CN101151047A - 使用肺施用的胰岛素组合基础胰岛素来在糖尿病中控制血糖 - Google Patents
使用肺施用的胰岛素组合基础胰岛素来在糖尿病中控制血糖 Download PDFInfo
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Abstract
本发明提供了下述方法,所述方法涉及治疗糖尿病和改善血葡萄糖水平控制。尤其提供了下述方法,所述方法通过施用适用于肺施用形式的胰岛素组合物有效降低餐后葡萄糖偏移,同时降低临床上显著的晚期餐后低血糖的发病率。另外,提供了下述方法,所述方法通过将适用于肺施用形式的胰岛素组合物与长效基础胰岛素一起施用而有效降低餐后葡萄糖偏移,同时降低临床显著晚期餐后低血糖的发病率。
Description
与相关申请的交叉引用
本申请基于35 U.S.C.§119(e)要求于2005年3月31日提交的美国临时专利申请No.60/667,393的优先权,并且是2006年1月10日提交的U.S.专利申请No.11/329,686的部分连续申请,每份文献都通过引用整体并入本文。
技术领域
本发明涉及治疗糖尿病和改善血糖控制的方法。具体地,本发明的方法通过模仿非糖尿病个体的胰岛素应答动力学提供对餐后糖水平的高级控制,同时降低晚期餐后低血糖的风险。
发明背景
糖尿病目前折磨着全世界至少2亿人。1型糖尿病占该数量的约10%,其由胰岛中分泌胰岛素的β-细胞的自身免疫破坏引起。存活依赖于每日多次胰岛素注射。2型糖尿病占据剩余的90%受影响个体,并且发病率在递增。2型糖尿病通常,但不总是与肥胖症相关,尽管之前其被称为晚发(late-onset)或成人糖尿病,但其目前越来越出现在更年轻的个体中。其由胰岛素抵抗和胰岛素分泌不足引起。
在非应激的正常个体中,由于内在的反馈回路,基础葡萄糖水平将趋向于天天保持相同。血浆葡萄糖浓度上升的任何趋势被胰岛素分泌的提高和胰高血糖素分泌的抑制抗衡,所述胰岛素分泌的提高和胰高血糖素分泌的抑制调节肝葡萄糖生成(糖异生和从糖原储存中释放)和组织葡萄糖吸收以维持血浆葡萄糖浓度不变。如果个体增重或由于任何其它原因成为胰岛素抗性,则血糖水平会上升,引起提高的胰岛素分泌以补偿胰岛素抵抗。因此,葡萄糖和胰岛素水平被调节以使得这些浓度的改变最小化,同时维持相对正常的葡萄糖产生和利用。
已鉴定出了五个不同的胰岛素分泌期:(1)基础胰岛素分泌,其中胰岛素在吸收后(postabsorptive)状态中释放;(2)头期,其中胰岛素分泌在肠吸收任何营养之前由看见、闻到和尝到食品引发,由胰腺神经支配介导;(3)第一期胰岛素分泌,其中胰岛素的最初猝发在β-细胞暴露于快速提高的葡萄糖或其它促分泌物之后的第一个5-10分钟之内释放;(4)第二期胰岛素分泌,其中胰岛素水平更渐进地上升,并与刺激的程度和持续时间相关,和(5)仅在体外描述的第三期胰岛素分泌。在这些过程中胰岛素像许多其它激素一样,以脉冲形式分泌,导致血中浓度振荡。振荡包括与较慢振荡(每80-120分钟发生)重叠的快速脉冲(每8-15分钟发生),所述较慢振荡与血糖浓度中的波动相关。
胰岛素分泌可由除葡萄糖外的其它有活力的物质(特别是氨基酸)以及激素和药物诱导。众所周知食物摄取后所观察到的胰岛素应答不能仅通过血糖水平的升高解释,其还取决于其它因素,如膳食中游离脂肪酸和其它促分泌物的存在、神经激活的头期和胃肠道激素。
当个体被给予静脉内葡萄糖激发时,观察到双阶段胰岛素应答,其包括快速上升到峰、峰间最低值和随后的较慢增长阶段。该双阶段应答仅在葡萄糖浓度快速上升时(例如在葡萄糖推注或葡萄糖输注之后)被观察到。在生理条件下观察到的葡萄糖施用的较慢提高诱导更逐渐增长的胰岛素分泌,而不是应答于葡萄糖剂团输注而观察到的明确的双阶段应答。
在正常生理条件下模拟第一期胰岛素应答表明:比起静脉剂团注射葡萄糖(在约3-10分钟内达到Cmax)来说,餐后葡萄糖浓度上升地更加渐进(在约20分钟内达到Cmax)。
健康的胰腺β-细胞产生对膳食样葡萄糖接触的早期应答,其在门脉循环和外周中快速提高血清胰岛素。相反,具有受损的第一期胰岛素应答的缺陷型β-细胞对膳食样葡萄糖接触产生缓慢的应答。
越来越多的证据表明葡萄糖摄取之后的早期相对快速的胰岛素应答在餐后葡萄糖稳态维持中起关键性作用。胰岛素浓度的早期波动能够限制初始葡萄糖偏差,这主要通过抑制内源葡萄糖产生。因此,糖尿病患者中快速胰岛素应答的诱导预期能产生经改善的血糖稳态。
在正常个体中膳食诱导胰岛素突发分泌,在血清胰岛素浓度中产生相对陡的尖峰,所述尖峰随后相对快速地衰退(见图1)。该早期胰岛素应答负责葡萄糖从肝释放的关闭。然后稳态机制使胰岛素分泌(和血清胰岛素水平)与葡萄糖负荷匹配。这观察为适度提高的血清胰岛素水平缓慢衰减至基线,并且为第二期动力学。
2型糖尿病通常显示对血糖水平上升的延迟应答。虽然正常个体通常在摄食后2-3分钟内开始释放胰岛素,但是2型糖尿病可不分泌内源胰岛素直到血糖开始上升,然后为第二期动力学,即浓度缓慢上升至经扩展的平台。因此,内源葡萄糖产生不关闭并在耗尽后持续,且患者经历高血糖(提高的血糖水平)。
进食诱导的胰岛素分泌缺失是β-细胞功能的最早障碍之一。尽管遗传因素起重要作用,但是一些胰岛素分泌障碍似乎是后天的,并可通过最适葡萄糖控制至少部分地可逆。通过餐后胰岛素疗法的最适葡萄糖控制能通过要求正常组织对所施用的胰岛素应答和血清胰岛素浓度突然上升引起天然葡萄糖诱导的胰岛素释放的显著改善。因此,2型糖尿病早期(其不具有β-细胞功能的过大损失)治疗中存在的挑战在于恢复餐后胰岛素的快速提高。
除了第一期动力学的缺失外,早期2型糖尿病在餐后不关闭葡萄糖释放。随着疾病的发展,胰腺负担的需求进一步降低其制造胰岛素和控制血糖水平逐渐改变的能力。如果未被检测出,则该疾病可发展至胰岛素制造中的不足逼近典型的发展完全的1型糖尿病的点。然而,1型糖尿病可涉及最初的危险之后的“蜜月”阶段,其中胰岛素仍然产生,但是显示与早期2型糖尿病类似的释放缺陷。
大部分早期2型糖尿病患者目前用口服剂治疗,但是成功率有限。皮下注射对向2型糖尿病患者提供胰岛素也很少理想,这实际上可因为延迟的、可变的和浅的作用发生而使得胰岛素作用更为恶化。然而已显示:如果随膳食静脉内施用胰岛素,早期2型糖尿病患者会经历肝葡萄糖释放停止,并显示出提高的生理学葡萄糖控制。另外,他们的游离脂肪酸水平比起无胰岛素治疗更快的速率下降。尽管在治疗2型糖尿病中可能有效,但是静脉内施用胰岛素不是合理的解决方法,因为对患者而言每餐静脉施用胰岛素不是安全或可行的。
糖尿病中显著的病理学(和发病率)伴随着不足的血糖控制。血糖浓度高于或低于所期望的正常范围的偏移是有问题的。在不能模拟生理胰岛素释放的治疗中,胰岛素浓度的上升不产生显著的高葡萄糖消除率,以完全应答进餐引起的葡萄糖负荷。这可通过葡萄糖从肝的释放关闭失败进一步恶化。另外,使用许多形式的胰岛素疗法时,膳食葡萄糖负荷减轻后,血清胰岛素水平和葡萄糖消除率仍保持为被提高的,产生低血糖的威胁。通过提高胰岛素剂量企图更好地控制峰值葡萄糖负荷的努力进一步增加了该危险。事实上,餐后低血糖是胰岛素疗法的常见结果,其通常导致患者在两餐之间食用点心,或者必须食用,这取决于低血糖的严重性,或甚至需要。这导致通常伴随着胰岛素疗法的体重增加。这些风险及其发生的频率和严重性为本领域公知。
目前的胰岛素治疗方式可补充或代替内源制造的胰岛素以提供基础和第二期样的图,但是不能模仿第一期动力学(见图2)。另外,传统的胰岛素疗法通常涉及每天仅注射一次或两次胰岛素。然而更强烈的疗法(如每天施用三次或更多,提供更好的血糖水平控制)是明确有益的(参阅例如Nathan,D.M.,et al.,N Engl J Med 353:2643-53,2005),但是许多患者不愿接受额外的注射。
直至最近,皮下(SC)注射已成为将胰岛素递送给1型和2型糖尿病患者的唯一途径。然而,SC胰岛素施用不能引起所施用的胰岛素的最佳药效。进入血的吸收(即便与速效胰岛素类似物一起)不模拟血清胰岛素浓度中陡峰的膳食生理学胰岛素分泌模式。自从发现胰岛素后,已经研究过备选的施用途径在促进所施用的胰岛素的药效和通过降低SC注射相关不适而促进顺应性中的可行性。
已详细评价过的胰岛素施用的备选途径包括经皮、经口、经颊、经鼻和肺的途径。经皮应用胰岛素不能导致可再现的和足够的跨越高度有效的皮肤屏障的胰岛素转移。有效的胰岛素口施用尚未到达,主要因为蛋白质的消化和肠中缺乏特异的肽载体体系。经鼻应用胰岛素引起跨越鼻粘膜的更快速的胰岛素吸收,然而没有第一期动力学。经鼻施用胰岛素的相对生物利用度低,并且存在高发生率的副作用和治疗失败。颈颊吸收的胰岛素也不能模拟第一期释放(Raz,I.et al.,Fourth Annual Diabetes Meeting,Philadelphia,PA,2004)。
近来肺应用胰岛素已成为可行的胰岛素递送体系。一些发展中的肺胰岛素制剂与典型的皮下递送产品相比,能使得胰岛素在血中更快出现(见图3),但是显然不能充分地再现第一期动力学的所有方面。
因此,存在对下述胰岛素制剂的需要,所述胰岛素制剂能够模拟第一期动力学,以提供生理学的餐后胰岛素药物代谢动力学和药物效应动力学用于经改进的血糖水平控制。
发明内容
本发明提供了治疗糖尿病和在糖尿病患者中产生血糖水平高级控制的方法。所述方法通过在用餐时或用餐开始后不久施用吸入式胰岛素组合物,使得能够再建餐后血糖水平稳态控制,同时降低低血糖的风险,所述胰岛素组合物模拟非糖尿病个体的胰岛素释放动力学。
在根据本发明的一个实施方案中,提供在患有胰岛素相关疾病的患者中减小餐后葡萄糖偏差的方法,所述方法包含以适用于肺施用的方式施用胰岛素组合物,其中临床相关晚期餐后低血糖发病率被降低。
在另一根据本发明的实施方案中,胰岛素组合物在接近于开始进餐时施用。在一个实施方案中,胰岛素组合物从开始进餐前约10分钟到开始进餐后约30分钟施用。
还在另一实施方案中,胰岛素组合物包含哌嗪二酮和人胰岛素之间的复合物,且所述哌嗪二酮为延胡索酰哌嗪二酮。在根据本发明的一个实施方案中,所述组合物作为干粉通过吸入施用。
还在本发明的另一实施方案中,提供了在患有胰岛素相关疾病的患者中降低餐后葡萄糖偏移的方法,所述方法包含以适用于肺施用的方式施用胰岛素组合物,其中临床相关晚期餐后低血糖发病率被降低,其还包含施用长效的基础胰岛素。
在一个实施方案中,胰岛素相关疾病为糖尿病。在另一实施方案中,胰岛素相关疾病为2型糖尿病。还在另一实施方案中,胰岛素相关疾病为1型糖尿病。
在另一实施方案中,提供了在患有胰岛素相关疾病的患者中用于降低餐后葡萄糖偏移的方法,所述方法包含以适用于肺施用的方式施用胰岛素组合物,其中餐后葡萄糖偏移比由皮下施用的胰岛素给药(其提供类似的胰岛素接触)产生的餐后葡萄糖偏移小,并且其中平均葡萄糖偏移比皮下施用至少少约25%。
还在另一实施方案中,与用适当的胰岛素单独皮下给药治疗所产生的相比,餐后葡萄糖偏移被降低。
在另一实施方案中,与用适当的胰岛素单独皮下给药治疗相比,临床相关晚期餐后低血糖偶发的频率被降低。
在根据本发明的另一实施方案中,提供了在患有胰岛素相关疾病的患者中降低餐后葡萄糖偏移的方法,所述方法包括在接近开始用餐时施用包含人胰岛素和延胡索酰哌嗪二酮的吸入式胰岛素组合物,其中临床相关晚期餐后低血糖发病率被降低。在一个实施方案中,胰岛素组合物从开始进餐前约10分钟到开始进餐后约30分钟施用。在另一实施方案中,胰岛素相关疾病为糖尿病。还在另一实施方案中,所述方法还包含施用长效基础胰岛素。
