Transdermal Drug Delivery System

Transdermal drug
delivery system

Introduction1,2 -
The use of the transdermal route has been well established since the1800s.
There is considerable interest in the skin as a site of drug application both
for local and systemic effects.

Transdermal drug delivery systems allow delivery of a drug into the
systemic circulation via permeation through skin layers at a controlled rate.

The skin poses an extremely good barrier to drug penetration and it is
usually necessary to employ enhancement strategies.

Innovative research exploiting penetration-enhancing strategies, such as
iontophoresis, electroporation, microneedles, and sonophoresis, holds
promise for the successful use of these drugs as consumer-
friendly, transdermal dosage forms in clinical practice.
optimpharma.blogspot.in

Objective -

To explore skin as a site for drug administration.
To identify physicochemical properties of drug
required in development of TDDs.
To study various methods for preparation of TDDs.
To study various methods for evaluation of TDDs.


Advantages of TDDS2 -
Avoids the risk and inconvenience of intravenous therapy.
Usually provides less chance of an overdose or under dose.
Permit both local and systemic effects .
Reduces dosing frequency.
Avoids hepatic first pass elimination and gastrointestinal irritation.
Non-invasive drug delivery system.
Improve physiological and pharmacological responses.
Reduction of fluctuations in plasma levels of drugs.
Allow easy termination.
Utilization of drug candidates with short half-life and low therapeutic index.
Reduction of dosing frequency and patient compliance.


Disadvantages of TDDS7 -

TDDS cannot deliver ionic drugs.

TDDS cannot achieve high drug levels in blood/plasma.

Cannot develop TDDS for drugs of large molecular size.

TDDS cannot deliver drugs in a pulsatile fashion.

Cannot develop TDDS, if drug or formulation causes irritation
to skin.


PERCUTANEOUS ABSORPTION7 -
Percutaneous absorption is defined as penetration of substances into
various layers of skin and permeation across the skin into systemic
circulations.

The percutaneous absorption is a step-wise process and can be divided into
three parts:

Penetration : is the entry of a substance into a particular layer.

Permeation : is the penetration from one layer into another, and is different
both functionally and structurally from the first layer.

Absorption : is the uptake of a substance into systemic circulation.

ANATOMY OF SKIN ALONG WITH ROUTES
OF PENETRATION2 -

Fig1: Anatomy of skin. optimpharma.blogspot.in

Anatomy of skin cont…
Drug molecules in contact with skin surface can penetrated by three
potential pathways, through
*sweat
ducts, *via the
hair follicles and *sebaceous
glands. *Stratum
corneum.


Ideal properties of drug used for
TDDS1
Parameter Properties
 Dose  Should be low (>20 mg/day)
 Half life in „h‟  10 or less
 Molecular weight  <400
 Partition coefficient  Log P (octanol-water)
between 1-4
 Skin permeability coefficient  >0.510
-3 cm/hr
 Skin reaction
 Non irritating and non
sensitizing
 Oral bioavailability
 Low
 Therapeutic index
 Low


Approaches of TDDS3,4,6,7.
Various technologies have been developed to bypass or modulate the barrier
function of the skin and to allow easier passage of drugs into the dermal
microcirculation; these can be categorized into physical and chemical.

Physical Approaches Chemical Approaches.
Iontophoresis .
Electroporation .
prodrug approaches.
Microporation.
penetration Enhancer.
Heat.
Needless injection.
Medicated tattos.
Sonophoresis.
Pressure valve
Radio Frequency.
Magnetophoresis

Physical Approaches.
1. Iontophoresis-
Iontophoresis is the process of enhancing the permeation of topically
applied therapeutic agents.
The drug is applied under an electrode of the same charge as the drug, and
an indifferent counter electrode is positioned elsewhere on the body.
The active electrode effectively repels the active substance and forces it
into the skin and rough the skin by the application of electric current.

Mechanisms.
First mechanism proposes that the drug is forced across the skin by simple
electronic repulsion of similar charges. Anionic drugs can cross the skin by
using a negatively charged working electrode. Similarly, cationic drugs can
cross the skin when a positively charged electrode is used.
The second the electric current enhances the permeation by inhibiting the
skin's ability to perform its protective barrier function.

Mechanism of Iontophoresis


2. Electroporation.
Electroporation is another electrical enhancement method which involves the
application of short (microsecond or millisecond), high voltage (50-1000
volts) pulses to the skin.

