CN113925830A - 一种包含美洛昔康的可注射的药物组合物及其制备方法 - Google Patents
一种包含美洛昔康的可注射的药物组合物及其制备方法 Download PDFInfo
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Abstract
一种包含美洛昔康的可注射的药物组合物及其制备方法。该药物组合物包含美洛昔康纳米颗粒、表面稳定剂和沉降抑制剂。其稳定性好,不易发生沉降,适于工业化大生产。
Description
本申请是申请号为201880004385.5,申请日为2018年08月23日,发明名称为“一种包含美洛昔康的可注射的药物组合物及其制备方法”的中国专利申请的分案申请。
技术领域
本发明涉及药物制剂领域,具体涉及一种包含美洛昔康的可注射的药物组合物及其制备方法。
背景技术
美洛昔康是一种高效的非甾体类抗炎药,用于治疗类风湿性关节炎、骨关节炎和术后疼痛。美洛昔康选择性地抑制COX-2同工酶,具有高效抗炎和止痛的效果,且具有较低的胃肠道反应。目前上市的品种包括美洛昔康片、美洛昔康胶囊等口服剂型及美洛昔康注射液肌肉注射剂。口服剂型缺点在于:因原料润湿性差和溶解度低(pH 1.2和4.0,溶解度仅为0.6μg/mL)而导致吸收较慢,不能用于急性风湿、关节炎和疼痛。肌肉注射剂虽然改善了药物的吸收,但吸收速率依然受到原料药溶解度的限制,且还会造成局部组织疼痛。因此,增溶是改善美洛昔康体内药代动力学参数的关键。
提高美洛昔康溶解的方法有多种,如纳米晶、胶束、包合物、脂质体等,其中美洛昔康纳米晶具有明显的临床优势,其无需载体材料,仅需少量表面稳定剂,没有赋形剂带来的毒性问题(如溶血、过敏反应等),不受包封率及载药量的制约,能够满足高剂量、高浓度制剂的的需求。与传统美洛昔康制剂相比,纳米晶的优势还体现在以下几个方面:
1)起效快,可用于急性疼痛的治疗。药物快速起效的关键是纳米尺寸的药物颗粒溶解度高、溶出速率快,达峰时间短,仅数十分钟,而传统制剂Tmax长达5-10h。
2)纳米晶技术明显提高了美洛昔康生物利用度,其AUC和Cmax分别是等剂量片剂的1.2倍和1.3倍。
3)扩大美洛昔康适应症。传统剂型主要用于类风湿性关节炎、疼痛性骨关节炎、强直性脊柱炎等,而美洛昔康静脉注射剂可用于术后急性疼痛的治疗。
4)不仅突破了传统制剂不能用于急性疼痛的局限,还保持了其长效的优势。传统制剂半衰期平均20h,而纳米晶药物虽为12h,但静脉注射15mg和60mg,药效也可维持至24h。
5)与阿片类镇痛药相比,美洛昔康静脉注射剂可避免呼吸抑制、恶心呕吐、过度镇静、精神依赖等严重不良反应。同时,美洛昔康作为COX-2选择性抑制剂,与其他非甾体抗炎药相比,具有较小的不良反应。
6)降低消化道溃疡等不良反应。此外,口服制剂还会引起严重的胃肠道反应,发生率约1.9%-7.8%。纳米晶药物注射后被巨噬细胞吞噬,富集在肝脏、脾脏、肺组织,避免游离药物与胃肠道、血小板等正常组织上COX受体的结合,从而降低传统制剂存在的副作用。
纳米晶是一种固体颗粒在纳米级别的混悬液,是一种热力学不稳定体系,易产生沉降,导致注射液无法使用。CN101175481A公开了一种可注射的他克莫司纳米颗粒制剂中加入至少一种表面稳定剂,使得组合物当分散在生物相关介质中基本上保持纳米颗粒粒度,很少聚集。
US9345665公开了一种美洛昔康纳米颗粒注射液,其包含纳米级的美洛昔康颗粒、表面表面稳定剂,以及糖或缓冲剂等,能够减轻纳米颗粒注射液中产生的沉降,但是注射液在放置1到3个月后仍然会存在部分不溶性微粒,影响注射液的稳定性。
因此,开发可用于临床使用且质量稳定的美洛昔康纳米颗粒注射液是非常必要的。
发明内容
本发明一方面提供了一种稳定的美洛昔康纳米颗粒注射液,具体地说,本发明提供了一种可注射的药物组合物,包含美洛昔康纳米颗粒和表面稳定剂,所述药物组合物还包含沉降抑制剂。
