AAPS PharmSciTechPub Date : 2025-06-26DOI: 10.1208/s12249-025-03170-z
Bao Ngoc Tran, Cam Le Ha, Duyen Thi Thuy Vu, Chien Ngoc Nguyen
{"title":"Development and In Vitro Characterization of Azithromycin-PLGA Nanoparticles Loaded Thermoresponsive Hydrogels: A Quality by Design Approach Toward Intra-Articular Delivery of Macrolides.","authors":"Bao Ngoc Tran, Cam Le Ha, Duyen Thi Thuy Vu, Chien Ngoc Nguyen","doi":"10.1208/s12249-025-03170-z","DOIUrl":"https://doi.org/10.1208/s12249-025-03170-z","url":null,"abstract":"<p><p>Azithromycin (AZT), a macrolide antibiotic, has recently been explored as an injection therapy for osteoarthritis. However, its instability and poor solubility limit its effect due to an insufficient quantity and duration at the target sites. To address these challenges, this study developed poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) for AZT delivery, which were subsequently incorporated into a thermoresponsive injectable hydrogel suitable for intra-articular administration. The formulation was developed using a Quality by Design (QbD) approach, focusing on two steps: (i) preparation of AZT-PLGA NPs and (ii) loading the NPs into a poloxamer-based hydrogel. Critical material attributes (AZT, PLGA, surfactants) were evaluated for their impacts on the critical quality attributes (CQAs) of the NP formulation (size distribution and encapsulation efficiency). The optimized AZT-PLGA NPs exhibited a mean particle size of ~ 150 nm and a PDI of < 0.2, ensuring uniformity and stability. Secondly, these NPs were then embedded into a novel thermoresponsive hydrogel. The effects of NPs, hyaluronic acid, and mannitol on physical appearance, thermal sensitivity, the rheology (shear-thinning and thixotropic), pH, and sustained release properties of the final formulation were systematically investigated. Fourier-transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) analyses revealed interactions between AZT and PLGA, which, while not affecting the drug assay, enhanced the structural integrity and modified the thermal properties of the final product. Using QbD principles, a risk-based assessment was proposed for future drug development. This study introduced a novel thermoresponsive injectable hydrogel for the intra-articular delivery of AZT using PLGA nanoparticles.</p>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"26 6","pages":"171"},"PeriodicalIF":3.4,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504367","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":"Optimizing Extended-release Formulation of l-tetrahydropalmatine Based on In Vivo Outcomes Using Integrated Modeling Approaches.","authors":"Thi-Phuong-Dung Pham, Huy Minh Dao, Nguyen-My-Linh Pham, Thanh-Vinh Dang, Hoang-Anh Nguyen, Cao-Son Tran, Linh Nguyen Tran, Nguyen-Thach Tung","doi":"10.1208/s12249-025-03165-w","DOIUrl":"https://doi.org/10.1208/s12249-025-03165-w","url":null,"abstract":"<p><p>l-Tetrahydropalmatine (l-THP) is a promising drug candidate for addiction treatment and needs to be delivered in extended-release dosage forms for safety and efficiency. This study aims to optimize extended-release formulations containing l-THP to achieve desired in vivo outcomes (C<sub>max</sub>, onset of action, and duration of action) by integrating multiple computational tools including in vitro-in vivo correlation (IVIVC), physiologically based pharmacokinetic (PBPK), and design of experiments (DoE). The in vivo predictable dissolution method was chosen based on level A IVIVC. Then, PBPK model was developed and validated to explore the influences of physiological and formulation factors on the bioavailability of l-THP from hydrophilic matrix tablets. Finally, the PBPK model was incorporated with DoE to investigate the impact of formulation variables on in vivo outcomes and optimize the hydrophilic matrix tablet formulation for desired C<sub>max</sub>, start time of action, and duration of action. USP Apparatus I, 450 ml HCl 0.1 N, 100 rpm demonstrated the highest level of correlation between in vitro dissolution and in vivo absorption, among the tested conditions. The PBPK model accurately predicted l-THP pharmacokinetics, meeting U.S.FDA requirements for prediction errors. The PBPK model identified dissolution parameters and gut first-pass extraction as key factors affecting l-THP bioavailability. The optimized formulation was estimated to exhibit an early onset of action (0.68 h), remain effective for more than 11.4 h, and be safe with C<sub>max</sub> consistently falling within the therapeutic window. The present approach can be applied to design other drug delivery systems for flexible in vivo outcomes.