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Topical formulations
Alton
Chapter 6 and 38
The skin:its function
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Thick skin
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Thin skin
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Mechanical protection
(dermis)
 Changes over time
 The outer layer of skin
should contain 10-20%
water to have the proper
elasticity
Protection from
 Bacteria and viruses,
foreign substances
 Dehydration, radiation
Temperature regulation
Production of vitamin D
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The skin:Anatomy
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Epidermis
Stratum corneum
Sebaceous
glands
Dermis
Sweat glands
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The heaviest organ in the
body
Epidermis
 Stratum corneum
 Viable epidermis
Dermis
Subcutaneous fat tissue
Appendages of the skin
 Sweat glands
• Eccrine sweat
glands
• Apocrine sweat
glands
 Hair follicles
 Sebaceous glands
Passage through the skin effects of the route
• The appendages
 Two types
• hair follicles
• sweat ducts
 Low available surface
area 0.1%
 Can be important for ions
and large hydrophilic
molecules such as in
immunization through the
skin
 Colloidal particles such
as liposomes or small
crystals of 3-10µm size
can be used to target the
appendages
• Epidermis
 Main transport barrier stratum corneum
• 10 mm in dry state,
Swells in water
• Intracellular matrix of
lipids and proteins
 The viable layer has some
enzymatic activity
 The dermis is strongly
vascular and often
functions as a perfect
sink
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Stratum corneum
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Dead cells: no-active transport
Network of lipids and proteins
giving two possible “transport
canals”
Organized like a brick wall
 Bricks (Corneocytes)
• Dense layer of dead cells
containing keratin (protein)
¬ Mortar
• Lipids and some water
(bilayer), ceramides, fatty
acids, cholesterol
• The layer where most
substances are transported
Passage through the skin-Interactions,
reactions and other problems
Partition
Diffusion
Binding
in depot
Metabolic
site
Binding to
receptors
Binding
in depot
Binding
in depot
• Binding of active
substance to skin
components such as dead
tissue, to cell receptors
and to fat tissue
• Precipitation when
partitioning from a lipidrich to a water-rich
environment
• Metabolism by the cells
• Fast clearance in the
dermis
• Rediffusion
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Passage through the skin - effects
of biological factors
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Age of the skin
 Higher penetration for
children and elderly
Condition of the skin
 Disease can cause
increased thickness or
damage to the skin
 Damaged skin show
enhanced permeability
 3 days needed to obtain a
protective layer
Regional skin sites
 Hands- feet - eyelids scrotum
Evaluation of uptake and
dissolution
Dissolution
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Release without use of a ratelimiting membrane
Release with use of a rate-limiting
membrane
 Types of membrane
• Simulated skin: cellulose
acetate, silicone rubber
• Natural skin: stratum
corneum, whole skin
Uptake
•
Franz
Bronaugh
No good animal models - pig best
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Strategies for delivery
• Local treatment
 Surface treatment
• Bacteria and fungal
creams
• Deodorants
• Insect repellents
 Stratum corneum
• Moisturizing agents
 Skin appendages
• Antiperspirants such
as aluminium
• Treatment of acne
• Antibiotics and
Antifungals
 Viable epidermis and
dermis
• Anti-inflammatory
• Anaesthetics
• Antiprutric
• Antihistamines
• Transcutaneous immunization
(in the development stage)
• Systematic treatment
 Often depot formulations
• Testosterone,
Estrogens
• Nicotine
• Nitroglycerine
Factors affecting development of a
formulation
•
Patients’ compliance
 Products that are easy to
transfer from the container to
the skin
 Products that spread easily
and evenly
 Products that leave no visible
residues on the skin
 Products that do not feel
tacky or sticky
 Products that do not sting
• Safety
 Need of dose accuracy
 Microbiological safety
• Enhancement of drug
penetration
 Drug properties
• Prodrugs
• Ion pairs
 Hydration of the skin
• Moistering
• Occlusion
 Chemical activity and
solubility of the drug
• Supersaturation
• Lipophilic or
hydrophilic drug
vehicle
 Adding excipients that
enhance penetration
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Penetration enhancers
Definition
A substance that
temporarily diminishes the
impermeability of the skin
• Example of enhancers
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DMSO
Pyrrolidols
Surfactants
Azone
(Water)
The ideal enhancer
