CN1366878A - 含有活性成分的质地遮蔽颗粒 - Google Patents
含有活性成分的质地遮蔽颗粒 Download PDFInfo
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- CN1366878A CN1366878A CN01145483A CN01145483A CN1366878A CN 1366878 A CN1366878 A CN 1366878A CN 01145483 A CN01145483 A CN 01145483A CN 01145483 A CN01145483 A CN 01145483A CN 1366878 A CN1366878 A CN 1366878A
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- Prior art keywords
- granule
- agent
- mixture
- film forming
- coating
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- 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
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- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
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Abstract
本发明公开了一种质地遮蔽颗粒以及由其制得的咀嚼药片。质地遮蔽颗粒由含有活性成分的芯,任选的基本上覆盖芯的遮味剂组成的第一涂层和任选地可基本上覆盖第一涂层或芯的第二涂层组成,其中所述的第二涂层由薄膜成型聚合物和抗砂砾剂组成。该颗粒可生产成可即时释放活性成分的片剂例如咀嚼药片。
Description
本发明涉及含有活性成分、水溶性或水膨胀薄膜成型聚合物与抗砂砾剂(anti-grit agent)的聚合保护涂层混合物的质地(texture)遮蔽颗粒。涂覆的颗粒可制成咀嚼药片或在没水的情况下便于用药的快速分解药片。
发明背景
口服药一般为固体形式如片剂、胶囊、药丸、锭剂或粒剂。片剂可整个吞服,在口中咀嚼或溶解在口腔中。咀嚼药片通常由包括活性药物颗粒和其它非活性成分(赋形剂)的混合物制成,并经常用在片剂不能整个吞服的地方。咀嚼的作用就象药片分解一样是帮助药片颗粒破碎并可增加消化道的吸收速率。通常用咀嚼药片来改善小儿科和老年病人的用药。
某些药物颗粒有苦味或令人不愉快的味道。为了由这些颗粒制出适口的咀嚼药片,它们的味道必须通过用如US4851226,US5489436,US5529783,US5215755,US5260072,US5460825,US4800087,US5814332和US5075114中所披露的涂覆组合物分散或涂覆颗粒来遮蔽,在这里将上述专利作为参考文献引入。通常人们研究的方向集中在通过用延迟溶解直至药物脱离口腔的聚合物涂覆药物颗粒来遮蔽药物不愉快的味道。可是,在药片基层中的其它成分溶解掉后,通常在口中留下的涂覆药物颗粒具有砂粒质的、泥沙样的质地。现在特别要关注的是越来越受人们欢迎的快速分解的剂型。
为了防止药物颗粒在摄取时粘在口腔粘膜上,人们已进行了各种尝试来加强药物颗粒的质地。例如,WO8806893公开了一种口服组合物,该组合物由活性物质和胶凝剂或能在含水载体中的颗粒周围形成粘性介质的溶胀剂组成。不利的是这种组合物在摄取前为了在不咀嚼的情况下便于快速吞服,它必须在水中分解形成液体悬浮液。
人们希望得到一种可有效遮蔽活性材料,例如药物颗粒的质地或其味道和质地的口服剂型以便在摄取时可不用喝水并且还可以咀嚼。
发明概述
本发明提供一种质地遮蔽的颗粒,它包括:
a)含有活性成分的芯;
b)由基本上覆盖了芯的遮味剂组成的第一涂覆层;和
c)在第一涂覆层表面上的第二涂覆层,该第二涂覆层由下面的成分组成:
i)薄膜成型聚合物;和
ii)抗砂砾剂。
