Will Inhaled Insulin Really Take Your Breath Away?
by John Walsh, P.A., C.D.E.
The FDA approved the first inhaled version of insulin called Exubera from Pfizer Inc. in January 2006. It was available in September 2006, 84 years after the first insulin injections were given. It is approved for those over 18 years of age with diabetes, but realistically is only appropriate for those with Type 1 who are on larger doses of insulin, such as 60 or more units per day, or those with Type 2 who can tolerate larger doses of insulin.
Artist's Concept, 1996Background
Over the years, various attempts have been made to capture the $3 billion injected insulin market. Two alternative sites of delivery have fared well in the competition: into the lungs and through the stomach.
Delivery of an insulin pill through the stomach has two hurdles to overcome: getting intact insulin molecules past acidity and digestive enzymes in the stomach and intestines, and then opening the intestinal membranes to insulin transport. These problems have stymied researchers for at least 40 years, although a new novel approach discussed below offers some hope.
Delivery of insulin to the small bath towel size area of the upper nasal airways suffers from poor transport across the nasal membranes. This requires very large doses of insulin or use of a chemical to enhance insulin transport. Chemicals used to enhance insulin transport often cause nasal irritation and a runny nose. Even a mild cold or stuffiness could easily change the intended insulin dose. About 100 units of insulin must be deposited into the nose to deliver 10 units into the blood. Insulin production costs would seem prohibitive except that a similar ratio applies to lung delivery where insulin delivery is rapidly progressing.
Compared to nasal delivery, transport of insulin through the lungs allows transport across a surface area the size of a singles tennis court. Absorption into the bloodstream occurs through the thin alveolar walls of the lungs and this appears to be the most promising approach for delivery at this time. However, there is concern about the long-term effects of inhaling a growth protein into the lungs over time. It is hoped the large surface area over which it is spread will minimize negative effects, but small decreases in oxygen transport have already been noted in some research studies.
Exubera
Exubera is the first of the inhaled insulin to be released. It is a short-acting powder form of insulin that is inhaled before each meal. A long-acting insulin still needs to be given each day by injection. In developing Exubera, Pfizer and Aventis have collaborated with Nektar Therapeutics (formerly Inhale Therapeutics), a company that specializes in finding delivery solutions for oral, injectable and pulmonary drug administration to create an inhaler. The Exubera inhaler weighs about 4 ounces and is about the size of an eyeglass case when closed. It opens to about 12 inches for delivery. It is portable but not discreet.
Similar to other inhaled insulins, a number of side effects have been reported. These include coughing, shortness of breath, sore throat and dry mouth. Exubera is not approved for smokers or anyone who has smoked in the last six months because almost twice as much of the inhaled insulin can enter the bloodstream and increase the possibility of an overdose. It is also not improved for anyone with a lung disorder, such as asthma, emphysema, or chronic obstructive pulmonary disease. Exercise also increases transport and likelihood of lows.
A major problem with Exubera is the inability to deliver precise insulin doses. The smallest blister pack available contains the equivalent of 3 units of Regular insulin. A 3 unit dose would make it difficult for many people using insulin to achieve accurate control which is the real goal of any insulin therapy. Using the 1800 Rule for Regular insulin, someone on 60 units of insulin per day would lower their blood sugar about 90 mg/dl (5 mmol) per 3 unit pack, while someone on 30 units a day would drop 180 mg/dl (10 mmol) per pack. Precise control flies out the window with this sledge hammer approach, especially compared to an insulin pump that can deliver one twentieth of a unit with precision.
Pfizer hopes to make Exubera available in September of 2006. Although no price has been published, it will certainly be higher than bottled insulin. It is not clear how soon Medicare, Medicaid, and insurance policies will begin to cover inhaled insulin.
How Exubera Works
The most critical element in delivering a drug to the massive surface area of the lungs is to create a particle small enough to get past the back of the throat yet large enough so it is not breathed right back out of the lungs into the air.
