CN101820866A - 用于固体剂型的机械保护层 - Google Patents
用于固体剂型的机械保护层 Download PDFInfo
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- CN101820866A CN101820866A CN200880110438A CN200880110438A CN101820866A CN 101820866 A CN101820866 A CN 101820866A CN 200880110438 A CN200880110438 A CN 200880110438A CN 200880110438 A CN200880110438 A CN 200880110438A CN 101820866 A CN101820866 A CN 101820866A
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- Prior art keywords
- mechanical protection
- protection layer
- polyethylene glycol
- plasticizer
- solid dosage
- Prior art date
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Abstract
本发明涉及一种包含至少两种增塑剂的用于微丸的机械保护层，也涉及一种制备该机械保护层的方法和一种包含该机械保护层的固体制剂。
Description
技术领域
本申请涉及一种用于微丸的机械保护层、一种制备该机械保护层的方法和一种包含该机械保护层的固体剂型。
背景技术
在本领域使用的药物剂型具有不同功能的不同层。生产过程中，固体剂型经历压缩过程，在此过程中一些层被部分破坏，因此需要一种额外的保护层或对现有的层进行改进。当所述层具有功能特性并在物理破坏后会失去这些特性时，这是至关重要的，尤其是当所述功能层是保护活性物质免于胃液伤害的肠溶层时。如果肠溶层被破坏，那么活性物质就可能被胃的高酸性环境破坏。
国际专利申请WO 96/01624涉及一种药物多单元片剂型，其包含一种酸敏感的H+K+-ATP酶抑制剂，其中活性物质是压缩成片的独立的肠溶包衣层单元的形式。包覆活性物质的独立单元的肠溶包衣层是可塑的，可以将肠溶包衣层单元压缩成一种片剂，而不会显著影响独立的肠溶包衣层单元对酸的抵抗力。
在WO 99/59544和Chem.Pharm.Bull.，2003，51(10)，1121-1127中，描述了具有肠溶包衣微粒的口腔崩解片剂。所述微粒具有一个层，该层由一种水溶性糖醇、优选甘露糖醇制成，并包覆可由几层增塑过的肠溶包衣层构成的增塑的肠溶层。
US2005266078描述了一种具有至少一种可变形的有机组分(例如，聚乙二醇(PEG)6000-20000)的保护性的包衣，其保护一种缓释颗粒，所述颗粒由有机分层过程制得。
