CN113274368A - 一种用于治疗脂肪性肝炎的药物组合物及其制备方法 - Google Patents
一种用于治疗脂肪性肝炎的药物组合物及其制备方法 Download PDFInfo
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- CN113274368A CN113274368A CN202110194256.0A CN202110194256A CN113274368A CN 113274368 A CN113274368 A CN 113274368A CN 202110194256 A CN202110194256 A CN 202110194256A CN 113274368 A CN113274368 A CN 113274368A
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- polyethylene glycol
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Abstract
Description
技术领域
本发明属于药物制剂领域,具体涉及一种用于治疗脂肪性肝炎的药物组合物及其制备方法。
背景技术
式(I)所示化合物(分子式为C28H32ClO5P,分子量为514.98,CAS登记号为852948-13-1)是一种新型口服甲状腺激素β受体激动剂(THR-beta agonist),其通过选择性激活THR-β,调控下游CYP7A和SREBP-1c等的基因表达,有效促进脂肪酸的分解和刺激线粒体的生物发生,降低低密度脂蛋白、甘油三酯水平,进而减少脂肪毒性并改善肝功能,减少肝脏脂肪,是一款高效低毒的非酒精性脂肪性肝炎(nonalcoholic steatohepatitis,NASH)的候选药物。
式(I)所示化合物为强脂溶性的难溶性药物。测定其在37℃±0.5℃下的平衡溶解度结果发现,在pH1.0-pH9.0的不加表面活性剂的盐酸溶液、缓冲液和水中,平衡溶解度均低于0.5ng/mL。药物在胃肠道中的溶解是跨膜转运吸收进入人体,进而发挥药效的前提条件,式(I)所示化合物极低的溶解性限制了其作为候选药物开发的前景。
常见的药物增溶技术通常包括成盐、固体分散体技术、环糊精包合、自乳化系统以及纳米技术等。固体分散体技术是最常见并被广泛应用的增溶技术,该技术通常包括研磨法,熔融法、溶剂法、溶剂喷雾干燥法等,其中热熔融挤出和溶剂喷雾干燥制备固体分散体是产业化应用最广泛的两种固体分散体制备技术。
式(I)所示化合物的熔点较低,为65℃~95℃(依据晶型不同而变化),其在高温下不稳定,在80℃下加热3.5h即有10.2%的药物发生降解反应。式(I)所示化合物在高温下的不稳定性限制了其热熔法,尤其是那些在大于100℃的玻璃化转变温度(Tg值)下制备固体分散体的热熔法的应用。此外,对于溶剂法来说,水中难溶性的药物通常先采用甲醇、丙酮、二氯甲烷等溶解性良好的溶剂将药物溶解在其中,再加入适宜的高分子材料,使药物溶液充分溶解或分散于其中,通过溶剂挥发法或者喷雾干燥等方法去除有机溶剂获得药物均匀分散在载体材料中的固体分散体。该方法适合热不稳定的固体分散体的制备,但存在需要在严格控制的防爆车间内生产、有机溶剂使用量大、有机溶剂去除缓慢(需要多次反复烘箱干燥-真空烘箱干燥除去)、残留的有机溶剂对人体产生危害等的缺陷。此外,前期研究还发现式(I)所示化合物容易形成溶剂化物,因此溶剂法还存在在固体分散体制备过程中,式(I)所示化合物转变为溶剂化物析出的缺陷。
