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TRANSDERMAL DRUG DELIVERY SYSTEM
1. TRANSDERMAL DRUG
DELIVERY SYSTEM (TDDS)
Dr. Gajanan S. Sanap M.Pharm.,Ph.D
Department of Pharmaceutics
Ideal College of Pharmacy and Research
Kalyan 421- 306
2. CONTENTS
INTRODUCTION
ADVANTAGES AND LIMITATIONS
SKIN AND EPIDERMIS STRUCTURE
COMPONENTS OF TRANSDERMAL PATCH
TYPES OF TRANSDERMAL PATCH
FACTORS AFFECTING TRANSDERMAL PERMEABILITY
POLYMERS
THERAPIES THAT USE TRANSDERMAL DELIVERY OF
DRUGS
CLASSIFICATION OF TDDS
BASIC COMPONENTS OF TDDS
EVALUATION
REFERENCE
3. When one hears the words 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
History of TDDS
4. Transdermal drug delivery system was first introduced more than 20
years ago.
The technology generated tremendous excitement and interest amongst
major pharmaceutical companies in the 1980s and 90s.
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, more than 35 transdermal patch products,
spanning 13 molecules.
1970-- Alza Research (US) began first development of the modern
transdermal
1980-- Scopolamine first transdermal reached US
2002– Many Rx and non-RX products in US market.
Transdermals deliver drugs from a few hours up to
7 days.
5. Transdermal delivery represents an attractive alternative to oral
delivery of drugs and is poised to provide an alternative to
hypodermic injection too.
For thousands of years, people have placed substances on the skin
for therapeutic effects.
Definition:
Transdermal drug delivery is defined as a self contained discrete
dosage form, which when applied to the intact skin, will deliver the
drug at a controlled rate to the systemic circulation.
Or
Transdermal drug delivery systems (patches) are dosage forms
designed to deliver a therapeutically effective amount of drug across
a patient’s 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.
6. 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
7. Principles of diffusion through membranes
Homogenous
membrane
Aqueous
pores
Cellulose
fibres
(1) Diffusion - random molecular motion. Must have concentration gradient.
9. POTENTIAL BENEFITS OF TRANSDERMAL DRUG
DELIVERY (ADVANTAGES)
• Easy to use.
• Avoid GIT absorption problems for drugs.
• Avoids FP hepatic metabolism of drugs.
• More improved and convenient patient compliance.
• Rapid termination in case of toxicity is possible.
• Self medication is possible.
• Reduces frequency of dosing.
• Maintains therapeutic level for 1 to 7 days.
• Controlled delivery resulting in more reliable and predictable
blood levels.
10. DISADVANTAGES
• Daily dose of more than 10mg is not possible.
• Local irritation is a major problem.
• Drug requiring high blood levels are unsuitable.
• Drug with long half life can not be formulated in TDDS.
• Uncomfortable to wear.
• May not be economical.
• Barrier function changes from person to person and within the
same person.
• Heat, cold, sweating (perspiring) and showering prevent the
patch from sticking to the surface of the skin for more than one
day. A new patch has to be applied daily.
11. LIMITATIONS OF TDD
Limited skin permeability
Significant lag time
Cannot be used for large molecule (>500 Dalton)
Restricted to potent drug
Skin irritation and allergic response
Tolerance inducing drugs or those (e.g., hormones) requiring
chronopharmacological management are not suitable candidates.
• Skin structure poses a barrier on the mw of the drug (< 500 Da)
• Usually reserved for drugs which are extremely potent (thus
requiring a dosage of only a few mg).
– The largest daily dose of a drug from a patch is the nicotine
patch, with delivers a daily dose of only 21 mg.
12. Consideration of TDS development
Bioactivity of drug
Skin characteristics
Formulation
Adhesion
System design
Factors influence the permeation of drugs
Skin structure and its properties.
