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Mpharm first year
Department of pharmaceutics
College of pharmacy
Madras Medical College




• Introduction

• Advantages

• Disadvantages

• Anatomy of the skin

• Basic components of tdds

• Various approaches

• Evaluation




Introduction: Definition:


“Transdermal therapeutic systems are defined as
self-contained , discrete dosage forms which , when
applied to the intact skin , deliver the drug , through
the skin , at a controlled rate to the systemic


“A transdermal patch is defined as a medicated
adhesive patch which is placed above the skin to
deliver a specific dose of medication through the skin
with a predetermined rate of release to reach into the
bloodstream.” 3



WHY? • 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.

• Transdermal drug delivery can closely duplicate continuous
IV fusion . Hence is helpful in delivering drugs that undergo
significant first pass metabolism and/or have narrow
therapeutic index.




ADVANTAGES: • Easy to use

• Avoid GIT absorption problems for drugs

• Avoids FPM

• Self medication is possible

• Reduces frequency of dosing

• Have fewer side effects than oral medications or supplements

• Painless , non-invasive way to deliver substances directly
into the body

• Controlled delivery resulting in more reliable and predictable
blood levels

• Rapid termination in case of toxicity is possible 5



DISADVANTAGES: ▪ Limited skin permeability

▪ Significant lag time

▪ Cannot be used for large molecule (7500 Dalton)

▪ Restricted to potent drug

▪ Skin irritation and allergic response

▪ Drugs requiring chronopharmacological management are
not suitable candidates .

▪ Skin barrier

▪ Usually reserved for drugs which are extremely potent.

▪ Ucomfortable to wear

▪ May not be economical





Avoid hepatic Yes No Yes
first pass

Constant drug Yes No Yes

Self No Yes Yes

Termination of No Yes Yes








▪ Skin is the part of Integrated system i.e. it helps to maintain body temp 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…
❖ Stratum Corneum
❖ Stratum Lucidum
❖ Stratum Granulosm
❖ Stratum Spinosum
❖ Stratum Basal
3)Subcutaneous layer




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

It consists of Ceramides 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.
It is made up of three layers in thicker parts stratum granulosum, stratum lucidum,stratum

Removal of these layers results in increased permeability and water loss. 10







➢It forms the outermost layer of the epidermis.(about 20-25 layers)

➢It is compacted, flattened, dehydrated and keratinized cells. They are dead cells which is

converted to protein nature.

➢These cells have lost their nuclei and become dead cells


➢It is replenished about every 2 weeks in a mature adult.

➢The cells have a water content of only approximately 20% compared to normal

physiological level of 70% in stratum germinativum.

➢It requires a minimum moisture content of 10% w/w to maintain flexibility and softness.

➢It is responsible for the primary barrier to percutaneous absorption.



2)STRATUM LUCIDUM (clear layer)

➢It is made up of flattened epithelial cells.

➢Many cells have degenerated nucleus and in some cells, the nucleus is absent.

➢As these cells exhibit shiny character, the layer looks like a homogeneous translucent

zone. So this layer is called stratum lucidum (lucid= clear).

3)STRATUM GRANULOSUM (granular layer)

➢It is a thin layer with 2 to 5 rows of flattened

rhomboid cells.

➢Cytoplasm contains granules of a protein called

keratohyalin (precursor of keratin).



4)STRATUM SPINOSUM (prickly layer)

➢It is also known as prickle cell layer because, the cells of this layer possess some

spine-like protoplasmic projections.( 8-10 layers)

➢By these projections, the cells are connected to one another.





➢It is a thick layer made up of polygonal cells, superficially and columnar or cuboidal

epithelial cells in the deeper parts in which new cells are constantly formed by mitotic division.

➢The newly formed cells move continuously towards the stratum corneum.

➢The stem cells, which give rise to new cells are known as keratinocytes.





➢It is the inner layer of the skin.

➢It is made up of dense and stout collagen fibres of fairly uniform thickness, fibroblasts and histiocytes.

➢The network of gel containing oriented tropocollagen (polypeptide) macromolecules, which is responsible for

elastic properties of the skin.

➢There are two layers:
a) Superficial papillary layer b) Deeper reticular layer

➢SUPERFICIAL PAPILLARY LAYER- It projects into the epidermis which contain blood vessels, lymphatics

and nerve endings.

➢RETICULAR LAYER- It is made up of reticular and elastic fibres, which found around hair bulbs, sweet glands

and sebaceous glands.

➢It contains mast cells, nerve endings, lymphatics, epidermal appendages and fibroblasts.








➢It is also called Hypodermis.

➢It is a sheet of fat containing areolar tissue, known as superficial fascia which is present immediately

below the dermis.

➢It act as fat storage, participates in thermal regulation (helps us to heat up).

➢Lot of smooth muscles called arrector pili are also found in skin around the hair follicles.

➢The arrector pili muscle is responsible for the movement of hair when cold or scared.

➢The contraction of the muscle pulls on the hair follicle causing the hair to stand up and tightens the skin
around the hair forming goose bumps.




