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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 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 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 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. —NRR or S, wherein RandR are independently hydrogen, or a linear, 0.030 or a pharmaceutically acceptable salt or prodrug branched, or cyclic, Saturated or unsaturated, Substituted or thereof. unsubstituted C-Clso group, wherein if R and/or R are 0031 Compositions containing modified green tea cyclic, R12 and/or Rs are Cs-Cao groups; polyphenols are provided as well as methods of using the US 2014/025661.6 A1 Sep. 11, 2014

compositions. In particular, compositions containing the dis 0040. The term “cell refers to a membrane-bound bio closed modified green tea polyphenols in combination with a logical unit capable of replication or division. Surfactant, detergent, oil, wax, or other hydrophobic vehicle 0041. The term "emulsion” refers to a mixture prepared are provided. One or more of the disclosed compounds and from two mutually insoluble components. It is possible to compositions can be used to treat skin disorders, for example generate mixtures of homogenous macroscopic appearance dermatitis. from these components through proper selection and manipu lation of mixing conditions. The most common type of emul DETAILED DESCRIPTION sions are those in which an aqueous component and a lipo philic component are employed and which in the art are I. Definitions frequently referred to as oil-in-water and water-in-oil emul 0032. Before explaining the various embodiments of the sions. In oil-in-water emulsions the lipophilic phase is dis disclosure, it is to be understood that the invention is not persed in the aqueous phase, while in water-in-oil emulsions limited in its application to the details of construction and the the aqueous phase is dispersed in the lipophilic phase. Com arrangement of the components set forth in the following monly known emulsion based formulations that areapplied to description. Other embodiments can be practiced or carried the skin include cosmetic products such as creams, lotions, out in various ways. Also, it is to be understood that the washes, cleansers, milks and the like as well as dermatologi phraseology and terminology employed herein is for the pur cal products comprising ingredients to treat skin conditions, pose of description and should not be regarded as limiting. diseases or abnormalities. 0033. Throughout this disclosure, various publications, 0042. The term “Green Tea Polyphenols or GTP refers to patents and published patent specifications are referenced. polyphenolic compounds present in the leaves of Camellia Where permissible, the disclosures of these publications, pat Sinensis. Green tea polyphenols include, but are not limited to ents and published patent specifications are hereby incorpo (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epi rated by reference in their entirety into the present disclosure catechin-3-gallate (ECF), to more fully describe the state of the art. (-)-epigallocatechin-3-gallate (ECGC), proanthocyanidins, enantiomers thereof, epimers thereof, isomers thereof, com 0034) To facilitate understanding of the disclosure, the binations thereof, and prodrugs thereof. Modified green tea following definitions are provided: polyphenols refers to a green tea polyphenol having one or 0035. As used herein, the singular forms “a,” “an and more hydrocarbon chains, for example C to Co and the “the include plural referents unless the context clearly dic compounds according to Formula I and II disclosed herein. tates otherwise. Thus, for example, reference to “a factor” 0043 “Hydrophilic” as used herein refers to substances refers to one or mixtures of factors, and reference to “the that have strongly polar groups that readily interact with method of treatment includes reference to equivalent steps Water. and methods known to those skilled in the art, and so forth. 0044) “Hydrophobic' as used herein refers to substances 0036 Acyloxy’, as used herein, refers to a substituent that lack an affinity for water; tending to repel and not absorb having the following chemical formula: water as well as not dissolve in or mix with water. 0045. The term “host” refers to a living organism, includ ing but not limited to a mammal Such as a primate, and in particular a human. 0046 “Lipid soluble' as used herein refers to substances - X. that have a solubility of greater than or equal to 5 g/100 ml in a hydrophobic liquid Such as castor oil. wherein R is a linear, branched, or cyclic alkyl, alkenyl, or 0047. The term “lipid-soluble green tea polyphenol alkynyl group. refers to agreen tea polyphenol having one more hydrocarbon 0037 “Alkoxy carbonyl', as used herein, refers to a sub chains having for example C to Co groups linked to the stituent having the following chemical formula: polyphenol. C to Cogroups include for example cholesterol. Representative lipid-soluble green tea polyphenols include those according to Formula I and Formula II disclosed herein. The term is used interchangeably with “modified green tea polyphenol. 0048. The term “pharmaceutically acceptable carrier' refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. wherein R is a linear, branched, or cyclic alkyl group. 0049. The term “pharmaceutically acceptable salt” refers 0038. The term “alkenyl refers to a monovalent, to those salts which retain the biological effectiveness and unbranched or branched hydrocarbon chain having one or properties of the free bases and which are obtained by reac more double bonds therein. The double bond of an alkenyl tion withinorganic or organic acids Such as hydrochloric acid, group can be unconjugated or conjugated to another unsatur hydrobromic acid, Sulfuric acid, nitric acid, phosphoric acid, ated group. methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic 0039. The term “alkynyl refers to a monovalent, acid, salicylic acid, malic acid, maleic acid, Succinic acid, unbranched or branched hydrocarbon chain having one or tartaric acid, citric acid, and the like. more triple bonds therein. The triple bond of an alkynyl group 0050 A“pharmaceutical composition” refers to a mixture can be unconjugated or conjugated to another unsaturated of one or more of the green tea polyphenols described herein, group. or a pharmaceutically acceptable salts thereof, with other US 2014/025661.6 A1 Sep. 11, 2014

