Advanced Insulin Delivery Systems:Present Trends And Future Directions

This article provides an evidence to prove that advance insulin delivery system maintains required glycemic control in diabetes mellitus and are efficient in preventing complications associated with diabetes mellitus. The subcutaneous injection replacement therapy has been in vogue since discovery of insulin.

The key to restrict glycemic control with use of exogenous insulin lies in creation of delivery system that will emulate physiological insulin. In addition to the advances in insulin delivery systems like insulin pumps, needle less jet delivery systems, research in gene therapy , stem cell technology may take us to threshold of developing a practically applicable artificial pancreas.

Introduction:

Advent of insulin revolutionized treatment of diabetes mellitus and it might be one of the outstanding achievements of twentieth century. Reference of diabetes mellitus was made early at 1550 BC. Aretaeus (2^nd century AD) gave the clinical description of diabetes mellitus, in 17^th century Thomas Willis detected the sweet taste of urine, in 18^th century: Matthew Dobson showed that sugar in urine originated from blood, in 19^th century: Minkowski and von Mering proved that pancreatectomy caused diabetes,19^th century: Paul Langerhans identifies pancreatic islets, in 20^th century: Banting & Best extract and apply hypoglycemic extracts (insulin) clinically for the first time

Diabetes Mellitus is a group of metabolic diseases characterized by hyperglycaemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycaemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart and blood vessels.

Type 1 - Insulin dependent ,Type 2 - Non-insulin dependent, GDM- Gestational diabetes mellitus, IGT - Impaired glucose tolerance

For last 75 years, subcutaneous injection has been only route of insulin delivery to diabetic patient. However this traditional insulin delivery carries many complications viz.

· Little variation in serum glucose concentration for same dose of insulin injected.

· Stable blood glucose values are difficult to achieve and there is a high risk of severe hypoglycemia.

· There is a possibility of weight gain.

Recently there is increase in awareness and acceptance of the need to achieve and sustain the normoglycemia. The present article aims to review and examine the improved aspect of insulin delivery and its future prospectives.^1-3

Advanced Insulin Delivery Systems

• Insulin Pump

• Needleless Insulin Delivery

• Oral Insulin Delivery System

• Inhaled Insulin Delivery System

• Gene Therapy

• Vaccines

• Stem cell Technology

I) INSULIN PUMP ⁴

The Pump mimics the Pancreas

What is an insulin pump?

An insulin pump is a pager size device with an insulin reservoir. It delivers the insulin to the body (most of the time in the area around the belly button) of the diabetic patient via an infusion set.

· Basic features:

-It delivers a continuous basal rate.

-It delivers a bolus ‘on demand’

-The user wears it 24/7/365

-It delivers fast acting insulin only

-There is less variability with insulin pump

Insulin Pump Therapy: Benefits

• Maintain blood glucose levels normal
• Avoid short-term trouble (Hypo and Hyper)
• Prevent and postpone long-term complications
• Improved Control
• Decreases Hypoglycemia
• Improved Quality of Life
• Better control makes patients feel better
• No more schedules to follow
• Patients can eat what they want and when they want
• Insulin delivery can be adjusted to daily needs

Future pump therapy

Future of the pump therapy will see an implantable closed loop insulin pump which will automatically dose and dispense the insulin as per the requirement against the blood sugar level.

This implantable closed loop pump is currently under trials & is expected to be launched by 2007.

II) NEEDLESS INSULIN DELIVERY SYSTEM ^5-7

What is needleless insulin injector?

A needleless insulin delivery system consists of a device which is as similar as that of a pen is a needle-free injector system that uses a patented "soft-shot" technology to deliver insulin under the skin without a needle.

It provides a safe, discrete, and virtually painless option for subcutaneous injections, and it is clinically proven to be just as effective as a needle and syringe.

About jet injectors

 

Fig 1: Needle pattern Fig 2: Jet Injector Pattern

 

Dispersal Patterns

Needle Pattern

Insulin injected via a needle produces a pool of insulin beneath the skin, as shown in the first image. The insulin is absorbed by the body only on the periphery of the pool of insulin.

