[go: up one dir, main page]

WO2016029870A1 - 用于减少局部脂肪与减少体重的组合物及其医药品与应用 - Google Patents

用于减少局部脂肪与减少体重的组合物及其医药品与应用 Download PDF

Info

Publication number
WO2016029870A1
WO2016029870A1 PCT/CN2015/088340 CN2015088340W WO2016029870A1 WO 2016029870 A1 WO2016029870 A1 WO 2016029870A1 CN 2015088340 W CN2015088340 W CN 2015088340W WO 2016029870 A1 WO2016029870 A1 WO 2016029870A1
Authority
WO
WIPO (PCT)
Prior art keywords
fat
composition
cells
body weight
reducing
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2015/088340
Other languages
English (en)
French (fr)
Inventor
凌玉芳
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Caliway Biopharmaceuticals Co Ltd
Original Assignee
Caliway Biopharmaceuticals Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Caliway Biopharmaceuticals Co Ltd filed Critical Caliway Biopharmaceuticals Co Ltd
Priority to EP20214023.2A priority Critical patent/EP3811935A1/en
Priority to SG11201701476PA priority patent/SG11201701476PA/en
Priority to AU2015309353A priority patent/AU2015309353B2/en
Priority to US14/914,971 priority patent/US9987325B2/en
Priority to CA2959185A priority patent/CA2959185C/en
Priority to KR1020177008265A priority patent/KR101859345B1/ko
Priority to DK15836003.2T priority patent/DK3187178T3/da
Priority to KR1020187013247A priority patent/KR101935219B1/ko
Priority to MX2017002585A priority patent/MX385905B/es
Priority to CN201580045335.8A priority patent/CN106604724B/zh
Priority to SI201531877T priority patent/SI3187178T1/sl
Priority to JP2017530388A priority patent/JP6473505B2/ja
Priority to ES15836003T priority patent/ES2924879T3/es
Priority to PL15836003.2T priority patent/PL3187178T3/pl
Priority to EP15836003.2A priority patent/EP3187178B1/en
Priority to TW104131193A priority patent/TWI580422B/zh
Publication of WO2016029870A1 publication Critical patent/WO2016029870A1/zh
Priority to EP25196769.1A priority patent/EP4647070A2/en
Priority to MX2018002462A priority patent/MX384073B/es
Priority to LTEPPCT/IB2016/055102T priority patent/LT3381451T/lt
Priority to PL16840922.5T priority patent/PL3381451T3/pl
Priority to CA2995155A priority patent/CA2995155C/en
Priority to TW105127451A priority patent/TWI630922B/zh
Priority to CN202211455288.2A priority patent/CN115778928B/zh
Priority to HRP20251142TT priority patent/HRP20251142T1/hr
Priority to SM20250365T priority patent/SMT202500365T1/it
Priority to EP16840922.5A priority patent/EP3381451B1/en
Priority to KR1020207012125A priority patent/KR102356390B1/ko
Priority to IL257784A priority patent/IL257784B2/en
Priority to CN202411262786.4A priority patent/CN119157850A/zh
Priority to MX2018002461A priority patent/MX387266B/es
Priority to AU2016314546A priority patent/AU2016314546C1/en
Priority to JP2018510970A priority patent/JP7063803B2/ja
Priority to US15/754,363 priority patent/US20180243211A1/en
Priority to SG11201801111RA priority patent/SG11201801111RA/en
Priority to ES16840922T priority patent/ES3041835T3/es
Priority to BR112018003892-0A priority patent/BR112018003892A2/pt
Priority to EP16840921.7A priority patent/EP3381473A4/en
Priority to US15/754,429 priority patent/US10610496B2/en
Priority to CN201680046431.9A priority patent/CN109069655B/zh
Priority to CA2995158A priority patent/CA2995158C/en
Priority to FIEP16840922.5T priority patent/FI3381451T3/fi
Priority to KR1020207007953A priority patent/KR102240221B1/ko
Priority to TW105127452A priority patent/TWI604859B/zh
Priority to PCT/IB2016/055102 priority patent/WO2017037594A2/zh
Priority to PCT/IB2016/055101 priority patent/WO2017037593A2/zh
Priority to KR1020187008138A priority patent/KR102107917B1/ko
Priority to AU2016314545A priority patent/AU2016314545C1/en
Priority to PT168409225T priority patent/PT3381451T/pt
Priority to CN201680046418.3A priority patent/CN108697668B/zh
Priority to BR112018003877-6A priority patent/BR112018003877A2/pt
Priority to JP2018510971A priority patent/JP7063804B2/ja
Priority to KR1020187008137A priority patent/KR20180037058A/ko
Priority to DK16840922.5T priority patent/DK3381451T3/da
Priority to US15/440,469 priority patent/US10226503B2/en
Anticipated expiration legal-status Critical
Priority to MX2021010359A priority patent/MX2021010359A/es
Priority to CONC2018/0003424A priority patent/CO2018003424A2/es
Priority to AU2019201635A priority patent/AU2019201635B2/en
Priority to AU2019246808A priority patent/AU2019246808B2/en
Priority to AU2019280037A priority patent/AU2019280037B2/en
Priority to US16/749,266 priority patent/US11433034B2/en
Priority to US16/749,347 priority patent/US11318110B2/en
Priority to JP2020081316A priority patent/JP7095903B2/ja
Priority to JP2020081311A priority patent/JP7054540B2/ja
Priority to AU2021202349A priority patent/AU2021202349B2/en
Priority to US17/875,679 priority patent/US12357588B2/en
Priority to US18/169,585 priority patent/US20230190674A1/en
Ceased legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A61K8/347—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/35—Ketones, e.g. benzophenone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783—Angiosperms [Magnoliophyta]
    • A61K8/9794—Liliopsida [monocotyledons]
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/08—Solutions
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/06—Preparations for care of the skin for countering cellulitis

