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 peptide drug delivery which is able to increase the stability of the model substrate N-alpha-benzoyl-L-arginine ethyl ester (BAEE) against degradation by trypsin. Different capsule formulations, containing carbomer (C934P) and its neutralized freeze-dried modification (FNaC934P), were investigated in a specially designed dissolution test apparatus. The 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 dependent on both the swelling velocity of the polymers and the pre-incubation time of trypsin with the poly(acrylates) in the incubation medium. Pre-incubation for at least 20 min in carbomer or FNaC934P dispersions was required to achieve sufficient trypsin inhibition. From all the formulations investigated, a two-phase capsule preparation consisting of a rapid swelling FNaC934P part as the first phase and microparticles of polyglycerol esters of fatty acids containing carbomer particles and the peptide model drug BAEE as the second phase, had the most profound effect on trypsin activity inhibition.