Biopharmaceutical Properties of Patches 16.06.2015 Relevant for Transdermal Drug Absorption

Biopharmaceutical Properties of Patches Relevant for Transdermal Drug Absorption – Confounding Factors and In‐Vitro Testing

Johannes Bartholomäus Pharmakreativ Consulting, Aachen

Skin as Barrier to Transdermal Absorption

And that’s from what Mother Nature did not design all the difficulties in transdermal drug skin as an absorption site. delivery arise. It‘s much more the opposite!

Stratum corneum as lipophilic barrier

June 16, 2015 J. Bartholomäus: Biopharmaceutical Properties of Patches 2

© Johannes Bartholomäus 1 Biopharmaceutical Properties of Patches 16.06.2015 Relevant for Transdermal Drug Absorption

Definition TDDS by Guidelines

. Transdermal drug delivery systems . Transdermal patch:** Flexible single‐ (TDDS):* A TDDS or transdermal dose preparation intended to be patch is a flexible pharmaceutical applied to the unbroken skin to preparation of varying size containing obtain a systemic delivery over an one or more active substance(s) to be extended period of time. applied on the intact skin for systemic . Transdermal patches consist of a availability. backing sheet supporting a reservoir . There are two main types of or a matrix containing the active transdermal patch systems substance(s) and on the top a depending on how the drug pressure‐sensitive adhesive, which substance is dispersed in other patch assures the adhesion of the components: preparation to the skin. – Matrix systems with drug release based on . The backing sheet is impermeable to the diffusion of drug substance. the active substance(s) and normally – Reservoir systems containing a specific liquid drug compartment and release is impermeable to water. controlled by a membrane. *Guideline on the pharmacokinetic and clinical evaluation of **Guideline on quality of transdermal patches modified release dosage forms (EMA/CPMP/EWP/280/96 Corr1) (EMA/CHMP/QWP/608924/2014) June 16, 2015 J. Bartholomäus: Biopharmaceutical Properties of Patches 3

Reservoir TDDS

. Transdermal patch: ctd. from Guideline on quality of transdermal patches (EMA/CHMP/QWP/608924/2014) . In reservoir systems, the active substance may be dissolved or dispersed in a semi‐solid basis or in a solid polymer matrix, which is separated from the skin by a rate‐controlling membrane and a pressure sensitive adhesive. . The pressure‐sensitive adhesive may, in this case, be applied to some or all parts of the membrane, or only around the border of the membrane and the backing sheet. . The releasing surface of the patch is covered by a protective liner to be removed before applying the patch to the skin. Backing “First Generation Liquid, semi-solid or solid Design” e.g. polymer matrix drug reservoir Scopoderm, Rate-controlling Nitroderm, membrane Durogesic (old) Adhesive layer Protective liner

*Guideline on quality of transdermal patches (EMA/CHMP/QWP/608924/2014) June 16, 2015 J. Bartholomäus: Biopharmaceutical Properties of Patches 4

© Johannes Bartholomäus 2 Biopharmaceutical Properties of Patches 16.06.2015 Relevant for Transdermal Drug Absorption

Matrix TDDS

. Transdermal patch: ctd. from Guideline on quality of transdermal patches (EMA/CHMP/QWP/608924/2014) . Matrix systems contain the active substance in a solid or semi‐solid matrix, the properties of which control the diffusion pattern to the skin. The matrix system may also be a solution or solid dispersion of the active substance in the pressure‐sensitive adhesive. . The releasing surface of the patch is covered by a protective liner to be removed before applying the patch to the skin.

Backing

Drug in polymer matrix

Adhesive layer Protective liner

Backing “Drug in Adhesive” Drug in adhesive polymer Design currently matrix most used Protective liner

June 16, 2015 J. Bartholomäus: Biopharmaceutical Properties of Patches 5

Product Components and Formulation

. Special design with overlay – To increase adhesion to skin – To reduce „narcotic“ waste in manufacturing

June 16, 2015 J. Bartholomäus: Biopharmaceutical Properties of Patches 6

© Johannes Bartholomäus 3 Biopharmaceutical Properties of Patches 16.06.2015 Relevant for Transdermal Drug Absorption

Product Components and Formulation

. All Patches consist of – Protective liner (coated aluminium or polyester) • virtually no influence on in‐vivo performance but on manufacturing and quality and some support during application to patient/volunteer – Adhesive layer (might be integrated with drug formulation) • with influence on in‐vivo performance – Drug formulated in excipients • more or less complex with high influence on in‐vivo performance – Optional rate controlling membrane • with influence on in‐vivo performance – Backing membrane • with influence on in‐vivo performance