Jet Injector Pattern

Insulin injected via a jet injector produces a mist of insulin beneath the skin, as shown in the second image. Since the insulin is dispersed throughout the tissue, it is absorbed more quickly. Users of jet injectors often need to adjust their insulin dosage by a small amount to account for this effect.

Why jet injectors are painfree?

Proponents of jet injectors often claim that they are less painful than needles. Some even say they are painfree. By users of jet injectors, the fact is that it depends upon the individual. People with little body fat or thin skin, such as kids, are likely to find jet injectors and needles equally painful (or painfree). People with some body fat, who inject in that area, will likely find that the jet injector is nearly painless. The GentleJet is one jet injector specifically designed with kids in mind.

Also, each user must determine the proper injection pressure by trying out various settings. Bruises result from too much pressure, while leakage results from too little. Getting it just right is part of the training provided by the jet injector manufacturer and will be a bit uncomfortable. Different parts of the body may require different pressure settings

PARTS OF JET INJECTOR

III) ORAL INSULIN DELIVERY SYSTEM ⁸

 

Hydrogels:

Microparticles of Poly methacrylic acid and novel semi-interpenetrating network composed of Poly methacrylic acid-alginate (PMAA) were prepared and their application in oral insulin delivery was evaluated. The microparticles were characterized by scanning electron microscopy (SEM) for morphological studies. Insulin loading onto the microparticles was performed by the diffusion filling method and insulin encapsulated microparticles were subjected to in vitro release study in buffer solution of pH 1.2 and 7.4. The release kinetics at pH 7.4 exhibited sustained release of insulin for more than 5 hrs in case of PMAA microparticles whereas burst release of insulin (90% of total insulin loaded) within 1 hr of study was observed in the case of PMAA-alginate microparticles.

At pH 1.2, around 30% of insulin loaded was released from both microparticles within 2 hr of study. In an acidic environment, the polymers in the gel interact in such a way as to shrink the pores of the gel, keeping insulin trapped inside. When the gel reaches a less acidic environment, such as in the small intestine, the gel swells and its pores open up, allowing the drug to diffuse into the surrounding tissue and eventually into the blood stream. The method by which the drug is actually delivered into the blood stream is under investigation. The process by which the pores shrink and swell is called complexation. The gel itself has molecular-sized pores that open and close in response to changes in the pH level, or acidity, of the environment. Each pore has strands of a polymer anchored to its sides, with the other end floating free in the pore. In the acidic environment of the stomach, these tethered chains reach across the pore and form temporary bonds with the other side, creating a kind of mesh, or crosslinking. The pore is not only physically blocked, but it also gets significantly smaller because the crosslinks pull it in tight. When the gel passes into a less-acidic environment, the polymer chain immediately unlinks, the gel swells, and the pore size rapidly increases dramatically in size, releasing the drug. The gel also has adhesive properties, which may contribute to its effectiveness in delivering drugs. The gel gets more adhesive as it passes into the intestine so that it actually adheres to mucous in the intestine. More residence time probably helps the delivery of the insulin. Copolymer networks of poly(methacrylic acid) grafted with poly(ethylene glycol) (P(MAA-g-EG)) exhibit pH-dependent swelling behavior due to the formation/dissociation of interpolymer complexes. These complexes form in acidic media and serve as temporary, physical crosslinks and cause the gels to be in collapsed conformations. In solutions of pH greater than 5.0, the complexes dissociate due to ionization of the dependant acid groups resulting in a mesh size 3-5 times greater than in the collapsed state. These hydrogels are ideal for the oral delivery of peptides and proteins due to the large change in network structure over a small pH range. The diffusion of insulin through swollen complexation gels was studied. The release of insulin from drug loaded P(MAA-g-EG) hydrogels was examined in pH=1.3 and 7.4 solutions. In simulated gastric fluid, pH=1.3, less than 5% of the insulin loaded into the system was released in two hours. However, when the gels were placed into solutions of pH=7.4, the remainder of the insulin was released in less than two hours. Diffusion coefficients for insulin in the complexed gels were two orders of magnitude less than those in the uncomplexed gels.

