CN114010609A - 一种孟鲁司特钠冻干口崩片及制备方法 - Google Patents
一种孟鲁司特钠冻干口崩片及制备方法 Download PDFInfo
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- CN114010609A CN114010609A CN202111390992.XA CN202111390992A CN114010609A CN 114010609 A CN114010609 A CN 114010609A CN 202111390992 A CN202111390992 A CN 202111390992A CN 114010609 A CN114010609 A CN 114010609A
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- Prior art keywords
- liquid medicine
- freeze
- sodium
- orally disintegrating
- disintegrating tablet
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- LBFBRXGCXUHRJY-HKHDRNBDSA-M montelukast sodium Chemical compound [Na+].CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC([O-])=O)CC1 LBFBRXGCXUHRJY-HKHDRNBDSA-M 0.000 title claims abstract description 59
- 229960001951 montelukast sodium Drugs 0.000 title claims abstract description 56
- 239000006191 orally-disintegrating tablet Substances 0.000 title claims abstract description 54
- 238000002360 preparation method Methods 0.000 title claims abstract description 46
- 239000003814 drug Substances 0.000 claims abstract description 117
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 45
- 239000007788 liquid Substances 0.000 claims description 127
- 238000004108 freeze drying Methods 0.000 claims description 46
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 39
- 238000007710 freezing Methods 0.000 claims description 39
- 230000008014 freezing Effects 0.000 claims description 38
- 239000000463 material Substances 0.000 claims description 36
- 238000003756 stirring Methods 0.000 claims description 34
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 30
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- 239000004471 Glycine Substances 0.000 claims description 15
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- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 13
