Pharmaceutical Development and Technology最新文献

{"title":"Formulation and optimization of glycyrrhetinic acid-modified pH-sensitive curcumin liposomes for anti-hepatocellular carcinoma.","authors":"Jie Wang, Xuemei Gu, Xia Gao, Jing Chen, Zhiyang Lv, Siyu Zhang, Siyu Ni, Fei Shi, Xialin Chen, Liang Cao, Zhenzhong Wang, Wei Xiao","doi":"10.1080/10837450.2025.2465549","DOIUrl":"10.1080/10837450.2025.2465549","url":null,"abstract":"<p><p>In order to enhance the therapeutic value of curcumin in liver cancer treatment, glycyrrhetinic acid-modified pH-sensitive curcumin liposomes (GA-pH-Lip@Cur) was developed.GA-pH-Lip@Cur was prepared using a thin film dispersion ultrasonication method, and the optimal formulation process was selected through single-factor experiments and a Box-Behnken design-response surface methodology. The liposomes were evaluated for their morphological appearance, particle size, <i>in vitro</i> release at different pH levels, and biocompatibility. The anti-tumor effect of GA-pH-Lip@Cur was assessed using cell viability assays (CCK-8). The <i>in vivo</i> hepatic targeting and anti-liver tumor efficacy of GA-pH-Lip@Cur were evaluated through pharmacokinetic and pharmacological experiments. The results indicated that optimized GA-pH-Lip@Cur exhibited uniform particle size distribution, good stability, pH-sensitive <i>in vitro</i> release with sustained behavior. Compared to conventional liposomes, GA-pH-Lip@Cur showed prolonged average retention time <i>in vivo</i> and significantly increased curcumin distribution in liver tissues, indicating excellent liver targeting. Both <i>in vitro</i> and <i>in vivo</i> evaluations demonstrated the effectiveness of GA-pH-Lip@Cur in inhibiting liver cancer cell proliferation and suppressing liver tumor growth in tumor-bearing mice. In conclusion, GA-pH-Lip@Cur, by leveraging the acidic tumor microenvironment and overexpression of glycyrrhetinic acid receptors in liver cells, encapsulates curcumin to improve its bioavailability, and target its delivery to the liver tumor sites.</p>","PeriodicalId":20004,"journal":{"name":"Pharmaceutical Development and Technology","volume":" ","pages":"233-245"},"PeriodicalIF":2.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ocular polymeric nanomicelles for the posterior eye segment in the management of retinoblastoma: formulation, optimization, <i>in vitro</i> and <i>ex vivo</i> evaluations.","authors":"Mudassir Ansari, Yogesh A Kulkarni, Kavita Singh","doi":"10.1080/10837450.2025.2469321","DOIUrl":"10.1080/10837450.2025.2469321","url":null,"abstract":"<p><p>The existing study focuses on the development, optimization, and evaluation of sorafenib-loaded polymeric nanomicelles for posterior segment delivery in treating retinoblastoma. The formulation involved adjusting various process and product parameters to create effective drug-loaded polymeric nanomicelles. The particle size, PDI, and zeta potential of optimized formulation were found to be 65.52 ± 1.18 nm, 0.14 ± 0.01, and -3.26 ± 0.66 mV, respectively. The entrapment efficiency and drug release were estimated to be 98.84% ± 0.001 and 99.99% in 6 h, respectively. Additionally, the optimized formulation demonstrated acceptable outcomes for solid-state analysis, osmolality, pH, residual solvent, and morphological properties. After 8 h, the <i>ex vivo</i> transcleral permeation and scleral deposition were 629.05 ± 124.11 ng/cm² and 4.10 ± 0.54 µg, respectively. Y-79 (human retinoblastoma) cell line study using standard drug, test drug, and optimized formulation revealed anticancer potential at all time points (6, 12, 18, and 24 h) with comparable IC50 values. Furthermore, the optimized formulation exhibited no toxicity on the ARPE-19 (human retinal pigmented epithelium) cell line over 24 h. The optimized formulation was non-irritating to the eye (HET-CAM) and remained stable for 6 months. Thus, drug delivery to the posterior eye segment for the treatment of retinoblastoma appears to be possible with the help of established technology.