Dawning of a new drug delivery era?

Insulin is one of the world's oldest and most well-known biological drugs, and the need for it is not going to go away as the number of patients diagnosed with diabetes continues to increase. A wealth of clinical evidence shows that good, long-term glucose control in diabetes is key to avoiding complications such as kidney disease, blindness and heart problems.

Susan Aldridge

The way insulin is delivered plays a vital role in helping patients manage their condition. As with all peptide or protein drugs, insulin cannot be administered orally because it is degraded by gastric fluids, and pharma companies have long been searching for more convenient and acceptable ways of delivering insulin as opposed to the conventional syringe and needle. Pen injectors are now well-established, but other routes under investigation include inhalers, eye drops, needle-free injections, nose drops, patches and even oral formulations.

Inhaled insulin has had a tough time recently. In February this year, Novo Nordisk (Denmark) announced it had ceased clinical development of its inhaled insulin, AERx iDMS, in Phase III. The news came only a few months after Pfizer (NY, USA) dropped its own inhaled insulin, Exubera. The reasons had nothing to do with safety, although some physicians do have reservations about the long-term impact of delivering an active drug to the lungs on a chronic basis; the Exubera inhaler was rejected by patients and doctors because it was too bulky, complicated and inconvenient.

But these setbacks do not herald the end for inhaled insulin. Eli Lilly (NJ, USA), who worked with Frederick Banting and Charles Best at the University of Toronto (ON, Canada) in the 1920s to make insulin first available as a drug to diabetics, now has an inhaled insulin in Phase III. MannKind (Valencia, CA), a company focused on medical devices, is also developing an inhaled insulin. Novo is still in the game too, committed to developing long-acting inhaled insulin in liquid and powder form.

Mads Thomsen, CSO at Novo, outlines the challenges in developing pulmonary drugs. According to him, there is plenty of experience in inhaler technology for asthma where the drug acts locally in the lung, but for diabetes, the lungs are a vehicle for transporting insulin into the blood, and this is an important difference. "The ideal insulin inhaler would look like an asthma inhaler," says Thomsen, "but it must perform much better. The amount of drug delivered in asthma is highly variable, but this doesn't matter as the patient can just take another puff. For insulin, exactly the same dose must be delivered every time."

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Bioavailability is another issue, as only 10% of the inhaled drug makes it from the lungs to the blood compared with 100% for an injection. "We need to improve both the half life and the bioavailability of insulin in the inhaled form," says Thomsen.

Novo is using its background in medical device manufacture to develop a new insulin inhaler. The company has made 100 million pen injectors for insulin, which is a great advance compared with the traditional syringe, but it is, in fact, only one of many pain-free or needle-free approaches to systemic drug delivery. One of the most novel of these devices coming to market is the Solid Dose Injector (SDI) being developed by Glide Pharma (UK).

The SDI is a tiny rod of solid dose form drug — smaller than a grain of rice — with a point at the end that is pushed gently into the skin. "This pushing action is very important," claims Charles Potter, Glide's CEO. "Other needle-free systems fire the drug at the skin and the drug penetrates to a varying depth because each patient's skin is different. The push is more accurate and reaches the same depth each time."

Use of a solid dosage is important too because it is more stable and has a longer shelf life than solution formulations. "The SDI, with its pen-sized, spring-powered actuator, is simple to manufacture and use", Potter adds. Glide will apply it for mass vaccination, in both industrialized and developing nations, and in emergencies (i.e., pandemics). "We can address all three vaccine markets because we have moved away from needles and cold storage, which make it very cheap for high volumes," Potter explains. The SDI can also be used for home use of proteins and peptides, such as insulin and interferon.

Glide is already working with big pharma and has recently signed an agreement with a leading company to evaluate the SDI technology for the delivery of a branded peptide product. It is Glide's third deal involving a biological product, and further agreements will be announced in the near future.

Meanwhile, Medgenics (Israel) is developing a drug delivery system for proteins that combines drug production and delivery in a single 'biopump', where a piece of the patient's own tissue is programmed to produce a therapeutic protein in the body. "We are taking a tiny biopsy — the size of half a toothpick — processing it outside the body and then replacing it beneath the dermis," explains Medgenics CEO Andy Pearlman. "This is truly personalized medicine. The patient receives a miniprotein production plant made of their own skin."

Medgenics's bioprocessing unit introduces a gene that transforms the required protein into the tissue, or 'micro-organ' as it is known. The resulting biopump then releases the protein drug into the patient's body. Although it may sound like gene therapy, it's not; in gene therapy it is hard to control where the virus carrying the therapeutic gene will be delivered, but with the biopump, you know exactly where the device has been implanted, and where it will produce and release the drug. The amount released to the patient can be controlled by implanting the required number of biopumps. For a higher dose, more biopumps are implanted and, to reduce the dose, they can be ablated. This gives a steady level of therapeutic protein with time as opposed to an injection that provides an initial peak concentration that falls during the days that follow at a rate dependent on its half life.

The company is developing the biopump for erythroprotein, which is used for treating chronic anaemia in kidney disease, and for interferon-alpha, used in the treatment of hepatitis C, where conventional injections are linked with severe side effects that the biopump may be able to alleviate. As far as regulation of this new therapy is concerned, it has been likened to a drug-eluting stent, and Medgenics is working closely with FDA to have it approved under the Centre for Biologics and Evaluation Research.

Pearlman believes that the field of drug delivery is becoming increasingly more 'patient-friendly' as it moves towards smart pills and needle-free injections, but he believes that what Medgenics has to offer goes even beyond this, representing a new paradigm in drug delivery. "This is really different — the protein is being produced fresh in the patient's body each time," he says.

Commenting on drug delivery trends during the next 10 years, Novo's Thomsen thinks pulmonary delivery will be important, and there is also room for improvement in drug delivery pumps, which are currently heavy, inconvenient and untidy. Innovation may come in the form of prefilled 'patch' pumps, which are mini-pumps in the form of patches. In the end, drug delivery may come full circle and there could be 'magic pills' — enhanced forms of oral delivery that allow biologic drugs to enter the blood without being degraded. Many such programmes are already underway for insulin. "This is a long-term ambition for us, and others," says Thomsen.

All of this should improve the quality of life for patients. Living with a chronic disease and managing it with medication is difficult and patients are right to demand better drug delivery techniques, but, of course, there is something in novel drug delivery for the companies as well. Beset by generic competition, and with productivity down, packaging an old drug into a new delivery system makes good business sense.