Abstract
Purpose. The long-term stability and nasal absorption characteristics of a basic nasal formulation of azetirelin, a thyrotropin-releasing hormone analog and its absorption enhancement by incorporation of acylcarnitines in the formulation were investigated.
Methods. The long-term stability of basic nasal azetirelin formulations at 25° C was predicted by calculation from the Arrhenius plot of the data on 6 months' storage at 40, 50 and 60° C. Nasal azetirelin absorption characteristics were kinetically examined by intranasal administration to rats, determination of plasma azetirelin level by radioimmunoassay, and fitting the data to a two-compartment model including absorption rate.
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° C was greater than 95%. Nasal absorption characteristics of this formulation in the pH 4.0−6.3 range showed pH-dependency, with pH 4.0 showing the highest absolute bioavailability (Bioav) of 17.1%. This nasal Bioav was 21 times greater than that of oral administration (0.8%). Acylcarnitines with 12 or more carbon atoms in the acyl chain greatly enhanced nasal absorption of azetirelin: Bioavs with lauroylcarnitine chloride (LCC) and palmitoylcarnitine chloride were 96.9% and 72.9%, respectively. This enhancement by LCC plateaued at the low concentration of 0.1%.
Conclusions. The basic nasal azetirelin formulation at pH 4.0 is stable and shows adequate absorption, with nasal absorption having greater Bioav than oral absorption. The 12-carbon acylate LCC was the strongest enhancer among acylcarnitines and provided near-total delivery of the administered dose to the blood.
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Kagatani, S., Inaba, N., Fukui, M. et al. Nasal Absorption Kinetic Behavior of Azetirelin and Its Enhancement by Acylcarnitines in Rats. Pharm Res 15, 77–81 (1998). https://doi.org/10.1023/A:1011952804479
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DOI: https://doi.org/10.1023/A:1011952804479