CN106727370A - 一种含有盐酸齐拉西酮的口崩片及其制备方法 - Google Patents
一种含有盐酸齐拉西酮的口崩片及其制备方法 Download PDFInfo
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- CN106727370A CN106727370A CN201611113790.XA CN201611113790A CN106727370A CN 106727370 A CN106727370 A CN 106727370A CN 201611113790 A CN201611113790 A CN 201611113790A CN 106727370 A CN106727370 A CN 106727370A
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- ziprasidone hcl
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- ziprasidone
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- 229960000607 ziprasidone Drugs 0.000 title 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
- A61K31/395—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
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Zoology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明公开了一种含有盐酸齐拉西酮的口崩片的制备方法。该口崩片含有盐酸齐拉西酮‑波拉克林钾复合物以及其它药学上可接受的辅料,采用离子交换技术进行掩味,湿法制粒压片制备口崩片,其在口腔内无需用水即可崩解,有效地掩盖了其主要活性成分盐酸齐拉西酮的苦、麻、辣感,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, 具体涉及一种离子交换技术方法进行掩味的药物组合物及其口崩片制备方法。
背景技术
卓乐定(英文商品名为Geodon ®,盐酸齐拉西酮胶囊)是由辉瑞公司研发的抗抑郁药,属于选择性五羟色胺再摄取抑制剂 (SSRI),对多巴胺D2、5HT2A、5HT1D受体具有拮抗作用,对5HT1A受体具有激动作用,其活性成分齐拉西酮用于治疗精神分裂症,对精神分裂症相关症状(包括视听幻觉、妄想、动机缺乏和逃避社会)有效用于治疗抑郁症的相关症状,包括伴随焦虑、有或无躁狂史的抑郁症。疗效满意后,继续服用可有效地防止抑郁症的复发和再发。Geodon ®2000年首先在瑞典上市,其后在德国、香港、爱尔兰、以色列、挪威及菲律宾(2002)上市,至今己在世界69个国家地区上市,在抗抑郁药物市场上仍然占据不可取代的位置。盐酸齐拉西酮目前在美国以商品名GEODON销售,包括20mg、40 mg、60 mg、80 mg口服胶囊(以齐拉西酮计)以及20mg/ml的注射剂。口崩片目前国内没有上市。
口崩片是不需用水或只需用少量水,无需咀嚼,置于舌面,遇唾液迅速崩解后,借助吞咽力,药物即可入胃起效的片剂。其吸收快、生物利用度高,降低副作用,避免部分首过效应,服用方便,尤其适用于老人、小儿、精神类患者等吞咽困难的病人及取水不便者,增加了患者用药的顺应性。所以开发一种不需要用水送服、容易吞咽、随时随地可以服用而又快速起效的制剂是非常必要的。
专利CN02155139公开了一种齐拉西酮及其盐的水溶性包合物及其制备方法,其发明方法是将齐拉西酮或其盐投入含有环糊精的有机溶媒中,加热回流1~2h至药物完全溶解,在加热条件下真空挥干有机溶媒,即得包合物。但其生产工艺与口崩片制备方法相比,其制备方法繁琐,生产成本高,且增加生产过程中的安全隐患,不利于工业化生产。
