Polymeric prodrugs, 4. IN vitro study of the drug release on a model p‐nitroanilide bound onto polyanionic carrier

Abstract

The process of chymotrypsin catalysed hydrolysis of ~-phenylalanyl-4-nitroanilide (Phe-NNp) residues bound via 6-aminohexanoic acid (c-Ahx) spacer to the polyanionic carrier, poly(N-vinylpyrrolidone-co-maleic acid), was studied. The initial rate of hydrolysis was measured at pH 8 as a function of mole ratio of side chains (-e-Ahx-Phe-NNp) randomly distributed along the backbone. The polyanionic carrier studied shows a pronounced effect on the process, as overall kinetic parameters (kat and G ) of -&-Ahx-Phe-NNp, attached to the polymer, differ significantly from the respective values of the low-molecular-weight substrate analogue, succinyl-&-Ahx-Phe-NNp. Relationship between the side chain content and the kW, /& values, examined in the range of 1 to 20 mol-%, exhibits a saturation-profile. The limiting value of kWt /& (5 * Id 1 * mol-' * s -l ) appeared to be as much as 8-times higher than that of succinylc-Ahx-Phe-NNp. The course of chymotrypsin catalysed hydrolysis of the polymer-substrate bearing 20 mol-% of side chains shows first order kinetics, with the conversion approaching asymptotically 100%. pH dependence of the maximum velocity of hydrolysis (V,), determined in the range 5 -10, shows a maximum at about pH 8. The enzyme activity profile is broadened toward acidic region.

Bioactive polymers: Synthesis, release study and antimicrobial properties of polymer bound Ampicillin

“…Much attention has been lately paid to the preparation and properties of pharmacologically active polymers [2][3][4][5][6][7] , which can serve as a carrier for low molecular weight drugs to form prodrugs. The controlled slow release of pharmacologically active components in the body can be achieved from prodrugs which can be considered as a special type of drug delivery system from which drug release is accomplished by the cleavage of chemical bonds 8) .…”

Review : Biodegradability of Synthetic Polymers for Medical and Pharmaceutical Applications: Part 3—Pendent Group Hydrolysis and General Conclusions

“…The pyrrolidone unit favors water solubility even in those cases where the conjugated drug is hydrophobic. The spacer group -NH(CH2)SCOOH allows for higher loading and improved water solubility [258]. The reported in vivo and in vitro hydrolysis studies of these polymeric prodrugs demonstrate enzymatic participation when phenylanaline occupies the position between the spacer and the drug model, p-nitroanilide.…”

“…The alternating copolymer of maleic anhydride and N-vinyl-2-pyrrolidone poly(COOH-1) (Table 1) appears to have some intrinsic advantages over PMA and PMMA [257,258]. The maleic anhydride unit is easily converted to esters or amides and provides at the same time a built-in catalyst to promote hydrolysis.…”