WO2021160144A1 - 阿哌沙班注射剂用于预防或者治疗血栓栓塞的方法 - Google Patents

阿哌沙班注射剂用于预防或者治疗血栓栓塞的方法 Download PDF

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WO2021160144A1
WO2021160144A1 PCT/CN2021/076419 CN2021076419W WO2021160144A1 WO 2021160144 A1 WO2021160144 A1 WO 2021160144A1 CN 2021076419 W CN2021076419 W CN 2021076419W WO 2021160144 A1 WO2021160144 A1 WO 2021160144A1
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apixaban
injection
preferably less
thromboembolism
povidone
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French (fr)
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刘伊娜
董平
袁开红
孙琼
刘廷
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Jiangsu Hengrui Medicine Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents

Definitions

  • the present disclosure belongs to the field of medicine, and relates to a method for preventing or treating thromboembolism with apixaban injection.
  • Thromboembolism is the most serious complication of nephrotic syndrome (NS). Thrombosis is due to clotting of blood in a blood vessel leading to thrombosis and obstruction of blood flow. Thrombosis may form in arteries or veins. Embolism occurs when all or part of the thrombus ruptures and flows downstream in the circulation, thereby preventing the flow to vital organs. These phenomena are collectively referred to as thromboembolism. As early as 1840, renal vein thrombosis was considered the first thromboembolism associated with NS. Since then, people have realized that NS-related thromboembolism can basically be seen in any major blood vessel. Although modern anticoagulation and thrombolytic therapy can reduce the risk of thrombosis-related death, thromboembolism is still a common complication of NS.
  • Apixaban (trade name Eliquis) is a selective activation of factor Xa inhibitor. Bristol-Myers Squibb and Pfizer jointly developed a tablet with the trade name Eliquis, which was approved for marketing in the European Union in March 2011 In December 2012, the FDA approved the drug to be marketed in the United States. Subsequently, the drug was subsequently marketed in other regions and countries. It was approved in China for the prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery. ).
  • VTE venous thromboembolism
  • the present disclosure provides a method for preventing or treating thromboembolism of patients with nephrotic syndrome with apixaban for injection, which comprises injecting and administering an effective amount of apixaban to the patient.
  • the present disclosure provides a method for preventing or treating thromboembolism in patients with nephrotic syndrome, including administering to the patient an effective amount of apixaban for treatment or prevention, wherein the apixaban is administered in the form of injection.
  • the nephrotic syndrome described in the present disclosure is primary or secondary nephrotic syndrome.
  • the nephrotic syndrome may be selected from but not limited to membranous nephropathy, mesangial proliferative glomerulonephritis, IgA nephropathy, minimal change nephropathy, focal segmental glomerulosclerosis, allergy Purpura nephritis, renal amyloidosis, lupus nephritis, diabetic nephropathy, myeloma nephropathy, etc.
  • the thromboembolism of the nephrotic syndrome patient is venous thromboembolism.
  • the thromboembolism of the nephrotic syndrome patient is arterial thromboembolism.
  • the thromboembolism of the nephrotic syndrome patient may be selected from but not limited to deep vein thrombosis, renal vein thrombosis, pulmonary embolism and the like.
  • the thromboembolism refers to venous thromboembolism in patients with nephrotic syndrome.
  • the patients with nephrotic syndrome refer to patients with nephrotic syndrome with plasma albumin ⁇ 30g/L or ⁇ 25g/L, 24-hour urine protein quantification>3.0g.
  • apixaban injection is administered to the patient by subcutaneous injection.
  • the apixaban injection contains apixaban nanoparticles and a surface stabilizer.
  • the average particle diameter D of apixaban nanoparticles 2000nm may be less than 50, preferably less than 1000nm, and more preferably less than 500 nm, more preferably less than 200 nm, more preferably less than of 170 nm, more preferably less than 160nm, most preferably less than 150nm.
  • the apixaban injection containing apixaban nanoparticles and a surface stabilizer may also contain a sedimentation inhibitor.
  • the sedimentation inhibitor inhibits the sedimentation or aggregation of nanoparticles within a certain period of time.
  • apixaban injection is formed after reconstitution of a lyophilized pharmaceutical composition.
  • a pharmaceutical composition containing a liquid medium can be obtained, and the liquid medium can be selected from water, saline solution, safflower seed oil, ethanol, and tert-butyl.
  • the liquid medium can be selected from water, saline solution, safflower seed oil, ethanol, and tert-butyl.
  • the content of apixaban nanoparticles can be selected from 0.1-100 mg/mL, preferably 0.5-100 mg/mL, more preferably 1-100 mg/mL, most preferably 2-10 mg/mL (for example 2.5mg/mL).