The penetrating molecule and its physical-chemical
relationship to skin and the delivery platform
The platform or delivery system carrying the penetrant
The combination of skin, penetrant and delivery system
14. Epidermis:
The outer layer of skin is made up of Stratified Squamous epithelial
cells.
Epidermis is thickest in palms and soles.
The stratum corneum forms the outer most layer (10-15µm thick ) which
consists of many layers of compacted , flattened, dehydrated keratinized
cells.
Keratin contains cells called as Corneosites.
Stratum corneum layer forms permeability barrier for external
environment.
Water content of stratum corneum is around 20%.
The moisture required for stratum corneum is around 10% (w/w) to
maintain flexibility and softness.
It consists of Cermides and neutral lipids such as Sterols, free fatty acids
and triglycerides.
The stratum corneum is responsible for the barrier function of the skin
and behaves as a primary barrier to the percutaneous absorption.
15. It is made up of three layers in thicker parts stratum granulosum,
stratum lucidum,stratum spinosum.
Removal of these layers results in increased permeability and water
loss.
18. DERMIS:
The dermis is made up of regular network of robust collagen fibers of fairly
uniform thickness with regularly placed cross striations .
This network or the gel structure is responsible for the elastic properties of the
skin.
It is supplied by blood to convey nutrients, remove waste & regulate body
temp.
Drug is well absorbed by this route.
Upper portion of the dermis is formed into ridges containing lymphatics and
nerve endings.
SUBCUTANEOUS TISSUE:
This is a sheet of the fat containing areolar tissue known as the
superficial fascia attaching the dermis to the underlying structures .
SKIN APPENDAGES:
Sweat glands produces sweat of pH 4-6.8 & absorbs drugs, secretes
proteins, lipids and antibodies. Its function is to control heat.
HAIR FOLLICLES
They have sebaceous glands which produces sebum and includes
glycerides, cholesterol and squalene.
19. ROUTES OF DRUG PENETRATION
SWEAT DUCT
ACROSS STRATUM CORNEUM
HAIR FOLLICLES
INTERCELLULAR
TRANSCELLULAR
Macro routes
Micro routes
It involves passive diffusion of substance through skin.
PERCUTANEOUS ABSORPTION
22. Trans follicular route:
Fractional area available through this route is 0.1 %
Human skin contains 40-70 hair follicles, 200 to 250 sweat glands on every sq.cm.
of skin area.
Mainly water soluble substance are diffused faster through appendages than that of
other layers.
Sweat glands and hair follicles act as a shunt i.e. easy pathway for diffusion throug
h rate limiting ST corneum.
Trans Epidermal route
Epidermal barrier function mainly resides in horny layer
The viable layer may metabolize, inactivate or activate a prodrug.
Dermal capillary contains many capillaries so residence time of drug is only one
minute.
Within stratum corneum molecule may penetrate either transcellularly or intercellular.
Intracellular region is filled with lipid rich amorphous material.
23. Routes of drug absorption through skin
Trans follicular route
Trans epidermal route
25. Mechanism of absorption through skin
Mechanism involved is passive diffusion
This can be expressed by FICK’s LAW of DIFFUSION
dq = D K A ( c1 – c2 )
dt h
dq /dt = rate of diffusion
D = diffusion co-efficient
K = partition co- efficient
A = surface area of membrane
H = thickness of membrane
26. FACTORS AFFECTING TRANSDERMA
L PERMEABILITY
Physico chemical properties of parent molecule
Solubility and partition co- efficient
pH condition
Penetrant concentration
Physico chemical properties of drug delivery system
Release characteristic
Composition of drug delivery system
Permeation enhancer used
27. Physiological and pathological condition of skin
Lipid film
Skin hydration
Skin temperature
Effect of vehicle
Pathological injury to skin
Biological factors
Skin age
Thickness of S. Corneum
Skin condition
28. Solubility and partition co- efficient:
Solubility of a drug influences its ability to penetrate the skin.
pKa is index of solubility of drug in vehicle and ST corneum has
influence on transfer of drug from vehicle to skin.