Larger macromolecules have also been delivered by
electroporation, including insulin, vaccines, oligonucleotides, and
microparticles.

A few model compounds such as calcein and LHRH drugs have also been
studied for increased transdermal absorption by electroporation.

Mechanism.

The mechanism of penetration is the formation of transient pores due to
electric pulses that subsequently allow the passage of macromolecules from
the outside of the cell to the intracellular space via a combination of processes

3.Microporation -
 Microporation involves the use of microneedles that are
applied to the skin so that they pierce only the stratum
corneum and increase skin permeability.

 Microneedles are needles that are 10 to 200 µm in height and
10 to 50 µm in width. Microneedles do not stimulate the
nerves, so the patient does not experience pain or discomfort.

 They are usually drug coated projections of solid silicon or
hollow, drug filled metal needles.


4 .Heat -
Heat enhances the skin permeation of drugs by increasing body fluid
circulation, blood vessel wall permeability, rate-limiting membrane
permeability, and drug solubility, thus facilitating drug transfer to the
systemic circulation.
Example:
The effect of temperature on in vitro transdermal fentanyl flux was
estimated at temperatures of 32 and 37 C. Drug flux approximately
doubled over this 5 range.
Heat may also cause changes in physiochemical properties of
patches, sweating, and increased hydration of skin, thus increasing the
permeation of drugs.
Mechanism :
When heat is applied, the kinetic energy of drug
molecules, proteins, lipids, and carbohydrates is known to increase in the
cell membrane. Also, drug solubility both in the patch and within the skin
may increase with a rise in temperature.

5.Needleless injection -
Needleless injection involves a pain-free method of administration of
drugs to the skin.

This technique involves firing the liquid or solid particles at supersonic
speeds through the stratum corneum.

Problems with this technique include the high developmental cost for both
the device and dosage form and the inability to program or control drug
delivery to compensate for intersubject differences in skin permeability.
Mechanism
The mechanism involves forcing compressed gas such as helium or
nitrogen through the nozzle with the resultant drug particles entrained
within the jet flow, reportedly traveling at sufficient velocity for skin
penetration.

6.Medicated tattoos -
Medicated tattoos are a modification of temporary tattoos which contain an
active drug medicament for transdermal delivery.

They are very attractive and fun to wear and are applied by wetting with water
and pressing against the skin.

The tattoo contains a drug layer, a colour design layer, and an adhesive layer
that binds to the skin. There is no predetermined duration of therapy. The
manufacturer provides a colours chart that can be compared to the colours of
the patient's tattoo to determine when the tattoo should be removed.

It gives a visual indication as the drug is absorbed into the skin. Upon
absorption, the tattoo gradually fades away and is painless to remove with a
simple astringent wash containing isopropyl alcohol. The drugs used in
medicated tattoos prototypes include acetaminophen, vitamin C etc.


7.Pressure waves -
Pressure waves generated by intense laser radiation, can permeabilize the
stratum corneum as well as the cell membrane.
PW is only applied for a very short time (100ns-1µs). It is thought that the
pressure waves form a continuous or hydrophilic pathway across the skin
due to expansion of lacunae domains in the stratum corneum.A single
pressure wave is sufficient to permeabilize the stratum corneum and allow
the transport of macromolecules into the epidermis and dermis.
In addition, the drug delivered into the epidermis can enter the vasculature
and produce a systemic effect.
Example:
Insulin delivered by pressure waves resulted in reducing the blood glucose
level over many hours. The application of pressure waves does not cause
any pain or discomfort and the barrier function of the stratum corneum
always recovers.


8.Sonophoresis -
Sonophoresis is a technique which involves the use of ultrasonic energy to
enhance skin penetration of active substances.
Transdermal enhancement is particularly significant at low frequency
regimes (20 KHz < f <100 KHz) than when induced by high frequency
ultrasound.
Ultrasound parameters such as treatment duration, intensity, pulse
length, and frequency are all known to affect percutaneous absorption with
frequency being the most important.
Example:
Sonophoresis of hypotensive agents and papain has been used in the
treatment of eye diseases. Several antibiotics including
tetracycline, biomycin, and penicillin have been sonophoretically
administered for the therapy of skin diseases.