对于难溶性药物来说,体外溶出评价不仅是预测和比较体内溶出的一个简便有效的方法,也是筛选处方进行质量控制的一个重要评判标准。由于式(I)所示化合物在不含表面活性剂的介质中溶解度均低于0.5ng/mL,故对于10mg/单元剂量制剂开发来说,如要在常规的900mL溶出介质中完全溶出,需至少增溶至11.11μg/mL,即增溶数万倍及以上才能实现理想的增溶效果。对于难溶性药物开发来说,常规增溶技术一般仅能实现增溶数倍至几百倍的目标,数千倍甚至上万倍的增溶诉求往往会让制剂工作者束手无策。这种情况下,那些有明确药效但不能够满足增溶需求的候选药物往往因溶出限制在早期开发阶段被淘汰。
发明内容
因此,本发明要解决的技术问题是提供一种适合工业化生产的包含式(I)所示化合物的组合物及其制备方法,本发明的技术能最大幅度地增加式(I)所示化合物的溶出,且制备工艺简单易行,无需使用有机溶剂和超过100℃的高温,确保式(I)所示化合物的稳定性不受制备工艺的影响。
本发明是通过以下技术方案实现的:
本发明提供了一种用于治疗脂肪性肝炎的药物组合物,以重量份数计,其包含下列组分:
(a)1份式(I)所示化合物;
(b)16.0份至600份可熔融分散载体;其中,所述可熔融分散载体包含泊洛沙姆和聚乙二醇,其中泊洛沙姆和聚乙二醇的重量比为1:(0.5~27);和
(c)0.2份至100份非挥发性弱酸。
优选地,以重量份数计,所述药物组合物包含18份至500份可熔融分散载体;更优选地,以重量份数计,所述药物组合物包含98份可熔融分散载体。
优选地,在所述可熔融分散载体中,泊洛沙姆和聚乙二醇的重量比为1:(2~25);更优选地,在所述可熔融分散载体中,泊洛沙姆和聚乙二醇的重量比为1:4.44。
优选地,以重量份数计,所述药物组合物包含0.3份至75份非挥发性弱酸;更优选地,以重量份数计,所述药物组合物包含1份非挥发性弱酸。
根据本发明的一个优选实施方案,以重量份数计,所述药物组合物包含1份式(I)所示化合物,18份泊洛沙姆,80份聚乙二醇和1份非挥发性弱酸。
在所述药物组合物中,式(I)所示化合物可以以不包含溶剂或结晶水的结晶型粉末或者无定形形式存在,也可以以水合物或者溶剂化物形式存在。
在所述药物组合物中,所述泊洛沙姆为α-氢-ω-羟基聚(氧乙烯)-聚(氧丙烯)-聚(氧乙烯)嵌段共聚物。根据结构中聚氧丙烯单元和平均分子量的不同,泊洛沙姆可以选自泊洛沙姆407、泊洛沙姆401、泊洛沙姆338、泊洛沙姆331、泊洛沙姆237、泊洛沙姆188、泊洛沙姆181或泊洛沙姆108中的一种或多种;优选地,所述泊洛沙姆为聚氧丙烯单元数为75~85,平均分子量为7680~9510的泊洛沙姆188。
在所述药物组合物中,所述非挥发性弱酸包括但不限于苹果酸、马来酸、烟酸、酒石酸、磷酸、一水合枸橼酸、无水枸橼酸、维生素C或酸性氨基酸中的一种或多种。优选地,所述非挥发性弱酸为无水枸橼酸、一水合枸橼酸或其混合物。
在所述药物组合物中,所述聚乙二醇包括但不限于平均分子量在200至20000之间的聚乙二醇,例如聚乙二醇300、聚乙二醇400、聚乙二醇600、聚乙二醇1000、聚乙二醇1500、聚乙二醇3350、聚乙二醇4000、聚乙二醇6000、聚乙二醇8000、聚乙二醇10000或聚乙二醇20000等中的一种或多种;优选地,所述聚乙二醇选自聚乙二醇1000、聚乙二醇1500、聚乙二醇3350、聚乙二醇4000、聚乙二醇6000、聚乙二醇8000或聚乙二醇10000中的一种或多种。
