Seminar presentation

Principles of Topical Therapy

Moderator:- Dr. R. S. Meena

• The skin has a surface area of 1.6-2 m2• This area enables the enhancement of

systemic treatment measures• An extensive region for the application and

absorption of topical medications• The active ingredients penetrate the skin

either via transepidermal or transfollicular pathways

• Sensible topical drug therapy involves not only the selection of an appropriate agent, but also a thoughtful consideration of the areas of the body affected.

• Basic principles-1. State of the diseased skin(Pathologic changes)2. Age of patient3. Area of the body4. Concentration of the drug5. Type of vehicle (e.g., ointment, cream, lotion)6. Method of application7. A defined duration of use that both maximizes efficacy and

minimizes adverse side effects.

CUTANEOUS DRUG DELIVERY

Therapeutic efficacy-relates to both its inherent potency and its ability to penetrate the skin. Percutaneous absorption necessitates passage through the stratum corneum, epidermis, papillary dermis, and into the bloodstream. Topical medicines generally have a poor total absorption . But it does not necessarily translate into low efficacy.

Stratum Corneum

Rate-limiting barrier to percutaneous drug delivery. Composed of ceramides, free fatty acids, and cholesterol in a 1:1:1 molar ratio and By weight 50%, 35 % and 15% respectively. Drug penetration, will vary depending on body site, due to its thickness. Diseased skin- Abraded or eczematized skin presents less of a barrier. Solvents, surfactants, and alcohols can denature the cornified layer and increase penetration

Occlusion

Range from application under an airtight dressing such as vinyl gloves or plastic wrap, to occlusion with cotton gloves or socks at night for treatment of hands and feet, to application of a medication already impregnated into an airtight dressing, as seen in flurandrenolide (Cordran) tape.Greatest benefit-should hydrate the skin by immersion in water.It increased- both efficacy and side effects .

FACTORS THAT AFFECT ABSORPTION

• Regional Differences in Penetration in decreasing orders• 1.Mucous membrane• 2. Scrotum• 3. Eyelids• 4. Face• 5.Chest and back• 6.Upper arm and legs• 7.Lower arm and legs• 8.Dorsa of hand and feets• 9.Palmer and planter skin• 10.Nails

Frequency of Application• Must be specified in order to maximize the response whilst

avoiding side effects such as irritation.• Emollients should be applied frequently enough to maintain

their physical effect. • Active preparations are usually applied just once or twice a

day. • As a general rule, twice daily application of drugs such as

corticosteroids or deltanoids is only marginally more effective than once daily application.

• Increasing the interval between applications can be a useful method of gradually reducing the intensity of a treatment, especially when it is difficult to do so by using a lower concentration or less potent agent.

Drug concentration

• The concentration is usually written as a percentage representing the proportion of the formulation, by weight, which is the active constituent.

• A concentration of 1% indicates that 1 g of drug will be contained in 100 g of the formulation.

• 1% solution contains 1 g of drug in 100 ml of the formulation.• Abbreviations w/w (weight in weight) and w/v (weight in

volume) are often employed to indicate which convention is being used.

• Concentration of a solution is in ‘parts’; thus a 1 part in 1000 solution of potassium permanganate contains 1 g in 1 L of solution, which could be expressed as 0.1% (w/v).

Quantity of Application• The total quantity to be dispensed should be specified and it

is helpful to inform the patient how long the prescribed quantity is expected to last.

• Estimates of the quantity of cream or ointment have varied.• In one study a range of 12–27 g (average 18 g) was required

for applications by ‘trained operators’, whilst a range of 8–115 g (average 44 g) was required when the treatment was self administered.

• In a more recent study, male patients treating themselves applied an average of 20 g of ointment, and females applied 17 g.

• Quantity required for 1 week of once-daily application to the whole body would be approximately 140 g for males and 120 g for females.

Age RequirementDaily (g) 8 Weekly (g)

3 months 8 566months 10 67

12 months 12 8418 months 13 93

2 years 14 953 years 16 1124 years 19 1355 years 20 1407 years 25 172

10 years 30 21012 years 37 256

Quantities (g) of medication required for twice daily application to the entire body at various ages.

Anatomical region Males FemalesTrunk (including buttocks) 6.6 5.8One leg 2.9 2.5One foot 0.9 0.7One arm and forearm 1.7 1.3One hand 0.6 0.5Face, neck and ears 1.3 0.9Whole body 20 17

Approximate quantities (g) required for each application of Medication to different anatomical regions.

