Introduction:

Insulin can efficiently control blood glucose levels in diabetes when conventional anti-diabetic drugs fail. Until recently, injections were considered the most effective way of delivering insulin into the human body. However, research now suggests that another delivery mechanism inhalation may be a more effective and practical way of delivering insulin. Inhalable Insulin is structured such that it can diffuse through the upper airways and reach the lungs. Most of the previous attempts to deliver insulin via inhalation failed because these formulations were unable to pass beyond the upper respiratory system. The drug has to reach the lung lining to be absorbed, and this presented quite a problem. Now we have the technology to produce a miniaturized version of insulin, called PEGylated Insulin (or Polyethyleneglycol complexed insulin) that can effectively reach the lung capillaries.

Some clinical trials demonstrate that inhaled insulin can correct long term makers of diabetic control like HbA1c more efficiently than injectable insulin. The complications of continuous therapy with Inhalation Insulin are still not clear. However, data suggests that Inhalable Insulin will be more convenient as well as more efficient in controlling diabetes with fewer side effects than conventional therapy.

There are a number of companies, which are working on the prospects of Inhalable Insulin. The various Companies include:

• Flamel Technologies (FLML);
• Sonus Pharmaceuticals (SNUS);
• Aradigm (ARDM);
• Nektar Therapeutics (NKTR);
• Pfizer (PFE); MannKind (MNKD);
• Novo Nordisk A/S (NVO);
• Eli Lilly (LLY);
• Alkermes (ALKS);
• Emisphere Technologies (EMIS);
• DURECT (DRRX) Carrington Laboratories Inc (CARN),
• Antares Pharma Inc (AIS),
• Aksys Ltd (AKSY)

Other Insulin delivery Mechanisms and Inhalation Insulin

From 1923 onwards, Injectable Insulin was the prime mode of delivering Insulin into the blood stream. This was an arduous process and often needed assistance. People with uncontrolled blood glucose levels often hesitate switching over to Insulin Injections. There has always been a need for better methods of delivering Insulin. Many alternatives like Insulin Patches, Pumps and oral Insulin were developed. These were more convenient but failed to be effective enough for everyday use.
Inhalable Insulin is more promising. It has achieved better control over the high blood glucose levels in patients. Inhalable Insulin is also easy to take and has fewer side effects.

Indications for using Inhalation Insulin:

Patients with Type I Diabetes or Insulin dependant diabetes mellitus (IDDM) who have to take Insulin shots are those who would be most benefited by Inhalable Insulin therapy. Inhalable insulin does not completely eliminate the need for Injectable Insulin. It may only supplement mealtime injection of Insulin. Nighttime Injection of Insulin is still required to keep the disease under reins. Non-Insulin dependant diabetics (NIDDM) who can control their blood sugar levels with medications would not need Inhalable Insulin therapy unless those medications become either less effective or ineffective.

Inhalable Insulin may act as a suitable support for oral hypoglycemic drug therapy because of its quick action. The people who would most benefit from Inhalable Insulin are those who travel frequently, sports people and juvenile diabetics who need parental assistance whilst taking insulin injections and can now use the Inhalable Insulin effectively themselves.

Juvenile diabetes and Inhalation Insulin therapy

In juvenile diabetes there is no secretion of natural Insulin because the Insulin secreting cells are destroyed. These diabetics are completely dependant on injectable Insulin. Insulin is also a growth factor. It causes excessive growth that is compounded in a child because of their natural growing mechanism. Inhalable Insulin can overcome these difficulties because it has a short and quick span of action. It does the work it is called for and is eliminated by the body quickly without causing undesirable side effects.

Inhalable Insulin has been accused of reducing the pulmonary capacity. This may be a concern in the long run for juveniles, as they require long years of therapy. Recent research has largely been able to dispel any such fear. The effect on the respiratory system, if any, has been document to be infrequent and reversible. Presently there seems to be no concern in this regard. Adequate exercise and asanas that enhance lung capacity can overcome such effects. Inhalable Insulin cannot replace injected Insulin though. It can only reduce the number of shots required. The juvenile diabetic will still require nighttime injections of Insulin.

