CN115154429A - 一种他达拉非口腔崩解组合物 - Google Patents
一种他达拉非口腔崩解组合物 Download PDFInfo
- Publication number
- CN115154429A CN115154429A CN202110365346.1A CN202110365346A CN115154429A CN 115154429 A CN115154429 A CN 115154429A CN 202110365346 A CN202110365346 A CN 202110365346A CN 115154429 A CN115154429 A CN 115154429A
- Authority
- CN
- China
- Prior art keywords
- tadalafil
- orally disintegrating
- disintegrating composition
- sodium
- mannitol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 22
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 19
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- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical group [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 14
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
本发明公开了一种他达拉非口腔崩解剂的药用组合物及其制备方法,所述的药用组合物包含他达拉非及其盐5‑20重量分,崩解剂10‑15重量分,增溶剂0‑5重量分,填充剂65‑75重量分,矫味剂1‑4重量分,润滑剂1‑2重量分。本发明所涉及的他达拉非口腔崩解剂质量可控、稳定性好、生物利用度高、工业化操作方便,克服了现有他达拉非口服剂型方面的不足,该崩解剂在口腔中仅需十几秒即可迅速崩解或溶解,服用时不必饮水,随唾液下咽即可完成服药,为医生和患者提供一种服用方便、吸收起效快、生物利用度高的他达拉非口腔崩解组合物,帮助患者实现自然满意性生活需求。
Description
技术领域
本发明属于药物制剂领域,涉及一种具有快速释放药物、且味道良好的口腔崩解片组合物,具体来说为他达拉非口腔崩解片。
背景技术
他达拉非(Tadalafil),商品名希爱力(Cialis),为可逆的、选择性磷酸二酯酶-5抑制剂(PDE5),由礼来公司开发治疗男性勃起功能障碍(ED),2003年11月23日经FDA批准上市,也是FDA批准的第三个用于ED的新药。他达拉非具体的作用机制为:一氧化氮(NO)是引起海绵体平滑肌松弛和勃起的主要介质。他达拉非为磷酸二酯酶(PDE)V选择性抑制剂,能增强在性刺激下NO释放引起的阴茎勃起生理反应。NO从神经末梢和内皮细胞释放出来与海绵体平滑肌上的受体结合,激活细胞内可溶性鸟苷酸环化酶,后者在Mn2+参与下,促使三磷酸鸟苷(GTP)变为环单磷酸鸟苷(cGMP),cGMP激活蛋白激酶G(PKG)和小部分蛋白激酶A(PKA),激活的PKG和PKA通过活化Ca2+泵使细胞内游离Ca2+水平降低,从而导致海绵体平滑肌松弛,动脉血流入,阴茎充血、坚硬、勃起。在人海绵体组织和血管平滑肌中存在PDEV,能使cGMP水解为GMP,阻断使阴茎勃起的NO-cGMP途径。他达拉非为PDEV选择性抑制剂,能防止cGMP的降解,从而能加强性兴奋的阴茎勃起反应。
