International Journal of Pharmaceutics最新文献_第7页

In vivo pharmacokinetic study and PBPK modeling: Comparison between 3D-printed nanocrystals and solid dispersions 体内药代动力学研究和PBPK建模：3d打印纳米晶体和固体分散体的比较。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-01-25 DOI: 10.1016/j.ijpharm.2024.125063

Lucia Lopez-Vidal , Mariano Tinti , Maria Elisa Melian , Lucila Canton , Matias Lorenzutti , Laureano Schofs , Maria Lina Formica , Alejandro J. Paredes , Sergio Sanchez Bruni , Nicolas Litterio , Ricardo Faccio , Santiago Daniel Palma , Juan Pablo Real

The solubility of drugs remains one of the most challenging aspects of formulation development. Several technologies exist to enhance the properties of poorly soluble drugs, with nanocrystal (NC) and solid dispersion (SD) technologies being among the most important. This work compared NCs and SDs under identical conditions using albendazole as a model drug and 3D printing technology as the delivery method. SDs were initially prepared and characterized, and then compared to the NCs system. Techniques such as TGA, DSC, XRD, FTIR, SEM, and confocal Raman microscopy were employed to assess the solid-state properties and formulation homogeneity. Solubility and dissolution profiles were evaluated under simulated gastric and intestinal conditions. An in vivo pharmacokinetic study was performed in dogs comparing 3D-printed formulations (NC-3D and SD-3D) with a control group treated with the pure drug (ABZ-C). A PBPK model was developed also in dogs to further analyse the results. While no statistically significant differences were observed in the in vitro dissolution profiles in 0.1 N HCl, differences emerged in precipitation time and solubility at intestinal pH (6.8). The pharmacokinetic study revealed improvements in the pharmacokinetic profile of both systems compared to the control, as expected. Between the NCs and the SD, the NC system demonstrated significantly superior pharmacokinetic parameters of interest. The PBPK model helped to explain the differences observed in the in vivo study. The results suggest that nanocrystal technology is more effective at enhancing the in vivo performance of Class II drugs, at least when using albendazole as the model drug.

药物的溶解度仍然是配方开发中最具挑战性的方面之一。目前有几种技术可以提高难溶性药物的性能，其中纳米晶体（NC）和固体分散（SD）技术是最重要的技术。本研究以阿苯达唑为模型药物，以3D打印技术为给药方式，在相同条件下比较了NCs和SDs。初步制备SDs并对其进行表征，并与NCs体系进行比较。采用TGA、DSC、XRD、FTIR、SEM和拉曼光谱等技术评估了固体性能和配方均匀性。在模拟胃和肠道条件下评估溶解度和溶解谱。将3d打印制剂（NC-3D和SD-3D）与使用纯药物（ABZ-C）的对照组进行狗体内药代动力学研究。为了进一步分析结果，还在狗身上建立了PBPK模型。虽然0.1 N HCl的体外溶出曲线无统计学差异，但在沉淀时间和肠道pH（6.8）下的溶解度存在差异。药代动力学研究显示，与对照组相比，两种系统的药代动力学特征都有所改善，正如预期的那样。在NC系统和SD系统之间，NC系统表现出显著优于感兴趣的药代动力学参数。PBPK模型有助于解释体内研究中观察到的差异。结果表明，纳米晶体技术在提高二类药物的体内性能方面更为有效，至少在以阿苯达唑为模型药物时是如此。

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引用次数: 0

Redox/NIR dual-responsive glutathione extended polyurethane urea electrospun membranes for synergistic chemo-photothermal therapy 氧化还原/近红外双响应谷胱甘肽延伸聚氨酯尿素静电纺丝膜协同化学光热治疗。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-01-25 DOI: 10.1016/j.ijpharm.2024.125108

Annalisa Martorana , Giorgia Puleo , Giovanni Carlo Miceli , Francesco Cancilla , Mariano Licciardi , Giovanna Pitarresi , Luigi Tranchina , Maurizio Marrale , Fabio Salvatore Palumbo

