International Journal of Pharmaceutics最新文献_第10页

Liposome-loaded dissolvable microneedle patches for more efficient intradermal antigen delivery of Hepatitis B vaccine 载脂质体的可溶微针贴剂用于更有效的皮内乙肝疫苗抗原递送。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-01-25 DOI: 10.1016/j.ijpharm.2024.125023

Ping Wen , Yunyang Wang , Chenghao Zhang , Peng He , Zhuming Lin , Zhongyu Hu , Weiyue Lu

The aim of this study was to improve the efficacy of Hepatitis B surface antigen (HBsAg) vaccination via liposome-loaded dissolvable microneedle (Lipo-dMN) patches. HBsAg liposomes were prepared using the thin-film hydration method and subsequently incorporated into dissolvable microneedle patches via a pre-vacuum approach. Liposomes, dissolvable microneedle patches (dMN), and Lipo-dMN were characterized for encapsulation efficiency, mechanical properties, morphology, skin insertion, in vitro release, cellular uptake, and in vivo vaccination studies. The HBsAg was encapsulated into liposomes with encapsulation efficiencies around 50 %, particle size around 160 nm, and zeta potential around −20 mV. HBsAg can maintain its activity during the preparation of dMN and Lipo-dMN. The intact pyramid microneedle has a sharp end and strong mechanical properties that allow easy insertion into the ex vivo pig skin. The dMN and Lipo-dMN, with a mechanical property of 1.6 N, readily penetrate the epidermis and release the HBsAg and HBsAg liposome to modulate the immune response. A comprehensive comparison of HBsAg subcutaneous injection and intradermal delivery of HBsAg and HBsAg liposome by dMN revealed different levels of anti-HBsAg IgG antibody. Inoculation with dMN and Lipo-dMN resulted in significantly higher levels of anti-HBsAg IgG antibodies (p < 0.01) compared to subcutaneous injection of HBsAg. In addition, we found that IgG levels increased significantly (P < 0.05) with increased dose of subcutaneous injection of HBsAg and intradermal delivery of dMN, but the opposite effect was observed in Lipo-dMN. The possible mechanism for this observation may be the increased cellular uptake of liposomes by BMDCs upon long-term incubation. In summary, this study presents a promising approach to enhance HBsAg vaccination efficacy through the synergistic combination of liposomes and dissolvable microneedles at reduced vaccine doses.

本研究的目的是通过脂质体负载的可溶微针（lipom - dmn）贴剂提高乙型肝炎表面抗原（HBsAg）疫苗接种的效果。采用薄膜水化法制备HBsAg脂质体，并通过预真空方法将其掺入可溶解的微针贴片中。脂质体、可溶微针贴剂（dMN）和lipop -dMN的包封效率、机械性能、形态、皮肤插入、体外释放、细胞摄取和体内疫苗接种研究均被表征。将HBsAg包封在脂质体中，包封效率约为50% %，粒径约为160 nm， zeta电位约为-20 mV。HBsAg在dMN和lipoo -dMN制备过程中保持活性。完整的金字塔微针具有锋利的末端和强大的机械性能，可以轻松插入离体猪皮肤。dMN和lipop -dMN的力学性能为1.6 N，容易穿透表皮，释放HBsAg和HBsAg脂质体，调节免疫反应。综合比较经dMN皮内给药和皮下注射的HBsAg及脂质体，发现其抗HBsAg IgG抗体水平不同。接种dMN和lipop -dMN可显著提高抗hbsag IgG抗体水平(p

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引用次数: 0

Intelligent responsive nanogels: New Horizons in cancer therapy 智能反应纳米凝胶：癌症治疗的新视野。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-01-25 DOI: 10.1016/j.ijpharm.2024.125050

