Combined hydroxypropyl-beta-cyclodextrin and poly(anhydride) nanoparticles improve the oral permeability of paclitaxel.

The aim of this work was to study the effect of the combination between 2-hydroxypropyl-beta-cyclodextrin (HPCD) and bioadhesive nanoparticles on the encapsulation and intestinal permeability of paclitaxel (PTX). In this context, a solid inclusion complex between PTX and HPCD was prepared by an evaporation method. Then, the complex was incorporated in poly(anhydride) nanoparticles by a solvent displacement method. The resulting nanoparticles, PTX-HPCD NP, displayed a size of about 300 nm and a drug loading of about 170 microg/mg (500-fold higher than in the absence of HPCD). The effect of these nanoparticles on the permeability of intestinal epithelium was investigated using the Ussing chamber technique. The apparent permeability (P(app)) of PTX was found to be 12-fold higher when formulated as PTX-HPCD NP than when formulated as Taxol (control). Furthermore, when interaction between nanoparticles and the mucosa was avoided, the permeability of PTX significantly decreased. In summary, the association between PTX-HPCD and poly(anhydride) nanoparticles would induce a positive effect over the intestinal permeability of paclitaxel, being the bioadhesion a mandatory condition in this phenomena.

[1]  P. Söderkvist,et al.  Pharmacogenetic studies of Paclitaxel in the treatment of ovarian cancer. , 2009, Basic & clinical pharmacology & toxicology.

[2]  M. A. Arangoa,et al.  Nanoparticles with specific bioadhesive properties to circumvent the pre-systemic degradation of fluorinated pyrimidines. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[3]  Kwok-Kin Wong,et al.  Molecular determinants of response to matuzumab in combination with paclitaxel for patients with advanced non-small cell lung cancer , 2009, Molecular Cancer Therapeutics.

[4]  I. Bravo-Osuna,et al.  Specific permeability modulation of intestinal paracellular pathway by chitosan-poly(isobutylcyanoacrylate) core-shell nanoparticles. , 2008, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[5]  Sung-Joo Hwang,et al.  Enhanced Oral Bioavailability of Paclitaxel by Coadministration of the P-Glycoprotein Inhibitor KR30031 , 2004, Pharmaceutical Research.

[6]  T. Kiss,et al.  P-glycoprotein inhibition by membrane cholesterol modulation. , 2008, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[7]  M. Monzó,et al.  Weekly paclitaxel for platin-resistant stage IV head and neck cancer patients , 2009, Acta oto-laryngologica.

[8]  D. Aggarwal,et al.  Paclitaxel and its formulations. , 2002, International journal of pharmaceutics.

[9]  K. Zhu,et al.  Synthesis, characterization and in vitro release of 5-aminosalicylic acid and 5-acetyl aminosalicylic acid of polyanhydride--P(CBFAS). , 2003, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[10]  G. Nicolardi,et al.  Hypotonicity induced K+ and anion conductive pathways activation in eel intestinal epithelium , 2005, Journal of Experimental Biology.

[11]  T. Walle.  Assays of CYP2C8- and CYP3A4-mediated metabolism of taxol in vivo and in vitro. , 1996, Methods in enzymology.

[12]  G. Ponchel,et al.  Combined Poly(isobutylcyanoacrylate) and Cyclodextrins Nanoparticles for Enhancing the Encapsulation of Lipophilic Drugs , 1998, Pharmaceutical Research.

[13]  M. Varma,et al.  Enhanced oral paclitaxel absorption with vitamin E-TPGS: effect on solubility and permeability in vitro, in situ and in vivo. , 2005, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[14]  J. Schellens,et al.  Oral Delivery of Taxanes , 2001, Investigational New Drugs.

[15]  Minoru Ishikawa,et al.  Interaction of Modified Cyclodextrins with Cytochrome P-450 , 2005, Bioscience, biotechnology, and biochemistry.

[16]  R. Liggins,et al.  In vitro human plasma distribution of nanoparticulate paclitaxel is dependent on the physicochemical properties of poly(ethylene glycol)-block-poly(caprolactone) nanoparticles. , 2009, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[17]  Thorsteinn Loftsson,et al.  Evaluation of cyclodextrin solubilization of drugs. , 2005, International journal of pharmaceutics.

