CN1195992A - 增强肠胃外营养用的方法和组合物 - Google Patents
增强肠胃外营养用的方法和组合物 Download PDFInfo
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- CN1195992A CN1195992A CN96196938A CN96196938A CN1195992A CN 1195992 A CN1195992 A CN 1195992A CN 96196938 A CN96196938 A CN 96196938A CN 96196938 A CN96196938 A CN 96196938A CN 1195992 A CN1195992 A CN 1195992A
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Abstract
描述了用于改善营养物施用的组合物和方法。该方法包括共同施用或分开施用营养源(特别是糖类)和促胰岛素肽以及衍生物、类似物、片断等。该方法和组合物提供高糖类营养而同时避免了高血糖症、低血糖症及其伴随的有害作用。
Description
发明背景
患各种各样疾病的患者常常需要通过消化道以外的途径摄取营养。需手术的患者、昏迷患者、有消化道疾病的患者、中风患者以及治愈过程中的患者常常接受经肠胃外施用的糖类和伴随的脂类、电解质、无机物、维生素和氨基酸的不同组合。尽管可以经皮下、肌内、腹膜或其它方法施用，但典型的是通过静脉注射或输注完成。
健康护理专业人员施用肠胃外营养时，要注意避免血糖过高(高血糖症)。很多情况下，连那些代谢健康的患者都可完成肠胃外营养，并且通过共同施用胰岛素可将血糖维持在恰当水平。然而由于胰岛素半衰期短，可引起血糖水平的显著变化，所以这种施用有时存在严重的缺陷。因此对于要大量接受葡萄糖的患者，通常滴定其血糖水平并输注相应的胰岛素来平衡血糖。由于输注胰岛素优选是连续的，并通过一系列血糖测定来控制，所以这种滴定过程费时且费用高。
已证实营养不良的患者可大大得益于大量营养物的快速补给。通常采用口服法补给这些营养，使患者的健康和消化功能得以维持。必须用非口服营养途径时，即使共同施用胰岛素，发生高血糖症及其伴随的对渗透压、肾组织、视网膜组织、血管和心血管系统有害作用的可能性也很大。因此传统的营养治疗常常不用胰岛素，而要求经肠胃外非常低速地施用营养物。当一个典型患者接受这样的肠胃外营养时，施用速度维持在低值，使血糖(葡萄糖)水平不超过约60-150mg/dl的正常生理范围。低速施用保证了适度的安全性，避免了高血糖症。速度通常为每小时50-150ml浓度为5-40wt/wt％的葡萄糖溶液。
然而，营养是使患者治愈和恢复的基本需求。患者若不能接受适当的营养，就会象传统肠胃外营养多次发生的情况一样，治愈时间延长，与患者最初不良营养状态有关的附属问题经常发生。所以在避免高血糖症的有害作用和避免重复或连续施用胰岛素和滴定的情况下，常常要求以尽可能高的速度给患者补给肠胃外营养。
发明概述
通过本发明达到了这些和其他目的，本发明涉及一种用于最大程度的肠胃外营养而大体上无急性或慢性高血糖症的组合物和方法。组合物在本发明的方法中的应用使补给的必需营养物能满足患者治愈组织的热量需求，同时能维持适当的血糖水平。
