General principles of topical therapy

 

General principles of topical therapy

 

Topical therapy has an important role in the treatment of dermatological conditions. It is employed to deliver active ingredients to the skin, either at the stratum corneum or via percutaneous absorption into the dermis and appendage areas, to provide a protective barrier, or to hydrate and moisturise the skin.

 

Dermatological vehicles

 

All dermatological vehicles are composed of one or more of the following ingredients: powders, eg zinc oxide, starch, calamine, talc; liquids, eg water, alcohol, glycerol, propylene glycol; oils, greases or waxes, eg peanut oil, castor oil, liquid paraffin, white and yellow soft paraffin, wool fat, hard paraffin, beeswax, polyethylene glycols (macrogols). These ingredients are combined to produce ointments, creams, gels, powders, lotions, paints, tinctures and pastes.

Types of dermatological vehicle

 

Ointments consist of organic hydrocarbons, alcohols and acids, with little or no water. These vehicles are generally greasy, due to their high content of oils and fats, but can be rendered water miscible if an emulsifying agent is included, see Table1. They have emollient, protective and occlusive properties. Application in thick layers and to large areas reduces perspiration and should be avoided. Greasy ointments can be sticky and difficult to remove, and for this reason they are often not well received by patients. Nongreasy ointments such as macrogol ointment consist of polyethylene glycols and are water soluble. They spread well on the skin and wash off with water. In most cases, ointments are not prone to mould or bacterial growth and therefore do not require the addition of preservatives, which can cause contact dermatitis.

Creams are emulsions of an ointment and water, with the aid of an emulsifying agent to stabilise the otherwise immiscible media. The stability and the drug carrying ability of these finely balanced emulsions are dependent on the pH of the creams, the type and amount of emulsifying agents used, and the chemical properties of the active ingredients.

Oil-in-water (aqueous) creams - These creams are emulsions of oil in water and are therefore water-miscible. They generally spread well and are ‘vanishing’, ie they rub into the skin and disappear with little trace. These creams are useful for delivering water-soluble drugs to body surfaces. They also act as emollient moisturisers, see Table 2.

Aqueous creams can be classified as anionic, cationic and nonionic, depending on the chemical type of emulsifying agent used, see Table 1 . Anionic creams, eg aqueous cream, contain emulsifying agents that yield large anions and are potentially incompatible with cationic drugs. Cationic creams, eg cetrimide cream, are potentially incompatible with anionic drugs. Nonionic creams, eg cetomacrogol cream, are usually compatible with both anionic and cationic drugs. Cetomacrogol (sorbolene) cream and aqueous cream are commonly used oil-in-water cream bases.

Water-in-oil (oily) creams - These creams are emulsions of water in oil and are therefore oil-miscible. They provide a wide range of consistencies and are greasier than oil-in-water creams but less greasy than ointments. Oily creams have a soothing effect when the water content evaporates and also offer a protective surface to the skin. They are effective in delivering oil-soluble drugs. Examples of water-in-oil creams include cold cream, zinc cream oily and calamine cream oily.

Lotions are liquid preparations intended for application to the skin without friction. They may be aqueous or alcoholic solutions, suspensions, or emulsions. They offer good spreadability, cooling effects and low irritation to the skin. They are often selected to deliver a thin layer of powder to the affected surface over a large, or hairy area. Shake lotions such as calamine lotion tend to evaporate quickly, providing a cooling effect but leaving a layer of powder on the skin, which many patients regard as cosmetically unacceptable.

Gels are water-miscible, viscous preparations which contain no oil. They contain a gelling agent such as tragacanth, gelatin, or hydroxypropyl- cellulose, together with a solvent such as glycerol, propylene glycol or alcohol, and a preservative. Gels form a durable film which stays on the skin surface longer than a water-miscible cream. They are nongreasy and water-miscible and therefore are suitable for the delivery of water-soluble drugs. They are very easy to spread and have a cooling effect. Gels are particularly well received by patients and are suitable for use in hair-bearing areas. However, many gels contain various forms of alcohol and may sting on raw or damaged skin surfaces. They are prone to evaporation and should be stored in airtight containers.

