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WO2017037593A2 - 用于减少局部脂肪的医药组成物及其用途 - Google Patents

用于减少局部脂肪的医药组成物及其用途 Download PDF

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Publication number
WO2017037593A2
WO2017037593A2 PCT/IB2016/055101 IB2016055101W WO2017037593A2 WO 2017037593 A2 WO2017037593 A2 WO 2017037593A2 IB 2016055101 W IB2016055101 W IB 2016055101W WO 2017037593 A2 WO2017037593 A2 WO 2017037593A2
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WO
WIPO (PCT)
Prior art keywords
resveratrol
pharmaceutical composition
fat
drug
weight
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/IB2016/055101
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English (en)
French (fr)
Other versions
WO2017037593A3 (zh
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
Caliway (usa) Co Ltd
Original Assignee
Caliway Biopharmaceuticals Co Ltd
Caliway (usa) 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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=58186932&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2017037593(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from PCT/CN2015/088340 external-priority patent/WO2016029870A1/zh
Priority to CN201680046431.9A priority Critical patent/CN109069655B/zh
Priority to US15/754,363 priority patent/US20180243211A1/en
Priority to KR1020187008137A priority patent/KR20180037058A/ko
Priority to CA2995155A priority patent/CA2995155C/en
Priority to MX2018002461A priority patent/MX387266B/es
Priority to BR112018003892-0A priority patent/BR112018003892A2/pt
Priority to CN202411262786.4A priority patent/CN119157850A/zh
Priority to KR1020207007953A priority patent/KR102240221B1/ko
Priority to AU2016314545A priority patent/AU2016314545C1/en
Priority to JP2018510971A priority patent/JP7063804B2/ja
Application filed by Caliway Biopharmaceuticals Co Ltd, Caliway (usa) Co Ltd filed Critical Caliway Biopharmaceuticals Co Ltd
Priority to EP16840921.7A priority patent/EP3381473A4/en
Publication of WO2017037593A2 publication Critical patent/WO2017037593A2/zh
Priority to TW106128816A priority patent/TWI667044B/zh
Priority to EP17843043.5A priority patent/EP3505168A1/en
Priority to KR1020197008320A priority patent/KR20190040305A/ko
Priority to CN201780050055.5A priority patent/CN109640969A/zh
Priority to US16/327,466 priority patent/US10716824B2/en
Priority to JP2019510854A priority patent/JP2019528297A/ja
Priority to RU2019108198A priority patent/RU2753507C2/ru
Priority to PCT/IB2017/055129 priority patent/WO2018037384A1/zh
Priority to CA3033041A priority patent/CA3033041A1/en
Anticipated expiration legal-status Critical
Publication of WO2017037593A3 publication Critical patent/WO2017037593A3/zh
Priority to AU2019246808A priority patent/AU2019246808B2/en
Priority to US16/926,631 priority patent/US20200338152A1/en
Priority to AU2021202349A priority patent/AU2021202349B2/en
Priority to US18/169,585 priority patent/US20230190674A1/en
Ceased legal-status Critical Current

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    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
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    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
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    • A61K36/18—Magnoliophyta (angiosperms)
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    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/86—Polyethers
    • 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
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
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    • A61Q19/06—Preparations for care of the skin for countering cellulitis

Definitions

  • the present invention relates to a pharmaceutical composition for reducing local fat, and more particularly to a pharmaceutical composition comprising a plurality of drug-containing micelles and resveratrol coated in a drug-containing micelle, and The pharmaceutical composition is used to reduce localized fat.
  • the method of reducing local fat is mainly liposuction.
  • the liposuction process causes serious damage to nerves, blood vessels, and other body tissues, and has infection, large amount of bleeding, excessive anesthesia, and prevention. Fat embolism and the risk of death from anesthesia allergy.
  • it is also prone to severe redness, severe pain, recovery period of up to 3 months to more than 6 months, and unevenness of liposuction. Therefore, statistics show that although most people want to use liposuction to improve local subcutaneous fat accumulation or body curve, the actual number of people who have undergone liposuction surgery is less than 40%, indicating that most consumers who want to improve the body curve or reduce local fat. , will be abandoned by the side effects of liposuction and postoperative pain or risk.
  • the present invention provides a pharmaceutical composition for reducing localized fat, comprising a plurality of drug-containing micelles formed by a surfactant, and white coated in the drug-containing micelles Resveratrol.
  • the pharmaceutical composition for reducing local fat can reduce fat at the application site, and has the advantages of high stability, high adipose tissue bioavailability, low side effects, and sustained release.
  • the invention can promote the apoptotic reaction (apoptosis) of the fat cells at the application site, and achieve the purpose of reducing the local fat at the application site.
  • the invention can greatly improve the conventional technology to make the peripheral cells necrosis (necrosis;), and the adverse reaction of inflammation Should be side effects, and the effect of local fat reduction is significantly better than other non-surgical reduction of local fat pharmaceutical composition.
  • the present invention is suitable for application to a site requiring reduction of subcutaneous fat by transdermal absorption, such as direct injection, subcutaneous implantation, implantable infusion, ointment or patch, without any intervention or assistance of surgery or instrumentation.
  • the subcutaneous fat layer is applied to the localized part by subcutaneous fat injection.
  • injecting dosage pharmaceutical composition of the present invention include, but are not limited to injection, or injection of 1 J Qi Qi powder ll (powder for injection, or powder for solution for injection).
  • the topical fat referred to in the present invention includes, but is not limited to, the waist, the abdomen, the legs, the arms, the chin, and the face.
  • resveratrol refers to resveratrol obtained from natural plant extract or commercially available.
  • the resveratrol has a purity of from 90% to 100%.
  • the green tea extract refers to a mixture of green tea components extracted by any solvent and any extraction method, a commercially available green tea extract, and any one containing at least 45% by weight. ;) a mixture of epigallocatechin gallate (EGCG), or a commercially available epigallocatechin gallate.
  • EGCG epigallocatechin gallate
  • a micelle refers to a micro-structure formed by a surfactant having a hydrophilic end and a lipophilic end (lipophilic end), and the surfactant is The micro-structure is formed with the hydrophilic end outward and the lipophilic end (lipophilic end) inward.
  • the microstructure is a spherical, spheroidal, or other microstructured structure.
  • the drug-containing microsphere refers to a resveratrol-containing microcapsule; that is, the drug-containing microsphere refers to a microcapsule coated or containing resveratrol.
  • the second liposoluble drug microsphere refers to a microcell containing a fat-soluble drug other than resveratrol. That is, the second liposoluble drug microsphere refers to a microcapsule coated or containing other fat-soluble drug.
  • the other lipophilic drug means that at least a lipophilic drug than curcumin (Cur CU min), quercetin (q Ue r C etin), puerarin (puerari n), and the other resveratrol Or a combination thereof; or, other fat-soluble drugs refer to fat-soluble drugs other than resveratrol.
  • the water-soluble drug refers to green tea extract, epigallocatechin gallate, epicchinchin, epicchin gallate, Epigallocatechin, Gallocatechin gallate ⁇ Gallocatechin; Catechin gallate; Catechin; Epigallocatechin gallate (EGCG), caffeine (Caffeine), carnitine (Carnitine; also known as carnitine or carnitine), L-carnitine; At least one or a combination of Synephrine; Chlorogenic acid, and other water soluble drugs.
  • the term "state in which no precipitate is produced” means any precipitate which is not visible to the human eye, that is, without the use of an artificial device.
  • the invention provides a pharmaceutical composition for reducing local fat, comprising:
  • the drug-containing micelle is a micro-junction formed by a pharmaceutically acceptable surfactant.
  • the surfactant has a hydrophilic-lipophilic balance value (HLB value;) of more than 10.
  • the drug-containing micelles have a particle size of 3 250 nm.
  • the drug-containing micelles have a particle size of 5 to 50 nm.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable aqueous solution, and the drug-containing micelles are uniformly distributed in the pharmaceutically acceptable aqueous solution.
  • the pharmaceutically acceptable aqueous solution is water for injection, water for injection, or physiological saline.
  • the surfactant is a nonionic surfactant.
  • the nonionic surfactant is polysorbate 80 (T ween 80), 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15), polyoxyethylene castor oil (polyoxyethylene castor oil) At least one or a combination of derivatives;), and other nonionic surfactants.
  • the polyoxyethylene castor oil derivative is a polyoxyethylene 35 castor oil (Cremophor ELP;), polyoxyethylene 40 hydrogenated castor oil (Cremophor RH 40), and other polyoxyethylene castor oil derived At least one or a combination thereof.
  • the weight ratio of resveratrol to the surfactant is from 1:4 to 1:500.
  • the weight ratio of resveratrol to the surfactant is from 1:5 to 1:200.
  • the weight ratio of resveratrol to the surfactant is from 1:8 to 1:80.
  • the pharmaceutical composition is maintained at an accelerated stability test under conditions of a temperature of 25 ° C ⁇ 2 ° C, a relative humidity of RH 60% ⁇ 5%, and direct light exposure. No precipitate is produced for at least 24 hours.
  • the pharmaceutical composition is maintained at an accelerated stability test under conditions of a temperature of 25 ° C ⁇ 2 ° C, a relative humidity of RH 60% ⁇ 5%, and direct light exposure. No sediment is produced for at least 6 months.
  • the concentration of resveratrol in the pharmaceutical composition is from 0.2 to 166.7 mg/mL.
  • the concentration of resveratrol in the pharmaceutical composition is from 2.5 to 60 mg/mL.
  • the pharmaceutical composition further comprises a green tea extract, and the green tea extract is dissolved in the pharmaceutically acceptable aqueous solution; wherein the green tea extract comprises:
  • a first green tea extract component wherein the first green tea extract component is epigallocatechin gallate (EGCG).
  • EGCG epigallocatechin gallate
  • the concentration of epigallocatechin gallate in the pharmaceutical composition is from 0.25 to 300. In a preferred embodiment, epigallocatechin gallate is in the pharmaceutical composition. The concentration is 1 200. In a preferred embodiment, the table has the content of gallocatechin gallate, based on the total weight of the green tea extract. In a preferred embodiment, the weight ratio of the resveratrol to the green tea extract is from 30:1 to 1:30.
  • the weight ratio of the resveratrol to the green tea extract is from 20:1 to 1:20.
  • the weight ratio of the resveratrol to the green tea extract is from 10:1 to 1:10.
  • the total weight of the resveratrol and the green tea extract is one unit of weight, and the surfactant has a weight of 0.24 70 units by weight; or is the resveratrol
  • the weight ratio of the total weight of the green tea extract to the surfactant is from 4:1 to 1:70.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable aqueous solution and a second liposoluble drug microcapsule, the second liposoluble drug cell being uniformly distributed in the pharmaceutically acceptable aqueous solution in.
  • the second fat-soluble drug microcell is another micro-structure formed by the second surfactant, and another fat-soluble drug (or a second fat-soluble drug) is coated on the second fat-soluble drug microcapsule in.
  • the second surfactant has a hydrophilic-lipophilic balance value (HLB value) greater than 10.
  • the second surfactant is a nonionic surfactant.
  • the nonionic surfactant is polysorbate 80 (T ween 80),
  • polyoxyethylene castor oil derivatives (polyoxyethylene castor oil derivatives;), and at least one of other nonionic surfactants or combinations thereof.
  • the polyoxyethylene castor oil derivative is a polyoxyethylene 35 castor oil (Cremophor ELP;), polyoxyethylene 40 hydrogenated castor oil (Cremophor RH 40), and other polyoxyethylene castor oil derived At least one or a combination thereof.
  • the fat-soluble drug is quercetin, synephrine, puerarin, curcumin (C UrCU mi n ), and resveratrol At least one or a combination of the fat-soluble drugs.
  • the weight ratio of the resveratrol to the second fat-soluble drug is 30 1 to 1 20. In a preferred embodiment, the resveratrol and the second fat-soluble drug are The weight ratio is 20 1 -1. In a preferred embodiment, the weight ratio of the resveratrol to the second fat-soluble drug is 15 1 -1. In a preferred embodiment, the pharmaceutical composition further comprises A pharmaceutically acceptable aqueous solution and a water soluble drug.
  • the water soluble drug is green tea extract, epigallocatechin gallate, epicchin, Epicachin gallate, Epigallocatechin, Gallocatechin gallate, Gallocatechin, catechin gallate (Catechin) Gallate;), catechin (Catechin;), epigallocatechin gallate (EGCG;), caffeine (Caffeine;), carnitine (Carnitine; also known as carnitine or carni Ting), L-carni (L-carni Tine;), Synephrine;, chlorogenic acid At least one or combination of acid and other water soluble drugs.
  • the weight ratio of the resveratrol to the water-soluble drug is from 20:1 to 1:30.
  • the weight ratio of the resveratrol to the water-soluble drug is from 15:1 to 1:20.
  • the weight ratio of the resveratrol to the water-soluble drug is from 10:1 to 1:15.
  • the water-soluble drug is epigallocatechin gallate
  • the concentration of epigallocatechin gallate in the pharmaceutical composition is from 0.25 to 300 mg/mL.
  • the water-soluble drug is epigallocatechin gallate
  • the concentration of epigallocatechin gallate in the pharmaceutical composition is from 1 to 200 mg/mL.
  • the water soluble drug is a green tea extract
  • the weight ratio of the resveratrol to the green tea extract is from 30:1 to 1:30.
  • the water soluble drug is a green tea extract
  • the weight ratio of the resveratrol to the green tea extract is from 20:1 to 1:20.
  • the water soluble drug is a green tea extract
  • the weight ratio of the resveratrol to the green tea extract is from 10:1 to 1:10.
  • the pharmaceutical composition further comprises a cosolvent to increase the solubility of the drug.
  • the co-solvent is at least one of polyethylene glycol, propylene glycol, ethanol, and other co-solvents, or a combination thereof.
  • the polyethylene glycol is polyethylene glycol 200 (PEG 200), polyethylene glycol 400 (PEG 400), polyethylene glycol 600 (PEG 600), and other polyethylene glycols. At least one of or a combination thereof.
  • the pharmaceutical composition further comprises a suspending agent (also known as a suspending agent;) for reducing the rate of sedimentation of the drug or micelle.
  • a suspending agent also known as a suspending agent;
  • the suspending agent is sodium alginate, glycerol, carboxymethylcellulose sodium, mannitol, and other suspending agents. At least one or a combination thereof.
  • the pharmaceutical composition further comprises oil phase excipients for increasing the stability of the pharmaceutical composition and the solubility of the drug.
  • the oil phase excipient is at least one or a combination of an unsaturated fatty acid, glycerol, triglyceride, and other oil phase excipients.
  • the unsaturated fatty acid is oleic acid, castor oil, sesame oil, cottonseed oil, soybean oil, red At least one or a combination of safflower oil, corn oil, and other unsaturated fatty acids.
  • the triglyceride is at least one of a medium chain triglycerides ⁇ and other triglycerides or a combination thereof.
  • the pharmaceutically acceptable aqueous solution comprises a local anesthetic.
  • the local anesthetic is amide, para-aminobenzamine, and amino ether. One less or a combination thereof.
  • the amide is Dibucaine, Lidocaine, Mepivacaine HC1, Bupivacine HC1 At least one or a combination of pyrrocaine HCl, prilocaine HCl, Digammacaine, and Oxethazaine.
  • the p-aminobenzamine lipid is at least one of or a combination of butacaine (Butacaine;), dimethocaine, and tococaine (Tutocaine) .
  • the amino ether is at least one of quinicaine (Quinisocaine;) and pramocaine or a combination thereof.
  • the pharmaceutically acceptable aqueous solution contains an antioxidant.
  • the antioxidant is beta-carotene, lutein, lycopene, bilirubin, vitamin A (vitamin A) ;), vitamin C (vitamin C; also known as ascorbic acid, ie, vitamin E), uric acid, nitric oxide, nitroxide, pyruvate (pyruvate), catalase; superoxide dismutase; glutathione peroxidases; N-acetylcysteine At least one of cysteine;), and naringenin or a combination thereof.
