Insulin Formulations Research Articles

Role of Nanotechnology in Diabetic Management.

Diabetes Mellitus (DM) has emerged as an epidemic that has affected millions of people worldwide in the last few decades. Nanotechnology is a discipline that is concerned with material characteristics at nanoscale and offers novel techniques for disease detection, management and prevention. Diabetes mellitus is an epidemic disease that has affected millions of people globally. Nanotechnology has greatly enhanced the health status by providing non-obtrusive techniques for the management and treatment of diabetic patients. In diabetes research, the nanotechnology has encouraged the advancement of novel glucose monitoring and several modalities for insulin delivery holding possibilities to enhance the personal satisfaction and life quality for diabetic patients. Nanoparticles hold a great potential in the areas of drug delivery and are explored as vehicles for orally administered insulin formulations. Glucose biosensors equipped with nanoscale materials such as Quantum Dots (QDs), Carbon Nanotubes (CNTs), Magnetic Nanoparticles (MNPs) etc. have shown greater sensitivity. Nanotechnology in diabetic research is heading towards the novel techniques which can provide continuous glucose monitoring offering accurate information and improving patient's compliance. The present review addresses the different aspects of nanoparticles and recent patents related to diabetic management based on nanotechnology.

Comparison of pharmacodynamics and pharmacokinetics of insulin degludec and insulin glargine 300 U/mL in healthy cats

Insulin glargine 300 U/mL (IGla-U300) and insulin degludec (IDeg) are synthetic insulin analogs designed as basal insulin formulations. In people, IGla-U300 is more predictable and longer acting compared with glargine 100 U/mL. The duration of action of IDeg in people is > 42 h, allowing flexibility in daily administration. We hypothesized that IDeg would have longer duration of action compared with IGla-U300 in healthy purpose-bred cats. Seven cats received 0.4 U/kg (subcutaneous) of IDeg and IGla-U300 on two different days, >1 wk apart. Exogenous insulin was measured and pharmacodynamic parameters were derived from glucose infusion rates during isoglycemic clamps and suppression of endogenous insulin. The Shapiro-Wilk test was used to assess normality, and normally distributed parameters were compared using paired t-tests. There was no difference between IDeg and IGla-U300 in onset, peak action, or total metabolic effect. On average, time to peak action (TPEAK) of IGla-U300 was 145 ± 114 min (95% confidence interval [CI] = 25–264) longer than TPEAK of IDeg (P = 0.03) and duration of action (TDUR) of IGla-U300 was 250 ± 173 min (95% CI = 68–432) longer than TDUR of IDeg (P = 0.02). The “flatness” of the time-action profile (as represented by the quotient of peak action/TDUR) was significantly greater for IGla-U300 compared with IDeg (P = 0.04). Overall, insulin concentration measurements concurred with findings from isoglycemic clamps. Based on these data, IDeg is not suitable for once-daily administration in cats. The efficacy of once-daily IGla-U300 in diabetic cats should be further investigated.

OR14-1 Pharmacodynamics, Safety, Tolerability, and Efficacy of Oral Insulin Formulation (Oshadi Icp) among Young Adults with Type 1 Diabetes: A Summary of Clinical Studies Phases I, Ib, and Ii

