In Vitro and in Vivo Optimization of Phase Sensitive Smart Polymer for Controlled Delivery of Rivastigmine for Treatment of Alzheimer’s Disease

Abstract

Purpose

Alzheimer’s disease is a neurodegenerative disorder, and most common form of dementia afflicting over 35 million people worldwide. Rivastigmine is a widely used therapeutic for ameliorating clinical manifestations of Alzheimer’s disease. However, current treatments require frequent dosing either orally or via transdermal patch that lead to compliance issues and administration errors risking serious adverse effects. Our objective was to develop a smart polymer based delivery system for controlled release of rivastigmine over an extended period following a single subcutaneous injection.

Methods

Rivastigmine release was optimized by tailoring critical factors including polymer concentration, polymer composition, drug concentration, solvent composition, and drug hydrophobicity (rivastigmine tartrate vs base). Optimized in vitro formulation was evaluated in vivo for safety and efficacy.

Results

Formulation prepared using PLGA (50:50) at 5% w/v in 95:5 benzyl benzoate: benzoic acid demonstrated desirable controlled drug release characteristics in vitro. The formulation demonstrated sustained release of rivastigmine tartrate for 7 days in vivo with promising biocompatibility and acetylcholinesterase inhibition efficacy for 14 days.

Conclusion

The results exemplify an easily injectable controlled release formulation of rivastigmine prepared using phase-sensitive smart polymer. The optimized formulation significantly increases the dosing interval, and can potentially improve patient compliance as well as quality of life of patients living with Alzheimer’s disease.

This is a preview of subscription content, access via your institution.

We’re sorry, something doesn't seem to be working properly.

Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

References

  1. 1.

    National Institute of Aging. Alzheimer's Disease Fact Sheet.; Accessed: 2019 12/20. Available from: https://www.nia.nih.gov/health/alzheimers-disease-fact-sheet.

  2. 2.

    Weuve J, Hebert LE, Scherr PA, Evans DA. Deaths in the United States among persons with Alzheimer's disease (2010-2050). Alzheimers Dement. 2014;10(2):e40–6.

    PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Alzheimer's association. Generation alzheimer's the defining disease of the baby boomers.; Accessed: 2019 12/20. Available from: https://act.alz.org/site/DocServer/ALZ_BoomersReport.pdf?docID=521.

  4. 4.

    National Cancer Institute. NCI Budget and Appropriations.; Accessed: 2019 12/20. Available from: https://www.cancer.gov/about-nci/budget.

  5. 5.

    Mather M, Harley CW. The locus Coeruleus: essential for maintaining cognitive function and the aging brain. Trends Cogn Sci. 2016;20(3):214–26.

    PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Kumar A, Singh A. Ekavali. A review on Alzheimer's disease pathophysiology and its management: an update. Pharmacol Rep. 2015;67(2):195–203.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Nagy B, Brennan A, Brandtmuller A, Thomas SK, Sullivan SD, Akehurst R. Assessing the cost-effectiveness of the rivastigmine transdermal patch for Alzheimer's disease in the UK using MMSE- and ADL-based models. Int J Geriatr Psychiatry. 2011;26(5):483–94.

    PubMed  Article  Google Scholar 

  8. 8.

    Kracmarova A, Drtinova L, Pohanka M. Possibility of Acetylcholinesterase overexpression in Alzheimer disease patients after therapy with Acetylcholinesterase inhibitors. Acta Med (Hradec Kralove). 2015;58(2):37–42.

    Article  Google Scholar 

  9. 9.

    Williams BR, Nazarians A, Gill MA. A review of rivastigmine: a reversible cholinesterase inhibitor. Clin Ther. 2003;25(6):1634–53.

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Eskander MF, Nagykery NG, Leung EY, Khelghati B, Geula C. Rivastigmine is a potent inhibitor of acetyl- and butyrylcholinesterase in Alzheimer's plaques and tangles. Brain Res. 2005;1060(1–2):144–52.

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Cotrell V, Wild K, Bader T. Medication management and adherence among cognitively impaired older adults. J Gerontol Soc Work. 2006;47(3–4):31–46.

    PubMed  Article  Google Scholar 

  12. 12.

    Dhillon S. Spotlight on rivastigmine transdermal patch: in dementia of the Alzheimer's type. Drugs Aging. 2011;28(11):927–30.

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Alva G, Grossberg GT, Schmitt FA, Meng X, Olin JT. Efficacy of rivastigmine transdermal patch on activities of daily living: item responder analyses. Int J Geriatr Psychiatry. 2011;26(4):356–63.

    PubMed  Article  Google Scholar 

  14. 14.

    Uwano C, Suzuki M, Aikawa T, Ebihara T, Une K, Tomita N, et al. Rivastigmine dermal patch solves eating problems in an individual with advanced Alzheimer's disease. J Am Geriatr Soc. 2012;60(10):1979–80.

    PubMed  Article  Google Scholar 

  15. 15.