June 16, 2015 J. Bartholomäus: Biopharmaceutical Properties of Patches 7

Product Components and Formulation

. Drug formulated in excipients and Adhesive – Drug needs to be dissolved for release to and absorption by skin • For low dose drugs „easily and voluntarily“ passing the skin simple solutions (optionally including suspended drug in excess) in water or alcohol in the „reservoir“ suits („old“ fentanyl, scopolamin, GTN) and even a rate controlling membrane may be added; adhesive can be chosen to perform „best adhesion and tolerance“ e.g. silicone

June 16, 2015 J. Bartholomäus: Biopharmaceutical Properties of Patches 8

© Johannes Bartholomäus 4 Biopharmaceutical Properties of Patches 16.06.2015 Relevant for Transdermal Drug Absorption

Product Components and Formulation

. Drug formulated in excipients and Adhesive – Drug needs to be dissolved for release to and absorption by skin; supersaturation is one principle to achieve „high thermodynamic activity“ • In matrix patches a polymer is mostly used as solvent, as release control and often also as adhesive (PSA: Pressure Sensitive Advesive) – Selection often because of solubility of drug in polymer – Best solubility often in poly(meth)acrylate polymers substituted with different All of additional ester compounds leading to dissolving power and adhesion; influence often specific P(M)As aretailoredforusein patches on skin – Best skin tolerability often with silicones but less dissolving power (dispersion of sensitation PMA in silicones used to increase dissolution) irritation – Some (rare) formulations use polyisobutylene and • Further polymers used to increase solubility or stabilize against adhesion crystallization, e.g. povidone • „Softeners“ are sometimes used e.g. oleic acid, oleic alcohol, oleyloleate • Permeation enhancers are rare in today‘s formulations June 16, 2015 J. Bartholomäus: Biopharmaceutical Properties of Patches 9

Product Components and Formulation

. Backing membrane “Rounded Edges” – Usually made of polyester (e.g. PET) Influ‐ ence – Impermeable to active substance and normally also on to water adhe‐ – To protect from „water“ and „touching“ sion – Supports application to skin – Needs to be flexible otherwise „tissue movement“ Influ‐ tears of patch ence • For large areas woven material on in‐ – Some prefer transparent vivo („invisible“) backing, others adhe‐ opaque („wound patch look“) sion – Guidelines are not in favour study of „invisible patches“INK

June 16, 2015 J. Bartholomäus: Biopharmaceutical Properties of Patches 10

© Johannes Bartholomäus 5 Biopharmaceutical Properties of Patches 16.06.2015 Relevant for Transdermal Drug Absorption

Manufacturing Process DIA TDDS

Important steps for exact amount of drug in patch 1. Homogeneous 1 2 Backing liner roll distribution in coating mass

Protective 2. Exact and liner roll homogeneous 3 thickness from coating step 3. Exact cutting of patch 3 area

Modified from http://optimags.de/tds‐odf.php

June 16, 2015 J. Bartholomäus: Biopharmaceutical Properties of Patches 11

Special Features of TDDS

. Dose is not defined as the usual total amount of drug contained in the dosage form („mg“) but as amount active substance released per unit time („µg/h“) . Only a part of the total amount is delivered to patient, (larger) remaining amount is discarded to waste after use – Reason: Pseudo 0‐order release is only achieved for „first part“ of drug released from total amount contained

June 16, 2015 J. Bartholomäus: Biopharmaceutical Properties of Patches 12

© Johannes Bartholomäus 6 Biopharmaceutical Properties of Patches 16.06.2015 Relevant for Transdermal Drug Absorption

Special Features of TDDS Goal for „Blood Levels“

Needs 0‐order drug release rate / overdosed absorption rate from patch Optimal therapy

underdosed

serum concentration Drug

1 9 18 27 36 4554 63 72h

June 16, 2015 J. Bartholomäus: Biopharmaceutical Properties of Patches 13

Special Features of TDDS Basic Release Kinetics

100 90 80 70 60 50 40

Release in % in Release 30 20 10 0 0 6 12 18 24 Time in h

0-order 1. order Square root t-kinetic Pseudo 0-ordnung by 1. order Pseudo 0-order by root t

June 16, 2015 J. Bartholomäus: Biopharmaceutical Properties of Patches 14

© Johannes Bartholomäus 7 Biopharmaceutical Properties of Patches 16.06.2015 Relevant for Transdermal Drug Absorption

Special Features of TDDS

. Composition of patch dictates amount released / absorbed per area unit of patch . Total „dose“ released / absorbed is proportional to „active area“ of patch . Thickness of matrix layer determines duration of „constant release / absorption“ (change interval)

. Bear in mind: Release from patch is not always equivalent to absorption into blood stream

June 16, 2015 J. Bartholomäus: Biopharmaceutical Properties of Patches 15

Special Features of TDDS

Definition Patch area activity:* . Expressed in %/cm²; it is a measure of the formulation’s intrinsic capability to release active substance from the patch in vivo and as such a surrogate measurement of thermodynamic activity. . Indirect tool to determine appropriateness of formulation development for a generic transdermal patch by putting two major product development parameters into relation: patch area and overall amount of active substance necessary to achieve bioequivalence to the reference product.

