CN111388443B - 一种纤维素空心胶囊及其胶囊剂 - Google Patents
一种纤维素空心胶囊及其胶囊剂 Download PDFInfo
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- CN111388443B CN111388443B CN202010407368.5A CN202010407368A CN111388443B CN 111388443 B CN111388443 B CN 111388443B CN 202010407368 A CN202010407368 A CN 202010407368A CN 111388443 B CN111388443 B CN 111388443B
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Abstract
本发明提供了一种纤维素空心胶囊。其特征在于至少含有一层基体层和外涂层，所述的外涂层设置于基体层的外侧。外涂层有效隔绝紫外线对色素的影响并具有一定强度，避免成品由于容易变色而使客户质疑成品品质，增加了胶囊的商品性。本发明，方法简单、容易实现，且效果突出。并且在纤维素空心胶囊中未使用金属离子，避免了金属离子对药物溶出度的影响。
Description
技术领域
本发明涉及材料领域，具体涉及一种纤维素空心胶囊。
背景技术
为适应治疗或预防，药物常需制备成不同的剂型，其中注射剂、片剂和胶囊剂占据了主要的市场随着全球药品行业的蓬勃发展，胶囊剂因其外观好、研发效率高和生产成本低等优点深受消费者的青睐。对于胶囊剂而言，患者使用方便，易于接受，不仅药物用量准确，同时增加了药物的稳定性，有时还可减少毒副作用，也便于药物的贮存、运输和携带，所以胶囊剂的比重正在不断上升，与之同时，胶囊剂的主要的药用辅料——药用空心胶囊也有着巨大的发展。2015年，国内胶囊总产能大约在2000亿左右；近几年，该市场扩张保持增长的趋势，目前我国每年空心胶囊的使用量达3000亿粒，人均使用量超过230粒/年。目前市场上胶囊剂大多以明胶为囊壳，来源于动物皮骨的明胶胶囊存在安全隐患。
而纤维素空心胶囊，主要是羟丙甲基纤维素(HPMC)空心胶囊，相比明胶空心胶囊有其独特的优势：性质惰性，不会影响胶囊的崩解和药物的溶出。水分含量低，不会因为水分的流失而导致胶囊易碎，更适合放置吸水性药物。纤维素空心胶囊不带电荷，静电吸附作用小，更有利于药品的封装。碎片率低，更适合干粉吸入剂。储存环境要求较低，可以在25～35℃、65～80％RH长期储存。安全性好。纤维素化学性质稳定，不与空气和水发生化学反应，且纤维素具有代谢惰性，在体内不被吸收，直接排出体外。不易生长微生物，所以正常条件下，长时间放置不会发生分解变质。
因此，纤维素胶囊可用于更广泛的药物产品和制剂。具体而言，纤维素胶囊能够包装吸湿、对水分敏感或与明胶化学不相容的内容物。此外，HPMC等改性纤维素由于是一种半合成聚合物，具有非动物来源性，因此更易于被素食主义者、宗教信仰者接受。羟丙甲纤维素空心胶囊解决了中药胶囊剂易发脆及交联固化等难题，被广泛适用于吸湿性强的中成药或保健食品的填充。目前，纤维素胶囊在英、美等发达国家已经比较成熟。
为了让人们从感官上更能接受药物(或保健品)，也为了能够区分多种胶囊剂，和保护对光敏感的药物，对空心胶囊进行着色。一般使用食用色素对胶囊进行着色。但是大多数食用色素，在光照和氧气的环境下，极其容易变色。而胶囊出现变色的现象会严重影响顾客的购买欲。
为此，需要一种可以在光照环境下不易变色，性质稳定的纤维素空心胶囊。
发明内容
为解决上述问题，本发明提供了一种纤维素空心胶囊，包括有一层基体层与一层外涂层，所述的外涂层含有30重量％以上的功能性化合物，所述的功能性化合物具有共轭双键。
其中，基材层是空心胶囊的主要组分，是胶囊的基本骨架，保证胶囊具有足够的力学强度、溶出度等使用性能。
