Naratriptan Hydrochloride

Naratriptan hydrochloride is a second-generation triptan with high selectivity for serotonin 5-HT1B and 5-HT1D receptor subtypes. The drug acts at multiple sites within the trigeminovascular system to alleviate migraine pain. On cranial blood vessels, naratriptan prevents painful dilatation and constricts dilated intracranial vessels. At peripheral trigeminovascular nerve endings, the drug inhibits the release of pro-inflammatory sensory neuropeptides such as calcitonin gene-related peptide and substance P.
At the first-order synapse of the trigeminal sensory system in the trigeminal nucleus caudalis, naratriptan selectively suppresses neurotransmission from dural and vascular sensory fibers while sparing other trigeminal inputs, most likely through inhibition of neuropeptide transmitter release. In the periaqueductal gray matter and nucleus raphe magnus, naratriptan activates inhibitory neurons that project to the trigeminal nucleus and spinal cord, exerting descending inhibitory control on trigeminovascular sensory input. The drug also has a therapeutic effect on migraine-associated nausea, possibly acting at the level of the nucleus tractus solitarius.

Fig. 1 Possible sites of action of naratriptan in migraine. (Lambert G A.; et al. 2005)

Naratriptan hydrochloride was encapsulated into ethosomes using the thin film hydration method optimized by a 3² factorial design. The optimized ethosome formulation NE6 containing 3 percent soya lecithin and 50 percent ethanol exhibited vesicle size of 135 nm, zeta potential of -28.4 mV, and entrapment efficiency of 78.6 percent. The ethosomes were incorporated into poloxamer 407 and carbopol 934-based thermoreversible in situ gels. The in situ gels exhibited gelation at nasal temperature, sustained drug release for 24 hours, and improved ex vivo nasal permeation. Histopathology confirmed no damage to nasal mucosa. This ethosomal in situ gel system enables direct nose-to-brain delivery of naratriptan with enhanced bioavailability for acute migraine treatment.

Fig. 2 Overlay plot showing the working space for optimization of the ethosomes. (Shelke S.; et al. 2020)