CN1671385A - 含有瑞帕霉素羟基酯的胃肠外制剂 - Google Patents
含有瑞帕霉素羟基酯的胃肠外制剂 Download PDFInfo
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Abstract
本发明提供了3-羟基-2-(羟基甲基)-2-甲基丙酸的瑞帕霉素42-酯(CCI-779)的胃肠外制剂。
Description
发明背景
本发明涉及3-羟基-2-(羟基甲基)-2-甲基丙酸的瑞帕霉素42-酯(CCI-779)的胃肠外制剂。
瑞帕霉素是由吸水链霉菌制得的大环三烯抗生素,它被发现在活体内和活体外均具有抗真菌活性,尤其是抗白色念珠菌[C.Vein等人,J.Antibiot.28,721(1975);S.N.Sega等人,J.Antibiot.28,727(1975);H.A.Baker等人,J.Antibiot.31,539(1978);美国专利3,929,992;和美国专利3,993,749]。另外,瑞帕霉素单独(美国专利4,885,171)或与沙培林组合使用(美国专利4,401,653)已表明具有抗肿瘤活性。
瑞帕霉素的免疫抑制作用已被发现。环孢霉素A和FK-506(其他种大环分子)也表现出了作为免疫抑制剂的有效性,因此能用于防止移植排斥[R.Y.Calne等人,Lancet 1183(1978);和美国专利5,100,899]。R.Martel等人[Can.J.Physiol.Pharmacol.55,48(1977)]发现了瑞帕霉素在实验性过敏性脑脊髓炎模型,多发性硬化模型,辅助关节炎模型,类风湿性关节炎模型中都有效;并且有效抑制类IgE抗体的形成。
瑞帕霉素也可以用来预防或治疗全身性红斑狼疮[美国专利5,078,999],肺炎[美国专利5,080,899],胰岛素依赖性糖尿病[美国专利5,321,009],皮肤病,比如牛皮癣[美国专利5,286,730],肠病[美国专利5,286,731],平滑肌细胞增生和血管损伤后的内膜增厚[美国专利5,288,711和5,516,781],成人T-细胞性白血病/淋巴瘤[欧洲专利申请525,960 A1],眼炎症[美国专利5,387,589],恶性癌病[美国专利5,206,018],心炎症性疾病[美国专利5,496,832],和贫血[美国专利5,561,138]。
与3-羟基-2-(羟基甲基)-2-甲基丙酸的瑞帕霉素42-酯(CCI-779)是瑞帕霉素的酯,它在活体内和活体外模型中对肿瘤生长均有显著的抑制作用。瑞帕霉素羟基酯(包括CCI-779)的制法和用途在美国专利5,362,718中公开了。
CCI-779表现出细胞生长繁殖抑制性,而非细胞毒性,它可以延迟肿瘤的发展时间或肿瘤的复发时间。CCI-779的作用机理被认为同西罗莫司的作用机理类似。CCI-779与胞质蛋白FKBP结合并形成复合体,它抑制酶mTOR(瑞帕霉素的哺乳动物靶,也称为FKBP12-瑞帕霉素相关蛋白[FRAP])。mTOR激酶活性的抑制使得多个信号传导路径得到抑制,包括细胞因子刺激的细胞增殖,mRNA对多种关键蛋白的翻译,这些蛋白调节细胞周期的G1相,和IL-2-诱导转录,由此抑制细胞周期从G1到S的进程。导致从G1到S相阻滞的CCI-779的作用机理对于抗癌药物是一种新的机理。
在活体外,CCI-779已发现抑制多种组织各异性肿瘤细胞的生长。中枢神经系统(CNS)癌,白血病(T-细胞),乳腺癌,前列腺癌,黑素瘤系属于对CCI-779最为敏感的。此化合物在细胞周期的G1相中捕集细胞。
对裸鼠的活体内试验研究表明,CCI-779具有对抗不同组织类型的人类肿瘤异种移植物的活性。神经胶质瘤对CCI-779尤其敏感,而且此化合物在裸鼠中在同位神经胶质瘤模型中表现活性。活体外人类恶性胶质瘤细胞系的生长因子(血小板衍生)诱导刺激被CCI-779明显地抑制。在裸鼠中几种人类胰腺肿瘤的生长以及活体内研究的两种乳腺癌系之一的生长也被CCI-779抑制。
