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Enhancement of solubility and dissolution of cilostazol by solid dispersion technique

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Abstract

Cilostazol is practically insoluble in water and thus results in poor bioavailability. Only a few approaches have been reported for improving the bioavailability of cilostazol. Solid dispersion technique via solvent evaporation method was applied to improve the solubility and dissolution of cilostazol. Various polymers, mixture of polymer and surfactant, and mixture of polymers were screened as a carrier for the solid dispersion. Solubility of cilostazol was improved significantly when Eudragit® L100 was used as a carrier. However, addition of surfactant to Eudragit® L100 decreased the solubility slightly. Whereas, the mixture of Eudragit® L100 and Eudragit® S100 as a carrier system further increased the solubility. Based on the highest solubility obtained among the carriers screened, 1:1 ratio of Eudragit® L100 and Eudragit® S100 was selected as a carrier, and drug to carrier ratio was optimized to 1:5. Differential scanning calorimetry and X-ray diffraction studies showed that the characteristic peak of cilostazol disappeared in the solid dispersion, indicating that cilostazol existed in amorphous form in this formulation. Spray drying method was superior to vacuum drying method in terms of dissolution rate. Meanwhile, it was observed that the disintegration rate and the concentration of polymer had some effect on the crystallization of cilostazol in dissolution medium. Tablet formulation containing spray dried solid dispersion showed significant improvement in dissolution as compared to the commercial tablet.

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References

  • Amidon, G.L., H. Lennernas, V.P. Shah, and J.R. Crison. 1995. A theoretical basis for a biopharmaceutic drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharmaceutical Research 12: 413–420.

    Article  CAS  PubMed  Google Scholar 

  • Chiou, W.L., and S. Riegelman. 1971. Pharmaceutical applications of solid dispersion systems. Journal of Pharmaceutical Sciences 60: 1281–1302.

    Article  CAS  PubMed  Google Scholar 

  • Chow, A.H.L., C.K. Hsia, J.D. Gordon, J.W.M. Young, and E.I. Vargha-Butler. 1995. Assessment of wettability and its relationship to the intrinsic dissolution rate of doped phenytoin crystals. International Journal of Pharmaceutics 126: 21–28.

    Article  CAS  Google Scholar 

  • Davis, S.S. 1986. Transit of pharmaceutical dosage forms through the small intestine. Gut 27: 886.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Dindyal, S., and C. Kyriakides. 2009. A review of cilostazol, a phosphodiesterase inhibitor, and its role in preventing both coronary and peripheral arterial restenosis following endovascular therapy. Recent Patents on Cardiovascular Drug Discovery 4: 6–14.

    Article  CAS  PubMed  Google Scholar 

  • Ghebremeskel, A.N., C. Vemavarapu, and M. Lodaya. 2007. Use of surfactants as plasticizers in preparing solid dispersions of poorly soluble API: Selection of polymer-surfactant combinations using solubility parameters and testing the processability. International Journal of Pharmaceutics 328: 119–129.

    Article  CAS  PubMed  Google Scholar 

  • Hamming, J.J. 1959. Intermittent claudication at an early age, due to an anomalous course of the popliteal artery. Angiology 10: 369.

    Article  CAS  PubMed  Google Scholar 

  • Hasegawa, A., M. Taguchi, R. Suzuki, T. Miyata, H. Nakagawa, and I. Sugimoto. 1988. Supersaturation mechanism of drugs from solid dispersions with enteric coating agents. Chemical & Pharmaceutical Bulletin 36: 4941–4950.

    Article  CAS  Google Scholar 

  • Jinno, J., N. Kamada, M. Miyake, K. Yamada, T. Mukai, M. Odomi, H. Toguchi, G.G. Liversidge, K. Higaki, and T. Kimura. 2006. Effect of particle size reduction on dissolution and oral absorption of a poorly water-soluble drug, cilostazol, in beagle dogs. Journal of Controlled Release 111: 56–64.

    Article  CAS  PubMed  Google Scholar 

  • Joe, J.H., W.M. Lee, Y.-J. Park, K.H. Joe, D.H. Oh, Y.G. Seo, J.S. Woo, C.S. Yong, and H.-G. Choi. 2010. Effect of the solid-dispersion method on the solubility and crystalline property of tacrolimus. International Journal of Pharmaceutics 395: 161–166.

    Article  CAS  PubMed  Google Scholar 

  • Kim, M.-S., S. Lee, J.-S. Park, J.-S. Woo, and S.-J. Hwang. 2007. Micronization of cilostazol using supercritical antisolvent (SAS) process: Effect of process parameters. Powder Technology 177: 64–70.

    Article  CAS  Google Scholar 

  • Kimura, Y., T. Tani, T. Kanbe, and K. Watanabe. 1985. Effect of cilostazol on platelet aggregation and experimental thrombosis. Arzneimittel-Forschung 35: 1144–1149.

    CAS  PubMed  Google Scholar 

  • Konno, H., T. Handa, D.E. Alonzo, and L.S. Taylor. 2008. Effect of polymer type on the dissolution profile of amorphous solid dispersions containing felodipine. European Journal of Pharmaceutics and Biopharmaceutics 70: 493–499.

    Article  CAS  PubMed  Google Scholar 

  • Leuner, C., and J. Dressman. 2000. Improving drug solubility for oral delivery using solid dispersions. European Journal of Pharmaceutics and Biopharmaceutics 50: 47–60.

