Transcript الشريحة 1

Include drug delivery systems and dosage
forms intended to be applied to the skin.
Ointments
Pastes
Creams
Gels
Preparations are applied to the skin for:
Physical effects
skin protection, lubricants, emollients, drying agents
Medical effects
•Treatment of skin conditions (non-systemic topical effect)
as skin infections, itching, burns, diaper rash, insect
stings and bites, corns, calluses, warts, dandruff, acne,
psoriasis, and eczema.
• Systemic effect
The Skin
The skin has a wide variety of functions:
Protect the organism from water loss and
mechanical, chemical, microbial, and physical
influences.
Structure of the Skin
The skin is the largest human organ and is composed of:
 A film of emulsified material present upon the surface of
the skin composed of a complex mixture of sebum, sweat
 Blood capillaries and
nerve fibers
 Sweat glands
 Hair follicles
 Three functional layers:
 Epidermis,
 Dermis (true skin)
 Hypodermis
(Subcutaneous fat layer).
The epidermis is the outermost layer of the skin
 0.02 to 5 mm thickness
 It has five layers,
o Horny layer
(stratum corneum)
 The uppermost layer
Composed of dead epidermal cells forms the permeability barrier
o Barrier layer (stratum germinativum)
 Beneath the hornylayer
 Composed of living epidermal cells
The stratum corneum consists of:
Horny skin cells (corneocytes) which are connected
via protein-rich attachments of the cell membrane
The corneocytes are embedded in a lipid matrix in
“Brick and mortar” structure.
The corneocytes of hydrated keratin comprise the
bricks and the epidermal lipids fill the space
between the dead cells like mortar
Routes of skin Penetration
There are two diffusional routes to penetrate intact skin:
The Transappendageal route:
1
2
Include transport via:
1- Hair follicles and sebaceous
glands
2- Sweat glands
These routes avoid penetration through the stratum
corneum and therefore known as shunt routes.
 Although these routes offer high permeability, they are of
minor importance because of their relatively small area,
0.1% of the total skin area.
The transappendageal route
seems to be most important for
ions and large polar molecules
which hardly permeate through
the stratum corneum.
1
2
Transepidermal transport
means that molecules cross
the intact horny layer
Two potential micro-routes are existing
*The transcellular (intracellular) rout
*The intercellular pathways
The principal pathway taken by
drugs is decided by its partition
coefficient
Hydrophilic drugs partition into the intracellular pathways,
whereas lipophilic drugs traverse the stratum corneum via
the intercellular route.
Factors Affecting Percutaneous Absorption
Percutaneous absorption is the absorption of substances
from outside the skin to positions beneath the skin,
including entrance into the blood stream.
 Factors concerning the nature of the drug
 Factors concerning the nature of the vehicle
 Factors concerning the condition of the skin
 Factors concerning the nature of the drug
1. Drug concentration
2.
Percutaneous absorption
Drug partition coefficient (greater attraction to the skin
than to the vehicle)
3.
Percutaneous absorption
Molecular weight below 800
Percutaneous absorption
4.
Particle Size
Percutaneous absorption
5.
Solubility in mineral oil and water
Percutaneous absorption
Factors concerning the nature of the vehicle
1. Spreadability of the vehicle
Percutaneous absorption
2. Mixing with the sebum
Percutaneous absorption
3. Hydration of the skin
Percutaneous absorption
Oleaginous vehicles act as moisture barriers through
which the sweat from the skin cannot pass, thus
increased hydration of the skin beneath the vehicle and
increase Percutaneous absorption.
 Factors concerning the condition of the skin
Transdermal absorption follow Fick’s First Law of Diffusion
Js = Km D Cs
E
Js = Flux of solute through the skin
Km = Distribution coefficient of drug between vehicle and
stratum corneum
Cs = Concentration difference of solute across the
membrane
D = Membrane Diffusion coefficient for drug in stratum
corneum
E = Thickness of stratum corneum
1.
The thickness stratum corneum
Percutaneous absorption
2.
Multiple application dosing
Percutaneous absorption than single Application
3.
Time of contact with the skin
Percutaneous absorption
4.
