Skip to main content Skip to main navigation menu Skip to site footer
  • \
    Start Submission Become a Reviewer

    Development of a Eudragit-Chitosan Nanosystem for the pH-Dependent Transport of Duloxetine to the Brain: Synthesis, Characterization and In Silico Modeling Analysis

    • Pierre P. D. Kondiah
    • Sipho Mdanda
    • Sifiso S. Makhathini
    • Thankhoe A. Rants’o
    • Yahya E. Choonara


    Abstract

    The purpose of this study was to synthesize duloxetine (DLX)- loaded Eudragit-Chitosan (Eud-CHT) nanoparticles enclosed in an oral gelatin capsule and to evaluate the potential to transport DLX to the blood-brain barrier (BBB)for improved neuro-availability. The utilization of Eudragit® with chitosan offers a pH-dependent controlled drug release. The physicochemical properties of the formulated DLX-loaded Eud-CHT nanosystem were confirmed using various characterization techniques. SEM confirmed the nanoparticle morphology and pore size distribution. The particle size was 100 ± 73,41 nm, with a polydispersity index (PDI) of 0,283 and zeta potential of 16±2,79 mV. Drug entrapment efficacy (DEE) of 72% was attained, and molecular modelling predicted an efficient and controllable drug delivery system. The release of DLX from the nanosystem was evaluated at pH1.2, pH 6.8 and pH 7.4. At a pH of 6.8, 40 % of DLX was released, with only 20 % at pH 1.2 and 35% at pH 7.4. This demonstrated DLX's pH-dependent release and the Eud-CHT nanosystem's shielding effect at gastric pH.  In addition, HEK 293 neural cells confirmed the non-toxicity of the DLX-Eud-CHT nanosystem. In silico modelling revealed a DLX-Eud-CHT composite with an outer cationic surface attributable to the EUD moieties on nanoparticles for preferential cell recognition and uptake at the anionic cell interface. The combined trials and results from the synthesis of DLX-Eud-CHT nanoparticles showed that these nanoparticles could be utilized as a potentially invaluable formulation for oral drug delivery of duloxetine with improved neuro-availability.

    Keywords: Duloxetine eudragit-chitosan (Eud-CHT) nanoparticles oral delivery pH-dependent
    Section