    Article  CAS  PubMed  Google Scholar 

  • Marques, M. 2004. Dissolution media simulating fasted and fed states. Dissolution Technologies 11: 16.

    Article  Google Scholar 

  • Moustafine, R.I., T.V. Kabanova, V.A. Kemenova, and G. Van Den Mooter. 2005. Characteristics of interpolyelectrolyte complexes of Eudragit E100 with Eudragit L100. Journal of Controlled Release 103: 191–198.

    Article  CAS  PubMed  Google Scholar 

  • Park, Y.-J., D.-H. Oh, Y.-D. Yan, Y.-G. Seo, S.-N. Lee, H.-G. Choi, and C.-S. Yong. 2010. Surface-attached solid dispersion. Journal of Pharmaceutical Investigation 40: 103–112.

    Article  Google Scholar 

  • Patel, S.G., and S.J. Rajput. 2009. Enhancement of oral bioavailability of cilostazol by forming its inclusion complexes. AAPS PharmSciTech 10: 660–669.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pouton, C.W. 2006. Formulation of poorly water-soluble drugs for oral administration: Physicochemical and physiological issues and the lipid formulation classification system. European Journal of Pharmaceutical Sciences 29: 278–287.

    Article  CAS  PubMed  Google Scholar 

  • Quadir, A., and K. Kolter. 2006. A comparative study of current superdisintegrants. Pharmaceutical Technology 30: s38–s42.

    Google Scholar 

  • Sekiguchi, K., and N. Obi. 1961. Studies on absorption of eutectic mixture. I. A comparison of the behavior of eutectic mixture of sulfathiazole and that of ordinary sulfathiazole in man. Chemical & Pharmaceutical Bulletin 9: 866–872.

    Article  CAS  Google Scholar 

  • Serajuddin, A.T.M., P.-C. Sheen, and M.A. Augustine. 1990. Improved dissolution of a poorly water-soluble drug from solid dispersions in polyethylene glycol: Polysorbate 80 mixtures. Journal of Pharmaceutical Sciences 79: 463–464.

    Article  CAS  PubMed  Google Scholar 

  • Shimizu, T., T. Osumi, K. Niimi, and K. Nakagawa. 1985. Physico-chemical properties and stability of cilostazol. Arzneimittel-Forschung 35: 1117–1123.

    CAS  PubMed  Google Scholar 

  • Srinarong, P., J.H. Faber, M.R. Visser, W.L.J. Hinrichs, and H.W. Frijlink. 2009. Strongly enhanced dissolution rate of fenofibrate solid dispersion tablets by incorporation of superdisintegrants. European Journal of Pharmaceutics and Biopharmaceutics 73: 154–161.

    Article  CAS  PubMed  Google Scholar 

  • Taylor, L.S., and G. Zografi. 1997. Spectroscopic characterization of interactions between PVP and indomethacin in amorphous molecular dispersions. Pharmaceutical Research 14: 1691–1698.

    Article  CAS  PubMed  Google Scholar 

  • Turnbull, D., and J.C. Fisher. 1949. Rate of nucleation in condensed systems. Journal of Chemical Physics 17: 71–73.

    Article  CAS  Google Scholar 

  • Usui, F., K. Maeda, A. Kusai, M. Ikeda, K. Nishimura, and K. Yamamoto. 1998. Dissolution improvement of RS-8359 by the solid dispersion prepared by the solvent method. International Journal of Pharmaceutics 170: 247–256.

    Article  CAS  Google Scholar 

  • Vasconcelos, T., B. Sarmento, and P. Costa. 2007. Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs. Drug Discovery Today 12: 1068–1075.

    Article  CAS  PubMed  Google Scholar 

  • Yamashita, K., T. Nakate, K. Okimoto, A. Ohike, Y. Tokunaga, R. Ibuki, K. Higaki, and T. Kimura. 2003. Establishment of new preparation method for solid dispersion formulation of tacrolimus. International Journal of Pharmaceutics 267: 79–91.

    Article  CAS  PubMed  Google Scholar 

  • Yonemochi, E., S. Kitahara, S. Maeda, S. Yamamura, T. Oguchi, and K. Yamamoto. 1999. Physicochemical properties of amorphous clarithromycin obtained by grinding and spray drying. European Journal of Pharmaceutical Sciences 7: 331–338.

    Article  CAS  PubMed  Google Scholar 

  • Yonemochi, E., Y. Ueno, T. Ohmae, T. Oguchi, S.-I. Nakajima, and K. Yamamoto. 1997. Evaluation of amorphous ursodeoxycholic acid by thermal methods. Pharmaceutical Research 14: 798–803.

    Article  CAS  PubMed  Google Scholar 

  • Yoshioka, M. 1994. Crystallization of indomethacin from the amorphous state below and above its glass transition temperature. Journal of Pharmaceutical Sciences 83: 1700.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

All authors (J.-H. Park and H.-K. Choi) declare that they have no conflict of interest. This study was supported by research funds from Chosun University, 2014.

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  1. College of Pharmacy, Chosun University, 375 Seosuk-dong, Dong-Gu, Gwangju, 501-759, Korea

    Jun-Hyung Park & Hoo-Kyun Choi

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  1. Jun-Hyung Park
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Correspondence to Hoo-Kyun Choi.

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Park, JH., Choi, HK. Enhancement of solubility and dissolution of cilostazol by solid dispersion technique. Arch. Pharm. Res. 38, 1336–1344 (2015). https://doi.org/10.1007/s12272-014-0547-6

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