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:*