Transdermal drug delivery system

1. TRANSDERMAL DRUG DELIVERY
SYSTEM

2.  INTRODUCTION
 ADVANTAGES
 DISADVANTAGES
 STRUCTURE OF SKIN
 PENETRATION PROCESS
 FACTORS AFFECTING PERCUTANEOUS ABSORPTION
 BASIC COMPONENTS OF TDS
 TYPES OF TRANSDERMAL PATCH
 EVALUATION METHOD
 APPLICATION AND FUTURE SCOPE
 CONCLUSION
 REFERENCES

3.  Continuous intravenous infusion at
programmed rate has been recognized as
superior mode of drug delivery.
 Recently ,the i.v infusion is duplicated
without its potential hazards by continuous
transdermal drug administration through
intact skin.

4. Transdermal drug delivery system can be
defined as a delivery device ,which upon
application on a suitable skin surface will
able to deliver drug into the systemic
circulation at sufficient concentration to
ensure therapeutic efficacy.

7.  Avoid first pass effect.
 Steady permeation of drug across the skin
allowing consistent serum drug level.
 Non invasive
 Flexibility of terminating the drug
administration by simply removing the patch
from the skin.
 As an alternate delivery system for patients
who cannot tolerate oral dosage forms
 Self administration is possible.

8.  Drugs that cause gastrointestinal upsets can
be good candidates.
 Use for drugs with narrow therapeutic
window
 Provide extended therapy with single
application, improving compliance over other
dosage form requiring frequent dose
administration.
 Allows continued drug administration
permitting the use of a drug with short
biological half life.

9.  Skin irritation and hypersensitivity reaction
may occur.
 The barrier function of the skin changes from
site to site, person to person and with age.
 Drugs with hydrophilic structures permeate the
skin too slowly.
 Only small lipophilic drugs can be delivered
currently.
 Not suitable for high drug doses.
 Drug molecules must be potent because patch
size limits amount that can be delivered.
 Drugs which require high blood level cannot be
administered.
 High cost

10.  The skin of an average adult human covers a
surface area of nearly 2m2 and receives
about one third of blood circulating through
body .
EPIDERMIS
DERMIS
SUBCUTANEOUS
TISSUE

13.  Outer layer of skin,composed of stratified
squamous epithelial cells
 Held together by highly convoluted interlocking ,
which are responsibe for the unique integrity of
skin
 Classified into two :
 Non viable epidermis :
- consist of multiple layers of horny
dead cells which are compacted,
flattened,dehydrated and keratinized.

14.  .
 Sc is the primary barrier to percutaneous absorption.
 PH of skin surface is between 3&4.
-
Water
content-20%
Moisture
content 10%
Maintain
flexibility
and
softness

15.  Viable epidermis:
• an aqueous solution of protien
encapsulated into cellular compartments by thin
cell membranes,which are fused together by
tonofibrils.
• s
• Stratum lucidum lies just below sc is the site
where nuclei disintegrate and keratinization
occurs.
• Removal of these three layers → water loss and
enhancement of skin permeability.
Germinal
layer
Stratum
spinosum
Stratum
granulosum

16.  Made of network of robust collagen fibers of
uniform thickness with regularly spaced cross
striations → elastic properties of skin.
 Dermis is the locus of blood vessels, sensory
nerve segments of sweat glands & lymphatics.
 Only nerve fibers reach into the germinative zone
of epidermis.

17.  A sheet of fat containing areolar tissue where
fat is manufactured and stored.
 Act as heat insulator and shock absorber.
 No effect on percutaneous absorption,since
they lies below vascular system.

18. PENETRATION PROCESS
TRANSCORNEAL
PENETRATION
INTRACELLULAR
PENETRATION
INTERCELLULAR
PENETRATION
TRANSAPPENDAGEAL
PENETRATION

19.  Intracellular penetration
- Here drug molecules passes through the intercellular
spaces between cells of sc eg : hydrophilic drugs.
-As sc hydrates ,water accumulates near the outer
surface of the protien filament.
 Intercellular penetration
-Drug diffusion via continuous lipid matrix, where drug
must sequentially partition into and diffuse through
repeated aqueous and lipid domains.
- eg : small uncharged molecules

20.  The drug molecule may transverse through
the hair follicles ,sweat glands or sebaceous
pathway.
 Because of its relatively smaller area (≤ 0.1%
of total surface area) minor importance.