Definitions

  • the present invention relates to a composition, and more particularly to a composition for reducing local fat and reducing body weight; the invention relates to the use of the composition, in particular for reducing local fat and reducing body weight; The invention further relates to a pharmaceutical product comprising the composition, in particular to a pharmaceutical product which can be used for reducing local fat and reducing body weight; the invention further relates to an application, in particular to the use of the medicament for reducing local fat and Weight loss application.
  • the well-known liposuction operation has been developed since the 1970s.
  • the liposuction method used at that time was to perform dry liposuction directly under negative pressure without any infusion. This method caused great damage to the subcutaneous nerves and blood vessels. Injury, and the amount of bleeding is high. Subsequently, it developed the methods of inflated liposuction and ultra-wet liposuction.
  • the inflated liposuction is to add an anesthetic and vasoconstrictor to the input solution.
  • This method replaces the liposuction process of the original intravenous anesthesia with local anesthesia, but a large amount of infusion
  • the result is that the anesthetic takes at least 12 hours to be metabolized in the body, and also increases the local anesthetic to the human body. May be harmful.
  • the method used by a physician for a large amount of liposuction is ultra-wet liposuction, which is characterized in that the input fluid is the same as the amount of fat to be extracted, and the possibility of infusion overload can be effectively reduced.
  • phosphosphatidylcholine or sodium deoxycholate as an active ingredient to be injected into an obese site for lipolysis.
  • Such components are similar to cell membrane components.
  • Cell membranes that destroy fat cells promote cell necrosis.
  • the injection of such drugs into the mesoderm will cause fat to be eluted after a large number of fat cells are necrotic.
  • the drug is not specific, it is not only for the action of fat cells, so many normal cells in the periphery are also affected and necrosis.
  • necrosis causes a series of inflammatory reactions in the peripheral tissues, which in turn causes inflammatory reactions and severe painful swelling in the site of implementation, and even causes local tissue necrosis or infection.
  • the injection-type lipolysis method can overcome the limitation of the treatment site when using large instruments, in order to achieve the fat-dissolving effect, it is often necessary to score dozens of needles for one treatment, and the treatment is about once every two weeks, and a total of 1 treatment is needed. Between -6 times, although the anesthetic is added to the injection component, the injection department still has considerable inflammation and pain after the anesthesia is removed, and the number of treatments and the size of the needle need to be improved.
  • the present invention provides a composition for reducing local fat and reducing body weight comprising resveratrol and turmeric extract in a weight ratio of 1:30 to 10:1.
  • the weight ratio of resveratrol to turmeric extract is 1:19.
  • the composition of the invention can inhibit the growth of fat cells and cause planned apoptosis of the adipocytes, thereby reducing the effect of local fat accumulation and reducing fat cells, and also reducing body weight, but does not cause peripheral cells and Inflammatory reaction or tissue necrosis of the tissue, and no inflammatory reaction or severe pain in the peripheral tissues, so that the above-mentioned tissue damage and inflammation pain caused by liposuction or low-invasive fat-dissolving instruments can be avoided, and there is no dissolution.
  • Lipid injections, phosphatidylcholine or sodium deoxycholate cause problems such as peripheral tissue inflammation and necrosis caused by cell disintegration and necrosis.
  • the invention can also reduce body weight.
  • turmeric extract refers to an extract comprising curcumin, wherein curcumin comprises from 80% to 100% of the turmeric extract.
  • the invention further provides a method of making a composition comprising resveratrol and turmeric extract comprising combining a composition comprising resveratrol and turmeric extract with at least one pharmaceutically acceptable salt
  • An injection composition is prepared by mixing a composition, a pharmaceutically acceptable stabilizer or bacteriostatic agent, or a pharmaceutically acceptable emulsifier, an excipient such as a surfactant, an anesthetic or the like.
  • the stabilizers include, but are not limited to, xylitol, sorbitol, polydextrose, isomalt, and dextrose.
  • the "pharmaceutically acceptable excipient” includes, but is not limited to, a lubricant, a suspending agent, a solubilizer glidant, an emulsifier ( Emulsifier) or surfactant.
  • a lubricant e.g., a talc, a kaolin, a kaolin, a kaolin, a kaolin, a kaolin, a solubilizer glidant, an emulsifier ( Emulsifier) or surfactant.
  • the amount of excipient used depends on how much active ingredient is used, and one excipient can perform more than one function.
  • 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 includes, but is not limited to, hydroxypropyl-beta-cyclodextrin, tween 80, castor oil.
  • 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 emulsifier may be a naturally occurring phospholipid, including but not limited to soybean phospholipids, lecithin, monoglycerides, diglycerides, sodium stearate, sorbitan esters of ftty Acids) or polyoxyethylene sorbitan monooleate.
  • soybean phospholipids including but not limited to soybean phospholipids, lecithin, monoglycerides, diglycerides, sodium stearate, sorbitan esters of ftty Acids) or polyoxyethylene sorbitan monooleate.
  • the surfactant includes, but is not limited to, polyoxyethylene-sorbitan fatty acid ester (Tween), polyethylene-polypropylene glycol, polyoxyethylene-stearate, polyoxyethylene alkyl ether. (e.g., polyoxyethylene monolauryl ether), alkyl phenyl polyoxyethylene ether (Triton-X), polyoxyethylene-polyoxypropylene copolymer (Poloxamer, Pluronic), and sodium dodecyl sulfate (SDS).
  • Teween polyoxyethylene-sorbitan fatty acid ester
  • Polyethylene-polypropylene glycol polyoxyethylene-stearate
  • polyoxyethylene alkyl ether e.g., polyoxyethylene monolauryl ether
  • Triton-X alkyl phenyl polyoxyethylene ether
  • Polyoxyethylene-polyoxypropylene copolymer Polyoxyethylene-polyoxypropylene copolymer
  • SDS sodium dodecyl
  • the invention further provides for the use of the composition in the manufacture of a medicament for reducing localized fat and reducing body weight.
  • the present invention further provides a pharmaceutical for reducing local fat and reducing body weight, wherein the medicament comprises an effective amount of the composition for reducing local fat and reducing body weight, and a pharmaceutically acceptable carrier thereof. .
  • 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 (such as injectable and infusible solutions), dispersions, suspensions, powders, lyophilized powders or liposomes, or by transdermal absorption of ointments and patches.
  • liquid solutions such as injectable and infusible solutions
  • dispersions such as suspensions, powders, lyophilized powders or liposomes, or by transdermal absorption of ointments and patches.
  • 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 infusible solution, and the preferred mode of administration is a parenteral mode, such as an injectable solution.
  • a medicament comprising a composition comprising resveratrol and turmeric extract effective to reduce a topical fat dose is administered by subcutaneous injection; more preferably, comprising an effective reduction of topical fat dose.
  • a pharmaceutical having a composition of resveratrol and turmeric extract is administered subcutaneously to a subcutaneous fat layer.
  • the formulation of the ointment includes, but is not limited to, active agents, waxes, water, petrolatum, preservatives, higher alcohols, polyhydric alcohols, emulsifiers, solvents, and additions. Thickeners, plasticizers, fragrances, buffers, antibiotics, stabilizers or mixtures thereof.
  • the content of the pharmaceutical composition of the present invention can be appropriately adjusted according to different parameters.
  • the above parameters include, but are not limited to, the type of receptor, the body weight of the receptor, the thickness and area of the receptor local fat, and the like.
  • the pharmaceutical composition of the present invention can be administered at a time, administered multiple times or continuously within 24 hours, or administered several times a week or several times or continuously.
  • the mode of administration is injection, subcutaneous implantation, implantable infusion, ointment or patch.
  • the manner of injection includes, but is not limited to, skin. Injection, subcutaneous implantation, intravenous drip, intravenous pump, implantable syringe pump.
  • the present invention further provides an application for reducing local fat and reducing body weight by using the pharmaceutical product, wherein an effective amount of a pharmaceutical composition comprising a composition of resveratrol and turmeric extract is administered to a local part of a recipient In order to achieve localization of the receptor to inhibit fat cell growth, promote fat cell apoptosis, reduce fat deposition and reduce body weight.
  • the receptor is a human or an animal.
  • the effective dose refers to a pharmaceutical having a dose of from 0.4 mg/kg to 100 mg/kg per administration of the recipient; more preferably, the effective dose is that each time the recipient is administered The dosage is from 1 mg/Kg to 60 mg/Kg of the drug.
  • said reducing body weight means reducing body weight gain by 5% to 30% of the receptor.
  • reduced local fat refers to a composition comprising resveratrol and turmeric extract after administration of an effective amount of the present invention, which inhibits fat cell growth and an adipogenesis process.
  • the phenomenon of sexual or planned death, and the reduction of locally deposited fat, as in the case of the present invention, the reduction of topical fat can be achieved by topical application of a specific range of amounts of resveratrol and turmeric extract, and at specific times The changes in the rate of growth inhibition of adipose cells, the degree of apoptosis, the amount of subcutaneous fat and the amount of visceral fat in rats were measured in the range.
  • the topical fat includes, but is not limited to, subcutaneous fat, visceral fat, locally deposited fat or fat cells.
  • the partial fat site includes, but is not limited to, a face, a chin, an arm, a waist, an abdomen or a thigh.
  • composition or medicament of the present invention is not only superior in efficacy to resveratrol or turmeric extract alone, but has never been previously used alone or in combination with resveratrol or turmeric extract by local injection.
  • the method of administration is to reduce the local fat; in addition, the present invention mainly reduces the local fat by inhibiting the growth of fat cells and promoting the apoptosis of the fat cells by local injection, without affecting other peripheral cells or tissues.
  • the obvious side effects are not observed in the animal test. Therefore, the composition or the pharmaceutical product of the present invention has higher safety and lower side effects, and the technical level is completely different from other current technologies or products, and the existing ones can be avoided.
  • Liposuction equipment such as liposuction surgery, ultrasonic focusing lipolysis, or lipolysis needle components such as phospholipid choline and sodium deoxycholate cause local cell necrosis and severe pain, causing problems such as inflammatory reaction and necrotic infection of surrounding tissues, and can be greatly reduced.
  • Fig. 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).
  • Fig. 2 is a bar graph showing the effect of each group on the growth inhibition of adipocytes in differentiation by the cell viability assay (MTT assay).
  • Figure 3 is a bar graph of the effect of UL003C and sodium deoxycholate on the growth inhibition of mature adipocytes in the cell viability assay (MTT assay) of the present invention.
  • Figure 4 is a bar graph of the detection of UL003A, UL003C, and UL003R for adipocyte apoptosis by flow cytometry after staining with Annexin V/PI.
  • Fig. 5 is a bar graph of the detection of UL003A, UL003C, and UL003R for promoting apoptosis of adipocytes by flow cytometry after staining with caspase 3.
  • Figure 6 is a bar graph of the inhibition of turmeric extract, resveratrol, and UL003C on adipocyte apoptosis by flow cytometry after staining with caspase 3.
  • Figure 7 is a bar graph showing the apoptosis of adipocytes induced by UL003C and sodium deoxycholate by flow cytometry after staining with Annexin V/PI.
  • Fig. 8 is a line graph showing changes in body weight of each group after the rats were fed with high fat diet to induce local fat increase and administered locally.
  • Figure 9 is a graph showing the reduction ratio of subcutaneous fat in each group after the rats were fed with high fat diet to induce local fat increase and administered by local injection.
  • Fig. 10A is a graph showing the serum biochemical value (creatinine, glutamic oxaloacetic transaminase, GOT) of each group after the rats were fed with high fat diet to induce local fat increase and administered by local injection. )) Histogram.
  • Fig. 10B is a graph showing the serum biochemical value (urea, glutamic pyruvic transaminase (GTP)) of each group after the rats were fed with high fat diet to induce local fat increase and administered by local injection. Histogram.
