CN1553799A - 具有延长的活性成分释放的剂型 - Google Patents
具有延长的活性成分释放的剂型 Download PDFInfo
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- CN1553799A CN1553799A CNA028176308A CN02817630A CN1553799A CN 1553799 A CN1553799 A CN 1553799A CN A028176308 A CNA028176308 A CN A028176308A CN 02817630 A CN02817630 A CN 02817630A CN 1553799 A CN1553799 A CN 1553799A
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Classifications
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- A—HUMAN NECESSITIES
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
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- A—HUMAN NECESSITIES
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- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
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- A—HUMAN NECESSITIES
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Abstract
一种药物单位剂型，它包括治疗有效剂量的4－苯基丁酸盐，它具有活性成分的延长释放、适合于当每天一次或两次口服给药时缓解并治愈各种疾病；所述药物制剂的制备方法及其在治疗良性前列腺增生、癌症、白血病、囊性纤维化、AIDS、肾脏和肝脏疾病、珠蛋白生成障碍性贫血和尿素循环障碍中的应用，包括给患者每天两次口服施用其治疗有效的剂量。
Description
发明领域
本发明涉及具有延长的活性成分释放、用于每天一次或两次给药的固体、可口服给药的药物剂型，它含有4-苯基丁酸盐作为活性成分，涉及生产它们的方法和它们在治疗各种疾病中的应用，其中已知所述疾病将有益地受到该活性成分的影响。
发明背景
4-苯基丁酸钠盐(4-苯基丁酸钠)及其在治疗各种疾病如良性前列腺增生、癌症、囊性纤维化、HIV、肾脏和肝脏衰竭、珠蛋白生成障碍性贫血和尿素循环障碍上的应用是已知的。例如，WO85/04805(Brusilow)揭示了在人类中除去废氮的方法，其中施用4-苯基丁酸盐。DE19810383(Manhart等)公开了4-苯基丁酸盐作为瘤的治疗用凋亡诱导剂。WO9937150(Pandolfi et al.)公开了使用视黄酸和/或组蛋白脱乙酰酶抑制剂进行癌症的转录治疗。WO 93/07866、WO9510271或EP 725635(Samid)揭示了使用苯基乙酸衍生物的组合物和方法用于治疗和预防许多病理，其中包括癌症、AIDS、贫血和严重的β-链血红蛋白病(这在许多美国专利中出现)。WO 9856370(USP6,207,195，Walsh等)公开了含有4-苯基丁酸钠的治疗纳米球，用于通过CFTR基因治疗来治疗囊性纤维化。WO 9840078(Rephaeli)揭示了脂肪酸β-氧化抑制剂对氧化烯二酯和丁酸衍生物的治疗增强作用。
4-苯基丁酸在人体内通过β-氧化快速地分解成苯基乙酸。该酸从细胞内除去谷氨酰胺，而谷氨酰胺对癌症的生长是重要的。癌细胞内谷氨酰胺的不足导致细胞凋亡。为了阻碍4-苯基丁酸盐从体内快速除去，对每个患者每天给药约10-40g。为了在血浆内达到并维持恒定水平的活性成分，也使用输注溶液。然而，对于急救治疗来说，这些不是合适的。大量4-苯基丁酸盐的使用也是商业问题。活性化合物非常昂贵且必须服用数月一直到数年。
因此，希望具有4-苯基丁酸盐制剂，它避免了与使用大量的该化合物有关的问题。该制剂在较低用量活性成分的情况下应当有效。当反复给药时，应当提供恒定的治疗有效的血浆水平，在血液内显示活性成分的最大和最小浓度之间的最小波动。可通过在比使用常规制剂情况下更长的时间段内，控制活性成分的溶解，来实现降低活性成分的注入时间和使波动最小的可能方法。通过治疗体系OROS提供解决该问题的方法(F.Theeuwes，J.Pharm.Sci.，Vol.64，12，1987-1991，1975)。OROS体系的缺点是在技术上难以生产它们。
