Transcript Transdermal Drug Delivery Systems

Transdermal Drug Delivery
Systems
Transdermal drug delivery system are
topically administered medicaments
in the form of patches that deliver drugs
for systemic effects at a predetermined
and controlled rate.
Advantages of TTS
1. Avoid first-pass effect in intestine and the acidic
environment of stomach
2. Transdermal systems are non-invasive and can be
self-administered.
3. They can provide release of drug for long periods of
time (up to one week) without dose dumping.
4. They can improve patient compliance since single
application is administered for several days
5. Easy removal or termination of the device if needed
6. Avoid risks and inconvenience of IV therapy
Limitation of TTS
1. Drug may be metabolized by bacteria on skin
surface since the hydration of skin can encourage
bacterial growth
2. Enzymatic activity to certain drug by skin enzymes.
3. Molecular size is critical (max size is 400D).
4. The slow transport of drug across skin limit this
approach for potent drugs (max conc. 20mg/day)
5. Skin pores may be blocked and cause problems
because of long term appliaction
The skin site for transdermal drug
administration
• Skin is one of the most accessible organs of human
body
• It has an average surface area of 2 m2 and few
millimeters in thickness
• It also receives one third of circulating blood
• Physiologically it serves as a barrier against physical
and chemical attacks and protects the vital organs
from microbial invasions
• It is function as first line of defense of human body
Anatomy of human skin
•
Skin is a multilayered organ composed of three
layers: epidermis, dermis and subcutaneous fat
1. Epidermis:
- The outerlayer of the skin, composed of
multilayered stratified squamous epithelial cells.
- It is non vascular but contain amino acids.
- Epidermis has varying thickness ranging from
very thin covering the eyelids to thickest on the
palms and soles
- Normal epidermis is renewed as it is worn off
Epidermis composed of two main parts:
1 - Stratum corneum ( Horny layer)
2 - The viable epidermis (stratum germinativum)
1. (Stratum corneum):
• The outermost layer of the epidermis
• Composed of many layers of compact flattened
dehydrated, keratinized cells in stratified layers
• Cells have lost their nuclei and are inactive
• Thickness is variable, dependent on abrasion and
pressure, swells several folds in water
• Cells are formed and replaced by migrating cells from
stratum germinativum about every 2 weeks in adults
• Composition: only 20% water, keratin, lipids
• Stratum corneum requires min. of 10% moisture
content to maintain softness and flexibility
• Considered as the main barrier for percutaneous
absorption
2. (Startum germinativum):
• Cells of the deepest layer of the epidermis that divide and
migrate upwards, as these migrate, the cells loose their
nucleus and give rise to the dead keratinized outmost layer
of the skin ( Stratum corneum)
• It is known as regenerative layer of the epidermis
• Contains 70% water content
• The germinativum zone to horny layer is made of three
layers:
1. Stratum spinosum (pricky layer),
2. Stratum granulosum (granular layer) and
3. Stratum lucidum (clear layer)
2. Dermis layer
Just below the epidermis
• Composition: it is made of network of collagen fibers of
uniform thickness
• It gives the skin its elasticity
• It is the vascular part of the skin, where it contains
blood vessels, lymphatics and nerve endings
• It is considered as the sink of the skin
• It also contains skin appendages (sweat glands,
sebaceuos glands and hair follicles)
3. Subcutaneous fat
Sheet of fat tissue attaching the dermis to underlying
structures,
It provide mechanical cushion and thermal insulator
The skin appendages
• Sweat glands: they aid in heat control and secrete sweat
• Hair follicles: develop all over the skin except the red
part of the lips, the palms and soles. One or more
sebaceous glands, and some times sweat glands open
into the follicle.
• Sebaceous glands: most numerous on the face,
forehead, in the ear. These produce sebum (principle
components are glycerides, free fatty acids, cholesterol,
cholesterol esters, wax esters and squalene).
Approaches to topical formulation
•
•
•
•
•
Surface treatment
Stratum corneum treatment
Skin appendages treatment: hyperhydrosis, Acne,
Depilatories
Viable epidermis and dermis: psoriasis,
anaesthetics, anti pruritics, Premalignant and
malignant tumours
Systemic treatment
Fundamentals of skin penetration
• Stratum corneum as skin permeation barrier
- The barrier can be viewed as three layers:
stratum corneum (15 µm thick), viable
epidermis (150 µm thick), the papillary layer
of the dermis (100-200 µm thick)
- The above structure is pierced in various
places by two types of shunts: sweat glands
and hair follicles
Routes for skin penetration
• There are 3 potential entry routes of drug to
the viable tissue (dermis):
1. Hair follicles and their associated
sebaceous glands,
2. Via the sweat ducts, or
3. Across the continuous stratum corneum
Routes of Skin Penetration
Skin appendages
• The average human skin contains 40-70 hair follicles
and 200-250 sweat ducts per square centimeter
• These only occupy 1% of the total cross sectional
area of the skin.
• Water soluble and large molecules can penetrate into
the skin via these appendages at a faster rate than
through the intact area of the stratum corneum
• Skin appendages may act as shunts at short time
period prior to steady state diffusion, nevertheless,
very limited contribution in the overall profile of skin
permeation
Epidermal route
• The main barrier is the stratum corneum
• Molecules may penetrate either intercellularly or
transcellularly.
• Molecules partition into and diffuse through the
network according to their polarity.
• The intercellular route is rich in neutral lipids
• The percutaneous absorption of drugs can be
considered as a series of three steps:
1.
Sorption of penetrant molecule onto the surface layers of
stratum corneum
2.
Diffusion through stratum corneum and the viable epidermis
3.
At the papillary layer of dermis, the molecule is taken up by
the capillaries for subsequent systemic absorption