MiriGuli Musa , Xinxin Sun , Jianbin Shi , Jing Li , Shenwu Zhang , Xianbao Shi

Biologically engineered nanogels formed through sophisticated intramolecular crosslinking processes represent the forefront of next-generation drug delivery systems. These innovative systems offer many advantages, like adjustable size, satisfactory biocompatibility, and minimal toxicity. Their unique attributes facilitate deep penetration and long-term retention of drugs in tumors, effectively enhancing the anti-tumor effects. Nonetheless, the rapid disintegration of nanogels and the subsequent triggering of drug release at the tumor site pose significant challenges in achieving more effective and precise tumor treatments. Therefore, increasing research has been dedicated to exploring stimulus-responsive nanogels for enhancing tumor therapy. This review aims to encapsulate the research advancements in emerging stimulus-responsive antitumor nanogels. Firstly, a detailed exposition is provided on various endogenous stimulus-responsive nanogels, encompassing factors such as pH, hypoxia, enzymes, reactive oxygen species (ROS), and glutathione (GSH). Secondly, various nanogels triggered by exogenous stimuli such as light, ultrasound, temperature, and magnetic fields are elaborately presented. Furthermore, nanogels with multifaceted stimulus-responsive properties are also skillfully designed. Finally, the future directions, application prospects, and challenges of intelligent responsive nanogels in cancer treatment are highlighted.

通过复杂的分子内交联过程形成的生物工程纳米凝胶代表了下一代药物输送系统的前沿。这些创新的系统具有许多优点，如可调节的尺寸，令人满意的生物相容性和最小的毒性。其独特的属性有利于药物在肿瘤内的深度渗透和长期滞留，有效增强抗肿瘤作用。然而，纳米凝胶的快速分解和随后在肿瘤部位触发药物释放对实现更有效和精确的肿瘤治疗提出了重大挑战。因此，越来越多的研究致力于探索刺激反应纳米凝胶以增强肿瘤治疗。本文综述了近年来刺激反应性抗肿瘤纳米凝胶的研究进展。首先，详细介绍了各种内源性刺激反应纳米凝胶，包括pH、缺氧、酶、活性氧（ROS）和谷胱甘肽（GSH）等因素。其次，详细介绍了由光、超声、温度和磁场等外源刺激引发的各种纳米凝胶。此外，具有多方面刺激响应特性的纳米凝胶也被巧妙地设计出来。最后，重点介绍了智能响应纳米凝胶在癌症治疗中的未来发展方向、应用前景和面临的挑战。

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引用次数: 0

Core-shell aerogel design for enhanced oral insulin delivery 增强口服胰岛素输送的核-壳气凝胶设计。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-01-25 DOI: 10.1016/j.ijpharm.2024.125038

Gozde Ozesme Taylan , Carlos Illanes-Bordomás , Ozge Guven , Ece Erkan , Sevil Çıkrıkcı Erünsal , Mecit Halil Oztop , Carlos A. García-González

Current protein-based therapies often rely on intravenous and subcutaneous injections leading to patient discomfort due to the need for frequent administration. Oral administration route presents a more patient-friendly alternative, but overcoming the challenge of low drug bioavailability remains paramount. This limitation is primarily attributed to protein degradation in the harsh gastric environment, enzymatic breakdown, and poor intestinal permeability. With their unique properties, such as high porosity and surface area, and easy scalability, aerogels offer a promising platform for oral delivery of therapeutic proteins. This study focused on the development and characterization of both conventional and core–shell aerogels derived from natural polysaccharides for the oral delivery of insulin, utilizing Humulin R® U-100 as the insulin source for the first time. Aerogels were produced via supercritical carbon dioxide (sc-CO₂) drying of alginate gel beads. Scanning Electron Microscopy (SEM) images confirmed that the core–shell aerogels had higher uniformity in size and a more well-defined porous structure in comparison to conventional aerogels. Structural differences of two alginate sources were evaluated by Fourier Transform Infrared (FTIR) spectroscopy. A notable difference in encapsulation efficiencies was observed between conventional (12 %) and core–shell (53 %) aerogels, highlighting the superior carrier characteristics of the latter ones. In vitro insulin release profiles from the core–shell aerogels demonstrated their potential suitability for delivering regular/short-acting insulin therapeutics since only 30 % of insulin was released in Simulated Gastric Fluid (SGF) after 120 min, whereas 60 % of insulin was released in Simulated Intestinal Fluid (SIF) within the first hour followed by a sustained release stage.