具有缓慢释放速度、提供低血浆水平波动(在相对长的时间段内维持恒定)的制剂将是所需的。缓慢释放制剂或延迟释放制剂是药物领域已知的。然而，它们不能简单地用于特定的问题，对于每种活性成分和对于每种适应症，必须独立地设计。这要求一些创造性的设计。
活性成分从片剂或粉剂中释放的速度受到活性成分的溶解度特征影响，而这反过来取决于溶解度、粒度、比表面积和与其它赋形剂的相互作用。可借助在片剂芯内或在薄膜包衣内的扩散阻挡剂延迟溶解。原则上常使用借助在芯内的扩散阻挡剂来延迟溶解，基于它的技术简单。有可能使用各种赋形剂，例如膨胀剂、亲脂物质或塑料作为扩散阻挡剂。基质(也就是说均质物质组合物)可使得通过溶解了的活性成分的扩散，特别地通过在片剂芯内被水-填充的孔，和视需要在通过延迟物质扩散的特定情况下，发生活性成分的释放，其中为了该目的，所述延迟物质必须处于合适的结构形式。或者，基质可处于经历缓慢侵蚀且按照这一方式影响活性成分的延迟释放的形式。
在所有那些情况下，用于释放的扩散途径和活性扩散表面随时间而变化。由于该原因，显而易见的是，利用基质体系，在体内和体外通常均不可能预计具有线性动力学，即0级的任何释放。相反，释放通常是时间的平方根的函数(Square root dissolution；Higuchi；J.Pharm.Sci.52，12，1963，1145)。在许多出版物中也证明了Higuchi定律对水胶体基质的有效性(Ford等，Int.J.Pharm.，24，1985，327-338；339-350；1985)。
其中药物被掺入可溶或可侵蚀的基质内的治疗剂型将是所需的，这是由于考虑到它们的制造容易、不同制造工艺之间的低变化程度和由于相对低的成本。
使用亲水树胶，如羟丙基甲基纤维素作为延迟基质材料是已知的且已用许多活性成分进行了测试。迄今为止，为了达到所需的目的，在使用4-苯基丁酸盐情况下，尚没有制剂是合适的。
不可能计算或通常预测当与延迟赋形剂结合时，特定药物的行为。尽管影响从基质体系内释放的基本因素已进行了充分的研究，但一方面延迟材料与其它赋形剂之间的相互作用以及另一方面活性成分与其它赋形剂之间的相互作用可能以各种方式影响延迟作用。
释放动力学的问题是多因素的问题。主要因素除了活性成分的溶解性能之外，还有吸水速度以及要穿透的界面的膨胀速度、通过已膨胀物料的物质扩散系数以及其与时间有关的厚度。可明显地推测，通过在片剂的侵蚀与活性成分的溶解性能之间平衡的存在，导致0级释放，以便在溶解时间过程中物质的扩散途径保持恒定。
然而，重要的是要意识到不可能预测释放速度将是0级还是任何其它级。需要从大量已知的药物赋形剂中选择适合于所需目的且以合适的定量比例(必须同样地选择所述比例)加工它们的那些，以形成有效的基质体系。
本发明的问题
构成本发明基础的问题是在缓能和治愈各种疾病中克服使用4-苯基丁酸盐的已有缺点。由于该物质及其有益的治愈能力长时间来是已知的，因此，对开发技术上容易且能便宜地生产和当低于通常用量地每天一次或两次应用时将产生它的治疗效果的固体、可口服给药的药物剂型必然存在偏见。
满足降低剂量而没有降低治疗活性，可更容易和更便宜地生产，且在延长的急救治疗中可更容易地应用的药物剂型常常是一种幸运的发现。患者的治疗和使用它所达到的出乎意料的成功可作为创造性步骤的量度。
本发明提供这种出乎意料的剂型。
发明详述
本发明涉及一种药物单位剂型，它包括治疗有效量的4-苯基丁酸盐，它具有活性成分的延长释放，并且当每天一次或两次地对所述患者口服给药时适合于缓解和治愈人类患者的各种疾病。
药物单位剂型特别地是片剂和引入到胶囊，例如硬质明胶胶囊内的粉剂。
4-苯基丁酸盐可以是碱金属或碱土金属类型，例如锂、钠、钾、镁或钙。优选钠盐。单位剂型含有约50-1000mg，优选约100-500mg，最优选约250mg的活性化合物。
活性成分的延长释放应特别地理解为在约6-12或最多24小时的时间段内活性成分的释放速度。
延长释放剂型或延迟剂型是包括约20-80％，优选约35wt％4-苯基丁酸盐，呈粉剂或优选呈片剂形式的均质基质。
此处之前和之后所使用的与重量或其它测量值有关的术语“约”应当表示+/-5至10％的可能偏差。
通过约5-50％，优选约20wt％分子量范围为约20000-250000的羟丙基甲基纤维素，和取决于所需的释放延迟性性，2-25wt％控制释放的赋形剂和使剂型重量达到100％的任选其它药物上可接受的赋形剂提供基质。
