US 2014025,6616A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0256616 A1 Hsu (43) Pub. Date: Sep. 11, 2014 (54) MODIFIED GREEN TEA POLYPHENOL Publication Classification FORMULATIONS (51) Int. Cl. (71) Applicant: Georgia Regents Research Institute, A613 L/353 (2006.01) Inc., Augusta, GA (US) A638/2 (2006.01) A63/546 (2006.01) (72) Inventor: Stephen D. Hsu, Evans, GA (US) A613 L/7036 (2006.01) A613 L/7048 (2006.01) A613 L/496 (2006.01) (73) Assignee: Georgia Regents Research Institute, A61E36/82 (2006.01) Inc., Augusta, GA (US) A613 L/43 (2006.01) A613 L/65 (2006.01) 52) U.S. C. (21) Appl. No.: 14/280,805 (52) CPC ............... A61 K3I/353 (2013.01); A61K 31/43 (2013.01); A61 K38/12 (2013.01); A61 K (22) Filed: May 19, 2014 3 1/546 (2013.01); A61 K3I/65 (2013.01); A6 IK3I/7048 (2013.01); A61 K3I/496 O O (2013.01); A61 K36/82 (2013.01); A61 K Related U.S. Application Data 3/7036 (2013.01) (63) Continuation of application No. 13/305,296, filed on USPC ............ 514/2.9; 514/456; 514/198: 514/202; Nov. 28, 2011, which is a continuation of application 514/154: 514/29: 514/254.11: 514/37 No. 12/063,139, filed on Feb. 7, 2008, now Pat No. (57) ABSTRACT 8,076.484, filed as application No. PCT/US06/31120 Modified green tea polyphenols and methods of their use are on Aug. 10, 2006. provided. One aspect provides compounds and compositions (60) Provisional application No. 60/707,234, filed on Aug. containing green tea polyphenols with one on more ester 11, 2005. linked fatty acids. US 2014/025661.6 A1 Sep. 11, 2014 MODIFIED GREEN TEA POLYPHENOL or ketoconazole as active ingredients. Salicylic acid helps FORMULATIONS dissolve skin flakes. Pyrithione helps to kill fungus. Coal tar is believed to help reduce inflammation and sebum and to CROSS-REFERENCE TO RELATED prevent the reoccurrence of flakes and scalp build-up. Coaltar APPLICATION is a combination of compounds produced from by-products 0001. This application is a continuation of U.S. Ser. No. of coal distillation, and a number of studies report that coal tar 13/305,296 filed Nov. 28, 2011, which is a continuation of is toxic or carcinogenic. For example, coal tar contains benzo U.S. Ser. No. 12/063,139 filed Feb. 7, 2008, issued U.S. Pat. apyrene, a highly potent carcinogen. Studies have shown No. 8,076,484, which is a national phase filing under 35 that topical application of compositions containing coal tar U.S.C. S371 of PCT/US2006/031120 filed under the Patent are toxic and may cause DNA damage (Thein, N. etal. (2000) Cooperation Treaty on Aug. 10, 2006, which claims benefit of Muta Res 468(2): 117-24; Rojas, M. etal. (2001) Carcinogen and priority to U.S. Provisional Patent Application No. esis 22(7): 1015-8; Vogel, U. et al. (2001) Pharmacol Toxicol. 60/707,234 filed Aug. 11, 2005, all of which are incorporated 89(1):30-4). herein by reference in their entirety. 0010 Green tea polyphenols are known phytochemicals that have antioxidant, anti-microbial, anticancer, and anti TECHNICAL FIELD inflammation properties, and were recently found to promote 0002 Aspects of the disclosure are generally related to skin homeostasis and protect against autoimmune diseases. green tea polyphenol compositions, more particularly, to Extracts of green tea have been used for medicinal purposes lipid-soluble green tea polyphenol compositions. for generations in China. Green tea polyphenols in extracts are mostly water-soluble, and can be easily oxidized if they BACKGROUND are mixed in emulsions containing water, such as detergents and cosmetics. Additionally, conventional green tea polyphe 0003 More than 15 million people in the U.S. have symp nols are not permeable to the skin, and therefore their activity toms of a skin disorder, for example dermatitis. Dermatitis is is significantly reduced. a term literally meaning “inflammation of the skin'. It is usually used to refer to eczema, and several different forms 0011 Thus, there is a need for additional green tea are recognized including cercarial dermatitis, dermatitis her polyphenol compositions and methods for preventing and petiformis, atopic dermatitis, seborrhoeic dermatitis, and treating skin disorders or symptoms thereof. contact dermatitis. 