Transcript Topical Treatment

Topical Treatment
in skin disorders
皮肤病的外用药治疗
Professor Zheng Min
郑敏教授
Pharmacokinetics and Topical
Applications of Drugs
in skin disorders therapy
1.
2.
3.
Topical formulations may undergo radical
changes in composition and structure.
The effectiveness of the skin barrier often
changes with time.
The skin barrier is influenced by the type
and progression of a disease.
4.
5.
6.
There is regional variation in the barrier
properties of the skin.
The viable tissues themselves respond to
topical applications in manners that may
either enhance or retard percutaneous
absorption.
Drugs influence all of these processes in a
more or less specific manner.
THREE-COMPARTMENT MODEL

Although pharmacokinetic analysis of topical
applications may require the description of a
relatively large number of compartments, this
discussion is confined to the three outlined in



the skin surface,
the stratum corneum
the viable tissue.
Diagrammatic representation
of three compartments of
the skin:



Following surface
applications, evaporation and
structural/compositional
alterations in the applied
formulation may play an
important role in determining
the bioavailability of drugs.
The stratum corneum, the
outermost layer, plays the
most significant role in
determining the diffusion of
compounds into the body.
Following absorption,
compounds may bind or
diffuse within the viable
tissues or become resorbed by
the cutaneous vasculature.




A schematic drawing of the basic organization of the stratum corneum,
indicating
the overlapping of the corneocytes
the tortuous path of the intercellular lipid domain (shaded gray).
Though the corneocytes occupy the bulk of the stratum corneum, the
only continuous domain is the intercellular lipid, which is followed by
compounds undergoing percutaneous absorption.


Compartments
Encountered by
Substances
Undergoing
Percutaneous
Absorption:
General
Relevance of
Processes to
Bioavailability



The principal factors determining the
pharmacokinetics of a topical application are the
physiochemical properties of the bioactive
molecule.
Hydrophobicity, molecular weight, and ionic
charge determine the feasibility of transdermal
delivery for any particular compound.
Formulations influence the pharmacokinetics
largely from considerations of the thermodynamic
activity of the compound.



However, one should not exclude the impact of
changes in the formulation that occur following
topical application.
Evaporation, and changes in the structure of
emulsions, may bring dramatic changes in the
thermodynamic activity of the compound at the
skin surface.
Under some circumstances, this may lead to the
retention of the drug on the skin surface.
Topical Therapy
1. topical agents
2. formulation
3. therapy principle
The function of topic preparations

The main function of common topic preparation









（1） Cleansing agents
（2） Barrier Preparations
（3） Antipruritics agents
（4） Antibacterial agents
（5） Antifungals agents
（6） Antivirals agents
（7） Antiinflammtory and Anti-allergics agents
（8） Keratoplastics Agents
（9） Keratolytics agents
Cleansing agents



Cleansing agents are used to remove debris and to
combat infection.
Some are astringents which precipitate protein
and in doing as help to seal the moist surface of
weeping eczema or a stasis ulcer.
preparations




Physiologic saline；
1：8000 potassic permanganate；
2％∽4％boric acid；
Vegetable oil and liquid paraffin;
Barrier Preparations


Barrier Preparations are used to
protect the skin from irritants
preparations





Talcum powder
Zinc oxide
calamina
Starch
Vegetable oil
Antipruritics agents

Preparations that could stop itchness by cooling,
local anaesthesia, dimimish inflammation

Preparations：



0.5%∽2%mint
2％comphor
1％∽2％Dyclonine
Antibacterial agents

The ideal priparation should have





high antibacterial activity,
low allergenicity,
the durg should not be available for systemic use
This combinaton is hard to find.
Some compromises are given following


Bactroban ointment (mupirocin)
Fucidin ointment,cream or gel (fusidic acid)
Antifungals agents

kill or inhibition fungals agents







5-10%sulphur
5-30% Glacial Acetic Acid
6-12% Benzonic acid
3-10 % Salicylic acid clotrimazole
1-3% Miconazole
1% Econazole
1% Terbinafine
Antifungals agents



The first- and second-generation imidazoles include
clotrimazole,26 econazole, ketoconazole, miconazole, and
sulconazole as topical therapies; they have similar
spectrums of efficacy and activity.
They function by blocking synthesis of ergosterol, which
plays an integral role in cell membrane structure and
function.
The imidazoles delay or inhibit cellular growth at low
concentrations and are fungicidal at 5 to 10 times the
minimum inhibitory concentration.
Antivirals agents



These have little part to play in the management
of herpes zoster
However, if used early and frequently, they may
help with recurrent herpes simplex infections
Preparations




