通过原子层涂层提高生物利用率:非诺贝特案例研究

IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Journal of pharmaceutical sciences Pub Date : 2024-11-01 DOI:10.1016/j.xphs.2024.10.052
Balaji Ganapathy, Vijayendra Redasani, Sujit Debnath, Neha Gupta, Ankur Kadam, Fei Wang, Pravin Narwankar
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引用次数: 0

摘要

生物制药分类系统(BCS)II 类药物在体内的溶解性差,渗透性高。非诺贝特(Fenofibrate,FF)是 BCS II 类药物的典型代表,用于治疗血液中胆固醇和甘油三酯(类脂肪物质)水平过高。原子层包衣(ALC)是从半导体工业发展而来的一种表面工程技术,即在活性药物成分(API)颗粒上一次包覆一层金属氧化物。事实证明,ALC 涂层能改善加工性能、改变亲水性、提高稳定性并微调药物的释放。在此,我们报告了 ALC 包衣对提高水溶性差的药物(非诺贝特)在动物模型中的生物利用度的干预。我们比较了未包衣非诺贝特与氧化锌包衣和氧化硅包衣非诺贝特的物理性质。经 1H NMR 和粉末 X 射线衍射分析证实,涂覆涂层后,活性药物成分(API)的结构完整性(化学稳定性和固态稳定性)仍未受到影响。值得注意的是,氧化锌包衣的非诺贝特具有良好的流动特性,而氧化硅包衣的非诺贝特则没有明显的流动性增强。接触角测量结果表明,氧化硅包覆的非诺贝特具有优异的润湿性,接触角接近 0°。与未涂层的活性药物成分(API)相比,ALC 的应用提高了溶解速率,同时其平衡溶解度不受影响。在原料药上涂覆氧化硅可提高颗粒的亲水性和润湿性,而涂覆氧化锌则有助于颗粒的去团聚,从而增强它们与水介质的相互作用。在啮齿动物和大型动物(狗)模型上进行的体内生物利用度研究表明,根据曲线下面积(AUC)测定,与未包衣的原料药相比,包衣氧化硅的原料药的生物利用度大幅提高(约 2 倍)。此外,氧化硅包衣原料药的 Cmax 值也比未包衣原料药显著增加(约 3 倍)。值得注意的是,对 ALC 硅涂层非诺贝特进行的口服亚急性毒性研究表明,涂层不会产生任何毒性反应。这项研究强调了 ALC 在提高 BCS(II)药物生物利用度方面的潜力。
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Bioavailability improvement by atomic layer coating: Fenofibrate a case study.

Biopharmaceutical Classification Systems (BCS) class II drugs show poor solubility and high permeability in the body. Fenofibrate (FF) is a classic example of a BCS class II drug, used to treat high cholesterol and triglyceride (fat-like substances) levels in the blood. Atomic layer coating (ALC) is a surface engineering technology adapted from the semiconductor industry, where metal oxides are coated one atomic layer at a time over the active pharmaceutical ingredients (API) particles. ALC coating was proven to improve the processability, alter the hydrophilicity, improve the stability, and fine-tune the release of drugs. Herein, we report the intervention of ALC coating in enhancing the bioavailability of a poorly water-soluble drug (fenofibrate) in the animal model. The physical properties of uncoated fenofibrate were compared with those of zinc oxide-coated and silicon oxide-coated fenofibrate. Following the application of the coatings, the structural integrity (both chemical stability and solid-state stability) of the active pharmaceutical ingredient (API) remained uncompromised, as corroborated by 1H NMR and powder X-ray diffraction analyses. Notably, zinc oxide-coated fenofibrate exhibited favorable flow characteristics, whereas no discernible enhancement in flow behavior was observed for silicon oxide-coated fenofibrate. The results from contact angle measurements suggest that the silicon oxide-coated fenofibrate exhibits superior wetting behavior, as indicated by a contact angle nearing 0°. The application of ALC demonstrates an enhanced dissolution rate when compared to the uncoated active pharmaceutical ingredient (API) while leaving its equilibrium solubility unaffected. Coating the API with silicon oxide improves particle hydrophilicity and wetting properties, whereas zinc oxide coating aids in particle de-agglomeration, thereby enhancing their interaction with an aqueous medium. In vivo bioavailability studies conducted on rodents and larger animal (dog) models indicate a substantial increase in bioavailability (approximately 2 times) for the silicon oxide-coated API in comparison to the uncoated API, as determined by the area under the curve (AUC). Furthermore, the Cmax values for the silicon oxide-coated API also demonstrate a significant increase (approximately 3 times) over the uncoated API. Notably, an oral subacute toxicity study of ALC silicon-coated fenofibrate revealed no toxic effects attributable to the coating. This study underscores the potential of ALC in augmenting the bioavailability of BCS(II) drugs.

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来源期刊
CiteScore
7.30
自引率
13.20%
发文量
367
审稿时长
33 days
期刊介绍: The Journal of Pharmaceutical Sciences will publish original research papers, original research notes, invited topical reviews (including Minireviews), and editorial commentary and news. The area of focus shall be concepts in basic pharmaceutical science and such topics as chemical processing of pharmaceuticals, including crystallization, lyophilization, chemical stability of drugs, pharmacokinetics, biopharmaceutics, pharmacodynamics, pro-drug developments, metabolic disposition of bioactive agents, dosage form design, protein-peptide chemistry and biotechnology specifically as these relate to pharmaceutical technology, and targeted drug delivery.
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