Release and transport of drugs in some complex and interacting systems

Sammanfattning: Drug formulations come in many forms, some intended for direct and immediate action and others aiming at a controlled manner of drug delivery. Viewed in a more general way drug transport often involves charged units, it takes place in a medium which in many respects must be considered complex - to some degree even reactive. Drug transport may also be competitive because of thermo- and hydrodynamic interactions, These three aspects of drug transport in general is discussed and exemplified in specific studies: 1) A conductivity study as a fundamental investigation for iontophoretic drug delivery; 2) a methodological development and diffusivity investigation of a steroidal hormone transport in silica containing silicone; 3) an investigation of competitive diffusion transport of small amphiphilic molecules in a polyelectrolyte containing semi-solid system.Iontophoresis - drug administration by electric current - normally requires charged drug molecules, hence their mobility and state of dissociation are essential parameters. The medium in which the drug is situated regulates the electrolytic drug content (e.g. dissociation equilibrium) and thus the iontophoretic efficiency. The conductivity of the local anesthetic, IidocaineHCl was investigated by high precision conductometry in aqueous and octanol solutions. From conductivity data and applied advanced electrolyte theory drug mobility parameters as well as, dissociation and association constants were obtained. The drug ion mobility was found, to be a factor 50 lower in octanol. The equilibrium constants obtained show that increasing drug concentration favors ion formation in water while favoring ion pair association in octanol. Hence, such a drug behaves very differently in different media, with obvious clinical implications.The dynamic diffusion in the complex system silicone/silica/estradiol was studied by means of a new equipment design which has considerably improved the possibility to perform precise quantitative dynamic diffusion measurements in such systems, The method avoids all disturbing interfaces between different media and allows for a precise spatial resolution of concentration of the diffusing drug. Data showed the method to be dependable and accurate. The effect on estradiol diffusivity due to varied silica content in the silicone is found to be paramount, increasing [SiO2] from 17 to 30% decreased the diffusivity by 68%. Some mechanisms are discussed.The diffusion of amphiphiles within and the release from agarose hydrogels containing the polyelectrolyte carrageenan was investigated. All drugs exhibit same apparent diffusivity in pure agarose gel. The diffusivity decreased when carrageenan was introduced in the gel. The order of the decrease follows the order of increased hydrophobic character of the drug. Competing diffusion was studied for amitriptyline and chlorpromazine, the former released significantly faster than chlorpromazine when simultaneously released from a hydrogel slab. Data indicate the possibility to adjust the simultaneous release rates individually for the two drugs by means of polyion charge density.