WO2018090805A1 - Composition de protection de la peau contenant des ingrédients à base de dendrobium - Google Patents

Composition de protection de la peau contenant des ingrédients à base de dendrobium Download PDF

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WO2018090805A1
WO2018090805A1 PCT/CN2017/107798 CN2017107798W WO2018090805A1 WO 2018090805 A1 WO2018090805 A1 WO 2018090805A1 CN 2017107798 W CN2017107798 W CN 2017107798W WO 2018090805 A1 WO2018090805 A1 WO 2018090805A1
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skin
compound
resveratrol
independently selected
dihydro
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PCT/CN2017/107798
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English (en)
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Hongjie Zhang
Siu Wai Tsang
Yu Zhu
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Hong Kong Baptist University
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Priority claimed from US15/351,636 external-priority patent/US9738581B2/en
Application filed by Hong Kong Baptist University filed Critical Hong Kong Baptist University
Priority to CN201780069402.9A priority Critical patent/CN109952286B/zh
Priority to JP2019524017A priority patent/JP7051843B2/ja
Priority to MYPI2019002612A priority patent/MY187342A/en
Priority to TW106138517A priority patent/TWI732967B/zh
Publication of WO2018090805A1 publication Critical patent/WO2018090805A1/fr

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    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C07C69/708—Ethers
    • C07C69/712—Ethers the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
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    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/205—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring the aromatic ring being a non-condensed ring
    • C07C43/2055—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring the aromatic ring being a non-condensed ring containing more than one ether bond
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    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/215—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring having unsaturation outside the six-membered aromatic rings
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    • C07C69/22—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety
    • C07C69/30—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety esterified with trihydroxylic compounds
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    • C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
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    • C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
    • C07C69/614—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety of phenylacetic acid
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    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C07C69/92—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with etherified hydroxyl groups
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    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention relates to a skin-protection composition that comprises stilbenoid (s) and/or stilbenoid-containing extract (s) isolated from Dendrobium plants, such as Dendrobium officinale and Dendrobium nobile for the management of melanogenesis, skin-darkening and skin-aging. More particularly, it relates to the usage of Dendrobium ingredients to reduce the formation of melanin in melanocytes. It also relates to the usage of Dendrobium ingredients to reduce the generation of reactive oxygen species and oxidative free radicals in melanocytes. The present invention further relates to the use of Dendrobium-derived extracts or ingredients in the formulation of skin-protection, skin-whitening and/or anti-skin aging products.
  • UV radiation ultraviolet
  • ROS reactive oxygen species
  • melanin-producing cells or melanocytes, located in the skin’s epidermis are prone to produce more melanin in order to minimize the indirect damages of body cells
  • the elevation of melanin production is actually a defense mechanism against UV radiation; however, the accumulation of melanin may result in deleterious biological effects, including abnormal pigmentation, skin darkening as well as aesthetic problems, e.g. freckles or chloasmata [Mishima Y, Imokawa G. Selective aberration and pigment loss in melanosomes of malignant melanoma cells in vitro by glycosylation inhibitors: premelanosomes as glycoprotein. Journal of Investigative Dermatology 1983; 81: 106-114] .
  • the formation of ROS and free radicals plays a pivotal mechanism leading to skin-darkening and skin-aging.
  • melanin refers to a group of endogenous pigments that give multitude of skin colors, i.e. from the basic skin tone to freckles, birth marks, age spots, also in eyes and hair.
  • melanins are produced by melanocytes and classified into three major types: eumelanin, pheomelanin and neuromelanin. They differ in chemical structures and physical properties, and thus they are elicited upon different biological responses against external stimuli.
  • Eumelanin and pheomelanin are the two types of melanin that can be found in the skin. Eumelanin provides primarily dark brown to black colors whereas pheomelanin produces reddish colors [Maresca V, Flori E, Picardo M.
  • tyrosinase is the major rate-limiting enzyme for regulating melanin production in epidermal melanocytes whereas tyrosinase-related proteins (TRPs) are melanogenic enzymes that control the proportion of carboxylated subunits in melanin biopolymers.
  • TRPs tyrosinase-related proteins
  • ⁇ -MSH alpha-melanocyte-stimulating hormone
  • the present invention provides a composition that efficiently attenuates the biosynthesis of melanin as well as oxidative substances. By any means of mechanism, the present invention is able to restrain melanin accumulation and/or oxidative damage in the skin, hence skin protection can be achieved.
  • the composition of present invention comprises stilbenoids and/or extracts obtained from plants of the genus Dendrobium (Orchidaceae family, commonly called “Shi Hu” ) , particularly from the species D. officinale and D. nobile.
  • the said stilbenoids, explicitly trans-resveratrol and dihydro-resveratrol, and extracts can be formulated into a cosmetic blend of skin-protection, skin-whitening and/or anti-skin aging products for human skin as they are found to attenuate the generation of ROS and oxidative free radicals, and/or reduce cellular melanin content in melanocytes.
  • the reduction of melanin formation may be associated with an inhibition of the activity of pigment-producing enzymes, namely tyrosinase, TRP-1 and TRP-2.
  • the objective of this invention relates to a skin-protection composition that comprises stilbenoid (s) and/or stilbenoid-containing extract (s) isolated from Dendrobium plants, such as Dendrobium officinale and Dendrobium nobile.
  • This invention also relates to the use of Dendrobium-derived extracts or ingredients in reducing melanin formation in melanocytes for the management of melanogenesis and skin-darkening.
  • this invention also relates to the use of Dendrobium-derived extracts or ingredients in the formulation of skin-protection, skin-whitening and/or anti-skin aging products.
  • Said compound has a formula of
  • R 2 and R 4 are each independently selected from -OR 11 and -OC (O) R 11 ;
  • R 1 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from hydrogen, halogen, trifluoromethyl, -OR 11 and -OC (O) R 11 ; or R 2 and R 3 , or R 7 and R 8 may be taken together with the carbon atoms to which they are attached to form a cyclic group;
  • R 11 is independently hydrogen or selected from hydrocarbyl and heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ;
  • R 12 is independently selected from halogen, trifluoromethyl, cyano, nitro, oxo, -OR 13 , -C (O) R 14 , -C (O) N (R 13 ) R 14 , -C (O) OR 13 , -OC (O) R 14 , -S (O) 2 R 13 , -S (O) 2 N (R 13 ) R 14 , -N (R 13 ) R 14 ;
  • R 13 and R 14 are each independently hydrogen or selected from hydrocarbyl and heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, cyano, amino, hydroxy, C 1-6 alkyl and C 1-6 alkoxy;
  • a method for suppressing fibrotic mediator (s) in stellate cells present in an internal organ of a subject in need thereof comprising administering a composition comprising one or more compounds of formulae (i) to (viii) or dihydro-resveratrol [i.e., formula (2) ] to a subject in need thereof.
  • a method for suppressing fibrotic mediator (s) in stellate cells present in an internal organ of a subject in need thereof wherein the composition is administered to a subject in need thereof with a dosage of at least 1.622 mg/kg/day wherein said composition consists of a compound with a formula of
  • a third embodiment of the second aspect of the present invention there is provided a method for suppressing fibrotic mediator (s) in stellate cells present in an internal organ of a subject in need wherein the said subject is human.
  • a fourth embodiment of the second aspect of the present invention there is provided a method for suppressing fibrotic mediator (s) in stellate cells present in an internal organ of a subject in need wherein the composition is administered orally to said subject in need thereof.
  • said composition is administered to said subject orally.
