CN116421595B - 一种达格列净药物组合物及制备方法和应用 - Google Patents
一种达格列净药物组合物及制备方法和应用 Download PDFInfo
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- CN116421595B CN116421595B CN202310144287.4A CN202310144287A CN116421595B CN 116421595 B CN116421595 B CN 116421595B CN 202310144287 A CN202310144287 A CN 202310144287A CN 116421595 B CN116421595 B CN 116421595B
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- PZIRUHCJZBGLDY-UHFFFAOYSA-N Caffeoylquinic acid Natural products CC(CCC(=O)C(C)C1C(=O)CC2C3CC(O)C4CC(O)CCC4(C)C3CCC12C)C(=O)O PZIRUHCJZBGLDY-UHFFFAOYSA-N 0.000 claims abstract description 37
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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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
- A61K9/14—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
本发明公开了一种达格列净药物组合物及制备方法和应用。所述的达格列净药物组合物包含达格列净和绿原酸及药用载体。本发明的达格列净药物组合物以无定型态存在,在人工气候箱(40℃、75%RH)条件下放置30天不发生晶型转变。该达格列净药物组合物的引湿性低于无定型。同时,该达格列净药物组合物拥有较好的热稳定性,根据其玻璃化转变温度,远高于制剂工艺的高温加工要求。
Description
技术领域
本发明属于药物制剂领域,具体的,本发明涉及一种达格列净药物组合物及制备方法和应用。
背景技术
达格列净(dapagliflozin)是由百时美施贵宝和阿斯利康公司联合开发的一种抗糖尿病药物,于2012年11月12日被欧洲药品管理局(EMA)批准上市,是首个获准上市用于治疗2型糖尿病的SGLT2抑制剂。
达格列净在降糖过程中,不需要依赖胰岛素,能将多余的糖分从尿中排出,减轻患者的水钠潴留情况,从而能显著改善患者的血糖、减轻体重,降低其心血管事件的风险,该药物有助于糖尿病的全面管理。
文献中表明达格列净具有生殖感染和尿路感染的风险。(牟伦盼,蒋建家,张雅萍等.达格列净与利格列汀对口服降糖药控制不佳的超重或肥胖2型糖尿病患者的疗效和安全性比较[J].中华糖尿病杂志,2019,11(3):190-195.)。绿原酸是一种天然产物提取物,主要存在于忍冬科忍冬属、菊科蒿属植物中,具有抗氧化、抗菌、抗病毒、抗癌、抗紫外光与辐射、免疫调节、降血脂、降血糖等药理作用。绿原酸可能通过抑制α-淀粉酶的活性来降低淀粉所致的血糖浓度上升。同时,其易溶于水,在25℃下溶解度为4%。
达格列净原研采用以(s)-丙二醇一水合物的固态形式上市,其中包含了溶剂(s)-丙二醇是手性分子,对脑、消化系统、血液存在一定的毒性,而且价格昂贵,导致药物成本高。当前文献中报道了多种溶剂合物,但均无法获取非溶剂化的单一晶型。
药物的固体形态除晶态外,还有无定型状态,药物的无定型状态作为固体物质的一种特殊形态,在药物制备中有着重要的用途。一般由于晶态物质分子的有序和周期性排列,降低了分子间相互作用的能量,能量较低,而无定型态的分子处于高度无序状态,物质的表面自由能更大,固体物质中的分子较晶态固体物质中的分子有更高的能量,更容易分散,增加其溶出度,提高药物的生物利用度。
结合现有技术的方案描述现有技术的缺点
达格列净无定型有较强引湿性,吸湿后容易变粘稠或成油,导致其稳定性差。达格列净上市药物形式为达格列净-(S)丙二醇-水共溶剂合物,熔点在70℃左右。根据中国专利CN05524033公开的内容可知,达格列净无定形和达格列净-(S)丙二醇-水共溶剂合物的高温、高湿稳定性均较差,对制剂开发具有较大挑战。
为了解决达格列净的固态稳定性及避免引入如同丙二醇等具有毒性的溶剂的溶剂合物,降低达格列净的生殖系统感染的副作用,开发一种高稳定性、具有增溶效果的、降低副作用的达格列净的药物组合物的具有明显的意义。