发明的组合物包括营养源和促胰岛素肽，施用营养来源后，可直接或间接地提供糖类。营养源优选包括己糖、戊糖、其醇等，尤其是那些在水性介质中高度溶解的。例子包括葡萄糖、果糖、半乳糖、山梨糖醇、甘露糖醇、木糖醇(zylitol)或其任意组合。还可任选包括氨基酸、电解质、脂类、游离脂肪酸、甘油单酯、甘油二酯、甘油三酯、甘油、盐和无机物。促胰岛素肽包括胃抑制性肽和它的衍生物，胰高血糖素样肽如GLP-1(1-37)和GLP-1(7-36)及其有促胰岛素活性的衍生物，包括官能团修饰物如GLP-1(1-37)酰胺和GLP-1(7-36)酰胺和GLP-1(7-36)甲酯，它们的肽序列片段如GLP-1(7-34)、GLP-1(7-37)、GLP-1(7-36)、GLP-1(7-35)，它们的肽序列取代物如GLP-1(7-34)Ala Phe Ala，它们的肽序列缺失物如去(Lys)GLP-1(7-37)酰胺，包括那些有非天然氨基酸残基的肽序列类似物，以及它们的小有机分子模拟物。促胰岛素肽可能是一种纯的单一化合物，或是半纯的单一化合物，或是化合物的任何混合物如GLP-1和GIP的混合物。营养源和促胰岛素肽可组合在一个单一的水性介质中或者可分别包含在各水性介质中，优选如试剂盒形式。此外，促胰岛素肽可分别配制成片剂或持释基质形式，用来经颊、皮下或其他吸收途径补给。组合物中营养物和促胰岛素肽的浓度在下面描述。
本发明的方法通过肠胃外肽混合物施用营养源和促胰岛素肽来完成。可通过以下方法完成施用：将营养源和肽先组合，将它们由各自来源共同施用，将它们分别但伴随施用或首先施用促胰岛素肽而将它们分别、依次施用。可将前面描述的单独肽化合物以及肽化合物的混合物作为促胰岛素肽施用。施用营养物的途径可以是任何肠胃外途径如腹腔内和静脉内，而促胰岛素肽的途径可以和营养物的途径相同或不同。所用促胰岛素肽的浓度可以是任意浓度，该浓度能产生和/或维持正在按照发明接受营养源的患者的正常血糖水平。营养源中营养物的浓度至少与典型用于肠胃外补给的浓度相同，施用速度至少相同于但优选高于典型规定的速度，例如优选能达到每个患者每天1000g葡萄糖或等同物的速度。促胰岛素肽的合适剂量由其相对于血糖水平的S型的剂量-反应曲线确定。因此促胰岛素肽的施用服从阈值/增长/平台的规律，并与营养源的施用速度相平衡，从而在营养源补给时达到或维持正常的血糖水平，此营养源的施用速度在无促胰岛素肽的情况下会使血糖水平超过其正常范围。营养源中的糖类浓度用其重量相对于营养源的全部重量描述，优选在2％-50％葡萄糖或其等同物的范围内。优选地，计算促胰岛素肽的施用速度，以提供和/或维持周期性血肽水平至少在每升血浆0.1pmol到0.1mmol之间。
发明详述
本发明涉及一种用于患者肠胃外营养尤其是糖类营养而不引起患者血糖水平有害波动的组合物和方法。因此相对于传统的肠胃外营养，本发明可达到更快的营养物补给，几乎总是满足患者治愈细胞的热量需求，而患者血糖水平并无显著变化。通过应用组合物可达到这些意料不到的重要的医疗效果，该组合物包括促胰岛素肽和营养物如糖类、氨基酸、脂类、甘油单酯、甘油二酯、甘油三酯、脂肪酸、盐、电解质和/或无机物。
尽管促胰岛素肽如GLP-1、GIP以及至少某些它们的片段、类似物、衍生物和其他相似的化合物为人所知已有一段时间，它们的应用仅仅涉及糖尿病患者。尚无人提出它们在非糖尿病人中的应用和作用。确实，用来治疗糖尿病患者的促胰岛素肽的建议性应用表明，促胰岛素肽在这些患者平常的血糖水平下将有胰岛素刺激作用。根据这种建议，似乎在胰岛素营养性施用时发生的困难在促胰岛素肽的营养性应用时也会发生。这种应用需要滴定血糖水平并连续监测肽的补给。
按照本发明，令人惊异地发现外源性施用的促胰岛素肽并不显著提高有正常(非糖尿病)血糖水平的患者的胰岛素释放。而且，按本发明已发现当通过非肠胃途径对正常(非糖尿病)患者施用葡萄糖时，用于内源性促胰岛素肽产生、释放、受体相互作用和/或过去受体事件的正常调节路径和机制或者不出现或者被绕过。已发现这样的非糖尿病患者经历血糖水平的变化超过其正常值时，例如通过非肠胃施用葡萄糖，由外源性施用的促胰岛素肽引起的胰岛素刺激作用会出现，从而将血糖水平降低到正常值。按照本发明，这些发现已经导致一种高效快速的营养方法，该方法可避免高血糖症，还可避免由于胰岛素过多、血糖过低引起的低血糖症的危险。