</p>","PeriodicalId":20004,"journal":{"name":"Pharmaceutical Development and Technology","volume":" ","pages":"246-258"},"PeriodicalIF":2.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the application of single-step drying in lyophilization of high protein concentration formulations.","authors":"Qi Zeng, Zhaowei Jin, Jeremy Guo","doi":"10.1080/10837450.2025.2476707","DOIUrl":"10.1080/10837450.2025.2476707","url":null,"abstract":"<p><strong>Objectives: </strong>Single-step drying integrates sublimation and desorption process in one step. The applicability of single-step drying in high protein concentration formulations with or without viscosity reducers remains to be explored. And drying behavior of single-step drying remains to be monitored.</p><p><strong>Methods: </strong>Firstly, in formulations without viscosity reducers (sucrose and mannitol), the method of single-step drying at shelf temperature (Ts) of 25 °C and chamber pressure (Pc) of 0.3 mbar with aggressive annealing (-3 °C) was tested; secondly, two viscosity reducers (ArgHCl and NaCl) were applied to further explore the application of single-step drying in viscosity reducer-containing formulations; finally, drying behavior of single-step drying was monitored in real time by tunable diode laser absorption spectroscopy(TDLAS).</p><p><strong>Results: </strong>In single-step drying process, significant cycle time reduction (68%) was achieved compared to traditional two-step drying. Good cake appearance was observed in all formulation combinations with comparable pre- and post-lyophilization quality attributes as well as reconstitution time. Three times faster sublimation rate was monitored in single-step drying process compared to traditional two-step drying.</p><p><strong>Conclusion: </strong>Single-step drying was proved to be applicable to high protein concentration formulations with or without viscosity reducers. Significant cycle time reduction in drying process was achieved. Sublimation rate resulted in a more efficient drying cycle as a whole even though an increase of product resistance.</p>","PeriodicalId":20004,"journal":{"name":"Pharmaceutical Development and Technology","volume":" ","pages":"342-349"},"PeriodicalIF":2.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ezetimibe oral solid lipid nanoparticle by effervescent dispersion method: <i>in vitro</i> characterization and <i>in vivo</i> pharmacokinetic study in rats.","authors":"Ruba S Darweesh, Farah S Al-Qawasmi, Mai S Khanfar","doi":"10.1080/10837450.2025.2471461","DOIUrl":"10.1080/10837450.2025.2471461","url":null,"abstract":"<p><p>Ezetimibe (EZT) is a class II drug of the Biopharmaceutics classification system (BCS), with limited aqueous solubility and high permeability. This study aims to enhance the solubility and oral bioavailability of EZT by developing EZT solid lipid nanoparticles (SLNs). EZT-SLNs were developed through the effervescent dispersion technique. Different amounts of Tween-80, Compritol ATO 888, and mannitol as cryoprotectant were used. F11 was the optimum formula with 154 nm in size and 90.26% entrapment efficiency. It demonstrates significant enhancements in solubility across various pH values. In addition, F11 shows a significantly higher drug release than pure EZT at all time points, and that's related to the reduction in the particle size and increasing its surface area along with the transformation from a crystalline state to an amorphous state. The powder X-ray diffraction and Differential Scanning Calorimetry tests confirmed this conversion from crystalline form to amorphous. The <i>in vivo</i> animal study demonstrated that the C_max and <math><mrow><msubsup><mrow><mtext>AUC</mtext></mrow><mrow><mn>0</mn></mrow><mrow><mtext>∞ </mtext></mrow></msubsup></mrow></math> of the EZT-SLNs group were significantly higher than the pure EZT group, after oral administration. In conclusion, EZT-SLNs with enhanced <i>in vitro</i> and <i>in vivo</i> properties were successfully developed using the effervescent dispersion technique.