Background Replacement of subcutaneous (SC) insulin by oral insulin for Type I diabetes (T1D) could promote patient compliance and minimize hyperinsulinemia. Oshadi Drug Administration Ltd. has developed an oral carrier for proteins delivery, composed of known ingredients, including polysaccharides and nano-silica , and based on quantum theory of biochemical reactions. Objectives To assess the pharmacodynamics of Oshadi oral insulin formulation (Oshadi-I) and the safety, tolerability and glucose-lowering effect of Oshadi oral insulin, proinsulin and c-peptide formulation (Oshadi-Icp) in young patients with T1D. Methods Phase I: a single blinded crossover between Oshadi-I and placebo. Glucose concentration was followed over 13 hours post a single dose. Phase Ib: a crossover open label comparison between 2 sessions of 3 days of Oshadi-Icp or placebo. During both sessions patients stayed at the research unit, provided with identical low carbs diet and minimal doses of SC insulin. Phase II:a prospective 4 weeks open-label follow-up of patients using an insulin pump combined with Oshadi-Icp at home. During Phases Ib and II iinterstitial glucose (IG) was monitored by CGMS, and capillary glucose by finger pricks (CG). Mean IG, mean CG, their area under the curve (AUC), weight adjusted total daily dose (TDD) of SC insulin, BMI, HbA1c, fructosamine, and safety parameters were compared. Results Eight patients, mean age 27.7±4.8 years, 5 males, were included in Phase I study, 10 patients mean age 26.2±4.7 years, 7 males, were included in Phase Ib study, and 16 patients mean age 23.5± 4.6 years, 12 males, were included in Phase II study. Oshadi-Icp was well tolerated, with no adverse events nor clinically relevant changes in vital signs, electrocardiograms, and standard safety laboratory parameters during all study phases. Phase I demonstrated a significantly lower plasma glucose AUC within 7 hours post Oshadi-I compared with placebo: 1116.1mg/dl±107.0 vs. 1345.7mg/dl ±82.0, p <0.01. Phase Ib study demonstrated significantly lower mean post meals GC, AUC-GC and mean insulin TDD at the third day during Oshadi-Icp session compared to placebo: 207.5mg/dl± 6.0 vs. 265.4mg/dl±3.9, p<0.001, 3107.57mg/dl±20.5 vs. 4031.58mg/dl±26.76, p<0.001, 0.14 ±0.04 IU/kg/day vs. 0.18 ±0.06 IU/kg/day, p≤0.01. Four episodes of GC ≤70mg/dL were detected during the Oshadi Icp session and 1 episode of mild DKA was detected during the placebo session. Phase II study demonstrated the ratio of SC insulin dose to carbohydrate intake was significantly lower during Oshasi-Icp month 78-80% for each week compared to baseline 100%. Fructosamine was stable throughout the study, with no episodes of severe hypoglycemia and DKA. Conclusions A substantial safety and glucose lowering effect of Oshadi-Icp formulation were demonstrated. Its clinical potential and beneficial effect for patients with T1D should be further studied.

SUN-186 Insulin Antibody Associated Severe Insulin Resistance Leading to Uncontrolled Hyperglycemia

Background: Severe insulin resistance is unusual in young patients with type 1 DM and normal BMI. We report a case of severe insulin resistance attributed to the development of insulin antibodies. Clinical Case: An 18 year old male with uncontrolled Type 1 DM was admitted to psychiatry for management of a delusional disorder. His home insulin regimen consisted of degludec 56 units daily and aspart 30 units before meals. He weighed 75 kg with a BMI of 27.5 kg/m2. Initial blood work revealed hyperglycemia with glucose of 549 mg/dl, HbA1C of 10%, C-peptide of <0.1 ng/ml (0.9-7.1 ng/ml), and no evidence of urinary ketones, acidemia, hyperosmolarity or thyroid dysfunction. He was started on a basal bolus regimen with a total daily dose of 0.9 units/kg. His hyperglycemia persisted despite rising standing insulin doses and metformin 1000 mg twice daily was added with minimal improvement in glycemic control. Due to persistent hyperglycemia despite rising insulin doses, insulin antibody titers were measured and found to be elevated at 4.4 U/ml (<0.4 U/ml.) When his psychiatric symptoms stabilized, he was discharged on a basal bolus regimen with total daily dose of 2.6 units/kg and metformin 1000 mg twice a day with improved glycemic control. Conclusion: Development of insulin antibodies is known to occur in type 1 diabetics using animal preparations of insulin but far less commonly in patients receiving recombinant human insulin or insulin analogues. Factors related to their development include the type of insulin (animal insulin having higher immunogenicity), mode of delivery (increased levels seen with insulin pump use and more frequent injections) and predisposing genetic factors such as certain HLA types. In some individuals, these antibodies may be clinically insignificant while others may develop severe insulin resistance with highly variable glycemic control. Often these patients experience marked hypoglycemia at night yet are hyperglycemic during the day. Treatment options include switching insulin formulations, insulin sensitization with metformin or thiazolidinediones, stimulation of insulin production with sulfonylureas or GLP-1 receptor agonists and immunosuppression with glucocorticoids, mycophenolate or cyclophosphamide. In patients who fail these treatments, plasmapheresis has been described as an alternative. In conclusion, the presence of insulin antibodies should be considered in patients with severe hyperglycemia despite increasing doses of insulin.

Insulin Mucoadhesive Liposomal Gel for Wound Healing: a Formulation with Sustained Release and Extended Stability Using Quality by Design Approach.

