European Journal of Pharmaceutics and Biopharmaceutics最新文献

{"title":"Exploring the physicochemical interactions and loading strategies of mesoporous silicon dioxide nanoparticles for drug delivery","authors":"Svetlana Yu. Kovtareva ,&nbsp;Eldar E. Kopishev ,&nbsp;Hongbo Zhang ,&nbsp;Sergey K. Filippov","doi":"10.1016/j.ejpb.2025.114654","DOIUrl":"10.1016/j.ejpb.2025.114654","url":null,"abstract":"<div><div>Mesoporous silica nanoparticles play an important role in drug delivery due to their high surface area, porous structure, tunable pore size, chemical stability and functionalization capability. Such properties make them a good candidate for drug encapsulation. However, molecular binding is another parameter that govern drug loading apart of pores’ structure and size. There is a lack of comprehensive reviews on that topic nowadays. This paper overviews the latest publications on the physicochemical aspects of the interaction of mesoporous silica nanoparticles with drugs. The review is focused primarily on a such parameters of the intermolecular binding between a drug and silica nanoparticle as a binding constant, enthalpy and entropy changes and experimental methods with the emphasis on the principles of thermodynamic parameters characterization. Such information would be very important for the development and optimization of drug delivery strategies based on mesoporous silica nanoparticles.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"208 ","pages":"Article 114654"},"PeriodicalIF":4.4,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254960","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":"Alteration of gel point of poloxamer 338 induced by pharmaceutical actives and excipients","authors":"Natalie Deiringer,&nbsp;Fabian Fischer,&nbsp;Martin Hofsäss,&nbsp;Meik Ranft,&nbsp;Sophia Ebert","doi":"10.1016/j.ejpb.2025.114628","DOIUrl":"10.1016/j.ejpb.2025.114628","url":null,"abstract":"<div><div>Poloxamer 338 is used as versatile thermo-responsive gelling agent in topical and sub-cutaneous applications. Due to application specific needs a gel point below body or even below room temperature is required. The influence of inorganic salts and active pharmaceutical ingredients (APIs) on the gel point was investigated using oscillatory rheology to identify the driving forces and predictors for gel point alteration. While most inorganic salts decreased the gel point, API salts exhibited an increase. Consistent with previous findings, the extent of gel point alteration caused by inorganic salts could be empirically described by the Hofmeister series, primarily influenced by the anion. Notably, this study revealed a concentration-dependent increase in the gel point in the presence of API salts. Moreover, this increase could be accurately predicted in a linear manner by considering the respective logP value. By utilizing the proposed prediction model, the effect of API addition on the gel point can be estimated, facilitating formulation development to achieve the desired gelling behavior for specific applications.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"207 ","pages":"Article 114628"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970234","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":"Robust near-infrared modeling for pharmaceutical powder streams: External variable augmented iterative optimization technology (EVA-IOT)","authors":"Natasha L. Velez-Silva,&nbsp;Adam J. Rish,&nbsp;James K. Drennen III,&nbsp;Carl A. Anderson","doi":"10.1016/j.ejpb.2025.114626","DOIUrl":"10.1016/j.ejpb.2025.114626","url":null,"abstract":"<div><div>The adoption of pure component models, such as iterative optimization technology (IOT) algorithms, is gaining significant interest in the pharmaceutical industry, primarily because of their calibration-free/minimal calibration requirements for process analytical technology applications. The IOT methods have recently demonstrated great potential for monitoring the quality of continuous powder mixtures by near-infrared (NIR) spectroscopy. However, the dynamic conditions of continuous manufacturing processes may limit the effectiveness of such approaches. Density variations introduced to NIR spectra that are collected from dynamic powder mixtures at different process conditions is detrimental to the drug prediction accuracy and robustness of IOT methods. This work introduces a new method, called external variable augmented iterative optimization technology (EVA-IOT), which incorporates the shape of non-chemical external sources of variability into the pure component spectra matrix to improve the prediction accuracy and robustness of the base IOT algorithm. This approach derives the shape of non-chemical external variables from the latent structure of decomposition methods using NIR spectra acquired from a single mixture at known levels of the external variable. A density-augmented EVA-IOT method was developed and implemented to quantify the active pharmaceutical ingredient (API) in continuous powder mixtures flowing at varying process conditions in a simulated continuous process. The EVA-IOT method demonstrated a significantly enhanced API prediction accuracy and robustness against process variation compared to alternative IOT methods. The overall prediction performance of EVA-IOT was comparable to that of global partial least square (PLS) regression models while reducing the calibration burden up to 97%. This makes EVA-IOT a material-sparing alternative to calibration-intensive robust decomposition modeling approaches for monitoring the quality of continuous pharmaceutical powder streams.