This document discusses iontophoresis and sonophoresis drug delivery systems. Iontophoresis uses a low-intensity electrical current to deliver ionized drugs through the skin. It works by three mechanisms: ion-electric field interaction, increasing skin permeability, and electro-osmosis. Sonophoresis uses ultrasound to increase skin permeability and the absorption of topical compounds. Both systems aim to disrupt the lipid bilayers in the stratum corneum to enhance drug penetration without needles. The document outlines the components, principles, advantages, and factors affecting iontophoresis delivery. It also briefly discusses sonophoresis and provides a high-level overview of both non-invasive delivery methods.

1. TOPIC:IONTOPHORESIS-
SONOPHORETIC SYSTEM
S U B M I T T E D B Y : C H A I T R A L I G I J A R E
Subject: NOVEL DRUG DELIEVERY SYSTEM
2PH801

2. CONTENTS
Introduction
• Iontophoretic drug delivery system
• Sonophoretic drug delivery system
• Iontophoretic Vs sonophoretic drug delivery system
• Reference

3. INTRODUCTION
THE SKIN-
Protective layer with large no. of dead cells, hence acts as barrier to
penetration. The skin accounts for about 15% of adult’s wt.
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.

5. IONTOPHORETIC DRUG DELEIVERY SYSTEM
Iontophoresis can be defined as the permeation of ionized drug molecules
across biological membranes under the influence of electrical current.
Principles of Iontophoresis :
Electrode placement is dependent on the electric charge of the ion which is to
be delivered into the tissue.
A positive ion will be delivered from the positive electrode and a negative ion
will be delivered by the negative electrode.
Electrical energy assists the movement of ions across the stratum corneum
according to the basic electrical principle “like charges repel each other and
opposite charges attract each other.”

8. ADVANTAGES OF IONTOPHORESIS
1) Virtually painless when properly applied.
2) Provides option for patients unable to receive injections.
3) Reduced risk of infection due to non-invasive nature.
4) Medications delivered directly to the treatment site.
5) Minimizes potential for tissue trauma from an injection.
6) Treatments are completed in minutes.

9. DRAWBACK
1) Excessive current density usually results in pain.
2) Burns are caused by electrolyte changes within the tissues.
3) The high current density and time of application would generate extreme
pH, resulting in a chemical burn.
4) This change in pH may cause the sweat duct plugging perhaps precipitate
protein in the ducts.
5) Electric shocks may cause by high current density at the skin surface.
6) Ionic form of drug in sufficient concentration is necessary for iontophoretic
delivery.

10. IONTOPHORETIC DRUG DELIVERY SYSTEM WORKS
BY THREE MECHANISM
(a) Ion-electric field interaction provides an additional force that drives ions
through the skin.
(b) The flow of electric current increases the permeability of the skin.
(c) Electro-osmosis produces bulk motion of solvent that carries ions or
neutral species with the solvent stream. Electro-osmotic flow occurs in a
variety of membranes and is in the same direction as the flow of counter-
ions. It may assist or hinder drug transport.

11. COMPONENTS
1. Power source for generating controlled direct current.
2. Electrodes that contain and disperse the drug.
3. Negatively or positively charged aqueous medication.
4. A localized treatment site

12. MOVEMENT OF IONS IN SOLUTION
Ionization- Soluble compounds dissolve into ions suspended in solutions that
are called electrolytes.
Electrophoresis- Movement of ions in solution according to the electrically
charged currents acting on them.
Cathode = Negatively charged electrode
i. Highest concentration of electrons
ii. Repels negatively charged ions
iii. Attracts positively charged ions
iv. Accumulation of positively charged ions in a small area creates an alkaline
reaction.

13. CONTD…
Anode = Positively charged electrode
i. Lower concentration of electrons
ii. Repels positively charged ions
iii. Attracts negatively charged ions
iv. Accumulation of negatively charged ions in a small area creates an acidic
reaction
Positively charged ions are driven into tissues from positive pole
Negatively charged ions are driven into tissues from negative pole
Knowing correct ion polarity is essential.

14. CONTD…
Force which acts to move ions through the tissues is determined by
i. Strength of the electrical field
ii. Electrical impedance of tissues to current flow.
Strength of the electrical field is determined by the current density
i. Difference in current density between the active (Active electrode- the one being
used to drive the ion into the tissue)and inactive electrodes establishes a gradient
of potential difference which produces ion migration within the electrical field.
Current density may be altered by
i. Increasing or decreasing current intensity
ii. Changing the size of the electrode:Increasing the size of the electrode will
decrease current density under that electrode.