The present study deals with the formulation of topical insulin for wound healing with extended stability and sustained release, by applying quality by design concepts. Insulin has been promoted as a promising therapeutic wound healing agent. Topical formulation of insulin faced major problems, as it cannot be delivered safely to the wound with a controlled rate. Formulation of insulin-loaded vesicles in optimized bio-adhesive hydrogels has been explored to ensure a safe delivery of insulin to wounds in a controlled manner. Quality by design (QbD) was applied to study the effect of several critical process parameters on the critical quality attributes. Ishikawa diagram was used to identify the highest risk factors, which were screened by a fractional factorial design and augmented by Box-Behnken design. The optimized formula was incorporated into a mucoadhesive gel, which was further subjected to stability and clinical studies. An optimized formula was obtained with a particle size of 257.751nm, zeta potential - 20.548mv, 87.379% entrapment efficiency, and a release rate of 91.521μg/cm2/h. The results showed that liposomal insulin remained stable for 6months in aqueous dispersion state at 4°C. Moreover, the release was sustained up to 24h. The clinical study showed an improvement in the wound healing rate, 16 times, as the control group, with magnificent reduction in the erythema of the ulcer and no signs of hypoglycemia. Insulin-loaded liposomal chitosan gel showed a promising drug delivery system with high stability and sustained release.

Recent advances in diabetes treatments and their perioperative implications.

Purpose of reviewThe implications for perioperative management of new oral antihyperglycemic medications and new insulin treatment technologies are reviewed.Recent findingsThe preoperative period represents an opportunity to optimize glycemic control and potentially to reduce adverse outcomes. There is now general consensus that the optimal blood glucose target for hospitalized patients is approximately 106–180 mg/dl (6–10 mmol/l). Recommendations for the management of antihyperglycemic medications vary among national guidelines. It may not be necessary to cease all antihyperglycemic agents prior to surgery. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are associated with higher rates of ketoacidosis especially in acutely unwell and postsurgical patients. The clinical practice implications of new insulin formulations, and new systems for insulin delivery, are not clear. The optimal perioperative management of these will vary depending on local institutional factors such as staff skills and existing clinical practices. Improved hospital care delivery standards, quality assurance, process improvements, consistency in clinical practice, and coordinated multidisciplinary teamwork should be a major focus for improving outcomes of perioperative patients with diabetes.SummarySulfonylureas and SGLT2i should be ceased before moderate or major surgery. Other oral antihyperglycemic therapies may be continued or ceased. Complex patients and/or new therapies require specialized multidisciplinary management.

Are newer insulins always the better option?

Since its discovery almost a century ago, there have been numerous advancements in the formulations of insulin. The newer insulin analogs have structural modifications with the goal of altering pharmacokinetics to achieve either quick onset and offset of action (mealtime bolus analogs), or a prolonged steady action (basal analogs). These analogs offer many advantages over older human insulins but are several-fold more expensive. The aim of this review is to evaluate reasons for the exorbitant price of the newer insulins, to examine the evidence regarding their clinical advantages and to make value-based prescribing recommendations. The higher cost of newer insulins cannot be justified based on drug development or manufacturing costs. Compared with older insulins, newer analogs do not offer significant advantage in achieving hemoglobin A1c targets, but they reduce risk of hypoglycemia. The reductions in hypoglycemia are relatively modest and most apparent in those with type 1 diabetes, possibly because these individuals are more prone to hypoglycemia. When cost considerations are important, the older insulins (regular and NPH insulin) can be used safely and effectively for most individuals with type 2 diabetes who have a low risk of hypoglycemia.

Clinical challenges with excipients in insulin formulations and role of concentrated insulin

Most of the insulin formulations in clinical use contain phenol, meta-cresol or both as excipients. These excipients in insulin preparations provide stability and have antimicrobial properties. However, they are reported to be associated with undesirable side-effects especially localised allergic reactions. Amount of excipients injected per unit dose of insulin is a major determining factor in causation of these reactions. This review discusses the excipients in different insulin formulations available in India with potential of precipitating undesirable effects and the use of concentrated insulins to reduce these complications. To avoid the detrimental effects associated with excipients, removal of preservatives or use of insulin preparations devoid of excipients can be an option. Besides these approaches, one approach that can be considered is the use of concentrated insulin to reduce the volume of insulin dose and thereby the excipients. Concentrated insulins address the high insulin requirements of the growing population of patients with type 2 diabetes who require higher insulin doses. Concentrated insulins help in reduction of dose volume as well as amount of excipients injected per unit dose of insulin. U200 (concentrated r-DNA Human Insulin Premix 30/70-200 IU/ml) can be advantageous with better absorption from smaller quantity injected, lesser variability in absorption, lesser pain and discomfort due to smaller quantity, lesser chances of hypoglycaemia all of which can lead to better patient compliance. Thus, concentrated insulin U200 can be one of the alternatives to prevent/reduce clinical complications with excipients in insulins.

