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Challenges in Formulating Adhesives for
Transdermal Drug Delivery
Wiliam G Meathrel, Adhesives Research, Inc The recognized benefits of the transdermal
for solid-dose formats coming off patent protection.
patch (Figure 1) as a viable means of drug
Drug developers also are investigating the patch plat- delivery is driving the development of new forms
form as an alternative delivery system for peptide of transdermal drug delivery systems (TDDS).
These new types can deliver larger compounds
drugs that are vulnerable to proteolytic attack and such as proteins and smal peptides through the
that tend to undergo aggregation, adsorption, and stratum corneum. As patches increase in their
denaturation [3].Additional y, the benefits of patches value and reliability for drug delivery, however,
are well-recognized regarding avoidance of manufacturers face chal enges in formulating
unwanted side effects, particularly with compro- adhesives that are functional, precise, and safe.
The science of formulating adhesives for TDDS
Work to expand the range of use for passive TDDS requires a careful balance; that is, the adhesive
must deliver functionality while it also provides a
first began with incorporating chemical penetration safe format. The adhesive must be compatible
enhancers that decrease the barrier resistance of the both with the active pharmaceutical ingredients
stratum corneum, to al ow delivery of compounds (APIs) and with the patient’s skin and must
with a higher molecular weight. An adhesive patch deliver a reliable and reproducible therapeutic
may include one or more compounds to increase dif- dose. To deliver precise control and perfor-
mance, pharmaceutical-grade adhesives
today provide highly specialized chemistries
designed to overcome unique chal enges spe-
cific to each application.
weights, such as those that provide treatment for short-term conditions like motion sickness, or that provide longer-term therapies, such as hormone replacement. Scientists are developing new patches to treat chronic conditions through the continued use of a daily delivery device. Examples include the first rivastigmine patch for the treatment of Alzheimer’s disease [1] and the rotigotine patch that recently launched in Europe [2] for treatment of some forms of Parkinson’s disease. Fueling this trend are drug manufacturers’ ef orts to extend lifecycle applications fusion, including sulfoxides, alkyl-azones, pyrroli- bonding characteristics and that often are a good dones, alcohols and alkanols, glycols, surfactants, and choice for TDDS. Acrylate-based adhesives may terpenes [4]. The increased demand to deliver drug absorb up to 5% of moisture from the skin, which compounds with higher molecular weights, however, potential y could af ect drug bioavailability.Also, the has spurred development of active TDDS, including manufacturer needs to eliminate any acrylic-acid applications using ultrasound, microneedles, and ion- monomer in an acrylate-based adhesive to assure tophoresis [5]. Whichever type of system the drug that the pH of the adhesive is neutral [5] and that it developer considers a TDDS to be, passive or active, does not irritate the skin. In iontophoretic drug deliv- the products of er companies a unique set of adhesive ery, pH changes can affect delivery rates; so acrylate- ransdermal bonding and dermatologic chal enges.
based adhesives must be free of residual acrylic-acid monomer to avoid a potential reaction with the active Drug Compatibility
drug or device components. See Table 1.
One of the most significant obstacles to overcome in formulating adhesives for TDDS is the difficulty in maintaining compatibility between the API or Also, compatibility can change as components age; medicament and the adhesive’s chemistry to assure so scientists must perform accelerated and real-time that the drug will not change potency. Adhesive aging studies to ensure that the product maintains manufacturers must offer formulations with care- its adhesive properties and drug bioavailability dur- ful y selected chemistries that wil not react with the ing the shelf life of the drug delivery device. If the API or change its physical properties.
delivery device requires sterilization, the manufac- turer must take measures to ensure that the adhesive will withstand the sterilization procedures and For example, compatibility can become a chal enge dosage while maintaining its adhesive properties with acrylate-based adhesives that of er skin-friendly Advanced Adhesives and Polymer Coatings for Drug Delivery Systems [6]
Adhesive Description
Functional Properties for Drug Delivery
Skin-friendly PSAs
Formulations tailored to bond with various for wear times ranging from minutes to days Electrically and
conductive coatings
adhesive to allow current or ion transport Dissolvable films
and erodable PSAs
Ethanol- and
enhancer chemicals found in drug delivery coatings
Ultraclean and
Porous adhesives

