Predicció de la permeació a través de la pell a partir de mesures físico-químiques

• Autores: Sara Soriano Meseguer
• Directores de la Tesis: Martí Rosés Pascual (dir. tes.), Adriana Port Casamitjana (dir. tes.)
• Lectura: En la Universitat de Barcelona ( España ) en 2020
• Idioma: español
• Tribunal Calificador de la Tesis: Clara Ràfols Llach (presid.), Sonia Espinosa García (secret.), Ana Melero Zaera (voc.)
• Programa de doctorado: Programa de Doctorado en Química Analítica y Medio Ambiente por la Universidad de Barcelona
• Calificación: Sobresaliente Cum Laude
• Materias:
  • Química
    • Química analítica
      • Análisis cromatográfico
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• Resumen

  • Dermal absorption is a key process in drug delivery studies of pharmaceutical and cosmetic industries. This process is typically described by skin permeability coefficient (Kp) and can be determined using experimental techniques, both in vivo and in vitro. Among the in vitro models, the Franz cell diffusion method is the most popular. However, these methods are laborious, costly and ethically questionable. An alternative can be an artificial skin membrane, skin PAMPA, or subrogation through physico-chemical parameters, as chromatographic retention. In the present work a methodology based on measurements in an HPLC system with a C18 column, and another based on skin-PAMPA permeability measurements with optimal assay conditions of 4 hours of incubation time and with the use of stirring to decrease the thickness of the aqueous boundary layer, have been established for a wide set of drugs to predict Kp values of neutral species. Both models have been successfully validated in terms of robustness and prediction ability. To extent these methods to ionized species is necessary to study the influence of acid-base ionization in chromatographic retention, skin PAMPA permeability and skin permeability. Therefore, property vs. pH profiles of drugs of different acid-base nature have been obtained through a general equation which relates the measured property with the pH. Fitting of these equations provides the corresponding values of the neutral and ionic form and the pKa values of the drugs in the media solution. In all cases the values of the anions and cations are much lower than that of the neutral forms and the pKa values obtained from the fitting can be linearly related to the aqueous pKa values of the drugs. Anomalous values due to the loss of membrane integrity at basic pH have been found in the skin PAMPA permeability at pH higher than 8. From these results, the relationship between skin permeability and chromatographic retention, corrected by the volume, and skin PAMPA permeability of ionized species has been established and validated correctly. Finally, Kp values of drugs, belonging to different Esteve’s research programs, have been obtained from previous models at pH 5.5 and 7.4 with good predictions. Compounds with favorable permeability coefficient and appropriate pharmacokinetic parameters can be selected as potential candidates to topical administration.