CN116785251A - 一种达格列净片剂及其制备方法 - Google Patents
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- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 title claims abstract description 83
- 229960003834 dapagliflozin Drugs 0.000 title claims abstract description 83
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 239000000945 filler Substances 0.000 claims abstract description 23
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 20
- 239000000314 lubricant Substances 0.000 claims abstract description 18
- 239000002994 raw material Substances 0.000 claims abstract description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 36
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 239000000377 silicon dioxide Substances 0.000 claims description 17
- 239000007962 solid dispersion Substances 0.000 claims description 13
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 12
- 235000013539 calcium stearate Nutrition 0.000 claims description 12
- 239000008116 calcium stearate Substances 0.000 claims description 12
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- 229930195725 Mannitol Natural products 0.000 claims description 11
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 2
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- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 2
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- OKODKVMXHLUQSW-JITBQSAISA-M sodium;(e)-4-hydroxy-4-oxobut-2-enoate;octadecanoic acid Chemical compound [Na+].OC(=O)\C=C\C([O-])=O.CCCCCCCCCCCCCCCCCC(O)=O OKODKVMXHLUQSW-JITBQSAISA-M 0.000 claims description 2
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- WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 description 2
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- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
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- GOADIQFWSVMMRJ-UPGAGZFNSA-N dapagliflozin propanediol monohydrate Chemical compound O.C[C@H](O)CO.C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl GOADIQFWSVMMRJ-UPGAGZFNSA-N 0.000 description 1
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- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
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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
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- 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
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- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/52—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an inorganic compound, e.g. an inorganic ion that is complexed with the active ingredient
