seminar on topical therapy

Topical therapy: Dr Mesfin Hunegnaw

Consultant Dermatologist & Venerologist

AAU, Medical faculty

Dept. of Dermtovenerology

Introduction• Topical remedies

• Frazier and Blank:

“As a dog licks his wounds, so man is inclined to salve his skin.”

• The skin – accessible and visible – uniquely amenable to external remedies.

• indisputable evidence.

Introduction

• Successful dermatologic therapy depends on – the active drug – the physical properties of the formulation applied.

• The efficacy and tolerability of topical therapy depends:– the choice of vehicle– the form of medication– the frequency and quantity of application – the anatomic location and – the state of the affected skin

THEORETICAL ADVANTAGES

• Improved patient compliance

• Improved efficacy

• Reduced toxicity: • No 'peaks' and lower total

absorbed dose

• Bypass hepatic first-pass metabolism

• Avoid local GI side effects/metabolism

• Decreased dosing frequency

• Avoid painful injections

• Decreased costs to patient due to decreased:

• total dose and • dosing frequency

(increased efficiency)

Pharmacokinetics

• Pharmacokinetics of topical applications of drugs deals with

– the time-dependent passage of drugs out of a vehicle or device

and – their subsequent passage through the skin barrier into

• the underlying skin layers

• the general systemic distribution

Pharmacokinetics

Obscure: following application

– May undergo radical changes in composition and structure

– The skin barrier • effectiveness changes with time.

• is influenced by the type/progression of a disease.

• regional variation in barrier properties.

– The viable tissues affect percutaneous absorption.

– Drugs influence all of these processes

Pharmacokinetics

Diffusion• The principal factors that determine the flux of a compound

– the concentration gradient– the path length, and – the diffusion coefficient.

• Diffusion is a very effective transport mechanism over very short

distances but not over long ones.

Pharmacokinetics

Three-Compartment Model– the skin surface – the stratum corneum, and – the viable tissue.

• General Relevance of Processes to Bioavailability

• Within each compartment, the compound may – diffuse down its concentration gradient– bind to specific components, or – be metabolized.

Pharmacokinetics

In order to undergo percutaneous absorption, a compound must

• be released from its formulation ▼• encounter the skin surface ▼• penetrate the stratum corneum ▼• diffuse through the viable epidermis into the dermis, and ▼• access the systemic compartment through the vascular system.

Pharmacokinetics

The Skin Surface– Surface Applications of Formulations– Formulations– Liposomes as Transdermal Delivery Systems

• Liposomes are microscopic spheres comprising a bilayer that

encloses an inner aqueous core.

Formulations• Applications can be differentiated on the basis of whether

– compounds remain on skin surface (cosmetics)– are delivered to compartments in the skin (topical formulations) or – travel across the skin into the central compartment (transdermal formlns).

Pharmacokinetics

Percutaneous absorption: parameters– its structure – the thermodynamic activity of the active ingredient– the amount of compound that can be incorporated into

the formulation– the stability of the formulation at the skin surface (e.g.,

emulsions should break easily)– the partition coefficient of the active ingredient between

the vehicle and the stratum corneum, and – the enhancer activity.

Pharmacokinetics

The Skin Barrier

– Corneocytes

– Intercellular Lipid

– Appendages

– Pathways across the Stratum Corneum

– Inter- and Intra individual Variation in Skin-Barrier Function• The most accurate and reproducible measurement of skin barrier

activity is transepidermal water loss (TEWL).

HOW STRATUM CORNEUM LIPIDS MEDIATE BARRIER FUNCTION

• Extracellular localization: only intercellular lipids play a role

• Amount of lipid (lipid wt %)

• Elongated, tortuous pathway: increases diffusion length

• Organization into lamellar membrane structures

• Hydrophobic composition: absence of polar lipids and presence of very long chain, saturated fatty acids

• Correct molar ratio: approximately 1:1:1 of three key lipids: ceramides, cholesterol, and free fatty acids

• Unique molecular structures (e.g. acylceramides)

Pharmacokinetics

The Viable Tissue

I. Skin Metabolism : Metabolic activity is found in: – Skin-surface microorganisms– Appendages– The stratum corneum– The viable epidermis, and – The dermis.

• Metabolism is one of the latest insight

II. Resorption– Is the uptake of compounds by the cutaneous microvasculature.

– Is directly related to the surface area of the exchanging capillaries & blood flow.

