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AAPS PharmSciTech

, 20:302 | Cite as

Preparation of Deoxycholate-Modified Docetaxel-Cimetidine Complex Chitosan Nanoparticles to Improve Oral Bioavailability

  • Yingxin Xu
  • Tianxu Fang
  • Yifan Yang
  • Li’ang Sun
  • Qi ShenEmail author
Research Article
  • 28 Downloads

Abstract

Docetaxel (DTX) was effective in the treatment of neoplasm but could only be administered intravenously with the poor oral bioavailability owing to its undesirable solubility, remarkably metabolic conversion, and other factors. Cimetidine (CMD), a classic CYP3A4 isozyme inhibitor, had exhibited a wide range of inhibition on the metabolism of many drugs. The aim of this study was to construct the novel docetaxel-cimetidine (DTX-CMD) complex and the chitosan-deoxycholate nanoparticles based on it to confirm whether this formulation could show advantages in terms of solubility, dissolution rate, small intestinal absorption, and oral bioavailability in comparison with the pure drug. The solid-state characterization was carried out by powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FT-IR), and simultaneous DSC-TGA (SDT). Dissolution rate and kinetic solubility study were determined by evaluating the amount of DTX in distilled water and phosphate buffer solution (pH = 7.4), respectively. And small intestinal absorption and pharmacokinetics study were conducted in rats. The results of this study demonstrated that we successfully constructed DTX-CMD complex and its chitosan-deoxycholate nanoparticles. Furthermore, the DTX-CMD complex increased the solubility of DTX by 2.3-fold and 2.1-fold in distilled water and phosphate buffer solution, respectively. The ultimate accumulative amount of DTX-CMD complex nanoparticles through rat small intestinal in 2 h was approximately 4.9-fold and the oral bioavailability of the novel nanoparticles was enhanced 2.8-fold, compared with the pure DTX. The superior properties of the complex nanoparticles could both improve oral bioavailability and provide much more feasibility for other formulations of DTX.

KEY WORDS

docetaxel-cimetidine complex nanoparticles intestinal absorption pharmacokinetics 