</p>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"26 6","pages":"170"},"PeriodicalIF":3.4,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493362","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}
AAPS PharmSciTechPub Date : 2025-06-13DOI: 10.1208/s12249-025-03160-1
Li Wang, Xiaoyang Zhang, Jianlu Qu, Zhanrui Zhang, Wei Wu, Wenlong Li
{"title":"Development, Characterization, and Molecular Dynamics Simulation of Andrographolide Nanosuspensions Utilizing Hummer Acoustic Resonance Technology.","authors":"Li Wang, Xiaoyang Zhang, Jianlu Qu, Zhanrui Zhang, Wei Wu, Wenlong Li","doi":"10.1208/s12249-025-03160-1","DOIUrl":"https://doi.org/10.1208/s12249-025-03160-1","url":null,"abstract":"<p><p>Andrographolide (AG) is a diterpenoid lactone, widely recognized for its potent anti-inflammatory and immunomodulatory properties. However, AG's clinical applications are significantly limited due to its poor water solubility. The aim of this study was to rapidly develop an andrographolide nanosuspension (AG-NS) using Hummer Acoustic Resonance (HAR) technology to enhance AG's solubility. AG-NS was prepared using HAR technology for high-throughput screening of stabilizers. Quality risk assessment was performed to identify critical formulation and process variables influencing AG-NS. A Box-Behnken design (BBD) was applied to evaluate the effects of these critical variables on AG-NS. Following lyophilization, the redispersibility of AG-NS was evaluated, and physicochemical characterization was conducted to verify the absence of significant interactions between AG and the excipients. The optimized AG-NS formulation exhibited a Z-Ave of 183.96 ± 4.40 nm, a PDI of 0.151 ± 0.065, and a zeta potential of -42.85 ± 1.09 mV. MD simulations revealed the internal mechanisms of AG-NS stabilization. Lyophilized AG-NS demonstrated excellent redisperseability. In vitro dissolution studies showed that the lyophilized AG-NS had a significantly faster dissolution rate and higher cumulative dissolution (120 min) compared to AG crude powder and the physical mixture (PM). The optimized AG-NS demonstrated favorable physicochemical properties and enhanced dissolution performance. The lyophilized formulation exhibited excellent redispersibility upon reconstitution. HAR technology is an innovative and efficient approach for the rapid development and optimization of nanosuspension formulations.</p>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"26 5","pages":"169"},"PeriodicalIF":3.4,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293143","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":"Taste Masking of Primaquine Phosphate: A Comparative Evaluation of Three Taste Masking Agents.","authors":"Galande Ankit, Gagare Tejashree, Sahu Surbhi, Kulkarni Madhur","doi":"10.1208/s12249-025-03162-z","DOIUrl":"https://doi.org/10.1208/s12249-025-03162-z","url":null,"abstract":"<p><p>The work involved taste masking of primaquine phosphate (PMQ), an intensely bitter drug used in the prevention and treatment of relapses of malarial infections caused by Plasmodium vivax and ovale. Drug and cation exchange resins viz, AmberLite™ IRP 64, 69, and 88 (IER 64, IER69, and IER88) were subjected to complex formation in 1:1 and 1:2 ratios using the shake flask method. Inclusion complexes of PMQ with hydroxypropyl beta cyclodextrin (HPBCD) were prepared to employ co-grinding, kneading, co-evaporation, and spray drying methods. Solid dispersions of PMQ with Eudragit E 100 (E 100) were prepared in various ratios by spray drying. In vitro, drug release studies of the composites were performed in 0.1N HCl and pH 6.8 phosphate buffer. The composites showing the least drug release in pH 6.8 buffer without compromising the release in an acidic medium were also evaluated for drug release in simulated salivary