其中,所述的沉降抑制剂可以选自多元醇或高分子聚合物,如甘油、丙二醇、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4000)、白蛋白、羟乙基淀粉、羧甲基纤维素钠、羟丙基-β-环糊精中的一种或几种,优选甘油、聚乙二醇和羟乙基淀粉中的一种或几种,更优选甘油。沉降抑制剂主要在储藏过程中提高体系的稳定性,防止美洛昔康颗粒发生聚集和沉淀。
所述的美洛昔康与所述沉降抑制剂的重量比为1:0.1~1:100,优选1:0.1~1:50,更优选1:0.5~1:20,最优选1:0.5~1:10。
在某些实施方式中,所述的表面稳定剂可以是非离子,阴离子,阳离子和两性离子化合物或表面活性剂,例如聚乙烯吡咯烷酮、聚乙烯醇、羟丙甲基纤维素、吐温80、泊洛沙姆、15-羟基硬脂酸聚乙二醇酯、卵磷脂、脱氧胆酸钠、胆酸钠、十二烷基磺酸钠、十二烷基硫酸钠中的一种或多种。
可用的非离子表面稳定剂包括但不限于羟丙基甲基纤维素(HPMC)、聚乙烯吡咯烷酮、泊洛沙姆、吐温-80、聚羟基硬脂酸羟基硬脂酸酯15。
可用的阴离子表面稳定剂包括但不限于二辛基琥珀酸钠(DOSS)、十二烷基璜酸钠、十二烷基硫酸钠(SDS)、多库酯钠、胆酸钠和脱氧胆酸钠。
可用的阳离子表面稳定剂包括但不限于聚合物、生物聚合物、聚-N-甲基吡啶鎓、硫酸吡啶鎓氯化物、阳离子磷脂、壳聚糖、聚赖氨酸、聚乙烯咪唑、聚苯乙烯、聚甲基丙烯酸甲酯三甲基溴化铵(PMMTMABr)、己基甲基三甲基溴化铵(HDMAB)和聚乙烯吡咯烷酮-2-二甲氨基乙基甲基丙烯酸二甲酯硫酸盐。
可用的两性离子表面稳定剂包括但不限于蛋白质、磷脂、两性离子聚合物和两性离子表面活性剂分子,例如可以是磷脂酰胆碱、卵磷脂、明胶等。
所述的表面稳定剂不包含甘油。
其中,所述美洛昔康与所述表面稳定剂的重量比可为1:0.01~1:100,优选1:0.01~1:50,更优选1:0.05~1:5,最优选1:0.1~1:1。
在某些优选的实施例中,所述的表面稳定剂包含第一表面稳定剂和第二表面稳定剂,其中第一表面稳定剂可以是非离子或两性离子表面稳定剂,可选自聚乙烯吡咯烷酮、聚乙烯醇、吐温80、泊洛沙姆、15-羟基硬脂酸聚乙二醇酯、卵磷脂等,优选聚乙烯吡咯烷酮、泊洛沙姆、吐温80;第二表面稳定剂可以是阴离子表面稳定剂,可选自脱氧胆酸钠、胆酸钠、十二烷基磺酸钠、十二烷基硫酸钠等,优选脱氧胆酸钠、胆酸钠。
其中,美洛昔康与所述第一表面稳定剂的重量比可为1:0.01~1:100,优选1:0.01~1:50,更优选1:0.05~1:5,最优选1:0.1~1:1。
其中,美洛昔康与所述第二表面稳定剂的重量比可为1:0.01~1:100,优选1:0.01~1:50,更优选1:0.01~1:5,最优选1:0.01~1:1。
在某些优选的实施例中,优选的组合包括第一表面稳定剂选自聚乙烯吡咯烷酮,第二表面稳定剂选自脱氧胆酸钠,沉降抑制剂选自甘油、聚乙二醇、羟乙基淀粉中的一种或几种,优选甘油。
本发明所述的美洛昔康纳米颗粒的平均粒径小于2000nm,例如可以小于1500nm,优选小于1000nm,更优选小于500nm,最优选小于200nm。
本发明所述的可注射的药物组合物还可包含液体介质,所述液体介质选自水、盐水溶液、植物油(例如红花籽油)和有机溶剂(例如乙醇,叔丁醇,己烷和乙二醇)等,优选水。
在药物组合物中,所述的美洛昔康的含量为10~100mg/mL,优选10~50mg/mL,更优选15~35mg/mL,最优选25mg/mL。
在药物组合物中,所述沉降抑制剂含量可以是0.1~100mg/mL,优选0.1~50mg/mL,更优选1~20mg/mL。
在药物组合物中,所述第一表面稳定剂的含量为0.1~100mg/mL,优选1~50mg/mL,更优选1~20mg/mL;所述第二表面稳定剂的含量为0.1~100mg/mL,优选1~50mg/mL,更优选1~10mg/mL。
本发明另一方面还提供了一种可注射的药物组合物,包含:(1)美洛昔康纳米颗粒、(2)聚乙烯吡咯烷酮、(3)脱氧胆酸钠、(4)沉降抑制剂和(5)水,
