CN101810561B - Hirudin polyion micelle composition - Google Patents
Hirudin polyion micelle composition Download PDFInfo
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- CN101810561B CN101810561B CN 200910078181 CN200910078181A CN101810561B CN 101810561 B CN101810561 B CN 101810561B CN 200910078181 CN200910078181 CN 200910078181 CN 200910078181 A CN200910078181 A CN 200910078181A CN 101810561 B CN101810561 B CN 101810561B
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- hirudin
- polyethylene glycol
- chitosan
- polyion
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Abstract
Description
技术领域 technical field
本发明涉及一种可用于注射和口服的聚乙二醇接枝壳聚糖包载水蛭素的聚离子胶束组合物及其制备方法。The invention relates to a polyethylene glycol-grafted chitosan-loaded polyion micelle composition of hirudin which can be used for injection and oral administration and a preparation method thereof.
背景技术 Background technique
血栓栓塞是多种心脑血管疾病发病的原因，威胁中老年人身体健康，每年死于中风等心脑血管性疾病的人数已超过250万人。血栓的形成具有多种机制，其中动脉硬化、血管内皮损伤、内外凝血系统异常或血流动力学异常等是主要的诱发原因。针对这些机制，临床上有抑制血栓形成的抗凝防栓、抗血小板药物和溶栓的药物。其中抗凝防栓类药物在血栓形成的初始阶段，以及溶栓治疗后的二次血栓预防过程中发挥重要作用。针对血栓形成前和溶栓后，肝素、华发林等一线抗凝剂虽药效显著，但均具有诱发出血等副作用，存在安全隐患。Thromboembolism is the cause of various cardiovascular and cerebrovascular diseases, threatening the health of middle-aged and elderly people. The number of people who die of stroke and other cardiovascular and cerebrovascular diseases has exceeded 2.5 million people every year. The formation of thrombus has multiple mechanisms, among which arteriosclerosis, vascular endothelial injury, abnormal internal and external coagulation system or abnormal hemodynamics are the main inducing causes. For these mechanisms, there are anticoagulant antithrombotics, antiplatelet drugs and thrombolytic drugs that inhibit thrombus formation in clinical practice. Among them, anticoagulant and antithrombotic drugs play an important role in the initial stage of thrombosis and in the secondary thrombosis prevention process after thrombolytic therapy. For pre-thrombosis and after thrombolysis, first-line anticoagulants such as heparin and warfarin are effective, but they all have side effects such as inducing bleeding, which poses safety risks.
水蛭素是由65个氨基酸构成的分子量为6950Da的单链多肽，具酸性氨基酸，等电点为3.8。上世纪中期由markwardt从水蛭的唾液腺中提取出来，是迄今为止最强的凝血酶抑制剂，并以其高效性、专一性、无抗原性、低毒性、无出血副作用等赢得广泛关注。1986年，基因发酵工程所得重组水蛭素的成功问世，以其相对较低的成本和相对较高的产率，标志着水蛭素进入临床应用的可能。该药物可用于急性冠脉综合征、链激酶溶栓的辅助治疗、深静脉血栓血管形成术、肝素诱发的血小板减少、血液透析、弥散性血管内凝血等。但水蛭素生物半衰期较短，可快速经肾脏排出体外，导致临床给药次数多，累计给药量大，治疗费用昂贵。针对此问题，侯蓓蓓等(Hou Beibei，Li Shirong，Li Xiaohuiand Xiu Zhilong.Des ign，Preparation and in vitro Bioact ivity ofMono-PEGylated Recombinant Hirudin.Chin.J.Chem.Eng，2007 15(6)：775-780)尝试了PEG化的水蛭素，有效地延长了药物半衰期，然而水蛭素结构改造会潜在地影响药物的疗效和药物的消除。孟萌等(Meng Meng，Yu Liu，Yi-BoWang，Jian-Cheng Wang，Hua Zhang，Xue-Qing Wang，Xuan Zhang，Wan-LiangLu，Qiang Zhang.Increase of the pharmacological and pharmacokineticefficacy of negatively charged polypeptide recombinant hirudin in ratsvia parenteral route by as sociation with cationic liposomes.Journal ofControlled Release，2008，128(2)：113-9)报导了阳离子脂质体包载重组水蛭素-2的静脉注射剂，但药物包封率低，水蛭素易泄漏，脂质体的稳定性差，不适于工业化生产，且采用的膜材具有细胞毒性。郁琴等(郁琴，贺进田，莫炜，等.重组双功能水蛭素PLGA微球的制备及其特性.复旦学报(医学版)，2006，33(1)：17-23.)制备了用于注射的PLGA微球作为重组双功能水蛭素的载体，但微球的粒径较大，易被体内吞噬系统摄取而被代谢。