Mechanism

The mechanism of transdermal skin permeation involves the disruption
of the stratum corneum lipids by the formation of gaseous cavities, thus
allowing the drug to pass through the skin.


9.Magnetophoresis -

The term, "magnetophoresis" was used to indicate application of a magnetic
field and acts as an external driving force to enhance drug delivery across the
skin.
It induces alteration in the skin's structure that could contribute to an increase
in permeability.
Magnetoliposomes consist of magnetic nanoparticles wrapped by a
phospholipid bilayer which can be successfully applied for drug delivery
systems, magnetic resonance imaging markers for cancer diagnosis, and
thermal cancer therapy.


10.Radiofrequency -

Radiofrequency involves exposure of the skin to a high frequency
alternating current of 100 KHz that results in the formation of heat-induced
microchannels in the cell membrane.

The drug delivery rate is controlled by the number and depth of
microchannels formed, which depends on the properties of the
microelectrodes in contact with the skin during treatment.

Skin delivery of testosterone and human growth hormone are in progress
by use of this method.


Chemical approaches


1. Penetration enhancer -
Incorporation of penetration enhancers facilitates the absorption of drugs
by altering the barrier property of the stratum corneum.
A permeation enhancer should be pharmacologically
inert, nontoxic, nonirritating, nonallergic, odorless, tasteless, colorless, com
patible with most drug and excipients, inexpensive, and have good solvent
properties.

Different classes of penetration enhancers includes:
Alcohols and polyols (ethanol, propylene glycol).
Surfactants (Tween, Span, SLS).
Fatty acids (Oleic acid).
Amines and amides (Azone, N -methylpyrrolidone).
Terpenes (limonene).
Sulfoxides (dimethylsulfoxide)
Esters(isopropylmyristate).

Mechanism:
Permeation enhancers can enhance the skin permeability by a variety of
mechanisms, including
1. Interaction with intercellular lipids leading to disruption of their
organization and increasing their fluidity.
2. Extraction of lipids from the stratum corneum.
3. Displacement of bound water,
4. Loosening of horny cells,
5. Delamination of stratum corneum.
6. Enhancing solubility and
7. Increasing partitioning into the stratum corneum,
8. Interaction with intercellular protein, and keratin denaturation.

2.Prodrug -
Prodrugs are therapeutically inactive derivatives of therapeutically active
drugs.
A prodrug undergoes metabolism to produce the therapeutically active
drug.
A prodrug is more lipophilic than the parent drug and has different
physicochemical properties.
Different prodrugs were developed for estradiol and "Transdermal
Bioactive Hormone Delivery" devices were developed based on the results.
The release rate of estradiol from Transdermal Bioactive Hormone
Delivery is dependent on the chain length of the ester group at the 17 th
position.
Alkyl ester prodrugs of ketorolac having optimum lipophilicity could
improve the transdermal delivery of ketorolac. Also, the prodrug approach
is a very feasible way to increase the skin permeation of protein/peptide
drugs.

Fig. Schematic representation of pro-drug approach to increase
drug penetration across skin7 .

Formulation aspects1:

Basic Components Of TDDS:
Polymer matrix / Drug reservoir

Drug

Permeation enhancers

Pressure sensitive adhesive (PSA)

Backing laminates

Release liner

Other excipients like plasticizers and solvents


Polymer matrix / Drug reservoir -

Polymers are the backbone of TDDS, which control the release of the drug
from the device.

Polymer matrix can be prepared by dispersion of drug in liquid or solid
state synthetic polymer base.

Polymers used in TDDS should have biocompatibility and chemical
compatibility with the drug and other components of the system such as
penetration enhancers and PSAs.

Additionally they should provide consistent and effective delivery of a
drug throughout the product‟s intended shelf life and should be of safe
status.

Examples:

Natural Polymers:
e.g. cellulose derivatives, zein, gelatin, shellac, waxes, gums, natural
rubber and chitosan etc.
 Synthetic Elastomers:
e.g. polybutadiene, hydrin rubber, polyisobutylene, silicon rubber,
nitrile, acrylonitrile, neoprene, butylrubber etc.
Synthetic Polymers:
e.g. polyvinyl alcohol, polyvinylchloride, polyethylene, polypropylene,
polyacrylate, polyamide, polyurea, polyvinylpyrrolidone,
polymethylmethacrylate etc.


