Insulin Formulations Research Articles

Current barriers to initiating insulin therapy in individuals with type 2 diabetes.

Insulin is an essential drug in the treatment of diabetes, often necessary for managing hyperglycemia in type 2 diabetes mellitus (T2DM). It should be considered in cases of severe hyperglycemia requiring hospitalization, after the failure of other treatments, in advanced chronic kidney disease, liver cirrhosis, post-transplant diabetes, or during pregnancy. Moreover, in specific patient subgroups, early initiation of insulin is crucial for hyperglycemia control and prevention of chronic complications. Clinical guidelines recommend initiating insulin when other treatments fail, although there are barriers that may delay its initiation. The timing of initiation depends on individual patient characteristics. Typically, insulinization starts by adding basal insulin to the patient's existing treatment and, if necessary, progresses by gradually introducing prandial insulin. Several barriers have been identified that hinder the initiation of insulin, including fear of hypoglycemia, lack of adherence, the need for glucose monitoring, the injection method of insulin administration, social rejection associated with the stigma of injections, weight gain, a sense of therapeutic failure at initiation, lack of experience among some healthcare professionals, and the delayed and reactive positioning of insulin in recent clinical guidelines. These barriers contribute, among other factors, to therapeutic inertia in initiating and intensifying insulin treatment and to patients' non-adherence. In this context, the development of once-weekly insulin formulations could improve initial acceptance, adherence, treatment satisfaction, and consequently, the quality of life for patients. Currently, two once-weekly basal insulins, insulin icodec and basal insulin BIF, which are in different stages of clinical development, may help. Their longer half-life translates to lower variability and reduced risk of hypoglycemia. This review addresses the need for insulin in T2DM, its positioning in clinical guidelines under specific circumstances, the current barriers to initiating and intensifying insulin treatment, and the potential role of once-weekly insulin formulations as a potential solution to facilitate timely initiation of insulinization, which would reduce therapeutic inertia and achieve better early control in people with T2DM.

Exercising Safely with the MiniMed™ 780G Automated Insulin Delivery System.

The physical and psychological benefits of exercise are particularly pertinent to people with type 1 diabetes (T1D). The variability in subcutaneous insulin absorption and the delay in offset and onset in glucose lowering action impose limitations, given the rapidly varying insulin requirements with exercise. Simultaneously, there are challenges to glucose monitoring. Consequently, those with T1D are less likely to exercise because of concerns regarding glucose instability. While glucose control with exercise can be enhanced using automated insulin delivery (AID), all commercially available AID systems remain limited by the pharmacokinetics of subcutaneous insulin delivery. Although glycemic responses may vary with exercises of differing intensities and durations, the principles providing the foundation for guidelines include minimization of insulin on board before exercise commencement, judicious and timely carbohydrate supplementation, and when possible, a reduction in insulin delivered in anticipation of planned exercise. There is an increasing body of evidence in support of superior glucose control with AID over manual insulin dosing in people in T1D who wish to exercise. The MiniMed™ 780G AID system varies basal insulin delivery with superimposed automated correction boluses. It incorporates a temporary (elevated glucose) target of 8.3 mmol/L (150 mg/dL) and when it is functioning, the autocorrection boluses are stopped. As the device has recently become commercially available, there are limited data assessing glucose control with the MiniMed™ 780G under exercise conditions. Importantly, when exercise was planned and implemented within consensus guidelines, %time in range and %time below range targets were met. A practical approach to exercising with the device is provided with illustrative case studies. While there are limitations to spontaneity imposed on any AID device due to the pharmacokinetics associated with the subcutaneous delivery of current insulin formulations, the MiniMed™ 780G system provides people with T1D an excellent option for exercising safely if the appropriate strategies are implemented.

In Vitro and In Vivo Evaluation of Chitosan/HPMC/Insulin Hydrogel for Wound Healing Applications.

