依诺肝素钠(学术交流)

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浅析药品依诺肝素钠的生产工艺

浅析药品依诺肝素钠的生产工艺作者：薛发珍来源：《科技创新与应用》2015年第11期摘要：这项生产工艺是本课题大量实验的相关成果，借鉴法国公司依诺肝素钠生产情况，采用一种原材料，经过科学、严谨的生产过程，所研制的依诺肝素钠样品符合欧洲药典标准。

根据实验情况，文章总结了生产过程中需要重视的环节，使这种药品国产化成为可能。

关键词：依诺肝素钠；生产；酯化率；成环率；纯化药品依诺肝素钠（enoxaparin sodium）是一种低分子肝素药物，这种药品是治疗预防与脑血栓的最佳药品之一，具有抗血栓作用强、出血危险性小等特征，经临床试验表明，依诺肝素钠能达到抗凝血、抗血栓形成的显著疗效，故此，这种药品具有重要的医疗价值，对生物制药企业而言，大面积生产这种药品，能带来大量的经济效益，同时也能满足我国的医疗需求。

1 依诺肝素钠的生产工艺1.1 依诺肝素钠现行的生产工艺依诺肝素钠主要特征为分子中有一个4-烯吡喃糖醛酸结构（图1）。

目前，医疗上使用的依诺肝素钠都由法国Aventis公司研发，并由这家公司在1993年申请专利。

由于这项专利未涉及生产过程中酯化率、成环率及产物纯化等关键工艺，因此存在一定的缺陷，这就使得法国这家公司运用该专利生产的药物样品时，距离欧洲药典4.0版规定的标准尚有一定的距离。

1.2 这项生产工艺的研究目的这项研究主要是通过对相关反应条件的控制，研制出可以实现流水线生产依诺肝素钠的生产工艺，生产出来的样品，经过多次实验，表明这些样品的溶液颜色符合欧洲药典4.0版要求，其余质量指标均符合欧洲药典5.3版。

1.3 这项工艺所需的仪器与试剂根据生产过程的相关要求，结合前期的研究情况，这项工艺所需的仪器、设备和试剂，有如下几种：1100型高效液相色谱仪、TSK-GEL 凝胶色谱柱及1100型示差检测仪均为Agilent产品；UV-2101PC型紫外检测仪（日本岛津）。

肝素钠（南京健友公司）；苄索氯铵[benz e thoniumchloride，化学名为苄基二甲基[2-[2-[4-（1，1，3，3-四甲基丁基）苯氧基]乙氧基]乙基]氯化铵，Sigma公司]；二氯甲烷、氯苄（上海三爱思试剂有限公司）；H103型非极性大孔聚苯乙烯吸附树脂（南开大学化工厂，柱径3.6cm，柱床体积550ml）；依诺肝素钠标准品（欧洲药典标准品）；其他试剂均为分析纯。

依诺的肝素的制备和纯化剖析

江西浩然生物医药有限公司项目研发计划项目名称：HR-08技术研究负责人：起止时间：项目编号：HR-08-1503002目录内容页码一背景资料………………………………………………………二立项目的………………………………………………………三研究内容………………………………………………………四资金预算…………………………………………………五实验研究时间计划……………………………………一、背景资料依诺肝素钠(enoxaparin sodium，1)属于低分子肝素⋯，主要特征为分子中有一个4一烯吡喃糖醛酸结构(图1)。

本品抗血栓作用强、出血危险性小，是目前抗凝血、抗血栓形成的主要治疗药物之一，肝素通过酶或化学的方法部分降解就可以获得低分子肝素。

低分子肝素因为分子量较小，不易被I V因子中和，抗凝血效果和纤溶作用得以增强，而抗血小板，影响血小板功能，影响血液的凝固性，诱发出血的作用大为减弱，加之生物利用度高达98%，量效关系明确，抗凝效果易于预防，血浆半衰期较普通肝素长2-3倍，同时具有快速和持续的抗血栓形成作用，改善血流动力学。

依诺肝素钠由法国AVentis 公司研发，并与1993年申请专利。

但该专利未涉及生成过程中酯化率，成环率及生产纯化等关键工艺。

采用该转利生成的样品无法达到欧洲药典4.0版规定的标准。

本研究通过控制上述反应条件，得到适合于工业生成的依诺肝素钠工艺，所得的成品溶液颜色符合欧洲药典4.0版要求，其余质量指标均符合欧洲药典5.3版。

二、实验目的建立HR－０８制备和纯化的工艺技术参数，进行工艺放大和工艺稳定性研究。

三、实验内容：实验步骤：3.1．成盐：3.1.1 称取06样品（例如100g）用纯化水(1000ml)溶解到10%溶液，边加入边搅拌，至均匀；称取06样品质量2.5倍的苄索氯胺(250g)用纯化水(1250ml)溶解至20%溶液；3.1.2将上述20%苄索氯胺溶液缓缓加入肝素钠溶液中，边加边搅拌，加完后继续搅拌0.5小时；3.1.3将反应液离心收集沉淀（离心速率与时间根据离心机直径调整，一般来说离心上清越清越好，离心效果直接与回收率相关，一般选用沉降式离心机？；3.1.4将沉淀捣碎（尽量捣碎）加入1.1中肝素钠质量10倍量的纯化水(1000ml)搅拌洗涤0.5小时，离心收集沉淀（离心速率与时间根据离心机直径调整，一般来说离心上清越清越好，离心效果直接与回收率相关。

