CN1356102A - 掩味药物颗粒 - Google Patents
掩味药物颗粒 Download PDFInfo
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- CN1356102A CN1356102A CN01123387A CN01123387A CN1356102A CN 1356102 A CN1356102 A CN 1356102A CN 01123387 A CN01123387 A CN 01123387A CN 01123387 A CN01123387 A CN 01123387A CN 1356102 A CN1356102 A CN 1356102A
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- Prior art keywords
- coating
- polymer
- granule
- active component
- tablet
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Abstract
公开了掩味颗粒及由其制备的咀嚼片。该掩味颗粒包括含活性组分的核芯和包衣所述核芯的连续聚合物包衣,所述包衣含有a)肠溶聚合物;和b)不溶性成膜聚合物的混合物,所述颗粒的表面没有活生组分。该咀嚼片提供了活性组分的立即释放。
Description
本申请要求美国临时专利申请No.60/215505(2000年6月30日递交)的利益。
本发明涉及掩味药物颗粒，其中含有聚合物包衣，该包衣是肠溶聚合物和不溶性成膜聚合物的混合物。此包衣的颗粒可以用来制备咀嚼片，此片剂惊人地表现出即释特性。
用于口服的药物一般以固体形式如片剂、胶囊、丸剂、锭剂或颗粒剂提供。片剂可以整片吞咽、在嘴中咀嚼或在口腔中溶解。咀嚼片一般由包括活性药物颗粒和其它非活性组分(赋形剂)的混合物制备，且常常在提供整个吞咽的片剂不切实际的情况下用于给药。对于咀嚼片，咀嚼活动有助于片剂崩解时破碎颗粒并可以增加消化道的吸收速度。咀嚼片常常用来改善儿科和老年患者的给药。
某些药物颗粒有苦味或其它令人不愉快的味道。为了由它们制备咀嚼片，其味道必须加以掩盖，例如，通过分散或用包衣组合物包衣这些颗粒。根据包衣组合物的性质，可以改变颗粒及由其制备的片剂的溶解或释放特性。
例如Abramowitz等的美国专利5536507涉及三组分药物制剂，其中含有一种或多种药物活性物质，其中超过80％的活性物质将在大肠中释放。该制剂含有一个核芯，其中含有药物活性物质、微晶纤维素、pH敏感聚合物及可有可无的渗透压调节剂。在核芯的外围是延迟释放包衣，其中含有非水溶性聚合物如Eudragit RS30D(聚(丙烯酸乙酯，甲基丙烯酸甲酯)三甲基铵基乙基甲基丙烯酸酯氯化物))或纤维素、增塑剂和抗附聚剂。在延迟释放包衣外部是肠溶包衣，如邻苯二甲酸乙酸纤维素、三金属化醋酸纤维素(cellulose acetate trimetallate)或Eudragit L30D(聚(甲基丙烯酸，丙烯酸乙酯))。
Savastano等的美国专利5681584涉及另一种延迟释放药物转运药具。在此专利中，药物转运的靶位点在胃肠道，特别是结肠内。该药具由含活性组分的固体核芯组成，该核芯被三个分离的层包衣：1)含有粘合剂、渗透压调节剂和润滑剂的延迟外层；2)可以由醋酸纤维素、乙基纤维素、邻苯二甲酸乙酸纤维素或Eudragit NE30D(聚(丙烯酸乙酯，甲基丙烯酸甲酯))、Eudragit RL(聚(丙烯酸乙酯，甲基丙烯酸甲酯)三甲基铵基乙基甲基丙烯酸酯氯化物)或Eudragit RS(聚(丙烯酸乙酯，甲基丙烯酸甲酯)三甲基铵基乙基丙烯酸酯氯化物)；及3)肠溶聚合物如邻苯二甲酸乙酸纤维素或邻苯二甲酸羟丙甲基纤维素。
加拿大专利申请No.2068366描述了微囊组合物及其制备方法。当在pH约6.8检测时该微囊的溶解特性比标准微囊片剂降低了约25％，优选约40％，更优选约50％。加拿大专利申请No.2068366的微囊组合物是通过将存在于包衣溶液中的药物活性组分的悬浮液或分散液喷雾干燥制备的。该包衣溶液含有3至75％的不溶于水的聚合物。该包衣溶液可以选择性地含有肠溶、反向肠溶(reverse enteric)或水溶性聚合物。在该申请的实施例3中，将含有乙基纤维素、琥珀酸乙酸羟丙甲基纤维素和二氯甲烷的肠溶包衣与双氯芬酸钠一起喷雾干燥。肠溶包衣的双氯芬酸的释放特性示于图3，其表明在pH7.5的溶液中在30分钟后已释放的药物少于80％。
Mehta的美国专利4800087涉及掩味药物组合物，其中药物活性化合物用聚合物包衣进行微囊包封。该聚合物包衣含有与增塑剂或低温成膜聚合物混合的高温成膜聚合物。该高温成膜聚合物可以是乙基纤维素或另一种纤维素聚合物或优选Eudragit L30D，其是优选的肠溶聚合物。该低温成膜聚合物优选是Eudragit NE30D，其是在水溶液中膨胀的非肠溶聚合物。
申请人现在发现了具有即释特性的掩味药物制剂，其可以用连续聚合物包衣制备，该包衣中含有肠溶聚合物和不溶性成膜聚合物。此聚合物包衣用来覆盖药物颗粒的整个表面，使得颗粒的表面基本上没有活性组分。本发明的包衣颗粒有利地表现出足够的弹性，在制片期间不需要增塑剂来维持完整性，并在咀嚼期间防止药物释放到口中。由这些包衣颗粒制备的咀嚼片具有优异的味道，并仍惊人地表现出即释特性。
本发明提供了掩味颗粒，其中包括含活性组分的核芯和覆盖所述核芯的聚合物包衣，所述包衣含有a)肠溶聚合物；和b)不溶性成膜聚合物的混合物，所述颗粒的表面没有活性组分。
本发明还提供了咀嚼片，其中含有掩味颗粒的颗粒附聚物，每个颗粒包括含活性组分的核芯和覆盖所述核芯的聚合物包衣，所述包衣含有a)肠溶聚合物；和b)不溶性成膜聚合物的混合物，所述颗粒的表面没有活性组分。
本发明还提供了含活性组分的掩味颗粒的制备方法，其中包括在所述颗粒涂覆连续聚合物包衣，所述包衣含有a)肠溶聚合物；和b)不溶性成膜聚合物的混合物。
此掩味颗粒的核芯可以含有多种活性组分中的任何一种。适宜的活性组分广义地包括止痛剂、减充血剂、祛痰剂、镇咳剂、抗组胺剂、胃肠用药、利尿药、支气管扩张剂、安眠药、维生素和矿物质添加剂、抗感染药及其混合物，特别是具有令人不快的味道的那些。一类优选的活性组分包括非甾类抗炎药(NSAIDs)，如布洛芬、酮洛芬、氟比洛芬、萘普生、双氯芬酸、rofecoxib、celecoxib和阿斯匹林。此活性组分可以择一地选自对乙酰氨基酚、假麻黄硷、苯丙醇胺、氯苯吡胺、右甲吗南、苯海拉明、晕海宁、美克洛嗪、法莫替丁、洛派丁胺、雷尼替丁、西米地丁、阿司咪唑、氯雷他定、desloratadine、非索那汀、西替利嗪、抗酸剂、其混合物及其药用盐或其代谢物。首选，活性组分选自对乙酰氨基酚、布洛芬、假麻黄硷、右甲吗南、苯海拉明、氯苯吡胺、氯雷他定、碳酸钙、氢氧化镁、碳酸镁、氧化镁、氢氧化铝、其混合物及其药用盐。