Treatment of chronic wounds is challenging, and the development of different formulations based on insulin has shown efficacy due to their ability to regulate oxidative stress and inflammatory reactions. The formulation of insulin with polysaccharides in biohybrid hydrogel systems has the advantage of synergistically combining the bioactivity of the protein with the biocompatibility and hydrogel properties of polysaccharides. In this study, a hydrogel formulation containing insulin, chitosan, and hydroxypropyl methyl cellulose (Chi/HPMC/Ins) was prepared and characterized by FTIR, thermogravimetric, and gel point analyses. The in vitro cell viability and cell migration potential of the Chi/HPMC/Ins hydrogel were evaluated in human keratinocyte cells (HaCat) by MTT and wound scratch assay. The hydrogel was applied to excisional full-thickness wounds in diabetic mice for twenty days for in vivo studies. Cell viability studies indicated no cytotoxicity of the Chi/HPMC/Ins hydrogel. Moreover, the Chi/HPMC/Ins hydrogel promoted faster gap closure in the scratch assay. In vivo, the wounds treated with the Chi/HPMC/Ins hydrogel resulted in faster wound closure, formation of a more organized granulation tissue, and hair follicle regeneration. These results suggest that Chi/HPMC/Ins hydrogels might promote wound healing in vitro and in vivo and could be a new potential dressing for wound healing.

The Basis for Weekly Insulin Therapy: Evolving Evidence With Insulin Icodec and Insulin Efsitora Alfa.

Basal insulin continues to be a vital part of therapy for many people with diabetes. First attempts to prolong the duration of insulin formulations were through the development of suspensions that required homogenization prior to injection. These insulins, which required once- or twice-daily injections, introduced wide variations in insulin exposure contributing to unpredictable effects on glycemia. Advances over the last 2 decades have resulted in long-acting, soluble basal insulin analogues with prolonged and less variable pharmacokinetic exposure, improving their efficacy and safety, notably by reducing nocturnal hypoglycemia. However, adherence and persistence with once-daily basal insulin treatment remains low for many reasons including hypoglycemia concerns and treatment burden. A soluble basal insulin with a longer and flatter exposure profile could reduce pharmacodynamic variability, potentially reducing hypoglycemia, have similar efficacy to once-daily basal insulins, simplify dosing regimens, and improve treatment adherence. Insulin icodec (Novo Nordisk) and insulin efsitora alfa (basal insulin Fc [BIF], Eli Lilly and Company) are 2 such insulins designed for once-weekly administration, which have the potential to provide a further advance in basal insulin replacement. Icodec and efsitora phase 2 clinical trials, as well as data from the phase 3 icodec program indicate that once-weekly insulins provide comparable glycemic control to once-daily analogues, with a similar risk of hypoglycemia. This manuscript details the technology used in the development of once-weekly basal insulins. It highlights the clinical rationale and potential benefits of these weekly insulins while also discussing the limitations and challenges these molecules could pose in clinical practice.

Oral nanotherapeutic formulation of insulin with reduced episodes of hypoglycaemia

Injectable insulin is an extensively used medication with potential life-threatening hypoglycaemic events. Here we report on insulin-conjugated silver sulfide quantum dots coated with a chitosan/glucose polymer to produce a responsive oral insulin nanoformulation. This formulation is pH responsive, is insoluble in acidic environments and shows increased absorption in human duodenum explants and Caenorhabditis elegans at neutral pH. The formulation is sensitive to glucosidase enzymes to trigger insulin release. It is found that the formulation distributes to the liver in mice and rats after oral administration and promotes a dose-dependent reduction in blood glucose without promoting hypoglycaemia or weight gain in diabetic rodents. Non-diabetic baboons also show a dose-dependent reduction in blood glucose. No biochemical or haematological toxicity or adverse events were observed in mice, rats and non-human primates. The formulation demonstrates the potential to orally control blood glucose without hypoglycaemic episodes.

Design and Development of Insulin Loaded Microspheres for Oral Delivery

Protease inhibitor-encapsulated human insulin microspheres were developed and evaluated in this research in order to determine the optimal formulation. Manufacturing human insulin microspheres involved coating them with eudragit S-100, stabilizing them with polyvinyl alcohol, and evaporating the solvent from w/o/w multiple emulsions. Excellent encapsulation efficiency and pH-dependent controlled release were demonstrated by human insulin-loaded eudragit L-100 microspheres with a protease inhibitor. This helped encapsulate and transfer insulin to the best absorption zone. Thus, insulin absorption and physiological response increased. Thus, insulin formulations enhance efficacy, making microsphere insulin injection more efficient as a diabetic treatment. Drug-polymer ratio affects microsphere size and form. The effect of emulsifying agent amount on microsphere size and manufacturing yield. Eudrajit RL, microspheres loaded with insulin, are more successfully formulated and manufactured at optimal concentrations of polymer and emulsifying agent

Week-long normoglycaemia in diabetic mice and minipigs via a subcutaneous dose of a glucose-responsive insulin complex.

