The outer layer of the skin forms an effective barrier to retain water within the body and keep exogenous compounds out of the body. As a result, the major problem in dermal and transdermal drug deliveries is the low penetration of drug compounds through the stratum corneum. Dermal drug delivery comprises the topical application of drugs for the local treatment of skin diseases. It requires the permeation of a drug through the outer skin layers to reach its site of action within the skin, with little or no systemic uptake. The application of drugs to the skin for systemic therapy is referred to as transdermal drug delivery. Hence, it is required that a pharmacologically potent drug reaches the dermis where it can be taken up by the systemic blood circulation. In either case, the drug has to cross the outermost layer of the skin, the stratum corneum. Candidates for passive transdermal delivery therefore share three common traits: effectiveness at relatively low doses, molecular mass less than 400 Da, and lipophilicity. Drugs delivered from conventional passive transdermal patches usually reach therapeutic plasma levels with lag times of hours^2,3.

It is therefore desirable to devise strategies both to enhance the penetration of molecules, which can already breach the skin barricade passively to some extent, and also to widen the spectrum of drug molecules that can penetrate the skin at therapeutically beneficial doses. Many tactics have been utilized to help overcome the barrier function. These include chemical means (e.g., chemical penetration enhancers or entrapment of molecules within lipid vesicles) or physical methods (such as ultrasound, microneedles, or electrical assisted methods). The description “electrically assisted” is being used to refer to deliver drugs by Iontophoresis, Sonophorsis and Phonophoresis, Electroporation, Photomechanical waves and Magnetophoresis, that are based on two strategies: enhancing skin permeability and/or providing a driving force acting on the drug.

1. IONTOPHORESIS-

Iontophorosis is a process or a technique involving the transport of ionic or charged molecules into a tissue by the passage of direct or periodic electric current through an electrolyte solution containing the ionic molecules to be delivered using an appropriate electrode polarity. Iontophoresis passes a few milliamperes of current (approximately 0.5 mA/cm²) to a few square centimeters of skin through the electrode placed in contact with the formulation, which facilitates drug delivery across the barrier. Efficiency of transport depends mainly on polarity, valency and mobility of the charged species, as well as electrical duty cycles and formulation components⁴.

This technique is far from new, Leduc having shown nearly 100 years ago that the technique could be used to deliver active drugs across mammalian skin in vivo^5,6. Since then, iontophoresis has been variously used to administer pilocarpine in the diagnosis of cystic ﬁbrosis, to treat hyperhidrosis of palms and soles (tap water iontophoresis), to induce local anesthesia in the skin and in the external ear canal, to aid penetration of ﬂuoride ions in dentistry, and so on. Yet it was only 20 years ago, following the initial success of passive transdermal drug delivery, that iontophoresis received attention as a way to expand the range of drugs that could be administered via the skin. At the same time, it was fully appreciated that the permeation of water, neutral and zwitterionic compounds could also be enhanced by iontophoresis, thereby expanding its potential applications. This observation and the recognition of the skin as a perm selective membrane, focused attention on convective solvent ﬂow (electroosmosis) as a second mechanism of electrotransport. The advantages of iontophoresis as a controlled and versatile drug administration technique were soon identiﬁed for peptides and drugs for the treatment of Parkinson’s disease, migraine, pain, etc. Within the last 10 years, the symmetrical nature of iontophoresis (i.e., that the passage of current across the skin causes ions to move into and out of the membrane at the same time) has led to its application as a noninvasive method of extracting endogenous substances. This so-called reverse iontophoresis procedure is exempliﬁed by the Glucowatch Biographer recently approved by the FDA for glucose monitoring^5-15.

Mechanism of permeation-Increased drug permeation as a result of this methodology can be attributed to either one or a combination of the following three mechanisms:

(a) Electro-repulsion-: charged species are driven primarily by electrical repulsion from the driving electrode;

(b) Electro-pertubation-: the ﬂow of electric current may increase the permeability of skin; and

An iontophoretic system (Figure 1) works similarly to an electrolytic cell¹². Electrical energy is supplied from an external voltage source such that oxidation and reduction reactions are driven at the electrodes (usually Ag=AgCl). Oxidation occurs at the positively charged anode whereas reduction takes place at the negatively charged cathode. Electrolytic half-cells are typically connected by a salt bridge through which the ions generated at the electrode reactions are transported to maintain electroneutrality. In transdermal iontophoresis, the circuit is completed via the skin. Thus, some distinctive characteristics of iontophoresis as a transdermal enhancement technique can be deduced:

1. The same amount of charge, which is carried by electrons through the external circuit, will be transported through the skin by ions. The amount of charge is externally controlled by manipulation of the power supply; it follows that the extent of the ionic transport through the skin (including that of the drug) can be precisely determined.