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- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
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Abstract
本发明提供了一种达格列净片剂,包括以下重量百分比的原辅料组成,达格列净10~20%、崩解剂4%~21%、润滑剂1~15%、助流剂6~22%和填充剂40%~75%。本发明提供了一种达格列净片剂,解决了达格列净溶出速度差的问题,制得的片剂稳定性高,均匀度高,溶出速度快,药效好。本发明提供了一种达格列净片剂的制备方法,制备方法简单易于操作,且可以使用药厂的现有设备,从而节约了生产成本,便于大范围的推广和使用。
Description
技术领域
本发明属于药物制剂技术领域,具体涉及一种达格列净片剂及其制备方法。
背景技术
2型糖尿病是心力衰竭的独立危险因素之一,约1/4的2型糖尿病患者合并心力衰竭,两种疾病相互促进、相互影响,极易形成共病状态,增加治疗的难度。因此慢性心力衰竭合并2型糖尿病的治疗也成为临床研究的热点问题。达格列净因其较好的降糖效果、对心血管系统显著的保护作用而备受关注。达格列净(Dapagliflozin)是由百时美施贵宝公和阿斯利康公司联合开发的一种新型的抗糖尿病药物,于2012年在欧洲上市,FDA也于2014年批准其为2型糖尿病治疗药。但是达格列净水溶性差,如何提高制剂的体外溶出度是影响其疗效的关键所在。CN 106606490 A公开了一种达格列净药物组合物及其制备工艺,所述的达格列净药物组合物含有达格列净和载体材料,其中载体材料选自聚维酮、波洛沙姆、聚乙二醇、羟丙基纤维素、聚氧化乙烯。CN 105853386 B公开了一种含有达格列净的片剂的制备工艺,其特征在于首先将达格列净丙二醇水合物溶解在溶剂中制成药物溶液,然后将该药物溶液与稀释剂、粘合剂、崩解剂、润滑剂通过湿法制粒压片,从而得到含有达格列净的片剂。但是现有的制剂的均匀度、稳定性和溶出速度并不理想,存在生产成本较高的问题,因此需要一种新型制剂用于提高药效,降低生产成本。
发明内容
本发明的目的是提供一种达格列净片剂,具有均匀度高、稳定性强和溶出速度快的优点,制备方法简单易行。
为了实现上述目的,本发明提供了以下技术方案:一种达格列净片剂,包括以下重量百分比的原辅料组成,达格列净10~20%、崩解剂4%~21%、润滑剂1~15%、助流剂6~22%和填充剂40%~75%。
优选的,包括以下重量百分比的原辅料组成,达格列净12~17%、崩解剂10%~15%、润滑剂5~10%、助流剂9~17%和填充剂45%~65%。
进一步优选的,包括以下重量百分比的原辅料组成,达格列净14%、崩解剂12%、润滑剂8%、助流剂14%和填充剂52%。
在一些优选实施方式中,所述崩解剂选自羧甲基淀粉钠、交联聚维酮、羟丙纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠中的一种或多种;所述助流剂选自胶态二氧化硅、介孔二氧化硅、滑石粉中的一种或两种;所述润滑剂选自硬脂酸镁、硬脂酸钙、硬脂酸富马酸钠中的一种或多种,所述填充剂选自木糖醇、甘露醇和乳糖、微晶纤维素、预胶化淀粉中的一种或多种。
优选的,所述崩解剂为羟丙纤维素;为了提高均匀度和溶解速度,进一步优选的,所述羟丙纤维素的重均分子量370000,布氏粘度150~400mPa.s,购自上海临辰医药。
优选的,所述助流剂为介孔二氧化硅;进一步优选的,所述介孔二氧化硅为中空介孔二氧化硅,表面基团为-SiOH,粒径直径350-450nm。购自先锋纳米104014。
发明人经过研究发现,介孔二氧化硅可以改善片剂的均匀度,溶出速率也有显著提高。介孔二氧化硅在与达格列净和崩解剂混合后,达格列净以分子形式存在于含介孔二氧化硅的达格列净固体分散体中,提高了分散体的物理稳定性,使达格列净固体分散体对生产条件不敏感,均匀度更高。此时达格列净的分子间相互作用力较小,溶出过程中不需要较高的能量去打破晶格能,同时介孔二氧化硅具有较高的比表面积能够使达格列净在其中高度分散,防止聚集。介孔二氧化硅表面的羟基具有亲水性,当接触到胃肠液时,使胃肠液渗入到固体分散体中,起到了很好的润湿作用,保证了达格列净与胃肠液的充分接触,从而提高了溶出速率基。在本发明中羟丙纤维素除了起到传统的崩解剂的作用,由于介孔二氧化硅表面能较高,很容易团聚,本发明通过加入羟丙纤维素,同时提高分散体的表面活性,降低介孔二氧化硅表面能,防止发生团聚,有利于片剂均匀度和溶出速率的提升。
为了提高降低颗粒之间的摩擦,提高片剂的均匀度,所述润滑剂选自硬脂酸镁和硬脂酸钙。进一步优选的,所述硬脂酸镁和硬脂酸钙的重量比为1:1~5。进一步优选的,所述硬脂酸镁和硬脂酸钙的重量比为1:3。通过硬脂酸镁和硬脂酸钙的合理配比,具有稳定协同的效果,可以提供片剂更合适的黏度,片剂稳定性更强。所述硬脂酸镁购自默克PHR1316,所述硬脂酸钙购自默克26411。
优选的,所述填充剂选自木糖醇、甘露醇和乳糖。进一步优选的,所述填充剂中木糖醇、甘露醇和乳糖的重量百分比为1:1:2~10。进一步优选的,所述填充剂中木糖醇、甘露醇和乳糖的重量百分比为1:1:5。
发明人发现填充剂影响片剂的均匀度,木糖醇、甘露醇和乳糖混合后在本发明中更适于与达格列净配合的填充剂。药物与辅料在混合过程中,最为关键的影响因素是药剂的混合药物控制不合理,使药剂的含量控制工作实施均匀度效果不明显。填充剂对骨架片的药物释放具有一定的影响。本发明的填充剂具有致孔作用,因此能够增大片剂的空隙率,减小药物扩散的阻力,从而加快药物的释放,而本发明选用填充的种类和配比,更加适合达格列净的药物体系,与其余辅料的协同增效,提高均匀度。
本发明第二方面提供了所述的一种达格列净片剂的制备方法,包括以下步骤:
(1)将达格列净溶于甲醇,加入助流剂、崩解剂,搅拌至完全溶解,60~70℃干燥去除溶剂,得达格列净固体分散体,过筛;(2)将达格列净固体分散体、润滑剂和填充剂混合,经粉末直压后得到达格列净片剂。
为了提高片剂的均匀度,优选的,所述步骤(1)中过筛后粒径为50~80μm;所述步骤(2)中使用高速混合制粒机混合,搅拌桨的转速为12-15r/min,剪切刀的转速为8-15r/min。