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"207 ","pages":"Article 114626"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143002751","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":"A novel levodopa-carbidopa three-layer gastroretentive tablet for improving levodopa pharmacokinetics","authors":"Xiangcheng Zhao ,&nbsp;Peng Yan ,&nbsp;Hailong Zhang ,&nbsp;Wenhu Zhou ,&nbsp;Jinsong Ding","doi":"10.1016/j.ejpb.2025.114633","DOIUrl":"10.1016/j.ejpb.2025.114633","url":null,"abstract":"<div><div>The narrow absorption window of levodopa and the significant impact of peripheral decarboxylase are the most limiting factors in maintaining prolonged and smooth plasma concentration in patients with Parkinson’s disease (PD). Therefore, this study aims to design a novel gastroretentive carbidopa-levodopa three-layer tablet, which consists of an expansion layer, an immediate-release layer, and a sustained-release layer. The expansion layer rapidly expanded with sufficient structural strength and stayed in the beagle’s stomach for more than 10 h, delineating excellent gastric retention effects. The immediate-release layer quickly released the drug and the sustained-release layer maintained a stable drug concentration. Importantly, pharmacokinetic data obtained under fed conditions demonstrated that the duration of efficacy of the three-layer tablets was significantly superior to that of the commercially available product Sinemet® CR, with effective levodopa blood levels remaining for up to 12 h. This is expected to offer more convenient clinical medication options for patients with PD.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"207 ","pages":"Article 114633"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143002565","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":"Effect of protein corona on drug release behavior of PLGA nanoparticles","authors":"Damla Kelle ,&nbsp;Kai R. Speth ,&nbsp;María Martínez-Negro ,&nbsp;Volker Mailänder ,&nbsp;Katharina Landfester ,&nbsp;Banu Iyisan","doi":"10.1016/j.ejpb.2024.114611","DOIUrl":"10.1016/j.ejpb.2024.114611","url":null,"abstract":"<div><div>Poly(lactic-co-glycolide) (PLGA) nanoparticles are highly attractive for drug delivery due to their biocompatibility, biodegradability, and potential for controlled release and targeting. Despite these outstanding properties, challenges remain for clinical translation as nanomedicines. One significant factor to address is highlighting the protein corona structure and its effect on the drug release behavior. Protein corona forms upon contact with the bloodstream and influences the fate of the nanoparticles in the body. Here, we synthesize PLGA nanoparticles by miniemulsion/solvent evaporation technique, followed by the formation of protein corona on their surface using either human plasma or fetal bovine serum (FBS). Analysis by both sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) and liquid chromatography-mass spectrometry (LC-MS) reveals that dysopsonin proteins, mainly albumin, dominate the protein corona structure, suggesting prolonged blood circulation for the PLGA nanoparticles. As an anticancer drug, doxorubicin is encapsulated into PLGA nanoparticles, and <em>in vitro</em> drug release is performed at pH 7.4. While there is a minimal change in cumulative drug release after protein corona formation, our comprehensive analysis through different kinetic models shows that the protein corona alters the drug release profile of PLGA nanoparticles to a modest extent.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"207 ","pages":"Article 114611"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823811","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 naproxen crystallization by polymers: The role of topology and chain length of polyvinylpyrrolidone macromolecules","authors":"Luiza Orszulak ,&nbsp;Patryk Włodarczyk ,&nbsp;Barbara Hachuła ,&nbsp;Taoufik Lamrani ,&nbsp;Karolina Jurkiewicz ,&nbsp;Magdalena Tarnacka ,&nbsp;Marek Hreczka ,&nbsp;Kamil Kamiński ,&nbsp;Ewa Kamińska","doi":"10.1016/j.ejpb.2024.114581","DOIUrl":"10.1016/j.ejpb.2024.114581","url":null,"abstract":"<div><div>This paper presents an innovative approach that utilizes self-synthesized homopolymers of polyvinylpyrrolidone (PVP) with different architectures as effective matrices for inhibiting the crystallization of naproxen (NAP). We have thoroughly investigated amorphous solid dispersions containing NAP and (<em>i</em>) self-synthesized linear PVP, (<em>ii</em>) self-synthesized three-armed star-shaped PVP, and (<em>iii</em>) self-synthesized linear PVP with a mass (M_n) corresponding to the length of one arm of the star polymer, as well as (<em>iv</em>) commercial linear PVP K30 as a reference. Differential scanning calorimetry, X-ray diffraction, and infrared spectroscopy studies, as well as molecular dynamics simulations were conducted