CN1152867A - 用于胰岛素肺部给药的方法和组合物 - Google Patents

用于胰岛素肺部给药的方法和组合物 Download PDF

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CN1152867A
CN1152867A CN95191910A CN95191910A CN1152867A CN 1152867 A CN1152867 A CN 1152867A CN 95191910 A CN95191910 A CN 95191910A CN 95191910 A CN95191910 A CN 95191910A CN 1152867 A CN1152867 A CN 1152867A
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约翰·S·帕顿
琳达·C·福斯特
罗伯特·M·普莱兹
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Abstract

通过胰岛素的干粉烟雾剂的吸入进行哺乳动物宿主的胰岛素系统释放。发现胰岛素干粉能够经肺的肺泡区域快速吸收。

Description

用于胰岛素肺部给药的方法和组合物
本申请是1994年3月7日申请的申请序号08/207,472的部分续申请，全部公开在此作为参考。
本发明涉及用于糖尿病人的胰岛素呼吸(道)释放的方法和组合物。更具体的说，本发明涉及通过肺进行迅速机体吸收的干粉胰岛素的肺部释放。
胰岛素是一个50个氨基酸的多肽激素，分子量大约为6000，在正常个体(非糖尿病的)胰岛的β-细胞内生成。胰岛素是调节糖代谢，降低血糖水平所必需，系统性缺乏将导致糖尿病。糖尿病人的存活依赖于长期频繁地施用胰岛素来维持可接受的血糖水平。
胰岛素最常用的给药方法是皮下注射，一般注入腹部或大腿上部。为了维持可接受的血糖水平，通常需要每天注射胰岛素至少一次或者两次，并在必要时补充注射速效胰岛素。当糖尿病人使用家用诊断器密切监测血糖水平时，将需要更为频繁的注射来进行治疗。具体的讲，本发明是关于迅速起效胰岛素的施用方法，该方法可使血清胰岛素在一小时之内达峰，葡萄糖在90分钟内达到谷底。
通过注射施用胰岛素在许多方面不理想。首先，许多病人发现，为满足维持正常血糖水平的需要而频繁地给自己注射既困难又麻烦。这种不情愿可能会导致不遵医嘱，这在一些非常严重的病例中会危及生命。此外，皮下注射胰岛素的机体吸收也相对缓慢，即使使用速效胰岛素的制剂时，也经常需要45至90分钟。因此，提供可以避免自我注射同时胰岛素又可被机体迅速利用的其它胰岛素制剂和给药途径，长期以来一直是人们的一个目标。
现已提出了许多这种替代性的胰岛素给药途径，包括鼻内、直肠内以及阴道内的给药方法。
当这些技术避免了皮下注射的不适以及不协调的同时，它们也都遭受了自身的限制。直肠内及阴道内给药不方便，不舒适，而且后者也不能用于所有的糖尿病人。鼻内释放将方便一些，可能也比注射更容易接受，但由于鼻粘膜有一层厚的阻止大分子通过的上皮层，需要使用有潜在毒性的“增透剂”来影响胰岛素透过鼻粘膜。本发明的特殊兴趣在于肺部胰岛素给药，在此，病人吸入一种胰岛素制剂并通过肺泡区的薄的上皮细胞层进行机体吸收。看起来这种肺部胰岛素给药的机体吸收比皮下注射更为迅速，同时还避免了用针。但是，肺部胰岛素给药仍需得到广泛的接受。以前，肺部给药经常是通过液体胰岛素制剂的喷雾法来完成，这需要使用笨重的液体喷雾器。此外，由这种喷雾器形成的气雾剂只有非常低的胰岛素浓度，需要吸入相当多的次数来达到足够的剂量。胰岛素浓度的受限归因于胰岛素在合适的水溶液中的溶解度不好。在一些情况下，需要80次或以上的呼吸来达到足够的剂量，致使一次用药的时间为10至20分钟，甚至更长。
提供用于胰岛素肺部给药的改良的方法和组合物是诱人的。如果这种方法和组合物足够方便，能够允许甚至在户外时也可以自我给药，并且可以通过相对较少的呼吸次数(最好少于10次)传送需要的总剂量这将格外诱人。这种方法和组合物还应提供机体对胰岛素的迅速吸收，最好能在45分钟或更少的时间内达到血清峰值，并在1小时或更少的时间内达到血糖谷值。这种迅速起效的制剂将较好地适用于攻击性治疗记录，从而减少或消除速效或长效胰岛素的注射。本发明的组合物还应该是稳定的，最好由浓缩的干粉制剂组成。
许多文献中都描述了雾化的胰岛水溶液的呼吸给药，首先是Gansslen(1925)，Klin.Wochenschr.4：71，还有Laube等(1993)，JAMA 269：2106-21-9；Elliott(1987)，Aust.Paediatr.J.23：293-293；Wigley等(1971)，Diabetes 20：552-556.Corthorpe等(1992)，Pharm Res.9：764-768；Govinda(1959)，Indian J.Physiol.Pharmacol.3：161-167；Hastings等(1992)，J Appl.Physiol.73：1310-1316；Liu等(1993)，JAMA 269：2106-2109；Nagano等(1985)，Jikeikai Med.J.32：503-506；Sakr(1992)Int.J.Phar.86：1-7；和Yoshida等(1987)，Clin.Res.35：160-166。