在根据本发明的一个实施方案中,提供了在用基础胰岛素治疗的患有胰岛素相关疾病的患者中降低餐后葡萄糖偏移的方法,所述方法包括在接近用餐开始时施用包含人胰岛素和延胡索酰哌嗪二酮的吸入式胰岛素组合物,其中临床相关晚期餐后低血糖的发病率被降低。
在本发明的另一实施方案中,提供了在患有胰岛素相关疾病的患者中降低餐后葡萄糖偏移的方法,所述方法包括以适用于肺施用的方式施用胰岛素组合物,其中患者的总胰岛素接触(INS-AUC0-y,3≤y≤6)实质上不需要超过由适当的胰岛素皮下给药所产生的接触,并且其中餐后葡萄糖偏移被降低。还在所述方法的另一实施方案中,晚期餐后低血糖的风险未提高。
附图概述
图1描绘了对通过输注葡萄糖剂团进行人工刺激后第一期胰岛素释放动力学的测量。
图2描绘了皮下(SC)施用常规人胰岛素或SC施用快速作用胰岛素(NovologTM)后的血清胰岛素浓度。NovologTM为Novo NordiskPharmaceuticals,Bagsvaerd,Denmark的注册商标。
图3描绘了来自不同制造商(来自Br J Diab Vasc.Dis 4:295-301,2004)的多种吸入(MannKind,Pfizer/Aventis/Nektar,Alkermes,Aerogen,KOS,Novo Nordisk/Aradigm)和注射(Lispro SC)形式胰岛素的时间-作用图的组合。
图4描绘了根据本发明的教导,对于速效皮下施用的胰岛素(SC)和与延胡索酰哌嗪二酮(Technosphere/胰岛素,TI)配制的肺干粉胰岛素而言,随时间进展的血清胰岛素浓度和作为葡萄糖钳(clamp)下的葡萄糖输注速率(GIR)的葡萄糖消除率之间的关系。
图5描绘了根据本发明的教导,在患有2型糖尿病的个体中,Technosphere/胰岛素(48 U TI)对比速效皮下施用的胰岛素(24 IU SC)而言提高的餐后葡萄糖消除。
图6A-B描绘了根据本发明的教导,在多个时间点针对皮下的(SC)和肺的(TI)而言,对患者内部GIR多样性(图6A)和患有2型糖尿病个体中胰岛素浓度(图6B)的比较。
图7A-B描绘了根据本发明的教导,在患有2型糖尿病的个体中不同的TI和SC胰岛素剂量水平下,平均血清胰岛素浓度(图7A)和作为AUC的胰岛素吸收(图7B)。
图8描绘了根据本发明的教导,对施用48 U的TI后在患有2型糖尿病的个体中随时间进展的胰岛素浓度和葡萄糖消除速率之间的比较。
图9A-B描绘了根据本发明的教导,施用14 IU SC胰岛素或48 U TI后,患有2型糖尿病的个体中血胰岛素(图9A)和葡萄糖水平(图9B)。
图10描绘了根据本发明的教导,施用14 IU SC胰岛素或48 U TI后在患有2型糖尿病的个体中,伴随类似胰岛素接触的经改善的餐后葡萄糖接触。
图11描绘了根据本发明的教导,用TI或安慰剂(PL)胰岛素治疗三个月后在患有2型糖尿病的个体中吸入的胰岛素对餐后葡萄糖水平效应的维持。
图12A-B描绘了根据本发明的教导,施用TI或PL后,患有2型糖尿病的个体中总的(图12A)和最大的(图12B)餐后葡萄糖偏移。
图13描绘了根据本发明的教导,与对照组(对照)中设想的剂量相比,患有2型糖尿病的个体中施用TI后对最大餐后葡萄糖偏移的剂量效应。
图14A-B描绘了根据本发明的教导,在患有2型糖尿病的个体中施用TI后对TI和内源胰岛素而言的随时间进展的胰岛素出现速率。
图15描绘了根据本发明的教导,施用静脉内(IV,5 IU)、SC(10IU)或吸入的(TI,100 U)胰岛素后,患有2型糖尿病的个体中胰岛素浓度和葡萄糖清除速率之间的关系。
图16描绘了根据本发明的教导,患有2型糖尿病的个体中施用TI或SC胰岛素后的C-肽水平。
图17描绘了根据本发明的教导,在患有2型糖尿病的个体中施用TI或安慰剂12周后,平均糖基化血红蛋白(HbAlc)水平的改变。
图18描绘了根据本发明的教导,在施用了TI或安慰剂(PL)的患有2型糖尿病的个体中的体重水平。
图19A-B描绘了根据本发明的教导,在三个月的安慰剂受控的临床研究中随时间进展的肺功能,这表示为一秒钟用力呼气量(FEV1,图19A)和用力肺活量(FVC,图19B)。
图20描绘了实施例6中公开的临床试验的研究方案。
图21A-B描绘了根据本发明的教导施用TI和等热量餐(图21A)或高热量餐(图21B)后处理组相对于时间的经基线校正过的血糖浓度。
图22A-B描绘了根据本发明的教导在施用TI和等热量餐(图22A)和高热量餐(图22B)后处理组相对于时间的经基线校正过的血清胰岛素浓度。
图23A-B描绘了根据本发明的教导在施用IV、SC或TI(经吸入的)后随时间进展的平均血葡萄糖水平(图23A)或C-肽水平(图23B)。
图24A-B描绘了根据本发明的教导施用IV、SC或TI(经吸入的)后随时间进展的葡萄糖输注率(图24A)或平均胰岛素浓度(图24B)。
术语定义
在展示本发明之前,提供下文中将使用的某些术语的理解可能是有帮助的:
干粉:本文使用“干粉”是指未悬浮于或溶解于推进剂、载体或其它液体中的精细微粒组合物。其并非旨在表示完全不含任何水分子。
早期:本文使用“早期”是指应答于进餐而被诱导的血胰岛素浓度上升。应答于进餐的该早期胰岛素上升有时被称为第一期。
偏移:本文使用“偏移”是指变成高于或低于餐前基线或其它起点的血葡萄糖浓度。偏移通常被表示为血葡萄糖随时间进展图曲线下的面积(AUC)。AUC可以以多种方式表示。在一些情况下,会存在高于或低于基线的改变,产生正的或负的面积。一些计算会从正的AUC中减去负的AUC,而另一些计算会将它们的绝对值相加。正的AUC和负的AUC还可单独考虑。也可使用更高级的统计学评估。在一些情况下,其还可以指上升或下降至正常范围外的血葡萄糖浓度。正常的血葡萄糖浓度通常为禁食个体在70和110mg/dL之间,进餐后两小时少于120mg/dL和进餐后小于180mg/dL。
第一期:本文使用“第一期”是指由团剂静脉内注射葡萄糖诱导的胰岛素水平的尖峰。第一期胰岛素释放在血胰岛素浓度中产生尖峰,即随后衰减得相对迅速的陡峰。
葡萄糖消除速率:本文使用“葡萄糖消除速率”是葡萄糖从血中消失的速率,并由维持稳定血葡萄糖(研究周期中通常在120mg/dL左右)所需的葡萄糖输注数量确定。该葡萄糖消除速率等于缩写为GIR的葡萄糖输注速率。
高血糖:本文使用的“高血糖”是高于正常禁食的血葡萄糖浓度,通常为126mg/dL或更高。在一些研究中,高血糖发作定义为超过280mg/dL(15.6mM)的血葡萄糖浓度。
低血糖:本文使用的“低血糖”是低于正常血葡萄糖的浓度,通常低于63mg/dL(3.5mM)。临床相关低血糖定义为低于63mg/dL或引起患者例如张力过低、潮红或虚弱的症状(其被识别为低血糖的症状并在适当的能量摄入后消失)的血葡萄糖浓度。严重的低血糖定义为需要胰高血糖素注射、葡萄糖输注或他人帮助的低血糖发作。
接近:本文与进餐相关时使用的“接近”是指接近开始进餐时间的时间段。
胰岛素组合物:本文使用的“胰岛素组合物”是指适用于施用给哺乳动物的任何形式的胰岛素,其包括从哺乳动物分离的胰岛素、重组的胰岛素、与其它分子结合的胰岛素,还包括通过任何途径施用的胰岛素,所述途径包括肺的、皮下的、经鼻的、经口的、经颊的和舌下的。胰岛素组合物可以被配制为用于吸入的干粉或水性溶液、用于皮下、舌下、经颊、经鼻或经口施用的水性溶液和用于经口和舌下施用的固体剂型。
胰岛素相关疾病:本文使用的“胰岛素相关疾病”是指哺乳动物中涉及胰岛素制造、调节、代谢和作用的疾病。胰岛素相关疾病包括但不限于1型糖尿病、2型糖尿病、低血糖、高血糖、胰岛素抵抗、胰腺β-细胞功能缺失和胰腺β-细胞缺失。
微粒:本文使用术语“微粒”包括具有下述外壳的微胶囊,所述外壳由哌嗪二酮单独组成或由哌嗪二酮和一种或多种药物的组合组成。其还包括含有分散在球体各处的药物的微球、不规则性状的颗粒和其中药物包被在颗粒表面或填充其中孔隙的颗粒。
近餐的(periprandial):本文使用“近餐的”是指摄入膳食或点心之前不久开始和之后不久结束的时间段。
餐后的:本文使用“餐后的”是指摄入膳食或点心之后的时间段。本文使用晚期餐后是指摄入膳食或点心后3、4或更多小时的时间段。
增强(potentiation):通常,增强是将一些药剂的效力或活性提高至其所能到达的水平上的条件或作用。相似地,其可直接指经提高的状态或活性。本文使用“增强”尤其是指经提高的血胰岛素浓度扩大随后的胰岛素水平例如提高葡萄糖消除速率的效率的能力。
餐食的(prandial):本文使用的“餐食的”是指膳食或点心。
第二期:本文使用“第二期”是指经过第一期后,适度上升的血胰岛素水平缓慢衰减至基线。第二期还可指应答于经提高的血葡萄糖水平的非尖峰胰岛素释放。
Technosphere/胰岛素:本文使用的“Technosphere/胰岛素”或“TI”是指包含常规人胰岛素和Technosphere/胰岛素微粒、药物递送体系的胰岛素组合物。Technosphere微粒包含哌嗪二酮,特别是3,6-二(延胡索酰-4-氨基丁基)-2,5-哌嗪二酮(延胡索酰哌嗪二酮,FDKP)。特别地,Technosphere/胰岛素包含FDKP/人胰岛素组合物。
本文使用的“哌嗪二酮”或“DKP”包括落入通式1中的哌嗪二酮及其盐、衍生物、类似物和修饰,其中在位置1和4上的环原子E1和E2为O或N,并且分别位于位置3和6的侧链R1和R2中至少一个包含羧酸(羧化物)基团。根据式1的组合物包括,但不仅限于哌嗪二酮、吗啉二酮和二氧六环二酮(diketodioxane)及其取代类似物。
式1
除了可用于制造空气动力学合适的微粒外,哌嗪二酮还便于跨细胞层转运,进一步加速进入循环的吸收。哌嗪二酮可形成整合药物的颗粒,或药物在其上面可被吸收的颗粒。药物和哌嗪二酮的组合可赋予经改善的药物稳定性。这些颗粒可通过多种施用途径施用。作为干粉,这些颗粒可根据颗粒大小通过吸入呼吸系统的特定区域递送。另外,所述颗粒可做得足够小,以用于并入静脉的悬浮液剂型中。也可用并入悬浮液、药片或胶囊的颗粒口服递送。哌嗪二酮也可有助于所结合的药物吸收。
在本发明的另一实施方案中,DKP是3,6-二(4-氨基丁基)-2,5-哌嗪二酮的衍生物,其可通过(热)缩合氨基酸赖氨酸形成。示例性的衍生物包括3,6-二(琥珀酰-4-氨基丁基)-、3,6-二(马来酰-4-氨基丁基)-、3,6-二(戊二酰-4-氨基丁基)-、3,6-二(丙二酰-4-氨基丁基)-、3,6-二(乙二酰-4-氨基丁基)-和3,6-二(延胡索酰-4-氨基丁基)-2,5-哌嗪二酮。DKP用于药物递送的用途为本领域已知(参阅例如U.S.专利Nos.5,352,461、5,503,852、6,071,497和6,331,318″,其中每份资料的有关哌嗪二酮和哌嗪二酮介导的药物递送所教导的全部内容,通过引用并入本文)。DKP盐的用途描述于2005年八月23日提交的co-pending U.S.专利申请No.11/210,710中,其关于哌嗪二酮盐所教导的全部内容通过引用并入本文。使用DKP微粒的肺药物递送公开于U.S.专利No.6,428,771,其通过引用整体并入本文。
Technosphere/安慰剂:本文使用“Technosphere/安慰剂”是指未与胰岛素结合的Technosphere颗粒。
测量单位:皮下和静脉内胰岛素剂量表达为IU,其由标准化的生物学测量定义。与延胡索酰哌嗪二酮配制的胰岛素数量也像血中胰岛素测量一样以IU报告。Technosphere/胰岛素剂量以任意单位(U)表达,其在数字上等于所述剂量中配制的胰岛素数量。
