Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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Compatibility Study of Excipients for Pravastatin Tablet

Pravastatin 정제 연구를 위한 첨가제와의 적합성 연구

  • Kim, Kang Min (Department of Pharmaceutical Science and Technology, Kyungsung University)
  • 김강민 (경성대학교 제약공학과)
  • Received : 2017.11.09
  • Accepted : 2017.12.01
  • Published : 2018.04.30
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Abstract

Pravastatin sodium is a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor used in the treatment of hypercholesterolemia by reducing cholesterol biosynthesis. Pharmaceutical excipients of commonly used including water, diluents, stabilizers, disintegrants, lubricants and colorants, and were identified for compatibility. All tests were performed by means of physical mixture of pravastatin and the excipients, which were placed in a press-through-pack (PTP) and incubated under accelerated conditions ($40^{\circ}C$ and 75% relative humidity) for 3 months. The blends of pravastatin with all excipients developed white, off white, and light brown powders, which showed no changes upon visual analysis. Accelerated conditions changed the degradation profile of pravastatin calcium in the HPLC system when mixed with different excipients. Although most excipients can have minor effects on pravastatin stability, the major degradation product from pravastatin was lactone. Low-level interaction (assay and impurity) was induced by all excipients except for microcrystalline cellulose and croscarmellose sodium. These excipients increased lactone impurity in 3 months by as much as 0.22% and 0.18% respectively. The total mixture slightly increased the lactone impurity (by 0.43% in 3 months) of pravastatin. There was no change in the assays of all excipients. These results will be helpful in studying tablet size reductions for convenience of use.

Pravastatin은 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) 환원효소 억제제이며, 혈청 콜레스테롤 농도를 낮추어 심혈 관계 위험성 및 사망률을 감소시킨다. 이번 연구는 부형제, 안정화제, 붕해제, 활택제, 착색제로 사용되는 첨가제들 및 pravastatin과의 적합성 연구를 위해 진행되었다. 모든 첨가제들과의 혼합은 PTP 포장으로 포장되어 가속시험장치($40^{\circ}C/75%$ Relative Humidity)에서 3개월 동안 진행하였다. 가시적인 시험결과로는 백색의 가루 또는 밝은 갈색으로 변화는 없었다. 모든 첨가제들과 pravastatin 혼합 시 pravastatin 함량 및 순도에 있어 아주 적은 수준으로 영향을 주었으며, 그 중 pravastatin의 lactone 함량의 변화가 조금 있는 첨가제로는 microcrystalline cellulose 및 croscamellose sodium이었다. 초기의 pravastatin의 lactone 함량과 비교 시 약 0.22% 및 0.18%로 증가하였고 모든 첨가제들과의 전체 혼합 시도 3개월에서 lactone 함량이 0.43%로 증가하는 것을 확인 하였다. 이번 연구 결과들은 복용편리성을 위한 pravastatin 정제 크기 감소 연구에 크게 기여 할 것으로 판단된다.

Keywords

References

  1. Almeida, S., Filipe, A., Almeida, A., Gich, I., Antonijoan, R., Puntes, M., Barbanoj, M. and Caturla, M. C. 2006. Comparative study on the bioequivalence of two formulations of pravastatin. Arzneimittelforschung 56, 70-75.
  2. Bharate, S. S., Bharate, S. B. and Bajaj, A. N. 2010. Interactions and incompatibilities of pharmaceutical excipients with active pharmaceutical ingredients: a comprehensive review. J. Excip. Food Chem. 1, 3-26.
  3. Brain-isasi, S., Requena, C. and Alvarez-lueje, A. 2008. Stability study of pravastatin under hydrolytic conditions assessed by HPLC. J. Chil. Chem. Soc. 53, 1684-1688.
  4. Drug-excipient compatibility studies. 2014. http://pharmaquest.weebly.com/uploads/9/9/4/2/9942916/drug_excipient_compatibility_study.pdf
  5. Gao, J., Fu, X., Ding, M. and Fu, Q. 2010. Studies on partial compatibility of PP and PS. Chin. J. Polym. Sci. 28, 647-656. https://doi.org/10.1007/s10118-010-9150-6
  6. Hirano, T., Komuro, F., Furukawa, S., Nagano, S. and Takahashi, T. 1990. Effect of pravastatin sodium, a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on very-low-density lipoprotein composition and kinetics in hyperlipidemia associated with experimental nephrosis. Metabolism 39, 605-609. https://doi.org/10.1016/0026-0495(90)90026-9
  7. International Conference on Harmonisation (ICH) guideline. 2009. Pharmaceutical development Q8 (R2). Step 5 versions.
  8. Jeong, Y. J., Kim, J. M., Jang, S. J., Bang, J. H., Jung, Y. G., Kim, S. T., Kang, S. H., Choi, J. I., Kim, S. S. and Kang, M. Y. 2017. The effect of pravastatin on insulin resistance in hyperglycemic patients. J. Kor. Diabetes 18, 53-61. https://doi.org/10.4093/jkd.2017.18.1.53
  9. Kim, K. M. and Kang, J. S. 2017. Design of experiments for coating process of valsartan and pravastatin fixed-dose combination tablet. Indian J. Pharm. Educ. 51, 128-135. https://doi.org/10.5530/ijper.51.1.17
  10. Kivisto, K. T., Grisk, O., Hofmann, U., Meissner, K., Moritz, K. U., Ritter, C., Arnold, K. A., Lutjoohann, D., von Bergmann, K., Kloting, I., Eichelbaum, M. and Kroemer, H. K. 2005. Disposition of oral and intravenous pravastatin in MRP2-deficient TR- rats. Drug Metab. Dispos. 33, 1593-1596. https://doi.org/10.1124/dmd.105.006262
  11. Malgorzata, P., Mohamed, S., Polonca, T. and Drago, K. 2010. Stability studies of cholesterol lowering statin drugs in aqueous samples using HPLC and LC-MS. Environ. Chem. Lett. 8 185-191. https://doi.org/10.1007/s10311-009-0207-0
  12. Marian, E., Jurca, T., Kacso, I., Borodi, G., Rus, L. M. and Bratu, I. 2015. Compatibility study between simvastatin and excipients in their physical mixtures. Rev. Chim. 66, 803-807.
  13. Ministry of Food and Drug Safety. 2015. http://www.mfds.go.kr/index.do?cd=&searchkey=title:contents&mid=914&pageNo=6&seq=22056&cmd=v
  14. Ministry of Food and Drug Safety. Korean pharmacopoeia 11th. Notification No. 2017-63.
  15. Rowe, R. C., Sheskey, P. J. and Owen, S. C. 2006. Handbook of pharmaceutical excipients. 5th ed. Pharmaceutical press, London, UK.
  16. Sohn, Y. T. and Lee, A. K. 1999. Compatibility study using differential scanning calorimetry. J. Kor. Pharm. Sci. 29, 117-126.
  17. U.S. Pharmacopeia 31-NF 26, second supplement. 2008. http://www.uspnf.com/uspnf/pub/index?usp=31&nf=26&s=1
  18. U.S. Pharmacopeia 38-NF 33, 2015. The United States Pharmacopoeia, Rockville, MD: United States Pharmacopoeial Convention Inc., pp. 4966-4967.