Transdermal Drug Delivery

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Transdermal Drug Delivery

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Transdermal Drug Delivery Structure, Function & Topical treatment of Human Skin Anatomy & Physiology The epidermis 0.8 mm (Palms & soles) 0.006 mm eyelids. – PowerPoint PPT presentation

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Title: Transdermal Drug Delivery

1
Transdermal Drug Delivery
2
Structure, Function Topical treatment of Human
Skin

Anatomy Physiology

3
Drugs enter different layers of skin via
intramuscular, subcutaneous, or transdermal
delivery methods.
4

The epidermis
0.8 mm (Palms soles)
0.006 mm eyelids.
Stratum Germinativum divide migrate to produce
Stratum corneum or horny layer.
This permit to human to survive.
The dermis (corium) 3-5 mm thick
The subcutaneous tissue ( sibcutis, hypoderm)
(fat)

The skin appendages
The eccrine sweat glands (2-5 million)
produce sweat ..
Secrete drugs, proteins, antibodies antigens.
Emotional stress increase its secretion (clammy
palm syndrome)

6
An eccrine sweat gland most of the body's sweat
production is the result of eccrine gland activity
7

The aporine sweat glands
Develop at the pilosebaceous follicle in the
armpit.
Its milky or oily secretion may be colored
contains
Proteins, lipids, lipoproteins saccarides.
Bacteria metabolize this odorless secretion to
give the characteristic human smell.

8
An apocrine gland, which produces little sweat
but is responsible for the body's natural 'scent'

Hair follicles
Nails

Function of the Skin
I. Mechanical function
This depends on a correct balance of lipids,
water-soluble hygroscopic substances
(..)
Water.
The tissue requires 10 -20 of moisture to
maintain its suppleness.

Protective function
Microbiological barrier
Acid mantle ...
The following gland secretion have antibacterial
activity
..
...

Chemical barrier
The appendageal shunt route provide only a small
fractional area (0.1).
C. Radiational barrier
The UV light 290-400 nm is the most damaging.
Short irradiation produces
..
..
...

Chronic irradiation produces
..
..
Malignancy.
Sun damaged skin produces
..
..
..
..
...

Heat barrier temperature regulation
To conserve heat ...
To lose heat blood vessel dilate, eccrine sweat
glands pour out their dilute saline secretion,
water evaporates.
Electrical barrier
Dry skin has low conductivity
V. Mechanical shock

Rational approach to drug delivery to via the
skin
There are 3 main ways to manipulate the problem
of formulating a successful topical dosage form
For epidermal or surface treatment (i.e.
..)
For viable skin tissue ( without oral drugs)
For systemic treatment.

Dermatologists target the following skin regions
Skin surface
Horny layer
viable epidermis upper dermis
Skin glands systemic circulation. Fig
33.1-33.2

Surface treatment
(i.e. camouflage or cosmetic, deodorants, surface
antiseptic or antibiotics).
...
Stratum corneum (S.C.) treatment
(i.e. ..)
Skin appendages treatment
(i.e. ...)
Viable epidermis dermis treatment

Cream gels
Topical steroids
..
..
Topical 5-fluorouracil methotrexate eradicate
premalignant some malignant skin tumors,
...
Psoralens UVA therapy (PUVA) mitigate
psoriasis
5-amino-levulinic acid visible light
irradiation (photodynamic therapy) ...

Transcutaneous immunization
Vaccine Antigens developing transcutaneous
immunization ()
Systemic treatment via
Problems of this way
The body absorbs drugs
Drugs are lost by .

Drug Transport Through the Skin
Basic principles of diffusion through membranes
The diffusion process
Ficks Law of Diffusion
Fig 33.3

Complex Diffusional Barrier
Skin Transport
Relate the intrinsic properties of the skin with
the properties of the drug.
Routes of Penetration
Figure 33.1

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Sebum Surface Material (0.4-10 ?m)
It hardly affect the Transdermal absorption (TDA)
Skin Appendages (0.1 of the total available
area)
Acts before the steady state.

After the steady state is considered neglect.
Uses
Immunization (i.e. naked DNA in topical
application)
Anti hair loss of alkaloids of transgenic plant
()
Liposomes.
Usually
Molecules gt 10 ?m
Molecules around 3-10 ?m
Molecules lt 3 ?m .