Paints are liquid preparations that dry rapidly once applied to the skin. Alcohol-based paints are often referred to as tinctures. They are suitable for application to small localised areas of skin and for rapidly delivering an active ingredient to areas with skin folds such as between toes, the groin, and under breasts. Given the high alcohol content, tinctures may sting when applied to raw and damaged surfaces.

Pastes are stiff, semi-solid preparations containing a high proportion of powders, such as zinc oxide or starch, usually in an ointment base. They have occlusive and protective properties, and are suitable for application to small, localised areas of skin.

Dusting powders consist of powders such as talcum, zinc oxide and starch, which may be combined with an active drug, perfume or colouring agent. They are particularly useful in intertriginous areas to separate apposed skin surfaces and enhance evaporation.

Additives in dermatology preparations

Preservatives are added to products with high water content, eg creams, lotions and shampoos, to inhibit the growth of moulds or bacteria and prevent spoilage. All preservatives are capable of producing irritant or allergic contact dermatitis. Patients may react to one particular preservative but not another. This may influence the choice of vehicle or the particular brand of a proprietary preparation. Contact dermatitis from preservatives in topical preparations may confuse assessment of treatment outcome.

A number of chemical agents can be added to the vehicle base to enhance percutaneous absorption of certain drugs. These agents include propylene glycol, dimethylsulfoxide (DMSO), cetrimide and sodium lauryl sulfate.

DMSO is an excellent solvent that is highly miscible with water, alcohol and organic substances. It is a very useful vehicle for enhancing topical drug penetration. In high concentrations it may cause skin irritation and a burning sensation, and could produce a garlic-like odour due to the formation of dimethylsulfide.

Propylene glycol is used to enhance the solubility of the drugs, thus enabling better skin penetration.

Antioxidants are sometimes added to topical preparations to increase the stability of formulations, that are susceptible to oxidation. These agents act by either reacting with free radicals and blocking oxidation, by competing for oxidation (reducing agents), or by enhancing the action of other antioxidants. Examples of antioxidants include alkyl gallates, butylated hydroxyanisole, butylated hydroxytoluene, nordihydroguaiaretic acid, tocopherols, ascorbic acid and its derivatives, sodium metabisulfite, sodium sulfite, thiodipropionic acid, citric acid and lecithin.

Emulsifiers are added to many topical formulations to stabilise the complex ingredients, vehicles and additives. For water-based preparations, the issue of ion compatibility must be considered when emulsifiers are selected. Commonly used emulsifiers are included in Table 4.9.

 

Emulsifying agent	Properties
cetomacrogol emulsifying wax (cetostearyl alcohol plus cetomacrogol)	nonionic
	used in oil-in-water formulations
	can cause hypersensitivities
emulsifying wax (cetostearyl alcohol plus sodium lauryl sulfate)	anionic
	used in oil-in-water formulations
	nongreasy and vanishing
soaps and surfactants - alkyl sulfates (sodium lauryl sulfate), stearates and oleates.	anionic
	used to stabilise oil-in-water formulations
	may remove the natural oils from the stratum corneum and cause irritant dermatitis
cetrimide	cationic
	used in oil-in-water formulations
	antiseptic
wool fat (lanolin) and wool alcohols (alcohol derivatives of wool fat)	water-in-oil emulsifier for creams and ointments
	emollient actions
	potential to cause skin irritations

Properties of dermatological vehicles

The vehicle is a critical factor in the effectiveness of all topical therapies. Some vehicle-related key factors which may influence therapeutic outcome in topical therapy are water/lipid miscibility, occlusive properties and durability.

In general, water soluble drugs can be delivered more effectively by aqueous vehicles such as aqueous creams, gels and lotions. Similarly, lipid-soluble drugs are best delivered by oily creams and ointments. Where percutaneous absorption is desirable, enhancing concentration of active ingredients in the vehicle often enhances absorption.

Pastes and ointments form an occlusive layer which increases water retention in the stratum corneum, increases the temperature of the skin, and encourages blood circulation to the area covered. All of these may contribute to achieving the therapeutic outcome and may enhance percutaneous absorption of the active ingredients.

