Therapeutic innovation generally involves the introduction of new active principles, but the concept can be extended to any novel ingredient that provides the prescriber with new resources. Between 1995 and 2005 the fertile combination of chemical industry innovations and the demand for certain types of treatments brought a large number of new vehicles to the market.8 The most important novel vehicles available are described below.

Topical therapy continues to be the pillar of psoriasis management given that around 70% of patients with mild to moderate disease use this modality exclusively.10 The remaining 30% of patients have severe disease and take additional systemic drugs. Studies confirm that combining topical treatment (corticosteroids, vitamin D analogs, or tazarotene) with a systemic drug provides such patients with additional benefits, favoring faster clearing of lesions or allowing for a lower dose of the systemic agent. Nonetheless, 40% of patients report low adherence to topical therapy.11 To optimize such treatment, it is insufficient to offer safe, effective active agents. The product must also be convenient and easy to use. To that end, vehicles must be appropriate to the area of the body where the formulation will be applied. In fact, the best vehicle is whichever one the patient is most likely to use. The compounding of customized formulations is advantageous in both topical and systemic psoriasis treatments: the product can be tailored with consideration of the type of psoriasis and area of skin affected and can also be provided in the amount needed, making self-medication less likely. Adherence to topical treatment is facilitated if active principles are compounded with secondary ingredients in practical formulations that have both moisturizing and emollient properties. A personalized formulation of a systemic treatment, which is prescribed according to patient weight, will make it easier to take the dose over an appropriate number of days.12

Compounded preparations contain active ingredients that are already available on the market, but the advantage of the customized forms is that they widen our choice by providing concentrations of active drug that are dissolved in appropriate vehicles.

The most important contributions of these formulations to the treatment of psoriasis in recent years are listed in Tables 7 and 8.

Moisturizers, humectants, and emollients are essential components of topical treatments and although their active contribution is considered secondary, their beneficial effects when used alone have been attributed to their ability to restore hydration and the water barrier function in the area of the psoriatic plaque, reducing the need to apply corticosteroids.13 Compounding allows moisturizers and emollients to be used together with other active ingredients in the interest of improving adherence. Ammonium lactate 12% is noteworthy among the moisturizers applied in this setting because of its recognized ability to mitigate the atrophy induced by topical corticosteroids.14 We can recommend compounding ammonium lactate and urea for the synergistic effect of this combination.

Vitamin B12 is important among the active principles used in formulations for plaque psoriasis because it is effective in this disease15,16 and very safe. This vitamin is ideal for maintenance therapy and can be combined with other more potent agents, such as corticosteroids for flare-ups. A concentration of 0.07% is sufficient because efficacy has not been found to increase at a higher concentration of 0.14%.16 Tacrolimus can be used at concentrations of 0.3% or 0.1% in carbohydrate-based emulsions for sensitive skin17 or at concentrations of 0.3% to 0.5% for application on other areas. These concentrations are not available commercially but are particularly useful when plaques cause itching. However, in a trial comparing calcipotriol to tacrolimus at high concentrations, calcipotriol proved more effective for normalizing epidermal differentiation markers.18

Compounding can also resolve the problem of orphan drugs. Recent years have seen commercial plaque psoriasis treatments using dithranol and tar derivatives disappear from the market, for example, because they were unprofitable. The physical properties of these active ingredients are of little cosmetic interest, but they remain useful in certain situations in which commercial products are not indicated. In this line, in 2008 Zampetti and colleagues19 described their 15-year experience with topical psoriasis treatments in 666 patients, observing that the most effective treatment was to use 2 formulations—one of clobetasol propionate 0.05% plus an eosin 2% solution, the other of eosin 2% plus cade oil (a classic tar)—on alternate days.

Both dithranol therapy and the Goeckerman regimen (with modifications) continue to be used to treat psoriasis, even in children. In Europe, these therapies, which are prescribed more often outside Spain20,21 than here, are the ones associated with longer periods of remission. To maximize adherence to these treatments, the dermatologist must explain them in detail. Ichthyol (Ichthyol Pale) has been added to preparations for application on sensitive skin and the scalp in recent years, for its utility as a well-tolerated reducing agent with good cosmetic properties.

