Intranasal Delivery of Cetrorelix Via Lipid Liquid Crystal Nanoparticles: Characterization and Pharmacokinetic Studies in Rats

Abstract

Nasal sprays are extensively researched due to their rapid absorption, high bioavailability, and low side effects. Lipid liquid crystal nanoparticles (LLCNs) are being considered as potential carriers for intranasal delivery. LLCs loaded with cetrorelix (GnRH antagonist) were utilized for intranasal drug delivery to enhance brain targeting while minimizing systemic exposure. A single-phase formulation incorporating HPMC as a mucoadhesive was developed to extend nasal residence time. Following intranasal administration of cetrorelix in rats, its distribution in various brain regions and serum was assessed using LC–MS-MS. In the LLC formulation, the particle diameter, PDI, and Zeta potential were measured as 204.92 ± 0.89 nm, 0.188 ± 0.019, and -21.63 ± 1.72 mV, respectively. A monomodal distribution and low polydispersity index were observed, along with a negative zeta potential. Cetrorelix was released from the LLC in a biphasic profile, with an initial burst release of 30%, followed by a gradual and sustained release phase.

The LLCs containing cetrorelix exhibited lower cytotoxicity compared to the LLC base. The nasal administration of cetrorelix via LLCs presents a promising advancement for nose-to-brain drug transport. The pharmacokinetic data demonstrated that the AUC_0-360min for brain tissue analysis, following nasal administration of the single-phase formulation, was 3.104 ng/ml.min. The value was 7.104 ng/ml.min for LLC nasal administration and 6.104 ng/ml.min for subcutaneous injection. The maximum concentration (C_max) values for brain tissue analysis indicated a significant increase with LLC nasal administration (238 ± 6. 2 ng/ml) in comparison to the single-phase formulation (202.5 ± 6.3 ng/ml) and subcutaneous injection (218.2 ± 3. 1 ng/ml). In serum analysis, the C_max values were significantly elevated, with subcutaneous injection achieving (4983.3 ± 2.5 ng/ml), followed by LLC nasal administration at (93.1 ± 6.2 ng/ml), and the single-phase formulation at (43.7 ± 2.2 ng/ml).

This innovative method aims to target the brain directly, eliminating the need for needles, and reducing adverse effects, hence offering new hope for brain-targeted drug delivery. This study introduces, for the first time, a cetrorelix-loaded lipid liquid crystal (LLC) nanoparticle formulation for intranasal nose-to-brain delivery. The LLC system achieved enhanced brain targeting efficiency while reducing systemic exposure compared to conventional subcutaneous injections and simple nasal formulations, representing a promising advancement in GnRH drug delivery strategies.

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Materials

Cetrorelix was supplied by Tofigh Daru, located in Karaj, Iran. The cetrorelix standard was obtained from Sigma (USA)., Pluronic-F127, phosphoric acid, 3-(4,5-dimethylthiazol-2-yl)−2,5-diphenyltetrazolium bromide (MTT), hydroxypropyl methylcellulose, benzalkonium chloride, glycerol monooleate (GMO), and dextran 70, all were sourced from Sigma-Aldrich (Darmstadt, Germany). HPLC-grade methanol and acetonitrile were acquired from DAEJUNG (Siheung-si, South Korea). DMEM high glucose medium, fetal bovine serum (FBS), and penicillin/streptomycin were procured from Gibco (Inchinnan, UK).

Tafazzoli Mehrjardi, S., Tafaghodi, M., Malek, S. et al. Intranasal Delivery of Cetrorelix Via Lipid Liquid Crystal Nanoparticles: Characterization and Pharmacokinetic Studies in Rats. AAPS PharmSciTech 26, 176 (2025). https://doi.org/10.1208/s12249-025-03169-6