Broken skin permit (remove of the stratum corneum)
Percutaneous absorption
Percutaneous Absorption Enhancers
Mechanisms
of
action
by
which
Materials
enhance
absorption through stratum corneum is either by
 Enhancing drug release from the formulation to the skin
 Reduction of the resistance of the stratum corneum by
altering it physicochemical properties
This can be achieved by the following mechanisms:
 Alteration of the hydration of the stratum
corneum using occlusive formulations
 Carrier mechanisms in the transport of ionisable
drugs
 Enhance absorption by directly influencing
the stratum corneum
(CHEMICALLY or PHYSICALLY)
Chemicals used to enhance absorption by directly
influencing the stratum corneum
Chemicals interact with the keratin structure in the stratum
corneum and open the tight protein structure, this leads
increase the diffusion coefficient D for substances which use
the transcellular route:
Surfactants, Dimethylsulfoxide (DMSO) and Urea
Solvents extract lipids and making the stratum corneum more
permeable: Dimethylsulfoxide (DMSO) and Ethanol
Chemical enhancers which intercalate into the structured
lipids of the horny layer and disrupt the packing. Thus
make the regular structure more fluid and increases the
diffusion coefficient of drugs:
Azone, Oleic acid, and isopropyl myristate
Solvents increase solubility and improve partitioning:
Alcohol, acetone, polyethylene and propylene glycol
Ointments are semisolid preparations intended for
external application.
 Ointments may be medicated or non-medicated
Non-medicated ointment bases used for their
emollient, lubricating effect or as vehicles in the
preparation of medicated ointments
Ointment Bases
Ointment bases are classified into 4 groups:
(1) Hydrocarbon bases (Oleaginous Base)
(2) Absorption bases
(3) Water-removable bases
(4) Water soluble bases
Hydrocarbon bases (oleaginous bases)
1. Water-free
2. Difficult to wash off
3. Aqueous preparations are difficult to be
incorporated into them
4. Used as occlusive dressings for their emollient effect
(helps the skin retain moisture)
It can treat diaper rash (protect skin from
urine) and dry skin (retain moisture)
5. Stable, don’t dry upon aging
Petrolatum (Soft Paraffin)
Yellow Petrolatum (Vaseline)
Mixture of semisolid hydrocarbons obtained from petroleum.
Melts at temperatures between 38° and 60°C
Form an ointment-like gel with Polyethylene (PLASTIBASE)
which is compatible with most medicaments.
White Petrolatum (White Vaseline)
Decolorized petrolatum
More esthetically acceptable to patients than petrolatum.
Yellow Ointment (Simple Ointment)
Contains 5% of yellow wax and 95 % of petrolatum.
Yellow Wax, is the purified wax obtained from the honey
White Ointment (Simple Ointment)
Contains 5% of White wax and 95 % of White petrolatum
Absorption Bases
An absorption base is an oleaginous base that permit the
incorporation of aqueous solutions, and can be used as
emollients
Like the oleaginous bases,
• Absorption bases are not water washable
• They can incorporate 50% of their volume water,
where aqueous solution first incorporated into the
absorption base, then added into the oleaginous base
There are two types of absorption bases:
1) Contains a w/o emulsifying agent:
When water is taken up into the base, it will form a w/o
emulsion
(e.g. Hydrophilic Petrolatum and Anhydrous Lanolin)
2) Water-in-oil emulsions (emulsion bases) that permit the
incorporation of small, additional quantities of aqueous
solutions
(e.g. Lanolin and Cold cream)
Hydrophilic Petrolatum (Aquaphor)
Hydrophilic Petrolatum is composed of 3% cholesterol,
3% stearyl alcohol, 8% white wax, and 86% white
petrolatum.
It has the ability to absorb
water (upto 3 times its
weight), with formation of
water-in-oil emulsion W/O
Anhydrous Lanolin (Wool Fat)
It is insoluble in water, but mixes
without separation with water twice
its
weight
of
water
with
the
formation of a waterin-oil emulsion
Lanolin (Hydrous Wool Fat)
Obtained from the wool of sheep
 It is a water-in-oil emulsion W/O that contains between
25 and 30% water Additional water may be incorporated into
lanolin by mixing
Water-Removable Bases
oil-in-water emulsions
 Oil in Water emulsions
 Have the general formula: 30 % Emulsifying wax
50 % White soft Paraffin
20 % Liquid Paraffin
 Water washable
 They can be diluted with water or with aqueous
solutions. “water-loving “
 They have the ability to absorb serous discharges
in dermatologic conditions
Hydrophilic Ointment
Have the general formula:
Sodium Lauryl Sulfate
1 %
emulsifying agent
Stearyl Alcohol
25 %
emulsifying agent
White Petrolatum
25 %
oleaginous phase
Propylene Glycol
12 %
aqueous phase
Purified Water
37 %
aqueous phase
Methyl and propyl parabens are used as preservatives
Water-Soluble Bases (greaseless bases)
Unlike water-removable bases,
which contain both water-soluble and water-insoluble
components, water-soluble bases contain only watersoluble
components with the absence of any oleaginous materials
Like water-removable bases,
They are water washable
Because they soften greatly with the addition of water, aqueous
solutions are not preferred to be incorporated into these bases.
They are better used for the incorporation of nonaqueous or
solid substances
Polyethylene Glycol Ointments
Polyethylene glycols are polymers of ethylene oxide and
water represented by the formula
HOCH2(CH2OCH2)nCH2OH
The chain length varied to achieve polymers with different
physical form (liquid, semisolid, or solid).
