Pharmaceutical Research最新文献

{"title":"Influence of Milling Parameters on Crystal Morphology, Thermal Behavior, and Dissolution of Mesalamine Nanocrystals.","authors":"Sakshi Kunjir, Prajakta Pathare, Sonam Sharma, Jyoti Deoriya, Subramanian Natesan, Rajkumar Malayandi","doi":"10.1007/s11095-025-03891-7","DOIUrl":"https://doi.org/10.1007/s11095-025-03891-7","url":null,"abstract":"<p><strong>Purpose: </strong>The low aqueous solubility limits the therapeutic potential of both new and existing drug molecules. Mesalamine (MES), a primary therapeutic agent for inflammatory bowel diseases, has low aqueous solubility and incomplete dissolution in the colon; hence, it requires a high administered dose (maximum daily dose of 4.8 g/day). This study attempts to improve the dissolution velocity and solubility by designing MES nanocrystals.</p><p><strong>Methods: </strong>MES nanocrystals were prepared using the dry ball milling (BM) process. MES nanocrystals (NCs) were prepared using Soluplus as stabilizer, and milling parameters were optimized to obtain the desirable particle size and other pharmaceutical attributes.</p><p><strong>Results: </strong>The prepared MES NCs were characterized to understand the influence of key milling parameters like time, speed, and stabilizer concentration. Variations in these parameters resulted in diverse morphologies, including rectangular bars, elongated hexagons, spheroids, and plates. Batch 29 (40/1/400) exhibited a plate-like crystal habit with a particle size of 435 nm and a PDI of 0.39, demonstrating an improved dissolution efficacy (84% in 60 min). Spectroscopic, microscopic, and thermal analyses confirmed the influence of ball milling on solubility, dissolution rate, particle size, and crystal habits.</p><p><strong>Conclusion: </strong>The study outcomes could be useful for the successful scale-up and commercialization of drug products based on the dry BM platform technology.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144699199","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}

{"title":"Correction: \"Simultaneous Pharmacokinetic Modeling of Gentamicin, Tobramycin and Vancomycin Clearance From Neonates to Adults: Towards a Semi-physiological Function for Maturation in Glomerular Filtration\".","authors":"R F De Cock, K Allegaert, J M Brussee, C M Sherwin, H Mulla, M de Hoog, J N van den Anker, M Danhof, C A Knibbe","doi":"10.1007/s11095-025-03895-3","DOIUrl":"https://doi.org/10.1007/s11095-025-03895-3","url":null,"abstract":"","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144691198","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}

{"title":"Dissolution Profiles Comparison Using Various Model Independent Statistical Approaches: Can We Increase Chance of Similarity?","authors":"Rajkumar Boddu, Karthik Parsa, Priyansh Pandya, Sivacharan Kollipara","doi":"10.1007/s11095-025-03892-6","DOIUrl":"https://doi.org/10.1007/s11095-025-03892-6","url":null,"abstract":"<p><strong>Purpose: </strong>In vitro dissolution testing is a critical quality attribute for solid dosage forms. Apart from similarity factor (f2), other alternatives namely model independent and dependent methods are suggested by regulatory agencies. Current manuscript attempts to compare various model independent approaches on dissolution similarity.</p><p><strong>Methods: </strong>Dissolution data with various degrees of variability (10-20%, 40-50%, 70-80%) are compared using similarity factor f2 (estimated, expected, bias corrected with percentile & BCa intervals) and novel approaches such as EDNE, SE, T2EQ, and MSD. Further, a flow chart is proposed to assist selection of suitable methodology.</p><p><strong>Results: </strong>The expected f2 was stringent as compared to other f2 types and the Bca confidence intervals approach increased chance of acceptance as compared to conventional f2 bootstrap. Further, EDNE results synchronized with f2 analysis. Outcome from SE, T2EQ approaches depends on value of equivalence margin. MSD approach was most stringent as compared to others. Finally, a decision tree has been proposed to facilitate the selection of appropriate methodology for similarity analysis with consideration of regulatory perspectives.</p><p><strong>Conclusions: </strong>Overall, various model independent approaches are compared for dissolution similarity analysis. This comprehensive guidance will assist formulation and biopharmaceutics scientists to enhance the success rate of similarity while ensuring regulatory compliance and thus helps to achieve drug product with consistent performance.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659876","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}

