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.
While aggressive adhesion assures a secure bond to skin for addressing dosing concerns, it can potentially cause discomfort upon patch removal. In these situations, the adhesive removes skin cells and/or hair when the device is pulled away. Additionally, an adhesive that releases uncleanly may leave behind an unwanted residue on the skin that is difficult to remove.
As more patch products become available for diverse consumer populations with skin of varying ages and conditions, developers are seeking adhesive technologies that continue to demonstrate high levels of reliable adhesion, but offer a more gentle removal experience for the user. This is becoming more evident as designs for longer-wear applications are being considered. Also a factor is the emergence of new transdermal treatments for chronic conditions that require repeated patch placement to a specific skin site. As more active transdermal treatments employ mechanical preparation of the skin prior to, or as part of, a treatment regimen, the need for more adhesive choices providing low- to no-pain removal is growing.
Adhesives Research (Glen Rock, PA) is addressing the growing need for skinfriendly adhesives while overcoming the thickness issues of gel formats through the development of low-trauma adhesive (LTA) technology for gentle removal. This high-MVTR, customizable pressure-sensitive adhesive (PSA) technology maintains intimate skin contact for up to five days with painless and residue-free removal. The adhesive is formulated to cleanly release from hair and the top layer of skin with a pain index of <2.5 on the Wong-Baker FACES Pain Scale5. For comparison purposes, a standard skin-friendly adhesive has a pain index rating of 4 to 5 on this scale based on internal studies.
Some LTA formulations exhibit good to excellent ratings for resistance to gamma sterilization techniques, which is an important consideration in active patch designs utilizing microneedles, abrasion, or other techniques to prepare the skin prior to, or as a step in the proper application of a patch device. Three versions of this technology are currently offered and the properties are outlined in Table 2 (see page 6).
Careful Thickness Control
Tight tolerances for control of adhesive and substrate thicknesses from lot to lot are critical for applications where any variations in thickness can have a negative impact upon dosing. For example, scientists have designed some drug delivery patches with microprojections, which are arrays of solid metal, hollow metal, or polymer drug-treated micro needles that adhere to the skin with a PSA. The combined thickness of the components of the device controls the depth of penetration of the microneedles to release the drug into the bloodstream or lymphatic system. If penetration through the skin is too shallow, the user may not receive the proper dose; alternatively, if the needles penetrate too deeply, the user could experience un wanted discomfort and pain.
Enabling Adhesive and Coating Technologies
While transdermal patches offer many advantages, passive systems are restricted to low-dosage lipophilic and low molecular- weight molecules (<500 Daltons)6. Much of the current growth for transdermal drug delivery is focused on active systems to deliver a wider range of drug molecules, including proteins such as vaccines. As transdermal product designs and capabilities continue to evolve, adhesive manufacturers are embracing opportunities to formulate highly specialized PSAs, coatings, and related polymer technologies to meet the requirements of these delivery systems.
Electrically Conductive Adhesives for Iontophoretic Delivery
PSAs perform multiple functions in iontophoretic drug delivery systems, including bonding to the skin, creating a protective seal, and forming conductive bonds for internal electronic component assemblies.
Iontophoretic devices offer a noninvasive alternative for delivering therapeutic substances via the electro transport of molecules that would not normally diffuse across the skin. A small electric current passes through the patient's skin, between positively and negatively charged electrodes. The drug or active substance is located at one of the electrode sites, depending on the drug’s polarity. The active electrode repels the charged drug, forcing it into the skin by electro repulsion, where it is picked up by the blood or lymph system. Charged drug molecules are attracted to electrodes of the opposite polarity. The rate of drug delivery is controlled by the strength of the electrical current to transport the drug rapidly and accurately, via on-demand dosing or patterned/modulated drug delivery7.
