**2. Chemical enhancers**

Chemical percutaneous enhancers have long been used to increase the range of drugs that can be effectively delivered through the skin (López-Castellano & Merino, 2010). To date, a plethora of chemicals have been evaluated as enhancers, but their inclusion in topical or transdermal formulations is limited due to fact that the underlying mechanisms of action of these agents remain unclear. Although different chemicals are employed by the industry as percutaneous enhancers, some of which have several desirable properties, to date none has proved to be ideal. An ideal chemical penetration enhancer should have the following attributes (Barry, 1983; López- Castellano & Merino, 2010): a) It should be non-toxic, nonirritating and non-allergenic, b) It should work rapidly, and its activity and duration of effect should be both predictable and reproducible, c) It should exert no pharmacological activity within the body, d) It should work unidirectionally, e) When removed, the skin's barrier properties should return both rapidly and fully, f) It should be compatible with both excipients and drugs, and g) It should be cosmetically acceptable and, ideally, odourless and colourless.

#### **2.1 Percutaneous penetration routes of drugs**

There are three major potential routes of percutaneous penetration: appendageal, transcellular (through the stratum corneum), and intercellular (through the stratum corneum) (Figure 1). There is a weight of evidence that suggests that passage through the intact stratum corneum constititutes the predominant route by which most molecules penetrate the skin, as the appendageal route is characterized by a limited available fractional

Fig. 1. Processes of percutaneous absorption

Chemical percutaneous enhancers have long been used to increase the range of drugs that can be effectively delivered through the skin (López-Castellano & Merino, 2010). To date, a plethora of chemicals have been evaluated as enhancers, but their inclusion in topical or transdermal formulations is limited due to fact that the underlying mechanisms of action of these agents remain unclear. Although different chemicals are employed by the industry as percutaneous enhancers, some of which have several desirable properties, to date none has proved to be ideal. An ideal chemical penetration enhancer should have the following attributes (Barry, 1983; López- Castellano & Merino, 2010): a) It should be non-toxic, nonirritating and non-allergenic, b) It should work rapidly, and its activity and duration of effect should be both predictable and reproducible, c) It should exert no pharmacological activity within the body, d) It should work unidirectionally, e) When removed, the skin's barrier properties should return both rapidly and fully, f) It should be compatible with both excipients and drugs, and g) It should be cosmetically acceptable and, ideally, odourless and colourless.

There are three major potential routes of percutaneous penetration: appendageal, transcellular (through the stratum corneum), and intercellular (through the stratum corneum) (Figure 1). There is a weight of evidence that suggests that passage through the intact stratum corneum constititutes the predominant route by which most molecules penetrate the skin, as the appendageal route is characterized by a limited available fractional

**2. Chemical enhancers** 

**2.1 Percutaneous penetration routes of drugs** 

Fig. 1. Processes of percutaneous absorption

area of 0.1%. In this way, diffusion through the skin is controlled by the particular characteristics of the stratum corneum. In order to obtain a sufficient drug flux and, in turn, the therapeutical objectives in question, an alternative is to use chemical percutaneous enhancers. These substances alter some of the properties of the stratum corneum. (López-Castellano & Merino, 2010)

#### **2.2 Direct effects on the skin due to the use of transdermal penetration enhancers**

The lipid–protein-partititioning theory sets out the mechanisms by which enhancers alter skin lipids, proteins and/or partitioning behaviour (Barry, 1991): i) They act on the stratum corneum intracellular keratin by denaturing it or modifying its conformation, causing subsequent swelling and increased hydration; ii) They affect the desmosomes that maintain cohesion among corneocytes; iii) They modify the intercellular lipid domains to reduce the barrier-like resistance of the bilayer lipids. Disruption to the lipid bilayers can be homogeneous when the enhancer is distributed evenly within the complex bilayer lipids, but the accelerant is more likely to be heterogeneously concentrated within the domains of the bilayer lipids and iv) They alter the solvent nature of the stratum corneum, thus aiding the partitioning of the drug or a co-solvent into the tissue.(López-Castellano & Merino, 2010)

#### **2.3 Indirect effects on the skin due to the use of transdermal penetration enhancers**

Chemical enhancers can produce: *a)* Modification of the thermodynamic activity of the vehicle. The permeation of a good solvent from the formulation, such as ethanol, can increase the thermodynamic activity of a drug; *b)* It has been suggested that, by permeating through the membrane, a solvent can 'drag' the permeant with it, though this concept is somewhat controversial and requires confirmation; *c)* Solubilising the permeant within the donor, especially when solubility is very low, as in the case of aqueous donor solutions, can reduce depletion effects and prolong drug permeation.(López-Castellano & Merino, 2010)

#### **2.4 Classification of percutaneous chemical enhancers**

The classification of percutaneous enhancers is frequently based on the chemical class to which the compounds belong. Table 1 shows the principal classes of percutaneous enhancers.