治疗有效量是在约24小时的时间段内，维持所需的治疗效果，特别地抑制谷氨酸代谢所要求的用量。迄今为止已知剂型的治疗有效量为每天10000-40000mg。在本发明中，有效的每日用量显著降低。一个单位剂型含有约20-1000mg 4-苯基丁酸盐，优选约250mg。当每天两次给药时有效的剂量合计为每天仅40-2000mg，优选500mg。
在中草药中基质定义为充分混合的均质物质组合物，它可被压制，形成片剂或可将它以粉剂形式引入到胶囊内，优选引入到硬质明胶胶囊内。
片剂或胶囊含有例如100-500mg，优选250mg的活性成分，例如4-苯基丁酸钠。
药物上可接受的释放控制赋形剂是改善延迟基质的膨胀过程的亲脂或亲水物质(释放延迟剂、释放控制剂)。
亲水释放延迟剂是固体聚乙二醇，例如聚乙二醇4000或6000，或聚乙烯吡咯烷酮，例如各种粘度的Kollidone25、Kollidone30或Kollidone90(BASF GmbH的商品名)以及乙烯基吡咯烷酮/醋酸乙烯酯共聚物，例如Kollidone VA64(BASF GmbH的商品名)。
亲脂释放延迟剂是熔点高于60℃、呈固体片剂形式的药物上可接受的植物脂肪衍生物，如链长为至少16个碳原于的植物脂肪酸，例如硬脂酸C16、棕榈酸C18或其混合物，和特别地通过氢化而硬化的植物油，例如氢化蓖麻油，如Cutina HR(Henkel的商品名)或氢化棉籽油，如Emvelop或Lubritab(Mendell的商品名)。为了制备片剂，亲脂释放延迟剂必须适合于压片。使用约2-25％的释放延迟剂，基于片剂或胶囊的最终重量。
本发明优选使用的且代表延迟原理的羟丙基甲基纤维素(HPMC)属于2208 USPXXII类型，它的分子量为20,000-250,000，优选20,000-120,000，优选粘度为100-15,000 cps。特别合适的是产生最快速膨胀的Methocel K类型，例如Methocel K100M Premium(Prochem Chemical Co.)、Methocel K100LV，Methocel K4M和Methocel K15M(商品名，DOW CHEMICAL CO.)或实际上等价的Metolose 90SH类型，例如Metolose 90SH100、Metolose 90SH4000和Metolose 90SH15000(商品名，Shin-Etsu Chemical Co.Ltd.)。使用约5-50wt％，优选10-40wt％的HPMC，基于片剂或胶囊填充物的最终重量。
其它的赋形剂是一些填料、润滑剂和流动调节剂，它们同样可对释放动力学产生影响，但影响小。
填料是玉米淀粉、乳糖、微晶纤维素、甘露糖醇或磷酸氢钙及其混合物。有用的是例如75％乳糖和25％微晶纤维素的混合物，例如Cellactose(Meggle GmbH的商品名)。必须仔细地选择合适用量的填料和恰当地与特定的制剂相匹配。另外，应当注意压缩性能。以使片剂重量达到100％的用量使用它们。
润滑剂是例如硬脂酸镁、合适质量的硬脂酸、硬脂酸钙及其混合物，其中优选硬脂酸镁，和优选以0.1-1％的用量使用它，基于制剂的最终重量。
对待装入胶囊或压缩的粉剂的流动性起作用的合适试剂(流动调节剂)是例如高度分散的二氧化硅，优选以0.25-1％的用量存在，基于制剂的最终重量。
可给片剂提供中性薄膜包衣或延迟活性成分释放，也就是说，产生滞后时间的薄膜包衣。优选耐胃消化的薄膜包衣。
不具有延迟作用的薄膜包衣例如由成膜剂、颜料、抗粘剂和增塑剂组成。这种成膜剂可由速溶成分组成。在此情况下，优选使用低粘度的2910 USPXXII型羟丙基甲基纤维素，例如MethocelE5或E 15(Dow Chemicals Ltd.)或Pharmacoat606(Shin-Etsu)。
具有延迟作用的薄膜包衣可由水不溶但水可渗透的聚合物组成，它作为扩散阻挡剂，不仅在一开始时产生滞后时间，而且起始改变的渗水作用导致在长时间内影响芯的膨胀行为。优选的水不溶聚合物是甲基丙烯酸的水不溶衍生物，例如丙烯酸甲酯/乙酯，如EudragitRS或RL和EudragitNE(商品名，Rhm Pharma GmbH)及其混合物。
薄膜包衣也可含有在薄膜包衣方法中常规的赋形剂，如光-保护颜料，例如氧化铁，其用量为约40-80％，或二氧化钛，其用量为约100-150％，抗粘剂，例如滑石，其用量为约50-200％，和同样合适的是与聚合物相匹配的聚乙二醇系列增塑剂，例如PEG 400或PEG6000，或在基于甲基丙烯酸衍生物的情况下，为柠檬酸三乙酯，如EudragitRS/RL和NE，其用量为约30-60％(在每一种情况下百分数以干燥包衣物质为基础)。当使用所述Eudragit型的含水分散液时，则例如Tween80作为聚集抑制剂是必须的。