2％∽3％ aciclovir cream；
Penciclovir cream
Phthiobuzone cream
Imiqiumod cream；
Antiinflammtory and Anti-allergics agents


Antiinflammtory agents
 Coal Tar
Anti-allergics agents
 Topical Glucocorticoids
Antiinflammtory agents

COAL TAR




Coal tar is manufactured as the by-product of
processing coke and gas from bituminous coal
Studies suggest that tars depress DNA synthesis and
have an antimitotic effect.
Coal tar applied to normal skin produces early
suppression of epidermal DNA synthesis followed by
a proliferative response.37
When applications are continued for up to 40 days,
there is a cytostatic effect resulting in epidermal
thinning.
SHALE TAR


Shale tar (ichthammol) originates from
shale oil that undergoes chemical
degradation with ammonia and sulfuric
acid to form a sulfur-rich substance.
It is most often formulated with glycerin
and is thought to have both antiinflammatory and vasoactive properties.
WOOD TAR



Wood tars are obtained by distilling wood under
controlled conditions.
They can be added to arachis oil (peanut oil) or
simple bases as an application to the scalp in
seborrheic dermatitis and psoriasis.
Oil of cade is also a major ingredient in the 2010-5 ointment, which consists of 20% oil of cade,
10% sulfur, and 5% salicylic acid.
Anti-allergics agents

Topical Glucocorticoids



Hydrocortisone, the first topically effective
glucocorticoid, was introduced by Sulzberger and
Witten in 1952.1
Subsequently, a succession of ever more potent
glucocorticoid preparations have been developed.
Currently, topical steroids are the most frequently
prescribed of all dermatologic drug products.

Steroids can be divided into two classes:




Fluorinated
nonfluorinated.
The term fluorinated steroid is used when
referring to the steroids that have been chemically
altered to increase their potency.
The strength of a steroid can be increased by
halogenation at the 9a position, which allows
improved activity within the target cell and
decreased breakdown into inactive metabolites.

Topical glucocorticoid research has focused on
strategies to optimize potency while minimizing
side effects.



One strategy is to develop compounds with enhanced
anti-inflammatory effects and minimal unwanted
atrophogenic and adrenal suppressive effects.
Another strategy is to develop compounds that exert
their effects on the epidermis and then are quickly
broken down into inactive metabolites.
Research to develop a nonsteroidal compound with
the same anti-inflammatory effects of glucocorticoids
but without the side effects is currently ongoing.
The clinical effectiveness of glucocorticoids

The clinical effectiveness of glucocorticoids is
related to four basic properties:
vasoconstriction,
 antiproliferative effects,
 immunosuppression,
 anti-inflammatory effects.
Topical steroids cause capillaries in the superficial dermis to
constrict, thus reducing erythema.
The ability of a given glucocorticoid agent to cause
vasoconstriction usually correlates with its anti-inflammatory
potency
thus vasoconstriction assays are often used to predict the
clinical activity of an agent. These assays in combination with




Responsiveness of Dermatoses to Topical Application of Corticosteroids
ADVERSE EFFECTS

Striae and atrophy


the most commonly observed side effects,
occur with prolonged use and are more likely
to occur in areas of sweating, occlusion, or
high penetration such as the axilla or groin
In general, atrophy does not occur until the
agent has been used for 3 to 4 weeks and is
usually reversible. .

Topical steroids can also cause suppression of the
pituitary-adrenal axis


Most topical and systemic side effects are readily
reversible if recognized early by the clinician
Patients treated with topical glucocorticoids may
develop a contact or irritant dermatitis to the
steroid itself or, more commonly, to one of the
ingredients used as a preservative.
Keratoplastics Agents




Promote normal keratosis
Shrink blood vessel
Reduce effusion and inflammatory infiltration
Preparations






5-40% pityrol
2-5％ coal tar
2-5% resorcinol；
3％ salicylic acid
3-5％ sulphur
0.1-1% anthralin；
Keratolytics agents


Make keratinocytes loose and separate and
fall off
Preparations






10-30% Glacial Acetic Acid
6-15 ％ salicylic acid
10％sulphur
15-30％urea
0.01－0.1％ retinoid acid
6-15% resorcinol
The other functions of topic preparations






antiperapirants
astringent
caustic agents
antineoplastics
sunsreens and sunblocks
depigmenting agents ( or bleaching agents)
Principles of topical therapy



(1) classification and clinical application of
topical formulations
(2) review of vehicle ingredients
commonly used in topical medicaments
(3) appropriate administration and dosage
of topical therapy
CLASSIFICATION AND CLINICAL
APPLICATION OF TOPICAL
FORMULATIONS



The term vehicle is used for those substances
that bring specific drugs into contact with the
skin.
The vehicle itself may have beneficial
nonspecific, or “bland,” effects on the skin by
possessing cooling, protective, emollient,
occlusive, or astringent properties.
For any drug to be effective topically, it must
be formulated at the proper concentration and
in the proper vehicle.

