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Formulation and In-vivo Pharmacokinetic Consideration of Intranasal Microemulsion and Mucoadhesive Microemulsion of Rivastigmine for Brain Targeting

  • Research Paper
  • Theme: Drug Discovery, Development and Delivery in Alzheimer’s Disease
  • Published:
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Abstract

Purpose

Presence of tight junctions in blood brain barrier (BBB) pose a major hurdle for delivery of drug and severely affects adequate therapeutic concentration to reach the brain. In present work, we have selected Rivastigmine hydrogen tartrate (RHT), a reversible cholinesterase inhibitor, which exhibits extensive first-pass metabolism, resulting in limited absolute bioavailability (36%). RHT shows extremely low aqueous solubility and poor penetration, resulting in inadequate concentration reaching the brain, thus necessitating frequent oral dosing. To overcome these problems of RHT, microemulsion (ME) and mucoadhesive microemulsion (MME) of RHT were formulated for brain targeting via intranasal delivery route and compared on the basis of in vivo pharmacokinetics.

Methods

ME and MME formulations containing RHT were developed by water titration method. Characterization of ME and MME was done for various physicochemical parameters, nasal spray pattern, and in vivo pharmacokinetics quantitatively and qualitatively (gamma scintigraphy studies).

Results

The developed ME and MME were transparent having globule size approximately in the range of 53–55 nm. Pharmacokinetic studies showed higher values for Cmax and DTP for intranasal RHT: CH-ME over RHT-ME, thus indicating the effect of chitosan in modulating tight junctions, thereby enhanced paracellular transport of RHT.

Conclusion

Gamma scintigraphy and in vivo pharmacokinetic study suggested enhanced RHT concentration, upon intranasal administration of RHT:CH-ME, compare with other groups administered formulations intranasally. These findings suggested the potential of non-invasive intranasal route for brain delivery, especially for therapeutics, facing challenges in oral administration.

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Abbreviations

%T:

Transmittance (%)

BBB:

Blood brain barrier

CH:

Chitosan

CTAB:

Cetyl trimethyl ammonium bromide

DS:

Drug solution

DTE:

Drug targeting efficiency

DTP:

Direct transport percentage

IN:

Intranasal

IV:

Intravenous

ME:

Microemulsion

MME:

Mucoadhesive microemulsions

RHT:

Rivastigmine hydrogen tartrate

WHO:

World health organization

References

  1. World Health Organization (WHO). Neurological disorders: public health challenges. Geneva: World Health Organization; 2006.

    Google Scholar 

  2. Pardridge WM. Blood–brain barrier delivery. Drug Discov Today. 2007;12(1):54–61.

    Article  CAS  PubMed  Google Scholar 

  3. Lu CT, Zhao YZ, Wong HL, Cai J, Peng L, Tian XQ. Current approaches to enhance CNS delivery of drugs across the brain barriers. Int J Nanomedicine. 2014;9:2241.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Schinkel AH. P-Glycoprotein, a gatekeeper in the blood–brain barrier. Adv Drug Deliv Rev. 1999;36(2):179–94.

    Article  CAS  PubMed  Google Scholar 

  5. Pires A, Fortuna A, Alves G, Falcao A. Intranasal drug delivery: how, why and what for? J Pharm Phrma Sci Sci. 2009;12:288–311.

    Article  CAS  Google Scholar 

  6. Shah B, Khunt D, Misra M, Padh H. Non-invasive intranasal delivery of quetiapine fumarate loaded microemulsion for brain targeting: formulation, physicochemical and pharmacokinetic consideration. Eur J Pharm Sci. 2016;91:196–207.

    Article  CAS  PubMed  Google Scholar 

  7. Alam MI, Beg S, Samad A, Baboota S, Kohli K, Ali J, et al. Strategy for effective brain drug delivery. Eur J Pharm Sci. 2010;40(5):385–403.

