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Evaluation of the Combination of L‑leucine to Chitosan on Sustained Release of Inhalable Heparin Sodium Microparticles. L -亮氨酸与壳聚糖复合对可吸入肝素钠缓释的影响。
IF 3.5 3区 医学
Pharmaceutical Research Pub Date : 2025-07-01 DOI: 10.1007/s11095-025-03883-7
Zhewei Liu, Ying Ma, Yuanyuan Shao, Xiaoyang Wei, Binjie Hu, Jesse Zhu
{"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}
引用次数: 0
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. 药物性质和肥胖严重程度通过肾小球滤过和活跃小管分泌对肾脏药物清除的影响:使用PBPK模型的系统分析
IF 3.5 3区 医学
Pharmaceutical Research Pub Date : 2025-06-27 DOI: 10.1007/s11095-025-03885-5
Tan Zhang, Elisa A M Calvier, Elke H J Krekels, Catherijne A J Knibbe
{"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<sub>GF</sub>) and active tubular secretion (ATS/CL<sub>ATS</sub>) 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<sub>GF</sub> and CL<sub>ATS</sub> for 11,520 hypothetical drugs in typical subjects with body mass index (BMI) between 20 and 60. Correlations between changes in CL<sub>GF</sub> and CL<sub>ATS</sub> 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/m<sup>2</sup> 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/m<sup>2</sup>, 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}
引用次数: 0
Traditional Chinese Medicine, Ziyin-Mingmu Decoction, Regulates Cholesterol Metabolism, Oxidative Stress, Inflammation and Gut Microbiota in Age-related Macular Degeneration Models. 中药紫银明目汤调节老年性黄斑变性模型的胆固醇代谢、氧化应激、炎症和肠道微生物群
IF 3.5 3区 医学
Pharmaceutical Research Pub Date : 2025-06-26 DOI: 10.1007/s11095-025-03887-3
Xing Li, Khalid S Ibrahim, Michal R Baran, Gabriel Mbuta Tchivelekete, Xinzhi Zhou, Yi Wu, James Reilly, Zhoujin Tan, Zhiming He, Xinhua Shu
{"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 H<sub>2</sub>O<sub>2</sub> 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}
引用次数: 0
First-in-Class Clinically Investigated Oral Factor D Inhibitors for the Treatment of Complement-Mediated Diseases. 口服因子D抑制剂治疗补体介导性疾病的临床研究
IF 3.5 3区 医学
Pharmaceutical Research Pub Date : 2025-06-25 DOI: 10.1007/s11095-025-03882-8
Venkat R Gadhachanda, Jason A Wiles, Steven D Podos, David Boyer, Jane Thanassi, Dhara Patel, Yongsen Zhao, Lijuan Wang, Mingjun Huang
{"title":"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/s11095-025-03882-8","DOIUrl":"https://doi.org/10.1007/s11095-025-03882-8","url":null,"abstract":"<p><strong>Objective: </strong>The global of the study was to discover small molecular inhibitors of complement factor D (FD), an essential protease for activation of the alternative pathway (AP) of complement, that possess the characteristics for clinical investigation in complement-mediated diseases such as paroxysmal nocturnal hemoglobinuria (PNH).</p><p><strong>Methods: </strong>Compounds were synthesized and tested in vitro for potency, selectivity, and metabolic stability. The optimized compounds were subjected further to a panel of in vitro tests for primary and secondary pharmacology including inhibitory effects on FD, different complement pathways and disease models, as well as to pharmacokinetic and pharmacodynamic evaluations in animals.</p><p><strong>Results: </strong>Following multiple rounds of optimization, danicopan and later vermicopan were chosen as candidates for clinical investigation. Both compounds demonstrated potent and selective inhibitory effects on FD and AP, suitable pharmacokinetic characteristics for oral dosing, and efficacy in PNH in vitro disease models. In addition to enhanced in vitro potency, vemircopan exhibited lower clearance and higher bioavailability in animal studies compared with danicopan.</p><p><strong>Conclusion: </strong>Preclinical evaluations of danicopan and vermicopan provided rationales to conduct clinical studies in complement-mediated diseases. Recently, danicopan was approved as an add-on therapy to the C5 inhibitors ravulizumab or eculizumab for the treatment of extravascular hemolysis in patients with PNH.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144497664","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