美国专利5,254,330描述了在大颗粒载体赋形剂上的干粉药物如胰岛素的肺部给药。Lee和Sciara(1976)在J.Pharm.Sci.65：567-572中描述了用于传送悬浮于抛射剂上的结晶胰岛素的计量剂量吸入器(MDI)。美国专利5230094描述了一个将胰岛素传送到一个空隙中来调节吸气流速的MDI。重组胰岛素的支气管给药由Schluter等(摘要，1984年，Diabetes 33：75A)和Kohler等(1987年，Atemw.Lungenkrkh13：230-232)作了简要描述。美国专利5011678和Nagai当(1984)J.Contr.Rel.1：15-22)描述了在增强剂的存在下，包括胰岛素在内的多种多肽的鼻内及呼吸给药。美国专利5204108；4294829；和4153689；PCT申请WO93/02712，WO 91/02545，WO 90/09780和WO 88/04556；英国专利1527605；Ryden和Edman(1992)Int.J.Pharm.83：1-10；以及Bjork和Edman(1988，Int.J.Pharm.47：233-238)描述了含有增强剂并且/或者包含于控释制剂中的胰岛素的鼻内给药，无定形胰岛素的制备和稳定性由Rigsbee和Pikal(American Association of Pharmaceutical Sciences(AAPS)，1993年12月14-18日，Lake Buena Vista，佛罗里达)作了描述。在载体上喷雾干燥多肽、多核苷酸以及其他不稳定药物以形成无定形结构来稳定药物的方法在欧洲专利申请520748中作了描述。
根据本发明，对一个哺乳动物，具体的讲是一个患有糖尿病的病人，胰岛素的烟雾化以及机体给药的方法和组合物在避免了皮下注射的同时，还可以迅速吸收进入血液循环。具体的讲，本发明的方法基于以干粉的形式进行胰岛素的肺部给药。令人惊奇的是，已经发现吸入的干胰岛素粉末沉积于肺泡区，并被肺泡的上皮细胞迅速吸收进入血液循环。因此，胰岛素粉末的肺部给药可以成为皮下注射给药的一个有效的替代方法。
本发明的第一个方面，所用的胰岛素是干的粉末，通常但并不必须是一个大体无定形状态，将其分散于空气或其它生理上可接受的气流中以形成烟雾剂。将该烟雾俘获于一个有喷嘴的容器中，病人可以通过喷嘴吸入烟雾。随需要，干粉胰岛素可与药物上可接受的干粉载体组合，这在下面有更详细的描述。胰岛素的干粉优选地由直径低于10μm颗粒组成，更为优选的低于7.5μm，最为优选的低于5μm，通常在0.1μm至5μm的范围之内。令人惊奇的是，本发明的干粉胰岛素组合物在肺内吸收时，无需使用象那些通过鼻粘膜及上呼吸道进行吸收时所需的增透剂。
第二个方面，本发明提供的胰岛素组合物，主要由平颗粒尺寸低于10μm的干粉胰岛素组成，其中可能组合有干粉药物载体。胰岛素组合物中最好不含增透剂并且所包含的颗粒直径优选低于10μm，更为优选低于7.5μm，最为优选低于5μm，通常在0.1至5μm范围之间。通常，在干粉胰岛素中含有重量比为5％至95％的胰岛素，更为常用的是从15％至80％附着在一个合适的载体上，通常是糖、有机盐、氨基酸、多肽或蛋白质，此后会有更详细的描述。
本发明的第三个方面，胰岛素干粉的制备是通过将胰岛素溶于一个缓冲水溶液中，然后将该溶液喷雾干燥制得颗粒尺寸低于10μm至5μm之间大体无定形颗粒，随需要，将药物载体也溶于缓冲液中形成一个均相溶液，在将此溶液喷雾干燥时制得包含有胰岛素、载体、缓冲剂以及溶液中存在的所有其它成份的独立颗粒。优选载体是糖，有机盐，氨基酸，多肽或蛋白质，这些载体在喷雾干燥中可以制得大体无定形的结构。无定形载体既可以是玻璃状的，也可以是橡胶状的，可以增加胰岛素在贮存过程中的稳定性。在利的是，这种稳定了的制剂还可以在吸入到肺泡区后有效地将胰岛素释放进入血液。
通过参阅剩余部分的详细说明及插图，对于本发明的性质及优点的深入了解将变得明显。
图1是一个根据本发明的方法雾化胰岛素制剂的系统的图解说明。
图2是病人从图1的系统中吸入雾化的胰岛素的图解说明。
图3A和3B是用曲线来说明在雾化三种不同的干粉制剂后，大鼠对重组人胰岛的吸收以及引起的血糖反应。每一个点代表三只不同大鼠的平均值。在时间零点开启干粉烟雾发生器。对87％胰岛素/柠檬酸盐，20％胰岛素-甘露糖醇/柠檬酸盐，20％胰岛素-棉子糖/柠檬酸盐粉末的烟雾化作用分别在5分钟，14分钟和20分钟时完成。动物禁食过夜。
4A和4B是用曲线说明平均血清胰岛素和葡萄糖的时间-浓度曲线，对Cynomolgus猴的烟雾剂及皮下给药分别进行了比较。烟雾剂组中报道的是三只猴子平均值，皮下组中报道的是四只猴子的平均值。
图5A是用曲线说明人皮下注射(○)和吸入三次喷射(●)的平均胰岛素浓度随时间的变化。
图5B显示与5A中胰岛素浓度相对应的平均葡萄糖浓度。
图6A是人皮下注射(○)和吸入三次喷雾给药(●)所引起的血渍胰岛素浓度对时间变化的曲线说明。
图6B是对应于6A中的胰岛素水平的血清葡葡糖水平的曲线说明.