Glucose-responsive formulations of insulin can increase its therapeutic index and reduce the burden of its administration. However, it has been difficult to develop single-dosage formulations that can release insulin in both a sustained and glucose-responsive manner. Here we report the development of a subcutaneously injected glucose-responsive formulation that nearly does not trigger the formation of a fibrous capsule and that leads to week-long normoglycaemia and negligible hypoglycaemia in mice and minipigs with type 1 diabetes. The formulation consists of gluconic acid-modified recombinant human insulin binding tightly to poly-L-lysine modified by 4-carboxy-3-fluorophenylboronic acid via glucose-responsive phenylboronic acid-diol complexation and electrostatic attraction. When the insulin complex is exposed to high glucose concentrations, the phenylboronic acid moieties of the polymers bind rapidly to glucose, breaking the complexation and reducing the polymers' positive charge density, which promotes the release of insulin. The therapeutic performance of this long-acting single-dose formulation supports its further evaluation and clinical translational studies.

Hypoglycemic Effect of Orally Delivered Insulin Nanoparticles Compared to Subcutaneous Recombinant Human Soluble Insulin in Hyperglycemic Male Rats

Background: Insulin is available as an injectable drug and remains the mainstay of therapy. Researchers have attempted to develop an oral formulation of insulin, particularly utilizing nanoparticles (NPs). Objective: To assess the efficacy and safety of insulin-loaded D-α-Tocopherol polyethylene glycol succinate (TPGS)-emulsified PEG-capped PLGA NP in comparison to insulin-loaded PLGA NP and subcutaneous (SC) insulin in an in vitro and in vivo diabetic rat model. Methods: Two biocompatible and biodegradable NPs were used, in which 20 IU/kg of recombinant human soluble insulin was incorporated. NP1 was PLGA-loaded with human insulin, while NP2 was PLGA-PEG-TPGS-loaded with human insulin. The physical characteristics of the NPs were examined in an in vitro and in vivo study on a hyperglycemic rat model for a 24-hour duration. Results: For the first 3 hours, SC insulin showed a better reduction in serum glucose levels (SG) compared to both NP1 and NP2. A smooth, sustained reduction in SG was observed and maintained till the end of 24 hours with both NPs. NP1 maintained SG reduction for 6 hours before experiencing an increase, while NP2 demonstrated superior sustained reduction in SG beyond the 12-hour evaluation period. Conclusions: PLGA-PEG-TPGS NP can act as a potential carrier for oral insulin delivery and maintain good glycemic control for up to 24 hours.

Diselenide-bond replacement of the external disulfide bond of insulin increases its oligomerization leading to sustained activity

Seleno-insulin, a class of artificial insulin analogs, in which one of the three disulfide-bonds (S-S’s) of wild-type insulin (Ins) is replaced by a diselenide-bond (Se-Se), is attracting attention for its unique chemical and physiological properties that differ from those of Ins. Previously, we pioneered the development of a [C7UA,C7UB] analog of bovine pancreatic insulin (SeIns) as the first example, and demonstrated its high resistance against insulin-degrading enzyme (IDE). In this study, the conditions for the synthesis of SeIns via native chain assembly (NCA) were optimized to attain a maximum yield of 72%, which is comparable to the in vitro folding efficiency for single-chain proinsulin. When the resistance of BPIns to IDE was evaluated in the presence of SeIns, the degradation rate of BPIns became significantly slower than that of BPIns alone. Furthermore, the investigation on the intermolecular association properties of SeIns and BPIns using analytical ultracentrifugation suggested that SeIns readily forms oligomers not only with its own but also with BPIns. The hypoglycemic effect of SeIns on diabetic rats was observed at a dose of 150 μg/300 g rat. The strategy of replacing the solvent-exposed S-S with Se-Se provides new guidance for the design of long-acting insulin formulations.

