CN115300506A - 含有坦索罗辛和米拉贝隆的复方制剂及其制备方法 - Google Patents
含有坦索罗辛和米拉贝隆的复方制剂及其制备方法 Download PDFInfo
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- CN115300506A CN115300506A CN202210961886.0A CN202210961886A CN115300506A CN 115300506 A CN115300506 A CN 115300506A CN 202210961886 A CN202210961886 A CN 202210961886A CN 115300506 A CN115300506 A CN 115300506A
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- Prior art keywords
- mirabegron
- tamsulosin
- granules
- sodium
- preparation
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- DRHKJLXJIQTDTD-OAHLLOKOSA-N Tamsulosine Chemical compound CCOC1=CC=CC=C1OCCN[C@H](C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 DRHKJLXJIQTDTD-OAHLLOKOSA-N 0.000 title claims abstract description 35
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Abstract
含有坦索罗辛和米拉贝隆的复方干混悬剂及其制备方法,坦索罗辛和米拉贝隆独立制粒,坦索罗辛与丙烯酸乙酯‑甲基丙烯酸甲酯(2:1)共聚物喷雾包衣至60‑80目的微晶纤维素丸芯上,再包一层甲基丙烯酸‑丙烯酸乙酯(1:1)共聚物的肠溶衣;米拉贝隆与聚苯乙烯磺酸钠混合,通过湿法制粒制成颗粒。本发明的干混悬剂缓慢释放,稳定性好,具有掩味效果。
Description
技术领域
本发明属于生物制药领域,涉及包含坦索罗辛和米拉贝隆的复方制剂,具体地说,本发 明涉及包含盐酸坦索罗辛和米拉贝隆的复方干混悬剂,含有独立制备的盐酸坦索罗辛缓释颗 粒和米拉贝隆颗粒。
背景技术
良性前列腺增生(benignprostatic hyperplasia,BPH)是中老年男性人群中的常见疾病, 主要症状为下尿路症状(lower urinary tract symptoms,LUTS),包括尿急、尿频、尿不尽等, 严重时可能出现膀胱出口梗阻(bladder outlet obstruction,BOO)。BPH发病原因尚不明确,其 发病率随年龄的增加而增加,有报道50岁以上男性人群中发病率超过50%,80岁以后发病 率接近90%。BPH诊断治疗指南推荐的药物大多为α-受体阻滞剂、5α-还原酶抑制剂,α-受体 阻滞剂类药物主要有哌唑嗪、多沙唑嗪、特拉唑嗪、阿呋唑嗪、坦索罗辛、萘哌地尔等,5α- 还原酶抑制剂类药物主要有非那雄胺、度他雄胺、爱普列特等。
坦索罗辛为第三代选择性α1受体阻滞剂,对平滑肌的α1受体具有强大的拮抗作用,选择 性作用于下尿路平滑肌产生尿膀胱和前列腺周围的平滑肌松弛。盐酸坦索罗辛化学名为 (-)-(R)-5-[2-[[2-(2-乙氧基苯氧基)乙基]氨基]丙基]-2-甲氧基苯-1-磺酰胺盐酸盐,分子式为 C20H28N2O5S·HCl,其结构式如下图1。
