SONOPHORETIC
DRUG DELIVERY
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Contents
1. Introduction
2. Sonophoresis: a historical perspective
3. Generation of ultrasound
4. Biological effect of ultrasound
5. Mechanism of sonophoresis
6. Synergetic effect with other enhancers
7. Safety
8. Future trends
9. Applications of sonophoresis
10. Advantages
11. Limitations
12. Drugs used by sonophoretic drug delivery
13. Conclusion
14. References
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2. Sonophoresis: a historical
perspective
Sonophoresis was shown to enhance transdermal
drug transport about 40 years ago by Fellinger and
Schmidt who showed that application of ultrasound
increases transport of hydrocortisone across the skin.
ultrasound was also reported for local anesthetics.
Hofman and Moll who studied the percutaneous
absorption of benzyl nicotinate.
Bommannan et al. hypothesized that since the
absorption coefficient of the skin varies directly with
the ultrasound frequency
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1. Introduction
Definition: sonophoresis is the enhancement of
migration of drug molecules through the skin by
ultrasonic energy
Sonophoresis occurs because ultrasound waves
stimulate micro-vibrations within the skin epidermis
and increase the overall kinetic energy of molecules
When sound is emitted at a particular frequency, the
sound waves disrupt the lipid bilayers
The higher the frequency, the more dispersed the
transmission
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The skin
Protective layer with large no. of dead cells, hence
acts as barrier to penetration.
Penetration varies with humidity, pigmentation, age,
chemical status
Of all layers Stratum Corneum (SC) offers
maximum resistance. SC consists of keratinocytes
and lipid bilayer
Permeability can be increased by Chemicals,
Electrical Fields or Ultrasound which disrupt lipid
bilayer of SC and increase permeability.
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Figure 1: Ultrasonic generation system
Pulse generator Amplifier
Gate H. F. Generator
(20 KHz – 20MHz)
Transducer
Ultrasound gel
+ Drug Skin + Transducer interface
Stratum cornium
Skin
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3. Generation of ultrasound
Ultrasound is a sound wave possessing frequencies above 20 kHz .
The waves used for sonophoresis which reduce the resistance
offered by SC lie in the frequency range of 20 KHz to 20 MHz
Voltage generator produces a voltage which is applied to the
crystal of the transducer generating energy between 1 to10watts.
Ultrasound is generated with the help of a device called sonicator
which is a AC electric signal generator. It produces a AC electric
signal which is applied across a piezoelectric crystal i.e.
transducer. (The active element the transducer – it converts the electrical
energy to acoustic energy, and vice versa.)
Transducer made up of quartz, rochelle salt, lithium sulphate,
ammonium dihydrogen phosphate
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Conti…
Ultrasound is applied by bringing the transducer in
contact with the skin.
For sonophoretic delivery, the desired drug is
dissolved in a solvent and applied to the skin.
The coupling medium can be the same as the
solvent used to dissolve the drug or it can be a
commercial ultrasound coupling e.g. gel.
It Helps to match impedence of tissue with the
impedence of the transducer, so that the Ultrasound
gets properly into the tissue.
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Selection of ultrasound parameters
(1) Ultrasound frequency
a) Therapeutic Frequency Ultrasound (1-3 MHz)
b) Low Frequency Ultrasound (Below 1MHz)
c) High Frequency Ultrasound (Above 3MHz)
(2) Ultrasound intensity
Various ultrasound intensities in the range of 0.1 to 2 W/cm2
(3) Pulse length
Ultrasound can be applied in a continuous or pulse mode.
The pulse mode is frequently used because it reduces
severity of side effects such as thermal effects.
It was also found that permeability of membrane increased
from 6 to 56% as pulse length increased from 100 to 400 ms.
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4. Biological effect of ultrasound
Significant attention has thus been given to
investigating the effects of ultrasound on biological
tissues.
