본문 바로가기
HOME> 논문 > 논문 검색상세

논문 상세정보

Effect of Solubilizing and Microemulsifying Excipients in Polyethylene Glycol 6000 Solid Dispersion on Enhanced Dissolution and Bioavailability of Ketoconazole

Heo, Min-Young   (National Research Laboratory for Bioavailability Control, College of Pharmacy, Kangwon National UniversityUU0000037  ); Piao, Zong-Zhu   (National Research Laboratory for Bioavailability Control, College of Pharmacy, Kangwon National UniversityUU0000037  ); Kim, Tae-Wan   (National Research Laboratory for Bioavailability Control, College of Pharmacy, Kangwon National UniversityUU0000037  ); Cao, Qing-Ri   (National Research Laboratory for Bioavailability Control, College of Pharmacy, Kangwon National UniversityUU0000037  ); Kim, Ae-Ra   (National Research Laboratory for Bioavailability Control, College of Pharmacy, Kangwon National UniversityUU0000037  ); Lee, Beom-Jin   (National Research Laboratory for Bioavailability Control, College of Pharmacy, Kangwon National UniversityUU0000037  );
  • 초록

    Polyethylene glycol (PEG) 6000-based solid dispersions (SDs), by incorporating various pharmaceutical excipients or microemulsion systems, were prepared using a fusion method, t o compare the dissolution rates and bioavailabilities in rats. The amorphous structure of the drug in SDs was also characterized by powder X-ray diffractometry (XRD) and differential scanning calorimetry (DSC). The ketoconazole (KT), as an antifungal agent, was selected as a model drug. The dissolution rate of KT increased when solubilizing excipients were incorporated into the PEG-based SDs. When hydrophilic and lipophilic excipients were combined and incorporated into PEG-based SDs, a remarkable enhancement of the dissolution rate was observed. The PEG-based SDs, incorporating a self microemulsifying drug delivery system (SMEDDS) or microemulsion (ME), were also useful at improving the dissolution rate by forming a microemulsion or dispersible particles within the aqueous medium. However, due to the limited solubilization capacity, these PEG-based SDs showed dissolution rates, below 50% in this study, under sink conditions. The PEG-based SD, with no pharmaceutical excipients incorporated, increased the maximum plasma concentration (C $_{max}$ ) and area under the plasma concentration curve (AUC $_{0-6h}$ ) two-fold compared to the drug only. The bioavailability was more pronounced in the cases of solubilizing and microemulsifying PEG-based SDs. The thermograms of the PEG-based SDs showed the characteristic peak of the carrier matrix around 60 $^{\circ}C$ , without a drug peak, indicating that the drug had changed into an amorphous structure. The diffraction pattern of the pure drug showed the drug to be highly crystalline in nature, as indicated by numerous distinctive peaks. The lack of the numerous distinctive peaks of the drug in the PEG-based SDs demonstrated that a high concentration of the drug molecules was dissolved in the solid-state carrier matrix of the amorphous structure. The utilization of oils, fatty acid and surfactant, or their mixtures, in PEG-based SD could be a useful tool to enhance the dissolution and bioavailability of poorly water-soluble drugs by forming solubilizing and microemulsifying systems when exposed to gastrointestinal fluid.


  • 주제어

    Solid dispersion .   Pharmaceutical excipients .   Solubilizing and microemulsifying .   Dissolution rate .   Bioavailability .   Crystal structure.  

