Electrolyte structures and ionization conditions for iontophoretic drug formulation of local anesthetics

Sammanfattning: Iontophoresis is a modern method of drug delivery by which charged bioactive molecules (drugs) are transferred from an electrolytic reservoir into and through a tissue, normally skin, by means of a weak electric current. The drug is placed in a conductive medium, usually an aqueous solution or a hydrogel, between the "active" electrode and the skin. The circuit is completed by a second "passive" electrode and the skin. Although iontophoresis is a well-known method for transdermal delivery of drugs, basic physicochemical knowledge of this phenomenon is still lacking.This thesis aimed to obtain a wide understanding of electrolyte structures and ionization conditions in iontophoresis, and a firm physicochemical basis for improvement of iontophoretic drug formulation of local anesthetics. The precision conductometric technique was used mainly. Lidocaine hydrochloride (LidHCl) was selected as a model local anesthetic substance. The conductance theory of Fuoss, Hsia and Fernandez-Prini was used to interpret the experimental data, with respect to ionization and mobility of LidHCl in different solvent media. LidHCl was studied in the following solvents:, water, propylene glycol (a transdermal enhancer),aqueous propylene glycol (20 weight-% PG) and 1-octanol. To compare the ionization properties of prilocaine hydrochloride (PrilHCl) with those of LidHCl, PrilHCl was studied in the same pharmaceutical aqueous-enhancer medium. Furthermore, the molecular diffusive transport properties of the local anesthetics lidocaine-, prilocaine-,bupivacaine-, etidocaine-, mepivacaine- and ropivacaine hydrochloride in an agarose hydrogel (1 weight-% agarose) were studied. The results indicate that, for the solvents studied, LidHCl has the highest ionic mobility in aqueous propylene glycol; u(LidH+) = 1.35 mm2 V-1 min-1. No measurable difference in ionization properties and ionic mobility between LidHCl and PrilHCl in aqueous propylene glycol was observed. Within the concentration range investigated in this solvent, more than 98% of both LidHCl and PrilHCl are in ionized form (LidH+ and PrilH+). Of the six local anesthetics studied by diffusion measurements in agarose hydrogel (1 weight-% agarose) as medium, LidHCl and PrilHCl have the highest diffusion coefficients; D(lido) = 7.79 · 10-6 and D(prilo) = 7.76  · 10-6 cm2/s.From a pharmaceutical point of view, it might be interesting to study the possibility of combining lidocaine- and prilocaine hydrochloride in an aqueous-enhancer medium as an iontophoretic drug formulation of local anesthetics.