CN1025151C - 含酸不稳定化合物的口服药用制剂的制备方法 - Google Patents
含酸不稳定化合物的口服药用制剂的制备方法 Download PDFInfo
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Abstract
本文叙述了由芯子材料、一层或多层隔离层和肠溶衣层组成的药用制剂,它们的制备方法及在治疗胃肠疾病中的应用。其中芯子材料含有酸不稳定化合物与呈碱性反应的化合物,或含有酸不稳定化合物有选择的碱性盐与碱性化合物,隔离层含有在水中可溶解的或能迅速崩解的呈惰性反应的化合物,或水中可溶的能形成膜的聚合化合物,还可有选择地含有缓冲pH的碱性化合物。
Description
本发明是关于用于口服的含有酸不稳定物质的新的药用制剂,制备该制剂的方法,以及当应用该制剂时影响胃酸分泌并提供胃肠道细胞保护作用的方法。
当配制用于口服的药用剂型时,酸不稳定物质会给配方设计师带来一个问题。为了避免该物质在口服后与酸性胃液接触,解决该问题的一般方法是使该剂型包以肠溶衣。肠溶衣是一组物质/聚合物,它们的共同特点是它们实际上不溶于酸性介质而可溶于中性或碱性物质。对于在酸性介质中不稳定但是在中性和碱性介质中具有较好稳定性的物质,当制备和贮存时,加入呈碱性反应的无效成分以增加有效化合物的稳定性通常是有利的。
具有上述稳定性特点的一组化合物是具有通式(Ⅰ)的取代的苯并咪唑,或是化合物2-[(2-二甲氨基苄基)亚硫酰基]-苯并咪唑:
(Ⅰ)
式(Ⅰ)中A是有选择取代的杂环,R1、R2、R3和R4可以相同或不同,其定义见下面,R5是氢或低级烷基。
具有通式(Ⅰ)的化合物本身在生物学上实际是无活性的,但在酸性介质中可以降解/转变成某些酶系统的有效抑制剂。
具有上述性质的化合物的实例,可以提到的有专利US-A-4045563、
EP-Bl-0005129和BE-898880;专利申请EP-85850258、EP-Al-0080602、EP-0127736、EP-0134400、EP-0130729、EP-0150586、DE-3415971、GB-2082580和SE-A-8504048-3。最后的专利申请叙述了2-(2-二取代的-氨基苄基)亚硫酰基苯并咪唑,例如2-(2-二甲氨基苄基)亚硫酰基苯并咪唑(亦称为NC-13000),并由S、OKabe教授在1985年10月17日在日本名古屋召开的“药物作用研讨会”上介绍,于壁细胞内在酸降解后,该类化物可与HK-三磷酸腺苷酶相互作用[例如,可参见B.Wallmark,A.Brandstrom和H.Larsson”在壁细胞内酸引起的奥美普拉唑(omepr azole)转变成HK-三磷酸腺苷酶有效抑制剂的证明”,Biochemicaet Biophysica Acta 778,549-558,1984]。在专利US-4182766和专利申请GB-2141429,EP-0-146370及GB-2082580中还提到了具有相同性质的另外一些化合物。这些化合物的共同特点是在酸介质中,经过迅速地降解/转变,它们可以变化为生物学上有效的化合物。
具有上述通式(Ⅰ)的一些化合物的稳定性的实例列于下表1,其中给出在pH2和7的溶液中降解/转变的半存留期。