PEG
APPEARANCE AT 25° C
PH
AVERAGE
MOLECULAR
WEIGHT
MELTING
POINT
HYDROXYL
VALUE
MOISTURE
CONTENT
MAX.
PEG-200
Clear viscous colorless
liquid
4.0-7.0
190-210
<65°C
500-550
1.0%
PEG-300
Clear viscous colorless
liquid
4.0-7.0
290-310
<15°C
340-394
1.0%
PEG-400
Clear viscous colorless
liquid
4.0-7.0
390-410
4-8°C
264-300
1.0%
PEG-600
Clear viscous colorless
liquid
4.0-7.0
590-610
15-17°C
176-200
1.0%
PEG-1000
White waxy solid
4.0-7.0
950-1050
37-38°C
105-120
1.0%
PEG-1500
White waxy solid
4.0-7.0
1450-1550
44-45°C
70-90
1.0%
PEG-2000
White flakes
4.0-7.0
1950-2050
45-46°C
50-70
1.0%
PEG-4000
White flakes
4.0-7.0
3800-4200
53-56 °C
30-36
1.0%
PEG-6000
White flakes
4.0-7.0
5500-6500
55-63 °C
16-20
1.0%
Preparation of polyethylene glycol
ointment base:
Combine polyethylene glycol 3350 (solid)
40 %
and
60 %
polyethylene glycol 400 (liquid)
If an aqueous solution is to be incorporated into the base,
substitution some of polyethylene glycol 3350 with an equal
amount of stearyl alcohol would be advantageous to render
the final product more firm.
OLEAINOUS G
OINTMENT
BASES
ABSORPTION
OINTMENT
BASES
WATER-REMOVABLE
OINTMENT BASES
WATERSOLUBLE
OINTMENT
BASES
Oleaginous
bases +
w/o surfactant
Oleaginous base +
Polyethylene
Water (> 45%) +
Glycols (PEGs)
O/W surfac. (HLB >9)
Anhydrous
anhydrous
hydrous
anhydrous,
hydrous
Affinity for
Water
Hydrophobic
hydrophilic
hydrophilic
hydrophilic
Spreadability
difficult
difficult
easy
moderate to
easy
Washability non-washable
non-washable
washable
washable
oils poor;
hydrocarbons
better
oils poor;
hydrocarbons
better
unstable
stable
Solids
Oils (oil
soluble drugs)
Solids
Oils
Aqueous
solutions
 Solid
 Aqueous solutions
(small amounts)
Solid
Aqueous
solutions
Non-aqueous
solutions
Oleaginous
Composition
compounds
Water
Content
Stability
Drug
Incorporati
on
Potential
Continue
OLEAGINOUS
OINTMENT
BASES
ABSORPTION
OINTMENT BASES
WATERREMOVABLE
OINTMENT BASES
WATERSOLUBLE
OINTMENT
BASES
poor
but > oleaginous
fair to good
good
yes
yes
no
no
Uses
Protectants
Emollients
 Vehicles for
hydrolysable
drugs
Protectants
Emollients
Vehicles for
aqueous
solutions, solids,
and non
hydrolyzable
drugs
Emollients
 Vehicles for
solid, liquid, or
non-hydrolyzable
drugs
Drug
vehicles
Examples
Yellow
Petrolatum
 White
Petrolatum
 Yellow
Ointment
 White
Ointment
 Hydrophilic
Petrolatum
(Aquaphor®),
 Anhydrous
Lanolin
 Lanolin
Hydrophilic
Ointment
PEG
Ointment
Drug Release poor
Occlusiveness
Selection of the Appropriate Base
The selection of the base of an ointment
depends on many factors:
Patient Factors
The condition of the patient's skin, e.g. oozing or dry
The rule in dermatology that
if a patient's skin is dry-wet it, If it is wet-dry it
if a patient's skin is dry, occlusive ointment base that retain
moisture is preferable
Physicochemical Factors
1
The desired release rate of the drug from the ointment base
2
The desired enhancement of the percutaneous absorption
of the drug
3
The desired occlusion of moisture from the skin by the base
4
The stability of the drug in the ointment base, for a drug that
hydrolyzes rapidly as antibiotics, a hydrocarbon base would
provide the greatest stability
5
The influence of the drug on the consistency of the ointment
base
6
The influence of the drug on the consistency of the ointment
base
7
The desired washability of the base as for application to
hairy regions, a Polyethylene Glycol base is preferred
8
For ophthalmic ointments, non-irritant bases are desired.
