CN1805733A - 吸收促进剂例如bht、bha或没食子酸丙酯 - Google Patents
吸收促进剂例如bht、bha或没食子酸丙酯 Download PDFInfo
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- CN1805733A CN1805733A CNA2004800162227A CN200480016222A CN1805733A CN 1805733 A CN1805733 A CN 1805733A CN A2004800162227 A CNA2004800162227 A CN A2004800162227A CN 200480016222 A CN200480016222 A CN 200480016222A CN 1805733 A CN1805733 A CN 1805733A
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- aromatic alcohol
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Abstract
本发明提供包含以下的混合物的药用组合物:(a)活性大分子组分,和(b)选自丁羟甲苯、丁羟茴醚及其类似物和衍生物的芳族醇吸收促进剂,其中所述芳族醇吸收促进剂以大于或等于活性大分子组分的量(重量)存在,并且另外提供包含以下的混合物的药用组合物:(a)活性大分子组分,(b)选自没食子酸丙酯、丁羟甲苯、丁羟茴醚及其类似物和衍生物的芳族醇吸收促进剂,其中所述芳族醇吸收促进剂以大于或等于活性大分子组分的量(重量)存在,和(c)一种能够增加芳族醇吸收促进剂在含水介质中的溶解度的增溶助剂。
Description
本发明涉及芳族醇促进分子(包括生物活性大分子)适宜于从肠腔跨肠壁摄入体内的用途。本发明尤其涉及包含优选跨肠壁吸收到体内的活性大分子组分的新的药用组合物。
亲水性芳族醇,尤其是其中羟基不直接连接于芳族核的芳族醇例如苯氧基乙醇、苯乙醇和苄醇,作为溶剂和增塑剂已用于药学实践多年,并且当通过多种途径包括口服途径给药时具有低的毒性。那些化合物在室温下全部为液体并且可易于溶解在含水介质中。
亲水性芳族醇例如苯氧基乙醇和相关化合物包括苯乙醇和苄醇,对肠细胞具有多种作用,其中一种作用是当以相对高的局部浓度存在时,芳族醇瞬时(transiently)增加肠细胞屏障层的通透性。
推定这是由于打开了这些细胞之间的紧密连接,产生甚至大的分子(大分子)可经扩散通过的孔的缘故。
在发现仅仅在相对高的局部浓度的亲水性芳族醇存在下可观察到肠细胞屏障层的渗透性增加的基础上,申请人的研究已显示与可检测的分子一起口服给予亲水性芳族醇的溶液(作为酏剂)对摄取没有产生促进作用。推测这是因为在它到达吸收部位(在肠道)之前,亲水醇在胃肠道迅速稀释到低于它不能发挥其作用的浓度。另外,人们正在探寻其摄取的分子在到达肠之前也被稀释。目前已经发现另一类芳族醇也显示出渗透促进剂的特性。这些化合物具有直接连接于芳族核的羟基和在OH基团的对位的另外的取代基,并且一般显示抗氧化剂性质,该性质可能与它们用做渗透促进剂的能力有关或者无关。这类化合物的实例为没食子酸丙酯、丁羟甲苯(BHT)和丁羟茴醚(BHA)。令人惊奇的是,虽然这些原料已常规用于药学实践(主要用于基于脂类的制剂中,通常用作抗氧化剂)至少20年,但是从未观察到这些原料能够作为渗透促进剂起作用。这可能是因为这些化合物全部是极难溶于水的固体,因此使其难以以高的浓度溶合到以水为基质的药用制剂中,并且也阻止它们在制剂分散于肠腔时以可溶解的形式得到,以便在升高的浓度下作为促进剂起作用,或者在需要渗透促进作用的部位接近于任何其它粘膜表面。
没食子酸酯或者尤其是没食子酸丙酯作为小分子的生物利用度的促进剂的用途分别描述于US 6180666和US 5962522中,其通过其中没食子酸丙酯抑制细胞色素P450(尤其是CY3PA,位于内质网)活性,由此减少小分子在它们通过肠细胞的通道(称作跨细胞途径)上的代谢降解的机制起作用。没食子酸丙酯和其它的没食子酸酯似乎是细胞色素P450的有效抑制剂,并且主张可将足够的没食子酸丙酯引入到制剂中以发挥显著的作用而不需要增溶助剂。然而,对没食子酸丙酯描述的酶抑制剂的作用机理不能预期增加大分子的生物利用度,因为大分子不能独立地进入肠细胞中,并且因此不会与酶所在位置的内质网接触。另外,大分子例如肽和蛋白远没有小的药物分子对细胞色素P450的作用敏感,以致经这种酶的降解作用不是来自肠道或者其它粘膜组织的大分子生物利用度不佳的主要原因。一个更大的障碍只是分子本身的大小,这阻止它们独立进入或者通过细胞衬粘膜组织,其中这些组织衬里的细胞形成连续的不可通过的屏蔽。
目前已经令人惊奇地发现芳族醇例如没食子酸丙酯、BHT、BHA及其类似物和衍生物能够通过增加粘膜细胞的物理通透性促进大分子通过粘膜屏障的能力。发生这种情况的一种可能的机制是通过暂时打开这些细胞之间的紧密连接,产生大分子可沿着通道通过的通道(细胞旁路)。另一种作用方式是增强流动相胞饮作用(pinocytosis),导致液泡内与大分子一起的主体流体的内在化,使流体从细胞的一侧转移到另外一侧。虽然还可能有其它尚未清楚地明了的机理,但认为大分子事实上已获准进入细胞的内胞质室则是不太可能的。已经发现这个现象与浓度有关,并且前提是以高浓度存在的芳族渗透促进剂增强体内作用。结果,使用增溶助剂(solubilisation aids)对这些化合物是有利的,尤其是在没食子酸丙酯的情况下,能够增加粘膜组织的大分子的生物利用度。
目前也已经发现存在一些试剂(在此称作增溶助剂),它们可用于促进溶解这些芳族醇渗透促进剂,并且当暴露于含水介质时,它们还可增加其溶解性和/或溶出速率。如果这些原料作为渗透促进剂能发挥其最大的作用,这一点显然是重要的。
本发明提供包含以下组分的混合物的药用组合物:
(a)活性大分子组分;和
(b)选自丁羟甲苯、丁羟茴醚及其类似物和衍生物的芳族醇吸收促进剂,其中芳族醇吸收促进剂以大于或等于活性大分子组分的量(重量)存在。
本发明另外提供包含以下组分的混合物的药用组合物:
(a)活性大分子组分;和
(b)选自没食子酸丙酯、丁羟甲苯、丁羟茴醚及其类似物和衍生物的芳族醇吸收促进剂,和
(c)能够增加芳族醇吸收促进剂在含水介质中的溶解度的增溶助剂,其中芳族醇吸收促进剂以大于或等于活性大分子组分的量(重量)存在。
本发明也提供芳族醇在药用组合物中作为大分子吸收到体内的促进剂的用途,所述芳族醇选自丁羟甲苯、丁羟茴醚及其类似物和衍生物。
在另一个实施方案中,本发明提供选自丁羟甲苯、丁羟茴醚及其类似物和衍生物的芳族醇在制备包含活性大分子组分的药物(药用组合物)中的用途,以促进活性大分子组分在人或者动物体内的吸收。
本发明也提供芳族醇与能够增加芳族醇吸收促进剂在含水介质中的溶解度的增溶助剂一起在药用组合物中作为大分子体内吸收促进剂的用途,所述芳族醇选自没食子酸丙酯、丁羟甲苯、丁羟茴醚及其类似物和衍生物。
