Route Of Insulin Administration Research Articles

Managing diabetes with inhaled insulin

The incidence of diabetes is increasing world-wide. Many individuals with diabetes require insulin to control their blood sugar and prevent both microvascular and macrovascular complications associated with this chronic disease. Current regimens involve delivery of subcutaneous insulin by injection or continuous insulin infusion. One area of research to advance diabetes care is aimed at developing alternate routes of insulin administration that will make daily management less invasive for patients. This review will focus on inhaled insulin, a novel formulation which takes advantage of drug delivery through the pulmonary system. The pharmacology, efficacy, and safety of inhaled insulin will be discussed. In addition, the status of inhaled insulin as a potential therapy for individuals with diabetes will be reviewed.

Effect of addition of hyaluronic acid to highly concentrated insulin on absorption from the conjunctiva in conscious diabetic dogs.

Insulin absorption from the conjunctiva was investigated in five pancreatectomized diabetic mongrel dogs, with the nasolacrimal ducts occluded by micro plugs to prevent insulin absorption from nasolacrimal membrane. In the anaesthetized state, highly concentrated porcine insulin (1000 units mL-1, pH 7.4) was absorbed rapidly and significantly from the conjunctiva. Plasma immunoreactive insulin concentrations increased significantly up to 3 h after insulin administration to conjunctival membranes. Plasma glucose concentration decreased significantly compared with saline control experiments after insulin administration (10 units kg-1) at 3 h (8.3 +/- 0.1 vs 15.6 +/- 0.6 mmol, P < 0.01). However, in the conscious state, there was no significant increase in the plasma insulin levels after topical insulin administration. To improve insulin absorption in the conscious state, we examined the effect of increasing viscosity of insulin preparation with hyaluronic acid. In anaesthetized experiments, there were no significant changes in the bioavailability of insulin after addition of hyaluronate (0.84 +/- 0.11 vs 0.87 +/- 0.05%). In the conscious state, with addition of hyaluronic acid, the area under the curve of plasma insulin concentration was significantly increased (1842 +/- 383 vs 75 +/- 24 m units min L-1, P < 0.01). The bioavailability of insulin absorption was significantly increased after addition of hyaluronate (0.68 +/- 0.14 vs 0.03 +/- 0.01%, P < 0.01). From this study we could demonstrate that the conjunctiva is a potential route for insulin administration, and increased viscosity by the addition of hyaluronate was found effective in increasing the bioavailability of insulin absorption from conjunctival membrane in the conscious state.

New ways of insulin delivery

New ways of insulin delivery

Novel Approaches for Oral Delivery of Insulin and Current Status of Oral Insulin Products

Diabetes mellitus is a serious pathologic condition that is responsible for major healthcare problems worldwide and costing billions of dollars annually. Insulin replacement therapy has been used in the clinical management of diabetes mellitus for more than 84 years. The present mode of insulin administration is by the subcutaneous route through which insulin is presented to the body in a non-physiological manner having many challenges. Hence novel approaches for insulin delivery are being explored. Challenges to oral route of insulin administration are: rapid enzymatic degradation in the stomach, inactivation and digestion by proteolytic enzymes in the intestinal lumen and poor permeability across intestinal epithelium because of its high molecular weight and lack of lipophilicity. Liposomes, microemulsions, nanocubicles, and so forth have been prepared for the oral delivery of insulin. Chitosan-coated microparticles protected insulin from the gastric environment of the body and released intestinal pH. Limitations to the delivery of insulin have not resulted in fruitful results to date and there is still a need to prepare newer delivery systems, which can produce dose-dependent and reproducible effects, in addition to increased bioavailability.

