Transdermal Technology

Transdermal drug delivery systems (TDDS) are widely proven and accepted forms for predictable and reproducible drug delivery. TDDS bypass the hepatic first-pass effect and potentialgastrointestinal side effects of oral dosage forms, as the drug isabsorbed directly through the skin for delivery to the blood orlymphatic system. Treatment is quickly and easily terminated iftoxicities (such as drug allergies) occur, simply by removing thepatch. This drug delivery platform improves patient compliance for chronic or maintenance treatments by virtue of its ease of use,fewer side effects, relatively low cost in comparison to alternativedevices, and minimal risk of trauma or infection (1).

Pharmaceutical-grade pressure-sensitive adhesives (PSAs) have played a critical role in the function and accurate delivery of TDDS ever since the launch of the scopolamine transdermalpatch in the late 1970s for motion sickness (2). Most drugdelivery development projects begin by considering an existingbase adhesive technology. However, the end result is typically acustomised adhesive based on design input for the application and the requirements of each customer’s manufacturing process.The base adhesive chemistries for passive TDDS includepolyisobutylene, acrylics and silicone formulations in severaltypes of patch constructions (3):

� Single-layer drug in adhesive – the adhesive layer contains an active pharmaceutical ingredient (API) and affixes the patch to the skin

� Multiple-layer drug in adhesive – more than one adhesive layercontains an API and bonds multiple component layers togetherwhile affixing the patch to the skin

� Drug matrix in adhesive – a semi-solid matrix drug layer issurrounded by an adhesive overlay that affixes the patch to skin

� Drug reservoir – a liquid drug compartment, containing a drugsolution or suspension, is separated from the adhesive layer by a diffusion-controlling membrane

Transdermal patches offer many treatment advantages but passive systems are restricted to low-dosage lipophilic and lowmolecular-weight molecules (<500 daltons) (4). Pharmaceuticalcompanies have developed chemical enhancers to extend theapplication of diffusion systems by altering the permeability ofthe stratum corneum layer of the skin to allow delivery of highermolecular weight compounds. Penetration enhancers may includechemicals such as ethanol, propylene glycol, oleic acid, azone,terpenes and bile acids (5). Adhesive manufacturers haveresponded by developing ‘enhancer-tolerant’ adhesive

formulations that maintain their PSA properties when exposed to chemical enhancers.

The use of enhancers only slightly broadens the rangeof drugs eligible for passive delivery. Many of thedevelopment efforts in transdermal drug deliveryare focused on active systems for deliveringa wider range of drug molecules,including proteins such as vaccines.Targeted drug delivery applications foralternative treatment sites beyondskin delivery are another area ofdevelopment that can furtherbenefit from TDDS adhesives and polymer coatings.

CHALLENGES OFFORMULATING ADHESIVESFOR TDDS

As the scope for transdermal drug delivery capability widens,component suppliers are raising the performance characteristics of related materials to further the advancement of these systems.One example can be found in pharmaceutical-grade PSAs thatoffer functionality in addition to good skin adhesion. Electricallyconductive and porous PSAs, hydrogels and molecularlyimprinted polymers are a few examples of pharmaceuticaladhesives that are formulated to improve device performancewhile bonding components or affixing a drug delivery device toskin. The science of formulating adhesives for transdermals is acareful balance of delivering functionality in a safe, compatibleformat to the device’s other components. Today’s adhesives arehighly specialised chemistries designed to overcome challengesthat are specific to each application, in order to deliver preciseperformance. A number of these challenges are discussed indetail below.

Drug CompatibilityOne of the most significant obstacles to overcome in formulatingadhesives for TDDS is maintaining compatibility between the APIor compound with the adhesive chemistry. Adhesive manufacturersmust offer formulations that are free of acrylic acid monomer whiletaking precautions to assure that the adhesive’s pH is neutral (3). Anyresidual monomers or leachable components must also be removed.Compatibility can change as components age, so accelerated andreal-time ageing studies are required to ensure that the adhesiveproperties and drug bioavailability are maintained throughout theshelf-life of the drug delivery device. If the delivery device requires

John O’Mahony of Adhesives Research Ireland Ltd discusses the challenges of formulating adhesives for transdermal drug delivery systems

sterilisation, measures must be taken to ensure that the adhesivewill withstand the sterilisation dosage and procedures, whilemaintaining its adhesive properties and compatibility with the API.