本发明还提供一种质地遮蔽的颗粒,它包括:
a)含有活性成分的芯;和
b)在芯的表面上的质地遮蔽的涂层,该质地遮蔽涂层由下面的成分组成:
i)薄膜成型聚合物;和
ii)抗砂砾剂。
本发明还提供一种将含有活性成分颗粒进行质地遮蔽的方法,该方法包括:
a)将基本上连续的第一涂层涂覆在颗粒上,第一涂层包括遮味剂;和
b)将第二涂层涂覆在第一涂层上,第二涂层包括a)薄膜成型聚合物和b)抗砂砾剂的混合物。
本发明还提供一种将含有活性成分颗粒进行质地遮蔽的方法,该方法包括:
将涂层涂覆在含有活性成分的芯表面上,该涂层包括a)薄膜成型聚合物和b)抗砂砾剂的混合物。
本发明还提供一种生产含有活性成分的质地遮蔽颗粒的方法,该方法包括:
喷雾干燥混合物,该混合物包括
a)含有有效量的用于活性成分质地遮蔽的薄膜成型聚合物和抗砂砾剂;和
b)活性成分。
本发明还提供一种由基体组成的质地遮蔽颗粒,该基体包括:
a)活性成分,
b)薄膜成型聚合物,和
c)抗砂砾剂,
其中,薄膜成型聚合物和抗砂砾剂暴露在颗粒的表面上,其用量可有效地对活性成分进行质地遮蔽。
根据本发明,用含有薄膜成型聚合物和抗砂砾剂混合物的保护涂层制备具有即时释放性能(immediate release profile)的质地遮蔽的药品配方。该质地遮蔽保护涂层不仅克服了药物颗粒的砂粒质质地,而且还易于吞服。此外,该配方在没有水的情况下也很容易咽下。本发明涂覆颗粒的好处在于,其在成片过程中显示出足够的弹性,因而无需加入用以保持其整体性的增塑剂并且还可防止在咀嚼期间药物释放到嘴里。由这些涂覆颗粒制成的咀嚼药片具有极佳的味道并且还具有即时释放性能(immediate release profile)。
本发明的详细描述
在这里所用术语“基本覆盖”或“基本上连续”指的是涂层通常连续覆盖了芯或底层的整个表面,以致于基本上没有活性成分或底层暴露在外。
质地遮蔽颗粒的芯可包含任何一种活性成分。广泛适用的活性成分包括药用活性成分,食品强化剂,营养物,nutriceuticals等。更具体地说,它们包括镇痛剂、减充血剂、祛痰药、止咳药、抗组胺剂、肠胃病药、利尿剂、支气管扩张剂、安眠药(sleep-inducing agents)、维他命、矿物质、抗感染药、营养素和其混合物。一类优选的活性成分包括不含类固醇的抗发炎药(NSAIDs),例如布洛芬、酮丙酸、氟联苯丙酸、萘普生、环氟拉嗪、rofecoxib、celecoxib和阿斯匹林。活性成分也可选自醋氨酚,假麻黄碱,苯丙醇胺,氯屈米,美沙芬,苯海拉明,乘晕宁,美其敏,法莫替丁,洛哌丁胺,雷尼替丁,甲腈咪胺,双乙酰氧苯基甲基吡啶,欧车前,阿司咪唑,氯雷他啶(loratadine),desloratadine,fexofenadine,西替利嗪(cetirizine),解酸剂,其混合物和制药上可接受的盐或其代谢物。最优选的活性成分选自醋氨酚,布洛芬,假麻黄碱,美沙芬,苯海拉明,氯屈米,氯雷他啶(loratadine),碳酸钙,氢氧化镁,碳酸镁,氧化镁,氢氧化铝,其混合物和其制药上可接受的盐。
颗粒的芯可包含纯的、结晶活性成分或活性成分与任选成分例如工艺中已知的粘合剂,赋形剂等的混合物。芯可用各种已知的制粒方法形成,这些方法包括高纯(high sheer)湿制粒法,喷雾干燥和流化床制粒法(包括旋转流化床制粒),优选颗粒芯用流化床制粒法生产。优选颗粒芯的平均直径为约80~约300微米。
在一个实施方案中,由遮味剂组成的第一涂层基本上覆盖了芯。适合的遮味剂例子包括,但不限于,乙酸纤维素,乙基纤维素,聚(丙烯酸乙酯,甲基丙烯酸甲酯,三甲基胺基乙基甲基丙烯酸酯氯化物(trimethylammonioethyl methacrylate chloride)),其可商购于Rohm Pharma,商品名为“EUDRAGIT”,羟丙基甲基纤维素,羟丙基纤维素,羟乙基纤维素和其混合物。
在另一实施方案中,遮味剂由a)肠溶性聚合物和b)不溶性薄膜成型聚合物的混合物组成。肠溶性聚合物可选自已知肠溶性聚合物中的任何一种,例如邻苯二甲酸羟丙基甲基纤维素,乙酸琥珀酸羟丙基甲基纤维素,乙酸邻苯二甲酸纤维素,聚乙酸邻苯二甲酸乙烯基酯(polyvinylacetate phthalate)和聚甲基丙烯酸酯基聚合物例如聚(甲基丙烯酸,甲基丙烯酸甲酯)1∶2,其可商购自Rohm Pharma GmbH,商品名为“EUDRAGIT S”聚合物,和聚(甲基丙烯酸,甲基丙烯酸甲酯)1∶1,其可商购自Rohm Pharma GmbH,商品名为“EUDRAGIT L”聚合物。也可使用肠溶性聚合物的组合。