表1 具有下述结构式的化合物降解/转变的速率
化合 A R2R3转变为有效部分的半存留期(分钟)
物号 pH=2 pH=7
取代的亚砜(例如EP-Bl-0005129中所述的取代苯并咪唑类)是胃酸分泌的有效抑制剂。在呈酸性反应的介质和中性的介质中,取代的苯并咪唑类易于降解/转变。
需要在壁细胞内在酸性环境中活化其活化部分才能有效,这是上述化合物固有的特点。在壁细胞内,活化了的化合物与酶相互作用,在胃粘膜中壁细胞是生成盐酸的媒介。已知含有亚砜基、可与H+K+-三磷酸腺苷酶在壁细胞内相互作用的所有取代的苯并咪唑类化合物均在酸性介质中降解。
避免使酸不稳定物质与酸性胃液接触的药用剂型必须要包肠溶衣。但是普通的肠溶衣是由酸性化合物制备的。如果用这样普通的肠溶衣进行包衣,那么酸不稳定物质会由于直接或间接地与这样的酸性肠溶衣接触而迅速地分解,结果使制剂明显地变色,并且随时间的推移有效化合物的含量要减少。
为了提高贮存稳定性,含有酸不稳定物质的芯子还必须含有呈碱性反应的成分。如果该碱性芯子用适量的普通肠溶衣聚合物包衣,例如用乙酸邻苯二甲酸纤维素包衣,那么在该剂型进入小肠之前存在于胃中时就会使包衣溶解,并使芯子中所含的有效药物在邻近小肠的部位溶解,这将使水或胃液通过肠溶衣扩散进入芯子。扩散的水或胃液将会溶解紧贴近肠溶衣层的芯子,并且在包衣剂型的里面形成碱性溶液。该碱性溶液将会影响肠溶衣并且最终使肠溶衣溶解。
在DE-Al-3046559中叙述了使剂型包衣的方法。为了得到在结肠中才释放有效药物的剂型,首先用含微晶纤维素的水不溶层包衣,然后第二层包肠溶衣。在小肠中,该制备方法不能按所希望的方式释放出上述具有通式(Ⅰ)的化合物。
US-A-2540979叙述了口服的肠包衣剂型,其中肠溶衣与第二层和/或第一层不溶的“蜡”层合并。该制备方法不适用于含有式(Ⅰ)化合物
的芯子,因为像乙酸邻苯二甲酸纤维素(CAP)这样的物质与式(Ⅰ)化合物之间直接地接触会使式(Ⅰ)化合物降解和变色。
DE-B2-2336218叙述了由一种或多种普通的肠溶衣聚合物和一种或多种不溶性的纤维素衍生物组成的透析膜的制备方法。在胃液中,这样的膜不会给予酸不稳定的式(Ⅰ)化合物适当的保护。
DE-Al-1204363叙述了三层包衣的方法。第一层在胃液中可溶,但在肠液中不可溶。第二层是与pH无关的水可溶层,第三层是肠溶衣。该制剂以及在DE-Al-1617615中所述的制剂结果形成在胃液中不溶解并仅在肠液中慢慢溶解的剂型。如果要求药物在小肠中迅速地释放,那么该类制剂不能用于式(Ⅰ)化合物。为了使药物在回肠中释放,DE-Al1204363叙述了三层包衣,但该目的不属于本发明的范围。GB-A-1485676叙述了得到在小肠中发气泡的制剂的方法。该制剂可由含有效药物和起泡成分组成系统(如碳酸盐和/或碳酸氢盐及药用合格的酸的组合物)的芯子包肠溶衣而得到。该配方不适用于含式(Ⅰ)化合物的药用剂型,因为在芯子中式(Ⅰ)化合物与存在的酸接触结果会导致式(Ⅰ)化合物降解。