  • apixaban injection is a pharmaceutical composition comprising a liquid medium, which may be selected from water, saline solution, safflower seed oil, ethanol, tert-butanol, hexane, and ethylene glycol, One or more of water, saline solution and safflower seed oil is preferred, and water is most preferred.
  • the content of apixaban nanoparticles can be selected from 0.1-100 mg/mL, preferably 0.5-100 mg/mL, more preferably 1-100 mg/mL, most preferably 2-10 mg/mL (for example 2.5mg/mL or 5mg/mL).
  • the apixaban injection contains apixaban nanoparticles, povidone, and sodium deoxycholate.
  • the apixaban injection contains apixaban nanoparticles, povidone, sodium deoxycholate, and mannitol.
  • the apixaban injection contains apixaban nanoparticles, povidone, sodium deoxycholate and mannitol, and the weight-to-volume ratio of apixaban nanoparticles is preferably 0.1-1%, and more preferably 0.1-0.5% (such as 0.25% or 0.5%); the weight-volume ratio of povidone is preferably 0.1-5%, more preferably 0.1-1% (such as 0.24%, 0.575% or 0.525%); sodium deoxycholate The weight-volume ratio is preferably 0.1-3%, more preferably 0.1-0.5% (such as 0.12%, 0.2875% or 0.25%); the weight-volume ratio of mannitol is preferably 1-10%, and more preferably 2-7% (such as 2.375 % Or 5.32%).
  • the weight ratio of apixaban nanoparticles: povidone: sodium deoxycholate in apixaban injection is 10:2:1, and preferably contains 10% apixaban nanoparticles in a weight-to-volume ratio.
  • the apixaban injection comprises 0.5% apixaban nanoparticles, 0.575% povidone, 0.2875% sodium deoxycholate, and 2.375% mannitol in a weight-to-volume ratio.
  • the apixaban injection contains 0.25% apixaban nanoparticles, 0.525% povidone, 0.25% sodium deoxycholate, and 5.32% mannitol in a weight-to-volume ratio.
  • the apixaban injection comprises 0.25% apixaban, 0.24% povidone K17, 0.12% sodium deoxycholate, and 5.32% mannitol in a weight-to-volume ratio.
  • apixaban injection contains 0.5% apixaban, 0.24% povidone K17, 0.12% sodium deoxycholate, and 2%-7% mannitol in a weight-to-volume ratio.
  • the content of apixaban nanoparticles in a unit dose of apixaban injection may range from 2.0 mg to 5.0 mg, preferably 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0mg.
  • the average particle size of apixaban nanoparticles may be less than 500nm, preferably less than 300nm, more preferably less than 200nm, more preferably less than 170nm, more preferably less than 160nm, most preferably less than 150nm .
  • the PDI of apixaban nanoparticles may be less than 0.5, preferably less than 0.3, and most preferably less than 0.2.
  • apixaban injections, apixaban nanoparticles D 50 may be less than 500 nm, preferably less than 300 nm, more preferably less than 200 nm, most preferably less than 170nm.
  • the apixaban injection of the present disclosure is particularly suitable for subcutaneous injection administration.
  • the apixaban injection of the present disclosure has high bioavailability after subcutaneous injection, stable drug-time curve, and better safety and effectiveness.
  • the apixaban injection of the present disclosure is suitable for administration once a day, twice a day or once every two days.
  • the dosage of apixaban of the present disclosure may be selected from 1-10 mg, preferably 2-5 mg, more preferably 2 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3 mg, 3.25 mg, 3.5 mg, 3.75 mg, 4.0 mg, 4.25mg, 4.5mg, 4.75mg or 5.0mg.
  • the administration cycle of apixaban injection of the present disclosure may be selected from 2 days, 3 days, 4 days, 5 days, 7 days, 10 days, 12 days, 14 days, 15 days, 21 days , 28 days, 35 days, 42 days, 49 days, 56 days, 2 months, 3 months, 4 months, 5 months or 6 months.
  • the "effective amount” or “therapeutically effective amount” in the present disclosure includes an amount sufficient to improve or prevent the symptoms or conditions of a medical disorder.
  • An effective amount also means an amount sufficient to allow or facilitate diagnosis.
  • the effective amount for a particular patient or veterinary subject can vary depending on factors such as the condition to be treated, the patient's general health, the method of administration and dosage, and the severity of side effects.
  • the effective amount can be the maximum dose or dosing schedule that avoids significant side effects or toxic effects.
  • the "weight-to-volume ratio" mentioned in the present disclosure refers to the weight (unit g) of the component contained in every 100 mL of the liquid system, that is, g/100 mL.