将CCI-779调配成胃肠外剂形时首先遇到的障碍是其水溶性较差,小于1μg/ml。此药是非电解质,不能通过pH值调节和成盐等方法来提高其水溶性。CCI-779在药物可接受植物油中的溶解性很差,但是可溶于某些胃肠外给药可接受的水混溶性有机溶剂中。这些溶剂包括乙醇、丙二醇、聚乙二醇和二甲基乙酰胺。在这些有机溶剂中调配CCI-779时存在两个问题或限制。第一,实际上在所有的溶剂中都观察到化学不稳定性。这种不稳定性是由于CCI-779的氧化性降解或内酯键的断裂而造成的,其导致开环断-CCI-779的形成。第二,CCI-779在有机溶剂中的制剂在用输注水溶液或血液稀释时会产生沉淀,该输注水溶液比如是0.9%氯化钠注射液或5%葡萄糖注射液。这是使用水混溶性有机溶剂(也称为助溶剂)作为高度水不溶性化合物的载体时的一个主要限制。
发明概述
本发明通过以胃肠外可接受助溶剂使CCI-779增溶,同时在溶液中伴存抗氧剂和/或螯合剂,由此解决了上述的问题。另外,此胃肠外制剂还包括胃肠外可接受的表面活性剂。
在一方面,本发明提供了一种CCI-779助溶剂浓缩液,它包括CCI-779、醇溶剂和抗氧剂。
另一方面,本发明提供了一种胃肠外制剂,其包含CCI-779,醇溶剂,抗氧剂,稀释剂溶剂和表面活性剂。
还一方面,本发明提供了一种制备胃肠外CCI-779制剂的方法,其中混合胃肠外可接受溶剂、抗氧剂和CCI-779以提供助溶剂浓缩液;混合稀释剂溶剂和表面活性剂以制得稀释剂;然后混合助溶剂浓缩液和稀释剂,以得到CCI-779胃肠外制剂。
本发明的其他方面和优点将在以下本发明的详细描述中变得更为清楚。
发明的详细描述
因此,本发明提供了一种CCI-779助溶剂浓缩液,如上描述,它包含胃肠外可接受溶剂和抗氧剂,以及包含CCI-779的胃肠外制剂,它由CCI-779,胃肠外可接受助溶剂,抗氧剂,稀释剂溶剂和表面活性剂组成。
在本发明的任何给定制剂中可含有每类组分中的多种成分。比如,胃肠外可接受溶剂可包括非醇溶剂,醇溶剂,或它们的混合物。合适的非醇溶剂的例子包括,比如二甲基乙酰胺,二甲基亚砜或乙腈,或它们的混合物。“醇溶剂”可含有一种或多种醇作为制剂的醇溶剂组分。在本发明制剂中有用的溶剂的例子包括但不限于,乙醇,丙二醇,聚乙二醇300,聚乙二醇400,聚乙二醇600,聚乙二醇1000或它们的混合物。特别希望使用这些助溶剂,因为经由氧化和内酯断解的降解因这些助溶剂而降低至较低程度。进一步地,乙醇和丙二醇能够组合而产生更不易燃的产物,但是更为大量的乙醇在混合物中一般会导致更好的化学稳定性。优选混合物中乙醇浓度为30-100%v/v。
在本发明中,由于制剂中抗氧剂的添加,CCI-779在胃肠外可接受醇助溶剂中的稳定性得到了提高。可接受的抗氧剂包括但不限于,柠檬酸,d,l-α-维生素E,BHA,BHT,一巯基甘油,抗坏血酸,没食子酸丙酯,和它们的混合物。本发明制剂中所含抗氧剂组分在助溶剂浓缩液中的浓度一般是0.001%-1%w/v,或0.01%-0.5%w/v,虽然根据需要可以降低或升高浓度。抗氧剂尤其希望使用d,l-α-维生素E,它在助溶剂浓缩液中的浓度是0.01%-0.1%w/v,优选浓度是0.075%w/v。
在某些实施方案中,本发明制剂中的抗氧剂组分也表现出螯合活性。这类螯合剂的例子包括,比如柠檬酸,乙酸和抗坏血酸(它们在本发明制剂中可兼用作经典的抗氧剂和螯合剂)。其他螯合剂包括那些能够结合溶液中的金属离子的物质,比如乙二胺四乙酸(EDTA)及其盐,或能够提高CCI-779的稳定性的氨基酸比如甘氨酸。
在某些实施方案中,具有螯合活性的组分被包含在本发明的制剂中作为单独的“抗氧剂组分”。这类金属结合组分当作为螯合剂使用时,一般使用本文针对抗氧剂组分所提供的浓度范围的低端。在一个例子中,当使用浓度小于0.01%w/v时,柠檬酸提高CCI-779的稳定性。浓度越高,溶液的稳定性越差,因此是有待以液体形式长期贮存的产品所越不希望的。另外,此螯合剂可被用于与其他的抗氧剂组合作为本发明中抗氧剂组分的一部分。例如,一种可接受的制剂可包含柠檬酸和d,l-α-维生素E。基于本文提供的信息,本领域技术人员很容易确定所选抗氧剂的理想浓度。
