WO2016029868A1 - 用于减少体重及减少体脂肪的组合物及其医药品与应用 - Google Patents

用于减少体重及减少体脂肪的组合物及其医药品与应用 Download PDF

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Publication number
WO2016029868A1
WO2016029868A1 PCT/CN2015/088338 CN2015088338W WO2016029868A1 WO 2016029868 A1 WO2016029868 A1 WO 2016029868A1 CN 2015088338 W CN2015088338 W CN 2015088338W WO 2016029868 A1 WO2016029868 A1 WO 2016029868A1
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Prior art keywords
fat
composition
weight
extract
body weight
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PCT/CN2015/088338
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English (en)
French (fr)
Inventor
凌玉芳
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康霈生技股份有限公司
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Priority to US15/025,898 priority Critical patent/US10537605B2/en
Priority to CA2960075A priority patent/CA2960075C/en
Priority to KR1020177008266A priority patent/KR101923840B1/ko
Priority to CN201580045334.3A priority patent/CN106794215A/zh
Priority to EP15836301.0A priority patent/EP3187189B1/en
Priority to MX2017002584A priority patent/MX2017002584A/es
Priority to ES15836301T priority patent/ES2851680T3/es
Priority to JP2017530387A priority patent/JP6446552B2/ja
Application filed by 康霈生技股份有限公司 filed Critical 康霈生技股份有限公司
Priority to AU2015309351A priority patent/AU2015309351B2/en
Priority to TW104131194A priority patent/TWI580427B/zh
Publication of WO2016029868A1 publication Critical patent/WO2016029868A1/zh
Priority to US15/936,695 priority patent/US10537548B2/en
Priority to AU2018278907A priority patent/AU2018278907B2/en
Priority to US16/686,965 priority patent/US20200230102A1/en

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    • 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)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger
    • 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
    • A61K31/05—Phenols
    • 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)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/82—Theaceae (Tea family), e.g. camellia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the invention relates to a composition, in particular to a plant extract comprising a specific weight ratio of green tea extract and turmeric extract; the invention relates to the use of a composition, in particular to a weight loss by preparation of the composition.
  • the invention relates to a pharmaceutical product comprising the composition, in particular to a pharmaceutical product which can be used for reducing body weight and reducing body fat; the invention further relates to the application of the pharmaceutical product In particular, the use of an effective amount of the medicament for reducing body weight and body fat.
  • BMI body mass index
  • BMI greater than 30 is defined as obesity.
  • the World Health Organization's research report also pointed out that among the global risk of death, overweight and obesity ranked sixth. According to research data, at least 3.4 million adults died of chronic diseases caused by overweight or obesity in 2013, 44 of them. The medical burden of % diabetes and 23% of ischemic heart disease can be attributed to obesity. Many data also show that the age of obese people is gradually decreasing.
  • Obesity is currently a health issue that is highly valued worldwide. Research indicates that the causes of obesity are very complex and multiple factors are involved. More and more evidence also shows that obesity is not a simple problem that can be improved by self-control, but a complex symptom involving appetite regulation and energy metabolism in the body. It is a disease with metabolic imbalance in the body. Obesity not only causes an increase in mortality and a huge medical burden, but also affects the quality of life of human beings. Although the cause of obesity is not fully established, it is thought to be related to factors of genetics, metabolism, biochemistry, culture and spiritual society. Studies have shown that humans have many causes of death and obesity.
  • weight-reducing drugs can be divided into two major categories, namely, suppressing appetite and blocking the absorption of the intestinal tract for food fat.
  • appetite suppression is the main mechanism of past and current market-based weight-loss drugs.
  • These drugs include Sibutramine, Lorcaserin, Qsymia and Contrave.
  • the side effects are serious and have a certain degree of cardiovascular risk.
  • Sibutramine which has a market share of 70%, is a dual effect of increasing satiety through the central nervous system and increasing the body's metabolic rate in the periphery to achieve weight loss.
  • Sibutramine is an inhibitor of noradrenaline and serotonin re-recovery, which can increase satiety to suppress appetite and achieve weight loss.
  • the increase in satiety is the reabsorption of serotonin and noradrenaline. Inhibition, by the action of ⁇ 1- and ⁇ 1-adrenergic receptors ( ⁇ 1-adrenoceptors or ⁇ 1-adrenoceptors) and 5-HT2 receptor subtypes.
  • ⁇ 1- and ⁇ 1-adrenergic receptors ⁇ 1-adrenoceptors or ⁇ 1-adrenoceptors
  • 5-HT2 receptor subtypes The central role of this drug may lead to increased blood pressure and rapid heartbeat, and in recent years it has been confirmed that Nome Ting will increase the risk of cardiovascular disease, so the EU, the United States, Australia, Taiwan, etc. have announced that they will contain Sibutramine in 2010. The diet pills are off the shelf.
  • the weight-loss drug that blocks part of the absorption of dietary fat by the intestines is Orlistat, which is the only legally long-term weight-loss drug ingredient in most countries. It is a specific and reversible gastrointestinal fat. Decomposing enzyme inhibitors, acting in the stomach and small intestine, forming a covalent bond with the lipolytic enzyme secreted by the stomach and pancreas at its activated serine position, deactivating the lipolytic enzyme, making the lipolytic enzyme unable to hydrolyze the diet The fat in the presence of triglyceride is converted into free fatty acids and monoglycerides which can be absorbed.
  • weight loss drugs have attracted various pharmaceutical companies to invest in research and development, but drug safety is a major test for weight loss drugs, serious drug side effects and cardiovascular disease risks, resulting in FDA not approved for several years before 2012. Any new drug for weight loss, the stock price of many manufacturers even fell so much, causing the market to be silent. In 2012, the US FDA finally approved four new weight-loss drugs, namely Belviq, Qsymia, Contrave and Saxenda, which are expected to reactivate the weight loss drug market.
  • Qysmia and Belviq the main components are Phentermine-topiramate and Lorcaserin.
  • the mechanism of action is mainly to increase satiety and suppress appetite to achieve weight loss.
  • Qysmia contains two old pharmaceutical ingredients, Phentermine and Topiramate.
  • Phentermine is a central nervous system stimulant.
  • the main appetite suppressing mechanism is to stimulate the adrenal gland to secrete norepinephrine by letting the hypothalamus of the brain stimulate the adrenal gland;
  • Topiramate's mechanism of action is to promote the activity of the neurotransmitter GABA, block the sodium ion channel, antagonize the glutamine receptor and inhibit carbonic anhydrase to suppress appetite and increase satiety.
  • Phentermine's diet pill Fen-Phen fenfluramine/dexfenfluramine-phentermine
  • Phentermine has been banned in many countries because it has caused serious cardiovascular risks in the past; another component, Topiramate, was approved for the treatment of epilepsy.
  • Topiramate was approved for the treatment of epilepsy. It is currently known that the side effects of Phentermine-topiramate include tingling, dizziness, dysgeus, insomnia, constipation and dry mouth.
  • Lorcaserin is a 5-HT2C receptor activator that produces ⁇ -MSH (melanocyte stimulating hormone) by activating pro-opiomelanocortin neurons (POMC neurons), which induces satiety, suppresses appetite and reduces Dietary energy intake.
  • Lorcaserin is highly selective for the 5-HT2C receptor and has a low effect on 5-HT2A and 5-HT2B receptors, so it is thought to reduce the risk of previous severe cardiovascular side effects, but its associated side effects include heart valves.
  • the FDA still requires the operator to carry out follow-up clinical monitoring, and if Lorcaserin is not relieved for 3 consecutive months, it is necessary to stop the drug immediately.
  • Contrave is a dopamine, norepinephrine reuptake inhibition, acting on the central nervous system, can suppress appetite, Contrave side effects are suicidal tendency, nausea, constipation, headache, vomiting, dizziness and so on.
