Development of a rebamipide solid dispersion system with improved dissolution and oral bioavailability

Abstract

The purpose of this study was to improve the gastric solubility and bioavailability of rebamipide (RBM) by preparing the RBM solid dispersion tablet (RBM-SDT) from solid dispersion powder prepared by spray-drying technique. For preparation of rebamipide solid dispersions (RBM-SDs), solubility study was performed in various hydrophilic carriers and alkalizers, among which sodium alginate and sodium carbonate were selected as the hydrophilic polymer and alkalizer, respectively. Different combinations of drug–polymer–alkalizer were dissolved in aqueous solution and spray-dried in order to obtain solid dispersions. Noticeable improvement in aqueous solubility (approximately 200 times) and in vitro dissolution rate was observed by RBM-SDs, compared to RBM powder. The optimized formulation of RBM-SD powder consisted of RBM powder/sodium alginate/sodium carbonate at the weight ratio of 1/2/2. The transformation of crystalline RBM to amorphous RBM-SD powder was clearly demonstrated by powder X-ray diffraction, differential scanning calorimetry (DSC) and scanning electron microscopy. The optimized RBM-SD was formulated in tablet dosage form, containing approximately 2 % sodium lauryl sulphate and poloxamer F68 as wetting agents. The RBM-SDT exhibited enhanced dissolution in hydrochloric acid buffer (pH 1.2) and distilled water. Moreover, pharmacokinetic study in rats showed higher AUC and Cmax for RBM-SDT than those for RBM powder and commercial product. Thus, the developed RBM-SDT formulation can be more efficacious for improving oral bioavailability of RBM.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

References

  1. Alam, M.A., R. Ali, F.I. Al-Jenoobi, and A.M. Al-Mohizea. 2012. Solid dispersions: A strategy for poorly aqueous soluble drugs and technology updates. Expert Opinion on Drug Delivery 9: 1419–1440.

    Article  CAS  PubMed  Google Scholar 

  2. Anderson, N.R., G.S. Banker, and G.E. Peck. 1982. Quantitative evaluation of pharmaceutical effervescent systems I: Design of testing apparatus. Journal of Pharmaceutical Sciences 71: 3–6.

    Article  CAS  PubMed  Google Scholar 

  3. Arakawa, T., K. Kobayashi, T. Yoshikawa, and A. Tarnawski. 1998. Rebamipide: overview of its mechanisms of action and efficacy in mucosal protection and ulcer healing. Digestive Diseases and Sciences 43: 5–13.

    Google Scholar 

  4. Atkinson, R.M., C. Bedford, K.J. Child, and E.G. Tomich. 1962. The effect of griseofulvin particle size on blood levels in man. Antibiotics and Chemotherapy 12: 232–238.

    CAS  PubMed  Google Scholar 

  5. Bassi, P., and G. Kaur. 2010. pH modulation: A mechanism to obtain pH-independent drug release. Expert Opinion on Drug Delivery 7: 845–857.

    Article  CAS  PubMed  Google Scholar 

  6. Chaumeil, J.C. 1998. Micronization: A method of improving the bioavailability of poorly soluble drugs. Methods and Findings in Experimental and Clinical Pharmacology 20: 211–215.

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Choi, H., Y. Oh, and C. Kim. 1998. In situ gelling and mucoadhesive liquid suppository containing acetaminophen: Enhanced bioavailability. International Journal of Pharmaceutics 165: 23–32.

    Article  CAS  Google Scholar 

  9. Choi, H.G., B.J. Lee, C.S. Yong, J.D. Rhee, J.H. Han, M.K. Lee, K.M. Park, and C.K. Kim. 2001. Terfenadine-β-cyclodextrin inclusion complex with the anti-histaminic activity enhancement. Drug Development and Industrial Pharmacy 27: 857–862.

    Article  CAS  PubMed  Google Scholar 

  10. Engel, G.L., N.A. Farid, M.M. Faul, L.A. Richardson, and L.L. Winneroski. 2000. Salt form selection and characterization of LY333531 mesylate monohydrate. International Journal of Pharmaceutics 198: 239–247.

