CN113384581B - 一种包含促性腺激素释放激素拮抗剂的药物组合物 - Google Patents
一种包含促性腺激素释放激素拮抗剂的药物组合物 Download PDFInfo
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- CN113384581B CN113384581B CN202110267916.3A CN202110267916A CN113384581B CN 113384581 B CN113384581 B CN 113384581B CN 202110267916 A CN202110267916 A CN 202110267916A CN 113384581 B CN113384581 B CN 113384581B
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 61
- 229940121381 gonadotrophin releasing hormone (gnrh) antagonists Drugs 0.000 title claims abstract description 5
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- 239000003795 chemical substances by application Substances 0.000 claims description 16
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- 239000011734 sodium Substances 0.000 claims description 14
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 12
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 6
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical group [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims description 6
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- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
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Classifications
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
Abstract
本发明提供了一种包含促性腺激素释放激素拮抗剂的药物组合物,所述药物组合物在多种溶出环境中均具有良好的溶出特性,影响因素试验表明本发明药物组合物稳定性高,在储存过程中杂质总量、最大单杂含量、式I杂质含量等均较低,且在长期储存过程中杂质含量增幅明显低于现有制剂,药物质量得到显著提升,有利于提高用药安全性。
Description
技术领域
本发明涉药物制剂领域,具体涉及一种包含促性腺激素释放激素拮抗剂的药物组合物。
背景技术
子宫内膜异位症是指有活性的内膜细胞种植在子宫内膜以外的位置而形成的一种女性常见妇科疾病。此病多发生于生育年龄的女性,青春期前不发病,绝经后异位病灶可逐渐萎缩退化。临床表现为痛经、不孕、月经异常、性交疼痛和其他尿频、尿痛、血尿等。
目前,还没有治愈这种疾病的方法,一般采用药物来对抗或抑制卵巢的周期性内分泌刺激。有假孕疗法及假绝经疗法,通常使用孕激素类药物或雄激素的衍生物治疗,但药物效果不明显且副作用大。此外,还可手术治疗,腹腔镜手术和GnRHa(促性腺激素释放激素类似物)药物的结合,已成为越来越广泛的治疗方案,但这些并不适用于所有患者。
噁拉戈利钠(Elagolix Sodium)是由Abbvie与Neurocrine Biosciences Inc合作开发的一种口服活性非肽促性腺激素释放激素(GnRH)拮抗剂,通过与脑垂体中的GnRH受体竞争性结合来抑制内源性GnRH信号传导。该药物于2018年被美国FDA批准用于治疗子宫内膜异位症。Elagolix目前在中国暂无上市产品,鉴于其临床价值,有必要开发一款安全、有效、质量稳定的Elagolix制剂产品,以满足患者的临床需求。
发明内容
