Journal of the Korea Academia-Industrial cooperation Society (한국산학기술학회논문지)

The Korea Academia-Industrial cooperation Society (한국산학기술학회)
권호 표지
DOI QR코드

DOI QR Code

Immediate Drug Release Enhancement of Nateglinide Using Fumaric Acid

푸마르산을 이용한 나테글리니드 함유 속방출형 제형의 약물방출 개선에 관한 연구

  • Lee, Sung-Hoon (Department of pharmaceutical Engineering, Cheongju University)
  • 이성훈 (청주대학교 제약공학과)
  • Received : 2016.09.09
  • Accepted : 2017.01.06
  • Published : 2017.01.31
Download PDF
⟨ Previous Next ⟩

Abstract

The purpose of this study was to improve release rate and bioavailability of nateglinide formulation. Polymorphism selection and particle size control were performed to enhance formulation dissolution rate, and a pH modifier was included in the formulation to overcome pH-dependent solubility of nateglinide. The enhanced dissolution rate was characterized by using a dissolution test. The results showed that H-type raw material had a higher dissolution rate than that of B-type raw material. There was 6.2% difference in dissolution between the two materials at 60 min. With regard to particle size, raw material with a $1.13{\mu}m$ particle size showed a 20% faster release rate than that of raw material with a $2.28{\mu}m$ particle size. Furthermore, fumaric acid was included in formulation as a pH modifier. That addition produced a greater than 50% improvement in dissolution rate. In conclusion, dissolution rate of nateglinide can be enhanced by optimizing its polymorphism and particle size; moreover, a synergistic effect on the enhancement of dissolution rate is obtained by including fumaric acid, a pH modifier, in the formulation.

본 연구의 목적은 나테글리니드를 함유하는 제형에 있어서 약물방출 속도 및 생체이용률을 개선하는 것이다. 이를 위해, 약물의 결정형의 선택 및 입자 크기의 최적화를 진행하였으며, 약물의 pH 의존적인 용해도를 극복하기 위하여 제형에 pH 조절제를 포함하여 pH에 따른 약물의 용출속도 저하를 개선하고자 하였다. 또한 개선된 약물방출 속도 확인을 위하여 용출시험을 실시하였다. 약물의 결정형에 따른 용출속도를 비교한 결과로는 H-type의 원료가 B-type에 비해 60분에서의 용출률이 6.2% 더 빠르게 나타나는 것을 확인하였으며, 약물의 입도 차에 따라서는 평균입도 $1.13{\mu}m$인 원료가 $2.28{\mu}m$인 원료에 비해 60분에서의 용출률이 약 20% 빠르게 나타나는 것을 확인할 수 있었다. 또한 pH 조절제로서 유기산인 푸마르산을 제형에 포함시킨 결과, 용출시험 60분 경과 후 50% 이상의 용출 속도 개선을 확인할 수 있었다. 결론적으로, 약물의 결정형 및 입도의 조절을 통해 나테글리니드의 용출 속도를 증가시킬 수 있으며, pH 조절제로서 푸마르산을 제형에 적용할 경우 용출속도 개선 측면에서 동반상승 효과를 얻을 수 있다.