他达拉非,已被用来治疗勃起功能障碍,上市制剂为片剂,为一种普通薄膜包衣片,该产品含有他达拉非和以下非活性成分:交联羧甲基纤维素钠、羟丙基纤维素、羟丙基甲基纤维素、氧化铁、一水乳糖、硬脂酸镁、微晶纤维素、月桂基硫酸钠、滑石粉、二氧化钛和三乙酸甘油酯。
目前现有技术制备的他达拉非的制剂主要是薄膜包衣片,在口腔中随水被直接吞咽入胃,不会有活性物质的释放。专利CN102727455B公开了他达拉非口崩片的组合物及其制剂制备工艺,该专利中公开了他达拉非口崩片的一般处方组成:
同时公开了通过喷雾干燥制粒再压片的方法来现实他达拉非口崩片的制备,上述专利公开的处方工艺制备他达拉非片工序繁琐,且喷雾干燥过程极难实现,有机试剂丙酮残留较为严重。
专利CN101143145B报道他达拉非口香糖制剂,其在说明书中也提到这种制剂能够提到提高生物利用度,但没有明确其机理,并且作为药学工作者不难知道,口香糖并不是一种临床使用的有效药物制剂,此外,他达拉非是一种难溶性药物,在口香糖基质中很难完全释放,不利于其药用。
专利CN103191075B公开了一种他达拉非口腔崩解片及其制备方法,该发明中采用湿法制粒,使用乳糖为填充剂,口崩片具有多孔结构,与传统片剂相比,它在保质期内对水分更敏感,在他达拉非的口腔崩解片中使用乳糖,使制剂本身存在较大的吸湿性,不利于制剂的稳定存储。
他达拉非为难溶性药物,生物利用度比较低,因此服用的无效剂量比较大,会产生多种不良反应,不合理用药可造成视力损伤或丧失。因此,开发稳定、起效快、服用方便、生物利用度高的他达拉非制剂将造福广大ED患者。
发明内容
本发明的目的在于改进现有的他达拉非口服剂型方面的不足,向医生和患者提供一种服用方便、吸收起效快、生物利用度高、稳定性好、易于产业化的他达拉非口腔崩解组合物,以帮助患者实现自然满意性生活的需求。
本发明的目的在于公开一种他达拉非口腔崩解组合物,能在口腔中快速崩解,所述的口腔崩解组合物各组分以重量百分比计为:
其中,他达拉非口腔崩解片单位剂量中他达拉非及其盐含量选自10mg-20mg,优选为10mg,20mg。
在本发明的一个实施方案中,发现他达拉非口崩片中含有的他达拉非的粒径分布对他达拉非的生物利用度影响较大。经过大量研究确认,预先对他达拉非进行微粉化处理,口崩片的生物利用度明显提高。研究表明,在制备处方前控制他达拉非的粒径D90≤30μm能显著提高制剂的生物利用度。
进一步地,本发明所述的他达拉非口腔崩解组合物中,填充剂选自甘露醇、木糖醇、山梨醇、麦芽糖、赤蘚醇、微晶纤维素、硅化微晶纤维素、乳糖、蔗糖、糊精和淀粉之一或其混合物;
增溶剂选自十二烷基硫酸钠、山梨坦酯、聚山梨酯、泊洛沙姆、聚氧乙烯山梨醇脂肪酸酯、多库酯钠;
崩解剂选自交联聚乙烯吡咯烷酮(PVPP)、羧甲基淀粉钠(CMS-Na)、低取代羟丙基甲基纤维素(L-HPC)、交联羧甲基纤维素钠(CCNa)、羧甲基纤维素、羧甲基纤维素钙之一或其混合物;
矫味剂选自甘露醇、木糖醇、甜菊素、蔗糖、山梨醇、阿斯巴甜、酒石酸、枸橼酸、天然香精或人工合成香精;
润滑剂选自硬脂酸镁、硬脂富马酸钠、聚乙二醇、氢化植物油、硬脂酸、蔗糖酯、胶态二氧化硅、微粉硅胶和滑石粉。
优选地,他达拉非口腔崩解组合物中,填充剂选自甘露醇、木糖醇、山梨醇;
增溶剂选自十二烷基硫酸钠、聚山梨酯、多库酯钠;
崩解剂选自交联羧甲基纤维素钠;
矫味剂选自是阿斯巴甜、甜菊素、天然香精;
润滑剂选自硬脂酸镁、硬脂富马酸钠、胶态二氧化硅。
更进一步地,在本发明的一个实施方案中,在本发明的制剂中崩解剂是交联羧甲基纤维素钠,以提供多孔ODT(Orally disintegrating tablets,口腔速崩片)结构。经过大量研究发现,使用特定粒径的交联羧甲基纤维素钠,可大大增加制剂的溶解度,避免他达拉非微粉化对流动性的影响。经研究发现本发明所述的他达拉非口腔崩解组合物中交联羧甲基纤维素钠的粒径控制在D50≤50μm能显著降低他达拉非微粉化对流动性的影响,优选为7至20μm。
