**4. Iontophoresis**

408 Pharmacology

barrier function.

repair.

of SLS.

sonophoresis.

minutes.

Sonophoresis at 15 MHz did not alter

This study reveals a positive ultrasonic effect of Panax notoginseng extract for improving the strength of ligament

LTRs and the non-LTRs exhibit significant decreases in skin electrical resistivity relative to untreated skin, suggesting the existence of two levels of significant skin structural perturbation due to ULTS exposure in the presence

Significant fractions (30%) of the intercellular lipids of SC were removed during the application of low frequency

heat-stripped SC samples

ULTS significantly increased the

frequency of occurrence of the otherwise scattered and separated lacunar spaces in the SC. A significant increase in lacunar dimensions was observed when 1% w/v sodium lauryl sulfate was added to the coupling medium.

"Complete flattening" of keloids in two young men when 1 MHz at 0.8 W/cm 2 was applied for approximately 4

An effective antitumor effect was demonstrated in solid tumors of both

murine and human cell lines.

A short application of ULTS enhanced the transport of fluorescein across human skin by a factor in the range of 2–9 for full thickness skin samples and by a factor in the range of 2–28 000 for

Menon et al.,

1994.

Ng et al., 2008.

Kushner IV et al., 2004.

Alvarez-Roman et al.,

Cancel et al.,

Paliwal et al.,

Walker, 1983.

Larkin et al., 2008.

2003.

2004.

2006.

**Calcium**

SC.

rats.

Manipulation of the Ca2+ content of

sonophoresis across hairless mouse

Effect of a therapeutic US coupled with a Panax notoginseng gel for medial collateral ligament repair in

*i)To study the mechanisms of penetration* 

permeability through the localized transport regions (LTRs) from the

ULTS/ Sodium lauryl sulphate

To shed light on the mechanism(s) by which low-frequency ULTS (20 KHz) enhances the permeability of

sonication effects of human skin at variable intensities and on the dynamics of fluorescein transport

Use of quantum dots as a tracer and

transmission electron microscopy (TEM) as visualization methods, on low frequency sonophoresis.

ULTS therapy with a water-based

Optimization of ULTS parameters for *in vivo* bleomycin delivery

Investigation of short time

confocal microscopy and

the upper epidermis by

**Panax notoginseng**

**Other applications** 

exposure to the

(SLS) system.

the skin.

*ii)Kelloids*

gel alone

*iii) Tumours*

across the skin.

*due to US throughout the skin* To demonstrate the calcein

> Transdermal iontophoresis consists of the application of a low density current and low voltage (typically 0.5 A/cm2) via an electrical circuit constituted by two drug reservoirs (anode and cathode) deposited on skin surface. During application of the current, the drug is repelled by the corresponding electrode and pushed through the stratum corneum. A substance can pass through the skin by electromigration, electroosmosis or passive diffusion. The latter of the three mechanisms is a result of changes caused by the electric field to the permeability of the skin, and its effects are negligible compared with those of the other two mechanisms. When ions are repelled by the electrode of the same charge and attracted by the electrode of the opposite charge is electromigration. When neutral substances are transported with the solvent flow is electroosmosis, which at physiological pH favours the movement from the anode to the skin.

> The advantages and disadvantages that the iontophoretic technique offers are summarized in Table 5.

#### **4.1 Mechanisms of action**

Skin is a complex membrane and controls the movement of molecules across it in the presence of an electric field. Skin has an isoelectric point (pI) of 4–4.5. Above this pH, the carboxylic acid groups are ionized. Therefore, at higher pH values, the skin behaves as a permselective membrane which especially attracts cations that have been repelled by the anode, thus favouring the passage of molecules by electromigration (Merino et al., 1999). The movement of small sized cations (mainly Na+) generates a solvent flow that promotes the passage of non-charged molecules through the skin. This process is identified as electroosmosis (Delgado-Charro and Guy, 1994). Electrical mobility decreases with

Chemical and Physical Enhancers for Transdermal Drug Delivery 411

allows the movement of neutral and positively charged entities into the cathode while negatively charged entities move into the anode. The main problem with this is that skin contains some of the entities to be analyzed, which implies that there is a period of time within which it is necessary to withdraw skin reserves and after which it is possible to correlate extracted levels of the analytes with levels in the blood (Leboulanger et al., 2004).

