european journal of pharmaceutical sciences 34 (2008) 203–222
Liposomes and skin: From drug delivery to model membranes
G.M. El Maghraby a,b, B.W. Barryc , A.C. Williams d,∗
a College of Pharmacy, King Saud University, Riyadh 11451, P.O. Box 2457, Saudi Arabia
b College of Pharmacy, University of Tanta, Tanta, Egypt
c Drug Delivery Group, School of Pharmacy, University of Bradford, Bradford BD7 1DP, UK
d School of Pharmacy, University of Reading, Whiteknights,
P.O. Box 224, Reading, Berkshire RG6 6AD, UK
Transdermal drug delivery offers many advantages over other traditional routes of administration. Unfortunately, the barrier nature of the skin presents a signifificant obstacle for most drugs to be delivered into and through it (Barry, 1983). Accordingly, researchers are investigating various strategies to overcome these barrier properties. Ideally, these investigations should employ human skin. However, samples of human skin of suffificient size and quality for penetration experiments are not readily accessible to most investigators and in any case are only available in limited amounts. Thus, many models have been explored to replace human tissue and this in itself is an active area of research. Liposomes have been claimed to serve both uses; they can improve transdermal drug delivery and can be used as a model for the skin membrane. This review deals with the potential of liposomes as a skin drug delivery system and on their use as a skin model.
2. Skin structure
The structure of the skin and its barrier functions have been extensively described in the literature (Scheuplein and Blank, 1971; Elias, 1981; Orland, 1983; Barry, 1983; Williams, 2003). The skin barrier in the healthy and diseased state has also been recently reviewed (Bouwstra and Ponec, 2006). Human skin comprises a series of layers penetrated by hair shafts and gland ducts (Fig. 1). The major skin layers, from inside to outside, comprise the fatty subcutaneous layer (hypodermis), the dermis of connective tissue and the stratifified avascular, cellular epidermis.
The dermis, at 3–5mm thick, is composed of fibrous proteins (collagen and elastin) and an interfibrillar gel of glycosaminoglycans, salts and water. Blood and lymphatic vessels, nerve endings, pilosebaceous units (hair follicles and sebaceous glands) and sweat glands are embedded within the dermis. The hair follicles and sweat ducts open directly into the environment at the skin surface and provide the so-called appendageal route of skin permeation (Barry, 1983; Bissett, 1987).
The epidermis contains no blood vessels so nutrients and waste products must diffuse across the dermal–epidermal junction to maintain its vitality. The epidermis consists of five layers, which from inside to outside are the stratum germinativum (basal layer), stratum spinosum (spinous layer), stratum granulosum (granular layer), stratum lucidum and stratum corneum (SC). Because the SC cells are dead, the epidermis without the SC is usually termed the viable epidermis (Barry, 1983; Bissett, 1987).
The SC is considered as the rate limiting barrier in transdermal permeation of most molecules (Barry, 1983). The SC comprises 15–20 layers of corneocytes and when dry it has a thickness of 10–15μm (Christophers and Kligman, 1964; Christophers, 1971). Upon hydration, the SC swells and its thickness can reach 40μm (Scheuplein, 1967). The structure of the SC is often depicted in the so-called bricks and mortar arrangement (Michaels et al., 1975), where the keratin-rich corneocytes (bricks) are embedded in the intercellular lipid-rich matrix (mortar). This arrangement is illustrated in Fig. 2.
For any molecules applied to the skin, two main routes of skin permeation have been defifined; the transappendageal and transepidermal pathways (Scheuplein, 1965). The transappendageal routes are also known as the shunt routes and include permeation through the sweat glands and across the hair follicles with their associated sebaceous glands. Recent studies have re-examined the long held assumption that the follicles occupy approximately 0.1% of the surface area of human skin (Scheuplein, 1967). Otberg et al. (2004) showed that follicular number, opening diameter and follicular volume are important considerations in drug delivery through these appendages and indeed the forehead provides13.7mm2/cm2 as the follicular infundibula, i.e. approximately 13.7% of the surface area of the forehead is available as follicles. Interestingly, the same study also showed that the historically held view of the follicles providing approximately 0.1% of the surface area of the stratum corneum appears to be valid for forearm skin.