Effect of different enhancers on the transdermal permeation of insulin analog

Using chemical penetration enhancers (CPEs), transdermal drug delivery (TDD) offers an alternative route for insulin administration, wherein the CPEs reversibly reduce the barrier resistance of the skin. However, there is a lack of sufficient information concerning the effect of CPE chemical structure on insulin permeation. To address this limitation, we examined the effect of CPE functional groups on the permeation of insulin. A virtual design algorithm that incorporates quantitative structure–property relationship (QSPR) models for predicting the CPE properties was used to identify 43 potential CPEs. This set of CPEs was pre-screened using a resistance technique, and the 22 best CPEs were selected. Next, standard permeation experiments in Franz cells were performed to quantify insulin permeation. Our results indicate that specific functional groups are not directly responsible for enhanced insulin permeation. Rather, permeation enhancement is produced by molecules that exhibit positive log K ow values and possess at least one hydrogen donor or acceptor. Toluene was the only exception among the 22 potential CPEs considered. In addition, toxicity analyses of the 22 CPEs were performed. A total of eight CPEs were both highly enhancing (permeability coefficient at least four times the control value) and non-toxic, five of which are new discoveries.

New ways of insulin delivery

New ways of insulin delivery

Inhaled insulin: overview of a novel route of insulin administration.

Diabetes is a chronic disease characterized by inadequate insulin secretion with resulting hyperglycemia. Diabetes complications include both microvascular and macrovascular disease, both of which are affected by optimal diabetes control. Many individuals with diabetes rely on subcutaneous insulin administration by injection or continuous infusion to control glucose levels. Novel routes of insulin administration are an area of interest in the diabetes field, given that insulin injection therapy is burdensome for many patients. This review will discuss pulmonary delivery of insulin via inhalation. The safety of inhaled insulin as well as the efficacy in comparison to subcutaneous insulin in the various populations with diabetes are covered. In addition, the experience and pitfalls that face the development and marketing of inhaled insulin are discussed.

Peri-operative glycaemic control regimens for preventing surgical site infections in adults

Surgical site infections (SSIs) are associated with significant morbidity, mortality, and resource utilization and are potentially preventable. Peri-operative hyperglycaemia has been associated with increased SSIs and previous recommendations have been to treat glucose levels above 200 mg/dL. However, recent studies have questioned the optimal glycaemic control regimen to prevent SSIs. Whether the benefits of strict or intensive glycaemic control with insulin infusion as compared to conventional management outweigh the risks remains controversial. To summarise the evidence for the impact of glycaemic control in the peri-operative period on the incidence of surgical site infections, hypoglycaemia, level of glycaemic control, all-cause and infection-related mortality, and hospital length of stay and to investigate for differences of effect between different levels of glycaemic control. A search strategy was developed to search the following databases: Cochrane Wounds Group Specialised Register (searched 25 March 2009), The Cochrane Central Register of Controlled Trials, The Cochrane Library 2009, Issue 1; Ovid MEDLINE (1950 to March Week 2 2009); Ovid EMBASE (1980 to 2009 Week 12) and EBSCO CINAHL (1982 to March Week 3 2009). The search was not limited by language or publication status. Randomised controlled trials (RCTs) were eligible for inclusion if they evaluated two (or more) glycaemic control regimens in the peri-operative period (within one week pre-, intra-, and/or post-operative) and reported surgical site infections as an outcome. The standard method for conducting a systematic review in accordance with the Cochrane Wounds Group was used. Two review authors independently reviewed the results from the database searches and identified relevant studies. Two review authors extracted study data and outcomes from each study and reviewed each study for methodological quality. Any disagreement was resolved by discussion or by referral to a third review author. Five RCTs met the pre-specified inclusion criteria for this review. No trials evaluated strict glycaemic control in the immediate pre-operative period or outside the intensive care unit. Due to heterogeneity in patient populations, peri-operative period, glycaemic target, route of insulin administration, and definitions of outcome measures, combination of the results of the five included trials into a meta-analysis was not appropriate. The methodological quality of the trials was variable. In terms of outcomes, only one trial demonstrated a significant reduction in SSIs with strict glycaemic control, but the quality of this trial was difficult to assess as a result of poor reporting; furthermore the baseline rate of SSIs was high (30%). The other trials were either underpowered to detect a difference in SSIs, due to a low baseline rate (less than or equal to 5%), or did not report SSIs as a single outcome but as part of a composite. Of the three trials reporting hypoglycaemia (which was not consistently defined) all had a higher rate in the strict glycaemic control group but none attributed significant morbidity to the hypoglycaemia. Adequacy of glucose control between groups was measured differently among studies. Studies could not be compared due to differences in target ranges, and were susceptible to measurement bias due to differences in frequency of measurement and lack of blinding by the providers following the glycaemic protocols. Infection-related mortality was not reported in any of the trials, and no trials demonstrated a significant difference in all-cause mortality. Length of hospital stay was significantly reduced in the strict glycaemic control groups in only one trial. There is insufficient evidence to support strict glycaemic control versus conventional management (maintenance of glucose < 200 mg/dL) for the prevention of SSIs. No trials were found that evaluated strict glycaemic control in the immediate pre-operative period or outside the setting of an intensive care unit. The trials were limited by small sample size, inconsistencies in the definitions of the outcome measures and methodological quality. Further large randomised trials are required to address this question and may be most appropriately performed in patients at high risk for SSIs.