  • Saxenda is a weight-loss drug for subcutaneous injection. Saxenda's mechanism of action is mainly to reduce weight by increasing the rate of gastric emptying and increasing satiety. Side effects are nausea, hypoglycemia, diarrhea, constipation, vomiting, Headache, loss of appetite, etc.
  • Phentermine a component of Qsymia, has been banned in Taiwan and many other countries because it has caused serious cardiovascular disease in the past.
  • the main problem in the development of diet pills is the safety issues such as long-term use of cardiovascular risk or mental safety concerns, and side effects such as dizziness, insomnia, palpitations, constipation and cardiovascular risk make many users unable to maintain long-term safety.
  • the heart uses existing weight loss medications.
  • Currently approved weight-loss drugs due to high side effects, poor tolerance, cardiovascular risk and other reasons, the overall market for weight loss drugs is not consistent with the global obesity population and weight loss needs.
  • Five of the 10 weight-loss drugs listed from 1957 to 2014 were removed from the market because of cardiovascular risk or mental safety concerns.
  • the main mechanism of action is to reduce body weight by suppressing appetite, including listing in 2002. After that, 70% of Sibutramine (trade name Noume Ting) was obtained.
  • the present invention provides a plant extract composition for reducing body weight and body fat, comprising green tea extract and turmeric extract, and based on the total weight of the plant extract composition, the weight percentage of the green tea extract and the turmeric extract 30% to 75% and 20% to 55%, respectively.
  • the plant extract composition of the present invention further comprises resveratrol, and the resveratrol comprises from greater than 0% to 30% by weight of the total composition.
  • the plant extract composition of the present invention is effective in reducing body weight and body fat. It is worth noting that animal experiments show that resveratrol administered separately has no effect on reducing body weight and body fat, and the effect of applying turmeric extract alone is not obvious, which is consistent with past research results, and the present invention is not only When the plant extract composition of the present invention is administered simultaneously in the process of inducing obesity, it can be observed that the plant extract composition of the present invention has a remarkable effect of reducing body weight and body fat, and further discovers that even in obesity which has induced obesity In the mouse mode, the plant extract composition of the present invention is further administered, and the effect of the present invention for significantly reducing the body weight and body fat of the mouse can be clearly observed, and the plant extract composition of the present invention and the commercially available weight loss drug Roche fresh Compared with Orlistat, the effect of reducing body weight and body fat of the present invention is significantly better than that of the commercially available weight loss drug Orlistat (p ⁇ 0.001), and the mode of first inducing obesity is more common than
  • turmeric extract refers to an extract comprising curcumin, wherein curcumin accounts for 80% to 100% of the concentration of the turmeric extract;
  • green tea extract is used herein to include An extract of catechins, wherein the catechins comprise from 75% to 100% of the green tea extract.
  • the present invention further provides a method of producing a plant extract composition comprising green tea extract and turmeric extract, comprising: a plant extract composition comprising green tea extract and turmeric extract and a pharmaceutically acceptable salt composition
  • a pharmaceutically acceptable tranquilizer or pharmaceutically acceptable excipient is mixed into a capsule, a lozenge or a coated ingot or an infusion.
  • the method further comprises adding resveratrol to form a plant extract composition comprising green tea extract, turmeric extract and resveratrol.
  • the stabilizers include, but are not limited to, xylitol, sorbitol, polydextrose, isomalt, and dextrose.
  • the present invention further provides the use of the plant extract composition for reducing body weight and body fat in the preparation of a medicament for reducing body weight and body fat.
  • the present invention further provides a pharmaceutical for reducing body weight and body fat comprising an effective amount of the plant extract composition for reducing body weight and body fat, and a pharmaceutically acceptable excipient.
  • the pharmaceutical product further comprises resveratrol effective to reduce body weight and body fat dosage.
  • the "pharmaceutically acceptable excipient” includes, but is not limited to, a disintegrant, a binder, a filler, a lubricant, a suspending agent ( Suspending agent), solubilizer and glidant.
  • a disintegrant e.g., a sulfate, a sulfate, a sulfate, a sulfate, a sulfate, a sulfate, a sulfate, a sulfate, a lubricant, a suspending agent ( Suspending agent), solubilizer and glidant.
  • Suspending agent Suspending agent
  • solubilizer solubilizer
  • glidant glidant.
  • the amount of excipient used depends on how much active ingredient and dosage form are used, and one excipient can perform more than one function.
  • the disintegrant includes, but is not limited to, agar, algionic acid, calcium carbonate, carboxymethylcellulose, cellulose, clay ( Clays), colloidal silica, croscarmellose sodium, cross-linked povidone, gum, magnesium aluminum silicate, Methyl cellulose, polacrilin potassium, sodium alginate, low substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone hydroxypropyl fiber Crosslinked polyvinylpyrrolidone hydroxypropylcellulose, sodium starch glycolate and starch.
  • the binder includes, but is not limited to, microcrystalline cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, and polyvinyl pyrrolidone.
  • the filler includes, but is not limited to, calcium carbonate, calcium phosphate, dibasic calcium phosphate, tribasic calcium sulfate, Calcium carboxymethylcellulose, cellulose, dextrin, salt, dextrin, dextrose, fructose, lactitol ), lactose, carbonate, magnesium oxide, maltitol, maltodextrin, maltose, sorbitol, starch, sucrose Sucrose), sugar and xylitol.
  • the lubricant includes, but is not limited to, agar, calcium stearate, ethyl oleate, ethyl laurate, glycerin, stearic acid.
  • Glyceryl palmitostearate hydrogenated vegetable oil, magnesium oxide, magnesium stearate, mannitol, poloxamer, ethylene glycol (ethylene glycol), sodium benzoate, sodium lauryl sulfate, sodium stearoyl acid, sorbitol, stearic acid, talc (talc) and hard Zinc stearate.
  • the suspending agent comprises, but is not limited to, mannitol, carboxymethyl cellulose (CMC) and sodium carboxymethyl cellulose (CMC-Na).
  • the co-solvent comprises, but is not limited to, hydroxypropyl-beta-cyclodextrin, tween 80, castor oil and polyethylene glycol (PEG). .
  • the glidant includes, but is not limited to, magnesium stearate, silicon dioxide, magnesium trisilicate, powdered cellulose, starch. , talc, tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silica, and silicon hydrogel.
  • the pharmaceutical products of the present invention may exist in various forms. These forms include, but are not limited to, liquid, semi-solid, and solid pharmaceutical forms such as liquid solutions (eg, injectable and infusible solutions), dispersions or suspensions, lozenges, pills, powders, liposomes, and suppositories.
  • liquid solutions eg, injectable and infusible solutions
  • dispersions or suspensions lozenges
  • pills pills
  • powders powders
  • liposomes suppositories.
  • suppositories a pharmaceutical composition
  • the preferred form depends on the intended mode of administration and therapeutic application; preferably, the pharmaceutical of the present invention is in the form of an orally or infusible solution.
  • a pharmaceutical composition for reducing body weight and body fat comprises an effective amount of a combination of a green tea extract and a turmeric extract, which is administered orally, and the plant extract composition according to the present invention is suitable for and subjected to Preferred oral dosage forms are tablets, granules, coated tablets, capsules, lozenges and other solid oral dosage forms which are also encompassed within the scope of the invention.
  • the present invention further provides an application of the pharmaceutical product for reducing body weight and body fat, which is administered to a recipient by an effective amount of a pharmaceutical extract comprising a green tea extract and a plant extract composition of turmeric extract.
  • a pharmaceutical extract comprising a green tea extract and a plant extract composition of turmeric extract.
  • the body is a human or an animal. In order to achieve the effect of reducing body weight and body fat.
  • the administration mode is oral administration or injection administration.
