CN108938578A - 阿立哌唑分散片及其制备方法 - Google Patents
阿立哌唑分散片及其制备方法 Download PDFInfo
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- CN108938578A CN108938578A CN201710379925.5A CN201710379925A CN108938578A CN 108938578 A CN108938578 A CN 108938578A CN 201710379925 A CN201710379925 A CN 201710379925A CN 108938578 A CN108938578 A CN 108938578A
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- aripiprazole
- dispersible tablet
- microcrystalline cellulose
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- 229960004372 aripiprazole Drugs 0.000 title claims abstract description 55
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 title claims abstract description 54
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims 1
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- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
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- MHUWZNTUIIFHAS-CLFAGFIQSA-N dioleoyl phosphatidic acid Chemical group CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(O)=O)OC(=O)CCCCCCC\C=C/CCCCCCCC MHUWZNTUIIFHAS-CLFAGFIQSA-N 0.000 description 1
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Classifications
-
- 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
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- 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
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Zoology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
Abstract
本申请公开了一种阿立哌唑分散片及其制备方法,所述阿立哌唑分散片包括如下组分:阿立哌唑,微晶纤维素与亲水性辅料的重量比为1:1‑1:3,崩解剂和润滑剂。其制备方法包括如下步骤:取阿立哌唑与亲水性辅料进行预混后再加入填充剂、崩解剂、润滑剂;取预处理后的混合物,加入润湿剂制软材;将软材通过筛网制得颗粒;颗粒干燥后折算润滑剂用量,加入润滑剂混合均匀,得总混物料,取总混物料进行压片。制得的分散片溶出迅速,生物利用度高,携带方便,可以含服、吞服、冲服,不仅适用于成人,更适合于儿童及老年人患者。
