AAPS Journal最新文献

Impact of Gastric Emptying Kinetics on Dipyridamole Dissolution Using a Gastrointestinal Simulator. 胃肠模拟器研究胃排空动力学对双嘧达莫溶出的影响。

IF 5 3区医学

AAPS Journal Pub Date : 2025-07-22 DOI: 10.1208/s12248-025-01110-0

Alejandro Ruiz-Picazo, Luis Jimenez, Marta Gonzalez-Alvarez, Oscar Reinoso, Isabel Gonzalez-Alvarez, Marival Bermejo

{"title":"Impact of Gastric Emptying Kinetics on Dipyridamole Dissolution Using a Gastrointestinal Simulator.","authors":"Alejandro Ruiz-Picazo, Luis Jimenez, Marta Gonzalez-Alvarez, Oscar Reinoso, Isabel Gonzalez-Alvarez, Marival Bermejo","doi":"10.1208/s12248-025-01110-0","DOIUrl":"https://doi.org/10.1208/s12248-025-01110-0","url":null,"abstract":"Gastric emptying plays a crucial role in the dissolution and absorption of oral drugs, particularly those with pH-dependent solubility, such as dipyridamole. This study evaluates the impact of gastric emptying kinetics on dipyridamole dissolution using a Gastrointestinal Simulator. A dynamic dissolution model incorporating first-order and Weibull kinetics was applied to simulate different gastric emptying profiles. Results indicate that dissolution behavior is significantly influenced by the rate and pattern of gastric emptying, affecting drug solubility and potential bioavailability. The Weibull model provided a more flexible fit to experimental data, but the external control shows that significant differences exist between theorical and experimental gastric volumes. These findings highlight the importance of integrating physiologically relevant gastric emptying models into biopharmaceutical assessments to improve the prediction of in vivo drug performance. This approach could enhance the design of oral formulations by optimizing dissolution profiles for weak base drugs.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 5","pages":"121"},"PeriodicalIF":5.0,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144692336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Nanomicelles Platform Delivery System for Water-Insoluble Corticosteroid to Treat Anterior Uveitis. 水不溶性皮质类固醇纳米胶束平台递送系统治疗葡萄膜前炎。

IF 5 3区医学

AAPS Journal Pub Date : 2025-07-22 DOI: 10.1208/s12248-025-01103-z

Priyadarshini Sathe, Srujana Mosalikanti Sai Kameshwari, Jayabalan Nirmal

{"title":"A Nanomicelles Platform Delivery System for Water-Insoluble Corticosteroid to Treat Anterior Uveitis.","authors":"Priyadarshini Sathe, Srujana Mosalikanti Sai Kameshwari, Jayabalan Nirmal","doi":"10.1208/s12248-025-01103-z","DOIUrl":"https://doi.org/10.1208/s12248-025-01103-z","url":null,"abstract":"Difluprednate is marketed as an emulsion due to its poor aqueous solubility. Emulsions are known to cause ocular discomfort and require frequent dosing to show therapeutic activity. Nanomicelles are well known to improve the solubility and permeation of water-insoluble drugs. Therefore, to enhance the water solubility and reduce the dosing frequency by improving difluprednate permeation across the cornea, we formulated nanomicelles. Difluprednate loaded nanomicelles (Dicel) was prepared by thin film hydration method and optimized using Box-Behnken design. The Dicel formulated had a particle size, polydispersity index, zeta potential and entrapment efficiency of 21.9 nm, 0.15, -7.55 mV and 75.4%, respectively. Transmission electron microscopy analysis showed spherical nanomicelles. The Dicel showed a sustained release profile for 48 h. The difluprednate permeation across the cornea from Dicel was enhanced by twofold compared to commercially available emulsion. Also, it was found to be stable upon dilution with simulated tear fluid and was biocompatible. Further, Dicel improved the anti-inflammatory activity of difluprednate at one and two times a day administration compared to four times a day administration of difluprednate emulsion. The present study highlights the role of topical nanomicelles in delivering difluprednate, which is better than the existing marketed emulsion in the management of ocular inflammation.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 5","pages":"122"},"PeriodicalIF":5.0,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144692335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Response to the Commentary from A Dissolution Working Group on "The Effect of Sampling Cannula on In Vitro Dissolution Testing with USP Paddle Method": Clarifications and Opportunities for Engagement. 对溶出度工作组关于“取样套管对USP桨法体外溶出度检测的影响”的评论的回应：澄清和参与的机会。

