**5. Introduction to chemical and physical transdermal drug delivery methods**

The stratum corneum provides a barrier to any chemical entering the body and only small molecules having a molecular weight of less than 500 Da (Daltons) can passively diffuse through the skin at rates resulting in therapeutic effects. There are several methods for overcoming this barrier such as using chemical enhancers or physical ways using electric current or plasma discharge.

## **5.1. Chemical enhancers in transdermal drug delivery**

further shortening of the chain leads to increased resistance to penetration almost as good as that of ceramides from healthy skin (24 carbons long on average) [33]. In order to enhance skin permeability, mechanisms like alternation of lipids of stratum corneum and its fluidity or creation of the disordering effect between alkyl chains of lipids of stratum corneum have been

**4. Diagnostics of barrier properties of the skin—TEWL (transepidermal**

There are wide varieties of methods available for analysing skin structure and other properties including its barrier function, such as Raman spectroscopy [35], X-ray diffraction [36], electron diffraction [37] and transmission electron microscopy [38]. Barrier properties of the stratum corneum can be confirmed by the transepidermal water loss (TEWL) test, which indicates water evaporation from the inner body through skin [21]. This test expresses the amount of water in grams evaporated per square metre in 1 h. Stratum corneum is a barrier against water diffusion and some other chemicals. The better the barrier function of the skin, the higher the water content and the lower the TEWL value. The tape striping test was described for the first time by Pinkus [39] in 1951. This method is based on removing of stratum corneum layers of the skin. The amount of removed stratum corneum is not constant and it depends on many parameters such as cohesion between cells, hydration or body sites [40]. This technique has been used for evaluation of the barrier function of skin, i.e. for investigating the depth of penetration of drugs [41], the influence of drug enhancers on stratum corneum [42], pH profiles [43] and many others. The tape stripping test (TST) is a representative method for estimating the barrier performance of skin and other properties of the stratum corneum [44]. When the

**water loss), TST (tape stripping test), ATR-FTIR (attenuated total**

**reflection-Fourier transform infrared spectroscopy)**

proposed [34].

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**Figure 1.** Stratum corneum layer with intercellular space [31].

Chemical enhancers are substances that change properties of skin for better penetration of drugs. The most well-known chemical enhancers are alcohols, fatty acids, terpenes and azone. An increase in permeability is very often caused by fluidising the lipids in stratum corneum. However, it is not valid for high concentration of short chain alcohols (like ethanol), where there was observed only a decrease of the absorbance of CH2 stretching bands and no shift of their position; thus, there is only the extraction of lipids [53]. Many enhancers have long hydrocarbon chains, and it was found out that for fatty acids and fatty alcohols, enhancement is related to the length of the hydrophobic group chain [32]. Enhancer can interact with polar head or with hydrophobic tails of lipid bilayer or with proteins. Water increases fluidity of stratum corneum by insertion of water molecules between polar head groups. Dimethylsulfoxide (DMSO) interacts with intercellular lipids and keratin. Azone disrupts lipid structure, and oleic acid increases fluidity of intercellular lipids. The most effective enhancers are those which interact with lipids and also with proteins of stratum corneum [54]. Combinations of chemical enhancers have been used to maximize the effect of the permeability of drugs, and chemical enhancers are also combined with physical enhancing methods such as iontophoresis [55].

## **5.2. Iontophoresis in transdermal drug delivery**

Iontophoresis (**Figure 2**) is a class of noninvasive methods to increase penetrations of ions through the skin by applying electric current using low voltages of up to 10 V (**Figure 2**).

