Study On Sustained-release Matrix Tablets Of Memantine Hydrochloride

Memantine hydrochloride is an amantadine derivative. It is a moderate affinity, non-competitive N-methyl-D-aspartate (NMDA) antagonist. It was originally developed by Merz for the treatment of Alzheimer's disease (AD), neuropahtic pain and AIDS-related dementia. Memantine hydrochlonde also has potential in the treatment of cerebral pain, spinal spasticity and glaucoma.To reduce the side effects and maintain relatively constant plasma concentration, sustained-release matrix tablets of once daily administration was developed and prepared by using hydroxypropylmethylcellulose (HPMC) as basic matrix material and other matrix expedients. In vivo and in vitro procedures were developed to make a scientific evaluation on this sustained release matrix system.GC-FID chromatogram was developed for assessment of the drug content and release behavior. This method was proved to be simple, accurate, reliable and reproducible.Single factor test revealed that for drug formulation, the amount and viscosity of HPMC were the controlling factors; whereas, for process technique, the tablet hardness was the controlling factor. On the basis of the test, orthogonal design was used to optimize drug formulation and process technique. The drug release from the matrix tablets was studied by comparing with zero order, first order, Higuchi, Ritger-Peppas,Baker-Lonsdale equations et al. Release data were in good linearization with the first-order equation with correlation coefficient r value of-0.9943. The release data also fitted Ritger-Peppas equation with the correlation coefficient r value of 0.9885 and k value of 0.518, between 0.45-0.89, indicating that Fick's diffusion is the prevailing release mechanism with erosion as a supplementary release mechanism.Release conditions, including pH of dissolution medium, rotating speed, and paddle or basket method were evaluated. The optimal release conditions were as follows, water, lOOrpm and basket method. On the basis of the established conditions, in vitro release experiments were carried out as a function of time.Preliminary stability studies showed that memantine hydrochloride matrix tablets were stable to light, temperature, humidity and air. Two months accelerated test revealed that the appearance, content and release behavior were of little changes indicating that the matrix tablets were in stable condition and met quality specifications.The quantitative determination of memantine in beagle dog plasma was performed by GC with hydrogen flame ionization detection and the amantadine hydrochloride was chosen to be the internal standard. The standard curve was linear in the range of 12.5~200ng/ml with a correlation efficient r value of 0.9973. It was proved that the recovery and the inter / intra day precision of this method conformed to specification. The lower detection limit was found to be Ing, indicating that the GC method was accurate.In vivo study, pharmacokinetic parameters and relative bioavailability of beagle dogs were investigated by comparing sustained-release matrix tablets with common reference memantine hydrochloride tablets. The data were processed with 3p87 pharmacokinetic program. The bioavailability of sustained-release matrix tablets was compared against the common reference tablets. Correlation between the in vitro release profile and the in vivo absorption profile was analyzed as well.Data by using sustained-release matrix tablets of memantine hydrochloride in Beagle dog indicated that under single dose regimen, the absorption profile fitted the one-compartment model with 1st order kinetic. The lower Cmax, delayed Tmax and...