Studies on the oral dosage form of low molecular weight heparin

Heparin and low molecular weight heparin (LMWH) are widely used anticoagulants for the treatment and prevention of deep vein thrombosis and pulmonary embolism. Because heparin is safer and more effective than other oral anticoagulants, its use has certain advantages. However, because in comparison with heparin, LMWHs, which are obtained by fractioning or de-polymerization of heparin, have a higher bioavailability and lower risk of bleeding, they are chosen more frequently than heparin. LMWH preparations are currently available to patients only by parenteral administration. Because LMWH is highly negatively charged, highly hydrophilic and has large a molecular structure, its oral bioavailability is limited. However, parenteral administration is painful for patients and parenteral preparations are more difficult and more expensive. Therefore, various formulations are being investigated for alternative routes of administration. The aim of this study is to develop a formulation for the oral administration of LMWH, which would be effective as an anticoagulant. For this purpose, chitosan microparticles and tablets, solution with and without cyclodextrin and alginate beads were prepared. The formulations containing chitosan were unsuccessful. Using Z3 factorial design, the effect on the duration for 50 % of the drug to be released (f50%) and encapsulation efficiency of parameters such as active substance:polymer ratio, concentration of the hardening agent and hardening time was investigated. Beads were formed based on the ionic interactions between alginate and CaCI2. Concentration of alginate was 2 %, active substance:polymer ratio was 1:l and 1:2, CaCI2 concentration was 0.2 and 0.5 M and hardening duration was 15 and 30 minutes.Through all formulations, encapsulation efficiencies varied between 55.8 and 85.4 %. The encapsulation efficiencies increased related to increasing CaCI2 ratio and active substancelalginate ratio. With increasing hardening duration, encapsulation efficiency decreased to an insignificant degree. Drug release studies were carried out on beads using pH 1.2 for 2 hours and then using pH 6.8 for one hour. All bead formulations, at pH 1.2, swelled slightly, but did not disintegrate and released 37.7-62.0 % of their active substance in 2 hours. On the other hand, when those beads were placed in pH 6.8 solutions, all the active substance was released in half an hour. When the active substance:alginate ratio was 1:2, LMWH release rate increased with increasing CaCI2 concentration. However, when the active substance:alginate ratio was I :I, the release rate decreased with increasing CaC12 concentration. Therefore, release rate was affected only to an insignificant degree by hardening duration but was affected by concentration of the hardening agent. Variance analysis was used to establish the effect of independent factors on dependent factors such as encapsulation efficiency and f50%. In addition, 23 factorial design was applied to linear models. Therefore, we observed that active substancelalginate ratio, CaCI2 concentration and hardening duration have a significant effect. Active substancelalginate ratio and CaCI2 concentration have a more significant effect than hardening duration. The formulation (FH7) consisting of 1:2 active substance:alginate and hardened using 0.5 M CaCI2 for 15 minutes gave the best result in terms of encapsulation efficiency, t50% and bead yield. The yield of all formulations varied between 79.5 and 98.7 %. Alginate bead size measured 1325-1 584 vm. DSC, X-ray diffraction and FT-IR tests on alginate beads showed that LMWH was pure and that is was loaded on alginate beads.