European Journal of Pharmaceutics and Biopharmaceutics最新文献_第10页

Control of encapsulation efficiency and morphology of poly(lactide-co-glycolide) microparticles with a diafiltration-driven solvent extraction process 用重过滤驱动的溶剂萃取工艺控制聚（乳酸-共聚-乙二醇）微颗粒的封装效率和形态

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics

Pub Date : 2024-09-24 DOI: 10.1016/j.ejpb.2024.114515

Florian Kias, Roland Bodmeier

The removal of organic solvents during the preparation of biodegradable poly(D,L-lactide-co-glycolide) (PLGA) microparticles by an O/W- solvent extraction/evaporation process was investigated and controlled by diafiltration. Emulsification and steady replacement of the aqueous phase were performed in parallel in a single-vessel setup. During the process, the solidification of the dispersed phase (drug:PLGA:solvent droplets) into microparticles was monitored with video-microscopy and focused beam reflectance measurement (FBRM) and the residual solvent content was analyzed with headspace gas chromatography (organic solvent) and coulometric Karl-Fischer titration (water). Microparticles containing dexamethasone or risperidone were characterized with regard to particle size, morphology, encapsulation efficiency and in-vitro release. Diafiltration-accelerated solvent extraction shortened the process time by accelerating solidification of dispersed phase but reduced the residual dichloromethane content only in combination with increased temperature. Increasing the diafiltration rate increased particle size, porosity, and the encapsulation efficiency of risperidone. The latter effect was particularly evident with increasing lipophilicity of PLGA. A slower and more uniform solidification of end-capped and increased lactide content PLGA grade was identified as the reason for an increased drug leaching. Accelerated solvent extraction by diafiltration did not affect the in-vitro release of risperidone from different PLGA grades. The initial burst release of dexamethasone was increased by diafiltration when encapsulated in concentrations above the percolation threshold. Both porosity and burst release could be reduced by increasing the process temperature during diafiltration. Residual water content was established as an indicator for porosity and correlated with the burst release of dexamethasone.

研究了通过 O/W- 溶剂萃取/蒸发工艺制备可生物降解的聚（D,L-乳酸-共聚乙二醇）（PLGA）微粒过程中有机溶剂的去除情况，并通过重过滤进行了控制。乳化和水相的稳定置换在单容器装置中同时进行。在此过程中，使用视频显微镜和聚焦光束反射测量法（FBRM）监测分散相（药物：PLGA：溶剂液滴）凝固成微颗粒的过程，并使用顶空气相色谱法（有机溶剂）和库仑法卡尔-费歇尔滴定法（水）分析残留溶剂含量。含有地塞米松或利培酮的微颗粒在粒度、形态、包封效率和体外释放方面均有表征。重过滤-加速溶剂萃取法通过加速分散相的凝固缩短了工艺时间，但只有在温度升高的情况下才能减少二氯甲烷的残留量。提高重滤速率可增加利培酮的粒度、孔隙率和封装效率。随着聚乳酸甘油酯亲脂性的增加，后一种效果尤为明显。药物浸出增加的原因是，端帽聚乳酸含量增加的聚乳酸凝固速度更慢、更均匀。通过重滤加速溶剂萃取不会影响不同等级 PLGA 中利培酮的体外释放。当地塞米松的封装浓度高于渗滤阈值时，重滤会增加地塞米松的初始猝灭释放。在重滤过程中提高工艺温度可降低孔隙率和猝灭释放率。残余水含量被确定为孔隙率的指标，并与地塞米松的猝发释放相关。

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引用次数: 0

Targeted nanomedicine for reprogramming the tumor innate immune system: From bench to bedside 重编程肿瘤先天免疫系统的靶向纳米药物：从工作台到床边。

