Pharmaceutical Research

, Volume 25, Issue 4, pp 845–852 | Cite as

In Situ-Forming Oleogel Implant for Rivastigmine Delivery

  • Anda Vintiloiu
  • Michel Lafleur
  • Guillaume Bastiat
  • Jean-Christophe Leroux
Research Paper

Abstract

Purpose

To provide a simplified dosing schedule and potentially reduce side effects associated to peak plasma concentrations, an in situ-forming oleogel implant was studied for the sustained-release of rivastigmine.

Materials and methods

The gel was prepared by dissolving 5–10% (w/w) N-stearoyl l-alanine methyl ester (SAM) organogelator in safflower oil containing either dissolved rivastigmine or its dispersed hydrogen tartrate salt. Rheological analysis, differential scanning calorimetry, and infrared spectroscopy were carried out to assess the impact of drug incorporation on the oleogel; this was followed by in vitro and in vivo release studies.

Results

A weakening of intermolecular interactions was suggested by gel-sol transition temperature drops of 10–15°C upon incorporation of dissolved drug. Meanwhile, the dispersed drug salt induced minimal or no changes in transition temperature. Gels containing dispersed rivastigmine had the lowest burst in vitro (<15% in 24 h). In vivo, the 10% SAM formulation containing dispersed rivastigmine provided prolonged drug release within the therapeutic range for 11 days, with peak plasma levels well below the toxic threshold and up to five times lower than for the control formulation.

Conclusions

This study established SAM gels to be a promising option for sustained-release formulations in the treatment of Alzheimer’s Disease.

Key words

Alzheimer’s disease implant organogel rivastigmine sustained release 

Supplementary material

11095_2007_9384_MOESM1_ESM.doc (122 kb)
Supporting information(DOC 122 KB)