Drug solubility determines concentration presented to absorption
site which will effect rate and extent of absorption.
Skin permeation can be enhanced by increasing lipophilic character
of drug, so that drug penetrates through STC but not through
epidermis due to decreased water solubility.
Drug which is lipid & water soluble is favored.
29. pH & penetration concentration:
Moderate pH is favorable because if solutions with high
or low pH will result in destruction to the skin.
Higher the concentration of the drug in vehicle faster the
absorption.
At higher concentrations than solubility the excess solid
drug will function as a reservoir and helps to maintain a
constant drug constitution for prolonged period of time.
30. Physico-chemical properties of drug delivery system
Release characteristic
Solubility of drug in vehicle determines the release rate.
Composition of drug delivery system
It not only effects the rate of drug release but also the
permeability of STC by means of hydration mixing with skin lipids.
Example methyl salicylate is more lipophilic than its parent acid
(Salicylic acid). When applied to skin from fatty vehicle
methylsalicylate yielded higher absorption.
FACTORS AFFECTING TRANSDERMAL
PERMEABILITY
31. Physiological and pathological condition of skin
Lipid film:
It acts as protective layer to prevent removal of
moisture from skin. Defeating of this film will decrease TD
absorption.
Skin hydration:
It can be achieved by covering skin with plastic
sheeting, which leads to accumulation of sweat, condensed
water vapors, increase hydration and increase porosity.
FACTORS AFFECTING TRANSDERMAL
PERMEABILITY
32. Effect of vehicle:
A vehicle can influence absorption by its effect on
physical state of drug and skin. Example greases, paraffin
bases are more occlusive while water in oil bases are less.
Humectants in bases will dehydrate the skin and decrease
percutaneous absorption.
FACTORS AFFECTING TRANSDERMAL
PERMEABILITY
33. Biological factors:
Skin age:
Skin of foetus, young ones and elders is more
permeable than adult tissue.
Skin metabolism:
Viable epidermis is metabolically active than
dermis. If topically applied drug is subjected to
biotransformation during permeation local and systemic
bioavailability is affected.
FACTORS AFFECTING TRANSDERMAL
PERMEABILITY
34. 1. Must be non-ionic
2. Low molecular weight (less than 500 Daltons)
3. Lipophilicity (Log Ko/w: 1-3)
4. Low melting point (less than 200 degree C)
5. Dose is less than 50 mg per day, and ideally less t
han 10 mg per day.
IDEAL DRUG CANDIDATE FOR TDD
35. BASIC COMPONENTS OF TDDS
Polymer matrix
The drug
Permeation enhancers
Other excipients
1.Polymer matrix
Ideal polymer
MWT, and chemical functionality of the polymer should not affect
the diffusivity of drug and its release
Stable
non reactive
easily manufactured
easily fabricated into desired product
Inexpensive
degaradation product must be non toxic or non antagonistic to the host
Should retain its mechanical properties when the large amount of drug is
loaded in to it.
37. 2. Suitable drug candidate
Physico chemical properties of drug
Should have MW less than 1000 daltons(800-1000)
Should have affinity for both lipophilic and hydrophilic phases
Should have low melting pont
Biological properties of drug
Should be potent(less than 20mg)
Half life should be short
Must not induce a cutaneous irritant or allergic response
Drugs which degrade in the GI tract or inactivated by hepatic first
pass effect are suitable candidate
Tolerance to the drug must not develop
Drugs which has to be administered for a longer period of time can
be formulated
Drugs which cause adverse effects to non target tissues can also be
formulated
38. 3.PERMEATION ENHANCERS
(to enhance stratum corneum permeability)
Solvents
Increases penetration by swelling the polar pathway transport or fluidising lipids
Eg.water,ethanol,methanol,DMS,homologs of methyl sulphoxide,dimethyl acetamide,and
DMF,2-pyrrolidone,N-methyl,2-pyrrolidone,laurocapram,PG,glycerol,silicone fluids,isopr
opyl palmitate.