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics

Pub Date : 2024-09-21 DOI: 10.1016/j.ejpb.2024.114510

Kunal Pednekar , Julia Minnee , I. Jolanda M. de Vries , Jai Prakash

Tumor-associated innate immune cells such as tumor-associated macrophages, neutrophils, dendritic cells play a crucial role in tumor progression, angiogenesis and metastasis. These cells also control the efficacy of chemotherapy and immunotherapy by inducing drug resistance and immunosuppression, leading to therapeutic failures. Therefore, targeting the tumor-associated innate immune cells has gained high attention for the development of effective cancer therapy. Nanomedicine based strategies to target these cells are highly relevant and can be used to reprogram these cells. In this review, we discuss the fundamental roles of the tumor-associated innate immune cells in the tumor microenvironment and different strategies to modulate them. Then, nanomedicine-based strategies to target different tumor innate immune cells are explained in detail. While the clinical development of the targeted nanomedicine remains a great challenge in practice, we have provided our perspectives on various factors such as pharmaceutical aspects, preclinical testing and biological aspects which are crucial to consider before translating these targeting strategies to clinics.

肿瘤相关先天性免疫细胞，如肿瘤相关巨噬细胞、中性粒细胞、树突状细胞，在肿瘤进展、血管生成和转移中发挥着至关重要的作用。这些细胞还通过诱导耐药性和免疫抑制控制化疗和免疫疗法的疗效，导致治疗失败。因此，针对肿瘤相关先天性免疫细胞开发有效的癌症疗法已受到高度关注。以纳米药物为基础的靶向这些细胞的策略具有高度相关性，可用于对这些细胞进行重编程。在这篇综述中，我们将讨论肿瘤相关先天性免疫细胞在肿瘤微环境中的基本作用以及调节这些细胞的不同策略。然后，详细解释了针对不同肿瘤先天性免疫细胞的基于纳米药物的策略。虽然靶向纳米药物的临床开发在实践中仍是一个巨大的挑战，但我们从制药方面、临床前测试和生物学方面等各种因素提出了自己的观点，这些因素在将这些靶向策略转化为临床药物之前至关重要。

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引用次数: 0

Pharmaceutical approaches for enhancing solubility and oral bioavailability of poorly soluble drugs 提高难溶性药物溶解度和口服生物利用度的制药方法。

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics

Pub Date : 2024-09-21 DOI: 10.1016/j.ejpb.2024.114513

Isaïe Nyamba , Charles B Sombié , Moussa Yabré , Hermine Zimé-Diawara , Josias Yaméogo , Salfo Ouédraogo , Anna Lechanteur , Rasmané Semdé , Brigitte Evrard

High solubility in water and physiological fluids is an indispensable requirement for the pharmacological efficacy of an active pharmaceutical ingredient. Indeed, it is well established that pharmaceutical substances exhibiting limited solubility in water are inclined towards diminished and inconsistent absorption following oral administration, consequently resulting in variability in therapeutic outcomes. The current advancements in combinatorial chemistry and pharmaceutical design have facilitated the creation of drug candidates characterized by increased lipophilicity, elevated molecular size, and reduced aqueous solubility. Undoubtedly, the issue of poorly water-soluble medications has been progressively escalating over recent years. Indeed, 40% of the top 200 oral medications marketed in the United States, 33% of drugs listed in the US pharmacopoeia, 75% of compounds under development and 90% of new chemical entities are insufficiently water-soluble compounds. In order to address this obstacle, formulation scientists employ a variety of approaches, encompassing both physical and chemical methods such as prodrug synthesis, salt formation, solid dispersions formation, hydrotropic substances utilization, solubilizing agents incorporation, cosolvent addition, polymorphism exploration, cocrystal creation, cyclodextrins complexation, lipid formulations, particle size reduction and nanoformulation techniques. Despite the utilization of these diverse approaches, the primary reason for the failure in new drug development persists as the poor aqueous solubility of pharmaceutical compounds. This paper, therefore, delves into the foundational principles that underpin the implementation of various formulation strategies, along with a discussion on the respective advantages and drawbacks associated with each approach. Additionally, a discourse is provided regarding methodological frameworks for making informed decisions on selecting an appropriate formulation strategy to effectively tackle the key challenges posed during the development of a poorly water-soluble drug candidate.

