Influence of the spacer on the inhibitory effect of different polycarbophil-protease inhibitor conjugates.
Within the present study various polycarbophil (PCP)-serine protease inhibitor conjugates were synthesized and the influence of different spacers on their inhibitory efficacy was evaluated in vitro. Results demonstrated that 4.2+/-0.15 units (n=3; +/-SD) of alpha-chymotrypsin were inhibited by 50% utilizing 0.86% (w/v) of a PCP-tetramethylenediamine (TMDA)-chymostatin 20:1 conjugate. In contrast, only 0.6+/-0.05 units (n=3; +/-SD) of alpha-chymotrypsin were inhibited by a corresponding PCP-poly(ethylene glycol) (PEG)-chymostatin conjugate. Inhibitory effects of PCP-TMDA-antipain and -elastatinal conjugates towards trypsin and elastase, respectively, were also significantly higher (P<0.05) than those of corresponding PCP-PEG-inhibitor conjugates. Hence, the great impact of the molecular size as well as the structure of the spacer on resulting polymer-inhibitor conjugates could be demonstrated. The small and rigid C4-spacer TMDA (molecular weight (MW) 161.1) was thereby shown to be highly advantageous over a long, hydrophilic and flexible PEG-diamine spacer (MW 3400). Results obtained should provide helpful basic knowledge for the development of mucoadhesive polymer-inhibitor conjugates used as auxiliary agents for the oral administration of peptide drugs.
Marschütz
M K
MK
Center of Pharmacy, Institute of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.
Veronese
F M
FM
Bernkop-Schnürch
A
A
D000180:Acrylic Resins / Q000737:chemistry*; D000269:Adhesives / Q000737:chemistry; D002400:Cathartics / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D016503:Drug Delivery Systems; D011480:Protease Inhibitors / Q000737:chemistry*
D000180:Acrylic Resins; D000269:Adhesives; D002400:Cathartics; D011480:Protease Inhibitors; C030312:calcium polycarbophil