Introduction

Skin is the major organ of the human body that serves as a unique and ultimate interface between the body and the external environment. It has been extensively investigated for drug delivery due to its easy accessibility and large surface area. As a drug administration route, skin has mainly been utilized for topical (dermal) delivery where a drug is localized in skin layers, or transdermal delivery where a drug passes through the skin and reaches blood circulation (Neubert 2011). Transdermal drug delivery has several advantages over conventional routes of administration. The key benefits of transdermal drug delivery are convenience, better patient compliance, noninvasiveness, low cost, and an easily accessible and large skin surface area for drug absorption. This type of delivery also permits bypassing the first pass metabolism thereby improving drug’s bioavailability, circumventing the factors associated with variable drug absorption in the gastrointestinal tract (influence of pH, food, enzymes, GI motility), eschewing serious side effects of drugs, providing lower fluctuations in drug plasma levels, and abstaining patient phobia, risk factors and inconvenience associated with parenteral delivery (Barry 2004; Ranade and Cannon 2011). However, transdermal delivery of drugs has certain limitations too. The major one is the excellent barrier property of the outermost layer of skin, the “stratum corneum” which resists most of drug molecules to pass through it (Barry 1983; El Maghraby et al. 2001). Therefore, the stringent physicochemical conditions such as molecular weight, partition coefficient, lipophilicity and ionization imposed by this route restricts its use to only a few drugs with a specific set of properties (Khan et al. 2015; Prausnitz et al. 2004). The principal aim of this review is to describe in detail the hurdles associated with efficient skin delivery and to present the most promising types of nanoparticulate carriers and their applications in overcoming the skin barrier for drug delivery.

Skin structure

Skin is the largest organ of the human body, making up about 15% of total body mass with a surface area of about 2 m2 (Hadgraft 2001; Kanitakis 2002). It represents a primary barrier between the body and the external environment (Hadgraft 2004). It functions to protect the body against external elements, maintain homeostasis and perform sensory role (Kenneth and Michael 2002). Skin structure is composed of three layers: the epidermis, dermis and hypodermis (Kenneth and Michael 2002) and associated appendages including the hair follicles, sebaceous glands, sweat glands and nails (Barry 2001; Rosen 2005). A diagrammatic illustration of skin structure is presented in Fig. 1a.

Fig. 1
figure 1

Diagrammatic illustration of a skin’s structure and b routes of drug permeation through the skin

Full size image

The epidermis is the topmost, 50–100 µm thick layer of skin that separates the interior of the human body from the outer milieu. It consists of keratinocytes, which are specialized epithelial cells producing keratin, and is regularly renewed through the process of desquamation and cell growth (Khan et al. 2015). The epidermis is an avascular layer and is conveniently divided (from top to bottom) into the stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum and stratum basale. These epidermal layers show different levels of keratinocyte differentiation. Keratinocytes in the stratum basale are single layered, columnar shaped and mitotically active, while the topmost 15–20 layers of polygonal shaped, fully differentiated, dead and non-nucleated keratinocytes (now known as corneocytes) form the least permeable “stratum corneum” of the skin (Christophers 1971; Menon 2002). Corneocytes are embedded in a matrix of lipid bilayers mainly consisting of ceramides, cholesterol, free fatty acids, triglycerides, cholesterol sulfate and sterol (Bouwstra and Ponec 2006). A 10–15 µm thick stratum corneum is made up of about 5–15% lipids and 75–85% proteins on a dry weight basis (Pegoraro et al. 2012).

The dermis is a 3–5 mm thick layer beneath the epidermis, comprising of a network of collagen and elastin fibers with an interfibrillar gel of glycosaminoglycans, salts and water (El Maghraby et al. 2008). The dermis supplies nutrition and provides a structural support to the skin as well as shelters a number of structures including blood vessels, lymph vessels, hair follicles, sweat and sebaceous glands, sense receptors and nerve endings (Cevc et al. 1996; Cevc and Vierl 2010). The hypodermis is the deepest layer of skin comprising of adipose and loose connective tissues that functions as an insulator and shock absorber (Pegoraro et al. 2012).

Drug permeation pathways through the skin

The stratum corneum represents the principal permeability barrier that controls drug transport across the skin (Scheuplein 1976). Drug transport via skin mainly occurs by two macro diffusional routes (Fig. 1b), namely trans-epidermal and trans-appendageal pathways (Hadgraft 2001; Trommer and Neubert 2006).

