Pub Date : 2024-10-02DOI: 10.1016/j.ijpharm.2024.124781
Coacervation, a common method for microspheres preparation, has not been given sufficient attention and study. This study aims to clarify the key factors in the phase separation step. Firstly, based on the thermodynamics of polymer solutions, the phase equilibrium time, binodal line, and the relationship between the concentration of lactic-glycolic acid copolymer (PLGA) in the coacervate phase (CPLGA) and the concentration of polydimethylsiloxane (PDMS) in the PLGA-lean phase (CPDMS) were determined. It was found that the lactic:glycolic ratio (L:G) significantly influences phase separation, and we introduced a method to calculate the compositions and masses of both the coacervate and PLGA-lean phases after phase separation of a system composed of PLGA, PDMS, and dichloromethane (DCM). Furthermore, some impellers aimed at producing narrow size distribution microspheres were designed, and the stirring states were analyzed visually using Computational Fluid Dynamics (CFD), explaining the impact of impeller types and clearance between impeller and vessel on particle size distribution. Measurements of the viscosities of the coacervate and continuous phases, coupled with emulsion theories, clarified the behavior of emulsion during the phase separation step, while also highlighting that the key to preparing narrow size distribution microspheres lies in weakening the coalescence of coacervate droplets. Finally, in vitro release demonstrated that CPLGA and the particle size distribution of coacervate droplets are key factors in the phase separation step.
{"title":"Investigating key factors in the phase separation step of microspheres fabrication via coacervation","authors":"","doi":"10.1016/j.ijpharm.2024.124781","DOIUrl":"10.1016/j.ijpharm.2024.124781","url":null,"abstract":"<div><div>Coacervation, a common method for microspheres preparation, has not been given sufficient attention and study. This study aims to clarify the key factors in the phase separation step. Firstly, based on the thermodynamics of polymer solutions, the phase equilibrium time, binodal line, and the relationship between the concentration of lactic-glycolic acid copolymer (PLGA) in the coacervate phase (C<sub>PLGA</sub>) and the concentration of polydimethylsiloxane (PDMS) in the PLGA-lean phase (C<sub>PDMS</sub>) were determined. It was found that the lactic:glycolic ratio (L:G) significantly influences phase separation, and we introduced a method to calculate the compositions and masses of both the coacervate and PLGA-lean phases after phase separation of a system composed of PLGA, PDMS, and dichloromethane (DCM). Furthermore, some impellers aimed at producing narrow size distribution microspheres were designed, and the stirring states were analyzed visually using Computational Fluid Dynamics (CFD), explaining the impact of impeller types and clearance between impeller and vessel on particle size distribution. Measurements of the viscosities of the coacervate and continuous phases, coupled with emulsion theories, clarified the behavior of emulsion during the phase separation step, while also highlighting that the key to preparing narrow size distribution microspheres lies in weakening the coalescence of coacervate droplets. Finally, <em>in vitro</em> release demonstrated that C<sub>PLGA</sub> and the particle size distribution of coacervate droplets are key factors in the phase separation step.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-02DOI: 10.1016/j.ijpharm.2024.124787
Nanoparticles (NPs) have gained significant attention in recent years due to their potential applications in pharmaceutical formulations, drug delivery systems, and various biomedical fields. The versatility of colloidal NPs, including their ability to be tailored with various components and synthesis methods, enables drug delivery systems to achieve controlled release patterns, improved solubility, and increased bioavailability. The review discusses various types of NPs, such as nanocrystals, lipid-based NPs, and inorganic NPs (i.e., gold, silver, magnetic NPs), each offering unique advantages for drug delivery. Despite the promising potential of NPs, challenges such as physical instability and the need for surface stabilization remain. Strategies to overcome these challenges include the use of surfactants, polymers, and cyclodextrins (CDs). This review highlights the role of CDs in stabilizing colloidal NPs and enhancing drug solubility. The combination of CDs with NPs presents a synergistic approach that enhances drug delivery and broadens the range of biomedical applications. Additionally, the potential of CDs to enhance the stability and therapeutic efficacy of colloidal NPs, making them promising candidates for advanced drug delivery systems, is comprehensively reviewed.
