DefinePK

Abstract

This study introduces the design and complete assessment of a thermosensitive in situ nasal gel of Zolmitriptan, which was created to improve the drug delivery effectiveness in the acute treatment of migraine attacks. Zolmitriptan is a highly active serotonin (5-HT₁B/₁D) receptor agonist used effectively for migraine therapy but has poor oral bioavailability (~40%) with extensive hepatic first-pass metabolism and gastric motility problems during migraine attacks, causing delay in drug absorption. To counter these disadvantages and allow for swift onset of action, a new nasal delivery system was developed based on thermoresponsive and mucoadhesive polymers. The gel formulations were developed using the cold method from a series of combinations of Poloxamer 407 (20% w/v) and Poloxamer 188 (10% w/v) due to their temperature-dependent sol-gel transition characteristics. Mucoadhesiveness and increasing nasal residence time were imparted using Chitosan (0.75% w/v) and HPMC K15M (1% w/v). Zolmitriptan was complexed with Hydroxypropyl-β-cyclodextrin (HP-β-CD) in varying molar ratios (1:1, 1:2, 1:3) to improve its aqueous solubility and stability, the complex being validated through FTIR and DSC studies. Among the four developed formulations (F1–F4), Formulation F4 stood out as optimized, showing optimum gelation temperature (31.2 ± 0.3°C) consistent with nasal mucosal temperature, quick gelation time (32 ± 2 seconds), good mucoadhesive strength (1250 ± 35 dyne/cm²), and appropriate viscosity (1850 ± 50 cP). The drug content was within limiting values (99.12 ± 1.08%), with even distribution and fine clarity (Grade 0). Rheological analysis validated pseudoplastic, thixotropic properties required for good sprayability and mucosal spreading. Sprayability testing revealed reproducible round spray patterns with actuation volumes in the optimal range (0.05–0.1 mL). The in vitro gelation experiment proved that the optimized gel formulation gelled immediately on contact with simulated nasal fluid (SNF) and lasted for more than an hour. The accelerated stability testing as per ICH Q1A(R2) at 40°C/75% RH for 3 months showed no appreciable changes in pH, viscosity, drug content, or gelation parameters. The sterility tests also showed that the formulation was as per pharmacopeial requirement and free from microbial impurities. The optimized thermosensitive nasal gel formulation of Zolmitriptan not only provides rapid onset of therapeutic action, improved bioavailability, and a decreased chance of systemic side effects, but also presents a non-invasive, patient-compliant, and economically viable alternative to traditional oral or parenteral migraine treatments. This innovative platform presents important potential for use in central nervous system (CNS) drug delivery, particularly for drugs that are in need of swift systemic absorption through the nasal mucosa.