在水和生理液体中的高溶解度是活性药物成分发挥药效不可或缺的条件。事实上，众所周知，在水中溶解度有限的药物在口服后会出现吸收减少和吸收不一致的情况，从而导致治疗效果的变化。目前，组合化学和药物设计的进步促进了以亲脂性增强、分子尺寸增大和水溶性降低为特征的候选药物的诞生。毫无疑问，近年来水溶性差的药物问题一直在逐步升级。事实上，在美国市场上销售的前 200 种口服药物中有 40%、33% 的药物被列入美国药典、75% 的在研化合物和 90% 的新化学实体都是水溶性不足的化合物。为了解决这一障碍，制剂科学家采用了多种方法，包括物理和化学方法，如原药合成、制盐、固体分散体的形成、亲水性物质的利用、增溶剂的加入、共溶剂的添加、多态性的探索、共晶体的创造、环糊精的复合、脂质制剂、粒度的减小和纳米制剂技术。尽管采用了这些不同的方法，但新药开发失败的主要原因仍然是药物化合物的水溶性差。因此，本文深入探讨了实施各种制剂策略的基本原则，并讨论了每种方法各自的优缺点。此外，本文还论述了在选择合适的制剂策略方面做出明智决策的方法框架，以有效应对开发水溶性差的候选药物过程中面临的关键挑战。

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引用次数: 0

Intratracheal delivery of macrophage targeted Celastrol-loaded PLGA nanoparticles for enhanced anti-inflammatory efficacy in acute lung injury mice 气管内给药巨噬细胞靶向 Celastrol 负载 PLGA 纳米粒子，增强急性肺损伤小鼠的抗炎疗效。

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics

Pub Date : 2024-09-21 DOI: 10.1016/j.ejpb.2024.114511

Yinlian Yao , Shilong Fan , Yinqiang Fan , Xin Shen , Xingxing Chai , Jiang Pi , Xueqin Huang , Yiming Shao , Zhikun Zhou , Yue Zhao , Hua Jin

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common causes of respiratory failure in critically ill patients. There is still a lack of definitive and effective treatment options, and the mortality rate remains as high as 30% to 40%. Effective therapeutics for ALI/ARDS are greatly hindered by the side effects resulting from inefficient delivery to the disease lesions and off-targeting biodistribution of drugs. Macrophages play an integral role in maintaining the steady state of the immune system and are involved in inflammation processes. Thus, nanodrug to accurately target macrophages have the potential to transform disease treatment. Here, we developed an mannosylated drug delivery system to target and deliver celastrol (Cel) to the alveolar macrophages for enhanced alleviating the cytokines in LPS-induce ALI mice. In vitro data demonstrated that the as-synthesized Man@Cel-NPs significantly improved the targeting of Cel into the inflammatory macrophages via mannose receptor-mediated phagocytosis. In vivo experiments further showed that intratracheal delivery of Man@Cel-NPs can improve the dysregulation of inflammatory response in LPS-induced mice by inhibiting the release of inflammatory cytokines and increasing autophagy and decreasing apoptosis in lungs. This work provides a potential NP platform for the locally tracheal delivery of herbal ingredients and exhibits promising clinical potential in the treatment of numerous respiratory diseases, including ALI/ARDS.

急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）是重症患者呼吸衰竭的常见原因。目前仍缺乏明确有效的治疗方案，死亡率仍高达 30% 至 40%。有效治疗 ALI/ARDS 的药物因不能有效送达病灶和药物的生物分布偏离靶点而产生副作用，从而大大阻碍了治疗的效果。巨噬细胞在维持免疫系统稳定状态方面发挥着不可或缺的作用，并参与炎症过程。因此，精确靶向巨噬细胞的纳米药物有可能改变疾病治疗。在此，我们开发了一种甘露糖基化的药物递送系统，将 Celastrol（Cel）靶向递送至肺泡巨噬细胞，以增强对 LPS 诱导的 ALI 小鼠细胞因子的缓解作用。体外实验数据表明，合成的 Man@Cel-NPs 通过甘露糖受体介导的吞噬作用，显著提高了 Cel 进入炎性巨噬细胞的靶向性。体内实验进一步表明，气管内给药 Man@Cel-NPs 可抑制炎症细胞因子的释放，增加自噬，减少肺部细胞凋亡，从而改善 LPS 诱导的小鼠炎症反应失调。这项研究为气管局部给药中草药成分提供了一个潜在的 NP 平台，在治疗包括 ALI/ARDS 在内的多种呼吸系统疾病方面具有广阔的临床前景。