盐酸坦索罗辛由山之内制药(现安斯泰来制药)开发,1993年在日本获批上市,商品名 harnal,为0.1mg、0.2mg的口腔崩解片,仅用唾液就能在口腔内崩解,对于吞咽功能下降的 老年患者服用比较有利。1997年在美国获批上市的盐酸坦索罗辛胶囊,商品名为规格为0.4mg,每日服药1次,服用时不能压碎、嚼碎或打开胶囊。此盐酸坦索罗辛制剂为 缓释胶囊,一个剂量能维持24小时药效。
米拉贝隆,是具有下列结构式的β3-肾上腺素受体激动剂,其化学名为(R)-2-(2-氨基噻唑 -4-基)-4-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰苯胺,临床用于成年膀胱过度活动症 (overactive bladder,OAB)患者尿急、尿频或急迫性尿失禁的对症治疗。米拉贝隆是第一个用 于治疗OAB的β3-肾上腺素受体激动剂,通过抑制膀胱传入神经活动,尤其是抑制与膀胱微 小收缩相关的δ纤维来调节膀胱逼尿肌的收缩,松弛逼尿肌,延迟膀胱排尿反射,使两次排尿 间隔延长。临床所用为米拉贝隆缓释片,有25mg、50mg两个规格,老年患者推荐剂量为50mg, 每日一次,服用时应整片吞服,不得咀嚼、掰开或压碎。其结构式如下图2。
一些研究表明,在男性群体中OAB、BOO、BPH三者为常见合并症状。坦索罗辛和米拉贝隆的作用靶点不同,将坦索罗辛和米拉贝隆制成复方制剂,可以改善BPH患者的储尿、排尿及混合症状,尤其对于治疗伴有OAB症状的男性BPH患者,具有更佳的治疗效果。与 同时服用两种药物相比,复方制剂可减少患者每次用药数量,提高顺应性,也能减少费用, 可以为BPH患者提供更理想的治疗方案。坦索罗辛和米拉贝隆组成复方制剂也有相关报道,韩国专利KR20190089768A记录了含有坦索罗辛和米拉贝隆的组合物,分成两个部分制备,米拉贝隆部分含有聚乙烯醇作为稳定剂,制成双层片或胶囊剂形式。KR20210012082A记录了含有坦索罗辛和米拉贝隆的双层控释片。
BPH的发病率与年龄相关,随年龄增加患病率增加,老年患者可能会存在吞咽困难、肝 肾功能不全等情况,这些患者片剂、胶囊剂等制剂可能并不适用,而混悬剂则更方便服用、 也容易分剂量。干混悬剂以固体状态运输、储存,使用时临时加水成混悬水溶液,运输方便 也利于吞咽服药,而且容易分剂量。
发明内容
本发明提供了一种含有坦索罗辛和米拉贝隆两个活性成分的复方干混悬剂,具有缓慢释 放的特性。两个活性成分独立地制粒,各自含有不同的树脂材料,其中一种颗粒进行包衣, 使两个活性成分物理隔绝,避免主成分间的相互作用,提高了稳定性。
混悬剂系指难溶性固体药物以微粒状态分散于分散介质中形成的非均匀的液体制剂,干混悬剂 是按照混悬剂的要求将药物用适宜方法制成粉末状或颗粒状制剂,使用时加水即迅速分散成混悬剂。 干混悬剂比混悬剂更便于运输、储存,稳定性也更好。缓释制剂系指在规定的释放介质中,按要求 缓慢地非恒速释放药物,与相应的普通制剂比较,给药频率减少,且能显著增加患者依从性的制剂。
坦索罗辛和米拉贝隆的联合应用已有报道,单独的坦索罗辛缓释制剂和米拉贝隆缓释制剂也已 上市,但含这两个成分的复方缓释干混悬剂目前尚无。这需要有一种技术能将这两个成分制成一个 复方制剂,不仅能发挥缓释作用,以满足一天用药一次,而且需解决两个成分潜在的相互作用,保 证混悬剂的化学稳定性,另外需满足混悬剂良好的口味要求,本发明提供的含坦索罗辛和米拉贝隆 的复方干混悬剂很好的满足了上述要求。
本发明采用将坦索罗辛和米拉贝隆各自单独制粒,分别制成包含坦索罗辛和丙烯酸乙酯-甲基 丙烯酸甲酯(2:1)共聚物的颗粒和包含米拉贝隆和聚苯乙烯磺酸钠的颗粒,两种颗粒混合其 它助剂后形成具有缓释特性的干混悬剂。本专利发明人通过研究发现,在坦索罗辛颗粒制备 中使用丙烯酸乙酯-甲基丙烯酸甲酯(2:1)共聚物,在米拉贝隆颗粒的制备过程中使用聚苯乙 烯磺酸钠,可以达到所需要的缓释作用,同时树脂材料能很好的掩盖化学药物的不良臭味, 在加入其它助剂后具有良好的口感。通过颗粒包衣,将两种活性成分进行物理隔离,保证了 混悬剂的化学稳定性。
本发明采用的制备技术具体如下:
