溶解介质 pH 值和药物电离状态对无定形固体分散体释放性能的影响

IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL
Anura S Indulkar, Samantha Alex, Geoff G Z Zhang
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引用次数: 0

摘要

无定形固体分散体(ASD)被广泛用作改善水溶性差的化合物口服生物利用度的一种策略。通常情况下,基于聚乙烯吡咯烷酮-醋酸乙烯酯(PVPVA)的无定形固体分散体在相对较低的药物负载极限下可达到最佳溶解性能。超过一定的药物载量(称为 "一致性极限"(LoC)),ASD 的释放量就会明显降低。迄今为止,大多数溶解行为都是在药物主要以联合形式存在的条件下进行测试的。在这项工作中,研究了溶解环境的 pH 值对可离子化药物的 ASD 释放性能的影响。以 pKa 为 4.5 的弱碱性药物阿扎那韦(ATZ)为模型化合物,以 PVPVA 为非离子化基质聚合物。采用伍德仪器测量溶解速率,该仪器将溶解片剂的表面积归一化。溶解介质的 pH 值在 1 到 6.8 之间变化,在这一范围内,ATZ 以大于 99% 的离子化或联合化形式存在。在 pH 值为 6.8 时,只有当药物载量≤ 6% 时才能观察到接近完全的释放。与通常观察到的 PVPVA 基 ASD 在 LoC 以上的释放行为急剧下降不同,当 DL 增加到 8%时,ATZ ASD 的溶解行为逐渐下降。这是因为可能形成了 ATZ-PVPVA 关联相,其溶解速度比纯 PVPVA 慢。然而,10% DL ASD 的 ATZ 释放量可忽略不计。在另一个极端条件下(pH 值为 1),ATZ 的离子化程度为 100%,ATZ 的溶解速度比 PVPVA 快。研究发现,ASD 的溶解速度比纯药物慢,但比 PVPVA 快,有趣的是,ASD 的溶解速度并不随 DL 的变化而变化。这可能是由于形成了离子化的 ATZ-PVPVA 相,从而控制了 ASD 的溶解速率。在 pH 值为 3 时,药物离子化率为 97%,当药物负载量≤ 8%时,药物几乎完全释放。要观察到药物负载量明显增加并接近完全释放,ATZ 的电离率必须大于 98%。在 pH 值为 2 时,ATZ 的电离度为 99.7%,当药物含量达到 30%时,可观察到接近完全的释放。此外,在 pH 值为 2 时,溶解性能随着药物载量的增加而逐渐下降。我们推测,电离导致的溶解性能提高是电离 ATZ-PVPVA 相形成的结果,电离 ATZ-PVPVA 相增加了 ASD 的亲水性和混溶性。这有助于在 ASD 溶解过程中抵制水引起的相分离,从而实现药物和聚合物的连续一致溶解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Impact of dissolution medium pH and ionization state of the drug on the release performance of amorphous solid dispersions.

Amorphous solid dispersions (ASDs) are widely employed as a strategy to improve oral bioavailability of poorly water soluble compounds. Typically, optimal dissolution performance from a polyvinylpyrrolidone vinyl acetate (PVPVA) based ASD is observed at relatively low drug loading limit. Above a certain drug load, termed limit of congruency (LoC), the release from ASDs significantly decreases. So far, the majority of the dissolution behavior has been tested in conditions where the drug primarily exists in unionized form. In this work, the impact of pH of the dissolution environment on the release performance of ASDs of an ionizable drug was studied. Atazanavir (ATZ), a weakly basic drug with a pKa of 4.5 was used as a model compound and PVPVA was used as a non-ionizable matrix polymer. Dissolution rate was measured using Wood's apparatus which normalizes the surface area of the dissolving tablet. The pH of the dissolution media was varied between 1 and 6.8, cover a range where ATZ exists as >99% ionized or unionized species. At pH 6.8, near complete release was observed only when the drug load was ≤ 6%. Unlike typically observed drastic decline in release behavior for PVPVA based ASDs above LoC, ATZ ASDs underwent gradual decline in dissolution behavior when the DL was increased to 8%. This was attributed to potential formation of an ATZ-PVPVA associated phase with dissolution rate slower than neat PVPVA. However, the 10% DL ASD showed negligible ATZ release. On another extreme (pH 1) where ATZ is ∼100% ionized, the dissolution rate of ATZ was faster than that of PVPVA. ASD dissolution rate was found to be slower than that of the neat drug but faster than PVPVA and interestingly, did not change with DL. This can be attributed to formation of an ionized ATZ-PVPVA phase which controls the dissolution rate of the ASD. At pH 3, where the drug is ∼97% ionized, near complete release was observed for drug loads ≤ 8%. To observe significant increase in drug loading with near complete release, >98% ionization of ATZ was required. At pH 2 where ATZ is ∼99.7% ionized, near complete release was observed for drug loads up to 30%. Furthermore, the deterioration in dissolution performance with an increase in drug load continued to be gradual at pH 2. The enhancement in dissolution performance did not correlate with solubility enhancement of ATZ due to ionization. We theorize that the enhancement in the dissolution performance due to ionization is the result of formation of an ionized ATZ-PVPVA phase which increases the hydrophilicity and the miscibility of the ASD. This can help resist water induced phase separation during ASD dissolution and therefore, result in continuous, and congruent dissolution of the drug and polymer.

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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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