CN1477950A - 用于严重疾病、慢性疾病和营养不良患者的肠胃外营养或部分肠道/口服营养的肠道给予的补剂 - Google Patents
用于严重疾病、慢性疾病和营养不良患者的肠胃外营养或部分肠道/口服营养的肠道给予的补剂 Download PDFInfo
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Abstract
本发明涉及一种经肠道给予用于保持或恢复严重疾病、慢性疾病和营养不良患者的肠道屏障的补剂。该补剂以溶液的形式,分别基于日剂量包含:a)15~70g的谷酰胺和/或谷酰胺前体,b)至少两种来自充当抗氧化剂物质的代表物,和c)0.5~10g的短链脂肪酸和/或短链脂肪酸前体。
Description
本发明涉及对严重疾病(重症监护患者或外科患者)、慢性疾病和营养不良患者除肠胃外或不充分的口服营养之外的一种经肠道或可以经肠道给予的增补食品(在下文中称为补剂),应该具有针对肠道屏障严重破坏的患者预防保护或在其施用后进行治疗的意义。
在本发明的意义中,肠道屏障不仅包括肠粘膜的上皮层还包括微生物群、蠕动性、粘液分泌和作为肠道淋巴组织(GALT)组分的区域性免疫防御。肠道屏障因而代表了对抗病原体和毒素的危险性地侵入的第一道防线,下文中称这种侵入为易位(translocation)。其“护理”的重要性已经表明与对严重疾病患者的早期肠道营养相关。
其它器官特别地如心脏、肺和肾危及性命的功能破坏目前可以通过器官置换或其它治疗手段而充分地得到补偿。这不适用于肠。“肠”以其至关重要的屏障功能从而再三成为上述患者预后的最重要的器官。
在本发明的意义中,被视为重病或极重病患的是指患者处于如下的病理状况,如其处于严重感染和创伤、多处创伤、急性辐射损伤、严重灼伤,还包括经历大手术,及危及性命的功能破坏,如呼吸、循环的稳定性或排泄的功能破坏。在本发明的意义中,被视为慢性疾病的是指患者具有良性或恶性慢性损耗性病理状况不发展为危及致命功能的。这些患者也经常因为其有缺陷的消化和同化作用只能不充分地摄入常规的经肠道/口服营养,例如免疫系统受到抑制的慢性炎性肠病(节段性回肠炎或溃疡性结肠炎)或如肿瘤患者。在本发明的意义中,被视为营养不良的是指因各种原因而不能充分摄入食物患者,例如营养不良的老年患者。
严重创伤患者的早期死亡率的降低令人信服地证明对此类患者的初始处理已经取得了重大的进展。然而,严重创伤、严重疾病患者的后期死亡率仍然由于脓毒症和多器官衰竭的高发生率NOV而加重。已经认识到胃肠的肠道屏障的崩溃是病原体和毒素的基本进入点。活细菌和毒素通过肠道壁进入到门脉循环的“易位”之后不断地被摄入到其它器官如肝和肺中。特别是肝的网状内皮系统的枯否细胞和肺的尘细胞参与介导随之发生的应激反应。已知它们是生产促炎症介质如白细胞介素I1-1、I1-2,肿瘤坏死因子TNF-α和前列腺素E2的位点。这些介质是临床上惊人的全身炎症反应的原因和调节物质,该炎症反应在下文中被称为“全身性炎症反应综合症”(SIRS)。简而言之,对内脏性系统炎症的认识概述为多器官衰竭的“肠作为起动器”和“肝作为发动机”的原理。
根据新的认识,营养治疗的因素如营养不良的状况或缺乏肠道营养可促进细菌易位现象的发展。这特别适用于严重疾病患者,其由于当前的肠道低灌注(hypoperfusion)和在再次灌注(reperfusion)中自由基不断的形成而使肠道屏障处于破坏的高度危险之中。渐渐地已表明肠道营养措施可对维持肠粘膜的结构和功能有重要贡献。另外,有明确的证据表明细菌易位和由此而产生的系统性感染的危险可以通过经肠道补充底物而减到最小。对严重疾病患者的早期肠道营养的可能优势目前可概述为四点:
1.对严重疾病患者的早期肠道营养对于肠道屏障的保护及其在先前粘膜创伤后(如内脏血流灌注不足)的再生有贡献并基于肠道易位活动的减少而减少感染和器官功能异常的发生。
2.创伤后数小时内开始的最小量肠道营养导致减少应激激素和介质的释放并因而减弱应激反应,这具有随后对患者较低能量消耗和降低分解代谢的作用。
3.对更多生理的肠道给予途径的选择,其中包括内脏首次通过效应(visceral first pass effect)导致底物利用中的改进,以及
4.底物耐受性的提高。底物利用的增加不仅从更多有利的底物动态平衡和内脏蛋白质合成的增加得以证明,而且最终在营养状况的最适化中得到证明。底物耐受性的提高在临床上是通过副作用的较低比率来证明的。这特别地涉及内脏器官如胰、肝、肠,且在完整性参数的较小增加和对肠道吸收能力的较好的维持中是明显的。另外,已经重复地观察到了胃肠出血的发生率的减少。
因此,根据目前的观点,只要肠仍然可以至少部分地发挥其功能,对严重疾病患者的营养不必以完全地避开肠道为指导方针。这也可以扩大到慢性疾病患者,尤其是那些炎性肠病患者。
然而,严重疾病患者以及具有炎性肠病的慢性疾病患者对大量的常规肠道营养溶液经常只显示不充分的胃肠耐受性。尤其是对于满足卡路里和氮需要量的供应物(葡萄糖、脂肪、氨基酸)。用于肠道给予满足需要量的常规营养溶液的必需量一般为日剂量1.5~2升(经管子给食),且这些患者即使当营养溶液是通过空肠给予途径给予时也几乎不能忍受。经胃的给予由于胃排空的紊乱而往往特别困难。
另外,严重和慢性疾病患者两者都承受持久的严重代谢压力,即损伤后的综合症,其与增加的静态能量需求的分解代谢状态有关联。这导致对选择的常量营养物和微量营养物如谷酰胺或特定的维生素和微量元素的需求增加。其缺乏与免疫和器官功能的严重的损害有关联,且导致发病率和死亡率的增加。