The fingertip unit.

fingertip unit

Fingertip unit- An approximate but practical measure of topical medication is the fingertip unit. •This is the quantity of ointment, extruded from a tube with a nozzle of 5 mm diameter (note that nozzles do vary somewhat), extending from the distal crease of the forefinger to ventral aspect of the fingertip.•This unit weighs approximately 0.49 g in males and 0.43 g in females and covers, on average, an area of approx 300 cm2.

Fingertip units required for a single treatment of various regions in children and adults adapted from. The unit is measured using an adult finger.

Age Face andneck

One upperlimb

One lowerlimb

Trunk Whole body

3–6 month 1 1 1.5 2.5 8.5

1–2 years 1.5 1.5 2 5 13.5

3–5 years 1.5 2 3 6.5 18

6–10 years 2 2.5 4.5 8.5 24.5

Adult 2.5 4.5 7.6 13.5 40

Compliance

• Generally, adherence to a treatment regimen is associated with female gender, employment, being married, and low prescription costs.

• Lower adherence is seen for patients with extensive disease, and paradoxically, Disease on the face.

• Furthermore, compliance is negatively affected by depression, which is common in people with chronic skin conditions and found in up to 20 percent of patients with psoriasis.

Miscellaneous Factors

• Vigorous rubbing or massaging of the drug -increases the surface area and blood supply to the area locally, augmenting systemic absorption .

• Presence of hair follicles on a particular body site also enhances drug delivery with the Scalp and beard areas presenting less of a barrier when compared with the relatively Hairless body sites.

• Skin of older individuals is poorly hydrated, with fewer hair follicles and therefore may impede drug delivery.

• Reducing the particle size of the active ingredient increases its surface area-volume ratio, allowing for a greater solubility of the drug in its vehicle.

CLASSIFICATION AND CLINICAL APPLICATION OF TOPICAL FORMULATIONS

• The vehicle is the inactive part of a topical preparation that brings a drug into contact with the skin.

• Beneficial non-specific effects-Cooling, protective, emollient, occlusive, or astringent properties.

• Functions optimally when it is stable both chemically and physically and does not inactivate the drug.

• It also should be nonirritating, nonallergenic, cosmetically acceptable, and easy to use.

• Additionally, the vehicle must release the drug into the pharmacologically important compartment of the skin.

• Finally, the patient must accept using the vehicle or else compliance will be poor.

Lipids Castor oil, Cetyl alcohol, Cocoa butter, Isopropyl myristate,Isopropyl palmitate, Lanolin, Liquid paraffin, Shea butter, Stearic acid, Stearyl alcohol, White soft paraffin (petrolatum)

Emulsifiers Alkyl sulphates and sulphonates, Glyceryl monostearate, Lanolin and derivatives, Phosphoric acid esters, Polyethylene glycols, Polyvalent metallic soaps, Propylene glycol fatty acid esters, Quaternary ammonium cationic compounds, Sorbitan monolaurate, monopalmitate and mono-oleate, Triethanolamine oleate

Humectants Gelatine, Glycerin, Propylene glycol, Pyrrolidone carboxylic acid, Sorbitol, Urea

Penetration enhancers

Azone, Dimethyl sulphoxide, Propylene glycol, Salicylic acid, Urea

Preservatives

Benzyl alcohol, Butylated hydroxyanisole, Butylated hydroxytolueneChlorocresol, Edetic acid/disodium edetate, Hydroxybenzoates (parabens), Propylene glycol, Sodium metabisulphite, Sorbic acid/sorbates

Solvents Acetone, Ethanol, Ether, Chloroform, Glycerin, Isopropyl alcoholMethanol, Propylene glycol, Water

Frequently employed constituents of vehicles

Powders Absorb moisture and decrease friction

Used in the intertriginous areas and on the feet Eg. antifungals

Contain zinc oxide eg. calamine (antiseptic and covering properties), talc (lubricating and drying properties), and stearate (improved adherence)

Poultices(cataplasm

)

Wet solid mass of particles, sometimes heated, that is applied to diseased skin

Used as wound cleansers and absorptive agents in exudative lesions such as decubiti and leg ulcers.

Historically, contained meal, herbs, plants, and seeds. Modern poultice often consists of porous beads of dextranomer.

Ointments Semisolid preparations that spread easily.

Protective, hydrating, and lubricating.

Classified into five categories: Hydrocarbon bases, Absorption bases, Emulsions of water-in-oil, Emulsions of oil-in-water, and Water-soluble bases.

Dermatologists commonly refer to the hydrocarbon bases and absorption bases as ointments and the water-in-oil/oil-in-water emulsion bases as creams.In pharmaceutical terms, all of these preparations are ointments.