15. CONTD…
Current density should be reduced at the cathode
i. Alkaline reaction is more likely to produce tissue damage than acidic
reaction.
ii. Thus negative electrode should be larger to reduce current density.
Higher current intensities necessary to create ion movement in areas where
skin and fat layers are thick further increasing chance of burns around
negative electrode
Sweat ducts are primary paths by which ions move through the skin and act to
decrease impedance facilitating the flow of direct current as well as ions.
The quantity of ions transferred into the tissues through iontophoresis is directly
proportional to
i. Current density at the active electrode
ii. Duration of the current flow
iii. Concentration of ions in solution
Once the ions pass through skin they recombine with existing ions and free
radicals in the blood thus forming the necessary new compounds for
favorable therapeutic interactions .

16. IONTOPHORESIS GENERATOR
 Produce continuous direct current in the order as per the
requirement.
 Assures unidirectional flow of ions.
 It also consist of a timer for regulating the supply of current. 11
 Intensity control:
1 to 5 mA
Constant voltage output that adjusts to normal variations in tissue
impedance thus reducing the likelihood of burns.
Automatic shutdown if skin impedance reduces to preset limit.
 Adjustable Timer for giving the duration of treatment.

18. ELECTRODES OF IONTOPHORESIS
Active pad- This electrode have a small chamber covered by a semipermeable
membrane into which ionized solution may be injected.
Dispersive pad- Also known as Inactive pad. Dispersive pad should be larger
than active pad to reduce the current density leading to reduction of
irritation.
The polarity of these electrode depends on the characterictics of drugs and
these electrodes self adheres to the skin .

19. Electrodes Material
The electrode materials used for iontophoretic delivery are to be harmless to
the body and sufficiently flexible to apply closely to the body surface.
The most common electrodes used for iontophoretic drug delivery are :
1. Aluminum foil
2. Platinum and
3. Silver/Silverchloride
A better choice of electrode is silver/silver chloride because it minimizes
electrolysis of water during drug delivery.

20. Electrode Preparation
To ensure maximum contact of electrodes skin should be
shaved and cleaned prior to attachment of the electrodes.
Do not excessively abrade skin during cleaning since
damaged skin has lowered resistance to current and a burn
might occur more easily.
Attach self-adhering active electrode to skin.
Inject ionized solution into the chamber.
Attach self-adhering inactive electrode to the skin and attach
lead wires from generator to each.
Electrode Placement
• Size and shape of electrodes can cause variation in current
density (smaller = higher density)
• Inactive electrodes should be separated by a distance atleast
the diameter of active electrode

21. FACTORS AFFECTING IONTOPHORETIC DRUG
DELEIVERY SYSTEM
Operational factor
1) Composition of the formulation
 Concentration of the drug
solution
 pH of the donor solution
 Ionic strength
 Presence of co-ions
2) Physicochemical properties
 Molecular size
 Polarity
 Charge
 Molecular weight

22. 3) Experimental conditions
 current density
 polarity of electrodes
 electrode material
4) Biological factors
 Intra and inter variability
 Regional blood flow
 Skin pH
 Condition of skin

23. IONTOPHORESIS FORMULATION
Solvent
• Water
Co-solvent
• PEG
• glycerol
• Ethanol
• PG
Matrix
• Hydrophillic
• Nonionizing polymer
Drug salt
• Halide salt
Counter reservoir
• Weak acid
• Weak base

24. Iontotrophic patch

25. SONOPHORETIC DRUG DELIEVERY SYSTEM
Sonophoresis, is a process that exponentially increases the absorption of
topical compounds (transdermal delivery) with high-frequency ultrasound.
Sonophoresis occurs because ultrasound waves stimulate micro-vibrations
within the skin epidermis and increase the overall kinetic energy of
molecules making up topical agents.
It is thought that high-frequency ultrasound can influence the integrity of the
stratum corneum and thus affect its penetrability.
Among the agents examined are
hydrocortisone,
lidocaine,
salicylic acid

26. 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.

27. CONTD…
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.

28. 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.

29. UNDERSTANDING THE DRUG DELIVERY
Sonophoresisor ultrasound can be used to
create holes in the skin for fluids to
travel into or out of the skin. By emitting
sound at a particular frequency, the
sound waves disrupt the lipid-bilayer of
the stratus corneum (outermost layer of
skin which has the most barrier
properties), creating more and larger
microchannels in the skin. Drugs can be
administered through these channels .

30. 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.
The crystal undergoes rhythmic deformation due to electric current, producing
ultrasonic vibrations.
In the process of ultrasonic wave generation, electric energy is converted into
mechanical energy in the form of oscillations, which generates acoustic

32. 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.

33. 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

34. VARIOUS TYPES OF MECHANISM FOR
SONOPHORESIS
Although considerable attention has been given to the investigation
of sonophoresis in the past years, its mechanisms were not clearly
understood, reflecting the fact that several phenomena may occur in the
skin upon ultrasound exposure. These include:
1) Cavitation (generation and oscillation of gas bubbLes).
2) Thermal effects (temperature increase).
3) Induction of convective transport.
4) Mechanical effects (occurrence of stresses due to pressure variation
induced by ultrasound.)