优选肠溶性聚合物选自非丙烯酸酯化合物,具体为邻苯二甲酸羟丙基甲基纤维素,乙酸琥珀酸羟丙基甲基纤维素,乙酸邻苯二甲酸纤维素和聚乙酸邻苯二甲酸乙烯基酯(polyvinylacetate phthalate)。优选为非丙烯酸酯的,因为丙烯酸酯聚合物在高温下会发粘并成团。纤维素聚合物比丙烯酸酯聚合物具有更高的热稳定性。此外,已知丙烯酸酯聚合物具有略微难闻的味道,而纤维素聚合物具有更为中性的味感。
不溶性薄膜成型聚合物也可选自许多已知的化合物,包括乙酸纤维素,乙基纤维素和聚(丙烯酸乙酯,甲基丙烯酸甲酯,三甲基胺基乙基甲基丙烯酸酯氯化物)1∶2∶0.1,其可商购于Rohm Pharma,商品名为“EUDRAGIT RS”。可使用一种或一种以上的不溶性薄膜成型聚合物。优选不溶性薄膜成型聚合物是不渗透性的并且在含水的环境下也不膨胀。更优选不溶性薄膜成型聚合物选自乙酸纤维素和乙基纤维素。
在聚合涂层中肠溶性聚合物与不溶性薄膜成型聚合物的重量比优选在约20∶80~约80∶20,更优选在约40∶60~约70∶30的范围内。
遮味剂可与其它任选的成分结合。在一个实施方案中,遮味剂与一或多种非肠溶性,水溶性聚合物结合,例如羟丙基纤维素和聚(丙烯酸乙酯,甲基丙烯酸甲酯)其可商购自Rohm Pharma GmbH,商品名为“EUDRAGIT NE 30D”。当聚合涂层中存在非肠溶性,水溶性聚合物时,非肠溶性,水溶性聚合物的量优选为聚合涂层的约10%~约30%。
遮味剂也可任选地与表面活性剂结合。适合的表面活性剂包括来自于合成和天然来源的离子和非离子材料,它包括,但不限于,卵磷脂,甘油酯,糖酯,聚山梨醇酯,脂肪酸的一和二甘油酯,丙二醇酯,蔗糖脂防酸酯,脱水山梨糖醇脂肪酸酯的聚氧化乙烯的衍生物和其混合物。有用的聚山梨醇酯的例子包括失水山梨醇三油酸酯,失水山梨糖醇单棕榈酸酯,失水山梨糖醇单月硅酸酯,丙二醇单月硅酸酯,甘油单硬脂酸酯,二甘油单硬脂酸酯,甘油乳酰棕榈酸酯。乳酸衍生物包括硬脂酰乳酸钠和硬脂酰乳酸钙。当表面活性剂存在于第一涂层中时,基于第一涂层总量的表面活性剂的存在量为约2%~约10%。
特别优选第一涂层含有约53wt%的邻苯二甲酸羟丙基甲基纤维素,约43wt%的乙酸纤维素和约4wt%的聚山梨醇酯。
优选用流化床技术,例如Wurster涂覆和转子涂覆将第一涂层以溶液形式施加在颗粒芯上。所用的溶剂包括药用有机溶剂中的任何一种,例如丙酮,甲醇,乙醇,异丙醇;水溶剂例如水,以及其混合物。一种合适的溶剂混合物包括比例为约85∶15~约95∶5的丙酮和水。
涂覆在芯上的第一层的厚度通常为约1微米~约20微米,例如从约2微米~约15微米,或从约4微米~约9微米。在添加质地遮蔽保护涂层之前,第一涂层的存在量基于遮味颗粒的总重量为约5%~约50%,例如从约15%~约25%。
然后用由水溶性和/或水溶胀薄膜成型聚合物与抗砂砾剂组成的质地遮蔽涂层涂刷第一涂层。合适的薄膜成型聚合物的例子包括,但不限于,所有药用水溶性纤维素聚合物,这些聚合物非仅包括羟丙基甲基纤维素(“HPMC”),羟丙基纤维素(“HPC”),羟乙基纤维素(“HEC”)和羧基甲基纤维素钠(“钠CMC”);淀粉;藻酸盐;聚乙烯醇;黄厚胶;瓜尔胶;多糖;果胶;树胶和其混合物,优选为HPMC。适合的抗砂砾剂例子包括,但不限于,聚乙二醇(“PEG”),聚氧化乙烯(“PEO”),矿物油,蜡,硅氧烷衍生物和其混合物,优选为PEG和PEO,特别优选为PEG。
在质地遮蔽层中,薄膜成型聚合物与抗砂砾剂的重量比为约10∶90~约90∶10,例如约20∶80~约80∶20,约60∶40~约40∶60,或约50∶50~约50∶50。
在一个实施方案中,质地遮蔽涂层由约50wt%的HPMC和约50wt%的PEG组成。特别优选的HPMC为取代型2910(USP)或2208(USP)并且在2%水溶液中的粘度为约6厘泊。特别优选的PEG的分子量约为8000道尔顿。
