit particle system (MUPS) containing metoprolol succinate","authors":"Lee Roy Oldfield , Björn Fischer , Tobias Auel , Anne Seidlitz","doi":"10.1016/j.ejps.2025.107380","DOIUrl":"10.1016/j.ejps.2025.107380","url":null,"abstract":"<div><div>This study presents the development and characterisation of dual extrusion 3D printed multiple unit particle system (MUPS) tablets incorporating metoprolol succinate. Pharmaceutical-grade filaments were prepared via hot-melt extrusion, comprising a drug loaded sustained release formulation of Eudragit® RL PO, and a rapidly disintegrating tablet shell formulation based on Kollicoat® IR. The use of fused filament fabrication enabled the integration of drug-loaded cylindrical particles within the tablet shell. Comprehensive morphological and structural analyses, including scanning electron microscopy, X-ray micro-computed tomography, and digital microscopy, confirmed uniform particle geometry and distribution. The manufactured tablets met European Pharmacopoeia (Ph. Eur.) specifications for mass uniformity. Disintegration testing demonstrated complete disintegration of the tablet shell within 15 min. X-ray powder diffraction indicated the active pharmaceutical ingredient (API) was present in an amorphous state post-processing. High-performance liquid chromatography analysis revealed thermal degradation during 3D printing, with a reduction in API content from 97.8 % in the extruded filament to 65.9 % in the printed MUPS tablets. A linear correlation between the number of printed particle layers and the final drug content was shown, supporting the concept of dose individualisation. In vitro dissolution testing showed that 80 % of the incorporated API was released within 105 to 150 min. The findings confirm the feasibility of producing API-3D-MUPS tablets using pharmaceutical-grade materials, while also identifying critical product defects, formulation and process parameters such as thermal instability of the API or particle agglomeration - that require further optimisation of formulation and process parameters to enable broader application in personalised drug delivery.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"216 ","pages":"Article 107380"},"PeriodicalIF":4.7,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-12DOI: 10.1016/j.ejps.2025.107378
Jiahua Zhao , Yuheng Shan , Yuying Cen , Mengyao Wang , Tiantian Zhuang , Yibing Li , Yuxuan Liu , Zhiyong Nie , Jianwei Xie , Jiatang Zhang
Acyclovir (ACV) is a widely used antiviral agent for the treatment of herpes simplex virus encephalitis. Dexamethasone (DEX) is often co-administered as an adjunctive therapy. Tariquidar (TQD), a potent and selective inhibitor of P-glycoprotein, has been demonstrated to enhance the brain accumulation of ACV. This study is designed to systematically investigate the impact of varying DEX dosages on the blood-brain barrier (BBB) transport of ACV, elucidate the mechanisms involved, and evaluate the therapeutic potential of TQD in the management of herpes simplex virus encephalitis. Microdialysis, coupled with high-performance liquid chromatography, was employed to measure unbound ACV concentrations in blood and brain tissue at pre-determined time intervals. The effects of low (0.5 mg/kg), moderate (1 mg/kg), and high (3 mg/kg) doses of DEX, administered continuously for 4 days, on the pharmacokinetic parameters of ACV were evaluated in the presence and absence of tariquidar (TQD, P-glycoprotein inhibitor, 8 mg/kg). The BBB transport of ACV was assessed by calculating the ratio of the area under the unbound brain drug concentration-time curve to the area under the unbound blood drug concentration over time, to reflect changes in the BBB transport (Kp,uu,brain) of ACV. The mean of the area under the unbound brain and blood drug concentration-time curve, and Kp,uu,brain in rats of the solvent control (SC) group were 2674 ± 448 min·μg/mL, 564 ± 136 min·μg/mL, and 20.9 %, respectively. In the low-dose DEX group, the Kp,uu,brain of ACV was 19.5 %, with no statistically significant difference compared with the SC group (P > 0.05). In the moderate- and high-dose DEX groups, the Kp,uu,brain of ACV decreased to 17.0 % and 14.0 %, respectively, with a statistically significant difference compared with the SC group (P < 0.001). Pairwise comparisons further revealed significant differences in the Kp,uu,brain of ACV among different DEX dose groups. Conversely, TQD administration increased the Kp,uu,brain of ACV by 1.40-fold (P < 0.001). The Kp,uu,brain in the TQD plus low-dose DEX group was 27.1 %, significantly higher than that of the SC group (P < 0.001). The Kp,uu,brain of the TQD plus moderate-dose DEX and TQD plus high-dose DEX groups was 21.6 % and 18.4 %, respectively, with no significant difference compared to the SC group (P > 0.05). Low-dose DEX does not significantly alter the BBB transport of ACV. However, moderate to high doses of DEX exhibit a dose-dependent reduction in ACV penetration across the BBB. Co-administration of TQD with DEX counteracts this effect, and even enhancing the BBB transport of ACV.