35.  CAVITATION EFFECTS:
Cavitation is the formation of gaseous cavities in a medium ultrasound
exposure. The primary cause for cavitation is ultrasound -induced pressure
variation in the medium . It is further of 2 types
1. Inertial cavitation: The rapid growth and collapse of a bubble.
2. Stable cavitation: The slow oscillatory motion of a bubble in an ultrasound
field.
Collapse of cavitation bubbles releases a shock wave that can cause structural
alteration in the surrounding tissue. The cavitational effects vary inversely
with ultrasound frequency and directly with ultrasound intensity
At higher frequencies it becomes difficult to generate cavitation due to
the fact that the time between the positive and negative acoustic pressures
becomes too short, diminishing the ability of dissolved gas within the
medium to diffuse into the cavitation nuclei . For example, application of
ultrasound at 20 kHz induced transdermal transport enhancements of up to

36. FIGURE: CAVITATIONAL EFFECT

37.  Thermal effects
Ultrasound does not pass through tissues with 100% efficiency. During its
propagation, the ultrasound wave is partially scattered and absorbed by
the tissue medium, resulting in attenuation of the emitted wave. The lost
energy is converted into heat, while the remainder of the wave
penetrates into and propagates through the medium
 Convective transport
Fluid velocities are generated in porous medium exposed to ultrasound
due to interference of the incident and reflected ultrasound waves in the
diffusion cell and oscillations of the cavitation bubbles. Experimental findings
suggest that convective transport does not play an important role in the

38.  Mechanical effects
Ultrasound is a longitudinal pressure wave inducing sinusoidal pressure
variations in the skin, which, in turn, induce sinusoidal density variation. At
frequencies greater than 1 MHz, the density variations occur so rapidly
that a small gaseous nucleus cannot grow and cavitational effect cease.
But other effects 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. Lipid bilayers, being self-assembled
structures, can easily be disordered by ese stresses, which result in an
increase in the bilayer permeability. This increase is, however, non-significant
and hence mechanical effects do not play an important role in therapeutic
sonophoresis. Thus, cavitation induced lipid bilayer disordering is found to
be the most important cause for ultrasonic enhancement of transdermal

39. DEPENDENCE OF SONOPHORETIC SKIN
PERMEABILISATION ON
ULTRASOUND
 Frequency: Attenuation of an acoustic wave is inversely proportional to
its frequency, and thus as the frequency increases, the ultrasound
penetrates less deeply into the skin. Low-frequency ultrasound(f~20
kHz) is significantly more potent in enhancing skin permeability
compared to therapeutic ultrasound (f~1-3 MHz)
 Intensity: The skin conductivity increases with increasing intensity,
but upto a certain point, and then drops off. This is due to the increase
in the total energy put into the system with increasing ultrasound
intensity. The linearity between skin conductivity and ultrasound
intensity may break down at higher intensities (>15 W/cm2 ) due to
other effects such as ‘acoustic decoupling’ which is a phenomena
where cavitation generated near the ultrasound source results in
the formation of large number of gaseous cavities, thus reducing the
amount of energy delivered to the system. The intensity is directly
dependent on the acoustic energy emitted and the speed of sound in the
medium.

40.  Mode: Ultrasound can be applied in continuous or pulsed (sequential)
mode. The rise in temperature is faster and more intense with the
continuous mode.
 Threshold energy: Skin conductivity enhancement is directly
proportional to the incident ultrasound energy density. There exists a
threshold ultrasound energy below which the effect of ultrasound on skin
conductivity cannot be detected, and beyond the threshold value the
conductivity increases with the energy density.

41. VARIATION IN ENHANCEMENT OF SONOPHORESIS FOR
VARIOUS DRUGS
The observed enhancement for a particular drug depends significantly
on the physicochemical and pharmacokinetic properties of the
permeant, and hence varies from drug to drug. Another factor
of great importance in the selection of drugs is their biological half-
life; the lower the half-life, the faster the rate at which steady state
levels in blood are attained. The sonophoretic enhancement of
transdermal drug transport can be quantitatively predicted based
on knowledge of two physiochemical properties of the drug:
passive skin permeability, and octanol–water partition coefficient, K
o/w.

42. MARKETED PRODUCTS
Microlysis:
The Microlysis developed by Ekos is designed to deliver ultrasound
and thrombolytic (clot-dissolving) drug directly into the area of a brain
clot. The Microlysis device is a miniature catheter that is inserted into
an artery in the brain until it reaches the clot. 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.