按照本发明，促胰岛素肽与营养介质组合应用来提供肠胃外营养。随着外源性促胰岛素肽的肠胃外补给，可既容易又显著地达到血糖水平的稳定。特别是在肠胃外施用营养物的过程中以这种方式高度调节胰岛素的分泌，使血糖水平的增高显著低于没有促胰岛素肽时的情况。因为已发现非糖尿病患者对促胰岛素肽有耐受，直到葡萄糖水平超出其正常禁食血糖水平，又因为已发现血中胰岛素水平随着血糖水平的增加和血中促胰岛素肽增加至平台而继续升高，又因为即使血中促胰岛素肽水平保持在平台水平，血中胰岛素水平随着血糖水平的增加而继续升高，优选可将待施用的促胰岛素肽的数量标准化而不考虑待补给的葡萄糖数量。所以，与无促胰岛素肽的营养方案相比，通过实施本发明可在较短时间内对患者施用更多的葡萄糖或其等同物，更加迅速满意地满足患者的热量缺乏。按照本发明可达到这些结果，而没有任何高血糖症或低血糖症引起的相应的副作用。
按照本发明，施用的组合物可仅包括糖类如己糖或戊糖，具体的例子是葡萄糖、果糖、半乳糖、木糖醇、甘露糖醇和山梨糖醇等。此外组合物可包括葡萄糖的间接来源如脂类、脂肪酸、甘油二酯、甘油单酯、甘油和/或氨基酸，它们通过糖异生作用可转化为葡萄糖。电解质和无机物如氯化钠、氯化钾、硫酸镁、葡糖酸钾、醋酸钠、磷酸二氢钾、醋酸钾、多种维生素和微量元素如铬也可以存在。组合物优选包括可溶性糖类来源如葡萄糖或容易被机体转化为葡萄糖的来源。本发明的组合物中包括的其他成分优选包括载体物质如人血清白蛋白和电解质如氯化钠、氯化钾、氯化镁、缓冲剂、稳定剂和防腐剂。
可通过注射或输注以及通过肌内、皮下、静脉内、关节内、腹膜内、颊(仅用于肽)、鼻膜(仅用于肽)和其他非肠胃途径补给组合物。营养物和促胰岛素肽可通过相同或不同的途径补给。通过静脉内途径补给组合物或者通过静脉内途径补给营养物和通过颊途径补给肽尤其有益。
组合物中营养物的浓度和它们的补给速度设计为在24小时的时间内补给比单独应用葡萄糖溶液可能达到的值更多的热量。人们熟知的i.v.补给应用中典型的标准的葡萄糖溶液为含有一些电解质的5-40wt/wt％葡萄糖水溶液。通常按每小时50-100ml速度补给这种标准溶液，以便维持100-150mg/dl的正常血糖水平。尽管通过本发明方法可维持相同的血糖水平，现在可能应用更高浓度的营养物溶液并以较快速度进行补给。特别是本发明的组合物可能含有大约5 0wt％那么多的葡萄糖或其等同物。补给速度可能提高从而补给2wt％、5wt％、10wt％、15wt％、25wt％、40wt％或50wt％葡萄糖或其等同物溶液，提供每个患者每天多达1000gm葡萄糖或其等同物。当然需要加以注意，使补给高浓度溶液引起的注射部位的组织休克不会发生。
按照本发明，通过共同施用促胰岛素肽可使血糖水平维持在正常值。这些肽可以单独的纯的化合物或半纯的化合物或各种肽的混合物的形式施用。因此，当本申请书中应用术语“促胰岛素肽”时，它们表示包括各种纯度的肽和单独形式的各种肽以及任意组合的混合物。典型地，肽的补给能使血中肽浓度为picomoles/L到micromoles/L的数量级。可通过以下形式使促胰岛素肽与营养物组合：在施用前立刻与营养物组合；与营养物共同施用给患者，通过应用用于肽的一条分开的管，该管通向共用施用管线或分开的管线；或者可与营养物在生产时组合，并保存在适当条件下保护肽的完整。此外，可将促胰岛素肽制备成药学上可接受的吸收性的片剂，或者持释基质如聚交酯-乙交酯基质。将这些固体形式设计为肽的短期到中期释放和吸收，并为本领域所知如WO/96/07398、DE3822459和“药物开发和工业药学”，21(17)，2013-2019(1995)，其公开的内容并入本文作参考。
