The aim of this study was to evaluate the factors, which affect insulin release and stability in simulated gastrointestinal fluid that ultimately will reduce the bioavailability of insulin in a nanoparticulate oral delivery system. The focus was on nanoparticulate carriers developed by C. Reis, which have the highest level of bioavailability reported in the literature thus far. Particles observed by TEM were spherical and particle analyzer data showed that the peak of the distribution was 10 nm. Entrapment efficiency of insulin was 85%. Insulin retention/release was evaluated in both enzymatic and enzyme-free simulated digestive fluids. HPLC measurement showed that insulin was stable in acid condition in presence and absence of pepsin. By changing the pH to 6.8 in an intestinal simulation, the amount of insulin decreased such that at the end of the 5 h simulation, 71% of the insulin was measureable in simulated GI fluid in presence of enzymes. Insulin release profile from nanoparticles was low in gastric condition. After changing the pH to 6.8, an initial release of insulin occurred in the first 1h followed by plateau state in the remaining 2h. After a total of 5h in acidic followed by neutral pH medium, the formulation retained 48% of the insulin in the particles in simulated GI fluid in presence of enzyme. As confirmation of the amount of retained insulin, after 5h, particles were dissolved and the formulation was shown to fully retain up to 45% of the insulin in extended simulated gastrointestinal condition in the presence of enzymes. Insulin release behavior was investigated in different simulated small intestinal media by incorporating phosphate buffer or bicarbonate buffer and physiological electrolytes. The release rate from particles in the phosphate buffer was faster compared to bicarbonate buffers. KBB-C showed a release profile that was very different from other media, with about 10% released in the first 30 min and 70% of the insulin remaining entrapped within the particles at the end of the experiment. Release in this buffer was reduced due to the decreased sodium to calcium ratio compared to the other KBB media. / Thesis (Master, Chemical Engineering) -- Queen's University, 2013-08-26 13:02:50.837

The goal of this study was to develop a model of the gastrointestinal tract (GIT) to be used for in vitro testing of oral insulin delivery devices. The method and intensity of mixing and effects of gastrointestinal fluids with and without enzymes were evaluated. Comparisons were made between an actively mixed simulator and a passively mixed simulator, where the actively mixed simulator is a magnetically stirred flask while the passively mixed simulator is a flexible container on a rocking stage. Slower mixing times and larger time constants for mixing were seen for the passively mixed simulator during a pH tracer experiment. Release studies were performed with several oral insulin delivery device models to evaluate the effects of different mixing techniques on insulin release. In all cases, the more intense mixing of the actively mixed simulator resulted in more insulin release. When using a nanoparticle model in intestinal fluid for example, 100% insulin release was observed in the actively mixed simulator while only 53% was released in the passively mixed simulator after 1 hour. Trypsin and pepsin were used to determine the ability of a drug delivery device to protect insulin from enzymatic degradation in which trypsin was added to simulated intestinal fluid and pepsin was added to simulated gastric fluid. Premature insulin release and insulin denaturation at body temperature occurred in the intestinal fluid so the protective effects against trypsin were unable to be effectively evaluated. An increase in insulin loss from 70% to 95% was detected in the presence of pepsin compared to gastric fluid without enzymes in the actively mixed simulator, indicating that acid hydrolysis of insulin as well as protease attack by pepsin will impact the behavior of an insulin delivery device. An improvement in insulin retention was observed in the passively mixed simulator. After 1 hour, insulin retained was increased from 4% in the actively mixed simulator to 10% in the passively mixed simulator, and after 2 hours, this increase was 2% to 7%. Premature insulin release from the delivery device, acid hydrolysis, temperature denaturation, and enzymatic degradation are factors limiting the effectiveness of oral insulin. / Thesis (Master, Chemical Engineering) -- Queen's University, 2011-08-19 19:29:52.804