含坦索罗辛的颗粒制备方法:将盐酸坦索罗辛均匀分散于相当于盐酸坦索罗辛重量3-6 倍的丙烯酸乙酯-甲基丙烯酸甲酯(2:1)共聚物的溶液中,使用流化床将溶液喷雾至60-80目 的微晶纤维素丸芯上,再将包衣材料的溶液喷雾在含盐酸坦索罗辛的颗粒上,形成一层包衣 层。采用的包衣材料为甲基丙烯酸-丙烯酸乙酯(1:1)共聚物。
含米拉贝隆的颗粒制备方法:将米拉贝隆与相当于米拉贝隆重量1-3倍的聚苯乙烯磺酸 钠放入制粒机,搅拌混合,再加入粘合剂,湿法制粒制成颗粒。加入的粘合剂可以是羟丙基 纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、羧甲基纤维素、羧甲基纤维素钠、甲基纤维 素的一种,优选采用羟丙基甲基纤维素。
本发明采用的其它助剂为混悬剂常规所需的助悬剂、抑菌剂、矫味剂等,其中所述的助 悬剂包括但不限于阿拉伯胶、西黄耆胶、黄原胶、卡拉胶、海藻酸钠、羧甲基纤维素、羟乙 基纤维素的一种或几种,优选为黄原胶;其中所述的抑菌剂采用羟苯甲脂、羟苯丁酯;其中 所述的矫味剂包括但不限于甘露醇、山梨醇、蔗糖、葡萄糖、麦芽糖醇、糖精钠、甜蜜素、甜菊糖苷、阿斯巴甜、乙酰磺胺酸钾中的一种或几种。
附图说明
图1示出了本发明盐酸坦索罗辛化学结构式,图2示出了本发明米拉贝隆化学结构式。
图3示出了本发明盐酸坦索罗辛的溶出曲线,图4示出了本发明米拉贝隆的溶出曲线。
具体实施方式
通过下面的实施例对本发明进行进一步描述,然而,本发明的范围并不限于下述实施例,以下 实施例并不限制本发明。
实施例1:复方坦索罗辛米拉贝隆干混悬剂1
1、盐酸坦索罗辛颗粒制备:取盐酸坦索罗辛5g加入50ml纯化水中,搅拌使溶解,依次加入滑 石粉1.5g,丙烯酸乙酯-甲基丙烯酸甲酯(2:1)共聚物15g,搅拌混合均匀,得到药物溶液,备 用;依次将柠檬酸三乙酯1g、滑石粉2.5g、甲基丙烯酸-丙烯酸乙酯(1:1)共聚物30g加入30ml 纯化水中,搅拌混合均匀,得包衣液;取80-100目的纤维素丸芯500g加入流化床,控制物料温度 25-35℃,进风风量1-1.5m3,雾化压力1-2bar,先后喷入上述药物溶液和包衣液,两次喷液中间干燥 5-10min,即得。
2、米拉贝隆颗粒制备:取米拉贝隆500g,聚苯乙烯磺酸钠500g,羟丙基纤维素600g,加入高 速制粒机,搅拌速度100rpm混合15min,加入适量纯化水,搅拌100rpm,切碎1500rpm制粒,60℃ 烘干,即得。
3、制备干混悬剂:根据颗粒含量将盐酸坦索罗辛颗粒、米拉贝隆颗粒加入混合机,分别加入占 总重0.2%的黄原胶、0.1%的羟苯甲脂、0.01%的羟苯丙酯、0.01%的糖精钠,混合30min,即得。
实施例2:复方坦索罗辛米拉贝隆干混悬剂2
1、盐酸坦索罗辛颗粒制备:取盐酸坦索罗辛5g加入50ml纯化水中,搅拌使溶解,依次加入滑 石粉2.3g,丙烯酸乙酯-甲基丙烯酸甲酯(2:1)共聚物23g,搅拌混合均匀,得到药物溶液,备用; 依次将柠檬酸三乙酯1g、滑石粉2.5g、甲基丙烯酸-丙烯酸乙酯(1:1)共聚物30g加入30ml纯化 水中,搅拌混合均匀,得包衣液;取80-100目的纤维素丸芯500g加入流化床,控制物料温度25-35℃, 进风风量1-1.5m3,雾化压力1-2bar,先后喷入上述药物溶液和包衣液,两次喷液中间干燥5-10min, 即得。
2、米拉贝隆颗粒制备:取米拉贝隆500g,聚苯乙烯磺酸钠1000g,羟丙基甲基纤维素300g,加 入高速制粒机,搅拌速度100rpm混合15min,加入适量纯化水,搅拌100rpm,切碎1500rpm制粒, 60℃烘干,即得。
3、制备干混悬剂:根据颗粒含量将盐酸坦索罗辛颗粒、米拉贝隆颗粒加入混合机,分别加入占 总重0.2%的黄原胶、0.1%的羟苯甲脂、0.01%的羟苯丙酯、0.01%的糖精钠,混合30min,即得。
实施例3:复方坦索罗辛米拉贝隆干混悬剂3
