CN116549396A - 一种含有瑞德西韦的固体分散体、固体剂型及制备方法 - Google Patents
一种含有瑞德西韦的固体分散体、固体剂型及制备方法 Download PDFInfo
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- CN116549396A CN116549396A CN202310043859.XA CN202310043859A CN116549396A CN 116549396 A CN116549396 A CN 116549396A CN 202310043859 A CN202310043859 A CN 202310043859A CN 116549396 A CN116549396 A CN 116549396A
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- adefovir
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- solid dosage
- copovidone
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Classifications
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
-
- 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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Virology (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供一种含有瑞德西韦的固体分散体,和含有该固体分散体的固体剂型,属于药物制剂技术领域。本发明还提供上述固体分散体及固体剂型的制备方法。本发明的含有瑞德西韦的固体剂型,首先采用热熔挤出技术制备含有瑞德西韦和共聚维酮的固体分散体,然后与填充剂、崩解剂、助流剂和润滑剂制备成混合物,最后再将混合物制成固体剂型,比如片剂。本发明提供的瑞德西韦固体剂型提高了口服固体制剂中药物的溶出度和生物利用度,有较大的临床应用价值;此外,本发明制备的瑞德西韦固体剂型质量稳定、可控,便于工业化生产。
Description
本申请为2021年05月10日提交的申请号为202110506396.7专利申请的分案申请。
技术领域
本发明属于药物制剂技术领域,具体涉及一种含有瑞德西韦的固体分散体,以及该固体分散体的制备方法,和含有该固体分散体的固体剂型,以及该固体剂型的制备方法。
背景技术
新型冠状病毒(COVID-19),与严重急性呼吸综合征(SARS)冠状病毒(SARS-CoV)存在密切的亲缘关系。2020年10月22日,美国食品药品管理局(FDA)批准了吉利德科学的注射用瑞德西韦用于治疗新型冠状病毒感染住院患者,成为美国首个正式获批的新型冠状病毒感染治疗药物。然而,目前为止还没有特效口服药物来治疗新型冠状病毒感染。因此,迫切需要一种有效的口服抗病毒药物来对抗这种疾病。
瑞德西韦即Remdesivir是美国制药企业吉利德公司开发的一种广谱抗病毒药物,起初被计划用来治疗埃博拉病毒,前期细胞实验与动物实验显示,其可通过抑制RNA聚合酶从而对SARS冠状病毒和MERS冠状病毒产生良好的抗病毒活性。2018年11月,为应对埃博拉疫情,刚果(金)在世卫组织倡议下启动了临床对照试验,测试Remdesivir、MAb114、REGN-EB3和Zmapp等4款新药的疗效。这场竞赛只花了9个月时间就决出胜负。由于REGN-EB3和mAb-114的领先优势十分明显,委员会在2019年8月决定提前结束试验,将两款药物大范围推广。瑞德西韦由此早早退出抗击埃博拉的战役。不过,在此期间,吉利德并未停止研究瑞德西韦在其他领域的作用,包括冠状病毒,为此次“复出”埋下了伏笔。