The viscosity of the vehicle sometimes determines the durability of the preparation on the skin surface and hence the duration of action of the preparation. Gels, ointments and pastes are generally more durable than creams and lotions.

The following guide can be used in the selection of an appropriate vehicle or base for a particular use.

Creams and ointments are the most commonly used bases and the selection usually depends on the degree of hydration of the skin as well as cosmetic factors. Creams are generally used on normal or moist skin. They are cosmetically acceptable for use on the face, and are suitable for use in the flexures and for application to large areas. However, some creams can be drying if the skin is already very dry. The preservatives in creams can also cause contact dermatitis in some patients.

Ointments are generally used when the skin is dry, when enhanced absorption is required (ointments are generally more effective than creams) and when avoidance of preservatives is desirable.

Lotions are generally used on wet surfaces, eg wet rashes (soaks or wet dressings) and oral mucosa (mouthwashes), or on hairy areas, eg scalp, axillae and pubic area.

Gels are used as alternatives to lotions in hairy areas and where a drying effect is beneficial, especially gels with an alcoholic base, eg in acne. Gels or lotions containing alcohol should not be applied to excoriated or abraded skin, as they will sting.

Pastes are used for occlusion and protection, and where substantive effects are required, allowing the drug to stay in contact with the skin for prolonged periods. They are also used in the application of an irritant drug to a limited area of skin, eg dithranol, high concentration of salicylic acid.

Paints are used on small, localised skin areas, on areas with skin folds, eg between toes, under breasts, in groin, and where a drying effect is required (alcoholic paints). However, paints or tinctures containing alcohol may sting and should not be used on raw areas.

Dusting powders are generally used in areas where absorption of moisture would be advantageous, eg between toes, under breasts. However, they may not be as effective as other bases in delivering the active ingredient to the site of action.

 Moisturisers

 

Moisturisers can be categorised into emollient, humectant and occlusive, see Table 2, below. Excessive soaking in water damages the waterproof seal on the skin, allowing a net water loss and resulting in dehydration. The best time to apply a moisturiser is therefore immediately after a handwash or a bath. Fully hydrated stratum corneum swells and when subsequently dried, shrinks and becomes brittle and may lead to skin damage and dehydration. Repeated washing and drying of skin surfaces should be discouraged.

Emollients are preparations of emulsified oils and fatty acids, which replace the natural oils in the stratum corneum. These molecules are incorporated into the epidermal structure, repairing the epidermis and providing a humidifying barrier to loss of water from between the cells of the keratin layer, which is the main source of loss, as well as from the skin surface, thereby increasing the water holding capacity of the skin.

Humectants contain chemicals that attract and retain water due to their hygroscopic or osmotic properties. They act by causing a migration of water from the epidermis to the skin surface as well as trapping water on its way out.

Occlusive preparations provide an external physical barrier over the skin surface to prevent transepidermal water loss, at the same time replacing the natural oils in the stratum corneum. They are very effective but are greasy and often not cosmetically acceptable to patients.

Emollient	Humectant	Occlusive
aqueous cream sorbolene cream peanut oil 5% cream olive oil 10% cream	urea 10% cream glycerol 10% cream	white soft paraffin 50% in liquid paraffin white/yellow soft paraffin

Topical antipruritics

 

Calamine is zinc carbonate or zinc oxide powder mixed with a small amount of ferric oxide, which gives its pink colour. It is a mild astringent and antipruritic, and is used as a soothing and protective application in dusting powders, creams, lotions and ointments.

This is a white crystalline ketone, which acts as a mild topical analgesic and a counter-irritant. It is readily absorbed from all surfaces and systemic adverse effects such as nausea, dizziness, headache and breathing difficulties may occur.

Menthol is a crystalline substance obtained from mint oils or prepared synthetically. When applied topically, it will dilate the blood vessel and cause a cooling and analgesic effect. It is used in creams and ointments to relieve itching in pruritus. However, it has the potential to cause allergic reactions and contact dermatitis, and may sting if applied to broken skin.