*Guideline on quality of transdermal patches (EMA/CHMP/QWP/608924/2014) June 16, 2015 J. Bartholomäus: Biopharmaceutical Properties of Patches 16

© Johannes Bartholomäus 8 Biopharmaceutical Properties of Patches 16.06.2015 Relevant for Transdermal Drug Absorption

Special Features of TDDS

Example Patch area activity:* . Transdermal patch dosage strength 25 μg/h, application time 72h, patch size 15cm2, overall amount of active substance incorporated 4.8 mg:72h X 25μg/h = 1.8 mg; . 1.8 mg corresponds to 37.5 % release related to 4.8 mg overall amount in the patch; . 37.5% / 15 cm²=2.5%/cm² patch area activity.

*Guideline on quality of transdermal patches (EMA/CHMP/QWP/608924/2014) June 16, 2015 J. Bartholomäus: Biopharmaceutical Properties of Patches 17

Special Features of TDDS

Patch area activity of various Fentanyl 25µg/h patches

Durogesic® Durogesic® Generic 1 Generic 2 Generic 3 Generic 4 Generic 5 Generic 6 Reservoir SMAT

Fentanyl per patch 2.5 mg 4.2 mg 2.75 mg 4.8 mg 5.8 mg 5.1 mg 6.0 mg 9.2 mg Utilized after 3 days 72 %43 %65 %38 %31 %35 %30 %19 % Release area 10 cm² 10.5 cm² 8.4 cm² 15 cm² 10.5 cm² 8.5 cm² 10cm² 18.9 cm²

Patch area activity 7.2 %/cm² 4.1 %/cm² 7.8 %/cm² 2.5 %/cm² 3.0 %/cm² 4.1 %/cm² 3.0 %/cm² 1.0 %/cm²

EC‐Decision on Generic 6: The CHMP confirmed its previous position and recommended the refusal of the marketing authorisation and, where appropriate, the suspension of the marketing authorisation of the following Fentanyl containing transdermal patches XXX, from YYY. The CHMP had adopted a negative opinion in November 2007, because it concluded that the product failed to show adequate characteristics which are key requirements for a product of this type in order to guarantee its safety and efficacy. In a re‐examination procedure, requested by the company, the CHMP confirmed this outcome for all dose forms concerned.

June 16, 2015 J. Bartholomäus: Biopharmaceutical Properties of Patches 18

© Johannes Bartholomäus 9 Biopharmaceutical Properties of Patches 16.06.2015 Relevant for Transdermal Drug Absorption

Special Features of TDDS

Today‘s requirement for Generic or Abbriged Applications*: “Generic patches should have preferably either the same or a higher patch area activity compared to the reference product. However, if justified that the benefit / risk has otherwise improved e.g., with respect to skin tolerability, adhesion properties, potential crystallisation, cold flow a larger patch can be accepted. Nevertheless, patch area activity comparison to the reference product should be a crucial aim of the pharmaceutical development.”

*Guideline on quality of transdermal patches (EMA/CHMP/QWP/608924/2014) June 16, 2015 J. Bartholomäus: Biopharmaceutical Properties of Patches 19

Determination of in‐vivo release rate

. Determine amount of drug in patch before and after application in man („patch return analysis“) . Difficulties: – Reconcile all drug that is not absorbed after application of patch (including remaining drug on skin) – Detect representative amount per patch before application without analyzing the to be used patch with respect to homogeneity of manufacturing . Specific protocols necessary

June 16, 2015 J. Bartholomäus: Biopharmaceutical Properties of Patches 20

© Johannes Bartholomäus 10 Biopharmaceutical Properties of Patches 16.06.2015 Relevant for Transdermal Drug Absorption

Determination of in‐vivo release rate

Source: M. Sournac, Transdermal Drug Delivery – an Industrial View Point, 1st European Meeting on Pharmaceutics, Reims 04/2015 June 16, 2015 J. Bartholomäus: Biopharmaceutical Properties of Patches 21

Determination of in‐vivo release rate

. Coating process might lead to different thickness across area . Representative samples for analysis to be taken close to area of later used clinical patch . Drawback for presented method: Collection from A and C virtually not possible after slicing to small rolls, but this type of testing is often done at labscale at beginning of development

