Drug delivery Systems - * DDT April 2009 …...DRUG DELIVERY Skin-friendly PSAs Acrylic, polyisobutylene, silicone, and hybrid chemistries Tailored to bond in various skin types and

April 2009 Vol 9 No 4 www.drugdeliverytech.com

IN THISISSUE

ClickSoftTM

Microinjection 22Pankaj Modi, PhD, MD

OcularDelivery 34Misty Hughes

AdhesivesEvolution 40William G. Meathrel, PhD

OsmoticTablets 45Jayvadan Patel, PhD

CROTrends 64Cindy H. Dubin

InsomniaMarket 69Gary Cupit, PharmD

The science & business of drug development in specialty pharma, biotechnology, and drug delivery

FEATURING

Derrek G.Hennecke,MBAGrowth or Recession:Selling Solutions is theAnswer

BillMartineau,MBAA Look at Fast-Dissolving DrugDelivery Systems

Anil K.Philip, PhDColon-SpecificDelivery:HistomorphologicalAnalysis &Targeted ProdrugApproach

INTERVIEW WITHINOVIO BIOMEDICAL’SPRESIDENT & CEO

AVTAR DHILLON, MD

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ADHESIVEST E C H N O L O G Y

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ABSTRACT

As transdermal product designs andcapabilities continue to evolve, adhesivemanufacturers are embracing opportunitiesto formulate highly specialized pressure-sensitive adhesives, coatings, and relatedpolymer technologies to meet therequirements of these delivery systems.The following reviews the evolution andformulation challenges of adhesivetechnologies from their use in passivetransdermal drug delivery systems to theiruse in cutting-edge active delivery devicesand novel forms for alternative sitedelivery.

INTRODUCTION

The transdermal drug delivery system(TDDS), or patch, is a proven and widelyaccepted form for predictable andreproducible drug delivery. Because thedrug is absorbed through the skin fordelivery to the blood or lymphatic systems,the TDDS bypasses the hepatic first-passeffect and potential gastrointestinal sideeffects. Treatment is easily terminated iftoxicities, such as drug allergies, occursimply by removing the patch forimmediate discontinuance of drugdelivery. The TDDS has improved patientcompliance for chronic or maintenancetreatments, such as hormone replacement,which was previously available only in anoral dosage format, by virtue of its ease ofuse, fewer side effects, relatively low costin comparison to alternative devices, andminimal risk of trauma or infection.1

Since the introduction of thescopolamine transdermal patch in the late1970s for motion sickness,pharmaceutical-grade pressure-sensitiveadhesives (PSAs) have played a critical

role in the function and accurate deliveryof TDDS.2 An adhesive developmentproject may begin with an existing basetechnology; however, the result is typicallya customized adhesive based on designinput for each application, which alsoconsiders the requirements of thecustomer’s manufacturing process. Baseadhesive chemistries for passive systems

may include polyisobutylene, acrylics, andsilicone formulations in several types ofthe following passive transdermal patchconstructions:

SINGLE-LAYER DRUG-IN-ADHESIVE - Theadhesive layer of this system contains theactive pharmaceutical ingredient (API) andperforms two functions: bonding multiple

F I G U R E 1

Pressure-sensitive adhesives play a critical role in the function and accurate delivery of TDDS.

The Evolution of Adhesives: From Transdermal Drug Deliveryto Other Novel Delivery FormatsBy: William G. Meathrel, PhD

40-44 DDT Apr 2009- Adhesives Technology:Layout 1 3/26/09 11:40 AM Page 40


component layers of the patch together whileaffixing the device to the skin.

DRUG MATRIX-IN-ADHESIVE - A semi-solidmatrix drug layer is surrounded by an adhesiveoverlay that affixes the patch to the skin.

DRUG RESERVIOR - A liquid drug compartmentcontaining a drug solution or suspension isseparated from the adhesive layer by adiffusion-controlling membrane.

While transdermal patches offer manyadvantages, passive systems are restricted tolow-dosage lipophilic and low molecular-weight molecules (< 500 Daltons).3 To extendthe application of diffusion systems,pharmaceutical companies developed chemicalenhancers that alter the permeability of thestratum corneum layer of the skin for thedelivery of higher weight molecules.Penetration enhancers may include chemicals,such as ethanol, propylene glycol, oleic acid,azone, terpenes, and bile acids.4 Adhesivemanufacturers responded by developing“enhancer-tolerant” adhesive formulations thatmaintain their PSA properties when exposed tochemical enhancers. What this means is thatthe use of enhancers slightly broadens therange of drugs that can be delivered throughpassive systems.