除此之外,本发明的药物组合物还可以包含其他相容性组分,包括但不限于如十六醇、十六十八醇、十八醇、油酸、硬脂酸、中链甘油三酯、双棕榈酸硬脂酸甘油酯、丙二醇单辛酸酯、山嵛酸甘油酯(888 ATO)、聚氧乙烯-8山嵛酸甘油酯(5ATO)、单双硬脂酸甘油酯、大豆油混合脂肪酸甘油酯、聚乙二醇-32硬脂酸酯(48/16)、月桂酰聚氧乙烯-32甘油酯(44/14)、硬脂酰聚氧乙烯甘油酯(50/13)、丙二醇二辛酸癸酸酯、油酰聚氧乙烯甘油酯、辛酸癸酸聚乙二醇甘油酯、丙二醇单月桂酸酯、单亚油酸甘油酯、单油酸甘油酯、聚甘油油酸酯、双硬脂酸甘油酯、二乙二醇单乙基醚、15-羟基硬脂酸聚乙二醇酯(HS15)、聚氧乙烯(35)蓖麻油(ELP)、聚氧乙烯40氢化蓖麻油(RH40)、维生素E或氢化蓖麻油等中的一种或者多种。
本发明的药物组合物的一个特点是其熔融温度在35℃~65℃之间。该药物组合物熔融后能以透明均一相形式存在。该药物组合物熔融后(灌装时)的粘度小于1500mPa·S。
本发明的药物组合物为口服制剂,优选为胶囊,更优选为明胶胶囊或羟丙基甲基纤维素胶囊。其中,胶囊内的药物组合物(内容物)总量可在100mg~650mg之间,内容物可灌入明胶材质的胶囊,也可灌入羟丙基甲基纤维素材质的胶囊中。根据内容物的质量,选择灌入适宜型号的囊壳之中,可供选择的胶囊型号包括5号胶囊、4号胶囊、3号胶囊、2号胶囊、1号胶囊和0号胶囊。
本发明的药物组合物的制备方法可以包括以下步骤:
(1)在高于聚乙二醇的熔化温度5~15℃条件下,按熔点从低至高的顺序,依次加入聚乙二醇、泊洛沙姆和非挥发性弱酸;
(2)加入式(I)所示化合物使之熔化,得到熔融内容物。
在上述制备方法中,优选地,在所述步骤(1)和(2)之间还包括除气泡步骤;更优选地,所述除气泡步骤采用静置、超声或者负压进行。
优选地,上述制备方法还包括将步骤(2)得到的熔融内容物灌装胶囊的步骤;优选地,所述灌装胶囊的步骤在55℃±5℃温度下进行,灌装时间小于等于4小时。
根据本发明的一个具体实施方案,所述药物组合物的制备方法包括以下步骤:
(1)配制空白基质:在高于载体(如聚乙二醇)的熔化温度5~15℃条件下,按熔点从低至高的顺序,依次加入载体辅料(如聚乙二醇、泊洛沙姆)和pH调节剂(非挥发性弱酸);(2)除气泡:静置、超声或者负压除去气泡;(3)加药:搅拌状态下加入式(I)所示化合物原料药,继续搅拌使之完全熔于基质之中;(4)灌胶囊:将配制完成的熔融内容物转移至胶囊填充机的预热的保温料筒中,开启搅拌功能,以预设的填充参数,将熔融的内容物灌入明胶硬胶囊体内(控制平均装量差异≤2.5%,单粒装量差异≤5.0%),盖上囊帽,封口(也可选择不封口);(5)冷却:选择以装有压缩空气的传输带或者平铺于室温环境中,使内容物快速冷却固化;(6)包装:将胶囊装入隔湿的包装,如高密度乙烯瓶,或者复合铝膜包装之中。
本组合物制备的胶囊需在低于室温(不超过15℃)的阴凉处密闭保存,优选在2~8℃下密闭冷藏保存。
本发明提供了所述的药物组合物或如所述的制备方法制备的药物组合物在制备用于治疗脂肪性肝炎的药物中的用途。
本发明人经过长期反复的实验研究意外地发现,通过将式(I)所示化合物设计成特定处方比例的半固体胶囊,有助于大幅度提高其体外溶出度,同时还由于制备条件温和,能确保式(I)所示化合物的稳定性。
本发明的优点在于:
(1)采取本发明的药物组合物能大幅度提高式(I)所示化合物的溶出度,可实现增溶1万倍以上的目标;
(2)由于采取了本发明的药物组合物,可在相对温和的温度(<65℃)下制备式(I)所示化合物的药物制剂,避免了高温工艺下的药物降解反应的发生;
