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

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

DOI QR Code

Development of Pharmaceutical Dosage Forms with Biphasic Drug Release using Double-Melt Extrusion Technology

이중 고온용융 압출 성형된 이중 방출능을 가지는 제형의 개발

  • Received : 2016.08.09
  • Accepted : 2016.09.09
  • Published : 2016.09.30
Download PDF
⟨ Previous Next ⟩

Abstract

The aim of this study was to develop pharmaceutical dosage forms with a bi-phasic drug using a double extrusion approach. Hot melt extrusion was performed using a co-rotating twin-screw extruder. The. 1st melt extrusion was performed using polymer with a relatively higher Tg, such as HPMC and the 2nd melt extrudate was obtained using the 1st extrudate and polymers with a lower Tg, such as HPMC-AS and PEO. In addition, the formulation with all the content in the same proportion as the double extudate was produced using single extrusion for comparison. Physical characterization was performed on the formulations employing differential scanning calorimetry (DSC). In vitro release tests were studied using a USP Type-I apparatus at $37{\pm}0.5^{\circ}C$ and 100 rpm. The similarity factor (f2) was also used to check the difference statistically. The DSC results indicated that the crystallinity of ibuprofen was changed to an amorphous state after extrusion in both double and single melt extrusion. Double melt extrudate with ibuprofen showed the desired release in acidic media (pH 1.2) in the first two hours and basic (pH 6.8) during six hours. Double melt extrudate with glimepiride showed faster release in 60 min of over 80%, whereas the single extrudate with glimepiride showed retarded release due to the interaction with HPMC. The similarity factor(f2) value was 28.5, which demonstrates that there were different drug release behavior between the double and single extrusion. Consequently, the double melt extrudated formulation was robust and gave the desired drug release pattern.

본 이 연구의 목적은 이중 고온용융 압출법을 이용하여 기존의 방법으로 가지기 어려운 이상성의 약물방출 양상을 가지는 제형을 개발하는 것이다. 이 고온용융 압출물은 동회전 능을 가지는 두 개의 스크류가 장착된 압출기를 이용하여 제조되었다. Hydroxpropylmethylcellulose(HPMC) 같은 상대적으로 유리전이 온도가 높은 고분자를 이용하여 1차로 고온용융 압출물이 제조되었고, 이 1차 압출물과 상대적으로 유리전이 온도가 낮은 HPMC-AS(Acceate succinate)나 PEO(polyethlene oxide)를 이용하여 2차로 고온용융 압출물이 제조되었다. 또한 이중 고온용융 압출물과의 비교시험을 위해 같은 조성과 같은 조건하에서 일반적인 한 번의 고온용융 압출물도 제조되었다. 시차주사 열량계를 통해 물리적인 성질이 평가되었고, 미국약전의 제 1법에 따라 $37{\pm}0.5^{\circ}C$와 100 rpm의 조건에서 약물방출 시험이 진행되었으며 그 약물방출은 유사성인자($f_2$)를 이용하여 평가되었다. 시차주사 열량계 결과는 이부프로펜의 결정성이 이중 고온용융 압출법에서나 한번 고온용융 압출법 모두에서 무정형으로 변화된 것을 확인할 수 있었으며, 용출시험에서는 이중 고온용융 압출법에서 더욱 더 이상적인 이부프로펜의 방출을 인공위액(pH 1.2)에서 2시간, 0차 방출을 인공장액(pH 6.8)에서 6시간 동안 확인할 수 있었다. 빠른방출이 요구되는 글리메피라이드의 경우는 이중 고온용융 압출물에서는 60분에 80% 이상의 빠른 약물 방출을 보인 반면, 한번 고온용융 압출물에서는 약물방출이 HPMC와의 상호작용 때문에 느려져서 기준을 만족하지 못했다. 유사성 인자($f_2$) 값도 28.5로 매우 다른 방출을 보여주고 있음이 통계적으로 확인되었다. 이상의 결과들을 종합해 볼 때, 이중 고온용융 압출법은 완건성이 좋은 또 원하는 약물방출을 얻을 수 있는 방법이라 할 수 있다.

