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Chapter 12

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Non-deformable Nanoparticles and Transdermal Penetration

Majella E. Lane and Annisa Rahma

12.1 Structure of Human Skin

The skin is the largest human organ with an average total surface of 2 m2 (Hadgraft

2001). It serves as a unique interface between the human body and the outside

environment, prevent ing the egress of water and the ingress of toxins, ultraviolet (UV) radiation, or foreign organisms (Lane et al. barrier role, human skin plays a role in homeostasis, maintaining body temperature and blood pressure (Benson 2012). Human skin is also a major sensory organ, transmitting information regarding temperature, pressure, pain, and itch to the central nervous system (Zimmerman et al. 2014).

Human skin may be divided into four main regions: the stratum corneum (SC) (non-viable epidermis), the viable epidermis, dermis, and the subcutaneous tissue (hypodermis) (Katz and Poulsen (HFs) and apocrine sweat glands are also associated with the skin (Fig. 12.1). Potential pathways through the skin are also shown in Fig. 12.1 and will be discussed in more detail in the next section.

The subcutaneous tissue (subcutis, also known as hypodermis) is the innermost layer of the skin and is responsible for attachment of the overlying dermis to underlying muscle, fascia, or periosteum (Diegel et al. of fat cells and is divided by ﬁbrous septae into separate anatomical units, arranged as lobules. The lobules are connected by veins and arteries (Stecco et al.

1971). Appendages such as hair follicles

2012). As well as its physical

2013). The subcutis consists

2015). The

M. E. Lane (✉) School of Pharmacy, University College London, London, UK e-mail: m.lane@ucl.ac.uk

A. Rahma Pharmaceutics Department, School of Pharmacy, Institut Teknologi Bandung, Bandung, Indonesia

https://doi.org/10.1007/978-3-031-59478-6_12

295

296 M. E. Lane and A. Rahma

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Fig. 12.1 Cross section of human skin

subcutis also contains nerve bundles and it primarily serves to provide heat insulation, energy storage, and protection against physical shock (Benson 2012).

The dermis is the 2–5 mm thick connective layer sandwiched between the epidermis and subcutaneous tissue. The dermis is subdivided into the papillary dermis and reticular dermis. The papillary dermis is a thin layer in contact with the epidermis basement zone and is rich in blood vessels and sensory nerve endings; the reticular dermis is a thick layer in contact with the subcutis (Lai-Cheong and McGrath

2009). The dermis consists mainly of the extracellular matrix made up of

collagen, elastin, and ground substance. Collagen accounts for 70% of the dry weight of the dermis, providing support and strength, and elastic ﬁbres make up 5% of the dry weight of the dermis, providing elasticity and ﬂexibility (Lai-Cheong and McGrath

2009). The basic cellular components found in the dermis are the

ﬁbroblasts that produce the three extracellular components, namely, collagen, elastin, and ground substance (Haskell responses, and melanocytes involved in pigm ent production (Benson

2010), mast cells responsible for immune

2012). Various

appendages including sweat glands, hair follicles, and sebaceous glands originate within the dermis. Blood and lymph vessels and nerves perm eate this layer supplying both nutrition and sensation (Fenner and Clark 2016).

The viable epidermis is a stratiﬁed squamous epithelium and varies in thickness from 0.16 mm on the eye lid to 0.8 mm found on the palms and soles. There are no blood vessels in the epidermis and epidermal cells source nutrients and clear waste by diffusion through the epidermal-dermal layer (Benson

2012). As shown in

Fig. 12.2, the epidermis consists of multilayers, and from the outmost layer these are stratum corneum, stratum granulosum, stratum spinosum, and stratum basale (also known as stratum germinativum) (Katz and Poulsen

1971). Furthermore, a

layer known as the stratum lucidum can be found only in glabrous skin between the stratum corneum and stratum granulosum layers (Gould

2018).