References

  1. 1.
    C. Mount and C. Downton. Alzheimer disease: progress or profit? Nat. Med. 12:780–784 (2006).PubMedCrossRefGoogle Scholar
  2. 2.
    R. Katzman. Alzheimer’s disease. NEJM 314:964–973 (1986).PubMedGoogle Scholar
  3. 3.
    C. G. Ballard. Advances in the treatment of Alzheimer’s disease: benefits of dual cholinesterase inhibition. Eur. Neurol. 47:64–70 (2002).PubMedCrossRefGoogle Scholar
  4. 4.
    A. Lleo, S. M. Greenberg, and J. H. Growdon. Current pharmacotherapy for Alzheimer’s disease. Ann. Rev. Med. 57:513–533 (2006).PubMedCrossRefGoogle Scholar
  5. 5.
    S. Gauthier. Long-term efficacy of cholinesterase inhibitors. Brain Aging 2:9–22 (2002).Google Scholar
  6. 6.
    V. W. DeLaGarza. Pharmacologic treatment of Alzheimer’s disease: an update. Am. Fam. Physician. 68:1365–1372 (2003).PubMedGoogle Scholar
  7. 7.
    V. Cotrell, K. Wild, and T. Bader. Medication management and adherence among cognitively impaired older adults. J. Gerontol. Soc. Work 47:31–46 (2006).PubMedCrossRefGoogle Scholar
  8. 8.
    D. G. Wilkinson, A. P. Passmore, R. Bullock, S. W. Hopter, R. P. Smith, F. C. Protocnik, C. M. Maud, I. Engelbrecht, C. Hock, J. R. Ieni, and R. S. Bahra. A mutinational, randomised, 12-week, comparative study of donepezil and rivastigmine in patients with mild to moderate Alzheimer’s disease. Int. J. Clin. Pract. 56:441–446 (2002).PubMedGoogle Scholar
  9. 9.
    G. Singh, S. K. Thomas, S. Arcona, V. Lingala, and A. Mithal. Treatment persistency with rivastigmine and donepezil in a large state medicaid program. J. Am. Geriatr. Soc. 53:1269–1270 (2005).PubMedCrossRefGoogle Scholar
  10. 10.
    K. L. Lanctôt, N. Herrmann, K. K. Yau, L. R. Khan, B. A. Liu, M. M. Loulou, and T. R. Einarson. Efficacy and safety of choliesterase inhibitors in Alzheimer’s disease: a meta-analysis. Can. Med. Assoc. J. 169:557–564 (2003).Google Scholar
  11. 11.
    J. Birks, J. Grimley Evans, V. Iakovidou, and M. Tsolaki. Rivastigmine for Alzheimer’s disease. Cochrane Database Syst. Rev. 4:CD001191 (2000).PubMedGoogle Scholar
  12. 12.
    W. H. Liu, J. L. Song, K. Liu, D. F. Chu, and Y. X. Li. Preparation and in vitro and in vivo release studies of huperzine A loaded microspheres for the treatment of Alzheimer’s disease. J. Control Release 107:417–427 (2005).PubMedCrossRefGoogle Scholar
  13. 13.
    X. Fu, Q. Ping, and Y. Gao. Effects of formulation factors on encapsulation efficiency and release behaviour in vitro of huperzine A-PLGA microspheres. J. Microencapsul. 22:705–714 (2005).PubMedCrossRefGoogle Scholar
  14. 14.
    P. Gao, P. Ding, H. Xu, Z. Yuan, D. Chen, J. Wei, and D. Chen. In vitro and in vivo characterization of huperzine A loaded microspheres made from end-group uncapped poly(d,l-lactide acid) and poly(d,l-lactide-co-glycolide acid). Chem. Pharm. Bull. 54:89–93 (2006).PubMedCrossRefGoogle Scholar
  15. 15.
    Q. Yang, D. Williams, G. Owusu-Ababio, N. K. Ebube, and M. J. Habib. Controlled release tacrine delivery system for the treatment of Alzheimer’s disease. Drug Deliv. 8:93–98 (2001).PubMedCrossRefGoogle Scholar
  16. 16.
    F. L. Tse, and R. Laplanche. Absorption, metabolism, and disposition of [14C]SDZ ENA 713, an acetylcholinesterase inhibitor, in minipigs following oral, intravenous, and dermal administration. Pharm. Res. 15:1614–1620 (1998).PubMedCrossRefGoogle Scholar
  17. 17.
    V. R. Sinha, and A. Trehan. Biodegradable microspheres for protein delivery. J. Control Release 90:261–280 (2003).PubMedCrossRefGoogle Scholar
  18. 18.
    C. B. Packhaeuser, J. Schnieders, C. G. Oster, and T. Kissel. In situ forming parenteral drug delivery systems: an overview. Eur. J. Pharm. Biopharm. 58:445–455 (2004).PubMedCrossRefGoogle Scholar
  19. 19.
    S. Bhattacharya, and Y. Krishnan-Gosh. First report of phase selective gelation of oil from oil/water mixture. Possible implications toward containing oil spills. Chem. Commun. 2:185–186 (2001).CrossRefGoogle Scholar
  20. 20.
    A. C. Couffin-Hoarau, A. Motulsky, P. Delmas, and J. C. Leroux. In situ-forming pharmaceutical organogels based on the self assembly of l-alanine derivatives. Pharm. Res. 21:454–457 (2004).PubMedCrossRefGoogle Scholar
  21. 21.
    A. Motulsky, M. Lafleur, A. C. Couffin-Hoarau, D. Hoarau, F. Boury, J. P. Benoit, and J. C. Leroux. Characterization and biocompatibility of organogels based on l-alanine for parenteral drug delivery implants. Biomaterials 26:6242–6253 (2005).PubMedCrossRefGoogle Scholar
  22. 22.
    F. Plourde, A. Motulsky, A. C. Couffin-Hoarau, D. Hoarau, H. Ong, and J. C. Leroux. First report on the efficacy of l-alanine-based in situ-forming implants for the long-term parenteral delivery of drugs. J. Control Release 108:433–441 (2005).PubMedCrossRefGoogle Scholar
  23. 23.
    K. Fredholt, D. H. Larsen, and C. Larsen. Modification of in vitro drug release rate from oily parenteral depots using a formulation approach. Eur. J. Pharm. Sci. 11:231–237 (2000).PubMedCrossRefGoogle Scholar
  24. 24.
    B. M. Rao, M. K. Srinivasu, K. P. Kumar, N. Bhradwaj, R. Ravi, P. K. Mohakhud, G. O. Reddy, and P. R. Kumar. A stability indicating LC method for rivastigmine hydrogen tartrate. J. Pharm. Biomed. Anal. 37:57–63 (2005).PubMedCrossRefGoogle Scholar
  25. 25.
    S. M. Nuno-Donlucas, J. C. Sanchez-Diaz, M. Rabelero, J. Cortes-Ortega, C.C. Luhrs-Olmos, V. V. Fernandez-Escamilla, E. Mendizabal, and J. E. Puig. Microstructured polyacrylamide hydrogels made with hydrophobic nanoparticles. J. Colloid. Interface Sci. 270:94–98 (2004).PubMedCrossRefGoogle Scholar
  26. 26.
    R. Schmidt, M. Schmutz, M. Michel, G. Decher, and P. J. Mesini. Organogelation properties of a series of oligoamides. Langmuir 18:5668–5672 (2001).CrossRefGoogle Scholar
  27. 27.
    M. R. Farlow. Update on rivastigmine. Neurology 9:230–234 (2003).CrossRefGoogle Scholar
  28. 28.
    Novartis. Exelon TM: Rivastigmine hydrogen tartrate, cholinesterase inhibitor, Compendium of pharmaceutical specialties (CPS), Canadian Pharmacists Association, Ottawa, pp 835–840 (2004).Google Scholar
  29. 29.
    S. W. Coppack, T. J. Yost, R. M. Fisher, R. H. Eckel, and J. M. Miles. Periprandial systemic and regional lipase activity in normal humans. Am. J. Physiol. 270:E718–E722 (1996).PubMedGoogle Scholar
  30. 30.
    B. Jeong, Y. K. Choi, Y. H. Bae, G. Zentner, and S. W. Kim. New biodegradable polymers for injectable drug delivery systems. J. Control Release 62:109–114 (1999).PubMedCrossRefGoogle Scholar
  31. 31.
    L. Appel, K. Engle, J. Jensen, L. Rajewski, and G. Zentner. An in vitro model to mimic in vivo subcutaneous monoolein degradation. Pharm. Res. 11:S-217 (1994).Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Anda Vintiloiu
    • 1
  • Michel Lafleur
    • 2
  • Guillaume Bastiat
    • 1
  • Jean-Christophe Leroux
    • 1
  1. 1.Canada Research Chair in Drug Delivery, Faculty of PharmacyUniversity of MontrealMontrealCanada
  2. 2.Department of ChemistryUniversity of MontrealMontrealCanada

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