图7B和7A给出了皮下给药(○)和喷雾给药(●)的血清胰岛素(7A)和葡萄糖水平(7B)的个体间差异比较。
图8A，8B和8C显示了人胰岛素的反相HPLC(rpHPLC)。图8A是一个胰岛素标准品的色谱分析，在25℃下溶于10mMHCl中，显示人胰岛素在23.87分钟洗脱，脱氨基胰岛素在30.41分钟洗脱。图8B显示一个相似的人胰鸟素标准品的色谱图。图8C显示根据本发明制备本发明制备的喷雾干燥的重组胰岛素制剂的相似的色谱图。
图9显示了一个胰岛素制剂在喷雾干燥前后的紫外光谱。在可见光谱内没有观察到光的散射，表明胰岛素在喷雾干燥过程中没有发生聚集。
根据本发明，胰岛素是做为干粉出现。“干粉”意味着粉末中的水分含量低于重量比的大约10％，通常低于重量比的大约5％，优选低于重量比的大约3％。“粉末”意味着胰岛素包含具有选择尺寸的自由流动的颗粒，以允许穿透到肺泡中，优选直径小于10μm，更为优选低于7.5μm，最优选的低于5μm，通常是直径在0.1μm到5μm之间。
本发明至少是部分地基于干粉胰岛素可通过宿主的肺方便迅速地吸收这一意外的观察结果。很奇怪干粉胰岛素能够到达肺泡区，因为已经知道诸如胰岛颗粒等水溶性药都是吸湿的。参见Byron等编辑，Respiratory Drug Delivery，CRC Press，Baca Raton，(1990)，150页。因此，曾经预测，为颗粒经过肺的导气管时(其中37℃时的相对温度超过99％)，各颗粒将有吸水并长大形成一个有效颗粒大小超过本发明中10μm的上限的趋向。如果一个胰岛素颗粒的实在部分大于目标中的尺寸范围，预期这些颗粒将会沉积在肺的中央导气管内而不是肺泡区，从而限制了(药物)的释放及随后的机体吸收。此外，肺上皮细胞上的流动层非常薄，通常只有给药胰岛素粉末直经的几分之一。因此，在本发明之前很难预料于的胰岛素颗粒在沉积于肺泡区时是否会溶解。另人惊奇的是，干的胰岛素粉末显然既可以进入肺泡区内又可以在其沉积于肺泡区后立刻溶解。溶解了的胰岛素就可以透过上皮细胞进入循环。
现在确信，胰岛素的有效吸收是由于它在肺泡的超薄(＜0.1μm)流动层中的迅速溶解。本发明中颗粒的平均尺寸比肺流动层大10到50倍，而颗粒的溶解及机体对胰岛素的吸收却非常迅速，使人很感意外。的确，正如在此后的实验部分中所显示的，本发明的干胰岛素制剂可以提供比目前最常用的皮下注射给药方法更为迅速的血清胰岛素峰值以及葡萄糖下降。然而，实施在此描述的本发明无需对于精确机制的了解。
根据本发明，优选的组合物中将基本不含增透剂。“增透剂”是表面活性化合物，它可以促进胰岛素(或其它药物)穿透粘膜，建议在鼻内、直肠内、阴道内给药的制剂中使用。增透剂的范例包括：胆汁盐，如牛磺胆酸盐、甘胆酸盐和脱氧胆酸盐；褐霉酸，如牛磺脱氢褐霉素以及生物可容性洗涤剂，如吐温，Laureth-9以及类似物质。然而，在用于肺部的制剂中使用增透剂通常是不合适的，因为这些表面活性化合物会对肺内的上皮血液屏障产生不利影响。令人惊奇的是，已经发现本发明的干粉胰岛素组合物无需使用增透剂在肺内也很容易吸收。
适于本发明使用的胰岛素干粉包括无定形胰岛素、结晶胰岛素以及无定形和结晶胰岛素二者的混合物。干粉胰岛素优选通过一定条件下的喷雾干燥来制备，生成大体无定形粉末，颗粒的尺寸在上述范围之内。除此之外，无定形胰岛素的制备可以通过将合适的胰岛素溶液在一定条件下冷冻干燥、真空干燥、蒸发干燥来形成无定形结构。这样制得的无定形胰岛素然后可以经过研磨或碾碎制得在适宜尺寸范围之内的颗粒。结晶干粉胰岛素可以通过研磨或喷射碾碎大块的结晶胰岛素形成。形成含有颗粒在适宜尺寸范围之内的胰岛素粉末的优选方法是喷雾干燥，首先将纯净的大块胰岛素(通常是结晶的形式)溶于生量上可接受的缓冲水溶液，一般来说是PH值在2到9范围之间的柠檬酸盐缓冲液。溶解的胰岛素浓度从重量的0.01％到重量1％，通常中从0.1％到0.2％。该溶液然后可以用传统喷雾干燥设备(来自于Buchi，Niro等供应商)喷雾干燥，生成大体无定形的颗粒产品。
干胰素粉应主要由在要求尺寸范围之内的胰岛素颗粒组成，基本不含其它任何生物活性物质，药物载体等。这种“纯净”制剂可能包括一些微量成份，如防腐剂，它存在的量很少，一般低于重量的10％，通常低于重量的5％。使用这种纯净制剂，即使是大剂量所需的吸入次收也可以大大减少，通常仅需一次呼吸。
本发明的胰岛素粉末可任意地与适于呼吸和肺部给药的药物载体或赋形剂组合。当想要降低用于病人的粉末中的胰岛素浓度时，这些载体可能仅起填充剂的作用，但它同样也可以起到增加胰岛素组合物的稳定性和改善粉末在粉末分散器中的分散性，从而提供更为有效、更易重现的胰岛素释放；以及改善胰岛素的工艺性能如流动性和稠度，以易于生产和粉末填充的作用。
适宜的载体材料可以是无定形粉末，结晶粉末，或者无定形与结晶粉末的组合。适宜的材料包括(a)糖：如果糖、半乳糖、葡萄糖、D-甘露糖、山梨糖等的单糖；像乳糖、海藻糖、纤维素二糖等二糖；环糊精：如2-羟丙基-β环糊精；像棉子糖、麦芽糖糊精、葡聚糖等多糖；(b)氨基酸：如甘氨酸、精氨酸、天冬氨酸、甘氨酸、半胱氨酸、赖氨酸等。(c)由有机酸及有机碱制备的有机盐：如柠檬酸钠、抗坏血酸钠、葡萄糖酸镁、葡萄糖酸钠，氨基丁三醇盐酸盐等。(d)多肽和蛋白：如天冬酰苯氨酸甲酯人血清白蛋白、明胶及此类。(e)alditols，如甘露糖醇、木糖醇等。优选的载体组群包括乳糖、海藻糖、棉子糖、麦芽糖糊精、甘氨酸、柠檬酸钠、氨基丁三醇盐酸盐、人血清白蛋白及甘露糖醇。
