WO2017084631A9 - 预防或治疗脂肪胰、改善脂肪胰引起的胰病变、糖尿病或其他相关病症之组合物及方法 - Google Patents

预防或治疗脂肪胰、改善脂肪胰引起的胰病变、糖尿病或其他相关病症之组合物及方法 Download PDF

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WO2017084631A9
WO2017084631A9 PCT/CN2016/106607 CN2016106607W WO2017084631A9 WO 2017084631 A9 WO2017084631 A9 WO 2017084631A9 CN 2016106607 W CN2016106607 W CN 2016106607W WO 2017084631 A9 WO2017084631 A9 WO 2017084631A9
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combination
mannitol
eriodictyol
sucralose
pancreatic
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PCT/CN2016/106607
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English (en)
French (fr)
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WO2017084631A8 (zh
WO2017084631A1 (zh
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胡幼圃
何欣恬
吴永恩
唐熙卉
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财团法人国际教育基金会
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Application filed by 财团法人国际教育基金会 filed Critical 财团法人国际教育基金会
Priority to DK16865806.0T priority Critical patent/DK3378481T3/da
Priority to CN201680067605.XA priority patent/CN109715170A/zh
Priority to ES16865806T priority patent/ES2949047T3/es
Priority to EP16865806.0A priority patent/EP3378481B1/en
Priority to PL16865806.0T priority patent/PL3378481T3/pl
Priority to JP2018526113A priority patent/JP6914256B2/ja
Priority to US15/777,385 priority patent/US20180325840A1/en
Priority to FIEP16865806.0T priority patent/FI3378481T3/fi
Publication of WO2017084631A1 publication Critical patent/WO2017084631A1/zh
Publication of WO2017084631A8 publication Critical patent/WO2017084631A8/zh
Publication of WO2017084631A9 publication Critical patent/WO2017084631A9/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to a composition and method for preventing or treating fatty pancreas, ameliorating pancreatic lesions caused by fatty pancreas, diabetes or other related disorders.
  • the pancreas is an exocrine and endocrine organ in the human body.
  • the exocrine part includes acinar cells, which can secrete a variety of digestive enzymes.
  • the endocrine part includes islets, which can secrete insulin and other hormones, which play an important role in maintaining blood sugar levels. Fat accumulation in the pancreas may affect pancreatic function, further causing pancreatic lesions, diabetes, or other related conditions.
  • diabetes is a disease of abnormal glucose metabolism.
  • non-insulin-dependent or adult-type also known as type II diabetes
  • insulin-dependent or infant-type also known as type I. diabetes.
  • type 2 diabetes usually occurs in adults and is highly associated with obesity, and can be controlled through appropriate exercise, diet, and medications; type I diabetes is more common in children and adolescents, and the patient's body does not produce enough Insulin must be sustained by injection of insulin.
  • the present invention provides for the efficacy of one or more compounds having reduced pancreatic fat content, preventing or treating fatty pancreas, ameliorating pancreatic lesions caused by fatty pancreas, diabetes or other related disorders in an individual selected from the group consisting of: Poncirin, isovitexin, eriodictyol, ergosterol, ⁇ -myrcene, hyperoside, catechin ((+ )-catechin), palmitic acid ethyl ester, galangin, Morin, sciadopitysin, didymin, gossypin, luteolin-7-Glucoside, dihydroquercetin ((+)-taxifolin), citric acid (trans-cinnamic acid), xysmin, linarin, homoorientin, xylitol, rhinofolium ( Luteolin), swertiamarin, sodium lauryl sulfate, menthol, sucralose, mannitol, crospovid
  • the present invention provides the compound or a derivative, metabolite or decomposition product thereof for use in preparing an individual to reduce pancreatic fat content, prevent or treat fatty pancreas, improve pancreatic lesions caused by fat pancreas, diabetes or other Use of a composition of a related disorder.
  • the present invention also proposes to reduce pancreatic fat content, prevent or treat fatty pancreas, improve pancreatic lesions caused by fat pancreas, diabetes or other by administering the compound or a derivative, metabolite or decomposition product thereof in an individual in need thereof. Methods of related disorders.
  • the compound is selected from the group consisting of menthol, mannitol, eriodictyol, sucralose, and any combination thereof.
  • the compound is (1) menthol, mannitol, and eriodictyol, (2) mannitol, and eriodictyol. Combination, (3) combination of mannitol and sucralose, (4) combination of eriodictyol and sucralose, (5) menthol and mannitol a combination of (mannitol), or (6) a combination of eriodictyol, mannitol, and sucralose.
  • pancreatic lesions or related conditions include alcoholic fatty pancreatic disease and nonalcoholic fatty pancreatic disease, wherein alcoholic fatty pancreatic diseases include, but are not limited to, alcoholic fatty steatopancreatitis and alcoholic Pancreatitis (alcoholic Pancreatitis), as well as nonalcoholic fatty pancreatic diseases including, but not limited to, nonalcoholic fatty steatopancreatitis, pancreatic lipomatosis, pancreatic steatosis, fatty pancreas ), lipomatous pseudohypertrophy of pancreas, fatty replacement of pancreas, and fatty infiltration of pancreas (Nat. Rev. Gastroenterol. Hepatol. 8, 169–177 (2011) ); World J Gastroenterol. 2006 Dec 14; 12(46)
  • the compounds of the invention may be formulated into pharmaceuticals, food supplements or health foods.
  • the present invention provides a composition comprising a combination of any two or more compounds selected from the group consisting of: poncirin, isovitexin, Eriodictyol, ergosterol, myrcene, hyperoside, catechin ((+)-catechin), palmitic acid ethyl (palmitic acid ethyl) Ester), galangin, morin, sciadopitysin, didymin, gossypin, luteolin-7-glucoside (luteolin- 7-Glucoside), (+)-taxifolin, trans-cinnamic acid, diosmin, linarin, homoorientin, wood Xylitol, luteolin, swertiamarin, sodium lauryl sulfate, menthol, sucralose, mannitol , crospovidone, sorbitol, saccharin, glycerin, sodium benzoate Oxidized iron red, pregelatinized starch
  • compositions of the present invention comprise a combination of any two or more compounds selected from the group consisting of: menthol, mannitol, eriodictyol ) and sucralose.
  • compositions of the present invention comprise a combination selected from the group consisting of: (1) a combination of menthol, mannitol, and eriodictyol, ( 2) Combination of mannitol and eriodictyol, (3) combination of mannitol and sucralose, (4) eriodictyol and sucralose Combination, (5) a combination of menthol and mannitol, or (6) a combination of eriodictyol, mannitol, and sucralose.
  • the present invention also provides for the efficacy of one or more compounds to modulate pancreatic function, particularly to reduce impaired pancreatic function and symptoms of diabetes due to accumulation of fat, for example, against insulin resistance and hypoglycemia.
  • One or more of the compounds described herein as set forth herein include the compound itself, as well as derivatives, metabolites, and decomposition products thereof.
  • Such derivatives include, but are not limited to, structural isomers, complexes, salts, esters, chelates or any precursors which can be used to produce the compounds described herein in vivo.
