CN108619523A - 一种可用于快速热塑包衣制剂的包衣膜片及其制备方法 - Google Patents
一种可用于快速热塑包衣制剂的包衣膜片及其制备方法 Download PDFInfo
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Abstract
本发明涉及一种可用于快速热塑包衣制剂的包衣膜片及其制备方法，包衣膜片厚度0.01mm‑1mm，由药用聚合物和增塑剂组成。其制备方法包括：1)将包衣膜片置于制剂内芯表面，加热使其软化；2)施加机械压、空气压或离心力使其变形，直至包衣膜片完全粘附和熔融于固体制剂表面，冷却切割，必要时翻面包衣或继续包衣。本发明提供的包衣膜片及其制备方法，膜层均匀，衣膜一次成型，不需要层层包衣或逐步包衣，衣膜更均匀质量更可控，整个包衣过程一步完成，简单快速，包衣过程无需任何溶剂，耗能少，无污染。
Description
技术领域
本发明涉及一种包衣膜片及其制备方法，特别是涉及一种可用于快速热塑包衣制剂的包衣膜片及其制备方法。
背景技术
对固体制剂包衣可以实现缓释、肠溶、掩味和防潮等功能。目前工业上通常采用溶剂包衣，包括水性包衣和有机溶剂包衣两类。溶剂的添加，会导致敏感性药物不稳定性；溶剂的挥发过程耗时耗能；且有机溶剂的使用有安全隐患并导致污染。对固体制剂进行干粉包衣或热塑包衣，可解决溶剂包衣带来的药物稳定性问题和有机溶剂污染问题，而且具有设备简单、操作简便、节省环保、一体化和工业化程度高等优点。
现有非溶剂包衣主要包括粉末压制包衣和粉末层层包衣两类。粉末压制包衣是将粉末直接压在内芯外，设备类似压片机。外层粉末颗粒没经塑化融熔，粉末间孔隙大，需要较大包衣增重。粉末层层包衣是在静电力及液体粘附力的作用下，将粉末包覆在内芯外，经加热老化成膜。要求粉末具有极细粒径，液体增塑剂用量较大；且需要层层包衣，逐步才能达到合适的包衣增重。
本发明提供了可用于快速热塑包衣制剂的包衣膜片和制备方法，可以很好的解决上述问题。将预先制备的包衣膜片加热软化，选择机械压、空气压和离心力等使包衣膜片变形粘附于制剂内芯表面，融合冷却，得到包衣制剂。通过选择不同材料、密度和厚度的包衣膜片可以直接得到不同的包衣制剂，实现多种包衣效果。基于包衣膜片的机械性质和包衣制剂的体外释放等指标，进一步研究发现包衣膜片和制备工艺对最终包衣制剂有影响，所以优选了包衣膜片和制备工艺，以充分保证制剂包衣的完整性和功能性。本发明的优点在于：制剂包衣一次成型，不需要层层包衣或逐步包衣，制剂包衣更均匀质量更可控。整个包衣过程一步完成，简单快速；包衣过程无需任何溶剂，耗能少，无污染。
发明内容
为解决现有制药技术中水性包衣和有机溶剂包衣包覆固体制剂时，会导致敏感性药物不稳定，溶剂的挥发过程耗时耗能，且有机溶剂的使用有安全隐患并导致污染等问题。
本发明提供了一种一次成型，不需要层层包衣或逐步包衣，包衣过程无需任何溶剂，耗能少，无污染，制剂包衣更均匀、质量更可控的用于快速热塑包衣制剂的包衣膜片及其制备方法。
本发明解决技术问题所采用的技术方案为：
一种可用于快速热塑包衣制剂的包衣膜片，其特征在于：所述包衣膜片厚度0.01mm-1mm，由药用聚合物和增塑剂组成，所述药用聚合物包括缓释聚合物、肠溶聚合物、胃溶聚合物、防潮聚合物中的任意一种或几种；
所述增塑剂为柠檬酸三乙酯、聚乙二醇400、三乙酸甘油酯和癸二酸二丁酯中的任意一种或几种的混合。
作为优选，所述缓释聚合物为尤特奇RS PO(丙烯酸乙酯∶甲基丙烯酸甲酯∶甲基丙烯酸氯化三甲胺基乙酯＝1∶2∶0.1)、尤特奇RL PO(丙烯酸乙酯∶甲基丙烯酸甲酯∶甲基丙烯酸氯化三甲胺基乙酯＝1∶2∶0.2)中的一种或两者的混合物。
作为优选，所述尤特奇RS PO和尤特奇RL PO的混合质量比为1∶1-10∶1。