**Figure 2.** Application of iontophoresis to skin.

Various waveforms of applied current have been investigated [56], and it has been shown that various waveforms have various effectivities for skin permeability [57]. Iontophoresis enhances transdermal drug delivery by three mechanisms:


Iontophoresis is used for ionisable drugs, and it is most effective for molecules with weight of up to 7 kDa [58] or 10–15 kDa according to Kalluri and Banga [59]. The disadvantages of iontophoresis are: difficulties with stabilizing the therapeutic agent in the application vehicle, complexity of the drug release system and prolonged skin exposure to an electric current [60]. The main changes on skin after iontophoresis are an increase of the hydration of stratum corneum and a decrease of electrical resistance of the skin [61]. Analysis of asymmetric CH2 peak, in ATR-FTIR spectra, did not show lipid alkyl chain disorders characterised by band shift or band broadening even at high current densities in some previous works [61–64]. On the other hand, in the recent work of Prasad et al. [65], they observed a shift of asymmetric CH2 band with increasing of current density that achieved 8 cm−1 at 0.2 mA/cm2 . Also decreasing of lipid and protein bands intensity indicates lipid and protein extraction. The spectra also demonstrated a split in amide II band into 1553 and 1541 cm−1. The split could be due to the disruption in hydrogen bonding associated with the head of ceramides, breaking interlamellar hydrogen bonding of the lipid bilayer and disrupting the barrier property of stratum corneum, resulting in loosening of lipid-protein domains, thus allowing higher flux as compared to the passive treatment [65]. Reversibility studies were conducted *in vivo* after 24 and 48 h of the application of iontophoresis. It was observed that the recovery process had started in 24 h and almost total recovery of epidermal as well as dermal changes was found in 48 h with low current density DC iontophoresis. However, with iontophoresis using 0.5 mA/cm2 current density, edema along with focal disruption of the epidermis persisted [65].

## **5.3. Electroporation in transdermal drug delivery**

**5.2. Iontophoresis in transdermal drug delivery**

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**Figure 2.** Application of iontophoresis to skin.

through the skin.

ces transdermal drug delivery by three mechanisms:

**2.** Flow of electric current increases skin permeability.

charged skin due to amino acids in cell membranes.

Iontophoresis (**Figure 2**) is a class of noninvasive methods to increase penetrations of ions through the skin by applying electric current using low voltages of up to 10 V (**Figure 2**).

Various waveforms of applied current have been investigated [56], and it has been shown that various waveforms have various effectivities for skin permeability [57]. Iontophoresis enhan-

**1.** Ion-electric field interaction causing moving of drug (ions) away from the electrode

**3.** Electro-osmosis caused by solvent flow from the anode to cathode because of negatively

Iontophoresis is used for ionisable drugs, and it is most effective for molecules with weight of up to 7 kDa [58] or 10–15 kDa according to Kalluri and Banga [59]. The disadvantages of iontophoresis are: difficulties with stabilizing the therapeutic agent in the application vehicle, complexity of the drug release system and prolonged skin exposure to an electric current [60]. The main changes on skin after iontophoresis are an increase of the hydration of stratum corneum and a decrease of electrical resistance of the skin [61]. Analysis of asymmetric CH2 peak, in ATR-FTIR spectra, did not show lipid alkyl chain disorders characterised by band shift or band broadening even at high current densities in some previous works [61–64]. On the other hand, in the recent work of Prasad et al. [65], they observed a shift of asymmetric

ing of lipid and protein bands intensity indicates lipid and protein extraction. The spectra also

. Also decreas-

CH2 band with increasing of current density that achieved 8 cm−1 at 0.2 mA/cm2

Unlike iontophoresis, electroporation (**Figure 3**) uses high voltage (HV) (over 100 V) pulses for short time (in range of microseconds to milliseconds). Cells exposed to an electrical pulse open pores in the cell membrane and allow macromolecules to enter. It was confirmed that delivery of drugs of at least 40 kDa can be achieved [66]. The disadvantages of electroporation are as follows: (1) if the pulses have not adequate length and intensity, pores can be too large or cause cell damage, non-specific amount of material can be released to the cell [67]. (2) The created pores can persist for several hours, which allow a higher amount of drug to be delivered [30].

**Figure 3.** Application of electroporation application.