Appropriate Titration of Basal Insulin in Type 2 Diabetes and the Potential Role of the Pharmacist.

A substantial proportion of patients with suboptimal control of their type 2 diabetes experience delays in treatment intensification. Additionally, patients often experience overuse of basal insulin, commonly referred to as “over-basalization,” whereby basal insulin continues to be uptitrated in order to meet targets, when addition of a mealtime bolus insulin dose may be a more appropriate option. In order to overcome these challenges, there is a need to develop the capacity of allied healthcare professionals to provide appropriate support to these patients, such as during initiation or titration of basal insulin. Pharmacists play an integral role in healthcare delivery, with patients seeing their pharmacist, on average, seven times more often than their primary care physician. This places pharmacists in a unique position to provide diabetes education and care, which may help patients avoid clinical inertia. Nevertheless, the management of the disease with basal insulin is becoming increasingly complex, with growing numbers of treatment options (such as recent second-generation longer-acting basal insulin formulations) and frequently updated titration algorithms. The two most common titration schedules specify either increasing doses by a set amount every 2–3 days or a treat-to-target strategy. Neither schedule has been shown to be superior, and the decision to use one or the other should be based on a discussion between the clinician and patient after assessment of mental and physical acumen, comfort of both parties, and follow-up plans. This review article discusses basal insulin therapy options and titration algorithms from the unique perspective of the pharmacist in order to help ensure that optimal antidiabetes therapy is initiated, appropriately titrated, and maintained.Funding: Sanofi US, Inc.

Quantitative determination of beta-cyclodextrin in a powder insulin formulation for nasal delivery using hydrophilic interaction chromatography with evaporative light scattering detection

This study demonstrated the first application of hydrophilic interaction chromatography (HILIC) with evaporative light scattering detection (ELSD) for the analysis of beta-cyclodextrin in a peptide nasal formulation. The method utilized an Accucore™ 150 Amide HILIC packing together with an isocratic mobile phase of 65% acetonitrile/35% water with a runtime of 10 minutes and easily separated alpha-, beta- and gamma-cyclodextrins. The method was validated with respects to accuracy, precision, reproducibility, stability, specificity and sensitivity. This method provided better sensitivity compared to other reversed phase HPLC methods and was easier to run than other techniques for the quantitation of cyclodextrins in pharmaceutical formulations.

Insulin aggregation assessment by capillary gel electrophoresis without sodium dodecyl sulfate: Comparison with size-exclusion chromatography

Size-exclusion chromatography (SEC) is a method of choice for the analysis of protein aggregates in pharmaceuticals. The United States and European Pharmacopoeias currently use a SEC method with an acidic pH mobile phase to assess the content of aggregates in insulin formulations.In this article, we analyzed aggregated human insulin samples and demonstrated that both methods under neutral conditions, namely neutral pH SEC (nSEC) and capillary gel electrophoresis (CGE), yield to similar aggregate content contrary to SEC under acidic conditions (aSEC). aSEC showed polymeric complexes that were not observed in nSEC and CGE. During method development, the effect on SEC profiles of arginine and acetonitrile were highlighted. In CGE, the effect of SDS on disruption of non-covalent insulin aggregates was confirmed and the benefit of sodium deoxycholate addition in sieving gel was discussed. The three methods were applied to the analysis of an insulin formulation and similar results to those obtained for human insulin as raw material were observed. Finally, the CGE method was used to study the stability of human insulin under different storage conditions.In view of the obtained results one may question the relevance of the current pharmacopoeia method to study insulin aggregates by emphasizing the importance of the mobile phase composition and pH in SEC. The new CGE method developed is an easy method for studying non-covalent aggregates of insulin, which could be applied to other proteins.

