European Journal of Pharmaceutics and Biopharmaceutics最新文献

{"title":"Low pinocytic brain endothelial cells primarily utilize membrane fusion to internalize extracellular vesicles","authors":"Jhanvi R. Jhaveri ,&nbsp;Purva Khare ,&nbsp;Paromita Paul Pinky ,&nbsp;Yashika S. Kamte ,&nbsp;Manisha N. Chandwani ,&nbsp;Jadranka Milosevic ,&nbsp;Nevil Abraham ,&nbsp;Ming Sun ,&nbsp;Donna B. Stolz ,&nbsp;Kandarp M. Dave ,&nbsp;Si-yang Zheng ,&nbsp;Lauren O’Donnell ,&nbsp;Devika S Manickam","doi":"10.1016/j.ejpb.2024.114500","DOIUrl":"10.1016/j.ejpb.2024.114500","url":null,"abstract":"<div><div>Extracellular vesicles (<strong>EVs</strong>) are an emerging class of drug carriers and are primarily reported to be internalized into recipient cells via a combination of endocytic routes such as clathrin-mediated, caveolae-mediated and macropinocytosis pathways. In this work, (1) we investigated potential effects of homotypic <em>vs</em>. heterotypic interactions by studying the cellular uptake of homologous EVs (EV donor cells and recipient cells of the same type) <em>vs</em>. heterologous EVs (EV donor cells and recipient cells of different types) and (2) determined the route of EV internalization into low pinocytic/hard-to-deliver cell models such as brain endothelial cells (<strong>BECs</strong>). Homotypic interactions led to a greater extent of uptake into the recipient BECs compared to heterotypic interactions. However, we did <em>not</em> see a complete reduction in EV uptake into recipient BECs when endocytic pathways were blocked using pharmacological inhibitors and our findings from a R18-based fusion assay suggest that EVs primarily use membrane fusion to enter low-pinocytic recipient BECs instead of relying on endocytosis. <em>Lipophilic PKH67 dye-labeled EVs</em> but not intravesicular esterase-activated calcein ester-labeled EVs severely reduced particle uptake into BECs while phagocytic macrophages internalized EVs labeled with both dyes to comparable extents. Our results also highlight the importance of carefully choosing labeling dye chemistry to study EV uptake, especially in the case of low pinocytic cells such as BECs.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"204 ","pages":"Article 114500"},"PeriodicalIF":4.4,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282533","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":"Advancing pharmaceutical Intelligence via computationally Prognosticating the in-vitro parameters of fast disintegration tablets using Machine Learning models","authors":"Dhruv Gupta,&nbsp;Anuj A Biswas,&nbsp;Rohan Chand Sahu,&nbsp;Sanchit Arora,&nbsp;Dinesh Kumar,&nbsp;Ashish K Agrawal","doi":"10.1016/j.ejpb.2024.114508","DOIUrl":"10.1016/j.ejpb.2024.114508","url":null,"abstract":"<div><p>The field of Machine Learning (ML) has garnered significant attention, particularly in healthcare for predicting disease severity. Recently, the pharmaceutical sector has also adopted ML techniques in various stages of drug development. Tablets are the most common pharmaceutical formulations, with their efficacy influenced by the physicochemical properties of active ingredients, in-process parameters, and formulation components. In this study, we developed ML-based prediction models for disintegration time, friability, and water absorption ratio of fast disintegration tablets. The model development process included data visualization, pre-processing, splitting, ML model creation, and evaluation. We evaluated the models using root mean square error (RMSE) and R-squared score (R²). After hyperparameter tuning and cross-validation, the voting regressor model demonstrated the best performance for predicting disintegration time (RMSE: 21.99, R²: 0.76), surpassing previously reported models. The random forest regressor achieved the best results for friability prediction (RMSE: 0.142, R²: 0.7), and the K-nearest neighbor (KNN) regressor excelled in predicting the water absorption ratio (RMSE: 10.07, R²: 0.94). Notably, predicting friability and water absorption ratio using ML models is unprecedented in the literature. The developed models were deployed in a web app for easy access by anyone. These ML models can significantly enhance the tablet development phase by minimizing experimental iterations and material usage, thereby reducing costs and saving time.