Trans-epidermal transport implies the transport of drugs via an intact stratum corneum and includes transcellular and intercellular micro routes. Transcellular transport involves the passage of drugs through a relatively hydrophilic environment of corneocytes followed by passage via the highly lipophilic intercellular lipid matrix (Trommer and Neubert 2006). Although it offers the shortest route and is predominantly favored for the transport of hydrophilic molecules, such drugs are also required to pass through the intercellular hydrophobic domain (Benson 2006). The intercellular route of drug transport offers a continuous and tortuous pathway through the lipophilic matrix between the corneocytes. The intercellular route is regarded as the main route of drug transport for small, uncharged and lipophilic molecules (Johnson et al. 1997). Drug transport through the skin’s appendages including the sweat glands, hair follicles and sebaceous glands constitutes the trans-appendageal or “shunt” route. It offers a highly permeable and continuous conduit directly across the stratum corneum. However, it is responsible for a very low contribution in overall drug transport via skin as appendages occupy only 0.1% of the skin’s total area (Barry 2002; Moser et al. 2001). The shunt route is of relative importance for the passage of ions and large polar molecules through hair follicles (Barry 2002; Scheuplein 1965). In a particular transport, more than one of these pathways might be contributing simultaneously with the relative importance of any route being dictated by the physicochemical properties of that permeant (El Maghraby et al. 2008).

Nanoparticulate carriers for skin delivery

In the past few decades, nanoparticulate carriers have been the focus of great attention across a broad range of fields including pharmaceutical technology. In the context of drug delivery, nanoparticulate carriers generally refer to colloidal particulate systems with a size range below 500 nm (Neubert 2011). Nanoparticulate carriers can be utilized to alter the physicochemical properties of drugs and their interactions with physiological systems. Application of nanoparticulate carriers for skin delivery is especially important because it not only circumvents the limitations of conventional delivery systems but also enhances the skin permeation of drugs (Uchechi et al. 2014). Nanoparticulate carriers can improve drug transport across the skin by ensuring direct contact with the stratum corneum and skin appendages, controlling drug release, increasing contact time with the skin and protecting drugs against physical and chemical instabilities (Contri et al. 2011). The permeation of drugs after incorporation into nanoparticulate carriers is controlled by the physicochemical properties of the carriers such as the composition, method of preparation, particle size, particle shape, surface charge and flexibility. The skin permeation potential of some promising nanoparticulate carriers is described in this section along with a summary of studies showing improved drug delivery through various skin models (Tables 1, 2, 3, 4, 5).

Table 1 Summary of representative studies using conventional liposomes for skin drug delivery
Full size table
Table 2 Applications of deformable liposomes to drug delivery through skin
Full size table
Table 3 Summary of studies investigating the potential of ethosomes for skin drug delivery
Full size table
Table 4 Summary of reported studies applying niosomes to skin drug delivery
Full size table
Table 5 Applications of solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) for improving skin drug delivery
Full size table

Conventional liposomes

Liposomes are hollow, self-enclosing lipid colloidal particles arranged in a bilayer confirmation surrounding an aqueous volume as illustrated in Fig. 2a (El Maghraby et al. 2006). Phospholipids, usually egg yolk or soy phosphatidylcholine, are the main constituents of conventional liposomes, while the addition of cholesterol in lipid bilayers increases the stability and rigidity of bilayer membranes (Elsayed et al. 2007). The hydro-soluble molecules find their place in the central aqueous core and the aqueous phase between the lipid bilayers, while the lipid soluble molecules are incorporated into one or more concentric lipid bilayers via hydrophobic interactions (Honeywell-Nguyen and Bouwstra 2005). Since their development in the 1960s by Alec Bangham, conventional liposomes have gained widespread attention in drug delivery and biomedical applications (Torchilin 2005). In the last two decades, a number of liposomal products and technologies have received approval for practical use. The clinical applications of liposomal drug delivery are well-recognized with a number of drug products available in the market or under clinical trials. Recently, a number of advancements have been made in basic liposomes structure aimed to reduce problems with liposomal drug delivery and to incorporate attractive features to liposomal delivery. A few examples of these developments include long circulatory liposomes, immuno-liposomes, targeted liposomes and pH-sensitive liposomes (Torchilin 2005).

