CN117482053A - 一种替米沙坦的制粒方法及其固体制剂的制备方法 - Google Patents
一种替米沙坦的制粒方法及其固体制剂的制备方法 Download PDFInfo
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- 239000005537 C09CA07 - Telmisartan Substances 0.000 title claims abstract description 60
- 229960005187 telmisartan Drugs 0.000 title claims abstract description 60
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 24
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Abstract
本发明涉及一种替米沙坦的制粒方法,采用一步制粒法和干法制粒结合的方式,通过改变溶剂种类及用量,同时在一步制粒过程中通入气体,可有效解决较低温度下带来的塌床问题,提高了生产效率。
Description
技术领域
本发明属于药物制剂技术领域,具体而言,涉及一种治疗高血压的药物制剂,尤其涉及一种替米沙坦的制粒方法及其固体制剂的制备方法。
背景技术
替米沙坦(telmisartan),化学名为4'-[[4-甲基-6-(1-甲基-2-苯并咪唑基)-2-丙基-1-苯并咪唑基]甲基]-2-联苯甲酸。分子式为C33H30N4O2,分子量:514.63,结构式如下:
替米沙坦片由勃林格殷格翰(Boehringer Ingelheim)开发,首先于1998年11月10日获美国食品药品管理局(FDA)批准,之后于1998年12月11日获得欧洲药物管理局(EMA)批准,替米沙坦是一种血管紧张素II受体阻断剂(ARB),可选择性地与血管紧张素II ATl受体亚型持久结合,达到稳定降血压效果。该药适用治疗高血压,以减少中风和心肌梗塞等致命和非致命性心血管事件的风险;同时可用于无法接受血管紧张素转换酶(ACE)抑制剂患者的心血管(CV)风险的降低。
替米沙坦是BCS2类药物,为白色或类白色结晶性粉末,无臭,无味在三氯甲烷中溶解,在二氯甲烷或N,N-二甲基甲酰胺中略溶,在甲醇中微溶,在乙醇中极微溶解,在水中几乎不溶;在1mol/L氢氧化钠溶液中易溶,在0.1mol/L盐酸溶液中极微溶解。替米沙坦的吸收很快,但吸收量却有差异。替米沙坦的平均绝对生物利用度大约为50%。当替米沙坦与食物同服时,替米沙坦的血浆浓度-时间曲线下面积(AUC)降低大约6%(40mg剂量)至19%(160mg剂量)。空腹服用或与食物同服替米沙坦在给药3小时后血浆药物浓度相似。AUC少量降低预计不会导致治疗有效性降低。
US 8980870 B2原研厂家主要通过如下技术来解决替米沙坦片的溶出问题:将替米沙坦溶于氢氧化钠溶液中,加入葡甲胺使其形成替米沙坦钠盐,然后通过喷雾干燥技术形成固体分散体粉末,再外加辅料压片,但是此工艺需具备大型喷雾干燥设备,使生产具有局限性。
CN107811984A公开了一种替米沙坦片剂的制备方法,将替米沙坦、氢氧化钠、聚维酮、溶于纯化水中制浆,以甘露醇为底粉在流化床中制粒,得到干燥的颗粒,再外加乳糖、葡甲胺及硬脂酸镁压片,制粒过程中进风温度90-95℃,生产中温度很高,容易引起药物的有关物质增多,葡甲胺在含药颗粒的外部加入,只能与药物部分直接接触,会造成药物溶解度提高不明显的问题。
