Transdermal drug delivery system (TDDS) adhesion as a critical safety, efficacy and quality attribute

doi:10.1016/j.ejpb.2006.03.009

European Journal of Pharmaceutics and Biopharmaceutics

Volume 64, Issue 1, August 2006, Pages 1-8

https://doi.org/10.1016/j.ejpb.2006.03.009 Get rights and content

Abstract

Transdermal drug delivery systems (TDDS), also known as “patches,” are dosage forms designed to deliver a therapeutically effective amount of drug across a patient’s skin. The adhesive of the transdermal drug delivery system is critical to the safety, efficacy and quality of the product. In the Drug Quality Reporting System (DQRS), the United States Food and Drug Administration (FDA) has received numerous reports of “adhesion lacking” for transdermal drug delivery systems. This article provides an overview of types of transdermals, their anatomy, the role of adhesion, the possible adhesion failure modes and how adhesion can be measured. Excerpts from FDA reports on the lack of adhesion of transdermal system products are presented. Pros and cons of in vitro techniques, such as peel adhesion, tack and shear strength, in vivo techniques used to evaluate adhesive properties are discussed. To see a decrease in “adhesion lacking” reports, adhesion needs to become an important design parameter and suitable methods need to be available to assess quality and in vivo performance. This article provides a framework for further discussion and scientific work to improve transdermal adhesive performance.

Introduction

Transdermal drug delivery systems (TDDS), also known as “patches,” are dosage forms designed to deliver a therapeutically effective amount of drug across a patient’s skin. Several TDDS containing drugs such as clonidine, estradiol, fentanyl, nicotine, nitroglycerin, oxybutynin and scopoloamine are available in the United States. In the Drug Quality Reporting System (DQRS), the United States Food and Drug Administration (FDA) has received numerous reports of “adhesion lacking” for transdermal drug delivery systems (see Table 1).

The adhesive of the TDDS is critical to the safety, efficacy and quality of the product. To begin with, the therapeutic effect of the drug is linked to the adhesive performance of the TDDS. Reduction in the surface area of contact as a result of patch lift, or even the patch falling off, diminishes the delivery of drug from the patch. In other words, poor adhesion results in improper dosing of patients. Secondly, patches that fail to adhere for their prescribed time period must be replaced more often, thereby increasing the patient’s cost. Thirdly, lack of adhesion is a safety issue. There is potential accidental dosing of children who may pick up fallen patches. Death and other serious medical problems have occurred when accidentally exposed to certain patches (e.g. transfer of a patch from an adult to a child while hugging, accidentally sitting or lying on a patch) [1], [2]. Many prescribing information sheets for TDDS state that adhesion has not been studied. This article provides an overview of the significance of the adhesive in a transdermal drug delivery system and the necessity for adhesion testing.

Section snippets

Types of TDDS

Broadly speaking, most commercially available TDDS (e.g. Catapres-TTS^®, Climara^®, Climara Pro^®, Combipatch^®, Duragesic^®, Menostar^®, Ortho Evra^®, Oxytrol^®, Transderm Scop^®, Vivelle^®, Vivelle-Dot^®) can be categorized as reservoir systems, matrix systems without a rate-controlling membrane or matrix systems with a rate-controlling membrane (see Fig. 1). Reservoir systems consist of three major components: the drug reservoir, the rate-controlling membrane and the adhesive. Typically, the drug

Release liner

During storage the patch is covered by a protective liner that is removed and discarded before the application of the patch to the skin. Since the liner is in intimate contact with the TDDS, the liner should be chemically inert.

Backing

Backings are chosen for appearance, flexibility and need for occlusion. Examples of backings are polyester film, polyethylene film and polyolefin film. Other considerations are the backing additives leaching out and diffusion of excipients, drug or enhancer through the

Role of adhesion in drug delivery

Adhesion or the lack of adhesion of transdermal systems to the skin is a critical factor directly related to drug delivery and therapeutic effect. Since the drug absorption process is related to the drug partition between the TDDS and the skin and the drug permeation process, complete skin contact over the entire delivery surface for the entire label application period is essential. If the TDDS lifts or partially detaches, the effective area of TDDS/skin contact, and thus the drug absorption,

Modes of failure in TDDS

Removal of the TDDS from a substrate (e.g. skin) involves the work done in the extension of the adhesive, in the distortion of the backing during the stripping action and in the separation of the adhesive/surface interface. When a TDDS is peeled away from a substrate, it can debond via different modes of failure. When the patch is peeled, it is expected that it will strip cleanly from the skin, leaving no visible residue [24]; this type of failure is an adhesive failure, Case I. If the adhesive

Techniques to measure adhesive properties

The adhesive performance of TDDS is a critical factor determining its drug delivery, therapeutic effect and patient compliance. Several in vitro techniques have been used to monitor adhesive performance such as peel adhesion, tack and shear strength. However, these tests were developed for industrial pressure sensitive tapes (see Table 2). Peel adhesion, tack and shear measurements are not true material properties of the adhesive since they depend on substrate, backing material and test