对严重和慢性疾病患者用于维持或恢复肠道屏障的特定营养物的供应不足,首先是基于可能的肠道摄入是不充分的,其次是基于对这些底物增加的需求。在严重营养不良患者中,易位同样可由于底物不足和随后肠道屏障的破坏而发生,且也可以在这些患者中导致全身炎症,尽管该炎症比在严重和慢性疾病患者中表现稍低的显著程度,但是同样地可以导致感染并发症。
迄今为止,保护肠道屏障的重要底物主要是由肠胃外途径提供的。然而,通过该途径尚不可能达到对肠道屏障的所希望的保护和治疗作用。
对可以通过肠道给予的底物已经作了描述。因而,EP-A-875,155公开了一种除了糖类之外还含有谷酰胺或谷酰胺前体的围手术饮料。WO-A-98/41216公开了一种预防肝脂肪变性的组合物,该组合物除了胆汁酸的络合剂之外还可含有免疫营养物。
WO-A-92/09277公开了一种可经口或肠胃外给予的组合物,该组合物除了自由的L-谷酰胺之外,还含有至少一种L-谷酰胺的衍生物和适当时至少一种谷酰胺的前体。
本发明基于如下目的,即在部分或完全的肠胃外营养或不足的肠道/口服营养之外,对严重疾病和慢性疾病患者或营养不良患者经肠道给予或可以经肠道给予提供一种补剂,以维持或恢复肠道屏障功能。进一步的目的是提供一种适用于当前的应激状况的包含肠胃外和肠道营养的营养系统。目的在于在严重疾病和慢性疾病或营养不良患者中抵消“肠衰竭”的威胁、降低感染和器官衰竭状况的发生率、降低死亡率并将必需的肠胃外营养的时间减至最少。
这些目的通常是除部分或完全的肠胃外营养或不足的肠道/口服营养之外通过提供一种肠道给予的补剂而达到的,其中补剂是这样规定的以使得a)对肠道屏障具有保护/治疗作用的肠道给予的底物从满足能量和蛋白质需求的必需量的底物供应物中分离;b)确保保护/治疗的底物的“腔道”(肠道)必需供应;c)确保保护/治疗的剂量;和d)保护/治疗的底物是在“整合系统”中给予的,即以特定的量的比率,因为其理想效果是与所有单独的底物的同时适当的可用性相关的。
这些目的特别是通过基于日剂量向经肠道给予的补剂中加入下述组合而达到的,即a)量为15~70g的谷酰胺和/或谷酰胺前体,b)至少两种来自充当抗氧化剂类的代表物,和c)量为0.5~10g的短链脂肪酸和/或其前体,特别是三丁酸甘油酯,共同在适当时与根据特定病理学状况导向的进一步的免疫/药物营养物一起。
术语谷酰胺前体指含有在代谢活动中释放谷酰胺的化合物。谷酰胺前体的实例为谷酰胺的衍生物,如酯、酰胺、N-烷基化的谷酰胺、盐或谷酰胺的酮基前体如α-酮戊二酸,以及含谷酰胺的短链肽如二肽至十肽,优选三肽,且特别优选二肽。三肽的实例为X-Gln-X’、X-X’-Gln和X-Gln-Gln,其中X和X’是天然存在的氨基酸。优选的三肽为Ala-Gln-Ala、Ala-Ala-Gln、Ala-Gln-Gln、Gly-Gln-Gly、Gly-Gly-Gln、Gly-Gln-Gln、Ala-Gln-Gly、Gly-Gln-Ala、Ala-Gly-Gln和Gly-Ala-Gln。
二肽的实例为X-Gln,其中X代表天然存在的氨基酸。优选的二肽为Ala-Gln和Gly-Gln。
在谷酰胺前体检验中规定的量是基于这些前体中谷酰胺的含量。
术语短链脂肪酸指含有2~5个,优选2~4个碳原子的羧酸。其实例为乙酸、丙酸、α-甲基丙酸、戊酸,特别优选丁酸。
术语短链脂肪酸的前体指含有在代谢活动中释放短链脂肪酸的化合物。其实例为短链脂肪酸的盐或酯。该酯可衍生自一元或多元醇。酯的实例为甲酯或乙酯、磷脂或特别是甘油酯。多元醇的酯除短链的之外可含有中等或长链的脂肪酸。在多元醇和不同脂肪酸的酯的情况下,所有酸的部分优选地衍生自短链脂肪酸。
短链脂肪酸的甘油酯是优选的,且三丁酸甘油酯(即丁酸甘油三酯)是特别优选的。在短链脂肪酸前体情况下规定的量是基于短链脂肪酸在这些前体中的含量。
术语免疫/药物营养物指存在于每日总营养供应中的营养成分,其以相应的比根据RDA(建议的饮食允许量)建议的日剂量高的浓度经肠道和适当时经肠胃外给予。这个除肠胃外营养或除部分的口/肠道营养之外,直接作用于肠粘膜和经由门静脉作用于肝的具有免疫/药物营养物的营养的观念,用于可以补偿由于局部应激状况和与之相关的损害或至关重要的代谢功能的丧失而导致的底物浓度的下降,以有利的方式协助或调节免疫系统和/或某些生物化学/生理学代谢过程,并确保肠道屏障的完整性。
术语日剂量指本发明的补剂用于具体病例所给予的量。一般的日剂量可达2000ml,且优选为200~1000ml,且特别优选为400~500ml。
本发明的补剂因而作为一种可经肠道给予或将经肠道给予的用于所有上述患者的附加的食物,所述患者的营养必须经肠胃外得以保证或可仅部分地经肠道/口实现其营养。本发明的补剂现在使决定性地改善肠道屏障的功能并因而改善对患者的预后成为可能,只要其预后是由肠道屏障功能决定的。早期肠道营养或肠道最小营养的早先实践不能做出这样的治疗贡献,因为其基本上是直接针对能量和蛋白质的可靠供应量。本发明的补剂是第一个以必需的浓度和量的比率提供底物的,其中的底物对于维持快速增生的组织如粘膜细胞或免疫活性细胞的结构和功能是不可缺少的。正是在下文中描述的本发明补剂中的底物的高剂量的肠道供应对维持(保护)和恢复(治疗)肠道屏障具有巨大的重要性。
根据本发明,肠道补剂是低能量的,然而肠胃外营养充当能量供应和氮供应物、水和电解质的主要来源,尤其在严重疾病患者的人工营养的初期。肠道补剂可以溶解于适当的溶剂中,优选为水,以一般不超过1升的日剂量或者经口或者通过放置在胃肠腔的管子给予。本发明的补剂除溶解的成分之外也可包含分散的、悬浮的和/或乳化的成分。
在对严重或慢性疾病患者的治疗初期以日剂量为500ml的补剂量开始是有益的。当患者的全面状况逐步改善时,递增地通过肠道给予途径提供满足卡路里和蛋白质需求的能量和氮供应物,以及水和电解质就是可能的了。