Epidermal Route (stratum corneum)
Intracellular ?-route (bricks) s.c.
corneocytes, consisting of hydrated keratin
Intercellular ?-route (mortar) composed of
Lipid cholesterol ceramide ..etc.

Topically applied agents (steroids,
creseofulvin,..) form a depot by binding within
the stratum corneum.
Thus, psoriasis .
Viable layer (particularly the epidermis)
.
Dermis layer contains capillaries so the
residence time of a hydrophilic drug .
Dermis may bind lypophilic drugs ( testosterone)

Conclusions
S.c. is the rate limiting step.
The fraction of a drug that penetrates the skin
via any route depends on
Physicochemical nature of the drug (),
Timescale of observation,
,
,
How vehicle components temporarily change the
properties of the S.C.

Properties That influence Transdermal Delivery
Release of the drug
Penetration through
Activation of the .
Figure 33.4

Factors that complicate drug penetration
The non homogeneity of tissue

6.
7. Cell transport to through S.C
8.
9.
10. The drug emulsion components may modify
progressively the skin.

Factors that complicate the skin absorption
Biological factors
Physicochemical Factors.
Biological Factors
Skin Conditions
Chemicals solvents may open the complex dense
structure of the skin ().
Skin Age
gt permeable than adult tissue, but there
is no dramatic difference.

Permeability depends on
.
Plantar palmar Callus (400-600 ?m), while other
sites (10-20 ?m),
But permeability of plantar palmer is gt than
other sites.

Why Post Auricular skin was employed for the
administration of Hyoscine (scopolamine)?
a. Thinner skin
b. Less dens skin
c.
d.
e. .
Face skin is gtgt permeability than other sites.

Skin metabolism
About 5 of topical drugs can be metabolized by
the skin.
Species differences.
Physicochemical Factors such as
Skin Hydration
Moisturizers such .
Dryer such as .
Order of Occlusion
Plastic film of TD patch gt lipophilic ointment gt
W/O gt O/W creams. Table33-1

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Temperature pH
D ? T
Occlusive vehicles ?? T (few degree)
Regarding pH, .
Diffusion coefficient (D)
D of gases gt than D of liquids gt than D of
molecules in s.c. gt than D of solids.
D depends also on many intrinsic factors like
Binding (depot) of drugs to s.c. ? L

36
So, binding or gives L, therefore, in
order to see mgt 0 we have to saturate all
binding sites in s.c., thus the remaining drug
permeates starts to increase
37

Drug Concentration
Eq. 33,3
Partition coefficient (K)
K varies .
Triamcinolone systemic .
Triamcinolone topical .
Triamcinolone acetonide topical .
Of 23 esters of betamethasone tested, the
17-valerate has .

In the family of Hydrocortisone
Side chain lengthens from 0 to 6 C , ? K the
anti-inflammation activity.
For C gt than 6, K ?, while the anti-inflammations
index ?.
Maximizing solubility ? ? C but ? K, so it is
better to non over-solubilize the drug, if the
aim is to ? drug penetration.
Surface activity Micellization,
Effect of surfactant on skin
? interfacial tension ()
Changes
Disruption of intercellular lipid packing in the
s.c.

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Molecular size shape
Absorption depends on
.
All the above factors are difficult to be
evaluated.
Ideal Molecular Properties for Drug Penetration
A low MW (lt 600 Da) when D will tend to be ?
An adequate solubility in oil water
? melting point .
Nicotine Patches has all the above mentioned.

The nicotine patch is a type of transepidermal
patch designed to deliver nicotine, the addictive
substance contained in cigarettes, directly
through the skin and into the blood stream.
The drug leeches slowly out of the reservoir,
releasing small amounts of the drug at a constant
rate for up to 24 hours

Drug permeation through Skin
S.C. rate Controlling Step
Assumptions
S.C. ? the rate-limiting step
Skin is homogenous intact membrane
Appendages are unimportant
Only a single non-ionic drug species is
important, dissolving to form an ideal solution
unaffected by pH, dissolution is not rate
limiting
Only drug diffuse from the vehicle.
Formulation components neither diffuse nor
evaporate, skin secretions do not dilute the
vehicle

Diffusion coefficient is constant with time or
position in the vehicle or horny layer
Penetrant reaching viable tissue sweeps into the
circulation maintaining sink conditions below the
S.c
Donor phase depletes negligibly, i.e. constant
drug in the vehicle
Vehicle doesn't alter skin permeability during an
experiment (i.e. changing s.c. hydration or
acting as penetration enhancer)
Drug remains intact unaltered
Flux estimates are steady-state value.

