Transdermal delivery is finding wider therapeutic application but when it comes to making the device stick, every drug has different requirements and considerations. Jeff Purnell, Adhesives Research, explains.
The recognised 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 advance technologies to overcome the complex bonding challenges and clear the way for 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 skin’s stratum corneum layer and allow delivery of higher molecular weight compounds. An adhesive patch may include one or more compounds to increase diffusion, including sulfoxides, alkyl-azones, pyrrolidones, alcohols and alkanols, glycols, surfactants and terpenes.1
However, the increased demand to deliver drug compounds with higher molecular weights has evolved into active TDDS, including applications using ultrasound, microneedles and iontophoresis.2 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.
Drug compatibility: 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 chemistries 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 but compatibility issues can occur because these chemistries may absorb up to 5% of moisture from the skin, which could potentially affect drug bioavailability. Also, the adhesive formulators must eliminate any acrylic-acid 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 monomer to avoid a potential reaction with the active drug or device components (see Table 1).
| Table 1: Advanced adhesives and polymer coatings for drug delivery systems2 | ||
| Skin-friendly PSAs | Acrylic, polyisobutylene, silicone and hybrid chemistries | Formulations tailored to bond with various skin types and in various environments, for wear times ranging from minutes to days |
| Electrically and ionically conductive coatings | Acrylic and polyisobutylene chemistries | Polymer formulations that overcome traditional insulative properties of an adhesive to allow current or ion transport |
| Long-Term Wear Adhesives | Acrylic | Polymer chemistry and formulations are designed to provide customisable wear times up to 7 days with minimal edge lift |
| Dissolvable films and erodible PSAs | Hydrophilic copolymers | Polymer coatings designed to erode at predetermined rates when in contact with biological fluids |
| Ethanol- and enhancer-tolerant coatings | Acrylate chemistry | PSAs that can withstand exposure to enhancer chemicals found in drug delivery systems |
| Ultraclean and nonreactive adhesives | Acrylate chemistry | Chemically inert coatings that are compatible with APIs and excipients |
| Porous adhesives | Acrylic, rubber, polyurethane chemistries | Coated polymer systems with tailored pore size to allow controlled fluid transfer, with doping used to create biphasic formulations |
| Hydrogels and organogels | Hydrophilic polymers and copolymers | High-fluid content coatings that form an interface between the skin and a sensing element in device-assisted delivery |
| Hybrid PSAs | Rubber and acrylic graft | Polymer matrix that offers high tack and chemical stability |
Compatibility can change as components age so accelerated and real-time ageing studies must be conducted to ensure that the product maintains its adhesive properties and drug bioavailability during the shelf life of the delivery device. If the device requires sterilisation, the manufacturer must take measures to ensure that the adhesive will withstand the sterilisation procedures and dosage while maintaining its adhesive properties and compatibility with the API.
Biocompatibility: An adhesive formulation’s biocompatibility with skin is a significant concern in any transdermal patch design. The adhesive must be non-irritating and free of any residual monomers, leachable components and 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. 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 response,4 important factors to be considered in the design of longer-wear patches and devices.
Balancing 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 ensure 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 degrees 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 more extended-wear products designed to be worn for multiple days.
Controlled breathability: It is important that the adhesives selected 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, resulting in pain during patch removal.
Skin breathability or transpiration through a TDDS affects wearability and depends on the moisture-vapour 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 utilising an adhesive thickness of less than 30µm. 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 adhesive-free 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.
Skin-friendly adhesives for long-term wear: More products are becoming available that require wear times of multiple days, and in the case of insulin infusion pumps, the adhesive must reliably attach a device to skin while bearing load. Although aggressive adhesion assures a secure bond to skin for addressing dosing concerns, it can potentially cause discomfort upon patch/device removal. Pain is caused when the adhesive removes skin cells and/or hair when the device is pulled away. Also, an aggressive adhesive that does not release cleanly may leave behind an unwanted residue on the skin that is difficult to remove.
Adhesives Research has designed a tailorable, high MVTR pharmaceutical-grade acrylic adhesive technology that meets the critical design parameters for securing a patch or device for periods up to seven days to ensure adequate skin bonding with residue-free removal. In spite of the adhesive’s aggressive nature, the pain experienced upon removal is considered to be low-to-moderate and studies have shown that removal of the adhesive tape does not cause disruption of the stratum corneum.
