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Review on Recent Innovations on Transdermal Drug

Delivery Systems
Dhrumil C. Patel*, Rinku J. Patel, Jignesh C. Patel, Foram
P. Patel, Tejas B. Parmar
Student of Quality Assurance, K.B.Raval College of Pharmacy,
Gujarat Technology University, Sertha, Gujarat, India
Email address:

The delivery of drugs to systemic circulation through the skin is
recognized as an alternative to taking it orally as it provides
better patient compliance, bypass the GI tract and provide much
steady absorption of drugs over hours. There have been several







enhancement of Transdermal penetration of drugs that could

result in new products with better therapeutic potential.
Recently, there are many innovations done on Transdermal










microneedle array, sonophoretic enhanced microneedles array

(SEMA), microneedle rollers, nanoparticles, carbon nanotubes,






technological advancements and potential in the field of

Transdermal drug delivery is discussed in this review.
Key words: TDDS, iontophoresis, microemulsion, microneedle
array, ultrasound

Transdermal permeation:
Earlier skin was considered as an impermeable protective
barrier, but later investigations were carried out which proved
the utility of skin as a route for systemic administration.[1]
Skin is the most intensive and readily accessible organ of the
body as only a fraction of millimeter of tissue separates its
surface from the underlying capillary network. The various
steps involved in transport of drug from patch to systemic
circulation are as follows: [2, 3]
1. Diffusion of drug from drug reservoir to the rate
controlling membrane.
2. Diffusion of drug from rate limiting membrane to
stratum corneum.
3. Sorption by stratum corneum and penetration through
viable epidermis.
4. Uptake of drug by capillary network in the dermal
papillary layer.

5. Effect on target organ.

Advantages and limitations of transdermal:
The potential advantages which have been described including
the following:
1. Dosage intervals not limited by gastric transit time.
2. Elimination of vagaries of gastro intestinal absorption
that normally affect drugs after taken orally.
3. Elimination of pulse entry of drugs into the systemic
circulation, thereby reducing side effects.
4. Reduction of drug metabolism, due to initial by pass of
the liver.
5. Utilization of drugs with short half life, which cannot be
successfully delivered by conventional dosage forms to
maintain the therapy.
6. Elimination of hazards and difficulties to intravenous
infusion or intramuscular injections.
7. Improved control of the concentrations of drugs with
small therapeutic indices.

8. Single application has capacity for multi-day therapy,

thereby improving patient compliance.
9. Immediate termination of drug effect is possible by
removal of the delivery system whenever required.
10. Medication can be identified quickly in case of
emergencies, in case of nonresponsive, unconscious or
comatose patient.
11. Easy to prepare and easy to transport.
12. Self medication is possible with these systems.
These systems are however, having some limitations these
include the following:
1. It is required to have some optimum physicochemical
properties for the drug to penetrate through stratum
corneum and the drug dose required for therapeutic
value should be 10mg/day, otherwise the delivery
through Transdermal route will be very difficult and
some time it may not be possible. Normally, drugs with
therapeutic dose less than 5 mg/day are preferred to be
delivered through Transdermal route.

2. Skin






sometimes due to some of the excipients are penetration

enhancers are another limitation for such delivery.
3. Clinical is also an area that has to be examined carefully
before a decision is made to develop a Transdermal
4. The barrier function of the skin for penetration of the
drug is found to vary between subjects and sometimes
within subjects too and with age.
Basic components of transdermal therapeutic systems:
Polymer matrix:
A polymeric backbone governs the drug release from device. A
polymer matrix, to qualify its use in transdermal drug delivery
systems has to comply with some general requirements, which
include (1) Molecular weight, glass transition temperature and
chemical functionality of the polymer should be such that the
specific drug could diffuse properly and get release through it,
(2) The polymer should be stable enough, nonreactive with
drug, and should support easy manufacturing and fabrication

into the desired product, (3) The polymer and its degradation
product must be non-toxic or nonantagonistic to the body
tissues in general and to the skin in particular, (4) The
mechanical properties of the polymer should not deteriorate
excessively when large amount of active agents are
incorporated into it, (5) it is desired to be economically sound.
Possibly useful polymers for transdermal devices are:
Natural polymers: Cellulose derivates, Zein, Gelatin, Shellac,
Proteins, Gums and their derivates, natural rubber and starch
etc. Recently some natural polymer latex like jackfruit latex,
plum latex and other semi synthetic polymers have undertaken
for research to be utilized in TDDS.





Polysiloxane, Silicone rubber, Nitrile, Acrylonitrile, Butyl

rubber, Styrene butadiene rubber, Neoprene etc.
Synthetic polymers: Polyvinyl alcohol, Polyvinyl chloride,
Polyethylene, Polyacrylate, Polyamide,
Polyurea, Polyvinylpyrrolidone, Polymethacrylate, Epoxy etc.

The permeation enhancers and some other additives like

plasticizers, adhesives etc. are often required to be added with
the polymer matrix as per the formulation requirements.
The Drug:
Most drugs are not suitable candidate for Transdermal drug
delivery for one or more reasons: the easy to deliver drugs
have already been commercialized into TDDS. To date only 10
drugs out of 100 listed in the USP or Physician Desk
Reference (PDR) have been commercialized into TDD
products. Since the Transdermal patches was approved in 1981
to prevent nausea and vomiting associated with motion
sickness, the FDA has approved through the past 22 years,
more than 35 Transdermal patch products spanning 13






biopharmaceutical Pharmacokinetic attributes of drug for

passive TDD include (1) low daily dose ordinarily, less than
20mg/day (2) short half life i.e. 10 hr or less (3) molecular
weigh less than 400 Dalton (4) low melting point, >200C (5)
high lipid solubility, should have octanol-water partition
coefficient (log P) value in range of 1.0 4.0 (6) skin

permeability coefficient greater than 0.5-10 cm/hr (7) nonirritating and non- sensitizing to skin (8) low oral
bioavailability e.g. preclude oral delivery (9) low therapeutic
index i.e. required tight control of plasma levels. The listed
parameters are by no means all- inclusive and there are many
other desirable attributes for selecting drug for transdermal
drug delivery system. A single drug could meet only a few of
desirable attribute and an acceptable balance between them
needs to be established. The high oral dose, large patch size,
skin irritation and/or sensitization are often the main barriers












preformulation investigation is carried out for selection and

optimization of drug candidate and formulation to have an
acceptable compromise in desired and practical properties of a
promising drug for which transdermal delivery is sought.
Technological framework of transdermal patches:
Backing support:

It is used to provide a base on to which the drug incorporated

polymers are casted. This may act as occlusive as well as nonocclusive. The backing support also provides a unidirectional
flow of drug from transdermal patch to skin only and prevent
from any loss to external environment. Examples are
Aluminized plastic, Aluminized polyester etc.
Drug reservoir:
The drug reservoir consist of the medicament to be delivered, it
may be in the form of dispersion of single drug in liquid state
embedded into polymer matrix or may be a drug core
enveloped with permeation controlled polymeric membrane.
The reservoir compartment may also have core of the drug
covered with impermeable cover having window for drug
release provided with a controlling membrane.
Adhesive film:
It is used to provide an intimate contact of drug releasing liver
of Transdermal patch with skin. In some cases drug is
incorporated in it and act as a reservoir for drugs. Adhesives are
used sometimes for delivering of loading dose initially

followed by maintenance dose of matrices. These are three








biocompatible; they are silicones, polyisobutylenes and

Release liner:
It is an occlusive i.e. drug impermeable plastic film or metallic
plastic laminate. It is used to control the release of drug to a
particular surface area of the skin. A protective peel strip of
siliconized polyester which cover the above mentioned layer
which should be served for the prevention of the contamination
of the Transdermal patches from the dust and foreign matter,
which should be peeled out before administration.
Penetration Enhancers:
A popular approach is the use of penetration enhances, which
reduce reversibly the permeability barrier of the stratum
corneum (SC). Such materials known also as accelerant or
sorption promoters, if they are safe and non-toxic can be used
clinically enhance the penetration rate of co-administered drug
or even to treat patient systematically by the dermal route.

These agents partition into, and interact with SC constituents to

induce a temporary, reversible increase in skin permeability. In
this way many compounds such as isopropyl myristates,
hydrogenated soya phospholipids, essential oils, butanol, noctanol, and decanol, terpens, and surfactant have been
reported to enhance the permeability of drugs by various
Types of devices:
1. According to drug release mechanism:
The transdermal devices based on their technological
construction for drug release can be of four types, viz. matrix





microsealed dissolution controlled, and adhesive dispersion

type systems.
Matrix diffusion controlled TDDS: These are also called as
monolithic drug delivery systems. These devises consist of
solid drug particles in a polymer backbone governing the
diffusion from self contained reservoir. The drug is released
from this system by dissolution and followed by diffusion.

Parameters are dependent upon the structural and molecular

factors of the polymer drug matrix i.e. polarity, hydrogen
bonding, glass transition temperature of the polymer, solvating
or plasticizer effect of excipients and drug upon the polymer
chains the concentration of the different drugs also has
significant effect upon its release. The matrix diffusion type
drug delivery systems offer several advantages which include
the ease of fabrication, sustained release of macromolecules
etc. The one major drawback in matrix diffusion controlled
drug delivery system is that it generally does not display the
desired zero order kinetics e.g. Nitrop-Dur transdermal infusion
Membrane permeation controlled TDDS: This type of systems
are composed of a drug reservoir in the form core of pure solid
drug particles or a suspension of drug solid particles in a liquid
medium, encapsulated in a compartment walled by a constant
surface of permeation controlled polymeric membrane, for
monitoring the rate of drug release from the system. The
membrane permeation controlled drug delivery system provide
a constant zero-order drug release profile, while it is more

difficult to fabricate and has a potential risk of dose dumping

due to membrane breakage e.g. Scopolamine releasing
Transderm V system and nitro glycerin releasing Transdermnitro system.
Micro reservoir type or microsealed dissolution controlled
TDDS: These systems are manufactured by homogenously
dispersing the drug in reservoir or a liquid suspension of solid
drug particles in water soluble liquid type polymers or in a
silicone elastomer, before cross linking the elastomer to form a
stable dispersion. This is then molded into any shape of device,
walled with impermeable membrane laminates with an opening
of constant surface which can be covered with a permeation
controlling polymeric membrane to provide an additional
controlling step on the release of the drug molecules. The
system is a hybrid type system with homogenous, microscopic
diffusion of drug reservoir in polymer matrix to maximize the
advantages and to minimize the disadvantages of both matrix
diffusion controlled and membrane permeation controlled drug
delivery system. It is a matrix in physical appearance and
delivers the drug at a rate, which follows either zero-order or









physicochemical properties of drug in the system.

Adhesive dispersion type system: This is the simplified form of
the membrane permeation controlled systems. The drug
reservoir is formulated by directly dispersing the drug in an
adhesive polymer e.g. poly(isobutylene) or poly(acrylic)
adhesive and then spreading the medicated adhesive by solvent
casting or hot melt in to a flat sheet of drug impermeable
metallic plastic backing to form a thin drug reservoir layer. On
the top of the reservoir layer, thin layers of non-medicated ratecontrolling adhesive polymer of a specific permeability and
constant thickness are applied to produce an adhesive diffusion
controlled delivery system. For example isosorbide dinitrate
transdermal therapeutic system.
2. According to rate controlling step:
The transdermal devices, based on rate controlling step may be
of two types, the first those they control the rate of drug
delivery to the skin and, second those that allow the skin to
control the rate of drug absorption. The former is for drugs,

which are potent, for which it is important to control the rate of

drug derive in order to maintain the minimum effective
concentration while the later type is useful for the drugs having
wide range of plasma concentration over which the drug is
effective but not toxic.
3. According to polymer:
Hydrophilic or hydro gel systems: In this type hydrophilic
polymer are used for preparation of transdermal patches e.g.
hydro gel, which releases the drug by swelling mechanism
therefore patch of this type absorb the water of skin and skin
appendages then swell and release the drug to the skin surface.
Hydro gel type of transdermal patches can overcome the side
effect like skin irritation and other problem associated with
TDDS. Hydro gel have high skin compatibility, probably due to
water exchange with the skin, and many therefore are suitable
for skin complaint transdermal drug delivery system.
Hydrophobic or occlusion systems: The hydrophobic polymers
are used for preparation of such transdermal patches. The
release of drug involves occluding the skin with impermeable

hydrophobic film, preventing from losing the surface water

from skin etc. The concomitant swelling of Horney layer
extensively decrease the protein network density and diffisional
path length to drug. Also the occlusion of skin surface increases
skin temperature resulting in increasing molecular motion and
skin permeation. However, long application of this occlusive
TDDS may evoke number of unwanted side effects like,
clogging of sweat ducts resulting in sweat retention syndrome,
accumulation of harmful bacteria in accumulated water and
sweat that may infect the skin, and risk of allergies or irritation
Table 1: Currently available medications for transdermal
Type of



Manufacturer Indication


Fentanyl Duragesic Reservoir Alza / Janssen





Drug in Schwarz Pharma







Drug in Pharmaceuticals




Searle, USA



reservoir Pharmaceuticals




Reservoir ElanCorp/Lederi Smoking

Drug in

e Labs


Cygnus Inc.


