Development and in vivo evaluation of an oral delivery system for low molecular weight heparin based on thiolated polycarbophil

Purpose. It was the purpose of this study to develop a new oral drug delivery system for low molecular weight heparin ( LMWH) providing an improved bioavailability and a prolonged therapeutic effect. Methods. The permeation enhancing polycarbophil - cysteine conjugate (PCP-Cys) used in this study displayed 111.4 +/- 6.4 muM thiol groups per gram polymer. Permeation studies on freshly excised intestinal mucosa were performed in Ussing chambers demonstrating a 2-fold improved uptake of heparin as a result of the addition of 0.5% (w/v) PCP-Cys and the permeation mediator glutathione (GSH). Results. Tablets containing PCP-Cys, GSH, and 279 IU of LMWH showed a sustained drug release over 4 h. To guarantee the swelling of the polymeric carrier matrix in the small intestine tablets were enteric coated. They were orally given to rats. For tablets being based on the thiomer/GSH system an absolute bioavailability of 19.9 +/- 9.3% ( means +/- SD; n = 5) vs. intravenous injection could be achieved, whereas tablets comprising unmodified PCP did not lead to a significant ( p < 0.01) heparin concentration in plasma. The permeation enhancing effect and subsequently a therapeutic heparin level was maintained for 24 h after a single dose. Conclusions. Because of the strong and prolonged lasting permeation enhancing effect of the thiomer/GSH system, the oral bioavailability of LMWH could be significantly improved. This new delivery system represents therefore a promising tool for the oral administration of heparin.