| Low molecular weight heparin calcium (LMWH-Ca) is a class of medication used as an anticoagulant in diseases that feature thrombosis, as well as for prophylaxis in situations that lead to a high risk of thrombosis. They are obtained by various of fractionation in the acid solution. They have a high anti-factor Xa activity (AFXa) and low anti-IIa activity (AFIIa) and the ratio of anti-factor Xa activity to anti-thrombin activity is between 4:1 and 2:1. Comparatively, LMWH-Ca has higher antithrombotic effect and lower anticoagulant effect than heparin. It has good absorption, high bioavailability, long half-life in vivo, the advantages of small bleeding tendency though subcutaneous injection. Now it was widely clinical applied.Because LMWH-Ca belongs to the prescriptional drugs, so it is only used to the patient in the hospital, which limits the scope of its use. In order to expand the application of LMWH-Ca in the clinical use, we intented to study the LMWH-Ca oral preparations, which will benefit the non-hospitalized patients.Due to the larger molecular weight and very strong negative charge of LMWH-Ca, oral absorption has been a problem. The study was on the preparation and screening of three oral LMWH-Ca formulas to get optimal prescription using uniform design, and select a relatively ideal formulation through the oral bioavailability in rat experiments.In this study, we aimed to investigate the oral preparations of LMWH-Ca and the absorption of LMWH-Ca in the preparations administered orally.Preparation of three oral preparations of the LMWH-Ca: LMWH-Ca preparations were prepared by microencapsulation with PEG 6000, inclusion withβ-CD or adding sodium N-[10-(2-hydroxybenzoyl)amino] decanoate (SNAD) to enhance the absorption of LMWH-Ca from the gastrointestinal tract.Determination of the anti-Xa activity of the LMWH-Ca in vitro and in vivo: The method for determining the anti-Xa potency of the three LMWH-Ca oral formulations using the chromogenic substrate method in vitro was investigated. The quantites of LMWH-Ca in the plasma absorbed from the gastrointestinal tract was determined using the chromogenic substrate method after the oral LMWH-Ca fluids administration in vivo.Determination the bioavailability of the three LMWH-Ca oral formulations using the chromogenic substrate method after the oral administration into the SD rats: SDrats were given three LMWH-Ca formulations orally, in accordance with the dose of oral anti-Xa preparations activity and the weight of the animal. In the allotted time, the blood of the SD rats was collected from the heart, and the chromogenic substrate method was used to determine the concentrations of LMWH-Ca in the plasma at different time points. The concentrations of LMWH-Ca of each oral formulation at different time points were used to make the drug concentration-time curve, and subcutaneous injection treatment group was set to calculate each oral formulations bioavailability.The main results and conclusions in this paper are summarized as follows:Three oral preparations of LMWH-Ca were prepared, the optimal prescriptions wasobtained through screening from the different prepration adopting the uniform design.Verify the method of anti-Xa activity in vitro and in vivo through a linear, precision , stability, and so on. The in vitro results showed that the linear was good, relevant coefficient was 0.99; the RSD of precision was 0.26 %; the RSD of the stability was 0.44%. The in vivo results showed that the linear was good, relevant coefficient was 0.98; the RSD of precision was 0.28 %; the RSD of the stability was 0.48%. The bioavailability of the three oral preparations of the LMWH-Ca was about 4.9%, 2.6%, 19% respectively.Among the preparations of LMWH-Ca, the one containing SNAD had better absorption. The bioavailability of the other two formulations is very low, almost no absorption.SNAD has good ability to enhance absorption of oral LMWH-Ca from the gastrointestinal tract. It would be good to take further study on LMWH-Ca oral preparations.
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