    References

    1. Abdelfatah, Kang K, Pournik M, Shiau B, Harwell J, Haroun MR, Rahman MM. (2017). Study of nanoparticle adsorption and release in porous media based on the DLVO theory. In SPE Latin America and Caribbean Petroleum Engineering Conference. OnePetro.
    2. Adibkia, K., Javadzadeh, Y., Dastmalchi, S., Mohammadi, G., Niri, F. K., & Alaei-Beirami, M. (2011). Naproxen–eudragit® RS100 nanoparticles: Preparation and physicochemical characterization. Colloids and Surfaces B: Biointerfaces, 83(1), 155-159.
    3. Akechi, T., Mantani, A., Kurata, K. i., Hirota, S., Shimodera, S., Yamada, M., . . . Furukawa, T. A. (2019). Predicting relapse in major depression after successful initial pharmacological treatment. Journal of Affective Disorders, 250, 108-113.
    4. Akhtar, B., Muhammad, F., Aslam, B., Saleemi, M. K., & Sharif, A. (2020). Biodegradable nanoparticle based transdermal patches for gentamicin delivery: Formulation, characterization and pharmacokinetics in rabbits. Journal of Drug Delivery Science and Technology, 57, 101680.
    5. Boisseau, P., & Loubaton, B. (2011). Nanomedicine, nanotechnology in medicine. Comptes Rendus Physique, 12(7), 620-636.
    6. Chahal, S. K., Sodhi, R. K., & Madan, J. (2020). Duloxetine hydrochloride loaded film forming dermal gel enriched with methylcobalamin and geranium oil attenuates paclitaxel-induced peripheral neuropathy in rats. IBRO reports, 9, 85-95.
    7. Chatzitaki, A.-T., Jesus, S., Karavasili, C., Andreadis, D., Fatouros, D. G., & Borges, O. (2020). Chitosan-coated PLGA nanoparticles for the nasal delivery of ropinirole hydrochloride: In vitro and ex vivo evaluation of efficacy and safety. International journal of pharmaceutics, 589, 119776.
    8. Chaves, L. L., Lima, S. A. C., Vieira, A. C., Barreiros, L., Segundo, M. A., Ferreira, D., . . . Reis, S. (2018). Development of PLGA nanoparticles loaded with clofazimine for oral delivery: Assessment of formulation variables and intestinal permeability. European Journal of Pharmaceutical Sciences, 112, 28-37.
    9. Chen, S., Guo, F., Deng, T., Zhu, S., Liu, W., Zhong, H., . . . Deng, Z. (2017). Eudragit S100-coated chitosan nanoparticles co-loading tat for enhanced oral colon absorption of insulin. Aaps Pharmscitech, 18(4), 1277-1287.
    10. Choi, Y.K., Tadmor E.B., Heinz H. (2021). CHARMM-GUI Nanomaterial Modeler for Modeling and Simulation of Nanomaterial Systems. Journal of Chemical Theory and Computation, 18(1), 479-493.
    11. Daina, A., Michielin, O., Zoete, V., SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports, 2017. 7: p. 42717.
    12. Dening, T. J., Rao, S., Thomas, N., & Prestidge, C. A. (2016). Oral nanomedicine approaches for the treatment of psychiatric illnesses. Journal of Controlled Release, 223, 137-156.
    13. Dong, P., Sahle, F. F., Lohan, S. B., Saeidpour, S., Albrecht, S., Teutloff, C., . . . Haag, R. (2019). pH-sensitive Eudragit® L 100 nanoparticles promote cutaneous penetration and drug release on the skin. Journal of Controlled Release, 295, 214-222.
    14. DuBay, K.H., Hall, M.L., Hughes, T.F., Wu, C., Reichman, D.R., Friesner, R.A. (2012). Accurate force field development for modeling conjugated polymers. Journal of Chemical Theory and Computation, 8(11), 4556-69.
    15. Gagliardi, A., Bonacci, S., Paolino, D., Celia, C., Procopio, A., Fresta, M., & Cosco, D. (2019). Paclitaxel-loaded sodium deoxycholate-stabilized zein nanoparticles: characterization and in vitro cytotoxicity. Heliyon, 5(9), e02422.
    16. Gartner III TE, Jayaraman A. (2019). Modeling and simulations of polymers: a roadmap. Macromolecules, 52(3), 755-786.
    17. Ghaffari, A., Navaee, K., Oskoui, M., Bayati, K., Rafiee-Tehrani, M. (2007). Preparation and characterization of free mixed-film of pectin/chitosan/Eudragit® RS intended for sigmoidal drug delivery. European Journal of Pharmaceutics and Biopharmaceutics, 67(1), 175-186.
    18. Guo, S., Wang, G., Wu, T., Bai, F., Xu, J., & Zhang, X. (2017). Solid dispersion of berberine hydrochloride and Eudragit® S100: Formulation, physicochemical characterization and cytotoxicity evaluation. Journal of Drug Delivery Science and Technology, 40, 21-27.
    19. Indurkhya, A., Patel, M., Sharma, P., Abed, S. N., Shnoudeh, A., Maheshwari, R., . . . Tekade, R. K. (2018). Influence of drug properties and routes of drug administration on the design of controlled release system Dosage form design considerations (pp. 179-223): Elsevier.
    20. Jafari, S., Maleki-Dizaji, N., Barar, J., Barzegar-Jalali, M., Rameshrad, M., & Adibkia, K. (2016). Physicochemical characterization and in vivo evaluation of triamcinolone acetonide-loaded hydroxyapatite nanocomposites for treatment of rheumatoid arthritis. Colloids and Surfaces B: Biointerfaces, 140, 223-232.
    21. Jana, U., Mohanty, A. K., Manna, P. K., & Mohanta, G. P. (2014). Preparation and characterization of nebivolol nanoparticles using Eudragit® RS100. Colloids and Surfaces B: Biointerfaces, 113, 269-275.
    22. Jothimani, B., Sureshkumar, S., & Venkatachalapathy, B. (2017). Hydrophobic structural modification of chitosan and its impact on nanoparticle synthesis–A physicochemical study. Carbohydrate polymers, 173, 714-720.
    23. Keck, C. M., & Müller, R. H. (2006). Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation. European journal of pharmaceutics and biopharmaceutics, 62(1), 3-16.
    24. Khosa, A., Reddi, S., & Saha, R. N. (2018). Nanostructured lipid carriers for site-specific drug delivery. Biomedicine & Pharmacotherapy, 103, 598-613.
    25. Kondiah, P. P., Tomar, L. K., Tyagi, C., Choonara, Y. E., Modi, G., du Toit, L. C., . . . Pillay, V. (2013). A novel pH-sensitive interferon-β (INF-β) oral delivery system for application in multiple sclerosis. International journal of pharmaceutics, 456(2), 459-472.
    26. Lolicato, F., Akola, J., Martinez-Searaa, H., Vattulainen, I. (2017). Nanoparticle builder: new software for preparing nanoparticles for molecular dynamics simulations. European Biophysics Journal, 46(1 Supplement), S222.
    27. Mani, G., Pushparaj, H., Peng, M. M., Muthiahpillai, P., Udhumansha, U., & Jang, H. T. (2014). Synthesis and characterization of pharmaceutical surfactant templated mesoporous silica: Its application to controlled delivery of duloxetine. Materials Research Bulletin, 51, 228-235.
    28. Marwaha, T.K., Madgulkar, A., Bhalekar, M., & Asgaonkar, K. (2020). Molecular docking, synthesis, and characterization of chitosan-graft-2-mercaptobenzoic acid derivative as potential drug carrier. Journal of Applied Polymer Science, 137, e49551.
    29. Mavrantzas, V.G., (2021). Using Monte Carlo to simulate complex polymer systems: recent progress and outlook. Frontiers in Physics, 9, 661367.
    30. Martín-Illana, A., Cazorla-Luna, R., Notario-Pérez, F., Rubio, J., Ruiz-Caro, R., Tamayo, A., & Veiga, M. (2022). Eudragit® L100/chitosan composite thin bilayer films for intravaginal pH-responsive release of Tenofovir. International journal of pharmaceutics, 616, 121554.
    31. McNally, H., Pingle, M., Lee, S., Guo, D., Bergstrom, D. E., & Bashir, R. (2003). Self-assembly of micro-and nano-scale particles using bio-inspired events. Applied Surface Science, 214(1-4), 109-119.
    32. Menezes, J., dos Santos, H., Ferreira, M., Magalhães, F., da Silva, D., Bandeira, P., . . . Cruz, B. (2020). Preparation, structural and spectroscopic characterization of chitosan membranes containing allantoin. Journal of Molecular Structure, 1199, 126968.
    33. Mohammadi, G., Namadi, E., Mikaeili, A., Mohammadi, P., & Adibkia, K. (2017). Preparation, physicochemical characterization and anti-fungal evaluation of the Nystatin-loaded Eudragit RS100/PLGA nanoparticles. Journal of Drug Delivery Science and Technology, 38, 90-96.
    34. Nasef, A. M., Gardouh, A. R., & Ghorab, M. M. (2017). Formulation and in-vitro evaluation of pantoprazole loaded pH-sensitive polymeric nanoparticles. Future Journal of Pharmaceutical Sciences, 3(2), 103-117.
    35. Nataraj, D., Sakkara, S., Meghwal, M., Reddy, N. (2018). Crosslinked chitosan films with controllable properties for commercial applications. International Journal of Biological Macromolecules, 120, 1256-64.
    36. Pantshwa, J., Choonara, Y. E., Kumar, P., du Toit, L. C., Penny, C., & Pillay, V. (2017). Synthesis of novel amphiphilic poly (N-isopropylacrylamide)-b-poly (aspartic acid) nanomicelles for potential targeted chemotherapy in ovarian cancer. Journal of Drug Delivery Science and Technology, 39, 308-323.
    37. Patel, N. V., Sheth, N. R., & Mohddesi, B. (2015). Formulation and evaluation of genistein–a novel isoflavone loaded chitosan and eudragit® nanoparticles for cancer therapy. Materials Today: Proceedings, 2(9), 4477-4482.
    38. Paulzen, M., Gründer, G., Veselinovic, T., Wolf, B., Hiemke, C., & Lammertz, S. E. (2016). Duloxetine enters the brain–But why is it not found in the cerebrospinal fluid. Journal of Affective Disorders, 189, 159-163.
    39. Posadas, I., Monteagudo, S., & Ceña, V. (2016). Nanoparticles for brain-specific drug and genetic material delivery, imaging and diagnosis. Nanomedicine, 11(7), 833-849.