The most extended uses of iontophoresis are the treatment of palmoplantar hyperhidrosis and the diagnosis of cystic fibrosis. However, iontophoresis is also used for the topical delivery of others drugs such as lidocaine, acyclovir and dexamethasone. The only system commercially available at present is the fentanyl iontophoretic transdermal system. It is indicated for the shortterm management of acute postoperative pain in adult patients requiring opioid analgesia during hospitalization. Currently, the iontophoretic delivery of apomorphine for the treatment of idiopathic Parkinson's disease is being evaluated in human subjects. Peptide drugs including various series of amino acid derivatives and tripeptides, thyrotropin release hormones, LHRH and analogues, vasopressin and calcitonin can also be administered by means of this technique. One peptide that has focused the

Electroporation is the phenomenon in which cell membrane permeability to ions and macromolecules is increased by exposing the cell to short high electric field pulses. The increase in permeability is attributed to the electric field induced "breakdown" of the cell membrane and the formation of nano- scale defects or "pores" in the membrane – and hence electro-"poration". Electroporation can be of two types - reversible and irreversible. In irreversible electroporation the electric field is such that the membrane permeabilization leads to cell death. This may be caused by either permanent permeabilization of the membrane and cell lysis (necrosis) or by temporary permeabilization of a magnitude which can cause a severe disruption of the cell homeostasis that can finally results in cell death, either necrotic or apoptotic. In reversible electroporation the electric pulse causes only a temporary increase in permeability and the cell survives. The reversible electroporation mode has numerous applications in biotechnology and medicine both, *in vitro* and *in vivo*. Irreversible electroporation has applications in the food industry, for sterilization and in

The theory postulates two paths for electroporation induced transdermal transport, through pores formed in the multiple lipid bilayers connecting corneocytes and through appendage cells. Small lipid-soluble molecules can partition into the SC, and then diffuse across the lipid bilayer membranes, but water soluble molecules, particularly charged molecules, cannot penetrate significantly by this route. High voltage pulsing (> 50V) creates aqueous pathways ("pore") through stratum corneum (SC) lipid bilayer membranes, and short pathway segments are formed across 5--6 lipid bilayer membranes which connect adjacent corneocyte interiors forming transcellular straight-through pathways. Moderate voltage (= 5

**4.3 Applications of iontophoresis** 

**5. Electroporation** 

attention of researchers in the field of iontophoresis is insulin.

medicine for tissue ablation (Ball et al., 2010).

**5.1 Mechanisms of transdermal electroporation** 

molecular weight, and, as a consequence, the electroosmotic contribution becomes increasingly important for larger molecules (Guy et al., 2000). The dependence of iontophoretic flux on the intensity of the current applied has been clearly demonstrated by Faraday's law (Sage et al., 1992): where Ja is the flux (in moles per unit time), ta is the transport number, Za is the valence of ion a, I is the current applied (Amperes), and F is Faraday's constant (Coulombs/mol). The transport number, ta, is the fraction of the total current transported by a specific ion, and is a measure of its efficiency as a charge carrier: ta=Ia / I. It follows that knowledge of a compound's transport number allows the feasibility of its iontophoretic delivery or extraction to be predicted. The sum of the transport numbers of all the ions present during iontophoresis equals 1 (Σti=1), illustrating the competitive nature of electrotransport.


Table 5. Advantages and disadvantages of using iontophoresis as a physical penetration enhancer.