本发明的底物组合物依照下面的量而有变化,在下文中区分了补剂I(较小的量如500ml)和补剂II(较大的量如1000ml)。
补剂I:
本发明通过肠道给予的补剂I,除谷酰胺和/或谷酰胺前体以及短链脂肪酸和/或其前体如三丁酸甘油酯作为基本成分之外,还含有至少两种,但优选为多种抗氧化剂或具有抗氧化剂活性的营养物,它们可例如维生素C、维生素E、S-腺苷甲硫氨酸、半胱氨酸、胱氨酸、牛磺酸、谷胱甘肽、硒、锌、多酚和类胡萝卜素,优选为β-胡萝卜素,它们一般可以维持肠道屏障且可特别地以协同的方式用于控制在氧化应激中产生的自由基。
本发明的肠道补剂也可有利地具有用于DNA和RNA合成的前体物质,优选以核苷酸的形式。本发明的补剂另外也含有在正常状况下由微生物作用于膨胀剂形成的并有利于结肠细胞代谢的底物,例如一种或多种具有钙-拮抗作用的物质,特别是甘氨酸。
除完全的肠胃外营养或除肠道/口服营养之外,拟定在治疗初期将富含谷酰胺的补剂通过肠道途径给予营养不良和严重或慢性疾病患者,该补剂含有抗氧化剂和短链脂肪酸和/或其前体如三丁酸甘油酯,其中还在规定的浓度范围限制之内优选地添加核苷酸和/或甘氨酸。作为提到的物质的替代,也能采用具有相同生理学作用的化合物,如用α-酮戊二酸替代谷酰胺。
患者可通过口或者经由管子来摄入补剂。优选溶解于水的补剂优选以日剂量配分,并在此情形下例如提供以500ml袋装或瓶装的溶液。然而,也可以例如以250ml的量配分,在这种情况下基于日剂量的规定量是以500ml计。
因为在本发明意义内的严重或慢性疾病患者的治疗初期,完全满足所必需的能量和氮的营养供应是经肠胃外给予的,因为它们几乎不或根本不被肠道途径耐受,所以在治疗初期经肠道给予的补剂I必须几乎是不含卡路里的,即不应该超过每日400kcal的总能量。因此根据本发明,用于严重或慢性疾病患者的治疗初期的肠道补剂除组分c)之外是不含脂肪的,并且作为蛋白质成分最多含有氨基酸谷酰胺、甘氨酸和视需要的丙氨酸(例如在与谷酰胺一起的二肽中)和半胱氨酸(作为抗氧化剂),而且不应该超过最高为20g糖类的日剂量。
补剂I的应用范围的实施例为:
·对于底物的肠道给予无禁忌症候的肠胃外给予营养的患者,在对常规的肠道营养溶液具有高度的不耐性的同时(例如在SIRS、脓毒、高剂量儿茶酚胺治疗、多器官衰竭、灼伤的情况下),
·大型腹部手术,
·在诊断程序和外科治疗之前必须空腹的患者,
·炎性肠病(节段氏回肠炎、溃疡性结肠炎),
·粘膜炎(mucositis)、口腔炎(在化学疗法、放射疗法、骨髓移植之后的),
·短肠综合症,
·急性胰腺炎。
本发明也涉及上述组分a)到c)生产经肠道给予的补剂以治疗上述的疾病的应用。
补剂II:
在肠功能明显地稳定之后和当较大剂量如500ml的补剂I可被耐受时,部分肠胃外的完全营养就可以通过适用于这些目的的肠道补剂II来给予。这种情况下,除已经以小量初始补剂(补剂I)存在的营养物之外,基于日剂量,向肠道补剂中添加最高达30g的蛋白质,优选以来自乳清的蛋白质水解产物的形式,和/或最高达45g的脂肪,优选以中等链(C6-C12)的甘油三酯(MCT)和必需脂肪酸的形式。然后除可能的部分肠胃外营养之外,对于营养不良和严重或慢性疾病患者,较大量在肠道补剂II中的糖类的日剂量可增加到115g。
此外有利的是在部分肠胃外营养之外,向经肠道给予的补剂II中加入最高达1mg的铬,如以三氯化铬的形式。
除可能的部分肠胃外营养或除部分的肠道/口服营养之外,含有这样的组合成的给予营养不良或严重或慢性疾病患者的补剂,一般可服用日剂量达1000ml,且提供高达1000kcal。然后可将该补剂分成袋装或瓶装的1000ml、500ml和250ml量,其中对日剂量的规定量是以1000ml计。
补剂II的应用范围的实施例为:
·对于底物的肠道给予无禁忌症侯的经肠胃外给予营养的患者,对常规的肠道营养溶液具有较小表现的不耐性,
·如下的营养不良
-慢性肠病症
-老年患者
-神经学紊乱
-粘膜炎/口腔炎
-肿瘤恶病质
-保护性术前营养
本发明也涉及上述组分a)到c)生产经肠道给予的补剂以治疗上述的疾病的应用。
本发明的补剂基于日剂量对于各个限定的底物在下面规定的量,代表了对营养不良和严重或慢性疾病患者的一种平衡的混合物,其可以弥补由分解负荷所诱发的损失并从而可被治疗,或者在病症初期已出现缺乏状态,在肠道屏障崩溃之前从保护的意义上阻止其发生。此外确保组合中提供的底物的协同作用可获利用,可以避免以极其高剂量单独服用各个底物出现的不平衡及随后的代谢紊乱。
谷酰胺对于健康者而言是非必需氨基酸,其在氮的代谢中作为中间产物充当中心的作用。谷酰胺在嘌呤、嘧啶、核苷酸、氨基糖类和谷胱甘肽的合成中充当氮供体,且是肾中形成氨(酸/碱平衡的调节)的最重要的底物。谷酰胺此外在许多组织之间充当氮的转运物质。最后,谷酰胺是胃肠管道细胞(肠细胞、结肠细胞)代谢和快速增生细胞如免疫系统的细胞的最重要的能量供应物。
在严重疾病患者中,如在选择性手术之后,在较重的创伤、灼伤、感染或也在胰腺炎范围内的患者中,提高的分解代谢和代谢的状态是与肌细胞中谷酰胺浓度的显著减少有关的,不考虑当前主要的营养状态。另外,在分解代谢应激期间或在携带具有肿瘤的宿主中周边谷酰胺储备更快地减少,其中氨基酸作为能量来源被优先地转运到肠或肿瘤中。于是,加速的降解导致那里谷酰胺的贫乏,即导致肠细胞和免疫细胞中谷酰胺的缺乏。因此建议将谷酰胺在分解代谢应激期间,如创伤或脓毒(参见EP-A-238,553),视为一种条件性必需蛋白质。
