Issue:May 2016

PULMONARY DELIVERY – Pulmonary Delivery of Insulin to Treat Diabetes – A Debacle


Diabetes is a disease in which the body does not produce and/or properly use insulin, ie, insulin resistance. According to the American Diabetes Association, 20.8 million people in the US – or 7% of the population – have diabetes. One out of every 10 healthcare dollars spent in the US goes to treat diabetic patients. The treatment of type I and some cases of type II diabetes is with subcutaneous insulin injections. It is associated with lack of compliance due to the pain of multiple daily injections, especially in type I juvenile diabetics. Hence, there is an enormous demand for insulin that can be administered without painful shots. Development of such an insulin delivery system would open the way to a multibillion-dollar market, while also making diabetics more treatment-compliant.

Let us look at why the lungs are a preferred target route of many therapeutic agents, including insulin. The human lungs have a combined surface area of 50 m2 to 100 m2 (1,076 ft2 compared to 2 m2 or 22 ft2 of skin) exposed from within and to the surroundings for a multitude of infections and adverse environmental conditions besides air to supply life-supporting oxygen and removal of carbon dioxide. If all of the capillaries surrounding the lungs’ alveoli were unwound and laid end to end, they would extend for about 992 kilometers (616 miles). Both lungs contain approximately 2,400 kilometers (1,440 miles) of airways and 274-790 million alveoli (estimated by counting their openings at the level of the free septal edges, where they form a two-dimensional network) involved in gas and liquid exchange and transport of liquids delivered to the alveoli to the blood.1,2 Hence, the alveoli and its associated vascular network is sought after as a method of delivering many therapeutic agents, including insulin, to systemic circulation for treating various pulmonary and systemic afflictions, such as diabetes. Delivery of corticosteroids, bronchodilators, and therapeutic agents to treat cystic fibrosis of lungs and many others are very effective, and much desired, but not insulin.

The search for a non-injectable form of insulin continues, and the diabetic population all over the world is exploding, needing insulin and other anti-hypoglycemic agents. Fear of needles and the inconvenience of insulin injections have created a market for alternative methods of treating diabetes needing insulin injections to control blood sugar. An apparent breakthrough arrived with the development of a preparation that required no needles; instead insulin could simply be inhaled (Figure 1).

While the FDA has deemed this novel insulin preparation safe and effective, many questions regarding its long-term health effects remain unresolved. After I published the article on the cancer-causing effects of inhaled insulin using the device called Exubera, Pfizer withdrew the drug from the market, took a $2.5-billion dollars loss.2-4 This is not the end of the story – they also reported the development of lung cancer (Figure 2) in six patients who used Exubera to treat their diabetes, as we predicted.3,4 Their withdrawal was timely and saved hundreds of diabetics using inhalation insulin from developing lung cancer.

Now what is the problem? On June 27, 2014, the FDA approved AFREZZA®, a novel, rapid-acting insulin in powder form with a special, smaller delivery device (compared to the original bulky device of Exubera abandoned by Pfizer). After Pfizer withdrew the drug, another pharmaceutical company and developer of this method of insulin delivery spent more than $1 billion dollars to develop this special form of insulin and its miniaturized delivery system. It is obvious the FDA did not look at the ill effects of inhaled insulin. We have sent our publications to the FDA and diabetic agencies, including the developer of this mode of administration of insulin; still it was ignored. We sent the latest publication to all the agencies responsible for the approval and the drug companies marketing it under license, including Sanofi-Aventis US LLC. Finally, the law firm representing Sanofi-Novartis sent a notice informing the developer of Afrezza, terminating the agreement because the prescription levels of Afrezza failed to meet modest expectations.8 Could it be they realized the long-term negative health effects by its long-term use, such as cancer, as we reported in our articles, and its legal implications?1-4

Though both drug giants (Pfizer and Sanofi) dropped marketing inhaled insulin based on a failure to meet their modest expectations, we believe that one can assume they realized the carcinogenic effects of inhaled insulin as we reported in many publications, and with multiple litigations against the product and the company that markets it. Inhaled insulin, in addition to being anti-diabetic, is carcinogenic when inhaled.1-4

After Pfizer and Sanofi dropped marketing pulmonary delivery of insulin, the developer of this inhaled insulin established a new collaboration and license agreement with Receptor Life Sciences.7 The newly formed entity covers the development of multiple inhaled therapeutic products to treat chronic pain, neurologic diseases, and inflammatory disorders in addition to this product. Our stand on the pulmonary delivery of insulin has not changed, and we hope the developer and promoters abandon this mode of insulin delivery. They need to remember what Albert Einstein said on such an effort “Insanity: doing the same thing over and over again and expecting different results.”

