Low swelling, crosslinked guar and its potential use as colon-specific drug carrier.
OBJECTIVE
(a) To reduce the swelling properties of guar gum (GG) by crosslinking it with glutaraldehyde (GA), while maintaining its degradation properties in the presence of typical colonic enzymes, (b) to characterize the modified GG and to examine its degradation properties in vitro and in vivo, and (c) to assess, by drug probes with different water solubilities, the potential of the crosslinked GG to serve as a colon-specific drug carrier.


METHODS
GG was crosslinked with increasing amounts of GA under acidic conditions to obtain different products with increasing crosslinking densities. These products were characterized by measuring (a) their swelling properties in simulated gastric and intestinal fluids, (b) their crosslinking densities, (c) the release kinetics of three different drugs: sodium salicylate (SS), indomethacin (Indo) and budesonide (Bud) from the crosslinked products into buffer solutions, with or without a mixture of galactomannanase and alpha-galactosidase, and (d) their in vivo degradation in the cecum of conscious rats with and without antibiotic treatment.


RESULTS
Significant reduction in GG swelling properties, in both simulated gastric and intestinal fluids, was accomplished by its crosslinking with GA. The crosslinking density of the modified GG products was GA concentration-dependent. The release of SS from crosslinked GG discs was completed within 120 minutes. During the same period of time and for more than 10 hours the release of Indo and Bud was negligible. The release rate of the latter two drugs was enhanced when galactomannanase and alpha-galactosidase were added to the dissolution media. Discs made of the crosslinked GG were implanted in the cecum of rats and their degradation was assessed after 4 days. The extent of degradation was dependent on the amount of GA used for the crosslinking. After 4 days the same discs were recovered intact from rats exposed to antibiotic treatment and from simulated gastric and intestinal fluids.


CONCLUSIONS
Reducing the enormous swelling of GG by crosslinking it with GA resulted in a biodegradable hydrogel which was able to retain poorly water soluble drugs, such as Indo and BUD, but not highly water soluble drugs, such as SS, in artificial gastrointestinal fluids. A variety of hydrogels with increasing crosslinking densities were produced and tested for their potential use as colon-specific drug platforms in vitro and in vivo. Their performance did not depend on creating physical barriers by means of compression.
The Hebrew University of Jerusalem, School of Pharmacy, Israel.
I
I
Gliko-Kabir
B
B
Yagen
A
A
Penhasi
A
A
Rubinstein
D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D019819:Budesonide / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D002240:Carbohydrate Sequence; D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical; D002627:Chemistry, Physical; D003106:Colon / Q000378:metabolism*; D003432:Cross-Linking Reagents / Q000737:chemistry*; D004337:Drug Carriers; D005685:Galactans / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D005753:Gastric Mucosa / Q000378:metabolism; D005976:Glutaral / Q000737:chemistry; D007213:Indomethacin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D007700:Kinetics; D008351:Mannans / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D008969:Molecular Sequence Data; D053149:Plant Gums; D051381:Rats; D012680:Sensitivity and Specificity; D012980:Sodium Salicylate / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics
D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003432:Cross-Linking Reagents; D004337:Drug Carriers; D005685:Galactans; D008351:Mannans; D053149:Plant Gums; D019819:Budesonide; C007894:guar gum; D005976:Glutaral; D012980:Sodium Salicylate; D007213:Indomethacin