{"title":"IVPT Data Challenges in the Real World: Outliers, Anomalous and Aberrant Data: Examples.","authors":"Paul A Lehman","doi":"10.1007/s11095-025-03893-5","DOIUrl":"https://doi.org/10.1007/s11095-025-03893-5","url":null,"abstract":"<p><strong>Background: </strong>The in vitro permeation test (IVPT) is a sensitive and robust model system that has been vital in elucidating the fundamental parameters surrounding the absorption of both therapeutic agents and industrial chemicals through skin. Unlike most clinical bioequivalence study designs, the IVPT method allows for the evaluation of multiple replicates (skin sections) from the same donor (\"subject\") at the same time. Though this should provide an advantage for a better characterization of the topical permeation kinetics within a donor, it also comes with the likelihood that any given skin replicate within the same donor, may demonstrate an unusual or anomalous absorption profile. These are often described as 'outliers', those sections demonstrating a substantial difference in percutaneous absorption kinetics to the other replicates.</p><p><strong>Methods: </strong>A retrospective analysis of data from the authors' archives has been screened with the objective of finding and addressing a number of questions regarding skin section and donor data outliers, anomalous data, missing data and the establishment of a representative J_max.</p><p><strong>Conclusion: </strong>When the IVPT method has been properly designed and performed, outliers reflect anomalies in the donor's skin and donor population rather than as an artifact of the IVPT method. Identification and statistical confirmation approaches help to differentiate anomalous data from the core data set. In addition, missing data, and determining a representative J_max, confound the accurate determination of BE for topical formulations.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144650121","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}

{"title":"Correction: First-in-Class Clinically Investigated Oral Factor D Inhibitors for the Treatment of Complement-Mediated Diseases.","authors":"Venkat R Gadhachanda, Jason A Wiles, Steven D Podos, David Boyer, Jane Thanassi, Dhara Patel, Yongsen Zhao, Lijuan Wang, Mingjun Huang","doi":"10.1007/s11095-025-03894-4","DOIUrl":"https://doi.org/10.1007/s11095-025-03894-4","url":null,"abstract":"","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144637722","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}

{"title":"Inhalable N-Acetylcysteine-loaded Lactose-coated PLGA Nanoparticles for Tuberculosis Treatment.","authors":"Kabi Raj Chaudhary, Cláudia Viegas, Paola Pirela, Mariana Atalaia, Beatriz Ruivinho, Sanchit Arora, Arti Singh, Pedro Brandão, Charan Singh, Pedro Fonte","doi":"10.1007/s11095-025-03889-1","DOIUrl":"https://doi.org/10.1007/s11095-025-03889-1","url":null,"abstract":"<p><strong>Objective: </strong>Glutathione (GSH), known for having mucolytic, anti-inflammatory, and antioxidant activities, is used in clinical practice in several pathologies, including tuberculosis (TB). N-acetylcysteine (NAC) has been primarily used to treat lung conditions and paracetamol-induced liver toxicity. However, NAC exhibits potential antimycobacterial activity through several mechanisms including immunomodulation, enhancement of GSH levels, and direct antimycobacterial effect. In this work, we aim to develop an effective drug delivery system for NAC for inhalable formulations.</p><p><strong>Methods: </strong>Herein, we report the development of lactose-coated NAC-loaded Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NAC-PLGA NPs) obtained by double emulsion methodology. Lactose has a double role, as a cryoprotectant agent and dispersant for inhalable formulations. The physicochemical properties of lactose-coated NAC-PLGA NPs were examined in terms of particle size, polydispersity index (PdI), zeta potential (ZP), encapsulation efficiency, and morphology. The in vitro release and lung deposition studies were assessed.</p><p><strong>Results: </strong>The physicochemical characterization studies revealed the compatibility of the drug with the selected excipients. Moreover, lactose-coated NAC-PLGA NPs showed particle size of 310 ± 3 nm, PdI of 0.15 ± 0.01, and of -11.5 ± 0.4 mV. The in vitro release study suggested a biphasic release profile. Likewise, in vitro lung deposition studies revealed desirable lung deposition parameters, indicating effective particle size for efficient pulmonary delivery. Additionally, in vitro studies for antimycobacterial activity exhibited superior antibacterial activity against Mycobacterium Tuberculosis (MTB) H37Rv.</p><p><strong>Conclusions: </strong>These preliminary findings suggest that lactose-coated NAC-PLGA NPs can open the door to new therapeutic options against one of the most drug-refractory and drug-resistant infectious diseases, TB.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144609040","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}