上面所述用于第一层中的任何一种任选的成分都可以相同的含量用在质地遮蔽保护涂层中。
在涂覆芯上的质地遮蔽保护涂层的厚度通常为约1~约20微米,例如约2~15微米,或约4微米~约9微米。基于遮味颗粒重量的质地遮蔽保护涂层的存在量为约2%~约40%,例如约3%~约20%或约5%~约10%。
可用上述任何一种方法将质地遮蔽的保护涂层施加在涂覆芯上从而涂覆具有第一遮味层的芯。施加质地遮蔽保护涂层的优选方法是:用流化床技术,例如Wurster涂覆或转子涂覆将薄膜成型聚合物和抗砂砾剂溶解在适当的溶剂中,然后把涂覆溶液涂覆在涂有遮味层或未涂有遮味层的颗粒芯上。所用溶剂包括任何一种药用有机溶剂,例如丙酮,甲醇,乙醇,异丙醇;水溶剂例如水,以及其混合物。优选的溶剂混合物为乙醇和水。在该实施方案中,乙醇和水在涂覆溶液中的比通常为约10∶90~约90∶10,例如从约50∶50~约80∶20。为了实现液体涂覆溶液涂覆速率与溶剂蒸发速率间的平衡以便在不使颗粒表面过湿的情况下将质地遮蔽涂层均匀地沉积在颗粒上形成完整薄膜,必须对涂覆条件,如溶液喷涂速率、干燥空气的温度和流动速率进行调整,这对于本领域的技术人员来说是很容易理解的。这些方法的具体内容在工艺上是众所周知的,它披露在诸如Lieberman等人的“药品剂型—片剂:第3册”,第3章:颗粒涂覆法(1990),在这里将其作为参考文献引入。
在另一实施方案中,未涂覆的芯层,即没有遮味涂层的芯层基本上被质地遮蔽保护涂层所涂覆。上述用于第一层中的任选成分中的任意一种均可以同样的含量添加入质地遮蔽保护涂层中。在该实施方案中,质地遮蔽保护涂层基于芯和质地遮蔽保护涂层总量的存在量为约2%~约40%,例如从约3%~约20%重量。用上述任何一种方法都可将质地遮蔽保护涂层涂覆在未涂覆的芯上从而把遮味涂层涂覆在芯上。
在另一实施方案中,质地遮蔽颗粒可用喷雾干燥法来制造,通常活性成分同薄膜成型聚合物和抗砂砾剂和任选的其它成分一起悬浮或溶解在适当的溶剂中。适合的溶剂包括任何一种药用有机溶剂,例如丙酮,甲醇,乙醇,异丙醇;水溶剂例如水,以及其混合物。之后将溶液或悬浮液喷向热的干燥空气流,从而导致溶剂蒸发。为了获得最佳的颗粒尺寸和形态,必须对喷雾干燥条件,如干燥器的配置,喷射速率,喷雾条件,干燥空气的温度和流速进行调整,这一点对于本领域的技术人员来说是很容易理解的。这些方法的具体内容在工艺上是众所周知的,它披露在诸如Masters的“喷雾干燥手册,(1979)”中,在这里将其作为参考文献引入。
在该实施方案中,质地遮蔽颗粒是用喷雾干燥法生产的,该质地遮蔽颗粒包括一活性成分基层,薄膜成型聚合物和抗砂砾剂,从而所有这些成分均可存在于颗粒的表面。颗粒用薄膜成型聚合物和抗砂砾剂在颗粒的表面上以能对活性成分进行有效质地遮蔽的量进行质地遮蔽。本实施方案中质地遮蔽颗粒的平均直径为约50~约500微米,例如从约80~约400微米。在喷雾干燥的质地遮蔽颗粒中,薄膜成型聚合物与抗砂砾剂的重量比为约10∶90~约90∶10,例如约20∶80~约80∶20,约60∶40~约40∶60,或约50∶50~约50∶50。薄膜成型聚合物和抗砂砾剂的量为质地遮蔽的喷雾干燥颗粒重量的约25~约90%,例如约40~约80%或约50~约75%。
适合用于喷雾干燥质地遮蔽颗粒的任选成分包括,但不限于填料,包括水溶性可压缩糖类,例如蔗糖、甘露糖醇、山梨糖醇、麦芽糖醇、木糖醇、赤藓醇、乳糖和其混合物;常规的干粘合剂,包括纤维素、纤维素衍生物、聚乙烯基吡咯烷酮、淀粉、改性淀粉、麦芽糖糊精和其混合物,特别优选为微晶的纤维素、麦芽糖糊精和淀粉;甜味剂,包括天冬酰苯丙氨酸甲酯、乙酰舒泛钾(acesulfame potassium)、sucralose和糖精;崩解剂,例如微晶纤维素、淀粉、淀粉羟基乙酸钠、交联的聚乙烯基吡咯烷酮、交联的羧甲基纤维素;防腐剂,调味剂,酸化剂,抗氧化剂,助流剂,表面活性剂和着色剂。
由本发明颗粒组成的片剂可用工艺中已知的任何方法来生产。具体地说,这些片剂可以由遮味和质地遮蔽颗粒,质地遮蔽颗粒或其组合与工艺中已知的普通片剂赋形剂的混合物组成。
