WO2014094269A1 - 薏苡子麸皮的萃取物及其应用 - Google Patents

薏苡子麸皮的萃取物及其应用 Download PDF

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Publication number
WO2014094269A1
WO2014094269A1 PCT/CN2012/086998 CN2012086998W WO2014094269A1 WO 2014094269 A1 WO2014094269 A1 WO 2014094269A1 CN 2012086998 W CN2012086998 W CN 2012086998W WO 2014094269 A1 WO2014094269 A1 WO 2014094269A1
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WIPO (PCT)
Prior art keywords
bran
skin
extract
hazelnut
alcohol
Prior art date
Application number
PCT/CN2012/086998
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English (en)
French (fr)
Inventor
曾焕中
黄乔志
贾铜安
Original Assignee
乔本生医股份有限公司
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Filing date
Publication date
Priority to SI201231024T priority Critical patent/SI2937095T1/sl
Priority to HUE12890400A priority patent/HUE034481T2/en
Priority to PL12890400T priority patent/PL2937095T3/pl
Priority to JP2015548137A priority patent/JP6029770B2/ja
Priority to PT128904000T priority patent/PT2937095T/pt
Priority to LTEP12890400.0T priority patent/LT2937095T/lt
Priority to ES12890400.0T priority patent/ES2638149T3/es
Priority to PCT/CN2012/086998 priority patent/WO2014094269A1/zh
Application filed by 乔本生医股份有限公司 filed Critical 乔本生医股份有限公司
Priority to EP12890400.0A priority patent/EP2937095B1/en
Priority to RS20170831A priority patent/RS56192B1/sr
Priority to DK12890400.0T priority patent/DK2937095T3/en
Publication of WO2014094269A1 publication Critical patent/WO2014094269A1/zh
Priority to HRP20171171TT priority patent/HRP20171171T1/hr
Priority to CY20171100883T priority patent/CY1119360T1/el

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/899—Poaceae or Gramineae (Grass family), e.g. bamboo, corn or sugar cane
    • A61K36/8994—Coix (Job's tears)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones

Definitions

  • the present invention relates to hazelnut bran extracts and uses thereof; in particular, for the treatment of skin and/or subcutaneous tissue diseases. Background technique
  • the skin is the main barrier between the body's largest organ and the body and the environment, resisting microbial pathogens and physical and chemical stress or stimulation on the first line.
  • the skin not only provides physical and chemical protection, but also an immune organ that can effectively cause passive and active immune responses, thereby protecting the human body.
  • the skin is divided into three layers of epidermis, dermis and subcutaneous tissue from the outside to the inside.
  • the outermost epidermis is responsible for the protective function; the dermis layer located in it is the most important part of the skin, which is responsible for supporting the epidermis and various fibers. Interwoven into a support net, and can distribute blood vessels, lymphatic vessels, nerves, sebaceous glands, sweat glands, and edulis; the innermost layer of the skin is the subcutaneous tissue, which is broadly referred to as the deep layer of the spinal dermal dermis. It refers to the fat connective tissue between the dermis and the bones and muscles below it. There is no obvious boundary between the dermis and the dermis. It is mainly formed by fat cells, which is responsible for thermal barrier, absorbs vibration and provides a source of energy, and is also a fat metabolism. The main place.
  • Skin and/or subcutaneous tissue can cause various diseases due to congenital or acquired factors, causing discomfort to the patient, and the patient's psychological burden due to changes in appearance, and the skin and/or subcutaneous tissue used today.
  • the drug is either a steroid or an acidic drug, and if it is not properly used, it is not a suitable treatment.
  • Radiotherapy In skin and/or subcutaneous tissue diseases, damage caused by radiation therapy is an important category. Radiotherapy often causes side effects such as radiation dermatitis, fatigue, radiation pneumonia and lymphedema. ⁇ McCormick et al" 1989, Int J Radiat Oncol Biol Phys., 17:1299-1302; Lingos et ah, 1991, Int. J. Radiat. Oncol. Biol. Phys., 21:355-360', Taylor et al., 1995, Int J. Radiat. Oncol. Biol. Phys., 31 ⁇ 753-764; Gorodetsky et al" 1999, Int. J. Radiat. Oncol. Biol.
  • ⁇ (Co x lachryma-jobi L. var. ma-yuen Stapf) is also known as the "Job's tears", one of the Chinese herbal medicines (TCM), which has long been used as an anti-inflammatory drug.
  • TCM Chinese herbal medicines
  • DA dehulled adlay
  • tweezers have anti-inflammatory and anti-oxidant effects (ee, M. ⁇ ; Tsai, S. ⁇ ; Kuo, ⁇ . ⁇ ; Chiang, W. Food Sci. Biotechnol. 2008, 17, 1265-1271; Kuo, C. C; Shih, M. C; Kuo, Y. K; Chiang, WJ Agric. Food Chem. 2001, 49, 1564- 1570).
  • Many of the potent ingredients contained in many different sources have been quantified (7: T.; Charles, AL; Huang, TC Food Chem. 2007, 104, 1509-1515).
  • the flavonoids and several phenolic compounds C3 ⁇ 4 a «g, DW; Kuo, ⁇ . ⁇ ; Lin, FY; Lin, Y. L; Chiang, WJ Agric. Food Chem. 2009, 57, 2259-2266; Huang, D. W; Chung, CP; Kuo, Y. K; Lin, Y. L; Chiang, WJ Agric. Food Chem. 2009, 57,
  • ferulic acid has been found to be an anti-inflammatory active ingredient after intensive research (C1 ⁇ 2 «g, CP; Hsu, ⁇ .; Huang, DW; Hsu, H. K; Lin, JT; Shih, CK; Chiang, WJ Agric. Food Chem. 2010, 58, 7676-7623).
  • the effect of treating skin and/or subcutaneous tissue diseases by the extract of gardenia in particular, providing radiation protection or enhancing the efficacy of radiation to reduce the radiation dose, can benefit cancer patients receiving radiation therapy.
  • the present invention provides a composition
  • an extract of scorpion bran (bran) comprising an alcohol extract (A) having a carbon number of 1 to 7 and a mash of scorpion bran Carbon dioxide supercritical fluid extract (B) of the bran skin, wherein the alfalfa bran has an alcohol extract of 1 to 7 carbon number (A) and a carbon dioxide supercritical fluid extract of the hazelnut bran (B)
  • the weight ratio is from about 3:1 to about 1:4.
  • the invention also provides the use of an extract of the aforementioned hazelnut bran for the manufacture of a medicament for the treatment of skin and/or subcutaneous tissue disorders.
  • the invention further provides a method of treating a skin and/or subcutaneous tissue disease in an individual comprising administering to the individual a therapeutically effective amount of an extract of scorpion bran and optionally a pharmaceutically acceptable carrier or U wu Shape agent.
  • the present invention further provides the use of the aforementioned extract of hazelnut bran for the manufacture of reduced interleukin (IL)-la, interleukin-1 ⁇ , interleukin-6, Drugs for tumor necrosis factor (TNF)-a, interleukin-8, prostaglandin 2 (PGE2) and/or C-reactive protein (CRP).
  • IL interleukin
  • TNF tumor necrosis factor
  • PGE2 prostaglandin 2
  • C-reactive protein C-reactive protein
  • the invention further provides a method for reducing interleukin-la, interleukin-1 ⁇ , interleukin-6, tumor necrosis factor- ⁇ , interleukin-8, prostaglandin 2 and/or C-reactive protein in an individual.
  • a method comprising administering to the individual a therapeutically effective amount of an extract of scorpion bran and optionally a pharmaceutically acceptable carrier or a granule.
  • Figure 1 shows an alcohol extract ( ⁇ ) having a carbon number of 1 to 7 of hazelnut bran according to the present invention. HPLC map.
  • Figure 2 shows an HPLC chromatogram of a carbon dioxide supercritical fluid extract (B) of hazelnut bran according to the present invention.
  • Fig. 3 shows an HPLC chromatogram of the alcohol extract (A) having a carbon number of 1 to ⁇ and the carbon dioxide supercritical fluid extract (B) of scorpion bran according to the present invention in a weight ratio of 1:4.
  • Figure 4 shows histopathological sections of the different feeding doses of scorpion capsule or clinical radiation treatment of the skin lesion drug Sulfasil, which causes radiation damage in the leg skin of mice.
  • RT indicates radiation therapy
  • sham indicates no radiation therapy
  • vehicle indicates carrier without scorpion extract.
  • Figure 5 shows the results of changes in body weight of the skin lesions Sulfasil, which is administered to tumor animals by radiotherapy while feeding different concentrations of scorpion capsules or clinical radiation.
  • RT indicates radiation therapy;
  • sham treatment indicates no radiation therapy;
  • carrier indicates carrier without scorpion extract.
  • Figure 6 shows the results of tumor volume changes in tumor-bearing animals treated with radiotherapy at different concentrations of scorpion capsules or clinical radiotherapy for the skin lesions Sulfasil.
  • RT indicates radiation therapy;
  • sham treatment indicates no radiation therapy;
  • carrier indicates carrier without scorpion extract.
  • Figure 7 shows the results of the changes in serum IL-la concentration in the serum of patients with tumors treated with different concentrations of scorpion capsules or clinical radiotherapy for the skin lesions Sulfasil.
  • RT indicates radiation therapy;
  • sham treatment indicates no radiation therapy;
  • carrier indicates carrier without scorpion extract.
  • Fig. 8 is a graph showing the results of changes in serum IL- ⁇ concentration in tumors treated with radiation therapy of different concentrations of scorpion capsules or clinical radiation treatment of Sulfasil.
  • RT indicates radiation therapy;
  • sham treatment indicates no radiation therapy;
  • carrier indicates carrier without scorpion extract.
  • Figure 9 is a graph showing the results of changes in serum IL-6 concentration in tumors treated with radiation therapy at different concentrations of scorpion capsules or clinical radiotherapy for Sulfasil.
  • RT indicates radiation therapy;
  • sham treatment indicates no radiation therapy;
  • carrier indicates carrier without scorpion extract.
  • Fig. 10 is a graph showing the results of changes in serum TNF- ⁇ concentration in a tumor animal treated with radiation therapy while administering different concentrations of scorpion capsule or clinical radiation treatment for skin lesion drug Sulfasil.
  • RT indicates radiation therapy; sham treatment indicates no radiation therapy; carrier indicates carrier without scorpion extract.
  • Figure 11 is a graph showing the results of changes in serum IL-8 concentration in tumors in which the tumor animals were given radiotherapy while feeding different concentrations of scorpion capsules or clinical radiation treatment of the skin lesion drug Sulfasil.
  • RT indicates radiation therapy; sham treatment indicates no radiation therapy; carrier indicates carrier without scorpion extract.
  • Fig. 12 is a graph showing the results of changes in the concentration of PGE2 in serum by administering a different dose of scorpion capsule or clinical radiotherapy to the skin lesion drug Sulfasil in tumor animals.
  • RT indicates radiation therapy
  • sham treatment indicates no radiation therapy
  • carrier indicates carrier without scorpion extract.
  • Fig. 13 is a graph showing the results of changes in serum CRP concentration in a tumor animal treated with radiation therapy at different concentrations of scorpion capsule or clinical radiotherapy for Sulfasil.
  • RT indicates radiation therapy;
  • sham treatment indicates no radiation therapy;
  • carrier indicates carrier without scorpion extract.
  • Figure 14 shows a histopathological section of 25 different feeding doses/combinations on the effects of radiation therapy on the damage of leg skin tissue in mice.
  • the horizontal axis and the vertical axis show the alcohol extract (A) having a carbon number of 1 to 7 and the carbon dioxide supercritical fluid extract of the hazelnut bran (B) feeding dose/combination (mg/kg).
  • A alcohol extract
  • B carbon dioxide supercritical fluid extract of the hazelnut bran
  • Each of the images shows the histopathological section of the fur tissue of mice fed different dose combinations in the mouse tumor radiotherapy process.
  • the present invention provides a composition
  • an extract of scorpion bran (bran) comprising an alcohol extract (A) having a carbon number of 1 to 7 and a mash of scorpion bran Carbon dioxide supercritical fluid extract (B) of sub-bron, wherein the alfalfa bran has an alcohol extract of 1 to 7 carbon number (A) and a carbon dioxide supercritical fluid extract of the hazelnut bran (B)
  • the weight ratio is from about 3:1 to about 1:4.