在另一个实施方案中,本发明提供能够增加芳族醇吸收促进剂在含水介质中的溶解度的增溶助剂一起的选自没食子酸丙酯、丁羟甲苯、丁羟茴醚及其类似物和衍生物的芳族醇在制备包含活性大分子组分的药物(药用组合物)中的用途,以促进活性大分子组分在人或者动物体内的吸收。
芳族醇吸收促进剂可以为没食子酸丙酯或者其类似物或衍生物,并且优选为没食子酸丙酯。没食子酸丙酯的合适的类似物和衍生物包括没食子酸酯。所述酯可为直链或支链C1-12烷基、C1-12烷氧基、C1-12烷硫基或者C2-12链烯基酯。这些化合物由卤素、直链或支链C1-12烷基、C1-12烷氧基、C1-12烷硫基或者C2-12链烯基酯任选取代。芳族醇吸收促进剂也可选自BHT、BHA及其类似物和衍生物。BHT或BHA的合适的类似物和衍生物包括羟基甲苯或者羟基茴醚的类似物和衍生物,其中甲基或者甲氧基连接于芳族环上和/或羟基邻位的氢由在任何位置上为未取代的或者被取代(尤其被卤素原子取代的)直链或支链C1-12烷基、C1-12烷氧基、C1-12烷硫基或者C2-12链烯基替代。优选地,芳族醇吸收促进剂选自没食子酸丙酯、BHT和BHA。
作为抗氧化剂用于药学实践的以上公开的芳族醇以最高达总制剂的0.1%w/v的浓度被包含在内(对单个化合物详见药用赋形剂手册(the Handbook of Pharmaceutical Excipients)的条目,编辑Wade &Weller,The Pharmaceutical出版社,伦敦UK,第2版,1994)。通常认为高浓度的化合物得到不须加入抗氧化剂的益处,并且因此这是限制制剂中抗氧化剂的浓度不大于0.1%的标准药学实践。然而当用作本发明的吸收促进剂时,这些化合物的效力依赖于更高水平的浓度,并且它们在药用制剂中的比例比现有技术中先前描述的高得多。
根据申请人的经验,现有技术中并未提示这些试剂在药用制剂中用作抗氧化剂的用途。这些试剂中没有一种在通过口服途径促进大分子的吸收方面起任何作用,或者这些试剂以高于抗氧化剂的标准药学实践的含量被包含在制剂中。
例如,EP-A-0295941公开了用于口服给药的制剂,其中可任选包含BHA、BHT或者PG,显而易见它们的存在对制剂的生物效力不是必须的。没有具体指明这些试剂的浓度,并且所述制剂打算作为控制释放的剂型存在,与其中需要立即溶出以确保从胶囊中快速释放的本发明形成显著对比。
WO-A-0222158提供了包含环胞菌素(不是大分子)和包含通常作为抗氧化剂的BHA、BHT和PG的组合物。虽然没有给出抗氧化剂的具体浓度,化合物作为抗氧化剂的用途提示其含量不大于0.1%wt。
US-A-5756450公开了包含低分子水不溶性化合物的组合物,包括水不溶性多肽,尤其是环肽例如环胞菌素。BHA或者BHT作为抗氧化剂以非常小的量被包含在内。
US-A-5342625也公开了包含环胞菌素的组合物。可以存在增溶助剂,以帮助形成环胞菌素微乳剂预浓缩物。BHA或者BHT作为抗氧化剂可以低含量存在。
BHA和BHT也可作为抗氧化剂存在于US-A-3996355的组合物中,后者包含任何药物,其在植物油媒介物的存在下是稳定的,更具体地讲水敏感药物具有苦味。大分子未被研究。
合适的增溶助剂包括(但不限于)胆汁酸或者盐例如牛磺胆酸钠或者牛磺去氧胆酸钠、苄醇、苯乙醇、苯氧基乙醇、乙二醇单乙基醚(transcutol)或异丙醇。
落入本发明范围内的活性大分子组分包括当吸收进入人或者动物体内尤其是能够通过肠壁时能够具有有益的作用的所有分子。有益的作用可为例如治疗、化妆或者预防作用例如预防或者避孕。活性大分子组分可以是天然(生物)的、合成的或者半合成来源的。
大分子可以优选定义为具有超过1000Da的分子量的分子,优选超过2000Da,并且最优选超过3000Da。包括大分子的活性大分子组分的大分子的实例包括:
1.多肽和蛋白质例如胰岛素,降钙素、人血清白蛋白、生长激素、生长激素释放因子、甘丙肽galanin、甲状旁腺激素、血液凝固蛋白例如kinogen、凝血酶原、纤维蛋白原、凝血因子VII、凝血因子VIII或者凝血因子IX,促红细胞生成素和EPO模拟物,集落刺激因子包括GCSF和GMCSF,血小板衍生生长因子、表皮生长因子、成纤维细胞生长因子、转化生长因子、GLP-1、GAG、细胞因子、胰岛素样生长因子、骨和软骨诱导因子、神经营养因子、白细胞介素包括IL-1、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12,干扰素包括干扰素γ、干扰素-1a、干扰素α,TNFα、TNFβ、TGF-β、霍乱毒素A和B片段、大肠杆菌肠毒素A和B片段、胰泌素,酶包括组蛋白脱乙酰酶、超氧化物歧化酶、过氧化氢酶、腺苷脱氨酶、胸苷激酶、胞嘧啶脱氨酶、蛋白酶、脂酶、糖酶、核苷酸酶、聚合酶、激酶和磷酸酶,转运或结合蛋白尤其是结合和/或转运维生素、金属离子、氨基酸或脂质或者脂蛋白的那些蛋白例如胆固醇酯转运蛋白、磷脂转运蛋白、HDL结合蛋白,结缔组织蛋白例如胶原蛋白、弹性蛋白或者纤连蛋白,肌肉蛋白质例如肌动蛋白、肌球蛋白、肌营养不良蛋白或者小肌营养不良蛋白,神经元,肝、心或者脂肪细胞蛋白,细胞毒素蛋白、细胞色素,能够引起细胞的复制、生长或者分化的蛋白、信号分子例如细胞内信号蛋白或者细胞外信号蛋白(例如激素),营养因子例如BDNF、CNTF、NGF、IGF、GMF、aFGF、bFGF、VEGF、NT3、T3和HARP,载脂蛋白、抗体分子,为可溶解形式的受体例如T-细胞受体和细胞因子受体,干扰素或者趋化因子,含有抗原决定部位epitopes和片段的蛋白质或者肽以及以上任何一种的衍生物、轭合物和序列变体。这些和其它的蛋白质可衍生于人、植物、动物、细菌或者真菌来源,或者提取自天然来源、作为发酵或者化学合成的重组物制备。
2.多核苷酸例如长链线形或者环形单-、二-或者三-股DNA,单-、二-或者三-股RNA,寡核苷酸例如反义DNA或者RNA及其类似物包括PNA和硫代磷酸酯(phosphothioate)衍生物。在一个实施方案中,优选本发明中使用的多核苷酸含有CpG基元。多核苷酸的编码序列可把治疗产物编码,尤其是所述编码序列可将以下蛋白编码:细胞外蛋白质(例如分泌性蛋白);细胞内蛋白质(例如胞质、核或者膜蛋白);存在于细胞膜上的蛋白,血液蛋白例如凝固蛋白(例如kinogen、凝血酶原、血纤维蛋白原、凝血因子VII、凝血因子VIII或者凝血因子IX);酶例如分解代谢的、胃肠道合成代谢的、代谢的(例如糖酵解或者Krebs循环)或者细胞信号酶,分解或者修饰脂质、脂肪酸、糖原、氨基酸、蛋白质、核苷酸、多核苷酸(例如DNA或者RNA)或者碳水化合物的酶(例如蛋白酶、脂酶或者碳水化合物分解酶),或者蛋白修饰酶,例如加入或者从蛋白质取下化学部分的酶(例如激酶或者磷酸酶);转运或结合蛋白(例如其结合和/或转运维生素、金属离子、氨基酸或脂质的蛋白,例如胆固醇酯转运蛋白、磷脂转运蛋白或者HDL结合蛋白);结缔组织蛋白(例如胶原蛋白、弹性蛋白或者纤连蛋白);肌肉蛋白质(例如肌动蛋白、肌球蛋白、肌营养不良蛋白或者小肌营养不良蛋白);神经元、肝、心或者脂肪细胞蛋白;细胞毒素蛋白;细胞色素;能够引起细胞的复