chemical components, such as physiologically acceptable range C to Cso includes C1, C2, Cs, Ca, Cs, Co., C7, Cs, Co. carriers and excipients. The purpose of a pharmaceutical Co. C11, C12, C13, C14, C1s, C6, C7, C8, C19 etc. up to Cso composition is to facilitate administration of a compound to as wells as ranges falling within C to Co. for example, C to an organism. Co. C to Co. C to Cs, etc. The range also includes less than 0051. The term “prodrug” refers to an agent, including Co. less than Co. etc. nucleic acids and proteins, which is converted into a biologi 0053. The term “treating or treatment” refers to alleviat cally active form in vivo. Prodrugs are often useful because, ing, reducing, or inhibiting one or more symptoms or physi in some situations, they may be easier to administer than the ological aspects of a disease, disorder, syndrome, or condi parent compound. They may, for instance, be bioavailable by tion. oral administration whereas the parent compound is not. The 0054 “Water soluble' as used herein refers to substances prodrug may also have improved solubility in pharmaceutical that have a solubility of greater than or equal to 5 g/100 ml compositions over the parent drug. A prodrug may be con Water. Verted into the parent drug by various mechanisms, including 0055. It will be appreciated that a numerical range pro enzymatic processes and metabolic hydrolysis. Harper, N.J. vided herein includes each intervening integer (1962). Drug Latentiation in Jucker, ed. Progress in Drug Research, 4:221-294; Morozowich et al. (1977). Application II. Modified Green Tea Polyphenol Compositions of Physical Organic Principles to Prodrug Design in E. B. 0056 Compositions containing green tea polyphenols Roche ed. Design of Biopharmaceutical Properties through modified to increase the permeability of the green tea Prodrugs and Analogs, APhA; Acad. Pharm. Sci., E. B. polyphenols to skin and cell membranes or increase their Roche, ed. (1977). Bioreversible Carriers in Drug in Drug solubility in hydrophobic media relative to unmodified green Design, Theory and Application, APhA; H. Bundgaard, ed. tea polyphenols are provided. Green tea polyphenols that can (1985) Design of Prodrugs, Elsevier; Wang et al. (1999) Pro be modified include, but are not limited to (-)-epicatechin drug approaches to the improved delivery of peptide drug, (EC), (-)-epigallocatechin (EGC), (-)-epicatechin-3-gallate Curr. Pharm. Design. 5(4):265-287: Pauletti et al. (1997). (ECF), (-)-epigallocatechin-3-gallate (ECGC), proanthocya Improvement in peptide bioavailability: Peptidomimetics nidins, enantiomers thereof, epimers thereof, isomers thereof, and Prodrug Strategies, Adv. Drug. Delivery Rev. 27:235 combinations thereof, and prodrugs thereof. One embodi 256; Mizen et al. (1998). The Use of Esters as Prodrugs for ment provides a green tea polyphenol having an ester-linked Oral Delivery of B-Lactam , Pharm. Biotech. 11.: C to Cohydrocarbon chain, for example a fatty acid, at one 345-365; Gaignault et al. (1996). Designing Prodrugs and or more positions. Another embodiment provides a green tea Bioprecursors I. Carrier Prodrugs, Pract. Med. Chem. 671 polyphenol having one or more cholesterol groups linked to 696; M. Asgharnejad (2000). Improving Oral Drug Transport the polyphenol. The cholesterol group can be linked for Via Prodrugs, in G. L. Amidon, P.I. Lee and E. M. Topp, Eds. example by an ether linkage directly to the polyphenol or a C Transport Processes in Pharmaceutical Systems, Marcell to Co linker can connect the cholesterol group to the Dekker, p. 185-218: Balant et al. (1990) Prodrugs for the polyphenol. improvement of drug absorption via different routes of 0057 Another embodiment provides a green tea polyphe administration, Eur. J. Drug Metab. Pharmacokinet., 15(2): nol compound having one or more acyloxy groups, wherein 143-53; Balimane and Sinko (1999). Involvement of multiple the acyl group is C to Co. It is believed that the addition of transporters in the oral absorption of nucleoside analogues, alkyl, alkenyl, or alkynyl chains, for example via fatty acid Adv. Drug Delivery Rev. 39(1-3):183-209: Browne (1997). esterification, to green tea polyphenols increases the stability Fosphenyloin (Cerebyx), Clin. Neuropharmacol.20(1): 1-12; of the green tea polyphenols and increases the solubility of the Bundgaard (1979). Bioreversible derivatization of drugs— green tea polyphenols in hydrophobic media including lipids, principle and applicability to improve the therapeutic effects fats, soaps, detergents, Surfactants or oils compared to of drugs, Arch. Pharm. Chemi. 86(1): 1-39; H. Bundgaard, ed. unmodified green tea polyphenols. Green tea polyphenols (1985) Design of Prodrugs, New York: Elsevier; Fleisheretal. having one or more hydrocarbon chains, for example ester (1996). Improved oral drug delivery: solubility limitations linked C to Cao groups or C to Clso acyloxy groups are overcome by the use of prodrugs, Adv. Drug Delivery Rev. believed to more permeable to skin or cell membranes and 19(2): 115-130; Fleisher et al. (1985). Design of prodrugs for thereby enable the ester-linked hydrocarbon chain containing improved gastrointestinal absorption by intestinal enzyme or acyloxy containing green tea polyphenol to readily enter a targeting, Methods Enzymol. 112: 360-81: Farquhar D, et al. cell and have a biological effect on the cell, for example (1983). Biologically Reversible Phosphate-Protective modulating gene expression, compared to unmodified green Groups, J. Pharm. Sci., 72(3): 324-325; Han, H. K. et al. tea polyphenols. It will be appreciated that one or more (2000). Targeted prodrug design to optimize drug delivery, hydrocarbon chains can be linked to the green tea polyphenol AAPS PharmSci., 201): E6; Sadzuka Y. (2000). Effective using linkages other than ester linkages, for example thio prodrug liposome and conversion to active metabolite, Curr linkages. Esterified green tea polyphenols can be combined Drug Metab., 1(1):31-48; D. M. Lambert (2000) Rationale with oils, detergents, Surfactants, or combinations thereof to and applications of lipids as prodrug carriers, Eur. J. Pharm. produce compositions which clean the skin and delivergreen Sci., 11 Suppl 2:S15-27; Wang, W. et al. (1999) Prodrug tea polyphenols to the skin. The oils, detergents, or Surfac approaches to the improved delivery of peptide drugs. Curr. tants advantageously increase the stability of green tea Pharm. Des. 5(4):265-87. polyphenols by reducing contact of the green tea polyphenols 0052. The term "substituted C to Co” refers to an alkyl, with aqueous media. Certain embodiments provide single alkenyl, or alkynyl chain of one to thirty carbons wherein one optical isomers, enantiomers, or epimers of the disclosed or more carbons are independently substituted with one or modified green tea polyphenols. Other embodiments provide more groups including, but not limited to, halogen, hydroxy compositions containing single optical isomers, enantiomers, group, aryl group, heterocyclic group, or alkyl ester. The or epimers or the disclosed modified green tea polyphenols. US 2014/025661.6 A1 Sep. 11, 2014

0058 A. Modified Green Tea PolyPhenol O O 0059. One embodiment provides a compound according | to Formula I: -o-l- 7, or -C-O-R:

or a pharmaceutically acceptable salt or prodrug thereof, Formula I optionally in combination with an excipient. 0067 Still another embodiment provides a compound according to formula I as described above wherein at least four of R. R. R. R. or Rs are independently

O O -o-l- or -C-O-R7;|

or a pharmaceutically acceptable salt or prodrug thereof, optionally in combination with an excipient. 0060 wherein R. R. R. R. and Rs are each indepen 0068 Another embodiment provides a compound accord dently H, OH, ing to Formula II:

O Formula II -o-I-R. or -C-O-R7. R3 R4

0061 wherein R, is a linear, branched or cyclic, saturated R R6 or unsaturated, substituted or unsubstituted C-C group, 1 R. Rs wherein if R is cyclic, R, is a C-Clso group; and 0062 R is O. —NRR, or S, wherein Rs and Rs are Rs Ro independently hydrogen, or a linear, branched, or cyclic, Satu rated or unsaturated, Substituted or unsubstituted C-Clso R O group, wherein if Rs and/or R are cyclic, Rs and/or R are R10 Cs-Cso groups; 0063 wherein at least one of R. R. R. R. R. R. R. or 0069 wherein R. R. R. R. R. R. R., and Ro are each Ro is independently H, OH,

O O O -o-I-R, or -C-O-R7; -o-I-R, O -C-O-R;

