Transdermal Adhesives

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1 Transdermal Adhesives Considerations for Generic Product Development Tim Peterson October 28, 2015

2 3M s Stick to Skin Portfolio 2

3 s Transdermal Adhesive Basics

4 Transdermal System Designs Basic Approaches Reservoir Drug-in-Adhesive Multilaminate Backing Drug Membrane Adhesive Liner/Skin Three of the most utilized transdermal patch designs. 4

5 Key Aspects of Adhesive Performance in Transdermal Systems Secure the system to the skin Contribute to the stability of the system Provide a drug and excipient reservoir Biocompatible with skin Facilitate drug release from the system 5

6 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

7 Modulus 3M Health Care Business Group Adhesive Rheology Glassy Transition peel Rubbery apply Temperature or Time Flow Dahlquist tack criterion <3x10 6 dyne/cm 2 --crosslink, higher Mw --less flow --better shear 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 7 pressure.

8 Adhesives Currently Used in TDD Adhesive Polymers: Acrylate Silicone Polyisobutylene Synthetic Rubber (e.g. Kraton) Transdermal Reservoir System Androderm R (testosterone) BuTrans R (buprenorphine) Catapres-TTS R (clonidine) Climara R (estradiol) Climara Pro R (estradiol / levonorgestrel) Combipatch R (estradiol / norethindrone Daytrana R (methylphenidate) Duragesic R (fentanyl) Emsam R (selegiline) Exelon R (rivastigmine) Flector R (diclofenac epolamine) Lidoderm R (lidocaine) Minitran TM (nitroglycerin) Neupro R (rotigotine) Nicoderm CQ R (nicotine) Ortho Evra R (ethinyl estradiol / norelgestromin) Oxytrol R (oxybutynin) NitroDur R (nitroglycerin) Qutenza R (capsaicin) Sancuso R (granisetron) Transderm-Nitro R (nitroglycerin) Transderm Scop R (scopolamine) Vivelle Dot R (estradiol) Product Design Category Adhesive Category w/ Adh Matrix Overlay DIA Multilaminate PIB Acrylate Silicone 8

Polyacrylate PSAs Polymers designed to be PSAs Workhorse monomers 2-ethyl hexyl butyl n-vinyl pyrrolidone (2-EHA) (BA) (NVP) acrylic acid (AA) acrylamide (ACM) O O O O N O HO O H 2 N O -affords

9 Polyacrylate PSAs Polymers designed to be PSAs Workhorse monomers 2-ethyl hexyl butyl n-vinyl pyrrolidone (2-EHA) (BA) (NVP) acrylic acid (AA) acrylamide (ACM) O O O O N O HO O H 2 N O -affords tackiness -low Tg -reinforcing capability -polar, interact with substrates 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

Si CH 3 O Si CH 3 CH 3 CH 3 CH3 CH3 Advantages --low surface energy --non-interactive with drug

10 Silicone PSAs Silicone Polydimethylsiloxane, PDMS Dimethicone Si Si Si O O O O Si Tackify with silicate resin to make a PSA CH3 CH3 CH3 O Si O Si CH 3 CH 3 CH 3 silica CH 3 O Si CH 3 O CH 3 CH 3 Si CH 3 CH3 O Si CH 3 O Si CH 3 CH 3 CH 3 CH3 CH3 Advantages --low surface energy --non-interactive with drug --biocompatible --MVTR is great --low solubility Disadvantages --cost --material compatibility --low solubility 10

11 s Adhesion to Skin

12 Factors Affecting Good Skin Adhesion Key Characteristics of Skin Dead Skin Cells Sweat Salt Lotions & Powders Contaminated Surface Breathing, Sensitive Surface Allergies MVTR - Masceration Mechanical Trauma Cell Renewal Cycle Stratum corneum - 14 days Epidermis - 50 days Human Skin Hair & Growth Pores Skin Wrinkles Rough Texture Low Surface Energy Elastic Surface 25 dynes/cm (Skin) 31 dynes/cm (Polypropylene) >700 dynes/cm (Stainless) Reversible Stretch up to 50% 12