Drug:
The transdermal route is an extremely attractive option for the drugs with
appropriate pharmacology and physical chemistry.
Transdermal patches offer much to drugs which undergo extensive first
pass metabolism, drugs with narrow therapeutic window, or drugs with
short half life which causes non- compliance due to frequent dosing.
The foremost requirement of TDDS is that the drug possesses the right mix
of physicochemical and biological properties for transdermal drug delivery.
It is generally accepted that the best drug candidates for passive adhesive
transdermal patches must be;
non ionic,
of low molecular weight (less than 500 Daltons),
have adequate solubility in oil and water (log P in the range of 1-3),
a low melting point (less than 200 C)
potent (dose in mg per day).


Permeation Enhancers:
These are the chemical compounds that increase permeability
of stratum corneum so as to attain higher therapeutic levels of
the drug candidate.
Penetration enhancers interact with structural components of
stratum corneum i.e., proteins or lipids.
They alter the protein and lipid packaging of stratum
corneum, thus chemically modifying the barrier functions
leading to increased permeability .
Over the last 20 years, a tremendous amount of work has been
directed towards the search for specific
chemicals, combination of chemicals, which can act as
penetration enhancers.

Pressure sensitive adhesives:
A PSA is a material that helps in maintaining an intimate contact between
transdermal system and the skin surface.
It should adhere with not more than applied finger pressure, be aggressively
and permanently tachy, exert a strong holding force.
Additionally, it should be removable from the smooth surface without leaving a
residue.
Polyacrylates, polyisobutylene and silicon based adhesives are widely used in
TDDSs.
The selection of an adhesive is based on numerous factors, including
the patch design and drug formulation. For matrix systems with a peripheral
adhesive, an incidental contact between the adhesive and the drug and
penetration enhancer should not cause instability of the drug, penetration
enhancer or the adhesive.
In case of reservoir systems that include a face adhesive, the diffusing drug
must not affect the adhesive.
In case of drug-in-adhesive matrix systems, the selection will be based on the
rate at which the drug and the penetration enhancer will diffuse through the
adhesive.
Ideally, PSA should be physicochemically and biologically compatible and
should not alter drug release.


Backing Laminate:
While designing a backing layer, the consideration of chemical resistance of the
material is most important.
Excipient compatibility should also be considered because the prolonged
contact between the backing layer and the excipients may cause the additives to
leach out of the backing layer or may lead to diffusion of excipients, drug or
penetration enhancer through the layer.
However, an overemphasis on the chemical resistance may lead to stiffness and
high occlusivity to moisture vapor and air, causing patches to lift and possibly
irritate the skin during long wear.
The most comfortable backing will be the one that exhibits lowest modulus or
high flexibility, good oxygen transmission and a high moisture vapor
transmission rate.
Examples :
vinyl,
polyethylene
and polyester films.


Release Liner:
During storage the patch is covered by a protective liner that is removed and
discharged immediately before the application of the patch to skin.
It is therefore regarded as a part of the primary packaging material rather than a
part of dosage form for delivering the drug.
However, as the liner is in intimate contact with the delivery system, it should
comply with specific requirements regarding chemical inertness and
permeation to the drug, penetration enhancer and water.
Typically, release liner is composed of a base layer which may be non-
occlusive (e.g. paper fabric) or occlusive (e.g. polyethylene, polyvinylchloride)
and a release coating layer made up of silicon or teflon.
Other materials used for TDDS release liner include polyester foil and
metallized laminates.

Other excipients:

Various solvents such as chloroform, methanol, acetone, isopropanol and
dichloromethane are used to prepare drug reservoir .

In addition plasticizers such as dibutylpthalate, triethylcitrate, polyethylene
glycol and propylene glycol are added to provide plasticity to the
transdermal patch.


VARIOUS METHODS FOR PREPARATION
TDDS4:

a. Asymmetric TPX membrane method.

b. Circular teflon mould method.

c. Mercury substrate method.

d. By using “IPM membranes” method.

e. By using “EVAC membranes” method.

f. Aluminium backed adhesive film method.


Asymmetric TPX membrane method:

 A prototype patch can be fabricated for this a heat sealable
polyester film (type 1009, 3m) with a concave of 1cm diameter
will be used as the backing membrane.