对每个患者施用的促胰岛素肽的方案和数量要依赖于看护医生的判断和患者的特殊情况。作为指导，如果以较大速度给患者补给葡萄糖或其营养等同物，达到每天约1000g葡萄糖，就要补给相应较大量的一种或多种促胰岛素肽，达到每分钟每公斤患者体重约3pmol的平台水平。促胰岛素肽的这种S状剂量-反应曲线有一阈值水平，随着剂量逐渐增加曲线达到前述的平台水平。剂量-反应曲线依赖于施用的葡萄糖数量和患者的血糖水平。当患者的血糖水平在其正常范围内时，患者对促胰岛素肽的作用有耐受。当血糖水平超出非糖尿病患者的正常范围时，S状剂量-反应即出现。在平台水平或其以上时，胰岛素刺激作用继续并引起血中胰岛素的增加，但是这种增加并不跟随促胰岛素肽的水平，而是跟随血糖水平。
促胰岛素肽在应用前以分离的、无菌的固体状态存在。应用时，固态促胰岛素肽优选与无菌的水性缓冲介质组合，形成nmol/L-mmol/L浓度范围的促胰岛素肽。此外，肽可与持释基质组合，例如已知可提供肽持释的聚交酯、聚乙交酯、聚己酸内酯、水凝胶、微孔聚氨酯类、聚乙酸亚乙烯酯等。可控制这些配制物以提供短期到中期的肽释放。例如参看U.S.专利No.5,364,838、U.S.专利5,383,848，WO/96/07398、DE3822459、U.S.专利5,487,898、“药物开发和工业药学”，21(17)，2013-2019(1995)、“糖尿病护理”Vol，19(8)，843-848(1996)、“医学化学杂志”(Vol，38，pg.4257-4269)和WO/93/18785，其公开的内容并入本文作参考。
按照本发明应用的促胰岛素肽的配方包括所有已知形式的GLP-1和GIP(胰高血糖素样肽-1和胃抑制性肽)及它们的衍生物。特别是按照本发明可应用GLP-1和它的衍生物，包括肽片段如GLP-1(1-36)、GLP-1(1-37)、GLP-1(7-36)、GLP-1(7-37)、GLP-1(7-34)、GLP-1(7-35)，含有氨基酸取代基的相似物如GLP-1(7-34)Ala Phe Ala，缺失序列如去(Lys)GLP-1(7-36)酰胺，有非天然氨基酸残基(如牛磺酸残基、β和γ氨基酸残基和D-氨基酸残基)的类似物，C-末端官能团修饰物如酰胺、酯，以及C-末端酮修饰物和N-末端官能团修饰物如酰化的胺、席夫碱等以及exendin、肠高血糖素、糊精拮抗剂和以下描述的其他衍生物，如EP512042(Derwent 91-252609/34)、WO9325579A1(Derwent94-007457/01)、WO9318786(Derwent 93-3220451/40)、WO9011296(Derwent 90-320226/42)、U.S.专利No.5,545,618、JP63159323(Derwent 88-224231/32)、U.S.专利No.5,118,666、U.S.专利No.5,120,712、U.S.专利No.5,512,549、WO9606628和EP658568，其公开的内容并入本文作参考。也包括促胰岛素肽的传统的小有机分子模拟物，它们能适应促胰岛素肽受体的位点。
这些促胰岛素肽是已知的并描述于文献中。它们可从天然来源中获得，以及通过重组技术或自动的和经典的合成技术生产而获得。尤其可参考PCT专利申请书No.94/08125，该申请书描述了通过重组生物技术合成GLP-1(7-36)酰胺。促胰岛素肽的纯度可能从半纯到高纯之间变化。例如，根据一种分析方法可通过滴定获得它们在不同纯度状态下的活性，该分析方法用于葡萄糖盐水溶液中分离的大鼠胰腺B-细胞定量的胰岛素释放，由Schmidt在糖尿病学(Diabetologia)(1985)28：704-707中讲授。滴定将提供一个活性单位商数，此商数作为基础来测定相对于纯促胰岛素肽数量的待施用半纯促胰岛素肽的等同量。