  • a compound for use in treating pancreatogenic diabetes or Type 3c diabetes milieus in a subject in need thereof with a therapeutically effective amount of a compound of the following formula:
  • R 2 and R 4 are each independently selected from -OR 11 and -OC (O) R 11 ;
  • R 1 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from hydrogen, halogen, trifluoromethyl, -OR 11 and -OC (O) R 11 ; or R 2 and R 3 , or R 7 and R 8 may be taken together with the carbon atoms to which they are attached to form a cyclic group;
  • R 11 is independently hydrogen or selected from hydrocarbyl and heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ;
  • R 12 is independently selected from halogen, trifluoromethyl, cyano, nitro, oxo, -OR 13 , -C (O) R 14 , -C (O) N (R 13 ) R 14 , -C (O) OR 13 , -OC (O) R 14 , -S (O) 2 R 13 , -S (O) 2 N (R 13 ) R 14 , -N (R 13 ) R 14 ;
  • R 13 and R 14 are each independently hydrogen or selected from hydrocarbyl and heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, cyano, amino, hydroxy, C 1-6 alkyl and C 1-6 alkoxy;
  • a composition comprising compounds of the following formula:
  • R 2 and R 4 are each independently selected from -OR 11 and -OC (O) R 11 ;
  • R 1 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from hydrogen, halogen, trifluoromethyl, -OR 11 and -OC (O) R 11 ; or R 2 and R 3 , or R 7 and R 8 may be taken together with the carbon atoms to which they are attached to form a cyclic group;
  • R 11 is independently hydrogen or selected from hydrocarbyl and heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ;
  • R 12 is independently selected from halogen, trifluoromethyl, cyano, nitro, oxo, -OR 13 , -C (O) R 14 , -C (O) N (R 13 ) R 14 , -C (O) OR 13 , -OC (O) R 14 , -S (O) 2 R 13 , -S (O) 2 N (R 13 ) R 14 , -N (R 13 ) R 14 ;
  • R 13 and R 14 are each independently hydrogen or selected from hydrocarbyl and heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, cyano, amino, hydroxy, C 1-6 alkyl and C 1-6 alkoxy;
  • a method for treating pancreatogenic diabetes or Type 3c diabetes milieus
  • the composition is administered to a subject in need thereof with a dosage of at least 1.622 mg/kg/day wherein said composition consists of a compound with a formula of
  • a method for treating pancreatogenic diabetes or Type 3c diabetes milieus in a subject in need thereof wherein said subject is human.
  • a method for treating pancreatogenic diabetes or Type 3c diabetes milieus
  • the composition is administered orally to said subject in need thereof.
  • said compound is used in preparation of a composition for treating pancreatogenic diabetes (or Type 3c diabetes milieus) in said subject, and said subject is human.
  • a composition for use in treating pancreatogenic diabetes comprising a therapeutically effective amount of a compound of one of the following formulae:
  • compositions for treating pancreatogenic diabetes or Type 3c diabetes milieus
  • the composition is administered to said subject with a dosage of at least 1.622 mg/kg/day
  • said composition consists of a compound with a formula of
  • a composition for treating pancreatogenic diabetes or Type 3c diabetes milieus
  • said subject is human.
  • R 2 , R 4 , and R 8 are each independently selected from -OR 11 , -OCH 2 R 12 , -OC (O) R 11 , -OCH 2 C (O) OR 12 and -OC (O) CH 2 R 12 ;
  • R 1 , R 3 , R 5 , R 6 , R 7 , R 9 and R 10 are each independently selected from hydrogen, halogen, trifluoromethyl, -OR 12 and -OC (O) R 12 ; or R 2 and R 3 , or R 7 and R 8 may be taken together with the carbon atoms to which they are attached to form a cyclic group;
  • R 11 is independently selected from – (CH 2 ) -hydrocarbyl, C 2-10 alkyl, alkenyl, cycloalkyl, aryl and heterocyclyl, each of these groups is optionally substituted with 1, 2, 3, 4 or 5 R 13 ;
  • R 12 is independently selected from hydrocarbyl and heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 13 ;
  • R 13 is independently selected from halogen, trifluoromethyl, cyano, nitro, oxo, -OR 14 , -C (O) R 15 , -C (O) N (R 14 ) R 15 , -C (O) OR 14 , -OC (O) R 15 , -S (O) 2 R 14 , -S (O) 2 N (R 14 ) R 15 , -N (R 14 ) R 15 ;
  • R 14 and R 15 are each independently hydrogen or selected from hydrocarbyl and heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, cyano, amino, hydroxy, C 1-6 alkyl and C 1-6 alkoxy;
  • a compound of formula (4) wherein said compound is an optically pure stereoisomer, enantiomer, racemate or diastereomer thereof.
  • a pharmaceutical composition comprising an effective amount of the compound of formula (4) , the derivatives thereof, and a pharmaceutically acceptable carrier thereof.
  • a pharmaceutical composition comprising an effective amount of the skin whitening and skin protection compound of formula (4) , the derivatives thereof, and a pharmaceutically acceptable carrier thereof.
  • a compound of formula (4) wherein the compound is selected from DR1, DR2, DR3, DR4, DR5, DR6, DR7, DR8, DR9, DR10 or DR11 with the following formulae respectively:
  • a seventh embodiment of the fifth aspect of the present invention there is provided the use of the compound of formula (4) and/or the derivatives or chemical variants thereof alone and/or in combination with one or more other pharmaceutically acceptable skin-whitening and skin-protection agent (s) in the preparation of the composition for treatment, prevention or delay of progression of a skin darkening, wherein said subject is a human.
  • an eighth embodiment of the fifth aspect of the present invention there is provided a method of treating and preventing development and progression of a skin darkening comprising administering the compound of formula (4) and/or the derivatives thereof to a subject in need thereof.
  • a ninth embodiment of the fifth aspect of the present invention there is provided a method of treating and preventing development and progression of a skin darkening comprising administering the compound of formula (4) and/or the derivatives thereof to a subject in need thereof wherein said subject is a human.
  • a tenth embodiment of the fifth aspect of the present invention there is provided the use of the compound of formula (4) and/or the derivatives or chemical variants thereof alone and/or in combination with one or more other pharmaceutically acceptable skin-whitening and skin-protection agent (s) in the preparation of the composition for treatment, prevention or delay of progression of a skin darkening in a subject in need thereof, wherein the composition is applied topically.
  • the composition comprising the compound of formula (4) and/or the derivatives or chemical variants thereof alone and/or in combination with one or more other pharmaceutically acceptable skin-whitening and skin-protection agent (s) , wherein the composition is in the form of paste, solid, powder, particle, emulsion, a day cream, a night cream, a face lotion, a body lotion, a body butter, a skin peel, a mask, a shower gel, a sun cream, a sun lotion, an after sun cream, an after sun lotion, a lip balm, a lip gloss, or alike.
  • a skin whitening and skin protection against UV exposure, skin damage and aging compound of formula (5) in a first embodiment of a sixth aspect of the present invention there is provided a skin whitening and skin protection against UV exposure, skin damage and aging compound of formula (5) :
  • R 2 , R 4 , and R 8 are each independently selected from -OR 11 , -OCH 2 R 11 , -OC (O) R 11 , -OCH 2 C (O) OR 11 and -OC (O) CH 2 R 11 ;
  • R 1 , R 3 , R 5 , R 6 , R 7 , R 9 and R 10 are each independently selected from hydrogen, halogen, trifluoromethyl, -OR 11 and -OC (O) R 11 ; or R 2 and R 3 , or R 7 and R 8 may be taken together with the carbon atoms to which they are attached to form a cyclic group;
  • R 11 is independently hydrogen or selected from hydrocarbyl and heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ;
  • R 12 is independently selected from halogen, trifluoromethyl, cyano, nitro, oxo, -OR 13 , -C (O) R 14 , -C (O) N (R 13 ) R 14 , -C (O) OR 13 , -OC (O) R 14 , -S (O) 2 R 13 , -S (O) 2 N (R 13 ) R 14 , -N (R 13 ) R 14 ;
  • R 13 and R 14 are each independently hydrogen or selected from hydrocarbyl and heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, cyano, amino, hydroxy, C 1-6 alkyl and C 1-6 alkoxy;
  • a skin whitening and skin protection against UV exposure, skin damage and aging compound with a formula of:
  • a seventh aspect of the present invention there is provided a method of synthesizing the compound of formulae DR1 to DR11 from dihydro-resveratrol according to the following synthesis schemes, respectively:
  • R is -OR 11 , -OCH 2 R 11 or -OCH 2 C (O) OR 11 ;
  • R 11 is hydrocarbyl
  • R is -R 11 or -CH 2 R 11 ;
  • R 11 is hydrocarbyl, which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ;
  • R 12 is halogen or -OR 13 ;
  • R 13 is hydrogen or hydrocarbyl.
  • dihydro-resveratrol and RBr are added in dimethylformamide (DMF) and K 2 CO 3 to form a mixture.
  • the resulting mixture is stirred at room temperature until the starting material disappear on thin-layer chromatography (TLC) .
  • TLC thin-layer chromatography
  • the mixture is then diluted with H 2 O and washed with dichloromethane (DCM) three times to extract the organic phase.
  • dihydro-resveratrol and RCOCl are added into DCM and Et 3 N at 0 °C to form a mixture.
  • the resulting mixture is warmed to room temperature and stirred until the starting material disappear on TLC.