fluid (SSF). The selected composites were formulated into orally disintegrating tablets (ODTs) and subjected to human panel taste evaluation. PMQ-HPBCD spray-dried complex, PMQ-IER 69 (1:2) complex, and PMQ-E100 (1:4) dispersion exhibited drug release in decreasing order in SSF but > 85% release within 1 h in an acidic medium. Hence, these composites were formulated into ODTs. The human panel tasting indicated the most acceptable taste of the ODTs comprising PMQ-E 100 dispersion followed by PMQ- IER 69 (2) complex, and lastly PMQ HPBCD complex. The PMQ-E100 dispersion-based ODTs could thus be a promising option for treating pediatric and geriatric patients with PMQ.</p>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"26 5","pages":"168"},"PeriodicalIF":3.4,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144273926","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}
AAPS PharmSciTechPub Date : 2025-06-10DOI: 10.1208/s12249-025-03157-w
Rabab Kamel, Giuseppina Nocca, Elena Mazzinelli, Somaia S Abd El-Karim, Valerio Papa, Ilaria Cacciotti, Nermeen A Elkasabgy
{"title":"Unveiling the Potential of Nanoclays in Pharmaceuticals.","authors":"Rabab Kamel, Giuseppina Nocca, Elena Mazzinelli, Somaia S Abd El-Karim, Valerio Papa, Ilaria Cacciotti, Nermeen A Elkasabgy","doi":"10.1208/s12249-025-03157-w","DOIUrl":"https://doi.org/10.1208/s12249-025-03157-w","url":null,"abstract":"<p><p>Clay minerals or nanoclays are layered aluminosilicate nanoparticles with unique physicochemical properties, excellent biocompatibility, high surface area, lamellar structure, diverse ion-exchange capacity, tuneable surface chemistry enabling them to form different intermolecular interactions which offer supreme prospects for optimized pharmaceutical applications. This review article dives into the key characteristics of different types of nanoclays like Halloysite, Kaolinite, Sepiolite, Montmorillonite, Bentonite and Laponite, highlighting their possible exploitation within the pharmaceutical landscape. Also, the review describes the recent advances in nanoclay-based drug delivery systems and discusses the role of nanoclays as drug carriers and their use in tissue engineering and gene therapy. Nanoclays, are used to modulate drug release and stabilize the loaded active molecules as well as to enhance drug loading. Interdisciplinary research, advanced characterization techniques, and careful formulation designs are required to augment the use of nanoclays in various pharmaceutical applications. Despite the faced challenges, research on nanoclay-based drug delivery systems is growing. With targeted research and development, nanoclays are poised to redefine the biomedical domain, offering tailored and efficient therapies for a multitude of diseases.</p>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"26 5","pages":"167"},"PeriodicalIF":3.4,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265019","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":"Development and Evaluation of Huperzine A-Loaded Microneedles for Transdermal Delivery and Pretreatment of GD Poisoning.","authors":"Guixiang Yang, Yi Zhang, Chong Li, Xingle Xia, Qian Jin, Liqin Li, Xingxing Zong, Dongxin Liu, Jingchen Wei, Xuejun Chen, Chen Wang","doi":"10.1208/s12249-025-03149-w","DOIUrl":"https://doi.org/10.1208/s12249-025-03149-w","url":null,"abstract":"<p><p>Huperzine A (Hup A), a reversible acetylcholinesterase inhibitor, shows protective potential against neurotoxic poisoning. Current formulations (oral tablets/capsules and injectables) face limitations: oral administration suffers from first-pass metabolism and fluctuating plasma concentrations due to frequent dosing, while injectables require sterile administration, reducing long-term compliance. The aim of this study was to prepare dissolving microneedles (MNs) patches containing Hup A for pretreatment against soman (GD) poisoning. Hyaluronic acid (HA), polyvinylpyrrolidone K30 (PVP K30) and sorbitol were selected as matrix materials in specific proportions and concentration ranges based on single-factor screening experiments and orthogonal design optimization. In order to further evaluate the potential of the Hup A MNs, optimized formulations were selected for