In general, the most important vehicles for
topical use may be divided into




Monophasic
Biphasic
Triphasic forms
which can be further classified as shown in
the Fig.
The derivation of basic
forms of topical
application. , Monophasic
vehicles; biphasic vehicles;
triphasic vehicles.
(Modified from Polano,7
with permission.)
Monophasic Vehicles
Solutions


Liquids are used as solvents for drugs or are
made into gels by the addition of thickening
agents.
Clinical applications of liquid preparations
include






wet dressings
baths, tinctures
Paints
topical solutions
Aerosols
sprays.


Wet dressings are indicated in the treatment
of acute inflammatory states characterized
by oozing, weeping, and crusting and in
bullous disease, erosions, and ulcers.
Solutions of aluminum acetate (Burow's
solution; Domeboro) have been used since
the nineteenth century for wet dressings.
tinctures and spiritus




Tinctures and paints are organic solvent
solutions that evaporate rapidly after application
to the skin, leaving a film of active ingredient.
Tinctures were originally alcoholic solutions
derived from maceration of herbs.
The term paint refers to staining solutions such as
Castellani's paint.
Tinctures and paints are of limited use in modern
clinical setting because of their excessive drying
and staining properties.
powders




In general, powders promote drying.
Since they adhere poorly to the skin, their use is
almost completely limited to cosmetic and
hygienic purposes.
Most powders used for skin care consist of zinc
oxide or titanium oxide for covering properties,
talc (hydrous magnesium silicate) for smooth
application, and a stearate (usually zinc or
magnesium) for improved adherence to the skin.
注意事项：


不能用于摩烂处或有渗出处；
不能用于腔口附近及毛发处；
lotions


Lotions and solutions may also be
suspended in a propellant to be delivered to
the skin in the form of an aerosol or spray.
This form of delivery may be useful when
the degree of inflammation, tenderness, or
oozing makes direct application difficult or
painful.
oils



Oils are rarely used alone in topical therapy
because they do not adhere to the skin.
The principal use of oils (mineral oil,
cottonseed oil, etc.) is the removal of fatmiscible applications from the skin.
Oils added to baths, as mentioned earlier,
may function as emollients.
gel



Gels are transparent, colloidal dispersions
that liquefy on contact with skin.
They are not greasy and are cosmetically
acceptable.
When applied to the skin, gels dry as a
nonocclusive film and are appropriate for
use on hairy areas.


Most gels are solutions of solvents such as water,
acetone, alcohol, or propylene glycol thickened
with organic polymers such as carbopols.
While having the advantage of being waterwashable, nongreasy, and cosmetically elegant,
gels have the disadvantages of being easily
removed by perspiration and lacking any
protective or emollient properties.
Biphasic Vehicles
SHAKE LOTIONS



These are watery lotions to which powder is
added so that the area for evaporation is increased.
Generally, zinc oxide, talcum, calamine, glycerol,
alcohol, and water are used, to which specific
drugs and stabilizers may be added.
These lotions dry and cool wet, weeping skin.

The name shake lotion indicates one of the
drawbacks of this formulation:
a tendency to sedimentation requires shaking prior
to each use in order to obtain a homogeneous
suspension.
 In addition, when the water has evaporated from
the skin, the powder particles may clump together
and become abrasive.
 For this reason, patients should be instructed to
remove such residues carefully prior to
reapplication of shake lotions.

emulsion



CREAMS Creams are emulsions of oil-in-water
(O/W).
In a cream, the oil droplets are dispersed in a
continuous phase of water or a polar liquid.
Emulsifying agents are necessary for such
formulations to increase the surface area of the
dispersed phase and that of any therapeutic agent
in it.


Creams may also contain preservatives,
which may produce an allergic contact
dermatitis.
Creams are used widely for their cooling,
moisturizing, and emollient effects.
ointment


OINTMENTS These spread easily to form
a protective film on the skin and are more
lubricating than creams.
Due to their occlusive nature, ointment
vehicles generally provide better topical
penetration of incorporated drugs than do
creams or lotions.
paste



Pastes are ointments into which 20 to 50%
powder (e.g., zinc oxide, starch) is incorporated.
The powders must be insoluble in the ointment
base, usually petrolatum or carbowax, in order to
exert an absorbent effect.
Pastes are more drying, less greasy, and often
better tolerated than ointments.