  • D 50 refers to the particle size value when the light energy of a sample is accumulated to 50%.
  • D 10 and D 90 is analogous to D 50 .
  • Preparation method Dissolve the prescribed amount of surface stabilizer in water, add the apixaban raw material, stir to make the dispersion uniform, add the grinding beads and stir to make the dispersion uniform, grind on a ball mill for 4 hours to prepare apixaban nanoparticle suspension liquid.
  • the average particle size of the apixaban nanoparticle suspension of the present invention is between 100-500 nm, and the PDI is less than 0.5, and the particle size and distribution results of the drug are better.
  • Preparation method Recipe (4) Apixaban nanoparticle suspension is 2.5% mannitol, 2.5% glycerol aqueous solution, 10% sucrose aqueous solution, 2.5% mannitol + 0.5% povidone + 0.25% deoxygenated
  • the sodium cholate aqueous solution was diluted to apixaban concentration of 5mg/mL, and the particle size and distribution of the nanoparticles in the three dilutions were measured; the dilutions were stored at 2-8°C for 4 days, and the three dilutions were measured.
  • the particle size and distribution of the medium nano-particles; or the diluent is directly freeze-dried, and the particle size and distribution of the nano-particles after the three diluent formulations are lyophilized are measured.
  • the prescription (5) apixaban nanoparticle suspension was diluted with 5.6% mannitol + 0.5% povidone + 0.2368% sodium deoxycholate aqueous solution to a concentration of 2.5 mg/mL of apixaban, and the results were measured in After grinding, before freeze-drying, store at 2-8°C for 24h, the size and distribution of nano-particles after freeze-drying (remark: the nano-particle suspension of prescription (5) is diluted and sterilized by filtration with 0.22 micron filter element. Then freeze-dry).
  • the apixaban nanoparticle suspension of prescription (4) was diluted with an aqueous solution containing 2.5% mannitol + 0.5% povidone + 0.25% sodium deoxycholate, and the lyophilized formulation was heated at 2-8°C. , 25°C/60%RH and 40°C/75%RH conditions, after re-dissolving in water, check the particle size distribution, content and related substances, and check the stability. See Table 3 (Batch 1) for details.
  • the apixaban nanoparticle suspension of prescription (5) was diluted with an aqueous solution containing 5.6% mannitol + 0.5% povidone + 0.2368% sodium deoxycholate, and then the lyophilized preparation was heated at 25°C/60°C.
  • apixaban nanoparticle suspension of prescription (5) is diluted with an aqueous solution containing 5.6% mannitol + 0.5% povidone + 0.2368% sodium deoxycholate, lyophilized, and reconstituted with water to obtain apixaban 2.5mg/mL injection, 1mL was subcutaneously administered to 3 subjects, and the plasma drug concentration is shown in Table 5:
  • prescription (8) is that the formula of the diluent is 0.2% povidone K17, 0.1% sodium deoxycholate, 5.6% mannitol, and the balance is water.
  • the lyophilized preparation contains 0.25% apixaban, 0.24% povidone K17, 0.12% sodium deoxycholate, and 5.32% mannitol.
  • prescription (9) The difference between prescription (9) and prescription (5) is that the formula of the diluent is 0.156% povidone K17, 0.078% sodium deoxycholate, 5.6% mannitol, and the balance is water; the diluent is used to make the prescription (4 ) Dilute to apixaban concentration of 5.0mg/mL.
  • the lyophilized preparation contains 0.5% apixaban, 0.24% povidone K17, 0.12% sodium deoxycholate, and 5.04% mannitol.
  • the initial particle size of prescription (9) is an average particle size of 132.7 nm, PDI 0.123, D 10 87.3 nm, D 50 143 nm, and D 90 235 nm. Placed at 40°C/RH75% for 1 month, the average particle size is 133.3nm, PDI 0.139, D 10 89.0nm, D 50 147nm, D 90 241nm.
