CN1812968B - 4-[6-乙酰基-3-[3-(4-乙酰基-3-羟基-2-丙基苯硫基)丙基]-2-丙基苯氧基]丁酸的多晶型物 - Google Patents
4-[6-乙酰基-3-[3-(4-乙酰基-3-羟基-2-丙基苯硫基)丙基]-2-丙基苯氧基]丁酸的多晶型物 Download PDFInfo
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- CN1812968B CN1812968B CN200480017934.0A CN200480017934A CN1812968B CN 1812968 B CN1812968 B CN 1812968B CN 200480017934 A CN200480017934 A CN 200480017934A CN 1812968 B CN1812968 B CN 1812968B
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
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- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
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Abstract
一种药物组合物,该组合物包括:式(1)所示的化合物的多晶型物,以及药学上可接受的载体或赋形剂,其中化合物(1)以多晶型物的形式出现(如图6所示),其它的多晶型物基本上是合适的。
Description
技术领域
和其它的晶型相比,用粉末X-射线衍射分析的4-[6-乙酰基-3-[3-(4-乙酰基-3-羟基-2-丙基苯硫基)丙基]-2-丙基苯氧基]丁酸的多晶型物具有高溶解性和生物利用度。
背景技术
白三烯类化合物(Leukotrienes)是花生四烯酸通过5’-脂氧酶产生的代谢物,白三烯类化合物是变态响应非常重要的介体,如支气管哮喘中的介体。对白三烯类化合物施加对抗效应的药物对于治疗变应性病很有好处。
在Ohashi等人的美国专利US4985585中公开了许多苯氧烷基羧酸衍生物的合成和生物活性,这些衍生物是白三烯类化合物的对抗剂。这些化合物通过色谱的硅胶柱在实验室中从原料混合物中得到。溶剂蒸发后,得到的是淡黄色油或无色晶体,并没有特意对晶型进行控制。
我们发现,在Ohashi等人的实例33中,4-[6-乙酰基-3-[3-(4-乙酰基-3-羟基-2-丙基苯硫基)丙基]-2-丙基苯氧基]丁酸(1)口服用于治疗哮喘和过敏症,以及在大量制备时,固体化合物可以凝结成几种明显不同的形态。已经发现,结晶条件,特别是温度,对于制备不同的多晶型物是非常关键的。
我们也发现,这些多晶型物中的正交晶型(表1中的式V,图6中的晶型A)的溶解性和生物利用度比其它的晶型物高,因而晶型A提供改善的固体配方。
发明内容
本发明提供了一种药物组合物,该组合物包括式(1)表示的选择性晶型的化合物,
以及药学上可接受的载体或赋形剂;其中,选择性的晶型包括多晶型物,基本上没有不合适的晶型。“基本上没有”指的是通过粉末X-射线衍射方法(PXRD)测试不出不合适的晶型。通常,晶型的纯度大于90%(粉末X-射线衍射trace中的峰高定义的)。优选的,本发明合适的晶型至少含有约95%的多晶型物(图6),该多晶型物是通过9°2-θ区域的相对峰高测定的。
本发明也提供了一种制备式(1)所示的、在其它晶型物中的纯度至少为90%的多晶型物的方法。一种示例的结晶方法包括如下步骤:将式(1)的化合物溶于重量份数5-10的热乙醇和1-10份的水中,在20-25℃的情况下将得到的悬乳液搅拌15-60分钟,然后在5-10℃的情况下冷却1-4小时,加入5-15份水,在5-10℃的情况下搅拌混合物1-4小时,以及分离出式(1)的化合物晶体,该晶体中至少含有重量百分比约为90%的晶型(A)(图6)。
