US 2005O124697A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0124697 A1 Evans et al. (43) Pub. Date: Jun. 9, 2005 (54) NSAID-CONTAINING TOPICAL Publication Classification FORMULATIONS THAT DEMONSTRATE CHEMOPREVENTIVE ACTIVITY (51) Int. Cl." ............................................ A61K 31/192 (52) U.S. Cl. ............................................ 514/569; 514/570 (75) Inventors: Allan Evans, Rosslyn Park (AU); Ross McKinnon, Aberfoyle Park (AU) (57) ABSTRACT Correspondence Address: HOGAN & HARTSON LLP Disclosed herein are chemopreventive methods and topical IP GROUP, COLUMBIA SQUARE formulations for the prevention and treatment of ultraviolet 555 THIRTEENTH STREET, N.W. light-induced skin cancers, pre-cancerous lesions, and WASHINGTON, DC 20004 (US) hyperproliferative disorders in mammals, Such as humans, utilizing doses of non-Steroidal anti-inflammatory drugs. (73) Assignee: PharmaChest Pty Ltd Low doses of non-Steroidal anti-inflammatory drugs are present in the topical formulations and allow continued (21) Appl. No.: 11/037,260 regular use over an extended period of time to prevent Such (22) Filed: Jan. 19, 2005 disorders. In particular, the present invention is particularly Suitable for non-melanoma skin cancers as these cancers Related U.S. Application Data tend to appear in areas of the skin that have had exceSS Sun exposure (head, neck and arms) meaning that the chemo (62) Division of application No. 10/310,824, filed on Dec. preventive agent would not need to be applied over the entire 6, 2002. body of the typical patient. Moreover, it is possible to identify “high-risk” individuals within the populations (60) Provisional application No. 60/350,957, filed on Jan. because people who report one episode of NMSC tend to 25, 2002. have a high incidence of a Subsequent episode. Patent Application Publication Jun. 9, 2005 Sheet 1 of 7 US 2005/0124697 A1 O (M) O O C 0 O ) C () O E O C. O O O C. g O OG og O * O C. O)5 0 D C) s 5 0 ) < H 0 (EO< SEO) : E 0 (g D Z () O () ) D D D D Nu N. N vm SC S S S3 SS SS L. C. S. CN O. O. v. CN of 0 O C. O V L? V r of of GN CN v v. eSnou Jed Sunoun Snid Seuode US 2005/0124697 A1 ETFE?E Snoun + Seuoided Jo Jequn N Patent Applica tion Pub ication Jun. 9, 2005 Sheet 3 of 7 US 2005/0124697 A1 Patent Application Publication Jun. 9, 2005 Sheet 4 of 7 US 2005/0124697 A1 Patent Application Publication Jun. 9, 2005 Sheet 5 of 7 US 2005/0124697 A1 Patent Application Publication Jun. 9, 2005 Sheet 6 of 7 US 2005/0124697 A1 Patent Application Publication Jun. 9, 2005 Sheet 7 of 7 US 2005/0124697 A1 O V V i s O O. O. O. O. O. O. O. O. O. O O O OO N CO RO r C. CN vam vo Ouluoto go efóeueoue. US 2005/O124697 A1 Jun. 9, 2005 NSAID-CONTAINING TOPCAL FORMULATIONS 0008) Notably, 75% of all skin cancers are basal cell THAT DEMONSTRATE CHEMOPREVENTIVE carcinomas (“BCC”). Recent population studies in Australia ACTIVITY indicate incidence rates of between 1-2% for BCC. For CROSS REFERENCE TO RELATED example, the incidence rate in South eastern Queensland in APPLICATIONS particular for those aged 20-69 years was found to be 2.4%. In South Wales in 1998 the incidence of BCC in individuals 0001. This application claims benefit of priority from the over 75 years of age was approximately 5 times higher that filing date of U.S. provisional patent application Ser. No. that of individuals between 50 and 55 years old indicating an 60/350,957, filed Jan. 25, 2002. age related relationship. FIELD OF THE INVENTION 0009. In 1994, the incidence rate of BCC in America was 0002 The present invention relates to the prevention and calculated to be 0.3% with rates increasing at over 10% per treatment of Skin cancer and hyperproliferative Skin disor year with a lifetime risk of up to 30%. It is currently ders in mammals, including humans, with the use of topical projected by Some investigators that, given current rates, 1 medicaments. More particularly, the present invention in every 5 Americans will develop a skin cancer of Some Sort relates to the prevention and treatment of non-melanoma during their lifetime. skin cancers with topical medicaments that are Safe for continued use in target populations. 0010 Thus, NMSC, and BCC in particular, present a Significant health risk throughout the World and generate BACKGROUND Significant health care costs. 