Ionic liquids--pharmaceutical potential.

Abstract

1. Nature and scope of bio-active ionic liquids Ionic liquids (ILs) are a recently developed class of materials with the property of being both fully ionic as in a conventional salt but also liquid rather than as the familiar crystalline solid. They have been the subject of much interest in the last year, being the subject of two major international conferences and a number of reviews. The latter have covered: (i) their potential as 'green solvents' (1) (they have virtually zero vapour pressure) (ii) their thermochemistry (2); and (iii) their development and applications (3). One area not addressed in these otherwise very full treatments was the exciting prospects of ILs as agents in pharmacology, an area developing as rapidly as those many applications detailed in refs 1-3. The basic strategy in applying the solvent properties of ILs in pharmaceutical materials has been to develop ILs which contain a pharmaceutically active component as one of the two component ions, i.e. the medication exists in a liquid rather than a solid form, thereby facilitating more controllable and/or faster transport within the subject receiving the medication; an early achievement in this field was that of Rogers et al. (4) who patented the concept of 'Multi-functional ionic liquid compositions'. A further advantage of ILs as opposed to crystalline drugs is that the latter can be prone to polymorphic change on storage to give versions with differing solubilities. An illustrative example of an IL that incorporates pharmaceutical activity is that of 1-methyl-3-butylimidazolium ibuprofenate (BMImlbu), synthesised as shown in Scheme 1 (5). [FORMULA NOT REPRODUCIBLE IN ASCII.] In this example, the pharmaceutically active component is present in the anion but it is also possible to place the activity in the cation, or even in both anion and cation as in lidocaine docusate (6) (Structure 1). [FORMULA NOT REPRODUCIBLE IN ASCII.] Lidocaine in its hydrochloride form is used as a local surface anaesthetic in dentistry whilst the docusate anion acts as an emollient. Combinations of different cations and anions provide a wide range of possible ILs, some such combinations being listed in refs 6 and 7; ILs containing biologically-active cations include antibacterials (8), local anaesthetics, anticholinergics and antifungal agents (9,10), while active anions furnish emollients, anti-acne agents, antibiotics, non-steroidal anti-inflammatory drugs and vitamins, among other materials (6,7). 2. Aspects of drug delivery One aim of developing bio-active ILs is to achieve enhanced drug delivery. It was demonstrated in an early paper (6) that lidocaine docusate, a hydrophobic IL, when compared with lidocaine hydrochloride, exhibited modified solubility, increased thermal stability and significant enhancement in the efficacy of topical analgesia in two different models of mouse antinociception; this was attributed not simply to changes in the delivery system but also to the induction of a different activity mechanism. Subsequent approaches have included attempting to control the release of the drug by encapsulating the bio-active IL in the channels of a silica host using a one-step sol-gel process (5). BMImlbu (Scheme I) was synthesised and then employed in sol-gel synthesis using either pure tetramethoxysilane (TMOS) or mixtures of TMOS and methyltrimethoxysilane (MTMOS) in 75/25 or 50/50 proportions in the presence of dilute HCI; the product was a monolithic ionogel. The loading of the drug in the ionogel was found to be ca 50% by weight. The release kinetics of ibuprofen were determined by high performance liquid chromatography (HPLC) and the results are shown in Figure I. Clearly the encapsulation of the IL form of the drug has a major influence on its release kinetics. The authors surmise that the slower release from the more methylated ionogel is related to the more hydrophobic nature of the cavity walls following the gelation. …