Pharmaceutical Research

, Volume 30, Issue 12, pp 3101–3113 | Cite as

Bioavailability of Cinnarizine in Dogs: Effect of SNEDDS Loading Level and Correlation with Cinnarizine Solubilization During In Vitro Lipolysis

  • Anne T. Larsen
  • Pernilla Åkesson
  • Anna Juréus
  • Lasse Saaby
  • Ragheb Abu-Rmaileh
  • Bertil Abrahamsson
  • Jesper Østergaard
  • Anette Müllertz
Research Paper



To investigate the effect of increasing the loading level of the poorly soluble drug cinnarizine in a self-nanoemulsifying drug delivery system (SNEDDS) both in vitro and in vivo.


A fixed dose of cinnarizine was administered orally to dogs in solution in different amounts of SNEDDS vehicle. Furthermore, the SNEDDSs were characterised using the dynamic in vitro lipolysis model.


Statistical differences in bioavailability were not obtained between the different amounts of SNEDDS vehicle, in spite of differences in the tendency of cinnarizine to precipitate during in vitro lipolysis of the treatments. Use of the SNEDDS concept decreased the variation in cinnarizine exposure observed between dogs as compared to administering cinnarizine in an aqueous suspension.


Optimization of SNEDDSs towards keeping the drug compound in solution upon in vitro lipolysis of the SNEDDSs may not be as important as previously suggested.


bioavailability cinnarizine lipolysis oral drug delivery self-nanoemulsifying drug delivery systems 



Cytochrome P450


Phosphatidyl Choline


Simulated Intestinal Media


Self-Nanoemulsifying Drug Delivery System


Single Nucleotide Polymorphism


Sodium Taurocholate



Anne T. Larsen is thankful to AstraZeneca Pharmaceuticals (Sweden and UK) for financial and experimental support. Freja Jacobsen is greatly acknowledged for her contribution to determining the cinnarizine solubility in SIM and Anja G. Ohlsson is acknowledged for collaboration on the in vitro lipolysis experiments.

Supplementary material

11095_2013_1145_MOESM1_ESM.docx (73 kb)
ESM 1 (DOCX 73 kb)


