US20040220119A1 - Formulation of dual cycloxygenase (COX) and lipoxygenase (LOX) inhibitors for mammal skin care - Google Patents

Formulation of dual cycloxygenase (COX) and lipoxygenase (LOX) inhibitors for mammal skin care Download PDF

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US20040220119A1
US20040220119A1 US10/817,330 US81733004A US2004220119A1 US 20040220119 A1 US20040220119 A1 US 20040220119A1 US 81733004 A US81733004 A US 81733004A US 2004220119 A1 US2004220119 A1 US 2004220119A1
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cox
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flavan
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Qi Jia
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Unigen Inc
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Unigen Pharmaceuticals Inc
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Priority to US13/028,853 priority patent/US8790724B2/en
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    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
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    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
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Definitions

  • This invention relates generally to a method for the prevention and treatment of diseases and conditions mediated by cyclooxygenase (COX) and lipoxygenase (LOX).
  • COX cyclooxygenase
  • LOX lipoxygenase
  • the present invention relates to a novel composition of matter comprised of a mixture of a blend of two specific classes of compounds—Free-B-Ring flavonoids and flavans—for use in the prevention and treatment of diseases and conditions of the skin mediated by the COX and LOX pathways.
  • Included in the present invention is a method for the prevention and treatment of COX and LOX mediated diseases and conditions, including but not limited to sun burns, thermal burns, acne, topical wounds, minor inflammatory conditions caused by fungal, microbial and viral infections, vitilago, systemic lupus erythromatosus, psoriasis, carcinoma, melanoma, as well as other mammal skin cancers, skin damage resulting from exposure to ultraviolet (UV) radiation, chemicals, heat, wind and dry environments, wrinkles, saggy skin, lines and dark circles around the eyes, dermatitis and other allergy related conditions of the skin.
  • UV radiation ultraviolet
  • Use of the composition described herein also affords the benefit of smooth and youthful skin with improved elasticity, reduced and delayed aging, enhanced youthful appearance and texture, and increased flexibility, firmness, smoothness and suppleness.
  • UV radiation which has a wavelength from 200 nm to 400 nm.
  • UVA which has a wavelength range from 320-400 nm
  • UVB which has a wavelength range from 290-320 nm
  • UVC which has a wavelength range from 100-290 nm, can cause damage but not tanning.
  • AA arachidonic acid
  • LOX lipoxygenase
  • COX cyclooxygenase
  • the enzymes responsible for generating these mediators of inflammation have become the targets in the current invention to develop topically administered therapeutic agents aimed at the dual inhibition of inflammation resulting from both pathways which contribute to the physiological and pathological processes of diseases and conditions such as sun burn, thermal burns, scald, acne, topical wounds, lupus erythromatosus, psoriasis, carcinoma, melanoma, and other mammalian skin cancers.
  • COX-1 is a constitutive form of the enzyme that has been linked to the production of physiologically important prostaglandins, which help regulate normal physiological functions, such as platelet aggregation, protection of cell function in the stomach and maintenance of normal kidney function.
  • COX inhibitors In addition to their use as anti-inflammatory agents, another potential role for COX inhibitors is in the treatment of cancer. Over expression of COX has been demonstrated in various human malignancies and inhibitors of COX have been shown to be efficacious in the treatment of animals with skin tumors. While the mechanism of action is not completely understood, the over expression of COX has been shown to inhibit apoptosis and increase the invasiveness of tumorgenic cell types. (Dempke et al. (2001) J. Can. Res. Clin. Oncol. 127:411-17; Moore and Simmons (2000) Current Med. Chem. 7:1131-1144). Up regulated COX production has been implicated in the generation of actinic keratosis and squamous cell carcinoma in skin.
  • Topical application of anti-inflammatory drugs such as retinoids (Millikan (2003) J. Am. Acad. Dermatol. 4(2):75) and the COX inhibitor salicylic acid (Lee (2003) Dermnatol Surg 29(12):1196) have been clinically demonstrated as an effective and safe therapy for the treatment of acne.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • topical application of anti-inflammatory drugs have been clinically demonstrated as an effective and safe therapy for the treatment of acne.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • flavonoids include flavanols, flavones, flavan-3-ols (catechins), anthocyanins and isoflavones.
  • Free-B-Ring flavones and flavonols are a specific class of flavonoids, which have no substituent groups on the aromatic B ring (referred to herein as Free-B-Ring flavonoids), as illustrated by the following general structure:
  • R is an alkyl group having between 1-10 carbon atoms
  • X is selected from the group of pharmaceutically acceptable counter anions including, but not limited to hydroxyl, chloride, iodide, fluoride, sulfate, phosphate, acetate, carbonate, etc.
  • Free-B-Ring flavonoids are relatively rare. Out of 9,396 flavonoids synthesized or isolated from natural sources, only 231 Free-B-Ring flavonoids are known ( The Combined Chemical Dictionary , Chapman & Hall/CRC, Version 5:1 June 2001). Free-B-Ring flavonoids have been reported to have diverse biological activity. For example, galangin (3,5,7-trihydroxyflavone) acts as antioxidant and free radical scavenger and is believed to be a promising candidate for anti-genotoxicity and cancer chemoprevention. (Heo et al. (2001) Mutat. Res. 488(2):135-150).
  • the Chinese medicinal plant, Scutellaria baicalensis contains significant amounts of Free-B-Ring flavonoids, including baicalein, baicalin, wogonin and baicalenoside.
  • this plant has been used to treat a number of conditions including clearing away heat, purging fire, dampness-warm and summer fever syndromes; polydipsia resulting from high fever; carbuncle, sores and other pyogenic skin infections; upper respiratory infections, such as acute tonsillitis, laryngopharyngitis and scarlet fever; viral hepatitis; nephritis; pelvitis; dysentery; hematemesis and epistaxis.
  • This plant has also traditionally been used to prevent miscarriage.
  • Scutellaria baicalensis root extract has been formulated as a supplemental sun screen agent with additive effects of the cumulative SPFs of each individual component in a topical formulation (WO98/19651).
  • Chrysin has been used for its anxiety reducing properties (U.S. Pat. No. 5,756,538).
  • Anti-inflammatory flavonoids are used for the control and treatment of anorectal and colonic diseases (U.S. Pat. No. 5,858,371), and inhibition of lipoxygenase (U.S. Pat. No. 6,217,875). These compounds are also formulated with glucosamine collagen and other ingredients for repair and maintenance of connective tissue (U.S. Pat. No. 6,333,304).
  • Flavonoid esters constitute active ingredients for cosmetic compositions (U.S. Pat. No. 6,235,294).
  • U.S. application Ser. No. 10/091,362 filed Mar. 1, 2002, entitled “Identification of Free-B-Ring Flavonoids as Potent COX-2 Inhibitors,” and U.S. application Ser. No. 10/427,746, filed Jul.
  • Japanese Pat. No. 63027435 describes the extraction, and enrichment of baicalein and Japanese Pat. No. 61050921 describes the purification of baicalin.