  • the mixture is then diluted with H 2 O and washed with DCM three times to extract the organic phase.
  • a method of treating acute inflammatory condition of the pancreas and associated systemic complications by administering to a subject in needs thereof a composition comprising an effective amount of a stilbenoid derivative which comprises a compound of formula (1) , wherein R 1 , R 2 and R 3 are each independently selected from an alkyl group.
  • a stilbenoid derivative which comprises a compound of formula (1) , wherein R 1 , R 2 and R 3 are each independently selected from an alkyl group.
  • alkyl alone or in combination with other groups, includes reference to a straight chain alkyl moiety having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the term is further exemplified by such groups as methyl, ethyl, propyl (n-propyl or isopropyl) , butyl (n-butyl, sec-butyl and tert-butyl) , pentyl, hexyl and the like, and the derivatives or chemical variants thereof; or a mixture of said compound, the derivative and/or chemical variants thereof.
  • the stilbenoid derivative is trans-3, 5, 4'-trihydroxybibenzyl, or dihydro-resveratrol, which is a compound of formula (2) : and the derivatives or chemical variants thereof; or a mixture of said compound, the derivative and/or chemical variants thereof.
  • the invention includes all such variation and modifications.
  • the invention also includes all of the steps and features referred to or indicated in the specification, individually or collectively and any and all combinations or any two or more of the steps or features.
  • Figure 1 shows the gain of water content in rats due to effect of pancreatic edema as a result of cerulein-induced acute pancreatitis.
  • the obtained weights are expressed as a ratio percentage of pancreatic weight to body mass.
  • a p-value of less than 0.05 is considered as statistically significant. *p ⁇ 0.05 when comparing with control group whereas #p ⁇ 0.05 comparing with cerulein group.
  • Figures 2A to 2F show the architecture and morphological alteration in pancreatic tissues of control group (Figure 2A) , cerulein group (Figure 2B) and dihydro-resveratrol treatment groups (D-Res) ( Figures 2C to 2F) by means of hematoxylin and eosin (H&E) staining. Images are shown with a scale bar of 50 ⁇ m.
  • Figures 3A to 3E show the architecture and morphological alteration in pulmonary tissues of control group (Figure 3A) , cerulein group (Figure 3B) and dihydro-resveratrol treatment groups (D-Res) ( Figures 3C to 3E) by means of H&E staining. Images are shown with a magnification of 200 ⁇ .
  • Figure 4A shows the measurement of MPO activity which represents neutrophil sequestration in pancreatic tissues of control group, cerulein group and dihydro-resveratrol treatment groups (D-Res) by means of colorimetric spectrophotometry.
  • a p-value of less than 0.05 is considered as statistically significant. *p ⁇ 0.05 when comparing with control group whereas #p ⁇ 0.05 comparing with cerulein group.
  • Figure 4B shows the measurement of MPO activity which represents neutrophil sequestration in pulmonary tissues of control group, cerulein group and dihydro-resveratrol treatment groups (D-Res) by means of colorimetric spectrophotometry.
  • a p-value of less than 0.05 is considered as statistically significant. *p ⁇ 0.05 when comparing with control group whereas #p ⁇ 0.05 comparing with cerulein group.
  • Figure 5A shows the measurement of TNF- ⁇ level in pancreatic tissues of control group, cerulein group and dihydro-resveratrol treatment groups (D-Res) by means of enzyme-linked immunosorbent assay (ELISA) .
  • a p-value of less than 0.05 is considered as statistically significant. *p ⁇ 0.05 when comparing with control group whereas #p ⁇ 0.05 comparing with cerulein group.
  • Figure 5B shows the measurement of TNF- ⁇ level in pulmonary tissues of control group, cerulein group and dihydro-resveratrol treatment groups (D-Res) by means of ELISA.
  • a p-value of less than 0.05 is considered as statistically significant. *p ⁇ 0.05 when comparing with control group whereas #p ⁇ 0.05 comparing with cerulein group.
  • Figure 6A shows the measurement of glutathione levels in pancreatic tissues of control group, cerulein group and dihydro-resveratrol treatment groups (D-Res) by means of colorimetric spectrophotometry.
  • a p-value of less than 0.05 is considered as statistically significant. *p ⁇ 0.05 when comparing with control group whereas #p ⁇ 0.05 comparing with cerulein group.
  • Figure 6B shows the ameliorative effect of dihydro-resveratrol (D-res) and trans-resveratrol (Res) on reducing water content as a result of pancreatic edema in rats with cerulein-induced acute pancreatitis.
  • the obtained weights are expressed as a ratio percentage of pancreatic weight to body mass.
  • a p-value of less than 0.05 is considered as statistically significant. *p ⁇ 0.05 when comparing with saline-treated control group (Con) whereas #p ⁇ 0.05 comparing with cerulein-treated control group.
  • Figure 7 shows the measurement of metabolic rates by means of MTT cell proliferation in pancreatic acinar cells treated with dihydro-resveratrol and trans-resveratrol. *p ⁇ 0.05 when comparing with cells treated without dihydro-resveratrol or trans-resveratrol.
  • Figures 8A to 8H shows eight derivatives (i.e. Compound i to Compound viii) from dihydro-resveratrol (i.e. Compound 2) .
  • Figure 8I shows the chemical structure of dihydro-resveratrol (i.e. Compound 2) .
  • Figure 9 shows Western blotting of LTC-14 PSCs pre-incubated with TGF- ⁇ (5 ng/mL) , and treated with trans-resveratrol (Resv) or dihydro-resveratrol or stilbene compounds i to viii at 20 ⁇ g/mL for 24 hours. Control was not treated with Resv or any stilbenoids.
  • Figure 10 shows the probing of ⁇ -SMA and FN1 in Western blotting of LTC-14 cells pre-incubated with TGF- ⁇ (5 ng/mL) , and treated with trans-resveratrol or dihydro-resveratrol at the indicated concentrations.
  • Figure 11 shows the green fluorescent signal (identified by arrow marks) of fibrotic filaments ⁇ -SMA in LTC-14 cells implying the degree of PSC activation.
  • Figure 12 shows the fluorescent signal of fibronectin (FN1) deposition in pancreatic tissue sections for an estimation of the degree of fibrosis with and without treatment of dihydro-resveratrol (D-Res, 20 mg/kg/day) or trans-resveratrol (Res, 20 mg/kg/day) in cerulein (Cer) -induced chronic pancreatitis mice.
  • D-Res dihydro-resveratrol
  • Res trans-resveratrol
  • Figure 13 shows the glucose response of the normal mice (Control) and chronic pancreatitis mice (Cer) with or without treatment of dihydro-resveratrol (D-Res, 20 mg/kg/day) in the intraperitoneal glucose tolerance test. At all time-points, a significant difference (p ⁇ 0.05) is achieved between the Cer group and the Cer+D-Res group.
  • FIG 14 shows the fluorescent signal of insulin in pancreatic tissue sections for an evaluation of pancreatic insulin-secreting cell (i.e. beta-cell) area. The comparison is made among the control mice, chronic pancreatitis mice and the chronic pancreatitis mice with treatment of dihydro-resveratrol (D-Res) at 20 mg/kg/day.
  • D-Res dihydro-resveratrol
  • D-Res dihydro-resveratrol
  • Res trans-resveratrol
  • Figure 16 shows the suppressive effect of the Dendrobium stilbenoids (25 ⁇ M) , which are dihydro-resveratrol (D-Res) , trans-resveratrol (Res) and compounds DR1 to DR11, on cellular melanin content in A375 melanocytes.
  • D-Res dihydro-resveratrol
  • Res trans-resveratrol
  • Figure 17 shows the suppressive effect of D. nobile extract (JCSH, 50 ⁇ g/mL) , D. officinale extract (TPSH, 50 ⁇ g/mL) , trans-resveratrol (Res, 25 ⁇ M) and dihydro-resveratrol (D-Res, 25 ⁇ M) on cellular melanin content in B16 melanocytes.
  • Ascorbic acid (AC) is served as a positive control.
  • Figure 19 shows the inhibitory effect of the Dendrobium stilbenoids (25 ⁇ M) , which are dihydro-resveratrol (D-Res) , trans-resveratrol (Res) and compounds DR1 to DR11, on cellular tyrosinase activity in A375 melanocytes.