{"title":"The application of cyclodextrins in drug solubilization and stabilization of nanoparticles for drug delivery and biomedical applications","authors":"","doi":"10.1016/j.ijpharm.2024.124787","DOIUrl":"10.1016/j.ijpharm.2024.124787","url":null,"abstract":"<div><div>Nanoparticles (NPs) have gained significant attention in recent years due to their potential applications in pharmaceutical formulations, drug delivery systems, and various biomedical fields. The versatility of colloidal NPs, including their ability to be tailored with various components and synthesis methods, enables drug delivery systems to achieve controlled release patterns, improved solubility, and increased bioavailability. The review discusses various types of NPs, such as nanocrystals, lipid-based NPs, and inorganic NPs (i.e., gold, silver, magnetic NPs), each offering unique advantages for drug delivery. Despite the promising potential of NPs, challenges such as physical instability and the need for surface stabilization remain. Strategies to overcome these challenges include the use of surfactants, polymers, and cyclodextrins (CDs). This review highlights the role of CDs in stabilizing colloidal NPs and enhancing drug solubility. The combination of CDs with NPs presents a synergistic approach that enhances drug delivery and broadens the range of biomedical applications. Additionally, the potential of CDs to enhance the stability and therapeutic efficacy of colloidal NPs, making them promising candidates for advanced drug delivery systems, is comprehensively reviewed.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-02DOI: 10.1016/j.ijpharm.2024.124768
Poly(ethylene glycol) diacrylate (PEGDA) microneedles (MNs) are hydrogel-based devices that achieve controlled drug delivery kinetics by adjusting the crosslinking density. However, the biosafety of many crosslinking agents used to regulate crosslinking density is not ideal. To avoid crosslinking agents and simplify the preparation process, using two types of polymer homologues with different number-average molecular weights, we have successfully developed a series of PEGDA MNs with controllable crosslinking density (abbreviated as TP-X MNs). The research showed that the mechanical properties and drug release behavior of TP-X MNs could be tuned by simply controlling the weight proportion of two different PEGDA components in MNs. Ex vivo drug delivery experiments indicated that all TP-X MNs exhibited a sustained release profile, and their control range of 336-hour accumulative release rates was from 6.24% to 40.93%. Moreover, we prepared a novel dual-layer PEDGA MN, which can customize the drug loading and release rate in each layer of MN. This work demonstrates a new way to develop hydrogel MNs with adjustable crosslink density and broadens the applications of PEGDA MN in the biomedical field.
{"title":"Polymer homologue-mediated formation of hydrogel microneedles for controllable transdermal drug delivery","authors":"","doi":"10.1016/j.ijpharm.2024.124768","DOIUrl":"10.1016/j.ijpharm.2024.124768","url":null,"abstract":"<div><div>Poly(ethylene glycol) diacrylate (PEGDA) microneedles (MNs) are hydrogel-based devices that achieve controlled drug delivery kinetics by adjusting the crosslinking density. However, the biosafety of many crosslinking agents used to regulate crosslinking density is not ideal. To avoid crosslinking agents and simplify the preparation process, using two types of polymer homologues with different number-average molecular weights, we have successfully developed a series of PEGDA MNs with controllable crosslinking density (abbreviated as TP-X MNs). The research showed that the mechanical properties and drug release behavior of TP-X MNs could be tuned by simply controlling the weight proportion of two different PEGDA components in MNs. Ex vivo drug delivery experiments indicated that all TP-X MNs exhibited a sustained release profile, and their control range of 336-hour accumulative release rates was from 6.24% to 40.93%. Moreover, we prepared a novel dual-layer PEDGA MN, which can customize the drug loading and release rate in each layer of MN. This work demonstrates a new way to develop hydrogel MNs with adjustable crosslink density and broadens the applications of PEGDA MN in the biomedical field.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.ijpharm.2024.124762
Present study intends to develop aceclofenac-encapsulated organosomes (OS), which consist of phospholipids coupled with a combination of organic solvents, for the management of arthritis. The formulation was characterized and tested for efficacy using formalin-induced hyperalgesia, air pouch, and CFA-induced arthritic rat models. OS system exhibited spherical dimension, nanometric size with low PDI (278.3 ± 12.21 nm; 0.145), zeta potential (−24.56 ± 7.53 mV), drug entrapment (85.62 ± 7.2 %) and vesicles count (4.2x104 mm3). The gelled OS formulation demonstrated increased drug permeability and accumulation rate (51.77 ± 7.1 % and 396.19 ± 59.21 µg/cm2) compared to the MKT product (102.93 ± 13.78 µg/cm2 and 16.14 ± 4.3 %). Dermatokinetic assessments exhibited significantly higher drug levels in dermal layers compared to MKT product (p < 0.001), and CLSM studies further supported the OS system’s deeper penetration. The results of arthritic index significantly better (9 times) in the OS-treated group than the MKT product. OS system treatment significantly reduced biochemicals and cytokines levels, such as CRP, ESR, TLC, lymphocytes, TNF-α, IL-6, and IL-1β to levels of the control group (p < 0.001). Pseudoplastic behaviour of the developed product was indicated by the rheological results, and it also demonstrated biocompatibility through skin compliance studies. Based on the current findings, it appears that OS may be a better choice for managing arthritis and related inflammations.