  • the present invention further provides a subcutaneous fat layer injection or a hypodermic injection for reducing the amount of local subcutaneous fat, comprising - a pharmaceutically acceptable aqueous solution;
  • the drug-containing microcapsule is a micro-structure formed by a pharmaceutically acceptable surfactant, and the hydrophilic-lipophilic balance value (HLB value) of the surfactant is greater than 10.
  • the amount of topical subcutaneous fat is the amount of subcutaneous fat at the site of application.
  • the drug-containing micelles have a particle size of from 3 to 250 nm.
  • the drug-containing micelles have a particle size of 5 to 50 nm.
  • the pharmaceutically acceptable aqueous solution is water for injection, aqueous solution for injection, or physiological saline.
  • the surfactant is a nonionic surfactant.
  • the nonionic surfactant is polysorbate 80 (Tween 80),
  • At least one of 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15), polyoxyethylene castor oil derivatives, and other nonionic surfactants or combinations thereof.
  • the polyoxyethylene castor oil derivative is polyoxyethylene 35 castor oil (Cremophor ELP;), polyoxyethylene 40 hydrogenated castor oil (Cr e m O ph O r RH 40), and others At least one of polyoxyethylene castor oil derivatives Or a combination thereof.
  • the weight ratio of resveratrol to the surfactant is from 1:4 to 1:500.
  • the weight ratio of resveratrol to the surfactant is from 1:5 to 1:200.
  • the weight ratio of resveratrol to the surfactant is from 1:8 to 1:80.
  • the concentration of resveratrol in the subcutaneous fat layer injection or subcutaneous injection is
  • the concentration of resveratrol in the subcutaneous fat layer injection or subcutaneous injection is
  • the subcutaneous fat layer injection or subcutaneous injection further comprises a green tea extract, and the green tea extract is dissolved in the pharmaceutically acceptable aqueous solution; wherein the green tea extract comprises:
  • first green tea extract component is epigallocatechin gallate
  • EGCG epigallocatechin gallate
  • the concentration of epigallocatechin gallate in the subcutaneous fat layer injection or subcutaneous injection is 0.25 to 300 mg/mL.
  • the concentration of epigallocatechin gallate in the subcutaneous fat layer injection or subcutaneous injection is from 1 to 200 mg/mL.
  • the epigallocatechin gallate is present in an amount of from 45 to 100% by weight based on 100% by weight of the total of the green tea extract.
  • the weight ratio of the resveratrol to the green tea extract is from 30:1 to 1:30.
  • the weight ratio of the resveratrol to the green tea extract is from 20:1 to 1200.
  • the weight ratio of the resveratrol to the green tea extract is from 10:1 to 1 10 .
  • the total weight of the resveratrol and the green tea extract is one unit of weight, and the surfactant has a weight of 0.24 70 units by weight; or is the resveratrol
  • the weight ratio of the total weight of the green tea extract to the surfactant is from 4:1 to 1:70.
  • the application site of the application site is: 0.2 per square centimeter injection.
  • the application site of the application site 0.4 injection per square centimeter
  • the application site of the application site is 0.240 mg per kg.
  • the application site of the application site is 0.4 to 20 mg per kg.
  • the application frequency is from 1 to 12 administrations per interval from 1 day to 30 days. In a preferred embodiment, the application frequency is from 1 to 8 times per interval from 1 day to 21 days.
  • the subcutaneous fat layer injection or subcutaneous injection further comprises a second fat-soluble drug microcapsule, and the second fat-soluble drug microcell is uniformly distributed in the pharmaceutically acceptable aqueous solution. in.
  • the second fat-soluble drug micelle is a micro-structure formed by another surfactant, and the other fat-soluble drug is coated in the second fat-soluble drug micelle.
  • the hydrophilic-lipophilic balance of the other surfactant is greater than 10.
  • the additional surfactant is a nonionic surfactant.
  • the nonionic surfactant is polysorbate 80 (T ween 80),
  • At least one of 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15), polyoxyethylene castor oil derivatives, and other nonionic surfactants or combinations thereof.
  • the polyoxyethylene castor oil derivative is a polyoxyethylene 35 castor oil (Cremophor ELP;), polyoxyethylene 40 hydrogenated castor oil (Cremophor RH 40), and other polyoxyethylene castor oil derived At least one or a combination thereof.
  • the fat-soluble drug is at least one or a combination of curcumin, quercetin, puerarin, and other fat-soluble drugs other than resveratrol.
  • the pharmaceutically acceptable aqueous solution further comprises a water soluble drug.
  • the water-soluble drug is green tea extract, epigallocatechin gallate, epicchinchin, epicatechin gallate, and epicatechin gallate. ;), Epigallocatechin, Gallocatechin gallate ⁇ Gallocatechin; Catechin gallate; Catechin ;), epigallocatechin gallate (EGCG), caffeine (Caffeine), carnitine (Carnitine; also known as carnitine or carnitine), L-carnitine; At least one or a combination of, Synephrine; Chlorogenic acid, and other water soluble drugs.
  • the pharmaceutically acceptable aqueous solution comprises a local anesthetic.
  • the local anesthetic is at least one of an amide, a p-aminobenzamide, and an amino ether, or a combination thereof.
  • the amide is Dibucaine, Lidocaine, Mepivacaine HC1, Bupivacine HC1 At least one or a combination of pyrrocaine HCl, prilocaine HCl, Digammacaine, and Oxethazaine.
  • the p-aminobenzamide is at least one or a combination of butacaine (Butacaine;), dimethocaine, and Tutocaine.
  • the amino ether is at least one of quinicaine (Quinisocaine;) and pramocaine or a combination thereof.
  • the pharmaceutically acceptable aqueous solution contains an antioxidant.
  • the antioxidant is beta-carotene, lutein, lycopene, bilirubin, vitamin A (vitamin A) ;), vitamin C (vitamin C; also known as ascorbic acid, ie, vitamin E), uric acid, nitric oxide, nitroxide, pyruvate (pyruvate), catalase; superoxide dismutase (superoxide) At least one of or a combination of glutathione peroxidases, N-acetyl cysteine, and naringenin.
  • the present invention provides a method of reducing the amount of subcutaneous fat in a localized portion of an individual comprising administering a pharmaceutical composition to the localized portion of the individual, wherein the pharmaceutical composition comprises:
  • the drug-containing microcapsule is a picostructure formed by a pharmaceutically acceptable surfactant, and the hydrophilic-lipophilic balance value (HLB value) of the surfactant is greater than 10.
  • the drug-containing micelles have a particle size of from 3 to 250 nm.
  • the drug-containing micelles have a particle size of 5 to 50 nm.
  • the surfactant is a nonionic surfactant.
  • the nonionic surfactant is polysorbate 80 (T ween 80), 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15), polyoxyethylene castor oil (polyoxyethylene castor oil) At least one or a combination of derivatives;), and other nonionic surfactants.
  • the polyoxyethylene castor oil derivative is a polyoxyethylene 35 castor oil (Cremophor ELP;), polyoxyethylene 40 hydrogenated castor oil (Cremophor RH 40), and other polyoxyethylene castor oil derived At least one or a combination thereof.
  • the weight ratio of resveratrol to the surfactant is from 1:4 to 1:500. In a preferred embodiment, wherein the weight ratio of resveratrol to the surfactant is 1:
  • the weight ratio of resveratrol to the surfactant is from 1:8 to 1:80
  • the pharmaceutical composition further comprises a pharmaceutically acceptable aqueous solution and a second liposoluble drug microcapsule, the second liposoluble drug cell is uniformly distributed in the pharmaceutically acceptable In the aqueous solution; wherein the second fat-soluble drug micelle is another micro-shaped structure formed by the second non-ionic surfactant, and a second fat-soluble drug is coated on the second fat-soluble drug In the microcells.
  • the second nonionic surfactant has a hydrophilic-lipophilic balance value (HLB value) greater than 10.
  • the second nonionic surfactant is polysorbate 80 (T ween 80),
  • At least one of 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15), polyoxyethylene castor oil derivatives, and other nonionic surfactants or combinations thereof.
  • the second nonionic surfactant is polyoxyethylene 35 castor oil (Cremophor ELP), polyoxyethylene 40 hydrogenated castor oil (Cremophor RH 40), and other polyoxyethylene castor oil derived To One less or a combination thereof.
  • the second fat-soluble drug is quercetin, synephrine, puerarin, curcuminoid, curcumin, and At least one or a combination of other fat-soluble drugs other than resveratrol.
  • the weight ratio of the resveratrol to the second fat-soluble drug is: In a preferred embodiment, the weight ratio of the resveratrol to the second fat-soluble drug is: In a preferred embodiment, the weight ratio of the resveratrol to the second fat-soluble drug is: In a preferred embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable aqueous solution and a water-soluble drug. In a preferred embodiment, the water-soluble drug is a green tea extract, epigallocatechin gallate.
  • the weight ratio of the resveratrol to the water-soluble drug is 20
  • the weight ratio of the resveratrol to the water-soluble drug is 20. In a preferred embodiment, the weight ratio of the resveratrol to the water-soluble drug is
  • the water-soluble drug is epigallocatechin gallate
  • the concentration of epigallocatechin gallate in the pharmaceutical composition is 0.25 300 mg/mL.
  • the water-soluble drug is epigallocatechin gallate
  • the concentration of epigallocatechin gallate in the pharmaceutical composition is mg/mL.
  • the water soluble drug is a green tea extract
  • the weight ratio of the resveratrol to the green tea extract is .
  • the water soluble drug is a green tea extract
  • the weight ratio of the resveratrol to the green tea extract is .
  • the water-soluble drug is a green tea extract
  • the weight ratio of the resveratrol to the green tea extract is: to : .
  • the total weight of the resveratrol and the green tea extract is one unit of weight, and the surfactant has a weight of 0.24 70 units by weight; or is the resveratrol
  • the weight ratio of the total weight of the green tea extract to the surfactant is up to.
  • the pharmaceutical composition is administered at a localized dose of 0.2 to 20 mg per square centimeter.
  • the dose of the pharmaceutical composition applied at the local site is 0.4 ⁇ per square centimeter.
  • the pharmaceutical composition is administered at a localized dose of 0.2 to 40 mg per kilogram.
  • the pharmaceutical composition is applied at a localized dose of 0.4 to 20 mg per kg.
  • the frequency of administration of the pharmaceutical composition is from 1 to 12 times per one to one day interval.
  • the frequency of administration of the pharmaceutical composition is administered from 1 to 8 times per interval from 1 day to 21 days.
  • the individual is an animal or a human.
  • the pharmaceutical composition is injected, or applied to the localized portion of the individual.
  • the pharmaceutical composition further comprises at least one of a cosolvent, a suspending agent, and an oil phase excipients; combination.
  • the oil phase excipient and/or co-solvent together with the nonionic surfactant form the microstructure.
  • the present invention provides a pharmaceutical composition for the preparation of a medicament or a subcutaneous injection formulation for reducing the amount of subcutaneous fat in a localized part of an individual; the pharmaceutical composition comprising:
  • the drug-containing microsphere is a micro-structure formed by a pharmaceutically acceptable nonionic surfactant, and the hydrophilic-lipophilic balance value (HLB) of the nonionic surfactant Value ;) is greater than ⁇ .
  • HLB hydrophilic-lipophilic balance value
  • the drug-containing micelles have a particle size of 3 250 nm.
  • the drug-containing micelles have a particle size of 5 to 50 nm.
  • the nonionic surfactant is polysorbate 80 (T ween 80), 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15), polyoxyethylene castor oil (polyoxyethylene castor oil) At least one or a combination of derivatives;), and other nonionic surfactants.
  • the polyoxyethylene castor oil derivative is a polyoxyethylene 35 castor oil (Cremophor ELP;), polyoxyethylene 40 hydrogenated castor oil (Cremophor RH 40), and other polyoxyethylene castor oil derived At least one or a combination thereof.
  • the weight ratio of resveratrol to the nonionic surfactant is from 1:4 to 1:500.
  • concentration of resveratrol in the pharmaceutical composition is from 0.2 to 166.7 mg/mL.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable aqueous solution and a second fat-soluble drug microcell, the second liposoluble drug microcell is uniformly distributed in the pharmaceutically acceptable In the aqueous solution; wherein the second fat-soluble drug micelle is another micro-shaped structure formed by the second non-ionic surfactant, and a second fat-soluble drug is coated on the second fat-soluble drug micro In the cell.
  • the second nonionic surfactant has a hydrophilic-lipophilic balance value (HLB value) greater than 10.
  • the second nonionic surfactant is polysorbate 80 (T ween 80), 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15), polyoxyethylene castor oil derivative (polyoxyethylene) At least one of castor oil derivatives;), and other nonionic surfactants, or a combination thereof.
  • the second nonionic surfactant is polyoxyethylene 35 castor oil (Cremophor ELP) ⁇ polyoxyethylene 40 hydrogenated castor oil (Cremophor RH 40), and other polyoxyethylene castor oil derived At least one or a combination thereof.
  • the second fat-soluble drug is quercetin, synephrine, puerarin, curcuminoid, and other resveratrol. At least one or a combination of the other fat-soluble drugs.
  • the weight ratio of the resveratrol to the second fat-soluble drug is from 30:1 to 1:20.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable aqueous solution and a water soluble drug.
  • the water-soluble drug is green tea extract, Epigallocatechin gallate, Epicatechin, Epicatchin gallate, Epigallocatechin, Gallocatechin gallate, Gallocatechin; Catechin gallate; Catechin; Epigallocatechin gallate (EGCG;), caffeine (Caffeine;), carnitine (Carnitine; also known as carnitine or carnitine), L-carnitine; At least one or a combination of, Synephrine; Chlorogenic acid, and other water soluble drugs.
  • the weight ratio of the resveratrol to the water-soluble drug is from 20:1 to 1:30.
  • the water-soluble drug is epigallocatechin gallate
  • the concentration of epigallocatechin gallate in the subcutaneous fat layer injection or subcutaneous injection is 0.25-300 mg/ mL.
  • the water soluble drug is a green tea extract
  • the weight ratio of the resveratrol to the green tea extract is from 30:1 to 1:30.
  • the total weight of the resveratrol and the green tea extract is one unit of weight, and the weight of the nonionic surfactant is 0.24 70 units by weight; or alternatively, the chalk
  • the weight ratio of the total weight of rusol to the green tea extract to the nonionic surfactant is from 4:1 to 1:70.
  • the pharmaceutical or subcutaneous injection comprises a therapeutically effective amount of the pharmaceutical composition.
  • the therapeutically effective amount is from 0.2 to 20 mg per square centimeter of the topical portion.
  • the pharmaceutical composition is in a preferred embodiment, and a therapeutically effective amount is 0.2 40 mg of the pharmaceutical composition per kg of body weight.
  • the drug or subcutaneous injection is administered at a frequency of from 1 day to 30 days per interval. Use the site 1 to 12 times.
  • the individual is an animal.
  • the drug or subcutaneous injection is administered to the localized portion of the individual; or the drug is applied to the localized portion of the individual.
  • the pharmaceutical composition further comprises a cosolvent, a suspending agent, and at least one or a combination of oil phase excipients; .
  • the oil phase excipient and/or co-solvent together with the nonionic surfactant form the microstructure.
  • Figure 1A Bar graph of the effect of subcutaneous injection of resveratrol without microvesicles and subcutaneous injection of green tea extract without microvesicles on subcutaneous fat mass in rats.
  • Figure 1B Bar graph of the effect of murine-free resveratrol subcutaneous injection and micronucleated green tea extract subcutaneous injection on relative total weight gain in rats.
  • Figure 2A Bar graph of the effect of subcutaneous injection of resveratrol prepared by different excipients on local subcutaneous fat mass in rats.
  • Figure 2B Bar graph of the effect of subcutaneous injection of resveratrol prepared by different excipients on relative total weight gain in rats.
  • Figure 3 Bar graph of the effect of resveratrol pharmaceutical composition on subcutaneous fat mass in rats.
  • Figure 4A Bar graph of the effect of resveratrol combination medicinal composition on subcutaneous fat mass in rats.
  • Figure 4B Bar graph of the effect of resveratrol combination medicinal composition on relative total weight gain in rats.