Fig. 2
figure 2

Structure of a conventional liposomes, b deformable liposomes, c ethosomes, d niosomes and e lipid nanoparticles

Full size image

Conventional liposomes for skin delivery and the mechanisms of permeation

As a pharmaceutical nanocarrier, liposomes were first investigated for skin drug delivery in the 1980s where lotion incorporating liposomal triamcinolone acetonide had a greater deposition of drug in skin layers compared with the conventional dosage form (Mezei and Gulasekharam 1980). Since the first report, a large number of contradictory results have been published regarding the effectiveness of conventional liposomes in improving the skin permeation of drugs. Most of the published data supports the hypothesis that conventional liposomes only enhance drug deposition in the upper skin layers with little effect on skin permeation into blood circulation (Honeywell-Nguyen and Bouwstra 2005). Numerous mechanisms have been proposed for the skin penetration of conventional liposomes including free drug mechanism where drug penetrate the skin solitary after it is released from the vesicles, penetration enhancement mechanism whereby the liposomes disrupt the intercellular lipids of the stratum corneum by acting as a permeation enhancer and hence facilitating drug permeation via a structurally compromised skin barrier, vesicles absorption and fusion with the stratum corneum where the vesicles adsorb onto the stratum corneum thereby transferring their payload directly to the skin or fusing with lipids of the stratum corneum to enhance partitioning of the drug in skin and the intact vesicle penetration mechanism where the liposomes penetrate the skin in intact form by compromising its structural integrity (Elsayed et al. 2007).

Factors affecting the skin delivery of conventional liposomes

A number of factors including the liposomal size, surface charge, lamellarity, lipid composition and thermodynamic state of the lipid bilayers have been reported to affect skin drug delivery of conventional liposomes (Elsayed et al. 2007). Kitagawa and Kasamaki (2006) compared the effect of neutral liposomes [egg yolk phosphatidylcholine (egg yolk PC) liposomes] and cationic liposomes [1,2-dioleoyl-3-trimethylammonium propane (DOTAP) liposomes] on the skin delivery of retinoic acid in excised guinea pig skin. Egg yolk PC liposomes were two times more effective in increasing the skin delivery of retinoic acid than its solution in isopropyl myristate. Moreover, cationic DOTAP liposomes were 3.7-fold more effective in the skin delivery of retinoic acid compared with their neutral counterparts without DOTAP. It was concluded from the study that the surface charge of liposomes has an effect on the skin deposition and permeation of drugs. Similarly, Park et al. (2014a) studied the effect of liposome’s zeta potential on the skin permeation of resveratrol. The study aimed to investigate enhanced transdermal delivery of resveratrol via chitosan-coated liposomes. The skin permeation of resveratrol from 0.1% chitosan-coated egg PC liposomes (zeta potential + 26.5 mV) was found to be 126.93 µg/cm2 (40.4%) compared with 96.85 µg/cm2 (30.8%) with uncoated liposomes (zeta potential − 9.4 mV). The enhanced skin permeation of chitosan-coated liposomes was attributed to the stronger interaction between the negatively charged lipids of the stratum corneum with the positively charged liposomes.

The lipid composition (liquid-state or gel-state phospholipids) of liposomes also affects skin drug delivery. In a study, the influence of the fluidity of phospholipids on the skin permeation of liposomes was investigated (Perez-Cullell et al. 2000). Skin penetration of sodium fluorescein from liposomes prepared with unsaturated phosphatidylcholine (PC) and saturated, hydrogenated phosphatidylcholine (HPC) were compared. The ability of unsaturated PC liposomes to penetrate the skin was observed to be higher than those prepared with HPC due to the existence of PC in a liquid-state at the operating temperature of the study compared with the gel-state of HPC liposomes. The gel-state of phospholipids in the vesicles render them rigid and reduce their penetrability across the skin. In another study, Sinico et al. (2005) reported that unilamellar vesicles (ULVs) resulted in a higher amount of tretinoin deposited in a newborn pig skin after 9 h than those of multilamellar vesicles (MLVs) in both positive (23.5 vs. 13.5 µg) and negatively charged vesicles (32.7 vs. 30.4 µg).

