CN106699740A - 一种雷迪帕韦和索非布韦复方片剂及其制备方法和应用 - Google Patents
一种雷迪帕韦和索非布韦复方片剂及其制备方法和应用 Download PDFInfo
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- CN106699740A CN106699740A CN201611217403.7A CN201611217403A CN106699740A CN 106699740 A CN106699740 A CN 106699740A CN 201611217403 A CN201611217403 A CN 201611217403A CN 106699740 A CN106699740 A CN 106699740A
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Classifications
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- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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- C—CHEMISTRY; METALLURGY
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
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Abstract
本发明公开了一种雷迪帕韦和索非布韦复方片剂及其制备方法和应用。本发明提供了一种雷迪帕韦和索非布韦复方片剂,包括:无定形雷迪帕韦I和无定形索非布韦II。所述的雷迪帕韦和索非布韦复方片剂的制备方法,包括以下步骤:将无定形雷迪帕韦I和无定形索非布韦II以及药用辅料混合、制剂即可。本发明制备的雷迪帕韦和索非布韦复方片剂与原研片剂的晶型组合具有高度类似的体外溶出行为,而且合成工艺简便、操作安全、环境友好、适合于工业化生产。
Description
技术领域
本发明涉及一种雷迪帕韦和索非布韦复方片剂及其制备方法和应用。
背景技术
丙型病毒性肝炎,简称丙型肝炎,是一种有丙型肝炎病毒(HCV)引起的病毒性肝炎。根据世界卫生组织估计,全球丙肝感染率约为3%,估计约有1亿7千万人携带丙肝病毒。丙型肝炎可导致肝脏慢性炎症坏死和纤维化,部分患者可能发展为肝硬化甚至肝癌,对患者的健康和生命带来极大威胁。
慢性丙型肝炎的治疗目标是清除病毒,从而可限制或防止并发症的发生,而成功治疗的标准定义为停止治疗后的24周,患者血清中检测不到丙肝病毒的RNA。而目前丙型肝炎的治疗方法是聚乙二醇干扰素和利巴韦林联合方案,但该方法可能导致贫血,变态反应和抑郁样精神症等副作用,因此研究新型抗慢性丙型肝炎病毒药物一直是研究热门领域。2014年10月10日,吉利德科学(Gilead Sciences)研发的新型丙肝药物(雷迪帕韦+索非布韦的复方片剂)被美国FDA批准,成为世界第一个治疗基因1型成人丙型肝炎的全口服,不含干扰素和利巴韦林的治疗方案。雷迪帕韦,英文名:Ledipasvir,化学结构式如式I所示;索非布韦,英文名:Sofosbuvir,化学结构式如式II所示。
根据专利CN201480000286.1中报道,吉利德科学(Gilead Sciences)研发的雷迪帕韦索非布韦复方片剂中包含了适量的雷迪帕韦为非晶体形态,索非布韦则为晶体6。但是该复方片剂的合成工艺复杂,不太适合于工业化生产。因此,寻找合成工艺简单、生产成本低、适合于工业化生产的雷迪帕韦索非布韦复方片剂,是目前急需解决的技术问题。
