Dissolution, phase behavior and mass transport of amorphous solid dispersions in aspirated human intestinal fluids.

IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Journal of pharmaceutical sciences Pub Date : 2024-10-16 DOI:10.1016/j.xphs.2024.10.005
Ahmed Elkhabaz, Dana E Moseson, Joachim Brouwers, Patrick Augustijns, Lynne S Taylor
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Abstract

Amorphous solid dispersions (ASDs) typically show improved dissolution and generate supersaturated solutions, enhancing the oral bioavailability of poorly soluble drugs. To gain insights into intraluminal ASD behavior, we utilized two poorly soluble drugs with different crystallization tendencies, atazanavir and posaconazole, prepared as ASDs at a 10% drug loading with hydroxypropyl methylcellulose acetyl succinate (HPMCAS). We evaluated their release in aspirated fasted-state human intestinal fluid (FaHIF), and multi-component fasted-state simulated intestinal fluid (composite-FaSSIF), characterizing the supersaturation profiles and drug-rich nanodroplets that formed. Complete release was observed for atazanavir ASDs over a 90 min period. Flux for dissolved atazanavir ASDs remained high over the experimental time period of 3 h. In contrast, posaconazole solution concentrations were initially high and then decreased. Likewise, flux was initially high and then decreased where these changes are attributed to crystallization of the drug. Generation of spherical nano-sized amorphous droplets of ∼100-150 nm was found to occur in ex vivo FaHIF media for both ASDs, maximizing the diffusive flux during the supersaturation window. Moreover, buffer capacity differences were postulated to influence release rates of ASDs in simulated vs aspirated fluids. Importantly, the solution phase phenomena observed during ASD release in simulated fluids, namely amorphous nanodroplet formation and drug crystallization, were also found to occur in aspirated luminal fluids.

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无定形固体分散体在吸入人体肠液中的溶解、相态行为和质量传输。
无定形固体分散体(ASD)通常能改善溶解度并生成过饱和溶液,从而提高溶解度低的药物的口服生物利用度。为了深入了解无定形固体分散体在肠道内的表现,我们采用了两种具有不同结晶倾向的低溶性药物--阿扎那韦和泊沙康唑,用羟丙基甲基纤维素乙酰琥珀酸酯(HPMCAS)制备成药物载量为 10%的无定形固体分散体。我们评估了这两种药物在吸入的空腹状态人体肠液(FaHIF)和多组分空腹状态模拟肠液(复合-FaSSIF)中的释放情况,分析了过饱和度曲线和形成的富含药物的纳米液滴。观察到阿扎那韦 ASD 在 90 分钟内完全释放。相比之下,泊沙康唑溶液的浓度最初较高,随后有所下降。同样,通量也是先高后低,这些变化归因于药物的结晶。研究发现,两种 ASD 在体内外 FaHIF 培养基中都会产生 100-150 纳米大小的球形无定形液滴,从而在过饱和窗口期使扩散通量最大化。此外,还推测缓冲能力的差异会影响 ASD 在模拟液与吸入液中的释放率。重要的是,在模拟液体中观察到的 ASD 释放过程中的溶液相现象,即无定形纳米液滴的形成和药物结晶,在吸入的管腔液体中也会发生。
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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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