其中,所述沉降抑制剂选自甘油、聚乙二醇、羟乙基淀粉中的一种或几种,优选甘油;所述美洛昔康纳米颗粒的平均粒径小于500nm,优选小于200nm;所述美洛昔康与所述沉降抑制剂的重量比为1:0.5~1:20,优选1:0.5~1:10;所述美洛昔康与聚乙烯吡咯烷酮的重量比为1:0.05~1:5,优选1:0.1~1:1;所述美洛昔康与脱氧胆酸钠的重量比为1:0.05~1:5,优选1:0.1~1:1。
本发明另一方面还提供了一种美洛昔康可注射的药物组合物的制备方法,包括:
1)将表面稳定剂、美洛昔康以及任选的沉降抑制剂混合;
2)将上述混合体系进行研磨制备分散体;以及任选地,
3)将沉降抑制剂与上述分散体混合。
适用于本发明的研磨装置包括诸如球磨机、磨碎机、振动研磨机等分散研磨机和诸如砂磨机和珠磨机等介质研磨机。这些分散研磨机在本领域中是众所周知的。
尽管在美洛昔康纳米颗粒注射组合物中加入表面稳定剂能够提高美洛昔康纳米颗粒在制备过程中的分散性,但纳米颗粒制剂为混悬型液体,为热力学不稳定体系,在长期的贮存过程中会发生奥斯瓦尔德熟化现象而发生聚集和沉降,这阻碍了纳米颗粒制剂在临床上的应用。本发明通过在组合物中加入甘油等沉降抑制剂,可以提高溶液的密度或者粘度,抑制美洛昔康颗粒发生沉降,从而提高美洛昔康纳米颗粒在长期贮存过程中的稳定性,推进其在临床上的应用。
在本申请的说明书和权利要求书中,除非另有说明,否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。然而,为了更好地理解本发明,下面提供了部分相关术语的定义和解释。
本发明中所述的例如“平均粒径小于2000nm”是指按重量计算,至少50%的活性物质颗粒的粒径平均值小于约2000nm。
本发明所述的颗粒的平均粒径可通过本领域技术人员熟知的常规粒度测量技术测量颗粒的平均粒径。这样的技术包括例如沉降场流分级,光子相关光谱,光散射等。
本发明所述的“重量体积比”是指每100mL液体体系中含有所述成分的重量(单位g),即g/100mL。
本发明所述的“D10”是指一个样品的累计粒度分布百分数达到10%时所对应的粒径。“D50”是指一个样品的累计粒度分布百分数达到50%时所对应的粒径。“D90”是指一个样品的累计粒度分布百分数达到90%时所对应的粒径。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生,该说明包括该事件或环境发生或不发生地场合。例如,“任选包含沉降抑制剂”意味着沉降抑制剂可以但不必须存在,该说明包括包含沉降抑制剂的情形和不包含沉降抑制剂的情形。
具体实施方式
通过以下实施例和实验例进一步详细说明本发明。这些实施例和实验例仅用于说明性目的,而并不用于限制本发明的范围。
以下实施例中纳米颗粒注射液不溶性微粒的检测方法参照USP<788>通则项下,显微技术法测定,每个供试品容器中含10μm及以上微粒不得超过3000粒,含25μm及以上微粒不得超过300粒。
纳米颗粒注射液中杂质含量通过HPLC检测,其检测条件为ODS-2柱(5μm,4.6×150mm),流动相:甲醇/水,检测波长:260nm和350nm。
实施例1
以聚乙烯吡咯烷酮为第一表面稳定剂,脱氧胆酸钠为第二表面稳定剂,甘油作为沉降抑制剂,制备纳米颗粒注射液,具体处方组成及用量如下:
表1处方组成及用量
制备方法:
1)将处方量的PVP-K17和脱氧胆酸钠溶解于总重50%的水中;
2)将美洛昔康原料加入上述体系中,混合均匀;
3)将上述混合体系加入填充有研磨珠的研磨机腔体中进行研磨6h;
4)将沉降抑制剂加入上述研磨液中,并定至目标重量。
考察上述纳米颗粒注射液的粒径、pH值、渗透压、不溶性微粒和有关物质等指标,检测结果如下:
表2粒径、pH值、渗透压、不溶性微粒检测结果
表3有关物质检测结果
时间 | 最大单杂 | 总杂 |
起始 | 0.132% | 0.324% |
40d_10D | 0.164% | 0.367% |
结果显示,以2.5%甘油作为沉降抑制剂制备的注射液渗透压合格,在加速40℃条件下放置一定的时间,pH值、粒径、不溶性微粒和有关物质无明显变化。说明样品的稳定性良好。
实施例2