相应的,本发明提供了一种药物组合物,该组合物中含有式(1)表示的固体化合物,
以及药学上可接受的载体或赋形剂,如果式(1)的化合物是以多晶型物的形式出现的,则其它的多晶型物基本上是合适的。在本发明的优选实施例中,式(1)的化合物是正交晶体。本发明也可以制成药片或胶囊的形式。优选的,本发明的组合物的PXRD图基本显示的是图6中的多晶型物。而且,优选的是,至少约90%的式(1)的化合物是PXRD峰高约9°2-θ的多晶型物。组合物中可以进一步含有乳糖和微晶纤维素。药片的重量可以不同,如约在250-500毫克之间。
本发明也涉及一种含有式(1)化合物的分离晶体的组合物,
其中,化合物(1)的分离晶体以多晶型物的形式出现,其它晶型基本没有影响。在优选的实施例中,化合物(1)的分离晶体是正交晶体。本发明中的化合物(1)的分离晶体优选为PXRD图所示,基本是图6所示的多晶型物。特别优选的,本发明中的分离晶体至少含有约90%的多晶型物,其PXRD峰高约9°2-θ。
本发明也提供一种含有化合物(1)的分离晶体的组合物,该组合物中除了其它的多晶型物,至少约含有90%的多晶型物。
附图说明
图1:粉末X-射线衍射图和式I的DSC图。
图1a:式I的DSC图。
图2:粉末X-射线衍射图和式II的DSC图。
图3:粉末X-射线衍射图和式III的DSC图。
图4:粉末X-射线衍射图和式IV的DSC图。
图5:粉末X-射线衍射图和式V的DSC图。
图6:三种晶型的粉末X-射线衍射图。
图7:干法造粒的示意性工艺。
图8:湿法造粒的示意性工艺。
具体实施方式
酯(4)可以通过式(2)的酚和式(3)的镇静剂在有机溶剂中反应合成;其中R是酸的保护基团,如甲基或乙基;有机溶剂如丙酮、甲乙酮、二乙酮或二甲基甲酰胺。
该反应可以在低于室温的温度到溶剂的回流温度之间、并在无机碱存在的情况下进行,其中无机碱如碳酸钾或碳酸钠。也可以加入碘化钾。含有选择性离去基团的化合物(3)的类似物可以用于影响偶联反应,其中选择性离去基团如氯苄基(chloro)和甲苯磺酸基。
通过碱性酯的水解除去酸性保护基团,残留物化合物(1)成为白色的固体。
提纯晶型A(图6)(如90%或更多,优选至少为95%)而对白色固体的重结晶可以将化合物(1)溶于重量份数为5-10、温度为25-40℃的乙醇中生成黄色到桔黄色的溶液。乙醇溶液中充入1-10份的水,并在20-25℃的情况下搅拌15-60分钟,然后在5-10℃的情况下搅拌1-4小时,优选为2.0-3.0小时,从而得到灰白色的悬乳液。
在上述悬乳液中加入5-15份的水,混合物在5-10℃的情况下搅拌1-4小时,优选为1.5-2.0小时。白色和灰白色的固体产品通过真空过滤分离,滤饼用水清洗,并在真空、25-40℃下干燥12-24小时。
其它的重结晶条件也可以得到晶型A,如将化合物(1)溶于低级醇(如异丙醇)中,并冷却溶液形成晶体。
治疗制剂
含有化合物(1)的正交晶型的药物组合物可以和惰性赋形剂一起口服,惰性赋形剂如单独的淀粉粘结剂或淀粉粘结剂与微晶纤维素和合适的润滑剂组合使用。其它合适的赋形剂包括聚乙烯吡咯烷酮(polyvinylpyrrolidinone)、白明胶、羟基纤维素、阿拉伯树胶、聚乙二醇、甘露醇、氯化钠、柠檬酸钠或药物组合物领域的技术人员公知的其它赋形剂。
药片中的赋形剂通常根据它们的功能进行分类,如稀释剂(也称之为填装试剂和填装物)、粘结压缩药片组分的粘结剂、有助于分解液体中的药片而释放出有效组分的分解质、以及改善压缩药片从冲压机和模子中释放出的润滑剂。此外,药片中可以含有其它可以改善压片工艺的物质,如流动添加剂、香料、甜味剂和抗氧剂。
压片和胶囊的一些填充取决于粉末在压力下的粘结性能。压缩的药片可以通过湿法造粒、干法造粒或直接压制制备。湿法造粒工艺包括将组分以粉末的形式混合、制备粒化粘结溶液、将组分和粒化粘结溶液完全混合形成面团、用筛子对物质进行粗筛、干燥、造粒、加入润滑剂并用得到的混合物压制药片。