Despite advancements in cancer treatments, therapies frequently exhibit high cytotoxicity, and surgery remains the predominant method for treating most solid tumors, often with limited success in preventing post-surgical recurrence. Implantable biomaterials, designed to release drugs at a localised site in response to specific stimuli, represent a promising approach for enhancing tumour therapy. In this study, a redox-responsive glutathione extended polyurethane urea (PolyCEGS) was used to produce paclitaxel (PTX) and gold nanorods (AuNRs) loaded electrospun membranes for combined redox/near-infrared (NIR) light-responsive release chemotherapy and hyperthermic effect. Electrospinning conditions were optimized to fabricate AuNR-loaded scaffolds, at three different AuNRs concentrations. The obtained membranes were characterized by scanning electron microscopy (SEM) analyses and photothermal profiles were evaluated by a thermocamera, showing a temperature increase, up to 42.5 °C, when exposed to NIR light (810 nm) at 3 W/cm². The AuNRs/PTX loaded scaffolds exhibited sustained PTX release, with 15 % released over 30 days and almost 1.8 times more in a simulated reductive environment. Moreover, their excellent photothermal effects and NIR light-triggered release led to significant synergic cytotoxicity in human colon cancer (HCT-116) and human breast cancer (MCF-7) cell lines. This system potentially enables controllable locoregional PTX release at the tumour site post-surgery, preventing recurrence and enhancing cytotoxicity through combined drug and PTT effects, highlighting its potential for future anticancer treatments.

尽管癌症治疗取得了进步，但治疗方法经常表现出高细胞毒性，手术仍然是治疗大多数实体瘤的主要方法，通常在预防手术后复发方面收效甚微。植入式生物材料，设计用于在特定刺激下在局部部位释放药物，代表了加强肿瘤治疗的一种有前途的方法。本研究利用谷胱甘肽延伸聚氨酯脲（PolyCEGS）制备负载紫杉醇（PTX）和金纳米棒（aunr）的电纺丝膜，用于氧化还原/近红外（NIR）联合光敏释放化疗和热疗效果。在三种不同的aunr浓度下，对静电纺丝条件进行优化，制备负载aunr的支架。通过扫描电子显微镜（SEM）和热像仪对所得膜进行了表征，结果表明，当暴露在3 W/cm2的近红外光（810 nm）下时，膜的温度升高了42.5 °C。负载aunr /PTX的支架表现出持续的PTX释放，在30 天内释放了15% %，在模拟还原环境中释放了近1.8倍。此外，其优异的光热效应和近红外光引发的释放导致其对人结肠癌（HCT-116）和人乳腺癌（MCF-7）细胞系具有显著的协同细胞毒性。该系统有可能在术后肿瘤部位实现可控的局部区域PTX释放，通过药物和PTT联合作用预防复发和增强细胞毒性，突出其在未来抗癌治疗中的潜力。

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引用次数: 0

Time domain NMR for polymorphism characterization: Current status and future perspectives 多态表征的时域核磁共振：现状和未来展望。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-01-25 DOI: 10.1016/j.ijpharm.2024.125027

Luisa Souza Almeida , Jaqueline Carneiro , Luiz Alberto Colnago

Polymorphism is the ability of a compound to exist in multiple crystal forms while maintaining the same chemical composition. This phenomenon is reflected in different solid-state physicochemical properties due to variations in structural energy and the degree of lattice disorder. The pharmaceutical industry places significant emphasis on thoroughly characterizing polymorphism in Active Pharmaceutical Ingredients (APIs) because of its impact on the pharmacokinetic properties on the final medicine product. Standard characterization techniques are well documented in pharmacopeias and by international agencies. These techniques, whether applied individually or in combination, include crystallography (X-Ray Diffraction), thermal analysis (Differential Scanning Calorimetry), and various forms of spectroscopy, such as Near-Infrared, Raman, and solid-state Nuclear Magnetic Resonance (NMR). Analyzing NMR applications for solid-state characterization over the past five years, there has been a growing number of reports on the use of Time Domain NMR (TD-NMR) to evaluate polymorphism on APIs. Due to the increasing interest in this compelling technique, this study provides an overview of the current advancements in TD-NMR for polymorphism assessment in pharmaceutical products. Compared to high-field devices, TD-NMR has proven to be more convenient to industrial applications due to its smaller equipment size and shorter measurement times. This mini-review compares various applications of TD-NMR for API solid-state characterization and offer guidance for future research in this area.

