CN116650426A - 一种盐酸左西替利嗪片及其制备方法 - Google Patents
一种盐酸左西替利嗪片及其制备方法 Download PDFInfo
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- CN116650426A CN116650426A CN202210146081.0A CN202210146081A CN116650426A CN 116650426 A CN116650426 A CN 116650426A CN 202210146081 A CN202210146081 A CN 202210146081A CN 116650426 A CN116650426 A CN 116650426A
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- levocetirizine hydrochloride
- tablet
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- levocetirizine
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- ZKLPARSLTMPFCP-OAQYLSRUSA-N 2-[2-[4-[(R)-(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]ethoxy]acetic acid Chemical compound C1CN(CCOCC(=O)O)CCN1[C@@H](C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-OAQYLSRUSA-N 0.000 title claims abstract description 63
- 229960001508 levocetirizine Drugs 0.000 title claims abstract description 63
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 36
- 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 abstract description 26
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000008101 lactose Substances 0.000 claims abstract description 26
- 239000002994 raw material Substances 0.000 claims abstract description 22
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims abstract description 18
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- 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 claims abstract description 3
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- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims abstract description 3
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- PGLIUCLTXOYQMV-GHVWMZMZSA-N 2-[2-[4-[(r)-(4-chlorophenyl)-phenylmethyl]piperazine-1,4-diium-1-yl]ethoxy]acetic acid;dichloride Chemical compound Cl.Cl.C1CN(CCOCC(=O)O)CCN1[C@@H](C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 PGLIUCLTXOYQMV-GHVWMZMZSA-N 0.000 claims description 3
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- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 5
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- 239000002609 medium Substances 0.000 description 5
- PGLIUCLTXOYQMV-UHFFFAOYSA-N Cetirizine hydrochloride Chemical compound Cl.Cl.C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 PGLIUCLTXOYQMV-UHFFFAOYSA-N 0.000 description 4
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- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-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
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
-
- 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
-
- 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
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- 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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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
本发明属于医药口服固体制剂技术领域,具体涉及一种盐酸左西替利嗪片及其制备方法。本发明盐酸左西替利嗪片原辅料包含活性成分、填充剂、粘合剂、包合辅料、崩解剂、助流剂、润滑剂;其中填充剂由微晶纤维素、乳糖、玉米淀粉中的一种或几种组成;粘合剂由羟丙甲纤维素、羟丙纤维素和聚维酮中的一种或两种组成;崩解剂由低取代羟丙纤维素、交联聚维酮、羧甲淀粉钠中的一种或两种组成;助流剂由二氧化硅组成;润滑剂由硬脂酸镁组成,本品处方中使用包合技术将盐酸左西替利嗪包合,从根本上解决了压片时粘冲和原料粘附设备容器的问题;优化处方工艺,减少包衣步骤,解决了崩解时间长、溶出慢的问题。
Description
技术领域
本发明属于医药口服固体制剂技术领域,涉及一种盐酸左西替利嗪片及其制备方法。
背景技术
