We examined the usefulness of intranasal (i.n.) administration of a novel osteotropic prodrug of estradiol, estradiol-17β-succinate-(
L-aspartate)
6 (E
2·17D
6), for selective drug delivery to bone. E
2·17D
6 alone or with 5% 2,6-di-
O-methyl-β-cyclodextrin (DMβCD), 5% β-cyclodextrin (βCD), or 10% hydroxypropyl cellulose (HPC) as an absorption enhancer was administered to ovariectomized (OVX) mice
via the i.n. route. The oral and nasal bioavailability after
p.o. or i.n. administration of E
2·17D
6 (3.7 μmol/kg) in mice amounted to 9.9 and 23.0% of the dose, respectively. The values of nasal bioavailability of E
2·17D
6 administered with DMβCD, βCD, and HPC were 74.9, 55.8, and 49.1%, respectively. The plasma concentration of E
2·17D
6 after i.n. administration of E
2·17D
6-DMβCD decreased rapidly to the endogenous level by 6 h, but the concentration in the bone was about 200 times higher than that in plasma, and decreased slowly over a period of about a week. When E
2 (total dose 4.4 μmol/kg, i.n., every 3rd day) was administered to OVX mice for 35 d, bone mineral density (BMD), liver weight, and uterus weight increased, whereas E
2·17D
6-DMβCD (total dose 0.44 to 8.8 μmol/kg, i.n., every 7th day) increased only BMD in a dose-dependent manner. In conclusion, intranasally administered E
2·17D
6-DMβCD has a potent antiosteoporotic effect without side effects, and has potential to provide an improved quality of life for patients with osteoporosis.
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