这些载体材料可以与胰岛素在喷雾干燥前组合，也就是将载体材料加入到准备进行喷雾干燥的缓冲溶液中。在这种方法中，载体材料将作为胰岛素颗粒的一部分与其同时形成。一般地，当载体材料经喷雾干燥与胰岛素一起形成时，在各颗粒中胰岛素的含量将占重量百分比的5％到95％，优选从20％到80％。颗粒的其余部分主要是载体材料(一般占重量比的5％到95％，通常是20％到80％)，但也含缓冲剂，不可能包括上面所述的其他成份。已经发现，分散到肺泡区的颗粒(也就是那些小于10μm，在要求尺寸范围内的颗粒)中含有载体材料并不显著干扰机体对胰岛素的吸收。
此外，也可以将载体单独制成干粉形式并经混合与胰岛素组合在一起。单独制造的粉末载体通常是结晶(以防止吸水)，但在一些情况下也可以是无定形的或是结晶与无定形体的混合物。需对载体颗粒的大小进行选择以改善胰岛素粉的流动性，一般在20μm到100μm的范围内。在此尺寸范围内的载体颗粒通常并不进入肺泡区内，经常在吸入之前在给药装置内就与胰岛素相分离。因此，进入到肺泡区的颗粒主要包括胰岛素和缓冲剂。优选的载体材料是尺寸在上述范围内的甘露糖醇晶体。
本发明的干胰岛素粉也可以与其它活性物质组合。例如，在干胰岛素粉末中加入少量糊精或活性糊精类似物有利于改善对糖尿病的治疗。糊精是由正常(非糖尿病的)个体的胰腺β细胞与胰岛素同时分泌的一种激素。人们确信糊精在体内调节胰岛素的活性，而且有人提出将糊精与胰岛素同时给药可以加强对血糖的控制。将干粉糊精与本发明的组合物中的胰岛素组合，可以提供达到这种同时给药的非常方便的产品。糊精可以按重量比从0.1％到10％与胰岛素混合(基于药物中的胰岛素的总重量)，优选从重量比的0.5％到2.5％。糊精可以从供应商处买到(例如AniylinCorporation，San Diego，California)，并很容易调配到本发明的组合物中。例如，糊精可以与胰岛素、载体一起溶于水溶液或其它合适的溶液中，将该溶液喷雾干燥制得粉末产品。
本发明的干粉胰岛素组合物优选用常用的方法将其分散在流动的空气中或其它生理上可接受的气流中来烟雾化。在共同未决的申请号为07/910048，公开号为WO 93/00951的申请中描述了一个适用于这种分散的系统，其所有公开内容在此以参考。参阅图1，将干的，自由流动的胰岛素粉末加入高速的空气或气体流中，得到的分散物人存储室10(holding Chamber)中。存储室10设有喷嘴12，喷嘴位于空气粉末分散物入口的对面。室10的体积要足够大的俘获合适的剂量，随需要还可以设置挡板和/或单向阀门的防止污染。在室10中俘获了一次剂量的胰岛素粉末后，病人P(图2)从喷嘴12吸气，把雾化的分散物吸入肺中。当病人P吸气时，补充空气从切向空气入口14进入，进入的空气按通常的旋涡方式流动，把雾化的胰岛素从小室中带入病人的肺中。室的体积及雾化剂量的大小要使病人可以完全吸入伴有足够空气的全部胰岛素以保证胰岛素到达肺泡区的深处。
这种雾化的胰岛素粉末在替代皮下注射速效胰岛素来治疗糖尿病或相关的胰岛素缺乏症时特别有用。令人惊奇的是，已经发现由干粉胰岛素的喷雾给药引起的胰岛素吸收和血糖反应比皮下注射所引起的要明显快多。因此，本发明的方法和组合物在用于病人需频繁地监测血糖水平并在需要时施用胰岛素来维持目的血清浓度的治疗方案中特别有价值，也可以用以需要进行机体胰岛素给药的任何时候。病人可以像刚才所述那样通过吸入适量的胰岛素来达到需要的剂量。通过刚才所述的方法进行机体胰岛素释放的效率一般在大约15％到30％，每一次的剂量(基于每一次的吸入)一般在大给0.5mg到10mg。通常，在一次呼吸给药中适宜的胰岛素总剂量在大约0.5mg到15mg。因此，病人可以通过一至四次的呼吸来达到需要的剂量。
提供下述实例是为了进行说明而不是进行限定。
实验部分
材料和方法
材料
结晶人胰岛素锌，26.3unit/mg(Lilly Lot#784KK2，Eli Lilly and Company，Indianapolis，IN)反相HPLC检测，纯度大于99％。USP甘露糖醇(RoquetteCorporation，Gurnee，IL)。棉子糖(Pfanstiehl Laboratories，Waukegan，IL)。二水合柠檬酸钠，USP，ACS和一水合柠檬酸，USP(J.T.Baker，Phillipsburg，NJ)。
粉末的制备
胰岛素粉末的制备是将大块结晶胰岛素溶于含有赋形剂(甘露糖醇或棉子糖或不加)的柠檬酸钠缓冲溶液中，得到的最终固体浓度为7.5mg/ml，PH值为6.7±0.3。喷雾干燥器的操作在入口处的温度在110℃到120℃之间，供给液体速度为5ml/min，形成出口处的温度在70℃到80℃之间。然后将溶液滤过0.22μm的滤膜并在Buchi喷雾干燥器内喷雾干燥，形成良好的白色无定形粉末。生成的粉末在干燥环境中(相对＜温度10％)保存于盖紧盖子的容器内。