{"title":"Mechanism of pH-sensitive Amphiphilic Endosomal Escape of Ionizable Lipid Nanoparticles for Cytosolic Nucleic Acid Delivery.","authors":"Zheng-Rong Lu, Da Sun","doi":"10.1007/s11095-025-03890-8","DOIUrl":"https://doi.org/10.1007/s11095-025-03890-8","url":null,"abstract":"<p><p>Lipid nanoparticles (LNPs) are among the most successful classes of nonviral delivery systems for nucleic acid-based therapeutics in treating human diseases. One of the key challenges in achieving efficient cytosolic delivery of nucleic acids is overcoming endosomal entrapment within cells. Conventional lipid bilayer-forming cationic and amino lipids mediate endosomal escape via the mechanism of lamellar-to-inverted hexagonal phase transition, resulting in suboptimal cytosolic cargo delivery. pH-sensitive amphiphilic cell membrane disruption and endosomal escape have emerged as a strategy for designing protonatable or ionizable lipids, especially nonlamellar lipids, for efficient cytosolic nucleic acid delivery. Nonlamellar amino lipids possess a large wedge-shaped tail structure and do not form stable lipid bilayers. These lipids and their corresponding LNPs remain neutral, non-amphiphilic, or minimally amphiphilic at physiological pH (7.4). They become amphiphilic upon protonation or ionization in acidic endosomes (pH 6.5-5.4). The electrostatic interaction of ionized nonlamellar lipids with the negatively charged endosome membrane, combined with their large wedge-like structures, disrupts the lipid bilayer, facilitating efficient endosomal escape. Additionally, the nonlamellar ionizable lipids can be fine-tuned by altering the structure of amino head groups and lipid tails to achieve the precisely controlled pH-sensitive amphiphilic membrane disruption at endosomal pH. Therefore, these lipids exhibit excellent safety profiles and high efficiency for in vivo delivery of various therapeutic nucleic acids. pH-sensitive amphiphilic membrane disruption and endosomal escape provide a feasible and effective mechanism for designing ionizable lipids for safe and efficient in vivo nucleic acid delivery.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144591899","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}

{"title":"Evaluation of the Combination of L‑leucine to Chitosan on Sustained Release of Inhalable Heparin Sodium Microparticles.","authors":"Zhewei Liu, Ying Ma, Yuanyuan Shao, Xiaoyang Wei, Binjie Hu, Jesse Zhu","doi":"10.1007/s11095-025-03883-7","DOIUrl":"https://doi.org/10.1007/s11095-025-03883-7","url":null,"abstract":"<p><strong>Objective: </strong>This study explores the co-spray-drying of chitosan and L-leucine to optimize inhalable microparticles for heparin sodium. Chitosan provides sustained release and pulmonary retention, while L-leucine improves powder dispersibility and aerosolization performance. By tuning the chitosan-to-leucine ratio, the formulation achieves an optimal balance between deep lung deposition and prolonged therapeutic effect, offering a promising strategy for polysaccharide-based pulmonary delivery.</p><p><strong>Methods: </strong>Inhalable microparticles were prepared via co-spray-drying of heparin sodium with chitosan and L-leucine. In-vitro aerosolization performance was evaluated using the Next Generation Impactor. Particle morphology was examined via scanning electron microscopy (SEM). Solid-state properties were analyzed using X-ray powder diffraction (XRPD) to assess changes in crystallinity. Stability was assessed at 25 °C and 55% RH over 4 weeks. Drug release was studied using the in-vitro dialysis method and modeled with five kinetic models: Zero-order, First-order, Higuchi, Hixson-Crowell, and Korsmeyer-Peppas.</p><p><strong>Results: </strong>Heparin sodium microparticles containing chitosan and L-leucine exhibited favorable aerosolization performance, especially in the HSCL1 formulation. SEM showed that L-leucine-induced wrinkling improved dispersibility, while excess chitosan caused surface cracking. XRPD analysis indicated that chitosan suppressed crystallinity while L-leucine retained partial crystalline features, supporting matrix stability and powder dispersion. In-vitro release study demonstrated biphasic kinetics in chitosan-containing formulations. HSCL1 showed sustained, non-Fickian release and enhanced storage stability.</p><p><strong>Conclusion: </strong>Co-spray-dried heparin sodium microparticles with chitosan and L-leucine achieved balanced aerosolization performance, sustained release, and storage stability. Their combination overcomes the limitations of single-excipient systems. The optimized formulation demonstrates strong potential for effective pulmonary drug delivery with improved therapeutic consistency.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144541848","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}

