Rosiglitazone 가용화를 위한 PEG-PLA(PLGA) 고분자 미셀의 제조 및 특성분석

김연환; 임정혁; 민현수; 김준기; 이용규; 박고은; 조광재; 허강무; Yon-Hwan Kim; Jeong Hyuk Im; Hyun Su Min; Junki Kim; Yong-Kyu Lee; Go Eun Park; Kwang Jae Cho; Kang Moo Huh

Polymer(Korea), Vol.34, No.3, 274-281, May, 2010

Export Citation

Rosiglitazone 가용화를 위한 PEG-PLA(PLGA) 고분자 미셀의 제조 및 특성분석

Preparation and Characterization of PEG-PLA(PLGA) Micelles for Solubilization of Rosiglitazone

김연환, 임정혁, 민현수, 김준기¹, 이용규^{1, †}, 박고은², 조광재², 허강무 ^†

충남대학교 고분자공학
¹충주대학교 화공생물공학
²가톨릭대학교 의과대학 이비인후과학교실

Yon-Hwan Kim, Jeong Hyuk Im, Hyun Su Min, Junki Kim¹, Yong-Kyu Lee^{1, †}, Go Eun Park², Kwang Jae Cho², and Kang Moo Huh^†

Department of Polymer Science and Engineering, Chungnam National University, Daejeon 305-764, Korea
¹Department of Chemical and Biological Engineering, Chungju National University, Chungbuk 380-702, Korea
²Department of Otolaryngology-Head and Neck Surgery, College of Medicine, The Catholic University of Korea, Uijeongbu St. Mary’s Hospital, Gyeonggi-Do 480-717, Korea

E-mail:,

초록

본 실험에서는 일련의 poly(ethylene glycol)-poly(D,L-lactide)(또는 -poly(D,L-lactide-co-glycolide)) 이중블록 공중합체들을 D,L-lactide(또는 glycolide)의 고리열림 중합에 의해 합성하고, 당뇨병 치료제 일종인 rosiglitazone의 가용화를 위한 고분자 미셀 제형으로서의 특성을 평가하였다. 고체분산법을 이용하여 높은 봉입률의 약물함유 미셀 제형을 효과적으로 제조하였고, 미셀 제형의 수용액 내 안정성을 hydrotropic agent의 일종인 2-hydroxy-N-picolylnitinamide(HPNA)의 사용으로 더욱 향상시킬 수 있었다. 생체 외 세포생존평가에서 생체적합성과 낮은 독성을 보였고, 쥐를 이용한 동물실험에서도 약물을 함유한 고분자 미셀이 약물 대조군보다 혈당을 보다 효과적으로 감소시켰다.

In this study, PEG-PLA(or PLGA) amphiphilic di-block copolymers were synthesized by ring opening polymerization of D,L-lactide(or glycolide) and applied to polymeric micelle system for solubilization of a rosiglitazone as diabetes drug. The drug could be efficiently loaded into the polymer micelle by solid dispersion technique, and the drug-loaded micelles were characterized and evaluated as a drug delivery carrier by fluorescence spectrometer, DSC, and DLS measurements. The colloidal stability of drug loaded micelles in aqueous media could be enhanced by addition of 2-hydroxy-Npicolylnitinamide as a hydrotropic agent. The polymer micelles also showed biocompatible and nontoxic properties in vitro cell viability using MTT assay, and the drug loaded micelles were observed to be more effective than free drug for decreasing glucose in blood of rats.

Keywords:PEG-PLA(PLGA) diblock copolymer;polymer micelle;rosiglitazone;hydrotropic agent

[References]

Agrawal SK, Sanabria-DeLong N, Coburn JM, Tew GN, Bhatia SR, J. Control. Release, 112, 64 (2006)
Blanco E, Bey EA, Dong Y, Weinberg BD, Sutton DM, Boothman DA, Gao J, J. Control. Release, 122, 365 (2007)
Xu JP, Ji J, Chen WD, Shen JC, J. Control. Release, 107, 502 (2005)
Lavasanifar A, Samuel J, Kwon GS, J. Control. Release, 77, 155 (2001)
Park TG, Lu W, Crotts G, J. Control. Release, 33, 211 (1995)
Liggins RT, Burt HM, Adv. Drug Deliv. Rev., 54, 191 (2002)
Liu HB, Jiang A, Guo JA, Uhrich KE, J. Polym. Sci. A: Polym. Chem., 37(6), 703 (1999)
Bae YH, Huh KM, Kim Y, Park KH, J. Control. Release, 64, 3 (2000)
Huh KM, Bae YH, Polymer, 40(22), 6147 (1999)
Gaucher G, Dufresne MH, Sant VP, Kang N, Maysinger D, Leroux JC, J. Control. Release, 109, 169 (2005)
Kwon GS, Okano T, Adv. Drug Deliv. Rev., 21, 107 (1996)
Kim SC, Kim DW, Shim YH, Bang JS, Oh HS, Kim SW, Seo MH, J. Control. Release, 72, 191 (2001)
Huh KM, Lee SC, Cho YW, Lee J, Jeong JH, Park K, J. Control. Release, 101, 59 (2005)
Lavasanifar A, Samuel J, Kwon GS, Adv. Drug Deliv. Rev., 54, 169 (2002)
Yamamoto Y, Yasugi K, Harada A, Nagasaki Y, Kataoka K, J. Control. Release, 82, 359 (2002)
Cho YW, Lee J, Lee SC, Huh KM, Park K, J. Control. Release, 97, 249 (2004)
Na K, Lee KH, Lee DH, Bae YH, Eur. J. Pharm. Sci., 27, 115 (2006)
Ooya T, Huh KM, Saitoh M, Tamiya E, Park K, Sci. Tech. Adv. Mater., 6, 452 (2005)
Im JH, Lee YK, Huh KM, Polym.(Korea), 32(2), 143 (2008)
Kolte BL, Raut BB, Deo AA, Bagool MA, Shinde DB, J. Chromatogr. B, 788, 37 (2003)
Malinowski JM, Bolesta S, Clin. Ther., 22, 1151 (2000)
Derosa G, Salvadeo SAT, D'Angelo A, Fogari E, Ragonesi PD, Ciccarelli L, Piccinni MN, Ferrari I, Gravina A, Maffioli P, Cicero AF, Arch. Med. Res., 39, 412 (2008)
Hanefeld M, Patwardhan R, Jones NP, Nutr. Metab. Cardiovasc. Diseases, 17, 13 (2007)
Huh KM, Min HS, Lee SC, Lee HJ, Kim S, Park K, J. Control. Release, 126, 122 (2008)
Mansur CRE, Spinelli LS, Lucas EF, Gonzalez G, Colloids Surf. A: Physicochem. Eng. Aspects, 149, 291 (1999)
Lee SC, Acharya G, Lee J, Park K, Macromolecules, 36(7), 2248 (2003)
Tolman KG, Chandramouli J, Clin. Liver. Dis., 7, 369 (2003)
Kennedy EL, Tchao R, Harvison PJ, Toxicology, 186, 79 (2003)
Marfella R, Portoghese M, Ferraraccio F, Siniscalchi M, Babieri M, Di Filippo C, D'Amico M, Rossi F, Paolisso G, Heart, 95, 1020 (2009)

