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Clinical Study Shows Improved Absorption of Desmopressin with Novel Formulation

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Abstract

Purpose

To create improved pharmaceutical formulations for nasal and sublingual administration of desmopressin and investigate their pharmacokinetic profiles in comparison with a commercial nasal liquid spray and finally to evaluate the volunteers’ opinions on the different dosage forms.

Methods

Both formulations were based on the characteristics of interactive mixtures. The nasal powder spray was produced by a rotary evaporator technique with sodium starch glycolate as carrier material and the sublingual tablet by direct compression after dry mixing with mannitol as carrier. The clinical study was an open-label, randomised cross-over pharmacokinetic study in healthy volunteers.

Results

The nasal powder formulation gave a threefold increase in the absorption, unaltered time to maximum plasma concentration and a tendency to lower variability in the amount absorbed compared with the liquid spray. The powder was reported to be more irritating than the liquid but was still well accepted by the volunteers. The tablet did not improve the uptake of desmopressin, likely because of a poor disintegration sublingually.

Conclusions

The nasal powder formulation is a promising new dosage form for the delivery of desmopressin and other compounds. The sublingual tablet has a beneficial means of production and may be further developed by decreasing its disintegration time.

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References

  1. D. Harris, and J. R. Robinson. Drug delivery via the mucous membranes of the oral cavity. J. Pharm. Sci. 81:1–10 (1992) doi:10.1002/jps.2600810102.

    Article  PubMed  CAS  Google Scholar 

  2. A. Yamamoto, T. Iseki, M. Ochi-Sugiyama, N. Okada, T. Fujita, and S. Muranishi. Absorption of water-soluble compounds with different molecular weights and [Asu1.7]-eel calcitonin from various mucosal administration sites. J. Control Release. 76:363–374 (2001) doi:10.1016/S0168-3659(01)00454-0.

    Article  PubMed  CAS  Google Scholar 

  3. C. Joukhadar, B. Schenk, S. T. Kaehler, C. J. Kollenz, P. Bauer, M. Muller, and H. G. Eichler. A replicate study design for testing bioequivalence: a case study on two desmopressin nasal spray preparations. Eur. J. Clin. Pharmacol. 59:631–636 (2003) doi:10.1007/s00228-003-0682-3.

    Article  PubMed  CAS  Google Scholar 

  4. N. Eller, C. J. Kollenz, and G. Hitzenberger. A comparative study of pharmacodynamics and bioavailability of 2 different desmopressin nasal sprays. Int. J. Clin. Pharmacol. Ther. 36:139–145 (1998).

    PubMed  CAS  Google Scholar 

  5. S. T. Kaehler, I. M. Steiner, R. Sauermann, H. Scheidl, M. Mueller, and C. Joukhadar. A bioequivalence study of two oral desmopressin tablet formulations. Pharmacology. 77:46–52 (2006) doi:10.1159/000092625.

    Article  PubMed  CAS  Google Scholar 

  6. A. S. Harris, M. Ohlin, S. Lethagen, and I. M. Nilsson. Effects of concentration and volume on nasal bioavailability and biological response to desmopressin. J. Pharm. Sci. 77:337–339 (1988) doi:10.1002/jps.2600770412.

    Article  PubMed  CAS  Google Scholar 

  7. S. Bredenberg, M. Duberg, B. Lennernas, H. Lennernas, A. Pettersson, M. Westerberg, and C. Nystrom. In vitro and in vivo evaluation of a new sublingual tablet system for rapid oromucosal absorption using fentanyl citrate as the active substance. Eur. J. Pharm. Sci. 20:327–334 (2003) doi:10.1016/j.ejps.2003.07.002.

    Article  PubMed  CAS  Google Scholar 

  8. L. Li, N. R. Mathias, C. L. Heran, P. Moench, D. A. Wall, and R. L. Smith. Carbopol-mediated paracellular transport enhancement in Calu-3 cell layers. J. Pharm. Sci. 95:326–335 (2006) doi:10.1002/jps.20541.

    Article  PubMed  CAS  Google Scholar 

  9. H. L. Luessen, B. J. de Leeuw, M. W. Langemeyer, A. B. de Boer, J. C. Verhoef, and H. E. Junginger. Mucoadhesive polymers in peroral peptide drug delivery. VI. Carbomer and chitosan improve the intestinal absorption of the peptide drug buserelin in vivo. Pharm. Res. 13:1668–1672 (1996) doi:10.1023/A:1016488623022.