  • the effective dose refers to a pharmaceutical product which is administered from 1.8 mg to 145 mg per kilogram of the recipient per day, where the receptor is Human or animal, preferably human.
  • the effective dose means 5.4 mg to 70 mg of the drug per kilogram of the recipient per day, where the receptor is human or animal, preferably human.
  • the "effective dose” can be estimated herein according to the “Food and Drug Administration” (FDA) "estimating the maximum safe starting dose in initial clinical trials (estimating the maximum safe starting dose in initial Table 1 (Table 1) of clinical trials for therapeutics in adult healthy volunteers)” extrapolates the effective dose of different receptors.
  • FDA Food and Drug Administration
  • reduced body weight and body fat refers to a body weight and body after administration of an effective amount of a composition comprising green tea extract and turmeric extract, or a composition further comprising resveratrol.
  • the fats are each less than the obese control group, as in the example of the present invention, the body fat reduction can be achieved by administering a specific range of the composition of the green tea extract and the turmeric extract, or a composition further comprising resveratrol, and The amount of fat in the epididymis, the amount of fat in the peripheral kidney, the amount of fat in the mesenteric area, the amount of fat in the groin and the peritoneal cavity were measured in a specific time range.
  • the components of the plant extracting composition of the present invention are obtained by extracting from plants, and the experimental results show that the plant extracting composition of the present invention does not affect appetite or food intake, and does not affect other serum biochemical safety indicators. It is safer and safer and has no obvious side effects compared to other weight-reducing drugs currently on the market.
  • the plant extracting composition of the present invention not only reduces body weight, but also reduces the body weight by reducing the heat absorption by suppressing appetite or blocking the absorption of intestinal fat by the prior art. Effectively inhibits the proliferation of fat cells in the body, and also increases fat metabolism and energy utilization in the body, and improves the underlying causes of obesity to reduce the common re-fat problem of weight loss, and can improve various cardiovascular diseases such as blood lipids and blood sugar. Risk indicators reduce cardiovascular risk.
  • the plant extracting composition of the present invention can provide a safer and more effective method for reducing body weight and body fat in response to the current global obesity and overweight problem, and can be applied to related medicines or health care in the future. Food and other uses.
  • Figure 1 is a bar graph showing the effect of each group on the growth inhibition of precursor fat cells by the cell viability assay (MTT assay).
  • Figure 2 is a bar graph showing the effect of each group on the growth inhibition of differentiated adipocytes in a cell viability assay (MTT assay).
  • Fig. 3A is a bar graph of the present invention for detecting changes in body weight gain of mice in each group by simultaneously inducing obesity and administration.
  • Figure 3B shows the visceral fat, subcutaneous fat and total of mice in each group by simultaneously inducing obesity and administration. A histogram of fat weight changes in fat mass.
  • Fig. 4A is a bar graph showing changes in body weight gain of mice in each group by first inducing obesity and then administering it.
  • Fig. 4B is a bar graph showing changes in fat weight of visceral fat, subcutaneous fat, and total fat amount in each group of mice by first inducing obesity and then administering it.
  • Fig. 5A is a graph showing the trend of changes in body weight gain of rats in each group by simultaneously inducing obesity and administration.
  • Fig. 5B is a bar graph of the present invention for detecting changes in visceral fat of rats in each group by simultaneously inducing obesity and administration.
  • the precursor fat cell 3T3-L1 was cultured in a 96-well plate at 1 ⁇ 10 4 cells (cells/well) per well, except for the control group--DMSO solvent control group, and 50 ppm of resveratrol was added to each well.
  • 50 ppm turmeric extract, 80 ppm green tea extract, and 100 ppm of the plant extract compositions ME008A, ME008D, ME001, ME00C1, and ME00D1 of the present invention were tested in groups of 9 and each group was subjected to 3 replicates. After 48 hours of culture, the cells were photographed for growth, and the growth inhibition effect of each test substance on 3T3-L1 precursor fat cells was analyzed by cell viability assay (MTT assay).
  • MTT assay cell viability assay
  • the plant extract composition ME008A of the present invention comprises 50 wt% green tea extract, 25 wt% green coffee bean extract and 25 wt% resveratrol
  • ME008D contains 40 wt% green tea extract, 45 wt% green Coffee bean extract and 15wt% resveratrol
  • ME001 contains 60wt% green tea extract, 10wt% turmeric extract and 30wt% resveratrol
  • ME00C1 contains 40wt% green tea extract, 50wt% turmeric extract and 10wt% white Resveratrol
  • ME00D1 contained 75 wt% green tea extract and 25 wt% turmeric extract.
  • the plant extracting compositions ME00C1, ME001 and ME008D of the present invention can significantly inhibit the growth of the precursor fat cells (p ⁇ 0.05), wherein the plant extracting compositions of the present invention are among the groups.
  • ME00C1 was the best inhibitory effect on the growth of pre-adipocytes (p ⁇ 0.05), and the effect of composition ME00C1 on the growth inhibition of pre-adipocytes was also significantly higher than that of resveratrol, turmeric extract or green tea extract alone. Good (p ⁇ 0.05).
  • 3T3-L1 was cultured in a 12-well plate at 1 ⁇ 10 5 cells/well, and cultured until the fourth day, using 5 ⁇ g/ml of differentiation agent insulin per ml, and a micromolar concentration ( ⁇ M).
  • Dexamethasone (dexmethasone), 0.5 mmol molar volume (mM) of 3-isobutyl-1-methylxanthine in a medium to induce adipocyte differentiation, except for the control group - DMSO solvent control group, each group was added 50 ppm resveratrol, 50 ppm turmeric extract, 80 ppm green tea extract and 100 ppm of the plant extracting compositions ME008A, ME008D, ME001, ME00C1, ME00D1 of the present invention for experiment, a total of 9 groups of experiments And each set of experiments was performed in 3 replicates.
  • the cells were photographed for growth, and the inhibitory effect of each test substance on differentiated adipocytes was analyzed by cell viability assay (MTT assay).
  • the data of each group are expressed as mean ⁇ SD (Mean ⁇ SD).
  • the English letters a, b, c, d, e, and f are statistical results. Different letters indicate statistical differences between groups (p ⁇ 0.05). The letters indicate that there is no statistical difference between the groups (p>0.05).
  • each of the plant extracting compositions of the present invention significantly inhibited the growth of adipocytes in differentiation (p ⁇ 0.05) in comparison with the control group, wherein the plant extracting composition of the present invention was differentiated by ME00C1 in each group.
  • the inhibitory effect of medium fat cell growth was the best (p ⁇ 0.05), and the effect of composition MEOOC1 on the growth of differentiated adipocytes was also better than that of resveratrol, turmeric extract or green tea extract alone. ⁇ 0.05).
  • mice 8-week old B6 female mice were used and divided into normal control group, obese control group, resveratrol group (61.5 mg/kg BW), green tea extract group (123 mg/kg BW), and the present invention.
  • the plant extract composition ME001 (676.5mg/kg BW) was divided into 5 groups, and each group used 5 female animals for the test. During the test period, except for the normal control group, the normal feed was fed, and the other groups were high-fat for 8 weeks. The feed was used to induce the symptoms of obesity, and the test substance was administered daily for 8 weeks.
  • the obese control group was fed with an equal volume of sterile water to evaluate the difference in body weight and body fat between the groups. During the experiment, the weight and average food intake of each animal were recorded weekly.
  • mice were sacrificed, and the ovarian peripheral fat, the peripheral fat of the kidney, and the peripheral mesenteric fat were weighed to calculate the visceral fat mass.
  • the fat outside the peritoneal cavity was weighed to calculate the amount of subcutaneous fat.
  • the data of each group are expressed as mean ⁇ SD (Mean ⁇ SD).
  • the English letters a, b, c, d, e, and f are statistical results. Different letters indicate statistical differences between groups (p ⁇ 0.05). The letters indicate that there is no statistical difference between the groups (p>0.05).
