SBIR-STTR Award

The overall goal of this project is to develop and market a new topical treatment for acne that contains a 5-alkysulfonylsulfonylsalicylanilide as the active agent. The 5-alkylsulfonylsalicylanilides are a unique class of highly lipophilic compounds that possess both potent anti- inflammatory and antimicrobial activity against P. acnes while having virtually no potential for systemic toxicity. Topical pharmaceutical preparations containing 5-alkylsulfonylsalicylanilides are predicted to have utility in controlling acne by accumulating in sebum-filled papules and inhibiting inflammatory pathogenic bacteria as well as cell mediated inflammation. the specific goal of this proposal is to identify one "lead" and one "back-up" candidate compound from a small series of 5- alylsulfonylsalicylanilides. The compounds chosen will 1) be readily synthesized and formulated, 2) have maximum bioavailability and stability, 3) have a long term topical anti-microbial and anti- inflammatory efficacy (substantivity) and 4) exhibit no systemic toxicity when administered orally. In Phase II we intend to optimize formulations and determine long-term chemical, microbiological and physical stability. Additional safety and efficacy studies of the "lead" compound will be also conducted to support the filing of an IND application to the FDA for clinical studies beginning after the completion of Phase II. PROPOSED COMMERCIAL APPLICATION: Almost all people will have acne at some time in their life. Acne products are among the fastest growing over-the-counter medicinals sold at drug stores. In 1995 the total market for acne remedies was approximately $710 million. Many of the existing compounds which treat acne have side effects, some severe creating an outstanding marketing opportunity for drugs such as the 5-alkylsulfonylsalicylanidides, which are predicted to accomplish eradication without side effects.

Thesaurus Terms:
acne, antibacterial agent, antiinflammatory agent, chemical synthesis, drug design /synthesis /production, skin disorder chemotherapy alkyl group, hydropathy, phenylamide, salicylate, skin absorption, topical drug application laboratory mouse, tissue /cell cultureNational Institute of Arthritis and Musculosketal and Skin Diseases (NIAMS)

This Phase II grant application is to develop Trifluorosal (TMF-12), a derivative of lipophilic, 5-(n-alkylsulfonyl) salicylanilides. Since this agent is proposed to have anti-inflammatory properties and antimicrobial activity, including activity against P. acnes, a microbe that has been implicated in the pathogenesis of acne vulgaris. The investigators propose that this chemical may be useful as a topical anti-acne preparation. In the phase II studies, the investigators will continue their development of Trifluorosal to support the filing of an IND application for use as a topical acne treatment. This proposal will focus its attention on three issues: formulation, safety, and efficacy of their lead compound, TMF-12. In aim 1, they will incorporate their lead compound in 10 different formulations (5 gels and 5 lotions), and study tissue penetration in vitro using human skin in a Franz flow through chamber. They will also study its anti-inflammatory properties in the mouse TPA ear swelling model. In Aim 2, they will examine the safety of their formulated materials using 9 different standard animal models for eye, skin (irritation, sensitization, photoirritation/allergy and comedogenicity) and systemic toxicities. This aim is focused on providing background information for obtaining an IND from the FDA. Aim 3 will be mechanistic studies of TMF-12: inhibition of PKC, arachadonic acid release, inhibition of COX-1 and COX-2, and inhibition of cytokines and angiogenic factors. In aim 4, they will focus on pharmaceutical development (TMF-12 chemistry scale-up, preservative efficacy, packaging studies, validation of a analytical method applied the refined, formulated TMF-12, and accelerated stability studies). In aim 5, they will perform efficacy (reduction of skin surface P. acnes counts) and safety data (irritation/sensitization potential, phototoxicity/allergy) on human volunteers, with the collaboration of contract laboratories. PR0P0SED COMMERCIAL APPLICATION: The primary market category for Trifluorosal as an acne product in the U.S. - adolescents between ages of thirteen and nineteen - is expected to grow by 9.4% in the next five years to 32 million people. A large secondary market category is comprised of adult women who are also susceptible to acne during certain stages of their menstruation cycle. It is expected that Trifluorosal will have an outstanding opportunity to break into these market categories because most of the existing treatments either do not treat the underlying cause of the disease or have significant, dose limiting side effects, whereas Trifluorosal inhibits both bacterial growth and inflammation at doses that are non-toxic.