Oral Insulin Therapy (for Diabetes Mellitus)

                                                       Oral Insulin Therapy

                                       (A type of Novel Drug Delivery System)

Introduction:

In humans the blood glucose level is a very essential criteria for survival.

Human Blood Glucose is controlled by body its own metabolic mechanism. Most of the sugars in our diet are come from carbohydrate rich foods we eat. As we know that sugars / carbohydrates are the instant source of energy for our body.

Composite Gland ‘Pancreas’ which have both exocrine and endocrine functions; is responsible for maintenance of our blood sugar level.

Pancreas secrets Pancreatic juices as exocrine secretions through ducts in small intestine. And its endocrine part releases to Hormones i.e. Glucagon and Insulin which regulates body glucose level.

Endocrine part of pancreas:

The endocrine part of pancreas consists of group of Islets of Langerhans. The human pancreas has about 1 million islets. They are most numerous in the tail of the pancreas. Each islet of Langerhans consists of the following types of cells which secrete hormones to be passed into the circulatory blood.

      a)  Alpha cells. These cells are more numerous towards the periphery of the islet and constitute 15% of the islet of Langerhans. They produce glucagon hormone which converts glycogen into glucose in the liver. Thus glucagon is Diabetogenic hormone.

      b)   Beta cells. These cells are more numerous towards the middle of the islet and constitute 65% of the islet of Langerhans. They produce insulin hormone which converts glucose into glycogen in the liver and muscles. Deficiency of insulin causes diabetes mellitus.

      c)  Delta cells. These cells are also found towards the periphery of the islet and constitute 5% of the islets of Langerhans. They secrete Somatostatin hormone which inhibits the secretion of glucagon by alpha cells and secretion of insulin by Beta cells. This hormone also shows absorption of nutrients from the GIT.

      d)     Pancreatic polypeptide cells.

      

                    Insulin and Glucagon both are antagonistic to each other in their functions.

Glucagon:

Glucagon increases blood glucose level. It stimulate the liver to convert store glycogen into glucose. Glucagon is also called an “anti-insulin” hormone.

Target cells: Hepatocytes and adipose tissue.

Insulin:

    A)     Insulin converts glucose into glycogen in liver and muscles.

    B)      It promotes protein synthesis in the tissue from amino acids.

    C)     It reduces catabolism of protein. It is an anabolic hormone.

    D)     It increase the synthesis of fat in the adipose tissue from fatty acids.

    E)      It reduces the breakdown and oxidation of fat.

            

            Target cells: Insulin acts on the cells of the liver, muscles and adipose tissues.

       

Disorders of the pancreas:

     1)        Diabetes mellitus (hyperglycaemia). The most common endocrine disorder of the pancreas in diabetes mellitus, now recognized to exist in two forms:

Insulin dependent and insulin independent. The insulin dependent diabetes mellitus (IDDM) is caused by a failure of the Beta cells to produce adequate amount of insulin while the non-insulin dependent diabetes mellitus (NIDDM) appears to involve failure of insulin to facilitate the movement of glucose into cells. In both disorders the blood glucose concentration is elevated above normal range. Some of the glucose is excreted in the urine, and water follows the glucose, causing excessive urination and dehydration of body tissue. This causes excessive thirst (polydipsia). The cells are unable to utilize glucose and other carbohydrates for energy production. They utilize their proteins for it. The person becomes weak. Degradation of fats increases, producing ketone bodies (ketosis). The latter are acidic and poisonous. Blood cholesterol level rises. Healing power is impaired. Administration of insulin lowers the blood glucose level. It gives relief to patient. A tendency towards non-insulin dependent diabetes appears to be inherited as an autosomal recessive characteristic.

      2)       Hypoglycaemia. It occurs when the blood glucose level falls below normal. Theoretically, it may be caused by an excessive of insulin, a deficiency of glucagon, or a failure of the secretion of the two hormones to completely regulate the blood sugar. Some individual have been found to have few or no alpha cells and thus are deficient in glucagon, whereas others produce excess quantities of insulin usually because of a tumour of the beta cells. The excess insulin is more correctly referred to as hyperinsulinism. Symptoms of hypoglycaemia include weakness, profuse sweating, irritability, confusion, unconsciousness and convulsions. It needs urgent intake of sugar or glucose.

   Insulin is a naturally-secreted hormone that the body cannot function correctly without.

When insulin is depleted, impaired or destroyed within the body, it cannot regulate the amount of glucose in the blood. The body gains a significant proportion of its energy from glucose.

What is the role of insulin in diabetes treatment?

The answer to this question varies depending on what type of diabetes you suffer from. Type 1 diabetics, whose natural insulin is inadequate or completely destroyed, are heavily reliant on insulin therapy as their ongoing treatment.

When insulin treatment is irregular or poorly regimented type 1 diabetics may experience rising blood sugar levels. When this occurs, the body relies on its fat. If this condition is not checked, a life-threatening complication known as diabetic acidosis may occur.

