**3.4 Applications of ultrasound**

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


Chemical and Physical Enhancers for Transdermal Drug Delivery 405

unclear

volunteers.

the presence of ULTS.

Positive effects of sonophoresis using a pharmacologically active gel with ketoprofen were shown to be highly significant in assessments, objective (clinical examination) and subjective (interview). The pain symptoms in the elbow resolved in most of the patients.

Previously applied therapeutic ULTS irradiation enhances the percutaneous penetration of the topical diclofenac gel, although the mechanism remains

Using this *in vitro* model it is possible to compare the transdermal delivery of commercial flufenamic ointment in

Amphotericin B content in the skin and subcutaneous fatty tissues was much higher when the drug was delivered in

It was found that the tissue levels of tetracycline administered with the modified methods of electro and

in the current density or ULTS intensity, the procedure time and

The enhanced skin accumulation of Cyclosporin A by the combination of low-frequency ULTS and chemical enhancers could help significantly to optimize the targeting of the drug without of a concomitant increase of the

The study showed that LFS, a not aggressive technique, enhanced penetration of topic agents obtaining effects at the level of the epidermis, dermis and appendages (intradermal delivery), giving better results in the treatment of some cosmetic skin

antibiotic concentration.

systemic side effects.

disorders.

sonophoresis increased with an increase

Cabak et al., 2005.

Rosim et al., 2005.

Hippius et al., 1998.

Rornanenko & Araviiskii,

Ragelis et al.,

1991.

1981.

Liu et al., 2006.

Santoianni et al., 2004.

Examination of therapeutic effects of sonophoresis with ketoprofen in

gel form in patients with enthesopathy of the elbow.

Quantitative study of sodium diclofenac (Voltaren Emulgel, Novartis) phonophoresis in humans

Investigation of *in vitro* penetration

Effect of ULTS on the delivery of topically applied amphotericin B

Administration of tetracycline in

electrophoresis and sonophoresis

Investigated the topical transport of Cyclosporin A using low-frequency

Evaluation of the efficacy of low frequency sonophoresis (LFS) at 25KHz produced by a sonicator apparatus for treatment of alopecia areata, melasma and solar lentigo.

and the *in vivo* transport of flufenamic acid in dependence of

ointment in guinea pigs.

healthy rabbits using

**Immunosuppressives** 

US throughout rat skin

ULTS.

**Antibiotics**


penetration of lidocaine.

in the legs of hairless mice

anesthetic penetration

sonophoresis

NSAIDs

indomethacin

ULTS in conjunction with a topical aqueous lidocaine solution was rapidly effective in inducing an anesthetic effect

No detectable increase in the rate of

0.5 MHz ULTS in sonophoresis for conduction anesthesia using lidocaine hydrochloride for a nerve block, it is more effective than the 1 Mhz that is widely used in clinical situations

monolayer can be controlled by

Extent and velocity of the permeation of procaine hydrochloride through MDCK

Demonstrated the synergistic effect of temperature and ULTS operation parameters on drug transport of

Intensity and duration of application

A significant increase in permeation of

observed with the applied sonication at

The transdermal application of KT gel using sonophoresis had significant antihyperalgesic and anti-inflammatory effects. These findings suggest that the transdermal administration of a KT gel using sonophoresis with pulsed ULTS might be useful for treating acute

Analgesic efficacy of transcutaneous 5%

play an important role in the transdermal sonophoretic delivery; intensity of 0.75 W/cm2 for 10 min was

most effective for delivering

ketorolac through rat skin was

3 W/cm2 when compared with permeation at 1 and 2 W/cm2.

inflammation and pain.

gel nurofen in osteoarthrosis.

Griffin & Touchstone, 1972.

Tachibana et al., 1993

Williams et al., 1990.

Kim et al., 2007.

Hehn et al., 1996.

Meshali et al., 2008.

Miyazaki et al., 1992.

Tiwari et al., 2004.

Yang et al., 2008.