  • Figure 5 Effect of resveratrol-other fat-soluble drug combination medicinal composition on apoptosis of mature adipocytes.
  • Resveratrol is a polyphenolic compound found mainly in red grape skins, knotweed, or red wine. Resveratrol is used because resveratrol is difficult to dissolve in aqueous solution, is easily metabolized in the body to glucuronic acid and sulfate metabolites, is rapidly excreted in urine and feces, and its body availability is extremely poor.
  • the development of pharmaceutical compositions that reduce localized fats faces considerable difficulties. The inventor faced this dilemma at the beginning of the development of this pharmaceutical composition.
  • Experiment 1 Effect of subcutaneous injection of resveratrol and green tea extract on subcutaneous fat and body weight of rats.
  • Green tea extract subcutaneous injection Green tea extract was prepared into 5 mg/mL using water for injection. Aqueous solution. It was filtered through a 0.2 ⁇ filter, which was the subcutaneous injection of 5 mg/mL green tea extract described in this experiment. Store in a refrigerator at 4 °C in the dark.
  • Preparation of resveratrol subcutaneous injection Resveratrol is formulated into 5 by using polysorbate 80 (Tween 80), solvent ethanol, and water for injection, which are commonly used for water-insoluble pharmaceutical injections. Mg/mL solution.
  • the detailed preparation method is as follows: 0.5 g of resveratrol is mixed with an appropriate amount of solvent ethanol to completely dissolve the resveratrol, and then 0.1 g of polysorbate 80 (Tween 80) is added to completely dissolve the polysorbate; The gas is volatilized for 2 to 4 hours to volatilize the ethanol. After the ethanol is completely evaporated, the water for injection is added to make the total volume 100 mL. After stirring evenly, the membrane is filtered with a 0.2 ⁇ filter, which is 5 mg/ of the experiment. mL of resveratrol subcutaneous injection. Store in a refrigerator at 4 °C in the dark.
  • mice were fed with high-fat diet (Research Diets, Inc.; model #1) 12492;) to induce subcutaneous fat booster B, and continuously fed to rats weighing 330 ⁇
  • the rats were randomly divided into three groups: a high-fat control group, a resveratrol group, and a green tea extract group, with 6 rats in each group, so that there was no statistical difference in body weight between the groups.
  • the body weight of each rat was recorded and defined as the "pre-test weight" of each rat. Then, the drug is administered in the following manner.
  • resveratrol 5 mg/mL of resveratrol subcutaneous injection was injected into the subcutaneous fat layer of the inguinal region of rats in the resveratrol group, and each injection was injected with 8 mg (8 mg/kg) of chalk per kg body weight.
  • Resveratrol that is, 1.6 mL of the above 5 mg/mL resveratrol subcutaneous injection per kilogram of body weight.
  • 5 mg/mL of green tea extract was injected subcutaneously into the subcutaneous fat layer of the inguinal region of the green tea extract group, and 8 mg (8 mg/kg) of green tea extract per kg body weight was injected per injection; That is, 1.6 mL of the above 5 mg/mL green tea extract subcutaneous injection was injected per kilogram of body weight.
  • the same volume of water for injection was administered in the same manner as described above.
  • the above injection site was the lower inguinal fat of rats, which was injected on the left and right sides on average, and was injected once on the first, third and fifth days of the test.
  • High-fat diets were continuously administered during the test, and changes in body weight were recorded daily.
  • Drinking water was recorded once a week, fasted on the 20th day of the test, and rats were sacrificed with carbon dioxide on the 21st day.
  • the body weight of each rat was recorded and defined as the "post-test weight” of each rat.
  • the "post-test weight” was subtracted from the “post-test weight” of each rat to obtain “total weight gain”.
  • the total weight gain of each group of rats was divided by the total weight gain of the rats in the high-fat control group to obtain “relative total weight gain”.
  • the fat in the lower groin of the left and right sides of the rat was weighed, and the fat mass of the inguinal groin of each group was calculated. Average
  • FIG. 1A is a bar graph of the effect of subcutaneous injection of no-cell resveratrol subcutaneous injection and micro-free green tea extract on subcutaneous fat content in rats.
  • Fig. 1B is a bar graph of the effect of subcutaneous injection of resveratrol without a microcell and the subcutaneous injection of a non-micronized green tea extract on the relative total weight gain of rats.
  • the amount of the lower inguinal fat is the sum of the fat mass of the inferior groin on the left and right sides.
  • Figure 1A show that after three subcutaneous fat injections, the local fat mass at the injection site of the resveratrol group and the green tea extract group was not significantly reduced compared with the high-fat control group (p>0.05), showing direct Injection of the dissolved resveratrol or green tea extract into the subcutaneous fat layer does not reduce the local fat at the injection site.
  • Figure IB shows that after three subcutaneous fat injections, the weight of the rats in the resveratrol group and the green tea extract group was not significantly reduced compared with the high-fat control group (p>0.05), indicating that it would directly The dissolved resveratrol or green tea extract is injected into the subcutaneous fat layer and does not reduce body weight.
  • green tea extract is an excellent water-soluble component. Previous cell experiments have found that it can promote the apoptosis of fat cells, but the green tea extract is dissolved and injected directly into the subcutaneous fat, which can not reduce its local subcutaneous fat. It is also impossible to lose weight. It can be seen from this experiment that direct injection of resveratrol or green tea extract into the subcutaneous fat layer is not sufficient to reduce local fat and body weight. In order to overcome this problem, the inventors have further studied and developed the pharmaceutical composition of the present invention comprising resveratrol.
  • Experiment 2 Effect of different kinds of resveratrol subcutaneous injection on subcutaneous fat mass and body weight of rats
  • the resveratrol physiological saline solution, resveratrol PEG solution, and resveratrol ELP solution were prepared in the following manner.
  • resveratrol 500 mg was mixed with an appropriate amount of physiological saline for injection to make a final volume of 100 mL. Stirring was uniform, and resveratrol was completely dissolved to obtain a resveratrol physiological saline solution, and the concentration of resveratrol in the aqueous resveratrol physiological saline solution was 5 mg/mL.
  • the concentration of resveratrol in the resveratrol ELP solution is 5 mg/mL
  • the concentration of polyoxyethylene 35 castor oil (ELP) is about 20% (% by weight;)
  • resveratrol and polyoxyethylene The weight ratio of 35 castor oil is 1:40.
  • mice were fed with high-fat diet (Research Diets, Inc.; model #D12492) to induce subcutaneous fat booster, and the rats were continuously fed to a body weight of 330 ⁇ 10 g. Rats were randomly divided into 4 groups: control group, physiological saline group, PEG group and ELP group, with 5 rats in each group, so that there was no statistical difference in body weight of each group. The body weight of each rat was recorded and defined as the "pre-test weight" of each rat. Then, the drug is administered in the following manner.
  • the resveratrol physiological saline solution, the resveratrol PEG solution, and the resveratrol ELP solution were respectively injected into the subcutaneous fat layer of the inguinal region of the physiological saline group, the PEG group, and the ELP group, each injection.
  • the above injection site was the lower inguinal fat of rats, which was injected on the left and right sides on average, and was injected once on the first, second, third and fourth days of the test.
  • High-fat diets were continuously administered during the trial, and changes in body weight were recorded daily.
  • Drinks were recorded once a week for a total of 14 days. Rats were sacrificed with carbon dioxide on day 15.
  • the body weight of each rat was recorded and defined as the "post-test weight” of each rat.
  • the "post-test weight” was subtracted from the “post-test weight” of each rat to obtain “total weight gain”.
  • the total weight gain of each group of rats was divided by the total weight gain of the control group rats to obtain "relative total weight gain”.
  • the subcutaneous fat in the lower groin of the left and right sides of the rat was weighed, and the subcutaneous fat in the lower and inferior groin was added to calculate the subcutaneous fat mass in the inferior groin.
  • the subcutaneous fat mass of the inferior groin of each group of rats was divided by the subcutaneous fat mass of the inferior groin of the control group, and the "relative weight of subcutaneous fat in the lower inguinal region" was obtained.
  • Figure 2A is a bar graph of the effect of subcutaneous injection of resveratrol prepared by different excipients on the amount of subcutaneous fat in rats.
  • Fig. 2B is a bar graph of the effect of subcutaneous injection of resveratrol prepared by different excipients on the relative total weight gain of rats.
  • Fig. 2A The results of Fig. 2A showed that the relative weight of the subcutaneous fat in the lower inguinal region of the control group was 100 ⁇ 27.6%, and the relative weight of the subcutaneous fat in the lower inguinal region of the saline group was 108.2 ⁇ 24.7%, and the lower inguinal area of the PEG group was subcutaneously.
  • the relative weight of fat was 114.0 ⁇ 4.4%, and the relative weight of subcutaneous fat in the lower inguinal region of the ELP group was 72.5 ⁇ 0.0%.
  • the resveratrol composition must contain a nonionic surfactant in order to reduce subcutaneous fat (local fat) at the application site and reduce body weight. Further analysis revealed that the above-mentioned resveratrol PEG solution had no micelles, and the resveratrol ELP solution had micelles, and resveratrol was coated in the micelles formed by ELP. Therefore, it is more necessary to further explore the effects of micelles on reducing local fat and reducing body weight.
  • the resveratrol ELP partial microcyst dosage form, the resveratrol HS-15 partial microcyst dosage form, the resveratrol ELP microcyst dosage form, and the resveratrol HS-15 microcyte dosage form were prepared in the following manner.
  • Preparation method of resveratrol ELP partial microcyst dosage form Mix 20 g of polyoxyethylene 35 castor oil (ie, ELP) with an appropriate amount of physiological saline for injection, and make the final weight reach 100 ° evenly, so that polyoxyethylene 35 Castor oil (ie ELP) was completely dissolved and a 20% ELP solution was obtained. Mix 400 mg of resveratrol with an appropriate amount of 20% ELP solution to a final weight of 80 g. Stirring evenly, so that resveratrol is completely dissolved, the resveratrol ELP partial microcyst dosage form can be obtained.
  • ELP polyoxyethylene 35 castor oil
  • the concentration of resveratrol in the resveratrol ELP partial microcyst dosage form is about 5 mg/mL
  • the concentration of polyoxyethylene 35 castor oil (ELP) is about 20% (% by weight;)
  • resveratrol The weight ratio to polyoxyethylene 35 castor oil is about 1:40.
  • Method for preparing resveratrol HS-15 partial microcyst dosage form mixing 20 g of polyethylene glycol stearate 15 (Kolliphor HS 15, abbreviated as HS-15) with an appropriate amount of physiological saline for injection to make the final Weighs up to 100 g. Stir well and completely dissolve the polyethylene glycol stearate 15 (BP HS-15;) to obtain a 20% HS-15 solution. Mix 400 mg of resveratrol with an appropriate amount of 20% HS-15 solution to a final weight of 80 g. Stir well and completely dissolve resveratrol to obtain resveratrol HS-15 partial microcyst dosage form.
  • Polyethylene glycol stearate 15 Kerphor HS 15, abbreviated as HS-15
  • BP HS-15 polyethylene glycol stearate 15
  • the concentration of resveratrol in the resveratrol HS-15 partial microcyst dosage form is about 5 mg/mL, and the concentration of polyethylene glycol stearate 15 (ie, HS-15) is about 20% (% by weight) And the weight ratio of resveratrol to polyethylene glycol stearate 15 (ie, HS-15) is about 1:40.
  • Resveratrol Preparation of HS-15 microcyst dosage form Mix 500 mg of resveratrol with 80 140 mL of dichloromethane and stir at room temperature at 150-500 rpm until resveratrol is completely dissolved. Add 20 g of polyethylene glycol stearate 15 (Kolliphor HS 15, abbreviated as HS-15), stir evenly at a speed of 100 ⁇ 300 rpm to volatilize methylene chloride.
  • Polyethylene glycol stearate 15 Kerphor HS 15, abbreviated as HS-15
  • the physiological saline solution for injection is slowly added to make the final volume up to 100 g, and the mixture is uniformly stirred to form a plurality of drug-containing micelles, thereby obtaining a resveratrol HS-15 microcyst form.
  • the concentration of resveratrol in the resveratrol HS-15 microcyst dosage form is about 5 mg/g, and the concentration of polyethylene glycol stearate 15 (HS-15) is 20% (% by weight;), And the weight ratio of resveratrol to polyethylene glycol stearate 15 (HS-15) is 1:40.
  • the HS-15 partial microcyst dosage form, the resveratrol ELP microcyst dosage form, and the resveratrol HS-15 microcyte dosage form contain micelles and measure the particle size of the micelles.
  • the resveratrol ELP microcyst dosage form and the resveratrol HS-15 microcyte dosage form are clear and non-stratified, and the number of drug-containing micelles is large.
  • the resveratrol ELP partial microcyst form and the resveratrol HS-15 partial microcyst form contain a large amount of precipitate, the supernatant still contains micelles, therefore, resveratrol
  • the ELP partial microcyte dosage form, the resveratrol HS-15 partial microcyte dosage form, the resveratrol ELP microcyte dosage form, and the resveratrol HS-15 microcyte dosage form are all pharmaceutical compositions of the present invention.
  • the resveratrol ELP partial microcyst dosage form, the resveratrol HS-15 partial microcyst dosage form, the resveratrol ELP microcyst dosage form, and the resveratrol HS-15 microcyst dosage form are separately mixed (make part)
  • the precipitate in the microcytose formulation was uniformly suspended;), and injected into the subcutaneous fat layer of the inferior groin of the ELP partial microcell group, the HS-15 partial microcell group, the ELP microcell group, and the HS-15 microcell group, respectively.
  • the above injection site was the lower inguinal fat of rats, which was injected on the left and right sides on average, and was injected once on the first, second, third, fourth, fifth, and sixth days of the test.
  • High-fat diets were continuously administered during the test, and changes in body weight were recorded daily.
  • Drinks were recorded once a week for a total of 14 days. Rats were sacrificed with carbon dioxide on day 15.
  • the body weight of each rat was recorded and defined as the "post-test weight” of each rat.
  • the "post-test weight” was subtracted from the “post-test weight” of each rat to obtain “total weight gain”.
  • the total weight gain of each group of rats was divided by the total weight gain of the control group rats to obtain "relative total weight gain”.
  • the subcutaneous fat in the lower groin of the left and right sides of the rat was weighed, and the subcutaneous fat in the lower and inferior groin was added to calculate the subcutaneous fat mass in the inferior groin.
  • the subcutaneous fat mass of the inferior groin of each group of rats was divided by the subcutaneous fat mass of the inferior groin of the control group, and the "relative weight of subcutaneous fat in the lower inguinal region" was obtained.
  • the ELP concentration and the resveratrol concentration in the resveratrol ELP partial microcyst dosage form and the resveratrol ELP microcyst dosage form are the same, and only the microcapsules are contained.
  • the quantity varies. Therefore, compared with the resveratrol ELP partial microcyte dosage form, if the resveratrol ELP microcyst dosage form significantly reduces the local fat at the application site, it means that the formation of drug-containing microvesicles is a resveratrol composition which can significantly reduce the application site.
  • a key factor for topical fat if the resveratrol ELP microcyte dosage form results in a significant reduction in body weight, it is representative that the formation of drug-containing micelles is a key factor in the significant reduction in body weight of the resveratrol composition.
  • the HS-15 concentration of the resveratrol HS-15 partial microcyte dosage form and the resveratrol HS-15 microcyte dosage form were consistent and the number of drug-containing micelles was different. Therefore, compared with the resveratrol HS-15 partial microcyte dosage form, if the resveratrol HS-15 microcyst dosage form causes a significant decrease in local fat at the application site, it means that the formation of drug-containing microvesicles is a resveratrol composition.
  • the experimental results show that injection of the resveratrol ELP partial microcyst dosage form or the resveratrol HS-15 partial microcyst dosage form to the subcutaneous fat layer of the application site can reduce the fat (local fat) at the application site.
  • injection of the resveratrol ELP microcyst form or the resveratrol HS-15 microcyst form into the subcutaneous fat layer of the application site can also reduce the fat (local fat) at the application site.
  • the partial lipolysis effect of the resveratrol ELP microcyst dosage form was the best.
