CN101072551A - 包含二膦酸盐的缓释制剂 - Google Patents
包含二膦酸盐的缓释制剂 Download PDFInfo
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- CN101072551A CN101072551A CNA2005800416891A CN200580041689A CN101072551A CN 101072551 A CN101072551 A CN 101072551A CN A2005800416891 A CNA2005800416891 A CN A2005800416891A CN 200580041689 A CN200580041689 A CN 200580041689A CN 101072551 A CN101072551 A CN 101072551A
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- glutamate
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Classifications
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- A61K9/00—Medicinal preparations characterised by special physical form
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Abstract
本发明涉及用于非肠道施用的药物组合物,该药物组合物包含促生长素抑制素类似物的盐和水,所述的盐为天冬氨酸盐(例如单或二天冬氨酸盐)、乳酸盐、琥珀酸盐(例如单或二琥珀酸盐)、乙酸盐、谷氨酸盐(例如单或二谷氨酸盐)或柠檬酸盐,该药物组合物在注射后与体液接触形成胶凝贮库系统。
Description
本发明涉及液体药物组合物,特别涉及包含促生长素抑制素类似物的贮库制剂以及制备所述贮库制剂的方法。
贮库制剂典型地是非肠道施用的。促生长素抑制素贮库制剂可以通过小号针皮下或肌内注射施用或者通过插管将其置于可达到的组织位点施用。但是,非肠道施用可能是非常疼痛的,特别是如果需要重复注射时。另外,以液体形式施用并且注射后在体内形成固体植入物的贮库制剂可能存在困难。通常,在注射前注射器中开始凝固过程并且引起针堵塞。另外,这些贮库制剂可以包含聚合物或聚合物混合物,该聚合物或聚合物混合物必须溶于有机溶剂中,例如其可以包含多于50%的有机溶剂。如果有机溶剂存在于注射用溶液剂中,其可能在植入位点引起严重的组织刺激或坏死。
EP 779 805提供了药物组合物,该药物组合物包含可溶性肽盐(其将与体液接触形成凝胶)和占组合物重量至多30%的可药用载体。EP 779805中描述的肽为促生长素抑制素或促生长素抑制素类似物,例如兰瑞肽(lanreotide)。
令人惊奇的是,已经发现使用组合物可以得到有利的非肠道促生长素抑制素贮库制剂,该组合物包含促生长素抑制素类似物的盐和水(pH 3-7),而不使用聚合物并且不使用有机溶剂。
本发明一方面提供了用于非肠道施用的药物组合物,该药物组合物包含促生长素抑制素类似物的盐和水,所述的盐为天冬氨酸盐(例如单或二天冬氨酸盐)、谷氨酸盐(例如单或二谷氨酸盐)或琥珀酸盐(例如单或二琥珀酸盐)、乳酸盐、乙酸盐或柠檬酸盐,该药物组合物在注射后与体液接触形成胶凝贮库。促生长素抑制素类似物盐的盐:碱的比例范围可以为0.1-2并且其提供了促生长素抑制素类似物的盐的溶解性。药物组合物的pH在约3.0和7.0之间,优选在4.0和6.0之间并且更优选在约4.0和5.0之间。任选该组合物可以包含一定量的可药用缓冲剂以将pH稳定在约3.0和7.0之间,优选在约4.0和6.0之间,最优选在4.0和5.0之间。