0064 or a pharmaceutically acceptable salt or prodrug 0070 R is a linear, branched, or cyclic, saturated or unsaturated, Substituted or unsubstituted C-C group. thereof, optionally in combination with an excipient. wherein if R is cyclic, R is a C-Clso group; 0065 One embodiment provides a compound according 0071 Rs and R are independently O. —NRR or S, to formula I as described above wherein at least two of R. R. wherein R and R are independently hydrogen, or a linear, R. R. or Rs are independently branched, or cyclic, saturated or unsaturated, Substituted or unsubstituted C-C group, wherein if R and/or R are cyclic, R12 and/or Rs are Ca-Cao groups; and O O 0072 wherein at least one of R. R. R. R. R. R. R. -o-l- or -C-O-R7; and Ro are independently

O O or a pharmaceutically acceptable salt or prodrug thereof, optionally in combination with an excipient. -o-I-R, or -C-O-R; 0066. Another embodiment provides a compound accord ing to formula I as described above wherein at least three of 0073 or a pharmaceutically acceptable salt or prodrug R. R. R. R. or Rs are independently thereof, optionally in combination with an excipient. US 2014/025661.6 A1 Sep. 11, 2014

0074 Another embodiment provides a composition I0082 and wherein R is not including a compound according to formula II wherein at least two of R. R. R. R. R7, Rs. Ro, and Rio are indepen dently O -o-Itchin-ch O O -o-I-R, or -C-O-R; when R. R. R. R. R. R., and Ro are OH: I0083 or a pharmaceutically acceptable salt or prodrug thereof, optionally in combination with an excipient. 0075 or a pharmaceutically acceptable salt or prodrug I0084 Another embodiment provides a green tea polyphe nol esterified with at least two fatty acids. Representative thereof, optionally in combination with an excipient. green tea polyphenols include, but are not limited to (-)- 0076 Another embodiment provides a composition epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epicat including a compound according to formula II as described echin-3-gallate (ECF), (-)-epigallocatechin-3-gallate above wherein at least three of R. R. R. R. R. R. R. and (ECGC). Representative fatty acids include, but are not lim Ro are independently ited to butanoic acid, hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, 9-hexadecenoic acid, octadecanoic acid, 9-octadecenoic O O acid, 11-octadecenoic acid, 9,12-octadecadienoic acid, 9,12, 15-octadecatrienoic acid, 6.9,12-octadecatrienoic acid, -o-I-R, or -C-O-R; eicosanoic acid, 9-eicosenoic acid, 5,8,11,14-eicosatet raenoic acid, 5,8,11,14, 17-eicosapentaenoic acid, docosanoic acid, 13-docosenoic acid, 4,7,10,13,16,19 optionally in combination with an excipient. docosahexaenoic acid, and tetracosanoic acid. I0085 a. Excipients 0077. Another embodiment provides a composition I0086 Formulations including the lipid soluble green tea including a compound according to formula II as described polyphenols according to Formula I. Formula II, or both may above wherein at least four of R. R. R. R. R. Rs. Ro, and be prepared using pharmaceutically acceptable excipients Ro are independently composed of materials that are considered safe and effective and may be administered to an individual without causing undesirable biological side effects or unwanted interactions. O O The excipients are all components present in the pharmaceu tical formulation other than the one or more lipid soluble -o-I-R, or -C-O-R; green tea polyphenol compounds disclosed herein. As gener ally used herein “excipient' includes, but is not limited to, Surfactants, emulsifiers, emulsion stabilizers, emollients, optionally in combination with an excipient. buffers, solvents and preservatives. 0078. Another embodiment provides a composition I0087 Preferred excipients include surfactants, especially including a compound according to formula II wherein R. non-ionic Surfactants; emulsifying agents, especially emulsi R. R. R. R. Rs. Ro, and Ro are each independently H, OH, fying waxes; and liquid non-volatile non-aqueous materials, particularly glycols such as propylene glycol. The oil phase may contain other oily pharmaceutically approved excipi O O ents. For example, materials such as hydroxylated castor oil or sesame oil may be used in the oil phase as Surfactants or -o-I-R, or -C-O-R; emulsifiers. 0088 Emollients I0089 Suitable emollients include those generally known 0079 R is a linear, branched, or cyclic, saturated or in the art and listed in compendia, such as the “Handbook of unsaturated, Substituted or unsubstituted C-Clso group, Pharmaceutical Excipients', 4' Ed., Pharmaceutical Press, wherein if R is cyclic, R is a C-Clso group; 2003. These include, without limitation, almond oil, castor 0080 Rs and R are independently O. —NR,R or S, oil, ceratonia extract, cetostearyl alcohol, cetyl alcohol, cetyl wherein RandR are independently hydrogen, or a linear, esters wax, cholesterol, cottonseed oil, cyclomethicone, eth branched, or cyclic, Saturated or unsaturated, Substituted or ylene glycol palmitostearate, glycerin, glycerin monostear unsubstituted C-Clso group, wherein if R and/or R are ate, glyceryl monooleate, isopropyl myristate, isopropyl cyclic, R12 and/or Rs are Ca-Cao groups; and palmitate, lanolin, lecithin, light mineral oil, medium-chain triglycerides, mineral oil and lanolin alcohols, petrolatum, 0081 wherein at least one of R. R. R. R. R. R. R. petrolatum and lanolin alcohols, soybean oil, starch, Stearyl and Ro are independently alcohol, sunflower oil, xylitol and combinations thereof. In one embodiment, the emollients are ethylhexylstearate and ethylhexyl palmitate. O O 0090 Surfactants -o-I-R, or -C-O-R; 0091 Suitable surfactants include anionic surfactants, nonionic Surfactants, cationic Surfactants and ampholytic Sur factants. Anionic Surfactants include alkaline salts, ammo nium salts, amine salts, amino alcohol salts and magnesium US 2014/025661.6 A1 Sep. 11, 2014