因此有利的是,在应激和营养不良患者的治疗中,额外采用谷酰胺对肠的腔道(肠道)营养,以改善肠道屏障的功能和免疫状况。在此谷酰胺的浓度应该在日剂量15~70g,优选为20~50g,特别优选20~45g。如果补剂溶液是在其给予之前不久制备的,那么谷酰胺可以以自由的形式或作为与Ala和/或Gly的二-或三肽的形式添加。如果用于经制得的补剂溶液的贮存和/或用于经制得的补剂溶液的灭菌,优选以Ala或Gly的二肽形式使用谷酰胺。在这种情况下,规定的量是分别基于二肽中谷酰胺的重量比例。
已知营养不良或严重及慢性疾病患者的氧化应激是暴露在如在局部缺血/再次灌注损害后特别显著地观察到的。就此出现酶系统的反常失调,其导致毒性的氧自由基的发生率增加。为对抗氧化应激,机体在正常状况下维持了各种还原的化合物(即抗氧化剂)的蓄积,例如抗坏血酸、类胡萝卜素、二氢硫辛酸。而微量元素如硒和锌也可充当抗氧化剂。然而这些内源的抗氧化剂在营养不良期间以及慢性疾病期间或在严重疾病患者遭受强应激活动之后,不足以捕获形成的高浓度的自由基或防止其生成。其造成在全身化的炎症中全身性炎症的病理学表观型进一步加重。因此当想要抵消自由基的作用及由此产生的氧化损害时,则需要适当的抗氧化剂的供应。
另外已知抗氧化剂在体内通过形成抗氧化剂螺旋(spiral)在消除机体中的自由基期间是以协同的方式与其再生相互依赖的。因而,如维生素C、维生素E、谷胱甘肽和NADP被氧化,并在它们被还原之后恢复其活性。对于维生素C和E、硒和锌的相互作用也已证明了这样的抗氧化剂螺旋。
由于这种不同底物的相互补充的抗氧化剂作用,因此除两种必需底物(谷酰胺和短链脂肪酸或其前体)之外,向本发明的补剂中加入至少两种在下文中描述的抗氧化剂,但优选多种,尤其是相互组合的维生素C和E、β-胡萝卜素以及微量元素硒和锌。
抗氧化剂的实例为具有抗氧化剂性质的维生素,如维生素C或维生素E;具有抗氧化剂性质的氨基酸或氨基酸衍生物,如S-腺苷甲硫氨酸、半胱氨酸、胱氨酸或谷胱甘肽;氨基磺酸如牛磺酸;具有抗氧化剂性质的微量元素如硒或锌;多酚和类胡萝卜素,优选为β-胡萝卜素。
营养不良和慢性或严重疾病患者对维生素C比健康人有更大的需求。因而,尽管每日给予超过200mg的维生素C,仍然在重症患者的血清中观察到明显低于健康人正常水平的抗坏血酸浓度。在灼伤的动物中,通过早期给予大量的抗坏血酸以减少应急治疗所必需的流体的量。因为在胶原的合成中也涉及维生素C,所以在这种病理状况下当伤口愈合需要时,高剂量的抗坏血酸是更加有利的。因此可将肠道补剂I和II中高的维生素C的剂量视为另外发生在营养不良和慢性或严重疾病患者中的维生素C缺乏表现的适当的补偿。因此在本发明的肠道补剂中可以含有维生素C的日剂量为0.5~4g,优选为1~2.5g。
脂溶性的维生素E(生育酚)保护蛋白质、核酸和特别是整合到膜中的不饱和脂肪酸以避免其被氧自由基氧化。严重或慢性疾病患者显示非常低的维生素E水平。由创伤导致的人头骨损伤后的二次损害的基本原因猜测是由于自由基所导致的损害。通过实验可以展示,早期加入α-生育酚或α-生育酚与抗坏血酸的组合能够减少脑中脂类过氧化产物的量,以此对细胞损害的扩散有保护性的作用。因此本发明的肠道补剂可含有日剂量0.2~2g的维生素E,优选为0.3~1.2g。
在文献中有许多证据表明类胡萝卜素,其中尤其是β-胡萝卜素,除了其已知的捕获激发态的三氧和单氧之外,还能够捕获过氧化氢自由基和其它形式的活性氧。这种性质在再次灌注损害的情况下特别重要。假定具有组织局部缺血/再次灌注损害的患者产生了相当多量的单氧,那么β-胡萝卜素就代表了中和这些特别活跃的氧的特定方法。因此本发明的肠道补剂I和II的日剂量可包含5~80mg的β-胡萝卜素,优选为10~60mg。
作为谷胱甘肽过氧化物酶活性中心的结构成分,硒代表了细胞内抗氧化剂体系的一种基本成分。这种硒依赖性的酶在保护细胞免受过氧化损害,尤其是脂类的过氧化作用的损害中发挥了重要的作用。因此硒表现为在调节炎症过程中发挥直接的作用。
在全身性炎症反应或脓毒中,患者遭受了严重的氧化应激反应。因此这些患者很快显示了大幅降低的硒水平,其与渐增的肾排失和过氧化物酶活性的减少以及脂类过氧化产物的增加有关联的。一些具有特定的病理学状况的患者特别易受这种关系的影响:即具有灼伤、创伤以及血透析的患者。因此,为了使营养不良和慢性或严重疾病患者达到使各种生物学功能正常化的目的,优选地要为肠道补剂提供0.2~1mg硒的日剂量,优选为0.2~0.6mg。
锌是100多种酶的基本辅因子。可以展示在锌缺乏时T-辅助细胞的功能和天然杀伤细胞的活性受到消弱。另外,也可观察到巨噬细胞的抗原相关的及免疫调节的功能和白细胞介素-1的释放的消弱。营养不良和严重或慢性疾病患者损伤的代谢是尿中锌损失增加的原因。锌的缺乏也可作为经皮肤损失的结果而发生于灼伤患者,以及由于利尿的增加而发生于创伤患者。分别根据病症的类型,建议添加15~40mg的锌。为了改善严重疾病患者的免疫状况,因此对于本发明的肠道补剂I和II提供10~60mg锌的日剂量,特别优选为20~40mg。
术语短链脂肪酸(SCFA)各自包含乙酸、丙酸、丁酸和戊酸(C2-C5)。其可以在哺乳动物的胃肠管道中通过糖类的微生物发酵形成。丁酸天然存在于许多水果和蔬菜中。最多产的来源是乳脂(奶油)(3-4%的丁酸),其中可以作为甘油酯存在。
乙酸、丙酸和丁酸由肠道细菌以几乎恒定的摩尔比率60∶25∶15形成,并由肠粘膜快速吸收。它们是相对富含卡路里的,由肠上皮细胞和肝进行代谢,并刺激大肠中水和钠的吸收。它们在肠粘膜上具有营养作用。另外,它们充当营养物并担当真正必需底物,这是因为当它们缺失时会消弱器官的功能。