12 Non-deformable Nanoparticles and Transdermal Penetration 297

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Fig. 12.2 Schematic representation of the cells in different layers of the epidermis

The stratum corneum (SC) is the outmost layer of the skin with an average thickness of 10–20 μm. The SC is also known as the non-viable epidermis. It serves as the major barrier of the skin, preventing the loss of water and the permeation of potentially harmful substances. This barrier consists of 8–16 sixteen layers of overlapped fully keratinized dead cells, corneocytes (Katz and Poulsen

1971). The

corneocytes are pentagonal or hexagonal in shape with high density and low hydration compared to other cells (Hadgraft and Lane 2011). The corneocytes are renewed and replaced approximately every 14 days as the outcome of epidermal proliferation and progressive differentiation (Hadgraft and Lane

2011; Menon et al.

2012). Corneocytes are connected by corneodesmosomes and embedded in a con-

tinuous intercellular lipid matrix (Hadgraft and Lane 2011). Ceramides, cholesterol, and free fatty acids are the main lipid components and are present in approximately equimolar proportions in the extracellular domain. Ceramides are a group of structurally heterogeneous sphingolipids composed of sphin gosine and long chain fatty acid and ceramides and make up half of the lipid by mass (Ng and Lau

2015).

Cholesterol and free fatty acids amount to 25 and 10% by weight of the SC lipid matrix, respectively (Menon et al. 2012).

The SC has been described as a “brick-and-mortar” model by Michaels et al. (1975), where the corneocytes are the “bricks” in a “mortar” composed of the intercellular lipids. Corneodesmosomes act as the molecular rivets holding the “bricks” together. The structure of the SC is crucial for its barrier function and is considered to be the major challenge to transdermal/dermal drug delive ry (Menon et al. 2012).

12.2 Permeation Pathways Through the Skin

As the main barrier protecting the human body from the outside world, the stratum corneum (SC) is well recognized as the rate-limiting step in the percutaneous penetration process (Hadgraft 2001; Trommer and Neubert 2006; Donnelly et al.

298 M. E. Lane and A. Rahma

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Fig. 12.3 Schematic representation of the possible penetration pathways through the stratum corneum (Hadgraft and Lane transappendageal pathway; route 2 (highlighted in blue) shows the transcellular pathway; and route 3 (highlight in orange) illustrates the intercellular pathway

2011). Route 1 (highlighted in red) represents the possible

2010; Coulman et al. 2011). As noted previously, the structure of the SC has been

investigated and likened to a “brick-and-mortar” model (Michaels et al. 1975). Theoretically, there are several possible pathways by which substances can penetrate through the SC, namely, transappendageal, transepidermal, and intracellular diffusion routes (Fig. skin absorption of high-molecular weight non-charged substances (Wiechers Considering

12.3). The appendages traversing the SC may serve as a route for

2008).

that the surface area of sweat glands and hair follicles accounts for less than 0.1% of the skin surface, the transappendageal pathway is not the predominant route followed by the majority of molecules (Lane

2013). Experimental evidence has

conﬁrmed that the intercellular space is the preferential transport pathway for skin penetration (Nemanic and Elias as 500 μm for water (Potts and Francoeur intercell

ular lipids are organized as multiple lamellar layers forming a continuous

1980) and the pathlength for diffusion was reported

1991)

. As shown in Fig. 12.3,

the

lipid domain. The intercellular route involves partition and diffusion into the lipid matrix, and it has been well established that most substances preferentially overcome the SC barrier via the intercellular lipid channels (Hadgraft

2004; Lane et al. 2012).

12 Non-deformable Nanoparticles and Transdermal Penetration 299

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12.3 The Physicochemical Properties of a Permeant That

Inﬂuence Skin Permeation and Fick’s Law of Diffusion

Partition Coefﬁcient

When a molecule is applied to the skin surface, it has ﬁrst to partition into the outermost layer of the SC, then to diffuse through the SC and ﬁnally to partition into the viable epidermis and dermis (Lane et al. the SC and vehicle determines the concentration of permeant in the outer layer of skin. The partition of the molecule into the SC of skin is related to its solubility in both the formulation and the SC (Lane et al. 1 to 3 will be good candidates for topical delivery (Hadgraft should have afﬁnity for both lipid vehicles and water to partition into the skin.