  • the test results are shown in FIG. 3A and FIG. 3B.
  • the total weight gain of the plant extract composition ME001 of the present invention is significantly decreased (p ⁇ 0.05), and the decrease is 47.2%. Therefore, the plant extract of the present invention is obtained.
  • Composition ME001 was effective in achieving weight loss (p ⁇ 0.05).
  • mice fed the resveratrol group alone had no weight gain, visceral fat mass, subcutaneous fat mass, and total body fat weight (including visceral fat and subcutaneous fat), compared with the obese control group. Difference (p>0.05).
  • the plant extract composition ME001 of the present invention showed a significant decrease in visceral fat weight, subcutaneous fat weight or total body fat weight (p ⁇ 0.05).
  • the plant extracting composition ME001 of the present invention can not only effectively reduce body weight and reduce body fat, but also has better efficacy than single plant extract group (p ⁇ 0.05), and has better weight loss than other groups. efficacy.
  • Obesity mice were randomly divided into 7 groups, including an obese control group, a Roche fresh drug control group (34.8 mg/kg BW), a turmeric extract group (41 mg/kg BW), and a plant of the present invention.
  • Extraction composition test group 4 including ME008A (676.5mg/kg BW), ME008D (676.5mg/kg BW), ME001 (676.5mg/kg BW) or ME00C1 (651.9mg/kg BW), each group used 5 Only female animals were tested.
  • the other 7 groups of obese mice continued to be given high-fat diet and given the test substance for 8 weeks daily by tube feeding.
  • the obese control group was given an equal volume of sterile water tube for feeding.
  • a total of 14 weeks of high-fat diet was sacrificed and sacrificed to assess differences in body weight and body fat between the groups.
  • the weight and average food intake of each animal were recorded weekly.
  • the mice were sacrificed, and the ovarian peripheral fat, the peripheral fat of the kidney, and the peripheral mesenteric fat were weighed to calculate the visceral fat mass.
  • the fat outside the peritoneal cavity was weighed to calculate the amount of subcutaneous fat.
  • the data of each group are expressed as mean ⁇ SD (Mean ⁇ SD), the English letters a, b, c, d, e represent the statistical results, different letters indicate statistical differences between groups (p ⁇ 0.05), the same letters Indicates that there is no statistical difference between the groups (p>0.05).
  • Fig. 4A and Fig. 4B The results of the test are shown in Fig. 4A and Fig. 4B.
  • the weight gain and body fat of the obese control group were significantly increased (p ⁇ 0.05), and the weight gain increased by 87.7%.
  • This example has successfully induced an increase in body weight in mice resulting in obesity.
  • the weight gains of the plant extracting compositions ME008D, ME001 and ME00C1 of the present invention were significantly decreased (p ⁇ 0.05), and the plant extracting composition ME00C1 of the present invention was the best and the effect was significantly better.
  • the body fats (including visceral fat and subcutaneous fat) of the plant extract compositions ME008D, ME001 and ME00C1 of the present invention were also significantly decreased (p ⁇ 0.05), and the body fat reductions were 10.3% and 36.9%, respectively. And 64.1%, wherein the plant extracting composition ME00C1 of the invention has the best effect, and is significantly better than the commercially available slimming drug Roche fresh (p ⁇ 0.05) and turmeric extract (p ⁇ 0.05). It is shown that the plant extract composition ME00C1 of the present invention has a better effect of reducing body weight and reducing body fat for obese mice. There was no statistical difference in the average weekly food intake between the groups fed the high fat diet during the trial (p>0.05).