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"204 ","pages":"Article 114508"},"PeriodicalIF":4.4,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142270678","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":"pH-Sensitive Tacrolimus loaded nanostructured lipid carriers for the treatment of inflammatory bowel disease","authors":"Sidra Altaf ,&nbsp;Mahira Zeeshan ,&nbsp;Hussain Ali ,&nbsp;Ahmed Zeb ,&nbsp;Iqra Afzal ,&nbsp;Ayesha Imran ,&nbsp;Danish Mazhar ,&nbsp;Salman Khan ,&nbsp;Fawad Ali Shah","doi":"10.1016/j.ejpb.2024.114461","DOIUrl":"10.1016/j.ejpb.2024.114461","url":null,"abstract":"<div><div>Inflammatory Bowel Disease is the chronic tissue inflammation of the lower part of the Gastrointestinal tract (GIT). Conventional therapeutic approaches face numerous challenges, often making the delivery system inadequate for treating the disease. This study aimed to integrate a pH-sensitive polymer and nanostructured lipid carriers (NLCs) to develop a hybrid nanocarrier system. Tacrolimus-loaded NLCs coated with Eudragit® FS100 (TAC-NLCs/E FS100) nanoparticles were prepared via double emulsion technique followed by an aqueous enteric coating technique. Various parameters, such as particle size, entrapment efficiency, and zeta potential were optimized using Design Expert software®. Cetyltrimethyl ammonium bromide (CTAB) was used as a cationic surfactant which induces a positive charge on the nanoparticles. These cationic NLCs can adhere to the mucosal surface, thereby enabling prolonged retention. In vitro drug release was assessed, and the results demonstrated that drug release was retarded at pH 1.2 corresponding to upper GIT pH and maximum drug was released at pH 7.4 (colonic pH). Moreover, we evaluated TAC-NLCs/E FS100 nanoparticles in murine colitis models to gauge the efficacy of both coated and uncoated NLCs formulation. The TAC-NLCs/E FS100 showed a pronounced reduction in induced colitis, as evident from the restoration of morphological features, improved histopathological scores, antioxidant levels, and decreased the levels of proinflammatory cytokines. Thus, pH-sensitive TAC-NLCs/EFS 100 are attributed to the enhanced localization and targeted delivery at the specific site.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"204 ","pages":"Article 114461"},"PeriodicalIF":4.4,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282534","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":"Inhibition of influenza virus infection in mice by pulmonary administration of a spray dried antiviral drug","authors":"Rick Heida ,&nbsp;Paulo H. Jacob Silva ,&nbsp;Renate Akkerman ,&nbsp;Jill Moser ,&nbsp;Jacqueline de Vries-Idema ,&nbsp;Aurélien Bornet ,&nbsp;Sujeet Pawar ,&nbsp;Francesco Stellacci ,&nbsp;Henderik W. Frijlink ,&nbsp;Anke L.W. Huckriede ,&nbsp;Wouter L.J. Hinrichs","doi":"10.1016/j.ejpb.2024.114507","DOIUrl":"10.1016/j.ejpb.2024.114507","url":null,"abstract":"<div><p>Increasing resistance to antiviral drugs approved for the treatment of influenza urges the development of novel compounds. Ideally, this should be complemented by a careful consideration of the administration route. 6′siallyllactosamine-functionalized β-cyclodextrin (CD-6′SLN) is a novel entry inhibitor that acts as a mimic of the primary attachment receptor of influenza, sialic acid. In this study, we aimed to develop a dry powder formulation of CD-6′SLN to assess its in vivo antiviral activity after administration via the pulmonary route. By means of spray drying the compound together with trileucine, a dispersion enhancer, we created a powder that retained the antiviral effect of the drug, remained stable under elevated temperature conditions and performed well in a dry powder inhaler. To test the efficacy of the dry powder drug against influenza infection in vivo, infected mice were treated with CD-6′SLN using an aerosol generator that allowed for the controlled administration of powder formulations to the lungs of mice. CD-6′SLN was effective in mitigating the course of the disease compared to the control groups, reflected by lower disease activity scores and by the prevention of virus-induced IL-6 production. Our data show that CD-6′SLN can be formulated as a stable dry powder that is suitable for use in a dry powder inhaler and is effective when administered via the pulmonary route to influenza-infected mice.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"204 ","pages":"Article 114507"},"PeriodicalIF":4.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0939641124003333/pdfft?md5=4d9f9df06c924b8074f1e7a658edf23a&pid=1-s2.0-S0939641124003333-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142270679","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}