粉末分析
粉末的颗粒尺寸分布的测量是将粉末在Sedisperse A-11(Micromeritics，Norcross，GA)内分散后用液体离心沉积法在Horiba CAPA-700颗粒尺寸分析仪上进行。粉末的水分含量的测定是通过Karl Fischer法在三菱CA-06湿度计上进行。
在粉末制作过程前后的胰岛素完整性的测量是以人胰岛素标准品为参照，将称量过的部分粉末重新溶于蒸馏水中并将重新溶解的溶液与加入喷雾干燥器内的原始溶液进行比较。通过反相HPLC中的保留时间和峰面积来测定胰岛素分子是否在此过程中发生了化学修饰或降解。运用紫外吸收来测定胰岛素的浓度(278μm)以及是否存在不溶性聚合物(400μm)。此外还要测量开始时以及新配制的溶液的PH值。通过偏光显微镜来确证胰岛素粉末的无定性特性。大鼠的烟雾剂接触
大鼠实验在喷雾剂接触室内进行。雌性大鼠(280-300gm)禁食过夜。将动物(每次实验21至24只)放置于有机玻璃管内，然后封固于有48个气门、只露鼻子的(mose-only)烟雾剂接触室内(In-Tox产品，Albuquerque，NM)。到达呼吸区域的空气流量保持在7.2-9.8L/min，并通过真空将其移走，因此用magnahelic计测量时，在室内会有轻微的负压(约1.5cm H2O)。根据充入室内的粉末的多少，烟雾剂的接触时间在5到20分钟之间。用手将粉末加入到一个小的文丘里氏喷嘴中来分散粉末颗粒，形成良好的烟雾云。文氏喷嘴的操作压力超过15psig，空气流量设置在7.21/min到9.81/min。文氏喷嘴装在清晰的有机玻璃分散室的底部，通过它将烟雾剂加入到只露鼻子的接触室中。大鼠烟雾剂室的校准
呼吸区内的粉末浓度测定通过使用In-Tox过滤器在21/min真空流量下收集呼吸区内大部分的计时过滤的样品，小室在有动物及没有动物时均进行了校准。粉末的质量用重量分析测定。呼吸区内粉末的颗粒大小通过设置在呼吸孔的阶式碰撞取样器(In Tox产品)在21/min的流量下测定。每一级的粉末质量用重量分析测定。
每次实验使用21至24只大鼠，烟雾剂接触时间持续5到20分钟。在时间零点和烟雾剂接触结束后大约7、15、30、60、90、120、180和240分钟各杀死三只大鼠。将大鼠麻醉，打开其腹部，从腹主动脉抽取大量血液样品。然后用颈部脱位法处死动物。
血液在室温下凝集30分钟，然后用血清分离试管在3500rmp下离心20分钟。血清可以立即进行分析，也可以在-80℃下冷冻直至分析。在烟雾剂给药结束后尽快(0-7min)处死三只大鼠，抽取其血液并半它们的肺用5ml的灌洗6次。最终混合的灌洗样品中的胰岛素含量在计算生物利用度时作为大鼠的烟雾剂的剂量。灵长类接触系统
使用幼小的野生雄性Cynomolgus猴种的fascicularis弥猴2-5kg(Charles RiverPrimates，Inc.)进行灵长类烟雾剂研究(每组3-4只动物)。对动物皮下注射胰岛素(Eli Lilly，Indianapolis，Indiana)或让其接触胰岛素粉末烟雾剂。每只动物均关在只露头部的接触单元中，以适当的流速(71/min)供给新鲜的实验气体的供给动物最少的氧气需要量。将动物固定在椅样的器具上使其处于直立的坐姿。罩子是清晰的，可以使动物完整地看到它们的周围环境。在(动物)腿上插上留置导管，从而可以在任意时间抽取血液样品。在整个过程中猴子完全清醒并表现得安静。灵长类的血液处理与大鼠相同(见上)。
灵长类类雾剂接触系统包括呼吸监测器，可以对每只猴子吸入的空气量进行定量。这个数值与测得的呼吸空气中的胰岛素浓度一起可以计算出每只动物确切吸入了多少胰岛素。
人体实验
对24个正常人分别用皮下注射和吸入雾化的干粉胰岛素进行胰岛素给药。每次皮下注射包括10.4单位的Humulin R，100u/ml(Eli Lilly，Indianapolis，Indiana)。干胰岛素粉是用上述的喷雾干燥的方法制备的无定形粉末，含有20％重量比的甘露糖醇赋形剂。将胰岛素干粉药物(5mg)在高速空气流中进行分散，形成良好的烟雾剂并将其俘获于小室中。每个个体对每一个烟雾剂团或每次“喷射”通过缓慢地深呼吸吸入烟雾剂粉末。粉末通过三次喷射给药(剂量为31.9单位)。如下所述，血清胰岛素及葡萄糖水平随时间进行测定。血清分析
大鼠、灵长类及人的血清胰岛素水平的测定应用适于人胰岛素的Coat-A-Count放射免疫分析仪(Diagnositc Products Corporation，Los Angeles，CA)。对每一组样品均做了标准曲线。分析的灵敏度大约为43pg/ml。评估内变化率(within assayvariability)＜5％(CV％)。葡萄糖分析由加利福尼亚兽医诊断公司(WestSacramento，CA)使用适于Boehringer Mannheim/Hitachi 747分析仪的葡萄糖/HK试剂系统包进行。评估内变化率(％CV)＜3％。