制、生长或者分化的蛋白;有助于转录或翻译基因或者调节转录或翻译的蛋白(例如转录因子或者结合转录因子的蛋白或者聚合酶);信号分子例如细胞内或者细胞外信号分子(例如激素);免疫系统蛋白例如抗体、T细胞受体、MHC分子、细胞因子(例如IL-1、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、TNF-、TNF-、TGF-)、干扰素(例如IFN-、IFN-、IFN-、)、趋化因子(例如MIP-1、MIP-1、RANTES)、免疫受体(例如细胞因子、干扰素或者趋化因子的受体,例如以上提及的细胞因子、干扰素或者趋化因子中任何一种的受体)或者细胞表面标记物(例如巨噬细胞、T细胞、B细胞、NK细胞或者树状细胞表面标记物)(例如CD1、2、3、4、5、6、7、8、16、18、19、28、40或45,或者其天然配体)、营养因子(例如BDNF、CNTF、NGF、IGF、GMF、aFGF、bFGF、VEGF、NT3、T5、HARP)或者载脂蛋白;肿瘤抑制剂(例如p53、Rb、Rap1A、DCC或者k-rev);自杀蛋白(胸苷激酶或者胞嘧啶脱氨酶)或者基因阻抑蛋白。由用于本发明的多核苷酸编码的蛋白质和肽可为免疫原性的,即包含对于其抗体由免疫系统产生的蛋白质的活性具有特异性的抗原。
所述多核苷酸可能具有连接于编码序列的控制序列(controlsequences)。这些控制序列一般可为任何真核生物的控制序列或者感染这样真核生物的病毒的控制序列。所述多核苷酸可包含复制来源。
所述多核苷酸可被化学修饰。这可以增强它们对核酸酶的抗性或者可以增强它们进入细胞的能力。例如可使用硫代磷酸酯寡核苷酸。其它的脱氧核苷酸类似物包括甲基膦酸酯、氨基磷酸酯、二硫代磷酸酯、N3’P5’-氨基磷酸酯和寡核糖核苷酸硫代磷酸酯和它们的2’-O-烷基类似物及2’-O-甲基核糖核苷酸甲基膦酸酯。可使用另一种混合的主链寡核苷酸(MBOs)。MBOs包含硫代磷酸酯寡脱氧核苷酸片段和适当放置的修饰的寡脱氧-或者寡核糖核苷酸片段。MBOs具有硫代磷酸酯连锁(linkage)片段和其它修饰的寡核苷酸的其它片段,例如膦酸甲基酯,它是非离子化的,并且对核酸酶或者2’-O-烷基寡核糖核苷酸是非常抗性的。
适用于本发明的多核苷酸优选以其中它基本上不含有或者与细胞或与细胞的、原核的、真核的(eukatyotic)、细胞核的、染色质、组蛋白或者蛋白质物质有关的形式存在。它基本上可以以分离的形式存在,或者以基本上纯的形式存在,在这种情况下它在制剂中通常包含大于90%,例如(多于或至少)95%、98%或者99%的多核苷酸或者干燥物质。因此所述多核苷酸可以为‘裸(naked)DNA’的形式。
3.多糖例如肝素、低分子量肝素、聚甘露糖、环糊精和脂多糖。
4.以上单独的或者彼此(例如以复共轭对配合物(heteroconjugate)的形式)或与另外的药物的联合中的任何一种或者所有组分。
在本发明的一个优选实施方案中,被吸收的活性大分子组分选自降钙素、胰岛素、低分子量肝素、红细胞生成素、人生长激素和甲状旁腺激素,尤其是降钙素、胰岛素和甲状旁腺激素。
依所使用的另外赋形剂的性质而定,本发明的药用组合物可以为液体、固体、半固体或者凝胶的形式。本发明的药用组合物适合于经可以进入不同粘膜组织例如颊和舌下粘膜、鼻腭、肺、直肠、肠道(包括大肠和小肠)以及阴道的任何途径给药。在液体、半固体或者凝胶制剂的情况中,这些制剂可为无水或者含水的。
当本发明组合物计划的作用部位为肠时,所述组合物被包封在肠溶衣中是合乎需要的,它可以经受住胃部,以致于制剂中的组分保持在一起,未稀释并处于紧密的混合中,直到它们到达小肠或者结肠组织。这样的制剂应适合为无水的。为液体形式的组合物适合作为肠溶衣胶囊给药,而固体制剂以肠包衣胶囊或者以片剂形式给药,优选作为肠包衣片剂给药。
适当地选择肠溶衣以经受住胃的自然条件并且在肠的所需部位变得可以渗透。这优选通过调节肠的长度的pH条件确定。当作用部位为小肠时,优选肠溶衣变得可以渗透并且在pH3-7,优选为5.5-7,更优选为5.5-6.5下释放其内容物。当计划的作用部位为结肠时,优选肠溶衣变得可以渗透并且在6.8或6.8以上的pH下释放其内容物。
合适的肠溶衣为本领域熟知的并且包括纤维素醋酸酯、苯二甲酸酯、紫胶和聚甲基丙烯酸酯,例如选自Eudragits的L和S系列的那些,尤其是Eudragits L12.5P、L12.5、L100、L100-55、L30、D-55、S12.5P、S12.5和S100。合适的增塑剂或者润湿剂例如枸橼酸三乙酯和聚山梨酯80也可被包含在包衣混合物中。
本领域技术人员基于他们的知识和可得到的支撑Eudragits产品的文献可易于选择胶囊的合适的包衣,胶囊优选为HPMC或者明胶胶囊。
当计划的作用部位为鼻粘膜时,所述制剂可以为水溶液的形式或者作为干燥粉末存在,其可作为喷雾剂给药。
当计划的作用部位为直肠时,合适的给药方法是包封在胶囊壳中的无水液体或者固体,或者混合到易受侵蚀的栓剂基质中。
对于阴道使用,给予凝胶形式的制剂也是合适的。
芳族醇吸收促进剂优选为不溶于水的。所述促进剂在组合物中适合以1-40%重量,优选为5-35%重量,更优选为10-30%重量的量存在。
在本发明的组合物中,芳族醇吸收促进剂以大于或等于活性大分子组分的量(重量)存在。这样在肠细胞屏障层(肠壁)可提供有效浓度的芳族醇吸收促进剂,以便在合适量的活性大分子组分共同存在时引起吸收增加,活性大分子组分在吸收时将发挥其正常有益的作用。在对疗效是必须的活性大分子组分的量(例如血液浓度水平)的基础上,本发明的专业人员将选择芳族醇吸收促进剂和活性大分子组分的量。在包含于胶囊中的混合物中的芳族醇吸收促进剂与活性大分子组分的重量比适合为至少1∶1,优选为至少5∶1,例如1∶1-100∶1,优选为3∶1-50∶1,最优选为5∶1-20∶1。
增溶助剂与芳族醇吸收促进剂的比率适合为至少1∶1,优选为1∶1-10∶1,并且最优选为1.5∶1-5∶1。
关于所使用的给药方案和有关的患者,在发挥正常的有益作用所需的物质剂量的基础上选择活性大分子组分的绝对量。这些量的确定落入本发明的专业人员的覆盖范围内。
在用于口服给药的组合物中,优选胶囊的内容物包含合适量的活性大分子组分以达到其正常的治疗作用。例如,所述组合物可含有0.05-50%,优选为0.1-25%,更优选为0.1-10%重量的活性大分子组分(基于胶囊内容物的重量,不包括胶囊本身的重量)。
本发明的组合物还可包含一种或更多种其它的吸收促进剂化合物,例如中链脂肪酸和中链单甘油酯。
本发明的组合物可任选另外包含用于药物制剂的任何常规添加剂,包括例如抗氧化剂、抗菌剂、悬浮剂、填充剂、稀释剂、吸收剂、助流剂、粘合剂、防结块剂、润滑剂、崩解剂、膨胀剂、粘度调节剂、增塑剂和酸度调节剂(特别是把肠环境调节至7-7.5的那些酸度调节剂)。合适的膨胀剂包括羟基乙酸淀粉钠、预凝胶淀粉、微晶纤维素、交联聚乙烯吡咯烷酮(crosprovidone)和硅酸镁铝或者它们的混合物。也可包含5-10%重量的量的基于羟基乙酸淀粉钠和其它多糖的膨胀剂。也可包含5-30%重量的量的交联聚乙烯吡咯烷酮。