{"title":"The Impact of Drug Properties and Severity of Obesity on Renal Drug Clearance Through Glomerular Filtration and Active Tubular Secretion: A Systematic Analysis Using PBPK Modeling.","authors":"Tan Zhang, Elisa A M Calvier, Elke H J Krekels, Catherijne A J Knibbe","doi":"10.1007/s11095-025-03885-5","DOIUrl":"https://doi.org/10.1007/s11095-025-03885-5","url":null,"abstract":"<p><strong>Objective: </strong>The influence of obesity on renal drug clearance (CLr) remains difficult to predict. This study quantifies obesity-related alterations in CLr for drugs eliminated via glomerular filtration (GF/CL_GF) and active tubular secretion (ATS/CL_ATS) and assesses the systematic accuracy of dosing based on allometric scaling with an exponent of 0.75 or flat dosing (exponent of 0).</p><p><strong>Methods: </strong>A physiologically-based pharmacokinetic (PBPK) approach was used to simulate CL_GF and CL_ATS for 11,520 hypothetical drugs in typical subjects with body mass index (BMI) between 20 and 60. Correlations between changes in CL_GF and CL_ATS and subject or drug properties were investigated. Moreover, for each drug, CLr values scaled to individuals with obesity from CLr values in normal-weight individuals were compared to PBPK predictions of CLr. Systematic scaling accuracy was defined as the prediction error being less than ± 30% for all drugs.</p><p><strong>Results: </strong>CLr through GF and ATS increased with BMI, albeit to different extents, depending on drug properties. When BMI was below 30 kg/m² and transporter activity remained unchanged, the CLr between subjects of normal weight and with overweight or obesity differed less than 30% and both scaling methods were systematically accurate. For individuals with higher BMI, drug properties need to be taken into account when defining scenarios of systematic scaling accuracy.</p><p><strong>Conclusion: </strong>In individuals with a BMI above 30 kg/m², neither 0.75 allometric scaling nor no scaling (flat dosing) is systematically accurate for renally cleared drugs. Strategies are provided to define systematic scaling accuracy a priori, based on subject and drug properties.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507525","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}

{"title":"Traditional Chinese Medicine, Ziyin-Mingmu Decoction, Regulates Cholesterol Metabolism, Oxidative Stress, Inflammation and Gut Microbiota in Age-related Macular Degeneration Models.","authors":"Xing Li, Khalid S Ibrahim, Michal R Baran, Gabriel Mbuta Tchivelekete, Xinzhi Zhou, Yi Wu, James Reilly, Zhoujin Tan, Zhiming He, Xinhua Shu","doi":"10.1007/s11095-025-03887-3","DOIUrl":"https://doi.org/10.1007/s11095-025-03887-3","url":null,"abstract":"<p><strong>Background: </strong>Age-related macular degeneration (AMD) is the commonest cause of retinal disorders in the aged population. Ziyin-Mingmu decoction (ZD) has been widely used to treat AMD patients over thousands of years, however the underlying functional mechanisms of ZD are largely elusive. In this study, we aim to elucidate the therapeutic mechanisms of ZD in AMD models.</p><p><strong>Methods: </strong>An in vivo AMD mouse model and an in vitro AMD model were established. Cholesterol level in mouse tissues was measured. Expression of antioxidant genes and proinflammatory cytokines in mouse tissues and in human retinal pigment epithelial (RPE) cells were detected using biochemical approaches. Gut microbiota community and functional pathways were analysed using bioinformatics approach. Compounds in ZD were identified using HPLC/MS.</p><p><strong>Results: </strong>High fat diet (HFD)-fed mice had significantly higher levels of cholesterol in the retina, RPE, liver and serum, and markedly decreased expression of cholesterol metabolism-associated genes in those tissues, compared to mice fed with normal diet. Similarly, expression of antioxidant and inflammation genes was dysregulated in HFD-fed mouse tissues. ZD treatment reversed these HFD-induced pathological effects. HFD also altered the composition of cecum bacterial communities and associated metabolic pathways, which returned to control levels by ZD. In vitro assays showed that H₂O₂ significantly increased oxidative stress and enhanced expression of proinflammatory cytokines. Co-treatment with ZD significantly counteracted these changes. HPLC/MS identified 105 compound in water extracted ZD and most are polyphenols.</p><p><strong>Conclusion: </strong>Our data suggests that protection of ZD against AMD is possibly through mitigating cholesterol level, oxidative stress and inflammation, and modulating gut microbiota by polyphenols.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507526","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}