有利地,在本发明的制剂中,通过使用稀释剂溶液中含有的表面活性剂,用含水输注液或血液稀释时CCI-779的沉淀问题得到解决。稀释剂中最重要的组分是胃肠外可接受表面活性剂。一种特别理想的表面活性剂是聚山梨醇酯20或聚山梨醇酯80。但是,本领域技术人员也可以容易地从胆汁酸(牛磺胆酸,甘氨胆酸,胆酸,脱氧胆酸等)的盐中选择其他合适的表面活性剂,它们任选同卵磷脂组合。或者,乙氧基化植物油,如pegylated蓖麻油[如PEG-35蓖麻油,比如巴斯夫公司以商品名Cremophor EL市售的],维生素E生育酚丙二醇琥珀酸酯(维生素E TGPS),和聚氧乙烯-聚氧丙烯嵌段共聚物可当作表面活性剂被用于稀释剂中,以及聚山梨醇酯族的其他成员如聚山梨醇酯20或60。稀释剂的其他组分可包括水,乙醇,聚乙二醇300,聚乙二醇400,聚乙二醇600,聚乙二醇1000,或包含一种或多种这些聚乙二醇的混合物,丙二醇和其他胃肠外可接受的助溶剂或调节溶液摩尔渗透压浓度的试剂,如氯化钠,乳糖,甘露醇或其他胃肠外可接受的糖、多元醇和电解质。在稀释剂溶液中表面活性剂的含量期望是2-100%w/v,5-80%w/v,10-75%w/v,15-60%w/v,并且优选至少是5%w/v或至少是10%w/v。
胃肠外制剂能制成单一溶液,或优选制成助溶剂浓缩液,它包含CCI-779,醇溶剂,和抗氧剂,其随后与含有稀释剂溶剂和合适表面活性剂的稀释剂组合。使用前,助溶剂浓缩液与含有稀释剂溶剂和表面活性剂的稀释剂混合。本发明中当CCI-779制成助溶剂浓缩液时,此浓缩液包含的CCI-779的浓度为从0.05mg/ml,2.5mg/ml,5mg/ml,10mg/ml或25mg/ml最高到约50mg/ml。最高按照约一份浓缩液对一份稀释剂的比例混合浓缩液和稀释剂,从而得到含有CCI-779浓度为从1mg/ml,5mg/ml,10mg/ml,20mg/ml,最高至约25mg/ml的胃肠外制剂。例如,在胃肠外制剂中CCI-779的浓度可以是约2.5-10mg/ml。本发明也涉及助溶剂浓缩液中CCI-779浓度更小的制剂,以及一份浓缩液与大于一份的稀释剂混合而制得的制剂,比如浓缩液:稀释剂比例为约1∶1.5,1∶2,1∶3,1∶4,1∶5,或1∶9v/v等,直至CCI-779浓度低至最低检测水平的CCI-779胃肠外制剂。
抗氧剂一般占制剂的约0.0005%到0.5%w/v。制剂中表面活性剂的含量比如是约0.5%到约10%w/v。醇溶剂占制剂比如为约10%到约90%w/v。
本发明的胃肠外制剂可用于生产适合于直接注射给药或通过添加到静脉内输注用无菌输注流体而给药的剂型。
下面提供的是本发明制剂的代表性实例。CCI-779的制备方法在美国专利5,362,718中有描述,这里引入作为参考。CCI-779的区域选择性制备方法在美国专利6,277,983中有描述,这里引入作为参考。
当该药物通过直接注射而提供时,稀释剂制剂如果主要是水性的则最合适,比如参见实施例3。当该药物通过添加到无菌输注液中给药时,稀释剂制剂可以主要是水性的,例如水,葡萄糖溶液,盐水,缓冲盐水等,或非水性的。在后一种情况中,水混溶性助溶剂替代了稀释剂中的水。实施例4是非水性制剂,其旨在在通过静脉内输注给药之前加入到无菌输注液中,比如0.9%氯化钠注射液、5%葡萄糖注射液、乳酸盐林格注射液和其他常用的静脉内输注液。
助溶剂浓缩液
实施例1
CCI-779 25mg
无水柠檬酸 0.005%w/v
无水乙醇,USP q.s.1.0ml
上面的制剂被包装在顶空为氮/空气的玻璃安瓿中,其在2-8℃下贮存时的贮存期限为18-30个月。
实施例2
CCI-779 25mg
无水乙醇,USP 0.395g
无水柠檬酸,USP 0.025mg[0.0025%w/v]
d,l-α-维生素E,USP 0.75mg[0.075%w/v]
丙二醇,USP q.s.1.0mL
