TOPICAL ADMINISTRATION:
• MUCOSAL MEMBRANES(eye drops, antiseptic, sunscreen, nasal, etc.)
•SKIN a. Dermal - rubbing in of oil or ointment
(local action)
b. Transdermal - absorption of drug through skin (systemic
action) i. stable blood levels
ii. no first pass metabolism iii. drug must be potent . 04/21/23 2 L9-10
Skin consist of three layersSkin consist of three layers ::
EpidermisEpidermisDermisDermis
Subcutaneous fat tissueSubcutaneous fat tissueThe main route for the penetration of the The main route for the penetration of the
drugs is generally through epidermal drugs is generally through epidermal layerlayer
Stratum corneum is the rate limiting Stratum corneum is the rate limiting barrier in passive percutaneous barrier in passive percutaneous absorption of drugabsorption of drug..
04/21/23 3 L9-10
Transdermal drug delivery systems
are designed to support the
passage of drug substances from
the surface of the skin, through its
various layers, and into the
systemic circulation,
offering a more sophisticated
and more reliable means of
administering drug through
the skin.
TRANSDERMAL DRUG DELIVERY SYSTEMS
1. Avoids gastrointestinal drug
absorption difficulties caused by
gastrointestinal pH, enzymatic
activity, drug interactions with
food, drink, or other orally
administered drugs.
2. Substitutes for oral administration
in cases of vomiting and/or
diarrhea.
3. Avoids first-pass effect avoiding
the drug's deactivation by digestive
and liver enzymes.
ADVANTAGES OF TRANSDERMAL DRUG DELIVERY SYSTEMS:ADVANTAGES OF TRANSDERMAL DRUG DELIVERY SYSTEMS:
4. Avoids the risks of parenteral therapy.
5. Provides the capacity for multiday therapy with a
single application.
6. Provides capacity to terminate drug effect rapidly.
7. Provides ease and rapid administration of the
medication in emergencies.
Disadvantages of transdermal drug delivery Disadvantages of transdermal drug delivery
systems:systems:
1. The transdermal route of administration is
unsuitable for drugs that irritate or sensitize the
skin.
2. Only relatively potent drugs are suitable for
transdermal delivery due to the natural limits of
drug entry by the skin's impermeability.
3. Technical difficulties with the adhesion of the
systems to different skin types and under various
environmental conditions.
The Skin The Skin
The skin has a wide variety of functions:The skin has a wide variety of functions:
Protect the organism from water loss and Protect the organism from water loss and
mechanical, chemical, microbial, and physical mechanical, chemical, microbial, and physical
influences. influences.
Structure of the SkinStructure of the SkinThe skin is the largest human organ and is composed of:The skin is the largest human organ and is composed of:
A film of emulsified material present upon the surface of A film of emulsified material present upon the surface of
the skin composed of a complex mixture of sebum, sweat.the skin composed of a complex mixture of sebum, sweat.
Three functional layers: Three functional layers:
Epidermis, Epidermis,
Dermis (true skin) Dermis (true skin) Hypodermis Hypodermis (Subcutaneous fat layer).(Subcutaneous fat layer).
Blood capillaries and Blood capillaries and
nerve fibers.nerve fibers.
Sweat glands.Sweat glands.
Hair follicles. Hair follicles.
04/21/23 10 L9-10
The epidermis is the outermost layer of the skinThe epidermis is the outermost layer of the skin
0.02 to 5 mm thickness 0.02 to 5 mm thickness
It has five layers,It has five layers,
o Barrier layer (stratum germinativum).Barrier layer (stratum germinativum).
Beneath the hornylayerBeneath the hornylayer
Composed of living epidermal cells.Composed of living epidermal cells.
o Horny layer Horny layer
(stratum corneum).(stratum corneum).
The uppermost layerThe uppermost layer
Composed of dead epidermal cells forms the permeability barrierComposed of dead epidermal cells forms the permeability barrier
The stratum corneum consists of:The stratum corneum consists of:
Horny skin cells (corneocytes) which are connected Horny skin cells (corneocytes) which are connected
via protein-rich attachments of the cell membrane.via protein-rich attachments of the cell membrane.
The corneocytes are embedded in a lipid matrix in The corneocytes are embedded in a lipid matrix in
““Brick and mortarBrick and mortar” structure.” structure.
The corneocytes of hydrated keratin comprise the The corneocytes of hydrated keratin comprise the
bricks and the epidermal lipids fill the space bricks and the epidermal lipids fill the space
between the dead cells like mortar.between the dead cells like mortar.