为了制备粉剂组分，以填充硬质明胶胶囊，有可能使用与制备片剂所使用的那些相同的粉剂组分。在片剂内的释放动力学同样取决于几何因素，如片剂的形状和尺寸。优选直径约5-11mm，特别地70-9mm，和厚度3-10mm，特别地6.8mm的双凸面片剂。
优选的片剂含有例如：
-约250mg苯基丁酸钠，
-约146mg 100或4000cps的2208 USPXXII型羟丙基甲基纤维素，
-约261g乳糖，
-约30-60mg，尤其31.25mg微晶纤维素(AvicePH102，SelectChemie或Cellactose，Meggle)，
-约10mg硬化植物油，或例如滑石，
-约1.5mg硬脂酸镁，和
-任选地约1mg高度分散的二氧化硅，
以便由其制备的芯重约0.7g。
有利地，例如通过使用含约7850g异丙醇，约3360g Eudragit L12.5，约66g邻苯二甲酸二丁酯，约18.0g Miglyol812，和约56g聚乙二醇PEG 400的胶态分散液，提供数量为24000个具有薄膜包衣的芯。
对于含100和500mg活性成分的片剂来说，应当使用赋形剂的相应等分试样。
优选的药物剂型含有250mg 4-苯基丁酸钠，且具体地是实施例1中所述的片剂。
根据上述说明，在进一步的实施方案中，本发明涉及制备药物剂型的方法，其特征在于以常规的方式制备剂型。
视需要，将片剂芯的成分研碎成所需的粒度，同时或以特定的顺序彼此均匀混合，和任选地通过用水润湿造粒，分散并干燥粒状物料。若混合物被造粒，则可在造粒之后，将填料、流动剂和润滑剂加入到粒料中。压制芯成分的混合物，形成硬度约50-100N，优选90N的片剂，或以原样引入到硬质明胶胶囊中。
通过将薄膜包衣的各成分与水混合，用其包被压制的片剂芯，并在约30-40℃，优选约35℃下干燥，以常规的方式进行薄膜包被。
根据本发明，在进一步的实施方案中，本发明涉及药物剂型的应用，用于可受到所述剂型影响的疾病的治疗，所述治疗包括每天一次或两次口服给需要治疗和将要治疗的患者施用药物本发明的药物剂型。
取决于患者的年龄和重量、疾病的性质和严重度以及患者的一般状况，同时取决于待施用的4-苯基丁酸盐，所使用的剂型含有约100-约1000mg，优选250mg活性成分。
可有益地受到本发明剂型影响的疾病尤其包括良性前列腺增生、癌症、白血病、囊性纤维化、AIDS、肾脏和肝脏疾病、珠蛋白生成障碍性贫血和尿素循环障碍。例如，通过每天两次，例如在早晨和晚上施用含250mg 4-苯基丁酸钠的药物片剂制剂，可进行前列腺癌的治疗。在治疗约1月之后，当疼痛消失时，治疗效果明显。可持续治疗数月或数年，一直到观察到满意的效果或患者完全没有疾病。甚至在长时间段的治疗之后，4-苯基丁酸钠也没有产生副作用。
下述实施例阐述本发明，但不构成其限制。
实施例1：含250mg 4-苯基丁酸钠的缓释片剂的生产
用4000.0g aqua purificata(通过反渗透纯化的水)润湿6000.0g获自Triple Crown America，Inc.的4-苯基丁酸钠、6,280.0g lactosummonohydricum、3,500.0g Methocel K100 M Premium(Prochem)和750.0g Avicel PH 102(Select Chemie)的混合物，并在冷空气中干燥18小时。使混合物受力通过筛IV mm，并在40℃的空气下再干燥10小时。在20分钟内混合240.0g滑石和30.0g硬脂酸镁的混合物，将该混合物压成各自重0.7g、厚约6.8mm和硬度为90牛顿的片剂。产量：24000个片剂芯。
使用Diosna混合机进行混合，在Lükon干燥室内进行干燥，用Khler & Bosshard筛选机筛分，和用Korsch压片机EK II压片。
例如通过使用含7850g异丙醇，3360g Eudragit L 12.5，66g邻苯二甲酸二丁酯，18.0g Miglyol 812，和56g聚乙二醇PEG 400的胶态分散液，提供具有薄膜包衣的芯。在3.5atm和25℃下，将该悬浮液喷洒在24000个芯上。在循环空气干燥室内，在35℃下干燥具有薄膜包衣的片剂至少4小时。
实施例2；人类试验结果
以下是从人类患者中获得的治疗和试验结果的说明。
患者Nr.1，MM，1909年2月5日出生。