Sweat glands produces sweat of pH 4-6.8 & absorbs drugs, secretes proteins, lipids and
antibodies. Its function is to control heat.
They have sebaceous glands which produces sebum and includes glycerides, cholesterol and


Sebaceous glands Sweat glands

Eccrine glands Apocrine glands





1. Distribution Throughout the body Only inn limited areas like
axilla, pubis, areola and

2. Secretion Clear and watery Thick and milky

3. Period of functioning Throughout life Only at puberty

4. Regulation of body Play important role in Do not play
temperature temperature regulation

5. Conditions when secretion During increased temperature Only during emotional
increases and emotional conditions conditions

6. Control of secretory activity Under nervous control Under hormonal control




Protection Sensory function Excretion

Regulation of Formation of
Water resistance

body temperature vitamin D





Routes of drug permeation
Drug release from dosage

Absorbed in surface of sebum

Transdermal Transfollicular

Stratum corneum Pilosebaceous unit Eccrine gland

Intracellular Intercellular Hair follicles Sebaceous gland

Viable epidermis

Dermis Microcirculation




The rate of permeation across the skin can be expressed accordingly Fick’s First law

dQ/dt =Ps ( Cd – Cr )

Where dQ/dt – Rate of permission

Ps – Permeability coefficient

Cd – Concentration of skin penetrant in donor compartment (Stratum corneum)

Cr – Concentration of skin penetrant in receptor compartment (body)





a) Transfollicular route ( shunt pathway)

Transfollicular route is the shortest pathway that drug has to follow to reach the

systemic circulation that provides a large area for diffusion of drugs.

b) Transcellular route

Drug delivering through this route passes from corneocytes which has highly

hydrated keratin creating hydrophilic pathway.

The drug passes through the corneocytes of stratum corneum.

c) Intercellular route

The drug diffuses through the continuous lipid matrix present between the cells.







The principle transport mechanism across mammalian skin is by passive diffusion. The factors

influencing and having differences in transdermal permeability of the stratum corneum.

1) Physico-chemical properties of penetrant molecule and drug delivery


a) Diffusion

b) Partition Coefficient

c) pH conditions

d) Concentration of penetrant molecule

e) Vehicle

f) Composition of drug delivery system

g) Molecular size and shape 26




❖The transport characteristics of the drugs are determined by its size and its level of interaction with

media through which diffusion takes place.

❖The drugs having molecular weight less than 500 daltons is acceptable transdermal patches for better


Partition coefficient:

❖A lipid/water solubilities of drug are absorbed through the skin which having partition coefficient of 1 or

greater is generally required for optimal transdermal permeability.

❖Partition coefficient of drug molecule altered by chemical modification of its functional groups.

pH condition:

❖pH values of solutions with very high or very low can be destructive to the skin.

❖With moderate pH, the flux of the ionizable drugs can be affected by changes in pH that alter the

transdermal permeability.( skin:5.0-5.5)



Concentration of penetrant molecule:

❖Concentration α diffusion flux.

❖If concentration of dissolved drug is higher across the barrier, the concentration

gradient will be more.


❖Solubility of the drug in the vehicle determines the release rate only not

increase the penetration of the drug into the body.

❖The drug release depends on lipophilic solvent vehicles which facilitate

penetration and pH of the vehicle.




Composition of drug delivery system:

❖It affects not only drug release rate but also permeability of stratum corneum by

means of hydration, mixing with skin lipid or other sorption promoting effects.

Molecular size and shape:

❖Drug absorption is inversely related to molecular weight, small molecules

penetrate faster than large ones.

❖The ideal molecular size of drug molecule for transdermal delivery is ≤ 400.

2) Biological conditions of the skin:

a) Lipid film d) Race

b) Hydration e) Age

c) Temperature and Humidity f) Anatomical site 29



Lipid film:

❖It acts as a protective layer to prevent the removal of moisture from the skin and

maintains basic function of stratum corneum.

❖Defatting of this film was found to decrease transdermal absorption.


❖Hydration on stratum corneum caused by occlusive vehicle.

❖As the hydration time increases, the low frequency impedance of the excised skin

decreases with time.

Temperature and Humidity:

❖↑ Temperature ↑ Rate of skin permeation.

❖Humidity is directly related to skin permeability by its effect on insensible perspiration.




❖Striking differences in skin coloration exist across races of the man, which

relates to nature, numbers and distribution of melanin pigment granules

deposited in the epidermis by melanocytes.


❖Skin of adults and young ones are more permeable than the older. Children

shows toxic effects because of the greater surface area per unit body weight.

Anatomical site:

❖Differences in the nature and thickness of the barrier layer of the skin cause

variation in permeability.




➢Polymer matrix/drug reservoir


➢Permeation enhancers

➢Pressure-sensitive adhesives (PSA)

➢Other excipients like plasticizers and solvents

➢Backing laminates

➢Release liner





➢Polymer matrix can be prepared by dispersion of drug in a liquid or solid state synthetic

polymer base.

➢Polymers are the backbone of TDDS, which control the release of the drug from the device.

➢Polymers used in TDDS should have biocompatibility and chemical compatibility with the

drug and other components of the system, such as penetration enhancers and PSAs.

➢Polymer must be following: Molecular weight, and chemical functionality of the polymer-

should be such that specific drug diffuses properly and gets released through it. Stable, non

reactive with the drug.Easily manufactured and fabricated into the desired product.

Inexpensive, degradation products of polymer – nontoxic.



