Pharmaceutics最新文献

{"title":"Altered Pharmacokinetics of Ropivacaine in Patients Undergoing Laparoscopic Major Hepatectomy.","authors":"Jun Zhang, Hongyuan Lv, Jiliang Shen, Zhichao Ai, Minjun Liu, Xiaorui Liu, Tieshuai Liu, Bo Shen, Hong Yu, Xin Yu","doi":"10.3390/pharmaceutics17030386","DOIUrl":"10.3390/pharmaceutics17030386","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Ropivacaine is primarily metabolized by the liver. High doses of ropivacaine, combined with altered pharmacokinetics due to hepatectomy, raise concerns about potential drug toxicity. We investigated the impact of LMH (laparoscopic major hepatectomy) on the pharmacokinetics of high-dose ropivacaine. <b>Methods:</b> Ten patients undergoing LMH received a BD-TAP (bilateral dual transversus abdominis plane) block with a high dose of ropivacaine (3 mg·kg^-1 in 60 mL). Plasma concentrations of total and free ropivacaine and AAG (alpha-1 acid glycoprotein) levels were measured. Liver volumes were calculated using three-dimensional liver reconstruction technology. <b>Results:</b> The peak total ropivacaine concentration occurred 45 min after the block, reaching 2031.5 (876.0) ng·mL^-1, with a tendency to exceed the toxicity threshold in patients with a CFLV (cut functional liver volume) exceeding 199.24 mL or a CFLV/TFLV (total functional liver volume) ratio surpassing 18.61%. The peak free ropivacaine concentration, 111.5 (31.3) ng·mL^-1, was observed 90 min after the block, potentially exceeding the toxicity threshold when CFLV exceeded 452.33 mL or the CFLV/TFLV ratio was greater than 42.16%. Plasma AAG levels increased approximately 1.5 times within 24 h, from 1519.7 (422.6) μg·mL^-1 preoperatively to 2253.6 (460.4) μg·mL^-1 postoperatively, effectively reducing the toxicity risk associated with free ropivacaine. <b>Conclusions:</b> Preoperative administration of high-dose ropivacaine can be safely utilized in patients undergoing major hepatectomy. The increased plasma AAG concentration due to surgical stress reduces free ropivacaine levels, enhancing patient tolerance to the drug. The CFLV and CFLV/TFLV ratio may be supplementary indicators for predicting ropivacaine toxicity.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 3","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11944703/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720978","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}

{"title":"Evaluating Manganese-Doped Magnetic Nanoflowers for Biocompatibility and In Vitro Magnetic Hyperthermia Efficacy.","authors":"Andreea-Elena Petru, Cristian Iacovita, Ionel Fizeșan, Roxana Dudric, Ionut-Valentin Crestin, Constantin Mihai Lucaciu, Felicia Loghin, Bela Kiss","doi":"10.3390/pharmaceutics17030384","DOIUrl":"10.3390/pharmaceutics17030384","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Magnetic hyperthermia (MH) has emerged as a promising alternative to conventional cancer treatments, offering targeted tumor destruction with minimal damage to healthy tissues. In this study, we synthesized manganese-doped magnetic nanoflowers (Mn-NFs) using a polyol-mediated approach to enhance heating efficiency and biocompatibility for MH applications. Our objective was to evaluate their structural, magnetic, and in vitro hyperthermic properties to determine their potential for lung cancer therapy. <b>Methods</b>: Mn-NFs, with the general formula MnxFe₃-xO₄ (x = 0, 0.3, 0.5, 0.7), were synthesized via a one-step polyol method and characterized using transmission electron microscopy (TEM), X-ray diffraction (XRD), and vibrating sample magnetometry (VSM). Their heating efficiency was assessed through specific absorption rate (SAR) measurements in aqueous and solid environments under an alternating magnetic field (AMF). Cytocompatibility was evaluated using the Alamar Blue assay on A549 lung carcinoma cells. Cellular uptake was quantified via a colorimetric iron determination method, while in vitro MH efficacy was tested by subjecting Mn-NF-loaded A549 cells to AMF exposure at different field strengths and nanoparticle concentrations. <b>Results</b>: Mn-NFs exhibited a flower-like morphology with enhanced magnetic properties, achieving high SAR values, particularly in immobilized conditions. Cytotoxicity assays confirmed high biocompatibility at relevant doses, with Mn-NFs of x = 0.3 showing optimal cellular uptake. MH studies demonstrated significant cancer cell death at AMF intensities of around 30 kA/m, with increased effectiveness following static magnetic field pre-alignment. <b>Conclusions</b>: The results highlight Mn-NFs, particularly those with a Mn content of x = 0.3, as promising candidates for MH-based lung cancer therapy, combining high heating efficiency, biocompatibility, and effective intracellular uptake. Further studies are needed to validate their therapeutic potential in vivo.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 3","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11944501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720998","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}