1、盐酸坦索罗辛颗粒制备:取盐酸坦索罗辛5g加入50ml纯化水中,搅拌使溶解,依次加入滑 石粉3g,丙烯酸乙酯-甲基丙烯酸甲酯(2:1)共聚物30g,搅拌混合均匀,得到药物溶液,备用; 依次将柠檬酸三乙酯1g、滑石粉2.5g、甲基丙烯酸-丙烯酸乙酯(1:1)共聚物30g加入30ml纯化 水中,搅拌混合均匀,得包衣液;取80-100目的纤维素丸芯500g加入流化床,控制物料温度25-35℃, 进风风量1-1.5m3,雾化压力1-2bar,先后喷入上述药物溶液和包衣液,两次喷液中间干燥5-10min, 即得。
2、米拉贝隆颗粒制备:取米拉贝隆500g,聚苯乙烯磺酸钠500g,羟丙基甲基纤维素300g,加 入高速制粒机,搅拌速度100rpm混合15min,加入适量纯化水,搅拌100rpm,切碎1500rpm制粒, 60℃烘干,即得。
3、制备干混悬剂:根据颗粒含量将盐酸坦索罗辛颗粒、米拉贝隆颗粒加入混合机,分别加入占 总重0.2%的黄原胶、0.1%的羟苯甲脂、0.01%的羟苯丙酯、0.01%的甜蜜素,混合30min,即得。
实施例4:复方坦索罗辛米拉贝隆干混悬剂4
1、盐酸坦索罗辛颗粒制备:取盐酸坦索罗辛5g加入50ml纯化水中,搅拌使溶解,依次加入滑 石粉2g,丙烯酸乙酯-甲基丙烯酸甲酯(2:1)共聚物20g,搅拌混合均匀,得到药物溶液,备用; 依次将柠檬酸三乙酯1g、滑石粉2.5g、甲基丙烯酸-丙烯酸乙酯(1:1)共聚物30g加入30ml纯化 水中,搅拌混合均匀,得包衣液;取80-100目的纤维素丸芯500g加入流化床,控制物料温度25-35℃, 进风风量1-1.5m3,雾化压力1-2bar,先后喷入上述药物溶液和包衣液,两次喷液中间干燥5-10min, 即得。
2、米拉贝隆颗粒制备:取米拉贝隆500g,聚苯乙烯磺酸钠1500g,羟丙基甲基纤维素300g,加 入高速制粒机,搅拌速度100rpm混合15min,加入适量纯化水,搅拌100rpm,切碎1500rpm制粒, 60℃烘干,即得。
3、制备干混悬剂:根据颗粒含量将盐酸坦索罗辛颗粒、米拉贝隆颗粒加入混合机,分别加入占 总重0.2%的羧甲基纤维素、0.1%的羟苯甲脂、0.01%的羟苯丙酯、0.02%的甜蜜素,混合30min,即 得。
比较例1:对比复方制剂1
1、盐酸坦索罗辛颗粒制备:取盐酸坦索罗辛5g加入50ml纯化水中,搅拌使溶解,依次加入滑 石粉3g,羟丙基纤维素20g,搅拌混合均匀,得到药物溶液,备用;依次将柠檬酸三乙酯1g、滑石 粉2.5g、甲基丙烯酸-丙烯酸乙酯(1:1)共聚物30g加入30ml纯化水中,搅拌混合均匀,得包衣 液;取80-100目的纤维素丸芯500g加入流化床,控制物料温度25-35℃,进风风量1-1.5m3,雾化压 力1-2bar,先后喷入上述药物溶液和包衣液,两次喷液中间干燥5-10min,即得。
2、米拉贝隆颗粒制备:取米拉贝隆500g,聚苯乙烯磺酸钠500g,羟丙基甲基纤维素300g,加 入高速制粒机,搅拌速度100rpm混合15min,加入适量纯化水,搅拌100rpm,切碎1500rpm制粒, 60℃烘干,即得。
3、制备干混悬剂:根据颗粒含量将盐酸坦索罗辛颗粒、米拉贝隆颗粒加入混合机,分别加入占 总重0.2%的黄原胶、0.1%的羟苯甲脂、0.01%的羟苯丙酯、0.02%甜蜜素的,混合30min,即得。
比较例2:对比复方制剂2
1、盐酸坦索罗辛颗粒制备:取盐酸坦索罗辛5g加入50ml纯化水中,搅拌使溶解,依次加入滑 石粉3g,丙烯酸乙酯-甲基丙烯酸甲酯(2:1)共聚物20g,搅拌混合均匀,得到药物溶液,备用; 取80-100目的纤维素丸芯500g加入流化床,控制物料温度25-35℃,进风风量1-1.5m3,雾化压力 1-2bar,喷入上述药物溶液,干燥5-10min,即得。
2、米拉贝隆颗粒制备:取米拉贝隆500g,微晶纤维素400g,羟丙基甲基纤维素400g,加入高 速制粒机,搅拌速度100rpm混合15min,加入适量纯化水,搅拌100rpm,切碎1500rpm制粒,60℃ 烘干,即得。