HYDR0-CARB0N BASES(oleaginous bases)

Composed of a mixture of hydrocarbons of varying molecular weights, m.c. petrolatum

Greasy and can stain clothing.stable and do not contain preservatives. not used for water- soluble drugs.

silicon ointments are composed of alternating oxygen and silicon atoms bonded to organic groups, such as phenyl or methyl, and are excellent skin protectants.

ABSORPTI0N BASES

Contain hydrophilic substances that allow for the absorption of water-soluble drugs.

Lubricating and hydrophilic, can form emulsions. Function as emollients and protectants

Greasy but easier to remove, do not contain water.Eg. anhydrous lanolin and hydrophilic petrolatum.

CREAMS(WATER-IN-0IL EMULSION)

By definition, contains <25% water, with oil being the dispersion medium.two-phase systems may separate unless shaken

Less greasy, spread easily, and provide a protective film of oil, slow evaporation of the water phase provides a cooling effect

Emulsifier( or surfactant) is soluble in both phases and surrounds the dispersed drops to prevent their coalescence. Preservatives are frequently added to increase the emulsion's shelf life. Eg. surfactants- sodium lauryl sulfate, the quaternary ammonium Compounds, Spans( sorbitan fatty acid esters), and Tweens (polyoxyethyiene sorbian fatty acid esters).

Oil-in-water Emulsions

Contains >31 % water. Contain preservatives, such as the parabens, to inhibit the growth of molds.

Spread very easily, are water washable and less greasy, and are easily removed from the skin and clothing.

Contain a humectant (an agent that draws moisture into the skin), such as glycerin, propylene glycol, or polyethylene glycol(PEG), to prevent the cream from drying out. oil phase may contain either cetyl or stearyl alcohol (paraffin alcohols) to impart a stability and velvety smooth feel upon application to the skin.

Water-soluble bases

Consist either primarily or completely of various PEGs. Depending on their M.W., PEGs are either liquid (eg. PEG 400) or solid (PEG 4000).

Water soluble, require no preservative additives. nonstaining, greaseless, and easiiy washed off of the skin

It will be useful in scenarios where the practitioner desires a high surface concentration and low percutaneous absorption of the drug. e.g. topical antifungal and antibiotics (mupirocin).

Gels Made from water-soluble bases by formulating water, propylene glycol, and/or PEGs with a cellulose derivative or carbopol. Newer gel contain the humectant glycerin, the emollient dimethicone, or the viscoelastic polysaccharide hyaluronic acid

Clear and ease of both application and removal. Easy to use on the hair-bearing body sites

They lack any protective or emollient properties.If they contain high concentrations of alcohol or propylene glycol, they tend to be drying or cause stinging. Gels require preservatives.After application the aqueous or alcoholic component evaporates, and the drug is deposited in a concentrated form.

Pastes High concentrations of powders (up to 50 %) into an ointment such as a hydrocarbon base or a water-in-oil emulsion

Must be insoluble in the ointment.Stiffer than the original ointment.Commonly used are zinc oxide, starch, calcium carbonate, and talc.

Function- localize the effect of a drug that may be staining or irritating (i.e. anthralin). Impermeable barriers that serve as protectants or sunblocks. Less greasy than ointments, more drying, and less occlusive.

Solution Dissolution of two or more substances into homogenous clarity

Liquid vehicle may be aqueous, hydroalcoholic, or non-aqueous (alcohol, oils, or propylene glycol).

Aqueous solution- aluminum acetate or Burow's solution.Hydroalcoholic solution with 50% alcohol is called a tincture.

Liniments

Non-aqueous solutions of drugs in oil or alcoholic solutions of soap.

Base of oil or soap facilitates application to the skin with rubbing or massage.

Used as counterirritants, astringents, antipruritics, emollients, and analgesics.

Coliodion Non-aqueous solution of pyroxylin in a mixture with ether and ethanolapplied to the skin with a soft brush

Flexible collodions have added castor oil and camphor and are used, eg. to deliver 10% salicylic acid as a keratolytic agent.

Suspension or Lotion

Two-phase system consisting of a finely divided, insoluble drug dispersed into a liquid in a concentration of up to 20%.

Eg. calamine lotion, steroid lotions, and emollients containing urea or lactic acideasier to apply and allow for uniform coating of the affected area, and are often the favorite preparation in treating children. more drying than ointments.

Shake lotions

Powder is added to Lotions to increase the surface area of evaporation

Application of shake lotions effectively dries and cools wet and weeping skin.consist of zinc oxide, talc, calamine, glycerol, alcohol, and water, to which specific drugs and stabilizers may be added.