值得一提的是,瑞德西韦GS-5734的原型药是GS-441524,该药是FDA批准的兽药,已被推荐用于猫传染性腹膜炎的治疗,这种病很少见但致命,是由猫冠状病毒引起。瑞德西韦目前被认为是最有可能实现抑制新型冠状病毒的潜在药物,在治疗新型冠状病毒感染(COVID-19)的最有潜力的药物之一。2020年5月7日,吉利德科学宣布,日本厚生劳动省(MHLW)已通过特殊审批途径,批准(注射用瑞德西韦)作为SARS-CoV-2感染的治疗药物;10月8日吉利德科学公布了注射用瑞德西韦三期临床数据,这些数据来自美国国家过敏和传染病研究所(NIAID)领导的生物随机双盲安慰剂对照的3期研究,涵盖了全球约1060例住院患者。数据显示,接受注射用瑞德西韦治疗的住院患者平均恢复时间快了五天,而患有严重疾病的患者则快了七天,而这些重病患者占研究总数的85%。2020年10月22日,美国食品药品管理局(FDA)批准了吉利德科学的注射用瑞德西韦用于治疗新型冠状病毒感染住院患者,成为美国首个正式获批的新型冠状病毒感染治疗药物。
瑞德西韦是一种具有广谱抗病毒活性的核苷类似物,能抑制RNA依赖性的RNA聚合酶(RNA-dependent RNA-polymerases,RdRp),活性成分GS-5734为1'-氰基腺苷类似物的氨基磷酸酯前体药,在细胞内代谢生成活性的三磷酸形式-NTP。瑞德西韦作为单磷酸前药可以通过将单磷酸输送到细胞中并有效地绕过限速第一磷酸化步骤来显著提高母体核苷的效力。结构中苯酚和氨基酸酯掩盖了单磷酸基团的负电荷,使其能够方便地被动渗透到细胞中。胞内酯酶(如羧基酯酶-1和组织蛋白酶A)将酯分解为羧基结构,然后继续分解为单磷酸核苷,最后被磷酸化为三磷酸核苷发挥抗病毒效果。
瑞德西韦的化学名称:(2S)-2-((S)-(((2R,3S,4R,5R)-5-(4-氨基吡咯并[2,1-f][1,2,4]三嗪-7-基)-5-氰基-3,4-二羟基四氢呋喃-2-基)甲氧基苯氧基磷酰基)氨基)丙酸-2-乙基丁酯,分子式C27H35N6O8P,分子量602.58。结构式如下式I:
瑞德西韦LogP为2.2,pKa为3.1,水性介质中溶解度较差。瑞德西韦目前临床使用的剂型为冻干粉针剂或注射液,规格100mg,需静脉输注给药,起效快,适用于病情严重的危重患者。FDA提示瑞德西韦可能存在的副作用包括:肝酶水平升高,过敏反应包括血压和心率的变化、低血氧、发烧、呼吸急促、气喘、肿胀(如嘴唇、眼周、皮下)、皮疹、恶心、出汗或发抖。对于轻中度患者,急需开发一种服用方便,增加患者用药顺应性、口服生物利用度高的瑞德西韦口服给药剂型。
目前临床使用的注射用瑞德西韦存在以下缺点:1.处理不当易产生全身性或局部性感染;2.药物过量或滴注过快,易产生不良反应,甚至危及生命;3.持续性的过量输注,易造成循环负荷过重,或电解质失衡;4.医源性疾病的增多。
瑞德西韦为低溶解度药物,药物的溶解度对体内生物利用度影响很大。因此,在进行药物制剂研究时提高其溶出度及生物利用度是本发明的关键。常用提高难溶性药物溶解度的方法有微粉化技术、环糊精包合技术等。
本品原料药微粉化处理会导致原料损失、易发生聚结的现象。考察了不同环糊精浓度中瑞德西韦的饱和溶解度,发现溶解100mg瑞德西韦,所需要磺丁基β环糊精量为1.3g,环糊精质粘,制备成口服片剂不易成型。
因此,目前急需一种处方工艺可操作性强、制备工艺简单、溶出度高的瑞德西韦口服片剂。
发明内容
本发明提供一种药物溶出度高、质量稳定、生物利用度好的含有瑞德西韦的固体剂型。本发明的固体剂型制备工艺简单、可操作性强、不使用有机溶剂、便于工业化放大生产。
本发明是采用热熔挤出技术(Hot-Melt Extrusion technique,HME),又可称为熔融挤出技术(Melt Extrusion technique),首先制备含有瑞德西韦的固体分散体,再将制得的固体分散体与填充剂、崩解剂、助流剂和润滑剂制成总混合物,最后再将总混合物制成片剂。本发明所得片剂比普通片剂大大提高了活性成份瑞德西韦的生物利用度,有较高的临床应用价值。