  • Range is generally expressed herein as "about” a particular value and/or to "about” another particular value.
  • a scheme is a range that includes one particular value and/or to another particular value.
  • values are expressed as approximations by the use of the word "about,” it should be understood that a particular value may form another.
  • each endpoint of each range is significant, and one endpoint is related to the other endpoint and independent of each other.
  • the term "individual” as used herein denotes any animal, preferably a mammal, and more preferably a human. Examples of individuals include humans, non-human primates, rodents, guinea pigs, rabbits, sheep, pigs, goats, cows, horses, dogs, and cats.
  • the term "effective amount" of a compound as provided herein means that the amount of the compound is sufficient to provide the desired modulation of the desired function, such as gene expression, protein function, or induction of a particular type of response. As indicated below, the exact amount of demand will vary from individual to individual, depending on the individual's disease condition, physical condition, age, sex, species and weight, characteristics of the composition, and formulation. The dosage regimen can be adjusted to induce an optimal therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced depending on the urgency of the treatment situation. Therefore, it is difficult to specify the exact "effective amount”.
  • treating as used herein means reversing, alleviating or ameliorating the condition or condition to which the term applies, or one or more symptoms of the condition or condition, or inhibiting its progression.
  • carrier or "excipient” as used herein refers to a carrier and/or diluent and/or adjuvant or vehicle that is not itself a therapeutic agent but is used to deliver a therapeutic agent to an individual.
  • Suitable carriers or excipients are well known to those of ordinary skill in the art of making pharmaceutical preparations or food products.
  • the carrier or excipient may include, by way of example and not limitation, buffers, diluents, disintegrating agents, binders, binders, wetting agents, polymers, lubricants, slip agents, masking or offsetting a substance or substance added by taste or smell A flavoring agent, a dye, a fragrance, and a substance added to improve the appearance of the composition.
  • Acceptable carriers or excipients include citrate buffers, phosphate buffers, acetate buffers, bicarbonate buffers, stearic acid, magnesium stearate, magnesium oxide, phosphoric acid, and sodium sulfate.
  • Salts and calcium salts magnesium carbonate, talc, gelatin, gum arabic, sodium alginate, pectin, dextrin, mannitol, sorbitol, lactose, sucrose, starch, gelatin, cellulosic materials (such as alkanoic acid fibers) Alizarin and cellulose alkyl esters), low melting waxes, cocoa butter, amino acids, urea, alcohols, ascorbic acid, phospholipids, proteins (eg serum albumin), ethylenediaminetetraacetic acid (EDTA), disulfoxide ( DMSO), sodium chloride or other salts, liposomes, mannitol, sorbitol, glycerin or powder, polymers (such as polyvinylpyrrolidone, polyvinyl alcohol and polyethylene glycol), and other pharmaceutically acceptable Accepted substance.
  • the carrier should not destroy the pharmacological activity of the therapeutic agent and should be non-toxic when administered at a dose sufficient to deliver
  • the composition according to the invention is an extract comprising hazelnut bran
  • the hazelnut bran according to the invention is preferably obtained from a dehulled tweezers
  • the term "dehulled tweezers” as used herein means no Seeds with shells, testas, coverings, shells or pods.
  • the manner in which the shell, sheath, outer shell or pod is removed from the raft is well known to those of ordinary skill in the art to which the present invention pertains.
  • shelled hazelnuts comprise bran and endosperm, and the manner in which the bran is obtained from the dehulled tweezers is well known to those of ordinary skill in the art to which the invention pertains.
  • the cockroach according to the present invention is not particularly limited, and preferably, the cockroach belongs to the grass family.
  • the cockroach is Coix lachryma-jobi, Coix lachryma-jobi L" Coix lachryma- jobi L. var. ma-yuen Stapf, Coix agrestis Lour., Coix arundinacea Lam., Coix exaltata J acq. or Coix lacryma L . . .
  • the extract of the hazelnut bran according to the present invention comprises an alcohol extract (A) having a carbon number of 1 to 7 of hazelnut bran and a carbon dioxide supercritical fluid extract (B) of hazelnut bran.
  • alcohol having a carbon number of 1 to fluorene as used herein means a straight or branched, substituted or unsubstituted, unit or polyvalent, saturated or unsaturated alcohol, preferably without substitution.
  • Base unit and saturated alcohol.
  • the alcohol having 1 to 7 carbon atoms is preferably an alcohol having 1 to 4 carbon numbers.
  • the alcohol having 1 to 7 carbon number is decyl alcohol, ethanol, n-propanol, isopropanol, n-butan, isobutyl (iso-butanol), sec-butanol, tert-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-mercapto-1-butanol, 2 - mercapto-2-butanol, 3-mercapto-2-butanol, 3-mercapto-1-butanol, 2,2-dimercapto-1-propanol, 1-hexanol, 2,4-dihexan-1-ol, 2-mercapto-cyclopentanol, cyclohexanol, 1-heptanol, 2-heptanol or cycloheptanol; particularly preferably, the alcohol It is sterol or ethanol; most preferably, the alcohol is ethanol.
  • the alcohol may be used
  • the alcohol having a carbon number of 1 to 7 as described herein is preferably an aqueous solution, preferably at a concentration of from about 49% to about 99.9% alcohol solution; more preferably from about 75% to about 99.9% alcohol solution; particularly preferred It is from about 90% to about 98.0% alcohol solution.
  • the "alcohol extract (A) having a carbon number of 1 to 7 in the hazelnut bran” described herein means an extract obtained by extracting hazelnut bran with an alcohol having a carbon number of 1 to 7.
  • the manner in which the seed site is extracted by solution is well known to those of ordinary skill in the art to which the present invention pertains.
  • the hazelnut bran is immersed in the alcohol solution for extraction, and more preferably, the hazelnut bran is immersed in the alcohol solution and ultrasonically oscillated for extraction. .
  • the temperature of the extraction is preferably from about 10 ° C to about 100 ° C; more preferably from about 15 ° C to about 50 ° C; particularly preferably from about 20 ° C to about 40 ° C.
  • the alcohol extract (A) having a carbon number of 1 to 7 of the hazelnut bran is prepared by a production method comprising the following steps:
  • step (c) extracting a small piece of the step (b) with an alcohol having a carbon number of 1 to 7 to provide the extract.
  • the hazelnut bran is preferably dried before the step (b).
  • step (b) further comprises crumbing the cake into a powder.
  • the manner of dicing and/or shredding is well known to those of ordinary skill in the art to which the invention pertains.
  • the ratio (w/v) of the dehulled hazelnut and the alcohol solution is not particularly limited and may be from about 1:1 to about 1:10; preferably, from about 1:3 to about 1:8; particularly preferably; 1:5.
  • the extracting step (c) can be repeated and the combined extracts collected.
  • the preparation method further comprises the step (d) of obtaining a liquid separation from the extract and removing the solid.
  • the method of removing the solid portion to obtain the liquid separation is well known to those of ordinary skill in the art to which the present invention pertains.
  • the preparation method further comprises a concentration step.
  • concentration is well known to those of ordinary skill in the art to which the present invention pertains, for example, using a reduced pressure concentrator.
  • the carbon dioxide supercritical fluid extract (B) of the hazelnut bran according to the present invention is referred to as two An extract obtained by extracting hazelnut bran from a carbon oxide supercritical fluid.
  • Supercritical fluid means that when the critical temperature and the critical pressure are exceeded, the properties of the gas and the liquid will be similar, and finally a homogenous fluid state will be achieved.
  • Supercritical fluids are similar to gases with compressibility and liquid-like fluidity. They can be used for extraction.
  • Commercially available supercritical fluid extraction equipment is also available. For example, NATEX, SEPAREX, UHDE and Taichao are commercially available.
  • the supercritical fluid extraction equipment, its model specifications are generally expressed in the capacity of the extraction tank, from 500 g to 2000 kg, you can choose the appropriate supercritical fluid extraction equipment.
  • the carbon dioxide supercritical fluid extract (B) of the hazelnut bran has an extraction pressure of from about 150 bar to about 500 bar; preferably from about 200 bar to about 400 bar; It is preferably from about 350 bar to about 380 bar.
  • the carbon dioxide supercritical fluid extract (B) of the hazelnut bran has an extraction temperature of from about 30 ° C to about 80 ° C; preferably from about 40 ° C to about 70 ° More preferably, it is from about 50 ° C to about 60 ° C.
  • the carbon dioxide flow rate of the carbon dioxide supercritical fluid extract (B) of the hazelnut bran is from about 20 kg/h to about 50 kg/h; preferably from about 30 kg/h. Up to about 45 kg/h; particularly preferably from about 38 kg/h to about 40 kg/h.
  • the carbon dioxide supercritical fluid extract (B) of the hazelnut bran has an extraction time of from about 40 minutes to about 100 minutes; preferably from about 50 minutes to about 80 minutes.
  • the carbon dioxide supercritical fluid extract (B) of the hazelnut bran is extracted in the presence of a co-solvent, for example, from about 1% to about 10% of 95%. Ethanol.
  • the supercritical fluid extraction method further comprises a concentration step.
  • concentration is well known to those of ordinary skill in the art to which the invention pertains, for example using a reduced pressure concentrator.
  • the weight ratio of the alcohol extract having a carbon number of 1 to 7 (A) of the hazelnut bran according to the present invention to the carbon dioxide supercritical fluid extract (B) of the hazelnut bran is from about 3:1 to about 1 : 4, within this ratio range, the therapeutic effect against skin and/or subcutaneous tissue diseases is very significant; preferably, the ratio is from about 3:2 to about 1:2; particularly preferably, the ratio is about 3 : 2, about 3: 1, about 1:2 or about 1:4.
  • the extract of the hazelnut bran is subjected to a high-efficiency liquid
  • High performance liquid chromatography (HPLC) analysis The sample is the same as the same
  • the solvent was formulated to a concentration of 1 g/mL and filtered through a 0.45 ⁇ filter. 20 ⁇ L of the filtered sample solution was injected into Hitachi® analysis HPLC for analysis of the column RP-18, photo-diode array detector.
  • the column was a reverse phase C18 column (250 x 4.6 mm id; YMC Co., INC).
  • the column temperature was 40 °C.
  • the chromatogram was monitored at 280 nm.
  • the mobile phase used A solution: 5% acetic acid in water; B solution: 0.5% acetic acid in water / 100% acetonitrile (1:1, v/v).
  • the elution gradient mode is shown in Table 1.
  • a map of the alcohol extract (A) having a carbon number of 1 to 7 in the hazelnut bran is shown in Fig. 1; a map of the carbon dioxide supercritical fluid extract (B) of the hazelnut bran is shown in Fig. 2;
  • a graph of the weight ratio of the alcohol extract having a carbon number of 1 to 7 (A) of the bran to the carbon dioxide supercritical fluid extract (B) of the hazelnut bran is 1:4, which is shown in Fig. 3
  • the following residence time comprises at least a peak: from about 12.5 minutes to about 13.5 minutes, from about 14 minutes to about 15.5 minutes, from about 15.5 minutes to about 16.5 minutes, from about 21 minutes to about 22.5 minutes, from about 32 minutes to about 35 minutes.
  • the composition according to the invention is preferably a pharmaceutical composition, a food composition or a cosmetic composition.
  • the pharmaceutical compositions of this invention may be administered topically or systemically by any method known in the art including, but not limited to, by intramuscular, intradermal, intravenous, subcutaneous, intraperitoneal, intranasal, oral, mucosal or external Route to give. Suitable routes of administration, methods of formulation, and schedule of administration can be determined by those skilled in the art.
  • the pharmaceutical composition can be formulated in various ways according to the respective administration routes, such as liquid solutions, suspensions, emulsions, syrups, troches, pills, capsules, sustained release preparations, powders, granules, ampoules, injections.
  • the external routes described herein may also be referred to as topical administration, including but not limited to administration by insufflation or inhalation.
  • topical administration examples include ointments, lotions, creams, gels, foams, preparations for transdermal patch delivery, powders for inhalation or insufflation, sprays, aerosols, capsules or medicines. ⁇ , or drops (such as drops for the eyes or nose), solutions/suspensions for nebulization, suppositories, vaginal suppositories, resident enemas and chewables or inhalable lozenges or tablets or lipids or It is a capsule preparation.
