Advertisement

Drug Delivery and Translational Research

, Volume 9, Issue 1, pp 311–318 | Cite as

Effect of polysorbate 80 on the intranasal absorption and brain distribution of tetramethylpyrazine phosphate in rats

  • Mingyue Gao
  • Dan Mei
  • Yingnan Huo
  • Shirui MaoEmail author
Original Article

Abstract

Drug delivery to the brain is limited by the blood-brain barrier (BBB). Intranasal delivery is a non-invasive route of drug administration which can bypass the BBB and contributed to a direct and rapid transport of drugs to the brain. However, intrinsic drug distribution to the brain after intranasal administration may not be sufficient to achieve required clinical efficacy. In this study, taking 2,3,5,6-tetramethylpyrazine (TMPP) as a model drug, the feasibility of using polysorbate 80 as an absorption enhancer and message guider to increase drug distribution in the brain was employed. After intravenous/intranasal administration of TMPP formulations with/without polysorbate 80, drug concentration in both plasma and brain was measured at specific time points, and the pharmacokinetic parameters were compared. It was demonstrated that compared with intravenous administration, brain targeting efficiency of TMPP was improved remarkably by intranasal route. Upon intranasal administration, the addition of polysorbate 80 significantly increased TMPP concentration in both plasma and brain linearly up to polysorbate 80 concentration 2%. Based on drug targeting efficiency, drug targeting index, and nose-to-brain direct transport percentage, polysorbate 80 decreased the nose-to-brain direct transport ratio of TMPP in a polysorbate 80 concentration-dependent manner although the total brain targeting efficiency was unchanged, with significantly enhanced absolute drug concentration in the brain achieved. In summary, polysorbate 80 is a promising excipient to increase drug concentration in both plasma and brain via intranasal route.

Keywords

Polysorbate 80 Absorption Brain distribution Nasal Tetramethylpyrazine phosphate 

Notes

Compliance with ethical standards

All institutional and national guidelines for the care and use of laboratory animals were followed.