目前基于蛋白质的治疗通常依赖于静脉注射和皮下注射，由于需要频繁给药，导致患者不适。口服给药途径是一种对患者更友好的选择，但克服低药物生物利用度的挑战仍然是最重要的。这种限制主要是由于在恶劣的胃环境中蛋白质降解、酶分解和肠通透性差。由于其独特的特性，如高孔隙率和表面积，以及易于扩展，气凝胶为口服递送治疗性蛋白质提供了一个很有前途的平台。本研究首次利用Humulin R®U-100作为胰岛素源，开发了用于口服胰岛素的常规气凝胶和天然多糖提取的核壳气凝胶。采用超临界二氧化碳（sc-CO2）干燥海藻酸盐凝胶球制备气凝胶。扫描电镜（SEM）图像证实，与传统气凝胶相比，核壳气凝胶具有更高的尺寸均匀性和更明确的多孔结构。利用傅里叶变换红外光谱（FTIR）分析了两种海藻酸盐源的结构差异。常规气凝胶（12 %）和核壳气凝胶（53 %）的包封效率有显著差异，表明后者具有更好的载体特性。核-壳气凝胶的体外胰岛素释放分析表明，由于在120 min后，模拟胃液（SGF）中只有30% %的胰岛素释放，而模拟肠液（SIF）中有60% %的胰岛素在第一个小时内释放，随后是一个持续释放阶段，因此它们具有提供常规/短效胰岛素治疗的潜在适应性。

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引用次数: 0

Combating tumor PARP inhibitor resistance: Combination treatments, nanotechnology, and other potential strategies 对抗肿瘤PARP抑制剂耐药性：联合治疗、纳米技术和其他潜在策略。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-01-25 DOI: 10.1016/j.ijpharm.2024.125028

Rong Wang , Yunxi Liu , Mingqi Liu , Meng Zhang , Chaoqun Li , Shanshan Xu , Sangsang Tang , Yidan Ma , Xiaodong Wu , Weidong Fei

PARP (poly (ADP-ribose) polymerase) inhibitors (PARPi) have demonstrated significant potential in cancer treatment, particularly in tumors with breast cancer susceptibility gene (BRCA) mutations and other DNA repair deficiencies. However, the development of resistance to PARPi has become a major challenge in their clinical application. The emergence of drug resistance leads to reduced efficacy of the PARPi over time, impacting long-term treatment outcomes and survival rates. PARPi resistance in tumors often arises as cells activate alternative DNA repair pathways or evade the effect of PARPi, diminishing therapeutic effectiveness. Consequently, overcoming resistance is crucial for maintaining treatment efficacy and improving patient prognosis. This paper reviews the strategies to overcome PARPi resistance through combination treatment and nanotechnology therapy. We first review the current combination therapies with PARPi, including anti-angiogenic therapies, radiotherapies, immunotherapies, and chemotherapies, and elucidate their mechanisms for overcoming PARPi resistance. Additionally, this paper focuses on the application of nanotechnology in improving the effectiveness of PARPi and overcoming drug resistance. Subsequently, this paper presents several promising strategies to tackle PARPi resistance, including but not limited to: structural modifications of PARPi, deployment of gene editing systems, implementation of “membrane lipid therapy,” and modulation of cellular metabolism in tumors. By integrating these strategies, this research will provide comprehensive approaches to overcome the resistance of PARPi in cancer treatment and offer guidance for future research and clinical practice.

PARP（聚（adp -核糖）聚合酶）抑制剂（PARPi）在癌症治疗中显示出巨大的潜力，特别是在乳腺癌易感基因（BRCA）突变和其他DNA修复缺陷的肿瘤中。然而，PARPi耐药的发展已成为其临床应用的主要挑战。随着时间的推移，耐药性的出现导致PARPi的疗效降低，影响长期治疗结果和生存率。肿瘤中PARPi的耐药性通常是由于细胞激活替代的DNA修复途径或逃避PARPi的作用，从而降低了治疗效果。因此，克服耐药性对于维持治疗效果和改善患者预后至关重要。本文综述了通过联合治疗和纳米技术治疗克服PARPi耐药的策略。我们首先回顾了目前PARPi的联合治疗，包括抗血管生成治疗、放疗、免疫治疗和化疗，并阐明了它们克服PARPi耐药的机制。此外，本文还重点介绍了纳米技术在提高PARPi有效性和克服耐药性方面的应用。随后，本文提出了几种有前途的策略来解决PARPi耐药性，包括但不限于：PARPi的结构修饰，基因编辑系统的部署，“膜脂疗法”的实施，以及肿瘤细胞代谢的调节。通过整合这些策略，本研究将为克服PARPi在癌症治疗中的耐药提供全面的途径，并为未来的研究和临床实践提供指导。