Polymers used in TDDS:

• Cellulose derivatives, shellac, waxes, gums, and their
Natural polymers

derivatives, etc.

• Polybutadiene, hydrin rubber, polysiloxane, silicone
Synthetic elastomers rubber, silicone rubber, nitrile, acrylonitrile, butyl

rubber, styrene, butadiene rubber, neoprene, etc.,

• Polyvinyl alcohol , Polyvinyl

Synthetic polymers ylate,polyvinyl pyrrolidine , polyamide,polymethyl
methacrylate 34




➢Drug should be potent in nature.

➢Drug to be used should be judiciously chosen on the basis of pharmacological or physiochemical properties.

➢Good solubility in oil and water.

➢It should not metabolize in skin.

➢Short biological half life(t1/2)

➢It should be non-irritant and free from allergic response.


1) Molecular weight – < 1000 daltons

2) Melting point – < 200 ̊ C

3) Dose – less than 20 mg/ day





➢These are the compounds which enhance the permeability of stratum corneum to attain the therapeutic level

and interact with proteins and lipids.

➢The methods employed for modifying the barrier properties of the SC to enhance the drug penetration

(absorption) through the skin can be categorized as

1. Chemical enhancers

2. Physical enhancers

3. Miscellaneous

1. Chemical enhancers:

❖Chemical enhancers are temporarily diminishing the barrier of the skin and known as accelerants or

sorption promoters can enhance drug flux.

❖MECHANISM- It help in permeation across the skin by disruption of the highly ordered structure of

stratum corneum lipid, interaction with intercellular protein (easy for lipid soluble drug rather than proteins).



Water , Lipids Water,Phospholipids

Hydrocarbons Alkanes,alkenes,mineral oil,halogens

Alcohols Glycerol,glycol,ethanol

Acids Oleic acids,undecanoic acids

Amines Primary,secondary,tertiary,cyclic and
acyclic amines

Esters Isopropyl myristate

Surfactant(anionic,cationic,non- Sodium lauryl sulfate,cetyltrimethyl
ionic,zwitterionic) ammonium bromide,span

20,polysorbate 80

Terpenes,Terpenoids and Essential Menthol,limonene
oils 37



a. Water:
Water causes the hydration of the skin and improves the permeability towards

various drug molecules. Water is present naturally in the skin. It causes the swelling of
the aqueous pores hence opening of the pores for transportation across the skin. Water
can be used as permeation enhancer for hydrophilic and lipophilic drugs.
b. Surfactants:

Surfactants lowers the interfacial tension between the skin and drug particles
and enhances the penetration tendency across the skin. Various types of surfactants
like cationic, anionic, non-ionic, amphoteric surfactants etc are used as penetration
enhancers. But a good choice of surfactant depends on the HLB value of surfactant,
surface charge and number of alkyl group attached to the tail. Mostly non-ionic and
anionic surfactants are preferred for skin permeation. E.g. Sorbitan monolaurate 20 is
reported to increase the permeation rate by 30% of diclofenac diethylamine.




c. Hydrocarbons:
The alkanes with long carbon chain (C7-C16) have been investigated as skin

penetration enhancers by non destructive alteration of stratum corneum. While short chain
alkenes (C5-C6) show greatest penetration enhancing property. Hydrocarbons acts by
partitioning into the skin lipid and disturbing the ordered structure of the lipid membrane.
Various hydrocarbons such as alkane, alkene, alkyne, and haloalkanes are used as
penetration enhancers.
d. Azone:

Azone is a colorless, odorless liquid having smooth and having a feel of oil but
non greasy. It has a melting point of -70 C and is highly lipophilic in nature having log P
value of 6.2. Azone partition in to lipid bilayer to disrupt packing of skin lipids. Azone
produce disorder in intercellular lipid of skin and increase the fluidity of the skin. It affects
both hydrophilic and lipophilic routes of drug absorption. It is used in very low
concentrations of 0.1-5%




e. Pyrrolidones:
Pyrrolidones are used as penetration enhancer for both hydrophilic and

lipophilic drugs. These partitions into the skin and increases the fluidity. Pyrrolidone
creates small reservoirs of the drug in the skin which can act as sustained release drug
delivery system. N-methyl-2-pyrrolidone was the first agent employed for skin
permeation of captopril.

f. Urea:
Urea causes the hydration of stratum corneum of the skin by forming

hydrophilic diffusion channels. Various cyclic urea derivatives have been investigated
for their permeation enhancement activity. Cyclic urea derivatives are non-toxic and
biodegradable. Mechanism of action of urea may be hydrophilic activity or lipid
disruption mechanism because of presence of both polar group and long chain alkyl




g. Essential oils and terpenes:
Essential oils are volatile and odorous naturally occurring oils which have a

tendency to pass across the skin. The main ring is made of terpenes (repeated isoprene units)
and contains other aromatic chemical compounds such as menthol, eugenol, limonene,
carvone, geraniol. Essential oils are obtained from various parts of the plants such as flowers,
leaves, roots and fruits of various plants by extraction process. Various plant oils are used
such as: Niaouli oil, Eucalyptus oil, Alpinia oxyphylla oil, Turpentine oil, Tulsi oil,
Cardamom oil, Peppermint oil, Fennal oil, Cumin oil etc. Apart from these essential oils
some fixed oils such as cod liver oil, fatty acids, and phospholipids, polysaccharides such as
chitisan, capsacin, and vitamin E are also utilized as penetration enhancers. Diffusion of
imipiramine is studied across hairless rat skin using L-menthol as permeation enhancer.
h. Amines, amides and esters:

Amines and amides are utilized as penetration enhancers as they partitioned drug in
the skin. Isopropyl myristate is the widely used ester as penetration enhancer. Various amino
acid derivatives such as N-dodecyl-L-amino acid ester and n-pentyl-N-acetyl prolinate have

the potential to improve the permeation through the skin.



i. Alcohols:
Various alcohols such as alkanols, alkenols and polyhydric alcohols are utilized

as solvents, drug carrier and penetration enhancers. Alcohol by their solvent effect
solubilises the skin lipids and extracts them out of the skin. They cause the swelling of
the stratum corneum and enhance the portioning of the drug in the skin.
j. Sulphoxides:

Sulphoxides such as dimethyl sulphoxide (DMSO) is most basic and most
extensively used penetration enhancers. DMSO is a strong aprotic solvent having the
capability to solubilize all kind of solutes and hence regarded as universal solvent.
DMSO partitioned the drug into the skin. It is required in concentration of 60% or more
for penetration enhancement. N, N-dimethyloctanamide and N, N-dimethyldecanamide
are established as effective penetration enhancer for NSAIDs like ibuprofen and
naproxan from PG vehicle through rat skin.




k. Oxazolidones:
The oxazolidone compounds because of structural similarity with ceramines,

sphingosine and other skin components have the ability to penetrate the skin easily and
hence can localize the co-administered drug in the skin layers easily. E.g. retinoic acid and
diclofenac sodium.
l. Fatty acids:

A number of long chain fatty acids are used as skin permeation enhancers.
Unsaturated fatty acids are found to be more effective than saturated one. Unsaturated
fatty acids found to enhance percutaneous absorption of flurbiprofen by 6.5 to 17.5 times
through rate skin. Examples of fatty acids are oleic acid, linoleic acid, palmitoleic acid.
m. Cyclodextrins:

These can form inclusion complex with lipophilic drugs and increase their aqueous
solubility. The ring has a hydrophilic exterior and lipophilic core in which organic
molecules can form an inclusion complex bound by non-covalent bonds. Cyclodextrins
are more effective along with other fatty acids than alone. An association of piroxicam
with β-CD complex increases the drug flux by 3 times. 43



2. Physical enhancers:

❖An enhancer is a technique that modify the penetration facility of drug

physically is called physical enhancer.

❖Some physical enhancers are:









Sonophoresis :
-It is also termed as phonophoresis or ultrasound.
-In this enhancement technique, permeation is increased via ultrasonic

waves which means frequency is 20 kHz – 16MHz.

(a) Application of sound waves to the skin increases to fluidity of lipids and

increases permeation via transcellular pathway

(b) Formation of bubbles which generates pores which even allows large

molecular weight drugs such as protein or vaccines.

(c) In the human body, ultrasound energy absorbed by tissue causes a local

temperature increase may enhance permeability due to an increase inn

diffusivity of the skin. Eg: lidocaine, dexamethasone.




Iontophoresis :

• It is defined as permeation of ionized drug through electrical impulses of 0.5 mA/cm²
by either galvanic or voltaic cell.

• Two electrodes: Anode (+) and Cathode (-)
• Electrical potential is applied across the electrode causing current to flow across the

skin and rate of permeation of ionic drugs can be increased.
• It controls the rate and extent of drug delivery by modulation of the intensity and

duration of current application.
Eg: Fentanyl, lidocaine




Electroporation :

• This technique consists of the application of a high electrical field pulses with the

purposes to create nano-sized pores (20-200 nm) in a cell membrane which increase the

passage of ions and macromolecules through the skin.

• Two types: a) Irreversible electroporation – used for treating local solid tumor

b) Reversible electroporation – used in biotechnology and medicine

Microneedles :

• Microneedles have a length of 100-500 µm which can deliver the drug by penetrating

the stratum corneum and epidermis.

Eg. Hydrocortisone, lidocaine, salicylic acid



Macro flux technique:
This technique involves a titanium disk fixed on an adhesive polymeric layer.

The titanium disk contains an array of 300 micro projections per cm of the disk having
less than 200 micrometer length. These micro projections are coated with drug and deliver
the drug to the skin by creating holes in dead cell layer of skin. Pain is not induced by
these micro projections as these do not penetrate up to the level of nerve endings. High
molecular weight substances such as insulin, hormones and vaccines can be delivered
Transdermaly easily. These micro projections may be coated with drug or a drug reservoir
embedded with titanium micro projections is produced.
Metered dose Transdermal delivery:

In this technology a solution of drug in a mixture of volatile and non-volatile
solvent is applied on the skin which delivers the drug through the skin at a sustained rate.
The volatile solvent evaporates immediately and leaves a film of drug with non- volatile
penetration enhancer (ethanol, azone etc.) which partitions the drug into the skin and
creates a drug reservoir in skin.




Radiofrequency :

• Radiofrequency uses a range frequency of 10 kHz – 900 MHz.

