NASAL ABSORPTION KINETIC-BEHAVIOR OF AZETIRELIN AND ITS ENHANCEMENT BY ACYLCARNITINES IN RATS

Purpose. The long-term stability and nasal absorption characteristics of a basic nasal formulation of azetirelin, a thyrotropin-releasing ho rmone analog and its absorption enhancement by incorporation of acylca rnitines in the formulation were investigated. Methods. The long-term stability of basic nasal azetirelin formulations at 25 degrees C was p redicted by calculation from the Arrhenius plot of the data on 6 month s' storage at 40, 50 and 60 degrees C. Nasal azetirelin absorption cha racteristics were kinetically examined by intranasal administration to rats, determination of plasma azetirelin level by radioimmunoassay, a nd fitting the data to a two-compartment model including absorption ra te. Results. Basic nasal azetirelin formulations of pH 4.0 and pH 5.1 were predicted to be highly stable. Residual azetirelin after 2 years storage at 25 degrees C was greater than 95%. Nasal absorption charact eristics of this formulation in the pH 4.0-6.3 range showed pH-depende ncy, with pH 4.0 showing the highest absolute bioavailability (Bioav) of 17.1%. This nasal Bioav was 21 times greater than that of oral admi nistration (0.8%). Acylcarnitines with 12 or more carbon atoms in the acyl chain greatly enhanced nasal absorption of azetirelin: Bioavs wit h lauroylcarnitine chloride (LCC) and palmitoylcarnitine chloride were 96.9% and 72.9%, respectively. This enhancement by LCC plateaued at t he low concentration of 0.1%. Conclusions. The basic nasal azetirelin formulation at pH 4.0 is stable and shows adequate absorption, with na sal absorption having greater Bioav than oral absorption. The 12-carbo n acylate LCC was the strongest enhancer among acylcarnitines and prov ided near-total delivery of the administered dose to the blood.