</p>","PeriodicalId":20004,"journal":{"name":"Pharmaceutical Development and Technology","volume":" ","pages":"268-279"},"PeriodicalIF":2.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineering orally disintegrating tablets for buccal delivery of cilostazol with enhanced dissolution and bioavailability: a novel dual porogenic approach, <i>in vitro</i> characterization, and <i>in vivo</i> evaluation in rats.","authors":"Shahinaze A Fouad, Nada Abdelaziz, Mahmoud H Teaima, Mohamed El-Nabarawi, Amal Anwar Taha, Rehab Abdelmonem, Khaled El-Refai","doi":"10.1080/10837450.2025.2472887","DOIUrl":"10.1080/10837450.2025.2472887","url":null,"abstract":"<p><p>Cilostazol (CTZ), is a BCS class II drug with limited bioavailability. In the current study, orally disintegrating tablets (ODTs) for buccal delivery of CTZ were prepared by two methods; lyophilization (Lyo-ODTs) and direct compression (DC-ODTs). All CTZ-ODTs were evaluated for <i>in vitro</i> disintegration time (DT) and wetting time (WT) tests, <i>in vitro</i> dissolution. Scanning electron microscopic (SEM) analysis was performed for the selected Lyo-ODT-7 and DC-ODT-2. Lyo-ODT-7 composed of aerosil^® 200 and PEG 4000 acquired the shortest DT (13.00 ± 0.14) and WT (33.00 ± 0.26) among the prepared ODTs. It also showed a 2.3 fold significantly enhanced dissolution profile at an early time point (5 min) that was maintained till 1 h, in simulated saliva fluid (pH ∼ 6.8), compared to Pletaal^® IR tablets (<i>p</i> < 0.0001). SEM analysis revealed the remarkable porosity of Lyo-ODT-7, confirming its successfully enhanced disintegration and dissolution. Lyo-ODT-7 showed significantly enhanced pharmacokinetic parameters with a 3.5 and 3.6 fold increase in C_max (<i>p</i> = 0.0493) and AUC_0-24 (<i>p</i> = 0.0470), respectively compared to Pletaal^® IR tablets. The relative bioavailability of CTZ after buccal administration of Lyo-ODT-7 to rats was 364.45%, compared to the market oral IR tablets; Pletaal^®. The enhanced bioavailability imposes the successful oromucosal absorption of CTZ <i>via</i> buccal delivery of Lyo-ODT-7. Our study demonstrated that Lyo-ODT-7 could represent a favorable buccal dosage form for patients with intermittent claudication, suffering from dysphagia. It can also be used in cases of acute cerebral or myocardial infarction due to its significantly enhanced rate and extent of absorption. It is considered a promising approach for buccal delivery of BCS class II active pharmaceutical ingredients (APIs) suffering from solubility problems and hepatic first pass effect.</p>","PeriodicalId":20004,"journal":{"name":"Pharmaceutical Development and Technology","volume":" ","pages":"280-294"},"PeriodicalIF":2.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143503322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of therapeutic effectiveness of developed colchicine transnovasomes in treatment of recurrent aphthous ulcer as monotherapy and combination therapy with platelet-rich plasma.","authors":"Soha M Kandil, Iman I Soliman, Marwa Hosni, Abeer Salama, Ebtisam M Abdou","doi":"10.1080/10837450.2025.2475967","DOIUrl":"10.1080/10837450.2025.2475967","url":null,"abstract":"<p><strong>Objectives: </strong>Transnovasomes is a new exciting class of lipid-based nanovesicles. Colchicine (COL) is a hydrophilic natural alkaloid with anti-inflammatory features having oral administration and permeation defects. Recurrent Aphthous Ulcer (RAU) is the most prevalent disease of the oral mucosa suffering from lack of a particular and final preventative therapy. So, designing a prolonged and effective specialized delivery system for ulcer treatment is important.</p><p><strong>Methods: </strong>Colchicine transnovasomes (COL-TNs) were prepared using surfactants (Span 60 & Span 80), free fatty acids (Oleic acid & Stearic acid), Cholesterol and Brij 58. COL-TNs were evaluated for their vesicle size (VS), polydispersity index (PDI), zeta potential (ZP), entrapment efficiency (EE%), and <i>ex-vivo</i> permeation after 12 h (Q_12h).