  • Figure 11 is a graph showing the expression of apoptosis-related proteins Bax and Bcl-2 and Bax/Bcl-2 in each group by Western blotting method after the rats were fed with high-fat diet to induce local fat increase and local injection. Ratio histogram.
  • the precursor fat cell 3T3-L1 was cultured in a 96-well plate at 1 ⁇ 10 4 cells (cells/well) per well, and 50 ppm of white cucurbit was added to each well except the DMSO solvent control group (control group).
  • the cell growth status was photographed, and the growth inhibition effect of each group on the precursor fat cell 3T3-L1 was analyzed by the cell viability assay (MTT assay).
  • the weight ratio of resveratrol to green tea extract in the UL003A group is 9:1
  • the weight ratio of resveratrol to turmeric extract in the UL003C group is 1:19
  • the resveratrol and turmeric extract in the UL003R group is 9:1.
  • Each group of data is expressed as mean ⁇ SD (Mean ⁇ SD).
  • the English letters a, b, c, d, and e represent statistical results, and different letters indicate statistical differences between groups (p ⁇ 0.05).
  • compositions of the present invention were effective in inhibiting the growth of precursor fat cells (p ⁇ 0.05) compared to the DMSO solvent control group, and compared to other single plant extract groups. It also had a better inhibitory effect and reached a significant difference (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, and DMSO solvent in separate wells
  • 50 ppm resveratrol, 50 ppm turmeric extract, 80 ppm green tea extract, and 100 ppm of the compositions UL003A, UL003C, UL003R of the present invention were tested for a total of 7 experiments and 3 replicates per set of experiments. After the treatment and culture for 48 hours, the cell growth status was photographed, and the inhibitory effect of each test substance on the differentiated fat cells was analyzed by the cell survival rate test.
  • Each group of data is expressed as mean ⁇ SD (Mean ⁇ SD).
  • the English letters a, b, c, d, e, and f represent statistical results, and different letters indicate statistical differences between groups (p ⁇ 0.05).
  • the compositions of the present invention significantly inhibited the growth of adipocytes in differentiation (p ⁇ 0.05), in which the composition was in the form of the composition UL003C.
  • the fat cell growth inhibition effect was the best, and the composition UL003C had a better inhibitory effect on the growth of adipocytes in differentiation compared to other single plant extract groups (p ⁇ 0.05).
  • This example compares the inhibitory effect of the composition of the present invention with the known topical lipolysis component sodium deoxycholate on mature adipocytes.
  • 3T3-L1 cells were cultured in a 3 well dish at 3 ⁇ 10 4 cells/well until the fourth day, and changed to 3-isobutyl-1-containing 5 ⁇ g/ml insulin, 1 ⁇ M dexamethasone, and 0.5 mM.
  • the culture medium of methylxanthine was changed to a medium containing 5 ⁇ g/ml of insulin for two days, and after 3T3-L1 cells were differentiated and matured, except for the two control groups of PBS and DMSO, respectively, in different wells.
  • the composition of the present invention can effectively inhibit the growth of mature adipocytes, and the composition of the present invention UL003C inhibits the growth of mature adipocytes significantly better than deoxycholesterol at two different doses of 50 ppm or 100 ppm.
  • Sodium p ⁇ 0.001.
  • 3T3-L1 was cultured in a 12-well tray at 1 ⁇ 10 5 cells/well until the fourth day, and changed to 3- ⁇ containing 5 ⁇ g/ml of differentiation agent insulin, 1 ⁇ M dexamethasone (dexmethasone), 0.5 mM.
  • the culture medium of 3-isobutyl-1-methylxanthine was cultured for four days in the culture medium containing the differentiation agent, and after the cells were differentiated and matured, each group was separately added except the DMSO solvent control group. 50 ppm of the compositions of the present invention UL003A, UL003C, UL003R were tested, and a total of 4 experiments were performed and 3 replicates were performed for each set of experiments.
  • Annexin V-PI- indicates the number of surviving mature adipocytes.
  • Annexin V+PI+ represents the number of mature adipose-derived cells, in this way to distinguish and evaluate the extent of apoptosis in different experimental groups after dosing.
  • the mature adipocytes were cultured for 24 hours after the above test substances, and the compositions of the present invention UL003A, UL003C and UL003R significantly promoted apoptosis of mature adipocytes compared with the DMSO solvent control group (p ⁇ 0.05), in which the effect of the composition UL003C to promote apoptosis of mature adipocytes was optimal, and the effect was significantly better than the compositions UL003A and UL003R (p ⁇ 0.05).
  • 3T3-L1 was cultured in a 12-well tray at 1 ⁇ 10 5 cells/well until the fourth day, and changed to 3- ⁇ containing 5 ⁇ g/ml of differentiation agent insulin, 1 ⁇ M dexamethasone (dexmethasone), 0.5 mM.
  • the culture medium of 3-isobutyl-1-methylxanthine was cultured in a medium containing a differentiation agent for four days. After the adipocytes were matured, 50 ppm of each group was added except for the DMSO solvent control group. And 100 ppm of the inventive compositions UL003A, UL003C, UL003R were tested in a total of 7 experiments and 3 replicates per set of experiments.
  • the cells were treated with the drug for 3 hours, the cells were collected for caspase 3 staining, and the apoptotic cells were analyzed by flow cytometry.
  • the cells infected with caspase 3 represent the apoptosis of the adipocytes. This approach was used to compare the extent of apoptosis in each group of test substances at different doses.
  • 3T3-L1 was cultured in a 12-well tray at 1 ⁇ 10 5 cells/well until the fourth day, and changed to 3- ⁇ containing 5 ⁇ g/ml of differentiation agent insulin, 1 ⁇ M dexamethasone (dexmethasone), 0.5 mM.
  • the culture medium of 3-isobutyl-1-methylxanthine was cultured in a medium containing a differentiation agent for four days.
  • 50 ppm of each group was added except for the DMSO solvent control group.
  • the turmeric extract, 50 ppm resveratrol, 50 ppm and 100 ppm of the inventive composition UL003C were tested in a total of 5 groups and 3 replicates per group of experiments.
  • resveratrol was more likely to be stained with caspase 3 after 16 hours of treatment.
  • the other groups were treated with medicated cells and cultured for 3 hours.
  • the cells were collected for caspase 3 staining and analyzed by flow cytometry.
  • Dead cells, cells infected with caspase 3 represent the number of apoptosis, in this way to compare the extent of apoptosis induced by the test substances at different doses.
  • This example compares the effect of the composition of the present invention UL003C with the known topical lipolysis component sodium deoxycholate on promoting apoptosis of mature adipocytes.
  • 3T3-L1 was cultured in a 12-well tray at 1 ⁇ 10 5 cells/well until the fourth day, and changed to 3- ⁇ containing 5 ⁇ g/ml of differentiation agent insulin, 1 ⁇ M dexamethasone (dexmethasone), 0.5 mM.
  • the culture medium of 3-isobutyl-1-methylxanthine was cultured in a medium containing a differentiation agent for four days. After the adipocytes were matured, 100 ppm of the present invention was added except for the DMSO solvent control group.
  • composition UL003C and sodium deoxycholate were tested, and a total of 3 experiments were performed and 3 replicates were performed for each set of experiments.
  • the cells were treated with the drug and cultured for 24 hours, the cells were collected for Annexin V/PI staining, and the apoptotic cells were analyzed by flow cytometry, wherein Annexin V-PI- indicates the number of surviving mature adipocytes, Annexin V+PI+ This represents the number of mature adipose-derived cells, in this way to compare the extent of apoptosis induced by the two groups of test substances.
  • the test group consisted of 3 groups, namely control group, UL003C-20 group (20mg/kg BW, also known as low dose group) and UL003C-40 group (40mg/kg BW, Also known as the high dose group). Each group was tested with 4 male rats of 7 weeks old. The initial body weight of the rats was about 207 ⁇ 6g. Each group was fed with high-fat diet for 2 weeks, so that the subcutaneous fat was thickened and the body weight was measured. The drug can be administered after 330 ⁇ 10 g. The drug is administered with different doses of the composition of the present invention UL003C by subcutaneous injection into subcutaneous fat.
  • the injection site is the lower inguinal fat on the left and right sides of the rat, and the upper and lower injection points (5 mg/kg/dot) on each side.
  • the total dose of rats injected was 20 mg (mg/kg/time) and 40 mg/kg/time of the recipient, respectively, while the control group was injected with an equal volume of 4 mL/kg/time of sterile water for injection ( Water for injection), once every 2 days, for a total of 3 injections.
  • the day of the start of the drug injection was set to the first day, and the administration was repeated in the above manner on the third day and the fifth day, and the daily change in body weight and the average daily feed intake were recorded during the test, and the measurement was performed on the 21st day.
  • liver and kidney function indicators which included glutamic pyruvic transaminase (GPT) and glutamic oxaloacetic transaminase. , GOT), creatinine and urea (urea).
  • GPT glutamic pyruvic transaminase
  • GOT glutamic oxaloacetic transaminase
  • urea creatinine and urea
  • the fat of the abdominal subcutaneous, upper groin and inferior groin was weighed and the subcutaneous fat was calculated.
  • the data of each group were expressed as mean ⁇ SD (Mean ⁇ SD), the English letters indicate statistical results, different letters indicate statistical differences between groups (p ⁇ 0.05), and the same letters indicate that there is no statistical difference between groups (p> 0.05).
  • the low-dose group and the high-dose group of the composition of the present invention were injected, and the total weight gain was lower than that of the control group, wherein the weight gain of the composition UL003C-40 group was significantly lower than that of the control group (p ⁇ 0.05), which reduced the body weight by 15.8%, while the weight gain of the composition UL003C-20 group decreased compared with the control group, and decreased by 11.1%, but did not reach significant statistical difference (p>0.05), Administration of the compositions of the invention by injection also reduces body weight and is dose dependent.
  • the rats in each group were measured for the reduction of subcutaneous fat at the injection site after sacrifice, and the composition of the present invention UL003C significantly reduced the subcutaneous fat at the injection site (p ⁇ 0.05), wherein the low dose was compared with the control group.
  • the amount of subcutaneous fat that was reduced in the injection area was 24.3% (p ⁇ 0.05); in the high-dose group, the amount of subcutaneous fat that was reduced in the injection area was 21.6% (p ⁇ 0.05).
  • Example 9 Apoptosis analysis of adipose tissue cells in rats under subcutaneous injection
  • Bcl-2 and Bax are two important regulatory factors in the apoptotic pathway, and the balance between them is to regulate apoptosis.
  • the Western blotting method was used to analyze the expression of anti-apoptotic protein Bcl-2 and the protein-promoting protein Bax2 in the adipose tissue of subcutaneous injection in each group, and the present invention was evaluated by the ratio of Bax to Bcl-2.
  • the composition UL003C causes an effect of adipose cell apoptosis.
  • the rats sacrificed in Example 8 were taken from the subcutaneous adipose tissue of the inguinal region at the point of drug injection, with 450 ⁇ l.
  • each group was quantitatively taken 30 ⁇ g of protein for polyacrylamide gel electrophoresis (SDS-PAGE), and the protein was transferred to PVDF membrane; Bcl-2 antibody for Western blotting method was purchased from Santa Cruz, model number sc-7382, Bax antibody was purchased from Santa Cruz, model number sc-526.
  • the data of each group were expressed as mean ⁇ SD (Mean ⁇ SD), the English letters indicate statistical results, different letters indicate statistical differences between groups (p ⁇ 0.05), and the same letters indicate that there is no statistical difference between groups (p> 0.05).
  • the composition of the present invention UL003C significantly increased the expression of Bcl-2 (p ⁇ 0.05) and significantly inhibited the expression of Bax in both the low dose and the high dose group as compared with the control group ( p ⁇ 0.05), the ratio of Bax/Bcl-2 was also significantly higher than that of the control group (p ⁇ 0.05), indicating that the rats can effectively promote the apoptosis of adipose tissue after injection of the composition of the present invention UL003C.
  • the invention can effectively promote the adipocyte to apoptosis and reduce the local fat amount, and the animal experiment results again prove that the combination of the invention can achieve the mechanism of reducing the fat cell and the local fat amount, mainly by increasing the apoptosis of the fat cell. way.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Botany (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Birds (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Medical Informatics (AREA)
  • Diabetes (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Obesity (AREA)
  • Organic Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Hematology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

