LBPO.ET01 · 实验与分子治疗 · Late-Breaking
口服氟维司群纳米粒实现高而持续的暴露：肌肉注射的一种替代方案
Oral fulvestrant nanoparticles deliver high, sustained exposure: An alternative to IM injection
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：氟维司群是一种用于ER⁺乳腺癌的选择性雌激素受体降解剂（SERD），目前仅有采用黏稠制剂的每月一次肌肉注射（IM）剂型，注射可能引起疼痛，且无口服产品可用。口服氟维司群可改善便利性和依从性；然而，极强的疏水性和广泛的首过代谢限制了以往的口服方法。我们开发了一种基于由药学上可接受的天然脂质构成的纳米粒的口服氟维司群制剂。
方法：使用溶剂辅助混合和超声处理将氟维司群载入纳米级天然脂质颗粒，随后干燥以获得适合口服胶囊或片剂制剂的自由流动粉末。雌性Sprague-Dawley大鼠以天然脂质纳米粒制剂口服接受10 mg/kg氟维司群。连续采集血样直至216 h。通过经验证的LC-MS/MS对血浆和全血中的氟维司群浓度进行定量，并进行非房室药代动力学分析。
结果：口服天然脂质制剂在水性介质中产生了稳定的纳米级颗粒（100-200 nm），粒径分布狭窄，表面电荷良好（−34.1 mV）。口服给予10 mg/kg氟维司群后，血浆浓度在72 h达到约505 ng/mL的峰值，AUC₀₋₇₂ h≈1.4×10⁴ ng·h/mL。暴露持久，氟维司群在216 h仍可定量（血浆C₂₁₆ h为110 ng/mL；全血为140 ng/mL）。观察到510 ng/mL（72 h，血浆）和470 ng/mL（120 h，全血）的峰浓度。天然脂质含量增加的第二种组分也实现了高全身暴露（血浆AUC₀₋₇₂ h为9.28×10³ ng·h/mL），支持了对制剂优化的稳健性。
结论：一种天然脂质纳米粒制剂在大鼠单次口服给药后实现了氟维司群高而持续的全身暴露。由于氟维司群水溶性差导致静脉给药不可行，未测定绝对生物利用度；又因为没有口服参比制剂能产生可定量的全身暴露，故无法评估相对生物利用度；因此，药代动力学评估聚焦于口服给药后的全身暴露。该制剂使用药学上可接受的天然脂质和标准单元操作（混合、干燥、研磨），产生适合固体口服剂型的自由流动粉末。这些发现支持对氟维司群及其他高度不溶性化合物的口服递送进行进一步评估和优化。已就该制剂和生产工艺提交了一份美国临时专利申请。资助：由NIH/NIMHD资助项目2U54MD007595支持。
查看英文原文 English abstract
Background: Fulvestrant, a selective estrogen receptor degrader (SERD) for ER⁺ breast cancer, is available only as a monthly intramuscular (IM) injection in a viscous formulation that can be painful, and no oral product is available. Oral fulvestrant could improve convenience and adherence; however, extreme hydrophobicity and extensive first-pass metabolism have limited prior oral approaches. We developed an oral fulvestrant formulation based on nanoparticles composed of pharmaceutically acceptable natural lipids.
Methods: Fulvestrant was incorporated into nanoscale natural-lipid particles using solvent-assisted mixing and sonication, followed by drying to yield a free-flowing powder suitable for oral capsule or tablet formulation. Female Sprague-Dawley rats received 10 mg/kg fulvestrant orally as the natural-lipid nanoparticle formulation. Serial blood samples were collected up to 216 h. Fulvestrant concentrations in plasma and whole blood were quantified by validated LC-MS/MS, and noncompartmental pharmacokinetic analysis was performed.
Results: The oral natural-lipid formulation produced stable nanoscale particles (100-200 nm) with a narrow size distribution and favorable surface charge (−34.1 mV) in aqueous media. After oral administration of 10 mg/kg fulvestrant, plasma concentrations peaked at ~505 ng/mL at 72 h, with AUC₀-₇₂ h ≈ 1.4 × 10⁴ ng·h/mL. Exposure was persistent, with fulvestrant remaining quantifiable at 216 h (C₂₁₆ h 110 ng/mL in plasma; 140 ng/mL in whole blood). Peak concentrations of 510 ng/mL (72 h, plasma) and 470 ng/mL (120 h, whole blood) were observed. A second composition with increased natural-lipid content also achieved high systemic exposure (plasma AUC₀-₇₂ h 9.28 × 10³ ng·h/mL), supporting robustness to formulation optimization.
Conclusions: A natural-lipid nanoparticle formulation achieved high and sustained systemic exposure of fulvestrant after a single oral dose in rats. Absolute bioavailability was not determined because intravenous fulvestrant dosing is not feasible due to poor aqueous solubility, and relative bioavailability could not be assessed because no oral reference formulation yields quantifiable systemic exposure; therefore, pharmacokinetic evaluation focused on systemic exposure following oral administration. The formulation uses pharmaceutically acceptable natural lipids and standard unit operations (mixing, drying, milling) and yields a free-flowing powder suitable for solid oral dosage forms. These findings support further evaluation and optimization of oral delivery for fulvestrant and other highly insoluble compounds. A U.S. provisional patent application covering the formulation and manufacturing process has been filed. Funding: Supported by NIH/NIMHD grant 2U54MD007595.
利益披露 Disclosure
R. A. Graves, None..
H. Ahamed, None..
C. Zhang, None..
G. Wang, None..
T. K. Mandal, None.