to gain comprehensive insights into the thermal and structural properties, as well as intermolecular interactions in the NAP-PVP systems. The main purpose of all experiments was to assess the impact of macromolecule structure (topology, molecular weight) on the kinetics of the crystallization of NAP – a drug that is very difficult to vitrify. Our studies clearly showed that the most effective matrix in inhibiting the NAP crystallization is linear, self-synthesized PVP with higher molecular weight (M_n) similar to that of the commercial PVP K30, but lower, strictly controlled dispersity. We also found that crystallization of API proceeds at a similar pace for the binary mixture composed of a star-shaped PVP and linear polymer with M_n corresponding to M_n of one arm of the star-shaped macromolecule in the vicinity of the <em>T</em>_g. The obtained data highlight the key role of polymer structure in designing new pharmaceutical formulations.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"207 ","pages":"Article 114581"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142750493","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":"In vivo systemic evaluation of nasal drug absorption from powder formulations in rats","authors":"Ryosuke Tatsuta ,&nbsp;Akiko Tanaka ,&nbsp;Ken-ichi Ogawara ,&nbsp;Kazutaka Higaki ,&nbsp;Tomoyuki Furubayashi ,&nbsp;Toshiyasu Sakane","doi":"10.1016/j.ejpb.2024.114612","DOIUrl":"10.1016/j.ejpb.2024.114612","url":null,"abstract":"<div><div>Despite the potential benefits of nasal drug delivery, there is a need for a systematic evaluation of the efficacy of powder formulations adhering to the nasal mucosa. This study aims to establish a systematic evaluation method for nasal drug absorption from powder formulations. We selected three model compounds—antipyrine, griseofulvin, and acyclovir—and analyzed their pharmacokinetics following nasal administration of powder formulations under physiological conditions. Our experimental design incorporated assessments of the drug absorption patterns. Antipyrine demonstrated rapid absorption exclusively from the nasal cavity. In contrast, griseofulvin exhibited absorption from the nasal cavity and the gastrointestinal tract. This phenomenon could be attributed to the rapid nasal clearance of the drug with an initial half-life of 5 min. To further establish the physiological validity of our method, we conducted an experiment to investigate the impact of changing the mucociliary clearance (MC) on nasal absorption that resulted in a 1.2-fold increase in the bioavailability of acyclovir upon prolonged MC. Our findings support the utility of established methods in evaluating nasal absorption and their behavior in the nasal cavity. This study holds a promising advancement toward effective drug delivery via nasal administration, potentially leading to targeted delivery and improved therapeutic outcomes.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"207 ","pages":"Article 114612"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817541","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":"Stearic acid-capped mesoporous silica microparticles as novel needle-like-structured drug delivery carriers","authors":"Mohamad Anas Al Tahan ,&nbsp;Ali Al-Khattawi ,&nbsp;Craig Russell","doi":"10.1016/j.ejpb.2024.114619","DOIUrl":"10.1016/j.ejpb.2024.114619","url":null,"abstract":"<div><div>Mesoporous silica are widely utilised as drug carriers due to their large pore volume and surface area, which facilitate effective loading. Additionally, they can be used to enhance drugs stability and protect against enzymatic degradation due to their silica framework. However, without the addition of a capping material, the loaded cargo may be prematurely released before reaching the target site. This work reports the functionalisation of a commercially available silica microparticle (SYLOID XDP 3050) with stearic acid at various stearic acid loading concentrations (20–120 % w/w). Scanning electron microscopy (SEM) analysis revealed that the pores were capped with stearic acid, with the filling ratio increasing proportionally to the loading concentration. Notably, needle-like structures appeared when the stearic acid amount exceeded 80 % w/w, surpassing the calculated theoretical maximum pore filling ratio (64.32 %). The molecular interactions were highlighted using Fourier-transform infrared spectroscopy (FTIR), as the intensity of the CH₃ increased with increased stearic acid loading concentrations. The needle-structures phenomenon was corroborated by 3D confocal imaging. It utilised the autofluorescence properties of stearic acid to demonstrate its presence within the carrier, with fluorescence intensity increasing alongside the stearic acid concentration. Differential scanning calorimetry (DSC) indicated the crystalline nature of these needle structures, which was further confirmed by X-ray diffraction (XRD) analysis, validating the crystallisation of the stearic acid needles. Moreover, nitrogen porosimetry was employed to assess the pore volume and surface area, where the formulation containing 120 % stearic acid exhibited the lowest pore volume (0.59 cc). This value was smaller than unloaded SYLOID (2.1 cc), indicating near-complete filling of the carrier. This newly developed SYLOID-stearic acid carrier will now be used to enhance formulation development as a platform to enhance protein oral drug delivery.