Abstract
Diabetes Mellitus is a condition that millions of people around the world suffer from. The hallmark of this disease is an insulin insufficiency. For decades researchers have sought to find and improve treatment methods for this disease, using various methods of insulin delivery. This article outlines some of the major techniques used over the past several years.
Introduction
Over the past several years, the prevalence of Diabetes Mellitus has been increasing worldwide, becoming one of the world’s most common non-communicable diseases. As of 2011, the International Diabetes Federation Reported that 366 million people worldwide suffer from this condition and the number is expected to grow to 552 million by the year 2030. These high occurrence rates are what have made diabetes one of the most common Most of the cases contributing to the increase in prevalence of Diabetes Mellitus are Type 2, but the number of type 1 cases are increasing as well.
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Diabetes Mellitus (T1DM) occurs when a patient is unable to produce an adequate amount of insulin, a peptide hormone that helps to lower blood glucose levels. Insulin is composed of two polypeptide chains connected by disulfide bridges between cysteine molecules. Human insulin is made in its inactive form (preproinsulin) and must be converted to an active form before it can be used by the body (Figure 1). In a healthy individual, insulin is released continuously in small quantities to reduce glucose output by the liver by directly inhibiting gluconeogenesis (glucose production) and glycogenolysis (breakdown of glycogen into glucose monomers). The indirect effects of insulin include inhibition of glucagon secretion, lipolysis of fat, and proteolysis in muscles. The quantity of insulin released increases after one consumes a meal in order to maintain euglycemia, or normal blood glucose concentration. Insulin is released from beta cells in the pancreas that each contain 10,000 to 13,000 secretory granules that each contain around 106 molecules of insulin.
Because of the insulin deficiency associated with T1DM, one of the most crucial aspects of treatment is the administration of insulin to maintain proper blood glucose levels and avoid hyper- and hypoglycemia. Insulin therapy was first used in 1922 by Banting and Best. In the early stages of insulin therapy development, insulin derived from bovine and porcine pancreases was used, resulting in high rates of immunological reactions, lipodystrophy, and unpredictable insulin absorption. These issues led to further research on purification of insulin, resulting in the various long and short acting insulins used today. Currently, research has shifted to focus on exogenous insulin secretion that mimics that of the pancreas in order to achieve tight glycemic control while avoiding hypoglycemia.
Insulin Therapy Today
Two of the most common methods of insulin therapy for T1DM today include Multiple Daily Injections (MDI) and continuous subcutaneous infusion using an external pump (CSII). Even with these effective methods, there is still a significant morbidity rate associated with T1DM. This can be attributed to patients having poor adherence to their insulin and glucose monitoring regime. Many factors affect this lack of cooperation with treatment, including pain of injections, cost, ability to self-administer injections, weight gain, and the psychological burden. Because of this failure of patients to adhere to their treatment plan, many researchers are focused on developing new insulin delivery methods. Currently, the highest priority has been placed on developing an artificial pancreas and delivery methods for adolescents with diabetes.
Non-Invasive Delivery
When insulin therapy was first introduced, the hormone was administered intramuscularly. This could be painful for patients, and this method has since been replaced by subcutaneous injections which are just as effective while causing significantly less trauma to the patient. Over time, several innovative approaches to insulin delivery have been suggested, including: transdermal, intranasal, oral, and pulmonary (Figure__) . Each of these methods have undergone various testing and have their own sets of pros and cons in clinical applications.
Transdermal
One of the biggest hurdles to overcome when developing transdermal methods of insulin delivery is physical and immunological barriers the skin presents. The skin is composed of three layers, the epidermis, dermis, and subcutaneous tissue. The epidermis is mainly composed of the stratum corneum, a thick layer of dead cells that serves to protect the underlying layers. The dermis is the middle section that contains blood vessels, hair follicles, sweat glands, and nerves. The innermost layer, the subcutaneous tissue, serves as a thermal insulator and energy storer. In order for insulin injections to reach the subcutaneous tissue, the needle must pass through the dermis, which is the reason pain is felt from these injections.
Many transdermal methods of delivery today use various methods of enhancing skin penetration to eliminate the need for needles that cause pain upon injection. There are four main penetration enhancing methods: increased drug solubility, optimization of the formula, increased diffusion coefficients, and provision of additional driving force. Each of these methods functions to increase skin permeability by creating nanometer-scale disruptions in the stratum corneum layer without disrupting the viable epidermis.
Ionophoresis has been researched as a potential method for increasing skin permeability to insulin. In this method, low level electric currents are used to disrupt the stratum corneum. An experiment was performed on hairless mice TALK ABOUT IT. Results of this experiment indicated that the type of insulin used mattered in its effectiveness, as the human analog of insulin produced a more significant change in blood glucose concentrations. This method has potential to meet basal insulin requirements, but not ???. Similarly, low frequency ultrasound was also shown to increase skin permeability, however the rate was not rapid enough to make it a feasible option for insulin administration.
Another method of bypassing the skin barrier is using transfersomes. These lipid vesicles are small enough to fit through pores much smaller than themselves. They can transport insulin with 50% of the bioavailability of subcutaneous injections, making them one of the better candidates for insulin delivery. This high bioavailability could meet the daily basal insulin needs of patients with type 1 diabetes.