salts of the following compounds: alkyl Sulphates, alkyl ether 0.100 Additional surfactants that can be used include, but Sulphates, alkylamido ether Sulphates, alkylaryl polyether are not limited to sodium dodecylsulfate (SDS), sodium cho Sulphates, monoglyceride Sulphates; alkyl Sulphonates, alky late, sodium deoxycholate (DOC), N-lauroylsarcosine lamide Sulphonates, alkylaryl Sulphonates, olefin Sulpho sodium salt, lauryldimethylamine-oxide (LDAO), cetyltrim nates, paraffin Sulphonates; alkyl Sulphosuccinates, alkyl ethylammoniumbromide (CTAB), and bis(2-ethylhexyl)sul ether Sulphosuccinates, alkylamide Sulphosuccinates; alkyl foSuccinate Sodium salt. Sulphosuccinamates; alkyl Sulphoacetates; alkyl phosphates, 0101 Additional non-ionic surfactants include emulsify alkyl ether phosphates; acyl sarcosinates, acyl isethionates ing wax, glyceryl monooleate, polyoxyethylene alkyl ethers, and N-acyl taurates. The alkyl or acyl group in these various polyoxyethylene castor oil derivatives, polysorbate, Sorbitan compounds generally consists of a carbon-based chain con esters, benzyl alcohol, benzyl benzoate, cyclodextrins, glyc taining from 8 to 30 carbon atoms. erin monostearate, poloxamer, povidone and combinations 0092 Suitable anionic surfactants include fatty acid salts thereof. In one embodiment, the non-ionic Surfactant is Such as oleic, ricinoleic, palmitic and Stearic acid salts; coco Stearyl alcohol. nut oil acid or hydrogenated coconut oil acid; acyl lactylates, 0102 Representative detergents include but are not lim in which the acyl group contains from 8 to 30 carbon atoms. ited to alkylbenzyldimethylammonium chloride, alkyldim 0093 Surfactants considered as weakly anionic can also ethylbenzylammonium chloride, sodium bis(2-ethylhexyl) be used, such as polyoxyalkylenated carboxylic alkyl or alky SulfoSuccinate, bis(2-ethylhexyl)sulfoSuccinate Sodium salt, laryl ether acids or salts thereof, polyoxyalkylenated car 3-(3-Cholamidopropyl)dimethylammonio-1-propane boxylic alkylamido ether acids or salts thereof, and alkyl Sulfonate. D-galactosiduronic acids or salts thereof. (0103 Emulsifiers 0094 Suitable amphoteric surfactants are secondary or 0.104 Suitable emulsifiers include acacia, anionic emulsi tertiary aliphatic amine derivatives, in which the aliphatic fying wax, calcium Stearate, carbomers, cetostearyl alcohol, radical is a linear or branched chain containing 8 to 22 carbon cetyl alcohol, cholesterol, diethanolamine, ethylene glycol atoms and which contains at least one carboxylate, Sulpho palmitostearate, glycerin monostearate, glyceryl nate, Sulphate, phosphate or phosphonate water-solubilizing monooleate, hydroxypropyl cellulose, hypromellose, lanolin, anionic group: (Cs-Co) alkylbetaines, Sulphobetaines, (C- hydrous, lanolin alcohols, lecithin, medium-chain triglycer Co) alkyl-amido (C-C) alkylbetaines or (Cs-Co) alkyl ides, methylcellulose, mineral oil and lanolin alcohols, amido (C-C) alkylsulphobetaines. monobasic sodium phosphate, monoethanolamine, nonionic 0095. The nonionic surfactants are chosen more particu emulsifying wax, oleic acid, poloxamer, poloxamers, poly larly from polyethoxylated, polypropoxylated or polyglyc oxyethylene alkyl ethers, polyoxyethylene castor oil deriva erolated fatty acids or alkylphenols or alcohols, with a fatty tives, polyoxyethylene Sorbitan fatty acid esters, polyoxyeth chain containing 8 to 30 carbon atoms, the number of ethyl ylene Stearates, propylene glycol alginate, self-emulsifying ene oxide or propylene oxide groups being between 2 and 50 glyceryl monostearate, sodium citrate dehydrate, Sodium lau and the number of glycerol groups being between 2 and 30. ryl Sulfate, Sorbitan esters, Stearic acid, Sunflower oil, traga 0096 Disodium cocoamphodiacetate, disodium lauroam canth, triethanolamine, Xanthan gum and combinations phodiacetate, disodium capryloamphodiacetate, disodium thereof. In one embodiment, the emulsifier is glycerol stear caproamphodiacetate, disodium cocoamphodipropionate, ate. disodium lauroamphodipropionate, disodium caproamphod 0105 Buffers ipropionate, disodium capryloamphodipropionate, lauroam 0106 Buffers preferably buffer the composition from a pH phodipropionate acid, and cocoamphodipropionate acid can of about 4 to a pH of about 7.5, more preferably from a pH of also be used. about 4 to a pH of about 7, and most preferably from a pH of 0097 Representative cationic surfactants are chosen in about 5 to a pH of about 7. particular from optionally polyoxyalkylenated primary, sec 0107 The disclosed compositions can also contain at least ondary or tertiary fatty amine salts; quaternary ammonium one adjuvant chosen from the adjuvants usually used in cos salts; imidazoline derivatives; or amine oxides of cationic metics. Such as fragrances, preserving agents, sequestering nature. agents, Wetting agents, Sugars, amphoteric polymers, men 0098 Suitable quaternary ammonium salts are tetraalky thol, nicotinate derivatives, agents for preventing hair loss, lammonium halides (for example chlorides) such as, for foam stabilizers, propellants, dyes, vitamins or provitamins, example, dialkyldimethylammonium or alkyltrimethylam acidifying or basifying agents or other well-known cosmetic monium chlorides, in which the alkyl radical contains from adjuvants. about 12 to 22 carbon atoms, in particular behenyltrimethy 0.108 b. Bioactive Ingredients lammonium, distearyl-dimethylammonium, cetyltrimethy 0109 Compositions containing the disclosed modified lammonium or benzyl-dimethylstearylammonium chloride green tea polyphenols optionally include one more bioactive or alternatively the stearamidopropyldimethyl(myristyl agents. In certain embodiments, one or more bioactive agents acetate)ammonium chloride. can be conjugated to the modified green tea polyphenol. 0099 Diacyloxyethyldimethylammonium, diacyloxyeth Bioactive agents include therapeutic, prophylactic and diag ylhydroxyethylmethylammonium, mono acyloxyethyldihy nostic agents. These may be organic or inorganic molecules, droxyethylmethylammonium, triacyloxyethylmethylammo proteins, peptides, Sugars, polysaccharides, tea Saponin, Vita nium and mins, cholesterol, or nucleic acid molecules. Representative monoacyloxyethylhydroxyethyldimethylammonium salts vitamins include, but are not limited to lipid soluble vitamins (chlorides or methyl Sulphate in particular) and mixtures Such as Vitamin D. Vitamin E, or combinations thereof. thereof can also be used. The acyl groups preferably contain Examples of therapeutic agents include proteins. Such as hor 14 to 18 carbon atoms and are more particularly obtained mones, antigens, and growth effector molecules; nucleic from a plant oil such as palm oil or Sunflower oil. acids, such as antisense molecules; and Small organic or inor US 2014/025661.6 A1 Sep. 11, 2014