Symptoms for this disorder are numerous, and at their worst may include unconsciousness. Usual signs include:

      a)       Paleness

      b)      Sweating

      c)       Increased heartbeat

      d)      Blurred vision

e)    Hunger

    

Type 2 diabetes is a slightly different disease.

The body has not actively destroyed its insulin stocks, but a combination of factors lead to increased resistance to the positive benefits of insulin.

Impaired glucose tolerance

At a pre-diabetes level this is known as impaired glucose tolerance.

At this stage, the pancreas begins to become overloaded, and cannot produce enough insulin to match the body’s needs. When the pancreas cannot cope, the patient will probably need insulin therapy. However, this only affects approximately 25% of type 2 diabetics (at advanced stages of their conditions), and in many instances this variant of the disease can be controlled through diet and exercise.

Why insulin does not given orally?

As we know that insulin is a peptide hormone. It is a protein made up to two chains A and B chain of 21 and 30 amino acids respectively. In its pro form a C chain is also present between A and B.

The A and B chains are linked together by Disulphide bonds (-s-s-).

The degradation of proteins starts in stomach by the action of pepsin in the stomach. After subsequently passing in GIT proteins further breakdown by the action of Trypsin and chymotrypsin. Proteases also work over it and convert them into peptones and peptides and finally in absorbable amino acids.

So, if insulin is taken orally in hyperglycaemia it will show no effect rather it becomes disintegrated.

It is the biggest challenge form a pharmacologist and pharmacist to invent a delivery system through which one can easily take insulin.

The patients today prefer minimum discomfort and instant relief. Due to complexities in life he avoids to be confined to bed or absent himself from duty.

Till today we are confined for parenteral administration of the insulin. Insulin is taken by the patient in form of injections. So this drug delivery is not patient compliance. It disturb the daily routine of patient’s life style.

Therefore, it is a need of hour to make a new drug delivery system for insulin which is better compliance, which should not disturb his routine life style as far as possible and should be acceptable aesthetically, organoleptic ally, therapeutically and from economic standpoint.

Challenges for oral insulin drug delivery:

1.Effective oral insulin is extremely difficult to create due to the thickness of the stomach wall.

2.Oral insulin research: expensive.

Several companies across the globe are solely concerned with the creation of effective oral insulin delivery mechanisms, and many major pharmaceutical companies are at the research and development stage.

Insulin pills and insulin inhalers have both been developed. Each has its own level of effectiveness. Insulin inhalers are still far from perfect.

It is thought that oral insulin could be developed that would be absorbed through buccal means (through the walls of the cheeks). This method could see insulin reaching the bloodstream intact.

Oral insulin testing on animals

Data obtained through testing oral insulin on animals has yielded some extremely positive results.

In 2003, Diabetes Care released reports of a small study that appeared to find oral insulin as effective as injectable insulin for type 2 diabetics.

Drug companies are obviously interested in the potential of oral insulin to net a massive share of the market, and therefore investment in research is substantial and ongoing.

Insulin Types-

Individual insulin products are numerous, but insulin may be divided into four major types.

Short-acting insulin - Soluble insulin acts quickly (30-60 minutes) and lasts for between 6 and 8 hours. Some types may be faster-acting and shorter-lasting.

Intermediate-acting - Isophane insulin acts slightly slower (1-2 hours) and lasts for between 10 and 14 hours.

Long-acting insulin - These insulin types (determir, glargine, protamine zinc, zinc suspension) act slowly (1-2 hours) and last much longer, for up to 24 hours.

Mixtures of insulin - Mixed short and intermediate-acting insulin, divided into different amounts depending on the individual case.

       Oral Insulin:

Oral insulin is a reality: it is simply a matter of when. The realisation that insulin injections are going to have to become a part of everyday life can be extremely harrowing for many diabetics.

       Injection takes time, interrupts daily schedules and is considered unpleasant by many people.

Children or adolescents who require daily insulin injections may find that the regimen impacts on their daily lifestyle to an even greater degree.

Using insulin therapeutically is not a new practice at all, but delivery methods to make the process more bearable have not gained widespread prominence as of yet.

Obviously, the priority in delivering insulin to a patient is to make sure it reaches the bloodstream intact.

Alternative insulin delivery methods

Many alternative delivery systems, although they work to some extent, leave the insulin broken down by digestive juices, usually too much for it to be of significant use to the body.

Furthermore, the complicated environment within the stomach means that simple tablets would be unpredictable and ineffective.

The solution will come, and may have already, when a pharmaceutical research company creates a tablet in which insulin can be enclosed and yet still pass through the stomach wall.