Routes of skin PenetrationRoutes of skin Penetration
Include transport via:Include transport via:
1-1- Hair follicles and sebaceous Hair follicles and sebaceous
glands glands
2-2- Sweat glandsSweat glands
1 2
These routes avoid penetration through the stratum These routes avoid penetration through the stratum
corneum and therefore known as corneum and therefore known as shunt routesshunt routes. .
These routes avoid penetration through the stratum These routes avoid penetration through the stratum
corneum and therefore known as corneum and therefore known as shunt routesshunt routes. .
The Transappendageal route:The Transappendageal route:The Transappendageal route:The Transappendageal route:
There are two diffusional routes to penetrate intact skinThere are two diffusional routes to penetrate intact skin::
1 2
Although these routes offer high permeability, they are of Although these routes offer high permeability, they are of
minor importance because of their relatively small area, minor importance because of their relatively small area,
0.1% of the total skin area. 0.1% of the total skin area.
The transappendageal route The transappendageal route
seems to be most important for seems to be most important for
ions and large polar molecules ions and large polar molecules
which hardly permeate through which hardly permeate through
the stratum corneum.the stratum corneum.
The transappendageal route The transappendageal route
seems to be most important for seems to be most important for
ions and large polar molecules ions and large polar molecules
which hardly permeate through which hardly permeate through
the stratum corneum.the stratum corneum.
Transepidermal transport Transepidermal transport
means that molecules cross means that molecules cross
the intact horny layer. the intact horny layer.
The The tra
nsepidermal ro
ute :
transepiderm
al route :
The The tra
nsepidermal ro
ute :
transepiderm
al route :
Two potential micro-routes are existTwo potential micro-routes are exist
The transcellular (or intracellular) rout.The transcellular (or intracellular) rout.
The intercellular pathways. The intercellular pathways.
The principal pathway taken by The principal pathway taken by
drugs is decided by its partition drugs is decided by its partition
coefficient. coefficient.
Hydrophilic drugs partition into the intracellular pathways, Hydrophilic drugs partition into the intracellular pathways,
whereas lipophilic drugs traverse the stratum corneum via whereas lipophilic drugs traverse the stratum corneum via
the intercellular route.the intercellular route.
Factors Affecting Percutaneous AbsorptionFactors Affecting Percutaneous Absorption
Factors concerning the nature of the drug Factors concerning the nature of the drug
Factors concerning the nature of the vehicleFactors concerning the nature of the vehicle
Factors concerning the condition of the skinFactors concerning the condition of the skin
Percutaneous absorptionPercutaneous absorption is the absorption of substances is the absorption of substances
from outside the skin to positions beneath the skin, from outside the skin to positions beneath the skin,
including entrance into the blood stream.including entrance into the blood stream.
1.1. Drug concentration Percutaneous absorption Drug concentration Percutaneous absorption
2.2. Drug partition coefficient (greater attraction to the skin Drug partition coefficient (greater attraction to the skin
than to the vehicle) Percutaneous absorptionthan to the vehicle) Percutaneous absorption
3.3. Molecular weight below 800 Molecular weight below 800
Percutaneous absorptionPercutaneous absorption
4.4. Particle SizeParticle Size
Percutaneous absorptionPercutaneous absorption
5. Solubility in mineral oil and water5. Solubility in mineral oil and water
Percutaneous absorptionPercutaneous absorption
Factors concerning the nature of the drug Factors concerning the nature of the drug
1.1. Spreadability of the vehicle Spreadability of the vehicle
Percutaneous absorptionPercutaneous absorption
2.2. Mixing with the sebum Mixing with the sebum
Percutaneous absorptionPercutaneous absorption
3.3. Hydration of the skin Percutaneous absorption Hydration of the skin Percutaneous absorption
Oleaginous vehicles act as moisture barriers through Oleaginous vehicles act as moisture barriers through
which the sweat from the skin cannot pass, thus which the sweat from the skin cannot pass, thus
increased hydration of the skin beneath the vehicle and increased hydration of the skin beneath the vehicle and
increase Percutaneous absorption.increase Percutaneous absorption.