本发明的组合物可任选另外包含其它的活性组分,它们可以以协同的方式增强组合物的要求的作用。例如,当活性大分子组分为胰岛素时,所述组合物也可包含能够增加身体对所吸收的胰岛素的应答的胰岛素增敏剂。能够以这种方式使用的增敏剂的实例为曲格列酮、吡格列酮、罗西格列酮和格列酮类分子的其它成员。
在本发明组合物中,其中胶囊或者片剂所包含的混合物包含芳族醇吸收促进剂和活性大分子组分,所述制剂优选基本上是无水的。在更优选的本发明实施方案中,整个组合物基本上是无水的。在本发明的内容中基本上无水意指少于5%,优选少于1%并且更优选少于0.5%重量的水(基于混合物的重量计)。
依所使用的活性大分子组分而定,本发明的组合物可经疗法用于治疗人或者动物体的多种病症和疾病,或者可用于引入对诊断人或者动物体的疾病和病症必需的大分子。本发明的组合物优选为药用组合物或者化妆用组合物。
在本发明的组合物中,包含在胶囊中的所述混合物可为液体、半固体或者凝胶,其以溶液或者微粒分散液的形式存在。这就是说用于吸收的活性大分子组分以溶液的形式或者作为微粒分散液混合到制剂中。或者,所述组合物可以为固体的形式。
通过制备活性大分子组分与芳族醇吸收促进剂的基本上无水的混合物,然后用混合物任选填充未包衣的胶囊并且任选用合适的聚合物混合物将它们包衣以得到所需的渗透性质,可以适当地制备本发明的组合物。
以下实施例用于阐述本发明,但不应认为是对本发明的限制。
实施例
实施例1在渗透细胞培养物单层中的作用
Caco-2细胞(一种衍生自人结肠腺癌的细胞系)在多孔膜的表面(孔大小0.4μm,表面积0.33cm2)作为汇合的单层生长,多孔膜分开为两个含水区室,上层区室充有200μl培养基,而下层区室含有600μl培养基。使用连接到插入于上层和下层区室中的单层任何一侧的培养基中的电极的上皮电压-电阻表测量跨所述单层的电阻。在把芳族醇加入到上层区室之前和加入后15分钟时立即测量这个跨上皮电阻(TEER)(在下表中给出一般结果)。对每一个化合物重复使用4次,其浓度显示于下表中。TEER的降低被认为是跨细胞单层的物质流量(包括总体流动相)增加的指征。
初始值的降低大于50%被认为是显著。观察到浓度降低趋向于减小作用。
试剂 | 浓度(mg/ml) | TEER(欧姆.cm2) | |
加入前 | 加入后15分钟 | ||
没食子酸丙酯 | 13 | 494 | -0.6 |
没食子酸丙酯 | 0.2 | 667 | 629 |
丁羟茴醚 | 0.3 | 564 | 183 |
丁羟甲苯 | 0.3 | 633 | 194 |
实施例2含有胰岛素、没食子酸丙酯和牛磺胆酸钠的制剂的制备
将150mg的量的牛磺胆酸钠与75mg没食子酸丙酯在玻璃小瓶中混合并加入825μl蒸馏水。在室温下甚至在延长振动下未产生溶解作用,但是在超声浴中经短暂超声作用温热后得到澄明的无色溶液。混合下向溶液中加入8.4mg的量的牛胰岛素,随后加入10μl冰醋酸,同时涡流胰岛素悬浮液。迅速得到澄明的溶液,pH为3.15。伴随振摇下迅速冷冻小瓶中的内容物并冻干过夜。第二天得到干燥的固体。称重10mg量的固体,加入到2ml小瓶中并加入50μl蒸馏水。迅速形成澄明的溶液。
实施例3含有胰岛素、没食子酸丙酯和牛磺去氧胆酸钠的制剂的制备
使用牛磺去氧胆酸盐(taurodeoxychlolate)替代牛磺胆酸盐,使用与在实施例2中描述的相同条件。干燥前最终溶液的pH为3.36。如前那样向干燥固体中加入蒸馏水后迅速形成澄明的溶液。
实施例4含有降钙素、没食子酸丙酯和牛磺胆酸钠的制剂的制备
除了将2.3mg鲑鱼降钙素溶于蒸馏水中并把整个溶液加入到牛磺胆酸钠和没食子酸丙酯的混合物中,使用与在实施例2中描述的相同条件。如前那样加入蒸馏水后迅速形成澄明的溶液。
实施例5含有降钙素、没食子酸丙酯和牛磺去氧胆酸钠的制剂的制备
除了使用牛磺去氧胆酸盐替代牛磺胆酸盐,使用与在实施例4中描述的相同条件。
实施例6含有甲状旁腺激素、没食子酸丙酯和牛磺胆酸钠的制剂的制备
除了使用0.5mg甲状旁腺激素替代降钙素,使用与在实施例4中描述的相同条件。
实施例7含有甲状旁腺激素、没食子酸丙酯和牛磺去氧胆酸钠的制剂的制备
除了使用牛磺去氧胆酸盐替代牛磺胆酸盐,使用与在实施例6中描述的相同条件。
实施例8含有甲状旁腺激素、没食子酸丙酯和牛磺去氧胆酸钠的制剂的制备
除了干燥胆汁盐/PG混合物并且不加入蛋白质,冻干后把甲状旁腺激素作为干燥粉末加入到干燥残余物中外,使用与在实施例7中描述的相同条件。
实施例9含有人生长激素、没食子酸丙酯和牛磺去氧胆酸钠的制剂的制备
除了使用20mg人生长激素替代甲状旁腺激素,使用与在实施例8中描述的相同条件。
实施例10含有降钙素、没食子酸丙酯和丙二醇的制剂的制备
通过涡流将75mg没食子酸丙酯溶于200μl丙二醇中。然后把200μl生成的溶液转移至含有1mg固体降钙素的小瓶中。把小瓶短暂涡流以分散固体,然后在37℃下振摇1小时,得到澄明的溶液。
实施例10含有降钙素、没食子酸丙酯和苄醇的制剂的制备
将100mg没食子酸丙酯在200μl苄醇中涡流,在室温下几分钟后得到澄明的溶液。然后把200μl生成的溶液转移至含有1mg固体降钙素的小瓶中。把小瓶短暂涡流以分散固体。
实施例11含有降钙素、没食子酸丙酯和乙二醇单乙基醚的制剂的制备
将100mg没食子酸丙酯在200μl乙二醇单乙基醚中涡流,在室温下1分钟后得到澄明的溶液。然后把200μl生成的溶液转移至含有1mg固体降钙素的小瓶中。在37℃下把小瓶短暂涡流1小时以分散固体,得到澄明的溶液。然后把200μl生成的溶液转移至含有1mg固体降钙素的小瓶中。把小瓶短暂涡流以分散固体,然后在37℃下振摇1小时,得到澄明的溶液。把100μl溶液转移至另外的小瓶中,向其中加入100μl蒸馏水。所有的组分作为单一相澄明的液体留在溶液中。
实施例12含有降钙素、丁羟甲苯和乙二醇单乙基醚的制剂的制备
将100mg丁羟甲苯在200μl乙二醇单乙基醚中涡流,在室温下几分钟后得到澄明的溶液。然后把200μl生成的溶液转移至含有1mg固体降钙素的小瓶中。把小瓶短暂涡流以分散固体,然后在37℃下振摇1小时,得到澄明的溶液。把100μl溶液转移至另外的小瓶中,向其中加入100μl蒸馏水,在37℃下得到澄明的乳白色溶液。
Claims (29)
1.一种包含以下组分的混合物的药用组合物:
(a)活性大分子组分,和
(b)选自丁羟甲苯、丁羟茴醚及其类似物和衍生物的芳族醇吸收促进剂,其中所述芳族醇吸收促进剂以大于或等于活性大分子组分的量(重量)存在。
2.一种包含以下组分的混合物的药用组合物:
(a)活性大分子组分,
(b)选自没食子酸丙酯、丁羟甲苯、丁羟茴醚及其类似物和衍生物的芳族醇吸收促进剂,其中所述芳族醇吸收促进剂以大于或等于活性大分子组分的量(重量)存在,和
(c)能够增加芳族醇吸收促进剂在含水介质中的溶解度的增溶助剂。
3.一种权利要求1或2的组合物,其中所述混合物包含少于5%重量的水。
4.一种权利要求1-3中任何一项的组合物,其中所述组合物用肠溶衣包衣,所述肠溶衣在pH 3-7时为可渗透的。