  • mice 8-week old SD strain male rats were used, and were divided into normal control group, obese control group, plant extracting composition ME00C1 (199.6 mg/kg BW) and ME00C1A (186 mg/kg BW).
  • the plant extract composition ME00C1A comprises 55.5 wt% green tea extract and 44.5 wt% turmeric extract, and each group is tested with 6 rats.
  • the normal three groups are continuously fed.
  • the week was fed with high-fat diet to induce obesity, while the test substance was administered daily by the tube, and the obese control group was given an equal volume of sterile water tube to evaluate the differences between the weight and visceral fat of the mice in each group.
  • the total body weight gain of the plant extracting compositions ME00C1 and ME00C1A of the present invention was significantly decreased as compared with the obese control group, and the plant extract composition of the present invention was compared with the obese control group.
  • ME00C1 weight gain was significantly reduced by 23.0% (p ⁇ 0.01t-test), while plant extract composition ME00C1A weight gain was significantly reduced by 29.8% (p ⁇ 0.001t-test).

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Abstract

本发明公开一种用于减少体重及减少体脂肪的组合物及其医药品与应用，该组合物包含绿茶萃取物与姜黄萃取物，且以该组合物的总重量为基础，绿茶萃取物与姜黄萃取物的重量百分比分别为30％至75％以及20％至55％。本发明所述的组合物在先诱导肥胖模式的动物试验或同时诱导肥胖的动物试验中，相较于施予单一植物萃取物或市售减肥药物Orlistat，皆具有显著减少体重与体脂肪的效果。

Description

用于减少体重及减少体脂肪的组合物及其医药品与应用 技术领域
本发明关于一种组合物，尤指包含特定重量比例的绿茶萃取物与姜黄萃取物的植物萃取物；本发明关于一种所述组合物的应用，尤指通过所述组合物在制备减少体重与体脂肪的医药品中的应用；本发明关于一种包含所述组合物的医药品，尤指可用于减少体重及减少体脂肪的医药品；本发明更关于一种所述医药品的应用，尤指通过有效剂量所述的医药品用于减少体重与体脂肪的应用。
背景技术
根据世界卫生组织对肥胖的定义，以身体质量指数(Body mass index，BMI)大于25定义为过重(overweight)，BMI大于30定义为肥胖(obesity)，统计资料指出2014年全球体重过重与肥胖的人口已经超过27亿人，其中大约有13％人口为肥胖人口，而这些肥胖的人罹患心血管疾病、高血脂症、糖尿病、癌症等相关疾病的机率也比一般人大幅增高。世界卫生组织的研究报告也指出，全球引起死亡风险的疾病中，超重和肥胖排名第6，根据研究数据显示，2013年至少有超过340万成人死于超重或肥胖所引起的慢性病，其中有44％的糖尿病及23％的缺血性心脏病医疗负担可归因于肥胖。许多数据也显示，肥胖者的年龄有逐渐下降的趋势，依据世界卫生组织的数据显示，2011年全世界约有4000多万5岁以下儿童超重。美国约翰霍普金斯大学彭博公共卫生学院(JohnsHopkins Bloomberg School of Public Health)在2007年报告指出，估计到2015年全美有75％成人体重过重，其中41％人口属于肥胖，且随着发展中国家的兴起，将使全球肥胖人口快速扩增，成为主要的流行病之一。美国CDC疾病管制局指出美国成人肥胖人口超过7200万人，而在全球肥胖人口中亚太地区就占40％，中国成年人过重和肥胖比率从2002年的25％大幅上升到2010年的38.5％，预测到2015年，中国将会有50％至57％的人口体重过重。
肥胖目前是全球都非常重视的健康问题，研究指出导致肥胖的原因非常复杂，有多重因子牵涉其中。越来越多的证据也显示肥胖并非自我控制就能改善的简单问题，而是涉及体内食欲调节与能量代谢的复杂症状，是一种体内代谢失衡的疾病。肥胖不仅造成死亡率提高及庞大医疗负担，也影响了人类的生活质量。虽然肥胖的病因并未完全被确立，但认为与遗传、代谢、生化、文化与精神社会的因子有关。研究显示人类有许多死因与肥胖有 关，包括恶性肿瘤、心血管疾病、脑血管疾病、糖尿病、慢性下呼吸道疾病、慢性肝病及肝硬化、高血压性疾病、肾脏疾病等，显示肥胖问题已成为全球皆极须重视的问题。近年来肥胖的盛行率愈来愈高，而伴随肥胖通常会逐渐出现高血压、高血糖和胰岛素阻抗及血脂异常等代谢异常现象而导致代谢症候群，很容易演变成糖尿病、心血管疾病、动脉粥状硬化、脑血管疾病及癌症等疾病，造成中风或心肌梗塞，甚至死亡。
目前减重药物的作用机制主要可分为两大类，分别为抑制食欲及阻断肠道对于食物脂肪的部分吸收二大类。其中抑制食欲是过去及目前市售减肥药物的主要机制，这一类药物包含Sibutramine(诺美婷)、Lorcaserin、Qsymia及Contrave等药物，副作用较严重而且具有一定程度的心血管风险；以之前下架减肥药Sibutramine(诺美婷)为例，其市场占有率曾高达7成，它是通过中枢神经作用来增加饱足感与在外围促使身体新陈代谢率增加的双重作用以达到体重减轻的效果，Sibutramine是一种去甲肾上腺素(noradrenaline)与血清素(serotonin)再回收的抑制剂，能增加饱足感以抑制食欲，达到减重的目的，饱足感的增加是serotonin与noradrenaline再吸收的抑制，通过α1-与β1-肾上腺素受体(α1-adrenoceptors or β1-adrenoceptors)以及5-HT2受体亚型(5-HT2receptor subtypes)作用而来。此药的中枢作用可能会导致血压升高及心跳加快，且近年来已被证实诺美婷会增加心血管疾病风险，因此欧盟、美国、澳洲、中国台湾等已在2010年宣布将含Sibutramine成分的减肥药下架。
而通过阻断肠道对于食物脂肪的部分吸收的减肥药物则为Orlistat，这也是在大部分国家唯一合法可长期使用的减肥药成分，它是一种具有专一性、可逆性的肠胃道脂肪分解酶抑制剂，作用在胃及小肠中，与胃和胰脏分泌的脂肪分解酶在其活化的丝氨酸(serine)位置形成共价键，将脂肪分解酶去活性，使得脂肪分解酶无法水解饮食中以三酸甘油酯存在的脂肪转换成可供吸收的游离脂肪酸及单酸甘油酯，因为未经消化的三酸甘油酯是无法吸收的，所以就会直接排出体外，通过抑制胰脏和肠道脂肪消化酶，而减少肠道对所摄食脂肪的吸收可达25至30％。由于Orlistat的主要作用方式是阻断油脂吸收，因此在服药期间可能会出现油便、排便次数增加、胃胀气等的胃肠道方面的副作用，也会干扰脂溶性维生素吸收，国外亦有造成肝损伤，胆结石等严重副作用的案例。
减重药物的高需求、高利润吸引各药厂投入研发，但药物安全性为减重药物的一大考验，严重的药物副作用及心血管疾病风险，导致FDA在2012年以前已有数年未核准任何减肥新药，多家厂商股价甚至因此重挫，造成市场沉寂。2012年开始美国FDA终于再次陆续批准了4个减肥新药，分别为Belviq、Qsymia、Contrave及Saxenda，预计将再度激活减重药物市场。