Description
技术领域
本申请涉及药物制剂领域,具体的涉及阿立哌唑分散片中填充剂微晶纤维素与亲水性辅料的重量比及其制备方法。
背景技术
阿立哌唑(Aripiprazole)化学名是7-{4-[4-(2,3-二氯苯基)-l-哌嗪基]丁氧基}-3,4-二氢-2(1H)-喹啉酮,其有效成分为阿立哌唑及其活性代谢物去氢阿立哌唑。阿立哌唑的结构式为:
。
阿立哌唑是日本大冢制药公司开发的一种新型非典型抗精神病药物,本品是多巴胺和5-羟色胺***的稳定剂,是突触后多巴胺受体的阻滞剂,同时又是突触前自主受体的激动剂,与D2和D3受体的亲和力非常强。本品是D2受体的部分激动剂,在活体多巴胺功能亢进模型中显示出较强的阻滞作用,而在多巴胺功能低下的模型中则表现出较强激动作用;本品能够抑制多巴胺激动剂引起的垂体前叶催乳素的升高,这种抑制作用可以被氟哌啶醇完全阻滞,因此,本品作用特点不是阻断而是稳定多巴胺***的作用。同时本品又是5-HT1A受体的部分激动剂和5-HT2A受体的阻滞剂。从而发挥抗精神***症的焦虑、抑郁、认知缺损和阴性症状。本品口服生物利用度为87%,达峰时间为3~5h,血浆蛋白结合率大于99%。药物在肝脏经细胞色素P450CYP3A4和CYP2D6代谢,代谢途径包括脱氢和羟基化。其主要代谢产物脱氢阿立哌唑占药时曲线下面积(AUC)的40%,对多巴胺D2受体的亲和力与母体化合物相似,并可能具有药理活性。给药量的25% 经肾***(其中原形药物少于1%),另有约55%随粪便排出体外(原形药物占18%)。其凭借作用机理和安全性评价被称为第三代抗精分药,自上以来获得了不菲的成绩。
目前国内已经获得批准上市的治疗抑郁症和精神***症的药物剂型有片剂、分散片、口腔崩解片、胶囊剂、颗粒剂、注射剂等。静脉注射对于患者来说是极不方便的,依从性差,片剂、胶囊剂、颗粒剂等口服制剂,患者服用时必须用水送服,不适合于老人、儿童以及吞咽困难的患者,而抑郁症和精神***症患者大多需要长期服药,且精神病患者存在认知障碍。分散片生物利用度高,携带方便,可以含服、吞服、冲服,不仅适用于成人,更适合于儿童及老年人患者。
发明内容
根据本申请一种阿立哌唑分散片及其制备方法,申请人惊喜的发现,所述阿立哌唑分散片中,当微晶纤维素与糖醇类亲水性辅料的重量比为1:1-1:3时,其溶出迅速。由于阿立哌唑的水溶性较差,溶出度作为药品的重要评价指标,当阿立哌唑分散片的溶出度下降时,直接影响药物的生物利用度,导致药效下降。
具体的,本申请的技术方案如下:
一种阿立哌唑分散片及其制备方法,所述阿立哌唑分散片包括如下重量比的组分:阿立哌唑2%-10%,微晶纤维素10%-25%,糖醇类亲水性辅料30%-75%,粘合剂2%-5%,崩解剂1%-10%,润滑剂0.1%-2%。其制备方法包括如下步骤:取阿立哌唑糖醇类亲水辅料进行预混合,取预混合后的混合物加入所述微晶纤维素、所述崩解剂、所述粘合剂、所述润滑剂进行处理;取所述混合物加入润湿剂得软材;取所述软材通过筛网得到颗粒;颗粒干燥后折算润滑剂用量,加入润滑剂混合均匀,得总混物料;取所述总混物料进行压片。
根据本申请一种阿立哌唑分散片及其制备方法,采用阿立哌唑与辅料通过湿法制粒工艺,与外加物料混合均匀后,进行压片,具有如下附加的技术特征:
一种阿立哌唑分散片,包括如下重量比的组分:阿立哌唑2%-10%,微晶纤维素10%-25%,亲水性辅料30%-75%,粘合剂2%-5%,崩解剂1%-10%,润滑剂0.1%-2%。
进一步地,所述的阿立哌唑分散片,糖醇类亲水性辅料包括甘露醇、乳糖、木糖醇中的一种或几种。
进一步地,所述的阿立哌唑分散片,崩解剂包括交联羧甲基纤维素钠、羧甲基淀粉钠、低取代羟丙基纤维素和交联聚维酮中的一种或几种。