Advances in medical treatment are leading away from generalized care towards intelligent systems or devices which can sense and respond to their environment. With these devices, the burden of monitoring and dosing for treatment can be removed from the doctor (or the patient) and be placed on the device itself. Implicit closed-loop control systems will allow the device to respond to its environment and release therapeutic agent in response to a specific stimulus. Environmentally responsive hydrogels show great promise in being incorporated in such an intelligent device, such as pH-responsive hydrogels which can swell and deswell in response to changes in the pH of the media. Thus, pH changes can be exploited for controlled and intelligent drug delivery when used in combination with these pH-responsive hydrogels. In this work, heterogeneous, thermal-redox initiated free-radical polymerizations were developed to synthesize novel pH-responsive hydrogels, microparticles, and nanogels. The specific disease of interest was type I diabetes, which requires daily doses of insulin both at a basal amount and either a postprandial or preprandial bolus in order to maintain blood glucose levels within safe limits. To allow pH-responsive hydrogels to be sensitive to glucose, glucose oxidase was incorporated which oxidizes glucose to gluconic acid. A novel inverse-emulsion polymerization method was developed for the synthesis of poly[2-(diethylaminoethyl methacrylate)-grafted-polyethylene glycol monoethyl ether monomethacrylate] (P(DEAEM-g-PEGMMA)) nanogels (100-400 nm) for intelligent insulin delivery. The new polymerization method allowed the incorporation of hydrophilic components, such as glucose oxidase and catalase, as well as PEG surface tethers of lengths 400 Da up to 2000 Da. Surface tethers successfully decreased the surface charge of the nanogels. Insulin loading and release was determined for microparticles which were able to imbibe substantial amounts of insulin from solution when swollen, entrap the insulin when collapsed, and then release the insulin in response to either a pH or glucose stimulus. / text

Type 1 diabetes in pregnancy is associated with higher rates of maternal and infant complications. The complications are associated with maternal hyperglycaemia. Thus, the main goal of treatment for these women is to optimise glycaemic control and thereby improve clinical outcomes for themselves and for their baby. This thesis examines glycaemic control in the mothers and infants of pregnancies affected by type 1 diabetes. I present the first home studies of closed-loop insulin delivery in this population. The aim of these studies was to assess the feasibility, efficacy, and utility of overnight and then day-and-night closed-loop insulin delivery in pregnant women with type 1 diabetes. The overnight study, which examined 16 pregnant women (mean age 34.1 years, HbA1c 6.8%, 14.4 weeks gestation), compared overnight use of the closed-loop system with sensor-augmented pump therapy in a 2x4-week randomised crossover design. We found that closed-loop therapy was associated with a 15% improvement in overnight time spent with target glucose concentration (3.5-7.8 mmol/L; 74.7% during closed-loop use vs 59.5% during sensor-augmented pump therapy use). The day-and night study also examined 16 pregnant women (mean age 32.8 years, HbA1c 8.0%, 16.4 weeks’ gestation) using a 2x4-week randomised crossover design to compare continuous day-and-night use of closed-loop insulin delivery with sensor-augmented pump therapy. This study enrolled a more diverse range of participants than the overnight study, but found that closed-loop therapy was associated with comparable glucose control and significantly less hypoglycaemia than sensor-augmented pump therapy. Chapter 4 examines women’s experiences of using the closed-loop system during pregnancy. While the system was generally well-received by participants, individual interactions and perceptions of the system varied markedly, and often did not align with biomedical measures of glycaemic response. After participation in either crossover study, participants could choose to continue using the technology until delivery (overnight study), or until 6 weeks post-partum (day and night study). Those data are presented in Chapters 2 and 3. The combined data from the women who used the closed-loop system during labour and delivery in either study are presented in Chapter 5. Tight glycaemic control during labour and delivery has traditionally been considered important for reducing rates of neonatal hypoglycaemia. However, despite very tight maternal glycaemic control in the women who used closed-loop insulin delivery, rates of neonatal hypoglycaemia were high. In order to better characterise the relationship between maternal glucose control in type 1 diabetes pregnancy and neonatal hypoglycaemia, Chapter 6 details an observational study in which continuous glucose monitoring was used to measure maternal and neonatal glycaemic control in 16 mother-infant pairs. The study found that, while neonatal hypoglycaemia was very frequent, it was generally, but not always, detected and treated effectively. Together, these studies suggest that a novel management tool, closed-loop insulin delivery, can improve overnight glycaemic control, and perhaps reduce hypoglycaemia during type 1 diabetes-affected pregnancies above what is possible with currently available treatments. However, complication rates remain high for these women and their babies. Further research is needed both to further develop treatments that can improve maternal glycaemic control, and to better understand the pathogenesis of diabetes-related pregnancy complications, with the ultimate goal of improving outcomes for women and their children. A definitive trial to assess the clinical efficacy, patient acceptability, and cost effectiveness of closed-loop is now warranted.