22. Diffusion of drug from drug reservoir to rate controliing membrane
Diffusion of drug from rate limiting membrane to stratum corneum
Sorption by stratum corneum and peneteration through viable
epidermis.
Uptake of drug by capillary network
Effect on target organ

23. Physicochemical
properties of
penetrant.
• Molecular size
• Partition
coefficient
• Solubility
• Ionization
• Penetrant
concentration
• Diffusion
coefficient
Physicochemical
properties of drug
delivery system
• Release
characteristics
• Composition of
drug delivery
system
• Modification of
diffusional
barrier
Physiological
properties
• Site of
application
• Skin temperature
• Skin condition
• Blood supply
• Skin metabolism
• Hydration state
of stratum
corneum
• Other biological
factors like
age,sex &race

24.  Polymer matrix
 Selection of drug
 Permeation enhancer
 Pressure sensitive adhesive
 Backing laminates
 Release liner
 Other exipients

26.  POLYMER MATRIX
 Control the release of drug from the device.
 Prepared by dispersion of drug in liquid or solid state
synthetic polymer base.
 Polymers used are :
 Natural polymers eg:gelatin,cellulose
derivatives,chitosan etc.
 synthetic elastomer eg : silicone
rubber,polybutadiene,neoprene,butyl rubber etc.
 synthetic polymer eg :PVA, PVP,PVC,polyethylene

27. SELECTION
OF DRUGS
Extensive
metabolism
Narrow
therapeutic
index
Short half
life
Low
molecular
weight
Low dose
Adequate
solubility in
oil & water
Low
melting
point

28.  Permeation enhancer :
 Compounds increase permeabilty of SC to attain high
therapuetic levels of the drug.
a)Drug and vehicle interaction:
- selection of prodrug
- chemical potential adjustment
-ion pairs &complex coacervates
-eutetic systems
b)stratum corneum modification:
-hydration
-chemical penetration enhancers.

29. c) stratum corneum bypassed:
- microneedle based devices
-needle –less injection
-radiofrequency
- suction ablation
-skin abrasion
d)electrically assisted methods:
-eletroporation
- ionotophoresis
-sonophorosis
-magnetophorosis
-laser radiation
-thermophoresis

30. e) vehicle & particles:
-micro or nanocapsules
-nanoemulsion
-solid lipid nanoparticles
-multiple emulsion
-liposomes
-niosomes
_transferosomes
_ethosomes
_ aquasomes

31.  Pressure sensitive adhesives (PSAs)
o Affixes TDS firmly to skin.
o Adhere with applied finger pressure ,be tacky &
exert a strong holding face.
o Additionally, should be removable without leaving a
residue.
o Commercially used PSAs:
polyacrylate,polyisobutylene& silicones
o Hot melt pressure sensitive adhesives(HMPSAs),
melt to a viscosity suitable for coating , but when
they are cooled generally stay in flawless state.

32.  Backing Laminates:
 Protect skin from outer environment.
 Commonly used materials are – polyesters and
elastomers in metalized form.
 Elastomeric material promote better adhesion.
o Low water vapour transmission rate promote skin
hydration and permeability.
 Release Liner:
o During storage the patch is covered by a protective
liner that is removed and discharged before
application to the skin.

33.  A part of primary packaging material.
 Typically composed of of a base layer (occlusive
or non- occlusive) and release coating layer
(silicon or teflon).
 Other Exipients:
 Solvents such as chloroform, methanol, acetone
etc used to prepare drug reservoir.
 Plasticisers such as triethyl
citrate,PEG,propylene glycol.

34. Single layer drug
in adhesives.
Multi-layer drug
in adhesives.
Vapour patch.
Polymer
membrane
permeation
controlled TDDS.
Adhesive
diffusion
controlled TDDS.
Matrix diffusion
controlled
TDDS.
Micro reservoir
controlled
TDDS.

35.  Single layer Drug in Adhesive
 The adhesive layer of this system also contains the
drug.
 Adhesive layer not only serves to adhere the various
layers together, along with the entire system to the
skin, but is also responsible for the releasing of the
drug.
 The adhesive layer is surrounded by a temporary
liner and a backing.