Surfactants
Enhances the polar pathway transport of hydrophilic drugs
Anionic surfactants
Dioctyl sulpho succinate,SLS,deco decylmethyl sulphoxide etc.
Non ionic surfactants
Pluronic F127,Pluronic F68,etc.
Bile salts
Sodium taurocholate,sodium deoxy cholate,sodium tauroglycocholate.
Binary systems
Propylene glucol-oleic acid and 1,4-butane diol-linoleic acid
Miscellaneous
Urea-hydrating and keratolytic agent,N,N-dimethyl-m-toluamide,calcium thioglycolate,ant
i cholinergic agents
Potential permetion enhancers
Euclyptol,di-o-methyl-ß-cyclodextrin and soyabean casein
39. Permeability Coefficient Is the Critical Predictor
of Transdermal Delivery
Transport = Flux = (mg/cm
2
/sec) = P x A x (Cd – Cr)
Permeability Coefficient = P = D x K (cm/sec)
h
Where A = Surface area of patch
D = Diffusivity of drug in membrane (skin)
K = Partition coefficient (patch/skin)
C = Concentration in donor or receptor
(patch or skin)
h = Thickness of membrane (skin)
40. General terms
Backing - The material, i.e. film, foam, nonwoven, etc.
, used as the outermost layer of the transdermal or
medical system to protect the product during the
wear period.
Membrane - A material placed between the drug
formulation and the final layer of adhesive. The diffusion
properties of the membrane are used to control
availability of the drug and/or excipients to the skin.
41. Liner - The film, removed and discarded prior to p
atch application, that protects the transdermal syst
em by covering the adhesive side.
Laminate - Two or more materials combined in lay
ers to form a single substrate.
Occlusive - Refers to a material’s ability to limit dif
fusion. Generally used in characterization of backin
gs with respect to moisture vapor and oxygen diffu
sion. An occlusive backing would have very low dif
fusion rates.
42. 4.OTHER EXCIPIENTS Adhesives
pressure sensitive polymeric adhesive .
Serves to adhere the components of the patch together along with adhering
the patch to the skin.
Ideal properties
Should not irritate or sensitize the skin or affect normal functions of the skin
Should adhere to the skin aggressively
Should be easily removed
Should not leave an un washable residue on the skin
Should have an intimate contact with the skin
Should be compatible with the drug,excipients and permeation enhancers
Permeation of drug should not be affected
THREE MAJOR FAMILIES OF PSAS:
1. Rubber-based PSAs,
2. Acrylic PSAs in the form of acrylic solutions,
3. Emulsion polymers or hot melts, and silicon PSAs
43. BACKING FILMS /membrane
ROLE OF FILM :
1. To protect the active layer and safeguard the stability of the
system,
2. To affect skin permeation and tolerance, depending on
occlusion or breathability.
3. It must also be flexible, comfortable and must present good
affinity with the adhesive, as well as excellent printability.
Ideal properties
Flexible and provide good bond to the drug reservoir
Prevent drug from leaving the dosage form
Should be impermeable
E.g. metallic plastic laminate, plastic backing with absorbent pad and
occlusive base plate, adhesive foam pad with occlusive base plate.
MOST COMMON MATERIALS USED : polypropylene,
polyethylene (both high and low density), aran, polyesters,
PVC,and nylon.
44. RELEASE LINERS
ROLE OF FILM :
1. To protect the system as long as it is in the package.
2. Play a crucial role in the stability of the product .
3. An incorrect release liner does not permit the easy release of the
patch, and can interfere with the active(s) or other components,
thereby reducing its shelf life.
MOST COMMON FILMS USED :
paper-based,
plastic film-based and
composite films.
TWO MAJOR CLASSES OF ANTI-ADHERENT COATING :
silicones and fluoro-polymers.