该患者在1995年4月24日表现出前列腺癌，其中前列腺特异抗原(PSA)为36μg/l，具有阳性前列腺活检，表明是前列腺的腺癌。阳性骨扫描表明腰椎和胸椎、肋骨和骨盆的多处骨转移。由于进展性的骨疼痛，他在1996年2月经历双侧睾丸切除术。一直到1998年11月当他再次遭受主要在其背部的骨疼痛之前，他没有疼痛。然后用250mg实施例1的苯基丁酸钠延迟片剂每天口服两次给他治疗。四周后，他没有疼痛。他维持这一药物治疗，一直到2001年6月，没有前列腺癌的任何其它症状。PSA和碱性磷酸酶总在正常范围内。
没有观察到归因于治疗的副作用。
2002年6月的工作表明没有活跃前列腺癌迹象的症状。他现在保持在完全缓解状态达12个月。
患者Nr.2，KR，1919年7月24日出生。
该患者在1997年3月表现出因转移破坏引起的第8胸椎的病理骨折。在两侧上，轻微增大的前列腺的多处活检对腺癌呈阳性。骨扫描表明在肋骨和脊椎上多处吸收。在1997年4月10日，他经历双侧睾丸切除术。从1997年5月一直到2000年9月，用250mg实施例1的4-苯基丁酸钠延迟片剂每天口服两次给他治疗。2001年8月的最后检验表明没有症状。骨扫描表明没有病理的吸收。非常耐受4-苯基丁酸盐，而没有副作用。
在20个月后，处于缓解状态下，他死于一种继发性疾病。他的尸检表明在前列腺或别的地方没有肿瘤组织。
患者Nr.3，M.W.，1911年3月11日出生。
在1997年10月，由于升高的PSA(17.5μg/l)进行前列腺活检，表明为前列腺癌。用LH-RH激动剂治疗(Decapeptyl延迟片剂每月治疗)。在1998年内，他的碱性磷酸酶开始从132上升到167UI(正常值＜110U/I)。从1998年11月开始，用250mg实施例1的4-苯基丁酸钠延迟片剂每天口服两次给他治疗。他的PSA下降到不可测量的水平，他的碱性磷酸酶在1999年12月14日逐渐下降到114U/I。他从来没有主诉骨疼痛。他由于充血性心力衰竭导致心脏病发作，死于2000年4月24日。非常耐受4-苯基丁酸盐，而没有副作用。
Claims (9)
1.一种药物单位剂型，它包括治疗有效量的4-苯基丁酸盐，它具有活性成分的延长释放，并且当对所述患者每天一次或两次口服给药时适合于缓解并治愈人类患者的各种疾病。
2.权利要求1的药物剂型，其特征在于4-苯基丁酸盐是4-苯基丁酸钠。
3.权利要求1的药物剂型，其特征在于通过分子量为20000-120000的羟丙基甲基纤维素实现延长的释放。
4.权利要求1的药物剂型，其特征在于它含有250mg4-苯基丁酸钠作为活性成分。
5.权利要求1的药物剂型，其特征在于它含有-约250mg苯基丁酸钠，
-约146mg100或4000cps的2208USPXXII型羟丙基甲基纤维素，
-约261g乳糖，
-约30-60mg，尤其31.25mg微晶纤维素(AvicelPH102，SelectChemie或Cellactose，Meggle)，
-约10mg硬化植物油，或例如滑石，
-约1.5mg硬脂酸镁，和
-任选地约1mg高度分散的二氧化硅，
以便由其制备的芯重约0.7g。
6.权利要求1的药物剂型，其特征在于由约7850g异丙醇，约3360g EudragitL12.5，约66g邻苯二甲酸二丁酯，约18.0gMiglyol812，和约56g聚乙二醇PEG400生产的薄膜包衣提供24000个芯。
7.权利要求1的药物剂型的制备方法，其特征在于以常规方式制备剂型。
8.权利要求1的药物剂型在治疗良性前列腺增生、癌症、白血病、囊性纤维化、AIDS、肾脏和肝脏衰竭、珠蛋白生成障碍性贫血和尿素循环障碍上的应用，包括给患者每天两次口服施用其治疗有效的剂量。
9.权利要求1的药物剂型在治疗腺癌上的应用，它包括给患者每天两次口服施用其治疗有效的剂量。
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| US20070004805A1 (en) * | 2005-07-01 | 2007-01-04 | Navinta Llc | Process for preparation of liquid dosage form containing sodium 4-phenylbutyrate |
| ZA200800901B (en) | 2005-07-14 | 2010-05-26 | Takeda San Diego Inc | Histone deacetylase inhibitors |