A valuation of patients' willingness-to-pay for insulin delivery in diabetes

The aim of this study was to determine the insulin-delivery system and the attributes of insulin therapy that best meet patients' preferences, and to estimate patients' willingness-to-pay (WTP) for them. This was a cross-sectional discrete choice experiment (DCE) study involving 378 Canadian patients with type 1 or type 2 diabetes. Patients were asked to choose between two hypothetical insulin treatment options made up of different combinations of the attribute levels. Regression coefficients derived using conditional logit models were used to calculate patients' WTP. Stratification of the sample was performed to evaluate WTP by predefined subgroups. A total of 274 patients successfully completed the survey. Overall, patients were willing to pay the most for better blood glucose control followed by weight gain. Surprisingly, route of insulin administration was the least important attribute overall. Segmented models indicated that insulin naïve diabetics were willing to pay significantly more for both oral and inhaled short-acting insulin compared with insulin users. Surprisingly, type 1 diabetics were willing to pay $C11.53 for subcutaneous short-acting insulin, while type 2 diabetics were willing to pay $C47.23 to avoid subcutaneous short-acting insulin (p < .05). These findings support the hypothesis of a psychological barrier to initiating insulin therapy, but once that this barrier has been overcome, they accommodate and accept injectable therapy as a treatment option. By understanding and addressing patients' preferences for insulin therapy, diabetes educators can use this information to find an optimal treatment approach for each individual patient, which may ultimately lead to improved control, through improved compliance, and better diabetes outcomes.

Oral insulin and buccal insulin: a critical reappraisal.

Despite the availability of modern insulin injection devices with needles that are so sharp and thin that practically no injection pain takes place, it is still the dream of patients with diabetes to, for example, swallow a tablet with insulin. This is not associated with any pain and would allow more discretion. Therefore, availability of oral insulin would not only ease insulin therapy, it would certainly increase compliance. However, despite numerous attempts to develop such a "tablet" in the past 85 years, still no oral insulin is commercially available. Buccal insulin is currently in the last stages of clinical development by one company and might become available in the United States and Europe in the coming years (it is already on the market in some other countries). The aim of this review is to critically describe the different approaches that are currently under development. Optimal coverage of prandial insulin requirements is the aim with both routes of insulin administration (at least with most approaches). The speed of onset of metabolic effect seen with some oral insulin approaches is rapid, but absorption appears to be lower when the tablet is taken immediately prior to a meal. With all approaches, considerable amounts of insulin have to be applied in order to induce therapeutically relevant increases in the metabolic effect because of the low relative biopotency of buccal insulin. Unfortunately, the number of publications about clinical-experimental and clinical studies is surprisingly low. In addition, there is no study published in which the variability of the metabolic effect induced (with and without a meal) was studied adequately. In summary, after the failure of inhaled insulin, oral insulin and buccal insulin are hot candidates to come to the market as the next alternative routes of insulin administration.

The Failure of Exubera: Are We Beating a Dead Horse?

Inhalation of insulin appears to have become an alternative for the subcutaneous injection of insulin for the time being. However, the recent withdrawal of one product that had already reached the marketplace or others that were close to approval raised severe concerns about the future of the pulmonary route for insulin administration. In view of the progress made with respect to the size of the inhaler and the many other options that would improve the pharmacodynamic properties of inhaled insulin, patient acceptance of this innovative approach, and (hopefully) a reduction in cost, we should begin with an open discussion about the future of inhaled insulin in order to avoid its premature death. This commentary discusses many of the advantages and disadvantages of inhaled insulin from the view of the patients, diabetologists, scientists, pharmaceutical industry, health care payers, and politicians. It is hoped that this unusual approach allows keeping an open mind about this interesting route of drug administration.