该颗粒的核芯含纯的结晶活性组分，或活性组分与选择性存在的本领域已知的组分如粘合剂、赋形剂等的混合物。用多种已知的制粒方法，包括高剪切湿法制粒、喷雾干燥和流化床制粒(包括旋转流化床制粒)，可以形成核芯。优选，颗粒核芯通过流化床制粒法来制备。
聚合物包衣覆盖此核芯。聚合物包衣含有a)肠溶聚合物和b)不溶性成膜聚合物的混合物。该肠溶聚合物可以选自多种已知肠溶聚合物中的任何一种，如邻苯二甲酸羟丙甲基纤维素、琥珀酸乙酸羟丙甲基纤维素、邻苯二甲酸乙酸纤维素、聚邻苯二甲酸醋酸乙烯基酯和基于聚甲基丙烯酸酯的聚合物如聚(甲基丙烯酸，甲基丙烯酸甲酯)1∶2(由Rohm Pharma GmbH以Eudragit S聚合物名称商业化提供)和聚(甲基丙烯酸，甲基丙烯酸甲酯)1∶1(由Rohm Pharma GmbH以Eudragit L聚合物名称商业化提供)。还可以使用肠溶聚合物的联合形式。
优选，此肠溶聚合物选自非丙烯酸酯化合物，特别是邻苯二甲酸羟丙甲基纤维素、琥珀酸乙酸羟丙甲基纤维素、邻苯二甲酸乙酸纤维素和聚邻苯二甲酸乙酸乙烯基酯。之所以优选非丙烯酸酯，是因为丙烯酸酯聚合物在高温下有变粘和附聚的趋势。纤维素聚合物比丙烯酸酯聚合物对热更稳定。此外，已知丙烯酸酯聚合物具有特殊的稍令人不快的味道，而纤维素聚合物具有更中性的味道特性。
不溶性成膜聚合物也可以选自一些已知的化合物，包括醋酸纤维素、乙基纤维素和聚(丙烯酸乙酯，甲基丙烯酸甲酯，三甲基铵基乙基甲基丙烯酸酯氯化物)1∶2∶0.1(由Rohm Pharma以Eudragit RS的商品名商购)。可以使用一种或一种以上的不溶性成膜聚合物。优选，此不溶性成膜聚合物是不渗透性的，并在含水环境中不膨胀。更优选，此不溶性成膜聚合物选自醋酸纤维素和乙基纤维素。
肠溶聚合物与不溶性成膜聚合物在此聚合物包衣中的重量比优选约20∶80至约80∶20，更优选约40∶60至约70∶30。
此聚合物包衣可以含有其它选择性存在的组分。优选，此聚合物包衣包括一种或多种非肠溶的、水溶性聚合物，如羟丙基纤维素和聚(丙烯酸乙酯，甲基丙烯酸甲酯)(由Rohm Pharma GmbH以Eudragit NE 30D的商品名商购)。当此聚合物包衣中存在非肠溶的、水溶性聚合物时，非肠溶的、水溶性聚合物的含量优选占此聚合物包衣的约10至约30％。
此聚合物包衣也可以优选含有表面活性剂。适宜的表面活性剂包括离子和非离子物质，其可以是合成的和天然的来源，包括但不限于卵磷脂、甘油酯、糖酯、聚山梨醇酯、脂肪酸的单和二甘油酯、丙二醇酯、蔗糖脂肪酸酯及脱水山梨醇脂肪酸酯的聚氧乙烯衍生物。可利用的聚山梨醇酯类的实例包括脱水山梨醇三油酸酯、脱水山梨醇单棕榈酸酯、脱水山梨醇单月桂酸酯、丙二醇单月桂酸酯、甘油单硬脂酸酯、一缩二甘油单硬脂酸酯、甘油乳酰基-棕榈酸酯。乳酸衍生物包括硬脂酰基乳酸钠和硬脂酰基乳酸钙。当此聚合物包衣中存在表面活性剂时，表面活性剂的含量优选占此聚合物包衣的约2至约10％。
特别优选的聚合物包衣含有约53％(重量)邻苯二甲酸羟丙甲基纤维素、约43％(重量)乙酸纤维素和约4％(重量)聚山梨醇酯。
有利的是，本发明聚合物包衣不需要增塑剂，但是仍能维持足以防止制片和咀嚼期间破裂的弹性。虽然增塑剂常掺入已知包衣系统中，但是它们增加了此系统的成本和加工复杂性。本发明避免了这些缺点。
此聚合物包衣优选以溶液的形式用流化床技术涂覆于颗粒核芯，如使用Wurster包衣或转动包衣。为此目的可利用的溶剂包括丙酮和水，其比例为约85∶15至约95∶5。
为了达到完全的掩味作用，重要的是此聚合物包衣是连续的并包封核芯的整个表面，以致于很少或没有活性组分暴露。暴露的活性组分在口腔中易于溶解，其一旦在溶液中，其可以通过味蕾检测。例如，用本发明的方法，现在能完全消除与布洛芬有关的“灼热”的感觉。包衣方法如喷雾干燥，其产生活性组分的骨架和包衣，会产生较差的掩味效果，因为喷雾干燥颗粒常常是多孔的并在表面可能有药物露出。
在核芯上聚合物包衣的厚度一般为约1至约20微米，优选约2至15微米，并更优选约4至9微米。此聚合物包衣优选占掩味颗粒重量的约5至约50％，更优选约15至约25％。
咀嚼片可以通过压制包括掩味颗粒的混合物制备。若干制片方法是本领域已知的，例如，包括用压制滚轴技术如chilsonator或降落滚轴机(drop roller)，或模铸、浇铸，或挤出技术。优选，包括掩味颗粒的片剂是使用本领域已知的旋转式压片机通过压制形成的。在旋转压片机中，将计量体积填入模具腔中，其作为“模具盘”的一部分从填状位置旋转到压制位置，其中颗粒在上部和下部冲头之间冲压到排出位置，所得片剂由下部冲头推出，并由固定的“取出”棒导向排出滑槽。
优选，制片进行得使此咀嚼片较软。片剂的硬度优选不超过约15千磅每平方厘米(kp/cm2)。更优选，此片剂的硬度为约1至约8，首选约2至约5kp/cm2。在本领域中用术语硬度描述通过常规药物硬度检测技术(如Schleuniger硬度检测计)检测的径向裂断强度。为了比较不同大小片剂之间的数值，断裂区域的断裂强度必须校准。此校准的数值，以kp/cm2表示，有时在本领域中称为片剂拉伸强度。对片剂硬度检测的总体讨论见Leiberman等，Pharmaceutical Dosage Forms-Tablets，第2卷，第二版，Marcel Dekker Inc.，1990，pp.213-217，327-329。
在此咀嚼片中活性组分以治疗有效量存在，该量是口服给药时产生所需的治疗反应的量，并可以由本领域技术人员容易地确定。在确定此量时，必须考虑所用的具体活性组分、该活性组分的生物利用度特性、剂量方案、患者的年龄和体重以及其它因素。
此咀嚼片可以含有其它常规组分如填充剂，包括水溶性可压制碳水化合物如蔗糖、甘露醇、山梨醇、麦芽糖醇、木糖醇、乳糖及其混合物；常规干燥粘合剂，包括纤维素、纤维素衍生物、聚乙烯吡咯烷酮、淀粉、改性淀粉及其混合物，并特别是微晶纤维素；甜味剂，包括阿司帕坦、合成糖精、sucralose和糖精；及润滑剂，如硬脂酸镁、硬脂酸、滑石和蜡。此咀嚼片还可以掺入药用辅剂，包括如防腐剂、矫味剂、抗氧化剂、表面活性剂和着色剂。