发明内容
本发明提出一种达格列净药物组合物及其制备方法、应用。该药物组合物主要由达格列净、绿原酸及药用载体组成。具有低吸湿性、高温稳定性,具有更高溶解度。该组合物可适用于片剂、胶囊等多种剂型配合不同的给药方式。
本发明的第一方面,提出一种达格列净药物组合物,包含达格列净和绿原酸及药用载体。
在本发明的一些实施方式中,所述药用载体选自共聚维酮(PVP VA64)、羟丙基甲基纤维素邻苯二甲酸酯(HPMCP)、乙酸纤维素偏苯三酸酯(CAT)、乙酸纤维素邻苯二甲酸酯(CAP)、邻苯二甲酸羟丙基纤维素乙酸酯(HPCAP)、邻苯二甲酸羟丙基甲基纤维素乙酸酯(HPMCAP)和邻苯二甲酸甲基纤维素乙酸酯(MCAP)其中至少一种。
在本发明的一些实施方式中,所述的达格列净与绿原酸的质量比为10:1~1:10,达格列净:药物载体的质量比为10:1~1:10。进一步优选,所述的达格列净与绿原酸的质量比为2:1~1:2,药物载体的质量比为3:2~1:4。
在本发明的一些实施方式中,所述的达格列净、绿原酸和药用载体的质量比为1:1:3。
本发明的第二方面,提出一种达格列净药物组合物的制备方法,是将达格列净、绿原酸和药用载体溶解于溶剂中,然后将溶剂除去获取。
在本发明的一些实施方式中,所用溶剂为甲醇、乙醇、二氯甲烷、丙酮、乙酸乙酯、水等中一种或几种形成的混合溶剂。
在本发明的一些实施方式中,达格列净、绿原酸和药用载体溶解于溶剂中形成溶液,并通过喷雾干燥的方式将溶剂除去。
本发明的第三方面,提出一种包含本发明达格列净药物组合物的药物制剂。本发明的药物制剂是可以将达格列净药物组合物与常用辅料根据公开的常规技术形成制剂。常用辅料包含填充剂、崩解剂、矫味剂、润滑剂、表面活性剂等其中的一种或多种。
在本发明的一些实施方式中,将达格列净药物组合物与填充剂、崩解剂及润滑剂等制备成片剂。
本发明的第四个方面是提供上述达格列净药物组合物或其药物制剂在制备抗糖尿病药物中的应用。
本发明具有如下有益的效果:
本发明的达格列净药物组合物以无定型态存在,在人工气候箱(40℃、75%RH)条件下放置30天不发生晶型转变。该达格列净药物组合物的引湿性低于无定型。同时,该达格列净药物组合物拥有较好的热稳定性,根据其玻璃化转变温度,远高于制剂工艺的高温加工要求。
附图说明
图1为实施例1中制得的达格列净:绿原酸:HPMCP药物组合物的X-射线粉末衍射图。
图2为实施例2中制得的达格列净:绿原酸:PVP VA64药物组合物的X-射线粉末衍射图。
图3为对照组1中制得的无定型达格列净的X-射线粉末衍射图。
图4为对照组2中制得的达格列净:PVP VA64药物组合物的X-射线粉末衍射图
图5为实施例2中制得的达格列净:绿原酸:PVP VA64药物组合物的差示扫描量热法测得图谱。
图6为对照组1制得无定型达格列净差示扫描量热法测得图谱。
图7为对照组2制得达格列净:PVP VA64药物组合物差示扫描量热法测得图谱。
图8为本发明实施例2制得达格列净:绿原酸:PVP VA64药物组合物的等温吸附图。
图9为本发明实施例2制得达格列净:绿原酸:PVP VA64药物组合物在40℃、75%RH条件下加速0、3、5、10、20、30天前后的X-射线粉末衍射图对比。
具体实施方式
现结合附图以及本发明的实施例对本发明作进一步的详细说明。以下说明仅仅是对本发明要求保护的技术方案的举例说明,并非对这些技术方案的任何限制。本发明的保护范围以所附权利要求书记载的内容为准。
实施例1
达格列净:绿原酸:HPMCP药物组合物的制备:
将0.2g达格列净、0.2g绿原酸和0.6g HPMCP(羟丙甲纤维素邻苯二甲酸酯)溶解在5mL甲醇/二氯甲烷(体积比1:1)混合溶剂中。将获取的溶液通过喷雾干燥仪进行喷雾干燥,设置喷雾干燥仪器的进口温度为75℃、出口温度为60℃、进料速率为5mL/min、抽吸力为100%以及雾化气流40mm。气流通过-20℃的冷凝器将溶剂蒸汽回收。通过旋风分离器下端收集器收集粉末。
将收集器中获取的产品置于35℃真空干燥箱,减压干燥24小时除去残留的溶剂,可得达格列净:绿原酸:HPMCP药物组合物。产品经过X-射线粉末衍射仪检测,结果图1所示,由图可确定其为无定型态。
实施例2
达格列净:绿原酸:PVP VA64药物组合物的制备:
将0.2g达格列净、0.2g绿原酸和0.6g PVP VA64溶解在5mL甲醇/二氯甲烷(体积比1:1)混合溶剂中。将获取的溶液通过喷雾干燥仪进行喷雾干燥,设置喷雾干燥仪器的进口温度为75℃、出口温度为60℃、进料速率为5mL/min、抽吸力为100%以及雾化气流40mm。气流通过-20℃的冷凝器将溶剂回收。通过旋风分离器下端收集器收集粉末。