ganic molecules such as , antihistamines, macrollides, , quinolones, Sulphonamides and immunomodulators, decongestants, neuroactive agents, diaminopyridines, tetracyclines, and miscellaneous. In a pre anesthetics, and sedatives. Examples of diagnostic agents ferred embodiment, the antibacterial agent is selected from include radioactive isotopes and radiopaque agents. the group consisting of , timidazole, secnida 0110 Anti-Psoriasis Agents Zole, erythromycin, bactoban, mupirocin, neomycin, bacitra 0111. In addition to the modified green tea polyphenols, cin, cicloproX, fluoroquinolones, , cephalexin, Suitable anti-psoriasis agents include without limitation sali , minocycline, rifampin, famciclovir, clindamy cylic acid; mometasone furoate; steroids including corticos cin, tetracycline and gentamycin. teroids such as cortisone and oluXclobetasol propionate; 0119 Suitable aminoglycosides include antibiotics 5-fluorouracil; epinephrine; anthralin; vitamin D3 analogs, derived from Streptomyces and other actinomycetales, Such as calcipotriene; methotrexate; masprocol; trimethaxate including streptomycin, framycetin, kanamycin, neomycin, gluconate; retinoids; cyclosporin; paclitaxel; 5-amino paramomycin, and tobramycin, as well as gentamycin, Sisso levulinic acid; bergasol; tin-ethyl etio purpurin; benzopor mycin, netilmycin, isepamicin, and micronomycin. phyrin derivatives; antibodies, such as ABX-IL8 antibody, I0120 Suitable antimycobacterials include , CD11a monoclonal antibody and ICM3 monoclonal anti , , rifabutinisoniazid, pyrazinamide, body; enzyme inhibitors, including tryptase inhibitor and ethambutol, Streptomycin, thiacetazone, aminosalicylic acid, phospholipase A-2 inhibitors; angiogenesis blocking agents; capreomycin, , , clofazimine, ethiona T-cell blocking agents and mixtures thereof. mide, prothionamide, ofloxacin, and minocycline. 0112 Anti-Fungal Agents I0121 and beta-lactams generally have 0113. A variety of known agents can be used to activity against gram-positive bacteria and newer generations prepare the described compositions. A list of potential anti of compounds have activity against gram-negative bacteria as fungal agents can be found in “Martindale The Complete well. Suitable cephalosporins and beta-lactams include: Drug Reference', 32nd Ed., Kathleen Parfitt, (1999) on pages 0.122 First generation; cephalothin, cephazolin, cephra 367-389. Suitable include, without limitation, dine, , , cephydroxil, , amphotericin, amorolfine, bifonazole, bromochlorosalicya cephalexin, pivoephalexin, , and . nilide, buclosamide, butenafine, , , I0123 Second generation; cephamandole, , chlormidazole, chlorphenesin, chlorXylenol, axetil, , , , and cephamycin. olamine, cillofungin, , croconazole, 0.124. Third generation; , cefinenoxime, cefo eberconazole, , enilconazole, fenticlor, fenticona dizime, , , , , cefe Zole, fluconazole, flucytosine, griseofulvin, , tamet, , , , , haloprogin, hydroxyStilbamine, isethionate, iodochlorohy , , and . droxyquinone, , itraconazole, ketoconazole, 0.125 Fourth generation: and ce?pirome lanoconazole, luflucarban, , , nafti 0.126 Other cephalosporins include cefoxitim, cefimeta fine, , neticonazole, nifuroxime, , omo Zole, , , cefiminox, , mero conazole, , pentamycin, propionic acid, protio , , , and . fate, pyrrolnitrin, ravuconazole, Saperconazole, selenium I0127 Chloramphenicols inhibit gram positive and gram Sulfide, Sertaconazole, Sulbentine, Sulconazole, terbinafine, negative bacteria. Suitable chloramphenicols include , , tolciclate, tolnaftate, triacetin, timi , its sodium Succinate derivative, thiam dazole, undecenoic acid, Voriconazole and combinations phenicol, and azidamfenicol. thereof. Some of these agents are known to have antibacterial I0128 Suitable glycopeptides include , teico activity as well. planin, and . Suitable lincosamides include linco 0114. In one embodiment, the anti-fungal agent(s) is an mycin and , which are used to treat primarily azole. Suitable and antifungal agents are aerobic . fluconazole, timidazole, secnidazole, miconazole nitrate, I0129 Macrollides have a lactam ring to which sugars are econazole, haloprogin, metronidazole, itraconazole, tercona attached. Suitable macrollides include erythromycin, as well Zole, posaconazole, raVuconazole, ketoconazole, clotrima as spiromycin, oleandomycin, josamycin, kitamycin, mide Zole, Saperconazole and combinations thereof. camycin, rokitamycin, azithromycin, clarithromycin, 0115. In an alternative embodiment, the anti-fungal agent dirithromycin, roXithromycin, flurithromycin, tylosin; and (s) is chlorXylenol, undecyclenic acid, selenium sulfide, streptgramins (or Synergistins) including pristinamycin, and iodochlorohydroxyquinone, bromochlorosalicyanilide, tri Virginiamycin; and combinations thereof. acetin or combinations thereof. 0.130 Suitable penicillins include natural and 0116. Other antifungal agents include bensuldazic acid, the semisynthetic penicillins F, G, X, K, and V. Newer peni benzoic acid, biphenamine, cloconazole, cloxyquin, dermo cillins include phenethicillin, , methicilin, clox statin, halethazole, monensin, oxiconazole, nitrate, pecilocin, acillin, dicloxacillin, , , , ampi pyrithione, rubijervine, terbinafine, ticonazole, and unde cillin, , , , , cylinic acid. , carbenecillin, , , Sul 0117 Antibacterial Agents benecillin, , , , , 0118. A variety of known antibacterial agents can be used , , and pivemecillinam. Lactamase to prepare the described compositions. A list of potential inhibitors such as , , and taZoba antibacterial agents can be found in “Martindale The Com cytam are often co-administered. plete Drug Reference', 32nd Ed., Kathleen Parfitt, (1999) on I0131 Suitable quinolones include , oxolinic pages 112-270. Classes of useful antibacterials include ami acid, , acrosoxacin, pipemedic acid, and the fluoro noglycosides, antimycobacterials, cephalosporins and beta quinolones , , , , lactams, chloramphenicols, glycopeptides, lincosamides, , , , , nor US 2014/025661.6 A1 Sep. 11, 2014