作为优选，所述肠溶聚合物为尤特奇L100-55(甲基丙烯酸∶丙烯酸乙酯＝1∶1)、Kollicoat MAE 100P(甲基丙烯酸∶丙烯酸乙酯＝1∶1)中的一种或两者的混合物。
作为优选，所述胃溶聚合物材料为尤特奇EPO(甲基丙烯酸丁酯∶甲基丙烯酸二甲胺基乙酯∶甲基丙烯酸甲酯＝1∶2∶1)。
作为优选，所述防潮聚合物为Kollicoat Protect(聚乙烯醇-聚乙二醇接枝共聚物)。
作为优选，所述增塑剂的用量为聚合物材料质量的5-30％。所述包衣膜片可由混合热压法或干粉包衣法等无溶剂制膜工艺制备，也可采用常规铺膜法、浸渍法等溶剂制膜工艺制备。
作为优选，所述混合热压法制备包衣膜片包括以下步骤：
1)聚合物和增塑剂物理混合，填充于热熔挤出机，在温度80-160℃，转速60-100rpm的条件下，混合10-20min后挤出；
2)将挤出条置于热压机，在温度60-120℃条件下，热压3-10min，得到厚度均匀的包衣膜片。
作为优选，所述干粉包衣法制备包衣膜片包括以下步骤：
1)液体喷枪将增塑剂喷于金属板表面，静电喷枪将聚合物喷于金属板表面，重复上述两个步骤直至得到一定厚度的衣膜；
2)将衣膜在温度60-100℃的条件下，固化30-150min，得到厚度均匀的包衣膜片。
作为优选，所述溶剂制膜工艺包括以下步骤：将聚合物材料及增塑剂溶解在良溶剂中，将包衣液平铺于平板上，挥干溶剂得到包衣膜片或将平板浸渍于包衣液中，挥干溶剂得到包衣膜片。
一种可用于快速热塑包衣制剂的制备方法，其特征在于，
1)将包衣膜片置于片剂、胶囊剂和丸剂等制剂内芯表面，加热使其软化：
2)施加机械压、空气压或离心力使其变形，直至包衣膜片完全粘附于内芯且接口处熔合，冷却切割，必要时翻面包衣或继续包衣。
作为优选，所述加热温度为100-150℃，时间为1-30min。
作为优选，所述机械压的大小为0.01-0.2MPa，施加时间为10-300s。
作为优选，所述空气压可采用膜片内减压或膜片外加压。膜内外压差的大小为0.01-0.2MPa，施加时间为10-300s。
作为优选，所述离心力的大小为30-1000(×g)，施加时间为10-300s。
本发明的有益效果是：
本发明提供了一种可用于快速热塑包衣制剂的包衣膜片和制备方法。制剂包衣一次成型，不需要层层包衣或逐步包衣，制剂包衣更均匀质量更可控；整个包衣过程一步完成，简单快速，包衣过程无需任何溶剂，耗能少，无污染。
附图说明
图1为可用于快速热塑包衣制剂的典型包衣膜片和制备方法；
a)肠溶包衣膜片在机械压作用下制备包衣片；
b)缓释包衣膜片在真空压作用下制备包衣胶囊；
c)防潮包衣膜片在离心力作用下制备包衣丸
图2为增塑剂用量对包衣膜片强度极限和断裂伸长率的影响；
图3为不同热压温度对包衣膜片厚度的影响；
图4为不同聚合物的包衣片2h累积释放率。
具体实施方式
下面通过具体实施例，并结合附图，对本发明的技术方案作进一步的具体说明。
实施例1：
1)以Kollicoat MAE 100P为聚合物，以15％的DBS为增塑剂，以乙醇/水溶剂为混合溶剂，配制包衣溶液；
2)采用平铺法，在金属平板上制备肠溶包衣膜片，挥尽溶剂，得到厚约0.1mm的包衣膜片。
将肠溶包衣膜片置于片芯两侧(如图1a)。通100℃热空气5min使膜软化；金属阴模分别从两侧施加0.1MPa机械压，使膜变形包覆于片芯表面；保持30s，保证包衣膜片完全粘附于内芯且接口处完全熔融。切割除去多余包衣膜片，停止通热风，即得肠溶包衣片。经外观观察，片芯外包衣完整均匀；经2h耐酸实验检测，包衣片剂具有良好的2h耐酸效果。
实施例2：
1)以尤特奇RS PO∶尤特奇RL PO＝1∶1为聚合物，以TEC为增塑剂，采用干粉包衣法制备缓释包衣膜片；
