Kubota Koji, Shibata Akira, Yamaguchi Toshikazu
Laboratory of Physical Chemistry, Department of Pharmacy, Faculty of Pharmacy, Yasuda Women's University, 6-13-1, Yasuhigashi, Asaminami-ku, Hiroshima-shi, Hiroshima 731-0153, Japan.
Laboratory of Physical Chemistry, Department of Pharmacy, Faculty of Pharmacy, Yasuda Women's University, 6-13-1, Yasuhigashi, Asaminami-ku, Hiroshima-shi, Hiroshima 731-0153, Japan.
Eur J Pharm Sci. 2016 Apr 30;86:75-83. doi: 10.1016/j.ejps.2016.03.002. Epub 2016 Mar 8.
In spite of numerous advantages, transdermal drug delivery systems are unfeasible for most drugs because of the barrier effect of the stratum corneum. Ionic liquids were recently used to enhance transdermal drug delivery by improving drug solubility. In the present study, safe and effective ionic liquids for transdermal absorption were obtained as salts generated by a neutralization reaction between highly biocompatible aliphatic carboxylic acids (octanoic acid or isostearic acid) and aliphatic amines (diisopropanolamine or triisopropanolamine) (Medrx Co., Ltd., 2009). The mechanism of skin permeability enhancement by ionic liquids was investigated by hydrophilic phenol red and hydrophobic tulobuterol. Further, the skin permeation enhancing effect was remarkably superior in the acid excess state rather than the neutralization state. Infrared absorption spectrum analysis confirmed that ionic liquids/aliphatic carboxylic acid/aliphatic amine are coexisting at all mixing states. In the acid excess state, ionic liquids interact with aliphatic carboxylic acids via hydrogen bonds. Thus, the skin permeation enhancing effect is not caused by the ionic liquid alone. The "liquid salt mixture," referred to as a complex of ingredients coexisting with ionic liquids, forms a molecular assembly incorporating hydrophilic drug. This molecular assembly was considered an effective and safety enhancer of transdermal drug permeation.
尽管透皮给药系统有诸多优点，但由于角质层的屏障作用，大多数药物的透皮给药仍不可行。离子液体最近被用于通过提高药物溶解度来增强透皮给药。在本研究中，通过高生物相容性脂肪族羧酸（辛酸或异硬脂酸）与脂肪族胺（二异丙醇胺或三异丙醇胺）之间的中和反应生成的盐，获得了用于透皮吸收的安全有效的离子液体（Medrx有限公司，2009年）。通过亲水性的酚红和疏水性的妥洛特罗研究了离子液体增强皮肤渗透性的机制。此外，在酸过量状态下，皮肤渗透增强效果明显优于中和状态。红外吸收光谱分析证实，离子液体/脂肪族羧酸/脂肪族胺在所有混合状态下均共存。在酸过量状态下，离子液体通过氢键与脂肪族羧酸相互作用。因此，皮肤渗透增强效果并非仅由离子液体引起。被称为与离子液体共存成分复合物的“液体盐混合物”形成了包含亲水性药物的分子聚集体。这种分子聚集体被认为是透皮药物渗透的有效且安全的增强剂。