WO 99/26608解决了压缩的问题。为了解决该问题提供了可压缩的球状体，其包含一个被弹性可变形的聚合物膜包覆的核心。该核心包含至少一种热塑形的赋形剂，在20℃时具有糊状到半固体的稠度，从而使其可塑性的变形，因此吸收一部分在可能的压缩步骤中所遭受的压力。包覆核心的包衣是可变形的弹性膜，其基于一种具有低于30℃的玻璃化转变温度的聚合材料(例如，一种PEG)，其提供保护，或掩盖味道，或控制有效成分的释放。
US 4684516描述了片剂，其主要包含(片剂的80-100％)用阻滞蜡包衣的缓释微丸。
WO 2005120468描述了一种缓释微丸，其包含一种增塑的乙基纤维素层和一个外部包衣，该外部包衣防止其在生产和给药过程中被腐蚀，其由一种filmogenic物质、色素和一种增塑剂制得。所述层能由Opadry制得，例如羟丙基甲基纤维素、PEG 400和PEG 6000。Opadry广泛用作微丸的最后的包衣，保护它们免受湿度、光照影响，并且也用作最终的包衣。
US 2002176894描述了一种非肠溶药物组合物，其包含一个核心和一种药物乳剂层，以及任选的一个保护层，其包含PEG 20000并包覆在乳剂层之上。没有提到任何关于压缩的东西。
附图说明
图1：生动地示出了实施例8中作为PEGequiv的函数的不同微丸中的胃液抗性(％)变量的结果。
发明内容
因此，压缩对于肠溶固体剂型的效果能影响成分的溶解行为，并直接关系到包衣层的分裂和破碎(例如肠溶层)，最终影响它在酸性情况下的胃液抗性。因此，本领域中存在一种需求，即提供一种用于固体剂型的保护层，从而防止由于机械侵蚀、尤其是压缩而带来的损耗。
根据一个方面，本发明涉及一种用于固体剂型的机械保护层，其包含两种或更多的增塑剂。
这种机械保护层提供的优点与本领域已知的剂型有关。例如，本发明的这种机械保护层可以与一种使用高浓度(例如27％固体)水溶液的喷雾干燥过程相结合，允许高含量肠溶微丸在一种固体剂型中(在一个片剂中高达93％w/w或更多)，并且因此，在一种固体剂型中存在高活性成分(例如在800mg片剂重量中有30mg到93.2mg肠溶兰索拉唑)，它也可以在没有进一步对现有其它层的改进的情况下使用在一种易碎的固体剂型中，赋予所述固体剂型极好的机械保护。
同样，这种新的机械保护层提供了具有高硬度的片剂，其硬度至少高达8.5Kp，且不依赖于颗粒的尺寸；至少高达0.8mm的微丸可以压缩到具有上述的特性。
根据第二个方面，本发明涉及一种用于制备所述机械保护层的方法，其包含使所有成分在水中分散，然后用所述分散液包衣固体剂型。
根据第三个方面，本发明涉及一种固体剂型，其包含本发明的机械保护层。
根据第四个方面，本发明涉及一种片剂，其包含本发明的机械保护层。
详细说明
如上所述，用于本发明的固体剂型的机械保护层包含两种或更多的增塑剂。
出于本发明的目的，“机械保护层”是一种能承受机械侵蚀(例如一种压片过程)同时保护在所述层中的内含物的层。
出于本发明的目的，一种“增塑剂”是一种物质，其通常用于提高由聚合物形成的膜的机械特性。它是一种在变形之后不会返回到它原始的形式的产品。当添加到聚合物中，增塑剂提供给材料改善的抵抗力和弹性。出于本发明的目的，增塑剂优选在室温下为固体，并且是水溶性的。