Nektar, with experience in protein delivery, was able to create a particle containing 20% insulin with a micron size that is just right for deep lung delivery. They created two dry powder blister packs, one with 9 units of insulin per pack and a smaller one that has 3 units per pack. These can be combined for a variety of doses in any multiple of 3 units.
Once the blister packs are loaded into the device, a trigger is squeezed to disperse the insulin powder as a cloud into the clear chamber above. A slow, deep breath then brings the finely powdered air cloud into the lungs. Consistent, reproducible delivery is aided by having the insulin as only a tiny portion of the inhaled air and placing it near the front of the air being inhaled. Breathing technique is critical and two or more breaths are required for delivery, according to manufacturers. One problem seen with similarly inhaled asthma drugs has been poor consistency of technique by the same individual over time. This problem may be reduced with an inhaler that uses a more normal breathing approach. The insulin powder appears to be stable for 6 to 24 months at room temperature.
Other Players
Aradigm Corporation of Hayward, California, working with Novo Nordisk, is developing a similar approach with its patented AERxTM Diabetes Management System. They also report that inhaled U250 and U500 Regular insulins are absorbed more quickly than injected Regular using their controlled breathing device. Action times of the inhaled Regular aerosol appear to be between that of injected Humalog and Regular insulins. Novo is planning to offer 1 unit dose increments in its product.
Andaris, a privately-held company with about 70 employees in Nottingham, England, was purchased in 2003 by Cambridge-based Quadrant. Started in 1994, Andaris began developing injectable microscopic contrast agents for diagnostic tests with ultrasound. In the process, they also developed a 5 micron hollow microcapsule of insulin using a low temperature, spray drying technique that preserves the insulin structure. This insulin microcapsule can be inhaled directly into the lungs for absorption. Quadrant is now working with Innovata, MicroDose Technologies, and Bristol-Meyers Squibb to develop the QDose inhaled insulin product. They are planning a more discreet inhaler for delivery.
by John Walsh, P.A., C.D.E.
The FDA approved the first inhaled version of insulin called Exubera from Pfizer Inc. in January 2006. It was available in September 2006, 84 years after the first insulin injections were given. It is approved for those over 18 years of age with diabetes, but realistically is only appropriate for those with Type 1 who are on larger doses of insulin, such as 60 or more units per day, or those with Type 2 who can tolerate larger doses of insulin.
Artist's Concept, 1996Background
Over the years, various attempts have been made to capture the $3 billion injected insulin market. Two alternative sites of delivery have fared well in the competition: into the lungs and through the stomach.
Delivery of an insulin pill through the stomach has two hurdles to overcome: getting intact insulin molecules past acidity and digestive enzymes in the stomach and intestines, and then opening the intestinal membranes to insulin transport. These problems have stymied researchers for at least 40 years, although a new novel approach discussed below offers some hope.
Delivery of insulin to the small bath towel size area of the upper nasal airways suffers from poor transport across the nasal membranes. This requires very large doses of insulin or use of a chemical to enhance insulin transport. Chemicals used to enhance insulin transport often cause nasal irritation and a runny nose. Even a mild cold or stuffiness could easily change the intended insulin dose. About 100 units of insulin must be deposited into the nose to deliver 10 units into the blood. Insulin production costs would seem prohibitive except that a similar ratio applies to lung delivery where insulin delivery is rapidly progressing.
Compared to nasal delivery, transport of insulin through the lungs allows transport across a surface area the size of a singles tennis court. Absorption into the bloodstream occurs through the thin alveolar walls of the lungs and this appears to be the most promising approach for delivery at this time. However, there is concern about the long-term effects of inhaling a growth protein into the lungs over time. It is hoped the large surface area over which it is spread will minimize negative effects, but small decreases in oxygen transport have already been noted in some research studies.
