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Insulin delivery methods: Past, present and future
Many patients with advanced type 2 diabetes mellitus T2DM and all patients with T1DM require insulin to keep blood glucose levels in the target range.
The most common route of insulin administration is subcutaneous insulin injections. There are many ways to deliver insulin subcutaneously such as vials and syringes, insulin pens, and insulin pumps.
Though subcutaneous insulin delivery is the standard route of insulin administration, it is associated with injection pain, needle phobia, lipodystrophy, noncompliance and peripheral hyperinsulinemia.
Therefore, the need exists for delivering insulin in a minimally invasive or noninvasive and in most physiological way. Inhaled insulin was the first approved noninvasive and alternative way to deliver insulin, but it has been withdrawn from the market.
Technologies are being explored to make the noninvasive delivery of insulin possible. Some of the routes of insulin administration that are under investigation are oral, buccal, nasal, peritoneal and transdermal. This review article focuses on the past, present and future of various insulin delivery techniques. This article has focused on different possible routes of insulin administration with its advantages and limitation and possible scope for the new drug development.
The prevalence of diabetes is increasing throughout the world. The International Diabetes Federation estimated million people had diabetes in and is expected rise to million by Discovery of insulin was one of the greatest medical discoveries of the last century. All patients with T1DM and many patients with long standing T2DM require insulin therapy to achieve good glycemic control.
Hence, initial research focused on the purification of insulin. Insulin is a peptide hormone, therefore, destroyed by gastric acid if taken orally.
Intradermal absorption of insulin is not reliable, and it cannot mimic physiological insulin secretion.
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In addition, intradermal, intramuscular and intravenous therapy is not suitable for self-administration daily. Subcutaneous route of administration is widely preferred method for administration of insulin because of the ease of self-administration. It has limitations like pain at injection site, lipodystrophy, noncompliance by the patient, etc.
This review article focuses on the development of the past and present methods to deliver insulin with a perspective on anticipated developments.
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Insulin can be administered subcutaneously via various methods such as vial and syringe, insulin pen and continuous subcutaneous insulin infusion CSII [ Figure 1 ]. The advantages and disadvantages of each subcutaneous insulin delivery system are reviewed here and summarized in Table 1.
In , 2 years after the discovery of insulin, Becton, Dickinson and Company BD made a syringe specifically designed for the insulin injection. To reduce the incidence of needle associated infections, disposable syringes were developed. BD mass produced the first glass disposable syringes in , called the BD Hypak. It is the first device to combine an injection port and an inserter in one complete set that eliminates the need for multiple injections without having to puncture the skin for each dose.
This device is helpful for the insulin requiring patients having needle phobia and helps them to achieve glycemic control effectively. Insulin injections using vial and syringe are limited by inconvenience and inaccuracy in preparing the insulin dose. The first insulin pen was manufactured by NovoNordisk in The newer insulin pens are reusable, more accurate and equipped with safety features such as audible clicks with each dose to improve accuracy and reduce the chances of human errors.
The newer smart pens are designed to guide the individual with insulin requiring diabetes about the insulin dosage by means of in-built calculators , memory functions to remember the amount and time of insulin dosage and automatic transmission of insulin dose to the mobile logbook through Bluetooth technologies.
More physiologic delivery of insulin has been a long-standing goal. In normal physiology, a continuous small amount of insulin secretion from the beta cells of the pancreas reduces hepatic glucose output, and a larger amount of insulin is secreted when food is ingested to maintain euglycemia. Hence, it is associated with high glycemic variability i.
The first portable insulin pump was invented by Kadish in ; however, it was limited by its size and technical issues. The first commercial insulin pump was introduced in in the USA.
With the improvements in continuous glucose monitors CGM , it has become feasible to combine two technologies pump and CGM in the management of diabetes.
The new generations of CGMs are more accurate, smaller in size and shown to improve glycemic control in patients with T1DM. The use of SAP reduces A1c by 0. This makes SAP susceptible to human errors. In addition, SAP therapy requires patients to wake up to manage nocturnal hypoglycemia.
Hypoglycemia is the most feared acute complication of insulin therapy in patients with T1DM. The threshold suspends TS system suspends the delivery of insulin for up to 2 h if a patient does not take action with a low glucose alarm. This feature is designed to reduce the severity and duration of hypoglycemia, although it will not prevent hypoglycemia. Future steps in the evolution of the artificial pancreas will be[ 47 ]:.
Use of predictive algorithms to minimize hypoglycemia even before hypoglycemia occurs.
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The subcutaneous route of insulin administration is associated with many drawbacks such as injection pain, inconvenience, variable compliance and difficulty in achieving postprandial blood glucose control. Currently, the pulmonary route of administration is approved and discussed as well as other routes under investigation. Insulin delivery to the lungs was the first reported alternate to subcutaneous injection. It has long been appreciated that insulin delivery by aerosol reduces blood glucose.
This product was withdrawn from the market by Pfizer in The onset of action of Afrezza inhaled insulin is 15 min and duration is h, which is ideal for postprandial blood glucose control.
