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3M Health Care Business Group

Transdermal Adhesives Considerations for Generic Product Development Tim Peterson

October 28, 2015


2 . All Rights Reserved. 28 October 2015 © 3M 3M Confidential.

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Transdermal Adhesive Basics



Transdermal System Designs

Basic Approaches

Reservoir Multilaminate

Drug-in-Adhesive

Backing Drug Membrane Adhesive Liner/Skin

Three of the most utilized transdermal patch designs.



Key Aspects of Adhesive Performance in Transdermal Systems Secure the

system to the skin

Provide a drug and excipient

reservoir

Facilitate drug release from the system

Biocompatible with skin

Contribute to the stability of

the system


What is a PSA and how does it work? PSA = Pressure Sensitive Adhesive

• Adheres to a surface using only light pressure

• Removable - no chemical bond between adhesive and substrate

For good adhesion:

• An adhesive must first “wet out” the substrate. The degree of wetting depends on the difference in surface energy between the adhesive and substrate

• High energy surface (metal, glass) = greatest wetting

• Low energy surface (polypropylene, teflon, skin)= more difficult wetting

• The adhesive must have the proper rheology to allow the wetting to occur rapidly (~1 sec)

Mechanisms for adhesion:

• Mechanical adhesion occurs when the adhesive flows into the texture of the substrate.

• Specific adhesive/substrate interactions include electrostatic forces, van der Waals forces and acid-base interactions

6



Mo

du

lus

Temperature or Time

Glassy

Transition

Rubbery

Flow

Dahlquist tack criterion

<3x106 dyne/cm2

Adhesive Rheology • Pressure Sensitive

Adhesives are viscoelastic

materials

• Dynamic Mechanical

Analysis enables

characterization

• Dahlquist criteria describes

behavior needed for

pressure sensitive materials

• To obtain good quick tack,

the elastic modulus must

be below ~0.3 MPa,

independent of the nature

of the adhesive the

substrate, or the applied

pressure.

--crosslink,

higher Mw

--less flow

--better shear

peel apply



Adhesives Currently Used in TDD

Adhesive Polymers:

• Acrylate

• Silicone

• Polyisobutylene

• Synthetic Rubber (e.g. Kraton)

Product Design Category Adhesive Category

Transdermal Reservoir

Systemw/ Adh

Overlay DIA Multilaminate PIB Acrylate Silicone

AndrodermR

(testosterone)

BuTransR

(buprenorphine)

Catapres-TTSR

(clonidine)

ClimaraR

(estradiol)

Climara ProR

(estradiol / levonorgestrel)

CombipatchR

(estradiol / norethindrone

DaytranaR

(methylphenidate)

DuragesicR

(fentanyl)

EmsamR

(selegiline)

ExelonR

(rivastigmine)

FlectorR

(diclofenac epolamine)

LidodermR

(lidocaine)

MinitranTM

(nitroglycerin)

NeuproR

(rotigotine)

Nicoderm CQR

(nicotine)

Ortho EvraR

(ethinyl estradiol / norelgestromin)

OxytrolR

(oxybutynin)

NitroDurR

(nitroglycerin)

QutenzaR

(capsaicin)

SancusoR

(granisetron)

Transderm-NitroR

(nitroglycerin)

Transderm ScopR

(scopolamine)

Vivelle DotR

(estradiol)

Matrix


Polyacrylate PSAs

Polymers designed to be PSAs

Workhorse monomers

acrylic acid acrylamide

(AA) (ACM)

OOH ONH2

-affords tackiness

-low Tg

-reinforcing capability

-polar, interact with substrates

OO OO

2-ethyl hexyl butyl n-vinyl pyrrolidone

(2-EHA) (BA) (NVP)

NO

Advantages

--very diverse chemistry, can adjust

adhesive properties and solubility

characteristics

--excipient/drug tolerant

--biocompatible

--Single polymer with no need to tackify

--good processability

Disadvantages

--high solubility

--can be cross-linked, but not advisable

with drug present



Advantages

--low surface energy

--non-interactive with drug

--biocompatible

--MVTR is great

--low solubility

SiSiSiSiO O O O

Silicone

Polydimethylsiloxane, PDMS

Dimethicone

“Tackify” with “silicate resin” to make a PSA

O Si

CH3

CH3

CH3

silica

OS

iC

H3

CH

3

CH

3

OSi

CH3

CH3

CH3

OSi

CH3

CH3

CH3

OS

i

CH

3 CH

3

CH

3

OSiC

H 3

CH 3

CH 3

Disadvantages

--cost

--material compatibility

--low solubility

Silicone PSAs


Adhesion to Skin



Factors Affecting Good Skin Adhesion Key Characteristics of Skin

Human

Skin

Breathing, Sensitive Surface

Cell Renewal

Cycle

Elastic Surface

Low Surface Energy

Rough Texture

Stratum corneum - 14 days

Epidermis - 50 days

Reversible Stretch up to

50%

25 dynes/cm (Skin)

