NOVEL PERORAL DOSAGE FORMS WITH PROTEASE INHIBITORY ACTIVITIES .2. DESIGN OF FAST DISSOLVING POLY(ACRYLATE) AND CONTROLLED DRUG-RELEASING CAPSULE FORMULATIONS WITH TRYPSIN INHIBITING PROPERTIES

The purpose of this study was to develop a dosage form for peroral pep tide drug delivery which is able to increase the stability of the mode l substrate N-alpha-benzoyl-L-arginine ethyl ester (BAEE) against degr adation by trypsin. Different capsule formulations, containing carbome r (C934P) and its neutralized freeze-dried modification (FNaC934P), we re investigated in a specially designed dissolution test apparatus. Th e capsules were placed in a dissolution medium with 10 IU trypsin/ml. Carbomer was found to be more efficient in inhibiting trypsin activity than FNaC934P. The recovery of the substrate BAEE was highly dependen t on both the swelling velocity of the polymers and the pre-incubation time of trypsin with the poly(acrylates) in the incubation medium. Pr e-incubation for at least 20 min in carbomer or FNaC934P dispersions w as required to achieve sufficient trypsin inhibition. From all the for mulations investigated, a two-phase capsule preparation consisting of a rapid swelling FNaC934P part as the first phase and microparticles o f polyglycerol esters of fatty acids containing carbomer particles and the peptide model drug BAEE as the second phase, had the most profoun d effect on trypsin activity inhibition.