Synthesis and Characterization of Novel pH-Sensitive Hydrogels Containing Ibuprofen Pendents for Colon-Specific Drug Delivery

Mehrdad Mahkam; Nahid Poorgholy; Laleh Vakhshouri

Macromolecular Research, Vol.17, No.9, 709-713, September, 2009

Mehrdad Mahkam^†, Nahid Poorgholy, and Laleh Vakhshouri

Chemistry Department, Azarbaijan University of Tarbiat Moallem, Tabriz, Iran

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The aim of this study was to develop novel intestinal specific drug delivery systems with pH sensitive swelling and drug release properties. The carboxyl group of ibuprofen was converted to a vinyl ester group by reacting ibuprofen and vinyl acetate as an acylating agent in the presence of catalyst. The glucose-6-acrylate-1, 2, 3, 4-tetraacetate (GATA) monomer was prepared under mild conditions. Cubane-1, 4-dicarboxylic acid (CDA) linked to two 2-hydroxyethyl methacrylate (HEMA) group was used as the crosslinking agent (CA). Methacrylic-type polymeric prodrugs were synthesized by the free radical copolymerization of methacrylic acid, vinyl ester derivative of ibuprofen (VIP) and GATA in the presence of cubane crosslinking agent. The structure of VIP was characterized and confirmed by FTIR, 1H NMR and 13C NMR spectroscopy. The composition of the cross-linked three-dimensional polymers was determined by FTIR spectroscopy. The hydrolysis of drug polymer conjugates was carried out in cellophane membrane dialysis bags, and the in vitro release profiles were established separately in enzyme-free simulated gastric and intestinal fluids (SGF, pH 1 and SIF, pH 7.4). The detection of a hydrolysis solution by UV spectroscopy at selected intervals showed that the drug can be released by hydrolysis of the ester bond between the drug and polymer backbone at a low rate. Drug release studies showed that increasing the MAA content in the copolymer enhances the rate of hydrolysis in SIF. These results suggest that these polymeric prodrugs can be useful for the release of ibuprofen in controlled release systems.

Keywords:glycopolymers;pH-sensitive;hydrogel;oral drug delivery;ibuprofen

[References]

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Bajpai SK, Saxena S, J. Appl. Polym. Sci., 92(6), 3630 (2004)
Brøndsted H, Kopecek J, Biomaterials, 12, 584 (1991)
Kim B, Peppas NA, J. Biomater. Sci. Polym. Edn., 13, 1271 (2002)
Baldwin SP, Saltzman WM, Adv. Drug Deliv. Rev., 33, 71 (1998)
Gombotz WR, Pettite DK, Bioconjug. Chem., 6, 332 (1995)
Saffran M, Kumar GC, Savariar C, Burnham JC, Williams F, Necker DC, Science, 233, 1081 (1986)
Chiu HC, Hsiue GH, Lee YP, Huang LW, J. Biomater. Sci. Polym. Ed., 10, 591 (1999)
Mahkam M, J. Bioact. Comp. Polym., 19, 209 (2004)
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Hoste K, Winne K, Schacht E, Int. J. Pharm., 277, 119 (2004)
Khandare J, Minko T, Prog. Polym. Sci., 31, 359 (2006)
Mahkam M, Doostie L, Drug Deliv., 12, 343 (2005)
D’Souza AJM, Topp EM, J. Pharm. Sci., 93, 1962 (2004)
Zhou WJ, Wilson ME, Kurth MJ, Hsieh YL, Krochta JM, Shoemaker CF, Macromolecules, 30(23), 7063 (1997)
Chen XM, Dordick JS, Rethwisch DG, Macromolecules, 28(18), 6014 (1995)
Martin BD, Ampofo SA, Linhardt RJ, Dordick JS, Macromolecules, 25, 7081 (1992)
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Ouchi T, Ohya Y, Prog. Polym. Sci., 20, 211 (1995)
Mahkam M, Assadi M, Mohammadzadeh R, Macromol. Res., 14(1), 34 (2006)
Khang G, Rhee JM, Jeong JK, Lee JS, Kim MS, Cho SH, Lee HB, Macromol. Res., 11, 2073 (2003)
Davaran S, Entezami AA, J. Control. Release, 47, 41 (1997)
Mahkam M, Sharifi N, Entezami AA, J. Bioact. Comp. Polym., 15, 396 (2000)
Mahkam M, Drug Deliv., 14, 147 (2007)
United States Pharmacopeia 26/National Formulary 21, US Pharmacopeial Convention, Rockwille 1999, pp 2130-2143
Ranga Rao KV, Buri P, Int. J. Pharma., 52, 265 (1989)
Yang H, Henke E, Bornscheuer UT, J. Org. Chem., 64, 1709 (1999)
Cai XQ, Wang N, Lin XF, J. Mol. Catal. B: Enzym., 40, 51 (2006)
Kumar TM, Paul W, Sharma CP, Kuriachan MA, Trends Biomater. Artif. Organs, 18, 198 (2005)
Mahkam M, Assadi MG, Golipour N, Des. Monomers Polym., 9, 607 (2006)
Kopecek J, Kopeckova P, Brøndsted H, Rathi R, Rihoa B, Yeh PY, Ikesue K, J. Control. Release, 19, 121 (1992)