Implications of Inhalation Insulin on the Diabetic Diet

Inhalable Insulin attempts to support insulin levels in diabetes. It does not replace the natural Insulin secretory mechanism of the human body. The necessary alterations in the life-style are still vital to effective control of diabetes. A balanced diet and good exercise, along with anti-diabetic therapy are the most effective way of achieving this.

Side Effects and Contraindications:

Most of the patients taking Inhalation Insulin in the clinical trials complained of cough. Though this causes some discomfort in the short-term, it generally disappears with continuous therapy. Drug delivery was unaffected by common cold or other respiratory tract infections. The inhaler also worked in smokers and people with asthma, emphysema (a condition where the elasticity of the lung is decreased), and chronic infection of the airways. Surprisingly smokers, without lung problems, demonstrated a higher absorption of insulin through this delivery mechanism.

However, conditions that affect the lung surface (lining), and present with breathing difficulty, do interfere with absorption of insulin through this route. For example, infections like pneumonia may make inhalation insulin ineffective.

Long-Term Therapy with Inhalation Insulin:

Long-term therapy with inhaled insulin may have the following effects:

• An initial and transient respiratory tract irritation causing cough
• Reversible compromise lung capacity: Potentially insulin, a growth promoting protein, can increase the amount of lung tissue. Over growth of tissue in the respiratory tracts can narrow them further. This has two possible side-effects:
1. Higher resistance to the passage of air in the respiratory tract, making inhalation insulin unsuitable for patients with obstructive lung diseases. This effect can be quantified by a parameter called FEV1.
2. Modifications of the lung lining (where gas exchange takes place) measured by changes carbon monoxide diffusion capacity.

Current data from numerous trials have, however has not documented such changes to be of any clinical significance. Subjects on Inhalable Insulin have not reported a restriction in their activity due to decreased breathing capacity. Also, most scientific evidence suggests that the respiratory tract reverts back to normal after discontinuing therapy.

On the other hand, Inhalable Insulin may have longer lasting respiratory changes in people with pre-existing respiratory diseases.

Economic Effects of Using Inhalation Insulin against other Insulin

Innovation has come with increasing cost. The retail prices of analog or pen injected insulin is significantly higher than those of conventional insulin preparations. In most cases, the cost of equivalent amounts of insulin, in terms of units of insulin, is at least 50% higher and often even more than 200% higher for the new insulin products and devices than for the conventional preparations in vials. The price of these insulin preparations are expected to come down once the marketing extravaganza settles. It is calculated that an average per year cost of using inhaled Insulin would be around $1500 to $1800.

Inhalation Insulin and Hypoglycemic Coma
Hypoglycemia, a state where the blood is depleted of glucose, remains a potential problem with injectable insulin. Severe hypoglycemia can damage the brain and cause coma. Inhalable Insulin acts for a very short duration. It never produces a sustained change in blood glucose levels, eliminating the risk of hypoglycemic coma.

References:

Insulin inhalation: NN 1998.
Drugs R D. 2004;5(1):46-9. Review.

Alternative routes of insulin delivery.
Diabet Med. 2003 Nov;20(11):886-98. Review.

New liquid aerosol generation devices: systems that force pressurized liquids through nozzles.
Respir Care. 2002 Dec;47(12):1392-404; discussion 1404-5.

Use of inhaled insulin in a basal/bolus insulin regimen in type 1 diabetic subjects: a 6-month, randomized, comparative trial.
Skyler JS - Diabetes Care - 01-JUL-2005; 28(7): 1630-5

Use of Inhaled Insulin in a Basal/Bolus Insulin Regimen in Type 1 Diabetic Subjects
A 6-month, randomized, comparative trial
Jay S. Skyler, MD1, Ruth S. Weinstock, MD, PHD2,3, Philip Raskin, MD4, Jean-François Yale, MD5, Eugene Barrett, MD6, John E. Gerich, MD7, Hertzel C. Gerstein, MD, MSC8 the Inhaled Insulin Phase III Type 1 Diabetes Study Group*