TOPICAL PREPARATIONS

Dr. Ayman Y. Waddad

Anatomy of the
Skin
Human skin → 3 tissue layers:
1.
•Epidermis
Consists of 5 layers:
• stratum corneum, stratum lucidum, stratum
granulosum, stratum, malphigi and stratum
germinativum.
• Thickness:
• face = 0.1mm, hand-palm = 0.8-1mm, eyelids = 0.006mm
• Stratum corneum → keratin phospholipid complex
of dead and relatively dry cells → barrier to
penetration of H2O and foreign bodies.
• No blood vessels/lymphatics.
• pH of skin → 5-6.
2. Dermis
• Connective tissue matrix woven from fibrous
proteins (collagen, elastin and reticulin).
• Nerves, blood vessels and lymphatic traverse the
matrix.
• Skin appendages (e.g. eccrine, sweat glands,
apocrine glands & pilosabaceous units) pierce it.
• Needs efficient blood supply to convey nutrients,
remove waste, regulate pressure and
temperature, mobilize defense forces.
3. Subcutaneous Tissue
• Layer of subcutaneous fat → provides
mechanical cushion to external injury, is
also a thermal barrier.

• Synthesizes and stores readily available high

energy chemicals.
 Absorption
 Condition of skin is important in terms of the
degree of absorption.

Absorption through skin → is a
passive process → can takes place in 2
ways:

1. Transepidermal →– surface area of

epidermis is 1000 times greater than any
other route of absorption. Penetration is fairly
rapid.
2. Transappendageal → refers to absorption
through glands, hair follicles, etc. Drugs
applied to the skin reach opening of sweat
glands and hair follicles directly.

Each hair follicle → has one/more connecting

sebaceous glands →which empties secretion
into follicular canal near surface of skin.

Canals are lined with stratified squamous

epithelium → readily penetrated by drugs.
 Percutaneous
Absorption

Simplified diagram of skin structure and macroroutes of drug

penetration: (1) via the sweat ducts; (2) across the
continuous stratum corneum or (3) through the hair follicles
with their associated sebaceous glands.
Simplified diagram of stratum corneum and
two microroutes of drug penetration.
 Factors Affecting
1.
Absorption
Vehicle 7. pH of the Skin
2. Occlusion 8. Skin Location
3. Rubbing 9. Hydration state of the Skin
4. Contact Time 10. Temperatur
5. Drug Release e
12. Hyperaemia
6. Lipid layers of the Skin11. Content of
Drug
 1. Vehicle
 Must easily cover skin surface.
 Must mix readily with sebum to bring the drug
in contact with skin.
 Absorption → is better from animal and vegetable oils
than from mineral oils. Mineral oils → can act as
barriers.
 Vehicle that ↑ moisture content of skin →can ↑
absorption.
 Oily bases act as moisture barriers i.e. sweat cannot
pass through and the skin remains occluded →
enables hydration of skin.
 Vehicles with humectants keep the ointment moist but
have a tendency to draw moisture from the skin
when humidity is low.
 2.
 Hydration is affected by the presence/absence of
Occlusion
a bandage and the type of bandage.

 Bandaging a non-occlusive application such as a

water-miscible vehicle will ↑ the moisturizing affect
→↑ absorption.

3. Rubbing
 Rubbing will ↑ absorption-Linked to blood flow.
Longer the period of rubbing → greater is the
absorption.
 4. Contact Time
 ↑ contact time →can ↑ absorption.

5. Drug Release
 Rate of absorption is dependant on rate of drug
release.
 Release rate is dependant on:
Partition co-efficient of drug between the base and
skin.
Whether drug is dissolved or suspended in the base.
Size of drug molecule.
 6. Lipid layers of the

Skin
Drug may be stored in the outer and deeper layers
of the skin.
 Drugs can be bound to protein (keratin).
 Lipid layers may act as barriers.

7. pH of the Skin
 Secretions in and on the epidermis determine the
pH of the skin (5-6) → pH has major influence
on drug penetration and absorption.
 Stratum corneum allows for penetration of
unionized drugs → pH of skin affects ionization
and absorption.
8. Skin
Location
 Thickness of skin influences absorption.
Thicker skin → slower absorption.

