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Piribedil loaded thermo-responsive nasal in situ gelling system for enhanced delivery to the brain: formulation optimization, physical characterization, and in vitro and in vivo evaluation

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Abstract

Methyl cellulose (MC) based nasal in situ gels were developed to enhance the brain delivery of piribedil (PBD), an anti-Parkinson’s drug. Different grades of MC and several solutes (NaCl, KCl, Na.Citrate, STPP, PEG-6000, sucrose, etc.) were screened to formulate thermo-responsive nasal in situ gelling systems. Formulations were evaluated for their sol-gel transition temperature and time, rheological behaviour, in vitro drug release, mucociliary clearance (MCC), ex vivo nasal toxicity, and in vivo brain availability studies in Wistar rats. Intranasal (i.n.) administration was carried out using a cannula-microtip setup to deliver PBD at the olfactory region of the nose. The concentration and viscosity grade of MC and also the concentration and type of solute used were found to affect the rheological behaviour of the formulations. Among the solutes tested, NaCl was found to be effective for formulating MC in situ gels. The developed in situ gels significantly delayed the MCC of PBD from the site of administration when compared with conventional suspension (p < 0.05). Further, formulations with higher gel strength showed lower in vitro drug release rate and longer intranasal residence (delayed MCC) (p < 0.05). The absolute brain availability (brain AUC0-t) of PBD increased to 35.92% with i.n. delivery when compared to 4.71% with oral administration. Overall, it can be concluded that intranasal delivery of PBD is advantageous when compared to the currently practiced oral therapy.

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References

  1. Türker S, Onur E, Ózer Y. Nasal route and drug delivery systems. Pharm World Sci. 2004;26:137–42.

    Article  Google Scholar 

  2. Bitter C, Suter-Zimmermann K, Surbera C. Nasal drug delivery in humans. Top Appl Mucosa. Basel: KARGER; 2011. p. 20–35.

    Google Scholar 

  3. Illum L. Is nose-to-brain transport of drugs in man a reality? J Pharm Pharmacol. 2004;56:3–17.

    Article  CAS  Google Scholar 

  4. Illum L. Intranasal Delivery to the central nervous system. In: Di L, Kerns EH, editors. Blood-Brain Barrier Drug Discov. Hoboken, NJ: John Wiley & Sons, Inc; 2015. p. 535–65.

    Google Scholar 

  5. Merkus FWHM, van den Berg MP. Can nasal drug delivery bypass the??Blood-brain barrier? Drugs R D. 2007;8:133–44.

    Article  CAS  Google Scholar 

  6. Mittur A. Piribedil: Antiparkinsonian properties and potential clinical utility in dopaminergic disorders. Curr Drug Ther. 2010;6:17–34.

    Article  Google Scholar 

  7. Deleu D, Northway MG, Hanssens Y. Clinical pharmacokinetic and pharmacodynamic properties of drugs used in the treatment of Parkinson’s disease. Clin Pharmacokinet. 2002;41:261–309.

    Article  CAS  Google Scholar 

  8. Torti M, Bravi D, Vacca L, Stocchi F. Are all dopamine agonists essentially the same? Drugs. 2019;79:693–703.

    Article  CAS  Google Scholar 

  9. Nodel MR, Obukhova AV, Yakhno NN. The efficacy of piribedil in the treatment of neuropsychiatric disorders at early stages of Parkinson’s disease. Nevrol Zhurnal Izdatel’stvo Meditsina. 2016;21:110–6.

    Google Scholar 

  10. Kaur P, Garg T, Rath G, Goyal AK. In situ nasal gel drug delivery: a novel approach for brain targeting through the mucosal membrane. Artif Cells Nanomed Biotechnol. 2016;44:1167–76.

    CAS  PubMed  Google Scholar 

  11. Ravi PR, Aditya N, Patil S, Cherian L. Nasal in-situ gels for delivery of rasagiline mesylate: improvement in bioavailability and brain localization. Drug Deliv. 2015;22:903–10.

    Article  CAS  Google Scholar 

  12. Zahir-Jouzdani F, Wolf JD, Atyabi F, Bernkop-Schnürch A. In situ gelling and mucoadhesive polymers: why do they need each other? Expert Opin Drug Deliv. Taylor & Francis. 2018;15:1007–19.