They may be useful in the treatment of ulcers and
in the management of chronic exudative
dermatoses and thick lichenified plaques.
In psoriasis therapy, incorporation of anthralin
(0.1 to 0.2%) in Lassar's paste (a stiff paste of
zinc oxide, cornstarch, and white petrolatum)
allows localization of anthralin to the psoriatic
plaques.
Triphasic Vehicles



Cooling pastes and cream pastes are triphasic
vehicles that consist of oil-water-powder mixtures
in varying proportions.
The first cooling paste was prepared by Unna in
1900.
Cooling pastes are useful for their soothing
properties on acutely inflamed and weeping skin,
and indications for their use are similar to those
for wet dressings.



They are less drying than shake lotions and have
the added benefit of cooling.
Cream pastes are obtained by adding zinc oxide
to O/W or W/O emulsions and are comparable to
the greasy pastes described earlier.
The basic formula for a cooling paste includes
zinc oxide, calcium hydroxide solution, and oil.7
Plasters



Drugs in Adhesiveness base（aluminium
oxide, rubber and lanolinum)
Better penitrativity 穿透性强；
precausing


Hypersensetivity
Hypertrichiasis skin
Formulation Ⅰ
Dosage form
powder
solution
lotion
cream
component
drug put into
zinc oxide , talc
liquid and soluble drug
action
indications
protection、cooling acute and subacute
astringency
inflammation but no
effusion
cooling、reduce
reduce inflammation
clear raw surface
acute inflammation
with lots of effusion
protection、cooling
acute and subacute
reduce inflammation
inflammation without
astringency
effusion
consisting of aqueous
protection、lubrication
subacute or chronic
and oily components
intenerate crust
O/W emulsion being readiy reduce inflammation
inflammation ,pruritus
powder and liquid
mixture
diluted with water,W/O
emulsion with oil
Formulation Ⅰ
Dosage form component
Gel
Propanediol gelatin
of organic polymer
＋drug
action
same as cream
indications
same as cream
Fomulation Ⅱ
dosage form component
Paste
cream including
25%-50% powder
ointment vehicle with vaseline
or lanolin
tincture resolve or steep
action
indications
protection、astringency
subacute inflammation,
intenerate crust
diminish inflammation
scar,erosion
strong action of
chronic inflammation
lubrication、penetration
ulcer
intenerate crust
diminish inflammation
drug by alcohol
antipruritic
chronic inflammation
sterilization
pruritus
Fomulation Ⅱ
dosage form
Plastics
component
organic menstruum
and aqueous solution
contain macromolecule
compound or film agent
action
protection
strong percutaneous
strong percutaneous
action
indications
chronic
inflammation
VEHICLE INGREDIENTS COMMONLY
USED IN TOPICAL PREPARATIONS







the general classes of commonly used vehicle
ingredients found in topical preparations:
emollients,
humectants,
solvents,
emulsifying agents,
stabilizers,
thickening agents.
Emollients




Emollients are occlusive agents that make the
skin soft and pliable by increasing hydration of
the stratum corneum.
Petrolatum is probably the most occlusive and
therefore the best emollient available.
Due to its inherent greasy feel, petrolatum is often
mixed with other materials to produce a more
cosmetically acceptable vehicle.
Cetyl alcohol and stearyl alcohol are mixtures of
solid aliphatic alcohols that lubricate the skin
without being greasy.
Humectants



These are hygroscopic agents that draw
moisture into the skin.
It should be noted, however, that under dry
atmospheric conditions humectants actually
withdraw water from the skin.
Glycerin, propylene glycol, and sorbitol are
examples of humectants used in topical
products.
Solvents


Solvents are used to increase the solubility
of the active drug in the formulation or to
solubilize other necessary ingredients in the
product.
Water, alcohol, glycerin, and propylene
glycol are commonly used solvents.
Emulsifying Agents

These are added to thermodynamically
unstable dispersions of two or more
immiscible liquid phases


usually an aqueous phase and an oil phase
to improve stability by decreasing surface
tension.
Stabilizers


Stabilizers include preservatives,
antioxidants, and chelating agents.
Preservatives are added to prevent or
inhibit microbial growth.
Thickening Agents


These include materials used to thicken or
increase the viscosity of products or to
suspend ingredients in the formulation.
They may act as emulsion stabilizers or as
ointment bases. Beeswax is used to
increase viscosity in ointments and enables
the incorporation of water in the
formulation to produce W/O emulsions.
APPLICATION AND DOSAGE
OF TOPICAL THERAPY
The three-phase model of drug
action

1.
The three-phase model of drug action
described by Arriens8 may be applied to
topical therapy:
The initial pharmaceutical phase is
represented by application of a drugvehicle combination to the skin.
Studies on the importance of the vehicle deal with
this phase.
2.
The pharmacokinetic phase covers the
penetration and permeation of the drug
into the skin.
After permeation through the skin, no further
therapeutic effect in the skin is expected.
Systemic effects follow.
3.
The pharmacodynamic phase refers to the
interaction of the drug with receptors in
the normal or diseased skin.

