2. CONTENTS
DEFINITION
ADVANTAGES
DISADVANTAGES
SKIN STRUCTURE
ROUTE OF TDDS
MECHANISM OF ABSORPTION
FACTORS AFFECTING PERCUTANEOUS ABSORPTION
APPROACHES TO INCREASE SKIN ENHANCERS
MECHANISM OF ENHANCERS
TRANSDERMAL PATCH
COMPONENT OF TRANSDERMAL(TD) PATCH
TYPES OF TD PATCH
CURRENT MARKETED TDDS
EVALUATION OF TD
REFERENCES
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3. DEFINITION
Transdermal therapeutic are defined as self contained
discrete dosage form which when applied to the intact
skin deliver the drugs, through the skin, at a controlled
rate to the systemic circulation.
OR
Transdermal drug delivery system (TDDS) are systems
that utilize skin as a site for continuous drug
administration into the systemic circulation.
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4. ADVANTAGES OF TDDS
Avoids chemically hostile GI environment (drug degradation
in acidic and basic environments is prevented).
No GI distress and the factors like Gastric emptying, intestinal
motility, transit time, donot effect this route as in oral route.
Avoidance of significant presystemic metabolism (degradation
in GIT or by the liver) and therefore need lower doses.
Allows effective use of drugs with short biological half-life.
Allow administration of drugs with narrow therapeutic
window because drug levels are maintained within the
therapeutic window for prolonged periods of time.
Reduced inter and intra patient variability.
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5. Enhance therapeutic efficacy, reduced fluctuations
(rapid blood level spikes-low and high) due to
optimization of blood concentration –time profile.
Reduction of dosing frequency and enhancement of
patient compliance.
Provides controlled plasma levels of very potent drugs.
Can provide adequate absorption of certain drugs.
Avoids the risk and inconveniences of parenteral
therapy (Painless method of drug administration).
Drug input can be promptly interrupted simply by
removal of the patch when toxicity occurs.
Provides suitability of self medication.
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6. Disadvantages of TDDS
Drugs that require high blood levels cannot be
administered –limited only to potent molecules, those
requiring a daily dose of 10mg or less.
Transdermal administration is not a means to achieve rapid
bolus type drug input, rather it is usually designed to offer
slow, sustained drug delivery.
Adequate solubility of the drug in both lipophilic and
aqueous environments, to reach dermal microcirculation
and gain access to the systemic circulation.
The molecular size of the drug should be reasonable that it
should be absorbed percutaneously.
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7. Tolerance inducing compounds are not an intelligent
choice for this mode of administration unless an
appropriate wash out period is programmed in
between the dosing regimen.
Difficulty of permeation of the drug through human
skin –barrier function of the skin.
Skin irritation or dermatitis due to excipients and
enhancers of drug delivery system used for increasing
percutaneous absorption is another major limitation.
Adhesive may not adhere well to all types of skin.
Uncomfortable to wear.
May not be economical.
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8. SKIN STRUTURE
THE SKIN SONSIDERED TO HAVE FOUR DISTINCT LAYERS OF
TISSUE :
1. NON VIABLE EPIDERMIS (STRATUM CORNEUM)
2. VIABLE EPIDERMIS
3. VIABLE DERMIS(CORIUM)
4. SUBCUTANEOUS CONNECTIVE TISSUE (HYPODERMIS)
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9. Non-viable Epidermis (Stratum Corneum)
Stratum corneum is the outer most layer of skin, physical barrier to most
substances that come in contact with the skin. Stratum corneum consists of
lipids(5-15%)including phospholipids, glycosphingolipids, cholesterol sulfate
and neutral lipids, proteins(75-85%),mainly keratin. The stratum corneum is
10 to 20 cell layers thick over most of the body.
Viable Epidermis
This layer of the skin resides between stratum corneum and the dermis.It has a
thickness ranging from 50 to 100 um. The water content is about 90%.
Dermis
Just beneath the viable epidermis is the dermis. It is a structural fabric and
very few cells are to be found histologically in normal tissue. The dermis
ranges from 2000 to 3000 um thick, consists of a matrix of loose connective
tissue composed of fibrous protein(collagen, elastin, and reticulum)embedded
in an amorphous ground substance.
Subcutaneous Connective Tissue
It is composed of loose textured, white, fibrous connective tissue in which fat
and elastic fibers are intermingled. It contains blood and lymph vessels, the
base of hair follicles, often the secretory portion of sweat glands, and
cutaneous nerves.
