The epidermal barrier functions to prevent entry of chemicals and noxious materials, 1 thus the most significant challenge in topical drug delivery is designing an appropriate vehicle. For this reason formulators must understand the structure and function of the stratum corneum in order to optimize delivery of drugs to the intended site of activity within the skin. Formulation development projects begin with the identification of the active ingredient to be used to provide a desired effect. A target product profile is developed, establishing the goals of vehicle development by exploring and answering a series of key questions about the formulation to be developed. Six primary considerations guide the development of a vehicle. The vehicle must:
- Efficiently deposit the drug on the skin with even distribution.
- Release the drug so it can migrate freely to the site of action.
- Deliver the drug to the target site.
- Sustain a therapeutic drug level in the target tissue for a sufficient duration to provide a pharmacologic effect.
- Be appropriately formulated for the anatomic site to be treated.
- Be cosmetically acceptable to the patent.
Due to the efficiency of the epidermal barrier, the amount of topical drug that gets through the stratum corneum is generally low. Rate and extent of absorption vary depending on characteristics of the vehicle but is also influenced by the active agent itself. Topical corticosteroids are representative of many commercially available topical drug products regarding bioavailability of lipid-like drugs through skin. These agents result in systemic absorption through intact, non-inflamed skin of typically less than 5% of applied drug.2
Knowledge of skin barrier function has expanded in the last two decades,3 elucidating both the manner in which drugs penetrate and the topical formulations that efficiently deliver drugs. This advancement in skin biology has fueled the development of novel vehicles that have advanced dermatologic therapy with both new formulations of old drugs and new drug entities.
Mechanisms of Drug Absorption. There are three primary mechanisms of topical drug absorption: transcellular, intercellular, and follicular.4 Most drugs pass through the torturous path around corneocytes and through the lipid bilayer to viable layers of the skin. The next most common (and potentially under-recognized in the clinical setting) route of delivery is via the pilosebaceous route. Follicular delivery is typical of several commonly used drugs that are present in vehicles as fine particulate suspensions: benzoyl peroxide, azeleic acid, and dapsone.
Follicular delivery is preferred for diseases of the pilosebaceous unit, such as acne, folliculitis, and hair loss, but is also utilized to create a reservoir effect.5 Drug microparticles deposited into the follicle may slowly dissolve over time, creating a controlled release or reservoir effect.
In practice, drugs are absorbed through combinations or perturbations of these pathways. For example, propylene glycol, because of its solvent and humectant properties, is a common ingredient in topical formulations. At relatively high concentrations, propylene glycol has been shown to promote desquamation, 6,7 thus widening the cellular pathways through which topically applied drugs may pass.
Hydration of the stratum corneum is an important tool for modifying drug delivery. As epidermal cells swell, the aqueous/lipid ratios within the skin are altered and, as a secondary effect, those cells no longer resist mechanical sheering and stress forces. Hydration also helps maintain normal desquamation, as the serine proteases that instigate dissolution of the desmosomes require water.8 In certain disease states, such as psoriasis, water can encourage desquamation of the corneocytes and thus enhance penetration of a drug through thick, scaly plaques.
Drug Metabolism. The epidermis is not simply a passive membrane that either blocks or permits entry of a drug. The skin, rich in enzymes, is the largest drug metabolizing tissue in the body. Research has identified 13 CYP2 genes expressed in human skin, with most expressed in the non-vascular tissue of the epidermis.9 Esterases and serine proteases are abundant. Biotransformation of compounds can and often does occur in the epidermis, presenting both challenges and opportunities to formulators. Epidermal biotransformation could render a drug such as a peptide ineffective before it reaches its target or, in the case of some pro-drugs, transform a biologically inactive molecule to an active form. Epidermal metabolism and inactivation of certain drugs may permit safe topical application of a drug that possesses systemic toxicity.
Gama benzene hexachloride (GBH, Lindane, Morton Grove Pharmaceuticals), for example, is largely biotransformed as it passes through the epidermis and into the dermis, therefore the risk of systemic toxicity associated with extensive topical application (up to 30-60mL) is relatively low. By contrast, less than 15mL of Lindane ingested orally is in the range of LD50 for humans. Topical tazarotene is another drug that is rapidly skin metabolized (to tazarotenic acid and other metabolites), 10 accounting for its relatively low risk of systemic exposure.
Cutaneous metabolism allows for the topical application of prodrugs that are transformed to active drugs. Retinol is metabolized in the dermis to retinoic acid.11 However, the efficiency of biotransformation of retinol to retinoic acid is relatively low, so retinol is considered safe for use as an ingredient in topical cosmetic products without retinoid safety labeling.