  • the present invention discloses that one or more of the compounds described above have the effect of reducing pancreatic fat content, preventing or treating fatty pancreas, improving pancreatic lesions caused by fatty pancreas, diabetes or other related conditions in an individual. Accordingly, the present invention provides the use of a compound as described in a composition for reducing pancreatic fat content, preventing or treating fatty pancreas, ameliorating pancreatic lesions caused by fatty pancreas, diabetes or other related disorders. The invention also provides a method of reducing pancreatic fat content, preventing or treating fatty pancreas, ameliorating pancreatic lesions caused by fatty pancreas, diabetes or other related disorders, comprising administering to a subject in need thereof an effective amount of said compound. The present invention also provides a composition for reducing pancreatic fat content, preventing or treating fatty pancreas, improving pancreatic lesions caused by fatty pancreas, diabetes or other related disorders in an individual.
  • One or more of the compounds as described above include the compound itself, derivatives, metabolites, and decomposition products thereof.
  • the foregoing derivatives include, but are not limited to, structural isomers, complexes, salts, esters A class, chelate or any precursor that can produce a compound described herein in vivo.
  • pancreatic fat content refers to the amount of fat accumulated in the pancreas in an individual, including lipids in a broad sense, such as triglyceride (TG) and cholesterol.
  • reducing pancreatic fat content generally means lowering the abnormal pancreatic fat content in an individual to a normal level or closer to a normal level, and may also refer to comparing the same individual before and after taking the drug, wherein the individual is after taking the agent.
  • the body's pancreatic fat content is lower than the body's pancreatic fat content before taking the drug.
  • the normal level of pancreatic fat content can be assessed by measuring and collecting pancreatic fat content of normal individuals in a population.
  • pancreatic fat content For example, for a group of people, such as the normal level of pancreatic fat content is 3% of the weight of the pancreas, when the fat weight in the pancreas exceeds 5% of the weight of the pancreas, it is an abnormal accumulation of fat, then "reduced pancreatic fat content.” It can mean that the abnormal pancreatic fat content in the individual is reduced to 3% of the weight of the pancreas (the above pancreatic fat content is a relative value and is exemplified, which may vary due to individual ethnic groups and other factors).
  • "fatty pancreas” may refer to a condition in which the pancreatic fat content in an individual is above normal levels. Standard methods of analysis can be used to assess pancreatic fat content, including but not limited to, ultrasound analysis, magnetic resonance imaging MRI, magnetic resonance spectrum MRS, computed tomography CT, pancreatic pathology.
  • the compound includes commonly used excipients and bioflavonoids, which are readily available in the field (such as commercially available), can be used to reduce pancreatic fat content, prevent or treat fat pancreas, and improve fat.
  • pancreatic lesions or conditions including abnormalities due to accumulation of pancreatic fat include alcoholic fatty pancreas and nonalcoholic fatty pancreas.
  • treatment refers to the administration or administration of a composition comprising one or more active agents to an individual having a disease, a symptom or condition of the disease, or a disease progression, the purpose of which is to treat, cure, relieve, Alleviate, alter, remedy, improve, improve, or affect the disease, the symptoms or conditions of the disease, the disability caused by the disease, or the deterioration of the disease.
  • prevention refers to a preventive or preventive measure for a disease, a symptom or condition of a disease, including but not limited to, the application or administration of one or more active agents to a possible unrecognized condition.
  • the words "individual” or “individual” as used herein include human or non-human animals, such as companionship. Animals (such as dogs, cats, etc.), farm animals (such as cattle, sheep, pigs, horses, etc.), or experimental animals (such as rats, mice, guinea pigs, etc.).
  • the term "effective amount” refers to the amount of active ingredient that produces a desired biological or medical effect on an individual being treated, for example, reducing the pancreatic fat content of an individual, preventing or treating fatty pancreas, and improving fatty pancreas. Caused by pancreatic lesions, diabetes or other related conditions.
  • a therapeutically effective amount of the active ingredient according to the invention may be formulated into a pharmaceutical composition in a suitable form with apharmaceutically acceptable carrier.
  • the term "pharmaceutically acceptable” means that the carrier is compatible with the active ingredient of the composition (without affecting the action of the active ingredient), and is preferably stable to the active ingredient and is safe for the individual to be treated .
  • the carrier can be a diluent, carrier, excipient, or vehicle of the active ingredient.
  • suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, poly Vinyl pyrrolidone, cellulose, sterile water, syrup, and methylcellulose.
  • the composition may additionally comprise a lubricant such as talc, magnesium stearate, and mineral oil; a wetting agent; an emulsifier and a suspending agent; a preservative such as methyl and propyl hydroxybenzoate; a sweetener; Agents, etc.
  • a lubricant such as talc, magnesium stearate, and mineral oil
  • a wetting agent such as talc, magnesium stearate, and mineral oil
  • an emulsifier and a suspending agent such as methyl and propyl hydroxybenzoate
  • a preservative such as methyl and propyl hydroxybenzoate
  • the composition may be in any form, for example, as a tablet, a pill, a powder, a lozenge, a sachet, a cachet, an elixir, a suspension, an emulsion, a solution, a syrup, a soft and hard gelatin capsule. , suppositories, sterile injections, and packaging powders.
  • compositions of the invention may be delivered via any physiologically acceptable route, for example, orally, parenterally (e.g., intramuscular, intravenous, subcutaneous, and intraperitoneal), transdermal, suppository, and intranasal methods, and the like.
  • parenterally e.g., intramuscular, intravenous, subcutaneous, and intraperitoneal
  • transdermal e.g., transdermal
  • suppository e.g., transdermal
  • intranasal methods e.g., transdermal
  • intranasal methods e.g., transdermal, suppository, and intranasal methods, and the like.
  • parenteral administration it is preferred to use a sterile aqueous solution which may contain other substances such as salts or glucose sufficient to render the solution isotonic with blood.
  • the aqueous solution is suitably buffered (preferably having a pH of 3 to 9) depending on the requirements.
  • the present invention also contemplates that one or more compounds have the effect of modulating pancreatic function, particularly reducing impaired pancreatic function due to accumulation of fat, for example, symptoms of diabetes.
  • the efficacy of the compounds of the invention includes combating insulin resistance and lowering blood glucose.
  • Standard analytical methods can be used to assess impaired pancreatic function and sugar Symptoms of urinary diseases, including but not limited to, blood glucose levels, glycosylated hemoglobin (HbA1C), glucose tolerance test (GTT), blood insulin concentration, homeostasis model assessment of insulin resistance , HOMA-IR), tumor necrosis factor-alpha analysis, interleukin-6 (IL-6) analysis, interleukin-1beta, IL- 1 ⁇ ) analysis and the like.
  • HbA1C glycosylated hemoglobin
  • GTT glucose tolerance test
  • HOMA-IR tumor necrosis factor-alpha analysis
  • IL-6 interleukin-6
  • IL-1beta interleukin-1beta
  • mice For the test animals B6 mice, only 4 rats in each group were pre-tested, and only 12 rats in each group were confirmed. Male mice were housed in the normal light and dark cycle (lighting period from 7:00 am to 7:00 pm, the rest is dark period), temperature 23 ⁇ 2 ° C, relative humidity 55 ⁇ 15% in the animal room, weight 18 ⁇ 23g . After being purchased into the National Defense Animal Center by Lesco Biotech Co., Ltd. (Taipei), the animal experiment was carried out in accordance with the National Health Center experimental guidelines. First, feed 3-5g per day with normal feed, keep 1-2 weeks to observe the state of health, water is unlimited supply, and the body weight is recorded once a week.