片剂生产的常规方法包括直接挤压(“干混合”),挤压后干制粒和在干燥和挤压后湿制粒。其它的方法包括利用辊压技术,如chilsonator,或递墨辊(drop roller),或模塑,铸塑或挤出技术。所有这些方法在工艺中都是众所周知的。并且它们均详细地描述在例如Lachman等人的“工业制药的理论和实践”第11章(第3版,1986)中,在这里将其作为参考资料引入。片剂优选是通过直接挤压法形成的,该方法包括直接挤压遮味并质地遮蔽颗粒、质地遮蔽颗粒或其组合与其它任何合适的任选成分的混合物。混合后,预定体积的颗粒装入旋转压片机的模腔中,该模腔作为“模台”的一部分从填料位置到挤压位置连续地旋转。颗粒在上穿孔器和下穿孔器间被挤压到排出位置,在该位置通过下穿孔器将所得片剂从模腔中推出并经固定的“引出”杆将其导入排出槽中。
在该实施方案中,希望得到的是咀嚼药片,控制颗粒的压实度以便使所得的片剂相对柔软,即它们的硬度最高为约15千磅/厘米2(kp/cm2),例如从约1kp/cm2~约10kp/cm2或从约2kp/cm2~约6kp/cm2。“硬度”是工艺中使用的一个用于描述直径裂断强度的术语,其中所述的裂断强度是用传统的药品硬度测试装置,如Schleuniger硬度测试仪测量的。为了比较不同大小的片剂值,裂断强度是以裂断的面积为标准的(它近似为片剂的直径×厚度)。以kp/cm2表示的该标准值有时在工艺上称为片剂的牵引韧力。片剂硬度测试的一般性论述可参见Leiberman等人的药品剂型—片剂,第2卷,第2版,Marcel Dekker Inc.,1990,pp.213-217,327-329(此后称为“Lieberman”)。
咀嚼药片中的活性成分应具有有效的治疗含量,这一含量在口服时要产生所希望的治疗作用并能被本领域的技术人员轻易地测定。在测定该含量时,必须考虑所给定的特定活性成分、活性成分的生物可利用率、剂量制度、病人的年龄和体重以及其它的因素。
咀嚼药片可含有其它常规的成分例如填料,包括可压缩的水溶性糖类,例如蔗糖、甘露糖醇、山梨糖醇、麦芽糖醇、木糖醇、赤藓醇、乳糖和其混合物;常规的干粘合剂,包括纤维素、纤维素衍生物、聚乙烯基吡咯烷酮、淀粉、改性淀粉和其混合物,特别优选为微晶的纤维素;甜味剂,包括天冬酰苯丙氨酸甲酯、乙酰舒泛钾(acesulfame potassium)、sucralose和糖精;崩解剂,例如微晶纤维素、淀粉、淀粉羟基乙酸钠;交联的聚乙烯基吡咯烷酮、交联的羧甲基纤维素;和润滑剂例如硬脂酸镁,硬脂酸,滑石和蜡。咀嚼药片还可加入制药上可接受的助剂,包括例如防腐剂,调味剂,酸化剂,抗氧化剂,助流剂,表面活性剂和着色剂。
根据本发明生产的质地遮蔽颗粒可有效地用在需要即时释放应用的场合,因为质地遮蔽涂层不会阻碍活性成分的溶解。对于其含有的特定活性成分来说,优选质地遮蔽颗粒符合USP溶解规定。在活性成分为对乙酰氨基酚的优选实施方案中,至少约70%的活性成分在45分钟内从颗粒中释放出来,这是用USP溶解装置II(桨式搅拌法)以75rpm在PH值为5.8的磷酸盐缓冲剂中测试的。在活性成分为布洛芬的优选实施方案中,至少约70%的活性成分在30分钟内从颗粒中释放出来,这是用USP溶解装置II(桨式搅拌法)以150rpm在PH值为7.2的磷酸盐缓冲剂中测试的。
本发明具体的实施方案将通过下面的实施例进行说明。本发明不受所述的这些实施例的限制,而是受所附权利要求范围的限定。除非另有说明,下面所给的百分比和比率均以重量计。
实施例
实施例1.比较咀嚼药片的制备
将下面表A中所述的成分放在塑料袋中并通过将袋翻转100次来混合:
表A:咀嚼颗粒的成分
成分 | 用量(mg/片) |
乙基纤维素包封的对乙酰氨基酚* | 274.7 |
天冬酰苯丙氨酸甲酯**** | 11.55 |
乙酰舒泛钾**(Acesulfame potassium) | 5.78 |
柠檬酸**** | 2.00 |
粒状甘露糖醇**** | 500 |
富马酸**** | 20 |
微晶纤维素*** | 77 |
橙味剂**** | 2 |
*包括基于总成分重量的被5.5%乙基纤维素涂层包围的94.5%的对乙酰氨基酚芯,其得自于Eurand America;
