CN114224855B - 一种甲磺酸多沙唑嗪口含片及其制备方法 - Google Patents
一种甲磺酸多沙唑嗪口含片及其制备方法 Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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Abstract
本发明提供一种甲磺酸多沙唑嗪口含片及其制备方法,所述甲磺酸多沙唑嗪口含片包括质量分数为2‑3%的D90<10μm的甲磺酸多沙唑嗪、77‑94%的可溶性填充剂和余量的助剂,所述助剂包括表面活性剂,所述可溶性填充剂具有网面结构和/或内部空隙。本发明通过将微粉化的甲磺酸多沙唑嗪吸附于可溶性填充剂的表面和/或内部结构,加之使用表面活性剂,可以使得活性成分在混合过程中易于混合均匀,并增大活性成分在溶出时的接触面积,从而能迅速溶出并在口腔中被吸收,大大提高了活性成分的溶解速率,进一步提高本品的生物利用度。即本发明的甲磺酸多沙唑嗪口含片具有质量均一、服用方便、溶出快、起效快、生物利用度高的特点。
Description
技术领域
本发明涉及医药技术领域,尤其涉及一种甲磺酸多沙唑嗪口含片及其制备方法。
背景技术
甲磺酸多沙唑嗪,是由美国辉瑞公司最早研发的一种长效、高选择性喹啉类α1受体阻滞剂,作用类似于哌唑嗪,药效较慢,较少出现“首剂反应”,卧立位血压差别较小,对交感神经无明显反射性增强,长期用药无耐药性。1995年美国FDA批准用于治疗良性前列腺增生,2002年9月在中国上市,目前已成为国内外治疗轻中度高血压的一线药物,也是治疗良性前列腺增生合并下尿路症状(BPH/LUTS)的一线用药。
甲磺酸多沙唑嗪目前市场上有普通片和控释片,服用普通片时,血浆药物浓度达峰时间约2-3小时,生物利用度约为65%,存在肝脏首过代谢,多沙唑嗪在肝脏被广泛代谢。与食物同服可降低多沙唑嗪的峰血浆浓度和药-时曲线下面积。多沙唑嗪的血浆清除呈双相,终末半衰期为22小时。服用缓释片时,应用足量的水将药片完整吞服,不得咀嚼、掰开或碾碎后服用,不受进食与否的影响,缓释片的相对生物利用度为54%,生物利用度低。
另外,片剂制备通常使用湿法制粒和干法制粒工艺。湿法制粒工艺主要包括:(1)将活性成分与赋形剂混合,加入粘合剂制软材,(2)将软材通过一定目数筛网制粒,并干燥,(3)将所制得颗粒与其他辅料混合均匀,(4)压片。干法制粒工艺包括:(1)将活性成分与赋形剂混合,干法制粒得到一定大小的颗粒,(2)将所制得颗粒与其他辅料混合均匀,(3)压片。干法制粒工艺还包括粉末直压工艺,即所有的物料直接混合均匀后压片。
但是,湿法制粒工艺由于需要加入粘合剂制粒,溶出慢,起效慢。类似地,干法制粒工艺由于需要制粒或者直接压片,会导致溶出慢,起效慢。同时干法制粒工艺,由于小剂量制剂颗粒大小不均一,容易出现含量均匀度差的问题。
发明内容
针对现有技术存在的问题,本发明提供一种甲磺酸多沙唑嗪口含片及其制备方法,解决了低剂量制剂粉末直压工艺中混合均匀度不合格的问题,避免了压片过程中粉末分层导致含量均匀度不合格的问题,得到了质量均一、服用方便、溶出快、起效快、生物利用度高的甲磺酸多沙唑嗪口含片。
一方面,本发明提供一种甲磺酸多沙唑嗪口含片,包括质量分数为2-3%的D90<10μm的甲磺酸多沙唑嗪、77-94%的可溶性填充剂和余量的助剂,所述助剂包括表面活性剂,所述可溶性填充剂具有网面结构和/或内部空隙。
本发明将甲磺酸多沙唑嗪制成口含片,相较于现有的普通片等制剂,不经过胃肠道吸收,从而避免了首过效应,提高了甲磺酸多沙唑嗪的生物利用度。另外,本发明将D90<10μm即微粉化的甲磺酸多沙唑嗪吸附于可溶性填充剂的表面和/或内部结构,加之使用表面活性剂,可以使得活性成分在混合过程中易于混合均匀,并增大活性成分在溶出时的接触面积,从而能迅速溶出并在口腔中被吸收,大大提高了活性成分的溶解速率,进一步提高本品的生物利用度。
在本发明的优选实施方式中,所述甲磺酸多沙唑嗪口含片包括以下重量份的组分:
在本发明的优选实施方式中,所述可溶性填充剂选自喷雾干燥乳糖、葡萄糖结合剂、甘露醇和山梨醇中的一种或多种。
在本发明的优选实施方式中,所述表面活性剂选自十二烷基硫酸钠、十二烷基磺酸钠和泊洛沙姆中的一种或多种。
在本发明的优选实施方式中,所述矫味剂选自三氯蔗糖、阿司帕坦和糖精钠中的一种或多种。