Then what is the problem of this mode of delivery of insulin one may ask? There are many problems with this mode of delivery as previously described.1-4 The respiratory passages within the lungs, in addition to the skin, are the only organs in the body that are constantly and directly open to the external environment, exposing them to epidemiological, environmental, occupational, personal, and social factors (close congested living) and their related diseases as exemplified by tuberculosis, pneumoconiosis, black lung disease, and others.5 The main problem with inhaled insulin is that the majority of insulin particles stick to the air passages before they reach the lung alveoli to be absorbed to the systemic circulation to reduce the blood sugar with dire consequences, such as induction of cell mitosis in normal and metaplasic cells leading to cancer. It is estimated less than 10% of the inhaled insulin reaches the lungs to exert the anti-diabetic therapeutic effects, and the rest of it sticks to the air passages, resulting in this disastrous outcome.

The issue that needs to be addressed is how to deliver insulin into the alveoli directly without a majority of it being deposited on the air passages on its way to the alveoli. So far, no such method has been developed, and it may be an impossibility especially due to the presence of billions of tentacles (cilia) on the surface of the cells lining the air passages that pick up any particulate matter from the breathed air that passes by, such as insulin particles of inhaled insulin of Afrezza, before they reach the alveoli as shown in Figure 3.

The problem with the inhaled form of insulin is that it is effective only when the administered dose is more than three or even up to ten times the amount given by subcutaneous injection, because little more than 10% of the inhaled insulin reaches the alveoli to produce a hypoglycemic effect. The interval between the administration of insulin and the onset of glucose-lowering activity is about 10 to 20 minutes. Given its rapid onset of activity, inhaled insulin is suitable for pre-prandial (before meal) but not for a long-term basal (baseline) use. Tight glucose control, however, may come at a price.

One area of potential concern regarding inhaled insulin is the possible effect on the tissues that it comes in contact with on its way to the alveoli, such as the linings of the mouth, throat, tongue, cheeks, gums, tonsils, trachea, bronchial tree, vocal cords, larynx, nose and nasal air sinuses, and olfactory mucosa (which has a direct connection to the brain). Even the modified dry form of special insulin delivered through the special delivery unit makes it no different. The powdered insulin will stick to the aforementioned breathing passages to the lungs before it reaches the alveoli to enter the blood. It is a known fact that insulin induces division of cells called mitogenic wherever it is deposited. Furthermore, because insulin is a growth factor, there is also the potential concern that inhaled insulin could support aberrant cell growth, and potentially even trigger and support cancer and change precancerous lesions to cancers. The report of the development of six cancer cases after using Exubera, an inhalation delivery method, tells us that no matter what kind of insulin you deliver, the powder insulin particulates stick to the naso-oro-laryngotrachea-bronchial tree. The majority of the special insulin delivered through Afrezza (human insulin) will be sticking to these structures before it reaches the alveoli and will act as mitogenic, turning some cells to cancer. It is a known fact that the cancer cells and pre-cancer cells have numerous insulin receptors compared to normal healthy calls, which lock the inhaled insulin, taken inside the cells and thus stimulating further multiplication of these cells (Figure 3) by supplying more glucose as the energy, and turning some of them to cancer growth.4

Research has noted that those with elevated blood sugar due to type II diabetes and other conditions are more prone to develop certain types of cancers than the healthy population. Numerous cancers, and even noncancerous fibrous tumors, have more than the normal amount of insulin receptors to facilitate the entry of large amounts of glucose into the tumor cells to support their energy needs, thus promoting their growth, multiplication, and spread – it is no different in trachea-bronchial air passages.