在大鼠实验中，烟雾剂的相对生物利用度的计算是通过将调整剂量的免疫活性胰岛素(IRI)浓度-时间曲线的曲线下面积(AUC)与由皮下注射所得到的进行比较。在大鼠中，用全部灌洗胰岛素的质量作为烟雾剂的剂量。一些胰岛素在肺部灌洗之前即被吸收，因此用这种方法估计的剂量可能稍微低估了沉积的总剂量。对这种推测的损失来进行校正。
在猴子实验中，除了用吸入的胰岛素的量代替肺灌洗胰岛素作为烟雾剂的剂量外，相对生物利用度的计算与上面大鼠的相似。在大鼠中，估算的剂量中只包括沉积于肺的物质，而不包括沉积于鼻腔和咽喉部位的胰岛素。在猴子中，估算的剂量中包括所有进入动物体内的胰岛素。大鼠胰岛素吸收结果
所有用于动物研究的胰岛素粉末的颗粒尺寸(集体平均直径)在1-3μ范围内，水份含量＜3％。用反相HPLC测得粉末中的胰岛素纯度＞97％。在图8C中显示了20％胰岛素制剂的代表性色谱图。粉末在重新溶于纯净水后得到澄清溶液，在400nm的紫外吸收小于0.01，pH值为6.7±0.3。在图9中显示了20％胰岛素制剂的代表性紫外图谱。
在In-Tox 48气门的接触室中，应用下面三种胰岛素粉末制剂作为烟雾剂进行了大鼠实验。
1. 87.9％胰岛素；11.5％柠檬酸钠；0.6％柠檬酸。
2. 20％胰岛素；66％甘露糖醇；12％柠檬酸钠，0.6％柠檬酸。
3. 20％胰岛素；66％棉子糖；12.4％柠檬酸钠，0.6％柠檬酸。
表1列出了三次不同大鼠接触研究的主要测量结果，包括在小室操作条件下呼吸区域内烟雾剂的特性。由于在填加粉末过程中粉末的碰撞以及不完全分散引起的在墙壁上的损失，只有部分加入文氏喷嘴的粉末到达了大鼠的呼吸区域(34-67％)。然而在呼吸区域的烟雾剂颗粒的尺寸对于肺部沉积比较理想(1.3-1.9μm)，并且比原始制剂的颗粒尺寸(2.0-2.8μm)稍微小了些，这是由于在动物接触室内选择性丢失了大的颗粒。
       表1.大鼠烟雾剂接触测量结果
   88％胰岛素   20％胰岛素甘露糖醇  20％胰岛素棉子糖
    室内流速     7.2L/min     9.6L/min     9.8L/min
    粉末集体平均直径(MMD)     2.2μm     2.8μm     2.0μm
    加入室内的粉末     70mgs     255mgs     260mgs
    粉末加入时间     5min     14min     20min
    呼吸区的粉末     40mgs     171mgs     88mgs
    呼吸区的胰岛素     35mgs     34mgs     18mgs
    呼吸区粉末总量(％)     57％     67％     34％
    集体平均空气动力学直径(MAD)     1.1mg/L     1.3mg/L     0.45mg/L
    呼吸区颗粒大小     1.4μm     1.9μm     1.3μm
    灌洗回收胰岛素量     30.7±5.2μg     12.7±6.9μg     31.6±12.9μg
    血清胰岛素AUC(ng min/ml)     104     201     150
表2显示了三次烟雾剂以及一次皮下研究的大鼠血清胰岛素及葡萄糖结果。图3A和3B显示了三种经烟雾剂给药的制剂的血清免疫活性胰岛素(IRI)时-量曲线以及血清葡萄糖时-量曲线。
表3给出了不同研究的胰岛素tmax和葡萄糖tmin以及与皮下注射相比较烟雾剂的相对生物利用度。
           表2.大鼠血清胰岛素和葡萄糖结果
       制剂    途径    时间(min)   血清胰岛素(pg/ml±1S.D)n＝3rats/timept   血清葡萄糖(pg/ml±1S.D)n＝3rats/timept
    80％胰岛素   烟雾剂     0     230±184    106±12
    (在5分钟   烟雾剂    12     1020±312    114±10
  完成烟雾剂接触)   烟雾剂    21     165±768    81±10
平均剂量＝31μg/大鼠   烟雾剂    36     876±764    66±7
  烟雾剂    66     684±416    62±15
  烟雾剂    96     568±128    65±10
  烟雾剂    126     568±260    73±11
  烟雾剂    186     712±140    93±5
 20％胰岛素-甘露糖醇   烟雾剂     0     476±56    165±18
    (在14分钟   烟雾剂    22     1476±428    117±15
  完成烟雾剂接触)   烟雾剂    35     2480±892    101±19
平均剂量＝13μg/大鼠   烟雾剂    57     1204±64     64±13
  烟雾剂    87     1084±396     63±17
  烟雾剂    117     664±180     105±38