III. The Influence of Pathologic Processes on Skin Barrier Fun

Vehicles:Classification and Application

I. Powders• Promote drying

• Usually 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.

• C/I in the flexures when skin is weeping. – as the application may mix with the exudate to form abrasive clumps.

• Starch containing powders

II. Liquids• Clinical applications of liquids

– wet dressings, baths, tinctures, – paints, topical solutions, aerosols,and sprays.

Wet dressings • acute inflammatory states

– oozing, weeping, crusting and in bullous disease, erosions, and ulcers. – E.g Solutions of aluminum acetate (Burow's solution).

Baths – cleanse the skin of adherent scale or debris – widespread, less exudative conditions.–The duration of immersion should be limited to 30 min.

• because baths and soaks tend to produce maceration,

Liquids…Tinctures and paints

– are organic solvent solutions that evaporate rapidly – leave behind a film of active ingredient.

Solutions • Are solvents in which active ingredients are dissolved to clarity. • As the aqueous phase evaporates, there is drying and cooling • exudative dermatoses.

• hairy and intertriginous regions. – relatively easy to apply and – do not predispose to folliculitis.

Liquids…

Gels • Are transparent, colloidal dispersions that liquefy on contact with skin.

• Advantage:– water-washable– nongreasy, and – cosmetically elegant.

• Disadvantages: – easily removed by perspiration

– lack any protective or emollient properties.

• Comparative

III. Greasy Bases

Oils •The principal use of oils (mineral oil, cottonseed oil.) is the

removal of fat-miscible applications from the skin.– Petrolatum (Vaseline) – white (decolorized) petrolatum

Petrolatum – commonly used for its emollient properties. – highly occlusive and water-insoluble – hydrates the skin by preventing water loss. – changes little with time hence

• does not require preservatives and • is not associated with allergic contact dermatitis.

Biphasic Vehicles

• Shake Lotions• Creams• Ointments• Pastes

Shake Lotions

• 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.

–Typical example: • Zinc Oxide 15 mg• Talc 15 mg• Glycerine 10 ml• Isopropyl alcohol 40 ml• Water 40 ml

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 creams to increase the surface

area of the dispersed phase and that of any therapeutic agent in it.

– May contain preservatives, which may produce an ACD.

– Used widely for their cooling, moisturizing and emollient effects.

Ointments• Spread easily and are more lubricating than creams.

• Provide better topical penetration of incorporated drugs.

• Ointment bases classified into four categories: – water-repellent hydrocarbons (e.g., petrolatum)– absorption bases ( hydrophilic petrolatum and Aquaphor ) – water-in-oil (W/O) emulsions (Hydrophilic ointment ), and– water-soluble ointments

• polyethylene glycol preparations (carbowaxes).

Pastes

– Are ointments into which 20 to 50% powder (Z, starch) is incorporated.

– The powders must be insoluble in the ointment base, usually petrolatum.

– Are more drying, less greasy, and often better tolerated than ointments.

– They may be useful in the treatment of • Ulcers,• Chronic exudative dermatoses and • Thick lichenified plaques.

Triphasic Vehicles • Are mixtures of oil-water-powder in varying proportions

– Cooling pastes – Cream pastes

• Cooling pastes – Indicated similarly as wet dressings. – Are less drying than shake lotions and have the added benefit of cooling.– Their basic formula includes zinc oxide, calcium hydroxide , and oil.

• Cream pastes – by adding zinc oxide to O/W or W/O emulsions – are comparable to the greasy pastes.

Commonly used Vehicle Ingredients

• Heterogeneous

• Emollients

• Humectants–These are hygroscopic agents that draw moisture into the skin.

• 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.

Commonly used Vehicle Ingredients

• Stabilizers– Stabilizers include preservatives, antioxidants, and chelating agents.

– Parabens– Antioxidants

• Thickening Agents– Materials used to thicken or increase the viscosity of products

– They may act as emulsion stabilizers or as ointment bases– Examples: Beeswax, Carbomers

Dosage of Topical Therapy

The three-phase model of drug action

• The initial pharmaceutical phase – application of a drug-vehicle combination to the skin.

• The pharmacokinetic phase – the penetration and permeation of the drug into the skin.

• The pharmacodynamic phase – the interaction of the drug with receptors in the normal or diseased skin.