用于提供SCFA的前体是膨胀剂。因此可以通过膨胀剂剂量的改变而影响SCFA的形成。与此相反,丁酸的浓度可以通过从膳食中去除膨胀剂而显著地减小。另外也可以展示丁酸代表了结肠细胞优选的能量底物。丁酸在预防某些结肠炎类型中发挥作用。在实验性的短肠综合症中,向肠道膳食中添加丁酸加速氨基酸从门静脉中的流出,这显示丁酸主要是在结肠中且经结肠发挥其营养作用的。也可以展示在以50~400mg/kg体重的日剂量口服甘油三丁酸酯超过3个星期后,血清中的丁酸浓度几乎增加到了0.5mmol,而不具有可探测的毒副作用(参见B.A.Conley等人,临床肿瘤研究(In ClinicalCancer Research),Vol.4,629-634,1998)。
由此可认为短链脂肪酸如丁酸,可作为肠道补剂I和II的附加底物而对肠中的消化和吸收有贡献。因此,这种化合物或其衍生物如三丁酸甘油酯以日剂量0.5~10g存在于本发明的补剂中,优选为1~6g。为了协助并改善营养不良和严重或慢性疾病患者的免疫状况,需要增加免疫细胞的繁殖,这依赖于增加的DNA和RNA合成速率。因此,在创伤后的感染中对核苷酸的需求增加以应付免疫细胞所必需的生产。从相应的高能脱氧核糖核苷和核糖核苷三磷酸得到DNA和RNA的多核苷酸链的合成是由各自的DNA和RNA聚合酶催化的。高能脱氧核糖核苷和核糖核苷三磷酸是从相应的脱氧核糖核苷单磷酸和核糖核苷单磷酸(即核苷酸)经磷酸化反应产生的。
核苷酸代表了合成DNA和RNA的重要成分。满足需求的核苷酸的合成要求足够量的嘌呤和嘧啶。对于健康者,这些是有效地从膳食中吸收的,正常状况下其中每日含量为1~2g。在核苷酸代谢中嘌呤和嘧啶或者从头合成或者通过回收反应获得(补救途径),借此核酸降解的中间物可以从完全的降解中援救出来并被再利用于核酸的重新合成。借此细胞能够节约大量的能量。
如果蛋白质的摄入是足够的,则对于健康者从头合成途径代表了维持核苷酸可供性的主要来源,其中谷酰胺作为主要的氮供体。
在营养不良和严重或慢性疾病患者中,核酸的充足可供性可能会受限制,因为在分解代谢的负荷下,从头合成途径中合成酶的表达明显减退,其这将导致核苷酸的贫乏。于是核苷酸的降低的可供性导致T-细胞功能的消弱、天然杀伤细胞活性的降低、延迟的宿主反应、淋巴细胞增生的抑制及减少的白细胞介素-2的生产。已可以展示在严重疾病患者中,从膳食中去除核苷酸会降低吞噬细胞的吞噬能力并损害了实验引入的病原体的清除。通过在供应的食物中重新包含核苷酸证明大多数这些作用是可逆的。
因此,在一个优选的具体实施例中,将合成DNA、RNA和/或高能磷酸的前体加入到本发明的肠道补剂中以支持并改善免疫状况,特别是以核苷酸的形式,优选地来自酵母。优选日剂量为1.5~15g,特别优选为2~6g。
在本发明的肠道补剂中的其它添加剂可为核糖、叶酸、B维生素和溶血磷脂酸。
甘氨酸是一种非必需氨基酸,且通常存在于人工营养的所有溶液中。依据最近的研究表明甘氨酸具有细胞保护性和抗炎症和抗肿瘤的性质。另外也可以展示在低氧(减小的氧分压)期间,甘氨酸可以维持细胞膜的完整性并因而能够防止细胞内酶的释放。在给予脂多糖后,甘氨酸能够通过减少细胞溶胶中的Ca水平而抑制肝中枯否细胞的促炎细胞因子及类二十烷酸的合成和释放。
由于其Ca-拮抗作用,对促炎细胞因子和类二十烷酸(系列2和4)的形成的抑制作用的结果对于免疫状况是有利的,可优选地将甘氨酸基于日剂量以5~70g的量加入到本发明的补剂中,特别优选为10~40g。如果甘氨酸与谷酰胺一起作为二肽来使用,则规定的量与二肽中甘氨酸的重量比例相关。
在一个特别优选的实施例中,本发明的补剂基于每日计量含有:20~45g的谷酰胺,优选30g;5~20g的甘氨酸,优选10g;1.5~5g的核苷酸,优选2g;0.5~5g的三丁酸甘油酯,优选1g;5~50g的麦芽糖糊精;2~30mg的β-胡萝卜素,优选10mg;200~1000mg的维生素E,优选500g;500~2000mg的维生素C,优选1500g;200~600μg的硒,优选300μg;和10~30mg的锌,优选20mg。
长久以来,已知铬与葡萄糖耐受性的改善有关,且葡萄糖的利用在铬缺乏时是消弱的。可以显示在非胰岛素依赖性糖尿病中对胰岛素的需求的下降,这表明铬能够增加胰岛素的作用。
营养不良和严重或慢性疾病患者可能产生强的胰岛素抗性,所以已经证明附加地给予铬对于这些患者是一种有利的治疗措施。三价的铬还表现为无毒性的。因而,对以肠胃外形式接受铬达21年的女性患者的尸体解剖没有发现致癌性质的证据。
因此除部分肠胃外营养之外,向将经肠道给予的补剂中加入最多达1mg的铬是有利的。
本发明的补剂的其它可能的成分是基于日剂量达30g的蛋白质,和/或基于日剂量达45g的附加的脂肪(基于短链脂肪酸或其前体的含量)。
蛋白质优选以蛋白质水解产物的形式使用。
附加的脂肪酸可为饱和和/或不饱和的中等链和/或长链的脂肪酸。也可使用这些脂肪酸的衍生物,如盐、酯,尤其是甘油酯或磷脂,或酰胺。中等链的脂肪酸具有6~12个碳原子。长链的脂肪酸具有13~22个碳原子。
脂类能够承担它们作为能量供应物或作为细胞结构成分的任务。脂类可作为药理学上的活性物质通过食物提供。这特别是指多不饱和脂肪酸(PUFAs)。
类似于那些如在鱼油中的二十碳五烯酸(EPA)和二十二碳六烯酸(DHA),增加n-3多不饱和脂肪酸(n-3 PUFAs)的量的肠道摄入改变了磷脂谱中n-3对n-6 PUFAs比例,并且倾向于n-3 PUFAs。这对免疫功能有影响,其中基本上是由于两个可能对免疫功能相互影响的作用:
1.膜流动性的变化和
2.膜结合的脂类的释放的变化,其通过膜相联的磷脂的水解而产生。
论证1)流动性的变化可以影响细胞因子和其它兴奋剂的受体结合。此外,膜流动性的状况对细胞内信号传递有影响,这可影响如G蛋白质的活性并随后导致酶系统活性的改变(腺苷酸激酶、磷脂酶A2、磷脂酶C)。另外,多不饱和脂肪酸是形成所谓的“第二信使”如二酰甘油和神经酰胺的重要前体。因此鱼油的给予是与细胞内信号转导的深处变化有关联的,这将影响细胞因子、白细胞介素和干扰素的产生和释放。