Characteristics, glycemic control and outcomes of adults with type-2 diabetes mellitus attending specialized clinics in primary healthcare centers in Bahrain-A cross-sectional study.

Diabetes mellitus is a global health challenge that requires continuous and multidisciplinary management. Suboptimal diabetes management results in serious complications that impose a huge burden on patients and the healthcare system. This study aimed to assess the characteristics, glycemic control and outcomes of patients with type-2 diabetes attending primary healthcare centers in Bahrain according to the new American Diabetes Association (ADA) guidelines. A cross-sectional study was conducted among adult patients with type-2 diabetes mellitus attending diabetic clinics in Bahrain. A multi-stage sampling technique was adopted. The data collection tool consisted of three parts: baseline and sociodemographic data, the physical measures of the patients and the most recent laboratory results. An A1C of less than 7% was indicative of good glycemic control. A total of 721 patients with type-2 diabetes mellitus were included with an average age of 58.4 years. Most patients were hypertensive (n = 457, 63.4%), and half of them were hyperlipidemic (n = 373, 51.7%). Around 57% (n = 402) of the patients adopted lifestyle modifications, 14.8% adopted diet control measures and around half performed weekly regular exercises. More than 92% of the cohort were on metformin, 52.0% (n = 375) were on Sulphonylurea medications and 41% (n = 298) were on insulin formulations. While only 40% of the patients had controlled diabetes (n = 283, 39.3%) and hypertension (n = 298, 41.3%), most patients achieved adequate cholesterol and low-density lipoprotein levels (83.2% and 76.6%, respectively). Non-Bahraini (P ≤ 0.001), young (P = 0.027) and obese patients (P = 0.003) had lower glycemic control measures. Adequate cholesterol levels were seen more in patients with a controlled glycemic index (P = 0.015). Considering the new glycemic targets, glycemic and hypertension control was poor among diabetic patients, especially non-Bahraini, obese and young patients. Urgent interventions by policymakers, physicians and caregivers are needed to improve the outcomes of diabetes.

Pramlintide an Adjunct to Insulin Therapy: Challenges and Recent Progress in Delivery.

Dysregulation of various glucoregulatory hormones lead to failure of insulin monotherapy in patients with diabetes mellitus due to various reasons, including severe hypoglycemia, glycemic hypervariability, and an increased risk of microvascular complications. However, pramlintide as an adjunct to insulin therapy enhances glucagon suppression and thereby offers improved glycemic control. Clinical studies have shown that pramlintide improves glycemic control, reduces postprandial glucose excursions, and promotes weight loss in patients with type 1 and type 2 diabetes. Although clinical benefits of pramlintide are well reported, there still exists a high patient resistance for the therapy, as separate injections for pramlintide and insulin must be administered. Although marketed insulin formulations generally demonstrate a peak action in 60-90 minutes, pramlintide elicits its peak concentration at around 20-30 minutes after administration. Thus, owing to the significant differences in pharmacokinetics of exogenously administered pramlintide and insulin, the therapy fails to elicit its action otherwise produced by the endogenous hormones. Hence, strategies such as delaying the release of pramlintide by using inorganic polymers like silica, synthetic polymers like polycaprolactone, and lipids have been employed. Also, approaches like noncovalent conjugation, polyelectrolyte complexation, and use of amphiphilic excipients for codelivery of insulin and pramlintide have been explored to address the issues with pramlintide delivery and improve patient adherence to the therapy. This approach may usher in a new era of diabetes management, offering patients multiple options to tailor their treatment and improve their quality of life. SIGNIFICANCE STATEMENT: To our knowledge, this is the first report that summarizes various challenges in insulin and pramlintide codelivery and strategies to overcome them. The paper also provides deeper insights into various novel formulation strategies for pramlintide that could further broaden the reader's understanding of peptide codelivery.