{mospagebreak title=Future Oral Insulin Delivery}

IV) FUTURE ORAL INSULIN DELIVERY

Casein Coated Microencapsule Loaded With Insulin

 

Casein

•The casein coated microencapsule having a core of insulin is under development which is expected to deliver insulin directly into intestine protecting it from acidic gastric contents.

•One company is also working on oral insulin that is absorbed through the buccal mucosa (inside of the cheek) in the mouth .

• Recent research shows trials for sodium alginate & b- cyclo dextrin coated insulin loaded microspheres.

 

 

V) INHALED INSULIN DELIVERY SYSTEM ⁹

The product of an inhaled short-acting insulin preparation for the treatment of type 1 and type 2 diabetes is most advanced , if approved, could eliminate the need for meal-time insulin injections in diabetic patients requiring insulin therapy.

       

Non-invasive insulin delivery:

At present, diabetics who require insulin to keep their blood sugar levels under tight control (target HbA1c levels of <7%) have to administer it by injection. The need for daily repeat injections is a major drawback for diabetics. It interferes with daily activities and can lead to patients developing needle phobia. Although special self-injection pens, which are easier to use and deliver an accurate dose of insulin, are available they do not remove the need for regular injections. However, injections are considered the most efficient and reliable way to deliver insulin to the bloodstream at present.

Pulmonary delivery of insulin:

The concept of delivering insulin directly to the lungs (pulmonary insulin) was first advanced in 1925. However, the technical hurdles are high. Most insulin sprayed or inhaled through the mouth tends to become deposited in the pharynx and never reaches the lungs.

A rapid-acting, fine dry-powder insulin in form of aerosol, enters the lungs. Apart from the benefit of needless administration, inhaled insulin enters the bloodstream more rapidly than by subcutaneous injection. This is likely to be especially beneficial when administering insulin just before meals and may aid treatment compliance.

Clinical trials suggest pulmonary delivery of insulin is effective:

Over 2,000 patients have so far received this in clinical trials worldwide, some for as long as five years. Results from the phase III clinical trials suggest that insulin may be as effective as injected insulin and superior to oral agents in lowering blood glucose in patients with diabetes. A phase III study involving 328 patients with type 1 diabetes, for example, showed that patients using insulin before meals plus two daily insulin injections had glycaemic control comparable to patients on four insulin injections. Compared with patients who received only insulin injections, patients receiving insulin experienced significant reductions in both fasting plasma glucose levels (blood glucose measured before breakfast) and two-hour post-prandial glucose levels (blood glucose measured after meals). Patients also preferred using insulin, were more satisfied with their overall treatment and showed greater improvements in symptoms and cognitive function (assessed by the Diabetes Quality of Life and Treatment Satisfaction questionnaire).

VI) INSULIN PEN ^10-12

The dosing dial on Insulin Pen, which can deliver insulin in half-unit increments.

 

 

Parts of Insulin Pen

VII) GENE THERAPY¹³

Two recent reports describe research into gene therapy for different aspects of diabetes. These reports are in the forefront of what will no doubt be ongoing and exciting research arising from the decoding of the human genome. Scientists have identified a gene called SHIP2 that appears to regulate insulin. Such findings make SHIP2 a potential gene therapy target for the treatment of type 2 diabetes aimed at improving the individual’s insulin regulation.

A protein that blocks the overgrowth of blood vessels in the eye is being studied as possible gene therapy for diabetic retinopathy. Scientists have developed a gene therapy strategy, applied in diabetic rats, to retool certain cells within digestive glands that already are capable of sensing blood sugar levels to produce and deliver insulin into the bloodstream and normalize blood sugar levels. The insulin-delivery process occurs automatically when food is eaten.

Adeno-associated virus (AAV) — A possible solution?

Adeno-associated virus gets its name because it is often found in cells that are simultaneously infected with adenovirus. However, by itself it seems to be harmless.

