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Implementation of Quality by Design for Formulation of Rebamipide Gastro-retentive Tablet

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Abstract

The purpose of the present study was to develop a rebamipide (RBM) gastro-retentive (GR) tablet by implementing quality by design (QbD). RBM GR tablets were prepared using a sublimation method. Quality target product profile (QTPP) and critical quality attributes (CQAs) of the RBM GR tablets were defined according to the preliminary studies. Factors affecting the CQAs were prioritized using failure mode and effects analysis (FMEA). Design space and optimum formulation were established through a mixture design. The validity of the design space was confirmed using runs within the area. The QTPP of the RBM GR tablets was the orally administered GR tablet containing 300 mg of RBM taken once daily. Based on the QTPP, dissolution rate, tablet friability, and floating property were chosen as CQAs. According to the risk assessment, the amount of sustained-release agent, sublimating material, and diluent showed high-risk priority number (RPN) values above 40. Based on the RPN, these factors were further investigated using mixture design methodology. Design space of formulations was depicted as an overlaid contour plot and the optimum formulation to satisfy the desired responses was obtained by determining the expected value of each response. The similarity factor (f2) of the release profile between predicted response and experimental response was 89.463, suggesting that two release profiles are similar. The validity of the design space was also confirmed. Consequently, we were able to develop the RBM GR tablets by implementing the QbD concept. These results provide useful information for development of tablet formulations using the QbD.

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References

  1. Yamasaki K, Kanbe T, Chijiwa T, Ishiyama H, Morita S. Gastric mucosal protection by OPC-12759, a novel antiulcer compound, in the rat. Eur J Pharmacol. 1987;142(1):23–9.

    Article  CAS  PubMed  Google Scholar 

  2. Tarnawski AS. 15th anniversary of rebamipide: looking ahead to the new mechanisms and new applications. Dig Dis Sci. 2005;50(1):S3–S11.

    PubMed  Google Scholar 

  3. Ogino K, Hobara T, Ishiyama H, Yamasaki K, Kobayashi H, Izumi Y, et al. Antiulcer mechanism of action of rebamipide, a novel antiulcer compound, on diethyldithiocarbamate-induced antral gastric ulcers in rats. Eur J Pharmacol. 1992;212(1):9–13.

    Article  CAS  PubMed  Google Scholar 

  4. Tarnawski A, Chai J, Pai R, Chiou S-K. Rebamipide activates genes encoding angiogenic growth factors and Cox2 and stimulates angiogenesis: a key to its ulcer healing action? Dig Dis Sci. 2004;49(2):202–9.

    Article  CAS  PubMed  Google Scholar 

  5. Murata H, Yabe Y, Tsuji S, Tsujii M, Fu HY, Asahi K, et al. Gastroprotective agent rebamipide induces cyclooxygenase-2 (COX-2) in gastric epithelial cells. Dig Dis Sci. 2005;50(1):S70–S5.

    Article  CAS  PubMed  Google Scholar 

  6. Ho L, Müller R, Römer M, Gordon K, Heinämäki J, Kleinebudde P, et al. Analysis of sustained-release tablet film coats using terahertz pulsed imaging. J Control Release. 2007;119(3):253–61.

    Article  CAS  PubMed  Google Scholar 

  7. Yamamoto T, Isono A, Mishina Y, Ebato T, Shirai T, Nakayama S, et al. Gastroduodenal mucosal injury in patients taking low-dose aspirin and the role of gastric mucoprotective drugs: possible effect of rebamipide. J Clin Biochem Nutr. 2010;47(1):27–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Araki H, Kato T, Onogi F, Ibuka T, Sugiyama A, Nakanishi T, et al. Combination of proton pump inhibitor and rebamipide, a free radical scavenger, promotes artificial ulcer healing after endoscopic submucosal dissection with dissection size >40 mm. J Clin Biochem Nutr. 2012;51(3):185–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Streubel A, Siepmann J, Bodmeier R. Drug delivery to the upper small intestine window using gastroretentive technologies. Curr Opin Pharmacol. 2006;6(5):501–8.

    Article  CAS  PubMed  Google Scholar 

  10. Talukder R, Fassihi R. Gastroretentive delivery systems: a mini review. Drug Dev Ind Pharm. 2004;30(10):1019–28.

    Article  CAS  PubMed  Google Scholar 

  11. Kim J-Y, Seo J-W, Rhee Y-S, Park C-W, Park E-S. Freeze-dried highly porous matrix as a new gastroretentive dosage form for ecabet sodium: in vitro and in vivo characterizations. J Pharm Sci. 2014;103(1):262–73.

    Article  CAS  Google Scholar 

  12. Oh TO, Kim JY, Ha JM, Chi SC, Rhee YS, Park CW, et al. Preparation of highly porous gastroretentive metformin tablets using a sublimation method. Eur J Pharm Biopharm. 2013;83(3):460–7.

    Article  CAS  PubMed  Google Scholar 

  13. Lopes CM, Bettencourt C, Rossi A, Buttini F, Barata P. Overview on gastroretentive drug delivery systems for improving drug bioavailability. Int J Pharm. 2016;510(1):144–58.

    Article  CAS  PubMed  Google Scholar 

  14. Chen YC, Ho HO, Lee TY, Sheu MT. Physical characterizations and sustained release profiling of gastroretentive drug delivery systems with improved floating and swelling capabilities. Int J Pharm. 2013;441(1–2):162–9.