THU278 Hidden In The Immune System: Exogenous Insulin Antibody Syndrome In A Patient With Latent Autoimmune Diabetes In Adults

Abstract Disclosure: H.L. King: None. R. Nagappan: None. A. Sliwinska: None. Hidden in the Immune System: Exogenous Insulin Antibody Syndrome in a Patient with Latent Autoimmune Diabetes in Adults Background: Exogenous insulin antibody syndrome (EIAS) is a rare syndrome associated with insulin antibodies induced by exogenous insulin, found predominantly in patients with type 2 diabetes using various insulin formulations. Here, we present a case of young man previously diagnosed with type 2 diabetes, who was found to have severe refractory diabetic ketoacidosis (DKA) due to EIAS. Clinical Case: A 46-year-old man with a history of type 2 diabetes presented to an outside hospital for one week of fever and malaise. Laboratory studies were notable for serum glucose of 600 mg/dL (70-90mg/dL), HCO3 3 mmol/L (22-28mmol/L), and creatinine of 3.9 mg/dL (0.7-1.3mg/dL). He was diagnosed with DKA, shock and renal failure. During hospital stay, he remained on an insulin drip due to multiple unsuccessful attempts of transitioning to subcutaneous insulin, requiring over 1000 Units of insulin daily. This prompted insulin antibody testing that resulted elevated at >50U/mL (0-0.4U/mL), concerning for EIAS. Treatment was initiated with 5 days of IVIG and mycophenolate mofetil. During this treatment, his baseline insulin infusion rate of 30 Units/hr declined to 18 Units/hr, however at day 3, insulin requirements again increased. For better evaluation, quantitative insulin antibody values were requested and resulted as 362.5U/mL, followed by 350.9U/mL post IVIG treatment. After no significant improvement, patient was transferred to our hospital for further management of EIAS. Plasmapheresis was initiated followed by rituximab with plans for long term maintenance therapy. Dexamethasone was trialed but shortly after discontinued due concern of increased insulin resistance and hyperglycemia. Metformin was also started but discontinued due to concern of worsening acidosis in the setting of acute renal failure requiring CRRT. Ultimately, the patient was transitioned to subcutaneous U500 BID 75-150 Units based on scale. At discharge, metformin and pioglitazone were started. Due to the history of early onset insulin-dependent diabetes at age 30, he was tested for GAD-65 which resulted as positive at 0.28 nmol/L (<=0.02 nmol/L) and C peptide of 0.9ng/mL (0.8 - 3.9 ng/mL) consistent with LADA. Conclusion: EIAS is a rare and very challenging entity, increasing risks of severe ketoacidosis, hypoglycemic episodes and numerous other complications. Although mostly reported in type 2 diabetes, EIAS can occur in patients with LADA suggesting that autoimmunity may play a role. There is no FDA approved treatment, however attempts focus on eliminating antibodies by plasmapheresis, IVIG and immunotherapeutic agents. Presentation: Thursday, June 15, 2023

Diabetes among Muslims during Ramadan: A narrative review.

Fasting during the month of Ramadan is one of the five fundamental principles of Islam, and it is obligatory for healthy Muslim adults and adolescents. During the fasting month, Muslims usually have two meals a day, suhur (before dawn) and iftar (after dusk). However, diabetic patients may face difficulties when fasting, so it is important for medical staff to educate them on safe fasting practices. Prolonged strict fasting can increase the risk of hypoglycemia and diabetic ketoacidosis, but with proper knowledge, careful planning, and medication adjustment, diabetic Muslim patients can fast during Ramadan. For this review, a literature search was conducted using PubMed and Google Scholar until May 2023. Articles other than the English language were excluded. Current strategies for managing blood sugar levels during Ramadan include a combination of patient education on nutrition, regular monitoring of blood glucose, medications, and insulin therapy. Insulin therapy can be continued during fasting if properly titrated to the patients' needs, and finger prick blood sugar levels should be assessed regularly. If certain symptoms such as hypoglycemia, hyperglycemia, dehydration, or acute illness occur, or blood glucose levels become too high (> 300 mg/dL) or too low (< 70 mg/dL), the fast should be broken. New insulin formulations such as pegylated insulin and medications like tirzepatide, a dual agonist of gastric-inhibitory peptideand glucagonlike-peptide 1 receptors, have shown promise in managing blood sugar levels during Ramadan. Non-insulin-dependent medications like sodium-glucose-cotransporter-2 inhibitors, including the Food and Drug Administration-approved ertugliflozin, are also being used to provide additional cardiovascular benefits in patients with type 2 diabetes.