Drug sample dispensed into concave
membrane

Covered by TPX (poly-4-mthl-1-
pentene)

Sealed by adhesive


Circular teflon mould method:
Polymer solution (in various ratio) + Organic Solvent

Drug dissolve in half amount of same organic
solvent calculated

Enhancer (in different concentration)+ Different
ratio of drug & solvent

Addition of Di-N-butylphthalate

Stir 12hrs & pour into Circular teflon
mould

The solvent is allowed to evaporate for 24 hrs. The dried films are to be stored for
another 24hrs at 25 0.5 C in a desiccators containing silica gel before evaluation to
eliminate aging effects. The type films are to be evaluated within one week of their
preparation. optimpharma.blogspot.in

Mercury substrate method:

Drug is dissolve in polymer solution
along with plasticizer

Stir for 10-15 minutes to produce a
homogenous dispersion

pour in to a leveled mercury
surface, covered with inverted funnel
to control solvent evaporation


By using “IPM membranes” method:
drug is dispersed in a mixture of water and
propylene glycol containing carbomer 940 polymer

stir for 12 hrs in magnetic stirrer

dispersion is to be neutralized and made viscous by
the addition of triethanolamine

Buffer pH 7.4 can be used in order to obtain
solution gel

The formed gel will be incorporated
in the IPM membrane


By using “EVAC membranes” method:

The proliposomes are prepared by carrier method
using film deposition technique.

From the earlier reference drug and lecithin in the
ratio of 0.1:2.0 can be used as an optimized one.

The proliposomes are prepared by taking5mg of
mannitol powder in a 100 ml round bottom flask
which is kept at 60-70 c temperature and the flask
is rotated at 80-90 rpm and dried the mannitol at
vacuum for30 minutes.


After drying, the temperature of the water
bathis adjusted to 20-30 C.

Drug and lecithin are dissolved in asuitable
organic solvent mixture, a 0.5ml aliquot of
theorganic solution is introduced into the
round bottomedflask at 37 C, after complete
drying second aliquots(0.5ml) of the solution
is to be added.

After the last loading, the flask containing
proliposomes are connected in a lyophilizer
and subsequently drug loaded mannitol
powders (proliposomes) are placed in a
desiccator over night and then sieved through
100 mesh.

The collected powder is transferred into a glass bottle and stored at
the freeze temperature until characterization.


Aluminium backed adhesive film method:
Free film of cellulose acetate is prepared by
casting on mercury surface.

A polymer solution 2% w/w is to be prepared by
using chloroform.

Plasticizers are to be incorporated at a
concentration of 40% w/w of polymer weight.

Five ml of polymer solution was poured in a
glass ring which is placed over the mercury
surface in a glass petri dish.
The rate of evaporation of the solvent is
controlled by placing an inverted funnel over the
petri dish.


The film formation is noted by observing the
mercury surface after complete evaporation of the
solvent.

The dry film will be separated out and stored
between the sheets of wax paper in a desiccator
until use.

Free films of different thickness can be prepared
by changing the volume of the polymer solution.


Evaluation1,4,7:

11. Peel Adhesion test:
1. Interaction studies:
2. Thickness of the patch: 12. Flatness test:
3. Weight uniformity: 13. Percentage Elongation break test:

4. Folding endurance: 14. Rolling ball tack test:
5. Percentage Moisture content: 15. Quick Stick (peel-tack) test:
16. Skin Irritation study:
6. Percentage Moisture uptake:
17. In vitro drug release studies:
7. Drug content:
18. In vitro skin permeation studies:
8. Water vapour permeability (WVP) 19. Stability studies:
evaluation:
9. Uniformity of dosage unit test:
10. Shear Adhesion test:

1. Interaction studies:
Excipients are integral components of almost all pharmaceutical dosage
forms. The stability of a formulation amongst other factors depends on the
compatibility of the drug with the excipients.
The drug and the excipients must be compatible with one another to
produce a product that is stable, thus it is mandatory to detect any possible
physical or chemical interaction as it can affect the bioavailability and
stability of the drug.
If the excipients are new and have not been used in formulations containing
the active substance, the compatibility studies play an important role in
formulation development.
Interaction studies are commonly carried out in Thermal analysis, FT-
IR, UV and chromatographic techniques by comparing their
physicochemical characters such as assay, melting
endotherms, characteristic wave numbers, absorption maxima etc.,

2. Thickness of the patch:

The thickness of the drug loaded patch is measured in different points by using
a digital micrometer and determines the average thickness and standard
deviation for the same to ensure the thickness of the prepared patch.

