CN102600096B - 一种达非那新缓释制剂及其制备方法 - Google Patents
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Abstract
本发明本提供一种患者顺应性好、副作用小、药效持久稳定的达非那新缓释制剂及其制备方法。该达非那新缓释制剂，包括主药和对pH敏感的高分子聚合物。进一步，当达非那新与辅料制备成片芯或微丸时，该高分子聚合物可以作为包衣层材料，作为缓释包衣层。该达非那新缓释制剂中，还包括疏水性基质。该疏水性物质可以根据制剂需求选择，即可以为填充剂，润滑剂等，还可以为缓释骨架材料，更进一步，还可以与该高分子聚合物一起控制达非那新释放。
Description
技术领域
本发明涉及一种达非那新缓释制剂及其制备方法，属于医药制剂技术领域。
背景技术
膀胱过度活动症(overactive bladder，简称OAB)是一种常见病，是以尿频、尿急和急迫性尿失禁为主要症状的综合征。中华医学会泌尿外科分会尿控学组《膀胱过度活动症临床指导原则》定义为：OAB是由尿频、尿急、急迫性尿失禁等组成的症侯，这些症状可以单独出现，也可以任何复合形式出现。其病因至今仍不十分清楚，它可能是由于中枢抑制性传出通路，外周感觉传入通路或膀胱肌肉本身受到损害造成的，这些原因可以单独或联合存在。造成运动急迫性尿失禁的原因有：1、膀胱以下尿路梗阻；2、神经系统疾病；3、原因不明的原发性运动急迫性尿失禁。引起感觉急迫性尿失禁的原因有非特异性细菌性膀胱炎、结核性膀胱炎、间质性膀胱炎、放射性膀胱炎、浸润性膀胱肿瘤、膀胱结石、膀胱异物、女性尿道综合征和萎缩性阴道炎等。这类尿失禁除了有上述典型症状外，还有下腹部及会阴部或腰背部疼痛不适以及由原发疾病引起的血尿和脓尿等表现。
目前治疗药物主要以抗胆碱药物为主，作用于中枢神经系统类药物，以及钙拮抗剂、膀胱内注射治疗及手术治疗等。常用的药物有：奥昔布宁，抗胆碱类药物，有效性得到公认，但选择性较低，同时阻断腮腺M受体，导致50％患者出现口干，其中25％因此退出治疗。托特罗定，抗胆碱类药物，亲和力和专一性较强，膀胱M受体20倍于腮腺M受体。丙米嗪，中枢神经系统类用药，不仅有抗胆碱拟交感作用，还有中枢性抑制排尿反射的作用，推荐用于混合性急迫-压力性尿失禁，缺点：起效慢，服用数周后才能见效。度洛西汀：通过抑制中枢对5-HT和去甲肾上腺素的再摄取，增加尿道外括约肌张力，2004年欧洲获准上市，治疗女性压力性尿失禁。
达非那新又称达菲那新(Darifenacin)是由辉瑞制药公司新药开发的选择性毒蕈碱拮抗剂，用于治疗伴有急迫性尿失禁、尿急、尿频症状的膀胱过动症(OAB)患者。本品可以选择性阻断毒蕈碱性M3受体，抑制膀胱逼尿肌收缩，从而达到治疗目的。
发明内容
本发明的目的在于提供一种患者顺应性好、副作用小、药效持久稳定的达非那新缓释制剂。该达非那新缓释制剂，包括主药和对pH敏感的高分子聚合物。该高分子聚合物在胃肠道中，在不同pH下具有不同的物理性质，简单来说，该高分子聚合物可以在胃的酸性环境下溶于水或逐渐溶胀，释放达非那新；同样，可以选择不同的高分子聚合物或他们之间的组合物，使之在小肠或大肠或直肠中给药，起到定位给药的作用。更进一步，所述缓释制剂，使得该高分子聚合物产生溶解性变化的pH值在1-14之间，优选在2-9之间。同时，该高分子聚合物可以作为缓释材料，即该高分子聚合物可以作为定位给药的载体，同时也可以作为控制达非那新释放的载体，简化了处方，降低了制备难度，更易工业大生产。发明人惊讶地发现，该制剂可用于制备各种达非那新的缓释剂型，而不依赖于达非那新的理化性质。