Notes

References

  1. 1.
    Li Y, Zheng X, Sun Y, Ren Z, Li X, Cui G. RGD-fatty alcohol-modified docetaxel liposomes improve tumor selectivity in vivo. Int J Pharm. 2014;468(1–2):133–41.PubMedGoogle Scholar
  2. 2.
    Moes JJ, Koolen SL, Huitema AD, Schellens JH, Beijnen JH, Nuijen B. Pharmaceutical development and preliminary clinical testing of an oral solid dispersion formulation of docetaxel (ModraDoc001). Int J Pharm. 2011;420(2):244–50.CrossRefGoogle Scholar
  3. 3.
    Khadka P, Ro J, Kim H, Kim I, Kim JT, Kim H, et al. Pharmaceutical particle technologies: an approach to improve drug solubility, dissolution and bioavailability. Asian J Pharm Sci. 2014;9(6):304–16.CrossRefGoogle Scholar
  4. 4.
    Mazzaferro S, Bouchemal K, Ponchel G. Oral delivery of anticancer drugs III: formulation using drug delivery systems. Drug Discov Today. 2013;18(1–2):99–104.CrossRefGoogle Scholar
  5. 5.
    Wu J, Shen Q, Fang L. Sulfobutylether-beta-cyclodextrin/chitosan nanoparticles enhance the oral permeability and bioavailability of docetaxel. Drug Dev Ind Pharm. 2013;39(7):1010–9.CrossRefGoogle Scholar
  6. 6.
    Al-Kassas R, Bansal M, Shaw J. Nanosizing techniques for improving bioavailability of drugs. J Control Release. 2017;260:202–12.CrossRefGoogle Scholar
  7. 7.
    Blagden N, de Matas M, Gavan PT, York P. Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates. Adv Drug Deliv Rev. 2007;59(7):617–30.CrossRefGoogle Scholar
  8. 8.
    Chadha R, Saini A, Arora P, Bhandari S. Pharmaceutical cocrystals: a novel approach for oral bioavailability enhancement of drugs. Crit Rev Ther Drug Carrier Syst. 2012;29(3):183–218.CrossRefGoogle Scholar
  9. 9.
    Fan X, Chen J, Shen Q. Docetaxel-nicotinamide complex-loaded nanostructured lipid carriers for transdermal delivery. Int J Pharm. 2013;458(2):296–304.CrossRefGoogle Scholar
  10. 10.
    Berry DJ, Steed JW. Pharmaceutical cocrystals, salts and multicomponent systems; intermolecular interactions and property based design. Adv Drug Deliv Rev. 2017;117:3–24.CrossRefGoogle Scholar
  11. 11.
    Healy AM, Worku ZA, Kumar D, Madi AM. Pharmaceutical solvates, hydrates and amorphous forms: a special emphasis on cocrystals. Adv Drug Deliv Rev. 2017;117:25–46.CrossRefGoogle Scholar
  12. 12.
    Wu J, Deng C, Meng F, Zhang J, Sun H, Zhong Z. Hyaluronic acid coated PLGA nanoparticulate docetaxel effectively targets and suppresses orthotopic human lung cancer. J Control Release. 2017;259:76–82.CrossRefGoogle Scholar
  13. 13.
    Ghassami E, Varshosaz J, Jahanian-Najafabadi A, Minaiyan M, Rajabi P, Hayati E. Pharmacokinetics and in vitro/in vivo antitumor efficacy of aptamer-targeted Ecoflex((R)) nanoparticles for docetaxel delivery in ovarian cancer. Int J Nanomedicine. 2018;13:493–504.CrossRefGoogle Scholar
  14. 14.
    Lee E, Kim H, Lee IH, Jon S. In vivo antitumor effects of chitosan-conjugated docetaxel after oral administration. J Control Release. 2009;140(2):79–85.CrossRefGoogle Scholar
  15. 15.
    Malingre MM, Richel DJ, Beijnen JH, Rosing H, Koopman FJ, Ten Bokkel Huinink WW, et al. Coadministration of cyclosporine strongly enhances the oral bioavailability of docetaxel. J Clin Oncol. 2001;19(4):1160–6.CrossRefGoogle Scholar
  16. 16.
    Song SY, Kim KP, Jeong SY, Park J, Park J, Jung J, et al. Polymeric nanoparticle-docetaxel for the treatment of advanced solid tumors: phase I clinical trial and preclinical data from an orthotopic pancreatic cancer model. Oncotarget. 2016;7(47):77348–57.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Sparreboom A, van Tellingen O, Nooijen WJ, Beijnen JH. Preclinical pharmacokinetics of paclitaxel and docetaxel. Anti-Cancer Drugs. 1998;9(1):1–17.CrossRefGoogle Scholar
  18. 18.
    Baker SD, Sparreboom A, Verweij J. Clinical pharmacokinetics of docetaxel. Clin Pharmacokinet. 2006;45(3):235–52.CrossRefGoogle Scholar
  19. 19.
    Brogden RN, Heel RC, Speight TM, Avery GS. Cimetidine: a review of its pharmacological properties and therapeutic efficacy in peptic ulcer disease. Drugs. 1978;15(2):93–131.CrossRefGoogle Scholar
  20. 20.
    Akiyoshi T, Saito T, Murase S, Miyazaki M, Murayama N, Yamazaki H, et al. Comparison of the inhibitory profiles of itraconazole and cimetidine in cytochrome P450 3A4 genetic variants. Drug Metab Dispos. 2011;39(4):724–8.CrossRefGoogle Scholar
  21. 21.
    Peng J, Yang Q, Li W, Tan L, Xiao Y, Chen L, et al. Erythrocyte-membrane-coated prussian blue/manganese dioxide nanoparticles as H2O2-responsive oxygen generators to enhance cancer chemotherapy/photothermal therapy. 2017;9(51):44410–22.Google Scholar
  22. 22.
    Li P, Chen X, Shen Y, Li H, Zou Y, Yuan G, et al. Mucus penetration enhanced lipid polymer nanoparticles improve the eradication rate of Helicobacter pylori biofilm. J Control Release. 2019;300:52–63.CrossRefGoogle Scholar
  23. 23.
