Nose-to-brain delivery of TS-002, prostaglandin D₂ analogue

Abstract

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.

Intranasal drug targeting of hypocretin-1 (orexin-A) to the central nervous system

“…These results demonstrate that intranasal delivery is a promising alternative to more invasive methods of drug delivery to rapidly target HC to the CNS for the treatment of narcolepsy or other disorders involving the hypocretinergic system in the CNS, including Alzheimer's disease,53 Parkinson's disease54 or depression 55. While we recognize the limitations associated with using rodent models for translation to humans, it is encouraging to note recent reports demonstrating similar nose‐to‐brain transport pathways in rats and monkeys47 and that intranasal administration of HC and other neuropeptides in nonhuman primates and in humans can significantly effect CNS functions 17, 18, 56–59…”

Inflammation and α-Synuclein’s Prion-like Behavior in Parkinson's Disease—Is There a Link?

“…ROS and cytokines produced by microglia disrupt the blood brain barrier (BBB) [136, 137], and the effect of these inflammatory mediators is more pronounced in the olfactory epithelium and OB where the BBB already is more permeable than the BBB of other structures [138–141]. Recently, the effect of TNF-α on BBB permeability was shown to favor CNS infection by the West Nile virus in mice [142].…”

Brain and Nasal Cavity Anatomy of the Cynomolgus Monkey: Species Differences from the Viewpoint of Direct Delivery from the Nose to the Brain

“…According to Kumar et al, after nasal spraying of progesterone, the concentration in the cerebrospinal fluid (CSF) in female rhesus monkeys was significantly higher than that after intravenous injection, although there were similar plasma concentrations [13]. A prostaglandin D agonist exhibited more potent pharmacological activity (sleep-inducing effect) in monkeys after nasal administration than after intravenous administration [14]. In the cynomolgus monkey, nasally administered interferon-β1b reached levels one order of magnitude higher in the olfactory bulb and trigeminal nerve than in other peripheral tissues.…”