Abstract
The influence of penetrant hydrophilicity on nasal pharmacokinetics and systemic bioavailability was studied in ovariectomized female New Zealand White rabbits. The systemic bioavailability of progesterone derivatives with one hydroxy (17-α-hydroxypro-gesterone, HP), two hydroxy (cortexolone, CT), and three hydroxy (hydrocortisone, HC) groups were compared to progesterone, in separate crossover studies, following i.v., oral, and nasal administrations. Nasal administration was accomplished using an immediate-release nasal spray formulation and a controlled-release nasal device. The rank order of systemic bioavailability after nasal spray was HP > P > CT > HC (97.10, 82.52, 71.99 and 60.90%, respectively), which correlates in a hyperbolic pattern with the nasal mucosa partition coefficients of the drugs. The controlled-release nasal device achieved a more prolonged and steady plasma level of drug than the other routes of administration. The systemic bioavailabilities of progesterone and its hydroxy derivatives after nasal administration were all significantly greater ( P < 0.01) than those after oral administration (P 7.87%; HP 5.93%; CT 5.88%; HC, 2.67%). The results of this investigation demonstrate that the extent of nasal absorption is influenced by both the mode of nasal administration and the hydrophilicity of the penetrant, as expressed by the nasal mucosa partition coefficient.
Published Version
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