发明内容
本发明针对现有技术喷雾干燥温度较高容易引起药物的有关物质增多的问题,试图开发一种能够在较低温度下进行替米沙坦制粒的方法,通过对溶剂的筛选以及工艺的优化,在一步制粒过程中通入氮气,明显解决较低温度下塌床问题、提高产品的生产效率,在一步制粒基础上再次进行干法制粒,可有效控制了产品体外溶出速率,确保与参比制剂体内外的一致性,有利于保证产品的安全性和有效性。
本发明具体技术方案如下:
一种替米沙坦的制粒方法,包括如下步骤:
(1)一步制粒法制粒:将氢氧化钠溶于乙醇水溶液中,加入替米沙坦、葡甲胺、聚维酮K25得到混合溶液,将山梨醇加入流化床,向混合溶液通入压缩空气或氮气喷入流化床进行一步制粒;
(2)干法制粒:步骤(1)制得的颗粒加入适量硬脂酸镁进行干法制粒。
优选的,所述步骤(1)乙醇水溶液的体积百分比为20~40%。
本发明所述替米沙坦的制粒方法,优选一步制粒参数为:雾化压力2.0bar,喷液速度75g/min~300g/min,温度50℃~60℃。干法制粒参数为:油泵压力10kg/cm3~50kg/cm3,整粒网孔径0.6mm~2.0mm,辊轮频率5Hz~30Hz。
上述方法中,各组分重量份如下:
替米沙坦32~48份、氢氧化钠2.688~4.032份、聚维酮K25 9.6~14.4份、葡甲胺9.6~14.4份、山梨醇134.912~202.368份、硬脂酸镁3.2~4.8份。
本发明另一目的在于提供一种替米沙坦固体制剂的制备方法,所述固体制剂采用本发明所述方法进行替米沙坦制粒。
所述的替米沙坦固体制剂还含有其它药物,其它药物使用混合直压工艺,将替米沙坦总混物与其它药物及辅料总混物压片。
本发明一个具体的示例,所述替米沙坦固体制剂为双层片剂,将替米沙坦总混物与其它药物及辅料总混物进行双层片压制。
本发明一个具体的示例,所述其它药物为苯磺酸氨氯地平,所述辅料包括微晶纤维素、预胶化淀粉、玉米淀粉、黄氧化铁、胶态二氧化硅和硬脂酸镁。优选各组分重量份如下:苯磺酸氨氯地平5.548~8.322份、微晶纤维素100.61~150.918份、预胶化淀粉42.4~63.6份、玉米淀粉8~12份、黄氧化铁0.24~0.36份、胶态二氧化硅1.6~2.4份、硬脂酸镁1.6~2.4份。本发明优点:
通过对溶剂的筛选以及工艺的优化,在一步制粒过程中通入氮气,明显解决较低温度下塌床问题、提高产品的生产效率,在一步制粒基础上再次进行干法制粒,可有效控制了产品体外溶出速率,确保与参比制剂体内外的一致性,有利于保证产品的安全性和有效性。
具体实施方式
1、物料信息
名称 | 批号 |
替米沙坦 | Y230206251 |
氢氧化钠 | F230207201 |
葡甲胺 | F220711253 |
山梨醇 | F221229251S1 |
聚维酮K25 | F221226251 |
无水乙醇 | 20230414 |
2、设备信息
名称 | 型号 |
TCS-8型电子台秤 | TCS-8型 |
TCS-100电子台秤 | TCS-100 |
流化床 | GPCG PRO 60 |
干法制粒机 | GL5-50 |
3、处方
实施例1~5一步制粒法制备替米沙坦固体制剂
将氢氧化钠溶于水或乙醇溶液中,然后加入替米沙坦、葡甲胺、聚维酮K25。将山梨醇加入流化床,将替米沙坦溶液以压缩空气或氮气的形式喷入流化床进行一步制粒,参数如表1所示。将干颗粒使用1.0mm筛网进行干整粒。整粒后加入适量硬脂酸镁进行总混。按处方表称取氨氯地平及其辅料进行总混。最后,将替米沙坦总混物与氨氯地平总混物进行双层片压制。