{"title":"Strategic development of aceclofenac loaded organosomes for topical application: An explorative ex-vivo and in-vivo investigation for arthritis","authors":"","doi":"10.1016/j.ijpharm.2024.124762","DOIUrl":"10.1016/j.ijpharm.2024.124762","url":null,"abstract":"<div><div>Present study intends to develop aceclofenac-encapsulated organosomes (OS), which consist of phospholipids coupled with a combination of organic solvents, for the management of arthritis. The formulation was characterized and tested for efficacy using formalin-induced hyperalgesia, air pouch, and CFA-induced arthritic rat models. OS system exhibited spherical dimension, nanometric size with low PDI (278.3 ± 12.21 nm; 0.145), zeta potential (−24.56 ± 7.53 mV), drug entrapment (85.62 ± 7.2 %) and vesicles count (4.2x104 mm<sup>3</sup>). The gelled OS formulation demonstrated increased drug permeability and accumulation rate (51.77 ± 7.1 % and 396.19 ± 59.21 µg/cm<sup>2</sup>) compared to the MKT product (102.93 ± 13.78 µg/cm<sup>2</sup> and 16.14 ± 4.3 %). Dermatokinetic assessments exhibited significantly higher drug levels in dermal layers compared to MKT product (p < 0.001), and CLSM studies further supported the OS system’s deeper penetration. The results of arthritic index significantly better (9 times) in the OS-treated group than the MKT product. OS system treatment significantly reduced biochemicals and cytokines levels, such as CRP, ESR, TLC, lymphocytes, TNF-α, IL-6, and IL-1β to levels of the control group (p < 0.001). Pseudoplastic behaviour of the developed product was indicated by the rheological results, and it also demonstrated biocompatibility through skin compliance studies. Based on the current findings, it appears that OS may be a better choice for managing arthritis and related inflammations.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-30DOI: 10.1016/j.ijpharm.2024.124784
Corneal alkali burn is a common and challenging ocular trauma, necessitating the use of dexamethasone (DXMS) as a therapeutic agent. However, prolonged and frequent administration of this drug can lead to undesirable side effects, limiting its clinical application. This study aimed to investigate the role and mechanism of action of exosomes as drug carriers in corneal alkali burn repair. We employed centrifugation to isolate milk exosomes (EXO) as nanocarriers. We observed that EXO enhanced the activity and migration of corneal epithelial cells, expediting the repair process following corneal injury. Additionally, a nano-drug delivery model (DXMS@EXO) was designed using ultrasound to load DXMS into exosomes, thus enabling targeted delivery to inflammatory cells and enhancing drug efficacy. DXMS@EXO inhibited the inflammatory processes in the corneal alkali burn model by modulating the classical Wnt signaling pathway, thereby promoting corneal re-epithelialization and wound healing and accelerating the repair process of corneal alkali burn. Neither EXO nor DXMS@EXO exhibited significant side effects during the course of treatment. This study highlighted the substantial potential of EXO and DXMS@EXO in improving drug efficacy and facilitating the repair of corneal alkali burn.