Deformable liposomes

Deformable liposomes were introduced for the first time in 1992 and were designed to improve the skin permeation of drug-loaded lipid vesicles across skin (Cevc and Blume 1992). This newer class of liposomes was firstly named Transfersomes® and is a proprietary technology of the Germany-based company, IDEA AG. Later on, the terms ultradeformable, elastic and ultraflexible liposomes emerged to represent these vesicles. This is a newer domain of liposomes with properties of pliability or deformability due to the presence of surfactant or “edge activator” along with double chain phospholipids (Fig. 2b), which makes them different from conventional liposomes in terms of composition (El Maghraby et al. 1999; Trotta et al. 2004). Deformable liposomes have the ability to preserve their structural integrity during passage through the tightest junctions of skin and carry their payload into systemic circulation. The function of the edge activator in deformable liposomes is to destabilize the lipid bilayer thereby increasing the deformability of the vesicle and enhancing their penetration through the skin (Gillet et al. 2011). The usual composition of deformable liposomes consists of phospholipid (70–95%) and edge activator (5–30%) such as the bile salts of cholic acids, Tweens, Spans, and dipotassium glycyrrhizinate (Benson 2006). For effective skin permeation, deformable liposomes are applied under non-occlusive conditions on the skin. Increased in vitro skin delivery and in vivo penetration is reported for a number of drugs utilizing deformable liposomes as they are capable of permeating through skin as intact vesicles (Cevc et al. 2002).

Deformable liposomes for skin delivery and the mechanisms of permeation

Deformable liposomes have the ability to squeeze themselves through pores much smaller than their own diameter. This unique capability is attributed to their inherent property of deforming and adapting their shape under stressful conditions such as increased pressure or a dry surface, thereby reaching the deeper skin unfragmented (Cevc et al. 2002). Application of deformable liposomes on a skin surface under non-occlusive condition provides them with the opportunity to follow an osmotic gradient between a relatively dry stratum corneum and hydrated viable epidermis (Cevc and Blume 1992). An occlusive application eliminates the deformable action by disrupting the osmotic gradient and hence demolishing the driving force to transport these vesicles across the skin. Contrary to deformable liposomes, rigid phospholipid bilayers of conventional liposomes confine them to the upper skin layer with diminished skin permeation (El Maghraby et al. 2008). Deformability and shape transformation in deformable liposomes are due to the incorporation of the edge activator, which causes local readjustments of the components of the lipid bilayer (Fig. 3). Exposure of deformable liposomes to space confinement or mechanical stress results in repositioning of the edge activator in zones of higher curvature and phospholipids in zones of smaller curvature. This repositioning brings about a reduction in the elastic energy of the lipid bilayers of vesicles and allows deformable liposomes to transform their shapes at much lower energy (Cevc 2012; Perez et al. 2016). Furthermore, it has also been proposed that deformable liposomes interact with the intercellular lipids of the stratum corneum to destabilize them and thereby produce a permeation enhancement effect (Elsayed et al. 2006). Combined together, deformable liposomes have enhanced the skin permeation of a number of drugs, irrespective of the mechanism of transport across skin.

Fig. 3
figure 3

Mechanism of deformable liposomes permeation through the skin

Full size image

Factors affecting the skin delivery of deformable liposomes

Factors that can influence the skin permeation of deformable liposomes include the type and amount of edge activator, fluidity and particle size. It has been reported that an increase in the concentration of the edge activator up to 15% resulted in an increase in the elasticity of the vesicles, while a further increase in concentration decreased the flexibility due to the formation of less deformable micellar structures along with the bilayer vesicles (Chaudhary et al. 2013). Similarly, the type of edge activator also has an influence on the skin permeation of deformable liposomes. Tween 80-incorporated deformable liposomes exhibited higher cumulative permeation and flux (470 µg and 20.2 µg/cm2/h) after 24 h than those of deformable liposomes containing sodium cholate (406 µg and 17.4 µg/cm2/h) as an edge activator (Zeb et al. 2016). The difference in the permeation profiles was attributed to their chemical structures, which in turn affect the deformability indices of deformable liposomes and permeation across skin. Verma et al. (2003) investigated the effect of particle size of deformable liposomes on the penetration of a hydrophilic dye (carboxyfluorescein, CF) into and across human skin. Smaller vesicles with a particle size of 120 nm resulted in a higher amount of CF accumulated in the stratum corneum (72.9%) than those with larger vesicles of 191 nm (65.2%), 377 nm (61.2%) and 810 nm (39.9%). The amount of CF accumulated by the smaller vesicles (120 nm) in the deeper layers was also enhanced by 4.68-, 7.29- and 33.57-fold compared with larger vesicles (191, 377 and 810 nm), respectively. The amount of CF permeated across the skin into the receptor fluid exhibited a similar trend. Particle size had similar effect on the penetration of a lipophilic dye in the same study. In another study, liposomal fluidity was reported to have an increasing effect on the skin penetration of entrapped dye (Subongkot and Ngawhirunpat 2015).