The viable tissue layer and capillaries are relatively
permeable and rapid.

The rate limiting step is often diffusion through stratum
corneum.

In SC no active transport as the cells are dead, but only
simple passive diffusion.
Factors influencing penetration
1. Biological Factors
• Skin age
• Site of application
• State of the skin
• Hydration of the skin
• Ageing and environmental factors
2.Physicochemical Factors
• Drug/skin interactions: skin hydration, drug
binding
• Vehicle/skin interactions: vehicle effects
on skin hydration, effect of temperature,
penetration enhancers
• Drug vehicle interactions
Evaluation of transdermal drug delivery systems
In vitro drug release kinetics
• The release kinetics of drug from the TDDS technology can be
evaluated using a two compartment diffusion cell assembly.
• Cellophan membrane is mounted on a vertical diffusion cell such
as Franz diffusion cell.
• The skin permeation profile is followed by sampling the receptor
solution at predetermined time intervals until steady state is
reached.
In vitro skin permeation kinetics
• The release and skin permeation kinetics of drug from the TDDS
technology can be evaluated using a two compartment diffusion
cell assembly.
• Skin is mounted on a vertical Franz diffusion
• In vivo studies
A. Animal models
B. Human studies
Approaches to enhance skin permeability
1. Physical approach
a. Stripping of stratum corneum: SC is considered as
the main barrier for drug absorption, its removal
enhances drug permeation.
b. Hydration of SC: SC can be hydrated and the dense
structure of keratin opens up making permeation
easier. SC can be hydrated by occlusion with water
immiscible dressings
c. Iontophoresis: Iontophoresis passes a few milliamperes of current to a few square centimeters of
skin through the electrode placed in contact with the
formulation, which facilitates drug delivery across
the barrier.
2. Chemical approach
a. Synthesis of lipophilic prodrugs: a drug with
poor skin permeability may be chemically
modified to a prodrug with improved skin
permeation characteristics. After SC
permeation, the prodrug is transformed by the
metabolic processes within the skin tissue to
regenerate the active drug.
E.g. ester type prodrugs of Estradiol
b.. Skin permeability promoters (absorption enhancers):
 Are Substances that temporarily diminish the
impermeability of the skin.
 These should be safe and non toxic, pharmacologically
inert, non irritating, non allergenic.
 Their action must be immediate and once removed the
skin should immediately and fully recover to its normal
barrier properties.
 The enhancement should not cause loss of body fluids,
electrolytes or any endogenous material
 The mechanism of action of various skin permeability
promoters may be due to their activity on the lipophilic
lipid matrix and/or hydrophilic protein gel in stratum
corneum
Examples:
 Solvents:
a.
b.
c.
d.
Alcohols
Alkylmethylsulfoxide: DMSO, DMF, DMA
Azone,
Pyrrolidones (NMF): free fatty acids, urea
 Surfactants(non-ionic SAA)
 Others: Cyclodextrins, glycolate salts