盐酸左西替利嗪是第二代H1抗组胺药,为长效的具选择性的口服强效抗变态反应药。H1受体拮抗剂具有良好的抗变态反应,常用于过敏性鼻炎、过敏性皮肤瘙痒、结膜炎等。盐酸左西替利嗪与其同类药如苯海拉明、异丙嗪、扑尔敏相比,其分子具有极性,极少透过血脑屏障,因而大大减少了中枢镇静作用又因选择性作用于H1受体,对毒覃碱样胆碱受体和5-HT受体作用甚微,故于抗胆碱能活性相关的副反应也很少。从国内外有关该品使用情况来看,本品具有强抗变态反应活性,对缩小组胺引起的风团面积,本品5mg一片与特菲那定60mg三片等效。本品抑制由组胺介导的变态反应“早期”,并进一步减少与变态反应“晚期”相关的炎症细胞移行和介质释放。花粉过敏引起的病人口服10或15mg,一日2次,可有效地减少哮喘、呼吸困难和咳嗽症状,且较特非那定60mg,一日2次疗效强。本品起效较阿司咪唑(国内商品名:息斯敏)快,基本不被代谢,耐受性良好。
由于盐酸左西替利嗪具有良好的抗过敏作用副反应少且可耐受,具有良好的临床应用前景。但其进口品售价昂贵,不能为广大患者所普遍接受。通过国内生产,降低其成本,将带来可观的经济利益和社会效益。
随着现代工业的发展,空气污染日益严重,外界有害物质如种种有害气体、粉尘、致敏微生物和致敏原直接吸入肺部,使呼吸系统疾病(特别是过敏性鼻炎和哮喘)发病率和死亡率都在增加。有统计显示:高达25%的世界人口患有不同类型的过敏性疾病。
本品为口服选择性组胺H1受体拮抗剂,是第2代抗组胺药盐酸西替利嗪的单一光学异构体,对H1受体的亲和力是盐酸西替利唪的2倍,口服吸收迅速,起效更快,效应强而持久(24小时)。每天服用的剂量仅为盐酸西替利嗪的一半。无明显抗胆碱和抗5-羟色胺作用,中枢抑制作用较小。服用更为安全,较盐酸西替利嗪的无镇静、嗜睡等中枢神经系统不良反应率更低。未发现第二代抗组胺药物(如特非那定、阿斯眯唑等)所具有的致心律失常作用。
盐酸左西替利嗪片主治季节性和常年性过敏鼻炎,鼻结膜炎,荨麻疹,由药品、食品和昆虫叮咬引起的过敏反应,是一种高选择性、强效的H1受体拮抗剂。本品规格小,性质不稳定,原料粘附性强,生产中易粘附设备和容器具,特别是压片时易受环境温湿度影响,导致粘冲现象,从而出现产品含量偏低的问题,影响治疗效果,降低生产效率。另外,用现有的制备技术工艺,混合时原料易聚团,不易混合均匀,出现含量均匀度差的问题。在储存期间,原料遇湿、热导致稳定性降低,出现含量出现下降的现象。
盐酸左西替利嗪作为酸性药物,具有腐蚀性,工艺和包装需要有较好的阻隔性和防潮性。选择一种合适的工艺尤为重要,对产品的稳定性、安全性和有效性起到较好的保护作用。
发明内容
现有技术工艺生产,原料遇湿、热发粘,易粘附设备和容器具,导致含量均匀度低,影响治疗效果;压片时易受环境温湿度影响,诱发原料的粘性,导致粘冲现象;工艺流程复杂,控制要求较高,产品储存过程中会出现含量下降等问题。
针对现有技术的不足,本发明的目的是提供一种简单易行的制备工艺,通过原料与倍他环糊精包合,形成了稳定的包合物,解决了原料粘附聚集问题;通过两种崩解剂的组成使用,减少了包衣步骤,在保证稳定性的情况下,减小了片剂的硬度,解决了崩解时间长、溶出慢的问题。
本发明所述的一种盐酸左西替利嗪片的制备方法,其特征在于:包含活性成分、填充剂、粘合剂、包合辅料、崩解剂、助流剂、润滑剂;填充剂由微晶纤维素、乳糖、玉米淀粉中的一种或几种组成;粘合剂由羟丙甲纤维素、羟丙纤维素和聚维酮中的一种或两种组成;崩解剂由低取代羟丙纤维素、交联聚维酮、羧甲淀粉钠中的一种或两种组成;助流剂由二氧化硅组成;润滑剂由硬脂酸镁组成。
优选的,本发明所述的盐酸左西替利嗪片,以重量份数计,原辅料处方组成如下:
处方组成如下:
填充剂由微晶纤维素、玉米淀粉和乳糖组成,筛选合适的比例配方,在高剪切湿法制粒混合机中,采用喷雾加浆的方式制粒,通过干燥时的水分控制和颗粒的粒度分布,使颗粒具有良好的流动性和可压性,同时调节崩解剂交联聚维酮XL-10和低取代羟丙纤维素的用量,优化了片剂的崩解时限,加快了溶出,增强了药物的治疗效果。
更优选的,以重量份数计,原辅料处方组成如下:
处方组成如下:
本发明所述盐酸左西替利嗪片的制备方法,包括以下步骤;
(1)包合:将倍他环糊精加热溶解后,加入盐酸左西替利嗪包合制备包合物;
(2)配料;称取处方量的原辅料;
(3)制粒;使用湿法制粒混合机制软材,干燥整粒;
(4)混合;将制得颗粒与外加辅料混合,最后加入硬脂酸镁总混;
(5)压片:使用压片机压片;