[18]  B. Leyland-Jones,et al.  Hypersensitivity reactions from taxol. , 1990, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  Si-Shen Feng,et al.  Poly(d,l-lactide-co-glycolide)/montmorillonite nanoparticles for oral delivery of anticancer drugs. , 2005, Biomaterials.

[20]  B. Overmoyer.  Options for the treatment of patients with taxane-refractory metastatic breast cancer. , 2008, Clinical breast cancer.

[21]  W. Couet,et al.  Enhanced Oral Paclitaxel Bioavailability After Administration of Paclitaxel-Loaded Lipid Nanocapsules , 2006, Pharmaceutical Research.

[22]  T. Higuchi,et al.  Phase solubility techniques , 1965 .

[23]  J. Irache,et al.  Bioadhesive properties and biodistribution of cyclodextrin-poly(anhydride) nanoparticles. , 2009, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[24]  G. Ponchel,et al.  Combined Poly(alkyl cyanoacrylate)/Cyclodextrin Nanoparticles , 2002 .

[25]  J. Beijnen,et al.  Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[26]  K. Kannan,et al.  Oral microemulsions of paclitaxel: in situ and pharmacokinetic studies. , 2009, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[27]  A. Csendes,et al.  Permeability of human jejunal segments to gonyautoxins measured by the Ussing chamber technique. , 2004, Toxicon : official journal of the International Society on Toxinology.

[28]  S. Benita,et al.  Enhanced Oral Absorption of Paclitaxel in a Novel Self-Microemulsifying Drug Delivery System with or Without Concomitant Use of P-Glycoprotein Inhibitors , 2004, Pharmaceutical Research.

[29]  Elias Fattal,et al.  Polyisobutylcyanoacrylate Nanocapsules Containing an Aqueous Core as a Novel Colloidal Carrier for the Delivery of Oligonucleotides , 2000, Pharmaceutical Research.

[30]  R. Panchagnula,et al.  Nanoemulsions as versatile formulations for paclitaxel delivery: peroral and dermal delivery studies in rats. , 2007, The Journal of investigative dermatology.

[31]  J. Irache,et al.  Bioadhesive properties of pegylated nanoparticles , 2005, Expert opinion on drug delivery.

[32]  J. Irache,et al.  Salmonella-like bioadhesive nanoparticles. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[33]  J. Irache,et al.  Bioadhesive mannosylated nanoparticles for oral drug delivery. , 2006, Journal of nanoscience and nanotechnology.

[34]  M. A. Arangoa,et al.  Influence of the surface characteristics of PVM/MA nanoparticles on their bioadhesive properties. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[35]  V. Roy,et al.  Phase II trial of weekly nab (nanoparticle albumin-bound)-paclitaxel (nab-paclitaxel) (Abraxane) in combination with gemcitabine in patients with metastatic breast cancer (N0531). , 2009, Annals of oncology : official journal of the European Society for Medical Oncology.

[36]  F. Hirayama,et al.  Contribution of P-glycoprotein to the enhancing effects of dimethyl-beta-cyclodextrin on oral bioavailability of tacrolimus. , 2001, The Journal of pharmacology and experimental therapeutics.

[37]  M. A. Arangoa,et al.  Quantification of the bioadhesive properties of protein-coated PVM/MA nanoparticles. , 2002, International journal of pharmaceutics.

[38]  P. Kintzel.  Prophylaxis for Paclitaxel Hypersensitivity Reactions , 2001, The Annals of pharmacotherapy.

[39]  R. Donehower,et al.  Drug therapy : paclitaxel (Taxol) , 1995 .

[40]  P. Gao,et al.  Development of a supersaturable SEDDS (S-SEDDS) formulation of paclitaxel with improved oral bioavailability. , 2003, Journal of pharmaceutical sciences.

[41]  Si-Shen Feng,et al.  Self-assembled nanoparticles of poly(lactide)--Vitamin E TPGS copolymers for oral chemotherapy. , 2006, International journal of pharmaceutics.

[42]  O. Camber,et al.  Nasal drug delivery--evaluation of an in vitro model using porcine nasal mucosa. , 1999, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[43]  J. Schellens,et al.  Improvement of oral drug treatment by temporary inhibition of drug transporters and/or cytochrome P450 in the gastrointestinal tract and liver: an overview. , 2002, The oncologist.