另一方面,本发明提供了用于非肠道施用的药物组合物,该药物组合物包含促生长素抑制素类似物的盐和水,所述的盐为天冬氨酸盐(例如单或二天冬氨酸盐)、谷氨酸盐(例如单或二谷氨酸盐)、乳酸盐、琥珀酸盐(例如单或二琥珀酸盐)、乙酸盐或柠檬酸盐,pH在约3.0和7.0之间,该药物组合物在注射后与体液接触形成胶凝贮库。
pH在约3.0和7.0之间的组合物提供了很好的溶解性并且因此本发明组合物可以贮存延长的时间而不产生沉淀。通过注射将组合物施用于患者,其中组合物在与患者体液相互作用之后而不是之前开始形成胶凝贮库。历经延长的时间周期,该胶凝贮库在患者体内释放促生长素抑制素类似物的盐,所述的盐为天冬氨酸盐、乳酸盐、琥珀酸盐、乙酸盐、谷氨酸盐或柠檬酸盐。
另一方面,本发明提供了制备贮库制剂的方法,该方法通过以下步骤进行:
i)将促生长素抑制素类似物的盐溶于水中,所述的盐为天冬氨酸盐(例如单或二天冬氨酸盐)、乳酸盐、琥珀酸盐(例如单或二琥珀酸盐)、乙酸盐、谷氨酸盐(例如单或二谷氨酸盐)或柠檬酸盐,
ii)任选加入缓冲剂以稳定溶液的pH,并且任选
iii)将溶液填充至注射器中。
另一方面,本发明提供了制备贮库制剂的方法,该方法通过以下步骤进行:
i)将促生长素抑制素类似物的盐溶于水中,所述的盐为天冬氨酸盐(例如单或二天冬氨酸盐)、乳酸盐、琥珀酸盐(例如单或二琥珀酸盐)、乙酸盐、谷氨酸盐(例如单或二谷氨酸盐)或柠檬酸盐,其pH在3.0和7.0之间,
ii)任选加入缓冲剂以稳定溶液的pH,并且任选
iii)将溶液填充至注射器中。
本发明涉及促生长素抑制素类似物的盐,所述的盐为天冬氨酸盐(例如单或二天冬氨酸盐)、乳酸盐、琥珀酸盐(例如单或二琥珀酸盐)、乙酸盐、谷氨酸盐(例如单或二谷氨酸盐)或柠檬酸盐。
促生长素抑制素为十四肽,其结构为
例如在WO 97/01579和WO 97/25977中已经描述了特别关注的促生长素抑制素类似物。所述的促生长素抑制素类似物包含式I的氨基酸序列
-(D/L)Trp-Lys-X1-X2-
其中X1为式(a)或(b)基团
其中R1为任选取代的苯基,其中取代基可以是卤素、甲基、乙基、甲氧基或乙氧基。
R2是-Z1-CH2-R1、-CH2-CO-O-CH2-R1、
其中Z1为O或S,并且
X2为Cα侧链上具有芳族残基的α-氨基酸或选自下列的氨基酸单元:Dab、Dpr、Dpm、His、(Bzl)HyPro、噻吩基-Ala、环己基-Ala和叔丁基-Ala,所述序列的残基Lys对应于天然促生长素抑制素-14的残基Lys9。
本文所应用的促生长素抑制素类似物指的是衍生自天然存在的促生长素抑制素-14的直链或环肽,其包含式I序列,并且另外其中一个或多个氨基酸单元被忽略和/或被一个或多个其它的氨基酸基团代替和/或其中一个或多个官能团被一个或多个其它的官能团代替和/或一个或多个基团被一个或一些其它的电子等排基团代替。通常,术语涵盖了天然促生长素抑制素-14的所有修饰衍生物,其包含以上式I序列,其与至少一种下文定义的促生长素抑制素受体亚型的结合亲和力在nM范围内。
优选促生长素抑制素类似物是其中促生长素抑制素-14的8至11位残基被以上定义的式I序列代替的化合物。
更优选促生长素抑制素类似物是以上公开的化合物,该化合物包含六肽单元,所述六肽单元的3至6位残基包含式I序列。特别优选促生长素抑制素六肽,其中六肽单元的1和2位残基可以是本领域中已知的任何残基(例如A.S.Dutta在Small Peptides,Vol.19,292-354,Elsevier,1993中公开的)或者作为促生长素抑制素-14的Phe6和/或Phe7的取代基。
更特别的是促生长素抑制素类似物是其中六肽单元是环状的化合物,例如6位残基的α-羰基和1位残基的α-氨基之间具有直接的肽键的化合物。
式I序列中的Lys、X1和X2具有L-构型。Trp可以是D-或L-构型。优选Trp具有D-构型。
X1优选为式(a)和(b)残基,R2优选为