  • D-Res dihydro-resveratrol
  • Res trans-resveratrol
  • Figure 20 shows the inhibitory effect of D. nobile extract (JCSH, 50 ⁇ g/mL) , D. officinale extract (TPSH, 50 ⁇ g/mL) , trans-resveratrol (Res, 25 ⁇ M) and dihydro-resveratrol (D-Res, 25 ⁇ M) on cellular tyrosinase activity in B16 melanocytes.
  • Ascorbic acid (AC) is served as a positive control.
  • Figure 21 shows suppressive effect of D. nobile extract (JCSH, L: 10; M: 25; H: 50 ⁇ g/mL) and D. officinale extract (TPSH, L: 10; M: 25; H: 50 ⁇ g/mL) , dihydro-resveratrol (D-Res, L: 25; H: 50 ⁇ M) , trans-resveratrol (Res, L: 25; H: 50 ⁇ M) and ascorbic acid (AC, H: 50 ⁇ g/mL) on protein levels of TRP-1, TRP-2, phospho-AKT and phospho-p38 in B16 melanocytes.
  • GAPDH is served as a loading reference.
  • Figure 23 shows the whitening effect of stilbenoid solution containing 2%trans-resveratrol (Res) or 2%dihydro-resveratrol (D-Res) on the arm of an individual human subject on day 7 and day 14.
  • hydrocarbyl as used herein includes reference to a moiety consisting exclusively of hydrogen and carbon atoms; such a moiety may comprise an aliphatic and/or an aromatic moiety. The moiety may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms.
  • hydrocarbyl groups include C 1-6 alkyl (e.g. C 1 , C 2 , C 3 or C 4 alkyl, for example methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl) ; C 1-6 alkyl substituted by aryl (e.g.
  • benzyl or by cycloalkyl (e.g. cyclopropylmethyl) ; cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) ; aryl (e.g. phenyl, naphthyl or fluorenyl) and the like.
  • cycloalkyl e.g. cyclopropylmethyl
  • cycloalkyl e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl
  • aryl e.g. phenyl, naphthyl or fluorenyl
  • alkyl as used herein includes reference to a straight or branched chain alkyl moiety having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms.
  • alkyl groups include “C 1-6 alkyl” and “C 2-10 alkyl” .
  • C 1-6 alkyl as used herein include reference to a straight or branched chain alkyl moiety having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • C 2-10 alkyl as used herein include reference to a straight or branched chain alkyl moiety having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • This term includes reference to groups such as methyl, ethyl, propyl (n-propyl or isopropyl) , butyl (n-butyl, sec-butyl or tert-butyl) , pentyl, hexyl and the like.
  • the alkyl moiety may have 1, 2, 3, 4, 5 or 6 carbon atoms.
  • alkenyl and C 2-6 alkenyl as used herein include reference to a straight or branched chain alkyl moiety having 2, 3, 4, 5 or 6 carbon atoms and having, in addition, at least one double bond, of either E or Z stereochemistry where applicable. This term includes reference to groups such as ethenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, 2-hexenyl and 3-hexenyl and the like.
  • alkynyl and C 2-6 alkynyl as used herein include reference to a straight or branched chain alkyl moiety having 2, 3, 4, 5 or 6 carbon atoms and having, in addition, at least one triple bond. This term includes reference to groups such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl and 3-hexynyl and the like.
  • alkoxy and C 1-6 alkoxy as used herein include reference to -O-alkyl, wherein alkyl is straight or branched chain and comprises 1, 2, 3, 4, 5 or 6 carbon atoms. In one class of embodiments, alkoxy has 1, 2, 3 or 4 carbon atoms. This term includes reference to groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, hexoxy and the like.
  • cycloalkyl as used herein includes reference to an alicyclic moiety having 3, 4, 5, 6, 7 or 8 carbon atoms.
  • the group may be a bridged or polycyclic ring system. More often cycloalkyl groups are monocyclic. This term includes reference to groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbomyl, bicyclo [2.2.2] octyl and the like.
  • aryl as used herein includes reference to an aromatic ring system comprising 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring carbon atoms.
  • Aryl is often phenyl but may be a polycyclic ring system, having two or more rings, at least one of which is aromatic. This term includes reference to groups such as phenyl, naphthyl, fluorenyl, azulenyl, indenyl, anthryl and the like.
  • Cyclic group means a ring or ring system, which may be unsaturated or partially unsaturated but is usually saturated, typically containing 5 to 13 ring-forming atoms, for example a 5-or 6-membered ring.
  • the ring or ring system may be substituted with one or more hydrocarbyl groups. Cyclic group includes carbocyclyl and heterocyclyl moeities.
  • carbocyclyl as used herein includes reference to a saturated (e.g. cycloalkyl) or unsaturated (e.g. aryl) ring moiety having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 carbon ring atoms.
  • carbocyclyl includes a 3-to 10-membered ring or ring system and, in particular, 5-or 6-membered rings, which may be saturated or unsaturated.
  • the ring or ring system may be substituted with one or more hydrocarbyl groups.
  • a carbocyclic moiety is, for example, selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo [2.2.2] octyl, phenyl, naphthyl, fluorenyl, azulenyl, indenyl, anthryl and the like.
  • heterocyclyl as used herein includes reference to a saturated (e.g. heterocycloalkyl) or unsaturated (e.g. heteroaryl) heterocyclic ring moiety having from 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, at least one of which is selected from nitrogen, oxygen, phosphorus, silicon and sulphur.
  • heterocyclyl includes a 3-to 10-membered ring or ring system and more particularly a 5-or 6-membered ring, which may be saturated or unsaturated.
  • the ring or ring system may be substituted with one or more hydrocarbyl groups.
  • a heterocyclic moiety is, for example, selected from oxiranyl, azirinyl, 1, 2-oxathiolanyl, imidazolyl, thienyl, furyl, tetrahydrofuryl, pyranyl, thiopyranyl, thianthrenyl, isobenzofuranyl, benzofuranyl, chromenyl, 2H-pyrrolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolizidinyl, imidazolyl, imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, piperidyl, piperazinyl, pyridazinyl, morph
  • heterocycloalkyl as used herein includes reference to a saturated heterocyclic moiety having 3, 4, 5, 6 or 7 ring carbon atoms and 1 , 2, 3, 4 or 5 ring heteroatoms selected from nitrogen, oxygen, phosphorus and sulphur.
  • the group may be a polycyclic ring system but more often is monocyclic.
  • This term includes reference to groups such as azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxiranyl, pyrazolidinyl, imidazolyl, indolizidinyl, piperazinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, quinolizidinyl and the like.
  • the ring or ring system may be substituted with one or more hydrocarbyl groups.
  • heteroaryl as used herein includes reference to an aromatic heterocyclic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, at least one of which is selected from nitrogen, oxygen and sulphur.
  • the group may be a polycyclic ring system, having two or more rings, at least one of which is aromatic, but is more often monocyclic.
  • the ring or ring system may be substituted with one or more hydrocarbyl groups.
  • This term includes reference to groups such as pyrimidinyl, furanyl, benzo [b] thiophenyl, thiophenyl, pyrrolyl, imidazolyl, pyrrolidinyl, pyridinyl, benzo [b] furanyl, pyrazinyl, purinyl, indolyl, benzimidazolyl, quinolinyl, phenothiazinyl, triazinyl, phthalazinyl, 2H-chromenyl, oxazolyl, isoxazolyl, thiazolyl, isoindolyl, indazolyl, purinyl, isoquinolinyl, quinazolinyl, pteridinyl and the like.
  • halogen as used herein includes reference to F, Cl, Br or I.
  • halogen containing moiety includes reference to a moiety comprising 1 to 30 plural valence atoms selected from carbon, nitrogen, oxygen and sulphur which moiety includes at least one halogen.
  • the moiety may be hydrocarbyl for example C 1-6 alkyl or C 1-6 alkoxy, or carbocyclyl for example aryl.
  • substituted as used herein in reference to a moiety means that one or more, especially up to 5, more especially 1, 2 or 3, of the hydrogen atoms in said moiety are replaced independently of each other by the corresponding number of the described substituents.
  • optionally substituted as used herein means substituted or un-substituted. It will, of course, be understood that substituents are only at positions where they are chemically possible, the person skilled in the art being able to decide (either experimentally or theoretically) without inappropriate effort whether a particular substitution is possible.
  • enantiomer as used herein means one of two stereoisomers that have mirror images of one another.
  • racemate as used herein means a mixture of equal amounts of enantiomers of a chiral molecule.
  • diastereomer as used herein means one of a class of stereoisomers that are not enantiomers, but that have different configurations at one or more of the equivalent chiral centers.