| US20070202164A1 (en) * | 2006-02-28 | 2007-08-30 | Hutchison Medipharma Enterprises Limited | Andrographis Extract Formulations |
| FR2959129B1 (fr) * | 2010-04-21 | 2013-02-01 | Lucane Pharma | Particules comprenant du 4-phenylbutyrate de sodium, procede de preparation et utilisations |
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| EP2397458A1 (en) | 2010-06-21 | 2011-12-21 | Lunamed AG | Organic salts and co-crystals of phenylbutyric acid |
| EP2599483A1 (en) | 2011-11-30 | 2013-06-05 | Lunamed AG | 4-Phenylbutyric acid formulation |
| EP2599477A1 (en) | 2011-11-30 | 2013-06-05 | Lunamed AG | 4-Phenylbutyric acid sustained release formulation |
| EP2599481A1 (en) * | 2011-11-30 | 2013-06-05 | Lunamed AG | 4-phenylbutyric acid for the treatment or prevention of various diseases |
| EP2599767A1 (en) | 2011-11-30 | 2013-06-05 | Lunamed AG | Phenylbutyl-derivatives |
| EP2599482A1 (en) * | 2011-11-30 | 2013-06-05 | Lunamed AG | Low dose therapeutic use of glyceryl tri-(4-phenylbutyrate) |
| EP2607366A1 (en) | 2011-12-21 | 2013-06-26 | Lunamed AG | Glycerol phenyl butyrate esters |
| EP2607367A1 (en) | 2011-12-21 | 2013-06-26 | Lunamed AG | Glycerol phenyl butyrate derivatives |
| EP2698156A1 (en) | 2012-08-16 | 2014-02-19 | Lunamed AG | Phenylbutyric acid for chemoprevention |
| EP2698155A1 (en) * | 2012-08-16 | 2014-02-19 | Lunamed AG | Pharmaceutical unit dosage form comprising 4-phenylbutyric acid |
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| WO2017160345A1 (en) * | 2016-03-15 | 2017-09-21 | Acer Therapeutics Inc. | Palatable compositions including sodium phenylbutyrate and uses thereof |
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| CN100508965C (zh) | 2009-07-08 |
| DE60235178D1 (de) | 2010-03-11 |
| EP1427396B1 (en) | 2010-01-20 |
| EP1291015A1 (en) | 2003-03-12 |
| US7611729B2 (en) | 2009-11-03 |
| CA2459165C (en) | 2011-07-19 |
| PT1427396E (pt) | 2010-04-14 |
| EP1427396A1 (en) | 2004-06-16 |
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