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Transdermal drug delivery system
1. Masters of pharmacy, Pharmaceutical technology (Pharmaceutics)
Subject- Advances in drug delivery (MPT-103T)
Lesion no- 5, Transdermal drug delivery systems By- Drx JAYESH M RAJPUT
Points: -
1) Transdermal drug delivery system
Transdermal drug delivery system (TDDS) are topically administered medicaments in the form of patches, which
when applied to intact skin, allows the delivery of contained drugs into the systemic circulation via permeation
through skin layers at a predetermined and controlled rate. Transdermal patches typically involve a liquid, gel, solid
matrix or pressure sensitive adhesive carrier into which the drug is incorporated. This approach of drug delivery is
more pertinent in case of chronic disorders (hypertension, diabetes) which require long term dosing to maintain
therapeutic drug concentrations.
Transdermal drug delivery is defined as self contained discrete dosage form, which when applied to the intact skin,
will deliver the drug at a controlled rate to the systemic circulation. Transdermal drug delivery systems (patches)
are dosage forms designed to deliver a therapeutically effective amount of drug across a patients skin also defined
as medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and
into the blood stream.
Why Transdermal drug delivery?
Continuous IV administration at a constant rate of infusion is a superior mode of drug delivery
IV administration avoids hepatic first-pass metabolism and maintain constant therapeutic drug levels in the
body
TDD can closely duplicate continuous IV fusion. Hence it is helpful in delivering drugs that undergo
significant first pass metabolism and/or have narrow therapeutic index
History of TDDS
When one hears the word Transdermal drug delivery, what comes to mind? More than likely one thinks about a
simple patch that one stick onto skin like an adhesive bandage such as nicotine patch. The NDDS may involve a
new dosage form e.g., from thrice a day dosage to once a day dosage form or developing a patch form in place of
injections, throughout the past 2 decades, the Transdermal patch has become a proven technology that offers a
variety of significant clinical benefits over other dosage forms. Because Transdermal drug delivery offers
controlled release of the drug into the patient, it enables a steady blood-level profile, resulting in reduced
systemic side effects and, sometimes, improved efficacy over other dosage forms.
o Transdermal drug delivery system was first introduced more than 20 years ago
o The technology generated tremendous excitement and interest amongst major pharmaceutical
companies in the 1980s and 1990s.
o First Transdermal patch was approved in 1981 to prevent the nausea and vomiting associated with
motion sickness, the FDA has approved, throughout the past 22 years, re than 35 Transdermal patch
products, spanning 13 molecules
o 1970- Alza research (US) began first development of the modern Transdermal
o 1980- scopolamine first Transdermal reached US
o 2002- many Rx and non-Rx products in the US market
2. o Transdermal deliver drugs from a few hours up to 7 days
o Transdermal delivery represents an attractive alternative to oral delivery of drugs and is poised to
provide an alternative to hypodermic injection too
o For thousands of years, people have placed substances on the skin for therapeutic effects
Advantages of TDDS
Avoidance of first pass effect
Long duration of action
Comparable characteristics with IV infusion
Ease of termination of drug action, if necessary
No interference with gastric and intestinal fluids
Suitable for administered of drug having- very short half life, e.g., nitroglycerine. Narrow therapeutic
window, poor oral bioavailability
Improves patient compliance, provides capacity for multi-day therapy with a single application. No pills
to remember
Slow and steady infusion of a drug over an extended period of time results in more consistent plasma
concentrations. Adverse effects or therapeutic failures (due to peaks and valley) frequently associated
with intermittent dosing can be avoided
Transdermal delivery can increase the therapeutic value of many drugs by avoiding specific problems
associated with the drug like: - G.I.irritation, low absorption, decomposition due to hepatic first pass
effect, formation of metabolites that cause side effects, short half life necessitating frequent dosing, etc
Dose of drug required is low than is necessary for drug dose given orally
Avoid GIT drug absorption difficulties caused by G.I pH, enzymatic activity and drug interactions with
food, drink or other orally administered drugs
Substitutes for oral administration of medication when the route is unsuitable as in case of vomiting or
diarrhea
Provide ease of rapid administration of medication in emergencies like unconsciousness, non-responsive
cases, etc
Avoid risk and inconveniences of parenteral therapy: -
Necessitates no hospitalization of patients
Close medical supervision of the medicament is not needed
Non invasive in nature
