M. Taglietti, MD1; C. N. Hawkins, BScH2; J. Rao, MD, FRCPC3
1. Forest Research Institute, Jersey City, NJ, USA
2. Queen’s University, Kingston, ON, Canada
3. Division of Dermatology, University of Alberta, Edmonton, AB, Canada
A vast spectrum of topical anti-acne agents has emerged in response to new insights that have been gained through the understanding of disease pathophysiology and the need for clinicians to adopt an individualized therapeutic approach. Because topical agents are most commonly used for acne management, this article reviews some novel vehicle delivery advances that are poised to further enhance the efficacy of topical acne formulations, and/or offer the possibility of simplified dosing regimens that may improve treatment outcomes.
acne vulgaris, drug administration, topical therapies
When it comes to the delivery of a drug to a specific site, topical formulations are probably among the most challenging products to develop. An effective topical formulation needs to provide a stable chemical environment in a suitable dispensing container in order to accommodate multiple compounds that may have different, if not incompatible, physicochemical characteristics. Once applied, a topical formulation must interact with the skin environment, which can influence the rate of the release of the compound(s) in order to achieve adequate skin absorption. The excipients themselves will exert additional physical effects on the skin, such as drying, occluding, or moisturizing. Research and technology have brought a better understanding of the physics, chemistry, pharmacodynamics, and pharmacokinetics for drugs used to treat acne. These insights have resulted in new delivery systems that are capable of enhancing the efficacy, tolerability, and cosmetic acceptability of topical formulations.1-3
The challenge of developing a successful topical product stems from the several requirements that a formulation must meet:
1. Container Selection and Product Stability
Depending on the properties of the combined ingredients, a dispensing container will be chosen (i.e., tube, jar, can, etc.) to provide a stable physicochemical environment that protects the active compound(s) from chemical degradation. The formulation can be a liquid or semi-solid, monophasic or multiphasic (e.g., oil-in-water or water-in-oil); it is largely dependent on the characteristics of the active compound(s) and on the condition of the skin to be treated.
2. Skin Penetration
Once the product is applied on the skin, a complex interaction occurs between the formulation, the active compounds, and the skin itself. The penetration of the active compound(s) into the skin follows Fick’s first law of diffusion, which describes the transfer rate of solutes as a function of the concentration of the various ingredients, the size of the treatment surface area, and the permeability of the skin. However, the skin’s permeability can be influenced by many factors, such as the drying, moisturizing, or occluding effects of the excipients in the formulation, which, in combination, can modulate the release of the product at the treatment site. In acne, the site of action is inside the pilosebaceous unit and, therefore, an efficacious anti-acne formulation should facilitate the penetration of the active compound(s) into this extremely lipophilic environment.
3. Cosmetic Acceptability
In today’s self-image conscious world, patients are looking for topical products that are not only safe and effective, but also cosmetically acceptable and easy to apply. This is especially true in acne, where the esthetic aspect is one of the primary reasons why patients seek dermatologic consultation. Moreover, acne patients are mainly comprised of teenagers or young adults, and therefore, products that offer convenience and are minimally disruptive to daily routines increase the level of compliance, and ultimately, the efficacy of the topical therapy. For example, vehicle considerations for prescribing should take into account the application of the drug on large, hairy surfaces like the chest and the back. This may require formulations that spread easily, or in the case of facial acne, the ideal formulation should leave minimal residue or oiliness.