Dosage of Topical Therapy…

The pharmacologic phases of skin therapy are influenced by

– The concentration of the active drug– The amount of the drug-vehicle applied to the skin – The frequency and Mode of application, and– Regional variation in absorption xics of different anatomic sites.

Concentration

– The concentration-response curves for various topical glucocorticoids • rise steeply to a plateau • further increases in concentration do not enhance the effect.

– The concentration at which the response plateaus is different for each glucocorticoid.

• optimal concentration is different for each drug.

– concentration-response curve for many topicals is nonlinear.

Frequency

• Potent fluorinated steroids form reservoirs in the strat.corneum. – vasoconstriction responses for several days after application of steroids

– ?? reservoirs have therapeutic significance.

• In a study of 12 patients with steroid-responsive dermatoses:– six daily treatments of a topical glucocorticoid were found to be no more effective than three daily applications.

Frequency…

• Percutaneous absorption of radioactive-labeled hydrocortisone was studied in rhesus monkeys:

– No significant difference in total absorption was demonstrated for a

given amount, whether applied as a single dose or in three divided

doses per day.

• In 52 patients with psoriasis One application of fluocinonide ointment was as effective as four applications a day

Frequency…

• Glucocorticoids: – Single daily application of a drug is a sufficient – Probably most effective – The nonspecific emollient or protective effect can be enhanced.

• Hence rational, safe, and economical topical regimens :–alternate use of specific pharmacologic agents

with

–nonspecific remedies.

Quantity of Application

• Dosage of topical therapy – Remains an elusive art form Vs systemic therapy. – Quantitative aspects too often neglected.

• Insufficient amounts result in – too sparing application or interruption of treatment

• Excessive amounts– Pose an unnecessary economic burden – wasteful.

Quantity of Application…

• Thickness of the layer applied to the skin does not enhance the penetration of a specific drug.

• Schalla et al: a thick layer of an ointment or cream gives no better therapeutic effect than a thin layer

• Shupack et al: the quantities used by different patients for similar lesions vary greatly without appreciable difference in the therapeutic outcome.


• One gram of cream covers an area approximately 10 by 10 cm. – An ointment spreads up to 10 percent further.

•Arndt et al: – 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; and • to the entire body, 30 g.


Total amount of topical application depends on– the estimated percent body surface area– frequency of application, and – duration of therapy

Surface Area Estimation

FTU• The amount of ointment

expressed from a tube applied to the finger tip

• ONE FTU ~ 0.5gm

Hand Unit• One side of the hand• ½ FTU covers one side of the

hand• ½ FTU weighs 0.25gm

Wt of one application = Number of Hand units x 0.25gm

Total amount

Surface Area Estimation___________Face & neck ~ 2.5 FTU

______Trunk (front OR back) ~7 FTU

_________One arm ~ 3 FTU

____ One hand (both sides) ~ 1 FTU

__________ One leg/thigh ~ 6 FTU

___________ One foot ~ 2 FTU

Regional Variations in Penetration

• 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.• MM Vs PP

– negligible and for practical purposes insignificant.

Variations in Penetration…

• Responsiveness

• The stratum corneum is considered to be the rate-limiting

barrier to percutaneous absorption. – Once the stratum corneum has been removed, no essential barrier– Stripping

The Role of Occlusion in Topical Therapy

• Airtight occlusive plastic dressing, their efficacy and absorption are increased 10 to 100 times.

• Occlusion with a plastic dressing – increases the skin surface area that can be treated – increases hydration and temperature– enhanced side effects

• Occlusive therapy: A/E– infection– folliculitis – miliaria and– interfere with heat exchange.

The Role of Occlusion in Topical Therapy

Hydrocolloid patch: • Advantages

– flexible, self-adhesive,– skin-colored, and waterproof

• can therefore cover up unsightly lesions and allow patients to bath or shower with the patch in place.

– there is no significant A/E• skin infection or irritation

Tips for Topical Therapy

• Simple hydration of skin before application of topical steroids – may increase penetration up to fivefold.– hydrate the skin by immersion in water for about 5 min.

• Timing– When? – How long exactly before sleep

• Washing and Baths

• Sensitizers: be ware of

?? Rationale for CompoundingFDA

– Efficacy– Peculiar advantage– Little indication

Pitfalls• Appropriate: PH, S, E…• Irreconcilable• Independently• Substandard pharmacies

– Competence– Ethics: Betnovate

• Cost• Untold miseries ▼ ▼• Hides > > > Skin ‘

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!! '

Thank You !!