{"title":"Anti-inflammatory and Restorative effects of milk exosomes and Dexamethasone-Loaded exosomes in a corneal alkali burn model","authors":"","doi":"10.1016/j.ijpharm.2024.124784","DOIUrl":"10.1016/j.ijpharm.2024.124784","url":null,"abstract":"<div><div>Corneal alkali burn is a common and challenging ocular trauma, necessitating the use of dexamethasone (DXMS) as a therapeutic agent. However, prolonged and frequent administration of this drug can lead to undesirable side effects, limiting its clinical application. This study aimed to investigate the role and mechanism of action of exosomes as drug carriers in corneal alkali burn repair. We employed centrifugation to isolate milk exosomes (EXO) as nanocarriers. We observed that EXO enhanced the activity and migration of corneal epithelial cells, expediting the repair process following corneal injury. Additionally, a nano-drug delivery model (DXMS@EXO) was designed using ultrasound to load DXMS into exosomes, thus enabling targeted delivery to inflammatory cells and enhancing drug efficacy. DXMS@EXO inhibited the inflammatory processes in the corneal alkali burn model by modulating the classical Wnt signaling pathway, thereby promoting corneal re-epithelialization and wound healing and accelerating the repair process of corneal alkali burn. Neither EXO nor DXMS@EXO exhibited significant side effects during the course of treatment. This study highlighted the substantial potential of EXO and DXMS@EXO in improving drug efficacy and facilitating the repair of corneal alkali burn.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-30DOI: 10.1016/j.ijpharm.2024.124785
The challenges of developing good quality low dose minitablets was assessed by systematically studying the effects of ibuprofen (IBU, a model compound) particle sizes (6–58 µm D50) and concentrations (0.1–3 %w/w), roller compaction forces (3–7 kN/cm), and the minitablet sizes (1.2, 1.5 and 2 mm diameter). A novel compression approach, where all three minitablet sizes were simultaneously produced in a single compression run was used. Roller compacted ribbons, granules, minitablets were characterized for physico-mechanical properties and minitablets were also characterized for stratified content uniformity and weight uniformity. The results showed that roll force was the more dominant factor to ribbon solid fraction or tensile strength and granule size enlargement. Minitablets obtained from the granules had good weight uniformity; all but one batch met the <Ph. Eur. 2.9.5 > criteria. The precise control of tooling lengths across the various sizes was found profoundly important for achieving expected weights, solid fraction, and tensile strength of the simultaneously produced minitablets. The roller compaction process considerably improved the CU variability of the minitablets as compared to the direct compression process. Smaller particle size and higher concentration of IBU, increased roller compaction force, and larger minitablet size improved the potency and content uniformity; however, only the minitablet size was a statistically significant factor in this study. As a product strategic design criterion, a threshold of 25 minitablets in a dosage unit would ensure robust downstream filling and weight verification operations as well as dose accuracy and uniformity (would pass <USP 905> stage 1 criteria). This study results demonstrated feasibility of the novel simultaneous compression approach and the roller compaction process in developing good quality minitablets.
通过系统研究布洛芬（IBU，一种示范化合物）的粒度（6-58 µm D50）和浓度（0.1-3 %w/w）、辊压力（3-7 kN/cm）以及迷你片尺寸的影响，评估了开发优质低剂量迷你片所面临的挑战。采用了一种新颖的压制方法，即在一次压制过程中同时生产三种尺寸（1.2、1.5 和 2 毫米）的小itablet。对轧辊压制的带状、颗粒状和小乳剂进行了物理机械性能表征，还对小乳剂的分层含量均匀性和重量均匀性进行了表征。结果表明，碾压力是影响带状固体成分或抗拉强度以及颗粒尺寸增大的主要因素。从颗粒中获得的迷你乳清片具有良好的重量均匀性；除一批外，其他所有批次均符合标准。精确控制各种规格的工具长度，对于同时生产的迷你片达到预期重量、固体分数和拉伸强度非常重要。与直接压制工艺相比，辊筒压制工艺大大改善了迷你板坯的 CU 变异性。更小的颗粒尺寸和更高的 IBU 浓度、更大的轧辊压实力和更大的迷你片尺寸都提高了药效和含量的均匀性；然而，在本研究中，只有迷你片尺寸是一个具有统计学意义的因素。作为产品战略设计标准，一个配料单位中 25 个小药包的阈值可确保下游灌装和重量验证操作的稳健性以及剂量的准确性和均匀性（通过第 1 阶段标准）。研究结果表明，新颖的同步压缩方法和辊压工艺在开发优质迷你片方面具有可行性。