Keratolytics

 

Keratolytics are used to remove hyperkeratosis in conditions such as dermatitis, seborrhoeic dermatitis, ichthyosis, psoriasis, palmoplantar keratoderma, warts and acne.

Salicylic acid and benzoic acid are keratolytic agents with mild bacteriostatic and antifungal properties. They are both mild irritants and could themselves cause dermatitis.

Salicylic acid has been used topically as a 2 to 10% cream or ointment for hyperkeratotic dermatitis, although concentrations as high as 50% have been used in palmoplantar keratoderma. A 2% alcoholic lotion is used in acne to unblock comedones. It is often combined with liquor picis carbonis (LPC) in the treatment of psoriasis and dermatitis or with sulfur in the treatment of ichthyosis. Salicylic acid 30% in mineral oil is used to remove scale from the scalp. For warts, a 10 to 15% paint or a 20 to 72% paste is used, eg Upton’s paste (salicylic acid 72% with trichloroacetic acid 12%).

Benzoic acid 6% is used with 3% salicylic acid (Whitfield’s ointment) for treating fungal infection of the skin.

Urea is a mild bactericidal keratolytic agent and promotes hydration of the skin by increasing the ability of the epidermis to absorb water. It is used as a 10% cream for moisturising, or a 20 to 60% soak solution for the treatment of hyperkeratotic dermatitis.

Propylene glycol is a keratolytic agent with some bactericidal and fungicidal properties. A 40 to 60% solution applied under occlusion can be used to clear scaling skin in hyperkeratotic eczema.

Tars

 

Tars act by reducing the thickness of the epidermis and are used for the treatment of psoriasis, dermatitis, seborrhoeic dermatitis and dandruff. Their efficacy is enhanced when ultraviolet B (UVB) therapy is given after application of the tar. Controversies exist in relation to the potential carcinogenic and teratogenic effects, and to the increased risk of carcinogenicity with concurrent use of tar application and ultraviolet (UV) therapy. Long-term treatment of high concentration tar preparations is not encouraged.

Coal tar is obtained from bituminous coals at high temperature. It has anti-inflammatory, antipruritic and mild antiseptic properties. Crude coal tar 0.5 to 5% is included in creams, ointments, pastes, shampoos and soaps, often in combination with salicylic acid. Coal tar solution (liquor picis carbonis or LPC), which is a 20% solution of coal tar in alcohol, is used in concentrations of 3 to 12%. Coal tar may cause skin irritation and photosensitivity but hypersensitivity reactions are uncommon. Preparations stain clothing and skin and have a mild odour, which may affect compliance.

Pine tar is obtained from the destructive distillation of the wood of Pinaceae trees. It has antipruritic properties, but does not have the anti-inflammatory properties or photosensitising potential of coal tar. It is included in a variety of proprietary preparations as solutions, cleansing bars, gels and bath oils.

Ichthammol is a black viscous liquid with a strong odour, consisting of a destructive distillation product of bituminous schist or shale together with ammonium sulfate. It has a mild antibacterial effect and is used in chronic dermatitis. It is a mild skin irritant. It is included in propriety preparations for the treatment of dermatitis, psoriasis and acne. A ichthammol 2% in glycerol lotion has been used for the treatment of ear psoriasis.

Dithranol

 

Dithranol is a yellow to orange powder of synthetic trihydroxyanthracene. When used in topical preparations, its strength starts at 0.05 or 0.1% and gradually increases to 3% as required. Strengths as high as 6% have been used in severe cases. It has anti-inflammatory properties. It stains skin and many fabrics and surfaces. Liquid paraffin may be used to remove dithranol products from the skin.

Dithranol reduces proliferation of the epidermis by inhibiting enzyme metabolism and reducing mitotic turnover. As it is irritant to mucosal surfaces, inflamed skins and other delicate skin areas, it should not be used on the face, groin and perilesional skin. Patients with fair skin are more sensitive. Concomitant use of coal tar may reduce its irritating effect. Dithranol can be localised to the plaques by application in Lassar’s paste. Application of white soft paraffin to the perilesional areas may provide further protection.