  • the resveratrol ELP microcyte formulation significantly reduced localized fat compared to the resveratrol ELP partial microcyte formulation.
  • the resveratrol HS-15 microcyte formulation significantly reduced localized fat compared to the resveratrol HS-15 partial microcyte formulation.
  • the formation of the microcapsule is a key factor for the resveratrol composition to significantly reduce the local fat at the application site, and the partial lipid solution of the drug-containing micelle formed by the polyoxyethylene castor oil derivative (for example, ELP). best effect.
  • the results of the experiment showed that the injection of the resveratrol ELP partial microcyst dosage form or the resveratrol HS-15 partial microcyst dosage form to the subcutaneous fat layer at the application site reduced body weight.
  • injection of the resveratrol ELP microcyst dosage form or the resveratrol HS-15 microcyst form into the subcutaneous fat layer of the application site can also reduce body weight.
  • the resveratrol ELP microcyst dosage form has the best weight loss effect.
  • a first pharmaceutical composition was prepared using resveratrol
  • a second pharmaceutical composition was prepared using resveratrol and green tea extract.
  • the steps for preparing the first pharmaceutical composition are as follows:
  • the drug-containing micelle is a micro-structure formed by a surfactant, and resveratrol is coated in the drug-containing micelle.
  • the third weight is greater than or equal to 0g.
  • the boiling point of the solvent is less than the boiling point of pure water.
  • the solvent is a hydrophilic solvent.
  • the hydrophilic solvent is at least one of methanol, ethanol, acetone, and other hydrophilic solvents, or a combination thereof.
  • the solvent in step (a) is a lipophilic solvent.
  • the lipophilic solvent is at least one of ether, benzene, chloroform, ethyl acetate, chloroform, hexamethylene and other lipophilic vehicles or a combination thereof.
  • the surfactant is a nonionic surfactant.
  • the nonionic surfactant is polysorbate 80 (Tween 80), 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15), polyoxyethylene castor oil derivatives ⁇ and At least one or a combination of other nonionic surfactants.
  • the polyoxyethylene castor oil derivative is polyoxyethylene 35 castor oil (Crem 0 ph 0 r ELP), polyoxyethylene
  • the weight ratio of the first weight of resveratrol to the second weight of surfactant is from 1:4 to 1:500.
  • the weight ratio of the first weight of resveratrol to the third weight of the pharmaceutically acceptable aqueous solution is from 1:400 to 3:50.
  • the pharmaceutically acceptable aqueous solution is water for injection, aqueous solution for injection, or physiological saline.
  • the pharmaceutically acceptable aqueous solution comprises a local anesthetic.
  • the local anesthetic is at least one of an amide, a p-aminobenzamide, and an amino ether or a combination thereof.
  • the amide is dibucaine; Lidocaine; mepivacaine hydrochloride (Mepivacaine HC1), bupivacine hydrochloride (Bupivacine HC1), pyrrole At least one or a combination of pyrrocaine HC1, prilocaine HCl, Digammacaine, and Oxethazaine.
  • the p-aminobenzamide is at least one or a combination of butacaine; dimethocaine; and totocaine.
  • the amino ether is at least one of quinicaine (Quinisocaine;) and pramocaine or a combination thereof.
  • the pharmaceutically acceptable aqueous solution contains an antioxidant.
  • the antioxidant is beta-carotene; lutein; lycopene; bilirubin; vitamin K; Vitamin C (also known as ascorbic acid), vitamin E, uric acid, nitric oxide, nitroxide, pyruvate , catalase, superoxide dismutase, glutathione peroxidases, N-acetyl cysteine; and pomelo At least one or a combination of naringenin.
  • the steps for preparing the second pharmaceutical composition are as follows:
  • the first pharmaceutically acceptable aqueous solution comprises a seventh weight of green tea extract; the green tea extract comprises a first green tea extract component, and the first green tea extract component is epigallocatechin gallate.
  • the boiling point of the solvent is less than the boiling point of pure water.
  • the solvent is a hydrophilic solvent.
  • the hydrophilic solvent is at least one of methanol, ethanol, acetone, and other hydrophilic solvents, or a combination thereof.
  • the solvent in step (al) is a lipophilic solvent.
  • the lipophilic solvent is at least one of ether, benzene, chloroform, ethyl acetate, chloroform, hexamethylene and other lipophilic vehicles or a combination thereof.
  • the surfactant is a nonionic surfactant.
  • the nonionic surfactant is polysorbate 80 (Tween 80), 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15), polyoxyethylene castor oil derivatives ⁇ and At least one or a combination of other nonionic surfactants.
  • the polyoxyethylene castor oil derivative is polyoxyethylene 35 castor oil (Crem 0 ph 0 r ELP), polyoxyethylene 40 hydrogenated castor oil (Cremophor RH 40), and other polyoxyethylene castor oil derivatives At least one of or a combination thereof.
  • step (cl) and step (dl) the method further comprises the steps of:
  • the green tea extract is dissolved in the first pharmaceutically acceptable aqueous solution
  • the medicated microcell is a micro-structure formed by a surfactant
  • resveratrol is coated in the In the drug-containing micelles.
  • the content of epigallocatechin gallate in the green tea extract in the first pharmaceutically acceptable aqueous solution is from 100 to 100 based on 100% by weight of the total weight of the green tea extract. %.
  • the weight ratio of the fourth weight of resveratrol to the seventh weight of the green tea extract is from 30:1 to 1:30.
  • the total weight of the fourth weight of resveratrol and the seventh weight of the green tea extract is one weight unit, and the fifth weight is surface active.
  • the weight of the agent is 0.24 70 units by weight; or alternatively, the weight ratio of the total weight of the resveratrol to the green tea extract to the surfactant is from 4:1 to 1:70.
  • the total weight of the fourth weight of resveratrol and the seventh weight of the green tea extract is one unit of weight
  • the total weight of the sixth weight of the first pharmaceutically acceptable aqueous solution and the eighth weight of the second pharmaceutically acceptable aqueous solution is 16,400 weight units; or is the sum of the fourth weight and the seventh weight :
  • the sum of the sixth weight and the eighth weight is 1:400 3:50.
  • the total weight of the resveratrol and the green tea extract is one unit of weight, and the total weight of the first pharmaceutically acceptable aqueous solution and the second pharmaceutically acceptable aqueous solution is 10 1000 weight units; Yes, the total weight of the resveratrol and the green tea extract: the total weight of the first pharmaceutically acceptable aqueous solution and the second pharmaceutically acceptable aqueous solution is from 1:1000 to 1:10.
  • the first pharmaceutically acceptable aqueous solution and the second pharmaceutically acceptable aqueous solution are water for injection, aqueous solution for injection, or physiological saline.
  • the first pharmaceutically acceptable aqueous solution comprises a local anesthetic.
  • the local anesthetic is at least one of an amide, a p-aminobenzamide, and an amino ether or a combination thereof.
  • the amide is dibucaine; Lidocaine; mepivacaine hydrochloride (Mepivacaine HC1), bupivacine hydrochloride (Bupivacine HC1), pyrrole At least one or a combination of pyrrocaine HC1, prilocaine HCl, Digammacaine, and Oxethazaine.
  • the p-aminobenzamide is at least one or a combination of butacaine; dimethocaine; and totocaine.
  • the amino ether is at least one of quinicaine (Quinisocaine;) and pramocaine or a combination thereof.
  • the pharmaceutically acceptable aqueous solution contains an antioxidant.
  • the antioxidant is beta-carotene, clutein, lycopene, bilirubin, vitamin K, vitamin C. Also known as ascorbic acid, vitamin E, uric acid, nitric oxide, nitroxide, pyruvate, catalase (catalase), superoxide dismutase, glutathione peroxidases, N-acetyl cysteine; and naringenin At least one of or a combination thereof.
  • a third pharmaceutical composition is prepared using resveratrol and a water-soluble drug
  • a fourth pharmaceutical composition and a fifth pharmaceutical composition are prepared using resveratrol and other fat-soluble drugs.
  • the first pharmaceutically acceptable aqueous solution comprises a water soluble drug.
  • the first pharmaceutically acceptable aqueous solution comprises a local anesthetic.
  • the local anesthetic is at least one of an amide, a p-aminobenzamide, and an amino ether or a combination thereof.
  • the amide is dibucaine; Lidocaine; mepivacaine hydrochloride (Mepivacaine HC1), bupivacine hydrochloride (Bupivacine HC1), pyrrole At least one or a combination of pyrrocaine HC1, prilocaine HCl, Digammacaine, and Oxethazaine.
  • the p-aminobenzamide is at least one or a combination of butacaine; dimethocaine; and totocaine.
  • the amino ether is at least one of quinicaine (Quinisocaine;) and pramocaine or a combination thereof.
  • the pharmaceutically acceptable aqueous solution contains an antioxidant.
  • the antioxidant is beta-carotene, lutein, lycopene, bilirubin, vitamin K, vitamin C (vitamin K), vitamin C (vitamin K), vitamin C (vitamin K), vitamin C (vitamin K), vitamin C (vitamin K) Vitamin C; also known as ascorbic acid, vitamin E, uric acid, nitric oxide, nitroxide, pyruvate, peroxidation Catalase, superoxide dismutase, glutathione peroxidases, N-acetyl cysteine; and naringenin At least one of naringenin) or a combination thereof.
  • the boiling point of the solvent is smaller than the boiling point of the pure water.
  • the solvent is a hydrophilic solvent.
  • the hydrophilic solvent is at least one of methanol, ethanol, acetone, and other hydrophilic solvents, or a combination thereof.
  • the solvent in step (a2) is a lipophilic solvent.
  • the lipophilic solvent is at least one of ether, benzene, chloroform, ethyl acetate, chloroform, hexamethylene and other lipophilic vehicles or a combination thereof.
  • the surfactant is a nonionic surfactant.
  • the nonionic surfactant is polysorbate 80 (Tween 80), 2-hydroxyethyl
  • At least one or a combination of 12-hydroxyoctadecanoate (solutol HS 15), polyoxyethylene castor oil derivatives, and other nonionic surfactants.
  • the polyoxyethylene castor oil derivative is polyoxyethylene 35 castor oil (Crem 0 ph 0 r ELP), polyoxyethylene 40 hydrogenated castor oil (Cremophor RH 40), and other polyoxyethylene castor oil derivatives At least one of or a combination thereof.
  • step (c2) the method further comprises the steps of: (c21) A second pharmaceutically acceptable aqueous solution is added and stirred well to completely dissolve the second pharmaceutically acceptable aqueous solution.
  • the water-soluble drug is dissolved in the first pharmaceutically acceptable aqueous solution
  • the drug-containing microcell is a micro-structure formed by a surfactant
  • resveratrol is coated in the In the drug cell.
  • the water-soluble drug in the first pharmaceutically acceptable aqueous solution is green tea extract, epigallocatechin gallate, epicchinchin, epicatechin gall.
  • the weight ratio of the resveratrol to the water-soluble drug is from 30:1 to 1:30.
  • the total weight of the resveratrol and the water-soluble drug is one unit of weight, and the weight of the surfactant is 0.24 70 weight units;
  • the weight ratio of the total weight of the resveratrol to the water-soluble drug to the surfactant is from 4:1 to 1:70.
  • the first pharmaceutically acceptable aqueous solution is based on the total weight of the resveratrol and the water-soluble drug in one weight unit.
  • the total weight of the second pharmaceutically acceptable aqueous solution is 16-400 weight units; or is the sum of the fourth weight and the seventh weight: the sum of the sixth weight and the eighth weight is 1:400 ⁇ 3:50.
  • the first pharmaceutically acceptable aqueous solution and the second pharmaceutically acceptable aqueous solution are water for injection, aqueous solution for injection, or physiological saline.
  • step (A) of preparing the drug-containing micro-cell composition comprises the following steps (a3) to (d3) :
  • the step (B) of preparing the second fat-soluble drug microcapsule composition comprises the following steps (a4) to (d4):
  • the filtrate is the second liposoluble drug cell sub-composition containing the second liposoluble drug micelle.
  • the drug-containing micelle is a micro-structure formed by the first surfactant, and resveratrol is coated in the drug-containing micelle.
  • the second fat-soluble drug micelle is a micro-structure formed by the second surfactant, and the other fat-soluble drug is coated in the second fat-soluble drug cell.
  • the fat-soluble drug is at least one or a combination of curcumin, quercetin, puerarin, and other fat-soluble drugs other than resveratrol.
  • the boiling point of the first solvent or / and the second solvent is less than the boiling point of pure water.
  • the first solvent or the second solvent is a hydrophilic solvent.
  • the hydrophilic solvent is at least one of methanol, ethanol, acetone, and other hydrophilic solvents, or a combination thereof.
  • the first solvent or / and the second solvent in the step (a3) or / and (a4) are lipophilic solvents.
  • the lipophilic solvent is at least one of ether, benzene, chloroform, ethyl acetate, chloroform, hexamethylene and other lipophilic vehicles or a combination thereof.
  • the first surfactant or / and the second surfactant are nonionic surfactants.
  • the nonionic surfactant is polysorbate 80 (Tween 80), 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15), polyoxyethylene castor oil derivatives ⁇ and At least one or a combination of other nonionic surfactants.
  • the polyoxyethylene castor oil derivative is polyoxyethylene 35 castor oil (Crem 0 ph 0 r ELP), polyoxyethylene 40 hydrogenated castor oil (Cremophor RH 40), and other polyoxyethylene castor oil derivatives At least one of or a combination thereof.
  • the weight ratio of the resveratrol to the first surfactant is from 1:4 to 1:500.
  • the weight ratio of the other fat-soluble drug to the second surfactant is from 1:4 to 1:500.
  • the weight ratio of the resveratrol to the pharmaceutically acceptable aqueous solution is from 1:400 to 3:50.
  • the weight ratio of the other fat-soluble drug to the pharmaceutically acceptable aqueous solution is 1: 400 to 3: 50.
  • the pharmaceutically acceptable aqueous solution is water for injection, aqueous solution for injection, or physiological saline.
  • the pharmaceutically acceptable aqueous solution comprises a local anesthetic.
  • the local anesthetic is at least one of an amide, a p-aminobenzamide, and an amino ether or a combination thereof.
  • the amide is dibucaine; Lidocaine; mepivacaine hydrochloride (Mepivacaine HC1), bupivacine hydrochloride (Bupivacine HC1), pyrrole At least one or a combination of pyrrocaine HC1, prilocaine HCl, Digammacaine, and Oxethazaine.
  • the p-aminobenzamide is at least one or a combination of butacaine; dimethocaine; and totocaine.
  • the amino ether is at least one of quinicaine (Quinisocaine;) and pramocaine or a combination thereof.
  • the pharmaceutically acceptable aqueous solution contains an antioxidant.
  • the antioxidant is beta-carotene, lutein, lycopene, bilirubin, vitamin K, vitamin C (vitamin K), vitamin C (vitamin K), vitamin C (vitamin K), vitamin C (vitamin K), vitamin C (vitamin K) Vitamin C; also known as ascorbic acid, vitamin E, uric acid, nitric oxide, nitroxide, pyruvate, peroxidation Catalase, superoxide dismutase, glutathione peroxidases, N-acetyl cysteine; and naringenin At least one of naringenin) or a combination thereof.
  • the steps for preparing the fifth pharmaceutical composition are as follows:
  • the range of the solvent, the surfactant, the pharmaceutically acceptable aqueous solution, and other fat-soluble drugs used in the fifth pharmaceutical composition is the same as that of the fourth pharmaceutical composition. Further, the range of the proportional relationship between the components in the fifth pharmaceutical composition is also the same as that of the fourth pharmaceutical composition.
  • the pharmaceutically acceptable aqueous solution comprises a local anesthetic or/and an antioxidant.
  • the range of the type of the local anesthetic or/and the antioxidant used in the fifth pharmaceutical composition is the same as that of the fourth pharmaceutical composition.
  • the pharmaceutical composition is allowed to stand for at least 20 minutes, and if delamination does not occur, it is further tested by a particle size analyzer.
  • the micelle was contained in the pharmaceutical composition by a particle size analyzer. If the pharmaceutical composition is analyzed by a particle size analyzer, the measured particle diameter is less than 250 nm, and the PDI value is less than 0.4.