</p><p><strong>Results: </strong>Values of VS, PDI, ZP, EE% and Q_12h of the optimized formulation were 256.74 ± 11.2 nm, 0.322 ± 0.08, -43.3 ± 0.62, 85.35 ± 3.7% and 72.69 ± 5.84% respectively. Drug accumulation from the optimized formulation was ninefold greater than drug solution after 8 h. <i>In-vivo</i>, COL-TNs formulation, alone or in combination with platelet-rich plasma (PRP), achieved complete healing of acetic-acid induced RAU restoring normal levels of assayed biomarkers and normal oral mucosa histological features.</p><p><strong>Conclusions: </strong>COL-TNs can be used as a promising, safe, efficient treatment of RAU, as monotherapy or combination therapy with PRP.</p>","PeriodicalId":20004,"journal":{"name":"Pharmaceutical Development and Technology","volume":" ","pages":"323-341"},"PeriodicalIF":2.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preparation of diltiazem HCl-modified release formulation using cation-exchange resin as a single excipient.","authors":"Khouloud A Alkhamis, Suhair S Al-Nimry","doi":"10.1080/10837450.2025.2474092","DOIUrl":"10.1080/10837450.2025.2474092","url":null,"abstract":"<p><strong>Objective: </strong>Modified released formulations of diltiazem were previously prepared using cation-exchange resins. However, multiple excipients were required to achieve the appropriate release rate. It was of interest to prepare a modified release dosage form of diltiazem using drug-resin complex alone.</p><p><strong>Methods: </strong>Adsorption experiments conducted using a rotating bottle apparatus. The procedure involved adding the resin to the bottles, followed by appropriate amount of drug solution. The bottles were rotated until equilibrium was reached and the concentrations were analyzed using a reversed phase HPLC method, which effectively separated the compound from its degradation product. Release studies were conducted using a USP dissolution apparatus 2 with phosphate buffer as the dissolution medium.</p><p><strong>Key findings: </strong>Diltiazem was unstable inside the resin when the H⁺ form was used. It became stable when the H⁺ was displaced with Na⁺. Langmuir-like equation was applied to the adsorption isotherms. The equation parameters were influenced by the resin's cross-linking and particle size. Maximum drug release is related to sample volume. Positive linear relationship was obtained between initial release rate and extent of uptake.</p><p><strong>Conclusion: </strong>This study successfully demonstrates that Dowex® 50WX8 (Na⁺ form) can be used as a single excipient in diltiazem formulations, providing both chemical stability and sustained release without requiring additional polymer coatings.</p>","PeriodicalId":20004,"journal":{"name":"Pharmaceutical Development and Technology","volume":" ","pages":"306-313"},"PeriodicalIF":2.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143524120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insight into manufacturing of bespoke combination drug products containing carvedilol and simvastatin by fused deposition modeling.","authors":"Lucas Korsgaard Andreasen, Emilie Victoria Slot Andreasen, Wuzhong He, Jukka Rantanen, Natalja Genina","doi":"10.1080/10837450.2025.2475965","DOIUrl":"10.1080/10837450.2025.2475965","url":null,"abstract":"<p><p>The goal of this study was to explore the fabrication of a combination drug product containing two poorly soluble active pharmaceutical ingredients (APIs), carvedilol (CAR) and simvastatin (SIM), in therapeutically relevant doses (25 mg of each API) with a distinct, easily distinguishable shape. Fused deposition modeling, combined with hot-melt extrusion (HME), was used to produce hollow heart-shaped dual-loaded tablets in which the two APIs were spatially separated with an intermediate API-free layer. Water-soluble hydroxypropyl methylcellulose of varying molecular weights was used as the primary polymer for HME. The incorporation of a processability-improving polymer, such as polycaprolactone, was necessary to facilitate the printing of these delicate geometries and lower the printing temperature. The 3D-printed tablets contained the therapeutic doses of both APIs; however, further optimization of manufacturing processes is required to improve drug content uniformity. The drug release from the printed tablets was sustained, with complete release of CAR observed after 24 h, demonstrating the suitability of the designed drug products for oral delivery.