依诺肝素钠学术交流-V1

依诺肝素钠学术交流-V1依诺肝素钠是一种被广泛使用于临床治疗中的抗凝药物。

它主要在心脏病患者尤其是心脏手术后的预防性抗凝治疗中使用，有效地降低了深静脉血栓和肺栓塞的发生率。

随着医学科技的不断发展，依诺肝素钠也逐渐成为了学术界研究、讨论的热点话题。

依诺肝素钠的使用依诺肝素钠是一种低分子肝素，其机制是通过抑制凝血酶活性来防止血栓的形成。

它不仅可以预防血栓形成，还可以防止血栓的成长和脱落。

因此，在患者术后，特别是心脏手术后，依诺肝素钠可以帮助患者避免出现术后并发症。

依诺肝素钠的优点相比传统的抗凝药物，依诺肝素钠的使用具有很多优点。

首先，依诺肝素钠是一种低分子肝素，具有分子量更小、生物利用度更高、体外半衰期更长等特点，因此更容易控制剂量和减少副作用的发生。

其次，依诺肝素钠的使用方法非常简单，仅需皮下注射即可。

最重要的是，依诺肝素钠能够帮助患者有效地预防血栓的形成，减少并发症的发生。

依诺肝素钠的学术交流近年来，随着依诺肝素钠在临床治疗中的广泛应用，学术界对其进行了大量的研究和讨论。

这些学术交流的内容主要涉及依诺肝素钠的临床应用、药理学、剂量的选择等方面。

通过这些研究和讨论，大家更深入地了解了依诺肝素钠在心脏手术、急性冠脉综合征等领域的应用，以及其在不同年龄和性别患者中的药物反应和剂量选择。

结语总的来说，依诺肝素钠是一种非常有效、安全的抗凝药物，在临床中被广泛应用。

它不仅能够预防血栓的形成，还能够减轻患者的术后疼痛和恢复时间。

随着学术界对其研究的深入，相信依诺肝素钠的应用将会更加精准和个性化，为患者提供更好的抗凝治疗效果。

一种依诺肝素钠及其生产纯化方法[发明专利]

专利名称：一种依诺肝素钠及其生产纯化方法
专利类型：发明专利
发明人：汤庆刚,季春香,王新扬,赵育,屈建兴,牛洪森申请号：CN201210029323.4
申请日：20120210
公开号：CN102585037A
公开日：
20120718
专利内容由知识产权出版社提供
摘要：本发明公开一种依诺肝素钠，依诺肝素钠的平均分子量在于3500-5500道尔顿之间，溶血栓生物活性100-125IU/mg，抗Xa与抗IIa的比值在3.3-5.3之间。

依诺肝素钠生产纯化方法：肝素苄索氯铵盐的制备；肝素苄酯的制备：肝素苄酯的纯化；依诺肝素钠的制备；依诺肝素钠的纯化。

依据本发明，并控制产品分子量和分布区间，最终得到的精品依诺肝素钠产品质量符合欧洲药典质量标准。

本发明以肝素钠粗品为起始原料，能有效降低生产成本；精制肝素苄酯，稳定了最终产品质量，简化纯化难度，有效解决生产中色素问题，提高产品质量。

申请人：麦科罗夫(南通)生物制药有限公司
地址：226000 江苏省南通市南通经济技术开发区中央路52号406室
国籍：CN
代理机构：南京正联知识产权代理有限公司
代理人：顾伯兴
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伊诺肝素钠