  • the solution in the pharmaceutical composition is visually observed to be clear and transparent, and the optical path can be observed after the laser irradiation solution is used. , on behalf of the pharmaceutical composition has a microcell.
  • the composition prepared is the medical composition of the present invention which can be used for reducing local fat.
  • the prepared composition is a preferred pharmaceutical composition of the present invention which can be used for reducing topical fat.
  • the particle size distribution (purchasing from Malvern) was used to determine the distribution of the particle size and the polydispersity index (PDI). If the polydispersity index is less than 0.4, the stability of the pharmaceutical composition is good. That is, the micelles in the pharmaceutical composition can exist stably.
  • the pharmaceutical composition of the present invention has a storage condition of 2 to 8 °C.
  • the inventors placed the pharmaceutical composition in a relatively high temperature and high humidity environment (temperature 25 ° C ⁇ 2 ° C, relative humidity RH 60% ⁇ 5%), observed in the pharmaceutical composition How long can the microvesicles be stable in a relatively high temperature state to predict how long the pharmaceutical composition can be stored at 2-8 °C.
  • the pharmaceutical composition can be stored for n months at 25 ° C, the pharmaceutical composition can be stored at 5 ° C for a period of time of 2 ((25 - 5) / 1Q) times n months. That is, the pharmaceutical composition can be stored at a temperature of 5 ° C for a length of 22 times, that is, 4 times.
  • the pharmaceutical composition is maintained in a precipitate-free manner when subjected to an accelerated test under the conditions of a temperature of 25 ⁇ 2 degrees (25 ⁇ 2 ° C;), a relative humidity of RH 60% ⁇ 5%, and avoiding direct light.
  • the state is at least 24 hours.
  • the pharmaceutical composition is maintained in a state free of precipitates for at least 6 months when the accelerated test is carried out under the conditions of a temperature of 25 ⁇ 2 degrees Celsius, a relative humidity of RH 60% ⁇ 5%, and direct light exposure.
  • the pharmaceutical composition is maintained in a state free of precipitates for at least 24 months at a temperature of 2 to 8 °C.
  • nonionic surfactants were used for this experiment.
  • the four nonionic surfactants are polyoxyethylene 35 castor oil (ie ELP), polyethylene glycol stearate 15 (ie HS-15), polyoxyethylene 40 hydrogenated castor oil (Cremophor RH 40, Referred to as RH 40), and polysorbate 80 (Tween 80).
  • the experiment was divided into 4 groups, namely ELP group, HS-15 group, RH40 group, and Tween 80 group.
  • composition to be tested After the solvent is completely volatilized, a composition is obtained, 20 g in total; 2 g of the composition is taken, and 8 g is slowly added (example of the third weight;) physiological saline for injection is stirred uniformly to obtain a composition to be tested. Things.
  • concentration of resveratrol in the composition to be tested was 20 mg/g, and the concentration of the nonionic surfactant was 18%.
  • the components to be tested in the ELP group, the HS-15 group, the RH40 group, and the Tween 80 group were allowed to stand for at least 20 minutes to observe whether stratification occurred. If delamination occurs, the concentration of resveratrol is too high to cause the microcells in the first stage composition to rupture, that is, the concentration of resveratrol cannot be prepared by using the nonionic surfactant. g of the pharmaceutical composition of the invention.
  • ELP is the preferred excipient for the preparation of the pharmaceutical compositions of the present invention.
  • concentration of resveratrol in the pharmaceutical composition prepared by ELP can reach 166.7 mg/g.
  • compositions of the present invention were prepared by using the ratio change of resveratrol and polyoxyethylene 35 castor oil (ELP), and stability analysis was carried out to know resveratrol and polyoxyethylene 35.
  • ELP castor oil
  • the experiment was divided into 9 groups, namely groups 1 to 9.
  • the preparation method of the pharmaceutical composition of each group was substantially the same as the experimental procedure of experiment 6, only the weight of resveratrol (the first weight in step (a'); The weight of the ELP (the second weight in the step (b');), the weight of the physiological saline for injection (the third weight in the step (c');) is different.
  • the principle of adding the weight of resveratrol (first weight;), the weight of ELP (second weight;), and the weight of physiological saline for injection are shown in Table 1.
  • the ratio of the resveratrol to ELP in the 1st to 9th groups is one to one (1:1), one to two five (1: 2.5), one to five (1: 5), one to eight (1:8), one to ten (1:10), one to forty (1:40), one to eighty (1:80), one to two hundred (1:200) And one to five hundred (1:500), and the final concentration of resveratrol in the pharmaceutical composition prepared in groups 1 to 9 is 1000 mg/g, 285.71 mg/g, and 166. 7 mg/ g, 60 mg/g, 30 mg/g, 7.5 mg/g, 3.75 mg/g, 0.5 mg/g, 0.2 mg/g.
  • the weight ratio of the resveratrol in the step ( a ') to the ELP in the step ( b ') (the ratio of the first weight to the second weight; ) in order of one to one, one to two five, one to five, one to eight, one to ten, one to forty, one to eighty, one to two hundred, and one to five hundred, and in steps (c')
  • the final concentrations of resveratrol are sequentially prepared at 1000 mg/g, 285.71 mg/g, 166.7 mg/g, 60 mg/g, 30 mg/ g, 7.5 mg/g, 3.75 mg/g, 0.5 mg/g, and 0.2 mg/g of pharmaceutical composition.
  • the final concentration of the drug when expressed in mg/g, it represents the number of milligrams of resveratrol contained per gram of the pharmaceutical composition.
  • a particle size analyzer was used to determine whether or not a micelle was contained in the pharmaceutical composition, and the particle size of the micelle was measured.
  • the particle size distribution and the polydispersity index (PDI) were measured using a particle size analyzer to evaluate the stability of the pharmaceutical composition.
  • the resveratrol content in the micelles was analyzed by high performance liquid chromatography (HPLC; for example, HPLC-UV) and defined as "initial drug content”.
  • the accelerated stability test was used to observe whether the medicinal composition was stratified under high temperature storage conditions (25 ⁇ 2 degrees Celsius; 3 months), and high performance liquid chromatography (HPLC); for example, HPLC -UV) Analyze the drug content in the micelles, defined as "the drug content after the accelerated experiment”. Divide the "drug content after accelerated experiment” by “starting drug content” to get “percentage of drug content”. If the percentage of the drug content is greater than or equal to 95%, it represents an excellent stability of the pharmaceutical composition.
  • Table 1 Sample preparation table for preparing pharmaceutical composition using ELP
  • Table 2 for the stability analysis results of pharmaceutical compositions.
  • Table 2 shows that when the weight ratio of resveratrol to ELP is 1:5 to 1:500, there are microcells in each group of pharmaceutical compositions, and the measured cell size is 10 250 nm, therefore, chalk
  • the pharmaceutical composition prepared by the ratio of rusol to ELP of 1:5 to 1:500 is a pharmaceutical composition which can be used for reducing local fat in the present invention.
  • the weight of the ELP should be greater than or equal to 5 weight units, based on the weight of the resveratrol.
  • the weight of the resveratrol is 1 weight unit, and the weight of the ELP is 5 500 weight units.
  • the weight of the resveratrol is one unit of weight, and the weight of the ELP is 10 80 units by weight.
  • the weight of the resveratrol is 1 unit by weight, and the weight of the ELP is 8 to 80 units by weight.
  • the blank field indicates that no analysis has been performed.
  • the third and fifth to seventh groups of pharmaceutical compositions were stored in an environment of 25 degrees Celsius for 3 months, and the percentage of resveratrol drug content in each group of samples was greater than 95%, and the initial There was no significant downward trend in drug content. From the results, it is understood that the pharmaceutical composition has good stability, and it is estimated according to the empirical rule of the accelerated experiment that the pharmaceutical compositions can be stored for at least 24 months under refrigeration at 2 to 8 °C.
  • Example 1 Preparation of resveratrol pharmaceutical composition using polyoxyethylene 35 castor oil and resveratrol
  • the filtrate is a pharmaceutical composition of resveratrol containing drug-containing micelles. Store in the dark.
  • the weight ratio of the first weight of resveratrol to the second weight of polyoxyethylene 35 castor oil (surfactant) is 0.4:4, i.e., the weight ratio is 1:10.
  • the weight ratio of the first weight of resveratrol to the third weight of the physiological saline for injection is 0.4: 80, that is, the weight ratio is 1: 200 ⁇
  • Example 2 Preparation of resveratrol compound medicine composition using polyoxyethylene 35 castor oil, resveratrol and green tea extract
  • the filtrate containing the drug-containing microvesicles is a resveratrol compound pharmaceutical composition. Store in cold storage.
  • the content of epigallocatechin gallate in the green tea extract is 95%.
  • the weight ratio of the fourth weight of resveratrol to the seventh weight of the green tea extract is 0.36: 0.04, i.e., the weight ratio is 9:1.
  • the specific gravity of the physiological saline for injection is 1 g/mL. Therefore, in the specific embodiment, the total weight of the sixth weight of the first injection physiological saline and the eighth weight second physiological saline is 80 mL, and the total weight of the physiological saline is 80 g. .
  • Example 3 Lipolysis effect of pharmaceutical composition of resveratrol
  • the 5 mg/mL resveratrol pharmaceutical composition of the above Example 1 was injected into the subcutaneous fat layer of the inguinal region of the rats in the low dose group of resveratrol, and the injection amount was 10 mg per kg body weight (10 mg per dose). /kg) Resveratrol; that is, 2 mL of the 5 mg/mL resveratrol pharmaceutical composition of the above Example 1 was injected per kg of body weight.
  • the 5 mg/mL resveratrol pharmaceutical composition of the above Example 1 was injected into the subcutaneous fat layer of the inguinal region of the rats in the high dose group of resveratrol, and the injection amount was 20 mg per kg body weight (20 mg per injection).
  • Resveratrol that is, 4 mL of the 5 mg/mL resveratrol pharmaceutical composition of the above Example 1 was injected per kg of body weight.
  • physiological saline solution for the same volume injection was administered by the same injection method as described above.
  • the above injection site was the lower inguinal fat of rats, which was injected on the left and right sides on average, and was injected once on the first, second, third and fourth days of the test.
  • high-fat diet was continuously administered, and changes in body weight were recorded daily.
  • Drinking water was recorded once a week, fasted on the 14th day of the test, and rats were sacrificed with carbon dioxide on the 15th day.
  • the fat in the lower groin of the left and right sides of the rat was weighed, and the fat mass of the inguinal groin of each group was calculated.
  • Data were presented as mean ⁇ SD and statistically analyzed by one-way ANOVA.
  • Statistical results are indicated by symbols or English letters. Different symbols or letters indicate statistical differences between groups (p ⁇ 0.05). The same symbols or letters indicate no statistical difference between groups (p > 0.05).
  • Figure 3 is a bar graph of the effect of the pharmaceutical composition of resveratrol on the amount of subcutaneous fat in rats.
  • Table 3 shows the extent to which the pharmaceutical composition of resveratrol reduces the amount of subcutaneous fat in rats.
  • the subcutaneous fat mass in the inferior groin is the sum of the fat weights on the left and right sides.
  • the frequency of administration for humans is 1 to 12 Times.
  • the frequency of administration to humans is from 1 to 12 times per interval from 1 day to 30 days.
  • the frequency of administration to humans is from 1 to 6 times per interval from 1 day to 30 days.
  • the dosage for humans is 0.2 40 mg/kg.
  • the dosage administered to humans is 0.4 20 mg/kg.
  • the dose applied to humans is 0.2 to 20 mg per square centimeter.
  • the dose applied to humans is 0.4 to 12 mg per square centimeter.
  • Example 4 Lipolysis and weight loss effects of resveratrol compound pharmaceutical composition
  • Green Tea Extract Composition The green tea extract was dissolved using physiological saline for injection to prepare a 5 mg/mL green tea extract composition.
  • mice were fed with high-fat diet to induce an increase in subcutaneous fat. After continuous feeding to a rat weighing 330 ⁇ 10 g, the rats were randomly divided into 4 groups: high-fat control group, green tea extract group, and white. The resveratrol group and the resveratrol-green tea extract compound group, 5 rats in each group, showed no statistical difference in body weight of each group of rats. The body weight of each rat was recorded and defined as the "pre-test weight" of each rat. Then, the drug is administered in the following manner.
  • the 5 mg/mL green tea extract composition of the present example was injected into the subcutaneous fat layer of the inguinal region of the green tea extract group, and each injection was injected with 10 mg (10 mg/kg) of green tea extract per kg of body weight. That is, 2 mL of the 5 mg/mL green tea extract composition of this example was injected per kg of body weight.
  • the 5 mg/mL resveratrol pharmaceutical composition of the above Example 1 was injected into the subcutaneous fat layer of the inguinal region of the rats in the resveratrol group, and the injection amount was 10 mg per kg body weight (10 mg/kg).
  • Resveratrol that is, 2 mL of the 5 mg/mL resveratrol pharmaceutical composition of the above Example 1 was injected per kg of body weight.
  • the 5 mg/mL resveratrol combination medicinal composition of the above Example 2 was injected into the subcutaneous fat layer of the inguinal region of the resveratrol-green tea extract compound group, and the injection amount was 10 per kg of body weight per injection.
  • Mg (10 mg/kg) resveratrol and green tea that is, 2 mL of the 5 mg/mL resveratrol combination medicinal composition of the above Example 2 was injected per kg of body weight.
  • the same volume of physiological saline for injection was administered in the same manner as described above.
  • the above injection site was the lower inguinal fat of rats, which was injected on the left and right sides on average, and was injected once on the first, second, third and fourth days of the test.
  • high-fat diet was continuously administered, and changes in body weight were recorded daily.
  • Drinking water was recorded once a week, fasted on the 14th day of the test, and rats were sacrificed with carbon dioxide on the 15th day.
  • the body weight of each rat was recorded and defined as the "post-test weight” of each rat.
  • the "post-test weight” was subtracted from the “post-test weight” of each rat to obtain “total weight gain”.
  • the total weight gain of each group of rats was divided by the total weight gain of the rats in the high-fat control group to obtain “relative total weight gain”.
  • the fat in the lower groin of the left and right sides of the rat was weighed, and the fat mass of the inguinal groin of each group was calculated.
  • Data were presented as mean ⁇ SD and statistically analyzed by one-way ANOVA.
  • Statistical results are indicated by symbols or English letters. Different symbols or letters indicate statistical differences between groups (p ⁇ 0.05). The same symbols or letters indicate no statistical difference between groups (p > 0.05).
  • the resveratrol-green tea extract compound group Since each group was given 10 mg/kg of the drug, the resveratrol-green tea extract compound group was partially localized. The lipolysis effect should be between the resveratrol group and the green tea extract group. If the resveratrol-green tea extract compound group has better partial lipolysis effect than the resveratrol and green tea extract group, it represents resveratrol and green tea extract in resveratrol-complex medicine composition. having a synergistic effect (sy nerg y) on the efficacy of local fat soluble.
  • Figure 4A is a bar graph of the effect of resveratrol combination medicinal composition on subcutaneous fat mass in rats.
  • Table 4 shows the degree of reduction of subcutaneous fat in rats by the compound composition of resveratrol.
  • the subcutaneous fat mass of the inferior groin is the sum of the fat weights of the left and right sides.
  • the results of the experiment in Fig. 4A showed that the subcutaneous fat at the injection site of the green tea extract group was not reduced as compared with the high fat control group (the administration dose was 10 mg of green tea extract per kg body weight). There was no statistical difference in the amount of subcutaneous fat at the injection site of the rats in the resveratrol group compared with the high-fat control group, but the percentage of local fat reduction was 5.6% (the dose was 10 mg per kg body weight). Resveratrol). The subcutaneous fat content at the injection site of the resveratrol-green tea extract group showed a significant decrease (p ⁇ 0.05), and the local fat reduction percentage reached 18.9% (the dose was 10 mg white per kg body weight). Resveratrol and green tea extract;). That is, the resveratrol compound medicine composition can significantly achieve the effect of reducing local fat, which is 3.4 times that of the resveratrol pharmaceutical composition.