  • Example 2 A multi-center, randomized, double-blind, positive drug parallel controlled clinical trial on the efficacy and safety of apixaban suspension for injection in preventing venous thromboembolism in patients with nephrotic syndrome
  • the clinical diagnosis is primary nephrotic syndrome
  • Plasma albumin ⁇ 25g/L
  • Test drug T1 prescription (8) Apixaban suspension (lyophilized powder, need to be reconstituted before use), specification: 2.5mg; produced and provided by Jiangsu Hengrui Pharmaceutical Co., Ltd., usage: 2.5mg, subcutaneous injection , Once a day;
  • Test drug T2 prescription (8) Apixaban suspension (lyophilized powder, need to be reconstituted before use), specification: 2.5mg; produced and provided by Jiangsu Hengrui Pharmaceutical Co., Ltd., usage: 3.75mg, subcutaneous injection , Once a day;
  • Test drug T3 prescription (9) Apixaban suspension (lyophilized powder, need to be reconstituted before use), specification: 5.0mg; produced and provided by Jiangsu Hengrui Pharmaceutical Co., Ltd., usage: 5.0mg, subcutaneous injection , Once a day;
  • Control drug R Enoxaparin Sodium Injection; Specification: 40mg; Manufacturer: SANOFI SYNTHELABO FRANCE; Usage: subcutaneous injection, once a day.
  • the two test groups received apixaban suspension for injection, the usage was 2.5 mg, subcutaneous injection, once a day and 3.75 mg, subcutaneous injection, once a day; the control group received enoxaparin Heparin sodium injection treatment, the usage is 40mg, subcutaneous injection, once a day.
  • Prothrombin fragment 1+2 at the second weekend of the treatment period.
  • Thrombin antithrombin (TAT) complex at the second weekend of the treatment period and at the end of the treatment period;
  • Venous thromboembolism non-fatal pulmonary embolism, symptomatic deep vein thrombosis, asymptomatic proximal deep vein thrombosis, renal vein thrombosis
  • death related to venous thromboembolism fatal pulmonary embolism or fatal pulmonary embolism

