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.
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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.
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.
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.
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.
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.
Al-Kassas R, Bansal M, Shaw J. Nanosizing techniques for improving bioavailability of drugs. J Control Release. 2017;260:202–12.
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.
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.
Fan X, Chen J, Shen Q. Docetaxel-nicotinamide complex-loaded nanostructured lipid carriers for transdermal delivery. Int J Pharm. 2013;458(2):296–304.
Berry DJ, Steed JW. Pharmaceutical cocrystals, salts and multicomponent systems; intermolecular interactions and property based design. Adv Drug Deliv Rev. 2017;117:3–24.
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.
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.
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.
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.
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.
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.
Sparreboom A, van Tellingen O, Nooijen WJ, Beijnen JH. Preclinical pharmacokinetics of paclitaxel and docetaxel. Anti-Cancer Drugs. 1998;9(1):1–17.
Baker SD, Sparreboom A, Verweij J. Clinical pharmacokinetics of docetaxel. Clin Pharmacokinet. 2006;45(3):235–52.
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.
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.
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.
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.
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.
Park J, Choi JU, Kim K, Byun Y. Bile acid transporter mediated endocytosis of oral bile acid conjugated nanocomplex. Biomaterials. 2017;147:145–54.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Jayasankar A, Good DJ, Rodriguez-Hornedo N. Mechanisms by which moisture generates cocrystals. Mol Pharm. 2007;4(3):360–72.
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.
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.
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.
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.
Benita S, Levy MY. Submicron emulsions as colloidal drug carriers for intravenous administration: comprehensive physicochemical characterization. J Pharm Sci. 1993;82(11):1069–79.
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.
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.
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.
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Xu, Y., Fang, T., Yang, Y. et al. Preparation of Deoxycholate-Modified Docetaxel-Cimetidine Complex Chitosan Nanoparticles to Improve Oral Bioavailability. AAPS PharmSciTech 20, 302 (2019). https://doi.org/10.1208/s12249-019-1520-y
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DOI: https://doi.org/10.1208/s12249-019-1520-y