Factors concerning the nature of the vehicleFactors concerning the nature of the vehicle
Factors concerning the condition of the skinFactors concerning the condition of the skin
Transdermal absorption follow Transdermal absorption follow Fick’s First LawFick’s First Law of of DiffusionDiffusion
Js = Js = Km D CsKm D Cs
EE
Js = Flux of solute through the skinJs = Flux of solute through the skin
Km = Distribution coefficient of drug between Km = Distribution coefficient of drug between vehicle and vehicle and
stratum corneumstratum corneum
Cs = Concentration difference of solute across the Cs = Concentration difference of solute across the
membranemembrane
D = Membrane Diffusion coefficient for drug in D = Membrane Diffusion coefficient for drug in stratum stratum
corneumcorneum
E = Thickness of stratum corneum E = Thickness of stratum corneum
1.1. The thickness stratum corneum The thickness stratum corneum
Percutaneous absorptionPercutaneous absorption
2.2. Multiple application dosing Multiple application dosing
Percutaneous absorption than single Application Percutaneous absorption than single Application
3.3. Time of contact with the skin Time of contact with the skin
Percutaneous Percutaneous
absorptionabsorption
4.4. Broken skin permit (remove of the stratum corneum) Broken skin permit (remove of the stratum corneum)
Percutaneous absorptionPercutaneous absorption
Percutaneous Absorption Enhancers
Mechanisms of action by which Materials enhance Mechanisms of action by which Materials enhance
absorption through stratum corneum is either by absorption through stratum corneum is either by
Enhancing drug release from the formulation to the skin. Enhancing drug release from the formulation to the skin.
Reduction of the resistance of the stratum corneum by Reduction of the resistance of the stratum corneum by
altering it physicochemical propertiesaltering it physicochemical properties
Alteration of the hydration of the stratum Alteration of the hydration of the stratum
corneum using occlusive formulations.corneum using occlusive formulations.
Carrier mechanisms in the transport of ionisable Carrier mechanisms in the transport of ionisable
drugs. drugs.
Enhance absorption by directly Enhance absorption by directly
influencing influencing
the stratum corneum the stratum corneum
(CHEMICALLY or PHYSICALLY).(CHEMICALLY or PHYSICALLY).
This can be achieved by the following This can be achieved by the following mechanisms:mechanisms:
Chemicals used to enhance absorption by directly Chemicals used to enhance absorption by directly
influencing the stratum corneuminfluencing the stratum corneum
Chemicals interact with the keratin structure in the stratum Chemicals interact with the keratin structure in the stratum
corneum and open the tight protein structure, this leads corneum and open the tight protein structure, this leads
increase the diffusion coefficient D for substances which use increase the diffusion coefficient D for substances which use
the transcellular route: the transcellular route:
Surfactants, Dimethylsulfoxide (DMSO)Surfactants, Dimethylsulfoxide (DMSO) and Urea.
Solvents extract lipids and making the stratum corneum more Solvents extract lipids and making the stratum corneum more
permeable: permeable: Dimethylsulfoxide (DMSO) and Ethanol.Dimethylsulfoxide (DMSO) and Ethanol.
Chemical enhancers which intercalate into the structured Chemical enhancers which intercalate into the structured
lipids of the horny layer and disrupt the packing. Thus lipids of the horny layer and disrupt the packing. Thus
make the regular structure more fluid and increases the make the regular structure more fluid and increases the
diffusion coefficient of drugs: diffusion coefficient of drugs:
Azone, Oleic acid, and isopropyl myristateAzone, Oleic acid, and isopropyl myristate
Solvents increase solubility and improve partitioning:Solvents increase solubility and improve partitioning:
Alcohol, acetone, polyethylene and propylene glycolAlcohol, acetone, polyethylene and propylene glycol
Physical methods can enhance drug flux up to several
orders of magnitude above that allowed by passive
diffusion (as conventional skin patches).
The effective delivery range for passive diffusion
across the skin is limited to small, hydrophobic
agents,
However, Physical delivery can be used for larger
hydrophilic molecules as peptide drug
administration.
IONTOPHORESISA physical method to enhance transdermal drug
delivery
and penetration.
It involves the delivery of charged chemical compounds
across the skin membrane using an applied electrical
field.
Mechanisms of TransportIontophoresis uses two electrodes, the
anode and the cathode, each of which is
in contact with a reservoir containing
the drug to be delivered as an
electrically conductive aqueous solution.
The reservoir containing the drug is in contact with the
electrode of the same charge which is (the active
electrode), while the other electrode named (passive
electrode).
An electrical potential is applied across the electrodes,
causing current to flow across the skin and facilitating
delivery of the therapeutic agent by repulsion.
Schematic of iontophoretic drug delivery system shows delivery of an anionic agent from the cathodal reservoir. The agent goes through the non vascularized epidermis
and into the dermis, where it can be transported into the blood through
the capillary loops.