本发明的目的之一是提供一种包含促性腺激素释放激素拮抗剂的药物组合物,所述药物组合物包含:噁拉戈利或其药学上可接受的盐、稳定剂及其他药物上可接受的辅料;其中,所述稳定剂选自氧化镁、氢氧化镁、碳酸镁、碳酸钙、葡甲胺。
所述药学上可接受的盐选自钠盐、钾盐、钙盐等,优选为钠盐;
本发明所述药物组合物中稳定剂的含量为组合物重量的5%以上,优选的稳定剂含量为组合物重量的8%以上,处于安全性考虑,在某些具体的实施方案中,本发明药物组合物中稳定剂用量为10.5%;
本发明所述药物组合物中,噁拉戈利或其药学上可接受的盐的含量一般依据临床需求而定。在某些具体的实施方案中,本发明药物组合物中所述噁拉戈利或其药学上可接受的盐的含量为药物组合物总重量的25%-40%;在某些具体的实施方案中,所述噁拉戈利或其药学上可接受的盐的含量为药物组合物总重量的31%-35%;在某些具体的实施方案中,所述噁拉戈利或其药学上可接受的盐的含量为药物组合物总重量的34.5%。在某些实施例中,本发明药物组合物中所述噁拉戈利或其药学上可接受的盐的含量为从25mg至650mg,在某些实施例中,本发明所述药物组合物中噁拉戈利或其药学上可接受的盐含量为从50mg至400mg,在某些实施例中,本发明所述药物组合物中噁拉戈利或其药学上可接受的盐含量为从100mg至350mg,例如150mg、200mg、300mg;
优选地,本发明所述药物组合物中包含崩解剂;
具体地,所述崩解剂选自如交联聚维酮、羧甲淀粉钠、低取代羟丙基纤维素、羧甲基纤维素钙、交联羧甲基纤维素钠中的一种或多种,优选地,所述崩解剂选自交联聚维酮和羧甲淀粉钠;
进一步,所述崩解剂的用量占药物组合物整体重量百分比的12%-24%;
优选的,所述崩解剂的用量占药物组合物整体重量百分比的17%-24%。
在某些实施例中,本发明所述药物组合物是一种口服制剂,如片剂、胶囊剂、颗粒剂等;在某些具体实施例中,所述药物组合物是片剂;
在某些实施例中,药物组合物制备工艺为粉末直压、流化床制粒、辊压制粒、干法制粒、湿法制粒、熔融制粒;在某些具体实施例中,药物组合物制备工艺为干法制粒。
本发明所述药学上可接受的辅料选自一种或多种下述的药用辅料:
填充剂,如葡萄糖、异麦芽糖醇、山梨醇、甘露醇、乳糖、蔗糖、预胶化淀粉、微晶纤维素;
粘合剂,如聚维酮、聚乙二醇、羟甲基纤维素钠、羟丙基纤维素、甲基纤维素、羟丙基纤维素;
表面活性剂,如十二烷基硫酸钠;
助流剂,如胶态二氧化硅;
润滑剂,如硬脂酸镁、硬脂酸钙。
在某些实施例中,本发明所述药物组合物由如下重量百分比的组分组成:
噁拉戈利或其药学上可接受的盐 25%-40%
填充剂 20%-50%
稳定剂 5%-17%
崩解剂 12%-24%
润滑剂 0.5-3.0%
可选地,进一步包含1-5%的薄膜包衣预混剂。
在某些实施例中,本发明所述药物组合物由如下重量百分比的组分组成:
噁拉戈利或其药学上可接受的盐 31%-35%
填充剂 25%-45%
稳定剂 5-10.5%
崩解剂 12%-24%
润滑剂 2.0%
可选地,进一步包含1-5%的薄膜包衣预混剂。
在某些实施例中,本发明所述药物组合物由如下重量百分比的组分组成:
噁拉戈利或其药学上可接受的盐 31%-35%
填充剂 29%-41%
稳定剂 10.5%
崩解剂 12%-24%
润滑剂 2.0%
可选地,进一步包含1-5%的薄膜包衣预混剂。
在某些实施例中,本发明所述药物组合物由如下重量百分比的组分组成:
噁拉戈利或其药学上可接受的盐 34.5%
填充剂 29%-36%
稳定剂 10.5%
崩解剂 17%-24%
润滑剂 2.0%
可选地,进一步包含1-5%的薄膜包衣预混剂。
在某些实施例中,本发明所述药物组合物由如下重量百分比的组分组成:
噁拉戈利或其药学上可接受的盐 34.5%
填充剂 36%
稳定剂 10.5%
崩解剂 17%
润滑剂 2.0%
可选地,进一步包含1-4%的薄膜包衣预混剂。
噁拉戈利或其药学上可接受的盐 34.5%
填充剂 34%
稳定剂 10.5%
崩解剂 19%
润滑剂 2.0%
可选地,进一步包含1-4%的薄膜包衣预混剂。
噁拉戈利或其药学上可接受的盐 34.5%
填充剂 33%
稳定剂 10.5%
崩解剂 20%
润滑剂 2.0%
可选地,进一步包含1-4%的薄膜包衣预混剂。
本发明进一步提供一种制备前述药物组合物的方法,包括如下步骤:
(1)预处理:将噁拉戈利或其药学上可接受的盐、填充剂分别粉碎或过筛;
(2)预混合:将噁拉戈利或其药学上可接受的盐、稳定剂、及其他药学上可接受的辅料进行预混合,即得;
(3)制粒:将预混完成后的物料进行干法制粒,得到合格的干颗粒;
(4)总混:将干颗粒与外加的辅料进行混合,得到总混颗粒;
(5)压片;
(6)包衣。