本发明公开一种用于减少局部脂肪与减少体重的组合物及其医药品与应用，所述组合物包括重量比为1∶30至10∶1的白藜芦醇与姜黄萃取物，本发明所述的组合物及其医药品可抑制脂肪细胞生长，并造成脂肪细胞计划性的凋亡，达到减少脂肪细胞、减少局部脂肪堆积及减少体重的效果，而不会引起周边细胞与组织的发炎反应或组织坏死，亦无外围组织的炎症或疼痛反应，进而避免现有技术利用抽脂手术或低侵入的溶脂仪器所造成的组织受损与发炎疼痛问题，也不会有溶脂注射剂成分磷脂胆碱（phosphatidylcholine）或是脱氧胆酸钠（sodium deoxycholate）造成细胞崩解坏死（necrosis）所引发的外围组织发炎与坏死感染等问题。

Description

用于减少局部脂肪与减少体重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，尤指一种用于减少局部脂肪与减少体重的组合物；本发明关于一种所述组合物的应用，尤指用于减少局部脂肪与减少体重的应用；本发明更关于一种包含有所述组合物的医药品，尤指可用于减少局部脂肪与减少体重的医药品；本发明更关于一种应用，尤指通过所述医药品用于减少局部脂肪与减少体重的应用。
背景技术
近年来由于越来越多人对美感观念的改变，以及自我健康、身型及体重标准的提升，减重、塑身不再只是肥胖者的关注议题，因此造就目前减重塑身与体重管理市场的蓬勃发展，带动的相关发展包含减重食品、塑身保养品、减肥临床管理、医疗仪器、健身运动器材等。根据Marketsand Markets的统计报告“Global Weight Loss and Gain Market2009-2014”，2014年全球体重管理(Weight Management)市场可达美金5863亿，到2015年时将成长到6509亿美元；其中又以美国为主要市场，其规模预计可达3100亿美元，其次是欧洲，预计市场规模为2380亿美元。同时由于消费者对于健康意识的重视，特别是肥胖对引发各种慢性疾病的后续影响，更是各国越来越重视的议题，除了针对肥胖族群，越来越多人对于健康族群的体重控制与美体雕塑积极发展，引领各界对于美体雕塑的重视以及产业发展热潮，以上因素都造成整体市场能稳定持续成长的主因。依2012年美国整形外科医师学会(American Society of Plastic Surgeons)统计显示美体雕塑(Body Contouring)的需求在整形外科领域中持续排名第一，并预估每年病患需求将以12.3％的成长率持续增加到2017年。根据Research and Markets出版的“Global Pipeline Analysis，Competitive Landscape and Market Forecasts”显示2010年全球美体雕塑仪器设备市场达9亿美元，预估到2017年时可增加到20亿美元。正因市场需求量不仅非常大且每年仍持续增长，市面上出现相关的抽脂、溶脂方式更是五花八门、琳琅满目，相对的许多风险高或不受保障的医疗行为也相继出现。
熟知的抽脂手术早从1970年代就开始发展，当时所采用的抽脂方式皆是在无任何输液情况的下直接以负压进行干式抽脂，该方式对皮下神经与血管造成极大的伤害，且出血量大手术风险高。后续又发展出膨胀式抽脂与超湿式抽脂等方式，膨胀式抽脂是在输入液中添加麻醉剂与血管收缩剂，此方法以局部麻醉取代了原本静脉麻醉的抽脂过程，然而大量输液的结果使麻醉剂在体内要至少12小时才能被代谢，也增加了局部麻醉剂对人体的 可能危害。近期较被医师使用于大量抽脂的方法是超湿式抽脂，其特点是输入液与要抽出的脂肪量相同及可，可有效减少输液过载的可能性。然而在临床上抽脂手术有其实施部位的限制，主要针对腹部、大腿等脂肪量较多的区域为主，同时抽脂手术的有效性与安全性完全取决于医师本身的技术与熟练度，抽脂过程对身体造成的伤害较大、耗费时间长，且仍会造成病人术后严重的瘀青、肿胀、疼痛与感觉麻痹、疤痕组织、皮肤表面不平整等副作用，恢复期更长达4至6周，因为手术时间较长，出血量较多也直接增加了手术的风险；因此各界也开始设计各种辅助抽脂的仪器，于是陆续出现超声波、雷射等辅助抽脂的方式，但关键仍在实施抽脂的医师技术。另外，相关辅助仪器也常发生组织灼伤或是成果不佳的案例。有鉴于各式抽脂方式面临的困境，各界不断在技术与设备上进行改善，自1980年代起欧美医学美容产业便着重于医学美容设备的开发。以美体雕塑而言各大厂商皆从传统抽脂演变为微创甚至非侵入式溶脂仪器为产品诉求，无论是消脂产品还是仪器，不难发现都以改善传统方式出血多、患者恢复期长、留有术后伤疤等缺点为主要诉求，尽量以低侵入式、高安全性、使用方便、减小伤口、缩短患者恢复期作为方向；更须同时兼顾功效性与价格竞争性，才有足够的优势进入目前的医学美容市场。
此外也有以中胚层疗法溶脂的方式，主要是利用磷脂胆碱(Phosphatidylcholine)或是脱氧胆酸钠(sodium deoxycholate)作为有效成分注射到肥胖部位进行溶脂，此类成分与细胞膜成分相似，能破坏脂肪细胞的细胞膜促使细胞崩解坏死(necrosis)。此类注射药物进到中胚层将造成脂肪细胞大量坏死后造成脂肪的溶出，但因为药物不具特异性，并非只针对脂肪细胞作用，因此外围许多正常的细胞也会受到影响而坏死(necrosis)，加上细胞坏死(necrosis)会引起外围组织一连串的发炎反应，进而造成实施部位的发炎反应与剧烈的疼痛肿胀，甚至造成局部组织坏死或感染等风险。利用注射剂型溶脂方式虽然可以克服使用大型仪器时遇到治疗部位的限制，但为了达到溶脂效果常常一次治疗需要打进数十针，疗程大约每两周就要注射一次，总共需要治疗1-6次不等，虽然注射成分里都会添加麻醉剂，但注射部位于麻醉退除后，仍会产生相当严重的发炎与疼痛感，同时治疗次数与扎针规模也有待改善。加上术后严重疼痛，神经麻痹感，局部组织坏死或感染等风险，单次注射的剂量非常有限，应用区域也仅在脸部，因此，大部份医师已不再注射上述成分来减少病人局部脂肪，虽然美国已通过了第一个脱氧胆酸钠(sodium deoxycholate)的溶脂针产品，但产品仍有上述一定程度的副作用，且仅能用于双下巴，其应用范围仍非常有限。
整体而言，目前市场上仍极欠缺一种能有效减少局部脂肪、且副作用更低、安全性更佳的产品。因此，在医师与消费者的高度需求下，开发一种兼具安全性、副作用低且排除 上述溶脂方法限制与缺点的局部注射针剂将是未来的市场趋势。
发明内容
本发明提供一种用于减少局部脂肪与减少体重的组合物，其包括重量比为1∶30至10∶1的白藜芦醇与姜黄萃取物。优选地，白藜芦醇与姜黄萃取物重量比例为1∶19。
本发明所述的组合物可抑制脂肪细胞生长，并造成脂肪细胞计划性的凋亡(apoptosis)，达到降低局部脂肪堆积与减少脂肪细胞的效果，亦能减少体重，但不会引起周边细胞与组织的发炎反应或组织坏死，也无外围组织的炎症反应或严重疼痛，因此可避免上述利用抽脂手术或低侵入的溶脂仪器所造成的组织受损与发炎疼痛问题，也不会有溶脂注射剂成分磷脂胆碱(phosphatidylcholine)或是脱氧胆酸钠(sodium deoxycholate)造成细胞崩解坏死(necrosis)所引发的外围组织发炎与坏死感染等问题。本发明亦可以减少体重。
依据本发明，“姜黄萃取物”于此处是指包含姜黄素的萃取物，其中姜黄素占姜黄萃取物的浓度为80％至100％。
本发明更提供一种制造包含有白藜芦醇与姜黄萃取物的组合物的方法，其包括将包含有白藜芦醇与姜黄萃取物的组合物与下列至少一种医药上可接受的盐类组合物、医药上可接受的安定剂或抑菌剂或医药上可接受的乳化剂、表面活性剂等赋形剂、麻醉剂等相混合后制成注射剂。
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。
较佳的，所述的“医药上可接受的赋形剂”包括但不限于润滑剂(lubricant)、助悬剂(suspending agent)、助溶剂(solubilizer)助流剂(glidant)、乳化剂(emulsifier)或表面活性剂(surfactant)。赋形剂的使用量取决于使用多少活性成分，且一种赋形剂可以执行一种以上的功能。
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)。
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。
较佳的，所述的乳化剂可为天然存在的磷脂，包括但不限于大豆磷脂、卵磷脂、单甘油脂、双甘油脂、硬酯酸钠、脱水山梨醇脂肪酸酯(sorbitan esters of ftty acids)或聚氧乙烯脱水山梨糖醇单油酸酯。
较佳的，所述的表面活性剂包含但不限于聚氧乙烯-脱水山梨糖醇脂肪酸酯(Tween)、聚乙烯-聚丙二醇、聚氧乙烯-硬脂酸酯、聚氧乙烯烷基醚(例如聚氧乙烯单月桂基醚)、烷基苯基聚氧乙烯醚(Triton-X)、聚氧乙烯-聚氧丙烯共聚物(Poloxamer、Pluronic)及十二烷基硫酸钠(SDS)。
本发明进一步提供所述组合物在制备减少局部脂肪与减少体重的医药品中的应用。
本发明更提供一种用于减少局部脂肪与减少体重的医药品，其中，该医药品包含有效剂量的所述用于减少局部脂肪与减少体重的组合物以及其医药学上可接受的载剂。
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、悬浮液、粉剂、冻干粉或脂质体，或通过经皮吸收的软膏及贴布等方式。较佳的形式取决于预期的给药模式及治疗应用；较佳的，本发明的医药品呈可输注溶液形式，且较佳的给药模式为非经肠模式，诸如注射溶液。在本发明的实施例中，包含有效减少局部脂肪剂量的包含有白藜芦醇与姜黄萃取物的组合物的医药品是通过皮下注射施予；更佳的，包含有效减少局部脂肪剂量的包含有白藜芦醇与姜黄萃取物的组合物的医药品是以皮下注射方式至皮下脂肪层。在具体实施例中，软膏的调配如本领域技术人员所知晓的那样，包括但不限于活性剂、蜡、水、凡士林、防腐剂、高级醇类、多羟基醇类、乳化剂、溶剂、增稠剂、增塑剂、芳香剂、缓冲剂、抗生素、安定剂或其混合。
本发明所述的医药组合物的含量可依照不同参数做适当的调整。上述参数包括但不限于受体的种类、受体的体重、受体局部脂肪的厚度与面积等。本发明所述的医药组合物可一次给予，24小时内多次给予或连续给予，亦可每周或每月多次或连续给予。施予方式是注射、皮下植入、埋植式输注、软膏或贴布，较佳的，所述的注射的方式包括但不限于皮 下注射、皮下植入、静脉注射点滴、静脉注射泵、埋植式注射泵。
本发明更提供一种以所述医药品用于减少局部脂肪与减少体重的应用，其是将有效剂量的包含有白藜芦醇与姜黄萃取物的组合物的医药品施予受体局部部位，以使受体局部部位达到抑制脂肪细胞生长、促进脂肪细胞凋亡、减少沉积脂肪以及减少体重的效果。
较佳的，所述的受体为人类或动物。
较佳的，所述的有效剂量是指每次施予受体的将剂量为0.4mg/Kg至100mg/Kg的医药品；更佳的，所述的有效剂量是指每次施予受体的剂量为1mg/Kg至60mg/Kg的医药品。
较佳的，所述的减少体重是指降低受体5％至30％的体重增重。
依据本发明，“减少局部脂肪”如此处是指经施予本发明所述的有效剂量的包含有白藜芦醇与姜黄萃取物的组合物后，可抑制脂肪细胞生长、且脂肪细胞产生程序性或计划性死亡的现象，并减少局部沉积的脂肪，其如本发明的示例，减少局部脂肪可通过局部施予特定范围量的白藜芦醇与姜黄萃取物的组合物，并于特定时间范围内测量脂肪细胞生长抑制率、细胞凋亡程度、大鼠皮下脂肪量及内脏脂肪量的变化而得。较佳的，所述的局部脂肪包括但不限于皮下脂肪、内脏脂肪、局部沉积脂肪或脂肪细胞。
较佳的，所述的局部脂肪部位包括但不限脸部、下巴、手臂、腰部、腹部或大腿等部位。
本发明所述的组合物或医药品不仅药效显著优于单独施予白藜芦醇或姜黄萃取物，且过去从未有前例单独或合并使用白藜芦醇或姜黄萃取物，通过局部注射给药方式来减少其局部脂肪；再者，本发明主要是通过局部注射施予药物来抑制脂肪细胞生长与促进脂肪细胞进行细胞凋亡来减少其局部脂肪，而并不影响其他外围细胞或组织，在动物试验中也未看到明显副作用，因此本发明所述的组合物或医药品安全性更高、副作用更低，其技术层次完全有别于目前其他技术或产品，可避免现有的抽脂手术、超声波聚焦溶脂等溶脂仪器、或磷脂胆碱、脱氧胆酸钠等溶脂针成分造成局部细胞坏死、剧烈疼痛，引起周边组织发炎反应与坏死感染等问题，更可大幅减轻病人术后的瘀青、肿胀疼痛与感觉麻痹，以及缩短术后恢复期。
附图说明
图1是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是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3是本发明以细胞存活率试验(MTT assay)检测UL003C与脱氧胆酸钠对于成熟脂肪细胞生长抑制效果的柱状图。
图4是本发明以Annexin V/PI染色后以流式细胞仪检测UL003A、UL003C、UL003R促进脂肪细胞凋亡的柱状图。
图5是本发明以caspase 3染色后以流式细胞仪检测UL003A、UL003C、UL003R促进脂肪细胞凋亡的柱状图。
图6是本发明以caspase 3染色后以流式细胞仪检测姜黄萃取物、白藜芦醇、UL003C促进脂肪细胞凋亡的柱状图。
图7是本发明以Annexin V/PI染色后以流式细胞仪检测UL003C与脱氧胆酸钠促使脂肪细胞凋亡的柱状图。
图8是本发明以高脂饲料喂食大鼠诱导局部脂肪增加并局部注射给药后，测量各组的体重变化折线图。
图9是本发明以高脂饲料喂食大鼠诱导局部脂肪增加并局部注射给药后，各组皮下脂肪减少比率。
