Prolongation of Antipyretic Action and Reduction of Gastric Ulcerogenicity in the Rat by Controlled-Release Granules of Bermoprofen, A New Nonsteroidal Anti-inflammatory Drug

Abstract

While bermoprofen [(±)-10,11-dihydro-α,8-dimethyl-11-oxodibenz[b,f]oxepin-2-acetic acid], a new nonsteroidal anti-inflammatory drug (NSAID), has potent antipyretic and analgesic activities with a short biological half-life, it shows ulcerogenic activity as a side-effect like other nonsteroidal anti-inflammatory drugs. A bermo-profen preparation was specially designed to prolong its duration of action and to reduce its side effect. Immediate-release granules (IRGs) were prepared by coating particles of Nonpareil 103 with bermoprofen. The IRGs were also coated by spraying a film solution composed of ethylcellulose and hydroxypropylmethylcellulose (3:2), and, thereby, three kinds of retard-release granules (RRGs) were obtained with the coating amounts of 1.5, 2.5, and 4%. Peak plasma bermoprofen levels were seen 0.5, 1, 2, and 3 h after single oral administrations of IRG, RRG(1.5%), RRG (2.5%), and RRG(4%), respectively, in rats. The potency order in ulcerogenic activity was RRG(1.5%) > IRG > RRG(2.5%) > RRG(4%) after a single oral dosage in rats. Then, IRG and RRG(4%) were mixed (in the ratio 3:7, which was calculated from their simulated plasma bermoprofen profiles) in order to get fast onset and long duration of antipyretic action. These mixed granules [i.e., the sustained-release granules (SRGs)] exhibited a flat plasma bermoprofen profile, and longer lasting antipyretic and lower ulcerogenic activities in rats in comparison with IRG or bermoprofen. From these results, it is suggested that a bermoprofen SRG preparation has more durable therapeutic activity and lower side-effects as a NSAID.