因此，优选地，至少一种增塑剂是选自由蜡、linoline型醇、明胶、聚乙二醇、聚丙二醇、三乙酸甘油酯、柠檬酸三丁酯、柠檬酸三乙酯、癸二酸二丁酯、中链长度的脂肪酸甘油三酸酯、树脂酸、长链脂肪酸(例如硬脂酸，棕榈酸)或它们的混合物组成的组中。
其它优选的增塑剂是那些具有润滑特性的，例如单硬脂酸甘油酯、硬脂酸、palmine硬脂酸甘油酯、二山嵛酸甘油酯等。
根据一个优选的实施例，本发明的机械保护层包含作为增塑剂的单硬脂酸甘油酯。
本发明的机械保护层可以包含本领域通常使用的其它物质，例如至少一种添加剂，该添加剂选自由下列组分组成的组中：通过溶胀和/或芯吸作用的崩解剂、润滑剂、着色剂、掩味剂、调味剂、稳定剂、粘合剂、填充剂、发泡剂、甜味剂、成孔剂、酸(例如柠檬酸或酒石酸)、氯化钠、碳酸氢盐(例如钠或钾)、糖和醇。
掩味剂的例子有：水不溶性聚合物如乙基纤维素，在唾液中不溶和在胃液中溶解的聚合物如甲基丙烯酸甲酯、甲基丙烯酸丁酯和甲基丙烯酸二乙胺乙酯的共聚物，和诸如此类的物质。
术语“崩解剂”应当理解成一种物质，其被添加到固体制剂中，在给药之后促进固体制剂的分裂或崩解，并容许活性成分尽可能有效的释放，从而使固体制剂可以快速溶解。作为崩解剂的例子有：淀粉如玉米淀粉和马铃薯淀粉、部分α淀粉、羧甲基淀粉钠、羧甲基纤维素、甲基纤维素钙、交联羧甲基纤维素钠、聚乙烯醇、交联聚维酮、低取代羟丙基纤维素、微晶纤维素、羧甲基淀粉等。同样，羟丙基纤维素可以用作崩解剂。
作为调味剂的例子有：香料、柠檬、柠檬莱姆、柑橘、薄荷脑、薄荷油、香草醛，或用糊精或环糊精吸收的这些物质的粉末，等等。
作为润滑剂的例子，可以是硬脂酸镁、硬脂酸延胡索酸酯、滑石粉、硬脂酸、胶体二氧化硅(Aerosil 200
)，等。
作为着色剂的例子，可以是食品染料如食品黄No.5、食品红No.3、食品蓝No.2、食品色淀染料、红色氧化铁等。
作为稳定剂或助溶剂的例子，取决于所使用的生理学活性成分，可以是抗氧化剂如抗坏血酸和生育酚，表面活性剂如聚山梨醇酯80等。
作为粘合剂的例子，可以是羟丙基甲基纤维素、羧乙烯基聚合物、羧甲基纤维素钠、α淀粉、聚乙烯吡咯烷酮、阿拉伯树胶、明胶、支链淀粉等。
作为填充剂的例子，可以是蔗糖、葡萄糖、乳糖、甘露醇、木糖醇、右旋糖、微晶纤维素、麦芽糖、山梨醇、磷酸钙、硫酸钙等。
作为发泡剂的例子，能使用碳酸氢钠。
作为甜味剂的例子，可以是糖精钠、甘草皂苷二钾、阿司巴甜、甜叶菊、索马甜等。
根据一个优选的实施例，本发明的机械保护层包含一种是第一聚乙二醇的第一增塑剂，以及更优选的一种是不同于第一聚乙二醇的第二聚乙二醇的第二增塑剂。能买到具有不同物理特性的不同类型的聚乙二醇。例如，可以从多个供应商那买到不同平均分子量或不同密度的聚乙二醇。
根据一个优选的实施例，所述第一聚乙二醇的平均分子量低于6000，优选在3000-6000之间，更优选在3000-5000之间。
根据一个进一步优选的实施例，第一聚乙二醇具有在3000-5000之间的平均分子量，更优选为4000，并且第二聚乙二醇具有6000的平均分子量。
根据一个优选的实施例，本发明的机械保护层包含一种第三增塑剂，其是一种不同于第一聚乙二醇和第二聚乙二醇的第三聚乙二醇。
获得了具有不同粘度和分子量的PEG的混合物的最佳结果。例如，如下列实施例中所示，PEG8000，6000和4000的混合物在压缩过程中提供了极好的机械抵抗性和弹性，从而具有更好的胃液抗性值。