Calcitriol, among the vitamin D derivatives available for extemporaneous preparations, is widely known to be effective. This ingredient is especially useful in the treatment of inverse psoriasis or for application on nonflexural areas where skin is sensitive (the face and genitals).22 As calcitriol is unstable and oxidizes easily it is inadvisable to combine it with other ingredients, with the exception of topical corticosteroids. Vitamin D derivative is compounded for 2 reasons, so that the right vehicle can be provided and so that another active principle (a corticosteroid) can be included.

Special tazarotene preparations with alternative, noncommercial vehicles have recently been tried. Our experience suggests that a tazarotene 0.1% ointment is as effective in nail psoriasis23 as has been reported for the commercial gel formulation.

Tazarotene and tacrolimus can be combined with other active ingredients, particularly medium-strength corticosteroids, which can also be combined with calcitriol. These synergistic associations serve to potentiate efficacy and reduce the toxicity of the agents used separately. The irritation caused by calcitriol, tazarotene, and tacrolimus on first application is well known. When a corticosteroid is added, irritation is reduced.

Several concentrations of topical methotrexate have been compounded with various vehicles for empirical use in plaque psoriasis and palmar-plantar pustular psoriasis even though scientific evidence is lacking. In 2006 Eskicirak and colleagues24 reported that a methotrexate 1% preparation was more effective and safer than placebo. Since this topical formulation is unavailable commercially, compounding is imperative.

Nail psoriasis presents therapeutic challenges for many patients and their dermatologists. It is important to classify lesions according to whether the bed or matrix is affected and to assess the intensity of involvement by means of one of the severity scoring systems, such as the Nail Psoriasis Severity Index (NAPSI) and the Physicians Global Assessment of nail activity. If the NAPSI is under 10, nail psoriasis is mild to moderate and may respond to topical treatment. Scientific evidence has shown that that vitamin D derivatives (calcipotriol25 and tacalcitol26 in particular) seem to be more effective when the nail bed is affected. Similarly, there is evidence in favor of treating onychomycosis with topical corticosteroids in high concentrations (e.g. clobetasol propionate 8%) in nail lacquers, as this vehicle facilitates optimal penetration through the nail; 2 clinical trials have shown the safety of this approach and the positive effects on nail activity in this disease, particularly for manifestations arising from changes in the nail bed.27,28 To prepare a medication that works in both the bed and the matrix, tacalcitol can be compounded in a clobetasol propionate 8% lacquer.28 In view of the greater prevalence of onychomycosis in patients with nail psoriasis, serial cultures should be obtained when using this treatment.29,30

Custom-made formulations are often prescribed for scalp psoriasis even though the new commercial products of recent years have significantly advanced therapy in this form of the disease, which is often refractory to treatment.31 We do not believe that old extemporaneous formulations of doubtful efficacy can justifiably be used today. Above all, preparations with objectionable physical properties that discourage their use cannot be defended, especially when promoting adherence to therapy obliges us to provide pleasing products that are easy to use. The dermatologist who prescribes compounded scalp treatments should choose appropriate vehicles (shampoos, hair oils, semiliquid gels, liquid emulsions) and bear in mind the toxicity of active principles (in particular, potent corticosteroids and salicylic acid).

In the treatment of moderate to severe plaque psoriasis narrow-band UV-B phototherapy is now pushing aside psoralen plus UV-A phototherapy (PUVA) for reasons of both safety and ease.32 Although it is recommended to avoid substances that can alter light penetration (salicylic acid) or that oxidize when exposed to UV light (vitamin D derivatives), our department undertook a study in which patients with plaque psoriasis underwent narrow-band UV-B phototherapy after application of a thin O/W emulsion containing oleic acid 5% (n=24) or without application of the emulsion (n=20).33 We found that with prior application of the oleic acid patients needed fewer doses of UV-B radiation (in mJ/cm2) and fewer sessions. Thus, this formulation allowed treatment to be optimized with lower exposure overall. Continuous PUVA therapy is still highly useful for treating patients with skin types IV-VI as well as in such conditions as extensive psoriasis with infiltration, cutaneous lymphoma, lichen planus, and morphea, among others. Extemporaneous formulation of psoralen, whether for systemic or topical administration, is customary in PUVA therapy. The preparation of a single dose of 8-methoxypsoralen (8-MOP) in capsule or suppository form (0.6mg/kg body weight) improves digestive tract tolerance of the chemical.34 In spite of the limitations of topical application of 8-MOP, this route is useful in hand eczemas that are refractory to treatment, in palmar-plantar psoriasis, and in other localized or extensive conditions in which systemic psoralen would be contraindicated (e.g., cataracts, liver disease).