 Slowest absorption → sole of foot.

 Fastest absorption → behind the ear.

 9. Hydration State of the
 Skin
Hydration affects the rate of penetration of
substances.
 Hydration → is due to water diffusing from
underlying epidermal layers or from perspiration
that accumulates after occlusion of skin.
 Water-soluble substances responsible for water
content of the skin e.g.
amino acids – 40%,
urea – 17%
 10. Temperature
 Diffusion co-efficient depends on temperature-
therefore ↑ temperature → increase rate of
diffusion.
 Also causes vasodilation.

11. Hyperaemia
 ↑ blood flow →↑ removal of drug →↑ concentration
gradient →↑ rate of absorption.

12. Content of Drug

 ↑ concentration of drug → ↑ absorption.
Types of Topical
Preparations
May contain:
i. Active ingredient
ii. No active → applied to act as a barrier

§ Preparation containing an active:

 Those acting on the surface of the skin.
 Those producing a therapeutic response
only when they reach the water containing
tissues
e.g. antihistamines and cortico-steroids.
Topical preparations divided into
3 broad categories
 1. Topical Powder Preparations
 2. Topical Liquid Preparations
A. Solutions for external use
B. Suspensions for external use
C. Liquid Emulsions for External use
 3. Topical Semi-Solid Preparations
A. Semi-Solid emulsions for external use - Creams
B. Ointments, Pastes and Gels
 1. Topical Powder Preparations
 Used to absorb moisture
from skin → keep skin dry
→ contain: starch,
bacteriostatics or
bacteriocides, and or
antiseptics.
 Dusting powders → for
applications to body
surfaces but not to open
wounds unless
sterilized
e.g. treatment of athletes
foot.
 2. Topical Liquid Preparations
A. Solutions for external use
• Liniments → solutions
formulated with alcoholic or
oily vehicle → intended for
rubbing into unbroken
skin.
• Active applied for counter-
irritant effect, analgesic effect
or warming effect.
• Must contain a preservative.
• Lotions → intended to be applied to
unbroken skin without friction.
• Vehicle may be alcoholic/acetone if intended
to evaporate rapidly from skin.

• Paints → applied to skin with a brush.

• Solvent → H2O or organic (if rapid
evaporation required).
B. Suspensions for external use
• Lotions containing suspended solids →
when they evaporate → it leaves a light deposit
of medicament on skin. The evaporation causes
a cooling effect → which can be ↑ by addition
of alcohol.
• Thickening agent is added which forms a strong,
non-sticky film → holds medicament in
contact with skin and gives protection.
• May require a preservative when applied
to broken skin.
C. Liquid Emulsions for External use
• Emulsions formulated as liniments and
lotions
→ must contain a preservative.
3. Topical Semi-Solid Preparations
A. Semi-Solid emulsions for external use
• Creams → viscous semi-solid
• o/w – aqueous creams
• w/o – oily creams
•Microbialcontamination → must be minimized.
Therefore, choose suitable preservative.
• Preparation must be under strict hygiene or
aseptic conditions → therefore prepare
with freshly boiled and cooled purified
water.
B. Ointments, Pastes and Gels
• Ointments → has emollient effect, for protection
of lesions and for topical medication.
• Pastes → contain large amounts of finely
powdered solids (up to 50%).
• Are emollients but porous and absorb
exudates.
• Usually used for chronic infections.
• Gels → water-soluble bases from natural
gums
e.g. alginates.
• May be used as dermatologicals or to lubricate
 Gel