45. A release liner is a film covered with an anti-adherent coating.
To protect the system as long as it is in the package, and it is
removed just before the adhesion of the TDDS to the skin.
During storage the patch is covered by a protective liner that is
removed & discharged immediately before the application of the
patch to the skin.
It is there fore regarded as a part of primary packing material rather
than a part of dosage form for delivering the drug.
46. MICROPOROUS OR SEMI-PERMEABLE MEMBRANES or rate
controlling mambrne
The function depends on the design of the specific system, the size
of the active component and the need to have a rate-limiting factor
in order to satisfy the release and absorption characteristics of the
system.
ROLE OF THE MEMBRANES
To limit the flow of the semi-solid content from the liquid reservoir,
and/or to act as a rate-limiting membrane for both liquid reservoir and
matrix systems.
TWO TYPES OF POROUS MEMBRANES
I Ethylene Vinyl Acetate Membranes (EVA)
II Microporous Polyethylene Membranes
47. POUCHING MATERIALS
ROLE :
1. Stability and integrity of the product
THREE MAIN LAYERS IN THE COMPOSITE
MATERIALS USED FOR POUCHES:
1. Internal plastic heat sealable layer,
2. Aluminium foil layer
3. External printable layer.
49. Formulation of TDDS
1.Membrane-moderated or Permeation controlled TDDS (Reservoir
type)
• Drug reservoir (homogenous dispersion of drug with polymeric matrix
or suspension of drug in un leachable viscous liquid medium such as
silicone fluid) is encapsulated within drug impermeable metallic plastic
laminate and a rate controlling polymeric membrane (ethylene vinyl
acetate co polymer)
• The cross sectional view of this system is shown in the following Fig.1
50. RESERVOIR SYSTEM ( MEMBRANE MODERATED TDDS )
TransdermScop® (Scopolamine) for 3 days protection of motion sickness
The drug reservoir is encapsulated in a shallow compartment moulded from a
drug impermeable metallic – plastic lamination whilst the drug delivery side is
covered by controlling polymeric membrane.
51. • A thin layer of silicone or poly acrylate adhesive may be applied to the
external surface of the rate controlling membrane to achieve intimate
contact of the TDDS and the skin surface
• Release rate of this TDDS depends upon the polymer composition,
permeability co efficient and thickness of the rate controlling membrane
and adhesive
• The intrinsic rate of drug release from this TDDS is calculated by the
following formula.1
CR
dQ/dt= --------------------
1/Pm+1/Pa
CR-con.of drug in the reservoir compartment
Pm-permeability co efficient of rate controlling polymeric
membrane
Pa- permeability co efficient of adhesive
52. Drug mixed with polymer
solution
Drug suspended in
polymer solution
Volume controlled
injection pump system
Molding as TDDS using
primary packing material
Packing machinery using
secondary packing material
Transdermal therapeutic
system
53. Example of this system are
1.Nitro glycerin releasing TDDS (Transderm-Nitro/ciba,USA)for once a
day medication in angina pectoris
2.Scopolamine releasing TDDS (Transderm-Scop/ciba,USA)for 72
hrs.prophylaxis of motion sickness
3. Estradiol releasing TDDS (Estraderm/ciba)for treatment of menopausal
syndrome
4. Clonidine releasing TDDS (Catapres/Boehringer Ingelheim)for 7 day
therapy of hyper tension
5. Prostaglandin-derivatives TDDS
54. 2.Adhesive diffusion/dispersion-controlled TDDS
Drug reservoir
– homogenous dispersion of drug with adhesive polymer
(poly(isobutylene) or poly acrylate)
– Then spreading of this medicated adhesive polymer on flat sheet of drug
impermeable metallic plastic backing to form thin drug reservoir layer
– On top of the drug reservoir layer, thin layers of rate controlling
adhesive polymer of specific permeability and constant thickness are
applied to produce an adhesive diffusion/dispersion-controlled TDDS
– The cross sectional view of this system is shown in the following Fig.2
55. • It is the simplified form of membrane moderated drug delivery system
• It is prepared by directly dispensing the drug in an adhesive polymer &
then spreading the medicated adhesive by solvent film casting method
over a flat sheet of drug impermeable metallic or plastic backing
membrane, this forms a thin drug reservoir layer.