Declaration

The experiments comply with the current laws of China.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Wolburg H, Lippoldt A. Tight junctions of the blood-brain barrier: development, composition and regulation. Vasc Pharmacol. 2002;38:323–37.CrossRefGoogle Scholar
  2. 2.
    Abolhasanzadeh Z, Ashrafi H, Badr P, Azadi A. Traditional neurotherapeutics approach intended for direct nose to brain delivery. J Ethnopharmacol. 2017;209:116–23.CrossRefGoogle Scholar
  3. 3.
    Kozlovskaya L, Abou-Kaoud M, Stepensky D. Quantitative analysis of drug delivery to the brain via nasal route. J Control Release. 2014;189:133–40.CrossRefGoogle Scholar
  4. 4.
    Marianecci C, Rinaldi F, Hanieh PN, Di Marzio L, Paolino D, Carafa M. Drug delivery in overcoming the blood-brain barrier: role of nasal mucosal grafting. Drug Des Dev Ther. 2017;11:325–35.CrossRefGoogle Scholar
  5. 5.
    Fortuna A, Alves G, Serralheiro A, Sousa J, Falcao A. Intranasal delivery of systemic-acting drugs: small-molecules and biomacromolecules. Eur J Pharm Biopharm. 2014;88:8–27.CrossRefGoogle Scholar
  6. 6.
    Abdelbary GA, Tadros MI. Brain targeting of olanzapine via intranasal delivery of core-shell difunctional block copolymer mixed nanomicellar carriers: in vitro characterization, ex vivo estimation of nasal toxicity and in vivo biodistribution studies. Int J Pharm. 2013;452:300–10.CrossRefGoogle Scholar
  7. 7.
    Pardridge WM. Molecular Trojan horses for blood-brain barrier drug delivery. Curr Opin Pharmacol. 2006;6:494–500.CrossRefGoogle Scholar
  8. 8.
    Khan AR, Liu M, Khan MW, Zhai G. Progress in brain targeting drug delivery system by nasal route. J Control Release. 2017;268:364–89.CrossRefGoogle Scholar
  9. 9.
    Gulyaev AE, Gelperina SE, Skidan IN, Antropov AS, Kivman GY, Kreuter J. Significant transport of doxorubicin into the brain with polysorbate 80-coated nanoparticles. Pharm Res. 1999;16:1564–9.CrossRefGoogle Scholar
  10. 10.
    Wilson B, Samanta MK, Santhi K, Kumar KPS, Paramakrishnan N, Suresh B. Targeted delivery of tacrine into the brain with polysorbate 80-coated poly(n-butylcyanoacrylate) nanoparticles. Eur J Pharm Biopharm. 2008;70:75–84.CrossRefGoogle Scholar
  11. 11.
    Wohlfart S, Khalansky AS, Gelperina S, Begley D, Kreuter J. Kinetics of transport of doxorubicin bound to nanoparticles across the blood-brain barrier. J Control Release. 2011;154:103–7.CrossRefGoogle Scholar
  12. 12.
    Yuan ZY, Hu YL, Gao JQ. Brain localization and neurotoxicity evaluation of polysorbate 80-modified chitosan nanoparticles in rats. PLoS One. 2015;10:e0134722.CrossRefGoogle Scholar
  13. 13.
    Ruan Y, Yao L, Zhang B, Zhang S, Guo J. Nanoparticle-mediated delivery of neurotoxin-II to the brain with intranasal administration: an effective strategy to improve antinociceptive activity of neurotoxin. Drug Dev Ind Pharm. 2012;38:123–8.CrossRefGoogle Scholar
  14. 14.
    Ruan Y, Yao L, Zhang B, Zhang S, Guo J. Antinociceptive properties of nasal delivery of neurotoxin-loaded nanoparticles coated with polysorbate-80. Peptides. 2011;32:1526–9.CrossRefGoogle Scholar
  15. 15.
    Bagad M, Khan ZA. Poly(n-butylcyanoacrylate) nanoparticles for oral delivery of quercetin: preparation, characterization, and pharmacokinetics and biodistribution studies in wistar rats. Int J Nanomedicine. 2015;10:3921–35.Google Scholar
  16. 16.
    Gajbhiye V, Jain NK. The treatment of glioblastoma xenografts by surfactant conjugated dendritic nanoconjugates. Biomaterials. 2011;32:6213–25.CrossRefGoogle Scholar
  17. 17.
    Kreuter J, Shamenkov D, Petrov V, Ramge P, Cychutek K, Koch-Brandt C, et al. Apolipoprotein-mediated transport of nanoparticle-bound drugs across the blood-brain barrier. J Drug Target. 2002;10:317–25.CrossRefGoogle Scholar
  18. 18.
    Guo SK, Chen KJ, Qian ZH, Weng WL, Qian MY. Tetramethylpyrazine in the treatment of cardiovascular and cerebrovascular diseases. Planta Med. 1983;47:89.CrossRefGoogle Scholar
  19. 19.
    Mei D, Mao S, Sun W, Wang Y, Kissel T. Effect of chitosan structure properties and molecular weight on the intranasal absorption of tetramethylpyrazine phosphate in rats. Eur J Pharm Biopharm. 2008;70:874–81.CrossRefGoogle Scholar
  20. 20.
    Chow HS, Chen Z, Matsuura GT. Direct transport of cocaine from the nasal cavity to the brain following intranasal cocaine administration in rats. J Pharm Sci. 1999;88:754–8.CrossRefGoogle Scholar
  21. 21.
    Zhang QZ, Jiang XG, Jiang WM, Lu W, Su LN, Shi ZQ. Preparation of nimodipine-loaded microemulsion for intranasal delivery and evaluation on the targeting efficiency to the brain. Int J Pharm. 2004;275:85–96.CrossRefGoogle Scholar
  22. 22.
    Wang F, Jiang XG. Lu W. Profiles of methotrexate in blood and CSF following intranasal and intravenous administration to rats. Int J Pharm. 2003;263:1–7.CrossRefGoogle Scholar
  23. 23.
    Cai W, Dong SN, Lou YQ. HPLC determination of tetramethylpyrazine in human serum and its pharmacokinetic parameters. Yao Xue Xue Bao. 1989;24:881–6.Google Scholar
  24. 24.
    Ross TM, Martinez PM, Renner JC, Thorne RG, Hanson LR, Frey WH. Intranasal administration of interferon beta bypasses the blood-brain barrier to target the central nervous system and cervical lymph nodes: a non-invasive treatment strategy for multiple sclerosis. J Neuroimmunol. 2004;151:66–77.CrossRefGoogle Scholar
  25. 25.
    Liang CC, Hong CY, Chen CF, Tsai TH. Measurement and pharmacokinetic study of tetramethylpyrazine in rat blood and its regional brain tissue by high-performance liquid chromatography. J Chrom B Biomed Sci Appl. 1999;724:303–9.CrossRefGoogle Scholar
  26. 26.
    Tsai TH, Liang C. Pharmacokinetics of tetramethylpyrazine in rat blood and brain using microdialysis. Int J Pharm. 2001;216:61–6.CrossRefGoogle Scholar
  27. 27.
    Kichler A, Chillon M, Leborgne C, Danos O, Frisch B. Intranasal gene delivery with a polyethylenimine-PEG conjugate. J Control Release. 2002;81:379–88.CrossRefGoogle Scholar
  28. 28.
    Lu W, Jiang W, Chen J, Yin M, Wang Z, Jiang X. Modulation of brain delivery and copulation by intranasal apomorphine hydrochloride. Int J Pharm. 2008;349:196–205.CrossRefGoogle Scholar
  29. 29.
    Lochhead JJ, Thorne RG. Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev. 2012;64:614–28.CrossRefGoogle Scholar
  30. 30.
    Kaneda A, Nishimura K, Muranishi S, Sezaki H. Mechanism of drug absorption from micellar solution. II. Effect of polysorbate 80 on the absorption of micelle-free drugs. Chem Pharm Bull. 1974;22:523–8.CrossRefGoogle Scholar
  31. 31.
    Som I, Bhatia K, Yasir M. Status of surfactants as penetration enhancers in transdermal drug delivery. J Pharm Bioall Sci. 2012;4:2–9.CrossRefGoogle Scholar
  32. 32.
    Kaur G, Mehta SK. Developments of polysorbate (Tween) based microemulsions: preclinical drug delivery, toxicity and antimicrobial applications. Int J Pharm. 2017;529:134–60.CrossRefGoogle Scholar
  33. 33.
    Buyukozturk F, Benneyan JC, Carrier RL. Impact of emulsion-based drug delivery systems on intestinal permeability and drug release kinetics. J Control Release. 2010;142:22–30.CrossRefGoogle Scholar
  34. 34.
    Levy G, Miller KE, Reuning RH. Effect of complex formation on drug absorption III: concentration- and drug-dependent effect of a nonionic surfactant. J Pharm Sci. 1966;55:394–8.CrossRefGoogle Scholar
  35. 35.
    Jin F, Lei B, Wen C. Insulin nasal powder inhalation: United states patent application publication. US 20100292141 A1, 2010.Google Scholar

Copyright information

© Controlled Release Society 2018

Authors and Affiliations

  1. 1.School of PharmacyShenyang Pharmaceutical UniversityShenyangChina

Personalised recommendations