(3)本发明的药物组合物制备工艺简单,核心工艺仅为熔融,适合产业化生产,还可有效避免制粒过程的粉尘污染、喷雾干燥固体分散体工艺的防爆和有机溶剂残留问题以及热熔挤出时高温降解等问题的发生。
附图说明
图1为实施例1中E1处方的胶囊的包装和外观;
图2为实施例1中按照A1~G1处方制备的胶囊在水中的溶出曲线示意图(n=6);
图3为对比实施例1中按照a1~e1处方制备的胶囊在水中的溶出曲线(n=6);
图4为对比实施例2中按照a2~d2处方制备的胶囊在水中的溶出曲线(n=6)。
具体实施方式
为了更详细地说明本发明,下面将结合具体实施例对本发明进行进一步的说明。但本发明的范围并非限定于此。
实施例1:
处方组成:
表1.实施例1的处方组成
制备工艺:
1.配制空白基质:在高于载体的熔化温度5~15℃条件下,按熔点从低至高顺序,依次加入聚乙二醇、泊洛沙姆188和无水枸橼酸;
2.除气泡:静置、超声或者负压除去气泡;
3.加入式(I)所示化合物:搅拌状态下加入式(I)所示化合物原料药,继续搅拌使之完全熔于基质之中;
4.灌胶囊:将配制完成的熔融内容物转移至胶囊填充机的预热的保温料筒中,开启搅拌功能,以预设的填充参数,将熔融的内容物灌入明胶硬胶囊体内(控制平均装量差异≤2.5%,单粒装量差异≤5.0%),盖上囊帽;
5.冷却:选择以装有压缩空气的传输带或者平铺于室温环境中,使内容物快速冷却固化;
6.包装:将胶囊装入高密度乙烯瓶中,铝膜封口;
7.保存:将包装完毕的瓶装式(I)所示化合物胶囊置于2~8℃保存。
对比实施例1:
处方组成:
表2.对比实施例1的处方组成
制备工艺:
处方a1,b1,c1和e1:
1.配制空白基质:在高于载体的熔化温度5~15℃条件下,将除式(I)所示化合物之外的成分按熔点从低至高顺序熔化;
2.除气泡:静置、超声或者负压除去气泡;
3.加入式(I)所示化合物:搅拌状态下加入式(I)所示化合物原料药,继续搅拌使之完全熔于基质之中;
4.灌胶囊:将配制完成的熔融内容物转移至胶囊填充机的预热的保温料筒中,开启搅拌功能,以预设的填充参数,将熔融的内容物灌入明胶硬胶囊体内(控制平均装量差异≤2.5%,单粒装量差异≤5.0%),盖上囊帽;
5.冷却:选择以装有压缩空气的传输带或者平铺于室温环境中,使内容物快速冷却固化;
6.包装:将胶囊装入高密度乙烯瓶中,铝膜封口;
7.保存:将包装完毕的瓶装式(I)所示化合物胶囊在2~8℃保存。
处方d1:
1.将式(I)所示化合物和粉碎后的无水枸橼酸,分别过40目和60目筛处理;
2.混合:将式(I)所示化合物和无水枸橼酸粉末混匀;
3.灌胶囊:以200mg/粒,胶囊板手工灌入1号胶囊中;
4.包装:将胶囊装入高密度乙烯瓶中,铝膜封口;
5.保存:将包装完毕的瓶装式(I)所示化合物胶囊在2~8℃保存。
对比实施例2:
处方组成:
表3.对比实施例2的处方组成
制备工艺:
1.配制空白基质:在高于载体的熔化温度5~15℃条件下,按熔点从低至高顺序,依次加入聚乙二醇、泊洛沙姆188和无水枸橼酸;
2.除气泡:静置除去气泡;
3.加入式(I)所示化合物:搅拌状态下加入式(I)所示化合物原料药,继续搅拌使之完全熔于基质之中;
4.灌胶囊:将配制完成的熔融内容物转移至胶囊填充机的预热的保温料筒中,开启搅拌功能,以预设的填充参数,将熔融的内容物灌入明胶硬胶囊体内(控制平均装量差异≤2.5%,单粒装量差异≤5.0%),盖上囊帽;
5.冷却:选择以装有压缩空气的传输带或者平铺于室温环境中,使内容物快速冷却固化;