基体层包含纤维素，所述的纤维素是指是由葡萄糖组成的大分子多糖。可以列举出：甲基纤维素、羟丙基甲基纤维素、羟甲基纤维素、羟丁基甲基纤维素、羟乙基纤维素，等。考虑到对药物的保护作用、作为药用辅料的安全性与成膜性能，优选的，所述的基体层包含羟丙甲基纤维素(HPMC)或其的衍生物中的一种或多种。所述的HPMC是纤维素在碱性条件下醚化而制得的白色或微黄色的粉状物或粒状物，其无味、无臭、对人体无危害，是一种非离子型纤维素混合醚。其结构主要包括β-1，4糖苷键组成的D-葡萄糖主链，且在2位、3位或6位进行甲基、羟丙基的修饰。经过醚化后的纤维素，分子内部的部分氢键被破坏，使其在水中更易溶解，所以应用范围较其它纤维素更广。羟丙甲基纤维素具有以下优点1、水溶性：在热水中分散溶胀，待温度降到50℃以下即可溶解。2、稳定性：对酸和碱都比较稳定，可在pH 3～11之间长期贮存，粘度无明显变化。HPMC水溶液具有抗霉作用，在长期储存过程中可保持较好的粘度稳定性。3、成膜性能好：它形成的膜具有无色、透明、坚韧的特点。4、抗酶性：可以减少发霉变质的可能。
基体层还可以包括胶凝剂，其用途是在胶囊制备过程中，使胶囊原料水溶液逐渐转变成均匀的半刚性固体凝胶、并保持原有形状，可以列举出乙酰化结冷胶、去乙酰化结冷胶、κ型卡拉胶、β型卡拉胶、ι型卡拉胶、琼脂、果胶、海藻酸钠、黄原胶、西黄芪胶、刺梧桐胶、刺槐豆胶、红藻胶、罗望子胶、他拉胶、菌核葡聚胶、微生物藻酸盐或卡波姆中的一种或多种。还可以包括促凝剂，其用途是提高胶囊原料水溶液逐渐转变成均匀的半刚性固体凝胶、并保持原有形状速率，可以列举出氯化钾、氯化钙、磷酸钾或柠檬酸钾中的一种或多种。
进一步的，基体层中含有色素。所述的色素是可食用色素，具体可以列举出苋菜红、胭脂红、赤藓红、新红、柠檬黄、日落黄、靛蓝、亮蓝、或钛白粉中的一种或多种。食用色素用于让人们从感官上更能接受药物(或保健品)，并区分多种胶囊剂，还可以保护对光敏感的药物。
为了使胶囊的药物溶出度更高、外观更透明、美观，进一步的，所述的基体层中含有85重量％以上的羟丙甲基纤维素。优选的，含有90重量％以上的羟丙甲基纤维素。如果，所述的基体层中羟丙甲基纤维素的含量小于85重量％，则胶囊的溶出度可能不足，使药效发挥变慢，或胶囊壳浑浊，不美观。
外涂层位于基材层的外侧，将基体层与外界环境隔离，具有保护基体层与基体层表面色素的作用。
所述的功能性化合物是具有共轭双键的化合物，具有抑制色素变色的能力。具体的，可以举例出：吡唑、乙妥因、头孢吡兰、头霉甲氧噻吩、头孢噻吩钠、头孢噻吩、共轭亚油酸、共轭亚麻酸、石榴酸、桐酸、蓝花楹酸、噻唑并吡啶羧酸等。
外涂层中具有功能性化合物，有助于提高空心胶囊抗变色的能力。
进一步的，所述的功能性化合物，在具有共轭双键的基础上，优选还具有氮杂环和/或硫杂环，以进一步提高空心胶囊抑制色素变色的能力。具体的，可以举例出：含有氮杂环的吡唑、乙妥因、头孢吡兰，含有硫杂环的头霉甲氧噻吩、头孢噻吩钠、头孢噻吩等。
进一步的，所述的功能性化合物，在具有共轭双键的基础上，优选还具有羧基，以进一步提高空心胶囊抑制色素变色的能力。具体的有共轭亚油酸、共轭亚麻酸、石榴酸、桐酸、蓝花楹酸等。
优选的，所述的功能性化合物是具有氮杂环和硫杂环的含共轭双键的羧酸，最优选噻唑并吡啶羧酸或其水合物或衍生物中的一种或多种。所述的噻唑并吡啶羧酸是具有如下结构(结构式1)的化合物。
所述的外涂层含有30重量％以上的功能性化合物，能够明显的抑制胶囊的变色。优选的，所述的外涂层含有50重量％以上的功能性化合物。
所述的外涂层中还含有1～10重量％的羧酸。发明人发现，羧酸与所述的功能性化合物具有协同效应，可以显著的提高空心胶囊抑制色素变色的能力。具体的，所述的羧酸包括丁酸、戊酸、己酸、辛酸、硬脂酸、油酸、苯甲酸、羟基丁酸、水杨酸、等一元酸，丁二酸、己二酸、癸二酸、酒石酸、1,2-苯二乙酸等二元酸，以及柠檬酸、均苯四甲酸、均苯三甲酸、偏苯三酸、丙三酸、环烷四酸等多元元酸。优选的，外涂层中含有柠檬酸、水杨酸、癸二酸，或这些物质的水合物或衍生物中的一种或多种。