发明内容
本发明所要解决的技术问题是为了克服现有技术中雷迪帕韦与索非布韦的复方片剂制备工艺复杂、生产成本高、不太适合于工业化生产等缺陷而提供了一种雷迪帕韦和索非布韦复方片剂及其制备方法和应用。本发明制备的雷迪帕韦和索非布韦复方片剂与原研片剂的晶型组合具有高度类似的溶出度,而且合成工艺简便、操作安全、环境友好、适合于工业化生产。
本发明提供了一种雷迪帕韦和索非布韦复方片剂,其包括:无定形雷迪帕韦I和无定形索非布韦II。所述的无定形雷迪帕韦I的纯度大于99.5%(HPLC纯度);所述的无定形索非布韦II的纯度大于99.5%(HPLC纯度)。
所述的雷迪帕韦和索非布韦复方片剂中,所述的无定形雷迪帕韦I与所述的无定形索非布韦II的质量比值优选(1:1)~(1:10),进一步优选(1:3)~(1:6),例如9:40。
本发明还提供了所述的雷迪帕韦和索非布韦复方片剂的制备方法,其包括以下步骤:将无定形雷迪帕韦I和无定形索非布韦II以及药用辅料混合、制剂即可。
所述的药用辅料可以为本领域中制备片剂常用的药用辅料:包括淀粉、纤维素及其衍生物;润滑剂,比如聚乙二醇、滑石粉、硬脂酸或硬脂酸镁;稀释剂,比如滑石粉、粉末纤维素、乳糖、淀粉比如玉蜀黍淀粉或玉米淀粉、甘露醇、山梨醇;助流剂,比如二氧化硅;崩解剂,比如微晶纤维素或交聚维酮;配体,比如甲基纤维素、羧甲基纤维素钠、交联羧甲基纤维素钠、海藻酸、海藻酸盐;甜味剂,比如蔗糖、葡萄糖、甘露醇、糖精;或矫味剂,比如天然油或合成油。
所述的混合、制剂可以为本领域中该类操作的常规方法。
本发明还提供了所述的无定形雷迪帕韦I的制备方法,其包括以下步骤:将雷迪帕韦原料药和有机溶剂形成的溶液与水混合,得到无定形雷迪帕韦I即可;
在所述的无定形雷迪帕韦I的制备方法中,所述的雷迪帕韦原料药包括目前已报道的各种雷迪帕韦晶型和雷迪帕韦溶剂化合物等,例如雷迪帕韦丙酮化物、雷迪帕韦晶型A、雷迪帕韦晶型B和雷迪帕韦晶型C等。(所述的雷迪帕韦丙酮化物、雷迪帕韦晶型A、雷迪帕韦晶型B和雷迪帕韦晶型C可以通过商购得到或者可以按照专利CN201410226164的方法制备得到)
在所述的无定形雷迪帕韦I的制备方法中,所述的有机溶剂优选乙酸乙酯、甲醇、乙醇、异丙醇、四氢呋喃、丙酮、乙腈、N,N-二甲基甲酰胺、二甲亚砜和乙二醇中的一种或多种,进一步优选乙腈、四氢呋喃、异丙醇或N,N-二甲基甲酰胺。
在所述的无定形雷迪帕韦I的制备方法中,所述的有机溶剂与所述的雷迪帕韦原料药的体积质量比值优选2mL/g~12mL/g,进一步优选4mL/g~8mL/g,例如6mL/g。
在所述的无定形雷迪帕韦I的制备方法中,所述的水优选纯化水。
在所述的无定形雷迪帕韦I的制备方法中,所述的水与所述的有机溶剂的体积比值优选2~10,进一步优选5~7,例如5.8。
在所述的无定形雷迪帕韦I的制备方法中,所述的加入的方式优选滴加。所述的滴加的速度优选10mL/min~100mL/min,例如10mL/min或100mL/min。