本发明提供一种含有瑞德西韦的固体分散体,包含活性成分瑞德西韦和药学上可接受的载体,所述药学上可接受的载体为共聚维酮,瑞德西韦与共聚维酮的重量比为1:1-1:4。
在本发明的一些实施方式中,共聚维酮为共聚维酮VA64,瑞德西韦与共聚维酮VA64的重量比为1:2-1:3。
本发明还提供一种含有瑞德西韦的固体分散体的制备方法,包含如下步骤:
(1)将瑞德西韦和共聚维酮以1:1-1:4的比例混合均匀,制成物理混合物;
(2)将双螺杆热熔挤出机的挤出温度设定为140℃-220℃,当达到预设温度后启动螺杆,将步骤(1)所得物理混合物加入到挤出机中,经螺杆挤出固状物,冷却;
(3)将步骤(2)所得固状物粉碎,过60-100目筛,即得到含有瑞德西韦的固体分散体。
本发明的上述制备方法,在一些实施方式中,步骤(1)中将瑞德西韦和共聚维酮VA64以1:2-1:3的比例混合均匀。
本发明还提供一种含有瑞德西韦的固体剂型,包含如上文任一处所述的固体分散体,以及填充剂、崩解剂、助流剂和润滑剂。
在一些实施方式中,本发明的含有瑞德西韦的固体剂型,包含各组分及重量百分比如下:
在一些实施方式中,本发明的含有瑞德西韦的固体剂型,包含各组分及重量百分比如下:
在一些实施方式中,本发明的含有瑞德西韦的固体剂型,包含各组分及重量百分比如下:
填充剂选自甘露醇、乳糖、微晶纤维素中的一种或几种的组合。
崩解剂选自交联羧甲纤维素钠、交联聚维酮、羧甲淀粉钠中的一种或几种的组合。
助流剂选自二氧化硅。
润滑剂选自硬脂酸镁、硬脂酸、氢化植物油、山嵛酸甘油酯、硬脂富马酸钠中的一种或几种的组合。
在至少一个实施方式中,填充剂为甘露醇或甘露醇和微晶纤维素的组合,崩解剂为交联羧甲纤维素钠,助流剂为二氧化硅,润滑剂为硬脂酸镁。
具体地,本发明提供一种含有瑞德西韦的固体剂型,包含各组分及重量百分比如下:
本发明提供的一种含有瑞德西韦的固体剂型的一个实施方式为:包含各组分及重量百分比如下:
本发明提供的一种含有瑞德西韦的固体剂型的一个实施方式为:包含各组分及重量百分比如下:
本发明还提供一种含有瑞德西韦的固体剂型的制备方法,包含如下步骤:
(1)将瑞德西韦和共聚维酮以1:1-1:4的比例混合均匀,制成物理混合物;
(2)将双螺杆热熔挤出机的挤出温度设定为140℃-220℃,当达到预设温度后启动螺杆,将步骤(1)所得物理混合物加入到挤出机中,经螺杆挤出固状物,冷却;
(3)将步骤(2)所得固状物粉碎,过60-100目筛,得到含有瑞德西韦的固体分散体;
(4)将步骤(3)所得固体分散体与填充剂、崩解剂、助流剂和润滑剂混合均匀,得到总混合物;
(5)将步骤(4)所得总混合物压片制成片剂。
本发明的上述制备方法,在至少一个实施方式中,步骤(1)中瑞德西韦和共聚维酮VA64以1:2-1:3的比例混合均匀。
本发明的上述制备方法,在一些实施方式中,填充剂选自甘露醇、乳糖、微晶纤维素中的一种或几种的组合;崩解剂选自交联羧甲纤维素钠、交联聚维酮、羧甲淀粉钠中的一种或几种的组合;助流剂选自二氧化硅;润滑剂选自硬脂酸镁、硬脂酸、氢化植物油、山嵛酸甘油酯、硬脂富马酸钠中的一种或几种的组合。
与现有技术相比,本发明具有如下优点:
(1)本发明采用热熔挤出技术制备的瑞德西韦固体剂型,为口服剂型,方便患者用药。
(2)本发明采用热熔挤出技术制备的瑞德西韦固体剂型,对于轻中度患者来说,增加患者的用药顺应性,并能避免注射用药物用药过量可能带来的风险。
(3)本发明采用热熔挤出技术制备的瑞德西韦固体剂型,比普通片剂溶出度高、体内吸收生物利用度更高。经动物实验证实:本发明的采用热熔挤出技术制备的瑞德西韦固体剂型(实施例1)是瑞德西韦普通片(对比例1)在Beagle犬体内口服生物利用度的3.5倍。
(4)本发明采用热熔挤出技术制备瑞德西韦固体分散体,通过熔融、螺杆剪切和挤压,实现了无粉尘、可连续化操作、良好的重现性,活性成分在载体材料中分散均匀,制备工艺过程简单,无溶剂残留,操作方便,整个过程中不会引入其它杂质,适合工业化大生产,且所得产品质量稳定可靠,具有较好的临床应用价值。
