Evaluation of gastric toxicity of indomethacin acid, salt form and complexed forms with hydroxypropyl-β-cyclodextrin on Wistar rats: histopathologic analysis

Abstract

Indomethacin (IM) is a non-steroidal anti-inflammatory drug which inhibits prostaglandin biosynthesis. It is practically insoluble in water and has the capacity to induce gastric injury. Hydroxypropyl-beta-cyclodextrin (HP-beta-CD) is an alkylated derivative of beta-CD with the capacity to form inclusion complexes with suitable molecules. IM is considered to form partial inclusion complexes with HP-beta-CD by enclosure of the p-chlorobenzoic part of the molecule in the cyclodextrin channel, reducing the adverse effects. The aim of this paper is to evaluate the gastric damage induced by the IM inclusion complex prepared by freeze-drying and spray-drying. A total of 135 Wistar rats weighing 224.4 +/- 62.5 g were put into 10 groups. They were allowed free access to water but were maintained fasted for 18 h before the first administration until the end of the experiment. IM acid-form, IM trihydrated-sodium-salt and IM-HP-beta-CD spray and freeze-dried, at normal and toxic doses, were administered through gastric cannula once/day for 3 days. Seventy-two hours after the first administration, the animals were sacrificed and the stomachs collected and prepared for morphological study by using the haematoxylin-eosin technique. Lesion indexes (rated 0/4) were developed and the type of injury was scored according to the severity of damage and the incidence of microscopic evidence of harm. Microscopic assessment demonstrated levels of injury with index one on 10-25%. The type of complexation method had different incidence but the same degree. The results show that IM inclusion complexation protects against gastric injury, reducing the incidence and the maximum degree of severity from 4 to 1, with a better performance of the spray-dried complex.

Influence of Cyclodextrin Complexation with NSAIDs on NSAID/Cold Stress-Induced Gastric Ulceration in Rats

“…Before the start of the experiments, food was withdrawn for 72 h but water was allowed ad libitum 13. Preliminary results have revealed that the pre-fasting condition alone doesn't induce ulcers, as evidenced by the absence of ulcers in some of the treated groups.…”

“…The gastric ulcerogenic action of NSAIDs is believed to occur mainly due to their local inhibitory effect on gastric prostaglandin E2 (PGE 2 ) and prostaglandin I2 (PGI 2 ) that are the main inhibitors of gastric acid secretion 13,14. The major contribution of the local ulcerogenic action of NSAIDs can be appreciated from the decreased incidence of ulcers following the use of NSAIDs enteric coated tablets.…”

“…CDs are non-reducing, water-soluble oligosaccharides with nonpolar cavities that allow complexation with the nonpolar portion of many drug molecules 13. Inclusion complexes of poorly soluble drugs with CDs present more solubilized drug, a greater rate of dissolution, and a more efficient absorption after oral administration, compared to uncomplexed drug 15,16.…”

“…Indomethacin is one of the first anti-inflammatory drugs introduced for closure of patent ductus arteriosus of newborns and treatment of various inflammatory conditions 13. The complex of indomethacin with CDs has been well studied 19-22 in solution and in the solid state 13,19,20.…”

“…The complex of indomethacin with CDs has been well studied 19-22 in solution and in the solid state 13,19,20. It accomplishes a 1:1 inclusion complex with β-CD or HP-β-CD 22 by inserting either the p-chlorobenzoic portion or the indole unit of the molecule into the CD cavity 23-25.…”