  1. 1.
    Attivi D, Ajana I, Astier A, Demore B, Gibaud S. Development of microemulsion of mitotane for improvement of oral bioavailability. Drug Dev Ind Pharm. 2010;36:421–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Dixit AR, Rajput SJ, Patel SG. Preparation and bioavailability assessment of SMEDDS containing valsartan. AAPS PharmSciTech. 2010;11:314–21.PubMedCrossRefGoogle Scholar
  3. 3.
    Shafiq S, Shakeel F, Talegaonkar S, Ahmad FJ, Khar RK, Ali M. Design and development of oral oil in water ramipril nanoemulsion formulation: in vitro and in vivo assessment. J Biomed Nanotechnol. 2007;3:28–44.CrossRefGoogle Scholar
  4. 4.
    Larsen AT, Ogbonna A, Abu-Rmaileh R, Abrahamsson B, Østergaard J, Mullertz A. SNEDDS containing poorly water soluble cinnarizine; development and in vitro characterization of dispersion, digestion and solubilization. Pharmaceutics. 2012;4:641–65.CrossRefGoogle Scholar
  5. 5.
    Larsen AT, Ohlsson AG, Polentarutti B, Barker RA, Phillips AR, Abu-Rmaileh R, et al. Oral bioavailability of cinnarizine in dogs: relation to SNEDDS droplet size, drug solubility and in vitro precipitation. Eur J Pharm Sci. 2013;48:339–50.PubMedCrossRefGoogle Scholar
  6. 6.
    Date AA, Nagarsenker MS. Design and evaluation of self-nanoemulsifying drug delivery systems (SNEDDS) for cefpodoxime proxetil. Int J Pharm. 2007;329:166–72.PubMedCrossRefGoogle Scholar
  7. 7.
    Date AA, Desai N, Dixit R, Nagarsenker M. Self-nanoemulsifying drug delivery systems: formulation insights, applications and advances. Nanomedicine. 2010;5:1595–616.PubMedCrossRefGoogle Scholar
  8. 8.
    Marasini N, Yan YD, Poudel BK, Choi HG, Yong CS, Kim JO. Development and optimization of self-nanoemulsifying drug delivery system with enhanced bioavailability by Box-Behnken design and desirability function. J Pharm Sci. 2012;101:4584–96.PubMedCrossRefGoogle Scholar
  9. 9.
    Holm R, Tonsberg H, Jorgensen EB, Abedinpour P, Farsad S, Mullertz A. Influence of bile on the absorption of halofantrine from lipid-based formulations. Eur J Pharm Biopharm. 2012;81:281–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Thomas N, Holm R, Mullertz A, Rades T. In vitro and in vivo performance of novel supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS). J Control Release. 2012;160:25–32.PubMedCrossRefGoogle Scholar
  11. 11.
    Thomas N, Holm R, Garmer M, Karlsson JJ, Mullertz A, Rades T. Supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS) enhance the bioavailability of the poorly water-soluble drug simvastatin in dogs. AAPS J. 2012;15:219–27.PubMedCrossRefGoogle Scholar
  12. 12.
    Grove M, Pedersen GP, Nielsen JL, Mullertz A. Bioavailability of seocalcitol I: relating solubility in biorelevant media with oral bioavailability in rats - effect of medium and long chain triglycerides. J Pharm Sci. 2005;94:1830–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Kossena GA, Charman WN, Boyd BJ, Porter CJ. A novel cubic phase of medium chain lipid origin for the delivery of poorly water soluble drugs. J Control Release. 2004;99:217–29.PubMedCrossRefGoogle Scholar
  14. 14.
    Larsen A, Holm R, Pedersen ML, Mullertz A. Lipid-based formulations for danazol containing a digestible surfactant, labrafil M2125CS: in vivo bioavailability and dynamic in vitro lipolysis. Pharm Res. 2008;25:2769–77.PubMedCrossRefGoogle Scholar
  15. 15.
    Zangenberg NH, Mullertz A, Kristensen HG, Hovgaard L. A dynamic in vitro lipolysis model II: evaluation of the model. Eur J Pharm Sci. 2001;14:237–44.PubMedCrossRefGoogle Scholar
  16. 16.
    Polentarutti B, Albery T, Dressman J, Abrahamsson B. Modification of gastric pH in the fasted dog. J Pharm Pharmacol. 2010;62:462–9.PubMedGoogle Scholar
  17. 17.
    Rautio J, Humphreys JE, Webster LO, Balakrishnan A, Keogh JP, Kunta JR, et al. In vitro P-glycoprotein inhibition assays for assessment of clinical drug interaction potential of new drug candidates: a recommendation for probe substrates. Drug Metab Dispos. 2006;34:786–92.PubMedCrossRefGoogle Scholar
  18. 18.
    Kleberg K, Jacobsen F, Fatouros DG, Mullertz A. Biorelevant media simulating Fed State intestinal fluids: colloid phase characterization and impact on solubilization capacity. J Pharm Sci. 2010;99:3522–32.PubMedCrossRefGoogle Scholar