{"title":"Effect of different doses of dexamethasone on the penetration of acyclovir across the blood-brain barrier","authors":"Jiahua Zhao , Yuheng Shan , Yuying Cen , Mengyao Wang , Tiantian Zhuang , Yibing Li , Yuxuan Liu , Zhiyong Nie , Jianwei Xie , Jiatang Zhang","doi":"10.1016/j.ejps.2025.107378","DOIUrl":"10.1016/j.ejps.2025.107378","url":null,"abstract":"<div><div>Acyclovir (ACV) is a widely used antiviral agent for the treatment of herpes simplex virus encephalitis. Dexamethasone (DEX) is often co-administered as an adjunctive therapy. Tariquidar (TQD), a potent and selective inhibitor of P-glycoprotein, has been demonstrated to enhance the brain accumulation of ACV. This study is designed to systematically investigate the impact of varying DEX dosages on the blood-brain barrier (BBB) transport of ACV, elucidate the mechanisms involved, and evaluate the therapeutic potential of TQD in the management of herpes simplex virus encephalitis. Microdialysis, coupled with high-performance liquid chromatography, was employed to measure unbound ACV concentrations in blood and brain tissue at pre-determined time intervals. The effects of low (0.5 mg/kg), moderate (1 mg/kg), and high (3 mg/kg) doses of DEX, administered continuously for 4 days, on the pharmacokinetic parameters of ACV were evaluated in the presence and absence of tariquidar (TQD, P-glycoprotein inhibitor, 8 mg/kg). The BBB transport of ACV was assessed by calculating the ratio of the area under the unbound brain drug concentration-time curve to the area under the unbound blood drug concentration over time, to reflect changes in the BBB transport (K<sub>p,uu,brain</sub>) of ACV. The mean of the area under the unbound brain and blood drug concentration-time curve, and K<sub>p,uu,brain</sub> in rats of the solvent control (SC) group were 2674 ± 448 min·μg/mL, 564 ± 136 min·μg/mL, and 20.9 %, respectively. In the low-dose DEX group, the K<sub>p,uu,brain<!--> </sub> of ACV was 19.5 %, with no statistically significant difference compared with the SC group (<em>P</em> > 0.05). In the moderate- and high-dose DEX groups, the K<sub>p,uu,brain<!--> </sub> of ACV decreased to 17.0 % and 14.0 %, respectively, with a statistically significant difference compared with the SC group (<em>P</em> < 0.001). Pairwise comparisons further revealed significant differences in the K<sub>p,uu,brain</sub> of ACV among different DEX dose groups. Conversely, TQD administration increased the K<sub>p,uu,brain</sub> of ACV by 1.40-fold (<em>P</em> < 0.001). The K<sub>p,uu,brain</sub> in the TQD plus low-dose DEX group was 27.1 %, significantly higher than that of the SC group (<em>P</em> < 0.001). The K<sub>p,uu,brain</sub> of the TQD plus moderate-dose DEX and TQD plus high-dose DEX groups was 21.6 % and 18.4 %, respectively, with no significant difference compared to the SC group (<em>P</em> > 0.05). Low-dose DEX does not significantly alter the BBB transport of ACV. However, moderate to high doses of DEX exhibit a dose-dependent reduction in ACV penetration across the BBB. Co-administration of TQD with DEX counteracts this effect, and even enhancing the BBB transport of ACV.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"216 ","pages":"Article 107378"},"PeriodicalIF":4.7,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145523294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-10DOI: 10.1016/j.ejps.2025.107374
Feng Liu , Wei Song , Shuang Jia , Guyuan Wang , Xue Zhang , Chen Lyu , Dahui Xing , Yidi Qu , Bo Liu , Runze Yu , Sukai Li , Renjun Gao , Jinliang Zhang
Bispecific Antibody-Drug Conjugates (BsADCs) represent a promising class of targeted therapeutics, combining the bispecific targeting with the potency of cytotoxic payloads. However, their inherent structural complexity poses unique stability and photosensitivity challenges in development, manufacturing, and storage. In this study, we assessed the stability of three BsADCs under different light sources. Fluorescent lamp consistently induced BsADCs photodegradation, implicating its ultraviolet component as a key driver. Subsequent research results on the mechanism of photodegradation indicated that the fluorescent lamp-induced instability in BsADCs is primarily driven by the generation of reactive oxygen species from the payload upon photoexcitation, which subsequently induces photodegradation of the BsADCs. Notably, BsADCs exhibited significantly higher oxidation at conventional methionine residues of the Fc region than unconjugated parental bispecific antibodies (BsAbs). Integrated with the results from the carboxyl group footprinting and thermal stress study, suggested the structural differences between BsADCs and parental BsAbs. Our findings highlight that payload-mediated photoreactivity and structural alterations upon conjugation are critical factors contributing to the photodegradation of BsADCs compared with parental BsAbs. These insights underscore the importance of rigorous photostability assessment and appropriate light protection strategies throughout BsADCs development, manufacturing, and storage.