上面的制剂被包装于顶空为氮/空气的管形瓶中。其在2-8℃和室温下贮存24个月之后表现出良好的稳定性。在5℃下24个月之后未观察到显著的降解。实施例1和实施例2两种制剂都能够通过无菌过滤进行消毒处理。
实施例3是含有非醇助溶剂作为主要载体的制剂:
实施例3
CCI-779 25mg
无水柠檬酸 0.025mg
D,L-α-维生素E,USP 0.75mg
N,N-二甲基乙酰胺 q.s.1.0ml
上面的制剂暴露在短时间温度应力下时是稳定的(暴露在应力温度条件(比如70℃)下至少24小时之后,大于97%的效力被保持)。稀释剂
实施例4
聚山梨醇酯80,NF 5%w/v
聚乙二醇400NF 5%w/v
注射用水,USP q.s.100%
该制剂被包装在管形瓶中,密封,然后通过高压灭菌进行消毒。上面的制剂优选与实施例1或实施例2的助溶剂浓缩液以9∶1v/v的比例组合,以得到浓度为2.5mg/ml的CCI-779溶液。得到的混合物能够直接注射或用0.9%氯化钠注射液或5%葡萄糖注射液进一步稀释而得到静脉内输注液。该混合物在室温下几个小时都是物理和化学稳定的。以上的稀释剂,在与实施例1和实施例2的CCI-779制剂组合时,可通过直接静脉内注射或静脉内输注而用于给药0.5-500mg CCI-779的剂量。
主要是水性组成的稀释剂制剂的其他实施例如下:
实施例5
Cremophor EL 10w/v%
注射用水 q.s.100w/v%
在该实施例中,稀释剂同等体积的CCI-779浓缩液(比如上述实施例2)组合,从而得到主要是水性的载体,其在室温下几个小时都是物理稳定的。该混合物适用于直接静脉内注射。
实施例6
维生素E TPGS NF 10w/v%
注射用水,USP q.s.100w/v%
将上面的制剂与等体积的CCI-779浓缩液(比如上述实施例2)组合,从而得到主要是水性的载体,其在室温下几个小时都是物理稳定的。所得到的浓缩液-稀释剂混合物也可以用0.9%氯化钠注射液稀释而不产生药物沉淀的迹象。
实施例6是适用于CCI-779直接静脉内注射(比如IV推)或在用无菌输注液稀释后进行静脉内输注的稀释剂。
实施例7
聚山梨醇酯20 10%w/v
注射用水,USP q.s.100%w/v
实施例7中的稀释剂与等体积CCI-779浓缩液(比如上述实施例2)组合,从而得到在室温下物理稳定几个小时的混合物。此浓缩液-稀释剂混合物可用于通过IV推给药CCI-779。
实施例8
聚山梨醇酯80,NF 40%w/v
无水乙醇,USP 19.9%w/v
聚乙二醇400,NF q.s.100%
上述制剂通过无菌过滤进行消毒。上述制剂可以与实施例1或2的助溶剂浓缩液组合,优选的体积比是1.5∶1,从而制得含10mg/mlCCI-779的溶液。此溶液可用0.9%氯化钠注射液或5%葡萄糖注射液进一步稀释,从而得到静脉内输注用溶液。这些混合物在室温下几小时都是物理和化学稳定的。上述稀释剂在与实施例1和实施例2中的CCI-779制剂组合时,可用于通过静脉内输注给药2-500mg的剂量。
实施例9
聚山梨醇酯20 20%w/v
聚乙二醇400 q.s.100%w/v
上述制剂与等体积的CCI-779浓缩液(比如实施例2)组合,以得到透明的混合物。此浓缩液-稀释剂混合物可用0.9%氯化钠注射液稀释而制得在室温下几小时都物理稳定的混合物。实施例9可用于通过静脉内输注进行CCI-779给药。
这些实施例举例说明了本发明的制剂及其制备方法,但并不是限定性的。很明显的是,其他溶剂,抗氧剂,稀释剂和/或表面活性剂同样可以用于本发明中。另外,对这些实施例各种变化都是以下权利要求所涵盖的。所有这里指出的文献都在此参考引入。
Claims (30)
1.CCI-779助溶剂浓缩液,其包含CCI-779、胃肠外可接受溶剂和抗氧剂组分。
2.权利要求1的助溶剂浓缩液,其中胃肠外可接受溶剂是二甲基乙酰胺。
3.权利要求1的助溶剂浓缩液,其中胃肠外可接受溶剂是醇溶剂。