  • Flavans include compounds illustrated by the following general structure:
  • R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of —H, —OH, —SH, —OCH 3 , —SCH 3 , —OR, —SR, —NH 2 , —NRH, —NR 2 , —NR 3 + X ⁇ , esters of the mentioned substitution groups, including, but not limited to, gallate, acetate, cinnamoyl and hydroxyl-cinnamoyl esters, trihydroxybenzoyl esters and caffeoyl esters, and their chemical derivatives thereof; a carbon, oxygen, nitrogen or sulfur glycoside of a single or a combination of multiple sugars including, but not limited to, aldopentoses, methyl aldopentose, aldohexoses, ketohexose and their chemical derivatives thereof; dimer, trimer and other polymerized flavans;
  • R is an alkyl group having between 1-10 carbon atoms
  • X is selected from the group of pharmaceutically acceptable counter anions including, but not limited to hydroxyl, chloride, iodide, sulfate, phosphate, acetate, fluoride, and carbonate, etc.
  • Catechin works both alone and in conjunction with other flavonoids found in tea, and has both antiviral and antioxidant activity. Catechin has been shown to be effective in the treatment of viral hepatitis. It also appears to prevent oxidative damage to the heart, kidney, lungs and spleen and has been shown to inhibit the growth of stomach cancer cells.
  • Catechin and its isomer epicatechin inhibit prostaglandin endoperoxide synthase with an IC 50 value of 40 ⁇ M.
  • IC 50 value 40 ⁇ M.
  • Five flavan-3-ol derivatives, including (+)-catechin and gallocatechin, isolated from four plant species: Atuna racemosa, Syzygium carynocarpum, Syzygium malaccense and Vantanea peruviana exhibit equal to weaker inhibitory activity against COX-2, relative to COX-1, with IC 50 values ranging from 3.3 ⁇ M to 138 ⁇ M (Noreen et al. (1998) Planta Med. 64:520-524).
  • (+)-Catechin isolated from the bark of Ceiba pentandra , inhibits COX-1 with an IC 50 value of 80 ⁇ M (Noreen et al. (1998) J. Nat. Prod. 61:8-12).
  • Commercially available pure (+)-catechin inhibits COX-1 with an IC 50 value of around 183 to 279 ⁇ M depending upon the experimental conditions, with no selectivity for COX-2. (Noreen et al. (1998) J. Nat. Prod. 61:1-7).
  • Green tea catechin when supplemented into the diets of Sprague dawley male rats, lowered the activity level of platelet PLA 2 and significantly reduced platelet cyclooxygenase levels.
  • (+)-catechin from red wine results from the antioxidant properties of catechin, rather than inhibitory effects on intracellular enzymes, such as cyclooxygenase, lipoxygenase, or nitric oxide synthase (Bastianetto et al. (2000) Br. J. Pharmacol. 131:711-720).
  • Catechin derivatives purified from green and black tea such as epigallocatechin-3-gallate (EGCG), epigallocatechin (EGC), epicatechin-3-gallate (ECG), and theaflavins showed inhibition of cyclooxygenase and lipoxygenase dependent metabolism of AA in human colon mucosa and colon tumor tissues (Hong et al.
  • Acacia is a genus of leguminous trees and shrubs.
  • the genus Acacia includes more than 1000 species belonging to the family of Leguminosae and the subfamily of Mimosoideae.
  • Acacias are distributed worldwide in tropical and subtropical areas of Central and South America, Africa, parts of Asia, as well as, Australia, which has the largest number of endemic species.
  • Acacias are very important economically, providing a source of tannins, gums, timber, fuel and fodder. Tannins, which are isolated primarily from bark, are used extensively for tanning hides and skins. Some Acacia barks are also used for flavoring local spirits. Some indigenous species like A.
  • saponins are any of various plant glucosides that form soapy lathers when mixed and agitated with water. Saponins are used in detergents, foaming agents and emulsifiers. The flowers of some Acacia species are fragrant and used to make perfume. The heartwood of many Acacias is used for making agricultural implements and also provides a source of firewood. Acacia gums find extensive use in medicine and confectionary and as sizing and finishing materials in the textile industry.
  • Flavonoids are the major class of compounds isolated from Acacias . Approximately 180 different flavonoids have been identified, 111 of which are flavans. Terpenoids are second largest class of compounds isolated from species of the Acacia genus, with 48 compounds having been identified. Other classes of compounds isolated from Acacia include, alkaloids (28), amino acids/peptides (20), tannins (16), carbohydrates (15), oxygen heterocycles (15) and aliphatic compounds (10). (Buckingham, The Combined Chemical Dictionary , Chapman & Hall CRC, version 5:2, December 2001).
  • Phenolic compounds, particularly flavans are found in moderate to high concentrations in all Acacia species. (Abdulrazak et al. (2000) Journal of Animal Sciences. 13:935-940). Historically, most of the plants and extracts of the Acacia genus have been utilized as astringents to treat gastrointestinal disorders, diarrhea, indigestion and to stop bleeding. (Vautrin (1996) Universite Bourgogne (France) European abstract 58-01C:177; Saleem et al. (1998) Hamdard Midicus. 41:63-67). The bark and pods of Acacia arabica Willd. contain large quantities of tannins and have been utilized as astringents and expectorants.
  • the extract from the bark of Acacia has been patented in Japan for external use as a whitening agent (Abe, JP10025238), as a glucosyl transferase inhibitor for dental applications (Abe, JP07242555), as a protein synthesis inhibitor (Fukai, JP 07165598), as an active oxygen scavenging agent for external skin preparations (Honda, JP 07017847, Bindra U.S. Pat. No. 6,1266,950), and as a hyaluronidase inhibitor for oral consumption to prevent inflammation, pollinosis and cough (Ogura, JP 07010768).
  • the present invention includes methods that are effective in simultaneously inhibiting both the cyclooxygenase (COX) and lipoxygenase (LOX) enzymes, for use in the prevention and treatment of diseases and conditions related to the skin.
  • the method for the simultaneous dual inhibition of the COX and LOX enzymes is comprised administering, preferably topically, a composition comprised of a mixture of Free-B-Ring flavonoids and flavans synthesized and/or isolated from a single plant or multiple plants to a host in need thereof.
  • This composition of matter is referred to herein as SoliprinTM.
  • SoliprinTM This composition of matter is referred to herein as SoliprinTM.
  • the efficacy of this method was demonstrated with purified enzymes, in different cell lines, in multiple animal models and eventually in a human clinical study.
  • the ratio of the Free-B-Ring flavonoids to flavans in the composition can be in the range of 99.9:0.1 of Free-B-Ring flavonoids:flavans to 0.1:99.9 Free-B-Ring flavonoids:flavans.
  • the ratio of Free-B-Ring flavonoids to flavans is selected from the group consisting of approximately 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80 and 10:90.
  • the ratio of Free-B-Ring flavonoids:flavans in the composition of matter is 80:20.
  • the Free-B-Ring flavonoids are isolated from a plant or plants in the Scutellaria genus of plants and the flavans are isolated from a plant or plants in the Acacia genus of plants.
  • the present invention also includes methods for the prevention and treatment of COX and LOX mediated diseases and conditions of the skin.
