Effects of various granulating systems on the bioavailability of naproxen sodium from polymeric matrix tablets

Naproxen sodium and a cellulose ether derivative were granulated with either water or a poly(meth)acrylic acid ester copolymer aqueous dispersion to make three controlled-release matrix dosage forms. The different polymeric matrix systems contained hydroxypropyl methylcellulose (formulation A), hydroxypropyl cellulose:poly(meth)acrylic acid ester copolymer (formulation B), and hydroxypropyl methylcellulose:poly(meth)acrylic acid ester copolymer (formulation C). All three hydrophilic matrix tablets demonstrated identical in vitro dissolution rates. The three controlled-release formulations were compared with a marketed immediate-release naproxen sodium dosage form (formulation D) in a single-dose crossover study in six healthy volunteers. The AUC values for controlled-release dosage forms A and C were larger than those for formulations B and D. However, the reasons why the AUC for formulations A and C is larger than that for formulations B versus D can be explained differently. Formulations A and C more effectively maintain naproxen plasma levels than formulation D by reducing the amount of naproxen unbound to plasma proteins, therefore reducing naproxen available for urinary excretion. Naproxen sodium delivered from formulations A and C is also probably much better absorbed than from that from formulation B, possibly due to less drug entrapment. More importantly, although all three CR formulations had identical in vitro dissolution profiles, naproxen sodium plasma levels were better maintained (based on AUC) in subjects taking formulations A and C, which contained a lower polymer content and did not use hydroxypropyl cellulose. The tmax values were larger for the three controlled-release dosage forms. Also, the Cmax value for the conventional dosage form was nearly twofold higher than that observed for the controlled-release dosage forms.