Nurse's knowledge and awareness regarding insulin therapy for diabetic patients in the emergency department at al diwaniyah teaching hospital

Background: Diabetes Mellitus has affected humans for many decades, and the descriptions of it are amazing important, which it's incidence is rising abruptly worldwide, Nowadays, the introduction of new insulin formulations and a new emphasis on tight blood glucose control make inpatient diabetes treatment has become more complicated, and it requires very careful monitoring by the nursing staff, while expanding their knowledge and practical skills to prevent dangerous side effects when giving insulin to patients. Objectives: The study aims to assess the nurse's knowledge and awareness regarding Insulin Therapy for Diabetic Patients in the emergency department at Al Diwaniyah Teaching Hospital, and finding the association between demographic data which as the gender, educational level, years of experiences in the emergency department, and training course and their level of nurse's knowledge. Materials and Methods: Descriptive study has been carried out to assess the nurse's knowledge and awareness regarding insulin therapy for diabetic patients in the emergency department at Al Diwaniyah Teaching Hospital for the period from 16 of January 2022 to 10 July of 2022. A purposive sample of (50) nurses who work in the emergency department at Al Diwaniyah Teaching Hospital. A questionnaire format was constructed to assess the knowledge of nurses about insulin therapy for diabetic Patients in the emergency department at Al Diwaniyah Teaching Hospital.The questionnaire was divide to two main parts: First Part: Demographic data of the sample include (Age, Gender, Educational level, Duration of work as a nurse, Years of experiences and training courses regarding management of diabetic patients and insulin therapy. Second Part: This part include 18 multiple questions to assess the knowledge of nurses and awareness about insulin therapy for diabetic Patients in the emergency department at Al Diwaniyah Teaching Hospital. Results: Results of the study shows the highest of nurses’ knowledge items are (Moderate). While (Bad) was the main nurses’ knowledge regarding to store insulin and perform a physical assessment to establish a baseline before beginning therapy. The majority of nurses 77.8% of nurses' knowledge have Moderate, while 11.1% of them have Bad and 11.1% of them have (Good) regarding to overall Assessment of nurses’ knowledge, there are a highly association between education level, and years of experience about management of diabetic Patients undergoing insulin therapy in the emergency department. Conclusion: The study concluded that the highest of nurses’ knowledge items are (Moderate). While (Bad) was the main nurses’ knowledge regarding to store insulin and perform a physical assessment to establish a baseline before beginning therapy. Also there are a highly association between level of education, and years of experience about insulin therapy for diabetic patients in the emergency department and their efficacy of nurses’ knowledge. Recommendations: Increasing the knowledge and awareness of nursing staff concerning insulin therapy for diabetic patients by improving training courses. Also establishing education programs to improve nurses' knowledge and awareness toward the newest issues related to insulin therapy in the emergency department.

Mast Cell Deficiency in Mice Attenuates Insulin Phenolic Preservative-Induced Inflammation.

One major obstacle that limits the lifespan of insulin infusion pumps is surmounting the tissue site reaction at the device implantation site. All commercial insulin formulations contain insulin phenolic preservatives (IPPs) designed to ensure insulin protein stability and prolong shelf-life. However, our laboratory demonstrated that these preservatives are cytotoxic and induce inflammation. Mature mast cells (MCs) reside in cutaneous tissue and are one of the first responders to an epidermal breach. Upon activation, MCs release proinflammatory and immunomodulatory prepacked mediators that exacerbate these inflammatory reactions. Thus, we hypothesized that once the epidermis is breached, cutaneous MCs are triggered inciting the inflammatory response to IPP-induced inflammation. This hypothesis was pursued utilizing our modified in vivo mouse air pouch model, including a c-kit dependent (C57BL/6J-kitW-sh/W-sh) and a c-kit independent (Cpa3-Cre; Mcl-1fl/fl) MC-deficient mouse model. Leukocytes were quantified in the mouse air pouch lavage fluid following flow cytometry analysis for IPP infusion under three different states, insulin-containing phenolic preservatives (Humalog®), insulin preservatives alone, and normal saline as a control. The air pouch wall was assessed using histopathological evaluations. Flow cytometry analysis demonstrated a statistically significant difference in inflammatory cell recruitment for both MC-deficient mouse models when compared to the control strain including infused control saline. Significantly less inflammation was observed at the site of infusion for the MC-deficient strains compared to the control strain. Overall, concordant results were obtained in both mouse types, C57Bl6-kitW-sh/W-sh and Cpa3-Cre; Mcl-1fl/fl. These findings in multiple model systems support the conclusion that MCs have important or possible unique roles in IPP-induced inflammation.