5.一种前述权利要求中任一项的组合物,其中所述混合物包含至少1%重量的芳族醇吸收促进剂。
6.一种前述权利要求中任一项的组合物,其中芳族醇吸收促进剂与活性大分子组分的重量比为至少5∶1。
7.一种前述权利要求中任一项的组合物,其中所述混合物为溶液或者微粒分散液的形式。
8.一种前述权利要求中任一项的组合物,其中所述混合物为固体形式。
9.一种前述权利要求中任一项的组合物,其中所述活性大分子组分为多肽或蛋白质、多核苷酸、多糖或其混合物。
10.一种前述权利要求中任一项的组合物,其中所述芳族醇吸收促进剂选自BHT、BHA及其类似物和衍生物,包括羟基甲苯或者羟基茴醚的类似物和衍生物,其中连接于芳族环的甲基或者甲氧基和/或羟基邻位的氢由在任何位置上为未取代的或者被取代的,尤其被卤素原子取代的直链或支链C1-12烷基、C1-12烷氧基、C1-12烷硫基或者C2-12链烯基替代。
11.一种权利要求2-9中任何一项的组合物,其中所述芳族醇吸收促进剂为没食子酸丙酯或者其类似物或衍生物,包括没食子酸酯,其中所述酯可为直链或支链C1-12烷基、C1-12烷氧基、C1-12烷硫基或者C2-12链烯基酯,并且所述化合物被卤素、直链或支链C1-12烷基、C1-12烷氧基、C1-12烷硫基或者C2-12链烯基酯任选取代。
12.一种权利要求2-11中任何一项的组合物,其中所述增溶助剂选自胆汁酸或者盐、苄醇、苯乙醇、苯氧基乙醇、乙二醇单乙基醚和异丙醇。
13.一种前述权利要求中任一项的组合物,其中所述活性大分子组分为胰岛素,降钙素、生长激素、甲状旁腺激素或者促红细胞生成素及衍生物和类似物,它们或者是合成的或者得自天然来源,均与衍生自人或者动物来源的结构一致。
14.一种前述权利要求中任一项的组合物,其中所述活性大分子组分为胰岛素、降钙素、甲状旁腺激素或者其衍生物或类似物,它们或者是合成的或者得自天然来源,与衍生自人或者动物来源的结构一致。
15.一种权利要求14的组合物,其中所述活性大分子组分为胰岛素或者其衍生物或类似物,它们或者是合成的或者得自天然来源,与衍生自人或者动物来源的结构一致,并且所述组合物还包含胰岛素增敏剂。
16.一种前述权利要求中任一项的组合物,它用于人或动物体的治疗或者诊断性治疗。
17.选自丁羟甲苯、丁羟茴醚及其类似物和衍生物的芳族醇在药用组合物中作为大分子跨肠壁吸收促进剂的用途。
18.选自丁羟甲苯、丁羟茴醚及其类似物和衍生物的芳族醇在制备含有活性大分子组分的药物中的用途,所述芳族醇增加活性大分子组分在人或者动物体内的吸收。
19.芳族醇与能够增加芳族醇吸收促进剂在含水介质中的溶解度的增溶助剂一起作为大分子跨肠壁吸收促进剂在药用组合物中的用途,所述芳族醇选自没食子酸丙酯、丁羟甲苯、丁羟茴醚及其类似物和衍生物。
20.芳族醇与能够增加芳族醇吸收促进剂在含水介质中的溶解度的增溶助剂一起在制备包含活性大分子组分的药物中的用途,所述芳族醇选自没食子酸丙酯、丁羟甲苯、丁羟茴醚及其类似物和衍生物,它们增加活性大分子组分在人或者动物体内的吸收。
21.权利要求17-20中任何一项的用途,其中所述组合物包含少于5%重量的水。
22.权利要求19或20中任何一项的用途,其中所述增溶助剂选自结合胆汁酸或者盐、苄醇、苯乙醇、苯氧基乙醇、乙二醇单乙基醚和异丙醇。
23.权利要求18或20中任何一项的用途,其中所述药物以溶液、作为微粒分散液或者作为固体的形式提供。
24.权利要求17-23中任何一项的用途,其中要吸收的所述大分子/活性大分子组分为多肽或蛋白质、多核苷酸、多糖或其混合物。
25.权利要求24的用途,其中要吸收的所述大分子/要吸收的活性大分子组分选自胰岛素、降钙素、生长激素、甲状旁腺激素和促红细胞生成素及其衍生物和类似物,无论是合成的还是得自天然来源的,与衍生自人或者动物来源的结构一致。
26.权利要求25的用途,其中要吸收的所述大分子/要吸收的活性大分子组分为胰岛素、降钙素、甲状旁腺激素或其衍生物或者类似物,无论是合成的还是得自天然来源的,与衍生自人或者动物来源的结构一致。
27.权利要求26的用途,其中所述大分子组分为胰岛素或其衍生物或者类似物,无论是合成的还是得自天然来源的,与衍生自人或者动物来源的结构一致,并且还存在胰岛素增敏剂。
28.一种促进活性大分子组分在患者体内吸收的方法,该方法包括给予所述患者如在权利要求1-16中任何一项所定义的组合物。
29.一种治疗患有通过给予权利要求1-16中任何一项的组合物可治疗的病症或疾病的患者的方法。
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JP (1) | JP5016919B2 (zh) |
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CN (1) | CN1805733A (zh) |
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BR (1) | BRPI0409440A (zh) |
CA (1) | CA2522098C (zh) |
GB (1) | GB0308732D0 (zh) |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101947315A (zh) * | 2010-09-03 | 2011-01-19 | 上海沈李科工贸有限公司 | 中药杏仁在溶菌酶海藻酸钠微球中的应用 |
CN101361881B (zh) * | 2008-09-09 | 2011-02-16 | 上海沈李科工贸有限公司 | 蛋白药物溶菌酶肠道吸收促进剂的制备方法 |
CN113382769A (zh) * | 2019-02-04 | 2021-09-10 | 玛路弘株式会社 | 皮肤用组合物 |
Families Citing this family (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0308734D0 (en) | 2003-04-15 | 2003-05-21 | Axcess Ltd | Uptake of macromolecules |
GB0308732D0 (en) * | 2003-04-15 | 2003-05-21 | Axcess Ltd | Absorption enhancers |
US7748144B2 (en) * | 2005-10-26 | 2010-07-06 | Pamela Denfeld | Vehicle shaped footwear |
GB0603252D0 (en) * | 2006-02-17 | 2006-03-29 | Axcess Ltd | Dissolution aids for oral peptide delivery |
MX2011009559A (es) | 2009-03-12 | 2012-01-12 | Nordic Bioscience As | Tratamiento de la diabetes y el sindrome metabolico. |