{"title":"Physiologically Based Biopharmaceutics Model of Apixaban for Biopharmaceutics Risk Assessment.","authors":"Paulo Paixão, Zvonimir Petric, José A G Morais","doi":"10.3390/pharmaceutics17030382","DOIUrl":"10.3390/pharmaceutics17030382","url":null,"abstract":"<p><p><b>Background/Objectives:</b> This study applies a Physiologically Based Biopharmaceutics Modeling (PBBM) framework to predict the bioavailability (BA) and bioequivalence (BE) of apixaban, a borderline BCS Class III/IV drug. It investigates how formulation factors, such as particle size, granulation method, and dissolution conditions, affect apixaban's in vivo behavior under fasting conditions. <b>Methods:</b> A PBBM approach was developed by integrating physicochemical, formulation, and drug-related parameters to simulate dissolution and absorption using a middle-out strategy for combining in silico, in vitro, and in vivo data. The Noyes-Whitney equation was used to predict dissolution influenced by particle size, granulation type, and in vitro dissolution conditions. This information was added to a compartmental absorption model of the gastrointestinal track connected to a classical compartmental model characterizing apixaban's disposition. <b>Results:</b> The study validated the apixaban PBBM predictions by comparing simulated and observed pharmacokinetic profiles across several doses and immediate release formulations (solution and tablets) administered through the oral route. Results demonstrated acceptable prediction accuracy for BA and BE under various conditions. The model's simulations identified a dissolution safe space, enabling regulatory and development insights into acceptable formulation characteristics. <b>Conclusions:</b> These findings highlight the potential of PBBM in streamlining drug development, reducing clinical studies, and supporting regulatory decisions. Specifically, for apixaban, the study demonstrated that particle sizes below 120 µm ensure BE with reference formulations, while formulations with faster dissolution rates, such as smaller particle sizes, align closely with BCS biowaiver criteria. This research emphasizes PBBM as a valuable tool for optimizing drug quality and lifecycle management.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 3","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11944388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143721053","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}

{"title":"Enhancing the Oral Bioavailability of Glutathione Using Innovative Analogue Approaches.","authors":"Naibo Yin, Paul W R Harris, Mengyang Liu, Jianguo Sun, Guanyu Chen, Jingyuan Wen, Margaret A Brimble","doi":"10.3390/pharmaceutics17030385","DOIUrl":"10.3390/pharmaceutics17030385","url":null,"abstract":"<p><p><b>Background:</b> Glutathione (GSH) is an essential antioxidant that protects against oxidative stress, but its oral bioavailability is below 1% due to enzymatic degradation and poor gastrointestinal absorption. Improving the oral bioavailability of GSH could significantly enhance its therapeutic efficacy. <b>Methods:</b> This study synthesised GSH analogues with chemical modifications to improve bioavailability. Seven GSH derivatives were designed: three analogues with altered stereochemistry (<b>1.62</b>, <b>1.63</b>, and <b>1.64</b>) and three <i>N</i>-methylated derivatives (<b>1.65</b>, <b>1.70</b>, and <b>1.71</b>), alongside a native GSH (<b>1.61</b>). The analogues were synthesised via Fmoc-solid-phase peptide synthesis, and they were characterised using reverse-phase high-performance liquid chromatography (RP-HPLC), electrospray ionisation mass spectrometry (ESI-MS), Fourier-transform infrared spectroscopy (FTIR), and nuclear magnetic resonance (NMR) spectroscopy. Their toxicity was assessed on Caco-2 cells for viability, and their antioxidant activity was assessed on UVA-irradiated fibroblast cells, enzymatic resistance, and interactions with GSH-metabolising enzymes. <b>Results</b>: Among the tested analogues, the <i>N-</i>methylated cysteine Compound (1.70) emerged as the most promising candidate. Compound <b>1.70</b> demonstrated superior resistance to enzymatic degradation, as well as showing enhanced cell viability and improved antioxidant activity. In vivo studies revealed a 16.8-fold increase in plasma half-life (t½) and a 16.1-fold increase in oral bioavailability compared to native GSH. <b>Conclusions</b>: Chemical modification strategies, particularly the <i>N-</i>methylation of GSH, present a viable approach to enhancing oral bioavailability. Compound <b>1.70</b> showed significant potential for therapeutic applications, warranting further investigation and development in clinical settings.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 3","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11945201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720994","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}

