Seminar on transdermal drug delivery system was delivered in NDDS lecture.Points such as introduction, permeation through skin,factors affecting, permeation enhancers,basic components, approaches of TDDS were covered.It was a wonderful experience.In introduction basic anatomy and physiology of skin, definition of Transdermal drug delivery system, advantages and disadvantages mechanism of Transdermal patch,Routes of skin permeation,ficks law was covered.Approaches was also taken in detail.factors was explained, components of Transdermal drug delivery was made clear point wise.
3. INTRODUCTION
Definition –
Transdermal drug delivery is defined as a self contained discrete dosages form, which
when applied to the intact skin, will deliver the drug at a controlled rate to the systemic
circulation
4. 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.
5. 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.
6. ANATOMY AND PHYSIOLOGY OF SKIN
Skin is the largest organ of human body and serves as a permeability barrier
against the transdermal absorption of various chemical and biological
agents
Human skin comprises of three distinct but mutually dependent tissues:
• Epidermis:
Stratum corneum (Horny cell layer)
Stratum lucidum (Clear layer)
Stratum granulosum (Granular layer)
Stratum spinosum (Prickly layer)
Stratum germinative
• Dermis:
• Hypodermis or Subcutaneous layer:
7. EPIDERMIS
Stratum corneum is the outermost layer of skin called as horny layer.
It contains 10 to 25 layers of dead, keratinized cells called corneocytes
It is flexible but relatively impermeable
The stratum corneum is the principle barrier for penetration of drug.
Going in words it consist of various layers such as Stratum lucidum, Stratum
granulosum , Stratum spinosum, stratum basal.
8. DERMIS
Dermis is 3 to 5 mm thick layer and is composed of a matrix of connective tissues, which
contains blood vessels, lymph vessels and nerves.
The cutaneous blood supply has essential function in regulation of body temperature.
Provides nutrients and oxygen to skin while removing toxin and waste products.
Capillaries reach to within 0.2 mm of skin surface and provide sink conditions for most
molecules penetrating the skin barrier.
Blood supply thus keeps the dermal concentration of permeate very low and the resulting
concentration difference across the epidermis across the epidermis provides essential
concentration gradient for transdermal permeation
9. HYPODERMIS
This fat tissues supports the dermis and epidermis.
It serves as a fat storage area.
Helps to regulate temperature, provide nutritional support and mechanically protection.
Carries principle blood vessel and nerves to skin and may contain sensory pressure organs.
For transdermal drug delivery, drug has to penetrate through all these three layers and reach
into systemic circulation while in case of topical drug delivery only penetration through
stratum corneum is essential and then retention of drug in skin layers is desire.
10. FUNCTION OF SKIN
Protection: an anatomical barrier from pathogens and damage between the internal and
external environment in bodily defence; Langerhans cells in the skin are part of the
immune system
Sensation: contains a variety of nerve endings that react to heat and cold, touch,
pressure, vibration and tissue injury.
Heat regulation: The skin contains a blood supply far greater than its requirements which
allow precise control of energy loss by radiation, convection and conduction. Dilated
vessel increase perfusion and heat loss, while constricted vessels greatly reduce
blood flow and conserve heat
Control of evaporation: the skin provides a relatively dry and semi-impermeable barrier
fluid loss. Loss of this function contributes to the massive fluid loss in burns.
11. Aesthetics and communication: other see our skin and can assess our mood,
physical stable and attractiveness.
Storage and synthesis: act as a storage centre for lipids and water, as well as means
of synthesis of vitamins D by action of UV on certain parts of the skin.
Excretion: sweat contain urea; however its concentration is 1/30th that of urine,
hence excretion by sweating is an almost a secondary function to temperature
regulation.
Absorption: in addition medicine can be administrated through the skin, by
ointments or by means of adhesive patch, such as the nicotine patch or
The skin is an important site of transport in many other organisms.
Water resistance: the skin act as a water resistant barrier so essential nutrients are
not washed out of the body.