Keywords

References

  1. M. M. Crowley, F. Zhang, M. A. Repka, S. Thumma, S. B. Upadhye, S. Kumar Battu, J. W. McGinity, C. Martin, "Pharmaceutical applications of hot-melt extrusion: part I", Drug development and industrial pharmacy, vol. 33, pp. 909-926, 2007. DOI: http://dx.doi.org/10.1080/03639040701498759
  2. J.-B. Park, C.-Y. Kang, W.-S. Kang, H.-G. Choi, H.-K. Han, B.-J. Lee, "New investigation of distribution imaging and content uniformity of very low dose drugs using hot-melt extrusion method", International journal of pharmaceutics, vol. 458, pp. 245-253, 2013. DOI: http://dx.doi.org/10.1016/j.ijpharm.2013.10.027
  3. J.-B. Park, S. Prodduturi, J. Morott, V. I. Kulkarni, M. R. Jacob, S. I. Khan, S. P. Stodghill, M. A. Repka, "Development of an antifungal denture adhesive film for oral candidiasis utilizing hot melt extrusion technology", Expert opinion ondrug delivery, vol. 12, pp. 1-13, 2015. https://doi.org/10.1517/17425247.2015.1074356
  4. M. B. Pimparade, J. T. Morott, J.-B. Park, V. I. Kulkarni, S. Majumdar, S. Murthy, Z. Lian, E. Pinto, V. Bi, T. Durig, "Development of taste masked caffeine citrate formulations utilizing hot melt extrusion technology and in vitro-in vivo evaluations", International journal of pharmaceutics, vol. 487, pp. 167-176, 2015. DOI: http://dx.doi.org/10.1016/j.ijpharm.2015.04.030
  5. P. H.-L. Tran, T. T.-D. Tran, J. B. Park, B.-J. Lee, "Controlled release systems containing solid dispersions: strategies and mechanisms", Pharmaceutical research, vol. 28, pp. 2353-2378, 2011. DOI: http://dx.doi.org/10.1007/s11095-011-0449-y
  6. M. A. Repka, S. K. Battu, S. B. Upadhye, S. Thumma, M. M. Crowley, F. Zhang, C. Martin, J. W. McGinity, "Pharmaceutical applications of hot-melt extrusion: Part II", Drugdevelopment and industrial pharmacy, vol. 33, pp. 1043-1057, 2007. DOI: http://dx.doi.org/10.1080/03639040701525627
  7. M. Maniruzzaman, M. Rana, J. Boateng, J. Mitchell, D. Douroumis, "Dissolution enhancement of poorly water-soluble APIs processed by hot-melt extrusion using hydrophilic polymers", Drug development and industrial pharmacy, vol. 39, pp. 218-227, 2013. DOI: http://dx.doi.org/10.3109/03639045.2012.670642
  8. W. Wang, Q. Kang, N. Liu, Q. Zhang, Y. Zhang, H. Li, B. Zhao, Y. Chen, Y. Lan, Q. Ma, "Enhanced dissolution rate and oral bioavailability of Ginkgo biloba extractby preparing solid dispersion via hot-melt extrusion", Fitoterapia, vol. 102, pp. 189-197, 2015. DOI: http://dx.doi.org/10.1016/j.fitote.2014.10.004
  9. A. Q. Vo, X. Feng, J. T. Morott, M. B. Pimparade, R. V. Tiwari, F. Zhang, M. A. Repka, "A novel floating controlled release drug delivery system prepared by hot-melt extrusion", European Journal of Pharmaceutics and Biopharmaceutics, vol. 98, pp. 108-121, 2016. DOI: http://dx.doi.org/10.1016/j.ejpb.2015.11.015