(6)包装:将制备好的盐酸左西替利嗪片进行包装。
其中:
步骤(1)为包合:将倍他环糊精加热溶解后,加入盐酸左西替利嗪包合制备包合物。
步骤(2)为配料:将乳糖过60目筛,称取处方量的原辅料。
步骤(3)为制粒:按照微晶纤维素、盐酸左西替利嗪包合物、玉米淀粉、低取代羟丙纤维素、乳糖的顺序将原辅料加入湿法制粒混合机中,混合时间为10分钟;配制4%的聚维酮K30的水溶液;制湿颗粒,干燥至颗粒水分≤4%,摇摆式颗粒机30目筛网整粒。
步骤(4)为混合:将颗粒、交联聚维酮XL-10、二氧化硅加入混合机中,混合20分钟,再加入硬脂酸镁混合6分钟。
步骤(5)为压片:用旋转压片机压片,模具规格为Φ6.5mm浅凹;按混合粉中盐酸左西替利嗪含量计算理论片重,压片速度为2~5千片/小时,主压力平均值8.0±3.0KN,片重范围:理论片重±7.5%,平均硬度80±30N,性状、片重差异、脆碎度、崩解时限、含量及含量均匀度、溶出度均符合规定。
步骤(六)为包装:将制备好的盐酸左西替利嗪片进行包装,使用泡罩包装机,包装材料:药用铝箔、聚氯乙烯固体药用硬片。
将制备好的盐酸左西替利嗪片进行包装,使用泡罩包装机,包装材料:药用铝箔、聚氯乙烯固体药用硬片,密封滚桶温度240℃~280℃,运行速度100~320板/分钟。
作为一种更优选的技术方案,本发明所述的一种盐酸左西替利嗪片的制备方法,包括以下步骤:
步骤(一)为包合:将倍他环糊精加入圆底烧瓶,85℃水浴溶解后,将盐酸左西替利嗪加入圆底烧瓶中,85℃水浴保温,包合制备盐酸左西替利嗪包合物,包合3个小时;将包合物真空抽滤,电热鼓风干燥箱65℃干燥6个小时。
步骤(二)为配料;将乳糖过60目筛,称取处方量的原辅料。
步骤(三)为制粒;按照微晶纤维素、盐酸左西替利嗪包合物、玉米淀粉、低取代羟丙纤维素、乳糖的顺序将原辅料加入湿法制粒混合机中,混合时间为10分钟;配制4%的聚维酮K30的水溶液;制湿颗粒,流化床制粒包衣机干燥至颗粒水分≤4%,摇摆式颗粒机30目筛网整粒。
步骤(四)为混合:交联聚维酮XL-10、二氧化硅加入多向运动混合机中,混合机频率50Hz,混合20分钟,再加入硬脂酸镁混合6分钟。
步骤(五)为压片:用旋转压片机压片,模具规格为Φ6.5mm浅凹;按混合粉中盐酸左西替利嗪含量计算理论片重,压片速度为2~5千片/小时,主压力平均值8.0±3.0KN,片重范围:理论片重±7.5%,平均硬度80±30N,性状、片重差异、脆碎度、崩解时限、含量及含量均匀度均符合规定,崩解时限5min。
步骤(六)为包装:将制备好的盐酸左西替利嗪片进行包装,使用泡罩包装机,包装材料:药用铝箔、聚氯乙烯固体药用硬片,密封滚桶温度240℃~280℃,运行速度100~320板/分钟。
与现有技术相比,本发明制备工艺简单易行,通过原料与倍他环糊精包合,形成了稳定的包合物,解决了原料粘附聚集、压片粘冲的问题;通过两种崩解剂的组成使用,减少了包衣步骤,在保证稳定性的情况下,减小了片剂的硬度,解决了崩解时间长、溶出慢的问题。
附图说明
图1为实施例1-3的盐酸左西替利嗪片溶出均一性图;
图2为实施例1溶出均一性图(介质pH6.8);
图3为实施例2溶出均一性图(介质pH6.8);
图4为实施例3溶出均一性图(介质pH6.8);
图5为参比制剂1溶出均一性图(介质pH6.8);
图6参比制剂2溶出均一性图(介质pH6.8);
图7为盐酸左西替利嗪片长期考察6个月溶出度比较图。
具体实施方式
下面结合具体实施例对本发明作进一步详细说明,但本发明的实施例方式并不受下述实施例的限制,其他任何在本发明实质的基础上所作的进一步改变、修饰、替代、组合以及简化均应视为等效替换,包含在本发明的能保护范围之内。
实施例1:盐酸左西替利嗪片
处方组成(1000片)
成分 | 重量(g) |
盐酸左西替利嗪 | 5份 |
倍他环糊精 | 15份 |
微晶纤维素 | 30份 |
乳糖 | 30份 |
玉米淀粉 | 10份 |
聚维酮K30 | 2份 |
交联聚维酮XL-10 | 5份 |