- 239000013078 crystal Substances 0.000 claims description 11
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 10
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- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 5
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- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 4
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
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- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 4
- 150000001413 amino acids Chemical class 0.000 claims description 4
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- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 4
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- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 4
- 239000001509 sodium citrate Substances 0.000 claims description 4
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 4
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- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 claims description 2
- 229920001817 Agar Polymers 0.000 claims description 2
- 108010011485 Aspartame Proteins 0.000 claims description 2
- 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 description 2
- 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 description 2
- 239000004375 Dextrin Substances 0.000 claims description 2
- 229920001353 Dextrin Polymers 0.000 claims description 2
- 108010082495 Dietary Plant Proteins Proteins 0.000 claims description 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 2
- 239000004386 Erythritol Substances 0.000 claims description 2
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 claims description 2
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- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- UEDUENGHJMELGK-HYDKPPNVSA-N Stevioside Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UEDUENGHJMELGK-HYDKPPNVSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
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- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
本发明提供了一种孟鲁司特钠冻干口崩片及其制备方法,属于药物制剂领域,该孟鲁司特钠冻干口崩片由孟鲁司特钠或孟鲁司特与其他基质组成,采用乳化液冻干直接赋型的方式制备,本发明的冻干口崩片制备方法分为散装药液配制、注模、快速预冻处理、低温冰晶重排、冷冻干燥、产品包装。本发明的孟鲁司特钠冻干口崩片服用简便,无需用水送服,相对于其他剂型,该制剂满足了吞咽障碍病患的用药安全需求和精确给药需求。
Description
技术领域
本发明涉及一种孟鲁司特钠冻干口崩片及其制备方法,制剂规格以孟鲁司特计4mg、5mg、10mg。属于医药技术领域。
背景技术
小儿哮喘(infantile asthma)是小儿常见的肺部疾患,是一种表现反复发作性咳嗽,喘鸣和呼吸困难,并伴有气道高反应性的可逆性、梗阻性呼吸道疾病。哮喘是一种严重危害儿童身体健康的常见慢性呼吸道疾病,其发病率高,常表现为反复发作的慢性病程,严重影响了患儿的学习、生活及活动,影响儿童的生长发育。不少哮喘患儿由于治疗不及时或治疗不当最终发展为成人哮喘而迁延不愈,肺功能受损,部分患儿甚至完全丧失体力活动能力。严重哮喘发作,若未得到及时有效治疗,可以致命。
世界各地哮喘的发病率在0.1%~32%之间。其原因可能与遗传基因,年龄,地理位置,气候,环境,种族,工业化,城市化,室内装修,生活水平,饮食习惯等有关。已经证实哮喘是一种慢性气道炎症性疾病,由于这种慢性炎症反应的持续存在,导致气道呈高反应状态,当接触诱因时即会反复出现症状。哮喘发病机理的研究已由痉挛学说,发展到气道慢性炎症学说,现已进入平滑肌功能障碍及气道炎症的平行学说。临床治疗也由反复解痉、注重抗炎同时抗炎和解除平滑肌痉挛的联合治疗。在50年代,哮喘的治疗以非选择性肾上腺素为解痉剂,1956年选择性强的短效β2受体激动剂问世(Short Acting Beta2 Agonist SABA)问世,1971年长效β2激动剂(Long Acting Beta2 Agonist LABA)问世。在60年代曾采用口服糖皮质激素来拮抗气道炎症,有效但副作用大,1972年研制成功二丙酸倍氯米松(BDP),80年代研制出布地奈德(BUD)以及丙酸氟替卡松(FP)等,这些吸入性糖皮质激素对气道局部有更强抗炎作用,而副作用明显减少。80年代末期世界各国先后制订了各自的防治指南。1994年世界卫生组织和美国国立卫生研究院心肺、血液研究所在纽约召集17个国家的30多位专家,制定了具有划时代意义的全球哮喘的创议即GINA(Global INitiative forAsthma)方案。2000年进行了三大洲16个国家的哮喘现状调查,2002年3月又对GINA进行了修改。我国也制定了儿童哮喘防治指南。在2000年的亚太地区哮喘现状研究——AIRAP(Asthma Insights and Reality In Asia Pacific)中,从中国区的调查报告显示,我国哮喘控制状况与GINA方案中提到的哮喘长期管理目标相去甚远。儿科医务工作者应不断提高儿童哮喘的诊治水平,特别应充分重视结合GINA方案所制定的有关儿童哮喘、小年龄组哮喘的诊断;重视治疗内容的理解和应用;重视哮喘缓解期的预防性治疗;认识到规范抗炎治疗的重要性和接受抗炎治疗越早越对病情有利的概念。虽然成人哮喘与儿童哮喘在病因学、流行病学、免疫学、发病机制、病理生理以及临床的诊断治疗原则有基本相似之处,但应充分理解儿童并非仅仅是“小成人”,也并非是“成人的缩影”。儿童哮喘与成人哮喘在某些方面仍然有着很大的差异。因儿童正处于智能、身体、免疫、心理等不断生长发育的过程,具有不断发育、不断完善的动态特点,尤其是在免疫学和病理生理学等方面。因此儿童哮喘有其特殊性,与成人哮喘有许多不同之处。儿科医生应充分利用儿童处于发育和不断完善的动态特点,积极地进行防治是可以达到临床治愈,也可以防止儿童哮喘发展成为具有气道重塑的严重哮喘。