Products Ltd.
Testostero Androderm Reservoir Thera Tech/GSK Hypogona

Testoderm Reservoir


dism in

Clonidine Catapres- Membran Alza/Boehinger Hypertensi


e matrix



Lidocaine Lidoderm

Drug in Cerner Multum, Anesthetic



Scopolami Transderm Membran Alza/Novartis



e matrix




Drug in 3M




adhesive Pharmaceuticals/

Berlex labs
Estraderm Drug in
Ortho Evra



Reservoir Pharma/Novartis
Drug in



Women First

Drug in Healthcare, Inc.



Johnson &


Chemical Penetration Enhancers for Transdermal Drug
Delivery Systems
Inayat Bashir Pathan and C Mallikarjuna Setty have discussed
skin as an important site of drug administration for both local
and systemic effects. However in skin, the stratum corneum is
the main barrier for drug penetration. Penetration enhancement
technology is a challenging development that would increase
the number of drugs available for transdermal administration.
The permeation of drug through skin can be enhanced by both
chemical penetration enhancement and physical methods. They
have also discussed the chemical penetration enhancement

technology for transdermal drug delivery as well as the

probable mechanisms of action.
Mechanism of chemical penetration enhancement:
1. Disruption of the highly ordered structure of stratum
corneum lipid.
2. Interaction with intercellular protein.
3. Improved partition of the drug, co enhancer or solvent
into the stratum corneum.
Chemical penetration enhancers:
1. Sulphoxides





sulphoxides (DMSO), DMAC, DMF)

2. Azone (1-dodecylazacycloheptan-2-one or laurocapran)
3. Pyrrolidones
4. Fatty acids
5. Glycols (diethylene glycol and tetra ethylene glycol),
6. Fatty acids (lauric acid, myristic acid and capric acid)

7. Nonic




polyoxy ethylene-2-stearly ether)

8. Essential oil, terpenes and terpenoids
9. (Eucalyptus, chenopodium, ylang-ylang)
10. Oxazolidinones
11. (4-decyloxazolidin-2-one)
12. Urea
They conclude that skin permeation enhancement technology is
a rapidly developing field which would significantly increase
the number of drugs suitable for transdermal drug delivery.
They focused on skin irritation with a view to selecting
penetration enhancers which possess optimum enhancement
effects with minimal skin irritation. [6]
Design and evaluation of transdermal drug delivery of
ketotifen fumarate
A. Shivaraj et al. were developed and evaluated matrix-type
transdermal therapeutic system containing Ketotifen fumarate
with different ratios of hydrophilic and hydrophobic polymeric

combinations by the solvent evaporation technique. They

prepared seven transdermal patch formulations (F1 to F7)





cellulose in the ratios of 10:0, 0:10, 1:9, 2:8, 3:7, 4:6 and 5:5,
respectively were prepared. All formulations carried 5 % v/w of
dimethyl sulfoxide as penetration enhancer and 10 % v/w of
dibutyl phthalate as plasticizer in chloroform and methanol
(1:1) as solvent system. Evaluation of system has been carried
out by following way:
Table 2: evaluation of different formulations of ketotifen
Formulation code

Tensile strength

% Drug content

% Drug release


3.84 0.125




2.96 0.110




3.13 0.080




3.22 0.056




3.27 0.045




3.34 0.062




3.41 0.079


The research work have been shown that the formulation F1

(Hydroxypropyl methyl cellulose E5 alone) had maximum
release of 95.521 0.982 % in 8 h, where as F2 (Ethyl
cellulose alone) showed maximum release of 67.078 1.875 %
in 24 h. The formulation, F7 with combination of polymers
(1:1) showed maximum release of 86.812 0.262 % in 24 h,
emerging to be ideal formulations for Ketotifen fumarate. The
release rate of drug through patches increased when the
concentration of hydrophilic polymer was increased. The
developed transdermal patches increase the efficacy of
Ketotifen for the therapy of asthma and other allergic
conditions. [7]
Potential use of iontophoresis for transdermal delivery of
NF-kB decoy oligonucleotides
Topical application of nuclear factor-kB (NF-kB) decoy
appears to provide a novel therapeutic potency in the treatment
of inflammation and atopic dermatitis. However, it is difficult
to deliver NF-kB decoy oligonucleotides (ODN) into the skin


by conventional methods based on passive diffusion because of

its hydrophilicity and high molecular weight.
Evaluation of the in vitro transdermal delivery of fluorescein
isothiocyanate (FITC)-NF-kB decoy ODN have been carried
out using a pulse depolarization (PDP) iontophoresis. In vitro






C57BL/6 mice skin using a horizontal diffusion cell. The

apparent flux values of FITC-NF-kB decoy ODN were
enhanced with increasing the current density and NF-kB decoy
ODN concentration by iontophoresis. Accumulation of FITCNF-kB decoy ODN was observed at the epidermis and upper
dermis by iontophoresis.
Their results shown that in mouse model of skin inflammation,
iontophoretic delivery of NF-kB decoy ODN significantly
reduced the increase in ear thickness caused by phorbol ester as
well as the protein and mRNA expression levels of tumor
necrosis factor (TNF) in the mice ears. These results suggest
that iontophoresis is a useful and promising enhancement
technique for transdermal delivery of NF-kB decoy ODN. [8]

A fast screening strategy for characterizing peptide delivery

by transdermal iontophoresis
Capillary zone electrophoresis (CZE) is a convenient
experimental tool for mimicking the low-throughput in vitro
skin model used to optimize the delivery of peptides by
transdermal iontophoresis.
In this study researcher devoted to the extraction of pertinent
molecular parameters from CZE experiments at different pH
values, the optimization of CZE experimental conditions, and
the development of an in silico filter useful for drug design and
The effective mobility ( eff) of ten model dipeptides was
measured by CZE at different pH values, enabling to determine
their pKa values, charge and eff at any pH. The best linear
correlation between the electro migration contributions to
transdermal iontophoretic flux (JEM) measured across porcine
skin with donor and acceptor compartments at pH 7.4 and
charge/MW ratio was obtained at pH 6.5, which seems to be the
most suitable pH to mimic the in vitro skin model.