Quantitative Investigation of Synthetic Mucus Effects on Spray Deposition in a 3D-Printed SLA Nasal Cavity Model. 合成黏液对3d打印SLA鼻腔模型喷雾沉积影响的定量研究。
IF 3.5 3区 医学
Pharmaceutical Research Pub Date : 2025-06-25 DOI: 10.1007/s11095-025-03886-4
Amr Seifelnasr, Xiuhua April Si, Jinxiang Xi
{"title":"Quantitative Investigation of Synthetic Mucus Effects on Spray Deposition in a 3D-Printed SLA Nasal Cavity Model.","authors":"Amr Seifelnasr, Xiuhua April Si, Jinxiang Xi","doi":"10.1007/s11095-025-03886-4","DOIUrl":"https://doi.org/10.1007/s11095-025-03886-4","url":null,"abstract":"<p><strong>Purpose: </strong>To quantify the deposition distribution of intranasally administered sprays in an anatomically accurate 3D-printed nasal model under varying conditions.</p><p><strong>Methods: </strong>A multipiece nasal cast was used to assess deposition under three head positions (upright, 22.5° backward tilt, and 45° backward tilt) and two airflow conditions (no flow and gentle sniff). Synthetic mucus coatings were prepared using saline-based xanthan gum (XG) solutions with two different XG concentrations: 0.25% w/v, representing a healthy state, and 1% w/v, representing a diseased state. Regional doses were quantified using salinity-based measurements for both uncoated and coated nasal casts.</p><p><strong>Results: </strong>The results demonstrate that synthetic mucus coatings significantly altered intranasal spray dosimetry, promoting broader spreading and deeper translocation compared to dry-wall models. In the middle turbinate region, the highest mean deposition occurred under sniff airflow at a 45° backward tilt with a 1% XG coating (76 ppm), representing a 244% increase over the dry condition (22 ppm). For the posterior nasal cavity, the most effective mean deposition was achieved at a 22.5° backward tilt with sniff airflow and a 0.25% XG coating (63 ppm vs. 0 ppm dry). The mucus viscosity can significantly alter regional distribution. A 0.25% XG coating facilitated deeper translocation to the posterior nasal cavity, while 1% XG enhanced retention in the middle turbinate region.</p><p><strong>Conclusions: </strong>These findings highlight the importance of incorporating synthetic mucus in in vitro nasal models to improve physiological relevance and provide insights for optimizing intranasal drug delivery techniques.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144497665","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
Efficient Cytosolic Delivery of siRNA Using Lyophilized and Reconstituted Polymer-siRNA Polyplexes. 利用冻干和重组的聚合物-siRNA复合物高效的siRNA细胞质递送。
IF 3.5 3区 医学
Pharmaceutical Research Pub Date : 2025-06-23 DOI: 10.1007/s11095-025-03884-6
Harini Nagaraj, Taewon Jeon, Yagiz Anil Cicek, Ritabrita Goswami, Nourina Nasim, Rukmini Mhaske, Vincent M Rotello
{"title":"Efficient Cytosolic Delivery of siRNA Using Lyophilized and Reconstituted Polymer-siRNA Polyplexes.","authors":"Harini Nagaraj, Taewon Jeon, Yagiz Anil Cicek, Ritabrita Goswami, Nourina Nasim, Rukmini Mhaske, Vincent M Rotello","doi":"10.1007/s11095-025-03884-6","DOIUrl":"https://doi.org/10.1007/s11095-025-03884-6","url":null,"abstract":"<p><strong>Purpose: </strong>siRNA enables highly specific and targeted gene silencing, offering potential treatment for a range of diseases. Cytosolic access of siRNA is essential for efficacy; Current delivery systems generally use endosomal uptake pathways, leading to siRNA degradation due to inefficient escape. Guanidinium functionalized poly(oxanorbornene)imide (PONI) polymers facilitate direct cytosolic siRNA delivery with excellent gene knockdown efficacy in vitro and in vivo. The use of lyophilization to generate stable powders that retain excellent delivery and knockdown activity when reconstituted is demonstrated, providing a key tool for translation.