• Radiofrequency ablation (RFA) is simple and safe technique and used in

electro-surgery and ablation of malignant tissues.

• It contains an electrode connected directly into the tumor, which the ions

in tissue try to follow the change in the direction of alternating current,

their movements result in frictional heating of the tumor, generating

coagulative necrosis and cell ablation.




3. Miscellaneous :
a. Dot matrix system:

This technique is developed by noven pharmaceuticals. In this system drug is first dispersed in
acrylic polymer and then the above dispersion is mixed with silicon polymer which acts as adhesive to the skin.
The drug microcells with a large surface area are formed in silicon polymer. These microcells can accumulate a
very high concentration of drug and due to a high concentration gradient drug diffuses across the skin at a
elevated rate.

b. Organogel and hydrogel system:
The organogel system has a very great tendency to permeate through the skin as it modifies the skin

lipid content and hence barrier function of the skin is overcome. These are clear, stable, viscous and
biocompatible gels and are safe for use. Potent and Non-irritant drugs having high lipid solubility are suitable to
formulate in organogel systems. They are thermodynamically stable and moisture insensitive, so there is a less
chance of contamination by microbes. A wide range of hydrophilic and lipophilic drugs can be incorporated in
organogel formulation successfully as these are balanced on hydrophilic- lipophilic scale. These are non-
irritant, biocompatible and non immunogenic so safe for use. Hydrogel are the water soluble gels which are
used for controlled delivery of transdermal drugs. Anionic hydrogel such as N-vinyl pyrollidone is an example
of such a system.




c. Liposome and niosome:
Liposomes are vesicular drug delivery systems which have several lipid bilayers

enclosing an aqueous core. Liposomes are made of phosphotidylcholine which is a lipid and
partitioned itself into the skin lipid and drug is transported across the membrane. Niosomes are
also a novel technique similar to liposomes but it contains non-ionic surfactant in addition to
phospholipids. The mechanism of action of all the novel system is similar to liposomes. The
problems associated with stability, storage, leaking, aggregation, fusion and sterilization of
Niosomes can be overcome by application of proniosomes which can be converted to noisome
on hydration immediately before use.
d. Transferosomes:

Transferosomes are similar to liposomes but these contain a surfactant in addition to
phospholipids. The Transferosomes are more flexible than liposomes and can easily squeeze
through the skin. They can be easily deformed and change their shape so can penetrate narrow
pores present in the skin. Both hydrophilic and hydrophobic drugs can be loaded in
Transferosomes. They are biocompatible and biodegradable having high entrapment efficiency.
They can be used for both systemic as well as topical delivery and release the drug at a 51

controlled rate.


e. Ethosome:
Ethosomes are non invasive drug carrier that penetrate the drug deeper in the kin and

finally deliver to the systemic circulation. These are produced by adding a quantity of alcohol
to the liposomes. Ethosomes are similar to liposomes and contains 20-50% of ethanol. Due to
presence of alcohol the penetration power of Ethosomes is higher than liposomes as the
disruption of skin lipid is much easier in case of ethosomes.
f. Aspasome:

Ascorbyl palmitate vesicles (Aspasomes) formed in presence of cholesterol and charge
inducer dicetyl phosphate has a very high tendency to permeate through the skin. The
antioxidant property and ability to permeate through the skin of these vesicles promises the
aspasomes as a carrier for transdermal drug delivery.
g. Eutectic systems:

Eutectic system is a binary mixture of two components which do not interact
chemically with each other but in a particular ratio they prevent the crystallization of each other
and lower the melting point of the mixture and hence increase the solubility. The eutectic
system enhances the drug delivery through the skin due to proper solubilization and 52

maximizing the thermodynamic activity of the drug.


h. Solid-Lipid Nanoparticles (SLP):
These are nanosized (200-500nm) colloidal systems for drug delivery which delivers the across

the skin at higher concentration. These are useful for transdermal drug delivery of high molecular weight
substances like Vitamin A & E, glucocorticoids and DNA.

i. Prodrugs and ion-pair:
Prodrugs are the chemicals which generally, but not always are inactive in their native form and

converted to active form after administration in the body by metabolism. The metabolites of Prodrugs are
responsible for therapeutic action of the drug. Prodrugs are designed by modification in the structure of the drug
to get the desired property such as partitioning in the skin, dissolution, lipophilicity etc. The ionized drugs are
very less permeable through the skin as compared to unionized drugs. So ion pairs are formulated by adding
opposite charge to the ionic drugs to neutralize the charge of the drug. Now this ion pair can easily penetrated
and transported across the skin.

j. Medicated tattoos:
These are conventional tattoos loaded with a drug. The medicated tattoo is applied to clean and

dry skin as normal tattoo which delivers the drug to the skin. The duration of medicated tattoo is determined by
comparing the color of the applied tattoo with the color chart provided by the manufacturer. The fading of color
determines the time at which tattoo should be changed or removed.




k. Skin abrasion:
Skin abrasion involves the partial or complete removal of the upper layers of the

skin to increase the penetration of the drug molecules through the skin.
Microdermabrasion and microsccisoring are the processes which creates micro pores by
eroding the outer layers of the skin.
l. Crystal Reservoir System:

In this technology polymer is supersaturated with drug so partial crystallization
of drug takes place which deliver the drug through the skin at an enhanced rate.
Molecular solute and solid crystals are present together at this stage which modifies the
drug release kinetics from the polymer and drug absorption parameters from the skin.
But various skin related parameters should be kept in mind like skin thickness, skin
vascularity and age. Supersaturation technique delivers the excess drug so it may cause
toxicity when applied to children’s skin as their skin is thin and highly vascular as
compared to aged skin.




m. Enzymes: The application of enzymes on the skin surface before the application of drug
can increase the permeation rate across the skin. An enzyme hydrolyzes or metabolizes the
skin components and increases the fluidity. Various enzymes like phospholipase C,
triacylglycerol hydrolase, acid phosphatase and phospholipase A2 are applied to observe
their effect on skin penetration of drugs like benzoic acid, mannitol etc. Papain is known to
reversibly change the protein structure of the skin for delivery of high molecular weight
n. Follicular drug delivery: Drug formulations applied on the skin also absorbed through
hair follicles and sweat glands. Initially it was thought that only 0.1% of the drug is
absorbed through this route but the root of hair follicles reaches deeper into the skin layer
and provides a very high surface area so a significant amount of drug is absorbed through
hair follicles and sweat glands. Later it was investigated that skin acts as reservoir of drug
for short term only because of continuously replacement of dead cells of the skin but hair
follicles and sweat glands can provide a continuous supply of drug for more than 10 days as
their depletion occurs comparatively slow process of sebum production and hair growth.
This route is suitable for hydrophilic and high molecular weight drugs. 55



o. Lipid Synthesis Inhibitors:
The human skin is mainly composed of lipid components like cholesterol, free fatty

acids and ceramides and these are responsible for its barrier function. The inhibition of
skin lipids delays the recovery of skin damage caused by the penetration enhancers. So
these lipid inhibitors mainly boost the action of other penetration enhancers like
DMSO, acetone.
p. Phospholipids:

The phospholipid derivatives containing hydrophobic groups can acts as strong
penetration enhancers for various drugs applied topically. E.g. Phosphotidyl choline
derivative increase the percutaneous absorption of erythromycin.





➢Various solvent such as chloroform, methanol, acetone, isopropanol are used

to prepare drug reservoir.

➢Plasticizers: Dibutylpthalate, propylene glycol added to provide flexibility and

reduce tensile strength.


➢Hold and protect the drug reservoir from exposure to atmosphere.

➢Avoid loss of drug.

➢They should a low moisture vapour transmission rate.

➢They must have optimal elasticity, flexibility and tensile strength.

➢Eg: Vinyl, polyethylene, polyester film and aluminum foil. 57




➢Protects the patch during storage.

➢The liner is removed prior to use.

➢Because the liner is in intimate contact with the TDDS, the liner should be

chemically inert.

➢Eg: Polyester foil, metalized laminates.


➢Eg: Polyisobutylenes and Silicones





• Polymer membrane permeation controlled TDD system

• Adhesive dispersion type system

• Polymer matrix drug dispersion-type

• Drug reservoir gradient-controlled TDDS

• Microreservoir dissolution controlled TDDS




▪ Polymer Membrane Permeation-Controlled TDD System:

➢In this system the drug reservoir is sandwiched between a drug-impermeable backing laminate and a rate-

controlling polymeric membrane.

➢The drug molecules are permitted to release only through the rate-controlling polymeric membrane.

➢Drug reservoir compartment –
•Dispersed on solid polymer matrix eg:polyisobutylene
•Suspended in unleachable viscous liquid medium eg: silicone fluid
• Dissolved in solvent-alkyl alcohol

➢Rate controlling membrane –
• Microporous, nonporous
eg: ethylene vinyl acetate copolymer

➢Adhesive layer –
• Thin layer of adhesive
• Drug compatible, hypo allergic
• eg: silicone adhesive




* CR – Drug concentration in the reservoir compartment.
* Km/r & Ka/m -Partition coefficient of the drug molecule from reservoir to the membrane &
from membrane to adhesive.
* Dm & Da -Diffusion coefficients in the rate controlling membrane and in adhesive layer.
* hm & ha -Thickness of rate controlling membrane and adhesive layer.

Eg: Transderm-Nitro system once-a-day angina pectoris.
Transderm-Scop system for 3-day protection of motion sickness.




Fabrication of drug reservoir compartment :

Drug solids Drug solids

Dispersed homogeneously Dispersed homogeneously
in a solid polymer matrix in a solid polymer matrix
Eg – Polyisobutylene Eg – Polyisobutylene

Homogenous dispersion Homogenous dispersion

Suspended in a unleachable, Dissolved in a
Viscous liquid medium releasable solvent
E.g – Silicone fluid E.G – Alkyl alcohol

Paste like suspension Clear drug solution




❑ Adhesive dispersion type system :

➢In this approach the drug reservoir is formed by homogeneously dispersing the drug solids in a

hydrophilic or lipophilic polymer matrix (silicone elastomers, polyurethanes, polyvinyl alcohol),

medicated polymer formed is then molded into medicated disks with a defined surface area and

controlled thickness.

➢This drug reservoir-containing polymer disk is then mounted onto an occlusive baseplate in a

compartment fabricated from a drug-impermeable plastic backing.