能用于本发明实施的促胰岛素肽的贮存液包括等渗盐溶液如0.9％NaCl溶液，它含有0.1-5％(体积/体积)的载体物质如人血清白蛋白，伴随有1nmol/L-1mmol/L的促胰岛素肽如GLP-1(7-36)酰胺。应用这种贮存液时可用一个20的系数稀释，与营养物溶液一起输注。促胰岛素肽的合适输注速度将在每分钟每公斤患者体重0.01-50pmol肽的范围内，优选在每分钟每公斤患者体重0.2-2.5pmol肽的范围内。与促胰岛素肽共同施用的葡萄糖的施用速度特别优选可达到每天1000g葡萄糖或其等同物，和/或达到每天约10-约800g氨基酸混合物。
特别适合按照本发明治疗的患者包括有葡萄糖代谢异常如胰岛素抵抗但无明显糖尿病的患者，以及因为某种原因不能通过消化道接受营养的患者。这样的患者包括手术患者、昏迷患者、中风患者、有胃肠疾病的患者、有消化激素疾病的患者等。特别是肥胖患者、动脉粥样硬化患者、血管病患者、妊娠性糖尿病患者、肝病如肝硬化患者、肢端肥大症患者、糖皮质激素过量如氢化可的松治疗或库兴式病的患者、例如创伤、事故和手术等后可能发生的有激活的逆调节性激素的患者、高甘油三酯血症患者和慢性胰腺炎患者按照本发明能轻易、恰当地得到营养而无低血糖症或高血糖症。给这样的患者施药的目的特别是提供一种能尽快地满足患者营养和热量需求的治疗方法，而保持其血浆葡萄糖低于所谓的肾阈值即约160-180mg葡萄糖/dl血。尽管如以上所述，按照本发明也能治疗血糖水平不恰好低于肾阈值的正常患者，但对于有葡萄糖代谢异常的患者如高血糖症患者(其血浆葡萄糖水平恰好高于肾阈值)，这种治疗方法也适合他们的情况。特别是有一定程度的高血糖症、在周期性间隔内低于肾阈值的患者可按照以下方案中任一种接受营养物和促胰岛素肽的组合治疗。也可按照以下方案中任一种治疗没有高血糖症的正常患者。
方案A
患者将接受促胰岛素肽如GLP-1的固定的静注剂量，为每分钟每公斤患者体重1-2pmol。滴定共同施用给患者的静注的营养物，以达到一个稳定状态的血浆葡萄糖水平，约150mg/dl或恰好低于患者的肾阈值。通过一条共同的静注路线分别施用促胰岛素肽和营养组合物。
方案B
患者按照其营养需求接受固定数量的静注营养物，并滴定促胰岛素肽如GLP-1(7-37)，从每分钟每公斤患者体重约0.4pmol开始上升到恰好低于最大值，最大输注速度为每分钟每公斤患者体重约3pmol。
方案C
患者接受营养组合物中固定量的营养物(例如达到每天1000g葡萄糖)和与其组合的固定量的促胰岛素肽(如GLP-1(7-34)，输注速度为每分钟每公斤患者体重2pmol)。通过分开的或共同的静脉输注路线施用它们。
为应用本发明的组合物在最初阶段中和治疗过程中滴定或用其他方法定期跟随患者的进展，患者可接受以下检查。第一天约每隔1小时，以后约每隔5小时测定患者的血糖。在治疗前和治疗时要滴定患者血中胰岛素和高血糖素的水平以任选地测定患者血中胰岛素和高血糖素水平。为了测定患者的营养需要以及他的热量水平是需要增加、减少还是维持，患者可任选地接受间接测热法以测定其葡萄糖氧化率和能量消耗。
按照前面的描述，本发明的特点已得到充分表现。下面的实施例和资料提供了本发明一些方面的详细的实施方案。然而本发明并不限于这些实施方案和方面。
资料
肠胃外营养时肠降血糖素通过外源性GLP-1(7-36)酰胺对胰岛素分泌的刺激作用
本记录的目的是改善与肠胃外营养相关的问题。甚至对于没有恼人的高血糖症的代谢健康的人，输注所需数量的葡萄糖经常是不可能的(1)。所以对于非糖尿病患者有必要加入胰岛素。这导致了很多费时费钱的对照实验，并限制了葡萄糖吸收。