Acne is one of the most common reasons patients come to a dermatologist. Historically, compounding has proven useful and has been widely used in Spain, when legislation has allowed, for incorporating active ingredients unavailable commercially. For example, compounding has been used to combine ingredients, modify doses or vehicles, or provide adequate amounts of medication. Although more products are currently available on the market, compounding continues to play an important role in this disease.

Acne is classified as comedonal (acne vulgaris), papulopustular, or nodular. Acne vulgaris, or noninflammatory acne, requires an extemporaneous formulation when the dermatologist needs to prescribe a concentration that is lower or higher than those available on the market (e.g., oral isotretinoin 0.01% or 1%, or adapalene 3%35), when a different vehicle can improve tolerance (e.g., an emulsion to replace a hydroalcoholic gel), or when an amount must be provided for a large area (e.g., the upper chest or the back) (Table 9). Compounding plays only a small role in inflammatory, or papulopustular, acne because the commercial alternatives are abundant and meet expectations. Nonetheless, it has proven useful for incorporating new active principles like topical dapsone,36 which has proven effective at a concentration of 5% used for 2 to 4 weeks (Table 10). Custom-made preparations play a large role in mixed clinical forms of acne, the most common situation. In mixed acne comedones, papules, and pustules are all present and a product must contain both comedolytic and antibacterial agents. Combining active ingredients produces a synergistic effect and is often also associated with better tolerance than monotherapy, and of course adherence also improves when only a single product must be applied daily.

Not all the combinations a dermatologist might want to prescribe are chemically possible. With an antibiotic it is possible to combine a retinoid, glycolic acid, or benzoyl peroxide. The last can also be combined with adapalene. Combinations that are not recommended are retinoids with benzoyl peroxide (because of oxidation) and azelaic acid with antibiotics (because of chemical instability). Recently, however, a combination of azelaic acid 5% and erythromycin 2% was reported to be more effective than placebo or the administration of either of these 2 agents separately.37 The following combinations have been shown to be particularly useful for their efficacy, safety, and feasibility: retinoic acid with clindamycin38 or erythromycin; isotretinoin and erythromycin or clindamycin; glycolic acid and clindamycin; benzoyl peroxide and erythromycin or clindamycin.39 (Table 11).

A novel combination of tazarotene and clindamycin appears to be more effective than clindamycin and retinoic acid.40 Tazarotene has a more potent depigmentation effect on the postinflammatory hyperpigmentation associated with some forms of acne and can be compounded with creams or cream gels to provide a product that is less irritant than commercialized ones.40

The oral antibiotics or contraceptives used against acne are not customized. However, when the dosage of isotretinoin per body weight must be tailored to make it unnecessary for a patient to take several pills, to reduce costs, or to respond to swallowing problems, this active principle can be prepared in a suspension41 so that 3mL can be mixed with milk (or milk product such as a milk shake or yoghurt) (Table 12).

Acne is often associated with other skin diseases such as melasma in women, rosacea, seborrheic dermatitis, hirsutism, or atopic dermatitis. In such cases, the active principle appropriate for each condition can be compounded into a single vehicle to facilitate adherence (Table 13).

Patients with rosacea make up another group that has benefited from customized formulations because only a limited number of active principles and commercial presentations are currently available. Prescribers therefore often order special formulations and, evidently, tailored products achieve better results than those currently on the market.

The 4 types of rosacea, classified by clinical presentation, are erythematotelangiectatic, papulopustular, phymatous, and ocular.