Much of the current growth fortransdermal drug delivery is focused on activesystems to deliver a wider range of drugmolecules, including proteins such as vaccines.Targeted drug delivery applications for sitesbeyond traditional skin delivery, such as oculartreatments, are another exciting area ofdevelopment that can further benefit fromTDDS adhesive technology and polymercoatings.

CHALLENGES OF FORMULATINGADHESIVES FOR TDDS

As the scope for transdermal drugdelivery capability widens, the performanceexpectations of related materials are alsoraised. Pharmaceutical-grade PSAs offerfunctionality in addition to simply good skinadhesion. Some examples of PSAs with addedfunctionality are evident in electricallyconductive and porous PSAs, hydrogels, and

molecularly imprinted polymers. The scienceof formulating adhesives for transdermals is acareful balance of delivering functionality in asafe, compatible format to the device’s othercomponents. Today’s adhesives are highlyspecialized chemistries that overcome anumber of specific challenges to deliverprecise performance for each application. Anumber of these challenges are discussed indetail below.

Drug CompatibilityCompatibility of the API or compound

with the adhesive chemistry is one of the mostsignificant obstacles to be overcome informulating adhesives for TDDS. For example,acrylate-based adhesives are widely used inTDDS for their skin-friendly bondingcharacteristics but may absorb up to 5%moisture from skin, which could potentiallyaffect drug bioavailability. Because pH changescan affect iontophoretic drug delivery5,acrylate-based adhesives must be free ofresidual acrylic acid monomer to avoid reactionwith the active drug or device components. Toaddress challenges like these, adhesivemanufacturers must consider formulations thatare free of acrylic acid monomer while taking

precautions to ensure that the adhesive’s pH isneutral. Also, any residual monomers orleachable components must be removed.Compatibility can change as components age,so accelerated and real-time aging studies areneeded to ensure that the adhesive propertiesand drug bioavailability are maintained duringthe shelf-life of the drug delivery device. If thedelivery device requires sterilization, it isnecessary to ensure that the adhesive willwithstand the sterilization dosage andprocedure while maintaining its adhesiveproperties and compatibility with the API.

Moisture MaintenanceThe majority of transdermal patches

available today are removed within 24 hours;however, extended-wear patches can beenvisioned for time periods of 7 to 10 days. Toensure a healthy skin environment for properdosing, it is important that the adhesivesselected for longer-term wear enable the skin tobreathe to prevent over-hydration or skinmaceration, which can potentially affect drugbioavailability.

Adhesion & SealingGood adhesion performance is paramount

F I G U R E 2

Specialized pressure-sensitive adhesives, coatings, and related polymer technologies are integrated intoevolving drug delivery applications. Dr

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for preventing patch movement or shiftingduring the dosing period and even more so fortreatments requiring a skin preparation stepprior to applying the patch. A number offactors can impact adhesive performance, sothe formulation must ensure the following:

• the patch comfortably conforms to anumber of application sites, so allcomponent materials must be flexible toprevent pulling the patch away from theskin;

• the correct product geometry is used;because shape can potentially contributeto uplifting patch edges, rounded shapesare preferred;

• the product maintains proper adhesionduring movement and exposure tomoisture from sweating, showering, orswimming as most patches are worn byactive, ambulatory patients; and

• the protective adhesive film overlaysused to seal active compounds or highlysensitive electronic components preventany moisture exposure that couldpotentially affect bioavailability anddevice performance.

Adhesion Versus RemovabilityOne of the primary uses of adhesives in

TDDS is to effectively hold the patch or devicesecurely in place on the patient’s skin so the

patch that conveys the drug makes constantcontact for the desired dosing timeframe. Easeof removal following treatment is typically asecondary concern, but is gaining attention asTDDS developers consider the special needs ofdifferent skin types. Adhesives that aredesigned for ease of removal are formulated tobe softer, or more gel-like, than other forms.This is accomplished by forming polymerchains that are mobile and can stretch. Thechallenge then becomes maintaining a balancebetween secure skin adhesion and low-traumaremoval while eliminating any possiblenegative impact upon drug flux through theadhesive.