内源性胰岛素分泌不足的可能原因是缺乏肠降血糖素的刺激。口服葡萄糖后，肠降血糖素通过释放的肠道激素作用刺激胰岛素的分泌。这种刺激作用比由血浆中代用品如单独的葡萄糖和氨基酸的浓度增加引起的胰岛素增加好的多。肠道来的这些肠降血糖素中的两种GLP-1(7-37)(如酸)和GLP-1(7-36)酰胺，有很强的葡萄糖依赖性的促胰岛素和高血糖素稳定作用(glucagonostatic effect)。因为动物实验已发现在正常(适度)血浆葡萄糖值时这些肠降血糖素对胰岛素的分泌几乎无任何影响，所以高剂量的肠降血糖素不会导致健康人的低血糖症。
GLP-1(7-36酰胺)存在时可控制肠胃外营养过程中的胰岛素分泌，这样血浆葡萄糖的增加将少于没有GLP-1的情况。所以比用其他方法在24小时内可补给更多的葡萄糖。能较好地满足肠胃外营养患者的热量缺乏。
A部分
研究实施如下。患者包括两种性别，年龄在18-75岁，依赖于肠胃外营养。如果患者有急性病(例如发烧)、胰岛素依赖性糖尿病和肝肾功能限制(肌酸酐＞1.2mg/dl)、妊娠、贫血(血红蛋白＜10g/dl)以及用机械性呼吸支持和儿茶酚胺，就把他们排除在外。每个患者参与了一个研究日。
为开始研究，应当经中央静脉不断地输注葡萄糖/氨基酸混合物(Aminomix，Frescnius AG)，而不输注甘油三酯悬液，以便继续已在进行中的肠胃外营养。剂量相当于临床测定的患者的热量需求。血浆中天然存在的葡萄糖、游离脂肪酸、甘油三酯、氨基酸、胰岛素、C-肽和GLP-1(7-36酰胺)的浓度水平应每小时测定，用于以下4个小时的“稳定状态”。如果在这种“稳定状态”下葡萄糖浓度高于150mg/dl，在以下的4小时内应输注无菌、无热原的GLP-1(7-36酰胺)溶液(1.2pmol/kg/min)，应每小时再测定以上所有数值。这个剂量相当于肠降血糖素GLP-1(7-36)酰胺(0.3-0.4pmol/kg/min)的正常“代用品剂量”(2)和2型糖尿病的必需的药物学剂量(1.2pmol/kg/min)(7，8)。预期本治疗能刺激胰岛素分泌，结果使血浆葡萄糖正常化。本研究的补充是间接测热法(Deltratrak，Datex，Finland)。所以在8小时的GLP-1(7-36)酰胺输注的开始阶段、4小时后、最后阶段必须进行20min的测量。由这些测量也可能测定底物利用率(葡萄糖和脂类氧化，能量消耗)的变化。
B部分
每个患者参与了3个研究日。
为开始研究，应当经中央静脉不断地输注葡萄糖/氨基酸混合物(Aminomix，Fresenius AG)，而不输注甘油三酯悬液，以便继续已在进行中的肠胃外营养。按随机的研究日顺序输注安慰剂、GLP-1(7-36)酰胺(0.6pmol/kg/min)并按照A研究结果可能升至1.2pmol/kg/min，以及胰岛素(每小时2U)。在以后的6小时内应每半小时测定血浆葡萄糖浓度。应增加葡萄糖的输注，很快达到葡萄糖浓度的“稳定状态”即150mg/dl，并保持在此水平。为了补充本研究，应每小时测定葡萄糖、游离脂肪酸、甘油三酯、氨基酸、胰岛素、C-肽和GLP-1(7-36酰胺)。在6小时期间的开始和最后进行间接测热法。
除了中央静脉插管之外还必须放置一个外周静脉插管，以便取血样。缓慢输注生理性NaCl保持静脉“开放”。
应当将GLP-1(7-36)酰胺作为GMP产品接受，并作为无菌的贮存液(含1％人血清白蛋白的0.9％NaCl中)贮存在-30℃。输注前取样品，无菌过滤，用鲎分析(limulus assay)测试细菌生长和内毒素。
在以下时间点取血样：0，60，120，180，240，300，360，420，480(研究A)和：0，60，120，180，240，300，360，420，480，540，660，720(研究B)。
用变量的重复测定分析法进行统计分析，单因素ANOVA和t-检验作为补充。
实施例