One route of transdermal delivery that has received a lot of attention is the use of microneedles to create tiny holes in the skin for thin insulin to pass through. In 1998, the Prausnitz Lab at Georgia Institue of Technology first reported the creation of microneedles. These needles were able to pass through the dermal layer without stimulating the dermal nerves. This is a major SOMETHING because it helps eliminate the painful injections associated with MDI.
There are several different applications of microneedles in insulin delivery. Microneedles can be used to create holes in the skin where insulin can then been applied. They can also be coated in insulin that is absorbed upon application or the microneedles can be created from polymers that dissolve upon puncturing the skin. A final method of use would be to inject the insulin directly through the hollow microneedles into the skin.
Microneedle injection of insulin provides the treatment benefits of subcutaneously injected insulin through a painless, minimally invasive route. In multiple studies using microneedles, patients have reported the insertion as painless, more specifically “Significantly less painful than a 26-gauge hypodermic needle,” the size used for subcutaneous injections. They have also been shown to have better controlled distribution of insulin with lower variability. It is very likely that patients will have better compliance with their insulin regimen when using microneedles because needle anxiety and social difficulties associated with multiple injections can be eliminated.
Intranasal
Nasal delivery of drugs has been commonly used route in the past for molecules much smaller in size than insulin. Because insulin is a fairly large molecule, it has difficulty crossing the membrane in the nose. Absorption of nasally administered insulin is rapid and takes around 15 minutes to begin working. This is attractive because it closely mimics in the timeline of endogenously secreted insulin during a meal. Although, when administered nasally, the insulin reaches systemic circulation with a relatively low bioavailability ranging from 8-15% and is influenced by several factors, including dose, timing, frequency, and variable mucous production of the nasal mucosa. Because of this low bioavailability, permeability enhancers are incorporated into the formula of insulin administered. However in trials, lecithin, an enhancer, was associated with nasal irritation, 100% of patients reported nasal irritation due to the bile salt enhancers, adn 25-50% of patients reported irritation with laureth-9.
A study was conducted with 31 participants diagnosed with T1DM who received intranasal insulin therapy. Results of the study showed that the intranasal dose required to reach a certain level of glycemic control was 20 times that of subcutaneous administration. In addition, the concentration of insulin in the blood both increased and decreased more rapidly when given nasally vs subcutaneously.
These results indicate that the low bioavailability and high irritation rates make intranasal administration a poor alternative to subcutaneous delivery; however, when the two methods are combined, the results are promising. A 6 month, 16 T1DM patient study was performed using a gelified insulin combined with promoters. The study found that when combined with twice daily NPH injections, three preprandial nasal doses of insulin were equally as effective as three preprandial subcutaneous insulin injections. Although this route of nasal administration does appear more effective than that in the previous study, four participants had to quit the study do to treatment related side effects.
Although intranasal administration of insulin has potential as an alternative form of drug delivery, many obstacles must be overcome before it is a viable option, making it an unattractive option for most researchers.
Pulmonary
Pulmonary delivery of insulin is an appealing option for a wide array of reasons. The large surface area of the lungs allows for rapid absorption and the close proximity of air and blood compartments facilitate transfer of the insulin into the bloodstream. There are no peptidases in the the lungs, thus eliminating the issue of insulin breakdown before reaching the bloodstream. Pulmonary delivery also bypasses the first-pass metabolism of insulin. The delivery of insulin deep in the lungs is influenced by the particle size, particle speed, and ventilatory parameters. The efficiency of this method is measured by the “fraction of dose delivered from device, fraction deposited on alveolar region, and bioavailability of fraction absorbed.”
The first approved inhalable insulin formula, Exubera, was approved if 2006. It consisted of a dry-powder formulation that was administered in 1mg and 3mg doses using an inhaler. Exubera was successful at significantly reducing post-prandial blood glucose and A1c levels. However, it was removed from the market in 2007 due to low cost-effectiveness.
Pharmacokinetics studies revealed that the total exposure to insulin was comparable between inhaled and subcutaneously injected insulin, however the exposure time was much shorter for inhaled insulin. Another concern with this delivery route is that insulin is a growth factor and thus deposition of insulin in the alveoli could cause problems with pulmonary function.
Results of studies performed on inhaled insulin have proven that it is as clinically effective as short-acting injected insulin and tolerated well by T1DM patients. It is not currently a popular choice for course of treatment, however, due to its limited bioavailability leading to higher costs. The expenses and questions regarding safety and efficacy led many sponsors to end research endeavors into pulmonary insulin delivery systems.
Conclusion
While there is still much debate over which method of insulin delivery is most efficient and most plausible, there is still a great deal of research to be done on each method to improve efficacy. However, it is becoming apparent that the end-goal of research in insulin delivery is to develop an artificial pancreas, making disease management easier for all T1DM patients.
References
- 1. Shah, R., Patel M., Maahs D., Shah V. Insulin Delivery Methods: Past, Present and Future. International Journal of Pharmaceutical Investigation. 2016 Jan-Mar;6(1):1-9.
- 2. Hultstrom, M., MD, PhD, Roxhed, N., PhD, & Nordquist, L., PhD. Intradermal Insulin Delivery: A Promising Future for Diabetes Management. Journal of Diabetes Science and Technology. 2014; 453-457.
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