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Abstract

涉及阿哌沙班注射剂用于预防或者治疗血栓栓塞的方法。尤其是阿哌沙班纳米晶注射剂用于预防或者治疗肾病综合征患者血栓栓塞，特别是静脉血栓栓塞的方法。

Description

阿哌沙班注射剂用于预防或者治疗血栓栓塞的方法
本申请要求申请日为2020年2月13日的中国专利申请CN202010090076.3的优先权。本申请引用上述中国专利申请的全文。
技术领域
本公开属于医药领域，涉及阿哌沙班注射剂用于预防或者治疗血栓栓塞的方法。
背景技术
血栓栓塞是肾病综合征(NS)最严重的并发症。血栓形成是由于血管内血液凝结导致血栓形成而阻塞血流。血栓形成可能在动脉或静脉中形成。当全部或部分血栓破裂并在循环中向下游流动，从而阻止流向重要器官时，就会发生栓塞。这些现象统称为血栓栓塞症。早在1840年，肾静脉血栓形成被认为是与NS相关联的第一血栓栓塞。从那时起，人们已经认识到，与NS相关的血栓栓塞症基本上可以在任何主要血管中看到。尽管现代抗凝及溶栓疗法可降低血栓相关死亡的风险，血栓栓塞仍然是NS的常见并发症。
阿哌沙班(Apixaban，商品名Eliquis)是一种选择性活化Xa因子抑制剂，百时美施贵宝和辉瑞公司联合研发了片剂，其商品名为Eliquis，于2011年3月在欧盟批准上市，2012年12月FDA批准了该药在美国上市，随后该药在其它地区和国家相继上市，在中国获批适应症为髋关节或膝关节择期置换术的成年患者预防静脉血栓栓塞事件(VTE)。
本公开提供一种注射用阿哌沙班预防或者治疗肾病综合征患者血栓栓塞的方法，包括注射给予患者有效量的阿哌沙班。
发明内容
本公开提供一种预防或者治疗肾病综合征患者的血栓栓塞的方法，包括给予患者治疗或者预防有效量的阿哌沙班，其中阿哌沙班通过注射剂形式给药。
本公开所述的肾病综合征为原发性或者继发性肾病综合征。
在一些实施方案中，所述的肾病综合征可选自但不限于膜性肾病、系膜增生性肾小球肾炎、IgA肾病、微小病变型肾病、局灶节段性肾小球硬化、过敏性紫癜肾炎、肾淀粉样变性、狼疮肾炎、糖尿病肾病、骨髓瘤肾病等。
在一些实施方案中，所述的肾病综合征患者的血栓栓塞是静脉血栓栓塞。
在一些实施方案中，所述的肾病综合征患者的血栓栓塞是动脉血栓栓塞。
在一些实施方案中，所述的肾病综合征患者的血栓栓塞可选自但不限于深静脉血栓、肾静脉血栓、肺栓塞等。
在一些实施方案中，所述的血栓栓塞是指肾病综合征患者的静脉血栓栓塞。
在一些实施方案中，所述的肾病综合征患者指的是血浆白蛋白＜30g/L或者＜25g/L、24小时尿蛋白定量＞3.0g的肾病综合征患者。
在一些实施方案中，阿哌沙班注射剂通过皮下注射的方式给予患者。
阿哌沙班注射剂在WO2020034989A中得到描述，所述申请的全部内容通过引用并入本文。
在一些实施方案中，阿哌沙班注射剂包含阿哌沙班纳米颗粒和表面稳定剂。
在一些实施方案中，阿哌沙班纳米颗粒的平均粒径或D 50可小于2000nm，优选小于1000nm，更优选小于500nm，更优选小于200nm，进一步优选小于170nm，进一步优选小于160nm，最优选小于150nm。
包含阿哌沙班纳米颗粒和表面稳定剂的阿哌沙班注射剂还可以包含沉降抑制剂。沉降抑制剂在一定时间内抑制纳米颗粒的沉降或聚集。
在一些实施方案中，阿哌沙班注射剂是冻干的药物组合物复溶后形成的。
在一些实施方案中，冻干的药物组合物经液体介质复溶后，可以得到包含液体介质的药物组合物，所述液体介质可选自水、盐水溶液、红花籽油、乙醇、叔丁醇、己烷和乙二醇中的一种或多种，优选水、盐水溶液和红花籽油中的一种或多种，最优选水。复溶后的药物组合物中，阿哌沙班纳米颗粒的含量可选自0.1～100mg/mL，优选0.5～100mg/mL，更优选1～100mg/mL，最优选2～10mg/mL(例如2.5mg/mL)。
在一些实施方案中，阿哌沙班注射剂是包含液体介质的药物组合物，所述液体介质可选自水、盐水溶液、红花籽油、乙醇、叔丁醇、己烷和乙二醇，优选水、盐水溶液和红花籽油中的一种或多种，最优选水。包含液体介质的药物组合物中，阿哌沙班纳米颗粒的含量可选自0.1～100mg/mL，优选0.5～100mg/mL，更优选1～100mg/mL，最优选2～10mg/mL(例如2.5mg/mL或5mg/mL)。
在一些实施方案中，阿哌沙班注射剂包含阿哌沙班纳米颗粒、聚维酮以及脱氧胆酸钠。
在一些实施方案中，阿哌沙班注射剂包含阿哌沙班纳米颗粒、聚维酮、脱氧胆酸钠以及甘露醇。