The adhesive formulation can be tailored to a specific wear time target while also addressing the acceptable pain index for a specific application (see Figure 1).
Gently removable, low-trauma adhesives: 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 with a more gentle removal experience for the user. 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 is increasing for more adhesive choices that offer pain-free removal.
Adhesives Research is addressing the need for skin-friendly adhesives while overcoming the thickness issues of gel formats through the development of low-trauma adhesive (LTA) technology for gentle removal. This high-MVTR, customisable pressure-sensitive adhesive (PSA) technology maintains intimate skin contact for up to five days with virtually painless and residue-free removal because it is formulated to release cleanly from hair and the top layer of skin. Some LTA formulations exhibit good to excellent ratings for resistance to gamma sterilisation techniques, which is an important consideration in active patch designs utilising 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.
| Table 2: Attributes of Adhesives Research LTA Adhesives | |||
| Attribute | LTA 1 | LTA 2 | LTA 3 |
| One-hour forearm peel | 2–10oz/in | 4–14oz/in | 3–6oz/in |
| 24-hour forearm peel | 2–10oz/in | 4–16oz/in | 6–8oz/in |
| Peel (1-24 hours of wear) | insignificant | max 2oz/in | max 2oz/in |
| Percentage peel retention on reattachment | 80% | 70% | 85% |
| Residue on skin | none | none | none |
| MVTR– upright Payne cup (g/m2/day) 2mils PSA on 1mil PU | 450 | 750 | 1300 |
| Gamma sterilisation resistance | good | fair | excellent |
| Cytotoxicity (direct agarose overlay) | non-cytotoxic | non-cytotoxic | non-cytotoxic |
| Primary skin irritation – ISO | negligible (0.2) | negligible (0.4) | negligible (0.0) |
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 on dosing. For example, scientists have designed some drug delivery patches with micro-projections that 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 micro-needles 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; if the needles penetrate too deeply, the user could experience unwanted 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).5 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 specialised 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 non-invasive 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 delivery (see Figure 2).6
Figure 2: Iontophoretic device
Iontophoretic patch designs can benefit from electrically conductive PSA technology, such as Adhesives Research’s homogeneous, carbon-based electrically conductive PSA technology that has been proven 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.
Customisable coating technologies for drug delivery: A number of the technologies that have been perfected for TDDS over the past 20 years form the basis for a natural evolution into other novel forms for delivering APIs. ARx, a wholly-owned subsidiary of Adhesives Research, is one company leveraging the polymer chemistry and coating techniques used in TDDS in the form of custom-developed dissolvable films and adhesive platforms for oral drug delivery, trans-dermal 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 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 customised, including dissolution rates, thickness, material composition, taste masking and API absorption rates7 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 multilayer 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 disorders.8
In conclusion, TDDS continue to deliver increased patient compliance by providing predictable and reliable therapeutic dosages without limiting a patient’s normal daily activities, driving drug manufacturers to expand the application 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, PSAs 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 continue to push the capabilities of their technologies to meet the challenges of new and emerging transdermal applications.
References
1. Barry B., Williams A., Advanced Drug Delivery Reviews, Vol. 56, 5, pp 603–618, (March 2004)
2. O'Mahony, J., Pharmaceutical Manufacturing and Packaging Sourcer. May 2009, pp24–25
3. Meathrel, W., Drug Delivery Technology, Vol 7 No.9, pp40–44, (October 2007).
4. US Food and Drug Administration, Draft guidance on ethinyl estradiol; Norelgestromin, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM162407.pdf, accessed 5 July, 2010.
5. Karabiyikoglu, M. Drug Delivery Report. Spring/Summer 2007: 28−30.
6. Phipps JB, et al. E-trans technology. In: Rathbone MJ, Hadgraft J, Roberts MS, eds. Modified Release Drug Delivery Technology. New York, NY: Informa Healthcare; 2008: 499−511.
7. I. Muir. ONdrugDelivery – Oral Drug Delivery: When You Find the Holy Grail, http://www.ondrugdelivery.com/publications/Oral_Drug_Delivery_07.pdf, accessed 17 November, 2008.
8. Barnhart S, Vondrak B. Pharmaceutical Technology (suppl): s20−s26 (Apr 1, 2008).