{"title":"Design of Experiment Approach for Enhancing the Dissolution Profile and Robustness of Loratadine Tablet Using D-α-Tocopheryl Polyethylene Glycol 1000 Succinate.","authors":"Alhasan A Jabbar, Israa Al-Ani, Ramadan I Al-Shdefat, Nadia Ghazal, Anwar Jaffal, Mohamed H Fayed","doi":"10.3390/pharmaceutics17030380","DOIUrl":"10.3390/pharmaceutics17030380","url":null,"abstract":"<p><p><b>Background:</b> Formulating poorly water-soluble drugs poses significant challenges due to their limited solubility and bioavailability. Loratadine (LTD), classified as a BCS II molecule, exhibits notably low solubility, leading to reduced bioavailability. Objective: This study aims to enhance the dissolution rate of LTD through the utilization of the wet granulation process using Tocopheryl polyethylene glycol 1000 succinate (TPGS). <b>Methods</b>: A Design-of-Experiment methodology was adopted to investigate and optimize the formulation variables for preparing an oral delivery system of LTD with improved dissolution properties. The levels of TPGS (2-6% <i>w</i>/<i>w</i>), as a surfactant, and sodium starch glycolate (SSG; 2-8% <i>w</i>/<i>w</i>), as a super-disintegrant, were established as independent variables in the formulations. Loratadine was granulated in the presence of TPGS, and the resultant granules were subsequently compressed into tablets. The granules and tablets produced were then subjected to characterization. <b>Results</b>: ANOVA analysis indicated that both TPGS and SSG had a significant (<i>p</i> < 0.05) influence on the critical characteristics of the obtained granules and tablets, with TPGS showing a particularly notable effect. The optimal concentrations of TPGS and SSG for the development of LTD tablets with the necessary quality attributes were identified as 5.0% <i>w</i>/<i>w</i> and 2.0% <i>w</i>/<i>w</i>, respectively, through optimization utilizing the desirability function. The tablets produced at these optimized concentrations displayed favorable properties concerning their mechanical strength (5.72 ± 0.32 KP), disintegration time (7.11 ± 1.08 min.), and release profile (86.21 ± 1.61%). <b>Conclusions</b>: In conclusion, incorporating TPGS in the granulation process shows promise in improving the dissolution profile of poorly water-soluble drugs and demonstrated formulation robustness.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 3","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11946126/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720563","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}

{"title":"Oral Bioavailability Enhancement of Anti-Cancer Drugs Through Lipid Polymer Hybrid Nanoparticles.","authors":"Saud Almawash","doi":"10.3390/pharmaceutics17030381","DOIUrl":"10.3390/pharmaceutics17030381","url":null,"abstract":"<p><p>Cancer is considered as the second leading cause of death worldwide. Chemotherapy, radiotherapy, immunotherapy, and targeted drug delivery are the main treatment options for treating cancers. Chemotherapy drugs are either available for oral or parenteral use. Oral chemotherapy, also known as chemotherapy at home, is more likely to improve patient compliance and convenience. Oral anti-cancer drugs have bioavailability issues associated with lower aqueous solubility, first-pass metabolism, poor intestinal permeability and drug absorption, and degradation of the drug throughout its journey in the gastrointestinal tract. A highly developed carrier system known as lipid polymer hybrid nanoparticles (LPHNs) has been introduced. These nanocarriers enhance drug stability, solubility, and absorption, and reduce first-pass metabolism. Consequently, this will have a positive impact on oral bioavailability enhancement. This article provides an in-depth analysis of LPHNs as a novel drug delivery system for anti-cancer agents. It discusses an overview of the limited bioavailability of anti-cancer drugs, their reasons and consequences, LPHNs based anti-cancer drug delivery, conventional and modern preparation methods as well as their drug loading and entrapment efficiencies. In addition, this article also gives an insight into the mechanistic approach to oral bioavailability enhancement, potential applications in anti-cancer drug delivery, limitations, and future prospects of LPHNs in anti-cancer drug delivery.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 3","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11946161/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143721043","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}