多态是指化合物在保持相同化学成分的情况下以多种晶体形式存在的能力。由于结构能和晶格无序程度的变化，这种现象反映在不同的固态物理化学性质上。制药行业非常重视对活性药物成分（api）多态性的彻底表征，因为它对最终药品的药代动力学特性有影响。标准表征技术在药典和国际机构中有很好的记录。这些技术，无论是单独应用还是组合应用，包括晶体学（x射线衍射）、热分析（差示扫描量热法）和各种形式的光谱学，如近红外、拉曼和固态核磁共振（NMR）。在过去的五年中，分析核磁共振在固态表征方面的应用，有越来越多的报道使用时域核磁共振（TD-NMR）来评估api的多态性。由于对这一引人注目的技术的兴趣日益增加，本研究概述了TD-NMR用于药物产品多态性评估的当前进展。与高场设备相比，由于其更小的设备尺寸和更短的测量时间，TD-NMR已被证明更方便于工业应用。这篇综述比较了TD-NMR在原料药固态表征中的各种应用，并为该领域的未来研究提供指导。

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引用次数: 0

Self-assembled hyaluronic acid nanoparticles delivered by polymeric microneedles for targeted and long-acting therapy of psoriasis 聚合微针递送的自组装透明质酸纳米颗粒用于银屑病的靶向和长效治疗。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-01-25 DOI: 10.1016/j.ijpharm.2024.125073

Yongnian Zeng , Lujuan Wu , Xue Jiang , Yixin Hu , Yinli Jin , Hankun Hu , Wei Li

Psoriasis is an autoimmune-driven inflammatory skin disease, clinically characterized by skin thickening, erythema, and scaling, significantly impacting patients’ life quality and mental health. Clinically, oral pill or injection of methotrexate (MTX) formulation is a common route for psoriasis therapy, while both methods often cause undesired toxicity due to systemic administration, and limit patient compliance because of the frequent-dosing requirement. Here, we introduce a dissolvable microneedle (MN) patch made of polyvinyl alcohol (PVA) that incorporates self-assembled hyaluronic acid (HA) nanoparticles (NPs) conjugating MTX, which is designed for treating skin diseases, offering reduced adverse effects and improved patient adherence through its targeted and long-acting properties. Upon transdermal delivery via polymeric MNs, the HA-based therapeutic NPs actively target to the inflammatory skin cells via the interaction of HA group with CD44 protein that is highly expressed on the cell membrane in the psoriatic skin. Moreover, the HA-based NPs undergo slow dissociation, thereby achieving sustained release of the MTX drug at the lesion site over 7 days. Due to the favorite features, in the imiquimod (IMQ)-induced psoriatic mouse, only one application of the polymeric MN patch achieves diminished epidermal hyperplasia, and reduced inflammatory factors expression, ultimately improving the psoriasis-like skin condition in vivo.

银屑病是一种自身免疫性炎症性皮肤病，临床表现为皮肤增厚、红斑和脱屑，严重影响患者的生活质量和心理健康。临床上，口服药物或注射甲氨蝶呤（MTX）制剂是治疗银屑病的常用途径，但这两种方法往往会因全身给药而产生不良毒性，并因需要频繁给药而限制了患者的依从性。在这里，我们介绍了一种由聚乙烯醇（PVA）制成的可溶解微针（MN）贴片，它结合了自组装透明质酸（HA）纳米颗粒（NPs），专门用于治疗皮肤病，通过其靶向性和长效性减少了不良反应，提高了患者的依从性。通过聚合物 MNs 经皮给药后，基于 HA 的治疗 NPs 会通过 HA 基团与银屑病皮肤细胞膜上高表达的 CD44 蛋白的相互作用，主动靶向炎性皮肤细胞。此外，以 HA 为基质的 NPs 解离速度较慢，因此可在皮损部位持续释放 MTX 药物达 7 天之久。由于这些特性，在咪喹莫特（IMQ）诱导的银屑病小鼠中，只需使用一次聚合 MN 贴片，就能减少表皮增生和炎症因子的表达，最终改善体内银屑病样皮肤状况。