所述的无定形雷迪帕韦I的制备方法优选采用以下步骤:将雷迪帕韦原料药与有机溶剂形成的溶液滴加到剧烈搅拌的水中,搅拌、过滤、洗涤、干燥,得到无定形雷迪帕韦I即可。所述的滴加的速度优选10mL/min~100mL/min,例如10mL/min或100mL/min。所述的剧烈搅拌优选搅拌速度50rpm~500rpm,进一步优选200rpm~400rpm,例如200rpm、300rpm、350rpm或400rpm。所述的搅拌、过滤、洗涤和干燥可以采用本领域中该类操作的常规方法。所述的搅拌的温度优选20℃~30℃,所述的搅拌的时间优选0.5小时~1.5小时,例如0.5小时~1小时或1小时~1.5小时。所述的洗涤优选采用纯化水洗涤,洗涤用纯化水与所述的雷迪帕韦的体积质量比值优选1mL/g~5mL/g,例如2mL/g。所述的洗涤的次数优选1~3次。所述的干燥优选真空干燥,所述的真空干燥的温度优选50℃~60℃,所述的真空干燥的时间优选8小时~12小时,所述的真空干燥的压强优选-0.01MPa~-0.08MPa。
本发明还提供了所述的无定形索非布韦II的制备方法,其包括以下步骤:将索非布韦原料药与有机溶剂形成的溶液除去有机溶剂后、再加入溶剂得到无定形索非布韦II即可;所述的有机溶剂与所述的溶剂不同;
在所述的无定形索非布韦II的制备方法中,所述的索非布韦原料药包括目前已报到的各种索非布韦晶型和溶剂化合物,例如索非布韦晶型1、索非布韦晶型2、索非布韦晶型3、索非布韦晶型4、索非布韦晶型5、索非布韦晶型6、索非布韦的二氯甲烷化物和索非布韦的氯仿化物。(所述的索非布韦晶型1、索非布韦晶型2、索非布韦晶型3、索非布韦晶型4、索非布韦晶型5、索非布韦晶型6、索非布韦的二氯甲烷化物和索非布韦的氯仿化物可以通过商购得到或者可以采用专利CN201180017181.3的方法制备得到)
在所述的无定形索非布韦II的制备方法中,所述的有机溶剂优选极性有机溶剂;所述的极性有机溶剂优选乙酸乙酯、甲醇、乙醇、异丙醇、四氢呋喃、丙酮、乙腈,进一步优选乙酸乙酯、甲醇、丙酮和乙腈中的一种或多种。
在所述的无定形索非布韦II的制备方法中,所述的有机溶剂与所述的索非布韦原料药的体积质量比值优选2mL/g~12mL/g,进一步优选5mL/g~11mL/g,例如10mL/g。
在所述的无定形索非布韦II的制备方法中,所述的溶剂优选非极性有机溶剂;所述的非极性有机溶剂优选正庚烷、石油醚、环己烷、正己烷和甲苯中的一种或多种,进一步优选正庚烷、正己烷和甲苯中的一种或多种。
在所述的无定形索非布韦II的制备方法中,所述的溶剂与所述的索非布韦原料药的体积质量比值优选1mL/g~50mL/g,进一步优选10mL/g~20mL/g,例如15mL/g。
在所述的无定形索非布韦II的制备方法中,所述的除去有机溶剂优选减压蒸馏的方式,所述的减压蒸馏的温度优选10℃~90℃,进一步优选40℃~60℃,例如40℃~50℃。所述的减压蒸馏的压强优选0.01MPa~0.08MPa。
在所述的无定形索非布韦II的制备方法中,所述的加入溶剂的方式优选滴加。所述的滴加的速度优选40mL/min~500mL/min,例如40mL/min或500mL/min。
所述的无定形索非布韦II的制备方法优选采用以下步骤:将索非布韦原料药与有机溶剂形成的溶液,除去有机溶剂,再加入溶剂、搅拌、过滤、洗涤、干燥得到无定形索非布韦II。
所述的搅拌、过滤、洗涤和干燥可以采用本领域中该类操作的常规方法。所述的搅拌的温度优选0℃~30℃,进一步优选20℃~30℃。所述的洗涤优选采用非极性有机溶剂;所述的非极性有机溶剂优选正庚烷、石油醚、环己烷、正己烷和甲苯中的一种或多种,进一步优选正庚烷。洗涤用溶剂与所述的索非布韦的体积质量比值优选1mL/g~5mL/g,例如2mL/g。所述的洗涤的次数优选1~3次。所述的干燥优选真空干燥,所述的真空干燥的温度优选40℃~60℃,例如40℃,所述的真空干燥的时间优选8小时~12小时,所述的真空干燥的压强优选-0.01MPa~-0.08MPa。
本发明还提供了所述的雷迪帕韦和索非布韦复方片剂在制备治疗和/或预防丙肝的药物中的应用。
如本说明书所用的以下字词和短语通常具有以下规定的含义,除非其使用的文义另有所指。
