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Development of Morin-Loaded Nanoemulsions Containing Various Polymers; Role of Polymers in Formulation Properties and Bioavailability

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Abstract

Emulsions for oral delivery are not suitable for sustained drug absorption because such preparations diffuse rapidly in the gastrointestinal (GI) tract after oral administration. In order to generate sustained drug absorption and increase oral bioavailability, various polymers were added to a morin (MO) nanoemulsion to improve retention in the GI tract and alter the surface properties of oil droplets in the nanoemulsion. The influence of these polymers on the formulation properties was investigated. The area under the blood concentration–time curve (AUC) and the mean residence time (MRT) after oral administration of the nanoemulsions were measured, and the influence of the polymers on bioavailability was investigated. Chitosan (Chi) addition MO nanoemulsion (MO-Chi nanoemulsion) showed the highest AUC and MRT. MO-Chi nanoemulsion increased retention in the GI tract because of the relatively higher viscosity and high affinity between mucin and Chi covering the oil droplets. Furthermore, MO-Chi nanoemulsion could maintain the drug in oil droplets by suppression of drug release through the polymer hydration layer, and sustained drug release achieved continuous drug absorption. Nanoemulsions with sodium carboxymethylcellulose and poly-γ-glutamic acid potassium salt showed the next highest AUC and MRT after MO-Chi nanoemulsion. From these results, it was suggested that by increasing the viscosity of the nanoemulsion, there was high affinity between the added polymer and mucin, and sustained drug release was useful for enhancing the bioavailability of the polymer-containing nanoemulsions.

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References

  1. Caselli A, Cirri P, Santi A, Paoli P. Morin: a promising natural drug. Curr Med Chem. 2016;23:774–91.

    Article  Google Scholar 

  2. Mo JS, Choi D, Han YR, Kim N, Jeong HS. Morin has protective potential against ER stress induced apoptosis in renal proximal tubular HK-2 cells. Biomed Pharmacother. 2019. https://doi.org/10.1016/j.biopha.2019.108659.

  3. Ola MS, Aleisa AM, Al-Rejaie SS, Abuohashish HM, Parmar MY, Alhomida AS, et al. Flavonoid, morin inhibits oxidative stress, inflammation and enhances neurotrophic support in the brain of streptozotocin-induced diabetic rats. Neurol Sci. 2014;35:1003–8.

    Article  Google Scholar 

  4. Birt DF, Hendrich S, Wang W. Dietary agents in cancer prevention: flavonoids and isoflavonoids. Pharmacol Ther. 2001;90:157–77.

    Article  CAS  Google Scholar 

  5. Garcia-Lafuente A, Guillamon E, Villares A, Rostagno MA, Martinez JA. Flavonoids as anti-inflammatory agents: implications in cancer and cardiovascular disease. Inflamm Res. 2009;58:537–52.

    Article  CAS  Google Scholar 

  6. Sivaramakrishnan V, Devaraj SN. Morin fosters apoptosis in experimental hepatocellular carcinogenesis model. Chem Biol Interact. 2010;183:284–92.

    Article  CAS  Google Scholar 

  7. Al-Numair KS, Chandramohan G, Alsaif MA, Veeramani C, El Newehy AS. Morin, a flavonoid, on lipid peroxidation and antioxidant status in experimental myocardial ischemic rats. Afr J Tradit Complement Altern Med. 2014;11:14–20.

    Article  CAS  Google Scholar 

  8. Paoli P, Cirri P, Caselli A, Ranaldi F, Bruschi G, Santi A, et al. The insulin-mimetic effect of morin: a promising molecule in diabetes treatment. Biochim Biophys Acta. 1830;2013:3102–11.

    Google Scholar 

  9. Noor H, Cao P, Raleigh DP. Morin hydrate inhibits amyloid formation by islet amyloid polypeptide and disaggregates amyloid fibers. Protein Sci. 2012;21:373–82.

    Article  CAS  Google Scholar 

  10. Jin H, Lee WS, Eun SY, Jung JH, Park HS, Kim G, et al. Morin, a flavonoid from Moraceae, suppresses growth and invasion of the highly metastatic breast cancer cell line MDA-MB231 partly through suppression of the Akt pathway. Int J Oncol. 2014;45:1629–37.

    Article  CAS  Google Scholar 

  11. Brglez Mojzer E, Knez Hrnčič M, Škerget M, Knez Ž, Bren U. Polyphenols: extraction methods, antioxidative action, bioavailability and anticarcinogenic effects Molecules 2016. doi:https://doi.org/10.3390/molecules21070901.

  12. Choi YA, Yoon YH, Choi K, Kwon M, Goo SH, Cha JS, et al. Enhanced oral bioavailability of morin administered in mixed micelle formulation with PluronicF127 and Tween80 in rats. Biol Pharm Bull. 2015;38:208–17.

