CN112999181B - 一种富马酸沃诺拉赞片剂 - Google Patents
一种富马酸沃诺拉赞片剂 Download PDFInfo
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- CN112999181B CN112999181B CN201911317709.3A CN201911317709A CN112999181B CN 112999181 B CN112999181 B CN 112999181B CN 201911317709 A CN201911317709 A CN 201911317709A CN 112999181 B CN112999181 B CN 112999181B
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- ROGSHYHKHPCCJW-WLHGVMLRSA-N (e)-but-2-enedioic acid;1-[5-(2-fluorophenyl)-1-pyridin-3-ylsulfonylpyrrol-3-yl]-n-methylmethanamine Chemical compound OC(=O)\C=C\C(O)=O.C=1C=CN=CC=1S(=O)(=O)N1C=C(CNC)C=C1C1=CC=CC=C1F ROGSHYHKHPCCJW-WLHGVMLRSA-N 0.000 title abstract description 15
- 229950003825 vonoprazan Drugs 0.000 title abstract description 14
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims abstract description 48
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 46
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims abstract description 23
- 239000000600 sorbitol Substances 0.000 claims abstract description 23
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- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims abstract description 6
- 238000002844 melting Methods 0.000 claims abstract description 5
- 230000008018 melting Effects 0.000 claims abstract description 5
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 22
- 235000019359 magnesium stearate Nutrition 0.000 claims description 11
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 9
- 229930195725 Mannitol Natural products 0.000 claims description 9
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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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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
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- 238000010298 pulverizing process Methods 0.000 description 2
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
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- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 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 description 1
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- 206010030216 Oesophagitis Diseases 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229940123359 Potassium antagonist Drugs 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- 206010000059 abdominal discomfort Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
