New ways of insulin delivery

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 comparison with the years before, but also in general there were a limited number of publications about alternative routes of insulin 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 insulin/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. 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 development of an inhaled insulin formulation: MannKind has submitted a New Drug Application to the US Food and Drug Administration (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 absorption 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 inhalation of peptides (http://www.dancepharma.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 application in mind (2). It appears as if the submission of the necessary documents to the FDA and performance 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 particles (3). Two good reviews were published by the same authors about Technosphere insulin (4,5). MannKind also tried to support the position of inhaled insulin in general by performing surveys at the physician (6) and patient level (7). Also some pharmacokinetic/pharmacodynamic modelling papers about inhaled insulin were published that highlight the advantages of this route of insulin administration when it comes to insulin absorption, also in subjects with diabetic nephropathy, chronic liver disease and chronic obstructive pulmonary 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 serious 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 considering other novel methods of insulin delivery due to the amyloidogenic nature of this protein. Oral insulin (OI) has also seen some setbacks, resulting in the fact that only one paper presenting data from a clinical trial was published in the last year. The negative outcome of Biocon’s phase 2 trial with their OI candidate IN-105 led to a recent offer by this large Indian company that produce a lot of insulin to sell this development, i.e. they are looking for another company that is interested in pursuing this development further. Novo Nordisk reported in a press release that they have stopped the development of one of their OI candidates (NN-1952), which was a co-development with the Irish company Merrion Pharmaceuticals. Somewhat in contrast to previous years the publication activities of the Israel based company Oramed were reduced. Access Pharmaceuticals – which has an OI in which the insulin is bound to cobalamin (vitamin B12) – announced plans to initiate clinical trials; however, again no data have been presented so far. Nevertheless, a considerable number of papers about OI were published in pharmaceutical journals in the last year. We shall have to see how many, if any, of these approaches make it to clinical development. Rather different is the story of buccal insulin. For a number of years one company was quite prominent in the world of ARIA – the Canadian company Generex with their buccal insulin development. The company was present at many scientific congresses with a relatively large booth and has hired a number of renowned diabetologists. For a while the company also sent out press releases at weekly intervals that gave the impression that the product is highly successfully in a number of markets such as Ecuador and India. Also the start of a phase 3 study some time ago signals that this company was quite confident in the success of their development. Nevertheless, after a period of silence (accompanied by the lack of any publications and press releases …) it has become obvious that the fate of the development is uncertain. A new management is trying to sort out what the true level of development is and whether there is chance to develop this to a product also for highly regulated markets. It will be interesting to see how the story continues in the next few years. Khedkar A 1 , Iyer H 1 , Anand A 1 , Verma M 1 , Krishnamurthy S 1 , Savale S 2 , Atignal A 2 1 Research and Development, Biocon Limited, Bangalore, India, and 2 Clinigene International Limited, Bangalore, India Diabetes, Obesity Metab 2010; 12 : 659–64 Background: To evaluate the dose–response of an OI formulation (IN-105 tablets) and explore a possible therapeutic window in patients with type 2 diabetes (T2D) poorly controlled on oral antidiabetic agents. Methods: Primary endpoints were evaluation of the effect of sequential ascending doses of IN-105 on the plasma glucose levels under fed conditions. All participants received, sequentially, matching placebo or 10, 15, 20 and 30 mg IN-105 tablets in five consecutive periods 20 min prior to a meal in all periods. Plasma insulin, C-peptide and glucose levels were measured up to 180 min from the time of dosing. Comparison between the IN-105 tablets and placebo in the changes in postprandial glycaemic excursions at 120 min was done. Results: Decreases in plasma glucose from baseline (mean ± SD) at 140 min (2 h postprandial) were 94.8 ± 22.3, 79.5 ± 43.0, 70.7 ± 35.7, 63.5 ± 42.8 and 53.1 ± 47.3 mg/dl, respectively, and exhibited a linear dose–response. The maximal plasma insulin levels were observed to be 51 ± 26 mU/l for placebo, 100 ± 67 with 10 mg IN-105, 178 ± 150 with 15 mg IN-105, 246 ± 245 with 20 mg IN-105 and 353 ± 279 mU/l with 30 mg of IN-105. Conclusions: This OI formulation is absorbed in a dose-proportional relationship and circulating C-peptide levels were suppressed in proportion to the IN-105 exposure. The 2-h postprandial glycaemic excursion was in a dose-proportional relationship. The OI formulation seems to have a wide therapeutic window as no reduction in the clinical hypoglycaemia was observed at any of the doses studied. Comment: This clinical-experimental study investigated in 18 subjects with T2D the pharmacokinetic and pharmacodynamic properties of the only OI formulation that is in a later stage of clinical development. A rapidly absorbable OI formulation that allows a good coverage of prandial insulin requirements in such patients would be of high clinical relevance. Not only might it enable a good control of postprandial glycaemic excursions, due to a reduced entering barrier, such a pain-free insulin