Keywords

References

  1. A. J. Garber, "Current challenge in type 2 diabetes", Diabetes Obes. Metab. 14,1-3, 2012. DOI: https://doi.org/10.1111/j.1463-1326.2012.01572.x
  2. C. Makino, H. Sakai, A. Yabuki, "Nateglinide controlled release tablet containing compressionable enteric coated granules", Chem. Pharm. Bull. 58, 1136-1141, 2010. DOI: https://doi.org/10.1248/cpb.58.1136
  3. I. W. Campbell, "Nateglinide-current and future role in the treatment of patients with type 2 diabets mellitus", Int. J. Clin. Pract. 59, 1218-1228, 2005. DOI: https://doi.org/10.1111/j.1368-5031.2005.00669.x
  4. S. Hu, S. Wang, B. Fanelli, P. A. Bell, B. E. Dunning, S. Geisse, R. Schmitz, B. R. Boettcher, "Pancratic beta-cell K(ATP) channel activity and menbrane-binding studies with nateglinide: a comparison with sulfonylureas and repaglinide", J. Pharmacol. Exp. Ther. 293, 444-452, 2000.
  5. J. F. McLeod, "Clinical pharmacokinetics of nateglinide: a rapidly-absorbed, short-acting insulinotropic agent", Clin. Pharmacokinet., 43, 97-120, 2004. DOI: https://doi.org/10.2165/00003088-200443020-00003
  6. M. Kataoka, S. Itsubata, Y. Masaoka, S. Sakuma, S. Yamashita, "In vitro dissolution/permeation system to predict the oral absorption of poorly water-soluble drugs: effect of food and dose strength on it", Biol. Pharm. Bull. 34, 401-407, 2011. DOI: https://doi.org/10.1248/bpb.34.401
  7. A. Okamura, A. Emoto, N. Koyabu, H. Ohtani, Y. Sawada, "Transport and uptake of nataglinide in Caco-2 cells and its inhibitory effect on human monocarboxylate transporter MCT1", Br. J. Pharmacol. 137, 391-399, 2002. DOI: https://doi.org/10.1038/sj.bjp.0704875
  8. G. Bruni, V. Berbenni, C. Milanese, A. Girella, A. Cardini, E. Vigano, A. Marini, "Thermodynamic relationships between nateglinide polymorphs", J. Pharm. Biomed. Anal. 50, 764-770, 2009. DOI: https://doi.org/10.1016/j.jpba.2009.06.017
  9. G. Bruni, V. Berbenni, C. Milanese, A. Girella, A. Cardini, S. Lanfranconi, A. Marini, "New solid modifications of nateglinide", J. Pharm. Biomed. Anal. 51, 1054-1059, 2010. DOI: https://doi.org/10.1016/j.jpba.2009.11.019
  10. G. Bruni, V. Berbenni, C. Milanese, A. Girella, A. Cardini, A. Marini, " Determination of the nateglinide polymorphic purity through DSC", J. Pharm. Biomed. Anal. 54, 1196-1199, 2011. DOI: https://doi.org/10.1016/j.jpba.2010.12.003
  11. J. Tang, J. Sun, Z. G. He, "Self-emulsifying drug delivery systems: strategy for improving oral delivery poorly soluble drugs", Curr. Drug Ther. 2, 85-93, 2007. DOI: https://doi.org/10.2174/157488507779422400
  12. N. Bladgen, M. de Matas, P. T. Gavan, P. York, "Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates", Adv. Drug Deliv. Rev. 59, 617-630, 2007. DOI: https://doi.org/10.1016/j.addr.2007.05.011
  13. G. Bruni, M. Maietta, L. Maggi, M. Bini, D. Capsoni, S. Ferrari, M. Boiocchi, V. Berbenni, C. Milanese, A. Marini, "Perphenazine-fumaric acid salts with improved solubility: preparation, physico-chemical characterization and in vitro dissolution", Cryst. Eng. Commun. 14, 6035-6044, 2012. DOI: https://doi.org/10.1039/c2ce25846c
  14. G. Bruni, M. Maietta, V. Berbenni, M. Bini, S. Ferrari, D. Capsoni, M. Boiocchi, C. Milanese, A. Marini, "Preparation and characterization of carprofen co-crystals", Cryst. Eng. Commun, 14, 435-455, 2012. DOI: https://doi.org/10.1039/C1CE05571B
  15. A. Scholz, B. Abrahamsson, S. M. Diebold, E. Kostewicz, B. I. Polentarutti, A. L. Ungell, J. B. Dressman, "Influence of hydrodynamics and particle size on the absorption of felodipine in labradors", Pharm. Res. 19, 42-46, 2002. DOI: https://doi.org/10.1023/A:1013651215061
  16. R. Shegokar, R. H. Muller, "Nanocrystals: industrially feasible multifunctional formulation technology for poorly soluble actives", Int. J. Pharm. 399, 129-139, 2010. DOI: https://doi.org/10.1016/j.ijpharm.2010.07.044
  17. F. Meng, A. Trivino, D. Prasad, H. Chauhan, "Investigation and correlation of drug polymer miscibility and molecular interactions by various approaches for the preparation of amorphous solid dispersions", Eur. J. Pharm. Sci. 71, 12-24, 2015. DOI: https://doi.org/10.1016/j.ejps.2015.02.003
  18. G. A. Stephenson, J. Siepmann, A. Dashevsky, R. Bodmeier, "pH-independent release of a weakly basic drug from water-insoluble and -soluble matrix tablets", J. Control. Release. 67, 101-110, 2000. DOI: https://doi.org/10.1016/S0168-3659(00)00200-5
  19. L. Yu, "Amorphous pharmaceutical solids: preparation, characterization and stabilization", Adv. Drug Deliv. Rev. 4, 27-42, 2001. DOI: https://doi.org/10.1016/S0169-409X(01)00098-9
  20. D. Horter, J. B. Dressman, "Influence of physicochemical properties on dissolution of drugs in the gastrointestinal tract", Adv. Drug Deliv. Rev. 46, 75-87, 2001. https://doi.org/10.1016/S0169-409X(00)00130-7
  21. V. Sekar, V. R. Chellan, "Immediate release tablets of telmisartan using superdisintegrant - formulation, evaluation and stability studies", Chem. Pharm. Bull., 56, 575-577, 2008. DOI: https://doi.org/10.1248/cpb.56.575
  22. S. Mallick, S. Pattnaik, K. Swain, P. K. De, "Current prospectives of solubilization: Potential for improved bioavailability", Drug Dev. Ind. Pharm., 33, 865-873, 2007. DOI: https://doi.org/10.1080/03639040701429333
  23. M. Moneghini, A. Carcano, B. Perssutti, F. Rubessa, "Formulation design studies of atenolol tablets", Pharm. Dev. Technol., 5, 297-301, 2000. DOI: https://doi.org/10.1081/PDT-100100544
  24. S. U. Choi, S. W. Cho, "Formulation of liquid choline alphoscerate as a solid dosage form", Journal of the Korea Academia-Industrial cooperation Society, 14(12), 6324-6329, 2013. DOI: http://dx.doi.org/10.5762/KAIS.2013.14.12.6324
  25. Y. Zu, N. Li, X. Zhao, Y. Li, Y. Ge, W. Wang, K. Wang, Y. Liu, "In vitro dissolution enhancement of micronized l-nimodipine by antisolvent l-crystallization from its crystal form H", Int. J,. Pharm. 10, 1-9, 2014. DOI: https://doi.org/10.1016/j.ijpharm.2014.01.020