所述的外涂层中，含有的羧酸含量过多或过少，都对提高空心胶囊抑制色素变色的能力有不良的影响。优选的，所述的外涂层中含有3～8重量％的羧酸。
进一步的，所述的外涂层中含有柠檬酸和癸二酸，且柠檬酸和癸二酸的含量比值为3～10。优选的，所述外涂层中柠檬酸和癸二酸的含量比值为5～8。发明人发现，柠檬酸和癸二酸的含量比值在此含量范围内时，最能提高空心胶囊抑制色素变色的能力。
进一步的，所述的外涂层含有20重量％以上的羟丙甲基纤维素。羟丙甲基纤维素有助于外涂层的成型。若所述的外涂层中羟丙甲基纤维素的含量太低，则不能有良好的成膜性，无法有效的形成所需涂层。优选的，所述的外涂层中，羟丙甲基纤维素的含量为30～50重量％。若所述的外涂层中羟丙甲基纤维素的含量太高，则上述的功能性化合物和羧酸的含量过低，不利于抑制胶囊变色。
进一步的，所述的基体层中含有85重量％以上的羟丙甲基纤维素，所述的外涂层含有30重量％以上的羟丙甲基纤维素。优选的，所述的基体层中含有90重量％以上的羟丙甲基纤维素，所述的外涂层含有50重量％以上的羟丙甲基纤维素。
进一步的，所述的基体层的厚度是20～200微米。如果基体层的厚度小于20微米，则胶囊不能有效保护药物并且容易破碎；如果基体层的厚度大于200微米，则药物溶出速度慢，胶囊崩解时限长，不能及时发挥药效。优选，所述的基体层的厚度是50～120微米。
进一步的，所述的外涂层的厚度为1～40微米。如果外涂层厚度小于1微米，则不能有效的抑制色素变色。如果外涂层厚度大于40微米则会使胶囊难溶解，药物溶出速度慢，胶囊崩解时限长，不能及时发挥药效。优选的，所述的外涂层的厚度为5～30微米。
进一步的，所述的基体层和外涂层的厚度比值是5～20。如果比值小于5，则外涂层太厚，胶囊的价格昂贵。如果比值大于20，则外涂层可能不能够起到抑制胶囊变色的效果。优选的，所述的基体层和外涂层的厚度比值是6～12。
本发明所述的纤维素空心胶囊，具有独特的设计，可以抑制胶囊在光照环境下变色，稳定性好，且制备方法简单，韧性好，脆碎度低，在运输储存过程中不易破碎，崩解时限和溶出度等物性都符合药典规定和使用需求。
本发明还提供一种胶囊剂，包含上述的纤维素空心胶囊，用于药物或保健品。
具体实施方式
下面通过实施例的方式进一步说明本发明，并不因此将本发明限制在所述实施例范围之中。凡基于本发明上述内容所实现的技术均属于本发明的范围。对于熟悉本领域的人员而言，可容易地实现另外的修改，因此在不背离权利要求及等同范围所限定的一般概念下，本发明并不限于特定的细节。
下述实施例和对比例中的所用的原料、试剂如下
【纤维素】
A：羟丙甲基纤维。韩国乐天化学公司产，AN6型，粘度为6mPa·s，甲氧基含量28％-30％；羟丙基7-12％。
【功能性化合物】
B1：噻唑并吡啶羧酸(TPA)。按以下方法制备：将1.5g半胱氨酸和2.4g柠檬酸溶于10g水中，使用磁力搅拌器100℃，5h，得到含TPA的水溶液。
B2：吡咯。AR级，购自江苏清泉化学股份有限公司。
B3：共轭亚麻酸。AR级，购自成都艾科达化学试剂有限公司
【羧酸】
C1：柠檬酸。AR级，购自北京伊诺凯科技有限公司。
C2：癸二酸。AR级，购自上海士峰生物有限公司。
C3：水杨酸。AR级，购自上海众何化学科技有限公司。
C4：辛酸。超纯级，购自青鸟捷士康生物科技有限公司。
【色素】
亮蓝色素。购自梯希爱(上海)化成工业发展有限公司。
本发明涉及的测试项目及其测定方法如下，如无特别说明，各测试都在25℃下进行。
色差ΔE：在一台紫外老化箱中，在320-400nm波长的2根15w的紫外灯下，距离30cm照射30天。通过色差仪测量未紫外照射和紫外照射了30天的样品的L，a，b值，使用以下公式计算△E：△E＝[(△L)2+(△a)2+(△b)2]1/2。
