Skip to main content
SpringerLink
Log in

Influence of drug load and physical form of cinnarizine in new SNEDDS dosing regimens: in vivo and in vitro evaluations

  • Research Article
  • Published:
The AAPS Journal Aims and scope Submit manuscript

ABSTRACT

The aim of this work was to evaluate the influence of drug load and physical form of cinnarizine (CIN) in self-nanoemulsifying drug delivery systems (SNEDDS) on absorption in rats. Further, the predictivity of the dynamic in vitro lipolysis model was evaluated. The following dosing regimens were assessed: (1) CIN dissolved in SNEDDS at 80% of equilibrium solubility (Seq) (SNEDDS 80%); (2) supersaturated SNEDDS with CIN dissolved at 200% Seq (super-SNEDDS solution); (3) SNEDDS suspension with CIN added at 200% Seq (CIN partially dissolved and partially suspended) (super-SNEDDS suspension); (4) drug-free SNEDDS co-dosed with aqueous CIN suspension (Chasing principle), and (5) CIN aqueous suspension. The CIN dose was kept constant for all dosing regimens. Therefore, the super-SNEDDS solution and super-SNEDDS suspension contained 2.5-fold less SNEDDS pre-concentrate than SNEDDS 80% and the Chasing principle. In vivo, a higher AUC after dosing CIN in SNEDDS 80% and the Chasing principle was obtained when compared to the super-SNEDDS solution, super-SNEDDS suspension, and aqueous suspension. In vitro, a higher extent of CIN in the aqueous phase was observed for all SNEDDS-containing dosing regimens, compared to the aqueous suspension. Since the drug level in the aqueous phase is traditionally considered as the fraction available for absorption, a lack of in vitro-in vivo relation was observed. This study revealed that the physical form of CIN in the current SNEDDS does not affect CIN absorption and solubilization, whereas the drug load, or amount of co-dosed lipid, significantly influenced CIN bioavailability.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Gursoy RN, Benita S. Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. Biomed Pharmacother. 2004;58:173–82.

    Article  PubMed  Google Scholar 

  2. Kuentz M, Wyttenbach N, Kuhlmann O. Application of a statistical method to the absorption of a new model drug from micellar and lipid formulations—evaluation of qualitative excipient effects. Pharm Dev Technol. 2007;12:275–83.

    Article  CAS  PubMed  Google Scholar 

  3. Thomas N, Holm R, Müllertz 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.

    Article  CAS  PubMed  Google Scholar 

  4. Araya H, Tomita M, Hayashi M. The novel formulation design of self-emulsifying drug delivery systems (SEDDS) type O/W microemulsion II: stable gastrointestinal absorption of a poorly water soluble new compound, ER-1258 in bile-fistula rats. Drug Metab Pharmacokinet. 2005:257–67.

  5. 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.

    Article  CAS  PubMed  Google Scholar 

  6. Cui J, Yu B, Zhao Y, Zhu W, Li H, Lou H, et al. Enhancement of oral absorption of curcumin by self-microemulsifying drug delivery systems. Int J Pharm. 2009;371:148–55.

    Article  CAS  PubMed  Google Scholar 

  7. Dixit AR, Rajput SJ, Patel SG. Preparation and bioavailability assessment of SMEDDS containing valsartan. AAPS Pharmscitech. 2010;11:314–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kang BK, Lee JS, Chon SK, Jeong SY, Yuk SH, Khang G, et al. Development of self-microemulsifying drug delivery systems (SMEDDS) for oral bioavailability enhancement of simvastatin in beagle dogs. Int J Pharm. 2004;274:65–73.

    Article  CAS  PubMed  Google Scholar 

  9. Nielsen FS, Petersen KB, Müllertz A. Bioavailability of probucol from lipid and surfactant based formulations in minipigs: Influence of droplet size and dietary state. Eur J Pharm Biopharm. 2008;69:553–62.

    Article  CAS  PubMed  Google Scholar 

  10. Anton N, Vandamme TF. Nano-emulsions and micro-emulsions: clarifications of the critical differences. Pharmaceut Res. 2011;28:978–85.

    Article  CAS  Google Scholar 

  11. Pouton CW. Lipid formulations for oral administration of drugs: non-emulsifying, self-emulsifying and ‘self-microemulsifying’ drug delivery systems. Eur J Pharm Sci. 2000;11:93–8.

    Article  Google Scholar 

  12. Thomas N, Holm R, Rades T, Müllertz A. Characterising lipid lipolysis and its implication in lipid-based formulation development. AAPS J. 2012;14:860–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Anby MU, Williams HD, McIntosh M, Benameur H, Edwards GA, Pouton CW, et al. Lipid digestion as a trigger for supersaturation: evaluation of the impact of supersaturation stabilization on the in vitro and in vivo performance of self-emulsifying drug delivery systems. Mol Pharm. 2012;9:2063–79.

    Article  CAS  PubMed  Google Scholar 

  14. Larsen AT, Akesson P, Jureus A, Saaby L, Abu-Rmaileh R, Abrahamsson B, et al. Bioavailability of cinnarizine in dogs: effect of SNEDDS loading level and correlation with cinnarizine solubilization during in vitro lipolysis. Pharmaceut Res. 2013;30:3101–13.

    Article  CAS  Google Scholar 

  15. Thomas N, Holm R, Garmer M, Karlsson JJ, Müllertz 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. 2013;15:219–27.