优选的药片制剂是湿法造粒,并含有化合物(1)乳糖正常体的多晶型物、微晶纤维素101、杂交羧甲基纤维素(crosscarmellose)、硬脂酸镁和纯水,并涂敷一层欧巴代II型(OpadryII)白色。药片的重量为100-1000mg,优选为250-500mg。
干燥造粒包括如下步骤:混合粉末组分,将混合物压制成坚硬的块(slugs),将该块研磨成颗粒,粗筛,需要的时候加入其它的赋形剂,以及将该混合物压制成药片。最经济的压片方法,即直接压制,仅需要两步,即混合组分和将混合物压制成药片。
合适的直接压制粘结剂包括微晶纤维素、可压缩糖、某种钙盐、乳糖和葡萄糖。其中微晶纤维素是优选的。这种赋形剂也具有很好的分解性能。其它良好的粘结剂包括磷酸钙和可压缩糖。钙盐粘结剂通常需要使用分解质。甘露醇和山梨醇具有味觉的优势,但是它们缺乏粘结性能,因而需要分解质。
通常,药片的硬度大于2千克力(kp)/cm2,优选的药片硬度大于5,最优选的约为10-20kp/cm2,其分解时间小于30分钟,特别优选的小于15分钟,上述分解时间是用标准的美国标准药典(USP)的测试方法在水中测试的。
化合物(1)的多晶型物可以制成胶囊。固体载体包括淀粉、乳糖、硫酸钙、二水合物、特服阿巴(teffaalba)、硬脂酸镁或硬脂酸、云母、胶质、阿拉伯树胶、琼脂或白明胶。载体也可以包括缓释物质如甘油单硬脂酸或甘油二硬脂酸,或石蜡与甘油单硬脂酸或甘油二硬脂酸。固体载体的量可以不同,但每剂量单位优选约为20mg-1g。
可以用任何合适的方式进行封装,通常使用用于微胶囊的高分子膜、肠衣、多重膜和其类似物。高分子膜在和唾液接触时可以抗分解,但是在胃中和胃液一接触就立即释放出化合物,从而可以控制组合物的味道。相应的,高分子膜可以是防止胃液出现时快速分解的一种。合适的高分子膜包括生物可降解的高分子如聚乳酸、聚甘露酸、乳酸和甘露酸的共聚物、聚原磷脂和聚酐。化合物也可以用高分子膜制成胶囊,高分子膜如多糖(如甲基或乙基纤维素);或在脂质体输送系统中制成胶囊。美国专利US4462982、US4710384、US5178878和US5709886中公开了制备含有微胶囊活性组分的组合物的合适方法。优选的,微胶囊化合物的平均颗粒尺寸约为50微米-120微米(如约70微米-100微米)。
通常,化合物(1)在药片和胶囊中的剂量约为1.0mg/kg-100mg/kg。服用的间隔根据病人的年龄、体重和状态不同而不同。通常,药物每天服用1-4次。
实例
通常,药片用载体配制而成,载体如单独的改性淀粉,或改性淀粉和10wt%的羧甲基纤维素(Avicel)。压片形成过程中,制剂在1000-3000磅的压力下进行压制。药片优选的平均硬度约为1.5-8kp/cm2,优选为5.0-7.5kp/cm2。分解时间从30秒到15或20分钟。下述实例进一步给出本发明的具体实施例,但是这些实施例并不限制本发明的范围。
实施例1
乙基4-[6-乙酰基-3-[3-(4-乙酰基-3-羟基-2-丙基苯硫基)丙基]-2-丙基苯氧基]丁酸的合成
丙酮(30ml)中的乙基4-(6-乙酰基-3-羟基-2-丙基苯氧基)丁酸(1.6g)、碘化钾(0.5g)和碳酸钾(1.45g)的的搅拌混合物逐滴加入到丙酮(10ml)中的4-(3-溴丙基硫)-2-羟基-3-苯丙基-乙烯酮(ethanone)(1.9g)溶液中,并加热回流。回流6小时后,混合物冷却到室温,无机物通过过滤分离。滤出液进行浓缩,分离残留物并用色谱硅胶柱进行提纯,进而得到题述化合物的粗晶(2.1g,72.4%),该粗晶用乙醇重结晶,得到无色的晶体,熔点为65-66℃。
实例2
4-[6-乙酰基-3-[3-(4-乙酰基-3-羟基-2-丙基苯硫基)丙基]-2-丙基苯氧基]丁酸的合成