43. • SonoPrep:
Sontra Medical Corporation is the pioneer of SonoPrep, a
non-invasive and painless ultrasonic skin permeation
technology. The medical device uses an ultrasonic method
to make skin temporarily more permeable. The small,
battery-powered device applies a low-frequency, ultrasonic
energy to the skin for 15 seconds. The sound waves open small
cavities in the skin by disorganizing the lipid bi-layer, creating
tiny, reversible channels
through which fluids can be extracted and delivered. The
skin goes back to its normal state within 24 hours. Sontra
is investigating the delivery of several large proteins and
peptides by incorporating the use of the SonoPrep device
in combination with transdermal patches to deliver the drug
transdermally. Sontra Medical is also developing a vaccine
against dengue fever .

44. Sonoderm Technology: The sonoderm is a device based on the
generation of low frequency ultrasounds waves acting on a
vibratory and thermal way, this technology is called
ultrasonotherapy. ImaRx is now developing Sonolysis in which MRX-
801 microbubbles and ultrasound waves are used to disperse the
blood clots and restore blood flow.
Patch-Cap and U-strip: In June 2005, Dermisonics obtained the patent for
the ultrasonic Patch-Cap and a flexible patch for transdermal
delivery of drugs via ultrasound.The U-Strip is a drug delivery
system .

45. USES OF SONOPHORESIS
Sonophoresis also used in treatment of glaucoma and corneal infection,
to increase the permeability of drugs.
Ultrasound can also be used for nail delivery of drugs.
Ultrasound helps in treatment of wide varieties of sports injuries such as tennis
elbow, tendon problems, repairing damaged ligaments, muscle spasms,
stiff joints, fractured bones and cartilage. Also used in healing of
wounds, skin rejuvenation, nerve stimulation, and improving the strength
and elasticity of scar tissues
Sonophoresis is used in the treatment of damaged skin.
Process of cavitation takes place during the treatment but the cavities
disappear after the treatment and histological examination has shown
that the skin is normal after treatment.
Hormone delivery.
Low-frequency ultrasonic gene delivery.
Ultrasound is used for Calcific Tendinitis of the s.houlder

46. 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. Ultrasound could carry
hydrocortisone across a vascular membrane for the effective treatment of
polyarthritis
Also, hydrocortisone sonophoresis is useful in the treatment of numerous musculo-
skeletal injuries.
2) Sonophoresis with Salicylates:
In combination with ultrasound, Salicylate could be moved into deeper, subdermal
tissues to help to reduce pain.

47. 3) Sonophoresis with Anesthetics:
The effectiveness of sonophoresis has been explored extensively for
delivery of local anesthetics. Sonophoresis with Decadron and Lidocaine
results in relief from their trigger point pain.
4) Sonophoresis with other Drugs:
Ultrasound as an enhancer of benzydamine hydrochloride (3%) a
nonsteroidal anti-inflammatory drug.
Sonophoresis of D- mannitol, a diuretic.
Ultrasound with topically applied Amphotericin B.

50. SONOPHORETIC VS. IONTOPHORETIC DRUG
DELIVERY SYSTEM
Sonophoresis Iontophoresis
Sonophoresis is the enhancement of
migration of drug molecules by ultrasonic
energy.
Iontophoresis is movement of ions
of soluble salts across a membrane through the
skin under an externally applied potential
difference
Sonophoresis uses acoustic energy
(ultrasound) to drive molecules into tissues.
Iontophoresis uses electiral current to transport
ions into tissues
Proper choice of ultrasound parameters
including ultrasound energy dose, frequency,
intensity, pulse length and distance of
transducer from the skin, is critical for for
efficient sonophoresis.
Proper choice of electricity parameters including
Current density, Current profile, Duration of
treatment, Electrode material, Polarity of
electrodesis critical for efficient Iontophoresis.
Sonophoresis usually employs a ultrasound Iontophoresis usually employs a direct current

51. In sonophoresis drugs mixing with a
coupling agent like gel, cream,
ointment.
In Iontophoresis drug is mix with
solvent .
The main mechanism for transport of
drug is “Cavitation”
The main mechanism for transport of
drug is “Electroporation”
Drug should be in aqueous or non
aqueous and ionized or non in ionized
form.
Drug must be in aqueous and must be
ionized form.
Enhanced partitioning, Lipid bilayer
disordering, Keratin denaturation etc
gives the the synergetic effect of
sonophoresis
Electrophoresis, Lipid bilayer
disordering, Electroosmosis etc. Gives
synergetic effect of Iontophoresis .
Ultrasound can be applied in a Electrical current can be applied only
CONTD….

52. REFERENCES
• N.K.Jain, Sonophoresis: Biophysical of Transdermal Drug Delivery,
Controlled and Novel Drug Delivery, 1 st edition, 1997, page. 208-235
• James Swarbrick, Transdermal Delivery: Sonophoresis, Encyclopedia of
pharmaceutical technology, 3 rd 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
• Wikipedia
• slideshare

53. THANK YOU