Ethosomes

Ethosomes are fluidic lipid vesicles containing a higher concentration of ethanol with the potential for transdermal drug delivery (Touitou et al. 2000a). Ethosomes were first introduced by Touitou and coworkers for enhancing skin delivery of drugs and are composed of 2–5% phospholipid, 20–45% ethanol and water up to 100% (Touitou 1996). The structure of ethosome is illustrated in Fig. 2c. The incorporation of ethanol makes them soft and pliable colloidal carriers with unilamellar or multilamellar structure and concentric phospholipid bilayers surrounding an aqueous phase and entrapped drugs (Mbah et al. 2014). The function of ethanol is to impart membrane flexibility to ethosomes as that of the edge activator in deformable liposomes and confers 10-times more flexibility by fluidizing their lipid bilayers (Godin and Touitou 2003). It has been proposed that phospholipids form closed bilayer vesicles in up to 45% of ethanol; however, concentrations above 45% may solubilize the phospholipid contents (Romero and Morilla 2013). Ethosomal vesicles have a particle size much smaller than conventional liposomes and the presence of high ethanol contents makes their size independent of phospholipid concentration. It was reported that the particle size of ethosomes decreased from 193 to 103 nm as the concentration of ethanol was increased from 20 to 45%. In contrast, the increase in phospholipid concentration from 0.5 to 4% (eight-fold increase) increased the particle size from 118 to 249 nm (only two-fold), indicating the limited dependence of particle size on phospholipid concentration (Touitou et al. 2000a). In another study, increasing phospholipid concentration from 1 to 3% (w/v) at 45% (v/v) ethanol content brought about a very small increase in particle size from 111 to 143 nm (Dubey et al. 2007a). The smaller particle diameter of the ethosomal vesicles is due to the presence of a high quantity of ethanol with a resultant negative zeta potential (Lopez-Pinto et al. 2005). Ethosomes have been shown to increase the delivery of a number of hydrophilic and hydrophobic drugs into deeper layers of skin and to systemic circulation compared to conventional liposomes, ethanol, hydro-ethanolic solution and ethanolic phospholipid solution. In contrary to deformable liposomes, ethosomes can be applied occlusively in the form of patches where particle size and its distribution remains constant for up to 2 years (Touitou et al. 2000b).

Ethosomes for skin delivery and the mechanisms of permeation

Ethosomes possess malleable and less tightly packed phospholipid bilayer membranes due to the presence of ethanol and have superior skin permeation compared to conventional liposomes. The enhanced drug delivery via ethosomes is attributed to the cumulative effects of vesicles pliability, the fluidization effect of ethanol on stratum corneum lipids and vesicle membranes, a smaller vesicle diameter and the facilitated interaction of ethosomal vesicles with stratum corneum components (Touitou et al. 2000a). Ethanol has been used as an effective skin permeation enhancer to disrupt lipid organization in the stratum corneum and extract its lipidic layers with a subsequent reduction in lipid density and the skin’s impermeability towards the permeants (Barry 2001). The fluidization of lipid bilayers in the stratum corneum by ethanol makes it easy for small and malleable ethosomes to penetrate into the deeper skin layers (Mbah et al. 2014). In comparison to the structural adaptability mechanism of deformable liposomes, ethosomes mainly enhance drug permeation by interacting and disrupting the lipophilic barrier of skin (Van der Merwe and Riviere 2005). The capability of ethosomes to transport their payload to and through the skin has been widely investigated and found to be much greater than conventional liposomes, which remained in the upper layers of skin (Touitou et al. 2001).