    Article  PubMed  CAS  Google Scholar 

  10. L. Illum, H. Jorgensen, H. Bisgaard, O. Krogsgaard, and N. Rossing. Bioadhesive microspheres as a potential nasal drug delivery system. Int. J. Pharm. 39:189–199 (1987) doi:10.1016/0378-5173(87)90216-X.

    Article  CAS  Google Scholar 

  11. C. Callens, and J. P. Remon. Evaluation of starch–maltodextrin–Carbopol 974 P mixtures for the nasal delivery of insulin in rabbits. J. Control Release. 66:215–220 (2000) doi:10.1016/S0168-3659(99)00271-0.

    Article  PubMed  CAS  Google Scholar 

  12. E. Björk, U. Isaksson, P. Edman, and P. Artursson. Starch microspheres induce pulsatile delivery of drugs and peptides across the epithelial barrier by reversible separation of the tight junctions. J. Drug Target. 2:501–507 (1995) doi:10.3109/10611869509015920.

    Article  PubMed  Google Scholar 

  13. T. Nagai, Y. Nishimoto, N. Nambu, Y. Suzuki, and K. Sekine. Powder dosage form of insulin for nasal administration. J. Control Release. 1:15–22 (1984) doi:10.1016/0168-3659(84)90017-8.

    Article  CAS  Google Scholar 

  14. A. M. Dyer, M. Hinchcliffe, P. Watts, J. Castile, I. Jabbal-Gill, R. Nankervis, A. Smith, and L. Illum. Nasal delivery of insulin using novel chitosan based formulations: a comparative study in two animal models between simple chitosan formulations and chitosan nanoparticles. Pharm. Res. 19:998–1008 (2002) doi:10.1023/A:1016418523014.

    Article  PubMed  CAS  Google Scholar 

  15. N. Vivien, P. Buri, L. Balant, and S. Lacroix. Nasal absorption of metoclopramide administered to man. Eur. J. Pharm. Biopharm. 40:228–231 (1994).

    CAS  Google Scholar 

  16. R. J. Soane, M. Frier, A. C. Perkins, N. S. Jones, S. S. Davis, and L. Illum. Evaluation of the clearance characteristics of bioadhesive systems in humans. Int. J. Pharm. 178:55–65 (1999) doi:10.1016/S0378-5173(98)00367-6.

    Article  PubMed  CAS  Google Scholar 

  17. F. W. Merkus, J. C. Verhoef, N. G. Schipper, and E. Marttin. Nasal mucociliary clearance as a factor in nasal drug delivery. Adv. Drug Deliv. Rev. 29:13–38 (1998) doi:10.1016/S0169-409X(97)00059-8.

    Article  PubMed  Google Scholar 

  18. C. Callens, E. Adriaens, K. Dierckens, and J. P. Remon. Toxicological evaluation of a bioadhesive nasal powder containing a starch and Carbopol 974 P on rabbit nasal mucosa and slug mucosa. J. Control Release. 76:81–91 (2001) doi:10.1016/S0168-3659(01)00419-9.

    Article  PubMed  CAS  Google Scholar 

  19. Y. W. Chien, K. S. E. Su, and S.-F. Chang. Nasal systemic drug delivery. Marcel Dekker, New York, 1989.

    Google Scholar 

  20. R. C. Rowe, P. J. Sheskey, and S. C. Owen. Handbook of pharmaceutical excipients. 5Pharmaceutical Press, Somerset, UK, 2006, pp. 701–704.

    Google Scholar 

  21. N. Fransén, E. Björk, and K. Edsman. Changes in the mucoadhesion of powder formulations after drug application investigated with a simplified method. J. Pharm. Sci.(2008).

  22. N. Fransén, E. Björk, and C. Nyström. Development and characterisation of interactive mixtures with a fine-particulate mucoadhesive carrier for nasal drug delivery. Eur. J. Pharm. Biopharm. 67:370–376 (2007) doi:10.1016/j.ejpb.2007.03.006.

    Article  PubMed  CAS  Google Scholar 

  23. L. Pereswetoff-Morath, and P. Edman. Dextran microspheres as a potential nasal drug delivery system for insulin—in vitro and in vivo properties. Int. J. Pharm. 124:37–44 (1995) doi:10.1016/0378-5173(95)00070-Y.

    Article  CAS  Google Scholar 

  24. J. A. Hersey. Ordered mixing: a new concept in powder mixing practice. Powder Technol. 11:41–44 (1975) doi:10.1016/0032-5910(75)80021-0.