13 Skin / Adhesive Peel Interface Epidermal cells on surface of adhesive following removal from skin a) Gentle PSA tape, b) Aggressive PSA tape a) b) 13

14 s Design Considerations

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

16 Solubility of API in various TDD Adhesive Materials API #1 API #2 API #3 API #4 API #5 API #6 API solubility is highly dependent on adhesive selection There is no universal best choice depends on the API physicochemical properties

17 Fentanyl Solublity, % w/w 3M Health Care Business Group Choice of Acrylate Co-monomer Can Influence Solubility Fentanyl solubility in IOA/HEA adhesives Percent HEA in Soft Segment 17

18 Assessment of Drug Solubility in Adhesive Matrices Crystal Growth Method Growth Absorption 18

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

19 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 Crystallized API in Adhesive Matrix - Avoid This! The ability to screen multiple adhesives or modulate drug solubility within the adhesive is important. 19

20 s 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

21 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 Weakened polymer to polymer interaction Add excipient

22 Modulus Modulus 3M Health Care Business Group Excipients What is Happening to the Rheology? --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 Add excipients peel apply Temperature or Time peel apply Temperature or Time 22

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

24 Adhesive Compatibility with Other System Components Compatible with Drug and Excipients Adhesive Compatibility Compatible with Backing film Compatible with Release Liner 24

25 Adhesive Compatibility with Other System Components Compatible with Drug and Excipients Ensure low residuals Monomers Initiators Solvents Avoid strong intermolecular interactions with drug Adhesive Compatibility Compatible with Backing film Compatible with Release Liner 25

throughout the shelf life Normal for release liner peel force to build over time Acceptable

A. M., Shen, M., Doub, W. H., Machado, S. G. and Buhse, L. F.

26 Adhesive Compatibility with Other System Components Compatible with Drug and Excipients Adhesive Compatibility 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* Compatible with Backing film Compatible with Release Liner 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: doi: /jps

backing to prevent delamination Low surface

difficult May require surface treatment (e.g.

27 Adhesive Compatibility with Other System Components 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 Compatible with Drug and Excipients Adhesive Compatibility Compatible with Backing film Compatible with Release Liner 27