A systematic review on efficacy and safety of the current hypoglycemic agents in patients with diabetes during Ramadan fasting

The fasting in the holy month of Ramadan is passionately practised among the Muslims population around the world. Patients with diabetes are generally considered to have various risks with fasting. The recent pharmacologic and technical advances in the management of diabetes may have enabled these patients to practice safe fasting. The purpose of this review is to scientific evidence on the safety and efficacy of the current hypoglycemic agents during Ramadan. MethodsAn extensive Electronic search via PubMed and Google scholar was accomplished through using different search terms. The eligible studies were limited to only published Randomised controlled trial (RCT) and prospective observational studies from 2007 to 2018 on patients with all types of diabetes on any pharmacological management, who intended to fast in Ramadan. Results and ConclusionsThe current era witnessed a gradual shift in the management of these patients with diabetes who elected to fast in Ramadan, despite the variable health-related risks with fasting. Results from available RCTs and observational studies in patients with type 2 diabetes showed lower risk of hypoglycemia, similar or better efficacy for glycemic and weight control with SGLT2 inhibitors, incretin mimetics and the newer insulin analogues compared to Sulfonylurea. Gliclazide is a relatively safer option among all sulfonylurea. Patients requiring insulin did better with insulin analogues, especially the newer premixed formulation at the time of breaking fast compared to the former insulin formulation. Current commonly used newer hypoglycemic agents are generally safe during Ramadan, however, their safety in the higher risk diabetes patients is highly needed.

Fast-Acting Insulin Aspart and the Need for New Mealtime Insulin Analogues in Adults With Type 1 and Type 2 Diabetes: A Canadian Perspective.

Limiting postprandial glucose (PPG) excursions is an important aspect of overall glycemic control. Rapid-acting insulin analogues (RAIAs) aim to mimic the physiologic action of endogenous insulin observed in individuals without diabetes and prevent excessive PPG excursions. However, many people with type 1 diabetes and type 2 diabetes treated with RAIAs do not achieve glycated hemoglobin (A1C) targets, and there is an unmet need for further improvements in PPG control. Current RAIAs have a delayed onset and a longer duration of action compared with endogenous insulin secreted in response to meals. Approachesto developing new mealtime insulins with accelerated absorption kinetics include changing the route of administration (i.e. via inhalation) and changing the insulin formulation. Fast-acting insulin aspart (faster aspart) is a novel formulation of insulin aspart (IAsp) containing the excipients niacinamide and L-arginine. Faster aspart has an earlier onset of insulin exposure and a greater early glucose-lowering effect than IAsp. In large clinical trials, mealtime faster aspart demonstrated noninferiority to IAsp with respect to A1C reduction and provided superior PPG control with no increase in overall severe or blood glucose-confirmed hyperglycemia. In addition, faster aspart administered up to 20min after the start of a meal was noninferior to mealtime IAsp in terms of A1C control, highlighting the opportunity for postmeal dosing. Faster aspart is the first of a new generation of mealtime insulins to be approved in Canada for the treatment of adults with type 1 diabetes and type 2 diabetes, and it is included in the 2018 Diabetes Canada clinical practice guidelines.

Are newer insulin analogues better for people with Type 1 diabetes?

Achieving optimal blood glucose control in Type 1 diabetes is a delicate balance between ensuring tight glycaemic control and achieving this without the expense of hypoglycaemia and weight gain, two major factors impacting quality of life. This is a real challenge for people with Type 1 diabetes and underpins many of the struggles they face in self-managing on a day-to-day basis. The main goals of insulin delivery are to try to simulate the physiology of β-cell insulin secretion as closely as possible and to overcome the challenges of peripheral insulin administration by achieving rapidity of onset with mealtime insulins and stability of the glucose-lowering effects of long-acting insulins. Since the early days of human insulin use, there have been many developments in insulin formulations that aim to achieve these goals as much as possible, thus contributing to better glycaemic control whilst minimizing hypoglycaemia. In the present review we discuss the currently available insulin analogues and the challenges of achieving glucose control using current analogues in those on multiple daily injections, and appraise the evidence base for newer-generation insulin analogues, such as insulin degludec, glargine U300, faster-acting insulin aspart and BioChaperone lispro. We also highlight new insulins in development and unmet needs in people with Type 1 diabetes.

Basal insulin therapy: Unmet medical needs in Asia and the new insulin glargine in diabetes treatment.

