Thiolated polymers: synthesis and in vitro evaluation of polymer-cysteamine conjugates.
The purpose of the present study was to synthesize and characterize novel thiolated polymers. Mediated by a carbodiimide cysteamine was covalently linked to sodium carboxymethylcellulose (CMC) and polycarbophil (PCP). The resulting CMC-cysteamine conjugates displayed 77.9+/-6.7 and 365.1+/-8.7 micromol thiol groups per gram of polymer, whereas the PCP-cysteamine conjugates showed 26.3+/-1.9 and 122.7+/-3.8 micromol thiol groups per gram of polymer (mean+/-S.D.; n=3). In aqueous solutions above pH 5.0 both modified polymers were capable of forming inter- and/or intra-molecular disulfide bonds. The reaction velocity of this oxidation process was accelerated with a decrease in the proton concentration. The oxidation proceeded more rapidly within thiolated CMC than within thiolated PCP. Permeation studies carried out in Ussing-type chambers with freshly excised intestinal mucosa from guinea pigs utilizing sodium fluorescein as model drug for the paracellular uptake revealed an enhancement ratio (R=P(app) (conjugate)/P(app) (control)) of 1.15 and 1.41 (mean+/-S.D.; n=3) for the higher thiolated CMC-cysteamine (0.5%; m/v) and PCP-cysteamine conjugate (1.0%; m/v), respectively. The decrease in the transepithelial electrical resistance values was in good correlation with the enhancement ratios. Due to a high crosslinking tendency by the formation of disulfide bonds stabilizing drug carrier systems based on thiolated polymers and a permeation enhancing effect, CMC- and PCP-cysteamine conjugates represent promising excipients for the development of novel drug delivery systems.
Bernkop-Schnürch
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Center of Pharmacy, Institute of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria. andreas.bernkop-schnuerch@univie.ac.at
Clausen
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Hnatyszyn
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D000180:Acrylic Resins; D000818:Animals; D003543:Cysteamine / Q000138:chemical synthesis*; D016503:Drug Delivery Systems; D005079:Excipients / Q000138:chemical synthesis / Q000494:pharmacology; D019793:Fluorescein / Q000493:pharmacokinetics; D006168:Guinea Pigs; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D011108:Polymers / Q000138:chemical synthesis* / Q000494:pharmacology
D000180:Acrylic Resins; D005079:Excipients; D011108:Polymers; D003543:Cysteamine; C030312:calcium polycarbophil; D019793:Fluorescein