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use Lovenox safely and effectively. See full prescribing information for Lovenox.Lovenox® (enoxaparin sodium injection) for subcutaneous and intravenous useInitial U.S. Approval: 1993WARNING : SPINAL/EPIDURAL HEMATOMASee full prescribing information for complete boxed warning . • Enoxaparin use in patients undergoing spinal/epidural anesthesia or spinal puncture increases the risk of spinal or epidural hematoma, which may cause long-term or permanent paralysis (5.5) • Risk is increased by:o Indwelling epidural catheters for analgesia (5.5) o Drugs affecting hemostasis [e.g., nonsteroidal anti-inflammatory drugs, platelet inhibitors, anticoagulants] (5.5, 7)o Traumatic or repeated spinal or epidural puncture (5.5)-----------------------RECENT MAJOR CHANGES ------------------Indications and Usage (1.4), 5/2007 Dosage and Administration (2) 5/2007ST-segment Elevation Myocardial Infarction Warnings and Precautions (5.2) 5/2007 Percutaneous coronary revascularization procedures------------------INDICATIONS AND USAGE -------------------Lovenox is a low molecular weight heparin [LMWH] indicated for:• Prophylaxis of deep vein thrombosis (DVT) in abdominalsurgery, hip replacement surgery, knee replacement surgery, or medical patients with severely restricted mobility during acute illness (1.1)• Inpatient treatment of acute DVT with or without pulmonaryembolism (1.2)• Outpatient treatment of acute DVT without pulmonaryembolism. (1.2)• Prophylaxis of ischemic complications of unstable angina andnon-Q-wave myocardial infarction [MI] (1.3)• Treatment of acute ST-segment elevation myocardialinfarction [STEMI] managed medically or with subsequent percutaneous coronary intervention [PCI] (1.4)-------------------DOSAGE AND ADMINISTRATION--------------Indication Standard Regimen (2.1, 2.3) Severe RenalImpairment (2.2)DVT prophylaxis in abdominal surgery 40 mg SC once daily 30 mg SC once daily DVT prophylaxis in knee replacement surgery30 mg SC every 12 hours 30 mg SC once daily DVT prophylaxis in hip replacement surgery 30 mg SC every 12 hours or 40 mg SConce daily30 mg SC once daily DVT prophylaxis in medical patients 40 mg SC once daily 30 mg SC once daily Inpatient treatment of acute DVT with or without pulmonary embolism 1 mg/kg SC every 12 hours or 1.5 mg/kg SC once daily (with warfarin)1 mg/kg SC once daily Outpatient treatment acute DVT without of hours (with warfarin) g SC oncedaily pulmonary embolism 1 mg/kg SC every 12 1 mg/k Unstable angina and g SC once non-Q-wave MI 1 mg/kg SC every 12hours (with aspirin) 1 mg/k daily Acute STEMI in patients <75 years of CI, see 1)] hours with aspirin) by g SC once daily age[For dosing insubsequent P Dosage andAdministration (2.30 mg single IV bolus plus a 1 mg/kg SC dose followed by 1 mg/kg SC every 12 30-mg single IV bolus plus a 1 mg/kgSC dose followed 1 mg/k Acute STEMI in patients ≥75 years of 12 hours (no bolus) daily (no bolus) age0.75 mg/kg SC every 1 mg/kg SC once Do not use as intramuscular injection.For subcutaneous use, do not mix with other injections or fusions. --------------------DOSAGE FORMS AND STRENGTHS-------- • 60 mg/0.6 mL, 80 mg/0.8AINDICATIONS ----------------- i-platelet) oval5.3) arin or other LMWHs (5.6)notMultiple-dose formulations contain benzyl alcohol (5.8) --- adverse reactions (>1%) were bleeding, anemia, rombocytopenia, elevation of serum aminotransferase, diarrhea, ADVERSE REACTIONS, contact nofi-aventis at 1-800-633-1610 or FDA at 1-800-FDA-1088 or /medwatch. in--100mg/mL concentration (3.1):• Prefilled syringes: 30 mg/0.3 mL, 40 mg/0.4 mLGraduated prefilled syringes:mL,100 mg/1 mL• Multiple-dose vial: 300 mg/3 mL 150mg/mL concentration (3.2):• Graduated prefilled syringes: 120 mg/0.8 mL, 150 mg/1 mL------------------------------CONTR• Active major bleeding (4.1)Thrombocytopenia with a positive in vitro test for ant • antibody in the presence of enoxaparin sodium (4.2 Hypersensitivity to enoxaparin sodium (4.3)•• Hypersensitivity to heparin or pork products (4.4)-----------------------WARNINGS AND PRECAUTIONS ----------• Use caution in conditions with increased risk of hemorrhage(5.1)• Obtain hemostasis at the puncture site before sheath rem after percutaneous coronary revascularisation (5.2)• Use caution with concomitant medical conditions (• Use caution in case of history of heparin-inducedthrombocytopenia (5.4)• Monitor thrombocytopenia of any degree closely (5.5) •Do not exchange with hep • Pregnant women with mechanical prosthetic heart valves adequately studied (5.7)•• Periodic blood counts recommended (5.9)-----------------------------ADVERSE REACTIONS ----------------Most common th and nauseaTo report SUSPECTED sa w-----------------------------DRUG INTERACTIONS ----- hich may enhance hemorrhage risk prior to itiation of Lovenox or conduct close clinical and laboratory --------------Discontinue agents w in monitoring (5.9, 7).----------------USE IN SPECIFIC POP ------ULATIONS ------------ patients with• Hepatic Impairment (8.8)• Low-weight patients: Observe for signs of bleeding (8.9)• Severe renal impairment: Adjust dose for creatinine clearance <30 mL/min (2.2)See 17 for PATIENT COUNSELING INFORMATIONRevised: [m/year]WARNIN 1 INDIC ction)2 NGTHSon 4 5 ures ty with Other Heparinswith Mechanical Prosthetic Heart7 CTIONS8 USE IN SPECIFIC POPULATIONS8.1 Pregnancyical Prosthetic Heart Valves ent 11 12 LOGY13 OLOGYlity 14 Acute ardialections or subsections omitted from the full prescribing ation are not listedFULL PRESCRIBING INFORMATION: CONTENTS* G - SPINAL / EPIDURAL HEMATOMAS ATIONS AND USAGEProphylaxis of deep vein thrombosis in patients1.1 undergoing surgery and in medical patients with severely restricted mobility during acute illness Treatment of acute deep vein thrombosis1.2 1.3 Prophylaxis of ischemic complications of unstableangina and non-Q-wave myocardial infar 1.4 Treatment of acute ST-segment Elevation Myocardial Infarction (STEMI DOSAGE AND ADMINISTRATION2.1 Adult dosage 2.2 Renal impairment2.3 Geriatric patients with acute STEMI 2.4 Administration3 3.1 100-mg/mL concentrati DOSAGE FORMS AND STRE 3.2 150-mg/mL concentration CONTRAINDICATIONSWARNINGS AND PRECAUTIONS5.1 Increased risk of Hemorrhage5.2 Percutaneous coronary revascularization proced 5.3 Use of Lovenox with Concomitant Medical Conditions 5.4 History of heparin-induced thrombocytopenia 5.5 ThrombocytopeniaInterchan 5.6 geabili 5.7 Pregnant Women Valves5.8 Benzyl alcohol 5.9 Laboratory tests6 6.1 Clinical StudiesADVERSE REACTIONS6.2 Post-marketing experience DRUG INTERA 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use8.6 Patients with Mechan 8.7 Renal impairment 8.8 Hepatic impairm 8.9 Low-weight Patients 10 OVERDOSAGE DESCRIPTIONCLINICAL PHARMACO 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 PharmacokineticsNONCLINICAL TOXIC 13.1 Carcinogenesis, Mutagenesis, Impairment of Ferti 13.2 Animal ToxicologyICAL TRIALS EX CLIN PERIENCE14.1 Prophylaxis of deep vein thrombosis followingabdominal surgery14.2 Prophylaxis of deep vein thrombosis following Hip orKnee Replacement surgeryProphylaxis of deep vein thr 14.3 ombosis in MedicalPatients with Severely Restricted Mobility during Illness14.4 Treatment of acute deep vein thrombosis with orwithout pulmonary embolism14.5 Prophylaxis of ischemic complications in unstableangina and non-Q-wave myocardial infarction14.6 Treatment of acute ST-segment Elevation Myoc Infarction (STEMI)16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUSELING INFORMATION*S inform12FULL PRESCRIBING INFORMATIONWARNING: SPINAL / EPIDURAL HEMATOMAS3When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, 4patients anticoagulated or scheduled to be anticoagulated with low molecular weight 5heparins or heparinoids for prevention of thromboembolic complications are at risk of 6developing an epidural or spinal hematoma which can result in long-term or permanent 7paralysis.89The risk of these events is increased by the use of indwelling epidural catheters for 10administration of analgesia or by the concomitant use of drugs affecting hemostasis such as 11non steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other 12anticoagulants. The risk also appears to be increased by traumatic or repeated epidural or 13spinal puncture.1415Monitor patients for signs and symptoms of neurological impairment. If neurologic 16compromise is noted, urgent treatment is necessary.1718Consider the potential benefit versus risk before neuraxial intervention in patients 19anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and 20Precautions (5.1) and Drug Interactions (7)].2122232425262728293031323334353637383940414243 1 INDICATIONS AND USAGE1.1Prophylaxis of deep vein thrombosisLovenox is indicated for the prophylaxis of deep vein thrombosis, which may lead to pulmonary embolism:•in patients undergoing abdominal surgery who are at risk for thromboembolic complications [see Clinical Trials Experience 14.1].