Advancing bioavailability: Formulators expand therapeutic armamentarium with novel products

Key Points

Drug-induced irritation has also been reduced by manipulating the components of the formulation, such as by using a triple humectant-optimized vehicle containing glycerin, hyaluronic acid and panthenol to formulate benzoyl peroxide (Benziq, Graceway).

Formulator challenges

Creating a topical product involves both art and science, as formulators face a balancing act in trying to meet multiple technical and aesthetic goals. The final product must be able to be scaled up to commercial production levels. Additionally, it must be stable with a reasonable shelf life, it must deliver the active ingredient to its target site in a therapeutic concentration, and it must be aesthetically pleasing, because product acceptance underlies patient compliance, the ultimate determinant of treatment benefit.

"Product formulation has a real effect on compliance, and this is especially important considering that many skin diseases are chronic conditions that can be managed but not cured. For products requiring long-term use, developing formulations that offer better convenience and are acceptable to patients will enhance compliance, without which there is no efficacy," Dr. Fleischer explains.

"There is a supposition that the best medication may be the cheapest, but that doesn't hold sway if the patient doesn't use the product," Dr. Fleischer adds. "Therefore, physicians also face a balancing act at times in prescribing medications that our patients can both afford to buy and then will use."

For topical products, stability and compatibility issues can involve interactions between ingredients in the formulation as well as between ingredients and the container. In addition, the fact that topical preparations usually contain a proportionally large amount of water increases the potential for microbial growth and oxidative and/or hydrolytic reactions, says Susan Ciotti, Ph.D.

Dr. Ciotti is now director of formulation, research and development, NanoBio, Ann Arbor, Mich. She previously was involved with dermatology product formulations at Pfizer Global R&D, Ann Arbor, and at the Topical Formulations & Drug Delivery Technology Resource Center at Johnson & Johnson, Skillman, NJ.

Unique situations

Bioavailability is a particular challenge because the active ingredient must be released from the dosage form, penetrate into the protective barrier presented by the skin, and diffuse through to reach its structural target.

"There is no simple, cookbook approach for successful topical product formulation, nor are there any 'super' vehicles or bases that are optimal for all medications. Each drug entity with its physical and chemical properties, together with its intended indication, presents a unique situation, requiring customized formulation," says Gordon Dow, Pharm.D., founder and chief technical officer, Dow Pharmaceutical Sciences, Petaluma, Calif.

Despite notable exceptions, an active ingredient that is dissolved in the formulation generally provides better cutaneous bioavailability than an insoluble suspension of the drug in the formulation.

However, these theoretical principles must be confirmed experimentally; for example, by using in vitro skin penetration studies. Furthermore, creating a formulation with drug "in solution" is not always possible, because there may be tradeoffs relating to stability issues or the need for strong solvents that can introduce other problems, Dr. Dow says.

Skin penetration enhancers may also be used to improve bioavailability, or formulators can attempt to design a formulation that will achieve high drug delivery following the changes that occur after application to the skin. This latter approach is represented by properly designed aqueous or alcoholic gels that mix with the skin's hydrolipidic surface film and lead to super saturation of the active ingredient after evaporation of the volatile components, Dr. Dow explains.

"However, penetration enhancers and solvents can be double-edged swords. While they can enhance drug delivery, this benefit may occur with an increased risk of skin irritation and stability issues," Dr. Dow says.