Disadvantages of TDDS
Poor diffusion of large molecules
Skin irritation
Requires high load
Unsuitable-if drug dose is large
Absorption efficiency is vary with different sites of skin
The drug must have some desirable physicochemical properties for penetration throughout skin like
balanced hydrophilic and lipophilic nature, low molecular weight, etc
If the drug dose required for therapeutic value is more than 10 mg/day, the Transdermal delivery will be
very difficult if not possible. This means only potent drugs can be administered
Skin irritation or contact dermatitis due to the drug, excipients and enhancers of the drug used to
increase percutaneous absorption is another limitation
Some drugs that undergo local dermal metabolism cannot be administered
3. The barrier function of the skin changes from one site to another on the same person, from person to
person with age
Requires careful disposal as patch may still contain active medication
Technical difficulties are associated with adhesion of system to different skin types and under various
environmental conditions
High cost of such a system
2) Structure of Skin
Skin is a part of integrated system i.e., it helps to maintain body temperature and protect it from
surrounding environment, it covers an area of about 2m2 and 4.5-5 kg i.e. about 16% of total body weight in
adults. Thickness is in range of 0.5mm (on eyelids) to 4.0mm (on heels)
Skin has mainly 3 layers
4. 1) Epidermis
Stratum corneum (horny cell layer) - consists of 25 to 30 layers of flattened dead keratinocytes.
This makes it water repellant.
Stratum lucidium (clear layer)
Stratum granulosm (granular layer) - consists of 3 to 5 layers and undergoes apoptosis. It
contains granules known as keratohyalin. These granules release lipid rich secretion, which acts as
the water repellent
Stratum spinosum (prickly layer) - contains 8 to 10 layers of cells and it is closely arranged
Stratum basal- consists of single layer of cubical or columnar keratinocytes
2) Dermis
Composed of strong connective tissue containing collagen and elastic fibres, hence it can easily stretch and
recoil easily, blood vessels, nerves gland and hair follicles are embedded in this layer
3) Subcutaneous layer (hypodermis)
It is also called as hypodermis, it is made up of loose connective tissue, including adipose tissue, this helps
to insulate the body by monitoring heat gain and heat loss, the dermis is the layer of tissue that is deeper
and thicker than epidermis
Routes of drug penetration
Percutaneous absorption
It involves passive diffusion of substance through skin
Macro routes: - sweat duct, across stratum corneum, hair follicles
Micro routes: - intercellular, Transcellular
5. Trans-follicular route
o Fractional area available through this route is 0.1%
o Human skin contains 40-70 hair follicles, 200 to 250 sweat glands on every sq.cm of skin area
o Mainly water soluble substance are diffused faster through appendages than that of other layers
o Sweat glands and hair follicles act as a shunt i.e. easy pathway for diffusion through rate limiting
Stratum corneum
Trans-epidermal route
o Epidermal barrier function mainly resides in horny layer
o The viable layer may metabolize, inactivate or activate a prodrug
o Dermal capillary contains many capillaries so residence time of drug is only one minute
o Within stratum corneum molecule may penetrate either transcellularly or intercellularly
o Intracellular region is filled with lipid rich amorphous material
Process of Transdermal permeation: -
6. 3) Barriers of Transdermal permeability (factors affecting Transdermal permeability)
1) Physicochemical properties of drug molecule
Solubility and partition coefficient
pH conditions
penetrant concentrations
partition coefficient
drug concentration
molecular weight
2) Physicochemical properties of drug delivery system
release characteristics
composition of drug delivery system
enhancement of Transdermal permeation
use of permeation enhancer
3) Physiological and pathological conditions of skin
reservoir effect of horny layer
lipid film
skin hydration
skin temperature
effect of vehicle
pathological injury to skin
regional variation
4) Biological factors
skin age
skin condition
regional site
skin metabolism
circulatory effect species differences
1) Physiochemical properties of drug molecule: -
a) Solubility and partition coefficient
solubility character of a drug greatly influences its ability to penetrate skin
partition coefficient has profound influence on transfer of drug from vehicle to skin
drug solubility determines the concentration presented on absorption site, thus can affect the rate and
extent of drug absorption
Skin permeation can be increased by increasing the lipophilic character of drug, so that drug readily
penetrates through stratum corneum but may not penetrate viable epidermis because of its reduced
water solubility. Therefore a balance in lipophilic and hydrophilic nature is required for optimum skin
permeation
A lipid water partition coefficient of 1 or more is generally required for optimal skin permeation.
