As in passive TDDS, molecular weight is the major issue. Although large molecules can be delivered with iontophoresis, there are limitations with larger proteins. For example, there are conflicting reports on the iontophoretic delivery of insulin. "Several research groups have demonstrated delivery, and there are groups that have not achieved delivery of insulin with iontophoresis," says Upasani.

"From an engineering standpoint we use 10 kDa as a molecular weight guideline," says Thu-Ha Duncan, director of research and development at Empi. "Anything over that, we'd have to do some testing and really look at the molecular chain to see whether we can do it."

With the proper ratio, it may be possible to deliver two actives in one transdermal, but it is not easy. "The main challenge with the iontophoretic system is the competition between the drug and the excipients such as the buffers with the drug. The system depends on the relative size and charge of the molecules, and there would definitely be a preference for one passing through than the other," says Upasani.

"There's a fine art to developing a transdermal system," says Myers. She outlines three key objectives for designing a TDDS:

• Deliver the appropriate dose throughout the dosing interval
• Ensure the system is safe, including that it adheres effectively and is not irritating
• Aim to develop a product that is elegant, that the consumer will accept and can afford.

"The challenges are working through the various steps to achieve these three key objectives," says Myers.

In some cases there is a pH change across the skin layers, and the drug may not go all the way through because the charge on the molecule of interest changes as it travels through the skin. Extensive preformulation must be conducted to understand the physical and chemical characteristics of the drug.

To address these challenges, Sitz emphasizes the importance of a solid working partnership between the transdermal researchers and manufacturers."The average time for the development of a pharmaceutical product is roughly five to seven years; therefore, the health of the entire collaboration is critical," he said. "Having a strong communication channel is one of the most important tools for successfully initiating and managing the collaboration between all disciplines. Our research findings have proven that the most important attributes considered during a partnership are performance, commitment, and communication."

Advanced adhesives

The increasing scope of the transdermal delivery market, including the delivery of larger molecules such as proteins, has raised the bar in innovative TDDS components. TDDS that are worn for longer periods require adhesives that offer a breathable environment so that moisture can be removed from the skin surface. "Customers are requesting adhesives for active delivery applications that range in wear times from minutes to a week or longer. We formulate adhesives that will bond over these wear periods in various dermatological environments," says Scott Knorr, pharmaceutical business manager, Adhesives Research, Pharmaceutical Applications (Glen Rock, PA).

Some adhesives used in passive TDDS can also be used in active systems. Adhesives Research, for example, develops and manufactures acrylic, polyisobutylene, silicone, and hybrid (multichemistry) coatings for both formats. According to Knorr, additional considerations when designing an adhesive for active TDDS include the following:

• Wear considerations and bonding: An adhesive used in an active TDDS may be required to bond to unique surface energies such as the housing of a device over short-term (removable) or long-term (permanent) periods. In addition, skin-contact adhesives must often be designed to support the weight of the device and may encounter unique environmental conditions.
• Compatibility and stability: Pressure-sensitive adhesives used in active TDDS must not only be compatible with the active pharmaceutical ingredient (API) and formulation excipients, but also the device itself, which may include sensitive electronics.
• Multifunctionality: As the manufacture of active TDDS increases in complexity (relative to their passive transdermal counterparts), customers are asking adhesives to do more beyond simply bonding such as promoting electrical and ionic conductivity.