Formulation, in-vitro and in vivo evaluation of ketorolac tromethamine controlled release drug delivery system

Abstract

Ketorolac tromethamine is a potent non-steroidal drug with potent analgesic and anti-inflammatory activity.  Its oral administration is associated with a high risk of adverse effects such as irritation, ulceration and bleeding of gastrointestinal tract. The present study focuses on the development of controlled release drug delivery system of ketorolac microcapsules as one of the multi-particulate formulations and are prepared to obtain prolonged drug delivery in order to decrease ulcerogenicity, improve bioavailability and stability and also target a drug at specific sites. Microcapsules were prepared by air suspension technique using Eudragit RS100, Eudragit RL100 and ethyl cellulose in ratios of 1:1,1:2 and 1:3 drug to polymer. The effect of various  formulation  and  process  variables  on  the  flowability,  drug loading  and  in-vitro drug  release was studied. IR, DTA and X-ray investigations revealed that there was no interaction between the drug and the polymers used. The flow characteristic showed Hausner's ratios of <1.25 and Carr^'s index of 5-16 % of the systems prepared while those of the drug alone were >1.25 and > 40% indicating good and excellent flow of the systems and extremely poor flowability of the drug. Ketorolac tromethamine content in different microcapsules formulations was not affected by neither the polymer type nor drug to polymer ratio and ranged between 98 -99.5 %. The in-vitro  drug studies  showed that amounts  of  drugs  released  from Eudragit  RS100 based microcapsules at  pH 1.2 were 38 , 22,  and 14 % from drug to polymer ratios of 1:1, 1:2  and 1:3 respectively. Amounts of drug released at pH 7.4 were 72, 70, and 51% respectively. The amount of drug released from Eudragit RL100 based microcapsules at pH 1.2 were 35, 27and 19% drug to polymer ratios of 1:1, 1:2 and1:3 respectively. Amounts of drug released at pH 7.4 were 63, 61 and 52 %.  The amount of drug released from ethyl cellulose based microcapsules at pH 1.2 were 22, 16 and 13% drug to polymer ratios of 1:1, 1:2 and 1:3 respectively. Amounts of drug released at pH 7.4 were 75, 68 and 58% respectively. The in-vitro release studies showed that the release rate of the drug has been modified. This study presents a new approach based on microencapsulation technique for obtaining modified   release drug delivery system. The enteric-coated formulations which showed best release profiles were tested in vivo. The enteric-coated formulations using Eudragit RS100, Eudragit RL100 and ethyl cellulose at a ratio of (1:3) significantly suppressed ulceration by avoiding the exposure of ketorolac to ulcer prone area of gastro-intestinal tract.