在一些实施方案中，阿哌沙班注射剂包含阿哌沙班纳米颗粒、聚维酮、脱氧胆酸钠以及甘露醇，阿哌沙班纳米颗粒的重量体积比优选为0.1-1％，进一步优选0.1-0.5％(例如0.25％或0.5％)；聚维酮的重量体积比优选为0.1-5％，进一步优选0.1-1％(例如0.24％、0.575％或0.525％)；脱氧胆酸钠的重量体积比优选为0.1-3％，进一步优选0.1-0.5％(例如0.12％、0.2875％或0.25％)；甘露醇的重量体积比优选为1-10％，进一步优选2-7％(例如2.375％或5.32％)。
在一些实施方案中，阿哌沙班注射剂中阿哌沙班纳米颗粒：聚维酮：脱氧胆酸钠的重量比是10:2:1，优选包含重量体积比为10％阿哌沙班纳米颗粒、2％聚维酮、1％脱氧胆酸钠的药物组合物或者包含重量体积比为5％阿哌沙班 纳米颗粒、1％聚维酮、0.5％脱氧胆酸钠的药物组合物。
在一些实施方案中，阿哌沙班注射剂包含重量体积比为0.5％阿哌沙班纳米颗粒、0.575％聚维酮、0.2875％脱氧胆酸钠、2.375％甘露醇。
在一些实施方案中，阿哌沙班注射剂包含重量体积比为0.25％阿哌沙班纳米颗粒、0.525％聚维酮、0.25％脱氧胆酸钠、5.32％甘露醇。
在一些实施方案中，阿哌沙班注射剂包含重量体积比为0.25％阿哌沙班、0.24％聚维酮K17、0.12％脱氧胆酸钠、5.32％甘露醇。
在一些实施方案中，阿哌沙班注射剂包含重量体积比为0.5％阿哌沙班、0.24％聚维酮K17、0.12％脱氧胆酸钠、2％-7％甘露醇。在某些实施方案中，阿哌沙班注射剂单位剂量中阿哌沙班纳米颗粒的含量可为2.0mg-5.0mg，优选2.0mg、2.5mg、3.0mg、3.5mg、4.0mg、4.5mg、5.0mg。
在一些实施方案中，阿哌沙班注射剂中，阿哌沙班纳米颗粒的平均粒径可小于500nm，优选小于300nm，更优选小于200nm，更优选小于170nm，更优选小于160nm，最优选小于150nm。
在一些实施方案中，阿哌沙班注射剂中，阿哌沙班纳米颗粒的PDI可小于0.5，优选小于0.3，最优选小于0.2。
在一些实施方案中，阿哌沙班注射剂中，阿哌沙班纳米颗粒的D 50可小于500nm，优选小于300nm，更优选小于200nm，最优选小于170nm。
本公开的阿哌沙班注射剂，尤其适合皮下注射给药。本公开的阿哌沙班注射剂皮下注射后生物利用度高，药时曲线平稳，具有更好的安全性和有效性。本公开的阿哌沙班注射剂适合每日一次、每日两次或者每两日一次给药。
本公开的阿哌沙班的给药剂量可选自1-10mg，优选2-5mg，更优选2mg、2.25mg、2.5mg、2.75mg、3mg、3.25mg、3.5mg、3.75mg、4.0mg、4.25mg、4.5mg、4.75mg或者5.0mg。
在一些实施方案中，本公开的阿哌沙班注射剂的给药周期可选自2天、3天、4天、5天、7天、10天、12天、14天、15天、21天、28天、35天、 42天、49天、56天、2个月、3个月、4个月、5个月或者6个月。
本公开中所述“有效量”或“治疗有效量”包含足以改善或预防医学病症的症状或病症的量。有效量还意指足以允许或促进诊断的量。用于特定患者或兽医学受试者的有效量可依据以下因素而变化：如待治疗的病症、患者的总体健康情况、给药的方法途径和剂量以及副作用严重性。有效量可以是避免显著副作用或毒性作用的最大剂量或给药方案。
本公开所述的“重量体积比”是指每100mL液体体系中含有所述成分的重量(单位g)，即g/100mL。
本公开所述的“PDI”是指一个样品的粒度分布宽度的多分散指数。“D 50”是指一个样品的光能累积到50％时的粒径值，D 10、D 90的定义类比D 50。
具体实施方式
实施例1：注射用阿哌沙班混悬剂
阿哌沙班纳米颗粒混悬液处方
表1阿哌沙班纳米颗粒混悬液处方
Figure PCTCN2021076419-appb-000001
制备方法：将处方量的表面稳定剂加水溶解，加入阿哌沙班原料，搅拌使分散均匀，加入研磨珠后搅拌使分散均匀，在球磨机上研磨4h，制得阿哌沙班纳米颗粒混悬液。
除处方(2)外，本发明的阿哌沙班纳米颗粒混悬液平均粒径在100-500nm之间，且PDI在0.5以下，药物的粒径和分布结果较好。
处方(4)、(5)阿哌沙班纳米颗粒混悬液的稀释及冻干
表2阿哌沙班纳米颗粒混悬液稀释及冻干
Figure PCTCN2021076419-appb-000002
处方(5)
Figure PCTCN2021076419-appb-000003
制备方法：处方(4)阿哌沙班纳米颗粒混悬液分别以2.5％的甘露醇、2.5％的甘油水溶液、10％的蔗糖水溶液、2.5％甘露醇+0.5％聚维酮+0.25％脱 氧胆酸钠水溶液稀释至阿哌沙班浓度为5mg/mL，分别测出三种稀释液中纳米颗粒的粒径及分布情况；稀释液2-8℃储存4天，分别测出三种稀释液中纳米颗粒的粒径及分布情况；或者稀释液直接冻干，分别测出三种稀释液处方冻干后纳米颗粒的粒径及分布情况。将处方(5)阿哌沙班纳米颗粒混悬液以5.6％甘露醇+0.5％聚维酮+0.2368％脱氧胆酸钠水溶液稀释至阿哌沙班浓度为2.5mg/mL，分别测出在研磨后、冻干前、2-8℃储存24h、冻干后纳米颗粒的粒径及分布情况(备注：处方(5)的纳米颗粒混悬液稀释后，经0.22微米的滤芯过滤除菌，再进行冻干)。
