CN112057423A - 一种含有盐酸沙丙蝶呤的颗粒剂药物及其制备方法 - Google Patents
一种含有盐酸沙丙蝶呤的颗粒剂药物及其制备方法 Download PDFInfo
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- CN112057423A CN112057423A CN202011131060.9A CN202011131060A CN112057423A CN 112057423 A CN112057423 A CN 112057423A CN 202011131060 A CN202011131060 A CN 202011131060A CN 112057423 A CN112057423 A CN 112057423A
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- sapropterin hydrochloride
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Abstract
本发明申请公开了一种含有盐酸沙丙蝶呤的颗粒剂药物,由盐酸沙丙蝶呤、亲脂性表面活性剂和/或蜡质骨架材料、稳定剂、助漂剂或生物粘附剂、以及药物需要的赋形剂组成,本申请还公开了制备所述药物的方法,采用共微粉法或热熔制粒法。本发明的优点在于,改善了药物的口服生物利用度;该药物组合物可在常温下保持稳定,显著降低药品的储存和流通成本;该组合物剂型为颗粒剂,便于携带,适合于涉及剂量范围较广的特点,方便患者用药,且制剂制备工艺简单、成本适宜,适用于工业化大生产。
Description
技术领域
本发明属于药物技术领域,具体为一种含有盐酸沙丙蝶呤的颗粒剂药物及其制备方法。
背景技术
苯丙氨酸血症是一种先天性氨基酸代谢障碍,以苯丙氨酸羟化酶活性缺乏所导致的血浆中苯丙氨酸浓度升高为特征,常造成严重的智力发育迟缓。BH4缺乏症如果不进行及时的药物治疗,会造成儿童出现神经***疾病,而成人出现认知功能障碍和精神疾病方面的不可逆的临床表现。盐酸沙丙蝶呤是首个获准治疗苯丙酮尿症(PKU)的专一性治疗药,是苯丙氨酸、酪氨酸、色氨酸羟化酶的辅助因子,使用盐酸沙丙蝶呤治疗BH4缺乏症患者的原理是该药可代替缺乏的BH4,从而恢复苯丙氨酸羟化酶的活性。颗粒剂适用于儿童、老年人和不能吞服固体制剂的患者,因此,开发一种患者顺应性更好的适合儿童的盐酸沙丙蝶呤剂型刻不容缓。
另一方面,盐酸沙丙蝶呤极易溶于水,略溶于甲醇,极微溶解于乙醇,几乎不溶于二***。盐酸沙丙喋呤有很好的水溶性,但发现目前现有药物组合的生物利用度较低。盐酸沙丙蝶呤吸收部位为消化管,几乎不被胃吸收,主要从十二指肠的小肠中吸收。试验表明患者食用高脂肪、高热量的食物后比禁食时更容易吸收沙丙喋呤(服用后4-5小时Cmax升高41-84%)。然而,高脂肪、高热量的饮食不适用于需要严格控制饮食的HPA患者。
药物的吸收受到诸多因素的影响,如药物的溶解性、解离度、溶出度、粘膜透过性、首过效应,以及胃肠道的生理因素等。对于一些极性大、脂溶性差、分子量大的药物,由于其不易通过生物膜,口服生物利用度通常较低。盐酸沙丙蝶呤生物利用度低的原理极有可能是因为具有较弱的脂溶性导致药物不容易通过生物膜被吸收。一方面可通过加入脂溶性辅料共微粉化或将原料加入到熔融态脂溶性辅料中,使原料与脂溶性辅料充分接触而改善它的脂溶性来提高其生物利用度。再者,本发明还设想通过在胃部漂浮或增加其生物粘着来延长药物在胃肠道的停留时间,进而有效提高药物生物利用度。