Further, on–off current profiles and ‘‘delivery’’ pulses of different magnitude can be used to achieve complex and individualized drug input profiles¹³.

2. Ionic transport occurs in both directions across the skin. For example, to preserve electroneutrality at the anode, cations migrate into the body and anions migrate from the body into the electrode chamber. Hence, iontophoresis can be used for both drug delivery and noninvasive sampling¹⁴.

3. All the ions present in the system (above and below the skin) may contribute to charge transport. The transport number is defined as the fraction of the total charge transported by a specific ion during iontophoresis. Because the sum of all the transport numbers must equal 1, it follows that iontophoretic transport is competitive. The transport number of a drug is related to its effectiveness as a charge carrier, and to the presence of competitor co- and counter ions and their corresponding charge-carrying abilities.

Fig.1 Schematic representation of drug administration facilitated by iontophoresis

2. ULTRASOUND-

Ultrasound (Sonophoresis and Phonophoresis) is a technique for increasing the skin permeation of drugs using ultrasound as a physical force.

The ultrasound wave is longitudinal in nature (i.e., the direction of propagation is the same as the direction of oscillation) and is defined as a sound having a frequency above 18 kHz. Longitudinal sound waves cause compression and expansion of the medium at a distance of half the wavelength, leading to pressure variations in the medium. Most modern ultrasound devices are based on the piezoelectric effect. This is achieved by applying pressure to quartz crystals and some polycrystalline materials, such as lead–zirconate–titanium or barium titanate, causing electric charge to develop on the outer surface of the material. Application of a rapidly alternating potential across the opposite faces of a piezoelectric crystal will therefore induce corresponding alternating dimensional changes, thereby converting electrical energy into vibrational (sound) energy¹⁶.

Sonophoresis: Sonophoresis involves the usage of the frequency ultrasound waves. The ultrasound application has resulted in permeation of low frequency ultrasound was shown to increase the permeability of human skin to many drugs including high molecular weight protein by several orders of magnitude.

Phonophoresis: The movement of drugs through living intact skin and into soft tissues under the ultrasound perturbation is called phonophoresis. The technique involves placing an ultrasound-coupling agent on the skin over the area to be treated and massaging the area with an ultrasound source.

To transfer ultrasound energy to the body, a coupling medium is required to overcome the high impedance of air. The many types of coupling medium currently available for ultrasound transmission can be broadly classified as oils, water–oil emulsions, aqueous gels, and ointments.

This ultrasound device is battery-operated, handheld device consists of a control unit, ultrasonic horn with control panel, a disposable coupling medium cartridge, and a return electrode.

Ultrasound at various frequencies in the range of 20 kHz to 16 MHz has been used to enhance skin permeability. The low–frequency ultrasound (20 -100 KHZ) enhances skin permeability more effectively than high – frequency ultrasound (1 -16 MHZ).⁷

There are three distinct sets of ultrasound conditions based on frequency range and applications¹⁷:

-High-frequency or diagnostic ultrasound in clinical imaging (3–10 MHz)

-Medium-frequency or therapeutic ultrasound in physical therapy (0.7–3.0 MHz)

-Low-frequency or power ultrasound for lithotripsy, cataract emulsification, liposuction,

tissue ablation, cancer therapy, dental descaling, and ultrasonic scalpels (18–100 kHz)

Mechanism of permeation-The ultrasonic energy (at low frequency) disturbs the lipid packing in stratum corneum by cavitation. Shock waves of collapsing vacuum cavities increase free volume space in bimolecular leaﬂets and thus enhance drug penetration into the tissue. A corresponding reduction in skin resistance was observed due to cavitation, microstreaming and heat generation.

Physiotherapist used ultrasound to treat patients with local musco-skeletol inflammation using topically applied steroids¹. The preparation was applied topically and massaged the site with an ultrasound source. The procedure was later extended to transdermal drug delivery studies.

Low-frequency ultrasound has also been used by Mitragotri et al. to enhance the transport of various low-molecular-weight drugs, as well as high-molecular-weight proteins (including insulin, g-interferon, and erythropoietin), across human cadaver skin in vitro. The experimental findings suggest that, among all the ultrasound-related phenomena evaluated (cavitation, thermal effects, generation of convective velocities, and mechanical effects), cavitation plays the dominant role in low-frequency sonophoresis, suggesting that application of low-frequency ultrasound should enhance transdermal transport more effectively. Mitragotri et al. found that the enhancement induced by low-frequency ultrasound is up to 1000-fold higher than that induced by therapeutic ultrasound. For example, application of ultrasound (20 kHz, 225 mW/cm2 , 100 ms pulses applied every second) to a chamber glued onto the back of the rat and filled with insulin solution (100 U/ml) reduced the blood glucose level of diabetic hairless rats from approximately 400 to 200 mg/dl in 30 min.^16-23

3. ELECTROPORATION-

The process involves the application of transient high voltage electrical pulse to cause rapid dissociation of the stratum corneam through which large and small peptides, oligonucleotides and other drugs can pass in significant amounts. Electroporation or elecro-permeabilization involves changes in membrane cells due to application of large transmembrane voltage. The change in the membrane involves structural arrangement and conductance leading to temporary loss of semi-permeability of cell membranes suggesting formation of pores. High voltages in the form of direct current (100-1000 v/cm) caused by electrical pulses with short treatment durations (micro to milliseconds) are most frequently employed. Other electrical parameters that affect delivery include pulse properties such as waveform, rate and number.