  • the method for preventing and treating COX and LOX mediated diseases and conditions of the skin is comprised of administering, preferably topically, to a host in need thereof an effective amount of a composition comprising a mixture of Free-B-Ring flavonoids and flavans synthesized and/or isolated from a single plant or multiple plants and a pharmaceutically acceptable carrier.
  • the ratio of the Free-B-Ring flavonoids to flavans in the composition can be in the range of 99.9:0.1 of Free-B-Ring flavonoids:flavans to 0.1:99.9 Free-B-Ring flavonoids:flavans.
  • Free-B-Ring flavonoids also referred to herein as Free-B-Ring flavones and flavonols, that can be used in accordance with the following invention include compounds illustrated by the following general structure:
  • R 1 , R 2 , R 3 , R 4, and R 5 are independently selected from the group consisting of —H, —OH, —SH, OR, —SR, —NH 2 , —NHR, —NR 2 , —NR 3 + X ⁇ , a carbon, oxygen, nitrogen or sulfur, glycoside of a single or a combination of multiple sugars including, but not limited to aldopentoses, methyl-aldopentose, aldohexoses, ketohexose and their chemical derivatives thereof;
  • R is selected from an alkyl group having between 1-10 carbon atoms
  • X is selected from the group of pharmaceutically acceptable counter anions including, but not limited to hydroxyl, chloride, iodide, sulfate, phosphate, acetate, fluoride, carbonate, etc.
  • the Free-B-Ring flavonoids of this invention may be obtained by synthetic methods or extracted from the family of plants including, but not limited to Annonaceae, Asteraceae, Bignoniaceae, Combretaceae, Compositae, Euphorbiaceae, Labiatae, Lauranceae, Leguminosae, Moraceae, Pinaceae, Pteridaceae, Sinopteridaceae, Ulmaceae and Zingiberacea .
  • the Free-B-Ring flavonoids can be extracted, concentrated, and purified from the following genus of high plants, including but not limited to Desmos, Achyrocline, Oroxylum, Buchenavia, Anaphalis, Cotula, Gnaphalium, Helichrysum, Centaurea, Eupatorium, Baccharis, Sapium, Scutellaria, Molsa, Colebrookea, Stachys, Origanum, Ziziphora, Lindera, Actinodaphne, Acacia, Derris, Glycyrrhiza, Millettia, Pongamia, Tephrosia, Artocarpus, Ficus, Pityrogramma, Notholaena, Pinus, Ulmus and Alpinia.
  • R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of H, —OH, —SH, —OCH 3 , —SCH 3 , —OR, —SR, —NH 2 , —NRH, —NR 2 , —NR 3 + X ⁇ , esters of the mentioned substitution groups, including, but not limited to, gallate, acetate, cinnamoyl and hydroxyl-cinnamoyl esters, trihydroxybenzoyl esters and caffeoyl esters; thereof carbon, oxygen, nitrogen or sulfur glycoside of a single or a combination of multiple sugars including, but not limited to, aldopentoses, methyl aldopentose, aldohexoses, ketohexose and their chemical derivatives thereof; dimer, trimer and other polymerized flavans;
  • R is selected from an alkyl group having between 1-10 carbon atoms
  • X is selected from the group of pharmaceutically acceptable counter anions including, but not limited to hydroxyl, chloride, iodide, sulfate, phosphate, acetate, fluoride, carbonate, etc.
  • the flavans of this invention may be obtained from a plant or plants selected from the genus of Acacia .
  • the plant is selected from the group consisting of Acacia catechu, Acacia concinna, Acacia farnesiana, Acacia Senegal, Acacia speciosa, Acacia arabica, A. caesia, A. pennata, A. sinuata. A. mearnsii, A. picnantha, A. dealbata, A. auriculiformis, A. holoserecia and A. mangium.
  • the present invention includes a method for preventing and treating a number of COX and LOX mediated diseases and conditions of the skin including, but not limited to sun burns, thermal burns, acne, topical wounds, minor inflammatory conditions caused by fungal, microbial and viral infections, vitilago, systemic lupus erythromatosus, psoriasis, carcinoma, melanoma, as well as other mammal skin cancers.
  • the present invention includes a method for preventing and treating skin damage resulting from exposure to ultraviolet (UV) radiation, chemicals, heat, wind and dry environments.
  • the present invention includes a method for preventing and treating wrinkles, saggy skin, lines and dark circles around the eyes, dermatitis and other allergy related conditions of the skin.
  • the present invention further includes therapeutic compositions comprising the therapeutic agents of the present invention.
  • the therapeutic compositions described herein can also be used to sooth sensitive skin and to provide smooth and youthful skin with improved elasticity, reduced and delayed aging, enhanced youthful appearance and texture, and increased flexibility, firmness, smoothness and suppleness.
  • the method of prevention and treatment according to this invention comprises administering topically to a host in need thereof a therapeutically effective amount of the formulated Free-B-Ring flavonoids and flavans isolated from a single source or multiple sources.
  • the purity of the individual and/or a mixture of multiple Free-B-Ring flavonoids and flavans includes, but is not limited to 0.01% to 100%, depending on the methodology used to obtain the compound(s).
  • the present invention includes an evaluation of different compositions of Free-B-Ring flavonoids and flavans using enzymatic and in vivo models to optimize the formulation and obtain the desired physiological activity. The efficacy and safety of this formulation is also demonstrated in human clinical studies.
  • the compositions of this invention can be administered by any method known to one of ordinary skill in the art.
  • the modes of administration include, but are not limited to, enteral (oral) administration, parenteral (intravenous, subcutaneous, and intramuscular) administration and topical application.
  • the method of treatment according to this invention comprises administering topically to a host in need thereof a therapeutically effective amount of a mixture of Free-B-Ring flavonoids and flavans synthesized and/or isolated from a single plant or multiple plants.
  • FIG. 1 depicts graphically a profile of the inhibition of COX-1 and COX-2 by a standardized Free-B-Ring flavonoid extract (83% baicalin based on HPLC) which was isolated from Scutellaria baicalensis .
  • the extract was examined for its inhibition of the peroxidase activity of recombinant ovine COX-1 ( ⁇ ) and ovine COX-2 ( ⁇ ).
  • the data is presented as percent inhibition vs. inhibitor concentration ( ⁇ g/mL).
  • the IC 50 for COX-1 was calculated as 0.24 ⁇ g/mL/unit of enzyme while the IC 50 for COX-2 was calculated as 0.48 ⁇ g/mL/unit.
  • FIG. 2 depicts graphically a profile of the inhibition of COX-1 and COX-2 by the purified component baicalin which was isolated from Scutellaria baicalensis .
  • the compound was examined for its inhibition of the peroxidase activity of recombinant ovine COX-1 ( ⁇ ) and ovine COX-2 ( ⁇ ). The data is presented as percent inhibition vs. inhibitor concentration ( ⁇ g/mL).
  • the IC 50 for COX-1 was determined to be 0.44 ⁇ g/mL/unit of enzyme and the IC 50 for COX-2 was determined to be 0.28 ⁇ g/mL/unit.
  • FIG. 3 depicts graphically a profile of the inhibition of COX-1 and COX-2 by the purified component baicalein isolated from Scutellaria baicalensis .