31 dynes/cm (Polypropylene)

>700 dynes/cm (Stainless)

Hair & Growth

Pores

Skin Wrinkles

Dead Skin Cells

Sweat

Salt

Lotions & Powders

Allergies

MVTR - Masceration

Mechanical Trauma

Contaminated Surface



Epidermal cells on surface of adhesive following removal from skin

a) “Gentle” PSA tape, b) “Aggressive” PSA tape

Skin / Adhesive Peel Interface

a) b)


Design Considerations


Design Consideration #1: Choose an Adhesive with Optimal Solubility for the API


• API solubility is highly

dependent on adhesive

selection

• There is no universal

best choice – depends

on the API

physicochemical

properties

API #1

API #2

API #3

API #4

API #5

API #6

Solubility of API in various TDD Adhesive Materials



Fentanyl solubility in IOA/HEA adhesives

0

2

4

6

8

10

12

14

16

0 0.1 0.2 0.3 0.4 0.5

Percent HEA in Soft Segment

Fen

tanyl

Solu

blit

y, %

w/w

Choice of Acrylate Co-monomer Can Influence Solubility



Assessment of Drug Solubility in Adhesive Matrices Crystal Growth Method

Growth

Absorption



Optimal Solubility Choose an adhesive with solubility for the drug and excipients such that:

• Adhesive matrix has adequate solubility to keep drug and excipient in a

solvated state (unless the design calls for a drug suspension)

• Adhesive matrix has adequate solubility to maintain delivery for the

desired wear period

• Adhesive matrix does not have excess solubility, otherwise:

• Diffusional driving force is diminished (because the drug has lower

thermodynamic activity)

• High residual drug may remain in the patch at the end of the wear

period

The ability to screen multiple adhesives or modulate drug solubility within the

adhesive is important.

Crystallized API in Adhesive Matrix -

Avoid This!


Design Consideration #2: Choose an adhesive that has good mechanical properties (adhesion) even when loaded with drug and excipient


Effect of Excipient and Drug Loading

• Excipients (and drugs) alter the physical

properties of adhesives

• Higher loadings lead to larger effects

• Some adhesive polymers are more

tolerant of drug/excipient than others

H-bonding

polymer

Add excipient

Weakened

polymer to polymer

interaction



Mo

du

lus

Temperature or Time apply peel

Add excipients

Mo

du

lus

Temperature or Time apply peel

--Excipients are like plasticizers

--To accept higher excipient levels, the base adhesive may need to be stiff (high modulus)

Not a PSA…. above Dalhquist criterion Excipient loading creates PSA

Excipients – What is Happening to the Rheology?


Design Consideration #3: Choose an adhesive that is compatible with other components of the system



Adhesive Compatibility with Other System Components

Adhesive Compatibility

Compatible with Drug and

Excipients

Compatible with Release

Liner

Compatible with Backing

film






Excipients


Liner


film

• Ensure low residuals • Monomers • Initiators • Solvents

• Avoid strong intermolecular interactions with drug






Excipients


Liner


film

• Ensure release liner peel force remains within an acceptable range throughout the shelf life

• Normal for release liner peel force to build over time

• Acceptable upper limit is ~60 g/cm*

• Wokovich, A. M., Shen, M., Doub, W. H., Machado, S. G. and Buhse, L. F. (2010), “Release liner removal method for transdermal drug delivery systems (TDDS).” • J. Pharm. Sci., 99: 3177–3187. doi: 10.1002/jps.22067






Excipients


Liner


film

• Ensure adequate adhesion to backing to prevent delamination

• Low surface energy substrates )like PE) are more difficult

• May require surface treatment (e.g. corona) to obtain an adequate bond


Regulatory Considerations



Adhesives for Generic TDD Products

• For generic TDD products (in the U.S.), all components (including adhesive) should have a

history of use in previously approved products using the same route of administration and

dosage form.

• Necessitates the use of adhesives that have been used in previously approved TDD products.