将收集器中获取的产品置于35℃真空干燥箱,减压干燥24小时除去残留的溶剂,可得达格列净:绿原酸:PVP VA64药物组合物。产品经过X-射线粉末衍射仪检测,结果图2所示,由图可确定其为无定型态。
对照组1
无定型达格列净的制备:
按照专利CN 112239440A实施例5将达格列净(0.05g)溶于乙醇(0.3mL)。将上述溶液加入到20℃水(1.5mL)中,搅拌下析出白色固体,过滤,真空干燥,得到白色固体。获取产品经X-射线粉末衍射仪检测,测试结果如图3所示。由图可确定其为无定型态。
对照组2
达格列净:PVP VA64药物组合物制备:
将0.2g达格列净和0.8g PVP VA64溶解在5mL甲醇/二氯甲烷(体积比1:1)混合溶剂中。将获取的溶液通过喷雾干燥仪进行喷雾干燥,设置喷雾干燥仪器的进口温度为75℃、出口温度为60℃、进料速率为5mL/min、抽吸力为100%以及雾化气流40mm。气流通过-20℃的冷凝器将溶剂回收。通过旋风分离器下端收集器收集粉末。
将收集器中获取的产品置于35℃真空干燥箱,减压干燥24小时除去残留的溶剂,可得达格列净:PVP VA64药物组合物。产品经过X-射线衍射仪检测,结果图4所示,由图可确定其为无定型态。
实施例3:调制差示扫描量热法(MDSC)
实施例2制备的达格列净:绿原酸:PVP VA64药物组合物、对照组1制备的达格列净无定型、对照组2制备的达格列净:PVP VA64药物组合物利用调制差示扫描量热法,分析测试其玻璃化转变温度。差示扫描量热仪设置参数为:样品室的氮气吹扫气流为50mL/min、起始温度为40℃(无定型达格列净测试的起始温度为5℃)、调制周期为60s,振幅为0.8℃,升温速率为5℃/min以及结束温度为180℃。
测试结果图谱如图5~7所示,从图5中可知实施例2制备的达格列净:绿原酸:PVPVA64药物组合物的玻璃化转变温度约为99.5℃,从图6可知对照组1制备的达格列净无定型的玻璃化转变温度约为34.6℃。从图7中可知对照组2的达格列净:PVP VA64药物组合物的玻璃化转变温度为93.2℃。因此,实施例2制备的达格列净:绿原酸:PVP VA64药物组合物的热稳定性满足一般制药工艺要求。相对于对照组2制备的达格列净:PVP VA64药物组合物的玻璃化转变温度具有明显提升,即无定型的稳定性具有明显提升。
实施例4:药物组合物引湿性表征
药物的引湿性是指在一定温度及和湿度下吸收水分的能力和程度的特性,依据《中国药典》2020年版四部药物9103引湿性试验指导原则,称取相同质量的实施例1制备的达格列净:绿原酸:HPMCP药物组合物、实施例2制备的达格列净:绿原酸:PVP VA64药物组合物、对照组1制备的无定型达格列净、对照组2制备的达格列净:PVP VA64药物组合物。在25℃、80%RH条件下,放置24h,称取前后重量,并计算出24h后的增重比例。其结果如下表1所示,实施例2制备的达格列净:绿原酸:PVP VA64药物组合物虽然具有引湿性,但是相对于对照组2的达格列净:PVP VA64药物组合物引湿性具有明显降低,也避免了单一无定型直接潮解的问题。
表1
实施例5:药物组合物等温吸附考察
利用动态水分吸附仪对实施例2制备的达格列净:绿原酸:PVP VA64药物组合物进行等温吸附考察,动态水分吸附仪的测试方法为:采用动态蒸汽吸附仪Q5000(美国TA仪器)检测25℃时样品重量随湿度的变化。具体参数:在25℃、0%相对湿度条件下平衡200min,之后每150min进行10%的相对湿度跳跃,如果每15min内重量变化小于0.01%直接跳跃10%的相对湿度,相对湿度达到95%,150min后逆向进行一次相对湿度跳跃。相对湿度变化如下:0%—10%—20%—30%—40%—50%—60%—70%—80%—90%—95%—90%—80%—70%—60%—50%—40%—30%—20%—10%—0%。数据分析软件TA UniversalAnalysis(美国TA仪器)。达格列净:绿原酸:PVP VA64药物组合物的等温吸附图如图8所示,从图中可知,药物组合物的临界相对湿度为80%RH。理论储存条件的湿度应低于80%RH。即药物组合物可满足正常药物储存条件。
实施例6:药物组合物表观溶解度表征
对比测试实施例2制备的达格列净:绿原酸:PVP VA64药物组合物、对照组2制备的达格列净:PVP VA64药物组合物、对照组1制备的无定型达格列净及达格列净丙二醇一水合物的表观溶解度差异。