  • the compound was examined for its inhibition of the peroxidase activity of recombinant ovine COX-1 ( ⁇ ) and ovine COX-2 ( ⁇ ). The data is presented as percent inhibition vs. inhibitor concentration ( ⁇ g/mL).
  • the IC 50 for COX-1 was determined to be 0.18 ⁇ g/mL/unit of enzyme and the IC 50 for COX-2 was determined to be 0.28 ⁇ g/mL/unit.
  • FIG. 4 depicts graphically a profile of the inhibition of COX-1 and COX-2 by a standardized flavan extract containing 50% total flavans which was isolated from Acacia catechu .
  • the extract was examined for its inhibition of the peroxidase activity of recombinant ovine COX-1 ( ⁇ ) and ovine COX-2 ( ⁇ ).
  • the data is presented as percent inhibition vs. inhibitor concentration ( ⁇ g/mL).
  • the IC 50 for COX-1 was calculated as 0.17 ⁇ g/mL/unit of enzyme and the IC 50 for COX-2 was calculated as 0.41 ⁇ g/mL/unit.
  • FIG. 5 depicts graphically a profile of the inhibition of COX-1 and COX-2 by the a composition of matter comprised of greater than 90% flavans isolated from Acacia catechu .
  • the composition was examined for its inhibition of the peroxidase activity of recombinant ovine COX-1 ( ⁇ ) and ovine COX-2 ( ⁇ ). The data is presented as percent inhibition vs. inhibitor concentration ( ⁇ g/mL).
  • the IC 50 for COX-1 was calculated as 0.11 ⁇ g/mL/unit of enzyme and the IC 50 for COX-2 was calculated as 0.42 ⁇ g/mL/unit.
  • FIG. 6 depicts graphically a profile of the inhibition of COX-1 and COX-2 by a formulation produced by combining an extract of Free-B-Ring flavonoids isolated from the roots of Scutellaria baicalensis and an extract of flavans isolated from the bark of Acacia catechu in a ratio of 80:20.
  • This composition of matter referred to hereinafter as SoliprinTM, was examined for its inhibition of the peroxidase activity of recombinant ovine COX-1 ( ⁇ ) and ovine COX-2 ( ⁇ ). The data is presented as percent inhibition vs. inhibitor concentration ( ⁇ g/mL).
  • the IC 50 for COX-1 was calculated as 0.76 ⁇ g/mL/unit of enzyme and the IC 50 for COX-2 was calculated as 0.80 ⁇ g/mL/unit.
  • FIG. 7 depicts graphically a profile of the inhibition of COX-1 and COX-2 by a formulation produced by combining an extract of Free-B-Ring flavonoids isolated from the roots of Scutellaria baicalensis and an extract of flavans isolated from the bark of Acacia catechu in a ratio of about 50:50.
  • the composition, SoliprinTM was examined for its inhibition of the peroxidase activity of recombinant ovine COX-1 ( ⁇ ) and ovine COX-2 ( ⁇ ). The data is presented as percent inhibition vs. inhibitor concentration ( ⁇ g/mL).
  • the IC 50 for COX-1 was calculated as 0.38 ⁇ g/mL/unit of enzyme and the IC 50 for COX-2 was determined to be 0.84 ⁇ g/mL/unit.
  • FIG. 8 depicts graphically a profile of the inhibition of COX-1 and COX-2 by a formulation produced by combining an extract of Free-B-Ring flavonoids isolated from the roots of Scutellaria baicalensis and an extract of flavans isolated from the bark of Acacia catechu in a ratio of about 20:80.
  • the composition, SoliprinTM was examined for its inhibition of the peroxidase activity of recombinant ovine COX-1 ( ⁇ ) and ovine COX-2 ( ⁇ ). The data is presented as percent inhibition vs. inhibitor concentration ( ⁇ g/mL).
  • the IC 50 of this composition for COX-1 was 0.18 ⁇ g/mL/unit of enzyme and the IC 50 for COX-2 was 0.41 ⁇ g/mL/unit.
  • FIG. 9 depicts graphically a profile of the inhibition of 5-LO by the flavan extract from Acacia catechu .
  • the composition was examined for its inhibition of recombinant potato 5-lipoxygenase activity ( ⁇ ) as described in Example 4.
  • the data is presented as percent inhibition of assays without inhibitor.
  • the IC 50 for 5-LO was 1.38 ⁇ g/mL/unit of enzyme.
  • FIG. 10 illustrates the High Pressure Liquid Chromatography (HPLC) chromatogram of a typical formulation comprised of a mixture of Free-B-Ring flavonoids isolated from the roots of Scutellaria baicalensis and flavans isolated from the bark of Acacia catechu in a ratio of 80:20 carried out under the conditions as described in Example 9.
  • HPLC High Pressure Liquid Chromatography
  • FIG. 11 depicts graphically the effect of increasing concentrations of SoliprinTM on the amount of LPS-induced newly synthesized LTB 4 ( ⁇ ) as determined by ELISA in THP-1 or HT-29 cells (ATCC) as described in Example 10.
  • the SoliprinTM was produced through the combination of standardized extracts of Free-B-Ring flavonoids isolated from the roots of Scutellaria baicalensis and flavans isolated from the bark of Acacia catechu in a ratio of 80:20.
  • the activity of the SoliprinTM formulation is expressed as % inhibition of induced LTB 4 synthesis.
  • FIG. 12 compares the LTB 4 levels as determined by ELISA that remain in HT-29 cells after treatment with 3 ⁇ g/mL SoliprinTM in non-induced cells to treatment with 3 ⁇ g/mL ibuprofen as described in Example 10.
  • the SoliprinTM formulation demonstrated 80% inhibition of LTB4 production in the HT-29 cells after two days of treatment.
  • FIG. 13 illustrates graphically ear-swelling data as a measure of inhibition of inflammation as described in Example 11.
  • SoliprinTM produced through the combination of standardized extracts of Free-B-Ring flavonoids isolated from the roots of Scutellaria baicalensis and flavans isolated from the bark of Acacia catechu in a ratio of 80:20 was compared to untreated mice and mice given indomethacin (1.5 ⁇ g/kg) via oral gavage. The data is presented as the difference in micron measurement of the untreated vs. the treated ear lobe for each mouse.
  • FIG. 14 illustrates graphically the effect of 100 ⁇ g/kg of SoliprinTM, produced through the combination of standardized extracts of Free-B-Ring flavonoids isolated from the roots of Scutellaria baicalensis and flavans isolated from the bark of Acacia catechu in a ratio of 80:20 on the AA injected ankles of mice (SoliprinTM+arachidonic acid) compared to non-treated mice (no treatment+arachidonic acid), mice without AA injections (negative control) or mice that were injected with the liquid carrier (vehicle control).
  • FIG. 15 depicts graphically the changes in hairless mice skin erythema scores in different treatment groups as a function of time following irradiation of the mice with UV light as described in Example 12.
  • the mice in Groups B-1, A-1, B-2 and A-2 were treated with SoliprinTM either before (Groups B-1 and B-2) or after (A-1 and A-2) irradiation.
