Development of extended release dextromethorphan matrix tablets.

摘要

Dextromethorphan (DM) is a highly potent and commonly used anitussive agent. Dextromethorphan has no narcotic, analgesic or addictive properties and its potency as an antitussive agent is almost equal to that of codeine. At present there are no extended release dextromethorphan matrix tablets available in the USA. An extended release dextromethorphan tablet can lead to the reduction of the number of doses administered, leading to better patient compliance and less of a chance of overdose, in addition to which it can reduce the cost associated with treating cough symptoms.; It was the objective of this dissertation to develop and evaluate extended release dextromethorphan matrix tablets manufactured by the direct compression method.; Formulation and process variables on the effect of hydroxypropylmethylcellulose (HPMC K100LV) in combination with anionic methacrylic acid copolymer (Eudragit L100-55); and polyvinyl acetate/povidone (PVAP) (KollidonRTM SR) polymer concentrations in the tablet, filler excipient concentration, compression force, stability storage conditions and variable dissolution agitation rates were evaluated on the produced tablet characteristics. The extended release tablets were then compared to a marketed capsule product by applying the FDA dissolution recommended model independent f2 similarity test. Additionally, bioavailability and bioequivalence studies in healthy adult beagle dogs were performed.; It was found that HPMC (K100LV) at 20% level in combination with methacrylic acid copolymer (EudragitRTM 1-100-55) at 20% level produced extended release dextromethorphan matrix tablets that are similar to the marketed capsule product according to the model independent FDA guidelines (f2 factor).; Polyvinyl acetate/povidone (PVAP) (KollidonRTM SR) at 39.5% in combination with dibasic calcium phosphate also at 39.5% level produced extended release dextromethorphan tablets that are similar to the marketed capsule product according the model independent FDA guidelines (f2 factor).; The extended release dextromethorphan matrix tablets followed square root of time dependent kinetics for drug release indicating a diffusion controlled release mechanism.; Under long term storage conditions at 25°C and 60% RH, physical stability testing performed on the extended release dextromethorphan matrix tablets showed no significant change in the dissolution rates.; The extended release dextromethorphan matrix tablets were not bioequivalent to the marketed capsule product, however, the tablets had higher bioavailability as shown by the AUC(0-inf). In vitro/in vivo correlation between variable dissolution agitation rates and the dextromethorphan released and absorbed was not established for the extended release dextromethorphan matrix tablets.; It was concluded that extended release dextromethorphan tablets were developed using HPMC (K100LV) in combination with methacrylic acid copolymer (EudragitRTM L100-55); and PVAP (KollidonRTM SR) as the release extending excipients. In vitro testing indicated that the produced tablets had similar dissolution behavior to the marketed capsule product according to the model independent FDA guideline (f2 factor)