IF 5 3区医学

AAPS Journal Pub Date : 2025-07-16 DOI: 10.1208/s12248-025-01107-9

Zongming Gao, Anjanette Smith

引用次数: 0

Prospects and Challenges of Catechins in Cardiovascular Disease. 儿茶素在心血管疾病中的应用前景与挑战。

IF 5 3区医学

AAPS Journal Pub Date : 2025-07-14 DOI: 10.1208/s12248-025-01105-x

Yiyang Chen, Yeqing Ren, Kaixin Zhou, Wangrui Lei, Yang Yang, Xue Wang

引用次数: 0

Comparison of Surrogate Models in Tablet Dissolution Prediction: Addressing the Limitations of F₂ and Introducing Sum of Ranking Differences for Model Evaluation. 替代模型在片剂溶出度预测中的比较：解决F₂的局限性并引入排序差和用于模型评价。

IF 5 3区医学

AAPS Journal Pub Date : 2025-07-08 DOI: 10.1208/s12248-025-01100-2

Orsolya Péterfi, Béla Kovács, Tibor Casian, Erzsébet Orsolya Tőkés, Éva Katalin Kelemen, Katalin Zöldi, Zsombor Kristóf Nagy, Brigitta Nagy

{"title":"Comparison of Surrogate Models in Tablet Dissolution Prediction: Addressing the Limitations of F₂ and Introducing Sum of Ranking Differences for Model Evaluation.","authors":"Orsolya Péterfi, Béla Kovács, Tibor Casian, Erzsébet Orsolya Tőkés, Éva Katalin Kelemen, Katalin Zöldi, Zsombor Kristóf Nagy, Brigitta Nagy","doi":"10.1208/s12248-025-01100-2","DOIUrl":"https://doi.org/10.1208/s12248-025-01100-2","url":null,"abstract":"As process analytical technology (PAT) and real-time release testing (RTRT) are gaining momentum in the pharmaceutical industry, there is an increasing need for developing methods for the non-destructive and real-time characterization of the in vitro dissolution of pharmaceuticals. In recent years, several surrogate models relying on PAT measurements and advanced chemometric techniques have been published addressing this task. Nevertheless, methodologies for the fair comparison of the model performance and setting relevant acceptance criteria are still not well established. Therefore, this study aims to draw attention to appropriate model comparison when developing and applying surrogate dissolution models and highlight the limitations of the widely used dissolution curve comparison metrics, including the f2 similarity value. A set of 10 different artificial neural network (ANN) models were developed for the prediction of the dissolution profiles of clopidogrel tablets produced through hot-melt granulation and tableting. Models were fitted with diverse input data, including granulation nominal experiment settings and real recorded process parameters (e.g., air and material temperature, humidity, granulation and lubrication time, tableting pressure) and near-infrared spectra. The models' goodness was compared using the f2 factor, coefficient of determination (R2) and root mean square error (RMSE). The results demonstrated that these measures do not sufficiently reflect the discriminating ability of the models. We proposed for the first time the use of the sum of ranking differences (SRD) method for the comparison of the prediction models, which proved to be an effective tool to assess the discriminatory power of surrogate dissolution models during model development.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 5","pages":"118"},"PeriodicalIF":5.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144592799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Doxorubicin Stability-indicating Method and its Main Degradation Products In vitro Toxicity. 阿霉素稳定性指示法及其主要降解产物体外毒性研究。