低取代羟丙纤维素 | 5份 |
二氧化硅 | 2份 |
硬脂酸镁 | 1份 |
制备工艺:
包合制备盐酸左西替利嗪包合物。乳糖过60目筛,将微晶纤维素、盐酸左西替利嗪包合物、玉米淀粉、低取代羟丙纤维素、乳糖加入湿法制粒混合机中干混后,聚维酮K30配制制粒溶液,喷雾加浆湿法制粒,干燥整粒后,颗粒与交联聚维酮XL-10、二氧化硅混合均匀,加入硬脂酸镁混合均匀,压片,包装,即得。
实施例2:盐酸左西替利嗪片
处方组成(1000片)
成分 | 重量(g) |
盐酸左西替利嗪 | 5份 |
倍他环糊精 | 15份 |
微晶纤维素 | 20份 |
乳糖 | 40份 |
玉米淀粉 | 11份 |
聚维酮K30 | 1份 |
交联聚维酮XL-10 | 5份 |
低取代羟丙纤维素 | 5份 |
二氧化硅 | 2份 |
硬脂酸镁 | 1份 |
制备工艺:采用实施例1的制备方法。
实施例3:盐酸左西替利嗪片
处方组成(1000片)
制备工艺:采用实施例1的制备方法。
对比例1:盐酸左西替利嗪片
处方组成1000片
成分 | 重量(g) |
盐酸左西替利嗪 | 5份 |
微晶纤维素 | 30份 |
乳糖 | 45份 |
玉米淀粉 | 9份 |
聚维酮K30 | 3份 |
交联聚维酮XL-10 | 5份 |
低取代羟丙纤维素 | 5份 |
二氧化硅 | 2份 |
硬脂酸镁 | 1份 |
制备工艺:
乳糖过60目筛,将乳糖、盐酸左西替利嗪、玉米淀粉、低取代羟丙纤维素、二氧化硅湿法制粒混合机中干混后,聚维酮K30配制制粒溶液,喷雾加浆湿法制粒,干燥整粒后,颗粒与交联聚维酮XL-10、硬脂酸镁混合均匀,压片,包装,即得。
对比例2:盐酸左西替利嗪片
处方组成(1000片)
制备工艺:
包合制备盐酸左西替利嗪包合物。称取处方量的原辅料,将微晶纤维素PH102、盐酸左西替利嗪包合物、预胶化淀粉、低取代羟丙纤维素预混合10分钟,再加入乳糖30GR、二氧化硅混合10分钟,物料过50目筛,过筛后物料混合20分钟,最后加入硬脂酸镁混合5分钟,压片,包装,即得。
对比例3:盐酸左西替利嗪片
处方组成(1000片)
成分 | 重量(g) |
盐酸左西替利嗪 | 5份 |
倍他环糊精 | 15份 |
微晶纤维素 | 46份 |
乳糖 | 30份 |
二氧化硅 | 2份 |
交联聚维酮XL-10 | 5份 |
硬脂酸镁 | 2份 |
制备工艺:
包合制备盐酸左西替利嗪包合物。将乳糖、微晶纤维素、盐酸左西替利嗪包合物、交联聚维酮XL-10、二氧化硅混合机中混合10分钟,再加入硬脂酸镁混合5分钟,干法制粒,颗粒与硬脂酸镁混合5分钟,压片,包装,即得。
参比制剂选用市售UCB Farchim SA生产的Xyzal,规格为5mg。
1、试验效果对比
表1所得实施例和对比例片剂的基本参量分析
由表1可知:对比实例的崩解时限比参比制剂、实施例的崩解时间长,影响体内试验的生物等效性。
2、实施例和对比例所得片剂的稳定性比较
将实施例和对比例制备所得的片剂分别置于高温(40℃)、高湿(相对湿度75±5%)的恒温恒湿箱内加速试验6个月,分别于0天、6个月检测有关物质。
表2实施例和对比例加速6个月稳定性的比较
由表2的数据可知,经过加速试验分析结果可以看出,采用本发明制备的片剂在加速条件后产品杂质含量远低于实施例和原研参比制剂,所得产品质量稳定性更好。同时,在经过加速试验后产品的杂质仍符合质量标准,显著提高了产品的储存期限,有效延长了产品的保质期。
3、实施例和原研参比制剂含量对比
将实施例和对比例、参比制剂样品分别置于高温(40℃)高湿(相对湿度75±5%)的恒温恒湿箱内加速试验6个月,置于常温(30℃)湿度(相对湿度65±5%)试验6个月,分别于0天、加速3个月、加速和长期6个月取样,检测样品含量。
表3实施例和对比例加速和长期试验含量的比较
由表3的数据可知,经过加速和长期试验分析结果可以看出,采用本发明制备的片剂在加速条件后产品含量高于对比例和原研参比制剂,所得产品质量稳定性更好。