  • the SoliprinTM was produced through the combination of standardized extracts of Free-B-Ring flavonoids isolated from the roots of Scutellaria baicalensis and flavans isolated from the bark of Acacia catechu in a ratio of 80:20.
  • FIG. 15 it can be seen that topical applications of SoliprinTM, both before and after UV radiation, significantly reduced erythema scores as compared with the control group and the group that was administered the standard treatment agent-Sooth-a-caine.
  • a or “an” entity refers to one or more of that entity; for example, a flavonoid refers to one or more flavonoids.
  • a flavonoid refers to one or more flavonoids.
  • the terms “a” or “an”, “one or more” and “at least one” are used interchangeably herein.
  • Free-B-Ring Flavonoids as used herein are a specific class of flavonoids, which have no substitute groups on the aromatic B-ring, as illustrated by the following general structure:
  • R 1 , R 2 , R 3 , R4, and R 5 are independently selected from the group consisting of —H, —OH, —SH, OR, —SR, —NH 2 , —NHR, —NR 2 , —NR 3 + X ⁇ , a carbon, oxygen, nitrogen or sulfur, glycoside of a single or a combination of multiple sugars including, but not limited to aldopentoses, methyl-aldopentose, aldohexoses, ketohexose and their chemical derivatives thereof;
  • R is an alkyl group having between 1-10 carbon atoms
  • X is selected from the group of pharmaceutically acceptable counter anions including, but not limited to hydroxyl, chloride, iodide, sulfate, phosphate, acetate, fluoride, carbonate, etc.
  • Flavonoids as used herein refer to a specific class of flavonoids, which can be generally represented by the following general structure:
  • R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of H, —OH,
  • esters of substitution groups including, but not limited to, gallate, acetate, cinnamoyl and hydroxyl-cinnamoyl esters, trihydroxybenzoyl esters and caffeoyl esters and their chemical derivatives thereof; carbon, oxygen, nitrogen or sulfur glycoside of a single or a combination of multiple sugars including, but not limited to, aldopentoses, methyl aldopentose, aldohexoses, ketohexose and their chemical derivatives thereof; dimer, trimer and other polymerized flavans;
  • R is an alkyl group having between 1-10 carbon atoms
  • X is selected from the group of pharmaceutically acceptable counter anions including, but not limited to hydroxyl, chloride, iodide, sulfate, phosphate, acetate, fluoride, carbonate, etc.
  • “Therapeutic” as used herein, includes treatment and/or prophylaxis. When used, therapeutic refers to humans as well as other animals.
  • “Pharmaceutically or therapeutically effective dose or amount” refers to a dosage level sufficient to induce a desired biological result. That result may be the alleviation of the signs, symptoms or causes of a disease or any other alteration of a biological system that is desired.
  • “Placebo” refers to the substitution of the pharmaceutically or therapeutically effective dose or amount dose sufficient to induce a desired biological that may alleviate the signs, symptoms or causes of a disease with a non-active substance.
  • a “host” or “patient” is a living subject, human or animal, into which the compositions described herein are administered.
  • the invention described herein may be used for veterinary as well as human applications and the terms “patient” or “host” should not be construed in a limiting manner.
  • the dosage ranges can be determined as described below, taking into account the body weight of the animal.
  • the current invention provides methods for the extraction (Example 1, Table 1) of plants that contain Free-B-Ring flavonoids and flavans with organic and aqueous solvents.
  • the crude extracts were assayed for cyclooxygenase inhibitory activity (Example 2, Tables 2 and 3).
  • Purified Free-B-Ring flavonoids and flavans demonstrated inhibitory activity against cyclooxygenase (COX) and lipoxygenase (LOX), respectively, as shown in Examples 3 and 4.
  • Methods for analyzing and quantifying the extracts are described in Examples 5 and 6 and the procedures to generate standardized Free-B-Ring flavonoids and flavans from botanical origins are provided in Examples 7 and 8.
  • the standardized Free-B-Ring flavonoid extract is comprised of the active compounds having a purity of between 1-99% (by weight) of total Free-B-Ring flavonoids as defined in Examples 1, 2, 5 and 8.
  • Baicalin is the major active component in the extract, which accounts for approximately 50-90% (by weight) of the total Free-B-Ring flavonoids.
  • the standardized extract contains >70% total Free-B-Ring flavonoids in which >75% of the Free-B-Ring flavonoids is baicalin.
  • the standardized flavan extract is comprised of the active compounds having a purity of between 1-99% (by weight) total flavans as defined in Examples 1, 4, 6 and 7. Catechin is the major active component in the extract and accounts for 50-95% (by weight) of the total flavans.
  • the standardized flavan extract contains >80% total flavans in which >70% of flavans is catechin.
  • SoliprinTM is produced by mixing the above two extracts or synthetic compounds in a ratio from 99:1 to 1:99.
  • the preferred ratios of Free-B-Ring flavonoids to flavans are 80:20 as defined in Example 9 and Table 10 and 15:85 as defined in Example 9.
  • the concentration of Free-B-Ring flavonoids in SoliprinTM can be from about 1% to 99% and the concentration of flavans in SoliprinTM can be from 99% to 1%.
  • the concentration of total Free-B-Ring flavonoids in SoliprinTM is approximately 20% with a baicalin content of approximately 15% of total weight of the SoliprinTM; and the concentration of total flavans in SoliprinTM is approximately 75% with a catechin content of approximately 70%.
  • the total active components (Free-B-Ring flavonoids plus flavans) in SoliprinTM are >90% of the total weight.
  • the present invention includes methods that are effective in simultaneously inhibiting both the cyclooxygenase (COX) and lipoxygenase (LOX) enzymes, for use in the prevention and treatment of diseases and conditions related to the skin.
  • the method for the simultaneous dual inhibition of the COX and LOX enzymes is comprised of administering, preferably topically a composition comprised of a mixture of Free-B-Ring flavonoids and flavans synthesized and/or isolated from a single plant or multiple plants to a host in need thereof.
  • This composition of matter is referred to herein as SoliprinTM.
  • the efficacy of this method was demonstrated with purified enzymes, in different cell lines, in multiple animal models and eventually in a human clinical study.
  • the present invention also includes methods for the prevention and treatment of COX and LOX mediated diseases and conditions of the skin.
  • the method for preventing and treating COX and LOX mediated diseases and conditions of the skin is comprised of administering, preferably topically, to a host in need thereof an effective amount of a composition comprised of a mixture of Free-B-Ring flavonoids and flavans synthesized and/or isolated from a single plant or multiple plants and a pharmaceutically acceptable carrier.
  • the ratio of the Free-B-Ring flavonoids to flavans in the composition can be in the range of 99.9:0.1 of Free-B-Ring flavonoids:flavans to 0.1:99.9 Free-B-Ring flavonoids:flavans.
  • the ratio of Free-B-ring flavonoids to flavans is selected from the group consisting of approximately 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80 and 10:90.
  • the ratio of Free-B-Ring flavonoids:flavans in the composition of matter is 20:80.
  • the Free-B-Ring flavonoids are isolated from a plant or plants in the Scutellaria genus of plants and the flavans are isolated from a plant or plants in the Acacia genus of plants.