  • This example shows a combination pharmaceutical composition of resveratrol plus green tea extract of the present invention which has a better partial lipolysis effect than the same dose of resveratrol.
  • Figure 4B is a bar graph of the effect of resveratrol combination medicinal composition on relative total weight gain in rats.
  • Table 5 shows the degree of weight loss in rats treated with resveratrol compound medicinal composition.
  • resveratrol and other fat-soluble drugs were used to prepare a compound pharmaceutical composition to evaluate the fat-dissolving effect of various fat-soluble compound medicine compositions on mature fat cells.
  • MTT assay Cell viability assay
  • the DMSO control group cell culture solution, resveratrol cell culture solution, puerarin cell culture solution, quercetin cell culture solution, resveratrol-puerarin compound cell culture solution, and resveratrol were prepared in the following manner. Quercetin compound cell culture fluid.
  • DMSO control group Cell culture medium DMSO was mixed with an appropriate amount of sterile water to prepare a 0.5% DMSO solution.
  • a 0.5% DMSO solution was mixed with a cell culture solution (product name: Dulbecco's Modified Eagle Medium, available from Gibco) to prepare a DMSO control group cell culture solution, wherein the volume ratio of the 0.5% DMSO solution to the cell culture solution was 1 : 1000.
  • Resveratrol cell culture solution Resveratrol is mixed with an appropriate amount of 0.5% DMSO solution to prepare a solution of resveratrol.
  • the resveratrol solution was mixed with a cell culture solution (product name: Dulbecco's Modified Eagle Medium, available from Gibco) to prepare a resveratrol cell culture solution containing 50 ppm of resveratrol, wherein resveratrol
  • the volume ratio of the solution to the cell culture medium was 1:1000.
  • Puerarin cell culture solution Puerarin (purchased from Sigma-Aldrich) was mixed with an appropriate amount of 0.5% DMSO solution to prepare a puerarin solution. The puerarin solution was mixed with the cell culture solution to prepare a puerarin cell culture solution containing 50 ppm of puerarin, wherein the volume ratio of the puerarin solution to the cell culture solution was 1:1000.
  • Quercetin cell culture solution Quercetin (purchased from Sigma-Aldrich) was mixed with an appropriate amount of 0.5% DMSO solution to prepare a quercetin solution. The quercetin solution was mixed with the cell culture solution to prepare a quercetin cell culture solution containing 50 ppm of quercetin, wherein the volume ratio of the puerarin solution to the cell culture solution was 1:1000.
  • Resveratrol-puerarin compound cell culture solution Resveratrol, puerarin, and an appropriate amount of 0.5% DMSO solution are mixed to prepare a resveratrol-puerarin compound solution.
  • the weight ratio of resveratrol to puerarin is 2:3.
  • the resveratrol-puerarin compound solution is mixed with the cell culture solution to prepare a cell culture solution containing 50 ppm of resveratrol-puerarin compound drug, wherein the concentration of resveratrol is 20 ppm, puerarin The concentration was 30 ppm, and the volume ratio of the resveratrol-puerarin complex solution to the cell culture solution was 1:1000.
  • Resveratrol-quercetin compound cell culture solution Resveratrol, quercetin, and an appropriate amount of 0.5% DMSO solution are mixed to prepare a resveratrol-quercetin compound solution.
  • the weight ratio of resveratrol to quercetin is 2:3.
  • the resveratrol-quercetin compound solution is mixed with the cell culture solution to prepare a cell culture solution containing 50 ppm of resveratrol-quercetin compound drug, wherein the concentration of resveratrol is 20 ppm.
  • the concentration of quercetin was 30 ppm, and the volume ratio of the resveratrol-quercetin compound solution to the cell culture solution was 1:1000.
  • 3T3-L1 precursor fat cells purchased from Taiwan Food Industry Development Research Institute, abbreviated as BCRC
  • BCRC Taiwan Food Industry Development Research Institute
  • a cell-differentiated culture medium (DMI medium) containing 0.5 ⁇ ⁇ (purchased from Sigma-Aldrich), 0.1 ⁇ Dexamethasone (purchased from Sigma-Aldrich), and 5 ⁇ M ⁇ Insulin (purchased from Humunlin R) was used. .)) Culture for 2 days.
  • the mature adipocytes were divided into 6 groups: DMSO control group, resveratrol group, puerarin group, quercetin group, resveratrol-puerarin compound group, and resveratrol-quercetin compound group. .
  • DMSO control group cell culture medium, resveratrol cell culture solution, puerarin cell culture solution, quercetin cell culture solution, resveratrol-puerarin compound cell culture solution, and resveratrol-quercetin Compound cell culture solution, Mature fat cells in the DMSO control group, the resveratrol group, the puerarin group, the quercetin group, the resveratrol-puerarin combination group, and the resveratrol-quercetin combination group were cultured for 24 hours.
  • Annexin V protein purchased from eBioscience
  • PI Propidium iodide dye
  • flow cytometry was used to analyze each group of cells by Annexin V.
  • the ratio of protein and PI staining label to assess the proportion of mature adipocytes for apoptosis.
  • mature adipocytes which are simultaneously labeled with Annexin V protein and PI stain, represent that they have entered the apoptotic program; the more mature adipocytes undergo apoptosis, the better the lipolysis effect of the administered drugs is, and represents Lipolysis is through apoptotic procedures rather than necrosis;
  • the apoptosis effect of the resveratrol-puerarin combination group should be between the resveratrol group and the puerarin group. If the apoptosis effect of resveratrol- puerarin compound group is better than that of resveratrol group and puerarin group, it represents resveratrol and puerarin in resveratrol-puerarin compound medicine composition.
  • the effect of lipids has a synergistic effect ( Syner gy).
  • the apoptosis effect of the resveratrol-quercetin combination group should be between the resveratrol group and the quercetin group. If the resveratrol-quercetin combination group has better apoptosis than the resveratrol group and the quercetin group, it represents resveratrol and bismuth in the resveratrol-quercetin compound pharmaceutical composition. Peelin has a synergistic effect on the efficacy of lipolysis.
  • Figure 5 shows the effect of resveratrol-other fat-soluble drug combination on apoptosis of mature adipocytes.
  • the resveratrol-puerarin compound medicine composition has a synergistic effect on the efficacy of the lipolysis (sy nerg y).
  • the compound pharmaceutical composition formed by resveratrol and various fat-soluble drugs can achieve the fat-dissolving effect, and the synergistic effect of resveratrol and various fat-soluble drugs on the fat-soluble effect (sy nerg) y). Therefore, the present invention utilizes resveratrol and various fat-soluble drugs to prepare drug-containing micelles and second fat-soluble drug micelles, thereby preparing resveratrol-other fat-soluble drug compound medicine composition, which can be used as a local A pharmaceutical composition that dissolves fat and reduces weight.
  • the cell viability assay was used to assess whether 50 ppm caffeine (caffeine;), and L-camitine were toxic to cells other than adipocytes, and if not toxic, the lipolysis test was performed.
  • sterile water control group cell culture medium Preparing sterile water control group cell culture medium, resveratrol cell culture solution, caffeine cell culture solution, L-carnitine cell culture solution, resveratrol-caffeine compound cell culture solution, and white gourd in the following manner Alcohol-L-carnitine compound cell culture solution.
  • Aseptic water control group Cell culture medium Sterile water is mixed with the cell culture medium to prepare a sterile water control group cell culture solution. Wherein, the volume ratio of the sterile water to the cell culture solution is 1:1000.
  • Resveratrol cell culture solution The same procedure as for the resveratrol cell culture solution in Experiment 9-2.
  • Caffeine Cell Culture Solution Caffeine (purchased from Sigma-Aldrich) was mixed with an appropriate amount of sterile water to prepare a caffeine solution. The caffeine solution was mixed with the cell culture solution to prepare a caffeine cell culture solution containing 50 ppm of caffeine, wherein the volume ratio of the caffeine solution to the cell culture solution was 1:1000.
  • L-carnitine cell culture solution L-carnitine (purchased from Sigma-Aldrich) was mixed with an appropriate amount of sterile water to prepare a L-carnitine solution.
  • the L-carnitine solution was mixed with the cell culture solution to prepare a L-carnitine cell culture solution containing 50 ppm of L-carnitine, wherein the volume ratio of the L-carnitine solution to the cell culture solution was 1:1000.
  • Resveratrol-caffeine compound cell culture solution Resveratrol, caffeine, and an appropriate amount of sterile water are mixed to prepare a resveratrol-caffeine compound solution.
  • the weight ratio of resveratrol to caffeine is 2:3.
  • the resveratrol-caffeine compound solution is mixed with the cell culture solution to prepare a cell culture solution containing 50 ppm of resveratrol-caffeine compound, wherein the concentration of resveratrol is 20 ppm, caffeine The concentration was 30 ppm, and the volume ratio of resveratrol-caffeine complex solution to cell culture solution was 1:1000.
  • Resveratrol-L-carnitine compound cell culture solution Resveratrol, L-carnitine, and an appropriate amount of sterile water are mixed to prepare a resveratrol-L-carnitine compound solution.
  • the weight ratio of resveratrol to L-carnitine is 2:3.
  • the resveratrol-L-carnitine compound solution is mixed with the cell culture solution to prepare a cell culture solution containing 50 ppm of resveratrol-L-carnitine compound drug, wherein the concentration of resveratrol is 20 ppm.
  • the concentration of L-carnitine was 30 ppm, and the volume ratio of the resveratrol-L-carnitine compound solution to the cell culture solution was 1:1000.
  • the mature adipocytes were divided into 6 groups: sterile water control group, resveratrol group, caffeine group, L-carnitine group, resveratrol-caffeine compound group, and resveratrol-L-carnitine. Compound group.
  • Aseptic water control group cell culture solution, resveratrol cell culture solution, caffeine cell culture solution, L-carnitine cell culture solution, resveratrol-caffeine compound cell culture solution, and resveratrol-left-handed Carnitine compound cell culture medium, respectively, cultured sterile water control group, resveratrol group, caffeine group, L-carnitine group, resveratrol-caffeine compound group, and resveratrol-L-carnitine compound Mature fat cells in the group for 24 hours.
  • Annexin V protein purchased from eBioscience
  • PI Propidium iodide dye
  • flow cytometry was used to analyze the cells of each group by Annexin V protein and PI.
  • mature adipocytes which are simultaneously labeled with Annexin V protein and PI stain, represent that they have entered the apoptotic program; the more mature adipocytes undergo apoptosis, the better the lipolysis effect of the administered drugs is, and represents Lipolysis is through apoptotic procedures rather than necrosis;
  • the apoptosis effect of the resveratrol-caffeine compound group should be close.
  • the average value of the resveratrol group and the caffeine group If the apoptosis effect of the resveratrol-caffeine compound group is significantly better than that of the resveratrol group and the caffeine group, it represents resveratrol in the resveratrol-caffeine compound pharmaceutical composition.
  • caffeine has a synergistic effect on the efficacy of lipolysis.
  • the cells of the resveratrol-L-carnitine compound group The effect of death should be close to the average of the resveratrol group and the L-carnitine group. If the resveratrol-L-carnitine compound group has a significantly better apoptosis effect than the resveratrol group and the L-carnitine group, it represents the white peony in the resveratrol-L-carnitine compound medicine composition. Resveratrol and L-carnitine have a synergistic effect on the efficacy of lipolysis ( Syner gy).
  • Figure 6 shows the effect of resveratrol-other water-soluble drug combination medicinal composition on the decline of mature adipocytes.
  • Carnitine has a synergistic effect on the efficacy of lipolysis.
  • the compound pharmaceutical composition formed by resveratrol and various water-soluble drugs can achieve the fat-dissolving effect, and the resveratrol and various water-soluble drugs have a synergistic effect on the fat-soluble effect (sy nerg) y). Therefore, the present invention utilizes resveratrol and various water-soluble drugs to prepare a resveratrol-water-soluble pharmaceutical compound pharmaceutical composition comprising a drug-containing microcell, which can be used as a pharmaceutical composition for partial fatliquoring and weight loss.
  • the first pharmaceutical composition, the second pharmaceutical composition, the third pharmaceutical composition, the fourth pharmaceutical composition, the fifth pharmaceutical composition, and other pharmaceutical compositions provided by the present invention are provided by the present invention.
  • the first pharmaceutical composition, the second pharmaceutical composition, the third pharmaceutical composition, the fourth pharmaceutical composition, the fifth pharmaceutical composition, and other pharmaceutical compositions provided by the present invention can be used for the production.
  • Preparation of subcutaneous implants, subcutaneous implants, implantable infusions, ointment or salve, or patches which can be implanted subcutaneously, implanted, applied or applied.
  • the percutaneous absorption method is applied to a site where it is desired to reduce subcutaneous fat.
  • the first pharmaceutical composition, the second pharmaceutical composition, the third pharmaceutical composition, the fourth pharmaceutical composition, the fifth pharmaceutical composition, and other pharmaceutical compositions provided by the present invention are provided by the present invention.
  • Subcutaneous fat injection method reduces the fat at the application site. Therefore, the first pharmaceutical composition, the second pharmaceutical composition, the third pharmaceutical composition, the fourth pharmaceutical composition, the fifth pharmaceutical composition, and other pharmaceutical compositions provided by the present invention, which are provided by the present invention, can be used for preparation An injection or subcutaneous injection for subcutaneous fat layer to reduce local subcutaneous fat.

