Amphotericin B의 가용화 및 방출지속화를 위한 아르기닌 함유 폴록사머 하이드로젤의 제조 및 특성분석

신백기; 백은정; 김예태; 정지웅; 노영창; 임윤묵; 박종석; 허강무; 박정숙; Baek-Ki Shin; Eun Jung Baek; Ye-Tae Kim; Ji-Woong Jeong; Young-Chang Nho; Youn-Mook Lim; Jong-Seok Park; Kang Moo Huh; Jeong-Sook Park

Polymer(Korea), Vol.34, No.5, 459-463, September, 2010

Preparation and Characterization of L-Arginine Containing Poloxamer Hydrogels for Solubilization and Sustained Release of Amphotericin B

신백기, 백은정¹, 김예태, 정지웅, 노영창 ², 임윤묵², 박종석², 허강무 ^{1, †}, 박정숙^†

충남대학교 약학대학
¹충남대학교 고분자공학과
²한국원자력연구원 정읍방사선과학연구소 방사선공업환경연구부

Baek-Ki Shin, Eun Jung Baek¹, Ye-Tae Kim, Ji-Woong Jeong, Young-Chang Nho², Youn-Mook Lim², Jong-Seok Park², Kang Moo Huh^{1, †}, and Jeong-Sook Park^†

College of Pharmacy, Chungnam National University, Daejeon 305-764, Korea
¹Department of Polymer Science and Engineering, Chungnam National University, Daejeon 305-764, Korea
²Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, 1266 Sinjeong-dong, Jeongeup-si, Jeollabuk-do 580-185, Korea

E-mail:,

초록

전신 진균감염 치료에 널리 사용되는 광범위 항진균제이며 대표적인 소수성 약물인 amphotericin B(AmB)의 효과적인 점막부착형 약물전달체로서 가용화제인 L-arginine, 점착성 고분자인 카보폴 (carbopol), 온도감응성 고분자인 Poloxamer 407(P 407)로 구성된 하이드로젤 제형을 제조하였다. L-Arginine의 첨가로 AmB의 용해도가 2.6 mg/mL까지 향상되었으며, P 407 수용액은 20% w/v 이상의 농도에서 온도 변화에 따른 졸-젤-졸상전이(phase transition)를 보였다. 이러한 상전이 온도는 약물 및 L-arginine의 존재에 의해 영향을 받았고, 점착성 고분자인 카보폴의 혼합에 의해 상전이 영역이 확장되었다. L-Arginine의 가용화 효과로 AmB의 약물방출특성이 향상되었고, 점착성 고분자인 카보폴의 첨가는 농도에 의존하여 약물방출을 지연시키는 효과가 있었다.

Amphotericin B (AmB) is anti-fungal agent for the treatment of systemic fungal infections, but its poor solubility has limited clinical applications. In this study, a new gel formulation made up of L-arginine as solubilizer, thermosensitive Poloxamer 407 (P 407), and adhesive carbopol was designed for effective solubilization and delivery of AmB. The aqueous solubility of AmB was enhanced up to 2.6 mg/mL by addition of L-arginine. Aqueous P 407 solutions of more than 20% w/v showed thermo-induced sol-gel-sol phase transition. The phase transition behavior was affected by the presence of AmB and L-arginine, and the phase transition range was broadened by addition of carbopol. In vitro drug release was improved by the solubilizing effect of L-arginine, and the presence of mucoadhesive carbopol prolonged the release rate as a function of concentration.

Keywords:Poloxamer;amphotericin B;L-arginine;solubility;sustained release

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Bhardwaj R, Blanchard J, J. Pharm. Sci., 85, 915 (1996)
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[Referenced By]

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[1] Kleinberg M, Int. J. Antimicrob. Ag., 27S, S12 (2006)

[2] Mazerski J, Borowski E, Biophys. Chem., 57, 205 (1996)

[3] Bolard J, Biochim. Biophys. Acta, 864, 257 (1986)

[4] Brajtburg J, Elberg S, Schwartz DR, Vertut-Croquin A, Schlessinger D, Kobayashi GS, Medoff G, Antimicrob. Agents Chemother., 27, 172 (1985)

[5] Nahar M, Mishra D, Dubey V, Jain NK, Nanomedicine, 4, 252 (2008)

[6] Lavasanifar A, Samuel J, Kwon GS, J. Control. Release, 79, 165 (2002)

[7] Arakawa T, Tsumoto K, Biochem. Biophys. Res. Commun., 304(1), 148 (2003)

[8] Arakawa T, Kita Y, Ejima D, Tsumoto K, Fukada H, Protein Peptide Lett., 13, 921 (2006)

[9] Arakawa T, Ejima D, Tsumoto K, Obeyama N, Tanaka Y, Kita Y, Timasheff SN, Biophys. Chem., 127, 1 (2007)

[10] Arakawa T, Tsurnoto K, Nagase K, Ejima D, Protein Expr. Purif., 54(1), 110 (2007)

[11] Arakawa T, Tsumoto K, Kita Y, Chang B, Ejima D, Amino Acids, 33, 587 (2007)

[12] Ejima D, Yumioka R, Arakawa T, Tsumoto K, J. Chromatogr. A, 1094, 49 (2005)

[13] Tsumoto K, Ejima D, Nagase K, Arakawa T, J. Chromatogr. A, 1154, 81 (2007)

[14] Wang P, Johnston TP, Int. J. Pharm., 113, 73 (1995)

[15] Alexandridis P, Hatton TA, Colloid Surface A, 96, 1 (1995)

[16] Han YG, Kwon JW, Kim HY, Kim JS, Jo JS, Wi WL, Lee JH, J. Korean Ophthal. Soc., 44, 2137 (2003)

[17] Malmsten M, Soft Matter, 2, 760 (2006)

[18] Morikawa K, Okada F, Hosokawa M, Kobayashi H, Cancer Res., 47, 37 (1987)

[19] Bhardwaj R, Blanchard J, J. Pharm. Sci., 85, 915 (1996)

[20] Desai SD, Blanchard J, J. Pharm. Sci., 87, 226 (1998)

[21] Shin SC, Kim JY, Oh IJ, Drug Dev. Ind. Pharm., 26, 307 (2000)

[22] Ricci EJ, Bentley MVLB, Farah M, Bretas RES, Marchetti JM, Eur. J. Pharm. Sci., 17, 161 (2002)

[23] Laughlin RG, Aqueous Phase Behavior of Surfactants, Academic Press, London (1994)