对实施例和参比制剂进行溶出试验,溶出度测定的条件:按照溶出度测定方法(参照中国药典2010版二部附录XC第二法)测定实施例与参比制剂的的溶出度。以0.01mol/L盐酸为溶出介质,转速为每分钟50转,高效液相色谱法测定药物溶出量。具体结果见图1-7,由图1~图6可知,实施例批间溶出均一性较好,批内溶出均一性优于原研参比制剂。
Claims (10)
1.一种盐酸左西替利嗪片,其特征在于:包含活性成分、填充剂、粘合剂、包合辅料、崩解剂、助流剂、润滑剂;所述填充剂由微晶纤维素、乳糖、玉米淀粉中的一种或几种组成;所述粘合剂由羟丙甲纤维素、羟丙纤维素和聚维酮中的一种或两种组成;崩解剂由低取代羟丙纤维素、交联聚维酮、羧甲淀粉钠中的一种或两种组成;助流剂由二氧化硅组成;润滑剂由硬脂酸镁组成。
2.根据权利要求1所述的盐酸左西替利嗪片,其特征在于:以重量份数计,原辅料处方组成如下:
3.一种制备权利要求1所述盐酸左西替利嗪片的方法,其特征在于,所述制备方法,包括以下步骤;
(1)包合:将倍他环糊精加热溶解后,加入盐酸左西替利嗪包合制备包合物;
(2)配料;称取处方量的原辅料;
(3)制粒;使用湿法制粒混合机制软材,干燥整粒;
(4)混合;将制得颗粒与外加辅料混合,最后加入硬脂酸镁总混;
(5)压片:使用压片机压片。
4.根据权利要求3所述的盐酸左西替利嗪片,其特征在于:步骤(1)为包合:将倍他环糊精加热溶解后,加入盐酸左西替利嗪包合制备包合物。
5.根据权利要求3所述的盐酸左西替利嗪片,其特征在于:步骤(2)为配料:将乳糖过60目筛。
6.根据权利要求3所述的盐酸左西替利嗪片的制备方法,其特征在于:步骤(3)为制粒:按照微晶纤维素、盐酸左西替利嗪包合物、玉米淀粉、低取代羟丙纤维素、乳糖的顺序将原辅料加入湿法制粒混合机中,混合时间为10分钟;配制4%的聚维酮K30的水溶液;制湿颗粒,干燥至颗粒水分≤4%,摇摆式颗粒机30目筛网整粒。
7.根据权利要求3所述的盐酸左西替利嗪片的制备方法,其特征在于:步骤(4)为将颗粒、交联聚维酮XL-10、二氧化硅加入混合机中,混合20分钟,再加入硬脂酸镁混合6分钟。
8.根据权利要求3所述的盐酸左西替利嗪片的制备方法,其特征在于:步骤(5)为压片工序:用旋转压片机压片,模具规格为Φ6.5mm浅凹;按混合粉中盐酸左西替利嗪含量计算理论片重,压片速度为2~5千片/小时,主压力平均值8.0±3.0KN,片重范围:理论片重±7.5%,平均硬度80±30N,性状、片重差异、脆碎度、崩解时限、含量及含量均匀度、溶出度均符合规定。
9.根据权利要求3所述的盐酸左西替利嗪片的制备方法,其特征在于:将制备好的盐酸左西替利嗪片进行包装,使用泡罩包装机,包装材料:药用铝箔、聚氯乙烯固体药用硬片,密封滚桶温度240℃~280℃,运行速度100~320板/分钟。
10.根据权利要求3所述的盐酸左西替利嗪片的制备方法,其特征在于:
(1)包合:将倍他环糊精和纯化水加入圆底烧瓶,85℃水浴溶解后,将盐酸左西替利嗪加入圆底烧瓶中包合制备盐酸左西替利嗪包合物;将包合物抽滤,干燥,粉碎;
(2)配料;将乳糖过60目筛,称取处方量的原辅料;
(3)制粒;按照微晶纤维素、盐酸左西替利嗪包合物、玉米淀粉、低取代羟丙纤维素、乳糖的顺序将原辅料加入湿法制粒混合机中,混合时间为10分钟;配制4%的聚维酮K30的水溶液;制湿颗粒,流化床制粒包衣机干燥至颗粒水分≤4%,摇摆式颗粒机30目筛网整粒;
(4)混合:交联聚维酮XL-10、二氧化硅加入多向运动混合机中,混合机频率50Hz,混合20分钟,再加入硬脂酸镁混合6分钟;
(5)压片:用旋转压片机压片,模具规格为Φ6.5mm浅凹;按混合粉中盐酸左西替利嗪含量计算理论片重,压片速度为2~5千片/小时,主压力平均值8.0±3.0KN,片重范围:理论片重±7.5%,平均硬度80±30N,性状、片重差异、脆碎度、崩解时限、含量及含量均匀度均符合规定,崩解时限5min。
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