The recognized benefits of the transdermal patch as a viable drug delivery system are driving the development of new forms of transdermal drug delivery systems (TDDS). These products can deliver larger compounds such as proteins and small peptides through the stratum corneum. As new transdermal patches broaden in scope and capability, patch product developers are turning to adhesive manufacturers to develop the latest technologies to overcome complex bonding challenges while enabling the next generation of transdermal patch products.
Work to expand the range of use for passive TDDS first began with incorporating chemical penetration enhancers into patch adhesives to decrease barrier resistance of the stratum coreum layer of the skin to allow delivery of higher molecular weight compounds. An adhesive patch may include one or more compounds to increase diffusion, such as: sulfoxides, alkyl-azones, pyrrolidones, alcohols and alkanols, glycols, surfactants, and terpenes1. However, the increased demand to deliver drug compounds with higher molecular weights has evolved into active TDDS, including applications using ultrasound, micro - needles, and iontophoresis2. Whether the TDDS product is considered to be active or passive, a unique set of adhesive bonding and dermatological challenges must be overcome for any product construction.
One of the most significant obstacles to overcome in formulating adhesives for TDDS is to ensure compatibility between the Active Pharmaceutical Ingredient (API) or medicament and the adhesive’s chemistry. Adhesive manufacturers avoid this by offering formulations with carefully selected chem istries that are inert to the API without changing the drug’s therapeutic properties.
For example, acrylate-based adhesives offer skin-friendly bonding characteristics and are often a good choice for TDDS. However, compatibility issues can occur because these chemistries may absorb up to 5% of moisture from the skin, which potentially could affect drug bioavailability. Also, the adhesive formulators must eliminate any acrylicacid monomer in an acrylate-based adhesive to assure that the adhesive’s pH is neutral3 and that it does not irritate the skin. In iontophoretic drug delivery, pH changes can affect delivery rates, so acrylate-based adhesives must be free of residual acrylic-acid mo - nomer to avoid a potential reaction with the active drug or device components. See Table 1.
Compatibility can change as components age, so accelerated and real-time aging studies must be conducted to ensure that the product maintains its adhesive properties and drug bioavailability during the shelf life of the drug delivery device. If the delivery device requires sterilization, the manufacturer must take measures to ensure that the adhesive will withstand the sterilization procedures and dosage while maintaining its adhesive properties and compatibility with the API.
Biocompatibility of an adhesive formulation with skin is a significant concern in any transdermal patch design. The adhesive must be nonirritating and free of any residual monomers, leachable components, or reactive materials. Allergic reactions are possible, caused by irritation from and sensitivity to a number of chemical compounds, particularly acrylics and natural rubber-based adhesives. Adhesive manufacturers address these concerns by modifying formulations to benefit the population of patients while maintaining drug compatibility and functionality of the patch.
A recent draft guidance from the FDA for an extended release patch provides meaningful guidelines for evaluating performance for safety and bioequivalence of transdermal patch performance. These recommendations now provide a measurable standard for evaluating adhesion and dermal response4 — important factors to consider in the design of longer-wear patches and devices.
The Balance Between Adhesion and Removability
Human skin is an extremely variable substrate. As a general rule, adhesives for transdermal patches are formulated to present aggressive bonds with flexibility and conformability to assure the patch remains firmly in place without lifting or fall-off, to assure a therapeutic dose. The adhesive/skin bond must withstand physical activity, constant friction from clothing, periodic moisture exposure, and varying de - grees of skin porosity and oil levels without shifting or moving. The majority of transdermal patches available today are daily-wear devices that are typically removed within 24 hours of application; however, formulators are developing extended-wear patches designed to be worn for multiple days.
It is important that the adhesives selected for a transdermal device promote skin breathability to ensure a healthy environment for proper dosing and patch comfort. Controlled hydration is a desirable attribute at the adhesive/skin interface for enhancing drug flux while preventing macerated skin. The latter condition can potentially affect drug bioavailability while causing the skin to become weak, increasing the possibility of tearing, and resulting in pain during device removal.
Skin breathability or transpiration through a transdermal drug delivery system affects device wear ability and depends on the moisture vapor transmission rate (MVTR) of the design and the adhesive construction. Several approaches are used to improve MVTR. These include substrate selection, adhesive coat weight, and zone or pattern coating. Performance properties can be improved by utilizing an adhesive coat weight of less than 30 microns. However, this approach can reduce the mass of the adhesive, compromising the ability to achieve a reliable skin bond. Techniques such as zone or pattern coating to provide adhesivefree areas and mechanical poration are processes that can prepare an adhesive for improved moisture transmission when used in combination with high MVTR substrates to enable breathability.