Unlike adenovirus, AAV

•does not stimulate inflammation in the host

•does not elicit antibodies against itself

•can enter non-dividing cells

•integrates successfully into one spot in the genome of its host

(on chromosome 19 in humans).

As for the last criterion — how to get the transgene to be expressed appropriately — that may be solved by using two AAV vectors simultaneously:

•one carrying the desired gene (e.g., for factorVIII or adenosine deaminase or in the case illustrated here, erythropoietin) into the cells of the host;

•the other carrying genes for the components of the transcription factors needed to turn that gene on.

Vector 1

This piece of DNA contained (among other things):

•the DNA of adeno-associated virus (AAV)

•a gene encoding a protein containing two domains:

•a portion of the molecule ("p65") that is needed to activate gene transcription but that by itself cannot bind to DNA

•a portion ("FRB") that binds the drug rapamycin.

•a gene encoding another protein with two domains:

•a portion of molecule ("ZFHD1") that binds specifically to the DNA sequence in the promoter of the erythropoietin gene but that by itself cannot activate transcription of the gene;

•a portion ("FKBP12") that also binds to rapamycin.

•Promoters (not shown) that allow continuous expression (transcription and translation) of the two genes. But note that, by themselves, the two gene products are inactive.

Vector 2

This piece of DNA contained (among other things):

•the DNA of adeno-associated virus (AAV);

•12 identical promoters (green boxes) of the erythropoietin gene;

•the structural gene for erythropoietin (EPO) itself.

The Experiment

The experimental animals were injected (in their skeletal muscles) with many copies of both vectors. Skeletal muscle was chosen because muscle fibers are multinucleate. Once across the plasma membrane, there are many nuclei which the vectors can enter and hence many opportunities to integrate into the DNA of the host. Later the animals were injected with rapamycin. This small molecule is an immunosuppressant and is currently being tested in transplant recipients to help them avoid rejection of the transplant. It was used here because of its ability to simultaneously bind to the FRB and FKBP12 domains of the two gene products of vector 1. The resulting trimer is an active transcription factor for the erythropoietin gene.

Researchers in Seoul, Korea reported in the 23 November 2000 issue of Nature that they have used an AAV-type vector to cure mice with inherited IDDM rats with IDDM induced by chemical destruction of their insulin-secreting beta cells.

Both groups of animals were injected (in their hepatic portal vein) with billions of copies of a complex vector containing: AAV , the complementary DNA(cDNA) encoding a synthetic version of insulin , a promoter that is active only in liver cells and is turned on by the presence of glucose the DNA encoding a signal sequence (so that the insulin can be secreted) ,an enhancer to elevate expression of this artificial gene.

Both groups of animals gained control over their blood sugar level and kept this control for over 8 months. When given glucose, they proceeded to synthesize the synthetic insulin which then brought their blood glucose back down to normal levels.

VIII) VACCINE FOR DIABETES¹⁴

A world-leading medical trial conducted in Melbourne suggests that the onset of type 1 diabetes could be prevented in many at-risk people by a new nasal insulin vaccine. The phase 2 trial at The Royal Melbourne Hospital in children at high risk of developing type 1 diabetes. Of the 38 children in the trial, 12 who started with very little or no insulin-producing function went on to develop diabetes within one to two years. However, of the other 26, all of whom began the trial with some of their own insulin-producing function, none developed diabetes after three years."Type 1 diabetes is an autoimmune disease in which the body's own immune system mistakes 'self' as being a 'non-self' invader and mounts an attack against healthy tissue. In type 1 diabetes, 'self' is actually the hormone insulin in the beta cells of the pancreas. The guardian immune cells of the body, the killer T cells, attack the insulin-producing beta cells, leading to a lack of insulin. Without insulin, which normally controls the level of glucose in the body, the level of the hormone in the bloodstream increases abnormally.

