Thermosensitive mucoadhesive gel formulation loaded with 5-Fu: cyclodextrin complex for HPV-induced cervical cancer

Creative Commons License

Bilensoy E., Cirpanli Y., Sen M., Dogan A. L., Calis S.

JOURNAL OF INCLUSION PHENOMENA AND MACROCYCLIC CHEMISTRY, vol.57, pp.363-370, 2007 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Volume: 57
  • Publication Date: 2007
  • Doi Number: 10.1007/s10847-006-9259-y
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.363-370
  • Keywords: 5-fluorouracil, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, thermosensitive, mucoadhesive, cyclodextrin, vaginal gel, cervical cancer, HPV, OCULAR DELIVERY-SYSTEM, HUMAN-PAPILLOMAVIRUS, CONTROLLED-TRIAL, DOUBLE-BLIND, BETA, 5-FLUOROURACIL, LIPOSOMES, THERAPY, RELEASE
  • Hacettepe University Affiliated: Yes


Inclusion complexes of the poorly-soluble antiestrogen drug tamoxifen citrate (TMX) were prepared with β-cyclodextrin (β-CD) and 2,3-di-O-hexanoyl-β-cyclodextrin (β-CDC6) being natural and amphiphilic cyclodextrins, respectively using the co-lyophilization technique. Complexation occurred in aqueous medium for natural cyclodextrin β-CD and a medium of water:ethanol mixture for the amphiphilic cyclodextrin β-CDC6. The complexes were characterized using analytical techniques including Differential Scanning Calorimetry (DSC), Fourier Transform Infrared spectroscopy (FTIR) and proton Nuclear Magnetic Resonance Spectrometry (1H NMR). Anticancer efficacies of the complexes were determined against MCF-7 human breast carcinoma cell line with MTT assay. It was found that tamoxifen citrate can be incorporated in the cavity for β-CD and both in the cavity and the aliphatic chains for β-CDC6. The latter having two hydrophobic sites for inclusion of water-insoluble drug exhibited significantly higher anticancer efficacy accordingly.

Human Papilloma Virus (HPV) infections are the major cause of cervical cancers. To achieve a better therapeutic efficacy and patient compliance in the treatment for HPV-induced cervical cancers, anticancer agent 5-fluorouracil has been formulated in a vaginal gel using the thermosensitive polymer Pluronic (R) F127 together with alternative mucoadhesive polymers e.g., hyaluronic acid, Carbopol 934 and hydroxypropylmethylcellulose. To increase its aqueous solubility and to achieve the complete release of 5-FU from the gel, the drug was incorporated as its inclusion complex with 1:1 molar ratio with either beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin. Following the characterization of drug:CD complexes, thermosensitive gel formulations containing different mucoadhesive polymers and the drug in free or complexed form were characterized in vitro by determining the gelation temperature and the rheological behavior of different formulations along with the in vitro release profiles of these formulations in pH 5.5 citrate buffer. It was observed that complexation with cyclodextrin accelerated the release of 5-FU with the exception of formulation containing Carbopol 934 as mucoadhesive polymer. As far as rheological properties are concerned, favorable thermosensitive in situ gelling properties were obtained with formulations containing HPMC as mucoadhesive polymer. Complete release of 5-FU from gels were obtained with both complexes of beta-CD and HP-beta-CD and cytotoxicity studies against HeLa human cervical carcinoma cells demonstrated that 1% 5-FU:CD complexes were equally effective as 1% free 5-FU indicating better therapeutic efficacy with lower dose.