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10. ROUTES OF TDDS
1. Transcellular permeation through the stratum corneum
2. Intercellular permeation through the stratum corneum
3. Transappendageal permeation via the hair follicles, sebaceousand sweat glands.
The first two mechanisms require further diffusion through the rest ofthe epidermis
and dermis. The third mechanism allows diffusion alleakage into the epidermis
and direct permeation into the dermis.
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11. MECHANISM OF ABSORPTION
Percutaneous absorption involves passive diffusion of substances through the
skin. The mechanism of permeation can involve passage through the
epidermis itself (transepidermal absorption) or diffusion through shunts.
Transepidermal pathway is principally responsible for diffusion across the
skin. Stratum corneum is barrier layer of the skin permeation involves
partitioning of into stratum corneum and permeation via intracellular
lipoidal route.
Fick’s First Law of Diffusion
Percutaneous absorption of most drugs is a passive-diffusion process that can
be described by Fick’s first law of diffusion
dQ/dt = JT= PAΔC
ŠJT is the total flux transported through a unit area of skin per unit time in
steady state (µg/hr) Š
A is area of the skin Š
P is the effective permeability coefficient Š
ΔC is the drug concentration gradient across the skin
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12. FACTORS AFFECTING PERCUTANEOUS
ABSORPTION
Physicochemical factors
o Partition coefficient
o Solubility
o Ionization / pKa
o Molecular size and weight
o Stability or half-life
Biological factors
o PHof the environment
o Area of application
o Age, Sex, Race
o Condition of the skin
•Integrity and Thickness of stratum corneum
•Pathological conditions of skin
•Hydration
•Metabolism
•Temperature
Formulation factors
o Vehicle-solubility of the drug
•Lipophilicity of the solvent
•PHof the vehicle
o Composition of drug delivery system
•Surfactants
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14. CHEMIACAL APPROACH
o USE OF PENETRATION ENHANCER
o DEPLITION OF STRATUM CORNEUM
o SYNTHESIS OF LIPOPHILIC ANALOGS
o BIOLOGICAL APPROACH
PHYSICAL APPROACH
o IONTOPHORESIS
o SONOPHORESIS
o THERMAL ENERGY
o STRIPPNING OF STRATUM CORNEUM
o HYDRATION OF STRATUM CORNEUM
CARRIER SYSTEM
o VESICULAR SYSTEM
o MICROPARTICULATE CARRIER
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16. MECHANISM OF PENETRATION
ENHANCER
DISTRUPTION OF THE HIGHLY ORDERED
STRUCTURE OF STRATUM CORNEUM LIPIDS.
INTERACTION WITH INTRACELLULAR PROTEIN.
IMPROVED PARTITIONING OF A DRUG, CO-
ENHANCER ORSOLVENT INTO THE STRATUM
CORNEUM.
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17. PHYSICAL TECHNIQUES
PHYSICAL TECHNIQUES CAN BE EMPLOYED TO
FACILITATE TRANSDERMAL TRANSPORT OF
DRUG MOLECULES , WHICH ARE
INAPPROPRIATE FOR PASSIVE TRANSPORT.
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18. IONTOPHORESIS
IT IS A PROCESS OR TECHNIQUE INVOLVING
THE TRANSPORT OF IONIC OR CHARGED
MOLECULES INTO A TISSUE BY THE PASSAGE
OF DIRECT OR ALTERING ELECTRIC CURRENT
THROUGH AN ELECTROLYTE SOLUTION
CONTAINING THE IONIC MOLECULES TO BE
DELIVERED USING APPROPRIATE ELECTRODE
POLARITY.
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19. ELECTROPORATION
THE PROCESS INVOLVE THE APPLICTAION OF
TRANSIENT HIGH VOLTAGE ELECTRICAL PULSE
TO CAUSE RAPID DISSOCITION OF THE STRATUM
CORNEUM THROUGH WHICH LARGE AND SMALL
PEPTIDES, OLIGONUCLEOTIDES AND OTHER
DRUGS CAN PASS IN SIGNIFICANT AMOUNTS.
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20. SONOPHOESIS
USING OF HIGH FREQUENCY ULTRASOUND
WAVES. THE APPLICATION OF LOW FREQUENCY
ULTRASOUND CAN INCREASE THE
PERMEABILITYOF HUMAN SKIN TO MANY DRUGS
INCLUDING HIGH MOLECULAR WEIGHT
PROTEINS BY SEVERAL ORDERS OF MAGNITUDE,
THUS MAKING TRANSDERMAL ADMINISTRATION
OF THESE MOLECULES POTENTIALLY FEASIBLE.
