Modern Drug Transport Systems Report

SONOPHORESIS

By

BARTU ŞİMŞEK AND BURAK YILMAZ

Department of Biomedical Engineering

Faculty of Engineering

Yeditepe University
Istanbul, Turkey
April 2021
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SONOPHORESIS: AN OVERVIEW

By

BARTU ŞİMŞEK AND BURAK YILMAZ

APPROVED BY:

Assoc. Prof. Dr. Feride Şermin Utku ………………………………

DATE OF APPROVAL: 21 April 2021

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ABSTRACT

SONOPHORESIS

In this review study, the use of sonophoresis in transdermal drug delivery has been
discussed. The functions of sonophoresis are explained both theoretically and practically.
The mechanism of sonophoresis is covered in the theoretical section. Although the
theoretical mechanism of sonophoresis is still unknown, it is a useful in clinical practice
for increasing skin permeability. The effect of sonophoresis in high and low frequency
applications has been explained. In the practical section is focused on the SonoPrep ®
device. Additionally, an overview of sonophoresis applications is included.

Keywords: Sonophoresis, Transdermal drug delivery, Cavitation effect, Applications

of sonophoresis
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ÖZET

SONOFOREZ

Bu inceleme çalışmasında, transdermal ilaç tesliminde kullanılan sonoforezin işleyişi

tartışılmıştır. Sonoforezin teorik ve pratik işleyişi izah edilmiştir. Teorik bölümde
sonoforezin mekanizmasına yer verilmiştir. Sonoforezin teorik mekanizması halen tam
olarak anlaşılamamış olsa da klinik uygulamada cilt geçirgenliğini artırmakta faydası
görülmektedir. Sonoforezin yüksek ve düşük frekans uygulamalarındaki tesiri
açıklanmıştır. Pratik bölümde SonoPrep® cihazına odaklanılmıştır. Bunlara ek olarak
sonoforezin uygulamalarına genel bir bakış sunulmuştur.

Anahtar Kelimeler: Sonoforez, Transdermal ilaç teslimi, Kavitasyon etkisi, SonoPrep

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TABLE OF CONTENTS

ABSTRACT................................................................................................................iii

ÖZET...........................................................................................................................iv

LIST OF FIGURES.....................................................................................................vi

LIST OF ABBREVIATIONS....................................................................................vii

1. INTRODUCTION...................................................................................................1

2. MECHANISIM OF SONOPHORESIS...................................................................2

2.1. Cavitation Effects.............................................................................................2

2.2. Thermal Effects................................................................................................2

2.3. Mechanical Effects...........................................................................................3

3. ULTRASOUND AND SONOPHORESIS..............................................................4

3.1. High and Low Frequency Levels......................................................................4

3.2. Preprocess of Sonophoresis..............................................................................5

3.2. Checkpoint of Sonophoresis: Probes and Sensors............................................5

3.3. SonoPrep® Device.............................................................................................6

4. ADVANTAGES AND DISADVANTAGES OF SONOPHORESIS.....................8

5. DISEASES USED SONOPHORESIS....................................................................9

6. CONCLUSION......................................................................................................10

REFERENCES...........................................................................................................11
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LIST OF FIGURES

Figure 1.1 A cross section of the skin from Nagayama et al. 2018................................. 1

Figure 2.1 Cavitation occurring in the keratinocytes from Escobar-Chavez et al. 2009. 3

Figure 3.1 Basic principle of sonophoresis from Escobar-Chavez et al. 2010................ 4

Figure 3.2 The SonoPrep® device when applied to the skin from Gupta et al. 2009....... 6

Figure 3.3 The sketch head piece of the SonoPrep® device from Farinha et al. 2006..... 6
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LIST OF ABBREVIATIONS

