Heinemann L, Pfützner A, Heise T
Profil Institute for Metabolic Research, Stresemannallee 6, 41460 Neuss, Germany.
Curr Pharm Des. 2001 Sep;7(14):1327-51. doi: 10.2174/1381612013397384.
For the past 75 years subcutaneous injections have been the only route of delivery of insulin therapy to diabetic patients. During this time, numerous attempts have been made to explore alternative routes for systemic insulin administration. However, thus far, no feasible other way of non-invasive insulin delivery has been developed. Dermal insulin application does not result in a reproducible and sufficient transfer of insulin across the highly efficient skin barrier. The dream of an "insulin tablet" has also not become a reality, the main problem being digestion and a lack of a specific peptide carrier system in the gut. Nasal insulin application was considered for a number of years as a potential method, because of the rapid absorption of insulin across the nasal mucosa. However, relative bioavailability was low and required use of absorption enhancers and more importantly, the metabolic effect lasted too short to be of clinical usefulness. To date the most promising alternative route of insulin administration, is the pulmonary delivery of insulin by inhalation which will likely lead to a practically usable system within the next few years. For maximal rate of absorption insulin must be applied deep into the lung, i.e., into the alveoli. A considerable number of inhalers (in combination with appropriate insulin formulations), which are ask to generate insulin particles with an appropriate size for pulmonary delivery, are currently in the clinical phase of development. The pharmaco dynamic effects of insulin formulations administered via the lung are comparable to, or even faster than, those of s.c. injected regular insulin or rapid-acting insulin analogues. The relative biopotency of inhaled insulin in most cases is approximately 10%, i.e., the dose of insulin administered must be 10-fold higher than with s.c. application. The published results of clinical trials thus far, indicate that metabolic control is comparable to that of s.c. insulin therapy. As of to date no serious side effects have been reported from these human trials. In summary, it appear that after several decades of research, for the first time a feasible alternative route for insulin administration is within reach.
在过去75年里，皮下注射一直是糖尿病患者接受胰岛素治疗的唯一给药途径。在此期间，人们进行了无数次尝试，探索胰岛素全身给药的替代途径。然而，迄今为止，尚未开发出可行的非侵入性胰岛素给药方法。经皮应用胰岛素无法使胰岛素可重复且充分地穿过高效的皮肤屏障。“胰岛素片”的梦想也尚未实现，主要问题在于胰岛素在肠道内会被消化且缺乏特定的肽载体系统。由于胰岛素可通过鼻黏膜快速吸收，鼻用胰岛素给药多年来一直被视为一种潜在方法。然而，其相对生物利用度较低，需要使用吸收促进剂，更重要的是，代谢作用持续时间过短，不具有临床实用性。迄今为止，最有前景的胰岛素给药替代途径是通过吸入进行肺部给药，这可能会在未来几年内带来一种切实可用的系统。为实现最大吸收速率，胰岛素必须深入肺部给药，即进入肺泡。目前有相当数量的吸入器（与合适的胰岛素制剂联合使用）正处于临床开发阶段，这些吸入器需要产生适合肺部给药的合适尺寸的胰岛素颗粒。通过肺部给药的胰岛素制剂的药效学作用与皮下注射常规胰岛素或速效胰岛素类似物相当，甚至更快。在大多数情况下，吸入胰岛素的相对生物效价约为10%，即给药的胰岛素剂量必须比皮下给药高10倍。迄今为止已发表的临床试验结果表明，代谢控制与皮下胰岛素治疗相当。截至目前，这些人体试验尚未报告严重的副作用。总之，经过几十年的研究，似乎首次有了一种可行的胰岛素给药替代途径。
