Phonophoresis

1. “PHONOPHORESIS”
By : Dr. Urfeya Mirza
(Dept. Of Veterinary Surgery & Radiology)
Credit Seminar Titled

2.  Introduction
 Phonophoresis : A Historical Perspective
 Phonophoretic System
 Types Of Phonophoresis
 Commercially Used Devices In Phonophoresis
 Method Of Phonophoresis
 Mechanism Of Phonophoresis
 Applications Of Phonophoresis
 Advantages And Disadvantages
 Commonly Used Drugs
 Future Trends And Research
 Conclusion
OVERVIEW

3. INTRODUCTION
Phonophoresis (sonophoresis or ultrasonophoresis) is a
transdermal drug delivery system that uses ultrasound to
enhance the delivery of topically applied drugs
Nancy N Byl; 1995
Phonophoresis = -phono (sound) + -phoresis (transmission)
Transdermal drug delivery offers an attractive alternative
to the conventional drug delivery methods of oral and
parentral administration

4. Protective layer with large number of dead cells, hence acts as barrier to
penetration.
 Three layers:
Epidermis (Stratum corneum)
Dermis
Subcutaneous layer
Of all layers, Stratum Corneum offers maximum resistance. It consists of
keratinocytes and lipid bilayer.
“SKIN – A BARRIER” Contd,…

5. Contd,…
Skin – can be a good route of drug delivery..

6. Ultrasound waves when passed through the probe into the skin fluidize
the lipid bilayers of stratum corneum, enhancing the delivery of
topically applied drugs into the skin by a phenomenon –
‘PHONOPHORESIS’
Contd,…
Skin barrier can be crossed through US...

7. PHONOPHORESIS: A HISTORICAL
PERSPECTIVE
Fellinger and
Schmidt;
(1954)
reported First
successful
Phonophoretic
treatment using
hydrocortisone for
polyarthritis of the
hand’s digital
joints
Cameroy;
(1966)
reported
success using
carbocaine
sonophoresis
for closed
Colle’s
fractures
McElnay;
(1985)
reported
improved
dermal
penetration
using
ultrasound
for local
anesthetics
Bommannan
et al.
(1992)
Hypothesized
that the
absorption
coefficient of
skin varies
directly with
ultrasound
frequency
Hofman and
Moll;
(1993)
studied the
effect of
ultrasound on
penetration
of benzyl
nicotinate

8. Pulse generator Amplifier
H. F. Generator
(20 KHz – 20MHz)
Gate
Stratum cornium
Skin
Skin + Transducer
interface
Ultrasound gel
+ Drug
Transducer
Phonophoretic system

9. Basic components
Power
supply
Oscillator
circuit
Transformer Coaxial cable
Transducer
Coupling
medium
Contd,…

10. Types Of
Phonophoresis
1. Low
Frequency
Phonophoresis
Or Power
Ultrasound
(3–10 MHz)
2. Medium
Frequency
Phonophoresis
Or Therapeutic
Ultrasound
(1–3 MHz)
3. High
Frequency
Phonophoresis
Or Diagnostic
Ultrasound
(5–100 kHz)
Ashish Pahade et al.; 2010

11. Or Power Ultrasound (3–10 MHz)
Use:
For lithotripsy, cataract emulsification, liposuction, cancer therapy,
dental descaling and ultrasonic scalpels
Application of lower frequencies enhances transdermal transport of
low mol. wt drugs like corticosterone, hydrocortisone & high mol.wt
protiens like insulin, γ-interferon
Mitragotri et al.(1996)
1) Low frequency Phonophoresis

12. Or Therapeutic Ultrasound (1–3 MHz)
Intensity upto 2W/cm²
Use: For Physical therapy
Application of US in the therauptic range delivered hydrocortisone
about 5cm deep in pig tissues. This property has been used to deliver
hydrocortisone to joints in treatment of rheumatoid arthritis
Fellinger and Schmid(1954)
Kozanoglu et al.; (2003)
2) Medium frequency Phonophoresis