{"title":"Hydrophobic solid lipid-based microparticles for the protection of gastric-sensitive hydrophilic active biomolecules for oral administration in the treatment of EPI","authors":"Alexis Bages ,&nbsp;Mickaël Castelain ,&nbsp;Nicolas Dietrich ,&nbsp;Rosanne Raynal ,&nbsp;Karim Ioualalen","doi":"10.1016/j.ejpb.2024.114504","DOIUrl":"10.1016/j.ejpb.2024.114504","url":null,"abstract":"<div><div>Exocrine Pancreatic Insufficiency (EPI), induced by conditions such as cystic fibrosis, chronic pancreatitis, and Crohn’s disease, is a frequently overlooked and underdiagnosed gastrointestinal disorder. It leads to inadequate intestinal digestion due to insufficient secretion of pancreatic juice, resulting in discomfort, pain, and ultimately severe malnutrition. Despite numerous treatments proving ineffective over the past three decades, a strictly hydrophobic solid lipid formulation, administered orally, is proposed in this study to restore digestive function. This technology relies on the hydrophobic nature of the matrix to physically protect the hydrophilic active principle from the gastric environment while enabling its immediate release in the duodenum by targeting the amphiphilic nature of bile salts. Results demonstrate that this formulation effectively protects an acid-sensitive active ingredient during gastric passage (Simulated Gastric Fluid or SGF), facilitating its rapid release upon entering an artificial duodenal environment (Simulated Intestinal Fluid or SIF). Furthermore, it has been demonstrated that the preservation of a protein-based active ingredient extends beyond its primary protein structure to include its functional aspects, such as enzymatic activity. This drug delivery technology could enable the protection of hydrophilic active biomolecules, such as pancreatin, which are sensitive to gastric acidity, while promoting their immediate release upon contact with bile salts in the proximal duodenum, with the ultimate goal of correcting the digestive defect induced by EPI.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"204 ","pages":"Article 114504"},"PeriodicalIF":4.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282517","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":"Enhanced photodynamic therapy of curcumin using biodegradable PLGA coated mesoporous silica nanoparticles","authors":"Muhammad Umair Amin ,&nbsp;Sajid Ali ,&nbsp;Konrad H. Engelhardt ,&nbsp;Usman Nasrullah ,&nbsp;Eduard Preis ,&nbsp;Jens Schaefer ,&nbsp;Josef Pfeilschifter ,&nbsp;Udo Bakowsky","doi":"10.1016/j.ejpb.2024.114503","DOIUrl":"10.1016/j.ejpb.2024.114503","url":null,"abstract":"<div><div>Since the available treatments are not highly effective to combat cancer, therefore, the alternative strategies are unavoidable. Photodynamic therapy (PDT) is one of the emerging approaches which is target specific and minimally invasive. This study explores the successful development of Poly (D,L-lactide-co-glycolide) (PLGA) coated mesoporous silica nanoparticles (MSNs) and their augmented effects achieved by integrating curcumin (Cur) and cetyltrimethylammonium bromide (CTAB) in the polymeric layer and silica’s pores, respectively. The synthesized nanocarriers (Cur-PLGA-cMSNs) have shown preferential targeting to the cellular organelles facilitated by CTAB’s and Cur’s affinity to mitochondria. CTAB and Cur-based PDT induced oxidative stress and generation of reactive oxygen species (ROS), resulting in dysfunctional mitochondria and triggered apoptotic pathways. PLGA coating has produced multifunctional effects, including; gatekeeping effects at pore openings, providing an extra loading site, enhancing the hemocompatibility of MSNs, and masking the free cur-related prolonged coagulation time. Cur-PLGA-cMSNs, as a multifaceted and combative approach with synergistic effects demonstrate promising potential to enhance outcomes in cancer treatment.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"204 ","pages":"Article 114503"},"PeriodicalIF":4.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0939641124003291/pdfft?md5=4c737250f21726a79db9be66c1b4ad91&pid=1-s2.0-S0939641124003291-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282516","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}