发明详述
胰岛素疗法用于治疗糖尿病的常见问题在于:足够控制餐后葡萄糖负荷的胰岛素剂量在扩大的间隔内产生餐后可持续的提高的葡萄糖消除速率,引起餐后低血糖。与正常个体中所见到的对膳食葡萄糖的生理应答相比,在糖尿病中皮下施用后胰岛素血水平的提高显著更慢。因此,引起血清胰岛素水平更快上升(其然后下降)的胰岛素组合物和方法导致产生了更多达到最大葡萄糖消除速率的生理学手段。这具有下述效应:将所施用的胰岛素的大部分效应压缩在近餐的时间间隔中,从而降低餐后低血糖的风险,并导致对膳食葡萄糖的更正常的生理胰岛素应答。
通常假设任何时间点的葡萄糖消除速率是该时间点胰岛素浓度的函数。实际上,任何具体的胰岛素浓度所达到的葡萄糖消除速率都会受到先前的胰岛素浓度的影响。因此葡萄糖消除速率被先前的高胰岛素水平增强,所以对于任何具体的胰岛素浓度而言,当患者在先前的时间间隔中经历了高胰岛素浓度时,葡萄糖消除速率更大。本发明人目前惊奇地发现,与更加渐进地到达峰值胰岛素浓度时相比,该增强作用更快地将葡萄糖消除速率推动至应答于胰岛素浓度的大又陡的峰的最大值。
在开始进餐时或之后不久施用本发明的吸入式的胰岛素组合物——一种胰岛素/哌嗪二酮微粒(Technosphere/胰岛素,TI)时,进餐后的血葡萄糖水平比起当患者试图用皮下胰岛素或口服药物控制他们的疾病时受到更紧密的控制。
使用典型的速效皮下(SC)施用的胰岛素,可在约30到45分钟内达到最大胰岛素浓度,并在该平台维持若干小时(图2)。然而,葡萄糖消除速率(作为葡萄糖输注速率[GIR]测量)在整个平台期保持上升(图5),仅在胰岛素浓度开始衰减时达到峰值(图4)。相反,进行模拟生理的第一期胰岛素释放的施用时,胰岛素浓度在更高水平达到峰值,并在约15分钟后开始下降(图1)。然而,GIR在胰岛素浓度到达峰值之后继续上升,但是在小于1小时内到达其最大值,然后与胰岛素浓度一致下降(图4)。经过三个小时后,大部分该胰岛素应达到的葡萄糖消除已经发生,但是皮下胰岛素仅发挥了其效力的不到三分之一(图5)。
通过利用胰岛素浓度陡峰的增强效应,模拟第一期动力学的胰岛素治疗方法可提供若干优点。这类胰岛素配方与通常在餐前固定时间段使用的更缓慢吸收的胰岛素不同,后者通常在进餐开始的几分钟内被施用。间隔通常取决于达到按照默认假设(葡萄糖消除速率是胰岛素浓度的函数)的最大胰岛素浓度所学的时间。然而,由于在胰岛素浓度的整个平台中葡萄糖消除速率持续上升,足够大从而保持葡萄糖水平不超出正常范围的剂量造成这样的风险:得到的餐后数小时的高葡萄糖消除速率会引起低血糖。由于胰岛素制剂的引起血清胰岛素浓度陡峰的增强效应,其可更容易地与进餐协调。最大葡萄糖消除速率的快速获得非常适合进餐时间施用,或甚至适合开始进餐后至多一小时施用。胰岛素浓度的第二期衰退降低餐后数小时诱导低血糖的风险。在保留一些胰岛素生产能力的糖尿病患者中发现了其它优点:他们的内源第二期和基础胰岛素也会被增强,这提高了有限胰岛素的效率并降低了胰腺压力。通过外源施用本发明的胰岛素组合物来降低胰腺压力的方法公开于题为″Methods of Preserving the Function ofInsulin-Producing Cells in Diabetes″的共同未决的美国临时专利申请No.60/704,295中,该资料中关于通过施用哌嗪二酮/胰岛素组合物降低胰腺压力的方法的所有教导都通过引用并入本文。外源胰岛素的施用也抑制来自胰腺的胰岛素分泌。由快速达到峰值的胰岛素所达到的到基线的更快回归允许更早的胰腺分泌再现和血葡萄糖水平稳态控制的再建,进一步降低治疗后低血糖的风险和血葡萄糖水平偏差。对于不生产显著水平胰岛素的糖尿病患者而言,预期有来自被组合的陡峰和长效外源胰岛素的相似优点。
本文使用的模拟生理进餐时间或第一期胰岛素释放(或药物代谢动力学)并不表示必须精确地复制生理应答的所有特征。其可以指产生血中胰岛素浓度突起或峰的方法,所述突起或峰构成浓度相对快的上升(从施用起小于约15分钟或第一次偏离基线)和下降(峰后经80分钟,优选地50分钟,更优选地35分钟,下降通过最大值的一半)。这与下述方法相反,所述方法产生更渐进地上升(从大于20分钟到若干小时)至所达到的最大胰岛素浓度和在最大浓度附近的延长的平台。其还可以指下述方法,其中胰岛素浓度的突起可以与进餐开始可靠地协调。其还可以指在施用后约30-90分钟之内,优选地45-60分钟左右达到最大葡萄糖消除速率的方法。模拟第一期释放的方法通常也是可以由糖尿病患者在自身上实践的方法,而不需要特别的医疗训练,如静脉内注射的训练。特别的医疗训练不包括使用通常由非医学专业人员使用的医疗用具,如干粉吸入器。本文使用“膳食”、“进餐”和/或“进餐时间”等包括传统的进餐和进餐时间;然而这些术语也包括无论大小和/或时间的任何食物的摄入。
高级血糖控制可被理解为对(上升的)葡萄糖浓度(AUCGLU)的减少的接触、降低的HbAlc(糖基化的血红蛋白)、减小的低血糖可能性(风险)或发病率、降低的对治疗应答的变异性等。糖基化的血红蛋白水平在过去的三个月中与所有血糖控制相关。一般地,对不同的时间间隔比较相似胰岛素暴露水平(AUCINS)上不同操作的结果。葡萄糖接触和低血糖风险根本上取决于随时间进展葡萄糖清除速率与葡萄糖负荷的匹配情况。这随后通常取决于胰岛素浓度曲线的性状,而不是简单地取决于曲线下的面积。典型的生理第一期应答的胰岛素浓度快速上升和下降非常适合于与餐后葡萄糖负荷的葡萄糖消除速率匹配。
可通过肺施用干粉胰岛素配方获得所期望的第一期动力学,所述配方包含与3,6-二(延胡索酰-4-氨基丁基)-2,5-哌嗪二酮(下文称为延胡索酰哌嗪二酮或FDKP)络合的胰岛素。哌嗪二酮用于药物递送的用途是本领域已知的(参阅例如题为″Self Assembling Diketopiperazine Drug DeliverySystem”的美国专利No.5,352,461、题为”Method for Making Self-Assembling Diketopiperazine Drug Delivery System”的U.S.专利No.5,503,852、题为”Microparticles for Lung Delivery ComprisingDiketopiperazine”的U.S.专利No.6,071,497和题为”Carbon-SubstitutedDiketopiperazine Delivery System”的U.S.专利No.6,331,318,每份资料中关于哌嗪二酮和哌嗪二酮介导的药物递送的所有教导都通过引用并入本文)。使用哌嗪二酮和其它微粒的肺药物递送公开于题为″Method for DrugDelivery to the Pulmonary System″的US专利6,428,771中,所述资料关于将以哌嗪二酮为基础的组合物递送到肺系统的所有教导都通过引用并入本文。胰岛素和FDKP的络合物、它们的形成、性质和用途被公开于题为″Purification and Stabilization of Peptide and Protein Pharmaceutical Agents″的U.S.专利Nos.6,444,226和6,652,885中,每份资料关于FDKP-络合剂的形成和施用的所有教导都通过引用并入本文。哌嗪二酮和胰岛素络合物的其它制造方法被公开于题为″Method of Drug Formulation Based on Increasingthe Affinity of Active Agents for Crystalline Microparticle Surfaces″的共同未决的美国临时专利申请No.60/717,524中,所述资料关于哌嗪二酮和胰岛素络合物制造的所有教导通过参考并入本文。用于递送粉末的具体的有利的装置被公开于题为″Unit Dose Cartridge and Dry Powder Inhaler″的U.S.专利申请No.10/655,153和题为″Inhalation Apparatus″的U.S.专利No.6,923,175中,每份资料关于肺递送胰岛素组合物的所有教导都通过引用并入本文。
与皮下施用的胰岛素相比,通过吸入施用Technosphere/胰岛素导致血清胰岛素水平更快上升,更密切地接近正常个体中对进餐相关葡萄糖的胰岛素应答。另外,施用TI后葡萄糖的餐后偏移在餐后时间段中受到比SC施用的胰岛素更大程度的限制(图10)。在受控的临床试验中,无论患者是否被施用TI或SC,患者与胰岛素的总接触是相同的,但是使用TI胰岛素时相对正常血葡萄糖水平的餐后偏移显著小于(约一半)使用SC胰岛素时(图10)。因此以接近健康个体胰岛素应答的方式递送胰岛素允许患有糖尿病的患者在餐后时间段达到对他们血葡萄糖水平的更大控制。
在患有中等严重程度HbAlc(在三个月的时间周期中血葡萄糖水平控制的标记物)的患者中,用TI治疗导致与对照处理个体相比HbAlc水平的降低(图17),展示了TI治疗随时间进展的对血葡萄糖水平的高级控制。
另外,向常规基础胰岛素施用添加TI能产生统计学上显著的、依赖于剂量的HbAlc水平降低和针对餐后葡萄糖偏移的依赖于剂量的效应。
TI基本上模拟对葡萄糖的正常胰岛素应答和大量降低餐后葡萄糖偏移的能力可对糖尿病患者的一般健康具有额外的益处。过量的餐后葡萄糖偏移与动脉粥样硬化和糖尿病性血管疾病(影响yeye、kinesy和外周自主神经系统的一种糖尿病并发症)有关。因此根据本发明的教导施用TI提供葡萄糖水平的高级控制,其因其对糖尿病症状的更好治疗和糖尿病患者更好的整体健康。
哌嗪二酮中大聚合体(如蛋白质和肽)的络合可用于去除杂质或污染物,例如金属离子或其它小分子。哌嗪二酮还用于稳定和增强经络合材料的递送。还开发了配方,用于帮助活性剂穿过生物膜的转运。这些配方包括由以下成分形成的微粒:(i)活性剂,其可以是带电荷的或中性的,和(ii)掩蔽剂的电荷和/或与膜形成氢键的转运促进剂(facilitator)。所述配方可在施用配方后提供血中活性剂浓度的快速上升。
Technosphere是指以哌嗪二酮为基础的药物递送体系,其能够将肽络合并稳定在小颗粒中。哌嗪二酮,具体地,延胡索酰哌嗪二酮(FDKP),自我装配为约2微米平均直径的微粒。在该过程中,其可以在自我装配中或之后与溶液中存在的肽(如胰岛素)包载或络合。干燥后这些微粒便成为适用于肺递送至体循环的合适组合物。通过肺途径施用时,Technosphere颗粒溶解于深肺的pH中性的环境中,并有助于肽进入体循环的快速和有效的吸收。在施用几小时内,FDKP分子不经代谢而排泄于尿中。
另外,如题为″Diketopiperazine Salts for Drug Delivery and RelatedMethods″的共同未决的美国专利申请No.11/210,710所公开的,哌嗪二酮盐可用于本发明的组合物中,所述资料关于哌嗪二酮盐及其在肺递送胰岛素中的用途的所有教导通过引用并入本文。
胰岛素——具有6,000道尔顿额定分子量的一种多肽——传统上通过加工猪和牛胰腺以分离天然产物来生产。然而近来已使用重组技术体外生产人胰岛素。水性溶液中的天然的和重组的人胰岛素是六聚体构型,即,六个重组胰岛素分子在存在锌离子时溶解于水中后以六聚体络合物的形式非共价结合。六聚体胰岛素不能被快速吸收。为了让重组的人胰岛素能够吸收进患者的循环中,六聚体形式必须在材料可进入血流之前首先被解离为二聚体和/或单体形式。