一个60岁的患者因为炎性肠病接受肠胃外喂养，体重75kg。经中央静脉导管通过浸剂(infusomate)补给肠胃外营养，浸剂含1.5升40％葡萄糖溶液，于24小时内补给大约600g葡萄糖，以及1升10％商用氨基酸混合物。无GLP-1(7-36)酰胺时获得的血糖值为160-190mg/dl。然后施用GLP-1(7-36)酰胺，即使继续高速施用给患者葡萄糖，血糖水平降低到约100mg/dl。
GLP-1或GIP可用作配套的药物。用正常生理盐水以20∶1稀释下述肽的贮存液，制备促胰岛素肽药剂。制备GLP-1的贮存液，它含50μg/ml，溶解在加有人血清白蛋白(终浓度1％vol/vol)的0.9％NaCl中。检测溶液的细菌污染和热原，可贮存3个月(在-30℃冷冻)。
Claims (16)
1.一种用于非肠胃营养的方法，它包括对需要营养的患者施用一种药物组合物，该药物组合物包括一种营养源和一种或多种促胰岛素肽。
2.一种按照权利要求1的方法，其中所述的营养源是一种糖类来源。
3.一种按照权利要求2的方法，其中所述的糖类来源是己糖、戊糖、己糖醇、戊糖醇，或其任意组合。
4.一种按照权利要求3的方法，其中所述的糖类来源是葡萄糖、果糖、半乳糖、木糖醇(zylitol)、甘露糖醇、山梨糖醇，或其任意组合。
5.一种按照权利要求1的方法，其中所述的营养源是一种或多种能同化的氨基酸、脂类、游离脂肪酸、甘油单酯、甘油二酯或甘油。
6.一种按照权利要求2的方法，其中所述的对患者施用糖类来源产生一个血糖水平，患者中该血糖水平不多于从每分升血约80到180mg葡萄糖，计算糖类来源施用速度为达到每天每个患者约1000g葡萄糖或其等同物。
7.一种按照权利要求1的方法，其中所述的施用促胰岛素肽产生一个在1 pmol/L血浆-1mmol/L血浆范围内的血肽水平。
8.一种按照权利要求1的方法，其中所述的促胰岛素肽是GLP-1、GIP、GLP-1(7-34)、GLP-1(7-35)、GLP-1(7-36)、GLP-1(7-37)，其缺失序列，其天然的和非天然的氨基酸残基取代物，其C-末端的羧酰胺，其C-末端的酯，其C-末端的酮修饰物，其N-末端的修饰物，或其任意混合物。
9.一种按照权利要求2的方法，其中所述的药物组合物包括在第一水性介质中的糖类来源和在第二水性介质中或在药学上可接受的固体或凝胶药片或持释基质中的一种或多种促胰岛素肽。
10.一种药物组合物，它包含组合或分离形式的一种营养源和一种或多种促胰岛素肽。
11.一种按照权利要求10的药物组合物，其中所述的营养源是糖类来源。
12.一种按照权利要求11的药物组合物，其中所述的糖类来源以每升约2wt％到约50wt％葡萄糖或其等同物的浓度存在。
13.一种按照权利要求10的组合物，其中促胰岛素肽以约1nmol/L-约1mmol/L的浓度存在。
14.一种药物组合物，它包括一个试剂盒，该试剂盒含有：营养源的第一水性混合物，包含在一种用于肠胃外施用的形式里；以及一种或多种促胰岛素肽的第二水性混合物或固体或凝胶药片或持释基质，包含在一种用于肠胃外施用的形式里。
15.按照权利要求10的药物组合物在患者营养中的应用。
16.应用于患者营养的药物组合物的生产方法，它包括制备营养源的一种药学上可接受的配制物和制备一种或多种促胰岛素肽的一种药学上可接受的配制物。
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- 1996-08-22 WO PCT/US1996/013615 patent/WO1997007814A1/en not_active Application Discontinuation
- 1996-08-22 DK DK96929722T patent/DK0851763T3/da active
- 1996-08-22 CZ CZ98508A patent/CZ50898A3/cs unknown