    Article  CAS  Google Scholar 

  13. Tian XJ, Yang XW, Yang X, Wang K. Studies of intestinal permeability of 36 flavonoids using Caco-2 cell monolayer model. Int J Pharm. 2009;367:58–64.

    Article  CAS  Google Scholar 

  14. Zhang J, Peng Q, Shi S, Zhang Q, Sun X, Gong T, et al. Preparation, characterization, and in vivo evaluation of a self-nanoemulsifying drug delivery system (SNEDDS) loaded with morin-phospholipid complex. Int J Nanomedicine. 2011;6:3405–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Khani S, Keyhanfar F, Amani A. Design and evaluation of oral nanoemulsion drug delivery system of mebudipine. Drug Deliv. 2016;23:2035–43.

    Article  CAS  Google Scholar 

  16. Chen BH, Stephen IB. Nanoemulsion and nanoliposome based strategies for improving anthocyanin stability and bioavailability. Nutrients. 2019. https://doi.org/10.3390/nu11051052.

  17. Li-Blatter X, Nervi P, Seelig A. Detergents as intrinsic P-glycoprotein substrates and inhibitors. Biochim Biophys Acta Biomembr. 1788;2009:2335–44.

    Google Scholar 

  18. Rege BD, Kao JP, Polli JE. Effects of nonionic surfactants on membrane transporters in Caco-2 cell monolayers. Eur J Pharm Sci. 2002;16:237–46.

    Article  CAS  Google Scholar 

  19. Hugger ED, Novak BL, Burton PS, Audus KL, Borchardt RT. A comparison of commonly used polyethoxylated pharmaceutical excipients on their ability to inhibit P-glycoprotein activity in vitro. J Pharm Sci. 2002;91:1991–2002.

    Article  CAS  Google Scholar 

  20. Lo YL. Relationships between the hydrophilic–lipophilic balance values of pharmaceutical excipients and their multidrug resistance modulating effect in Caco-2 cells and rat intestines. J Control Release. 2003;90:37–48.

    Article  CAS  Google Scholar 

  21. Nielsen CU, Abdulhussein AA, Colak D, Holm R. Polysorbate 20 increases oral absorption of digoxin in wild-type Sprague Dawley rats, but not in mdr1a(-/-) Sprague Dawley rats. Int J Pharm. 2016;513:78–87.

    Article  CAS  Google Scholar 

  22. Sharom FJ. Complex interplay between the P-glycoprotein multidrug efflux pump and the membrane: its role in modulating protein function. Front Oncol. 2014. https://doi.org/10.3389/fonc.2014.00041.

  23. Constantinides PP, Wasan KM. Lipid formulation strategies for enhancing intestinal transport and absorption of P-glycoprotein (P-gp) substrate drugs: in vitro/in vivo case studies. J Pharm Sci. 2007;96:235–48.

    Article  CAS  Google Scholar 

  24. Cornaire G, Woodley J, Hermann P, Cloarec A, Arellano C, Houin G. Impact of excipients on the absorption of P-glycoprotein substrates in vitro and in vivo. Int J Pharm. 2004;278:119–31.

    Article  CAS  Google Scholar 

  25. Martin-Facklam M, Burhenne J, Ding R, Fricker R, Mikus G, Walter-Sack I, et al. Dose-dependent increase of saquinavir bioavailability by the pharmaceutic aid cremophor EL. Br J Clin Pharmacol. 2002;53:576–81.

    Article  CAS  Google Scholar 

  26. Zhang H, Yao M, Morrison RA, Chong S. Commonly used surfactant, Tween 80, improves absorption of P-glycoprotein substrate, digoxin, in rats. Arch Pharm Res. 2003;26:768–72.

    Article  CAS  Google Scholar 

  27. Ikeuchi-Takahashi Y, Kobayashi A, Ishihara C, Matsubara T, Matsubara H, Onishi H. Influence of polysorbate 60 on formulation properties and bioavailability of morin-loaded nanoemulsions with and without low-saponification-degree polyvinyl alcohol. Biol Pharm Bull. 2018;41:754–60.

    Article  CAS  Google Scholar 

  28. Huang Y, Zhang S, Shen H, Li J, Gao C. Controlled release of the nimodipine-loaded self-microemulsion osmotic pump capsules: development and characterization. AAPS PharmSciTech. 2018;19:1308–19.

    Article  CAS  Google Scholar 

  29. Yanfei M, Guoguang C, Lili R, Pingkai O. Controlled release of glaucocalyxin - a self-nanoemulsifying system from osmotic pump tablets with enhanced bioavailability. Pharm Dev Technol. 2017;22:148–55.

    Article  Google Scholar 

  30. Palmer D, Levina M, Nokhodchi A, Douroumis D, Farrell T, Rajabi-Siahboomi A. The influence of sodium carboxymethylcellulose on drug release from polyethylene oxide extended release matrices. AAPS PharmSciTech. 2011;12:862–71.

