**3. Sonophoresis**

400 Pharmacology

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

Some examples of drugs delivered throughout the skin using chemical enhancer are shown

*Drug Chemical enhancer*

Azone®

Transcutol ®

Urea

Alcohols

Pyrrolidones

Fatty acids

Terpenes

Surfactants

**2.5 Determination of permeation enhancement** 

receptor compartments. (López-Castellano & Merino, 2010)

*Sodium salicylate* (Hadgraft et al., 1985; Smith & Irwin, 2000); *Sodium naproxen* (Escobar-Chavez et al., 2005); *Ibuprofen* (Philips & Michniak,1995; Shen et al., 2007); *Nonivamide acetate* (Fang et al., 1997); *Meloxicam* (Zhang et al., 2009); *Flurbiprofen* (Ma et al., 2010); *Naloxone* (Xu et al., 2007); *Furosemide* (Agyralides et al., 2004); *Methotrexate* (Allan, 1995); *Sumatriptan* 

et al., 2003); *Lidocaine* (Cazares-Delgadillo et al., 2005); *Testosterone* (Hathout et al., 2010); *Mometasone furoate* (Senyiğit et al., 2009); *Ketorolac*

*Lidocaine* (Lee et al., 2006); *Bupranolol* (Babu et al., 2008); *Propanolol*  (Amnuaikit et al., 2005); *Acyclovir* (Montenegro et al., 2003).

*Retinol* (Mélot et al., 2009); *Morphine* (Monti et al., 2001); *Arginine* 

*Sodium naproxen* (Escobar-Chavez et al., 2005); *Sodium diclofenac* (Escribano

*Haloperidol* (Vaddi et al., 2009); *Indomethacin* (Ogiso et al., 1995); *Leuprolide*

*Tizanidine hydrochloride* (Mutalik et al., 2009); *Minoxidil* (Mura et al., 2009); *Metopimazine* (Bounoure et al., 2008); *Nortriptyline hydrochloride* (Merino et

*Tizanidine hydrochloride* (Mutalik et al., 2009); *Daphnetin* (Wen et al., 2009);

*Diclofenac* (Kigasawa et al., 2009); *Nortiptyline hydrochloride* (Merino et al., 2008); *Verapamil hydrochloride* (Güngör et al., 2008); *Minoxidil* (Mura et al.,

*vasopressin* (Nair&Pachangula, 2003); *Insulin* (Pillai & Pachangula, 2003);

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

**2.6 Uses in topical/transdermal formulations** 

*succinate* (Balaguer-Fernandez et al., 2010).

al., 2008; Escobar-Chavez et al., 2011).

*Nitrendipin* (Mittal et al., 2008).

*Enoxacin* (Fang et al., 1998).

in Table 2.

(Amrish et al., 2009).

(Lu et al., 1992).

2009)

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

## **3.1 The ultrasound**

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 frequency and the size of transducer.

#### **3.2 Mechanisms of action**

#### **3.2.1 Cavitation effects**

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).

Chemical and Physical Enhancers for Transdermal Drug Delivery 403

however, non-significant and hence mechanical effects do not play an important role in therapeutic sonophoresis. Thus cavitation induced lipid bilayer disordering is found to be

Sonophoresis is capable of expanding the range of compounds that can be delivered transdermally. In addition to the benefits of avoiding the hepatic first-pass effect, and higher patient compliance, the additional advantages and disadvantages that the sonophoretic

Table 3. Advantages and disadvantages of using sonophoresis as a physical penetration

Table 4 summarizes the research on sonophoresis uses in the transdermal administration of

**Anesthetics** 

cream by using ULTS

concentrations.

ULTS frequencies and drug

Topical skin penetration of lidocaine Increase in the concentration of

ULTS

**Research Outcome References** 

lidocaine transmitted into rabbit subdermal tissues when topical application was followed by use of

No increase in absorption of lidocaine

Other variables include differences in

**Advantages Disadvantages** 

al., 1992).

penetration.

Can be time-consuming to administer.

Minor tingling, irritation, and burning have been reported (these effects can often be minimized or eradicated with proper ULTS adjustment (Maloney et

SC must be intact for effective drug

Wells et al., 1977.

McEnlay et al., 1985.

Novak et al.,

1964.

the most important cause for ultrasonic enhancement of transdermal transport.

