친수성 고분자를 이용한 에프로살탄 고체분산체의 제조 및 특성 분석

황준석; 고지은; 김소희; 허강무; Jun Seok Hwang; Ji Eun Ko; So Hee Kim; Kang Moo Huh

Polymer(Korea), Vol.36, No.4, 500-506, July, 2012

Export Citation

친수성 고분자를 이용한 에프로살탄 고체분산체의 제조 및 특성 분석

Preparation and Characterization of Solid Dispersions of Eprosartan with Hydrophilic Polymers

황준석, 고지은, 김소희, 허강무 ^†

충남대학교 고분자공학과

Jun Seok Hwang, Ji Eun Ko, So Hee Kim, and Kang Moo Huh^†

Department of Polymer Science and Engineering, Chungnam National University, Daejeon 305-764, Korea

E-mail:

초록

본 연구에서는 고혈압 치료제로 사용되고 있는 난용성 약물인 에프로살탄의 용해도 개선을 위한 고체분산체제제를 개발하기 위한 제조방법 및 조성비를 최적화하였다. 친수성 고분자 기제로 poly(ethylene glycol)(PEG)와 poly(vinyl pyrrolidone)(PVP)를 이용하여, 약물과 고분자의 조성비가 1:1에서 1:5 사이의 고체분산체를 용매증발법과 열용융법에 의해 제조한 후 비교 평가하였다. 용매증발법이 균일한 고체분산체 제조에 효과적이었고, 고분자의 조성비 증가와 함께 약물 결정성이 감소되었다. PEG 보다는 PVP가 약물과의 우수한 상용성을 바탕으로 결정화도 감소와 용해도 개선 효과가 우수하였다. 또한 고체분산체 제조 시 고분자 계면활성제인 poloxamer 407를 첨가한 경우, 약물의 결정성이 대부분 사라져 고체분산체 내 대부분의 약물 분자들이 무정형으로 분산되어 있음을 알 수 있었고, 약물의 용해도 또한 3~4배 이상 향상되었다.

In this study, we developed and optimized hydrophilic polymer based solid dispersion formulations (SDs) for enhancing the aqueous solubility of eprosartan, one of poorly soluble drugs, that has been broadly used for the treatment of high blood pressure. Poly(ethylene glycol) (PEG) and poly(vinyl pyrrolidone) (PVP) based SDs were prepared by hot melting and solvent evaporation methods and the drug/polymer composition varied in the range of 1:1~1:5 with or without poloxamer 407 (P407) as a polymeric surfactant. The SDs prepared by solvent evaporation showed more reduced crystallinity than ones by hot melting, and PVP based SDs showed more enhanced solubility and lower crystallinity than PEG based SDs. Furthermore, it was observed from DSC and PXRD analysis that the SDs with P407 (drug:polymer:P407 = 1:5:1) demonstrated no crystallinity and the most enhanced solubility (more than 3~4 times).

Keywords:eprosartan;poly(ethylene glycol);poly(vinyl pyrrolidone);poloxamer 407;solid dispersion;solubility.

[References]