{"title":"The impacts of roller compaction on the quality attributes of simultaneously compressed micro and minitablets","authors":"","doi":"10.1016/j.ijpharm.2024.124785","DOIUrl":"10.1016/j.ijpharm.2024.124785","url":null,"abstract":"<div><div>The challenges of developing good quality low dose minitablets was assessed by systematically studying the effects of ibuprofen (IBU, a model compound) particle sizes (6–58 µm D<sub>50</sub>) and concentrations (0.1–3 %w/w), roller compaction forces (3–7 kN/cm), and the minitablet sizes (1.2, 1.5 and 2 mm diameter). A novel compression approach, where all three minitablet sizes were simultaneously produced in a single compression run was used. Roller compacted ribbons, granules, minitablets were characterized for physico-mechanical properties and minitablets were also characterized for stratified content uniformity and weight uniformity. The results showed that roll force was the more dominant factor to ribbon solid fraction or tensile strength and granule size enlargement. Minitablets obtained from the granules had good weight uniformity; all but one batch met the <Ph. Eur. 2.9.5 > criteria. The precise control of tooling lengths across the various sizes was found profoundly important for achieving expected weights, solid fraction, and tensile strength of the simultaneously produced minitablets. The roller compaction process considerably improved the CU variability of the minitablets as compared to the direct compression process. Smaller particle size and higher concentration of IBU, increased roller compaction force, and larger minitablet size improved the potency and content uniformity; however, only the minitablet size was a statistically significant factor in this study. As a product strategic design criterion, a threshold of 25 minitablets in a dosage unit would ensure robust downstream filling and weight verification operations as well as dose accuracy and uniformity (would pass <USP 905> stage 1 criteria). This study results demonstrated feasibility of the novel simultaneous compression approach and the roller compaction process in developing good quality minitablets.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-29DOI: 10.1016/j.ijpharm.2024.124783
Dry eye syndrome (DES) presents a significant challenge in ophthalmic care, necessitating innovative approaches for effective management. This research article introduces a multifaceted strategy to address DES through the development of ocular inserts utilizing advanced technologies such as hot-melt extrusion (HME) and the CaliCut post-extrusion system. The formulation includes key ingredients targeting different layers of the tear film and associated inflammation, including hydroxypropyl cellulose (HPC), polyethylene glycol (PEG), castor oil, and dexamethasone. The study incorporates a Design of Experiments (DoE) approach, integrating HME and the precise stretching and cutting technique of CaliCut for manufacturing consistency and dimensional control of the inserts. The developed insert(s) have been systematically characterized for their physicochemical properties, release profile, and in vivo efficacy. In silico molecular docking studies have also been conducted to assess the binding affinities of formulation components with ocular mucin, elucidating their binding affinities. Preliminary results demonstrate promising potential for the developed insert in managing DES, offering preservative-free treatment, sustained drug delivery, and improved patient compliance. This study highlights the integration of advanced technologies and formulation strategies in ocular drug delivery for effective DES management.