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[2] Blanco E, Bey EA, Dong Y, Weinberg BD, Sutton DM, Boothman DA, Gao J, J. Control. Release, 122, 365 (2007)

[3] Xu JP, Ji J, Chen WD, Shen JC, J. Control. Release, 107, 502 (2005)

[4] Lavasanifar A, Samuel J, Kwon GS, J. Control. Release, 77, 155 (2001)

[5] Park TG, Lu W, Crotts G, J. Control. Release, 33, 211 (1995)

[6] Liggins RT, Burt HM, Adv. Drug Deliv. Rev., 54, 191 (2002)

[7] Liu HB, Jiang A, Guo JA, Uhrich KE, J. Polym. Sci. A: Polym. Chem., 37(6), 703 (1999)

[8] Bae YH, Huh KM, Kim Y, Park KH, J. Control. Release, 64, 3 (2000)

[9] Huh KM, Bae YH, Polymer, 40(22), 6147 (1999)

[10] Gaucher G, Dufresne MH, Sant VP, Kang N, Maysinger D, Leroux JC, J. Control. Release, 109, 169 (2005)

[11] Kwon GS, Okano T, Adv. Drug Deliv. Rev., 21, 107 (1996)

[12] Kim SC, Kim DW, Shim YH, Bang JS, Oh HS, Kim SW, Seo MH, J. Control. Release, 72, 191 (2001)

[13] Huh KM, Lee SC, Cho YW, Lee J, Jeong JH, Park K, J. Control. Release, 101, 59 (2005)

[14] Lavasanifar A, Samuel J, Kwon GS, Adv. Drug Deliv. Rev., 54, 169 (2002)

[15] Yamamoto Y, Yasugi K, Harada A, Nagasaki Y, Kataoka K, J. Control. Release, 82, 359 (2002)

[16] Cho YW, Lee J, Lee SC, Huh KM, Park K, J. Control. Release, 97, 249 (2004)

[17] Na K, Lee KH, Lee DH, Bae YH, Eur. J. Pharm. Sci., 27, 115 (2006)

[18] Ooya T, Huh KM, Saitoh M, Tamiya E, Park K, Sci. Tech. Adv. Mater., 6, 452 (2005)

[19] Im JH, Lee YK, Huh KM, Polym.(Korea), 32(2), 143 (2008)

[20] Kolte BL, Raut BB, Deo AA, Bagool MA, Shinde DB, J. Chromatogr. B, 788, 37 (2003)

[21] Malinowski JM, Bolesta S, Clin. Ther., 22, 1151 (2000)

[22] Derosa G, Salvadeo SAT, D'Angelo A, Fogari E, Ragonesi PD, Ciccarelli L, Piccinni MN, Ferrari I, Gravina A, Maffioli P, Cicero AF, Arch. Med. Res., 39, 412 (2008)

[23] Hanefeld M, Patwardhan R, Jones NP, Nutr. Metab. Cardiovasc. Diseases, 17, 13 (2007)

[24] Huh KM, Min HS, Lee SC, Lee HJ, Kim S, Park K, J. Control. Release, 126, 122 (2008)

[25] Mansur CRE, Spinelli LS, Lucas EF, Gonzalez G, Colloids Surf. A: Physicochem. Eng. Aspects, 149, 291 (1999)

[26] Lee SC, Acharya G, Lee J, Park K, Macromolecules, 36(7), 2248 (2003)

[27] Tolman KG, Chandramouli J, Clin. Liver. Dis., 7, 369 (2003)

[28] Kennedy EL, Tchao R, Harvison PJ, Toxicology, 186, 79 (2003)

[29] Marfella R, Portoghese M, Ferraraccio F, Siniscalchi M, Babieri M, Di Filippo C, D'Amico M, Rossi F, Paolisso G, Heart, 95, 1020 (2009)