    Fan W, Xia D, Zhu Q, Li X, He S, Zhu C, et al. Functional nanoparticles exploit the bile acid pathway to overcome multiple barriers of the intestinal epithelium for oral insulin delivery. Biomaterials. 2018;151:13–23.CrossRefGoogle Scholar
  24. 24.
    Park J, Choi JU, Kim K, Byun Y. Bile acid transporter mediated endocytosis of oral bile acid conjugated nanocomplex. Biomaterials. 2017;147:145–54.CrossRefGoogle Scholar
  25. 25.
    Kim KS, Suzuki K, Cho H, Youn YS, Bae YH. Oral nanoparticles exhibit specific high-efficiency intestinal uptake and lymphatic transport. 2018;12(9):8893–900.Google Scholar
  26. 26.
    Qiao N, Li M, Schlindwein W, Malek N, Davies A, Trappitt G. Pharmaceutical cocrystals: an overview. Int J Pharm. 2011;419(1–2):1–11.CrossRefGoogle Scholar
  27. 27.
    Kokalj M, Kolar J, Trafela T, Kreft S. Differences among Epilobium and Hypericum species revealed by four IR spectroscopy modes: transmission, KBr tablet, diffuse reflectance and ATR. Phytochem Anal. 2011;22(6):541–6.CrossRefGoogle Scholar
  28. 28.
    Agueros M, Ruiz-Gaton L, Vauthier C, Bouchemal K, Espuelas S, Ponchel G, et al. Combined hydroxypropyl-beta-cyclodextrin and poly(anhydride) nanoparticles improve the oral permeability of paclitaxel. Eur J Pharm Sci. 2009;38(4):405–13.CrossRefGoogle Scholar
  29. 29.
    Fan R, Wang Y, Han B, Luo Y, Zhou L, Peng X, et al. Docetaxel load biodegradable porous microspheres for the treatment of colorectal peritoneal carcinomatosis. Int J Biol Macromol. 2014;69:100–7.CrossRefGoogle Scholar
  30. 30.
    Tantishaiyakul V, Songkro S, Suknuntha K, Permkum P, Pipatwarakul P. Crystal structure transformations and dissolution studies of cimetidine-piroxicam coprecipitates and physical mixtures. AAPS PharmSciTech. 2009;10(3):789–95.CrossRefGoogle Scholar
  31. 31.
    Cheng H, Liu H, Zhang Y, Zou G. Interaction of the docetaxel with human serum albumin using optical spectroscopy methods. J Lumin. 2009;129(10):1196–203.CrossRefGoogle Scholar
  32. 32.
    Tudor AM, Davies MC, Melia CD, Lee DC, Mitchell RC, Hendra PJ, et al. The applications of near-infrared Fourier transform Raman spectroscopy to the analysis of polymorphic forms of cimetidine. Spectrochim Acta A: Mol Spectrosc. 1991;47(9):1389–93.CrossRefGoogle Scholar
  33. 33.
    de Souza FS, Macedo RO, Veras JWE. Studies of cimetidine pre-formulated and tablets for TG and DSC coupled to the photovisual system. Thermochim Acta. 2002;392–393:99–106.CrossRefGoogle Scholar
  34. 34.
    Chen Y, Chen C, Zheng J, Chen Z, Shi Q, Liu H. Development of a solid supersaturatable self-emulsifying drug delivery system of docetaxel with improved dissolution and bioavailability. Biol Pharm Bull. 2011;34(2):278–86.CrossRefGoogle Scholar
  35. 35.
    Jayasankar A, Good DJ, Rodriguez-Hornedo N. Mechanisms by which moisture generates cocrystals. Mol Pharm. 2007;4(3):360–72.CrossRefGoogle Scholar
  36. 36.
    Glezer AM, Sundeev RV, Shalimova AV. The cyclic character of phase transformations of the crystal ⇔ amorphous state type during severe plastic deformation of the Ti50Ni25Cu25 alloy. Dokl Phys. 2011;56(9):476–8.CrossRefGoogle Scholar
  37. 37.
    Mugabe C, Liggins RT, Guan D, Manisali I, Chafeeva I, Brooks DE, et al. Development and in vitro characterization of paclitaxel and docetaxel loaded into hydrophobically derivatized hyperbranched polyglycerols. Int J Pharm. 2011;404(1–2):238–49.CrossRefGoogle Scholar
  38. 38.
    Yamamura S, Gotoh H, Sakamoto Y, Momose Y. Physicochemical properties of amorphous salt of cimetidine and diflunisal system. Int J Pharm. 2002;241(2):213–21.CrossRefGoogle Scholar
  39. 39.
    Zhang T, Chen J, Zhang Y, Shen Q, Pan W. Characterization and evaluation of nanostructured lipid carrier as a vehicle for oral delivery of etoposide. Eur J Pharm Sci. 2011;43(3):174–9.CrossRefGoogle Scholar
  40. 40.
    Benita S, Levy MY. Submicron emulsions as colloidal drug carriers for intravenous administration: comprehensive physicochemical characterization. J Pharm Sci. 1993;82(11):1069–79.CrossRefGoogle Scholar
  41. 41.
    Samstein RM, Perica K, Balderrama F, Look M, Fahmy TM. The use of deoxycholic acid to enhance the oral bioavailability of biodegradable nanoparticles. Biomaterials. 2008;29(6):703–8.CrossRefGoogle Scholar
  42. 42.
    Lewis DF, Lake BG, Dickins M. Quantitative structure-activity relationships (QSars) in CYP3A4 inhibitors: the importance of lipophilic character and hydrogen bonding. J Enzyme Inhib Med Chem. 2006;21(2):127–32.CrossRefGoogle Scholar
  43. 43.
    Liu Y, Chen D, Li J, Xia D, Yu M, Tao J, et al. NPC1L1-targeted cholesterol-grafted poly(beta-amino ester)/pDNA complexes for oral gene delivery. 2019;8(8):e1800934.Google Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Yingxin Xu
    • 1
  • Tianxu Fang
    • 1
  • Yifan Yang
    • 1
  • Li’ang Sun
    • 1
  • Qi Shen
    • 1
    Email author
  1. 1.School of PharmacyShanghai Jiao Tong UniversityShanghaiChina

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