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"207 ","pages":"Article 114619"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881221","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":"Fishroesomes show intrinsic anti-inflammatory bioactivity and ability as celecoxib carriers in vivo","authors":"Marta Guedes ,&nbsp;Joana Vieira de Castro ,&nbsp;Ana Cláudia Lima ,&nbsp;Virgínia M. F. Gonçalves ,&nbsp;Maria Elizabeth Tiritan ,&nbsp;Rui L. Reis ,&nbsp;Helena Ferreira ,&nbsp;Nuno M. Neves","doi":"10.1016/j.ejpb.2024.114587","DOIUrl":"10.1016/j.ejpb.2024.114587","url":null,"abstract":"<div><div>According to the World Health Organization (WHO), chronic inflammatory-related diseases represent the greatest threat to human health. Indeed, failure in the resolution of inflammation leads to serious pathological conditions, such as cardiovascular diseases, arthritis, cancer, diabetes, autoimmune diseases, and neurodegenerative disorders that are often associated with extremely high human suffering and societal and economic burdens. Despite the number and efficacy of available therapeutic agents have been increased, the serious side effects associated with some of them often create a very high risk/benefit ratio for patients. Therefore, herein, a drug delivery system was engineered to overcome important drawbacks of conventional therapies and to have a synergistic action with the incorporated drug. Indeed, it will have an added beneficial role in controlling inflammation. For that, sardine (<em>Sardina pilchardus</em>) roe was used as the lipidic source to produce bioactive liposomes, namely fishroesomes. These spherical vesicles with ≈326 nm in size and a significant negative surface charge (≈-31 mV) were able to encapsulate and control the release of the anti-inflammatory drug celecoxib. Moreover, fishroesomes were cytocompatible for different cell types (chondrocytes and macrophages), at concentrations in which they present anti-inflammatory properties. Importantly, fishroesomes were more effective in reducing pro-inflammatory mediators than the free drug. We also demonstrated that a single intra-articular injection of the fishroesomes encapsulating or not celecoxib in an experimental rat model of inflammatory arthritis was safe and more effective in controlling the pain and reducing the synovial inflammation compared to the free drug. Notably, as the celecoxib concentration in the sardine roe-derived liposomes was less than half of the amount of free drug, this study demonstrates the value of fishroesomes in counteracting inflammation. Therefore, the developed formulations may be considered a promising therapeutic option for inflammatory conditions.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"207 ","pages":"Article 114587"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791338","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":"Nanomedicine for pediatric healthcare: A review of the current state and future prospectives","authors":"Jiayi Chen,&nbsp;Zhifeng Zhao,&nbsp;Doaa Alantary,&nbsp;Jingjun Huang","doi":"10.1016/j.ejpb.2024.114597","DOIUrl":"10.1016/j.ejpb.2024.114597","url":null,"abstract":"<div><div>Nanomedicine has emerged as a valuable treatment and diagnosis option, due to its ability not only to address formulation challenges associated with new therapeutic moieties, but also to improve the existing drugs efficacy. Nanomedicine provides appealing advantages such as increased drug payload, enhanced stability, tailored drug release profile, improved bioavailability and targeted drug delivery, etc. Tremendous research and regulatory efforts have been made in the past decades to advance nanomedicine from the benchtop to clinic. Numerous nanotechnology-based formulation approaches have been seen succeeding in commercialization. Despite the progress in nanomedicine use in adults, the advancement in pediatric population has been much slower. Clearly the treatment of disease in children cannot be simplified by dose adjustment based on body weight or surface, due to the significant differences in physiology thus the drug absorption, distribution, metabolism, excretion and transport (ADMET), between children and adults. This inherent variable among others poses much more challenges when developing pediatric-specific nanomedicine or translating adult nanodrug to pediatric indication. This review therefore intends to highlight the physiological differences between children and adult, and the common pediatric diseases which are good candidates for nanomedicine. The formulation approaches utilized in the marketed nanomedicine with pediatric indications, including liposomes, nanocrystals, polymeric nanoparticles and lipid nanoemulsions are elaborated. Finally, the challenges and gaps in pediatric nanomedicine development and commercialization, and the future prospectives are discussed.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"207 ","pages":"Article 114597"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794402","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}