专利CN1393266A公开了水蛭素口服缓(控)释剂型；CN 101176785A公开了一种重组功能水蛭素口服制剂及其制备方法；CN 1428173A公开了重组水蛭素口服肠溶缓释制剂等。但上述制剂的给药剂量大，生物利用度低，生产成本极高。因此，仍需要研制出一种制备方法简单、粒径较小、包封率高、稳定性好、体内循环时间长、适于工业化生产的用于注射和口服的水蛭素组合物。Hirudin is a single-chain polypeptide with a molecular weight of 6950 Da composed of 65 amino acids, with an acidic amino acid and an isoelectric point of 3.8. Extracted from the salivary glands of leeches by Markwardt in the middle of the last century, it is the strongest thrombin inhibitor so far, and has won widespread attention for its high efficiency, specificity, non-antigenicity, low toxicity, and no bleeding side effects. In 1986, the successful introduction of recombinant hirudin obtained from gene fermentation engineering, with its relatively low cost and relatively high yield, marked the possibility of hirudin entering clinical application. The drug can be used for acute coronary syndrome, adjuvant therapy of streptokinase thrombolysis, deep vein thrombosis, heparin-induced thrombocytopenia, hemodialysis, disseminated intravascular coagulation, etc. However, hirudin has a short biological half-life and can be quickly excreted through the kidneys, resulting in many times of clinical administration, a large cumulative dosage, and expensive treatment costs. For this problem, Hou Beibei et al. ) tried PEGylated hirudin, which effectively prolongs the half-life of the drug, but the structural modification of hirudin will potentially affect the efficacy of the drug and the elimination of the drug. Meng Meng, Yu Liu, Yi-BoWang, Jian-Cheng Wang, Hua Zhang, Xue-Qing Wang, Xuan Zhang, Wan-LiangLu, Qiang Zhang. Increase of the pharmacological and pharmacokinetic efficacy of negatively charged polypeptide recombinant hirudin in ratsvia parenteral route by as society with cationic liposomes.Journal of Controlled Release, 2008,128(2):113-9) reported the intravenous injection of cationic liposome-loaded recombinant hirudin-2, but the drug encapsulation efficiency was low, and the leech The liposome is easy to leak, the stability of the liposome is poor, it is not suitable for industrial production, and the membrane material used has cytotoxicity. Yu Qin et al. (Yu Qin, He Jintian, Mo Wei, et al. Preparation and properties of recombinant bifunctional hirudin PLGA microspheres. Fudan Journal (Medical Edition), 2006, 33(1): 17-23.) prepared a The injected PLGA microspheres are used as the carrier of recombinant bifunctional hirudin, but the microspheres have a large particle size and are easily absorbed and metabolized by the phagocytic system in the body. Patent CN1393266A discloses hirudin oral sustained (controlled) release dosage form; CN 101176785A discloses a recombinant functional hirudin oral preparation and its preparation method; CN 1428173A discloses recombinant hirudin oral enteric-coated sustained release preparation, etc. However, the dosage of the above preparation is large, the bioavailability is low, and the production cost is extremely high. Therefore, there is still a need to develop a hirudin composition for injection and oral administration that is simple in preparation method, small in particle size, high in encapsulation efficiency, good in stability, long in vivo circulation time, and suitable for industrial production.