Deponit® (Nitroglycerine) for once a day medicatin of angina pectoris.
56. • The rate of drug release in this system is defined by
Ka/r.Da
dQ/dt= -----------------cR
ha
Where
Ka/r-partition co-efficient of drug bw adhesive layer and reservoir layer
Da-diffusion co-efficient of drug in the adhesive layer
ha-thickness of adhesive layer
Examples for this system
1.Iso sorbide dinitrate-releasing TDDS
2.Verapamil releasing TDDS
57. 3.Matrix diffusion-controlled TDDS
Drug reservoir
• homogenous dispersion of drug with hydrophilic or lipophilic polymer
matrix by any one of the following methods
• Homogenous dispersion of finely ground drug particles with liquid polymer
or highly viscous base polymer followed by cross linking of polymer chains
• Homogenous mixing of drug solid with rubbery polymer at an elevated
temperature
• Dissolving the drug and polymer in a common solvent followed by solvent
evaporation in a mould at an elevated temperature or under vacuum.
• Medicated polymer is moulded in to desired surface area and controlled
thickness
• This medicated polymer disc is pasted on to an occlusive base plate with
impermeable plastic backing
• Then the adhesive polymer is spread along the circumference to form a strip
of adhesive rim around the medicated disc
58. Example of this system are
1.Nitro glycerin releasing TDDS (Nitro-Dur and Nitro-Dur II /Key
pharmaceuticals,USA)
2. Estradiol di acetate releasing TDDS
3. Verapamil releasing TDDS
The cross sectional view of this system is shown in the following Fig.3
59. MATRIX SYSTEM --- MATRIX DISPERSION SYSTEM
(MATRIX DIFFUSION CONTROLLED SYSTEM)
MATRIX SYSTEM --- MATRIX DISPERSION SYSTEM
(MATRIX DIFFUSION CONTROLLED SYSTEM)
Nitro Dur® (Nitroglycerine) used for once a day medication of angina
pectoris.
60. • the rate of drug release from this sytem is defined as
where
A initial drug loading dose
Cp and Dp are solubility and diffusivity of drug in poymer matrix
the rate of drug release from this system at steady state is defined as
Q/t1/2= [(2A-Cp) Cp Dp] 1/2
61. 4.Micro reservoir type/micro sealed dissolution- controlled TDDS
Combination of the reservoir and matrix diffusion
Drug reservoir
Suspension of drug with aqueous solution of water soluble liquid polymer
Homogenous dispersion of drug suspension in a lipophilic polymer(silicone
elastomer)
As a result discrete un leachable microscopic spheres of drug reservoir is
formed which is stabilized by cross linking
Medicated polymer is moulded in to desired surface area and controlled
thickness and it is coated with a layer of bio compatible polymer to modify
mechanism and rate of drug release
This medicated polymer disc is pasted on to an occlusive base plate with
impermeable plastic backing
Then the adhesive polymer is spread along the circumference to form a strip
of adhesive rim around the medicated disc
62. Example of this system are
1.Nitro glycerin releasing TDDS (Nitro-Dur and Nitro-Dur II /Key
pharmaceuticals,USA)
2. Estradiol di acetate releasing TDDS
3. Verapamil releasing TDDS
The cross sectional view of this system is shown in the following Fig.4
76. 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.
77. 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.
78. 3. The blending solvent is
removed in the large arch tunnel
oven
79. 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
80. 5. Rolling of the laminate
The laminate rolls are then sent through punching, pouching and
cartoning machines specially configured for each product.