Factors affecting the skin delivery of ethosomes

The skin permeation capacity of ethosomes is governed by ethanol concentration, vesicular size, phospholipid and cholesterol content. Ethanol binds to the polar heads of lipids thereby lowering the melting point of lipids in the stratum corneum and enhancing membrane fluidity and penetrability (Harris et al. 1987). On increasing ethanol concentration from 15 to 45%, the vesicular elasticity and skin permeation flux of drugs from ethosomes was reported to be increased from 20.3 to 38.6 and 24.8 to 68.4 µg/cm2/h, respectively (Jain et al. 2007). The increased skin permeation of drug was ascribed to a significantly reduced particle size at 45% ethanol content and higher membrane elasticity compared to ethosomes with 15% ethanol. However, the transdermal flux was reduced to 12.5 µg/cm2/h with a further increase in ethanol to 60% due to membrane solubilizing and the deteriorating effects of ethanol at higher concentrations. The addition of cholesterol in the lipid bilayers of ethosomes increases membrane rigidity and particle size, resulting in low deformability and skin permeation (Jain et al. 2007; Lopez-Pinto et al. 2005). In another study, variation in the amount of phospholipid did not show any significantly effect on the transdermal flux of ketoprofen (Chourasia et al. 2011). Transdermal flux was reduced from 207 to 192 µg/cm2/h by increasing phospholipid concentration from 1 to 3%, indicating a non-significant influence. Taking these factors together, the overall composition of ethosomes contributes to the interaction of these vesicles with stratum corneum lipids and transport into and across the skin with ethanol being the most influential factor (Dayan and Touitou 2000).

Niosomes

Niosomes are nanosized colloidal vesicular structures formed by the self-assembly of non-ionic surfactants in an aqueous environment resulting in a bilayer configuration (Uchegbu and Vyas 1998). Non-ionic surfactants form a bilayer configuration by orienting their polar groups towards water and nonpolar groups facing each other (Fig. 2d). This vesicular morphology allow niosomes to accommodate hydrophilic drugs in aqueous volumes and lipophilic drugs in bilayer domains (Moghassemi and Hadjizadeh 2014). Some commonly used non-ionic surfactants include alkyl ethers, alkyl amides, alkyl esters, alkyl glyceryl ethers and esters of fatty acids (Kumar and Rajeshwarrao 2011). Non-ionic surfactants are preferred as they have less potential to cause irritation compared with their cationic and anionic counterparts (Moghassemi and Hadjizadeh 2014). Niosomal vesicles are either unilamellar or multi-lamellar in structure and have similar physical properties and preparation methods as those of conventional liposomes. Drug encapsulation efficiency and the formation of vesicles is dependent on the HLB value of surfactants. Surfactants with HLB values of 4–8 form vesicular structures, while surfactants with high HLB values (14–17) are not suitable for niosomes production as their high aqueous solubility hinder the association of freely hydrated surfactant into a lamellar structure (Marianecci et al. 2014). The first niosomal vesicular system based on the hydration of single alkyl chain non-ionic surfactant with cholesterol was reported in 1979 for cosmetic application (Handjani-Vila et al. 1979). Later on, niosomes received great attention for drug delivery applications compared to liposomal vesicles because of their advantages such as low cost, superior chemical stability, and easy scale up and large scale production (Alsarra et al. 2005). Niosomes have been successfully utilized for drug delivery to various organs such as the skin, liver, lungs, brain, tumor organs and ocular systems (Hamishehkar et al. 2013).

Niosomes for skin delivery and the mechanisms of permeation

Niosomes have the potential for skin delivery of drugs for a number of attractive reasons including increased skin permeation, sustained drug release via local depot and controlling systemic drug absorption through the skin (Muzzalupo and Tavano 2015). The skin deposition and permeation of a number of drugs have been enhanced by using niosomal vesicles. A number of mechanisms have been proposed for enhanced drug transfer into and across the skin by niosomes. Niosomal vesicles may act as a permeation enhancer to disrupt the intercellular organization of lipids in the stratum corneum, making the lipid barrier permeable (Fang et al. 2001). Adhesion and fusion of niosomes on a skin surface creates a high thermodynamic activity gradient of drugs at the niosome-stratum corneum interface, providing a driving force for enhanced permeation of drugs (Mali et al. 2013). Reduction of transepidermal water loss to increase skin hydration, diffusion of intact niosomes across the skin and reformation of niosomes into smaller vesicles are some alternative proposed mechanisms to explain the enhanced skin permeation of niosomes (Muzzalupo and Tavano 2015). Furthermore, the permeation enhancing effects of non-ionic surfactants themselves might also contribute to the enhanced skin permeation of niosomal vesicles (Javadzadeh et al. 2010).