7. b) pH conditions
Application of a solution whose pH value are very high or very low can be destructive to skin, hence
moderate pH is favorable
The flux of ionizable drugs can be affected by changes in pH as it alters the ratio of charged and
uncharged species and their Transdermal permeability
c) Penetrant concentration
As skin permeation follows passive diffusion, concentration is the driving force in penetration of drug
through skin
Higher the concentration of dissolved drug in vehicle faster is the absorption
Above saturation point, excess solid drug functions as a reservoir and helps to maintain a constant drug
release for prolonged period of time
2) Physicochemical properties of drug delivery system: -
a) Release characteristic
Solubility of drug in the vehicle determines release rate, the mechanism of drug release depends on: -
Whether drug molecules are dissolved or suspended in the delivery system
Interfacial partition coefficient of drug from delivery system to skin tissue
pH of vehicle
b) Composition of drug delivery systems
it not only affects the rate of drug release but also permeability of stratus corneum by means of
hydration mixing with skin lipids or other sorption promoting effects
e.g., methyl salicylate is more lipophilic than its parent acid. When applied to skin from fatty vehicle, the
methyl salicylate yielded higher skin absorption than salicylic acid
c) Enhancement of Transdermal permeation
Majority of drugs will not penetrate the skin at rates sufficiently high for therapeutic efficiency, hence addition
of permeation enhancers is required to increase skin permeation
3) Physiological and pathological conditions of skin
a) Reservoir effect of horny layer
the horny layer can sometimes act as a depot and modify Transdermal permeation characteristics of
some drugs
reservoir effect is due to the irreversible binding of part of applied drug with skin
this binding can be reduced by the treatment of skin surface with anionic surfactants
b) Lipid film
lipid films on skin surface act as protective layer to prevent removal of moisture from skin and helps in
maintaining barrier function of stratum corneum
deffating of this film will decrease Transdermal absorption
8. c) Skin hydration
it enhances permeability
it can be achieved simply by covering or occluding skin with plastic sheeting, leading to accumulation of
sweat, condensed water vapors which increases hydration and porosity of skin due to opening up of
dense, closely packed cells of skin
d) Skin temperature
it is directly proportional to skin penetration due to
thermal energy required for diffusivity
solubility of drug in skin tissue
increased vasodilation of skin vessels
occlusions on skin surface increase the temperature by 2 to 30 C which causes an increase in molecular
motion and skin permeation
e) Effect of vehicle
it influences the percutaneous absorption by its potential effect on physical states of drug and skin. E.g., greases,
paraffin bases are most occlusive while W/O bases are less.
4) Penetration enhancers
The aim of drug administration via skin can be either the local therapy or the Transdermal drug delivery of the
systemic circulation; Transdermal system delivers medications through the skin direct into the blood stream. One
long standing approach to increase the range of drugs that can effectively deliver via this route has been to use
penetration enhancers; chemicals that interact with skin constituents to promote drug flux.
Percutaneous absorption: - it involves passive diffusion of substance through skin, transcorneal penetration intra
cellular penetration, inter cellular penetration. Transappendegeal penetration.
Factors affecting percutaneous absorption: -
solubility in stratum corneum
diffusion through stratum corneum
partitioning
diffusion through viable skin tissue
condition of skin
effect of moisture
effect of vehicles
9. effect of concentration of medicament
effect of surfactant
Penetration enhancement
Skin penetration enhancement technique has been developed to improve bioavailability and increase the range
of drugs for which topical and Transdermal delivery. Penetration enhancers penetrate through skin to decrease
the barrier resistance. Alternatively, physical mechanism such as Iontophoresis and phonophoresis can be used
for certain cases of drugs.
Chemical enhancers
Chemical enhancers or penetration enhancers or absorption promoters are the agents that interact with skin
constituents to promote the drug flux. Many agent have studied and evaluated for enhancement properties. Yet
their inclusion in skin formulation is limited due to unknown mechanism and toxicity.