•in patients undergoing hip replacement surgery, during and following hospitalization.•in patients undergoing knee replacement surgery.•in medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness.1.2Treatment of Acute Deep Vein ThrombosisLovenox is indicated for:•the inpatient treatment of acute deep vein thrombosis with or without pulmonary embolism, when administered in conjunction with warfarin sodium;•the outpatient treatment of acute deep vein thrombosis without pulmonary embolism when administered in conjunction with warfarin sodium.1.3Prophylaxis of Ischemic Complications of Unstable Angina and Non-Q-wave Myocardial InfarctionLovenox is indicated for the prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction, when concurrently administered with aspirin.44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 1.4 Treatment of acute ST- segment Elevation Myocardial Infarction (STEMI)Lovenox has been shown to reduce the rate of the combined endpoint of recurrent myocardial infarction or death in patients with acute STEMI receiving thrombolysis and being managed medically or with Percutaneous Coronary Intervention (PCI).2 DOSAGE AND ADMINISTRATIONAll patients should be evaluated for a bleeding disorder before administration of Lovenox, unless the medication is needed urgently. Since coagulation parameters are unsuitable for monitoring Lovenox activity, routine monitoring of coagulation parameters is not required [see Warnings and Precautions (5.9)].For subcutaneous use, Lovenox should not be mixed with other injections or infusions. For intravenous use (i.e., for treatment of acute STEMI), Lovenox can be mixed with normal saline solution (0.9%) or 5% dextrose in water.Lovenox is not intended for intramuscular administration.2.1 Adult DosageAbdominal Surgery: In patients undergoing abdominal surgery who are at risk for thromboembolic complications, the recommended dose of Lovenox is 40 mg once a day administered by SC injection with the initial dose given 2 hours prior to surgery. The usual duration of administration is 7 to 10 days; up to 12 days administration has been administered in clinical trials. 65 66 67 68 69 70Hip or Knee Replacement Surgery: In patients undergoing hip or knee replacement surgery, the recommended dose of Lovenox is 30 mg every 12 hours administered by SC injection. Provided that hemostasis has been established, the initial dose should be given 12 to 24 hours after surgery. For hip replacement surgery, a dose of 40 mg once a day SC, given initially 12 (±3) hours prior to surgery, may be considered. Following the initial phase of thromboprophylaxis in hip replacement surgery patients, it is recommended that continued prophylaxis with Lovenox 40 mg once a day is administered by SC injection for 3 weeks. The usual duration of administration is 7 to 10 days; up to 14 days administration has been administered in clinical trials. 71 72 73 74 75 76 77 78 79 80Medical Patients During Acute Illness: In medical patients at risk for thromboembolic complications due to severely restricted mobility during acute illness, the recommended dose of Lovenox is 40 mg once a day administered by SC injection. The usual duration of administration is 6 to 11 days; up to 14 days of Lovenox has been administered in the controlled clinical trial. 81 82 83 84 85 86Treatment of Deep Vein Thrombosis With or Without Pulmonary Embolism: In outpatient treatment , patients with acute deep vein thrombosis without pulmonary embolism who can be 87 88treated at home, the recommended dose of Lovenox is 1 mg/kg every 12 hours administered SC. In inpatient (hospital) treatment , patients with acute deep vein thrombosis with pulmonary embolism or patients with acute deep vein thrombosis without pulmonary embolism (who are not candidates for outpatient treatment), the recommended dose of Lovenox is 1 mg/kg every 12 hours administered SC or 1.5 mg/kg once a day administered SC at the same time every day. In both outpatient and inpatient (hospital) treatments, warfarin sodium therapy should be initiated when appropriate (usually within 72 hours of Lovenox). Lovenox should be continued for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been achieved (International Normalization Ratio 2.0 to 3.0). The average duration of administration is 7 days; up to 17 days of Lovenox administration has been administered in controlled clinical trials. 89 90 91 92 93 94 95 96 97 98 99 100Unstable Angina and Non-Q-Wave Myocardial Infarction: In patients with unstable angina or non-Q-wave myocardial infarction, the recommended dose of Lovenox is 1 mg/kg administered SC every 12 hours in conjunction with oral aspirin therapy (100 to 325 mg once daily). Treatment with Lovenox should be prescribed for a minimum of 2 days and continued until clinical stabilization. The usual duration of treatment is 2 to 8 days; up to 12.5 days of Lovenox has been administered in clinical trials. [See Warnings and Precautions (5.2) and Clinical Trials Experience (14.5)]. 101 102 103 104 105 106 107 108Treatment of acute ST-segment Elevation Myocardial Infarction: In patients with acute ST-segment Elevation Myocardial Infarction, the recommended dose of Lovenox is a single IV bolus of 30 mg plus a 1 mg/kg SC dose followed by 1 mg/kg administered SC every 12 hours (maximum 100 mg for the first two doses only, followed by 1 mg/kg dosing for the remaining doses). Dosage adjustments are recommended in patients ≥75 years of age [see Dosage and Administration (2.3)]. 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132When administered in conjunction with a thrombolytic (fibrin-specific or non-fibrin specific), Lovenox should be given between 15 minutes before and 30 minutes after the start of fibrinolytic therapy. All patients should receive acetylsalicylic acid (ASA) as soon as they are identified as having STEMI and maintained with 75 to 325 mg once daily unless contraindicated. In the pivotal clinical study, the Lovenox treatment duration was 8 days or until hospital discharge, whichever came first. An optimal duration of treatment is not known, but it is likely to be longer than 8 days.For patients managed with Percutaneous Coronary Intervention (PCI): If the last Lovenox SC administration was given less than 8 hours before balloon inflation, no additional dosing is needed. If the last Lovenox SC administration was given more than 8 hours before balloon inflation, an IV bolus of 0.3 mg/kg of Lovenox should be administered [see Warnings and Precautions (5.2)].2.2 Renal ImpairmentAlthough no dose adjustment is recommended in patients with moderate (creatinine clearance 30-50 mL/min) and mild (creatinine clearance 50-80 mL/min) renal impairment, all such patients should be observed carefully for signs and symptoms of bleeding.133 134 135 136 137 The recommended prophylaxis and treatment dosage regimens for patients with severe renal impairment (creatinine clearance <30 mL/min) are described in Table 1 [see Use in SpecificPopulations (8.6) and Clinical Pharmacology (12.3)].Table 1Dosage Regimens for Patients with Severe Renal Impairment(creatinine clearance <30mL/minute)Indication DosageRegimen Prophylaxis in abdominal surgery 30 mg administered SC once dailyProphylaxis in hip or knee replacement surgery 30 mg administered SC once dailyProphylaxis in medical patients during acute illness 30 mg administered SC once dailyInpatient treatment of acute deep vein thrombosis withor without pulmonary embolism, when administered inconjunction with warfarin sodium1 mg/kg administered SC once dailyOutpatient treatment of acute deep vein thrombosiswithout pulmonary embolism, when administered inconjunction with warfarin sodium1 mg/kg administered SC once dailyProphylaxis of ischemic complications of unstableangina and non-Q-wave myocardial infarction, whenconcurrently administered with aspirin1 mg/kg administered SC once dailyTreatment of acute ST-segment Elevation MyocardialInfarction in patients <75 years of age30 mg single IV bolus plus a 1 mg/kgSC dose followed by 1 mg/kgadministered SC once daily.Treatment of acute ST-segment Elevation MyocardialInfarction in geriatric patients ≥75 years of age1 mg/kg administered SC once daily(no initial bolus)138 139140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 2.3 Geriatric patients with acute ST-Elevation Myocardial InfarctionFor treatment of acute ST-segment Elevation Myocardial Infarction in geriatric patients ≥75 years of age, do not use an initial IV bolus. Initiate dosing with 0.75 mg/kg SC every 12 hours (maximum 75 mg for the first two doses only, followed by 0.75 mg/kg dosing for the remaining