therapeutic option might allow insulin therapy to be started at an earlier stage in many patients. This well performed study showed that tablet administration 20 min before a carbohydrate-rich meal led to a clear dose-dependent change in PK properties and also in postprandial glycaemic excursions. However, the drop in glycaemia was not much different with the three highest of four OI doses tested. Also the observed considerable inter-subject variability in insulin levels after OI application is of note. Adequately designed and performed studies addressing intra-individual variability are needed to evaluate the therapeutic relevance of OI. The first insulin pen was introduced into the marketplace by Novo Nordisk in 1985 (Novo Pen I). After more than 25 years we have to acknowledge that not many devices have revolutionised diabetes therapy as insulin pens did, probably with the exception of blood glucose monitors (15). In some countries/continents >75% of patients are using insulin pens nowadays. However, in other countries, like the USA, the market share is much lower, but with a clear increase also in recent years. Reflecting their widespread usage today, insulin pens are the only way of insulin administration which has gained more attraction in the last few years when it comes to publications. Practically all of these publications were sponsored by one of the companies which have insulin pens in their portfolio. There is a certain feature war about pens (each company is promoting which property of their pen is better than that of the competitor, using scientific publications as ammunition); however, some people do believe that we are close to having the ideal insulin pen in the near future. Kreugel G, Keers JC, Kerstens MN, Wolffenbutte BHR University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Diabetes Technol Ther 2011; 13 : 737–41 Background: To evaluate the influence of two different needle lengths on metabolic control and patient preference in obese patients with type 1 (T1D) and type 2 (T2D) diabetes. Methods: This is a comparison of a multicentre, open-label crossover study of insulin pen needles with 5- and 8-mm lengths. Insulin-treated obese patients (n = 130; body mass index 30 kg/m²) with T1D and T2D were randomised, and 126 patients completed the study. Patients started using the 5-mm needle for 3 months and thereafter they switched to injecting insulin with the 8-mm needle for another 3 months, or vice versa. The endpoints were HbA1c, fructosamine and 1,5-anhydroglucitol, and self-reported side effects and patient preference. Results: With respect to HbA1c, serum fructosamine, 1,5-anhydroglucitol, hypoglycaemic events, bruising and pain no within-group differences were observed. There was a small difference between needle lengths (5 mm, HbA1c 7.5 ± 0.9%; 8 mm, 7.6 ± 1.0%; p = 0.02). Patients reported less bleeding with the 5-mm needle (p = 0.04) and less insulin leakage from the skin with the 8-mm needle (p = 0.01). There were no significant differences in patient preference. Conclusions: Use of a 5-mm needle led to a similar outcome as use of an 8-mm needle in obese patients with diabetes with respect to metabolic control, injection-related complaints or patient preference, and shorter needles can be used safely in this population. Comment: Different lengths of pen needles are a hot topic (at least for some companies). Currently in Europe, 92% of adult patients on insulin treatment were using an insulin pen with a disposable needle, and 63% were using an 8-mm needle or longer. There were concerns that in overweight people shorter needles do not result in proper subcutaneous administration. However, recent studies have shown that the body mass index has only a small impact on skin thickness, but clearly a large impact on the thickness of the subcutaneous tissue layer. In this clinical study with a considerable sample size and an adequate study design a small but significant benefit of a shorter needle length on insulin action (measured by HbA1c when data of all subjects were pooled) could be shown in obese subjects. This means that also in obese subjects shorter needles can be used safely. Penfornis A Department of Endocrinology – Metabolism and Diabetology – Nutrition, University of Franche-Comté, Besançon, France Diabetes Technol Ther 2011; 13 : 373–9 Background: This was a multinational study that compared the simplicity of use and performance of the ClikSTAR insulin pen with other commonly used reusable pens based on participant and interviewer assessments. Methods: In total 654 patients with diabetes were asked to demonstrate four pens consecutively – ClikSTAR, Lilly Luxura and NovoPen 3 and 4 – according to the instruction manuals. Assessment was performed by a rating from the participants and the interviewer. While the patients focused on the pen’s ease of use, the interviewer considered the patients’ difficulty in preparing and delivering a 40 U dose. Results: Up to 24% of participants had T1D. Approximately 50% of participants had prior insulin pen experience. A higher proportion of patients, including those with dexterity or visual impairments, reported ClikSTAR as easier to use than other pens (p < 0.05). Patients assessed the ClikSTAR and NovoPen 4 as the most highly rated pens. The number of patients not requiring help in completing the tasks with ClikSTAR was rated as higher than, or similar to, that with the other pens. Conclusions: One of the reusable insulin pens, the ClikSTAR was significantly easier to use, which, taken together with overall performance, meets the need of people with diabetes. Comment: Comparison of widely used reusable insulin pens is of high importance. Clearly the question is which factors/features are regarded as important and which not. A stated above, each company clearly has an interest in having the most ‘attractive’ pen (see below). For different patient groups (depending on age, visual impairment etc.) pens might differ in their usability; most probably there is no pen ‘that fits all patients’. Such an assessment is based on the assumption that all pens deliver the selected dose precisely, that no handling errors can take place