CN107349183A - 一种依匹哌唑分散片及其制备方法 - Google Patents
一种依匹哌唑分散片及其制备方法 Download PDFInfo
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- CN107349183A CN107349183A CN201710097727.XA CN201710097727A CN107349183A CN 107349183 A CN107349183 A CN 107349183A CN 201710097727 A CN201710097727 A CN 201710097727A CN 107349183 A CN107349183 A CN 107349183A
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- piperazine azoles
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- mesh sieves
- piperazine
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- QPUMEZIFDXYGPG-UHFFFAOYSA-N piperazine 1H-pyrrole Chemical class N1CCNCC1.N1C=CC=C1 QPUMEZIFDXYGPG-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
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- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 17
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 12
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- 235000009499 Vanilla fragrans Nutrition 0.000 claims description 2
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- ZKIAIYBUSXZPLP-UHFFFAOYSA-N brexpiprazole Chemical compound C1=C2NC(=O)C=CC2=CC=C1OCCCCN(CC1)CCN1C1=CC=CC2=C1C=CS2 ZKIAIYBUSXZPLP-UHFFFAOYSA-N 0.000 description 5
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 4
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- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- 102100022738 5-hydroxytryptamine receptor 1A Human genes 0.000 description 1
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- 241000790917 Dioxys <bee> Species 0.000 description 1
- AQLLBJAXUCIJSR-UHFFFAOYSA-N OC(=O)C[Na] Chemical compound OC(=O)C[Na] AQLLBJAXUCIJSR-UHFFFAOYSA-N 0.000 description 1
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- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 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
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
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- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
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- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 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