36.  Multi layer Drug in Adhesive
 Here both adhesive layers are also responsible for
the releasing of the drug.
 One of the layers is for immediate release of the
drug and other layer is for control release of drug
from the reservoir.
 This patch also has a temporary liner-layer and a
permanent backing.

38.  Vapour Patch
 Here the adhesive layer not only serves to
adhere the various layers together but also to
release vapour.
 Commonly used for releasing essential oils for up
to 6 hours and are used in cases of decongestion
mainly.
 Also used to improve the quality of sleep and
reduces cigarette smoking conditions.

39.  Polymer Membrane permeation controlled TDDS:
 Drug reservoir is embedded between an impervious
backing layer & a rate controlling polymeric
membrane → microporous or non-porous.
 Rate of drug release is affected by:
•composition of polymer
•permeability coefficient
• thickness
Example:- Transderm Nitro,Transderm scop

41.  Adhesive dispersion type systems
 Drug reservoir :
•Dispersing drug in an adhesive polymer.
• Spread the medicated polymer by melting
the adhesive on to impermeable metallic
plastic baking.
•The drug reservoir is then covered by a non
medicated rate controlling adhesive polymer.
Eg :Isosorbide dinitrate releasing TDDS
(Frandol tape)

43.  Matrix diffusion controlled systems
 Homogeneously dispersing the drug particles in a
hydrophilic or lipophilic polymer matrix.
 It is then pasted on to an occlusive base plate in a
compartment fabricated from a drug impermeable
plastic backing layer.
 Adhesive polymer is then spread along the
circumference to form a strip of adhesive rim
Eg:Nitro Dur.

45.  Micro-reservoir type controlled systems
 Combination of reservoir & matrix diffusion type
drug delivery systems.
 Drug reservoir is formed by first suspending the
drug solids in an aqueous solution of a water
soluble polymer.
 Then dispersing the solution homogeneously in a
lipophilic polymer to form thousands of
microscopic spheres of drug reservoirs
 Example: Nitro Dur.

47.  Poroplastic type systems
 It is made utilizing the concept of the water
coagulation of cellulose triacetate solution in
organic acids at low temp.
 The water may be exchanged subsequently for
another vehicle by a diffusional exchange
process.

50.  Physico chemical evaluation:
 Interaction studies:
 Interaction between drug & excipient effect,
bioavailability & stability of the drug.
 Studies are carried out by thermal analysis,FT-IR
UV& chromatographic techniques.

51.  Thickness of patch:
Thickness measured using digital
micrometer
Determine the average thickness
And standard deviation to ensure the
thickness of prepared patch.

52.  Weight uniformity:
Weigh 10 randomly selected patches
Calculate the average weight
individual weight should not deviate
significantly from average weight

53.  Folding endurance:
Specific area of strip is cut & repeatedly
folded at the same place till it breaks
Number of times the film could be folded
without breaking gives folding endurance

54.  Percentage moisture content:
Prepared patches are weigh individually
Kept in desicator containing fused Cacl2
at room temperature
After 24 hrs films are reweighed
Determine percentage moisture content by given
formula:
Percentage moisture content=
(initial weight –final weight/final weight)*100

55.  Water vapour permeability evaluation:
 Determined by natural air circulation method
WVP= W/A
W=Amount of vapour permeated through patch
A=Surface area of exposed samples

56.  Flatness study:
Three longitudinal strips are to be cut from the
centre & other two from each side of patches
Length of each strip is measured
Variation in length is measuerd by determinig
percentage constriction
 Zero constriction is equilent to 100% flatness
% constriction=(initial length-final
length/initial length)*100

57.  Percentage elongation break test:
 Noting the length just before the break point.
 Elongation percentage=
(final length-initial length/initial length )*100

58.  Drug content determination:
An accuratly weighed portion of film is dissolved
in 100 ml suitable solvent.
shaken continuously for 24 hrs in shaker incubator
whole solution is sonicated
Solution is then filtered through a filter medium
Drug in solution estimated spectroscopically.

59.  Content uniformity test:
 10 patches are selected &content is determined
for individual patches
 If 9 of 10 patches have content 85%-115% patches
passes the test
 If 3 patches have content 75%-125%,additional
20patches are tested
 Drug content of 20 patches -85%-115%,pass test.