{"title":"PK/PD of Positively Charged ADC in Mice.","authors":"Hsuan-Ping Chang, Huyen Khanh Le, Shufang Liu, Dhaval K Shah","doi":"10.3390/pharmaceutics17030377","DOIUrl":"10.3390/pharmaceutics17030377","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Antibody-drug conjugates (ADCs) show significant promise in oncology but often suffer from a narrow therapeutic window. Introducing a positive charge on the antibody is one proposed strategy to enhance tumor distribution and efficacy of ADC. Accordingly, this study evaluates the pharmacokinetics (PK) and pharmacology of an ADC developed using a positively charged (+5) version of anti-HER2 antibody trastuzumab conjugated with vc-MMAE linker-payload. <b>Methods</b>: A positively charged variant of trastuzumab was generated and conjugated to vc-MMAE. In vitro cytotoxicity assays were performed in cell lines with varying HER2 expression levels: N87 (high), MCF-7 (low), and MDA-MB-468 (non-expressing). In vivo biodistribution of wild-type (WT) and positively charged (+5) ADC was investigated in plasma, tumors, liver, and spleen. A pilot efficacy and toxicity study was also conducted in N87 tumor-bearing mice. <b>Results</b>: The charged ADC showed differential potency and PK behavior compared to the WT ADC. The charged ADC had similar potency in N87 cells but demonstrated ~20-fold and ~60-fold higher potency in MCF-7 and MDA-MB-468 cells. Plasma exposures of all the analytes were found to be reduced following the administration of charged ADC. However, total antibody exposure was found to increase in liver, spleen, and low antigen-expressing MCF-7 tumors. Tumor payload exposures were found to be significantly reduced for the charged ADCs, but liver and spleen displayed higher peak concentrations and increased tissue-to-plasma exposure ratios for the payload, suggesting preferential distribution of ADC with high drug-antibody ratio (DAR) to liver and spleen. Consistent with reduced tumor exposures, charged ADC showed lower efficacy in N87 tumor-bearing mice. No overt toxicity was observed for the charged ADC. <b>Conclusions</b>: Our findings suggest that while positively charged ADCs may be more potent in vitro, their efficacy in vivo may be compromised due to altered PK behavior. Thus, introducing a positive charge into the antibody framework may not be a viable strategy for improving the therapeutic potential of ADCs.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 3","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11944646/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720984","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}

{"title":"Clinical Applications of Targeted Nanomaterials.","authors":"Ankesh Kumar, S K Shahvej, Pankaj Yadav, Unnati Modi, Amit K Yadav, Raghu Solanki, Dhiraj Bhatia","doi":"10.3390/pharmaceutics17030379","DOIUrl":"10.3390/pharmaceutics17030379","url":null,"abstract":"<p><p>Targeted nanomaterials are at the forefront of advancements in nanomedicine due to their unique and versatile properties. These include nanoscale size, shape, surface chemistry, mechanical flexibility, fluorescence, optical behavior, magnetic and electronic characteristics, as well as biocompatibility and biodegradability. These attributes enable their application across diverse fields, including drug delivery. This review explores the fundamental characteristics of nanomaterials and emphasizes their importance in clinical applications. It further delves into methodologies for nanoparticle programming alongside discussions on clinical trials and case studies. We discussed some of the promising nanomaterials, such as polymeric nanoparticles, carbon-based nanoparticles, and metallic nanoparticles, and their role in biomedical applications. This review underscores significant advancements in translating nanomaterials into clinical applications and highlights the potential of these innovative approaches in revolutionizing the medical field.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 3","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11944548/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143721010","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}