聚乙二醇接枝壳聚糖是壳聚糖的改良产物，在壳聚糖的氨基上引入亲水性长链聚乙二醇，有效地提高了壳聚糖的水溶性和生物相容性，在聚离子引发剂的作用下可在水溶液中自组装形成聚离子胶束。聚乙二醇接枝壳聚糖聚离子胶束，作为一种新型的药物载体，除具有传统聚合物胶束的特点：结构稳定、粒径小且分布均匀；保护包载的药物不受周围环境的破坏；安全性好；制备工艺简单；易于贮存外，还具有自身的独特优势：壳聚糖上大量的游离氨基在酸性环境下质子化，依靠静电作用与负电性药物结合，形成胶束的疏水端，其上接枝的聚乙二醇在疏水内芯外形成致密的水化外壳，可避免胶束被免疫系统摄取，延长药物在体内的循环时间，达到长循环的目的。除此之外，聚离子胶束载药系统还具有包封率高、载药范围广泛、载药过程基本在水溶液中进行，避免有机溶剂的使用，可消除溶剂残留引发的毒副作用等优点。Polyethylene glycol grafted chitosan is an improved product of chitosan, which introduces hydrophilic long-chain polyethylene glycol into the amino group of chitosan, which effectively improves the water solubility and biocompatibility of chitosan , under the action of polyion initiators, they can self-assemble in aqueous solution to form polyion micelles. Polyethylene glycol-grafted chitosan polyion micelles, as a new type of drug carrier, have the characteristics of traditional polymer micelles: stable structure, small particle size and uniform distribution; Destruction of the environment; good safety; simple preparation process; easy to store, but also has its own unique advantages: a large number of free amino groups on chitosan are protonated in an acidic environment, and rely on electrostatic interaction to combine with negatively charged drugs to form micelles The hydrophobic end of the grafted polyethylene glycol forms a dense hydration shell outside the hydrophobic inner core, which can prevent the micelles from being taken up by the immune system, prolong the circulation time of the drug in the body, and achieve the purpose of long circulation. In addition, the polyionic micellar drug loading system also has the advantages of high encapsulation efficiency, wide range of drug loading, and the drug loading process is basically carried out in aqueous solution, avoiding the use of organic solvents, and can eliminate toxic and side effects caused by solvent residues.
发明内容 Contents of the invention
一方面，本发明提供一种聚乙二醇接枝壳聚糖包载水蛭素的聚离子胶束组合物。In one aspect, the present invention provides a polyion micelles composition of polyethylene glycol grafted chitosan encapsulating hirudin.
另一方面，本发明提供的聚乙二醇接枝壳聚糖包载水蛭素的聚离子胶束组合物可用于注射给药和/或口服给药。On the other hand, the hirudin-loaded polyion micelles composition provided by the invention can be used for injection and/or oral administration.
根据本发明的一个方面，其提供的用于注射和口服给药的聚乙二醇接枝壳聚糖包载水蛭素的聚离子胶束组合物，含有水蛭素及聚乙二醇接枝壳聚糖、聚离子引发剂等任选的药用辅料。According to one aspect of the present invention, the polyethylene glycol grafted chitosan entrapped hirudin polyion micelles composition that it provides for injection and oral administration contains hirudin and polyethylene glycol grafted shell Optional pharmaceutical excipients such as polysaccharides and polyion initiators.
本发明还涉及聚离子胶束组合物的制备方法。包括：用醋酸-醋酸钠缓冲液配制聚乙二醇接枝壳聚糖溶液，搅拌下滴入水蛭素溶液，搅拌反应后滴加聚离子引发剂水溶液，密封搅拌后用滤器过滤，即得包载水蛭素的聚乙二醇接枝壳聚糖聚离子胶束。其中的醋酸-醋酸钠缓冲液的pH范围为4.0-5.4，优选4.6-5.2，更优选4.8-5.0。聚乙二醇接枝壳聚糖与水蛭素重量比为5∶2-20∶2，优选10∶2-16∶2。聚乙二醇接枝壳聚糖与聚离子引发剂的重量比为10∶1-0.5∶1，优选4∶1-3∶1。其中胶束的平均粒径在200nm以下，包封率高于80％。The present invention also relates to a method for preparing the polyionic micellar composition. It comprises: preparing polyethylene glycol grafted chitosan solution with acetic acid-sodium acetate buffer solution, adding hirudin solution dropwise under stirring, adding polyion initiator aqueous solution dropwise after stirring, sealing and stirring, and filtering with a filter to obtain the package Hirudin-loaded polyethylene glycol-grafted chitosan polyion micelles. The pH range of the acetic acid-sodium acetate buffer is 4.0-5.4, preferably 4.6-5.2, more preferably 4.8-5.0. The weight ratio of polyethylene glycol grafted chitosan to hirudin is 5:2-20:2, preferably 10:2-16:2. The weight ratio of polyethylene glycol grafted chitosan to polyion initiator is 10:1-0.5:1, preferably 4:1-3:1. Wherein the average particle size of the micelles is below 200nm, and the encapsulation efficiency is higher than 80%.