3、制备干混悬剂:根据颗粒含量将盐酸坦索罗辛颗粒、米拉贝隆颗粒加入混合机,分别加入占 总重0.2%的黄原胶、0.1%的羟苯甲脂、0.01%的羟苯丙酯、0.02%的甜蜜素,混合30min,即得。
比较例3:对比复方制剂3
1、盐酸坦索罗辛颗粒制备:取盐酸坦索罗辛5g加入50ml纯化水中,搅拌使溶解,依次加入滑 石粉3g,丙烯酸乙酯-甲基丙烯酸甲酯(2:1)共聚物20g,搅拌混合均匀,得到药物溶液,备用; 依次滑石粉2.5g、羟丙基纤维素30g加入30ml纯化水中,搅拌混合均匀,得包衣液;取80-100目 的纤维素丸芯500g加入流化床,控制物料温度25-35℃,进风风量1-1.5m3,雾化压力1-2bar,先后 喷入上述药物溶液和包衣液,两次喷液中间干燥5-10min,即得。
2、米拉贝隆颗粒制备:取米拉贝隆500g,聚苯乙烯磺酸钠1000g,羟丙基甲基纤维素300g,加 入高速制粒机,搅拌速度100rpm混合15min,加入适量纯化水,搅拌100rpm,切碎1500rpm制粒, 60℃烘干,即得。
3、制备干混悬剂:根据颗粒含量将盐酸坦索罗辛颗粒、米拉贝隆颗粒加入混合机,分别加入占 总重0.2%的黄原胶、0.1%的羟苯甲脂、0.01%的羟苯丙酯、0.01%的阿斯巴甜,混合30min,即得。
试验例1:溶出度试验
将实施例1-5和比较例1-4按以下试验条件进行溶出度试验。
1、坦索罗辛的溶出:采用中国药典2020年版四部0931溶出度与释放度测定法第二法(桨法), 转速为75转/分钟,温度37℃,以750ml人工胃液(pH1.2)为溶出介质,2小时加入250ml0.2mol/L 磷酸钠溶液和5ml吐温80,分别于2、3、4、6、8、12、24小时取样测定,结果见表1和附图3。
2、米拉贝隆的溶出:采用中国药典溶出度试验第2法(桨法),转速为75转/分钟,温度37℃, 以含0.2%SDS的pH4.5醋酸盐缓冲液900ml作为溶出介质,分别于1、2、4、6、8、12、24小时取 样测定,结果见表2和附图4。
从溶出结果显示,比较例1-3中盐酸坦索罗辛的释放较快,丙烯酸乙酯-甲基丙烯酸甲酯 (2:1)共聚物和甲基丙烯酸-丙烯酸乙酯(1:1)共聚物对坦索罗辛的释放产生明显影响,比 较例2可见聚苯乙烯磺酸钠对米拉贝隆的释放影响明显,可见树脂材料对药物的缓慢释放影响较 大。
试验例2:稳定性测定
将实施例1-5和比较例1-4按置于50℃,RH75%条件下放置1个月,检查含量变化,结果见表 3,从结果可见,50℃放置1个月后,比较例2中坦索罗辛和米拉贝隆的含量出现下降,说明坦索罗 辛的包衣可以提高制剂的稳定性。
试验例3:口味测定
找6个人将实施例1-5和比较例1-4制剂加水混悬后,找6个人尝试混悬剂的口味,用口感良好 (3)、口感一般(1)、口感较差(0)进行打分,汇总6人的评价进行综合评分。结果见表4,结果 显示比较例1和2的口味评分较低,说明树脂材料可以改善口味。
表1:盐酸坦索罗辛的溶出(%)
时间(小时) | 2 | 3 | 4 | 6 | 8 | 12 |
实施例1 | 0 | 34.6 | 55.9 | 74 | 82.1 | 91.3 |
实施例2 | 0 | 25.1 | 48.3 | 71.2 | 79.6 | 87.5 |
实施例3 | 0 | 15.9 | 33.6 | 57.3 | 68.5 | 79.3 |
实施例4 | 0 | 23.4 | 43.6 | 67.9 | 77.4 | 83.3 |
比较例1 | 0 | 45.5 | 76.9 | 93.9 | 97.2 | 96.8 |
比较例2 | 0 | 24.4 | 44.7 | 66.8 | 75.1 | 85.5 |
比较例3 | 19.2 | 47.3 | 66.4 | 83.2 | 91 | 95.5 |
表2:米拉贝隆的溶出(%)
时间(小时) | 1 | 2 | 4 | 6 | 8 | 12 |
实施例1 | 23.5 | 35.4 | 59.1 | 74 | 83.8 | 92.3 |