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引用次数: 0

Alginate-based microencapsulation as a strategy to improve the therapeutic potential of cannabidiolic acid 海藻酸微胶囊化是提高大麻二酚酸治疗潜力的一种策略。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-01-25 DOI: 10.1016/j.ijpharm.2024.125076

Pablo E. Antezana , Sofía Municoy , Fresia M. Silva Sofrás , Martín G. Bellino , Pablo Evelson , Martín F. Desimone

Cannabidiolic Acid (CBDA) is a promising natural compound with potent antioxidant, anti-inflammatory, and anti-emetic properties. Its antioxidant activity rivals that of vitamin E, while its anti-inflammatory effects are also remarkable. Additionally, CBDA has been shown to effectively reduce nausea and emetic attacks. As a more natural and water-soluble alternative to CBD, CBDA offers improved bioavailability and absorption. However, despite its promising potential, the development of effective CBDA delivery systems is still in its early stages. Among the various materials suitable for drug delivery, alginate is a widely used biopolymer due to its abundance and common availability in nature. This study aimed to develop an efficient CBDA delivery carrier using a microflow-dripping method to microencapsulate CBDA into alginate carriers (Alg-CBDA). The antioxidant, antimicrobial, and cytotoxicity properties of these Alg-CBDA capsules were then evaluated. Our results demonstrated that encapsulating CBDA within alginate capsules yielded a novel multifunctional biomaterial with prolonged antioxidant activity up to 72 h and antimicrobial activity against Gram-positive bacteria. Furthermore, the encapsulation process significantly reduced CBDA’s cytotoxicity, broadening its potential applications. To our knowledge, this is the first study demonstrating the advantages of CBDA within a drug delivery framework.

大麻二酚酸（CBDA）是一种很有前途的天然化合物，具有有效的抗氧化，抗炎和止吐特性。它的抗氧化活性可与维生素E相媲美，同时它的抗炎作用也很显著。此外，CBDA已被证明能有效减少恶心和呕吐发作。作为一种更天然和水溶性的CBD替代品，CBDA提供了更好的生物利用度和吸收。然而，尽管其潜力巨大，有效的CBDA输送系统的发展仍处于早期阶段。海藻酸盐是一种广泛应用的生物高分子材料，具有丰富的资源和广泛的可得性。本研究旨在开发一种高效的CBDA给药载体，采用微流滴法将CBDA微胶囊化到海藻酸盐载体（Alg-CBDA）中。然后评估这些Alg-CBDA胶囊的抗氧化、抗菌和细胞毒性。我们的研究结果表明，将CBDA包埋在海藻酸盐胶囊中可以获得一种新的多功能生物材料，其抗氧化活性高达72 h，并且对革兰氏阳性细菌具有抗菌活性。此外，包封工艺显著降低了CBDA的细胞毒性，扩大了其潜在的应用范围。据我们所知，这是第一个在给药框架内证明CBDA优势的研究。

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引用次数: 0

Intracellular mechanistic insights into cRGD-modified Bi2Se3 nanofoams for enhanced photothermal therapy via exocytosis inhibition crgd修饰的Bi2Se3纳米泡沫通过胞外分泌抑制增强光热治疗的细胞内机制。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-01-25 DOI: 10.1016/j.ijpharm.2024.125093

Li Ding , Xinghua Yu , Shihao Cai , Azhar Mahmood , Wenjing Meng , Xiaotong Liu , Jiahan Liu , Jieyun Li , Xuejuan Zhang , Chuanbin Wu

The cRGD peptide surface coating strategy for photothermal therapy nanoplatforms shows great promise in developing safe and effective cancer therapies. However, the precise intracellular mechanisms of these platforms remain unclear due to the complexity of intracellular trafficking and nano-bio interactions. This study investigates the nano-bio interactions of Bi₂Se₃ nanofoams, a representative photothermal therapy nanoplatform, coated with cRGD peptide in cancer cells, focusing on endocytosis, exocytosis, and cellular trafficking. Our findings reveal that the cRGD-coated Bi₂Se₃ nanofoams are internalized through three distinct endocytosis pathways: Rab34-mediated macropinocytosis, caveolae-dependent, and clathrin-dependent endocytosis. These nanofoams then accumulate in lysosomes via autophagy. Furthermore, inhibiting exocytosis reduces the loss of these nanofoams from cancer cells, enhancing photothermal and chemotherapy effects. This exocytosis-inhibiting strategy demonstrates significant potential for cancer therapy, validated by successful in vitro and in vivo results.