|Common Topical Acne Treatments||Cutaneous Side-effects||Potential Novel Systems for Agent Delivery|
|Retinoids (e.g., adapalene, tazarotene, tretinoin)||Burning, peeling, erythema, dryness, photosensitivity||Microsponges, liposomes, nanoemulsions, aerosol foams|
|Benzoyl peroxide||Dryness, erythema, peeling, hair and clothing discoloration||Polymers, fullerenes|
|Clindamycin phosphate||Erythema, dryness, allergic contact dermatitis||Aerosol foams, polymers, nanomemulsions|
|Erythromycin||Dryness, erythema, peeling, allergic contact dermatitis||Aerosol foams, polymers, nanomemulsions|
|Salicylic acid||Dryness, erythema, peeling||Polymers, microsponges|
|Table 1: Cutaneous side-effects from topical acne treatments and potential novel systems for agent delivery|
Current Topical Therapy for Acne Vulgaris
Topical treatment is the most common and popular way to manage acne and there are a variety of therapies available (Table 1) that are frequently administered in combination in order to target concurrent multiple pathogenic factors. In general, topical monotherapy is indicated for mild-to-moderate acne, such as comedonal and/or papular variants; combination therapy is reserved for more severe or refractory disease.
Novel Topical Delivery Systems
Aerosol foams have become an increasingly popular type of topical formulation for a variety of skin conditions including acne vulgaris. The vehicle base of the foam can have a liquid or semi-solid consistency that shares the same physicochemical characteristics of conventional vehicles like creams, lotions and gels, but it maintains desirable properties such as moisturizing/ fast-drying effects, or higher drug bioavailability. The aerosol base is dispensed through a gas-pressurized can that discharges the foam. The product characteristics (i.e., texture, bubble size and thickness, viscosity, density, persistence, stability, and spreadability) are determined by the type of formulation and the dispensing container that are selected to suit the specific treatment needs. In acne, foams may be preferred for application on large hairy surfaces (e.g., chest and back) or on the face as cleansers, because they are easier to apply.
Liposomes are frequently used as vehicles in pharmaceuticals and cosmetics for a controlled and optimized delivery to particular skin layers. Liposomes are spherical vesicles whose membrane consists of amphiphilic lipids (i.e., lipids that are hydrophilic on one side and lipophilic on the other side) that enclose an aqueous core, similar to the bilayer membranes of living cells. Because liposomes offer an amphiphilic environment, they may encapsulate hydrophilic substances in their aqueous core and lipophilic substances in their lipid bilayer. This unique dual release capability enables the delivery of 2 types of substances once they are applied on the skin; each differs in its effects on skin permeability, which may enhance the desired therapeutic benefit.4,5
Nanoemulsions are a class of emulsions (i.e., water-in-oil or oil-in-water formulations) that are characterized by the dispersion of very small-sized droplets when mixed. Nanoemulsions are not formed spontaneously, as they require unique thermodynamic conditions, specialized manufacturing processes, and specific surfactants that can stabilize the nano droplets. Nanoemulsions are suitable for the transport of lipophilic compounds into the skin and, therefore, they may be an ideal vehicle for use in acne to increase the penetration of the active compounds inside the lipophilic environment of the pilosebaceous unit. In addition, nanoemulsion particulates will not clog the pores and they can produce additional therapeutic effects, such as increased skin hydration and viscoelasticity.6
Polymers are large molecules consisting of repeating structural units, or monomers that are connected by covalent chemical bonds. These compounds serve as the building blocks of natural (e.g., paper and amber), biological (e.g., proteins and nucleic acid), or synthetic (e.g., plastics and polyethylene) materials. Today, applications for synthetic polymers can be found in nearly every industry, and their versatility has given rise to technological advancements within the pharmaceutical sector that address a variety of medical needs. For example, in dermatology, there are new acrylic-acid polymers that turn into a gel in the presence of water by trapping water into microcells. Inside these aqueous microcells, hydrophilic compounds can remain in a solution, whereas non-hydrophilic compounds may be dispersed in suspension. The result is a stable gel-like formulation that is easy to use and releases the active compound(s) once they are applied on the skin. Moreover, these polymer-based gels can be mixed with other excipients, such as moisturizers and emollients, to provide additional clinical benefits. Recently introduced anti-acne formulations that combine clindamycin 1% with benzoyl peroxide 5% (Duac®, Stiefel Laboratories; BenzaClin®, Dermik) utilize this novel polymer-based gel technology that exhibits efficacy and excellent tolerability.7
Microsponges are biologically inert particles that are made of synthetic polymers with the capacity to store a volume of an active agent up to their own weight. Furthermore, the particles serve to protect the entrapped active compound from physical and environmental degradation. The microsponge technology can be utilized in a variety of formulations, but is more frequently manufactured as gels. Once applied on the skin, microsponges slowly release the active agent(s).