{"title":"Insight on photosensitivity of bispecific antibody-drug conjugates: ROS-mediated degradation and payload conjugation-induced structure alterations","authors":"Feng Liu , Wei Song , Shuang Jia , Guyuan Wang , Xue Zhang , Chen Lyu , Dahui Xing , Yidi Qu , Bo Liu , Runze Yu , Sukai Li , Renjun Gao , Jinliang Zhang","doi":"10.1016/j.ejps.2025.107374","DOIUrl":"10.1016/j.ejps.2025.107374","url":null,"abstract":"<div><div>Bispecific Antibody-Drug Conjugates (BsADCs) represent a promising class of targeted therapeutics, combining the bispecific targeting with the potency of cytotoxic payloads. However, their inherent structural complexity poses unique stability and photosensitivity challenges in development, manufacturing, and storage. In this study, we assessed the stability of three BsADCs under different light sources. Fluorescent lamp consistently induced BsADCs photodegradation, implicating its ultraviolet component as a key driver. Subsequent research results on the mechanism of photodegradation indicated that the fluorescent lamp-induced instability in BsADCs is primarily driven by the generation of reactive oxygen species from the payload upon photoexcitation, which subsequently induces photodegradation of the BsADCs. Notably, BsADCs exhibited significantly higher oxidation at conventional methionine residues of the Fc region than unconjugated parental bispecific antibodies (BsAbs). Integrated with the results from the carboxyl group footprinting and thermal stress study, suggested the structural differences between BsADCs and parental BsAbs. Our findings highlight that payload-mediated photoreactivity and structural alterations upon conjugation are critical factors contributing to the photodegradation of BsADCs compared with parental BsAbs. These insights underscore the importance of rigorous photostability assessment and appropriate light protection strategies throughout BsADCs development, manufacturing, and storage.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"216 ","pages":"Article 107374"},"PeriodicalIF":4.7,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145502650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<div><div>This study aimed to investigate the in vitro lipolysis of five different self-nanoemulsifying drug delivery system (SNEDDS) formulations and to test the formulations by combining the in vitro lipolysis with ex vivo permeability and in situ perfusion methods as permeation steps, and then to compare the methods. Exemestane (EXE) was selected as the model drug due to its low solubility and nonionic nature. Four SNEDDS formulations, differing from the main formulation (MCF<sub>K40</sub>) in terms of cosolvent content (MCF<sub>CoS</sub>), oil type (LCF), digestible surfactant content (MCF<sub>T80</sub>), and oil amount (MCF<sub>I988</sub>), were prepared to contain equal EXE amounts and characterized. Firstly, a classical (without permeation step) in vitro lipolysis study was conducted for SNEDDS formulations and reference product. During lipolysis, higher drug precipitation, in other words, free drug fraction, was observed in formulations containing digestible excipients (MCF<sub>T80</sub> and MCF<sub>I988</sub>) and reference. Subsequently, a sequential lipolysis – ex vivo permeability study was conducted for SNEDDS formulations and reference using a vertical Franz diffusion cell with porcine intestinal tissue with samples taken from lipolysis medium at different times (0., 15., and 60. min). The similar permeated EXE% and the area under the permeated EXE% − time curve values were obtained for all SNEDDS regardless of the free drug fraction. The different stages of SNEDDS lipolysis did not affect EXE permeability. Subsequently, the lipolysis study was coupled with an in situ perfusion study that would allow simultaneous lipolysis and permeation. MCF<sub>K40</sub> and MCF<sub>I988</sub>, which were selected due to their differences in lipolysis extent and free drug fraction, and EXE solution were examined with this method. Despite the in vitro formulation differences, the two SNEDDS formulations showed similar effective permeability coefficient (<em>P<sub>eff</sub></em>) values to each other and those of the EXE solution. It was shown that EXE’s bioavailability problem due to low solubility could be overcome with SNEDDS formulations. Furthermore, the sequential lipolysis – ex vivo permeability study was found to capture the results of the