GB201020032D0 (en) * | 2010-11-25 | 2011-01-12 | Sigmoid Pharma Ltd | Composition |
CA2733836A1 (en) * | 2011-03-09 | 2012-09-09 | Coorga International Holding Ltd. | Oral dietary supplementation for addressing of human canities |
KR102019911B1 (ko) | 2011-11-02 | 2019-09-09 | 키바이오사이언스 아게 | 질병 및 장애 치료용 펩타이드 유사체 |
HUE039105T2 (hu) | 2011-11-02 | 2018-12-28 | Keybioscience Ag | Kalcitonin mimetikumok betegségek és rendellenességek kezelésére |
EP2949331A1 (en) | 2012-10-17 | 2015-12-02 | Methylation Sciences International SRL | Compositions comprising s-adenosylmethionine and a gallic acid ester |
WO2014179325A1 (en) * | 2013-04-29 | 2014-11-06 | Matinas Biopharma, Inc. | Omega-3 fatty acid formulations for use as pharmaceutical treatment |
US10232021B2 (en) | 2013-11-14 | 2019-03-19 | Keybioscience Ag | Calcitonin mimetics for treating diseases and disorders |
GB201500263D0 (en) | 2015-01-08 | 2015-02-25 | Keybioscience Ag | Calcitonin analogues for treating diseases and disorders |
RU2019105756A (ru) | 2016-08-05 | 2020-09-08 | ТАУРУС ДИВЕЛОПМЕНТ КОМПАНИ ЭлЭлСи | Стабильный при комнатной температуре пероральный состав кальцитонина |
GB201704429D0 (en) | 2017-03-21 | 2017-05-03 | Keybioscience Ag | Calcitonin mimetics for treating diseases and disorders |
GB201707955D0 (en) | 2017-05-18 | 2017-07-05 | Keybioscience Ag | Dual amylin and calcitonin receptor agonists for treating diseases and disorders |
GB201813677D0 (en) | 2018-08-22 | 2018-10-03 | Keybioscience Ag | Calcitonin mimetics for treating diseases and disorders |
GB201813678D0 (en) | 2018-08-22 | 2018-10-03 | Keybioscience Ag | Acylated calcitonin mimetics |
KR20210026408A (ko) | 2019-08-30 | 2021-03-10 | 좋은영농조합법인 | 항산화 활성을 갖는 비파잎 추출물 및 이의 제조방법 |
Family Cites Families (43)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US618066A (en) * | 1899-01-24 | Fence-post | ||
GB354184A (en) | 1929-04-30 | 1931-07-29 | Pharmagans Pharmaceutisches In | An improved process for the production of hormone preparations |
US3996355A (en) * | 1975-01-02 | 1976-12-07 | American Home Products Corporation | Permanent suspension pharmaceutical dosage form |
JPS5257313A (en) | 1975-11-07 | 1977-05-11 | Yamanouchi Pharmaceut Co Ltd | Manufacture of micellar insuline emulsion preparations |
JPS56138168A (en) * | 1980-03-31 | 1981-10-28 | Teijin Ltd | Movel active vitamin d3 derivative composition |
FR2500097B1 (fr) * | 1981-02-17 | 1986-04-04 | Commerce Internal Echanges Tec | Support amortisseur antivibratile, antichocs |
IL68769A (en) | 1983-05-23 | 1986-02-28 | Hadassah Med Org | Pharmaceutical compositions containing insulin for oral administration |
JPS61267528A (ja) * | 1984-11-26 | 1986-11-27 | Yamanouchi Pharmaceut Co Ltd | 吸収促進剤を含有するカルシトニン経鼻剤 |
IE59934B1 (en) | 1987-06-19 | 1994-05-04 | Elan Corp Plc | Liquid suspension for oral administration |
US4789660A (en) * | 1987-09-10 | 1988-12-06 | American Home Products Corporation | Insulin administration using methyl and propyl paraben |