- A61K9/2004—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
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K9/2009—Inorganic compounds
-
- 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
-
- 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
- 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
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明公开了一种含有依匹哌唑‑亲水性材料共混物的分散片的制备方法。该分散片含有依匹哌唑‑亲水性材料共混物以及其它药学上可接受的辅料,采用湿法制粒压片制备分散片,其分散均匀性良好,可有效地提高依匹哌唑固体制剂的溶出速度,提高了患者服用的依从性以及药品的生物利用度,用于精神分裂症,工艺简便,适于工业化生产。
Description
技术领域
本发明属于药物制剂技术领域,具体涉及一种提高依匹哌唑在固体制剂中溶出度的技术及其固体制剂分散片的制备方法。
背景技术
2014年9月25日FDA正式收到并开始审核公司和日本大冢制药共同研发的brexpiprazole新药申请(NDA)。2015年7月10日依匹哌唑(Brexpiprazole)经FDA批准,可用于精神分裂症和重度抑郁症的辅助治疗。
灵北共提交7项II和III期临床研究,其中3项为精神分裂,4项为重度抑郁症的辅助治疗,共有超过6000名患者参与。
精神分裂适应症的2个III期临床研究共有超过1200名患者参与。患者在接受治疗6周之后的阳性和阴性症状量表(PANSS)分数有大幅度的提升。PANSS为精神疾病病的评定工具。
在重度抑郁症的辅助治疗方面,brexpiprazole在II项临床III期试验中表现也要优胜于安慰剂。
灵北制药和大冢制药共同开发的brexpiprazole是一款实验性血清素-多巴胺活动调节剂(SDAM) ,可作用于多巴胺D2和5-HT2A受体。 在多巴胺D2类受体中,D2受体部分激动剂对中脑边缘通路可产生功能性拮抗作用,能有效的改善精神分裂症因D2过度活动引起的阳性症状;对中脑皮层通路可产生功能性激动作用,可改善D2功能低下所引起的阴性症状、认知损害。brexpiprazole是一种新型多靶点作用机制的用于精神障碍疾病的治疗药物,除主要具备多巴胺D2受体部分激动作用之外,还具备D3受体部分激动作用、5-HT1A部分受体激动作用和5-HT2A部分受体拮抗作用,是针对单胺类神经递质多靶点开发的同时具有抗精神分裂和抗抑郁作用的新药,目前正在进行Ⅲ期临床试验。
发明内容
本发明的目的在于提供一种工艺简单、溶出速度快、药物生物利用度高的分散片。本发明涉及了一种利用亲水性材料与依匹哌唑预混,内外法加入崩解剂,使制剂溶出速率增加的方法。其特征是先将原料药依匹哌唑粉碎过200目筛,然后和亲水性材料过80目筛混合若干次,其中亲水性材料为乳糖、甘露醇、山梨醇中的一种或几种;依匹哌唑与亲水性材料的重量比为1:1~1:20,优选1:15~1:20;过80目筛混合3~8次,优选5~6次,形成依匹哌唑-亲水性材料共混物。加入其余内加辅料混合均匀,其中填充剂为乳糖、甘露醇、山梨醇、微晶纤维素、木糖醇、果糖、淀粉及淀粉衍生物中的一种或几种,优选乳糖和微晶纤维素;崩解剂为预胶化淀粉、羧甲基淀粉钠、羧甲基纤维素钠、交联聚维酮、低取代羟丙基纤维素、交联羧甲基纤维素钠中的一种或几种,优选羧甲基淀粉钠和交联聚维酮;内加崩解剂量为30%~70%,优选40%~50%。加入粘合剂,粘合剂为羟丙纤维素、聚维酮、乙醇、水中的一种或几种,优选羟丙纤维素和水,过24目筛制粒。50 ℃鼓风干燥,水分烘至1~3%。将烘干颗粒称重,折算收率外加,外加崩解剂为预胶化淀粉、羧甲基淀粉钠、羧甲基纤维素钠、低取代羟丙基纤维素、交联羧甲基纤维素钠中的一种或几种,优选羧甲基淀粉钠和交联聚维酮;外加润滑剂为硬脂酸镁、硅酸铝镁、硬脂富马酸钠、蔗糖脂肪酸酯、单硬脂酸甘油酯、滑石粉、硬脂酸、二氧化硅中的一种或几种,优选硬脂酸镁和二氧化硅;外加矫味剂为阿司帕坦、薄荷脑、安赛蜜、甜菊苷、薄荷香精、香草香精中的一种或几种,优选阿司帕坦、薄荷香精。
采用本方法制备的分散片服用方便,口感良好,分散均匀性良好,15min溶出度大于85%,属于快速溶出。
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。
(一)分散片的制备
实施例1:
制备工艺:
