Pharmacokinetic advantage of an intranasal preparation of a novel anti-osteoporosis drug, L-Asp-hexapeptide-conjugated estradiol.

We examined the usefulness of intranasal (i.n.) administration of a novel osteotropic prodrug of estradiol, estradiol-17beta-succinate-(L-aspartate)6 (E2.17D6), for selective drug delivery to bone. E2.17D6 alone or with 5% 2,6-di-O-methyl-beta-cyclodextrin (DMbetaCD), 5% beta-cyclodextrin (betaCD), 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 E2.17D6 (3.7 micromol/kg) in mice amounted to 9.9 and 23.0% of the dose, respectively. The values of nasal bioavailability of E2.17D6 administered with DMbetaCD, betaCD, and HPC were 74.9, 55.8, and 49.1%, respectively. The plasma concentration of E2.17D6 after i.n. administration of E2.17D6-DMbetaCD 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 E2 (total dose 4.4 micromol/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 E2.17D6-DMbetaCD (total dose 0.44 to 8.8 micromol/kg, i.n., every 7th day) increased only BMD in a dose-dependent manner. In conclusion, intranasally administered E2.17D6-DMbetaCD has a potent antiosteoporotic effect without side effects, and has potential to provide an improved quality of life for patients with osteoporosis.