Advanced Technologies and Treatments for Diabetes New ways of insulin delivery L. Heinemann Science & Co, Kehler Str. 24, 40468, Du ¨ sseldorf, Germany Introduction The last year was not a good year for new ways of insulin delivery, at least when you regard the number of publications about this topic as a reflection about the scientific and commercial interest in this area of research. Not only has the number of papers published from the middle of 2010 to the middle of 2011 about inhaled insulin decreased in com- parison with the years before, but also in gen- eral there were a limited number of publications about alternative routes of insu- lin administration (ARIA). Thus the number of clinical studies published in leading peer- reviewed journals that can be presented here is small. Simply no data from a clinical study were published about nasal insulin, dermal insulin or transdermal insulin developments; it appears as if there is a standstill with these approaches. It would be quite helpful for this area of research if at least one product came to the market in 2012 (e.g. inhaled insu- lin ⁄ Technosphere insulin). It might be that an oral insulin formulation will come to the market in the next few years, but most probably in less regulated markets. The story is clearly different when it comes to insulin pens; there is an increasing number of publications about these widely used devices. INHALED INSULIN Clearly the failure of Exubera (combined with the stop of the clinical development of most other inhaled insulin programmes) is the major reason for the drastic decline in the number of publications about clinical trials with inhaled insulin. Currently there is only one company active in the clinical develop- ment of an inhaled insulin formulation: MannKind has submitted a New Drug Appli- cation to the US Food and Drug Administra- tion (FDA) and received a certain setback from this regulatory authority, but is still in a good mood that they will get market approval sometime in the near future. However, as we have learned from the Exubera story, market approval is not all, without appropriate acceptance by the market (= sales); also an inhaled insulin with demonstrated and unique advantages when it comes to insulin absorp- tion and insulin action might fail in the long run. Market approval for Afrezza would be good news also for another company that has a profound scientific background in the inha- lation of peptides (http://www.dancephar- ma.com) and that is interested in starting over with the clinical development of inhaled insulin formulations (1). Also a good review was published that argues for keeping inhaled insulin as a valid option for insulin applica- tion in mind (2). It appears as if the submission of the nec- essary documents to the FDA and perfor- mance of additional clinical studies has required a lot of focus inside this company; there were no publications by MannKind about clinical studies in the last year that can be presented here. However, they published a number of other interesting studies, some more methodological, that will be presented here in brief only, e.g. one human study about lung deposition of Technosphere parti- cles (3). Two good reviews were published by the same authors about Technosphere insulin (4,5). MannKind also tried to support the posi- tion of inhaled insulin in general by perform- ing surveys at the physician (6) and patient level (7). Also some pharmacokinetic ⁄ phar- macodynamic modelling papers about inhaled insulin were published that highlight the advantages of this route of insulin administra- tion when it comes to insulin absorption, also in subjects with diabetic nephropathy, chronic liver disease and chronic obstructive pulmo- nary disease (8–11). There might be special paediatric cases in which treatment with inhaled insulin is helpful to overcome massive subcutaneous insulin resistance, but a number of aspects have to be considered (12,13). One animal study was published that declares to have identified a potentially seri- ous side effect of inhalation based insulin delivery, the formation of aggregates of inhaled insulin at the interface presented in the lungs through an amyloid formation mechanism (14). The authors state that their data highlight the need for caution when con- sidering other novel methods of insulin deliv- ery due to the amyloidogenic nature of this protein. ORAL INSULIN Oral insulin (OI) has also seen some setbacks, resulting in the fact that only one paper pre- senting data from a clinical trial was pub- lished in the last year. The negative outcome of Biocon’s phase 2 trial with their OI candi- date IN-105 led to a recent offer by this large Delivery ª 2012 Blackwell Publishing Ltd Int J Clin Pract, February 2012, 66 (Suppl. 175), 35–39 doi: 10.1111/j.1742-1241.2011.02852.x 35