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. Topical formulations may undergo radical changes in composition and structure.

2. The effectiveness of the skin barrier often changes with time.

3. The skin barrier is influenced by the type and progression of a disease.

4. There is regional variation in the barrier properties of the skin.

5. The viable tissues themselves respond to topical applications in manners that may either enhance or retard percutaneous absorption.

6. 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 application

s, 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 agents2. formulation3. 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 an

d 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 protec

t the skin from irritants preparations

Talcum powder Zinc oxide calamina Starch Vegetable oil

Antipruritics agents Preparations that could stop itchness by cooling, l

ocal 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 clotri

mazole,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 o

f 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 anti-inflammatory 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 20-10-5 ointment, which consists of 20% oil of cade, 10% sulfur, and 5% salicylic acid.

Anti-allergics agents

Topical Glucocorticoids Hydrocortisone, the first topically effective glucocort

icoid, 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, occ

ur 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 rev

ersible 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 solution

s 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 fat-miscible applications from the skin.

Oils added to baths, as mentioned earlier, may function as emollients.

gel Gels are transparent, colloidal dispersions t

hat liquefy on contact with skin. They are not greasy and are cosmetically a

cceptable. When applied to the skin, gels dry as a non

occlusive 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 water-washable, 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% powde

r (e.g., zinc oxide, starch) is incorporated. The powders must be insoluble in the ointment ba

se, 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 ⅠDosage form component action indications

powder drug put into protection 、 cooling acute and subacute

zinc oxide , talc astringency inflammation but no effusion solution liquid and soluble drug cooling 、 reduce acute inflammation reduce inflammation clear raw surface with lots of effusion lotion powder and liquid protection 、 cooling acute and subacute mixture reduce inflammation inflammation without astringency effusion cream consisting of aqueous protection 、 lubrication subacute or chronic and oily components intenerate crust O/W emulsion being readiy reduce inflammation inflammation ,pruritus diluted with water,W/O

emulsion with oil

Formulation Ⅰ

Gel Propanediol gelatin same as cream same as cream

of organic polymer

＋ drug

Dosage form component action indications

dosage form component action indications

Fomulation Ⅱ

Paste cream including protection 、 astringency subacute inflammation,

25%-50% powder intenerate crust scar,erosion diminish inflammation

ointment vehicle with vaseline strong action of chronic inflammation

or lanolin lubrication 、 penetration ulcer intenerate crust

tincture resolve or steep diminish inflammation chronic inflammation

drug by alcohol sterilization antipruritic pruritus

Plastics organic menstruum protection chronic

and aqueous solution strong percutaneous inflammation

contain macromolecule strong percutaneous

compound or film agent action

Fomulation Ⅱ

dosage form component action indications

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 sof

t 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 mo

isture 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

The three-phase model of drug action described by Arriens8 may be applied to topical therapy:

1. The initial pharmaceutical phase is represented by application of a drug-vehicle 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 r

eservoirs in the stratum corneum.10 Although it is possible to elicit vasoconstriction re

sponses for several days after application of these steroids, it is not clear whether or not the reservoirs have thera

peutic 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 more effusion—solution (hydropathic compress) no effusion--powder 、 lotion

subacute lesion: effusion—paste no effusion--power 、 lotion 、 cream

chronic lesion: cream 、 ointment 、 tincture 、plastics

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 derm

atotherapy, and the risks of systemic side-effects 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

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