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- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
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- 238000001514 detection method Methods 0.000 description 1
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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 description 1
- 201000010099 disease Diseases 0.000 description 1
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- 238000010828 elution Methods 0.000 description 1
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- 208000006881 esophagitis Diseases 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
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- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
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- 230000000269 nucleophilic effect Effects 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
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- 150000004965 peroxy acids Chemical group 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
- 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
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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Abstract
本发明属于医药技术领域,具体涉及一种富马酸沃诺拉赞片剂,其由富马酸沃诺拉赞、山梨醇和其他药学可接受的辅料组成;将山梨醇加入到熔融制粒机中,加热熔融,然后将富马酸沃诺拉赞加入到熔融液中,搅拌均匀,在搅拌粉碎下冷却至室温,然后加入药学上常用的辅料,混合均匀,压片,包衣;该方法制备的富马酸沃诺拉赞片剂外观良好、稳定性好、工艺简单、适合工业化生产。
Description
技术领域
本发明属于医药技术领域,具体涉及一种富马酸沃诺拉赞片剂。
背景技术
富马酸沃诺拉赞(TAK-438,Vonoprazan fumarate),化学名为1-[5-(2-氟苯基)-1-(吡啶-3-基磺酰基)-1H-吡咯3-基]-N-甲基甲胺富马酸单盐,分子式:C21H20FN3O6S,分子量:461.46,结构式如下:
富马酸沃诺拉赞是由日本武田公司开发的一种新型的PPI-钾离子竞争性酸阻滞剂,通过竞争性抑制氢离子/钾离子-ATP酶中的钾离子而起作用,是一种可逆的钾离子拮抗剂,于2014年12月首次在日本获批上市,商品名Takecab,用于治疗幽门螺杆菌感染、胃食管反流、消化性溃疡、十二指肠溃疡、食管炎、胃溃疡等胃酸相关性疾病(ARDs)。富马酸沃诺拉赞结构中带有高度亲核性的仲氨基,当制剂处方中含有痕量的碱性成分包含在赋形剂中时,碱性成分可起到碱性催化剂的作用,引起原料药中富马酸与α或β-不饱和羰基化合物的Michael加成反应。
中国专利申请CN102743330A指出在处方中加入链状有机酸作为稳定剂防止上述反应进行,此外为了提高制剂的光稳定性,抑制由于包衣试剂中二氧化钛(TiO2)产生光屏蔽效应而造成强烈的氧化作用所产生的分解产物。中国专利CN102743330A通过将链状有机酸加入到药物组合物核芯或膜中,达到药物组合物在光照期间抑制分解产物的作用。
中国专利申请CN107224438A提供了一种含有活性成分富马酸沃诺拉赞的药物组合物和使其稳定的方法,药物组合物不含增塑剂,但也加入了重量比为0-5%的富马酸,以达到药物组合物具有良好的制剂稳定性,在高温环境和光照期间也均具有良好的稳定性。