28 s Regulatory Considerations

29 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 29

30 Adhesives listed in the FDA s Inactive Ingredient Database Ingredient_Name Route Dosage_Form CAS_Num ber UNII Potency_A mount ACRYLATES COPOLYMER TRANSDERMAL FILM, CONTROLLED RELEASE N/A MG ACRYLATES COPOLYMER TRANSDERMAL PATCH, CONTROLLED RELEASE N/A MG ACRYLIC ACID-ISOOCTYL ACRYLATE COPOLYMER TRANSDERMAL FILM, CONTROLLED RELEASE Pending 56.4 MG ACRYLIC ADHESIVE 788 TRANSDERMAL FILM N/A MG ACRYLIC ADHESIVE 788 TRANSDERMAL FILM, CONTROLLED RELEASE N/A 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 HNO1SIH DIMETHYLAMINOETHYL METHACRYLATE - BUTYL METHACRYLATE - METHYL METHACRYLATE COPOLYMER TRANSDERMAL PATCH HNO1SIH DIMETHYLAMINOETHYL METHACRYLATE - BUTYL METHACRYLATE - METHYL METHACRYLATE COPOLYMER TRANSDERMAL PATCH, ELECTRICALLY CONTROLLED HNO1SIH 10 MG DURO-TAK TRANSDERMAL FILM, CONTROLLED RELEASE N/A PotencyUni t DURO-TAK TRANSDERMAL FILM, CONTROLLED RELEASE N/A 37.4 MG DURO-TAK TRANSDERMAL FILM, CONTROLLED RELEASE N/A 172 MG DURO-TAK TRANSDERMAL FILM, CONTROLLED RELEASE N/A DURO-TAK TRANSDERMAL FILM, CONTROLLED RELEASE N/A MG DURO-TAK TRANSDERMAL FILM N/A MG DURO-TAK TRANSDERMAL FILM, CONTROLLED RELEASE N/A MG DURO-TAK TRANSDERMAL PATCH, CONTROLLED RELEASE N/A 43 MG DURO-TAK TRANSDERMAL PATCH N/A MG DURO-TAK TRANSDERMAL PATCH, CONTROLLED RELEASE N/A MG DURO-TAK TRANSDERMAL FILM, CONTROLLED RELEASE N/A GELVA 737 TRANSDERMAL FILM, CONTROLLED RELEASE Pending POLYISOBUTYLENE TRANSDERMAL FILM N/A MG POLYISOBUTYLENE TRANSDERMAL FILM, CONTROLLED RELEASE N/A 119 MG POLYISOBUTYLENE TRANSDERMAL PATCH, CONTROLLED RELEASE N/A 10.5 MG POLYISOBUTYLENE ( MW) TRANSDERMAL FILM, CONTROLLED RELEASE FLT10CH37X 69 MG POLYISOBUTYLENE ( MW) TRANSDERMAL PATCH FLT10CH37X MG POLYISOBUTYLENE (2300 MW) TRANSDERMAL FILM, CONTROLLED RELEASE DSQ2V1DD1K MG POLYISOBUTYLENE (35000 MW) TRANSDERMAL FILM, CONTROLLED RELEASE S1MHQ 86 MG POLYISOBUTYLENE (55000 MW) TRANSDERMAL FILM TQ77WR8A MG POLYISOBUTYLENE (55000 MW) TRANSDERMAL PATCH TQ77WR8A MG POLYISOBUTYLENE ( MW) TRANSDERMAL FILM Y132ZOQ9H7 159 MG POLYISOBUTYLENE LOW MOLECULAR WEIGHT TRANSDERMAL PATCH, CONTROLLED RELEASE N/A 8.13 MG POLYISOBUTYLENE MEDIUM MOLECULAR WEIGHT TRANSDERMAL PATCH, CONTROLLED RELEASE N/A 1.63 MG POLYISOBUTYLENE/POLYBUTENE ADHESIVE TRANSDERMAL FILM, CONTROLLED RELEASE N/A MG SILICONE TRANSDERMAL FILM, CONTROLLED RELEASE N/A MG SILICONE TRANSDERMAL PATCH N/A 30