Ideal properties
non toxic, non irritating, non allergic
ideally work rapidly
pharmacologically inert
its duration of action should be predictable and reproducible
should work unidirectionally
when removed from skin barrier properties should return both rapidly and fully
cosmetically acceptable
compatible with both excipients and drug
Diffusion through skin
Fick’s second law of diffusion
dc/ dt= D d2C/dx2---------------------- (1)
Where, C= concentration of drug, x= space co-ordinate, D= diffusion coefficient, t= time
Under steady state condition,
dm/ dt= DC0 /h -------------------------(2)
Where, m= cumulative mass of drug that passes per unit area of membrane in time t
C0= concentration of diffusant in the first layer of membrane at the skin surface, h= membrane thickness
C0= P C’0--------------------------------- (3)
Where, P= partition coefficient
Substituting equation 3 in equation 2 gives
dm/ dt= D C’0 P/h -----------------------(4)
from the given equation it can be seen that : -
10. 1) diffusion coefficient of drug in stratum corneum, 2) dissolved effective concentration of drug in the vehicle,
3) partition coefficient of the drug between the formulation and stratum corneum, 4) membrane thickness.
Effective penetration enhancer may act: -
by increasing the diffusion coefficient of the drug
by increasing the effective concentration of the drug in the vehicle
by improving partition between the formulation and the stratum corneum
by decreasing the skin thickness
Classification of chemical penetration enhancers
1) Surfactants: -
a) Ionic: - SLS, Na laureate, etc
b) Non-ionic: - tween 80, polysorbates, etc
2) Bile salts and derivatives: -
e.g., Na glycolate, Na deoxycholate
3) Fatty acid and derivatives: -
e.g., oleic acid, caprylic acid, etc
4) Chelating agents: -
e.g., EDTA, citric acid, etc
5) Sulphoxide
e.g., DMSO, DMA, DMF, etc
6) Polyols: -
e.g., PG, PEG, glycerol, etc
7) Monohydric alcohols: -
e.g., ethanol, 2-propanol, etc
8) Miscellaneous: -
e.g., urea and its derivatives, terpenes and terpenoids, phospholipids, water
Water: - the water content of human stratum corneum is typically around 15-20% of tissue dry weight. Soaking
the skin in water, exposing the membrane to high humidities or, occluding allow the stratum corneum to reach
water contents in equilibrium with underlying epidermal skin cells. Water content increases to 400%. In
general, increased tissue hydration appears to increase Transdermal delivery of both hydrophilic and lipophilic
permeants. Water present in stratum corneum is in two form, bound and free, free from act as a solvent for
polar permeates to diffuse.
11. MOA: - free water act as a solvent and alter solubility of permeants and so it’s partitioning. The corneocytes
take up water and swell, such swelling of cells would impact upon the lipid structure between the corneocytes
causing some disruption to the bilayer packing.
Sulphoxide and its analogues: - dimethyl Sulphoxide (DMSO), aprotic solvent which form hydrogen bond
with itself rather than with water. Used in many areas of pharmaceutical sciences as a “universal solvent”.
Promotes both hydrophilic and hydrophobic permeates. Effect is concentration dependent (˃ 60% needed for
optimum action). At high concentration- erythema and whales, may denature proteins, metabolite dimethyl
sulfide produces foul odor on breath. To avoid above side effects researchers have investigated chemically
related materials- DMAC and DMF
MOA: - denature protein, changes the keratin confirmation from α- helical to β- sheet, interacts with the head
groups of some bilayer lipids to distort to the packing geometry, also may facilitate drug partitioning from
formulation to this universal solvent.
Azones: -
first chemically designed molecule as penetration enhancer
promote flux both hydrophilic and lipophilic permeants
highly lipophilic with log o/w= 6.2
Effective at low concentration (0.1-5%)
soluble in and compatible with most organic solvents
enhances permeation of steroids, antiviral and antibiotics
MOA: - interact with the lipid domains of the stratum corneum. Partition into the lipid bilayer to disrupt their
packing arrangement.
Pyrrolidone: -
mostly used number: 2-pyrrolidone (2p) and N-methyl-2-pyrrolidone (NMP)
NMP and 2P are miscible with most organic solvents
Used for numerous molecules including hydrophilic (e.g., mannitol, and 5-fu) and lipophilic
(hydrocortisone and progesterone) permeants
Greater effect on hydrophilic drugs
MOA: - may act by altering the solvent nature of the membrane and pyrrolidones has been used to generate
“reservoirs” within skin membranes. Such a reservoir effect offers potential for sustained release of a permeant.