**3.3 Advantages and disadvantages of sonophoresis** 

technique offers can be summarized as follows in Table 3.

Enhanced drug penetration (of selected drugs) over

Allows strict control of transdermal penetration rates. Permits rapid termination of drug delivery through

Skin remains intact, therefore low risk of

In many cases, greater patient satisfaction.

Not immunologically sensitizing.

**3.4 Applications of ultrasound** 

Double blind, vehicle-controlled, crossover trial in healthy volunteers

Trial in healthy volunteers for

for lidocaine cream

lidocaine oil

Less anxiety provoking or painful than injection

Less risk of systemic absorption than injection.

passive transport.

termination of ULTS.

introducing infection.

enhancer.

drugs.

Fig. 2. Enhanced permeation by disruption of lipid barrier and cavitation by use of ULTS.

#### **3.2.2 Thermal effects**

Absorption of ULTS increases temperature of the medium. Materials that possess higher ULTS absorption coefficients, such as bone, experience severe thermal effects compared with muscle tissue, which has a lower absorption coefficient (Lubbers et al., 2003). The increase in the temperature of the medium upon ULTS exposure at a given frequency varies directly with the ULTS intensity and exposure time. The absorption coefficient of a medium increases directly with ULTS frequency resulting in temperature increase.

#### **3.2.3 Convective transport**

Fluid velocities are generated in porous medium exposed to ultrasound due to interference of the incident and reflected ULTS waves in the diffusion cell and oscillations of the cavitation bubbles. Fluid velocities generated in this way may affect transdermal transport by inducing convective transport of the permeant across the skin, especially through hair follicles and sweat ducts.

#### **3.2.4 Mechanical effects**

ULTS is a longitudinal pressure wave inducing sinusoidal pressure variations in the skin, which, in turn, induce sinusoidal density variation. At frequencies greater than 1 MHz, the density variations occur so rapidly that a small gaseous nucleus cannot grow and cavitational effects cease. But other effects due to density variations, such as generation of cyclic stresses because of density changes that ultimately lead to fatigue of the medium, may continue to occur. Lipid bilayers, being self-assembled structures, can easily be disordered by these stresses, which result in an increase in the bilayer permeability. This increase is,

Fig. 2. Enhanced permeation by disruption of lipid barrier and cavitation by use of ULTS.

Absorption of ULTS increases temperature of the medium. Materials that possess higher ULTS absorption coefficients, such as bone, experience severe thermal effects compared with muscle tissue, which has a lower absorption coefficient (Lubbers et al., 2003). The increase in the temperature of the medium upon ULTS exposure at a given frequency varies directly with the ULTS intensity and exposure time. The absorption coefficient of a medium

Fluid velocities are generated in porous medium exposed to ultrasound due to interference of the incident and reflected ULTS waves in the diffusion cell and oscillations of the cavitation bubbles. Fluid velocities generated in this way may affect transdermal transport by inducing convective transport of the permeant across the skin, especially through hair

ULTS is a longitudinal pressure wave inducing sinusoidal pressure variations in the skin, which, in turn, induce sinusoidal density variation. At frequencies greater than 1 MHz, the density variations occur so rapidly that a small gaseous nucleus cannot grow and cavitational effects cease. But other effects due to density variations, such as generation of cyclic stresses because of density changes that ultimately lead to fatigue of the medium, may continue to occur. Lipid bilayers, being self-assembled structures, can easily be disordered by these stresses, which result in an increase in the bilayer permeability. This increase is,

increases directly with ULTS frequency resulting in temperature increase.

**3.2.2 Thermal effects** 

**3.2.3 Convective transport** 

follicles and sweat ducts.

**3.2.4 Mechanical effects** 

however, non-significant and hence mechanical effects do not play an important role in therapeutic sonophoresis. Thus cavitation induced lipid bilayer disordering is found to be the most important cause for ultrasonic enhancement of transdermal transport.

## **3.3 Advantages and disadvantages of sonophoresis**

Sonophoresis is capable of expanding the range of compounds that can be delivered transdermally. In addition to the benefits of avoiding the hepatic first-pass effect, and higher patient compliance, the additional advantages and disadvantages that the sonophoretic technique offers can be summarized as follows in Table 3.


Table 3. Advantages and disadvantages of using sonophoresis as a physical penetration enhancer.