Qysmia与Belviq，其主要成分分别为芬特明-托吡酯(Phentermine-topiramate)及氯卡色林(Lorcaserin)，作用机制主要都在于增加饱足感、抑制食欲，来达到减重的目的。Qysmia含芬特明(Phentermine)与托吡酯(Topiramate)两种老药成分，其中phentermine是属于中枢神经兴奋剂，其主要抑制食欲的机制是通过让脑部下视丘刺激肾上腺分泌去甲肾上腺素；Topiramate的作用机制是促进神经传导物质GABA的活性、阻断钠离子通道、拮抗谷氨酰胺(glutamine)接受体及抑制碳酸酐酶(carbonic anhydrase)来达到抑制食欲及增加饱足感的效果。
然而早在1997年时就有24个受试者在使用含有Phentermine的减肥药Fen-Phen(fenfluramine/dexfenfluramine-phentermine)后出现心脏瓣膜问题，也因此造成fenfluramine及dexfenfluramine被美国FDA要求下架。Phentermine因为过去曾有导致严重的心血管风险，因此在许多国家仍然禁用；另一成分Topiramate过去则是被核准用于治疗癫痫的药物。目前知道Phentermine-topiramate药物的副作用包括手脚出现刺麻感、昏眩、味觉障碍、失眠、便秘及口干等情形。
Lorcaserin是5-HT2C受体活化剂，通过活化下视丘黑色素皮质素神经元(pro-opiomelanocortin neurons，POMC neurons)产生α-MSH(melanocyte stimulating hormone)，进而诱发产生饱足感，抑制食欲和减少饮食能量摄入。Lorcaserin是通过高度选择性作用于5-HT2C受体，对于5-HT2A与5-HT2B受体作用低，故从机制上认为可减少先前严重心血管副作用发生风险，但其相关的副作用包含心脏瓣膜损伤、头痛、恶心、疲劳和泌尿道感染，因此FDA仍然要求业者需进行后续临床监测，同时若是服用Lorcaserin连续3个月体重未减轻就需立即停用药物。
纳曲酮(Contrave)是一种多巴胺、去甲肾上腺素再吸收抑制，作用于中枢神经系统，能够抑制食欲，Contrave副作用为自杀倾向、恶心、便秘、头痛、呕吐、头晕等。Saxenda则为皮下注射给药的减肥药物，Saxenda的作用机制主要是通过减少胃排空的速度，增加饱足感，来达到减重的目的，副作用为恶心、低血糖、腹泻、便秘、呕吐、头痛、食欲下降等。整体而言，目前上市的减重新药对于心血管疾病产生的风险及长期使用的安全性仍须更长时间监测，故不适合原本有心血管疾病的患者服用，且仍具有许多副作用与安全性疑虑，尤其Qsymia所含的成分Phentermine因为过去曾导致严重的心血管疾病，因此在中国台湾及许多国家仍然禁用。
减肥药应用发展的主要问题在于长期使用的心血管风险或精神方面安全性疑虑等安全性问题，而头晕、失眠、心悸、便秘等副作用及心血管风险也让许多使用者无法长期安 心使用现有的减肥药物。目前核准通过的减肥药物，由于副作用高，耐受性差、心血管风险等原因，使得减重药品整体市场并未与全球肥胖过重人口及减重需求一致。从1957年至2014年上市的10个减肥药物中，就有5个因为造成心血管风险或精神方面安全性疑虑而下架，其主要作用机制皆是通过抑制食欲来减轻体重，包含2002年上市后即得到7成以上市占率的Sibutramine(商品名诺美婷)。
由此可见，目前的减肥药物仍存在程度不一的心血管风险与安全性疑虑，市场上仍需要一种安全性更高、副作用低、无心血管风险疑虑且同时可有效减轻体重与体脂肪，并降低心血管危险的减肥药品。
发明内容
本发明提供一种用于减少体重与体脂肪的植物萃取组合物，其包含绿茶萃取物与姜黄萃取物，并以植物萃取组合物的总重量为基础，绿茶萃取物与姜黄萃取物的重量百分比分别为30％至75％以及20％至55％。
于较佳的实施例中，本发明所述的植物萃取组合物进一步包含有白藜芦醇，且该白藜芦醇占组合物的总重量为大于0％至30％。
本发明所述的植物萃取组合物可有效减少体重与体脂肪。其中值得注意的是，动物实验显示单独分别施予白藜芦醇对于减少体重以及体脂肪并没有效果，单独施予姜黄萃取物效果也不明显，这与过去的研究结果相符，而本发明不仅在诱导肥胖过程同时给予本发明所述的植物萃取组合物，可观察到本发明所述的植物萃取组合物具有显著减少体重与体脂肪的效果，更进一步发现，即使在已诱导肥胖的肥胖小鼠模式下再给予本发明所述的植物萃取组合物，亦能明显观察到本发明显著降低小鼠体重与体脂肪的效果，且本发明所述的植物萃取组合物与市售减肥药物罗氏鲜(Orlistat)相比，本发明减少体重与体脂肪的效果，皆显著优于市售减肥药物Orlistat(p＜0.001)，而且此种先诱导肥胖的模式比起传统常见的同时诱导肥胖的动物模式，更难减少其体重与体脂肪，却也更接近实际治疗人体过重与肥胖的情况，在此条件下本发明植物萃取组合物依然能达到如此显著减少体重与体脂肪的效果，且效果显著超越市售减肥药物及单一植物萃取物，足见本发明的组合物并非轻易可达成。
依据本发明，“姜黄萃取物”于此处指包含姜黄素的萃取物，其中姜黄素(curcumin)占姜黄萃取物的浓度为80％至100％；“绿茶萃取物”于此处指包含儿茶素(catechins)的萃取物，其中儿茶素占绿茶萃取物的浓度为75％至100％。
本发明更提供一种制造包含有绿茶萃取物与姜黄萃取物的植物萃取组合物的方法，包括将包含有绿茶萃取物及姜黄萃取物的植物萃取组合物与医药上可接受的盐类组合物、医药上可接受的安定剂或医药上可接受的赋形剂相混合成胶囊、锭剂或制成包衣锭或注射输液。
较佳的，所述的方法中进一步包括加入白藜芦醇，以形成包含有绿茶萃取物、姜黄萃取物及白藜芦醇的植物萃取组合物。
较佳的，所述的安定剂包括但不限于木糖醇、山梨糖醇、聚葡萄糖、异麦芽糖醇及右旋葡萄糖。
本发明进一步提供所述用于减少体重与体脂肪的植物萃取组合物在制备减少体重与体脂肪的医药品中的应用。
本发明更提供一种用于减少体重与体脂肪的医药品，其包含有效剂量的所述用于减少体重与体脂肪的植物萃取组合物以及医药学上能够接受的赋形剂。
在较佳的实施例中，该医药品中更包含有效减少体重与体脂肪剂量的白藜芦醇。
依据本发明，所述的“医药上可接受的赋形剂”包括但不限于崩解剂(disintegrant)、黏合剂(binder)、填充剂(filler)、润滑剂(lubricant)、助悬剂(suspending agent)、助溶剂(solubilizer)及助流剂(glidant)。赋形剂的使用量取决于使用多少活性成分与剂型，且一种赋形剂可以执行一种以上的功能。
较佳的，所述的崩解剂包括但不限于琼脂(agar)、海藻酸(alginic acid)、碳酸钙(calcium carbonate)、羧甲基纤维素(carboxymethylcellulose)、纤维素(cellulose)、黏土(clays)、胶体二氧化硅(colloidal silica)、交联羧甲基钠(croscarmellose sodium)、交联聚维酮(cross-linked povidone)、胶(gum)、硅酸镁铝(magnesium aluminum silicate)、甲基纤维素(methyl cellulose)、波拉克林钾(polacrilin potassium)、藻酸钠(sodium alginate)，低取代的羟丙基纤维素(low substituted hydroxypropyl cellulose)、交联聚乙烯吡咯烷酮羟丙基纤维素(crosslinked polyvinylpyrrolidone hydroxypropylcellulose)、丙基纤维素(sodium starch glycolate)及淀粉(starch)。
较佳的，所述的黏合剂包括但不限于微晶纤维素(microcrystalline cellulose)、羟甲基纤维素(hydroxymethyl cellulose)、羟丙基纤维素(hydroxypropyl cellulose)及聚乙烯吡咯烷酮(polyvinyl pyrrolidone)。
较佳的，所述的填充剂包括但不限于碳酸钙(calcium carbonate)、磷酸钙(calcium phosphate)、磷酸氢钙(dibasic calcium phosphate)、磷酸三硫酸钙(tribasic calcium sulfate)、 羧甲基纤维素钙(calcium carboxymethylcellulose)、纤维素(cellulose)、糊精(dextrin)、盐(salt)、糊精(dextrin)、右旋糖(dextrose)、果糖(fructose)、乳糖醇(lactitol)、乳糖(lactose)、碳酸盐(carbonate)、氧化镁(magnesium oxide)、麦芽糖醇(maltitol)、麦芽糊精(maltodextrin)、麦芽糖(maltose)、山梨糖醇(sorbitol)、淀粉、蔗糖(sucrose)、糖(sugar)及木糖醇(xylitol)。