半胱氨酰白三烯(LTC4,LTD4,LTE4)是强效的炎症介质,由包括肥大细胞和嗜酸性粒细胞在内的多种细胞释放。这些重要的哮喘前介质与半胱氨酰白三烯(CysLT)受体结合。I型半胱氨酰白三烯(CysLT1)受体分布于人体的气道(包括气道平滑肌细胞和气道巨噬细胞)和其他的前炎症细胞(包括嗜酸性粒细胞和某些骨髓干细胞)。CysLTs与哮喘和过敏性鼻炎的病理生理过程相关。在哮喘中,白三烯介导的效应包括一系列的气道反应,如支气管收缩、粘液分泌、血管通透性增加及嗜酸性粒细胞聚集。在过敏性鼻炎中,过敏原暴露后的速发相和迟发相反应中,鼻粘膜均会释放与过敏性鼻炎症状相关的CysLTs。鼻内CysLTs激发会增加鼻部气道阻力和鼻阻塞的症状。
孟鲁司特钠是一种能显著改善哮喘炎症指标的强效口服制剂。生物化学和药理学的生物测定显示,孟鲁司特钠对CysLT1受体有高度的亲和性和选择性(与其它有药理学重要意义的气道受体如类前列腺素、胆碱能和β-肾上腺能受体相比)。孟鲁司特钠能有效地抑制LTC4、LTD4和LTE4与CysLT1受体结合所产生的生理效应而无任何受体激动活性。目前的研究认为孟鲁司特钠并不拮抗CysLT2受体。6~14岁儿童:在一项为期12个月、在6至14岁患轻度持续性哮喘的儿童中进行的研究(简称MOSAIC,孟鲁司特钠治疗儿童哮喘的研究)中,比较了孟鲁司特钠与吸人氟替卡松控制哮喘的疗效。孟鲁司特钠提高哮喘无急救天数的百分率的作用不劣于氟替卡松(平均值分别为83.6%和86.4%)。孟鲁司特钠和氟替卡松均可有效控制哮喘:包括提高一秒钟用力呼气量(FEV1,分别比基线提高0.27L和0.30L,P=0.232)和降低使用β-受体激动剂的天数(分别比基线降低22.7%和25.4%。组间P=0.003)。在一项为期12个月、在2至5岁的轻度间歇性哮喘和有病毒感染诱发加重的儿童中进行的安慰剂对照研究(简称PREVIA,孟鲁司特钠预防病毒引起的哮喘的研究)中,与安慰剂相比,每日一次服用孟鲁司特钠4mg可显著减少哮喘加重的发作频率。
根据WHO公布的资料(2015年)表明,全世界近60%病患人群具有不同程度吞咽障碍,包括吞咽障碍、胃肠道应激反应强烈、意识不清、无自主意识、精神异常不配合等特殊人群,其中用药过程中,全世界约有1/3的死亡病例的原因来自用药的不合理性,而非疾病本身,因此提高给药依从性、提高给药剂量准确度是提高药物治疗效果、减少不合理用药的关键节点。
冻干口崩片使一种由水溶性骨架材料经冷冻干燥制成的空间网状的布满缝隙的速溶制剂,特点在于冻干片剂以单剂量规格为给药单位,无需水送服,直接放入口腔后,冻干片剂接触口腔唾液即迅速溶解,分散于唾液中,口服吸收快,药物活性成分可通过口腔粘膜进入人体循环,生物利用度高,避免肝脏受过效应,获得同等治疗效果时,降低了给药剂量,降低毒副作用,提高了用药安全性。
本发明所述的孟鲁司特钠冻干口崩片成功规避了其他口服制剂服用过程需要以水送服的特点,对于哮喘急性发作的病人特别是不配合服药的儿童病患群体,该药仅需放入口腔内,利用口腔内极少量的唾液即可使其在2S内完全溶化,降低了哮喘急性发作期服药呛水导致的危险。
发明内容
本发明中所说的孟鲁司特钠冻干口崩片是指在制备过程中采用孟鲁司特或孟鲁司特钠盐为制剂原料的冻干口腔速溶片剂。
本发明中所说的孟鲁司特钠冻干口崩片使用孟鲁司特钠盐,孟鲁司特钠的水溶性较孟鲁司特好,便于其溶解和分散在药液体系中,因此在制备冻干口崩片过程中的预冻工序,孟鲁司特钠与辅料及溶剂形成低共熔物,在干燥过程中冰晶消除,可能导致产品萎缩和塌陷。
本发明的目的是提供一种给药量精准且便于服用的孟鲁司特钠冻干口崩片,采用真空冷冻干燥技术制成,服用过程不需要任何辅助形式送服,方便哮喘急性发作期的服用,并兼顾预防哮喘人群给药。
本发明提供了一种孟鲁司特钠冻干口崩片,该口崩片由基质和有效剂量的孟鲁司特钠盐制成,其特征在于:骨架支撑材料占制剂总固形物重量的1%~60%,冻干保护剂占制剂总固形物重量的0~5%;有效成分孟鲁司特钠占制剂总固形物重量的5~80%。
本发明提供了一种孟鲁司特钠冻干口崩片,其特征在于:骨架支撑材料由单一辅料或由多种辅料组成,骨架支撑材料包括粘合剂和骨架剂。