0004 Cercarial dermatitis is a short-term, immune reac SUMMARY tion occurring in the skin of humans that have been infected by water-borne trematode parasites. Symptoms, which 0012 Aspects of the disclosure generally provide modi include itchy, raised papules, commonly occur within hours fied green tea polyphenol compositions having one or more of infection and do not generally last more than a week. ester-linked C to Clso fatty acids or hydrocarbons. Choles 0005 Dermatitis herpetiformis (DH) or Duhring's Dis terol can also be linked to green tea polyphenols via an ether ease, is a skin disorder often associated with celiac disease. It linkage. Green tea polyphenols that can be modified include, is a chronic, extremely itchy rash consisting of papules and but are not limited to (-)-epicatechin (EC), (-)-epigallocat vesicles. Dermatitis herpetiformis is associated with sensitiv echin (EGC), (-)-epicatechin-3-gallate (ECF), (-)-epigallo ity of the intestine to gluten in the diet. catechin-3-gallate (EGCG), proanthocyanidins, enantiomers 0006 Atopic dermatitis, sometimes called eczema, is a thereof, epimers thereof, isomers thereof, combinations kind of dermatitis, an atopic skin disease. Skin of an affected thereof, and prodrugs thereof. The modified green tea person reacts to irritants, food and air allergens and becomes polyphenols are more lipid-soluble than unmodified green tea red, flaky and very itchy. It also becomes vulnerable to polyphenols. It is believed that the increased lipid solubility inflammations caused by bacteria. Atopic dermatitis very increases the bioavailability of the green tea polyphenols and often occurs together with otheratopic diseases like hay fever, thereby increases the effectiveness of the green tea polyphe asthma and conjunctivitis. nols. Green tea polyphenols are known to modulate gene 0007 Seborrheic dermatitis is a disease that causes flaking expression and have been used in the treatment of cancer. of the skin. It particularly affects the sebum-gland rich areas 0013 One aspect provides a compound according to For of skin. It can also affect the face and chest, and the creases of mula I: the arms, legs and groin. Seborrheic dermatitis usually causes the skin to look a little greasy and scaly or flaky. It is thought to be caused by a fungal infection caused by the yeast Formula I Malassezia furfur in individuals with decreased immunity and increased sebum production. 0008 Domestic pets and animals also suffer from skin disorders including atopic dermatitis. Atopic dermatitis is one of the most common skin diseases of dogs. As with humans, the principal causes of atopic dermatitis are external aller gens, e.g., house dust mites, pollens, molds, etc. Treatments include allergen avoidance and prevention of allergen con tact, symptomatic anti-inflammatory pharmacotherapy, aller gen-specific immunotherapy, and antimicrobial therapy. 0009 Topical treatments for seborrheic dermatitis include shampoos containing coal tar, Zinc pyrithione, salicylic acid US 2014/025661.6 A1 Sep. 11, 2014 wherein R. R. R. R. Rs are each independently H, OH, 0022 wherein R is not O O O -o-I-R. or -C-O-R: -o-Itchhi-ch when R. R. R. R7, Rs. Ro, and Ro are OH: 0014 wherein R, is a linear, branched or cyclic, saturated 0023 wherein at least one of R. R. R. R. R. R. or Rio or unsaturated. Substituted or unsubstituted C-C group, is wherein if R is cyclic, R, is a C-C group; and 0015 R is O. —NRR, or S, wherein Rs and R are independently hydrogen, or a linear, branched, or cyclic, Satu O rated or unsaturated, Substituted or unsubstituted C-Clso -o-I-R, or -C-O-R; group, wherein if Rs and/or R are cyclic, Rs and/or Ro are C-Clso groups; 0024 or a pharmaceutically acceptable salt or prodrug 0016 wherein at least one of R. R. R. R. Rs is thereof. 0025. Another aspect provides a compound according to Formula II: O -o-I-R. or -C-O-R7; Formula II R3 0017 or a pharmaceutically acceptable salt or prodrug R4 thereof. 0018. Another aspect provides a compound according to R R6 Formula II: R. Rs Rs R9 Formula II R2 O R3 R10 R4 0026 wherein R. R. R. R. R. Rs. Ro, and Ro are each R R independently H, OH, 6 R R8 O O Rs R9 -o-I-R, or -C-O-R; R O R10 0027 R is a linear, branched, or cyclic, saturated or unsaturated, Substituted or unsubstituted C-Clso group, 0.019 wherein R. R. R. R. R. Rs. Ro, and Ro are each wherein if R is cyclic, R is a C-Clso group; independently H, OH, 0028 Rs and R are independently O. —NR,R or S, wherein R and Rs are independently hydrogen, or a linear, branched, or cyclic, saturated or unsaturated, Substituted or unsubstituted C-Clso group, wherein if R and/or R are O O cyclic, R12 and/or Rs are Cs-Cao groups; -o-I-R, or -C-O-R; 0029 wherein at least two of R. R. R. R. R. R. R. or Ro are 0020 R is a linear, branched, or cyclic, saturated or unsaturated, Substituted or unsubstituted C-Clso group, O O wherein if R is cyclic, R is a C-Clso group; -o-I-R, or -C-O-R; 0021 Rs and R are independently O.