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.

Iontophoretic delivery of 5-aminolevulinic acid and its methyl ester using a carbopol gel as vehicle.

The aim of this study was to evaluate a Carbopol gel as a vehicle for iontophoretic delivery of 5-aminolevulinic acid (ALA) and its methyl ester (m-ALA). The formulation was characterized rheologically and the passive diffusion of ALA and m-ALA in the gels was measured. Addition of ALA and m-ALA did not change the rheological behavior of the gel and the diffusion coefficients of ALA and m-ALA were 4.4 +/- 1.2 x 10(-6) and 3.08 +/- 0.7 x 10(-7) cm2 s(-1), respectively. The anodal iontophoretic transport of ALA and m-ALA through porcine skin in vitro was followed for 15 h at a constant current of 0.4 mA. When incorporating ALA in the gel, the steady-state was reached in 10-12 h at a flux level of approx. 65 nmol cm(-2) h(-1) compared to 2.5-4 h and a level of approximately 145 nmol cm(-2) h(-1) for m-ALA. The total amount of m-ALA delivered after 15 h of iontophoresis resulted in a six-fold enhancement over ALA delivery. Iontophoretic delivery from the gel formulation seems to be better than, or comparable to, the passive delivery from formulations commonly used clinically, in spite of the 10-20 times lower concentration of the drug in the gel formulation. The skin uptake after iontophoresis for m-ALA showed a nine-fold increase over that of ALA in the stratum corneum (SC).

Transport properties and association behaviour of the zwitterionic drug 5-aminolevulinic acid in water. A precision conductometric study.

The behavior of the hydrochloride salt of 5-aminolevulinic acid (ALA-HCl) with respect to transport properties and dissociation in aqueous solution at 25 degrees C has been studied using precision conductometry within the concentration range 0.24-5.17mM. The conductivity data are interpreted according to elaborated conductance theory. The carboxyl group appears to be, in practice, undissociated. The dissociation constant, K(a), of the NH(3)(+) form of the amino acid molecules is determined to 6.78x10(-5) (molarity scale); pK(a)=4.17. The limiting molar conductivity of the ALA-H(+) ion, lambda(0)=33.5cm(2)Omega(-1)mol(-1); electric mobility u=3.47x10(-4)cm(2)V(-1)s(-1), is close to the electric mobilites of the acetate and benzoic ions.

Improvements of conductivity measurements of electrolyte solutions using a new conductometric cell design.

A new conductometric cell design, for precise conductance measurements, has been developed and tested using aqueous lidocaine hydrochloride as a model system. A small portion of a stock solution in the conductivity cell is diluted stepwise by pure solvent. The resistance of the cell is measured by means of a precision conductance bridge. Contrary to conventional technique in precision conductometry, the temperature is allowed to change during the measurements and corrected to the desired standard temperature. The temperature is determined using a thermistor immersed in the cell solution, which is agitated during the entire experiment. Using this new approach, significant improvements over conventional conductivity technique were observed. The time required for the measurements was considerably reduced, by a factor of at least ten. The amounts, especially of costly drugs, required in the measurements are also reduced. The pK(a) value obtained, 7.28, is close to the previously reported conductometrically determined average, 7.18. The precision of the single conductivity value is equally high, if not higher, as that obtained using conventional conductivity technique.