60.  In vitro evaluation:
 Invitro release studies:
 To study the drug release , paddle over disc method is
used.
 Procedure:
Dry films of known thickness is cut , weighed & fixed
over a glass plate with an adhesive
Placed the glass plate in 500ml phosphate buffer (ph7.4)
maintained at 32+-5c
Paddle set at a distance of 2.5 cm from glass plate &
operated at 50rpm
5ml samples are withdrawn at appropriate time intervals
upto 24 hrs &analyzed by UV spectrophotometer.

61.  Invitro skin permeation studies:
 Study carried out using diffusion cell
 Procedure:
Skin of male wristar rats (200-250g) are taken.
Hair removed from abdominal region & demal
side,cleaned with distilled water
Equilibrated for an hour in phosphate buffer&
Placed on magnetic stirrer with small magnetic needle
for uniform distribution of the diffusant.

62. Temperatue of the cell was maintained at 32+-50c
The isolated rat skin is mounted between the
compartments of diffusion cell.
Equal volume of fresh samples are replaced
Samples are filterd & analyzed
spectrophotometrically
o Permeability coefficient= flux/initial drug load
o Flux - slope of the curve between steady
state values of the amount of drug permeated
vs time .

63.  In vivo evaluation:
 Animal studies:
 Animal studies are preferred at small scale.
 Most common species used are mouse,guinea
pig,rabbit,hairless rat, dog, rhesus monkey etc.
 Human models:
 Clinical trials are conducted to asses efficacy risk
involved,side effects,patient compliance etc.

64.  Skin irritation test:
 Skin irritation &senzitised test can be performed on
healthy rabbit.
 Procedure:
Dorsal surface of rabbit is cleaned & removed the hair
Clean the surface by rectified spirit & representative
formulation can be applied over skin.
Patch is to be removed after 24 hrs
skin is observed & classified into 5 grades on the basis
severity of skin injury.

65.  Stability studies :
 Conducted according to ICH giudlines by storing
TDDS samples at 40+-0.50c & 75
+-5% RH for 6 months.
 Samples were withdrawn at 0,30,60,90,&180
days.
 Analyze suitably for dug content.

66.  Peel adhesion test
 Thumb crack test
 Rolling ball test
 Quick test
 Probe tack test
 Shear strength properties

68. Types of
transdermal patches
available today
Nicotine
patch
Patch for
severe
pain
Antihypert
ensive
patch
Vitamin
B12 patch
Antideppe
ressent
patch
Easy
breath
patch
Patch for
hyper
activity
disorder
Patch for
hormone
therapy

71. SC

72. SC
SC

73. SC SC

74. SC
SC

75. SC
SC

76. SC

79. SC

80.  An insulin patch
 Sufentanil patch for chronic cancer pain
 Varenicilin patch for smoking cessation
 Seligiline patch for deppression in elderly &
coccaine addiction
 Dexamethasone iontophoretic delivery for
the treatment of tennis elbow.
 An iontophoretic sumatriptan patch for
migrain treatment
 Transdermal glyceryl trinitrate for acute
stoke therapy

81.  TDDS is useful for topical &local action of drugs
 The drugs showing first pass metabolism & unstable
in GI conditions are suitable candidates for TDDS.
 Due to recent advances in technology & the
incorportion of drug to site of action without
rupturing the skin membarane, transdermal route is
becoming widely accepted route for drug
administration.
 Many new researches are going on in the present day
to incorporate newer drugs via this system.
 Thus tdds could be one day ,one of the best novel
drug delivery system.

82.  S.P Vyas and Roop .K.Kumar; 2009.Control
Drug Delivery Concepts and Advances
;Transdermal Drug Delivery; 10;411-446.
 Yie W. Chien ; 2009.Transdermal Drug
Delivery Systems ;second edition ; 301 -380.
 Loyd V . Allen , Nicholas G Popovich,Howard
C Ansel ; Ansels pharmaceutical dosage form
and drug delivery systems ;8 ;298 -315.
 Bhavesh pharma et al ; 2012.Transdermal
drug delivery system : A Review : The Pharma
Innovation;4;78-87.