  19. 19.
    Artursson P, Karlsson J. Correlation between oral-drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (caco-2) cells. Biochem Biophys Res Commun. 1991;175:880–5.PubMedCrossRefGoogle Scholar
  20. 20.
    Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12:413–20.PubMedCrossRefGoogle Scholar
  21. 21.
    Fagerberg JH, Tsinman O, Sun N, Tsinman K, Avdeef A, Bergstrom CA. Dissolution rate and apparent solubility of poorly soluble drugs in biorelevant dissolution media. Mol Pharm. 2010;7:1419–30.PubMedCrossRefGoogle Scholar
  22. 22.
    Constantinides PP, Wasan KM. Lipid formulation strategies for enhancing intestinal transport and absorption of P-glycoprotein (P-gp) substrate drugs: in vitro/in vivo case studies. J Pharm Sci. 2007;96:235–48.PubMedCrossRefGoogle Scholar
  23. 23.
    Cornaire G, Woodley J, Hermann P, Cloarec A, Arellano C, Houin G. Impact of excipients on the absorption of P-glycoprotein substrates in vitro and in vivo. Int J Pharm. 2004;278:119–31.PubMedCrossRefGoogle Scholar
  24. 24.
    Kariya S, Isozaki S, Uchino K, Suzuki T, Narimatsu S. Oxidative metabolism of flunarizine and cinnarizine by microsomes from B-lymphoblastoid cell lines expressing human cytochrome P450 enzymes. Biol Pharm Bull. 1996;19:1511–4.PubMedCrossRefGoogle Scholar
  25. 25.
    Narimatsu S, Kariya S, Isozaki S, Ohmori S, Kitada M, Hosokawa S, et al. Involvement of Cyp2D6 in oxidative-metabolism of cinnarizine and Flunarizine in human liver-microsomes. Biochem Biophys Res Commun. 1993;193:1262–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J. 2005;5:6–13.PubMedCrossRefGoogle Scholar
  27. 27.
    Paulson SK, Engel L, Reitz B, Bolten S, Burton EG, Maziasz TJ, et al. Evidence for polymorphism in the canine metabolism of the cyclooxygenase 2 inhibitor, celecoxib. Drug Metab Dispos. 1999;27:1133–42.PubMedGoogle Scholar
  28. 28.
    Martignoni M, Groothuis GMM, de Kanter R. Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin Drug Metab Toxicol. 2006;2:875–94.PubMedCrossRefGoogle Scholar
  29. 29.
    Schmidt R, Baumann F, Hanschmann H, Geissler F, Preiss R. Gender difference in ifosfamide metabolism by human liver microsomes. Eur J Drug Metab Pharmacokinet. 2001;26:193–200.PubMedCrossRefGoogle Scholar
  30. 30.
    Jarvinen T, Jarvinen K, Schwarting N, Stella VJ. Beta-cyclodextrin derivatives, Sbe4-beta-Cd and Hp-beta-Cd. Increase the oral bioavailability of cinnarizine in beagle dogs. J Pharm Sci. 1995;84:295–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Han SF, Yao TT, Zhang XX, Gan L, Zhu CL, Yua HZ, et al. Lipid-based formulations to enhance oral bioavailability of the poorly water-soluble drug anethol trithione: effects of lipid composition and formulation. Int J Pharm. 2009;379:18–24.PubMedCrossRefGoogle Scholar
  32. 32.
    Porter CJH, Kaukonen AM, Boyd BJ, Edwards GA, Charman WN. Susceptibility to lipase-mediated digestion reduces the oral bioavailability of danazol after administration as a medium-chain lipid-based microemulsion formulation. Pharm Res. 2004;21:1405–12.PubMedCrossRefGoogle Scholar
  33. 33.
    Kossena GA, Charman WN, Wilson CG, O’Mahony B, Lindsay B, Hempenstall JM, et al. Low dose lipid formulations: effects on gastric emptying and biliary secretion. Pharm Res. 2007;24:2084–96.PubMedCrossRefGoogle Scholar
  34. 34.
    Sassene PJ, Knopp MM, Hesselkilde JZ, Koradia V, Larsen A, Rades T, et al. Precipitation of a poorly soluble model drug during in vitro lipolysis: characterization and dissolution of the precipitate. J Pharm Sci. 2010;99:4982–91.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Anne T. Larsen
    • 1
  • Pernilla Åkesson
    • 2
  • Anna Juréus
    • 3
  • Lasse Saaby
    • 4
  • Ragheb Abu-Rmaileh
    • 5
  • Bertil Abrahamsson
    • 2
  • Jesper Østergaard
    • 1
  • Anette Müllertz
    • 4
  1. 1.Department of Pharmacy, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
  2. 2.AstraZeneca, Pharmaceutical DevelopmentMölndalSweden
  3. 3.AstraZeneca, Innovative MedicinesSödertäljeSweden
  4. 4.Bioneer: FARMACopenhagenDenmark
  5. 5.AstraZeneca, Pharmaceutical DevelopmentMacclesfieldUK

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