3. Weight uniformity:
The prepared patches are to be dried at 60 c for 4hrs before testing.
A specified area of patch is to be cut in different parts of the patch and
weigh in digital balance.
The average weight and standard deviation values are to be calculated
from the individual weights.

4. Folding endurance:
A strip of specific are is to be cut evenly and repeatedly folded at the same
place till it broke.
The number of times the film could be folded at the same place without
breaking gave the value of the folding endurance.

5. Percentage Moisture content:
The prepared films are to be weighed individually and to be kept in a
desiccator containing fused calcium chloride at room temperature for 24
hrs.
After 24 hrs the films are to be reweighed and determine the
percentage moisture content from the below mentioned formula.

Percentage moisture content = [Initial weight- Final weight/
Final weight] 100.

6. Percentage Moisture uptake:
The weighed films are to be kept in a desiccator at room temperature for 24
hrs containing saturated solution of potassium chloride in order to maintain
84% RH.
After 24 hrs the films are to be reweighed and determine the percentage
moisture uptake from the below mentioned formula.
Percentage moisture uptake = [Final weight- Initial weight/
initial weight] 100.

7. Drug content:
A specified area of patch is to be dissolved in a suitable solvent in specific
volume.
Then the solution is to be filtered through a filter medium and analyse the
drug contain with the suitable method (UV or HPLC technique).
Each value represents average of three different samples.

8. Water vapour permeability (WVP) evaluation:

The WVP can be determined by the following formula

Water vapour permeability can be determined with foam dressing method the

air forced oven is replaced by a natural air circulation oven.

WVP=W/A

Where, WVP is expressed in gm/m2 per 24hrs,

W is the amount of vapour permeated through the patch expressed in gm/24hrs

and A is the surface area of the exposure samples expressed in m2.


9. Uniformity of dosage unit test:

An accurately weighed portion of the patch is to be cut into small pieces
and transferred to a specific volume volumetric flask, dissolved in a
suitable solvent and sonicate for complete extraction of drug from the patch
and made up to the mark with same.

The resulting solution was allowed to settle for about an hour, and the
supernatant was suitably diluted to give the desired concentration with
suitable solvent.

The solution was filtered using 0.2m membrane filter and analysed by
suitable analytical technique (UV or HPLC) and the drug content per piece
will be calculated.


10. Shear Adhesion test:

This test is to be performed for the measurement of the cohesive strength of
an adhesive polymer.

It can be influenced by the molecular weight, the degree of crosslinking
and the composition of polymer, type and the amount of tackifier added.

An adhesive coated tape is applied onto a stainless steel plate; a specified
weight is hung from the tape, to affect it pulling in a direction parallel to
the plate.

Shear adhesion strength is determined by measuring the time it takes to pull
the tape off the plate. The longer the time take for removal, greater is the
shear strength.


11. Peel Adhesion test:
In this test, the force required to remove an adhesive coating form a test
substrate is referred to as peel adhesion.
Molecular weight of adhesive polymer, the type and amount of additives
are the variables that determined the peel adhesion properties.
A single tape is applied to a stainless steel plate or a backing membrane of
choice and then tape is pulled from the substrate at a 180º angle, and the
force required for tape removed is measured.

12. Flatness test:
Three longitudinal strips are to be cut from each film at different portion
like one from the center, other one from the left side, and another one from
the right side.
The length of each strip was measured and the variation in length because of
non-uniformity in flatness was measured by determining percent
constriction, with 0% constriction equivalent to 100% flatness.


13. Percentage Elongation break test:
The percentage elongation break is to be determined by noting the length
just before the break point, the percentage elongation can be determined
from the below mentioned formula.
Elongation percentage = L1-L2 100
L2
Where, L1is the final length of each strip and L2 is the initial length of each
strip.

14. Rolling ball tack test:
This test measures the softness of a polymer that relates to talk.
In this test, stainless steel ball of 7/16 inches in diameter is released on an
inclined track so that it rolls down and comes into contact with
horizontal, upward facing adhesive.
The distance the ball travels along the adhesive provides the measurement
of tack, which is expressed in inch.

