Tadini Maraine Catarina, Fernandes Fernanda Santos, Ozelin Saulo Duarte, de Melo Matheus Reis Santos, Mansur Ana Luiza, de Toledo Thaís Bueno, de Albuquerque Nayara Cristina Perez, Tavares Denise Crispim, Marquele-Oliveira Franciane, de Oliveira Anderson Rodrigo Moraes
Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo 14040-901, Brazil; Eleve Science Pesquisa e Desenvolvimento Supera Innovation and Technology Park, Supera Parque Av. Dra. Nadir Aguiar, n. 1805, Ribeirão Preto, São Paulo 14056-680, Brazil.
University of Franca, Av. Dr. Armando Salles Oliveira, N. 201, Franca, São Paulo 14404-600, Brazil.
Eur J Pharm Sci. 2022 Jun 1;173:106173. doi: 10.1016/j.ejps.2022.106173. Epub 2022 Mar 22.
Amphotericin B (AmB) has been the gold standard to treat systemic fungal infections. The use of AmB is restricted to hospitals because it poses several risks, mainly risks related to its high nephrotoxicity. Given the importance of this drug in medicine, new therapeutics and AmB formulations with nanotechnological improvements are required and could bring many benefits to patients. A new drug formulation with gastro-resistant coated granules has been proposed. The lipid-based system containing AmB was produced and used as raw material in the granulation/coated process. The new developed formulation (AmB-NP-GR) was characterized by optical microscopy, granulometry, and atomic force microscopy (AFM) after disintegration test. AmB-NP-GR showed granular shape, with most granules measured between 250 and 500 µm (37 ± 7% w/w). The AFM images indicated that the granule formulation should disintegrate in the intestine, to release the lipid-based carriers, making them available for absorption and allowing them to reach the blood circulation. The developed formulation was administered to rats in a single dose of 4.0 or 8.0 mg kg and the pharmacokinetics was studied. The samples were analyzed by liquid chromatography coupled to mass spectrometry. Before the pharmacokinetic studies were conducted, the bioanalytical method was validated according to the EMA guideline and all evaluated parameters agreed with this guideline. The pharmacokinetic results showed that C was similar for both doses and that t was reached at 4-12 h for dose of 4.0 mg kg and 4 h for dose of 8.0 mg kg. The half-life related to the dose of 8.0 mg kg increased significantly compared to the dose of 4.0 mg kg (an increase of more than 3 times). In addition, the mean residence time related to the dose of 8.0 mg kg was 4 times higher than for the lower dose. The clearance value showed to be higher for the lower dose. Together, these results provide important conclusions for experimental design of other in vivo safety and efficacy studies of AmB-NP-GR.
两性霉素B（AmB）一直是治疗系统性真菌感染的金标准。由于存在多种风险，主要是与其高肾毒性相关的风险，AmB的使用仅限于医院。鉴于这种药物在医学上的重要性，需要新的治疗方法以及具有纳米技术改进的AmB制剂，这可能会给患者带来诸多益处。一种具有胃抗性包衣颗粒的新药物制剂已被提出。制备了含AmB的脂质基体系，并将其用作制粒/包衣过程的原料。新开发的制剂（AmB-NP-GR）在崩解试验后通过光学显微镜、粒度分析和原子力显微镜（AFM）进行表征。AmB-NP-GR呈颗粒状，大多数颗粒尺寸在250至500 µm之间（37±7% w/w）。AFM图像表明颗粒制剂应在肠道中崩解，以释放脂质基载体，使其可用于吸收并进入血液循环。将开发的制剂以4.0或8.0 mg/kg的单剂量给予大鼠，并研究其药代动力学。通过液相色谱-质谱联用对样品进行分析。在进行药代动力学研究之前，根据欧洲药品管理局（EMA）指南对生物分析方法进行了验证，所有评估参数均符合该指南。药代动力学结果表明，两种剂量的C相似，4.0 mg/kg剂量在4至12小时达到t，8.0 mg/kg剂量在4小时达到t。与4.0 mg/kg剂量相比，8.0 mg/kg剂量的半衰期显著增加（增加超过3倍）。此外，8.0 mg/kg剂量的平均驻留时间比低剂量高4倍。较低剂量的清除率值更高。总之，这些结果为AmB-NP-GR的其他体内安全性和有效性研究的实验设计提供了重要结论。