Hence, the important possible threat about treatment with inhaled insulin is therefore the potentially increased risk of lung cancer, which has been already reported by Pfizer.4 Studies of human bronchial epithelial cells suggest that insulin-receptor activation is in itself insufficient for malignant transformation. However, once malignant transformation has been induced by other agents (environmental, coal miners, smoking, age related, trachea, and bronchial afflictions, etc), the insulin receptor pathway with attachment of inhaled insulin promotes rapid malignant progression of these cells.1-5 Because almost 90% of the inhaled insulin comes in direct contact with so many tissues before it reaches the lung alveoli, it is crucial that future research examines its impact on normal, pre-cancerous, and cancerous cells of the naso-oropharyngeal-tracheal-bronchial respiratory and digestive systems.


Questions about carcinogenic effects that inhaled insulin has shown in a small number of cases using similar methods like the one recently approved by the FDA still do not remain resolved about the potential health risks of inhaled insulin. The documented and possible health risks of insulin inhalation and oral route of administration are explained by us in our extensive article.1-4, 6, 8-10 Due to potentially increased tumor incidence in the tissues of the respiratory tract, and as previously mentioned, Pfizer withdrew inhalation insulin from the market and reported six cases of lung cancer in the users after its withdrawal.4,8

Exubera rode a wave of anticipation that it would free patients from the need for daily painful injections. Regrettably, that wave was either not big enough or crashed on the rocks of safety and price concerns before it could be fully used as an alternate choice to injections. This may explain why Afrezza, arguably an improvement on Exubera, has not been able to reach even the level of prescriptions and sales achieved by Exubera. There is no longer any wave of excitement and anticipation for an inhaled insulin.

As reported by Josef Bassart in the March 2016 issue of this publication (Afrezza – Another Lesson for Drug Delivery Professionals?) on pulmonary delivery “the lung is not like the skin, the nose, or even the stomach.” He appropriately pointed out that “Insulin delivery to the skin offers a number of safety benefits. It presents a large surface area that permits delivery sites to be rotated, and it is also easily inspected for tolerability and safety issues by the health professional and the patient.6 In a worst-case situation, sections of skin can be removed and repaired with grafts. Insulin delivery to the lung is a bit of a black hole. Selective delivery to distinct areas of the lung is hard to accomplish, rotating pulmonary delivery sites is hard to imagine, and assessing ongoing safety can only be performed through indirect testing. There is no simple ‘look and-see’ approach to head off more serious problems.”6

With large-scale prolonged use of inhalation insulin, this will become more apparent with increased tumors of the nasal sinuses, nasopharyngeal cavity, laryngeal and respiratory tracheobronchial passages, as well as the esophagus.

Oral-rectal insulin delivery, according to a published report, also cannot be used to treat insulin-dependent diabetes due to similar health risks.8,9 These authors reported the possibility of more gastrointestinal tumors due to prolonged use of insulin and its mitotic effects. We know that the lining of the gastrointestinal mucosa is highly mitotic and sheds completely every 7-10 days. These cell linings are replaced by other newly formed cells from the crypts, which are highly mitotic and become even more mitotic with oral insulin, ultimately leading to increased incidences of GI tumors. The true health risks of pulmonary, oral, and nasal delivery of insulin to treat diabetes could take a long time to reveal themselves, as has occurred with other drugs, such as Vioxx® (an anti-inflammatory), Avandia® (an oral anti-diabetic drug), and Phenphen diet drugs and other such therapeutic agents. In addition to the eye-opening health risks of inhaled or oral insulin, it is more expensive than other insulin preparations.


There are many concerns about the promises of pulmonary delivery of insulin.1-7,10 The future of insulin delivery other than the pulmonary route with the fewest side effects with almost painless delivery may come from the following:

1. Transdermal delivery of insulin with a physical approach to facilitate its uptake without using needles and/or a special method to absorb the insulin from the patch.
2. Development of a human gene that transforms pancreatic ducts or other stem cells into insulin-producing islets (already named Human Proislet Peptide-HIP).
3. Development of an insulin pump or microdermal needles to deliver insulin under the skin.
4. Development of methods to activate and induce primordial β stem cells in the pancreas’ insulin-producing islet cells or their primordial cells.
5. To ease the painful delivery of insulin by injections, development of a transmucosal and transdermal delivery insulin patch as described in US Patent Publication 2009/0304776 Al.
6. Development of a local anesthetic patch to deliver insulin shots painlessly and make the patients more compliant when insulin injections are needed as described in US Patent Publication 883487 B2 and 883488 B2.
7. Other therapeutic hypoglycemic agents that are akin to insulin, but need not be injected to lower the blood sugar, administered sublingually, transdermally, and by other routes.