Fatty acids: -
Oleic acid and other long chain fatty acid are used
Effective at low concentration (≺10%)
Used both for hydrophilic and lipophilic drugs
Saturated alkyl chain lengths of around C10-C12 attached to a polar head group yields a potent enhancer
In unsaturated compounds, the bent cis configuration is expected to disturb intercellular lipid packing
more than trans
Used for estradiol, acyclovir, 5 fluorouracil, salicylic acid
MOA: - interacts with and modifies the lipid domains of stratum corneum discrete lipid domains are induced
within stratum corneum bilayer lipid on exposure to oleic acid.
12. Alcohols, fatty alcohols and glycols: -
Ethanol is used most commonly in patches
Used for levonorgestrol, estradiol, 5FU, etc
Its effect is concentration dependent, at high concentration causes dehydration of biological membrane
and decreases the permeation
Applied in concentration range from 1-10%
Branched alcohols lower activity
1-butanol most effective
1-octanol and 1-propanolol to be effective enhancers for salicylic acid and nicotinamide
MOA: - act as solvent, alter solubility property of tissue leads to improvement in drug partitioning. Volatile
nature of ethanol helps in modifying thermodynamic activity of drug. Due to evaporation of ethanol drug
concentration increases providing supersaturated state with greater driving force. Solvent drag may carry
permeant into the tissue, as volatile solvent may extract lipid fraction from skin.
Surfactant: -
Are made up of alkyl or aryl side chain with polar head group
Have potential to damage human skin
Both anionic and cationic surfactant can be used, but non ionic surfactant are safe
Non-ionic- minor effect, anionic- pronounced effect
MOA: - solubilize the lipophilic active ingredient and also have potential to solubilize lipids within the stratum
corneum.
Essential oils, terpenes and terpenoids
Used as medicines, flavoring and fragrancing agents
Hydrocarbon terpenes less potent, alcohol/ ketone containing terpenes moderate and oxide and
terpenoids shows greatest enhancement
Smaller terpenes are more active than larger
Non polar (limonene) agents active for lipophilic drugs and polar (menthol) for hydrophilic drugs
MOA: - modify the solvent nature of the stratum corneum, improving drug partitioning. Alters thermodynamic
activity of the permeant. Terpenes may also modify drug diffusivity through the membrane.
Urea: -
Hydrating agent, have been used in scaling conditions such as psoriasis and other skin conditions. It
produces significant stratum corneum hydration, produces hydrophilic diffusion channels. Have
keratolytic properties, usually when used in combination with salicylic acid for keratolysis. Urea itself
possesses only marginal penetration enhancing activity. Cyclic urea analogues and found them to be as
azone for promoting indomethacin.
Phospholipids: -
Generally employed as vesicles (liposomes) to carry drugs
In a non-vesicular form as penetration enhancers
Phosphatidylcholine and hydrogenated soybean phospholipids have been reported to enhance
penetration of theophylline and diclofenac respectively
13. MOA: - occlude the skin surface and thus increase tissue hydration. Phospholipids fuse with stratum corneum
lipids. This collapse of structure liberates permeant into the vehicle where the drug is poorly soluble and hence
thermodynamic activity could be raised so facilitating drug delivery.
Physical enhancement techniques
1) Needle-free jet injectors
2) Phonophoresis
Basic principle of phonophoresis, ultrasound pulses are passed through the probe into the skin fluidizing the
lipid bilayers by the formation of bubbles caused by cavitation.
3) Ultrasound to enhance skin permeability
4) Iontophoresis
Basic principle of Iontophoresis a current passed between the active electrode and the indifferent electrode
repelling electrode repelling drug away from the active electrode and into the skin.
5) Electroportation: -
Skin electroportation (electropermeabilization) creates transient aqueous pores in the lipid by application of
high voltage of electrical pulses of approximately 100-1000 V/Cm for short time (milliseconds). These pores
provide pathways for drug penetration that travel straight through the horny layer. This technology has been
14. successfully used to enhance the skin permeability of molecules with differing lipophilicity and size including
biopharmaceuticals with molecular weights greater that 7KDA.
Basic principle of electroportation, high voltage current is applied to the skin producing hydrophilic pores in
the intercellular bilayers via momentary realignment of lipids.
6) Microneedle: -
Basic design of Microneedle delivery system devices. Needles with or without hollow centre channels are
placed onto the skin surface so that they penetrate the SC and epidermis without reaching the nerve endings
present in the upper epidermis.