    Adler G, Mueller B, Articus K. The transdermal formulation of rivastigmine improves caregiver burden and treatment adherence of patients with Alzheimer's disease under daily practice conditions. Int J Clin Pract. 2014;68(4):465–70.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Cortez Pinto L, Martinho Pimenta AJ, Figueira ML, Fernandes JM. More Patients Show Reduced Agitation/aggression with Rivastigmine Transdermal Monotherapy Than with Oral Monotherapies for Alzheimer’s Disease – Results From the Exept Study in Portugal. European Psychiatry 2015 28–31 March 2015;30:1445.

  17. 17.

    Dhillon S. Rivastigmine Transdermal Patch Drugs 2011;71(9).

  18. 18.

    Pratten MK, Lloyd JB, Hörpel G, Ringsdorf H. Micelle-forming block copolymers : pinocytosis by macrophages and interaction with model membranes. Die Makromol Chemie. 2003;186(4):725–33.

    Article  Google Scholar 

  19. 19.

    Chen S, Singh J. Controlled delivery of testosterone from smart polymer solution based systems: in vitro evaluation. Int J Pharm. 2005;295(1–2):183–90.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Rao BM, Srinivasu MK, Kumar KP, Bhradwaj N, Ravi R, Mohakhud PK, et al. A stability indicating LC method for Rivastigmine hydrogen tartrate. Journal of Pharmaceutical and Biomedical Analysis 2005 7 February 2005;37(1):57–63.

  21. 21.

    Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016;7(2):27–31.

    PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Wake MC, Gupta PK, Mikos AG. Fabrication of pliable biodegradable polymer foams to engineer soft tissues. Cell Transplant. 1996;5(4):465–73.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Bonacucina G, Cespi M, Mencarelli G, Giorgioni G, Filippo PG. Thermosensitive self-assembling block copolymers as drug delivery systems. Polymers. 2011;3(2):779–811.

    CAS  Article  Google Scholar 

  24. 24.

    Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys. 1959;82(1):70–7.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Yamada K, Nabeshima T. Animal models of Alzheimer's disease and evaluation of anti-dementia drugs. Pharmacol Ther. 2000;88(2):93–113.

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Chen S, Singh J. In vitro release of levonorgestrel from phase sensitive and thermosensitive smart polymer delivery systems. Pharm Dev Technol. 2005;10(2):319–25.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Chen S, Pederson D, Oak M, Singh J. In vivo absorption of steroidal hormones from smart polymer based delivery systems. J Pharm Sci. 2010;99(8):3381–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Tang Y, Singh J. Thermosensitive drug delivery system of salmon calcitonin: in vitro release, in vivo absorption, bioactivity and therapeutic efficacies. Pharm Res. 2010;27(2):272–84.

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Tang Y, Singh J. Biodegradable and biocompatible thermosensitive polymer based injectable implant for controlled release of protein. Int J Pharm. 2009;365(1–2):34–43.

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Chen S, Pieper R, Webster DC, Singh J. Triblock copolymers: synthesis, characterization, and delivery of a model protein. Int J Pharm. 2005;288(2):207–18.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Al-Tahami K, Oak M, Mandke R, Singh J. Basal level insulin delivery: in vitro release, stability, biocompatibility, and in vivo absorption from thermosensitive triblock copolymers. J Pharm Sci. 2011;100(11):4790–803.

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Oak M, Singh J. Controlled delivery of basal level of insulin from chitosan-zinc-insulin-complex-loaded thermosensitive copolymer. J Pharm Sci. 2012;101(3):1079–96.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Oak M, Singh J. Chitosan-zinc-insulin complex incorporated thermosensitive polymer for controlled delivery of basal insulin in vivo. J Control Release. 2012;163(2):145–53.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Oak M, Mandke R, Lakkadwala S, Lipp L, Singh J. Effect of molar mass and water solubility of incorporated molecules on the degradation profile of the triblock copolymer delivery system. Polymers. 2015;7(8):1510–21.

    CAS  Article  Google Scholar 

  35. 35.

    Sharma D, Arora S, Singh J. Smart thermosensitive copolymer incorporating chitosan–zinc–insulin electrostatic complexes for controlled delivery of insulin: effect of chitosan chain length. Int J Polym Mater Polym Biomater. 2019.

  36. 36.

    Shaikh J. Benzyl Benzoate. In: Wexler P, editor. Encyclopedia of Toxicology. 2nd ed.: Elsevier; 2005. p. 264–265.

  37. 37.

    Schwendeman SP, Shah RB, Bailey BA, Schwendeman AS. Injectable controlled release depots for large molecules. J Control Release. 2014;190:240–53.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

ACKNOWLEGEMENTS AND DISCLOSURES

This research was supported by the National Institutes of Health (NIH) grant# R15GM114701. The authors declare no conflict of interest regarding the publication of this article.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Amrita Banerjee.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lipp, L., Sharma, D., Banerjee, A. et al. In Vitro and in Vivo Optimization of Phase Sensitive Smart Polymer for Controlled Delivery of Rivastigmine for Treatment of Alzheimer’s Disease. Pharm Res 37, 34 (2020). https://doi.org/10.1007/s11095-020-2757-6

Download citation

Key Words

  • alzheimer’s disease
  • controlled release
  • phase sensitive
  • rivastigmine
  • smart polymers