但是,与传统PPI类抑制剂在肠道崩解释放不同,富马酸沃诺拉赞片在酸性条件下稳定,口服后在胃内迅速崩解释放并离子化,离子化形式通过离子型结合抑制氢离子/钾离子-ATP酶,升高胃内pH值。处方中加入链状有机酸后降低了药物组合物本身酸度,导致人体口服富马酸沃诺拉赞片后,在富马酸沃诺拉赞发挥抑酸作用前,胃内接触过酸的药物组合物,造成胃部不适。
中国专利申请CN105106203B提供了一种含有富马酸沃诺拉赞、增塑剂和赋形剂的药物组合物,其具有良好的制剂稳定性,而且在光照期间也具有良好的稳定性。但增塑剂具有一定的副作用,长时间服用会带来安全隐患。
因此,制备一种稳定性好、用药安全性高的富马酸沃诺拉赞片剂是十分必要的。
发明内容
现有技术中,为解决制剂处方中含有痕量碱的问题,采取了添加有机酸或者在包衣中添加特定增塑剂,给用药带来一定隐患或者不便。
鉴于此,发明人拟提供一种片芯中不含有机酸的富马酸沃诺拉赞片剂,且对包衣组分有无增塑剂或者增塑剂种类无特殊要求的稳定的富马酸沃诺拉赞片剂。
发明人考虑到,对于片芯而言,即使添加有机酸,但片剂中常用的辅料如润滑剂硬脂酸镁,为偏碱性辅料,仍然存在与药物配伍的风险。如果采用现有技术如将原料与部分辅料制备微丸,工艺又复杂,且存在压片微丸破碎及与外加辅料分层的风险。意外的,发明人考虑到富马酸沃诺拉赞对热稳定性良好,如果将辅料如甘露醇熔融后,再加入原料,冷却,粉碎,将药物包裹在甘露醇中,理论上可以提高稳定性,但经查阅资料,甘露醇熔点为166℃,在此温度下,药物有降解。意外的,发明人考虑到,可以用甘露醇的同分异构体山梨醇代替甘露醇,其熔点较低为90℃。实验结果证明以此技术制备的产品,质量稳定。
具体而言,本发明提供了一种富马酸沃诺拉赞片剂,其由富马酸沃诺拉赞、山梨醇和其他药学可接受的辅料组成。
优选地,在本发明一实施例中富马酸沃诺拉赞片剂由湿法制粒方法制备:将适量水溶液加入到富马酸沃诺拉赞、山梨醇、其他药学可接受的辅料中湿法制粒。干燥、整粒,加入润滑剂总混。然后将所得颗粒压片;
将上述获得的素片(片芯片剂),用膜包衣溶液喷涂,获得膜包衣片剂。
更优选地,在本发明一实施例中富马酸沃诺拉赞片剂由干法制粒方法制备:将处方量的富马酸沃诺拉赞、山梨醇及处方量润湿剂、崩解剂混合均匀;将获得的混合物干法制粒,压力控制在5-25MPa,颗粒粒度在0.1-1.0mm;然后将获得的颗粒与润滑剂混合均匀,进行压片,制得片芯;
将上述获得的素片(片芯片剂),用所示成分的膜包衣溶液喷涂,获得膜包衣片剂。
进一步优选地,本发明富马酸沃诺拉赞片剂由熔融制粒方法制备,其由富马酸沃诺拉赞、山梨醇和其他药学可接受的辅料组成。由如下方法制备:山梨醇加入到熔融制粒机中,加热熔融,将富马酸沃诺拉赞加入到熔融液中,搅拌均匀,在搅拌粉碎下冷却至室温,然后加入药学上常用的辅料,混合均匀,压片,包衣。
所述富马酸沃诺拉赞与山梨醇的重量比为1:2-12。
优选地,所述富马酸沃诺拉赞与山梨醇的重量比为1:3-10。
更优选地,所述富马酸沃诺拉赞与山梨醇的重量比为1:7。
所述辅料为填充剂、崩解剂、润滑剂。
优选地,所述崩解剂为羧甲基淀粉钠、交联羧甲基纤维素钠、交联聚维酮、低取代羟丙基纤维素中的一种或多种。
优选地,所述填充剂为微晶纤维素、乳糖、预胶化淀粉、甘露醇、淀粉中的一种或多种。
优选地,所述润滑剂为硬脂酸镁、硬脂酸富马酸钠、滑石粉、二氧化硅中的一种或多种。
优选地,所述薄膜包衣层包含羟丙甲纤维素、聚乙烯醇、聚乙二醇、色淀中的一种或多种。
与现有技术相比,本发明具有如下优势:本发明制备的富马酸沃诺拉赞制剂处方先进,在高温、高湿、强光条件下均表现出优良的制剂稳定性,有效地解决了富马酸沃诺拉赞稳定性的问题,同时能够减少服用富马酸沃诺拉赞所带来的副作用。而且,本发明富马酸沃诺拉赞片剂制备工艺简单,适于工业化生产。
具体实施方式
以下实施例进一步描述本发明的有益效果,实施例仅用于例证的目的,不限制本发明的范围,同时本领域普通技术人员根据本发明所做的显而易见的改变和修饰也包含在本发明范围之内。
实施例1
片芯组成:
包衣组成:
制备工艺:
山梨醇加入到熔融制粒机中,95℃加热熔融,将富马酸沃诺拉赞加入到熔融液中,搅拌均匀,在搅拌粉碎下冷却至室温,然后和处方量的微晶纤维素、交联羧甲基纤维素钠,混合均匀,再加入硬脂酸镁,混合,压片,包衣。
实施例2
片芯组成:
包衣组成:
制备工艺:
山梨醇加入到熔融制粒机中,105℃加热熔融,将富马酸沃诺拉赞加入到熔融液中,搅拌均匀,在搅拌粉碎下冷却至室温,然后和处方量的微晶纤维素、羧甲基淀粉钠、混合均匀,再加入硬脂酸镁,混合,压片,包衣。
实施例3
片芯组成:
包衣组成:
制备工艺:
山梨醇加入到熔融制粒机中,100℃加热熔融,将富马酸沃诺拉赞加入到熔融液中,搅拌均匀,在搅拌粉碎下冷却至室温,然后和处方量的微晶纤维素、羧甲基淀粉钠,混合均匀,再加入硬脂酸镁,混合,压片,包衣。
实施例4
片芯组成:
包衣组成:
制备工艺:
山梨醇加入到熔融制粒机中,105℃加热熔融,将富马酸沃诺拉赞加入到熔融液中,搅拌均匀,在搅拌粉碎下冷却至室温,然后和处方量的微晶纤维素、羧甲基淀粉钠,混合均匀,再加入硬脂酸镁,混合,压片,包衣。
实施例5
片芯组成:
包衣组成:
制备工艺:
山梨醇加入到熔融制粒机中,105℃加热熔融,将富马酸沃诺拉赞加入到熔融液中,搅拌均匀,在搅拌粉碎下冷却至室温,然后和处方量的微晶纤维素、羧甲基淀粉钠,混合均匀,再加入硬脂酸镁,混合,压片,包衣。
实施例6
片芯组成:
包衣组成:
制备工艺:
山梨醇加入到熔融制粒机中,105℃加热熔融,将富马酸沃诺拉赞加入到熔融液中,搅拌均匀,在搅拌粉碎下冷却至室温,然后和处方量的乳糖、交联聚维酮,混合均匀,再加入硬脂酸镁,混合,压片,包衣。
