King's College London, Institute of Pharmaceutical Science, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK.
Pharm Res. 2012 Dec;29(12):3434-42. doi: 10.1007/s11095-012-0838-x. Epub 2012 Aug 30.
To understand in situ drug thermodynamic activity when embedded in a supramolecular structured hydrophilic matrix that simultaneously self-assembled during drug supersaturation.
A propylene glycol (PG)/water, hydroxypropyl methyl cellulose matrix containing ethanol was used to support diclofenac supersaturation. Phase behaviour, thermodynamics and drug transport were assessed through the determination of evaporation kinetics, supersaturation kinetics and transmembrane penetration.
Initial ethanol evaporation from the drug loaded matrix (2.9 ± 0.4 mg.min(-1).cm(-2)) was comparable to that of the pure solvent (ca. 3 mg.min(-1).cm(-2)). When 25% w/w of the total ethanol from the applied phase was lost (ethanol/water/PG molar ratio of 7:5:1.2), an inflection point in the evaporation profile and a sudden decrease in drug solubility demonstrated that a defined supramolecular structure was formed. The 55-fold decrease in drug solubility observed over the subsequent 8 h drove in situ supersaturation, the rate of which was a function of the drug load in the matrix (y = 0.0078x, R(2) < 0.99).
The self-assembling supramolecular matrix prevented drug re-crystallisation for >24 h, but did not hinder mobility and this allowed the thermodynamic activity of the drug to be directly translated into highly efficient transmembrane penetration.
当药物嵌入同时自组装形成超分子亲水基质中时，理解其原位药物热力学活性。
采用含乙醇的丙二醇（PG）/水、羟丙基甲基纤维素基质来支持双氯芬酸过饱和。通过蒸发动力学、过饱和动力学和跨膜渗透的测定来评估相行为、热力学和药物传输。
从负载药物的基质中初始乙醇蒸发（2.9±0.4 mg.min-1.cm-2）与纯溶剂相当（约 3 mg.min-1.cm-2）。当施加相中的总乙醇的 25%（w/w）损失时（乙醇/水/PG 的摩尔比为 7:5:1.2），蒸发曲线出现拐点且药物溶解度突然下降，表明形成了明确的超分子结构。随后 8 小时内药物溶解度下降 55 倍导致原位过饱和，其速率是基质中药物负载的函数（y=0.0078x，R2<0.99）。
自组装的超分子基质阻止药物再结晶超过 24 小时，但不阻碍药物的迁移性，这使得药物的热力学活性能够直接转化为高效的跨膜渗透。