  • test animals were randomly divided into a blank control group (Blank), a high-fat control group (HFD), a positive control group (PS), and a test group.
  • the blank control group was given normal feed; the high-fat control group was given high-fat diet; the positive control group was given high-fat diet and tube fed silymarin (5 mg/kg/day) (Iranian Journal of Pharmaceutical Research (2016), 15(3): 493-500; Life Sciences 75 (2004) 2167-2180; and Pharm Biol. 2016 Jul 8: 1-6); and the test group is for the administration of high fat feed and individual tube test components.
  • the blank control group was given normal feed for 12 weeks, and the high-fat control group, the positive control group and the experimental group were High-fat diet for 12 weeks. After 8 weeks of feeding, the blank control group and the high-fat control group were given deionized water once a day; the control group was given a silymarin once a day; the test group was given a test compound once a day for 4 weeks.
  • Serum triglyceride (TG) and total cholesterol (TCHO, TC) were measured by an automatic blood biochemical analyzer.
  • pancreatic biochemical function blood glucose analysis (GLU, blood glucose analysis)
  • Blood glucose analysis was performed using a Roche ACCU-CHEK Active blood glucose machine. One day before the blood collection, the mice were fasted overnight. Insert the code card of the blood glucose test paper into the blood glucose meter, and then insert the blood glucose test paper. The blood drop pattern appears on the standby device. A blood drop is taken from the cheek vein of the mouse to the blood glucose machine test paper to record the blood glucose meter. Blood glucose data.
  • pancreatic biochemical function intraperitoneal glucose tolerance test (IPGTT)
  • mice were moved to a clean cage for fasting overnight, where there was no food or feces in the feeding funnel or bottom of the clean cage, ensuring that the animals had access to drinking water at all times.
  • the body weight of the mice was measured, and the volume of the glucose solution required for intraperitoneal (IP) injection was calculated (concentration: 250 mg/mL, 2 g glucose/mouse body weight, kg, required volume ( ⁇ l) was 8 x body weight (g)) .
  • IP intraperitoneal
  • the mice were removed, and an appropriate amount of glucose solution was intraperitoneally injected into the mice, and the injection time was recorded.
  • blood was taken from the tail of the mouse, blood glucose concentration was measured, and blood glucose analysis was performed using a Roche ACCU-CHEK Active blood glucose machine.
  • mice were fasted for blood collection at the end of the test (12 weeks) and were performed according to the instructions of the mouse ultrasensitive insulin ELISA kit (ALPCO).
  • ALPCO mouse ultrasensitive insulin ELISA kit
  • mice were fasted for blood collection at the end of the test (12 weeks), and blood glucose and insulin concentrations were measured and calculated according to the following formula:
  • pancreas specimens were taken by laparotomy, and the pancreas weight/body weight ratio was compared after weighing. In addition, the remaining pancreas was cryopreserved for detection of triglyceride and total cholesterol in the pancreas.
  • test results are calculated by the single factor analysis of variance (ANOVA) test to determine whether there is a statistically significant difference, using the Statistical Package of the Social Science program (Version 13, SPSS Inc.) software package to calculate; then use the post hoc test least significant difference method to make multiple comparisons to confirm significant differences between ethnic groups; significant differences in ethnic averages are p ⁇ 0.05.
  • SD standard deviation
  • ANOVA single factor analysis of variance
  • the other animals were given high-fat diet.
  • the animals in each group were given different treatments for 4 weeks, among which, the blank control group and high fat.
  • the control group was given deionized water
  • the control group was given silymarin
  • the test group was given different test compounds, including puerarin, phloridzin, eriodicty, sucralose, mannitol, saccharin, orange peel, menthol, or A combination of test compounds.
  • puerarin phloridzin, eriodicty, sucralose, mannitol, saccharin, orange peel, menthol, or A combination of test compounds.
  • test compounds are safe and sound.
  • test compound has the effect of reducing pancreatic lipids
  • Table 1 Test compounds reduce pancreatic lipids in animals (during 4 weeks of dosing).
  • eriodictyol, mannitol, saccharin, sucralose, orange peel, puerarin, menthol, phloridzin can significantly reduce total cholesterol in the pancreas, a decrease of about 28% -51%; in particular, saccharin treatment At 4 weeks, the excellent effect was achieved, which reduced the total cholesterol content of the pancreas by about 51% (p ⁇ 0.005).
  • a combination of menthol and mannitol or a combination of menthol, mannitol and eriodictin, wherein the dose of each component is maintained at the same or each dose as used alone.
  • a similar or better reduction in triglyceride effect can be achieved when the dosage of the other ingredients is lower than the dosage used alone (for example, about three-thirds of the dose used alone).
  • a combination of specific test compound combinations can reduce the amount of drug, but maintain similar or better efficacy, resulting in a synergistic effect.
  • test compound has the function of regulating pancreatic function and treating diabetes symptoms
  • Test compound can regulate pancreatic function and reduce pancreatic function damage in animals (during 4 weeks of administration)
  • Test compound can regulate pancreatic function and reduce pancreatic function damage in animals (during 4 weeks of administration)
  • This experiment detects whether the test compound can regulate pancreatic function and reduce the damage of pancreatic function in animals, especially for carbohydrate metabolism.
  • pancreatic metabolism function of the pancreas of the high fat diet mice was impaired (GLU, IPGTT, fasting insulin concentration, HOMA-IR value increased).
  • Sucralose, menthol, mannitol, and saccharin can significantly reduce GLU when administered a single test compound; eriodictyol, sucralose, menthol, mannitol, saccharin, and puerarin can significantly reduce sugar Tolerance; phlorizin, eriodicty, sucralose, menthol, mannitol, saccharin, and puerarin significantly reduced fasting insulin concentrations and insulin resistance.
  • test compound has the effect of reducing triglyceride in plasma
  • Table 3 Test compounds reduce triglycerides in plasma of animals (during 4 weeks of dosing)
  • the combination of menthol and mannitol or the combination of eriodictin and sucralose can significantly reduce triglycerides in plasma when a combination of two test compounds is administered.
  • menthol mannitol
  • eriodictol effectively lowers triglycerides in plasma at low doses when a combination of three test compounds is administered.
  • the compound provided by the invention can reduce pancreatic fat content and improve related diseases in individuals, and the compounds belong to low molecular natural plant phenolic compounds, which are widely present in fruits and vegetables, grains, rhizomes, flowers, teas and red wines, and are tested by animals. Confirmed safe and flawless, with the potential to develop pancreatic fat, prevent or treat fatty pancreas, improve pancreatic lesions caused by fat and pancreas, diabetes or other related conditions, regulate pancreatic function, and especially improve insulin resistance. .