    Article  CAS  PubMed  Google Scholar 

  11. Fix, J.A. 1987. Absorption enhancing agents for the GI system. Journal Controlled Release 6: 151–156.

    Article  CAS  Google Scholar 

  12. Fujii, M., H. Okada, Y. Shibata, H. Teramachi, M. Kondoh, and Y. Watanabe. 2005. Preparation, characterization, and tableting of a soild dispersion of indomethacin with Crospovidone. International Journal of Pharmaceutics 293: 145–153.

    Article  CAS  PubMed  Google Scholar 

  13. Gibaldi, M., and D. Perrier. 1982. Pharmacokinetics, 2nd ed. New York: Marcel-Dekker.

    Google Scholar 

  14. Gupta, M.K., D. Goldman, R.H. Bogner, and Y.C. Tseng. 2001. Enhanced drug dissolution and bulk properties of solid dispersions granulated with a surface adsorbent. Pharmaceutical Development and Technology 6: 563–572.

    Article  CAS  PubMed  Google Scholar 

  15. Javaid, K.A., and D.E. Cadwallader. 1972. Dissolution of aspirin from tablets containing various buffering agents. Journal of Pharmaceutical Sciences 61: 1370–1373.

    Article  CAS  PubMed  Google Scholar 

  16. Karanth, H., V.S. Shenoy, and R.R. Murthy. 2006. Industrially feasible alternative approaches in the manufacture of solid dispersions: A technical report. AAPS PharmSciTech 87: 31–38.

    Article  Google Scholar 

  17. Khalafallah, N., M.W. Gouda, and S.A. Khahl. 1975. Effect of surfactants on absorption through membranes: IV. Effects of dioctylsulfosuccinate on absorption of a poorly absorbable drug in human. Journal of Pharmaceutical Sciences 64: 991–994.

    Article  CAS  PubMed  Google Scholar 

  18. Kikuchi, S. 2002. Epidemiology of Helicobacter pylori and gastric cancer. Gastric Cancer 5: 6–15.

    Article  PubMed  Google Scholar 

  19. Li, D., Y. Oh, S. Lim, J. Kim, H. Yang, J. Sung, C. Yong, and H. Choi. 2008. Novel gelatin microcapsule with bioavailability enhancement of ibuprofen using spray-drying technique. International Journal of Pharmaceutics 355: 277–284.

    Article  CAS  PubMed  Google Scholar 

  20. Li, J., P. Liu, J.P. Liu, W.L. Zhang, J.K. Yang, and Y.Q. Fan. 2012a. Novel Tanshinone II A ternary solid dispersion pellets prepared by a single-step technique: In vitro and in vivo evaluation. European Journal of Pharmaceutics and Biopharmaceutics 80: 426–432.

    Article  CAS  PubMed  Google Scholar 

  21. Li, S., C. Pollock-Dove, L.C. Dong, J. Chen, A.A. Creasey, and W.G. Dai. 2012b. Enhanced bioavailability of a poorly water-soluble weakly basic compound using a combination approach of solubilization agents and precipitation inhibitors: A case study. Molecular Pharmaceutics 9: 1100–1108.

    CAS  PubMed  Google Scholar 

  22. Lindmark, T., Y. Kimura, and P. Artursson. 1998. Absorption enhancement through intracellular regulation of tight junction permeability by medium chain fatty acids in Caco-2 cells. Journal of Pharmacology and Experimental Therapeutics 284: 362–369.

    CAS  PubMed  Google Scholar 

  23. Marasini, N., T.H. Tran, B.K. Poudel, H.J. Cho, Y.K. Choi, S.C. Chi, H.G. Choi, C.S. Yong, and J.O. Kim. 2013. Fabrication and evaluation of pH-modulated solid dispersion for telmisartan by spray-drying technique. International Journal of Pharmaceutics 441: 424–432.

    Article  CAS  PubMed  Google Scholar 

  24. Mason, W.D., and N. Winer. 1981. Kinetics of aspirin, salicylic acid and salicyluric acid following oral administration of aspirin as a tablet and two buffered solutions. Journal of Pharmaceutical Sciences 70: 262–265.