Conclusions

Currently, many of the clinical trials utilize placebo patches to determine the adhesion performance of new drug products [41], [42], [44], [45]. Use of placebo patches cannot be justified because the type and concentration of the drug, the compatibility of the drug with the TDDS components and the compatibility of the drug with the excipients may have an effect on the adhesive properties of the TDDS. Some patient instructions allow for taping of the edges of a patch that is lifting. It seems

References (45)

M.H. Qvist et al.
Release of chemical penetration enhancers from drug-in-adhesive transdermal patches
Int. J. Pharm.
(2002)
M.A. Repka et al.
Bioadhesive properties of hydroxypropylcellulose topical films produced by hot-melt extrusion
J. Control. Release
(2001)
R. Toddywala et al.
Evaluation of silicone-based pressure-sensitive adhesives for transdermal drug delivery. I. Effect of penetrant hydrophilicity
J. Control. Release
(1990)
M.A. Ashburn et al.
The pharmacokinetics of transdermal fentanyl delivered with and without controlled heat
J. Pain
(2003)
S.K. Gupta et al.
System functionality and physiochemical model of fentanyl transdermal system
J. Pain Symptom Manage.
(1992)
J.E. Riviere et al.
Potential and problems of developing transdermal patches for veterinary applications
Adv. Drug Delivery Rev.
(2001)
M.E. Ginn et al.
The contact angle of water on viable human skin
J. Colloid Interface Sci.
(1968)
J.H. Kim et al.
Effect of additives on the crystallization and the permeation of ketioprofen from adhesive matrix
Int. J. Pharm.
(2002)
D.G. Maillard-Salin et al.
Physical evaluation of a new patch made of a progestomimetic in a silicone matrix
Int. J. Pharm.
(2000)
R.D. Toddywala et al.
Effect of physicochemical properties of an adhesive on the release, skin permeation and adhesiveness of adhesive-type transdermal drug delivery systems (a-TDD) containing silicone-based pressure-sensitive adhesives
Int. J. Pharm.
(1991)

A.J. Steven-Fountain et al.

The effect of flexible substrates on pressure-sensitive adhesive performance

Int. J. Adhes. Adhes.

(2002)

R.A. Chivers

Easy removal of pressure sensitive adhesives for skin applications

Int. J. Adhes. Adhes.

(2001)

H. Rozenbaum et al.

Comparison of two estradiol transdermal systems (Oesclim^® 50 and Estraderm TTS^® 50). I. tolerability, adhesion and efficacy

Maturitas

(1996)

J.A. Erianne et al.

Comparison of the local tolerability and adhesion of a new matrix system (Menorest^®) for estradiol delivery with an established transdermal membrane system (Estraderm TTS^®)

Maturitas

(1997)

E. Gomez-Panzani et al.

Application and maintenance habits do make a difference in adhesion of Alora^® transdermal systems

Maturitas

(2000)

ISMP, Little patches … big problems, Institute for Safe Medication Practices: Medication Safety Alert!, 4(9) September...

Janssen, Dear Healthcare Professional letter, June (2005) <http://www.fda.gov/medwatch/SAFETY/2005/duragesic_ddl.pdf/>...

M. Lee et al.

Transdermal patches: high risk for error?

Drug Top.

(2002)

Janssen, Duragesic® (fentanyl transdermal system) full prescribing information, Titusville, NJ, May...

C.U. Ko, Effect of skin penetration enhancers in transdermal drug delivery adhesives on skin adhesion and irritation,...

P. Minghetti et al.

Evaluation of adhesive properties of patches based on acrylic matrices

Drug Dev. Ind. Pharm.

(1999)

T.S. Spencer et al.

Adhesive interactions between polymers and skin in transdermal delivery systems

Poly. Mater. Sci. Eng.

(1990)

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Published by Elsevier B.V.

Review articleTransdermal drug delivery system (TDDS) adhesion as a critical safety, efficacy and quality attribute

Abstract

Introduction

Section snippets

Types of TDDS

Release liner

Backing

Role of adhesion in drug delivery

Modes of failure in TDDS

Techniques to measure adhesive properties

Conclusions

Int. J. Pharm.

J. Control. Release

J. Control. Release

J. Pain

J. Pain Symptom Manage.

Adv. Drug Delivery Rev.

J. Colloid Interface Sci.

Int. J. Pharm.

Int. J. Pharm.

Int. J. Pharm.

Int. J. Adhes. Adhes.

Int. J. Adhes. Adhes.

Maturitas

Maturitas

Maturitas

Transdermal patches: high risk for error?

Drug Top.

Evaluation of adhesive properties of patches based on acrylic matrices

Drug Dev. Ind. Pharm.

Adhesive interactions between polymers and skin in transdermal delivery systems

Poly. Mater. Sci. Eng.

Review article
Transdermal drug delivery system (TDDS) adhesion as a critical safety, efficacy and quality attribute