  • Example of diasteromers are epimers that differ in configuration of only one chiral center.
  • stereoisomer as used herein means one of a class of isomeric molecules that have the same molecular formula and sequence of bonded atoms, but different three-dimensional orientations of their atoms in space.
  • a prodrug is a medication that is administered as an inactive (or less than fully active) chemical derivative that is subsequently converted to an active pharmacological agent in the body, often through normal metabolic processes.
  • morphological alterations of organ architecture including interstitial edema, cellular damage, leukocyte infiltration and hemorrhage are characterized as the histological and/or pathological parameters.
  • aberrant MPO activity is often measured for assessing the severity of neutrophil-mediated inflammatory condition.
  • Both the local and systemic inflammatory responses can be further confirmed by the high levels of pro-inflammatory cytokines present in the homogenates of affected tissues.
  • glutathione depletion a defense mechanism, is one of the most common parameters for assessing the severity of tissue injury.
  • the subject to be treated by the method of this invention may be a human or an animal.
  • the present invention is applicable to various forms of acute pancreatitis, and particularly to the acute pancreatitis associated systemic complications including pulmonary injury.
  • Dihydro-resveratrol also known as trans-3, 5, 4'-trihydroxybibenzyl, is a derivative of polyphenol belonging to the family of stilbenoids, which are often obtained from plant extracts.
  • dihydro-resveratrol is a phytoalexin produced by various plant species including Orchidaceae and Cannabis sativa L. against abiotic and biotic challenges, particularly in the case of fungal infection as reported in Fritzemeier, K.H., Kindl, H. 1983. 9, 10-dihydrophenanthrenes as phytoalexins of Orchidaceae.
  • the present invention relates to the usage of a polyphenol derivative of the stilbenoid family with formula (1) :
  • R 1 , R 2 and R 3 are each independently selected from an alkyl group.
  • alkyl alone or in combination with other groups, includes reference to a straight chain alkyl moiety having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the term is further exemplified by such groups as methyl, ethyl, propyl (n-propyl or isopropyl) , butyl (n-butyl, sec-butyl and tert-butyl) , pentyl, hexyl and the like, to ameliorate tissue injury of the pancreas and lungs.
  • the present invention further relates to the usage of a stilbene compound containing trans-3, 5, 4'-trihydroxybibenzyl, also known as dihydro-resveratrol, see Compound of formula (2) :
  • this particular stilbenoid derivative was obtained as white powders through dehydrogenation of trans-resveratrol.
  • the invention is concerned with a process for the manufacture of the above compound, pharmaceutical preparations which contain such compound, and the use of this compound for the production of pharmaceutical preparations.
  • mice with acute pancreatitis are shown to have lessened pancreatic water content due to an attenuation of pancreatic edema ( Figure 1) , lowered plasma level of ⁇ -amylase (Table 1) , more intact acinar morphology ( Figures 2C to 2F) and reduced thickening of alveolar wall and hemorrhage ( Figures 3C to 3E) .
  • Plasma ⁇ -amylase activities are expressed as U/ ⁇ l/minute. A p-value of less than 0.05 is considered as statistically significant and S. D. stands for standard derivation. *p ⁇ 0.05 when comparing with control group whereas #p ⁇ 0.05 comparing with cerulein group.
  • Cerulein-induced elevated levels of neutrophil sequestration which is quantified as the activity of MPO, are significantly suppressed in pancreatic and pulmonary tissues by the administration of dihydro-resveratrol ( Figures 4A and 4B) .
  • Cerulein-induced elevated levels of TNF- ⁇ in the pancreas and lungs are significantly suppressed by the administration of dihydro-resveratrol ( Figures 5A and 5B) .
  • Glutathione depletion is a distinctive sign of tissue injury.
  • the cerulein-induced declined levels of glutathione in the pancreas are significantly restored by the administration of dihydro-resveratrol (Figure 6A) .
  • dihydro-resveratrol completely and easily dissolves in 0.5% (weight/volume, w/v) methanol whereas trans-resveratrol, with vigorous shaking, dissolves in 2.5% (w/v) methanol (Table 2) .
  • the solubility of dihydro-resveratrol is at least 5 times higher than that of trans-resveratrol.
  • the ameliorative effect of dihydro-resveratrol was more promising than that of trans-resveratrol on reducing water content as a result of pancreatic edema in rats with cerulein-induced acute pancreatitis ( Figure 6B) .
  • Table 2 Solubility of Dihydro-resveratrol and Trans-resveratrol in methanol.
  • the cytotoxicity of dihydro-resveratrol in pancreatic acinar cells is determined to be approximately 500 ⁇ M whereas that of trans-resveratrol is roughly 250 ⁇ M ( Figure 7) .
  • the cytotoxicity of dihydro-resveratrol was 50%lower than that of trans-resveratrol.
  • dihydro-resveratrol Preparation and structural identification of dihydro-resveratrol.
  • the molecular formula of dihydro-resveratrol was established as C 14 H 14 O 3 , which was obtained as white powders through hydrogenation of trans-resveratrol.
  • a solution of trans-resveratrol (10 g, 43.8 mmol) in anhydrous EtOH (150 ml) was stirred at room temperature under 5 atm H 2 pressure in the presence of 10%Pd/C (0.2 g) . The reaction was quenched after 8 hours (h) , by filtering off the catalyst.
  • Sprague-Dawley rats aged 28 days weighing in the range of 70 to 90 g were randomly assigned into 6 groups of 6 to 8 individuals.
  • the rats were housed with an ambient temperature of 23 ⁇ 2°C, a relative humidity of 60 to 80%and a 12-h light/dark cycle. Prior to the experiment, the rats were starved overnight but allowed with free access to water.
  • Experimental acute pancreatitis was induced in the rats by six hourly i. p. injections of cerulein at the supramaximally stimulating dose (50 ⁇ g/kg) followed by a single dose of LPS at 7.5 mg/kg 1 h after the last cerulein injection, and this group of rats was designated as the cerulein group.
  • the control group received injections of 0.9%saline instead of cerulein in the same volume and at same time intervals.
  • the treatment groups given with cerulein and oral doses of dihydro-resveratrol (10, 20 or 50 mg/kg) were designated as Cerulein + D-res 10 or 20 or 50 mg/kg.
  • the therapeutic intervention was given 30 minutes after the first cerulein injection for three consecutive hours.
  • pancreata were immediately removed, weighed, trimmed from fat and fixed in 4 %paraformaldehyde-phosphate buffered saline overnight at 4 °C. Samples were then processed, embedded in paraffin wax, sectioned and subjected to H&E staining. Levels of TNF- ⁇ in pancreatic and pulmonary samples were determined using commercial ELISA kits. Tissue homogenates were subjected to biochemical assays for the evaluation of MPO activity and glutathione content.
  • acini Functional intact acini were dissociated from pancreatic tissue using collagenase digestion with mild shearing forces.
  • Acini were cultured in Dulbecco’s modification of Eagle’s medium (GIBCO) supplemented with 5%fetal bovine serum (GIBCO) , 1%penicillin-streptomycin (GIBCO) in a 5%CO 2 , 95%air humidified atmosphere at 37°C.
  • LTC-14 cells were seeded at a density of 1 ⁇ 10 4 /well in a 96-well plate, and incubated with different concentrations of dihydro-resveratrol or trans-resveratrol (dissolved in DMSO) for 24 hours.
  • MTT reagent was added to the cells at the end of the 24-hour treatment period. After a 3-hour reaction time, MTT products were dissolved in DMSO and absorbance at 570 nm was taken.
  • pancreas to body in the acute pancreatitis rats was drastically increased by roughly 60%when compared with the non-cerulein induced controls due to the occurrence of pancreatic edema.
  • the oral administration of dihydro-resveratrol at an adequate dosage of not less than 20 mg/kg notably reduced the pancreatic edema as reflected by the significant decrease in the weight ratio of pancreas to body.
  • the ameliorative effect of dihydro-resveratrol on reducing pancreatic edema was more promising than that of trans-resveratrol, the accredited antioxidant.
  • the comparable dosage is 3.24 mg/kg based on the standard dosage conversion according to Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. FASEB J 22 (3) : 659–661.
  • the levels of pro-inflammatory cytokine TNF- ⁇ as well as MPO activities were significantly reduced in the pancreatic and pulmonary tissues by the oral administration of dihydro-resveratrol.
  • the level of glutathione in cerulein-induced pancreatic tissue was depleted drastically by more than 50%when compared to the non-cerulein-treated control.