处方(4)、(5)冻干制剂的性质考察
处方(4)的阿哌沙班纳米颗粒混悬液用包含2.5％甘露醇+0.5％聚维酮+0.25％脱氧胆酸钠的水溶液稀释后，又经冻干的制剂分别于2-8℃、25℃/60％RH及40℃/75％RH条件下放置，使用水复溶后，检测粒度分布、含量及有关物质，考察稳定性，具体见表3(批次1)。处方(5)的阿哌沙班纳米颗粒混悬液用包含5.6％甘露醇+0.5％聚维酮+0.2368％脱氧胆酸钠的水溶液稀释后，又经冻干的制剂分别于25℃/60％RH及40℃/75％RH条件下放置，使用水复溶后，检测粒度分布及有关物质，考察稳定性，具体见表3(批次2、3、4)。处方(5)的阿哌沙班纳米颗粒混悬液用包含5.6％甘露醇+0.5％聚维酮+0.2368％脱氧胆酸钠的水溶液稀释后，经历冻干，再用水复溶，考察室温及2-8℃条件下，1h、2h、4h、6h、24h、48h后的粒度分布情况，具体见表4。
表3处方(4)、(5)冻干制剂的稳定性考察
Figure PCTCN2021076419-appb-000004
Figure PCTCN2021076419-appb-000005
表4粒度分布稳定性
Figure PCTCN2021076419-appb-000006
从表3的结果可以看出，阿哌沙班纳米颗粒冻干制剂在不同条件下均较为稳定，粒度分布、含量及有关物质与起始相比均无明显变化；从表4的结果可以看出，阿哌沙班纳米颗粒冻干制剂复溶后粒度分布均匀，表明阿哌沙班纳米颗粒冻干制剂复溶后粒度分布稳定性良好。阿哌沙班含量及有关物质的含量测定均采用HPLC方法。
药代动力学研究
处方(5)的阿哌沙班纳米颗粒混悬液，用包含5.6％甘露醇+0.5％聚维酮+0.2368％脱氧胆酸钠的水溶液稀释，冻干，加水复溶，得到阿哌沙班2.5mg/mL的注射液，分别给3个受试者皮下给药1mL，血浆药物浓度如表5所示：
表5阿哌沙班血浆药物浓度(ng/mL)随时间的变化
Figure PCTCN2021076419-appb-000007
实验数据显示，阿哌沙班纳米颗粒药物组合物皮下注射的半衰期为11.1小时，表明纳米颗粒药物组合物皮下给药在人体上有缓释效果；PK曲线较平缓，给药后1-16小时，血药浓度均高于21ng/mL，可满足1天给药1次的方式；2.5mg单次皮下给药的C max较低(51.2ng/ml)，给药的安全性可控。
处方(8)
处方(8)与处方(5)的不同之处在于稀释液的配方为0.2％聚维酮K17、0.1％脱氧胆酸钠、5.6％甘露醇、余量为水。冻干后的制剂包含0.25％阿哌沙班、0.24％聚维酮K17、0.12％脱氧胆酸钠、5.32％甘露醇。
处方(9)
处方(9)与处方(5)的不同之处在于稀释液的配方为0.156％聚维酮K17、0.078％脱氧胆酸钠、5.6％甘露醇、余量为水；使用稀释液将处方(4) 稀释至阿哌沙班浓度为5.0mg/mL。冻干后的制剂包含0.5％阿哌沙班、0.24％聚维酮K17、0.12％脱氧胆酸钠、5.04％甘露醇。
处方(9)初始粒径为平均粒径132.7nm，PDI 0.123，D 10 87.3nm，D 50 143nm，D 90 235nm。置于40℃/RH75％条件下放置1个月，平均粒径为133.3nm，PDI 0.139，D 10 89.0nm，D 50 147nm，D 90 241nm。
实施例2：注射用阿哌沙班混悬剂预防肾病综合征患者静脉血栓栓塞的疗效及安全性的多中心、随机、双盲、阳性药物平行对照临床试验
入组标准：
患者必须满足以下所有入选标准才可入组本试验：
1、18岁≤年龄≤75岁，性别不限；
2、临床诊断为原发性肾病综合征；
3、所有患者需有明确肾脏病理诊断，可接受入组前6个月内的肾脏病理诊断；
4、血浆白蛋白＜25g/L；
5、24小时尿蛋白定量＞3.0g；
研究药物：
试验药T1：处方(8)阿哌沙班混悬剂(冻干粉，使用前需复溶)，规格：2.5mg；江苏恒瑞医药股份有限公司生产并提供，用法：2.5mg，皮下注射，每日一次；
试验药T2：处方(8)阿哌沙班混悬剂(冻干粉，使用前需复溶)，规格：2.5mg；江苏恒瑞医药股份有限公司生产并提供，用法：3.75mg，皮下注射，每日一次；
试验药T3：处方(9)阿哌沙班混悬剂(冻干粉，使用前需复溶)，规格：5.0mg；江苏恒瑞医药股份有限公司生产并提供，用法：5.0mg，皮下注射，每日一次；
对照药R：依诺肝素钠注射液；规格：40mg；生产企业：SANOFI  SYNTHELABO FRANCE；用法：皮下注射，每日一次。