乙醇(10ml)中的乙基4-[6-乙酰基-3-[3-(4-乙酰基-3-羟基-2-丙基苯硫基)丙氧基]-2-丙基苯氧基]丁酸(2.1g)加入到溶入水(10ml)中的氢氧化钠(0.26g)溶液中。水浴加热5分钟后,混合物通过加入冰水冷却,并加入盐酸,接着用乙酸乙酯萃取。有机层用水清洗,用硫酸钠干燥并浓缩。得到的残留物用色谱硅胶柱(洗提,乙醇∶三氯甲烷=3∶100)分离和提纯,从而得到题述化合物(1.3g)的无色晶体,熔点为79-81℃。
实例3
多晶型物(Crystallinepolymorphism)
用单一的溶剂重结晶后,化合物(1)用粉末X-射线衍射测量、热分析和醚中的溶解性分析;因而对多晶型物进行评价。结果表明化合物(1)具有5种不同的晶型。
图1-5显示了I-V的亚稳晶型的粉末X-射线衍射图和DSC。表1显示了I-V的制备过程和醚中的溶解性。
表1多晶型物的制备及其在醚中的溶解性
晶型 | 制备工艺 | 溶解性 (mg/ml) |
I | 化合物(1)加热并溶于4倍量的异丙基醚后,得到的溶液 冷却到室温(结晶发生在40℃左右)。相应的,化合物加 热并溶于5倍量的乙氰后,得到的溶液在保温箱中保持40 ℃。 | 36.7 |
II | 化合物(1)加热并溶于10倍量的乙氰后,冷却得到的溶 液并在冰浴中搅拌。 | 40.5 |
III | 化合物(1)加热并溶于10倍量的乙氰后,得到的溶液在 保温箱中保持25℃。 | 35.3 |
IV | 化合物(1)加热并溶于5倍量的乙醇后,在热的时候加入 2.5倍量的水,然后冷却到室温。 | 45.8 |
V | 化合物(1)加热并溶于5倍量的乙醇后,得到的溶液在冰 浴中冷却搅拌,并在冷的时候加入2.5倍量的水。 可选择的,化合物(1)加热并溶于3.5倍量的异丙醇中, 得到的溶液在冰箱中保持0℃。 | 47.6 |
表1表明:结晶温度在制备多晶型物中是非常重要的。在制备主要组分时,大量发生结晶,精确控制温度的失败将产生稳定的或亚稳定的晶体,从而使产品中的物化性能和生物利用度的差异较大,这是要小心避免的。
实例4
获得正交晶型、晶型V(晶型A)的大量结晶过程
34g的灰白色化合物(1)溶于204ml(重量份数为6份的干燥滤饼)的乙醇(40℃)中,生成黄色到桔黄色的溶液。中度搅拌,乙醇溶液中加入43ml(1.3份)的水。反应混合物冷却到20-25℃,并在20-25℃下搅拌约15分钟,然后在10-15℃下冷却1-2小时,得到的是一种灰白色的悬乳液。
得到的悬乳液然后加入364ml(10.7份)的水,混合物在5-10℃下搅拌1-2小时。白色和灰白色固体产品用真空过滤进行分离。滤饼用2×30ml的水进行清洗。灰白色固体在真空、35-40℃下干燥24小时。
实例5
化合物(1)在乙醇/水(2∶1)中的溶解性数据
温度 | 期望的多晶型物V(晶型A) | 不想得到的单斜晶型 |
22℃ | 6.7g/l | 3.4g/l |
30℃ | 15.7g/l | 6.1g/l |
40℃ | 46g/l | 17.2g/l |
化合物(1)的样品(5g)在乙醇/水(2∶1,100ml)中悬浊,并在温度22℃、30℃和40℃下分别搅拌1小时。过滤悬乳液,固体在真空炉中、室温下干燥过夜,得到不溶性物质。溶解性以重新得到的物质为基础,通过减量方式进行计算。
实例6
通常,湿法造粒药片用粘结溶液制成,该粘结溶液含有羟丙基纤维素。造粒在高速造粒机中进行,得到的湿的物料在流化床中干燥、粉碎、并和大粒的赋形剂混合以助于分解、流动和压制,并随后在压片机上制成药片。这些药片用膜涂敷,从而使外观一致,并改善相容性(即易于吞咽)。赋形剂包括但不限于杂交羧甲基纤维素钠、硬脂酸镁、羟丙基纤维素、羟丙基甲基纤维素、乳糖、山萮酸甘油酯、聚乙烯吡咯烷、甘露醇、二氧化钛和微晶纤维素。
实例7
通常,干法造粒制剂通过干法混合(在反转搅拌机或高速混合器中)部分粘结、分解和润滑粉末得到。这种干燥粉末混合通过使用带有震荡(高速)造粒机的滚筒捣碎机而形成颗粒。调试网孔、分类间距、差力、滚筒速度和造粒速度,从而使制剂的物理外观参数最优是制药领域的普通技术人员公知的。赋形剂包括但不限于杂交羧甲基纤维素钠、硬脂酸镁、羟丙基纤维素、羟丙基甲基纤维素、乳糖、山萮酸甘油酯、聚乙烯吡咯烷、甘露醇、二氧化钛和微晶纤维素。