2)液体喷枪将TEC喷于金属板表面，静电喷枪将聚合物喷于金属板表面，控制两者用量比为3∶10；
3)重复上述两个步骤4次，将衣膜在70℃条件下固化60min，得到厚约0.3mm的包衣膜片。
将缓释包衣膜片置于胶囊芯两侧(如图1b)。红外线加热(60℃，10min)，使膜软化；快速抽真空(膜内外气压差约1个大气压＝0.1MPa)，使膜变形包覆于胶囊芯表面。保持膜内外气压差200s，保证包衣膜片完全粘附于内芯，且接口处完全熔融。切割除去多余包衣膜片，停止红外线，即得缓释包衣胶囊。经外观观察，胶囊芯外包衣完整均匀；经体外释放实验，包衣胶囊具有24h缓释效果。
实施例3：
1)以Kollicoat Protect为聚合物，以TEC为增塑剂，采用混合热压法制备防潮包衣膜片；
2)聚合物和增塑剂物理混合，填充于热熔挤出机，在120℃，以60rpm，混合15min，挤出直径为2.0mm的长条；
将挤出条置于热压机，在100℃条件下，热压10min，得到厚约0.5mm的包衣膜片。
将防潮包衣膜片置于丸芯一侧(如图1c)。红外线加热(80℃，10min)，使膜软化；高速旋转产生约800(×g)的离心力，使膜变形完全包覆于丸芯的一侧。离心60s，保证包衣膜片完全粘附于内芯，切割除去多余包衣膜片。停止红外线，得到半边包衣的丸剂。改变包衣方向，重复包衣过程，使膜完全包覆于丸芯的另一侧，且接口处完全熔融，得到完整包衣的防潮包衣丸剂。经外观观察，丸芯外包衣完整均匀；经吸湿实验，包衣丸剂具有良好的防潮效果。离心力由式1计算所得：
RCF＝1.118×10-5N2r 式1
(式中RCF表示相对离心力，单位为×g，表示为重力加速度的倍数；N表示转速，单位为rpm；r表示离心半径，单位为cm。)
对比研究1：以尤特奇RS/RL为例，用干粉包衣法做包衣薄片，研究增塑剂用量对膜片强度极限和断裂伸长率的影响
将400g尤特奇RS和40g尤特奇RL混合均匀，制成包衣混合粉末。先用液体喷枪喷TEC(0.05g/min，气压5psi)，紧接着静电枪喷包衣混合粉末(0.2g/min，电压60KV，气压15psi)。重复上述步骤直至聚合物薄膜到达一定厚度。置于60℃烘箱中固化2h。
将制得的聚合物薄膜切成长50.0mm，宽10.0mm的矩形，采用拉伸法测测膜的机械性质。膜的初始宽度为W0和初始厚度为T0；初始长度为L0和断裂伸长为ΔL；断裂力为Fmax。强度极限(σb)和断裂伸长率(εb)由式2-3计算：
εb(％)＝ΔL/L0×100％ 式3
由图2可知：增塑剂用量对包衣膜片的强度极限和断裂伸长率影响很大。在上述处方工艺条件下，增塑剂的用量需要达到15％以上，所得包衣膜片才有良好的断裂伸长率，从而保障快速热塑包衣制剂的包衣均匀性和完整性。
对比研究2：以尤特奇RS/RL为例，用混合热压法制备包衣膜片。研究热压温度对包衣膜片厚度的影响
将400g尤特奇RS和40g尤特奇RL混合均匀，再加入88g TEC混合，于100℃热熔挤出。将挤出条分别在40、50、60、70和80℃条件下热压5min，得到包衣膜片。
由图3可知：热压温度对包衣膜片厚度有明显影响。在上述处方条件下，优选的热压温度为70℃。
对比研究3：以溶剂法制备不同聚合物的包衣膜片，研究聚合物种类对包衣完整性的影响
分别将60g TEC和PEG 400溶于2000mL无水乙醇中，分别加入300g Kollicoat MAE100P、尤特奇RL和尤特奇EPO，置于50℃水浴中溶解2h。即得包衣液。将包衣液平铺于特氟龙金属板，室温完全干燥，得到不同聚合物的包衣膜片。
称取200g酒石酸美托洛尔、300g微晶纤维素、480g乳糖和20g硬脂酸镁，混合均匀，用7mm浅弧模冲压片制备片芯(约50mg主药/片)。采用实施例1中的方法，对片芯进行包衣，得到包衣片。