Theoretically, pro-drugs could be used in topical formulations as a strategy to alter the physicochemical properties of the active ingredient to improve delivery into the skin or to minimize toxicity. Suppose a biologically activated drug is intended for delivery to the dermis but is inactivated in the epidermis. An inactive prodrug molecule might pass through the epidermis and be metabolized to the biologically active drug at the dermal layer, where it can produce the desired effect.
Disease Sites and Anatomic Treatment Areas. The site of the disease within the skin—whether it be the epidermis, dermis, capillaries, or the pilosebaceous unit— must be taken into account in designing an effective vehicle for a drug. With the modern understanding of skin biology, formulators can target delivery of a particular drug molecule by the skillful selection of excipients and their concentration, proper choice of vehicle type, and careful attention to the physical state of the active ingredient (i.e., the degree of solubility in vehicle or particle size in the case of suspensions) and control of the characteristics of the secondary formulation. Similarly the anatomic location(s) of treatment and the range of body surface area guide development of a vehicle that will allow the drug to be applied uniformly and with relative ease.
Clinicians know that choice of vehicles depends on the location being treated as well as the skin disease. For example, an ointment is not cosmetically acceptable for application to the hair-dense scalp for many people. The scalp is an interesting delivery area to consider in terms of product formulation because of the variability of density and texture. Unless the topical formulation can be applied directly to the scalp skin (e.g., a foam or spray applied via a delivery tube to pass through the hair), scalp treatment involves a greatly increased skin and appendage surface area that will interface with the topical delivery system. Scalp and other very hairy areas generally require the application of more drug formulation per square centimeter than glabrous skin. Additionally, the scalp is almost always covered by a thin layer of sebum. Sebum incorporates into the formulation after application to the scalp skin, potentially altering the kinetics of intercellular transport. For this reason effective topical formulations take into consideration the in vivo environment from which the active ingredient is delivered to the site of action within the skin.
Drug-Specific Considerations. Specific properties of the drug to be delivered guide the development of the vehicle. Ideal vehicles are drug-specific; There are no vehicles that without customization work efficiently for a wide variety of drug molecules. The stability of the active ingredient and its bioavailability are primary considerations in creating an optimal vehicle. Based on the physicochemical properties of the drug, a rational strategy can be developed to create the vehicle. Key factors include: a.) degree of solubility or insolubility in various excipients such as oils, humectants, and water, b.) compatibility or incompatibility with potential excipients, and c.) sensitivities to molecule degradation and instability. With this knowledge, the formulator can create multiple vehicles for the drug with the goal that one will survive stability testing, assessement of cosmetic and functional properties, in vitro skin penetration studies, antimicrobial preservative effectiveness testing, and other screening criteria. The development process is lengthy and far from simple.
Secondary Formulations. Beyond the physicochemical considerations and requirements for the formulation and its physical container to provide stability and uniformity, formulators also must consider the physical changes that occur as a formulation is applied to the skin. When present in a vehicle, volatile components such as water, alcohol, and propellants, all eventually evaporate, thereby concentrating the active drug and non-volatile excipients. During the application process these residual components become mixed with the hydrolipidic film on the skin surface, creating what some call the “secondary formulation.” It is from this secondary formulation that drug is typically delivered into the skin. Consider difficult-to-solubilize dapsone that has been formulated into a gel (Aczone, Allergan). The marketed formulation contains water along with a solvent called diethylene glycol monoethyl ether (also known as DGME, Transcutol® or ethoxydiglycol). DGME solubilizes a percentage of the dapsone in the formulation; the remaining undissolved dapsone particles remain in suspension.
Once the gel is applied to the skin, water—the highly volatile component—dissipates, and dapsone particles become concentrated in the residual non-volatile solvent DGME. As the gel is rubbed in, mechanical rubbing action helps to further dissolve dapsone into the solvent, while undissolved particles are deposited in the follicle, creating a reservoir of drug slowly dissolved by sebum over time. At the same time, sebum and other debris on the surface of the skin become incorporated into the secondary formulation.
Of the many topical solubilizing agents used, propylene glycol may be the most widely used and best known. At high concentrations (greater than 10%) propylene glycol can be more irritating to the skin or provoke allergic reactions, though it is generally well-tolerated at moderate and low concentrations. High concentrations of PG may be problematic for some individuals; The incidence of positive patch reactions for allergic contact dermatitis in those using up to 30% concentration of PG is about 3.5 percent.12