• FDA’s Inactive Ingredient Database (IID) provides information on which adhesives have been

used in previously approved products



Adhesives listed in the FDA’s Inactive Ingredient Database Ingredient_Name Route Dosage_Form

CAS_Number

UNII Potency_A

mount PotencyUni

t ACRYLATES COPOLYMER TRANSDERMAL FILM, CONTROLLED RELEASE N/A 382.22 MG

ACRYLATES COPOLYMER TRANSDERMAL PATCH, CONTROLLED RELEASE N/A 677.68 MG

ACRYLIC ACID-ISOOCTYL ACRYLATE COPOLYMER TRANSDERMAL FILM, CONTROLLED RELEASE 9017689 Pending 56.4 MG

ACRYLIC ADHESIVE 788 TRANSDERMAL FILM N/A 10.17 MG

ACRYLIC ADHESIVE 788 TRANSDERMAL FILM, CONTROLLED RELEASE N/A 20.08 MG

ACRYLIC ADHESIVE 788 TRANSDERMAL PATCH N/A

ADHESIVE TAPE TRANSDERMAL FILM, CONTROLLED RELEASE N/A

DIMETHYLAMINOETHYL METHACRYLATE - BUTYL METHACRYLATE - METHYL METHACRYLATE COPOLYMER TRANSDERMAL FILM, CONTROLLED RELEASE 24938167 905HNO1SIH

DIMETHYLAMINOETHYL METHACRYLATE - BUTYL METHACRYLATE - METHYL METHACRYLATE COPOLYMER TRANSDERMAL PATCH 24938167 905HNO1SIH

DIMETHYLAMINOETHYL METHACRYLATE - BUTYL METHACRYLATE - METHYL METHACRYLATE COPOLYMER TRANSDERMAL PATCH, ELECTRICALLY CONTROLLED 24938167 905HNO1SIH 10 MG

DURO-TAK 280-2516 TRANSDERMAL FILM, CONTROLLED RELEASE N/A

DURO-TAK 387-2516 TRANSDERMAL FILM, CONTROLLED RELEASE N/A 37.4 MG

DURO-TAK 80-1196 TRANSDERMAL FILM, CONTROLLED RELEASE N/A 172 MG



DURO-TAK 87-2287 TRANSDERMAL FILM N/A 537.7 MG


DURO-TAK 87-2296 TRANSDERMAL PATCH, CONTROLLED RELEASE N/A 43 MG

DURO-TAK 87-2888 TRANSDERMAL PATCH N/A 175.9 MG

DURO-TAK 87-2888 TRANSDERMAL PATCH, CONTROLLED RELEASE N/A 175.9 MG


GELVA 737 TRANSDERMAL FILM, CONTROLLED RELEASE Pending

POLYISOBUTYLENE TRANSDERMAL FILM 9003274 N/A 16.83 MG

POLYISOBUTYLENE TRANSDERMAL FILM, CONTROLLED RELEASE 9003274 N/A 119 MG

POLYISOBUTYLENE TRANSDERMAL PATCH, CONTROLLED RELEASE 9003274 N/A 10.5 MG

POLYISOBUTYLENE (1100000 MW) TRANSDERMAL FILM, CONTROLLED RELEASE 9003274 FLT10CH37X 69 MG

POLYISOBUTYLENE (1100000 MW) TRANSDERMAL PATCH 9003274 FLT10CH37X 22.65 MG

POLYISOBUTYLENE (2300 MW) TRANSDERMAL FILM, CONTROLLED RELEASE 9003274 DSQ2V1DD1K 121.68 MG

POLYISOBUTYLENE (35000 MW) TRANSDERMAL FILM, CONTROLLED RELEASE 9003274 98553S1MHQ 86 MG

POLYISOBUTYLENE (55000 MW) TRANSDERMAL FILM 9003274 TQ77WR8A02 238.44 MG

POLYISOBUTYLENE (55000 MW) TRANSDERMAL PATCH 9003274 TQ77WR8A02 28.32 MG

POLYISOBUTYLENE (800000 MW) TRANSDERMAL FILM 9003274 Y132ZOQ9H7 159 MG

POLYISOBUTYLENE LOW MOLECULAR WEIGHT TRANSDERMAL PATCH, CONTROLLED RELEASE 9003274 N/A 8.13 MG

POLYISOBUTYLENE MEDIUM MOLECULAR WEIGHT TRANSDERMAL PATCH, CONTROLLED RELEASE 9003274 N/A 1.63 MG

POLYISOBUTYLENE/POLYBUTENE ADHESIVE TRANSDERMAL FILM, CONTROLLED RELEASE N/A 221.25 MG

SILICONE TRANSDERMAL FILM, CONTROLLED RELEASE 63394025 N/A 353.51 MG

SILICONE TRANSDERMAL PATCH 63394025 N/A



Adhesives listed in the FDA’s Inactive Ingredient Database Ingredient_Name Route Dosage_Form