干眼症（DES）是眼科护理中的一项重大挑战，需要采用创新方法进行有效管理。这篇研究文章介绍了一种多方面的策略，通过利用热熔挤出（HME）和 CaliCut 后挤出系统等先进技术开发眼部插件来解决 DES 问题。配方中含有针对不同泪膜层和相关炎症的关键成分，包括羟丙基纤维素 (HPC)、聚乙二醇 (PEG)、蓖麻油和地塞米松。该研究采用了实验设计（DoE）方法，将 HME 与 CaliCut 精确拉伸和切割技术相结合，以实现插件制造的一致性和尺寸控制。已对开发的插入物的理化性质、释放曲线和体内疗效进行了系统表征。此外，还进行了硅学分子对接研究，以评估制剂成分与眼部粘蛋白的结合亲和力，阐明其结合亲和力。初步结果表明，所开发的插入物在管理 DES 方面具有广阔的潜力，可提供无防腐剂治疗、持续给药和改善患者依从性。这项研究强调了在眼部给药中整合先进技术和制剂策略以有效管理 DES 的重要性。
{"title":"Investigating a novel therapeutic composition for dry eye syndrome management: In vitro and in vivo studies","authors":"","doi":"10.1016/j.ijpharm.2024.124783","DOIUrl":"10.1016/j.ijpharm.2024.124783","url":null,"abstract":"<div><div>Dry eye syndrome (DES) presents a significant challenge in ophthalmic care, necessitating innovative approaches for effective management. This research article introduces a multifaceted strategy to address DES through the development of ocular inserts utilizing advanced technologies such as hot-melt extrusion (HME) and the CaliCut post-extrusion system. The formulation includes key ingredients targeting different layers of the tear film and associated inflammation, including hydroxypropyl cellulose (HPC), polyethylene glycol (PEG), castor oil, and dexamethasone. The study incorporates a Design of Experiments (DoE) approach, integrating HME and the precise stretching and cutting technique of CaliCut for manufacturing consistency and dimensional control of the inserts. The developed insert(s) have been systematically characterized for their physicochemical properties, release profile, and <em>in vivo</em> efficacy. <em>In silico</em> molecular docking studies have also been conducted to assess the binding affinities of formulation components with ocular mucin, elucidating their binding affinities. Preliminary results demonstrate promising potential for the developed insert in managing DES, offering preservative-free treatment, sustained drug delivery, and improved patient compliance. This study highlights the integration of advanced technologies and formulation strategies in ocular drug delivery for effective DES management.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-29DOI: 10.1016/j.ijpharm.2024.124770
Wound bacterial infections can significantly delay the healing process and even lead to fetal sepsis. There is a need for multifunctional dressings that possess antibacterial property, tissue adhesive property, self-healing capability, and biocompatibility to effectively treat bacteria-infected wound. In this study, we report a dual dynamically crosslinked hydrogel, OHA-PBA/PVA/Gen, which incorporates the antibiotic gentamicin (Gen) as a dynamic crosslinker. The hydrogel is formed through the formation of Schiff base bonds between phenylboronic acid-grafted oxidized hyaluronic acid (OHA-PBA) and Gen, as well as boronic acid ester bonds between OHA-PBA and polyvinyl alcohol (PVA). This unique composition imparts tissue adhesiveness, injectability and self-healing property to the hydrogel. The hydrogel also exhibits pH-responsive antibiotic release behavior due to the acid-responsive dissociation of Schiff base bonds. As a result, it demonstrates strong antibacterial activity against both Gram-positive bacteria S. aureus and Gram-negative bacteria E. coli through contact killing and diffusion killing mechanisms. Importantly, the OHA-PBA/PVA/Gen hydrogel avoids incorporation of toxic small molecular crosslinking agents, and all the components of the hydrogel are biocompatible, ensuring its biosafety. In a S. aureus-infected wound mouse model, this hydrogel effectively eradicated bacteria and promoted angiogenesis, leading to significantly accelerated wound healing. These results highlight the potential of the dual dynamically crosslinking hydrogel OHA-PBA/PVA/Gen as a multifunctional wound dressing for the treatment of bacteria-infected wound.