进一步地,所述的阿立哌唑分散片,粘合剂包括:聚维酮,羟丙基纤维素,羟丙基甲基纤维素中的一种或几种。
进一步地,所述的阿立哌唑分散片,润滑剂包括硬脂酸镁、硬脂富马酸钠、二氧化硅中的一种或几种。
进一步地,所述的微晶纤维素与亲水性辅料重量比为1:1-1:3。
进一步地,所述的微晶纤维素,其型号可以是PH101、PH102、PH105、PH112和PH301。
进一步地,所述阿立哌唑分散片,其制备方法包括如下步骤:
(1)取阿立哌唑与糖醇类亲水性辅料进行预处理;
(2)取预处理后阿立哌唑与糖醇类亲水性辅料的混合物与微晶纤维素,崩解剂,粘合剂充分混合均匀后,加入润湿剂,搅拌均匀后得软材;
(3)取软材通过筛网制得湿颗粒;
(4)取湿颗粒通过干燥后得到干燥颗粒,整粒,外加润滑剂充分混合均匀,得总混物料;
(5)将总混物料进行压片。
进一步地,所述的微晶纤维素,其在分散片中的加入方式可以是内加、外加、内外加。
进一步地,所述阿立哌唑分散片的制备方法,所述润湿剂为纯化水、乙醇或者二者组成的混合物。
具体实施方式
下面用实施例来进一步说明本申请,进一步了解一种阿立哌唑分散片及其制备方法,但本申请不受其限制。
以下各实施例压制的片剂,如未另外说明,片重均为95mg,硬度范围20N-40N。溶出试验方法均为桨法,pH1.2介质,转速每分钟50转,15min取样,计算溶出度(%)。
实施例1 2mg规格阿立哌唑分散片的制备
处方组成:
。
制备工艺:
(1)原辅料预处理:将阿立哌唑粉碎过80目筛,乳糖、微晶纤维素、交联羧甲基纤维素钠、羟丙基纤维素和硬脂酸镁分别过60目筛,备用;
(2)制软材:称取预处理过的处方量的阿立哌唑、乳糖于湿法制粒机中混合均匀,加入微晶纤维素,羟丙基纤维素和交联羧甲基纤维素钠再次混合均匀;向湿法制粒机中加入适量纯化水作为润湿剂,搅拌均匀得软材;
(3)湿法制粒:将软材通过30目筛制湿颗粒;
(4)颗粒干燥:将所述湿颗粒于50-55℃干燥至颗粒水分小于3%,并用30目筛网整粒;
(5)压片:折算硬脂酸镁用量,混合均匀后压片。
实施例2 2mg规格阿立哌唑分散片的制备
处方组成:
。
制备工艺:
(1)原辅料预处理:将阿立哌唑粉碎过80目筛,乳糖、微晶纤维素、交联羧甲基纤维素钠、羟丙基纤维素和硬脂酸镁分别过60目筛,备用;
(2)制软材:称取预处理过的处方量的阿立哌唑、乳糖于湿法制粒机中混合均匀,加入微晶纤维素,羟丙基纤维素和交联羧甲基纤维素钠再次混合均匀;向湿法制粒机中加入适量纯化水作为润湿剂,搅拌均匀得软材;
(3)湿法制粒:将软材通过30目筛制湿颗粒;
(4)颗粒干燥:将所述湿颗粒于50-55℃干燥至颗粒水分小于3%,并用30目筛网整粒;
(5)压片:折算硬脂酸镁用量,混合均匀后压片。
实施例3 2mg规格阿立哌唑分散片的制备
处方组成:
制备工艺:
。
制备工艺:
(1)原辅料预处理:将阿立哌唑粉碎过80目筛,乳糖、微晶纤维素、交联羧甲基纤维素钠、羟丙基纤维素和硬脂酸镁分别过60目筛,备用;
(2)制软材:称取预处理过的处方量的阿立哌唑、乳糖于湿法制粒机中混合均匀,加入微晶纤维素,羟丙基纤维素和交联羧甲基纤维素钠再次混合均匀;向湿法制粒机中加入适量纯化水作为润湿剂,搅拌均匀得软材;
(3)湿法制粒:将软材通过30目筛制湿颗粒;
(4)颗粒干燥:将所述湿颗粒于50-55℃干燥至颗粒水分小于3%,并用30目筛网整粒;
(5)压片:折算硬脂酸镁用量,混合均匀后压片。
实施例4 2mg规格阿立哌唑分散片的制备
处方组成:
。
制备工艺:
(1)原辅料预处理:将阿立哌唑粉碎过80目筛,乳糖、微晶纤维素、交联羧甲基纤维素钠、羟丙基纤维素和硬脂酸镁分别过60目筛,备用;
(2)制软材:称取预处理过的处方量的阿立哌唑、乳糖于湿法制粒机中混合均匀,加入微晶纤维素,羟丙基纤维素和交联羧甲基纤维素钠再次混合均匀;向湿法制粒机中加入适量纯化水作为润湿剂,搅拌均匀得软材;
