Review
Novel mechanisms and devices to enable successful transdermal drug delivery

https://doi.org/10.1016/S0928-0987(01)00167-1Get rights and content

Abstract

Optimisation of drug delivery through human skin is important in modern therapy. This review considers drug–vehicle interactions (drug or prodrug selection, chemical potential control, ion pairs, coacervates and eutectic systems) and the role of vesicles and particles (liposomes, transfersomes, ethosomes, niosomes). We can modify the stratum corneum by hydration and chemical enhancers, or bypass or remove this tissue via microneedles, ablation and follicular delivery. Electrically assisted methods (ultrasound, iontophoresis, electroporation, magnetophoresis, photomechanical waves) show considerable promise. Of particular interest is the synergy between chemical enhancers, ultrasound, iontophoresis and electroporation.

Introduction

Recently, the transdermal route has vied with oral treatment as the most successful innovative research area in drug delivery. In the USA (the most important clinical market), out of 129 drug delivery candidate products under clinical evaluation, 51 are transdermal or dermal systems; 30% of 77 candidate products in preclinical development represent such drug delivery. The worldwide transdermal patch market approaches £2 billion, yet is based on only ten drugs — scopolamine (hyoscine), nitroglycerine, clonidine, estradiol (with and without norethisterone or levonorgestrel), testosterone, fentanyl and nicotine, with a lidocaine patch soon to be marketed. The fundamental reason for such few transdermal drugs is that highly impermeable human skin limits daily drug dosage, delivered from an acceptable sized patch, to about 10 mg. This review deals with ways to raise significantly this low limit for topical systems in general.

Section snippets

Drug transport through human skin

Human skin is an effective, selective barrier to chemical permeation (Barry, 1983). In general, the epidermis (specifically, the stratum corneum) provides the major control element — most small water-soluble non-electrolytes diffuse into the systemic circulation a thousand times more rapidly when the horny layer is absent. Thus, to maximise drug flux we usually try to reduce this barrier’s hindrance, although sometimes the follicular route may also be important. This review considers how

Routes of penetration

At the skin surface, molecules contact cellular debris, microorganisms, sebum and other materials, which negligibly affect permeation. The penetrant has three potential pathways to the viable tissue — through hair follicles with associated sebaceous glands, via sweat ducts, or across continuous stratum corneum between these appendages (Fig. 1).

Fractional appendageal area available for transport is only about 0.1%; this route usually contributes negligibly to steady state drug flux. The pathway

Optimising transdermal drug delivery

Fig. 3 summarises some ways for circumventing the stratum corneum barrier.

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