Exubera
Exubera is the first of the inhaled insulin to be released. It is a short-acting powder form of insulin that is inhaled before each meal. A long-acting insulin still needs to be given each day by injection. In developing Exubera, Pfizer and Aventis have collaborated with Nektar Therapeutics (formerly Inhale Therapeutics), a company that specializes in finding delivery solutions for oral, injectable and pulmonary drug administration to create an inhaler. The Exubera inhaler weighs about 4 ounces and is about the size of an eyeglass case when closed. It opens to about 12 inches for delivery. It is portable but not discreet.
Similar to other inhaled insulins, a number of side effects have been reported. These include coughing, shortness of breath, sore throat and dry mouth. Exubera is not approved for smokers or anyone who has smoked in the last six months because almost twice as much of the inhaled insulin can enter the bloodstream and increase the possibility of an overdose. It is also not improved for anyone with a lung disorder, such as asthma, emphysema, or chronic obstructive pulmonary disease. Exercise also increases transport and likelihood of lows.
A major problem with Exubera is the inability to deliver precise insulin doses. The smallest blister pack available contains the equivalent of 3 units of Regular insulin. A 3 unit dose would make it difficult for many people using insulin to achieve accurate control which is the real goal of any insulin therapy. Using the 1800 Rule for Regular insulin, someone on 60 units of insulin per day would lower their blood sugar about 90 mg/dl (5 mmol) per 3 unit pack, while someone on 30 units a day would drop 180 mg/dl (10 mmol) per pack. Precise control flies out the window with this sledge hammer approach, especially compared to an insulin pump that can deliver one twentieth of a unit with precision.
Pfizer hopes to make Exubera available in September of 2006. Although no price has been published, it will certainly be higher than bottled insulin. It is not clear how soon Medicare, Medicaid, and insurance policies will begin to cover inhaled insulin.
How Exubera Works
The most critical element in delivering a drug to the massive surface area of the lungs is to create a particle small enough to get past the back of the throat yet large enough so it is not breathed right back out of the lungs into the air.
Nektar, with experience in protein delivery, was able to create a particle containing 20% insulin with a micron size that is just right for deep lung delivery. They created two dry powder blister packs, one with 9 units of insulin per pack and a smaller one that has 3 units per pack. These can be combined for a variety of doses in any multiple of 3 units.
Once the blister packs are loaded into the device, a trigger is squeezed to disperse the insulin powder as a cloud into the clear chamber above. A slow, deep breath then brings the finely powdered air cloud into the lungs. Consistent, reproducible delivery is aided by having the insulin as only a tiny portion of the inhaled air and placing it near the front of the air being inhaled. Breathing technique is critical and two or more breaths are required for delivery, according to manufacturers. One problem seen with similarly inhaled asthma drugs has been poor consistency of technique by the same individual over time. This problem may be reduced with an inhaler that uses a more normal breathing approach. The insulin powder appears to be stable for 6 to 24 months at room temperature.
Other Players
Aradigm Corporation of Hayward, California, working with Novo Nordisk, is developing a similar approach with its patented AERxTM Diabetes Management System. They also report that inhaled U250 and U500 Regular insulins are absorbed more quickly than injected Regular using their controlled breathing device. Action times of the inhaled Regular aerosol appear to be between that of injected Humalog and Regular insulins. Novo is planning to offer 1 unit dose increments in its product.
Andaris, a privately-held company with about 70 employees in Nottingham, England, was purchased in 2003 by Cambridge-based Quadrant. Started in 1994, Andaris began developing injectable microscopic contrast agents for diagnostic tests with ultrasound. In the process, they also developed a 5 micron hollow microcapsule of insulin using a low temperature, spray drying technique that preserves the insulin structure. This insulin microcapsule can be inhaled directly into the lungs for absorption. Quadrant is now working with Innovata, MicroDose Technologies, and Bristol-Meyers Squibb to develop the QDose inhaled insulin product. They are planning a more discreet inhaler for delivery.
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