S.C. not rate controlling
This happens in absence of s.c. (i.e. damaged
skin) or in the presence of TDS.
Here the release of the drug from the vehicle ?
the rate-limiting step the skin act as a sink.
Absorption from solution skin a perfect sink
Assumption
Only a single drug species is important, it is in
true solution, it is initial uniformly
distributed through the skin
Only the drug diffuses out of the vehicle.

Other components do not diffuse or evaporate
skin secretion do not pass into the vehicle.
The D does not alter with time or position within
the vehicle
When the penetrant reaches the skin, it absorbs
instantaneously.

46
Under these limitation eq. 33.9 represents the
relationship between m, the quantity of
drug released to the sink/unit of area Co, the
initial concentration of solute in the
vehicle Dv, the diffusion coefficient of the
drug in the vehicle, t, the time after
application. Fig 33.5, 33.6
47

Absorption from suspensions skin a perfect sink
Equation 33.11 is derived for a simple model
system under the following conditions
The suspended drug is micronized so that particle
? are ltlt than the vehicle
The particles are uniformly distributed do not
sediment in the vehicle
The total amount of drug, soluble suspended,
/unit volume (A) is much gtgt than Cs, the
solubility of the drug in the vehicle

d. The surface to which the vehicle is applied is
immiscible with the vehicle, i.e. skin secretions
do not enter the vehicle
e. Only the drug diffuses out of the vehicle
components neither diffuse nor evaporate
f. The receptor, Which is the skin, operates as a
perfect sink.

Methods for studying transdemal drug delivery
What is the drug flux through the skin how do
the apparent D, K, SARs control it?
What is the main penetration route-across the
s.c. or via the appendages?
Which is gt important clinically or
toxicologically-transient diffusion (possibly
down the appendages) or steady-state permeation
(usually across the intact s.c.)?
Does the drug bind to the s.c., the viable
epidermis?
Does it form a depot in the subcutaneous fat or
penetrate to the deep muscle layers?

6. What is the rate limiting step in
permeation-drug dissolution or diffusion within
the vehicle or patch partitioning into, or
diffusion through, the skin layers or removal by
the blood, lymph or tissue fluids?
7. How do skin condition, age, site, blood flow
metabolism affect topical bioavailability?
8. Are differences between animal species
important?
9. How do vehicles modify the release
absorption of the medicament?
10. What is the optimal formulation for a
specific drug-an aerosol spray, a solution,
suspension, gel, powder, ointment, cream, paste,
tape or delivery devices?

11. Are vehicle components inert, or do they
modify the permeability of the s.c., if only by
changing its hydration state?
12. To increase the drug flux, should we use
stratagems such as penetration enhancer,
iontophoresis?
13. Is the formulation designed correctly to
treat intact s.c., thickened epidermis or damaged
skin?
14. Should the experimental design produce a
pharmacokinetic profile, measuring absorption,
distribution, metabolism excretion in vivo?
No single method can answer all questions
provide a full picture of the complex process of
TD absorption.

In vitro methods
Excised skin
Fig 33.7, 33.8, 33.9
Artificial membranes
Release methods without a rate-limiting membrane
Fig 33.10, eq 33.9-33.14
However Exp. With animal cant fully substitute
for human studies.

In vitro method
Differences between human animal skins
.
The papillary blood supply biochemical aspects.

Few techniques produce Anima diseases similar to
human afflictions.
The Animal models are important for
a. Studying the anatomy, Physiology
biochemistry of the skin
b.
c.
d. Preliminary biopharmaceutical investigations.

I. Histology
Exper. To locate skin penetration of the drug
Microscopic section
But
The cut, handling development of skin section
encourage
Leaching,
Translocation of drug ()
Histochemical techniques for
Drug which produce colored end products after
chemical reaction.

Mistake of the past
Colour the drug with dye Examine skin section
to locate drug.
Why?
Because each chemical species .
Better to use
Fluorescence Method (.)
Tritium-labeled

Not Useful
?-emitters because darken areas up to 2 or 3 mm
away ()
Confocal Microscopy
.

Microdialysis
Also needs very sensitive analytical techniques
Especially when protein-binding occurs.