12. MECHANISM OF ABSORPTION THROUGH SKIN
Mechanism involved is passive diffusion
This can be expressed by FICK’s LAW of DIFFUSION
dq = DKA (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
13. ROUTE OF DRUG ABSORPTION THROUGH SKIN
Trans follicular route
Trans epidermal route
14. 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 substances are diffused faster through appendages that of other layers.
Sweat glands and hair follicles act as a shunt i.e. easy pathway for diffusion through rate limiting ST
corneum.
This route comprises transport via the sweat glands and the hair follicles with their associated
sebaceous glands.
Although these routes offer high permeability, they are consider to be of minor importance because of
their relatively small area, approximately 0.1% area of the total skin.
This route seems to be most important for ions and large polar molecules which hardly permeate
through the stratum corneum.
15. TRANS EPIDERMAL ROUTE
In trans epidermal transport, molecules cross the intact horny layer.
Two potential micro-routes of entry exist:
1) transcellular
2) intercellular.
The principle pathway taken by a penetrant is decided mainly by the partition
coefficient (log K).
Hydrophilic drugs partition preferentially into the intracellular domains, whereas
lipophilic permeants (octanol/water log K>2) traverse the stratum corneum via
the intercellular route.
16. FACTORS AFFECTING TRANSDERMAL PENETRATION-
1) PHYSICOCHEMICAL PROPERTIES OF DRUG :
2) a) Partition Coefficient- lipophilic drugs penetrate via trans/ intracellular route while hydrophilic drugs
penetrate via intercellular route
3) b) Molecular Weight- molecular weight of penetrant should be 100-500 Dalton c) Ionisation - Unionised form
gets absorb in significant manner2)PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS OF SKIN : a) Reservoir
Effect Of Horny Layer- IT is due to irreversible binding of drug to the skinb) skin hydration - hydration
increasespenetration by opening the dense,closely packed cells and increase its porosity
4) c) skin temperature - increase in skin temperature increases it's permeability due to availability of energy for
diffusivity
5) d) Regional variation - The variability in penetration is due to differences in thickness of barrier
6) e) pathological injuries to skin - It increases permeability due to disruption of stratum corneum and increase in
vasodilation
7) f) cutaneous self metabolism - catabolic enzymes present in cutaneous layer may render inactive the drug by
metabolism and decrease it's bioavailability
8) g) Skin barrier properties in neonates and young infant- pH of skin surface of newborn is higher as compared to
adult and the skin surface is relatively hydrophobic
9) h) Skin barrier properties in aged skin - The permeability decreases due to -increase in the size of corneocytes
which tend to decreases the intercorneocyete space - moisture content of decreases with ageingi) Race- Black
skin shows increased intracellular cohesion , higher lipid content and higher electrical resistance levels than
whitesJ) Body sites - permeability varies with site of application- Genital tissues usually provide higher
permeability compared to other sites of body.
17. 3) ENVIRONMENTAL FACTORS :
1) a) sunlight- sunlight results in thinning of blood vessels
2) b) cold season - In cold season skin becomes dry which decreases permeability
3) c ) Air pollution- Dust can clog the pores and increase bacteria on skin which may lead to decrease in
permeability of skin
4) 4)PERMETION ENHANCERS :-Substances that reduce the skin's ability to perform it's barrier function
collectively known as Permeation Enhancers- They make the skin more permeable and allow drug
molecules penetrate the skin at faster rate- also known as sorption promoters and accelerants- the flux
of drug accross the skin can be written as :J = D dc/dx where , J = flux D=
Diffusion coefficient C= concentration of diffusing species
X= spatial cordinateThey act by three mechanisms:- By altering physicochemical properties of stratum
corneum.- By changing hydrating property of stratum corneum. -By altering structure of lipids and
protein in intercellular channel via carrier mechanism
TYPES ION ENHANCERS OF PERMEATION–
physical enhancersChemical enhancersideal properties of an Permeation Enhancers-
1) it should be odorless and colorless;
1) (2) it should be specific in its mode of action;
2) (3) it should be pharmacologically inert;
3) (4) it should be compatible with drugs and other excipients;
4) (5) it should be chemically and physically stable
18. PERMEATION
ENHANCERS
• INCREASES THE ABSORPTION OF PENETRANT THROUGH THE SKIN.