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Lin SL, Menig J, J. Pharma. Sci., 57, 2143 (1968)
Ford JL, Pharma. Acta Helvetiae., 61, 69 (1986)
Lee EY, Oh MJ, Kim SH, Seong KY, Lee YH, Kim SJ, She HS, Lee D, Khang G, Polym.(Korea), 35(2), 113 (2011)
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Nashed YE, Mitra AK, Spectrochim. Acta Part A: Mol.Biomol. Spectrosc., 59, 2033 (2003)
Nielsen CU, Andersen R, J. Control. Release., 76, 129 (2001)
McGuigan C, Slater MJ, Bioorg. Med. Chem. Lett., 10, 645 (2000)
Jeong JK, Khang G, Rhee JM, Shin HC, Lee HB, J.Kor. Pharm. Sci., 30, 235 (2000)
Hergert LA, Escandar GM, Talanta., 60, 235 (2003)
Yue ME, Jiang TF, Talanta., 62, 695 (2004)
Prince LM, J. Colloid Interface Sci., 23, 165 (1967)
Kim HS, Lee SK, Choi SU, Park HS, Jeon HJ, Choi YW, J. Kor. Pharm. Sci., 32, 27 (2002)
Attwood D, Mallon C, Int. J. Pharma., 84, R5 (1992)
Sekiguchi K, Obi N, Chem. Pharma. Bull., 9, 866 (1961)
Sekiguchi K, Obi N, Ueda Y, Chem. Pharma. Bull., 12, 134 (1964)
Van Drooge DJ, Hinrichs WLJ, Int. J. Pharma., 310, 220 (2006)
Pokharkar VB, Mandpe LP, Padamwar MN, Ambike AA, Mahadik KR, Paradkar A, Powder Technol., 167(1), 20 (2006)
Rodier E, Lochard H, Eur. J. Pharma. Sci., 26, 184 (2005)
Vilhelmsen T, Eliasen H, Int. J. Pharma., 303, 132 (2005)
Ghaderi R, Artursson P, Pharma. Res., 16, 676 (1999)
Martin DE, Tompson D, Boike SC, Tenero D, Ilson B, Citerone D, Jorkasky DK, Br. Pharma. Soc., 43, 661 (1997)
Ruilope L, Jaker B, Exp. Opinion Pharma., 4, 107 (2003)
Innes GT, Br. J. Hospi. Med., 62, 773 (2001)
Shusterman NH, Am. Heart J., 138, S238 (1999)
Dubois JL, Ford JL, J. Pharma. Pharmacol., 37, 494 (1985)
Kassem AA, Zaki SA, Mursi NM, Tayel SA, Die Pharmazie., 34, 43 (1979)

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[2] Lin SL, Menig J, J. Pharma. Sci., 57, 2143 (1968)

[3] Ford JL, Pharma. Acta Helvetiae., 61, 69 (1986)

[4] Lee EY, Oh MJ, Kim SH, Seong KY, Lee YH, Kim SJ, She HS, Lee D, Khang G, Polym.(Korea), 35(2), 113 (2011)

[5] Khang G, Jeong JK, Rhee JM, Jee JS, Lee HB, Macromol. Chem. Symp., 14, 123 (2001)

[6] Nashed YE, Mitra AK, Spectrochim. Acta Part A: Mol.Biomol. Spectrosc., 59, 2033 (2003)

[7] Nielsen CU, Andersen R, J. Control. Release., 76, 129 (2001)

[8] McGuigan C, Slater MJ, Bioorg. Med. Chem. Lett., 10, 645 (2000)

[9] Jeong JK, Khang G, Rhee JM, Shin HC, Lee HB, J.Kor. Pharm. Sci., 30, 235 (2000)

[10] Hergert LA, Escandar GM, Talanta., 60, 235 (2003)

[11] Yue ME, Jiang TF, Talanta., 62, 695 (2004)

[12] Prince LM, J. Colloid Interface Sci., 23, 165 (1967)

[13] Kim HS, Lee SK, Choi SU, Park HS, Jeon HJ, Choi YW, J. Kor. Pharm. Sci., 32, 27 (2002)

[14] Attwood D, Mallon C, Int. J. Pharma., 84, R5 (1992)

[15] Sekiguchi K, Obi N, Chem. Pharma. Bull., 9, 866 (1961)

[16] Sekiguchi K, Obi N, Ueda Y, Chem. Pharma. Bull., 12, 134 (1964)

[17] Van Drooge DJ, Hinrichs WLJ, Int. J. Pharma., 310, 220 (2006)

[18] Pokharkar VB, Mandpe LP, Padamwar MN, Ambike AA, Mahadik KR, Paradkar A, Powder Technol., 167(1), 20 (2006)

[19] Rodier E, Lochard H, Eur. J. Pharma. Sci., 26, 184 (2005)

[20] Vilhelmsen T, Eliasen H, Int. J. Pharma., 303, 132 (2005)

[21] Ghaderi R, Artursson P, Pharma. Res., 16, 676 (1999)

[22] Martin DE, Tompson D, Boike SC, Tenero D, Ilson B, Citerone D, Jorkasky DK, Br. Pharma. Soc., 43, 661 (1997)

[23] Ruilope L, Jaker B, Exp. Opinion Pharma., 4, 107 (2003)

[24] Innes GT, Br. J. Hospi. Med., 62, 773 (2001)

[25] Shusterman NH, Am. Heart J., 138, S238 (1999)

[26] Dubois JL, Ford JL, J. Pharma. Pharmacol., 37, 494 (1985)

[27] Kassem AA, Zaki SA, Mursi NM, Tayel SA, Die Pharmazie., 34, 43 (1979)