本发明提供了一种孟鲁司特钠冻干口崩片,其特征在于:单一辅料组成的骨架支撑材料,其特征在于:具有较高的粘性和良好的空间支撑性能和成膜性能。
本发明提供了一种孟鲁司特钠冻干口崩片,其特征在于:骨架支撑材料可作为冻干保护剂、助悬剂。
本发明提供了一种孟鲁司特钠冻干口崩片,其特征在于:骨架材料为水溶性材料。
本发明提供了一种孟鲁司特钠冻干口崩片,其特征在于:骨架剂包括但不限于高聚物、高聚糖、糖醇类、糖类或氨基酸类。
本发明提供了一种孟鲁司特钠冻干口崩片,其特征在于:骨架剂选自甘露醇、木糖醇、山梨糖醇、麦芽糖醇、乳糖醇、赤藓糖醇、糊精、右旋糖苷、普鲁兰多糖、乳糖、海藻糖、聚乙烯醇、甘氨酸中的一种或几种。
本发明提供了一种孟鲁司特钠冻干口崩片,其特征在于:粘合剂包括但不限于蛋白、植物胶、氨基酸、多肽、高聚糖、高聚物类。
本发明提供了一种孟鲁司特钠冻干口崩片,其特征在于:粘合剂选自水溶性多肽、阿拉伯胶、琼脂、右旋糖苷、普鲁兰多糖、聚乙烯醇中的一种或几种。
本发明提供了一种孟鲁司特钠冻干口崩片,其特征在于冻干保护剂选自海藻糖、乳糖、甘露醇、普鲁兰多糖、水溶性多肽、甘氨酸中的一种或几种。
本发明提供了一种孟鲁司特钠冻干口崩片,其特征在于该冻干口崩片中还可以含有矫味剂、pH调节剂、抗氧剂、防腐剂、着色剂等。
本发明提供了一种孟鲁司特钠冻干口崩片,其特征在于:矫味剂包括甜味剂和/或不同口味的香精,其中甜味剂选自:阿斯巴甜、安赛蜜、三氯蔗糖、甜菊苷中的一种或几种;香精包括但不限于:柠檬酸钠、草莓味香精、香橙味香精、柳橙味香精、西瓜味香精、牛奶味香精、巧克力味香精、香草味香精、薄荷味香精。
本发明提供了一种孟鲁司特钠冻干口崩片,其特征在于:pH调节剂包括但不限于无机盐、有机盐、弱酸、弱碱、缓冲对;无机盐包括但不限于氯化钠、碳酸氢钠、碳酸氢钾、磷酸氢二钠、磷酸二氢钠等,有机盐包括但不限于:枸橼酸钠、琥珀酸钠等;弱酸包括:枸橼酸、琥珀酸、马来酸等;弱碱包括但不限于:氢氧化钙等;缓冲对包括但不限于:磷酸氢二钠—磷酸二氢钠,枸橼酸—枸橼酸钠等。
本发明提供了一种孟鲁司特钠冻干口崩片,其特征在于:抗氧剂包括但不限于亚硫酸钠、依地酸二钠、焦亚硫酸钠、硫代硫酸钠等。
本发明提供了一种孟鲁司特钠冻干口崩片,其特征在于:防腐剂可以采用水溶性材料,亦可以采用脂溶性材料,包括但不限于苯甲醇、尼泊金甲酯、尼泊金丙酯、尼泊金甲酯钠、尼泊金丙酯钠等。
本发明提供了一种孟鲁司特钠冻干口崩片,其特征在于:可食用着色剂可选择水溶性材料,亦可以选择脂溶性材料,包括但不限于天然色素、合成色素等。
本发明提供了一种孟鲁司特钠冻干口崩片,其特征还在于溶剂包括纯化水、乙醇、叔丁醇中的一种或几种,其中有机溶剂占溶剂总量的0~50%。
本发明提供了一种孟鲁司特钠冻干口崩片,其特征还在于:散装药液的pH≤4.5,其最佳pH范围为2.0~3.5。
本发明还提供了一种孟鲁司特钠冻干口崩片的制备方法,步骤如下:
散装药液配制:将骨架材料溶于8~80℃纯化水中,搅拌至完全溶解,加入其他辅料继续搅拌至完全溶解,将药液温度降低至室温;孟鲁司特钠加入至上述药液并以纯化水定容至处方量,搅拌至药液均呈无色澄清透明状,完成散装药液配制;
灌装:将散装药液灌装至已成型的冷冲压成型复合硬片或PVC/PVDC泡罩中;
预冻:泡罩中药液至于-40℃~-110℃环境下使药液迅速冷冻成固态,或在-10℃~-110℃环境下连续梯度降温使药液迅速冷冻成固态;
冷冻控制:在-6±2℃环境中,固化的药液进行低温冰晶重排,降温制-15℃及以下,完成冷冻控制;
冻干:冻干机设定搁板预冷模式,设定温度-10℃~-30℃,将装有已固化药液的泡罩放入冻干机中,开始进行冻干,冻干曲线如下表所示:
表1 冻干曲线
包装:在相对湿度5~25%环境下覆铝纸复合膜,喷墨打印生产日期和批号。
对于预冻工序,药液在冷冻过程中可能因冻结速率差异导致局部药液中固形物浓度发生改变,为了降低或杜绝该现象,在制备过程中选择液氮速冻或以低温硅油作为传热介质将预冻腔体内温度降低至-50℃以下,腔体内采用低送风方式进行冷量传导,使药液迅速冻结为固体;亦可设定速冻腔体内多温度梯度降温方式:不同温度梯段腔体段温度以20℃为梯度,起始腔体内温度-10℃直至最后一个腔体内温度-110℃,使药液保持过冷形成更多的晶核。上述两种预冻方式均有利于药液中固形物的分散,防止预冻过程中相分离现象的发生。