例如,已发现胰岛素可以在延胡索酰哌嗪二酮配方中被递送进肺,在3-10分钟内达到峰值血浓度。相反,典型地,不使用延胡索酰哌嗪二酮通过肺途径施用的六聚体要耗费25-60分钟才达到峰值血浓度,而通过皮下注射施用时,六聚体胰岛素要耗费30-90分钟达到峰值血浓度。该结果已在若干物种(包括人)中被成功重现若干次。
典型地,从胰岛素中去除锌,产生具有不期望的短半衰期的不稳定胰岛素。使用哌嗪二酮微粒,已经展示了纯化以去除锌、稳定胰岛素和增强的胰岛素递送的过程。与延胡索酰哌嗪二酮络合的胰岛素的配方被发现是稳定的,并具有可接受的半衰期。锌水平测量证明:当包括洗涤步骤时,在络合步骤中锌已被大量去除,得到稳定递送配方中的单体胰岛素。
本发明的胰岛素组合物可被施用给需要胰岛素治疗的患者。优选地,所述组合物以微粒的形式被施用,其可以是用于肺施用的干粉形式,或悬浮于适当的药物载体如盐水中。
所述微粒优选以干燥的或低压冻干的形式储存直到立刻要施用之前。然后可将微粒作为干粉,使用例如本领域已知的干粉吸入器通过例如吸入直接施用。或者,所述微粒可被悬浮于足够体积的药物载体(例如水性溶液)中作为气雾剂用于施用。还可通过经口、皮下和静脉内途径施用所述微粒。
可吸入的胰岛素组合物可以被施用至任何靶向的生物膜,优选患者的粘膜。在一个实施方案中,患者为遭受胰岛素相关疾病(如糖尿病)的人。在另一实施方案中,可吸入胰岛素组合物将生物学活性形式的胰岛素递送给患者,这提供血清胰岛素浓度突起,所述突起刺激对进食的正常应答。
在另一实施方案中,可吸入的胰岛素组合物与长效基础胰岛素组合施用给患者。长效基础胰岛素的剂量和施用由患者的医生根据标准医学实践来确定。根据本发明的教导,在近餐时施用可吸入的胰岛素组合物,这独立于基础胰岛素的施用参数。因此就本公开文件的目的而言,“组合”是指本发明的可吸入胰岛素组合物同长效基础胰岛素均被施用给患者,然而所述两种胰岛素的形式被独立施用。
在本发明的一个实施方案中提供了药物组合物,所述药物组合物包含适用于肺施用的形式的胰岛素,与皮下施用的胰岛素相比,所述胰岛素在接近开始进餐时被施用后在95%置信区间内诱导更低的胰岛素接触变异系数(INS-AUC0-X,x≤3),其中总胰岛素接触[INS-AUC0-y,3≤y≤6]基本相似。
在本发明的一个实施方案中提供了药物组合物,所述药物组合物包含适用于肺施用的形式的胰岛素,与皮下施用的胰岛素相比,所述胰岛素在接近开始进餐时被施用后能在95%置信区间内诱导更低的葡萄糖消除变异系数,其中葡萄糖消除作为葡萄糖输注速率(GIR-)AUC0-X,x≤3小时被测量,其中总胰岛素接触[INS-AUC0-y,3≤y≤6]基本相似。
还在本发明的另一实施方案中提供了药物组合物,所述药物组合物包含适用于肺施用的形式的胰岛素,与皮下施用的胰岛素(其剂量能提供基本类似的胰岛素接触)相比,所述胰岛素在接近开始进餐时被施用后提供更小的平均葡萄糖偏移,其中所述平均葡萄糖偏移比皮下施用少至少约28%,具体地至少约25%。
在本发明的一个实施方案中提供了药物组合物,所述药物组合物包含适用于肺施用的形式的胰岛素,与皮下施用的胰岛素(其剂量能提供基本类似的胰岛素接触)相比,所述胰岛素在接近开始进餐时被施用后提供更小的葡萄糖接触,其中所述平均葡萄糖接触比皮下施用小至少约35%,优选地比皮下施用小约50%。
在本发明的另一实施方案中提供了药物组合物,所述药物组合物包含适用于肺施用的形式的胰岛素,与皮下施用的胰岛素(其剂量能提供基本类似的胰岛素接触)相比,所述胰岛素在接近开始用餐时被施用后显示出更小的处理后HbAlc与处理前HbAlc比例。
在本发明的一个实施方案中提供了药物组合物,所述药物组合物包含适用于肺施用的形式的胰岛素,与皮下施用的胰岛素(其剂量能提供基本类似的胰岛素接触)相比,所述胰岛素在接近开始用餐时被施用后显示出更小的葡萄糖接触AUCGLU(分钟*mg/dL)与胰岛素接触AUGINS(μU/mL)的比例。
在本发明的另一个实施方案中提供了药物组合物,所述药物组合物包含适用于施用给走动患者的快速吸收形式的胰岛素,所述胰岛素在接近开始用餐时被施用后显示出小于1的葡萄糖接触AUCGLU(分钟*mg/dL)与胰岛素接触AUGINS(μU/mL)的比例。在本发明的一个实施方案中,所述药物组合物适用于肺递送。
在本发明的一个实施方案中提供了药物组合物,其中胰岛素与哌嗪二酮微粒(优选地延胡索酰哌嗪二酮)络合。
在本发明的另一实施方案中,提供了改善胰岛素治疗再现性的方法,所述方法包含在接近开始用餐时施用药物组合物。
在本发明的一个实施方案中,提供了治疗胰岛素相关疾病的方法,所述方法包含向患有胰岛素相关疾病的患者施用经外源施用的组合物,从而使得所述经外源施用的胰岛素组合物模拟第一期胰岛素动力学,其中所述经外源施用的胰岛素组合物不由静脉内施用。
在本发明的治疗胰岛素相关疾病方法的另一个实施方案中,经外源施用的胰岛素组合物包含哌嗪二酮和人胰岛素之间的络合物。在另一个实施方案中,哌嗪二酮为延胡索酰哌嗪二酮。还在另一个实施方案中,经外源施用的胰岛素组合物被吸入。
在本发明治疗胰岛素相关疾病方法的另一个实施方案中,胰岛素相关疾病为糖尿病,例如1型或2型糖尿病。
在本发明的一个实施方案中,提供了在患有胰岛素相关疾病的患者中将血葡萄糖水平维持在正常范围内的方法,所述方法包含提供经外源施用的胰岛素组合物,其中在施用约30分钟内、备选地在施用约15分钟内获得第一期胰岛素药物代谢动力学,其中经外源施用的胰岛素组合物不由静脉内施用。
在本发明维持血葡萄糖水平的方法的另一个实施方案中,经外源施用的胰岛素组合物包含哌嗪二酮和人胰岛素之间的络合物。在另一个实施方案中,哌嗪二酮为延胡索酰哌嗪二酮。
在本发明维持血葡萄糖水平的方法的另一个实施方案中,经外源施用的胰岛素组合物为非天然存在的胰岛素形式。
在本发明的另一个实施方案中,提供了在需要的患者中恢复正常胰岛素动力学的方法,所述方法包含向患有胰岛素相关疾病的患者施用经吸入的胰岛素组合物,从而使得经吸入的胰岛素组合物模拟第一期胰岛素动力学。在另一实施方案中,胰岛素相关疾病为糖尿病。在又一个实施方案中,所述方法还包含施用长效基础胰岛素。
实施例
实施例1
不同剂量水平的胰岛素浓度指示线性吸收
向人受试者施用多种剂量的Technosphere/胰岛素(T1,MannKindCorporation),并测量血中的胰岛素浓度(图7A)。对至少高至100 U TI的剂量而言,胰岛素吸收(AUC)是线性的(图7B)。
实施例2
与具有更慢生物利用率的胰岛素相比,可快速生物利用的、经吸入的胰岛
素在人中对早期胰岛素应答的模拟加速了餐后葡萄糖处理
在同等血糖钳(isoglycemic clamp)中,在患有2型糖尿病的12个患者的组中研究时间、胰岛素浓度和葡萄糖消除速率之间的关系。每个患者在交叉设计的独立研究日接受24 IU皮下胰岛素(Actrapid,NovoNordisk)或48 U的Technosphere/胰岛素(TI)。
由在540分钟研究周期中维持稳定的120mg/dL血葡萄糖所需的葡萄糖输注量来确定葡萄糖消除速率(GIR)(图4)。四十八个单位的TI提供了114.8±44.1(均值±SD)mIU/L的平均最大胰岛素浓度(Cmax),并具有15分钟的到达最大浓度的中位时间(Tmax),而24 IU的皮下胰岛素(SC)具有63±10.1mlU/L的Cmax和150分钟的Tmax。Technosphere/胰岛素在45分钟时达到最大GIR值3.33±1.35mg/min/kg,而在该时间点SC仅为1.58±1.03,并在255分钟之前都未到达最大值3.38±1.45,尽管胰岛素浓度几乎不变。对于TI的GIR和胰岛素浓度数据也与时间相对描绘在图8中。一旦达到最大胰岛素效应,则对TI和SC而言浓度-效应的关系是相同的(图4)。在180分钟时,对于TI葡萄糖处理是326±119mg/kg或61%,对于SC是330±153mg/kg(总量的27%)。
与早期胰岛素应答相似的胰岛素浓度的迅速的、尖锐的上升提供了最大的葡萄糖消除速率。四十八单位TI在45分钟内达到最大值,而24 IU的SC达到相似效应花费270分钟。该现象不是由两种胰岛素类型的剂量-效应关系的差异造成的,而是反映了应答中的区别:当胰岛素浓度增加随时间进展更加温和时,相反地,Technosphere/胰岛素所提供的胰岛素可更快地被生物利用。这可具有餐后葡萄糖控制的效果。
另外,给药后三小时,48 U的TI和24 IU的SC显示出了相同的葡萄糖减少效应。然而仅获得了SC剂量获得的总葡萄糖减少效应的不到三分之一。餐后180分钟内所提供的总葡萄糖减少效应的百分比对TI而言是74%,对SC胰岛素而言是29%(图5)。如果在餐后三小时向着血糖量正常的目标滴定膳食胰岛素剂量,则与TI相比,SC胰岛素大量残留的葡萄糖减少效应可提高晚期餐后低血糖的风险。除了将大部分葡萄糖减少活性限制在更类似于进餐所产生的葡萄糖负荷的时间段内,TI所显示的动力学还允许内源胰岛素分泌更快重现,即血糖控制返回稳态机制。在晚期时间点(>150分钟),胰岛素浓度的下降滞后于根据较早时间点观察到的衰变率所期望的结果。这应当被理解为下降的外源胰岛素(来自TI)和上升的内源胰岛素的重叠(图14)。
内源胰岛素分泌应当伴随C-肽的生产。针对经吸入的TI和可注射的SC常规胰岛素的随时间进展的平均血清C-肽浓度在图16中显示。在SC处理中C-肽浓度基本不变,但是对TI而言,其以与图14所描绘的模型一致的时间表上升。
患有2型糖尿病的患者中,药物治疗最为重要的目的之一在于恢复或替换进餐相关胰岛素应答的第一期,其在2型糖尿病的进展中早已缺失。经吸入的TI的快速起始和短暂的作用持续时间使其适用于替换患有糖尿病的患者中的膳食胰岛素分泌。
实施例3
快速的胰岛素突起不提高低血糖的风险
人们可能会担心高浓度的胰岛素(特别是结合了它们的增强效应)会将葡萄糖清除速率推动得过高,使得它们形成诱导低血糖的风险。然而事实并非如此。正常血糖钳下的健康人被给予静脉内、皮下或肺胰岛素,并在施用后20分钟开始针对血胰岛素浓度描绘GIR。如上述实施例1所公开的,在正常受试者中胰岛素应答的GIR滞后比起2型糖尿病患者中不明显得多。因此对于正常受试者,胰岛素施用之后和之前20分钟,GIR和胰岛素浓度的关系近似为真正的数学函数。据观察,在较低的胰岛素浓度处函数似乎为线性,较高浓度的考虑显示所述关系实际上是对数型的;随着胰岛素浓度上升,获得不断减小的GIR增加(图15)。因此葡萄糖消除未达到灾难性高速率,并且似乎不能达到。
实施例4
经吸入的Technosphere
/胰岛素的变异性和时间-作用图与皮下人常规胰岛
素有利地比较
胰岛素代谢效应的时间表和再现性对达到接近正常的葡萄糖控制和对于使患者和医生能够进行适当的剂量调整是必须的。比较重复剂量的48 U经吸入的Technosphere/胰岛素(TI)和24 UI经皮下注射的人常规胰岛素(SC)之间在胰岛素吸收和胰岛素效应方面的时间-作用图和受试者内变异性。
在随机排序的12个患有2型糖尿病的经胰岛素处理的受试者(10个男性,10个女性,年龄为56(范围40-65)岁,糖尿病持续时间14.4(3-29)年,HbAlc±0.9%(均值±SD),完全正常的肺功能(预测为正常的FVC、FEV和VC=80%))中,在各处于单独研究日的三种独立情况下给予Technosphere/胰岛素和SC。使用血糖正常的葡萄糖钳(钳水平120mg/dL),在每种形式的胰岛素施用后540分钟中测量药物代谢动力学(PK)和药物动力学(PD)时间-作用情况。作为AUC0-t表达的吸收和效应变异性在给药后120、180和540分钟测定。