Cathode
Blood
Dermis
Cl-,anionsAnionic drug delivered
Indifferent electrode Donor + anionic drug
+ -
Epidermis
Anode
V
Variables affecting iontophoresis:
The electrical current.
Which may be direct, alternate or pulsed
Biological factors:
Involve the presence of thickness,
permeability and porous of the skin.
Physicochemical factors:
Include charge, size, structure and lipophilicity of
the drug with small or large molecular size.
The drug should be water soluble, of low dose and
ionizable with high charge density.
Formulation factors:
Include dug concentration, pH, ionic strength and
viscosity.
Increasing drug concentration results in greater drug
delivery.
The inclusion of buffer ions in a formula will compete
with the drug for the delivery current and decrease
the quantity of drug delivered, especially since buffer
ions are smaller and more mobile than the large
active drug. The pH of the solution can be adjusted
and maintained by large molecules as ethanolamine :
ethanolamine HCL.
An increase in the ionic strength of the system will
increase the competition for the available current
especially when the active drugs are potent and
present in small concentration.
They are also poorly
absorbed from the
transdermal route, because
of their large molecular size,
ionic character, and
impenetrability of the skin.
A number of drugs have been used including,
lidocaine, amino acids, peptides and insulin.
These agents are presently delivered by injection,
because of their rapid metabolism and poor
absorption following oral delivery.
SONOPHORESIS
Sonophoresis (Phonophoresis)
in which High-frequency ultrasound,
is used to enhance transdermal drug delivery.
Among the drugs used are hydrocortisone, lidocaine,
and salicyclic acid in the form of gels, creams, e lotions
(coupling agents) followed by ultrasound unit.
The high-frequency ultrasound (1 MHZ at 0.5 to 1
W/cm2) can disrupt the stratum corneum which
influence the integrity of and thus affect its
penetrability.
Involves the formation and
collapse of very small air bubbles
in a liquid in contact with
ultrasound waves.
These air bubbles can disperse the
ultrasound waves resulting in
heating at the liquid air interfaces.
Three effects are results from ultrasound
include:
Cavitation, microstreaming and heat generation.
Cavitation:
Micro-streaming:
Closely associated with cavitation results in efficient
mixing by inducing vortexes (currents) in small
volume elements of a liquid, this may enhance
dissolution of suspended drug particles results in s
higher concentration of drug near the skin for
absorption.
Heat generation:
Heat results from the conversion of ultrasound energy
to heat energy and can occur at the surface of the
skin and deeper layers of the skin.
The vehicle containing the drug must be formulated to
provide good conduction of the ultrasonic energy to
the skin.
The product must be smooth and non-gritty as they
will be rubbed into the skin by the head of the
transducer.
The product should have low viscosity for easy of
application and easy of movement of the transducer
(as gels).
Emulsions can be used but the oil/ water interfaces
can disperse the ultrasonic waves, resulting in a
reduction of the intensity of the energy reaching
the skin. It may case some localized heat.
There are two basic types of transdermal
dosing systems:
Those that control the rate of drug released to
the skin.
Those that allow the skin to control the rate of
drug absorption.
Drug delivery systems have been developed to
control the rate of drug delivery to the skin over a
period of time for subsequent absorption.
Requirements for rate-controlling
transdermal
drug delivery systems:
l. Deliver the drug substances at a controlled
rate, to the intact skin of patients, for
absorption into the systemic circulation.
2. The system should possess the proper
physicochemical characteristics to permit the
release of the drug substance and facilitate its
partition from the delivery system into the stratum
corneum.
3. The system should occlude the skin to ensure
the one-way flux of the drug substance.
4. The transdermal system
should have a therapeutic
advantage over other dosage
forms and drug delivery
systems.
5. The system's adhesive,
vehicle, and active agent
should be nonirritating and
non-sensitizing to the skin of
the patient.
6. The patch should adhere well
to the patient's skin.
7. The system should not permit
the proliferation of skin
bacteria beneath the
occlusion.
Technology of Transdermal Delivery
Patches
Technically, transdermal drug delivery systems may
be categorized into two types:
Monolithic systems
membrane-controlled systemsMonolithic system
Membrane-controlled Membrane-controlled
systemsystem
The drug-matrix layer is
composed of a polymeric
material in which the
drug is dispersed.
The polymer matrix
controls the rate at
which the drug is
released for
percutaneous
absorption.
Monolithic Transdermal
Patches
Incorporate a drug matrix layer between backing and
frontal layers.
