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药物的成玻璃能力与过饱和度倾向之间是否存在相关性?

Is there a correlation between the glass forming ability of a drug and its supersaturation propensity?

机构信息

Department of Pharmacy, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.

Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland.

出版信息

Int J Pharm. 2018 Mar 1;538(1-2):243-249. doi: 10.1016/j.ijpharm.2018.01.013. Epub 2018 Jan 16.

Abstract

The use of an enabling formulation technique, such as amorphization of a poorly water-soluble crystalline drug, can result in supersaturation with respect to the crystalline form of the drug and thus potentially in a higher degree of absorption after oral administration. The ease with which such drugs can be amorphized is known as their glass forming ability (GFA). In this study, a potential correlation between GFA and supersaturation propensity is investigated. The GFA of 23 different drugs was determined by melt quenching or milling the crystalline drugs to obtain their respective amorphous forms. The inherent propensity of the drug to supersaturate, i.e. the maximal apparent degree of supersaturation (aDS), and the time until precipitation at a given aDS were determined. Supersaturation was induced via a solvent shift method where the drug was initially dissolved in dimethyl sulfoxide and then added to a biorelevant medium (fasted state simulated intestinal fluid).The study showed that drugs which are good glass formers also have the potential to supersaturate to a high degree (high maximal aDS) whereas drugs that are modest glass formers supersaturate only to a low degree. This correlation was confirmed by principal component analysis, which also indicated that melt enthalpy inversely correlated with both GFA and maximal aDS. However, no correlation between GFA of a drug and the time until precipitation at a given aDS was found.

摘要

使用赋形剂配方技术,如将水溶性差的结晶药物非晶化,可以使药物的结晶形式达到过饱和状态,从而在口服后可能具有更高的吸收程度。药物的非晶化容易程度被称为其玻璃化形成能力(GFA)。在这项研究中,研究了 GFA 与过饱和倾向之间的潜在相关性。通过熔融淬火或研磨结晶药物来确定 23 种不同药物的 GFA,以获得各自的无定形形式。通过溶剂转移方法确定药物的固有过饱和倾向,即最大表观过饱和度(aDS)以及在给定 aDS 下沉淀的时间。初始将药物溶解在二甲基亚砜中,然后将其添加到生物相关介质(禁食状态模拟肠液)中,从而诱导过饱和。研究表明,良好的玻璃形成剂药物也有可能高度过饱和(高最大 aDS),而中等玻璃形成剂药物仅过饱和到低水平。主成分分析证实了这种相关性,这也表明熔融焓与 GFA 和最大 aDS 均呈反比关系。但是,没有发现药物的 GFA 与其在给定 aDS 下沉淀的时间之间存在相关性。

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