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引用次数: 0

Pirfenidone microcrystals for pulmonary delivery: Regulation of the precipitation behavior in the supercooled droplet 用于肺部给药的吡非尼酮微晶：过冷液滴中沉淀行为的调节。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-01-25 DOI: 10.1016/j.ijpharm.2024.125074

Kangwei Lu, Shen Yan, Baoyun Li, Jingye Ma, Xinpei Wu, Wenqi Yan, Shengyu Zhang, Xiao Dong Chen, Winston Duo Wu

Pirfenidone (PFD) is one of the first-line drugs for treating idiopathic pulmonary fibrosis, while directly delivering PFD to lung showed better efficiency. However, PFD is a non-glass former and easily precipitates into larger-sized crystals that are undesirable for pulmonary delivery. Hence, the fabrication of PFD particles with pulmonary delivery efficiency remains challenging. Herein, a series of particles were prepared by spray freeze drying a PFD and leucine mixed solution. The sub-ambient behavior of the mixed solution was evaluated via a differential scanning calorimeter. The effects of the PFD/leucine mass ratio and freezing temperature on the particle morphology, size, crystal polymorphism, molecular structure and in vitro aerosol performance were investigated. Shortening the lifetime of the droplet and adding proper amounts of leucine are the keys to decreasing the PFD crystal size and improving its dispersity. The optimal sample is SF_-80D-P₉₅L₅-2, with high FPF and eFPF values of ∼ 65.97 % and ∼ 27.86 %, and owing to its high drug loading (95 %), the FPD and eFPD are extremely high at ∼ 6.27 mg and ∼ 2.65 mg, respectively, equivalent to ∼ 6.27 mg and ∼ 2.65 mg PFD deposited in the lungs and alveoli, respectively, when 10 mg dry powder is inhaled. This work provides a potential strategy for tuning the precipitation behavior of PFD microcrystals with high pulmonary drug delivery efficiency.

吡非尼酮（PFD）是治疗特发性肺纤维化的一线药物之一，而直接给肺治疗效果更好。然而，PFD是一种非玻璃原体，容易沉淀成较大的晶体，这是不希望肺部输送的。因此，制造具有肺输送效率的PFD颗粒仍然具有挑战性。本文以PFD和亮氨酸混合溶液为原料，采用喷雾冷冻干燥法制备了一系列颗粒。通过差示扫描量热计评估了混合溶液的亚环境行为。研究了PFD/亮氨酸质量比和冷冻温度对颗粒形态、大小、晶体多态性、分子结构和体外气溶胶性能的影响。缩短液滴寿命和加入适量亮氨酸是减小PFD晶体尺寸和提高其分散性的关键。最优样本sf - 80 d - p95l5 - 2,基维辛迪和eFPF值高的 ∼ 65.97 %和 ∼ 27.86 %,并由于其高药物加载(95 %),火焰和eFPD极高在 ∼ 6.27 mg和 ∼  2.65毫克,分别相当于 ∼  6.27毫克和 ∼ 2.65 毫克PFD沉积在肺部和肺泡,分别在10 毫克干粉吸入。这项工作为调整PFD微晶体的沉淀行为提供了一种具有高肺给药效率的潜在策略。

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引用次数: 0

Artificial intelligence-driven hydrogel microneedle patches integrating 5-fluorouracil inclusion complex-loaded flexible pegylated liposomes for enhanced non-melanoma skin cancer treatment 人工智能驱动的水凝胶微针贴片整合了装载5-氟尿嘧啶包涵复合物的柔性聚乙二醇脂质体，用于加强非黑素瘤皮肤癌的治疗。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-01-25 DOI: 10.1016/j.ijpharm.2024.125072

Phuvamin Suriyaamporn , Chaiyakarn Pornpitchanarong , Thapakorn Charoenying , Koranat Dechsri , Tanasait Ngawhirunpat , Praneet Opanasopit , Boonnada Pamornpathomkul