13. Or Diagnostic Ultrasound (5–100 kHz)
Use: For Clinical imaging
Effect of high frequency US on permeability of salicylic acid through
hairless guinea pig skin was studied and it was found that application of
US at 2MHz did not significantly enhance amount of salicylic acid
penetration, while 10 MHz resulted in 4 fold increase
Robert S. Oziomek et al.;(1991)
3) High frequency Phonophoresis

16. Commercial Phonophoretic
devices
Rekha Rao and Sanju Nanda; 2009

17. The SonoPrep device consists of a battery
operated power and control unit, a
handpiece containing the ultrasonic horn
and the disposable coupling medium
cartridge, and a return electrode
Ultrasonic horn vibrates 55,000 times per
sec applying energy to skin and creates
cavitation bubbles that expand and
contract which disrupts lipid bilayer
creating reversible microchannels in skin
through which large drug molecules can
be delivered
SonoPrep Skin Permeation Device :
Muktamath et al.; (2009)
Contd,…

18. ImaRx Sonoderm Device
It involves the administration of
their MRX-801 microbubbles and
ultrasound with or without
thrombolytic drug to break up
blood clots and restore blood
flow to oxygen-deprived tissues
MRX-801 microbubbles are a
proprietary formulation of a lipid
shell encapsulating an inert
biocompatible gas
Contd,…

19. Ekos Microlysis Device
The Microlysis device is a miniature
neurothrombectomy catheter that is
inserted into an artery in the brain until it
reaches the clot for the treatment of acute
ischemic stroke
Drug is infused through the catheter to
the tip, where a tiny ultrasound
transmitter is located
The ultrasound and drug are designed to
be administered simultaneously because
it has been shown that ultrasound energy
induces a temporary change in the
structure of a clot that allows the drug to
penetrate more efficiently into the inner
reaches of the blockage
Contd,…

20. Patch-Cap and U-strip applicator device
The U-strip Insulin Patch is an
ultrasonic drug delivery system
using an alternating sonic
transmission to effect pore dilation
and deposit large-molecule drugs
into the dermis
Skin pore expands to nearly twice
its original size and the insulin is
deposited in less than 3 seconds,
which can be detected by Pore
Expansion Visual and Dye Marker
Penetration Test
Contd,…

21. Visual demonstration of insulin (marked with a blue dye)
being deposited into an expanded skin pore via U-strip
ultrasonic Appplication…

22. METHOD OF PHONOPHORESIS
Lower ultrasonic frequencies and pulsing lead to deeper penetration
Standard duration is 5-10 minutes
Standard intensity is 1-2 W/cm²
Ultrasound is then applied as a direct contact method
Some gel mixed with standard ultrasound gel placed over transducer
head as coupling medium
Adequate quantity of drug rubbed into the skin over the target area

24. MECHANISM OF
PHONOPHORESIS
Transport Across
Skin
Intercellular
Appendageal
Transcellular
Modi et al., 2012

25. Mechanical pressure
from US beam/ micro-
massage
Acoustic streaming
Local heat from US
Temporary change in
Stratum corneum
Cavitation
Modi et al., 2012
Mechanism Contd,…
Ultrasound exerts its effect through :

27. Micro-massage :
It is a mechanical effect in which the
ultrasound wave traveling through
tissues will cause cells to vibrate,
possibly enhancing tissue fluid
movement and interchange
Mechanism Contd,…

28. Acoustic streaming :
It is a small scale eddying of fluids
near a vibrating structure such as
cell membranes & the surface of
stable cavitation gas bubble.
Or it is the steady, circular flow of
cellular fluid induced by US
Mechanism Contd,…

29. Temporary change in
stratum corneum:
Increases the diameter of skin
portals(Pores, Hair follicles,
Sweat glands) to allow the
medication to pass
Mechanism Contd,…

30. Local heat from Ultrasound:
Energy absorbed by the tissues, will cause oscillation of
the molecules of that tissues about their mean position,
and thus result in heat generation.
The thermal effects of ultrasound are :
*Acceleration of metabolic rate
*Alteration of nerve cond. velocity
*Increased circulation
*Increased soft tissue extensibility
Mechanism Contd,…