在本发明的优选实施方式中,所述崩解剂选自羧甲基淀粉钠、交联羧甲基纤维素钠和交联聚维酮中的一种或多种。
在本发明的优选实施方式中,所述粘合剂选自羟丙基纤维素、乙基纤维素和聚维酮中的一种或多种。
在本发明的优选实施方式中,所述润滑剂选自硬脂酸镁、硬脂富马酸钠和山嵛酸甘油酯中的一种或多种。
另一方面,本发明提供上述甲磺酸多沙唑嗪口含片的制备方法,包括以下步骤:
(1)将甲磺酸多沙唑嗪微粉化至粒度D90<10μm;
(2)将微粉化的甲磺酸多沙唑嗪与可溶性填充剂混合,使甲磺酸多沙唑嗪微粉吸附于填充剂表面和/或内部空隙;
(3)将步骤(2)所得混合物与其余组分混合,得到混合粉末;
(4)将步骤(3)所得混合粉末压片。
进一步地,步骤(1)中优选将甲磺酸多沙唑嗪微粉化至粒度D90<5μm。
进一步地,步骤(2)具体包括:将所述可溶性填充剂加入高效混合机中,采用压缩空气将甲磺酸多沙唑嗪微粉喷入所述高效混合机中,充分搅拌。
进一步地,所述高效混合机采用以下参数:压力为0.6~0.8Mpa,搅拌速度为120rpm,切割速度为1500rpm。
本发明提供了一种甲磺酸多沙唑嗪口含片及其制备方法,通过将微粉化的甲磺酸多沙唑嗪吸附于可溶性填充剂的表面和/或内部结构,加之使用表面活性剂,可以使得活性成分在混合过程中易于混合均匀,并增大活性成分在溶出时的接触面积,从而能迅速溶出并在口腔中被吸收,大大提高了活性成分的溶解速率,进一步提高本品的生物利用度。即本发明的甲磺酸多沙唑嗪口含片具有质量均一、服用方便、溶出快、起效快、生物利用度高的特点。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚,下面对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
以下实施例中所涉及的原料及辅料,若无特别声明,均可通过市售购得。
实施例1
本实施例提供一种甲磺酸多沙唑嗪口含片,其制备方法如下:
(1)将2.43g甲磺酸多沙唑嗪采用气流式粉碎机粉碎,得到甲磺酸多沙唑嗪粉末,进气压力为0.6Mpa,进料速度为15rpm,搅拌速度为100rpm,采用马尔文激光粒度仪(干法)检测甲磺酸多沙唑嗪粉末的粒度,检测数据为D90=4.821μm。
(2)将85g葡萄糖结合剂置于混合机中,雾化加入甲磺酸多沙唑嗪粉末,快速搅拌,使甲磺酸多沙唑嗪粉末充分吸附于葡萄糖结合剂的表面和/或内部空隙,雾化压力0.6Mpa,搅拌速度120rpm,切割速度1500rpm;
(3)在上述混合物中加入0.57g阿司帕坦、5g交联羧甲基纤维素钠、4g羟丙基纤维素、2g十二烷基硫酸钠,混合均匀,混合时间15min,转速10rpm;
(4)加入1g硬脂酸镁继续混合均匀,混合时间5min,转速10rpm;
(5)将上述物料压成1000片。
实施例2-4
制备过程同实施例1,具体组分用量及甲磺酸多沙唑嗪微粉后的粒度见下表。
表1实施例2-4的样品组成
对比例1甲磺酸多沙唑嗪口含片的制备(湿法制粒工艺)
(1)将2.43g甲磺酸多沙唑嗪、88g山梨醇、0.57g阿司帕坦、粉碎过80目。
(2)粘合剂溶液配制:将3g聚维酮K30配置成3%水溶液,备用。
(3)制粒:甲磺酸多沙唑嗪、山梨醇、阿司帕坦加入高效湿法制粒机中,混合均匀,加入上述粘合剂溶液制软材,制粒,干燥,得到颗粒。
(4)将上述颗粒、5g交联羧甲基纤维素钠和1g硬脂酸镁加入总混机混合均匀,压成1000片。
对比例2甲磺酸多沙唑嗪口含片的制备(粉末直压工艺)
(1)将2.43g甲磺酸多沙唑嗪、86g山梨醇粉碎过80目。
(2)5g羟丙基纤维素、5g交联羧甲基纤维素钠、0.57g阿司帕坦、1g硬脂酸镁过120目备用。
(3)压片:甲磺酸多沙唑嗪、山梨醇、阿司帕坦加入高效湿法制粒机中,混合均匀,再加入羟丙基纤维素、交联羧甲基纤维素钠、硬脂酸镁混合均匀。
(4)将上述颗粒压成1000片。
试验例1
药品含量均匀度是指单剂量的固体、半固体和非均相液体制剂含量符合标示量的程度,反映了药品质量的均一性和剂量的准确性。本发明实施例1-4和对比例1-2的含量均匀度如下表。
表2实施例1-4和对比例1-2的含量均匀度检测数据
上表显示,本发明实施例1-4的含量均匀度符合规定(A+2.2S<L),且本发明实施例1-4的A+2.2S明显小于对比例,进一步说明本发明质量更为均一。