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21. MICROFABRICATED MICRONEEDLES
RECENTLY THE NOVEL METHOD HAS BEEN DEVLOPED
DEVELOPED FOR ENHANCING TRASPORT OF
MOLECULES ACROSS THE SKIN. THS TECHNIQUE IS
EMPLOYS IN MICRO-SIZED NEEDLES MADE FROM
SILICON THESE MICRONEEDLE ARRAYS, AFTER
INSERTION INTO THE SKIN, CREATE CONDUITS FOR
TRANSPORT OF ACROSS THE STRATUM CORNEUM.
MICRONEEDLES PENETRATES THE SKIN ABOUT 10-15
mm DEEP INSIDE THE SKIN BUT DO NOT REACH THE
NERVE FOUND IN DEEP TISSUE, SO ARE PAINLESS.
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22. VESICULAR CARRIER
THE RECENT APPROACH FOR INCREASING THE SKIN PERMEATION OF
DRUG MOLECULES IS THE USE OF VESICULAR CARRIER LIKE
LIPOSOMES, NIOSOMES, TRANSFERSOMES AND ETHOSOMES.
VESICLES MAY SERVE AS RATE-LIMITING MEMBRANE BARRIER FOR
SYSTEMIC ABSORPTION OF DRUGS.
BECAUSE OF THEIR AMPHIPHILIC NATURE, THESE VESICLES MAY
SERVE AS NON-TOXIC PENETRATION ENHANCER FOR DRUGS.
THEY MAY SERVE AS ORGANIC SOLVENT FOR THE STABILIZATION
OF POORELY SOLUBLE DRUGS.
VESICLES CAN INCORPORATE BOTH HYDROPHILIC AND LIPOPHILIC
DRUGS.
LIPOSOMES :- LIPOSOMES ARE COLLOIDAL PARTICLE, TYPICALLY CONSISTING
OF PHOSPHOLIPIDS FORMS BIMOLECULAR LAYERS THAT MAY ENTRAPE
AND DELIVER THE DRUGS TO THE SKIN.
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23. TRANSDERMAL PATCH
A TRANSDERMAL PATCH IS AMEDICATED ADHESIVE
PATCH THAT IS PLACED ON THE SKIN TO DELIVER A
TIME RELEASED DOSE OF MEDICATION THROUGH THE
SKIN AND INTO THE BLOODSTREAM.
MANY PATIENTS FEEL THE DIFFICULTY IN
SWALLOWING TABLETS OR GETTING INJECTIONS.
PATCHES ARE ACTIVE FOR LONGER PERIODS OF THAN
TABLETS SO PATIENTS DO NOT HAVE TO REMEMBER
AND FOLLOW FREQUENT SCHEDULESFOR TAKING A
MEDICATION AT ASPECIFIC TIME.
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24. COMPONENT OF TRANSDERMAL PATCH
LINER : PROTECTS THE PATCH DURING
STORAGE, IT IS REMOVED PRIOR TO USE
DRUG : DRUG SOLUTION IN DIRECT CONTACT
WITH RELEASE LINER.
ADHESIVE : SERVES TO ADHERE THE COMPONENTS
OF THE PATCH TOGETHER ALONG WITH
ADHERING THE PATCH TO SKIN.
MEMBRANE : CONTOLS THE RELEASE OF THE DRUG
FROM THE RESERVOIR AND MULTILAYER
PATCHES.
BACKING : PROTECTS THE PATCH FROM THE
OUTER ENVIRONMENT.
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25. TYPES OF TD PATCHES
SINGLE LAYER DRUG IN ADHESIVE:
IN THIS TYPE OF PATCH THE ADHESIVE LAYER NOT ONLY SERVES TO
SDHERE THE VARIOUS LAYERS TOGETHER, ALONG WITH THE ENTIRE
SYSTEM TO SKIN, BUT ALSO RESPONSIBLE FOR RELEASING THEDRUGS.
MULTILAYER DRUG IN ADHESIVE:
SIMILAR TO SINGLE LAYER SYSTEM IN BOTH ADHESIVE LAYERS ARE
RESPONSIBLE FOR RELESING THE DRUGS. IT DIFFERENT IS THAT ADDS
ANOTHER LAYER OF DRUG IN ADHESIVE, USUALLY SEPERATED BY
MEMBRANE.
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26. RESERVOIR TYPE :
THE DRUG LAYER IS A LIQUID COMPARTMENT CONTAINING
A DRUG SOLUTION OR SUSPENSION SEPARATED BYTHE
ADHESIVE LAYER.