图10A是本发明以高脂饲料喂食大鼠诱导局部脂肪增加并局部注射给药后，测量各组的血清生化值(肌酐(creatinine)、麸胺酸草乙酸转胺酶(glutamic oxaloacetic transaminase，GOT))柱状图。
图10B是本发明以高脂饲料喂食大鼠诱导局部脂肪增加并局部注射给药后，测量各组的血清生化值(尿素(urea)、丙胺酸胺基转化酶(glutamic pyruvic transaminase，GTP))柱状图。
图11是本发明以高脂饲料喂食大鼠诱导局部脂肪增加并局部注射给药后，以西方墨点法测量各组的细胞凋亡相关蛋白Bax、Bcl-2表达量以及Bax/Bcl-2比值柱状图。
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 DMSO溶剂对照组(控制组)外，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本发明的组合物：UL003A、UL003C、UL003R，共7组且每组实验进行3重复。经加药处理并培养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)分析各组别对于前驱脂肪细胞3T3-L1的生长抑制效果。其中UL003A组的白藜芦醇与绿茶萃取物的重量比为9∶1、UL003C组的白藜芦醇与姜黄萃取物的重量比为1∶19以及UL003R组的白藜芦醇与姜黄萃取物的重量比为9∶1。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有统计差异(p＜0.05)。
结果如图1所示，与DMSO溶剂对照组相比，本发明组合物UL003A、UL003C以及UL003R皆能有效抑制前驱脂肪细胞的生长(p＜0.05)，且相较于其他单一植物萃取物组别亦具有较佳的抑制效果，且达到显著差异(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，并于不同孔中分别加入DMSO溶剂作为对照组、50ppm白藜芦醇、50ppm姜黄萃取物、80ppm绿茶萃取物以及100ppm本发明的组合物UL003A、UL003C、UL003R以进行实验，实验共7组且每组实验进行3重复。经加药处理并培养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有统计差异(p＜0.05)。
结果如图2所示，与DMSO溶剂对照组相比，本发明组合物UL003A、UL003C及UL003R皆能显著抑制分化中的脂肪细胞生长(p＜0.05)，其中又以组合物UL003C对分化中的脂肪细胞生长抑制效果最佳，且组合物UL003C相较于其他单一植物萃取物组别，组合物UL003C对于分化中的脂肪细胞生长亦具有较佳的抑制效果(p＜0.05)。
实施例3.成熟脂肪细胞生长抑制实验
本实施例比较本发明的组合物与已知的局部溶脂成分脱氧胆酸钠(sodium deoxycholate)对成熟脂肪细胞的抑制效果。本实施例将3T3-L1细胞以3×104cells/well培养于12孔盘培养至第四天改用含有5μg/ml胰岛素、1μM地塞米松、0.5mM的3-异丁基-1-甲基黄嘌呤的培养液，两天后换成含有5μg/ml胰岛素的培养液持续培养四天，待3T3-L1细胞分化成 熟后，除PBS及DMSO两种溶剂对照组外，在不同孔中分别加入50ppm、100ppm的组合物UL003C与脱氧胆酸钠以进行实验，实验共6组且每组实验进行3重复。经加药处理并培养48小时后，拍照记录细胞生长状况，并以细胞存活率试验分析各实验物质对于成熟脂肪细胞的抑制效果。
结果如图3所示，本发明组合物能有效抑制成熟的脂肪细胞生长，且不论在50ppm或100ppm两种不同剂量下，本发明组合物UL003C抑制成熟脂肪细胞生长的效果皆显著优于脱氧胆酸钠(p＜0.001)。
实施例4.脂肪细胞凋亡(apoptosis)实验I
本实施例将3T3-L1以1×105cells/well培养于12孔盘养至第四天改用含有5μg/ml分化剂胰岛素、1μM地塞米松(dexmethasone)、0.5mM的3-异丁基-1-甲基黄嘌呤(3-isobutyl-1-methylxanthine)的培养液，在含有分化剂的培养液中培养四天后，待细胞分化成熟后，除DMSO溶剂对照组外，每组分别添加50ppm本发明组合物UL003A、UL003C、UL003R进行实验，实验共4组且每组实验进行3重复。于加药处理细胞并培养24小后，收集细胞并利用Annexin V/PI染色，并以流式细胞仪分析凋亡细胞(apoptotic cells)，其中Annexin V-PI-表示存活的成熟脂肪细胞的数量，Annexin V+PI+则代表成熟脂肪发生细胞凋亡的数量，以此方式来区别并评估不同的实验组别于加药后发生细胞凋亡(apoptosis)程度。
结果如图4所示，成熟的脂肪细胞以上述各试验物质培养24小时后，与DMSO溶剂对照组相比，本发明组合物UL003A、UL003C及UL003R皆能显著促使成熟脂肪细胞凋亡(p＜0.05)，其中又以组合物UL003C促使成熟脂肪细胞凋亡的效果最佳，其效果显著优于组合物UL003A以及UL003R(p＜0.05)。
实施例5.脂肪细胞凋亡实验II
本实施例将3T3-L1以1×105cells/well培养于12孔盘养至第四天改用含有5μg/ml分化剂胰岛素、1μM地塞米松(dexmethasone)、0.5mM的3-异丁基-1-甲基黄嘌呤(3-isobutyl-1-methylxanthine)的培养液，在含有分化剂的培养液中培养四天于脂肪细胞成熟后，除DMSO溶剂对照组外，每组分别添加50ppm以及100ppm的本发明组合物UL003A、UL003C、UL003R进行实验，实验共7组且每组实验进行3重复。于加药处理细胞并培养3小后，收集细胞进行caspase 3染色，并以流式细胞仪分析凋亡细胞，染到凋亡蛋白酶3(caspase 3)的细胞代表发生的脂肪细胞凋亡，以此方式来比较在不同剂量下各组试验物质促使细胞凋亡程度。
结果如图5所示，与DMSO溶剂对照组相比，无论给予脂肪细胞50ppm或100ppm 本发明组合物UL003C，细胞染到caspase 3的数量皆显著高于DMSO溶剂对照组(p＜0.001)，显示组合物UL003C能显著促使成熟脂肪细胞进行细胞凋亡，且具有最佳的效果。
实施例6.脂肪细胞凋亡实验III
本实施例将3T3-L1以1×105cells/well培养于12孔盘养至第四天改用含有5μg/ml分化剂胰岛素、1μM地塞米松(dexmethasone)、0.5mM的3-异丁基-1-甲基黄嘌呤(3-isobutyl-1-methylxanthine)的培养液，在含有分化剂的培养液中培养四天于脂肪细胞成熟后，除DMSO溶剂对照组外，每组分别添加50ppm姜黄萃取物、50ppm白藜芦醇、50ppm及100ppm的本发明组合物UL003C进行实验，实验共5组且每组实验进行3重复。根据文献得知白藜芦醇加药处理16小时较可能染到caspase 3，其余各组则于加药处理细胞并培养3小后，收集细胞进行caspase 3染色，并以流式细胞仪分析凋亡细胞，染到caspase 3的细胞代表发生的细胞凋亡数量，以此方式来比较在不同剂量下各组试验物质促使细胞凋亡程度。
结果如图6所示，成熟脂肪细胞给予50ppm组合物UL003C培养后，细胞染到caspase3的数量显著高于DMSO溶剂对照组(p＜0.001)，亦显著高于相同剂量的姜黄萃取物组(p＜0.05)与白藜芦醇组(p＜0.001)，显示本发明组合物UL003C促使成熟脂肪细胞进行细胞凋亡的效果显著优于单独使用其中任一植物萃取物成分。
实施例7.脂肪细胞凋亡实验IV
本实施例比较本发明组合物UL003C与已知的局部溶脂成分脱氧胆酸钠(sodium deoxycholate)对于促进成熟脂肪细胞凋亡的效果。本实施例将3T3-L1以1×105cells/well培养于12孔盘养至第四天改用含有5μg/ml分化剂胰岛素、1μM地塞米松(dexmethasone)、0.5mM的3-异丁基-1-甲基黄嘌呤(3-isobutyl-1-methylxanthine)的培养液，在含有分化剂的培养液中培养四天于脂肪细胞成熟后，除DMSO溶剂对照组外，分别添加100ppm本发明组合物UL003C及脱氧胆酸钠进行实验，实验共3组且每组实验进行3重复。于加药处理细胞并培养24小后，收集细胞进行Annexin V/PI染色，并以流式细胞仪分析凋亡细胞，其中Annexin V-PI-表示存活的成熟脂肪细胞的数量，Annexin V+PI+则代表成熟脂肪发生细胞凋亡的数量，以此方式来比较两组试验物质促使细胞凋亡程度。
结果如图7所示，与DMSO溶剂对照组及相同浓度的脱氧胆酸钠相比，组合物UL003C能显著增加成熟脂肪细胞凋亡(p＜0.001)；反之，脱氧胆酸钠则与DMSO溶剂对照组没有显著差异(p＞0.05)。显示本发明组合物可显著增加成熟脂肪细胞凋亡，而已知的局部溶脂成分脱氧胆酸钠则否。
实施例8.大鼠动物实验
本实验使用8周龄SD品系雄性大鼠，试验共设置3组，分别为控制组、UL003C-20组(20mg/kg B.W.，又称低剂量组)以及UL003C-40组(40mg/kg B.W.，又称高剂量组)。每组各以4只七周龄的雄性大鼠进行试验，大鼠初始体重约为207±6g，各组先连续2周以高脂饲料喂食，使大鼠皮下脂肪量增厚并秤量体重达330±10g后即可开始给予药物。药物以皮下注射至皮下脂肪的方式施予不同剂量的本发明组合物UL003C，注射部位为大鼠左右两侧的下腹股沟脂肪处，每侧上下两个注射点(5mg/kg/点)，每只大鼠注射的总剂量分别为受体每次每公斤20毫克(mg/kg/次)以及40mg/kg/次，而控制组则是注射等体积4mL/kg/次的无菌注射用水(water for injection)，每2天注射1次，共注射给药3次。以开始进行药物注射当日设定为第1天，并于第3天与第5天时以上述方式重复给药，试验期间每日纪录体重变化与平均每日饲料摄取量，到第21天量测最后一次体重后将大鼠禁食24小时，并采血测量肝肾功能指标，该指标包含丙氨酸胺基转化酶(glutamic pyruvic transaminase，GPT)、麸胺酸草乙酸转胺酶(glutamic oxaloacetic transaminase，GOT)、肌酐(creatinine)与尿素(urea)。并于大鼠牺牲后取其腹部皮下、上腹股沟与下腹股沟的脂肪进行称重计算其皮下脂肪量。各组数据均以平均值±SD(Mean±SD)表示，英文字母表示统计的结果，不同字母表示组间具有统计差异(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8所示，注射本发明组合物UL003C低剂量组与高剂量组，其体重总增重皆低于控制组，其中组合物UL003C-40组体重增加量显著低于控制组(p＜0.05)，可减少15.8％体重，而组合物UL003C-20组的体重增加量与控制组相比虽有下降趋势，并减少11.1％体重，但未达显著统计差异(p＞0.05)，显示以注射方式给予本发明组合物亦能降低体重且与剂量相关。
如图9所示，各组大鼠牺牲后测量注射处皮下脂肪减少的结果，与控制组相比，本发明组合物UL003C可显著减少药物注射处的皮下脂肪(p＜0.05)，其中低剂量组在注射区域可减少的皮下脂肪量达24.3％(p＜0.05)；而在高剂量组在注射区域可减少的皮下脂肪量达21.6％(p＜0.05)。
如图10A、10B所示，各组大鼠的肌酐、尿素、GOT、GPT血清生化值并无统计差异(p＞0.05)，显示注射本发明组合物UL003C低剂量或高剂量后，并不影响安全性指标，显示本发明组合物具备良好的安全性。
实施例9.大鼠皮下注射处脂肪组织细胞凋亡分析
Bcl-2及Bax为细胞凋亡途径中的二个重要调控因子，两者间的平衡是调控细胞凋亡 的重要机制，Bcl-2的高度表现会抑制细胞凋亡，而Bax表现则会促进细胞凋亡，两者的比值高低能决定细胞会趋向于存活还是细胞凋亡。
本实验以西方墨点法分析各组大鼠皮下注射处脂肪组织中抗细胞凋亡蛋白Bcl-2与促进细胞凋亡蛋白Bax2的蛋白质表达量，并通过Bax与Bcl-2的比值评估本发明组合物UL003C造成脂肪细胞凋亡的效果。实验将实施例8中牺牲的大鼠取其药物注射处下腹股沟皮下脂肪组织，以450μl
Figure PCTCN2015088340-appb-000001
进行蛋白质萃取，各组定量取30μg蛋白质进行聚丙烯酰胺凝胶电泳(polyacrylamide gel electrophoresis，SDS-PAGE)，并将蛋白质转移至PVDF膜；其中用于西方墨点法的Bcl-2抗体购自于Santa Cruz，型号为sc-7382，Bax抗体购自于Santa Cruz，型号为sc-526。各组数据均以平均值±SD(Mean±SD)表示，英文字母表示统计的结果，不同字母表示组间具有统计差异(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11所示，与控制组相比，，本发明组合物UL003C无论在低剂量与高剂量组皆能显著增加Bcl-2的表达量(p＜0.05)并显著抑制Bax的表达量(p＜0.05)，其Bax/Bcl-2的比值亦显著高于控制组(p＜0.05)，显示大鼠经注射本发明组合物UL003C后，能有效促使脂肪组织的脂肪细胞凋亡。本发明确实能有效促使脂肪细胞走向细胞凋亡，并减少其局部脂肪量，经动物实验结果再次证实本发明组合能达到减少脂肪细胞与局部脂肪量的机制，主要是通过增加脂肪细胞凋亡的途径。
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 (12)