本发明中,所述的术语“晶型”是化合物分子或原子在晶格空间排列不同而形成的不同固体状态。
本发明中,所述的术语“无定形”是指一些非完全晶体无定形区(非晶区)的结构或者一些无定形固体(非晶体)的构成方式。
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明中,所述的室温是指环境温度,为10℃~35℃。
本发明的积极进步效果在于:本发明制备的雷迪帕韦和索非布韦复方片剂与原研(专利CN201480000286.1)制得的片剂的晶型组合具有相似的体外溶出行为,而且合成工艺简便、操作安全、环境友好、适合于工业化生产。
附图说明
图1为实施例1-5中采用的雷迪帕韦无定形固体原料药的XRPD谱图;
图2为实施例1-5中采用的雷迪帕韦无定形固体原料药的差示扫描量热(DSC)曲线;
图3为实施例6-10中采用的索非布韦无定形固体原料药的XRPD谱图;
图4为实施例6-10中采用的索非布韦无定形固体原料药的差示扫描量热(DSC)曲线;
图5为实施例11制得的索非布韦(400mg)/雷迪帕韦(90mg)复方片剂中雷迪帕韦在四种不同溶出介质下的溶出曲线图。
表示索非布韦(400mg)/雷迪帕韦(90mg)复方片剂中雷迪帕韦在0.1mol/L盐酸介质中的溶出曲线图
表示索非布韦(400mg)/雷迪帕韦(90mg)复方片剂中雷迪帕韦在pH4.5醋酸盐缓冲液中的溶出曲线图(含0.4%SLS);
表示索非布韦(400mg)/雷迪帕韦(90mg)复方片剂中雷迪帕韦在pH6.8磷酸盐缓冲液中的溶出曲线图(含0.4%SLS);
表示索非布韦(400mg)/雷迪帕韦(90mg)复方片剂中雷迪帕韦在水中的溶出曲线图(含0.4%SLS)。
图6为实施例11制得的索非布韦(400mg)/雷迪帕韦(90mg)复方片剂与原研吉利德公司对照药在0.1mol/L盐酸介质中,索非布韦的溶出曲线对比图;其中:
表示原研吉利德公司对照药在0.1mol/L盐酸介质中,索非布韦的溶出曲线图;
表示实施例11中描述的索非布韦(400mg)/雷迪帕韦(90mg)复方片剂在0.1mol/L盐酸介质中,索非布韦的溶出曲线图。
图7为实施例11制得的索非布韦(400mg)/雷迪帕韦(90mg)复方片剂与原研吉利德公司对照药在0.1mol/L盐酸中,索非布韦的溶出曲线对比图;其中:
表示原研吉利德公司对照药中索非布韦的溶出曲线图;
表示实施例11中描述的索非布韦(400mg)/雷迪帕韦(90mg)复方片剂中索非布韦的溶出曲线图。
图8为实施例11制得的索非布韦(400mg)/雷迪帕韦(90mg)复方片剂与原研吉利德公司对照药在0.1mol/L盐酸介质中,雷迪帕韦的溶出曲线对比图;
表示原研吉利德公司对照药中雷迪帕韦的溶出曲线图;
表示实施例11中描述的索非布韦(400mg)/雷迪帕韦(90mg)复方片剂中雷迪帕韦的溶出曲线图。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
实施例1-5中采用的雷迪帕韦无定形固体原料药的XRPD谱图见图1,根据XRPD显示,其固体为无定形。实施例1-5中采用的雷迪帕韦无定形固体原料药的差示扫描量热(DSC)曲线见图2,根据DSC曲线显示,其固体的玻璃化转化温度为166℃左右。实施例6-10中采用的索非布韦无定形固体原料药的XRPD谱图见图3,根据XRPD显示,其固体为无定形。实施例6-10中采用的索非布韦无定形固体原料药的差示扫描量热(DSC)曲线见图4,根据DSC曲线显示,其固体无明显吸热峰,250℃左右分解。
实施例1 雷迪帕韦无定形固体原料药的制备