SUBSTANCES ADDED TO PHARMACEUTICAL FORMULATION IN ORDERED TO INCREASE THE MEMBRANE
PERMEATION OR ABSORPTION RATE OF A CO-ADMINISTERED DRUG.
19. CLASSIFICATION OF PENETRATION ENHANCERS:
1.Chemical Enhancers;
e.g. Azone, Pyrrolidone, Fatty acids, Essential oils,
terpenes, organic solvents.
2.Physical Enhancers;
e.g. lonotophoresis, electroporation, Microneedles.
21. PROPERTIES FOR IDEAL PENETRATION
ENHANCERS
1.Non-toxic, non-irritating and non-allergic.
2.Rapid working.
3.No pharmacological activity within the body.
4. Work unidirectionally.
5. When removed from the skin, barrier properties
should return both rapidly and fully.
6.Compatible with both excipients and drugs.
7. Cosmetically acceptable.
22. USES OF PENETRATION ENHANCERS
• 1. To increase the delivery of ionisable drugs.Example: timolol maleate.
• 2. To deliver the impermeable drugs. Example: heparin.
• 3. To maintain level of drug into blood stream.
• 4. To improve the efficacy of less potent drugs with higher
• dose. Example: oxymorphane.
• 5. To deliver the drugs having high molecular weight like peptide and hormones
• 6. To decrease lag time of transdermal drug delivery system
29. 3.Permeation Enhancer
To increase permeability of stratum corneum so as to
attain higher therapeutic levels of drug.
Permeation enhancers interact with structural
components of stratum corneum i.e proteins or lipids.
Different penetration enhancing techniques are-
1.chemical enhancer:-e.g sulfoxides and similar
compounds,azone,fatty acids ,
essential oils etc.
2.Physical enhancer:-e.g electrically based techniques
invovles iontophoresis ,electroporation,
ultrasound etc.
30. 3. Structure based techniques:-it invovles use of
microneedles.
Penetration enhancer may act by three main
mechanism :
1.Disruption of the highly ordered stucture
Of stratum corneum lipids.
2. Interaction with intercellular protein.
3. Improved partitioning of drug ,co-enhancer
Or solvent into the stratum corneum.
31. 4.Adhesive
-Adhesive makes an intimate contact between the skin
And transdermal system.
- It carries the drug which is dissolved or dispersed in
solution or suspention form.
-The quality of drug diffused in to skin depending on
the holding power.
E.g. Polyisobutylenes.
-Pressure sensitive adhesives are used to achieve contact
between the transdermal patch and the skin
32. The ideal characters of adhesive materials are ;
1.High biocompatibility ( low irritancy,toxicity,
allergic reaction etc.)
2.Good adhesive to oily,wet and hairy skin.
3.Good environment resistance against water
and humidity.
4.Easy to remove from the skin.
5.Non-reactive towards drug.
33. 5.Backing membrane
- Backing layer protects patch from outer environment .
While designing the backing layer following points
must taken in to consideration:
1.Backing membrane must be flexible.
2.It should be compatible with transdermal system
as remain in use while applying.
3. It should be chemically resistant.
4. It should have good tensile strength.
5. It should have non-irritant.
34. Examples of backings laminate are polyethylene
film, polyester film, and aluminium vapour
coated layer .
35. 6.Other excipients
A. Plasticizers
- Plasticizers have also been used in many
formulation ranging from 5 to 20%(w/w,dry basis)
- It is responsible for adhesiveness of the film with
Other surfaces or membranes or improvement in
Strength of film.
-some of its examples are glycerol or sorbital,
at 15% ,w/w,dry basis ,Phosphate,Phosphate
esters ,fatty acid esters.