HFP High-Frequency Sonophoresis

LFP Low-Frequency Sonophoresis

SC Stratum Corneum

Wrms Watt Root Mean Square

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1. INTRODUCTION

The passage of drugs through the skin under the influence of ultrasound called as
“sonophoresis” [1]. More than half a century, researchers have been studying the use of
ultrasound to improve drug delivery through the skin [2]. The skin consists of stratum
corneum (SC), epidermis, dermis, and skin appendages, shown in Figure 1.1 from
Nagayama et al. 2018 [3]. Under normal conditions, only lipophilic drugs can be delivered
by using traditional transdermal delivery methods [4]. Such drugs have a molecular weight
of less than 500 Da [4], [5]. Higher molecular weight drug molecules are penetrated using
sonophoresis. Since, transport is barred by the SC, the outermost layer of the skin [1].
Sonophoresis is the one of the ways that to reduce the SC barrier function and promote
transdermal drug delivery. The key mechanism of sonophoresis is considered to be the
cavitation effect [6]. Cavitation effects which are created by ultrasound waves allows drug
molecules to penetrate deeper into the skin due to temporarily disordering the structured
lipids of the SC [7], [8]. Specific devices such as SonoPrep® can be used in sonophoresis
applications.

Figure 1.1 A cross section of the skin from Nagayama et al. 2018.
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2. MECHANISIM OF SONOPHORESIS

The exact mechanism of sonophoresis is not known. It is believed that ultrasonic

waves may promote the permeability through cavitation effects, thermal effects,
mechanical effects [9], [10].

2.1. Cavitation Effects

Cavitation effect is the formation, growth, and collapse of gas bubbles cavitation
both inside and outside the skin [4], [7]. “It can generate violent micro streams, which
increase the bioavailability of the drugs” [11]. When the pressure increases during the
positive phase of the ultrasound waves, the radius of the bubble decreases; during the
negative phase, the radius of the bubbles approaches the equilibrium radius (inertial
cavitation). These pressure changes create cavitation inside the skin, Figure 2.2 from
Escobar-Chavez et al. 2009. Also, it is possible that slow oscillatory motion of a bubble
(stable cavitation) [7], [11], [12]. The collapse of cavitation bubbles outside the skin
releases a shock wave [4],[12]. The cavitation effect can disrupt the lipid bilayer of the SC,
alter the structure of the SC, increase the SC’s interstitial space, and create a water
pathway between keratinocytes [9]. The permeability of the skin increases because of these
factors. It should be remembered that cavitation effects vary inversely with ultrasound
frequency and directly with ultrasound intensity [7][10]. Due to the short time between
positive and negative acoustic pressures and diminishing the ability of dissolved gas within
the medium to diffuse into the cavitation nuclei, it becomes more difficult to generate
cavitate at higher frequencies [4][4].

2.2. Thermal Effects

The mechanical energy of ultrasonic waves transforms into heat energy and causes
heat generation. Different tissues have different absorption coefficients. The thermal effect
is increased by a high absorption coefficient [12]. The degree and intensity of heat
generation have a positive correlation [9].
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Figure 2.2 Cavitation occurring in the keratinocytes from Escobar-Chavez et al. 2009.

2.3. Mechanical Effects

“At frequencies greater than 1 MHz, changes in intensity occur so rapidly” [12].
Thus, a small gas core cannot grow and cavitational effect cannot be observed. “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” [13]. However, this
increase is negligible.
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3. ULTRASOUND AND SONOPHORESIS

3.1. High and Low Frequency Levels

In medicine, ultrasound frequencies are used between 20 kHz-16 MHz. Sonophoresis

can be work in the same frequency range and the intensity is as high as 15 W/cm 2, to
enhance skin permeability, see Figure 3.3 from Escobar-Chavez et al. 2010 [8], [9],[13].
There are two main conditions to used for sonophoresis: Low-frequency (LFS, 20-100
kHz) and high-frequency (HFS, 0.7-1.6 MHz) [7].

Figure 3.3 Basic principle of sonophoresis from Escobar-Chavez et al. 2010.

