(12) United States Patent (10) Patent No.: US 7,615,546 B2 Gupta (45) Date of Patent: Nov
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USOO761.5546B2 (12) United States Patent (10) Patent No.: US 7,615,546 B2 Gupta (45) Date of Patent: Nov. 10, 2009 (54) TOPICAL DELIVERY SYSTEM FOR 6,407,085 B1* 6/2002 Kief ........................... 514, 182 PHYTOSTEROLS * cited by examiner (75) Inventor: Shyam K Gupta, Scottsdale, AZ (US) Primary Examiner Shaojia Anna Jiang Assistant Examiner Eric S Olson (73) Assignee: BioDerm Research, Scottsdale, AZ (US) (57) ABSTRACT (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 This invention relates to certain Sugaresters of phytosterols of U.S.C. 154(b) by 0 days. formula (I). These esters are useful for topical application, and for the treatment of skin condition, including age spots, (21) Appl. No.: 12/210,266 acne, loss of cellular antioxidants, collagen loss, loss of skin pliability, loss of skin Suppleness, skin wrinkles including (22) Filed: Sep.15, 2008 fine lines, oxidation, damage from radiation, malfunction of matrix metalloproteases, malfunction of tyrosinases, damage (65) Prior Publication Data from free radicals, damage from UV, dry skin, Xerosis, ich US 2009/0042846A1 Feb. 12, 2009 thyosis, dandruff, brownish spots, keratoses, melasma, len tigines, liver spots, pigmented spots, dark circles under the Related U.S. Application Data eyes, skin pigmentation including darkened skin, blemishes, (63) Continuation-in-part of application No. 1 1/161,856, oily skin, warts, eczema, pruritic skin, psoriasis, inflamma filed on Aug. 19, 2005, now abandoned, and a continu tory dermatoses, topical inflammation, disturbed keratiniza ation-in-part of application No. 12/139,659, filed on tion, skin changes associated with aging, nail or skin requir ing cleansers, conditioning or treatment, and hair or scalp Jun. 16, 2008. requiring shampooing or conditioning, and combinations (51) Int. Cl. thereof; A6 IK3I/58 (2006.01) A 6LX 3/575 (2006.01) A63L/23 (2006.01) (I) A6 IK 3L/22 (2006.01) CO7I 53/00 (2006.01) C07J 9/00 (2006.01) C07C 69/017 (2006.01) (52) U.S. Cl. ....................... 514/172: 514/173; 514/546; 514/552; 552/510:552/514: 552/544: 552/547: Wherein, 56Of 129 n=0, 1, 2, or 3; and (58) Field of Classification Search ....................... None R=H, CH-OH, CH(OH) CH-OH, -CH(OH) CH See application file for complete search history. (OH) CH-OH; and (56) References Cited R'=Substituent selected from a sapogenin, steroid, or ter penoid. U.S. PATENT DOCUMENTS 5,733,572 A * 3/1998 Unger et al. ................ 424/450 17 Claims, 9 Drawing Sheets U.S. Patent Nov. 10, 2009 Sheet 1 of 9 US 7.615,546 B2 O OH R n R N O OH OH Sugar Ester of a Polycyclic Polyisoprenoid Wherein, n = 0, 1, 2, or 3, and R = H, -CHOH, -CH(OH)-CHOH, -CH(OH)-CH(OH)-CHOH, and R = Substituent selected from a Sapogenin, steroid, or triterpenoid Steroid HC CH HC Triterpenoid Sapogenin 1 Ergosterol HC HC CH CH Lanosterol Diosgenin HC Cholesterol Cycloartenol CH HC Solanogenin COOH Sitosterol Betulinic Acid HC CH Fig. 1. Sugar Esters of Polycyclic Polyisoprenoids U.S. Patent Nov. 10, 2009 Sheet 2 of 9 US 7.615,546 B2 H3C CH3 Fig. 2. Polycyclic Polyisoprenoid Substituents in Fig 1. U.S. Patent Nov. 10, 2009 Sheet 3 of 9 US 7.615,546 B2 HO (XIX). Fig. 3. Additional Polycyclic Polyisoprenoid Substituents in Fig 1. U.S. Patent Nov. 10, 2009 Sheet 4 of 9 US 7.615,546 B2 Steroid Gluconates CH OH OH O HO S apogeninin GluconatesGl OH, OH O Triterpenoid Gluconates HC o CH3 Ergosterol Gluconate (XXI) CH3 HC Hac-\ O CH CH O OH CH 3 O OH, OH OH OH O HC O Diosgenin Gluconate (XX) OH, OH 3 OH, OH CH 3 CH3 OH OH O re-ell O (XXIV) OH, OH Cholesterol Gluconate CH3 H3C HC CH3 OH, OH (XXIII) 's- OH OH, OH Solanogenin Gluconate (XXVI) Cycloartenol Gluconate OH OH O HO O OH OH HOOC Sitosterol Gluconate (XXV) CH3 O OH OH CH O 2- OH OH OH HC CH Betulinic Acid Gluconate (XXVII) Fig. 4. Gluconate Esters of Sapogenins, Steroids, and Triterpenoids U.S. Patent Nov. 10, 2009 Sheet 5 Of 9 US 7.615,546 B2 OH OH O re O OH OH (XXVIII) HC Divergioic Acid Gluconate 3 (XXXI) Hc Tormetic Acid Gluconate HOOC CH3 ch, Boswellic Acid Gluconate (XXXV) Moronic Acid Gluconate (XXXVI) Ruscogenin Gluconate (XXXVII) HO Fig. 5. Gluconate Esters of Polycyclic Triterpenoids U.S. Patent Nov. 10, 2009 Sheet 6 of 9 US 7.615,546 B2 HC 3 o CH3 HC N-Yo CH3 HC HC 3 O CH3 O O CH3 H O OH OH OHO -- O 50-120' O All ) OH OH Phytosterol (Diosgenin) HO OH (XX) OH Phytosterol Sugar Ester (Diosgenin Gluconate) Sugar Lactone (Gluconolactone) Fig. 6. Process of Phytosterol Sugar Esters from A Phytosterol (Diosgenin) & A Natural Sugar Lactone (Gluconolactone) U.S. Patent Nov. 10, 2009 Sheet 7 Of 9 US 7.615,546 B2 Guggul Sterols Gluconolactone H Y-CH3 O CH CH CH3 C All OH CH O11 Z-Guggul Sterol Gluconate CHf O OH OH CH OH O OH OH E-Guggul Sterol Gluconate Guggul Sterol III Gluconate CH CH3 3 O OH OH CH - No ----orr T 1. OH OH Guggul Sterol IV Gluconate Fig. 7. Guggul Sterols Gluconates & somers U.S. Patent Nov. 10, 2009 Sheet 8 of 9 US 7.615,546 B2 Forskohlin Gluconates Garcinol Gluconates R, R2 = OH; and/or to-illOH OH O OH OH Fig. 8 Polyisoprenoid Gluconates U.S. Patent Nov. 10, 2009 Sheet 9 Of 9 US 7.615,546 B2 HC R CH3 CH3 CH3 HC OH OH O HO O OH OH Campesterol Gluconate : R = CH A. Campestanol: R = CH Sitosterol: R = -CHCH. A Stigmastanol: R = -CHCH Stigmasterol: R = -CHCH A5, 22 Fig. 9. Tall Oil (Pine) Sterols Gluconates US 7,615,546 B2 1. 