The researcher concludes the experimental strategy can be

considerably shortened by using a single eff measurement at
pH 6.5 as a predictor of JEM. Additionally, pKa prediction
software packages offer a fast access to charge/MW ratio using
consensual molecular charges at pH 6.5, which suggests that
this simple in silico filter can be used as a preliminary
estimation of JEM. [9]
Enhanced transdermal delivery of an anti-HIV agent via
ethanolic liposome
Indinavir, as a protease inhibitor with a short biological half
life, variable pH-dependent oral absorption, and extensive firstpass metabolism, presents a challenge with respect to its oral
administration. Researcher utilized Soya phosphatidylcholine
(soya PC) (99% pure) and phosphotungstic acid, Indinavir
sulfate, and triple-distilled water was used wherever required.
In the study they formulate and characterize indinavir bearing
ethanolic liposomes (ethosomes), and to investigate their


delivery potential.



ethanolic liposomes were characterized to be spherical,

unilamellar structures having low polydispersity, nanometric

size range, and improved entrapment efficiency over other
delivery formulations. Results of the study states that
permeation studies of indinavir across human cadaver skin
resulted in enhanced transdermal flux from ethanolic liposomes
that was significantly greater than that with ethanolic drug
solution, conventional liposomes, or plain drug solution.
The ethanolic liposomes showed the shortest lag time for
indinavir, thus presenting a suitable approach for transdermal
delivery of this protease inhibitor. They conclude that enhanced
transdermal delivery of indinavir via ethanolic liposome. [10]
Clinical update on transdermal buprenorphine
A transdermal patch formulation of buprenorphine with three
different patch strengths: 35, 52.5 and 70 g/h (Transtec ) is







continuously delivers buprenorphine for up to 96 h (4 days)

across the skin and into the systemic circulation, corresponding
to 0.8, 1.2 and 1.6 mg/day for the 35, 52.5 and 70 g/h patch
strengths, respectively. The release of buprenorphine from the

matrix system is regulated mainly by the concentration gradient

across the skin and patch. Recently, a second transdermal
buprenorphine patch has been introduced in the UK, Germany
and some other countries (Norspan, Butrans). This low-dose
patch comes in patch strengths of 5, 10 and 20 g/h released for
7 days to treat chronic pain after failure of non-opioid
analgesics. [11]
Randomized, cross-over, comparative bioavailability trial of
matrix type transdermal drug delivery system (TDDS) of
carvedilol and hydrochlorothiazide combination in healthy
human volunteers: A pilot study
This study deals with transdermal drug delivery system
(TDDS) of Carvedilol (CRV) and Hydrochlorothiazide
(HCTZ). They compare the bioavailability of these two study
drugs from a TDDS with conventional immediate release oral
tablets in healthy volunteers. They was also evaluated the
TDDS for any adverse drug reaction.
This was an open-label, randomized, single centre, two
treatments, two period, single dose, crossover pilot study of two

formulations of cardiovascular agents. Subjects (n=10) were

randomized to have a TDDS applied to their abdominal skin for
72 h or receive one oral tablet each of CRV and HCTZ
respectively in period I, followed by 1-week washout period.
They received the alternative treatment in period II.






bioavailability with the transdermal patches over oral tablets as

observed by the mean AUC values 4004.37180.98 and
1824.3017.43 ng h/mL respectively for CRV and HCTZ as
compared to 753.4653.34 and 392.8934.23 ng h/mL
respectively, with the oral tablets.
They concluded that the TDDS developed in our laboratory
produced therapeutically effective plasma concentrations of the
cardiovascular agents up to a range of 60 to 72 h (in different
volunteers with a mean=66 h). From these observations
conclusion can be that the TDDS meets the intended goal of at
least 2 day management of stage II hypertension with
application of a single transdermal patch, hence improving
patient compliance over the inconvenience seen with frequent
oral administration. [12]

Transdermal drug delivery by in-skin electroporation using

a micro needle array
The aim of that worked was to develop a minimally invasive
system for the delivery of macromolecular drugs to the deep
skin tissues, so-called in-skin electroporation (IN-SKIN EP),
using a micro needle (MN) electrode array. They used
fluorescein isothiocyanate (FITC)-dextran (FD-4: average
molecular weight, 4.3 kDa) as the model macromolecular drug.
MNs were arranged to puncture the skin barrier, the stratum
corneum, and electrodes were used for EP. High electric field
could be applied to skin tissues to promote viable skin delivery.
In vitro skin permeation experiments showed that IN-SKIN EP
had a much higher skin penetration-enhancing effect for FD-4
than MN alone or ON-SKIN EP (conventional EP treatment),
and that higher permeation was achieved by applying a higher
voltage and longer pulse width of EP. In addition, no marked
skin irritation was observed by IN-SKIN EP, which was
determined by the LDH leaching test. They conclude that INSKIN EP can be more effectively utilized as a potential skin

delivery system of macromolecular drugs than MN alone and

conventional ON-SKIN EP. [13]
Effect of surfactant concentration on transdermal lidocaine
delivery with linker microemulsions
A limited numbers of studies have been conducted to







microemulsion-mediated transdermal transport. Some studies

suggest that increasing surfactant concentration reduces the
partition of the active in the skin, and the overall transport.
Other studies suggest that increasing surfactant concentration
improves mass transport across membranes by increasing the
number of carriers available for transport. To decouple these
partitions and mass transport effects, a three-compartment
(donor, skin, and receiver) mass balance model was introduced.
The model has three permeation parameters, the skin-donor
partition coefficient (Ksd), the donor-skin mass transfer
coefficient (kds) and the skin-receiver mass transfer coefficient
(ksr), also known as skin permeability. The model was used to
fit the permeation profile of lidocaine formulated in oil-inwater (Type I) and water-in-oil (Type II) lecithinlinker

microemulsions. The results show that surfactant concentration

has a relatively minor effect on the mass transfer coefficients,
suggesting that permeation enhancement via disruption of the
structure of the skin is not a relevant mechanism in these
lecithinlinker microemulsions. The most significant effect was
the increase in the concentration of lidocaine in the skin with
increasing surfactant concentration. For Type I systems such
increase in lidocaine concentration in the skin was linked to the
increase in lidocaine solubilization in the microemulsion with
increasing surfactant concentration. For Type II systems, the
increase in lidocaine concentration in the skin was linked to the
increase in skin donor partition. A surfactant-mediated
absorption/permeation mechanism was proposed to explain the
increase in lidocaine concentration in skin with increasing










consistent with the proposed mechanism. [14]

Microemulsion formulations for the transdermal delivery of

The objective of researcher was to develop a microemulsion

formulation for the transdermal delivery of testosterone. The
microemulsions were characterized visually, with the polarizing
microscope, and by dynamic light scattering. In addition, the
pH, conductivity and viscosity of the formulations were
measured. Moreover, differential scanning calorimeter and
diffusion-ordered nuclear magnetic resonance spectroscopy
were used to study the formulations investigated. Conductivity
measurements revealed, as a function of the weight fraction of
the aqueous phase, the point at which the microemulsion made
the transition from water-in-oil to discontinuous. Alterations in






incorporation of testosterone, have been evaluated using the

same physical parameters and via Fourier-transform infrared
spectroscopy (FT-IR), 1H NMR and 13C NMR. These methods
were also used to determine the location of the drug in the
colloidal formulation. Testosterone delivery from selected
formulations was assessed across porcine skin in vitro in Franz
diffusion cells. Microemulsion formulations were prepared
using oleic acid as the oil phase, Tween20 as a surfactant,