Ultrasound affects biological tissues via three main
effects
(1) Thermal effect may important when,
The tissue has a high protein content
A high intensity of continuous wave ultrasound is used
Vascularization is poor
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Conti…
(2) Cavitation effect
Bubble formation takes place. These bubbles grow and collapse and
results in cavitation.
may important when,
Low-frequency ultrasound is used
Small gas filled space are exposed
The tissue temperature is higher than normal
(3) Acoustic streaming – unidirectional fluid movement at velocity
gradient in US field. It increases heat transfer and acceleration of
fluid transport.
may important when,
The medium has an acoustic impedance different from its surrounding
The fluids in the biological medium is free to move
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5. Mechanism of sonophoresis
(1) Cavitation
Cavitation occurs due to the nucleation of small gaseous
cavities during the negative pressure cycles of ultrasound
This cavitation leads to the disordering of the lipid
bilayers and formation of aqueous channels in the skin
through which drugs can permeate
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Conti…
The minimum ultrasound intensity required for the onset
of cavitation, referred to as cavitation threshold
a) Cavitation inside skin
cavitation bubbles near the keratinocytes–lipid bilayers
interfaces may, in turn cause oscillations in the lipid
bilayers, thereby causing structural disorder of the SC
lipids
b) Cavitation out side skin
cavitation bubbles can potentially play a role in the
observed transdermal transport enhancement. these
bubbles cause skin erosion, due to generation of shock
waves, thereby enhancing transdermal transport
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Conti…
(2) Convective transport
Fluid velocities generated in this way may affect
transdermal transport by inducing convective
transport of the permeant across the skin.
especially through hair follicles and sweat ducts
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Conti…
(3) Mechanical stress
Ultrasound is a longitudinal pressure wave inducing
pressure variations in the skin, which, in turn, induce
density variation
Due to density variations, such as generation of
cyclic stresses because of density changes that
ultimately lead to fatigue of the medium
Lipid bilayers, being self-assembled structures, can
easily be disordered by these stresses, which result
in an increase in the bilayers permeability
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6. Synergistic effect with other enhancer
(1) Chemical enhancer
Enhanced Partitioning
Lipid Bilayer Disordering
Keratin Denaturation
e.g. Application of SLS alone for 90 min induced about 3-
fold increase in mannitol permeability, while application
of ultrasound alone for 90 min induced about 8-fold
enhancement. However, when combined, application of
ultrasound from 1% SLS solution induced about 200-fold
increase in skin permeability to mannitol
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Conti…
(2) Iontophoresis
Electrophoresis
Lipid Bilayer Disordering
Electroosmosis
e.g. The enhancement of heparin flux due to ultrasound +
iontophoresis treatment was about 56-fold. This
enhancement was higher than the sum of those obtained
during ultrasound alone (3-fold) and iontophoresis alone
(15-fold).
Thus, the effect of ultrasound and iontophoresis on
transdermal heparin transport was truly synergistic.
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7. Applications
1) Sonophoresis is used in the treatment of damaged
skin.
2) Hormone Delivery.
3) In surgery it helps in dissection and treatment of
biological tissue.
4) Low-Frequency Ultrasonic Gene Delivery.
5) Sonophoresis is also very useful in drug
enhancement in tumors. Most cancer therapy drugs
act intracellularly.
6) Ultrasound is used for Calcific Tendinitis of the
Shoulder.
8) Ultrasound Helps in Treating Tennis Elbow.
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8. Advantages
1) Avoids problems associated with gastrointestinal absorption due
to pH, enzymatic activity, drug-food interactions etc.
2) Substitute oral administration when the route is unsuitable as in
case of vomiting, diarrhea.
3) Avoids hepatic “first pass” effect.
4) Avoids the risks and inconveniences of parenteral therapy.
5) Reduces daily dosing, thus, improving patient compliance.
6) Extends the activity of drugs having short plasma half-life
through the reservoir of drug present in the therapeutic delivery
system and its controlled release characteristics.
7) Rapid termination of drug effect by removal of drug application
from the surface of the skin.
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Conti…
8) Elimination of the hazards and difficulties of I.V. infusions or
I.M. injections.
9) Enhance therapeutic efficacy, reduced side effects due to
optimization of the blood concentration-time profile and
elimination of pulse entry of drugs into the systemic
circulation.
10) Provide predictable activity over extended duration of time and
ability to approximate zero-order kinetics.
11) Improved control of the concentrations of drug with small
therapeutic indices.
12) Minimize inter and intrapatient variation.
13) Suitability for self-administration.
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9. Limitations
1) Only limited number of drugs can be absorbed in therapeutic
dose.
2) Many systemically effective therapeutic drugs produce skin
irritation.
3) The drug must have some desirable physicochemical properties
for penetration through stratum corneum.
4) If the drug dosage required for therapeutic value is more than
10mg/day, the transdermal delivery will be very difficult.
5) The barrier function of the skin changes from one site to another
on the same person, from person to person and with age
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10. Drug used by sonophoresis
(1) Sonophoresis with Corticosteroid
Majority of studies on sonophoresis, ultrasound was used
to enhanced the delivery of steroidal anti-inflammatory
drugs (e.g. hydrocortisone).