6.包装:将胶囊装入高密度乙烯瓶中,铝膜封口;
7.保存:将包装完毕的瓶装式(I)所示化合物胶囊在2~8℃保存。
效果实施例1:
取实施例1项下的E1处方,在Z4型液体胶囊机(山东新马制药装备有限公司,SHANDONG SMA PHARMATECH Co.,Ltd),对本生产技术进行中试和放大研究,试制规模为1万粒/批。设置搅拌桶温度为55℃,加热块温度为52℃,液体搅拌速度为30.0rpm。
分别在灌装的前期(第1000粒~3000粒),中期(4000粒~6000粒)和后期(7000粒~9000粒),随机连续取样10粒,称取胶囊总重和每粒胶囊重量,扣除空白囊壳后,计算得到平均装量和装量标准偏差。考察不同生产条件下的装量差异如表4所示,终产品的外观如图1所示。
表4.式(I)所示化合物胶囊灌装速度及不同阶段下的平均重量和偏差
在不同灌装温度(50℃、55℃和60℃)和时间(0h、1h、2h、4h)下的搅拌桶中的物料进行取样,测定有关物质,考察温度和加热时间对样品稳定性的影响,结果如表5所示。
有关物质测定法:采用十八烷基硅烷键合硅胶为填充剂(ACE UltraCore2.5SuperC18(4.6*150mm)或效能相当的色谱柱);以10mM磷酸二氢钾水溶液为流动相A,以乙腈为流动相B,按下表进行梯度(体积比)洗脱;流速:1.0mL/min,检测波长:230nm,柱温:45℃。
取式(I)所示化合物及杂质对照品适量,加乙腈溶解并稀释制成每1ml中分别含0.5mg式(I)所示化合物及0.001mg杂质的溶液,作为系统适应性试验溶液。精密量取10μl注入液相色谱仪,记录色谱图。已知杂质与相邻峰的分离度应不小于1.5。取本品10粒,精密称定,将内容物倾入100ml量瓶中,用乙腈分次洗涤胶囊内壁,洗液并入量瓶中,加乙腈溶解并制成每1ml中含0.5mg式(I)所示化合物的溶液作为供试品溶液;精密量取供试品溶液10μl,注入液相色谱仪,记录色谱图。按峰面积归一化法计算式(I)所示化合物胶囊中杂质和所有杂质的总量。
结果:①4个不同灌装速度下,该组合物和工艺项下的装量准确性(实际平均灌装量-理论灌装量/理论灌装量)<1.0%,精密度(标准偏差/平均装量)<1.0%,合格品率均>90%。
②在55℃±5℃温度下,物料在搅拌桶内保存4h,有关物质总杂增加<0.2%,未见有明显的新增单杂产生。
表5.不同灌装温度和灌装时间对式(I)所示化合物有关物质的影响
结论:式(I)所示化合物胶囊制备工艺简单,1万/批的收率均大于90%;灌装后,胶囊能在室温条件下迅速固化(5分钟内),不会发生囊壳和囊帽间内容物泄漏现象(见图1);该工艺55℃±5℃温度下制备,灌装4个小时有关物质总杂增加<0.2%,可有效避免了高温工艺下的药物降解发生。
效果实施例2
溶出曲线测定。取实施例1项下的A1~G1和对比实施例1项下的a1~e1组项下胶囊,以及对比实施例2项下a2~d2组项下胶囊置沉降篮,在37℃±0.5℃,900mL脱气的水中,桨法50rpm,分别在10、20、30、45、60、90和120min取样,取续滤液,加等比例的甲醇稀释,以HPLC法测定式(I)所示化合物的浓度,计算不同时间点下胶囊中式(I)所示化合物的累积溶出百分比。
HPLC测定条件:选择十八烷基硅烷键合硅胶为填充剂(Welch XB-C184.6*150mm,5μm,或与之相当的色谱柱)的色谱柱,以0.05%三氟乙酸水溶液-乙腈(30:70)为流动相,流速1.0ml/min,柱温30℃,检测波长230nm。精密量取对照品溶液和供试品溶液各20μl,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粒的溶出量。
