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MICROCHANNEL BASED TRANSDERMAL DELIVERY
USING RADIO FREQUENCY: A NOVEL APPROACH
Author
Name : Parikh Ankitkumar
Yogeshbhai.
College: Institute of pharmacy;
Nirma university,
Year: 4th year
E mail id:
[email protected]
o.in
Profile link:
http://www.pharmainfo.net/
ankit
Co-author
Name: Shah Jigar Nareshkumar Faculty
College: Institute of Pharmacy,
Nirma University,
Ahmedabad.
Email id: [email protected],
[email protected]
Profile link:
http://www.pharmainfo.net/
jigsh12
Introduction
DEFINATION:
Transdermal permeation (percutaneous absorption):
• The passage of substance from the outside of the skin
through its various layers into the bloodstream.
Drug
• Transdermal permeation
Particles
•
Transdermal permeation
Basic Advantages of transdermal
delivery system
• Avoids first-pass effect
• Allows effective use of drugs with short biological
half-life
• Allow administration of drugs with narrow
therapeutic window
• Provides controlled plasma level of very potent drugs
• Drug input can be promptly interrupted when toxicity
occurs
• Increased patient compliance
Disadvantages of TDS
• Drug that require high blood levels cannot be
administered
• Adhesive may not adhere well to all types of skin
• Drug or drug formulation may cause skin irritation or
sensitization
• Uncomfortable to wear
• May not be economical.
Factors Consideration for TDS
development
•
•
•
•
•
Skin Characteristics
Bioactivity of drug
Formulation
Adhesion
System design
The Structure of Human Skin:
Factor influence the transdermal route
• Time scale of permeation (steady-state vs.
transient diffusion)
• Physicochemical properties of penetrant (pKa,
molecular size, stability, binding affinity,
solubility, partition coefficient)
• Integrity and thickness of stratum corneum
• Density of sweat glands and folicles
• Skin hydration
• Metabolism
• Vehicle effects
Process of transdermal permeation
Various
Various approaches
approches
Active
Passive
Suffers from various
limitations, primarily
due to lack of
permeability of many
drugs & skin nature.
Iontophoresis
Electroporation
Micro needle
Microchannel
based system
Rf
systems
Various Approaches
a) Transdermal diffusion, possibly in the presence of a chemical enhancer, takes
place by a tortuous route across the stratum corneum, winding around cells and
occurring along the interfaces of extracellular lipid bilayers.
b) Low-voltage electrical enhancement by iontophoresis can make transport
pathways through hair follicles and sweat ducts more accessible.
c) High-voltage enhancement by electroporation has been shown to occur via
transcellular pathways made accessible by disrupting lipid bilayers. The
application of ultrasound seems to make pathways a and c more permeable by
disorganizing lipid bilayer structure.
d) Microneedles and RF cell ablation create micron-scale holes in skin to
provide pathways for drug transport.
Limitation of passive & various active
drug delivery system
• Most of the methods suitable for small
molecules
• Not practical enough to offer viable solutions
for pharmaceutical needs. This is due to
various limitations such as an insufficient
delivered dose or duration of delivery.
• Electric charge required (Iontophoresis)
• Required pH environment for effective
delivery of drug
Micro channel based trans delivery
system using RF
•
A novel system for active transdermal drug
delivery, based on creating microchannels in the
skin using radio-frequency (RF) electrical current.
• This novel and unique approach provides various
advantages such as;
- A predicted and precisely controlled drug delivery
rate,
- Efficient delivery of a wide range of molecular sizes
including proteins and other macromolecules,
- A convenient, pain-free system suitable for self
application at home.
Micro channel based trans delivery
system using RF
Principle
• It is based on principle of RF ablation, a wellknown medical technology to eliminate living
cells which used to cut through tissues in
minimally invasive operations or to destroy
small tumors in the kidney and liver by passing
an alternating electrical current at a frequency
above 100 KHz (radio frequency) through the
area.
Method
Application of RF
device by placing a
closely spaced array
of tiny electrodes with
very
precise
dimensions against the
skin
Application of transdermal patch
and microchannels serve as
aquatic channels into the inner
layers of the skin
Alternating electrical current is
transferred through each of the
microelectrodes
Cell ablation and
microscopic passage
form
Formation
of
microchannels
consistent,
controlled depths
RF
with
well-
the
electrode
Passig
current
patch
Formationof
microchanne
l
Release of
drug
Drug delivery device
• The system consists of the device, which is used to
pretreat the skin and form the RF microchannels in
the outer layers of the skin, and a patch containing the
drug, which is placed on top of the pretreated skin.