US5756450A (en) * | 1987-09-15 | 1998-05-26 | Novartis Corporation | Water soluble monoesters as solubilisers for pharmacologically active compounds and pharmaceutical excipients and novel cyclosporin galenic forms |
US5342625A (en) * | 1988-09-16 | 1994-08-30 | Sandoz Ltd. | Pharmaceutical compositions comprising cyclosporins |
US5002771A (en) * | 1989-02-06 | 1991-03-26 | Rorer Pharmaceutical Corp. | Calcitonin suppository formulations |
IT1251685B (it) | 1991-10-11 | 1995-05-19 | Isf Spa | Composizioni farmaceutiche contenenti una calcitonina |
US5206219A (en) * | 1991-11-25 | 1993-04-27 | Applied Analytical Industries, Inc. | Oral compositions of proteinaceous medicaments |
US5849704A (en) * | 1991-12-20 | 1998-12-15 | Novo Nordisk A/S | Pharmaceutical formulation |
US5849700A (en) * | 1991-12-20 | 1998-12-15 | Novo Nordisk A/S | Pharmaceutical formulation |
JPH05246846A (ja) * | 1992-03-03 | 1993-09-24 | Taiyo Kagaku Co Ltd | 蛋白質の消化促進組成物 |
GB9405304D0 (en) * | 1994-03-16 | 1994-04-27 | Scherer Ltd R P | Delivery systems for hydrophobic drugs |
GB9417524D0 (en) * | 1994-08-31 | 1994-10-19 | Cortecs Ltd | Pharmaceutical compositions |
US5653987A (en) * | 1995-05-16 | 1997-08-05 | Modi; Pankaj | Liquid formulations for proteinic pharmaceuticals |
US5916566A (en) | 1995-06-07 | 1999-06-29 | Avmax, Inc. | Use of benzoin gum to inhibit P-glycoprotein-mediated resistance of pharmaceutical compounds |
AU1808897A (en) | 1995-12-13 | 1997-07-03 | Dullatur Limited | A calcitonin preparation |
CA2198966C (en) * | 1996-03-04 | 2011-06-21 | Yuji Suzuki | Method for cleaving chimeric protein using processing enzyme |
US5912014A (en) | 1996-03-15 | 1999-06-15 | Unigene Laboratories, Inc. | Oral salmon calcitonin pharmaceutical products |
GB9613858D0 (en) * | 1996-07-02 | 1996-09-04 | Cortecs Ltd | Hydrophobic preparations |
US5912240A (en) * | 1997-04-10 | 1999-06-15 | Loria; Roger M. | 5-androstene 3β, 17α diol as an inhibitor of tumor growth |
US5962522A (en) * | 1997-09-05 | 1999-10-05 | Avmax, Inc. | Propyl gallate to increase bioavailability of orally administered pharmaceutical compounds |
US6180666B1 (en) * | 1997-09-05 | 2001-01-30 | Anmax, Inc. | Use of gallic acid esters to increase bioavailability of orally administered pharmaceutical compounds |
EP1049486A4 (en) * | 1997-12-05 | 2006-01-04 | Lilly Co Eli | GLP-1 FORMULATIONS |
AU1071200A (en) | 1998-10-19 | 2000-05-08 | Biotech Australia Pty Limited | Systems for oral delivery |
US6342249B1 (en) * | 1998-12-23 | 2002-01-29 | Alza Corporation | Controlled release liquid active agent formulation dosage forms |
ATE234017T1 (de) | 2000-03-31 | 2003-03-15 | Council Scient Ind Res | Getreidenahrungsmittel mit hohem nährwert |
WO2001085256A2 (en) * | 2000-05-05 | 2001-11-15 | Novo Nordisk A/S | Critical illness neuropathy |
SI1333851T1 (sl) | 2000-09-18 | 2008-02-29 | Rpg Life Sciences Ltd | Sestavek, ki sam po sebi tvori emulzijo, z izboljsanimi bioabsobcijskimi in imunosupresijskimi aktivnostmi |