  • Ointments, creams and gels may, for example, be formulated with an aqueous or oily base, and may be formulated with suitable thickening and/or gelling agents and/or solvents.
  • the substrate may thus comprise, for example, water and/or oil, such as a liquid alkane or vegetable oil, such as peanut oil or castor oil, or a solvent such as polyethylene glycol.
  • Thickeners and gelling agents which can be used depending on the nature of the matrix include soft paraffins, aluminum stearate, cetyl stearyl alcohol, polyethylene glycol, hair fat, beeswax, carboxypolyarylene and cellulose. Derivatives, and / or glyceryl monostearate, and / or nonionic emulsifiers.
  • the emulsions may be formulated with an aqueous or oily base and usually contain one or more emulsifiers, stabilizers, dispersing agents, suspending agents or thickening agents.
  • the powder for external application can be formed with any suitable powdery matrix, such as talc, lactose or starch.
  • the drops may be formulated with an aqueous or non-aqueous base and also include one or more dispersing agents, solubilizing agents, suspending agents or preservatives.
  • the spray composition can, for example, be formulated as an aqueous solution or suspension, or as an aerosol delivered from a pre-pressurized bag, such as a dose inhaler, in conjunction with a suitable liquefied propellant.
  • Aerosol compositions suitable for inhalation may be suspensions or solutions, which may optionally contain additional formulation adjuvants known in the art, such as surfactants such as oleic acid or lecithin and cosolvents, for example Ethanol.
  • the topical preparation can be administered by one or more administrations per day to the area to be treated; and a cover patch is preferably used on the skin area. Delivery can be continued or extended by the adhesive storage system.
  • the cosmetic composition according to the invention may be an aqueous phase preparation which essentially comprises water; it may also comprise a mixture of water and a water-miscible solvent (greater than 50% by weight of water at 25 ° C), for example 1 a lower carbon monool of up to 5 carbon atoms, such as ethanol or isopropanol, a diol having 2 to 8 carbon atoms, such as propylene glycol, ethylene glycol, 1,3-butylene glycol, or dipropylene glycol, C 3 -C 4 ketone with C 2 -C 4 aldehyde, and glycerol.
  • the aqueous phase formulation is preferably in the form of an aqueous gel or hydrogel formulation.
  • the hydrogel formulation contains a thickening agent to thicken the liquid solution.
  • thickeners include, but are not limited to, carbonates, cellulose based materials, gums, seaweed, guar gum, pectin, carrageenin, gelatin, mineral or modified mineral thickeners, poly Ethylene glycol with polyols, polyacrylamides, and other polymeric thickeners.
  • the cosmetic composition according to the invention may be in the form of an emulsion or cream formulation. It may contain an emulsified surfactant which may be selected from anionic and nonionic surfactants.
  • an emulsified surfactant which may be selected from anionic and nonionic surfactants.
  • anionic and nonionic surfactants For the nature and function of the surfactant (emulsification), refer to the document "Encyclopedia of Chemical Technology, Kirk-Othmer", Vol. 22, pp. 333-432, 3rd edition, 1979, Wiley, for anionic and nonionic surfaces. Active agents, especially pages 347-377 of this reference.
  • the surfactant used in the composition of the present invention is selected from the group consisting of: nonionic surfactants: fatty acids, fatty alcohols, polyethoxylated or pegylated fatty alcohols, such as polyethoxylated stearyl alcohol or cetyl hard Fatty alcohol, fatty acid ester of sucrose, alkyl glucose ester, especially polyoxyethylated fatty acid ester of C r C 6 alkyl glucose, and mixtures thereof; anionic surfactant: by amine, ammonia or alkali salt Neutralized C 16 -C 3Q fatty acids, and mixtures thereof. It is preferred to use a surfactant which can provide an oil-in-water or water-in-wax emulsion.
  • nonionic surfactants fatty acids, fatty alcohols, polyethoxylated or pegylated fatty alcohols, such as polyethoxylated stearyl alcohol or cetyl hard Fatty alcohol, fatty acid ester of sucrose
  • the cosmetic composition according to the present invention may further comprise an effective amount of a physiologically acceptable antioxidant selected from the group consisting of butylated p-nonylphenol, butylated hydroquinone monoterpene ether and tocopherol.
  • a physiologically acceptable antioxidant selected from the group consisting of butylated p-nonylphenol, butylated hydroquinone monoterpene ether and tocopherol.
  • compositions of the present invention may further comprise natural or modified amino acids, natural or modified sterol compounds, natural or modified gum proteins, silk proteins or soy proteins.
  • compositions of the present invention are preferably formulated for topical application to keratin materials such as skin, hair, eyelashes, or finger lice. It can be any form of expression normally used in this type of application, especially aqueous or oily solutions, oil-in-water or water-in-oil emulsions, silicone emulsions, microemulsions or nanoemulsions, aqueous or oily gels or liquids, slurries Form of a hydrated product or a solid.
  • the invention may generally be a fluid and may have the appearance of a white or colored cream, ointment, milk, lotion, serum, slurry, mousse, or gel. It may be applied topically to the skin in the form of an aerosol, patch or powder as desired. It can also be in solid form, such as in the form of a stick. It can be used as a skin care product and/or a cosmetic product. Alternatively, it can be formulated as a shampoo or a conditioner.
  • composition of the present invention may also contain additives and adjuvants commonly used in cosmetics, such as hydrophilic or lipophilic gelling agents, preservatives, antioxidants, solvents, perfumes, fillers, pigments, odor absorption. Agent, with dye.
  • the extract of the hazelnut bran may be added to a conventional food composition (also an edible food or drink or a precursor thereof) in the food manufacturing process.
  • the extract of the hazelnut bran according to the present invention can be added to almost all food compositions.
  • a food composition to which an extract of the hazelnut bran according to the present invention may be added includes, but is not limited to, confectionery, baking Baked goods, ice cream, dairy products, desserts and flavors, snacks, meat substitutes, snack foods, soups, pasta, noodles, canned foods, frozen foods, dried foods, frozen foods, fats, baby food, soft Food, or bread spread or a mixture thereof.
  • the invention also provides the use of an extract of the aforementioned hazelnut bran for the manufacture of a medicament for the treatment of skin and/or subcutaneous tissue disorders.
  • the invention further provides a method of treating a skin and/or subcutaneous tissue disease in an individual comprising administering to the individual a therapeutically effective amount of an extract of scorpion bran and optionally a pharmaceutically acceptable carrier or wu Shape agent.
  • skin and/or subcutaneous tissue disease refers to a lesion that occurs in the skin and/or subcutaneous tissue.
  • it is selected from the group consisting of inflammation, edema damage, and skin atrophy ( Skin atrophy), Bruising, Burn, Cheilitis, Dry skin, Flushing, alopecia, Hyperpigmentation, Pigmentation Hypopigmentation, Induration, Fibrosis, Inhibition site reaction, extravasation change, Nail change, photosensitivity ), Itching (Pruritus/Itching), Rash/Desquamation, Acne/Acneiform, Dermatitis associated with radiation, Erythema multiforme, Hand/foot skin reaction (Hand-foot skin reaction), skin breakdown, decubitus ulcer, striae, telangiectasia, ulcer (Ulc Elation), urticaria
  • the skin and/or subcutaneous tissue disease is a disease of the skin and/or subcutaneous tissue caused by radiation exposure.
  • the radiation irradiation is preferably radiation irradiation of tumor radiation therapy, and the tumor is preferably breast cancer or lung cancer.
  • the present invention further provides the use of the aforementioned extract of hazelnut bran for the manufacture of a reduced interleukin-1 ⁇ , interleukin-1 ⁇ , interleukin-6, tumor necrosis factor- ⁇ , interleukin -8, prostaglandin 2 and / or C-reactive protein drugs.
  • the invention further provides a method for reducing interleukin-1 ⁇ , interleukin-1 ⁇ , interleukin-6, tumor necrosis factor- ⁇ , interleukin-8, prostaglandin 2 and/or C-reactive protein in an individual.
  • a method comprising administering to the individual a therapeutically effective amount of an extract of hazelnut bran and optionally a pharmaceutically acceptable carrier or! !Vulture agent.
  • Tweezers were purchased from farmers in Taichung County, Taiwan. They were planted in 2009 and are Taichung Shuenyu no. 4 (TCS4) ⁇ (C. lachrymajobi L.).
  • Alcohol extract with a carbon number of 1 to 7 in hazelnut bran Remove the shell and seed coat of the hazelnut with a grinder, bake the bran, grind it into powder, and soak it in 3 times the amount at 95 °C. In ethanol (w/v), extraction was carried out for 24 hours under ultrasonic vibration. After the three extracts were mixed, they were concentrated under reduced pressure at 50 ° C to obtain an ethanol extract of hazelnut bran.
  • the carbon dioxide supercritical fluid extract of hazelnut bran is removed by a grinder to remove the shell and seed coat of the hazelnut, and then bran, ground into a powder, and the hazelnut bran is placed in a stainless steel extraction inner tank, and then the inner tank is placed.
  • the supercritical extraction device is extracted in the tank.
  • the extraction conditions were as follows: extraction pressure: 360 bar; extraction temperature: 55 °C; carbon dioxide flow rate: 38 to 40 kg/h; cosolvent: 2% 95% ethanol; extraction time: 60 minutes.
  • the extract was collected and concentrated under a reduced pressure concentrator.
  • the feeding dose of the hazelnut bran extract was selected at a feeding dose of 100 mg/Kg for 100 days, and the tube feeding volume was 100 mice.
  • the hazelnut bran extract used in the experiment was suspended in 0.5% ⁇ 10 by ultrasonic vibration; carboxymethyl cellulose ( &13 ⁇ 40 « 11 ⁇ 1 ⁇ 1 cellulose)) and carried out by tube feeding, and on the 35th day Sacrifice the mouse.
  • Tumor size, body weight, and blood stasis were measured every 5 days during the experiment. And treating the skin with current clinical radiotherapy
  • the skin damage drug Sulfasil was used as a control group.
  • the histopathological sections of the tumor radiotherapy site were used for pathological examination of epidermis and hairy tissue sections, and TU EL assay combined with pathology to judge the damage of epidermal cells and fibroblasts in epidermal tissue, and immunostaining was used.
  • the expression of inflammatory response-related molecules such as NF-kB, COX-2, IL- ⁇ , and TNF- ⁇ was examined, and the results of the sectioning are shown in Fig. 4.
  • the results of the change in body weight are shown in Fig. 5.
  • the test samples were administered to the tumor animals at the same time, and the changes in body weight were not significantly different between the groups; and as shown in Fig. 6, the radiation treatment of the tumor animals was given simultaneously.
  • the tumor volume of the sample was significantly lower than that of the blank group, and there was no significant difference between the groups given the radiation therapy.
  • the extract of the scorpion bran of the invention can be used to treat skin and/or subcutaneous tissue diseases, particularly inflammation, edema damage, hair loss, radiation dermatitis and/or skin reaction of the hands/foot.
  • Example 2 Human trial to reduce the side effects of radiotherapy in breast cancer patients
  • the clinical trials were divided into two groups according to prospective, randomized and double-blind methods, and were divided into two phases: The first phase was to test the reaction of sputum sputum in the average person, and take two after each morning and evening. Granules (500 mg/grain), four capsules a day, for four weeks in a row. Blood tests before the test: including general blood, liver function (including GOT, GPT), renal function (including BU, CRTN), general functions (including cholesterol, HDL, LDL, TG, AC-sugar).
  • the same blood test is performed once, and after confirming that there are no major side effects, the second phase test is started: Test whether the silicone sputum can effectively reduce the skin reaction caused by radiation when the breast cancer patient receives radiation therapy, and then Improve the quality of life; and by blood testing, to understand the changes in immune function of breast cancer patients before and after radiation therapy, whether it can effectively improve immune function, and statistical analysis of clinical skin reactions and physiological changes.
  • the first stage 10 ordinary people
  • the second stage 80 breast cancer patients in the experimental group and the control group.
  • Radiotherapy will determine the scope and volume of the treatment through computerized tomography, and the computerized treatment computing system will know the dose distribution and dose, and the patient will report the skin reaction and other side effects every week.