盐酸沙丙蝶呤具有A、B、F、J、K等多种晶型,其中B晶型最为稳定,适用于制剂开发。然而,盐酸沙丙喋呤制备成制剂后稳定性比原料差,特别是在水溶液中容易发生降解。现有技术中沙丙蝶呤的生物利用度较差。
发明内容
为了解决现有技术中的盐酸沙丙蝶呤药物口服生物利用率较低的问题,本发明提供了一种含有盐酸沙丙蝶呤颗粒剂药物及其制备方法,实现的目的为改善主药盐酸沙丙蝶呤药物脂溶性,稳定药物在体内的稳定性,增加生物粘着性来延长药物在胃肠道停留的时间,进而有效提高药物生物利用度,将主药制备颗粒剂剂型,进而改善盐酸沙丙蝶呤口服生物利用率。
为了实现上述目的,本发明提供以下技术方案:本发明提供的一种含有盐酸沙丙蝶呤的颗粒剂药物,由盐酸沙丙蝶呤、亲脂性表面活性剂和/或蜡质骨架材料、稳定剂、助漂剂或生物粘附剂、以及药物需要的赋形剂组成,盐酸沙丙蝶呤占药物重量的10%,亲脂性表面活性剂和/或蜡质骨架材料占药物重量的25-35%,稳定剂占药物重量的5-10%,助漂剂或生物粘附剂占药物重量的10-15%,余下为药物需要的赋形剂。需要说明的是,该颗粒药物一般还需要质子交换聚合物,因质子交换聚合物可以是:羧酸小分子如马来酸、富马酸和柠檬酸,或者无机小分子如磷酸、乙酸和它们的盐形式。诸如聚合羧酸类等药用可接受的酸,包括聚甲基丙烯酸、卡波姆、聚卡波非、Eudragit、酸式交联羧甲基纤维素(crosscarmelose)和淀粉乙醇酸等。而这些成分从不同的功效也可以分类为生物黏附剂或者稳定剂等,所以所述配方里的物黏附剂或者稳定剂等可以充当质子交换聚合物的功能。
进一步的,赋形剂由填充剂、粘合剂、崩解剂组成,填充剂占药物重量的40-50%,粘合剂占药物重量的1-2%,崩解剂占药物重量的2-5%。
优选的,所述亲脂表面活性剂和/或蜡质骨架材料为硬脂酰甘油酯、聚乙二醇、硬脂酸、蜡质类、甘油二十二烷酸酯、山嵛甘油酯、硬脂酸棕榈酸甘油酯、单硬脂酸甘油酯、氢化蓖麻油、硬脂醇、聚氧乙烯蓖麻油、聚山梨酯、卵磷脂、椰子油Cs/Cio聚乙二醇甘油酯、杏仁油聚乙二醇甘油酯、聚乙二醇-8-甘油辛酸/癸酸酯、聚氧乙烯(20)山梨酸油酸酯中的一种或一种以上。
优选的,所述蜡质类包括微晶蜡、石蜡。
优选的,所述稳定剂为酒石酸、柠檬酸、丙二酸、马来酸、富马酸、己二酸、苹果酸、L-半胱氨酸盐酸盐、抗坏血酸中一种或一种以上。
优选的,所述助漂剂为十六醇、十八醇单硬脂酸甘油、十八醇、硬脂酸、单硬脂酸甘油酯、巴西棕榈蜡、白蜡、氢化植物油中一种或一种以上。
优选的,所述生物粘附剂为卡波姆、丙烯酸、甲基丙烯酸、黄原胶、卡波姆、羧甲基壳聚糖、海藻酸钠、壳聚糖、山嵛酸甘油酯、羟丙基甲基纤维素、羟丙基纤维素中一种或一种以上。
优选的,所述填充剂为微晶纤维素、乳糖、蔗糖、赤藓糖醇、D-甘露醇中任意一种或一种以上。
优选的,所述粘合剂为淀粉浆、聚维酮、交联聚乙烯比咯烷酮、聚乙二醇、乙基纤维素中一种或一种以上。
优选的,所述崩解剂为交联羧甲基纤维素钠、交联聚维酮、羧甲基淀粉钠、低取代羟丙基纤维素中一种或一种以上。
本发明采用上述成分制备得到的药物通过加入亲脂性表面活性剂和/或蜡质骨架材料、质子交换聚合物等促渗剂来改善药物脂溶性;加入合适的酸性抗氧化剂来稳定药物在体内的稳定性;加入助漂剂、生物黏附剂等辅料来实现胃部漂浮或增加其生物粘着来延长药物在胃肠道的停留时间,进而有效提高药物生物利用度。