doses)[see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)].No dose adjustment is necessary for other indications in geriatric patients unless kidney function is impaired [see Dosage and Administration (2.2)].2.4 AdministrationLovenox is a clear, colorless to pale yellow sterile solution, and as with other parenteral drug products, should be inspected visually for particulate matter and discoloration prior to administration.The use of a tuberculin syringe or equivalent is recommended when using Lovenox multiple-dose vials to assure withdrawal of the appropriate volume of drug.156157 158 159 160 161 162 163 Lovenox must not be administered by intramuscular injection. Lovenox is intended for use under the guidance of a physician.For subcutaneous administration, patients may self-inject only if their physicians determine that it is appropriate and with medical follow-up, as necessary. Proper training in subcutaneous injection technique (with or without the assistance of an injection device) should be provided. Subcutaneous Injection Technique: Patients should be lying down and Lovenox administered by deep SC injection. To avoid the loss of drug when using the 30 and 40 mg prefilled syringes, do not expel the air bubble from the syringe before the injection. Administration should be alternated between the left and right anterolateral and left and right posterolateral abdominal wall. The whole length of the needle should be introduced into a skin fold held between the thumb and forefinger; the skin fold should be held throughout the injection. To minimize bruising, do not rub the injection site after completion of the injection.164 165 166 167 168 169 170171 172 173 174 175 176 177 178 Lovenox prefilled syringes and graduated prefilled syringes are available with a system that shields the needle after injection.1. Remove the needle shield by pulling it straight off the syringe (see Figure A). If adjusting the dose is required, the dose adjustment must be done prior to injecting the prescribed dose to the patient.Figure A179 180181 182 183 184 2. Inject using standard technique, pushing the plunger to the bottom of the syringe (see FigureB).Figure B185 186187 188 3. Remove the syringe from the injection site keeping your finger on the plunger rod (see FigureC).189Figure C190 191 192 193 194 195 196198199 200 201 2024. Orient the needle away from you and others, and activate the safety system by firmly pushing the plunger rod. The protective sleeve will automatically cover the needle and an audible “click” will be heard to confirm shield activation (see Figure D).Figure D1975. Immediately dispose of the syringe in the nearest sharps container (see Figure E).Figure E203 204 205 206 207 208 209 210 211 212 213NOTE:• The safety system can only be activated once the syringe has been emptied.• Activation of the safety system must be done only after removing the needle from the patient’s skin.• Do not replace the needle shield after injection. • The safety system should not be sterilized.Activation of the safety system may cause minimal splatter of fluid. For optimal safety activate the system while orienting it downwards away from yourself and others.Intravenous (Bolus) Injection Technique: For intravenous injection, the multiple-dose vial should be used. Lovenox should be administered through an intravenous line. Lovenox should not be mixed or co-administered with other medications. To avoid the possible mixture of Lovenox with other drugs, the intravenous access chosen should be flushed with a sufficient amount of saline or dextrose solution prior to and following the intravenous bolus administration of Lovenox to clear the port of drug. Lovenox may be safely administered with normal saline solution (0.9%) or 5% dextrose in water.214 215 216 217 218 219 220 221222223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 3 DOSAGE FORMS AND STRENGTHSLovenox is available in two concentrations:3.1 100 mg per mL-Prefilled Syringes 30 mg / 0.3 mL, 40 mg / 0.4 mL-Graduated Prefilled Syringes 60 mg / 0.6 mL, 80 mg / 0.8 mL, 100 mg / 1 mL-Multiple-Dose Vials 300 mg / 3 mL3.2 150 mg per mL-Graduated Prefilled Syringes 120 mg / 0.8 mL, 150 mg / 1 mL4 CONTRAINDICATIONS•Active major bleeding.•Thrombocytopenia associated with a positive in vitro test for anti-platelet antibody in the presence of enoxaparin sodium.•Known hypersensitivity to enoxaparin sodium (e.g., pruritus, urticaria, anaphylactoid reactions) [see Adverse Reactions (6.2)].•Known hypersensitivity to heparin or pork products.•Known hypersensitivity to benzyl alcohol (which is in only the multi-dose formulation of Lovenox).5 WARNINGS AND PRECAUTIONS5.1 Increased Risk of HemorrhageCases of epidural or spinal hematomas have been reported with the associated use of Lovenox and spinal/epidural anesthesia or spinal puncture resulting in long-term or permanent paralysis. The risk of these events is higher with the use of post-operative indwelling epidural catheters or by the concomitant use of additional drugs affecting hemostasis such as NSAIDs[see boxed Warning, Adverse Reactions (6.2) and Drug Interactions (7)].Lovenox should be used with extreme caution in conditions with increased risk of hemorrhage, such as bacterial endocarditis, congenital or acquired bleeding disorders, active ulcerative and angiodysplastic gastrointestinal disease, hemorrhagic stroke, or shortly after brain, spinal, or ophthalmological surgery, or in patients treated concomitantly with platelet inhibitors.Major hemorrhages including retroperitoneal and intracranial bleeding have been reported. Some of these cases have been fatal.Bleeding can occur at any site during therapy with Lovenox. An unexplained fall in hematocrit or blood pressure should lead to a search for a bleeding site.5.2Percutaneous coronary revascularization proceduresTo minimize the risk of bleeding following the vascular instrumentation during the treatment of unstable angina, non-Q-wave myocardial infarction and acute ST-segment elevation myocardial267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 infarction, adhere precisely to the intervals recommended between Lovenox doses. It is important to achieve hemostasis at the puncture site after PCI. In case a closure device is used, the sheath can be removed immediately. If a manual compression method is used, sheath should be removed 6 hours after the last IV/SC Lovenox. If the treatment with enoxaparin sodium is to be continued, the next scheduled dose should be given no sooner than 6 to 8 hours after sheath removal. The site of the procedure should be observed for signs of bleeding or hematoma formation [see Dosage and Administration (2.1)].5.3 Use of Lovenox with Concomitant Medical ConditionsLovenox should be used with care in patients with a bleeding diathesis, uncontrolled arterial hypertension or a history of recent gastrointestinal ulceration, diabetic retinopathy, and hemorrhage.5.4 History of Heparin-induced ThrombocytopeniaLovenox should be used with extreme caution in patients with a history of heparin-induced thrombocytopenia.5.5ThrombocytopeniaThrombocytopenia can occur with the administration of Lovenox.Moderate thrombocytopenia (platelet counts between 100,000/mm3 and 50,000/mm3) occurred at a rate of1.3% in patients given Lovenox, 1.2% in patients given heparin, and 0.7% in patients given placebo in clinical trials.Platelet counts less than 50,000/mm3 occurred at a rate of 0.1% in patients given Lovenox, in 0.2% of patients given heparin, and 0.4% of patients given placebo in the same trials. Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm3, Lovenox should be discontinued. Cases of heparin-induced thrombocytopenia with thrombosis have also been observed in clinical practice. Some of these cases were complicated by organ infarction, limb ischemia, or death [see Warnings and Precautions (5.4)].5.6 Interchangeability with Other HeparinsLovenox cannot be used interchangeably (unit for unit) with heparin or other low molecular weight heparins as they differ in manufacturing process, molecular weight distribution, anti-Xa and anti-IIa activities, units, and dosage. Each of these medicines has its own instructions for use.5.7 Pregnant Women with Mechanical Prosthetic Heart ValvesThe use of Lovenox for thromboprophylaxis in pregnant women with mechanical prosthetic heart valves has not been adequately studied. In a clinical study of pregnant women with mechanical prosthetic heart valves given enoxaparin (1 mg/kg twice daily) to reduce the risk of thromboembolism, 2 of 8 women developed clots resulting in blockage of the valve and leading to maternal and fetal death. Although a causal relationship has not been established these deaths may have been due to therapeutic failure or inadequate anticoagulation. No patients in the。