本发明的组合物可根据任何常规方法配制成各种制剂，例如口服液、片剂、胶囊剂、注射剂等。The composition of the present invention can be formulated into various preparations according to any conventional method, such as oral liquid, tablet, capsule, injection and the like.
本发明组合物可用于制备治疗急性冠脉综合征、链激酶溶栓的辅助治疗、深静脉血栓血管形成术、肝素诱发的血小板减少、血液透析、弥散性血管内凝血等相关疾病的药物。The composition of the invention can be used to prepare medicines for treating acute coronary syndrome, adjuvant therapy of streptokinase thrombolysis, deep vein thrombosis, heparin-induced thrombocytopenia, hemodialysis, disseminated intravascular coagulation and other related diseases.
本发明组合物用于治疗上述疾病的药物可通过口服和注射途径给药。优选注射给药。The medicaments of the composition of the present invention for treating the above diseases can be administered orally and by injection. Administration by injection is preferred.
本发明的组合物包括作为活性成分的水蛭素，还包括由聚乙二醇接枝壳聚糖、聚离子引发剂构成的聚离子胶束。本发明的组合物经注射给药后，水蛭素在体内的循环时间延长；经口服给药后，生物利用度大大提高。本发明组合物中的水蛭素的代表性例子是天然水蛭素、基因工程发酵所得的重组水蛭素，及其变异体。本发明组合物中的水蛭素至少是其中的一种，组合物中水蛭素的载药量为0.1％-50％，优选0.3％-20％，更优选0.5-10％，以组合物的总重量计。The composition of the invention includes hirudin as an active ingredient, and also includes polyion micelles composed of polyethylene glycol grafted chitosan and polyion initiator. After the composition of the invention is administered by injection, the circulation time of the hirudin in the body is prolonged; after the composition is administered orally, the bioavailability is greatly improved. Representative examples of hirudin in the composition of the present invention are natural hirudin, recombinant hirudin obtained by genetic engineering fermentation, and variants thereof. The hirudin in the composition of the present invention is at least one of them, and the drug loading amount of hirudin in the composition is 0.1%-50%, preferably 0.3%-20%, more preferably 0.5-10%, based on the total amount of the composition weighing scale.
聚乙二醇接枝壳聚糖是构成本发明组合物中胶束的主要成分，是聚乙二醇与壳聚糖的接枝产物，其中的聚乙二醇为聚乙二醇或聚乙二醇单甲醚，具有400-20000Da的分子量，优选2000Da-6000Da。所述的壳聚糖为壳聚糖或其衍生物，具有5-2000kDa的分子量，优选10-1000kDa，更优选10-600kDa。所述的壳聚糖或其衍生物具有70％-95％的脱乙酰度，优选75％-90％。所述的聚乙二醇与壳聚糖上氨基的摩尔比例为1∶4-1∶30，优选1∶10-1∶20。Polyethylene glycol-grafted chitosan is the main component of micelles in the composition of the present invention, and is a graft product of polyethylene glycol and chitosan, wherein polyethylene glycol is polyethylene glycol or polyethylene glycol. Glycol monomethyl ether has a molecular weight of 400-20000Da, preferably 2000Da-6000Da. The chitosan is chitosan or its derivatives, with a molecular weight of 5-2000kDa, preferably 10-1000kDa, more preferably 10-600kDa. The chitosan or its derivatives have a deacetylation degree of 70%-95%, preferably 75%-90%. The molar ratio of polyethylene glycol to amino groups on chitosan is 1:4-1:30, preferably 1:10-1:20.