  • the oral administration of dihydro-resveratrol significantly suppressed glutathione depletion in the cerulein-induced pancreata.
  • the solubility of dihydro-resveratrol in a methanol-based solvent was at least 5 times higher than that of trans-resveratrol.
  • the cytotoxicity of dihydro-resveratrol was shown to be approximately 500 ⁇ M whereas that of trans-resveratrol was roughly 250 ⁇ M.
  • the cytotoxicity of dihydro-resveratrol was 50%lower than that of trans-resveratrol.
  • a method of treating acute inflammatory condition of the pancreas and associated systemic complications by administering to a subject in needs thereof a composition comprising an effective amount of a stilbenoid derivative which comprises a compound of formula (1) , wherein R 1 , R 2 and R 3 are each independently selected from an alkyl group.
  • a stilbenoid derivative which comprises a compound of formula (1) , wherein R 1 , R 2 and R 3 are each independently selected from an alkyl group.
  • alkyl alone or in combination with other groups, includes reference to a straight chain alkyl moiety having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the term is further exemplified by such groups as methyl, ethyl, propyl (n-propyl or isopropyl) , butyl (n-butyl, sec-butyl and tert-butyl) , pentyl, hexyl and the like, and the derivatives or chemical variants thereof; or a mixture of said compound, the derivative and/or chemical variants thereof.
  • a method of treating acute inflammatory condition of the pancreas and associated systemic complications wherein the stilbenoid derivative is trans-3, 5, 4'-trihydroxybibenzyl, or dihydro-resveratrol, which is a compound of formula (2) : and the derivatives or chemical variants thereof; or a mixture of said compound, the derivative and/or chemical variants thereof.
  • a method of treating acute inflammatory condition of the pancreas and associated systemic complications wherein the subject is a human or an animal.
  • a fourth embodiment of the first aspect of the present invention there is provided a method of treating acute inflammatory condition of the pancreas and associated systemic complications wherein the composition is administered orally.
  • a method of treating acute inflammatory condition of the pancreas and associated systemic complications wherein the acute inflammatory condition of the pancreas comprises all forms of acute pancreatitis and associated systemic complications comprise pulmonary injury.
  • a method of treating acute inflammatory condition of the pancreas and associated systemic complications wherein said composition is administered at no less than 20 mg/kg to said subject for no less than 3 times a day.
  • a seventh embodiment of the first aspect of the present invention there is provided a method of treating acute inflammatory condition of the pancreas and associated systemic complications wherein said composition is administered at no less than 3.24 mg/kg to said subject for no less than 3 times a day.
  • a method for preparing a compound of molecular formula C 14 H 14 O 3 and of formula (2) which is a stilbenoid derivative having a chemical name of trans-3, 5, 4'-trihydroxybibenzyl by hydrogenating of trans-resveratrol.
  • TGF- ⁇ has been reported by some previous studies as a potent inducer of PSC activation in which a series of fibrotic mediators, including FN1, are being up-regulated.
  • LTC-14 cells which are immortalized PSCs from rat
  • the expression levels of fibrotic filament ⁇ -SMA and ECM protein FN1 are remarkably elevated by the exogenous addition of recombinant TGF- ⁇ (5 ng/mL) .
  • the inventors discover that the administration of dihydro-resveratrol significantly attenuate the expression levels of ⁇ -SMA and FN1 in rat PSCs upon the challenge of TGF- ⁇ .
  • dihydro-resveratrol exerts similar suppressive effect in PSCs.
  • the inhibitory effect of dihydro-resveratrol is more significant.
  • dihydro-resveratrol exerts the most potent anti-fibrotic effect in PSCs despite they possess modest structural differences.
  • the present invention provides a compound for suppressing a fibrotic mediator of stellate cells present in an internal organ of a subject in need with a formula of
  • R 2 and R 4 are each independently selected from -OR 11 and -OC (O) R 11 ;
  • R 1 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from hydrogen, halogen, trifluoromethyl, -OR 11 and -OC (O) R 11 ; or R 2 and R 3 , or R 7 and R 8 may be taken together with the carbon atoms to which they are attached to form a cyclic group;
  • R 11 is independently hydrogen or selected from hydrocarbyl and heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ;
  • R 12 is independently selected from halogen, trifluoromethyl, cyano, nitro, oxo, -OR 13 , -C (O) R 14 , -C (O) N (R 13 ) R 14 , -C (O) OR 13 , -OC (O) R 14 , -S (O) 2 R 13 , -S (O) 2 N (R 13 ) R 14 , -N (R 13 ) R 14 ;
  • R 13 and R 14 are each independently hydrogen or selected from hydrocarbyl and heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, cyano, amino, hydroxy, C 1-6 alkyl and C 1-6 alkoxy;
  • the present invention further provides nine embodiments of compounds for suppressing a fibrotic mediator of stellate cells present in an internal organ of a subject in need with formula of:
  • the internal organ can be, for example, pancreas, liver, kidney and lung of a subject.
  • the subject can be a human subject.
  • LTC-14 cells were cultured at 37°C under a humidified condition of 95%air and 5%CO 2 in IMDM supplemented with 10%fetal bovine serum (FBS) . Cells used in all the experiment were among passages 9 to 25. LTC-14 cells were seeded at a density of 1 ⁇ 10 5 /well in a 12-well plate, and incubated with recombinant TGF- ⁇ at 5 ng/mL with dihydro-resveratrol at 0, 1, 5, 10 and 20 ⁇ g/mL in IMDM supplemented with 0.2%FBS for 24 hours. Cells were then harvested for protein extraction and Western blotting analysis or immunofluorescent staining.
  • FBS fetal bovine serum
  • Total proteins of the LTC-14 cells are extracted using RIPA lysis buffers containing protease inhibitors. Cell lysates were loaded and separated by SDS-polyacrylaminde gel electrophoresis. After wet electroblotting, proteins were transferred onto PVDF membranes (Bio-rad) , blocked with 5 %non-fat milk, probed with antibodies and visualized by utilization of an ECL kit (GE Healthcare) .
  • LTC-14 cells were seeded at a density of 1 ⁇ 10 5 onto the poly-L-lysine-coated cover slips in a 24-well plate, incubated with TGF- ⁇ at 5 ng/mL with dihydro-resveratrol at 0, and 10 ⁇ g/mL in IMDM supplemented with 0.2%FBS for 24 hours. Cells were then fixed, blocked with 3%BSA, probed with antibodies and mounted with fluorescence mounting medium containing 4’, 6-diamidino-2-phenylindole (DAPI) . Images were captured using the Nikon microscope and analyzed by the SPOT advanced software.
  • DAPI 6-diamidino-2-phenylindole
  • mice C57/BL6 mice aged 28 days weighing in the range of 20 to 25 g were randomly assigned into 4 groups of 6 to 8 individuals. The mice were housed with an ambient temperature of 23 ⁇ 2°C, a relative humidity of 60 to 80%and a 12-h light/dark cycle. Prior to the glucose tolerance test, the mice were starved overnight but allowed with free access to water. Experimental chronic pancreatitis was induced in the mice by four hourly i. p. injections of cerulein at the supramaximally stimulating dose (50 ⁇ g/kg) a day, 3 days a week, in a total of 6 weeks. The control group received injections of 0.9%saline instead of cerulein in the same volume and at same time intervals.
  • the treatment groups given with cerulein and oral doses of dihydro-resveratrol (20 mg/kg/day) were designated as Cer+D-res.
  • a dosage of dihydro-resveratrol at 50 mg/kg/day had also been attempted in the treatment course, but no statistically significant difference from the dose at 20 mg/kg/day in fibrosis formation was achieved. Nevertheless, no adverse effect was obtained from this higher dosage in the in vivo trial. Thus, it concludes that an effective dosage of dihydro-resveratrol is at least 20 mg/kg/day.
  • the group given with trans-resveratrol was designated as Cer+Res.
  • the drug intervention of both compounds was given from the first day of week 4 till the end of experiment, i.e.
  • mice were subjected to the intraperitoneal glucose tolerance test (IPGTT) .
  • IPGTT intraperitoneal glucose tolerance test
  • Mice had been starved for 14 hours prior to the IPGTT, in which a 15%(w/v) glucose solution was injected to individual animals at 1.5 g glucose per kg body weight.
  • About 1 ⁇ L of blood will be obtained from the tail vein, and blood glucose levels were monitored 30 min before (i.e. fasting level) and 10, 20, 30 and 60 min after glucose injection using a glucometer (Medisign, Korea) .