按照本发明制备的片剂不溶解于口中，但是溶解于胃肠道的上部区域。本发明的掩味颗粒的释放特性还可以通过改变在此包衣配方中肠溶性与不溶性成膜聚合物的比例进行改变。但是，一般来说，按照本发明制备的片剂中的活性组分，当按照美国药典(USP)方法II在50rpm下检测时，在30分钟内至少80％溶解于pH7.2的磷酸盐缓冲液中，而当按照美国药典(USP)方法II在50rpm下检测时，在60分钟内至少70％溶解于pH5.6的乙酸盐缓冲液中。因此，本发明的咀嚼片提供了掩味和即释特性的有所改进的联合。
本发明的特定实施方案通过下列实施例举例说明。本发明不限于这些实施例中给出的特定限制，而是限于所附权利要求的范围内。除非特别说明，百分比和比例是重量的。
实施例1、对比颗粒的制备
布洛芬与聚维酮、十二烷基硫酸钠和淀粉羟乙酸钠用纯水在旋转流化床制粒机中按照美国专利5320855公开的方法制粒，此公开内容引入本文以共参考。然后按照US5320855公开的方法，将布洛芬颗粒用存在于水中的羟乙基纤维素(Natrosol)和羟丙甲基纤维素(MethocelE5)50∶50混合物包衣，至包衣水平占完成包衣颗粒重量的22％。
实施例2、制备本发明的掩味颗粒
通过将乙酸纤维素、邻苯二甲酸羟丙基纤维素(HPMCP-50)和吐温80分散于溶剂中，该溶剂由85％丙酮和15水组成，以便该包衣材料占如下最终溶液的10％：
包衣溶液
| 组分 | 重量百分比 |
| 丙酮 | 5100 |
| 水 | 900 |
| HPMCP-50 | 353.34 |
| 乙酸纤维素 | 286.67 |
| 吐温80 | 26.67 |
| 总计 | 6666.67 |
将1800g布洛芬粉末和200g微晶纤维素(AvicelPH101)加入到旋转流化床包衣机(Glatt GPCG-5)中。用速度300rpm的转鼓和0.1-0.2英寸水的空气流量使此粉末床流动。通过切线方向的喷嘴以80g每分钟的速度将包衣溶液喷到颗粒上。入口空气温度为42℃。将所有的溶液喷雾后，在100rpm的低速转鼓上将所得包衣颗粒干燥8分钟。最终干燥物重2141g(收率80％)。包衣材料的水平占最终总包衣颗粒重量的25％。
所得包衣颗粒平均直径为323微米，按照正常的分布模型其标准偏差为122微米(r2＝0.984)。
实施例3：包衣颗粒的体外溶解
将实施例1和2的颗粒溶解，通过USP桨式方法在pH7.2的磷酸缓冲液中以50rpm检测。在小于30分钟内，从颗粒的两种形式中都释放出了100％的布洛芬活性组分。
实施例4：制备对比咀嚼片
将实施例1的包衣颗粒(22％水平的HPMC/HCE)与阿司帕坦、合成糖精、枸橼酸、粒状甘露醇、富马酸、微晶纤维素和矫味剂在塑料袋中通过颠倒100次混合。加入硬脂酸镁，并再将此混合物通过颠倒20次混合。
| 组分 | 量(mg/片) |
| HPMC/HEC包衣的布洛芬(76.25％活性成分) | 131.1 |
| 阿司帕坦NF | 11.55 |
| 合成糖精 | 5.78 |
| 枸橼酸USP，无水 | 2.00 |
| 甘露醇USP，颗粒 | 515 |
| 微晶纤维素(Avicel PH101) | 77 |
| 富马酸NF(细颗粒) | 20 |
| 桔味矫味剂 | 2 |
| 硬脂酸镁NF | 5.78 |
| 总计 | 770.21 |
将所得混合物在旋转制片机上以40rpm的转速用15/32″直径的平面斜边制片工具压制出平均片重量770.2mg、片硬度3.2kp，而片厚度0.24英寸。通过USP方法检测的脆性为2.7％。
实施例5：制备本发明的咀嚼片
将实施例2的包衣颗粒(22％水平的CA/HPMCP-50/吐温80)与阿司帕坦、合成糖精、枸橼酸、粒状甘露醇、富马酸、微晶纤维素和矫味剂在塑料袋中通过颠倒100次混合。加入硬脂酸镁，并再将此混合物通过颠倒20次混合。
| 组分 | 量(mg/片) |
| CA/HPMCP-50/吐温8包衣的布洛芬(67.5％活性成分) | 148.1 |
| 阿司帕坦NF | 11.55 |
| 合成糖精 | 5.78 |
| 枸橼酸USP，无水 | 2.00 |
| 甘露醇USP，颗粒 | 498 |
| 微晶纤维素(Avicel PH101) | 77 |
| 富马酸NF(细颗粒) | 20 |
| 桔味矫味剂 | 2 |
| 硬脂酸镁NF | 5.78 |
| 总计 | 770.21 |
将所得混合物在旋转制片机上以40rpm的转速用15/32″直径的平面斜边制片工具压制出平均片重量770.2mg、片硬度3.2kp，而片厚度0.25英寸。通过USP方法检测的脆性为2.2％。
实施例6：评价实施例4和5的咀嚼片
评价实施例4和5制备的片剂的“咽喉灼热感”的强度，该灼热感是布洛芬的味觉特性。发现实施例4的片剂具有高度的咽喉灼热感或发生一些应激期咽喉麻痹。实施例5的片剂感觉上没有咽喉灼热感。
实施例7、制备本发明的掩味颗粒
通过将乙酸纤维素、邻苯二甲酸羟丙甲基纤维素(HPMCP-50)和羟丙基纤维素(Klucel-EF)在85％丙酮和15％水组成的溶液中分散，制备包衣溶液，包衣材料占最终溶液的10％。包衣材料的相对量(占最终包衣的百分数)为：
乙酸纤维素 45％
HPMCP-50 35％
羟丙基纤维素 20％
按照实施例2的方法用此溶液包衣布洛芬(80％)、微晶纤维素(10％)和富马酸(10％)的混合物。包衣材料占最终总包衣颗粒重量的20％。所得包衣颗粒平均直径为166微米，通过USP方法II以50rpm转速检测，其在pH5.6乙酸盐缓冲液中在60分钟内溶解释放97％。
实施例8、咀嚼片的制备和生物利用度实验
用Manesty Beta旋转压片机压制掺入了实施例7的包衣颗粒的咀嚼片。此片剂的所选单位剂量配方如下：
| 咀嚼组合物(100mg布洛芬，桔味矫味剂)，片重770mg | ||
| 组分 | ％ | mg/片 |
| 包囊的布洛芬* | ||
| FD&C黄色No.6铝色淀(颜色) | 0.23 | 1.76 |
| 微晶纤维素(AVICEL PH-101 NF)(助流剂) | 10.0 | 77.0 |
| 阿司帕坦NF(甜味剂) | 1.5 | 11.55 |
| 合成糖精(甜味剂) | 0.75 | 5.78 |
| 富马酸(颗粒)(酸化剂) | 2.59 | 20 |
| 枸缘酸USP(矫味剂) | 0.26 | 2.0 |
| 天然桔味矫味剂5-11757 | 0.26 | 5.78 |
| 硬脂酸镁NF(润滑剂) | 0.75 | 5.77 |