Coated polymer systems with tailored pore size to allow controlled fluid transfer, with doping used to create biphasic formulations Hydrogels and organogels
sensing element in device-assisted delivery Hybrid PSAs
Molecularly imprinted
release of targeted APIs or other chemical moieties Biocompatibility
can impact adhesive performance; so the con- Biocompatibility of an adhesive formulation with the skin is a significant concern in the design of any • All component materials are flexible, and the transdermal patch. The adhesive must be nonirritat- patch comfortably adheres and conforms to a ing and free of any residual monomers, leachable components, and reactive materials. Al ergic reac- • Careful consideration of product geometry avoids tions are possible, caused by irritation from and sen- uplifting of patch edges. Rounded edges are sitivity to a number of chemical compounds, partic- preferable to prevent patch lifting and to avoid ularly acrylics and natural, rubber-based adhesives.
irritation at corners. To avoid high concentrations ransdermal Adhesive manufacturers address these concerns by of electrical current that could cause burns, round modifying formulations to benefit the population of edges are particularly important in applications patients while maintaining drug compatibility and that use an electrical y conductive adhesive.
• The product maintains proper adhesion during physical activity and normal exposure to mois- In a recent draft offering guidance for an extended- ture, including sweating, showering, or swim- release patch, the FDA provides meaningful guide- lines for evaluating the performance of transdermal • Protective, adhesive-film overlays seal active com- patches regarding safety and bioequivalence. These pounds or highly sensitive electronic components recommendations now provide a measurable stan- in active transdermal devices and prevent any dard for evaluating adhesion and dermal response moisture exposure that potentially could affect [7], which are important factors to consider in bioavailability and performance of the device.
designing longer-wearing patches and devices.
The Balance between Adhesion and
Proper Moisture
Consumers remove the majority of transdermal The primary function of the adhesive in TDDS is to patches available today within 24 hours; however, secure the patch or device on the patient’s skin for manufacturers are developing extended-wear the desired dosing timeframe, thereby assuring reli- patches for time periods of up to seven days [8]. To able and accurate drug transmission, without caus- ensure a healthy skin environment for proper dos- ing significant irritation. Ease of patch removal after ing, it is important that the adhesives selected for treatment has tended to be a secondary concern but longer-term wear enable the skin to breathe, which is gaining more attention as TDDS developers con- prevents over-hydration that potential y could affect sider the special needs of different skin types. Adhe- drug bioavailability. Longer-wear devices should sives that are formulated for ease of removal tend to combine these adhesives with breathable materials be gel-like in form or softer than other adhesives.
such as polyurethane films that offer high moisture- Patch developers achieve this characteristic by form- vapor transmission rates and gas-exchange proper- ing polymer chains that are mobile and can stretch.
ties to promote a healthy skin site.
The chal enge then becomes balancing secure skin adhesion and low-trauma removal. The developer Adhesion and Sealing Performance
must accomplish this balance using a formulation Good adhesion performance is paramount for that careful y limits any possible impact upon drug prevention of movement or shifting of the patch during the dosing period, and even more so, for delivery of treatments that require a skin-prepa- Skin Types
ration step prior to applying the patch. Any lift- While manufacturers formulate adhesives to benefit ing from the skin can affect whether the patch is the targeted patient population as a whole for the delivering an effective dose. A number of factors patch, dif erent skin types present their own unique bonding chal enges. These chal enges depend upon a 2. Medical News Today, Neupro (rotigotine transdermal patch) consumer’s health, age, and race and on the moisture- can now be prescribed to all patients with iodiopathic Parkinson’s vapor transmission rates, porosity, and oil levels, etc of http://www.medicalnewstoday.com/articles/155718.php. July his or her skin. For example, a manufacturer would design a patch for an older population of patients to 3. Amsden B and Goosen M. Transdermal delivery of peptide be softer in its formulation to address reduced skin and protein drugs: An overview. AIChE Journal. 2004, 41(8):1972– elasticity and to provide less trauma to the skin upon 4. Barry B and Williams A. Penetration enhancers. Advanced removal.Apatch designed for a younger population, Drug Delivery Reviews. 2004, 56:603-618.
such as a birth-control patch, would need to take into 5. Meathrel W. The evolution of adhesives: From transdermal consideration strong adhesion rates to withstand drug delivery to other novel delivery formats. Drug Delivery active lifestyles, movement, and exposure to moisture 6. O’Mahony J. Adhesives for transdermal drug delivery systems.
Pharmaceutical Manufacturing and Packaging Sourcer. 2009, pp24– Careful Thickness Control
7. US Food and Drug Administration. Draft guidance on ethinyl Tight tolerances for control of adhesive and substrate http://www.fda.gov/downloads/Drugs/GuidanceComplianceRe thicknesses from lot to lot are critical for applications gulatoryInformation/Guidances/UCM162407.pdf, July 2010.
where any variations in thickness can have a nega- 8. Kydonieus A, Conway RG, Rossi TM. Dermal Delivery Device, tive impact upon dosing. For example, scientists have designed some patches with microprojections; that Wil iam Meathrel, PhD, is a senior scientist with Adhesives Research. is, an array of drug-treated microneedles — solid With over 30 years of experience in product development and applied metal, hollow metal, or polymer needles — that research, his career has focused on polymers, adhesives, and coatings, and he has secured numerous patents for his work. He holds three degrees from adhere to the skin with a PSA. The combined thick- the University of Toronto, including a PhD in organic chemistry, a ness of the components of the device controls the Master’s of Science in biological chemistry, and a Bachelor’s of Science in depth of penetration of the microneedles for release chemistry. He also possesses a diploma in Chemical Engineering from the of the drug into the bloodstream or lymphatic sys- tem. If penetration through the skin is too shal ow, Contact Dr Meathrel at Adhesives Research, P.O. Box 100, Glen Rock, PA the user may not receive the proper dose; alterna- 17327; E-mail: [email protected] or Phone: +1 717 227 3460. tively, if the needles penetrate too deeply, the user could experience unwanted discomfort and pain.
As TDDS continues to deliver patients’ increased compliance by providing predictable and reliable therapeutic dosages without limiting patients’ nor- mal activities, drug manufacturers continue to expand the scope of the drug delivery system.As the scope widens, adhesive manufacturers are respond- ing by developing a range of skin-friendly and API- compatible formulations that withstand the increased exposure to moisture and movement related to a more active population. On the horizon, functionality and fashion may come together as improvements in design make patches appear more seamless and compatible with clothing, all in the References
1. Frölich L. A review of the first transdermal treatment for Alzheimer’s disease — The Rivastigmine patch. European Psychiatric Review. 2008, 1(1):33–35.

Source: http://www.adhesivesresearch.com/wp-content/uploads/2012/08/Transdermal-Magazine-Sept-2010.pdf

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