Current Status of Weekly Insulin Analogs and Their Pharmacokinetic/Pharmacodynamic Evaluation by the Euglycemic Clamp Technique.

Diabetes mellitus represents a significant global health threat characterized by hyperglycemia caused by inadequate insulin secretion and/or insulin resistance. Exogenous insulin supplements had been recognized as a crucial treatment for achieving successful glycemic control in patients with Type 1 and most patients with Type 2 diabetes. Over the past century, substantial progress has been made in the development of novel insulin formulations, including the super-fast-acting and long-acting basal insulin analogs, of which the latter is indispensable for the management of nocturnal fasting and intraprandial blood glucose within the normal physiological range. Recently, combining chemical and genetic engineering with drug optimization have resulted in a formidable evolution in ultra-long-acting weekly insulin. Here, the current state of once-weekly insulin analogs and the euglycemic clamp technique used in the early clinical development to elucidate the pharmacokinetics and pharmacodynamics of this type of novel weekly insulin analogs were systematically overviewed.

A Comparison of Faster Insulin Aspart with Standard Insulin Aspart Using Hybrid Automated Insulin Delivery System in Active Children and Adolescents with Type 1 Diabetes: A Randomized Double-Blind Crossover Trial.

Objective: To evaluate the use of faster acting (FIA) and standard insulin aspart (SIA) with hybrid automated insulin delivery (AID) in active youth with type 1 diabetes. Research Design and Methods: In this double-blind multinational randomized crossover trial, 30 children and adolescents with type 1 diabetes (16 females; aged 15.0 ± 1.7 years; baseline HbA1c 7.5% ± 0.9% [58 ± 9.8 mmol/mol]) underwent two unrestricted 4-week periods using hybrid AID with either FIA or SIA in random order. During both interventions, participants were using the hybrid AID (investigational version of MiniMed™ 780G; Medtronic). Participants were encouraged to exercise as frequently as possible, capturing physical activity with an activity monitor. The primary outcome was the percentage of sensor glucose time above range (180 mg/dL [10.0 mmol/L]) measured by continuous glucose monitoring. Results: In an intention-to-treat analysis, mean time above range was 31% ± 15% at baseline, 19% ± 6% during FIA use, and 20% ± 6% during SIA use with no difference between treatments: mean difference = -0.9%; 95% CI: -2.4% to 0.6%; P = 0.23. Similarly, there was no difference in mean time in range (TIR) (78% and 77%) or median time below range (2.5% and 2.8%). Glycemic outcomes during exercise or postprandial periods were comparable for the two treatment arms. No severe hypoglycemia or diabetic ketoacidosis events occurred. Conclusions: FIA was not superior to SIA with hybrid AID system use in physically active children and adolescents with type 1 diabetes. Nonetheless, both insulin formulations enabled high overall TIR and low time above and below ranges, even during and after documented exercise. Trial Registration Clinicaltrials.gov: NCT04853030.

Transferosomal gel for transdermal delivery of insulin: Formulation development and ex vivo permeation study

The study was to develop a transdermal formulation of insulin, determine its pharmaceutical characteristics, and finally test its efficacy. In the current study - Transfersomes were selected as the carrier system for insulin. The transfersomes were produced by the hand-shaking method using soy lecithin phospholipid and sodium deoxycholate as the objective of the surfactant. The prepared transfersomes were subjected to characterization with optical microscopy and scanning electron microscope to estimate the shape and size of transfersomes respectively. In addition, the physical and drug-excipient interaction studies were carried out and the transfersomes were also studied for the insulin entrapment efficiency.Results of the study showed the shape of the transfersomes was well defined and spherical. The mean size of transfersomes was estimated to be 130 ​nm The transfersomes were found to be stable over a period of four weeks. The insulin entrapment efficiency of the transfersomes was estimated to be 87.3%. The ex-vivo skin permeation study employing goat ear skin with the transfersomes hydrogel revealed that there was a slow and sustained release of insulin till 180 ​min. From the above study, it may be concluded that transfersomes are suitable carriers of insulin across biological membranes.