因此，根据一个优选的实施例，本发明的机械保护层包含平均分子量在3000-5000之间、优选是4000的第一聚乙二醇，平均分子量在5000-7000之间、优选是6000的第二聚乙二醇，和平均分子量在7000-9000、优选是8000的第三聚乙二醇。
根据一个特定实施例，第一聚乙二醇的平均分子量大于或等于6000，优选在6000-7000之间。
根据一个特定实施例，本发明的机械保护层包含平均分子量在6000-7000之间、优选是6000的第一聚乙二醇，和平均分子量在7000-9000、优选是8000的第二聚乙二醇。
本发明的机械保护层可以在不改进固体剂型中的现有的其它层的结构的情况下使用。
根据一个优选的实施例，机械保护层包含至少80％w/w的增塑剂，优选至少90％w/w的增塑剂，更优选至少95％w/w的增塑剂。
在本发明的一个优选的实施例中，所有增塑剂在一个单层中混合。然而，如果本发明的机械保护层包含两层或更多的亚层，每个亚层包含一种或多种增塑剂，也可以达到保护的效果。根据一个特定实施例，本发明的机械保护层包含两层或更多的亚层，其中每个亚层包含一种增塑剂。
根据一个进一步优选的实施例，本发明的机械保护层能在一个压缩过程(例如压片)中承受机械侵蚀，同时保护所述层中的内含物。
如上所述，本发明的一个进一步的方面是包含本发明的机械保护层的一种固体剂型，优选药学上可接受的固体剂型。
术语“固体剂型”可理解为固体状态的制剂，例如一种片剂、颗粒、胶囊、迷你药片、微粒、包衣层，等等，其优选包含一种能在一种合适的介质中(例如唾液、胃液、水、皂液、牛奶等)释放的生理学活性成分。
术语“药学上可接受的固体剂型”可理解为一种固体状态的制剂，例如一种片剂、颗粒、胶囊、迷你药片、微粒、包衣层，等等，其包含一种药学活性成分。
“药学上可接受”也涉及一种固体剂型，当给药到人体时，其是生理上可耐受的，且不会典型的产生过敏或类似的不利反应，例如反胃，头昏眼花等。优选，这里所用的术语“药学上可接受”是指被联邦或州政府的管理机构所核准，或列在美国药典中，或其他普遍公认的可使用在动物上、尤其是人身上。
术语“胃液抗性”可理解为根据USP23对肠溶包衣制品的要求，在0.1NHCl中在37℃下处理2小时后活性成分的释放量(非独立单元值超出10％的溶解量)。
包含本发明的机械保护层的所述固体剂型在压缩后具有极好的胃液抗性。例如，聚有高达93％的肠溶微丸含量的片剂能保持胃液抗性值低于10％。
本发明的固体剂型优选包含至少一种生理学上的活性成分，其选自一种药学活性成分、一种调味成分和一种营养成分。在一个特定的实施例中，本发明的固体剂型是药学上可接受的，并包含一种药学活性成分。在另一个特定实施例中，固体剂型是一种营养制品，其包含一种营养成分。
作为药学活性成分，例如，一种或多种选自下列组的成分，该组包括：胃肠功能调节剂、抗炎剂、止痛药、抗偏头痛剂、抗组胺剂、心血管药物、利尿剂、抗高血压药物、降血脂药、抗溃疡药、止吐药、抗哮喘药、抗抑郁剂、维他命、抗血栓药物、化疗剂、激素、驱蠕虫剂、抗糖尿病药、抗病毒剂和它们的混合物。