室温下(10℃~15℃),将雷迪帕韦晶型A原料药(10.0g)加入至60ml乙腈中,搅拌溶清。将上述所得溶液在6分钟内加入350ml剧烈搅拌(搅拌速度200rpm)的纯化水中,体系析出大量类白色固体。滴加完毕,保持20℃~30℃搅拌0.5-1小时。过滤,滤饼用20ml纯化水淋洗一次,后置于真空烘箱内(压强-0.1MPa~-0.08MPa),50℃烘干8~12小时,得无定形雷迪帕韦8.7g,收率87%,HPLC纯度99.87%,de>99.0%。
实施例2 雷迪帕韦无定形固体原料药的制备
室温下(15℃~20℃),将雷迪帕韦晶体形态A原料药(1.0Kg)加入至6L乙腈中,搅拌溶清。将上述所得溶液在60分钟内滴加入35L剧烈搅拌(转速200rpm)的纯化水中,体系析出大量类白色固体。滴加完毕,保持20℃~30℃搅拌1-1.5小时。过滤,滤饼用2L纯化水淋洗一次,后置于真空烘箱内(压强-0.1MPa~-0.08MPa),50℃烘干8~12小时,得无定形雷迪帕韦0.9Kg,收率90%,HPLC纯度99.93%,de>99.0%。
实施例3 雷迪帕韦无定形固体原料药的制备
室温下(20℃~25℃),将雷迪帕韦晶型B原料药(10.0g)加入至60ml四氢呋喃中,搅拌溶清。将上述所得溶液在6分钟内加入350ml剧烈搅拌(转速300rpm)的纯化水中,体系析出大量类白色固体。滴加完毕,保持20℃~30℃搅拌0.5-1小时。过滤,滤饼用20ml纯化水淋洗一次后置于真空烘箱内(压强-0.1MPa~-0.08MPa),50℃烘干8~12小时,得无定形雷迪帕韦8.3g,收率83%,HPLC纯度99.92%,de>99%。
实施例4 雷迪帕韦无定形固体原料药的制备
室温下(25℃~30℃),将雷迪帕韦晶型C原料药(10.0g)加入至60ml异丙醇中,搅拌溶清。将上述所得溶液在6分钟内加入350ml剧烈搅拌(转速400rpm)的纯化水中,体系析出大量类白色固体。滴加完毕,保持20℃~30℃拌0.5-1小时。过滤,滤饼用20ml纯化水淋洗一次,后置于真空烘箱内(压强-0.1MPa~-0.08MPa),50℃烘干8~12小时,得雷迪帕韦无定形原料药8.5g,收率85%,HPLC纯度99.90%,de>99.0%。
实施例5 雷迪帕韦无定形固体原料药的制备
室温下(30℃~35℃),将雷迪帕韦丙酮化物原料药(10.0g)加入至60ml N,N-二甲基甲酰胺中,搅拌溶清。将上述所得溶液在6分钟内加入350ml剧烈搅拌(转速350rpm)的纯化水中,体系析出大量类白色固体。滴加完毕,保持20℃~30℃搅拌0.5-1小时。过滤,滤饼用20ml纯化水淋洗一次,后置于真空烘箱内(压强-0.1MPa~-0.08MPa),50℃烘干8~12小时,得雷迪帕韦无定形原料药7.6g,收率76%,HPLC纯度99.94%,de>99.0%。
实施例6 索非布韦无定形固体原料药的制备
室温下(10℃~15℃),将索非布韦晶型1原料药(8.0g)加入至80ml乙酸乙酯中,搅拌溶清。将上述所得溶液减压浓缩至无液滴(40~50℃,0.08Mpa)。体系在3分钟内加入120ml正庚烷,搅拌降温至20℃~30℃后继续搅拌1~2小时。过滤,滤饼用16ml正庚烷淋洗一次,后置于真空烘箱内(压强-0.1MPa~-0.08MPa),40℃烘干8~12小时,得索非布韦无定形原料药7.3g,收率91.3%,HPLC纯度99.79%,de>99.0%。
实施例7 索非布韦无定形固体原料药的制备