较佳的，所述的润滑剂包括但不限于琼脂、硬脂酸钙(calcium stearate)、油酸乙酯(ethyl oleate)、月桂酸乙酯(ethyl laurate)、甘油(glycerin)、硬脂酸棕榈酸甘油酯(glyceryl palmitostearate)、氢化植物油(hydrogenated vegetable oil)、氧化镁(magnesium oxide)、硬脂酸镁(magnesium stearate)、甘露醇(mannitol)、泊洛沙姆(poloxamer)、乙二醇(ethylene glycol)、苯甲酸钠(sodium benzoate)、月桂基硫酸钠(sodium lauryl sulfate)、硬脂酸钠(sodium stearoyl acid)、山梨糖醇、硬脂酸(stearic acid)、滑石(talc)和硬脂酸锌(zinc stearate)。
较佳的，所述的助悬剂包含但不限于甘露醇、羧甲基纤维素(carboxymethyl cellulose，CMC)及羧甲基纤维素钠(CMC-Na)。
较佳的，所述的助溶剂包含但不限于羟丙基β环糊精(hydroxypropyl-beta-cyclodextrin)、吐温80(tween 80)、蓖麻油(castor oil)与聚乙二醇(PEG)。
较佳的，所述的助流剂包括但不限于硬脂酸镁(magnesium stearate)、二氧化硅(silicon dioxide)、三硅酸镁(magnesium trisilicate)、粉状纤维素(powdered cellulose)、淀粉、滑石、磷酸三钙(tribasic calcium phosphate)、硅酸钙(calcium silicate)、硅酸镁(magnesium silicate)、胶体二氧化硅及硅凝胶(silicon hydrogel)等材料。
本发明所述的医药品可以多种形式存在。这些形式包括但不限于液体、半固体及固体药剂形式，诸如液体溶液(例如可注射及可输注溶液)、分散液或悬浮液、锭剂、丸剂、粉剂、脂质体及栓剂。较佳的形式取决于预期的给药模式及治疗应用；较佳的，本发明的医药品是呈可口服或可输注溶液形式。在本发明的实施例中，用于减少体重与体脂肪的医药品包含有效剂量的绿茶萃取物与姜黄萃取物的组合物是通过口服施予，且根据本发明的植物萃取组合物适用及受偏好的口服剂型有药片、颗粒、包衣锭、胶囊、锭剂及其他固体口服剂型亦涵盖于本发明范围中。
本发明更提供一种以所述医药品用于减少体重与体脂肪的应用，其是通过有效剂量的包含有绿茶萃取物与姜黄萃取物的植物萃取组合物的医药品施予受体，受体为人类或动物。以达到减少体重与体脂肪的效果。
较佳的，施予方式是口服施予或注射施予。
较佳的，有效剂量是指每天每公斤施予受体1.8mg至145mg的医药品，此处受体为 人类或动物，优选人类。
较佳的，有效剂量是指每天每公斤施予受体5.4mg至70mg的医药品，此处受体为人类或动物，优选人类。
依据本发明，“有效剂量”于此处可根据美国食品药物管理局(food and drug administration，FDA)所公告的“于初期临床试验估算成人最大安全起始剂量(estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers)”的表1(Table 1)推算出不同受体的有效剂量。
依据本发明，“减少体重与体脂肪”如此处是指经施予有效剂量的包含有绿茶萃取物与姜黄萃取物的组合物后，或进一步包含白藜芦醇的组合物后，体重以及体脂肪皆分别少于肥胖对照组，其如本发明的示例，减少体脂肪可通过施予特定范围量的绿茶萃取物与姜黄萃取物的组合物，或进一步包含白藜芦醇的组合物，并于特定时间范围内测量附睾外围脂肪量、肾脏外围脂肪量、肠系膜外围脂肪量、鼠蹊部及腹膜腔外的脂肪量变化而得。
本发明的植物萃取组合物的各组分皆由植物萃取而得，实验结果显示本发明所述的植物萃取组合物不会影响食欲或摄食量，亦不会影响其他血清生化的安全指标，因此安全性较高，相较于目前市面上其他减重药物，更为安全也没有明显副作用。此外，相较于现有技术的减肥药物通过抑制食欲或是阻断肠道脂肪吸收的方式来减少热量吸收以达到减轻体重效果，本发明所述的植物萃取组合物不仅能减轻体重，更可以有效抑制体内脂肪细胞的增生，同时亦能增加体内脂肪代谢与能量利用，且针对肥胖的根本原因进行改善，以降低减重常见的复胖问题，并能改善血脂质及血糖等多种心血管危险指标，降低心血管风险。
由此可知本发明所述的植物萃取组合物更能针对目前全球的肥胖与过重问题，提供一个安全性更高且能有效减少体重及体脂肪的方案，未来可应用于相关医药品或保健食品等用途。
附图说明
图1为本发明以细胞存活率试验(MTT assay)检测各组对于前驱脂肪细胞生长抑制效果的柱状图。
图2为本发明以细胞存活率试验(MTT assay)检测各组对于分化中脂肪细胞生长抑制效果的柱状图。
图3A为本发明通过同时诱导肥胖与给药以检测各组小鼠的体重增加变化的柱状图。
图3B为本发明通过同时诱导肥胖与给药以检测各组小鼠的内脏脂肪、皮下脂肪及总 脂肪量的脂肪重量变化的柱状图。
图4A为本发明通过先诱导肥胖后再给药以检测各组小鼠的体重增加变化的柱状图。
图4B为本发明通过先诱导肥胖后再给药以检测各组小鼠的内脏脂肪、皮下脂肪及总脂肪量的脂肪重量变化的柱状图。
图5A为本发明通过同时诱导肥胖与给药以检测各组大鼠的体重增加变化的趋势图。
图5B为本发明通过同时诱导肥胖与给药以检测各组大鼠的内脏脂肪变化的柱状图。
具体实施方式
以下配合附图及本发明的较佳实施例，进一步阐述本发明为达成预定发明目的所采取的技术手段。
实施例1.前驱脂肪细胞生长抑制实验
本实施例将前驱脂肪细胞3T3-L1以每孔1×104细胞(cells/well)培养于96孔盘，除控制组外-DMSO溶剂对照组，于不同孔中分别加入50ppm白藜芦醇、50ppm姜黄萃取物、80ppm绿茶萃取物以及100ppm本发明的植物萃取组合物ME008A、ME008D、ME001、ME00C1及ME00D1，实验共9组且每组实验进行3重复。加药后培养48小时后，拍照记录细胞生长状况，并以细胞存活率试验(MTT assay)分析各试验物质对于3T3-L1前驱脂肪细胞生长抑制效果。其中控制组为溶剂对照组DMSO，本发明的植物萃取组合物ME008A包含50wt％绿茶萃取物、25wt％绿咖啡豆萃取物及25wt％白藜芦醇、ME008D包含40wt％绿茶萃取物、45wt％绿咖啡豆萃取物及15wt％白藜芦醇、ME001包含60wt％绿茶萃取物、10wt％姜黄萃取物及30wt％白藜芦醇、ME00C1包含40wt％绿茶萃取物、50wt％姜黄萃取物以及10wt％白藜芦醇，以及ME00D1包含75wt％绿茶萃取物与25wt％姜黄萃取物。各组数据均以平均值±SD(Mean±SD)表示，英文字母a、b、c、d、e、f、g表示统计的结果，不同字母表示组间具统计上差异(p＜0.05)，相同字母则表示组间不具有统计差异(p＞0.05)。
结果如图1所示，与控制组相比，本发明植物萃取组合物ME00C1、ME001及ME008D三组皆能显著抑制前驱脂肪细胞生长(p＜0.05)，其中本发明植物萃取组合物各组当中又以ME00C1对于前驱脂肪细胞的生长抑制效果最佳(p＜0.05)，且组合物ME00C1对于前驱脂肪细胞的生长抑制效果亦明显比单独施予白藜芦醇、姜黄萃取物或绿茶萃取物更佳(p＜0.05)。
实施例2.分化中脂肪细胞生长抑制实验
本实施例将3T3-L1以1×105cells/well培养于12孔盘，培养至第四天改用含有每毫升5微克(μg/ml)分化剂胰岛素、1微摩尔体积浓度(μM)地塞米松(dexmethasone)、0.5毫摩尔体积浓度(mM)的3-异丁基-1-甲基黄嘌呤(3-isobutyl-1-methylxanthine)的培养液以诱导脂肪细胞分化，除控制组外-DMSO溶剂对照组，各组分别加入50ppm白藜芦醇、50ppm姜黄萃取物、80ppm绿茶萃取物以及100ppm本发明植物萃取组合物ME008A、ME008D、ME001、ME00C1、ME00D1以进行实验，实验共9组且每组实验进行3重复。加药后培养48小时后，拍照记录细胞生长状况，并以细胞存活率试验(MTT assay)分析各实验物质对于分化中脂肪细胞的抑制效果。各组数据均以平均值±SD(Mean±SD)表示，英文字母a、b、c、d、e、f表示统计的结果，不同字母表示组间具统计上差异(p＜0.05)，相同字母则表示组间不具有统计差异(p＞0.05)。