当X2的Cα侧链上包含芳族残基时,其可以适当地为天然或非天然α-氨基酸,例如Phe、Tyr、Trp、Nal、Pal、苯并噻吩基-Ala、Tic和甲状腺原氨酸,优选Phe或Nal,更优选Phe。X2优选为Cα侧链上具有芳族残基的α-氨基酸。
当R1为取代的苯基时,其可以适当地例如在邻位和/或对位被卤素、甲基、乙基、甲氧基或乙氧基取代。更优选R1为未取代的苯基。Z1优选为O。
本发明的代表性化合物是例如式(II)化合物
其中
X1和X2如上定义,
A为选自下列的二价残基:Pro、
其中R3为NR8R9-C2-6亚烷基、胍基-C2-6亚烷基或C2-6亚烷基-COOH,R3a为H、C1-4烷基或独立地具有R3的含义之一,R3b为H或C1-4烷基,Ra为OH或NR5R6,Rb为-(CH2)1-3-或-CH(CH3)-,R4为H或CH3,R4a任选为环取代的苄基,R5和R6各自独立地为H、C1-4烷基、ω-氨基-C1-4亚烷基、ω-羟基-C1-4亚烷基或酰基,R7为直接的键或C1-6亚烷基,R8和R9各自独立地为H、C1-4烷基、ω-羟基-C2-4亚烷基、酰基或CH2OH-(CHOH)c-CH2-(其中c为0、1、2、3或4),或R8和R9与它们所连接的氮原子一起形成杂环基,该杂环基可以包含另外的杂原子,并且R11任选为环取代的苄基、-(CH2)1-3-OH、CH3-CH(OH)-或-(CH2)1-5-NR5R6,并且
ZZa为天然或非天然α-氨基酸单元。
ZZa可以具有D-或L-构型。当ZZa为天然或非天然α-氨基酸单元时,其可以适当地为例如Thr、Ser、Ala、Val、Ile、Leu、Nle、His、Arg、Lys、Nal、Pal、Tyr、Trp、任选环取代的Phe或Nα-苄基-Gly。当ZZa为Phe时,其苯环可以被例如NH2、NO2、CH3、OCH3或卤素取代,优选对位取代。当ZZa为Phe时,其苯环优选为未取代的。
当A包含Pro氨基酸残基时,脯氨酸环上存在的任何取代基(例如R3-NH-CO-O-等)优选在4位。该取代的脯氨酸残基可以以顺式形式存在,例如
也可以以反式形式存在。每个单一的几何异构体及其混合物是本发明的化合物。
当A为
其中NR8R9形成杂环基,该基团可以是芳族的或饱和的并且可以包含一个氮原子或一个氮原子和选自氮和氧的第二个杂原子。优选杂环基为例如吡啶基或吗啉代。该残基中的C2-6亚烷基优选-CH2-CH2-。
A中作为R5、R6、R8和R9的任何酰基可以是例如R12CO-,其中R12为H、C1-4烷基、C2-4链烯基、C3-6环烷基或苄基,优选为甲基或乙基。当A中R4a或R11是环取代的苄基时,苯环可以如以上ZZa中所述的被取代。
特别优选游离形式、盐形式或保护形式的式III化合物
其中C-2的构型为(R)或(S)或它们的混合物,并且
其中R为NR10R11-C2-6亚烷基或胍基-C2-6亚烷基,并且R10和R11各自独立地是H或C1-4烷基,其合成可以如例如WO 2002/10192(其并入本文作为参考)中描述的进行。
通过例如WO 2002/10192(其并入本文作为参考)中描述的方法制备盐。
优选R为NR10R11-C2-6亚烷基。优选的式II化合物为其中R是2-氨基-乙基的游离形式、盐形式或被护形式的式II化合物,即环[{4-(NH2-C2H4-NH-CO-O-)Pro}-Phg-DTrp-Lys-Tyr(4-Bzl)-Phe](本文中指化合物A)和环[{4-(NH2-C2H4-NH-CO-O-)Pro}-DPhg-DTrp-Lys-Tyr(4-Bzl)-Phe]。Phg指的是-HN-CH(C6H5)-CO-并且Bzl指的是苄基。
保护形式的本发明的盐对应于促生长素抑制素类似物,该促生长素抑制素类似物中至少一个氨基是被保护的并且通过脱保护形成式II化合物,优选生理学上可除去的。适合的氨基保护基为例如“Protective Groups inOrganic Synthesis”,T.W.Greene,J.Wiley&Sons NY(1981),219-287中公开的,其内容并入本文作为参考。此类氨基保护基的实例为乙酰基。