进一步，当达非那新与辅料制备成片芯或微丸时，该高分子聚合物可以作为包衣层材料，作为缓释包衣层。此时高分子聚合物分子量大于5000更利于达非那新释放。
进一步，所述高分子聚合物含有阴离子或阳离子，包括但不限于海藻酸及其盐或壳聚糖或卡波姆或泊洛沙姆。
进一步，该达非那新缓释制剂中，其特征在于，还包括疏水性基质。该疏水性物质可以根据制剂需求选择，即可以为填充剂，润滑剂等，还可以为缓释骨架材料，更进一步，还可以与该高分子聚合物一起控制达非那新释放。
进一步，上述缓释制剂，可以为片剂或胶囊。其制备方法如现有技术，包括但不限于下列方式：将各物料干法或湿法制粒后与其他药学上可接受的辅料符合，压片或压片后包衣或压片后装入胶囊。
进一步，所述润滑剂可选用硬脂酸、硬脂酸镁、滑石粉、硬脂酸钙。所述填充剂选自微晶纤维素、磷酸氢钙、碳酸钙等。
进一步，所述制剂中还包含黏合剂或润湿剂。
本发明所述的达非那新缓释制剂，其特征在于按重量百分比计算，其组成为：
| 达非那新 | 40～99％ |
| 高分子聚合物 | 1～60％ |
本发明所述的缓释制剂，其特征在于按重量百分比计算，其组成为：
| 达非那新 | 40～80％ |
| 高分子聚合物 | 1～50％ |
| 疏水性基质 | 5～50％ |
本发明所述的达非那新缓释制剂，其特征在于按重量百分比计算，优选其组成为：
| 达非那新 | 1～70％ |
| 高分子聚合物 | 5～40％ |
| 疏水性基质 | 5～40％ |
本发明所述的达非那新缓释制剂，其特征在于按重量百分比计算，优选其组成为：
| 达非那新 | 1～50％ |
| 高分子聚合物 | 5～40％ |
| 疏水性基质 | 5～40％ |
| 填充剂 | 5～20％ |
| 润滑剂 | 0.1～2％ |
进一步，将上述处方通过干法或湿法制粒后压片，还可进一步包衣，或者压制成小片装入胶囊。
具体实施方式
本发明用下面的实施例及实施例进行举例说明。应当理解，这些实施例及实施例仅是对本发明的具体说明，而不是限制本发明的范围。
实施例1：达非那新缓释片
| 达非那新 | 75.0g |
| 海藻酸钠 | 80.0g |
| 磷酸氢钙 | 37.0g |
| 聚维酮K30 | 7.0g |
| 水 | 适量 |
| 硬脂酸镁 | 1.0g |
| 共制成 | 1000片 |
制备方法：
将处方中主药、海藻酸钠、磷酸氢钙、聚维酮K30混合后加入水作为润湿剂，制粒，50℃干燥，20目筛整粒后加入硬脂酸镁，压片。
实施例2：达非那新缓释片
| 达非那新 | 10.0g |
| 壳聚糖 | 10.0g |
| 巴西棕榈蜡 | 10.0 |
| 磷酸氢钙 | 164.0g |
| 聚维酮K30 | 5.0g |
| 水 | 适量 |
| 硬脂酸镁 | 1.0g |
| 共制成 | 1000片 |
制备方法：
1.主药达非那新微粉化，粒径10μm；
2.将处方中主药、壳聚糖、巴西棕榈蜡、磷酸氢钙、聚维酮K30混合后加入水作为润湿剂，制粒，50℃干燥，20目筛整粒后加入硬脂酸镁，压片。
实施例3：达非那新缓释片
| 达非那新 | 100.0g |
| 海藻酸 | 50.0g |
| 微晶纤维素 | 44.0g |
| 聚维酮K30 | 5.0g |
| 水 | 适量 |
| 硬脂酸镁 | 1.0g |
| 共制成 | 1000片 |
制备方法：
1.主药达非那新微粉化，粒径10μm；