An example of how compatibility may become a challenge canbe seen with acrylate-based adhesives that offer skin-friendlybonding characteristics and are often a good choice for TDDS.Acrylate-based adhesives may absorb up to five per centmoisture from skin, which could potentially affect drugbioavailability. In iontophoretic drug delivery, pH changes canaffect delivery rates, so acrylate-based adhesives must be free of residual acrylic acid monomer to avoid a potential reactionwith the active drug or device components (6).

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Maintaining Proper MoistureThe majority of transdermal patchesavailable today are removed within 24hours; however, manufacturers are hoping todevelop extended-wear patches which canbe worn for seven to 10 days. To ensure ahealthy skin environment for proper dosing,it is important that the adhesives selected forlonger-term wear enable the skin to breathe,for preventing over-hydration that canpotentially affect drug bioavailability.

Adhesion and Sealing PerformanceGood adhesion performance is paramountfor preventing patch movement or shiftingduring the dosing period and even more sofor treatments requiring a skin preparationstep prior to applying the patch. A numberof factors can affect adhesive performance.The construction must ensure that:

� All component materials are flexibleso the patch comfortably adheres and conforms to a number ofapplication sites

� Uplifting of patch edges is avoidedthrough careful consideration ofproduct geometry; rounded edges are preferred

� The product maintains properadhesion during movement andnormal exposure to moistureincluding sweating, showering or swimming

� The protective adhesive film overlays used to seal activecompounds or highly sensitiveelectronic components prevent any moisture exposure that couldpotentially affect bioavailability and device performance

The Balance Between Adhesion and RemovabliltyThe primary function of the adhesives usedin TDDS is to secure the patch or device tothe patient’s skin for the desired dosingtimeframe to assure complete and accuratedrug transmission. Ease of patch removalpost-treatment tends to be a secondaryconcern, but is gaining more attention asTDDS developers consider the specialneeds of different skin types. Adhesivesthat are formulated for ease of removaltend to be gel-like in form or ‘softer’ thanother adhesives. This characteristic isachieved by forming polymer chains thatare mobile and can stretch. The challengethen becomes balancing secure skinadhesion and low-trauma removal. Thismust be accomplished with a formulationthat carefully limits any possible impactupon drug flux through the adhesive.

Maintaining Careful Thickness ControlTight tolerances for adhesive and substratethickness control from lot to lot are criticalfor applications where any thicknessvariations can have a negative impact upondosing. For example, some microprojectiondesigns are based on a patch with an arrayof drug-treated microneedles – solid metal,hollow metal or polymer needles – that areadhered to the skin with a PSA. Thecombined thickness of the device’scomponents controls the penetration depthof the microneedles to release the drug intothe bloodstream or lymphatic system. Ifpenetration through the skin is too shallow,the user may not receive the proper dose;alternatively, if the needles penetrate toodeeply, the user could experiencediscomfort and pain.

Challenges Specific to Polymer CoatingsA number of the technologies that havebeen perfected for TDDS over the last 20 years form the basis for a naturalevolution into other novel forms fordelivering APIs that present their ownformulating challenges. Some companiesare currently utilising the polymerchemistry and coating techniques used inTDDS in the form of custom-developeddissolvable films and adhesive platformsfor oral drug delivery, transdermal drugdelivery and biopharmaceuticals.

Oral thin films (OTFs), based on thedissolvable film platform, are best knownas a proven technology for the systematicdelivery of APIs to patients for over-the-counter (OTC) medications and are alsoin the clinical stages for prescriptiondrugs. OTFs offer accurate dosing in asafe, effective format that is convenientand portable, without the need for wateror measuring devices. A number of thedissolvable films’ physical characteristicscan be customised, including dissolutionrates, thickness, material composition,taste masking and API absorption rates to broaden its potential for application in other areas including:

� Transdermal, topical and alternativesite treatments

� Binding agents� Buccal, sublingual and mucosal

delivery systems� Gastro-retentive dosage systems

While some of the formulationchallenges of dissolving films arecomparable to those of adhesives for

TDDS (including API compatibility withchemical ingredients) this technologyposes its own unique formulationchallenges. Dissolvable films oftenincorporate APIs with a narrowtherapeutic index, so tight manufacturingtolerances must be held to deliver auniform pharmaceutical product. Acommon misconception of the dissolvingfilm format is that it is limited in regardsto the loading capacity of APIs. Somedocumentation suggests a limitation of30mg of API content as the maximumconcentration. A more accurate statementis that dissolving films have thecapability to load APIs up to 50 per cent of the unit dose mass. Dose isincreased simply by adjusting the size of the film strip.