Serikov et al.,

2007.

Skin lidocaine penetration 250 kHz induced the highest

Anesthetic effect of lidocaine in legs

Sonophoresis of topical benzocaine

monolayers applying therapeutical

**Analgesic and anti-inflammatory** 

Effect of intensity, mode, and duration of ULTS application on the transport of three non steroidal antiinflammatory drugs (NSAIDs) across cellulose membrane and

Effect of an ULTS (1 MHz) on transdermal absorption of

Study of the influence of ultrasound on percutaneous absorption of ketorolac

To determine if a ketorolac tromethamine (KT) gel solution could be administered *in vivo* via phonophoretic transdermal delivery using pulsed ULTS by examining its anti-inflammatory effects in a rat carrageenan inflammation model.

indomethacin from an ointment in

tromethamine *in vitro* across hairless

Application of ultraphonophoresis of 5% ibuprofen nurofen gel to affected joints of 20 patients.

hairless rabbit-skin

Administration of lidocaine hydrochloride trandermally on healthy volunteers applying 0.5

Permeation of procaine hydrochloride through cell

of hairless mice

and dibucaine

MHz ULTS.

ULTS.

**drugs**

rats

rat skin


Chemical and Physical Enhancers for Transdermal Drug Delivery 407

The highest permeation of TA was observed under the ULTS treatment conditions of low frequency, high intensity, and in continuous mode.

There was no enhancement of digoxin absorption across human skin by ULTS.

ULTS treatment applied prior to methyl

percutaneous absorption of the drug

Skin exposure to HUS or LUS before application of 1% dodecylamine for 30 min had no superior enhancement effect over application of either LUS or HUS alone. Application of drug loaded SLM offered skin protection against the irritation effect produced by TS and 1%

Synovial fluid analysis revealed increased absorption and fluorescence microscopy showed deeper penetration

of both HA1000 and HA3000.

solutes examined.

pulsed mode.

the total exposed skin area.

Good correlations were observed between the 3H2O flux and solute clearances and, unexpectedly, the slope values obtained from linear regression of the plots were consistent for all

Microscopic evaluations using revealed heterogeneous penetration into the skin. Heterogeneous penetration led to the formation of localized transport pathways, which occupied about 5% of

Discontinuous ULTS mode was found to be more effective in increasing transdermal penetration of fentanyl while transdermal transport of caffeine was enhanced by both continuous and

nicotinate led to enhanced

DA.

Yang et al., 2006.

Machet et al.,

McEnlay et al., 1993.

El-Kamel et al., 2008.

Park et al., 2005.

Morimoto et al., 2005.

Tezel et al., 2004.

Boucaud et al., 2001.

1996.

Designing a sonophoretic drug delivery system to enhance the triamcinolone acetonide (TA)

The sonophoresis of digoxin *in vitro* through human and hairless mouse

Skin penetration enhancement effect of ULTS on methyl nicotinate in 10

Effect of permeation enhancers and application of low frequency (LUS) and high frequency ultrasound (HUS) on testosterone (TS) transdermal permeation after application of testosterone solid lipid microparticles (SLM).

The effectiveness of sonophoresis on the delivery of high molecular weight (MW) hyaluronan (HA) into synovial membrane using an animal

model of osteoarthritis (OA).

The skin permeation clearance of model hydrophilic solutes, calcein (MW 623) and-labeled dextrans [MW 4400 (FD-4) and MW 38000 (FD-40)], across the skin under the

Assessment of the potential of low frequency ULTS (20 kHz, 2.4 W/cm2) in delivering

therapeutically significant quantities of anti-sense oligonucleotides into

The effect of low-frequency sonophoresis on fentanyl and caffeine permeation through human

and hairless rat skin.

healthy human volunteers.

permeability.

**Cardiotonics**

**Vasodilators**

**Hormones**

**Cicatrizants**

**Calcein**

skin.

**Stimulants**

influence of ULTS.

**Oligonucleotids**

skin.


from the skin surface.