依诺肝素外科课件

除且患者不需卧床休息时 • 矫形外科手术中，连续三依诺周肝素外，科 4000AxaIU（0.4ml）qd,ih
注意事项
如出现过量情况，可用盐酸/硫酸鱼精蛋白中和本品
• 8小时以内100AxaIU国际单位需给予100单位鱼精蛋白 • 超过8小时或再次给药100AxaIU国际单位需给予50单位鱼精
蛋白 • 超过12小时不需要给予鱼精蛋白
（0.2ml）或4000AxaIU（0.4ml）qd,ih • 普外手术中，应于术前2小时给予第一次皮下注射。 • 有高度血栓形成倾向时（如矫形外科手术），推荐术前12小时
开始给药， 4000AxaIU（0.4ml）qd,ih
• 一般持续治疗7至10天 • 如有静脉栓塞倾向时，应延长治疗至静脉血栓栓塞危险消
目录
疾病知识回顾依诺肝素产品介绍
依诺肝素外科
低分子肝素通过与抗凝血酶结合使凝血因子Xa和凝血因子IIa失活而起到抗凝作用
……
AATTIIIIII IIa
低分子肝素
使Xa失活的活性更强，而且对凝血因子IIa的作用较小,依诺肝素抗Xa/抗IIa比=3~4:1
ATIII IIa
低分子肝素（普通肝素）
好的低分子肝素的特征
• 抗Xa/抗IIa比值高
• 药代动力学特点
•生物利用度高 •血浆抗Xa因子活性 •半衰期长 •达峰时间短
• 不同临床情况下应用的可靠性
•在足够多的患者中进依诺行肝素了外科研究
欧洲药典显示低分子肝素依诺肝素的抗Xa/IIa 比值最高：4.1
Enoxaparin1 Nadroparin1 Reviparin2 Dalteparin1 Certoparin1 Tinzaparin1 UFH3
使凝血因子IIa失活至少需