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Abstract

一种预防或治疗脂肪胰、改善脂肪胰引起的胰病变、糖尿病或其他相关病症之组合物及方法。

Description

预防或治疗脂肪胰、改善脂肪胰引起的胰病变、糖尿病或其他相关病症之组合物及方法
相关申请案
本案主张2015年11月19日申请之美国临时申请案第62/257,707号之优先权，其内容在此全部并入作为参考资料。
技术领域
本发明关于一种预防或治疗脂肪胰、改善脂肪胰引起的胰病变、糖尿病或其他相关病症之组合物及方法。
背景技术
胰脏是人体中具有外分泌与内分泌的器官，外分泌部份包括腺泡，可分泌多种消化酶，内分泌部份包括胰岛，可分泌胰岛素等激素，对维持血糖水平有十分重要的作用。胰脏的脂肪累积可能影响胰脏功能，进一步引起胰病变、糖尿病或其他相关病症。特定而言，糖尿病是一种糖代谢异常疾病，有两种不同类型的糖尿病，包括非胰岛素依赖或成人型，亦称为第II型糖尿病；以及胰岛素依赖或幼儿型，亦称为第I型糖尿病。一般来说，第II型糖尿病通常发生于成人且与肥胖具有高度关联性，可透过适当的运动、饮食和药物来控制；第I型糖尿病患者多发于儿童及青少年，病患身体不能产生足够的胰岛素，必须藉由注射投与胰岛素维持生命。
因此，仍有需要寻求一种有效的降低个体之胰脂肪含量及改善相关病症之有效成分。
发明内容
本发明提出一或多种化合物具有于个体中降低胰脂肪含量、预防或治疗脂肪胰、改善脂肪胰引起的胰病变、糖尿病或其他相关病症之功效，该化合物选自以下所组成之群：枸橘苷(poncirin)、异牡荆素(isovitexin)、圣草酚(eriodictyol)、麦角固醇(ergosterol)、月桂烯(β-myrcene)、金丝桃苷(hyperoside)、儿茶素((+)-catechin)、十六酸乙酯(palmitic acid ethyl ester)、高良姜素(galangin)、 桑叶素(morin)、金松双黄酮(sciadopitysin)、香风草甙(didymin)、棉纤维素(gossypin)、木犀草素-7-葡萄糖甙(luteolin-7-Glucoside)、双氢槲皮素((+)-taxifolin)、肉桂酸(trans-cinnamic Acid)、香叶木素(diosmin)、蒙花甙(linarin)、异红草素(homoorientin)、木糖醇(xylitol)、犀草素(luteolin)、獐牙菜苦素(swertiamarin)、硫酸月桂酸钠(sodium lauryl sulfate)、薄荷醇(menthol)、三氯蔗糖(sucralose)、甘露醇(mannitol)、交联聚维酮(crospovidone)、山梨醇(sorbitol)、糖精(saccharin)、甘油(glycerin)、苯甲酸钠(sodium benzoate)、氧化铁红(oxide red)、预糊化淀粉(pregelatinized starch)、环己烷氨基磺酸钠(sodium cyclamate)、山梨酸(sorbic acid)、柠檬油(lemon oil)、麦芽糖糊精(maltodextrin)、柠檬酸(citric acid)、及丁基羟基茴香醚(butylated hydroxyanisole)、及其衍生物、代谢物及分解物、及其任何组合。
因此，在一方面，本发明提出所述化合物或其衍生物、代谢物或分解物用于制备于个体中降低胰脂肪含量、预防或治疗脂肪胰、改善脂肪胰引起的胰病变、糖尿病或其他相关病症之组合物的用途。本发明也提出藉由投用所述化合物或其衍生物、代谢物或分解物以于有需要的个体中降低胰脂肪含量、预防或治疗脂肪胰、改善脂肪胰引起的胰病变、糖尿病或其他相关病症之方法。
在部份具体实例中，该化合物选自于以下所组成群组：薄荷醇(menthol)、甘露醇(mannitol)、圣草酚(eriodictyol)、三氯蔗糖(sucralose)及其任何组合。
在部份具体实例中，该化合物为(1)薄荷醇(menthol)、甘露醇(mannitol)及圣草酚(eriodictyol)之组合、(2)甘露醇(mannitol)及圣草酚(eriodictyol)之组合、(3)甘露醇(mannitol)及三氯蔗糖(sucralose)之组合、(4)圣草酚(eriodictyol)及三氯蔗糖(sucralose)之组合、(5)薄荷醇(menthol)及甘露醇(mannitol)之组合、或(6)圣草酚(eriodictyol)、甘露醇(mannitol)及三氯蔗糖(sucralose)之组合。
在部份具体实例中，本发明的化合物可用于预防或治疗脂肪胰、改善脂肪胰引起的胰病变、糖尿病或其他相关病症。在部分具体实施例中，胰病变或相关病症包括酒精性脂肪胰疾病和非酒精性脂肪胰疾病，其中酒精性脂肪胰疾病包括但不限于酒精性脂肪胰脏炎(alcoholic fatty steatopancreatitis)及酒精性胰脏炎(alcoholic  pancreatitis)，以及非酒精性脂肪胰疾病包括但不限于非酒精性脂肪胰脏炎(nonalcoholic fatty steatopancreatitis)、胰腺脂肪过多(pancreatic lipomatosis)、胰脏脂肪变性(pancreatic steatosis)、脂肪胰(fatty pancreas)、胰脏脂肪假性增生(lipomatous pseudohypertrophy of pancreas)、胰脏脂肪替代(fatty replacement of pancreas)及胰脏脂肪浸润(fatty infiltration of pancreas)(Nat.Rev.Gastroenterol.Hepatol.8,169–177(2011)；World J Gastroenterol.2006 Dec 14；12(46):7421–7427；以及Alcohol Clin Exp Res.1982 Winter；6(1):117-21)。
在部份具体实例中，本发明的化合物可制成药物、食品添加物或健康食品。
在又一方面，本发明提供一种组合物，其包括选自于以下所组成之群组的任何两种或以上的化合物的组合：枸橘苷(poncirin)、异牡荆素(isovitexin)、圣草酚(eriodictyol)、麦角固醇(ergosterol)、月桂烯(β-myrcene)、金丝桃苷(hyperoside)、儿茶素((+)-catechin)、十六酸乙酯(palmitic acid ethyl ester)、高良姜素(galangin)、桑叶素(morin)、金松双黄酮(sciadopitysin)、香风草甙(didymin)、棉纤维素(gossypin)、木犀草素-7-葡萄糖甙(luteolin-7-Glucoside)、双氢槲皮素((+)-taxifolin)、肉桂酸(trans-cinnamic Acid)、香叶木素(diosmin)、蒙花甙(linarin)、异红草素(homoorientin)、木糖醇(xylitol)、犀草素(luteolin)、獐牙菜苦素(swertiamarin)、硫酸月桂酸钠(sodium lauryl sulfate)、薄荷醇(menthol)、三氯蔗糖(sucralose)、甘露醇(mannitol)、交联聚维酮(crospovidone)、山梨醇(sorbitol)、糖精(saccharin)、甘油(glycerin)、苯甲酸钠(sodium benzoate)、氧化铁红(oxide red)、预糊化淀粉(pregelatinized starch)、环己烷氨基磺酸钠(sodium cyclamate)、山梨酸(sorbic acid)、柠檬油(lemon oil)、麦芽糖糊精(maltodextrin)、柠檬酸(citric acid)、及丁基羟基茴香醚(butylated hydroxyanisole)、及其衍生物、代谢物及分解物。