聚离子引发剂也是构成本发明组合物的成分，优选三聚磷酸钠。A polyionic initiator, preferably sodium tripolyphosphate, is also a constituent of the composition of the present invention.
另外，本发明的组合物还包括任选的药学上可接受的添加剂。In addition, the compositions of the present invention also include optional pharmaceutically acceptable additives.
为了达到本发明的目的，本发明进行了静脉注射本发明组合物的药代动力学试验。In order to achieve the object of the present invention, the present invention has carried out the pharmacokinetic test of intravenous injection of the composition of the present invention.
附图说明 Description of drawings
参考附图1和2，通过本发明的以下描述，本发明的上述及其它目的和特征将是显而易见的。附图1显示了本发明实施例1的粒径分布。附图2显示了市售水蛭素注射剂和本发明实施例1静脉注射给药的药时曲线。The above and other objects and features of the present invention will be apparent from the following description of the invention with reference to the accompanying
如上所述，本发明的组合物使水蛭素注射给药后在体内的循环时间延长。As mentioned above, the composition of the present invention prolongs the circulation time of hirudin in vivo after injection.
以下实施例用于进一步详细说明本发明，但绝对不是对本发明范围的限制。The following examples are used to further describe the present invention in detail, but are absolutely not intended to limit the scope of the present invention.
具体实施方案specific implementation plan
实施例1：注射液的制备Embodiment 1: the preparation of injection
将16mg聚乙二醇接枝壳聚糖溶于10ml pH4.9的醋酸-醋酸钠缓冲液，电磁搅拌下加入10ml浓度为0.2mg/mL的水蛭素溶液，搅拌反应45min后滴加4ml浓度为1.1mg/mL引发剂三聚磷酸钠水溶液，密封搅拌40min。用0.45μm的滤器过滤，即得水蛭素的聚乙二醇接枝壳聚糖聚离子胶束组合物。16mg polyethylene glycol grafted chitosan is dissolved in the acetic acid-sodium acetate buffer solution of 10ml pH4.9, adds the hirudin solution that 10ml concentration is 0.2mg/mL under electromagnetic stirring, after stirring reaction 45min, dropwise add 4ml concentration to be 1.1mg/mL initiator sodium tripolyphosphate aqueous solution, sealed and stirred for 40min. Filtrate with a 0.45 μm filter to obtain the polyethylene glycol-grafted chitosan polyion micelles composition of hirudin.
向所得组合物中加入适量的抑菌剂苯甲醇水溶液，混合均匀，过滤，灌封，辐射灭菌即得。An appropriate amount of benzyl alcohol aqueous solution is added to the obtained composition, mixed evenly, filtered, potted and sterilized by radiation.
实施例2：冻干粉针的制备Embodiment 2: the preparation of freeze-dried powder injection
将12mg聚乙二醇接枝壳聚糖溶于10mLpH4.8的醋酸-醋酸钠缓冲液，电磁搅拌下加入20ml浓度为0.3mg/mL的水蛭素溶液，搅拌反应30min后滴加5ml浓度为0.9mg/mL引发剂三聚磷酸钠水溶液，密封搅拌30min。用0.45μm的滤器过滤，即得水蛭素的聚乙二醇接枝壳聚糖聚离子胶束组合物。Dissolve 12mg of polyethylene glycol-grafted chitosan in 10mL of acetic acid-sodium acetate buffer solution at pH 4.8, add 20ml of hirudin solution with a concentration of 0.3mg/mL under electromagnetic stirring, and add 5ml of hirudin solution with a concentration of 0.9mg/mL dropwise after stirring for 30min. mg/mL initiator sodium tripolyphosphate aqueous solution, sealed and stirred for 30min. Filtrate with a 0.45 μm filter to obtain the polyethylene glycol-grafted chitosan polyion micelles composition of hirudin.
在所得的胶束组合物中加入适量的葡萄糖和甘露醇，混合均匀，冻干，密封，辐射灭菌即得。Add appropriate amount of glucose and mannitol into the obtained micelle composition, mix uniformly, freeze-dry, seal and sterilize by radiation.