实例8
干法造粒的具体配方
表3.4.1:干法造粒样品的初始配方
编号 | 组分 | 样品1(mg/药片) | 样品2(mg/药片) |
1 | 化合物(1),类型V(晶型A) | 250 | 250 |
2 | 乳糖正常体/快速流动 | 7.5 | -- |
3 | 微晶纤维素PH101 | 31 | 31 |
4 | 杂交羧甲基纤维素钠 | 20 | 20 |
5 | 羟丙基纤维素 | 80 | -- |
6 | 硬脂酸镁 | 2.0 | -- |
7 | 羟丙基甲基纤维素2910 | 8.0 | -- |
8 | 二氧化钛 | 1.0 | -- |
9 | 棕榈蜡 | 0.5 | 0.5 |
10 | 聚乙烯吡咯烷酮 | -- | 85 |
11 | 甘露醇 | -- | 3.5 |
12 | 山萮酸甘油酯 | -- | 2.0 |
13 | 欧巴代II型 | -- | 8.0 |
总计 | 400mg | 400mg |
实例9
湿法造粒的具体配方
表3.4.2:湿法造粒样品的初始配方
编号 | 组分 | 样品1(mg/药片) | 样品2(mg/药片) |
1 | 化合物(1),类型V(晶型A) | 250 | 250 |
2 | 乳糖正常体/快速流动 | 7.5 | -- |
3 | 微晶纤维素PH101 | 32 | 32 |
4 | 杂交羧甲基纤维素钠 | 25 | 25 |
5 | 羟丙基纤维素 | 25 | -- |
6 | 硬脂酸镁 | 2.0 | -- |
7 | 羟丙基甲基纤维素2910 | 7.0 | -- |
8 | 二氧化钛 | 1.0 | -- |
9 | 棕榈蜡 | 0.5 | 0.5 |
10 | 聚乙烯吡咯烷酮 | -- | 30 |
11 | 甘露醇 | -- | 3.5 |
12 | 山萮酸甘油酯 | -- | 2.0 |
13 | 欧巴代II型 | -- | 7.0 |
总计 | 350mg | 350mg |
湿法造粒工艺的流程如图8所示。
上面对本发明的优选实施例进行了详细的说明。对上述实施例进行改变或改进对本领域的技术人员来说是显而易见的。前述的实施例不是对本发明的说明书和权利要求书的限制。
实例10
PXRD分析
样品通过正常的前包装技术制备,并在西门子D5000衍射系统上进行测试。使用高分辨率的Cu-Kα-源,在50kV/35mA下操作。次级光束通过Kevex固态侦测器变为单色。逐步扫描方式用于收集2.5°-35°(2-θ)范围的数据。得到的数据用DiffracPlusTM软件处理。
图6显示了三种不同晶型的部分衍射图,即晶型A(可能是正交结构,特定的V形)、晶型B(I)和晶型(C)(II)(两者都是单斜晶型)。
可以看出,顶部的图和另外两个有很大的差别。这些差别清楚的用箭头表示出。较上部的图的大部分单峰在另外两个上成为双重线。这强烈的表明降低整体的对称将发生结构转换。为了找出更好的区别这些多晶型的一些标准,对未知的晶格进行了标定指数。结果表明显示了一个正交晶型(顶部trace,晶型A)和一个单斜(中间trace,晶型B)。底部trace(晶型C)的单斜晶型和晶型B的非常相似,但是遗失的一些影像(用箭头表示)导致结构上存在差异。
晶型A的结构和图5、表1中的晶型V很接近,尽管它们在19-25°2-θ的范围内有些差别。另一方面,多晶型I和II的衍射图和晶型B和C匹配的很好,由于降低了正交到单斜的整体对称性,它们主要的影像看起来有些分开。
由于表1中的5中晶型的结晶特征不易再现,本发明仅用PXRD通过外观对化合物(1)在药物样品中的结构状态进行了描述。
Claims (9)
2.根据权利要求1所述的组合物,其中进一步包括乳糖和微晶纤维素。
4.一种含有权利要求1-3中任一权利要求所述的组合物或晶形的药片。
5.一种含有权利要求1-3中任一权利要求所述的组合物或晶形的胶囊。