floxacin, ofloxacin, , , , tro indole-3-carbinol, thiosulfonates, phytosterols, beta-sito vafloxacin, danofloxacin, , and . sterol, anthraquinones, Senna, barbaloin, hypericin, capsai 0132) Sulphonamides and diaminopyridines include the cin, piperine, chlorophyll, betaine and combinations thereof. original of the “sulfa drugs, Sulphanilamide, and a large 0140. A wide variety of sunscreen actives are suitable. The number of derivatives, including , , exact amount and type of Sunscreen that is used depends on , , , Sul the level of photoprotection that is desired. Generally any fadimethoxydiazine, , Sulfametopyrazine, silver agent offering protection against ultraviolet radiation by Sulfadiazine, acetate, and Sulfasalizine, as well as absorbing, scattering or reflecting the ultraviolet radiation related compounds including , baduiloprim, may be used herein. The Sunscreen agents used herein may , ormetoprim, , and in combinations offer protection against one or more of the following forms of with other drugs such as co-trimoxazole. sunlight radiation UVA, UVB, UVC, visible light and infra 0.133 Tetracyclines are typically broad-spectrum and red radiation. Generally the sunprotection factor (SPF) in the include the natural products chlortetracycline, Oxytetracy final formulation varies between 2 and 30, although products cline, tetracycline, demeclocycline, and semisynthetic meth with SPFs up to 100 may be formulated. The sunscreen used acycline, doxycycline, and minocycline. herein may offer chemical or physical photoprotection. 0134) Suitable antibacterial agents that do not fit into one 0141 Suitable sunscreen agents include those selected of the categories above include spectinomycin, mupirocin, from the group comprising amino benzoic acid and deriva neomycin, , fusidic acid, polymixins, , tives. Such as para-amino benzoic acid (PABA), glyceryl , , , , chloroquinal PABA (Lisadimate), Padimate O, Roxadimate; anthrinalates, dol, haloquinal, nitrofurantonin, (including including methylanthrynilate; benzophenones, including metronizole, timidazole and secnidazole), and hexamine. dioxybenzone, oxybenzone and Sulisobenzone, 3-benzophe 0135 The and antifungal agents may be present none (Uvinul M40) 4-N,N-dimethylaminobenzoic acid ester as the free acid or free base, a pharmaceutically acceptable with 2,4-dihydroxybenzophenone; camphor derivatives salt, or as a labile conjugate with an ester or other readily including 3-(4-methylbenzylidene) camphor, 3-benzylidene hydrolysable group, which are suitable for complexing with camphor, cinnamates including DEA-p-methoxycinnamate, the ion-exchange resin to produce the resinate. ethyl-hexyl p-methoxy cinnamate, octocrylene, octyl meth 0.136 Agents oxy cinnamate: dibenzoyl methanes including butylmethoxy 0.137 Antiseptic agents can be included in compositions dibenzoylmethane, salicylates including, homomethyl sali formulated for topical administration. Suitable antiseptic cylate, octyl salicylate, trolamine methyl salicylate; metal agents include iodine, iodophores including cadeXomer oxides including titanium dioxide, Zinc oxide and iron oxide; iodine, chlorhexidine, gluconate, thimerosal, hydrogen per 2-phenylbenzimidazole-5-sulfonic acid; 4.4-methoxy-t-bu oxide, and peroxides and perchlorates including organic per tyldibenzoylmethane; and mixtures thereof. oxides and perchlorate salts. 0.142 Further non-limiting examples of sunscreens useful 0138 Skin Protectants in accordance with the present invention are described in U.S. 0139 Skin protectants can be included in compositions Pat. No. 5,087.445 to Haffey et al., U.S. Pat. No. 5,073.372 to formulated for topical administration. Such agents not only Turneretal. and U.S. Pat. No. 5,160,731 to Sabatelli et al., all Soothe the skin but may also aide in maintaining the integrity of which are incorporated herein by reference in their entirety. of the skin to prevent damage. Suitable skin protectants 0.143 Local Anesthetics or Antihistamines include allantoin: cocoa butter, dimethicone; kaolin; shark 0144. Local anesthetics or antihistamines may also be liver oil; petrolatum; lanolin; vegetable oils; ethoxylated oils employed in the topical formulation in order to lessen the pain and lipids; polymers such as polyalkylene oxides, polyvi and itching caused by the local infection. Suitable local anes nylpyrrolidone, polyvinyl alcohol, poly(meth)acrylates, eth thetics and antihistamines include benzocaine, lidocaine, ylvinyl acetate, polyalkylene glycols; polysaccharides and dibucaine, etidocaine, benzyl alcohol, camphor, resorcinol, modified polysaccharides Such as hyaluronic acid, cellulose menthol, and diphenhdramine hydrochloride. ehers, cellulose esters, hydroxypropyl methylcellulose, 0145 c. Veterinary Compositions crosscarmelose, and Starch; natural gums and resins which may be gelling or non-gelling such as alginates, carrageen 0146. One embodiment includes the disclosed lipid ans, agars, pectins, glucomannans (guar, locust bean, etc.). soluble green tea polyphenols formulated for veterinary use, galactomannans (e.g. konjac), gum arabic, gum traganth, for example for domestic pets including domestic mammals Xanthan, Schleroglucan and shellac; and colloidal insolubles Such as dogs and cats. Topical veterinary formulations, for Such as Zinc oxide and other insoluble Zinc salts, talcum example shampoos, typically include weak detergents powder and other micronized natural minerals; and colloidal because animals have fewer layers of skin than humans. For silicas, aluminas and other metal oxides. Additional pro example a cat’s skin is 2-3 cell layers thick, while a dog's skin tectants include phenolic or non-phenolic phytochemicals is 3-5 layers. Human skin, by contrast, is 10-15 cell layers including, but not limited to lycopene, beta-carotene, alpha thick. carotene, lutein, Zeaxanthin, astaxanthin, non-carotenoid, 0147 Additionally, topical veterinary formulations erpeniods, perillyl alcohol, Saponins, terpeneol, terpene optionally include a pesticide or insecticide to help control limonoids, anthocyanins, catechins, isoflavones, hesperetin, fleas, ticks, mites, mosquitoes, parasites, etc. Suitable pesti naringin, rutin, quercetin, sily marin, tangeretin, tannins, phe cide or insecticide additives include natural or synthetic pyre nolic acids, elagic acid, chlorogenic acid, p-coumaric acid thrins such as pyrethrin I and II, cinevin I and II, jasmolin I (para-coumeric acid), phytic acid, ferulic acid, Vanillin, cin and II, allethrin, resmethrin, phenothrin, and permethrin or namic acid, hydroxycinnamic acids, curcumin, resveratrol, combinations thereof. lignans, glucosinolates, isothiocyanates, phenethyl, Sothio 0.148. Organophosphates and organocarbamates can also cyanate, benzyl isothiocyanate, Sulforaphane, indoles, be used with the disclosed compositions. Suitable organo US 2014/025661.6 A1 Sep. 11, 2014