在部份具体实例中，本发明的组合物包括选自于以下所组成之群组的任何两种或以上的化合物的组合：薄荷醇(menthol)、甘露醇(mannitol)、圣草酚(eriodictyol)及三氯蔗糖(sucralose)。
在部份具体实例中，本发明的组合物包括选自于以下所组成之群组的组合：(1)薄荷醇(menthol)、甘露醇(mannitol)及圣草酚(eriodictyol)之组合、(2) 甘露醇(mannitol)及圣草酚(eriodictyol)之组合、(3)甘露醇(mannitol)及三氯蔗糖(sucralose)之组合、(4)圣草酚(eriodictyol)及三氯蔗糖(sucralose)之组合、(5)薄荷醇(menthol)及甘露醇(mannitol)之组合、或(6)圣草酚(eriodictyol)、甘露醇(mannitol)及三氯蔗糖(sucralose)之组合。
本发明也提出一或多种化合物具有调节胰脏功能之功效，特别是降低因脂肪累积而导致的胰脏功能受损及糖尿病症状，例如，对抗胰岛素抗性及降血糖。
本发明提出的一或多种此处所述的化合物包括该化合物本身、及其衍生物、代谢物、及分解物。前述衍生物包括但不限于结构上之异构物、错化物、盐类、酯类、螯合物或任何可于体内生成此处所述化合物之前驱物。
无须进一步的阐述，咸相信本发明所属技术領域中具有通常知識者基于前述說明即可利用本发明至最广的程度。因此，可以理解以下的說明仅仅是作为例示說明之用，而非以任何方式限制其余的揭露内容。
具体实施方式
除非另有指明，所有在此处使用的技术性和科学性术语具有如同本发明所属技艺中之通常技术者一般所了解的意义。
本文所使用的「一」乙词，如未特别指明，系指至少一个(一个或一个以上)之数量。
本发明揭示一或多种如上所述的化合物具有于个体中降低胰脂肪含量、预防或治疗脂肪胰、改善脂肪胰引起的胰病变、糖尿病或其他相关病症之作用。因此，本发明提供一种所述之化合物在制备于个体中降低胰脂肪含量、预防或治疗脂肪胰、改善脂肪胰引起的胰病变、糖尿病或其他相关病症之组合物之用途。本发明亦提供一种降低胰脂肪含量、预防或治疗脂肪胰、改善脂肪胰引起的胰病变、糖尿病或其他相关病症之方法，其包括对有需要的个体投予有效量之所述的化合物。本发明亦提供一种可供于个体中降低胰脂肪含量、预防或治疗脂肪胰、改善脂肪胰引起的胰病变、糖尿病或其他相关病症之组合物。
本文所揭示一或多种如上所述的化合物包括该化合物本身、其衍生物、代谢物、分解物。前述衍生物包括但不限于结构上之异构物、错化物、盐类、酯 类、螯合物或任何可于体内生成此处所述化合物之前驱物。
本文所使用的「胰脂肪含量」是指个体内累积于胰脏的脂肪含量，包括广义的脂质，例如，三酸甘油脂(triglyceride，TG)及胆固醇等。本文所使用的「降低胰脂肪含量」通常是指使个体内的异常胰脏脂肪含量降低至正常水平或较接近正常水平，也可指同一个体服用药剂之前后比较，其中，该个体服用药剂之后的体内胰脏脂肪含量较服用药剂之前的体内胰脏脂肪含量为低。所述胰脏脂肪含量之正常水平可经测量并收集一族群中正常个体的胰脏脂肪含量评估而得。例如，针对一族群，如胰脏脂肪含量之正常水平为占胰脏重量的3％，当胰脏内的脂肪重量超过胰脏重量的5％时则属于脂肪异常累积，则「降低胰脂肪含量」可指使个体内的异常胰脏脂肪含量降低至胰脏重量的3％(上述胰脏脂肪含量为相对数值且为举例说明，可能因个体族群及其他因素有所变动)。本文所使用的「脂肪胰」可指个体内的胰脏脂肪含量高于正常水平之状况。标准的分析方式可用以评估胰脂肪含量，包括但不限于，超音波分析、磁振造影MRI、磁共振频谱MRS、计算机断层扫描CT、胰脏病理切片。
根据本发明，所述的化合物包括常用的赋形剂及生物类黄酮，可由此领域容易取得(如从商业上获得)，可供于个体中降低胰脂肪含量、预防或治疗脂肪胰、改善脂肪胰引起的胰病变、糖尿病或其他相关病症。在部分具体实施例中，胰病变或包括因胰脂肪累积异常导致的病症，包括，酒精性脂肪胰和非酒精性脂肪胰。
本文所使用的「治疗」乙词是指施加或投予包括一或多种活性药剂的组合物至具有疾病、疾病之症状或病况、或疾病恶化之个体，其目的在于治疗、治愈、缓解、减轻、改变、补救、改善、改进、或影响疾病、疾病之症状或病况、疾病引发之失能、或疾病恶化。
本文所使用的「预防」乙词是指对疾病、疾病之症状或病况的预防的或防止措施，包括但不限于，施加或投予一或多种活性药剂的至可能是尚未被诊断为罹患此疾病、疾病之症状或病况，但对其易感受或有其倾向之个体，其目的在于避免、阻止或推迟此疾病、疾病之症状或病况的发生。
本文所使用的「个人」或「个体」等词包括人类或非人类动物，例如陪伴 动物(如狗、猫等)、农场动物(如牛、绵羊、猪、马等)、或实验动物(如大鼠、小鼠、天竺鼠等)。
本文所使用的「有效量」乙词是指于接受处理的个体产生所欲的生物功效或医疗效果的活性成分的量，例如，降低个体的胰脂肪含量、预防或治疗脂肪胰、改善脂肪胰引起的胰病变、糖尿病或其他相关病症。
为达输送及吸收目的，根据本发明之治疗有效量之活性成分可与医药上可接受载体配制成适当形式之医药组合物。
本文所使用的「医药上可接受」乙词是指载体与组合物之活性成分相容(不影响活性成分的作用)，且较佳为可稳定该活性成分且对于接受治疗之个体具安全性。该载体可为活性成分之稀释剂、载剂、赋形剂、或介质。适用之赋形剂的一些实例包括乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、无菌水、糖浆、及甲基纤维素。本组合物可额外包含润滑剂如滑石、硬脂酸镁、及矿物油；润湿剂；乳化剂及悬浮剂；防腐剂如甲基及丙基羟基苯甲酸酯；增甜剂；以及调味剂等。在投予至病患后，本发明之组合物可提供活性成分快速、持续、或缓慢释放之效果
依据本发明，该组合物之形式可任何形式，例如，为片剂、丸剂、粉剂、锭剂、囊剂、扁囊剂、酏剂、悬剂、乳液、溶液、糖浆、软与硬明胶胶囊、栓剂、无菌注射液、及包装粉剂等。
本发明之组合物可经由任何生理上可接受途径输送，例如，口服、非口服(如肌内、静脉、皮下、及腹腔)、经皮、栓剂、及鼻内方法等。关于非口服投予，较佳为使用无菌水溶液，其可包含其他物质，如足以使溶液与血液等张的盐类或葡萄糖。水溶液可视需求适当地经缓冲(较佳为具pH值3至9)。本领域之技术人员可由习知之标准药理学技术于无菌条件下制备适合的非口服组合物。
本发明也提出一或多种化合物具有调节胰脏功能之功效，特别是降低因脂肪累积而导致的胰脏功能受损，例如，糖尿病症状。本发明之化合物的功效包括对抗胰岛素抗性及降血糖等。标准的分析方式可用以评估胰脏功能受损及糖 尿病症状，包括但不限于，血糖值、糖化血色素(HbA1C)、葡萄糖耐受性测试(glucose tolerance test，GTT)、血液胰岛素浓度、胰岛素抗性的稳态模型评估(homeostasis model assessment of insulin resistance，HOMA-IR)、肿瘤坏死因子-阿法(tumor necrosis factor-alpha)分析、介白素-6(interleukin-6，IL-6)分析、介白素-1贝塔(interleukin-1beta，IL-1β)分析等。