{"title":"Utilizing a hydrophobic primary container surface to reduce the formation of subvisible particles in monoclonal antibody solution caused by fluid shear","authors":"Xinyue Wang ,&nbsp;Junjie Wang ,&nbsp;Yang Han ,&nbsp;Xingchun Jiang ,&nbsp;Sixian Cao ,&nbsp;Dongze Xu ,&nbsp;Tiancheng Xiong ,&nbsp;Xiang Guo ,&nbsp;Cui Wang ,&nbsp;Sha Guo ,&nbsp;Hongying Song ,&nbsp;Ting Dong ,&nbsp;Le Zhang ,&nbsp;Zhenming An ,&nbsp;Jun Liu ,&nbsp;Jing Han ,&nbsp;Hao Wu","doi":"10.1016/j.ejpb.2024.114502","DOIUrl":"10.1016/j.ejpb.2024.114502","url":null,"abstract":"<div><div>The exposure of protein molecules to interfaces may cause protein aggregation and particle formation in protein formulations, especially hydrophobic interfaces, which may promote protein aggregation in solution. In this study, we found that modification of the surface properties by application of a hydrophobic Octadecyltrichlorosilane (OTS) could reduce the generation of protein aggregates and particles in protein solution induced by fluid shear. A stable protein adsorption layer was formed at the hydrophobic interface through the strong hydrophobic interaction between the protein and hydrophobic surface, which could prevent the aggregated protein from falling off into the bulk solution to form subvisible particles and insoluble protein aggregates. In addition, human complement enzyme linked immunosorbent assay results showed that the particles that were generated in the OTS-coated container did not activate human complement which indicated the OTS-coated container could be used as primary containers for certain types of monoclonal antibody formulation.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"204 ","pages":"Article 114502"},"PeriodicalIF":4.4,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282536","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":"Dosage by design – 3D printing individualized cabozantinib tablets with immediate release","authors":"Jonas Lenhart,&nbsp;Dominique J. Lunter","doi":"10.1016/j.ejpb.2024.114501","DOIUrl":"10.1016/j.ejpb.2024.114501","url":null,"abstract":"<div><div>Production of patient-specific dosage forms is important to improve patient adherence and effectiveness while reducing the prevalence and severity of adverse effects. Due to its possibility of rapid prototyping 3D printing can be used to produce individual dosages while utilizing techniques such as hot melt extrusion to increase the bioavailability of poorly soluble drugs. In this work, Parteck MXP and Kollicoat IR were used as water-soluble polymer bases for formulation development for 3D printing of various dosages incorporating cabozantinib while enabling immediate release. The effect of tablet design and the excipients sorbitol, croscarmellose sodium, and sodium starch glycolate was investigated for this goal. A way to calculate the size of tablets for predetermined dosages is proposed to enable the printing of individual strengths from one formulation. Rheological data were collected to deepen the understanding of the role of melt viscosity in 3D printing and hot melt extrusion processes. The production of immediate-release cabozantinib tablets containing every therapeutically relevant dosage in a single unit produced by two-step 3D printing was realized.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"204 ","pages":"Article 114501"},"PeriodicalIF":4.4,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0939641124003278/pdfft?md5=51bc06c5a32ccc2ffa4abcaf1de58807&pid=1-s2.0-S0939641124003278-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282515","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}

{"title":"Dissolving microneedle patches for delivery of amniotic mesenchymal stem cell metabolite products for skin regeneration in UV-aging induced mice","authors":"Andang Miatmoko ,&nbsp;Berlian Sarasitha Hariawan ,&nbsp;Devy Maulidya Cahyani ,&nbsp;Qonita Kurnia Anjani ,&nbsp;Febri Annuryanti ,&nbsp;Rifda Tarimi Octavia ,&nbsp;Djoko Legowo ,&nbsp;Kusuma Eko Purwantari ,&nbsp;Noorma Rosita ,&nbsp;Purwati ,&nbsp;Ryan F. Donnelly ,&nbsp;Dewi Melani Hariyadi","doi":"10.1016/j.ejpb.2024.114482","DOIUrl":"10.1016/j.ejpb.2024.114482","url":null,"abstract":"<div><p>Microneedles offer a promising solution to enhancing dermal delivery of amniotic mesenchymal stem cell metabolite product (AMSC-MP), which contains hydrophilic protein components with high molecular weight, for the purposes of skin rejuvenation and improving human health. This study aimed to evaluate the physicochemical characteristics and in vivo efficacy of AMSC-MP-loaded microneedle patches for