Design, Characterization and Evaluation of Anti-epileptic Activity of Nanoprecipitating Preconcentrate of Carbamazepine

Ankitkumar S.      Jain; Abhijit A.      Date; Mangal S.      Nagarsenker

Abstract

A preconcentrate containing Carbamazepine (CBZ) was designed, with the objective to improve its oral bioavailability, which on dilution with aqueous vehicles in vitro/in vivo would yield CBZ nanosuspension in situ. When preconcentrate containing hydrophilic stabilizer alone was diluted with aqueous medium, CBZ precipitated as needle shaped crystals within few minutes, due to Ostwald ripening and probably, due to conversion to dihydrate polymorph. Combination of lipophilic stabilizers and hydrophilic stabilizers imparted adequate colloidal stability to CBZ nanosuspension. Preconcentrate containing a mix of different stabilizers which could yield nanosuspension in situ was optimized with respect to colloidal stability and mean particle size. Preconcentrate containing Tween 80 (31.4% w/v) as hydrophilic stabilizer and Labrafil M1944 CS (20.9 %w/v) as lipophilic stabilizer yielded mean particle size and polydispersity index of 192.7± 5.65 nm and 0.35± 0.02, respectively, on dilution with aqueous medium in situ. This optimized formula of nanoprecipitating preconcentrate (NPP) yielded CBZ nanosuspension in situ on dilution with aqueous media. The size of CBZ NPP dispersed in water was confirmed with TEM studies, which also provided information on surface morphology of CBZ nanosuspension. The CBZ NPP preconcentrate was converted to free flowing granules (NPPG 1) by adsorption on to Aerosil R 974, for ease of handling. Amorphous state of CBZ in NPPG 1 system as indicated by XRD studies coupled with greater surface area of nanosized CBZ particles could have resulted in improved dissolution velocity of CBZ as compared to CBZ suspension, as observed during in vitro dissolution testing. Anti-epileptic studies in mice demonstrated CBZ NPP superior to plain CBZ suspension in delaying onset of seizures and in reducing mortality.

Keywords: Carbamazepine, anti-epileptic, in situ, lipophilic stabilizer, nanoprecipitating, nanosuspension, Ostwald ripening, preconcentrate.