simultaneous lipolysis - in situ perfusion study, which more closely simulates in vivo. This was attributed to the use of intestinal tissue as a permeation barrier, which allowed the diffusion of colloidal-sized micelles, vesicles, and lipid digestion products in the ex vivo study. Since the in situ perfusion method is not suitable for screening of lipid-based formulations (LBF), the first data for using in vitro lipolysis combined with Franz diffusion cell with intestinal tissue instead were presented in this study. Combining lipolysis with the permeation step is necessary for the evaluation of LBF. Although both methods used in this study are promising, further evaluations are needed regarding horizo
{"title":"Comparison of in vitro lipolysis, sequential lipolysis – ex vivo permeability, and simultaneous lipolysis - in situ perfusion for exemestane-loaded lipid-based formulations","authors":"Burcu Timur , Seval Olgac , Yilmaz Usta , Murside Ayse Demirel , Zeynep Safak Teksin","doi":"10.1016/j.ejps.2025.107372","DOIUrl":"10.1016/j.ejps.2025.107372","url":null,"abstract":"<div><div>This study aimed to investigate the in vitro lipolysis of five different self-nanoemulsifying drug delivery system (SNEDDS) formulations and to test the formulations by combining the in vitro lipolysis with ex vivo permeability and in situ perfusion methods as permeation steps, and then to compare the methods. Exemestane (EXE) was selected as the model drug due to its low solubility and nonionic nature. Four SNEDDS formulations, differing from the main formulation (MCF<sub>K40</sub>) in terms of cosolvent content (MCF<sub>CoS</sub>), oil type (LCF), digestible surfactant content (MCF<sub>T80</sub>), and oil amount (MCF<sub>I988</sub>), were prepared to contain equal EXE amounts and characterized. Firstly, a classical (without permeation step) in vitro lipolysis study was conducted for SNEDDS formulations and reference product. During lipolysis, higher drug precipitation, in other words, free drug fraction, was observed in formulations containing digestible excipients (MCF<sub>T80</sub> and MCF<sub>I988</sub>) and reference. Subsequently, a sequential lipolysis – ex vivo permeability study was conducted for SNEDDS formulations and reference using a vertical Franz diffusion cell with porcine intestinal tissue with samples taken from lipolysis medium at different times (0., 15., and 60. min). The similar permeated EXE% and the area under the permeated EXE% − time curve values were obtained for all SNEDDS regardless of the free drug fraction. The different stages of SNEDDS lipolysis did not affect EXE permeability. Subsequently, the lipolysis study was coupled with an in situ perfusion study that would allow simultaneous lipolysis and permeation. MCF<sub>K40</sub> and MCF<sub>I988</sub>, which were selected due to their differences in lipolysis extent and free drug fraction, and EXE solution were examined with this method. Despite the in vitro formulation differences, the two SNEDDS formulations showed similar effective permeability coefficient (<em>P<sub>eff</sub></em>) values to each other and those of the EXE solution. It was shown that EXE’s bioavailability problem due to low solubility could be overcome with SNEDDS formulations. Furthermore, the sequential lipolysis – ex vivo permeability study was found to capture the results of the simultaneous lipolysis - in situ perfusion study, which more closely simulates in vivo. This was attributed to the use of intestinal tissue as a permeation barrier, which allowed the diffusion of colloidal-sized micelles, vesicles, and lipid digestion products in the ex vivo study. Since the in situ perfusion method is not suitable for screening of lipid-based formulations (LBF), the first data for using in vitro lipolysis combined with Franz diffusion cell with intestinal tissue instead were presented in this study. Combining lipolysis with the permeation step is necessary for the evaluation of LBF. Although both methods used in this study are promising, further evaluations are needed regarding horizo","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"216 ","pages":"Article 107372"},"PeriodicalIF":4.7,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145488223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Patient outcomes in skin cancer are compromised by invasive treatments, demanding a paradigm shift toward effective, non-invasive strategies. This study aimed to