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Schematic drawing of the principle of
microdialysis
61

Analysis of Body tissue or fluids
Needs calibration of the subject by
A slow I.V. inj. simultaneous Det. Of blood
level.
(Gives Pharmacokinetic Information
Some drugs have??? affinity to animal organs
.
4. Tissue Biopsies individual sections
measured.
Adhesive tape strip sequential layers of s.c.
which should be analyzed.

Observation of Pharmacological or Physiological
response
Like
Allergic Response ()
Blood Pressure ().
Figure 33.11
Physical properties of the skin
To evaluate the skin using
.
.

Bioassays
Bioassays are typically conducted to measure the
effects of a substance on a living organism.
Bioassays may be qualitative or quantitative .
Many specialized bioassays screen topical
formulations prior to clinical trial (i.e.
Anti-bacterials, antifungals,etc.).

Maximizing Bioavailabilty of Drugs Applied to
Skin
Drugs or prodrugs selection
Chemical Potential Adjustment
Ultrasound
Disturbs the lipid-Packing in the intercellular
spaces of s.c.
Disadvantage
.

65
Basic principle of phonophoresis. Ultrasound
pulses are passed through the probe into the skin
fluidizing the lipid bilayer by the formation of
bubbles caused by cavitation.
66

Iontophoresis
Disadvantages
.

Basic principle of iontophoresis. A current
passed between the active electrode and the
indifferent electrode repelling drug away from
the active electrode and into the skin.
67

Electrophoresis
Creation of Aqueous-Pores ins.c. by Application
of currents for m. seconds (100-1000 v/cm)
Disadvantages
Electroporation Iontophoresis ? .

68
Basic principle of electroporation. Short pulses
of high voltage current are applied to the skin
producing hydrophilic pores in the intercellular
bilayers via momentary realignment of lipids.
69

Stratum corneum removal
Laser ablation
Disadvantages
Adhesive tape
Keratolytic agents.
Photochemical wave
A drug solution is placed on the skin
Covered by a black polysterene target
.

70
Photomechanical wave
71

Needle array
400 ?needles
Flux ?? to 100,000 folds
There is needle array Iontophoresis technique
combination.

72
Basic design of ?needle delivery devices. Needles
of approximately with or without centre hollow
channels are placed onto the skin surface so that
they penetrate the stratum corneum and epidermis
without reaching the nerve endings present in the
upper dermis.
73

Penetration enhancers
Characteristics of ideal penetration enhancer
2.
3. Upon removal of the material, the skin should
immediately fully recover its normal barrier
property
4. Should not cause loss of body fluids,
electrolytes, or other endogenous materials

Should be cosmetically acceptable ()
Should formulate into all the variety of
preparations used topically
Should be odourless, tasteless, colourless
inexpensive.

Some penetration enhancers
Water Sulphoxides (DMSO)
Fatty acids alcohols
Pyrrolides
Azone
Surfactants
Urea its derivatives
Alcohols glycols
Essential Oils, Terpenes derivatives
Synergistic mixtures.

76
Chemical structure of typical chemical
penetration enhancers
77

Mechanism of Penetration enhancers
The Lipid-Protein-Partitioning theory (is the
most accredited)
Lipid action
The enhancer interact with the lipid structure of
s.c.,
Solvent action
The enhancer (solvent) extracts lipid from s.c.?
Surfactant action

Formulation approach
Nanodispersed vehicle systems
Liposomes, Nanoemulsions, Solid-Lipid
Nanoparticles .
Liposomes are colloidal particles composed mainly
of phospholibids colesterol, to which other
ingredients may be added.
Most reports cite a localizing effect whereby the
carriers accumulate in s. c. or other upper skin
layers.
Generally, these colloidal carriers are not
expected to penetrate into viable skin.

79
Structure of nanodispersed vehicle systems
80

Transfersomes
A new type of liposomes called transferosomes has
been introduced.
Transferosomes consist of phospholipids,
cholesterol additional surfactant molecules
such
Transferosomes are ultradeformable (105 gt than
liposomes) squeeze through pores lt 0.1 of their
?.
Thus 200 to 300 nm ? transferesomes are claimed
to penetrate intact skin.

Penetration of these colloidal particles works
best
.
e.g. 50 of topical insulin penetrates skin into
30 minutes.

Microemulsions.
Such systems consist of water, oil, amphiphilic
compounds (surfactant and co-surfactant) which
yield a
Transparent, single optically isotropic,
thermodynamically stable liquid.
?-emulsions can be either oil continuous, water
continuous, or bi-continuous.
.