NicoDerm® CQ® nicotine transdermal system
Designed to contain a drug reservoir,
usually in liquid or gel form, a rate-
controlling membrane, and backing,
adhesive, and protecting layers.
Examples are Transderm-Nitro (Summit) and
Transderm-Scop (CIBA)
and levonorgestrel/estradiol
for hormonal contraception.
Membrane-controlled Transdermal
Patches
Polymer
membrane permeation-controlled
TDDS
Figure: 1 Polymer membrane permeation-controlled TDDS
•TransdermScop (Scopolamine) for 3 days protection of motion sickness and TransdermNitr(Nitroglycerine)
for once a day medication of angina pectoris.
Adhesive diffusion controlled TDDS
Figure: 2 Adhesive diffusion controlled TDDS
Deponit (Nitroglycerine) for once a day medication ofangina pectoris.
Matrix diffusion controlled TDDS
Figure: 3 Matrix diffusion controlled TDDS
Nitro Dur (Nitroglycerine) used for once a day medication of angina pectoris.
Microreservoir controlled TDDS
Figure 4: Microreservoir controlled TDDS
Nitro- dur® System (Nitroglycerin) for once a daytreatment of angina pectoris.
Basic Components of TDDS •Polymer matrix / Drug reservoir •Drug •Permeation enhancers •Pressure sensitive adhesive (PSA) •Backing laminates •Release liner •Other excipients like plasticizers and
solvents
Formulation of TDDS
The Polymer controls the release of the drug from the device.
Possible useful polymers for transdermal devices are:
A-Natural Polymers: e.g. Cellulose derivatives, Gelatin, Shellac, Waxes, Proteins, Gums and their derivatives, Natural rubber, Starch.
B- Synthetic Elastomers: e.g. Polybutadieine, Styrene butadieine, Polysiloxane, Silicone rubber, Acrylonitrile, Butyl rubber, Neoprene.
C- Synthetic Polymers: e.g. Polyvinyl alcohol, Polyvinyl chloride, Polyacrylate, Polyvinylpyrrolidone, Polymethylmethacrylate, Epoxy.
The matrix may be with or without an excess of drug
with regard to its equilibrium solubility and
steady-state concentration gradient at the stratum
corneum.
In types having no excess, drug is available to
maintain the saturation of the stratum corneum
only as long as the level of drug in the device
exceeds the solubility limit of the stratum
corneum.
As the concentration of drug in the device
diminishes below the skin's saturation limit, the
transport of drug from device to skin gradually
declines.
In monolithic systems that have an excess amount
of drug present in the matrix, a drug reserve is
present to assure continued drug saturation at the
stratum corneum, this assures continuous drug
availability and absorption.
The rate of drug decline is less than in the type
designed with no drug reserve.
Examples of monolithic systems are NitroDur
(Key) and Nitrodisc (Searle).
In the preparation of monolithic systems, the drug
and the
polymer are dissolved or blended together, cast as
the
matrix, and dried.
The gelled matrix may be produced in sheet or
cylindrical
form, with individual dosage units cut and
assembled
between the backing and frontal layers.
Membrane-controlled systems have the advantage
over
monolithic systems:
As the drug solution in the reservoir remains
saturated, the release rate of drug through the
controlling membrane remains constant.
In membrane systems, a small quantity of drug is
frequently placed in the adhesive layer to initiate
prompt drug absorption and pharmaco-therapeutic
effects upon skin placement.
Membrane controlled systems may be prepared by
preconstructing the delivery unit, filling the drug
reservoir, and sealing, or by a process of lamination,
which involves a continuous process of construction,
dosing, and sealing.
General Considerations in the proper Use
of Transdermal Drug Delivery Patches:
1.The site for application should be clean, dry, and
hairless (but not shaved).
Nitroglycerin patches are generally applied
to the chest, estradiol to the abdomen,
scopolamine behind the ear,
nicotine to the upper trunk or upper outer arm for
smoking cessation.
Because of the possible of skin irritation, the site
of application must be rotated, that skin sites must
not reused for a week.
2. The transdermal patch should not be applied to
skin that is oily, irritated, cut or abraded to assure
the intended amount and rate of transdermal drug
delivery and absorption.
3. The patch should be removed from its protective
package, being careful not to tear or cut it. The
patch's protective backing should be removed to
expose the adhesive layer, and it should be applied
firmly with the palm or heal of the hand until
securely in place.
4. The patient should be instructed to cleanse the
hands before and after applying the patch.
5. Care should be taken not to rub the eyes or
touch the mouth during handling of the patch.
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