结果:
①如图2所示,在筛选得到的处方和比例下(实施例1),式(I)所示化合物均可实现20~40分钟之间溶出>85%的结果,且能维持较长的过饱和时间;
②式(I)所示化合物可以快速熔融于单一聚乙二醇1000、聚乙二醇6000或泊洛沙姆188中,冷却固化得到均一半固体。如图3所示,对比实施例1下的该三种辅料单用时,其水中的最高点溶出分别仅为22.0%,11.8%和67.3%。无水枸橼酸对式(I)所示化合物无增溶效果,2h内溶出均低于0.5%。在不含泊洛沙姆188的处方e1中,式(I)所示化合物的最高溶出也仅有14.5%。
③对比实施例2中,a2处方中,式(I)所示化合物处方比例为6%(大于优化比例的上限5%),虽然聚乙二醇、泊洛沙姆188和无水枸橼酸在比例范围内,但该处方的20分钟的最高溶出度小于50%。处方b2和c2中,泊洛沙姆188用量分别超过优化范围的上下限,所得胶囊的最高的溶出度均小于70%。
结论:单独采用聚乙二醇为载体的处方,虽然式(I)所示化合物能熔融分散其中,形成固体分散体,但总体溶出效果不佳,最高值均小于25%;泊洛沙姆188单独使用虽然能增加式(I)所示化合物的溶出,但与聚乙二醇配合使用后,才能更好地发挥其增溶效果。故对式(I)所示化合物胶囊处方来说,各组分保持合理的比例,并联合使用,才能获得令人满意的增溶效果。
效果实施例3
稳定性考察:取实施例1项下的E1和对比实施例2项下的d2的胶囊30粒,置于高密度聚乙烯瓶中,铝膜封口后,在5℃±3℃下进行长期留样考察3个月,以分别在预设的时间点取样,测定有关物质。
有关物质测定法:同效果实施例1项下有关物质测定法。
结果:如表6所示,其制成胶囊剂后,实施例1的E1处方组(含无水枸橼酸比例为1.0%)能明显抑制和降低杂质Z3的形成和增长,而对比实施例2中的d2处方组(含无水枸橼酸比例为0.1%),不能抑制和降低杂质Z3的形成和增长,在稳定性留样过程中,单杂Z3和总杂均有增加的趋势。
表6枸橼酸用量对式(I)所示化合物有关物质的影响
结论:在本发明的处方中,加入并维持一定浓度的无机弱酸,能抑制和降低制备工艺及长期储存过程中杂质Z3的增加,对确保制剂的稳定性至关重要。
Claims (10)
2.如权利要求1所述的药物组合物,其特征在于,以重量份数计,所述药物组合物包含18份至500份可熔融分散载体;优选地,以重量份数计,所述药物组合物包含98份可熔融分散载体;
优选地,在所述可熔融分散载体中,泊洛沙姆和聚乙二醇的重量比为1:(2~25);更优选地,在所述可熔融分散载体中,泊洛沙姆和聚乙二醇的重量比为1:4.44;
优选地,以重量份数计,所述药物组合物包含0.3份至75份非挥发性弱酸;更优选地,以重量份数计,所述药物组合物包含1份非挥发性弱酸;
进一步优选地,以重量份数计,所述药物组合物包含1份式(I)所示化合物,18份泊洛沙姆,80份聚乙二醇和1份非挥发性弱酸。
3.如权利要求1或2所述的药物组合物,其特征在于,式(I)所示化合物以不包含溶剂或结晶水的结晶型粉末或者无定形形式存在,或以水合物或者溶剂化物形式存在;
优选地,所述泊洛沙姆选自泊洛沙姆407、泊洛沙姆401、泊洛沙姆338、泊洛沙姆331、泊洛沙姆237、泊洛沙姆188、泊洛沙姆181和泊洛沙姆108中的一种或多种;更优选地,所述泊洛沙姆为聚氧丙烯单元数为75~85,平均分子量为7680~9510的泊洛沙姆188;