Inhaled Insulin: Take a Deep Breath, but How?

Inhalation of insulin is the first alternative route of insulin administration, which has been developed to such a mature status that the first product (Exubera, Pfizer) was made available to the market and subsequently withdrawn as of early 2008. In view of the relatively low bioavailability of inhaled insulin and the intraindividual variability of the metabolic effect induced (which is in the range of that of subcutaneously applied regular insulin), one wonders how to improve both aspects. Unfortunately, it appears as if the impact of the inhalation maneuver on insulin deposition in the deep lung has not been studied extensively. We present some thoughts and data from an alveolar model and propose an experimental procedure that might be helpful in the quantitative evaluation of the impact of the insulin inhalation maneuver.

Preferences of Patients with Diabetes Mellitus for Inhaled versus Injectable Insulin Regimens

In clinical trials, patients have expressed greater satisfaction with inhaled human insulin (EXUBERA, Pfizer) than with injectable insulin. No studies to date have attempted to quantify the strength of preferences for these alternative routes of administration. To elicit health state preference values from people with diabetes mellitus for treatment with inhaled human insulin compared with injectable insulin. A patient preference study. Written descriptions were developed for five clinical scenarios: two for type 1 diabetes and three for type 2 diabetes. Each scenario required adjustment or initiation of insulin treatment because of poor glycaemic control. Two alternative insulin regimens were described for each scenario: injectable-only or inhaled human insulin to replace or reduce the number of daily injections. Equal efficacy was assumed within each of these scenario pairs.A total of 344 UK adults (66% male), 132 (mean age 49 years) with type 1 diabetes and 212 (mean age 63 years) with type 2 diabetes, rated scenario pairs corresponding to their own type of diabetes and rated their own health by time trade-off (TTO), by correspondence with EQ-5D health descriptions and on the EQ-5D visual analogue scale. Respondents stated their preference for, or indifference between, the injection-only or inhalation variant comprising each scenario pair. TTO utilities and EQ-5D utilities by UK community tariff were compared within each scenario pair, for the total sample rating, each scenario pair, and by subgroups of stated preference for each variant. A majority, ranging from 63% to 81% across the scenarios, preferred inhalation. Mean differences in TTO scores were 0.074, 0.076, 0.088, 0.053 and 0.043 for the five scenarios, respectively (p < 0.005 for all). Mean EQ-5D differences were 0.043, 0.029, 0.037, 0.020 and 0.021 for the five scenarios, respectively (p < 0.05 for scenarios 1 and 3), driven mainly by differences on the pain/discomfort dimension of the EQ-5D. Differences in favour of inhalation among those preferring inhalation, were greater than differences in favour of injections among those preferring injections. Mean self-rated health was similar between respondents with type 1 and type 2 diabetes, at 0.83 (TTO) and 0.75 (EQ-5D). The TTO was more sensitive than EQ-5D. Self-rated health by EQ-5D compared closely with reported values from the UK Prospective Diabetes Study (UKPDS). This study highlights the utility differences that people with diabetes perceive between the prospect of inhaled and injected routes of insulin administration, even under the assumption of no difference in efficacy. These differences are magnified when the comparison in utility scores is between the majority who prefer the inhaled route and the minority who prefer the injectable route.