在本发明所述的他达拉非口腔崩解组合物中的一个实施方案中,所用的填充剂是甘露醇,并且粒径需选定特殊范围的。进一步发现,使用特定粒径的甘露醇,能避免他达拉非微粉化对流动性的影响。经研究发现,在制备处方前,本发明所述的他达拉非口腔崩解组合物中填充剂甘露醇的粒径控制在D50≤50μm能显著降低他达拉非微粉化对流动性的影响,优选为3-30μm。
本发明的另一目的在于公开一种产业化程度更高操作更方便的粉末直接压片的方法,关键操作是将增溶剂和他达拉非一同微粉化后加入,优化处方组成并加入了改善口感的矫味剂,制备得到不仅在口腔中能够快速崩解而且口感宜人的他达拉非口崩片,崩解时间最快为十几秒。相较于专利CN103191075B公开的湿法制粒的方法,本发明所采用的干法制粒压片具有工艺过程简单,不必制粒、干燥,节能省时,保护药物稳定性,提高药物溶出度,以及工业自动化程度高等优点。
本发明的一个实施方案中,在本发明的制剂中增溶剂是十二烷基硫酸钠,以增加他达拉非的溶出度。经过大量研究发现,将他达拉非和十二烷基硫酸钠一同微粉化处理,令人惊讶地发现制剂的溶解度显著增加。因而,他达拉非口崩片的制备工艺为:先将他达拉非和十二烷基硫酸钠一同微粉化,再与甘露醇、交联羧甲基纤维素钠、阿斯巴甜(阿司帕坦)和香草香精混合均匀,再加入硬脂酸镁,混合均匀,压片,即得。
与现有技术相比,本发明的有益效果是:1)本发明所公开的他达拉非口崩片溶出度高、稳定性好、工业化操作方便,并能够实现在口腔中仅需十几秒即可迅速崩解或溶解效果,服用时不必饮水,随唾液下咽即可完成服药,为医生和患者提供一种服用方便、吸收起效快、生物利用度高的他达拉非口腔崩解组合物,大大提高了本药物在临床使用时的依从性;2)本发明研究发现,使用特定粒径的甘露醇和交联羧甲基纤维素钠可大大增加制剂的溶解性,且用甘露醇作填充剂,不仅提高了他达拉非的口腔崩解片的稳定性,同时出人意料地解决了他达拉非的溶解性问题,并在此基础上制备得到了快速释放的高品相的他达拉非口崩片。
具体实施方式
给出以下本发明中具有代表性的实施例以说明本发明的内容,但是不意欲在任何方面限制本发明。实施例中的他达拉非即指他达拉非或其盐,给出的量均值重量比(w/w),且是基于他达拉非的量。
实施例1
他达拉非口崩片20mg
处方:1000片
操作方法:
将他达拉非和十二烷基硫酸钠微粉化,加入羧甲淀粉钠、甘露醇和阿司帕坦混合均匀,再加入滑石粉混合,压制成片。
实施例2
他达拉非口崩片10mg
处方:1000片
操作方法:将他达拉非和十二烷基硫酸钠微粉化,加入交联聚维酮、蔗糖和甜菊素混合均匀,再加入硬脂酸镁混合,压制成片。
实施例3
他达拉非口崩片20mg
处方:1000片
操作方法:将他达拉非和十二烷基硫酸钠微粉化,加入交联羧甲基纤维素钠、甘露醇、香草香精和阿司帕坦混合均匀,再加入硬脂酸镁混合,压制成片。
实施例4
他达拉非口崩片10mg
处方:1000片
操作方法:将他达拉非和十二烷基硫酸钠微粉化,加入交联羧甲基纤维素钠、甘露醇、香草香精和阿司帕坦混合均匀,再加入硬脂酸镁混合,压制成片。
实施例5
他达拉非口崩片20mg
处方:1000片
操作方法:将他达拉非和十二烷基硫酸钠微粉化,加入交联羧甲基纤维素钠、甘露醇、香草香精和阿司帕坦混合均匀,再加入硬脂酸镁混合,压制成片。
实施例6
他达拉非口崩片10mg
处方:1000片
操作方法:将他达拉非和十二烷基硫酸钠微粉化,加入交联羧甲基纤维素钠、甘露醇、香草香精和阿斯巴甜混合均匀,再加入硬脂酸镁混合,压制成片。
实施例7 样品测试
1、实施例1-6制得的样品与专利CN102727455B公开方法所制备的他达拉非口崩片样品的检测:
取不同实施例的口崩片置于2mL水中,测定完全崩解的时间;再随机选12名身体健康,无吸烟、酗酒等不良嗜好的20-40岁志愿者,男女各半,取不同实施例的口崩片供志愿者口服,每次吞服2min后吐出,并用温水漱口数次,评价口崩片的口感。
结果如表1所示:
表1 崩解时间与口感测试
2、将实施例3-6样品与专利CN103191075B公开方法所制备的他达拉非口崩片(对照例)进行溶出度比较测试
使用HPLC法测定实施例3-6所得的他达拉非片和对照例的溶出度,测试数据如表2所示:
表2 溶出度测试
可见,通过干法制粒工艺生产的他达拉非口崩片在溶出度方面具有一定优势,并且本发明的干法生产工艺大大简化了生产步骤,减少了物料损失,从而降低了生产成本。
3、 将最优的实施例4制备的他达拉非口崩片进行30天影响因素试验具体操作为:将他达拉非口崩片分别在高温(60℃)、高湿(92.5%)、光照(4500lux)条件下放置30天,观察片剂的外观,并通过HPLC法检测片剂的有关物质和含量。检测结果见表3、表4、表5:
表3 他达拉非口崩片在高温60℃条件下放置30天后测定结果
表4 他达拉非口崩片在高湿92.5%条件下放置30天后测定结果
表5 他达拉非口崩片在光照(4500lux)条件下放置30天后测定结果
根据表3~表5的数据可知影响因素30天条件下,本发明公开的他达那非口崩片稳定,不易降解,30天内口崩片的总杂没有明显变化,在合理的限度范围内,药品含量没有任何变化,表明用上述方法制得的口崩片质量可靠、稳定。
Claims (10)
2.根据权利要求1所述的他达拉非口腔崩解组合物,其特征在于所述的口腔崩解组合物单位剂量中他达拉非及其盐含量选自10mg-20mg。
3.根据权利要求2所述的他达拉非口腔崩解组合物,其特征在于所述的口腔崩解组合物单位剂量中他达拉非及其盐含量选自10mg,20mg。
4.根据权利要求1所述的他达拉非口腔崩解组合物,其特征在于所述的口腔崩解组合物含有的他达拉非及其盐粒径D90≦30μm。
5.根据权利要求1所述的他达拉非口腔崩解组合物,其特征在于:
所述的填充剂选自甘露醇、木糖醇、山梨醇、麦芽糖、赤蘚醇、微晶纤维素、硅化微晶纤维素、乳糖、蔗糖、糊精和淀粉之一或其混合物;
增溶剂选自十二烷基硫酸钠、山梨坦酯、聚山梨酯、泊洛沙姆、聚氧乙烯山梨醇脂肪酸酯、多库酯钠;
崩解剂选自交联聚乙烯吡咯烷酮(PVPP)、羧甲基淀粉钠(CMS-Na)、低取代羟丙基甲基纤维素(L-HPC)、交联羧甲基纤维素钠(CCNa)、羧甲基纤维素、羧甲基纤维素钙之一或其混合物;
矫味剂选自甘露醇、木糖醇、甜菊素、蔗糖、山梨醇、阿斯巴甜、酒石酸、枸橼酸、天然香精或人工合成香精;
润滑剂选自硬脂酸镁、硬脂富马酸钠、聚乙二醇、氢化植物油、硬脂酸、蔗糖酯、胶态二氧化硅、微粉硅胶和滑石粉。
6.根据权利要求5所述的他达拉非口腔崩解组合物,其特征在于:
所述的填充剂选自甘露醇、木糖醇、山梨醇;
增溶剂选自十二烷基硫酸钠、聚山梨酯、多库酯钠;
崩解剂选自交联羧甲基纤维素钠;
矫味剂选自是阿斯巴甜、甜菊素、天然香精;
润滑剂选自硬脂酸镁、硬脂富马酸钠、胶态二氧化硅。
7.根据权利要求6所述的他达拉非口腔崩解组合物,其特征在于,所述的崩解剂交联羧甲基纤维素钠的粒径D50≦50μm。
8.根据权利要求7所述的他达拉非口腔崩解组合物,其特征在于,所述的崩解剂交联羧甲基纤维素钠的粒径D50为7-20μm。
9.根据权利要求6所述的他达拉非口腔崩解组合物,其特征在于,所述的填充剂选自甘露醇,其粒径D50≦50μm。
10.根据权利要求9所述的他达拉非口腔崩解组合物,其特征在于,所述的填充剂甘露醇粒径D50为3-30μm。
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