附图说明
图1是实施例1-2及对比例1在纯化水+0.2%SDS溶出介质中的溶出曲线图。
具体实施方式
下面通过实施例来进一步说明本发明。应当理解为:本发明的实施例仅仅是用于说明本发明而给出,而不是对本发明的限制,在本发明技术方案的前提下对本发明的简单改进均属于本发明的保护范围。
实施例1
制备方法:
(1)将瑞德西韦和共聚维酮VA64按处方量混合均匀,制成物理混合物;
(2)将双螺杆热熔挤出机的挤出温度设定为140-220℃,当达到预设温度后启动螺杆,控制螺杆转速20rpm-400rpm,将步骤(1)中的物理混合物加入到挤出机中,经螺杆挤出固状物,冷却;
(3)将步骤(2)所得固状物粉碎,过60目筛,得到颗粒粒度分布均匀的固体分散体;
(4)将步骤(3)所得固体分散体与填充剂、崩解剂、助流剂和润滑剂按处方量混合均匀,得到总混合物;
(5)将步骤(4)所得总混合物压片制成片剂,控制平均重量差异±3%,压片硬度8-18kg。
实施例2
制备方法:与实施例1相同。
对比例1瑞德西韦普通口服片剂
原辅料名称 | 作用 | 每片(mg) | 含量(%) |
瑞德西韦 | 活性成份 | 100.00 | 29.85 |
甘露醇 | 填充剂 | 211.55 | 63.15 |
交联聚维酮 | 崩解剂 | 16.75 | 5.00 |
硬脂酸镁 | 润滑剂 | 6.70 | 2.00 |
片重 | - | 335.00 | 100.00 |
制备方法:
(1)将瑞德西韦和甘露醇按重量百分比混合均匀;
(2)加入交联聚维酮,与步骤(1)所得混合物混合均匀;
(3)将硬脂酸镁过40目筛与步骤(2)所得混合物混合混匀;
(4)将步骤(3)所得的混合物压片,控制平均重量差异±3%,压片硬度4kg-12kg。
实施例1-2及对比例1的质量评价实验
1、体外溶出实验
瑞德西韦口服固体剂型体外溶出曲线的测定,实验方法如下:采用桨法,转速为每分钟50转,900ml溶出介质。分别测定实施例1-2及对比例1所得产品在纯化水+0.2%SDS中的溶出曲线。分别于5min、10min、20min、30min、45min、60min时取溶出液适量,滤过,取续滤液作为供试品溶液;另精密称取瑞德西韦对照品(按照现有技术制备)适量,加甲醇溶解后,用溶出介质稀释成浓度约为0.1mg/ml的溶液,作为对照品溶液。按照高效液相色谱法(中国药典2015年版四部通则0512高效液相色谱法),用十八烷基硅胶键合硅胶为填充剂,以20mmol/L醋酸铵(以冰醋酸调节pH值至4.6)-甲醇(42:58)为流动相,检测波长为245nm,柱温为50℃,流速为1.0ml/min。精密量取对照品溶液和供试品溶液各5μl,分别注入液相色谱仪,记录色谱图,按外标法以峰面积计算溶出度,结果分别参见表1。
本发明的实施例1-2及对比例1所得的瑞德西韦片的体外溶出曲线参见图1。
表1实施例1-2及对比例1的瑞德西韦片在纯化水+0.2%SDS介质中的体外累积溶出度(%)
结论:由以上数据可知,在纯化水+0.2%SDS中,实施例1-2的瑞德西韦片明显比对比例1的瑞德西韦片溶出快,且溶出量高。由此可知,本发明的采用热熔挤出技术制备的瑞德西韦口服固体剂型与普通片剂相比,提高了体外溶出度。
2、稳定性考察
本研究将实施例1-2的瑞德西韦片分别采用口服高密度聚乙烯瓶(规格45ml)包装后进行影响因素试验,考察高温40℃和60℃条件下放置5天,对含量、溶出度及有关物质的影响,结果如表2所示:
表2实施例1-2的瑞德西韦片在加速条件下的稳定性结果
结果:实施例1-2的瑞德西韦片在高温40℃和60℃的影响因素试验条件下,含量变化不大、有关物质及溶出度均无明显变化,各项指标均符合质量标准要求,说明本品在高温条件下稳定。
3、生物利用度