| 甘露醇USP(颗粒)(FL2080)(填充剂) | ||
| 总计 | 100.0 | 770.0 |
*基于存在于包衣颗粒中的布洛芬调整计算布洛芬和甘露醇。
用如下方法制备此咀嚼片：
1.在双壳混合器(Patterson-Kelly Inc.)中将阿司帕坦、合成糖精、富马酸、微晶纤维素、着色剂、矫味剂、甘露醇、布洛芬混合15分钟。
2.然后将所得片剂混合物用15/32″圆形FFBE工具用旋转压片机(ManestyBeta Press)压制为预定重770mg、硬度8.0kp和厚度5.90mm。
按照确认的临床方案，在16名健康人自愿者中评价此咀嚼片的生物利用度(与儿童Mortrin咀嚼片参照产物对比)。评价下列药代动力学参数：血浆浓度-时间曲线下面积(AUC)、最大血浆浓度(Cmax)、达到峰值血浆浓度需要的时间(Tmax)和半数吸收时间(T1/2)。用来进行生物检测研究的制剂和生物研究的结果总结于下表中。
*—表示平均值
| 生物检测结果(770mg，100mg布洛芬，桔味矫味剂) | ||||||||||
| 片剂组合物和物理性质 | 药代动力学参数 | |||||||||
| 片剂性质 | *Cmax(ng/ml) | *Tmax(小时) | *AUC(ng/ml-hr) | *T1/2(小时) | ||||||
| 平均硬度(Kp) | 平均重量(mg) | Ave | CV | Ave | CV | Ave | CV | Ave | CV | |
| 参照产物 | 7.3 | 772 | 15.7 | 21.8 | 1.96 | 46.8 | 62.8 | 19.2 | 1.92 | 15.4 |
| 本发明片剂 | 8.70 | 769.3 | 16.5 | 11.7 | 2.2 | 33.5 | 59.4 | 14.8 | 1.91 | 14.9 |
CV—变异系数
NA—不适用
实施例9：制备本发明掩味颗粒
通过将乙酸纤维素、邻苯二甲酸羟丙甲基纤维素和吐温80在85％丙酮和15％水组成的溶剂中分散，制备包衣溶液(350kg)，让包衣材料占最终溶液的10％。
将112kg布洛芬粉末、7kg微晶纤维素(Avicel PH101)、7kg淀粉羟乙酸钠和14kg富马酸加入到旋转流化床包衣机(GlattGRG 200)中。用200rpm转速和2400CFM的风量使此粉末床流动。通过垂直向喷嘴以初始速度1200g每分钟将包衣溶液喷到颗粒上。入口空气温度为41℃。在整个处理过程中控制粒度。当小于125微米的颗粒部分降低至少于20％(约175kg的溶液已喷雾)时，将喷雾速度降低至1000g/分钟。当小于125微米的颗粒部分降低至15％(约235kg的溶液已喷雾)时，将喷雾速度降低至800g/分钟。所有的溶液都已喷雾完毕后，以100rpm的转速干燥所得包衣颗粒直到产物温度达到38℃(3-5分钟)。最后干燥的物料重155.7kg(收率91％)。总的加工时间少于6小时。
包衣材料占最终总包衣颗粒重量的20％。约75％的最终包衣颗粒的粒度为150至420微米。通过USP浆式方法以50rpm转速在pH7.2的磷酸盐缓冲液中检测，在45分钟内超过90％的活性布洛芬溶解。
Claims (10)
1.掩味颗粒，其中包括含活性组分的核芯和包衣所述核芯的连续聚合物包衣，所述包衣含有a)肠溶聚合物；和b)不溶性成膜聚合物的混合物。
2.权利要求1的颗粒，其中所述颗粒的表面基本上没有活性组分。
3.权利要求1的颗粒，其中包衣基本上不含增塑剂。
4.权利要求1的颗粒，其中活性组分是非甾类抗炎药。
5.权利要求1的颗粒，其中还含有非肠溶性的水溶性聚合物。
6.含有掩味颗粒的咀嚼片，其中每个颗粒包括含活性组分的核芯和包衣所述核芯的连续聚合物包衣，所述包衣含有a)肠溶聚合物；和b)不溶性成膜聚合物的混合物。
7.权利要求6的咀嚼片，其中所述颗粒的表面基本上没有活性组分。
8.权利要求6的咀嚼片，其中包衣基本上不含增塑剂。
9.权利要求1的咀嚼片，其中活性组分是非甾类抗炎药。
10.含有活性组分的掩味颗粒的制备方法，其中包括将连续聚合物包衣涂覆在所述颗粒上，所述包括含有a)肠溶聚合物；b)不溶性成膜聚合物的混合物。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US21550500P | 2000-06-30 | 2000-06-30 | |
| US60/215,505 | 2000-06-30 |
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| CN1356102A true CN1356102A (zh) | 2002-07-03 |
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| CN01123387A Pending CN1356102A (zh) | 2000-06-30 | 2001-06-29 | 掩味药物颗粒 |
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| Country | Link |
|---|---|
| US (2) | US7223421B2 (zh) |
| EP (1) | EP1166777B1 (zh) |
| JP (1) | JP2002087952A (zh) |
| KR (1) | KR20020002321A (zh) |
| CN (1) | CN1356102A (zh) |
| AR (1) | AR029546A1 (zh) |
| AT (1) | ATE404180T1 (zh) |
| AU (1) | AU784613B2 (zh) |
| BR (1) | BR0103033A (zh) |
| CA (1) | CA2351814C (zh) |
| CO (1) | CO5271674A1 (zh) |
| DE (1) | DE60135273D1 (zh) |
| ES (1) | ES2311500T3 (zh) |
| MX (1) | MXPA01006803A (zh) |
| NZ (1) | NZ512683A (zh) |
| SA (1) | SA01220402B1 (zh) |