以PVP-K17为第一表面稳定剂,胆酸钠为第二表面稳定剂,甘油作为沉降抑制剂,制备纳米颗粒注射液,具体处方组成及用量如下:
表4处方组成及用量
制备方法:
1)将处方量的PVP-K17和胆酸钠溶解于总重50%的水中;
2)将美洛昔康原料加入上述体系中,混合均匀;
3)将上述混合体系加入填充有研磨珠的研磨机腔体中进行研磨8h;
4)将沉降抑制剂加入上述研磨液中,并定至目标重量。
考察上述纳米颗粒注射液的粒径、pH值、渗透压、不溶性微粒和有关物质等指标,检测结果如下:
表5粒径、pH值、渗透压、不溶性微粒检测结果
表6有关物质检测结果
时间 | 最大单杂 | 总杂 |
起始 | 0.138% | 0.343% |
40d 10天 | 0.152% | 0.328% |
结果显示,以5%甘油作为沉降抑制剂制备的注射液渗透压符合规定,在加速40℃条件下放置一定的时间,pH值、粒径、不溶性微粒和有关物质无明显变化。说明样品的稳定性良好。
实施例3
通过观察外观考察不同沉降抑制剂抑制纳米颗粒组合物沉降的能力。所用的纳米颗粒组合物中均含有以重量体积比计的2.5%美洛昔康、0.5%PVP-K17和0.25%脱氧胆酸钠和不同种类和用量的沉降抑制剂(详见表7),采用实施例1相同的制备方法制备纳米颗粒注射液,检测结果如下表7。
表7不同沉降抑制剂对沉降的抑制作用
结果显示,温度对产品稳定性有一定的影响,温度越高,体系越不稳定。此外,甘油相比其他沉降抑制剂具有更好的抑制析晶作用。
实施例4
通过检测样品中不溶性微粒来考察不同种类的沉降抑制剂的效果。所用的纳米颗粒组合物中均含有以重量体积比计的2.5%美洛昔康、0.5%PVP-K17和0.25%脱氧胆酸钠和不同种类和用量的沉降抑制剂(详见表8)。40℃放置15d和1M的不溶性微粒检测结果如下表8所示。
表8不同沉降抑制剂对产品不溶性微粒的影响
结果显示,采用蔗糖、右旋糖酐40和磷酸盐缓冲液作为沉降抑制剂时,产品在加速条件下放置1M出现不溶性微粒增加和沉降现象,而以甘油作为沉降抑制剂,不溶性微粒数较少,纳米颗粒体系稳定性良好。
实施例5
考察不同沉降抑制剂对产品稳定性的影响。所用的纳米颗粒组合物中均含有以重量体积比计的2.5%美洛昔康、0.5%PVP-K17和0.25%脱氧胆酸钠和不同种类和用量的沉降抑制剂(详见表9)。40℃和60℃放置10d的pH值、粒径和不溶性微粒检测结果如下表9所示。室温25℃放置1M,外观结果如表10所示。
表9 pH值、粒径和不溶性微粒检测结果
表10含不同沉降抑制剂的样品室温放置1M外观
沉降抑制剂 | 时间 | 外观 |
5%甘油 | 室温1M | 淡黄色乳状液,无沉降,外观良好 |
2.5%甘油 | 室温1M | 淡黄色乳状液,无沉降,外观良好 |
2.5%甘露醇 | 室温1M | 淡黄色乳状液,有沉降,底部出现黄色片状固体 |
结果显示,1)以5%甘油、2.5%甘油和2.5%甘露醇作为沉降抑制剂在40℃和60℃条件下放置10d,pH值变化不大;2)40℃条件下放置10d,含5%甘油、2.5%甘油和2.5甘露醇的样品不溶性微粒变化不大,60℃条件下放置10d,含5%甘油和2.5%甘露醇的样品出现小幅增加趋势,但含2.5%甘油的样品无明显变化。3)室温放置1M,以2.5%甘露醇样品作为沉降抑制剂的样品底部出现片状析晶,而以甘油作为沉降抑制剂的样品外观良好。以甘油作为沉降抑制剂的产品相比2.5%甘露醇作为沉降抑制剂的产品的稳定性更好。
实施例6
将实施例1所得的纳米颗粒注射液分别于(25℃±2℃、RH60±5%)以及(2~8℃)的条件下放置6个月,测试样品的稳定性,结果如表11、12所示。
表11加速试验结果
表12长期试验结果
结果显示,样品在各条件下长时间放置,性状、pH、粒度、杂质含量等均无明显变化,稳定性良好。
Claims (13)
1.一种可注射的药物组合物,包含美洛昔康纳米颗粒和表面稳定剂,其特征在于,所述药物组合物还包含沉降抑制剂,其中所述的沉降抑制剂选自甘油;所述沉降抑制剂含量为0.1~100mg/mL,优选0.1~50mg/mL。