上述的胃肠功能调节剂的代表性例子包括溴必利、胃复安、西沙比利和多潘立酮；抗炎剂，醋氯芬酸、双氯芬酸、氟苯布洛芬、舒林酸和塞来考昔；止痛药，对乙酰氨基酚、布洛芬和阿司匹林；抗偏头痛剂，舒马曲坦和麦角胺；抗组胺剂，氯雷他定、非索非那定及西替利嗪；心血管药物，硝酸甘油和硝酸异山梨酯；利尿剂，呋塞米和螺内酯；抗高血压药物，心得安、氨氯地平、非洛地平、卡托普利、雷米普利、氯沙坦、缬沙坦、依普罗沙坦、厄贝沙坦、他索沙坦、替米沙坦；降血脂药，辛伐他汀、阿托伐他汀和普伐他汀；抗溃疡药物，西咪替丁、雷尼替丁、法莫替丁、兰索拉唑、奥美拉唑、雷贝拉唑和泮托拉唑；止吐药，盐酸敏克静、奥坦西隆、格拉司琼、雷莫司琼和托烷司琼；抗哮喘药，氨茶碱、茶碱、特布他林、非诺特罗、福莫特罗和酮替芬；抗抑郁药，氟西汀和舍曲林；抗血栓药物，磺吡酮、双嘧达莫及噻氯匹定；化疗剂，头孢克洛、巴氨西林、新诺明和利福平；激素，地塞米松，甲睾酮；驱蠕虫剂，驱蛔灵、伊维菌素和甲苯咪唑；抗糖尿病药物，阿卡波糖，甲磺吡脲和格列吡嗪。
在本发明的一个特定的实施例中，药学活性成分是一种抗溃疡剂或一种H+/K+-ATP酶抑制剂，优选是一种苯并咪唑化合物或一种它的对映体或一种它的盐，更优选是兰索拉唑，奥美拉唑，雷贝拉唑或泮托拉唑，更优选为兰索拉唑。
在另一个特定实施例中，药学活性成分是一种非甾体抗炎药或它的盐，更优选是阿司匹林。
固体剂型中包括的营养成分可选自以下组：维他命，例如维他命A、维他命D、维他命E(d-α-生育酚乙酸)、维他命B1(二苯酰硫胺，呋喃硫胺盐酸盐)、维他命B2(四丁酸核黄素酯)、维他命B6(盐酸吡哆辛)、维他命C(抗坏血酸，L-抗坏血酸钠)和维他命B12(羟钴胺素醋酸盐)；矿物质如钙，镁和铁；蛋白质；氨基酸；寡糖；不饱和脂肪酸；草本植物和它们的混合物。
本发明的一个额外的优点是无需改进微丸的结构，只要应用本发明的机械保护层(或用本发明的机械保护层代替一个最终层)。举例来说，在一个胶囊剂型中使用的相同的易碎的肠溶微丸，也能在一个片剂中使用，只要用本发明的机械保护层包衣并将其与一种维持它的特性和释放曲线的压缩基质(混合物)一起进行压缩。另外，本发明的机械保护层也可以提供掩味和
根据一个优选的实施例，固体剂型包含一个包括一个惰性粒子的核心，其被所述机械保护层包衣。
根据一个进一步优选的实施例，固体剂型包含一个调节释放层，优选一个肠溶层。
根据一个优选的实施例，所述剂型是颗粒或微丸。
本发明的另一个方面是一种片剂，其包含许多包含了本发明的机械保护层的颗粒或微丸。优选，所述片剂包含大于80％w/w的颗粒或微丸，更优选地包含大于90％w/w的颗粒或微丸。
根据另一个方面，本发明涉及本发明的机械保护层用于制备固体剂型的用途。
本发明的机械保护层可以按本领域已知的下列方法生产。根据另一个方面，本发明涉及一种用于制备本发明的机械保护层的方法，其包括将所有成分分散在水中，然后用所述分散液包衣固体剂型。
本发明的所有片剂强度用Schleuniger Tablet Tester 8M装置测定。
具体实施例
例1：没有机械保护层的肠溶包衣兰索拉唑微丸
制备没有机械保护层的肠溶包衣兰索拉唑微丸，其具有如表1所示的成分：
表1