  1. 一种用于减少局部脂肪与减少体重的组合物，其特征在于，所述组合物包括重量比为1∶30至10∶1的白藜芦醇与姜黄萃取物。
  2. 根据权利要求1所述的组合物，其特征在于，该白藜芦醇与姜黄萃取物的重量比例为1∶19。
  3. 一种权利要求1或2所述的组合物在制备减少局部脂肪与减少体重的医药品中的应用。
  4. 一种用于减少局部脂肪与减少体重的医药品，其特征在于，所述医药品包含有效剂量的权利要求1或2所述的组合物以及其医药学上可能够接受的载剂。
  5. 一种权利要求4的医药品在制备减少局部脂肪与减少体重的医药品中的应用，其特征在于，将医药品以有效剂量施予受体局部部位，以使受体局部部位达到减少脂肪以及减少受体体重的效果。
  6. 根据权利要求5所述的应用，其特征在于，受体为动物或人类。
  7. 根据权利要求5所述的应用，其特征在于，局部部位包括脸部、下巴、手臂、腰部、腹部或大腿等。
  8. 根据权利要求5所述的应用，其特征在于，施予方式是注射、皮下植入、埋植式输注、软膏或贴布。
  9. 根据权利要求8所述的应用，其特征在于，注射施予是皮下注射。
  10. 根据权利要求9所述的应用，其特征在于，皮下注射是注射至脂肪层。
  11. 根据权利要求8所述的应用，其特征在于，有效剂量是指每次以剂量为0.4mg/Kg至100mg/Kg的医药品施予受体。
  12. 根据权利要求11所述的应用，其特征在于，有效剂量是指每次以剂量为1mg/Kg至60mg/Kg的医药品施予受体。
PCT/CN2015/088340 2014-08-28 2015-08-28 用于减少局部脂肪与减少体重的组合物及其医药品与应用 Ceased WO2016029870A1 (zh)

Priority Applications (66)