2023年关于“依诺肝素钠”解析

5、有任何作用，须将正在使用的药物明告医生或药师。不推荐联合使用下述药物（合用可增加出血倾向）：用于解热镇痛剂量的乙酰水杨酸（及其衍生物），非甾体消炎药（全身用药），酮洛酸，右旋糖酐40（肠道外使用）。当本品与下列药物共同使用时应注意：口服抗凝剂，溶栓剂，用于抗血小板凝集剂量的乙酰水杨酸（用于治疗不稳定性心绞痛及非Q波心肌梗死），糖皮质激素（全身用药）。
谢谢大家
注意事项
1、特别警告：禁止肌肉内给药；远离儿童放置。
2、由于分子量，抗Ⅹa活性及剂量不同，不同的低分子肝素不可相互替代使用。应特别注意并遵守相应产品的使用方法。当有肝素诱导的血小板减少症病史的患者使用本品时，应特别小心。
3、在蛛网膜下腔/硬膜外麻醉：
（1）与抗凝剂相同，在蛛网膜下腔/硬膜外麻醉中，同时使用低分子肝素，极少有椎管内血肿导致永久性瘫痪的报导。当术后保留硬膜外导管时，可能增大出现上述症状的危险。须进行神经学监测。
2023年关于“依诺肝素钠”解析
定义
依诺肝素钠，西药名。常用剂型有注射剂。为抗凝血药。用于预防静脉栓塞性疾病，尤其与某些手术有关的栓塞；也用于血液透析体外循环中，防止血栓形成等。
适应症
1、预防静脉栓塞性疾病（防止静脉内血栓形成）尤其与某些手术有关的栓塞。 2、用于血液透析体外循环中，防止血栓形成。 3、治疗深静脉血栓形成。 4、治疗急性不稳定性心绞痛及非Q波心肌梗死，与阿司匹林同用。
药理作用
本品具有高抗Ⅹa（100I.U./mg）活性和较低抗Ⅱa或抗凝血酶（28I.U./mg左右）活性的低分子肝素。在不同适应症所需的剂量下，本品并不延长出血时间。在预防剂量时，本品对APTT没有明显改变。既不影响血小板聚集，也不影响纤维蛋白原与血小板的结合。

科内会

有效期
24个月
贮藏
25℃以下储存
包装
预填充式注射器 2支/小包装（盒） 360支/大包装（箱）
31
静平产品特性
32
总结
不同的低分子肝素是不同的不同的药物不同的依诺肝素是适应症最全面，全球研究最充分、循证医学支持最多的低依诺肝素分子肝素静平抗凝效果稳定，出血风险小，是效价比最高的依诺肝素
经过酶解和提纯后产生
肝素的原料提取于猪小肠粘膜
6
低分子肝素的生产
肝素通过化学方法降解，生成分子量较小的低分子肝素不同的生产方法产生不同的低分子肝素
方法
亚硝酸降解过氧化氢降解 β-消除降解肝素酶降解
优点
工艺简单，成本低硫酸化程度较高，成本适中硫酸化程度较高硫酸化程度较高
缺点
可能引入异物,硫酸化程度低可能引入异物稳定性较差稳定性较差，成本较高
22
静平 – 分子量更均一的依诺肝素
Data on file
23
静平 – 抗凝效果更稳定的依诺肝素
Data on file
24
静平 – 价格最优的依诺肝素
25
静平 – 先天优势
Xa/Ⅱa>4:1，高于其它种类的低分子肝素分子量分布好，平均分子量4500D 出血风险小
26
静平 – 后天优势
治疗已形成的静脉血栓预防血液透析时体外循环中血栓的形成治疗不稳定性心绞痛和非Q波心梗
17
静平的药物动力学
皮下注射后完全吸收，达到血浆平均最大抗Xa活性为3小时皮下给药抗Xa活性清除半衰期约为4-4.4小时，大部分在肝脏代谢失活，部分以活性形式经肾脏清除推荐剂量下为线性药动学特性，抗凝作用与剂量相关

依诺肝素钠学术交流(1)

依诺肝素钠学术交流(1)依诺肝素钠是一种常用的抗凝药物，其作用是预防血栓的形成，已经广泛应用于手术后的预防、心脑血管疾病、肺栓塞等领域。

随着研究的逐渐深入，依诺肝素钠的应用也得到了不断优化和改进，为医学研究提供了新的思路和方法，成为国内外医学学术交流的重要议题。

以下针对“依诺肝素钠学术交流”进行了探讨：一、依诺肝素钠的药理作用依诺肝素钠是一种低分子量肝素，其药理作用机制是通过抑制血液凝固过程中的凝血酶活性，从而阻止血栓的形成。