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引用次数: 0

Characterization of naproxen salts with amino acid esters and their application in topical skin preparations 氨基酸酯类萘普生盐的特性及其在局部皮肤制剂中的应用。

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics

Pub Date : 2024-09-19 DOI: 10.1016/j.ejpb.2024.114505

Ewelina Kopciuch , Ewa Janus , Paula Ossowicz-Rupniewska , Anna Nowak , Wiktoria Duchnik , Łukasz Kucharski , Urszula Adamiak-Giera , Zofia Lendzion-Bieluń

In the study, the modification of naproxen (NAP) with esters of four amino acids (AAs): glycine (GlyOiPr), L-proline (ProOiPr), L-leucine (LeuOiPr), and L-serine (SerOiPr) isopropyl ester was performed to improve water solubility and enhance the permeation of the drug through the skin in comparison to the parent NAP. The NAP derivatives were prepared using the equimolar ratio of the components. In-depth NMR and FTIR analysis revealed that the salts formed with the proton transfer from the carboxylic group of NAP to the amine group of the appropriate AA ester. The NAP salts exhibited improved solubility in water and PBS solution (pH 7.4) when compared to parent NAP. The values of the partition coefficient (log P_O/W) for prepared salts were lower than for NAP, however, the salts maintained hydrophobic character determined by the positive values of log P. The In vitro permeation through the pig skin performed in Franz diffusion cells showed that all NAP salts exhibited a higher cumulative mass of permeated NAP (Q_24h) than the parent acid. The highest permeation value was noted for [ProOiPr][NAP], with a pseudo-steady state flux (J_ss) 32.5 µg NAP cm⁻²h⁻¹, and Q_24h = 246.4 µg NAP cm⁻², it was 2.5 % of the applied dose. Moreover, topical preparations with [ProOiPr][NAP] and NAP were prepared based on two vehicles − Celugel® and Pentravan®- approved in pharmacy recipes. The permeation experiments through the Strat-M® showed, that both the J_ss and Q_24h of permeated drug from preparations containing [ProOiPr][NAP], were statistically several times greater than from the respective preparations with the unmodified acid. Additionally, preparations with [ProOiPr][NAP] provided significantly improved permeation of NAP than two commercial preparations, one of which contained naproxen as the acid and the other – as the sodium salt.

本研究用甘氨酸（GlyOiPr）、L-脯氨酸（ProOiPr）、L-亮氨酸（LeuOiPr）和 L-丝氨酸（SerOiPr）四种氨基酸（AAs）的异丙基酯对萘普生（NAP）进行了改性，以提高其水溶性，并增强药物在皮肤中的渗透性。NAP 衍生物的制备采用了各组分的等摩尔比。深入的核磁共振和傅立叶变换红外分析表明，这些盐是通过质子从 NAP 的羧基转移到适当 AA 酯的胺基上形成的。与母体 NAP 相比，NAP 盐在水和 PBS 溶液（pH 值为 7.4）中的溶解度有所提高。所制备盐类的分配系数（log PO/W）值低于 NAP，但盐类仍具有疏水性，这由 log P 的正值决定。渗透值最高的是[ProOiPr][NAP]，其假稳态通量（Jss）为 32.5 µg NAP cm-2/h-1，Q24h = 246.4 µg NAP cm-2，是施用剂量的 2.5%。此外，还利用两种载体--Celugel® 和 Pentravan®--制备了[ProOiPr][NAP]和 NAP 的局部制剂，这两种载体已被批准用于药剂配方。通过 Strat-M® 进行的渗透实验表明，含有[ProOiPr][NAP]的制剂渗透药物的 Jss 和 Q24h 都比含有未改性酸的制剂高出数倍。此外，与两种商用制剂相比，含有[ProOiPr][NAP]的制剂对萘普生的渗透率明显提高，其中一种制剂含有萘普生酸，另一种制剂含有萘普生钠盐。

