Approaches for breaking the barriers of drug permeation through transdermal drug delivery

Abstract

Transdermal drug delivery system (TDDS) utilizes the skin as executable route for drug administration but the foremost barrier against drug permeability is the stratum corneum and therefore, it limits therapeutic bioavailability of the bioactive. This review focuses on the recent advancements in the TDDS which include iontophoresis, sonophoresis, electroporation, microneedles, magnetophoresis, photomechanical waves and electron beam irradiation. These advancements are exhaustively discussed with techniques involved with their beneficial claims for different categories of bioactive. However, a lot of research has been carried out in TDDS, still the system has many pros and cons such as inconsistent drug release, prevention of burst release formulation and problems related to toxicity. In addition to that, to exploit the TDDS more efficiently scientists have worked on some combinational approaches for manufacturing TDDS viz., chemical–iontophoresis, chemical–electroporation, chemical–ultrasound, iontophoresis–ultrasound, electroporation–iontophoresis electroporation–ultrasound and pressure waves–chemicals and reported the synergistic effect of the same for safe, effective and practical use of TDDS. The present article covers all the above-mentioned aspects in detail and hence the article will assuredly serve as an enlightening tool for the visionaries working in the concerned area.

Introduction

Transdermal drug delivery system (TDDS) is an appealing alternative to minimize and avoid the limitations allied with oral and parenteral administration of drugs. Later delivery systems, suffer from certain restrictions like Peak and Valley phenomenon i.e. they exhibit fluctuations in plasma drug levels and do not render sustained effect [1] while the TDDS meets the requisitions and provides a proper and prolonged delivery of drug, in a steady-state profile and reduces the prospects of peak-associated side effects, and ensures that the level of the drug is above the minimal therapeutic concentration. Overall, as a form of controlled drug delivery, transdermal patches are extremely commodious, user-friendly and provides the ease of termination, if need arises (e.g. systemic toxicity) with less pain sensation while administrating drug candidates [2]. Transdermal delivery allows the permeation of drugs across the skin and into the systemic circulation thus avoiding the hepatic first-pass effect observed during oral administration and the inconvenience of frequent parenteral administration [3].

However, the penetration of drugs across the skin and their percutaneous delivery are limited by the barrier function of the enormously organized structure of Stratum corneum (SC) [4]. As we know that, the skin occupies about 15% of the total body weight of an adult and has a surface area of about 2 m². The skin is a multilayered organ composed of many histological layers generally described in terms of tissue layers i.e. the epidermis and the dermis [5] as shown in (Fig. 1). Epidermis, composed of keratinocyte (95% of cells) which is the principal cell forms a ‘brick and mortar’ structure that has been used to conceptualize the barrier property of skin inclusion melanocytes, langerhans cells and merkel cells (minor components). These cells proliferate and commit daughter cells to terminal differentiation, which ends in the formation of the SC [6]. The corneocytes of hydrated keratin comprise the ‘bricks’, embedded in a ‘mortar’ composed of multiple lipid bilayers of ceramides, fatty acids, cholesterol and cholesterol esters. These bilayers form regions of semi crystalline gel and liquid crystal domains [7]. The second layer beneath the epidermal layer is dermis which is much thicker than the epidermis (usually 1–4 mm). The main components of the dermis are collagen and elastic fibers. Compared to the epidermis, there are much fewer cells and much more fibers in the dermis [8]. TDDS or skin patch is used for the delivery of a controlled dose of a drug through the skin over a period of time [9], [10].

The components of TDDS are liners, adherents, drug reservoirs, drug release membrane etc. [11] that play an imperative role in the release of the drug through the skin as shown in (Fig. 2). It is considered that a well-designed TDDS can supply the drug at a rate, to sustain the required therapeutic plasma concentration without much fluctuation that may cause basic manifestation or therapeutic inefficacy [12]. Lag times to reach steady state fluxes are in hours as the transport of most drugs across the skin is very slow. Attainment of a therapeutically effective drug level is, therefore, difficult without enhancing skin permeation. Consequently, there has been intensive study of strategies to undermine, in a controlled and reversible fashion, the permeability barrier of the SC [13]. A number of techniques have been developed to enhance and control transport across the skin, and enlarge the range of drugs delivered. These involve chemical and physical methods, based on two strategies: increasing skin permeability and/or providing driving force acting on the drug [14]. There have been many ingenious technologies developed to enhance TDDS for therapeutic and diagnostic purposes ranging from chemical enhancers to iontophoresis, electroporation, and pressure waves generated by ultrasound effects or the synergistic mixtures of both the mechanism [15]. The transdermal route has become a most accepted and innovative spotlight for researchers in drug delivery which is proved in quantitative research with around 40% of the drug moiety being under clinical evaluation and also approved by FDA (Food and Drug Administration). The transdermal product has foreseeable future because of its noteworthy upward trend. The TDDS products have continued to provide bona fide therapeutic benefits to patients around the world. In the year 2005, the global market for drug delivery systems was $12.7 B and is projected to be $32 B by 2015 [16]. The fate of effectiveness of TDD system lies on the drug's ability to invade the skin barrier and how its reaches the targeted site [17].

There are many factors which affect the penetration through the skin namely; species differences, skin age and site, skin temperature, state of the skin (normal, abraded, or diseased), area of application, contact time, degree of hydration of the skin, pretreatment of the skin, and physical characteristics of the penetrant. The mechanism of drug penetration through the skin primarily and diffusion is, concentration dependent [18]. Majorly the molecules permeate across the SC by intercellular, intracellular (transcellular) and follicular (appendage) pathways. As per the Elias scheme, SC assumes a structural picture of the two-compartment model [19] as shown in (Fig. 3).