Achieving tight glucose control safely in type 1 diabetes with currently available methods of insulin delivery is challenging. Aggressive regimens carry an increased risk of hypoglycaemia, particularly overnight. Both alcohol consumption and exercise predispose further to low glucose levels. The demands are even greater in pregnancy where, in addition to limiting hypoglycaemia, avoidance of postprandial hyperglycaemia is critical to minimising adverse obstetric outcomes. The aim of my studies was to evaluate feasibility and safety of a closed-loop or ’artificial pancreas’ system linking insulin delivery with continuous glucose monitoring (CGM), in adults with type 1 diabetes in a controlled setting. Three randomised crossover studies compared closed-loop insulin delivery with conventional insulin pump therapy on two separate occasions, matched in meals and activities. During closed-loop visits, CGM values were entered into a computer containing a model predictive control algorithm which advised on basal insulin infusion for subcutaneous delivery, every 15 minutes. During control visits, usual insulin pump regimen was continued. The feasibility study evaluated overnight closed-loop in 12 adults (seven females, mean age 37.7 years, HbA1c 7.8%) following 60g- carbohydrate evening meal. A follow-up study assessed overnight closed-loop in 12 further adults (seven females, mean age 37.2 years, HbA1c 7.8%) following 100g-carbohydrate meal and (mean 564 ml) white wine. The third study evaluated 24 hours of closed-loop in 12 pregnant women (mean age 32.9 years, 19 to 23 weeks gestation, HbA1c 6.4%) during normal daily activities, including low and moderate intensity exercise. Activity and glucose levels were also measured during free-living. CGM performance during exercise was evaluated. Overnight closed-loop insulin delivery in adults, compared with conventional pump therapy, increased time spent with plasma glucose in target range (3.9−8.0 mmol/l) following both standard meal (81% versus 57%; p = 0.012) and large meal accompanied by alcohol (70% versus 46%; p = 0.012). Glycaemic variability, and time spent in hypo- and hyper- glycaemia were lowered. In pregnant women, day and night closed-loop insulin delivery was as effective as usual pump regimen (81% versus 81% time spent with plasma glucose 3.5−7.8 mmol/l; p = 0.754). Hypoglycaemia occurred following exercise, although closed-loop prevented nocturnal episodes. Glycaemic control during free-living was suboptimal, compared with controlled diet and exercise conditions. Accuracy of CGM was lower during exercise. In conclusion, these studies confirm the feasibility and efficacy of overnight closed-loop insulin delivery in adults with type 1 diabetes. Closed-loop is safe during pregnancy and may be beneficial in women with suboptimal glycaemic control. Meals and physical activity currently limit optimal daytime use of closed-loop.