Technosphere/胰岛素比SC显示更快的作用开始(INS-Tmax 17±6 vs.135±68min,TI vs.SC,p<0.0001)和更高的峰胰岛素浓度(INS-Cmax)(表1)。在79±47分钟Technosphere/胰岛素已经达到最大的葡萄糖输注速率(GIR)值,而SC的最大效应在293±83分钟(p<0.00001)仍未发生。在施用后第一个二小时和三小时中,TI的INS和GIR曲线的AUC与SC的相比均更高(表1)。在施用后第一个二小时和三小时中,TI的胰岛素浓度和胰岛素作用与SC的相比均更低。特别地,与SC的39%、33%和18%相比,对于TI而言,在120、180和540分钟,胰岛素效应变异性(GIR)分别为23%、22%和26%(图6A)。胰岛素浓度变异性(图6B)遵循相似的模式(对TI为19%、18%和16%,对SC为27%、25%和15%)。在270分钟时,对于TI而言GIR回归至基线,在540分钟测量的血浆胰岛素变异性可与SC的改变相比(CV%:GIR-AUC0-540分钟26%对18%(TI vs.SC);INS-AUC0-540分钟16%对15%)。
与皮下的常规人胰岛素相比,Technosphere/胰岛素显示了更快速的发生和更短的作用时间,这使得它适用于在2型糖尿病患者中代替胰腺胰岛素分泌。具体地,与SC相反,TI能够提供较低的晚期餐后低血糖风险,其大部分葡萄糖降低效应在三小时时间点之前发生。另外,患者内重复吸入TI的变异性在给药后第一个三小时内高于SC胰岛素,这有助于剂量调整(dose titration)。
表1.肺施用TI后的药物代谢动力学参数
经吸入的Technosphere/胰岛素 | SC人常规胰岛素 | |||
平均±SD | CV(%)[95%CI] | 平均±SD | CV(%)[95%CI] | |
基于葡萄糖输注速率(GIR)的药物动力学(PD)参数 | ||||
GIR-AUC0-2h(mg/kg) | 265±83(总量的44%) | 23.4[13.9-33.0] | 211±84(总量的16%) | 39.2[23.2-55.2] |
GIR-AUC0-3h(mg/kg) | 355±119(总量的59%) | 21.7[12.9-30.6] | 363±153(总量的27%) | 33.4[19.8-47.1] |
GIRmax(mg/kg) | 4.5±1.0+ | 22.0[13.0-30.9] | 5.5±1.4 | 17.3[10.3-24.4] |
基于血浆胰岛素(INS)浓度的药物代谢动力学(PK)参数 | ||||
INS-AUC0-2h(μU/ml) | 6965±2233*(总量的56%) | 19.1[11.3-26.9] | 5509±1094(总量的24%) | 27.116.1-38.2[] |
INS-AUC0-3h(μU/ml) | 8030±2561(总量的64%) | 18.2[10.8-24.6] | 8672±1442(总量的38 | 25.0[14.8-35.2] |
%) | ||||
INS-Cmax(μU/ml) | 124±44+ | 20.4[12.1-28.8] | 63±10 | 29.2[17.3-41.2] |
Cl:置信区间
*p<0.05vs.SC,+p<0.0005vs.SC(ANOVA,混合效应模型)
实施例5
存患有2型糖尿病的患者中对经吸入的Technosphere
/胰岛素的效力
和安全性进行随机的、双盲的、安慰剂做为对照的研究
通过小型MannKindTM吸入器递送的Technosphere干粉肺胰岛素具有模仿正常的、进餐相关的、第一期或早期胰岛素释放的生物活性。该多中心的、随机的、双盲的、安慰剂作为对照的研究在2型糖尿病患者中进行,所述2型糖尿病患者受食谱或口服药治疗的不足控制(HbAlc>6.5%到10.5%)。总共招收了123名患者,并将119名打算被治疗的群体(intention-to-treat,ITT)以1∶1的比例随机化以接受从单位剂量药筒中用餐时吸入的Technosphere/胰岛素(TI)或吸入的Technosphere/安慰剂12周,其中所述单位剂量药筒含有6到48单位之间的人胰岛素(rDNA来源)。TI在一天的每个主要或大量进餐的第一口食物时被吸入,贯穿整个12周试验,每天3或4次施用。受试者继续使用进入该研究之前他们所使用的任何口服糖尿病药物。在进餐激发后测定来自第一次和最后一次治疗观察的HbAlc差异,和第一次和第二次中间观察之间的差异,以及血葡萄糖改变和不同时间点的AUC和Cmax及Tmax。
在研究中患者被给予若干次标准化的进餐,并测量了他们的血葡萄糖水平。该研究药物与在所述位点制备的标准化的早餐(Uncle Ben′sBreakfast BowlTM)一起在所述研究位点施用。餐前立即测量禁食血浆葡萄糖。在患者采取第一剂研究药物之前进行呼吸量测定法然后患者吸入研究药物并在60秒之内进行单次呼吸量测定方法。在吸入研究药物90秒内和呼吸量测定之后,患者开始食用测试餐。一旦完成进餐,则获得开始进餐前即刻的和之后30分钟、60分钟和120分钟的血浆葡萄糖数值和葡萄糖计器读数。
对接受TI或安慰剂的患者而言,血葡萄糖在进餐激发后上升,但是TI组显著更小,并且不久回归至基线(图11)。因此被表示为AUC0-120(图12A)的总葡萄糖接触和最大葡萄糖偏移(Cmax,图12B)被降低。图13显示了接受不同剂量TI的患者与对照臂(control arm)的患者之间观察到的最大葡萄糖偏移差异。注意到:针对TI患者在30U剂量时的最大葡萄糖偏移为对照组患者水平的50%。还注意到平均葡萄糖偏移为约28mg/dL对当TI患者进入该研究时的50mg/dL。仅28mg/dL的偏移在临床治疗目的的范围内。
通过预先确定的统计学分析计划对糖基化血红蛋白Alc(HbAlc)结果进行分析,分析其初级效力群体(Primary Efficacy Population,PEP,由坚持研究要求的人定义为un-blinding之前,所述研究要求包括最小剂量和不调整伴随的糖尿病药物)、PEP亚组A(具有6.6%到7.9%基线HbAlc的那些)、PEP亚组B(具有8.0%到10.5%基线HbAlc的那些)以及ITT。这些结果概括于表2中,对PEP亚组B概括于表17中。在该“个体化剂量”研究中,活性治疗组中,每次进餐前食用的TI的平均剂量约为30单位,其中在PEP亚组A中使用28个单位,PEP亚组B中使用33.5个单位。
表2.HbAlc药物代谢动力学
Technosphere/安慰剂 | Technosphere/胰岛素 | |
PEP n=90 | n=42 | n=48 |
平均HbAlc基线(%) | 7.75 | 7.74 |
与基线相比的平均Δ | -0.32(p=0.0028) | -0.76(p<0.0001) |
与安慰剂比较 | p=0.0019 | |
PEP亚组B n=35 | n=18 | n=17 |
平均HbAlc基线 | 8.52 |
(%) | ||
与基线相比的平均Δ | -0.51(p=0.0094) | -1.37(p<0.0001) |
与安慰剂比较 | p=0.0007 | |
PEP亚组An=55 | n=24 | n=31 |
平均HbAlc基线(%) | 7.16 | 7.19 |
与基线相比的平均Δ | -0.18(p=0.1292) | -0.43(p=0.0001) |
与安慰剂比较 | P<0.05 | |
IIT(LOCF)n=119 | n=61 | n=58 |
平均HbAlc基线(%) | 7.78 | 7.87 |
与基线相比的平均Δ | -0.31(p=0.0020) | -0.72(p<0.0001) |
与安慰剂比较 | p=0.0016 |
在TI组中没有发生严重的低血糖发作。接受安慰剂和接受TI的患者之间低血糖事件发生率不存在统计学显著的差异。(表3)。
表3.肺施用TI后低血糖发病率
Technosphere/胰岛素 | Technosphere/安慰剂 | |
低血糖(%患者) | 42.6% | 35.5% |
低血糖(事件/周) | 0.16 | 0.20 |
肺功能检测显示:使用TI的患者和他们的基线值相比或与接受安慰剂的患者的结果相比之间不存在显著差异,所述肺功能检测包括Dlco(肺一氧化碳弥散量)(表4)、FEV1(一秒钟用力呼气量)和总肺泡容量(用力肺活量,FVC)(图19)。
表4.肺施用TI后的肺功能
Dlco | Technosphere/胰岛素 | Technosphere/安慰剂 |
0周 | 24.9±4.8 | 26.5±5.6 |
12周 | 25.0±4.5 | 25.7±5.2 |
在接触的12周时间段中不存在TI对胰岛素抗体的诱导(表5)或体重增加(图18)的迹象。
表5.肺施用TI后胰岛素抗体的发生率
Technosphere/胰岛素 | Technosphere/安慰剂 | |
观察1为阴性/观察9为阴性 | 38 | 34 |
观察1为阴性/观察9为阳性 | 2 | 3 |
观察1为阳性/观察9为阳性 | 8 | 10 |
观察1为阳性/观察9为阴性 | 2 | 4 |
总而言之,该研究说明Technosphere肺胰岛素用在之前仅依赖于食谱和单独的运动或依赖于口服药治疗的不足血糖控制的患者中时,复制胰岛素释放的早期动力学,安全并显著地改善了血糖控制而没有显著提高的低血糖迹象、没有诱导胰岛素抗体、没有体重增加的趋势、没有对肺功能整体影响的迹象。
实施例6
开始进餐前10分钟到之后30分钟使用时,FDKP/胰岛素提供血糖控制
进行临床试验,评估肺施用作为干粉的FDKP-胰岛素复合物时间表的效应(FDKP/胰岛素,也称为Technosphere/胰岛素,TI)。受试者为未接受下述任何的1型糖尿病患者:除胰岛素外的用于治疗他们糖尿病的任何药物,或影响碳水化合物代谢任何其它药物。所述试验是预期的(prospective)、单中心的、随机的、交叉的、标签公开(open-label)的研究。在8个处理观察的每个中,人受试者在食用等热量(I;约500kal)或高热量(H;约720kal)餐之前10分钟(B10)、之前立即(C0)之后15分钟(A15)或之后30分钟(A30)吸入单次个体化的剂量。每个受试者在独立情况和随机顺序下接受八种可能的施用/进餐时间表组合(即B10I、B10H、C0I、C0H、A15I、A15H、A30I和A30H)之一,处理观察之间经过1到14天(见图20)。使用吸入TI和进餐消耗之前和之后采取的血样来测定葡萄糖和胰岛素的药物代谢动力学参数。
TI的剂量针对每个受试者被个体化。经个体化的剂量以处理观察中要被消耗的膳食中碳水化合物含量、TI生物利用度校正因子和受试者的个体“胰岛素因子”(FI)为基础,所述胰岛素因子在第一次处理观察前的预观察中测定。剂量个体化的方法在每个处理观察中根据下式计算:
IUdose=(BE*Fi)/0.30
其中Iudose为要施用的TI的IU数
BE(Brot-Einheit,粮食单位(bread unit))为要被消耗的膳食的碳水化合物含量(以克计)的1/10(等热量和高热量分别为5和8.5)
Fi为个体胰岛素因子,等于掩蔽一个BE所需的胰岛素单位。
0.30为TI生物可利用度的校正因子。
计算后TI剂量可位于可使用多个TI药筒施用的最近剂量左右,其含有6U、12U或24U胰岛素。