The main difference between ? -emulsions
?-emulsions lies in
The ?-emulsions ( 10 200 nm) are little smaller
than the conventional emulsions (1 20 µm).
Typical properties of ?-emulsions include
,
,

84
Figure 33.12
85

Penetration enhancement from ?-emulsions is
mainly due to an ? in drug which ? a ? ?C from
the vehicle to the skin.
Also, the surfactants the oil from the
?-emulsion interact with the rigid lipid bilayer
structure acts as a chemical enhancer.

High velocity particles
The powder Ject system fires solid particles
through the s.c. into the lower skin layers,
using a supersonic shockwave of helium gas
traveling at Mach 2-3.

Injections without needles Dermal PowderJect
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Advantages
Targeting to a specific tissue, such as a vaccine
delivered to epidermal cells

6.
7.
8. Safety - the device avoids-
Splash back of body fluids ()

Disadvantages
No home use
Problems arising with
Bruising of the skin
Bouncing off the skin surface.

Transdermal Therapeutic Systems (TTS) or (TDDS)
Advantages
Eliminate variables in the G.I.T. absorption
Controlled release ? improves patient
compliance

5. Can use drug with low therapeutic index
6.
Disadvantages
Drugs must be stable have correct
physichochemical properties.

Device Design
Types of TTS Devices
Monolith or matrix system
(Higuchi eq.)
m is the amount of drug
A is the volume of the applied vehicle
Dv is the diffusion coefficient in the vehicle
Cs is the solubility of the drug (in the vehicle)
at time t
The amount of drug released depends meanly on Cs
which depends on the equilibrium between the
crystals and the dissolved amount.

Rate-Limiting Membrane
(Ficks law)
The amount of drug released depends on The
presence of rate-limiting membrane.

Fig. 33.1333.1433.1533.16

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Future Trend
Why monolith system is the most popular?
Because the trend is to concentrate on simple
designs that are
Less obstructive ()
The result is a move towards the simple adhesive
matrix patch ( figure 33.17)

Clinical Patches
Transdermal Scopolamine (hyoscine)
It can control the emetic side-effects of
anticancer drugs
This TDDs Patch overcomes the side-effects of
hyoscine injection or tablets
.

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Transdermal Nitroglycerin (Glyceryl Trinitrate)
(TDDS)
Transdermal Oestradiol (TDDS)
Advantages
Such dosing doesnt affect the blood levels of
proteins produced by the liver

102

Transdermal clonidine
Transdermal fentanyl
This TTS patch treats chronic intractable pain
last for 72-h.
A TTS gives 25 ?g of fentanyl /h 0.6 mg/day
The oral administration of 90 mg of morphine
sulphate /day.

103

Transdermal Nicotine
TTSs of nicotine provide an alternative route of
Nicotine.
Chewing gum Lozenge Sublingual tablets Nasal
Sprays Inhalers.
Advantages of nicotin TTS
Maintain labour ()
Improve the activity of anti-Tourettes syndrome
drugs.

104

TTS Testosterone
a. Hypogonadism (due to testicular or pituitary
disorder)
b. Testosteron deficiency due to orchidectomy.

105

General conclusions on the usage of transdermal
patches
A vibrant developmental area within the
pharmaceutical industry
No marketed patch fully controls the drug flux
Movement from a complex patch structure towards
matrix formulation
Future progress will depend on
.

106

There is a need to solve problems relating to,
e.g.
,
,
,
,

107

Wearability of the patch for up to 7 days the
device must
,
,

108

Formulation of Dermatological vehicles
Old Formulator developed formulations for
Stability,
Compatibility,
Patient acceptability.
2. Modern Formulator developed formulations for
.

109

Dermatological formulations
Liquid preparations
Liniments
Lotions
Paints
Varnishes
Tinctures
Ear drops
Soak ( provides drug in aqueous solution or
suspension)
Gums, gelling agents change consistency from
mobile liquid to stiff gels.
Oilatum Emolient deposit a layer of liquid
paraffin on the s.c..

110

Gels (Jellies)
Are two- component semisolid systems rich in
liquid. (water polymer) ? TD structures.
Powders
Ointments
Hydrocarbon bases
Plastibases (Polyethylene in paraffin oil)
Advantages
,
,
,
,
,
,

111