    How to Cite

    Development of a Eudragit-Chitosan Nanosystem for the pH-Dependent Transport of Duloxetine to the Brain: Synthesis, Characterization and In Silico Modeling Analysis. (2022). Nanofabrication, 7, 195-216. https://doi.org/10.37819/nanofab.007.246
    ACM ACS APA ABNT Chicago Harvard IEEE MLA Turabian Vancouver
    Download Citation
    Endnote/Zotero/Mendeley (RIS) BibTeX

    How to Cite

    Development of a Eudragit-Chitosan Nanosystem for the pH-Dependent Transport of Duloxetine to the Brain: Synthesis, Characterization and In Silico Modeling Analysis. (2022). Nanofabrication, 7, 195-216. https://doi.org/10.37819/nanofab.007.246

    HTML
    272

    Total
    113 4

    Share

    Search Panel

    Pierre P. D. Kondiah
    Google Scholar
    Pubmed
    JDMFS Journal

    Sipho Mdanda
    Google Scholar
    Pubmed
    JDMFS Journal

    Sifiso S. Makhathini
    Google Scholar
    Pubmed
    JDMFS Journal

    Thankhoe A. Rants’o
    Google Scholar
    Pubmed
    JDMFS Journal

    Yahya E. Choonara
    Google Scholar
    Pubmed
    JDMFS Journal

    Downloads

    Article Details

    Most Read This Month

    License

    Copyright (c) 2022 Pierre P. D. Kondiah, Sipho Mdanda, Sifiso S. Makhathini, Thankhoe A. Rants’o, Yahya E. Choonara

    Creative Commons License

    This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License.

    Most read articles by the same author(s)

    Copyright © 2023 EurAsia Academic Publishing Group. All rights reserved