  • pancreases were immediately removed, weighed, trimmed from fat and fixed in 4%paraformaldehyde-phosphate buffered saline overnight at 4°C. Samples were then processed, embedded in paraffin wax, sectioned and subjected to immunostaining.
  • human equivalent dosage (mg/kg) Animal dose (mg/kg) multiplied by animal Km/human Km, where mouse Km is 3 and human Km is 37 (Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers)
  • the effective human equivalent dosage of dihydro-resveratrol of the present invention is at least 1.622 mg/kg/day.
  • LTC-14 cells were pre-incubated with TGF- ⁇ (5 ng/mL) , and treated with trans-resveratrol (Resv) or dihydro-resveratrol (D-Res) or stilbene compounds i-viii at 20 ⁇ g/mL for 24 hours. Control was not treated with Resv or any stilbenoids. Total proteins were extracted and analyzed using Western blotting. This is shown in Figure 9.
  • LTC-14 cells are pancreatic stellate cells.
  • ⁇ -SMA is the hallmark component of fibrogenesis whereas ⁇ -actin serves as a loading control.
  • the expression level of ⁇ -SMA implies the degree of PSC activation.
  • TGF- ⁇ was added since it is regarded as a potent inducer of fibrotic events.
  • Suppressive effect on ⁇ -SMA expression level is tested among dihydro-resveratrol and compounds i to viii in relation to trans-resveratrol (Resv) . All of the testing compounds exert suppressive effect of ⁇ -SMA expression level.
  • LTC-14 cells were pre-incubated with TGF- ⁇ (5 ng/mL) , and treated with trans-resveratrol or dihydro-resveratrol at the indicated concentrations. Total proteins were extracted and analyzed using Western blotting. This is shown in Figure 10.
  • FN1 is a major extracellular matrix protein produced during fibrogenesis or upon the activation of pancreatic stellate cells. Its expression level implies the degree of fibrogenesis. Suppressive effect on levels of FN1 and ⁇ -SMA is tested between dihydro-resveratrol (i.e. compound 2) and trans-resveratrol.
  • LTC-14 cells were pre-incubated with TGF- ⁇ (5 ng/mL) , and treated with dihydro-resveratrol at 20 ⁇ g/mL for 24 hours prior to immunofluorescent staining.
  • LTC-14 cells are pancreatic stellate cells.
  • ⁇ -SMA is the hallmark component of fibrogenesis whereas ⁇ -actin serves as a loading control.
  • the green fluorescent signal (identified by arrow marks in Figure 11) of ⁇ -SMA implies the degree of PSC activation.
  • TGF- ⁇ was added since it is regarded as a potent inducer of fibrotic events. Suppressive effect of dihydro-resveratrol on ⁇ -SMA expression level is tested.
  • Pancreatic tissue sections are stained with antibody against FN1; thus, the immunostaining signals imply the degree of FN1 deposition in the parenchyma.
  • the treatment with dihydro-resveratrol at 20 mg/kg/day reduces such deposition in chronic pancreatitis in a manner more significant to trans-resveratrol (Cer+Res) . This is shown in Figure 12.
  • C57/BL6 mice aged 28 days weighing in the range of 20 to 25 g were randomly assigned into 4 groups of 6 to 8 individuals. The mice were housed with an ambient temperature of 23 ⁇ 2°C, a relative humidity of 60 to 80%and a 12-h light/dark cycle.
  • dihydro-resveratrol 20 mg/kg/day
  • the fasting blood glucose levels of the chronic pancreatitis mice (Cer) become markedly higher than those of the control group, indicating these chronic pancreatitis mice develop hyperglycemia, a discernible feature of diabetes.
  • their impaired glucose tolerance has been significantly rectified by the 3-week dihydro-resveratrol treatment (Cer+D-Res) .
  • the hyperglycemic condition of the chronic pancreatitis mice is improved. This is shown in Figure 13.
  • dihydro-resveratrol Cer+D-Res
  • the severity of pancreatitis and the shrinkage and destruction of islets, explicitly beta cells are notably ameliorated.
  • the pancreatic beta-cell area is reflected by the immunofluorescent insulin signals.
  • a reduced beta-cell area or mass implicates the deficiency in glucose tolerance, or the development of diabetes.
  • the restoration of beta-cell area by the dihydro-resveratol treatment indicates this stilbenoid is beneficial to the treatment of pancreatogenic diabetes (i.e. Type3c DM) .
  • human equivalent dosage (mg/kg) Animal dose (mg/kg) multiplied by animal Km/human Km, where mouse Km is 3 and human Km is 37 (Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers)
  • the effective human equivalent dosage of dihydro-resveratrol of the present invention is at least 1.622 mg/kg/day.
  • Dendrobium plants commonly called “Shi Hu”
  • TCM Chinese medicine
  • Dendrobium-derived extracts or ingredients contain substantial amounts of various stilbenoids, such as trans-resveratrol and dihydro-resveratrol, which are potential compounds for combating oxidative stress in the human body.
  • stilbenoids such as trans-resveratrol and dihydro-resveratrol
  • the present invention relates to the use of Dendrobium-derived stilbenoids, particularly trans-resveratrol, dihydro-resveratrol or dihydro-resveratrol derivatives in reducing melanin formation with a potential to inhibit the generation of oxidative radicals and ROS.
  • the present composition is applied to the subject in need thereof via topical administration.
  • the present composition is in the form of a day cream, a night cream, a face lotion, a body lotion, a body butter, a skin peel, a mask, a shower gel, a sun cream, a sun lotion, an after sun cream or an after sun lotion.
  • the present composition comprises one or more extract (s) derived from Dendrobium plants.
  • the present composition comprises one or more stilbenoids with the following formula:
  • R 2 , R 4 , and R 8 are each independently selected from -OR 11 , -OCH 2 R 12 , -OC (O) R 11 , -OCH 2 C (O) OR 12 and -OC (O) CH 2 R 12 ;
  • R 1 , R 3 , R 5 , R 6 , R 7 , R 9 and R 10 are each independently selected from hydrogen, halogen, trifluoromethyl, OR 12 and -OC (O) R 12 ; or R 2 and R 3 , or R 7 and R 8 may be taken together with the carbon atoms to which they are attached to form a cyclic group;
  • R 11 is independently selected from – (CH 2 ) -hydrocarbyl, C 2-10 alkyl, alkenyl , cycloalkyl, aryl and heterocyclyl, Each of these groups is optionally substituted with 1, 2, 3, 4 or 5 R 13 ;
  • R 12 is independently selected from hydrocarbyl and heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 13 ;
  • R 13 is independently selected from halogen, trifluoromethyl, cyano, nitro, oxo, -OR 14 , -C (O) R 15 , -C (O) N (R 14 ) R 15 , -C (O) OR 14 , -OC (O) R 15 , -S (O) 2 R 14 , -S (O) 2 N (R 14 ) R 15 , -N (R 14 ) R 15 ;
  • R 14 and R 15 are each independently hydrogen or selected from hydrocarbyl and heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, cyano, amino, hydroxy, C 1-6 alkyl and C 1-6 alkoxy;
  • the present composition comprises stilbenoid (s) with the following formula: which is dihydro-resveratrol, and the derivatives or chemical variants thereof; or a mixture of said compound, the derivative and/or chemical variants thereof, or with a formula of:
  • composition for skin whitening and skin protection comprises stilbenoid (s) with the following formula:
  • R 2 , R 4 , and R 8 are each independently selected from -OR 11 , -OCH 2 R 11 , -OC (O) R 11 , -OCH 2 C (O) OR 11 and -OC (O) CH 2 R 11 ;
  • R 1 , R 3 , R 5 , R 6 , R 7 , R 9 and R 10 are each independently selected from hydrogen, halogen, trifluoromethyl, -OR 11 and -OC (O) R 11 ; or R 2 and R 3 , or R 7 and R 8 may be taken together with the carbon atoms to which they are attached to form a cyclic group;
  • R 11 is independently hydrogen or selected from hydrocarbyl and heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 12 ;
  • R 12 is independently selected from halogen, trifluoromethyl, cyano, nitro, oxo, -OR 13 , -C (O) R 14 , -C (O) N (R 13 ) R 14 , -C (O) OR 13 , -OC (O) R 14 , -S (O) 2 R 13 , -S (O) 2 N (R 13 ) R 14 , -N (R 13 ) R 14 ;
  • R 13 and R 14 are each independently hydrogen or selected from hydrocarbyl and heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, cyano, amino, hydroxy, C 1-6 alkyl and C 1-6 alkoxy;
  • a spectrophotometric decolorization assay complemented with pre-formed radical monocation of 2, 2'-azinobis- (3-ethylbenzothiazoline-6-sulfonic acid) , also known as ABTS is used.