在治疗观察中,胰岛素以1IU/小时的速率被静脉内输注,葡萄糖以下述速率被输注:所述速率被调整为在进餐消耗和/或TI吸入之前达到80到140mg/dL范围内的稳定毛细血管血葡萄糖浓度。该输注在研究中继续,不再进行调整。在改变的时间间隔处收集静脉血样,从进餐消耗前45分钟开始并持续到消耗后4小时。样品被用于血(血清)葡萄糖和血清胰岛素浓度的测定。
所述初级效力变量为血葡萄糖浓度。除提供TI和进餐施用之前和之后的血葡萄糖浓度情况外,血葡萄糖浓度值也被用于计算以下的药物代谢动力学参数以描述总葡萄糖偏移:
开始进餐消耗之后的最大(Cmax)和最小(Cmin)血葡萄糖浓度,经基线值校正。
TI吸入后最小血葡萄糖浓度(Cmin),经基线值校正。
到达Cmax的时间(Tmax)、到达Cmin(Tmin)的时间和开始进餐后将葡萄糖偏移持续在基线水平以上的时间(Tx)。
使用梯形方法来计算三个独立时间段的血葡萄糖浓度曲线(AUC)下的面积:
AUC:从开始进餐前10分钟到之后240分钟
AUC1:从之前10分钟到Tx,和
AUC2:从Tx到开始进餐后240分钟
开始进餐后1小时(BG1)和2小时(BG2)的血葡萄糖浓度。
为了确保处理间的基线是可比较的,以餐前-45、-30和-20分钟测量的均值为基础计算血葡萄糖和血清胰岛素基线。
次级效力变量是血清胰岛素浓度。胰岛素吸收被假设为独立于相对于进餐的给药时间。以针对剂量被标准化的血清胰岛素值为基础、对所有数据组使用T=0的给药时间来测定胰岛素的药物代谢动力学情况。计算平均Cmax(峰胰岛素浓度)、AUC(胰岛素浓度曲线下的面积)、Tmax(从给药到峰浓度的时间)、从给药到到达50%Cmax的时间(早期T50%)和从Tmax到Cmax下降50%的时间(晚期T50%)。对个体剂量标准化(对假定的100IU)后,测定个体内和个体间差异为个体Cmax和AUC均值的CV%。
初级效力变量为血葡萄糖浓度。在图21中针对初级效力群体说明了:TI施用对等热量或高热量餐之前或之后的平均(SD)经基线校正过的血葡萄糖浓度的影响。总而言之,尽管高热量餐后可比较的血葡萄糖偏移大于等热量餐,但是其对于这两种进餐类型来说是相似的,虽然这取决于施用TI的时间表(图21)。值得注意的是,当各餐前10分钟吸入TI时,存在初始的血葡萄糖水平下降。在开始进餐后10分钟到达最低值后,血葡萄糖水平在约30分钟后上升超过基线水平。通过比较,当在进餐开始后15或30分钟吸入TI时,葡萄糖水平在开始进餐消耗后约10-15分钟上升超过基线(图21)。
表6中针对初级效力群体显示了对每种类型进餐后血葡萄糖的和每种TI施用时间表的药物动力学参数比较。如平均最小血葡萄糖水平(Cmin)和初始时间段的葡萄糖浓度曲线下的面积(AUC1)所指示的,血葡萄糖的最大降低发生在受试者开始食用等热量或高热量餐之前10分钟吸入TI时(Cmin分别为-21mg/dL和-27mg/dL;AUC1分别为-722和-907分钟*mg/dL)(表6)。当在进餐消耗之前10分钟或之前立刻吸入TI时,血葡萄糖水平在约10到13分钟内达到最低值(如Tmin所示),并且直到之后20到30分钟才上升超过基线水平(如中位Tx所示)(表6)。作为比较,当在进餐消耗开始之后15分钟或30分钟吸入TI时,血葡萄糖减少更小(Cmin-10到-13mg/dL;AUC1-141到-176分钟*mg/dL),其发生得更快(时间3到5分钟)并且更短效(约6到7分钟)。血葡萄糖的最大个体减少是在等热量或高热量餐消耗之前立刻吸入TI的受试者中(Cmin分别为-58mg/dL和-57mg/dL)。
表6.对进餐的血葡萄糖药物代谢动力学参数和施用Technosphere/胰岛素的计时概述
参数 | 等热量餐 | 高热量餐 | ||||||
给药计时 | 给药计时 | |||||||
B10 | C0 | A15 | A30 | B10 | C0 | A15 | A30 | |
(N=12) | (N=12) | (N=12) | (N=12) | (N=12) | (N=12) | (N=12) | (N=12) | |
Cmin(mg/dL) | -21(14) | -18(15) | -11(14) | -13(7) | -27(8) | -16(14) | -11(7) | -10(7) |
Tmin(分钟) | 10 | 13 | 5 | 5 | 13 | 10 | 5 | 3 |
Cmax(mg/dL) | 86(28) | 84(38) | 88(36) | 81(23) | 119(46) | 130(40) | 116(50) | 113(47) |
Tmax(分钟) | 165 | 135 | 150 | 120 | 180 | 180 | 150 | 165 |
AUC1(分钟*mg/dL) | -722(950) | -648(840) | -154(180) | -176(176) | -907(511) | -418(549) | -149(148) | -141(149) |
AUC2(分钟 | 11499 | 10989 | 13055 | 12431 | 14818 | 17395 | 16346 | 18402 |
*mg/dL) | (4640) | (7030) | (7616) | (4682) | (6018) | (6050) | (8326) | (8968) |
AUC (分钟*mg/dL) | 10777(5339) | 10342(7349) | 12901(7739) | 12255(4895) | 13911(5840) | 16977(6008) | 16197(8407) | 18261(8982) |
BG1(mg/dL) | 21(32) | 23(25) | 41(32) | 55(23) | 16(23) | 33(21) | 38(31) | 65(24) |
BG2(mg/dL) | 68(34) | 71(34) | 78(32) | 68(32) | 81(28) | 101(33) | 82(47) | 89(46) |
Tx(分钟) | 36.6 | 36.9 | 11.7 | 11.3 | 42.2 | 33.2 | 12.4 | 10.3 |
除了Tmin、Tmax和Tx为中位数外,所有数值作为均值(SD)出现。
无论TI在具体类型的餐前或餐后被给予,平均Cmax值(被表示为与基线相比的改变)、AUC和AUC2通常是可比较的,尽管其在等热量餐后均低于高热量餐(表6)。达到Cmax的中位时间(Tmax)对等热量餐在120和165分钟范围内,对高热量餐杂150到180分钟范围内。开始进餐后一小时(BG1)和两小时(BG2)的平均血葡萄糖水平未显示与相对于每种餐的TI吸入时间有一致的关系(表6),尽管当TI在开始进餐前10分钟被给予时BG1最低,在开始进餐后30分钟被给予时最高。
不同次TI吸入对所选择的葡萄糖药物代谢动力学参数的比较效应被表达为每种进餐类型相对应的C0处数值的比例(即B10/C0、A15/C0和A30/C0)。这些比例连通其95%置信区间(CI)一起概括于表7中(初级效率群体)。这些结果表明:进餐消耗前即刻吸入T1的比较效应与进餐消耗前10分钟吸入的比较效应在任何药物代谢动力学参数上没有差异(即大部分B10/C0比例接近1,且95%CI范围内包括1)。大部分比较在进餐消耗之前即刻和之后15或30分钟TI之间也未产生差异。
表7.与进餐消耗之前即刻吸入Technosphere/胰岛素相关的血葡萄糖药物代谢动力学参数
等热量餐 | 高热量餐 | |||||
测试与参考参数的比例 | 测试与参考参数的比例 | |||||
B10/C0 | A15/C0 | A30/C0 | B10/C0 | A15/C0 | A30/C0 | |
参数 | (N=12) | (N=12) | (N=12) | (N=12) | (N=12) | (N=12) |
Cmin | 0.997(0.470,2.112) | 0.425(0.210,0.860) | 0.581(0.302,2.112) | 1.748(0.470,2.112) | 0.988(0.470,2.112) | 0.532(0.470,2.112) |
AUC1 | 0.608(0.133,2.775) | 0.300(0.067,1.334) | 0.214(0.053,0.853) | 1.995(0.803,4.762) | 0.381(0.154,0.942) | 0.334(0.137,0.814) |
Cmax | 1.002(0.809,1.240) | 1.088(0.887,1.334) | 0.953(0.784,1.157) | 0.848(0.630,1.143) | 0.778(0.581,1.041) | 0.814(0.616,1.076) |
AUC2 | 1.077(0.727,1.596) | 1.035(0.711,1.506) | 1.158(0.809,1.657) | 0.780(0.497,1.226) | 0.771(0.496,1.198) | 0.907(0.594,1.385) |
AUC | 1.105(0.555,2.200) | 0.722(0.378,1.380) | 1.245(0.671,2.310) | 0.727(0.426,1.238) | 0.753(0.448,1.266) | 0.910(0.553,1.500) |
BG1 | 0.833(0.451,1.536) | 1.203(0.656,2.207) | 7.932(1.143,3.267) | 0.768(0.491,1.200) | 1.256(0.810,1.948) | 1.985(1.379,2.857) |
BG2 | 0.630(0.258,1.536) | 1.109(0.468,2.627) | 0.906(0.399,2.058) | 0.771(0.533,1.114) | 0.665(0.464,0.953) | 0.758(0.537,1.069) |
所有值作为比例存在(95%置信区间)。
次级效力变量为血清胰岛素浓度。吸入TI后平均(SD)经基线校正过的血清胰岛素浓度情况在图22中针对初级效力群体阐述。吸入TI后立即存在血清胰岛素的急剧提高,这不依赖于给药时间和进餐类型。与第一次消除一致,血清胰岛素浓度在给药后约15分钟为峰值,之后快速下降,直到施用后60分钟,之后存在较慢的下降。
表8显示了针对初级效力群体而言,相对于各种类型进餐的每种TI施用时间表的血清胰岛素药物代谢动力学参数比较。总而言之,对于血清胰岛素而言,平均Cmax(被表达为与基线相比的改变)和AUC值通常是可比较的,不论进餐类型和TI是否在进餐之前或之后给予(表8)。不论进餐类型和相对于进餐的给药时间,血清胰岛素浓度在TI吸入后快速上升,其早期T50%在三到五分钟范围内并且峰值浓度在施用后10到20分钟被观察到。之后,血清胰岛素浓度下降,其晚期T50%在33和43分钟范围内,仍未显示吸入TI的时间或进餐类型的一致改变(表8)。
表8.按照进餐和Technosphere/胰岛素施用时间表的血清胰岛素药物代谢动力学参数
参数 | 等热量餐 | 高热量餐 | ||||||
给药时间 | 给药时间 | |||||||
B10 | C0 | A15 | A30 | B10 | C0 | A15 | A30 | |