Diabetes remains a global epidemic and a tremendous health challenge, especially in the Asian population. Dramatic increases in the prevalence of diabetes across different countries or areas in Asia have been reported in recent epidemiological studies. Although clinical guidelines have strengthened appropriate antihyperglycemic medications and lifestyle modifications for optimal diabetes management, inadequate glycemic control still occurs in many patients with an increased risk of developing microvascular and macrovascular complications. Insulin administration is the main therapy for diabetes in response to the inability to secrete insulin, and is recommended in current guidelines to treat patients with type 2 diabetes after failure of oral antidiabetic drugs. Clinical studies have shown that long‐acting insulin analogs improve basal glycemic control with reduced risk of hypoglycemia. In the present review, we discuss previous challenges with basal insulin therapy in Asia, the pharmacological development of insulin analogs to overcome the unmet medical needs and recent clinical studies of the new ultra‐long‐acting insulin analog, insulin glargine U300. Furthermore, relevant findings of current real‐world evidence are also included for the comparison of the efficacy and safety of different insulin formulations. Based on the accumulating evidence showing a low incidence of hypoglycemia and technical benefits of dose titration, treatment with glargine U300 can be a promising strategy for Asian diabetes patients to achieve glycemic targets with favorable safety.

Acute effects of zinc and insulin on arcuate anorexigenic proopiomelanocortin neurons.

Acute insulin administration hyperpolarized, with concomitant decrease of firing rate, a subpopulation of arcuate proopiomelanocortin (POMC) and neuropeptide Y/agouti-related peptide cells. This rapid effect on cellular activity has been proposed as a cellular correlate of insulin effects on energy balance and glucose homoeostasis. Recent evidence suggests that zinc in mammalian insulin formulations is required for the insulin-induced inhibition of arcuate POMC neurons, while guinea pig insulin, which fails to bind zinc, activates POMC neurons in mice. Here, we tested the effects of zinc and insulin formations on arcuate POMC neurons. Effects of zinc and insulin formulations were assessed through whole-cell patch clamp recordings on transgenic mice in vitro. Insulin formulations containing zinc hyperpolarized POMC neurons. Zinc also hyperpolarized arcuate POMC neurons, albeit at much higher concentration than found in various insulin formulations. Chelation of zinc inhibited the zinc-induced hyperpolarization of POMC neurons, whereas effects of insulin on POMC cellular activity were unchanged after chelation. Zinc-free insulin also hyperpolarized arcuate POMC neurons. Insulin failed to hyperpolarize POMC neurons deficient for insulin receptors, suggesting that insulin receptors are required for these effects. Activation of POMC neurons by guinea pig insulin was independent of insulin receptors but was inhibited by PDGF receptor antagonism or loss of TRPC5 channel subunits. Together, these findings suggest that insulin inhibited arcuate POMC neurons independent of zinc and highlights a possible role of putative PDGF receptors in the acute effects of guinea pig insulin.

ORAL DRUG DELIVERY OF INSULIN IN DIABETES MELLITUS: AN ATTRACTIVE ALTERNATE TO OVERCOME INVASIVE ROUTE

The subcutaneous injection of insulin for the treatment of diabetes mellitus can lead to patient non-compliance, discomfort, pain and local infection is a chronic metabolic health disease affecting the homeostasis of blood sugar levels in human beings. Oral route of drug delivery system has been the most widely accepted means of drug administration other than invasive drug delivery systems. For the development of an oral insulin delivery system, we have to focus on overcoming the various gastro-intestinal barriers for insulin uptake from the gastrointestinal tract. To overcome these barriers various types of formulations such as insulin conjugates, micro/nanoparticles, liposomes, hydrogel, capsule, and tablets are designed to deliver insulin orally. Various potential ways to administer insulin orally has been explored over years but a fluctuating level of insulin release have been recorded. A number of advancement has taken place in the recent years for understanding the needs of improved oral delivery systems of insulin. This review article concentrates on the challenges for oral drug delivery of insulin as well as various carriers used for the oral drug delivery of insulin and also provides the relevant information about the clinical tested formulations of oral insulin and its patents.