光热治疗纳米平台的cRGD肽表面涂层策略在开发安全有效的癌症治疗方法方面具有很大的前景。然而，由于细胞内运输和纳米生物相互作用的复杂性，这些平台的精确细胞内机制尚不清楚。本研究研究了具有代表性的光热治疗纳米平台Bi2Se3纳米泡沫包被cRGD肽在癌细胞中的纳米生物相互作用，重点研究了内吞作用、胞吐作用和细胞运输。我们的研究结果表明，crgd包被的Bi2Se3纳米泡沫通过三种不同的内吞途径被内化：rab34介导的巨噬细胞作用、小泡依赖的内吞作用和网格蛋白依赖的内吞作用。这些纳米泡沫随后通过自噬在溶酶体中积累。此外，抑制胞吐可以减少这些纳米泡沫从癌细胞中流失，增强光热和化疗效果。这种胞吐抑制策略证明了癌症治疗的巨大潜力，成功的体外和体内结果验证了这一点。

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引用次数: 0

Impact of route of particle engineering on dissolution performance of posaconazole 颗粒工程路线对泊沙康唑溶解性能的影响。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-01-25 DOI: 10.1016/j.ijpharm.2024.125025

Tianyi Xiang , Zijian Wang , Marina Solomos , Stephanus Axnanda , Chienhung Chen , Margaret Figus , Luke Schenck , Changquan Calvin Sun

Even when they have similar particle size, micron sized drug crystals prepared via different process routes may still exhibit considerable variability in pharmaceutical properties, due to the anisotropy of molecular crystals. This study aims to evaluate the dissolution performance of micronized posaconazole obtained through both milling and precipitation, with and without polymer coating. To overcome the problem of pressure-induced amorphization of posaconazole, powder dissolution was performed instead of intrinsic dissolution, which requires compressing powder into pellets. However, direct powder dissolution was challenged by the poor dispersibility of micronized posaconazole powders because of their extremely poor wettability. To solve this problem, we pretreated powders by dispersing them in an aqueous solution with a surfactant. Despite posaconazole forming a hydrate after pretreatment, differences in measured powder dissolution rates are meaningful in predicting impact of routes of API engineering on biopharmaceutical performance since hydration of posaconazole also occurs in vivo. This case study presents a systematic approach in addressing challenges when characterizing dissolution performance of drug powders.

由于分子晶体的各向异性，即使它们具有相似的粒径，通过不同工艺路线制备的微米级药物晶体仍可能表现出相当大的药物性能差异。本研究的目的是评价通过研磨和沉淀得到的微粉泊沙康唑在有和没有聚合物包衣的情况下的溶出性能。为了克服泊沙康唑的压力诱导非晶化问题，采用粉末溶出法代替将粉末压缩成颗粒的固有溶出法。然而，由于微沙康唑粉末的润湿性极差，其分散性较差，直接粉末溶解受到了挑战。为了解决这个问题，我们将粉末分散在有表面活性剂的水溶液中进行预处理。尽管泊沙康唑在预处理后会形成水合物，但由于泊沙康唑在体内也会水化，因此测定的粉末溶出率的差异对于预测原料药工程路线对生物制药性能的影响具有重要意义。本案例研究提出了一种系统的方法来解决表征药物粉末溶解性能时的挑战。

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引用次数: 0

How can language models assist with pharmaceuticals manufacturing deviations and investigations? 语言模型如何协助药品生产偏差和调查？

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-01-25 DOI: 10.1016/j.ijpharm.2024.125100

