Properties of in situ gelling nasal inserts containing estradiol/methyl β-cyclodextrin

The purpose of the study was to incorporate estradiol into in situ gelling nasal inserts by complexation with methyl-beta-cyclodextrin (MbetaCD) and to evaluate the in vivo performance of estradiol-loaded inserts, solutions,and microparticles in rats. Aqueous solutions of estradiol/MbetaCD complexes and hydrophilic polymers(carrageenan, sodium alginate, HPMC, PVP90, and xanthan gum) were freeze-dried to form solid, sponge-like nasal inserts. The drug release, water and moisture uptake,and bioadhesion potential of inserts were investigated. The inserts were administered nasally to male rats and the serum estradiol level was followed for 6 h by RIA. The addition of MbetaCD to carrageenan solutions increased the viscosity significantly, which could be explained by the dehydration of carrageenan, the addition of cations as impurities in MbetaCD, and interactions between carrageenan and MbetaCD. The bioadhesion potential of HPMC K15M was reduced by the addition of MbetaCD. The water uptake of carrageenan inserts was not influenced while the moisture sorption was enhanced due to the hygroscopicity of MbetaCD. The release of the drug complex from inserts was as follows: HPMC E5 > PVP 90 > sodium alginate > xanthan gum > carrageenan. Neither the estradiol dose nor the complex molar ratio had an effect on the drug release from inserts. In vivo estradiol levels after nasal application of an aqueous solution (Aerodiol) and microparticles resulted in high peaks (approx. 0.42-0.47 pg/ml/g/mug) with short t(max). Carrageenan microparticles showed a delayed serum peak level compared to PVP 90 (t(max): 30 and 10 min, respectively), both reached 80-90% relative bioavailability. Nasal inserts led to a more gradual absorption of estradiol with lower peak serum levels (0.13-0.14 pg/ml/g/mug). Gelled carrageenan inserts were still present in the nasal cavity 6 h post-administration. The relative bioavailability of carrageenan inserts was slightly higher than for PVP 90 (49 vs. 40%).