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引用次数: 0

Design and development of Fujicalin-based axitinib liquisolid compacts for improved dissolution and bioavailability to treat renal cell carcinoma 设计和开发基于藤黄素的阿西替尼利尿固化物，提高其溶解度和生物利用度，以治疗肾细胞癌。

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics

Pub Date : 2024-09-19 DOI: 10.1016/j.ejpb.2024.114506

Priyanka S. Yadav , Ashok A. Hajare , Kiran S. Patil

Poor dissolution of axitinib (AXT) limits its effectiveness through the oral route. The present study investigated, prospective of liquisolid (LS) technology to improve dissolution rate and oral bioavailability of AXT to treat renal cell carcinoma. LS compacts were fabricated with PEG 200, Fujicalin SG, and Aerosil 200 as solvent, carrier, and coat material, respectively. The behavior of LS-systems during tabletting was investigated using Kawakita, Heckel, and Leuenberger analysis. LS compacts were examined for P-XRD, DSC, SEM, and in vitro drug dissolution. For optimization, a 3² full factorial design was utilized. Cell line A498 was utilized for in vitro cytotoxicity study. A bioavailability study was performed using rabbits. DSC and P-XRD analysis confirmed the transition of crystalline AXT to its partial amorphization and molecular dispersion. Consequently, LS6 demonstrated a significantly rapid drug dissolution (Q₂₀; >99 %) than the directly compressed tablets (18.05 %). Additionally, 2.03-fold increase in oral bioavailability, and inhibited dose-dependent cell growth with 1.75-fold increased apoptosis rate. Overall, an LS6 compact consisting of 15 % AXT concentration in PEG 200 and a 20 w/w ratio of Fujicalin SG: Aerosil 200 exhibited improved formulation properties, enhanced dissolution rate, and bioavailability. Thus developed potential product may contribute low-cost production with patient-improved survival expectations.

阿西替尼（AXT）的溶解度较低，限制了其通过口服途径的有效性。本研究探讨了利用Liquisolid（LS）技术提高阿西替尼溶解率和口服生物利用度以治疗肾细胞癌的前景。研究人员分别以 PEG 200、Fujicalin SG 和 Aerosil 200 作为溶剂、载体和包衣材料，制成了液相固体。使用 Kawakita、Heckel 和 Leuenberger 分析法研究了 LS 系统在压片过程中的行为。此外，还对 LS 紧凑型产品进行了 P-XRD、DSC、SEM 和体外药物溶解度检测。在优化方面，采用了 32 全因子设计。体外细胞毒性研究采用了 A498 细胞系。利用兔子进行了生物利用度研究。DSC 和 P-XRD 分析证实了 AXT 结晶向部分非晶化和分子分散的转变。因此，与直接压片（18.05%）相比，LS6 的药物溶出速度（Q20；>99%）明显更快。此外，LS6 的口服生物利用度提高了 2.03 倍，并能抑制剂量依赖性细胞生长，使细胞凋亡率提高了 1.75 倍。总之，由 15 % AXT 浓度的 PEG 200 和 20 w/w 比率的藤黄素 SG: Aerosil 200 组成的 LS6 密实剂具有更好的制剂特性、更高的溶出率和生物利用率。因此，所开发的潜在产品可实现低成本生产，并提高患者的存活率。

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引用次数: 0

Low pinocytic brain endothelial cells primarily utilize membrane fusion to internalize extracellular vesicles 低针叶脑内皮细胞主要利用膜融合来内化细胞外囊泡。

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics

Pub Date : 2024-09-19 DOI: 10.1016/j.ejpb.2024.114500

Jhanvi R. Jhaveri , Purva Khare , Paromita Paul Pinky , Yashika S. Kamte , Manisha N. Chandwani , Jadranka Milosevic , Nevil Abraham , Ming Sun , Donna B. Stolz , Kandarp M. Dave , Si-yang Zheng , Lauren O’Donnell , Devika S Manickam