Molecular Weight

Since drug permeation across the skin is governed by passive diffusion, small molecules traverse human skin faster than larger molecules. The drug ﬂux (J)is inversely proportional to the mol ecular weight of the permeant. A relationship between the permeability coefﬁcient (k

), and its molecular weight (MW) was deﬁned by Potts and Guy (1992)

oct

according to Eq. 12.1:

2012). The partition coefﬁcient between

2012). Molecules with a log P value of

2001). Therefore, drugs

) of a molecule, the partition coefﬁcient

log k

= 0:71 log K

–0:0061MW - 2:7 n = 93 r2 = 0:67 ð12:1Þ

oct

As the molecule becomes larger, diffusion in the skin is reduced. Bos and Meinardi (2000) proposed the “500 Dal ton” rule for skin permeation of compounds, where a remarkable decrease in human skin absorption was recorded with molecules over 500 Dalton. A correlation between MW and J found to be the main predictor of J

for 87 compounds (Magnusson et al. 2004)as

max

was also observed, where MW was

max

shown in Eq. 12.2.

log J

=-3:90–0:0190 MW n = 87, r2 = 0:847 ð 12:2Þ

max

Solubility

The solubility of a drug in the intercellular SC lipid inﬂuences its permeation across the skin. Moreover, drug concentration in the applied vehicle is also an important factor. According to Fick’s ﬁrst law, J is linearly related to the concentration of solute in the vehicle C

, up to the saturated solubility of the solute in the vehicle, that

is, increasing the concentration of a solute in the formulation resulted in enhanced ﬂux (Lippold and Schneemann 1984).

pH Variation and Ionization

Because of the skin lipophilicity, the ionization state of the permeant also plays a role in skin permeability. Ionization inﬂuences both the solubility of a permeant in the applied vehicle and its partition into the skin (Hadgraft 2004). Since the majority of

300 M. E. Lane and A. Rahma

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drugs are weak acids or weak bases, their degree of ionization depends on the pH of the applied vehicle and the pK

of the molecule. Thus, the pH of the topically applied

formulation is important in the penetration of an ionized molecule through the skin (Wester and Maibach

1985).

12.4 Passive Permeation and Fick’s First Law of Diffusion

In general, permeation of a molecule across the SC is basically a passive diffusion process which is described by Fick’s ﬁrst law (Eq. 12.3):

- C

ðÞ

DK C

= k

- C

ðÞ 12:3Þ

p Cv

where J D (cm

cient, C

(μg/cm2 /h) is the steady-state ﬂux of the permeant through a membrane,

/h) is the diffusion coefﬁcient, K is the vehicle-membrane partition coefﬁ-

- Cr (μg/cm3 ) is the concentration gradient of the permeant between

the vehicle and the receptor phase, h (cm) is the length of the diffusion path within the membrane, and k SC. As in most cases C

From Eq. 12.4, D, K, and C

(cm/h) is the permeability coefﬁcient of the permeant in the

>> Cr, Eq. 12.3 can be rewritten in the following form:

DKC

are the main determinants that govern the drug

= k

pCv

ð12:4Þ

permeation throu gh the skin. Therefore, the ﬂux across the skin may be enhanced by increasing D, K, and/or C

. These parameters can be affected by interactions between

the vehicle and skin and between the vehicle and drug.

12.5 Nanoparticles and the Skin

In this section, studies on the interaction of various non-deformable solid/rigid nanoparticles with the skin will be reviewed. Only those in vitro and in vivo studies conducted with human or porcine skin are considered as rodent and murine skin models are known to overestimate human skin exposure and/or permeation.