7.根据权利要求6所述的方法,其中步骤(a)包括将化合物(1)在25-40℃溶于重量份数为5-10份的热乙醇中,并在乙醇溶液中加入1-10份的水。
8.根据权利要求6或7所述的方法,其中步骤(c)进行2.0-3.0小时。
9.根据权利要求6或7所述的方法,其中步骤(c)进行1.5-2.0小时。
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PCT/US2004/020154 WO2005000243A2 (en) | 2003-06-24 | 2004-06-24 | The polymorphic form a of 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butryric acid |
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US7064146B2 (en) * | 2003-06-24 | 2006-06-20 | Medicinova, Inc. | Pharmaceutical compositions of isolated orthorhombic crystalline 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyric acid and methods of use |
WO2005105073A1 (en) | 2004-04-27 | 2005-11-10 | Medicinova, Inc. | Phenoxyalkycarboxylic acid derivatives in the treatment of inflammatory diseases |
US8962687B2 (en) | 2012-12-05 | 2015-02-24 | Medicinova, Inc. | Method of treating liver disorders |
JP2013119550A (ja) | 2011-12-08 | 2013-06-17 | Medicinova Inc | 非アルコール性脂肪性肝疾患及び非アルコール性脂肪性肝炎の処置方法 |
WO2015013395A1 (en) | 2013-07-25 | 2015-01-29 | Medicinova, Inc. | Methods for reducing triglyceride, total cholesterol and low density lipoprotein blood levels |
US9346754B2 (en) | 2014-05-08 | 2016-05-24 | Medicinova, Inc. | Method of treating advanced non-alcoholic steatohepatitis |
US20150321989A1 (en) | 2014-05-08 | 2015-11-12 | Medicinova, Inc. | Method of treating idiopathic pulmonary fibrosis |
WO2015187548A1 (en) * | 2014-06-02 | 2015-12-10 | Medicinova, Inc. | Method of inhibiting or treating fibrosis |
US11197896B2 (en) | 2014-08-25 | 2021-12-14 | Société des Produits Nestlé S.A. | Egg protein formulations and methods of manufacture thereof |
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