Abstract
Ion pairing is a strategy used to increase the permeation of topically applied ionised drugs. Formation occurs when the electrostatic energy of attraction between oppositely charged ions exceeds their mean thermal energy, making it possible for them to draw together and attain a critical distance. These ions then behave as a neutral species, allowing them to partition more readily into a lipid environment. Partition coefficient studies may be used to determine the potential of ions to pair and partition into an organic phase but cannot be relied upon to predict flux. Early researchers indicated that temperature, size of ions and dielectric constant of the solvent system all contributed to the formation of ion pairs. While size is important, this may be outweighed by improved lipophilicity of the counter ion due to increased length of the carbon chain. Organic counter ions are more effective than inorganic moieties in forming ion pairs. In addition to being used to increase permeation, ion pairs have been used to control and even prevent permeation of the active ingredient. They have also been used to stabilise solid lipid nanoparticle formulations. Ion pairs have been used in conjunction with permeation enhancers, and permeation enhancers have been used as counter ions in ion pairing. This review attempts to show the various ways in which ion pairs have been used in drug delivery via the skin. It also endeavours to extract and consolidate common approaches in order to inform future formulations for topical and transdermal delivery.
Highlights
The application of drugs via the skin provides a number of benefits
Cumulative permeation amounts of aminolevulinic nolevulinic acid (ALA) through porcine skin after 4 h showed that, with the exception of cetyltrimethylammonium bromide, all anionic and cationic counter ions increased the cumulative permeation of ALA through porcine skin
This study demonstrated that the solubility of unionised salicylic acid (SA) in a suspension remained constant at different pH values, indicating a method of overcoming the impact of pH on solubility and maintaining maximum solubility [47]
Summary
The application of drugs via the skin provides a number of benefits. These include the potential to provide a steady-state release [1], the avoidance of first-pass metabolism in the case of transdermal formulations and the localisation of application for topical formulations [2]. The outermost layer, known as the stratum corneum (SC), provides such an effective barrier that in the case of many topical formulations, only approximately 1–2% of the applied drug or active ingredient permeates [5]. This is partly due to the majority of pharmaceutical compounds being either weak acids or bases, with concomitant low aqueous solubility. Pharmaceutics 2021, 13, 909 the permeation of drugs, a number of different methods have been explored These can be divided into two groups, namely active and passive. In order to obtain data as best aligned to human skin responses as possible, permeation data are drawn exclusively from studies utilising human or porcine membranes [12]
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