本申请发明人在长期的研发实践中发现,噁拉戈利钠在长期储存中容易产生复杂的有关物质,导致产品质量下降,影响药物安全性和有效性,例如下式I所示的杂质即为非常关键的有关物质之一,研究表明它是具有致突变作用的杂质(可能为基因毒性杂质或含有警示结构的杂质),需要严格控制其在药物组合物中的含量。同时,包含噁拉戈利或其药学上可接受的盐(如噁拉戈利钠)的制剂在不同的溶出介质中的溶出特性存在明显差异,直接影响药物在体内的释放和吸收。因此,开发一种长期稳定性好,溶出迅速且稳定的噁拉戈利制剂对于该产品的临床应用具有重要意义。
本发明药物组合物在多种溶出环境中均具有良好的溶出特性,影响因素试验表明本发明药物组合物稳定性高,在储存过程中杂质总量、最大单杂含量、式I杂质含量等均较低,且在长期储存过程中杂质含量增幅明显低于现有制剂,药物质量得到显著提升,有利于提高用药安全性。
具体实施例方式
通过以下具体实施例对本发明作进一步的说明,但不作为本发明的限制。除特殊说明外,本发明所用试剂材料均为公共商业渠道获得(如辅料为药用级)。
本发明所用噁拉戈利及其钠盐按照US20110098472A1实施例1、5公开的合成路线制备得到。
本发明药物组合物的制备工艺如下:
将噁拉戈利或其药学上可接受的盐、填充剂分别粉碎或过筛;与其他药学上可接受的辅料进行预混合,将预混合后的物料进行干法制粒,得到的干颗粒与外加辅料进行总混合,得到总混颗粒;然后进行压片,包衣,内包装,即得。
本发明中有关物质检测方法如下:
取待测样品适量,用乙腈-水(50:50)溶解并稀释制成每1ml中约含1mg的溶液,作为供试品溶液;按照髙效液相色谱法(中国药典2015年版四部通则0512)测定,用十八烷基硅烷键合硅胶为填充剂(ACE UltraCore2.5 Super C18,4.6mm×100mm或效能相当的色谱柱);以乙酸铵缓冲液(10mM乙酸铵溶液,用乙酸调pH至5.0)为流动相A;以乙酸铵缓冲液(100mM乙酸铵溶液,用乙酸调pH至5.0)-乙腈(10:90)为流动相B,检测波长为274nm,流速每分钟lm1,柱温60℃,按下表进行梯度洗脱。精密量取供试品溶液10μl注入液相色谱仪,记录色谱图。供试品溶液图谱中如有杂质峰,扣除溶剂峰后,按面积归一化法计。式I杂质的相对保留时间为1.14。
时间(分钟) | 流动相A(%) | 流动相B(%) |
0 | 75 | 25 |
20 | 25 | 75 |
27 | 25 | 75 |
27.1 | 75 | 25 |
34 | 75 | 25 |
本发明中溶出试验方法为USP仪器装置Ш,溶出介质体积:900ml;溶出介质:pH2.0盐酸溶液;pH5.0磷酸盐缓冲液;温度在37±0.5℃、转速:100rpm、篮法条件下进行,取样时间:5min、10min、15min、20min、30min、45min、60min、90min。
实施例1
将原料药和各个辅料按照一定的比例(见表1)平行放置于50℃、75%RH条件下,闭口放置,分别于7天、14天、30天取样检测总杂、最大单杂(含量最高的单杂)以及式I杂质的含量,结果见表1、表2。
表1总杂、最大单杂(含量最高的单杂)含量
表2式I杂质的含量
实施例2
按照表3中的原辅料比例制备药物组合物,根据稳定剂的不同,将药物组合物分为不同的试验组,各试验组于50℃、75%RH条件下,同时分敞口和闭口放置,分别于7天、14天、30天取样检测有关物质含量。
表3药物组合物处方表
闭口和敞口条件下,各试验组药物组合物中有关物质含量检测结果如下表4至表7:
表4闭口条件下不同稳定剂制备的药物组合物中总杂和最大单杂含量
表5敞口条件下不同稳定剂制备的药物组合物中总杂和最大单杂含量
表6闭口条件下不同稳定剂制备的药物组合物中式I杂质的含量
表7敞口条件下不同稳定剂制备的药物组合物中式I杂质的含量
实施例3
按照表8中处方比例制备药物组合物制剂,在40℃,75%RH相对湿度加速试验条件下,考察结果如下表9-10:
表8
表9本发明药物组合物在40℃/75%RH加速条件下稳定性结果
注:杂质增量是指加速之后相对于加速之前(0天),样品中相应杂质增加的质量百分比,下同。
表10本发明药物组合物在40℃/75%RH加速条件下式I杂质的含量变化
实施例4
参照表8的处方,以氧化镁作为稳定剂,考察不同比例的稳定剂对制剂稳定性的影响,氧化镁占处方比例分别为0.0%、5.0%、8.0%、10.5%,在50℃/75%RH闭口条件下稳定性结果如下表11:
表11不同比例的稳定剂稳定性数据对比表
实验表明,添加稳定剂的药物组合物相对于未添加稳定剂的药物组合物,在稳定性试验中最大单杂和总杂含量增幅明显更低,且随着稳定剂含量增加,稳定效果相应增强。出于安全性考虑,本发明药物组合物中稳定剂用量优选为药物组合物总质量的5%-10.5%,最优选为10.5%。
实施例5