(a) THE DEVICE
(b) THE MICROELECTRODE ARRAY
(c) THE PATCH
Stained microchannel
Effect of patch technology on
pharmacokinetic profiles:
• For drug delivery, the microchannels may last up to
24 h. At 36 h, the delivery through treated skin
returns to the values of intact skin.
• To achieve a sustained drug flux for 24 h,
incorporating the active material into a moist matrix
such as a hydrogel that serves as an infinite reservoir.
• The study was conducted on six healthy adult
volunteers in each test group by Galit Levin. The
results revealed differences in the plasma-drug levels
and profiles between the treatments.
Effect of patch technology on
pharmacokinetic profiles
• The results revealed differences in the plasma-drug levels and
profiles between the treatments studied by Galit Levin.
Effect of patch technology on
pharmacokinetic profiles
• The transdermal delivery through microchannels
resulted in a concentration increase up to 9h and
a constant level up to 24 h.
• This finding confirms that RF microchannel
formation is uniform and reproducible.
• A microelectronic system based on RF cell
ablation using printed-protein patches resulted
in very high bioavailability of up to 40%.
Effect of patch technology on
pharmacokinetic profiles
Table shows the bioavailability of three drug molecules studied by Galit Levin.
Factors influences this system:
•
•
•
•
•
•
•
•
•
Molecular size of the molecule delivered
Water solubility
Concentration
Microchannel density
Duration of delivery
Dosage forms
Drug profile
Type of patches
Drug accumulation.
Factors influences this system
• Molecular size: In case of small-molecule drugs, size
can be increased significantly by pretreatment & for
macromolecules, like peptides and proteins, also help
in delivering them systemically through the skin by
this technology.
• Water solubility: Water-soluble molecules, can be
easily delivered. Water-insoluble drugs can be
delivered by increasing the water solubility through a
suitable formulation.
• Concentration: In contrast to any passive delivery, It
is help in increasing the drug concentration on the
skin in the vicinity of the microchannels will result in
a higher delivery rate.
Factors influences this system
• Microchannel density: By increasing the
microchannel density (MCs/cm2 ), a higher amount of
drug can be delivered in efficient manner.
• Duration of delivery: The drug delivery can be
enhanced up to 24 h using this technology
• Dosage forms: A patch is the most convenient
dosage form for drug delivery. Beside this, gels,
Creams & the other semisolid dosage forms can be
used.
• Drug profile: The result of the transdermal delivery
using RF cell ablation can be a peak-plasma profile or
a constant blood level, depending on the type of patch
technology used
Factors influences this system
• Type of patches: A reservoir patch, usually a waterbased hydrogel, can be used to incorporate small or
large molecules and apply them on the skin. For
proteins, the use of a printed patch is advisable for
stability purposes.
• Lack of reservoir in the skin: In contrast to passive
delivery, the microelectronic system based on RF cell
ablation used in this study delivered water-soluble
drugs that cannot be accumulated in the lipidic
stratum corneum. No issue of reservoir formation
exists.
Main Application
For protein
delivery
For hydrophilic
drug &
hydrophobic
drug
For
macromolecules
Patch technology for protein delivery:
• Transdermal delivery of large proteins is a novel and
exciting method because no commercial technology
currently available incorporates proteins into
transdermal patches.
• The manufacturing method involves dispensing very
small droplets of a concentrated protein solution on a
transdermal liner in a predetermined pattern.
• The liquid is dried, leaving a dry and thin layer of
formulated protein on top of the liner.
• The highly water-soluble proteins are dissolved by
the interstitial fluid that is secreted from the skin
through the RF microchannels, thus forming a highly
concentrated protein solution in situ.
Patch technology for protein delivery:
Patch technology for protein delivery:
• The diffusion of the dissolved molecules occurs
through the RF microchannels into the viable tissues
of the skin across a steep concentration gradient.
• This process brings about a high delivery rate and a
peak-blood profile of the drug resembling that of a
subcutaneous injection.
• This manufacturing method enables complete and
flexible control of the drug load on the patch, control
of patch size and shape, and high manufacturing yield
with minimal protein losses.
• In addition, this method fully retains the stability and
biological activity of the protein drug.
Patch technology for hydroplilic
drug & hydrophobic drug
• Under this technique, pretreating the skin
allows aquatic channels to form across the
stratum corneum, which provides significant
enhancement in the permeability of watersoluble compounds.