试验例2
药品的溶出度和崩解时限是与药品在体内释放相关的,反映了药品从药品剂型中释放到胃肠道的过程。
溶出度和崩解时限检测的具体方法如下:
溶出度按照溶出度与释放度测定法(通则0931第二法)测定。
溶出条件:以0.1mol/L的盐酸溶液900ml为溶出介质,转速为每分钟50转,依法操作,经15分钟时取样。
供试品溶液:取溶出液10ml,用0.45μm滤膜滤过,取续滤液。
对照品溶液:取甲磺酸多沙唑嗪对照品10mg,精密称定,置500ml量瓶中,加溶出介质300ml,超声使溶解,放冷,用溶出介质稀释至刻度,摇匀,精密量取适量,用溶出介质定量稀释制成每1ml中约含多沙唑嗪2μg的溶液。
测定法:精密量取供试品溶液与对照品溶液,分别注入液相色谱仪,记录色谱图。按外标法以峰面积计算每片的溶出量。
崩解时限按照崩解时限测定法(通则0921)测定。
检查法:将吊篮通过上端的不锈钢轴悬挂于支架上,浸入1000ml烧杯中,并调节吊篮位置使其下降至低点时筛网距烧杯底部25mm,除另有规定外,按上述装置和方法检查,各片均应在10分钟内全部崩解或溶化。如有1片不符合规定,应另取6片复试,均应符合规定。
杯内盛有温度为37℃±1℃的水,调节水位高度使吊篮上升至高点时筛网在水面下15mm处,吊篮顶部不可浸没于溶液中。
本发明实施例和对比例检测结果见下表。
表3实施例1-4和对比例1-2的溶出度和崩解时限检测数据
样品 | 溶出度 | 崩解时限 |
实施例1 | 99% | 2min |
实施例2 | 98% | 4min |
实施例3 | 98% | 3min |
实施例4 | 101% | 2min |
对比例1 | 85% | 8min |
对比例2 | 88% | 7min |
上表显示,本发明实施例1-4的崩解时限为2~4min,溶出度为98%~101%,说明本发明实施例的产品能迅速溶出,起效快,对比例1-2的崩解时限为7~8min,溶出度为85%~88%,进一步说明本发明相比于湿法制粒和干法制粒制备的口含片,提高了溶出速率,具有溶出快、起效快的特点。
最后应说明的是:以上实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的精神和范围。
Claims (6)
1.一种甲磺酸多沙唑嗪口含片,其特征在于,
由以下重量份的组分组成:
甲磺酸多沙唑嗪 2-3份
可溶性填充剂 77-94份
表面活性剂 0.5-3份
崩解剂 2-5份
粘合剂 1-5份
润滑剂 0.5-2份
矫味剂 0-5份;
所述表面活性剂为十二烷基硫酸钠;所述可溶性填充剂选自喷雾干燥乳糖、葡萄糖结合剂、甘露醇和山梨醇中的一种或多种;
所述甲磺酸多沙唑嗪口含片的制备方法包括以下步骤:
(1)将甲磺酸多沙唑嗪微粉化至粒度D90<10μm;
(2)将所述可溶性填充剂加入高效混合机中,采用压缩空气将微粉化的甲磺酸多沙唑嗪喷入所述高效混合机中,充分搅拌使甲磺酸多沙唑嗪微粉吸附于填充剂表面和/或内部空隙,得到混合物;
(3)将步骤(2)所得混合物与其余组分混合,得到混合粉末;
(4)将步骤(3)所得混合粉末压片。
2.根据权利要求1所述的甲磺酸多沙唑嗪口含片,其特征在于,所述矫味剂选自三氯蔗糖、阿司帕坦和糖精钠中的一种或多种。
3.根据权利要求1所述的甲磺酸多沙唑嗪口含片,其特征在于,所述崩解剂选自羧甲基淀粉钠、交联羧甲基纤维素钠和交联聚维酮中的一种或多种。
4.根据权利要求1所述的甲磺酸多沙唑嗪口含片,其特征在于,所述粘合剂选自羟丙基纤维素、乙基纤维素和聚维酮中的一种或多种。
5.根据权利要求1所述的甲磺酸多沙唑嗪口含片,其特征在于,所述润滑剂选自硬脂酸镁、硬脂富马酸钠和山嵛酸甘油酯中的一种或多种。
6.权利要求1-5任一项所述的甲磺酸多沙唑嗪口含片的制备方法,其特征在于,包括以下步骤:
(1)将甲磺酸多沙唑嗪微粉化至粒度D90<10μm;
(2)将所述可溶性填充剂加入高效混合机中,采用压缩空气将微粉化的甲磺酸多沙唑嗪喷入所述高效混合机中,充分搅拌使甲磺酸多沙唑嗪微粉吸附于填充剂表面和/或内部空隙,得到混合物;
(3)将步骤(2)所得混合物与其余组分混合,得到混合粉末;
(4)将步骤(3)所得混合粉末压片。
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