  • 참고문헌 (20)

    1. Caliph, S., Charman, W. N., and Porter, C. J. H., Effect of short-medium- and long-chain fatty acid-based vehicles on the absolute oral bioavailability and intestinal lymphatic transport of halofantrine and assessment of mass balance in lymphcannulated and non-cannulated rats. J. Pharm. Sci., 89, 1073-1084 (2000) 
    2. Constantinides, P. P., Lipid microemulsions for improving drug dissolution and oral absorption: physical and biopharmaceutical aspects. Pharm. Res., 12, 1561-1572 (1995) 
    3. Cornaire, G., Woodley, J., Hermann, P., Cloarec, A., Arellano, C., and Houin, G., Impact of excipients on the absorption of P-glycoprotein substrates in vitro and in vivo. Int. J. Pharm., 278, 119-131 (2004) 
    4. Porter, C. J. H. and Charman, W. N., Intestinal lymphatic drug transport: an update. Adv. Drug Del. Rev., 50, 61-80 (2001) 
    5. Sheen, P. C., Khetarpal, V. K., Cariola, C. M., and Rowlings, C. E., Formulation studies of a poorly water-soluble drug in solid dispersions to improve bioavailability. Int. J. Pharm., 118, 221-227 (1995) 
    6. Verheyen, S., Blaton, N., Kinget, R., and Mooter, G. V., Mechanism of increased dissolution of diazepam and temazepam from polyethylene glycol 6000 solid dispersions. Int. J. Pharm., 249, 45-58 (2002) 
    7. Wang, S.-W., Monagle, J., McNulty, C., Putnam, D., and Chen, H., Determination of P-glycoprotein inhibition by excipients and their combinations using an integrated high-throughput process. J. Pharm. Sci., 93, 2755-2767 (2004) 
    8. Attama, A. A., Nzekwe, I. T., Nnamani, P. O., Adikwu, M. Y., and Onugu, C. O., The use of solid self-emulsifying systems in the delivery of diclofenac. Int. J. Pharm., 262, 23-28 (2003) 
    9. Kim, T.-W., Choi, C.-Y., Cao, Q.-R., Kwon, K. A., and Lee, B.-J., Dissolution profiles of solid dispersions containing poorly water-soluble drugs and solubilizing compositions. J. Kor. Pharm. Sci., 32, 191-197 (2002) 
    10. Morris, K. R., Knipp, G. T., and Serajuddin, A. T. M., Structural properties of polyethylene glycol-polysorbate 80 mixture, a solid dispersion vehicle. J. Pharm. Sci., 81, 1185-1188 (1992) 
    11. Serajuddin, A. T. M., Solid dispersion of poorly water-soluble drugs: Early promises, subsquent problems, and recent breakthroughs. J. Pharm. Sci., 88, 1058-1066 (1999) 
    12. Mura, P., manderioli, A., Bramanti, G., and Ceccareli, L., Properties of solid dispersions of naproxen in various polyethylene glycols. Drug Dev. Ind. Pharm., 22, 909-916 (1996) 
    13. Alden, M., Tegenfeldt, J., and Saers, E. S., Structures formed by interactions in solid dispersions of the system polyethylene glycol-griseofulvin with charged and noncharged surfactants added. Int. J. Pharm., 94, 31-38 (1993) 
    14. Betageri, G. V. and Makarla, K. R., Characterization of glyburide-polyethylene glycol solid dispersions. Drug Dev. Ind. Pharm., 22, 731-734 (1996) 
    15. Baxter, J. G., Brass, C., Schentag, J. J., and Slaughter, F. L., Pharmacokinetics of ketoconazole administered intravenously to dogs and orally as ablet and solution to humans and dogs. Pharm. Res., 75, 443-447 (1986) 
    16. Franco, M., Trapani, G., Latrofa, A., Tullio, C., Provenzano, M. R., Serra, M., Muggironi, M., Biggio, G., and Liso, G., Dissolution properties and anticonvulsant activity of phenytoinpolyethylene glycol 6000 and polyvinylpyrrolidone K-30 solid dispersions. Int. J. Pharm., 225, 63-73 (2001) 
    17. Cao, Q.-R., Kim, T.-W., Choi, C.-Y., Kwon, K .A., and Lee, B.-J., Preparation and dissolution of PVP-based solid dispersion capsules containing solubilizers. J. Kor. Pharm. Sci., 33, 7-14 (2003) 
    18. Chiou, W. L. and Riegelman, S., Pharmaceutical applications of solid dispersion system. J. Pharm. Sci., 60, 1281-1302 (1971) 
    19. Joshi, H. N., Tejwani, R. W., Davidovich, M., Sahasrabudhe, V. P., Jemal, M., Bathala, M. S., Varia, S. A., and Serajuddin, T. M., Bioavailability enhancement of a poorly water-soluble drug by solid dispersion in polyethylene glycol-polysorbate 80 mixture. Int. J. Pharm., 269, 251-258 (2004) 
    20. Owusu-Ababio, G., Ebube, N. K., Reams, R., and Habib, M., Comparative dissolution studies for mefenamic acidpolyethylene glycol solid dispersion systems and tablets. Pharm. Dev. Technol., 3, 405-412 (1998) 
  • 이 논문을 인용한 문헌 (5)