Extracellular vesicles (EVs) are an emerging class of drug carriers and are primarily reported to be internalized into recipient cells via a combination of endocytic routes such as clathrin-mediated, caveolae-mediated and macropinocytosis pathways. In this work, (1) we investigated potential effects of homotypic vs. heterotypic interactions by studying the cellular uptake of homologous EVs (EV donor cells and recipient cells of the same type) vs. heterologous EVs (EV donor cells and recipient cells of different types) and (2) determined the route of EV internalization into low pinocytic/hard-to-deliver cell models such as brain endothelial cells (BECs). Homotypic interactions led to a greater extent of uptake into the recipient BECs compared to heterotypic interactions. However, we did not see a complete reduction in EV uptake into recipient BECs when endocytic pathways were blocked using pharmacological inhibitors and our findings from a R18-based fusion assay suggest that EVs primarily use membrane fusion to enter low-pinocytic recipient BECs instead of relying on endocytosis. Lipophilic PKH67 dye-labeled EVs but not intravesicular esterase-activated calcein ester-labeled EVs severely reduced particle uptake into BECs while phagocytic macrophages internalized EVs labeled with both dyes to comparable extents. Our results also highlight the importance of carefully choosing labeling dye chemistry to study EV uptake, especially in the case of low pinocytic cells such as BECs.

细胞外囊泡（EVs）是一类新兴的药物载体，据报道主要通过多种内吞途径内化到受体细胞，如凝胶酶介导、洞穴介导和大蛋白胞吞途径。在这项工作中，(1) 我们通过研究同源 EV（EV 供体细胞和同种类型的受体细胞）与异源 EV（EV 供体细胞和不同类型的受体细胞）的细胞摄取，调查了同型与异型相互作用的潜在影响；(2) 确定了 EV 内化到低针胞/难于递送细胞模型（如脑内皮细胞（BECs）和吞噬细胞模型（如巨噬细胞）的途径。与异型相互作用相比，同型相互作用导致受体 BECs 更大程度的吸收。然而，当使用药理抑制剂阻断内吞途径时，我们并没有看到受体BECs对EV的摄取完全减少，我们基于R18融合试验的研究结果表明，EV主要通过膜融合而不是依靠内吞作用进入低刺吸细胞受体BECs。亲脂性 PKH67 染料标记的 EV 而非静脉内酯酶激活的钙黄绿素酯标记的 EV 严重降低了 BECs 对颗粒的摄取，而吞噬型巨噬细胞内化这两种 EV 标记颗粒的程度相当。我们的研究结果还强调了仔细选择标记染料化学成分来研究EV摄取的重要性，尤其是对于像BECs这样的低针状细胞。

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引用次数: 0

Advancing pharmaceutical Intelligence via computationally Prognosticating the in-vitro parameters of fast disintegration tablets using Machine Learning models 通过计算推进制药智能化利用机器学习模型预测快速崩解片剂的体外参数

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics

Pub Date : 2024-09-19 DOI: 10.1016/j.ejpb.2024.114508

Dhruv Gupta, Anuj A Biswas, Rohan Chand Sahu, Sanchit Arora, Dinesh Kumar, Ashish K Agrawal

The field of Machine Learning (ML) has garnered significant attention, particularly in healthcare for predicting disease severity. Recently, the pharmaceutical sector has also adopted ML techniques in various stages of drug development. Tablets are the most common pharmaceutical formulations, with their efficacy influenced by the physicochemical properties of active ingredients, in-process parameters, and formulation components. In this study, we developed ML-based prediction models for disintegration time, friability, and water absorption ratio of fast disintegration tablets. The model development process included data visualization, pre-processing, splitting, ML model creation, and evaluation. We evaluated the models using root mean square error (RMSE) and R-squared score (R²). After hyperparameter tuning and cross-validation, the voting regressor model demonstrated the best performance for predicting disintegration time (RMSE: 21.99, R²: 0.76), surpassing previously reported models. The random forest regressor achieved the best results for friability prediction (RMSE: 0.142, R²: 0.7), and the K-nearest neighbor (KNN) regressor excelled in predicting the water absorption ratio (RMSE: 10.07, R²: 0.94). Notably, predicting friability and water absorption ratio using ML models is unprecedented in the literature. The developed models were deployed in a web app for easy access by anyone. These ML models can significantly enhance the tablet development phase by minimizing experimental iterations and material usage, thereby reducing costs and saving time.

