Emerging Trends In Insulin Delivery System

Mr.Anil M. Pethe

In today's era, insulin delivery by alternative route is a area of current interest in the design of drug delivery system. Most of the global pharmaceutical companies are showing encouraging progress in their attempts to develop alternative insulin delivery technologies.

For most patients with type 1 diabetes, the tedious part of the treatment is to tolerate needle after needle, both for glucose measurement and to deliver insulin. The intr   oduction of insulin therapy years ago has saved the lives of millions of patients with diabetes. The development of technologies in the last decade have brought to limelight the strategies that hold some promise in turning non-injectable insulin delivery from theory to reality.

A rigorous research effort has been undertaken worldwide to replace the authentic subcutaneous route by a more accurate and non-invasive route. Considerable progress has been made to achieve new milestones for effective treatment of diabetes. Peroral, nasal, and pulmonary administration has demonstrated good potential for treatment of diabetes. In addition, transmucosal, buccal, ocular, rectal, and vaginal routes of insulin have also shown to decrease serum glucose concentrations. The transdermal route using various technologies also exhibits success in delivering insulin.

Introduction: 

The demand for novel drug delivery technologies is ever increasing. These drug delivery technologies can be broadly classified into four principle routes like oral, transdermal, inhalation and parenteral. The main goal for the delivery of any drug therapy is oral administration with once or twice daily dosing. However, there are large number of therapies, particularly protein-based, gene-based, vaccine-based that cannot be delivered by this route for example insulin, growth hormones and other similar biologics¹.

Pulmonary delivery is another non-invasive alternative method that is suitable for small molecules and proteins. However, for drugs with very large molecular weights, such as monoclonal antibodies, penetration through the lung for systemic delivery may require some type of transport enhancement mechanism, of which there are several still at the primordial research stage. Therefore, most protein-based drugs are still being developed as injectables for initial market launch².

History About Disease:

As reported by the World Health Organization (WHO), 200 million people around the world suffering from diabetes in 2005³. Diabetes is a serious condition and its rapidly increasing prevalence on the global scale is a significant cause for concern. By 2030, the WHO estimates that the number of people with diabetes will almost double to 366 million⁴. 

About 40% of people with diabetes rely on insulin to maintain control of their blood glucose levels. Patients with Type 1 diabetes are completely dependent on insulin injections. For patients with Type 2 diabetes, which comprises 90% of the world’s diagnosed cases of diabetes, about one-third of them rely on insulin as part of their regimen for controlling their blood glucose levels. Normal blood sugar is around 90 to 120 mg/dL⁵.

Needle Free Technology:

The reason this topic fits is that the diabetes market, and particularly insulin development is, by its nature, a hotbed for new ideas in drug delivery. It is difficult to think of one other therapeutic area, let alone another single disease, where so many factors align to drive the development of novel delivery systems⁶.

For some, especially those suffering from chronic diseases requiring injectable products two or three times a day, this process is an ongoing reality of daily life for example diabetics-accepted, but always with the hope that something new will replace the ritual of needle insertion. To overcome the problems related to needle based injections, there is one technology that has received considerable attention during the past few years and that offers all of the sought after benefits is—Needle Free Injection Technology (NFIT)⁷.

This technology was first described in the 19th century in France, when the French company-H Galante-manufactured an ‘apparatus for aquapuncture’. Since then, the demand had increased considerably. It was first commercialised in the US in 1960s. Bioject had summed up the reasons for it in their brochure stating ‘‘Patients hate needles, healthcare professionals fear accidental needle stick injuries, drug companies are looking for new and innovative ways of delivering their products⁸. 

This technology achieved the Food and Drug Administration (FDA) approval in 1996 for the subcutaneous delivery of insulin and is CE marked for sale throughout the Europe. This system has been used to give thousands of successful injections without the use of a needle⁹.

Factors influencing blood glucose and free insulin levels following insulin delivery:

In addition to the delivery system, a wide range of other factors influence blood glucose and free insulin levels following insulin delivery.  These include:

(1)Delivery site (inter- and intra-site variations)

- A primary influence, responsible for large variations in insulin absorption,   even between the commonly-used sites, which patients are recommended to  rotate sites between successive insulin deliveries.

- Insulin delivered in the abdomen is absorbed 86% faster than that delivered in the thigh and 30% faster than in the arm¹⁰.

- This variation in absorptions directly affects bl¹²ood glucose levels¹¹, with 29% lower post-prandial blood glucose levels for deliveries in the abdomen compared with the thigh.

-Duration of insulin action varies with delivery site .

(2)Liver and kidney function¹³:

(3)Skin temperature and fat thickness at injection site¹⁴:

(4)Presence and degree of lipodystrophy :

- The prevalence of lipodystrophy in diabetic patients has been assessed at as  igh as 52%¹⁵ .