Emulsifier-free formulations are also a growing area of development for dermatologic and cosmetic products. Most skin care products are emulsions, i.e., a mixture of 2 or more materials that are not miscible with each other; as such, according to the second law of thermodynamics, they are inherently unstable. As a result, they require the addition of surfactants (“emulsifiers”) that stabilize the formulation to guarantee an adequate shelf life. Furthermore, once these surfactant agents are applied on the skin, they tend to emulsify and remove the natural lipids of the epidermis. Consequently, the pharmaceutical industry has been developing surfactant-free emulsions as alternatives to conventional formulations by using stabilizers, such as polymeric emulsifiers or solid particles, in order to yield sufficiently stable products with a cosmetically pleasant appearance.
Fullerenes are molecules composed entirely of carbon that resemble a hollow sphere. Rouse, et al., showed that once fullerenes come into contact with the skin, they migrate through the skin intercellularly, as opposed to moving through cells.8 Therefore, a fullerene could be used to “trap” active compounds and then release them into the epidermis once they are applied on the skin. Moreover, fullerenes, themselves, are thought to be potentially potent antioxidants. Data are reported in the literature showing that fullerenes are well tolerated and they hold substantial promise in dermatologic and cosmetic applications.9,10
Much progress has been made to improve the performance of topical anti-acne care products in recent years. New excipients, refined processing techniques, and a better knowledge of the physicochemical properties of vehicles and drugs have led to the development of new delivery systems that may result in more advanced anti-acne therapies. Well controlled clinical trials will be required to confirm the clinical benefits of these new formulations in terms of efficacy, tolerability, compliance, and cosmetic acceptability.
- Date AA, Naik B, Nagarsenker MS. Novel drug delivery systems: potential in improving topical delivery of antiacne agents. Skin Pharmacol Physiol 19(1):2-16 (2006).
- Katz MA, Cheng CH, Nacht S. Methods and compositions for topical delivery of benzoyl peroxide. US Patent No 5,879,716 (1999 Mar 9).
- Ting WW, Vest CD, Sontheimer RD. Review of traditional and novel modalities that enhance the permeability of local therapeutics across the stratum corneum. Int J Dermatol 43(7):538-47 (2004 Jul).
- Schafer-Korting M, Korting HC, Ponce-Poschl E. Liposomal tretinoin for uncomplicated acne vulgaris. Clin Investig 72(12):1086-91 (1994 Dec).
- Brisaert M, Grabriels M, Matthijs V, et al. Liposomes with tretinoin: a physical and chemical evaluation. J Pharm Biomed Anal 26(5-6):909-17 (2001 Dec).
- Yilmaz E, Borchert HH. Effect of lipid-containing, positively charged nanoemulsions on skin hydration, elasticity and erythema–an in vivo study. Int J Pharm 307(2):232-8 (2006 Jan 13)
- Zerweck C, Grove G, Fraser JM. Moisturization potential of two acne gels containing 5% benzoyl peroxide and 1% clindamycin. Presented at: AAD Summer Academy Meeting, July 26-30, 2006, San Diego, CA; P100.
- Rouse JG, Yang J, Ryman-Rasmussen JP, et al. Effects of mechanical flexion on the penetration of fullerene amino acid-derivatized peptide nanoparticles through skin. Nano Lett 7(1):155-60 (2007 Jan).
- Huczko A, Lange H. Fullerenes: experimental evidence for a null risk of skin irritation and allergy. Fullerene Sci Technol 7:935-9 (1999).
- Fumelli C, Marconi A, Salvioli S, et al. Carboxyfullerenes protect human keratinocytes from ultraviolet-B-induced apoptosis. J Invest Dermatol 115(5):835-41 (2000 Nov).