{"title":"Applications of Cyclodextrin-Based Drug Delivery Systems in Inflammation-Related Diseases.","authors":"Zelan Dai, Huijuan Yang, Peng Yin, Xingkang Liu, Ling Zhang, Youwei Dou, Shibo Sun","doi":"10.3390/pharmaceutics17030378","DOIUrl":"10.3390/pharmaceutics17030378","url":null,"abstract":"<p><p>Currently, inflammation diseases are one of the leading causes of mortality worldwide. The therapeutic drugs for inflammation are mainly steroidal and non-steroidal anti-inflammatory drugs. However, the use of these anti-inflammatory drugs over a prolonged period is prone to causing serious side effects. Accordingly, it is particularly critical to design an intelligent target-specific drug delivery system to control the release of drugs in order to mitigate the side effects of anti-inflammatory drugs without limiting their activity. Meanwhile, cyclodextrin-based nano-delivery systems have garnered significant attention in contemporary pharmaceutical research owing to their capacity to enhance drug bioavailability, enable site-specific targeted accumulation, prolong the systemic circulation duration, facilitate synergistic therapeutic outcomes, and exhibit superior biocompatibility profiles. It is worth noting that cyclodextrin-based drug delivery systems show great potential in inflammation-related diseases. However, few studies have systematically reviewed their design strategies and application advancements. Here, we summarize the structural and chemical modification strategies of cyclodextrins, as well as cyclodextrin-based drug delivery systems and their applications in inflammation-related diseases. In summary, the aim is to provide a bit of insight into the development of cyclodextrin-based drug delivery systems for inflammation-related diseases.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 3","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11945956/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720963","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}

{"title":"Burst-Free Sustained Release of Proteins from Thermal Gelling Polymer Solutions.","authors":"Yuxing Zhang, Xixi Zou, Qiran Du, Xiaotao Dong, Uday Kumar Chinta, Ruyue Yu, Fei Wu, Tuo Jin","doi":"10.3390/pharmaceutics17030376","DOIUrl":"10.3390/pharmaceutics17030376","url":null,"abstract":"<p><p><b>Objectives</b>: Thermo-gelling hydrophilic polymers like PLGA-PEG-PLGA are known as injectable sustained-release depots for biologics, but they face challenges due to the occurrence of severe burst release. This study aimed to develop a strategy to avoid the initial burst release by pre-encapsulating proteins in polysaccharide microparticles through an aqueous-aqueous emulsion mechanism, thereby enhancing therapeutic retention and linear release kinetics. <b>Methods</b>: Five model proteins (G-CSF, GM-CSF, IGF-1, FVIII, BSA) were encapsulated in dextran microparticles, using an organic solvent-free aqueous-aqueous emulsion method. These particles were dispersed in a 23% (<i>w</i>/<i>w</i>) PLGA-PEG-PLGA solution and injected into a 37 °C release buffer to form a gel depot. The in vitro release profiles were quantified using ELISA and MicroBCA assays over 9-42 days. The bioactivity of the proteins was validated using cell proliferation assays (NFS-60, TF-1, MCF-7) and chromogenic kits. The in vivo pharmacokinetics of the FVIII-loaded formulations were evaluated in Sprague-Dawley rats (n = 5/group) over 28 days. <b>Results</b>: Protein-loaded dextran particles retained their structural integrity within the hydrogel and exhibited minimal burst release (≤5% within 30 min vs. >25% for free proteins). Sustained near-linear release profiles were observed for all the proteins, with complete release by day 9 (G-CSF, GM-CSF, BSA) or day 42 (FVIII). Rats administered with the thermal gel with FVIII-dextran particles showed a significantly lower peak plasma concentration (C_max: 88.25 ± 30.21 vs. 132.63 ± 66.67 ng/mL) and prolonged therapeutic coverage (>18 days vs. 15 days) compared to those administered with the thermal gel with the FVIII solution. The bioactivity of the released proteins remained at ≥90% of the native forms. <b>Conclusions</b>: Pre-encapsulation in dextran microparticles effectively mitigates burst release from thermosensitive hydrogels, while preserving protein functionality.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 3","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11945406/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143721005","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}