Dithranol is better absorbed through plaques of psoriasis than good skin. There are two methods of dithranol treatment: low-strength, long-contact therapy and high-strength, short-contact therapy, see Points on difficult to use preparations.

It is also used in the treatment of alopecia areata. While its mode of action is unknown, it is not effective unless skin irritation is produced.

Dithranol preparations have many problems with stability, which decreases with the strength of the preparations. Addition of salicylic acid, ascorbic acid or oxalic acid as an antioxidant stabilises dithranol products and prevents discolouration and inactivation. White soft paraffin appears to be the most stable base while cream bases are least stable. Dithranol must be protected from light and should be supplied in appropriate light-occlusive containers.

Antiseptics

 

Benzoyl peroxide has mild keratolytic, antiseptic and bleaching properties. It is used in the treatment of acne as a 2.5 to 10 % gel. Its antiseptic properties are probably the result of its oxidising effect. Bleaching of clothing may occur where it is in contact with the agent. As irritation is common, caution is needed when applying it near the eyes and other mucosal surfaces. The irritation usually resolves on continued use.

It has been reported that the incidence and severity of skin reactions is increased by ultraviolet radiation exposure. Benzoyl peroxide and its breakdown product, benzoic acid, absorb strongly in the UVB spectrum. It may also generate free radicals in the skin under UVA light. Both may contribute to skin irritation. Patients using benzoyl peroxide should be cautioned if high exposure to UV light is anticipated.

Chlorhexidine is a bisbiguanide antiseptic that is commonly used in topical preparations with or without cetrimide. It is used as the acetate, gluconate or hydrochloride in sprays, creams, gels, solutions, dressings and powders in concentrations ranging from 0.02 to 5%.

Its salts are incompatible with many agents and their antimicrobial activities may be reduced with kaolin, tragacanth, cork, starch, magnesium, calcium and zinc compounds and many other salts. Physical mixing or concurrent application of chlorhexidine products with other preparations is therefore not recommended.

Chlorhexidine salts may cause skin reactions, irritate mucosal surfaces and interrupt wound healing. Discolouration of the teeth, tongue and the buccal cavity associated with chlorhexidine mouthwash or oral gel has been reported.

Cetrimide is a quaternary ammonium antiseptic with surfactant properties. It has been used alone or with chlorhexidine in topical preparations in concentrations ranging from 0.1 to 3%. Skin sensitivity may occur, particularly with repeated and prolonged applications. Application to mucosal surfaces should be avoided.

Povidone iodine is an iodine complex which has antibacterial, antifungal and antiviral properties. It is used in mouthwash/gargles, skin cleansers and antiseptic creams, ointments, solutions and paints, in concentrations ranging from 5 to 14%. It is also used in some antiseptic swabs and wound dressings.

It can cause skin irritation and is absorbed via damaged skin. Application over a large broken skin surface is not recommended.

Triclosan is a bisphenol antiseptic agent commonly used in medicated soaps and topical preparations in concentrations of up to 2%. It is a mild irritant and allergic contact dermatitis has been reported.

Sunscreens

 

Sunscreen active agents work by either absorbing or reflecting UV radiation. Absorbent sunscreen chemicals act mainly in the UV range, whereas reflectants provide a barrier against UV, visible light and infra-red radiation. A list of the commonly used sunscreen agents is included.

The majority of sunscreen products combine agents that absorb in the UVB range (wavelengths 290 to 320nm) with agents that absorb in the UVA range (wavelengths 320 to 360nm) to provide broad-spectrum coverage. Many products also include a reflectant, such as titanium dioxide, which increases the protection but can give the skin a white appearance. Zinc oxide is used as a physical sun barrier for the protection of the ears and nose, which often receive high sun exposure.

The use of sunscreens in the prevention of sun-related skin tumours and the application of sun protection factor (SPF) values to sunscreens are discussed in detail in Prevention of sun-related tumours.

UVA absorbers and reflective sunscreens are used to protect against drug-induced photosensitivities, see Photosensitiip.89, and photosensitive disorders (eg polymorphic light eruption and porphyria cutanea tarda) which are mainly UVA-related but may also involve visible light. However, the use of protective clothing is preferable to sunscreens to ensure adequate protection.

