EVALUATION CRITERIA FOR TOPICAL DRUG DELIVERY SYSTEMS
Topical preparations must be formulated, manufactured and packaged in order to meet
general standards of:
bioavailability
physical stability (of the system)
chemical stability (of the ingredients)
freedom from contamination
elegance
As the pharmacist, you should understand the unique problems associated with topical dosage forms in order
to formulate them or evaluate them.
Physical and Chemical Evaluation Criteria:
1) Stability of active ingredients and adjuvants
2) Cosmetic criteria (appearance, odour, ease and feel of application)
3) Rheological characteristics (viscosity, extrudability)
4) Phase Distribution (homogeneity, phase separation, bleeding)
5) Particle size distribution of dispersed phases
6) Loss of water and other volatile vehicle preparations
7) Particulate contamination
8) Microbial contamination/sterility (unopened container/under conditions of use)
9) Bioavailability (release, factors affecting percutaneous penetration)
Semisolid systems are chemically complex, with vehicle components often interfering with analytical assays.
All the factors mentioned must be acceptable initially and all must remain so over the stated lifetime of the
product (shelf-life)
1) Stability of active ingredients and adjuvants
These systems exhibit phase changes on heating, so elevated temperature kinetics are unsuitable for early
stability prediction. Testing has to be conducted at room temperature where marginal instability may not be
detected until studies have been in progress for a protracted period.
Qualitative indicators of chemical degradation are the development/change of colour, and the
development of a disagreeable odour. Products may yellow or brown with age, indicating oxidative changes in
the constituents of the base (found with lanolins, natural fats and oils).
Extensive oxidation (rancidification) is accompanied by the development of a disagreeable odour and possibly
phase and texture changes - the pharmacist should remove any of these from circulation.
2) Cosmetic Criteria
A number of attributes of topical drug systems may be classified as cosmetic: ease of application, the feel of a
preparation once it is on the skin, and the appearance of the applied film.
2.1) Ease and method of application
This depends on the physicochemical attributes of the formulation.
Solutions and other highly fluid systems may be swabbed on, sprayed on, or rolled on.
Soft, semisolid systems may be spread evenly and massaged into the skin with the fingers.
The spreadability is a rheological quality related to the nature and degree of internal structure of the
formulation. Stiff products tend to be hard to apply and this can be painful over broken and irritated skin.
Stiffness can be adjusted by:
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manipulating the concentration of waxy components of the vehicle and by adjusting
the phase/volume ratio of semisolid emulsions
in ointments, increased spreadability can be obtained by decreasing the ratio of thewaxy components
(waxes and petrolatum) to fluid vehicle components (mineral oil).
in o/w creams, decreasing the ratio of the internal phase to the external phase, or substituting liquid
oils for high-melting waxy components tends to make the system more fluid.
2.2) Feel of a preparation on the skin
Tackiness and greasiness are determined by physicochemical properties of the vehicle constituents that
comprise the formed film on the skin. A sticky film is extremely uncomfortable.
In creams, the use of waxy materials such as stearic acid and cetyl alcohol produce noticeably non-tacky films.
The presence of natural and synthetic gums as thickening and suspending agents into the aqueous phases tend
to increase tackiness - and so must be used in minimal amounts.
A number of semisolid preparations contain dispersed solids. This particulate phase must be in a physical state
such that individual particles are impalpable (incapable of being individually perceived as particles by touch),
otherwise they will feel gritty.
Particles below 50 µm are regarded as impalpable.
If there are palpable particles present, they will feel abrasive when applied to sensitive damaged skin. In an
ophthalmic ointment, severe eye irritation and damage are possible - here the size should be below 10 µm.
2.3) Appearance of the applied film
The degree of opacity of the topical applications is due mainly to the presence of insoluble solids which impart
a powdery-to-crusty appearance to applied films.
Sometimes the ingredients are functional e.g. calamine lotion, zinc oxide paste, and are an unadjustable
feature of the preparation.
Sometimes insoluble solids are added as tints to match the color of the skin, but this is generally unsuccessful
as they cannot be supplied with sufficient color variations to meet the needs of all users.
3) Rheological Characteristics
The time-dependent rheological behaviour of the formulation is also a good indicator of physical and chemical
change. Observed viscosity changes have to be substantial before a system is discarded as unstable.
4) Phase Distribution
Phase changes are a problem and if such changes occur, the product should be regarded as unstable and
unusable.
Phase changes may be the result of breaking of an emulsion, it may appear as "bleeding" or the formation of
droplets of clear liquid internal phase. Storage at warm temperatures can accelerate the problem.
5) Particle Size Distribution
Changes in the particle size or particulate nature of a suspended phase must be viewed as extremely serious
physical alterations and may be due to crystal growth, changes in crystalline habit, or reversion of crystalline
materials to a more stable polymorphic form.
This may result in a pronounced reduction in the drug delivery capabilities of a formulation.
6) Loss of volatile ingredients
This may be due to:
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inappropriate choice of package (some plastic materials) allowing diffusive loss through container
walls
improper sealing of the closure allowing diffusive leakage around the seams of tubes or the caps of
tubes and jars.
This may cause stiffening of the formulation and a corresponding weight loss. The entire system may shrink
and separate from the wall of the container (exacerbated if stored in dry, hot conditions).
7) Particulate Contamination
A problem source of contamination is associated with tin and aluminium collapsible tubes.