develop dual-strategy nanocomposite hydrogel platforms for enhanced, localized delivery of curcumin against skin cancer cells. Two distinct nanocarriers, curcumin nanosuspensions (CUR-Ns) and curcumin liposomes (CUR-Lip), were engineered and embedded within a bioadhesive Gantrez™/gelatin hydrogel. Anticancer activity, cellular uptake, and apoptosis induction were assessed in A431 skin cancer cell line. Nanocomposite hydrogels were fabricated by EDC/NHS crosslinking, with nanocurcumin pre-mixed in gelatin to ensure uniform dispersion. Ex vivo skin permeation was evaluated using Franz diffusion cells with neonatal porcine skin. Both formulations demonstrated potent anticancer activity against A431 cells, with CUR-Lip (IC₅₀ = 9.32 µg/mL) and CUR-Ns (IC₅₀ = 13.43 µg/mL) dramatically outperforming free CUR (IC₅₀ = 44.73 µg/mL) while maintaining excellent biocompatibility. Physicochemical characterizations of the hydrogel demonstrated high moisture content, fluid absorbency, and adequate mechanical strength. These favorable properties facilitated effective delivery. Crucially, the nanocarriers displayed unique therapeutic kinetics. CUR-Ns provided a rapid onset of action, characterized by faster initial skin permeation. In contrast, CUR-Lip offered superior sustained efficacy, showing greater cytotoxicity, and achieving significantly higher cumulative skin deposition, with a transdermal flux of 105.52 ng/cm²/h. The hydrogel platform successfully preserved these distinct permeation profiles, confirming its utility as a versatile delivery vehicle. This dual-strategy approach enables tailored curcumin delivery offering either rapid or sustained release and represented a significant advancement in developing non-invasive therapies for skin cancer.
{"title":"A dual-strategy nanocomposite hydrogel platform of nanosuspensions and deformable liposomes for enhanced curcumin delivery against skin cancer cells","authors":"Khin Cho Aye , Supusson Pengnam , Boonnada Pamornpathomkul , Thapakorn Charoenying , Prasopchai Patrojanasophon , Praneet Opanasopit , Chaiyakarn Pornpitchanarong","doi":"10.1016/j.ejps.2025.107373","DOIUrl":"10.1016/j.ejps.2025.107373","url":null,"abstract":"<div><div>Patient outcomes in skin cancer are compromised by invasive treatments, demanding a paradigm shift toward effective, non-invasive strategies. This study aimed to develop dual-strategy nanocomposite hydrogel platforms for enhanced, localized delivery of curcumin against skin cancer cells. Two distinct nanocarriers, curcumin nanosuspensions (CUR-Ns) and curcumin liposomes (CUR-Lip), were engineered and embedded within a bioadhesive Gantrez™/gelatin hydrogel. Anticancer activity, cellular uptake, and apoptosis induction were assessed in A431 skin cancer cell line. Nanocomposite hydrogels were fabricated by EDC/NHS crosslinking, with nanocurcumin pre-mixed in gelatin to ensure uniform dispersion. <em>Ex vivo</em> skin permeation was evaluated using Franz diffusion cells with neonatal porcine skin. Both formulations demonstrated potent anticancer activity against A431 cells, with CUR-Lip (IC₅₀ = 9.32 µg/mL) and CUR-Ns (IC₅₀ = 13.43 µg/mL) dramatically outperforming free CUR (IC₅₀ = 44.73 µg/mL) while maintaining excellent biocompatibility. Physicochemical characterizations of the hydrogel demonstrated high moisture content, fluid absorbency, and adequate mechanical strength. These favorable properties facilitated effective delivery. Crucially, the nanocarriers displayed unique therapeutic kinetics. CUR-Ns provided a rapid onset of action, characterized by faster initial skin permeation. In contrast, CUR-Lip offered superior sustained efficacy, showing greater cytotoxicity, and achieving significantly higher cumulative skin deposition, with a transdermal flux of 105.52 ng/cm²/h. The hydrogel platform successfully preserved these distinct permeation profiles, confirming its utility as a versatile delivery vehicle. This dual-strategy approach enables tailored curcumin delivery offering either rapid or sustained release and represented a significant advancement in developing non-invasive therapies for skin cancer.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"216 ","pages":"Article 107373"},"PeriodicalIF":4.7,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145488149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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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