**得自于Hoechst,GmbH,其商品名为“SUNETT”;
***得自于FMC公司,其商品名为“AVICEL PH101”;
****这些成分易于得到并且可从“药品赋形剂手册”(第2版,1994)中所述的任何一个供应商处商购到。
在向其中加入了5.78mg的硬脂酸镁后,通过把袋再翻转20次来进一步混合所得的混合物。
然后从袋中取出所得的混合物,为了生产出重898.8mg,硬度为3.1kp(由Lieberman所述硬度试验测定)和厚度为0.19英寸的药品,用19/32”直径的平面斜边制片工具在40rpm的旋转压片机上对所得混合物进行挤压。
实施例2:质地遮蔽颗粒的制备
A质地遮蔽涂覆溶液的制备:
通过将等量的羟丙基甲基纤维素和聚乙二醇800与乙酰舒泛钾(acesulfamepotassium)(1%的固体)分散在含有77%乙醇和23%水的溶剂中来制备质地遮蔽的涂覆溶液从而使固体材料占最终溶液的10%。最终溶液中的成分列于下述表B中:
表B:质地遮蔽涂覆溶液组合物:
成分 | 用量(g) |
乙醇*** | 604.72 |
纯净水 | 177.89 |
羟丙基甲基纤维素* | 43.05 |
聚乙二醇8000*** | 43.05 |
乙酰舒泛钾**(Acesulfame potassium) | 0.87 |
总量 | 869.58 |
*得自于Shin Etsu,其商品名为“PHARMACOAT 606”;
**得自于Hoechst,GmbH,其商品名为“SUNETT”;
***这些成分易于得到并且可从“药品赋形剂手册”(第2版,1994)中所述的任何一个供应商处商购到。
B.用质地遮蔽溶液涂覆活性成分
将1000g来自实施例1中的包裹的对乙酰氨基酚起始材料装入旋转流化床涂料器(Glatt GPCG-5)。用速度为300rpm的转子和0.65英寸水的气体体积来驱动粉剂床。用成切线取向的喷嘴以30g/分钟的速率将质地遮蔽涂覆溶液喷射在颗粒上。入口空气的温度为50℃。在所有的溶液喷洒后,在100rpm降低的转速下将所得的质地遮蔽涂覆颗粒干燥5分钟。最终的干燥批料重1061g(97%的产率)。质地遮蔽涂覆材料的用量占最终质地遮蔽并遮味涂覆颗粒总量的7%重量。根据标准的分布模型(r2=0.984),所得涂覆颗粒的平均直径为380微米,标准偏差为70微米。73.8%颗粒的平均直径在300~425微米之间。
实施例3.咀嚼药片的制备
来自于实施例2的涂覆颗粒(在涂覆有乙基纤维素的对乙酰氨基酚上有7%的HPMC/PEG8000的质地遮蔽保护涂层)与天冬酰苯丙氨酸甲酯、acesulfamepotassium、柠檬酸、粒状甘露糖醇、富马酸、微晶纤维素和调味剂在塑料袋中通过翻转100次来混合。加入硬脂酸镁并通过来回翻转20次进一步混合混合物。所得混合物的组分列于下面的表C中。
表C:咀嚼混合物的组分
组分 | 用量(mg/片) |
包裹并涂覆的对乙酰氨基酚(87.9%的活性成分)* | 290.7 |
天冬酰苯丙氨酸甲酯*** | 11.55 |
乙酰舒泛钾**(acesulfame potassium) | 5.78 |
柠檬酸*** | 2.00 |
甘露糖醇*** | 500 |
微晶纤维素**** | 77 |
富马酸NF*** | 20 |
橙味剂*** | 2 |
硬脂酸镁*** | 5.78 |
总量 | 914.81 |
*在实施例2中制备的;
**得自于Hoechst,GmbH,其商品名为“SUNETT”;
***这些成分易于得到并且可从“药品赋形剂手册”(第2版,1994)中所述的任何一个供应商处商购到。
用19/32”直径的平面斜边制片工具在40rpm的旋转压片机上对所得混合物进行挤压从而得到平均片剂重量为914.8mg,药片硬度为3.1kp(由Lieberman所述硬度试验测定)和药片厚度为0.2英寸的片剂。由USP法测定的脆性为3.3%。
实施例4:实施例1和3咀嚼药片的评估
由专门小组成员对分别由实施例1和3制备的片剂进行单独取样,该专门小组成员分别评估每种片剂的味道、质地和溶解作用。
大多数小组成员发现两种片剂具有相似的味道,略微的苦味。实施例1的片剂可看到有砂砾,其范围由“微小”~“明显”可见并且表面粗糙。与之相比,根据实施例3生产的本发明的“质地遮蔽”颗粒没有发现有砂砾,质地光滑并且“熔化良好”,即仅需最小的咀嚼就可将片剂快速清除出空腔。