  • Blood was taken before and after taking the test product. After continuous use for four weeks, one person felt bloating. After no adverse events or major side effects, the second phase trial was started. The number of subjects was 67, and the number of cases received was 51. Among the 16 subjects who did not intend to participate in the program, such as: skin allergies, chemotherapy caused by lower limb edema discomfort, untimely work time, unwillingness, too much medication, participation in signing, consent Blood, skin physiology, photographic records of the affected area, questionnaires, and test products.
  • the treatment plan was about 5-7 weeks per person, and the plan is expected to accept 160 people.
  • the ratio of the experimental group to the control group has been adjusted from 1:1 to 2:1. There are 27 cases in which the data can be analyzed. The analysis results are shown in Tables 3 to 6.
  • Table 3 shows the comparison of the mean blood draw before and after taking the sputum sputum in the first stage. The difference between the test group and the control group before and after taking the drug showed that the sputum sputum did not affect liver and kidney function. Table 3: P-values measured before pre-test
  • Table 4 shows the RTOG/EORTC index of skin reactions in breast cancer patients. The preliminary results showed that the skin reaction Grade > 1 and the test group had 3/14 (21.4%). ), the control group was 6/13 (46.2%).
  • Level 1 Follicles, erythema, hair loss, reduced sweating and dry peeling
  • Table 5 shows the clinicopathological features of breast cancer patients who completed sputum sputum, and there was no difference between the experimental group and the control group. Value
  • Intensity-modulated radiation therapy (intensity 8 (57.1%) 9 (69.2%) Having modulated radiation)
  • the results of this example show that dry skin, infiltration, peeling, scaling, acne, multiple erythema, skin damage and/or ulceration of breast cancer patients can be improved, so
  • the extract of the hazelnut bran according to the present invention can be used for the treatment of skin and/or subcutaneous tissue diseases, particularly dry skin, infiltration, peeling, scaling, acne, multiple erythema, skin damage and/or ulceration.

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Abstract

一种薏苡子麸皮的萃取物，包含薏苡子麸皮的具有1至7碳数的醇萃取物及薏苡子麸皮的二氧化碳超临界流体萃取物。该薏苡子麸皮的萃取物具有治疗皮肤及或皮下组织疾病的效果。

Description

薏苡子扶皮的萃取物及其应用 技术领域
本发明涉及薏苡子麸皮萃取物及其用途； 具体言之， 用于治疗皮肤及 / 或皮下组织疾病。 背景技术
皮肤为人体中最大的器官与身体和环境间的主要屏障，可在第一线抵御 微生物病原和物理及化学性压力或剌激。 皮肤不仅提供物理与化学性保护， 也为能有效引起被动和主动免疫反应的免疫器官， 进而保护人体。
皮肤由外到内， 可分成表皮、 真皮及皮下组织三层结构， 最外层的表皮 负责保护功能； 位于其中的真皮层是构成皮肤的最主要部份， 其负责支撑表 皮及以各种纤维交织成支撑网， 并可使血管、 淋巴管、 神经、 皮脂腺、 汗腺 及毛嚢等分布于其中； 皮肤的最里层则为皮下组织， 广义来说是指脊推动物 真皮的深层， 狭义来说则指真皮与其下方骨胳、 肌肉之间的脂肪结締组织， 其与真皮之间无明显界限， 主要是由脂肪细胞所形成， 负责热阻隔、 吸收震 动以及提供能量的来源， 也是脂肪代谢的主要地方。
皮肤及 /或皮下组织会因先天或后天的因素而产生各种疾病，造成患者的 不适， 且因外观上的变化使患者产生心理上的负担， 而现今所釆用的皮肤及 /或皮下组织药物或为类固醇， 或为酸性药物， 如应用不当副作用大， 并非适 合的治疗方式。
皮肤及 /或皮下组织疾病中， 因放射线治疗而造成的损害为一重要类别， 放射线治疗时常并发放射线皮肤炎、 疲倦感、 放射线肺炎及淋巴水肿等副作 用 {McCormick et al" 1989, Int J Radiat Oncol Biol Phys., 17:1299-1302; Lingos et ah, 1991 , Int. J. Radiat. Oncol. Biol. Phys., 21:355-360', Taylor et al., 1995 , Int J. Radiat. Oncol. Biol. Phys., 31·· 753— 764; Gorodetsky et al" 1999, Int. J. Radiat. Oncol. Biol. Phys., 45:893-900; Erickson et al., 2001 , J. Natl. Cancer Inst, 93:96-111). 以乳癌为例， 其中约有 50%至 60%的乳癌病患需接受手术 后放射线治疗。 这些病患在接受手术切除及全身化学药物治疗后， 常合并掉 发、 白血球低下、 恶心、 呕吐等副作用。 可能让患者因恐惧而逃避或拒绝治 疗。 而医学界也一直由治疗设备、 技术的改良， 以期减少放射线治疗的副作 用， 其中因放射线引起的皮肤红斑、 色素沉淀， 甚至少数患者会产生溃疡等 较严重的副作用， 医界也一直努力尝试使用一些放射线保护剂 (如
Amifostine)(Yuhas et al. , 1980, Cancer Clin. Trials., 3:211-216)。 然而这些药物 同时伴随副作用太强或效果不彰，或是价格昂贵，在实际医疗上仍甚少使用。 业界仍须开发达到放射线保护或加强放射线疗效、 以降低其放射线剂量的药 剂， 以造福接受放射线治疗的癌症病患。
薏苡 (Co x lachryma-jobi L. var. ma-yuen Stapf)子又称约 4白的目艮泪 (Job's tears), 为中药材 (TCM)之一， 长久以来做为抗发炎药， 用于治疗疣 (warts)、 皮肤龟裂 (chapped skin)、 风湿病 (rheumatism)及神经痛（neuralgia)( 梦者， 本草纲目， 159 )。 最近一份研究报告显示， 去壳薏苡子 (dehulled adlay, DA) 可调节大鼠肠道的微生物丛 (microbiota)(C nVz«g， W.; Cheng, C; Chiang, Μ·; Chung, Κ· T. J. Agric. Food Chem. 2000, 48, 829-832), 而体外试验也证实薏苡 子具有抗发炎与抗氧化的疗效 ( ee， M.∑; Tsai, S. Η·; Kuo, Υ. Κ; Chiang, W. Food Sci. Biotechnol. 2008, 17, 1265-1271; Kuo, C. C; Shih, M. C; Kuo, Y. K; Chiang, W. J. Agric. Food Chem. 2001, 49, 1564-1570)。 许多不同来源薏苡子 中， 所含的多种强效成分皆已定量出（ ， 7： T.; Charles, A. L.; Huang, T. C. Food Chem. 2007, 104, 1509-1515). 薏苡子可分离出数种酚类抗氧化剂， 且 萃取出的生物活性成分， 在处理过程中皆相当稳定 (7¾M， H.∑; Lin, B. K; Lin, J.∑; Kuo, C. C; Chiang, W. J. Agric. Food Chem. 2003, 51, 3763-3769)。釆用分 析导向进行分离 （assay-guided isolation)时， 可自薏苡壳 (adlay hull , AH)分离 出木酚素 (Lignan)与酚类化合物 (&/o， C. C; Shih, M. C; Kuo, Y. K; Chiang, W. J. Agric. Food Chem. 2001, 49, 1564-1570)。 分离薏苡子的抗发炎成分时， 贝 可分离出黄酮类与数种酚酸化合物 C¾ a«g， D. W.; Kuo, Υ. Η·; Lin, F. Y.; Lin, Y. L; Chiang, W. J. Agric. Food Chem. 2009, 57, 2259-2266; Huang, D. W; Chung, C. P.; Kuo, Y. K; Lin, Y. L; Chiang, W. J. Agric. Food Chem. 2009, 57,
10651-10657; Chen, H. J.; Chung, C. P.; Chiang, W.; Lin, Y. L. Food Chem. 2011, 126， 1741-1748。 研究发现， 薏苡种皮 (adlay testa, AT)中的酚醇具有抗过敏 活性 (CAe«， H. J.; Shih, C. K.; Hsu, H. Y.; Chiang, W. J. Agric. Food Chem. 2010, 58, 2596-2601), 去壳薏苡子与薏苡子麸皮 (adlay bran, AB)具有抗发炎活性， 能延緩癌症形成 (5¾·Α， C. K.; Chiang, W.; Kuo, M. L. Food Chem. Toxicol. 2004， 42， 1339-1347; Li, S. C; Chen, C. Μ·; Lin, S. K; Chiang, W.; Shih, C. K. J. Sci. FoodAgric. 2011, 91, 547-552), 而阿魏酸 (ferulic acid)经深入研究后发现为抗 发炎的活性成分 (C½«g， C. P.; Hsu, Η· Υ.; Huang, D. W.; Hsu, H. K; Lin, J. T.; Shih, C. K.; Chiang, W. J. Agric. Food Chem. 2010, 58， 7676-7623)。