称取一定量实施例2制备的达格列净:绿原酸:PVP VA64药物组合物、对照组2制备的达格列净:PVP VA64药物组合物、对照组1制备的无定型达格列净、达格列净丙二醇一水合物(目前产品所用晶型)分别加入5mL的pH=1的盐酸溶液、pH=6.8的磷酸盐缓冲溶液及去离子水介质中,在37℃、条件下超声30min,利用滤头过滤,滤液采用紫光光谱仪测试,波长为276nm。通过配制标准溶液,计算出各个物质的表观溶解度。从表2中可知,达格列净:绿原酸:PVP VA64药物组合物在pH=1、pH=6.8和水中表观溶解度比达格列净丙二醇一水合物、达格列净:PVP VA64药物组合物提高了4~5倍。
表2
实施例7:达格列净药物组合物的稳定性考察
对实施例2中制备的达格列净:绿原酸:PVP VA64药物组合物的稳定性进行考察。将实施例2获取的达格列净药物组合物放置在40℃、75%RH条件下放置30天。并在第3天、5天、10天、20天及30天取样采用X-射线粉末衍射仪检测确定其物理状态仍为无定型,如图9所示。
实施例8:达格列净药物组合物片剂的制备
制备方法:
(1)称量:按照上表处方比例称量各组分。
(2)初混:将达格列净:绿原酸:PVP VA64药物组合物(1:1:3)与微晶纤维素、交联羧甲基纤维素钠混合过40目筛,过筛后的粉末置于多向运动混合机中混合15min。
(3)干法制粒:混合后物料加入干法制粒机中制粒。
(4)总混:将干法制粒后颗粒与胶态二氧化硅混合过20目筛,再加入硬脂酸镁,混合10min。
(5)压片:总混颗粒用压片机压制成片压片。硬度控制在50~70N。
Claims (5)
1.一种达格列净药物组合物,其特征在于,其制备方法是:将0.2 g达格列净、0.2 g绿原酸和0.6 g羟丙甲纤维素邻苯二甲酸酯或PVP VA64溶解在5 mL甲醇/二氯甲烷,体积比1:1的混合溶剂中,然后将溶剂除去获取达格列净药物组合物。
2.一种权利要求1所述的达格列净药物组合物的制备方法,其特征在于,是将达格列净、绿原酸和羟丙甲纤维素邻苯二甲酸酯或PVP VA64溶解于溶剂中,然后将溶剂除去获取。
3.根据权利要求2所述的制备方法,其特征在于,是将达格列净、绿原酸和羟丙甲纤维素邻苯二甲酸酯或PVP VA64溶解于溶剂中形成溶液,并通过喷雾干燥的方式将溶剂除去。
4.一种包含权利要求1所述的达格列净药物组合物的药物制剂。
5.权利要求1所述的达格列净药物组合物或权利要求4所述的药物制剂在制备抗糖尿病药物中的应用。
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CN105555258A (zh) * | 2013-07-22 | 2016-05-04 | 桑多斯股份公司 | 包含无定形达格列净的制剂 |
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WO2017068069A1 (fr) * | 2015-10-20 | 2017-04-27 | Valbiotis | Composition comprenant un melange de molecules particulieres et utilisation pour agir sur le metabolisme glucidique et/ou lipidique |
CN110051851A (zh) * | 2019-05-31 | 2019-07-26 | 江苏苏中药业集团股份有限公司 | 一种钠-葡萄糖共转运蛋白-2抑制剂与黄蜀葵花提取物的组合 |
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CN105555258A (zh) * | 2013-07-22 | 2016-05-04 | 桑多斯股份公司 | 包含无定形达格列净的制剂 |
WO2016161995A1 (en) * | 2015-04-08 | 2016-10-13 | Zentiva, K.S. | Solid forms of amorphous dapagliflozin |
WO2017068069A1 (fr) * | 2015-10-20 | 2017-04-27 | Valbiotis | Composition comprenant un melange de molecules particulieres et utilisation pour agir sur le metabolisme glucidique et/ou lipidique |
CN110051851A (zh) * | 2019-05-31 | 2019-07-26 | 江苏苏中药业集团股份有限公司 | 一种钠-葡萄糖共转运蛋白-2抑制剂与黄蜀葵花提取物的组合 |
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