Transcutol as cosurfactant, and water. Formulation containing

3% (w/v) of the active drug and the composition (w/w) of 16%
oleic acid, 32% Tween20, 32% Transcutol and 20% water.
Testosterone was delivered successfully across the skin from
the microemulsions examined, with the highest flux achieved
(4.60.6gcm2 h1). They conclude that the microemulsions
considered offer potentially useful vehicles for the transdermal
delivery of testosterone. [15]
Evaluation needle length and density of microneedle arrays
in the pretreatment of skin for transdermal drug delivery
Solid silicon microneedle arrays with the needle lengths ranged
from 100 to 1100m, and needle densities ranged from 400 to
11,900needles/cm2, Human cadaver skin, female hairless rats
older than 8 weeks. They used solid silicon microneedle arrays
with different needle lengths (ranging from 100 to 1100m)
and needle densities (ranging from 400 to 11,900needles/cm 2)
were used to penetrate epidermal membrane of human cadaver
skin. After this pretreatment, the electrical resistance of the skin
and the flux of acyclovir across the skin were monitored. A
linear correlation between the acyclovir flux and the inverse of

the skin electric resistance was observed. Microneedle arrays

with longer needles (>600m) were more effective in creating
pathways across skin and enhancing drug flux, and microneedle
arrays with lower needle densities (<2000 needles/cm2) were
more effective in enhancing drug flux if the microneedles with
long enough needle length (>600m). [16]






anastrozole: In vitro and local tissue disposition evaluation

Anastrozole is a potent aromatase inhibitor and there is a need
for an alternative to the oral method of administration to target
cancer tissues. They prepared a drug-inadhesive transdermal
patch for anastrozole and evaluate this for the site-specific






permeation enhancers and amounts of anastrozole were

investigated for promoting the passage of anastrozole through
the skin of rats in vitro. They was obtained the best in vitro skin
permeation profile with the formulation containing DUROTAK 87-4098, IPM 8% and anastrozole 8%. For local tissue
disposition studies, the anastrozole patch was applied to mouse
abdominal skin, and blood, skin, and muscle samples were

taken at different times after removing the residual adhesive

from the skin. High accumulation of the drug in the skin and
muscle tissue beneath the patch application site was observed
in mice compared with that after oral administration.
They conclude that anastrozole transdermal patches are an
appropriate delivery system for application to the breast tumor
region for site-specific drug delivery to obtain a high local drug
concentration. [17]





Improving the efficiency of transdermal drug delivery

Researcher proposed a solution for two main problems related
to transdermal drug delivery (TDD): How to improve the
delivery rate? and How to deliver large molecular weight






microneedles array (SEMA), is a combination between two

already proven TDD methods. Enhancements are achieved due
to two effects, namely mechanical (hollow microneedles) and
sonophoretic (low frequency). They used the drugs tested in the
experiments were calcein and bovine serum albumin (BSA),

both at a concentration of 103 mol/l. They used Franz diffusion

cells for the in vitro drug release. An array of hollow
microneedles breaks the stratum corneum and hydrophilic
microfluidic channels within the microneedles bring the drug
directly to the epidermis, allowing deeper diffusion into the

Figure 1: In vitro transdermal drug delivery study with

microneedles and ultrasound enhancers
A sonophoretic emitter provides energy to the fluid media and
induces acoustic cavitations that facilitate diffusion of large
molecular compounds into the skin by improving diffusion
rates. [18]






transdermal patches
Among the various additives tested, PVP was found to be the
most effective in inhibiting the crystallization of both drugs
captopril and levonorgestrel. They used levonorgestrel,







tetrahydrofuran, propylene glycol, phosphoric acid and hairless

rats. Incorporation of PVP in patches (PVP stabilized patches)
allowed incorporation of both drugs in amounts higher than
their respective saturation solubility in pure adhesives
(saturated patches). Skin permeation profiles of the drugs from
the patches across hairless rat skin were obtained using Franz
diffusion cells. For the hydrophilic drug captopril the skin flux
over the first 24 h was the same for the saturated and PVP
stabilized patches, but after 24 h the PVP stabilized patches
produced higher skin flux values. However this may be because
the saturated patch was depleted of the drug after 24 h. They
are not clear if PVP performs as a solubilizer or a
crystallization inhibitor for hydrophilic drugs. For the lipophilic
drug levonorgestrel, the skin flux profile from the saturated and

PVP stabilized patches was the same as the captopril. PVP acts
as a drug solubilizer by crystallization inhibitor and does not
produce supersaturation. [19]
Electrokinetic platform for iontophoretic transdermal drug
The main goal of them is to investigate whether transdermal
transport of non polar macromolecular drugs such as insulin
and terbinafine can be safely enhanced as a result of their
polarization and activation by AC electrokinetic forces. They
developed transdermal non invasive delivery of medication
through a biological membrane is motivated by a combination
of AC electrokinetic and AC iontophoresis protocols generated
on a device located external to the membrane. For this drug
delivery model quantification of the amounts of transported
drugs and their relationship to experimental parameters, such as
AC voltage amplitude and frequency, treatment time, and
membrane thickness were investigated.

Figure 2: experimental set-up of iontophoretic transdermal drug

Cross-section (A) and top view with counter electrode removed
(B) of the experimental set-up: 1-counter Electrode 1; 2-Teflon
spacer; 3-medication; 4-comb-shaped Electrodes 2 and 3; 5 -air
channels through Electrodes 2-3; 6-biological tissue membrane;
7-spring supports; 8- B-Cell housing; 9-electrical connectors to
Electrodes 1-3; 10-receiver solution or absorbent cloth; 11temperature probe.
Result of the study states that in an average transdermal
delivery of 57% of insulin and 39% of terbinafine during

several minutes long delivery cycle, which is at least an order

of magnitude improvement over the results reported for these
drugs in the literature for various passive and active
transdermal delivery protocols. This transdermal approach
overcomes many limitations of existing drug delivery
technologies, providing efficient, regulated, localized, non
invasive and safe delivery method for high molecular weight
non polar macromolecules such as insulin. [20]







permeation of insulin analog

Using chemical penetration enhancers (CPEs), transdermal
drug delivery (TDD) offers an alternative route for insulin
administration, wherein the CPEs reversibly reduce the barrier
resistance of the skin. All enhancers, Lispro (insulin refers to
the Lispro analog), Ethanol USP, and HPLC grade acetonitrile.
They examined the effect of CPE functional groups on the
permeation of insulin. A virtual design algorithm that