- 1996-08-22 EP EP96929722A patent/EP0851763B1/en not_active Expired - Lifetime
- 1996-08-22 PL PL325117A patent/PL191022B1/pl not_active IP Right Cessation
- 1996-08-22 CN CNB2003101141278A patent/CN100374155C/zh not_active Expired - Fee Related
- 1996-08-22 CA CA002227278A patent/CA2227278A1/en not_active Abandoned
- 1996-08-22 AT AT96929722T patent/ATE226830T1/de not_active IP Right Cessation
- 1996-08-22 JP JP51044597A patent/JP3839485B2/ja not_active Expired - Fee Related
- 1996-08-22 DE DE69624580T patent/DE69624580T2/de not_active Expired - Fee Related
- 1996-08-22 CN CNB961969385A patent/CN1145497C/zh not_active Expired - Fee Related
- 1996-08-22 HU HU9903534A patent/HUP9903534A3/hu unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016180353A1 (zh) * | 2015-05-13 | 2016-11-17 | 杭州九源基因工程有限公司 | 一种包含glp-1类似物的药物制剂及其制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2227278A1 (en) | 1997-03-06 |
| CZ50898A3 (cs) | 1999-01-13 |
| AU6900696A (en) | 1997-03-19 |
| DE69624580T2 (de) | 2004-04-22 |
| CN1145497C (zh) | 2004-04-14 |
| EP0851763B1 (en) | 2002-10-30 |
| AU723383B2 (en) | 2000-08-24 |
| WO1997007814A1 (en) | 1997-03-06 |
| JP3839485B2 (ja) | 2006-11-01 |
| ATE226830T1 (de) | 2002-11-15 |
| DE19530865A1 (de) | 1997-02-27 |
| HUP9903534A3 (en) | 2000-04-28 |
| CN100374155C (zh) | 2008-03-12 |
| DE69624580D1 (de) | 2002-12-05 |
| HUP9903534A2 (hu) | 2000-03-28 |
| DK0851763T3 (da) | 2003-03-03 |
| PL191022B1 (pl) | 2006-03-31 |
| EP0851763A1 (en) | 1998-07-08 |
| JPH11514972A (ja) | 1999-12-21 |
| CN1541708A (zh) | 2004-11-03 |
| PL325117A1 (en) | 1998-07-06 |
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