Systematic Review on the Effectiveness of Strategies for Increasing Insulin Bioavailability in Oral Route Delivery Systems Based on Manufacturing Techniques and Materials Used

Diabetes is a metabolic disease characterized by hyperglycemia due to impaired insulin secretion, insulin action, or both. All patients with type 1 diabetes and many type 2 diabetes require insulin therapy to achieve reasonable glycemic control. During this time, insulin is given through the subcutaneous injection route because it can be destroyed by gastric acid when given orally. Until now, many studies have developed oral insulin therapy using various delivery system strategies. This systematic literature review aims to answer several questions about the effect of technique and material on increasing oral insulin bioavailability and the best technique and type of material that can produce the best oral insulin bioavailability. We searched for published articles regarding the development of oral route insulin. Bioavailability parameters were assessed based on plasma insulin levels for relative bioavailability values and/or plasma glucose levels for pharmacological bioavailability values. Conclusion: The manufacturing technique in the delivery system affects insulin stability in maintaining its conformation to provide a therapeutic effect. The type of substance affects insulin bioavailability through its properties in paving the way for insulin across various barriers in the digestive tract. To date, the best results in the development of oral insulin have obtained oral insulin bioavailability of 73.10% achieved by mesoporous silica nanoparticles (MSN) delivery system with layer-by-layer technique coated with [poly (methacrylic acid-co-vinyl triethoxylsilane)] (PMV)]. Keywords: bioavailability, diabetes, insulin, nanoparticles, oral delivery system.

An Overview of Microparticulate Drug Delivery System and its Extensive Therapeutic Applications in Diabetes

Microparticulate drug delivery system (MDDS) has attained much consideration in the modern era due to its effectiveness in overcoming traditional treatment problems. Microparticles are spherical particles of a diameter ranging from 10 μm to 1000 μm. Microparticles can encapsulate both water-soluble and insoluble compounds. MDDS proved their efficacy in improving drugs bioavailability, stability, targeting, and controlling their release patterns. Microparticles also offer comfort, easy administration, and improvement in patient compliance by reducing drugs toxicity and dosage frequency. This review elucidates the fabrication techniques, drug release, and therapeutic application of MDDS. Further details concerning the therapeutic applications of antidiabetic drugs-loaded microparticles were also reviewed, including controlling drugs release by gastroretention, improving drugs dissolution, reducing side effects, localizing drugs to the site of disease, improving insulin stability, natural products loaded with microparticles, sustained drug release, mucosal delivery, and administration routes. Additionally, the current situation and future prospects in developing microparticles loaded with antidiabetic drugs were discussed.

Addition of Regular Insulin to Ternary Parenteral Nutrition: A Stability Study

Background: Parenteral nutrition (PN) is a complex medium in which added insulin can become unstable. The aim of this study is, therefore, to evaluate the stability of insulin in PN and to identify influencing factors. Methods: A total of 20 IU/L of regular insulin was added to PN in either glass or Ethylene Vinyl Acetate (EVA) containers. A 24 h stability study was performed via an electrochemiluminescence immunoassay in different media: A ternary PN admixture, separate compartments of the PN bag and a binary admixture. This study was repeated in the absence of zinc, with the addition of serum albumin or tween and with pH adjustment (3.6 or 6.3). Insulin concentration at t time was expressed as a percentage of the initial insulin concentration. Analysis of covariance (ANCOVA) was applied to determine the factors that influence insulin stability. Results: In all PN admixtures, the insulin concentration ratio decreased, stabilising at a 60% and then plateauing after 6 h. At pH 3.6, the ratio was above 90%, while at pH 6.3 it decreased, except in the amino acid solution. ANCOVA (r2 = 0.68, p = 0.01) identified dextrose and pH as significant factors influencing insulin stability. Conclusion: A low pH level seems to stabilise insulin in PN admixtures. The influence of dextrose content suggests that insulin glycation may influence stability.

Zinc Determines Dynamical Properties and Aggregation Kinetics of Human Insulin

Protein aggregation is a widespread process leading to deleterious consequences in the organism, with amyloid aggregates being important not only in biology but also for drug design and biomaterial production. Insulin is a protein largely used in diabetes treatment and its amyloid aggregation is at the basis of the so-called insulin-derived amyloidosis. Here we uncover the major role of zinc in both insulin dynamics and aggregation kinetics at low pH, where the formation of different amyloid superstructures (fibrils and spherulites) can be thermally induced. Amyloid aggregation is accompanied by zinc release and the suppression of water-sustained insulin dynamics, as shown by particle-induced X-ray emission and X-ray absorption spectroscopy and by neutron spectroscopy, respectively. Our study shows that zinc binding stabilizes the native form of insulin by facilitating hydration of this hydrophobic protein and suggests that introducing new binding sites for zinc can improve insulin stability and tune its aggregation propensity.Statement of SignificanceLocalized amyloidosis occurs at insulin injection sites for diabetes treatment, leading to deleterious inflammations known as insulin-derived amyloidosis. Amyloid superstructures are also promising candidates in the field of biomaterials. Here we revealed that zinc, coordinated to insulin in the native form, is released upon amyloid aggregation, when insulin forms superstructures known as fibrils and spherulites. Zinc release leads to a full suppression of functionally essential protein dynamics through a modification of the protein’s hydration properties and completely modifies insulin amyloid kinetics. The results suggest that changes in protein hydration upon zinc binding/release modifies both stability and dynamics of insulin and might then be a general strategy to control protein stability and tune protein aggregation into amorphous and ordered superstructures.