phosphates and organocarbamates include dichlorvos, cyth ming lotion; bath effervescent tablets; a hand and nail cream; ioate, diazinon, malathion, carbaryl, fenthione, methylcar a bath/shower gel; a shower cream; a cellulite Smoothing bamate, and prolate. product; a deodorant; a dusting powder; an antiperspirant; a 0149 Additional insecticides include imidacloprid, depilatory cream; a shaving product e.g. a shaving cream, a fipronil, amitraz, Selamectin, nitenpyram, or combinations gel, a foam and an after-shave, after-shave moisturizer; and thereof. combinations thereof. 0150. Insect growth regulators and insect development 0157 Suncare products which may be prepared using the inhibitors can also be used. Suitable insect growth regulators disclosed compositions include a Sunscreen; a Sunblocker; an include methoprene, fenoxycarb, and pyriproxyfen. Suitable after Sun lotion milks and gel; a burn lotion; a tanning lotion, insect growth inhibitors include lufenuron and diflubenzuron. spray and milk; a Sunless self-tanning cream, spray and 0151 d. Personal Care Products lotion; a combined Sunscreen-insect repellant formulation 0152 Personal care products containing one or more of and combinations thereof. the modified green tea polyphenols can vary widely and 0158 Make-up or cosmetic products that may be prepared include a skin care product, a hair care product, a beauty using the disclosed lipid-soluble green tea polyphenols treatment product, a perfume, a bath and body product, a include a mascara (thickening, lengthening, waterproof); a Suncare product, a make-up and a toothpaste. These products blush (cream and powder); a lipstick; a foundation cream may be prepared as formulations intended for specific use by (stick or liquid); a foundation powder, a concealer; an eye individuals belonging to different age categories (babies, shadow (cream and powder); an eye pencil; an eye liquid line; teenagers etc.), having different skin types (e.g. maturing, a bronzing powder; a lip pencil; a lip gloss; a lip conditioner; aged, dry, oily, mixed, combined or complexities thereof) or a make-up remover (e.g. eye make-up remover); a liquid lip in accordance with the intended functionality of the product color; a brow pencil; a lip balm; a nail polish (base and top (for example products that prevent or reverse dehydration, coat and nail blush); and a combination thereof. replenish moisture, modulate pigmentation, prevent or 0159 e. Dermatological Products reverse stretch marks, products for treatment or reversal of 0160 Representative dermatological compositions con skin changes associated with aging Such as wrinkles, blotches taining one or more of the disclosed lipid-soluble green tea and atrophy or elastotic changes associated with intrinsic polyphenols include products which may be used to treat or aging of the skin, as well as changes caused by external reverse skin changes associated with aging such as wrinkles, factors for example Sunlight radiation, X-ray radiation, air blotches and atrophy or elastotic changes associated with pollution, wind, cold, dampness, dryness, heat, Smoke and intrinsic aging of the skin as well as changes caused by cigarette Smoking) external factors for example Sunlight radiation; X-ray radia 0153. Examples of skin care products which may be pre tion; air pollution; wind; cold; dampness; dryness; heat; pared using the disclosed compositions, for example emul Smoke and cigarette Smoking; external infectious agents such sion formulations, include without limitation a skin cream; a as fungi and bacteria; and combinations thereof. The dis facial cream; a cleanser, a toner, a day cream; a night cream; closed compositions can be used to reduce hyperproliferation a day lotion; an eye cream; a facial mask (e.g. firming, mois of keratinocytes. turizing, purifying, deep-cleansing); an anti-aging cream; an 0.161 Additional skin conditions which may be treated anti-wrinkle cream; an anti-puffiness product; a cold weather include products to treat infectious and non-infectious skin cream; a foot cream; a facial Scrub; an anti-acne product; a diseases. Infectious diseases include for example impetigo hand cream; an insect repellant formulation; or combinations and leprosy. Non-infectious skin diseases include without thereof. The disclosed personal care products generally limitation autoimmune disorders such as psoriasis, cutaneous include an amount of one or more of the disclosed modified systemic lupus, cutaneous rheumatoid arthritis, allergic skin green tea polyphenols, for example a compound according to disorders (e.g. eczema), and pemphigoid. It is believed that formula I or II, effective to reduce hyperproliferation of kera topical application of modified green tea polyphenols will tinocytes or reduce inflammation. protect the epidermis from Symptoms associated with psoria 0154 Suitable hair care products that may be prepared sis by attenuating three keratinocyte-based mechanisms of with the disclosed compositions include for example a sham pathogenesis: aberrant caspase 14 processing/nuclear local poo; a conditioner, a re-conditioner, a mousse; a gel; a hair ization, inflammation and hyperproliferation. spray; a hair mascara; a hot oil treatment product; a dye; a hair 0162 Various manifestations of eczema, psoriasis and mask; a deep conditioning treatment product; a coloring acne may also be treated using the emulsions containing the product; a hair-repair product and permanent wave productor disclosed modified green tea polyphenols. Clinical manifes combinations of thereof. tations of eczema which may be treated include, inter alia, 0155 Representative beauty treatment products that can atopic eczema, allergic contact dermatitis; irritant contact be produced using the disclosed compositions include with dermatitis; infantile seborrhoeic eczema; adult seborrhoeic out limitation, a waxing product, a pedicure product, a mani eczema; varicose eczema and discoid eczema. The manifes cure product, a facial product, a beauty lift product, a massage tations of psoriasis that may be treated include chronic, product and an aroma-therapy product; and combinations plaque-type psoriasis; guttate psoriasis; psoriatic erytho thereof. derma; and pustular psoriasis. Acne conditions which may be 0156 Bath and body products which may be prepared treated include Superficial acne (acne Vulgaris), low grade with the disclosed compositions include for example a acne, pre-acne and acne lesions including comedones and shower gel; including an exfoliating shower gel; a foaming micro comedones. bath product (e.g., gel, Soap or lotion); a milk bath; a body 0163 Still further examples of dermatological products wash; a soap including liquid and bar soap; a cleanser, includ which may be formulated using the disclosed modified green ing agel cleanser, a liquid cleanser and a cleansingbar; abody tea polyphenols include without limitation products to treat lotion; a body spray, mist or gel; an essential lotion; a slim hyper and hypopigmented skin, age spots, palmar or plantar US 2014/025661.6 A1 Sep. 11, 2014 hyperkeratosis, pruritis ichthyosis, Darier's disease, lichen preferably between 5% and 50% by weight, relative to the simplex chronicus, hemorrhoids, inflammatory dermatosis, total weight of the composition and in particular between 8% Xeroderma pigmentosum, skin cancers including basal cell and 35%. carcinoma, malignant cell carcinoma, squamous cell carci 0172. The concentration of the emulsifier(s) is from about noma, malignant melanoma, and AIDS-related Karposi sar 0.5% to about 50% by weight of the final composition. The coma, premalignant skin lesions including actinic keratosis, concentration of the buffer(s) is from about 1% to about 25% Xerosis, athletes foot, Scabies, warts, herpes and dermatoses. by weight of the final composition and the concentration of 0164. The particular product and the particular form in the stabilizer(s) is from about 1% to about 25% by weight of which the modified green tea polyphenols are present depend the final composition. on how the product is applied. It is to be understood that the 0173 The composition of the lipid soluble green tea emulsion formulated with the modified green tea polyphenols polyphenol is about 0.01% to about 40% by weight of the may be applied in any product which is applied to the Surface final composition, in particular about 0.1%, 1.0%, 5%, 10%, area of the human body. 15%, 20%, 25%, 30%, or 35%. In certain embodiments one or more lipid soluble green tea polyphenols are present in an III. Method of Making the Compositions amount effective to reduce inflammation of the skin or treat (0165 a. Modified Green Tea Polyphenols dandruff when administered. The amount of the lipid soluble 0166 Modified green tea polyphenols having increased green tea polyphenol will vary according to skin disorder to lipid solubility compared to unmodified green tea polyphe be treated nols can be produced for example, by the method described in 0.174. The concentration of an optional topical anesthetics Chen and Du, (2003) Chinese J Chem, 21:979-981, which is from about 1% to about 10% by weight and the concentra where permissible is incorporated by reference in its entirety. tion anti-fungals and other antibiotics is from about 0.3% to Briefly, agreen tea polyphenol is reacted with an acyl chloride about 5% by weight. The concentration of insecticide can be having a desired number of carbons in ethyl acetate. The from about 0.01% to about 10% by weight. reaction is filtered and the reaction solution is washed with deionized water. The upper organic layer is evaporated and IV. Methods of Use dried under vacuum. The lipid soluble green tea polyphenol 0.175. The disclosed compositions containing one or more can be isolated using high-speed counter-current chromatog lipid-modified green tea polyphenols are useful in topical raphy as described for example in Chen et al. (2002) J. Chro application to the Surface area of the human or animal body, matography,982:163-165, which where permissible is incor including skin, hair, teeth, nails and lips. The compositions porated by reference in its entirety. The isolated lipid soluble include personal care and dermatological products. Personal green tea polyphenol can then be formulated into a composi care products refer to all cosmetics, cosmeceuticals and tion, for example topical formulations. beauty care products, all of which may be prepared in accor 0167. The water in oil topical compositions may be in the dance with the present disclosure. Dermatological products form of emulsions such as creams, lotions, ointments, pow refers to all products to treat or ameliorate skin conditions, ders, micro emulsions, liposomes, or in the form of gels, abnormalities or diseases and contain one or more of the liquids, and foams. They may also be presented in dry powder disclosed green tea polyphenols capable of improving said formulations. condition, abnormality, disease. These products include any (0168 b. Emulsions and all products that may be used to treat or ameliorate any 0169 Generally emulsions are prepared in the presence of pathological conditions of the dermis or epidermis. It is noted a multiplicity of other substances in order to achieve a desir that the modified green tea polyphenols may be applied in able balance of emulsification, Viscosity, stability and appear compositions which vary considerably in physical properties ance. For example, the formulation of emulsions usually and use. The types and quantities of ingredients used to pre requires at least one, and frequently a combination of several, pare different products will depend on the desired use of the emulsifying agents. These agents facilitate the dispersal of product and may be varied in accordance with practices well one immiscible phase into the other and assist in stabilizing known to those of ordinary skill in the art of formulating skin the emulsion. A comprehensive overview of emulsifying care and dermatological products. agents and their applications may be found in Becher, P. 0176 One embodiment provides compositions including Encyclopedia of Emulsion Technology, Dekker Ed., 1983. one or more of the disclosed modified green tea polyphenols, 0170 In one embodiment, the oil phase is prepared by for example those according to Formulas I or II, for treating mixing together one or more surfactant(s), optionally, one or dermatitis. Such compositions are formulated for topical more emulsifier(s), and one or more of the disclosed lipid application to the skin as described above. The formulations soluble green tea polyphenols to melt if necessary. The aque can be applied directly to the skin in the form of lotions, ous phase is prepared separately by dissolving the preserva creams, salves, ointments, fluids, hydrogels, foams, colloids, tives in water with heating as needed. The aqueous phase is Suspensions, or dry powder. In certain embodiments, the one added to the oil phase, for example with continuous high or more of the disclosed modified green tea polyphenols, for shear mixing to produce a milky emulsion. The emulsion is example those according to Formulas I or II or both, are cooled and the pH is adjusted by the addition of a buffer. The formulated in a shampoo or rinse for applying to the hair and formulation is brought to the final weight by the addition of Scalp, for example a dandruff shampoo optionally including Water. one or more anti-dandruff agents including but not limited to 0171 The surfactants or detergents are optionally used in Zinc pyrithione, Salicylic acid or ketoconazole. The disclosed the compositions in proportions of between 0.01% and 50% compositions can be used for treating dermatitis including by weight, relative to the total weight of the composition. dandruff. The disclosed modified green tea polyphenols can When the compositions are in the form of shampoos, they are also be used in cosmetics, lip Sticks, moisturizing lotions, and generally used in a proportion of at least 1% by weight, the like. US 2014/025661.6 A1 Sep. 11, 2014