The results from the trial are very encouraging. First, the use of nasal insulin has been established as being safe. Second, it was found that nasal insulin issued protective instructions to the immune system in humans, as we found in the mice that were protected from diabetes by this treatment. The hope is that these instructions will stop the self-destructive process in people at risk of developing the type 1 type of diabetes .

IX) STEMCELL TECHNOLOGY^{15 -16}

 

A better treatment for type I diabetes is just one of the hopes for stem cell therapy.Stem cells are a type of cell that can be transformed into virtually any of the 200 kinds of cell in the human body. This means that in theory at least, they can be 'grown to order' to help people suffering from degenerative diseases. In practical terms, there are two big challenges: persuading the stem cells to develop into exactly the kind of cell you want, and persuading the body to accept them. It's not easy, but progress has been rapid since the first human stem cell line was created just three years ago. The first big problem with stem cells is where to get them. Everyone has stem cells — they exist in the bone marrow, for example, where new blood cells are constantly regenerating — but in adults and children, these are already partly specialised. Many researchers doubt that they are truly capable of developing into any kind of cell.

Scientifically more promising, but ethically more problematic, are stem cells derived from human embryos. Most of the stem cells now being used in research were originally sourced either from leftover IVF embryos or from aborted foetuses. In the case of IVF procedures, a five-day-old embryo — called a blastocyst — is implanted into a woman's uterus, and hopefully, nine months later, a baby is born. Any extra embryos are usually kept in case of miscarriage, or for a future pregnancy, but they are not always required. To create human embryonic stem cells for research, some of the blastocyst's cells are isolated, harvested and allowed to grow in a separate dish. To turn them into long-lasting stem cell lines, the cells are fed special growth factors. The embryo is destroyed in the process.

 

This is how stem cell works for diabetes.

Conclusion:

Traditional insulin delivery carries many complications of variation in serum glucose concentration, hypoglycemia, possibility of weight gain etc. stable blood glucose values are difficult to achieve in traditional insulin delivery systems and requires continuous monitoring. The advanced insulin delivery system would gradually progress to physiological insulin replacement and will reduce the long term complications of diabetes mellitus. To summarize feasible alternative route for insulin delivery system is likely to emerge in future that may not be far off.

References :

1.Indian Journal of Pharmacology 2002

2.Journal Of Biomaterial Application

3.Anti Aging Guide 2004

4.www.medtronic.com

5.Carousel Medical Systems.Inc

6.www.biosantepharma.org

7.www.sbaoi.org

8.www.lifeclinic.com

9.www.drugdevlopment-technology.com

10.www.entrzpubmed.comogy.com

11.www.obgy.net

12. www.news-medical.net

13.www.webmdhealth.com

14.www.scientificamerican.com

15.www.insulindevices.com

16.www.minimed.com

17.All the approved medical professionals were approached for the article in pune region.

About the Authors

 

Dr. Parakh S.R., Jagdale S.C. ^* and Deokar V. D

MAEER's Maharashtra Institute of Pharmacy, S. No. 124, Ex-Serviceman colony,MIT campus Paud road, Kothrud, Pune – 411038

* Corresponding author Ms. Swati Changdeo Jagdale is presently working as Assistant Professor in Pharmaceutics at MAEER's Maharashtra Institute of Pharmacy, Pune, India.She is first University rank holder at M.Pharm ( Pharmaceutics) in Pune University.She has also qualified GATE examination at National level with 99.09%.Besides her academic excellance and experience, she also has Industrial experience in Research and Development department .

Dr. Parakh S.R. is Principal and Professor in Pharmaceutics at MAEER’S Maharashtra Institute of Pharmacy. He is a member of Senate, University of Pune. He is working in board of studies of Pharmaceutics of University of Pune. He has several National and International publications to his credit. He had eight years of Industrial experience and twenty one years of Academic experience. He is active member of Indian Pharmaceutical Association, Association of Pharmaceuticals Teachers of India.

Deokar V. Dis studying in Third year B.Pharm at MAEER's Maharashtra Institute of Pharmacy, S. No. 124, Ex-Serviceman colony, MIT campus Paud road, Kothrud, Pune – 411038.