In their trimming, slivers and shavings may adhere electrostatically to the tubing walls. The pharmacist must
be alert to this in commercial products and, if packing a tube "temporaneously”, should clean the tube
suitably.
8) Bioavailability
The main requirement for topical therapy is that the drug in the vehicle reach the skin surface at an adequate
rate and in sufficient concentration.
The physicochemical properties of a drug that determine its ability to permeate skin are.
- the drug's diffusion coefficients within the various skin strata
- the drug's distribution coefficients between the vehicle and the tissues
- the concentration of the drug in the applied vehicle phase.
8.1) Concentration of drug
As the concentration of drug in the vehicle increases, so does the amount of drug absorbed per unit area.
More drug is absorbed when the drug is applied over a larger surface.
8.2) Site of application
Absorption from different sites varies depending on the thickness of the horny layer.
Absorption from palms of the hands and soles of the feet, which have thick horny layers, is comparatively
slow.
Skin that has been cut, broken or abraded will allow substances direct access to the underlying tissue.
8.3) Contact time with the skin
The longer the preparation is rubbed in, the greater the absorption.
The longer the contact time with the skin, the greater the absorption.
8.4) Partitioning and solubility
The skin membranes should have a greater attraction for the drug than does the vehicle in order for the drug
to partition in favour of the skin. However, the drug must not have such great affinity for the tissue that it
remains tightly bound and fails to penetrate as deeply as may be required.
Generally, the greater the oil solubility of the drug, the greater its percutaneous absorption.
However, some degree of solubility in both oil and water is thought to be essential for effective absorption.
The solubility of a topical drug in its formulation is important in choosing an appropriate vehicle.
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If the drug is only fractionally soluble in the vehicle, release from the vehicle may be compromised.
Poor release into the surface tissues is associated with less than maximal activity.
If the drug is so soluble in the vehicle film that in its formulated concentration it is in a highly
unsaturated state the drug will fail to effectively partition into the skin and will tend to remain in the
film, so biovailability again be poor.
The optimum is to have essentially all the drug in solution, but at the same time the vehicle is saturated or
nearly saturated with the drug. This optimizes vehicle/skin partitioning.
For this reason, propylene glycol and other solubilizing solvents have been added to cream vehicles to keep
drugs in solution in the vehicle film formed after application.
Note of caution for the Pharmacist. The common practices of extemporaneously compounding mixtures of
commercial products (e.g. mixing steroid with an antibiotic, or diluting a product) are suspect because the
biovailabilityof a previously carefully designed system may be compromised.
8.5) Hydrating the SC
Hydration of the SC appears to increase absorption of all substances that penetrate the skin.
This is probably due to softening of the tissue and the consequent "sponging" effect with an increase in the
size of the pores and increased diffusive mobility of drugs within the SC.
Covering the skin with a water-impermeable dressing forms an occlusive film which suppresses water loss
through evaporation and hydrates and softens the SC.
Absorption may increase 5 to 10-fold. This is clinically important - used with corticosteroids in the treatment
of psoriasis.
8.6) Use of penetration enhancers
Non-aqueous solvents e.g. DMSO (dimethyl sulfoxide) have been touted as skin penetration enhancers.
They cause a reversible denaturation of keratin which presumably "opens up" the protein matrix, facilitating
diffusive permeation.
It has also been suggested that the solvents are imbibed by the SC and increase the solubility of the drugs in
SC.
Individual sheets of cells in the SC may be delaminated and affect the SC as a skin barrier. Much of the
enhancement is lost if the solvents are diluted with water. This whole practice has not become an established
one.
Surfactants have been used as penetration enhancers e.g. sodium lauryl sulphate alters the SC chemically,
facilitating absorption.
8.7) Influence of the vehicle
Drug absorption appears to be best from vehicles that easily cover the skin surface, mix readily with the sebum
and bring the drug into contact with the tissue cells for absorption.
Absorption is better from vegetable and animal oils than from mineral oils as the former penetrate the skin
more readily.
Organic solvents such as ether, acetone and benzene can enhance the absorption of a drug dissolved in them
through their penetrability.
Vehicles that increase the amount of moisture retained by the skin usually increase absorption. Oleaginous
vehicles act as moisture barriers through which sweat cannot pass and the skin remains occluded, resulting in
increased hydration of the skin. w/o emulsions are probably next in enhancing hydration of the skin. Vehicles
containing humectants like glycerin to keep the ointment moist and from drying out have a tendency to draw
moisture from the skin in low humidity conditions.
Volatile vehicle constituents can also be used to modulate percutaneous absorption. Creams (80-85% water),
lotions and gels contain large proportions of volatile constituents - these formulations evaporate to a
concentrate after application. The drug delivery system is the formed, concentrated film, not the composition
as it is expressed from the tube/poured from bottle.
Vasoconstriction from steroids is more pronounced at low concentrations when applied in volatile ethanol
than when applied in propylene glycol. Apparently evaporation helps drive drug into the skin surface.
Much of the research into topical vehicles has been unrealistic as thick slabs of the vehicle have been
evaluated for their release characteristics and this does not resemble the real situation.
"In days when topical biovailability was little understood and therefore ignored, formulators concentrated
on vehicle elegance and stability. Attempts were made to design vehicles compatible with all types of drugs,
so-called universal vehicles. These are still discussed in many standard texts. Today's technology and science
clearly indicate that the universal vehicle is akin to a unicorn, beautiful but totally mythical. In the real
world, each system must be designed around the drug it contains to optimize the clinical potential of the
active ingredient"