➢In this system the adhesive polymer is applied along the circumference of the patch to form a strip of

adhesive rim surrounding the medicated disk.

➢The rate of drug release from this polymer matrix drug dispersion-type TDD system is defined as




oLd – Drug loading dose initially dispersed in polymer matrix.
oCp & Dp – Solubility and diffusivity of drug in matrix.




❑ Polymer matrix drug dispersion-type:

➢Dispersing the drug in a pressure-sensitive adhesive polymer,

e.g.polyacrylate and then coating the drug dispersed adhesive polymer by

solvent casting or hot melt Onto a flat sheet of a drug-impermeable backing

laminate to form a single layer of drug reservoir.

➢This yields a thinner and/or smaller TDD patch.





➢Polymer matrix drug dispersion-type TDD systems can be modified, drug

reservoir- drug loading level is varied in an incremental manner, forming a

gradient of drug reservoir along the diffusional path across the multi laminate

adhesive layers.




➢ Eg: Nitroglycerin-releasing TDD system, the Deponit system

➢The rate of drug release from this type of drug reservoir gradient-

controlled TDD system can be expressed by

ha(t) – thickness of the adhesive layer for drug molecule diffuse
increases with time.





➢This type of drug delivery system can be considered a hybrid of the reservoir-

and matrix dispersion-type drug delivery systems.




In this approach the drug reservoir
formed by

First suspending the drug solids

Water-miscible drug solubilizer e.g., polyethylene glycol

Homogeneously dispersing the drug suspension, with controlled aqueous solubility, in a lipophilic polymer
by high shear

mechanical force

Form thousands of unleachable microscopic drug reservoirs.

Thermodynamically unstable dispersion is quickly stabilized

by immediately

Cross-linking the polymer chains in situ, which produces a medicated polymer disk with a constant surface

area, fixed thickness

TDD system is then produced by mounting the medicated disk at the center of an adhesive pad. 69



➢The rate of drug release from a microreservoir drug delivery system is defined by

❖B -Ratio of the drug concentration at the inner edge of the interfacial barrier over the

drug solubility in the polymer matrix.

❖Kl, Km, Kp -Partition coefficient for interfacial partitioning of drug from the liquid

compartment to the polymer matrix, from polymer matrix to the polymer coating

membrane, from the polymer coating membrane to the elution solution.

❖Dl, Dp, Ds -Drug diffusivities in the liquid compartment, polymer coating membrane,

and elution solution.

❖Sl, Sp – Solubilities of the drug in the liquid compartment & in the polymer matrix.




❖a – ratio of drug concentration in bulk of elution solution over drug solubility in the

same medium.

❖b – ratio of drug concentration at the outer edge of the polymer coating membrane

over the drug solubility in same polymer.

❖hi-Thickness of the liquid layer surrounding the drug particles,

❖hp -Thickness of polymer coating membrane surrounding the polymer matrix,

❖hd -Thickness of hydrodynamic diffusion layer surrounding the polymer coating

membrane, respectively.

➢Eg: Combination of a potent progestin and a natural estrogen at different daily dosage

rates for weekly fertility regulation in females .




These evaluation are predictive of transdermal dosage form and it classified into following :

I. Physicochemical evaluation


➢Weight uniformity

➢Folding endurance

➢Percentage moisture content

➢Percentage moisture uptake

➢Drug content determination

➢Content uniformity test


➢Tensile strength

➢Evaluation of adhesive



➢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.

➢Weight uniformity:

❖The prepared patches are to be dried at 60°C for 4h before testing.

❖A specified area of patch is to be cut in different parts of the patch and weighed in a

digital balance.

❖The average weight and standard deviation values are to be calculated from the

individual weights.



➢Folding endurance

❖It determines the folding capacity of film.

❖A strip of the specific area is to be cut evenly and repeatedly folded at the same place till it


❖The number of times the film can be folded at the same place without breaking gives the value

of the folding endurance.

➢Percentage moisture content

❖The prepared films are to be weighed individually and are to be kept in a desiccator containing

fused calcium chloride at room temperature for 24hr.

❖After 24hr, the films are to be reweighed to determine the percentage moisture content.


Percentage moisture content = Initial weight – Final weight ×100

Final weight 74



➢Percentage moisture uptake:

❖The weighed films are to be kept in a desiccator at room temperature for 24hr, which

contains saturated solution of potassium chloride in order to maintain 84% RH.

❖After 24hr, the films are to be reweighed to determine the percentage moisture

uptake from the below mentioned formula:

Percentage moisture uptake = Final weight -Initial weight ×100

Initial weight




➢Drug content determination:

Accurately weighed portion of film (100mg) is dissolved in 100ml
of suitable solvent & shaken continuously for 24 hr, then sonicated

After sonication and subsequent filtration, drug in solution is
estimated spectrophotometrically by appropriate dilution




➢Content uniformity test:

10 patches are selected and content is determined for individual
patches. If 9 out of 10 patches have content between 85% to 115%
of specified value, patches pass the test.

If 3 patches range 75% to 125%, then additional 20 patches are
tested .If these 20 patches have range 85% – 115%,then patches
pass the test.





❖A transdermal patch should possess a smooth surface and should not constrict with time. This can be

demonstrated with flatness study.