专利CN201310367472公开了一种齐拉西酮及其盐的药物树脂盐及其制备方法,其发明的树脂盐为齐拉西酮或其盐与弱酸性阳离子交换树脂形成的药物树脂复合物,目的在于为患者提供一种吸收快、生物利用度高的包含齐拉西酮及其盐的制剂。但其生产工艺与口崩片制备工艺相比较为繁琐,在实际生产中很难达到实用效果。
本发明采用将盐酸齐拉西酮和波拉克林钾制备成盐酸齐拉西酮-波拉克林钾离子交换树脂复合物,再与药学上的辅料混合,湿法制粒压片,该制备工艺简单,且能有效达到掩味效果,成本低,易于实现大生产。
发明内容
本发明的目的在于提供一种掩味效果好、工艺简单的口崩片。本发明涉及了一种利用波拉克林钾离子交换树脂来达到掩味效果的方法。其特征是先将原料药盐酸齐拉西酮和波拉克林钾在纯化水中磁力搅拌,盐酸齐拉西酮和波拉克林钾的重量比为1:1.5~1:4,优选1:1.4;盐酸齐拉西酮-波拉克林钾复合物和纯化水的重量比为1:30~1:50,优选1:35~1:45;磁力搅拌时间为2~6h,离心,收集沉淀物,50℃干燥,研磨,制备成盐酸齐拉西酮-波拉克林钾离子交换树脂复合物。加入其余内加辅料过80目筛混合均匀,其中填充剂为微晶纤维素、甘露醇、木糖醇、山梨醇中的一种或几种,优选微晶纤维素和甘露醇;崩解剂为羧甲基淀粉钠、预胶化淀粉、交联聚维酮、交联羧甲基纤维素钠中的一种或几种,优选交联聚维酮和羧甲基淀粉钠。加入粘合剂,粘合剂为聚维酮、羟丙纤维素中的一种或几种,优选水和羟丙纤维素,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;外加润滑剂为滑石粉、硬脂酸镁、蔗糖脂肪酸酯、硅酸铝镁、二氧化硅、硬脂富马酸钠、单硬脂酸甘油酯、硬脂酸中的一种或几种,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,优选薄荷香精、香草香精、阿司帕坦。Φ8平冲压片,片重200mg,硬度为20~40N。
采用本方法制备的口崩片口感良好、服用方便,口腔崩解时间小于60S, 口感无苦、麻、辣等刺激性口感。
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)口崩片的制备
实施例1:
,
制备工艺
将盐酸齐拉西酮和波拉克林钾在50倍重量纯化水中磁力搅拌3h,4000rpm离心10分钟,收集沉淀物50℃干燥,研磨,加入微晶纤维素、甘露醇和羧甲基淀粉钠过80目筛3次混匀,水作为润湿剂,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、微晶纤维素、安赛蜜和硬脂酸镁,Φ8平冲压片,片重200mg,硬度20-40N。 该处方制得的制剂入口甜,过后苦、麻、辣感较明显,口腔崩解时间大于60s。
实施例2:
,
制备工艺
将盐酸齐拉西酮和波拉克林钾在50倍重量纯化水中磁力搅拌3h,4000rpm离心10分钟,收集沉淀物50℃干燥,研磨,加入微晶纤维素、甘露醇和羧甲基淀粉钠过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、微晶纤维素、安赛蜜和硬脂酸镁,Φ8平冲压片,片重200mg,硬度20-40N。 该处方制得的制剂入口甜,苦、麻、辣感明显改善,口腔崩解时间小于60s。
实施例3:
,
制备工艺
将盐酸酸齐拉西酮和波拉克林钾在30倍重量纯化水中磁力搅拌4h,4000rpm离心10分钟,收集沉淀物50℃干燥,研磨,加入微晶纤维素、甘露醇和羧甲基淀粉钠过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、微晶纤维素、安赛蜜 和硬脂酸镁,Φ8平冲压片,片重200mg硬度20-40N。该处方制得的制剂入口甜,过后苦、麻感明显,仍有少许后劲,口腔崩解时间大于60s。
实施例4:
,
制备工艺
将盐酸酸齐拉西酮和波拉克林钾在40倍重量纯化水中磁力搅拌4h,4000rpm离心10分钟,收集沉淀物50℃干燥,研磨,加入微晶纤维素、甘露醇和羧甲基淀粉钠过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、微晶纤维素、安赛蜜和硬脂酸镁,Φ8平冲压片,片重200mg硬度20-40N。该处方制得的制剂入口甜,过后苦、麻、辣感稍有改善,口腔崩解时间大于60s。