4.权利要3的助溶剂浓缩液,其中醇溶剂包含乙醇、丙二醇、聚乙二醇300、聚乙二醇400、聚乙二醇600或聚乙二醇1000。
5.权利要求1到4任一项的助溶剂浓缩液,其中抗氧剂组分包含柠檬酸、甘氨酸、d,l-α-维生素E、BHA、BHT、一巯基甘油、抗坏血酸或没食子酸丙酯。
6.CCI-779助溶剂浓缩液,其包含CCI-779、柠檬酸和无水乙醇。
7.CCI-779助溶剂浓缩液,其包含CCI-779、无水乙醇、d,l-α-维生素E和丙二醇。
8.权利要求7的助溶剂浓缩液,其进一步包含柠檬酸。
9.权利要求1到8任一项的助溶剂浓缩液,其中CCI-779的含量为约0.05mg/ml到约50mg/ml。
10.权利要求1到8任一项的助溶剂浓缩液,其中CCI-779的含量为约25mg/ml。
11.权利要求1到10任一项的助溶剂浓缩液,其中抗氧剂的含量为约0.001%到1.0%w/v。
12.胃肠外制剂,其包含CCI-779、醇溶剂、抗氧剂、稀释剂溶剂和表面活性剂。
13.权利要求12的制剂,其中醇溶剂是乙醇、丙二醇、聚乙二醇300、聚乙二醇400、聚乙二醇600或聚乙二醇1000。
14.权利要求12或13的制剂,其中抗氧剂是柠檬酸、甘氨酸、d,l-α-维生素E、BHA、BHT、一巯基甘油、抗坏血酸或没食子酸丙酯。
15.权利要求12到14任一项的制剂,其中稀释剂溶剂是水、乙醇、聚乙二醇300、聚乙二醇400、聚乙二醇600、聚乙二醇1000或丙二醇。
16.权利要求12到15任一项的制剂,其中表面活性剂是聚山梨醇酯20、聚山梨醇酯80、胆汁酸、卵磷脂、乙氧基化植物油、维生素E生育酚丙二醇琥珀酸酯或聚氧乙烯-聚氧丙烯嵌段共聚物。
17.权利要求12到16任一项的制剂,其中CCI-779的含量为约1mg/ml到约25mg/ml。
18.权利要求12到16任一项的制剂,其中CCI-779的含量为约2.5mg/ml到约10mg/ml。
19.权利要求12到18任一项的制剂,其中抗氧剂占制剂的约0.0005%到0.5%w/v。
20.权利要求12到18任一项的制剂,其中表面活性剂占制剂的约0.5%到约10%w/v。
21.权利要求12到18任一项的制剂,其中溶剂占制剂的约10%到约90%w/v。
22.胃肠外CCI-779制剂的制备方法,其包括:
(a)使CCI-779与胃肠外可接受溶剂和抗氧剂组分混合,以得到助溶剂浓缩液;
(b)使稀释剂溶剂和表面活性剂混合而制得稀释剂;以及
(c)使该助溶剂浓缩液和该稀释剂混合,以制得CCI-779胃肠外制剂。
23.权利要求22的方法,其中溶剂是醇溶剂,其包括乙醇、丙二醇、聚乙二醇300、聚乙二醇400、聚乙二醇600或聚乙二醇1000。
24.权利要求22或23的方法,其中抗氧剂组分包括柠檬酸、d,l-α-维生素E、BHA、BHT、一巯基甘油、抗坏血酸或没食子酸丙酯。
25.权利要求22到24任一项的方法,其中稀释剂溶剂是水、乙醇、聚乙二醇300、聚乙二醇400、聚乙二醇600、聚乙二醇1000或丙二醇。
26.权利要求22到25任一项的方法,其中表面活性剂是聚山梨醇酯20、聚山梨醇酯80、胆汁酸、卵磷脂、乙氧基化植物油、维生素E生育酚丙二醇琥珀酸酯或聚氧乙烯-聚氧丙烯嵌段共聚物。
27.权利要求22到25任一项的方法,其中溶剂是无水乙醇,抗氧剂是柠檬酸,稀释剂溶剂是水和聚乙二醇400,并且表面活性剂是聚山梨醇酯20或聚山梨醇酯80。
28.权利要求22到25任一项的方法,其中溶剂是无水乙醇,抗氧剂是柠檬酸,稀释剂溶剂是无水乙醇和聚乙二醇400,并且表面活性剂是聚山梨醇酯20或聚山梨醇酯80。
29.权利要求22到25任一项的方法,其中溶剂是无水乙醇和丙二醇,抗氧剂是d,l-α-维生素E,稀释剂溶剂是水和聚乙二醇400,并且表面活性剂是聚山梨醇酯20或聚山梨醇酯80。
30.权利要求22到25任一项的方法,其中溶剂是无水乙醇和丙二醇,抗氧剂是d,l-α-维生素E,稀释剂溶剂是无水乙醇和聚乙二醇400,并且表面活性剂是聚山梨醇酯20或聚山梨醇酯80。