Thickness ControlAdhesive and substrate thickness control

from lot to lot is crucial for applications inwhich any thickness variations can negativelyimpact dosing. For example, somemicroprojection designs involve an array ofdrug-treated microneedles (solid metal, hollowmetal, or polymer needles) that are adhered tothe skin with a PSA. The combined thicknessof the device’s components controls howdeeply the microneedles penetrate the skin torelease the drug into the bloodstream orlymphatic system. If penetration is too shallow,the user may not receive the proper dose;alternatively, if the needles penetrate toodeeply, the user could experience somediscomfort or pain.

EVOLUTION OF TDDSTECHNOLOGY IN FORM &

FUNCTION

As transdermal product designs andcapabilities continue to evolve, adhesivemanufacturers are embracing opportunities toformulate highly specialized PSAs, coatings,and related polymer technologies to meet therequirements of these delivery systems.

Needle-Free Delivery of VaccinesNeedle-free delivery of therapeutics and

vaccines can potentially address the growingglobal issues associated with diseases that arepassed intravenously through the improper useand disposal of needles. Patch-based needle-free immunization systems for the safe andconvenient delivery of vaccines are currently inclinical trials.6 The construction of the vaccinepatch is similar to that of a transdermal patch,but contains an antigen and an immune-boosting adjuvant to stimulate the body’simmune system. The patch works by deliveringthe vaccine to a group of antigen-presentingcells in the skin called Langerhans cells, whichtransport the vaccine to nearby lymph nodes toproduce a sustained immune response.

When considering adhesive andcomponent materials for this type of deliverysystem, formulators must assure the properchemical compatibility of these materials withthe device’s proteins and active ingredients.Device component materials cannot containany biocides or toxic leachables that couldpotentially denature proteins or interfere withbiological activities or targeted immunizationresponse. Skin-contact adhesives shoulddemonstrate good wear properties and moisturecontrol to prevent lateral movement of thevaccine, which could alter dosage and decreasedevice efficacy.

Iontophoretic Drug DeliveryPSAs perform multiple functions in

iontophoretic drug delivery systems, such asbonding to the skin, creating a protective seal,and forming conductive bonds for internalelectronic component assemblies.

Iontophoretic devices offer a non-invasivealternative for delivering therapeutic substances

F I G U R E 3

In iontophoretic patches, electrically conductive pressure-sensitive adhesives transmit an electric currentthrough layers of the device while bonding electrical components within the patch.


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via the electro-transport of molecules thatwould not normally diffuse across the skin. Asmall electric current passes through thepatient’s skin, between positively andnegatively charged electrodes. The drug oractive substance is located at one of theelectrode sites, depending upon the drug’spolarity. The active electrode repels the chargeddrug, forcing it into the skin by electro-repulsion, where it is picked up by the blood orlymphatic system. Charged drug molecules areattracted to electrodes of the opposite polarity.The rate of drug delivery is controlled by thestrength of the electrical current to transportthe drug rapidly and accurately, via on-demanddosing or patterned/modulated drug delivery.7

Iontophoretic patches benefit fromcustomized electrically conductive and skin-contact adhesive components. Electricallyconductive PSAs transmit the current throughlayers of the device while bonding electricalcomponents within the patch. In some versionsof these devices, the electrically conductivelayer may contain conductive fillers to lowerthe resistance of the interface and to formelectrical connections. A PSA membraneoverlay may be used to adhere the patch to theuser’s skin while bonding and protectingcomponents within the device’s housing. It isimportant to ensure that this PSA is compatiblewith the drug, bonds without interfering withthe electrical charge of the drug compounds,and facilitates bioavailability.

Novel Coating Technologies forDrug Delivery

A number of the technologies that havebeen perfected for TDDS throughout the past20 years form the basis of a natural evolutioninto other novel forms for delivering APIs.ARx, LLC is one company leveraging thepolymer chemistry and coating techniques usedin TDDS in the form of custom-developeddissolvable films and adhesive platforms fororal drug delivery, transdermal drug delivery,and biopharmaceuticals.