• Drugs that exhibit insufficient solubility in
water can still benefit from the technology.
• By increasing solubility using various
formulation approaches, such as drugcyclodextrin complexes or dissolving the drug
in a water-alcohol mixture, the drugs are also
able to permeate the skin.
Patch technology for hydroplilic
drug & hydrophobic drug
•Table I shows the in vitro skin permeability of various
drugs in a dynamic diffusion-cell model using fullthickness porcine skin. The results show enhanced
transdermal
delivery
with
the
hydrophilic
compounds—granisetron hydrogen chloride (HCl) and
lidocaine HCl which is study by Galit Levin.
Patch technology for hydroplilic
drug & hydrophobic drug
• The results show enhanced transdermal delivery
with the hydrophilic compounds—granisetron
hydrogen chloride (HCl) and lidocaine HCl.
Lidocaine HCl is more water-soluble than
diclofenac sodium and had higher delivery rates.
• The effect of the compound concentration on its
delivery rate was shown with testosterone (2%
versus 6% in aqueous solution) and lidocaine HCl
(2% versus 5% in aqueous solution).
• The delivery rate increased linearly with the
concentration of the loaded compound.
Patch technology for Macromolecules
• The delivery of these macromolecules
through a full-thickness porcine skin that
had been pretreated with the device. An
increase in molecular size brought about
a decrease in delivery rate.
• The largest 70-kDa molecule was
successfully delivered transdermally
through the RF microchannels.
A convenient, painless,
and
less
invasive
alternative to injection, a
common method for
administering
large
proteins and peptides in
low manufacturing cost.
In contrast to oral delivery ,
this avoid first pass effect and
offers
the
benefit
of
immediate cessation of drug
administration in case of an
adverse effect or overdose.
In contrast to passive
delivery , this allow for
the delivery of watersoluble drugs
So, Microchannel
basedother
Trans Delivery
Advantage over
Systemconventional
by using Radio
Frequency ( RF) is
techniques
a Novel Approch for Drug delivery system
In contrast to Iontophoresis , this
is use for long time There is also
no molecular size limitation, no
molecular
electrical
charge
requirement, and no specific
formulation pH constraint.
In contrast to micro needle ,
this is use for potent & less
potent drug, the more
extended release the delivery
system
Acknowledgement
• Writing this acknowledgement has provided me with the great
opportunity to note the enormous help & guidance given by
various persons whose work was note worthy & can’t be
diminished from my mind & soul.
• I would like to thank www.pharmainfo.net to give me
opportunity of presenting power point presentation regarding
my interested topic.
• I would like to thank our principal Dr. Avani F. Amin & other
faculty members who encourage me for this purpose.
• I would also like to thank librarian of my institute for giving
me permission to utilize our library resources.
• Finally, I would like to mention a very special thank to my coauthor who give me his valuable time, support and constant
guidance with continuous suggestions to make this
presentation very effective.
References
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• A. Hines-Peralta and S.N. Goldberg, "Review of
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Cancer Res. 10 , 6328S–6334S (2004).
• S. Nahum Goldberg, "Radiofrequency Tumor Ablation:
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147 (2001).
• L. Solbiati et al., "Radiofrequency Thermal Ablation of
Hepatic Metastases," Eur. J. Ultrasound, 13 (2), 149–158
(2001).
• F.J. McGovern et al., "Radiofrequency Ablation of Renal Cell
Carcinoma via Image Guided Needle Electrodes," J. Urol. 161
(2), 599–600 (1999).
References
• A.S. Sintov et al., "Radiofrequency-driven Skin
Microchanneling as a New Way for Electrically Assisted
Transdermal Delivery of Hydrophilic Drugs," J. Controlled
Release, 89 (2), 311–320 (2003).
• Z. Avrahami, "Transdermal Drug Delivery and Analyte
Extraction," US Patent No. 6,148,232 (2000).
• Z. Sohn and Z. Avrahami, "Monopolar and Bipolar Current
Application for Transdermal Drug Delivery and Analyte
Extraction," US Patent No. 6,611,706 (2001).
• G. Levin et al., "Transdermal Delivery of Human Growth
Hormone through RF-Microchannels," Pharm. Res. 22 (4),
550–555 (2005).
• M.R. Prausnitz, S. Mitragotri, and L. Langer, "Current Status
and Future Potential of Transdermal Drug Delivery," Nature
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Thank you