薏苡子的许多用途虽已经报导， 但薏苡子的萃取物的不同应用仍待开 发。 发明内容
于本发明中， 由薏苡子萃取物而达到治疗皮肤及 /或皮下组织疾病的效 果， 特别是提供放射线保护或加强放射线疗效、 以降低其放射线剂量， 可造 福接受放射线治疗的癌症患者。
本发明提供一种组合物， 其包含薏苡子麸皮 (bran)的萃取物， 该薏苡子 麸皮的萃取物包含薏苡子麸皮的具有 1至 7碳数的醇萃取物 (A)及薏苡子麸 皮的二氧化碳超临界流体萃取物 (B) , 其中该薏苡子麸皮的具有 1至 7碳数 的醇萃取物 (A)与该薏苡子麸皮的二氧化碳超临界流体萃取物 (B)的重量比为 自约 3: 1至约 1 :4。
本发明亦提供一种前述的薏苡子麸皮的萃取物的用途， 其用于制造治疗 皮肤及 /或皮下组织疾病的药物。
本发明又提供一种于个体中治疗皮肤及 /或皮下组织疾病的方法，其包含 给予该个体治疗有效量的薏苡子麸皮的萃取物及视需要的医药上可接受的 载剂或 U武形剂。
本发明又提供一种本发明再提供一种前述的薏苡子麸皮的萃取物的用 途， 其用于制造降低介白素 (IL)-la、 介白素 -1β、 介白素 -6、 肿瘤坏死因子 (TNF)-a、 介白素 -8、 前列腺素 2(PGE2)及 /或 C反应蛋白（CRP)的药物。
本发明再提供一种于个体中降低介白素 -la、 介白素 -1 β、 介白素 -6、 肿 瘤坏死因子 -α、 介白素 -8、 前列腺素 2及 /或 C反应蛋白的方法， 其包含给予 该个体治疗有效量的薏苡子麸皮的萃取物及视需要的医药上可接受的载剂 或!!武形剂。 附图说明
图 1显示根据本发明的薏苡子麸皮的具有 1至 7碳数的醇萃取物 (Α)的 HPLC图谱。
图 2显示根据本发明的薏苡子麸皮的二氧化碳超临界流体萃取物 (B)的 HPLC图谱。
图 3显示根据本发明的薏苡子麸皮的具有 1至 Ί碳数的醇萃取物 (A)及 薏苡子麸皮的二氧化碳超临界流体萃取物 (B)重量比为 1 :4的 HPLC图谱。
图 4显示不同喂食剂量薏苡子胶嚢或临床放射线治疗皮肤损伤药物 Sulfasil, 对放射线治疗引发小鼠腿部毛皮组织损伤效应的组织病理切片图。 RT表示放射线治疗； 假治疗（sham)表示未进行放射线治疗； 载剂（vehicle)表 示不含薏苡子萃取物的载剂。
图 5显示肿瘤动物给予放射线治疗同时管喂不同浓度薏苡子胶嚢或临床 放射线治疗皮肤损伤药物 Sulfasil, 体重变化结果图。 RT表示放射线治疗； 假治疗表示未进行放射线治疗； 载剂表示不含薏苡子萃取物的载剂。
图 6显示肿瘤动物给予放射线治疗同时管喂不同浓度薏苡子胶嚢或临床 放射线治疗皮肤损伤药物 Sulfasil, 肿瘤体积变化结果图。 RT表示放射线治 疗； 假治疗表示未进行放射线治疗； 载剂表示不含薏苡子萃取物的载剂。
图 7显示肿瘤动物给予放射线治疗同时管喂不同浓度薏苡子胶嚢或临床 放射线治疗皮肤损伤药物 Sulfasil, 血清中 IL-la浓度变化结果图。 RT表示 放射线治疗； 假治疗表示未进行放射线治疗； 载剂表示不含薏苡子萃取物的 载剂。
图 8显示肿瘤动物给予放射线治疗同时管喂不同浓度薏苡子胶嚢或临床 放射线治疗皮肤损伤药物 Sulfasil, 血清中 IL-Ιβ浓度变化结果图。 RT表示 放射线治疗； 假治疗表示未进行放射线治疗； 载剂表示不含薏苡子萃取物的 载剂。
图 9显示肿瘤动物给予放射线治疗同时管喂不同浓度薏苡子胶嚢或临床 放射线治疗皮肤损伤药物 Sulfasil, 血清中 IL-6浓度变化结果图。 RT表示放 射线治疗； 假治疗表示未进行放射线治疗； 载剂表示不含薏苡子萃取物的载 剂。
图 10显示肿瘤动物给予放射线治疗同时管喂不同浓度薏苡子胶嚢或临 床放射线治疗皮肤损伤药物 Sulfasil, 血清中 TNF-α浓度变化结果图。 RT表 示放射线治疗； 假治疗表示未进行放射线治疗； 载剂表示不含薏苡子萃取物 的载剂。 图 11显示肿瘤动物给予放射线治疗同时管喂不同浓度薏苡子胶嚢或临 床放射线治疗皮肤损伤药物 Sulfasil, 血清中 IL-8浓度变化结果图。 RT表示 放射线治疗； 假治疗表示未进行放射线治疗； 载剂表示不含薏苡子萃取物的 载剂。
图 12显示肿瘤动物给予放射线治疗同时管喂不同浓度薏苡子胶嚢或临 床放射线治疗皮肤损伤药物 Sulfasil, 血清中 PGE2浓度变化结果图。 RT表 示放射线治疗； 假治疗表示未进行放射线治疗； 载剂表示不含薏苡子萃取物 的载剂。
图 13显示肿瘤动物给予放射线治疗同时管喂不同浓度薏苡子胶嚢或临 床放射线治疗皮肤损伤药物 Sulfasil,血清中 CRP浓度变化结果图。 RT表示 放射线治疗； 假治疗表示未进行放射线治疗； 载剂表示不含薏苡子萃取物的 载剂。
图 14显示 25种不同喂食剂量 /组合对放射线治疗引发小鼠腿部毛皮组织 损伤效应的组织病理切片图。横轴与纵轴分别显示具有 1至 7碳数的醇萃取 物 (A)及薏苡子麸皮的二氧化碳超临界流体萃取物 (B)喂食剂量 /组合 (mg/kg)。 每张图分别显示小鼠肿瘤放射线治疗过程管喂不同剂量组合的小鼠的皮毛 组织的组织病理切片。 实施方式
本发明提供一种组合物， 其包含薏苡子麸皮 (bran)的萃取物， 该薏苡子 麸皮的萃取物包含薏苡子麸皮的具有 1至 7碳数的醇萃取物 (A)及薏苡子麸 皮的二氧化碳超临界流体萃取物 (B), 其中该薏苡子麸皮的具有 1至 7碳数 的醇萃取物 (A)与该薏苡子麸皮的二氧化碳超临界流体萃取物 (B)的重量比为 自约 3:1至约 1:4。
参考以下对本发明的各方案、 实例、 及伴随相关描述的化学图式及表格 的佯细描述， 可更容易地了解本发明。 在揭示及描述本发明的化合物、 组合 物及 /或方法之前， 应了解， 除非由权利要求另外特别地指出， 否则本发明不 受限于特定制备方法、 载剂或制剂、 或将本发明化合物调配成用于局部、 经 口或非经肠给予的产物或组合物的特定模式， 此是由于本领域技术人员非常 清楚此等事情是可以加以变化的。 亦应了解， 本文所用的术语仅用于描述特 定方案的目的而不意欲用于限制性本发明的范围。 除非另外指出， 否则如本发明所用的以下术语应解释为具有以下含义。 范围在本文中通常表述为"约"一个特定值及 /或至"约"另一个特定值。 当 表述此类范围时，一方案为包括一个特定值及 /或至另一个特定值的范围。类 似地， 当值通过使用字"约"表述为近似值时，应了解特定值可形成另一方案。 另外应了解，每一范围的各端点皆有显著性，一端点与另一端点既有相关性， 亦彼此独立。
"视情况"或"视情况地"意指随后所述的事件或状况可能发生或可能不发 生， 且该描述包括该事件或状况发生的情况及其未发生的情况。 举例而言， "视情况包含药剂"意指该药剂可能存在或可能不存在。
必须指出， 除非上下文另外清楚规定， 否则如本说明书及随附权利要求 中所用的单数形式"一"及"该"包括复数个所指标的物。 因此， 除非上下文另 外需要， 否则单数术语应包括复数且复数术语应包括单数。
如本文所用的术语"个体"表示任何动物， 优选为哺乳动物， 且更优选为 人类。 个体的实例包括人类、 非人类灵长类动物、 啮齿动物、 天竺鼠、 兔、 绵羊、 猪、 山羊、 母牛、 马、 狗及猫。
术语如本文所提供的化合物的"有效量 "意指该化合物的量足以提供对 所需功能 (诸如基因表现、 蛋白质功能或诱导特定类型的反应)的所需调节。 如下文所指出， 确实的需要量将在个体之间有变化， 此视个体的疾病病况、 身体状况、 年龄、 性别、 物种及体重、 组合物的特性及配方等而定。 给药方 案可经调整以诱导最佳治疗反应。 举例而言， 可每日给予若干分次剂量， 或 可依治疗情形的紧急程度按比例减少剂量。因此，很难指定确实的"有效量"。 如本文所用的术语 "治疗 "表示逆转、 减轻或改善此术语所适用的病症或 病状、 或该病症或病状的一或多种症状， 或抑制其进展。
如本文所用的术语 "载剂 "或"赋形剂 "是指自身并不为治疗剂， 而是用作 用于将治疗剂传递至个体的载剂及 /或稀释剂及 /或佐剂或媒剂， 或添加至制 适于经口给予的剂量单位 (诸如胶嚢或锭剂）的任何物质。 适合的载剂或赋形 剂为一般熟习制造医药制剂或食品的通常知识者所熟知。载剂或赋形剂可包 括 (举例而言但不限于)緩冲剂、 稀释剂、 崩解剂、 粘合剂、 粘着剂、 湿润剂、 聚合物、 润滑剂、 滑动剂、 为遮蔽或抵消不良味道或气味而添加的物质、 调 味剂、 染料、 芳香剂及为改善组合物的外观而添加的物质。 可接受的载剂或 赋形剂包括柠檬酸盐緩冲剂、 磷酸盐緩冲剂、 乙酸盐緩冲剂、 碳酸氢盐緩冲 剂、 硬脂酸、 硬脂酸镁、 氧化镁、 磷酸及硫酸的钠盐及钙盐、碳酸镁、 滑石、 明胶、 阿拉伯胶、 海藻酸钠、 果胶、 糊精、 甘露糖醇、 山梨糖醇、 乳糖、 蔗 糖、 淀粉、 明胶、 纤维素物质 (诸如烷酸的纤维素酯及纤维素烷基酯)、 低熔 点蜡、 可可脂、 氨基酸、 尿素、 醇类、 抗坏血酸、 磷脂、 蛋白质 (例如血清 白蛋白）、 乙二胺四乙酸 (EDTA)、 二曱亚砜 (DMSO)、 氯化钠或其他盐、 脂质 体、 甘露糖醇、 山梨糖醇、 甘油或粉末、 聚合物 (诸如聚乙烯吡咯烷酮、 聚 乙烯醇及聚乙二醇)、 及其他医药学上可接受的物质。 载剂不应破坏治疗剂 的药理学活性， 且在以足以传递治疗量的药剂的剂量给予时应无毒性。
根据本发明的组合物是包含薏苡子麸皮的萃取物，根据本发明的薏苡子 麸皮优选是自去壳薏苡子中所得， 本文中所述的 "去壳薏苡子"一词是指不具 有壳、 种皮 (testas)、 夕卜皮 (coverings), 夕卜壳（shells)或荚 (pods)的种子。 自薏苡 子中去除壳、 外皮、 外壳或荚的方式为本发明所属技术领域中具通常知识者 所熟知。 一般而言， 去壳薏苡子包含麸皮及胚乳 (endosperm) , 自去壳薏苡子 取得麸皮的方式为本发明所属技术领域中具通常知识者所熟知。
本发明所述的薏 子并无特殊限定， 优选地， 该薏 属于禾本科
(Gramineae family)、 黍亚 ^(Panicoideae sub-family)、 薏苡 ^Coix species) , 或姜目 {Poales order)、 早熟禾科 (尸 oaceae？ family)、 薏苡属。 更优选地， 该薏 为 Coix lachryma-jobi、 Coix lachryma-jobi L" Coix lachryma- jobi L. var. ma-yuen Stapf、 Coix agrestis Lour. , Coix arundinacea Lam.、 Coix exaltata J acq. 或 Coix lacryma L.。
根据本发明的薏苡子麸皮的萃取物包含薏苡子麸皮的具有 1至 7碳数的 醇萃取物 (A)及薏苡子麸皮的二氧化碳超临界流体萃取物 (B)。
本文中所述的 "具有 1至 Ί碳数的醇"一词是指直链或支链、 具有取代基 或不具有取代基、 单元或多元、 饱和或不饱和的醇， 优选为不具有取代基、 单元及饱和醇。 另一方面， 该具有 1至 7碳数的醇优选为 1至 4碳数的醇。 于本发明的一优选具体实施例中， 该具有 1至 7碳数的醇为曱醇、 乙醇、 正 丙酉孚 (n-propanol)、 异丙 ^(isopropanol)、 正丁孚、 异丁 ^(iso-butanol)、 仲丁 醇 (sec-butanol)、 叔丁醇 (tert-butanol)、 1-戊醇、 2-戊醇、 3-戊醇、 2-曱基 -1- 丁醇、 2-曱基 -2-丁醇、 3-曱基 -2-丁醇、 3-曱基 -1-丁醇、 2,2-二曱基 -1-丙醇、 1-己醇、 2,4-己二婦 -1-醇、 2-曱基-环戊醇、 环己醇、 1-庚醇、 2-庚醇或环庚 醇； 尤其优选地， 该醇为曱醇或乙醇； 最优选地， 该醇为乙醇。 该醇可单独 使用或混合多种使用。