机器学习（ML）领域备受关注，尤其是在预测疾病严重程度的医疗保健领域。最近，制药行业也在药物开发的各个阶段采用了 ML 技术。片剂是最常见的药物制剂，其药效受活性成分的理化性质、加工过程参数和制剂成分的影响。在本研究中，我们针对快速崩解片剂的崩解时间、易碎性和吸水率开发了基于 ML 的预测模型。模型开发过程包括数据可视化、预处理、拆分、ML 模型创建和评估。我们使用均方根误差（RMSE）和 R 平方得分（R2）对模型进行了评估。经过超参数调整和交叉验证后，投票回归模型在预测解体时间方面表现最佳（RMSE：21.99，R2：0.76），超过了之前报道的模型。随机森林回归模型在易碎性预测方面取得了最佳结果（RMSE：0.142，R2：0.7），K-近邻（KNN）回归模型在吸水率预测方面表现出色（RMSE：10.07，R2：0.94）。值得注意的是，使用 ML 模型预测易碎性和吸水率在文献中是前所未有的。开发的模型被部署在一个网络应用程序中，任何人都可以轻松访问。这些 ML 模型可以最大限度地减少实验迭代和材料使用，从而降低成本并节省时间，从而大大提高片剂开发阶段的效率。

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引用次数: 0

pH-Sensitive Tacrolimus loaded nanostructured lipid carriers for the treatment of inflammatory bowel disease 用于治疗炎症性肠病的 pH 值敏感的他克莫司负载纳米结构脂质载体。

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics

Pub Date : 2024-09-19 DOI: 10.1016/j.ejpb.2024.114461

Sidra Altaf , Mahira Zeeshan , Hussain Ali , Ahmed Zeb , Iqra Afzal , Ayesha Imran , Danish Mazhar , Salman Khan , Fawad Ali Shah

Inflammatory Bowel Disease is the chronic tissue inflammation of the lower part of the Gastrointestinal tract (GIT). Conventional therapeutic approaches face numerous challenges, often making the delivery system inadequate for treating the disease. This study aimed to integrate a pH-sensitive polymer and nanostructured lipid carriers (NLCs) to develop a hybrid nanocarrier system. Tacrolimus-loaded NLCs coated with Eudragit® FS100 (TAC-NLCs/E FS100) nanoparticles were prepared via double emulsion technique followed by an aqueous enteric coating technique. Various parameters, such as particle size, entrapment efficiency, and zeta potential were optimized using Design Expert software®. Cetyltrimethyl ammonium bromide (CTAB) was used as a cationic surfactant which induces a positive charge on the nanoparticles. These cationic NLCs can adhere to the mucosal surface, thereby enabling prolonged retention. In vitro drug release was assessed, and the results demonstrated that drug release was retarded at pH 1.2 corresponding to upper GIT pH and maximum drug was released at pH 7.4 (colonic pH). Moreover, we evaluated TAC-NLCs/E FS100 nanoparticles in murine colitis models to gauge the efficacy of both coated and uncoated NLCs formulation. The TAC-NLCs/E FS100 showed a pronounced reduction in induced colitis, as evident from the restoration of morphological features, improved histopathological scores, antioxidant levels, and decreased the levels of proinflammatory cytokines. Thus, pH-sensitive TAC-NLCs/EFS 100 are attributed to the enhanced localization and targeted delivery at the specific site.