以甘露醇和预胶化淀粉为填充剂、氧化镁作为稳定剂、硬脂酸镁为润滑剂,其中稳定剂用量为处方总重量的10.5%,润滑剂用量为处方总重量的2%,噁拉戈利钠用量为处方总重量的34.5%,其余为填充剂和崩解剂。考察不同种类和不同用量的崩解剂(表12、14)对溶出的影响,溶出对比结果如下表13、15、16:
表12
表13不同崩解剂种类和用量的组合物在酸性介质(pH2.0)中的溶出数据
注:本发明中相似因子f2的计算方法参照普通口服固体制剂溶出度试验技术指导原则(中国),一般情况下,f2值高于50,可认为两条曲线具有相似性,受试制剂与参比制剂具有等效性;参比制剂为市售噁拉戈利片(购自Abbvie)。
表14
表15不同崩解剂种类和用量的组合物在酸性介质(pH2.0)中的溶出数据
表16不同崩解剂种类和用量的组合物在溶出介质(pH5.0)中的溶出数据
样品 | 参比制剂 | 样品7 | 样品8 | 样品9 | 样品10 | 样品11 | 样品12 | 样品13 |
5min | 10 | 7 | 8 | 8 | 11 | 10 | 10 | 4 |
10min | 33 | 19 | 23 | 22 | 28 | 27 | 25 | 18 |
15min | 51 | 35 | 40 | 42 | 45 | 45 | 41 | 34 |
20min | 66 | 50 | 55 | 57 | 62 | 63 | 55 | 48 |
30min | 85 | 73 | 80 | 78 | 81 | 80 | 77 | 72 |
45min | 93 | 83 | 91 | 90 | 89 | 87 | 91 | 89 |
60min | 95 | 87 | 95 | 95 | 95 | 91 | 96 | 94 |
90min | 96 | 90 | 96 | 98 | 98 | 96 | 99 | 98 |
相似因子f2 | / | 42 | 51 | 58 | 65 | 64 | 51 | 40 |
实施例6
以氧化镁作为稳定剂,不同组方配比见表17,稳定性结果及溶出结果如下表18-表20。
表17
表18敞口条件下(50℃,75%RH)药物组合物中总杂和最大单杂含量
表19不同处方组合物在酸性介质(pH2.0)中的溶出数据
样品 | 参比制剂 | 处方1 | 处方2 |
5min | 16 | 25 | 30 |
10min | 45 | 51 | 57 |
15min | 71 | 73 | 79 |
20min | 90 | 90 | 95 |
30min | 101 | 102 | 101 |
45min | 102 | 103 | 102 |
60min | 102 | 103 | 102 |
90min | 102 | 104 | 102 |
相似因子f2 | / | 63 | 55 |
表20不同处方组合物在溶出介质(pH5.0)中的溶出数据
虽然,上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述,但在本发明基础上,可以对之作一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上所做的这些修改或改进,均属于本发明要求保护的范围。
Claims (5)
1.一种包含促性腺激素释放激素拮抗剂的药物组合物,其特征在于,所述药物组合物由如下成分组成:促性腺激素释放激素拮抗剂、稳定剂、填充剂、崩解剂和润滑剂;
所述促性腺激素释放激素拮抗剂为噁拉戈利钠,其含量为药物组合物重量的34.5%;
所述稳定剂为氧化镁,其含量为药物组合物重量的10.5%;
所述崩解剂为交联聚维酮和羧甲淀粉钠,其含量为药物组合物重量的17%-24%;
所述填充剂为甘露醇和预胶化淀粉,其含量为药物组合物重量的29%-36%;
所述润滑剂为硬脂酸镁,其含量为药物组合物重量的2%;
所述药物组合物为片剂。
2.根据权利要求1所述的药物组合物,其特征在于,所述药物组合物由如下重量百分比的组分组成:
噁拉戈利钠 34.5%
填充剂 36%
稳定剂 10.5%
崩解剂 17%
润滑剂 2.0%。
3.根据权利要求1所述的药物组合物,其特征在于,所述药物组合物由如下重量百分比的组分组成:
噁拉戈利钠 34.5%
填充剂 34%
稳定剂 10.5%
崩解剂 19%
润滑剂 2.0%。
4.根据权利要求1所述的药物组合物,其特征在于,所述药物组合物由如下重量百分比的组分组成:
噁拉戈利钠 34.5%
填充剂 33%
稳定剂 10.5%
崩解剂 20%
润滑剂 2.0%。
5.根据权利要求1-4中任一项所述的药物组合物,其特征在于,还包括含量为所述药物组合物重量1-5%的薄膜包衣预混剂。
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