(N=12) | (N=12) | (N=12) | (N=12) | (N=12) | (N=12) | (N=12) | (N=12) | |
Cmax(mIU/L) | 207(145) | 179(125) | 188(137) | 215(196) | 211(138) | 137(74) | 191(114) | 193(163) |
Tmax(分钟) | 13 | 15 | 15 | 15 | 10 | 20 | 15 | 15 |
AUC (分钟*mIU/L) | 12635(15681) | 11291(17449) | 11642(18373) | 12649(14838) | 10654(7623) | 7710(7313) | 12874(16785) | 11662(13210) |
早期T50%(分钟) | 4 | 4 | 3 | 3 | 4 | 5 | 4 | 3 |
晚期T50%(分钟) | 40 | 40 | 33 | 43 | 43 | 42 | 39 | 39 |
除了Tmax和T50%为中位数外,所有的值作为均值(SD)存在。
因此个体化的TI剂量的吸入在消耗等热量餐或高热量餐的患有1型糖尿病的受试者中提供血糖控制。以相对于进餐的施用时间为基础,不存在胰岛素药物代谢动力学的差异。在第一口食物之前10分钟和开始进餐后多达30分钟之间施用TI在餐后时间段中提供可比较的血糖控制。
实施例7
哌嗪二酮肺配方中胰岛素的生物可利用度
受试者和方法
用5个健康的男性志愿者进行研究。选择标准为通过体格检判断为健康、年龄18到40岁、体重指数18到26kg/m2、通过计算机辅助呼吸量测定法测量的达到峰吸气流的能力≥4L/sec、等于或大于据预测的正常值80%的FEV1(FEV1=一秒钟用力呼气量)。淘汰标准为1型或2型糖尿病,患有人胰岛素抗体,对研究药物或具有相似化学结构的药物有超敏反应史,严重或多重变态反应史,在参与研究前最近三个月中受任何其它试验药物治疗,进行性不治之症,药物或酒精滥用史,正在用其它药物治疗,严重的心血管、呼吸、胃肠、肝、肾、神经、神经病和/或血液疾病史,进行中的呼吸道感染或被定义为具有烟草或尼古丁使用迹象或使用史的吸烟者的受试者。
研究开展方案
在研究日的早晨,受试者在7:30a.m.来到医院(除水外,从午夜开始禁食)。在每个治疗日之前24小时中,受试者被限制进行过度的体力活动和酒精摄入。他们被随机地分配至三个处理臂(arm)之一中。在时间点0之前两小时的时间段中,受试者接受到不变的静脉内常规人胰岛素输注,所述输注被控制在0.15mU分钟-1kg-1使得血清胰岛素浓度被确定在10-15μU/mL。该低剂量输注贯穿所述测试被持续以抑制内源胰岛素分泌。贯穿葡萄糖钳,血葡萄糖被葡萄糖受控的输注系统(BiostatorTM)控制在90mg/dL的水平不变。葡萄糖钳算法是以真实测量的血葡萄糖浓度和在计算血葡萄糖输注速率之前分钟内的变异性为基础,用于保持血葡萄糖浓度不变的。使用市售吸入设备(Boehringer Ingelheim)应用的胰岛素应用(5IUIV或10IU SC注射或每个胶囊三次深呼吸吸入(2个胶囊每个含50U))必须在时间点0之前立刻结束。钳试验的持续时间为从时间点0开始6小时。测量葡萄糖输注速率、血葡萄糖、血清-胰岛素和C-肽。
生物效力和生物可利用度
为了测定生物效力,对施用后第一个三小时(AUC0-180)和对施用后六小时(AUC0-360)的整个观察时间段计算葡萄糖输注速率曲线下的面积,并与所应用的胰岛素数量相关。为了测定生物可利用度,对施用后第一个三小时(AUC0-180)和对施用后六小时(AUC0-360)的整个观察时间段计算胰岛素浓度曲线下的面积,并与所应用的胰岛素数量相关。
在该钳研究中,100U Technosphere/胰岛素吸入被良好地耐受,并被证明具有重大的血葡萄糖减少效应,根据从所达到的血清胰岛素浓度计算其在第一个三小时中具有25.8%的相对生物可利用度。Technosphere是由哌嗪二酮形成的微粒(在本文中也称为微球),所述哌嗪二酮在具体的pH下,典型地在低pH下自身装配为有序的点阵列。它们通常被生产为具有约1μm和约5μm之间的平均直径。
结果
药物代谢动力学结果在图23和图24和表9中阐述。
效力结果
100U TI的吸入在13分钟后显示了胰岛素浓度峰值(静脉内(IV)(5IU):5分钟,皮下(SC)(10IU):121分钟),在180分钟后胰岛素水平回归至基线(IV:60分钟,SC:360分钟)。通过葡萄糖输注速率测量的生物作用在39分钟后达到峰值(IV:14分钟,SC:163分钟)并持续大于360分钟(IV:240分钟,SC:>360分钟)。绝对生物可利用度(与IV应用相比)对第一个三小时是14.6±5.1%,对第一个六小时是15.5±5.6%。相对生物可利用度(与SC应用相比)对第一个三小时是25.8±11.7%,对第一个六小时是16.4±7.9%。
表9.肺施用TI后的药物代谢动力学参数
药物代谢动力学参数 | |||
静脉内施用 | 经吸入的TI | 皮下施用 | |
根据葡萄糖输注率计算的参数 | |||
T50% * | 9分钟 | 13分钟 | 60分钟 |
Tmax | 14分钟 | 39分钟 | 163分钟 |
T-50% ** | 82分钟 | 240分钟 | 240分钟 |
到达基线的T | 240分钟 | >360分钟 | >360分钟 |
根据胰岛素水平计算的参数 | |||
T50% * | 2分钟 | 2.5分钟 | 27分钟 |
Tmax | 5分钟 | 13分钟 | 121分钟 |
T-50% ** | 6分钟 | 35分钟 | 250分钟 |
到达基线的T | 60分钟 | 180分钟 | 360分钟 |
*从基线到一半最大值的时间
**在越过Tmax后从基线到一半最大值的时间
安全性结果
Technosphere/胰岛素在所有患者中都显示为安全的。一个患者在吸入中咳嗽,但没有任何其它症状或呼吸系统恶化的迹象。
结论
吸入100U TI被良好耐受,并被证明具有重大的血葡萄糖减少效应,从所达到的血清胰岛素浓度计算,针对最初的三小时,其具有25.8%的相对生物可利用度。
概述
在该研究中,TI的吸入被证明在健康人受试者中具有下述时间-作用情况:具有胰岛素浓度的陡峰(Tmax:13分钟)和作用的快速开始(Tmax:39分钟)和在多于六小时期间的持续作用。在吸入100U TI后测量的总代谢效应大于皮下注射10IU胰岛素之后。TI的相对生物效力经计算为19.0%,而在第一个三小时内相对生物可利用度经测定为25.8%。
数据还显示:与SC胰岛素注射相比,吸入TI引起快得多的作用起始,这接近于IV胰岛素注射的作用起始,而TI作用的持续时间可与SC胰岛素注射时间相比。
所述药物被良好耐受并且在整个试验中未报告任何严重的副作用。
实施例8
与膳食的皮下胰岛素相比,膳食的Technosphere
/胰岛素提供显著更好的
进餐-相关葡萄糖偏移控制
Technosphere/胰岛素是干粉人胰岛素配方,其包含与延胡索酰微粒络合的胰岛素。通过肺施用,用干粉吸入器(MedToneInhaler)递送Technosphere/胰岛素,其伴随着快速的作用起始,以及足够长到能够覆盖进餐-相关的葡萄糖吸收的作用持续时间。该研究的主要目的在于在7天处理时间段中根据血葡萄糖浓度评价餐前施用的TI与皮下(SC)常规胰岛素相比的安全性和效力。
在该随机的、公开标记的、两周期交叉研究中,招募了十六个受试者,它们患有2型糖尿病,不吸烟,并经加强的胰岛素治疗过,(年龄59(范围36-69)岁,BMI 29.6(23.8-34.9)kg/m2,平均糖尿病持续时间12.3年,具有正常的肺功能(一秒钟用力呼气体积和用力肺活量>80%预测的正常值)。在一周的处理周期中,受试者分别通过吸入的TI或通过SC胰岛素满足其膳食胰岛素需要,同时维持他们的日常基础胰岛素治疗。在24小时室内周期中,在随机化之前测定TI和SC胰岛素的剂量。通过手提式吸入器,使用12U和24U药筒,吸入Technosphere/胰岛素。经过门诊患者周期(其中受试者被施用给使用SC或TI的指定的餐前治疗,进行4点血葡萄糖自测并将他们的日常活动和食谱持续5到7天)后,在摄入补充有48±9(均值±SD)U的TI或14±5IU的SC胰岛素的标准早餐(496kcal,55%碳水化合物)后,在室内条件下测定餐后血葡萄糖和血清胰岛素(INS)偏移。
用SC胰岛素处理后,受试者显示出了120分钟的Tmax和54μU/mL的中位Cmax。作为比较,用TI处理时,受试者显示出了14分钟的Tmax和102μU/mL的中位Cmax(图9)。对于SC和TI而言,每个处理循环的总胰岛素接触是可以比较的,其经测量的AUCINS分别为9155和9180μU/mL(图10)。对于SC而言,与基线相比的平均葡萄糖偏移为85mg/dL,AUCGLU为10925分钟*mg/dL。作为比较,对于TI而言,与基线相比的平均葡萄糖偏移为59mg/dL,AUCGLU为6969分钟*mg/dL(图10)。因此,上述单位的葡萄糖偏差对胰岛素暴露的比例——被吸收的胰岛素剂量效力的指标——对于TI和SC仅分别为约0.76对约1.2。所述数据说明,TI相对于SC而言,在所测量的240分钟中,平均葡萄糖偏移下降31%(p=0.0022),葡萄糖暴露下降36%(p=0.0073)。
具有对胰岛素(如在血浆中所测量的)、对用餐数量和对用餐组成的可比较的接触时,与SC相比,膳食TI导致显著改善的餐后峰值葡萄糖和总葡萄糖接触控制。疗法之间仅有的差异在于胰岛素配方和胰岛素施用的方法。TI提供的Tmax模拟第一期胰岛素释放的动力学并在被期望对肝糖释放具有影响的时间发生。在早期餐后时间段内,皮下胰岛素水平比TI的低得多,没有像TI那样显示明显的“峰”,并显示达到最大浓度的缓慢上升——太晚而不能被期望控制肝糖释放,但是足够代表晚期餐后低血糖风险。
实施例9
在患有2型糖尿病的受试者中,与SC注射的常规胰岛素相比,通过吸入
的Technosphere
/胰岛素显著降低的餐后葡萄糖偏移——用ANOVA再分
析实施例8的数据
对TI和SC而言,经基线调整果的餐后总胰岛素接触(INS-AUC0-240分钟)是可以比较的(8187±4269 vs 8302±4025分钟*μU/dL;ns),而TI的经基线调整果的餐后葡萄糖接触(BG-AUC0-240分钟)仅为SC的不到50%(5095±5923分钟*mg/dL vs 9851±5593分钟*mg/dL;p<0.008)。因此上述单位的葡萄糖接触对胰岛素接触的比例——被吸收的胰岛素剂量效力的指标——针对TI仅为约0.62,而对SC为约1.2。换言之,被吸收的胰岛素单位对单位时,TI将葡萄糖从血中去除几乎是两倍有效的。使用TI时,与SC相比Tmax更短(15 vs 120分钟;p<0.001),Cmax更高(100vs 54μU/mL;p=0.001)。因此,TI的经餐后最大值调整过的血葡萄糖接触比起SC的小28%(49 vs 82mg/dL;p<0.003)。低血糖的指标(BG<63mg/dL或低血糖症状)在TI和SC之间是可以比较的(6 vs.5次发作),像由处理引起的(轻度到中度)负作用(5 vs.4次发作)一样。用TI时高血糖(BG>280mg/dL)发生得更为经常(12 vs.4次发作)——两个患者单独总计8次发作。