31. Cavitation :
The formation of gas filled bubbles within the tissues & body fluids during
the phase of relaxation or rarefaction of US waves.
Stable cavitation
*Occurs at therapeutic doses of US
Formation & growth of gas bubbles by accumulation
of dissolved gas in the medium
Unstable (transient) cavitation
*Occurs at higher US intensities
Formation of bubbles at the low pressure part of the
US cycle
These bubbles then collapse very quickly releasing a large amount of
energy which is detrimental to tissue viability
Mechanism Contd,…

33. 1) In the treatment of damaged skin
2) Hormone Delivery
3) Ultrasonic Gene Delivery
4) Phonophoresis is also very useful in drug enhancement in granulomas and
tumors. Most cancer therapy drugs act intracellularly
5) Ultrasound is used for Calcific Tendinitis of the Shoulder
6) Ultrasound Helps in Treating Tennis Elbow and Tendon Problems
7) The Dolphin Therapy and Sonophoretic model
Lopes CM et al.; 2015
APPLICATIONS OF PHONOPHORESIS

34. •Skin aging results in loss of collagen and fat cells in subcutaneous layer of skin.
•Retinoids and vitamin C are excellent anti-aging and anti-wrinkle agents that
enhance the new collagen production in the skin.
•With phonophoresis it is possible to get 4000% better penetration after 2
minutes at 20 KHz than with topical application.
Applications Contd,…

35. Ultrasound Helps In Treating Tennis Elbow And Tendon Problems
•It is possible to successfully treat chronic tendon problems such as “Tennis
Elbow”, “Jumper’s Knee” with the help of ultrasound as an alternative to
surgery.
Applications Contd,…

36. The dolphin therapy
arouses a great interest
in the whole world,
since it causes analgesic
effect, removal of
depression and
improvement of
learning abilities of the
children suffering from
autism.
The Dolphin Therapy And Sonophoretic Model
Applications Contd,…

37. Applications In Veterinary Medicine
Phonophoresis is a safe alternative due to the ease of
administration compared to oral and parentral medication
Subcutaneous administration of anti-inflammatory medications,
such as hydrocortisone treat bursitis, tendonitis and other
myofascial pathologies
Ultrasound with topical anesthesia rapidly decreases pain of
intravenous cannulation in animals
Treatment of localized swellings and granulomas

39. ADVANTAGES OF PHONOPHORESIS :
Enhanced drug penetration
Strict control of penetration rate
Avoids risks and inconveniences of parenteral therapy
Avoids hepatic first pass metabolism and gastric irritation
Allows easy termination of drug effect simply by stoping drug application
Sreerai SR; 2003

40. Not immunologically sensitizing
Low risk of introducing infection
Noninvasive, painless technique which permits both local and systemic
treatment effects
Extends activity of short plasma half-life drugs by its controlled release
characteristics
Suitability for self-administration
Sreerai SR; 2003
Contd,…

41. DISADVANTAGES
Stratum corneum must be intact for effective drug penetration
Time consuming
Minor tingling, irritation and burning
LIMITATIONS
The barrier function of skin changes varies according to species,
application site and age
Low skin permeability
Limited number of drugs

42. Commonly used Drugs
Compound Formulation Experimental
conditions
Membrane
used
Results
Caffeine Solution in pH 7.4
phosphate buffer
40 KHz,
0.44 W/cm², C
Hairless mouse
skin In vitro
4‐fold ↑ in conc. Of
drug in skin
Campos et al.,(2007)
Corticosterone
(either ³H or ¹⁴C
labelled)
Solution of the
Radio-labelled
permeant in PBS
20 KHz,
125mW/cm²,
100msec pulses
applied every sec
Human cadaver
Skin In vitro
80‐fold ↑ in conc. of
drug in skin
Benson et al.,(1989)
Doxorubicin Micellar
encapsulated
doxorubicin
20,476 KHz,
1 W/cm²,
15 min treatment
Rats
In vivo
Application of
ultrasound in
combination with
drug therapy was
effective in reducing
tumor growth rate,
irrespective of
which frequency
was employed
Huseini et al.,(2005)