论证2)在磷脂酶A2的影响下,PUFAs可以从膜磷脂中释放。当其水解后,其作为形成脂类中介体的前体。在环加氧酶和脂肪氧化酶途径中多不饱和脂肪酸被转变为类二十烷酸。与衍生自n-6 PUFAs的类二十烷酸相比较,衍生自n-3 PUFAs的类二十烷酸的主要优势可总结如下:
1.在环加氧酶途径中衍生自二十碳五烯酸(EPA)的血栓烷A3(TxA3)具有比衍生自n-6 PUFAs的TxA2较轻凝集和从而较轻的作用于血小板的凝血酶原作用。
2.在脂肪氧化酶途径中EPA转变为LTB5,其具有比LTB4(来自n-6 PUFAs)相当低的活性,并因此诱导了显著降低的趋化性诱导的迁移和免疫活性细胞较轻的内皮粘着。
3.衍生自n-3 PUFAs的PGE2具有比衍生自n-6 PUFAs的PGE2显著较小的免疫抑制作用。
通过这些作用机制,n-3 PUFAs以两种途径影响在创伤或感染中消弱的免疫反应:
1.经常存在的高度炎症(hyperinflammation)有所降低。
2.在应激代谢状况下免疫学防御功能有所增强。
论证1)可以展示通过与n-6脂肪酸相比增加的n-3脂肪酸的给予可以减轻高度炎症过程。特别是EPA减少了具有促炎症活性的细胞因子如IL-1、IL-6和TNF-α和-β的释放。另外,鱼油的给予导致促炎症物质如白细胞介素B4和PAF的释放的减少,并减少了血栓烷A2的局部形成。特别是通过节段氏回肠炎和溃疡性结肠炎的实施例可以证明,可以通过在膳食中提供鱼油来减轻现存的炎症信号。
论证2)在严重疾病患者中,有证据表明n-3 PUFAs对细胞防御功能有增大的影响,其使得系列2的前列腺素(如PGE2)的减少与降低的反馈抑制相关,并与由此随之而产生的作用于细胞防御功能的“激发作用(Boostereffekt)”相关联。该想法得到了研究发现的支持,即显示在SIRS或脓毒期间,n-3 PUFAs的给予增加了细胞因子的生产,使抗原呈递最适化,增强了脾细胞的增生,促进了调理能力并减少了死亡率。
经肠道给予n-3 PUFAs的益处总结如下:
1.炎症性免疫反应的减少。
2.通过减少应激诱导的PGE2的释放使免疫活性细胞发防御功能恢复。
3.抗心率不齐的特性。
4.抗凝的特性。
5.微循环的维持。
由此,补剂II中的脂肪部分(最多45g脂肪)除中等链的三酰甘油(MCT)外,还优选含有鱼油,该鱼油已知是富含n-3脂肪酸EPA和DHA的。在此n-3脂肪酸是存在于三酰甘油复合结构中的。补剂II可以优选地含有基于日剂量5~15g的n-3脂肪酸,特别优选为6~10g。鱼油应优选单独使用,或者以n-3脂肪酸对n-6脂肪酸的比例为1∶1的这种比例的混合使用。
在一个尤其特别优选的实施例中,本发明的补剂基于日剂量含有:20~45g的谷酰胺,优选30g;5~20g的甘氨酸,优选10g;1.5~5g的核苷酸,优选2g;0.5~5g的三丁酸甘油酯,优选1g;5~100g的麦芽糖糊精,优选90g;2~30mg的β-胡萝卜素,优选10mg;200~1000mg的维生素E,优选500mg;500~2000mg的维生素C,优选1500mg;200~600μg的硒,优选300μg;10~30mg的锌,优选20mg;200~600μg的铬,优选400μg;15~30g的蛋白质水解产物,优选20g;总计15~30g的附加的脂肪,优选22g,其中7~12g为中等链的脂肪酸,优选10g,4~8g为来自鱼油且n-3/n-6的比例≥1∶1的n-3脂肪酸,优选6g;其它的维生素、微量元素和矿物质。
本发明以下述实施例更详细地进行解释。
实施例1(相应于补剂I):
除肠胃外完全营养或除肠道/口服营养之外,在治疗初期对营养不良或严重或慢性疾病患者经肠道给予的液体补剂,基于日剂量含有如下的组合物:
体积:500ml
谷酰胺 30g
甘氨酸 10g
麦芽糖糊精 16g
三丁酸甘油酯 1g
核苷酸 2g
抗氧化剂:
β-胡萝卜素 10mg
维生素C 1500mg
维生素E 500mg
硒 300μg
锌 20mg
补剂提供约250kcal并具有约0.5kcal/ml的卡路里浓度、对于水的500mosmol/kg的重量摩尔渗透压浓度和对于水的455mosmol/liter摩尔渗透压浓度。
实施例2((相应于补剂II):
除部分肠胃外营养或除肠道/口服营养之外,对营养不良或严重或慢性疾病患者经肠道给予的液体补剂,基于日剂量含有如下的组合物:
体积:1000ml
蛋白质水解产物(来自乳清) 20g
谷酰胺 30g
甘氨酸 10g
麦芽糖糊精 90g
三丁酸甘油酯 1g
核苷酸 2g
抗氧化剂:
β-胡萝卜素 10mg
维生素C 1500mg
维生素E 500mg
硒 300μg
锌 20mg
脂肪: 22g
n-3脂肪酸(来自鱼油) 6g
n-3/n-6比例 1/1
铬 400μg
补剂提供约800kcal并具有约0.8kcal/ml的卡路里浓度、对于水的530mosmol/kg的重量摩尔渗透压浓度和对于水的425mosmol/liter摩尔渗透压浓度。蛋白质∶糖类∶脂肪的重量百分比约为30∶45∶25。补剂II此外包含其它维生素和微量元素,以及与能量含量相关的量的矿物质。
实施例3:本实施例描述了将本发明的组合物给予外科患者对血清水平的影响。
从术后第1天开始将每天1500ml下述的组合物经10天借助进食泵连续地给予外科患者。
组合物的日剂量包含30g的谷酰胺、10g的甘氨酸、224g的麦芽糖糊精、1g的三丁酸甘油酯、10mg的β-胡萝卜素、1500mg的维生素C、500mg的维生素E、300μg的硒、20mg的锌、68g的乳清蛋白质水解产物和65g的脂肪,其中6g n-3脂肪酸来自鱼油。