HFS was first researched for transdermal delivery, and it is still in use today [2].
Thermal effect in HFS is effective in increasing skin permeability [9]. After the cooling
system was used in high frequency ultrasound, many molecules with a molecular weight of
138-781 kDa, transdermal permeability could not be observed [14][13]. Distinguished
from HFP, thermal effects have little effect on LPF [9].

The research of LFS is widely used to clinically increase the permeability of skin to
various drugs and therapeutic compounds. Relation between frequency and cavitation
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effect, as mentioned in 2.1. and 2.3., because of its high cavitation effect LFS is preferred
in sonophoresis. The HFS (1 MHz at 0.5 to 1 W/cm 2) can disrupt the SC which influence
the integrity of and thus affect its penetrability too [12].

In addition, “double (high and low) frequency ultrasound was used to enhance the
skin permeability and shorten the treatment time compared to single frequency ultrasound”
[15].

3.2. Preprocess of Sonophoresis

Both the drug and the connected device should deliver the ultrasound effectively.
The following factors may lead to a greater drug distribution. The skin must be rehydrated
using a warm, moist towel for about 10-15 minutes for effective sonophoresis since lack of
moisture impedes sound transfer [4]. After that, a occlusive dressing helps maintain skin
hydration, warmth and capillary dilation and keeps the drug in close contact with the skin
for better absorption [4].

3.2. Checkpoint of Sonophoresis: Probes and Sensors

The probes used in sonophoresis vary according to the region. Echo probe, convex
probe, linear probe and continuous wave doppler probe are used in clinically. Echo probe
is used in brain examinations and cardiac examinations. Convex probe is used in
abdominal examinations and diagnosis of organs. Linear probe is used in vascular
examinations and blood vessel imaging. Continuous wave doppler probe is used to
measure blood flow and the velocity of sound in the blood. Depending on the disease,
different ultrasound probes can be preferred for sonophoresis. While sonophoresis is used
in small areas such as elbows, on the other hand, larger areas may be required for
anesthesia applications. For larger areas, convex or linear probes may be preferable.

Sonophoresis can also benefit from sensors. For example, with infrared sensors, it
can be useful to detect vascular regions. Also, capacitive sensors that depending on the
frequency are the most possible sensors that can be used to measure skin permeability in
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the sonophoresis. Capacitive contact imaging has shown significant potential in measuring
skin properties.

3.3. SonoPrep® Device

SonoPrep® is one of the instruments used for sonophoresis, see Figure 3.2 [16]. A
control console, an ultrasonic hand piece, a reference electrode, a 12 Volt battery charger, a
coupling medium disposable cartridge, and a cleaning kit make up the this device [17],
[18]. It is a low-frequency ultrasound device that using for transdermal drug delivery [19].

Figure 3.2 The SonoPrep® device when applied to the skin from Gupta et al. 2009.

Figure 3.3 The sketch head piece of the SonoPrep® device from Farinha et al. 2006.

The ultrasonic horn is 7.5 millimeters from the skin [20]. ”The reservoir is filled with
coupling buffer consisting of a phosphate buffered saline solution and 1% sodium dodecyl
sulfate,” see Figure 3.3 [17],[19]. The treated area has a cross sectional area of 0.8 cm 2 and
an internal diameter of 1.0 cm (diameter) [20]. To activated the ultrasonic horn, the hand
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piece is pressed against the skin of the patient. The ultrasonic control system delivers the
energy (12 Wrms) to the ultrasonic horn inside the hand piece and vibrates at 55 kHz for
approximately 15 seconds [16], [18]. Hence, the intensity that expressed as the number of
Watts (W) per square centimeter (cm2) is 15 W/cm2. Also, Gupta et al. provides same
intensity [20]. By this way cavitation bubbles occur on the skin with the energy passing
through the liquid coupling medium. Thus, as mentioned in 2.1., cavitation disorganizes
the lipid bilayer of the SC [19]. The skin impedance is determined by passing current
through the return electrode [17]. “The return electrode is kept by the patient. The control
system delivers a very low current through the ultrasonic coupling medium (maximum of
100 A), which is returned through a hand grip reference sensor” [20]. When the device
detects a enough change in the skin permeability, it automatically shuts down. It is worth
noting that Gupta et al. by measuring the impedance of the skin, they were show that
sonophoresis applied with SonoPrep® device makes the skin permeable for 42-48 hours
[16], [20].
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4. ADVANTAGES AND DISADVANTAGES OF SONOPHORESIS