通过在流化床装置中在之前的包衣上连续喷洒不同的分散液以及进一步干燥来获得每个膜包衣(FC)。即，首先提供一个纤维素惰性粒。制备具有第一个膜包衣(FC1)的组分的分散液，喷洒到惰性粒上。然后，FC2的分散液喷洒到FC1上，最后FC3的分散液喷洒到FC2上。
例2：合成本发明的机械保护层的方法
首先，边搅拌边将TEWN80和单硬脂酸甘油酯一起加入到60-75℃的纯净水中。混合物冷却到25-30℃并且添加PEG 4000、PEG 6000、PEG 8000、糖精钠和草莓调味剂。最后，搅拌的同时添加作为红色着色剂氧化铁。如此制备的分散液可用于包衣。
例3：采用本发明的机械保护层的一般的包衣方法
本发明的机械保护层(如根据例2的一般方法制备的)在流化床装置中喷洒到例1的肠溶包衣兰索拉唑微丸上，并在下列情况下进一步干燥：入口温度：50-55℃，入口空气流：7,000-8,000m3/h，产品空气温度：40-42℃，微气候：1巴，雾化空气压力：3.0巴，流速：0.8-0.9L/h
例4：包含本发明的机械保护层的微丸
按例3的一般方法，例1的兰索拉唑微丸被本发明的机械保护层所包衣，其具有如表2中所示的成分。
表2
例5：PEG6000保护性包衣(比较例)
在流化床装置中，例1的微丸用PEG6000按US2005266078所描述的方法包衣，但是使用一种水性分层过程。由此获得的包衣微丸，与例4获得的本发明的包衣微丸进行比较。在流化床中的喷洒过程中，例4获得的本发明的微丸比本例中获得的微丸显示出更少的结块。
用于测定胃液抗性的一般方法
在例6-10中在压片过程之前和之后，通过按USP23对肠溶包衣制品的要求测定在0.1M HCl中处理2小时后兰索拉唑的释放量(胃液抗性值)，由此评估保护层的质量，包括本发明的新的机械保护层。
为了获得例6-10描述的片剂，微丸(26.93wt％)以表3中显示出的比例与压缩基质混合，然后压缩成一个片剂。
表3
例6：比较-兰索拉唑释放
例4和5的微丸(26.93wt％)以表3中示出的比例与压缩基质混合，然后压缩成具有4-6Kp最终硬度的片剂；测量两种片剂的胃液抗性。
用例4的微丸获得的片剂(PEG 4000+PEG 6000+PEG 8000保护性包衣)相较于没有压缩的实施例4的微丸仅仅将胃液抗性值提高了50-60％，同时用例5的微丸获得的片剂(只有PEG 6000保护性包衣)相较于没有压缩的实施例5的微丸将胃液抗性值提高了100-140％。因此，本发明的机械保护层明显改进了胃液抗性。低胃液抗性值说明更少数量的活性成分释放到酸性介质中，因此更有效的保护了肠溶层。
例7：低分子量PEG的影响
本实施例中显示了具有低于6000的平均分子量的PEG对本发明的机械保护层的增塑效果。
按例3的方法，例1的兰索拉唑微丸被一个具有表4所示的组合物的本发明的机械保护层包衣，由此获得微丸7a-7d。这四种表4所示的机械层按例2所述的相同方法准备。层的组合物的区别仅仅在于不同PEG的相对数量上。总的增塑剂的量(PEG+单硬脂酸甘油酯)在所有的情况下实质上保持一致。
表4
PEGequiv为组合物中PEG的“平均”分子量。例如，PEG 6000和PEG 8000的1∶1混合物的PEGequiv为7000.因此，一种PEGequiv为7000的PEG混合物不等同于PEG7000.