本发明组合物可以包含缓冲剂。适合的缓冲剂包括但不限于乙酸盐缓冲剂、乳酸盐缓冲剂、甘氨酸缓冲剂和酒石酸盐缓冲剂。缓冲剂的浓度可以是约5mM至30mM,优选约10mM至25mM。
另一方面,本发明提供了粘性液体形式的药物组合物,该组合物可以通过18G至25G、例如20G的针用注射器注射。通过0.2μM滤器灭菌过滤后(其粘度为1至104mPa.s)或灭菌过滤并且通过蒸发或升华除去溶剂后(其粘度为102至106mPa.s),可以将溶液剂置于注射器中。溶剂除去可以在将溶液剂置于注射器后进行。
注射器中的溶液剂可以通过针(例如20G的针)表皮下、肌内、真皮下或腹膜内注射入体内或通过插管置于可达到的组织位点。一旦该溶液剂在适当的位置与患者的体液接触,就形成了胶凝贮库。非肠道施用的液体组合物可以填充至注射器中,优选预填充注射器可以和使用说明书一起提供。
另一方面,本发明提供了药用活性剂的缓释贮库制剂。注射入体内后形成的植入物可以历经延长的时间周期释放活性剂。释放期的范围可以是1至至多90天,例如1至至多60天,例如30至60天。
本发明组合物用于治疗特殊活性剂的已知适应证。包含促生长素抑制素类似物的盐(所述的盐为天冬氨酸盐、乳酸盐、琥珀酸盐、乙酸盐、谷氨酸盐或柠檬酸盐)的本发明组合物可以用于下述适应证:
a)用于预防或治疗具有包括过量的GH-分泌和/或IGF-1的过量或与过量的GH-分泌和/或IGF-1的过量有关的病因学的障碍,例如治疗肢端肥大症以及治疗I型或II型糖尿病,特别是它们的并发症,例如血管病、糖尿病增殖性视网膜病变、糖尿病性黄斑水肿、肾病、神经病和黎明现象,以及其它的与胰岛素和胰高血糖素释放有关的代谢障碍,例如肥胖症,例如病态肥胖或下丘脑性肥胖或血胰岛素增多性(hyperinsulinemic)肥胖,
b)用于治疗肠皮瘘和胰皮瘘、肠易激惹综合征、炎性疾病(例如格雷夫斯病、炎性肠病、银屑病或类风湿性关节炎)、多囊肾病、倾倒综合征、水样腹泻综合征、AIDS-相关腹泻、化疗诱导的腹泻、急性或慢性胰腺炎和胃肠激素分泌肿瘤(例如GEP肿瘤,例如血管活性肠多肽瘤、胰升糖素瘤、胰岛素瘤、类癌等)、淋巴细胞恶性(例如淋巴瘤或白血病)、肝细胞癌以及胃肠出血(例如静脉曲张食管出血),
c)用于预防或治疗血管生成、上述炎性障碍包括炎性眼病、黄斑水肿,例如囊样黄斑水肿、特发性囊样黄斑水肿、渗出性年龄相关性黄斑变性、脉络膜新血管形成相关障碍和增殖性视网膜病变,
d)用于预防或抵抗移植物血管病,例如同种异体移植物或异种移植物血管病,例如在器官移植(例如心脏、肺、心肺联合、肝、肾或胰移植)中的移植物血管动脉粥样硬化,或者用于预防或治疗静脉移植物狭窄、再狭窄和/或血管损伤后的血管闭塞,该血管损伤是由例如导管插入术过程或血管刮伤过程例如经皮腔内血管成形术、激光治疗或其它破坏血管内膜或内皮完整性的侵害性过程引起的,
e)用于治疗促生长素抑制素受体表达或蓄积肿瘤例如垂体瘤(例如库欣病),胃肠胰、类癌、中枢神经系统、乳腺、前列腺(包括激素升高的顽固性前列腺癌)、卵巢或结肠肿瘤、小细胞肺癌、恶性肠梗阻、副神经节瘤、肾癌、皮肤癌、神经母细胞瘤、嗜铬细胞瘤、甲状腺髓样癌、骨髓瘤、淋巴瘤、霍奇金和非霍奇金淋巴瘤、骨瘤及其转移,以及自身免疫或炎性障碍,例如类风湿性关节炎、格雷夫斯病或其它的炎性眼病。
本发明组合物优选用于治疗肢端肥大症、类癌和/或库欣病。
本发明液体组合物的活性和特征可以在标准临床试验或动物试验中说明。
本发明组合物的适合剂量将当然例如取决于待治疗的病症(例如抵抗性的疾病类型)、所用的药物、预期的作用和施用方式而不同。
