9.3.1 Principles of galenic formulations for topical drugs

Topical therapies are a main stay in treatment in dermatology. It involves the external application of a drug on the affected skin. Topical agents consist of one or more active ingredients in a vehicle (non-active base). In topical therapy, choosing a proper vehicle can be as important as choosing a suitable active ingredient.

When using topical therapy, the following factors should be considered:

• active ingredients
• vehicle, preservatives and stabilizers
• correct mode of application
• condition of the skin to be treated (acute, subacute, chronic)

The goal of most topical drugs is penetration through the stratum corneum (SC) and upper dermis with direct action to the skin. Penetration through the SC is accomplished by a transepidermal or transappendageal pathway. There are several steps in this process. In each step, it is essential that the active ingredient is more soluble or driven by concentration gradient, enabling the active substance to penetrate the skin.

• Liberation – the release of the active ingredient from the vehicle
• Adsorption – binding of the active ingredient to skin structures (i.e. stratum corneum)
• Absorption – uptake of the active ingredient from the vehicle
• Penetration – passage through the stratum corneum
• Permeation – transepidermal and transfollicular passage of active substances throughout the skin
• Resorption – the uptake of topically applied substances with transfer to blood vessels or lymphatics

These include

• the thickness and integrity of the SC (a thicker SC decreases absorption)
• anatomic location (the absorption is highest on mucous membranes, scrotum, and eyelids; and lowest on palms and soles)
• skin hydration (increased hydration increases absorption)
• patient's age (higher absorption in neonates because of their suboptimal skin barrier)
• occlusion with airtight dressings and greasy ointment bases, which increase percutaneous absorption.

Topical medications consist of one or more active ingredients combined with a vehicle. The vehicle contains a base to which may be added preservatives, stabilizers, emulsifiers, fragrances and other products.

The choice of vehicle is one of the critical tasks in topical prescribing, as it is very important for determining the pharmacokinetics (i.e. the active ingredient must be more soluble in the outer layer of SC than in the vehicle, or diffusion will not start).

Vehicles are divided into two groups:

• liquid (solutions, emulsions, shake lotions)
• semi-solid vehicles (gels, creams, ointments and paste)

Most commonly used types of vehicles:

• Cream – two forms: oil in water and water in oil
• Lotion – thin cream, easier to apply
• Solution – alcoholic vehicle
• Ointment – greasy and occlusive
• Gel – semi-solid – converts to liquid when rubbed into the skin
• Paste – ointment + powder – protective
• Shake lotion – water and powder

Ointments are used for dry skin; creams are most commonly used; gels and lotions are used when an easy application is preferred and for the scalp and hairy parts of the body.

Active ingredients are added to the vehicle. Ideally, the product should contain only one active ingredient, but in some cases, two or more active ingredients can be combined. The most commonly used active substances in dermatotherapy are:

• Antiseptics - used against different microbials
• Antibiotics – used against superficial bacterial infections. As resistance to antibiotics is increasing in recent years, topical antibiotics are not always effective in the treatment of superficial bacterial infections
• Antifungals – act by attaching to the cellular walls of fungi, inhibiting biosynthesis
• Antivirals
• Antiparasitics
• Corticosteroids – very commonly used in dermatology to reduce inflammation, by vasoconstriction, diminution of membrane permeability, inhibition of inflammatory chemical mediators, immunosuppression and inhibion of cell division. Topical steroids are classified by strength from high potency steroids to the mild ones. They should be given carefully to avoid side effects, i.e. skin atrophy, striae distensae, steroid acne, rosacea-like dermatitis, hypertrichosis etc.
• Topical hormonal treatments
• Calcineurin inhibitors
• Immunosuppressants
• Immunomodulators
• Cytostatics
• Retinoids
• Vitamin D analogues
• Keratolytics

Currently there are many different commercially available products with a standard, fixed combination of active ingredient(s) and vehicle. However, some dermatologists prescribe variable, personalized compound prescriptions which may have some advantage for individual needs of the patient. An advantage of this is the possibility of individualized adjustment of the dose and vehicle.

Topical preparations are applied to the skin most commonly once or twice daily. The patient should be prescribed an adequate quantity of the topical drug to be able to follow recommendations. For the entire body, about 30 g of the cream is needed. It can be easily quantified using the measure of „fingertip unit“ (the amount of ointment or cream expressed from a tube with a 5 mm diameter nozzle, applied from the distal skin-crease to the tip of the index finger of an adult) which is equal to ca. 0.5 g.

Topical JAK inhibitors have been examined in the treatment of alopecia areata, atopic dermatitis, vitiligo and psoriasis. Topical phosphodiesterase 4 (PDE4) inhibitors have shown promising results in the treatment of mild to moderate atopic dermatitis.