WO85/03436叙述了一种药用制剂,其中芯子含有效药物与缓冲剂成分(例如磷酸二氢钠)的混合物,以便保持恒定的pH和恒定的扩散速率,该芯子用能控制扩散的第一包衣层包衣。如果要求有效药物在小肠内迅速地释放,那么该配方不能适用于酸不稳定的化合物。在芯子上直接应用肠溶衣也会有害地影响上述含酸不稳定化合物的剂型的贮存稳定性。
按照本发明,已经发现已知的酸不稳定化合物[式(Ⅰ)]可以配制成肠溶衣剂型,通式(Ⅰ)中,R1、R2、R3和R4可以相同或不同,并且可以是
(a)氢
(b)卤素,例如F、Cl、Br、I
(c)-CN
(d)-CHO
(e)CF3
(g)-O-C-R12
(h)-CH(OR13)2
(i)-(Z)n-B-D
(j)含直到10个碳原子的芳基
(k)含直到10个碳原子的芳氧基,该芳氧基可由含1-6个碳原子的烷基有选择地取代。
(l)含1-6个碳原子的烷硫基
(m)-NO2
(n)含1-6个碳原子的烷基亚硫酰基
(o)或者其中相邻的基团R1、R2、R3和R4与苯并咪唑环中相邻的碳原子一起共同形成五、六或七元单环,或九、十、十一元的双环,这些环可以是饱和的或不饱和的,并且可以含0-3个选自-N-和-O-的杂原子,并且可以用1-4个取代基有选择地取代,这些取代基可以选自带有1-3个碳原子的烷基,含4-5个碳原子的亚烷基,结果形成了螺环化合物,或者2个或4个上述取代基一起共同形成一个或2个氧代基(
),因此,如果R1和R2,R2和R3或R3和R4与苯并咪唑环中相邻的碳原子共同形成2个环,那么它们可以相互稠合,在该式中R11和R12(可以相同或不同)为:
(a)含直到10个碳原子的芳基
(b)含1-4个碳原子的烷氧基
(c)在各烷氧基部分含1-3个碳原子的烷氧基烷氧基
(d)在烷氧基部分含1-2个碳原子、并且在芳基部分含直到10个碳原子的芳基烷氧基
(e)含直到10个碳原子的芳氧基
(f)在烷基部分含1-3个碳原子的二烷基氨基,或者
(g)用含1-3个碳原子的烷基有选择取代的吡咯烷子基(pyrroli-dino)或者哌啶子基;
R13是
(a)含1-4个碳原子的烷基,或
(b)含2-3个碳原子的亚烷基;
n是零或1;
B是
(a)含1-6个碳原子的亚烷基
(b)含3-6个碳原子的环亚烷基
(c)含2-6个碳原子的亚链烯基
(d)含3-6个碳原子的环亚烷基,或
(e)含2-6个碳原子的亚炔基;
D是
(a)H
(b)-CN
其中R9是
(a)含1-5个碳原子的烷氧基,或
(b)在烷基部分含1-3个碳原子的二烷基氨基;
m是零或1;
r是零或1;
Y是
(a)-O-
(b)-NH-
(c)-NR10-;
R10是
(a)H
(b)含1-3个碳原子的烷基
(c)在烷基部分含1-2个碳原子并且在芳基部分含直到10个碳原子的芳基烷基
(d)含直到10个碳原子的芳基;
A主要是吡啶基其中R6和R8可以相同或不同,它们是
(a)H或
(b)含1-6个碳原子的烷基;
R7是
(a)H
(b)含1-8个碳原子的烷基
(c)含1-8个碳原子的烷氧基
(d)含2-5个碳原子的链烯氧基
(e)含2-5个碳原子的炔氧基
(f)在各烷氧基中含1-2个碳原子的烷氧基烷氧基
(g)含直到10个碳原子的芳基
(h)在烷基部分含1-6个碳原子并且在芳基部分含直到10个碳原子的芳基烷基
(i)含直到10个碳原子的芳氧基,该芳氧基可以由含1-6个碳原子的烷基有选择地取代