2 TOPCAL DELVERY SYSTEM FOR ditioning or treatment, and hair or scalp requiring shampoo PHYTOSTEROLS ing or conditioning, and combinations thereof. The present invention is a continuation-in-part of U.S. DESCRIPTION OF THE RELATED ART patent application Ser. No. 1 1/161,856 (filed on 19 Aug. The polycyclic polyisoprenoids are a class of polycyclic 2005) now abandoned , and continuation-in-part of U.S. compounds biogenetically derived from isoprene units. The patent application Ser. No. 12/139,659 (filed on 16 Jun. most important of these—sterols, Sapogenins, terpenoids, 2008). and phytosterols—have structures similar to plant and animal 10 steroids. Most of these are obtained from natural source, for BACKGROUND OF THE INVENTION example, Wong et al. (Journal of Wood Science, Vol. 47, 400 (2001); Foster et al., TAPPI, Vol. 63, No. 12, 103 (1980); and Phytosterols are a class of polycyclic polyisoprenoids Robinson et al. (U.S. Pat. No. 6,057.462). compounds biogenetically derived from isoprene units. For Steroids are waxy, Soapy or greasy in texture, thus are more practical purpose, the term “phytosterol and “polycyclic 15 soluble in oil than water. The best-known animal sterol is polyisoprenoid’ are used interchangeably in the present cholesterol, which, despite its negative connotation, is essen invention. The most important of these—sterols, Sapogenins, tial for life and a critical component of cell membranes, phytosterols, and terpenoids—have structures similar to plant organs, the brain and the nervous system. Just as cholesterol is the human precursor to all steroid hormones, such as cor and animal steroids, which have a basic structure of three tisol, estrogen, progesterone, and testosterone, beta-sitosterol linked six-membered rings and one five-membered ring. Ste is the plants precursor to growth and reproductive hormones. roids and terpenoids with hydroxyl groups have names that Sapogenins that are stored in plants with Sugars attached end in “ol’ such as cholesterol and menthol, respectively. A are called Saponins. Some Sapogenins, the non-Sugar portion number of these are known to have medicinal properties of a saponin, can mimic or regulate steroid hormones or (Singh et al., Current Science, Vol. 89, No. 2, 269-290 25 hormone precursors. Yams (Dioscorea spp.), which contain (2005)). Most of these polycyclic polyisoprenoids are known variable amounts of the Sapogenin diosgenin, can be con to be water insoluble, which results in their poor bioavailabil Verted into corticosteroids, dehydroepiandrosterone ity from any topical compositions. (DHEA), estrogen and progesterone in the laboratory, The present invention relates to Sugar esters of said phy whereas the body cannot convert diosgenin into steroid hor tosterols, which are conjugates of phytosterols with certain 30 mones. Diosgenin has a weak estrogenic or progesteronic Sugar lactones; in their optically active, inactive, or racemic effect, which may account for its historical folk use by forms (such as d, 1.dll, and meso): wherein phytosterol moiety WOle. provides the alcohol part, and the Sugar lactone moiety pro The yam North American herbalists use most often is D. vides the carbonyl part of said Sugar esters. These esters are villosa, which isn't as rich in diosgenin as are other species. 35 Yam species used for food are lower in Sapogenins than their useful for the treatment of multiple skin conditions and ail wild progenitors (saponins are distasteful and can be toxic). ments, including age spots, acne, loss of cellular antioxidants, Sapon, which means soap, refers to the Saponins tendency to collagen loss, loss of skin pliability, loss of skin Suppleness, foam in water. skin wrinkles including fine lines, oxidation, damage from Fenugreek (Trigonella foenum-graecum) is richer in dios radiation, malfunction of matrix metalloproteases, malfunc 40 genin and other Saponins thanyams. Traditionally, fenugreek tion of tyrosinases, damage from free radicals, damage from was prescribed to increase breast milk production and breast UV, dry skin, Xerosis, ichthyosis, dandruff, brownish spots, size.