Intranasal targeting of neuropeptides to the central nervous system: Evaluation of pharmacokinetics, pharmacodynamics, and a novel vasoconstrictor formulation

Delivery of therapeutics to the central nervous system (CNS) for the treatment of neurological and psychiatric diseases and disorders is a formidable challenge due to the presence of the blood-brain barrier (BBB). The intranasal route of administration is a noninvasive method to bypass the BBB and rapidly target therapeutics to the CNS by utilizing the olfactory and trigeminal neural pathways connecting the nasal mucosa to the brain and spinal cord. Despite the enormous potential of the intranasal method, it is limited by the low efficiency of delivery to the CNS.;The overall objective of this research was to assess targeting of neuropeptides to the CNS following intranasal administration by evaluating pharmacokinetics, pharmacodynamics, and a novel vasoconstrictor formulation. To assess if intranasal administration targeted the neuropeptide, hypocretin-1 (HC), to the CNS, pharmacokinetics and targeting were compared over a two hour period following intranasal and intravenous administration of 10 nmol of 125I-HC to anesthetized rats. Results indicated that intranasal administration resulted in less exposure to the blood and peripheral tissues (∼10-fold), similar brain concentrations, increased tissue-to-blood concentration ratios (trigeminal nerve, 14-fold; olfactory bulbs, 9-fold), and greater drug targeting efficiency to the brain (5- to 8-fold) compared to an equivalent intravenous dose. Approximately 80% of the brain exposure after intranasal administration was due to direct transport pathways from the nasal passages. Results from these studies indicated that intranasal administration targets HC to the CNS within 30 minutes of dosing, along direct pathways involving the trigeminal and olfactory nerves.;To determine if intranasal administration resulted in pharmacodynamic effects in the CNS, food consumption, water intake, and wheel running activity were monitored following intranasal administration of 100 nmol of HC. Further, HC signaling pathways were investigated to understand the molecular mechanisms underlying the behavioral effects of intranasal HC. Intranasal administration of HC increased food consumption and wheel running activity over the first four hours following dosing, but had no effect on water intake. Intranasal HC activated HC signaling pathways in the diencephalon and in the brainstem, which are brain areas involved in the regulation of appetite and locomotor activity. These findings indicate that intranasal HC reaches the CNS in its biologically active form and at concentrations sufficient to affect HC-mediated behaviors and to activate signaling pathways. To determine if a vasoconstrictor nasal formulation could enhance targeting to the CNS, drug targeting was compared 30 minutes following intranasal administration of 125I-labeled neuropeptides (HC; L-Tyr-D-Arg, D-KTP) in the presence and absence of a vasoconstrictor (phenylephrine, PHE). Results showed that intranasal administration of HC or D-KTP with 1% PHE reduced absorption into the blood, increased deposition in the olfactory epithelium, and increased delivery to the olfactory bulbs. Concentrations in the remaining brain regions and in the trigeminal nerve were reduced in the presence of the vasoconstrictor. The dramatic reduction in the blood concentrations contributed to tissue-to-blood ratios that were increased for HC throughout the brain. For D-KTP, ratios were increased in the olfactory bulbs with 1% PHE, and throughout the brain using a higher concentration of 5% PHE. Use of vasoconstrictor formulations could be used with CNS therapeutics having adverse side effects, where systemic exposure would be limited.;The key findings of this research are that intranasal administration targets neuropeptides to the CNS compared to intravenous administration, with brain concentrations that are sufficient to affect CNS-mediated behaviors and signaling pathways. Intranasal administration of HC and other neuropeptides has potential for treating CNS diseases involving the hypocretinergic system, including narcolepsy, Alzheimer's disease, and appetite disorders. In addition, use of a vasoconstrictor nasal formulation could improve intranasal treatments by reducing systemic exposure and enhancing delivery to rostral brain areas, which could be important for CNS therapeutics having adverse systemic effects.