Transdermal delivery of morphine derivatives : a qualitative structure-in vitro permeability relationship

The in vitro permeability of six different morphine derivatives (morphine, codeine, hydromorphone, hydrocodone, oxymorphone, oxycodone) through human epidermis was studied to elucidate the influence of three different substituents, namely the methoxyl (CH3O), carbonyl (CO) and hydroxyl (OH) groups in position 3, 6 and 14, respectively. The in vitro permeation studies were performed using the Franz diffusion cells and aqueous saturated solutions. At the end of experiment (i.e. 24h), the maximum flux (J) and the permeation coefficient [pKp=-log(J/S), where S is the drug solubility at saturation] were calculated and a statistical analysis of possible structure-permeability relationship was performed. The substituents of each tested compound and the related pKp values are listed in Table 1. The pKp values of hydromorphone and hydrocodone were not statistically different from morphine and codeine ones indicating that the 6-CO group did not influence the permeation through human epidermis. Conversely, the 3-CH3O group lead to a significant increase of the permeation coefficient (<pKp). Indeed, the pKp values of codeine derivatives (3-CH3O) were at least 25% lower than morphine derivative ones (p<0.01). Furthermore, 14-OH had a synergic effect with 3-CH3O on pKp: the pKp of oxycodone (3-CH3O, 14-OH) was 40% lower than one of oxymorphone (14-OH). The permeation of tested morphine derivatives through human epidermis appears influenced by the polarity distribution in the molecular structure. Table 1 - The substituents of morphine derivatives and the related pKp values Compound 3-CH3O 6-CO 14-OH pKp Morphine - - - 3.9±0.2 Oxymorphone - + + 3.7±0.2 Hydromorphone - + - 4.1±0.2 Codeine + - - 2.9±0.0 Oxycodone + + + 2.3±0.5 Hydrocodone + + - 3.0±0.1