胶囊松紧度：按2015年版《中国药典》四部明胶空心胶囊松紧度测试方法测试。
胶囊脆碎度：按2015年版《中国药典》四部明胶空心胶囊脆碎度的测试方法进行测试。
胶囊溶出度：内容物为800mg硝酸钾，溶出介质为800mL 0.1moL/L HCl，采用转篮法，转速100r/min，温度37℃。在15min时取10ml溶出介质稀释5倍，在236nm下测试吸光度A；设置参比：取800mg硝酸钾溶于800mL 0.1moL/L盐酸，取10ml稀释5倍，在236nm下测试吸光度A0；溶出度＝A/A0。
含水量：将样品放置在烘箱中105℃，30min，得到样品的干燥重量m0；将样品放置在25℃、54％RH的密闭环境内，24h；取出样品，得到控制水量后的重量m1，含水量＝(m1-m0)/m0。
胶囊的厚度：将胶囊或胶囊基体层的体和帽剪开，使用测厚仪分别测试胶囊或胶囊基体层的体和帽的6个点，平均值即为胶囊或胶囊基体层的厚度。胶囊外涂层的厚度＝胶囊厚度-胶囊基体层厚度。
实施例1～27、对比例1～2
根据表1所示的配方，按如下方法制备0#(0号)纤维素空心胶囊。
步骤1：室温下将亮蓝色素(占步骤2中羟丙甲基纤维素的0.1wt％)用去离子水溶解成溶液；
步骤2：将步骤1的溶液加热至95℃后，加入羟丙甲基纤维素，配制成羟丙甲基纤维素浓度为25重量％的溶液；
步骤3：将步骤2的溶液继续加热2～4小时，得到25℃下粘度约200000mPa·s的基体层胶液；
步骤4：将步骤3的基体层胶液，用0#胶囊的体模具和帽模具分别进行蘸胶后，于40℃干燥一定时间，即分别得到体和帽的基体层。通过控制蘸胶量、挥发时间，按表1控制胶囊体和帽的基体层的厚度；
步骤5：将功能性化合物、羧酸用去离子水溶解成溶液。
步骤6：将步骤5的溶液加热至95℃后，加入适量的羟丙甲基纤维素，配制成浓度为15重量％的外涂层溶液；
步骤7：将步骤6的外涂层溶液胶液，分别用步骤4得到含有体或帽的基体层的模具进行蘸胶后，于40℃干燥一定时间，即分别得到体和帽。通过控制蘸胶量、挥发时间，胶囊体和帽的厚度都为100μm±5μm，含水量为8wt％±1wt％；
步骤8，再经脱模、切割、套合、检验和包装，即得到0#空心胶囊样品。
其中，对比例1不设置外涂层，仅通过步骤1～4、8进行制备。
将实施例和对比例的制备的各样品按照本发明提供的检测方法进行性能测定，测定结果如表2所示。
从表2可看到，各纤维素组合物制成的胶囊的松紧度和脆碎度符合中国药典(2015版)的标准。含功能性化合物的外涂层能有效抑制色素变色。外涂层中含有羧酸，抑制变色能力进一步提高。
上述实施例中记载的空心纤维素胶囊的组成和制备方法以及仅是一些示例，也可以使用其它的组成或方法制备本发明所述的空心纤维素胶囊。
表1
注：表中的含量都为重量百分含量。
表2实施例和对比例的性能
Claims (6)
1.一种纤维素空心胶囊，其特征在于，至少含有一层基体层和一层外涂层，所述的外涂层含有30重量％以上的功能性化合物，所述的功能性化合物是噻唑并吡啶羧酸或其水合物中的一种或多种。
2.根据权利要求1所述的纤维素空心胶囊，其特征在于，所述的基体层中含有85重量％以上的羟丙甲基纤维素，所述的外涂层含有20重量％以上的羟丙甲基纤维素。
3.根据权利要求1所述的纤维素空心胶囊，其特征在于，所述的外涂层中还含有1～10重量％的羧酸，所述的羧酸是柠檬酸、水杨酸、癸二酸，或这些物质的水合物中的一种或多种。
4.根据权利要求3所述的纤维素空心胶囊，其特征在于，所述的外涂层中含有柠檬酸和癸二酸，且柠檬酸和癸二酸的含量比值为3～10。
5.根据权利要求1所述的纤维素空心胶囊，其特征在于，所述的基体层的厚度为20～200微米，外涂层的厚度为1～40微米，且基体层和外涂层的厚度比值为5～20。
6.一种胶囊剂，包含权利要求1～5任一项所述的纤维素空心胶囊。
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