2.根据权利要求1所述的药物组合物,其特征在于,所述的美洛昔康与所述沉降抑制剂的重量比为1:0.1~1:100,优选1:0.1~1:50,更优选1:0.5~1:20,最优选1:0.5~1:10。
3.根据权利要求1所述的药物组合物,其特征在于,所述的表面稳定剂选自聚乙烯吡咯烷酮、聚乙烯醇、羟丙甲基纤维素、吐温80、泊洛沙姆、15-羟基硬脂酸聚乙二醇酯、卵磷脂、脱氧胆酸钠、胆酸钠、十二烷基磺酸钠、十二烷基硫酸钠中的一种或多种。
4.根据权利要求1所述的药物组合物,其特征在于,所述美洛昔康与所述表面稳定剂的重量比为1:0.01~1:100,优选1:0.01~1:50,更优选1:0.05~1:5,最优选1:0.1~1:1。
5.根据权利要求1所述的药物组合物,其特征在于,所述表面稳定剂不包含甘油。
6.根据权利要求1所述的药物组合物,其特征在于,所述的表面稳定剂包含第一表面稳定剂和第二表面稳定剂,其中第一表面稳定剂选自非离子或两性离子表面稳定剂,优选聚乙烯吡咯烷酮、聚乙烯醇、羟丙甲基纤维素、吐温80、泊洛沙姆、15-羟基硬脂酸聚乙二醇酯、卵磷脂等,更优选聚乙烯吡咯烷酮、泊洛沙姆、吐温80;第二表面稳定剂选自阴离子表面稳定剂,优选脱氧胆酸钠、胆酸钠、十二烷基磺酸钠、十二烷基硫酸钠,更优选脱氧胆酸钠、胆酸钠。
7.根据权利要求6所述的药物组合物,其特征在于,所述美洛昔康与所述第一表面稳定剂的重量比为1:0.01~1:100,优选1:0.01~1:50,更优选1:0.05~1:5,最优选1:0.1~1:1;所述美洛昔康与所述第二表面稳定剂的重量比为为1:0.01~1:100,优选1:0.01~1:50,更优选1:0.01~1:5,最优选1:0.01~1:1。
8.根据权利要求1所述的药物组合物,其特征在于,所述的美洛昔康纳米颗粒的平均粒径小于2000nm,优选小于1000nm,更优选小于500nm,最优选小于200nm。
9.根据权利要求1所述的药物组合物,其特征在于,所述的药物组合物还包含液体介质,所述液体介质选自水、盐水溶液、红花籽油、乙醇、叔丁醇、己烷和乙二醇,优选水。
10.根据权利要求9所述的药物组合物,其特征在于,以活性物质与药物组合物的重量体积比计算,所述的美洛昔康的含量为10~100mg/mL,优选10~50mg/mL,更优选15~35mg/mL,最优选25mg/mL。
11.一种可注射的药物组合物,包含:(1)美洛昔康纳米颗粒、(2)聚乙烯吡咯烷酮、(3)脱氧胆酸钠、(4)沉降抑制剂和(5)水,
其中,所述沉降抑制剂选自甘油、聚乙二醇、羟乙基淀粉中的一种或几种,优选甘油;所述美洛昔康纳米颗粒的平均粒径小于500nm,优选小于200nm;
所述沉降抑制剂含量为0.1~100mg/mL,优选0.1~50mg/mL。
12.根据权利要求11所述的药物组合物,其特征在于,所述美洛昔康与所述沉降抑制剂的重量比为1:0.5~1:20,优选1:0.5~1:10;所述美洛昔康与聚乙烯吡咯烷酮的重量比为1:0.05~1:5,优选1:0.1~1:1;所述美洛昔康与脱氧胆酸钠的重量比为1:0.05~1:5,优选1:0.1~1:1。
13.一种制备如权利要求1~12所述的可注射的药物组合物的制备方法,包括:
1)将表面稳定剂、美洛昔康以及任选的沉降抑制剂混合;
2)将上述混合体系进行研磨制备分散体;以及任选地,
3)将沉降抑制剂与上述分散体混合。
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Cited By (6)
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CN114504553A (zh) * | 2022-02-28 | 2022-05-17 | 沈阳信达泰康医药科技有限公司 | 一种含有卵磷脂的美洛昔康的纳米分散体系 |
CN114569553A (zh) * | 2022-02-28 | 2022-06-03 | 沈阳信达泰康医药科技有限公司 | 一种不含高分子稳定剂的美洛昔康纳米分散体系 |