(j)在烷氧基部分含1-6个碳原子并且在芳基部分含直到10个碳原子的芳基烷氧基
(h)二烷基氨基烷氧基,其中在氨基氮上有含1-2个碳原子的烷基取代基并且在烷氧基中含1-4碳原子
(l)含1个氧原子和3-7个碳原子的氧杂环烷基
(m)含2个氧原子和4-7个碳原子的氧杂环烷氧基
(n)含1个氧原子和4-7个碳原子的氧杂环烷基烷基
(o)含2个氧原子和4-6个碳原子的氧杂环烷基烷氧基,或
(p)R6和R7,或R7和R8与在吡啶环中相邻的碳原子一起共同形成环,其中由R6和R7,或R7和R8构成的部分是
-CH=CH-CH=CH-
-O-(CH2)p-
-S-(CH2)v-
-CH2(CH2)p-
-O-CH=CH-
-NH-CH=CH-
其中p是2、3或4,v是2或3,氧和氮原子总是连接在吡啶环的4位;
条件是R6、R7和R8中至多1个是氢。
本发明的目的在于研究定义如上的具有通式(Ⅰ)的酸不稳定化合物[除奥美普拉唑(Omeprazole)之外]的肠溶衣剂型,化合物奥美普拉唑的化学名为5-甲氧基-2-[[(4-甲氧基-3,5-二甲基-2-吡啶基)甲基]亚硫酰基]-1H-苯并咪唑。按照本发明,另一个可以是肠溶衣的化合物为2-(2-二甲基氨基苄基)亚硫酰基苯并咪唑。新的制剂在酸性介质中抗溶解,在中性-碱性介质中可迅速地溶解,并且在长期贮存中具有良好的稳定性。新剂型的特征叙述如下。将含有酸不稳定的化合物与碱性化合物的混合物,或酸不稳定化合物有选择的碱性盐与碱性化合物的混合物的芯子包二层或二层以上,第一层在水中可溶,或在水可迅速地崩解,并且第一层由非酸性的,可供药用的惰性物质所组成。第一层(隔离层)将碱性芯子材料与外层(即肠溶衣)隔开。以适当的方法处理最后的肠包衣剂型,使水份含量降低到很低的水平,以便得到在长期贮存中具有良好的稳定性的剂型。
特别适用于本发明药用剂型的化合物的实例列于表1。
在pH小于4的水溶液中,表1中化合物1-6降解的半存留期在大多数情况下不到10分钟。在中性pH值,降解反应也进行得较快,例如在pH=7,降解的半存留期为10分钟至65小时。而在较高的pH值,溶液中大多数化合物有较好的稳定性。在固体状态稳定性是相同的。降解可由呈酸性反应的物质催化。酸不稳定的化合物在与呈碱性反应的物质的混合物中是稳定的。
从上述关于酸不稳定化合物的稳定性特点中可以看出,上述化合物的口服剂型必须要保护,使其免于与呈酸性反应的胃液接触,以便到达小肠而未降解。
芯子
酸不稳定的有效化合物与惰性的、最好为水可溶的普通药用成分相混合,以便在最终混合物中得到合适浓度的有效化合物,并且与呈碱性反应的或惰性的药学上可以接受的一些物质混合,当水被混合物的颗粒吸收时或水小量地被加到混合物中时,结果在有效化合物各个颗粒的周围形成了pH大于7,最好不小于8的“微观pH”(“micro-pH”)。这样的物质可从下述物质中进行选择;但并不限于下述物质,例如磷酸、碳酸、柠檬酸或其他合适的弱的无机酸或有机酸的钠、钾、钙、镁和铝盐;通常用于抗酸制剂的物质,例如氢氧化铝、氢氧化钙和氢氧化镁;氧化镁或复合物,例如Al2O3·6MgO·CO2.12H2O、(Mg6Al2(OH)16CO3.4H2O)、MgO.Al2O3.2SiO2.nH2O,其中n不是整数并小于2,或为类似化合物;有机的pH-缓冲物质,例如三羟甲基氨基甲烷或其他类似的药用合格的pH缓冲物质。通过应用有效化合物呈碱性反应的盐,例如酸不稳定化合物的钠、钾、镁、钙盐等,或者单独应用,或者与上述普通的缓冲物质合并使用,也可以获得粉状混合物稳定的高pH值。