60 min

Dramatic reductions of the tumor size

Ultrasonication produced a decrease in percutaneous drug penetration. This effect was due to the diffusive loss of the hydrophilic substance 5-fluorouracil

Using the rectangular cymbal array, the glucose decreased faster and to a level of -200.8±5.9 mg/dL after 90 min.

For the ULTS-insulin group, the glucose level was found to decrease to -132.6 ± 35.7 mg/dL from the initial baseline in

For the 60-min ULTS exposure group, the glucose level was found to decrease from the baseline to -267.5 ± 61.9 mg/dL in 1 h. Moreover, to study the effects of ULTS exposure time on insulin delivery, the 20-min group had essentially the same result as the 60-min

exposure at a similar intensity.

The effects of sonophoresed

saturated the skin.

tissue

A sonophoretic effect occurred with dexamethasone when its application

dexamethasone can be measured in terms of reduced collagen deposition as far down as the subcutaneous tissue but not in the submuscular or subtendinous

Significant improvement in total WOMAC scores was observed in 15 (60%) and 16 (64%) patients in the PH

and ION groups respectively,

the improvement rate.

indicating no significant difference in

by a factor of four. Aoi et al.,

2007.

Meidan et al., 1999.

Luis et al., 2007.

Lee et al., 2004.

Smith et al., 2003.

Saliba et al., 2007.

Byl et al., 1993.

Akinbo et al.,

2007.

**Anticancer drugs** 

activation therapy.

**Insulin**

rabbits.

transducer.

**Corticosteroids**

dexamethasone.

corticosteroids.

osteoarthritis

Application of a method using ULTS and nano/microbubbles to cancer gene therapy using prodrug

Investigation of competitive transport across skin of 5-

fluorouracil into coupling gel under the influence of ULTS, heat-alone and Azone® enhancement.

To determine if the 3x1 rectangular cymbal array perform significantly better than the 3x3 circular array for glucose reduction in hyperglycemic

To demonstrate ultrasonic transdermal delivery of insulin *in vivo* using rabbits with a novel, lowprofile two-by-two ULTS array.

The purpose of this study was to demonstrate the feasibility of ULTSmediated transdermal delivery of insulin *in vivo* using rats with a novel, low profile two-by-two US array based on the "cymbal"

Determination of the effect of ULTS on the transcutaneous absorption of

To determine if ULTS enhances the diffusion of transdermally applied

Comparison of effectiveness of 0.4% Dexamethasone sodium phosphate (DEX-P) sonophoresis (PH) with 0.4% DEX-P iontophoresis (ION) therapy in the management of patients with knee joint


Chemical and Physical Enhancers for Transdermal Drug Delivery 409

times up to 24 h.

The HIFU exposure shortened the peak tumor uptake time (24 vs. 48 h for the control) and increased the peak tumor uptake value (38 vs. 25 %ID/g for the control). The HIFU effect on enhancing tumor uptake was greater at earlier

sonophoresis of ethylenediaminetetra acetic acid with the quinoxaline antibiotic dioxidine was effective in accelerating wound purification an delimination of necrotic issues

Sonophoresis of a 1% papain solution together with dimethyl sulfoxide was an effective method for treating purulent wounds and inflammatory

Khaibullina et al., 2008.

Levenets et al., 1989.

Matinian et al., 1990.

Table 4. Research on uses of sonophoresis to administer different drugs through the skin

infiltrates.

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

The advantages and disadvantages that the iontophoretic technique offers are summarized

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

**4. Iontophoresis** 

Investigation of high-intensity focused ULTS (HIFU) exposure of

Treatment of suppurative wounds

Treatment of suppurative wounds

(111) In-MX-B3.

**Supurative wounds**

with ULTS.

with ULTS.

in Table 5.

**4.1 Mechanisms of action** 

pH favours the movement from the anode to the skin.



Table 4. Research on uses of sonophoresis to administer different drugs through the skin