本发明通过下面的实施例进一步的说明，下面的实施例仅提供作为示范目的，而非限制本发明。本领域的技术人员应能根据本发明了解，不脱离本发明的精神和范围，而对本发明所公开的特定具体实施例中进行许多改变，仍然能获得相同或相似的结果。
实例
1.材料方法
1.1试验动物
采用之试验动物B6小鼠，预试验每组试验动物只数≧4只，确认试验每组试验动物只数≧12只。雄性小鼠饲养于正常明暗周期(上午7:00到下午7:00为亮期，其余为暗期)，温度23±2℃，相对湿度55±15％的动物房内，体重为18～23g。由乐斯科生物科技股份有限公司(台北)购买入国防动物中心后，动物实验遵照国卫院实验指南进行。先以一般饲料每天喂食3-5g，饲养1-2周观察健康状态，水则无限供应，每周记录体重一次。
1.2动物组别
将试验动物随机分组，分为空白对照组(Blank)、高脂对照组(HFD)、正向对照组(Positive control，PS)与试验组。空白对照组为给予正常饲料；高脂对照组为给予高脂饲料；正向对照组为给予高脂饲料与管喂水飞蓟素(silymarin，5mg/kg/day)(Iranian Journal of Pharmaceutical Research(2016),15(3):493-500；Life Sciences 75(2004)2167–2180；以及Pharm Biol.2016Jul 8:1-6)；以及试验组为给予高脂饲料与个别管喂试验成分。
1.3喂食方式
空白对照组以正常饲料任食12周，高脂对照组、正向对照组与试验组则以 高脂饲料任食12周。开始喂食8周后，空白对照组与高脂对照组每天一次管喂给予去离子水；正向对照组每天一次管喂给予水飞蓟素；试验组每天一次管喂给予试验化合物，为期4周。
1.4采血及各种分析
试验开始前及试验开始后之第8、12周，以脸颊或心脏采血。最后于结束时秤重后全部牺牲，以脸颊或心脏采血。小鼠血液样品在室温下放置1小时以使其凝结。再以冷冻离心机于4℃下15,700x g离心5分钟，分离血清。
1.4.1三酸甘油脂(TG)及总胆固醇(TCHO，TC)血清分析
以血液自动生化分析仪检测血清中的三酸甘油脂(TG)及总胆固醇(TCHO，TC)。
1.4.2胰脏生化功能分析：血糖分析(GLU，blood glucose analysis)
以罗氏ACCU-CHEK Active血糖机进行血糖分析。在采血前一天，小鼠禁食隔夜。将血糖试纸之密码卡(Code Card)插入血糖机，然后插入血糖试纸，待机器出现血滴图案，以颊针于小鼠脸颊静脉处采一滴血滴入血糖机试纸，纪录血糖机所显示之血糖数据。
1.4.3胰脏生化功能分析：腹腔注射葡萄糖耐受性测试(Intraperitoneal glucose tolerance test，IPGTT)
将小鼠移至洁净笼禁食隔夜，其中，洁净笼的喂食漏斗或底部没有食物或粪便，确保动物在任何时候都能获得饮用水。测量小鼠体重，并计算腹腔(intraperitoneally,I.P.)注射所需要的葡萄糖溶液的体积(浓度为250mg/mL，2g葡萄糖/小鼠体重，公斤，所需体积(μl)为8x体重(g))。将小鼠移出，将适当含量的葡萄糖溶液以腹腔注射于小鼠，并记录注射时间。在葡萄糖溶液注射后0、15、30、60、120及150分钟，由小鼠尾部取血，测量血糖浓度，使用罗氏ACCU-CHEK Active血糖机进行血糖分析。
1.4.4胰脏生化功能分析：禁食胰岛素浓度分析
小鼠于试验中止时(12周)禁食采血，依鼠超灵敏胰岛素ELISA检测套组(Mouse ultrasensitive insulin ELISA kit(ALPCO))之操作说明书进行。
1.4.5胰脏生化功能分析：胰岛素抗性的稳态模型评估(homeostasis model  assessment of insulin resistance，HOMA-IR)
小鼠于试验中止时(12周)禁食采血，测量血糖和胰岛素浓度，依以下公式计算：
禁食血液胰岛素浓度(ng/mL)x禁食血糖浓度(mg/dL)
405
1.4.6胰脏组织的三酸甘油脂(TG)及总胆固醇(TCHO，TC)分析
小鼠牺牲后，剖腹取出胰脏标本，秤重后比较其胰重/体重比值。另外将其余胰脏冷冻保存，进行检测胰脏中三酸甘油酯、总胆固醇含量。
1.5统计分析
所有的数据皆以平均±标准偏差(SD)表示，试验结果以单因子变异数分析(ANOVA)测试法来计算是否具有统计上的显着差异，使用Statistical Package of the Social Science program(Version 13,SPSS Inc.)软件包来计算；随后使用事后比较(post hoc test)最小差异显着性(least significant difference)方法做多重比较，以确认族群间的显着差异；族群平均之显着差异为p<0.05。
2.结果
2.1动物实验
在动物实验中，除空白组给予正常饲料外，其余动物给予高脂饲料，8周后，各组动物除维持给予原饲料外，再给予不同处理达4周，其中，空白对照组及高脂对照组给予去离子水，正向对照组给予水飞蓟素，以及试验组给予不同试验化合物，包括葛根素、根皮苷、圣草酚、三氯蔗糖、甘露醇、糖精、橙皮、薄荷醇、或部分试验化合物之组合。各组间动物之体重增加量与每日饲料摄取量在统计上均无显着差异(p>0.05)。
此外，试验组投予不同试验化合物后，动物无任何异常症状，试验期间无造成任何动物的死亡，试验后牺牲动物剖检，亦无观察到因试验化合物所造成之病变或临床征状的发生，故该等试验化合物安全无虞。
2.2试验化合物具降低胰脏脂质的作用
动物实验的结果显示，多种试验化合物在为期4周的给药期间后，显示降低动物胰脏脂质的作用。结果显示于表1。
表1：试验化合物可降低动物之胰脏脂质(4周的给药期间)。
Figure PCTCN2016106607-appb-000001
结果显示，给予高脂饲料小鼠胰脏的三酸甘油酯及总胆固醇上升。在投予单一试验化合物时，圣草酚、甘露醇、糖精、三氯蔗糖、橙皮、葛根素、薄荷醇可显着降低胰脏中的三酸甘油酯，相较于高脂对照组，下降约33％-87％。尤其，圣草酚处理4周时，达优异效果，可降低约87％胰脏三酸甘油酯含量(p<0.005)。此外，圣草酚、甘露醇、糖精、三氯蔗糖、橙皮、葛根素、薄荷醇、根皮苷可显着降低胰脏中的总胆固醇，下降约28％-51％；尤其，糖精处理4周时，达优异效果，可降低约51％胰脏总胆固醇含量(p<0.005)。
在合并投与两种或三种化合物时，例如，薄荷醇与甘露醇之组合，或薄荷醇、甘露醇与圣草酚的组合，其中，各别成分之剂量维持与单独使用之剂量相同或各别成分之剂量低于单独使用之剂量(例如，约单独使用之剂量的三分之ㄧ)时，可达到相似或更佳的降低三酸甘油酯效果。因此，根据本发明，合并使用特定的试验化合物组合，可以降低药量，但维持相似或更佳的功效，产生协同效果。
2.3试验化合物具调节胰脏功能、治疗糖尿病症状的作用
动物实验的结果显示，多种试验化合物在为期4周的给药期间显示可调节胰脏功能、降低动物之胰脏功能受损情形，特别是针对糖类代谢功能。结果显示于表2-1。