| ZA (1) | ZA200105407B (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| US8268333B2 (en) | 2001-04-24 | 2012-09-18 | Lintec Corporation | Orally administered agent and an orally administered agent/supporting substrate complex |
| US9668993B2 (en) | 2003-03-21 | 2017-06-06 | Johnson & Johnson Consumer Inc. | Non-steroidal anti-inflammatory drug dosing regimen |
| CN112674348A (zh) * | 2020-12-23 | 2021-04-20 | 石药集团中诺药业（泰州）有限公司 | 一种b族维生素含片和咀嚼片制备方法 |
Families Citing this family (43)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6375957B1 (en) | 1997-12-22 | 2002-04-23 | Euro-Celtique, S.A. | Opioid agonist/opioid antagonist/acetaminophen combinations |
| UA55507C2 (uk) | 1997-12-22 | 2003-04-15 | Еро-Селтік, С.А. | Лікарська форма для перорального введення та спосіб запобігання зловживанню пероральною опіоїдною композицією |
| US20020119196A1 (en) * | 2000-12-21 | 2002-08-29 | Narendra Parikh | Texture masked particles containing an active ingredient |
| DE60238756D1 (de) | 2001-05-11 | 2011-02-10 | Endo Pharmaceuticals Inc | Opioid enthaltende arzneiform gegen missbrauch |
| US20040253312A1 (en) * | 2001-09-28 | 2004-12-16 | Sowden Harry S. | Immediate release dosage form comprising shell having openings therein |
| IL164106A0 (en) * | 2002-04-04 | 2005-12-18 | Pfizer Prod Inc | Palatable chewable tablet |
| HUE032656T2 (en) * | 2002-04-05 | 2017-10-30 | Euro Celtique Sa | Pharmaceutical composition containing oxicodone and naloxone |
| US8092831B2 (en) * | 2002-11-08 | 2012-01-10 | Andrx Pharmaceuticals, Llc | Antihistamine and decongestant system |
| US20040258752A1 (en) * | 2003-01-31 | 2004-12-23 | Paruthi Manoj Kumar | Taste masking pharmaceutical composition and process for its preparation |
| US20040213838A1 (en) * | 2003-04-24 | 2004-10-28 | Mazer Terrence B. | Medical food tablets containing free amino acids |
| US20040265372A1 (en) * | 2003-06-27 | 2004-12-30 | David Wynn | Soft tablet containing high molecular weight cellulosics |
| US20040265373A1 (en) * | 2003-06-27 | 2004-12-30 | David Wynn | Soft tablet containing high molecular weight cellulosics |
| WO2005000358A1 (ja) * | 2003-06-27 | 2005-01-06 | Wakunaga Pharmaceutical Co., Ltd. | 安定液剤 |
| JP3881640B2 (ja) * | 2003-08-08 | 2007-02-14 | 塩野義製薬株式会社 | ロラタジンを含むドライシロップ剤 |
| US20050095299A1 (en) * | 2003-10-30 | 2005-05-05 | Wynn David W. | Controlled release analgesic suspensions |
| US20050095300A1 (en) * | 2003-10-30 | 2005-05-05 | Wynn David W. | Controlled release analgesic suspensions |
| US7879354B2 (en) * | 2004-01-13 | 2011-02-01 | Mcneil-Ppc, Inc. | Rapidly disintegrating gelatinous coated tablets |
| US8067029B2 (en) | 2004-01-13 | 2011-11-29 | Mcneil-Ppc, Inc. | Rapidly disintegrating gelatinous coated tablets |
| US8062659B2 (en) * | 2004-02-20 | 2011-11-22 | Novartis Ag | Dietary fiber composition |