(a) Fellinger & Schmid (1954) showed that ultrasound could
carry hydrocortisone across a vascular membrane for the
effective treatment of polyarthritis
(b) Newman et al. (1992) suggested that hydrocortisone
sonophoresis is useful in the treatment of numerous
musculo-skeletal injuries.
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Conti…
(2) Sonophoresis with Salicylates
In combination with ultrasound it is thought that
Salicylate could be moved into deeper, subdermal tissues
to help to reduce pain.
(a) Ciccone et al. (1991) reported on a study to evaluate
ultrasound as an enhancer of topically applied Salicylates
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Conti…
(3) Sonophoresis with Anesthetics
The effectiveness of sonophoresis has been explored
extensively for delivery of local anesthetics.
(a) McElnay (1985) and associates described a sonophoresis
study using lignocain
(b) Moll (1979) studied the enhanced effects of topically
applied Lidocaine (140.7 mg) and Decadron (3.75 mg).
She obtained that 88% of the patients receiving
sonophoresis with Decadron and Lidocaine obtained
relief from their trigger point pain.
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Conti…
(4) Sonophoresis with other Drugs
(a) Benson and colleagues (1987, 1989) studied ultrasound
as an enhancer of benzydamine hydrochloride (3%) a
nonsteroidal anti-inflammatory drug.
(b) Levy et al. (1989) studied the sonophoresis of D-
mannitol, a diuretic.
(c) Romanenko (1992) used ultrasound with topically
applied Amphotericin B.
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Sonophoresis vs. iontophoresis
Both techniques deliver chemical to
biological tissues.
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Sr Sonophoresis Iontophoresis
no
1 Sonophoresis is the enhancement Iontophoresis is movement of ions
of migration of drug molecules of soluble salts across a membrane
through the skin by ultrasonic under an externally applied
energy potential difference
2 Sonophoresis uses acoustic energy Iontophoresis uses electiral current to
(ultrasound) to drive molecules transport ions into tissues
into tissues
3 Proper choice of ultrasound Proper choice of electricity
parameters including ultrasound parameters including Current density,
energy dose, frequency, intensity, Current profile, Duration of
pulse length, and distance of treatment, Electrode material,
transducer from the skin is critical Polarity of electrodes, is critical for
for efficient sonophoresis. efficient Iontophoresis
4 Sonophoresis usually employs a Iontophoresis usually employs a
ultrasound between 20 KHz to 20 direct current between 0.5 mA to 5.0
MHz mA
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5 In sonophoresis drugs mixing In Iontophoresis drug is mix with
with a coupling agent like gel, solvent
cream, ointment
6 The main mechanism for The main mechanism for transport of
transport of drug is “Cavitation” drug is “Electroporation”
7 Drug should be in aqueous or Drug must be in aqueous and must be
non aqueous and ionized or non in ionized form
ionized form
8 Enhanced partitioning, Lipid Electrophoresis, Lipid bilayer
bilayer disordering, Keratin disordering, Electroosmosis etc. gives
denaturation etc. gives the the synergetic effect of Iontophoresis
synergetic effect of sonophoresis
9 Ultrasound can be applied in a Electrical current can be applied only in
continuous or pulse mode continuous mode
10 Sonophoresis mostly used for Iontophoresis mostly used for
delivery of corticosteroids, local hyperhydrosis diagnosis of cystic
anesthetics and salicylates fibrosis, metallic and non-metallic ions
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13. Conclusion
Proper choice of ultrasound parameters including
ultrasound energy dose, frequency, intensity, pulse
length, and distance of transducer from the skin is
critical for efficient sonophoresis.
Various studies have indicated that application of
ultrasound under conditions used for sonophoresis
does not cause any permanent damage to the skin
Ultrasound also works synergistically with several
other enhancers including chemicals and
iontophoresis.
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14. References
N.K.Jain, Sonophoresis: Biophysical of Transdermal
Drug Delivery, Controlled and Novel Drug Delivery,
1st edition, 1997, page. 208-235
James Swarbrick, Transdermal Delivery:
Sonophoresis, Encyclopedia of pharmaceutical
technology, 3rd edition, Volume-6, 2007, page no.
3828-3842
Mr. Ashish Pahade, Dr. Mrs. V.M.Jadhav, Dr. Mr.
V.J.Kadam, Sonophoresis: an overview,
International Journal of Pharmaceutical Science,
2010, Volume 3, Issue 2, page. 24-32
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