然后,用一般的制剂方法将粉状混合物配制成小碎粒,即配制成丸剂或片剂。丸剂、片剂或明胶胶囊可被用作为下步过程的芯子。
隔离层
含有酸不稳定化合物的呈碱性反应的芯子必须与含游离羧基的肠溶衣聚合物隔离,否则在包衣过程中或在贮存中,会引起酸不稳定化合物的降解/变色。底衣层(隔离层)也可用作pH缓冲层,其中由外层向碱性芯子扩散的氢离子可以和从碱性芯子向包衣物表面扩散的羟基反应。选用通常用于抗酸配方中的一组化合物引入隔离层,该隔离层缓冲pH的作用可以进一步地增强,抗酸配方中的化合物有例如氧化镁,氢氧化镁或碳酸镁,氢氧化物铝或氢氧化钙,碳酸铝或碳酸钙,硅酸铝或硅酸钙;复合的铝/镁化合物,例如Al2O3.6MgO·CO2.12H2O,(Mg6Al2(OH)16CO3.4H2O),MgO.Al2O3.2SiO2.nH2O,其中n不是整数并小于2,或为类似化合
物;或者为其他药用合格的pH-缓冲物质,例如磷酸、柠檬酸或其他合适的弱无机酸或有机酸的钠、钾、钙、镁和铝盐。
隔离层由1个或多个水可溶的惰性层组成,该层选择性地含pH缓冲物质。
用普通包衣的方法,在合适的包衣锅或在流化床装置中,应用水和/或一般的有机溶剂作为包衣溶液,可以将隔离层包到芯子(丸剂或片剂)上。用作隔离层的材料系选自药用合格的水可溶的惰性化合物或用作包衣膜的聚合物,例如糖、聚乙二醇、聚乙烯吡咯烷酮、聚乙烯醇、羟丙基纤维素、羟甲基纤维素、羟丙基甲基纤维素等。隔离层的厚度不少于2微米,对于小的圆丸剂,最好不少于4微米;对于片剂,最好不少于10微米。
对于片剂,应用于包衣的另一个方法是干包衣技术。首先,含酸不稳定化合物的片剂按上述方法压制。应用合适的制片机,围绕上述片剂压制另一层。外层(隔离层)是由在水中可溶或在水中可迅速崩解的药用合格的片剂赋形剂所组成。隔离层的厚度不少于1毫米。普通的增塑剂、色素、二氧化钛、滑石和其他添加剂也可包含在隔离层中。
对于明胶胶囊,其本身可用作隔离剂。
肠溶衣层
用一般的包衣技术,例如锅包衣或流化床包衣,应用聚合物在水和/或合适有机溶剂中的溶液或应用该聚合物的胶乳混悬液,可以将肠溶衣层包到底包衣的芯子上。可以应用的肠溶衣聚合物有例如邻苯二甲酸乙酸纤维素、邻苯二甲酸羟丙基甲基纤维素、聚邻苯二甲酸乙酸乙烯酯、共聚的甲基丙烯酸/甲基丙烯酸甲酯[如商品名为EudragitRL 12,5或EudragitR100,(Rǒhm pharma)的已知化合物],或可用于得到肠溶衣的类似化合物。
水基聚合物分散剂,例如Aquateric(FMC公司)、EudragitRL100
-55(Rǒhm pharma)、包衣CE5142(BASF)也可以用作肠溶衣。肠溶衣层可以有选择地含有药用合格增塑剂,例如鲸蜡醇、甘油三乙酸酯、柠檬酸酯类[如商品名为CitroflexR(Rfizer)的柠檬酸三邻苯二甲酸酯、琥珀酸二丁酯或类似的增塑剂。