使用压缩基质以表格3中所示比例与微丸7a-7d(每种情况26.93wt％)压缩成最终硬度4-6Kp的片剂，并测定胃液抗性。结果显示在附图1中。
如附图1所示，平均分子量低于6000的PEG(例如PEG4000)的包裹体在压缩过程中提供更多的弹性和更好的变形性，所以，更多的保护了肠溶包衣，这转化为更好的胃液抗性。随着PEG分子量的增加胃液抗性值增加，因此说明胃液抗性的恶化。
因此，相比更高分子量的PEG，具有平均分子量低于6000的PEG的包裹体在增塑混合物似乎提供更好的弹性和更好的变形能力。
例8：活性成分剂量
本发明的机械保护层允许增加在片剂中的微丸数量，因此增加活性成分的剂量，保持片剂重量恒定。
表5显示了包含例1的用例4的层包衣的微丸的800mg片剂，与压缩基质按表3所示比例混合，但是以不同微丸比例，压缩来获得片剂(硬度范围4-6kp)：
表5
一般，在片剂中提高肠溶微丸对于压缩基质的百分比会在压片过程之后增加胃液抗性值，因为在压缩中微丸由于不能有效的被压缩基质缓冲而破碎。令人吃惊地，本发明的机械保护层允许在一个片剂中有高含量的肠溶微丸，并有胃液抗性的变化很小。
例9：片剂硬度
本发明的机械保护层允许使用具有增大硬度的片剂(高达8.5Kp)，因此可以施加高压力，维持胃液抗性值恒定。
表6示出了在不同最终硬度下800mg片剂的胃液抗性值，其包含被例4的保护层包衣并与压缩基质按表3所示的比例压缩的例1的27％的微丸。
表6
例10：微丸尺寸
具有本发明的机械保护层的微丸的胃液抗性不依赖于尺寸大小。例1的肠溶包衣兰索拉唑微丸用例4的保护层包衣。选择两种尺寸：0.4和0.8mm，和压缩基质按表3所示比例压缩成具有4-6kp硬度的片剂(26.93wt％微丸)。两种尺寸的微丸的胃液抗性值都是大约5％。
Claims (31)
1.一种用于固体剂型的机械保护层，包含两种或更多的增塑剂。
2.根据权利要求1所述的机械保护层，其特征在于，至少一种增塑剂是选自由蜡、linolin型醇、明胶、聚乙二醇、聚丙二醇、三乙酸甘油酯、柠檬酸三丁酯、柠檬酸三乙酯、癸二酸二丁酯、中链长度的脂肪酸甘油三酸酯、树脂酸、长链脂肪酸或它们的混合物组成的组。
3.根据权利要求2所述的机械保护层，其特征在于，其包含一种是第一聚乙二醇的第一增塑剂。
4.根据权利要求3所述的机械保护层，其特征在于，其包含一种是不同于第一聚乙二醇的第二聚乙二醇的第二增塑剂。
5.根据权利要求3或4所述的机械保护层，其特征在于，所述第一聚乙二醇的平均分子量低于6000。
6.根据权利要求5所述的机械保护层，其特征在于，第一聚乙二醇具有4000的平均分子量，第二聚乙二醇具有6000的平均分子量。
7.根据权利要求4-6中任一项所述的机械保护层，其特征在于，其包含一种第三增塑剂，该第三增塑剂是一种不同于第一聚乙二醇和第二聚乙二醇的第三聚乙二醇。
8.根据权利要求7所述的机械保护层，其特征在于，其具有平均分子量4000的第一聚乙二醇，平均分子量6000的第二聚乙二醇和平均分子量8000的第三聚乙二醇。
9.根据权利要求3或4所述的机械保护层，其特征在于，第一聚乙二醇的平均分子量大于或等于6000。
10.根据权利要求9所述的机械保护层，其特征在于，其包含平均分子量为6000的第一聚乙二醇，和平均分子量为8000的第二聚乙二醇。
11.根据前述任一项权利要求所述的机械保护层，其特征在于，其包含至少80％w/w的增塑剂。
12.根据权利要求11所述的机械保护层，其特征在于，其包含至少90％w/w的增塑剂。
13.根据权利要求12所述的机械保护层，其特征在于，其包含至少95％w/w的增塑剂。
14.根据前述任一项权利要求所述的机械保护层，其特征在于，所有增塑剂在一个单层中混合。
15.根据权利要求1-13中任一项所述的机械保护层，其特征在于，其包含两层或更多层的亚层，其中每个亚层包含一种或多种增塑剂。
16.根据权利要求15所述的机械保护层，其特征在于，其包含两层或更多层的亚层，其中每个亚层包含一种增塑剂。
17.根据前述任一项权利要求所述的机械保护层，其特征在于，所述增塑剂选自单硬脂酸甘油酯、硬脂酸、palmine硬脂酸甘油酯和二山嵛酸甘油酯。
18.根据权利要求17所述的机械保护层，其特征在于，单硬脂酸甘油酯作为增塑剂。
19.根据前述任一项权利要求所述的机械保护层，其特征在于，其包含至少一种添加剂，该添加剂选自由下列组分组成的组中：通过溶胀和/或芯吸作用的崩解剂、润滑剂、着色剂、掩味剂、调味剂、稳定剂、粘合剂、填充剂、发泡剂、甜味剂、成孔剂、酸、氯化钠、碳酸氢盐、糖和醇。
20.根据前述任一项权利要求所述的机械保护层，其特征在于，所述层能在压片过程中承受机械侵蚀同时保护所述层中的内含物。
