低抗凝肝素来源低分子肝素口服制剂的研究

以生产肝素的副产品——低抗凝肝素为原料,采用亚硝酸控制解聚法制得了低分子肝素,分子量为5300,抗凝活性为39.2u/mg,测定了理化指标。以对家兔实验性血栓形成的影响为药效学指标,确定低分子肝素口服制剂的处方组成为低分子肝素、油酸、牛胆盐。研究了所制备的低分子肝素胶囊对家兔血液流变学及血栓形成的影响,并试用于部分动脉粥样硬化症志愿者,表明该胶囊可有效地改善家免和动脉粥样硬化症志愿者血液流变性质,抑制血栓形成。

Studies on Oral Preparation of Low Molecular Weight Heparin from Low Anticoagulant Activity Heparin

Low molecular weight heparin (LMWH) is a kind of effective antithrombotic agent which is being developed in the last decade. It is prepared from commercial heparin by fractionation process or by chemical/enzymatic depolymerization with an average molecular weight of 3000~ 8000. Compared with commercial heparin, LMWH possesses high antithrombotic activity, but low anticoagulant activity. It has prolonged half-life, high bioavailability and little effect upon bleed-ing. It has been employed for the treatment of deep vein thrombosis, pulmonary embolism, dissemi-nated intravascular coagulation and so on. There are several preparations marked around the world. All of them are injections. We just prepared a LMWH from low anticoagulant activity heparin (LAAH) , a side product accompanying commercial heparin, by depolymerization with nitrous acid combined with ethyl alco-hol precipitation technique. The molecular weight of the product was determined with viscosity method, the anticoagulant activity according to USP, and also other physicochemical parameters by conventional methods. The components of oral preparation of LMWH was studied according to the effect upon rabbit experimental thrombus formation. We prepared capsule of LMWH and capsule of heparin with equal anticoagulant potency. Then the effect of both capsules upon rabbit thrombus formation and hemorhelogy was studied, and also tried out on atherosclerosis volunteers. The results showed that the average molecular weight of LMWH is 5300, and the anticoagu-lant activity 39. 2 u/mg which is lower than its raw materal's. The contents of hexosamine, hex-uronic acid and total sulfate were lower than that of LAAH. The experimental formalae are as followed. Preparation No 1 LMWH, bovine bile salt, oleic acid, lactose; No 2 LMWH, lactose; No 3 heparin, lactose; No 4 bovine bile salt, oleic acid; No 5 lactose. They were all made into capsules. The results of effect on rabbit experimental thrombus forma-tion after oral administration showed that preparation No 1 could shorten and lighten thrombus markedly, capsules No 2 and 3 had the tendency of restraining thrombus, No 4 had no obvious ef-fect on thrombus formation. The lactose capsule had the tendency of making the thrombus longer and heavier. On account of above, we decided that the formula conisists of LMWH (or heparin), bovine bile salt and oleic acid. The results of effect on rabbit thrombus formation showed that LMWH capsule and heparin capsule could shorten (4. 49 cm, 4. 31 cm) and lighten (68. 82 mg, 60. 33 mg) thrombus remark-ably. The results of effect on rabbit hemorhelogy showed that LMWH capsule could decrease whole blood high shear rate viscosity (0. 618) , whole blood low shear rate viscosity (1. 690) and erythro-cyte aggregation index (0. 39) markedly. Heparin capsule could decrease rabbits' whole blood high shear rate viscosity (0. 33) and erythrocyte rigidity index (0. 20) significantly. Both of them had no obvious effect on hematocrit, plasma viscosity, erythrocyte sendimentation rate and the content of fibrinogen. The results of effect on atherosolerosis volunteers' hemorhelogy showed that LMWH capsule could reduce whole blood high and low shear rate viscosty (0. 193, 1. 144), plasma viscosity (0. 152) , hematocrit (1. 909) , erythrocyte sedimentation rate (6. 0) and its K value (25. 59) , erythrocyte aggregation index (0. 176) remarkably. Experimental thrombus was measured for six of the volunteers, which showed that LMWH capsules could shorten (11. 83 mm) the thrombus sig-nificantly. Heparin capsules could reduce erythrocyte sedimentation rate (2. 587) and its K value (13. 71) remarkably, the others had no obvious changes.