Type 1 diabetes is one of the most common chronic conditions in childhood and adolescence. Despite ongoing development of more physiological insulin preparations, recent advancements in insulin pump technology and more accurate blood glucose monitoring, in clinical practice it remains challenging to achieve normoglycaemia whilst reducing the risk of hypoglycaemia, particularly in young people with type 1 diabetes. Closed-loop insulin delivery (the artificial pancreas) is an emerging technology gradually progressing from bench to clinical practice. Closed-loop systems combine glucose sensing with computer-based algorithm informed insulin delivery to provide real-time glucose-responsive insulin administration. The key objective of my thesis is to evaluate the safety, efficacy and utility of closed-loop insulin delivery in children and adolescents with type 1 diabetes outside of the research facility setting. Results of five clinical trials are presented in the main chapters of this thesis. In a mechanistic study, the impact of glucose sensor operation duration on efficacy of overnight closed-loop was investigated comparing closed-loop performance on day 1 of sensor insertion to day 3 to 4 of sensor. Twelve adolescents with type 1 diabetes attended the research facility for two overnight visits. The sequence of the interventions was random. Despite differences in sensor accuracy, overnight CL glucose control informed by sensor glucose on day 1 or day 3-4 after sensor insertion was comparable. The model predictive controller appears to mitigate against sensor inaccuracies. In home settings, overnight closed-loop application was evaluated over three months in 25 children and adolescents with type 1 diabetes aged six to 18 years. The study was conducted at three centres in the UK and adopted a randomised cross-over design. Compared to sensor-augmented pump therapy, overnight home use of closed-loop increased the proportion of time sensor glucose was in target, and reduced mean glucose and hypoglycaemia. Two randomised crossover studies evaluated the safety and efficacy of day-and-night hybrid closed-loop insulin delivery in young people with type 1 diabetes aged 10 to 18 years over seven days, and 21 days, respectively. A total of 24 subjects were enrolled in this single centre trial. Free-living home use of day-and-night closed-loop in suboptimally controlled adolescents with type 1 diabetes was safe, and improved glucose control without increasing the risk of hypoglycaemia. Finally, closed-loop technology was assessed in five very young children (aged one to seven years) with type 1 diabetes in a two-period, crossover study. Closed-loop was used during both 3-week intervention periods, either with standard strength insulin (U100), or with diluted insulin (U20). The order of intervention was random. Free-living home use of day-and-night hybrid closed-loop in very young children with type 1 diabetes was feasible and safe. Glucose control was comparable during both intervention periods. Thus, use of diluted insulin during closed-loop insulin delivery might not be of additional benefit in this population. In conclusion, studies conducted as part of my thesis demonstrate that use of hybrid closed-loop insulin delivery systems in children and adolescents aged one to 18 years in free daily living without remote monitoring or supervision is feasible, safe and effective. My work supports the progression of this technology from research to mainstream clinical practice.

No description available.

Objectif : Comparer les dispositifs de délivrance automatisée d’insuline open-source (DDAI-OS) et les DDAI commerciaux hybrides sur le contrôle glycémique, la qualité de vie rapportée, et la sécurité chez des adultes avec diabète de type 1 (DT1). Méthodes : Étude prospective, observationnelle, de non-infériorité, comparative et en vie réelle, incluant 78 adultes canadiens avec un DT1 et utilisant un DDAI ≥ 3 mois. Quatre semaines de mesure continue du glucose ont permis d’évaluer le % temps passé dans la cible de glucose (%TIR, 3,9-10,0 mmol/L). Les indicateurs de qualité de vie ont été évalués par des échelles de mesure validées. Les mesures de sécurité sont le temps passé en hypoglycémie, la survenue d’hypoglycémie sévère ou d’acido-cétose et les problèmes techniques. Résultats : Les participants du groupe DDAI-OS étaient non inférieurs au groupe DDAI commercial sur le %TIR (78,3% [SD 11,0] vs. 71,2% [SD 10,9], différence moyenne 7,2% [95% CI 1,9% à 12,5%], p<0.001), même après ajustement sur plusieurs facteurs confondants. Le groupe DDAI-OS a passé plus de temps en hypoglycémie (<3,9 