与膳食SC相比,Technosphere/胰岛素显著地改善了餐后葡萄糖控制,而在两种处理之间总血清胰岛素浓度是可以相比的。这归因于TI作用的快速起始,其中胰岛素Tmax模拟一期胰岛素释放动力学。相反,在早期餐后时间段内SC胰岛素水平比TI低得多,并且不显示在TI中所观察到的清晰的峰。这些结果支持下述结论:在提供膳食胰岛素需要和降低进餐相关的血葡萄糖偏移方面,餐前T1优于SC。
实施例10
能走动组中采用膳食TI的2型患者的多中心研究
使用Technosphere/胰岛素,通过肺吸入施用常规人胰岛素的药物代谢动力学和药物动力学研究指出:最大血浆胰岛素浓度可在吸入后约10到14分钟的中位数时达到,这对于替换第一期胰岛素释放是理想的。用其它目前可获得的胰岛素系统将具有这样高度再生性动力学情况的胰岛素施用给患有糖尿病的走动患者是不可能的。研究(例如上文所列举的)已证明:与餐前给予的生物可利用的相等剂量皮下胰岛素(SC)相比,使用TI将餐后葡萄糖偏移降低48%。在另一个多中心研究(能走动组的2型患者采用膳食TI 12周)中,餐后被监测到的低血糖频率比历史上报告的SC在能走动用途中的频率小10%。
在患有2型糖尿病的患者中对膳食Technosphere/胰岛素的受力的滴定的随机化、预期双盲、以安慰剂为对照的研究中,除基础施用SC肝精胰岛素(insulin glargine(Lantus;一种长效胰岛素形式)外,受试者接受膳食给药的经吸入的Technosphere/胰岛素(TI),227个患者被研究超过18周。在最初的4周中,患者被持续他们现存的治疗,然后被除去所有口服的抗高血糖治疗,并进行每天一次的固定剂量的SC肝精胰岛素,所述剂量足够复制他们被记录的操作前禁食血浆葡萄糖水平并稳定在该剂量。然后将患者对所添加的经吸入安慰剂盲剂量或经吸入TI的忙剂量随机化,所述经吸入的TI含有在多于4周的受力滴定过程中在一天中每次主餐时间被采用的14、28、42或56 U的常规人胰岛素。特别地,被分为五组的受试者最初接受安慰剂(不含任何胰岛素的Technosphere微粒)与SC长效胰岛素。一周后,一组继续接受安慰剂,四组改为14 U胰岛素的TI剂量。另一周后三组改为28 U的TI剂量,这样持续直到最后一组达到56 U的TI剂量。然后所有的组在试验剩下的八周中继续相同的剂量。
在随机化处理的开始和结束时,HbAlc水平和进餐激发(300分钟)在初始观察中被评价。比较在处理组和安慰剂组之间进行。通过被定义的低血糖发作的频率和测量系列肺功能检测(包括FEV1和DLCco)评价安全性。TI向肝精胰岛素中的添加产生HbAlc水平的依赖于剂量的降低。在56单位被处理八周的患者中,平均降低比在肝精胰岛素/安慰剂组中观察到的大0.79%(p=0.0002)。Technosphere/胰岛素还在餐后葡萄糖偏移中产生依赖于剂量的降低,其在56U处的最大偏移平均仅为34mg/dL(p<0.0001)。不存在严重的低血糖发作,轻度/中度低血糖发作的频率未增加至超过肝精胰岛素单独的受试者中的频率。未观察到在体重或肺功能中与基线相比或剂量组之间的改变。因此经吸入的TI能够改善2型糖尿病患者的血糖控制而不提高低血糖的风险。
实施例11
在1型糖尿病中经吸入的Technosphere
/胰岛素与经SC施用的快速作用胰
岛素类似物作为基础/膳食用药法中的膳食胰岛素的3个月的比较
该研究展示了对2型糖尿病患者中长期控制的首次评价,将Technosphere/胰岛素(TI)与作为比较物的快速作用胰岛素类似物(RAA,Novolog)比较。先前的TI研究已显示了2型糖尿病患者中,在240分钟期间,与常规人胰岛素相比显著更好的餐后控制。
随机化的、公开标记的研究招收1型糖尿病患者(111个受试者,18到80岁龄;HbAlc>7.0%和≤11.5%)),除基础胰岛素(Lantus)外他们接受TI或RAA作为进餐时胰岛素持续12周。膳食胰岛素和基础胰岛素的滴定在大夫的慎重考虑下被许可。在基线上,第8周和第12周,进行标准化的检测评价在300分钟期间(第12周时420分钟)的葡萄糖偏移,HbAlc水平和肺功能(FEV1和Dlco)在两组中均被评价。在接受TI胰岛素的组中,标准餐后第一个两小时内与SC胰岛素给药的组相比观察到更低的最大值和总葡萄糖偏移。在随后的3-4小时期间,在TI组中血糖被维持在接近基线的水平,但是在接受快速作用胰岛素的患者中下降至低于基线。两个处理组之间未观察到显著的HbAlc水平差异。与基线相比的降低在TI组中为0.83(1.11);p<001(均值(SD))和在接受SC RAA的组中为0.99(1.07);p<0.001,组间没有统计学差异(p=0.458)。同时,在TI组中体重减少0.41(2.22)kg,但是在接受SC胰岛素的组中增加0.89(1.92)kg。组间差异是统计学显著的(p=0.0016)。与接受RAA相比,接受TI的受试者中观察到餐后血葡萄糖接触的上升。观察10的最大餐后偏移为TI组的0.92mmol/L vs.RAA组的3.0mmol/L。总餐后葡萄糖偏移(AUCGLU)对TI组为96.7mmol/L*分钟,对RAA为400.6mmol/L*分钟。三个月的处理后未观察到对肺功能的负作用,(FEV1改变对TI是-0.064 I(0.189),对RAA是-0.072(0.193),而Dlco分别是-1.62(3.29)和-1.094(3.08)(p=0.39;n.s.))。因此,在1型糖尿病患者的基础/膳食给药法中,经吸入的TI是经SC施用的RAA的合适的备选方案,所述备选方案提供与RAA相似的整体血糖控制(被表达为与基线HbAlc比较的改变),同时餐后偏移显著更小。
除非另有说明,用于说明书和权利要求书中的表达成分数量、如分子量的性质、反应条件的所有数字等应理解为在所有情况下由术语“约”修饰。因此,除非指出反例,以下说明书和附加的权利要求书中公开的数量参数是近似值,其可根据本发明想要获得的所需性质而变化。至少,并不企图限制将等同原则应用于权利要求书的范围,每个数量参数至少应按照经报导的有效数字的位数并通过应用常规约数技术解释。不反对公开本发明广大范围的数量范围和参数为约数,而特定实施例中公开的数量值则是尽可能精确地报导的。然而,任何数量值固有地包含误差,这是从它们各自检测测量中发现的标准差必然地产生的。
除非在本文另有说明或同上下文明显抵触,描述本发明的上下文中(特别是在以下的权利要求书上下文中)使用的术语“一个”(″a″,″an″)和“这个”(″the″)和类似的指代被解释为包括单数和复数。对本文数值范围的叙述仅意图用作为引用落入该范围的每个单独的值的速记方法(shorthand method)。除非本文另有说明,每个单独的值都被并入说明书,就像其被单独地并入本文一样。除非在本文另有说明或与上下文明显抵触,本文所述的所有方法可以以任何合适的顺序进行。本文所提供的任何和所有实例或举例文字(例如“例如”)的使用仅意欲用来更好地阐述本发明,而非对本发明所要求保护的范围设定限制。说明书中没有提及的文字应被解释为指代实施本发明必需的任何不要求保护的元素。
本文公开的备选元素或实施方案的分组不应解释为限制。各组成员可被单独提到或要求保护,或与本文发现的组的其它成员或其它元素任意组合。应当理解,由于便利和/或专利的原因,一组的一个或多个成员可以被包括进一组中或从该组删除。当任何这类包括或删除发生时,本申请文件被认为含有经改写的组,以满足对附加的权利要求书中所用的所有马库什组的书面描述。
本文描述了根据本发明的某些实施方案,包括本发明的发明人已知的实现本发明的最佳模式。当然,本领域常规技术人员阅读上述描述后会明白这些实施方案的变更。本发明人预期熟练的技术人员能适当地采用这类变更,且本发明者意欲使得本发明以与本文特定描述不同的方式应用。因此,至少可适用的法律允许,本发明包括附加的权利要求书中所述的主体内容的所有修饰和等价物。另外,除非本文另有说明或与上下文明显抵触,在其所有可能变化中,上述元件的任何组合由本发明所包括。
另外,在本申请文件中,引用了大量专利和印刷出版物作为参考文献。上述各参考文献和印刷出版物通过引用其整体并入本文。
最后,应理解本文公开的本发明的实施方案仅用于阐述本发明的原则。其它可使用的修饰也在本发明的范围内。因此,通过示例而非限制的方式,可根据本文的教导利用本发明的备选形式。因此,本发明并非被限制为如精确地所示和所述的。
Claims (14)
1.胰岛素组合物在制造用于治疗患有胰岛素相关疾病患者的药物中的用途,其中所述组合物适用于肺施用,并与长效基础胰岛素一起使用用于在患有胰岛素相关疾病的患者中降低餐后葡萄糖偏移,其中临床相关的晚期餐后低血糖的发病率被降低。
2.如权利要求1所述的用途,其中所述胰岛素组合物在接近于用餐开始时施用。
3.如权利要求1所述的用途,其中所述胰岛素组合物包含哌嗪二酮和人胰岛素之间的复合物。
4.如权利要求3所述的用途,其中所述哌嗪二酮为延胡索酰哌嗪二酮。
5.如权利要求4所述的用途,其中所述胰岛素作为干粉通过吸入施用。
6.如权利要求2所述的用途,其中所述胰岛素组合物从用餐开始前约10分钟到用餐开始后约30分钟施用。
7.如权利要求1所述的用途,其中所述胰岛素相关疾病为糖尿病。
8.如权利要求7所述的用途,其中所述胰岛素相关疾病为2型糖尿病。
9.如权利要求7所述的用途,其中所述胰岛素相关疾病为1型糖尿病。
10.如权利要求1所述的用途,其中所述餐后葡萄糖偏移比提供基本上相似的胰岛素接触的皮下施用的胰岛素剂量所产生的餐后葡萄糖偏移要小,且其中平均葡萄糖偏移比皮下施用小至少约25%。
11.如权利要求1所述的用途,其中所述餐后葡萄糖偏移相对于由胰岛素单独的适当皮下给药治疗所产生的餐后葡萄糖偏移被降低。
12.如权利要求1所述的用途,其中与用胰岛素单独的适当皮下给药治疗相比,所述临床相关晚期餐后低血糖的发作频率被降低。
13.胰岛素组合物在制造用于治疗患有胰岛素相关疾病患者的药物中的用途,其中所述组合物适用于肺施用,并与长效基础胰岛素一起使用,用于在患有胰岛素相关疾病的患者中降低餐后葡萄糖偏移,其中患者的总胰岛素接触(INS-AUC0-y,3≤y≤6)实质上不超过由适当的胰岛素皮下给药所产生的接触,并且其中餐后葡萄糖偏移被降低。
14.如权利要求13所述的用途,其中晚期餐后低血糖的风险未提高。
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US11/329,686 US9006175B2 (en) | 1999-06-29 | 2006-01-10 | Potentiation of glucose elimination |
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PCT/US2006/012366 WO2006105501A2 (en) | 2005-03-31 | 2006-03-31 | Control of blood glucose in diabetes treatment using pulmonarily administered insulin in combination with basal insulin |
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WO2021143833A1 (zh) * | 2020-01-15 | 2021-07-22 | 西北大学 | 二酮哌嗪二聚体高产冠突散囊菌菌株及从其中分离纯化二酮哌嗪二聚体的方法 |
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