对于各个肠溶衣聚合物,通常要选定增塑剂用量的最佳数值,一般为肠溶衣聚合物的1-20%。分散剂(如滑石)、着色剂和色素也可以包含在肠溶衣层中。
本发明具体的制剂包括由酸不稳定的化合物与呈碱性反应的化合物相混合而得到的芯子,或者包括由酸不稳定化合物有选择的碱性盐与呈碱性反应的化合物相混合而得到的芯子。混悬于水中的芯子形成溶液或混悬液,混悬液的pH值高于其中用作肠溶衣的可溶性聚合物形成的溶液。芯子用水可溶的或在水中能迅速崩解的包衣材料包衣,该包衣材料有选择地含有pH缓冲物质,这样可使碱性芯子与肠溶衣隔开。如果没有该隔离层,那么抵抗胃液作用的时间会太短,因此该剂型的贮存稳定性将会是不能令人满意的短。底衣层剂型最后包肠溶衣,以使该剂型除了在中性-碱性介质(例如在小肠邻近部位的液体)中能迅速地崩解/溶解之外,该剂型不溶于酸性介质,小肠的邻近部位才是应该溶解的位置。
最后的剂型
最后的剂型或者是肠溶衣的片剂或胶囊剂,或者就肠溶衣的丸剂来说,可以将其分配在硬明胶囊或小药囊中,或者将丸剂配制成片剂。对于长期贮存的稳定性,含酸不稳定化合物的最后剂型(肠溶衣片剂、胶囊剂或丸剂)的水份含量要低,这是最重要的,水份最好不超过1.5%(重量)。
方法
制备口服剂型的方法是本发明的另一方面内容。在制得芯子之后,芯子首先包隔离层,然后包肠溶衣层。包衣按上述方法进行。
本发明的制剂在减少胃酸分泌和/或提供胃肠细胞保护作用方面特别的有利。通常一天服用本发明制剂1-数次。每天服用的有效物质的常用剂量可以改变,并可根据各种因素(如各个患者的需要,服用的方式和疾病的情况)变化。一般来说,剂量范围1-400毫克/天有效物质。应用新的口服剂型治疗上述疾病的方法是本发明又一方面内容。
以下述实例详细叙述本发明:
实例
实例1-3举例说明本发明。
实例1
未包衣的丸剂
将干燥的成分(Ⅰ)在混合器中予混合。加入混悬有效化合物的制颗粒液体(Ⅱ),并将块团用湿法混合均匀。湿的团块通过挤压机压制,并且制成小丸剂。使丸剂干燥,并分选合适大小的颗粒。
包底衣的丸剂
在流化床装置内,将聚合物溶液(Ⅲ)喷到未包衣的丸剂上。喷雾器放置在流化床的上方。
包有肠溶衣的丸剂
在流化床装置内,用置于流化床上方的喷雾器将聚合物溶液(Ⅳ)喷到包底衣的丸剂上。在干燥至水含量为0.5%之后,将包有肠溶衣的丸剂分类,并装入硬明胶胶囊,装的量为284毫克,相当于25毫克有效化合物1,将30粒胶囊与干燥剂一起装入容器内密闭。
实例2
用表1中化合物2的钠盐进行配制
未包衣的丸剂
按实例1所述方法配制,但用化合物2的钠盐与混合物Ⅰ中的其他
成分加在一起。
包底衣的丸剂
未包衣的丸剂 500克
Ⅲ
用Ⅲ包底衣的丸剂 500克
按以前所述,在流化床装置中以连续的顺序将底包衣层Ⅲ和Ⅳ应用于未包衣的丸剂。
包有肠溶衣的丸剂
底包衣的丸剂 500克
Ⅴ
按实例1所述方法配制肠溶衣丸剂。
实例3
用表1化合物6进行配制。本实例给出本发明的1单位剂量的成分。
片芯
化合物6(表1) 15毫克
乳糖 119毫克
羟丙基纤维素(低级取代) 5毫克
羟丙基纤维素 1毫克
滑石 5毫克
Mg(OH)215毫克
总量 160毫克
首先用已知的技术制备具有上述成分并且每片重为160毫克的片芯。
