PP> Vol.2 No.3, July 2011

Intranasal Delivery of Two Benzodiazepines, Midazolam and Diazepam, by a Microemulsion System

DownloadDownload as PDF (Size:541KB)  HTML    PP. 180-188  

ABSTRACT

Nasal application of benzodiazepines might be an alternative to intravenous administration in acute clinical situations such as seizures emergencies. However, irritation and pain as well as symptoms like teary eyes, dizziness, discomfort, nasal drainage and bad taste usually accompany subject received midazolam and diazepam via the nasal route. The purpose of this study was to evaluate the use of a new alcohol-free microemulsion system as a carrier for diazepam or midazolam given intranasally. Midazolam (base) or diazepam was solubilized in the microemulsion to obtain a high drug concentration of 25 mg/g (2.5% by weight), to provide 2.5 mg drug in 100 µl spray (d ≈ 1.00 g/ml). The nasal absorption of both drugs from the same microemulsion formulation (containing 20% aqueous phase) was found to be fairly rapid after administration of 0.4 mg/kg to rabbits. The absolute bioavailability of diazepam after intranasal administration using this formulation was 33.45% ± 12.36% and the tmax was 18.33 ± 23.09 min, which was twice longer than the tmax obtained after midazolam administration, 9.25 ± 6.75 min. The pharmacokinetic parameters of midazolam in W/O (20% water) microemulsion and their comparison with midazolam in O/W (50% water) microemulsion have shown that both formulations resulted in a relatively short time to reach the peak plasma level (tmax), that is, 9.25 ± 6.75 min and 6.75 ± 5.67 min, respectively. However, the peak plasma levels (Cmax) and the absolute bioavailability (FA) of midazolam were significantly higher after administration of the W/O formulation than those obtained after application of O/W formulation, i.e., 46.62 ± 17.38 µg/ml vs. 15.44 ± 4.00 µg/ml, and 35.19% ± 11.83% vs. 19.83% ± 16.32%, respectively. Our results suggest that the new microemulsion system may be useful for getting rapid-onset of midazolam and diazepam following intranasal administration, resulting in reasonable peak plasma levels and bioavailability, but most importantly, providing a high measure of tolerability and comfort.

Cite this paper

S. Botner and A. Sintov, "Intranasal Delivery of Two Benzodiazepines, Midazolam and Diazepam, by a Microemulsion System," Pharmacology & Pharmacy, Vol. 2 No. 3, 2011, pp. 180-188. doi: 10.4236/pp.2011.23026.