具体实施方式
以下实施例是为了更好的说明本发明,不用以限定本发明的保护范围。
实施例1:
本实施例提供了4mg规格(以孟鲁司特计)冻干口崩片及其制备方法:
表2 处方组成
冻干口崩片制备步骤如下:
散装药液配制:将明胶投入30ml纯化水中,使明胶充分溶胀,然后加热药液至60℃,搅拌至药液呈无色澄清透明状态;将水解明胶投上述水溶液中搅拌至药液呈无色澄清透明状;右旋糖苷加入至沸水中搅拌,至药液无色澄清透明;合并上述两种药液,并加入甘氨酸、枸橼酸、三氯蔗糖、草莓味香精和水溶性粉色食用色素,继续搅拌至完全溶解,将药液温度降低至室温;孟鲁司特钠加入上述药液并以纯化水定容至100ml,搅拌至药液呈粉色澄清透明状态,完成散装药液配制;
灌装:吸取0.2ml/片散装药液灌装至已成型的冷冲压成型复合硬片泡罩中;
预冻:泡罩中药液至于-80℃±10℃环境下使药液迅速冷冻成固态;
冷冻控制:在-6±2℃环境中,固化的药液进行低温冰晶重排,降温制-15℃及以下,完成冷冻控制;
冻干:冻干机设定搁板预冷模式,设定温度-20℃,将装有已固化药液的泡罩放入冻干机中,开始进行冻干,冻干曲线如下表所示:
表3 冻干曲线
包装:在相对湿度≤25%环境下覆铝纸复合膜,喷墨打印生产日期和批号。
实施例2:
本实施例提供了4mg规格(以孟鲁司特计)冻干口崩片及其制备方法:
表4 处方组成
冻干口崩片制备步骤如下:
散装药液配制:将普鲁兰多糖投入70ml热纯化水中,搅拌至药液呈无色澄清透明状;加入甘氨酸、枸橼酸、三氯蔗糖、草莓味香精及水溶性粉色食用色素,继续搅拌至完全溶解,将药液温度降低至室温;孟鲁司特钠加入上述药液并以纯化水定容至100ml,搅拌至药液呈粉色澄清透明状态,完成散装药液配制;
灌装:吸取0.2ml/片散装药液灌装至已成型的冷冲压成型复合硬片泡罩中;
预冻:泡罩中药液至于-80℃±10℃环境下使药液迅速冷冻成固态;
冷冻控制:在-6±2℃环境中,固化的药液进行低温冰晶重排,降温制-15℃及以下,完成冷冻控制;
冻干:冻干机设定搁板预冷模式,设定温度-20℃,将装有已固化药液的泡罩放入冻干机中,开始进行冻干,冻干曲线如下表所示:
表5 冻干曲线
包装:在相对湿度≤25%环境下覆铝纸复合膜,喷墨打印生产日期和批号。
实施例3:
本实施例提供了5mg规格(以孟鲁司特计)冻干口崩片及其制备方法:
表6处方组成
冻干口崩片制备步骤如下:
散装药液配制:将明胶投入30ml纯化水中,使明胶充分溶胀,然后加热药液至60℃,搅拌至药液呈无色澄清透明状态;将水解明胶投上述水溶液中搅拌至药液呈无色澄清透明状;右旋糖苷加入至沸水中搅拌,至药液无色澄清透明;合并上述两种药液,并加入甘氨酸、枸橼酸、三氯蔗糖、柳橙味香精和水溶性黄色食用色素,继续搅拌至完全溶解,将药液温度降低至室温;孟鲁司特钠加入上述药液并以纯化水定容至100ml,搅拌至药液呈淡黄色澄清透明状态,完成散装药液配制;
灌装:吸取0.2ml/片散装药液灌装至已成型的冷冲压成型复合硬片泡罩中;
预冻:泡罩中药液至于-80℃±10℃环境下使药液迅速冷冻成固态;
冷冻控制:在-6±2℃环境中,固化的药液进行低温冰晶重排,降温制-15℃及以下,完成冷冻控制;
冻干:冻干机设定搁板预冷模式,设定温度-20℃,将装有已固化药液的泡罩放入冻干机中,开始进行冻干,冻干曲线如下表所示:
表7 冻干曲线
包装:在相对湿度≤25%环境下覆铝纸复合膜,喷墨打印生产日期和批号。
实施例4:
本实施例提供了5mg规格(以孟鲁司特计)冻干口崩片及其制备方法:
表8 处方组成
冻干口崩片制备步骤如下:
散装药液配制:将普鲁兰多糖投入70ml热纯化水中,搅拌至药液呈无色澄清透明状;加入甘氨酸、枸橼酸、三氯蔗糖、柳橙味香精及水溶性黄色食用色素,继续搅拌至完全溶解,将药液温度降低至室温;孟鲁司特钠加入上述药液并以纯化水定容至100ml,搅拌至药液呈淡黄色澄清透明状态,完成散装药液配制;
灌装:吸取0.2ml/片散装药液灌装至已成型的冷冲压成型复合硬片泡罩中;
预冻:泡罩中药液至于-80℃±10℃环境下使药液迅速冷冻成固态;
冷冻控制:在-6±2℃环境中,固化的药液进行低温冰晶重排,降温制-15℃及以下,完成冷冻控制;
冻干:冻干机设定搁板预冷模式,设定温度-20℃,将装有已固化药液的泡罩放入冻干机中,开始进行冻干,冻干曲线如下表所示:
表9 冻干曲线
包装:在相对湿度≤25%环境下覆铝纸复合膜,喷墨打印生产日期和批号。
实施例5:
本实施例提供了10mg规格(以孟鲁司特计)冻干口崩片及其制备方法:
表10 处方组成
冻干口崩片制备步骤如下:
散装药液配制:将普鲁兰多糖投入70ml热纯化水中,搅拌至药液呈无色澄清透明状;加入甘氨酸、枸橼酸、三氯蔗糖及薄荷味香精,继续搅拌至完全溶解,将药液温度降低至室温;孟鲁司特钠加入上述药液并以纯化水定容至100ml,搅拌至药液呈无色澄清透明状态,完成散装药液配制;
灌装:吸取0.2ml/片散装药液灌装至已成型的冷冲压成型复合硬片泡罩中;
预冻:泡罩中药液至于-80℃±10℃环境下使药液迅速冷冻成固态;
冷冻控制:在-6±2℃环境中,固化的药液进行低温冰晶重排,降温制-15℃及以下,完成冷冻控制;
冻干:冻干机设定搁板预冷模式,设定温度-20℃,将装有已固化药液的泡罩放入冻干机中,开始进行冻干,冻干曲线如下表所示:
表11 冻干曲线
包装:在相对湿度≤25%环境下覆铝纸复合膜,喷墨打印生产日期和批号。
实施例6:
本实施例提供了4mg规格(以孟鲁司特计)冻干口崩片及其制备方法:
表12 处方组成
冻干口崩片制备步骤如下:
散装药液配制:将普鲁兰多糖投入140kg热纯化水中,搅拌至药液呈无色澄清透明状;加入甘氨酸、枸橼酸、三氯蔗糖、草莓味香精及水溶性粉色食用色素,继续搅拌至完全溶解,将药液温度降低至室温;孟鲁司特钠加入上述药液并以纯化水定容至201kg,搅拌至药液呈粉色澄清透明状态,完成散装药液配制;
灌装:吸取201mg/片散装药液灌装至已成型的冷冲压成型复合硬片泡罩中;
预冻:泡罩中药液至于-80℃±10℃环境下使药液迅速冷冻成固态;
冷冻控制:在-6±2℃环境中,固化的药液进行低温冰晶重排,降温制-15℃及以下,完成冷冻控制;
冻干:冻干机设定搁板预冷模式,设定温度-20℃,将装有已固化药液的泡罩放入冻干机中,开始进行冻干,冻干曲线如下表所示:
表13 冻干曲线
包装:在相对湿度≤25%环境下覆铝纸复合膜,喷墨打印生产日期和批号。
实施例7:
本实施例提供了5mg规格(以孟鲁司特计)冻干口崩片及其制备方法:
表14 处方组成
成分 | 含量(kg) | 作用 |
孟鲁司特钠 | 5.00 | 药物活性成份 |
普鲁兰多糖 | 6.40 | 粘合剂 |
甘氨酸 | 7.00 | 骨架剂 |
枸橼酸 | 1.12 | pH调节剂 |
三氯蔗糖 | 1.00 | 矫味剂 |
柳橙味香精 | 0.04 | 矫味剂 |
水溶性黄色食用色素 | 0.02 | 着色剂 |
纯化水 | 至201kg | 溶剂 |
冻干口崩片制备步骤如下:
散装药液配制:将普鲁兰多糖投入140kg热纯化水中,搅拌至药液呈无色澄清透明状;加入甘氨酸、枸橼酸、三氯蔗糖、柳橙味香精及水溶性黄色食用色素,继续搅拌至完全溶解,将药液温度降低至室温;孟鲁司特钠加入上述药液并以纯化水定容至201kg,搅拌至药液呈淡黄色澄清透明状态,完成散装药液配制;
灌装:吸取201mg/片散装药液灌装至已成型的冷冲压成型复合硬片泡罩中;
预冻:泡罩中药液至于-80℃±10℃环境下使药液迅速冷冻成固态;
冷冻控制:在-6±2℃环境中,固化的药液进行低温冰晶重排,降温制-15℃及以下,完成冷冻控制;
冻干:冻干机设定搁板预冷模式,设定温度-20℃,将装有已固化药液的泡罩放入冻干机中,开始进行冻干,冻干曲线如下表所示:
表15 冻干曲线
包装:在相对湿度≤25%环境下覆铝纸复合膜,喷墨打印生产日期和批号。
实施例8:
本实施例提供了10mg规格(以孟鲁司特计)冻干口崩片及其制备方法:
表16 处方组成
冻干口崩片制备步骤如下:
散装药液配制:将普鲁兰多糖投入140kg热纯化水中,搅拌至药液呈无色澄清透明状;加入甘氨酸、枸橼酸、三氯蔗糖及薄荷味香精,继续搅拌至完全溶解,将药液温度降低至室温;孟鲁司特钠加入上述药液并以纯化水定容至201kg,搅拌至药液呈无色澄清透明状态,完成散装药液配制;
灌装:吸取201mg/片散装药液灌装至已成型的冷冲压成型复合硬片泡罩中;
预冻:泡罩中药液至于-80℃±10℃环境下使药液迅速冷冻成固态;
冷冻控制:在-6±2℃环境中,固化的药液进行低温冰晶重排,降温制-15℃及以下,完成冷冻控制;