    Article  CAS  PubMed  Google Scholar 

  8. Illum L. Transport of drugs from the nasal cavity to the central nervous system. Eur J Pharm Sci. 2000;11(1):1–8.

    Article  CAS  PubMed  Google Scholar 

  9. Bshara H, Osman R, Mansour S, El-Shamy AE. Chitosan and cyclodextrin in intranasal microemulsion for improved brain buspirone hydrochloride pharmacokinetics in rats. Carbohydr Polym. 2014;99:297–305.

    Article  CAS  PubMed  Google Scholar 

  10. Shah B, Khunt D, Misra M, Padh H. Application of Box-Behnken design for optimization and development of quetiapine fumarate loaded chitosan nanoparticles for brain delivery via intranasal route. Int J Biol Macromol. 2016;89:206–18.

    Article  CAS  PubMed  Google Scholar 

  11. Patel RB, Patel MR, Bhatt KK, Patel BG, Gaikwad RV. Evaluation of brain targeting efficiency of intranasal microemulsion containing olanzapine: pharmacodynamic and pharmacokinetic consideration. Drug deliv. 2016;23(1):307–15.

    Article  CAS  PubMed  Google Scholar 

  12. Patel MR, Patel RB, Bhatt KK, Patel BG, Gaikwad RV. Paliperidone microemulsion for nose-to-brain targeted drug delivery system: pharmacodynamic and pharmacokinetic evaluation. Drug deliv. 2016;23(1):346–54.

    Article  CAS  PubMed  Google Scholar 

  13. Fazil M, Md S, Haque S, Kumar M, Baboota S. kaur Sahni J, Ali J. Development and evaluation of rivastigmine loaded chitosan nanoparticles for brain targeting. Eur J Pharm Sci. 2012;47(1):6–15.

    Article  CAS  PubMed  Google Scholar 

  14. Wavikar PR, Vavia PR. Rivastigmine-loaded in situ gelling nanostructured lipid carriers for nose to brain delivery. Journal of Liposome Res. 2015;25(2):141–9.

    Article  CAS  Google Scholar 

  15. Shah BM, Misra M, Shishoo CJ, Padh H. Nose to brain microemulsion-based drug delivery system of rivastigmine: formulation and ex-vivo characterization. Drug deliv. 2015;22(7):918–30.

    Article  CAS  PubMed  Google Scholar 

  16. Illum L. Nasal drug delivery: new developments and strategies. Drug Discov Today. 2002;7(23):1184–9.

    Article  CAS  PubMed  Google Scholar 

  17. Trows S, Wuchner K, Spycher R, Steckel H. Analytical challenges and regulatory requirements for nasal drug products in Europe and the US. Pharmaceutics. 2014;6(2):195–219.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Patil S, Babbar A, Mathur R, Mishra A, Sawant K. Mucoadhesive chitosan microspheres of carvedilol for nasal administration. J Drug Target. 2010;18(4):321–31.

    Article  CAS  PubMed  Google Scholar 

  19. Saha GB. Methods of radiolabeling. In: Saha GB, editor. Physics and radiobiology of nuclear medicine. New York: Springer-Verlag; 2010. p. 100–6.

    Google Scholar 

  20. Kumar M, Kakkar V, Mishra AK, Chuttani K, Kaur IP. Intranasal delivery of streptomycin sulfate (STRS) loaded solid lipid nanoparticles to brain and blood. Int J Pharm. 2014;461(1):223–33.

    CAS  PubMed  Google Scholar 

  21. FDA, US. Draft guidance for industry: bioavailability and bioequivalence studies for nasal aerosols and nasal sprays for local action. Rockville: Center for Drug Evaluation and Research, US Department of Health and Human Services; 2013. p. 1–37.

    Google Scholar 

  22. Kulkarni V, Shaw C. Formulation and characterization of nasal sprays. An examination of nasal spray formulation parameters and excipients and their influence on key in vitro tests. Inhalation. 2012;10–15.

  23. FDA, US, 2002. Guidance for industry: nasal spray and inhalation solution, suspension, and spray drug products — chemistry, manufacturing, and controls documentation. Fed Regist. 2002;1–49.