实施例2 | 19.8 | 32.8 | 53.7 | 67.5 | 76.8 | 85.3 |
实施例3 | 22.4 | 37.4 | 60.1 | 75 | 85.3 | 93.4 |
实施例4 | 17.5 | 29.5 | 47.3 | 60.5 | 71.8 | 80.4 |
比较例1 | 22.8 | 34.7 | 54.8 | 68 | 78.1 | 87.4 |
比较例2 | 55.3 | 78.4 | 95.2 | 97.9 | 98.1 | 98.4 |
比较例3 | 20.6 | 33.3 | 52.6 | 66.3 | 75.3 | 85 |
表3:稳定性试验的含量测定
表4:口味测定
口味 | 良好(3) | 一般(1) | 较差(0) | 综合评分 |
实施例1 | 3 | 2 | 1 | 11 |
实施例2 | 4 | 2 | 0 | 14 |
实施例3 | 4 | 2 | 0 | 14 |
实施例4 | 3 | 3 | 0 | 12 |
比较例1 | 0 | 2 | 4 | 2 |
比较例2 | 0 | 1 | 5 | 1 |
比较例3 | 2 | 3 | 1 | 9 |
Claims (5)
1.一种含有坦索罗辛和米拉贝隆的复方制剂,包含独立的含坦索罗辛的颗粒,独立的含米拉贝隆的颗粒,及其它助剂,其特征在于:其中所述的独立的含坦索罗辛的颗粒含有丙烯酸乙酯-甲基丙烯酸甲酯(2:1)共聚物和甲基丙烯酸-丙烯酸乙酯(1:1)共聚物,其中丙烯酸乙酯-甲基丙烯酸甲酯(2:1)共聚物的用量相当于盐酸坦索罗辛重量的3-6倍;其中所述独立的含米拉贝隆的颗粒含有聚苯乙烯磺酸钠,其用量相当于米拉贝隆用量的1-3倍。
2.根据权利要求1所述的含有坦索罗辛和米拉贝隆的复方制剂,其特征在于:其中所述的独立的含坦索罗辛的颗粒其制备方法为先将盐酸坦索罗辛均匀分散于丙烯酸乙酯-甲基丙烯酸甲酯(2:1)共聚物溶液中,再将溶液喷雾至60-80目的微晶纤维素丸芯上,外层再包一层甲基丙烯酸-丙烯酸乙酯(1:1)共聚物的肠溶衣;其中所述独立的含米拉贝隆的缓释颗粒其制备方法为将米拉贝隆与聚苯乙烯磺酸钠混合,加入粘合剂,通过湿法制粒制成颗粒。
3.权利要求1-2所述的含有坦索罗辛和米拉贝隆的复方制剂为干混悬剂。
4.根据权利要求1所述的含有坦索罗辛和米拉贝隆的复方制剂,其包含的其它助剂为助悬剂、抑菌剂、矫味剂等,其中所述的助悬剂为阿拉伯胶、西黄耆胶、黄原胶、卡拉胶、海藻酸钠、羧甲基纤维素、羟乙基纤维素的一种或几种,优选为黄原胶;其中所述的抑菌剂为羟苯甲脂、羟苯丁酯;其中所述的矫味剂为甘露醇、山梨醇、蔗糖、葡萄糖、麦芽糖醇、糖精钠、甜蜜素、甜菊糖苷、阿斯巴甜、乙酰磺胺酸钾中的一种或几种。
5.根据权利要求2所述的含米拉贝隆的缓释颗粒的制备方法,加入的粘合剂是羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、羧甲基纤维素、羧甲基纤维素钠、甲基纤维素的一种,优选为羟丙基甲基纤维素。
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Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1897923A (zh) * | 2003-12-23 | 2007-01-17 | 力奇制药公司 | 控释药物制剂 |
US20090130200A1 (en) * | 2004-07-14 | 2009-05-21 | Siegfried Generics International Ag | Granules for controlled release of tamsulosin |
CN102970985A (zh) * | 2010-05-04 | 2013-03-13 | 株式会社三养生物制药 | 包含坦洛新或其药学可接受的盐的控释药物组合物及包含所述药物组合物的口服制剂 |
