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Sonophorosis by akshay patel
1. A
Seminar on
SONOPHORETIC
DRUG DELIVERY
Prepared By:
Akshay.G.Patel
M.PHARM (SEM-3)
ROLL NO-5
DEPARTMENT OF PHARMCEUTICS
NOOTAN PHARMACY COLLEGE
2. 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
2
3. 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
3
4. 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.
4
5. 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
5
6. 3. Generation of ultrasound
Ultrasound is a sound wave possessing frequencies
above 20 kHz .
These waves are characterized by two main
parameters, frequency and amplitude
The waves used for sonophoresis which reduce the
resistance offered by SC lie in the frequency range
of 20 KHz to 20 MHz
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.
6
7. 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
7
8. 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.
8
9. 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 urea permeability of cuprophane
membrane increased from 6 to 56% as pulse length increased
from 100 to 400 ms.
9
10. 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
Bone is included in the heated volume
Vascularization is poor
10
11. Conti…
(2) Cavitation effect may important when,
Low-frequency ultrasound is used
Grassy fluids are exposed
Small gas filled space are exposed
The tissue temperature is higher than normal
(3) Acoustic streaming may important when,
The medium has an acoustic impedance different from its
surrounding
The fluids in the biological medium is free to more
Continuous wave application is used
11
12. 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
12
13. 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
13
14. 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
14
15. 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
15
16. 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
16
17. 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.
17
18. 7.Safety
The World Federation for Ultrasound in Medicine
and Biology (WFUMB) has issued several
publications related to safety of ultrasound
bioeffects, addressing specifically thermal bioeffects
and non-thermal bioeffects
ultrasound affecting the structure of the skin: is it a
reversible or irreversible change?
What is the role of the free radicals that are
generated during the cavitation process within the
skin?
18
19. 8. Future trends
(1) Vaccination
In recent years, the potential for exploiting the skin for
purposes of vaccination has received a great deal of
attention
One common strategy is to use an adjuvant, which is a
compound used to enhance the immune response to
vaccine compounds
Ultrasound can be used to enhance skin permeability to
both the adjuvant and the vaccine, and hence to facilitate
their delivery to the target cells.
19
20. Conti…
(2) Gene therapy
Gene therapy is a technique for correcting defective
genes that are responsible for disease development, most
commonly by replacing an „abnormal‟ disease-causing
gene with the „normal‟ gene
The most obvious candidate diseases for cutaneous gene
therapy are the severe forms of particular genodermatoses
(monogenic skin disorders), such as epidermolysis
bullosa
Other applications might be healing of cutaneous wounds
such as severe burns and skin wounds of diabetic origin
20
21. 9. Applications
1) Sonophoresis is used in the treatment of damaged skin.
2) Hormone Delivery.
3) In surgery it helps in dissection, connection, built-up and
treatment of biological tissue.
4) Low-Frequency Ultrasonic Gene Delivery.
5) Sonophoresis is also very useful in drug enhancement in
granulomas and tumors. Most cancer therapy drugs act
intracellularly.
6) Ultrasound is used for Calcific Tendinitis of the Shoulder.
7) The dolphin therapy and sonophoretic model.
8) Ultrasound Helps in Treating Tennis Elbow and Tendon
Problem.
21
22. 10. Advantages
1) Avoids vagaries 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.
8) Rapid identification of the medication in emergencies. (e.g..
Non-responsive, unconscious, or comatose patient.)
22
23. Conti…
9) Elimination of the hazards and difficulties of I.V. infusions or
I.M. injections.
10) 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.
11) Provide predictable activity over extended duration of time and
ability to approximate zero-order kinetics.
12) Improved control of the concentrations of drug with small
therapeutic indices.
13) Minimize inter and intrapatient variation.
14) Suitability for self-administration.
23
24. 11. Limitations
1) Only limited number of potent 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
24
25. 12. 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.
25
26. 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
26
27. 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.
27
28. 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.
28
30. 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
30
31. 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
31
32. 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.
32
33. 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
http://www.dolphintherapy.ru/en/sonoforez.shtml
33