(5)Exercise:

 - Absorption is affected in the region of an exercising muscle.

(6)Temperature of injected insulin:

-Insulin peak also occurs earlier when the insulin is stored in a fridge¹⁶.

Traditional insulin preparations such as NPH (Neutral Protamine Hagedom) insulin have duration of action 14 h and plasma insulin peak level 4-6 h after administration. As a consequence, NPH insulin may need to be administered up to three times daily in type 1 diabetic patients to provide sufficient insulin supply throughout the day²³.

Insulin complement:

Apart from the new insulin, one new drug, Symylin, is ready to be launched by Gibard Pharma, San Diego. Symylin is a synthetic version of the human hormone amylin, which moderates the glucose lowering effect of insulin. Symylin has been designed to complement insulin action and has been shown to reduce blood glucose without causing an increase in hypoglycemic episodes²⁴.

Implantable insulin pumps:

An implantable insulin pump works the same way as an external insulin pump with two major differences:

It is implanted just under the skin (usually in the abdominal area) and insulin is delivered into the peritoneal cavity not into the subcutaneous tissue.

Using a special, highly concentrated insulin, implantable insulin pumps have to be refilled every 2 to 3 months depending on the insulin requirements of the patient. Currently, implantable insulin pumps are used in selected centres in some countries in Europe by specialist doctors²⁵.

Transdermal patch:

The Altea Therapeutics PassPort™ System was the first product in development shown in US FDA clinical trials to provide a non-invasive, controllable and efficient way to deliver insulin via a patch on the skin. The PassPort™ System enables fast, controlled drug delivery without the pain of an injection or the possible complications associated with inhaled medications. It also avoids the first-pass gastro-intestinal and liver metabolism that occurs often after oral administration. It creates and effective, economical and patient-friendly delivery of insulin as well as the delivery of drugs for a wide variety of conditions²⁶.

Figure: The PassPort™ System is comprised of an
applicator (on the left) and a reservoir patch; the latter is placed
on the skin and provides for painless delivery of insulin.

The insulin transdermal patch maintains constant basal levels while avoiding  skin depots of insulin common with subcutaneous injections. As a safety feature, if a patient begins to experience the hypoglycaemia associated with an inadvertent overdose of insulin, they may simply remove the insulin transdermal patch, thus immediately ending the influx of insulin²⁷.

Islet cell transplant:

In contrast to conventional insulin treatment, islet transplantation is far superior for achieving a constant normoglycaemic state and avoiding hypoglycaemic episodes.

Insulin-producing beta cells are taken from a donor's pancreas and transferred into a person with diabetes. Once transplanted, the donor islets begin to make and release insulin, actively regulating the level of glucose in the blood²⁸.

Successful transplantation can provide the following benefits:

(1)It can eliminate the need for frequent blood glucose measurements and the need for daily insulin injections. Although only a few are free of insulin injections a year after transplantation.

(2) It can provide more flexibility with meal planning.

(3) It can help protect against the serious long-term complications of diabetes, including heart disease, kidney disease, stroke and nerve and eye damage²⁹.

Conclusion:

The advanced methods of insulin delivery systems would gradually progress toward physiological insulin replacement and reduce the long-term complications of diabetes mellitus. Thus, a feasible alternative route for insulin delivery is likely to emerge in the future. This new millennium promises a revolutionary change in the delivery of insulin, which is not too far off for billions of sufferers who are reliant on subcutaneous administration. The approaches that seem to hold potential must be consolidated and converted to a working protocol. Among the various alternative delivery systems, each have their own set of favourable and unfavourable properties. Some unfavourable aspects have to be circumvented to make this alternative insulin delivery system a reality and make them to reach the market.

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About Authors:

Mr.Anil M. Pethe

Corresponding Author

Assistant Professor in Department of Pharmaceutics And Technology, School of Pharmacy and Technology Management, SVKM’S NMIMS, University, Shirpur campus, Dist. Dhule-425405, Maharastra, INDIA
Ph no:(M) 09923598542;     EmailId: Anilpethe@Rediffmail.com

Mr.Chintan K. Sachde

Department of Pharmaceutics And Technology, School of Pharmacy and Technology Management, SVKM’S NMIMS
University, Shirpur campus, Dist. Dhule-425405, Maharastra, INDIA

Ph no:(M) 09921988433   Email Id: Chintan_sachde@Rediffmail.com

Mr. Pratik A. Gandhi

Department of Pharmaceutics And Technology,School of Pharmacy and Technology Management, SVKM’S NMIMS
University, Shirpur campus, Dist. Dhule-425405, Maharastra, INDIA

Mr. Pratik A. Pandya

Department of Pharmaceutics And Technology,School of Pharmacy and Technology Management, SVKM’S NMIMS University, Shirpur campus, Dist.Dhule-, Maharastra, INDIA