0.003 Skin cancer is one of the most frequently diagnosed cancers among the Western populations. Exposure to ultra 0011. Once a patient is diagnosed as having a BCC, the violet light (UV light) is widely acknowledged to be the risk of developing a new BCC is highest in the first year major etiologic factor in the development of Skin cancers thereafter. A recent analysis by Marcil and Stern, published Such as Squamous and basal cell carcinomas, and it is also in Archives of Dermatology in 2000, of the data collected in a risk factor for the development of melanomas. UV light 7 published studies has established that the 3-year cumula has also been found in various Studies to cause inflammation tive risk for developing a Subsequent BCC after the diag of the skin, epidermal hyperplasia, and changes in the nosis of a first BCC is 44% on average. Thus, a perSon once expression of numerous genes associated with cell prolif diagnosed as having a BCC can be considered to be part of eration and differentiation, eicosanoid and cytokine produc a high-risk population for developing new BCCs. Increases tion, and growth factor Synthesis and responsiveness. in risk for Subsequent development of Squamous cell carci nomas was also found. There is also a strong association 0004. An examination of the incidence of non-melanoma between the risk of developing a Subsequent skin cancer and skin cancer (“NMSC"), which includes squamous and basal the number of prior Skin tumours. In one Study the risk was cell carcinomas, indicates that it is a disease associated with increased from 38% for patients with fewer than 3 previous Significant morbidity and which generally requires Surgical NMSCs to 93% for patients with 3 to 9 previous NMSCs. intervention and costly medical care. Thus, the more prior Skin cancers a patient has had, the 0005 NMSC is the most common type of cancer for higher the risk is that that patient will develop skin cancers males and females in the white population, with most NMSC in the future. occurring in people over 40 years of age. People with light 0012 Although the use of physical and chemical Sun complexions, fair or red hair and who tend to burn easily on Screens plays an important role in protection of humans exposure to the Sun (Fitzpatrick skin grades 1 and 2) are against exposure to UV light, the high incidence of skin more prone to develop NMSCs than those with dark-skin. cancer among the population means that additional preven Males have been identified to be at higher risk. Recently, tion and treatment Strategies need to be developed. In Studies have Suggested that heavy exposure to the Sun in the particular, a Safe and effective preventive Strategy is needed first few decades of life may be of the greatest importance for use by those individuals who are most susceptible to this in determining risk. life-threatening disease. 0006 Incidence rates for NMSC in Australia are believed to be the highest in the world with a causal relationship with 0013 The use of specific natural or synthetic agents excessive exposure to Solar ultraViolet radiation. The Aus (usually non-cytotoxic) to reverse, Suppress or prevent can tralian Bureau of Statistics indicates approximately 270,000 cer is referred to as “cancer chemoprevention.” An ideal annual diagnoses of NMSC, which equates to approximately chemopreventive agent should not only be effective, but it 1.5% of the Australian population. It should be noted, should be Safe enough to be used in a target population however, that not all NMSCs are often reported to cancer without causing unnecessary or unacceptable toxicity. It is registries. Thus, it is likely that the number of actual annual important that the perceived benefit (lower risk of cancer) cases of NMSC is significantly higher. The incidence of should be balanced by its safety profile (low risk of adverse NMSC in white populations increases proportionally with events). Agents that have been found in Studies to hold proximity to the equator. In 1993-94 the direct cost of promise for cancer chemoprevention include Vitamin A and treatment of non-melanoma skin cancer in Australia was green tea for skin cancer and tamoxifen and raloxifene for estimated by the NSW Cancer Center at around S232 breast cancer. One group of drugs that has also been million-much more than any other cancer. researched as potential chemopreventive agents are the non-steroidal anti-inflammatory drugs ("NSAIDs"). 0007 Likewise, NMSC constitute more than one third of all cancers in the US. Healthcare costs associated with the 0014 NSAIDs are a group of structurally diverse com treatment of skin cancers have been reported to be over 500 pounds used clinically for the Successful treatment of a million annual in the US. range of disorders that are associated with pain and/or US 2005/O124697 A1 Jun. 9, 2005 inflammation (including arthritic disorders). NSAIDs are chemopreventive agent for NMSC. Currently, no such treat known to inhibit the cyclooxygenase (“COX”) enzymes, ment exists, otherwise the recurrence rate would not be So which catalyse the conversion of arachidonic acid to the high.