Aerosols Formulating the drug in a solution within a pure propellant. Propellant is a blend of nonpolar hydrocarbons.

Used to deliver drugs formulated as solutions, suspensions, emulsions, powders, and semisolids. applied to abraded or eczematized skin, aerosols lack the irritation of other formulations.

Aerosol foams

Contains the drug within an emulsion formulated with a foaming agent(a surfactant),A solvent system (such as water and ethanol), and a propellant.

Used to deliver corticosteroids such as betamethasone valerate and clobetasol propionate.On application, a foam lattice forms transiently until it is broken by both the heat of the skin and the heat of rubbing the foam onto the skin.

Thickening agents

Increase the viscosity of products or suspend ingredients in a formulation

Eg. beeswax and carbomers. Addition to functioning as an ointment vehicle, petrolatum may be added to an emulsion to increase its viscosity. Ingredient ay have a therapeutic effect as well as acting as part of a vehicle.

Stabilizers

• Non-therapeutic ingredients and include the preservatives, antioxidants, and chelating agents.

• Preservatives protect the formulation from microbial growth.

• The ideal preservative is effective at a low concentration against a broad spectrum of organisms, nonsensitizing, odor free, color free, stable, and inexpensive.

• Unfortunately, the ideal preservative does not exist.

• The parabens are the most frequent added preservatives, and are active against molds, fungi, and yeasts, but less effective against bacteria.

• Alternative agents include the halogenated phenols, benzoic acid, sodium benzoate, formaldehyde, the formaldehyde-releasing agents, and previously, thimerosal.

• Most commonly used preservatives may act as contact sensitizers.

• Antioxidants or preservatives prevent the drug or vehicle from degrading via oxidation.

• Examples include butylated hydroxyanisole and burylated hydroxytoluene, used in oils and fats.

• Ascorbic acid, sulfites, and sulfur-containing amino acids are used in water soluble phases.

• Chelating agents, such as sodium EDTA and citric acid, work synergistically with antioxidants by complexing heavy metals in aqueous phases.

When do we use topical treatment?

• If a patient has a skin disorder covering < 30% of body, the topical medication may be considered.

Choice of vehicles

• Three main determinants to choose the right vehicle are:

Patient’s skin type Degree of acuity of the disease Nature of the lesions

Choice of vehicles

• Skin type: About 50% of individuals have oily skin or seborrhea.

• They do better with creams, lotions, or shake lotions while the ones with dry skin do better with ointments or pastes.

• Degree of acuity: Acute inflammatory processes are best treted with creams or lotions.

• If the lesions are weeping, shake lotions are fine.

Choice of vehicles for different lesionsLesion Recommended AvoidedAcute erythema shake lotion, Ointment, lotion, cream pasteVesicles shake lotion, Paste, gel, lotion ointmentBlisters Wet dressings, Paste, shake lotions ointment, powderErosions Wet dressings, powder, ointment shake lotionCrusts Ointment, wet dr. Powder, gelCh. inflammation Ointment

Topical agents Ⅰ Classification Action Drug Concentration(%)

Smooth agents reduce friction calamine 10-15 avoid stimulation talc 10-70 zinc oxide 20-50Antimycotics kill or inhibition sulphur 5—10 Glacial Acetic Acid 5--30 benzonic acid 6--12 salicylic acid 5--10 clotrimazole 2---3 Miconazole 2 Terbinafine 1Antiseptics kill or inhibition boracic acid 3---4 potassium 1/2000 permanganate 1/5000 Neomycin 0.5-1 revanol 0.1

Topical agents Ⅱ

Classification Action Drug Concentration(%)

Antipruritics narcotism 、 cool 1---5 dimimish inflammation mint 0.2-3 stop itchness carbolic acid 1---2 bendazolecain 3---5 dexamethasone 0.025 triamcinolone 0.025Keratoplastics promote normal keratosis pityrol 3---5 shrink blood vessel coal tar 5--40 reduce effusion and resorcinol 2---5 inflammatory infiltration salicylic acid 3

Topical agents Ⅲ Classification Action Drug Concentration(%)

keratolytics hyperkeratosis salicylic acid 6--15 make keratinocytes loose resorcinol 6--15 separate and fall off Glacial Acetic Acid 10-30 urea 20-40 Caustics remove granulation carbolic acid pure tissue and neoplasm Glacial Acetic Acid >30 salicylic acid >20 trichloroaceticacid >30 sunscreen absorb or prevent Titanium dioxide 5 ultraviolet radiation depigmenting reduce pigmentation Hydroquinone 3 agents Azelaic Acid 20