The advantages and disadvantages of sonophoresis are parallel to those of

transdermal drug delivery systems. These are covered in detail by Ansel et al. [21][22].
The advantages are, it prevents gastrointestinal absorption problems caused by pH,
enzymatic activity, drug-food reactions and other factors, and increases patient compliance
by reducing daily dosing. It also eliminates the dangers, drawbacks of parenteral therapy
and hepatic “first pass” effect. Extends the activity of medications with a limited plasma
half-life by using the drug reservoir and controlled release properties of the drug delivery
system. Drug effect is quickly terminated by removing the drug application from the skin’s
surface. This eliminates the dangers and difficulties of intravenous infusions or
intramuscular injections. Finally, to optimize the treatment optimize the blood
concentration-time profile and eliminate pulse entry of drugs into the systemic bloodstream
to improve treatment effectiveness and minimize side effects; be able to have predictable
behavior over long periods of time and estimated zero-order kinetics.

There are not many disadvantages just minor tingling, irritation, and burning have
been reported but these effects can often be minimized or eradicated with proper
ultrasound adjustment and lastly can be time-consuming to administer. In addition to these
disadvantages, there are some limitations. For instance, transdermal delivery would be
problematic if the drug dose needed for medicinal value is greater than 10 mg/day. Also,
the SC structure varies from one location to the next on the same body, from person to
person, and with age.
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5. DISEASES USED SONOPHORESIS

From Pahade et al. 2010, the following list indicate which diseases are treated with
sonophoresis [7]:

i. Ultrasound helps in treating tennis elbow and tendon problems.

ii. Sonophoresis is used in the treatment of damaged skin.

iii. Painful muscular condition responds to noninvasive ultrasound treatment.

iv. Hormone delivery.

v. Ultrasound with topical anesthesia rapidly decreases pain of intravenous

cannulation.

vi. Low-frequency ultrasonic gene delivery.

vii. Ultrasound is used for calcific tendinitis of the shoulder.

viii. The dolphin therapy and sonophoretic model.

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6. CONCLUSION

Sonophoresis has an important place in transdermal drug delivery. The mechanism of

sonophoresis and how high and low frequencies create differences are discussed. It has
been explained that the reason why low-frequency applications are common is due to the
cavitation effect. Then, the SonoPrep ® device designed for LFS was introduced. Finally,
the advantages and disadvantages of sonophoresis, and some applications are given. In
light of the topics we covered in this sonophoresis overview, we think that this application
will be used more in clinics in the future. In addition, we only found a few publications in
the literature about sensors that can be used in sonophoresis. We believe it is a issue
worthy of further research.
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Technology, William Andrew, 2009.

[2] Dragicevic, N., and Maibach, H.I. (Eds.), Percutaneous Penetration Enhancers
Physical Methods in Penetration Enhancement, Springer-Verlag Berlin Heidelberg,
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[3] Nagayama, K., and Kurihara, T., “Numerical Simulation of Skin Formation: The
Relationship between Transepidermal Water Loss and Corneum Thickness”, Journal
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[4] Vranić, E., “Sonophoresis-Mechanisms and Application”, Bosnian Journal of Basic

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[5] Han, T., and Das, D.B., “Permeability Enhancement for Transdermal Delivery of
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[9] Miao, Y.Y., Wang, Z.L., and Zhang, P.Y., “2018 International Conference on
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[19] Lecomte, M.M., Atkinson, K.R., Kay, D. P., Simons, J. L., and Ingram, J.R., “A
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[21] Ansel, H.C., Popovich, N.G., and Allen, L.V., Ansel’s Pharmaceutical Dosage
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