The topical treatment of the first subtype, erythematotelangiectatic rosacea (Table 14) relies on substances to strengthen blood vessels (e.g., extracts of Indian horse chestnut, Ruscus aculeatus, Melilotus officinalis, or lemon myrtle) that tend to attenuate the persistent erythema and flushing that are characteristic of this phase of the disease. Because rosacea is difficult to treat with topical therapy alone, however, oral agents and physical modalities are often used in addition. Numerous products—thermal waters and a variety of creams, for example—are available, but pharmaceutical compounding offers the advantage of combining them with metronidazole or topical anti-irritants (e.g., enoxolone, alpha bisabolol) and venotonic agents to prevent disease progression.

Although oral clonidine chlorohydrate is not sold in Spain, the molecule 2-(2,6-dichlorophenylamine)imidazoline has been prescribed in oral form for years at dosages of 25 to 50 μg/d for flushing. This α2-adrenergic agonist can be used to reverse an acute episode (2 capsules at onset) or to prevent one (ongoing treatment with 2 capsules every 12 hours). Side effects, such as low blood pressure, dry mouth and constipation, are uncommon but gradual introduction of therapy is recommended to avoid them. The use of clonidine is justified more on the basis of clinical experience than on demonstration of efficacy from clinical trials.

The second subtype, papulopustular rosacea (Table 15), is treated with topical antibiotics, which seem to be effective because of their anti-inflammatory effects. The most widely used antibiotics are metronidazole 0.75%–1%, erythromycin 1%–2%, and clindamycin 1%–2%. Azelaic acid 10%–20% and sodium sulfacetamide 10% are second-line therapies.

Compounding allows metronidazole to be prepared at the higher concentration of 1% (doses higher than that are not more effective) in a more appropriate vehicle than the commercial one to reduce intolerance and to combine it with other antibiotics (erythromycin or clindamycin). Only clinical experience supports these associations in order to achieve a greater response to therapy in severely pustular forms of the disease.

An anti-inflammatory agent (e.g., enoxolone, aloe vera, or alpha bisabolol) can be incorporated if the patient's skin is highly sensitive.

In our opinion, azelaic acid is a second-line therapy in rosacea, although it has been reported to be as effective as metronidazole.42 This agent is used alone or as a complementary treatment (azelaic acid in the morning and metronidazole at night, for example). Because the process for working with azelaic acid is complicated, it is not often used in compounding. Nevertheless, an advantage this agent offers is its compatibility with many different vehicles as well as the fact that it can be combined with metronidazole.43

Sodium sulfacetamide 10% is often combined with organic sulphur 5% in the English-speaking world. This combination exhibits a drying effect and anti-inflammatory activity, is less potent than the previously mentioned options, and is prescribed for mild cases or as maintenance therapy. As it is not available on the Spanish market, the combination must be specially prepared.

When the patient also has seborrheic dermatitis, a common association with rosacea, it is much more useful to prepare a combination of metronidazole and hydrocortisone for short-term use, or to combine the antibiotic with an imidazole derivative (clotrimazole, ketoconazole, or ciclopirox olamine) or tacrolimus. This last drug acts against seborrheic dermatitis and also provides anti-inflammatory and anti-pruritic activity; it is therefore of interest in the treatment of rosacea, although cases of exacerbation have been reported.

When human demodicosis is suspected it can be treated with permethrin alone or in combination with metronidazole.

Moderate to severe rosacea requires the use of oral antibiotics (e.g., minocycline, doxycycline, metronidazole) in formulations that are not usually available commercially. Subantimicrobial doxycycline (40mg/d) in a delayed-release formulation was recently shown to stabilize disease long term44; if this treatment is prescribed in Spain, capsules must be specially prepared because a commercial formulation is not available.

Low-dose formulations of isotretinoin (2.5–5mg) can also be compounded when required.

Phymatous rosacea, the third subtype, is treated with physical modalities (electrocoagulation, carbon dioxide laser therapy, etc.), but the treatments used for papulopustular rosacea are often prescribed at the same time.

Compounding is highly useful in treating the fourth subtype, ocular rosacea, as metronidazole (at concentrations of 0.5% to 0.75%) can be added to vehicles for direct application to the conjunctiva of the eye (ointments, a sterile eye wash or drops) (Table 16).

Although pigmentation disorders are many and include both hyper- and hypopigmented conditions, we will discuss only those that most often generate visits to the clinical dermatologist: melasma, solar lentiginosis, postinflammatory pigmentation, and vitiligo.