(QSPR) models for predicting the CPE properties was used to

identify 43 potential CPEs. This set of CPEs was prescreened

using a resistance technique, and the 22 best CPEs were

selected. Next, standard permeation experiments in Franz cells
were performed to quantify insulin permeation. Those results
indicate that specific functional groups are not directly






permeation enhancement is produced by molecules that exhibit

positive log Kow values and possess at least one hydrogen
donor or acceptor. Toluene was the only exception among the
22 potential CPEs considered. In addition, toxicity analyses of
the 22 CPEs were performed. A total of eight CPEs were both
highly enhancing (permeability coefficient at least four times
the control value) and non-toxic, five of which are new
discoveries. Menthone, Octanal, Decanol, Cycloundecanone,
Oleic acid, cis-4-Hexen-1-ol, 4-Octanone, 2,4,6-Collidine etc.
are examples of CPEs (highly enhancing permeability
coefficient and non-toxic) [21]
Transdermal delivery of insulin using microneedle rollers in
Researcher has characterized skin perforation by commercially
available microneedle rollers and evaluated the efficacy of

transdermal delivery of insulin to diabetic rats. They used

recombinant human insulin, sodium pentobarbital, Evans blue
(EB), Male SpragueDawley rats, the microneedle rollers
(ZGTSTM) and three different models of ZGTSTM with
needle lengths of 250, 500 and 1000m. Each microneedle
roller contains 192 very fine medical grade stainless steel tiny
needles in eight rows in a cylindrical assembly (the diameter
and the length of the cylinder are 2 cm). There is a handle for
operation. They used three different needle lengths, 250, 500
and 1000m in this work. Creation and resealing of the skin
holes that were produced by the needles were observed by
Evans blue (EB) staining and transepidermal water loss
(TEWL) measurements. The extent of permeation was
demonstrated by insulin delivery in vivo. EB clearly showed
that microchannels were formed in the skin and that the pores
created by the longest microneedle (1000m) persisted no
longer than 8 h, while the hypodermic injury was still observed
24 h later. TEWL significantly increased after the application of
the needles and then decreased with time, which explains the
recovery of skin barrier function and agrees well with EB

results. The rapid reduction of blood glucose levels in 1 h was

caused by the increased permeability of the skin to insulin after
applying microneedle rollers. The reduced decrease after 1 h is
closely associated with pore recovery. They concluded that
microneedle rollers with 500-m or shorter lengths are safe and
useful in transdermal delivery of insulin in vivo. [22]
Nanoparticles made from novel starch derivatives for
transdermal drug delivery
The aim of the research was to formulate nanoparticles by
using two different propyl-starch derivatives referred to as
PS-1 and PS-1.45 with high degrees of substitution: 1.05 and
1.45 respectively. They used maize Starch polymer with an
amylose content of 25%, ethyl acetate, polyvinyl alcohol








Flufenamic acid, testosterone and caffeine. A simple o/w

emulsion diffusion technique, avoiding the use of hazardous
solvents such as dichloromethane or dimethyl sulfoxide, was
chosen to formulate nanoparticles with both polymers,
producing the PS-1 and PS-1.45 nanoparticles. Once the






characterization was carried out, including the evaluation of

nanoparticles stability and applicability for lyophilization.
Depending on this information, rules on the formation of PS-1
and PS-1.45 nanoparticles could be developed. Encapsulation
and release properties of these nanoparticles were studied,
showing high encapsulation efficiency for three tested drugs
(flufenamic acid, testosterone and caffeine); in addition a close
to linear release profile was observed for hydrophobic drugs
with a null initial burst effect. The potential use of these
nanoparticles as transdermal drug delivery systems was also
tested, displaying a clear enhancer effect for flufenamic acid.
The effect of carbon nanotubes on drug delivery in an
electro-sensitive transdermal drug delivery system
An electro-sensitive transdermal drug delivery system was
prepared by the electrospinning method to control drug release.
The effect of carbon nanotubes on drug delivery in an electrosensitive transdermal drug delivery system has been studied.
They prepared a semi-interpenetrating polymer network as the

matrix with polyethylene oxide and pentaerythritol triacrylate

polymers. They used multi-walled carbon nanotubes as an
additive to increase the electrical sensitivity. The release
experiment was carried out under different electric voltage
conditions. They observed carbon nanotubes in the middle of
the electrospun fibers by SEM and TEM. The amount of
released drug was effectively increased with higher applied
electric voltages. These results were attributed to the excellent
electrical conductivity of the carbon additive. The suggested
mechanism of drug release involves polyethylene oxide of the
semi-interpenetrating polymer network being dissolved under
the effects of carbon nanotubes, thereby releasing the drug. The
effects of the electro-sensitive transdermal drug delivery
system were enhanced by the carbon nanotubes. [24]
Self-microemulsifying and microemulsion systems for
transdermal delivery of indomethacin: Effect of phase
Investigation on the transdermal delivery of indomethacin





microemulsions and their phase transition systems has been

carried out using Indomethacin, Ethyl oleate (EO), Sorbitan

mono laurate (Span 20), polyoxyethylene 20 sorbitan monooleate (Tween 80), ethanol (96%), acetonitrile(HPLC grade)
and Water (double distilled). Selection of five formulations
with fixed surfactantoil ratio and increasing water content had
been done. These included a water free self-microemulsifying
drug delivery system (SMEDDS), microemulsions containing
water at 5%w/w (ME 5%) or at 10%w/w (ME 10%), a liquid
crystalline formulation containing water at 30%w/w (LC) and
coarse emulsion containing water at 80%w/w (EM). To clarify
the results they evaluated a microemulsion containing 10%w/w
of receptor fluid 30%v/v ethanol in phosphate buffered saline,
PBS (MEEB 10%) and a supersaturated system of ME 10%
(MESS 10%). These formulations increased the transdermal
drug flux compared to saturated drug solution in PBS (control)
with formulation being ranked as SMEDDS > MEEB 10%
ME 10% ME 5% > LC > EM > control. SMEDDS produced
the longest lag time. The MESS 10% produced a flux value
similar to that of SMEDDS but with shorter lag time suggesting
transformation of SMEDDS into microemulsion after topical