These pharmacologic phases of skin therapy are
influenced by a myriad of biologic and
physiochemical factors, the most pertinent of
which include



the concentration of the active drug;
the amount of the drug-vehicle applied to the skin;
the frequency, mode of application, and regional
variation in absorption characteristics of different
anatomic sites.
Concentration

The importance of the concentration of
active drug was recognized early because


most dermatologic drugs have the potential to
be irritants at high doses
some topically applied drugs have systemic
toxicity when applied to large areas in high
concentrations (e.g., salicylic acid, phenol).
Frequency


It is known that potent fluorinated steroids form
reservoirs in the stratum corneum.10
Although it is possible to elicit vasoconstriction
responses for several days after application of
these steroids,


it is not clear whether or not the reservoirs have
therapeutic significance
It is likely that a single daily application of a drug
(at least for glucocorticoids) is a sufficient, if not
the most efficient, schedule of delivery to the skin.
Quantity of Application



Dosage of topical therapy remains an elusive art
form, in marked contrast to scientifically guided
dosage for systemic therapy.
Quantitative aspects of topical therapy are too
often neglected.
It must be remembered that the quantity of
medication prescribed inevitably influences the
way the patient uses the remedy.


In general, thickness of the layer applied to
the skin does not appear to enhance the
penetration of a specific drug.16
Schalla et al. also maintain that a thick
layer of an ointment or cream gives no
better therapeutic effect than a thin layer.
Suggested Amounts of Topical Medications to
Dispense—Cream or Ointment


One gram of cream covers an area approximately
10 by 10 cm.
An ointment spreads up to 10 percent further.
According to Arndt, the amount needed for the
single application of a cream or ointment to




the face or hands is 2 g;
to one arm or the anterior or posterior trunk, 3 g;
to one leg, 4 g;
to the entire body, 30 g.



When a patient applies a dermatologic
preparation, the layer of a formulation covering
the skin is very thin (approximately 5 to 10 µm),
corresponding to a volume of between 1 and 3
µL/cm2.
Thicker layers are felt as “undesirable” and
consciously or subconsciously rubbed or spread
to larger surfaces.
This restricts the amount of compound that can
effectively come in contact with the skin surface
to approximately 10 to 30 µg/cm2 for a 1% (wt/wt)
topical formulation.
Regional Variations in
Penetration


the different regions of the body in order of
increasing resistance to penetration by
chemical agents.
There is marked regional variation in the
amount of drug absorbed from different
anatomic sites
Regional Differences in Penetration*
Therapeutic principle of topic
agents


1.Choice right drugs
2.Principles of formulation:

acute lesion



subacute lesion:



more effusion—solution (hydropathic compress)
no effusion--powder、lotion
effusion—paste
no effusion--power、lotion、cream
chronic lesion:
plastics
cream 、ointment、tincture、
 3. attentions:
a.concentration
b.peri-oral cavity
c.make right use of drug
d.irritation and allergic reaction
Physical Therapy(1)


Electrosurgery
electrodesiccation
coagulation
electrocautery
phototherapy
infrared
ultraviolet
PUVA
laser treatment
Dermatological Surgery




Dermabrasion(surgical skin planing)
Excision
Hair transplantation
epidermal transplantation: vitiligo
Physical Therapy(2)
 cryosurgery
 hydrotherapy
 radiotherapy
Summary



Treatment by topical application is important in
dermatotherapy, and the risks of systemic sideeffects are minimized.
The basic principles of prescribing and
formulating topical applications should not be
neglected in the medical curriculum.
A doctor today must not only ensure that
treatment is in the right form and contains the
most appropriate active ingredient, but must also
be able to instruct the patient how to use the
treatment and advise as to any likely side-effects.
Summary



According to the vehicle, external preparations
have been made classification system, such as the
simplest system consists of an initial division into
liquid, semisolid and powder. Different disease
have different causes.
According to the pathogenesis, a doctor can
choose different agent: topical antibiotics,
antifungal agents, antiviral agents, topical steroid,
topical cytotoxic drugs and immuntherapy and so
on.
Both the medication and vehicle chosen must be
appropriate for the condition being treated.
Thank you for
your attention！