室温下(15℃~20℃),将索非布韦晶型6的原料药(4Kg)加入至40L乙酸乙酯中,搅拌溶清。将上述所得溶液减压浓缩至无液滴(40~50℃,0.08Mpa)。体系内在120分钟内加入60L正庚烷,搅拌降温至20℃~30℃后继续搅拌1~2小时。过滤,滤饼用8L正庚烷淋洗一次,后置于真空烘箱内(压强-0.1MPa~-0.08MPa),40℃烘干8~12小时,得索非布韦非晶体形态原料药3.7Kg,收率92.5%,HPLC纯度99.83%,de>99.0%。
实施例8 索非布韦无定形固体原料药的制备
室温下(20℃~25℃),将索非布韦晶型6原料药(8.0g)加入至80ml甲醇中,搅拌溶清。将上述所得溶液减压浓缩至无液滴(40~50℃,0.08Mpa)。体系内在3分钟内加入120ml正己烷,搅拌降温至20℃~30℃后继续搅拌1~2小时。过滤,滤饼用16ml正己烷淋洗一次后置于真空烘箱内(-0.01MPa~-0.08MPa),40℃烘干8~12小时,得索非布韦无定形原料药7.1g,收率88.8%,HPLC纯度99.86%,de>99.0%。
实施例9 索非布韦无定形固体原料药的制备
室温下(15℃~20℃),将索非布韦晶型1原料药(8.0g)加入至80ml丙酮中,搅拌溶清。将上述所得溶液减压浓缩至无液滴(40~50℃,0.08Mpa)。体系内在3分钟内加入120ml甲苯,搅拌降温至20℃~30℃后继续搅拌1~2小时。过滤,滤饼用16ml甲苯淋洗一次,后置于真空烘箱内(-0.01MPa~-0.08MPa),40℃烘干8~12小时,得索非布韦无定形原料药6.9g,收率86.3%,HPLC纯度99.90%,de>99.0%。
实施例10 索非布韦无定形固体原料药的制备
室温下(25℃~30℃),将索非布韦晶型6原料药(8.0g)加入至80ml乙腈中,搅拌溶清。将上述所得溶液减压浓缩至无液滴(40~50℃,0.08Mpa)。体系内在3分钟内加入120ml正庚烷,搅拌降温至20℃~30℃后继续搅拌1~2小时。过滤,滤饼用16ml正庚烷淋洗一次,后置于真空烘箱内(-0.01MPa~-0.08MPa),40℃烘干8~12小时,得索非布韦无定形原料药7.2g,收率90.0%,HPLC纯度99.85%,de>99.0%。
实施例11 雷迪帕韦和索非布韦复方片剂的制备
将实施例7制得的索非布韦无定形原料药400mg,与实施例2制得的雷迪帕韦无定形原料药90mg与360mg甘露醇、296mg微晶纤维素、30mg交联羧甲基纤维素钠、5.4mg二氧化硅、9.0mg硬脂酸镁混合、制剂得到雷迪帕韦和索非布韦复方片剂。
制得的雷迪帕韦(90mg)和索非布韦(400mg)复方片剂中雷迪帕韦雷迪帕韦在四种不同溶出介质下的溶出曲线图见图5。制得的雷迪帕韦(90mg)和索非布韦(400mg)复方片剂与原研吉利德公司对照药在0.1mol/L盐酸介质中,索非布韦的溶出曲线对比图见图6。制得的索非布韦(400mg)/雷迪帕韦(90mg)复方片剂与原研吉利德公司对照药在0.1mol/L盐酸中,索非布韦的溶出曲线对比图见图7。制得的索非布韦(400mg)/雷迪帕韦(90mg)复方片剂与原研吉利德公司对照药在0.1mol/L盐酸介质中,雷迪帕韦的溶出曲线对比图见图8。
根据对比发现,本发明的雷迪帕韦(90mg)和索非布韦(400mg)复方片剂与原研吉利德对照品批号2EZPA07006具有相似的体外溶出行为。
Claims (10)
1.一种雷迪帕韦和索非布韦复方片剂,其特征在于其包括:无定形雷迪帕韦I和无定形索非布韦II。
2.如权利要求1所述的雷迪帕韦和索非布韦复方片剂,其特征在于:所述的无定形雷迪帕韦I的纯度大于99.5%;
和/或,
所述的无定形索非布韦II的纯度大于99.5%。