Iontophoretic patch designs can benefit from electrically conductive PSA technology, such as Adhesives Research’s homogeneous, carbon-based electrically conductive PSA technology, which has been used in the electronics industry for more than 20 years. These PSAs can be used for transmitting current through layers of a device, forming electrical interconnections and bonding electrical components within a patch. In some iontophoretic devices, the electrically conductive layer may contain conductive fillers to lower the bulk resistance in addition to resistance at the interface. A PSA membrane overlay may be used to adhere the patch to the user’s skin while bonding and protecting components within the device’s housing.
Customizable Coating Technologies for Drug Delivery
A number of the technologies that have been perfected for TDDS over the last 20 years now form the basis for a natural evolution into other novel forms for delivering APIs. ARx, LLC, a division of Adhesives Research, is leveraging the polymer chemistry and coating techniques used in TDDS in the form of customdeveloped dissolvable films and adhesive platforms for oral drug delivery, transdermal drug delivery, and biopharmaceuticals.
Dissolvable oral thin films (OTFs) are a proven technology for the delivery of APIs to patients for select over-the-counter (OTC) medications and prescription drugs. OTFs offer fast, accurate dosing in a safe, efficacious format that is convenient and portable, without the need for water or measuring devices.
A number of the film’s physical properties can be customized, including dissolution rates, thickness, material composition, taste masking, and API absorption rates8 to broaden its potential for application into other areas, including:
Topical applications: Films can deliver active agents such as analgesics or anti-microbial ingredients for wound care or other applications.
Binding agents: Dissolvable films are being considered in applications for enveloping active particles in multi-layer or combination systems to enable controlled release.
Buccal, sublingual, and mucosal delivery systems: Layers of dissolvable films with tailored dissolution rates may be combined with bioadhesives for the controlled release of APIs over a period of minutes or hours.
Gastro-retentive dosage systems: Water-soluble and poorly soluble molecules of different molecular weights can be contained in a film format to disintegrate at a specific pH or enzyme exposure within the gastrointestinal tract to treat GI disorders9.
As mentioned previously, coating techniques can be applied to improve the MVTR values of a PSA for skin-bonding applications. The concept of a porous adhesive serving a dual role for skin bonding while increasing device functionality is relatively new to the pharmaceutical industry. Adhesives Research’s porous technology is a super porous PSA offering hundreds of micrometer-sized open pores or cells in a low-density, highly permeable structure. The pores range in diameter from approximately 200 to 500 microns. The distribution of pores throughout the matrix results in 30 to 50% porosity, and a finished film thickness of 2–8 mils. The porous adhesive formulation is completely customizable for each application.
The adhesive’s pores form isolated channels through the adhesive as shown in Fig 1. These channels enable the free exchange of gases and fluids from one substrate to the next through the Z direction of the adhesive to offer enhanced high MVTR rates. As seen above in Table 3, the porous adhesive’s MVTR of about 9000 g/m2/day is extremely high when compared to conventional solid film PSAs that typically demonstrate MVTR of tens to several hundred g/m2/day.
Transdermal drug delivery systems continue to deliver patients increased compliance by providing predictable and reliable therapeutic dosages without limiting a patient’s normal daily activities, driving drug manufacturers to continue to expand the scope of this drug delivery system. As the scope widens, adhesive manufacturers are responding by developing a range of skin-friendly and API-compatible formulations for improved comfort and wear with less discomfort during removal.
Versatile in their chemistry and form, pressure-sensitive adhesives are critical components in achieving intended outcomes such as sustained skin adhesion, component bonding, electrical component bonding and assembly, moisture seals, and drug envelopments. While pharmaceutical product developers explore new methods for delivering a wider range of drugs through passive and active systems, PSA manufacturers will need to continue to push the capabilities of their technologies to meet the unique challenges of new and emerging transdermal applications
This article was written by Jeff Purnell, PhD, Medical and Pharmaceutical R&D Group Leader, and Bill Meathrel, PhD, Senior Scientist for Adhesives Research, Glen Rock, PA. Contact Dr. Purnell at
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