EPR Viscometric Measurements Using a 13C-Labeled Triarylmethyl Radical in Protein-based Biotherapeutics and Human Synovial Fluids.

The viscosity measurements are of clinical significance for evaluation of the potential pathological conditions of biological lubricants such as synovial fluids of joints, and for formulation and characterization of peptide- and protein-based biotherapeutics. Due to inherent potential therapeutic activity, protein drugs have proven to be one of the most efficient therapeutic agents in treatment of several life-threatening disorders, such as diabetes and autoimmune diseases. However, home-use applications for treating chronic inflammatory diseases, such as diabetes and rheumatoid arthritis, necessitate the development of high-concentration insulin and monoclonal antibodies formulations for patient self-administration. High protein concentrations can affect viscosity of the corresponding drug solutions complicating their manufacture and administration. The measurements of the viscosity of new insulin analogs and monoclonal antibodies solutions under development is of practical importance to avoid unwanted highly viscous, and therefore, painful for injection drug formulations. Recently, we have demonstrated capability of the electron paramagnetic resonance (EPR) viscometry using viscosity-sensitive 13C-labeled trityl spin probe (13C1-dFT) to report the viscosity of human blood, and interstitial fluids measured in various organs in mice ex-vivo and in anesthetized mice, in vivo. In the present work, we demonstrate utility of the EPR viscometry using 13C1-dFT to measure microviscosity of commercial insulin samples, antibodies solution, and human synovial fluids using small microliter volume samples (5-50 μL). This viscometry analysis approach provides useful tool to control formulations and administration of new biopharmaceuticals, and for evaluation of the state of synovial fluids of importance for clinical applications.

107-LB: Clinical Performance of Extended Mio 30 Infusion Set

Objective: Medtronic Mio™ 30 infusion set (M30IS) is a single use IS for pump users with pre-loaded inserter, a 30° insertion angle, and labeled for 3-day use. The M30IS wear duration is impacted by initial local trauma caused by insertion and sustained inflammation by cannula &amp; insulin infusion (insulin aggregates &amp; other impurities in the infusate), with the latter being predominant. An extended Mio™ 30 infusion set (EM30IS) was developed by improving insulin formulation stability in the fluid path. This study reports on the performance of the EM30IS in persons with T1D during an early feasibility trial (ClinicalTrials.gov: NCT05544643). Method: This is a X over study of EM30IS and M30IS on 21 subjects with type 1 diabetes. Each subject wore both sets 4-5 times each on a preferred site that was continuously infused with insulin lispro or aspart subcutaneously via a Medtronic 780G pump for 3 days (M30IS), 7 days (EM30IS) or until failure. Endpoints of safety and effectiveness (failure rate due to unexplained hyperglycemia &amp;lt;16%) were evaluated. Exploratory analyses related to performance and glycemic control were also evaluated. Results: The EM30IS survival rate at 6 days (70%) was comparable to M30IS survival rate at 3 days (63%). Glycemic control outcomes were equivalent (see Table 1) and there were no episodes of EM30IS-related severe hypoglycemia or DKA. Conclusion: The EM30IS was safe and its performance at 6 days was equivalent to the performance of M30IS at 3 days. Disclosure O. Cohen: Employee; Medtronic. Y. Cohen: None. S. Chattaraj: Employee; Medtronic. G. Zhang: Employee; Medtronic. E. Anselmo: Employee; Medtronic. A. Tirosh: Advisory Panel; Medtronic. Research Support; Medtronic. Speaker's Bureau; Medtronic. Advisory Panel; Novo Nordisk. Speaker's Bureau; Novo Nordisk. Advisory Panel; Sanofi. Speaker's Bureau; Sanofi. Research Support; Sanofi. Advisory Panel; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Funding Medtronic