血液样品是在手术前、手术后的第1天(在开始补充检验溶液之前)和手术后的第5和第11天从患者获取的。然后确定血清中经选择的底物的含量。
下表显示手术前和手术后第1、第5和第11天(分别为pre-OP、POD1、POD5和POD11)谷酰胺、锌、硒、β-胡萝卜素、维生素C和α-生育酚的测量的血清水平的情况。
表
血清组分 | 谷酰胺(umol/l) | 锌(μmol/l) | 硒(μg/l) | β-胡萝卜素(μmol/l) | 维生素C(μmol/l) | α-生育酚(μmol/l) |
pre-OP(n=14)*) | 599±121 | 8.44±2.29 | 60.4±18.6 | 0.16±0.11 | 15.08±12.34 | 15.50±3.99 |
POD1(n=14)*) | 508±165 | 4.38±1.57 | 46.0±20.1 | 0.12±0.08 | 10.06±8.54 | 11.08±2.76 |
POD5(n=13)*) | 600±102 | 7.01±1.98 | 69.5±17.2 | 0.22±0.11 | 34.75±19.47 | 29.86±10.64 |
POD11(n=9)*) | 597±83 | 9.20±3.16 | 104.2±35.8 | 0.47±0.22 | 34.51±13.37 | 40.20±14.94 |
*)经调查的患者数
结果显示在所有情况下得到了至少正常化的血清水平,并且对于一些关键的底物,与初始状态相比甚至可以确定有显著的增加或改善。该结果进一步显示,关键的底物是由人在肠中获取的,并因而对改善患者的抗氧化剂状态有贡献。
Claims (25)
1.用于维持或恢复严重或慢性疾病患者以及营养不良患者的肠道屏障的,经肠道给予的补剂,其特征在于,以溶液形式,分别基于日剂量,包含:
a)15~70g的谷酰胺和/或谷酰胺前体,其中在谷酰胺前体的情况下规定的量涉及其中谷酰胺的部分,
b)至少两种作为抗氧化剂活性物质的代表物,和
c)0.5~10g的短链脂肪酸和/或短链脂肪酸前体,其中在短链脂肪酸前体的情况下规定的量涉及其中短链脂肪酸的部分。
2.如权利要求1的补剂,其特征在于,包含200~1000ml的日剂量,优选为500ml。
3.如权利要求1或2任一项的补剂,其特征在于,是灭菌的和以备用的液体的形式提供的。
4.如权利要求1-3任一项的补剂,其特征在于,基于日剂量以谷酰胺计算,包含20~45g的谷酰胺和/或谷酰胺前体,优选为短链含谷酰胺的肽形式,特别优选为二肽的形式。
5.如权利要求1-4任一项的补剂,其特征在于,以短链脂肪酸甘油酯的形式包含短链脂肪酸前体,特别优选为三丁酸甘油酯。
6.如权利要求1-5任一项的补剂,其特征在于,抗氧化剂选自维生素C、维生素E、S-腺苷甲硫氨酸、半胱氨酸、胱氨酸、谷胱甘肽、牛磺酸、硒、锌、多酚和类胡萝卜素,优选为β-胡萝卜素。
7.如权利要求6的补剂,其特征在于,分别基于日剂量,含有含量为0.5~4g的抗氧化剂维生素C和/或含量为0.2~2g的维生素E和/或含量为5~80mg的β-胡萝卜素和/或含量为0.2~1mg的硒,优选为0.3~0.6mg,和/或含量为10~60mg的锌。
8.如权利要求6的补剂,其特征在于,组合地包含抗氧化剂维生素C、维生素E、β-胡萝卜素、硒和锌。
9.如权利要求1-8任一项的补剂,其特征在于,附加地包含合成DNA、RNA和高能磷酸的前体。
10.如权利要求9的补剂,其特征在于,该前体是相应的核苷酸。
11.如权利要求10的补剂,其特征在于,基于日剂量,包含含量为1.5~15g的核苷酸。
12.如权利要求1-11任一项的补剂,其特征在于,附加地包含一种或多种来自核糖、叶酸、B维生素和溶血磷脂酸的物质。
13.如权利要求1-12任一项的补剂,其特征在于,附加地包含至少一种具有Ca-拮抗作用的物质。
14.如权利要求13的补剂,其特征在于,包含甘氨酸作为具有Ca-拮抗作用的物质。
15.如权利要求14的补剂,其特征在于,基于日剂量,包含含量为5~70g的甘氨酸。
16.如权利要求1-13任一项的补剂,其特征在于,基于日剂量包含:20~45g的谷酰胺、5~20g的甘氨酸、1.5~5g的核苷酸、0.5~5g的三丁酸甘油酯、5~50g的麦芽糖糊精、2~30mg的β-胡萝卜素、200~1000mg的维生素E、500~2500mg的维生素C、200~600μg的硒和10~30mg的锌。
17.如权利要求1-16任一项的补剂,其特征在于,是与经肠胃外给予的完全营养作为人工营养系统组合,提供给营养不良或严重或慢性疾病患者的。
18.如权利要求1-17任一项的补剂,其特征在于,基于日剂量,另外包含含量高至30g的蛋白质和/或含量高至45g的脂肪和/或含量高至1mg的铬。
19.如权利要求18的补剂,其特征在于,以蛋白质水解产物的形式包含附加的蛋白质。
20.如权利要求18或19的补剂,其特征在于,附加的脂肪包含中等链的脂肪酸。
21.如权利要求18-20任一项的补剂,其特征在于,附加的脂肪包含高含量的n-3脂肪酸。
22.如权利要求21的补剂,其特征在于,n-3脂肪酸包含二十碳五烯酸和/或二十二碳六烯酸。
23.如权利要求21或22任一项的补剂,其特征在于,脂肪包括一种鱼油或不同鱼油的混合物。