  10. R. V. Tiwari, H. Patil, M. A. Repka, "Contribution of hot-melt extrusion technology to advance drug delivery in the 21st century", Expert opinion on drug delivery, vol. 13, pp. 451-464, 2016. DOI: http://dx.doi.org/10.1517/17425247.2016.1126246
  11. B. Claeys, A. Vervaeck, X. K. Hillewaere, S. Possemiers, L. Hansen, T. De Beer, J. P. Remon, C. Vervaet, "Thermoplastic poly-urethanes for the manufacturing of highly dosed oral sustained release matrices via hot melt extrusion and injection molding", European Journal of Pharmaceutics and Biopharmaceutics, vol. 90, pp. 44-52, 2015. DOI: http://dx.doi.org/10.1016/j.ejpb.2014.11.003
  12. M. Maniruzzaman, J. S. Boateng, M. Bonnefille, A. Aranyos, J. C. Mitchell, D. Douroumis, "Taste masking of paracetamol by hot-melt extrusion: an in vitro and in vivo evaluation", European Journal of Pharmaceutics and Biopharmaceutics, vol. 80, pp. 433-442, 2012. DOI: http://dx.doi.org/10.1016/j.ejpb.2011.10.019
  13. B. Suto, S. Weber, A. Zimmer, G. Farkas, A. Kelemen, M. Budai-Szucs, S. Berko, P. Szabo-Revesz, E. Csanyi, "Optimization and design of an ibuprofen-loaded nanostructured lipid carrier with a 23 full factorial design", Chemical Engineering Research and Design, vol. 104, pp. 488-496, 2015. DOI: http://dx.doi.org/10.1016/j.cherd.2015.09.010
  14. A. L. Sarode, S. Obara, F. K. Tanno, H. Sandhu, R. Iyer, N. Shah, "Stability assessment of hypromellose acetate succinate (HPMC-AS) NF for application in hot melt extrusion (HME)", Carbohydrate polymers, vol. 101, pp. 146-153, 2014. DOI: http://dx.doi.org/10.1016/j.carbpol.2013.09.017
  15. D.-W. Kim, "Evaluation of Sustained-release Dosage Form with Novel Metformin Salts", Journal of the Korea Academia-Industrial cooperation Society, vol. 16, pp. 7838-7843, 2015. https://doi.org/10.5762/KAIS.2015.16.11.7838
  16. J.-B. Park, "Development of Gastric Retentive Bi-layered Tablet using Floating Drug Delivery System", Journal of the Korea Academia-Industrial cooperation Society, vol. 16, pp. 7549-7554, 2015. DOI: http://dx.doi.org/10.5762/KAIS.2015.16.11.7549
  17. J. Urbanova, M. Andel, J. Potockova, J. Klima, J. Macek, P. Ptacek, T. Kumstyrova, P. Heneberg, "Half-Life of Sulfonylureas in HNF1A and HNF4A Human MODY Patientsis not Prolonged as Suggested by the Mouse Hnf1a/Model", Current pharmaceutical design, vol. 21, pp. 5736-5748, 2015. DOI: http://dx.doi.org/10.2174/1381612821666151008124036
  18. J.-Y. Kim, D.-W. Kim, Y.-M. Kuk, C.-W. Park, Y.-S. Rhee, T.-O. Oh, K.-Y. Weon, E.-S. Park, "Investigation of an active film coating to prepare new fixed-dose combination tablets for treatment of diabetes", International journal of pharmaceutics, vol. 427, pp. 201-208, 2012. DOI: http://dx.doi.org/10.1016/j.ijpharm.2012.01.057
  19. Y. H. Lee, K. Y. Weon, "Improving the stability of gel mass of vegetable soft capsule", Journal of the Korea Academia-Industrial cooperation Society, vol. 17, pp. 397-404, 2016. DOI: http://dx.doi.org/10.5762/KAIS.2016.17.5.397