冻干:冻干机设定搁板预冷模式,设定温度-20℃,将装有已固化药液的泡罩放入冻干机中,开始进行冻干,冻干曲线如下表所示:
表17 冻干曲线
包装:在相对湿度≤25%环境下覆铝纸复合膜,喷墨打印生产日期和批号。
口感测试:
自愿受试者60名,年龄25岁~45岁间,分别取具体实施例1~具体实施例8制备的孟鲁司特钠冻干口崩片5片进行口感测试,每片次测试前以120ml纯化水漱口3次,测试结果如表18所示:
表18 口感测试结果
含量及均匀度测定结果:
对实施例6~8进行含量均匀度测试,结果如下:
表19 含量及均匀度测试结果
Claims (10)
1.一种孟鲁司特钠冻干口崩片,该口崩片由基质与有效剂量的孟鲁司特钠制成,其特征在于:该制剂的基质包括:骨架支撑材料占制剂总固形物重量的1%~60%,冻干保护剂占制剂总固形物重量的0~5%;有效成分孟鲁司特钠占制剂总固形物重量的5~80%。
2.如权利要求1所述的冻干口崩片,其特征在于:骨架支撑材料由单一辅料或由多种辅料组成;由多种辅料组成的骨架支撑材料,其特征在于:骨架支撑材料由粘合剂和骨架剂组成;单一辅料组成的骨架支撑材料,其特征在于:具有较高的粘性和良好的空间支撑性能和成膜性能。
3.如权利要求1~2任一所述的骨架支撑材料,其特征还在于:可作为冻干保护剂、助悬剂。
4.如权利要求1~3所述的骨架材料,其特征在于:骨架材料为水溶性材料。
5.如权利要求1~4所述的骨架支撑材料,其特征在于骨架剂包括但不限于高聚物、高聚糖、糖醇类、糖类或氨基酸类,骨架剂选自甘露醇、木糖醇、山梨糖醇、麦芽糖醇、乳糖醇、赤藓糖醇、糊精、右旋糖苷、普鲁兰多糖、乳糖、海藻糖、聚乙烯醇、甘氨酸中的一种或几种。
6.如权利要求1~4所述的骨架支撑材料,其特征在于粘合剂包括但不限于蛋白、植物胶、氨基酸、多肽、高聚糖、高聚物类,选自水溶性多肽、阿拉伯胶、琼脂、右旋糖苷、普鲁兰多糖、聚乙烯醇中的一种或几种。
7.如权利要求1所述的冻干口崩片剂,其特征在于冻干保护剂选自海藻糖、乳糖、甘露醇、普鲁兰多糖、水溶性多肽、甘氨酸中的一种或几种。
8.如权利要求1~7所述的冻干口崩片剂,其特征在于该冻干口崩片中还可以含有矫味剂、pH调节剂、抗氧剂、防腐剂、着色剂等;矫味剂包括甜味剂和/或不同口味的香精,其中甜味剂选自:阿斯巴甜、安赛蜜、三氯蔗糖、甜菊苷中的一种或几种;香精包括但不限于:柠檬酸钠、草莓味香精、香橙味香精、柳橙味香精、西瓜味香精、牛奶味香精、巧克力味香精、香草味香精、薄荷味香精;pH调节剂包括但不限于无机盐、有机盐、弱酸、弱碱、缓冲对;无机盐包括但不限于氯化钠、碳酸氢钠、碳酸氢钾、磷酸氢二钠、磷酸二氢钠等,有机盐包括但不限于:枸橼酸钠、琥珀酸钠等;弱酸包括:枸橼酸、琥珀酸、马来酸等;弱碱包括但不限于:氢氧化钙等;缓冲对包括但不限于:磷酸氢二钠—磷酸二氢钠,枸橼酸—枸橼酸钠等;抗氧剂包括但不限于亚硫酸钠、依地酸二钠、焦亚硫酸钠、硫代硫酸钠等;防腐剂可以采用水溶性材料,亦可以采用脂溶性材料,包括但不限于苯甲醇、尼泊金甲酯、尼泊金丙酯、尼泊金甲酯钠、尼泊金丙酯钠等;可食用着色剂可选择水溶性材料,亦可以选择脂溶性材料,包括但不限于天然色素、合成色素等。
9.如权利要求1~8所述的冻干口崩片,其特征还在于溶剂包括纯化水、乙醇、叔丁醇中的一种或几种,其中有机溶剂占溶剂总量的0~50%。
10.一种权利要求1~9任一项所述的冻干口崩片的制备方法,步骤如下:
散装药液配制:将骨架材料溶于8~80℃纯化水中,搅拌至完全溶解,加入其他辅料继续搅拌至完全溶解,将药液温度降低至室温;孟鲁司特钠加入至上述药液并以纯化水定容至处方量,搅拌至药液呈无色澄清透明状,完成散装药液配制;
灌装:将散装药液灌装至已成型的冷冲压成型复合硬片或PVC/PVDC泡罩中;
预冻:泡罩中药液至于-40℃~-110℃环境下使药液迅速冷冻成固态,或在-10℃~-110℃环境下连续梯度降温使药液迅速冷冻成固态;
冷冻控制:在-6±2℃环境中,固化的药液进行低温冰晶重排,降温制-15℃及以下,完成冷冻控制;
冻干:冻干机设定搁板预冷模式,设定温度-10℃~-30℃,将装有已固化药液的泡罩放入冻干机中,开始进行冻干,冻干曲线如下表所示:
表1 冻干曲线
包装:在相对湿度5~25%环境下覆铝纸复合膜,喷墨打印生产日期和批号。
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