伤口细菌感染会严重延缓伤口愈合，甚至导致胎儿败血症。因此，需要具有抗菌性、组织粘附性、自愈合能力和生物相容性的多功能敷料来有效治疗细菌感染的伤口。在本研究中，我们报告了一种双重动态交联水凝胶 OHA-PBA/PVA/Gen，其中加入了抗生素庆大霉素（Gen）作为动态交联剂。这种水凝胶是通过苯硼酸接枝的氧化透明质酸（OHA-PBA）与 Gen 之间形成的席夫碱键以及 OHA-PBA 与聚乙烯醇（PVA）之间的硼酸酯键形成的。这种独特的成分赋予了水凝胶组织粘附性、注射性和自愈性。由于席夫碱键的酸响应解离作用，这种水凝胶还具有酸碱响应的抗生素释放特性。因此，通过接触杀灭和扩散杀灭机制，它对革兰氏阳性菌金黄色葡萄球菌和革兰氏阴性菌大肠杆菌都具有很强的抗菌活性。重要的是，OHA-PBA/PVA/Gen 水凝胶避免了加入有毒的小分子交联剂，而且水凝胶的所有成分都具有生物相容性，确保了其生物安全性。在金黄色葡萄球菌感染的小鼠伤口模型中，这种水凝胶能有效消灭细菌并促进血管生成，从而显著加快伤口愈合。这些结果凸显了双重动态交联水凝胶 OHA-PBA/PVA/Gen 作为多功能伤口敷料治疗细菌感染伤口的潜力。
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Pub Date : 2024-09-29DOI: 10.1016/j.ijpharm.2024.124775
Myricetin (MYR) is a natural flavonoid that has several biological functions. However, some of its beneficial effects are diminished due to low water solubility, stability, and bioavailability. Herein, several kinds of silica nanoparticles (MCM-41 and SBA-15) were loaded with MYR to improve its biological activity as an analgesic, antipyretic, and anti-inflammatory component, thereby overcoming its drawbacks. The nanoparticles (MYR@SBA-15) were formulated optimally, transforming MYR into an amorphous state. This transformation was confirmed via several strategies, including differential scanning calorimetry, Fourier transform infrared spectroscopy, and powder x-ray diffraction. As a result, there was a significant enhancement in the solubility and rate of dissolution in water. The anti-inflammatory benefits as an innovative strategy and the underlying mechanism of action of MYR and its SBA-15 silica nanoparticles (MYR@SBA-15) were investigated based on the biochemical, histological, immunohistochemical, and metabolomic assays alongside their antipyretic and analgesic characteristics. Compared to the usage of raw MYR, the administration of MYR@SBA-15 at doses of 25, 50, and 100 mg/kg significantly decreases pain perception by inhibiting the body’s writhing motions induced by acetic acid. Furthermore, it helps regulate increased body temperature caused by baking yeast and effectively stabilizes it. It reduces the release of NO and PGE-2 in a concentration-dependent manner by down-regulating iNOS and COX-2 expression in the inflammatory model. MYR and MYR@SBA-15 also inhibit the nuclear translocation of NF-κB, downregulate the expression of mitogen-activated protein kinases (MAPKs), such as p38, ERK1/2, and JNK protein, and reduce the generation of proinflammatory cytokines, such as TNF-α. In addition, inflammatory cardinal signs like paw edema caused by carrageenan in rats are greatly suppressed by MYR and MYR@SBA-15 treatment when compared to the untreated group. More noteworthy outcomes are shown in the MYR@SBA-15, particularly at a dose of 100 mg/kg. These results of biochemical and immuno-histochemistry suggest that MYR@SBA-15 may be a useful analgesic antipyretic and may also help reduce inflammation by altering MAPKs/NF-κB and COX-2/PGE-2 signaling cascades. Serum metabolomics study demonstrated modifications in various low molecular weight metabolites with arthritis development. These metabolite levels were restored to normal when MYR@SBA-15 was administered via modulating several metabolic pathways, i.e., pyrimidine, energy metabolism, and proteins. Overall, MYR-loaded SBA-15 silica nanoparticles have demonstrated significant promise in enhancing the disturbed metaboloic pathways and providing a substantial capacity to regulate several oxidative stress and inflammatory mediators.