etc. As with glucose meters where people tend to forget that the precision of glucose measurement is of higher than the of the or the size of the with each evaluation of an insulin pen the performance and the most important The of the evaluation of many of the in this performance study differ only between the pens if these differences are significant in some S Diabetes and Research Diabetes Technol 2010; 4 : To evaluate whether with diabetes can use the ClikSTAR a novel reusable insulin pen for injecting insulin or insulin Methods: This was an study in which patients with diabetes three 40 U insulin doses after from a diabetes = ± years, diabetes ± or after = similar to A but had not used an Administration of a dose of of the dose was considered and product complaints were Results: of the patients in A had prior in using insulin pen devices. All one participant in A successfully three insulin The for the success was higher than the of also showed of participants successfully completed three dose Conclusions: This study successfully the ClikSTAR pen for use by patients with diabetes. Comment: It is of interest to the paper for this publication The authors of this highlight that the sample of patients have a of diabetes patients, are For such patients, are a large of all patients with the dose and it is a such patients be in the development of these devices at an This would a better to the of a of patients and a new market for the of in of the small therapeutic window of it is obvious that each and patient in a good and prior to use of any insulin application of insulin In the of patients without adequate of the patients not the dose a to In of the many insulin doses patients with diabetes have to this is a much high It is also of that of the patients in this were due to difficulty in using the ClikSTAR In comparison of the two groups in the study was by the different size of the two patient It would have been of interest to see whether patients using a different pen a different would better or under the same conditions. M Research Diabetes Technol 2011; : To evaluate how successfully patients with diabetes are to between pens of the same pen type and insulin Methods: In all, patients with diabetes in the were about using a (n = or (n = insulin or (n = insulin A of each pen type was presented and participants were asked to the pen that they would use to at to and to at and how they between pens. The pen the insulin was and the patients were asked whether this was the pen to insulin or Results: patients successfully identified the pen the and the was significantly The most reason for all patients was the according to pen Conclusions: This handling study that the insulin pen with body the to between the pens for and insulin. This appears to be a compared with the of Comment: first this paper an evaluation that might as not for a scientific However, from a and of it is that patients with diabetes do not the insulin pen for prandial or insulin In many patients do not the differences between the insulin formulations and the of the different insulin they use is the with many of the patients We are a good about the and of patients with diabetes about insulin of insulin therapy etc. One can that there will be considerable differences in the outcome of such a on the patient considered that the patient to the insulin pen on first might be like the or other of the can be of significant for insulin Clearly of this studies under conditions. Nevertheless, publication of this relatively small study by a well also for the pen for the design of pens that enable of the pen by patients with diabetes for a therapeutic The two papers do not to new ways to deliver insulin in the however, they interesting for a insulin 1 , 1 , A 2 , 3 1 New USA, 2 India Diabetes Research Diabetes India, and 3 for Diabetes, University of 2011; : To diabetes treatment with a focus on patient to insulin Methods: As of the International Diabetes a using and methods was modelling was used to how product influence patients’ for diabetes Results: The was to patients with diabetes in 18 (n = with Administration oral was a of preference patient according to diabetes with T2D much higher to administration than those with T1D p < Patients with T2D with insulin less on administration than T2D patients p < T2D patients received diabetes gave a to administration compared with those not p < Conclusions: The insulin by patients with diabetes with their disease experience. While administration was the preference for patients, patients were with more as they gained with insulin. The with this that patients using insulin the of an between and Comment: The not of this study that treatment patients with diabetes have high insulin. interesting into the of this study can be on the , S , , 1 of USA, 2 University of Medical Department of USA, and 3 of 2010; : Background: is to be helpful in in patients with T1D. However, the question what do patients do in The number of used by with T1D and their to insulin were Methods: with T1D (n = completed a about a diabetes Results: of the reported using at least four in their while reported using only one A negative was between number of used and the number of by on of pain was the most Conclusions: In many with T1D not to to an adequate diabetes assessment of insulin is Also adequate be of Comment: Patients with diabetes they many when in diabetes and It is interesting to see how limited the of patients to such at least when it comes to It appears as if in patients most the insulin into that are for patients with diabetes is when insulin. the this in the fact that certain skin the subcutaneous tissue the are more to changes in in most The impact of such changes in the of the subcutaneous tissue on insulin absorption is not well studied. Also about the of is and diabetes much more the of their patients to make that they have no quite such changes in the subcutaneous tissue are not but they are is a of and for Research US and an of the clinical trials in with many pharmaceutical is not in any of the companies with which the clinical is a of and and has received from such

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.