IF 5 3区医学

AAPS Journal Pub Date : 2025-07-08 DOI: 10.1208/s12248-025-01104-y

Mariah de Almeida Ultramari, Ariane Rivellis Julio, Larissa Souza Passos, Alexander Ossanes de Souza, Núbia Pereira da Silva, Paloma Nathane Nunes de Freitas, Ernani Pinto

{"title":"Doxorubicin Stability-indicating Method and its Main Degradation Products In vitro Toxicity.","authors":"Mariah de Almeida Ultramari, Ariane Rivellis Julio, Larissa Souza Passos, Alexander Ossanes de Souza, Núbia Pereira da Silva, Paloma Nathane Nunes de Freitas, Ernani Pinto","doi":"10.1208/s12248-025-01104-y","DOIUrl":"https://doi.org/10.1208/s12248-025-01104-y","url":null,"abstract":"Human health and the environment are continuously impacted by anthropogenic activities, particularly those involving emerging compounds. As these compounds are newly identified or not yet fully documented in the literature, comprehensive knowledge of their specific toxicities remains limited. Among these, pharmaceutical compounds are of particular concern, as their mechanisms of action and the effects of their pharmaceutical impurities remain insufficiently understood. In this context, this study aimed to evaluate the behavior of the antineoplastic pharmaceutical doxorubicin (DOX) under stress conditions, including acid and base hydrolysis, oxidation, photolysis, and temperature variations. The goal was to identify the major degradation pathways and elucidate the structures of the main degradation products. A stability-indicating HPLC-DAD-MS method was developed and validated for this purpose. Throughout method development, several degradation products were identified, including 7-deoxydehydrodoxorubicinone, formed through acid hydrolysis, and a major thermal degradation product with a mass-to-charge ratio (m/z) of 530. This thermal degradation product was also detected in analyses of expired pharmaceutical formulations. Furthermore, the in vitro toxicity assessment of samples containing degradation products from thermal decomposition revealed cytotoxic effects on mononuclear cells. These findings underscore the importance of not only understanding the degradation pathways of pharmaceutical compounds but also evaluating the potential environmental and human health impacts of these degradation products.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 5","pages":"117"},"PeriodicalIF":5.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144592800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Simplifying Pharmacokinetics, Applying it to Drug and Dosage Form Development, and Making Drug Dosage Decisions in Clinical Medicine: The Adaptation of Kirchhoff's Laws from Physics. 简化药代动力学，应用于药物和剂型开发，临床用药剂量决策——从物理学角度对基尔霍夫定律的改编

IF 5 3区医学

AAPS Journal Pub Date : 2025-07-03 DOI: 10.1208/s12248-025-01099-6

Leslie Z Benet, Jasleen K Sodhi

{"title":"Simplifying Pharmacokinetics, Applying it to Drug and Dosage Form Development, and Making Drug Dosage Decisions in Clinical Medicine: The Adaptation of Kirchhoff's Laws from Physics.","authors":"Leslie Z Benet, Jasleen K Sodhi","doi":"10.1208/s12248-025-01099-6","DOIUrl":"https://doi.org/10.1208/s12248-025-01099-6","url":null,"abstract":"Over the past three years, we have published a series of nine manuscripts demonstrating that all relevant pharmacokinetic relationships may be simply derived independent of differential equations, offering an alternative to traditional pharmacokinetic analyses. These derivations are based on an understanding of parallel and in series rate-defining processes, and account for all relevant drivers, including organ blood flow and drug delivery clearance kinetics, across both linear and nonlinear scenarios. In this tutorial, we present the simple derivation of renal clearance and hepatic clearance directly relevant to clinical pharmacokinetics, as applied to making drug dosing decisions based on measures of systemic exposure. We further advocate for a more streamlined and practical approach to teaching and applying clinical pharmacokinetics, noting that compartmental modeling, protein binding in hypothetical compartments, trapezoidal AUC calculations, and alternative volume of distribution parameters, aside from (the unfortunately misnamed) volume of distribution steady-state, often overcomplicate pharmacokinetics in practice. The key advantage of this simplified methodology is the ability to directly incorporate clearance from the drug delivery site into systemic pharmacokinetic relationships. This enables a clear understanding of how entering clearance can influence systemic AUC, helping explain: enhanced pharmacodynamic outcomes of slow drug delivery versus immediate-release formulations; systemic bioavailability measures exceeding unity, statistically significant discrepancies between urinary and systemic bioavailability measures; and changes in renal clearance as a function of drug clearance from the delivery site. These key concepts are illustrated by applying the proposed methodology to an example drug, analyzing all relevant clinical pharmacokinetic relationships required for dosing decisions.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 5","pages":"116"},"PeriodicalIF":5.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144555644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dissolution of Oral Solid Dosage Formulations: Surrogate Models and Real-time Release. 口服固体剂型的溶出度：替代模型和实时释放。