31 Adhesives listed in the FDA s Inactive Ingredient Database Ingredient_Name Route Dosage_Form CAS_Num ber UNII Potency_A mount ACRYLATES COPOLYMER TRANSDERMAL FILM, CONTROLLED RELEASE N/A MG ACRYLATES COPOLYMER TRANSDERMAL PATCH, CONTROLLED RELEASE N/A MG ACRYLIC ACID-ISOOCTYL ACRYLATE COPOLYMER TRANSDERMAL FILM, CONTROLLED RELEASE Pending 56.4 MG From the 8/15/2015 Update of the IID ACRYLIC ADHESIVE 788 TRANSDERMAL FILM N/A MG ACRYLIC ADHESIVE 788 TRANSDERMAL FILM, CONTROLLED RELEASE N/A 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 HNO1SIH 37 entries that pertain to adhesives (after filtering on transdermal or topical patches) DIMETHYLAMINOETHYL METHACRYLATE - BUTYL METHACRYLATE - METHYL METHACRYLATE COPOLYMER TRANSDERMAL PATCH HNO1SIH DIMETHYLAMINOETHYL METHACRYLATE - BUTYL METHACRYLATE - METHYL METHACRYLATE COPOLYMER TRANSDERMAL PATCH, ELECTRICALLY CONTROLLED HNO1SIH 10 MG DURO-TAK TRANSDERMAL FILM, CONTROLLED RELEASE N/A Some entries are duplicative (~20 unique entries) PotencyUni t DURO-TAK TRANSDERMAL FILM, CONTROLLED RELEASE N/A 37.4 MG DURO-TAK TRANSDERMAL FILM, CONTROLLED RELEASE N/A 172 MG DURO-TAK TRANSDERMAL FILM, CONTROLLED RELEASE N/A DURO-TAK TRANSDERMAL FILM, CONTROLLED RELEASE N/A MG DURO-TAK TRANSDERMAL FILM N/A MG DURO-TAK TRANSDERMAL FILM, CONTROLLED RELEASE N/A MG Some entries are not very descriptive of the adhesive polymer DURO-TAK TRANSDERMAL PATCH, CONTROLLED RELEASE N/A 43 MG DURO-TAK TRANSDERMAL PATCH N/A MG DURO-TAK TRANSDERMAL PATCH, CONTROLLED RELEASE N/A MG DURO-TAK TRANSDERMAL FILM, CONTROLLED RELEASE N/A GELVA 737 TRANSDERMAL FILM, CONTROLLED RELEASE Pending POLYISOBUTYLENE TRANSDERMAL FILM N/A MG POLYISOBUTYLENE TRANSDERMAL FILM, CONTROLLED RELEASE N/A 119 MG POLYISOBUTYLENE TRANSDERMAL PATCH, CONTROLLED RELEASE N/A 10.5 MG POLYISOBUTYLENE ( MW) TRANSDERMAL FILM, CONTROLLED RELEASE FLT10CH37X 69 MG POLYISOBUTYLENE ( MW) TRANSDERMAL PATCH FLT10CH37X MG POLYISOBUTYLENE (2300 MW) TRANSDERMAL FILM, CONTROLLED RELEASE DSQ2V1DD1K MG POLYISOBUTYLENE (35000 MW) TRANSDERMAL FILM, CONTROLLED RELEASE S1MHQ 86 MG POLYISOBUTYLENE (55000 MW) TRANSDERMAL FILM TQ77WR8A MG POLYISOBUTYLENE (55000 MW) TRANSDERMAL PATCH TQ77WR8A MG POLYISOBUTYLENE ( MW) TRANSDERMAL FILM Y132ZOQ9H7 159 MG POLYISOBUTYLENE LOW MOLECULAR WEIGHT TRANSDERMAL PATCH, CONTROLLED RELEASE N/A 8.13 MG POLYISOBUTYLENE MEDIUM MOLECULAR WEIGHT TRANSDERMAL PATCH, CONTROLLED RELEASE N/A 1.63 MG POLYISOBUTYLENE/POLYBUTENE ADHESIVE TRANSDERMAL FILM, CONTROLLED RELEASE N/A MG SILICONE TRANSDERMAL FILM, CONTROLLED RELEASE N/A MG SILICONE TRANSDERMAL PATCH N/A 31

32 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): , (2004) 32

33 s Quality Tests that pertain to Transdermal Adhesives

34 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 34

35 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. 35

36 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: Adhesion to Steel vs Adhesion to Skin 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): LDPE 1513 PET 9877 PET Adhesive Type Acrylate Same as #1509 Synthetic Rubber Adhesion to Steel, Typical Initial Adhesion to Skin, Recorded Range 1450 g/in 1730 g/in 3400 g/n g/in g/in g/in 36

37 Tack Probe 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 37

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

38 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. 38

Shear Adhesion Intended to be a measurement of

experience shear testing is not correlated with

39 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. Dynamic Shear Static Shear 39

occurs) is usually time dependent A variety of test methods can

40 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 40

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

41 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 41

42 Acknowledgements Jim Dizio Keith Dahmen Kris Godbey Steven Schull 42

School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong. Transdermal Drug Delivery System

School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong. Transdermal Drug Delivery System Workshop in Celebration of 25 th Anniversary of the School of Pharmacy Biopharmaceutics of Modified Release Products and Challenging Drug Molecules Design and Regulatory Assessment of Transdermal Drug