Enhancement of postprandial endogenous insulin secretion rather than exogenous insulin injection ameliorated insulin antibody-induced unstable diabetes: a case report

BackgroundInsulin injection, especially with insulin analogs, occasionally induces the production of insulin antibodies with high binding capacity and low affinity, similar to the insulin autoantibodies characteristic of insulin autoimmune syndrome (IAS). Production of these “IAS-like” insulin antibodies causes marked glycemic fluctuations with postprandial hyperglycemia and fasting hypoglycemia.Case presentationA 66-year-old man with a 27-year history of diabetes was admitted because of marked glycemic fluctuations. Human insulin treatment had been initiated at age 56, followed by multiple daily injections of insulin analogs 5 years later. After the initial year of insulin analog treatment, the patient began to experience frequent morning hypoglycemic attacks and day-time hyperglycemia. Marked hyperinsulinemia (4500 μU/mL) and high titers of insulin antibodies (80.4%) with high binding capacity and low affinity indicated that IAS-like insulin antibodies were causing severe glucose fluctuations. Altering insulin formulations (insulin aspart → regular human insulin→ insulin lispro) proved to be ineffective. After several therapeutic trials, cessation of exogenous insulin and addition of mitiglinide to liraglutide with voglibose finally attenuated glycemic fluctuations with increased postprandial insulin secretion. Continuous glucose monitoring revealed improvement of morning hypoglycemia and postprandial hyperglycemia with smaller mean amplitude of glycemic excursion. Therefore, compared to exogenously injected insulin, endogenously secreted insulin directly and rapidly acts on hepatocytes and suppresses postprandial glucose output.ConclusionsProper enhancement of postprandial endogenous insulin aimed at suppressing postprandial glucose output without stimulating excessive glucose uptake in the periphery is potentially useful for treating diabetes with insulin antibody-induced glycemic instability.

Optimization of formulation for enhanced intranasal delivery of insulin with translationally controlled tumor protein-derived protein transduction domain

Intranasal delivery of insulin is an alternative approach to treat diabetes, as it enables higher patient compliance than conventional therapy with subcutaneously injected insulin. However, the use of intranasal delivery of insulin is limited for insulin’s hydrophilicity and vulnerability to enzymatic degradation. This limitation makes optimization of formulation intranasal insulin for commercial purpose indispensable. This study evaluated bioavailability (BA) of various formulations of insulin intranasally delivered with protein transduction domain (PTD) derived from translationally controlled tumor protein. The therapeutic efficacy of newly formulated intranasal insulin + PTD was compared in vivo studies with normal and alloxan-induced diabetic rats, to those of free insulin and subcutaneously injected insulin. BA of insulin in two new formulations was, respectively, 60.71% and 45.81% of subcutaneously injected insulin, while the BA of free insulin was only 3.34%. Histological analysis of tissues, lactate dehydrogenase activity in nasal fluid, and biochemical analysis of sera revealed no detectable topical or systemic toxicity in rats and mice. Furthermore, stability analysis of newly formulated insulin + PTD to determine the optimal conditions for storage revealed that when stored at 4 °C, the delivery capacity of insulin was maintained up to 7 d. These results suggest that the new formulations of intranasal insulin are suitable for use in diabetes therapy and are easier to administer.

Enhanced intranasal insulin delivery by formulations and tumor protein-derived protein transduction domain as an absorption enhancer

One of the key factors for successful development of an intranasal insulin formulation is an absorption enhancer that would deliver insulin efficiently across nasal membranes without causing damage to mucosa or inducing protein aggregation under physiological conditions. In the present study, a protein transduction domain (PTD1) and its L-form with the double substitution A6L and I8A (PTD4), derived from human translationally controlled tumor protein, were used as absorption enhancers. PTD4 exhibited higher compatibility with insulin in terms of biophysical properties analyzed using μDSC, DLS, and CD. In addition, thermodynamic properties indicated stable complex formation but higher propensity of protein aggregation. Arginine hydrochloride (ArgHCl) was used to suppress protein aggregation and carbohydrates (i.e., mannitol, sucrose, and glycerin) were used as osmolytes in the formulation. The relative bioavailability of insulin co-administered intranasally using PTD4, 16 mg/mL glycerin and 100 mM ArgHCl was 58% and that using PTD4, 1 w/v% sucrose, and 25 mM ArgHCl was 53% of the bioavailability obtained via the subcutaneous route. These values represented a remarkable increase in bioavailability of intranasal insulin, causing a significant decrease in blood glucose levels within one hour. The pharmacokinetic properties of intranasal absorption were dependent on the concentration of carbohydrates used. These results suggest that the newly designed formulations with PTD represent a useful platform for intranasal delivery of insulin and other biomolecules.