Table 1. Principal classes of percutaneous enhancers.

Chemical and Physical Enhancers for Transdermal Drug Delivery 401

Absorption of ultrasonic energy leads to tissue heating, and this has been used with therapeutic intent in many conditions. More recently it has been realized that benefit may also be obtained from the non-thermal effects that occur as ULTS travels through tissue. ULTS therapies can broadly be divided into ''high'' power and ''low'' power therapies where high power applications include high intensity focused ULTS and lithotripsy, and low power encompasses sonophoresis, sonoporation, gene therapy and bone healing. There are three distinct sets of ULTS conditions based on frequency range and applications: 1) High frequency (3–10 MHz) or diagnostic ULTS, 2) Medium frequency (0.7–3 MHz) or

The term ultrasonic refers to sound waves whose frequency is >20 KHz. The intensity (I, expressed in W/cm2), or concentration of power within a specific area in an ULTS beam, is proportional to the square of the amplitude, p, which is the maximum increase or decrease in the pressure relative to ambient conditions in the absence of the sound wave. The complete relationship is: I= p2/2ρc, where ρ is the density of the medium and c is the speed of the sound (in human soft tissue, this velocity is 1540 m/s). The intensity is progressively lost when a sound wave passes through the body or is deviated from its initial direction, a phenomenon referred to as attenuation. In homogeneous tissue, the attenuation occurs as a result of absorption, in which case the sound energy is transformed into heat and scattered. The sound waves are produced in response to an electrical impulse in the piezoelectric crystal, allowing the conversion of electrical into mechanical or vibrational energy; this transformation requires a molecular medium (solid, liquid, or gas) to be effective. The ULTS beam is composed of two fields, the ''near field,'' in the region closest to the transducer face, and the ''far field,'' corresponding to the conical diverging portion of the beam (Figure 2). The parameters controlling this configuration of the ULTS beam are principally the

Cavitation is the formation of gaseous cavities in a medium upon ULTS exposure. The primary cause of cavitation is ULTS-induced pressure variation in the medium. Cavitation involves both the rapid growth and collapse of a bubble (inertial cavitation), or the slow oscillatory motion of a bubble in an ULTS field (stable cavitation). Collapse of cavitation bubbles releases a shock wave that can cause structural alteration in the surrounding tissue (Clarke et al., 2004) ULTS can generate violent microstreams, which increase the bioavailability of the drugs (Tachibana & Tachibana, 1999). Tissues contain air pockets that are trapped in the fibrous structures that act as nuclei for cavitation upon ultrasound exposure. The cavitational effects vary inversely with ULTS frequency and directly with ULTS intensity. Cavitation might be important when low-frequency ULTS is used, gassy fluids are exposed or when small gas-filled spaces are exposed. Cavitation occurs due to the nucleation of small gaseous cavities during the negative pressure cycles of ULTS, followed by the growth of these bubbles throughout subsequent pressure cycles (Tang et al., 2001).

therapeutic ULTS, and 3) Low frequency (18 to 100 KHz) or power ULTS.

**3. Sonophoresis** 

**3.1 The ultrasound** 

frequency and the size of transducer.

**3.2 Mechanisms of action 3.2.1 Cavitation effects** 

#### **2.5 Determination of permeation enhancement**

The great majority of studies of the effects of enhancers on skin permeability have been carried out by means of *in vitro* diffusion experiments in which various kinds of diffusion cells have been used. The most well-known of these cells are the Franz diffusion systems. These cells have two receptor compartments - donor and receptor (donor positioned above receptor) – between which the skin is placed. In general, the skin is pretreated with a solution of the chemical enhancer to be evaluated. The transdermal flux (J) of drugs can be estimated from the slope of the linear region (steady-state portion) of the accumulated amount of drug in the receptor compartment versus time plot. Permeation enhancing activity, expressed as enhancement ratio of flux (ERflux), is determined as the ratio between the flux value obtained with the chemical enhancer and that obtained with the control. A number of variables can strongly influence the permeation enhancement of drugs. The most important are the skin used in the experiments, temperature, humidity, enhancer concentration, vehicle employed and degree of saturation of the drug in the donor and receptor compartments. (López-Castellano & Merino, 2010)

#### **2.6 Uses in topical/transdermal formulations**

Some examples of drugs delivered throughout the skin using chemical enhancer are shown in Table 2.


Table 2. Examples of drugs delivered throughout the skin using chemical penetration enhancers.