    Article  CAS  Google Scholar 

  13. Inactive Ingredient Search for Approved Drug Products. [cited 2020 Mar 9]. Available from: https://www.accessdata.fda.gov/scripts/cder/iig/index.cfm?event=BasicSearch.page. Accessed 12 Nov 2019.

  14. Jain S, Sandhu PS, Malvi R, Gupta B. Cellulose derivatives as thermoresponsive polymer: an overview. J Appl Pharm Sci. 2013;3:139–44.

    CAS  Google Scholar 

  15. Kundu P, Kundu M. Effect of salts and surfactant and their doses on the gelation of extremely dilute solutions of methyl cellulose. Polymer. 2001;42:2015–20.

    Article  CAS  Google Scholar 

  16. Liu SQ, Joshi SC, Lam YC. Effects of salts in the Hofmeister series and solvent isotopes on the gelation mechanisms for hydroxypropylmethylcellulose hydrogels. J Appl Polym Sci. 2008;109:363–72.

    Article  CAS  Google Scholar 

  17. Marzouk MA, Osman DA, Abd El-Fattah AI. Formulation and in vitro evaluation of a thermoreversible mucoadhesive nasal gel of itopride hydrochloride. Drug Dev Ind Pharm. 2018;44:1857–67.

    Article  CAS  Google Scholar 

  18. Wang Y, Jiang S, Wang H, Bie H. A mucoadhesive, thermoreversible in situ nasal gel of geniposide for neurodegenerative diseases. PLoS One. 2017;12:1–17.

    Google Scholar 

  19. Gavini E, Rassu G, Ferraro L, Beggiato S, Alhalaweh A, Velaga S, et al. Influence of polymeric microcarriers on the in vivo intranasal uptake of an anti-migraine drug for brain targeting. Eur J Pharm Biopharm. 2013;83:174–83.

    Article  CAS  Google Scholar 

  20. Mishra B, Sankar C, Mishra M. Polymer based solutions of bupranolol hydrochloride for intranasal systemic delivery. J Drug Target. 2011;19:204–11.

    Article  CAS  Google Scholar 

  21. Pásztor E, Makó Á, Csóka G, Fenyvesi Z, Benko R, Prosszer M, et al. New formulation of in situ gelling metolose-based liquid suppository. Drug Dev Ind Pharm. 2011;37:1–7.

    Article  Google Scholar 

  22. Bhowmik M, Das S, Chattopadhyay D, Ghosh LK. Study of thermo-sensitive in-situ gels for ocular delivery. Sci Pharm. 2011;79:351–8.

    Article  CAS  Google Scholar 

  23. Bain MK, Bhowmik M, Maity D, Bera NK, Ghosh S, Chattopadhyay D. Control of thermo reversible gelation of methylcellulose using polyethylene glycol and sodium chloride for sustained delivery of ophthalmic drug. J Appl Polym Sci. 2010;118:631–7.

  24. Bhowmik M, Bain MK, Ghosh LK, Chattopadhyay D. Effect of salts on gelation and drug release profiles of methylcellulose-based ophthalmic thermo-reversible in situ gels. Pharm Dev Technol. 2011;16:385–91.

    Article  CAS  Google Scholar 

  25. Quadir M, Zia H, Needham TE. Toxicological implications of nasal formulations. Drug Deliv J Deliv Target Ther Agents. 1999;6:227–42.

    CAS  Google Scholar 

  26. Sangfai T, Tantishaiyakul V, Hirun N, Li L. Microphase separation and gelation of methylcellulose in the presence of gallic acid and NaCl as an in situ gel-forming drug delivery system. AAPS PharmSciTech. 2017;18:605–16.

    Article  CAS  Google Scholar 

  27. Uppuluri CT, Dalvi AV, Bommireddy EP, Ravi PR. Development and validation of rapid and sensitive LC methods with PDA and fluorescence detection for determination of piribedil in rat plasma and brain tissues and their pharmacokinetic application. Biomed Chromatogr. 2018;32:1–10.

    Article  Google Scholar 

  28. Charlton ST, Davis SS, Illum L. Evaluation of bioadhesive polymers as delivery systems for nose to brain delivery: in vitro characterisation studies. J Control Release. 2007;118:225–34.