application with possible supersaturation. The viscosity

increased with increasing water content up to certain limit
above which the viscosity started to reduce. They can provide
the formula with high flexibility in selecting the optimum
viscosity as the tested preparations were able to enhance
transdermal delivery in the range between SMEDDS, ME and
the LC preparations with some enhancing ability for the EM.
Transdermal delivery of anticancer drug caffeine from
water-in-oil nanoemulsions
Caffeine has been investigated for the treatment of various
types of cancers upon oral administration. There is also some
evidence that dermally applied caffeine can protect the skin
from skin cancer caused by sun exposure. Therefore in this
research researcher have attempted to develop nanoemulsion
formulation of caffeine for transdermal drug delivery and
evaluated in the present investigation. They used Caffeine,
Caprylic/capric triglyceride polyethylene glycol-4 complex
(Labrafac), caprylo caproyl macrogol-8-glyceride, jojoba oil,
oleoyl macroglycerides EP, Lauroglycol- 90, Lauroglycol-FCC,

diethylene glycol monoethyl ether, Isopropyl alcohol (IPA),

glycerol triacetate, olive oil, Polyoxy-35-castor oil, Tween-80
and Tween-85. They prepared different w/o nanoemulsion
formulations of caffeine by oil phase titration method.
Thermodynamically stable nanoemulsions were characterized
for morphology, droplet size, viscosity and refractive index.
The in vitro skin permeation studies were performed on Franz
diffusion cell using rat skin as permeation membrane. The in
vitro skin permeation profile of optimized formulation was
compared with aqueous solution of caffeine. Significant







nanoemulsion formulations (P < 0.05) as compared to aqueous

solution of caffeine. The steady-state flux and permeability
coefficient for optimized nanoemulsion formulation (C12) were
found to be 147.558.21g/cm2/h and 1.475102 0.031102
cm/h, respectively. Enhancement ratio (Er) was found to be
17.37 in optimized formulation C12 compared with other
formulations. They suggested that w/o nanoemulsions are good
carriers for transdermal delivery of caffeine. [26]
A microneedle roller for transdermal drug delivery

Microneedle rollers have been used to treat large areas of skin

for cosmetic purposes and to increase skin permeability for
drug delivery. Researchers introduced a polymer microneedle
roller fabricated by inclined rotational UV lithography,
replicated by micromolding hydrophobic polylactic acid and
hydrophilic carboxy-methyl-cellulose. These microneedles
created micron-scale holes in human and porcine cadaver skin
that permitted entry of acetylsalicylic acid, Trypan blue and
nanoparticles measuring 50 nm and 200 nm in diameter. The
amount of acetylsalicylic acid delivered increased with the
number of holes made in the skin and was 12 orders of
magnitude greater than in untreated skin. Lateral diffusion in
the skin between holes made by microneedles followed
expected diffusional kinetics, with effective diffusivity values
that were 23160 times smaller than in water. Polymer
microneedle rollers, prepared from replicated polymer films,
offer a simple way to increase skin permeability for drug
delivery. [27]




delivery: Effects of terpenes and cosurfactants


Microemulsion systems composed of terpenes, polysorbate 80,

cosurfactants, and water were investigated as transdermal
delivery vehicles for curcumin. 1,8-Cineole, -terpineol,





isopropanol, Curcumin, Polysorbate 80 (commercially known

as Tween 80) have been used for study as a materials.
Pseudoternary phase diagrams of three terpenes (limonene, 1,8cineole, and -terpineol) at a constant surfactant/cosurfactant
ratio (1:1) were constructed to illustrate their phase behaviors.
They employed limonene combined with cosurfactants like
ethanol, isopropanol, and propylene glycol as microemulsion
ingredients to study their potential for transdermal curcumin
delivery. They evaluated the transdermal delivery efficacy and
skin retention of curcumin using neonate pig skin mounted on a
Franz diffusion cell. They observed significant effects on the
skin permeation rates from microemulsions containing different





examination of treated skin to investigate the change of skin

morphologies. They analyzed characteristics such as droplet
size, conductivity, interfacial tension, and viscosity to

understand the physicochemical properties of the transdermal

microemulsions. The curcumin permeation rates in the
limonene microemulsion studied were 30-fold to 44-fold higher
than those of 1,8-cineole and - terpineol microemulsions,
respectively. Conclusion of the study states that the limonene
microemulsion system is a promising tool for the percutaneous
delivery of curcumin. [28]
Transdermal fentanyl matrix patches Matrifen and
Durogesic DTrans are bioequivalent
The pharmacokinetic profiles of the two commercially
available transdermal fentanyl patches Matrifen (100 g/h)
and Durogesic DTrans (100 g/h), used to manage severe
chronic pain, were compared regarding their systemic
exposure, rate of absorption, and safety. Application of
Transdermal matrix fentanyl patches [Matrifen or Durogesic
DTrans (100 g/h)] for 72 h to 30 healthy male subjects in a
randomized, four-period (two replicated treatment sequences),







Determination of pharmacokinetic parameters of fentanyl for

144 h after application using plasma samples have been carried

out. They evaluated Safety of the patches (adverse events) and

performance (adhesion, skin irritation, residual fentanyl content
in the patch). The plasma concentrationtime curves of
Matrifen (Test) and Durogesic DTrans (Reference) were
similar. The geometric least square means of the Test/Reference
ratio (90% confidence intervals [CI]) were within the range of
80125%, demonstrating bioequivalence of Matrifen and
Durogesic DTrans: AUC0-t 92.5 (CI 88.796.4), AUC0-inf 91.7
(CI 88.095.7), and Cmax 98.3 (CI 92.9104.1). After 72 h
application, Matrifen had a more efficient utilization of
fentanyl (mean SD 82.39.43%) than Durogesic DTrans
(52.312.8%), with substantially lower residual fentanyl in
patch after use. The pharmacokinetic parameters showed lower
intra- and inter-subject variability for Matrifen than for
Durogesic DTrans patch. Conclusion of the study states that
the transdermal fentanyl patches Matrifen and Durogesic
DTrans are bioequivalent. Compared with Durogesic
DTrans, the Matrifen patch had lower initial and lower
residual fentanyl content, as well as lower intra- and inter-

subject variability, allowing reproducible drug delivery and

reliable analgesia. [29]
The in vitro and in vivo evaluation of new synthesized
prodrugs of 5-OH-DPAT for iontophoretic delivery
Researchers have investigated the feasibility of transdermal
iontophoretic transport of 4 novel ester prodrugs of 5-OHDPAT (glycine-, proline-, valine- and -alanine-5-OH-DPAT) in
vitro and in vivo. Based on the chemical stability of the
prodrugs, they selected the best candidates for in vitro transport