| US20050186271A1 (en) * | 2004-02-24 | 2005-08-25 | Sheskey Paul J. | Process for dispersing a fluid in a mass of solid particles |
| EP1604667A1 (en) * | 2004-06-08 | 2005-12-14 | Euro-Celtique S.A. | Opioids for the treatment of the restless leg syndrome |
| EP1604666A1 (en) * | 2004-06-08 | 2005-12-14 | Euro-Celtique S.A. | Opioids for the treatment of the Chronic Obstructive Pulmonary Disease (COPD) |
| CN101132772B (zh) * | 2005-01-28 | 2012-05-09 | 欧洲凯尔特公司 | 耐醇剂型 |
| EP1695700A1 (en) * | 2005-02-28 | 2006-08-30 | Euro-Celtique S.A. | Dosage form containing oxycodone and naloxone |
| EP1702558A1 (en) | 2005-02-28 | 2006-09-20 | Euro-Celtique S.A. | Method and device for the assessment of bowel function |
| EP1813276A1 (en) * | 2006-01-27 | 2007-08-01 | Euro-Celtique S.A. | Tamper resistant dosage forms |
| WO2007123153A1 (ja) * | 2006-04-19 | 2007-11-01 | Ono Pharmaceutical Co., Ltd. | 経口投与用カプセル |
| US20070264335A1 (en) * | 2006-05-09 | 2007-11-15 | Sherman Bernard C | Modified release tablets comprising tramadol |
| CA2654402A1 (en) * | 2006-06-01 | 2007-12-06 | Adel Penhasi | Multiple unit pharmaceutical formulation |
| WO2008008801A2 (en) * | 2006-07-11 | 2008-01-17 | Mcneil Nutritionals, Llc | Solid oral dosage vitamin and mineral compositions |
| AU2007308986A1 (en) * | 2006-10-25 | 2008-05-02 | Mcneil-Ppc, Inc. | Ibuprofen composition |
| FR2930147B1 (fr) * | 2008-04-18 | 2013-02-08 | Flamel Tech Sa | Forme orale solide dotee d'un double profil de liberation |
| US20110177133A1 (en) * | 2008-07-07 | 2011-07-21 | Michael Hopp | Use of opioid antagonists for treating urinary retention |
| SG174286A1 (en) | 2009-03-10 | 2011-10-28 | Euro Celtique Sa | Immediate release pharmaceutical compositions comprising oxycodone and naloxone |
| US20100239681A1 (en) * | 2009-03-20 | 2010-09-23 | Biokey, Inc. | Controlled Release Particulates Containing Water-Insoluble Drug |
| ES2543108T3 (es) * | 2010-03-31 | 2015-08-14 | Mochida Pharmaceutical Co., Ltd. | Preparación sólida fácilmente administrable |
| CN107049979B (zh) | 2011-09-30 | 2020-08-14 | 持田制药株式会社 | 易服用性固体制剂 |
| FR2999426B1 (fr) * | 2012-12-13 | 2015-01-02 | Flamel Tech Sa | Forme orale multiparticulaire a liberation immediate d'au moins un compose actif, comprenant des particules enrobees resistantes au broyage. |
| JP5836980B2 (ja) | 2013-01-11 | 2015-12-24 | 信越化学工業株式会社 | 薬物含有粒子、固形製剤及び薬物含有粒子の製造方法 |
| AU2014295042B2 (en) | 2013-07-23 | 2017-03-30 | Mundipharma Pty Limited | A combination of oxycodone and naloxone for use in treating pain in patients suffering from pain and a disease resulting in intestinal dysbiosis and/or increasing the risk for intestinal bacterial translocation |
| US20170042806A1 (en) | 2015-04-29 | 2017-02-16 | Dexcel Pharma Technologies Ltd. | Orally disintegrating compositions |