Local Insulin-Zinc Injection Accelerates Skin Donor Site Wound Healing

Systemically administered insulin has been shown to accelerate wound healing. To minimize the hypoglycemic and hypokalemic effects of insulin, we investigated a new route of insulin administration by local injection into skin wounds. Partial thickness skin donor site wounds were created on the backs of adult rabbits with a dermatome set at 0.015 inch. The wounds were covered by Aquaphor gauze (Smith and Nephew, Largo, FL), and OpSite membrane (Smith and Nephew, Hull, United Kingdom) and protected by rabbit jackets. Long-acting insulin-zinc suspension was selected for local injection. In study 1, insulin was injected into the wound at different doses, and the concentrations of blood glucose and wound insulin were measured to determine the proper dose and injection frequency. In study 2, wound healing days were compared between two groups (n = 7 each) receiving local injection of either insulin-zinc or zinc alone as control. Based on the results from study 1, a dose of 0.25 units of long-acting insulin-zinc suspension was injected into the wound every other day in the insulin group. After injection, 0.25 units of insulin decreased blood glucose concentration (minimum 60 mg/dL) during the first 3 h, which then returned to the preinjection level (80 mg/dL). One injection maintained wound insulin concentration above 50 muU/mL for more than 24 h. With local injection of 0.25 units insulin-zinc every other day, the wound healing time was 11.2 +/- 2.3 d, which was faster (P = 0.02) than 15.1 +/- 4.1 d in the control group. Local injection of long-acting insulin-zinc suspension accelerated skin wound healing without major systemic side effects, demonstrating its potential usefulness in burn treatment.

Pulmonary Function Changes Related to Acute and Chronic Administration of Inhaled Insulin

The need for frequent insulin injections to achieve optimal glycemic control remains a major barrier to initiating and maintaining insulin therapy in diabetes. The inhaled route of insulin administration offers many potential advantages. However, there are ongoing concerns regarding the pulmonary safety of inhaled insulin. Published studies reporting pulmonary safety and data submitted to the Food and Drug Administration were reviewed. All studies were open-label, included adult subjects with type 1 and 2 diabetes, and excluded patients with underlying lung disease. Inhaled insulin was compared with subcutaneous insulin and oral agents. Inhaled insulin is associated with small, consistent reductions in lung function, primarily forced expiratory volume in 1 s (FEV(1)) and diffusion capacity for carbon monoxide (DL(CO)). The small reductions in lung function occurred early (within 12 weeks) and did not progress over time. The magnitudes of the reductions were 30-50 mL for FEV(1) and 0.5-1.0 standard units for DL(CO). Collectively, the data indicate that inhaled insulin is safe in studies with duration up to 4 years. The Food and Drug Administration requires monitoring of lung function on a regular basis.

Insulin Causes a Transient Induction of Proliferation via Activation of the PI3-Kinase Pathway in Airway Smooth Muscle Cells

Insulin regulates glucose metabolism and activates cell growth. As the respiratory system is an alternative route for insulin administration in patients with diabetes mellitus, we studied the effect of insulin on rabbit tracheal airway smooth muscle (ASM) cell proliferation. We show that treatment of quiescent ASM cells with insulin for 24 h increased cell number compared to control cells. This increase was similar to the increase caused by the addition of fetal bovine serum (FBS). Moreover, in contrast to cells treated with FBS, exposure of ASM cells with insulin for longer periods (48 and 72 h) did not have any further influence on cell proliferation. In ASM cells, insulin activated the phosphatidylinositol 3-kinase (PI3 K) pathway, while FBS activated both PI3 K and the mitogen-activated protein kinase (MAPK) pathway. The PI3K pathway inhibitors LY294002 and wortmannin abolished the stimulation of cell proliferation by insulin, indicating a role for this pathway in the cellular response to insulin. These results show that while insulin has a mitogenic effect on ASM cells, prolonged insulin treatment does not lead to excessive ASM cell proliferation and suggest that the use of aerosolized insulin does not represent a potential hazard for airway remodeling.

Smoking enhances absorption of insulin but reduces glucodynamic effects in individuals using the Lilly‐Dura inhaled insulin system

To quantify the pharmacokinetic (PK) and glucodynamic (GD) impact of smoking on inhaled and subcutaneous (SC) insulin administration in healthy subjects. This study employed the euglycemic clamp procedure in a four-period, four-way randomized crossover design. Eight smoking and eight non-smoking healthy males were given SC insulin on two occasions and human insulin inhalation powder (HIIP) on two other occasions. Smokers exhibited greater insulin exposure (AUC(0-t')) than non-smokers, following both routes of insulin administration (HIIP, P = 0.003, 58% increase; SC, P = 0.006, 24% increase). The maximum insulin concentration (C(max)) following HIIP was greater in smokers by 172% (P = 0.001) compared with non-smokers. The glucodynamic effects were greater in smokers following HIIP, consistent with the insulin concentration difference observed. However, maximum glucose response (R(max)) following SC was decreased by 36% (P = 0.001) and obtained later [time of maximum glucose response (TR(max)); P < 0.001] in smokers than in non-smokers. Smokers appeared less sensitive to insulin [total glucose infused during the clamp procedure normalised by total insulin exposure (G(tot))/AUC(0-t')] than non-smokers following both SC (P = 0.001) and inhaled (P = 0.011) routes of administration. Smokers had substantially increased peak HIIP insulin concentration, but the glucodynamic effect was partially offset, most likely because of increased insulin resistance.