2.将处方中主药、海藻酸、微晶纤维素、聚维酮K30混合后加入水作为润湿剂，制粒，50℃干燥，20目筛整粒后加入硬脂酸镁，压片。
实施例4：达非那新缓释片
| 达非那新 | 200.0g |
| 蜂蜡 | 30.0g |
| 微晶纤维素 | 64.0g |
| 聚维酮K30 | 5.0g |
| 水 | 适量 |
| 硬脂酸镁 | 1.0g |
| 共制成 | 1000片 |
制备方法：
将处方中主药、蜂蜡、微晶纤维素、聚维酮K30混合后加入水作为润湿剂，制粒，50℃干燥，20目筛整粒后加入硬脂酸镁，压片。
3.包衣：将下列处方溶于丙酮，进行喷雾包衣
| 壳聚糖 | 8.0g |
| 已经纤维素 | 10.0g |
| 癸二酸二丁酯 | 2.0g |
将上述实施例各制剂用中国药典2010年版二部附录XD第一法测定该制剂的释放度，测定结果见表1。
表1实施例1-6制得的各达非那新缓释制剂释放度实施结果
| 1小时 | 2小时 | 4小时 | 8小时 | |
| 实施例1 | 21.3％ | 40.1％ | 77.1％ | 89.1％ |
| 实施例2 | 14.4％ | 31.5％ | 55.1％ | 85.1％ |
| 实施例3 | 21.1％ | 42.7％ | 81.5％ | 93.3％ |
| 实施例4 | 25.1％ | 55.1％ | 89.3％ | 98.1％ |
Claims (1)
1.一种达非那新缓释片剂，其特征在于，每1000片所述的缓释片剂由以下原料制成：75.0g达非那新、80.0g海藻酸钠、37.0g磷酸氢钙、7.0g聚维酮K30、1.0g硬脂酸镁和适量的水；或10.0g达非那新、10.0g壳聚糖、10.0g巴西棕榈蜡、164.0g磷酸氢钙、5.0g聚维酮K30、1.0g硬脂酸镁和适量的水；或100.0g达非那新、50.0g海藻酸、44.0g微晶纤维素、5.0g聚维酮K30、1.0g硬脂酸镁和适量的水；或200.0g达非那新、30.0g蜂蜡、64.0g微晶纤维素、5.0g聚维酮K30、1.0g硬脂酸镁和适量的水。
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| CN1195984A (zh) * | 1995-09-15 | 1998-10-14 | 辉瑞研究及发展公司 | 含有达非那新的药物制剂 |
| CN101084891A (zh) * | 2007-06-29 | 2007-12-12 | 北京本草天源药物研究院 | 一种用于口服的达非那新或其药用盐的药物制剂 |
| CN102048706A (zh) * | 2011-01-12 | 2011-05-11 | 山东创新药物研发有限公司 | 一种氢溴酸达非那新缓释片及制备方法 |
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| CN1195984A (zh) * | 1995-09-15 | 1998-10-14 | 辉瑞研究及发展公司 | 含有达非那新的药物制剂 |
| CN101084891A (zh) * | 2007-06-29 | 2007-12-12 | 北京本草天源药物研究院 | 一种用于口服的达非那新或其药用盐的药物制剂 |
| CN102048706A (zh) * | 2011-01-12 | 2011-05-11 | 山东创新药物研发有限公司 | 一种氢溴酸达非那新缓释片及制备方法 |
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