Metal Oxide Nanoparticles

Titanium dioxide (TiO of this group of nanomaterials because of their use in sunblock formulations. Protection against UVA (320–400 nm) and UVB (290–320 nm) radiation is provided by these materials via absorption of light energy and scattering and reﬂecting incident radiation (Hewitt 1992; Mitchnick et al. 1999). Pﬂücker et al. (2001) and

) and zinc oxide (ZnO) NP are the most widely characterized

12 Non-deformable Nanoparticles and Transdermal Penetration 301

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Schulz et al. (2002) investigated the dermal uptake in human volunteers of three types of sunscreens containing TiO

NP (10 – 15, 20, and 100 nm). The formulations

were applied for 6 h to the forearm; electron and light microscopy was used to investigate biopsy samples taken from the forearm. The NP could not be detected in the epidermis or dermis and were only found in the SC.

Gamer et al. (2006) exami ned the in vitro absorption of ZnO NP (mean primary

particle size of 80 nm with 90% of the particles being <160 nm) and TiO

(dimensions of 30–60 × 10 nm). The test formulations were applied to 1 cm exposed skin at 4 mg/cm2 for 24 h. The amounts of Zn found in the skin membrane and the receptor ﬂuid were comparable for control and NP formulations suggesting that only endogenous Zn was detected. No Ti was found in the receptor ﬂuid. Mavon et al. (

2007) studied a sunscreen containing TiO

(~20 nm) in full-thickness human

skin in vitro, and in human volunteers. A tape stripping technique was used in vivo and full and compartmental distribution (SC, epidermis, dermis, and receptor ﬂuid) was conducted after in vitro diffusion cell studies. Both in vitro and in vivo ﬁndings indicated that the majority of the TiO

was located in the stratum corneum and

particles did not penetrate the viable epidermis or dermis.

Cross and co-workers (2007) investigated human epidermal uptake of a transparent, nanoparticulate ZnO (20–30 nm) sunscreen formulation in vitro using Franz cell studies. Penetration of the nanoparticles was limited to the outer SC. The total amount of elemental zinc detected in the receptor phase was of the order of 0.03% of the applied dose. Zvyagin et al. (

2008) studied the skin uptate of ZnO NP

(26–30 nm) in vivo in humans. Multiphoton microscopy (MPM) imaging, scanning electron microscopy (SEM), and an energy-dispersive X-ray (EDX) technique conﬁrmed that nanoparticles remained in the stra tum corneum (SC), remaining in skin folds and/or hair follicles. Filipe et al. ( containing ZnO (20–60 nm) and TiO

(average size 20 nm). Biopsy samples were

2009) examined NP formulations

taken following application of the formulation to human subjects and imaged using a nuclear microprobe. NP were found only on the skin surface and outer stratum corneum.

Gontier and co-workers (2008) used Transmission Electron Microscopy (HRTEM) and Scanning Transmission Ion Microscopy (STIM) combined with Rutherford Backscattering Spectrometry (RBS) and PIXE to investigate permeation of TiO

nanoparticles (20–100 nm) ex vivo in porcine skin, healthy human skin, and

human skin grafted on a severe combined immuno-deﬁcient mouse model. The results conﬁrmed that penetration of TiO

nanoparticles was restricted to the topmost

3–5 corneocyte layers of the (SC).

The permeati on of TiO

2009a) in porcine skin both in vitro and in vivo. For porcine skin in vitro, no NP

(

nanoparticles (4–90 nm) was investigated by Wu et al.

permeation through the stratum corneum was observed but in vivo, penetration of the smaller particles to the basal layer of the skin was observed. Possible damage to the skin barrier in the pig study may have contributed to these ﬁndings because of hair removal in the in vivo study. Sadrieh et al. (2010) examined skin penetration of three types of TiO

particles (300–500 nm, uncoated 30–50 nm, coated 20–30 nm,

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