Nose, mouth and lungs

      Ideas & Theories (oral insulin):

       Advent of R-DNA technology in protein synthesis has given birth to new range of biopharmaceuticals. These therapeutic peptides and proteins are now emerging as an imperative part of various treatments protocols especially in the cancer. Despite extensive research efforts, oral delivery of therapeutic peptides or protein is still a challenge for pharmaceutical industries and researchers. Number of factors including high proteolytic activity and low pH conditions of GIT act as major barrier in successful delivery of intact proteins/ peptides to the target site. Low permeability of protein/ peptides across the intestinal barrier is also a factor adding to the low bioavailability. Therefore, because of the short circulatory half-life exhibited by peptides in vivo, they need to be administered frequently resulting in increased cost of treatment and low patient compliance. Nano-carrier-based delivery present an appropriate choice of drug carrier owing to their property to protect proteins from degradation by low pH conditions in stomach or by the proteolytic enzymes in the GIT.

Nanoparticles as carrier of peptides/ proteins:

Nanoparticles are colloidal particulate system in submicron range acting as carrier of drug molecules. Their size varies from 10 to 1000 nm. These carriers are amorphous, lipophilic with negative charge on their surface.

If we are able produce our molecule of action in the submicron range then it is very easy to transport/ deliver proteins orally.

New techniques are there to produce nanoparticles such as nanopercipitation, solvent evaporation, dialysis, salting out, and supercritical fluid technology etc.

The nanoparticles may able to deliver proteins/ peptides orally but this method is not economically viable on the point of view of pharmaceutical industries as well as the treatment cost will also increase.

  Liposomes:

Liposomes are artificial microscopic bilayer vesicles or sacs made of phospholipids and enclosing an aqueous compartment. They resembles cell membranes in structure and composition. Drugs incorporated in liposomes and administered into the body can be delivered at the desired site, in desired concentration, without being toxic.

Liposomes are a form of vesicles that consist either of many, few or just one phospholipid bilayers. The polar character of the liposomal core enables polar drug molecules to be encapsulated. Amphiphilic and lipophilic molecules are solubilized within the phospholipid bilayer according to their affinity towards the phospholipids.  Participation of nonionic surfactants instead of phospholipids in the bilayer formation results in noisome. Channel proteins can be incorporated without loss of their activity within the hydrophobic domain of vesicle membranes, acting as a size‐selective filter, only allowing passive diffusion of small solutes such as ions, nutrients and antibiotics.

Thus, drugs that are encapsulated in a nanocagefunctionalized with channel proteins are effectively protected from premature degradation by proteolytic enzymes.

The drug molecule, however, is able to diffuse through the channel, driven by the concentration difference between the interior and the exterior of the nanocage. Liposomes have the distinct advantages of being both nontoxic and biodegradable because they are composed of naturally occurring substances. Biologically active materials encapsulated within liposomes are protected to varying extent from immediate dilution or degradation, suggesting drug carrier systems for the transport of drugs and other bioactive capsules to disease‐affected organs. The unique ability of liposomes to entrap drugs both in an aqueous and a lipid phase make such delivery systems attractive for hydrophilic and hydrophobic drugs. Because of advancements in the methods of preparing and formulating liposomes, high‐entrapment efficiencies are possible for incorporating drugs into liposomes, creating a tremendous pharmaceutical impact. Furthermore, such encapsulation has been shown to reduce drug toxicity while retaining or improving the therapeutic efficacy. Several laboratories have reported the use of liposomes as drug carriers in the treatment of cancer, leishmaniasis, metabolic disorders, and fungal diseases.

Innovative research in liposomal drugs has led to commercialization of several anticancer therapeutics such as Doxil, Myocet, two liposome‐based anticancer drugs; doxorubicin; and an antifungal drug formulation, AmBisome, which is a liposomal formulation of amphotericin B used for systemic therapy. Liposomes may have a use in gene delivery to correct gene‐associated disorders or for vaccine therapy.

Now we are in that scenario in which we can able to produce liposomal form of delivery of insulin.

 Liposomal drug delivery is supposed to be ideal for oral insulin therapy. With few modification we are able to deliver Insulin Orally with the help of liposomes.

Suggestions:

    A)     We may produce a liposome having enteric coat over it which may also protect it from low pH of stomach and action of pepsin in the stomach.

    B)      We may also use R-DNA gene therapy for the total enzyme replacement therapy for insulin.

    C)     We may also put some surfactants and solubilising agents which can improve the permeability of the proteins/ peptides of insulin hormone.

Conclusion:

At the last but not the least I would like to conclude that, as there is enhancement in technology takes place; we will able to produce new drug delivery systems which will provide: Minimize drug degradation and loss, prevent harmful side-effects, increase drug bioavailability and the fraction of the drug accumulated in the required zone, various drug delivery and drug targeting systems are currently under development. Drug delivery focused on crossing particular physical barriers, in order to better target the drug and improve its effectiveness; or finding alternative and acceptable routes for the better pharmacological effects.

Oral Insulin Therapy is not just a hypothesis. We are on the right track to provide most effective dosage form for Insulin.