21.一种包含前述任一项权利要求所述的机械保护层的固体剂型。
22.根据权利要求21所述的固体剂型，其特征在于，其包含一个被所述机械保护层包覆的核心。
23.根据权利要求21或22所述的固体剂型，其特征在于，其包含一个改进释放层。
24.根据权利要求23所述的固体剂型，其特征在于，所述改进释放层是一个肠溶层。
25.根据权利要求21-24中任一项所述的固体剂型，其特征在于，所述剂型是一种颗粒或一种微丸。
26.一种根据权利要求21-25中任一项所述的药学可接受的固体剂型，其包含一种活性成分。
27.一种包含大量的权利要求25或26中所述的颗粒或微丸的片剂。
28.根据权利要求27所述的片剂，其特征在于，其包含大于80％w/w的颗粒或微丸。
29.根据权利要求28所述的片剂，其特征在于，其包含大于90％w/w的颗粒或微丸。
30.一种包含两种或更多种的增塑剂的机械保护层用于制备固体剂型的用途。
31.一种用于制备权利要求1-20中任一项所述的机械保护层的方法，其包括将所有成分分散在水中，然后用所述分散液包衣剂型。
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| CN116270514A (zh) * | 2023-03-22 | 2023-06-23 | 北京恒创星远医药科技有限公司 | 一种微丸片剂及其制备方法 |
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| EP2468263A1 (en) * | 2010-12-23 | 2012-06-27 | Laboratorios Del. Dr. Esteve, S.A. | Compressed solid dosage forms |
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| US10076494B2 (en) | 2016-06-16 | 2018-09-18 | Dexcel Pharma Technologies Ltd. | Stable orally disintegrating pharmaceutical compositions |
| JP7064683B2 (ja) * | 2017-01-27 | 2022-05-11 | 日本ケミファ株式会社 | 腸溶層破損防止用組成物 |
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| CN116270514A (zh) * | 2023-03-22 | 2023-06-23 | 北京恒创星远医药科技有限公司 | 一种微丸片剂及其制备方法 |
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| JP5442620B2 (ja) | 2014-03-12 |
| ES2507079T3 (es) | 2014-10-14 |
| CA2701556A1 (en) | 2009-04-09 |
| AU2008306846A1 (en) | 2009-04-09 |
| EP2207534B1 (en) | 2014-07-09 |
| CN101820866B (zh) | 2012-12-05 |
| KR20100091956A (ko) | 2010-08-19 |
| NZ584453A (en) | 2012-06-29 |
| RU2500389C2 (ru) | 2013-12-10 |
| MX2010003591A (es) | 2010-04-21 |
| IL204815A0 (en) | 2010-11-30 |
| HK1144180A1 (zh) | 2011-02-02 |
| RU2010117391A (ru) | 2011-11-10 |
| AU2008306846B2 (en) | 2013-09-05 |
| JP2010540596A (ja) | 2010-12-24 |
| ZA201002257B (en) | 2011-06-29 |
| BRPI0817863A2 (pt) | 2015-03-31 |
| EP2044932A1 (en) | 2009-04-08 |
| WO2009043929A1 (en) | 2009-04-09 |
| EP2207534A1 (en) | 2010-07-21 |
| US20100247641A1 (en) | 2010-09-30 |
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