Potency Class

Topical corticosteroid Formulation

Ultra high

I Clobetasol propionate Cream, 0.05%

    Diflorasone diacetate Ointment, 0.05%

High II Amcinonide Ointment, 0.1%

    Betamethasone dipropionate

Ointment, 0.05%

    Desoximetasone Cream or ointment, 0.025%

    Fluocinonide Cream, ointment or gel, 0.05%

    Halcinonide Cream, 0.1%

  III Betamethasone dipropionate

Cream, 0.05%

    Betamethasone valerate Ointment, 0.1%

    Diflorasone diacetate Cream, 0.05%

    Triamcinolone acetonide Ointment, 0.1%

Topical corticosteroids

Moderate IV Desoximetasone Cream, 0.05%

    Fluocinolone acetonide Ointment, 0.025%

    Fludroxycortide Ointment, 0.05%

    Hydrocortisone valerate Ointment, 0.2%

    Triamcinolone acetonide Cream, 0.1%

  V Betamethasone dipropionate Lotion, 0.02%

    Betamethasone valerate Cream, 0.1%

    Fluocinolone acetonide Cream, 0.025%

    Fludroxycortide Cream, 0.05%

    Hydrocortisone butyrate Cream, 0.1%

    Hydrocortisone valerate Cream, 0.2%

Low VI Betamethasone valerate Lotion, 0.05%

    Desonide Cream, 0.05%

    Fluocinolone acetonide Solution, 0.01%

  VII Dexamethasone sodium phosphate

Cream, 0.1%

    Hydrocortisone acetate Cream, 1%

    Methylprednisolone acetate Cream, 0.25%

Side effects of topical corticosteroids

• Epidermis : Atrophy• Hair follicles: Steroid acne• Dermis: Atrophy, striae• Pigmentation: Hypopigmentation• Vessels: Erythema, telangiectases

Hazards associated with topical treatment

• M.C. - Localized irritant or allergic reactions. • This can be minimized by applying treatment at the optimal

concentration and treatment intervals and by selection of the correct vehicle.

• Sensitization is more difficult to anticipate and to prevent.• Contact allergy can develop not only to the active

medicament but also to constituents of the vehicle. • Almost any component may sensitize; notable examples

include ethylenediamine, propylene glycol, emulsifiers, sorbic acid , cetyl and stearyl alcohols and fragrances.

• Patients with chronic venous eczema or leg ulcers appear to be particularly susceptible.

• Rare• Absorption varies very considerably depending on the region

of skin being treated. • Occlusion greatly enhances absorption.• Systemic exposure can be greater than expected in children

due to their relatively high ratio of skin surface to body mass. • In the elderly, penetration of drugs may be increased as a

result of changes in the structure of the skin. • This effect is most pronounced in drugs which are most

hydrophilic . • Inflammation of the skin impairs barrier function and

significantly increases drug absorption. • This is especially significant in the erythrodermic patient

Systemic Side Effects

•Thanks

Topical agents

• Keratolytic agents• Cytotatic agents: Podophyllin, 5-fluorouracil• Retinoids• Antibiotics, antifungals, antiviral agents• Corticosteroids• Combination products• Tacrolimus, pimecrolimus• Nonsteroidal antiinflammatory agents• Sunscreens

• Class I (weakest): Hydrocortisone, prednisolone

• Class II: Methylprednisolone aceponate, triamcinolone

• Class III: Betamethasone 17-valerate• Class IV (strongest): Clobetasol 17-propionate

Formulation Ⅰ Dosage form component action indications

Powder drug put into Absorb moisture acute and subacute inflammation zinc oxide, talc and decrease friction but no effusion and stearate astringency, protection, cooling Used in the intertriginous areas and on the feet Eg. antifungals Solution liquid and soluble drug cooling, clear raw surface 、 acute inflammation dissolution of two or reduce inflammation with lots of effusion more substances into eg. Aqueous solution- homogenous clarity aluminum acetate or Burrow’s solution

Lotion powder and liquid protection, cooling acute and subacute mixture- two phase reduce inflammation inflammation without system (conc. Up to 20%) astringency, more drying effusion, favourite for Eg. Calamine , steroid lotions, children emolient containing urea or lactic acid Cream consisting of aqueous protection 、 lubrication subacute or chronic and oily components intenerate crust inflammation ,pruritus O/W emulsion being readiy reduce inflammation diluted with water,W/O emulsion with oil Solution

Formulation Ⅰ

Gel Propanediol gelatin protection, lubrication subacute or chronic of organic polymer reduce inflammation

inflammation ,pruritus• drug Clear and ease of both application and removal. Easy to use on the hair-bearing body sites

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 Ⅱdosage form component action indications