实施例5:
,
制备工艺
将盐酸酸齐拉西酮和波拉克林钾在40倍重量纯化水中磁力搅拌4h,4000rpm离心10分钟,收集沉淀物50℃干燥,研磨,加入微晶纤维素、甘露醇和交联羧甲基纤维素钠过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,外加交联羧甲基纤维素钠、微晶纤维素、安赛蜜和硬脂酸镁,Φ8平冲压片,片重200mg硬度20-40N。该处方制得的制剂入口甜,苦、麻、辣感改善明显,口腔崩解时间小于60s。
实施例6:
,
制备工艺
将盐酸酸齐拉西酮和波拉克林钾在40倍重量纯化水中磁力搅拌4h,4000rpm离心10分钟,收集沉淀物50℃干燥,研磨,加入微晶纤维素、甘露醇和交联羧甲基纤维素钠过80目筛3次混匀,水作为润湿剂,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,外加交联羧甲基纤维素钠、微晶纤维素、安赛蜜和硬脂酸镁,Φ8平冲压片,片重200mg硬度20-40N。该处方制得的制剂入口甜,清凉,苦、麻、辣感改善明显,无不良口感,口腔崩解时间小于60s。
对比实施例
,
制备工艺
将盐酸齐拉西酮、甘露醇、微晶纤维素、羧甲基淀粉钠过80目筛3次混匀, 水作为粘合剂,加至内加物料的25%,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、安赛蜜硬脂酸镁,Φ8平冲压片,片重200mg,硬度20-40N。该处方制得的制剂口感苦、麻 辣感较强,口腔崩解时间大于60s。
通过对比实施例和实施例1~6的比较可知,直接将主药盐酸齐拉西酮采用常规湿法制粒压片后无法达到掩味效果,将盐酸齐拉西酮先同波拉克林钾制备成离子交换复合物,用水作为润湿剂,湿法制粒压片,同时结合不同的矫味剂, 最终能有效的达到掩味效果,方法简便,易于实现大生产。
以上所述实施例仅是为充分说明本发明而所举的较佳的实施例, 本发明的保护范围不限于此。本技术领域的技术人员在本发明基础上所作的等同替代或变换,均在本发明的保护范围之内。本发明的保护范围以权利要求书为准。
Claims (8)
1.盐酸齐拉西酮口崩片,其中所述口崩片的重量百分比为:
盐酸齐拉西酮 5-10%
波拉克林钾 5-50%
崩解剂 5-10%
填充剂 10-60%
粘合剂 15-30%
矫味剂 1-5%
润滑剂 3-20%。
2.据权利要求1所述的盐酸齐拉西酮口崩片,其特征在于:含有盐酸齐拉西酮-波拉克林钾离子交换树脂复合物, 此外还有粘合剂、 填充剂、 崩解剂、 润滑剂和矫味剂。
3.据权利要求2所述的离子交换树脂复合物,其特征在于:盐酸齐拉西酮和波拉克林钾的重量比为1:1~1:5,优选为1:1~1:4。
4.据权利要求2所述,离子交换树脂复合物的制备方法为:将原料药盐酸齐拉西酮和波拉克林钾在一定量纯化水中磁力搅拌形成复合物,离心,收集沉淀物,干燥,研磨后过筛,制备成盐酸齐拉西酮-波拉克林钾离子交换树脂复合物。
5.据权利要求1-2所述,其特征在于:粘合剂为聚维酮、羟丙纤维素、淀粉中的一种或几种。
6.据权利要求1-2所述,其特征在于:填充剂为微晶纤维素、淀粉、果糖、甘露醇、木糖醇、乳糖、山梨醇中的一种或几种。
7.据权利要求1-2所述,其特征在于:崩解剂为羧甲基淀粉钠、低取代羟丙基纤维素、预胶化淀粉、交联聚维酮、羧甲基纤维素钠、交联羧甲基纤维素钠中的一种或几种。
8.据权利要求1-7所述,盐酸齐拉西酮口崩片可由以下步骤制得:
(1)将原料药与波拉克林钾在一定量纯净水中磁力搅拌,离心,收集沉淀物,50℃干燥,研磨后过筛,制备成盐酸齐拉西酮-波拉克林钾离子交换树脂复合物,再加入其余内加辅料过80目筛混合均匀,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)的整粒颗粒称重,折算收率外加,Φ8平冲压片,片重200mg,硬度20~40N。
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