CAS_Number

UNII Potency_A

mount PotencyUni

t ACRYLATES COPOLYMER TRANSDERMAL FILM, CONTROLLED RELEASE N/A 382.22 MG

ACRYLATES COPOLYMER TRANSDERMAL PATCH, CONTROLLED RELEASE N/A 677.68 MG

ACRYLIC ACID-ISOOCTYL ACRYLATE COPOLYMER TRANSDERMAL FILM, CONTROLLED RELEASE 9017689 Pending 56.4 MG

ACRYLIC ADHESIVE 788 TRANSDERMAL FILM N/A 10.17 MG

ACRYLIC ADHESIVE 788 TRANSDERMAL FILM, CONTROLLED RELEASE N/A 20.08 MG

ACRYLIC ADHESIVE 788 TRANSDERMAL PATCH N/A

ADHESIVE TAPE TRANSDERMAL FILM, CONTROLLED RELEASE N/A

DIMETHYLAMINOETHYL METHACRYLATE - BUTYL METHACRYLATE - METHYL METHACRYLATE COPOLYMER TRANSDERMAL FILM, CONTROLLED RELEASE 24938167 905HNO1SIH

DIMETHYLAMINOETHYL METHACRYLATE - BUTYL METHACRYLATE - METHYL METHACRYLATE COPOLYMER TRANSDERMAL PATCH 24938167 905HNO1SIH

DIMETHYLAMINOETHYL METHACRYLATE - BUTYL METHACRYLATE - METHYL METHACRYLATE COPOLYMER TRANSDERMAL PATCH, ELECTRICALLY CONTROLLED 24938167 905HNO1SIH 10 MG



DURO-TAK 80-1196 TRANSDERMAL FILM, CONTROLLED RELEASE N/A 172 MG



DURO-TAK 87-2287 TRANSDERMAL FILM N/A 537.7 MG


DURO-TAK 87-2296 TRANSDERMAL PATCH, CONTROLLED RELEASE N/A 43 MG

DURO-TAK 87-2888 TRANSDERMAL PATCH N/A 175.9 MG

DURO-TAK 87-2888 TRANSDERMAL PATCH, CONTROLLED RELEASE N/A 175.9 MG


GELVA 737 TRANSDERMAL FILM, CONTROLLED RELEASE Pending

POLYISOBUTYLENE TRANSDERMAL FILM 9003274 N/A 16.83 MG

POLYISOBUTYLENE TRANSDERMAL FILM, CONTROLLED RELEASE 9003274 N/A 119 MG

POLYISOBUTYLENE TRANSDERMAL PATCH, CONTROLLED RELEASE 9003274 N/A 10.5 MG

POLYISOBUTYLENE (1100000 MW) TRANSDERMAL FILM, CONTROLLED RELEASE 9003274 FLT10CH37X 69 MG

POLYISOBUTYLENE (1100000 MW) TRANSDERMAL PATCH 9003274 FLT10CH37X 22.65 MG

POLYISOBUTYLENE (2300 MW) TRANSDERMAL FILM, CONTROLLED RELEASE 9003274 DSQ2V1DD1K 121.68 MG

POLYISOBUTYLENE (35000 MW) TRANSDERMAL FILM, CONTROLLED RELEASE 9003274 98553S1MHQ 86 MG

POLYISOBUTYLENE (55000 MW) TRANSDERMAL FILM 9003274 TQ77WR8A02 238.44 MG

POLYISOBUTYLENE (55000 MW) TRANSDERMAL PATCH 9003274 TQ77WR8A02 28.32 MG

POLYISOBUTYLENE (800000 MW) TRANSDERMAL FILM 9003274 Y132ZOQ9H7 159 MG

POLYISOBUTYLENE LOW MOLECULAR WEIGHT TRANSDERMAL PATCH, CONTROLLED RELEASE 9003274 N/A 8.13 MG

POLYISOBUTYLENE MEDIUM MOLECULAR WEIGHT TRANSDERMAL PATCH, CONTROLLED RELEASE 9003274 N/A 1.63 MG

POLYISOBUTYLENE/POLYBUTENE ADHESIVE TRANSDERMAL FILM, CONTROLLED RELEASE N/A 221.25 MG

SILICONE TRANSDERMAL FILM, CONTROLLED RELEASE 63394025 N/A 353.51 MG

SILICONE TRANSDERMAL PATCH 63394025 N/A

From the 8/15/2015 Update of the IID

37 entries that pertain to adhesives (after filtering on transdermal or topical patches)