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CN101605529B (zh) * | 2006-02-09 | 2013-03-13 | 参天制药株式会社 | 稳定制剂及它们的制备和使用方法 |
CN103099806A (zh) * | 2011-11-11 | 2013-05-15 | 山东新时代药业有限公司 | 一种注射用坦西莫司及其制备方法 |
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2012
- 2012-10-15 US US13/651,623 patent/US8455539B2/en not_active Expired - Lifetime
-
2013
- 2013-04-04 AR ARP130101103A patent/AR090603A2/es not_active Application Discontinuation
- 2013-05-13 US US13/892,389 patent/US8722700B2/en not_active Expired - Lifetime
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US8492400B2 (en) | 2006-02-09 | 2013-07-23 | Santen Pharmaceutical Co., Ltd. | Stable formulations, and methods of their preparation and use |
US8658667B2 (en) | 2006-02-09 | 2014-02-25 | Santen Pharmaceutical Co., Ltd. | Stable formulations, and methods of their preparation and use |
CN101605529B (zh) * | 2006-02-09 | 2013-03-13 | 参天制药株式会社 | 稳定制剂及它们的制备和使用方法 |
CN103099806B (zh) * | 2011-11-11 | 2016-12-14 | 山东新时代药业有限公司 | 一种注射用坦西莫司及其制备方法 |
CN103099806A (zh) * | 2011-11-11 | 2013-05-15 | 山东新时代药业有限公司 | 一种注射用坦西莫司及其制备方法 |
CN103989676A (zh) * | 2014-06-10 | 2014-08-20 | 福建省微生物研究所 | 可注射用的替西罗莫司组合物 |
CN103989676B (zh) * | 2014-06-10 | 2016-06-22 | 福建省微生物研究所 | 可注射用的替西罗莫司组合物 |
CN105640878A (zh) * | 2016-01-25 | 2016-06-08 | 宿州学院 | 一种坦西莫司注射用浓溶液及其制备方法 |
CN105687132A (zh) * | 2016-03-17 | 2016-06-22 | 鲁南贝特制药有限公司 | 一种坦西莫司注射用浓溶液及其制备方法 |
CN105687132B (zh) * | 2016-03-17 | 2020-06-12 | 鲁南贝特制药有限公司 | 一种坦西莫司注射用浓溶液及其制备方法 |
CN107550852A (zh) * | 2016-06-30 | 2018-01-09 | 山东新时代药业有限公司 | 一种坦西莫司注射液注射用溶剂及其制备方法 |
CN107550852B (zh) * | 2016-06-30 | 2021-05-14 | 山东新时代药业有限公司 | 一种坦西莫司注射液注射用溶剂及其制备方法 |
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