表1
项目 | 实施例1 | 实施例2 | 实施例3 | 实施例4 | 实施例5 |
纯化水(kg) | 72 | 72 | 50.4 | 50.4 | 50.4 |
无水乙醇(kg) | 0 | 0 | 21.6 | 21.6 | 21.6 |
雾化压力(bar) | 2.0 | 2.0 | 2.0 | 2.0 | 2.0 |
喷液速度(g/min) | 150 | 75 | 150 | 225 | 300 |
物料温度(℃) | 60 | 60 | 55 | 55 | 50 |
氮气 | 否 | 否 | 否 | 否 | 是 |
实施例1~5的一步制粒过程结果如表2所示。
表2
实施例 | 1 | 2 | 3 | 4 | 5 |
工艺可行性 | 塌床 | 耗时很长 | 耗时较长 | 良好 | 良好 |
制粒时间(h) | 10 | 21 | 10 | 7 | 5 |
结果显示一步制粒过程中仅使用水时,出现塌床现象,只能通过降低喷液速度缓解这一问题。在水中加入适量乙醇能够有效解决塌床问题,明显缩短制粒时间。若进一步将替米沙坦溶液通入氮气喷入流化床,可实现制粒温度降至50℃。
进一步考察实施例1~5的药物溶出情况,结果如表3所示。
表3(参比制剂批号:22B1423规格:40mg/5mg商品名:Twynsta生产商:BoehringerIngelheim International GmbH)
结果显示仅使用一步制粒法制粒制得的固体制剂溶出较快,效果不理想。
实施例6~10一步制粒法+干法制粒制备替米沙坦固体制剂
研究一步制粒法使用不同浓度乙醇溶液下结合干法制粒对固体制剂的影响。
表4
项目 | 实施例6 | 实施例7 | 实施例8 | 实施例9 | 实施例10 |
纯化水(kg) | 68.4 | 64.8 | 57.6 | 50.4 | 43.2 |
无水乙醇(kg) | 3.6 | 7.2 | 14.4 | 21.6 | 28.8 |
氮气 | 是 | 是 | 是 | 是 | 是 |
油泵压力(kg/cm3) | 50 | 50 | 50 | 10 | 50 |
整粒网孔径(mm) | 1 | 1 | 0.6 | 2 | 1 |
辊轮频率(Hz) | 25 | 25 | 30 | 5 | 25 |
将氢氧化钠溶于乙醇水溶液中,然后加入替米沙坦、葡甲胺、聚维酮K25。将山梨醇加入流化床,将替米沙坦溶液在雾化压力2.0bar,喷液速度300g/min,物料温度50℃条件下,以氮气的形式喷入流化床进行一步制粒。将干颗粒使用1.0mm筛网进行干整粒。整粒后加入适量硬脂酸镁,按照上表参数进行干法制粒,干法制粒颗粒加入适量硬脂酸镁总混。按处方表称取氨氯地平及其辅料进行混合。最后,将替米沙坦总混物与氨氯地平总混物进行双层片压制。
实施例6~10的一步制粒+干法制粒过程结果如表5所示。
表5
实施例 | 实施例6 | 实施例7 | 实施例8 | 实施例9 | 实施例10 |
工艺可行性 | 良好 | 良好 | 良好 | 良好 | 良好 |
辊轮粘附情况 | 粘 | 粘 | 不粘 | 不粘 | 不粘 |
结果显示乙醇重量百分比在5%~10%范围内,干法制粒出现辊轮粘附的现象,分析原因,可能是一步制粒过程中乙醇占比较小、纯化水占比较大,导致颗粒水分过大,使得干法制粒出现辊轮粘附。乙醇浓度在20%~40%范围内,干法制粒辊轮不粘附,故合适的乙醇浓度可以改善辊轮粘附情况。
进一步考察实施例6~10的药物溶出情况,结果如表6所示。