pharmacokinetics and pharmacodynamic effects of the prodrug

with highest transport efficiency in a rat model. They analyzed
the in vitro transport, plasma profile and pharmacological
response with compartmental modeling. Valine- and -alanine5-OH-DPAT were acceptably stable in the donor phase and
showed a 4-fold and 14-fold increase in solubility compared to
5-OH-DPAT. Compared to 5-OH-DPAT, valine- and -alanine5-OH-DPAT were transported less and more efficiently across
human skin, respectively. Despite a higher in vitro transport,
lower plasma concentration was observed following 1.5 h

current application (250 A/cm2) of -alanine-S-5-OH-DPAT in

comparison to S-5-OH-DPAT. However the prodrug showed
higher plasma concentrations post-iontophoresis, explained by
a delayed release due to hydrolysis and skin depot formation.
They resulted in a pharmacological effect with the same
maximum as 5- OH-DPAT, but the effect lasted for a longer
time. The suggestion from study is that -alanine-5-OH-DPAT
is a promising prodrug, with a good balance between stability,
transport efficiency and enzymatic conversion. [30]
Effects of ultrasound and sodium lauryl sulfate on the





Comparative in vitro studies with full-thickness and splitthickness pig and human skin
The research is to study simultaneous application of ultrasound
and the surfactant sodium lauryl sulfate (referred to as US/SLS)
to skin enhances transdermal drug delivery (TDD) in a
synergistic mechanical and chemical manner. Since fullthickness skin (FTS) and split-thickness skin (STS) differ in
mechanical strength, US/SLS treatment may have different
effects on their transdermal transport pathways. Therefore, they

evaluated STS as an alternative to the well-established

US/SLS-treated FTS model for TDD studies of hydrophilic
permeants. They utilized the aqueous porous pathway model to
compare the effects of US/SLS treatment on the skin
permeability and the pore radius of pig and human FTS and
STS over a range of skin electrical resistivity values. They
indicated that the US/SLS-treated pig skin models exhibit
similar permeability and pore radii, but the human skin models
do not. Furthermore, the US/SLS-enhanced delivery of gold
nanoparticles and quantum dots (two model hydrophilic
macromolecules) is greater through pig STS than through pig
FTS, due to the presence of less dermis that acts as an artificial
barrier to macromolecules. They suggested the use of 700 mthick pig STS to investigate the in vitro US/SLS-enhanced
delivery of hydrophilic macromolecules. [31]
A novel transdermal patch incorporating meloxicam: In
vitro and in vivo characterization
Design a monolithic drug-in-adhesive (MDIA) type patch
containing meloxicam (MX) with an acrylic adhesive, a
solubility modulator increasing MX solubility, and enhancers

have been developed. MDIA patches having one adhesive layer

between the backing and the release liner give high
productivity and improve patient compliance. The biggest
problem to prepare MDIA patch including MX was poor
solubility of MX. In this research, solubility modulators to
increase solubility of MX and acrylic adhesives and skin
permeation enhancers were investigated through solubility
tests, in vitro skin permeation tests, and stability tests.
Consequently, the composition of sodium methoxide (SM), an
acrylic adhesive containing poly(vinyl pyrrolidone) blocks





diisopropanolamine (DIPA) made it possible for MX to be

contained in an adhesive layer at a concentration of as much as
15 wt% without MX crystal and with high skin permeation over
400G/cm2. Finally, the patch formulation containing MX
(MX-patch) selected through our in vitro study was
characterized by in vivo using an animal study to acquire
pharmacokinetic (PK) parameters and to confirm the antiinflammatory efficacy of MX-patch. In the animal study, MXpatch was compared with a commercially available piroxicam

patch (PX-patch). The amount of MX delivered from MXpatch to the skin surface was believed to be higher than the
amount of MX diffused from the skin tissue to circulatory
system because the plasma concentration of MX continuously
increased up to 32 h, the end time of PK study, although the
patch samples were detached at 24 h. PX-patch produced a
Cmax at 8 h. MX-patch showed better significant efficacy than
PX-patch in adjuvant arthritis model. [32]
Super-short solid silicon microneedles for transdermal drug
delivery applications
Using Galanthamine, RNA extract kit, Male newly born SD
(age: 7 days), HWY/Slc hairless rats (age: 60 days) and Silicon
wafer Super-short solid silicon microneedles for transdermal
drug delivery applications have been developed. In this study,
fabrication of the super-short microneedles with a length of 70
80m using silicon wet etching technology was done. As
evident from the visual inspection of pierced human skin,
appearance of blue spots array after Evans Blue (EB)
application indicated that the super-short microneedles were
able to pierce into skin by pressing and swaying against the

microneedles backing layer continually with a finger. The

micro-conduits created in skin were validated by histological

Figure 3: The schematic diagram of super-short microneedles

piercing skin by hand
Skin pretreated with super-short microneedles resulted in a
remarkable enhancement of the galanthamine (GAL) transport,
and the permeated amount increased as the insertion force
increased. The super-short microneedles with flat tips were
better than that with sharp tips for enhancing skin permeability.
The longer time of super-short microneedles detained in skin
resulted in a higher increase of skin permeability. There was no

linear correlation between the GAL permeated through skin and

the number of microneedles. Researchers suggested that supershort microneedles may be a safe and efficient alternative for
transdermal drug delivery of hydrophilic molecules. [33]
Since 1981, transdermal drug delivery systems have been used
as safe and effective drug delivery devices. Their potential role
in controlled release is being globally exploited by the
scientists with high rate of attainment. If a drug has right mix of
physical chemistry and pharmacology, transdermal delivery is a
remarkable effective route of administration. Due to large
advantages of the TDDS, many new researches are going on in
the present day to incorporate newer drugs via the system. A
transdermal patch has several basic components like drug
reservoirs, liners, adherents, permeation enhancers, backing
laminates, plasticizers and solvents, which play a vital role in
the release of drug via skin. Transdermal patches can be
divided into various types like matrix, reservoir, membrane
matrix hybrid; micro reservoir type and drug in adhesive type
transdermal patches and different methods are used to prepare

these patches by using basic components of TDDS. After

preparation of transdermal patches, they are evaluated for
physicochemical studies, in vitro permeation studies, skin
irritation studies, animal studies, human studies and stability
studies. But all prepared and evaluated transdermal patches
must receive approval from FDA before sale. Future
developments of TDDSs will likely focus on the increased
control of therapeutic regimens and the continuing expansion of
drugs available for use. Transdermal dosage forms may provide
clinicians an opportunity to offer more therapeutic options to
their patients to optimize their care. Recently, there are many
innovations done on Transdermal drug delivery like chemical
penetration enhancers, iontophoresis, ethanolic liposomes,
microemulsion, microneedle array, sonophoretic enhanced









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