| US10076494B2 (en) | 2016-06-16 | 2018-09-18 | Dexcel Pharma Technologies Ltd. | Stable orally disintegrating pharmaceutical compositions |
| WO2024020361A2 (en) * | 2022-07-19 | 2024-01-25 | Michael Ogburn | Inhalable serotonin receptor agonist formulations |
Family Cites Families (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS48103718A (zh) | 1972-04-14 | 1973-12-26 | ||
| US4160827A (en) * | 1978-02-06 | 1979-07-10 | The Upjohn Company | Metronidazole phosphate and salts |
| JPS5535031A (en) * | 1978-09-04 | 1980-03-11 | Shin Etsu Chem Co Ltd | Enteric coating composition |
| JPS57120518A (en) * | 1981-01-19 | 1982-07-27 | Tanabe Seiyaku Co Ltd | Preparation of microcapsule |
| US4749575A (en) * | 1983-10-03 | 1988-06-07 | Bio-Dar Ltd. | Microencapsulated medicament in sweet matrix |
| IE58110B1 (en) * | 1984-10-30 | 1993-07-14 | Elan Corp Plc | Controlled release powder and process for its preparation |
| US4971791A (en) * | 1985-08-26 | 1990-11-20 | The Procter & Gamble Company | Taste masking compositions |
| US4800087A (en) * | 1986-11-24 | 1989-01-24 | Mehta Atul M | Taste-masked pharmaceutical compositions |
| US4916161A (en) * | 1988-10-25 | 1990-04-10 | Bristol-Myers Squibb | Taste-masking pharmaceutical agents |
| US5084278A (en) * | 1989-06-02 | 1992-01-28 | Nortec Development Associates, Inc. | Taste-masked pharmaceutical compositions |
| CA2063141C (en) * | 1989-08-04 | 1997-03-04 | Edward J. Roche | Rotogranulations and taste masking coatings for preparation of chewable pharmaceutical tablets |
| IT1246383B (it) * | 1990-04-17 | 1994-11-18 | Eurand Int | Metodo per il mascheramento del sapore di farmaci |
| FI922107A0 (fi) | 1991-05-10 | 1992-05-08 | Faulding F H & Co Ltd | Mikrokapselkomposition och foerfarande. |
| US5837277A (en) * | 1992-06-04 | 1998-11-17 | Smithkline Beecham Corporation | Palatable pharmaceutical compositions |
| ATE195252T1 (de) * | 1993-04-23 | 2000-08-15 | Novartis Erfind Verwalt Gmbh | Wirkstoffabgabevorrichtung mit gesteuerter freigabe |
| ZA945944B (en) * | 1993-08-13 | 1996-02-08 | Eurand America Inc | Procedure for encapsulating nsaids |
| GB9317897D0 (en) * | 1993-08-27 | 1993-10-13 | Plessey Telecomm | Telecommunications switching element |
| JPH07223970A (ja) * | 1994-02-10 | 1995-08-22 | Tanabe Seiyaku Co Ltd | 消化管内適所放出製剤 |
| US5536507A (en) * | 1994-06-24 | 1996-07-16 | Bristol-Myers Squibb Company | Colonic drug delivery system |
| JP3355593B2 (ja) * | 1994-08-19 | 2002-12-09 | 信越化学工業株式会社 | 固形腸溶製剤の製造方法 |
| WO1998014179A1 (en) * | 1996-10-01 | 1998-04-09 | Cima Labs Inc. | Taste-masked microcapsule compositions and methods of manufacture |
| US6046177A (en) * | 1997-05-05 | 2000-04-04 | Cydex, Inc. | Sulfoalkyl ether cyclodextrin based controlled release solid pharmaceutical formulations |