    1. 2010. "" Archives of pharmacal research : a publication of the Pharmaceutical Society of Korea, 33(6): 901~910     
    2. 2011. "" Archives of pharmacal research : a publication of the Pharmaceutical Society of Korea, 34(1): 51~57     
    3. 2011. "" Archives of pharmacal research : a publication of the Pharmaceutical Society of Korea, 34(5): 747~755     
    4. 2011. "" Archives of pharmacal research : a publication of the Pharmaceutical Society of Korea, 34(5): 757~765     
    5. 2011. "" Archives of pharmacal research : a publication of the Pharmaceutical Society of Korea, 34(11): 1909~1917     

 저자의 다른 논문

  • 김태완 (7)

    1. 1996 "Preparation and in Vitro Release of Melatonin-Loaded Multivalent Cationic Alginate Beads" Archives of pharmacal research : a publication of the Pharmaceutical Society of Korea 19 (4): 280~285    
    2. 1997 "Aspartate함유 복합성분과 Ethanol의 약물동태학적 거동" 藥劑學會誌 = Journal of Korean pharmaceutical sciences 27 (3): 181~187    
    3. 2002 "가용화 조성물과 난용성 약물군을 함유하는 고체분산체의 용출양상" 藥劑學會誌 = Journal of Korean pharmaceutical sciences 32 (3): 191~197    
    4. 2003 "캡사이신유도체를 함유하는 폴록사머 겔제제의 물리화학적 특성" 藥劑學會誌 = Journal of Korean pharmaceutical sciences 33 (1): 1~5    
    5. 2003 "가용화 조성물을 함유한 PVP형 고체분산체의 제조 및 특성" 藥劑學會誌 = Journal of Korean pharmaceutical sciences 33 (1): 7~14    
    6. 2005 "개선된 사람 혈장중 세파클러 농도 정량법을 이용한 세파클러 캡슐의 생체이용률 측정" 藥劑學會誌 = Journal of Korean pharmaceutical sciences 35 (2): 117~122    
    7. 2005 "개선된 HPLC분석법을 이용한 세파클러 모노하이드레이트 250 mg 캡슐의 생물학적동등성" 한국임상약학회지 = Korean journal of clinical pharmacy 15 (1): 21~26    
  • Lee, Beom-Jin (23)

 활용도 분석

  • 상세보기

    amChart 영역
  • 원문보기

    amChart 영역

원문보기

무료다운로드
유료다운로드

유료 다운로드의 경우 해당 사이트의 정책에 따라 신규 회원가입, 로그인, 유료 구매 등이 필요할 수 있습니다. 해당 사이트에서 발생하는 귀하의 모든 정보활동은 NDSL의 서비스 정책과 무관합니다.

원문복사신청을 하시면, 일부 해외 인쇄학술지의 경우 외국학술지지원센터(FRIC)에서
무료 원문복사 서비스를 제공합니다.

NDSL에서는 해당 원문을 복사서비스하고 있습니다. 위의 원문복사신청 또는 장바구니 담기를 통하여 원문복사서비스 이용이 가능합니다.

이 논문과 함께 출판된 논문 + 더보기