优选地,所述非挥发性弱酸选自苹果酸、马来酸、烟酸、酒石酸、磷酸、一水合枸橼酸、无水枸橼酸、维生素C或酸性氨基酸中的一种或多种;更优选地,所述非挥发性弱酸为无水枸橼酸、一水合枸橼酸或其混合物;
优选地,所述聚乙二醇为平均分子量在200至20000之间的聚乙二醇;更优选地,所述聚乙二醇选自聚乙二醇300、聚乙二醇400、聚乙二醇600、聚乙二醇1000、聚乙二醇1500、聚乙二醇3350、聚乙二醇4000、聚乙二醇6000、聚乙二醇8000、聚乙二醇10000及聚乙二醇20000中的一种或多种;进一步优选地,所述聚乙二醇选自聚乙二醇1000、聚乙二醇1500、聚乙二醇3350、聚乙二醇4000、聚乙二醇6000、聚乙二醇8000或聚乙二醇10000中的一种或多种。
4.如权利要求1至3中任一项所述的药物组合物,其特征在于,所述药物组合物还包含其他相容性组分;优选地,所述相容性组分组分选自十六醇、十六十八醇、十八醇、油酸、硬脂酸、中链甘油三酯、双棕榈酸硬脂酸甘油酯、丙二醇单辛酸酯、山嵛酸甘油酯(888ATO)、聚氧乙烯-8山嵛酸甘油酯(5ATO)、单双硬脂酸甘油酯、大豆油混合脂肪酸甘油酯、聚乙二醇-32硬脂酸酯(48/16)、月桂酰聚氧乙烯-32甘油酯(44/14)、硬脂酰聚氧乙烯甘油酯(50/13)、丙二醇二辛酸癸酸酯、油酰聚氧乙烯甘油酯、辛酸癸酸聚乙二醇甘油酯、丙二醇单月桂酸酯、单亚油酸甘油酯、单油酸甘油酯、聚甘油油酸酯、双硬脂酸甘油酯、二乙二醇单乙基醚、15-羟基硬脂酸聚乙二醇酯(HS15)、聚氧乙烯(35)蓖麻油(ELP)、聚氧乙烯40氢化蓖麻油(RH40)、维生素E和氢化蓖麻油中的一种或多种。
5.如权利要求1至4中任一项所述的药物组合物,其特征在于,所述药物组合物的熔融温度在35℃~65℃之间;优选地,所述药物组合物熔融后以透明均一相形式存在;更优选地,所述药物组合物熔融后的粘度小于1500mPa·S。
6.如权利要求1至5中任一项所述的药物组合物,其特征在于,所述药物组合物为口服制剂;优选地,所述口服制剂为胶囊;更优选地,所述胶囊为明胶胶囊或羟丙基甲基纤维素胶囊。
7.一种如权利要求1至6中任一项所述的药物组合物的制备方法,其包括以下步骤:
(1)在高于聚乙二醇的熔化温度5~15℃条件下,按熔点从低至高的顺序,依次加入聚乙二醇、泊洛沙姆和非挥发性弱酸;
(2)加入式(I)所示化合物使之熔化得到熔融内容物。
8.如权利要求7所述的制备方法,其特征在于,在所述步骤(1)和(2)之间还包括除气泡步骤;更优选地,所述除气泡步骤采用静置、超声或者负压进行。
9.如权利要求7或8所述的制备方法,其特征在于,所述制备方法还包括将步骤(2)得到的熔融内容物灌装胶囊的步骤;优选地,所述灌装胶囊的步骤在55℃±5℃的温度下进行,灌装时间小于等于4小时。
10.如权利要求1至6中任一项所述的药物组合物或如权利要求7至9中任一项所述的制备方法制备的药物组合物在制备用于治疗脂肪性肝炎的药物中的用途。
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US11752161B2 (en) | 2020-03-27 | 2023-09-12 | Gannex Pharma Co., Ltd. | Pharmaceutical compositions, method of making and method of using thereof |
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