采用桨法测定片芯和包衣片的体外释药行为。以500mL纯化水为释放介质，转速为75rpm，温度37±0.5℃，2h后取样10mL，0.45μm微孔滤膜过滤，274nm处测吸光度。经标准曲线计算浓度，得到2h释药百分率。
由图4可知：与片芯相比，包衣片的释药行为完全不同；在上述处方条件下，不同聚合物的包衣膜片，均能制得完整有效的包衣片。聚合物种类对包衣制剂的释药行为有影响。
以上所述的实施例只是本发明的一种较佳的方案，并非对本发明作任何形式上的限制，在不超出权利要求所记载的技术方案的前提下还有其它的变体及改型。
Claims (10)
1.一种可用于快速热塑包衣制剂的包衣膜片，其特征在于，所述包衣膜片厚度在0.01mm-1mm，由药用聚合物和增塑剂组成，所述药用聚合物包括缓释聚合物、肠溶聚合物、胃溶聚合物、防潮聚合物中的任意一种或几种；
所述增塑剂为柠檬酸三乙酯、聚乙二醇400、三乙酸甘油酯和癸二酸二丁酯中的任意一种或几种的混合。
2.如权利要求1所述的一种可用于快速热塑包衣制剂的包衣膜片，其特征在于，所述缓释聚合物为尤特奇RS PO、尤特奇RL PO中的一种或两者的混合物。
3.如权利要求2所述的一种可用于快速热塑包衣制剂的包衣膜片，其特征在于，尤特奇RS PO和尤特奇RL PO的混合质量比为1∶1-10∶1。
4.如权利要求1所述的一种可用于快速热塑包衣制剂的包衣膜片，其特征在于，所述肠溶聚合物为尤特奇L100-55、Kollicoat MAE 100P中的一种或两者的混合物。
5.如权利要求1所述的一种可用于快速热塑包衣制剂的包衣膜片，其特征在于，所述胃溶聚合物材料为尤特奇EPO。
6.如权利要求1所述的一种可用于快速热塑包衣制剂的包衣膜片，其特征在于，所述防潮聚合物为Kollicoat Protect。
7.如权利要求1所述的一种可用于快速热塑包衣制剂的包衣膜片，其特征在于，所述增塑剂的用量为聚合物材料质量的5-30％。
8.如权利要求1-7任意一项所述的包衣膜片的制备方法，其特征在于，所述制备方法为混合热压法、干粉包衣法、铺膜法和浸渍法中的任意一种。
9.根据权利要求8所述的包衣膜片的制备方法，其特征在于，
所述混合热压法的工艺包括以下步骤：1)聚合物和增塑剂物理混合，填充于热熔挤出机，在温度80-160℃，转速60-100rpm的条件下，混合10-20min后挤出；2)将挤出条置于热压机，在温度60-120℃条件下，热压3-10min，得到厚度均匀的包衣膜片；
所述干粉包衣法的工艺包括以下步骤：1)液体喷枪将增塑剂喷于金属板表面，静电喷枪将聚合物喷于金属板表面，重复上述两个步骤直至得到一定厚度的衣膜，将衣膜在温度60-100℃的条件下，固化30-150min，得到厚度均匀的包衣膜片；
所述溶剂制膜工艺包括以下步骤：将聚合物材料及增塑剂溶解在良溶剂中，将包衣液平铺于平板上，挥干溶剂得到包衣膜片；或将平板浸渍于包衣液中，挥干溶剂得到包衣膜片。
10.权利要求1-9任意一项所述包衣膜片用于快速热塑包衣制剂的制备方法，其特征在于，包括如下步骤：
1)将包衣膜片置于制剂内芯表面，加热使其软化，所述制剂包括片剂、胶囊剂和丸剂；
2)施加机械压、空气压或离心力使其变形，直至包衣膜片完全粘附于内芯且接口处熔合，冷却切割，必要时翻面包衣或继续包衣；
所述加热温度为100-150℃，时间为1-30min；
所述机械压的大小为0.01-0.2MPa，施加时间为10-300s；
所述空气压采用膜片内减压或膜片外加压，膜内外压差的大小为0.01-0.2MPa，施加时间为10-300s：
所述离心力的大小为30-1000(×g)，施加时间为10-300s。
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