  烟雾剂    147     1228±416     108±22
  烟雾剂    207     676±100     119±33
  20％胰岛素-棉子糖   烟雾剂     0     426±97     157±37
    (在20分钟   烟雾剂    27     2948±2816     139±46
  完成烟雾剂接触)   烟雾剂    42     1504±592     181±11
平均剂量＝32μg/大鼠   烟雾剂    57     1272±496     124±45
  烟雾剂    87     852±164     128±17
  烟雾剂    117     604±156     124±9
  烟雾剂    147     532±172     172±12
  烟雾剂    207     556±100     218±34
 20％胰岛素-甘露糖醇   皮下注射     0     360±140     107±5
    剂量＝30μg胰岛素/大鼠   皮下注射     15     14200±3160     53±2
  皮下注射     30     10160±720     24±5
  皮下注射     60     11000±1080     28±6
  皮下注射     90     2440±1160     25±7
  皮下注射     120     3520±840     49±3
  皮下注射     180     1280±800     4017
  皮下注射     240     400±260     77±34
     表3烟雾剂与皮下注射(SC)胰岛素在动物中的比较
  大鼠SC 大鼠88％胰岛素甘露糖醇烟雾剂 大鼠20％胰岛素甘露糖醇烟雾剂  大鼠20％胰岛素棉子糖烟雾剂   猴子SC  猴子20％胰岛素甘露糖烟雾剂
  胰岛素Max*   15min     16min     21min     17min   15min     30min
  葡萄糖min*   30min     31min     43min     37min   45min     45min
  葡萄糖下降   77％     42％     62％     21％   45％     73％
相对生物利用度   100％     10％**     44％**     14％**   100％     12％***
*T从烟雾剂接触结束计起
葡萄糖min＝在研究中观察到大于最大降低值的85％时的时间
**基于烟雾剂接触结束时从肺灌洗回收得到的胰岛素
***基于吸入的胰岛素，包括在鼻腔及咽喉内损失
所有三种制剂都对大鼠的机体循环提供了迅速吸收的胰岛素(图3A和3B)。20％胰岛素/甘露糖醇粉末的生物利用度及葡萄糖反应较高(表3)。不过没有进行许多重复实验，不能确定差别是否显著。灵长类结果
对4只猴子注射与人体实验相同的剂量(0.2u/kg，每只猴子约27μg)，得到皮下注射(SC)的数据与烟雾剂的结果进行比较(图4A和4B)。表4显示了猴子喷雾接触的数据，表5显示烟雾剂接触及皮下研究的平均血清胰岛素及葡萄糖(结果)。烟雾剂产生了很强的胰岛素及葡萄糖反应(高剂量)。图4显示了两次烟雾剂及一次皮下研究的平均血清胰岛素图形的比较。从这些图形的曲线下面积计算出烟雾剂胰岛素的相对生物利用度为12％。
    表4猴子烟雾剂接触数据
    动物(ID)  重力过滤质量(mg)   平均烟雾剂浓度(μg/L)   吸入体积(L) 吸入烟雾剂量计算算值(μg)  吸入胰岛素质量计算值(μg)   体重(kg)  胰岛素剂量计算值(μg/kg)     AUC(μgmin/ml)
  #1，23-46   1.07   178   8.96   1597     320   3.92   81.5     347
  #2，23-48   1.01   168   19.98   3363     673   3.81   176.6     1196
  #3，122-55   0.97   162   14.68   2373     475   4.1   115.7     739
  489±178
人体(实验)结果
下面的表5列出了呼吸给药与皮下注射的比较结果。呼吸烟雾剂给药的吸收(20分钟达峰)比皮下注射(60分钟达峰)快得多，引起的葡萄糖反应(60分钟达谷)也比皮下注射(90分钟达谷)快得多。胰岛素及葡萄糖反应在烟雾剂中的重现性与注射时至少同样的好。注射用的剂量根据体重做了仔细的调整，烟雾剂的剂量未调整。由葡萄糖反应得出的烟雾剂胰岛素的生物活性相对于注射为28-36％。由胰岛素曲线下面积得出的三次喷射给药组的烟雾剂胰岛素的生物利用度，相对于注射为22.8％。
表5人体实验的血清胰岛素和葡萄糖结果胰岛素个体编号#S      剂量/注       个体内的    血清胰岛素  最大值的  基于胰岛素曲线下面