为了研究瑞德西韦口服固体剂型的生物利用度,采用单剂量平行给药设计,将实施例1和对比例1的瑞德西韦片均以100mg/只的剂量给予6只Beagle犬(对实验的6只Beagle犬进行编号,分别为P11、P12、P13、P14、P15、P16),采集血浆样品并检测其中的瑞德西韦和主要代谢产物瑞德西韦核苷物(DHG)浓度,绘制药时曲线并计算药代动力学参数。瑞德西韦为前药,在吸收入血后迅速转化成DHG,因此本次试验的药代参数计算以DHG的浓度计算;将实施例1和对比例1的瑞德西韦片给药后获得的AUClast参数进行剂量归一化后,计算相对生物利用度。在下表3中列出了Beagle犬给予实施例1和对比例1的瑞德西韦片后的药物动力学参数:
表3瑞德西韦主要代谢产物瑞德西韦核苷物(DHG)的药物动力学参数
结论:Beagle犬分别给予瑞德西韦普通片(对比例1)和热熔挤出工艺制备的片剂(实施例1)100mg/只后,给药剂量折算后为8.61~15.34mg/kg,药后可测得的原型药物浓度点较少,DHG为测得的主要组分。以DHG的暴露量计算,热熔挤出工艺制备得到的瑞德西韦片剂,生物利用度为普通片剂的3.5倍。
Claims (10)
1.一种含有瑞德西韦的固体分散体,包含活性成分瑞德西韦和药学上可接受的载体,所述药学上可接受的载体为共聚维酮,其中所述瑞德西韦与共聚维酮的重量比为1:1-1:4。
2.根据权利要求1所述的固体分散体,其中所述共聚维酮为共聚维酮VA64,瑞德西韦与共聚维酮VA64的重量比为1:2-1:3。
3.一种含有瑞德西韦的固体分散体的制备方法,包含如下步骤:
(1)将瑞德西韦和共聚维酮以1:1-1:4的比例混合均匀,制成物理混合物;
(2)将双螺杆热熔挤出机的挤出温度设定为140℃-220℃,当达到预设温度后启动螺杆,将步骤(1)所得物理混合物加入到挤出机中,经螺杆挤出固状物,冷却;
(3)将步骤(2)所得固状物粉碎,过60-100目筛,即得到含有瑞德西韦的固体分散体;
优选地,其中所述步骤(1)中将瑞德西韦和共聚维酮VA64以1:2-1:3的比例混合均匀。
4.一种含有瑞德西韦的固体剂型,包含权利要求1-3中任一项所述的固体分散体,以及填充剂、崩解剂、助流剂和润滑剂。
5.根据权利要求4所述的固体剂型,包含各组分及重量百分比如下:
优选地,包含各组分及重量百分比如下:
更优选地,包含各组分及重量百分比如下:
6.根据权利要求4所述的固体剂型,其中所述填充剂选自甘露醇、乳糖、微晶纤维素中的一种或几种的组合;所述崩解剂选自交联羧甲纤维素钠、交联聚维酮、羧甲淀粉钠中的一种或几种的组合;所述助流剂选自二氧化硅;所述润滑剂选自硬脂酸镁、硬脂酸、氢化植物油、山嵛酸甘油酯、硬脂富马酸钠中的一种或几种的组合;
优选地,其中所述填充剂为甘露醇或甘露醇和微晶纤维素的组合,所述崩解剂为交联羧甲纤维素钠,所述助流剂为二氧化硅,所述润滑剂为硬脂酸镁。
7.一种含有瑞德西韦的固体剂型,包含各组分及重量百分比如下:
8.根据权利要求7所述的固体剂型,包含各组分及重量百分比如下:
或者
9.一种含有瑞德西韦的固体剂型的制备方法,包含如下步骤:
(1)将瑞德西韦和共聚维酮以1:1-1:4的比例混合均匀,制成物理混合物;
(2)将双螺杆热熔挤出机的挤出温度设定为140℃-220℃,当达到预设温度后启动螺杆,将步骤(1)所得物理混合物加入到挤出机中,经螺杆挤出固状物,冷却;
(3)将步骤(2)所得固状物粉碎,过60-100目筛,得到含有瑞德西韦的固体分散体;
(4)将步骤(3)所得固体分散体与填充剂、崩解剂、助流剂和润滑剂混合均匀,得到总混合物;
(5)将步骤(4)所得总混合物压片制成片剂,
优选地,其中所述步骤(1)中瑞德西韦和共聚维酮VA64以1:2-1:3的比例混合均匀。
10.根据权利要求9所述的固体剂型的制备方法,其中所述填充剂选自甘露醇、乳糖、微晶纤维素中的一种或几种的组合;崩解剂选自交联羧甲纤维素钠、交联聚维酮、羧甲淀粉钠中的一种或几种的组合;助流剂选自二氧化硅;润滑剂选自硬脂酸镁、硬脂酸、氢化植物油、山嵛酸甘油酯、硬脂富马酸钠中的一种或几种的组合。
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