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Abstract

本发明提供一种用于减少局部脂肪的医药组成物，包含医药上可接受的水溶液、表面活性剂所形成的多个含药微胞、以及被包覆在所述含药微胞中的白藜芦醇。所述用于减少局部脂肪的医药组成物可减少施用部位的脂肪，且具有高稳定性、高度脂肪组织生体可用率、低副作用、以及缓释等优点。

Description

用于减少局部脂肪的医药组成物及其用途 技术领域
本发明是关于一种用于减少局部脂肪的医药组成物，特别是关于一种包含多个含药微 胞以及被包覆在含药微胞中的白藜芦醇的医药组成物， 且该医药组成物用于减少局部脂 肪。 背景技术
近年来由于越来越多人对美感的观念改变， 以及对自我健康、 身型的标准提升， 人们 关注的议题已不再是单纯地减重， 而是更加重视减少局部脂肪或雕塑曲线， 以达到更健康 且身型更美观的效果。 况且， 一般的减重方式， 无论是饮食或运动等方式， 无法减少特定 单一部位的脂肪， 若要减少特定部位的脂肪 (例如腰部、 腹部、 腿部、 手臂、 下巴、 以及 脸部等)， 目前的技术只能用抽脂手术等方式达成。
目前， 减少局部脂肪的方法以抽脂手术为主， 然而抽脂过程会对神经、 血管、 及其他 身体组织造成严重的伤害， 且具有感染、 出血量大、 麻醉时间过长、 以及无法事先预防的 脂肪栓塞与麻醉过敏的致死风险。此外，抽脂手术后也易产生严重的瘀青红肿、剧烈疼痛、 恢复期长达 3个月至 6个月以上、 抽脂部位凹凸不平等问题。 因此， 统计显示虽然多数人 想利用抽脂改善局部的皮下脂肪囤积或身体曲线， 但实际进行抽脂手术的人数却还不到 4 成， 显示大多数要改善身体曲线或减少局部脂肪的消费者， 会受到抽脂手术副作用及术后 疼痛或风险等问题的影响而放弃。
虽然， 有一些非手术的局部减脂医药组成物或仪器能降低一部份副作用， 却大多疗效 不佳， 且会产生其他副作用， 例如使周边正常细胞坏死 (necrosis；)、 使周边组织发炎、 及引 发剧烈疼痛等， 且实施部位也有一定的限制。 因此， 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、 恢复期更短的局部减脂医药组成物。
在消费者与医师皆有高度需求的情况下，开发足以突破目前技术限制的局部减脂医药 组成物将是迫切需要被探讨及解决的课题。 发明内容
鉴于习知技术的缺陷， 本发明提供一种用于减少局部脂肪的医药组成物， 包含表面活 性剂所形成的多个含药微胞、 以及被包覆在所述含药微胞中的白藜芦醇。所述用于减少局 部脂肪的医药组成物可减少施用部位的脂肪，且具有高稳定性、高度脂肪组织生体可用率、 低副作用、 以及缓释等优点。
本发明能促使施用部位的脂肪细胞进行细胞凋亡反应 (apoptosis；)， 达到减少施用部位 局部脂肪的目的。 本发明能大幅改善习知技术使周边细胞坏死 (necrosis；)、 及发炎的不良反 应及副作用， 且局部减脂的效果显著优于其他非手术减少局部脂肪的医药组成物。本发明 适用于以直接注射、 皮下植入、 埋植式输注、 软膏或贴布等经皮吸收方式施用于需要减少 皮下脂肪的部位， 而无须任何外科手术或仪器的介入或辅助。 较佳者， 以皮下脂肪注射方 式施用于局部部位的皮下脂肪层。较佳者， 本发明的医药组成物的注射剂型包含但不限于 注射液齐1 J或注射用粉齐 ll(powder for injection, or powder for solution for injection)。 本发明中 所指的局部脂肪包含但不限于腰部、 腹部、 腿部、 手臂、 下巴以及脸部等部位。
本发明中， 白藜芦醇指的是自天然植物萃取所取得或商业上可取得的白藜芦醇。较佳 者， 白藜芦醇的纯度为 90%至 100%。
本发明中，绿茶萃取物指的是以任一种溶剂及任一种萃取方式所提取出的绿茶成分混 合物、商业上可取得的绿茶萃取物、任一种至少包含 45 % (重量百分浓度；)表没食子儿茶素 没食子酸酯 (epigallocatechin gallate, EGCG)的混合物、 或商业上可取得的表没食子儿茶素 没食子酸酯。
本发明中， 微胞 (micelle)指的是由表面活性剂所形成的一微形结构， 该表面活性剂具 有一亲水端以及一亲脂端 (亲油端)， 且该表面活性剂是以该亲水端向外、 亲脂端 (亲油端) 向内而所形成该微形结构。较佳者， 该微形结构为球形、类球形、或其他微形结构的结构。
本发明中， 含药微胞指的是含白藜芦醇的微胞； 亦即， 含药微胞指的是包覆或包含白 藜芦醇的微胞。
本发明中， 第二脂溶性药物微胞指的是含白藜芦醇以外的其他脂溶性药物的微胞。 亦 即， 第二脂溶性药物微胞指的是包覆或包含其他脂溶性药物的微胞。
其中，其他脂溶性药物指的是姜黄素 (CurCUmin)、槲皮素 (qUerCetin)、葛根素 (puerarin)、 及其他白藜芦醇以外的脂溶性药物中的至少一者或其组合； 亦或是， 其他脂溶性药物指的 是白藜芦醇以外的脂溶性药物。
本发明中， 水溶性药物指的是绿茶萃取物、 表没食子儿茶素没食子酸酯 (Epigallocatechin gallate；)、表儿茶素 (Epicatechin；)、表儿茶素没食子酸酯 (Epicatechin gallate；)、 表没食子儿茶素 (Epigallocatechin)、 没食子儿茶素没食子酸酯 (Gallocatechin gallate) ^ 没食 子儿茶素 (Gallocatechin；)、 儿茶素没食子酸酯 (Catechin gallate；)、 儿茶素 (Catechin；)、 表没食 子儿茶素没食子酸酉旨 (epigallocatechin gallate, EGCG)、 咖啡因 (Caffeine)、 肉碱 (Carnitine; 又称为卡尼丁或卡尼汀)、左旋肉碱 (L-carnitine；)、辛内弗林 (Synephrine；)、绿原酸（Chlorogenic acid) 、 及其他水溶性药物中的至少一者或其组合。
本发明中，所用的 "无沉淀物产生的状态"一词指不含人类肉眼可看到的任何沉淀物， 亦即， 无需藉助人工装置。
本发明提供一种用于减少局部脂肪的医药组成物， 包含：
多个含药微胞 (micelle), 均匀分布在该医药上可接受的水溶液中； 以及
被包覆在所述含药微胞中的白藜芦醇 (resveratrol);
于一较佳实施例中，所述含药微胞为医药上可接受的一表面活性剂所形成的一微形结 构， 且该表面活性剂的亲水亲油性平衡值 (hydrophilic-lipophilic balance value, HLB值;)大 于 10。
于一较佳实施例中， 该些含药微胞的粒径为 3 250 nm。
于一较佳实施例中， 该些含药微胞的粒径为 5 ~ 50 nm。
于一较佳实施例中， 该医药组成物中更包括一医药上可接受的水溶液， 且该含药微胞 均匀分布在该医药上可接受的水溶液中。该医药上可接受的水溶液为注射用水、 注射用水 溶液、 或生理食盐水。
于一较佳实施例中， 该表面活性剂为非离子性表面活性剂。
于一较佳实施例中， 该非离子性表面活性剂为聚山梨醇酯 80(Tween 80)、 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15)、 聚氧乙烯蓖麻油衍生物 (polyoxyethylene castor oil derivatives；)、 及其他非离子性表面活性剂中的至少一者或其组 合。
于一较佳实施例中，该聚氧乙烯蓖麻油衍生物为聚氧乙烯 35蓖麻油 (Cremophor ELP；)、 聚氧乙烯 40氢化蓖麻油 (Cremophor RH 40)、 及其他聚氧乙烯蓖麻油衍生物中的至少一者 或其组合。
于一较佳实施例中， 白藜芦醇与该表面活性剂的重量比为 1 : 4至 1 : 500。
于一较佳实施例中， 白藜芦醇与该表面活性剂的重量比为 1 : 5至 1 : 200。
于一较佳实施例中， 白藜芦醇与该表面活性剂的重量比为 1 : 8至 1 : 80。
于一较佳实施例中， 该医药组成物在温度 25°C±2°C、 相对湿度 RH60%±5%、 避免光 线直射的条件下进行加速稳定性试验时，该医药组成物仍维持于无沉淀物产生的状态至少 达 24小时。
于一较佳实施例中， 该医药组成物在温度 25°C±2°C、 相对湿度 RH60%±5%、 避免光 线直射的条件下进行加速稳定性试验时，该医药组成物仍维持于无沉淀物产生的状态至少 达 6个月。
于一较佳实施例中， 白藜芦醇在该医药组成物中的浓度为 0.2~166.7mg/mL。
于一较佳实施例中， 白藜芦醇在该医药组成物中的浓度为 2.5 〜 60 mg/mL。
于一较佳实施例中， 该医药组成物中更包含绿茶萃取物， 且该绿茶萃取物溶解在该医 药上可接受的水溶液中； 其中， 该绿茶萃取物包含：
一第一绿茶萃取成分， 所述第一绿茶萃取成分为表没食子儿茶素没食子酸酯 (epigallocatechin gallate, EGCG)。
于一较佳实施例中，表没食子儿茶素没食子酸酯在该医药组成物中的浓度为 0.25~ 300 于一较佳实施例中， 表没食子儿茶素没食子酸酯在该医药组成物中的浓度为 1 200 于一较佳实施例中， 该表没食子儿茶素没食子酸酯的含量， 以该绿茶萃取物的总重量 于一较佳实施例中， 该白藜芦醇与该绿茶萃取物的重量比为 30: 1至 1 : 30。
于一较佳实施例中， 该白藜芦醇与该绿茶萃取物的重量比为 20: 1至 1 : 20。
于一较佳实施例中， 该白藜芦醇与该绿茶萃取物的重量比为 10: 1至 1 : 10。
于一较佳实施例中， 以该白藜芦醇与该绿茶萃取物的总重量为一个重量单位计之， 该 表面活性剂的重量为 0.24 70个重量单位； 抑或是， 该白藜芦醇与该绿茶萃取物的总重量 与该表面活性剂的重量比为 4: 1至 1 : 70。
于一较佳实施例中，该医药组成物中更包含一医药上可接受的水溶液以及一第二脂溶 性药物微胞， 该第二脂溶性药物微胞均匀分布在该医药上可接受的水溶液中。
该第二脂溶性药物微胞为第二表面活性剂所形成的另一微形结构，且一其他脂溶性药 物 （或第二脂溶性药物） 被包覆在所述第二脂溶性药物微胞中。
于一较佳实施例中， 该第二表面活性剂的亲水亲油性平衡值 (hydrophilic-lipophilic balance value, HLB值)大于 10。
于一较佳实施例中， 该第二表面活性剂为非离子性表面活性剂。
于一较佳实施例中， 该非离子性表面活性剂为聚山梨醇酯 80(Tween 80)、
2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15)、 聚氧乙烯蓖麻油衍生物
(polyoxyethylene castor oil derivatives；)、 及其他非离子性表面活性剂中的至少一者或其组 合。
于一较佳实施例中，该聚氧乙烯蓖麻油衍生物为聚氧乙烯 35蓖麻油 (Cremophor ELP；)、 聚氧乙烯 40氢化蓖麻油 (Cremophor RH 40)、 及其他聚氧乙烯蓖麻油衍生物中的至少一者 或其组合。
于一较佳实施例中， 该脂溶性药物为槲皮素 (quercetin)、 辛弗林 (synephrine)、 葛根素 (puerarin), 姜黄素 (CUrCUmin)、 以及白藜芦醇以外的其他脂溶性药物中的至少一者或其组 合。
于一较佳实施例中， 该白藜芦醇与该第二脂溶性药物的重量比为 30 1 ~1 20 于一较佳实施例中， 该白藜芦醇与该第二脂溶性药物的重量比为 20 1 ~1 于一较佳实施例中， 该白藜芦醇与该第二脂溶性药物的重量比为 15 1 ~1 于一较佳实施例中，该医药组成物中更包括一医药上可接受的水溶液以及一水溶性药 于一较佳实施例中， 该水溶性药物为绿茶萃取物、 表没食子儿茶素没食子酸酯 (Epigallocatechin gallate)、表儿茶素 (Epicatechin)、表儿茶素没食子酸酯 (Epicatechin gallate)、 表没食子儿茶素 (Epigallocatechin)、 没食子儿茶素没食子酸酯 (Gallocatechin gallate)、 没食 子儿茶素 (Gallocatechin；)、 儿茶素没食子酸酯 (Catechin gallate；)、 儿茶素 (Catechin；)、 表没食 子儿茶素没食子酸酉旨 (epigallocatechin gallate, EGCG；)、 咖啡因 (Caffeine；)、 肉碱 (Carnitine; 又称为卡尼丁或卡尼汀)、左旋肉碱 (L-carnitine；)、辛内弗林 (Synephrine；)、绿原酸（Chlorogenic acid) 、 及其他水溶性药物中的至少一者或其组合。
于一较佳实施例中， 该白藜芦醇与该水溶性药物的重量比为 20: 1-1： 30。
于一较佳实施例中， 该白藜芦醇与该水溶性药物的重量比为 15: 1-1： 20。
于一较佳实施例中， 该白藜芦醇与该水溶性药物的重量比为 10: 1-1： 15。
于一较佳实施例中， 该水溶性药物为表没食子儿茶素没食子酸酯， 且表没食子儿茶素 没食子酸酯在该医药组成物中的浓度为 0.25 〜 300 mg/mL。
于一较佳实施例中， 该水溶性药物为表没食子儿茶素没食子酸酯， 且表没食子儿茶素 没食子酸酯在该医药组成物中的浓度为 1~200 mg/mL。
于一较佳实施例中， 该水溶性药物为绿茶萃取物， 且该白藜芦醇与该绿茶萃取物的重 量比为 30: 1至 1 : 30。
于一较佳实施例中， 该水溶性药物为绿茶萃取物， 且该白藜芦醇与该绿茶萃取物的重 量比为 20: 1至 1 : 20。
于一较佳实施例中， 该水溶性药物为绿茶萃取物， 且该白藜芦醇与该绿茶萃取物的重 量比为 10： 1至 1： 10。
于一较佳实施例中，该医药组成物中更包含助溶剂 (Cosolvent )，用以增加药物溶解度。 于一较佳实施例中， 该助溶剂为聚乙二醇 (polyethylene glycol)、 丙二醇 (； propylene glycol) ^ 乙醇 (ethanol)、 以及其他助溶剂中的至少一者或其组合。
于一较佳实施例中， 该聚乙二醇为聚乙二醇 200 (PEG 200)、 聚乙二醇 400 (PEG 400)、 聚乙二醇 600 (PEG 600)、 及其他聚乙二醇中的至少一者或其组合。
于一较佳实施例中， 该医药组成物中更包含助悬剂 (又称为悬浮剂； suspending agent；)， 用以降低药物或微胞的沉降速度。
于一较佳实施例中， 该助悬剂为海藻酸钠 (Sodium alginate)、 甘油 (glycerol)、 羟甲基纤 维素钠 (carboxymethylcellulose sodium；)、 甘露醇 (mannitol)、 以及其他助悬剂中的至少一者 或其组合。
于一较佳实施例中， 该医药组成物中更包含油相赋形剂 (oil phase excipients )， 用以增 加医药组成物的稳定性及药物的溶解度。
于一较佳实施例中， 油相赋形剂为不饱和脂肪酸、 甘油 (glycerol)、 三酸甘油脂 (triglyceride；)、 及其他油相赋形剂中的至少一者或其组合。
于一较佳实施例中， 该不饱和脂肪酸为油酸 (oleic acid；)、 蓖麻油 (castor oil)、 芝麻油 (sesame oil)、 棉子油 (cottonseed oil)、 大豆油 (soybean oil)、 红花子油 (safflower oil)、 玉米油 (corn oil), 以及其他不饱和脂肪酸中的至少一者或其组合。
于一较佳实施例中， 该三酸甘油脂为中链三酸甘油酯 (medium chain triglycerides) ^ 及 其他三酸甘油脂中的至少一者或其组合。
于一较佳实施例中， 该医药上可接受的水溶液中包含局部麻醉剂。
于一较佳实施例中， 该局部麻醉剂为酰胺类、 对氨基苯甲胺脂类、 及胺基醚类中的至 少一者或其组合。
于一较佳实施例中， 该酰胺类为待布卡因 (Dibucaine)、 利多卡因 (Lidocaine)、 甲哌卡 因盐酸盐 (Mepivacaine HC1 ) 、 布比卡因盐酸盐 (Bupivacine HC1 ) 、 吡咯卡因盐酸盐 (Pyrrocaine HC1 ) 、 丙胺卡因盐酸盐 (Prilocaine HC1 ) 、 Digammacaine、 及奥昔卡因 (Oxethazaine) 中的至少一者或其组合。
于一较佳实施例中， 该对氨基苯甲胺脂类为布他卡因（Butacaine；)、 二甲卡因 (Dimethocaine)、 及图托卡因 (Tutocaine)中的至少一者或其组合。
于一较佳实施例中， 该胺基醚类为奎尼卡因 (Quinisocaine；)、 及普莫卡因 (Pramocaine) 的至少一者或其组合。
于一较佳实施例中， 该医药上可接受的水溶液中包含抗氧化剂。
