Development and in vivo evaluation of an oral delivery system for low molecular weight heparin based on thiolated polycarbophil.
OBJECTIVE
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 microM 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.
Kast
Constantia E
CE
Center of Pharmacy Institute of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.
Guggi
Davide
D
Langoth
Nina
N
Bernkop-Schnürch
Andreas
A
D000180:Acrylic Resins / Q000737:chemistry*; D000284:Administration, Oral; D000465:Algorithms; D000818:Animals; D019540:Area Under Curve; D016503:Drug Delivery Systems; D005079:Excipients; D005978:Glutathione / Q000737:chemistry; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D007408:Intestinal Absorption; D007421:Intestine, Small / Q000378:metabolism; D010539:Permeability; D051381:Rats; D013607:Tablets
D000180:Acrylic Resins; D005079:Excipients; D006495:Heparin, Low-Molecular-Weight; D013607:Tablets; C030312:calcium polycarbophil; D005978:Glutathione