The current study focused on the development of crosslinked hydrogel microneedle patches (cHMNs) incorporating 5-FU-hydroxypropyl beta-cyclodextrin inclusion complex-loaded flexible PEGylated liposomes (5-FU-HPβCD-loaded FP-LPs) to enhance treatment efficacy and reduce drug toxicity. The research utilized artificial intelligence (AI) algorithms to design, optimize, and evaluate the cHMNs. Various AI models were assessed for accuracy, with metrics such as root mean square error and coefficient of determination guiding the selection of the most effective formulation. The physicochemical and mechanical properties, swelling behavior, in vitro skin permeation, and safety of the chosen cHMNs were tested. The results demonstrated that the 5-FU-HPβCD-loaded FP-LPs, stabilized with limonene, had an optimal particle size of 36.23 ± 2.42 nm, narrow size distribution, and zeta potential of –10.24 ± 0.37 mV, with high encapsulation efficiency. The cHMNs exhibited a conical needle shape with sufficient mechanical strength to penetrate the stratum corneum up to approximately 467.87 ± 65.12 μm. The system provided a high skin permeation rate of 41.78 ± 4.26 % and significant drug accumulation in the skin. Additionally, the formulation was proven safe in cell culture while effectively inhibiting cancer growth and promoting apoptosis. This study highlights the potential of AI-enhanced cHMNs for delivering 5-FU-HPβCD-loaded FP-LPs transdermally, offering a promising new treatment avenue for non-melanoma skin cancers.

目前的研究重点是开发交联水凝胶微针贴片（cHMNs），其中含有5-FU-羟丙基β-环糊精包合物-负载柔性PEG脂质体（5-FU-HPβCD-负载FP-LPs），以提高疗效并降低药物毒性。该研究利用人工智能（AI）算法来设计、优化和评估 cHMNs。对各种人工智能模型的准确性进行了评估，通过均方根误差和决定系数等指标来指导选择最有效的配方。对所选 cHMNs 的物理化学和机械性能、溶胀行为、体外皮肤渗透性和安全性进行了测试。结果表明，用柠檬烯稳定的负载 5-FU-HPβCD 的 FP-LPs 的粒度为 36.23 ± 2.42 nm，粒度分布窄，zeta 电位为 -10.24 ± 0.37 mV，封装效率高。cHMNs 呈锥形针状，具有足够的机械强度，可穿透角质层达约 467.87 ± 65.12 μm。该系统的皮肤渗透率高达 41.78 ± 4.26 %，药物在皮肤中的蓄积也很显著。此外，该制剂在细胞培养中被证明是安全的，同时还能有效抑制癌症生长并促进细胞凋亡。这项研究凸显了人工合成增强型 cHMNs 经皮递送 5-FU-HPβCD 载药 FP-LPs 的潜力，为非黑色素瘤皮肤癌的治疗提供了一条前景广阔的新途径。

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引用次数: 0

Mathematical models of dissolution testing: Challenges and opportunities toward real-time release testing 溶出测试的数学模型：实时释放测试的挑战和机遇。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-01-25 DOI: 10.1016/j.ijpharm.2024.125002

Kensaku Matsunami , Alexander Ryckaert , Valérie Vanhoorne , Ashish Kumar

Real-time release testing (RTRt) of tablet dissolution can significantly improve manufacturing efficiency along with the adoption of continuous manufacturing in the pharmaceutical industry. To assure product quality without destructive testing, models for RTRt should be sufficiently reliable and robust. Whereas mechanistic models have merits of broader applicability and interpretability, data-driven models have been common approaches due to computational speed. This paper discusses challenges and opportunities in the application of mechanistic models for dissolution testing to enable RTRt of solid dosage. After a comprehensive literature review on mechanistic dissolution models and RTRt, the potential benefits and challenges of mechanistic models are presented. Compared to data-driven models, mechanistic models require less experimental data that can reduce time and cost for RTRt development. However, to enable the implementation of mechanistic models in RTRt, computational time should be short either by using a simple mechanistic model or by applying surrogate models.