  • ABTS (Abcam, USA) is dissolved in water to a 7 mM concentration and ABTS radical cation is produced by reacting the ABTS stock solution with 2.45 mM ammonium persulfate (Sigma-Aldrich, USA) and allowing the mixture to stand in the dark at room temperature for 16 hours before use.
  • the ABTS radical solution is diluted with ethanol to an absorbance of 0.70 at 734 nm and equilibrated at 30°C.
  • the dilutions of testing samples (0.1 mL) or DMSO (0.1 mL) are incubated with ABTS radical solution (0.9 mL) for 15 min prior to the absorbance taking at 734 nm.
  • DMSO is served as a vehicle treatment
  • Trolox (Abcam, USA) , a renowned derivative vitamin E, ranging from 0.001 to 0.05 mg/mL is used as a positive drug reference.
  • the antioxidant capacity of testing samples is expressed as the amount equivalent to Trolox in milligrams (mg) according to the Trolox standard curve.
  • the cellular melanin content and tyrosinase activity are determined in cultured B16 and A375 melanocytes.
  • melanocytes are melanin-producing cells whereas melanin refers to groups of endogenous pigments that give multitude of skin colors.
  • B16 cells (Shanghai Institutes for Biological Science, Chinese Academy of Sciences, China) and A375 cells (American Type Culture Collection, USA) are routinely grown in DMEM medium (Gibco, USA) supplemented with 10%heat-activated fetal bovine serum (FBS, Gibco, USA) and 1%penicillin/streptomycin (Gibco, USA) in a humidified atmosphere of 95%air and 5%CO 2 at 37°C.
  • melanocytes are seeded in 12-well plates (8 ⁇ 10 4 cells/well) and stimulated with alpha-melanocyte-stimulating hormone ( ⁇ -MSH, 100 nM) for 24 hours.
  • ⁇ -MSH alpha-melanocyte-stimulating hormone
  • ⁇ -MSH alpha-melanocyte-stimulating hormone
  • cells are then treated with different Dendrobium extract samples or stilbenoid samples (5 ⁇ L) or DMSO (5 ⁇ L, Sigma-Aldrich, USA) for another 24 hours.
  • DMSO serves as a vehicle treatment.
  • cells are trypsinized for detaching from the culturing plates. After centrifugation, the melanin pellet of each sample is incubated with 100 ⁇ L of 1 N Sodium hydroxide solution (Sigma-Aldrich, USA) for 1.5 hours at 70°C. After cooling to room temperature, the solution is centrifuged at 15,000 ⁇ g for 10 min. The supernatant (100 ⁇ L) of each sample is transferred to 96-well plates for a reading of absorbance taken at 405 nm. Relative melanin content of each sample is normalized with its protein content and presented as the percentage change over the DMSO-treated cells.
  • 1 N Sodium hydroxide solution Sigma-Aldrich, USA
  • D-Res dihydro-resveratrol
  • Res trans-resveratrol
  • Dendrobium extract samples or other stilbenoid samples compounds DR1 to DR11
  • melanocytes are seeded in 12-well plates (8 ⁇ 10 4 cells/well) and stimulated with ⁇ -MSH (100 nM) for 24 hours. Post the ⁇ -MSH stimulation, cells are treated with different testing samples (5 ⁇ L) or DMSO (5 ⁇ L) for another 24 hours. At the end of experiment, the cells are washed with ice-cold phosphate buffer saline (PBS, pH 6.8) (Gibco, USA) twice and then lysed with 150 ⁇ L of PBS (pH 6.8) containing 0.1%Triton X-100 on ice. The cell lysates are centrifuged at 15,000 ⁇ g for 15 min at 4°C.
  • PBS ice-cold phosphate buffer saline
  • B16 or A375 cells are seeded in 12-well plates (8 ⁇ 10 4 cells/well) and stimulated with ⁇ -MSH (100 nM) for 24 hours.
  • ⁇ -MSH 100 nM
  • cells are trypsinized for detaching from the culturing plates and subjected to cellular ROS detection assay (Abcam) according to manufacturer’s instruction.
  • Abcam cellular ROS detection assay
  • cells are stained with 20 ⁇ M DCFDA for 30 min at 37°C.
  • ITA° ITA°
  • L* luminance
  • b* yellow-blue component
  • Two areas (2 cm ⁇ 2 cm each) are selected as treated areas whereas regions surrounding the treated areas on the arms are regarded as control areas.
  • a volume of 200 ⁇ L of the testing stilbenoids (2%by weight dissolved in ethanol) is applied to the designated area twice a day, day and night.
  • individuals are tested with the skin colorimeter for recording the data about using the stilbenoids for 7 days.
  • individuals are tested with the skin colorimeter for recording the data about using the stilbenoids for 14 days.
  • the ITA° readings are presented in Table 5. Overt whitening effect from dihydro-resveratrol or trans-resveratrol is obtained from most individuals.
  • a set of representative images taken from a human individual who uses the topical treatment is shown in Figure 23.
  • the R group in RBr can be OR 11 , -OCH 2 R 11 or -OCH 2 C (O) OR 11 , where R 11 is hydrocarbyl.
  • the R group in RCOCl can be -R 11 or -CH 2 R 11 , where R 11 is hydrocarbyl, which is optionally substituted with 1, 2, 3, 4 or 5 R 12 , and where R 12 is halogen or -OR 13 , and where R 13 is hydrogen or hydrocarbyl.
  • the present invention relates to a skin-protection composition that comprises stilbenoid (s) and/or stilbenoid-containing extract (s) obtained from Dendrobium plants, such as Dendrobium officinale and Dendrobium nobile for the management of melanogenesis, skin-darkening and skin-aging. More particularly, it relates to the usage of Dendrobium ingredients and stilbenoids to reduce the formation of melanin in melanocytes. It also relates to the usage of Dendrobium ingredients and stilbenoids to reduce the generation of reactive oxygen species and oxidative free radicals. This invention relates to the use Dendrobium-derived extracts or ingredients or stilbenoids in the formulation of skin-protection, skin-whitening and/or anti-skin aging products.

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Abstract

L'invention concerne une composition de blanchiment et de protection de la peau comprenant un(des) stilbénoïde(s) et/ou un(des) extrait(s) contenant un(des) stilbénoïde(s) obtenus à partir de plantes de Dendrobium, telles que Dendrobium officinale et Dendrobium nobile pour la gestion de la mélanogenèse, ainsi que de l'assombrissement et du vieillissement de la peau. Plus particulièrement, l'invention concerne l'utilisation d'ingrédients de Dendrobium et de stilbénoïdes pour réduire la formation de mélanine dans les mélanocytes. L'invention concerne également l'utilisation d'ingrédients de Dendrobium et de stilbénoïdes pour réduire la génération d'espèces réactives de l'oxygène et de radicaux libres oxydatifs. L'utilisation d'extraits ou d'ingrédients ou de stilbénoïdes dérivés de Dendrobium dans la formulation de produits de protection, de blanchiment et/ou de vieillissement de la peau. L'invention concerne en outre des composés destinés à être utilisés dans la préparation d'une composition pour le traitement, la prévention, et/ou le retardement de la progression de l'assombrissement de la peau ou pour une utilisation dans le blanchiment et dans la protection de la peau qui sont synthétisés à partir de dihydro-resvératrol et le procédé de synthèse associé.
PCT/CN2017/107798 2016-11-15 2017-10-26 Composition de protection de la peau contenant des ingrédients à base de dendrobium WO2018090805A1 (fr)

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Publication number Priority date Publication date Assignee Title
CN115634187A (zh) * 2022-12-26 2023-01-24 云南英格生物技术有限公司 铁皮石斛花提取物及制备方法和应用、铁皮石斛花提取液及应用、舒缓面霜及制备方法
CN115634187B (zh) * 2022-12-26 2023-03-31 云南英格生物技术有限公司 铁皮石斛花提取物及制备方法和应用、铁皮石斛花提取液及应用、舒缓面霜及制备方法

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CN109952286A (zh) 2019-06-28
TWI732967B (zh) 2021-07-11
TW201818956A (zh) 2018-06-01

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