  • the present invention includes a method for preventing and treating a number of COX and LOX mediated diseases and conditions of the skin including, but not limited to sun burns, thermal burns, acne, topical wounds, minor inflammatory conditions caused by fungal, microbial and viral infections, vitilago, systemic lupus erythromatosus, psoriasis, carcinoma, melanoma, as well as other mammal skin cancers.
  • the present invention includes a method for preventing and treating skin damage resulting from exposure to UV radiation, chemicals, heat, wind and dry environments.
  • the present invention includes a method for preventing and treating wrinkles, saggy skin, lines and dark circles around the eyes, dermatitis and other allergy related conditions of the skin.
  • the present invention further includes therapeutic compositions comprising the therapeutic agents of the present invention.
  • the therapeutic compositions described herein can be used to sooth sensitive skin and to provide smooth and youthful skin with improved elasticity, reduced and delayed aging, enhanced youthful appearance and texture, and increased flexibility, firmness, smoothness and suppleness.
  • the Free-B-Ring flavonoids that can be used in accordance with the instant invention include compounds illustrated by the general structure set forth above.
  • the Free-B-Ring flavonoids of this invention may be obtained by synthetic methods or may be isolated from the family of plants including, but not limited to Annonaceae, Asteraceae, Bignoniaceae, Combretaceae, Compositae, Euphorbiaceae, Labiatae, Lauranceae, Leguminosae, Moraceae, Pinaceae, Pteridaceae, Sinopteridaceae, Ulmaceae , and Zingiberacea .
  • the Free-B-Ring flavonoids can be extracted, concentrated, and purified from the following genus of high plants, including but not limited to Desmos, Achyrocline, Oroxylum, Buchenavia, Anaphalis, Cotula, Gnaphalium, Helichrysum, Centaurea, Eupatorium, Baccharis, Sapium, Scutellaria, Molsa, Colebrookea, Stachys, Origanum, Ziziphora, Lindera, Actinodaphne, Acacia, Derris, Glycyrrhiza, Millettia, Pongamia, Tephrosia, Artocarpus, Ficus, Pityrogramma, Notholaena, Pinus, Ulmus and Alpinia.
  • the flavans can be found in different parts of plants, including but not limited to stems, stem barks, trunks, trunk barks, twigs, tubers, roots, root barks, young shoots, seeds, rhizomes, flowers and other reproductive organs, leaves and other aerial parts. Methods for the isolation and purification of flavans are described in U.S. application Ser. No. 10/104,477, filed Mar. 22, 2002, entitled “Isolation of a Dual Cox-2 and 5-Lipoxygenase Inhibitor from Acacia ,” which is incorporated herein by reference in its entirety.
  • the biochemical assay used to measure inhibition of COX, relies on the protein's peroxidase activity in the presence of heme and arachidonic acid.
  • This study which is described in Example 3, showed that the purified Free-B-Ring flavonoids, baicalin and baicalein isolated from Scutellaria baicalensis and the flavan extract isolated from Acacia catechu , and each individual standardized extract containing high concentrations of Free-B-Ring flavonoids and flavans inhibited COX activity (FIGS. 1-5).
  • compositions having different ratios of each of the individual standardized extracts i.e., 80:20, 50:50 and 20:80 Free-B-Ring flavonoids:flavans
  • were all highly effective at inhibiting the COX activity in vitro (FIGS. 6-8).
  • the inhibition of LOX activity by a flavan extract isolated from Acacia catechu was assessed using a lipoxygenase screening assay in vitro as described in Example 4. The results are illustrated in FIG. 9.
  • cell assays that targeted inhibition of compounds in the breakdown of arachidonic acid in the LOX pathway, namely leukotriene B4 were performed using a SoliprinTM sample as described in Example 10.
  • the LTB 4 inhibition results by SoliprinTM are illustrated in FIGS. 11 and 12.
  • the erythema scores of the hairless mice from four SoliprinTM groups in both concentrations and regardless the applications time as before or after UV exposure, all showed much less redness in smaller skin areas as compared to severe and extended erythema in both the control group and the group that was treated with Sooth-A Cain.
  • Example 13 (Tables 11 and 12) describes a general method for the preparation of a SoliprinTM cream using pharmacologically, dermatologically and cosmetic acceptable excipients. For purposes of illustration this Example provides a detailed procedure for the preparation of both a 0.5 wt % and 1.5 wt % SoliprinTM cream. Finally, both of the SoliprinTM creams prepared as described in Example 13 were evaluated on human skin for potential irritation and induction of contact sensitization. A total of 97 and 101 subjects completed induction and challenge with the 0.5% and 1.5% SoliprinTM creams, respectively. Test results show that SoliprinTM creams at 0.5% and 1.5% concentration produced minimal irritation and did not elicit evidence of induced contact sensitization.
  • the present invention includes methods that are effective in simultaneously inhibiting both the COX and LOX enzymes.
  • the method for the simultaneous dual inhibition of the COX and LOX pathways is comprised of administering a composition comprising a mixture of Free-B-Ring flavonoids and flavans synthesized and/or isolated from a single plant or multiple plants to a host in need thereof.
  • the ratio of Free-B-Ring flavonoids to flavans in the composition can be in the range of 99:1 Free-B-Ring flavonoids:flavans to 1:99 of Free-B-Ring flavonoids:flavans.
  • the ratio of Free-B-Ring flavonoids to flavans is selected from the group consisting of approximately 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70,-20:80 and 10:90.
  • the ratio of Free-B-Ring flavonoids:flavans in the composition of matter is approximately 20:80.
  • the Free-B-Ring flavonoids are isolated from a plant or plants in the Scutellaria genus of plants and flavans are isolated from a plant or plants in the Acacia genus of plants.
  • the present further includes methods for the prevention and treatment of COX and LOX mediated skin diseases and conditions.
  • the method for preventing and treating COX and LOX mediated skin diseases and conditions is comprised of administering to a host in need thereof an effective amount of a composition comprising a mixture of Free-B-Ring flavonoids and flavans synthesized and/or isolated from a single plant or multiple plants together with a pharmaceutically acceptable carrier.
  • the ratio of Free-B-Ring flavonoids to flavans can be in the range of 99:1 Free-B-Ring flavonoids:flavans to 1:99 of Free-B-Ring flavonoids:flavans.
  • the present invention further includes therapeutic compositions comprising the therapeutic agents of the present invention including various formulations thereof. Methods for the preparation of these compositions, together with methods for the determination of their purity and specific composition are described in Examples 5-9 and FIG. 10.
  • doses of the mixture of Free-B-Ring flavonoids and/or flavans containing that same are an efficacious, nontoxic quantity generally selected from the range of 0.001% to 100% based on total weight of the topical formulation. Persons skilled in the art using routine clinical testing are able to determine optimum doses for the particular ailment being treated.
  • the composition can also include an adjuvant or a carrier.
