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Transdermal delivery enters active era

Interest in percutaneous methods of drug delivery is reviving now that molecules with higher weight can be administered using electrical current, infrared, ultrasound and microwaves 

The primary function of the skin is to protect against the rigours of the outside world, be they infections or physical damage, and it is a structure exquisitely fit for purpose.

From a pharmaceutical perspective, those qualities make it a challenging barrier to overcome and, for that reason, only a small proportion of pharmacologically-active compounds are suitable for conventional transdermal delivery.

The transdermal route of drug delivery first emerged in commercial pharmaceutical products in the early 1980s and has been used for years to administer drugs for a diverse range of conditions, including angina, osteoporosis and menopausal symptoms, pain and smoking cessation.

However, all the drugs delivered using creams, ointments, gels and patches tend to have various features in common, including a low molecular weight, a lipophilic (fat-soluble) molecular structure and relatively high potency. These features allow them to pass through the stratum corneum, a layer of the skin which serves as its principal barrier. For that reason, there are only about 40 transdermal products on the market currently, delivering around 20 drug molecules, based on these conventional, passive technologies.

"It became evident in the mid-to-late 1990s that passive transdermal delivery was only going to work with a small number of molecules," notes Dr Gary Cleary, president and chief technical officer at US transdermal delivery specialist Corium International.

With only a limited number of small-molecule drugs suitable for transdermal delivery, relying on traditional passive delivery techniques could have rendered patch-based delivery a niche segment of the pharmaceutical sector.

That would be a missed opportunity, however, as there are numerous benefits to delivering medicines across the skin. In addition to convenience for patients, it can reduce dose frequency, avoid so-called first-pass metabolism (a process in which a large proportion of an orally-delivered dose is cleared before it reaches the systemic circulation) and allow treatment to be withdrawn immediately if side effects develop. Furthermore, steady absorption of the drug over hours or days is generally preferable to the peaks and troughs associated with oral or injectable delivery.

Dwindling pharmaceutical pipelines are now driving drugmakers to look at innovative delivery technologies to help improve current therapies and extend patent lives, and the success of some transdermal products – notably the nicotine cessation brands which came to prominence in the 1990s – have brought new life to the sector. Another driver is the biopharmaceutical industry, which is trying to find more patient-friendly ways to deliver large therapeutic proteins and vaccines, most of which need to be given by injection at present.

A number of transdermal technologies have been developed which use external energy as a driving force and/or act to reduce the barrier nature of the stratum corneum in order to enhance permeation of drug molecules into the skin.

Trials are demonstrating the potential of active transdermal delivery technologies to open up new pharma applications

Those technologies (see table) include mechanical methods which breach the skin or the application of electromagnetic energy to drive molecules across it and are bringing the pharmaceutical sector closer to the goal of allowing painless, self-administered, needle-free delivery of small as well as large molecules such as peptides, proteins and nucleic acids.

No large biomolecules have reached the marketplace yet for either mechanical or electromagnetic approaches, but there are currently a dozen technologies in preclinical and clinical development, with some in the latter stages.

Mechanical methods
Microneedles were first patented in the US in 1976, but interest in them has gained pace in recent years as a result of improvements in materials science and microfabrication. They typically consist of multiple piercing microneedles, which can penetrate the stratum corneum barrier without stimulating the nerves. Some are coated with active ingredients; others are hollow and filled with a gel or liquid containing the active drug.

For example, 3M Drug Delivery has one of the most well-established microneedle-based delivery systems in development, and recently signed a development agreement with Radius Health to develop a microneedle patch formulation of BA058 (parathyroid hormone-related protein) that will be tested as a treatment for osteoporosis in phase II trials.

The technology also allows a large molecule drug such as a biologic to be dried directly on to the microneedles, relieving the need for temperature-controlled storage and shipping.

Drugmakers are starting to take notice of the potential of active delivery and the licensing deals are beginning to emerge. For example, another microneedle specialist – Zosano – announced a $32.5m licensing deal in October 2011 with Japan's Asahi Kasei Pharma for a recombinant parathyroid hormone product for osteoporosis which is in phase III testing.

