Phosphated crosslinked guar for colon-specific drug delivery II. In vitro and in vivo evaluation in the rat

被引:87
作者
Gliko-Kabir, I [1 ]
Yagen, B [1 ]
Baluom, M [1 ]
Rubinstein, A [1 ]
机构
[1] Hebrew Univ Jerusalem, Sch Pharm, Fac Med, David R Bloom Ctr Pharm, IL-91120 Jerusalem, Israel
关键词
hydrocortisone; crosslinked guar; colonic delivery; alpha-galactosidase; beta-mannanase; rat; guar diet; enzymes induction;
D O I
10.1016/S0168-3659(99)00180-7
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Targeting of drugs to the colon, following oral administration, can be accomplished by the use of modified, biodegradable polysaccharides as vehicles. In a previous study, a crosslinked low swelling guar gum (GG) hydrogel was synthesized by reacting it with trisodium trimetaphosphate (STMP). in the present study the functioning of GG crosslinked products (GGP) as possible colon-specific drug carriers was analyzed by studying (a) the release kinetics of pre-loaded hydrocortisone from GGP hydrogels into buffer solutions with, or without GG degrading enzymes (alpha-galactosidase and beta-mannanase) and (b) direct measurements of the polymers' degradation in the cecum of conscious rats. The effect of GG diet on alpha-galactosidase and beta-mannanase activity in the cecum of the rat and GGP degradation was also measured. It was found that the product GGP-0.1 (loosely crosslinked with 0.1 equivalents of STMP) was able to prevent the release of 80% of its hydrocortisone load for at least 6 h in PBS, pH=6.4. When a mixture of alpha-galactosidase and beta-mannanase was added to the buffer solution, an enhanced hydrocortisone release was observed. In-vivo degradation studies in the rat cecum showed that despite the chemical modification of GG, it retained its enzyme-degrading properties in a crosslinker concentration-dependent manner. Eight days of GG diet prior to the study increased alpha-galactosidase activity in the cecum of the rat three-fold, compared to its activity without the diet. However, this increase in the enzyme activity was unable to improve the degradation of the different GGP products. The overall alpha-galactosidase activity in the rat cecum was found to be extracellular, while the activity of beta-mannanase was found to be bacterial cell-wall associated. It is concluded that because CG crosslinked with STMP can be biodegraded enzymatically and is able to retard the release of a low water-soluble drug, this polymer could potentially be used as a vehicle for colon-specific drug delivery. (C) 2000 Elsevier Science B.V. All rights reserved.
引用
收藏
页码:129 / 134
页数:6
相关论文
共 16 条
[1]  
BERG JC, 1980, APPL ENVIRON MICROB, V40, P40, DOI 10.1128/AEM.40.1.40-47.1980
[2]   PURIFICATION AND CHARACTERIZATION OF 2 ALPHA-GALACTOSIDASES ASSOCIATED WITH CATABOLISM OF GUAR GUM AND OTHER ALPHA-GALACTOSIDES BY BACTEROIDES-OVATUS [J].
GHERARDINI, F ;
BABCOCK, M ;
SALYERS, AA .
JOURNAL OF BACTERIOLOGY, 1985, 161 (02) :500-506
[3]   PURIFICATION AND CHARACTERIZATION OF A CELL-ASSOCIATED, SOLUBLE MANNANASE FROM BACTEROIDES-OVATUS [J].
GHERARDINI, FC ;
SALYERS, AA .
JOURNAL OF BACTERIOLOGY, 1987, 169 (05) :2038-2043
[4]   CHARACTERIZATION OF AN OUTER-MEMBRANE MANNANASE FROM BACTEROIDES-OVATUS [J].
GHERARDINI, FC ;
SALYERS, AA .
JOURNAL OF BACTERIOLOGY, 1987, 169 (05) :2031-2037
[5]   Low swelling, crosslinked guar and its potential use as colon-specific drug carrier [J].
Gliko-Kabir, I ;
Yagen, B ;
Penhasi, A ;
Rubinstein, A .
PHARMACEUTICAL RESEARCH, 1998, 15 (07) :1019-1025
[6]   Phosphated crosslinked guar for colon-specific drug delivery I. Preparation and physicochemical characterization [J].
Gliko-Kabir, I ;
Yagen, B ;
Penhasi, A ;
Rubinstein, A .
JOURNAL OF CONTROLLED RELEASE, 2000, 63 (1-2) :121-127
[7]  
HAWKSWORTH G, 1970, J MED MICROBIOL, V4, P451
[8]   EFFECT OF DIFFERENT CARBOHYDRATES ON GROWTH, POLYSACCHARIDASE AND GLYCOSIDASE PRODUCTION BY BACTERIODES-OVATUS, IN BATCH AND CONTINUOUS CULTURE [J].
MACFARLANE, GT ;
HAY, S ;
MACFARLANE, S ;
GIBSON, GR .
JOURNAL OF APPLIED BACTERIOLOGY, 1990, 68 (02) :179-187
[9]   CELLULOLYTIC AND NON-CELLULOLYTIC BACTERIA IN RAT GASTROINTESTINAL TRACTS [J].
MACY, JM ;
FARRAND, JR ;
MONTGOMERY, L .
APPLIED AND ENVIRONMENTAL MICROBIOLOGY, 1982, 44 (06) :1428-1434
[10]   CHARACTERIZATION OF THE OLIGOSACCHARIDES PRODUCED ON HYDROLYSIS OF GALACTOMANNAN WITH BETA-D-MANNANASE [J].
MCCLEARY, BV ;
NURTHEN, E ;
TARAVEL, FR ;
JOSELEAU, JP .
CARBOHYDRATE RESEARCH, 1983, 118 (JUL) :91-109