subjected to characterization. This evaluation encompassed morphological observation, mechanical properties, skin penetration efficacy, recovery time, in vitro drug release study, permeability assays, pharmacokinetic study, and pharmacodynamic study. Statistical analyses were performed using Student's t-tests for pairwise comparisons and one-way ANOVA for multiple comparisons. The results demonstrated that prepared Hup A MNs had a conical shape with a smooth surface and sharp tips. Hup A MNs had sufficient mechanical strength (122.3 ± 15.3 N) to penetrate through the skin and could be quickly skin of recovery 6 min. In permeability assays, the cumulative Hup A release was about 35.4 μg at 2 h and 58 μg at 10 h. Pharmacodynamic results demonstrated that compared to oral administration, Hup A MNs reduced the onset time (30 min vs. 60 min) and extended the effective prevention duration against GD poisoning (6 h vs. 2 h). Pharmacokinetic analysis showed that MNS administration can maintain a more lasting and stable blood concentration as compared to oral administration. MNs are a valuable drug delivery system, benefiting the patients with minimal skin invasion. Taken together, these results demonstrated that Hup A-loaded MNs are acquiring a new alternative for pretreatment of OPNAs.</p>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"26 5","pages":"164"},"PeriodicalIF":3.4,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144245668","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}
AAPS PharmSciTechPub Date : 2025-06-06DOI: 10.1208/s12249-025-03151-2
Gaurav K Jain, Gaurav Chaudhary, Mohammad Akhlaquer Rahman, Musarrat Husain Warsi, Mohammad Imran
{"title":"Nanosizing and Surface Modification by Propellant Assisted Aerosolization Enhances Solubility and Dissolution of Estradiol.","authors":"Gaurav K Jain, Gaurav Chaudhary, Mohammad Akhlaquer Rahman, Musarrat Husain Warsi, Mohammad Imran","doi":"10.1208/s12249-025-03151-2","DOIUrl":"https://doi.org/10.1208/s12249-025-03151-2","url":null,"abstract":"<p><strong>Objective: </strong>A novel method for the development of uniform, nanosized, crystalline particles of estradiol valerate (EV) by the propellant assisted aerosolization (PAA) technique as an alternative to supercritical carbon dioxide assisted atomization is described.</p><p><strong>Methods: </strong>HFA 134a was used as a propellant. PAA process parameters such as nozzle diameter, pre-expansion pressure, and hot air pressure were optimized using 33 factorial Box-Behnken design for the preparation of uniform, nanosized EV (nano-EV). Nano-EV was characterized for physicochemical properties, crystallinity and enhancement of the solubility and dissolution.</p><p><strong>Results: </strong>The nano-EV, produced by the PAA technique, showed loose cuboidal aggregates with smooth surface morphology. PAA with 0.22 µm nozzle diameter, 120 psi pre-expansion pressure and 80 psi hot air pressure, yielded uniform (PDI, 0.27 ± 0.05) nano-EV particles with mean size of about 291 ± 5.8 nm. FTIR and DSC confirmed that no physical or chemical change occurred during nanosizing. XRD data showed that nano-EV particles were crystalline. The results demonstrated nearly twofold higher solubility and 2.3-fold enhanced dissolution of nano-EV compared to EV.</p><p><strong>Conclusion: </strong>The PAA process is a cost effective and scalable technique and has a potential industrial application for producing nanocrystals of BCS class II drugs.</p>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"26 5","pages":"165"},"PeriodicalIF":3.4,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144245669","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}
AAPS PharmSciTechPub Date : 2025-06-06DOI: 10.1208/s12249-025-03161-0
Sanjeevini M, Harini Priya Pa, Rakshitha L, Prajwal N Murthy, Pragathi S G, Anusha V Matadh, Srujana N Murthy, Srinath R, Shivakumar H N, Howard Maibach, S Narasimha Murthy