本发明还提供了一种制备上述药物的方法,包括如下步骤:
1)将盐酸沙丙蝶呤与亲脂性表面活性剂和/或蜡质骨架材料、助漂剂或生物黏附剂置于混合桶中混合均匀得到混合物1;采用气流粉碎机进行粉碎使其有效平均粒径D90小于50um,D50小于30um,得到微粉混合物;
2)将微粉混合物与填充剂、崩解剂置于混合桶中混合均匀得到混合物2;
3)用纯水将粘合剂、稳定剂溶解制成粘合剂溶液,使制得的粘合剂溶液的浓度为5-10%;
4)然后在高速混合机中,将粘合剂溶液加入到混合物2中,然后加入水,并将混合物捏合;
5)使用一台挤压整粒机,将捏合的产物挤出成颗粒,然后置流化床干燥机中干燥至水分≤0.9%,整粒,得到所需的颗粒。
本发明还提供了制备上述药物的另一种方法,包括如下步骤:
1)将盐酸沙丙蝶呤过80目筛,加入崩解剂、稳定剂、填充剂、助漂剂或生物黏附剂置于混合桶中混合均匀得到混合物1;
2)将亲脂性表面活性剂和/或蜡质骨架材料进行加热至熔融态,边搅拌边加入混合物1,继续搅拌使其慢慢冷却,得到凝固体;需要说明的是,亲脂性表面活性剂和/或蜡质骨架材料进行加热至熔融态后还可以充当粘合剂的作用。
3)使用一台挤压整粒机,将凝固体挤出成颗粒,然后置流化床干燥机中干燥至水分≤0.9%,整粒,得到所需的颗粒。
本发明采用共微粉化或热熔制粒等制剂工艺来使药物与脂溶性辅料充分接触,进而改善或最大化盐酸沙丙蝶呤的口服生物利用率。
综上,本发明采用上述技术方案,所具有的有益效果包括:本发明设计开发了一种以盐酸沙丙蝶呤为活性成分的口服固体给药组合物,该组合物改善了药物的口服生物利用度;该组合物可在常温下保持稳定,可显著降低药品的储存和流通成本;该组合物剂型为颗粒剂,便于携带,适合于涉及剂量范围较广的特点,方便患者用药,且制剂制备工艺简单、成本适宜,适用于工业化大生产。
附图说明
图1为盐酸沙丙蝶呤案例处方在pH6.8磷酸盐介质溶出曲线测定图(n=6)。
具体实施方式
下面通过具体的实施例对本发明做进一步的详细描述。
实施例一:本发明提供的一种盐酸沙丙蝶呤颗粒剂药物,成分见下表:
表1:药用组合物处方1
制备方法:采用共微粉法,
1):将盐酸沙丙蝶呤与硬脂酸棕榈酸甘油酯、卡波姆置于混合桶中混合均匀得到混合物1。采用气流粉碎机进行粉碎使其有效平均粒径D90小于50um,D50小于30um,得到微粉混合物。
2):将微粉混合物与D-甘露醇、低取代羟丙基纤维素置于混合桶中混合均匀得到混合物2。
3):用纯水将聚维酮、抗坏血酸、L-半胱氨酸盐酸盐、L-酒石酸溶解制成粘合剂溶液,使制得的粘合剂溶液的浓度为5-10%。
4):然后在高速混合机中,将粘合剂溶液加入到混合物2中,然后加入水,并将混合物捏合,加入水的量以能实现将混合物捏合为准。
5):使用一台挤压整粒机,将捏合的产物挤出成颗粒,然后置流化床干燥机中80℃干燥至水分≤0.9%,经1.0mm筛网进行整粒,得到所需的颗粒。
本发明制备方法中采用共微粉化技术的优越性:
药物颗粒的比表面积会影响到其溶解速率,进而影响到药物的疗效,而药物颗粒的比表面积又受到微粒的粒径、粒子形态等因素的影响,因此粒径大小不同,药物的疗效就存在差异。药物一旦成为微粉,其比表面积便会成倍增加,表面电子结构及晶体结构也均发生明显变化,产生了块状或粗粉药物所不具有的表面效应、小尺寸效应和量子效应,从而使微粉活性提高,吸附性能、表面电荷及表面黏着力发生显著变化。比表面积越大,与外界环境接触的面积越大,药物就越易溶解。共微粉化技术近年来应用于固体分散体的制备以提高难溶性药物的溶出度与生物利用度。该技术将固体分散技术与超微粉碎技术结合,不仅避免了传统固体分散技术中溶剂及温度对药物稳定性的影响,还可避免超微细粉由于粒子团聚而造成溶出度的降低,同时还可以增加药物的黏膜渗透和体内吸收。
实施例二:本发明提供的一种盐酸沙丙蝶呤颗粒剂药物,成分见下表:
表2:药用组合物处方2
处方组成 | 用途 | 每片含量(mg) |
盐酸沙丙蝶呤 | 活性成分 | 100 |
单硬脂酸甘油酯 | 亲脂表面活性剂/助漂剂 | 270 |
D-甘露醇 | 填充剂 | 500 |
聚维酮 | 粘合剂 | 10 |
抗坏血酸 | 稳定剂 | 20 |
L-半胱氨酸盐酸盐 | 稳定剂 | 20 |
L-酒石酸 | 稳定剂(具有促渗作用) | 60 |
交联羧甲基纤维素 | 崩解剂/质子交换聚合物 | 20 |
总重 | / | 1000 |
制备方法:采用共微粉方法:
1)将盐酸沙丙蝶呤与单硬脂酸甘油酯置于混合桶中混合均匀得到混合物1。采用气流粉碎机进行粉碎使其有效平均粒径D90小于50um,D50小于30um,得到微粉混合物。
2)将微粉混合物与D-甘露醇、交联羧甲基纤维素置于混合桶中混合均匀得到混合物2。
3)用纯水将聚维酮、抗坏血酸、L-半胱氨酸盐酸盐、L-酒石酸溶解制成粘合剂溶液,使制得的粘合剂溶液的浓度为10%。
4)然后在高速混合机中,将粘合剂溶液加入到混合物2中,然后加入水,并将混合物捏合。
5)使用一台挤压整粒机,将捏合的产物挤出成颗粒,然后置流化床干燥机中80℃干燥至水分≤0.9%,经1.0mm筛网进行整粒,得到所需的颗粒。
实施例三:本发明提供的一种盐酸沙丙蝶呤颗粒剂药物,成分见下表:
表3:药用组合物处方3
处方组成 | 用途 | 每片含量(mg) |
盐酸沙丙蝶呤 | 活性成分 | 100 |
山嵛甘油酯 | 蜡质骨架材料 | 290 |
卡波姆 | 生物黏附剂 | 100 |
D-甘露醇 | 填充剂 | 400 |
聚维酮 | 粘合剂 | 10 |
抗坏血酸 | 稳定剂/质子交换聚合物 | 10 |
L-半胱氨酸盐酸盐 | 稳定剂 | 10 |
L-酒石酸 | 稳定剂(具有促渗作用) | 30 |
低取代羟丙基纤维素 | 崩解剂 | 50 |
总重 | / | 1000 |
制备方法:采用热熔制粒法:
1):将盐酸沙丙蝶呤过80目筛,加入低取代羟丙基纤维素、抗坏血酸、L-半胱氨酸盐酸盐、L-酒石酸、D-甘露醇、卡波姆置于混合桶中混合均匀得到混合物1。
2):将山嵛甘油酯进行加热熔融,边搅拌边加入混合物1,继续搅拌使其慢慢冷却,得到凝固体。
3):使用一台挤压整粒机,将凝固体挤出成颗粒,然后置流化床干燥机中80℃干燥至水分≤0.9%,经1.0mm筛网进行整粒,得到所需的颗粒。
本发明采用的热熔制粒技术的优越性:
制粒是许多口服固体药物制剂生产中一项非常关键的步骤,热熔制粒为其中的一类方法。热熔制粒,是在较低温度下,可熔融的黏合剂将物料细粉有效地黏合在一起制成颗粒,或将物料直接熔融、冷却制成颗粒的操作。黏合剂有两种添加方式:一种是上喷工艺,将其加热熔融,以液体形式通过喷嘴加至物料粉末上;另一种是内熔工艺(原位熔融制粒工艺),固体黏合剂与其他物料混匀,黏合剂在工艺过程中受热熔融。热熔制粒技术可用来提高难溶性药物的溶出速度,也可延缓和控制药物的释放,这在很大程度上取决于不同性质黏合剂的选择。与湿法制粒相比,热熔制粒有许多优点:制粒过程不必使用水或有机溶剂,可避免药物水解和有机溶剂残留:免除千燥步骤,节能省时,无易燃易爆的潜在危险,更加环保:一步制粒,大大地缩短生产周期。干法制粒尽管也有这些长处,但所制得的颗粒形状不规则,密度大,压缩成型性不好";对药效高的药物,粉尘飞扬、设备吸附严重,制剂均匀性差。而热熔制粒则可克服干法制粒的这些不足。当然,热熔制粒自身也有缺点。根据黏合剂的熔点,需将物料升至一定温度,所以此类工艺不适于热敏性药物。对多晶型药物亦应谨慎使用,以免引起晶型的转变,进而影响药物的生物利用度。
需要说明的是,在成分的选择上,所述亲脂表面活性剂和/或蜡质骨架材料还可以为硬脂酰甘油酯、聚乙二醇、硬脂酸、蜡质类、甘油二十二烷酸酯、氢化蓖麻油、硬脂醇、聚氧乙烯蓖麻油、聚山梨酯、卵磷脂、椰子油Cs/Cio聚乙二醇甘油酯、杏仁油聚乙二醇甘油酯、聚乙二醇-8-甘油辛酸/癸酸酯、聚氧乙烯(20)山梨酸油酸酯中的一种或一种以上。所述蜡质类包括微晶蜡、石蜡。当然在添加量的选择上也不局限于上述给的最佳配方,例如脂性表面活性剂和/或蜡质骨架材料的添加量也可以取占药物重量的35%。
所述稳定剂还可以为柠檬酸、丙二酸、马来酸、富马酸、己二酸、苹果酸中一种或一种以上。
所述助漂剂还可以为十六醇、十八醇单硬脂酸甘油、十八醇、硬脂酸、巴西棕榈蜡、白蜡、氢化植物油中一种或一种以上。
所述生物粘附剂还可以为丙烯酸、甲基丙烯酸、黄原胶、卡波姆、羧甲基壳聚糖、海藻酸钠、壳聚糖、山嵛酸甘油酯、羟丙基甲基纤维素、羟丙基纤维素中一种或一种以上。
所述填充剂还可以为微晶纤维素、乳糖、蔗糖、赤藓糖醇中任意一种或一种以上。
所述崩解剂还可以为交联聚维酮、羧甲基淀粉钠中一种或一种以上。采用这些成分替换实施例一至实施例三中的成分,同样能够制得具有相同效果的颗粒剂药物,为了节省篇幅,仅以实施例一至实施例三作为举例,不再逐一进行赘述。
采用现有技术方法对实施例一至实施例三的药物进行性能检测:
(1)表4 10mg规格加速试验(40℃/75%RH)检测结果
(2)体外释药性能的研究
取处方一、二、三样品进行pH 6.8磷酸盐介质中溶出测定。溶出测定方法:浆法,转速50rpm,介质体积900ml,取样时间点10min、15min、20min、30min、45min、60min,根据测定结果绘制释药浓度-时间曲线如图1所示。
测试结果:三种处方在加速条件下稳定性:6月与0天相比,总杂均有增长的趋势但处方二增长趋势比处方一和三更为明显,且有继续增长的趋势。处方一和三总杂增长趋势相似,并且在三月就开始出现平台,由此可见处方一和三具有更好的稳定性。三种处方的体外溶出均相似,均为快速溶出,在15min内已达到85%以上,与预期目标一致。
以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (12)
1.一种含有盐酸沙丙蝶呤的颗粒剂药物,其特征在于,由盐酸沙丙蝶呤、亲脂性表面活性剂和/或蜡质骨架材料、稳定剂、助漂剂或生物粘附剂、以及药物需要的赋形剂组成,盐酸沙丙蝶呤占药物重量的10%,亲脂性表面活性剂和/或蜡质骨架材料占药物重量的25-35%,稳定剂占药物重量的5-10%,助漂剂或生物粘附剂占药物重量的10-15%,余下为药物需要的赋形剂。