炎症性肠病是胃肠道（GIT）下部的慢性组织炎症。传统的治疗方法面临诸多挑战，往往使给药系统不足以治疗这种疾病。本研究旨在整合 pH 值敏感聚合物和纳米结构脂质载体（NLCs），开发一种混合纳米载体系统。研究人员通过双乳液技术制备了涂有 Eudragit® FS100 的他克莫司 NLCs（TAC-NLCs/E FS100）纳米颗粒，然后采用水性肠溶包衣技术进行了包衣。使用 Design Expert 软件® 对粒度、夹持效率和 Zeta 电位等各种参数进行了优化。十六烷基三甲基溴化铵（CTAB）被用作阳离子表面活性剂，可使纳米颗粒带上正电荷。这些阳离子 NLC 可以附着在粘膜表面，从而延长药物的保留时间。我们对体外药物释放进行了评估，结果表明，药物释放在 pH 值为 1.2（相当于胃肠道上部 pH 值）时受阻，而在 pH 值为 7.4（结肠 pH 值）时释放最多。此外，我们还在小鼠结肠炎模型中评估了 TAC-NLCs/E FS100 纳米粒子，以衡量包衣和未包衣 NLCs 制剂的疗效。从形态特征的恢复、组织病理学评分的改善、抗氧化剂水平的提高以及促炎细胞因子水平的降低等方面可以看出，TAC-NLCs/E FS100 对诱导性结肠炎有明显的缓解作用。因此，对 pH 值敏感的 TAC-NLCs/EFS 100 可增强在特定部位的定位和定向递送。

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引用次数: 0

Inhibition of influenza virus infection in mice by pulmonary administration of a spray dried antiviral drug 通过肺部给药喷雾干燥抗病毒药物抑制小鼠感染流感病毒

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics

Pub Date : 2024-09-18 DOI: 10.1016/j.ejpb.2024.114507

Rick Heida , Paulo H. Jacob Silva , Renate Akkerman , Jill Moser , Jacqueline de Vries-Idema , Aurélien Bornet , Sujeet Pawar , Francesco Stellacci , Henderik W. Frijlink , Anke L.W. Huckriede , Wouter L.J. Hinrichs

Increasing resistance to antiviral drugs approved for the treatment of influenza urges the development of novel compounds. Ideally, this should be complemented by a careful consideration of the administration route. 6′siallyllactosamine-functionalized β-cyclodextrin (CD-6′SLN) is a novel entry inhibitor that acts as a mimic of the primary attachment receptor of influenza, sialic acid. In this study, we aimed to develop a dry powder formulation of CD-6′SLN to assess its in vivo antiviral activity after administration via the pulmonary route. By means of spray drying the compound together with trileucine, a dispersion enhancer, we created a powder that retained the antiviral effect of the drug, remained stable under elevated temperature conditions and performed well in a dry powder inhaler. To test the efficacy of the dry powder drug against influenza infection in vivo, infected mice were treated with CD-6′SLN using an aerosol generator that allowed for the controlled administration of powder formulations to the lungs of mice. CD-6′SLN was effective in mitigating the course of the disease compared to the control groups, reflected by lower disease activity scores and by the prevention of virus-induced IL-6 production. Our data show that CD-6′SLN can be formulated as a stable dry powder that is suitable for use in a dry powder inhaler and is effective when administered via the pulmonary route to influenza-infected mice.

由于用于治疗流感的抗病毒药物的抗药性不断增加，因此需要开发新型化合物。理想的情况是，在开发新型化合物的同时，还应仔细考虑给药途径。6′siallyllactosamine-functionalized β-环糊精（CD-6′SLN）是一种新型的进入抑制剂，它可以模拟流感的主要附着受体--sialic acid。本研究旨在开发一种 CD-6′SLN 干粉制剂，以评估其通过肺部途径给药后的体内抗病毒活性。通过将该化合物与三亮氨酸（一种分散增强剂）一起喷雾干燥，我们制成了一种粉末，该粉末保留了药物的抗病毒效果，在高温条件下保持稳定，并且在干粉吸入器中表现良好。为了测试干粉药物对流感感染的体内疗效，我们使用气溶胶发生器对受感染的小鼠进行了 CD-6′SLN 治疗，该气溶胶发生器可将粉末制剂控制性地施用到小鼠的肺部。与对照组相比，CD-6′SLN 能有效缓解疾病的进程，这体现在疾病活动评分降低以及病毒诱导的 IL-6 生成减少。我们的数据表明，CD-6′SLN 可以配制成稳定的干粉，适合在干粉吸入器中使用，通过肺部途径给流感感染小鼠用药时效果显著。

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引用次数: 0