The benzophenones also absorb some ultraviolet C (UVC) light with wavelengths of 250 to 290nm and may provide some protection against artificial UV sources such as arc welding and sunlamps.

Sunscreen should be applied to all exposed areas at least 30 minutes before UV exposure to enable skin penetration. Generous and frequent applications are necessary to ensure maximum protection, see Application of sunscreen.

Sunscreen sensitivity is common but is usually due to the irritancy of the ingredients in the sunscreen formulation rather than an allergic or photoallergic reaction to these ingredients. Allergies to the actual sunscreen agents are less common than allergies to ingredients in the base, eg preservatives or perfumes. With the exception of the aminobenzoates, photoallergy to suncreen agents is uncommon.

Other topical therapies

 

Topical antihistamines are poorly absorbed and not effective in the treatment of most skin conditions. Systemic H1-receptor antagonists should be considered when indicated.

Emulsifying ointment is a mixture of paraffin and emulsifying wax. It can act as a detergent or soap substitute and is particularly useful for patients with contact dermatitis in which the offending chemical is not known.

Lanolin (wool fat) is a purified anhydrous waxy substance obtained from the wool of sheep. It is used in creams and ointments to provide skin penetration properties. Lanolin is capable of absorbing about 30% of water, and hydrous lanolin is used as an ointment base. It is known to cause skin sensitivities. However, most lanolin-related sensitivities are found to be caused by residues of pesticide and detergent used on sheep. Removal of these impurities reduces the incidence of sensitisation markedly.

Podophyllum has an antimitotic action and is used in the treatment of warts. A combination of podophyllum resin and salicylic acid as a paint or ointment is used in the treatment of plantar warts. Podophyllotoxin 0.5% paint is used for anogenital warts. Podophyllum should not be used during pregnancy or in children.

Most local anaesthetic agents are well absorbed through mucous membranes and damaged skin but absorption through intact skin is poor. However, a eutectic mixture of lignocaine and prilocaine (EMLA) can produce effective surface analgesia of intact skin prior to minor medical or surgical procedures, and this effect is enhanced by occlusion. Lignocaine is used in a number of products for use on oral and other mucosal surfaces and ulcers.

Allergic contact sensitivity is rare with local anaesthetics but cross-reaction among different agents is common.

Choline salicylate is used as a local analgesic for oral lesions.

Zinc oxide is a mild astringent used as a soothing and protective application in dusting powders, pastes, ointments, creams and lotions, often combined with ingredients such as coal tar, ichthammol, salicylic acid, calamine or castor oil.

Common zinc oxide containing topical preparations include calamine cream and lotion, zinc cream, ointment and paste, Burow’s emulsion, and zinc and castor oil ointment.

Zinc oxide reflects UV radiation and is used in sunscreen preparations.

Complementary medicines in topical therapy

 

Extract from aloe vera has been used in a variety of creams, ointments, gels, lotions and shampoos. It has been suggested that aloe vera gel is useful for the treatment of mild burns and to promote wound healing as a result of antiseptic, anaesthetic, anti-inflammatory, antipruritic and moisturising properties.

While recent clinical studies have provided mixed findings about its effectiveness in the treatment of frostbite, wound healing and cuts, its topical use appears to be nontoxic.

Oil from the leaves of the tea tree (Melaleuca alternifolia) has traditionally been used for cuts, burns, and insect bites. It contains various terpene oils and sesquiterpenes. It may also contain cineole, which is known to be a skin irritant.

The antiseptic effect of tea tree oil is largely due to the presence of terpinen-4-ol. This is added to various commercial preparations. There are many in vitro studies demonstrating the antibacterial and antifungal effects of melaleuca oil. However, its antimicrobial activity is concentration dependent and clinical studies have not adequately demonstrated its effectiveness in the treatment of acne and skin infections such as tinea.

Papain is a proteolytic enzyme obtained from the fruit and leaves of papaya. It is used in cosmetic preparations to fade freckles. It is known to cause skin sensitisation and allergic reactions.