    Article  CAS  PubMed  Google Scholar 

  16. Thomas N, Müllertz A, Graf A, Rades T. Influence of lipid composition and drug load on the in vitro performance of self-nanoemulsifying drug delivery systems. J Pharm Sci. 2012;101:1721–31.

    Article  CAS  PubMed  Google Scholar 

  17. Thomas N, Richter K, Pedersen TB, Holm R, Müllertz A, Rades T. In vitro lipolysis data does not adequately predict the in vivo performance of lipid-based drug delivery systems containing fenofibrate. AAPS J. 2014;16:539–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Michaelsen MH, Wasan KM, Sivak O, Müllertz A, Rades T. The effect of digestion and drug load on halofantrine absorption from self-nanoemulsifying drug delivery system (SNEDDS). AAPS J. 2015;1-7

  19. Larsen A, Holm R, Pedersen ML, Müllertz A. Lipid-based formulations for danazol containing a digestible surfactant, labrafil M2125CS: in vivo bioavailability and dynamic in vitro lipolysis. Pharmaceut Res. 2008;25:2769–77.

    Article  CAS  Google Scholar 

  20. Godfraind T, Miller R, Wibo M. Calcium antagonism and calcium entry blockade. Pharmacol Rev. 1986;38:321–416.

    CAS  PubMed  Google Scholar 

  21. Zangenberg NH, Müllertz A, Gjelstrup Kristensen H, Hovgaard L. A dynamic in vitro lipolysis model: II: evaluation of the model. Eur J Pharm Sci. 2001;14:237–44.

    Article  CAS  PubMed  Google Scholar 

  22. Budavar S, O’Neil M, Smith A, Heckelman P. Cinnarizine. The Merck Index 11th edition. 1989. p. 359.

  23. Gu CH, Rao D, Gandhi RB, Hilden J, Raghavan K. Using a novel multicompartment dissolution system to predict the effect of gastric pH on the oral absorption of weak bases with poor intrinsic solubility. J Pharm Sci. 2005;94:199–208.

    Article  CAS  PubMed  Google Scholar 

  24. Lee KWY, Porter CJH, Boyd BJ. The effect of administered dose of lipid-based formulations on the in vitro and in vivo performance of cinnarizine as a model poorly water-soluble drug. J Pharm Sci. 2013;102:565–78.

    Article  CAS  PubMed  Google Scholar 

  25. Elgart A, Cherniakov I, Aldouby Y, Domb AJ, Hoffman A. Improved oral bioavailability of BCS class 2 compounds by self nano-emulsifying drug delivery systems (SNEDDS): the underlying mechanisms for amiodarone and talinolol. Pharm Res. 2013;30:3029–44.

    Article  CAS  PubMed  Google Scholar 

  26. Larsen AT, Ogbonna A, Abu-Rmaileh R, Abrahamsson B, Ostergaard J, Müllertz A. SNEDDS containing poorly water soluble cinnarizine; development and in vitro characterization of dispersion, digestion and solubilization. Pharmaceutics. 2012;4:641–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Porter CJH, Kaukonen AM, Taillardat-Bertschinger A, Boyd BJ, O’Connor JM, Edwards GA, et al. Use of in vitro lipid digestion data to explain the in vivo performance of triglyceride-based oral lipid formulations of poorly water-soluble drugs: studies with halofantrine. J Pharm Sci. 2004;93:1110–21.

    Article  CAS  PubMed  Google Scholar 

  28. Müllertz A, Ogbonna A, Ren S, Rades T. New perspectives on lipid and surfactant based drug delivery systems for oral delivery of poorly soluble drugs. J Pharm Pharmacol. 2010;62:1622–36.

    Article  PubMed  Google Scholar 

  29. 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.

    Article  CAS  PubMed  Google Scholar 

  30. 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.

    Article  CAS  PubMed  Google Scholar 

  31. Sassene P, Michaelsen M, Mosgaard M, Jensen M, Van Den Broek E, Wasan K, et al. In vivo precipitation of poorly soluble drugs from lipid based drug delivery systems. Mol Pharma. 2016.

  32. Tanaka Y, Hara T, Waki R, Nagata S. Regional differences in the components of luminal water from rat gastrointestinal tract and comparison with other species. J Pharm Pharm Sci. 2012;15:510–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Line H. Nielsen for her help with the pharmacokinetic studies. Funding for this project was provided by F. Hoffmann—La Roche Ltd., Basel, Switzerland. Scheyla Siqueira is grateful for the financial support from the CAPES Foundation, Ministry of Education of Brazil, Brasília.

Author information

Authors and Affiliations

  1. Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen, Denmark

    Scheyla D.V.S. Siqueira, Anette Müllertz, Georgia Kasten, Huiling Mu & Thomas Rades

  2. Roche Pharma Research and Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann—La Roche Ltd, Basel, Switzerland

    Kirsten Gräeser

Authors
  1. Scheyla D.V.S. Siqueira
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anette Müllertz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kirsten Gräeser
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Georgia Kasten
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Huiling Mu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thomas Rades
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anette Müllertz.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Siqueira, S.D., Müllertz, A., Gräeser, K. et al. Influence of drug load and physical form of cinnarizine in new SNEDDS dosing regimens: in vivo and in vitro evaluations. AAPS J 19, 587–594 (2017). https://doi.org/10.1208/s12248-016-0038-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12248-016-0038-4

KEY WORDS

Search

Navigation