Paste

Ointment

Cream
Preservation of Topical Preparations
 Plastic containers may absorb preservative
→leads to a ↓ in their concentration → this can ↓
effectiveness.
 Preservatives may sting or irritate mucous tissue
of the eye and nasal passages e.g. parabens
are more irritating to nasal passages than
quarternary ammonium compounds (QAC’s).
 Interaction of preservative with active or
excipients, storage temp → can ↓ concentration
of preservative → makes them ineffective.
 Preservative efficacy depend on concentration
of free preservative in the aqueous phase.
 Preservative solubilised with surfactants may be
bound within micelles and be activated.
 Minimum inhibitory concentration (MIC) of
preservatives must be established for
preparations via microbiological testing.
 Product must be tested for its ability to
withstand accidental or deliberate microbial
contamination → preservative challenge test.
 Good manufacturing practice employed in
manufacture → to ↓ contamination.
 Aseptic technique → important for certain
creams, ophthalmics and certain ointments.
 Oil/water partition co-efficient of preservative
is important.
 Ointment
 sGreasy, semi-solid preps, often anhydrous and
containing dissolved or dispersed medicaments.
 Medicament may be dissolved, suspended or
emulsified into the base.
Ideal ointment base:
Non-irritant
Smooth
Odourless
Physically and chemically stable
Compatible with a wide range of medicaments
Must not retard the healing process
Rheolog
y Ointments are visco-elastic material which
soften and spread easily when a shearing
stress is applied.
 Flow properties depend on nature and
quantities of constituents → waxes confer
structure and rigidity, fats/oils confer flexibility
as well as a matrix in which the constituents
may be carried.
Classification of Ointment
Bases
 Four main groups, according to USP and
Pharmaceutical Codex:
1. Hydrocarbon Bases
2. Absorption Bases
3. Water-miscible Bases
4. Water-soluble Bases
 1. Hydrocarbon
 Bases
These bases:
Are immiscible with H2O
Are not absorbed by skin
Are almost inert
Absorb very little H2O from the formulation or
from skin exudates
Inhibit H2O loss from skin
By improving hydration may encourage
absorption
 Constituents of hydrocarbon bases include:
Soft Paraffin, Hard Paraffin & Liquid Paraffin.
Paraffin Substitutes & Paraffin Ointment BP
A. Soft Paraffin – purified mix of semi-solids
hydrocarbons from petroleum or heavy
lubricating oils → 2 varieties – yellow & white.
• Melting range → 38-56°C.
• Yellow form → less likely to elicit an adverse
skin reaction.

B. Hard Paraffin – mixture of solid hydrocarbons

obtained from petroleum and shale oil.
• Colourless, odourless, translucent, wax-like
substance → slightly greasy.
• Solidified between 50-57°C.
• Used to stiffen ointment bases.
C. Liquid Paraffin – mixture of liquid hydrocarbons
obtained from petroleum.
• Transparent, colourless, almost odourless, oily.
• Liable to oxidation → include antioxidant.
• Used to soften ointment bases and to ↓ the
viscosity of creams.
D. Paraffin Substitutes – produced by dissolving
polyethylene in liquid paraffin with the aid of heat
and cooling the resulting solution rapidly to form a
gel → consistency varies little over temp range
-15°C to 60°C.
• compatible with most medicaments.
• readily applied to skin.
E. Paraffin Ointment BP – official ointment base.
 2. Absorption
A. Bases
Non emulsified → absorb H2O and aqueous
solution to produce w/o emulsions.
• Consists of a sterol-type emulgent with one or
more paraffins.
• Constituents include:
i. Wool fat: wax → can absorb ± 50% of its weight
of H2O.
• Patients may become sensitized.
• To sticky to be used on its own.
ii. Wool alcohols: emulsifying fraction of wool fat.
iii. Beeswax & Cholesterol: beeswax consists mainly of
myrical palmitate with small amounts of cholesterol.
• Has good water-absorbing properties.
B. Water-in oil Emulsions
• Greater water-absorbing properties.
• Advantages: less occlusive than hydrocarbon
bases, easier to spread, good emollient,
assists oil soluble medicaments in penetrating
the skin.
 3. Water-miscible
•
Bases
Easy to wash from skin.
• Can emulsify a large quantity of H2O but is
immiscible with an excess.
• Contains paraffins and an o/w emulgent.
• General formula: Emulsifying wax (30%)
White soft paraffin (50%)
Liquid paraffin (20%)
• Advantages: miscibility with exudates, good
contact with skin, high cosmetic acceptability, easy
removal from hair.
• May promote absorption of certain drugs.
 4. Water-soluble
•
Bases
Developed from macrogols → mixtures of
polycondensation products of ethylene oxide & H2O.
• Completely H2O soluble.
• Advantages: non-toxic and non-irritant to the skin
unless it is badly inflamed, non occlusive, miscible
with exudates, non-staining and easily removed by
washing.
• Disadvantage: very limited capacity to take up H2O
without physical change.
• Solidifying points range from 40-60°C depending on
molecular weight.
• 5% solutions → pH range 4 – 7.5
• ↓ activity of a no. of preservatives
• Reacts with plastics
 Expected effects of common vehicles on skin hydration and skin
permeability – in approximate order of decreasing hydration
Effect on skin
Vehicle Examples/constituents Effect on skin hydration
permeability
Occlusive Plastic film, unperforated Prevents water loss; full
Marked increase
dressing waterproof plaster hydration
Paraffins, oils, fats, waxes,
Prevents water loss; may
Lipophilic fatty acids, alcohols, esters, Marked increase
silicones. produce full hydration