对于包含促生长素抑制素类似物的盐(所述的盐为天冬氨酸盐、乳酸盐、琥珀酸盐、乙酸盐、谷氨酸盐或柠檬酸盐)的本发明组合物,可以通过下列施用获得满意结果:例如非肠道施用,剂量为约0.1mg至约100mg,优选约3mg/针/月至约60mg/针/月或约0.01mg至约4mg,优选0.1mg/kg动物体重/月至1mg/kg动物体重/月,一次性施用或分剂量施用。因此,患者的适合的月剂量为约0.1mg至约80mg促生长素抑制素类似物的盐(所述的盐为天冬氨酸盐、乳酸盐、琥珀酸盐、乙酸盐、谷氨酸盐或柠檬酸盐)。
本发明提供了促生长素抑制素类似物的盐和水的简单药物组合物,所述的盐为天冬氨酸盐(例如单或二天冬氨酸盐)、乳酸盐、琥珀酸盐(例如单或二琥珀酸盐)、乙酸盐、谷氨酸盐(例如单或二谷氨酸盐)或柠檬酸盐,其中盐:碱比例范围为0.1至2,定义的pH为3.0至7.0,优选约4.0至6.0,更优选约4.0至5.0。盐碱比例范围0.1至2提供了促生长素抑制素类似物盐在给定的pH下的溶解性以及与体液接触后沉淀和贮库的形成以及因此产生的环境pH的改变。可以用缓冲剂稳定pH。制备组合物的方法是简单的,其通过将水加入至促生长素抑制素类似物的盐中。在pH约4.0至6.0时,组合物表现出很好的溶解性并且因此避免了例如在预填充的注射器中产生沉淀或针堵塞。没有使用在施用部位可能产生严重副作用的有机溶剂。
以下仅通过本发明的方法和组合物的实施例的方式进行描述。
实施例1
原料 | 重量g | 需要的重量 | 实际的重量 |
促生长素抑制素二天冬氨酸盐 | 58.8235 | 0.8g | 0.8g |
注射用水(WFI) | 100 | 1.36mL | 1.36mL |
通过将0.8g促生长素抑制素二天冬氨酸盐和1.36mL注射用水混合制备2mL本发明药物组合物的溶液剂。
实施例2
含有实施例1中给出的组合物的药物产品在兔中的释放曲线。非肠道注射该组合物并且在2个月期间采集数次血样以测定促生长素抑制素二天冬氨酸盐。
兔血浆中的促生长素抑制素
时间[天]
实施例3
原料 | 需要的重量 | 实际的重量 |
促生长素抑制素二琥珀酸盐 | 1.0g | 0.999g |
注射用水(WFI) | 1.6mL | 1.6mL |
通过将0.999g促生长素抑制素二琥珀酸盐和1.6mL注射用水混合制备本发明药物组合物的二琥珀酸盐形式。
实施例4
原料 | 需要的重量 | 实际的重量 |
促生长素抑制素二谷氨酸盐 | 0.916g | 0.916g |
注射用水(WFI) | 1.44mL | 1.44mL |
通过将0.916g促生长素抑制素二谷氨酸盐和1.44mL注射用水混合制备本发明药物组合物的二谷氨酸盐形式。
实施例5
含有实施例3和4中给出的组合物的药物产品在兔中的释放曲线。非肠道注射该组合物并且在2个月期间采集数次血样以测定促生长素抑制素二琥珀酸盐和促生长素抑制素二谷氨酸盐。
Claims (16)
1.非肠道施用的药物组合物,该药物组合物包含促生长素抑制素类似物的盐和水,所述的盐为单或二天冬氨酸盐、单或二谷氨酸盐、单或二琥珀酸盐、乙酸盐或柠檬酸盐,该药物组合物在注射后与体液接触形成胶凝贮库系统。
2.非肠道施用的药物组合物,该药物组合物包含促生长素抑制素类似物的盐和水,所述的盐为单或二天冬氨酸盐、单或二谷氨酸盐、乳酸盐、单或二琥珀酸盐、乙酸盐或柠檬酸盐,pH在3.0和7.0之间,该药物组合物在注射后与体液接触形成胶凝贮库系统。
3.权利要求1或2的药物组合物,其中促生长素抑制素类似物的盐具有盐:碱的比例范围为0.1至2。
4.根据权利要求1的药物组合物,其pH在约4.0和6.0之间。
5.根据任何前述权利要求的药物组合物,其pH在约4.0和5.0之间。
6.根据任何前述权利要求的药物组合物,其包含一定量的可药用缓冲剂以提供pH在约3和7之间。
7.根据权利要求6的药物组合物,其pH在约4.0和5.0之间。
8.根据权利要求6和7的药物组合物,其中可药用缓冲剂选自下列缓冲剂中的至少一种:乙酸盐缓冲剂、酒石酸盐缓冲剂、甘氨酸缓冲剂和乳酸盐缓冲剂。
