Formulasi dan Evaluasi in Vitro-in Vivo Nanosuspensi Ketoprofen sebagai Antiinflamasi

Abstract

Ketoprofen is a non-steroidal anti-inflammatory drug that is poorly soluble in water and its use orally has side effects such as local irritation to the stomach. Irritation is caused by direct contact of insoluble drug crystals on the gastric mucosa. Nanosuspension is a technology for reducing drug particles into nanoscale which can be used to increase dissolution, bioavailability and reduce local irritation effects. This study aims to compare the dissolution rate, bioavailability, anti-inflammatory effect, and local irritation effect on the stomach between the ketoprofen nanosuspension and the ketoprofen suspension. This research was conducted by formulating a ketoprofen nanosuspension using the evaporative-precipitation method with Tween 80 and polyvinylpyrrolidone (PVP) as a preparation stabilizer and ethanol as a ketoprofen solvent. The dissolution test was carried out using the paddle method, determining the size of nanosuspension and suspension particles, zeta potential, and polydispersity index using a particle size analyzer. Observation of the surface morphology of nanoparticles by Transmission Electron Microscopy, and Differential Scanning Calorimetry to determine the crystalline state of the particles. The physical stability test of the preparation at room temperature was carried out for 3 months. The bioavailability test was carried out using a cross-over design method in rabbits. Determination of plasma levels of ketoprofen by high performance liquid chromatography. The anti-inflammatory effect test was carried out using the paw edema method on the rat's paw, and the irritation test of the preparation on the rat's stomach was carried out macroscopically. The research results obtained nanosuspension formula with a ratio of ketoprofen and PVP 1:1 (F3); 1:1.5 (F4); and 1:2 (F5), each having a particle size of 78.87 ± 7.92 nm, 179.9 ± 4.79 nm, and 345.6 ± 3.13 nm. Nanosuspension F3 is the best nanosuspension with the characteristics of clear preparation, no precipitate and agglomeration, smallest particle size, zeta potential -5.4 ± 0.3, and polydispersity index of 0.419 ± 0.061, spherical particle surface morphology and amorphous crystalline state. In addition, the F3 nanosuspension was more organoleptically stable for 3 months at room temperature storage than the other nanosuspensions. Furthermore, when compared with the ketoprofen suspension, the dissolution rate of the F3 nanosuspension was faster than that of the suspension. During 60 minutes the ketoprofen nanosuspension dissolved as much as 82.47%. Meanwhile, the ketoprofen suspension was only 3.53%. The bioavailability value of the F3 nanosuspension was higher than the ketoprofen suspension as indicated by the Tmax value 0.93 times faster, the Cmax value 1.42 times higher and the AUC value 1.42 times greater than the ketoprofen suspension. There was a very strong in vitro-in vivo correlation (dissolution rate with plasma drug levels in the ketoprofen nanosuspension (r = 0.9853) and there was also a very strong correlation between ketoprofen plasma levels and the percent inhibition of inflammation (r = 0.9734). Ketoprofen nanosuspension provided higher anti-inflammatory effect compared to ketoprofen suspension. Ketoprofen nanosuspension provided higher anti-inflammatory effect and lower gastric irritation effect than ketoprofen suspension. The conclusion of this study is that the ketoprofen nanosuspension with PVP and Tween 80 as a stabilizer has a higher dissolution rate, bioavailability value, anti-inflammatory effect, and lower irritating effect than ketoprofen suspension.