给药方案：
6周±2周，两个试验组接受注射用阿哌沙班混悬剂治疗，用法分别为2.5mg，皮下注射，每日一次和3.75mg，皮下注射，每日一次；对照组接受依诺肝素钠注射液治疗，用法为40mg，皮下注射，每日一次。
疗效指标：
主要疗效指标：
治疗期第2周末凝血酶原片段1+2。
次要疗效指标：
1、治疗结束时凝血酶原片段1+2；
2、治疗期第2周末与治疗结束时抗Xa活性；
3、治疗期第2周末与治疗结束时凝血酶抗凝血酶(TAT)复合物；
4、治疗期第2周末与治疗结束时D-二聚体；
5、治疗期及随访期间的静脉血栓栓塞症(非致死性肺栓塞、症状性深静脉血栓、无症状性近端深静脉血栓、肾静脉血栓)与静脉血栓栓塞相关死亡(致死性肺栓塞或不能排除静脉血栓栓塞原因的猝死)复合终点发生率；
6、治疗期及随访期间心肌梗死、卒中、全因死亡复合终点发生率。
安全性指标：
治疗期及随访期内大出血及临床相关的非大出血的发生率(ISTH定义)。

Claims (14)

  1. 一种预防或者治疗肾病综合征患者血栓栓塞的方法，包括给予患者治疗或者预防有效量的阿哌沙班，其中阿哌沙班通过注射剂形式给药。
  2. 根据权利要求1所述的方法，其中肾病综合征选自膜性肾病、系膜增生性肾小球肾炎、IgA肾病、微小病变型肾病、局灶节段性肾小球硬化、过敏性紫癜肾炎、肾淀粉样变性、狼疮肾炎、糖尿病肾病、骨髓瘤肾病。
  3. 根据权利要求1所述的方法，其中肾病综合征患者的血栓栓塞选自深静脉血栓、肾静脉血栓、肺栓塞。
  4. 根据权利要求1所述的方法，其中肾病综合征患者的血栓栓塞是静脉血栓栓塞。
  5. 根据权利要求1所述的方法，其中注射剂包含阿哌沙班纳米颗粒和表面稳定剂。
  6. 根据权利要求5所述的方法，其中阿哌沙班纳米颗粒的平均粒径或D 50小于2000nm，优选小于1000nm，更优选小于500nm，更优选小于200nm，进一步优选小于170nm，进一步优选小于160nm，最优选小于150nm。
  7. 根据权利要求5所述的方法，其中注射剂还包含沉降抑制剂。
  8. 根据权利要求1所述的方法，其中注射剂包含阿哌沙班纳米颗粒、聚维酮、脱氧胆酸钠以及甘露醇。
  9. 根据权利要求1所述的方法，其中注射剂包含重量体积比为0.25％阿哌沙班、0.24％聚维酮K17、0.12％脱氧胆酸钠、5.32％甘露醇。
  10. 根据权利要求1所述的方法，其中注射剂包含重量体积比为0.5％阿哌沙班、0.24％聚维酮K17、0.12％脱氧胆酸钠、2％-7％甘露醇。
  11. 根据权利要求1所述的方法，其中阿哌沙班的给药剂量选自1-10mg，优选2-5mg，更优选2mg、2.25mg、2.5mg、2.75mg、3mg、3.25mg、3.5mg、3.75mg、4.0mg、4.25mg、4.5mg、4.75mg或者5.0mg。
  12. 根据权利要求1所述的方法，其中阿哌沙班的单位剂量选自1-10mg/ml，优选2-5mg/ml，更优选2mg/ml、2.25mg/ml、2.5mg/ml、2.75mg/ml、3mg/ml、3.25mg/ml、3.5mg/ml、3.75mg/ml、4.0mg/ml、4.25mg/ml、4.5mg/ml、4.75mg/ml或者5.0mg/ml。
  13. 根据权利要求1所述的方法，其中注射剂通过皮下注射的方式给予患者。
  14. 根据权利要求1所述的方法，其中注射剂给药频次选自每日一次、每日两次或者每两日一次。
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ZHANG, GUANGQIU: "Pharmacological Characteristics and Application of New Oral Anticoagulants", CHINESE JOURNAL OF CLINICAL RATIONAL DRUG USE, vol. 12, no. 1C, 1 January 2019 (2019-01-01), pages 104 - 106, XP055835263 *
ZHANG, XIANLONG: "Apixaban, a New Oral Anticoagulant", CHINESE JOURNAL OF JOINT SURGERY (ELECTRONIC EDITION), vol. 8, no. 4, 1 August 2014 (2014-08-01), pages 543 - 546, XP055835256, ISSN: 1674-134X *

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