Other mechanical approaches involve pre-treating an area of the skin to create drug conduits. An abrasion approach developed by Intercell involves applying a device which, when pulled off, partially abrades the skin. A second patch containing a vaccine can then be applied, with studies indicating that this approach boosts cellular immunity to a diverse range of antigens. Intercell is currently developing a pandemic influenza vaccine based on the technology with the World Health Organisation, and has a development partnership with GlaxoSmithKline in place for a series of patch-based vaccines.

There are also various approaches which rely on liquid or solid carrier particles that are fired across the skin using applicator devices. These formats, typically described by their developers as needle-free injections, are in trials for the delivery of vaccines and higher molecular-weight drugs such as insulin.

Electromagnetic methods
The other main approach to active transdermal drug delivery relies on the application of electromagnetic energy, such as electrical current, radiofrequency, infrared, ultrasound and microwaves, to bring about a physical change in the skin that allows passage of molecules.

Two electromagnetic approaches, electroporation and iontophoresis, rely on the application of electrical current to the skin. Iontophoresis is a method of transferring substances across the skin by applying an electrical potential difference. This increases the transfer of charged ionic drugs and possibly high molecular-weight substances such as peptides.

Electroporation delivers voltage pulses to the skin, causing transient changes in cell membranes and the formation of microchannels. Sonophoresis makes use of ultrasound to create channels in the skin known as localised transport regions (LTRs) via disruption of the lipid bilayers in skin cell membranes, while other approaches use electricity, radiofrequency waves or lasers to ablate the skin. After the stratum corneum's integrity is breached, a passive patch carrying the active drug is sometimes applied to the area.

One company which has made significant progress in this area is Altea Therapeutics, whose electroporation-based PassPort patch technology is being tested as a delivery system for insulin (phase I/II) and the opioid pain relievers hydromorphone (phase II) and fentanyl citrate (phase I). The firm also has collaborative projects for PassPort formulations with Eli Lilly/Amylin and Hospira. The Lilly/Amylin project is focusing on its type 2 diabetes drug exenatide (phase I) while Altea is working with Hospira on a patch formulation of the blood thinner enoxaparin (phase I).

"Our technology has the potential to increase drug effectiveness by enhancing drug safety and patient convenience as compared to injections," says Steven Damon, senior vice president of business development at Altea.

The science behind these technologies is becoming increasingly robust and trials are demonstrating the potential of active transdermal delivery technologies to open up new pharma applications. That said, questions still remain about the willingness of doctors and patients to try them and, perhaps more crucially, the willingness of payers to reimburse them.

The electromagnetic-based approaches will probably be more expensive than those that use mechanically-based technology, as they tend to need batteries and hand-held devices with bulky microprocessors. On the other hand, mechanically-based technologies can be encumbered by somewhat more complex applicator devices and procedures that could serve as disincentives to their uptake.

With the downturn of the economy and rising healthcare costs, it will be interesting to see which technologies will be able to walk the tightrope of competing on price, appealing to government and private payers and achieving patient/physician acceptance.

Active transdermal drug delivery

Sponsors (Tech name)
Compounds in development
Mechanical energy
Corium (MicroCor)
Zosano (MacroFlux)
parathyroid hormone
3M (MTS)
influenza vaccine, BA058
Norwood Abbey/MIT
NanoPass Technologies
influenza vaccine
traveller's diarrhoea vaccine
Jet delivery
Glide Pharma

spectral energy
lidocaine (approved), zolmitriptan, NSAIDs
Incline Therapeutics (IonSys)
fentanyl (approved)
Travanti  (IontoPatch)
Electroporation Inovio
cervical cancer, HPV, influenza vaccines
Altea Therapeutics (PassPort)
hydromorphone, insulin, peptides
Echo Therapeutics
insulin, erythropoietin, heparin
TransPharma (ViaDerm)
parathyroid hormone, growth hormone

Phil Taylor
The Author
Phil Taylor
is a freelance journalist specialising in the pharmaceutical industry

19th December 2011


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