隔离层(内层)
羟丙基纤维素 2毫克
含水滑块石 0.3毫克
[Al2O3.6MgO.CO2.12H2O]
隔离层(外层)
羟丙基纤维素 2毫克
用已知的包衣技术,将两个隔离层包到片芯上。
肠溶衣层
邻苯二甲酸羟丙基甲基纤维素 7毫克
鲸蜡醇 0.5毫克
用已知的肠包衣技术,将肠溶衣溶液喷雾到包了两层隔离层的片芯上。
Claims (7)
1、酸不稳定的式(Ⅰ)的化合物(化学名为5-甲氧基-2-[[(4-甲氧基-3,5-二甲基-2-吡啶基)甲基]亚硫酰基]-1H-苯并咪唑的奥美普拉唑除外)或2-[(2-二甲基氨基苄基)亚硫酰基]-苯并咪唑作为有效成分的口服药用制剂的制备方法,式(Ⅰ)为
a)制备芯子材料,包括将上述式(Ⅰ)的酸不稳定化合物与一种或多种呈碱性反应的化合物混合制成片或小球,或可将式(Ⅰ)的酸不稳定化合物有选择的呈碱性反应的盐与呈碱性反应的化合物混合制成片或小球;所说呈碱性反应的化合物是选自氧化镁,氢氧化镁或碳酸镁,氢氧化铝,碳酸,磷酸或柠檬酸的铝、钙、钠或钾盐,复合的铝/镁化合物Al2O3·6MgO·CO2·12H2O或MgO·Al2O3·2SiO2·nH2O,其中n不是整数,并且小于2;
b)将芯子材料包上一层或多层惰性隔离层,该隔离层含有在水中可溶的或能迅速崩解的片剂赋形剂或水可溶的能形成膜的聚合化合物,在呈碱性反应的芯子和外层肠溶衣之间的隔离层,还可以有选择地含有缓冲pH的碱性化合物;所说隔离层选自氧化镁、氢氧化镁或复合物Al2O3·6MgO·CO2·12H2O或MgO·Al2O3·2SiO2·nH2O中一种或一种以上的物质,其中n不是整数,并且小于2,或选自羟丙基甲基纤维素、羟丙基纤维素或聚乙烯吡咯烷酮;
c)将包有隔离层的芯子用不溶于酸的肠溶衣包衣,肠溶衣中可有选择地含有增塑剂。
2、按照权利要求1的方法,其中隔离层包括二层或多层的隔离层。
3、按照权利要求1的方法,其中碱性芯子包括酸不稳定化合物和使酸不稳定化合物微小环境的pH大于7,最好不小于8的缓冲pH的碱性化合物。
4、按照权利要求1的方法,其中碱性芯子包括的酸不稳定化合物的碱性盐是其钠,钾,镁或钙盐。
5、按照权利要求1的方法,其中碱性芯子包括酸不稳定化合物的碱性盐与惰性碱性化合物的混合物。
6、按照权利要求1的方法,其中肠溶衣包括邻苯二甲酸羟丙基甲基纤维素、邻苯二甲酸乙酸纤维素、共聚的甲基丙烯酸/甲基丙烯酸甲酯或聚邻苯二甲酸乙酸乙烯酯,并可有选择地含有增塑剂。
7、按照权利要求1的方法,其中还包括将制得的含有酸不稳定化合物的最后剂型干燥至水份含量不超过1.5%(重量)。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1321642C (zh) * | 2003-12-12 | 2007-06-20 | 南京长澳医药科技有限公司 | 泮托拉唑钠肠溶微丸 |
CN101991543A (zh) * | 2009-08-10 | 2011-03-30 | 杭州赛利药物研究所有限公司 | 一种奥美拉唑肠溶干混悬剂及其制备方法 |
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