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Pharmacologically inert
Non-toxic, non-irritating
Immediate effect
Full recovery
Compatible with the drug
Good solvent for the drug
Not causing loss of water, ions
etc
Having a acceptable look, taste,
texture and odour
Inexpensive
In reality, it is difficult to find
enhancers that are safe and that
are accepted by authorities
Formulations that affect skin
hydration
Vehicle
Examples
Occlusive
dressings
Lipophilic
Waterproof
plaster
Waxes, oils
Effects on hydration
Preventing water loss, full
hydration
Preventing water loss,
might give full hydration
Absorption Anh. Lipids +
Prevent water loss,
base
W/O emulsifier marked hydration
Emulsion Anh. Lipids +
Prevent water loss,
base
O/W emulsifier marked hydration
W/O
Oily creams
Reduce water loss,
emulsions
increased hydration
O/W
Aqueous creams May donate water, slight
emulsions
increase in hydration
Humecant Glycerol
May withdraw water
Powders
Clay, Topical
Aiding evaporation of
powders
water
Effects on
permeability
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(-)
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Requirements on an ideal
formulation for local treatment
• Low penetration of the active substance to
avoid systemic delivery
• Non irritating
• Broad therapeutic window
• Not harming clothes and other things that
comes in contact with the formulation
• Good cosmetic properties
Requirements placed on
formulations for systemic delivery
• Usually a low daily dose, <20 mg/day
• An active substance that can penetrate the skin
• Low molecular weight < 600 Daltons
• A partitioning coefficient high enough to ensure penetration
through the lipid layers in the stratum corneum but not so high
that it risks precipitation in the dermis
• A non-charged species passes through the skin more easilly
• A low melting temperature leads to high intrinsic solubility
• Not causing irritation or sensitisation of the skin
• Easy to apply the correct dose - (transdermal patches)
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Special Quality considerations
• Stability of excipients,
especially of
 Preservatives
 Penetration enhancers
 Lipids
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Rheology
Water content
Phase changes
Particle and drop size
pH
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Test conditions
 Problems at elevated
temperatures
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Typical problems
 Volatile solvents can
evaporate
 Risk of oxidation of the lipid
components
 pH measurements are
difficult in complex systems
 Tests of dissolution
especially from plasters
Type of formulations
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Solutions (viscose or liquid)
 Liniments
 Lotions
 Tinctures
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Solution aerosols
Powders
Ointments
Pastes and ointment that
contains as much as than
50% solid material
Gels
Creams and semi solid
emulsions
Depot formulations such as
plasters
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Ointments
• Character
Greasy, sticky, semisolid
products normally containing
a hydrophobic component
such as oil, fat, hydrocarbons
or silicone
• Example of products
 Bactroban Nasal - local
treatment of
Staphylococcus aureus
infection
 Iodosorb® - Treatment of
open infected wounds,
also as a powder
• Advantages
 Increases hydration of
the skin
 Good chemical stability
if no water present
• Disadvantages
 Poor cosmetic
properties
Formulation of ointments
• Base
 Hydrocarbons
• Paraffin
• Plastibases
(polyethylene in
hydrocarbons)
 Fats and fixed-oils bases
• Semisolid vegetable
oils
 Silicones
• Water-repellent
 Water-soluble
• Polyethylene glycols
• Non-occlusive
 Absorption base
• Contain excipients that
create o/w emulsions
upon adsorption of water
 Emulsifying base
• Self-emulsifing systems
that are mixable with
water
• Other Excipients
 Usually low in water
content thus
bacteriosides are only
needed in special cases
 Antioxidants may be
needed especially for Fats
and fixed-oils bases
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Gels
• Characteristics
Two phase semisolids system
rich in liquids containing a
continuous structure
• Examples of products
 Divigel®- Oestrogen for
systemic treatment
 Oftagel - tear substitute
local treatment of the eye
 Crinone - a progesterone
replacement formulated
as a vaginal gel
 Basiron® - local treatment
of acne
• Advantages
 Good cosmetic properties
 Good release of
substances
 High water content can
hydrate the skin slightly
• Disadvantages
 Low chemical stability of
some excipients due to
high water content
 Low microbiological
stability
What defines a gel
A gel is a two-phase
semisolid product.
A gel consists of a network
that entraps the liquid phase.
A gel has viscoelastic
properties and is
characterised by losing its
elastic properties at high
stress.