effectively regenerating skin tissues in UV-aging induced mice. Dissolving microneedle patches, composed of polyvinyl alcohol with an MW of 9–10 kDa and polyvinylpyrrolidone with an MW of 56 kDa, were fabricated using the double-casting method at three AMSC-MP concentrations: i.e., 30 % (MN30), 25 % (MN25), and 20 % (MN20). The microneedles patches were then evaluated for morphological, mechanical resistance, and insertion properties. An ex vivo release study was also conducted using the Franz cell method, and in vivo efficacy and irritation were then determined through collagen density scores, fibroblast cell counts, and skin irritation studies of UV-aging induced mice. The AMSC-MP microneedles displayed a pyramidal shape with 500 µm sharp tips. Mechanical testing revealed that MN30 achieved its deepest insertion into Parafilm® M (447.44 ± 37.21 µm), while MN25 achieved its deepest insertion into full-thickness porcine skin (717.92 ± 25.40 µm). The study revealed a controlled EGF release for up to 24 h, with MN20 exhibiting the highest deposition (55.94 ± 12.34 %). These findings demonstrate the successful penetration of microneedles through the stratum corneum and viable epidermis. Collagen density scores and fibroblast cell counts were significantly higher in all microneedle formulations than the control, with MN30 having the highest values. Inflammatory cell counts indicated minimal presence suggesting non-irritation in the in vivo study. Dissolving microneedle patches exhibited favorable characteristics and efficiently delivered AMSC-MP with minimal potential for irritation, providing potential technology for delivering biological anti-aging agents for the purposes of fostering skin regeneration.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"204 ","pages":"Article 114482"},"PeriodicalIF":4.4,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142232231","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":"Double-layer dissolving microneedles for delivery of mesenchymal stem cell Secretome: Formulation, characterisation and skin irritation study","authors":"Avelia Devina Calista Nainggolan ,&nbsp;Pietradewi Hartrianti ,&nbsp;Qonita Kurnia Anjani ,&nbsp;Ryan F. Donnelly ,&nbsp;Agus Budiawan Naro Putra ,&nbsp;Katherine Kho ,&nbsp;Arief Kurniawan ,&nbsp;Rr. Kirana Andranilla ,&nbsp;Shereen Angelina Rattu ,&nbsp;Delly Ramadon","doi":"10.1016/j.ejpb.2024.114495","DOIUrl":"10.1016/j.ejpb.2024.114495","url":null,"abstract":"<div><p>Regenerative therapy based on stem cells have been developed, focusing on either stem cell or secretome delivery. Most marketed cellular and gene therapy products are available as injectable dosage forms, leading to several limitations requiring alternative routes, such as the intradermal route. Microneedles, capable of penetrating<!--> <!-->the <em>stratum corneum</em> <!-->barrier, offer a potential alternative for intradermal delivery. This present study aimed to develop double-layer dissolving microneedles (DMN) for the delivery of freeze-dried mesenchymal stem cell secretome. DMNs were fabricated using a two-step casting method and composed of two polymer combinations: poly(vinyl pyrrolidone) (PVP) with poly(vinyl alcohol) (PVA) or PVP with sodium hyaluronate (SH). The manufactured DMNs underwent assessments for morphology, mechanical strength, in skin dissolution, protein content, <em>in vitro</em> permeation, <em>in vivo</em> skin irritation, and physical stability. Based on evaluations of morphology and mechanical strength, two formulas (F5 and F12) met acceptance criteria. Evaluation of protein content revealed that F12 (PVP-SH combination) had a higher protein content than F5 (PVP-PVA combination), 99.02 ± 3.24 μg and 78.36 ± 3.75 μg respectively. <em>In vitro</em> permeation studies showed that F5 delivered secretome protein by 100.84 ± 0.88%, while F12 delivered 99.63 ± 9.21% in 24 h. After four days of observation on<!--> <em>Sprague-Dawley</em> <!-->rat’s skin, no signs of irritation, such as oedema and redness, was observed after applying both formulations. The safety of using PVP-PVA and PVP-SH combinations as excipients for DMN secretome delivery has been confirmed, promising significant advancements in biotherapeutic development in the future.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"204 ","pages":"Article 114495"},"PeriodicalIF":4.4,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142270677","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}