This device is in the FDA approval process. The AERx insulin Diabetes Management System, Aerodose, ProMaxx protein matrix microsphere and advance inhalational research are newer inhalational devices being investigated in clinical trials.
Although, the pulmonary route of insulin administration is noninvasive, it is limited by technical issues associated with inhaler devices, higher cost and long-term safety especially pulmonary function. The oral route of insulin administration may be the most patient-friendly way of taking insulin and it could more closely mimic physiological insulin delivery more portal insulin concentration than peripheral.
Several pharmaceutical companies are engaged in developing carriers to protect insulin from GI degradation and facilitate intestinal transport of insulin to deliver insulin to the circulation with sufficient bioavailability.
Certain oral insulin preparations such as Capsulin, ORMD, IN, oral hepatic directed vesicles and Eligen completed phase 1 and phase 2 trials with promising results.
Recently, multifunctional polymers and self nanoemulsifying drug delivery system SNEDDS has been tried for oral insulin by Sakloetsakun et al. Entrapment efficiency of insulin increased significantly when the thiolated chitosan was employed After 30 min, the in vitro release profile of insulin from the nanoemulsions was markedly increased compared with the control. A new strategy to combine SNEDDS and thiolated chitosan described in this study could therefore be a promising and innovative approach to improve oral bioavailability of insulin.
Oral colon delivery is currently considered of importance not only for the treatment of local pathologies, such as primarily inflammatory bowel disease, but also as a means of accomplishing systemic therapeutic goals. Large intestine is ideally not suited for absorption processes for drugs but it has certain advantages over small intestine like, long transit time, lower levels of peptidases prevent destruction of peptides and higher responsiveness to permeation enhancers.
Accordingly, it has been under extensive investigation as a possible strategy to improve the oral bioavailability of peptide and protein drugs. Oral delivery systems intended for colonic release of insulin were devised according to microflora-, pH-and time-dependent strategies were well described in a review by Maroni et al.
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Despite the enthusiasm and progress in making oral insulin, there is still a long way to go before these products will be available in the market. In theory, intranasal delivery has several advantages over oral bypass GI peptidases , subcutaneous noninvasive and painless and inhalation route no issue with lung function which makes this route attractive for the delivery of insulin.
Historically, intranasal delivery with early porcine and bovine insulins was investigated in patients with T1DM. The substances such as bile salt, surfactant and fatty acid derivatives are being investigated to enhance mucosal permeability of insulin but they increase the risks for local irritation, nasal secretion, sneezing or burning sensation.
Nasal insulin crosses the blood brain barrier hence it has a hypothesized effect on memory function. Treatment with intranasal insulin improved memory, preserved caregiver-rated functional ability and preserved general cognition without any significant hypoglycemic event.
Buccal delivery of insulin has similar benefits as oral insulin with the advantage of bypassing GI degradation. Furthermore, the relatively large surface area results in better bioavailability. Another molecule being developed by Shreya Life Sciences Pvt. Another method for delivery of insulin is fast dissolving films as an alternative to the oral tablets for rapid drug delivery.
No information is available on studies using this formulation. Trans-dermal insulin delivery eliminates the problems associated with needles and injections and large surface area of the skin makes it a convenient route for insulin delivery. Numerous methods have been explored to overcome the barrier of stratum corneum.
Iontophoresis, the technique that uses small electric currents,[ 85 ]. Sonophereis or phonopheresis uses ultrasound waves,[ 86 ]. Microdermal ablation by removing the stratum corneum,[ 87 ]. Electroporation utilizes high voltage pulses that are applied for a very short time,[ 88 ].
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Transfersulin is the insulin encapsulated in transferosome, an elastic, flexible vesicle which squeeze by itself to deliver drugs through skin pores,[ 89 ]. Recombinant human hyaluronidase rHuPH20 to increase insulin absorption from subcutaneous tissue.
The transdermal insulin delivery techniques are limited by skin injury, burn or blister formation and rarely significant pain and discomfort.
These technologies are still evolving and their long-term utility, safety and usefulness are not known at present. As discussed, the intravenous and subcutaneous route of insulin delivery are associated with peripheral hyperinsulinemia and considered nonphysiological.
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Direct delivery of insulin in the portal vein mimics the high portal insulin concentration. This route of insulin delivery has been investigated since the s. From this subcutaneous pocket, the peritoneum is opened, and the tip of the catheter is carefully inserted and directed towards the liver.
After implantation, the pump reservoir is refilled in the outpatient clinic transcutaneously at least every 3 months, depending on the individual insulin requirement. Until date, no human trial has been reported with this route and an animal study failed to achieve significant plasma insulin concentration.
Rectal gels[ ] and suppositories[ ] showed fair results. However, this route is not commercially viable. Administration of insulin was reported in [ ] but is not practical so not taken up for further development. There is a long history of research focusing on identifying a route of administration for insulin that is minimally or noninvasive, effective, safe, convenient and cost-effective for patients.
Each route and delivery method has its own potential advantages and disadvantages.