[Referenced By]

[1] Chourasia NK, Jain SK, J. Pharm. Pharma. Sci., 6, 33 (2003)

[2] Bajpai SK, Saxena S, J. Appl. Polym. Sci., 92(6), 3630 (2004)

[3] Brøndsted H, Kopecek J, Biomaterials, 12, 584 (1991)

[4] Kim B, Peppas NA, J. Biomater. Sci. Polym. Edn., 13, 1271 (2002)

[5] Baldwin SP, Saltzman WM, Adv. Drug Deliv. Rev., 33, 71 (1998)

[6] Gombotz WR, Pettite DK, Bioconjug. Chem., 6, 332 (1995)

[7] Saffran M, Kumar GC, Savariar C, Burnham JC, Williams F, Necker DC, Science, 233, 1081 (1986)

[8] Chiu HC, Hsiue GH, Lee YP, Huang LW, J. Biomater. Sci. Polym. Ed., 10, 591 (1999)

[9] Mahkam M, J. Bioact. Comp. Polym., 19, 209 (2004)

[10] Rubinstein A, J. Drug Devel. Res., 50, 435 (2000)

[11] Hoste K, Winne K, Schacht E, Int. J. Pharm., 277, 119 (2004)

[12] Khandare J, Minko T, Prog. Polym. Sci., 31, 359 (2006)

[13] Mahkam M, Doostie L, Drug Deliv., 12, 343 (2005)

[14] D’Souza AJM, Topp EM, J. Pharm. Sci., 93, 1962 (2004)

[15] Zhou WJ, Wilson ME, Kurth MJ, Hsieh YL, Krochta JM, Shoemaker CF, Macromolecules, 30(23), 7063 (1997)

[16] Chen XM, Dordick JS, Rethwisch DG, Macromolecules, 28(18), 6014 (1995)

[17] Martin BD, Ampofo SA, Linhardt RJ, Dordick JS, Macromolecules, 25, 7081 (1992)

[18] Dordick JS, Linhardt RJ, Rethwisch DG, Chemtech., 24, 33 (1994)

[19] Lin WP, Hu M, Hsieh YL, Kurth MJ, Krochta JM, J. Polym. Sci. A: Polym. Chem., 36(6), 979 (1998)

[20] Erdmann L, Campo C, Bedell C, Uhrich K, ACS Symp. Ser., 709, 83 (1998)

[21] Ouchi T, Ohya Y, Prog. Polym. Sci., 20, 211 (1995)

[22] Mahkam M, Assadi M, Mohammadzadeh R, Macromol. Res., 14(1), 34 (2006)

[23] Khang G, Rhee JM, Jeong JK, Lee JS, Kim MS, Cho SH, Lee HB, Macromol. Res., 11, 2073 (2003)

[24] Davaran S, Entezami AA, J. Control. Release, 47, 41 (1997)

[25] Mahkam M, Sharifi N, Entezami AA, J. Bioact. Comp. Polym., 15, 396 (2000)

[26] Mahkam M, Drug Deliv., 14, 147 (2007)

[27] United States Pharmacopeia 26/National Formulary 21, US Pharmacopeial Convention, Rockwille 1999, pp 2130-2143

[28] Ranga Rao KV, Buri P, Int. J. Pharma., 52, 265 (1989)

[29] Yang H, Henke E, Bornscheuer UT, J. Org. Chem., 64, 1709 (1999)

[30] Cai XQ, Wang N, Lin XF, J. Mol. Catal. B: Enzym., 40, 51 (2006)

[31] Kumar TM, Paul W, Sharma CP, Kuriachan MA, Trends Biomater. Artif. Organs, 18, 198 (2005)

[32] Mahkam M, Assadi MG, Golipour N, Des. Monomers Polym., 9, 607 (2006)

[33] Kopecek J, Kopeckova P, Brøndsted H, Rathi R, Rihoa B, Yeh PY, Ikesue K, J. Control. Release, 19, 121 (1992)