还可用USP桨式搅拌法(装置II)在75rpm,PH值为5.8的磷酸盐缓冲剂中评估实施例1和3片剂的溶解作用。在45分钟内实施例1和3片剂中释放出100%的对乙酰氨基酚活性成分。
该实施例表明,虽然本发明质地遮蔽涂覆片剂具有与现有技术片剂相似的味道,但前者更光滑,砂砾更少。所以质地遮蔽的涂覆片剂更适合于咀嚼药片剂型。
Claims (11)
1.一种质地遮蔽颗粒,包括
a)含有活性成分的芯;
b)由基本上覆盖了芯的遮味剂组成的第一涂覆层;和
c)在第一涂覆层表面上的第二涂覆层,该第二涂覆层由下面的成分组成:
i)薄膜成型聚合物;和
ii)抗砂砾剂。
2.根据权利要求1的颗粒,其中第二涂覆层基本上覆盖了第一涂覆层。
3.根据权利要求1的颗粒,其中活性成分选自不含类固醇的抗发炎药,醋氨酚,假麻黄碱,苯丙醇胺,氯屈米,美沙芬,苯海拉明,乘晕宁,美其敏,法莫替丁,洛哌丁胺,雷尼替丁,甲腈咪胺,阿司咪唑,氯雷他啶(loratadine),desloratadine,fexofenadine,西替利嗪(cetirzine),解酸剂,制药上可接受的盐,其代谢物和其混合物。
4.根据权利要求4的颗粒,其中肠溶性聚合物可选自邻苯二甲酸羟丙基甲基纤维素,乙酸琥珀酸羟丙基甲基纤维素,乙酸邻苯二甲酸纤维素和其混合物。
5.根据权利要求4的颗粒,其中不溶性薄膜成型聚合物选自乙酸纤维素,乙基纤维素和其混合物。
6.根据权利要求4的颗粒,其中在第一涂覆层中肠溶性聚合物与不溶性薄膜成型聚合物的重量比为约20∶80~约80∶20。
7.根据权利要求1的颗粒,对于含有特殊活性成分的即时释放剂型来说它符合USP溶解规定。
8.根据权利要求1的颗粒,其中薄膜成型聚合物选自羟丙基甲基纤维素,羟丙基纤维素,羟乙基纤维素和羧基甲基纤维素钠,淀粉,藻酸盐,聚乙烯醇,黄厚胶,瓜尔胶,多糖,果胶,树胶和其混合物。
9.根据权利要求1的颗粒,其中抗砂砾剂选自聚氧化乙烯、聚乙二醇和其混合物。
10.一种片剂,由权利要求1的颗粒组成。
11.一种含有活性成分的质地遮蔽颗粒的生产方法,该方法包括:
a)将基本上连续第一涂层涂覆在颗粒上,第一涂层包括遮味剂;和
b)将第二涂层涂覆在第一涂层的表面上,第二涂层包括1)薄膜成型聚合物和2)抗砂砾剂的混合物。
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US7223421B2 (en) * | 2000-06-30 | 2007-05-29 | Mcneil-Ppc, Inc. | Teste masked pharmaceutical particles |
-
2000
- 2000-12-21 US US09/745,243 patent/US20020119196A1/en not_active Abandoned
-
2001
- 2001-12-20 CA CA2365844A patent/CA2365844C/en not_active Expired - Fee Related
- 2001-12-21 NZ NZ516341A patent/NZ516341A/en unknown
- 2001-12-21 AU AU97361/01A patent/AU783593B2/en not_active Ceased
- 2001-12-21 JP JP2001390445A patent/JP2002272817A/ja active Pending
- 2001-12-21 EP EP01310751A patent/EP1219291B1/en not_active Expired - Lifetime
- 2001-12-21 DE DE60135435T patent/DE60135435D1/de not_active Expired - Lifetime
- 2001-12-21 BR BR0106912-8A patent/BR0106912A/pt not_active Application Discontinuation
- 2001-12-21 AR ARP010106010A patent/AR032037A1/es unknown
