Nose-to-brain delivery of TS-002, prostaglandin D2 analogue.
This study was conducted to investigate the possibility of performing nose-to-brain delivery of TS-002, which is an analog compound of prostaglandin D2 (PGD2) and thus would be a natural sleep inducer. The absolute bioavailability (BA) and sleep-inducing effect (SIE) following intranasal (IN) administration of TS-002 dry powder to cynomolgus monkeys were evaluated in comparison with intravenous (IV) administration. The SIE was evaluated as the accumulated time of sleeping-posture for 3 h. The brain distribution of TS-002 following IN administration of the dry powder was examined in rats. The absolute bioavailability (BA) in monkeys following IN administration of the dry powder (0.4-1.2 mg/body) was comparatively high (43.4-78.0%). The SIE following IN administration (0.05-0.4 mg/body) showed dose-dependency and its effect at 0.4 mg/body was twice as strong as that for IV administration (P < 0.05). The brain concentrations in rats following IN administration (0.1 mg/kg) were obviously higher than that for IV administration at the same dose. The highest content was observed in the olfactory bulb. These results demonstrated that TS-002 was directly transported from the olfactory region to brain, thereby showing that it may be possible to develop a novel sleep-inducing drug based on nose-to-brain delivery.
Yamada
Kenji
K
Research Strategy Division, Taisho Pharmaceutical Co., Ltd., 403, Yoshino-cho 1-chrome, Kita-ku, Saitama-shi, Saitama, 331-9530, Japan. kenji.yamada@po.rd.taisho.co.jp
Hasegawa
Masatoshi
M
Kametani
Shunichi
S
Ito
Shusei
S
D000281:Administration, Intranasal; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D016503:Drug Delivery Systems; D006993:Hypnotics and Sedatives / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D009330:Nebulizers and Vaporizers; D011208:Powders; D015230:Prostaglandin D2 / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012890:Sleep / Q000187:drug effects
D006993:Hypnotics and Sedatives; D011208:Powders; C519320:TS-002; D015230:Prostaglandin D2