-
2001
- 2001-06-08 US US09/878,034 patent/US7223421B2/en not_active Expired - Lifetime
- 2001-06-28 CA CA002351814A patent/CA2351814C/en not_active Expired - Fee Related
- 2001-06-29 ES ES01305664T patent/ES2311500T3/es not_active Expired - Lifetime
- 2001-06-29 EP EP01305664A patent/EP1166777B1/en not_active Expired - Lifetime
- 2001-06-29 AR ARP010103130A patent/AR029546A1/es unknown
- 2001-06-29 DE DE60135273T patent/DE60135273D1/de not_active Expired - Lifetime
- 2001-06-29 KR KR1020010038206A patent/KR20020002321A/ko not_active Application Discontinuation
- 2001-06-29 CN CN01123387A patent/CN1356102A/zh active Pending
- 2001-06-29 NZ NZ512683A patent/NZ512683A/xx unknown
- 2001-06-29 AT AT01305664T patent/ATE404180T1/de not_active IP Right Cessation
- 2001-06-29 AU AU54158/01A patent/AU784613B2/en not_active Ceased
- 2001-06-29 ZA ZA200105407A patent/ZA200105407B/xx unknown
- 2001-07-02 BR BR0103033-7A patent/BR0103033A/pt not_active Application Discontinuation
- 2001-07-02 MX MXPA01006803A patent/MXPA01006803A/es active IP Right Grant
- 2001-07-02 JP JP2001201173A patent/JP2002087952A/ja active Pending
- 2001-07-03 CO CO01052475A patent/CO5271674A1/es not_active Application Discontinuation
- 2001-09-29 SA SA01220402A patent/SA01220402B1/ar unknown
-
2007
- 2007-04-05 US US11/696,821 patent/US20070196489A1/en not_active Abandoned
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8268333B2 (en) | 2001-04-24 | 2012-09-18 | Lintec Corporation | Orally administered agent and an orally administered agent/supporting substrate complex |
| US9668993B2 (en) | 2003-03-21 | 2017-06-06 | Johnson & Johnson Consumer Inc. | Non-steroidal anti-inflammatory drug dosing regimen |
| CN101065113B (zh) * | 2004-12-10 | 2012-04-11 | 方济各安吉利克化学联合股份有限公司 | 口腔可分散的药物组合物及其制备方法 |
| CN112674348A (zh) * | 2020-12-23 | 2021-04-20 | 石药集团中诺药业（泰州）有限公司 | 一种b族维生素含片和咀嚼片制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| BR0103033A (pt) | 2002-03-05 |
| US20070196489A1 (en) | 2007-08-23 |
| CA2351814A1 (en) | 2001-12-30 |
| ES2311500T3 (es) | 2009-02-16 |
| AU5415801A (en) | 2002-01-03 |
| US7223421B2 (en) | 2007-05-29 |
| CO5271674A1 (es) | 2003-04-30 |
| ATE404180T1 (de) | 2008-08-15 |
| ZA200105407B (en) | 2003-01-02 |
| US20020031552A1 (en) | 2002-03-14 |
| AU784613B2 (en) | 2006-05-11 |
| EP1166777A1 (en) | 2002-01-02 |
| EP1166777B1 (en) | 2008-08-13 |
| CA2351814C (en) | 2009-11-17 |
| JP2002087952A (ja) | 2002-03-27 |
| DE60135273D1 (de) | 2008-09-25 |
| NZ512683A (en) | 2003-02-28 |
| MXPA01006803A (es) | 2003-08-20 |
| AR029546A1 (es) | 2003-07-02 |
| SA01220402B1 (ar) | 2007-02-07 |
| KR20020002321A (ko) | 2002-01-09 |
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