表6(参比制剂批号:22B1423规格:40mg/5mg商品名:Twynsta生产商:BoehringerIngelheim International GmbH)
结果显示,一步制粒后增加干法制粒的步骤可以减缓固体制剂的溶出速度,一步制粒过程中乙醇溶液浓度较低时,制得的替米沙坦干颗粒在干法制粒过程出现粘辊轮现象,乙醇浓度在20%~40%会改善粘辊轮现象,当油泵压力50kg/cm3,整粒网孔径1.0mm,辊轮频率25Hz,进行干法制粒,固体制剂的药物溶出行为比较理想。
实施例11
取36只雄性SD大鼠(体重180g~220g),随机分成四组,灌胃给药,给药剂量3.2mg/0.4mg/kg,分别给予实施例5、9、10制得的药物制剂,于给药前及给药后2min,5min,10min,15min,30min,45min,1h,1.5h,2h,4h,6h,8h眼静脉丛采血,测定血浆中的替米沙坦和氨氯地平的血药浓度。结果见表7。
表7
结果显示,采用一步制粒+干法制粒的方法进行替米沙坦制粒制得的固体制剂组大鼠AUC明显高于只采用一步制粒进行替米沙坦制粒制得到的固体制剂组,说明本发明的制备工艺可行性强,得到的替米沙坦氨氯地平片与原研更相近。
Claims (10)
1.一种替米沙坦的制粒方法,其特征在于包括如下步骤:
(1)一步制粒法制粒:将氢氧化钠溶于乙醇水溶液中,加入替米沙坦、葡甲胺、聚维酮K25得到混合溶液,将山梨醇加入流化床,向混合溶液通入压缩空气或氮气喷入流化床进行一步制粒;
(2)干法制粒:步骤(1)制得的颗粒加入适量硬脂酸镁进行干法制粒。
2.根据权利要求1所述替米沙坦的制粒方法,其特征在于所述乙醇水溶液的重量百分比为20~40%。
3.根据权利要求1所述替米沙坦的制粒方法,其特征在于,一步制粒参数为:雾化压力2.0bar,喷液速度75g/min~300g/min,干燥温度50℃~60℃。
4.根据权利要求1所述替米沙坦的制粒方法,其特征在于,干法制粒参数为:油泵压力10kg/cm3~50kg/cm3,整粒网孔径0.6mm~2.0mm,辊轮频率5Hz~30Hz。
5.根据权利要求1-4任一项所述替米沙坦的制粒方法,其特征在于各组分重量份如下:替米沙坦32~48份、氢氧化钠2.688~4.032份、聚维酮K25 9.6~14.4份、葡甲胺9.6~14.4份、山梨醇134.912~202.368份、硬脂酸镁3.2~4.8份。
6.一种替米沙坦固体制剂的制备方法,其特征在于采用权利要求1-5任一项所述方法对替米沙坦进行制粒。
7.根据权利要求6所述的替米沙坦固体制剂的制备方法,其特征在于所述固体制剂还含有其它药物,其它药物使用混合直压工艺,将含有权利要求1-5任一项所述方法制得的替米沙坦总混物与其它药物及辅料总混物压片。
8.根据权利要求6所述的替米沙坦固体制剂的制备方法,其特征在于所述替米沙坦固体制剂为双层片剂,将替米沙坦总混物与其它药物及辅料总混物进行双层片压制。
9.根据权利要求6-8任一项所述的替米沙坦固体制剂的制备方法,其特征在于所述其它药物为苯磺酸氨氯地平,所述辅料包括微晶纤维素、预胶化淀粉、玉米淀粉、黄氧化铁、胶态二氧化硅和硬脂酸镁。
10.根据权利要求9所述的替米沙坦固体制剂的制备方法,其特征在于其它药物和辅料的重量份如下:
苯磺酸氨氯地平5.548~8.322份、微晶纤维素100.61~150.918份、预胶化淀粉42.4~63.6份,玉米淀粉8~12份、黄氧化铁0.24~0.36份、胶态二氧化硅1.6~2.4份、硬脂酸镁1.6~2.4份。
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