GB2368792A (en) | 2000-10-06 | 2002-05-15 | Roger Randal Charles New | Absorption enhancers |
US20030096770A1 (en) * | 2001-07-11 | 2003-05-22 | Krotz Achim H. | Enhancement of the stability of oligonucleotides comprising phosphorothioate linkages by addition of water-soluble antioxidants |
US6770625B2 (en) | 2001-09-07 | 2004-08-03 | Nobex Corporation | Pharmaceutical compositions of calcitonin drug-oligomer conjugates and methods of treating diseases therewith |
US6951655B2 (en) * | 2001-10-11 | 2005-10-04 | Imi Biomed, Inc. | Pro-micelle pharmaceutical compositions |
CA2471081A1 (en) * | 2001-12-19 | 2003-07-03 | Alza Corporation | Formulation & dosage form for the controlled delivery of therapeutic agents |
GB0206792D0 (en) * | 2002-03-22 | 2002-05-01 | Leuven K U Res & Dev | Normoglycemia |
GB0308734D0 (en) * | 2003-04-15 | 2003-05-21 | Axcess Ltd | Uptake of macromolecules |
GB0308732D0 (en) | 2003-04-15 | 2003-05-21 | Axcess Ltd | Absorption enhancers |
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2003
- 2003-04-15 GB GBGB0308732.7A patent/GB0308732D0/en not_active Ceased
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2004
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- 2004-04-15 RU RU2005135433/15A patent/RU2341281C2/ru not_active IP Right Cessation
- 2004-04-15 BR BRPI0409440-9A patent/BRPI0409440A/pt not_active Application Discontinuation
- 2004-04-15 EP EP04727595A patent/EP1620073A1/en not_active Withdrawn
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- 2004-04-15 US US10/553,324 patent/US7651995B2/en not_active Expired - Fee Related
- 2004-04-15 CA CA2522098A patent/CA2522098C/en not_active Expired - Fee Related
- 2004-04-15 KR KR1020057019656A patent/KR101135822B1/ko active IP Right Grant
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2009
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101361881B (zh) * | 2008-09-09 | 2011-02-16 | 上海沈李科工贸有限公司 | 蛋白药物溶菌酶肠道吸收促进剂的制备方法 |
CN101947315A (zh) * | 2010-09-03 | 2011-01-19 | 上海沈李科工贸有限公司 | 中药杏仁在溶菌酶海藻酸钠微球中的应用 |
CN101947315B (zh) * | 2010-09-03 | 2013-01-30 | 上海沈李科工贸有限公司 | 中药杏仁促进溶菌酶海藻酸钠微球肠道吸收的应用 |
CN113382769A (zh) * | 2019-02-04 | 2021-09-10 | 玛路弘株式会社 | 皮肤用组合物 |
Also Published As
Publication number | Publication date |
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JP2006523662A (ja) | 2006-10-19 |
NZ543171A (en) | 2009-03-31 |
US20150093419A1 (en) | 2015-04-02 |
CA2522098A1 (en) | 2004-10-28 |
KR101135822B1 (ko) | 2012-04-16 |
AU2004229216B2 (en) | 2010-04-01 |
GB0308732D0 (en) | 2003-05-21 |
AU2004229216A1 (en) | 2004-10-28 |
RU2341281C2 (ru) | 2008-12-20 |
US7651995B2 (en) | 2010-01-26 |
KR20060023114A (ko) | 2006-03-13 |
RU2005135433A (ru) | 2006-06-10 |
ZA200508343B (en) | 2007-12-27 |
EP1620073A1 (en) | 2006-02-01 |
US20100056425A1 (en) | 2010-03-04 |
WO2004091584A1 (en) | 2004-10-28 |
CA2522098C (en) | 2013-11-12 |
US20060223740A1 (en) | 2006-10-05 |
BRPI0409440A (pt) | 2006-04-18 |
JP5016919B2 (ja) | 2012-09-05 |
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