2.根据权利要求1所述的含有盐酸沙丙蝶呤的颗粒剂药物,其特征在于,赋形剂由填充剂、粘合剂、崩解剂组成,填充剂占药物重量的40-50%,粘合剂占药物重量的1-2%,崩解剂占药物重量的2-5%。
3.根据权利要求1所述的含有盐酸沙丙蝶呤的颗粒剂药物,其特征在于,所述亲脂表面活性剂和/或蜡质骨架材料为硬脂酰甘油酯、聚乙二醇、硬脂酸、蜡质类、甘油二十二烷酸酯、山嵛甘油酯、硬脂酸棕榈酸甘油酯、单硬脂酸甘油酯、氢化蓖麻油、硬脂醇、聚氧乙烯蓖麻油、聚山梨酯、卵磷脂、椰子油Cs/Cio聚乙二醇甘油酯、杏仁油聚乙二醇甘油酯、聚乙二醇-8-甘油辛酸/癸酸酯、聚氧乙烯(20)山梨酸油酸酯中的一种或一种以上。
4.根据权利要求3所述的含有盐酸沙丙蝶呤的颗粒剂药物,其特征在于,所述蜡质类包括微晶蜡、石蜡。
5.根据权利要求1所述的含有盐酸沙丙蝶呤的颗粒剂药物,其特征在于,所述稳定剂为酒石酸、柠檬酸、丙二酸、马来酸、富马酸、己二酸、苹果酸、L-半胱氨酸盐酸盐、抗坏血酸中一种或一种以上。
6.根据权利要求1所述的含有盐酸沙丙蝶呤的颗粒剂药物,其特征在于,所述助漂剂为十六醇、十八醇单硬脂酸甘油、十八醇、硬脂酸、单硬脂酸甘油酯、巴西棕榈蜡、白蜡、氢化植物油中一种或一种以上。
7.根据权利要求1所述的含有盐酸沙丙蝶呤的颗粒剂药物,其特征在于,所述生物粘附剂为卡波姆、丙烯酸、甲基丙烯酸、黄原胶、卡波姆、羧甲基壳聚糖、海藻酸钠、壳聚糖、山嵛酸甘油酯、羟丙基甲基纤维素、羟丙基纤维素中一种或一种以上。
8.根据权利要求2所述的含有盐酸沙丙蝶呤的颗粒剂药物,其特征在于,所述填充剂为微晶纤维素、乳糖、蔗糖、赤藓糖醇、D-甘露醇中任意一种或一种以上。
9.根据权利要求2所述的含有盐酸沙丙蝶呤的颗粒剂药物,其特征在于,所述粘合剂为淀粉浆、聚维酮、交联聚乙烯比咯烷酮、聚乙二醇、乙基纤维素中一种或一种以上。
10.根据权利要求2所述的含有盐酸沙丙蝶呤的颗粒剂药物,其特征在于,所述崩解剂为交联羧甲基纤维素钠、交联聚维酮、羧甲基淀粉钠、低取代羟丙基纤维素中一种或一种以上。
11.一种制备权利要求1-10任意一项所述含有盐酸沙丙蝶呤的颗粒剂药物的方法,其特征在于,包括如下步骤:
1)将盐酸沙丙蝶呤与亲脂性表面活性剂和/或蜡质骨架材料、助漂剂或生物黏附剂置于混合桶中混合均匀得到混合物1;采用气流粉碎机进行粉碎使其有效平均粒径D90小于50um,D50小于30um,得到微粉混合物;
2)将微粉混合物与填充剂、崩解剂置于混合桶中混合均匀得到混合物2;
3)用纯水将粘合剂、稳定剂溶解制成粘合剂溶液,使制得的粘合剂溶液的浓度为5-10%;
4)然后在高速混合机中,将粘合剂溶液加入到混合物2中,然后加入水,并将混合物捏合;
5)使用挤压整粒机,将捏合的产物挤出成颗粒,然后置流化床干燥机中干燥至水分≤0.9%,整粒,得到所需的颗粒。
12.一种制备权利要求1-10任意一项所述含有盐酸沙丙蝶呤的颗粒剂药物的方法,其特征在于,包括如下步骤:
1)将盐酸沙丙蝶呤过80目筛,加入崩解剂、稳定剂、填充剂、助漂剂或生物黏附剂置于混合桶中混合均匀得到混合物1;
2)将亲脂性表面活性剂和/或蜡质骨架材料进行加热至熔融态,边搅拌边加入混合物1,继续搅拌使其慢慢冷却,得到凝固体;
3)使用挤压整粒机,将凝固体挤出成颗粒,然后置流化床干燥机中干燥至水分≤0.9%,整粒,得到所需的颗粒。
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