References

[1] J. McMullan, C. Sasson, A. Pancioli and R. Silbergleit, “Midazolam versus diazepam for the treatment of status epilepticus in children and young adults: a meta-analy- sis,” Academic Emergency Medicine, vol. 17, no. 6, June 2010, pp. 575-582.
[2] C. Campo-Soria, Y. Chang and D. S. Weiss, “Mechanism of action of benzodiazepines on GABAA receptors. Brit- ish Journal of Pharmacology,” vol. 148, no. 7, August 2006, pp. 984-990.
[3] E. Costa, A. Guidotti and C. C. Mao, “Evidence for in- volvement of GABA in the action of benzodiazepines: studies on rat cerebellum,” In: E. Costa and P. Greengard, Eds., Mechanism of Action of Benzodiazepines, Raven Press, New York, 1975, pp. 113-130.
[4] W. Haefely, A. Kulcsar and H. Moehler, “Possible in- volvement of GABA in the central actions of benzodi- azepines,” Psychopharmacological Bulletin, vol. 11, no. 4, October 1975, pp. 58-59.
[5] G. J. de Haan, P. van der Geest, G. Doelman, E. Bertram and P. Edelbroek, “A comparison of midazolam nasal spray and diazepam rectal solution for the residential treatment of seizure exacerbations,” Epilepsia, vol. 51, no. 3, March 2010, pp. 478-482.
[6] B. K. Alldredge, A. M. Gelb, S. M. Isaacs, M. D. Corry, F. Allen, S. Ulrich, M. D. Gottwald, N. O'Neil, J. M. Neuhaus, M. R. Segal and D. H. Lowenstein, “A com- parison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus,” New England Journal of Medicine, vol. 345, no. 9, August 2001, pp. 631-637.
[7] V. D. Ivaturi, J. R. Riss, R. L. Kriel and J. C. Cloyd, “Pharmacokinetics and tolerability of intranasal diazepam and midazolam in healthy adult volunteers,” Acta Neu- rologica Scandinavica, vol. 120, no. 5, November 2009, pp. 353-357.
[8] C. O'Dell, S. Shinnar, K. R. Ballaban-Gil, M. Hornick, M. Sigalova, H. Kang and S. L. Moshe, “Rectal diazepam gel in the home management of seizures in children,” Pe- diatric Neurology, vol. 33, no. 3, September 2005, pp. 166-172.
[9] P. Mittal, R. Manohar and A. Rawat, “Comparative study of intranasal midazolam and intravenous diazepam seda- tion for procedures and seizures,” Indian Journal of Pedi- atrics, vol. 73, no. 11, November 2006, pp. 975-978.
[10] E. Lahat, M. Goldman, J. Barr, T. Bistritzer and M. Berkovitch, “Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in chil- dren: prospective randomised study,” BMJ, vol. 321, no. 7253, July 2000, pp. 83-86.
[11] M. Scheepers, B. Scheepers, M. Clarke, S. Comish and M. Ibitoye. “Is intranasal midazolam an effective rescue me- dication in adolescents and adults with severe epilepsy?” Seizure, vol. 9, no. 6, September 2000, pp. 417-422.
[12] V. D. Ivaturi, J. R. Riss, R. L. Kriel, R. A. Siegel and J. C. Cloyd, “Bioavailability and tolerability of intranasal di- azepam in healthy adult volunteers,” Epilepsy Research, vol. 84, no. 2-3, April 2009, pp. 120-126.
[13] S. Gizurarson, F. K. Gudbrandsson, H. Jonsson and E. Bechgaard, “Intranasal administration of diazepam aim- ing at the treatment of acute seizures: clinical trials in healthy volunteers,” Biological & Pharmaceutical Bulle- tin, vol. 22, no. 4, April 1999, pp. 425-427.
[14] E. Bechgaard, S. Gizurarson and R. K. Hjortkjaer, “Pharmacokinetic and pharmacodynamic response after intranasal administration of diazepam to rabbits,” Journal of Pharmacy and Pharmacology, vol. 49, no. 8, August 1997, pp. 747-750.
[15] L. Li, S. Gorukanti, Y.M. Choi and K.H. Kim, “Rapid- onset intranasal delivery of anticonvulsants: pharma- cokinetic and pharmacodynamic evaluation in rabbits,” International Journal of Pharmaceutics, vol. 199, no. 1, April 2000, pp. 65-76.
[16] K. Lindhardt, S. Gizurarson, S. B. Stefansson, D. R. Olafsson and E. Bechgaard, “Electroencephalographic effects and serum concentrations after intranasal and in- travenous administration of diazepam to healthy volun- teers,” British Journal of Clinical Pharmacology, vol. 52, no. 5, November 2001, pp. 521-527.