5) Transdermal drug delivery systems formulation
1) Membrane permeation- controlled systems
Multilaminate Transdermal dosage form manufacturing process flow diagram
15. Form fill seal process flow diagram
2) Adhesive dispersion- type systems
16. 3) Matrix diffusion- controlled systems
4) Microreservoir type or micro sealed dissolution controlled systems
Designing of TDDS/ preparation of Transdermal patch from industrial point of view
17. Layout
Equipments
Drug in adhesive-
Mixer
Drier (explosion proof)
Coater-laminator
Slitter
Die-cutting
Pouching equipment
Drug in reservoir
For-fill-seal
Lamination
Die-cutting
Pouching
Adhesive layer may be preformulated (mixing, drying, lamination)
Manufacturing steps: -
1. Blending
The first step in manufacturing a patch is blending, where active drug compounds are mixed with
custom adhesives in large, specialized kettles. After blending is complete, the drug/adhesive mix is
pumped to the next machine for coating
2. Coating process
In the coating process, a thin, precise drug/adhesive layer is applied within tolerances of about one-
tenth the thickness of a human hair to long, broad sheets of release liner material.
3. The blending solvent is removed in the large arch tunnel oven
4. Lamination of backing
Then the final layer of the three layer patch, the backing is laminated. Although initially applied to
the release liner, the adhesive matrix permanently bonds to the patch backing. The completed
laminate is then rolled for the next production step.
5. Rolling of the laminate
The laminate rolls are then sent through punching, pouching and cartooning machines specially
18. Configured for each product.
6. Punching
Dosing is controlled in part by patch size, and patches of precisely the proper size are punched from
the laminate sheet.
7. Pouching and cartooning
Types of TDDS: -
1) Single layer drug in adhesive
o The single layer drug in adhesive system is characterized by the inclusion of the drug directly within
the skin contacting adhesive
o In the Transdermal system design, the adhesive not only serves to affix the system to the skin, but
also serves as the formulation foundation, containing the drug and all the excipients under a single
backing film
o The rate of release of drug from this type of system is dependent on the diffusion across the skin.
Backing, drug-in-adhesive, liner
2) Multi-layer drug in adhesive
o The multi layer drug in adhesive is similar to the single layer drug in adhesive in that the drug is
incorporated directly into the adhesive
o However, the multi layer encompasses either the addition of a membrane between two distinct drug
in adhesive layers or the addition of multiple drug in adhesive layers under a single backing film.
Backing, drug-in-adhesive, membrane, drug-in-adhesive, liner
3) Drug reservoir-in-adhesive
o The reservoir Transdermal system design is characterized by the inclusion of a liquid compartment
containing a drug solution or suspension separated from the release liner by a semi-permeable
membrane and adhesive
o The adhesive compartment of the product responsible for skin adhesion can either be incorporated
as a continuous layer between the membrane and the release liner or in a concentric configuration
around the membrane.
Backing, drug, membrane, adhesive, liner
19. 4) Drug matrix-in-adhesive
o The matrix system design is characterized by the inclusion of a semi-solid matrix containing a drug
solution or suspension which is in direct contact with the release liner
o The component responsible for skin adhesion is incorporated in an overlay and forms a concentric
configuration around the semisolid matrix.
Backing, adhesive, drug, liner
6) Transdermal drug delivery systems evaluation
I. Evaluation of adhesive: -
Pressure sensitive adhesives are evaluated for the following properties: -
a. Peel adhesion properties: -
Peel adhesion is the force required to remove an adhesive coating from the test substance
It is important in Transdermal devices because the adhesive should provide adequate contact
of the device with the skin and should not damage the skin on removal
Peel adhesion properties are affected by: - molecular weight of the adhesive polymer, the type
and amount of adhesives added in it, polymer composition.
Procedure: -
It is tested by measuring the force required to pull a single coated tape, applied to a substrate, at a
1800 angle.
Result: -
No residue on the substrate indicates “adhesive failure” which is desirable for Transdermal devices.
Reminents on the substrate indicate “cohesive failure” signifying a deficit of cohesive strength in the
coating.
b. Tack properties
Tack is the ability of the polymer to adhere to the substrate with little contact pressure. It is
important in Transdermal devices which are applied with finger pressure. Tack is dependent on: -
The molecular weight of polymer adhesive, composition of polymer, the use of tackifying resins in
the polymer
Tests for tack include
20. 1. Thumb tack test: - this is a subjective test in which evaluation is done by pressing the thumb
briefly on to the adhesive; experience is required for this test.
