Electrochemical Methods for Drug Characterisation and Transdermal Delivery : Capillary Zone Electrophoresis, Conductometry, and Iontophoresis

This thesis concerns the development and utilisation of techniques for characterisation and transdermal delivery of various systems for pharmaceutical applications. The degree of dissociation of drug molecules and the mobilities of the different species formed are essential factors affecting the rate of drug delivery by iontophoresis. Hence, determination of drug mobility parameters and equilibrium constants are important for the development of iontophoretic systems. With capillary zone electrophoresis using a partial filling technique and methyl-β-cyclodextrin as chiral selector, the enantiomers of orciprenaline were separated. The association constants between the enantiomers of the drug and the selector were also evaluated. Precision conductometry studies were performed for the hydrochloride salts of lidocaine and 5-aminolevulinic acid in aqueous propylene glycol and water as media, respectively. Iontophoresis is a technique for drug delivery where charged molecules are transported into and through skin by application of a weak direct electrical current. The drugs 5-aminolevulinic acid and its methyl ester were used as model compounds and incorporated in two different drug delivery vehicles, a sponge phase and carbopol gel. The bicontinuous structure of the sponge phase, constituted of monoolein and a mixture of propylene glycol and water, makes it interesting for use in iontophoretic delivery, since ions can move more or less freely in the aqueous as well as in the lipid domains. Furthermore, all three components are known for their penetration enhancing abilities. Hydrogels like carbopol gels are interesting media with respect to iontophoretic studies, since devices for iontophoresis often utilize hydrogels as contact interfaces between the skin and the electrodes. The results indicate that the transport achieved iontophoretically using the gel (1 % active substance) was comparable with the passive delivery of clinically used formulations (16 % - 20 % active substance)

Electrochemical Methods for Drug Characterisation and Transdermal Delivery : Capillary Zone Electrophoresis, Conductometry, and Iontophoresis

This thesis concerns the development and utilisation of techniques for characterisation and transdermal delivery of various systems for pharmaceutical applications. The degree of dissociation of drug molecules and the mobilities of the different species formed are essential factors affecting the rate of drug delivery by iontophoresis. Hence, determination of drug mobility parameters and equilibrium constants are important for the development of iontophoretic systems. With capillary zone electrophoresis using a partial filling technique and methyl-β-cyclodextrin as chiral selector, the enantiomers of orciprenaline were separated. The association constants between the enantiomers of the drug and the selector were also evaluated. Precision conductometry studies were performed for the hydrochloride salts of lidocaine and 5-aminolevulinic acid in aqueous propylene glycol and water as media, respectively. Iontophoresis is a technique for drug delivery where charged molecules are transported into and through skin by application of a weak direct electrical current. The drugs 5-aminolevulinic acid and its methyl ester were used as model compounds and incorporated in two different drug delivery vehicles, a sponge phase and carbopol gel. The bicontinuous structure of the sponge phase, constituted of monoolein and a mixture of propylene glycol and water, makes it interesting for use in iontophoretic delivery, since ions can move more or less freely in the aqueous as well as in the lipid domains. Furthermore, all three components are known for their penetration enhancing abilities. Hydrogels like carbopol gels are interesting media with respect to iontophoretic studies, since devices for iontophoresis often utilize hydrogels as contact interfaces between the skin and the electrodes. The results indicate that the transport achieved iontophoretically using the gel (1 % active substance) was comparable with the passive delivery of clinically used formulations (16 % - 20 % active substance)

Transdermal delivery from a lipid sponge phase—iontophoretic and passive transport in vitro of 5-aminolevulinic acid and its methyl ester

The hydrochloride salts of 5-aminolevulinic acid (ALA) and its methyl ester (m-ALA), respectively, were dissolved in a lipid sponge phase comprising monoolein, propylene glycol and aqueous buffer at concentrations of approximately 0.25% and 16% w/w m-ALA. The iontophoretic and passive delivery of ALA and m-ALA from this formulation through porcine skin in vitro were measured and compared to formulations used in clinical practice, 20% w/w ALA in Unguentum M and Metvix(R) (a cream containing 16% w/w m-ALA). A sponge phase with 16% w/w m-ALA showed a higher passive flux (approximately 140 nmol cm(-2) h(-1) at 5 h) but a lower iontophoretic flux (approximately 800 nmol cm(-2) h(-1) at 5 h) compared to the clinically used products but the differences are hardly significant due to large standard deviations. ALA and m-ALA in sponge phase formulation showed iontophoretic fluxes in the range 80-100 nmol cm(-2) h(-1) at 3 h, i.e. values comparable to the passive fluxes from the more concentrated vehicles. The results demonstrate that the lipid sponge phase, a thermodynamically stable liquid with amphiphilic character, may have potential as a transdermal drug delivery vehicle

Lipid cubic phases for improved topical drug delivery in photodynamic therapy.

We have evaluated the efficacy of lipid cubic phases, highly ordered self-assembly systems on the nanometer level, as drug delivery vehicles for in vivo topical administration of delta-aminolevulinic acid (ALA) and its methyl ester (m-ALA) on nude mice skin. ALA, a precursor of heme, induces the production of the photosensitizer protoporphyrin IX (PpIX) in living tissue. Measuring the PpIX fluorescence at the skin surface, after topical administration, makes indirect quantification of the penetration of ALA into the tissue possible. Cubic phases were formed of lipid (monoolein or phytantriol), water and drug. In some cases, propylene glycol was included in the cubic phase as well. The drug concentration was 3% (w/w, based on the total sample weight) in all investigated vehicles. When the formulations were applied for 1 h, the monoolein cubic systems and the three-component phytantriol sample showed higher fluorescence compared to the standard ointment during the 10 h of measurement. Both ALA and m-ALA yielded similar results, although the differences between the investigated vehicles were more pronounced when using m-ALA. For the 24-h applications, the monoolein cubic systems with m-ALA showed faster PpIX formation than the standard ointment, implying higher PpIX levels at short application times (less than 4 h). The systemic PpIX fluorescence of ALA was elevated by using the lipid cubic formulations. Notably, a small systemic effect was also observed for the monoolein cubic sample with m-ALA. These results imply improved PpIX formation when using the lipid cubic systems, most probably due to enhanced drug penetration