  • adjuvants are typically substances that generally enhance the biological response of a mammal to a specific bioactive agent. Suitable adjuvants include, but are not limited to, Freund's adjuvant; other bacterial cell wall components; aluminum-based salts; calcium-based salts; silica; polynucleotides; toxoids; serum proteins; viral coat proteins; other bacterial-derived preparations; gamma interferon; block copolymer adjuvants, such as Hunter's Titermax adjuvant (Vaxcel.TM., Inc.
  • Carriers are typically compounds that increase the half-life of a therapeutic composition in the treated host. Suitable carriers include, but are not limited to, polymeric controlled release formulations, biodegradable implants, liposomes, bacteria, viruses, oils, esters, and glycols.
  • the composition is prepared as a controlled release formulation, which slowly releases the composition of the present invention into the host.
  • a controlled release formulation comprises a composition of the present invention in a controlled release vehicle.
  • Suitable controlled release vehicles will be known to those skilled in the art.
  • Preferred controlled release formulations are biodegradable (i.e., bioerodible).
  • the therapeutic agents of the instant invention are preferably administered topically by any suitable means, known to those of skill in the art for topically administering therapeutic compositions including, but not limited to as an ointment, gel, lotion, or cream base or as an emulsion, as a patch, dressing or mask, a nonsticking gauze, a bandage, a swab or a cloth wipe.
  • Such topical application can be locally administered to any affected area, using any standard means known for topical administration.
  • a therapeutic composition can be administered in a variety of unit dosage forms depending upon the method of administration.
  • a therapeutic composition of the present invention can be formulated in an excipient of the present invention.
  • a therapeutic reagent of the present invention can be administered to any host, preferably to mammals, and more preferably to humans. The particular mode of administration will depend on the condition to be treated.
  • a suitable ointment is comprised of the desired concentration of the mixture of Free-B-Ring flavonoids and flavans, that is an efficacious, nontoxic quantity generally selected from the range of 0.001% to 100% based on total weight of the topical formulation, from 65 to 100% (preferably 75 to 96%) of white soft paraffin, from 0 to 15% of liquid paraffin, and from 0 to 7% (preferably 3 to 7%) of lanolin or a derivative of synthetic equivalent thereof.
  • the ointment may comprise a polyethylene—liquid paraffin matrix.
  • a suitable cream is comprised of an emulsifying system together with the desired concentration of the mixture of Free-B-Ring flavonoids and flavans as provided above.
  • the emulsifying system is preferably comprised of from 2 to 10% of polyoxyethylene alcohols (e.g.
  • Example 13 describes the formulation of two different concentrations of the composition of this invention as a cream and Example 14 describes a study undertaken to evaluate the cream for irritation and sensitization of the skin. From this study it was determined that SoliprinTM is a safe composition that can be applied topically at an efficacious concentration without causing irritation or sensitization of the skin.
  • a suitable gel is comprised of a semi-solid system in which a liquid phase is constrained within a three dimensional polymeric matrix with a high degree of cross-linking.
  • the liquid phase may be comprised of water, together with the desired amount of the mixture of Free-B-Ring flavonoids and flavans, from 0 to 20% of water-miscible additives, for example glycerol, polyethylene glycol, or propylene glycol, and from 0.1 to 10%, preferably from 0.5 to 2%, of a thickening agent, which may be a natural product, for example tragacanth, pectin, carrageen, agar and alginic acid, or a synthetic or semi-synthetic compound, for example methylcellulose and carboxypolymethylene (carbopol); together with one or more preservatives, for example from 0.1 to 2% of methyl 4-hydroxybenzoate (methyl paraben) or phenoxyethanol-differential.
  • Another suitable base is comprised of the desired amount of the mixture of Free-B-Ring flavonoids and flavans, together with from 70 to 90% of polyethylene glycol (for example, polyethylene glycol ointment containing 40% of polyethylene glycol 3350 and 60% of polyethylene glycol 400, prepared in accordance with the U.S. National Formulary (USNF)), from 5 to 20% of water, from 0.02 to 0.25% of an anti-oxidant (for example butylated hydroxytoluene), and from 0.005 to 0.1% of a chelating agent (for example ethylenediamine tetraacetic acid (EDTA)).
  • polyethylene glycol for example, polyethylene glycol ointment containing 40% of polyethylene glycol 3350 and 60% of polyethylene glycol 400, prepared in accordance with the U.S. National Formulary (USNF)
  • an anti-oxidant for example butylated hydroxytoluene
  • a chelating agent for example ethylenediamine tetraacetic
  • soft paraffin as used above encompasses the cream or ointment bases white soft paraffin and yellow soft paraffin.
  • lanolin encompasses native wool fat and purified wool fat. Derivatives of lanolin include in particular lanolins which have been chemically modified in order to alter their physical or chemical properties and synthetic equivalents of lanolin include in particular synthetic or semisynthetic compounds and mixtures which are known and used in the pharmaceutical and cosmetic arts as alternatives to lanolin and may, for example, be referred to as lanolin substitutes.
  • compositions of the invention may be produced by conventional pharmaceutical techniques.
  • the aforementioned compositions may conveniently be prepared by mixing together at an elevated temperature, preferably 60-70° C., the soft paraffin, liquid paraffin if present, and lanolin or derivative or synthetic equivalent thereof.
  • the mixture may then be cooled to room temperature, and, after addition of the hydrated crystalline calcium salt of mupirocin, together with the corticosteroid and any other ingredients, stirred to ensure adequate dispersion.
  • the specific dose is calculated according to the approximate body weight of the host. Further refinement of the calculations necessary to determine the appropriate dosage for treatment involving each of the above mentioned formulations is routinely made by those of ordinary skill in the art and is within the scope of tasks routinely performed by them without undue experimentation, especially in light of the dosage information and assays disclosed herein. These dosages may be ascertained through use of the established assays for determining dosages utilized in conjunction with appropriate dose-response data.
  • compositions of this invention can be administered by any method known to one of ordinary skill in the art.
  • the modes of administration include, but are not limited to, enteral (oral) administration, parenteral (intravenous, subcutaneous, and intramuscular) administration and topical application.
  • the method of treatment according to this invention comprises administering internally or topically to a patient in need thereof a therapeutically effective amount of a mixture of Free-B-Ring flavonoids and flavans synthesized and/or isolated from a single plant or multiple plants.
  • the composition is administered topically.
  • bioassay directed screening process for the identification of specific COX-2 inhibitors was designed to assay the peroxidase activity of the enzyme as described below.
  • Peroxidase Assay The assay to detect inhibitors of COX-2 was modified for a high throughput platform (Raz). Briefly, recombinant ovine COX-2 (Cayman) in peroxidase buffer (100 mM TBS, 5 mM EDTA, 1 ⁇ M Heme, 1 mg epinephrine, 0.094% phenol) was incubated with extract (1:500 dilution) for 15 minutes. Quantablu (Pierce) substrate was added and allowed to develop for 45 minutes at 25° C. Luminescence was then read using a Wallac Victor 2 plate reader. The results are presented in Table 2.
  • Table 2 sets forth the inhibition of enzyme by the organic and aqueous extracts obtained from five plant species, including the bark of Acacia catechu , roots of two Scutellaria species and extracts from three other plant species, which are comprised of structurally similar Free-B-Ring flavonoids. Data is presented as the percent of peroxidase activity relative to the recombinant ovine COX-2 enzyme and substrate alone. The percent inhibition by the organic extract ranged from 30% to 90%.