其特点是具有较高的生物利用度和较长的半衰期，可以长效地抑制血栓的形成，从而避免血栓造成的各种危害。

二、依诺肝素钠的临床应用依诺肝素钠的临床应用主要涉及到以下几个领域：1. 全身性疾病的预防。

依诺肝素钠可以预防心脑血管疾病、肺栓塞等全身性疾病的发生和进展。

2. 外科手术后的预防。

依诺肝素钠可以预防外科手术后的血栓形成，避免术后并发症的发生。

3. 止血管理。

依诺肝素钠可以在出血时迅速停止凝血，预防出血并发症的发生。

三、依诺肝素钠的不良反应依诺肝素钠作为一种药物，其不良反应也是需要重视的。

常见的不良反应包括出血、血小板减少、过敏反应等。

使用过程中需要密切观察患者的情况，及时发现并防止不良反应的发生。

四、依诺肝素钠的研究进展当前，依诺肝素钠的研究热点主要涉及到以下几个方面：1. 依诺肝素钠的抗凝效果。

近年来，研究人员通过比较依诺肝素钠与其他抗凝药物的效果，探索依诺肝素钠在抗凝治疗上的优势和不足。

2. 依诺肝素钠的药代动力学。

药代动力学的研究是了解依诺肝素钠在人体内代谢和运营情况的重要手段，通过药代动力学的研究，可以更好地规范依诺肝素钠的使用方法。

3. 依诺肝素钠的制备与开发。

依诺肝素钠作为一种药物，其制备和开发过程也是医学研究的重要领域。

近年来，研究人员通过不断改进制备方法和开发新的制剂，进一步提高了依诺肝素钠的药效和安全性。

综上所述，“依诺肝素钠学术交流”既是医学前沿研究的重要议题，同时也关系到医疗工作者科学合理运用依诺肝素钠的临床治疗技巧，具有重要的实践意义。

依诺肝素钠学术交流

6100
4~8ppm
＞20000
生产原料
• 降解方法和精确的制造过程决定不同的分子量分布，依诺肝素由于工艺的特点不引入亚硝酸化合物N-NO残留，临床使用安全性更佳。
1. Linhardt RJ, Gunay NS. Semin Thromb Hemost 1999;25(suppl 3):5-16 2. R.J.Linhardt,D.Loga Nathan,A.Al-Hakim et al 3. Oligosaccharide mapping of low Molecular Weight Heparins:Structure and activity differences. 4. J.Med. Chem;1990;33;1639-1645
依诺肝素钠注射液等效性研究结果
几何均值及比值 R（受试制剂） T（参比制剂） T/R(%)
CI‒90(%) （90%可信区间）
lower
Upper
Anti-Xamax AUEC 1ast AUEC inf Anti-lla max AUEC 1ast AUEC inf
0.763 5.821 6.331 0.361 1.290 1.400
依诺肝素抗Xa因子活性水平和达峰时间
均优于其他两种低分子肝素。
相应剂量（1000IU）下血浆抗 Xa 活性
AUC (IU/ml)
Anti-Xa 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2
0
依诺肝素
Enoxaparin
那曲肝素
Nadroparin
达肝素
Dalteparin
抗Xa活性达峰时间（均值±标准差）
1. JAMA.1993;270:1672 2. Chest 1998;114(5 suppl):561S-78S 3. Int Angiol.2006;25:101-61 4. WHO Working Group on Biological Standardization of Unfractionated Heparin, WHO Headquarters, Geneva,Switzerland,7-8 September,1999

依诺肝素钠学术交流

依诺肝素抗Xa因子活性水平和达峰时间
均优于其他两种低分子肝素。
相应剂量（1000IU）下血浆抗 Xa 活性
AUC (IU/ml)
Anti-Xa 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2
0
依诺肝素
Enoxaparin
那曲肝素
Nadroparin
达肝素
Dalteparin
抗Xa活性达峰时间（均值±标准差）
0.607 3.613 3.841 0.335 1.179 1.254
99.47 98.88 98.88 98.20 103.65 101.57
96.84 95.19 94.76 95.73 99.24 96.69
100.97 102.70 104.42 100.74 108.26 106.71
Power
1. 外科手术中预防血栓栓塞类疾病
中度风险（如腹部手术）
4000AXaIU，qd，皮下注射，持续7~10天
普外手术
术前2小时进行第一次皮下注射，持续7~10天
高度形成风险（如矫形手术）术前12小时开始给药，连续使用3周
2. 在内科治疗患者中预防血栓栓塞类疾病，4000AXaIU，qd，皮下注射，最少6天直至不再卧床，最长14天
注射用依诺肝素钠与参比制剂依诺肝素钠注射液在安全性与耐受性方面无明显差异
发生周期
受试者试验号
第一周期
001
001
003
004 第二周期
007
016
020
010
012
实验室检查 013
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依诺肝素钠治疗慢性阻塞性肺疾病血栓前状态的临床观察

依诺肝素钠治疗慢性阻塞性肺疾病血栓前状态的临床观察吕丽波
【期刊名称】《齐齐哈尔医学院学报》
【年(卷),期】2013(034)022
【摘要】目的观察依诺肝素钠治疗慢性阻塞性肺疾病(COPD)血栓前状态(prothrombotic state,PTS)的疗效.方法分析54例COPD伴血栓前状态患者的临床治疗,随机分为低分子肝素组和常规组两组,每组27例.低分子肝素组在常规治疗基础上加用依诺肝素钠4000 IU,1次/d皮下注射;两组疗程均为10d.比较两组治疗前后纤维蛋白原、D-二聚体水平、肺功能、指脉氧变化及症状缓解时间.结果依诺肝素钠组治疗后症状缓解时间、指脉氧及纤维蛋白原、D-二聚体水平变化改善优于常规组(P＜0.05).治疗后肺功能两组未见差别(P＞0.05).并且无出血、药物过敏等副作用.结论依诺肝素钠联用治疗COPD血栓前状态,能够迅速缓解症状、缩短住院时间、预防血栓,有效、方便、安全,没有增加风险,可以常规使用.
【总页数】2页(P3330-3331)
【作者】吕丽波
【作者单位】215004江苏,苏州金阊区人民医院呼吸科
【正文语种】中文
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