There is a has high mobility
of molecules in the liquid
phase
low amount of dispersed
phase (>1%) still provides
rigidity
• Uses of gels
 Topical formulations
 Stabilising foams,
emulsions and
dispersions
 “Cosmetic” factors
• Easy to handle
• Easy to spread
 Entrapment of active
substances to achieve
controlled release
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Formulation of gels
• The gel-forming
component
• Lyophilic sols
 Entangled networks
• Polyvinyl alcohols
• Cellulous derivates
 Covalent coupled
• Carbomers
 Ion-birding
• Alginic acid
 An aggregating structure
• Gelatin
• Carrageenan
• The solvent
 Water
 Additives to increase
vaporization -ethanol
 Buffers to control pH
• Other additives
 Antioxidants
 Perfumes, colour
 Bactericide and
preservatives
 Moisterises
• Flocculated lyophobic sols
 Clay and Bentonite
 Magnesium hydroxide
Types of networks
Networks can consist of
 Flocculated systems
• Normal hydrophobic
solids
• “Card house” flocks
of special crystal
particles
 Polymeric networks
• Covalent linked
networks
• Entangled networks
• Physically linked
networks
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Creams
• Characteristics
Semisolid emulsions for
topical use. O/W emulsions
and W/O emulsions
• Examples of products
 Garamycin® for Local
treatment of virus
infection
 Daktacort® for Local
treatment of fungal
infection
 EMLA- local treatment of
pain
• Advantages
 Good cosmetic properties
 Evaporation of the liquid
gives a soothing feeling
 When O/W emulsions are
rubbed into the skin the
water evaporates
 An effective formulation
for hydrophobic
substances
• Disadvantages
 Can be unstable systems
 Show complex release
patterns
Formulation of creams
• Contain all the ingredients
of gels and of emulsions
• It is sometimes not
necessary to stabilize the
emulsion by the use of a
gel. Especially if the
formulation contains high
amounts of the dispersed
phase for example Nivea
• Surfactants are needed to
stabilize the emulsion
component of the gel
• O/W creams
 Used for vanishing
creams as the oil is
rubbed into the skin
 Can increase the
amount of watersoluble substances in
the skin
• W/O creams
 Spread better than
ointments but are not
occlusive
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Transdermal Therapeutic systems TTS
”Plasters”
Occlusive or nonocclusive
• Advantage
 Possible controlled
release
 Easy to remove
 No peak concentration
 Avoiding the variability
seen in the
gastrointestinal systems
Backing membrane
Can be
combined
Drug reservoir
Dissolution control
• Disadvantages
Contact adhesive
 Low permeability
 Risk of skin irritation
 Only applicable for potent
drugs < 2 mg/day
“Plasters”- things to consider
• Site of application
 Buccal plasters
 Special locations on
the body
• Duration of a unit
 1-3 days
• Types of release control
 Polymeric membrane
 Rate-controlling
adhesive layer
 Polymeric matrix
 Microreservoir system
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Interactions with excipients
and the control system
 Penetration enhancers
Effect on occlusion of the
skin
 Hydration
Effect of adhesive on the skin
 Irritation
 Easy to remove
Long-term changes in the
matrix system
Temperature- and light.
stability of the matrix system
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Plasters- Example of products
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Nicotine plasters
 Nicotine passes easily
through the skin
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Steroid hormones
 Testosterone - Atmos®
 Oestrogen - Evorel®
Motion sickness
 Scopolamine Scopoderm®
Angina pectoris
 Nitroglycerine
Hypertension
 Clonidine
• Joint formulation
development between big
pharma and drug
formulation companies
(patent holder) are
common
 3M
 Alza
Iontophorecic drug delivery
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Molecules are transported
through the skin by the mean
of an electric current
Transport mainly through the
skin appendages, which have
the lowest impedance of any
of the skin components
Neutral molecules
transported due to low flow of
water - electro-osmosis
Other types of “external”
induced uptakes
 Phonophoresis - Ultrasound
 Electroporations
 Needle arrays
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Terms to know from today's
lecture
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Epidermis: the outer layer of the skin contains
Stratum corneum. the protective layer of the, skin containing dead cells
and a lipid matrix
Dermis; the lower parts of the skin which contains blood vessels
The appendages of the sin, sweat glands, hair follicles and sebaceous
glands
Penetration enhancers: excipients that increase penetration of the
epithelial cells or the skin
Ointments: topical formulations containing low amounts of water, often
lipophilic bases
Pasts: ointments with high particle content
Gels: Two phase semisolids system rich in liquid can be used for topical
formulations
Creams: semisolid emulsion for topical use.
Transdermal Therapeutic systems TTS - ”Plasters containing active drug
for slow release formulations
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