Factors affecting the skin delivery of niosomes

There are certain factors that might influence the formation, performance and hence permeation of niosomes through the stratum corneum. Some of these factors include the type of surfactant used, phase transition temperature of the surfactant, particle size of the niosomes, cholesterol content, encapsulation efficiency of the drug, presence of a solubilizer and HLB value of the surfactant. Non-ionic surfactants producing steric hindrance and electrostatic repulsion are desirable for the preparation of niosomes to prevent vesicle aggregation, as particle agglomerates of a larger size cannot permeate through the narrow channels of corneocytes (Solanki et al. 2010). It has also been suggested that surfactants with low phase transition temperatures produce vesicles with more flexible membranes and hence show better skin penetration than those formed from high phase transition temperature surfactants (Uchegbu and Vyas 1998). Smaller niosomal vesicles have shown better skin penetration than larger vesicles. In a study, Span 20 and Span 40 niosomes (214–252 nm) showed higher skin deposition of minoxidil compared to Brij 52 and Span 60 niosomes (1160–1240 nm), which was attributed to the smaller particle size and low phase transition temperatures of Span 20 and Span 40 (Balakrishnan et al. 2009). Cholesterol contents affect the structure, physical properties and elasticity of the niosomal membrane, which in turn affects the skin permeation of drugs. Higher cholesterol content produces a rigid vesicle, which reduces skin penetration (Balakrishnan et al. 2009; Liu et al. 2000). Higher entrapment efficiency of drug and the addition of solubilizers such as propylene glycol and polyethylene glycol 400 in niosomes have been reported to enhance skin penetration of drugs (Junyaprasert et al. 2012). The HLB values of surfactants also influence the physiochemical characteristics and skin permeation of niosomes. The percutaneous permeation of Span 80 niosomes was superior compared to those of Tween 80 niosomes due to its lower HLB value and better interaction with stratum corneum lipids. Furthermore, a proper balance between hydrophilic and hydrophobic surfactants was suggested for optimal performance of niosomes (Tavano et al. 2011).

Lipid nanoparticles

Solid lipid nanoparticles were introduced as first generation lipid nanoparticles in the early 1990s as alternative nanocarriers to liposomes, emulsions and polymeric nanoparticles (Muller et al. 1995). These colloidal carriers provide a highly lipophilic matrix for controlled drug release by restricting their mobility (Müller et al. 2000; Qureshi et al. 2017). Solid lipid nanoparticles are composed of solid lipids such as mono-, di- and triglycerides, fatty acids, steroids and waxes (Uner and Yener 2007). Surfactants including polaxamers, polysorbates and phospholipids have been utilized to provide steric stabilization to solid lipid nanoparticles (Zeb et al. 2017a). A diagrammatic illustration of a lipid nanoparticles composed of lipid matrix and surfactant shell is presented in Fig. 2e. With advantages of industrial large scale production, a sustained release effect, improved bioavailability and in vivo tolerability, solid lipid nanoparticles have been used as a potential colloidal carrier system for delivering active pharmaceutical ingredients to the brain, lungs, nose and skin (Din et al. 2017; Mehnert and Mäder 2012; Müller et al. 2000). The second generation of lipid nanoparticles, known as nanostructured lipid carriers, were introduced to overcome the drawbacks of drug leakage from solid lipid nanoparticles during storage (Wissing et al. 2004; Zeb et al. 2017a). Nanostructured lipid carriers contain oily nano-compartments in a solid lipid matrix (Han et al. 2008). The increased solubility of drug in a mixture of solid and liquid lipids significantly enhances drug encapsulation efficiency in nanostructured lipid carriers and reduces drug expulsion by providing an imperfect crystal (Müller et al. 2002a). Since their development, solid lipid nanoparticles and nanostructured lipid carriers have been extensively investigated for drug delivery applications to a number of inaccessible targets including skin.