Dissolvable oral thin films (OTFs) are aproven technology for the systematic deliveryof APIs to patients for OTC medications andare in the clinical stages for prescription drugs.OTFs offer fast, accurate dosing in a safe,

efficacious format that is convenient andportable, without the need for water ormeasuring devices.8

A number of the film’s physical formatscan be customized, including dissolution rates,thickness, material composition, taste-masking,and API absorption rates to broaden itspotential for application into other areas,including the following:9

TOPICAL APPLICATIONS - Films can deliveractive agents, such as analgesics orantimicrobial ingredients for wound care orother applications.

BINDING AGENTS - Dissolvable films are beingconsidered in applications for enveloping activeparticles in multi-layer or combination systemsto enable controlled release.

BUCCAL, SUBLINGUAL & MUCOSAL DELIVERYSYSTEMS - Layers of dissolvable films withtailored dissolution rates may be combinedwith bioadhesives for the controlled release ofAPIs over a period of minutes or hours.

GASTRO-RETENTIVE DOSAGE SYSTEMS - Water-soluble and poorly soluble molecules of

different molecular weights can be contained ina film format to disintegrate at a specific pH orenzyme exposure within the gastrointestinaltract to treat GI disorders.10

ALTERNATIVE TREATMENT SITES

This is an exciting time for adhesivemanufacturers as we leverage our knowledge ofpolymer chemistry and coating technologies foremerging formats for drug delivery. A numberof novel systemic and topical delivery formsare in the research stage or clinical trials fortargeted treatments to alternative delivery sites.Some examples follow.

The respiratory tract and nasal passageshold promise as alternative sites for drugdelivery due to fast absorption and rapid onsetof drug action. The inhalers and other devicesfor these drug delivery forms require inert,non-reactive components. Pharmaceutical-grade adhesives demonstrating low-extractable,low-leachable properties are ideally suited forassembling the drug cartridges tailored forpulmonary and nasal delivery formats.

Ocular treatments can potentially benefitfrom dissolvable film and TDDS adhesivetechnology. Ocular disease or wound


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ADHESIVE DESCRIPTION CHEMISTRY

FUNCTIONALPROPERTIES FORDRUG DELIVERY

Skin-friendly PSAs Acrylic, polyisobutylene, silicone, and hybrid chemistries

Tailored to bond in various skin types and environments for wear times ranging from minutes to days

Electrically & ionically conductive coatings

Acrylic and polyisobutylene chemistries

Polymer formulations that overcome traditional insulative properties of an adhesive to allow current or ion transport

Dissolvable films & erodable PSAs

Natural and synthetic polysaccharides, hydrophiliccopolymers

Polymer coatings designed to erode at predetermined rates when in contact with biological fluids

Ethanol- & enhancer-tolerant coatings Acrylate chemistry PSAs that can withstand exposure to enhancer

chemicals found in drug delivery systems

Ultra-clean & 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 sizeto allow controlled fluid transfer. Doping used to create biphasic formulations

Hydrogels & organogels Hydrophilic polymers and copolymers

High-fluid content coatings that form an interface between the skin and sensing element in device-assisted delivery

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

TA B L E 1

Advanced Adhesives & Polymer Coatings for Drug Delivery Systems




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treatments many times require an API to bemaintained at the treatment site for a period oftime to ensure good bioavailability. Given theeye’s natural tendency to wash away foreignsubstances and the low impermeability of thecornea to hydrophilic molecules, theeffectiveness of ocular treatments can bechallenging.11 Surface-contact films or tackypolymer “patches,” similar to the adhesive andpolymer technology used in transmucosal orbuccal drug delivery systems, can beconsidered for sustained delivery of oculardrugs. One example might be a dissolvablefilm loaded with APIs that is formulated toalso demonstrate PSA characteristics thatsafely adhere to the eye surface. Following thetreatment duration, the film would dissipatecompletely or be gently removed.

Another example of a localized alternativesite for drug delivery can be found indevelopmental nail patches, which would beused to treat chronic, highly resistant fungalinfections of human nails. Topical delivery ispreferred over systemic treatments because itdoesn’t cause adverse effects; however, topicaltreatments are limited in their ability topenetrate the nail to also treat the underlyingperionychium.12 A medicated nail patch with anAPI- and enhancer-loaded PSA matrix layerthat would cover the entire nail and treatmentsite for an extended period of time may offeran improved treatment regimen.13 The conceptof a nail patch can be applied to othertreatments, such as strengthening agents ornovel consumer applications of cosmetics fornails or skin.

