Preparation and evaluation of oral solid heparin using emulsifier and adsorbent for in vitro and in vivo studies

Oral anticoagulant therapy with heparin has been challenged by formulating heparin in oral solid preparation. As heparin, low molecular weight heparin (LMWH) was used. LMWH was dispersed with a surfactant used for the self-microemulsifying drug delivery system (SMEDDS), PEG-8 caprylic/capric glycerides (Labrasol), and the mixture was solidified with three kinds of adsorbents, microporous calcium silicate (Florite RE), magnesium alminometa silicate (Neusilin US(2)) and silicon dioxide (Sylysia 320). The in vitro release study showed that the T50%s were 3.2+/-0.1min for Sylysia 320, 4.6+/-0.2min for Florite RE, 13.7+/-0.1min for Neusilin US(2). The in vivo rat absorption study showed that Florite RE system had the highest C(max), 0.42+/-0.01IU/mL and AUC, 0.59+/-0.06IUh/mL, where plasma LMWH levels were measured as anti-Xa activity. Other preparations had the C(max) and AUC, 0.12+/-0.01IU/mL and 0.15+/-0.02IUh/mL for Neusilin US(2) and 0.25+/-0.02IU/mL and 0.40+/-0.03IUh/mL for Sylysia 320, respectively. The bioavailability (BA) of LMWH from the microporous calcium silicate preparation, Florite RE, was 18.8% in rats by comparing the AUC obtained after i.v. injection of LMWH, 40IU/kg to another group of rats. Florite RE system was evaluated in dogs after oral administration in an enteric capsule made of Eudragit S100 at the LMWH dose of 200IU/kg. High plasma anti-Xa activity levels were obtained, i.e., the C(max) was 0.48+/-0.11IU/mL and AUC was 1.64+/-0.32IUh/mL. These results suggest that adsorbent system is useful as an oral solid delivery system of poorly absorbable drugs such as LMWH.