</p><p><strong>Methods: </strong>PONI-Guan polymers were mixed with siRNA to form PONI-Guan/siRNA polyplexes. The generated polyplexes were lyophilized and stored at varying temperature conditions for a total duration of 4 weeks. After reconstitution and delivery, cytosolic access of siRNA was assessed through confocal laser scanning microscopy. Knockdown efficacy was assessed in GFP expressing reporter deGFP HEK 293 T cell line using flow cytometry. Efficacy of reconstituted PONI-Guan/si_STAT3 in 4T1 breast cancer cells was evaluated by quantifying gene expression levels (qRT-PCR) and cell growth inhibition (Alamar blue assay). Delivery and therapeutic efficiency were compared between lyophilized and freshly made polyplexes.</p><p><strong>Results: </strong>Lyophilized polyplexes retained critical functional features of freshly made polyplexes. Resuspended polyplexes facilitated effective cytosolic delivery siRNA and showed therapeutic relevance through the delivery of siRNA targeting STAT-3 gene in 4T1 cells with successful cell growth inhibition (~ 70%) and knockdown (~ 80%) of the gene.</p><p><strong>Conclusion: </strong>Overall, this strategy signifies a highly transferrable and versatile method for effective storage of siRNA.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144476294","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 New Analytical LC-MS/MS Method for Determination of Eight Standard Nitrosamines (NDMA, NMBA, NDEA, NEIPA, NDIPA, NMPA, NDPA, NDBA) in a Commercial Small Molecule Drug Product Capsules and its Active Pharmaeceutical Ingredient for Treatment of Fabry: A Rare Disease. 一种新的LC-MS/MS分析方法测定治疗罕见病法布里病市产小分子制剂胶囊中8种标准亚硝胺(NDMA、NMBA、NDEA、NEIPA、NDIPA、NMPA、NDPA、NDBA)及其活性成分
IF 3.5 3区 医学
Pharmaceutical Research Pub Date : 2025-06-17 DOI: 10.1007/s11095-025-03875-7
Krishnaiah Charagondla, Partha S Mukherjee, Kalyani Ginjupalli, Bing Hu, Simrat Kaur, Paresh Thanki, Tejas Tailor, Bhavin Prajapati, Saroj Ramdas
{"title":"A New Analytical LC-MS/MS Method for Determination of Eight Standard Nitrosamines (NDMA, NMBA, NDEA, NEIPA, NDIPA, NMPA, NDPA, NDBA) in a Commercial Small Molecule Drug Product Capsules and its Active Pharmaeceutical Ingredient for Treatment of Fabry: A Rare Disease.","authors":"Krishnaiah Charagondla, Partha S Mukherjee, Kalyani Ginjupalli, Bing Hu, Simrat Kaur, Paresh Thanki, Tejas Tailor, Bhavin Prajapati, Saroj Ramdas","doi":"10.1007/s11095-025-03875-7","DOIUrl":"https://doi.org/10.1007/s11095-025-03875-7","url":null,"abstract":"<p><strong>Purpose: </strong>This study aims to develop and validate a highly sensitive LC-MS/MS method for quantifying eight nitrosamine (NA) impurities NDMA, NMBA, NDEA, NEIPA, NDIPA, NMPA, NDPA, and NDBA in a small molecule commercial Active Pharmaceutical Ingredients (API) and Drug Product (DP) capsules used for the treatment of Fabry rare disease in global patients.</p><p><strong>Methods: </strong>The method utilized gradient separation on a C18 column, ensuring optimum resolution between NAs and internal standards. Elution was monitored at precursor and product ions. The method was validated according to ICH Q2 (R1) guidelines, assessing specificity, linearity, recovery, and repeatability in both API and capsule matrices.</p><p><strong>Results: </strong>Quantification of NAs ranged from 0.0215 to 0.780 ppm in relation to a 20.5 mg/mL sample concentration. Linearity coefficients ranged from 0.99 to 1.00. The Detection Limit (DL) was 0.154-0.560 ng/mL, and the Quantitation Limit (QL) was 0.438-1.590 ng/mL. Mean recoveries for all NAs were between 90 and 107%, and repeatability was under 15%. An Analytical Target Profile (ATP) concept was successfully employed to monitor Analytical Method Performance Characteristics (AMPC).</p><p><strong>Conclusions: </strong>The validated LC-MS/MS method proved effective for quantifying NAs (NDMA, NMBA, NDEA, NEIPA, NDIPA, NMPA, NDPA, and NDBA) in both API and capsule matrices, with results consistently below the Quantitation Limit (QL) in confirmatory testing. This approach supports the elimination of routine NA testing, adhering to FDA and EMA's conservative Acceptable Intake (AI) limits, ensuring safety and regulatory compliance for global patients.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144317625","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