(3)湿法制粒:将软材通过30目筛制湿颗粒;
(4)颗粒干燥:将所述湿颗粒于50-55℃干燥至颗粒水分小于3%,并用30目筛网整粒;
(5)压片:折算硬脂酸镁用量,混合均匀后压片。
对比实施例1 2mg规格阿立哌唑分散片的制备
处方组成:
。
制备工艺:
(1)原辅料预处理:将阿立哌唑粉碎过80目筛,乳糖、微晶纤维素、交联羧甲基纤维素钠、羟丙基纤维素和硬脂酸镁分别过60目筛,备用;
(2)制软材:称取预处理过的处方量的阿立哌唑、乳糖于湿法制粒机中混合均匀,加入微晶纤维素,羟丙基纤维素和交联羧甲基纤维素钠再次混合均匀;向湿法制粒机中加入适量纯化水作为润湿剂,搅拌均匀得软材;
(3)湿法制粒:将软材通过30目筛制湿颗粒;
(4)颗粒干燥:将所述湿颗粒于50-55℃干燥至颗粒水分小于3%,并用30目筛网整粒;
(5)压片:折算硬脂酸镁用量,混合均匀后压片。
对比实施例2 2mg规格阿立哌唑分散片的制备
处方组成:
。
制备工艺:
(1)原辅料预处理:将阿立哌唑粉碎过80目筛,乳糖、微晶纤维素、交联羧甲基纤维素钠、羟丙基纤维素和硬脂酸镁分别过60目筛,备用;
(2)制软材:称取预处理过的处方量的阿立哌唑、乳糖于湿法制粒机中混合均匀,加入微晶纤维素和交联羧甲基纤维素钠再次混合均匀;向湿法制粒机中加入适量纯化水作为润湿剂,搅拌均匀得软材;
(3)湿法制粒:将软材通过30目筛制湿颗粒;
(4)颗粒干燥:将所述湿颗粒于50-55℃干燥至颗粒水分小于3%,并用30目筛网整粒;
(5)压片:折算硬脂酸镁用量,混合均匀后压片。
溶出方法:取供试品12片,1000mLpH1.2盐酸介质中(37±0.5℃),转速75rpm,于30min取供试液进行测定。
根据上述溶出度测定方法,对实施例1-4制剂样品进行溶出度测定,结果如下:
。
由以上结果可知,微晶纤维素和糖醇类亲水性辅料乳糖的重量比为1:1-1:3时,原料药阿立哌唑的溶出显著提高。
尽管上面已经示出和描述了本发明的实施例,可以理解的是,上述实施例是示例性的,不能理解为对本发明的限制,本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
Claims (9)
1.一种阿立哌唑分散片,其特征在于由阿立哌唑,微晶纤维素,糖醇类亲水性辅料,粘合剂,崩解剂和润滑剂组成,其中微晶纤维素与糖醇类亲水性辅料的重量比为1:1-1:3。
2.根据权利要求1所述的亲水性辅料包括甘露醇、乳糖、木糖醇中的一种或几种。
3.根据权利要求1所述的崩解剂包括交联羧甲基纤维素钠、羧甲基淀粉钠、低取代羟丙基纤维素和交联聚维酮中的一种或几种。
4.根据权利要求1所述的粘合剂包括:聚维酮,羟丙基纤维素,羟丙基甲基纤维素中的一种或几种。
5.根据权利要求1所述的润滑剂包括硬脂酸镁、硬脂富马酸钠、二氧化硅中的一种或几种。
6.根据权利要求1述的微晶纤维素,其型号可以是PH101、PH102、PH105、PH112和PH301。
7.根据权利要求1-6任一权利要求所述的阿立哌唑分散片,其制备方法包括如下步骤:
(1)取阿立哌唑与糖醇类亲水性辅料进行预处理;
(2)取预处理后阿立哌唑与糖醇类亲水性辅料的混合物与微晶纤维素、粘合剂、崩解剂混合均匀后,加入润湿剂,搅拌均匀后得软材;
(3)取软材通过筛网制得湿颗粒;
(4)取湿颗粒通过干燥后得到干燥颗粒,整粒,外加润滑剂充分混合均匀,得总混物料;
(5)将总混物料进行压片。
8.根据权利要求1-8任一权利要求所述的微晶纤维素,其在分散片中的加入方式可以是内加、外加、内外加。
9.根据权利要求7所述的阿立哌唑分散片的制备方法,所述润湿剂为纯化水、乙醇或者二者组成的混合物。
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