As few dermatologic products are sold for these disorders, the prescriber often chooses to order an extemporaneous formulation.

Retinoic acid, hydroquinone cream, and topical corticosteroids are depigmentation agents. Kojic acid and azelaic acid are less potent agents that are used in mild cases, in summer, or for maintenance therapy.

Any of these agents might be used alone or in combination (for greater efficacy), in a variety of dosages, and in a wide range of possible vehicles.

The most effective combination, known as the Kligman triad, consists of hydroquinone, retinoic acid, and a topical corticosteroid. As this compound can irritate, however, many variations with lower doses of each of the active principles have been tried (Table 17).

For significant but highly localized hyperpigmentation, or to depigment areas that have not yet lost color in universal vitiligo, mequinol 10% or 20% can be used. However, this highly potent hydroquinone ester carries a high risk of irreversible depigmentation (Table 18).

A recently described combination of nicotinamide and ascorbic acid is less potent but useful in summer or for maintenance therapy.45

Recently appearing patches of vitiligo are treated with topical corticosteroids of varying potencies. Many products are available on the market. When these treatments are specially compounded the purpose is usually to provide large amounts to treat a large area. Tacrolimus is also used in commercial formulations or is specially compounded into less oily vehicles at a range of concentrations. Khellin 3% is also provided in extemporaneous formulation for this indication.

Compounded formulations of phenylalanine or oral or topical 8-MOP may be required for phototherapy, and 8-MOP can also be administered in suppository form if digestive problems develop (Table 18). Monobenzone is used when permanent depigmentation is desired for a few areas of pigmented skin left unaffected by a disorder, as mentioned earlier.

Very few commercial products are currently available for the topical treatment of the oral mucosa. Therefore, compounding is often required.

Because the oral mucosae are mostly nonkeratinized epithelial tissues, they are highly permeable to the active substances we wish to apply to them. However, traditional vehicles are difficult to use on surfaces that are highly mobile and bathed in saliva; appropriate vehicles are needed.46

Although hydroalcoholic solutions are traditional vehicles for scalp medications, it is important to be aware of new products that are appropriate for use on this area of the skin.

Variations of hydroalcoholic solutions can be created by incorporating a highly emollient ingredient such as isopropyl myristate to correct dryness or volatile silicones to correct the oily feeling left on the skin by formulations with high concentrations of propylene glycol. It is also possible to use hydroalcoholic solutions without propylene glycol, which is a cause of contact dermatitis, itching, and dry scalp. Semiliquid gels and compact gels facilitate more localized application of a medication. It is also possible to prescribe liquid O/W emulsions for the irritated scalp, where the use of alcohol should be avoided.

Certain diseases, such as psoriasis and some cases of seborrheic dermatitis, cause hyperkeratotic lesions that can become drier if treated with a hydroalcoholic solution. Patients with this problem can more easily manage treatment with emulsions. Also useful in these cases are hair oils that help eliminate scales and have a more pleasant appearance than emulsions. A specially prepared formulation of this type would combine conventional vegetable oils with high-quality cosmetic lipids and a volatile cyclomethicone. A drawback to this combination is that certain active principles—such as hydrocortisone, ketoconazole, and urea—cannot be added in high concentrations. Table 23 lists compatible agents.46

We will now focus on 2 of the most common scalp diseases, androgenic alopecia and alopecia areata.

Pharmaceutical compounding has generated considerable debate, but its role and usefulness in dermatology is increasingly clear. Personalizing medications allows us to fill gaps in the therapeutic arsenal, make agents easier for patients to use, and enhance adherence. The physician who prescribes compounded medications must understand the active principles, their dosing and interactions, and how their physical properties affect the preparation process. Good communication with the pharmacist is essential. Incomplete information and the lack of standardized product inserts for compounded products are the main problems. The prescribing dermatologist can compensate for these drawbacks with experience and a good understanding of the products in order to inform patients consistently and watch for adverse effects. The future may provide more detailed informative product inserts on the formulations that are used most often. If regulation is achieved and compounding is accepted by public health services, costs will come down.

The authors declare that they have no conflicts of interest.