43. Compound Formulation Experimental
conditions
Membrane used Results
Heparin Solution of
Heparin
20 KHz,
7 W/cm²,
P
Pig skin
In vitro
21‐fold ↑ in conc.
of drug in skin
Mitragotri & Kost,
(2001)
Insulin Insulin reservoir 20 KHz,
100 mW/cm²,
20 or 60 min
treatment
Rats
In vivo
For the 60 min
exposure group, the
glucose level was
found to decrease
from the baseline to
‐267.5 ± 61.9 mg/dL
in 1 hr.
Boucaud et al.,
(2001)
Morphine Solution in pH 7.4
phosphate
buffer
40 KHz,
0.44 W/cm²,
C
Hairless mouse skin
In vitro
10‐fold increased in
concentration of
drug in skin
Monti et al.,(2001)
Contd,…

44. FUTURE TRENDS
(1) Vaccination
Topical delivery of vaccines such as the tetanus toxoid offers several advantages
over needle-based immunisations, including ease of administration.
Tezel A et al.,2005
(2) Gene therapy
This is one of the most rapidly expanding fields of ultrasound therapy research.
Ultrasound has been shown to enhance gene transfer into cells. Significantly
better transfection is achieved in the presence of cavitation.
Vogel JC, 2000
(3) Ocular delivery
Ultrasound has the potential to provide an efficient and minimally invasive
method for drug delivery into the eye.
Application of 20 kHz ultrasound at intensity of 14 W/cm2 for enhancement of
corneal permeability to glaucoma drugs of different lipophilicity was investigated.
Zderic V et al.,2004
www.ajptr.com

45. Contd,...
(4) Nail delivery
It was recently reported that ultrasound can also be used for nail delivery of drugs.
Low-frequency ultrasound enhanced the permeability of the model nail plate to
topically applied drugs.
Torkar A et al.,2007
(5) Drug delivery to the brain
Ultrasound with a microbubble contrast agent can be used to transiently disrupt the
blood–brain barrier, allowing non-invasive localised drug delivery directly to amyloid
plaques in mouse models of Alzheimer’s disease.
Raymond S B et al.,2008
(6) Sports medicine
A new direction for ultrasound therapy has been revealed by recent research.
During fresh fracture repairs, low-intensity pulsed ultrasound reduced healing times
by 30–38%. When applied to non-united fractures, it stimulated union in 86% of cases.
Henzl MR, 2002
(7) Cardiovascular therapy
Ultrasound-targeted microbubble destruction is a promising new method.
Ultrasound transducer-tipped catheters are being developed for treatment of
cardiovascular diseases.
Bekeredjian R et al.,2005

46. Contd,…
(8) Hormone replacement therapy
Ultrasound is a feasible approach to externally affect the release rates of implantable
contraceptive delivery systems.
Kost J et al.,1994
(9) Sonoporation and sonodynamic therapy
Chemical activation of drugs by ultrasound energy for the treatment of cancer is
another new field recently termed ‘sonodynamic therapy’.
Cavitation can also aid delivery of drug contained within pluronic micelles.
Husseini G A et al.,2005
(10) Sonothrombolysis
An interesting application for therapeutic sonography is the thrombolytic effect of
ultrasound.
A positive effect of ultrasound on clot dissolution is reported.
Trubestein G et al.,1976
(11) Nanoparticles
Ultrasonic drug and gene delivery from nanocarriers has tremendous potential
because of the wide variety of drugs and genes that could be delivered to targeted
tissues by fairly non-invasive means.
Husseini GA et al.,2008

47. Future Research
Determining best ultrasound parameters
to maximize phonophoresis
Determining best phonophoresis
procedure
Determining local effect vs. systemic
effect
Determining a method of dosing the
drug when administered in this manner

48. 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 phonophoresis
Various studies have indicated that application of
ultrasound under conditions used for phonophoresis does
not cause any permanent damage to the skin
Ultrasound also works synergistically with several other
enhancers including chemicals and iontophoresis