表2-1：试验化合物可调节胰脏功能、降低动物之胰脏功能损伤情形(4周的给药期间)
Figure PCTCN2016106607-appb-000002
Figure PCTCN2016106607-appb-000003
表2-2：试验化合物可调节胰脏功能、降低动物之胰脏功能损伤情形(4周的给药期间)
Figure PCTCN2016106607-appb-000004
Figure PCTCN2016106607-appb-000005
本实验检测是否试验化合物可调节胰脏功能、降低动物之胰脏功能受损情形，特别是针对糖类代谢功能。
结果显示，给予高脂饲料小鼠胰脏的各项胰脏糖类代谢功能受损(GLU、IPGTT、禁食胰岛素浓度、HOMA-IR数值上升)。在投予单一试验化合物时，三氯蔗糖、薄荷醇、甘露醇、及糖精可显着降低GLU；圣草酚、三氯蔗糖、薄荷醇、甘露醇、糖精、及葛根素可显着降低糖耐受性；根皮苷、圣草酚、三氯蔗糖、薄荷醇、甘露醇、糖精、及葛根素可显着降低禁食胰岛素浓度以及胰岛素抗性。
在合并投与两种或三种化合物时，例如，薄荷醇与甘露醇之组合，或薄荷 醇、甘露醇与圣草酚的组合，其中，各别成分之剂量低于单独使用之剂量(例如，约单独使用之剂量的三分之ㄧ)时，可达到相似或更佳的降低禁食胰岛素浓度以及胰岛素抗性效果(显着降低禁食胰岛素浓度、HOMA-IR数值)。因此，根据本发明，显示合并使用特定的试验化合物组合，可以降低药量，但维持相似或更佳的功效，具协同效果。
2.4试验化合物具降低血浆中的三酸甘油酯的作用
动物实验的结果显示，多种试验化合物在为期4周的给药期间显示可降低动物之血浆中的三酸甘油酯。结果显示于表3。
表3：试验化合物可降低动物之血浆中的三酸甘油酯(4周的给药期间)
Figure PCTCN2016106607-appb-000006
Figure PCTCN2016106607-appb-000007
结果显示，给予高脂饲料小鼠诱导血浆中三酸甘油酯提升。在投予单一试验化合物时，圣草酚及根皮苷可显着降低血浆中的三酸甘油酯，相较于高脂对照组，最佳可降低约27％。
在投予二种试验化合物之组合时，薄荷醇与甘露醇的组合或圣草酚与三氯蔗糖的组合可显着降低血浆中的三酸甘油酯。
在投予三种试验化合物之组合时，薄荷醇、甘露醇与圣草酚的组合，在低剂量下可有效降血浆中的三酸甘油酯。
本发明所提供之化合物可于个体降低胰脂肪含量及改善相关病症，该等化合物属于低分子天然植物酚类化合物，广泛存在于蔬果、谷物、根茎、花卉、茶叶与红葡萄酒等，经动物试验确认安全无虞，具有发展成为降胰脂、预防或治疗脂肪胰、改善脂肪胰引起的胰病变、糖尿病或其他相关病症、调节胰脏功能，特别是改善胰岛素抗性之保健食品或药物之潜力。

Claims (16)

  1. 一种化合物用于制备于个体中降低胰脂肪含量、预防或治疗脂肪胰、改善脂肪胰引起的胰病变、糖尿病或其他相关病症的组合物的用途，其中该化合物选自于以下所组成群组：枸橘苷(poncirin)、异牡荆素(isovitexin)、圣草酚(eriodictyol)、麦角固醇(ergosterol)、月桂烯(β-myrcene)、金丝桃苷(hyperoside)、儿茶素((+)-catechin)、十六酸乙酯(palmitic acid ethyl ester)、高良姜素(galangin)、桑叶素(morin)、金松双黄酮(sciadopitysin)、香风草甙(didymin)、棉纤维素(gossypin)、木犀草素-7-葡萄糖甙(luteolin-7-Glucoside)、双氢槲皮素((+)-taxifolin)、肉桂酸(trans-cinnamic acid)、香叶木素(diosmin)、蒙花甙(linarin)、异红草素(homoorientin)、木糖醇(xylitol)、犀草素(luteolin)、獐牙菜苦素(swertiamarin)、硫酸月桂酸钠(sodium lauryl sulfate)、薄荷醇(menthol)、三氯蔗糖(sucralose)、甘露醇(mannitol)、交联聚维酮(crospovidone)、山梨醇(sorbitol)、糖精(saccharin)、甘油(glycerin)、苯甲酸钠(sodium benzoate)、氧化铁红(oxide red)、预糊化淀粉(pregelatinized starch)、环己烷氨基磺酸钠(sodium cyclamate)、山梨酸(sorbic acid)、柠檬油(lemon oil)、麦芽糖糊精(maltodextrin)、柠檬酸(citric acid)、及丁基羟基茴香醚(butylated hydroxyanisole)、及上述任一之衍生物、代谢物及分解物、及其任何组合。
  2. 根据权利要求1的用途，其中该化合物选自于以下所组成群组：薄荷醇(menthol)、甘露醇(mannitol)、圣草酚(eriodictyol)、三氯蔗糖(sucralose)及其任何组合。
  3. 根据权利要求1的用途，其中该化合物为(1)薄荷醇(menthol)、甘露醇(mannitol)及圣草酚(eriodictyol)之组合、(2)甘露醇(mannitol)及圣草酚(eriodictyol)之组合、(3)甘露醇(mannitol)及三氯蔗糖(sucralose)之组合、(4)圣草酚(eriodictyol)及三氯蔗糖(sucralose)之组合、(5)薄荷醇(menthol)及甘露醇(mannitol)之组合、或(6)圣草酚(eriodictyol)、甘露醇(mannitol)及三氯蔗糖(sucralose)之组合。
  4. 根据权利要求1的用途，其中该相关病症为酒精性脂肪胰和非酒精性脂肪胰。
  5. 根据权利要求1的用途，其中该组合物为药物、食品添加物或健康食品。
  6. 一种组合物，其包括选自于以下所组成之群组的任何两种或以上的化合物的组合：硫酸月桂酸钠(sodium lauryl sulfate)、薄荷醇(menthol)、三氯蔗糖(sucralose)、甘露醇(mannitol)、交联聚维酮(crospovidone)、山梨醇(sorbitol)、糖精(saccharin)、甘油(glycerin)、苯甲酸钠(sodium benzoate)、氧化铁红(oxide red)、预糊化淀粉(pregelatinized starch)、环己烷氨基磺酸钠(sodium cyclamate)、山梨酸(sorbic acid)、柠檬油(lemon oil)、麦芽糖糊精(maltodextrin)、柠檬酸(citric acid)、丁基羟基茴香醚(butylated hydroxyanisole)、枸橘苷(poncirin)、异牡荆素(isovitexin)、圣草酚(eriodictyol)、麦角固醇(ergosterol)、月桂烯(β-myrcene)、金丝桃苷(hyperoside)、儿茶素((+)-catechin)、十六酸乙酯(palmitic acid ethyl ester)、高良姜素(galangin)、桑叶素(morin)、金松双黄酮(sciadopitysin)、香风草甙(didymin)、棉纤维素(gossypin)、木犀草素-7-葡萄糖甙(luteolin-7-glucoside)、双氢槲皮素((+)-taxifolin)、肉桂酸(trans-cinnamic acid)、香叶木素(diosmin)、蒙花甙(linarin)、异红草素(homoorientin)、木糖醇(xylitol)、犀草素(luteolin)及獐牙菜苦素(swertiamarin)、及上述任一之衍生物、代谢物及分解物。