9.根据权利要求6至8的药物组合物,其中可药用缓冲剂为乙酸盐缓冲剂。
10.根据权利要求9的药物组合物,其中所用的乙酸盐缓冲剂的浓度为约10mM至25mM。
11.根据任何前述权利要求的药物组合物,其中所述的胶凝贮库系统历经1至90天的延长的时间周期在患者体内持续释放促生长素抑制素类似物的盐,所述的盐为天冬氨酸盐、乳酸盐、琥珀酸盐、乙酸盐、谷氨酸盐或柠檬酸盐。
12.权利要求11的药物组合物,其中所述的胶凝贮库系统历经1至60天的延长的时间周期在患者体内持续释放促生长素抑制素类似物的盐,所述的盐为天冬氨酸盐、乳酸盐、琥珀酸盐、乙酸盐、谷氨酸盐或柠檬酸盐。
13.根据任何前述权利要求的药物组合物,其粘度为1至106mPas。
14.预填充注射器,该注射器包括任何前述权利要求的组合物和使用说明书。
15.制备根据权利要求1至13中任意一项的药物组合物的方法,该方法包括
i)将促生长素抑制素类似物的盐溶于水中,所述的盐为单或二天冬氨酸盐、单或二谷氨酸盐、乳酸盐、单或二琥珀酸盐、乙酸盐或柠檬酸盐,
ii)任选加入可药用量的缓冲剂,并且任选
iii)将溶液填充至注射器中。
16.制备根据权利要求1至13中任意一项的药物组合物的方法,该方法包括
i)将促生长素抑制素类似物的盐溶于水中,所述的盐为单或二天冬氨酸盐、单或二谷氨酸盐、乳酸盐、单或二琥珀酸盐、乙酸盐或柠檬酸盐,
ii)加入可药用量的缓冲剂以获得pH在3.0和7.0之间,并且任选
iii)将溶液填充至注射器中。
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EP2067786A1 (en) | 2007-12-07 | 2009-06-10 | ITALFARMACO S.p.A. | Novel non selective analogs of somatostatin |
EP2225271B1 (en) | 2007-12-03 | 2013-07-31 | ITALFARMACO S.p.A. | New non-selective somatostatin analogues |
US9352012B2 (en) | 2010-01-13 | 2016-05-31 | Ipsen Pharma S.A.S. | Process for the preparation of pharmaceutical compositions for the sustained release of somatostatin analogs |
US8535544B2 (en) | 2010-07-26 | 2013-09-17 | International Business Machines Corporation | Structure and method to form nanopore |
WO2013131879A1 (en) | 2012-03-07 | 2013-09-12 | Novartis Ag | New application for pasireotide |
WO2018048609A1 (en) | 2016-09-06 | 2018-03-15 | Monell Chemical Senses Center | Method of regulating immunity in the intestines |
US11045482B2 (en) * | 2017-03-09 | 2021-06-29 | Corcept Therapeutics, Inc. | Use of glucocorticoid receptor modulators in the treatment of catecholamine-secreting tumors |
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