[17] D. P. Wermeling, K. A. Record, T. H. Kelly, S. M. Archer, T. Clinch and A. C. Rudy, “Pharmacokinetics and pharmacodynamics of a new intranasal midazolam formulation in healthy volunteers,” Anesthesia & Anal- gesia, vol. 103, no. 2, August 2006, pp. 344-349.
[18] Z. N. Kain, L. C. Mayes, C. Bell, S. Weisman, M. B. Hofstadter and S. Rimar, “Premedication in the United States: a status report,” Anesthesia & Analgesia, vol. 84, no. 2, February 1997, pp. 427-432.
[19] M. I. Ugwoke, R. U. Agu, N. Verbeke and R. Kinget, “Nasal mucoadhesive drug delivery: background, appli- cations, trends and future perspectives,” Advanced Drug Delivery Reviews, vol. 57, no. 11, November 2005, pp. 1640-1665.
[20] M. Bhattacharyya, V. Kalra and S. Gulati, “Intranasal midazolam vs rectal diazepam in acute childhood sei- zures,” Pediatric Neurology, vol. 34, no. 5, May 2006, pp. 355-359.
[21] P. D. Knoester, D. M. Jonker, R. T. Van Der Hoeven, T. A. Vermeij, P. M. Edelbroek, G. J. Brekelmans and G. J. de Haan, “Pharmacokinetics and pharmacodynamics of midazolam administered as a concentrated intranasal spray. A study in healthy volunteers,” British Journal of Clinical Pharmacology, vol. 53, no. 5, May 2002, pp. 501-507.
[22] S. Bjorkman, G. Rigemar and J. Idvall, “Pharmacokinet- ics of midazolam given as an intranasal spray to adult surgical patients,” British Journal of Anaesthesia, vol. 79, no. 5, November 1997, pp. 575-580.
[23] M. Holsti, B. L. Sill, S. D. Firth, F. M. Filloux, S. M. Joyce and R. A. Furnival, “Prehospital intranasal mida- zolam for the treatment of pediatric seizures,” Pediatric Emergency Care, vol. 23, no. 3, March 2007, pp. 148- 153.
[24] S. W. Provencher, “CONTIN: a general purpose con- strained regularization program for inverting noisy linear algebraic and integral equations,” Computer Physics Communications, vol. 27, no. 3, September 1982, pp. 229-242.
[25] A. C. Sintov, H. V. Levy and S. Botner, “Systemic deliv- ery of insulin via the nasal route using a new microemul- sion system: in vitro and in vivo studies,” Journal of Controlled Release, vol 148, no. 2, December 2010, pp. 168-176.
[26] M. Haschke, K. Suter, S. Hofmann, R. Witschi, J. Froh- lich, G. Imanidis, J. Drewe, T. A. Briellmann, F. E. Dussy, S. Krahenbuhl and C. Surber, “Pharmacokinetics and pharmacodynamics of nasally delivered midazolam,” British Journal of Clinical Pharmacology, vol. 69, no. 6, June 2010, pp. 607-616.
[27] A. Hoogerkamp, R. H. G. P. Arends, A. M. Bomers, J. W. Mandema, R. A. Voskuyl and M. Danhof, “Pharmacoki- netic/pharmacodynamic relationship of benzodiazepines in the direct cortical stimulation model of anticonvulsant effect,” The Journal of Pharmacology and Experimental Therapeutics, vol. 279, no. 2, November 1996, pp. 803- 812.
[28] L. Li, I. Nandi and K. H. Kim, “Development of an ethyl laurate-based microemulsion for rapid-onset intranasal delivery of diazepam,” International Journal of Pharma- ceutics, vol. 237, no. 1-2, April 2002, pp. 77-85.
[29] P. Kaur and K. Kim, “HPharmacokinetics and brain uptake of diazepam after intravenous and intranasal administra- tion in rats and rabbits,”H International Journal of Pharma- ceutics, vol. 364, no. 1, November 2008, pp. 27-35.
[30] S. Porecha, T. Shah, V. Jogani, S. Naik and A. Misra, “HMicroemulsion based intranasal delivery system for treatment of insomnia,”H Drug Delivery, vol. 16, no. 3, April 2009, pp. 128-134.
[31] K. Lindhardt, D. R. Olafsson, S. Gizurarson and E. Bechgaard, “Intranasal bioavailability of diazepam in sheep correlated to rabbit and man,” International Journal of Pharmaceutics, vol. 231, no. 1, January 2002, pp. 67- 72.

  
comments powered by Disqus

Copyright © 2014 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.