3.如权利要求1所述的雷迪帕韦和索非布韦复方片剂,其特征在于:所述的雷迪帕韦和索非布韦复方片剂中,所述的无定形雷迪帕韦I与所述的无定形索非布韦II的质量比值为(1:1)~(1:10)。
4.如权利要求3所述的雷迪帕韦和索非布韦复方片剂,其特征在于:所述的雷迪帕韦和索非布韦复方片剂中,所述的无定形雷迪帕韦I与所述的无定形索非布韦II的质量比值为(1:3)~(1:6),例如9:40。
5.如权利要求1~4任一项所述的雷迪帕韦和索非布韦复方片剂的制备方法,其特征在于其包括以下步骤:将无定形雷迪帕韦I和无定形索非布韦II以及药用辅料混合、制剂即可。
6.如权利要求5所述的雷迪帕韦和索非布韦复方片剂的制备方法,其特征在于:所述的无定形雷迪帕韦I的制备方法包括以下步骤:将雷迪帕韦原料药和有机溶剂形成的溶液与水混合,得到无定形雷迪帕韦I即可;
7.如权利要求6所述的雷迪帕韦和索非布韦复方片剂的制备方法,其特征在于:在所述的无定形雷迪帕韦I的制备方法中,所述的雷迪帕韦原料药包括雷迪帕韦丙酮化物、雷迪帕韦晶型A、雷迪帕韦晶型B和雷迪帕韦晶型C;
和/或,
在所述的无定形雷迪帕韦I的制备方法中,所述的有机溶剂为乙酸乙酯、甲醇、乙醇、异丙醇、四氢呋喃、丙酮、乙腈、N,N-二甲基甲酰胺、二甲亚砜和乙二醇中的一种或多种;
和/或,
在所述的无定形雷迪帕韦I的制备方法中,所述的有机溶剂与所述的雷迪帕韦原料药的体积质量比值为2mL/g~12mL/g;
和/或,
在所述的无定形雷迪帕韦I的制备方法中,所述的水为纯化水;
和/或,
在所述的无定形雷迪帕韦I的制备方法中,所述的水与所述的有机溶剂的体积比值为2~10;
和/或,
在所述的无定形雷迪帕韦I的制备方法中,所述的加入的方式为滴加;
和/或,
所述的无定形雷迪帕韦I的制备方法包括以下步骤:将雷迪帕韦原料药与有机溶剂形成的溶液滴加到剧烈搅拌的水中,搅拌、过滤、洗涤、干燥,得到无定形雷迪帕韦I即可。
8.如权利要求5所述的雷迪帕韦和索非布韦复方片剂的制备方法,其特征在于:所述的无定形索非布韦II的制备方法包括以下步骤:将索非布韦原料药与有机溶剂形成的溶液除去有机溶剂后、再加入溶剂得到无定形索非布韦II即可;所述的有机溶剂与所述的溶剂不同;
9.如权利要求8所述的雷迪帕韦和索非布韦复方片剂的制备方法,其特征在于:在所述的无定形索非布韦II的制备方法中,所述的索非布韦原料药包括索非布韦晶型1、索非布韦晶型2、索非布韦晶型3、索非布韦晶型4、索非布韦晶型5、索非布韦晶型6、索非布韦的二氯甲烷化物和索非布韦的氯仿化物;
和/或,
在所述的无定形索非布韦II的制备方法中,所述的有机溶剂为极性有机溶剂;
和/或,
在所述的无定形索非布韦II的制备方法中,所述的有机溶剂与所述的索非布韦原料药的体积质量比值为2mL/g~12mL/g;
和/或,
在所述的无定形索非布韦II的制备方法中,所述的溶剂为非极性有机溶剂;
和/或,
在所述的无定形索非布韦II的制备方法中,所述的溶剂与所述的索非布韦原料药的体积质量比值为1mL/g~50mL/g;
和/或,
在所述的无定形索非布韦II的制备方法中,所述的除去有机溶剂采用减压蒸馏的方式;
和/或,
在所述的无定形索非布韦II的制备方法中,所述的加入溶剂的方式为滴加;
和/或,
所述的无定形索非布韦II的制备方法采用以下步骤:将索非布韦原料药与有机溶剂形成的溶液,除去有机溶剂,再加入溶剂、搅拌、过滤、洗涤、干燥得到无定形索非布韦II。
10.如权利要求1所述的雷迪帕韦和索非布韦复方片剂在制备治疗和/或预防丙肝的药物中的应用。
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Application publication date: 20170524 |