SUMMARY

It is clear that pharmaceutical-gradeadhesive technologies that were originallyformulated for passive TDDS have evolved intohighly specialized adhesives and coatedpolymers that add functionality to the nextgeneration of drug delivery platforms. Versatilein their chemistry and form, PSAs are a criticalcomponent in achieving intended outcomes,such as sustained skin adhesion, componentbonding, electrical component bonding andassembly, moisture seals, and drugenvelopment. To overcome a number of

technical challenges, base adhesivetechnologies are customized to each uniqueapplication to ensure accurate and sustaineddrug delivery. As pharmaceutical productdevelopers explore new methods for deliveringa wider range of drugs and biopharmaceuticals,PSA manufacturers like Adhesives Researchwill continue to push the capabilities of ourtechnology to meet the unique challenges ofnew and emerging applications.

REFERENCES

1. Karabiyikoglu M. New frontiers in transdermal drug

delivery systems. Drug Delivery Report. Spring/Summer

2007; ISSN 4750-2322 #:28-30.

2. US Food and Drug Administration. FDA approves

scopolamine patch to prevent peri-operative nausea.

Available at:

http://www.fda.gov/bbs/topics/ANSWERS/ANS00834.ht

ml. Accessed November 17, 2008.

3. Rios M. Advances in transdermal technologies.

Pharmaceut Technol. 2007; 31 #:54-64.

4. Singh S. An overview of transdermal drug delivery. Drug

Delivery Report. Autumn/Winter 2005;ISSN 4750-2322

#:35-39.

5. Gupta R. Pharmaceuticals charging through. Medical

Design Technol. 2008;12(3):20-24.

6. Iomai registers needle-free vaccination patent. Available

at http://www.in-pharmatechnologist.com/Materials-

Formulation/Iomai-registers-needle-free-vaccination-

patent. Accessed November 17, 2008.

7. Phipps JB, Padmanabhan RV,Young W, Panos R, Chester

A. E-trans technology. In: Rathbone MJ, Hadgraft J,

Roberts MS, eds. Modified Release Drug Delivery

Technology. NewYork, NY: Informa Healthcare;

2008:499-511.

8. Frey P. Film strips and pharmaceuticals. Pharmaceutical

Manufacturing & Packaging Sourcer. Winter 2006; #:92-93.

9. Muir I. Growing sales and new opportunities for oral fast

dissolve. In: Furness G, ed. Oral Drug Delivery: When

You Find the Holy Grail. West Sussex, UK:

ONdrugDelivery;2007:4-6.

http://www.ondrugdelivery.com/publications/Oral_Drug_

Delivery_07.pdf. Accessed November 17, 2008.

10. Vondrak B, Barnhart S. Dissolvable films for flexible

product format in drug delivery. Pharmaceut Technol.

2008;32:s20-s26.

11. Rabinovich-Fuilatt L, Lambert G. Current ocular drug

delivery challenges. Drug Delivery Report.

Autumn/Winter 2005;ISSN 4750-2322 #:33-34.

12. Repka MA. Delivery of medicaments to the nail. US

Patent Application No. 20040197280. 2004.

13. Srinivasan V, Danyi Q. Pressure sensitive adhesive

matrix patch for the treatment of onychomycosis. US

Patent No. 6,727,401. 2004.

Dr. William Meathrel is a SeniorResearch Scientist at AdhesivesResearch. With over 30 years ofexperience in Product Developmentand Applied Research, his career hasfocused on Polymers, Adhesives, andCoatings, and he has securednumerous patents for his work. Heholds three degrees form theUniversity of Toronto, including aPhD in Organic Chemistry, an MS inBiological Chemistry, and a BS inChemistry. He also has a diploma inChemical Engineering from theRyerson Polytechnic University.He can be reached [email protected] or(717) 227-3460.

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Drug delivery Systems - * DDT April 2009 …...DRUG DELIVERY Skin-friendly PSAs Acrylic, polyisobutylene, silicone, and hybrid chemistries Tailored to bond in various skin types and