PEGylation of Propofol Reduces Its Adsorption to Extracorporeal Membrane Oxygenator (ECMO) Components. 异丙酚聚乙二醇化降低其对体外膜氧合器(ECMO)组分的吸附。
IF 3.5 3区 医学
Pharmaceutical Research Pub Date : 2025-06-05 DOI: 10.1007/s11095-025-03879-3
Benedetta Campara, Nitish Khurana, Andrea De Nadai, Venkata Yellepeddi, Kevin Watt, Gianfranco Pasut, Hamidreza Ghandehari
{"title":"PEGylation of Propofol Reduces Its Adsorption to Extracorporeal Membrane Oxygenator (ECMO) Components.","authors":"Benedetta Campara, Nitish Khurana, Andrea De Nadai, Venkata Yellepeddi, Kevin Watt, Gianfranco Pasut, Hamidreza Ghandehari","doi":"10.1007/s11095-025-03879-3","DOIUrl":"https://doi.org/10.1007/s11095-025-03879-3","url":null,"abstract":"<p><p>Extracorporeal membrane oxygenation (ECMO) is a life-saving cardiopulmonary bypass technology for critically ill patients. Patients treated with ECMO receive multiple drugs to treat critical illnesses, prevent infections, and maintain sedation. However, inaccurate dosing information of some of the administered drugs is a significant cause of ECMO related mortality. Hydrophobic drugs tend to adsorb on the surface of ECMO circuit components leading to suboptimal dosing and therapeutic failure. Modifying the drugs can be exploited as a strategy to reduce drug adsorption in ECMO circuits. Propofol (Diprivan®) is a widely used anesthetic in ECMO patients that is known to substantially adsorb to ECMO circuit components due to its hydrophobicity. The objective of this work was to evaluate the PEGylation of propofol as a strategy to reduce its adsorption to the ECMO circuit. Poly(ethylene glycol) (PEG) was covalently conjugated to propofol with varying PEG lengths, i.e., 3 monomers of PEG (PEG<sub>3</sub>), 5 monomers of PEG (PEG<sub>5</sub>) and 2 kDa molecular weight PEG (PEG<sub>2kDa</sub>). The conjugates were synthesized, characterized, and compared for their water solubility, ability to spontaneously form micelles, and in reducing adsorption to hydrophobic materials in an in vitro ECMO mimic assay. Further, the conjugates were tested for their anesthetic activity in a C57BL/6 mouse model. We demonstrated that PEG<sub>5</sub>-Propofol and PEG<sub>2kDa</sub>-Propofol had improved water solubility and significantly reduced the adsorption of propofol. PEG<sub>5</sub>-Propofol also demonstrated a similar anesthetic activity (520 ± 109 secs) to free propofol (485 ± 103 secs). Our results demonstrate that PEG<sub>5</sub>-Propofol is a promising anesthetic for administration to patients on ECMO.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234787","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
Development of Alogliptin Oral-Dissolving Films with Optimized Therapeutic Outcomes. 阿格列汀口服溶出膜的研制及最佳治疗效果。
IF 3.5 3区 医学
Pharmaceutical Research Pub Date : 2025-06-04 DOI: 10.1007/s11095-025-03873-9
Sagar Pathade, Varsha Balkrishna Mane, Nagesh Aloorkar, Divya Bhagat, Sanuja Kadam, Rushikesh Kshirsagar
{"title":"Development of Alogliptin Oral-Dissolving Films with Optimized Therapeutic Outcomes.","authors":"Sagar Pathade, Varsha Balkrishna Mane, Nagesh Aloorkar, Divya Bhagat, Sanuja Kadam, Rushikesh Kshirsagar","doi":"10.1007/s11095-025-03873-9","DOIUrl":"https://doi.org/10.1007/s11095-025-03873-9","url":null,"abstract":"<p><strong>Introduction: </strong>The work aims at formulating Alogliptin benzoate as fast-dissolving film to bypass first-pass metabolism to improve therapeutic benefits.</p><p><strong>Methods: </strong>Alogliptin Oral dissolving films (ODFs) prepared by solvent casting method and physico-chemically characterised. The in vitro dissolution was performed in pH 6.8 phosphate buffer. Accelerated stability studies were conducted.The antidiabetic activity of ODFs was assessed in diabetes-induced Wistar albino rats.