    Article  CAS  Google Scholar 

  29. Javia A, Thakkar H. Intranasal delivery of tapentadol hydrochloride–loaded chitosan nanoparticles: formulation, characterisation and its in vivo evaluation. J Microencapsul Taylor & Francis. 2017;34:644–58.

    Article  CAS  Google Scholar 

  30. Lale AM, Mason JDT, Jones NS. Mucociliary transport and its assessment: a review. Clin Otolaryngol Allied Sci. 1998;23:388–96.

    Article  CAS  Google Scholar 

  31. Mittal D, Ali A, Md S, Baboota S, Sahni JK, Ali J. Insights into direct nose to brain delivery: current status and future perspective. Drug Deliv. 2014;21:75–86.

    Article  CAS  Google Scholar 

  32. Fairclough JPA, Yu H, Kelly O, Ryan AJ, Sammler RL, Radler M. Interplay between gelation and phase separation in aqueous solutions of methylcellulose and hydroxypropylmethylcellulose. Langmuir. 2012;28:10551–7.

    Article  CAS  Google Scholar 

  33. Weng L, Chen X, Chen W. Rheological characterization of in situ crosslinkable hydrogels formulated from oxidized dextran and N-carboxyethyl chitosan. Biomacromolecules. 2007;8:1109–15.

    Article  CAS  Google Scholar 

  34. Fakhari A, Corcoran M, Schwarz A. Thermogelling properties of purified poloxamer 407, vol. 3. Heliyon: Elsevier Ltd.; 2017. p. e00390.

    Google Scholar 

  35. Freitas MN, Farah M, Bretas RES, Ricci E, Marchetti JM. Rheological characterization of Poloxamer 407 nimesulide gels. Rev Ciencias Farm Basica Apl. 2006;27:113–8.

    CAS  Google Scholar 

  36. Mathematical models of drug release. Strateg to Modify Drug Release from Pharm Syst. Elsevier; 2015. p. 63–86.

  37. Principi N, Esposito S. Nasal irrigation: an imprecisely defined medical procedure. Int J Environ Res Public Health. 2017;14:516.

  38. Baraniuk JN, Ali M, Yuta A, Fang SY, Naranch K. Hypertonic saline nasal provocation stimulates nociceptive nerves, substance P release, and glandular mucous exocytosis in normal humans. Am J Respir Crit Care Med. 1999;160:655–62.

    Article  CAS  Google Scholar 

  39. Bergmann C, Müller K, Thieme U, Zeman F, Huppertz G, Koller M, et al. Real-world data on the use of hypertonic saline nasal spray in ENT practice. SN Compr Clin Med. 2019;1:354–61.

    Article  CAS  Google Scholar 

  40. Horváth T, Bartos C, Bocsik A, Kiss L, Veszelka S, Deli MA, et al. Cytotoxicity of different excipients on RPMI 2650 human nasal epithelial cells. Molecules. 2016;21:1–5.

    Article  Google Scholar 

Download references

Acknowledgments

Chandra Teja Uppuluri thanks Lady Tata Memorial Trust for awarding a Junior Research Scholarship to pursue his doctoral studies. The authors thank the Central Analytical Laboratory of BITS-Pilani, Hyderabad Campus, for providing HPLC-Fluorescence and Rheometer facilities.

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Authors and Affiliations

  1. Department of Pharmacy, BITS-Pilani Hyderabad Campus, Jawaharnagar (Village), Kapra (M), Hyderabad, Telangana, 500078, India

    Chandra Teja Uppuluri, Punna Rao Ravi, Avantika V. Dalvi, Shafik Shakil Shaikh & Suvarna R. Kale

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  1. Chandra Teja Uppuluri
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  2. Punna Rao Ravi
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  3. Avantika V. Dalvi
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  4. Shafik Shakil Shaikh
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Correspondence to Punna Rao Ravi.

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All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted and ethical approval was obtained from institute animal ethics committee (IAEC), BITS-Pilani, Hyderabad Campus (Regn. No.: 1912/PO/RE/S/16/CPCSEA).

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Uppuluri, C.T., Ravi, P.R., Dalvi, A.V. et al. Piribedil loaded thermo-responsive nasal in situ gelling system for enhanced delivery to the brain: formulation optimization, physical characterization, and in vitro and in vivo evaluation. Drug Deliv. and Transl. Res. 11, 909–926 (2021). https://doi.org/10.1007/s13346-020-00800-w

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