将依匹哌唑粉碎过200目筛,然后与15倍重量乳糖过80目筛混合3次,加入剩余乳糖、微晶纤维素和羧甲基淀粉钠过80目筛3次混匀,2%羟丙基纤维素作为粘合剂,24目筛制粒,50℃鼓风干燥,水分烘至1~3%,将烘干颗粒过24目筛整粒,称重,折算收率,外加羧甲基淀粉钠、二氧化硅、阿司帕坦、薄荷香精和硬脂酸镁,Φ8平冲压片,片重250 mg,硬度20-40 N。
实施例2:
制备工艺:
将依匹哌唑粉碎过200目筛,然后与15倍重量甘露醇过80目筛混合3次,加入剩余甘露醇、微晶纤维素和羧甲基淀粉钠过80目筛3次混匀,2%羟丙基纤维素作为粘合剂,24目筛制粒,50 ℃鼓风干燥,水分烘至1~3%,将烘干颗粒过24目筛整粒,称重,折算收率,外加羧甲基淀粉钠、二氧化硅、阿司帕坦、薄荷香精和硬脂酸镁,Φ8平冲压片,片重250 mg,硬度20-40N。
实施例3:
制备工艺:
将依匹哌唑粉碎过200目筛,然后与15倍重量乳糖过80目筛混合5次,加入剩余乳糖、微晶纤维素和羧甲基淀粉钠过80目筛3次混匀,2%羟丙基纤维素作为粘合剂,24目筛制粒,50℃鼓风干燥,水分烘至1~3%,将烘干颗粒过24目筛整粒,称重,折算收率,外加羧甲基淀粉钠、二氧化硅、阿司帕坦、薄荷香精和硬脂酸镁,Φ8平冲压片,片重250 mg,硬度20-40 N。
实施例4:
制备工艺:
将依匹哌唑粉碎过200目筛,然后与35倍重量乳糖过80目筛混合3次,加入剩余乳糖、微晶纤维素和羧甲基淀粉钠过80目筛3次混匀,2%羟丙基纤维素作为粘合剂,24目筛制粒,50℃鼓风干燥,水分烘至1~3%,将烘干颗粒过24目筛整粒,称重,折算收率,外加羧甲基淀粉钠、二氧化硅、阿司帕坦、薄荷香精和硬脂酸镁,Φ8平冲压片,片重350 mg,硬度20-40 N。
实施例5:
制备工艺:
将依匹哌唑粉碎过200目筛,然后与20倍重量乳糖过80目筛混合3次,加入剩余乳糖、微晶纤维素和羧甲基淀粉钠过80目筛3次混匀,水作为粘合剂,24目筛制粒,50 ℃鼓风干燥,水分烘至1~3%,将烘干颗粒过24目筛整粒,称重,折算收率,外加羧甲基淀粉钠、二氧化硅、阿司帕坦、薄荷香精和硬脂酸镁,Φ8平冲压片,片重350 mg,硬度20-40 N。
实施例6:
制备工艺:
将依匹哌唑粉碎过200目筛,然后与20倍重量乳糖过80目筛混合7次,加入剩余乳糖、微晶纤维素和羧甲基淀粉钠过80目筛3次混匀,水作为粘合剂,24目筛制粒,50 ℃鼓风干燥,水分烘至1~3%,将烘干颗粒过24目筛整粒,称重,折算收率,外加羧甲基淀粉钠、二氧化硅、阿司帕坦、薄荷香精和硬脂酸镁,Φ8平冲压片,片重350 mg,硬度20-40 N。
实施例7:
制备工艺:
将依匹哌唑粉碎过200目筛,然后与20倍重量乳糖过80目筛混合5次,加入剩余乳糖、微晶纤维素和羧甲基淀粉钠过80目筛3次混匀,水作为粘合剂,24目筛制粒,50 ℃鼓风干燥,水分烘至1~3%,将烘干颗粒过24目筛整粒,称重,折算收率,外加羧甲基淀粉钠、二氧化硅、阿司帕坦、薄荷香精和硬脂酸镁,Φ8平冲压片,片重350 mg,硬度20-40 N。
对比实施例:
制备工艺:
将依匹哌唑粉碎过200目筛,然后与内加辅料过80目筛3次混匀,2%羟丙基纤维素作为粘合剂,24目筛制粒,50 ℃鼓风干燥,水分烘至1~3%,将烘干颗粒过24目筛整粒,称重,折算收率,外加羧甲基淀粉钠、二氧化硅、阿司帕坦、薄荷香精和硬脂酸镁,Φ8平冲压片,片重350mg,硬度20-40 N。
Claims (10)
1.一种依匹哌唑分散片,其特征在于:含有依匹哌唑-亲水性材料共混物,此外还有填充剂、崩解剂、粘合剂、润滑剂和矫味剂。
2.据权利要求1所述的依匹哌唑-亲水性材料共混物,其特征在于:亲水性材料为乳糖、甘露醇、山梨醇中的一种或几种。
3.据权利要求1所述的依匹哌唑-亲水性材料共混物,其特征在于:依匹哌唑与亲水性材料的重量比为1:1~1:30。
4.据权利要求4所述的依匹哌唑-亲水性材料共混物,其特征在于:依匹哌唑与亲水性材料的重量比为1:10~1:20。
5.据权利要求1所述,依匹哌唑-亲水性材料共混物的制备方法为:将原料药依匹哌唑和亲水性材料过80目筛混合若干次,形成依匹哌唑-亲水性材料共混物。
6.据权利要求6所述,其特征在于:依匹哌唑和亲水性材料过80目筛混合3~8次。
7.据权利要求1所述,其特征在于:填充剂为乳糖、甘露醇、山梨醇、微晶纤维素、淀粉及淀粉衍生物、果糖中的一种或几种。
8.据权利要求1所述,其特征在于:崩解剂为羧甲基淀粉钠、交联聚维酮、羧甲基纤维素钠、低取代羟丙基纤维素、交联羧甲基纤维素钠中的一种或几种。
9.据权利要求1所述,其特征在于:矫味剂为阿司帕坦、薄荷脑、安赛蜜、甜菊苷、薄荷香精、香草香精中的一种或几种。
10.据权利要求1所述,其制备过程为:
(1)将原料药依匹哌唑和亲水性材料过80目筛混合若干次,形成依匹哌唑-亲水性材料共混物,再加入填充剂和内加崩解剂混合均匀,加入粘合剂制软材,24目筛制粒;
(2)50 ℃烘箱鼓风干燥,水分烘至1~3%;
(3)将烘干颗粒取出,24目筛整粒;
(4)将步骤(3)的烘干颗粒称重,折算收率外加。
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