15. Quick Stick (peel-tack) test:
In this test, the tape is pulled away from the substrate at 90ºC at a speed of
12 inches/min.
The peel force required to break the bond between adhesive and substrate is
measured and recorded as tack value, which is expressed in ounces or
grams per inch width.

16. Skin Irritation study:
Skin irritation and sensitization testing can be performed on healthy rabbits
(average weight 1.2 to 1.5 kg).
The dorsal surface (50cm2) of the rabbit is to be cleaned and remove the
hair from the clean dorsal surface by shaving and clean the surface by using
rectified spirit and the representative formulations can be applied over the
skin.
The patch is to be removed after 24 hr and the skin is to be observed and
classified into 5 grades on the basis of the severity of skin injury.

17. In vitro drug release studies:
The paddle over disc method (USP apparatus V) can be employed for
assessment of the release of the drug from the prepared patches.
Dry films of known thickness is to be cut into definite shape, weighed, and
fixed over a glass plate with an adhesive.
The glass plate was then placed in a 500-ml of the dissolution medium or
phosphate buffer (pH 7.4), and the apparatus was equilibrated to 32 0.5 C.
The paddle was then set at a distance of 2.5 cm from the glass plate and
operated at a speed of 50 rpm. Samples (5- ml aliquots) can be withdrawn at
appropriate time intervals up to 24 h and analyzed by UV spectrophotometer or
HPLC.
The experiment is to be performed in triplicate and the mean value can be
calculated.


18. In vitro skin permeation studies:
An in vitro permeation study can be carried out by using diffusion cell.
Full thickness abdominal skin of male Wistar rats weighing 200 to 250g.
Hair from the abdominal region is to be removed carefully by using a electric clipper;
the dermal side of the skin was thoroughly cleaned with distilled water to remove any
adhering tissues or blood vessels, equilibrated for an hour in dissolution medium or
phosphate buffer pH 7.4 before starting the experiment and was placed on a magnetic
stirrer with a small magnetic needle for uniform distribution of the diffusant.
The temperature of the cell was maintained at 32 0.5 C using a thermostatically
controlled heater.
The isolated rat skin piece is to be mounted between the compartments of the diffusion
cell, with the epidermis facing upward into the donor compartment.
Sample volume of definite volume is to be removed from the receptor compartment at
regular intervals, and an equal volume of fresh medium is to be replaced.
Samples are to be filtered through filtering medium and can be analyzed
spectrophotometrically or HPLC.
Flux can be determined directly as the slope of the curve between the steady-state values
of the amount of
drug permeated (mg cm2) vs. time in hours and permeability coefficients were deduced
by dividing the flux by the initial drug load (mg cm2).


19. Stability studies:

Stability studies are to be conducted according to the ICH guidelines by
storing the TDDS samples at 40 0.5 c and 75 5% RH for 6 months.

The samples were withdrawn at 0, 30, 60, 90 and 180 days and analyze
suitably for the drug content.


Conclusion -

Transdermal drug delivery system has been recognized
as a potential delivery system in spite of its limitation.
Essentially this drug delivery system brings
ratecontrolled delivery with fewer side effects
, increased efficacy and constant delivery.
The skin has an extremely good barrier function and to
improve the penetration of active ingredients it is
frequently necessary to employ enhancement strategies.


References -
Geeta Agrawal,Dr.Sanjiv Dhawan,Development fabrication
and evaluation of TDDS, Review,Vol.7 Issue 5-2010
Pharmainfo.net
A. E. Benson TDDS Penetration enhancement Technology
2005 bentham Science Publisher limited.
Bharkatya M,Neema RK,Skin Penetration Enhancement
Technique,J Young Pharmacist 2009;110-5.
J Ashok Kumar ,Nikhila pullakandan, S. Lakshamana
prabu,V.Gopal,Faculty Of Pharmacist,PRIST
University, Thanjavur, Tamilnadu-614904.


Indian Journal Of Pharmaceutical Sciences, Review
Article,
Year-2008,Volume-70,Issue-1,Page no-5-10.
Swati Rawat, Sudha
Vengurlekar,B.Rakesh,S.Jain,G.Srikarti,Smriti
College Of Pharmaceutical Education Indore-
452010,India
Mathur et al Enhancer in TDDS,Asian Journal Of
Pharmaceutical Sciences, nov-2010.
Ramesh Panchagnula,Transdermal Delivery of drug
Indian Journal of Pharmacology July-1997.


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