Application Number Priority Date Filing Date Title
EP20214023.2A EP3811935A1 (en) 2014-08-28 2015-08-28 Composition for reducing local fat and body weight, and pharmaceuticals and use thereof
SG11201701476PA SG11201701476PA (en) 2014-08-28 2015-08-28 Composition for reducing local fat and body weight, and pharmaceuticals and use thereof
AU2015309353A AU2015309353B2 (en) 2014-08-28 2015-08-28 Composition for reducing local fat and body weight, and pharmaceuticals and use thereof
US14/914,971 US9987325B2 (en) 2014-08-28 2015-08-28 Plant extract composition for reducing localized fat and promoting weight loss as well as application thereof
CA2959185A CA2959185C (en) 2014-08-28 2015-08-28 Composition for reducing localized fat and body weight, and pharmaceuticals and use thereof
KR1020177008265A KR101859345B1 (ko) 2014-08-28 2015-08-28 국소 지방 및 체중 감소용 조성물 및 그의 제약 및 용도
DK15836003.2T DK3187178T3 (da) 2014-08-28 2015-08-28 Sammensætning og lægemidler til reducering af lokaliseret fedt og kropsvægt og anvendelse heraf
KR1020187013247A KR101935219B1 (ko) 2014-08-28 2015-08-28 국소 지방 및 체중 감소용 조성물 및 그의 제약 및 용도
MX2017002585A MX385905B (es) 2014-08-28 2015-08-28 Composicion para reducir la grasa local y el peso corporal y sustancias farmaceuticas y uso de las mismas.
CN201580045335.8A CN106604724B (zh) 2014-08-28 2015-08-28 用于减少局部脂肪与减少体重的组合物及其医药品与应用
SI201531877T SI3187178T1 (sl) 2014-08-28 2015-08-28 Sestavek in farmacevtska sredstva za zmanjševanje lokalizirane maščobe in telesne teže ter uporaba le-teh
JP2017530388A JP6473505B2 (ja) 2014-08-28 2015-08-28 局所の脂肪と体重の減少に用いられる組成物およびその医薬品と使用
ES15836003T ES2924879T3 (es) 2014-08-28 2015-08-28 Composición y productos farmacéuticos para reducir la grasa localizada y el peso corporal y su uso
PL15836003.2T PL3187178T3 (pl) 2014-08-28 2015-08-28 Kompozycja oraz leki do zmniejszania ilości zlokalizowanej tkanki tłuszczowej i masy ciała oraz ich zastosowanie
EP15836003.2A EP3187178B1 (en) 2014-08-28 2015-08-28 Composition and pharmaceuticals for reducing localized fat and body weight and the use thereof
TW104131193A TWI580422B (zh) 2014-08-28 2015-09-21 Compositions for reducing local fat and weight loss, and pharmaceuticals and applications thereof
EP25196769.1A EP4647070A2 (en) 2015-08-28 2016-08-26 A pharmaceutical composition for reducing local fat and uses thereof
MX2018002462A MX384073B (es) 2015-08-28 2016-08-26 Una composicion farmaceutica para reducir la grasa localizada y sus usos.
LTEPPCT/IB2016/055102T LT3381451T (lt) 2015-08-28 2016-08-26 Farmacinis junginys, naudojamas lokalizuotiems riebalams mažinti, ir farmacinio junginio naudojimas
PL16840922.5T PL3381451T3 (pl) 2015-08-28 2016-08-26 Kompozycja farmaceutyczna stosowana do redukcji zlokalizowanej tkanki tłuszczowej i zastosowanie kompozycji farmaceutycznej
CA2995155A CA2995155C (en) 2015-08-28 2016-08-26 A pharmaceutical composition for reducing local fat and uses thereof
TW105127451A TWI630922B (zh) 2015-08-28 2016-08-26 用於減少局部脂肪的醫藥組成物及其用途
CN202211455288.2A CN115778928B (zh) 2015-08-28 2016-08-26 用于减少局部脂肪的医药组成物及其用途
HRP20251142TT HRP20251142T1 (hr) 2015-08-28 2016-08-26 Farmaceutski pripravak koji se koristi za smanjenje lokaliziranih masnoća i uporaba farmaceutskog pripravka
SM20250365T SMT202500365T1 (it) 2015-08-28 2016-08-26 Composizione farmaceutica utilizzata per ridurre il grasso localizzato e uso della composizione farmaceutica
EP16840922.5A EP3381451B1 (en) 2015-08-28 2016-08-26 Pharmaceutical composition used for reducing localised fat and use of pharmaceutical composition
KR1020207012125A KR102356390B1 (ko) 2015-08-28 2016-08-26 국부 지방을 감소시키기 위해 사용되는 제약 조성물 및 그의 용도
IL257784A IL257784B2 (en) 2015-08-28 2016-08-26 Methods and compositions for reducing fat
CN202411262786.4A CN119157850A (zh) 2015-08-28 2016-08-26 用于减少局部脂肪的医药组成物及其用途
MX2018002461A MX387266B (es) 2015-08-28 2016-08-26 Una composicion farmaceutica para reducir la grasa localizada y sus usos
AU2016314546A AU2016314546C1 (en) 2015-08-28 2016-08-26 Pharmaceutical composition used for reducing localised fat and use of pharmaceutical composition
JP2018510970A JP7063803B2 (ja) 2015-08-28 2016-08-26 局所脂肪の減少に用いる医薬組成物およびその用途
US15/754,363 US20180243211A1 (en) 2015-08-28 2016-08-26 A pharmaceutical composition for reducing local fat and uses thereof
SG11201801111RA SG11201801111RA (en) 2015-08-28 2016-08-26 Pharmaceutical composition used for reducing localised fat and use of pharmaceutical composition
ES16840922T ES3041835T3 (en) 2015-08-28 2016-08-26 Pharmaceutical composition used for reducing localised fat and use of pharmaceutical composition
BR112018003892-0A BR112018003892A2 (pt) 2015-08-28 2016-08-26 ?composição farmacêutica e método para a redução da gordura?
EP16840921.7A EP3381473A4 (en) 2015-08-28 2016-08-26 PHARMACEUTICAL COMPOSITION FOR REDUCING LOCALIZED FAT AND USE OF THE PHARMACEUTICAL COMPOSITION
US15/754,429 US10610496B2 (en) 2015-08-28 2016-08-26 Pharmaceutical composition for reducing local fat and uses thereof
CN201680046431.9A CN109069655B (zh) 2015-08-28 2016-08-26 用于减少局部脂肪的医药组成物及其用途
CA2995158A CA2995158C (en) 2015-08-28 2016-08-26 A pharmaceutical composition for reducing local fat and uses thereof
FIEP16840922.5T FI3381451T3 (fi) 2015-08-28 2016-08-26 Lääkekoostumus käytettäväksi paikallisen rasvan vähentämisessä ja lääkekoostumuksen käyttö
KR1020207007953A KR102240221B1 (ko) 2015-08-28 2016-08-26 국부 지방을 감소시키기 위해 사용되는 제약 조성물 및 그의 용도
TW105127452A TWI604859B (zh) 2015-08-28 2016-08-26 用於減少局部脂肪的醫藥組成物及其用途
PCT/IB2016/055102 WO2017037594A2 (zh) 2015-08-28 2016-08-26 用于减少局部脂肪的医药组成物及其用途
PCT/IB2016/055101 WO2017037593A2 (zh) 2015-08-28 2016-08-26 用于减少局部脂肪的医药组成物及其用途
KR1020187008138A KR102107917B1 (ko) 2015-08-28 2016-08-26 국부 지방을 감소시키기 위해 사용되는 제약 조성물 및 그의 용도
AU2016314545A AU2016314545C1 (en) 2015-08-28 2016-08-26 Pharmaceutical composition used for reducing localised fat and use of pharmaceutical composition
PT168409225T PT3381451T (pt) 2015-08-28 2016-08-26 Composição farmacêutica utilizada para reduzir gordura localizada e utilização da composição farmacêutica
CN201680046418.3A CN108697668B (zh) 2015-08-28 2016-08-26 用于减少局部脂肪的医药组成物及其用途
BR112018003877-6A BR112018003877A2 (pt) 2015-08-28 2016-08-26 “composição farmacêutica, método para reduzir a gordura subcutânea, método para a redução de peso corporal e uso de uma composição farmacêutica”
JP2018510971A JP7063804B2 (ja) 2015-08-28 2016-08-26 局所脂肪減少に用いられる医薬組成物及びその用途
KR1020187008137A KR20180037058A (ko) 2015-08-28 2016-08-26 국부 지방을 감소시키기 위해 사용되는 제약 조성물 및 그의 용도
DK16840922.5T DK3381451T3 (da) 2015-08-28 2016-08-26 Farmaceutisk sammensætning brugt til at reducere lokaliseret fedt samt brug af den farmaceutiske sammensætning
US15/440,469 US10226503B2 (en) 2014-08-28 2017-02-23 Plant extract composition for reducing topical fat and promoting weight loss as well as applications thereof
MX2021010359A MX2021010359A (es) 2015-08-28 2018-02-27 Una composicion farmaceutica para reducir la grasa localizada y sus usos.
CONC2018/0003424A CO2018003424A2 (es) 2015-08-28 2018-03-27 Composición farmacéutica y formulación de inyección subcutánea que comprende micelas y curcuminoides para reducir la grasa localizada y método para preparar la misma”
AU2019201635A AU2019201635B2 (en) 2014-08-28 2019-03-08 Composition for reducing local fat and body weight, and pharmaceuticals and use thereof
AU2019246808A AU2019246808B2 (en) 2015-08-28 2019-10-09 A pharmaceutical composition for reducing localized fat and uses thereof
AU2019280037A AU2019280037B2 (en) 2015-08-28 2019-12-12 Pharmaceutical composition used for reducing localised fat and use of pharmaceutical composition
US16/749,266 US11433034B2 (en) 2015-08-28 2020-01-22 Pharmaceutical composition for reducing local fat and uses thereof
US16/749,347 US11318110B2 (en) 2015-08-28 2020-01-22 Pharmaceutical composition for reducing local fat and uses thereof
JP2020081316A JP7095903B2 (ja) 2015-08-28 2020-05-01 局所脂肪減少に用いられる医薬組成物及びその用途
JP2020081311A JP7054540B2 (ja) 2015-08-28 2020-05-01 局所脂肪の減少に用いる医薬組成物およびその用途
AU2021202349A AU2021202349B2 (en) 2015-08-28 2021-04-19 A pharmaceutical composition for reducing localized fat and uses thereof
US17/875,679 US12357588B2 (en) 2015-08-28 2022-07-28 Pharmaceutical composition for reducing local fat and uses thereof
US18/169,585 US20230190674A1 (en) 2015-08-28 2023-02-15 Methods for Reduction of Body Weight with Subcutaneous Formulations

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201462042864P 2014-08-28 2014-08-28
US62/042,864 2014-08-28

Related Child Applications (4)

Application Number Title Priority Date Filing Date
US14/914,971 A-371-Of-International US9987325B2 (en) 2014-08-28 2015-08-28 Plant extract composition for reducing localized fat and promoting weight loss as well as application thereof
US15/754,429 Continuation US10610496B2 (en) 2015-08-28 2016-08-26 Pharmaceutical composition for reducing local fat and uses thereof
PCT/IB2016/055102 Continuation WO2017037594A2 (zh) 2015-08-28 2016-08-26 用于减少局部脂肪的医药组成物及其用途
US15/440,469 Continuation-In-Part US10226503B2 (en) 2014-08-28 2017-02-23 Plant extract composition for reducing topical fat and promoting weight loss as well as applications thereof

Publications (1)

Publication Number Publication Date
WO2016029870A1 true WO2016029870A1 (zh) 2016-03-03

Family

ID=55398772

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/088340 Ceased WO2016029870A1 (zh) 2014-08-28 2015-08-28 用于减少局部脂肪与减少体重的组合物及其医药品与应用

Country Status (18)

Country Link
US (1) US9987325B2 (zh)
EP (2) EP3811935A1 (zh)
JP (1) JP6473505B2 (zh)
KR (2) KR101935219B1 (zh)
CN (1) CN106604724B (zh)
AU (2) AU2015309353B2 (zh)
CA (1) CA2959185C (zh)
CY (1) CY1125384T1 (zh)
DK (1) DK3187178T3 (zh)
ES (1) ES2924879T3 (zh)
HU (1) HUE059878T2 (zh)
MX (2) MX385905B (zh)
PL (1) PL3187178T3 (zh)
PT (1) PT3187178T (zh)
SG (1) SG11201701476PA (zh)
SI (1) SI3187178T1 (zh)
TW (1) TWI580422B (zh)
WO (1) WO2016029870A1 (zh)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109640969A (zh) * 2016-08-26 2019-04-16 康霈生技股份有限公司 用于減少体重的皮下注射剂及其用途
RU2753507C2 (ru) * 2015-11-20 2021-08-17 Калиуэй Байофармасьютикалз Ко., Лтд. Композиция подкожной инъекции для снижения массы тела и ее применения
US11318110B2 (en) 2015-08-28 2022-05-03 Caliway Biopharmaceuticals Co., Ltd. Pharmaceutical composition for reducing local fat and uses thereof
WO2025024299A1 (en) * 2023-07-21 2025-01-30 Arizona Board Of Regents On Behalf Of Arizona State University Resveratrol and quercetin-loaded nanoparticles and methods of use thereof