Lipid nanoparticles for skin delivery and the mechanisms of permeation

Lipid nanoparticles have been the focus of research as carriers for the topical delivery of cosmeceuticals as well as active pharmaceutical ingredients (Müller et al. 2002b). Lipid nanoparticles possess some valuable features for skin delivery such as controlled drug release, better tolerability, green chemistry and active ingredient stability over conventional topical formulations such as ointments, creams, lotions and tinctures (Wissing and Müller 2003). Topical use of lipid nanoparticles enhances skin penetration by maintaining a sustained release effect and close contact to the stratum corneum (Maia et al. 2000; zur Mühlen et al. 1998). The enhanced skin penetration of lipid nanoparticles is attributed to the formation of a lipid film on the skin’s surface owing to their inherent adhesive effect. Lipid film produces an occlusive effect to retard the escape of water and improves skin hydration with the resultant promoting effect on skin delivery of drugs (Choi et al. 2010). Furthermore, the smaller particle size of lipid nanoparticles offers a high surface area to ensure close contact of particles with the stratum corneum for effective drug delivery (Jenning et al. 2000). The combination of the effects of these contributing factors results in enhanced skin penetration of drugs through the skin barrier.

Factors affecting skin delivery of lipid nanoparticles

The particle size of lipid nanoparticles, nature and concentration of surfactants, surface charge on the particles and state of the lipid (liquid vs. solid) in nanoparticle’s core are the parameters that can affect the permeation of drugs across the skin. Skin penetration of lipid nanoparticles is based on an occlusive effect by forming a lipid film. Smaller particles produce increased adhesion and occlusion compared to larger particles, which in turn increase the skin permeation of drugs (Choi et al. 2010). In a study, an increase in particle size from 123 to 173 nm caused a reduction in the permeation flux from 3.1 to 1.9 µg/cm2/h (Mei et al. 2003). The surface charge on the lipid nanoparticles also influences the penetration of drugs to the deeper skin layers. The stratum corneum carries a negative charge; therefore, the application of positively charged lipid nanoparticles results in their interaction with a superficial layer of skin with limited penetration to deeper layers. Furthermore, the negative charge of the stratum corneum hinders the diffusion of negatively charged lipid nanoparticles into the skin. For these reasons, nanoparticles with a net neutral surface charge are suggested in order to perform effectively compared to their positively or negatively charged counterparts (Tupal et al. 2016). The type and concentration of the surfactant in lipid nanoparticle formulation plays a key role in penetration of skin. In a study, Tween 80 and soybean lecithin in different concentrations were used as the surfactant and the co-surfactant. The results reveal that skin uptake of lipid nanoparticles increased with increasing concentration of Tween 80, while skin penetration was decreased with an increase in lecithin concentration (Liu et al. 2007). Increased incorporation efficiency of drugs in lipid nanoparticles is also suggested to enhance skin penetration and reduce skin irritation (Liu et al. 2007). Solid lipid core (SLNs) or nanostructured lipid carriers (NLCs) with a binary mixture core of solid and liquid lipid also affect skin permeation of the lipid nanoparticles. It has been reported that NLCs and NLCs-loaded gel showed higher amount of cyclosporine and calcipotriol deposited in the pig ear skin compared to their SLNs counterparts (Arora et al. 2017). In addition, the severity of inflammation in terms of serum cytokines level and skin morphology was markedly reduced by drug-loaded NLCs in comparison to SLNs in psoriatic mice model. In another study, meloxicam-loaded NLCs exhibited enhanced anti-inflammatory activity having better erythema score (3 ± 0.0) compared to meloxicam-loaded SLNs (erythema score of 2.67 ± 0.5) in UV-induced erythema rats model (Khalil et al. 2014). These results suggest a higher skin penetration potential of lipid nanoparticles with a binary mixture core of solid and liquid lipid than those with a solid lipid core only.

Conclusion

In recent years, research in transdermal delivery has been revolutionized due to better understanding of the structure of the stratum corneum on a molecular level and the pathways of drug permeation across skin. Nanotechnology has recently been established as a promising tool to overcome the barrier function of skin. In this article, we discussed some of the attractive nanoparticulate carriers with their applications in enhancing drug transport across skin. The aforementioned results indicated the superior interaction of nanoparticulate carriers with skin structures to promote drug delivery. In this regard, a deformable liposomes-based product (TransfenacⓇ) developed by IDEA, Germany, has already proven its capability to carry a therapeutically significant amount of diclofenac into systemic circulation. A number of products based on nanoparticulate carriers and intended for skin delivery are in various phases of clinical trials. With advancements in material engineering, fabrication and characterization techniques, research has been focused on the development of newer nanoparticulate carriers with favorable properties for skin applications. Based on the amount of interest and research, it can be concluded that clinics might see more effective and safer transdermal formulations as an alternative to oral delivery in the near future.