Papain: an effective permeation enhancer for orally administered low molecular weight heparin.
OBJECTIVE
The purpose of this study was to evaluate an effect of the proteolytic enzyme papain on permeation of low molecular weight heparin (LMWH) in vitro and in vivo.


METHODS
In vitro permeation studies were performed using rat small intestine as permeation barrier. In order to determine the ratio of papain to heparin resulting in the highest heparin permeation rate, molar ratios 1:1, 1:2 and 2:1 of papain to heparin were tested. Interactions of heparin with papain were investigated spectro-photometrically. For in vivo studies, 15 mg tablets containing heparin (13%), papain (64%) and hydroxyethylcellulose (22%) were orally administered to rats.


RESULTS
Since molar ratio papain to heparin 1:1 resulted in the highest permeation rate, it was used for in vivo studies. The results of binding studies of papain with heparin indicated a strong interaction between papain and heparin. Oral administration of tablets containing LMWH/papain/HEC resulted in sevenfold improvement of plasma anti-Xa activity in comparison to control. For tablets based on heparin/papain/HEC, a relative bioavailability of 9.1% vs. subcutaneous injection was obtained, whereas the relative bioavailability of control was 2.4%.


CONCLUSIONS
The co-administration of papain with heparin represents a new approach in improvement of absorption and bioavailability of orally administered heparin.
Grabovac
Vjera
V
Institute of Pharmacy, Department of Pharmaceutical Technology, University of Innsbruck, Innrain 52, 6020, Innsbruck, Austria.
Schmitz
Thierry
T
Föger
Florian
F
Bernkop-Schnürch
Andreas
A
D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006863:Hydrogen-Ion Concentration; D007279:Injections, Subcutaneous; D007408:Intestinal Absorption / Q000187:drug effects*; D007421:Intestine, Small / Q000166:cytology / Q000378:metabolism; D008297:Male; D010206:Papain / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D013053:Spectrophotometry; D013607:Tablets
D000925:Anticoagulants; D006495:Heparin, Low-Molecular-Weight; D013607:Tablets; D010206:Papain