Absorption Anhydrous lipid material Prevents water loss;

Marked increase
base plus water/oil marked hydration
emulsifiers
Emulsifying Anhydrous lipid material Prevents water loss;
Marked increase
base plus oil/water marked hydration
emulsifiers
Water/oil Retards water loss; raised
Oily creams Increase
hydration
emulsion
Oil/water May donate water; slight
Aqueous creams Slight increase?
hydration increase
emulsion
Can decrease or act
Water-soluble bases, May withdraw water;
Humectant as penetration
glycerol, glycols decrease hydration enhancer
Aid water evaporation;
Clays, organics, inorganics, Little effect on
Powder decreased excess
‘shake’ lotions stratum corneum
Other Excipients of Ointment
Bases
1. Vegetable Oils: arachis, castor, coconut and
olive oils.
Used as emollients.
Disadvantages of natural substances i.e.
variation in composition and susceptibility to
oxidation.

2. Synthetic esters of fatty acids: e.g.

isopropyl myristate, palmitate-stearate.
More consistent in composition than vegetable
oils and more resistant to oxidation.
May be used as a substitute for vegetable oils.
3. Higher fatty alcohols: e.g. cetostearyl alcohol
Good emollient properties.
Non-greasy.
Do not rancidify.
Facilitates the incorporation of H2O.

4. Silicones: e.g. dimethicones, dimethyl

polysilicones.
Used in barrier ointments to protect skin
against water-soluble irritants.

5. Propylene glycol: used to disperse very small

quantities of actives through a relatively large
quantity of ointment base.
Other
Excipients
1. Antioxidants: e.g. BHA and BHT
• Chelating agents e.g. EDTA
• Must be compatible with ointment base,
active and other excipients.
2. Preservatives: may not be required in
anhydrous ointments. Most commonly used-
parabens, organic, mercurial and QACs.
Compounding of Ointments &
Pastes
Basic method of preparation of ointments:
• Weighing, measuring liquids, size reduction
and size separation and mixing.

Two techniques of mixing:

 Mixing by Fusion
 Mixing by Trituration
 1. Mixing by
 Fusion
Ingredients melted together and stirred to ensure
homogeneity.