Differences in protein and energy metabolism following portal versus systemic administration of insulin in diabetic dogs

In non-diabetic people, insulin levels in the liver are two-fold higher than those in the systemic circulation. In contrast, patients with type 1 diabetes have similar hepatic and systemic insulin levels because insulin is administered peripherally. The aim of this study was to compare the effects of systemic (SI) and pre-portal (PI) insulin administration on energy, glucose and protein metabolism in chronic insulin-dependent ketosis-prone diabetic dogs. We applied glucose-controlled insulin infusion, indirect calorimetry and stable isotope and radioisotope techniques to measure energy, protein and glucose metabolism. We maintained near-normoglycaemia at identical levels under both study conditions for 20 h. SI was associated with lower oxygen consumption (130+/-13 vs 161+/-8 ml/min), CO(2) production (99+/-10 vs 130+/-8 ml/min), respiratory quotient (0.76+/-0.02 vs 0.81+/-0.01) and energy expenditure (870+/-90 vs 1089+/-60 kcal/24 h) (p<0.05 for all differences). PI increased the respiratory quotient from the insulin-deprived state, whereas SI did not. Glucose kinetics were similar for SI and PI, whereas leucine oxidation (36+/-4 vs 54+/-5 micromol kg(-1) min(-1)) and the fractional synthesis rates of liver tissue protein (0.68+/-0.6 vs 0.83+/-0.07%/h), albumin (0.55+/-0.06 vs 0.68+/-0.4%/h), and fibrinogen (1.73+/-0.23 vs 2.59+/-0.25%/h) were all lower during SI than PI (p<0.05). The route of insulin administration did not alter glucose metabolism but did affect protein synthesis in the liver. The potential impact of this altered liver protein metabolism on chronic complications needs careful evaluation. A similar decrease in energy expenditure resulting from systemic insulin administration during tight glycaemic control is a potential cause of weight gain.

Noninjectable methods of insulin administration

Optimal glycemic control is essential for the prevention of diabetes-related complications, and the intensive insulin regimens that best resemble physiological insulin secretion are most likely to attain it. However, there are many limitations that preclude the early use of insulin by patients with type 2 diabetes or wider implementation of the intensive regimens in type 1 diabetes. More acceptable alternative routes of insulin administration and effective, noninvasive, patient-friendly delivery systems that alleviate the burden of insulin injections have been researched over the years. To date, only pulmonary inhalation of insulin has become a feasible alternative; it has proved to be as effective and well tolerated as the subcutaneously injected regular insulin and it has a pharmacodynamic profile well suited for mealtime insulin therapy. Several pulmonary insulin delivery systems are in different stages of development, and one (Exubera, Nektar Therapeutics/Pfizer Inc.-Sanofi-Aventis Group) has already become clinically available in the United States and Europe for patients with diabetes. Other noninjectable methods of insulin administration are reviewed.

The Modeling of Insulin Controlled Release Process From Fibrous Artificial Store

In the past, insulin was frequently administered by hypodermic injection, as liquids forms. To avoid problems incurred through the utilization of the injectable route of insulin administration, new dosage forms containing the insulin were introduced. Therefore, insulin delivery systems were developed to optimize the therapeutic properties of drug products and render them safer, more effective, and more reliable. The aim of this article is to present the modeling of the controlled releasing process of insulin from a fibrous artificial store. The release of insulin has been evaluated in both a physiological solution and blood serum in vitro and on experimental animals (mice) in vivo. On the basis of experimental results a mathematical model of diffusion-mediated release of insulin from cation-exchange fiber has been developed and presented in this paper.