    Article  CAS  PubMed  Google Scholar 

  15. Darandale SS, Vavia PR. Design of a gastroretentive mucoadhesive dosage form of furosemide for controlled release. Acta Pharm Sin B. 2012;2(5):509–17.

    Article  CAS  Google Scholar 

  16. Pund S, Joshi A, Vasu K, Nivsarkar M, Shishoo C. Gastroretentive delivery of rifampicin: in vitro mucoadhesion and in vivo gamma scintigraphy. Int J Pharm. 2011;411(1–2):106–12.

    Article  CAS  PubMed  Google Scholar 

  17. Jagdale S, Kurhe P, Kuchekar B, Chabukswar A. Application of design of experiments to optimizing novel gastroretentive drug delivery of simvastatin. Curr Drug Deliv. 2013;10(5):527–41.

    Article  CAS  PubMed  Google Scholar 

  18. Thakar K, Joshi G, Sawant KK. Bioavailability enhancement of baclofen by gastroretentive floating formulation: statistical optimization, in vitro and in vivo pharmacokinetic studies. Drug Dev Ind Pharm. 2013;39(6):880–8.

    Article  CAS  PubMed  Google Scholar 

  19. Zidan AS, Sammour OA, Hammad MA, Megrab NA, Habib MJ, Khan MA. Quality by design: understanding the formulation variables of a cyclosporine A self-nanoemulsified drug delivery systems by Box–Behnken design and desirability function. Int J Pharm. 2007;332(1–2):55–63.

    Article  CAS  PubMed  Google Scholar 

  20. Ibrahim HM, Ahmed TA, Hussain MD, Rahman Z, Samy AM, Kaseem AA, et al. Development of meloxicam in situ implant formulation by quality by design principle. Drug Dev Ind Pharm. 2014;40(1):66–73.

    Article  CAS  PubMed  Google Scholar 

  21. Shastri PN, Ubale RV, D’Souza MJ. Implementation of mixture design for formulation of albumin containing enteric-coated spray-dried microparticles. Drug Dev Ind Pharm. 2013;39(2):164–75.

    Article  CAS  PubMed  Google Scholar 

  22. Huang C-T, Tsai M-J, Lin Y-H, Fu Y-S, Huang Y-B, Tsai Y-H, et al. Effect of microemulsions on transdermal delivery of citalopram: optimization studies using mixture design and response surface methodology. Int J Nanomedicine. 2013;8:2295–304.

    Article  PubMed  PubMed Central  Google Scholar 

  23. El-Dahmy RM, Elsayed I, Elshafeey AH, Gawad NAAE, El-Gazayerly ON. Optimization of long circulating mixed polymeric micelles containing vinpocetine using simple lattice mixture design, in vitro and in vivo characterization. Int J Pharm. 2014;477(1–2):39–46.

    Article  CAS  PubMed  Google Scholar 

  24. ICH Expert Working Group. Pharmaceutical development Q8(R2). The International Council for Harmonisation. 2009. https://www.aaps.org/uploadedFiles/Content/Publications/Journals/AAPSPT%20Instructions%20for%20Authors_Updated%209.19.16(1).pdf.

  25. Lionberger RA, Lee SL, Lee L, Raw A, Lawrence XY. Quality by design: concepts for ANDAs. AAPS J. 2008;10(2):268–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lawrence XY. Pharmaceutical quality by design: product and process development, understanding, and control. Pharm Res. 2008;25(4):781–91.

    Article  Google Scholar 

  27. Fahmy R, Kona R, Dandu R, Xie W, Claycamp G, Hoag SW. Quality by design I: application of failure mode effect analysis (FMEA) and Plackett–Burman design of experiments in the identification of “main factors” in the formulation and process design space for roller-compacted ciprofloxacin hydrochloride immediate-release tablets. AAPS PharmSciTech. 2012;13(4):1243–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Vora C, Patadia R, Mittal K, Mashru R. Risk based approach for design and optimization of stomach specific delivery of rifampicin. Int J Pharm. 2013;455(1–2):169–81.

    Article  CAS  PubMed  Google Scholar 

  29. Hwang K-M, Cho C-H, Tung N-T, Kim J-Y, Rhee Y-S, Park E-S. Release kinetics of highly porous floating tablets containing cilostazol. Eur J Pharm Biopharm. 2017;115:39–51.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (grant number NRF-2016R1A2B4007101).

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Authors and Affiliations

  1. School of Pharmacy, Sungkyunkwan University, Jangan-gu, Suwon, Gyeonggi-do, 440-746, Republic of Korea

    Jung-Myung Ha, Jeong-Woong Seo, Su-Hyeon Kim & Eun-Seok Park

  2. College of Pharmacy, Woosuk University, Wanju, 565-701, Republic of Korea

    Ju-Young Kim

  3. College of Pharmacy, Chungbuk National University, Cheongju, 361-763, Republic of Korea

    Chun-Woong Park

  4. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, 660-751, Republic of Korea

    Yun-Seok Rhee

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  1. Jung-Myung Ha
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Correspondence to Eun-Seok Park.

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Ha, JM., Seo, JW., Kim, SH. et al. Implementation of Quality by Design for Formulation of Rebamipide Gastro-retentive Tablet. AAPS PharmSciTech 18, 3129–3139 (2017). https://doi.org/10.1208/s12249-017-0797-y

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