    Article  CAS  Google Scholar 

  31. Liao ZX, Peng SF, Ho YC, Mi FL, Maiti B, Sung HW. Mechanistic study of transfection of chitosan/DNA complexes coated by anionic poly(γ-glutamic acid). Biomaterials. 2012;33:3306–15.

    Article  CAS  Google Scholar 

  32. Naorem H, Singh NS. Effect of an anionic surfactant on the complexation of some nonionic polymers with iodine in aqueous media. J Phys Chem B. 2007;111:4098–102.

    Article  CAS  Google Scholar 

  33. Jain S, Reddy CSK, Swami R, Kushwah V. Amphotericin B loaded chitosan nanoparticles: implication of bile salt stabilization on gastrointestinal stability, permeability and oral bioavailability. AAPS PharmSciTech. 2018;19:3152–64.

    Article  CAS  Google Scholar 

  34. Ikeuchi-Takahashi Y, Ishihara C, Onishi H. Formulation and evaluation of morin-loaded solid lipid nanoparticles. Biol Pharm Bull. 2016;39:1514–22.

    Article  CAS  Google Scholar 

  35. Celli GB, Liu Y, Dadmohammadi Y, Tiwari R, Raghupathi K, Mutilangi W, et al. Instantaneous interaction of mucin with pectin- and carrageenan-coated nanoemulsions. Food Chem. 2020. https://doi.org/10.1016/j.foodchem.2019.125795.

  36. Sato T. Molecular theory on the viscosity of polymer solutions. Kobunshi Ronbunshu. 2012;69:613–22.

    Article  CAS  Google Scholar 

  37. Hassan EE, Gallo JM. A simple rheological method for the in vitro assessment of mucin-polymer bioadhesive bond strength. Pharm Res. 1990;7:491–5.

    Article  CAS  Google Scholar 

  38. Pagano C, Giovagnoli S, Perioli L, Tiralti MC, Ricci M. Development and characterization of mucoadhesive-thermoresponsive gels for the treatment of oral mucosa diseases. Eur J Pharm Sci. 2020. https://doi.org/10.1016/j.ejps.2019.105125.

  39. Mayol L, Quaglia F, Borzacchiello A, Ambrosio L, La Rotonda MI. A novel poloxamers/hyaluronic acid in situ forming hydrogel for drug delivery: rheological, mucoadhesive and in vitro release properties. Eur J Pharm Biopharm. 2008;70:199–206.

    Article  CAS  Google Scholar 

  40. Abd-Elsalam WH, ElKasabgy NA. Mucoadhesive olaminosomes: a novel prolonged release nanocarrier of agomelatine for the treatment of ocular hypertension. Int J Pharm. 2019;560:235–45.

    Article  CAS  Google Scholar 

  41. Saengkrit N, Saesoo S, Woramongkolchai N, Sajomsang W, Phunpee S, Dharakul T, et al. Dry formulations enhanced mucoadhesive properties and reduced cold chain handing of influenza vaccines. AAPS PharmSciTech. 2018;19:3763–9.

    Article  CAS  Google Scholar 

  42. Schipper NG, Vårum KM, Artursson P. Chitosans as absorption enhancers for poorly absorbable drugs. 1: influence of molecular weight and degree of acetylation on drug transport across human intestinal epithelial (Caco-2) cells. Pharm Res. 1996;13:1686–92.

    Article  CAS  Google Scholar 

  43. Schulz JD, Gauthier MA, Leroux JC. Improving oral drug bioavailability with polycations? Eur J Pharm Biopharm. 2015;97(Pt B):427–37.

    Article  CAS  Google Scholar 

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Funding

The authors received funding from Mitsubishi Chemical Corporation, Tokyo, Japan.

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Authors and Affiliations

  1. Department of Drug Delivery Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan

    Yuri Ikeuchi-Takahashi, Shingo Murata, Wataru Murata & Hiraku Onishi

  2. Osaka R&D Center, Mitsubishi Chemical Corporation, Ibaraki, Osaka, Japan

    Ayaka Kobayashi & Chizuko Ishihara

Authors
  1. Yuri Ikeuchi-Takahashi
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  2. Shingo Murata
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  3. Wataru Murata
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  4. Ayaka Kobayashi
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  5. Chizuko Ishihara
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  6. Hiraku Onishi
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Correspondence to Yuri Ikeuchi-Takahashi.

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Ikeuchi-Takahashi, Y., Murata, S., Murata, W. et al. Development of Morin-Loaded Nanoemulsions Containing Various Polymers; Role of Polymers in Formulation Properties and Bioavailability. AAPS PharmSciTech 21, 150 (2020). https://doi.org/10.1208/s12249-020-01670-8

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  • DOI: https://doi.org/10.1208/s12249-020-01670-8

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