{"title":"Skin can Modulate the pH of Topical Creams and Gels.","authors":"Sanjeevini M, Harini Priya Pa, Rakshitha L, Prajwal N Murthy, Pragathi S G, Anusha V Matadh, Srujana N Murthy, Srinath R, Shivakumar H N, Howard Maibach, S Narasimha Murthy","doi":"10.1208/s12249-025-03161-0","DOIUrl":"https://doi.org/10.1208/s12249-025-03161-0","url":null,"abstract":"<p><p>The pH of the formulation can affect the pH of the skin surface. However, the skin's pH is known to recover rapidly due to the substantial buffer capacity associated with the skin. The objective of the project was to investigate the effect of the buffer capacity of skin on the pH of the formulation. A few custom-made gel and cream formulations were used as test products in the study. Custom-made gel and cream formulations were prepared and applied to human skin, with parallel applications on an inert substrate serving as controls to isolate the effect of solvent evaporation. In the control group, pH changes due to evaporation were negligible across all formulations. In vivo application revealed that the skin's buffering capacity significantly modulates the pH of the applied formulation. When formulations had a pH higher than the skin's basal level, the skin responded by reducing the formulation pH. For instance, a cream adjusted to pH 9 showed a drop of more than one pH unit within 30 min post-application. Conversely, formulations with pH lower than the skin's baseline exhibited an increase in pH; creams adjusted to pH 4 increased by over 0.5 units in the same timeframe. This bidirectional shift highlights the skin's active role in restoring pH homeostasis. The incorporation of buffers with varying ionic strengths into the formulations reduced the extent of pH drift, offering greater resistance to skin-driven pH changes compared to unbuffered formulation.</p>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"26 5","pages":"166"},"PeriodicalIF":3.4,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144245670","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}
AAPS PharmSciTechPub Date : 2025-06-04DOI: 10.1208/s12249-025-03156-x
Anagha Damre, Aniruddha Banerjee
{"title":"Application of Physiologically Based Biopharmaceutics Modeling (PBBM) to Establish Clinically Relevant Dissolution Specifications for a Prolonged Release Tablet Formulation of Verapamil, a BCS Class I Drug.","authors":"Anagha Damre, Aniruddha Banerjee","doi":"10.1208/s12249-025-03156-x","DOIUrl":"https://doi.org/10.1208/s12249-025-03156-x","url":null,"abstract":"<p><p>Our work aimed at setting clinically relevant dissolution specifications for a prolonged release formulation of verapamil, a BCS Class I drug. We have used a two-pronged approach- a Level A IVIVC correlation supplemented with virtual bioequivalence assessment using Physiologically based biopharmaceutics modelling (PBBM). Dissolution studies were performed for two batches, Medium-release (BE batch) and Slow-release (non-BE batch), using a biorelevant method. Mechanistic absorption deconvolution method was used to obtain the in vivo release profiles and correlate with the respective in vitro release profiles to develop the IVIVC. Theoretical dissolution profiles for upper and lower limits were generated and used for convolution and calculation of Percent prediction errors (%PE). This was supplemented with virtual bioequivalence (VBE) assessments at each level to select clinically relevant dissolution specifications. A two-step deconvolution-correlation method resulted in a linear Level A IVIVC with R<sup>2</sup> = 0.951 which was internally and externally validated. Percent prediction errors (%PE) for C<sub>max</sub> and AUC were calculated for each level to accept/reject the limits. VBE trials showed that the 90% CI fell within the acceptable limits of 80-125% for C<sub>max</sub>, AUC<sub>0-t</sub> and AUC<sub>0-inf</sub> for the lower dissolution specification limit 5 and for the upper specification limit 3. The current investigation demonstrates new opportunities offered by mechanistic modelling and how this two-pronged approach (IVIVC and IVIVR-VBE) can be used to define clinically relevant dissolution specifications and the BE safe space, which can support post-approval changes for waiving bioequivalence studies and ensuring commercial product quality over the years.</p>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"26 5","pages":"163"},"PeriodicalIF":3.4,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144223924","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}