#### **4.2 Types of iontophresis**

#### **4.2.1 Direct iontophoresis**

Direct iontophoresis can be anodal if the drug is neutral or positively charged and cathodal if the drug is negatively charged. Although cations have better properties for iontophoresis, anions can also increase their transdermal drug flux with respect to passive diffusion.

#### **4.2.2 Reverse iontophoresis**

Reverse iontophoresis across the skin is a potentially useful alternative for non-invasive clinical and therapeutic drug monitoring. During current application, reverse iontophoresis allows the movement of neutral and positively charged entities into the cathode while negatively charged entities move into the anode. The main problem with this is that skin contains some of the entities to be analyzed, which implies that there is a period of time within which it is necessary to withdraw skin reserves and after which it is possible to correlate extracted levels of the analytes with levels in the blood (Leboulanger et al., 2004).

#### **4.3 Applications of iontophoresis**

410 Pharmacology

molecular weight, and, as a consequence, the electroosmotic contribution becomes increasingly important for larger molecules (Guy et al., 2000). The dependence of iontophoretic flux on the intensity of the current applied has been clearly demonstrated by Faraday's law (Sage et al., 1992): where Ja is the flux (in moles per unit time), ta is the transport number, Za is the valence of ion a, I is the current applied (Amperes), and F is Faraday's constant (Coulombs/mol). The transport number, ta, is the fraction of the total current transported by a specific ion, and is a measure of its efficiency as a charge carrier: ta=Ia / I. It follows that knowledge of a compound's transport number allows the feasibility of its iontophoretic delivery or extraction to be predicted. The sum of the transport numbers of all the ions present during iontophoresis equals 1 (Σti=1), illustrating the competitive

**Advantages Disadvantages** 

Table 5. Advantages and disadvantages of using iontophoresis as a physical penetration

Direct iontophoresis can be anodal if the drug is neutral or positively charged and cathodal if the drug is negatively charged. Although cations have better properties for iontophoresis, anions can also increase their transdermal drug flux with respect to passive diffusion.

Reverse iontophoresis across the skin is a potentially useful alternative for non-invasive clinical and therapeutic drug monitoring. During current application, reverse iontophoresis

Can be time-consuming to administer. The actual current density in the follicle maybe high enough to damage growing hair. SC must be intact for effective

drug penetration.

nature of electrotransport.

Enhance penetration of ionized and unionized molecules. Moreover, improving the delivery of polar molecules as well as high molecular weight compounds (e. g. peptides and oligonucleotides). Enabling continuous or pulsatile delivery of drug

Permitting easier termination of drug delivery. Offering better control over the amount of drug delivered since the amount of compound delivered depends on applied current, duration of applied current, and area of skin exposed to the current. Restoration of the skin barrier functions without

Ability to be used for systemic delivery or local

Reducing considerably the inter and intraindividual variability, since the rate of drug delivery is more dependent on applied current than on stratum

(depending on the current applied).

producing severe skin irritation.

(topical) delivery of drugs.

corneum characteristics.

**4.2 Types of iontophresis 4.2.1 Direct iontophoresis** 

**4.2.2 Reverse iontophoresis** 

enhancer.

The most extended uses of iontophoresis are the treatment of palmoplantar hyperhidrosis and the diagnosis of cystic fibrosis. However, iontophoresis is also used for the topical delivery of others drugs such as lidocaine, acyclovir and dexamethasone. The only system commercially available at present is the fentanyl iontophoretic transdermal system. It is indicated for the shortterm management of acute postoperative pain in adult patients requiring opioid analgesia during hospitalization. Currently, the iontophoretic delivery of apomorphine for the treatment of idiopathic Parkinson's disease is being evaluated in human subjects. Peptide drugs including various series of amino acid derivatives and tripeptides, thyrotropin release hormones, LHRH and analogues, vasopressin and calcitonin can also be administered by means of this technique. One peptide that has focused the attention of researchers in the field of iontophoresis is insulin.
