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Insulin delivery systems
To diabetic patients, the idea of delivering insulin to without being injected may no longer be just a dream. Exciting new drug delivery advancements have made one or more treatment options very real possibilities in the future.
Insulin delivery systems in the pipeline include two oral dosage forms, a transdermal skin patch, a mouth spray, and several versions of inhaled insulin. While most of the products are still several years away from market, the progress being made in injection alternatives is important to the field of diabetes management.
Currently, all approved insulin preparations are injected subcutaneously. The available methods of insulin delivery include syringe and vial, insulin pen and doser, jet injector, and external insulin pump. (See Table 1.)
The ideal insulin delivery system should provide accurate dosing and also be comfortable and convenient. Some other considerations for effective systems include patient safety, social acceptability, and affordability. The currently available insulin systems have some drawbacks, including compliance issues such as inconvenience of preparation and potential dosing errors. In addition, some patients may have a syringe phobia.
At this time, studies have demonstrated that two oral pills are effective in humans. One is from Emisphere Technologies, Tarrytown, N.Y. The company's oral delivery agent facilitates absorption to the liver and the systemic circulation, with maximum insulin concentrations seen within 15 to 25 minutes. This mimics the physiological production and excretion of insulin from the pancreas.
In a phase I study evaluating the safety and tolerability of the capsule, neither oral insulin nor the delivery agent alone had any impact on insulin levels. However, insulin combined with the delivery agent provided insulin absorption at clinically significant levels.
Hexy-Insulin Monoconjugate (HIM2), developed by Nobex Corp., Research Triangle Park, N.C., in collaboration with GlaxoSmithKline, is another oral insulin dosage form being studied. HIM2, which is currently in phase II clinical trials, uses polymer technology to resist enzymatic degradation of the hormone and promote absorption into the bloodstream.
Recent studies showed that HIM2 yielded maximum absorption when taken 15 minutes before a meal and that it showed insulin-lowering benefits equal to injected insulin when multiple doses were given over a three-day period.
A transdermal skin patch is in development at Altea Development Corp. in Atlanta. The patch, which uses Altea's "micropore system," is being developed to deliver insulin for continuous basal (the basic level of insulin a person needs throughout the day) dosing. Clinical feasibility has been demonstrated with insulin (as well as interferon and morphine), and an Investigational New Drug application was submitted to the Food & Drug Administration earlier this year. A patch for on-demand mealtime dosing of insulin is being developed as a potential second product.
Generex Biotechnology Corp., Toronto, is developing an oral spray, which uses the company's Rapid Mist device in conjunction with Oralin, a liquid aerosol version of insulin. It is a pain-free, needle-free, noninvasive drug delivery system that administers dosages accurately.
Research presented at the ADA meeting showed that the benefit from Oralin was identical to that of an insulin injection in its ability to lower glucose levels. In addition, Oralin was able to serve as the mealtime boost needed by some patients who were failing oral hypoglycemic drugs.
Several companies attending the ADA meeting said their research efforts were focused on developing an insulin which could be inhaled directly into the lungs.
Pfizer recently reported that patients with Type 2 diabetes who had failed to meet recommended blood glucose levels with combination non-insulin oral therapy achieved better glycemic control with Exubera, an inhaled insulin, than patients who received only oral agents. The three-month phase III study with 309 Type II-diagnosed patients examined whether Exubera, an inhalable rapid-acting dry powder insulin, could provide better glycemic control when taken alone or in combination with oral agents compared with patients taking only oral agents. Exubera was administered before meals.
"Currently, many patients with Type 2 diabetes fail to reach target glucose levels on oral agents, which will eventually lead to the need for insulin therapy," said Julio Rosenstock, M.D., Dallas Diabetes & Endocrine Center, and clinical professor of medicine at the University of Texas, Southwestern Medical Center. "This study shows that Exubera has the potential to help patients with Type 2 diabetes by providing an effective and highly acceptable treatment option."
Patients taking Exubera also showed significantly greater decreases in both fasting plasma glucose concentrations (a measurement taken before breakfast) and two-hour postprandial glucose levels (a measurement taken after a meal), compared with patients who took only oral agents, according to the company.
New York-based Pfizer and Aventis Pharma, Bridgewater, N.J., entered into a global agreement to codevelop, copromote and comanufacture the inhaled insulin. Pfizer is also collaborating with Inhale Therapeutic Systems, developers of the inhalation device and formulation process.
Novo Nordisk, headquartered in Princeton, N.J., is developing the AERx Insulin Diabetes Management System (iDMS) in collaboration with Aradigm Corp., Hayward, Calif. AERx iDMS, headed into phase III clinical trials, is the first electronic pulmonary diabetes management system. The system administers insulin via inhalation by producing a fine-particle aerosol from disposable insulin strips by extruding the prepackaged solution through hundreds of precise laser-drilled holes in a single-use nozzle.
Recent clinical data showed that the inhaled insulin administered through the AERx system achieves a level of glycemic control in people with Type 2 diabetes comparable to multiple injection therapy, which is the current gold standard. The study also showed that mealtime insulin could be delivered via AERx without compromising glycemic control.
Alkermes Inc., Cambridge, Mass., and Eli Lilly, Indianapolis, are working together to use Alkermes' proprietary AIR pulmonary drug delivery system to develop inhaled short- and long-acting formulations of insulin as well as other products used to treat diabetes. The technology uses an inhaler to efficiently deliver drug formulations deep into the lung.
The Aerodose Insulin Inhaler is designed to provide diabetic patients who require short-acting insulin with an alternative to daily pre-meal injections, according to Aerogen, of Mountainview, Calif.
The pocket-sized Aerodose insulin inhaler, which delivers a liquid insulin formulation, is breath activated and incorporates a titratable cartridge that allows patients to adjust dosing based on their insulin requirements.
Recent clinical results from a second phase II study indicate that Type 2 diabetes patients will be able to control their glucose levels with insulin as effectively with the Aerodose insulin inhaler as with subcutaneous injection. The studies show that the Aerodose insulin inhaler provides efficient drug delivery, does not change the metabolic effect of insulin, and provides a constant relative bioavailability.
While implantable pumps are in development, this avenue is costly and the devices must be surgically implanted. In addition, numerous surgeries may be required for maintenance of the device.
There are two types of implantable insulin pumps (IIPs): open-loop and closed-loop. Open-loop IIPs are in development in the United States and are approved in Europe. A patient activates the open-loop system and determines the appropriate insulin dose based on frequent blood glucose testing and planned food intake.
The closed-loop system, also known as the artificial pancreas, is a computerized feedback system with an infusion pump that is programmed to deliver insulin doses according to blood glucose concentrations as measured by a glucose sensor. However, a sensor has not been developed to reliably monitor glucose levels, so development of this type of product has been hampered.
Whole-organ pancreas transplantation is another option for diabetes patients. However, this avenue requires major abdominal surgery and includes numerous health risks, such as intra-abdominal infections and abscesses, as well as vascular graft thrombosis. A suitable donor may also be difficult to locate.
Transplantation of islet cells is less invasive but has not had long-term success.
Lisa Samalonis. Insulin injections may soon be a thing of the past. Drug Topics 2002;24:14s.