Resumen de Estudio in vitro de la absorción transdérmica de pizotifeno y paliperidona
The present doctoral thesis is part of a major project which aims to develop new therapeutic alternatives for the treatment of long-term diseases by the use of transdermal delivery systems. This work has been possible thanks to the funds obtained from ¿Fondo de Investigaciones Sanitarias¿ (Ministerio de Sanidad y Consumo) (Project PI060108), and the University CEU Cardenal Herrera (PRCEU-UCH01/09).
In the last years the use of transdermal route has increased its use because of the advantages that it can offer: constant maintenance of plasma concentrations of the drug, avoidance of first-pass metabolism, reduced side-effects, ability to end the drug administration and improvement of patient compliance.
The main objectives of the present work were to develop transdermal delivery systems of pizotifen malate and to evaluate the transdermal administration of paliperidone. In order to achieve these objectives the analytical method validation for both compounds was carried out. Afterwards, passive diffusion was determined and the effect of different enhancer strategies like chemical enhancers, iontophoresis and laser microporation was determined. Finally, pizotifen matrix patches were developed including the strategies that provided better results and their physicochemical properties were determined. In the case of the paliperidone, a preliminary gel formulation was developed and studied under microporated skin.
From the results obtained the following conclusions can be drawn: 1. Passive diffusion of pizotifen and paliperidone provided flow rates of 1.63 ± 0.76 ¿g/cm2h and 0.21 ± 0.15 ¿g/cm2h, respectively. Both flow rates are not enough to provide therapeutic concentrations by means of this administration pathway, therefore it is necessary to use transdermal enhancer techniques which increase their absorption through the skin.
2. The application of iontophoresis to pizotifen malate in solution provided a flow rate of 7.35 ± 0.34 ¿g/cm2h.
3. The fatty acids oleic and decenoic acid provided the highest increase of pizotifen transdermal absorption. The unsaturated bonds on the 9th carbon and the chain length are seems to be related with the enhancement effect of this group of transdermal enhancers. Although both parameters produce an increase in the transdermal absorption, the unsaturated bond on the 9th carbon is more pronounced.
4. A transdermal delivery system of pizotifen malate prepared with polyvinyl pirrolidone K90, Plastoid E35H, propylenglycol, ethanol and decenoic acid as chemical enhancer, provided a pizotifen transdermal flow rate of 3.41 ± 0.44 ¿g/cm2h. Moreover, the manufactured transdermal delivery system showed physical characteristics suitable for its use, these are good stacking, resistance and stability.
5. In the laser microporation treatment, the increase of the pores and pulses produced a significant increment on the absorption of paliperidone. However, the increase on the number of pores presents a limit where the increment on the transdermal absorption is decreased. Pretreatment with 900:3 produced similar transdermal flow rate than the rest of the treatments but being less invasive.
6. For both drugs was demonstrated in vitro that they can be administrated transdermaly in vitro. Furthermore, the enhancer strategies studied shown to be effective to increase the transdermal absorption of these drugs. However, the present thesis has to be considered as a preliminary study and the results need to be confirmed in vivo