本文中所述的具有 1至 7碳数的醇优选为水溶液， 其浓度优选为自约 49%至约 99.9%的醇溶液； 更优选为自约 75%至约 99.9%的醇溶液； 尤其优 选为自约 90%至约 98.0%的醇溶液。
本文中所述的 "薏苡子麸皮的具有 1至 7碳数的醇萃取物 (A)"—词是指以 具有 1至 7碳数的醇萃取薏苡子麸皮所得的萃取物。 以溶液萃取种子部位的 方式为本发明所属技术领域中具通常知识者所熟知。 于本发明的一优选具体 实施方案中， 该薏苡子麸皮浸于该醇溶液中以供萃取， 更优选地， 该薏苡子 麸皮浸于该醇溶液中， 并经超音波震荡以供萃取。
该萃取的温度优选为自约 10°C至约 100°C ; 更优选为自约 15°C至约 50°C ; 尤其优选为约 20°C至约 40°C。
于本发明的一优选具体实施方案中， 该薏苡子麸皮的具有 1至 7碳数的 醇萃取物 (A)是由包含下列步骤的制备方法所制备：
(a)提供薏苡子麸皮；
(b)将该薏苡子麸皮切成小块； 及
(c)以具有 1至 7碳数的醇萃取步骤 (b)的小块以提供该萃取物。
根据本发明的制备方法， 于步骤 (b)前该薏苡子麸皮优选经干燥。
于本发明的一优选具体实施方案中，步骤 (b)进一步包含将该小块搅碎为 粉末。 切块及 /或搅碎的方式为本发明所属技术领域中具通常知识者所熟知。
该去壳薏苡子及醇溶液的比例 (w/v)并无特殊限制，可为约 1:1至约 1:10; 优选地， 约 1:3至约 1 :8; 尤其优选地； 约 1:5。
于本发明的一优选具体实施方案中， 该萃取步骤 (c)可重复实施， 并收集 合并该萃取物。
优选地， 该制备方法进一步包含步骤 (d)自该萃取物获得液体分液， 并移 除固体。移除固体部份以获得该液体分液的方法为本发明所属技术领域中具 通常知识者所熟知。
优选地， 该制备方法进一步包含浓缩步骤。 浓缩的方法为本发明所属技 术领域中具通常知识者所熟知， 例如使用减压浓缩机进行。
根据本发明的该薏苡子麸皮的二氧化碳超临界流体萃取物 (B)是指以二 氧化碳超临界流体萃取薏苡子麸皮所得的萃取物。超临界流体是指当超过临 界温度及临界压力以上， 气体与液体的性质会趋近于类似， 最后会达成一个 均匀相 (homogenous)的流体状态。 超临界流体类似气体具有可压缩性， 兼具 有类似液体的流动性， 可用于萃取， 亦有商用的超临界流体萃取设备可供使 用， 例如 NATEX、 SEPAREX, UHDE及台超科皆提供有商用的超临界流体 萃取设备， 其型号规格一般都以萃取槽能处理的容量表示， 自 500 g至 2000 kg可供选择， 可依所需选取适宜的超临界流体萃取设备。
于本发明的一具体实施方案中， 该薏苡子麸皮的二氧化碳超临界流体萃 取物 (B)的萃取压力为自约 150 bar至约 500 bar;优选是自约 200 bar至约 400 bar; 更优选为自约 350 bar至约 380 bar。
于本发明的一具体实施方案中， 该薏苡子麸皮的二氧化碳超临界流体萃 取物 (B)的萃取温度为自约 30°C至约 80°C ; 优选是自约 40°C至约 70°C ; 更 优选为自约 50°C至约 60°C。
于本发明的一具体实施方案中， 该薏苡子麸皮的二氧化碳超临界流体萃 取物 (B)的二氧化碳流量为自约 20 kg/h至约 50 kg/h; 优选为自约 30 kg/h至 约 45 kg/h; 尤其优选为自约 38 kg/h至约 40 kg/h。
于本发明的一具体实施方案中， 该薏苡子麸皮的二氧化碳超临界流体萃 取物 (B)的萃取时间为自约 40分钟至约 100分钟； 优选为自约 50分钟至约 80分钟。
于本发明的一具体实施方案例中， 该薏苡子麸皮的二氧化碳超临界流体 萃取物 (B)是于共溶剂的存在下进行萃取， 该共溶剂例如约 1%至约 10%的 95%乙醇。
优选地， 该超临界流体萃取方法进一步包含浓缩步骤。 浓缩的方法为本 发明所属技术领域中具通常知识者所熟知， 例如使用减压浓缩机进行。
根据本发明的该薏苡子麸皮的具有 1至 7碳数的醇萃取物 (A)与该薏苡 子麸皮的二氧化碳超临界流体萃取物 (B)的重量比为自约 3: 1至约 1 :4, 于此 比例范围内， 针对皮肤及 /或皮下组织疾病的治疗效果十分显著； 优选地， 该 比例为自约 3:2至约 1 :2; 尤其优选地， 该比例为约 3:2、 约 3: 1、 约 1 :2或约 1 :4。
于本发明的一优选具体实施方案中，该薏苡子麸皮的萃取物进行高效液
4目层析 (high performance liquid chromatography , HPLC)分析。 样品以丙 Θ同为 溶剂， 配制成 1 g/mL的浓度， 并经由 0.45 μιη滤膜过滤。 取 20 μL过滤后的 样品液注入 Hitachi® analysis HPLC分析，分析管柱为 RP-18,侦测器光电二 极管阵列检测器 (photo-diode array detector)。该管柱为反相 C18管柱 (250x4.6 mm i.d.; YMC Co., INC)。 管柱温度为 40°C。 该层析于 280 nm监控。 该流动 相使用 A溶液： 5%醋酸于水中； B溶液： 0.5%醋酸于水中 /100%乙腈（1 : 1 , v/v)。 洗脱梯度模式示于表 1。
表 1 时间（分钟） 流速 (mL/分钟） 移动相 A(%) 移动相 B(%：)
0 1.0 90 10
10 1.0 85 15
20 1.0 84 16
35 1.0 83 17
50 1.0 79 21
55 1.0 79 21
该薏苡子麸皮的具有 1至 7碳数的醇萃取物 (A)的图谱示于图 1 ;该薏苡 子麸皮的二氧化碳超临界流体萃取物 (B)的图谱示于图 2;该薏苡子麸皮的具 有 1至 7碳数的醇萃取物 (A)与该薏苡子麸皮的二氧化碳超临界流体萃取物 (B)的重量比为 1 :4的图谱示于图 3 , 该图谱于下列滞留时间至少包含峰： 约 12.5分钟至约 13.5分钟、 约 14分钟至约 15.5分钟、 约 15.5分钟至约 16.5 分钟、 约 21分钟至约 22.5分钟、 约 32分钟至约 35分钟。
根据本发明的组合物优选为医药组合物、 食品组合物或化妆品组合物。 本发明的医药组合物可通过本发明领域中已知的任何方法局部或全身 给予， 包括但不限于通过肌肉内、 皮内、 静脉内、 皮下、 腹膜内、 鼻内、 经 口、 粘膜或外部途径给予。 适当的给药途径、 调配方法及给药时程可由本领 域技术人员来决定。 在本发明中， 医药组合物可根据相应给药途径以多种方 式调配， 诸如液体溶液、 悬浮液、 乳液、 糖浆、 锭剂、 丸剂、 胶嚢、 持续释 放制剂、 散剂、 颗粒、 安瓿、 注射液、 输注液、 套组、 软膏、 洗剂、 擦剂、 乳膏或其组合。 在必要时， 其可经灭菌或与任何医药学上可接受的载剂或赋 形剂混合， 其中有许多医药学上可接受的载剂或赋形剂已为一般技术者所 知， 例如参见 [实施方式]第 10段。
本发明所述的外部途径亦可称为局部给药， 包含但不限于以吹气或吸入 给药。 局部给药的各类制剂实例包含软膏、 乳液、 乳霜、 凝胶、 发泡体， 以 经皮贴片输送的制剂， 吸入或吹气用的粉末、喷雾剂、 气溶胶、胶嚢或药匣， 或滴剂（例如眼睛用或鼻子用滴剂），供雾化用溶液 /悬浮液、栓剂、 阴道药栓、 驻留灌肠剂及咀嚼剂或可吸入的锭剂或药片或脂质或为胶嚢制剂。
软膏、 乳霜及凝胶可例如配合水性或油性基质， 且添加适用增稠剂及 / 或胶凝剂及 /或溶剂调配。 该基质因此可包含例如水及 /或油， 如液态链烷或 植物油， 如花生油或蓖麻油， 或溶剂如聚乙二醇。 可依据基质性质使用的增 稠剂及胶凝剂包含软质链烷、硬脂酸铝、鲸酰硬脂基醇、 聚乙二醇、 毛脂肪、 蜜蜡、 羧基聚亚曱基及纤维素衍生物， 及 /或单硬脂酸甘油酯， 及 /或非离子 性乳化剂。
乳液可配合水性或油性基质调配， 且通常亦含有一或多种乳化剂、 安定 剂、 分散剂、 悬浮剂或增稠剂。
外涂用粉末可配合任何适用的粉末状基质形成，例如滑石、乳糖或淀粉。 滴剂可配合水性或非水性基质调配， 且亦包括一或多种分散剂、 溶解剂、 悬 浮剂或保存剂。
喷雾组合物可例如调配成水溶液或悬浮液， 或调配成自预加压袋输送的 气溶胶， 如剂量吸入器， 且配合使用适用的液化推进剂。 适用于吸入用的气 溶胶组合物可为悬浮液或溶液，该气溶胶组合物可视情况含有额外的本领域 已知的调配佐药， 如表面活性剂例如油酸或卵磷脂及共溶剂例如乙醇。
局部用制剂可通过每天对欲作用的区域施用一或多次给药； 且在皮肤区 域上优选使用覆盖贴片。 可通过粘着剂储存系统持续或延长输送。
根据本发明的化妆品组合物可为水相制剂， 其本质上包括水； 其亦可包 含水及与水互溶溶剂的混合物 (在 25°C为大于 50重量％的水互溶力），例如含 1至 5个碳原子的低碳单醇， 如乙醇或异丙醇， 含 2至 8个碳原子的二醇， 如丙二醇、 乙二醇、 1,3-丁二醇、 或二丙二醇， C3-C4酮与 C2-C4醛， 及甘油。 该水相制剂优选为水性凝胶或水凝胶制剂的形式。水凝胶制剂包含增稠剂以 将液态溶液增稠。增稠剂的实例包括但不限于碳合物、纤维素为主材料、胶、 海藻素、 瓜尔胶、 果胶、 鹿角菜苷、 明胶、 矿物性或经改性矿物性增稠剂、 聚乙二醇与多醇、 聚丙烯酰胺、 及其他的聚合增稠剂。 优选为使用对组合物 赋予安定性及最适流动特性的增稠剂。
根据本发明的化妆品组合物可为乳液或乳霜制剂的形式。其可含乳化表 面活性剂， 这些表面活性剂可选自阴离子及非离子表面活性剂。 对于表面活 性剂的性质及功能 (乳化）， 可参考文件 "Encyclopedia of Chemical Technology, Kirk-Othmer", 第 22卷， 第 333-432页， 第 3版， 1979, Wiley, 对于阴离子 及非离子表面活性剂， 特别是该参考资料的第 347-377页。
优选地， 用于本发明组合物的表面活性剂选自 ：非离子表面活性剂 ：脂 肪酸， 脂肪醇， 聚乙氧化或聚乙二醇化脂肪醇， 如聚乙氧化硬脂醇或鲸蜡基 硬脂醇， 蔗糖的脂肪酸酯， 烷基葡萄糖酯， 特别是 CrC6烷基葡萄糖的聚氧 亚乙基化脂肪酸酯， 及其混合物； 阴离子表面活性剂 ：经胺、 氨水或碱盐中 和的 C16-C3Q脂肪酸， 及其混合物。 优选为使用可得到水包油或水包蜡乳液 的表面活性剂。
根据本发明的化妆品组合物可进一步包含有效量的生理上可接受抗氧 化剂， 其选自丁基化对曱酚、 丁基化氢醌一曱醚与生育酚。
本发明的组合物可进一步包含天然或改性氨基酸、天然或改性固醇化合 物、 天然或改性胶蛋白、 丝蛋白或大豆蛋白。
本发明的组合物优选为调配成局部应用于角蛋白材料， 如皮肤、 毛发、 睫毛、 或指曱。 其可为正常用于此型应用的任何表现形式， 特别是水性或油 性溶液、 水包油或油包水乳液、 聚硅氧乳液、 微乳液或纳米乳液、 水性或油 性凝胶或液体、 浆状或固态水合产物的形式。
本发明通常可为流体且可具有白色或有色乳霜、 软膏、 乳汁、 洗剂、 浆 液、 浆料、 慕斯、 或凝胶的外观。 其可视需要以气溶胶、 贴片或粉末的形式 局部地应用于皮肤上。 其亦可为固态形式， 例如棒形式。 其可作为皮肤用保 养产品及 /或化妆产品使用。 或者， 其可调配成洗发精或润丝精。
在已知方式中， 本发明的组合物亦可含化妆品常用的添加剂及佐剂， 如 亲水性或亲脂性胶化剂、 防腐剂、 抗氧化剂、 溶剂、 香料、 填料、 颜料、 臭 味吸收剂、 与染料。
根据本发明的食品组合物中， 该薏苡子麸皮的萃取物可在食品制造过程 中， 添加于常用的食品组合物中（亦即可食用的食品或饮品或其前驱物）。 几 乎所有的食品组合物皆可添加根据本发明的该薏苡子麸皮的萃取物。可添加 根据本发明的该薏苡子麸皮的萃取物的食品组合物包含， 但不限于糖果、 烘 焙食品、 冰淇淋、 乳制品、 甜品及风味小点、 小吃、 肉类替代产品、 快餐食 品、 汤类、 面食、 面条、 罐头食品、 冷冻食品、 干制食品、 冷藏食品、 油脂、 婴儿食品、 软食物、 或面包涂酱或其混合物。