    Article  Google Scholar 

  25. S. Lundin, P. Melin, and H. Vilhardt. Plasma concentrations of 1-deamino-8-D-arginine vasopressin after intragastric administration in the rat. Acta Endocrinol. (Copenh). 108:179–183 (1985).

    CAS  Google Scholar 

  26. R. C. Lewontin. On the measurement of relative variability. Syst. Zool. 15:141–142 (1966) doi:10.2307/2411632.

    Article  Google Scholar 

  27. M. Kohler, and A. Harris. Pharmacokinetics and haematological effects of desmopressin. Eur. J. Clin. Pharmacol. 35:281–285 (1988) doi:10.1007/BF00558266.

    Article  PubMed  CAS  Google Scholar 

  28. A. Fjellestad-Paulsen, L. d'Agay-Abensour, P. Hoglund, and J. C. Rambaud. Bioavailability of 1-deamino-8-D-arginine vasopressin with an enzyme inhibitor (aprotinin) from the small intestine in healthy volunteers. Eur. J. Clin. Pharmacol. 50:491–495 (1996) doi:10.1007/s002280050146.

    Article  PubMed  CAS  Google Scholar 

  29. H. Vilhardt, and S. Lundin. Biological effect and plasma concentrations of DDAVP after intranasal and peroral administration to humans. Gen. Pharmacol. 17:481–483 (1986) doi:10.1016/0306-3623(86)90198-9.

    PubMed  CAS  Google Scholar 

  30. A. S. Harris, M. Ohlin, E. Svensson, S. Lethagen, and I. M. Nilsson. Effect of viscosity on the pharmacokinetics and biological response to intranasal desmopressin. J. Pharm. Sci. 78:470–471 (1989) doi:10.1002/jps.2600780610.

    Article  PubMed  CAS  Google Scholar 

  31. A. S. Harris, E. Svensson, Z. G. Wagner, S. Lethagen, and I. M. Nilsson. Effect of viscosity on particle size, deposition, and clearance of nasal delivery systems containing desmopressin. J. Pharm. Sci. 77:405–408 (1988) doi:10.1002/jps.2600770510.

    Article  PubMed  CAS  Google Scholar 

  32. D. Teshima, A. Yamauchi, K. Makino, Y. Kataoka, Y. Arita, H. Nawata, and R. Oishi. Nasal glucagon delivery using microcrystalline cellulose in healthy volunteers. Int. J. Pharm. 233:61–66 (2002) doi:10.1016/S0378-5173(01)00930-9.

    Article  PubMed  CAS  Google Scholar 

  33. R. Ryan, A. Elkind, C. C. Baker, W. Mullican, S. DeBussey, and M. Asgharnejad. Sumatriptan nasal spray for the acute treatment of migraine. Results of two clinical studies. Neurology. 49:1225–1230 (1997).

    PubMed  CAS  Google Scholar 

  34. I. M. Steiner, S. T. Kaehler, R. Sauermann, H. Rinosl, M. Muller, and C. Joukhadar. Plasma pharmacokinetics of desmopressin following sublingual administration: an exploratory dose-escalation study in healthy male volunteers. Int. J. Clin. Pharmacol. Ther. 44:172–179 (2006).

    PubMed  CAS  Google Scholar 

  35. O. Osterberg, R. M. Savic, M. O. Karlsson, U. S. Simonsson, J. P. Norgaard, J. V. Walle, and H. Agerso. Pharmacokinetics of desmopressin administrated as an oral lyophilisate dosage form in children with primary nocturnal enuresis and healthy adults. J. Clin. Pharmacol. 46:1204–1211 (2006) doi:10.1177/0091270006291838.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

Orexo AB is gratefully acknowledged for financial support. The devoted work of the whole project team is thankfully recognised.

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Authors and Affiliations

  1. Department of Pharmacy, Uppsala University, P.O. Box 580, 751 23, Uppsala, Sweden

    Nelly Fransén & Erik Björk

  2. Orexo AB, Virdings Allé 32A, P.O. Box 303, 75105, Uppsala, Sweden

    Susanne Bredenberg

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  1. Nelly Fransén
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Correspondence to Erik Björk.

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Fransén, N., Bredenberg, S. & Björk, E. Clinical Study Shows Improved Absorption of Desmopressin with Novel Formulation. Pharm Res 26, 1618–1625 (2009). https://doi.org/10.1007/s11095-009-9871-9

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  • DOI: https://doi.org/10.1007/s11095-009-9871-9

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