Taste masking plays a critical role in the success of an OTF’s acceptanceand is an equally critical component ofthe film’s formulation. When possible,taste-masking techniques resulting indiscrete particles larger than 250 microns should be avoided, as these could potentially present uniformitychallenges in the finished dosage form (7).

As dissolving films tend to be sensitive toenvironmental moisture, most dissolvablefilms are packed by unit in primarypackaging consisting of foil laminatedproducts to provide a high moisturebarrier. The primary packaging is criticalfor meeting the ICH stability requirementsfor extended expiration dating.

CONCLUSION

It is clear that pharmaceutical-gradeadhesive technologies that were originallyformulated for passive TDDS have evolvedinto highly specialised adhesives andcoated polymers that add functionality to the next generation of drug deliveryplatforms. Versatile in their chemistry andform, PSAs are a critical component inachieving intended outcomes such assustained skin adhesion, componentbonding, electrical component bonding and assembly, moisture seals and drugenvelopment. To overcome a number of technical challenges, base adhesivetechnologies are customised to each uniqueapplication to ensure accurate and effectivedrug delivery. As pharmaceutical productdevelopers explore new methods for

delivering a wider range of drugs andbiopharmaceuticals, PSA manufacturerswill continue to push the capabilities of thetechnology to meet the unique challengesof new and emerging applications.

References

1. Karabiyikoglu M, New frontiers intransdermal drug delivery systems,Drug Delivery Report, pp28-30,Spring/Summer 2007

2. US Food and Drug Administration,FDA approves scopolamine patch toprevent peri-operative nauseahttp://www.fda.gov/bbs/topics/ANSWERS/ANS00834.html, accessed 17th November, 2008

3. Meathrel W, The Evolution ofAdhesives, Drug DeliveryTechnology, pp40-44, April 2009

4. Rios M, Advances in TransdermalTechnologies, PharmaceuticalTechnology, pp54-64, October 2007

5. Singh S, An overview of transdermaldrug delivery, Drug Delivery Report,pp35-39, Autumn/Winter 2005

6. Gupta R, Pharmaceuticals chargingthrough, Medical DesignTechnology, pp20-24, March 2008

7. Frey P, Film Strips andPharmaceuticals, PharmaceuticalManufacturing & PackagingSourcer, pp92-93, Winter 2006

John O’Mahony,

PhD, is a Senior

Scientist and

team leader with

Adhesives Research

Ireland Ltd, where

he is responsible for

the development of new products for the

company’s medical and pharmaceutical

business units. John holds a degree in

Material Science from Trinity College

Dublin and a PhD in Chemical

Engineering, specialising in polymer

characterisation, from the University of

Queensland, Australia. John has previous

experience in polymer development at the

National Microelectronic Research Centre,

University College Cork, and as a Senior

Research Scientist at ICI Chemicals

and Polymers division in Runcorn, UK.

Email: jomahony@arglobal.com

About the author

Adhesive description Chemistry Functional properties for drug delivery

Skin-friendly PSAs Acrylic, polyisobutylene, Tailored to bond in various skin types and environmentssilicone and hybrid chemistries for wear times ranging from minutes to days

Electrically and ionically Acrylic and polyisobutylene chemistries Polymer formulations that overcome traditional insulativeconductive coatings properties of an adhesive to allow current or ion transport

Dissolvable films and erodable 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

Ultra-clean and non-reactive 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. 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 sensing element in device-assisted deliver

Hybrid PSAs Rubber/acrylic graft Polymer matrix that offers high tack and chemical stability

Molecularly imprinted polymers Acrylate chemistry Synthetic polymers for the capture and release of target APIs or other chemical moieties

Table 1: Advanced adhesives and polymer coatings for drug delivery systems