36. B.solvents
Various solvents such as methanol, chloroform ,
acetone, isopropanol and dichloromethane etc. Are
used to prepare drug reservoir.
37. FORMULATION APPROCHES OF
TDDS
1) MEMBRANE PERMEATION CONTROLLED SYSTEM ( RESERVOIR
TYPE)
2) ADHESIVE DISPERSION TYPE SYSTEM
3) MATRIX DIFFUSION –CONTROLLED SYSTEM
4) MICRORESERVOIR TYPE / MICROSEALED DISSOLUTION
1) Membrane permeation controlled system:-
• In this system, the drug reservoir is embedded between an impervious
backing layer and a rate controlling membrane. The drug releases only
through the rate controlling membrane,which can be micro porous or
non-porous.
• In the drug reservoir compartment ,the drug can be in the form of a
solution,suspension,or gel or dispersed in solid polymer matrix.On the
outer surface of the polymeric membrane a thin layer of drug
compatible,hypoallergenic adhesive polymer can be applied.
• The rate of drug release from this type of transdermal drug delivery
system can be tailored by varying the polymer composition, permeability
coefficient and thickness of the rate controlling membrane.
38. The intrinsic rate of drug release from this TDDS is calculated by following
formula:-
dQ/dt= Cr
1/Pm +1/Pa
Where, Cr = Conc. Of drug in the reservoir compartment.
Pm = permeability coefficient of rate controlling
polymer membrane.
Pa = Permeability coefficient of adhesive.
EXAMPLE :-
1) Nirtoglycerin releasing TDDS for Once a day medication in angina
pectoris
2) Scopalamine releasing TDDS for motion sickness.
3) Estradiol releasing TDDS for menposal sickness.
2. Adhesive dispersion type system:-
• The drug reservoir is formed by dispersing the drug in an adhesive
polymer and then spreading the medicated polymer adhesive polymer
and then spreading the medicated polymer adhesive by solvent
casting or by melting the adhesive onto an impervious backing layer.
39. • The drug reservoir layer is then covered by a non – medicated rate
controlling adhesive polymer of constant thickness to produce an
adhesive polymer of constant thickness to produce an adhesive
controlling drug delivery system.
The rate of drug release in this system is defined by
Dq/dt= ka /r.Da
ha
where, Ka/r = Partition coe. Between adhesive layer
resvoir layer.
Da = Diffusion coefficient of drug in the
adesive layer.
EXAMPLE:-
Isosorrbide dinitrate releasing TDDS for once a
day medication of angina pectoris.
3) Matrix diffusion controlled TDDS: -
• The drug is dispersed homogenously in a hydrophilic or lipophilic polymer
matrix .this drug containing polymer disk containing then is fixed onto an
occlusive base plate in a compartment fabricated from a drug impermeable
backing layer.
• Instead of applying the adhesive on the face of the drug reservoir ,it is spread along the
circumference to form a strip of adhesive rim.
40. dQ/dt = { A Cp DP/2t}
where, A = Intial drug loding dose in polymer.
Cp & Dp solubility and diffusibility polymer drug of matrix.
EXAMPLE:-
Nitro Dur ( Nitroglycerine) used for once a day medication of angina
pectoris.
4) Microreservoir controlled TDDS:-
• This drug delivery system is a combination of reservoir and matrix –
dispersion system.
The drug reservoir is formed by first suspending the drug in an aqueous
solution of water soluble polymer and then dispersing the solution
homogenously in alipophilic polymer to from the thousand of unreachable,
microscopic sphere of drug reservoirs .
• The thermodynamically unstable dispersion is stabilized quickly by immediately
crosslinking the polymer in situ. A Transdermal system therapeutic system thus
fromed as a medicated disc positioned at the centre and surrounded by an an
adhesive rim.
EXAMPLE:- Nitro-dur system ( nitroglycerine) for once a day treatment of angina
pectoris
The rate of drug release from this system is defined as
