Improving oral absorption of a rapidly crystallizing parent drug using prodrug strategy: Comparison of phosphate versus glycine based prodrugs.

IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Journal of pharmaceutical sciences Pub Date : 2024-10-03 DOI:10.1016/j.xphs.2024.09.012
Anura S Indulkar, Russell Slade, Navendu Jana, Robin R Frey, Thomas D Penning, Albert Lai, Alix F Leblanc
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Abstract

With an increasing number of Biopharmaceutical Classification System (BCS) II/IV pipeline compounds, solubilizing and supersaturating formulation strategies are becoming prevalent. Beyond formulation and solid form strategies, prodrugs are also employed to overcome solubility-limited absorption of poorly water-soluble compounds. Prodrugs can potentially yield supersaturated systems upon conversion to the parent drug intraluminally and thus enhance absorption. However, supersaturation also increases the driving force for crystallization, resulting in low solution concentrations, which can potentially negate the advantage of prodrugs. In this work, two unique solubility-enhancing prodrugs, phosphate and glycine esters, were investigated for a rapidly crystallizing parent drug. Ex vivo absorption studies using rat tissue and in vivo studies in dogs were performed. Conversion rate of the phosphate prodrug to the parent was dependent on the milieu and increased ∼24-fold in the presence of intestinal contents as medium and tissue relative to neat buffer. In contrast, conversion of the glycine prodrug was minimal under any conditions tested, suggesting that the conversion occurs after absorption into the enterocytes. Phosphate prodrug showed a non-linear increase in parent drug absorptive flux across rat intestinal tissue with concentration when intestinal contents were used as donor media. This was attributed to rapid conversion and high supersaturation of the parent drug which subsequently resulted in crystallization at high doses in the donor chamber. Glycine prodrug did not undergo complete conversion at high doses and was absorbed unchanged on the basolateral side, indicating saturation of the converting enzymes in the enterocytes. The combined flux (parent drug and glycine) showed a linear increase with dose and crystallization was not observed. Under physiological conditions, glycine prodrug that is absorbed unchanged from the intestine can potentially undergo complete conversion in hepatocytes after absorption and make the parent drug systemically available. Thus, glycine prodrug provided overall higher absorption compared to phosphate prodrug. The observed flux levels for both the prodrugs were higher compared to the parent drug alone, highlighting an advantage to use of a prodrug strategy to improve absorption of such compounds. Oral dosing in a dog PK study revealed that the bioavailability using the phosphate prodrug was ∼50% whereas, it was ∼100% with glycine prodrug, supporting the in vitro observations.

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利用原药策略改善快速结晶母药的口服吸收:磷酸盐原药与甘氨酸原药的比较。
随着生物制药分类系统(BCS)II/IV 级管线化合物数量的不断增加,增溶和过饱和制剂策略正变得越来越普遍。除了制剂和固体制剂策略外,原药也被用来克服水溶性差的化合物在吸收时受到的溶解度限制。原药在腔内转化为母药后有可能产生过饱和体系,从而促进吸收。然而,过饱和也会增加结晶的驱动力,导致溶液浓度过低,从而可能抵消原药的优势。本研究针对快速结晶的母药研究了磷酸酯和甘氨酸酯这两种独特的溶解度增强原药。利用大鼠组织进行了体内外吸收研究,并在狗身上进行了体内研究。磷酸酯原药向母药的转化率取决于环境,在有肠道内容物作为介质和组织的情况下,转化率比纯缓冲液高出 24 倍。相反,在任何测试条件下,甘氨酸原药的转化率都很小,这表明转化是在吸收进入肠细胞后发生的。当使用肠内容物作为供体介质时,磷酸盐原药在大鼠肠组织中的母药吸收通量随浓度的增加而呈非线性增加。这归因于母药的快速转化和高过饱和,从而导致供体室中的高剂量结晶。甘氨酸原药在高剂量时没有完全转化,在基底侧吸收时没有变化,这表明肠细胞中的转化酶达到饱和。综合通量(母药和甘氨酸)随剂量呈线性增加,未观察到结晶。在生理条件下,从肠道吸收的甘氨酸原药在吸收后可能会在肝细胞中发生完全转化,并使母药成为全身可用的药物。因此,与磷酸原药相比,甘氨酸原药的吸收率更高。与单独使用母药相比,两种原药的通量水平都更高,这凸显了使用原药策略改善此类化合物吸收的优势。在狗的口服 PK 研究中发现,使用磷酸原药的生物利用度为 50%,而使用甘氨酸原药的生物利用度为 100%,这支持了体外观察结果。
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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.
期刊最新文献
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