WO2013089489A1 (ko) * | 2011-12-14 | 2013-06-20 | 주식회사 바이오파마티스 | 구강 붕해정 및 이의 제조방법 |
CN108348475A (zh) * | 2015-07-17 | 2018-07-31 | 比利时法贝尔制造股份有限公司 | 处于液体剂型的多层药学活性化合物释放微粒 |
KR20190089768A (ko) * | 2018-01-22 | 2019-07-31 | (주)동구바이오제약 | 안정성이 향상된 미라베그론 및 탐스로신을 함유하는 약제학적 조성물 |
KR20210012082A (ko) * | 2019-07-23 | 2021-02-03 | 콜마파마(주) | 미라베그론 및 탐스로신을 포함하는 약학 조성물 |
CN114051407A (zh) * | 2019-07-01 | 2022-02-15 | 韩美药品株式会社 | 包含坦洛新或其盐酸盐的药物组合物和它的制备方法 |
CN114617881A (zh) * | 2022-02-19 | 2022-06-14 | 苏州海景医药科技有限公司 | 一种米拉贝隆组合物 |
-
2022
- 2022-08-11 CN CN202210961886.0A patent/CN115300506A/zh active Pending
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1897923A (zh) * | 2003-12-23 | 2007-01-17 | 力奇制药公司 | 控释药物制剂 |
US20090130200A1 (en) * | 2004-07-14 | 2009-05-21 | Siegfried Generics International Ag | Granules for controlled release of tamsulosin |
CN102970985A (zh) * | 2010-05-04 | 2013-03-13 | 株式会社三养生物制药 | 包含坦洛新或其药学可接受的盐的控释药物组合物及包含所述药物组合物的口服制剂 |
WO2013089489A1 (ko) * | 2011-12-14 | 2013-06-20 | 주식회사 바이오파마티스 | 구강 붕해정 및 이의 제조방법 |
CN108348475A (zh) * | 2015-07-17 | 2018-07-31 | 比利时法贝尔制造股份有限公司 | 处于液体剂型的多层药学活性化合物释放微粒 |
KR20190089768A (ko) * | 2018-01-22 | 2019-07-31 | (주)동구바이오제약 | 안정성이 향상된 미라베그론 및 탐스로신을 함유하는 약제학적 조성물 |
CN114051407A (zh) * | 2019-07-01 | 2022-02-15 | 韩美药品株式会社 | 包含坦洛新或其盐酸盐的药物组合物和它的制备方法 |
KR20210012082A (ko) * | 2019-07-23 | 2021-02-03 | 콜마파마(주) | 미라베그론 및 탐스로신을 포함하는 약학 조성물 |
CN114617881A (zh) * | 2022-02-19 | 2022-06-14 | 苏州海景医药科技有限公司 | 一种米拉贝隆组合物 |
Non-Patent Citations (1)
Title |
---|
朱彩燕;沈映冰;吕永丰;曾令杰;: "离心造粒法制备盐酸坦索罗辛缓释微丸胶囊的工艺影响因素及体外释放度考察", 中国药房, no. 13, pages 18 - 19 * |
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Application publication date: 20221108 |