IF 5 3区医学

AAPS Journal Pub Date : 2025-06-27 DOI: 10.1208/s12248-025-01102-0

Melanie Dumarey, Tessa M Carducci, Matthew J Walworth, Casey J Smith, Salvador García-Muñoz, Sarah Nielsen, Sylvaine Jacquart, Ana Tavares da Silva, Stan Altan, Martin Otava, Yanmei Lan, Nikolay Zaborenko

{"title":"Dissolution of Oral Solid Dosage Formulations: Surrogate Models and Real-time Release.","authors":"Melanie Dumarey, Tessa M Carducci, Matthew J Walworth, Casey J Smith, Salvador García-Muñoz, Sarah Nielsen, Sylvaine Jacquart, Ana Tavares da Silva, Stan Altan, Martin Otava, Yanmei Lan, Nikolay Zaborenko","doi":"10.1208/s12248-025-01102-0","DOIUrl":"10.1208/s12248-025-01102-0","url":null,"abstract":"In vitro dissolution testing is commonly performed to ensure that oral solid dosage medicines are of high quality and will achieve their targeted in vivo performance. However, this testing is time and material consuming. Therefore, pharmaceutical companies have been developing predictive dissolution models (PDMs) for drug product release based on fast at- and/or on-line measurements, including real-time release testing of dissolution (RTRT-D). Recently, PDMs have seen acceptance by major regulatory bodies as release tests for the dissolution critical quality attribute. In this paper, several methodologies are described to develop and validate a fit-for-purpose model, then to implement it as a surrogate release test for dissolution. These approaches are further exemplified by real-life case studies, which demonstrate that PDMs for release are not only viable but more sustainable than in vitro dissolution testing and can significantly accelerate drug product release. The rise of continuous manufacturing within the pharmaceutical industry further favors the implementation of real-time release testing. Therefore, a steep uptake of PDMs for release is expected once this methodology is globally accepted. To that end, it is advantageous for global regulators and pharmaceutical innovators to coalesce around a harmonized set of expectations for development, validation, implementation, and lifecycle of PDMs as part of drug product release testing.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 5","pages":"115"},"PeriodicalIF":5.0,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Enhanced Nanoprecipitation Method for the Production of PLGA Nanoparticles for Oncology Applications. 增强纳米沉淀法生产用于肿瘤应用的PLGA纳米颗粒。