24.如权利要求18-23任一项的补剂,其特征在于,基于日剂量包含:20~45g的谷酰胺、5~20g的甘氨酸、1.5~5g的核苷酸、0.5~5g的三丁酸甘油酯、5~100g的麦芽糖糊精、2~30mg的β-胡萝卜素、200~1000mg的维生素E、500~2000mg的维生素C、200~600μg的硒、10~30mg的锌、200~600μg的铬、15~30g的蛋白质水解产物、总计15~30g的附加的脂肪,其中7~12g为中等链的脂肪酸且4~8g为来自鱼油且n-3/n-6的比例≥1∶1的n-3脂肪酸、其它的维生素、微量元素和矿物质。
25.如在权利要求1中所阐明的成分a)到c)的使用,以生产经肠道给予的补剂,用于治疗肠胃外营养的患者,所述患者对底物的肠道给予不具有禁忌征侯且同时对常规的肠道营养溶液具有高度的不耐性或者对常规的肠道营养溶液具有较不显著的不耐受性,用于治疗营养不良或大的腹腔外科手术的情况,用于治疗在诊断措施和外科治疗之前必须保持空腹的患者,用于治疗在短肠综合症和急性胰腺炎中的炎性肠病、粘膜炎、口腔炎。
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DE10057290A DE10057290B4 (de) | 2000-11-17 | 2000-11-17 | Enteral zu verabreichendes Supplement zur parenteralen Ernährung oder partiellen enteralen/oralen Ernährung bei kritisch Kranken, chronisch Kranken und Mangelernährten |
DE10057290.1 | 2000-11-17 |
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US (1) | US7947303B2 (zh) |
EP (1) | EP1337236B1 (zh) |
JP (1) | JP2004513912A (zh) |
KR (2) | KR20080069280A (zh) |
CN (1) | CN1477950A (zh) |
AT (1) | ATE272390T1 (zh) |
AU (2) | AU2002224848B2 (zh) |
BR (1) | BRPI0115451B1 (zh) |
CA (1) | CA2429270C (zh) |
CZ (1) | CZ300129B6 (zh) |
DE (2) | DE10057290B4 (zh) |
DK (1) | DK1337236T3 (zh) |
EE (1) | EE05209B1 (zh) |
ES (1) | ES2223015T3 (zh) |
HR (1) | HRP20030395B1 (zh) |
HU (1) | HU228351B1 (zh) |
IL (2) | IL155840A0 (zh) |
IS (1) | IS2377B (zh) |
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NO (1) | NO333003B1 (zh) |
NZ (1) | NZ525812A (zh) |
PL (1) | PL202031B1 (zh) |
PT (1) | PT1337236E (zh) |
RU (1) | RU2295952C2 (zh) |
SI (1) | SI1337236T1 (zh) |
SK (1) | SK286199B6 (zh) |
WO (1) | WO2002039978A1 (zh) |
ZA (1) | ZA200303722B (zh) |
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CN103458887A (zh) * | 2011-03-31 | 2013-12-18 | 雀巢产品技术援助有限公司 | 用于增加精氨酸水平的营养组合物及其使用方法 |
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2000
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CN104705651B (zh) * | 2005-04-27 | 2018-05-29 | 努特里希亚公司 | 含脂类和不易消化的糖的营养品 |
CN101309678B (zh) * | 2005-11-15 | 2011-04-20 | 安特瑞斯公司 | 用于与软骨损伤有关的应用的药物 |
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CN103025178B (zh) * | 2010-04-26 | 2015-02-11 | 雀巢产品技术援助有限公司 | 用于从胃肠外营养转换至肠内营养的营养组合物和方法 |
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CN108208177A (zh) * | 2017-11-28 | 2018-06-29 | 上海交通大学医学院附属新华医院 | 含丁酸类化合物的组合物及其应用 |
CN116920075A (zh) * | 2023-09-15 | 2023-10-24 | 潍坊格菲特生物科技有限公司 | 一种肠内营养液及其制备方法 |
CN116920075B (zh) * | 2023-09-15 | 2024-01-02 | 潍坊市人民医院(潍坊市公共卫生临床中心) | 一种肠内营养液及其制备方法 |
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