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160129068A1 (en) * 2014-11-10 2016-05-12 Caliway Biomedical Co., Ltd. Composition of plant extract and its pharmaceutical composition and application thereof
WO2018144911A1 (en) * 2017-02-02 2018-08-09 Golo Llc Formulations for weight loss and methods of use
KR102093872B1 (ko) 2017-07-03 2020-03-27 진호성 지방제거용 주사제 조성물 및 이의 제조방법
CN118286185B (zh) * 2024-03-14 2025-01-21 南京大学 一种用于局部减脂的双层可溶性微针贴片及其制备方法和应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101095665A (zh) * 2006-06-27 2008-01-02 中国科学院上海生命科学研究院 Sirt1在预防、控制或治疗肥胖中的用途
CN101632655A (zh) * 2009-08-04 2010-01-27 南京大渊美容保健有限公司 延缓衰老的白藜芦醇和生物类黄酮营养组合物
CN102357226A (zh) * 2007-08-07 2012-02-22 北京北大维信生物科技有限公司 中草药姜黄提取物在制备减肥降脂药物或制备具有脂肪酶活性抑制作用的药物中的应用

Family Cites Families (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6475530B1 (en) 2000-05-31 2002-11-05 Eric H. Kuhrts Methods and compositions for producing weight loss
US20040146539A1 (en) * 2003-01-24 2004-07-29 Gupta Shyam K. Topical Nutraceutical Compositions with Selective Body Slimming and Tone Firming Antiaging Benefits
WO2005065667A2 (en) 2003-12-29 2005-07-21 President And Fellows Of Harvard College Compositions for treating or preventing obesity and insulin resistance disorders
ITFI20050031A1 (it) 2005-02-21 2006-08-22 Stefan Coccoloni Una composizione farmaceutica atta a prevenire l'invecchiamento e l'insorgere di malattie vascolari,neoplastiche,cutanee e dell'apparato pilifero
WO2007041276A2 (en) 2005-09-29 2007-04-12 New Chapter, Inc. Methods for modulating apoptosis, cellgrowth, and protein expression with herbal compositions
JP2007131603A (ja) 2005-11-14 2007-05-31 Kaneka Corp Ｌ−カルニチン合成系酵素遺伝子の転写促進用組成物
US20100015262A1 (en) 2006-03-31 2010-01-21 Regina Goralczyk Novel use of compounds and combinations of compounds for improving the physical appearance
US7977319B1 (en) 2006-04-03 2011-07-12 Scott David Levine Ultra-high fiber supplement and method of reducing weight, cardiovascular risks and ingested toxins
KR101665042B1 (ko) 2008-04-18 2016-10-11 리타 파마슈티컬스 잉크. 소염성 골격군을 포함하는 화합물 및 사용 방법
AU2009307753A1 (en) 2008-10-22 2010-04-29 Metaproteomics, Llc Novel mitochondrial uncoupling methods and compositions for enhancing adipocyte thermogenesis
JP5594819B2 (ja) 2009-12-22 2014-09-24 キリンホールディングス株式会社 脂質代謝改善用組成物
SI2588101T1 (sl) 2010-07-02 2015-01-30 Helix Biomedix, Inc. Derivati N-acil amino kisline za zdravljenje koĹľnih stanj, kot je celulitis
US8815310B2 (en) 2011-01-10 2014-08-26 Morteza Naghavi Compositions for boosting metabolism, assisting weight loss, and promoting cardiovascular health
WO2013100111A1 (ja) 2011-12-27 2013-07-04 油田 正樹 サーチュイン活性化剤
US8496979B1 (en) 2012-02-02 2013-07-30 Reliv International, Inc. Caffeine-free dietary supplements for increasing energy and methods of administering the same
US8652518B2 (en) * 2012-04-15 2014-02-18 Jahahreeh Finley Compositions and methods for the prevention and treatment of diseases or conditions associated with oxidative stress, inflammation, and metabolic dysregulation
US9211298B2 (en) 2012-11-16 2015-12-15 Song Gao Compositions containing enriched natural crocin and/or crocetin, and their therapeutic or nutraceutical uses
US10537605B2 (en) 2014-08-28 2020-01-21 Caliway Biopharmaceuticals Co., Ltd. Composition of plant extract and its pharmaceutical composition and application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101095665A (zh) * 2006-06-27 2008-01-02 中国科学院上海生命科学研究院 Sirt1在预防、控制或治疗肥胖中的用途
CN102357226A (zh) * 2007-08-07 2012-02-22 北京北大维信生物科技有限公司 中草药姜黄提取物在制备减肥降脂药物或制备具有脂肪酶活性抑制作用的药物中的应用
CN101632655A (zh) * 2009-08-04 2010-01-27 南京大渊美容保健有限公司 延缓衰老的白藜芦醇和生物类黄酮营养组合物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3187178A4 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11318110B2 (en) 2015-08-28 2022-05-03 Caliway Biopharmaceuticals Co., Ltd. Pharmaceutical composition for reducing local fat and uses thereof
US11433034B2 (en) 2015-08-28 2022-09-06 Caliway Biopharmaceuticals Co., Ltd. Pharmaceutical composition for reducing local fat and uses thereof
US12357588B2 (en) 2015-08-28 2025-07-15 Caliway Biopharmaceuticals Co., Ltd. Pharmaceutical composition for reducing local fat and uses thereof
RU2753507C2 (ru) * 2015-11-20 2021-08-17 Калиуэй Байофармасьютикалз Ко., Лтд. Композиция подкожной инъекции для снижения массы тела и ее применения
CN109640969A (zh) * 2016-08-26 2019-04-16 康霈生技股份有限公司 用于減少体重的皮下注射剂及其用途
WO2025024299A1 (en) * 2023-07-21 2025-01-30 Arizona Board Of Regents On Behalf Of Arizona State University Resveratrol and quercetin-loaded nanoparticles and methods of use thereof

Also Published As

Publication number Publication date
JP6473505B2 (ja) 2019-02-20
US20170157193A1 (en) 2017-06-08
KR20170043657A (ko) 2017-04-21
EP3187178B1 (en) 2022-06-08
CY1125384T1 (el) 2025-05-09
KR101859345B1 (ko) 2018-05-18
TW201707695A (zh) 2017-03-01
KR20180052785A (ko) 2018-05-18
AU2015309353A1 (en) 2017-03-16
EP3187178A1 (en) 2017-07-05
US9987325B2 (en) 2018-06-05
MX2021010638A (es) 2021-09-28
AU2015309353B2 (en) 2018-12-20
PT3187178T (pt) 2022-06-21
MX385905B (es) 2025-03-11
EP3811935A1 (en) 2021-04-28
CN106604724B (zh) 2020-05-26
CA2959185A1 (en) 2016-03-03
EP3187178A4 (en) 2018-02-14
JP2017525772A (ja) 2017-09-07
SI3187178T1 (sl) 2022-10-28
CA2959185C (en) 2021-03-02
AU2019201635B2 (en) 2021-01-28
SG11201701476PA (en) 2017-03-30
ES2924879T3 (es) 2022-10-11
CN106604724A (zh) 2017-04-26
KR101935219B1 (ko) 2019-01-03
TWI580422B (zh) 2017-05-01
PL3187178T3 (pl) 2022-11-21
MX2017002585A (es) 2017-05-25
DK3187178T3 (da) 2022-08-22
AU2019201635A1 (en) 2019-04-04
HUE059878T2 (hu) 2023-01-28

Similar Documents

Publication Publication Date Title
TWI580422B (zh) Compositions for reducing local fat and weight loss, and pharmaceuticals and applications thereof
KR101706549B1 (ko) 히알루로니다제를 포함하는 국소지방 제거용 주사제 조성물
US9511016B2 (en) Topical composition for treating pain
US10226503B2 (en) Plant extract composition for reducing topical fat and promoting weight loss as well as applications thereof
KR20140129370A (ko) 당뇨병성 궤양 치료를 위한 약제제조를 위한 약학 조성물의 용도
SG176206A1 (en) Methods for administration and formulations for the treatment of regional adipose tissue
KR20180100309A (ko) 데옥시콜산 및 이의 염을 사용한 축적된 지방의 치료 방법
EP3194025A1 (en) Methods for preventing or treating osteoarthritis
US20210220260A1 (en) Topical injectable composition
JP2012519189A (ja) 医学的美容脂肪萎縮方法
CN111297910B (zh) 五谷虫在制备预防和治疗乳腺增生药物中的应用
CN101310750B (zh) 一种治疗软组织损伤的外用药物及其制备方法
US10960011B2 (en) Compositions for the treatment of ischemic ulcers and stretch marks
US20220287862A1 (en) Topical treatment for anorectal disorders with and without seat cushion
US20210322418A1 (en) Methods and compositions for promoting wound healing in a subject suffering from ectodermal dysplasias
KR20180070708A (ko) 상처 치유를 위한 플라스미노겐 투여 요법
CN120771143A (zh) 穿心莲内酯在治疗关节置换术后淋巴水肿中的应用
Numan et al. Evaluation of the clinical use of silymarin in knee osteoarthritis: application of the dual inhibitory concept of cyclooxygenase and 5-lipoxygenase
KR20230174698A (ko) 대마종자유를 유효성분으로 함유하는 통증 치료용 약학적 조성물
Argilashki et al. CURCUMIN FOR EXTERNAL APPLICATION-CHALLENGES, SOLUTIONS AND PROSPECTS.
KR20240055438A (ko) 개선된 지방 분해 효과를 가지는 지방 분해용 조성물 및 이를 함유하는 주사 제제
CN116785270A (zh) 丹参素钠在制备治疗慢性疼痛药物、保健品中的应用
CN111632047A (zh) 木犀草素在预防和治疗子宫内膜异位症药物中的应用

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 14914971

Country of ref document: US

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15836003

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2959185

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: MX/A/2017/002585

Country of ref document: MX

ENP Entry into the national phase

Ref document number: 2017530388

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2015309353

Country of ref document: AU

Date of ref document: 20150828

Kind code of ref document: A

REEP Request for entry into the european phase

Ref document number: 2015836003

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2015836003

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 20177008265

Country of ref document: KR

Kind code of ref document: A