  • IC 50 is defined as the concentration at which 50% inhibition of enzyme activity in relation to the control is achieved by a particular inhibitor. In these experiments, IC 50 values were found to range from 6 to 50 ⁇ g/mL and 7 to 80 ⁇ g/mL for the COX-2 and COX-1 enzymes, respectively, as set forth in Table 3. Comparison of the IC 50 values of COX-2 and COX-1 demonstrates the specificity of the organic extracts from various plants for each of these enzymes.
  • the organic extract of Scutellaria lateriflora shows preferential inhibition of COX-2 over COX-1 with IC 50 values of 30 and 80 ⁇ g/mL, respectively. While some extracts demonstrate preferential inhibition of COX-2, others do not. Examination of the HTP fractions and purified compounds from these fractions is necessary to determine the true specificity of inhibition for these extracts and compounds.
  • Each inhibitor taken from a 10 mg/mL stock solution in 100% DMSO, was tested in triplicate at room temperature using the following range of concentrations: 0, 0.1, 1, 5, 10, 20, 50, 100, and 500 ⁇ g/mL.
  • 150 ⁇ L of 100 mM Tris-HCl, pH 7.5 was added along with 10 ⁇ L of 22 ⁇ M Hematin diluted in tris buffer, 10 ⁇ L of inhibitor diluted in DMSO and 25 units of either the COX-1 or COX-2 enzyme.
  • the components were mixed for 10 seconds on a rotating platform, followed by the addition of 20 ⁇ L of 2 mM N,N,N′N′-tetramethyl-p-phenylenediamine dihydrochloride (TMPD) and 20 ⁇ L of 1.1 mM arachidonic acid to initiate the reaction.
  • TMPD N,N,N′N′-tetramethyl-p-phenylenediamine dihydrochloride
  • TMPD N,N,N′N′-tetramethyl-p-phenylenediamine dihydrochloride
  • arachidonic acid 20 ⁇ L of 1.1 mM arachidonic acid
  • FIGS. 1, 2 and 3 The dose responses and IC 50 values for a standardized Free-B-Ring flavonoid extract, baicalin, and baicalein isolated from the roots of Scutellaria baicalensis are provided in FIGS. 1, 2 and 3 , respectively.
  • the dose responses and IC 50 values for two standardized flavan extract (50% and >90% flavans, respectively) isolated from the heartwood of Acacia catechu are provided in FIGS. 4 and 5, respectively.
  • FIGS. 4 and 5 The dose responses and IC 50 values for three formulations of Free-B-Ring flavonoids and flavans of varying composition are provided in FIG. 6 (80:20 blending), FIG. 7 (50:50 blending) and FIG. 8 (20:80 blending), respectively.
  • catechu containing >90% flavans directly inhibited LOX in vitro The 15-LO from soybeans normally used in the kit was replaced with potato LOX, after a buffer change from phosphate to a tris -based buffer using microfiltration was performed.
  • This assay detects the formation of hydroperoxides through an oxygen sensing chromagen. Briefly, the assay was performed in triplicate by adding 90 ⁇ L of 0.17 units/ ⁇ L potato 5-LO, 20 ⁇ L of 1.1 mM AA, 100 ⁇ L of oxygen-sensing chromagen and 10 ⁇ L of purified flavan inhibitor to final concentrations ranging from 0 to 500 ⁇ g/mL.
  • the IC 50 for 5-LO inhibition from this composition was determined to be 1.38 ⁇ g/mL/unit of enzyme. The results are set forth in FIG. 9.
  • mice were scored on level of erythema (redness) using the following scale: 0—no visible erythema; 1—very slight erythema; 2—well defined erythema; 3—severe erythema; and 4—tumor formation. Erythema was scored by eye for each group. The results are set forth in FIG. 15. With reference to FIG. 15 it can be seen that the control group (Group 1) had severe redness on day 3 (72 hours after the three day exposure to UV radiation). The Sooth-a-caine group also had maximum redness on day 3 (Group 2). The redness for the SoliprinTM treated groups (Groups 3-6) never exceeded a score of 2. These scores, though subjective, show that SoliprinTM is effective in both preventing and treating UV caused skin erythema.
  • Photographs of representative mice on day four clearly demonstrate differences between the control group, the Sooth-a-cainTM treated groups and the SoliprinTM treated groups (data not shown).
  • the control group and Sooth-a-cainTM treated animals exhibited very extensive patterns and redness of erythema compared to the animals treated with the SoliprinTM formulation both before and after UV exposure.
  • the animals treated before UV irradiation with 5 mg/mL SoliprinTM exhibited the least amount of erythema as compared to all of the other animals.
  • SoliprinTM (Lot #A1904) was dissolved in water at room temperature and homogenized with a blender until it was fully dispersed in solution (approximately 5 minutes). At room temperature and without stirring or agitating the solution, Ultrez-21 carbomer was added by sprinkling onto the surface of the solution and allowing it to fully wet (no white areas visible) and fall into the solution. With gentle stirring, the solution was then heated to 40° C. and glycerin was added (Part A). The mixture was then stirred for an additional 5 minutes. The remaining components (Part B) were weighed and heated to 40° C. while mixing.
  • Part B the remaining components
  • Part A the remaining components
  • Part B the remaining components
  • the emulsion was cooled to 30° C. and the pH was adjusted to approximately 5.5 (5.3 to 5.7) by titrating with neutralizer while stirring with a stir bar and/or spatula.
  • the emulsion became highly viscous due to neutralization-induced conformational change of the carbomer.
  • the emulsion eventually achieved a suitable viscosity for an emulsion cream.
  • the emulsion cream was then mixed until uniform after which it was poured into a clean storage vessel and stored at 2° to 8° C. for one month.
  • the SoliprinTM was tested on human skin using an adaptation of the Draize Patch Test (Marzulli and Maibach (1977) Contact Allergy: Predictive Testing in Humans. In Advances in Modem Toxicology, Dermatotoxicology and Pharmacology. Eds. Marzulli, F. N and Maibach, H. I. 4, 353-372).
  • the test sites were located on the upper arm or the paraspinal region of the back.
  • Each test article had an induction site and a challenge site.
  • the induction site was comprised of two sub-sites: an original-site and a move-site.
  • Patches which contains 0.2 ml of Soliprin cream on each patch, were applied repeatedly to the original-site unless a sufficiently strong irritation reaction developed, requiring the patch to be applied to the move-site. Patches were applied by a clinical research institute and were removed and discarded by the subjects approximately 24 or 48/72 hours later.
  • repetitive application of the test article to the same site on the skin and a total of 9 induction patches were applied within a 4-week period. The rest period was 10 to 21 days between application of the last induction patch and application of the challenge patch. During this time no test article or any other material was applied to the test area.
  • the test article was applied to a naive site on the opposite side of the body and discarded by the subjects approximately 24 or 48 hours later.
  • SoliprinTM is a safe ingredient that can be applied topically to human skin at an efficacious concentration without causing irritation or sensitization.

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