</p>","PeriodicalId":20004,"journal":{"name":"Pharmaceutical Development and Technology","volume":" ","pages":"314-322"},"PeriodicalIF":2.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143543001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preparation and characterization of immediate release 3D printed tablets using hot melt extruded amorphous cyclosporine a filament.","authors":"Jin-Hyuk Jeong, Chang-Soo Han, Ji-Hyun Kang, Kwang-Hwi Yoo, Woong-Young Jung, Yun-Sang Park, Dong-Wook Kim, Chun-Woong Park","doi":"10.1080/10837450.2025.2472893","DOIUrl":"10.1080/10837450.2025.2472893","url":null,"abstract":"<p><p>3D printing technology is gaining attention as a next-generation approach to drug formulation. Among 3D printing techniques, fused deposition modeling is cost-effective but depends heavily on suitable filaments. Hot melt extrusion enables filament production by incorporating poorly water-soluble drugs like cyclosporine A into polymers to form solid dispersions. However, achieving immediate release formulations with 3D printing remains challenging due to issues such as inadequate tablet disintegration or drug entrapment within the polymer matrix. This study aimed to develop and evaluate immediate release 3D-printed cyclosporine A tablets using HME filaments. Three parameters were modified in the 3D printing process: varying fill speeds, infill densities, and channel lengths. Filaments composed of Kollidon^® VA 64 and HPC-SSL (1:1) were used to print tablets. Solid-state analysis confirmed cyclosporine A 's amorphous state and partial crystallinity in Xylisorb^® 300. Dissolution studies revealed that lower infill densities (30%) and fewer walls enhanced drug release by increasing internal void space and reducing hardness. Conversely, greater tablet height (channel length) delayed dissolution. These findings emphasize the critical role of geometric design in drug release, showcasing the potential of 3D printing to create personalized dosage forms tailored to patient needs by optimizing structural parameters.</p>","PeriodicalId":20004,"journal":{"name":"Pharmaceutical Development and Technology","volume":" ","pages":"295-305"},"PeriodicalIF":2.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Saccharomyces cerevisiae</i>-derived vesicles loaded with dextromethorphan as a candidate for the management of neuroinflammation related to Alzheimer's disease.","authors":"Parastoo Valizadeh, Negin Mozafari, Hajar Ashrafi, Reza Heidari, Negar Azarpira, Amir Azadi","doi":"10.1080/10837450.2025.2470351","DOIUrl":"10.1080/10837450.2025.2470351","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a neurodegenerative disease that is associated with neuroinflammation. Dextromethorphan (DXM) exerts neuroprotective effects in many central nervous system injuries and neurodegenerative diseases. The cell wall of <i>Saccharomyces cerevisiae</i> is a cell-based drug delivery system that can be a suitable candidate for targeted drug delivery to the site of inflammation. In this study, nanoparticles (NPs) were prepared from <i>Saccharomyces cerevisiae</i> cell walls, coated with polysorbate-80, and loaded with DXM. NPs had favorable hemolytic behavior with a particle size distribution of 187.25 ± 73.37 nm and a zeta potential of +4.3 mV. Pathological examination in a mouse model of neuroinflammation showed that NPs had the ability to reduce brain inflammation and the adverse effects of DXM.</p>","PeriodicalId":20004,"journal":{"name":"Pharmaceutical Development and Technology","volume":" ","pages":"259-267"},"PeriodicalIF":2.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143524119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}