  24. Florence K, Manisha L, Kumar BA, Ankur K, Kumar MA, Ambikanandan M. Intranasal clobazam delivery in the treatment of status epilepticus. J Pharm Sci. 2011;100(2):692–703.

    Article  CAS  PubMed  Google Scholar 

  25. Nornoo AO, Zheng H, Lopes LB, Johnson-Restrepo B, Kannan K, Reed R. Oral microemulsions of paclitaxel: In situ and pharmacokinetic studies. Eur J Pharm Biopharm. 2009;71(2):310–7.

    Article  CAS  PubMed  Google Scholar 

  26. Koga K, Kusawake Y, Ito Y, Sugioka N, Shibata N, Takada K. Enhancing mechanism of Labrasol on intestinal membrane permeability of the hydrophilic drug gentamicin sulfate. Eur J Pharm Biopharm. 2006 Aug 31;64(1):82–91.

    Article  CAS  PubMed  Google Scholar 

  27. Javadzadeh Y, Adibkia K, Hamishekar H. Transcutol® (Diethylene Glycol Monoethyl Ether): A Potential Penetration Enhancer. Percutaneous Penetration Enhanc. Chem. Methods Penetration Enhanc. Heidelberg: Springer; 2015:195–205. https://doi.org/10.1007/978-3-662-47039-8_12

  28. Bickel U, Schumacher OP, Kang YS, Voigt K. Poor permeability of morphine 3-glucuronide and morphine 6-glucuronide through the blood-brain barrier in the rat. J Pharm Exp Ther. 1996;278(1):107–13.

    CAS  Google Scholar 

  29. Westin UE, Boström E, Gråsjö J, Hammarlund-Udenaes M, Björk E. Direct nose-to-brain transfer of morphine after nasal administration to rats. Pharm Res. 2006;23(3):565–72.

    Article  CAS  PubMed  Google Scholar 

  30. Md S, Khan RA, Mustafa G, Chuttani K, Baboota S, Sahni JK, et al. Bromocriptine loaded chitosan nanoparticles intended for direct nose to brain delivery: pharmacodynamic, pharmacokinetic and scintigraphy study in mice model. Eur J Pharm Sci. 2013;48(3):393–405.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments and Disclosures

Authors are grateful to B.V. Patel PERD Centre for providing research facilities. Brijesh Shah is thankful to Lady Tata Memorial Trust (Bombay, India) for providing financial assistance. The project was also partially funded by Department of Science and Technology (Grant No. - IFA-LSBM-13, Delhi, India) and Industries commissionerate (Govt. of Gujarat). Authors would like to acknowledge, head of the Dept. of Pharmacology and Toxicology at B.V. Patel PERD Centre, Ahmedabad for providing animal facilities. Authors would like to express their gratitude to Dr. Seamus Murphy (Manger-Imaging division, Oxford lasers Ltd., UK) and Mr. Jitendra Nadgeer (Product Manager, Inkarp Instruments, India) for their help in nasal spray pattern studies. The authors have no conflict of interest. The contents of the manuscript and its drafting is solely done by the authors.

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Authors and Affiliations

  1. Department of Pharmaceutics, B. V. Patel PERD Centre, Ahmedabad, 380054, India

    Brijesh Shah

  2. Department of Pharmaceutics, NIPER-Ahmedabad, Gandhinagar, 382355, India

    Dignesh Khunt & Manju Misra

  3. B. V. Patel PERD Centre, Ahmedabad, Gujarat, 380054, India

    Harish Padh

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  1. Brijesh Shah
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  2. Dignesh Khunt
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  4. Harish Padh
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Corresponding author

Correspondence to Harish Padh.

Additional information

Guest Editor: Davide Brambilla

Brijesh Shah is registered research scholar at Institute of Pharmacy, Nirma University.

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Shah, B., Khunt, D., Misra, M. et al. Formulation and In-vivo Pharmacokinetic Consideration of Intranasal Microemulsion and Mucoadhesive Microemulsion of Rivastigmine for Brain Targeting. Pharm Res 35, 8 (2018). https://doi.org/10.1007/s11095-017-2279-z

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