(0177. The disclosed modified green tea polyphenols can druff. The vehicle shampoo was replaced with dandruff-con also be used for treating dermatitis in animals such as domes trol shampoo described above. The shampoo was used twice tic mammals such as dogs and cats. Compositions including a day for two days followed by once daily. The shampoo was shampoos and lotions containing the compounds of Formula applied to the hair, massaged into the scalp, and rinsed. In 24 I, II or both can be applied to the skin of the animal and either h, visible changes occurred on the scalp with reduced flaking rinsed off or allowed to be absorbed as needed. For example, lesions and itchiness. After four days of treatment all lesions the disclosed compositions can be applied to “hotspots” of a were cleared and no itchiness was reported. pet to help reduce inflammation, itching, and permit the skin 1. (canceled) to heal. The term “hotspots” refers to pyotraumatic dermatitis 2. A pharmaceutical composition comprising and are surface skin infections caused when populations of agreen tea polyphenol esterified with one or more C1-C30 normal skin bacteria grow and overwhelm normal resistance. hydrocarbon chains, wherein the modified green tea polyphenol is selected from the group consisting of (-)- Example epicatechin, (-)-epigallocatechin, (-)-epicatechin-3- gallate, and (-)-epigallocatechin-3-gallate; and Dandruff-Control Shampoo an antibacterial agent in an amount effective to kill bacte (0178 A dandruff-control shampoo was formulated using 18. green tea polyphenols esterified with mono unsaturated fatty 3. The pharmaceutical composition of claim 1, wherein the acids (oleic acid, randomly esterified). A stock solution was one or more C1-C30 hydrocarbon chains is octadecanoic prepared by dissolving lipid-soluble green tea polyphenols in acid. 100% ethanol to produce a 60% w/v stock solution. The stock 4. The pharmaceutical composition of claim 1, wherein the Solution was mixed gently with commercially available stan antibacterial agent is selected from the group consisting of dard shampoo as a vehicle at 1:20 and mixed until the ethanol , bacitracin, cephalothin, chloramphenicol, doxy evaporated. The standard shampoos contained the following cycline, erythromycin, gentamicin, penicillin, , ingredients: water (Aqua), ammonium lauryl sulfate, ammo rifampin, streptomycin, and tetracycline. nium laureth sulfate, ammonium chloride, cocamide MEA, 5. The pharmaceutical composition of claim 1, wherein the PEG 5 cocamide, fragrance (Parfum), hydroxypropyl meth green tea polyphenol is (-)-epigallocatechin-3-gallate esteri ylcellulose, tetrasodium EDTA, DMDM hydantoin, citric fied at the 4' position. acid, tocopheryl acetate (vitamin E acetate), methylchlor 6. The pharmaceutical composition of claim 1, further oisothiazolinone, propylene glycol, honeysuckle extract comprising a pharmaceutically acceptable excipient. (Lonicera Caprifolium), methylisothiazolinone, aloe bar 7. A method of treating a bacterial infection in a subject badensis gel (Aloe Vera), D&C green 5 (CI-61570), FD&C comprising administering an effective amount of the pharma Yellow 5 (CI-19140). It will be appreciated that the vehicle ceutical composition of claim 1 to reduce or inhibit the bac can be any detergent, surfactant, oil, or emulsion. terial infection in the subject. (0179 The shampoo used as a vehicle was applied to 8. The method of claim 1, wherein the subject is human. patient for three months with no detectable reduction in dan