结果如图2所示，与控制组相比，本发明各植物萃取组合物皆能显著抑制分化中脂肪细胞生长(p＜0.05)，其中本发明植物萃取组合物各组当中又以ME00C1对于分化中脂肪细胞生长的抑制效果最佳(p＜0.05)，且组合物MEOOC1对于分化中脂肪细胞的生长抑制效果亦明显比单独施予白藜芦醇、姜黄萃取物或绿茶萃取物更佳(p＜0.05)。
实施例3.动物实验I(同时诱导肥胖与给药)
本实验例使用8周龄B6品系雌性小鼠，并分为正常对照组、肥胖对照组、白藜芦醇组(61.5mg/kg B.W.)、绿茶萃取物组(123mg/kg B.W.)、本发明的植物萃取组合物ME001(676.5mg/kg B.W.)共5组，每组各使用5只雌性动物进行试验，试验期间，除正常对照组喂食正常饲料外，其余各组皆连续8周以高脂饲料喂食，用以诱发肥胖症状，并同时每日管喂给予试验物质8周，肥胖对照组则管喂等体积无菌水，以评估各组小鼠体重与体脂肪的差异。实验过程中每周记录每只动物的体重与平均摄食量，试验完成后，将小鼠牺牲，取其卵巢外围脂肪、肾脏外围脂肪、肠系膜外围脂肪称重计算其内脏脂肪量，取其鼠蹊部及腹膜腔外的脂肪进行称重以计算皮下脂肪量。各组数据均以平均值±SD(Mean±SD)表示，英文字母a、b、c、d、e、f表示统计的结果，不同字母表示组间具统计上差异(p＜0.05)，相同字母则表示组间不具有统计差异(p＞0.05)。
试验结果如图3A、图3B所示，与肥胖对照组相比，本发明植物萃取组合物ME001体重总增重则明显降低(p＜0.05)，降低幅度为47.2％，因此，本发明植物萃取组合物ME001可有效达到减轻体重的效果(p＜0.05)。反之，单独施予白藜芦醇组的小鼠其体重总增重、内脏脂肪量、皮下脂肪量与体脂肪总重量(包含内脏脂肪与皮下脂肪)，相较于肥胖对照组则皆无统计差异(p＞0.05)。
本发明植物萃取组合物ME001与肥胖对照组相比，则无论在内脏脂肪重量、皮下脂肪重量或体脂肪总重量皆显著下降(p＜0.05)。此外，本发明植物萃取组合物ME001与其他各组相比，ME001不仅可有效降低体重与减少体脂肪，且功效皆优于单一植物萃取物组别(p＜0.05)，具有较佳的减重功效。
试验期间喂食高脂饲料的各组小鼠，其每周平均摄食量并无统计差异(p＞0.05)。
实施例4.动物实验II(先诱导肥胖再给药)
本实施例使用8周龄B6品系雌性小鼠，除正常对照组喂食正常饲料外，其他小鼠先连续6周以高脂饲料喂食，诱发成为肥胖小鼠后(肥胖小鼠体重与初始体重相比增加超过20％)，将肥胖小鼠随机分成7组，包含肥胖对照组、罗氏鲜药品对照组(34.8mg/kg B.W.)、姜黄萃取物组(41mg/kg B.W.)、及本发明的植物萃取组合物试验组4组，包含ME008A(676.5mg/kg B.W.)、ME008D(676.5mg/kg B.W.)、ME001(676.5mg/kg B.W.)或ME00C1(651.9mg/kg B.W.)，每组各使用5只雌性动物进行试验，除正常对照组外，其余7组肥胖小鼠再持续给予高脂饲料并每日以管喂方式给予试验物质8周，肥胖对照组则给予等体积无菌水管喂，总计共喂食14周高脂饲料后牺牲，以评估各组小鼠体重与体脂肪等项目的差异。实验过程中每周记录每只动物的体重与平均摄食量，试验完成后，将小鼠牺牲，取其卵巢外围脂肪、肾脏外围脂肪、肠系膜外围脂肪称重计算其内脏脂肪量，取其鼠蹊部及腹膜腔外的脂肪进行称重以计算皮下脂肪量。各组数据均以平均值±SD(Mean±SD)表示，英文字母a、b、c、d、e表示统计的结果，不同字母表示组间具统计上差异(p＜0.05)，相同字母则表示组间不具有统计差异(p＞0.05)。
试验结果如图4A、图4B所示，与正常对照组相比，肥胖对照组的小鼠体重增重与体脂肪皆明显增加(p＜0.05)，其体重增重增加幅度高达87.7％，表示本实施例已成功诱导小鼠体重上升造成肥胖。与肥胖对照组相比，本发明植物萃取组合物ME008D、ME001及ME00C1的体重增加量皆显著降低(p＜0.05)，其中又以本发明植物萃取组合物ME00C1效果最佳，且效果显著优于市售减肥药罗氏鲜(Orlistat)(p＜0.05)与姜黄萃取物(p＜0.05)。
与肥胖对照组相比，本发明植物萃取组合物ME008D、ME001及ME00C1的体脂肪(包含内脏脂肪与皮下脂肪)亦显著降低(p＜0.05)，其体脂肪降低幅度分别为10.3％、36.9％及64.1％，其中又以本发明植物萃取组合物ME00C1效果最佳，且显著优于市售减肥药罗氏鲜(p＜0.05)与姜黄萃取物(p＜0.05)。显示本发明植物萃取组合物ME00C1对于已肥胖的小鼠具有较佳的减轻体重与减少体脂肪的效果。试验期间喂食高脂饲料的各组小鼠，其每周平均摄食量并无统计差异(p＞0.05)。
实施例5.动物实验III(同时诱导肥胖与给药)
本实验例使用8周龄SD品系雄性大鼠，并分为正常对照组、肥胖对照组、本发明植物萃取组合物ME00C1(199.6mg/kg B.W.)及ME00C1A(186mg/kg B.W.)共4组，其中植物萃取组合物ME00C1A包含55.5wt％绿茶萃取物及44.5wt％姜黄萃取物，每组各使用6只大鼠进行试验，试验期间除正常对组以正常饲料喂食外，其余三组皆连续8周以高脂饲料喂食，用以诱发肥胖，同时每日管喂给予试验物质，肥胖对照组则给予等体积无菌水管喂，以评估各组小鼠体重与内脏脂肪等项目的差异。实验过程中每周记录每只动物的体重与平均摄食量，试验完成后，将大鼠牺牲，取其附睾外围脂肪、肾脏外围脂肪、肠系膜外围脂肪称重计算其内脏脂肪量。各组数据均以平均值±SD(Mean±SD)表示，英文字母a、b、c、d表示统计的结果，不同字母表示组间具统计上差异(p＜0.05)，相同字母则表示组间不具有统计差异(p＞0.05)。
试验结果如图5A所示，与肥胖对照组相比，施予本发明植物萃取组合物ME00C1与ME00C1A的大鼠体重总增重皆明显下降，与肥胖对照组相比，本发明植物萃取组合物ME00C1体重增重显著减少23.0％(p＜0.01t-test)，而植物萃取组合物ME00C1A体重增重更可显著减少29.8％(p＜0.001t-test)。图5B所示的实验结果亦显示，与肥胖对照组相比，本发明植物萃取组合物ME00C1A的大鼠附睾外围、肾脏外围及肠系膜外围等内脏脂肪皆显著降低(p＜0.05)，其内脏总脂肪重量可减少达35.7％，显示本发明植物萃取组合物ME00C1A降低体重与体脂肪的效果最佳。
以上所述仅是本发明的较佳实施例而已，并非对本发明做任何形式上的限制，虽然本发明已以较佳实施例揭露如上，然而并非用以限定本发明，任何本领域技术人员，在不脱离本发明技术方案的范围内，当可利用上述揭示的技术内容作出些许更动或修饰为等同变化的等效实施例，但凡是未脱离本发明技术方案的内容，依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰，均仍属于本发明技术方案的范围内。

Claims (8)

  1. 一种用于减少体重与体脂肪的植物萃取组合物，其特征在于，其包含绿茶萃取物与姜黄萃取物，并以植物萃取组合物的总重量为基础，绿茶萃取物与姜黄萃取物的重量百分比分别为30％至75％以及20％至55％。
  2. 根据权利要求1所述的植物萃取组合物，其特征在于，其进一步包含有白藜芦醇，且该白藜芦醇占组合物的总重量为大于0％至30％。
  3. 一种权利要求1或2所述的植物萃取组合物在制备减少体重与体脂肪的医药品中的应用。
  4. 一种用于减少体重与体脂肪的医药品，其特征在于，其包含有效剂量权利要求1或2所述的植物萃取组合物以及医药学上能够接受的赋形剂。
  5. 一种权利要求4的医药品在减少体重与体脂肪中的应用，其特征在于，将医药品以有效剂量施予受体，受体为人类或动物。
  6. 根据权利要求5所述的应用，其特征在于，施予方式为口服或注射方式施予。
  7. 根据权利要求6所述的应用，其特征在于，将医药品以口服方式或注射方式施予受体的有效剂量介于受体每公斤1.8mg/KG至145mg/KG。
  8. 根据权利要求7所述的应用，其特征在于，将医药品以口服方式或注射方式施予受体的有效剂量介于受体每公斤5.4mg/KG至70mg/KG。
PCT/CN2015/088338 2014-08-28 2015-08-28 用于减少体重及减少体脂肪的组合物及其医药品与应用 WO2016029868A1 (zh)

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