  7. 根据权利要求6的组合物，其包括选自于以下所组成之群组的任何两种或以上的化合物的组合：薄荷醇(menthol)、甘露醇(mannitol)、圣草酚(eriodictyol)及三氯蔗糖(sucralose)。
  8. 根据权利要求6的组合物，其包括选自于以下所组成之群组的组合：(1)薄荷醇(menthol)、甘露醇(mannitol)及圣草酚(eriodictyol)之组合、(2)甘露醇(mannitol)及圣草酚(eriodictyol)之组合、(3)甘露醇(mannitol)及三氯蔗糖(sucralose)之组合、(4)圣草酚(eriodictyol)及三氯蔗糖(sucralose)之组合、(5)薄荷醇(menthol)及甘露醇(mannitol)之组合、或(6)圣草酚(eriodictyol)甘露醇(mannitol)及三氯蔗糖(sucralose)之组合。
  9. 根据权利要求6的组合物，其供于个体中降低胰脂肪含量、预防或治疗脂肪胰、改善脂肪胰引起的胰病变、糖尿病或其他相关病症。
  10. 根据权利要求9的组合物，其中该相关病症为酒精性脂肪胰和非酒精性脂肪胰。
  11. 根据权利要求6的组合物，其为药物、食品添加物或健康食品。
  12. 一种在有需要的个体降低胰脂肪含量、预防或治疗脂肪胰、改善脂肪胰引起的胰病变、糖尿病或其他相关病症的方法，其包括将有效量的化合物投用于该个体，其中该化合物选自于以下所组成群组：枸橘苷(poncirin)、异牡荆素(isovitexin)、圣草酚(eriodictyol)、麦角固醇(ergosterol)、月桂烯(β-myrcene)、金丝桃苷(hyperoside)、儿茶素((+)-catechin)、十六酸乙酯(palmitic acid ethyl ester)、高良姜素(galangin)、桑叶素(morin)、金松双黄酮(sciadopitysin)、香风草甙(didymin)、棉纤维素(gossypin)、木犀草素-7-葡萄糖甙(luteolin-7-glucoside)、双氢槲皮素((+)-taxifolin)、肉桂酸(trans-cinnamic acid)、香叶木素(diosmin)、蒙花甙(linarin)、异红草素(homoorientin)、木糖醇(xylitol)、犀草素(luteolin)、獐牙菜苦素(swertiamarin)、硫酸月桂酸钠(sodium lauryl sulfate)、薄荷醇(menthol)、三氯蔗糖(sucralose)、甘露醇(mannitol)、交联聚维酮(crospovidone)、山梨醇(sorbitol)、糖精(saccharin)、甘油(glycerin)、苯甲酸钠(sodium benzoate)、氧化铁红(oxide red)、预糊化淀粉(pregelatinized starch)、环己烷氨基磺酸钠(sodium cyclamate)、山梨酸(sorbic acid)、柠檬油(lemon oil)、麦芽糖糊精(maltodextrin)、柠檬酸(citric acid)、及丁基羟基茴香醚(butylated hydroxyanisole)、及上述任一之衍生物、代谢物及分解物、及其任何组合。
  13. 根据权利要求12的方法，其中该化合物选自于以下所组成群组：薄荷醇(menthol)、甘露醇(mannitol)、圣草酚(eriodictyol)、三氯蔗糖(sucralose)及其任何组合。
  14. 根据权利要求12的方法，其中该化合物为(1)薄荷醇(menthol)、甘露醇(mannitol)及圣草酚(eriodictyol)之组合、(2)甘露醇(mannitol)及圣草酚(eriodictyol)之组合、(3)甘露醇(mannitol)及三氯蔗糖(sucralose)之组合、(4)圣草酚(eriodictyol)及三氯蔗糖(sucralose)之组合、(5)薄荷醇(menthol)及甘露醇(mannitol)之组合、或(6)圣草酚(eriodictyol)、甘露醇(mannitol)及三氯蔗糖(sucralose)之组合。
  15. 根据权利要求12的方法，其中该化合物为同时或依序投用。
  16. 根据权利要求12的方法，其中该相关病症为酒精性脂肪胰和非酒精性脂肪胰。
PCT/CN2016/106607 2015-11-19 2016-11-21 预防或治疗脂肪胰、改善脂肪胰引起的胰病变、糖尿病或其他相关病症之组合物及方法 WO2017084631A1 (zh)

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CN201680067605.XA CN109715170A (zh) 2015-11-19 2016-11-21 预防或治疗脂肪胰、改善脂肪胰引起的胰病变、糖尿病或其他相关病症之组合物及方法
ES16865806T ES2949047T3 (es) 2015-11-19 2016-11-21 Compuesto o composición para prevenir o tratar la infiltración grasa del páncreas
EP16865806.0A EP3378481B1 (en) 2015-11-19 2016-11-21 Compound or composition for preventing or treating pancreas fatty infiltration
PL16865806.0T PL3378481T3 (pl) 2015-11-19 2016-11-21 Związek lub kompozycja do zapobiegania lub leczenia nacieku tłuszczowego trzustki
JP2018526113A JP6914256B2 (ja) 2015-11-19 2016-11-21 膵臓脂肪浸潤を予防または治療し、膵臓脂肪浸潤に起因する膵臓病変、糖尿病または他の関連症状を緩和するための組成物、および方法
US15/777,385 US20180325840A1 (en) 2015-11-19 2016-11-21 Compositions and methods for preventing or treating fatty pancreas or ameliorating pancreas diseases caused by fatty pancreas, diabetes mellitus or other related disorders
FIEP16865806.0T FI3378481T3 (fi) 2015-11-19 2016-11-21 Yhdiste tai koostumus haiman rasva-infiltraation estoon tai hoitoon

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