Combination product offers stability, flexibility in acne patient care

Key Points

Las Vegas - A series of laboratory studies show that the tretinoin in a new clindamycin phosphate/tretinoin combination product (Zianis, Medicis) has a unique stability profile that may allow for increased versatility in acne patient care, according to a poster by James Q. Del Rosso, D.O., at the Fall Clinical Dermatology Conference.

Research demonstrates that tretinoin in the combination product has excellent photostability and is subject to minimal degradation upon exposure to benzoyl peroxide under dark conditions, either with direct admixture or sequential application of the two products.

"Other commercially available conventional formulations of tretinoin, other than the microsphere vehicle, are known to be degraded by benzoyl peroxide and are also photolabile.

"The results from the current stability studies show the fixed combination product of benzoyl peroxide/tretinoin offers the potential for flexibility in timing of application, especially in the evening. This would enable product use based on individual patient needs, a feature that, in turn, might be expected to maximize patient compliance and medication efficacy," he says.

Combination product details

The combination product contains clindamycin phosphate 1.2 percent and tretinoin 0.025 percent in a proprietary, aqueous-based, alcohol-free gel. The clindamycin phosphate is solubilized and equivalent to 1 percent clindamycin. The tretinoin is present as both solubilized ingredient and in a suspended crystalline form.

The particle size of the crystalline tretinoin is tightly controlled through the manufacturing process to produce small-sized particles intended to enhance follicular penetration.

"It has been suggested that this product provides initial rapid penetration of tretinoin from the solubilized portion, along with gradual penetration from the crystalline form as it solubilizes on the skin surface.

"The result is slow, sustained delivery of the tretinoin that could account for the favorable tolerability profile and low irritation potential documented for the combination product in clinical trials," Dr. Del Rosso tells Dermatology Times.

The stability of tretinoin after exposure to benzoyl peroxide was evaluated in one study in which the combination clindamycin/tretinoin product was mixed with an equal volume of a 6 percent benzoyl peroxide gel and then incubated at 35 degrees Celsius. Assays for tretinoin were performed at baseline and then after two, four, six, eight and 24 hours. At eight hours, about 96 percent of the original label amount of tretinoin remained intact, while almost 80 percent of the original label amount of tretinoin was present at 24 hours.

Investigation of the photostability of the tretinoin in the clindamycin/tretinoin gel was conducted in a Franz cell human skin penetration model using freshly harvested human cadaver skin.

A fixed dose of product was applied to the skin surface, and the Franz cell chambers were kept under dark or light conditions. After 48 hours, the amount of tretinoin recovered using the fixed combination was 116 percent of the original under dark conditions, and 89.8 percent under light conditions.

"Due to the potential for degradation with light exposure, it is usually recommended that commercially available conventional formulations of tretinoin be applied at night. The findings from this stability study suggest that for patients who might prefer daytime application, it is a viable alternative using this combination formulation," Dr. Del Rosso says.

Further investigation was performed by measuring penetration into human cadaver skin under a variety of conditions, including with or without ultraviolet light exposure and with or without sequential application of 5 percent benzoyl peroxide gel two hours later.

In all experiments, product was applied to the skin surface, and HPLC analysis was used to measure the amount of tretinoin recovered from a surface wash and in the stratum corneum, epidermis and dermis.

Serial sampling in skin treated only with the clindamycin/tretinoin product showed penetration of tretinoin occurred slowly with a gradual, progressive increase in tretinoin concentration in the epidermis and dermis.

In another model in which the samples were kept under dark conditions, tretinoin penetration between four and 24 hours was modestly increased by the sequential application of benzoyl peroxide.

However, with light exposure and the sequential application of benzoyl peroxide gel two hours later, recovery of tretinoin 24 hours post-application was significantly reduced to only 11.5 percent of the original labeled amount.

With sequential use of benzoyl peroxide and incubation of the skin specimens under dark conditions, the recovery of tretinoin was maintained at 75 percent of the applied dose between four and 12 hours and decreased to 61 percent at 24 hours.

"Tretinoin in commercially available conventional vehicle formulations is rapidly degraded by benzoyl peroxide, and it has been suggested that their application times be separated by eight to 12 hours. The results of these studies indicate benzoyl peroxide can be applied with the clindamycin/tretinoin product in a much closer sequence.

"It appears best to use these products together in the evening when there is less influence from ultraviolet light exposure. Results from the skin penetration data indicate there is no need to wait more than two hours between application times, whereas the admixture study results suggest the two products may even be applied sequentially," Dr. Del Rosso says.

Disclosure: Dr. Del Rosso is a speaker, consultant and/or investigator for Medicis and other companies marketing acne products.