81. 6. Punching
Dosing is controlled in part by patch size, and patches of
precisely the proper size are punched from the laminate
sheet
83. EVALUATION OF TDDS
TESTS DONE ON FINAL PRODUCT TESTS
CHEMICAL TEST
Content
Content uniformity
Purity
Residual solvent
PHYSICAL TEST
Release testing
USP apparatus 5 (Paddle over disk)
USP apparatus 6 (Cylinder)
USP apparatus 7 (Reciprocating disk)
Franz Diffusion Cell
Test for adhesion
Peel adhesion
Tack property
Thumb tack test
Rolling ball tack test
Quick-stick (peel tack test)
Probe tack test
Shear strength
CUTANEOUS TOXICITY
Contact dermatitis
Growth of microorganisms
Cytotoxicity
Sensitization study
PERCUTANEOUS ABSORPTION MODEL
In vitro testing
In vivo testing
Human IVIVC
84. 1. 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.
2. 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.
3. 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.
4. 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/ initial weight] ×100.
85. 5. 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
6. Water vapour permeability (WVP) evaluation:
Water vapour permeability can be determined with foam dressing method the air
forced oven is replaced by a natural air circulation oven. The WVP can be determined
by the following formula
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.
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.
86. ADHESION TEST
1 PEELADHESION TEST
BACKING LAYER
ADHESIVE LAYER
The force required to remove an adhesive coating from a test
substrate is referred to as peel adhesion.
The force is expressed in ounces (or grams) per inch width of tape.
If higher value then it indicates greater bond strength.
87.
88. 2. TACK PROPERTY :
2(a) THUMB TACK TEST
Qualitative test.
The thumb is simply pressed on the adhesive and relative tack property is
detected
2(b) ROLLING BALL TACK TEST
2(c) QUICK-STICK (PEEL TEST) TEST
90. 2(d) PROBE TACK TEST
Polyken probe tester
The tip of clean probe is brought into contact with
adhesive, and when a bond is formed between probe
and adhesive. The force required to pull the probe
away from the adhesive at fixed rate is recorded as
tack (Grams).
3 SHEAR STRENGTH TEST
91. Shear strength :
Shear strength is the measurement of the cohesive strength
of an adhesive polymer.
If transdermal device has adequate cohesive strength, it
will not slip after application and will leave no residue upon
removal. In this particular test, adhesive coated tape is
applied onto a stainless steel plate.
A specified weight is hung from the tape to affect its
pulling in a direction parallel to the plate. Shear strength is
determined by measuring the time it takes to pull the tape off
the plate.
The longer the time taken for removal, greater is the shear
strength.
93. Tensile strength
Tensile strength= F/a.b (1+L/l)
F - the force required to break
a - width of film
b - thickness of film
L - length of film
l - elongation of film at break point
94. INVITRO TESTING OF TDDS
SYSTEM DESIGN
SKIN PREPARATION CELL DESIGN
SELECTION
OF SKIN
SEPARATION
Human
Animal
Artificial
Heat
Chemical
Physical
One chambered
(Vertical type)
Two chambered
96. In-vitro testing
Importance
(1)Defining skin permeation kinetic studies using a
diffusion cell system and cadaver skin during the drug
development process.
(2) in vitro drug release kinetics, to be used for batch-to-
batch release and as a compendial test.
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97. Preparation of skin for permeation studies
• Intact Full thickness skin
• Separation of epidermis from full thickness
skin:
100. In-vivo assessment
1} Animal model
Mouse, hairless rat, hairless dog, hairless rhesus monkey, rabbit,
guinea pig
101. In-vivo assessment
2} Human model
. Phase I clinical trials are conducted to determine mainly safety in volunteers.
Phase II clinical trials determine short term safety and mainly effectiveness in
patients.
Phase III trials indicate the safety and effectiveness in large number of patient
population.
Phase IV trials at post marketing surveillance are done for marketed patches to
detect adverse drug reactions.
2/27/2016 101
102. Skin irritation studies
• Group I was served as normal, without any
treatment.
