title: Enhancement of nasal delivery of a renin inhibitor in the rat using emulsion formulations.
abstract: Nasal absorption of O-(N-morpholino-carbonyl-3-L-phenylaspartyl-L-leucinamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane (I), a renin inhibitor, was evaluated in two rat nasal models, one involving surgery and the other requiring no surgical intervention. Oleic acid/monoolein emulsion formulations were tested along with a control PEG 400 solution. The percent absolute bioavailability of the compound was enhanced from 3-6% (PEG 400 solution) to 15-27% when the emulsion formulations were used. The different nasal model techniques (with and without surgery) did not produce any statistical difference in the absolute bioavailability values for I. Emulsion formulations did not produce appreciable damage as assessed morphologically. It is suggested that emulsion formulations containing membrane adjuvants such as oleic acid and monoolein can be used to enhanced the nasal delivery of low-bioavailable, lipid-soluble drugs.
authors.affiliation: G. D. Searle & Co., Skokie, Illinois 60077.
authors.forename: T T
authors.initials: TT
authors.lastname: Kararli
authors.forename: T E
authors.initials: TE
authors.lastname: Needham
authors.forename: G
authors.initials: G
authors.lastname: Schoenhard
authors.forename: D A
authors.initials: DA
authors.lastname: Baron
authors.forename: R E
authors.initials: RE
authors.lastname: Schmidt
authors.forename: B
authors.initials: B
authors.lastname: Katz
authors.forename: B
authors.initials: B
authors.lastname: Belonio
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D004151:Dipeptides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004655:Emulsions; D005989:Glycerides / Q000737:chemistry; D008297:Male; D009025:Morpholines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D009297:Nasal Mucosa / Q000187:drug effects*; D019301:Oleic Acid; D009829:Oleic Acids / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013656:Taurocholic Acid / Q000737:chemistry; D000092502:Renin Inhibitors
chemical_list: D004151:Dipeptides; D004655:Emulsions; D005989:Glycerides; D009025:Morpholines; D019301:Oleic Acid; D009829:Oleic Acids; D013656:Taurocholic Acid; D000092502:Renin Inhibitors; C059277:SC 46944; C005953:monoolein