❖For flatness determination, one strip is cut from the centre and two from each side of patches.

❖The length of each strip is measured and variation in length is measured by determining percent


❖Zero percent constriction is equivalent to 100 percent flatness.

❖% constriction = L1 –L2 X 100


L2= Final length of each strip

L1 = Initial length of each strip




➢Tensile strength:

❖To determine tensile strength, polymeric films are sandwiched separately by corked linear iron


❖One end of the films is kept fixed with the help of an iron screen and other end is connected to

a freely movable thread over a pulley.

❖The weights are added gradually to the pan attached with the hanging end of the thread.

❖A pointer on the thread is used to measure the elongation of the film.

❖The weight just sufficient to break the film is noted.




Tensile strength = F 1 + L

a x b l

F– Force required to break

a- Width of film; b- thickness of film

L- Length of film

l- Elongation of film at break point




Evaluation of adhesive:

a. Peel adhesion test

b. Tack properties

b.1 Thumb tack test

b.2 Probe tack test

b.2 Rolling ball test

b.3 Quick stick (Peel tack) test

a. Peel adhesion test

➢In this test, the force required to remove an adhesive coating from a test

substrate is referred to as peel adhesion.



➢Molecular weight of the adhesive polymer, and amount of additives are the variables

that determine the peel adhesion properties.

➢A single tape is applied to a stainless steel plate or a backing membrane of choice and

then the tape is pulled from the substrate at a 180º angle, and the force required for tape

removal is measured.




b. Tack properties:
➢It is the ability of the polymer to adhere to substrate with little contact pressure.
Tack is dependent on molecular weight and composition of polymer.
b.1 Thumb tack test:
➢It is a qualitative test.
➢The force required to remove thumb from adhesive is a measure of tack.
b.2 Probe tack test
➢Force required to pull a probe away from an adhesive at a fixed rate is recorded as




b.3 Rolling ball test

➢This test involves measurement of the distance that stainless steel ball travels along an

upward facing adhesive.

➢The less tacky the adhesive, the further the ball will travel.

b.4 Quick stick (Peel tack) test

➢The peel force required required the bond between an adhesive and substrate is measured

by pulling the tape away from the substrate at 90 at the speed of 12 inch/min.




In vitro drug release studies:

➢The Paddle over disc method (USP apparatus V) can be employed for assessment of the release of

the drug from the prepared patches.

➢Dry films of known thickness are to be cut into a definite shape, weighed and fixed over a glass

plate with an adhesive.

➢The glass plate was then placed in 900mL of the dissolution medium or phosphate buffer (pH 7.4),

and the apparatus was equilibrated to 32 ± 0.5°C.

➢The paddle was then set at a distance of 2.5 cm from the glass plate and operated at a speed of 25-

50 rpm. Samples (5-mL aliquots) can be withdrawn at appropriate time intervals up to 24 hr and

analyzed by a UV spectrophotometer or HPLC. The experiment is to be performed in triplicate, and

the mean value can be calculated.




➢The paddle was then set at a distance of 2.5 cm from the glass plate and operated at a speed of 50

rpm. Samples (5-mL aliquots) can be withdrawn at appropriate time intervals up to 24 h and analyzed

by a UV spectrophotometer or HPLC.

➢The experiment is to be performed in triplicate, and the mean value can be calculated.




In vitro skin permeation studies:
➢An in vitro permeation study can be carried out by using diffusion cells (Franz
diffusion cell).
➢Membrane prep: Full-thickness abdominal skin of male Wistar rats weighing 200–
250 g was selected.
➢Hair from the abdominal region is to be removed carefully by using a electric clipper
.The dermal side of the skin was thoroughly cleaned with distilled water to remove any
adhering tissues or blood vessels
➢Condition: Equilibrated for 1 hr in dissolution medium or phosphate buffer pH 7.4
before starting the experiment and was placed on a magnetic stirrer with a small
magnetic needle for uniform distribution.
➢The temperature of the cell was maintained at 32 ± 0.5°C using a thermostatically
controlled heater.




➢The isolated rat skin piece is to be mounted between the compartments of the diffusion

cell, with the epidermis facing upward into the donor compartment(prepared film).

➢Definite volume of sample is to be removed from the receptor compartment at regular

intervals, and an equal volume of fresh medium is to be replaced.

➢Samples are to be filtered through the filtering medium, and can be analyzed

spectrophotometrically06o11r 4b0y1 3u3s4i4ng HPLC.







➢ ChienY.W.Novel drug delivery system.Second edition.50. New york :Marcel


➢ Joseph R. Robinson, Vincent H. L. Lee.Controlled Drug Delivery.Second edition.

New york :Marcel Dekkar,inc;p.523-552.

➢Y Madhusudan Rao, A V Jithan.Advances in Drug Delivery.Volume-II.p.1-49

➢ Vyas SP, Khar Roop K. Transdermal drug delivery. In: Jain MK, editor. Controlled
Drug Delivery: Concepts and Advances, 2nd ed. New Delhi: Vallabh Prakashan;
2012. p. 397-33.




➢Novel Drug Delivery by N.K.Jain

➢Transdermal drug delivery by Mark R.Prausnitz and Robert Langer

➢Skin structure and skin barrier by Sarankumar Das