Membrane Phospholipids and Polyphosphates as Cofactors and Binding Molecules of SERPINA12 (vaspin)

Visceral adipose tissue derived serine protease inhibitor (vaspin) is a member of the serpin family and has been shown to have beneficial effects on glucose tolerance, insulin stability as well as adipose tissue inflammation, parameters seriously affected by obesity. Some of these effects require inhibition of target proteases such as kallikrein 7(KLK7) and many studies have demonstrated vaspin-mediated activation of intracellular signaling cascades in various cells and tissues. So far, little is known about the exact mechanism how vaspin may trigger these intracellular signaling events. In this study, we investigated and characterized the interaction of vaspin with membrane lipids and polyphosphates as well as their potential regulatory effects on serpin activity using recombinant vaspin and KLK7 proteins and functional protein variants thereof. Here, we show for the first time that vaspin binds to phospholipids and polyphosphates with varying effects on KLK7 inhibition. Vaspin binds strongly to monophosphorylated phosphatidylinositol phosphates (PtdInsP) with no effect on vaspin activation. Microscale thermophoresis (MST) measurements revealed high-affinity binding to polyphosphate 45 (KD: 466 ± 75 nM) and activation of vaspin in a heparin-like manner. Furthermore, we identified additional residues in the heparin binding site in β-sheet A by mutating five basic residues resulting in complete loss of high-affinity heparin binding. Finally, using lipid overlay assays, we show that these residues are additionally involved in PtdInsP binding. Phospholipids play a major role in membrane trafficking and signaling whereas polyphosphates are procoagulant and proinflammatory agents. The identification of phospholipids and polyphosphates as binding partners of vaspin will contribute to the understanding of vaspins involvement in membrane trafficking, signaling and beneficial effects associated with obesity.

Insulin Storage: A Critical Reappraisal

Insulin, as a peptide hormone drug, is susceptible to changes in stability when exposed to environmental factors under storage. Proper storage according to the manufacturer’s recommendations is important to maintain its potency and enable precise dosing for people with diabetes (PwD). While it is reasonable to assume that transport conditions and temperature are well controlled during the supply chain, little is known about insulin storage after dispensing and insulin potency at the moment of administration. Insulin is exposed to various environmental factors when carried by PwD and storage recommendations are often not met when it is stored in household refrigerators. It is difficult to assess changes in insulin potency in clinical practice, and there is a gap in the current scientific literature on insulin stability. Package leaflet recommendations only give limited information on the impact of improper storage conditions on insulin stability and guidelines by health organizations are inconsistent. Given the importance of precise dosing in diabetes care, there is a need for more transparency on insulin stability, awareness for proper storage among health care professionals and PwD as well as clear guidelines and practical storage recommendations from manufacturers and health organizations.

Insulin Solution Stability and Biocompatibility with Materials Used for an Implantable Insulin Delivery Device Using Reverse Phase HPLC Methods

Insulin (Humulin® R IU500) has been delivered from an implantable artificial pancreas in diabetic rats and pigs. The artificial pancreas which was implanted in the peritoneum was fabricated from several biocompatible materials such as polycarbonate, stainless steel, polyurethane, titanium and a polyurethane resin. The device also contains a glucose responsive smart gel which controls the diffusion of insulin dependent on the surrounding glucose environment. As the insulin reservoir is refillable and in contact with the device materials, assessing its biocompatibility with these various device component materials was conducted. Insulin can undergo chemical degradation mainly via a deamidation reaction on glutamine and asparagine residues rendering its biological hormone functionality. Two Reverse Phase High Performance Liquid Chromatography (RP-HPLC) methods were developed and validated for detection of insulin and degradant Asn A21 desamido insulin (method A) and insulin and degradant Asn B3 desamido insulin (method B). Material biocompatibility studies show that stainless steel and titanium are suitable for an implantable insulin delivery device design over a 31-day period. The use of polycarbonate and polyurethane could be considered if the insulin reservoir in the device was only to remain in the device for less than 11 days after which time there is a loss in cresol which acts in a protective capacity for insulin stability.