- 2001-12-21 CN CNB011454830A patent/CN100544705C/zh not_active Expired - Fee Related
- 2001-12-21 ES ES01310751T patent/ES2311007T3/es not_active Expired - Lifetime
- 2001-12-21 ZA ZA200110547A patent/ZA200110547B/xx unknown
- 2001-12-21 CO CO01109552A patent/CO5390070A1/es not_active Application Discontinuation
- 2001-12-21 KR KR1020010082953A patent/KR20020050754A/ko not_active Application Discontinuation
- 2001-12-21 AT AT01310751T patent/ATE405250T1/de not_active IP Right Cessation
-
2002
- 2002-01-07 MX MXPA02000277A patent/MXPA02000277A/es active IP Right Grant
- 2002-10-11 HK HK02107435.6A patent/HK1045817B/zh not_active IP Right Cessation
- 2002-11-25 HK HK02108500.4A patent/HK1046865A1/zh unknown
-
2012
- 2012-06-12 US US13/494,361 patent/US20120251623A1/en not_active Abandoned
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112770733A (zh) * | 2018-11-04 | 2021-05-07 | 安布罗西亚速普赫伯有限公司 | 咀嚼片剂及其制备方法 |
Also Published As
Publication number | Publication date |
---|---|
HK1045817A1 (en) | 2002-12-13 |
JP2002272817A (ja) | 2002-09-24 |
EP1219291A1 (en) | 2002-07-03 |
ATE405250T1 (de) | 2008-09-15 |
HK1045817B (zh) | 2009-06-05 |
AR032037A1 (es) | 2003-10-22 |
ZA200110547B (en) | 2003-07-30 |
US20120251623A1 (en) | 2012-10-04 |
BR0106912A (pt) | 2003-09-16 |
CO5390070A1 (es) | 2004-04-30 |
EP1219291B1 (en) | 2008-08-20 |
ES2311007T3 (es) | 2009-02-01 |
MXPA02000277A (es) | 2004-05-21 |
KR20020050754A (ko) | 2002-06-27 |
CN100544705C (zh) | 2009-09-30 |
AU9736101A (en) | 2002-06-27 |
CA2365844C (en) | 2010-07-06 |
CA2365844A1 (en) | 2002-06-21 |
HK1046865A1 (zh) | 2003-01-30 |
NZ516341A (en) | 2003-08-29 |
AU783593B2 (en) | 2005-11-10 |
US20020119196A1 (en) | 2002-08-29 |
DE60135435D1 (de) | 2008-10-02 |
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