本发明亦提供一种前述的薏苡子麸皮的萃取物的用途， 其用于制造治疗 皮肤及 /或皮下组织疾病的药物。
本发明又提供一种于个体中治疗皮肤及 /或皮下组织疾病的方法，其包含 给予该个体治疗有效量的薏苡子麸皮的萃取物及视需要的医药上可接受的 载剂或 u武形剂。
本发明所述的"皮肤及 /或皮下组织疾病"是指发生于皮肤及 /或皮下组织 的病变， 于本发明的一优选具体实施方案中， 其选自发炎、 毛嚢损伤、 皮肤 萎缩 (skin atrophy), 瘀伤（Bruising)、 烧伤（Burn)、 口唇炎 (Cheilitis), 干性肌 肢 (Dry skin) ,面红 (Flushing)、脱发 (alopecia)、色素沉着症 (Hyperpigmentation)、 色素过少症 (Hypopigmentation)、 浸润 (Induration), 千维匕 (Fibrosis)、 注射部 位反应 (Inj ection site reaction)、 化学药物夕卜漏 (extravasation change)、 指曱改 变 (Nail change), 光敏感 (Photosensitivity), 搔痒 (Pruritus/Itching)、 脱皮脱屑 (Rash/Desquamation) , 痤疾 (Acne/Acneiform)、 放射线皮肢炎 (Dermatitis associated with radiation)、 多发性红斑 (Erythema multiforme)、 手 /足皮肤反应 (Hand-foot skin reaction)、 皮肢受损 (Skin breakdown)、 搏疾 (Decubitus ulcer)、 紋 (Striae)、 毛细血管扩张症 (Telangiectasia), 溃疡 (Ulceration), 荨麻疹
(Urticaria)„
于本发明的一更优选具体实施方案中，该皮肤及 /或皮下组织疾病为因放 射线照射所引起的皮肤及 /或皮下组织疾病。该放射线照射优选为肿瘤放射线 治疗的放射线照射， 该肿瘤优选为乳癌或肺癌。
本发明又提供一种前述的薏苡子麸皮的萃取物的用途， 其用于制造降低 介白素 -1α、 介白素 -1β、 介白素 -6、 肿瘤坏死因子 -α、 介白素 -8、 前列腺素 2 及 /或 C反应蛋白的药物。
本发明再提供一种于个体中降低介白素 -1α、 介白素 -1β、 介白素 -6、 肿 瘤坏死因子 -α、 介白素 -8、 前列腺素 2及 /或 C反应蛋白的方法， 其包含给予 该个体治疗有效量的薏苡子麸皮的萃取物及视需要的医药上可接受的载剂 或！!武形剂。
以下的非限制性的实施例有助于本发明所属技术领域中具通常知识者 实施本发明。 这些实施例不应视为过度地限制本发明。 本发明所属技术领域 中具有通常知识者可在不背离本发明的精神或范畴的情况下对本文所讨论 的实施例进行修改及变化， 而仍属于本发明的范围。 实施例
实施例 1 : 动物模式
药品及试剂 薏苡子购自台湾台中县农民， 于 2009年种植， 为台中选 育 4号 (Taichimg Shuenyu no. 4, TCS4)薏苡 (C. lachrymajobi L.)。
薏苡子麸皮的具有 1至 7碳数的醇萃取物 (A) 以研磨机去除薏苡子的壳 与种皮， 再薏苡麸皮， 研磨成粉， 25 °C下浸泡于 3倍量的 95%乙醇 (w/v)中， 于超音波震荡下萃取 24小时。 混合三次萃取液后， 于 50°C下减压浓缩而得 薏苡子麸皮的乙醇萃取液。
薏苡子麸皮的二氧化碳超临界流体萃取物 以研磨机去除薏苡子的壳 与种皮， 再薏苡麸皮， 研磨成粉， 将薏苡子麸皮装入不锈钢萃取内槽， 随后 将内槽放入超临界萃取设备萃取槽中。 萃取条件如下： 萃取压力： 360 bar; 萃取温度： 55 °C ; 二氧化碳流量： 38至 40 kg/h; 共溶剂： 2%的 95%乙醇； 萃取时间： 60分钟。 收取萃出物， 再以减压浓缩机进行浓缩。
萃取物重量比例-. 薏苡子麸皮萃取物喂食剂量的选定以 100 mg/Kg, 100 天的喂食剂量进行， 管喂体积为 100 小鼠。 实验所用的薏苡子麸皮萃 取物全部以超音波震荡方式悬浮于 0.5% ^10；羧曱基纤维素( &1¾0« 11^1^1 cellulose))并以管喂方式进行， 并于第 35天牺牲小鼠。 薏苡子麸皮的具有 1 至 7碳数的醇萃取物 (A)以 0、 100、 200、 300及 400 mg/kg及薏苡子麸皮的 二氧化碳超临界流体萃取物 (B)以 0、 100、 200、 300、 400 mg/kg, 彼此搭配 共 25种不同喂食剂量组合， 管喂体积为 ΙΟΟ μϋ小鼠 /天。
萃取物对动物肿瘤放射线治疗引发皮肤发炎反应副作用的活性与机制 探讨 以管喂方式喂食动物薏苡子胶嚢 (试验组，萃取物 Α:萃取物 Β为 1 :4), 测试不同剂量对减轻放射线治疗引发皮肤发炎反应副作用的效用。动物模式 为将小鼠乳癌细胞 (4T1 , lxlO6细胞 /小鼠)植入 BALB/c小鼠腿部， 肿瘤直径 约 4mm时开始管喂不同剂量试验样品， 两天后开始给予放射线治疗 (每天照 射 5Gy共五天)并持续每天管喂前述的薏苡子麸皮萃取物直至实验结束。 实 验过程中每隔 5天量测肿瘤大小、 体重及釆血。 并以现行临床放射线治疗皮 肤损伤药物 Sulfasil为对照组。 小鼠牺牲后针对肿瘤放射治疗部位组织进行 组织病理切片进行表皮及毛嚢组织切片病理学检测、 运用 TU EL assay 配 合病理学判断表皮组织中表皮细胞及纤维母细胞的损伤情况， 并利用免疫染 色侦测 NF-kB、 COX-2、 IL-Ιβ, TNF-α等发炎反应相关分子的表现， 其切片 结果示于图 4。
体重变化的结果如图 5所示，给予肿瘤动物放射线治疗的同时给予试验 样品， 其体重变化在各组之间均无显著差异； 而由图 6得知， 给予肿瘤动物 放射线治疗的同时给予试验样品， 其肿瘤体积相较于空白组均显著下降， 在 给予放射线治疗的各组之间不存在显著差异。
另一方面， 200与 400 mg/kg的薏苡子胶嚢 (试验组， 萃取物 A: 萃取物 B为 1 :4)均显著降低放射线治疗引发的皮肤发炎反应， 且可同时抑制放射线 治疗引发的血清 IL-la (图 7)、 IL-Ιβ (图 8)、 IL-6(图 9)、 TNF-a(图 10)、 IL-8(图 11)、 PGE2(图 12)与 CRP (图 13)的上升; 100 mg/kg薏苡子胶嚢则仅对当中某 些指标具有显著抑制的效果。 由以上结果可知， 200与 400 mg/kg薏苡子胶 嚢具有显著抑制皮毛组织损伤与动物体内发炎因子指标的功效。
减轻放射线治疗引发皮肤 或皮下疾病-. 进行步骤如前安全性评估所 述，但研究过程中每隔 7天评估肿瘤放射线治疗引发的活体表皮反应毒性分 级， 其中活体表皮反应毒性分级方法以临床治疗为最常使用于毒性评估的 CTCAE系统 (Common Terminology Criteria for Adverse Events v3.0), 分另 'J以 临床生理学肉眼观察及显微镜病理组织切片检查进行， 以皮肤反应评分表进 行量化评估。 并于治疗部位做病理组织切片。 其结果示于图 14。
量化皮肢反应以 CompuSyn (for Drug Combinations and for General Dose-Effect Analysis)软件程序计算出实验材料减轻放射线治疗引发皮肤反 应及毛皮组织损伤的加成作用条件组合， 其结果示于表 2:
表 2： 萃取物 (B) 萃取物 皮毛组织损伤程度
组合系数 (mg/kg) (A)(mg/kg) 的病理量化值
100.0 300.0 0.96 0.68150
200.0 300.0 0.96 0.75281
400.0 100.0 0.96 0.48865 400.0 200.0 0.96 0.69204 组合系数 (combination index, CI), 根据定义 CI值<1为加成效应， CI 值 =1为独立效应， （^1值>1为拮抗效应， 表 2中为实验中筛选所得四个最佳 的组合 (C 0.8), 可显著抑制皮毛组织发炎效果， 其中萃取物 A: 萃取物 B 的范围为 3:1至 1 :4。
由表 2及图 14的结果可知， 本实施例中动物肿瘤放射线模式中， 动物 所产生的发炎、 毛嚢损伤、 脱发、 放射线皮肤炎及 /或手 /足皮肤反应可获得 改善，因此根据本发明的薏苡子麸皮的萃取物可用于治疗皮肤及 /或皮下组织 疾病， 特别是发炎、 毛嚢损伤、 脱发、 放射线皮肤炎及 /或手 /足皮肤反应。
实施例 2: 减轻乳癌患者放疗副作用的人体试验
每日早晚餐后各服用薏苡子胶嚢 (试验组， 萃取物 A: 萃取物 B为 1 :4) 或橄榄油胶嚢 (对照组）两粒 (500 mg/粒）， 一天四粒。
本临床试验釆用前瞻性、 随机分组及双盲方式分为试验组及对照组设 计， 并分成两阶段进行： 第一阶段先测试薏苡胶嚢在一般人的反应， 每曰早 晚餐后各服用两粒 (500 mg/粒）， 一天四粒， 连续使用四周。 试验前接受血液 检测： 包括一般血液、肝功能（包括 GOT、 GPT)、 肾功能（包括 BU 、 CRTN)、 一般功能（包括胆固醇、 HDL、 LDL、 TG、 AC-sugar)等。 连续使用四周后， 再接受一次相同抽血检验， 确定无重大副作用后， 开始进行第二阶段试验： 测试薏苡胶嚢对于乳癌病患接受放射线治疗时，是否能有效减少放射线引起 的皮肤反应， 进而改善生活品质； 并由血液检测， 了解乳癌病患接受放射线 治疗前后免疫功能的变化， 是否薏苡胶嚢能有效改善免疫功能， 并与临床皮 肤反应及生理学变化作统计分析。
第二阶段试验中合乎受试者条件的乳癌患者随机分为两组： 一组为试验 组， 另一组为对照组。 试验组于接受放射线治疗期间， 每日早晚餐后各服用 两粒薏苡胶嚢 (500 mg/粒)， 一天四粒， 连续使用 5至 7周； 对照组则给予外 表包装一样的替代物 (安慰剂， 其内容物为橄榄油）， 服用方式一样。 两组治 疗前后皆会接受血液检测， 生活品质问卷调查、 皮肤生理学检查。
病患数目：
第一阶段： 10名一般人
第二阶段： 试验组及对照组各 80名乳癌患者。
两阶段共 170名受试者。 评估方法：
第一阶段测试安全性： 受试者抽血检测一般血液、 肝、 肾功能、 一般功 能， 以测试服用薏苡胶嚢是否有严重异常反应。 第二阶段： 乳癌病患在经过 解释， 同意接受此项试验并签署受试者同意书后， 随机分配为试验组或对照 组， 皆会接受血液检测： 包括一般血液、 肝功能（包括 GOT、 GPT)、 肾功能 (包括 BUN、 CRTN)、 细胞激素（包括 IL-1 , IL-6, IL-8)、 一般功能（包括胆固 醇、 HDL、 LDL、 TG、 AC-sugar)等， 生活品质及疲倦问卷调查， 皮肤生理 学检查 (项目包括： S史碱值、 皮肤表面水分及油脂、 保湿功能性、 颜色、 温 度、 弹性及皮肤血流超音波等)。 开始接受放射线治疗后， 每周记录病患疗 程中皮肤反应及理学检查， 包括胸壁治疗范围内皮肤反应及颜色变化。 接受 放射线治疗结束后， 再接受一次与治疗前相同抽血检验及生活品质问卷调 查、 皮肤生理学检查。
放射线治疗：
每位乳癌病患会接受 5至 7周的放射线治疗， 受试者每日须服用薏苡胶 嚢或替代物。 放射线治疗会经由电脑断层定位， 定出治疗范围及体积， 并由 电脑治疗运算系统， 得知剂量分布情形及剂量均勾度， 每周病患会回诊记录 皮肤反应及其他副作用。
结果：
于服用试验产品前后进行抽血， 连续使用四周， 有 1人觉得腹胀， 未有 任何不良事件或重大副作用后， 开始进行第二阶段试验， 受试者筛选数 67 人， 收案数 51人， 受试者中 16名没有意愿参与本计划的原因如： 皮肤容易 过敏、 化学治疗导致下肢水肿不适、 工作忙碌时间无法配合、 没有意愿、 已 服用太多药物不克参与， 进行签署同意书、 抽血、 皮肤生理检查、 患部照相 记录、 问卷填写及给予试验产品等。
第二阶段有 2人觉得腹胀， 1人拉肚子； 其中 1人因腹胀等副作用中止、
1人退出， 治疗计划每人约为 5-7周， 计划预计收案 160人。 为了提高受试 者参与本计划的意愿， 以提高样本数， 并增加资料搜集的可信度， 已将试验 组与对照组的比例由 1 :1调整为 2:1。 其数据可分析的个案共有 27例， 其分 析结果如表 3至表 6所示。