Some entries are duplicative (~20 unique entries)

Some entries are not very descriptive of the adhesive polymer



Relevant Regulatory Documents and Adhesive Tests • USP <3> Topical and Transdermal Drug Products – Product Quality Tests

• Peel Adhesion

• Release Liner Peel Test

• Tack - Probe or Rolling Ball (ASTM D3121)

• FDA Guidance on Residual Drug in Transdermal and Related Drug Delivery Systems

• EMA/CHMP/QWP/608924/2014 “Guideline on Quality of Transdermal Patches”

• Peel Adhesion, Liner Release, Tack, Cold Flow

• Ph. Eur. Monograph 1011 Transdermal Patches

• EMA Guideline on the Pharmacokinetic and clinical evaluation of modified-release dosage

forms.

• A useful reference:

• “Measuring Adhesive Performance in Transdermal Delivery systems”, P. Minghetti, F. Cilurzo and A. Casiraghi; Am J Drug Deliv 2

(3): 193-206, (2004)


Quality Tests that pertain to Transdermal Adhesives



Quality Testing of PSA Raw Materials

• Adhesive polymers used in TDD products are typically provided in solvent

• Typical Raw Material testing includes:

• ID

• % Solids

• Molecular Weight (or a surrogate such as Inherent Viscosity – I.V.)

• Residuals Content

• Initiator

• Monomers



Peel Adhesion

• Measurement of the force

required to peel an adhesive

system from a test substrate

• Can be quite sensitive to

environmental conditions

• Example test substrates are

stainless steel or HDPE

• Practical experience: There is

no test substrate that mimics

skin.



• There is no correlation between adhesion to steel and adhesion to skin

• Adhesion to steel is quite often (but not always!) substantially higher than adhesion to skin

• Increasing the adhesion to steel will not necessarily increase the adhesion to skin (sometimes just the opposite)

• Adhesion to steel is useful as a quality test only

• Useful reference: • Fauth C, Wiedersberg S, Neubert RHH, Dittgen M. Adhesive backing

foil interactions affecting the elasticity, adhesion strength of laminates, and how to interpret these properties of branded transdermal patches. Drug Dev Ind Pharm. 2002;28(10):1251-9.

Adhesion to Steel vs Adhesion to Skin

1509 LDPE 1513 PET 9877 PET

Adhesive Type Acrylate Same as #1509 Synthetic Rubber

Adhesion to Steel,

Typical

1450 g/in 1730 g/in 3400 g/n

Initial Adhesion to

Skin, Recorded Range

30-50 g/in 30-50 g/in 30-50 g/in



Tack

• Measurement of the force required to pull a probe

(usually stainless steel) away from the adhesive

• Intended to quantify the “quick stick” of the

adhesive

• Practical experience – probe tack values have no

correlation with adhesion to skin performance

Probe Tack



Release from Liner

• Measurement of the force required to peel

the adhesive system from the release liner

• Peel angle is usually 90 or 180 degrees

• Force is usually quite low (1-60 g/cm)

• This force is very representative of what the

patient experiences as they remove the liner

prior to patch application.



Shear Adhesion

• Intended to be a measurement of the

internal (cohesive) strength of the adhesive

matrix

• Testing can be either static (hanging weight)

or dynamic

• Practical experience – shear testing is not

correlated with in vivo adhesion to skin

performance.

Static Shear

Dynamic Shear



Cold Flow

• Measurement of the degree of adhesive

migration or detachment at the edge of the

TDD system

• Cold flow (when it occurs) is usually time

dependent

• A variety of test methods can be used:

• Visual

• Gravimetric

• Microscopic distance measurement

• Assay



Summary

• Adhesive polymers play a crucial role in the performance of

TDD products

• Selection of an appropriate adhesive for TDD systems

requires consideration of it’s impact on many dimensions of

product performance

• Adhesion to skin is a particular challenge, and in vitro quality

tests are not predictive of in vivo performance



Acknowledgements

Jim Dizio

Keith Dahmen

Kris Godbey

Steven Schull