Absorption O/W emulsion bases and water soluble bases
are irritants due to the effect of the surfactants in the base
It is preferred to use yellow paraffin but not white due to the
irritation effect of the bleaching agents
Preparation of Ointments
depending on the nature of the ingredients
ointments are prepared by two methods:
Incorporation method
A- INCORPORATION OF SOLIDS:
Using the geometric dilution method
The powdered components reduced to fine powders to
prevent grittiness
Fine powdered drugs are blended
Then powder are levigated with agent that is compatible
with the base, e.g., mineral oil or glycerin
The amount of levigating agent equal to the material to be
levigated
Solid materials soluble in a solvent that is compatible
with the product may first be dissolved
e.g., dissolve salicylic acid crystals in alcohol
Mix with a portion of the base until the product is smooth
and uniform
Another portion of the base is added to the
mixture
The process being repeated until all of the
ointment base has been incorporated
Ointment roller mills resulting in a products
that are smooth and uniform in composition
and texture
INCORPORATION OF LIQUIDS
For aqueous solutions:

Water-absorbable or hydrophilic ointment bases are suitable
 In oleaginous ointment base, a portion of the base must
be replaced with a hydrophilic base,
 Incorporates the solution in it, and mixes the product
with the original base
For Alcoholic solutions
 Oleaginous vehicles or emulsion bases are suitable
Other liquid materials as natural balsams
(Peru balsam)
 It is difficult to be incorporated into ointment bases
 Mix balsam with an equal portion of castor oil before
incorporating it into the base
This procedure reduces the surface tension of the balsam
and aid in distribution of the balsam through the vehicle
Fusion method
Ointment bases containing components as:
beeswax, paraffin, stearyl alcohol, and high molecular
weight polyethylene glycols, which do not mix well by
incorporation, are prepared by fusion
The components of an ointment are combined by being
melted together and cooled with constant stirring until
congealed
Components not melted are added to the congealing
mixture during cooling and stirring
Heat-labile and volatile substances are added when the
temperature of the mixture is low enough
Many substances are added to the congealing
mixture in solution, others are added as insoluble
powders levigated with a portion of the base
Once congealed, the ointment may be passed
through an ointment mill to ensure a uniform
texture
If the item having the highest melting point is
melted first and the other components are added to
this hot liquid, all the components will be subjected
to this high temperature, irrespective of their own
individual melting points
By melting the component having the lowest
melting point first and adding the components of
higher melting points in order of their individual
melting points a lower temperature is usually
sufficient to achieve fusion
*This is due to the solvent action exerted by the first
melted component on the other components
In the preparation of ointments having an
emulsion type:
Melting process and emulsification process are used

The water immiscible components such as oil and
waxes are melted together in a steam bath to about
70 to 75°C

Aqueous solution of all of the heat-stable, water-soluble
components is prepared in the amount of water in the
formula and heated to the same temperature as the
oleaginous components
The aqueous solution is slowly added to the melted
oleaginous mixture, with constant stirring
 The temperature is maintained for 5 to 10 minutes
to prevent crystallization of waxes.
Then the mixture is slowly cooled with the stirring
until congealing
Preservation of Ointments
 Semisolid preparations as ointments especially
those utilizing bases which contain water require
the addition of antimicrobial preservatives to
inhibit the contamination
Using preservatives as phydroxybenzoates,
phenols, benzoic acid, sorbic acid, quaternary
ammonium salts
Ultra filtration of the vehicle and using aseptic
manufacturing processes
Packaging and Storage of Ointments
Semisolid
preparations
must
be
protected
through proper packaging and storage from the
destructive influences of air, light, moisture, and
heat, and the possible chemical interactions
between the preparation and the container
Ointments are usually packaged
either in jars or in tubes
May be made of Plastic or glass,
uncolored, colored green, amber, or
blue, or opaque and porcelain-white.
Opaque and colored-glass containers are useful for
ointments containing drugs that are light sensitive
Jars for ointments may vary in size from as little as 1/2 oz
to 1lb or more
Ointment jars are filled by forcing the ointment down and
along the sides of the jar to avoid the entrapment of air
Ointments prepared by fusion may be poured directly into
the ointment jars for congealing within the jar
Most ointments must be stored at temperatures below
30°C to avoid the softening and liquefying of the base,
o to prevent settling of insoluble medicaments to the bottom
of the containers
o to prevent separation of emulsion
bases into two phases
Tubes
The collapsible tubes are
made of tin or plastic
Some tubes co-packaged with special tips when the
ointment is to be used for rectal, ophthalmic, vaginal or
nasal application
Tubes of ointments for ophthalmic use are
most commonly packaged in small, tin or
plastic collapsible tubes holding about 3.5 g
of ointment
Tubes of ointments for topical use are of 5 g to 30 g size
Tubes are filled by pressure fillers from the open back end
which is then closed and sealed
Ointments in tubes are less exposed to air and
contaminants and are more stable
1
than ointments packaged in jars
2
3