2. Rolling ball tag test: - this test involves the measurement of the distance that a stainless steel
ball travels along an upward facing adhesive.
The less tacky the adhesive, the farther the ball will travel.
3. quick stick (or peel tack) test: - the peel force required to break the bond between an adhesive
and substrate, is measured by pulling the tape away from the substrate at 900 at a speed of 12
inch/min
4. Probe tack test: -here the force required to pull a probe away from an adhesive at a fixed rate is
recorded as tack (grams)
c. Shear strength properties
It is a measurement of the cohesive strength of an adhesive polymer. For a polymer the adequate
cohesive strength will mean that the device will not slip on application and will leave no residue
on removal.
Shear stress is affected by: -
Molecular weight of polymer, the type and amount of tackifier added.
Stainless steel plate, adhesive coated tape, weight.
II. Thickness
The thickness of the patch is measured by using a digital screw gauge.
III. In-vitro drug release evaluation
Uses of in-vitro studies: -
1. Information such as time needed to attain steady state permeation and the permeation flux at steady
state can be obtained from in-vitro studies of the developed TDDS
21. 2. Used to optimize the formulation before more expensive in-vivo studies are performed
3. Studies on skin metabolism can also be performed
Excised skin used are- human cadaver skin, hairless mouse skin.
Several designs of in-vitro membrane permeation apparatus are in existence which include: -
a) Valia-chien (V-C) cell
b) Ghannam- chien (G-C) membrane permeation cell
c) Jhawer- lord (J-L) rotating disc system
d) Franz diffusion cell
e) Keshary- chien (K-C) cell.
IV. In-vivo evaluation
A. Animal models: -
Animal species used for in-vivo testing include mouse, rat, guinea pig, rabbit, rhesus monkey, dog,
cat, etc
Small hairy animals (rat, rabbit) are not good predictive models for human in-vivo TDD
delivery
Penetration values obtained with these animals are higher than those seen in man
The rhesus monkey is the most reliable model for in-vivo evaluation in man
Method: - standard radiotracer methodology is used
Application site: - forearm or abdomen which is least hairy sites on the animal body.
B. Human models: -
Feldmann and maibach model: -
The percentage of dose absorbed Transdermal is calculated as: -
% Dose absorbed =Total radioactivity excreted after topical administration X 100
Total radioactivity excreted after i.v administration
Completion time of test is 5 to 7 days.
Limitations: - no detailed kinetic analysis of data is possible since the radioactivity detected is a
mixture of parent chemical and metabolites, the origin of metabolites is unknown. Drugs successfully analyzed-
steroids, pesticides, and cosmetics.
Phase 1 clinical trials are conducted to determine mainly safety in volunteers
Phase 2 clinical trials determine short term safety and mainly effectiveness in patients
Phase 3 clinical trials indicate the safety and effectiveness in large number of patient population
Phase 4 clinical trials at post marketing surveillance are done for marketed patches to detect adverse drug
reactions.
V. Cutaneous toxicological evaluations: -
Contact irritant dermatitis: -
It results from direct toxic injury to cell membranes, cytoplasm on nuclei
Manifestations include
Inflammation
Cutaneous erythema
Itching
Contact dermatitis: -
Group 1 was served as normal, without any treatment
Group 2, control, was applied with marketed adhesive tape
Group 3 Transdermal systems (blank)
Group 4 Transdermal systems (drug loaded)
Group 5 standard irritant.
22. Ten day primary irritation test: -
A panel of 10 subjects has the test agent applied daily for two weeks at the site to be used in clinical
situations.
The ten agents are left in place over the weekend between the first and second five days of repeated
application.
Prior to the re application of the agent daily, adverse reactions like erythema and scaling are graded daily
on a 0 to 3 scale of none, mild, moderate and severe or a 0 to 6 scale to permit more discrimination.
Results: - a system which results in no erythema or scaling (0 rating) is safe, materials which induce
marked irritation (+2 or+3) are likely to induce significant contact irritation during clinical use. For
border line cases (+1 rating) the test is repeated using increased number of subjects and greater
application time.
__________________________________The end_____________________________________________