实施例7
片芯组成:
包衣组成:
制备工艺:
山梨醇加入到熔融制粒机中,105℃加热熔融,将富马酸沃诺拉赞加入到熔融液中,搅拌均匀,在搅拌粉碎下冷却至室温,然后和处方量的糊精、交联聚乙烯吡咯烷酮,混合均匀,再加入微粉硅胶,混合,压片,包衣。
对比实施例1
片芯组成:
包衣组成:
制备工艺:
甘露醇加入到熔融制粒机中,167℃加热熔融,将富马酸沃诺拉赞加入到熔融液中,搅拌均匀,在搅拌粉碎下冷却至室温,然后和处方量的微晶纤维素、羧甲基淀粉钠,混合均匀,再加入硬脂酸镁,混合,压片,包衣。
对比实施例2
片芯组成:
制备工艺:
将聚乙二醇6000与山梨醇分别过60目筛,加热至熔融,加入富马酸沃诺拉赞,在剧烈搅拌下迅速冷却固化;过30目筛粉碎;干燥至水分低于2%;加入处方量微晶纤维素、崩解剂、润滑剂混匀后,压片。
对比实施例3
片芯组成:
包衣组成:
制备工艺:
将羟丙基纤维素1.3g溶解于43.95g纯化水,得粘合剂溶液。将制备的粘合剂溶液加入到富马酸沃诺拉赞(13.36g)、甘露醇(64.99g)和微晶纤维素(23.75g)组成的辅料中湿法制粒。干燥后用30目筛整粒后加入硬脂酸镁(1.1g)和交联羧甲基纤维素钠(5.5g)总混。然后将所得颗粒采用6.5mm直径的冲模压制硬度为3~10kg的素片。
将上述获得的素片(片芯片剂),用所示成分的膜包衣溶液喷涂,获得膜包衣片剂。
验证实施例
1.包衣外观
将获得的膜包衣片剂放在透明的玻璃瓶中,紧密地密封,并在40℃,75%RH下保存6个月;在60℃下保存1个月;在光照(4500lx±500lx)下保存1个月。检查包衣外观,结果见表1。
表1各实施例片剂外观
各实施例 | 片子外观 |
实施例1 | 外观良好,硬度较好 |
实施例2 | 外观良好,硬度较好 |
实施例3 | 外观良好,硬度较好 |
实施例4 | 外观良好,硬度较好 |
实施例5 | 外观良好,硬度较好 |
实施例6 | 外观良好,硬度较好 |
实施例7 | 外观良好,硬度较好 |
对比例1 | 片面花斑,硬度较好 |
对比例2 | 压片粘冲 |
对比例3 | 片面良好,硬度较好 |
由包衣外观实验可以看出,本发明富马酸沃诺拉赞片剂外观良好,硬度较好。
2.稳定性试验
将上述样品不加包装,并在40℃,75%RH下保存6个月;在60℃下保存1个月;在光照(4500lx±500lx)下保存1个月。在样品保存之前和保存之后,检验对比包衣片的最大单杂和总杂,通过HPLC,用流动相A:流动相B=3:1的混合溶剂提取片剂,从而测定最大单杂和总杂,测定结果见表2、表3和表4。HPLC试验条件如下:
仪器及试剂:高效液相色谱仪、电子分析天平、乙腈、磷酸二氢钾、磷酸、水。
色谱条件:色谱柱:十八烷基硅烷键合硅胶为填充剂(Waters Xbridge BEH 2.5μm×4.6mm×100mm或柱效类似的色谱柱);流速为每分钟1.0mL;紫外分光光度计检测波长为230nm;柱温为25℃;进样体积为20μL。峰面积的测定范围为60分钟。
流动相A:pH3.0磷酸盐缓冲液,(称取磷酸二氢钾约13.6g,加水约900mL使溶解,用磷酸调节pH至3.0,再加水至1000mL)过滤,脱气。
流动相B:乙腈。
按下表进行梯度洗脱(流动相量可缩放、比例可适当调整)
时间(min) | 0 | 5 | 20 | 40 | 45 | 46 | 51 |
流动相A(%) | 90 | 90 | 70 | 40 | 40 | 90 | 90 |
流动相B(%) | 10 | 10 | 30 | 60 | 60 | 10 | 10 |
表2光照条件下(4500lx±500lx)不同实施例下的样品稳定性
表3 40℃,75%RH,无包装条件下不同样品的稳定性
表4 60℃条件下不同样品的稳定性
该实验结果均为多次实验测得数据的平均值,从实验结果可知,本发明富马酸沃诺拉赞片剂有关物质良好,富马酸沃诺拉赞片剂在高温、高湿、强光照射下均表现出优良的制剂稳定性,且片子外观良好,硬度较好,满足制剂要求。
Claims (6)
1.一种富马酸沃诺拉赞片剂,其特征在于,其由富马酸沃诺拉赞、山梨醇和其他药学可接受的辅料组成,所述富马酸沃诺拉赞与山梨醇的重量比为1:2-12,所述其他药学可接受的辅料为填充剂、崩解剂、润滑剂;所述富马酸沃诺拉赞片剂由如下方法制备:将山梨醇加入到熔融制粒机中,加热熔融,将富马酸沃诺拉赞加入到熔融液中,搅拌均匀,在搅拌粉碎下冷却至室温,然后加入其他药学可接受的辅料,混合均匀,压片,包衣。
2.根据权利要求1所述的富马酸沃诺拉赞片剂,其特征在于,所述富马酸沃诺拉赞与山梨醇的重量比为1:3-10。
3.根据权利要求1所述的富马酸沃诺拉赞片剂,其特征在于,填充剂为微晶纤维素、乳糖、预胶化淀粉、甘露醇、淀粉中的一种或多种。
4.根据权利要求1所述的富马酸沃诺拉赞片剂,其特征在于,所述崩解剂为羧甲基淀粉钠、交联羧甲基纤维素钠、交联聚维酮中的一种或多种。
5.根据权利要求1所述的富马酸沃诺拉赞片剂,其特征在于,所述润滑剂为硬脂酸镁、硬脂酸富马酸钠、滑石粉、二氧化硅中的一种或多种。
6.根据权利要求1所述的富马酸沃诺拉赞片剂,其特征在于,所述包衣步骤中薄膜包衣层包含羟丙甲纤维素、聚乙烯醇、聚乙二醇、色淀中的一种或多种。
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