实施例3：口服液的制备Embodiment 3: the preparation of oral liquid
将200mg聚乙二醇接枝壳聚糖溶于100ml pH5.0的醋酸-醋酸钠缓冲液，电磁搅拌下加入100ml浓度为0.5mg/mL的水蛭素溶液，搅拌反应120min后滴加40ml浓度为1.0mg/mL引发剂三聚磷酸钠水溶液，密封搅拌60min。用0.45μm的滤器过滤，即得水蛭素的聚乙二醇接枝壳聚糖聚离子胶束组合物。200mg polyethylene glycol grafted chitosan is dissolved in the acetic acid-sodium acetate buffer solution of 100ml pH5.0, adds the hirudin solution that 100ml concentration is 0.5mg/mL under the electromagnetic stirring, after stirring reaction 120min, dropwise add 40ml concentration to be 1.0mg/mL initiator sodium tripolyphosphate aqueous solution, sealed and stirred for 60min. Filtrate with a 0.45 μm filter to obtain the polyethylene glycol-grafted chitosan polyion micelles composition of hirudin.
然后将其灌装在西林瓶中，加盖，密封，辐射灭菌即得。Then it is filled in vials, capped, sealed, and sterilized by radiation.
实施例3：片剂的制备Embodiment 3: the preparation of tablet
将500mg聚乙二醇接枝壳聚糖溶于50ml pH4.9的醋酸-醋酸钠缓冲液，电磁搅拌下加入50ml浓度为2mg/mL水蛭素溶液，搅拌反应150min后滴加20ml浓度为12mg/ml引发剂三聚磷酸钠水溶液，密封搅拌90min。用0.45μm的滤器过滤，即得水蛭素的聚乙二醇接枝壳聚糖聚离子胶束组合物。在所得的胶束组合物中加入适量的葡萄糖和甘露醇，混合均匀，冻干得胶束冻干粉。Dissolve 500mg of polyethylene glycol-grafted chitosan in 50ml of acetic acid-sodium acetate buffer at pH4.9, add 50ml of hirudin solution with a concentration of 2mg/mL under electromagnetic stirring, and add 20ml of hirudin solution with a concentration of 12mg/mL dropwise after stirring for 150min. ml initiator sodium tripolyphosphate aqueous solution, sealed and stirred for 90min. Filtrate with a 0.45 μm filter to obtain the polyethylene glycol-grafted chitosan polyion micelles composition of hirudin. Add appropriate amount of glucose and mannitol to the obtained micelle composition, mix uniformly, and lyophilize to obtain micelle lyophilized powder.
[处方]胶束冻干粉1g[Prescription] Micellar freeze-dried powder 1g
乳糖10gLactose 10g
淀粉10gStarch 10g
滑石粉1gTalc powder 1g
微粉硅胶0.1g Micropowder silica gel 0.1g
硬脂酸镁0.1g Magnesium stearate 0.1g
羧甲基淀粉钠1.5g Sodium Carboxymethyl Starch 1.5g
共制50片A total of 50 tablets
等量递加法加入乳糖，过筛混合，再与淀粉混合均匀，加水制软材，过16目筛整粒，50℃干燥，再过16目筛整粒，加入硬脂酸镁，羧甲基淀粉钠，混匀后压片。Add lactose in an equal amount, sieve and mix, then mix with starch evenly, add water to make soft material, pass through a 16-mesh sieve for granulation, dry at 50°C, pass through a 16-mesh sieve for granulation, add magnesium stearate, carboxymethyl Sodium starch, mixed well and pressed into tablets.
实施例4：硬胶囊的制备Embodiment 4: the preparation of hard capsule
将500mg聚乙二醇接枝壳聚糖溶于50ml pH4.9的醋酸-醋酸钠缓冲液，电磁搅拌下加入50ml浓度为3mg/mL水蛭素溶液，搅拌反应150min后滴加20ml浓度为20mg/mL引发剂三聚磷酸钠水溶液，密封搅拌90min。用0.45μm的滤器过滤，即得水蛭素的聚乙二醇接枝壳聚糖聚离子胶束组合物。Dissolve 500mg of polyethylene glycol-grafted chitosan in 50ml of acetic acid-sodium acetate buffer at pH4.9, add 50ml of hirudin solution with a concentration of 3mg/mL under electromagnetic stirring, and add 20ml of hirudin solution with a concentration of 20mg/mL dropwise after stirring for 150min. mL initiator sodium tripolyphosphate aqueous solution, sealed and stirred for 90min. Filtrate with a 0.45 μm filter to obtain the polyethylene glycol-grafted chitosan polyion micelles composition of hirudin.