与现有技术相比,本发明的优点和有益效果为:
(1)本发明提供了一种达格列净片剂,解决了达格列净溶出速度差的问题,制得的片剂稳定性高,均匀度高,溶出速度快,药效好。
(2)本发明提供了一种达格列净片剂的制备方法,制备方法简单易于操作,且可以使用药厂的现有设备,从而节约了生产成本,便于大范围的推广和使用。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其它实施例,都属于本发明保护的范围。
实施例1
本实施例提供了一种达格列净片剂,包括以下重量百分比的原辅料组成,达格列净14%、崩解剂12%、润滑剂8%、助流剂14%和填充剂52%。所述崩解剂为羟丙纤维素;所述助流剂为介孔二氧化硅;所述润滑剂选自硬脂酸镁和硬脂酸钙,所述填充剂选自木糖醇、甘露醇和乳糖。所述填充剂中木糖醇、甘露醇和乳糖的重量比为1:1:5;所述硬脂酸镁和硬脂酸钙的重量比为1:3。
所述达格列净片剂的制备方法,包括以下步骤:(1)将达格列净溶于甲醇(0.1g原辅料对应1mL甲醇),加入助流剂、崩解剂,搅拌至完全溶解,65℃干燥去除溶剂,得达格列净固体分散体,过筛粒径为50~80μm;(2)将达格列净固体分散体、润滑剂和填充剂,使用高速混合制粒机混合40min,搅拌桨的转速为20r/min,剪切刀的转速为10r/min;经粉末直压后得到达格列净片剂。
实施例2
本实施例与实施例1的区别为:所述崩解剂为羧甲基淀粉钠。购自阿拉丁,C105665。
实施例3
本实施例与实施例1的区别为:一种达格列净片剂,包括以下重量百分比的原辅料组成,达格列净14%、崩解剂1%、润滑剂25%、助流剂4%和填充剂56%。
实施例4
本实施例与实施例1的区别为:本实施例提供了一种达格列净片剂,包括以下重量百分比的原辅料组成,达格列净14%、崩解剂15%、助流剂19%和填充剂52%。
实施例5
本实施例与实施例1的区别为:所述硬脂酸镁和硬脂酸钙的重量比为1:10。
实施例6
本实施例与实施例1的区别为:木糖醇、甘露醇和乳糖的重量比为1:1:1。
实施例7
所述达格列净片剂的制备方法,包括以下步骤:(1)将达格列净溶于甲醇(0.1g原辅料对应1mL甲醇),加入助流剂、崩解剂,搅拌至完全溶解,65℃干燥去除溶剂,得达格列净固体分散体;(2)将达格列净固体分散体、润滑剂和填充剂,使用高速混合制粒机混合25min,搅拌桨的转速为10r/min,剪切刀的转速为10r/min;经粉末直压后得到达格列净片剂。
性能测试
(1)分别取实施例1~7制备的达格列净片剂各10片,对照组市售达格列净片剂(安达唐)10片,每片置于50mL(5mg规格)量瓶中,加流动相适量,超声使药物溶解,加流动相稀释至刻度,摇匀,离心,取上清液滤过,精密量取续滤液4mL,置20mL量瓶中,加流动相稀释至刻度,摇匀,作为供试品溶液,HPLC法测定含量,按照《中国药典》2015版四部计算A+2.2S,测定均匀度。
(2)分别取实施例1~7制备的达格列净片剂,对照组市售达格列净片剂(安达唐),以pH为1.2的盐酸溶液900mL为溶出介质,采用桨法、50转每分钟进行溶出,分别于5分钟取溶液5mL,过滤,取续滤液作为供试品溶液,HPLC法测定溶出度。
表1性能测试结果
通过以上结果可知,本发明制备的达格列净片剂均匀度高,5分钟溶出度就可以达到90%,溶出速度快。与市面上现有的达格列净片剂相比,稳定性高整体性能具有很大的提升,对于2型糖尿病的治疗具有积极的意义。
以上所述是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明所述原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (10)
1.一种达格列净片剂,其特征在于,包括以下重量百分比的原辅料组成,达格列净10~20%、崩解剂4%~21%、润滑剂1~15%、助流剂6~22%和填充剂40%~75%。
2.根据权利要求1所述的一种达格列净片剂,其特征在于,所述崩解剂选自羧甲基淀粉钠、交联聚维酮、羟丙纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠中的一种或多种;所述助流剂选自胶态二氧化硅、介孔二氧化硅、滑石粉中的一种或多种;所述润滑剂选自硬脂酸镁、硬脂酸钙、硬脂酸富马酸钠中的一种或多种,所述填充剂选自木糖醇、甘露醇、乳糖、微晶纤维素、预胶化淀粉中的一种或多种。
3.根据权利要求1所述的一种达格列净片剂,其特征在于,包括以下重量百分比的原辅料组成,达格列净12~17%、崩解剂10%~15%、润滑剂5~10%、助流剂9~17%和填充剂45%~65%。
4.根据权利要求3所述的一种达格列净片剂,其特征在于,包括以下重量百分比的原辅料组成,达格列净14%、崩解剂12%、润滑剂8%、助流剂14%和填充剂52%。
5.根据权利要求2所述的一种达格列净片剂,其特征在于,所述崩解剂为羟丙纤维素;所述助流剂为介孔二氧化硅;所述润滑剂选自硬脂酸镁和硬脂酸钙,所述填充剂选自木糖醇、甘露醇和乳糖。
6.根据权利要求5所述的一种达格列净片剂,其特征在于,所述填充剂中木糖醇、甘露醇和乳糖的重量比为1:1:2~10;所述硬脂酸镁和硬脂酸钙的重量比为1:1~5。
7.根据权利要求5所述的一种达格列净片剂,其特征在于,所述羟丙纤维素的重均分子量370000,布氏粘度150~400mPa.s。
8.根据权利要求5所述的一种达格列净片剂,其特征在于,所述介孔二氧化硅为中空介孔二氧化硅,表面基团为-SiOH,粒径直径350-450nm。
9.权利要求1~8任一项所述的一种达格列净片剂的制备方法,其特征在于,包括以下步骤:(1)将达格列净溶于甲醇,加入助流剂、崩解剂,搅拌至完全溶解,60~70℃干燥去除溶剂,得达格列净固体分散体,过筛;(2)将达格列净固体分散体、润滑剂和填充剂过筛混合,经粉末直压后得到达格列净片剂。
10.根据权利要求9所述的制备方法,其特征在于,所述步骤(1)中过筛后粒径为50~80μm;所述步骤(2)中使用高速混合制粒机混合,搅拌桨的转速为15-25r/min,剪切刀的转速为8-15r/min。
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