Scale-up and Clinical Bioavailability Assessment of a 45% Drug Loaded Amorphous Nanoparticle Formulation of a BCS IV Compound for Oral Delivery.

IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL
Mengqi Yu, Deliang Zhou, Hardeep S Oberoi, Ahmed Hamed Salem, Laura A McKee, Jason R Arnholt, Hitesh S Purohit, Devalina Law
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Abstract

A 45% drug loaded (DL) amorphous nanoparticle (ANP) formulation for a BCS IV drug demonstrated promising pharmacokinetics in dogs (Purohit, et al, J. Pharm. Sci. 2023(113)1007-1019). This preclinical data enabled a human proof-of-concept assessment opportunity. The ANP freeze dried powder for oral suspension was prepared using solvent/antisolvent precipitation followed by organic solvent removal and freeze drying (FD). Challenges manifested during scale-up from 50g to 280g. Given the preclinical data, formulation change was restricted, therefore, process modifications were implemented. Cold collection after precipitation prevented particle growth but resulted in 75 nm particles at clinical scale (CS), compared to 150 nm at laboratory scale (LS). This size decrease rendered stabilizer amounts suboptimal for FD operation. Consequently, when FD powder was resuspended in water a smaller fraction of particles was below 450 nm (by filtration), ∼65% for CS compared to ∼85% for LS. Formulation was stable for > 6 months, evaluated by monitoring moisture content, assay, powder X-ray diffraction (PXRD), and redispersion time. Despite ∼65% re-dispersibility, this 45% DL formulation in humans had higher Cmax and AUC ∼73% and ∼46% respectively in fasted-state, and under fed-state it met bioequivalence criteria for AUC but Cmax was 20% lower compared to reference (10% DL ASD tablets) demonstrating advantage of ANP strategy over ASD approach.

口服给药 BCS IV 化合物的 45% 药物负载无定形纳米粒子制剂的放大和临床生物利用度评估。
一种用于 BCS 静脉注射药物的 45% 药物负载 (DL) 无定形纳米粒子 (ANP) 配方在狗体内显示出良好的药代动力学(Purohit 等人,J. Pharm.Sci.2023(113)1007-1019)。这一临床前数据为人体概念验证评估提供了机会。用于口服混悬液的 ANP 冻干粉采用溶剂/等溶剂沉淀法制备,然后去除有机溶剂并进行冷冻干燥 (FD)。在从 50 克放大到 280 克的过程中遇到了挑战。考虑到临床前数据,改变配方受到限制,因此对工艺进行了修改。沉淀后的冷收集可防止颗粒生长,但在临床规模(CS)下,颗粒的尺寸为 75 nm,而在实验室规模(LS)下,颗粒的尺寸为 150 nm。粒度的减小使稳定剂的用量成为 FD 操作的次优选择。因此,当 FD 粉末重新悬浮于水中时,低于 450 nm 的颗粒比例较小(通过过滤),CS 为 65%,而 LS 为 85%。通过监测含水量、化验、粉末 X 射线衍射(PXRD)和再分散时间,对配方的稳定性进行了评估,结果表明配方的稳定性大于 6 个月。尽管这种 45% DL 的制剂的再分散性为 65%,但在人体空腹状态下,其 Cmax 和 AUC 分别为 73% 和 46%,而在进食状态下,其 AUC 符合生物等效性标准,但 Cmax 比参照物(10% DL ASD 片剂)低 20%,这表明 ANP 策略比 ASD 方法更具优势。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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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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