A STUDY OF THE UTILITY OF THE NASAL ROUTE FOR DRUG ADMINISTRATION.

摘要

The low and variable bioavailability of propranolol and contraceptive steroids is known to be due to the metabolism of these drugs in the gastrointestinal wall or by first pass effect. In order to by-pass the gastrointestinal and liver metabolism, the utility of the nasal route for the administration of these drugs was studied in rats and dogs. Propranolol was rapidly absorbed from the nasal cavity of both rats and dogs. The blood levels after intravenous and nasal administrations were similar whereas oral administration resulted in low blood levels of the drug. It was also shown that it is possible to obtain sustained blood levels of the drug without compromising the total bioavailability by administering sustained release formulations of propranolol.;The nasal administration of 17(beta)-estradiol resulted in significantly higher blood levels of the steroid than those observed following intraduodenal administration. The nasal bioavailability of 17(beta)-estradiol was 50%, 71% and 84% at 5, 10 and 20 (mu)g/rat, respectively. On the other hand, the bioavailability of estradiol after intraduodenal administration was only 2-5% for the same doses. The ratios of estrone to estradiol obtained after nasal administration of the different doses were lower than those obtained after intraduodenal administration. This indicates that 17(beta)-estradiol is oxidized to estrone in the nasal cavity and that the extent of oxidation is lower than that observed after intraduodenal administration. The data also indicate that for both the intravenous and nasal routes of administration, estrone and estradiol constitute together 78% of the total unconjugated estrogens whereas for the intraduodenal route of administration the above two steroids constitute 10-20% of the total unconjugated estrogens.;The nasal administration of the synthetic steroid, 17(alpha)-ethinyl estradiol resulted in blood levels significantly higher than those obtained following intraduodenal administration. The bioavailability of 17(alpha)-ethinyl estradiol following nasal and intraduodenal administrations was found to be 80% and 25% of that following intravenous administration, respectively. Furthermore, the area under the blood level curve obtained after nasal administration was directly proportional to the dose administered.;To obtain further insight into the drug absorption process from the nasal cavity, the effect of pH, partition coefficient and the nature of the compound on the rate and extent of absorption was studied, using an in-situ technique in rats. It was found that both unionized and ionized species of benzoic acid were absorbed from the nasal cavity of rats and that the unionized species was absorbed three times faster than the ionized species.;Data obtained on the natural contraceptive steroids, progesterone and 17(beta)-estradiol in rats also indicate that these steroids are rapidly absorbed from the nasal cavity. The bioavailability of progesterone administered nasally was found to be 100% of that following intravenous administration at the three doses studied. The bioavailability of progesterone after intraduodenal administration of 50 (mu)g/rat was found to be 1.2% of that following intravenous administration.;The effect of partition coefficient on the extent of nasal absorption was examined at pH 6 using a series of barbiturates. The extent of absorption increased as the chloroform/water partition coefficient increased and the magnitude of increase in absorption was similar to that observed for gastrointestinal absorption.;Glucose and tyrosine were not absorbed from the nasal cavity of rats. This suggests that under these conditions these compounds are not actively absorbed from the nasal cavity.