            射或发泡       剂量*     增加μU/ml   时间     积的相对生物利用度1-24(SC注射)     10.4U         10.4U       5.8-20.9    60min         100.0％7-24(喷射)       76.0U         31.9U       6.1-28.5    20min          22.8％葡萄糖个体编号#S   平均血清葡萄糖  mg/dl下降量   最小值的   ％SC       基于胰岛素AUC
          的下降mg/dl                    时间               的相对生物利用度1-24(SC注射)   93.6-64.9        28.7        90min     100％          100％7-24(喷射)     91.8-67.6        24.2        60min     84.3％         27.4％*仪器效率＝42％
在图5A-5B中进一步显示了人体实验的结果。图5A显示皮下注射(○)及吸入(三次喷射，●)的平均血清胰岛素浓度随时间的变化。在图5B中的相似的方式显示了平均血清葡萄糖水平。在图6A和6B中分别显示了胰岛素的峰值与葡萄糖的谷值，在图7A和7B中分别显示了胰岛素与葡萄糖的个体间差异。
此外，在烟雾剂接触过程中，猴子的浅呼吸(潮式呼吸)不是用于肺部深处沉积的优选呼吸方式。如预期的那样，当使用最佳的呼吸方式，同时用嘴而不是用鼻子吸入烟雾剂团时，在人体实验中观察到了较高的生物利用度。
虽然前述的发明为达到使理解清楚的目的，以说明和实例的方式对某些细节做了描述，但那些可能实施的改变和修饰显然在附加的权利要求书的范围内。

Claims (25)

1.雾化胰岛素制剂的方法，所述方法包括：
提供干粉胰岛素；
将一定数量的所述干粉分散在气体流中形成烟雾剂；并且将烟雾剂俘获在设有供患者随后吸入的喷嘴的小室中。
2.如权利要求1所述的方法，其中的胰岛素基本不含增透剂。
3.如权利要求1所述的方法，其中的胰岛素附着于干粉载体上，重量浓度在5％至99％范围内。
4.如权利要求3所述的方法，其中的粉末载体包括糖、有机盐、氨基酸、多肽或蛋白质。
5.如权利要求1所述的方法，其中的胰岛素干粉包含平均尺寸小于10μm的颗粒。
6.如权利要求1所述的方法，其中的干粉包含含有胰岛素及载体两者的独立颗粒。
7.如权利要求6所述的方法，其中各个颗粒的胰岛素含量为从重量比的5％至99％。
8.胰岛素呼吸(道)释放的改进方法，其中的改进包括释放胰岛素干粉。
9.如权利要求8所述的改进方法，其中的胰岛素基本不含增透剂。
10.如权利要求8所述的改进方法，其中的胰岛素附着于干粉载体上，重量浓度在10％至99％范围内。
11.如权利要求10所述的改进方法，其中粉末载体包括糖、有机盐、氨基酸、多肽或蛋白质。
12.如权利要求8所述的改进方法，其中的胰岛素干粉包括平均尺寸小于10μm的颗粒。
13.如权利要求8所述的改进方法，其中的干粉包含有胰岛素及载体两者的独立颗粒。
14.如权利要求13所述的改进方法，其中各个颗粒胰岛素含量为从重量比5％至99％。
15.制备稳定的干粉胰岛素组合物的方法，所述方法包括：
将胰岛素溶于缓冲水溶液中形成溶液；以及
将溶液喷雾干燥制得平均尺寸小于10μm的大体无定形颗粒。
16.如权利要求15所述的方法，其中的胰岛素与药物载体一起溶于缓于水溶液中，其中在喷雾干燥中制得各个颗粒的胰岛素含量为从重量比5％至99％的干粉。
17.如权利要求16所述的方法，其中的药物载体是可以在喷雾干燥中产生粉末的糖、有机盐、氨基酸、多肽或蛋白质。
18.如权利要求17所述的方法，其中的糖选自甘露糖醇、棉子糖、乳糖、麦芽糖糊精和海藻糖。
19.如权利要求17所述的方法，其中的有机盐选自柠檬酸钠、乙酸钠、抗坏血酸钠。
20.用于肺部释放的胰岛素组合物，所述组合物包含附着于药物载体材料上的、胰岛素含量为重量比5％至99％，并且尺寸低于10μm的独立颗粒。
21.如权利要求20所述的胰岛素组合物，其中的组合物基本不含增透剂。
22.如权利要求20所述的胰岛素组合物，其中的药物载体材料包括糖，该糖选自甘露糖醇、棉子糖、乳糖、麦芽糖糊精和海藻糖。
23.如权利要求20所述的胰岛素组合物，其中的药物载体材料包括选自柠檬酸钠、葡萄糖酸钠、抗坏血酸钠的有机盐。
24.由权利要求15的方法制得的胰岛素组合物。
25.主要由平均颗粒尺寸小于10μm的干粉胰岛素组成的胰岛素组合物。
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105451716A (zh) * 2013-07-18 2016-03-30 曼金德公司 热稳定性干粉药物组合物和方法
CN106794156A (zh) * 2014-07-08 2017-05-31 美药星制药股份有限公司 微粒化胰岛素、微粒化胰岛素类似物及其制备方法

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