随着制药行业连续生产的采用，片剂溶出度实时释放试验（RTRt）可以显著提高生产效率。为了保证产品质量而不进行破坏性检测，RTRt模型必须足够可靠和健壮。机械模型具有更广泛的适用性和可解释性，而数据驱动模型由于计算速度快而成为常用的方法。本文讨论了应用溶出度测试机制模型实现固体剂量RTRt的挑战和机遇。通过对机械溶解模型和RTRt的文献综述，提出了机械溶解模型的潜在优势和挑战。与数据驱动模型相比，机制模型需要较少的实验数据，这可以减少RTRt开发的时间和成本。然而，为了在RTRt中实现机制模型，通过使用简单的机制模型或应用代理模型，应该缩短计算时间。

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引用次数: 0

Gelatin nanofibers coated with hyaluronic acid as a mesenchymal stromal cell scaffold for corneal regeneration 透明质酸包被明胶纳米纤维作为角膜间充质间质细胞再生支架。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-01-25 DOI: 10.1016/j.ijpharm.2024.125009

Gisele Rodrigues da Silva , Euisun Song , Karen M. Chen , Fang Chen , Li Jiang , Hyeonji Kim , Nae-Won Kang , Won-Gun Koh , David Myung

Electrospun gelatin nanofibers coated with hyaluronic acid (GelNF-HA) were synthesized as a scaffold for delivering human corneal mesenchymal stromal cells (C-MSCs) directly to deep corneal injuries. Aligned GelNFs were produced by electrospinning, crosslinked using vapor of glutaraldehyde, coated with HA, and crosslinked with EDC/NHS. The GelNF-HA was characterized by SEM, mechanical, and optical properties. It was then investigated as a substrate for C-MSC proliferation and migration in vitro and in a rabbit cornea culture model. The expression of α-smooth muscle actin (α-SMA) was determined in the ex vivo model. SEM showed that the GelNF-HA scaffold was composed of aligned GelNFs with 75 % of the fibers oriented against the same angle. It exhibited a Young’s modulus of 1.66 ± 0.59 MPa and approximately 93 % transmittance of visible light. The GelNF-HA membranes supported C-MSC proliferation in vitro. In a scratch migration assay, it facilitated complete wound closure after 48 h in culture. C-MSC-laden GelNF-HA scaffolds supported corneal wound healing in an ex vivo model as well, expressing a lower percentage of stromal α-SMA compared to both the no-treatment keratectomy-only and C-MSC groups (p < 0.05). The C-MSC-supportive GelNF-HA scaffolds hold therapeutic potential for stromal regeneration in the treatment of deep corneal defects.

制备透明质酸包被明胶纳米纤维（GelNF-HA）作为支架，将人角膜间充质间质细胞（C-MSCs）直接递送至角膜深部损伤。采用静电纺丝法制备排列凝胶，用戊二醛蒸汽交联，涂以透明质酸，并用EDC/NHS交联。GelNF-HA通过SEM、力学和光学性质进行了表征。然后在体外和兔角膜培养模型中研究其作为C-MSC增殖和迁移的底物。在离体模型中测定α-平滑肌肌动蛋白（α-SMA）的表达。扫描电镜显示GelNF-HA支架由排列整齐的gelnf组成，75% %的纤维朝向相同的角度。其杨氏模量为1.66 ± 0.59 MPa，可见光透过率约为93 %。GelNF-HA膜支持C-MSC体外增殖。在划痕迁移实验中，它在培养48 h后促进了伤口的完全闭合。在离体模型中，满载C-MSC的GelNF-HA支架也支持角膜创面愈合，与未治疗的角膜切除术组和C-MSC组相比，基质α-SMA的表达比例更低

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引用次数: 0

Nanostructured lipid carriers as a strategy to enhance oral levosulpiride delivery: An in vitro and ex vivo assessment 纳米结构脂质载体作为增强口服左磺必利递送的策略：体外和离体评估。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-01-25 DOI: 10.1016/j.ijpharm.2024.125047

Sadia Tabassam Arif , Muhammad Ayub Khan , Patrick Frøslev , Shahiq uz Zaman , Danai Anastasia Panou , Hanne Mørck Nielsen , Joanne Heade