    Article  CAS  PubMed  Google Scholar 

  25. Miyake, M., Y. Oka, T. Minami, H. Toguchi, M. Odomi, K. Ogawara, K. Higaki, and T. Kimura. 2003. Combinatorial use of sodium laurate with taurine or l-glutamine enhances colonic absorption of rebamipide, poorly absorbable antiulcer drug, without any serious histopathological mucosal damages. Journal of Pharmaceutical Sciences 92: 911–921.

    Article  CAS  PubMed  Google Scholar 

  26. Morris, K.R., M.G. Fakes, A.B. Thakur, A.W. Singh, and J.J. Venit. 1994. An integrated approach to the selection of optimal salt form for a new drug candidate. International Journal of Pharmaceutics 105: 209–217.

    Article  CAS  Google Scholar 

  27. Newa, M., K.H. Bhandari, D.X. Li, T.H. Kwon, J.A. Kim, B.K. Yoo, J.S. Woo, W.S. Lyoo, C.S. Yong, and H.G. Choi. 2007. Preparation, characterization and in vivo evaluation of ibuprofen binary solid dispersions with poloxamer 188. International Journal of Pharmaceutics 343: 228–237.

    Article  CAS  PubMed  Google Scholar 

  28. Newa, M., K.H. Bhandari, D.X. Li, J.O. Kim, D.S. Yoo, J.A. Kim, B.K. Yoo, J.S. Woo, W.S. Lyoo, C.S. Yong, and H.G. Choi. 2008. Preparation and evaluation of immediate release ibuprofen solid dispersions using polyethylene glycol 4000. Biological and Pharmaceutical Bulletin 31: 939–945.

    Article  CAS  PubMed  Google Scholar 

  29. O’Connor, K.M., and O.I. Corrigan. 2001. Comparison of the physicochemical properties of the N-(2-hydroxyethyl) pyrrolidine, diethylamine and sodium salt forms of diclofenac. International Journal of Pharmaceutics 222: 281–293.

    Article  PubMed  Google Scholar 

  30. Pabari, R.M., and Z. Ramtoola. 2012. Effect of a disintegration mechanism on wetting, water absorption, and disintegration time of orodispersible tablets. J. Young Pharmacists 4: 157–163.

    Article  CAS  Google Scholar 

  31. Prabagar, B., B.K. Yoo, J.S. Woo, J.A. Kim, J.D. Rhee, M.G. Piao, C.S. Yong, and H.G. Choi. 2007. Enhanced bioavailability of poorly water-soluble clotrimazole by inclusion with β-cyclodextrin. Archives of Pharmacal Research 30: 249–254.

    Article  CAS  PubMed  Google Scholar 

  32. Rho, J.I. 2003. A new rebamipide lysinate, rebamipide argininate and pharmaceutical preparation containing the same as active substance. Korea Patent 10 2003 0035382.

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

    Article  CAS  Google Scholar 

  34. Seo, S.W., H.K. Han, M.K. Chun, and H.K. Choi. 2012. Preparation and pharmacokinetic evaluation of curcumin solid dispersion using Solutol® HS15 as a carrier. International Journal of Pharmaceutics 424: 18–25.

    Article  CAS  PubMed  Google Scholar 

  35. Serajuddin, A.T.M. 1999. Solid dispersion of poorly water-soluble drugs: Early promises, subsequent problems, and recent breakthroughs. Journal of Pharmaceutical Sciences 88: 1058–1066.

    Article  CAS  PubMed  Google Scholar 

  36. Sheth, P., H. Sandhu, D. Singhal, W. Malick, N. Shah, and M.S. Kislalioglu. 2012. Nanoparticles in the pharmaceutical industry and the use of supercritical fluid technologies for nanoparticle production. Current Drug Delivery 9: 269–284.

    Article  CAS  PubMed  Google Scholar 

  37. Shin, B.S., C.H. Kim, Y.S. Jun, C.H. Yoon, J.I. Rho, K.C. Lee, H.S. Han, and S.D. Yoo. 2004. Oral absorption and pharmacokinetics of rebamipide and rebamipide lysinate in rats. Drug Development and Industrial Pharmacy 30: 869–876.