Source: M. Sournac, Transdermal Drug Delivery – an Industrial View Point, 1st European Meeting on Pharmaceutics, Reims 04/2015 June 16, 2015 J. Bartholomäus: Biopharmaceutical Properties of Patches 22

© Johannes Bartholomäus 11 Biopharmaceutical Properties of Patches 16.06.2015 Relevant for Transdermal Drug Absorption

In‐vitro release

. Since only a smaller part of the total loading dose of a patch is releases to / absorbed by patient in‐vitro release is of limited value for prediction of in‐vivo behavior of patch – virtually no in‐vitro‐in‐vivo correlation possible . Useful for quality control of patches – Testing time is usually shorter than application time of patches – Testing is done until full drug release

June 16, 2015 J. Bartholomäus: Biopharmaceutical Properties of Patches 23

In‐vitro release (ctd)

. In case in‐vitro‐in‐vivo correlation is of interest or predictions from in‐vitro test shall be made then use in‐vitro skin permeation tests (see Guideline on quality of transdermal patches) – Currently the understanding of in‐vitro skin permeations seems not to be consolidated between agencies and industry . New Guideline on quality of transdermal patches sets a frame under which conditions a biowaiver could be granted for bioequivalence after changes based on equivalence of in‐vitro skin permeation

June 16, 2015 J. Bartholomäus: Biopharmaceutical Properties of Patches 24

© Johannes Bartholomäus 12 Biopharmaceutical Properties of Patches 16.06.2015 Relevant for Transdermal Drug Absorption

In‐vitro release (ctd)

“In vitro permeation studies are not expected to correlate with in vivo release, but the characterisation of the permeation profile is considered a valuable measure of product quality and performance and may reflect the thermodynamic activity of the active substance in the product. Establishing the characteristic permeation profile of the drug product, using a discriminative in vitro skin permeation method, can be of value in change control during life cycle management. For the comparison of products, the need to perform bioequivalence studies may, in certain cases, potentially be waived. However, given that the product formulation may have a great impact on efficacy and modify skin permeation, the products to be compared should have the same or similar qualitative and quantitative excipient composition.” Currently it looks that not many in‐ vivo bioequivalence Guideline on quality of transdermal patches (EMA/CHMP/QWP/608924/2014) studies will be June 16, 2015 J. Bartholomäus: Biopharmaceutical Properties of Patcheswaived 25

Adhesion

. Adhesion to skin necessary for drug transfer from patch to skin (proportional to adhereing surface) . Adhesion changes over time – Change of patch composition during wearing time – Increasing by flow of adhesive on/in skin – Decreasing by hydration of skin (occlusion) – Sloughing of skin

A.M. Wokovich et al. / European Journal of Pharmaceutics and Biopharmaceutics 64 (2006) 1–8

June 16, 2015 J. Bartholomäus: Biopharmaceutical Properties of Patches 26

© Johannes Bartholomäus 13 Biopharmaceutical Properties of Patches 16.06.2015 Relevant for Transdermal Drug Absorption

Adhesion

. Difficult to measure – Quality test often done as peel adhesion from steel surface (not representative for skin) – Some groups tried from gelatin gels (collagen) – No quantitative in‐vivo methods established

http://www.testresources.net/application/adhesive‐tape‐peel‐testing

June 16, 2015 J. Bartholomäus: Biopharmaceutical Properties of Patches 27

Adhesion

. First principles for in‐vivo mesurement e.g. . Peel patch tester developed by Pierre Fabre (patent no FR2788342) . Used in preformulation and post marketing studies

Source: M. Sournac, Transdermal Drug Delivery – an Industrial View Point, 1st European Meeting on Pharmaceutics, Reims 04/2015 June 16, 2015 J. Bartholomäus: Biopharmaceutical Properties of Patches 28

© Johannes Bartholomäus 14 Biopharmaceutical Properties of Patches 16.06.2015 Relevant for Transdermal Drug Absorption

Adhesion

. State‐of‐the‐art for in‐vivo adhesion testing is (still) based on scoring systems

A.M. Wokovich et al. / European Journal of Pharmaceutics and Biopharmaceutics 64 (2006) 1–8

Guideline on the pharmacokinetic and clinical evaluation of modified release dosage forms (EMA/CPMP/EWP/280/96 Corr1)

June 16, 2015 J. Bartholomäus: Biopharmaceutical Properties of Patches 29

Conclusion

Compared to conventional dosage forms like e.g. tablets transdermal patches have a lot of peculiarities in composition, components, manufacturing process and interaction with skin that are of paramount importance to in‐vivo performance Combined and harmonized efforts between technical and clinical development are key to success

June 16, 2015 J. Bartholomäus: Biopharmaceutical Properties of Patches 30

© Johannes Bartholomäus 15