在所得的胶束组合物中加入适量的葡萄糖和甘露醇，混合均匀，冻干。然后将冻干粉填充在胶囊中，得到一粒胶囊。Add appropriate amount of glucose and mannitol into the obtained micelle composition, mix uniformly, and freeze-dry. Then the freeze-dried powder is filled in capsules to obtain one capsule.
试验例1：静脉注射给药的药代动力学试验Test Example 1: Pharmacokinetic test of intravenous administration
为了考察包含在本发明组合物中的水蛭素静脉注射的药代动力学特征，如下对实施例1中的本发明制剂、市售注射剂分别进行药代动力学研究。用异硫氰基荧光素(FITC)对水蛭素进行标记，用荧光光度方法测定血中水蛭素的含量。In order to investigate the pharmacokinetic characteristics of hirudin contained in the composition of the present invention by intravenous injection, pharmacokinetic studies were carried out on the preparation of the present invention and the commercially available injection in Example 1 respectively as follows. Hirudin was labeled with fluorescein isothiocyanate (FITC), and the content of hirudin in blood was determined by fluorescence photometry.
将10只体重约为250g的SD大鼠随机等分为两组。试验前12小时禁食，可自由饮水。称重后按2mg/kg剂量，一组尾静脉给予市售水蛭素注射剂，另一组尾静脉给予实施例1的本发明制剂。分别于给药后不同时间点眼眶静脉丛取血0.5mL(取血容器事先肝素化)，4000rpm离心10min，吸取上清100μl，稀释至一定浓度，测定荧光强度值。根据随行标准曲线计算血药浓度。结果如图2和表1。Ten SD rats weighing about 250 g were randomly divided into two groups. Fasting 12 hours before the test, free to drink water. After weighing, according to the dose of 2 mg/kg, one group was given the commercially available hirudin injection through the tail vein, and the other group was given the preparation of the present invention in Example 1 through the tail vein. At different time points after administration, 0.5 mL of blood was collected from the orbital venous plexus (the blood container was heparinized in advance), centrifuged at 4000 rpm for 10 min, 100 μl of the supernatant was drawn, diluted to a certain concentration, and the fluorescence intensity was measured. The plasma concentration was calculated according to the accompanying standard curve. The results are shown in Figure 2 and Table 1.
表1和图2的结果表明，与市售水蛭素注射剂相比，SD大鼠体内药代动力学显示，本发明的实施例1可显著延长水蛭素的体内驻留时间，具有长循环的特性。The results in Table 1 and Figure 2 show that compared with commercially available hirudin injections, the pharmacokinetics in SD rats shows that Example 1 of the present invention can significantly prolong the residence time of hirudin in vivo, and has the characteristics of long circulation .
表1市售水蛭素注射剂和实施例1的静脉注射给药的药代动力学参数The pharmacokinetic parameters of the intravenous administration of table 1 commercially available hirudin injection and
p＜0.05p<0.05
虽然已利用上述具体的实施方案对本发明进行了描述，但应认识到，本领域的技术人员还可进行各种的改进和改变，而且它们也应在如权利要求书限定的本发明的范围之内。Although the present invention has been described using the specific embodiments above, it should be recognized that those skilled in the art can also make various improvements and changes, and they should also be within the scope of the present invention as defined in the claims Inside.
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| Title |
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| 多功能聚合物胶束的最新研究进展;李平祝等;《中国新药杂志》;20081231;第17卷(第3期);第199-202页 * |
| 李平祝等.多功能聚合物胶束的最新研究进展.《中国新药杂志》.2008,第17卷(第3期),第199-202页. |
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| 聚乙二醇接枝壳聚糖离子胶束的制备与体外表征研究;杨可伟等;《中国新药杂志》;20071231;第16卷(第13期);第1030-1034页 * |
| 郝艳丽等.水蛭素的给药途径及其相关剂型研究进展.《中国新药杂志》.2007,第16卷(第8期),第595-599页. |
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