Hossein Salami , Brandye Smith-Goettler , Vijay Yadav

Large Language Models (LLM) such as the Generative-Pretrained-Transformer (GPT) and Large-Language-Model-Meta-AI (LLaMA) have attracted much attention. There is strong evidence that these models perform remarkably well in various natural language processing tasks. However, how to leverage them in domain-specific use cases and drive value remains an open question. Focusing on the digital transformation in the pharmaceutical manufacturing space, we propose that leveraging historical records of manufacturing deviations, as a mostly unstructured data source, in an organization can be beneficial for productivity, efficiency, quality, and compliance, specifically for addressing and closing new cases, or de-risking new manufacturing campaigns by identifying common themes and occurrences. Herein, by constructing an industrially relevant dataset, the ability of generative LLMs (e.g., GPT and Claude) and text embedding models in performing tasks related to pharmaceutical manufacturing deviations are studied. Generative models are evaluated for automating knowledge extraction from deviation reports in a mature organization, while embedding models are evaluated for identification of similar incidents from a large body of historical records using similarity analysis in vector space. Results show highly accurate outcomes for entity extraction tasks, especially with larger models, strong reasoning capabilities, as well as an interplay between the apparent reasoning and hallucination behavior of LLMs. Results also show the ability of embedding models for capturing semantics in certain deviation categories. Overall, these findings suggest significant potential for enhancing workflows in the pharmaceutical manufacturing through AI-driven tools, while also highlighting important questions that necessitate further research.

大型语言模型（LLM）如生成-预训练-转换（GPT）和大型语言模型-元人工智能（LLaMA）受到了广泛的关注。有强有力的证据表明，这些模型在各种自然语言处理任务中表现得非常好。然而，如何在特定于领域的用例中利用它们并驱动价值仍然是一个悬而未决的问题。专注于制药制造领域的数字化转型，我们建议在组织中利用制造偏差的历史记录，作为一个非结构化的数据源，可以有利于生产力、效率、质量和合规性，特别是用于解决和结束新案例，或通过识别共同主题和事件来降低新制造活动的风险。本文通过构建工业相关数据集，研究了生成法学硕士（例如GPT和Claude）和文本嵌入模型在执行与制药制造偏差相关的任务中的能力。在成熟的组织中，对生成模型进行评估，用于从偏差报告中自动提取知识，而对嵌入模型进行评估，用于使用向量空间中的相似性分析从大量历史记录中识别类似事件。结果表明，实体提取任务的结果非常准确，特别是在更大的模型、强大的推理能力以及llm的表观推理和幻觉行为之间的相互作用下。结果还显示了嵌入模型在某些偏差类别中捕获语义的能力。总的来说，这些发现表明，通过人工智能驱动的工具，在加强制药制造工作流程方面具有巨大潜力，同时也突出了需要进一步研究的重要问题。

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引用次数: 0

Probing the interplay between drug saturation, processing temperature and microstructure of amorphous solid dispersions with synchrotron X-ray phase-contrast tomography 用同步加速器x射线相衬断层成像技术探测药物饱和度、加工温度与非晶固体分散体微观结构的相互作用。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-01-25 DOI: 10.1016/j.ijpharm.2024.125018

Ecaterina Bordos , Gunjan Das , Sven L.M. Schroeder , Alastair Florence , Gavin W. Halbert , John Robertson

The impact of drug saturation and processing regime on the microstructure of amorphous solid dispersions (ASDs) produced by hot-melt extrusion (HME) has been investigated. By exploring various combinations of drug loadings and processing temperatures, a range of drug saturation points were obtained by HME. The process was monitored with an in-line low-frequency Raman probe to construct the respective solubility phase diagram (i.e., solubility of crystalline drug in molten/soften polymer). The resulting ASDs were analysed with synchrotron X-ray phase-contrast micro computed tomography (Sync-XPC-μCT) in conjunction with a tailored image segmentation strategy to extract quantitative and qualitative descriptors. Despite minimal elemental variability between the drug (paracetamol) and the polymer (HPMC), Sync-XPC-μCT provided sufficient contrast to identify multiple structural domains, including drug-rich crystalline clusters, impurities, polymer-related heterogeneities and voids/pores. Supersaturated ASDs (> 20 wt% drug loading) displayed higher structural complexity and showed a plethora of highly defective API-rich crystalline domains upon ageing, which were absent in the undersaturated ASDs. Beyond its impact on the API physical state, the HME processing regime influenced the degree of homogeneity within the polymer fraction, as well as total porosity, size, shape and pore connectivity. By correlating with fundamental API-polymer solubility data, this study offers additional insight into the dynamics of the drug’s solubilisation process during extrusion and the subsequent formation of microstructures within the ASD system, which have potential implications on product performance and stability.

