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Pharmacokinetic Characterization of Tizanidine Nasal Spray, a Novel Intranasal Delivery Method for the Treatment of Skeletal Muscle Spasm

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Abstract

Background and Objective

The skeletal muscle relaxant tizanidine is approved by the US FDA and the European Medicines Agency for treating spasticity and is supplied as tablets for oral administration. However, tizanidine has a poor bioavailability, due to extensive first-pass metabolism. Therefore, the nasal route of administration, which bypasses portal circulation, may increase the bioavailability of tizanidine and, possibly, reduce the time to peak plasma concentration, thereby shorting the latency of therapeutic effect. The objective of this study was to evaluate the pharmacokinetic profile of tizanidine nasal spray and compare it to the profile of tizanidine oral tablets.

Methods

This open-label, phase I study comprised two protocols: protocol 1, tizanidine HCl solution (32.73 mg/mL) intranasally at single doses of 2 and 4 mg versus 4 mg tizanidine oral tablets (randomized, three periods crossover, 12 healthy subjects); and protocol 2, tizanidine HCl solution (16.36 mg/mL) intranasally at a single dose of 1 mg vs. 4 mg tizanidine oral tablets (randomized, two periods crossover, 12 healthy subjects, one dropout). Tizanidine plasma concentrations were determined by liquid chromatography/mass spectrometry.

Results

There was a linear relationship between different dosages of intranasal formulation and the area under the concentration–time curve and maximum plasma concentration (C max). The relative bioavailability of the different dosages of intranasal formulation were 1.29, 1.93, and 4.23 for 1, 2, and 4 mg intranasal administration, respectively. Comparison of C max values gave the following ratios: 0.91, 1.39, and 2.73, for 1, 2, and 4 mg intranasal administration, respectively. The mean time to C max (t max) was 0.99, 0.43, and 0.63 h for 1, 2, and 4 mg intranasal administration, respectively, whereas it was 1.13 and 1.30 h for the two series of 4 mg tizanidine oral tablets.

Conclusions

The bioavailability of the tizanidine intranasal formulation was higher than that of tizanidine oral tablets. The t max was also shorter with the intranasal formulation. No serious adverse events occurred throughout the study, such that the two formulations resulted equally well-tolerated. The intranasal formulation of tizanidine results are therefore worthy of subsequent clinical testing in phase II.

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Acknowledgments

This study was supported by MDM SpA. The authors do not have any conflict of interest to disclose.

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Authors and Affiliations

  1. Pharmacokinetic Unit, Unifarm Research Center, Catania, Italy

    Daniela Cristina Vitale, Cateno Piazza, Tiziana Sinagra, Vincenzo Urso & Salvatore Salomone

  2. Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, Catania University, Viale A. Doria 6, 95125, Catania, Italy

    Tiziana Sinagra, Vincenzo Urso, Filippo Drago & Salvatore Salomone

  3. Polyclinic Vittorio Emanuele, University of Catania, Catania, Italy

    Francesco Cardì

Authors
  1. Daniela Cristina Vitale
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  2. Cateno Piazza
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Correspondence to Salvatore Salomone.

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Vitale, D.C., Piazza, C., Sinagra, T. et al. Pharmacokinetic Characterization of Tizanidine Nasal Spray, a Novel Intranasal Delivery Method for the Treatment of Skeletal Muscle Spasm. Clin Drug Investig 33, 885–891 (2013). https://doi.org/10.1007/s40261-013-0137-2

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  • DOI: https://doi.org/10.1007/s40261-013-0137-2

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