mmol/L) (3,9% [SD 3,1] vs. 1,8% [SD 1,3], p<0.001) et a rapporté moins de peur de l’hypoglycémie. Aucun épisode d’hypoglycémie sévère ou d’acido-cétose n’a été rapporté, avec un nombre de problèmes techniques similaires entre les deux groupes. Conclusion : Les DDAI-OS hybrides sont sécuritaires et non inférieurs aux DDAI commerciaux hybrides en termes de %TIR chez des adultes vivant avec un DT1 dans des conditions de vie réelle. Nos résultats soutiennent que les DDAI-OS peuvent être considérés pour la gestion du DT1. / Background: Comparison between unregulated open-source (OS) automated insulin delivery (AID) systems and commercial AID (C-AID) systems remains scarce. Objective: Compare both AID systems regarding glucose management, patient-reported outcomes (PROs), and safety among adults with type 1 diabetes (T1D) in real-life conditions. Design: Prospective, observational, non-inferiority, comparative, real-world study. Setting: On-site (a diabetes clinic in Montreal) and online (a T1D registry and social media platforms) across Canada. Participants: 78 adults with T1D, having used an AID system for ≥ 3 months, and living in Canada (26 OS-AID and 52 C-AID users). Measurements: 4-week’s data from a blinded continuous glucose monitor were used to assess effectiveness (primary outcome: 24h time in range % [TIR%], with a non-inferiority margin of 5%). Other outcomes included PRO measures using validated scales. Safety outcomes included time spent in hypoglycemia, severe hypoglycemia, diabetic ketoacidosis (DKA), and technical issues. Results: OS-AIDs were non-inferior to C-AIDs regarding 24h TIR% (78.3% [SD 11.0] vs. 71.2% [SD 10.9], mean difference 7.2% [95% CI 1.9% to 12.5%], p<0.001), even after adjusting for various confounding factors. OS-AIDs spent more time in hypoglycemia (<3.9 mmol/L) than C-AIDs (3.9% [SD 3.1] vs. 1.8% [SD 1.3], p<0.001) and reported less fear of hypoglycemia. No severe hypoglycemia or DKA was reported in either group, with a similar occurrence rate of technical issues between groups. Conclusion: OS-AIDs are safe and non-inferior to C-AIDs for TIR% among adults with T1D in real-world settings. Our findings support that both OS-AID and C-AID systems can be considered for T1D management.

An implantable closed-loop insulin delivery device (INsmart device) containing a glucose responsive gel has been developed within the INsmart research group, over a period of 10 years, to mimic pancreas. In this thesis, the reliability and performance capability of the INsmart device was studied for future clinical use. Investigations into the device material compatibility with insulin solution, assessed by monitoring insulin loss and degradant formation over a period of 31 days using RP-HPLC have shown that stainless steel and titanium are the most compatible materials. Polycarbonate contributes to insulin loss after 11 days, resin might not be the best material and polyurethane is the least compatible for future device designs. To study insulin delivery mechanism and kinetics from the device, fluorescently labelled human insulin (FITC-insulin) was synthesised and characterised using RP-HPLC and MS, to produce a product with predominantly di-labelled conjugate (>75%) with no unreacted FITC or native insulin. Clinically used insulin analogues were also fluorescently labelled to produce predominantly di-labelled FITC-insulin conjugate with potential future biological and in vitro applications. The drug release mechanism from the glucose sensitive gel held in the INsmart device, studied using fluorescein sodium was determined as a Fickian diffusion controlled release mechanism. The diffusion coefficient (D) for FITC-insulin in the non-polymerised dex2M-conA gel (NP gel) determined using mathematical models, QSS and TL slope methods was 1.05 ± 0.02 x 10-11 m2/s and in the cross-linked dex500MA-conAMA gel (CL gel) was 0.75 ± 0.06 x 10-11 m2/s. In response to physiologically relevant glucose triggers in the NP gel, the diffusivity of FITC-insulin increases with increasing glucose concentrations, showing a second order polynomial fit, device thus showing glucose sensitivity and graded response, mimicking pancreas. Rheological measurements further confirmed the gel glucose responsiveness demonstrated by a third order polynomial fit between FITC-insulin D and the NP complex viscosity in response to increasing glucose concentration. The knowledge of FITC-insulin diffusion kinetics in the gel has aided in making some theoretical predictions for the capability and performance of the INsmart device. Alternate device geometry and design optimisation is also explored.