The technology has been successfully used to enhance the skin permeability of molecules with differing lipophilicity and size (i.e. small molecules, proteins, peptides and oligonucleotides) including biopharmaceuticals with a molecular weight greater that 7kDA, the current limit for iontophoresis.

Its potential for increasing the transdermal delivery of molecules was first demonstrated in the 1990s and since then the technique has been combined with other enhancement strategies to examine if penetration of dermally absorbed drugs can be further increased, e.g., estradiol or to broaden the range of candidate drugs, which may be delivered by this route, e.g., insulin.

Mechanism of permeation-The mechanism of penetration is the formation of transient pores due to electric pulses that subsequently allow the passage of macromolecules from the outside of the cell to the intracellular space via a combination of possible processes such as diffusion and local elctrophoresis.

Increase in transdermal penetration of up to 10⁴ fold have been reported in vitro for various sizes of molecules such as metoprolol, lidocaine, tetracaine, vitamin C, timolol and fentanyl dyes and macromolecules up to 40 Kda.^24-28

4. PHOTOMECHANICAL WAVE-

Mechanical vibrations have also been recently found to increase the permeability of the skin. A drug solution, placed on the skin and covered by a black polystyrene target, is irradiated with a laser pulse (Fig.2). The resultant photomechanical wave stresses the horny layer and enhances drug delivery.

Pressure waves (PW), which can be generated by intense laser radiation, without incurring direct ablative effects on the skin. It is thought that PW form a continuous or hydrophilic pathway across the skin due to expansion of the lacunae domains in the SC. Important parameters affecting delivery such as peak pressure, rise time and duration has been demonstrated. The use of PW may also serve as a means of avoiding problems associated with direct laser radiation.

Bernabei used electrical pulses to increase the absorption of substances in conjunction with mechanical vibrations. The frequency and phase of electrical and mechanical vibrations were synchronized in order to increase the absorption effect. Permeants that have been successfully delivered in vivo include insulin, 40 kDa dextran and 20 nm latex particles. A design concept for a transdermal drug delivery patch based on the use of PW has been proposed by Doukas & Kollias.

Mechanism of permeation- Photomechanical waves are able to render the stratum corneum more permeable to macromolecules via a possible transient permeabilisation effect due to the formation of transient channels. The technique of photomechanical wave for increasing drug absorption through skin is likely to remain experimental^29-36.

Fig.2 Schematic representation of drug administration facilitated by Mechanical wave.

5. MAGNETOPHORESIS-

Magnetophoresis is a novel approach and still in the research phase in enhancing skin permeability by applying a magnetic field. The research data on animal models suggests that skin penetration can be enhanced by applying a magnetic field to therapeutic molecules that are diamagnetic in nature.

Mechanism of permeation- Skin exposure to a magnetic field might induce structural alterations that could contribute to an increase in permeability.

In vitro studies by Murthy showed a magnetically induced enhancement in benzoic acid (diamagnetic) flux, which was observed to increase with the strength of the applied magnetic field. Other in vitro studies using a magnet attached to transdermal patches containing terbutaline sulphate (TS), demonstrated an enhancement in permeant flux which was comparable to that attained when 4% isopropyl myristate (IPM) was used as a chemical enhancer. In the same paper the effect of magnetophoresis on the permeation of TS was investigated in vivo using guinea pigs.

The preconvulsive time (PCT) of guinea pigs for those subjected to magnetophoretic treatment was found to last for 36 h which was similar to that observed after application of a patch containing 4% IPM. This was in contrast to the response elicited by the control (patch without enhancer), when the increase in PCT was observed for only 12 h. In human subjects, the level of TS in the blood was higher but, not significantly different to that observed with the patch containing 4% IPM. The fact that this technique can only be used with diamagnetic materials will serve as a limiting factor in its applicability and probably explains the relative lack of interest in the method.

Langer discussed the interesting idea of employing intelligent systems based on magnetism or microchip technology to deliver drugs in controlled, pulsatile mode^37-41.

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Received on 11.03.2010

Accepted on 07.04.2010

Research Journal of Pharmaceutical Dosage Forms and Technology. 2(4): July-August 2010, 264-269