Oral absorption is limited for many small-molecule drugs due to their poor aqueous solubility as well as, for some, poor membrane permeation. One such is levosulpiride (LSP), used to treat psychotic and other conditions. The present study aims to explore the effect of nanostructured lipid carriers (NLCs) for the delivery of LSP. The permeation of LSP in vitro and ex vivo as well as effects on the epithelium and mucosa was monitored. In vitro and ex vivo permeation studies exhibited an 8-fold and 1.6-fold increase in the P_app of LSP respectively, as compared to unformulated LSP applied as a suspension. Transepithelial electrical resistance (TEER) measured in real-time by impedance spectroscopy decreased during exposure yet recovered upon removal of the NLCs. Together with the increased passage of the paracellular markers [¹⁴C]-mannitol and FD4 applied together with blank NLCs, but not the transcellular marker [³H]-metoprolol, this indicates permeation of LSP via the paracellular pathway. The reversible effect on integrity was associated with altered cell morphology confirmed by occludin and f-actin localization with insignificant effect on metabolic activity. These results suggest that the NLCs and/or components thereof can mediate improved absorption of drugs by increasing the permeability of the intestinal epithelial membrane, further facilitated by increased drug solubilization.

许多小分子药物的水溶性很差，有些药物的膜渗透性也很差，因此口服吸收受到限制。用于治疗精神病和其他疾病的左旋舒必利（LSP）就是其中之一。本研究旨在探索纳米结构脂质载体（NLCs）在递送左旋舒必利方面的效果。研究人员监测了 LSP 在体外和体内的渗透情况以及对上皮和粘膜的影响。体外和体内渗透研究表明，与以悬浮液形式应用的未配制 LSP 相比，LSP 的 Papp 分别增加了 8 倍和 1.6 倍。通过阻抗光谱实时测量的跨皮层电阻（TEER）在暴露过程中有所下降，但在去除 NLC 后又恢复了。与空白 NLCs 一起使用的细胞旁标记物[14C]-甘露醇和 FD4 的通过率增加，但跨细胞标记物[3H]-美托洛尔的通过率却没有增加，这表明 LSP 是通过细胞旁途径渗透的。对完整性的可逆影响与细胞形态的改变有关，通过闭塞素和 f-肌动蛋白定位证实了这一点，但对代谢活性的影响不大。这些结果表明，NLC 和/或其成分可通过增加肠上皮细胞膜的通透性来促进药物的吸收，而药物溶解度的增加又进一步促进了药物的吸收。

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引用次数: 0

4D printing of biodegradable intestinal drug delivery devices with shape-memory effect 具有形状记忆效应的可生物降解肠道给药装置的4D打印。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-01-25 DOI: 10.1016/j.ijpharm.2024.125051

Yulia Yuts , Reece McCabe , Maya Krell , Marilena Bohley , Jean-Christophe Leroux

Expanding devices designed to physically facilitate the permeation of drugs across the gastrointestinal mucosa are gaining attention for the oral delivery of therapeutic macromolecules. The ideal system should be biodegradable with latex-like properties, allowing it to withstand gut movement without breaking prematurely and preventing intestinal obstruction or damage. A highly foldable and elastic device is desirable because it can fit into commercial capsules by being compressed into confined spaces. However, this compression has limits due to the device’s tendency to spring back to its original shape driven by stored elastic energy after deformation. This challenge can be addressed by using shape-memory polymers. In this work, we report a photo-crosslinkable resin suitable for 3D printing by digital light processing that yields an elastomer with latex-like properties, shape-recovery at body temperature, and degradation within 6 h under simulated intestinal conditions. Thermal shape-memory was conferred by adding stearyl(acrylate) to poly(β-aminoester)-based inks, achieving high elasticity (>700 %) and strength (>7.5 MPa), along with strain-hardening properties.

为促进药物在胃肠道粘膜的渗透而设计的扩展装置在治疗性大分子的口服递送中越来越受到关注。理想的系统应该是可生物降解的，具有类似乳胶的特性，使其能够承受肠道运动而不会过早破裂，防止肠道阻塞或损伤。一种高度可折叠和弹性的装置是可取的，因为它可以通过压缩到有限的空间而装入商业胶囊。然而，这种压缩有局限性，因为设备在变形后会在储存的弹性能量的驱动下弹回其原始形状。这一挑战可以通过使用形状记忆聚合物来解决。在这项工作中，我们报告了一种适合通过数字光处理3D打印的光交联树脂，该树脂产生具有乳胶样性能的弹性体，在体温下恢复形状，并在模拟肠道条件下在6 h内降解。通过将硬脂酰（丙烯酸酯）添加到聚（β-氨基酯）基油墨中，获得了高弹性（>700 %）和强度（>7.5 MPa），以及应变硬化性能。

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