表 3为第一阶段一般人接受薏苡胶嚢服用前后抽血的平均值比较， 试验 组及对照组并没有服用前后的差异， 可说明薏苡胶嚢并不会影响肝肾功能。 表 3 : 前测 后测 p-值
平均 (±SD) 平均 (±SD) 年龄 54.9 (11.36)
身高 159.1 (4.31)
体重 58.3 (6.57)
RBC 4.4 (0.65) 4.4 (0.79) 0.648
血红素 13.3 (1.30) 13.3 (1.09) 0.870
WBC 5.7 (1.22) 5.6 (0.83) 0.799
Hct 38.8 (3.45) 39.5 (3.06) 0.285
血小板 267.1 (29.13) 265.7 (41.35) 0.859
BUN 11.2 (3.46) 12.0 (1.83) 0.375
肌酸酐 0.6 (0.10) 0.6 (0.13) 0.670
GOT 26.4 (5.85) 23.8 (5.27) 0.045
GPT 25.2 (10.1) 22.5 (9.64) 0.158
胆固醇 195.8 (44.70) 201.4 (33.07) 0.523
HDL 51.7 (13.84) 50.6 (11.39) 0.393
LDL 117.5 (34.46) 120.8 (25.63) 0.688
TG 100.2 (52.45) 105.8 (64.24) 0.491
AC sugar 103.0 (24.21) 109.6 (30.71) 0.024 表 4为乳癌病患接受治疗的皮肤反应 RTOG/EORTC指标分级， 初步的 分析结果可看出皮肤反应 Grade > 1 , 试验组有 3/14(21.4%), 对照组为 6/13(46.2%)。
表 4 试马全组 (n=14) 对照组 (n=13) p-值 皮肤反应 0.342
0级 4 (28.6%) 1 (7.7%)
1级 7 (50.0%) 6 (46.2%)
2级 3 (21.4%) 5 (38.5%)
3级 0 (0.0%) 1 (7.7%)
皮肤反应 0.173
1级 11 (78.6%) 7 (53.8%)
> 1级 3 (21.4%) 6 (46.2%)
0级： 无反应
试 τ
1级： 出现滤泡、 淡红斑、 脱毛、 减少出汗及干性脱皮
2级： 出现中度的红斑及片状浸润的脱皮验及水肿， 大多数患者在皮肤皱 折处更为明显 组
3级： 出现浸润脱皮及外伤与磨损及流血
对 ^
4级： 出现坏死、 溃疡及自发性流血等症状
3 、■ / )
5级： 死亡 照
表 5为完成薏苡胶嚢的乳癌病患临床病理特征， 试验组跟对照组分布上 组 并没有差异。 值
年龄 51.4 (士 13.7) 51.6 0.969
(±10.7) 原发部位肿瘤临床期别 0.733
0 1 (7.1%) 1 (7.7%)
1 3 (21.4%) 1 (7.7%) lb 0 (0.0%) 1 (7.7%) lc 3 (21.4%) 5 (38.5%)
2 5 (35.7%) 4 (30.8%) 1 (7.1%)
IS 1 (7.1%) 1 (7.7%)
0.340 la 3(21.4%) 1 (7.7%)
lb 3(21.4%) 3 (23.1%)
lc 3(21.4%)
3(21.4%) 2 (14.3%)
2 (14.3%)
IS 0 (0.0%) 2(14.3%)
病理分类 0.308 浸润性腺管癌（Infiltrating ductal
Figure imgf000021_0001
10 (76.9%)
carcinoma)
浸润 '1"生小 p†癌 (Infiltrating lobular
Figure imgf000021_0002
carcinoma)
1管原位癌 (Ductal carcinoma in 0 (0.0%) 2(15.4%)
situ)
手术分类 0.511 孔房保留手术 (breast conserving 12 (85.7%) 11 (84.6%)
surgery)
改良型乳房根除手术（modified
Figure imgf000021_0003
radical mastectomy)
其它 2 (14.3%)
Figure imgf000021_0004
放射治疗 0.363 传统体夕卜放射治疗（conventional 4 (28.6%) 4 (30.8%)
radiation therapy)
强度调控放射治疗（intensity 8(57.1%) 9 (69.2%) modulated radiation therapy)
影像导 I螺旋刀（tomotherapy)
Figure imgf000022_0001
表 6为已完成放射线治疗的乳癌病患治疗前后的抽血数值变化， 并无显 著差异。 试验组 (n=14) 对照组 (n=13)
RBC 0.323
前测 4.12 (0.40) 4.04 (0.40)
后测 4.37 (0.52) 4.13 (0.43)
Hgb 0.310
前测 12.04 (1.72) 12.11 (1.55)
后测 12.54 (1.25) 12.20 (0.94)
WBC 0.719
前测 5.24 (2.06) 5.74 (2.10)
后测 4.04 (0.89)
Hct 0.219
前测 35.42 (4.45) 35.56 (4.14)
后测 37.18 (3.17) 35.92 (2.54)
血小板 0.160
前测 231.60 (84.74) 273.54 (68.67)
后测 172.00 (46.44) 179.15 (67.65)
BUN 0.179
前测 10.45 (3.05) 11
后测 10.86 (3.59) 10.67 (3.95)
肌酸肝 0.193
前测 0.57 (0.12) 0.62 (0.17)
后测 0.59 (0.11) 0.61 (0.14)
GOT 0.207
前测 25.86 (5.93) 22.85 (5.40)
后测 25.50 (4.45) 25.62 (10.45) GPT 0.303
前 i 24.14 (10.10) 22.92 (11.18)
后泖 22.93 (6.74) 26.08 (15.75)
Cho 0.584
前 i 196.43 (35.72) 189.38 (29.11)
后泖 181.79 (35.71) 180.46 (24.44)
HD 'L 0.814
翁 i 46.30 (12.19) 54.69 (14.73)
后泖 45.57 (10.80) 54.59 (11.03)
LDL 0.593
121.26 (36.59) 54.69 (27.13)
111.35 (36.50) 97.13 (27.36)
TG 0.256
前 i 122.14 (60.31) 100.69 (50.44)
后泖 125.64 (51.51) 161.62 (215.25)
ACsug ar 0.866
前 i 99.64 (10.67) 103.62 (13.84)
后泖 97.93 (14.12) 101.38 (17.06) 本实施例的结果显示， 乳癌病患的干性肌肤、 浸润、 脱皮、 脱屑、 痤疮、 多发性红斑、皮肤受损及 /或溃疡可获得改善， 因此根据本发明的薏苡子麸皮 的萃取物可用于治疗皮肤及 /或皮下组织疾病，特别是干性肌肤、浸润、脱皮、 脱屑、 痤疮、 多发性红斑、 皮肤受损及 /或溃疡。
上述实施例仅为说明本发明的原理及其功效， 而非限制本发明。 熟知此 技术的人士对上述实施例所做的修改及变化仍不违背本发明的精神。本发明 的权利范围应如后述的权利要求所列。

Claims

权利要求书
1.一种组合物， 其包含薏苡子麸皮 (bran)的萃取物， 该薏苡子麸皮的萃 取物包含薏苡子麸皮的具有 1至 7碳数的醇萃取物 (A)及薏苡子麸皮的二氧 化碳超临界流体萃取物 (B) , 其中该薏苡子麸皮的具有 1至 7碳数的醇萃取 物 (A)与该薏苡子麸皮的二氧化碳超临界流体萃取物 (B)的重量比为自约 3: 1 至约 1 :4。
2.根据权利要求 1的组合物， 其中该薏苡为 Coix lcryma-jobi L.。
3.根据权利要求 1的组合物， 其中该具有 1至 7碳数的醇为乙醇。
4.根据权利要求 1的组合物，其中该具有 1至 7碳数的醇为浓度自约 49% 至约 99.9%的醇溶液。
5.根据权利要求 1的组合物， 其中该薏苡子麸皮的二氧化碳超临界流体 萃取物 (B)是于压力为自约 150 bar至约 500 bar及温度自约 30°C至约 80°C进 行萃取。
6.根据权利要求 1的组合物， 其中该薏苡子麸皮的具有 1至 7碳数的醇 萃取物 (A)及薏苡子麸皮的二氧化碳超临界流体萃取物 (B)的重量比为自约 3:2至约 1 :2。
7.根据权利要求 1的组合物， 其为医药组合物、 食品组合物或化妆品组 合物。
8.一种根据权利要求 1至 7任何一项的组合物的用途， 其用于制造治疗 皮肤及 /或皮下组织疾病的药物。
9.根据权利要求 8的用途，其中该皮肤及 /或皮下组织疾病选自发炎、毛 嚢损伤、 皮肤萎缩 (skin atrophy), 瘀伤 (Bruising)、 烧伤 (Burn)、 口唇炎 (Cheilitis), 干性肌肤 (Dry skin)、 面红 (Flushing)、 脱发 (alopecia)、 色素沉着 症 (Hyperpigmentation)、 色素过少症 (Hypopigmentation)、 浸润 (Induration)、 纤维化 (Fibrosis)、 注射部位反应（Inj ection site reaction)、 化学药物夕卜漏
(extravasation change)、 指曱改变 (Nail change)、 光敏感 (Photosensitivity)、 ¾ - 痒 (Pruritus/Itching)、 脱皮脱肩 (Rash/Desquamation)、 痤疾 (Acne/Acneiform)、 放射线皮肤炎 (Dermatitis associated with radiation)、 多发性红斑 (Erythema multiforme), 手 /足皮肤反应（Hand-foot skin reaction), 皮肤受损（Skin breakdown), 褥疾 (Decubitus ulcer)、 乡丈 (Striae)、 毛细血管扩张症 (Telangiectasia) , 溃癌 (Ulceration), 荨麻渗 (Urticaria)。
10. 根据权利要求 9的用途，其中该皮肤及 /或皮下组织疾病为因放射线 照射所引起的皮肤及 /或皮下组织疾病。
11. 根据权利要求 10的用途，其中该放射线照射为肿瘤放射线治疗的放 射线照射。
12. 一种根据权利要求 1至 7任何一项的组合物的用途， 其用于制造降 低介白素 (IL)-lou 介白素 -1β、 介白素 -6、 肿瘤坏死因子 (TNF)-ou 介白素 -8、 前列腺素 2(PGE2)及 /或 C反应蛋白（CRP)的药物。
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CY1119360T1 (el) 2018-02-14
EP2937095A1 (en) 2015-10-28
EP2937095B1 (en) 2017-06-07
DK2937095T3 (en) 2017-09-11
PL2937095T3 (pl) 2017-11-30
LT2937095T (lt) 2017-09-11
RS56192B1 (sr) 2017-11-30
JP6029770B2 (ja) 2016-11-24
HUE034481T2 (en) 2018-02-28
SI2937095T1 (sl) 2017-12-29
ES2638149T3 (es) 2017-10-18
PT2937095T (pt) 2017-08-29
EP2937095A4 (en) 2015-12-16
JP2016505577A (ja) 2016-02-25
HRP20171171T1 (hr) 2017-10-20

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