The future is now: Nanotechnology creates promising new tretinoin formulation

Key Points

"Drug-induced irritation is a well-recognized drawback of topical tretinoin therapy, and has been the motivation for many companies to develop synthetic retinoids or new delivery systems that would minimize this adverse effect without compromising efficacy.

"Based on our initial work, the calcium carbonate-coated tretinoin nanoparticles seem to have accomplished these goals," says Edward Hsia, Ph.D., associate director, research and preclinical development, Stiefel Laboratories.

"The next steps are to investigate stability and further optimize the formulation, recognizing that the effectiveness of a topical product depends on patient compliance that is improved by having a cosmetically elegant formulation.

"In that regard, another positive feature of the calcium carbonate-coated tretinoin nanoparticle technology is the ability to formulate it into a hydrogel vehicle that generally has good patient acceptance," Dr. Hsia says tells Dermatology Times.

Assembly of the calcium carbonate-coated tretinoin nanoparticles and formulation into a hydrogel vehicle was led by Mary Larm, B.Sc.(Hons) and her co-workers in the Center for Formulation Innovation, Stiefel Laboratories, Melbourne, Australia.

The concept was first described in an article published in 2005 by Japanese researchers and takes advantage of the fact that in an alkaline environment, tretinoin forms micelles that will bind positively charged calcium ions. Ms. Larm and her colleagues varied the chelating agents, pH and other factors in the manufacturing process to optimize assembly of the nanoparticles.

At Stiefel's Center for Skin Biology, Dr. Hsia and co-workers investigated the activity of the topical formulation in an in vitro skin model using reconstructed human epidermis cultures. Irritation potential was investigated by measuring proinflammatory cytokines, interleukin-1a as a general inflammation biomarker, and interleukin-8, which is more specific, for retinoid-induced irritation. Therapeutic activity was determined by measuring changes in tissue morphology and expression of keratin 10 and keratin 19 (markers of keratinocyte differentiation) by histology.

The hydrogel containing the calcium carbonate-coated tretinoin nanoparticles was compared with a tretinoin microsponge formulation (Retin-A Micro 0.04 percent, Ortho-Neutrogena) and a traditional gel formulation (Retin-A Gel 0.025 percent, Ortho-Neutrogena). All of the products showed similar activity, based on the evaluations of keratinocyte differentiation.

Results

The investigational formulation containing 0.04 percent calcium carbonate-coated tretinoin nanoparticles was judged to have less irritation than the tretinoin gel, as it was associated with about twofold lower release of the pro-inflammatory cytokines, while its retinoid activity was similar to the microsponge formulation.

"These results indicate we've hit our initial target in creating a tretinoin formulation with good activity and favorable safety, but this is just the beginning. Further research and development is under way to optimize the formulation and investigate whether it might have other potential advantages for overcoming existing challenges in tretinoin formulation, perhaps in terms of stability or for formulating a fixed combination product," Dr. Hsia says.