Transdermal patches: history, development and pharmacology

Abstract

Transdermal patches are now widely used as cosmetic, topical and transdermal delivery systems. These patches represent a key outcome from the growth in skin science, technology and expertise developed through trial and error, clinical observation and evidence-based studies that date back to the first existing human records. This review begins with the earliest topical therapies and traces topical delivery to the present-day transdermal patches, describing along the way the initial trials, devices and drug delivery systems that underpin current transdermal patches and their actives. This is followed by consideration of the evolution in the various patch designs and their limitations as well as requirements for actives to be used for transdermal delivery. The properties of and issues associated with the use of currently marketed products, such as variability, safety and regulatory aspects, are then described. The review concludes by examining future prospects for transdermal patches and drug delivery systems, such as the combination of active delivery systems with patches, minimally invasive microneedle patches and cutaneous solutions, including metered-dose systems.

Figure 1

Historical development of patches. Early topical products: (A) products from ancient times; (B) Galen's cold cream; (C) mercurial ointment; (D) mustard and belladonna plasters; controlled dosing of topical products. (E) First quantitative systemic delivery (Zondek's system). (F) Individualized delivery system: nitroglycerin ointment. (G) Topical delivery device (Wurster & Kramer's system). Passive non-invasive patches. (H) First patch system – the reservoir – introduced for scopolamine, nitroglycerin, clonidine and oestradiol. (I, J, K) Other types of patches – matrix and drug-in-adhesive (e.g. fentanyl and nicotine patches). Next-generation patches. (L) Cutaneous solutions (e.g. Patchless Patch®, Evamist®). (M) Active patches (e.g. iontophoresis, Zecuity®). (N) Minimally invasive patches (e.g. microneedles, Nanopatch®).

Figure 2

Manufacturing process for and potential failures of reservoir patches: (A) form-filling and sealing process; (B) coating and drying process; and (C) potential problems arising during patch reservoir manufacturing process.

Figure 3

Evolution of commercial topical and transdermal patches – transdermal reservoir: originator, generic; transdermal matrix: originator, generic; transdermal active in adhesive only: originator, generic; topical patches; transdermal next generation; topical next generation.

Figure 4

Transdermal delivery rate for currently marketed drugs in patches (log scale) (with symbol size being used to show the actual variation in molecular weight: 100 < MW < 200 Da; 200 ≤ MW < 300 Da; MW ≥ 300 Da) plotted against the active drug melting point (where unknown melting point given by an asterisk is represented as liquid at 25°C) and overlaid on the Berner–Cooper nomogram for a drug with a log P of 5 (Kydonieus et al., 1999). Also shown, as dashed black lines, are the estimated upper and lower boundary lines for marketed drug delivery rate from patches as defined by the rates for small (MW = 100), polar (log P = 1) and large (MW = 500), lipophilic (log P = 5) solutes respectively. [The dashed black lines are calculated from the expression: log maximum delivery rate (μg·cm⁻²·h⁻¹) = 1.6 + log MW − 0.0086 MW − 0.01 (MP − 25) − 0.219 log P and is based on a regression of maximum transdermal flux (in nmol, equation 7) versus MP, MW and log P for the combined data set of Magnusson et al. (2004) (Milewski and Stinchcomb, 2012). The level region in this plot recognises that 25°C is an approximate lower skin surface temperature for patches applied to human skin in vivo and at which all drugs with MP < 25°C will be liquid.]

Figure 5

Typical active plasma concentration profile after patch application showing the lag-time, reaching and achieving steady-state, depletion and patch removal as well as the corresponding profile for repeated p.o. dosing of the same active.