CN114796133A (zh) * | 2022-05-31 | 2022-07-29 | 浙江仙琚萃泽医药科技有限公司 | 一种注射用药物制剂及其制备方法 |
CN115300515A (zh) * | 2022-08-11 | 2022-11-08 | 南京红地生物科技有限公司 | 一种含有美洛昔康和盐酸曲马多的长效注射液 |
CN115844820A (zh) * | 2022-11-23 | 2023-03-28 | 石家庄四药有限公司 | 一种美洛昔康混悬注射液及其制备方法 |
CN116196273A (zh) * | 2023-03-31 | 2023-06-02 | 江苏慧聚药业股份有限公司 | 一种美洛昔康注射液及其制备方法 |
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US11040008B2 (en) | 2018-04-04 | 2021-06-22 | Slayback Pharma Llc | Pharmaceutical compositions of meloxicam |
US20210093642A1 (en) * | 2019-09-26 | 2021-04-01 | Cadila Healthcare Limited | STABLE AQUEOUS PARENTERAL SOLUTIONS OF NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) |
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CN114504553A (zh) * | 2022-02-28 | 2022-05-17 | 沈阳信达泰康医药科技有限公司 | 一种含有卵磷脂的美洛昔康的纳米分散体系 |
CN114569553A (zh) * | 2022-02-28 | 2022-06-03 | 沈阳信达泰康医药科技有限公司 | 一种不含高分子稳定剂的美洛昔康纳米分散体系 |
CN114796133A (zh) * | 2022-05-31 | 2022-07-29 | 浙江仙琚萃泽医药科技有限公司 | 一种注射用药物制剂及其制备方法 |
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CN116196273A (zh) * | 2023-03-31 | 2023-06-02 | 江苏慧聚药业股份有限公司 | 一种美洛昔康注射液及其制备方法 |
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CN109963555A (zh) | 2019-07-02 |
EP3673897A4 (en) | 2021-05-05 |
AU2018321744A1 (en) | 2020-04-02 |
RU2020108079A (ru) | 2021-09-24 |
TW201912148A (zh) | 2019-04-01 |
CA3070251A1 (en) | 2019-02-28 |
JP2020531424A (ja) | 2020-11-05 |
RU2020108079A3 (zh) | 2021-11-22 |
KR20200046018A (ko) | 2020-05-06 |
CN113925830B (zh) | 2023-07-14 |
BR112020001907A2 (pt) | 2020-08-04 |
US20200360268A1 (en) | 2020-11-19 |
CN109963555B (zh) | 2021-10-08 |
EP3673897A1 (en) | 2020-07-01 |
WO2019037757A1 (zh) | 2019-02-28 |
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