{"title":"Myricetin-loaded SBA-15 silica nanoparticles for enhanced management of pyrexia, pain, and inflammation through modulation of MAPK/NF-κB and COX-2/PGE-2 pathways: Evidence from the biochemical, histological, and metabolomic analysis","authors":"","doi":"10.1016/j.ijpharm.2024.124775","DOIUrl":"10.1016/j.ijpharm.2024.124775","url":null,"abstract":"<div><div>Myricetin (MYR) is a natural flavonoid that has several biological functions. However, some of its beneficial effects are diminished due to low water solubility, stability, and bioavailability. Herein, several kinds of silica nanoparticles (MCM-41 and SBA-15) were loaded with MYR to improve its biological activity as an analgesic, antipyretic, and anti-inflammatory component, thereby overcoming its drawbacks. The nanoparticles (MYR@SBA-15) were formulated optimally, transforming MYR into an amorphous state. This transformation was confirmed via several strategies, including differential scanning calorimetry, Fourier transform infrared spectroscopy, and powder x-ray diffraction. As a result, there was a significant enhancement in the solubility and rate of dissolution in water. The anti-inflammatory benefits as an innovative strategy and the underlying mechanism of action of MYR and its SBA-15 silica nanoparticles (MYR@SBA-15) were investigated based on the biochemical, histological, immunohistochemical, and metabolomic assays alongside their antipyretic and analgesic characteristics. Compared to the usage of raw MYR, the administration of MYR@SBA-15 at doses of 25, 50, and 100 mg/kg significantly decreases pain perception by inhibiting the body’s writhing motions induced by acetic acid. Furthermore, it helps regulate increased body temperature caused by baking yeast and effectively stabilizes it. It reduces the release of NO and PGE-2 in a concentration-dependent manner by down-regulating iNOS and COX-2 expression in the inflammatory model. MYR and MYR@SBA-15 also inhibit the nuclear translocation of NF-κB, downregulate the expression of mitogen-activated protein kinases (MAPKs), such as p38, ERK1/2, and JNK protein, and reduce the generation of proinflammatory cytokines, such as TNF-α. In addition, inflammatory cardinal signs like paw edema caused by carrageenan in rats are greatly suppressed by MYR and MYR@SBA-15 treatment when compared to the untreated group. More noteworthy outcomes are shown in the MYR@SBA-15, particularly at a dose of 100 mg/kg. These results of biochemical and immuno-histochemistry suggest that MYR@SBA-15 may be a useful analgesic antipyretic and may also help reduce inflammation by altering MAPKs/NF-κB and COX-2/PGE-2 signaling cascades. Serum metabolomics study demonstrated modifications in various low molecular weight metabolites with arthritis development. These metabolite levels were restored to normal when MYR@SBA-15 was administered via modulating several metabolic pathways, i.e., pyrimidine, energy metabolism, and proteins. Overall, MYR-loaded SBA-15 silica nanoparticles have demonstrated significant promise in enhancing the disturbed metaboloic pathways and providing a substantial capacity to regulate several oxidative stress and inflammatory mediators.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-28DOI: 10.1016/j.ijpharm.2024.124779
In recent years, chimeric antigen receptor (CAR)-T cell therapy has been highly successful in treating hematological malignancies, leading to significant advancements in the cancer immunotherapy field. However, the typical CAR-T therapy necessitates the enrichment of patients’ own leukocytes for ex vivo production of CAR-T cells, this customized pattern requires a complicated and time-consuming manufacturing procedure, making it costly and less accessible. The off-the-shelf universal CAR-T strategy could reduce manufacturing costs and realize timely drug administration, presenting as an ideal substitute for typical CAR-T therapy. Utilizing nanocarriers for targeted gene delivery is one of the approaches for the realization of universal CAR-T therapy, as biocompatible and versatile nanoparticles could deliver CAR genes to generate CAR-T cells in vivo. Nanoparticle-mediated in situ generation of CAR-T cells possesses multiple advantages, including lowered cost, simplified manufacturing procedure, and shortened administration time, this strategy is anticipated to provide a potentially cost-effective alternative to current autologous CAR-T cell manufacturing, thus facilitating the prevalence and improvement of CAR-T therapy.
{"title":"Nanoparticle-mediated universal CAR-T therapy","authors":"","doi":"10.1016/j.ijpharm.2024.124779","DOIUrl":"10.1016/j.ijpharm.2024.124779","url":null,"abstract":"<div><div>In recent years, chimeric antigen receptor (CAR)-T cell therapy has been highly successful in treating hematological malignancies, leading to significant advancements in the cancer immunotherapy field. However, the typical CAR-T therapy necessitates the enrichment of patients’ own leukocytes for ex vivo production of CAR-T cells, this customized pattern requires a complicated and time-consuming manufacturing procedure, making it costly and less accessible. The off-the-shelf universal CAR-T strategy could reduce manufacturing costs and realize timely drug administration, presenting as an ideal substitute for typical CAR-T therapy. Utilizing nanocarriers for targeted gene delivery is one of the approaches for the realization of universal CAR-T therapy, as biocompatible and versatile nanoparticles could deliver CAR genes to generate CAR-T cells in vivo. Nanoparticle-mediated in situ generation of CAR-T cells possesses multiple advantages, including lowered cost, simplified manufacturing procedure, and shortened administration time, this strategy is anticipated to provide a potentially cost-effective alternative to current autologous CAR-T cell manufacturing, thus facilitating the prevalence and improvement of CAR-T therapy.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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