ReviewElectrical, magnetic, photomechanical and cavitational waves to overcome skin barrier for transdermal drug delivery
Graphical abstract
Introduction
Skin comprises approximately 15% of the total adult body weight and has a surface area about 2 m2 [1]. The stratum corneum is the outermost layer of skin and the principal barrier to molecular transport across the skin and into the systemic circulation (Fig. 1) [2]. The stratum corneum consists of 10 to 15 layers of anucleated corneocytes (polygonal, elongated and flat; 0.2 to 1.5 μm thick; 34 to 46 μm wide) with thickness varying between 10 and 15 μm in dry state and 40 μm in hydration state [2], [3]. These corneocytes are filled with a matrix of crosslinked keratin fibers which are negatively charged at physiological conditions and responsible for the mechanical build up of the stratum corneum [4]. The keratin-rich corneocytes are arranged in brick-and-mortar like structure with intercellular matrix made of long chain ceramides, free fatty acids, triglycerides, cholesterol, cholesterol sulfate and sterol/wax esters, and intercellular spaces occupying 5 to 20% of the volume of stratum corneum [2], [3], [5]. The lipid lamellae are associated into lipid bilayer with hydrocarbon chains arranged in crystalline, lamellar gel and lamellar liquid crystal phases, and polar head groups into aqueous phase. The pH of skin surface is about 5 [4]. With pKa values of approximately 8, the head groups of stratum corneum lipids only ionize to a small extent. The physiological pH rises to 7.4 in deeper layers of stratum corneum. A greater population of lipids in this region is ionized with fatty acids of pKa between 4.8 and 6.3 responsible for negative net charge of skin.
Beneath the stratum corneum and epidermal layers is the dermis [1]. The dermis is thicker (approximately 1 to 4 mm) than the epidermis. The main extracellular matrix components of the dermis are collagen and elastin fibers. In the dermis, both blood capillaries and nerve endings are embedded [6].
Section snippets
Transdermal drug delivery
Trandermal drug delivery is mediated through direct transfer across the stratum corneum, through the sweat glands, or via hair follicles and sebaceous glands (shunt or appendageal route) [3]. It is recognized that appendages occupy an area for surface permeation of approximately 0.1% [3]. Their contribution to transdermal drug permeation can be minimal except in iontophoresis whereby electrical charges are used to drive the drug molecules into the skin via shunt routes as they provide less
Iontophoresis
Iontophoresis refers to a process whereby low amplitude electrical currents (0.5 mA/cm2) are applied on skin for minutes or hours to promote transdermal drug delivery (Fig. 2) [1], [3], [16], [17], [18]. Examples of drugs include charged and neutral molecules, as well as, low and high molecular weight drugs namely lidocaine [19], dexamethasone [20], piroxicam [21], diclofenac [21], ranitidine [22], donepezil [23], almotriptan [24], insulin [21], calcitonin [21] and luteinizing hormone-releasing
Electroporation
Electroporation utilizes short, high-voltage electrical pulses (50 to 1500 V) to promote transdermal drug delivery, typically tens to hundreds of volts for microseconds to milliseconds with intervals between pulses of a few seconds to a minute [1], [3], [14], [17]. The transdermal drug delivery increases with a rise in pulse voltage, number, duration and rate [14]. Electroporation of lipid bilayers results in phase transition and fluidization of lipids due to joule heating and localized
Sonophoresis/phonophoresis
Ultrasound of a wide ranging frequency between 20 kHz and 16 MHz with an amplitude between 1 and 5 bar for the order of tens of minutes is used in sonophoresis or phonophoresis [5], [17]. Sonophoresis can be broadly classified into three categories [7], [17]:
- 1.
Low frequency 20 kHz to 100 kHz.
- 2.
Therapeutic frequency 1 MHz to 3 MHz.
- 3.
High frequency 2 MHz to 16 MHz.
High frequency ultrasound is less associated with the applications for systemic delivery and only a limited number of drugs with molecular weight
Magnetophoresis
Magnetophoresis exploits a magnetic field (5 to 300 mT) to enhance transdermal drug delivery where diamagnetic drugs such as lidocaine can be repelled away from the magnetic field and migrated into the skin (Fig. 4a) [1], [7], [63]. The magnetophoretic drug permeation “flux enhancement factor” increases with an increase in the magnetic field strength [63]. The transdermal drug permeation is enhanced through modulating the permeability of stratum corneum [64].
Unlike iontophoresis, electroporation
Laser
Lasers are broadband, unipolar and compressible photomechanical waves (Fig. 4b) [7]. Unlike ultrasound, the photomechanical waves are characterized only by positive pressure and it has no negative pressure (tensile component) which is known to be responsible for cavitation effects in ultrasound [5]. Erbium-doped yttrium aluminium garnet, Q-switched ruby and carbon dioxide lasers have been used to increase skin permeability to drugs via ablation mechanism or lipid bilayer disruption in a process
Microwave
Microwave is a non-ionizing electromagnetic wave with wavelengths longer than those of terahertz waves, but relatively shorter than those of radiowaves [67]. It is characterized by frequencies between 300 MHz and 300 GHz. Broadly, the microwave is classified as ultra-high frequency (UHF) (0.3–3 GHz), super high frequency (SHF) (3–30 GHz) and extremely high frequency (EHF) (30–300 GHz) signals.
Microwave is generated by a magnetron which converts the electrical energy into an alternating
Conclusion
Iontophoretic delivery of lidocaine has been clinically approved for local anesthesia [15], [17]. High frequency ultrasound technique is used clinically to enhance transdermal delivery of steroids and anti-inflammatory drugs. The low frequency ultrasound technique has been developed and approved for topical lidocaine. The thermal technique has been tested in a number of human clinical trials on grainsetron, peptide fragment of human parathyroid hormone, insulin and human growth hormone [13],
Acknowledgment
The author wishes to thank REI UiTM for the given support during article preparation.
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