The market for new anti-diabetic therapeutic agents and their painless delivery is enormous. It is a multibillion dollar market open to such products. I am sure the drug companies and research scientists are in a race to develop safer methods other than the pulmonary and oral routes to deliver insulin to control elevated blood sugar to treat the ravages of diabetes, which has become an epidemic, though a controllable endocrine disease in the current century. This is the only endocrine disease in medicine that ravages millions of humans, resulting in millions of disability and premature deaths (costing billions of dollars in healthcare cost). Though the hormone responsible for diabetes was discovered in 1921 by Frederick Banting, and used on humans for the first time in January 1922 in Toronto, Canada, on a 14-year-old boy, Leonard Thompson, a type I diabetic teen was the first person to receive insulin by injection. Dr. Banting won the Nobel Prize in physiology in 1923 for insulin discovery. We are still battling how best to deliver this life-saving hormone to save millions of diabetics, though many billions of dollars have been spent on route of insulin delivery projects since the first insulin injection was given 94 years back, and still it is delivered under the skin, by injection – not by inhalation.


1. Shantha TR. Unknown health risks of inhaled insulin. Life Extension. September 2007:79-82.
2. Shantha TR. Unknown health risks of inhaled insulin. Life Extension. February 2015:63-69.
3. Shantha TR. Inhaled insulin increases lung cancer risk confirmed. Life Extension. September 2008:20.
4. Pfizer yanks Exubera; Novartis cutting jobs – Oct. 18, 2007; taking 2.5 billion dollar loss. Then Pfizer warns patients about Exubera lung cancer risk (6 cases reported) – New Jersey. April 9, 2008. Available at: warns patients.
5. Zhao YL, Piao CQ, Wu LJ, Suzuki M, Hei TK. Differentially expressed genes in asbestos-induced tumorigenic human bronchial epithelial cells: implication for mechanism. Carcinogenesis. 2000Nov;21(11):2005-2010.
6. Bossart J. Afrezza – Another lesson for drug delivery professional? Drug Development & Delivery. 2016;16(3):24-25.
7. MannKind: Sanofi Ends Licensing pact for diabetes medicine Afrezza. Sanofi calls it quits and hands Afreezza back to MannKind. Wall Street Journal Jan 5, 2016.
8. Shantha TR, Shantha JG. Inhalation insulin and oral and nasal insulin sprays for diabetics: panacea or evolving future health disaster, part 1. Townsend Letter. December 2008:94-98.
9. Shantha TR, Shantha JG. Inhalation insulin and oral and nasal insulin sprays for diabetics: panacea or evolving future health disaster, part II. Townsend Letter. January 2009:106-110.
10. Selam JL. Inhaled insulin: promises and concerns. J Diabetes Sci Technol. 2008;2(2):311-315.

Dr. T.R. Shantha has been a member of the faculty of Emory University School of Medicine, Medical College of Georgia, Grady Memorial Hospital, Georgia Baptist Hospital, and is presently a visiting professor at JJM Medical College. He has published more than 100 research articles since 1962, in peer-reviewed reputable journals, including Nature (7 papers), Science, NEJM, J Urology, Anesthesia, Anatomy, Exp. Eye Research, American J of Physiology, etc. He discovered Terbutalene as a treatment for Priapism, which is now used all over the world as the first line of treatment in the emergency rooms and by urologists. He has won numerous awards for his academic contributions, including AMA and GAPI distinguished physician awards. He was one of the nominees for the Nobel Prize in Physiology and Medicine in 2007 for his and Dr. Bourne’s research work on the membranes of the nervous system discovered at Emory University. His work is quoted in many medical textbooks and research literature. He has more than 56 patent applications, many published and issued. He is presently working on the treatment of Alzheimer’s and Parkinson’s disease, and has received two patents in the past 6 months for the treatment of sleep apnea. He has developed many innovative therapies, utilizing traditional and alternative methods for the treatment of cancers and many other incurable diseases. He has published 4 books on the brain and one on the breast from Emory University and Yerkes Primate Research Center of Emory University. At present, he is working on 3 books which will be published in the forthcoming year.