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27. MATRIX TYPE:
DESIGNED IN THE 1990’s. IN A MATRIX PATCHES ACTIVE
MEDICATION RELEASE IS CONTROLLED BY THE FILM OF THE
MEDICATION AND ADHESIVE BACKING AREINTO ONE LAYER
PATCHES AVAILABLE ARE USES MATRIX DESIGNS SUCH AS
HORMONE REPLACEMENT THERAPIES AND SMOKING
CESSATION PATCHES.
MICRO RESERVOIR TYPE MATRIX DISPERSION TYPE
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29. EVALUATION OF TRANSDERMAL
SYSTEM
PHYSICAL EVALUATION
o FILM THICKNESS
o PERCENTAGE FLATNESS
o PATCH THICKNESS
o FOLDING ENDURANCE
o TENSILE STRENGTH
WEIGHT VARIATION
DRUG CONTENT
PERCENTAGE OF MOISTURE CONTENT
PERCENTAGE OF MOISTURE UPTAKE
ADHESION TO STEEL (PEEL ADHESION)
SKIN IRRITANCY STUDIES
CONFOCAL LESSER SCANNING MICROSOPY(CLSM)
SLIN PERMEATION STUDY
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30. o FILM THICKNESS:
MEASURED BY ELECTRONIC VERNIER CALIPERS, FIVE DIFFERENT
POINTS ON THE FILM AVERAGE FIVE READINGS AT LEAST COUNT
OF 0.01 mm.
o PERCENTAGES FLATNESS :
THE PERCENT FLATNESS OF THE STRIPS IS SELECTED AS THE AVERAGE
PERCENT OF LENGTH CALCULATED FROM THE 7cm STRIPS.
o PATCH THICKNESS:
MEASURED BY USING DIGITAL um SCREW GAUGE AT 3DIFFERENT
PLACES.
o FOLDING ENDURANCE:
DETERMINED BY REPEATEDLY FOLDING A SMALL STRIP OF THE FILM
(2x2) AT THE SAME PLACE TILL IT BREAKS.
o TENSILE STRENGHT:
THE FORCE REQUIRED TO BREAK THE FILM IS THE TENDILE
STRENGTH CALCULATED AS kg/cm2
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31. o WEIGHT VARIATION:
INDIVIDUALLY WEIGHT 10 RANDOMLY PATCHES.
o DRUG CONTENT:
A 5 cm2 FILM IS CUT INTO SMALL PIECES, PUT INTO A 100 ml BUFFER
(Ph7.4) AND SHAKEN CONTINUOSLY FOR 24 Hrs THEN WHOLE SOLUION
IS ULTRASONICATED FOR 15 min. AND ESTIMATED
SPECTROPHOTOMETICALLY.
o PERCENTAGE OF MOISTURE CONTENT:
FILM IS WEIGHED INDIVIDUALLY AND KEPT IN DESCICATOR AT ROOM
TEMPERATURE FOR 24Hrs AND FILM IS WEIGHED TO CNSTANT
WEIGHT. CALCULATE THE DIFFERENCE BETWEEN INITIAL AND FINAL
WEIGHT.
o PERCENTAGE OF MOISTURE UPTAKE:
A WEIGHED FILM KEPT IN A DESCICATOR AT ROOM TEMPERATURE FOR 24
Hrs TAKEN OUR TO ESPOSED 84% RH AND WEIGHT TO CONSTANT.
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32. o ADHESION TO STEEL(PEEL ADHESION):
MEASURE BY USING 180° PEEL ADHESION TEST.
o SKIN IRRITENCY STUDY:
IT CAN BE CONDUCTED ON MICE/ ALBINO RAT EVALUATED BY MODIFIED
DRAIZE TEST. SCORE OF 0 TO 4.
o CONFOCAL LASER SCANNING MICROSCOPY:
DEPTH OF THE SKIN PENETRATION OF PATCH IS ASSESSED ON MICE.
APPLIED FOR 8 Hrs AND AFTER THE EXCISED SKIN IS CUT IN 1mm squre
AND SCANNED IN CLS MICROSCOPE.
o SKIN PERMEATION STUDY:
STUDIED BY FRANZ DIFFUSION CELL.
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33. REFERENCES
Jain N.K. Introduction to Novel Drug Delivery Systems
vallabh prakashan first edition 2010 pg no.97-117
Dipen Patel, Sunita A. Chaudhary, Bhavesh Parmar,
Nikunj Bhura, Vol. 1 No. 4, 2012 ,Pg no:78-87.
Controlled drug delivery –concepts and advances –by
S.P.Vyas R.K.Khar.
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