    Article  CAS  PubMed  Google Scholar 

  38. Society of Toxicology (SOT). 2008. Guiding Principles in the Use of Animals in Toxicology. www.toxicology.org/AI/FA/guidingprinciples.pdf. Accessed 20 Dec 2013.

  39. Tran, P.H., H.T. Tran, and B.J. Lee. 2008. Modulation of microenvironmental pH and crystallinity of ionizable TMS using alkalizers in solid dispersions for controlled release. Journal of Controlled Release 129: 59–65.

    Article  CAS  PubMed  Google Scholar 

  40. Tran, P.H., T.T. Tran, K.H. Lee, D.J. Kim, and B.J. Lee. 2010. Dissolution-modulating mechanism of pH modifiers in solid dispersion containing weakly acidic or basic drugs with poor water solubility. Expert Opinion on Drug Delivery 7: 647–661.

    Article  CAS  PubMed  Google Scholar 

  41. Tran, H.T.T., J.B. Park, K.H. Hong, H.G. Choi, H.K. Han, J. Lee, K.T. Oh, and B.J. Lee. 2011. Preparation and characterization of pH-independent sustained release tablet containing solid dispersion granules of a poorly water-soluble drug. International Journal of Pharmaceutics 415: 83–88.

    Article  CAS  PubMed  Google Scholar 

  42. Tran, T.H., B.K. Poudel, N. Marasini, S.C. Chi, H.G. Choi, C.S. Yong, and J.O. Kim. 2013. Preparation and evaluation of raloxifene-loaded solid dispersion nanoparticle by spray drying technique without an organic solvent. International Journal of Pharmaceutics 443: 50–57.

    Article  CAS  PubMed  Google Scholar 

  43. Tung, N.T., C.W. Park, T.O. Oh, J.Y. Kim, J.M. Ha, Y.S. Rhee, and E.S. Park. 2011. Formulation of solid dispersion of rebamipide evaluated in a rat model for improved bioavailability and efficacy. Journal of Pharmacy and Pharmacology 63: 1539–1547.

    Article  CAS  PubMed  Google Scholar 

  44. US Food and Drug Administration. 2009. Guidance for industry: Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070246.pdf. Accessed 15 Jan 2014.

  45. Visser, M.R., L. Baert, G.V. Klooster, L. Schueller, M. Geldof, I. Vanwelkenhuysen, H.D. Kock, S.D. Meyer, H.W. Frijlink, J. Rosier, and W.L.J. Hinrichs. 2010. Inulin solid dispersion technology to improve the absorption of the BCS Class IV drug TMC240. European Journal of Pharmaceutics and Biopharmaceutics 74: 233–238.

    Article  CAS  PubMed  Google Scholar 

  46. Yi, H.G., M.H. Chi, Y.I. Kim, J.S. Woo, and E.S. Park. 2008. Formulation of a extended release tablet containing dexibuprofen. Archives of Pharmacal Research 31: 1637–1643.

    Article  CAS  PubMed  Google Scholar 

  47. Yong, C.S., D.X. Li, D.H. Oh, J.A. Kim, B.K. Yoo, J.S. Woo, J.D. Rhee, and H.G. Choi. 2005. Retarded dissolution of ibuprofen in gelatin microcapsule by cross-linking with glutaraldehyde. Archives of Pharmacal Research 29: 431–534.

    Google Scholar 

  48. Zhang, Y., J. Zhang, T. Jiang, and S. Wang. 2011. Inclusion of the poorly water-soluble drug simvastatin in mesocellular foam nanoparticles: Drug loading and release properties. International Journal of Pharmaceutics 410: 118–124.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by a grant from the Medical Cluster R&D Support Project of Daegu Gyeongbuk Medical Innovation Foundation, Republic of Korea (2013) (No. HT13C0011).

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Chul Soon Yong or Jong Oh Kim.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Pradhan, R., Tran, T.H., Choi, J.Y. et al. Development of a rebamipide solid dispersion system with improved dissolution and oral bioavailability. Arch. Pharm. Res. 38, 522–533 (2015). https://doi.org/10.1007/s12272-014-0399-0

Download citation

Keywords

  • Rebamipide
  • Solubility
  • Solid dispersion
  • Spray-drying
  • Bioavailability