研究了药物饱和度和工艺条件对热熔挤压法制备的非晶固体分散体（ASDs）微观结构的影响。通过探索不同的载药量和加工温度组合，HME获得了一系列药物饱和点。用低频拉曼探针监测该过程，以构建各自的溶解度相图（即结晶药物在熔融/软化聚合物中的溶解度）。采用同步加速器x射线相衬微计算机断层扫描（Sync-XPC-μCT）对asd进行分析，并结合定制的图像分割策略提取定量和定性描述符。尽管药物（扑热息痛）和聚合物（HPMC）之间的元素差异很小，但Sync-XPC-μCT提供了足够的对比来识别多个结构域，包括富含药物的结晶团簇、杂质、聚合物相关的异质性和空隙/孔隙。过饱和asd （bbb20 wt%药物负荷）表现出更高的结构复杂性，老化后显示出大量高度缺陷的富含api的晶体结构域，而这些结构域在不饱和asd中是不存在的。除了对原料药物理状态的影响外，HME处理制度还影响聚合物组分内的均匀度，以及总孔隙度、大小、形状和孔隙连通性。通过与基本的api -聚合物溶解度数据相关联，本研究为药物在挤压过程中的溶解过程动力学以及ASD系统中随后形成的微观结构提供了额外的见解，这对产品的性能和稳定性有潜在的影响。

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引用次数: 0

The current state-of-the art in pharmaceutical continuous film coating – A review 医药用连续膜涂层技术现状综述。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-01-25 DOI: 10.1016/j.ijpharm.2024.125052

Dorián László Galata, Orsolya Péterfi, Máté Ficzere, Bence Szabó-Szőcs, Edina Szabó, Zsombor Kristóf Nagy

In this decade, one of the major trends in the pharmaceutical industry is the adoption of continuous manufacturing. This requires the development of continuous equivalents of essential pharmaceutical processes such as film coating. The process of film coating is the last step of the processing of solid dosage forms and is critical because it determines the visual appearance of the end product, along with ensuring its stability and possibly even defining the rate of drug release. Several manufacturers advertise continuous solutions for film coating, these include semi-continuous and fully continuous appliances. State-of-the-art continuous coaters can match the throughput of continuous manufacturing lines, because largest appliances have a capacity of 1200–1500 kg/h. The paper also describes the main challenges related to continuous film coating including waste production at the beginning and end of the process and the problem caused by elastic recovery of the tablets when film coating is performed immediately after tablet compression. Lastly, we give an overview of the in-line sensors that can be used to monitor the quality of the film coated tablets, enabling real-time quality control of the process. Near-infrared and Raman spectroscopy can measure the mass gain of the tablets, while terahertz pulsed imaging and optical coherence tomography enable coating thickness measurement of individual tablets and even the characterization of intra-tablet coating thickness variability. UV imaging and machine vision can also measure coating thickness, and they are also excellent for detecting tablets with defective coating.

在这十年中，制药行业的主要趋势之一是采用连续制造。这就要求开发连续等效的基本制药工艺，如薄膜涂层。薄膜涂层的过程是固体剂型加工的最后一步，因为它决定了最终产品的视觉外观，同时确保其稳定性，甚至可能确定药物释放的速度。一些制造商宣传薄膜涂层的连续解决方案，其中包括半连续和全连续设备。最先进的连续涂布机可以匹配连续生产线的吞吐量，因为最大的设备的容量为1200-1500 kg/h。本文还介绍了与连续涂膜有关的主要挑战，包括在该过程的开始和结束时产生的废物，以及在药片压缩后立即进行涂膜时引起的药片弹性恢复问题。最后，我们概述了可用于监测薄膜包衣片质量的在线传感器，从而实现过程的实时质量控制。近红外和拉曼光谱可以测量片剂的质量增益，而太赫兹脉冲成像和光学相干断层扫描可以测量单个片剂的涂层厚度，甚至可以表征片剂内涂层厚度的变化。紫外线成像和机器视觉也可以测量涂层厚度，它们也非常适合检测涂层有缺陷的片剂。

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