 Generally carried out in an evaporating basin over

a water bath-glazed porcelain or stainless steel
basins are preferred.
a) Preparation of ointment Base by
Fusion
- Constituents of the base should be placed in the
basin and allowed to melt together.
- To decrease the melting time - high melting point
ingredients are grated into the basin and melted
while the other ingredients are being massed.
- After melting, ingredients should be stirred gently
until cool.
- Localized cooling may result in separation of
hard lumps of high melting pt. ingredients.
- Foreign particles visible on melting may be removed
by decantation or by passage through a warm
strainer.
- If the product is granular after cooling → may be
remelted with minimum heat and stirred until
cold.
b) Preparation of Medicated Ointments and
Pastes by Fusion
- Solids that are completely/partially soluble in the base
should be added in fine powder and the mixture
stirred until cool.
- Liquids and semi-solids should be added just as
the base is thickening (approx. 40°C).
- When a solid is soluble in a liquid ingredient, it may
be more convenient to add it in solution.
- Insoluble solids (zinc) should be passed through a
180µm sieve and added in small amounts with
stirring to the melted base.
- If product contains liquid paraffin or a fixed oil, a
small amount can be used to levigate the powder
before adding to the base to produce a smoother
product.
 2. Mixing by
Trituration
Applicable when the medicament is a solid
which is insoluble in the base or a liquid
present in small amounts.
 Solids should be finely powdered and passed
through a sieve of appropriate size.
 A 250µm sieve is suitable unless the formula
specifies a fine powder (180µm) or a very fine
powder (125µm).
 Trituration can be carried out with an ointment
tile and spatula or using a mortar and pestle.
 1. Dissolution
• Similar to the tablet dissolution test.
• Sample of known strength is placed in a container
which has a cellulose acetate phthalate (CAP)
membrane of known surface area, which
separates the product from the sampling medium
(H2O at 37°C).
• Stirring paddle used to break up the boundary
layers → to maintain concentration gradient.
• Samples removed at set intervals and assayed for
drug concentration.
• Rate of release calculated and expressed i.t.o.
surface area.
 2. Physico-chemical
i. Properties
Stability
• Emulsion type bases → evaluated by
centrifugation.
• Semi-solid preps → determined by storage for
long period of time at normal temp.
• Bases prepared from oils, fats and waxes of
mineral/synthetic origin → stable.
• Fats and oils of vegetable origin → can lead to
oxidation → manifests as rancidity → detected by
smell or yellowing/browning.
ii. Rheological Properties
• Ideally prep should be plastic in nature with a
moderate yield value i.e. high viscosity at
low shearing stresses→ remains localized,
low viscosity when shearing stress is
applied.
• Thixotropic properties are advantageous.
• Phase separation can be monitored with a
viscometer.
iii. Particulate Matter
• Major hazard especially if preparation is applied
to broken skin/membranes e.g. opthalmics.
• USP particulate test for opthalmics (refer to
USP).

iv. Microbial Contamination

• Do not have to be sterile (excluding
opthalmics).
• Preserve efficacy must be evaluated by means
of a challenge test.
 3. Cosmetic
i. Criteria
Feel of the preparation
ii. Non-greasy & smooth (non-gritty)
• Ointments and pastes by nature are greasy
and visible on the skin.
• Synthetic bases (PEG’s) – less greasy.
• Waxy material (cetyl alcohol) – result in less tacky
films.
• Efficient particles size reduction → ↓ gritty feel –
particles < 20µm.
 Penetration
•Enhancers
Substances which temporarily diminish the
impermeability of the skin.
• Used to enhance the penetration rate of drugs
and possibly even treat patients systemically
through the dermal route → must be non-toxic.
 Ideal Penetration
i. Pharmacologically inert.
ii. Enhancer
Non-toxic, non-irritant and non-allergenic.
iii. Action should be immediate and the effect should be
suitable and predictable.
iv. Upon removal of the material, the skin should
immediately & fully recover its normal barrier
properties.
v. Should not cause loss of body fluids, electrolytes or
other endogenous materials.
vi. Compatible with all drugs and excipients.
vii. Good solvent for drugs.
viii. Cosmetically acceptable.
ix. The chemical should formulate into all varieties of
topical preparations.
x. Odourless, tasteless, colourless and inexpensive.
• Most effective penetration enhancers are
aprotic solvents e.g. dimethyl
sulphoxide (DMSO) dimethylformamide
(DMF) and dimethylacetamide (DMA).
• Accelerate penetration of many compounds e.g.
barbiturate, steroids, griseofluvin,
phenylbutazone, local anaesthetics, antibiotics.
• Pyrrolidones can be used.
• Surfactants.
• Combination of oleic acid or oleyl alcohol with
propylene glycol.
• H2O → best penetration enhancer - safety and
effectiveness.
Thank You