</p><p><strong>Results: </strong>The films were found to be slightly translucent, uniform, smooth and flexible in nature. The average weights were found to be 57.87 ± 4.59 mg. Optimized ODFs showed uniformity in drug content of 98.84 ± 2.22% while surface pH was found between 6.87 to 6.93. The FTIR analysis indicated no significant changes in the functional groups of Alogliptin benzoate in optimised formulation. The optimized Alogliptin benzoate ODF formulation shows altered thermal stability and retains the crystalline structure of the drug. Its rod-like crystals and formulation components enhance dissolution, enabling a rapid initial release. While the pure drug dissolves faster initially, ODF demonstrates efficient oral mucosa permeation and quicker blood glucose reduction within the first hour. The drug content in the formulation does not show any significant lowering (98.84 ± 2.22 initial and 96.89 ± 2.12 after 3 month of stability studies).Despite slightly lower glucose levels at 24 h, the ODF F formulation offers improved therapeutic efficiency and controlled release, making it effective for blood glucose management.</p><p><strong>Conclusion: </strong>The Alogliptin benzoate ODF offers a promising alternative for diabetes management, providing rapid onset and improved patient compliance through easier administration.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226276","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
The Next Frontier: Unveiling Novel Approaches for Combating Multidrug-Resistant Bacteria. 下一个前沿:揭示对抗多重耐药细菌的新方法。
IF 3.5 3区 医学
Pharmaceutical Research Pub Date : 2025-06-01 Epub Date: 2025-06-16 DOI: 10.1007/s11095-025-03871-x
Praveen Mallari, Leila D Rostami, Ida Alanko, Fadak Howaili, Meixin Ran, Kuldeep K Bansal, Jessica M Rosenholm, Outi M H Salo-Ahen
{"title":"The Next Frontier: Unveiling Novel Approaches for Combating Multidrug-Resistant Bacteria.","authors":"Praveen Mallari, Leila D Rostami, Ida Alanko, Fadak Howaili, Meixin Ran, Kuldeep K Bansal, Jessica M Rosenholm, Outi M H Salo-Ahen","doi":"10.1007/s11095-025-03871-x","DOIUrl":"10.1007/s11095-025-03871-x","url":null,"abstract":"<p><strong>Background: </strong>The rapid occurrence of bacterial antibiotic resistance poses a significant threat to public health worldwide. Since particularly multidrug-resistant (MDR) pathogens are becoming untreatable with currently available antibiotics, new treatment modalities must be deployed.</p><p><strong>Objectives: </strong>This review explores the recent advancements and the enduring challenges in new antibacterial development for drug-resistant organisms.</p><p><strong>Results: </strong>We describe how bacterial resistance to antibiotics arises and discuss why the traditional drug discovery routes are inefficient. The best alternative strategies to overcome these challenges might include exploring new bacterial pathways, utilizing compounds with antibacterial activities from the human microbiome, and repurposing existing drugs. Moreover, novel drug delivery mechanisms that leverage, for example, nanotechnology-based carriers may be breakthrough ideas that can increase antibiotic efficacy and, at the same time, reduce toxicity. Current clinical trials of next-generation drugs indicate that some treatments possess excellent potential to overcome the MDR issue.</p><p><strong>Conclusion: </strong>Despite the substantial obstacles to getting bench findings to the patient, numerous scientists are still working towards this goal. Both the application of antibiotic stewardship principles and timely considerations through the regulatory pathways are needed to release the next generation of antibiotics that are suitable for the fight against superbugs.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"859-889"},"PeriodicalIF":3.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12222395/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144310282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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