IF 5 3区医学

AAPS Journal Pub Date : 2025-06-27 DOI: 10.1208/s12248-025-01096-9

Hany Sadek Ayoub Ghaly, Naisana Seyedasli, Pegah Varamini

{"title":"Enhanced Nanoprecipitation Method for the Production of PLGA Nanoparticles for Oncology Applications.","authors":"Hany Sadek Ayoub Ghaly, Naisana Seyedasli, Pegah Varamini","doi":"10.1208/s12248-025-01096-9","DOIUrl":"https://doi.org/10.1208/s12248-025-01096-9","url":null,"abstract":"Herein, we report a new modified nanoprecipitation method for the fabrication of water-dispersible Poly(lactic-co-glycolic acid) (PLGA) nanoparticles encapsulating three poorly water-soluble anticancer agents as model drugs: paclitaxel (PTX), docetaxel (DTX) or curcumin (Cur). These nanoparticles were water dispersible with favourable size for anticancer applications (below 200 nm) and relatively high drug loading (6.3-8.9%). These nanoparticles were stable for four weeks in solid state and up to 48 h when dispersed in water. PTX and Cur nanoparticles showed a very minimal release of the payload during a 72-h in vitro release study. The new method also yielded reproducible results across three different batches of each type of nanoparticles and following three times upscaling of PTX nanoparticles. PTX and Cur nanoparticles were more effective than the free drugs against MDA-MB-231 cells (p < 0.05). In addition, PTX nanoparticles showed a significant enhanced induction of early apoptosis in MDA-MB-231 cells (42.3%) in comparison to free PTX (23.7%, p < 0.05). Both flow cytometry and confocal microscopy confirmed the uptake of the nanoparticles by MDA-MB-231 cells. In conclusion, our modified nanoprecipitation method produces PLGA nanoparticles loaded with different anticancer agents and suitable for cancer therapy.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 5","pages":"113"},"PeriodicalIF":5.0,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144509290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Procedural Variation May Contribute to 6-Minute Walk Distance Variability in Real-World Pediatric Pulmonary Arterial Hypertension Study. 在真实世界儿童肺动脉高压研究中，程序变异可能导致6分钟步行距离的变异。

IF 5 3区医学

AAPS Journal Pub Date : 2025-06-27 DOI: 10.1208/s12248-025-01098-7

Cynthia Kleppinger, Dunbar Ivy, Norman Stockbridge, Angela Bates, Stephanie Handler, Usha S Krishnan, Mary P Mullen, Delphine Yung, Rachel K Hopper, Nidhy P Varghese, Jeff Fineman, Eric D Austin, Catherine M Avitabile, Grace Freire, Jennifer Clark, Haihao Sun

{"title":"Procedural Variation May Contribute to 6-Minute Walk Distance Variability in Real-World Pediatric Pulmonary Arterial Hypertension Study.","authors":"Cynthia Kleppinger, Dunbar Ivy, Norman Stockbridge, Angela Bates, Stephanie Handler, Usha S Krishnan, Mary P Mullen, Delphine Yung, Rachel K Hopper, Nidhy P Varghese, Jeff Fineman, Eric D Austin, Catherine M Avitabile, Grace Freire, Jennifer Clark, Haihao Sun","doi":"10.1208/s12248-025-01098-7","DOIUrl":"10.1208/s12248-025-01098-7","url":null,"abstract":"The six-minute walk test (6MWT) is a common method to assess submaximal exercise capacity in children and adults with pulmonary arterial hypertension (PAH) and other chronic diseases. There is no guideline specifically for 6MWT in children. In this observational pilot study, we evaluated the impact of procedural variations on the outcome of the 6MWT in the real-world clinical setting at pediatric PAH programs. We collected 6MWT data from 33 children with PAH participating in a multicenter, prospective, non-interventional study. Data range/quantiles and standard deviation (SD) were used to describe distribution of the six-minute walk distance (6MWD) and data variability. Levene's test was used to test for heterogeneity of variance with the two sites of similar altitude and their age/height/weight-matched Panama Function Class II participants. We analyzed all 33 eligible participants and their qualified first walks at five centers (A-E) with 6MWD ranges of 420-570, 357-683, 418-481, 400-700, 377-549 m, respectively. Site D performed the 6MWT in a busy hallway and allowed parental/caregiver's cheering, while Site E performed the 6MWT in a secluded area with no parental/caregiver involvement. Mean 6MWD and SD for Sites D and E were 547 (125) and 432 (67.5) meters, respectively (p = 0.03). In conclusion, procedural variations seem to associate with 6MWD data variability. Although interpretation of our results is limited by the small sample size, our findings suggest that standardizing pediatric 6MWT procedures are needed.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 5","pages":"114"},"PeriodicalIF":5.0,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0