• Group II, control, was applied with marketed
adhesive tape.
• Group III Transdermal systems (blank)
• Group IV Transdermal systems (drug loaded)
• Group V standard irritant .
Contact dermatitis
105. Study Storage conditions Time period
Temperature Relative
humidity
Long Term 25°C± 2°C
OR
30°C± 2°C
60%± 5%
OR
65%± 5%
12 months
Intermediate 30°C± 2°C 65%± 5% 6 months
Accelerated 40°C± 2°C 75%± 5% 6 months
106. Table 1 Transdermal Controlled-
Release Products and Devices
Drug Trade Name Type of
Devices
Indication
Scopolamine Transderm-
Scop
Reservoir Motion
sickness
Nitroglycerine Transderm-
Nitro
Reservoir Angina
Nitro-Dur Monolithic
Nitrodisc Monolithic
Estradiol Estraderm Reservoir and
ethanol
enhancer
Hormone
treatment
107. Table 2 transdermal products under
development
Drug Trade name Producer-Marketer
Minocycline Sunstar American Cyanamide,
Takeda
Estradiol+Nore
thisterone
Estracombi
TIS
Ciba-Geigy, Alza
DHEA Pharmedic
Fentanyl
Triamcinolone
acetonide
Whitby Pharm.
109. Products on the market, or in development include:
• Clonidine
• Works as an agonist of adrenaline at the
presynaptic a2 adrenergic
• Product name = Catapres-TTS®
• used to treat hypertension
110. • Ethinylestradiol (EO) and norelgestromin (N)
• Product name = Ortho-Evra®
• Used for Contraception
• Type of patch = Drug-in-Adhesive
• Frequency of application = weekly
111. • Fentanyl
• Product Name = Duragesic®
• Used for: Analgesia
• Type of Patch = Drug-in-Adhesive
• Frequency of Application = Weekly
112. • Lidocaine
• Product Name = Lidoderm®
• Used for: analgesia of postherpetic neuralgia
(PHN), a painful condition caused by the
varicella zoster virus (herpes zoster = shingles)
114. • Nicotine
• Product name = Habitrol®, Nicoderm –
CQ®, Nicotrol®, Prostep®
• Used for: Smoking cessation
• Frequency of administration = Daily
115. • Nitroglycerin
• Works by producing nitric oxide (NO), which then acts as
a vasodilator
• Product Names = Nitro-Dur®, Transderm-Nitro®
• Used for: Angina
• Type of Patch = Nitro-Dur is Drug-in-adhesive
Nitrodisc is reservoir
• Frequency of administration = Daily
116. • Estradiol
• Product Name = Alora®, Climara®, Esclim®,
Estraderm®, FemPatch®, Vivelle®, Vivelle-DOT®
• Used for: Hormone replacement
• Type of Patch: Drug-in-adhesive
• Frequency of application = weekly
117. • Estradiol + Norethindrone
• Product name = CombiPatch®
• Used for: Hormone Replacement
118. • Oxybutynin
• Works as competitive antagonist of the
muscarinic acetycholine receptor
• Product name = Oxytrol®
• Used for: Overactive bladder (antispasmodic)
• Type of Patch: Drug-in-adhesive
• Frequency of application = twice a week
119. • Scopolamine
• Works as competitive antagonist of acetylcholine
at the muscarinic receptor
• Product Name = Transderm Scop®
• Used for: Motion Sickness
121. • Lidocaine + Epinephrine
• Product name = Lidosite
• Used for: Dermal anesthesia
• Type of Patch = Reservoir,
iontophoretic.
Epinephrine acts as vasoconstrictor, thus prolonging the
duration of action of lidocaine (by delaying resorption) at the site
129. The microneedle technology can result in more effective contact of the vaccine
with the antigen-presenting Langerhans cells
The needles can be fabricated to be long enough to penetrate the stratum
corneum, but short enough to not come into contact with nerve endings.
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