于一较佳实施例中， 该抗氧化剂为 β-胡萝卜素 (beta-carotene)、 叶黄素 (lutein)、 番茄红 素 (lycopene；)、 胆红素 (bilirubin；)、 维生素 A(vitamin A；)、 维生素 C (vitamin C; 又称为抗坏 血酸， 即 ascorbic acid)、维生素 E (vitamin E)、尿酸 (uric acid)、一氧化氮 (nitric oxide) 、 硝基氧（nitroxide)、丙酮酸盐（pyruvate)、过氧化氢酶 (catalase；)、超氧化物歧化酶 (superoxide dismutase；)、 谷胱甘肽过氧化物酶 (； glutathione peroxidases；)、 N-乙酰半胱氨酸 (N-acetyl cysteine；)、 及柚皮素 (naringenin)中的至少一者或其组合。
本发明再提供一种用于减少局部皮下脂肪量的皮下脂肪层注射针剂或皮下注射针剂， 包含- 医药上可接受的水溶液；
多个含药微胞 (micelle), 均匀分布在该医药上可接受的水溶液中； 以及
被包覆在所述含药微胞中的白藜芦醇 (resveratrol);
其中， 所述含药微胞为医药上可接受的一表面活性剂所形成的一微形结构， 且该表面 活性剂的亲水亲油性平衡值 (hydrophilic-lipophilic balance value, HLB值；)大于 10。
于一较佳实施例中， 所述局部皮下脂肪量为施用部位的皮下脂肪量。
于一较佳实施例中， 该些含药微胞的粒径为 3 ~ 250nm。
于一较佳实施例中， 该些含药微胞的粒径为 5 ~ 50 nm。
于一较佳实施例中， 该医药上可接受的水溶液为注射用水、 注射用水溶液、 或生理食 盐水。
于一较佳实施例中， 该表面活性剂为非离子性表面活性剂。
于一较佳实施例中， 该非离子性表面活性剂为聚山梨醇酯 80(Tween 80)、
2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15)、 聚氧乙烯蓖麻油衍生物 (polyoxyethylene castor oil derivatives；)、 及其他非离子性表面活性剂中的至少一者或其组 合。
于一较佳实施例中，该聚氧乙烯蓖麻油衍生物为聚氧乙烯 35蓖麻油 (Cremophor ELP；)、 聚氧乙烯 40氢化蓖麻油 (CremOphOr RH 40)、 及其他聚氧乙烯蓖麻油衍生物中的至少一者 或其组合。
于一较佳实施例中， 白藜芦醇与该表面活性剂的重量比为 1 : 4至 1 : 500。
于一较佳实施例中， 白藜芦醇与该表面活性剂的重量比为 1 : 5至 1 : 200。
于一较佳实施例中， 白藜芦醇与该表面活性剂的重量比为 1 : 8至 1 : 80。
于一较佳实施例中， 白藜芦醇在该皮下脂肪层注射针剂或皮下注射针剂中的浓度为
0.2 166.7 mg/mL。
于一较佳实施例中， 白藜芦醇在该皮下脂肪层注射针剂或皮下注射针剂中的浓度为
Figure imgf000009_0001
于一较佳实施例中， 该皮下脂肪层注射针剂或皮下注射针剂中更包含绿茶萃取物， 且 该绿茶萃取物溶解在该医药上可接受的水溶液中； 其中， 该绿茶萃取物包含：
一第一绿茶萃取成分， 所述第一绿茶萃取成分为表没食子儿茶素没食子酸酯
(epigallocatechin gallate, EGCG)。
于一较佳实施例中，表没食子儿茶素没食子酸酯在该皮下脂肪层注射针剂或皮下注射 针剂中的浓度为 0.25 ~300mg/mL。
于一较佳实施例中，表没食子儿茶素没食子酸酯在该皮下脂肪层注射针剂或皮下注射 针剂中的浓度为 1~200 mg/mL。
于一较佳实施例中， 该表没食子儿茶素没食子酸酯的含量， 以该绿茶萃取物的总重量 为 100重量百分比计之， 为 45 ~ 100%。
于一较佳实施例中， 该白藜芦醇与该绿茶萃取物的重量比为 30: 1至 1 : 30。
于一较佳实施例中， 该白藜芦醇与该绿茶萃取物的重量比为 20: 1至 1 20。
于一较佳实施例中， 该白藜芦醇与该绿茶萃取物的重量比为 10: 1至 1 10。
于一较佳实施例中， 以该白藜芦醇与该绿茶萃取物的总重量为一个重量单位计之， 该 表面活性剂的重量为 0.24 70个重量单位； 抑或是， 该白藜芦醇与该绿茶萃取物的总重量 与该表面活性剂的重量比为 4: 1至 1 : 70。
于一较佳实施例中， 该施用部位的施用剂 ：为每平方公分注射 0.2
于一较佳实施例中， 该施用部位的施用剂 ：为每平方公分注射 0.4
Figure imgf000009_0002
于一较佳实施例中， 该施用部位的施用剂 ：为每公斤 0.2 40毫克。
于一较佳实施例中， 该施用部位的施用剂 ：为每公斤 0.4~20毫克。
于一较佳实施例中， 施用频率为每间隔 1天至 30天施予该施用部位 1次至 12次。 于一较佳实施例中， 施用频率为每间隔 1天至 21天施予该施用部位 1次至 8次。 于一较佳实施例中，该皮下脂肪层注射针剂或皮下注射针剂中更包含一第二脂溶性药 物微胞， 且该第二脂溶性药物微胞为均匀分布在该医药上可接受的水溶液中。
该第二脂溶性药物微胞为另一表面活性剂所形成的一微形结构，且该其他脂溶性药物 被包覆在所述第二脂溶性药物微胞中。
于一较佳实施例中， 该另一表面活性剂的亲水亲油性平衡值 (hydrophilic-lipophilic balance value, HLB值)大于 10。
于一较佳实施例中， 该另一表面活性剂为非离子性表面活性剂。
于一较佳实施例中， 该非离子性表面活性剂为聚山梨醇酯 80(Tween 80)、
2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15)、 聚氧乙烯蓖麻油衍生物 (polyoxyethylene castor oil derivatives；)、 及其他非离子性表面活性剂中的至少一者或其组 合。
于一较佳实施例中，该聚氧乙烯蓖麻油衍生物为聚氧乙烯 35蓖麻油 (Cremophor ELP；)、 聚氧乙烯 40氢化蓖麻油 (Cremophor RH 40)、 及其他聚氧乙烯蓖麻油衍生物中的至少一者 或其组合。
较佳者， 该脂溶性药物为姜黄素 (Curcumin)、 槲皮素 (quercetin)、 葛根素 (puerarin)、 及 其他白藜芦醇以外的脂溶性药物中的至少一者或其组合。
于一较佳实施例中， 该医药上可接受的水溶液中更包含一水溶性药物。
于一较佳实施例中， 该水溶性药物为绿茶萃取物、 表没食子儿茶素没食子酸酯 (Epigallocatechin gallate；)、表儿茶素 (Epicatechin；)、表儿茶素没食子酸酯 (Epicatechin gallate；)、 表没食子儿茶素 (Epigallocatechin)、 没食子儿茶素没食子酸酯 (Gallocatechin gallate) ^ 没食 子儿茶素 (Gallocatechin；)、 儿茶素没食子酸酯 (Catechin gallate；)、 儿茶素 (Catechin；)、 表没食 子儿茶素没食子酸酉旨 (epigallocatechin gallate, EGCG)、 咖啡因 (Caffeine)、 肉碱 (Carnitine; 又称为卡尼丁或卡尼汀)、左旋肉碱 (L-carnitine；)、辛内弗林 (Synephrine；)、绿原酸（Chlorogenic acid) 、 及其他水溶性药物中的至少一者或其组合。
于一较佳实施例中， 该医药上可接受的水溶液中包含局部麻醉剂。
于一较佳实施例中， 该局部麻醉剂为酰胺类、 对氨基苯甲胺脂类、 及胺基醚类中的至 少一者或其组合。
于一较佳实施例中， 该酰胺类为待布卡因 (Dibucaine)、 利多卡因 (Lidocaine)、 甲哌卡 因盐酸盐 (Mepivacaine HC1 ) 、 布比卡因盐酸盐 (Bupivacine HC1) 、 吡咯卡因盐酸盐 (Pyrrocaine HC1 ) 、 丙胺卡因盐酸盐 （Prilocaine HC1 ) 、 Digammacaine、 及奥昔卡因 (Oxethazaine) 中的至少一者或其组合。
于一较佳实施例中， 该对氨基苯甲胺脂类为布他卡因（Butacaine；)、 二甲卡因 (Dimethocaine)、 及图托卡因 (Tutocaine)的至少一者或其组合。
于一较佳实施例中， 该胺基醚类为奎尼卡因 (Quinisocaine；)、 及普莫卡因 (Pramocaine) 的至少一者或其组合。
于一较佳实施例中， 该医药上可接受的水溶液中包含抗氧化剂。
于一较佳实施例中， 该抗氧化剂为 β-胡萝卜素 (beta-carotene)、 叶黄素 (lutein)、 番茄红 素 (lycopene；)、 胆红素 (bilirubin；)、 维生素 A(vitamin A；)、 维生素 C (vitamin C; 又称为抗坏 血酸， 即 ascorbic acid)、维生素 E (vitamin E)、尿酸 (uric acid)、一氧化氮 (nitric oxide) 、 硝基氧（nitroxide)、丙酮酸盐（pyruvate)、过氧化氢酶 (catalase；)、超氧化物歧化酶 (superoxide dismutase)、 谷胱甘肽过氧化物酶（glutathione peroxidases)、 N-乙酰半胱氨酸 (N-acetyl cysteine；)、 及柚皮素 (naringenin)中的至少一者或其组合。
本发明提供一种减少个体局部部位的皮下脂肪量的方法，包括在该个体的该局部部位 施用一医药组成物， 其中， 该医药组成物包含：
多个含药微胞 (micelle); 以及
被包覆在所述含药微胞中的白藜芦醇 (resveratrol);
其中， 所述含药微胞为医药上可接受的一表面活性剂而形成的一微形结构， 且该表面 活性剂的亲水亲油性平衡值 (hydrophilic-lipophilic balance value, HLB值；)大于 10。
于一较佳实施例中， 该些含药微胞的粒径为 3 〜 250 nm。
于一较佳实施例中， 该些含药微胞的粒径为 5 ~ 50 nm。
于一较佳实施例中， 该表面活性剂为非离子性表面活性剂。
于一较佳实施例中， 该非离子性表面活性剂为聚山梨醇酯 80(Tween 80)、 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15)、 聚氧乙烯蓖麻油衍生物 (polyoxyethylene castor oil derivatives；)、 及其他非离子性表面活性剂中的至少一者或其组 合。
于一较佳实施例中，该聚氧乙烯蓖麻油衍生物为聚氧乙烯 35蓖麻油 (Cremophor ELP；)、 聚氧乙烯 40氢化蓖麻油 (Cremophor RH 40)、 及其他聚氧乙烯蓖麻油衍生物中的至少一者 或其组合。
于-一较佳实施例中， 其中， 白藜芦醇与该表面活性剂的重量比为 1 : 4至 1 : 500。 于-一较佳实施例中， 其中， 白藜芦醇与该表面活性剂的重量比为 1 :
于-一较佳实施例中， 其中， 白藜芦醇与该表面活性剂的重量比为 1 : 8至 1 : 80
o 于-一较佳实施例中， 其中， 白藜芦醇在该医药组成物中的浓度为 0.2 〜166.7 mg/m oL。 于-一较佳实施例中， 其中， 白藜芦醇在该医药组成物中的浓度为 2.5 〜 60 mg/mL。 于-一较佳实施例中，该医药组成物中更包含一医药上可接受的水溶液以及一第二脂溶 性药物微胞， 该第二脂溶性药物微胞为均匀分布在该医药上可接受的水溶液中； 其中， 该 第二脂溶性药物微胞为第二非离子性表面活性剂所形成的另一微形结构，且一第二脂溶性 药物被包覆在所述第二脂溶性药物微胞中。
于一较佳实施例中， 该第二非离子性表面活性剂的亲水亲油性平衡值 (hydrophilic-lipophilic balance value, HLB值)大于 10。
于一较佳实施例中， 该第二非离子性表面活性剂为聚山梨醇酯 80(Tween 80)、
2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15)、 聚氧乙烯蓖麻油衍生物 (polyoxyethylene castor oil derivatives；)、 及其他非离子性表面活性剂中的至少一者或其组 合。
于一较佳实施例中， 该第二非离子性表面活性剂为聚氧乙烯 35 蓖麻油 (Cremophor ELP), 聚氧乙烯 40氢化蓖麻油 (Cremophor RH 40)、 及其他聚氧乙烯蓖麻油衍生物中的至 少一者或其组合。
于一较佳实施例中， 该第二脂溶性药物为槲皮素 (quercetin)、 辛弗林 (synephrine)、 葛 根素（puerarin)、 姜黄色素类物质（curcuminoid)、 姜黄素（curcumin)、 及其他白藜芦醇 (resveratrd)以外的脂溶性药物至少一者或其组合。
于一较佳实施例中， 该白藜芦醇与该第二脂溶性药物的重量比为 ： 。 于一较佳实施例中， 该白藜芦醇与该第二脂溶性药物的重量比为 ： 。 于一较佳实施例中， 该白藜芦醇与该第二脂溶性药物的重量比为 ： 。 于一较佳实施例中，该医药组成物中更包含一医药上可接受的水溶液以及一水溶性药 于一较佳实施例中， 该水溶性药物为绿茶萃取物、 表没食子儿茶素没食子酸酯 (Epigallocatechin gallate)、表儿茶素 (Epicatechin)、表儿茶素没食子酸酯 (Epicatechin gallate)、 表没食子儿茶素 (Epigallocatechin)、 没食子儿茶素没食子酸酯 (Gallocatechin gallate)、 没食 子儿茶素 (Gallocatechin；)、 儿茶素没食子酸酯 (Catechin gallate；)、 儿茶素 (Catechin；)、 表没食 子儿茶素没食子酸酉旨 (epigallocatechin gallate, EGCG；)、 咖啡因 (Caffeine；)、 肉碱 (Carnitine; 又称为卡尼丁或卡尼汀)、左旋肉碱 (L-carnitine；)、辛内弗林 (Synephrine；)、绿原酸（Chlorogenic acid) 、 及其他水溶性药物中的至少一者或其组合。
于一较佳实施例中， 该白藜芦醇与该水溶性药物的重量比为 20
于一较佳实施例中， 该白藜芦醇与该水溶性药物的重量比为 20 于一较佳实施例中， 该白藜芦醇与该水溶性药物的重量比为
于一较佳实施例中， 该水溶性药物为表没食子儿茶素没食子酸酯， 且表没食子儿茶素 没食子酸酯在该医药组成物中的浓度为 0.25 300 mg/mL。
于一较佳实施例中， 该水溶性药物为表没食子儿茶素没食子酸酯， 且表没食子儿茶素 没食子酸酯在该医药组成物中的浓度为 mg/mL。
于一较佳实施例中， 该水溶性药物为绿茶萃取物， 且该白藜芦醇与该绿茶萃取物的重 量比为 至 。
于一较佳实施例中， 该水溶性药物为绿茶萃取物， 且该白藜芦醇与该绿茶萃取物的重 量比为 至 。
于一较佳实施例中， 该水溶性药物为绿茶萃取物， 且该白藜芦醇与该绿茶萃取物的重 量比为 ： 至 ： 。
于一较佳实施例中， 以该白藜芦醇与该绿茶萃取物的总重量为一个重量单位计之， 该 表面活性剂的重量为 0.24 70个重量单位； 抑或是， 该白藜芦醇与该绿茶萃取物的总重量 与该表面活性剂的重量比为 至 。
于一较佳实施例中， 在该局部部位施用该医药组成物的剂量为每平方公分注射 0.2 ~ 20毫克。
于一较佳实施例中， 在该局部部位施用该医药组成物的剂量为每平方公分注射 0.4 ~ 于一较佳实施例中， 在该局部部位施用该医药组成物的剂量为每公斤 0.2 ~ 40毫克。 于一较佳实施例中， 在该局部部位施用该医药组成物的剂量为每公斤 0.4 ~ 20毫克。 于一较佳实施例中，施用该医药组成物的频率为每间隔 1天至 30天施予该施用部位 1 次至 12次。
于一较佳实施例中，施用该医药组成物的频率为每间隔 1天至 21天施予该施用部位 1 次至 8次。
于一较佳实施例中， 该个体为一动物或一人类。
于一较佳实施例中， 为在该个体的该局部部位注射、 或涂抹 (apply)该医药组成物。 于一较佳实施例中，该医药组成物中更包含一助溶剂 (cosolvent；)、一助悬剂 (suspending agent ) , 以及一油相赋形剂 (oil phase excipients；)中的至少一者或其组合。
于一较佳实施例中， 该油相赋形剂及 /或助溶剂与该非离子性表面活性剂共同形成该 微形结构。
本发明提供一种医药组成物在制备用于减少个体局部部位皮下脂肪量的药物或皮下 注射剂 (subcutaneous inj ection formulation)的用途； 该医药组成物包含：
多个含药微胞 (micelle); 以及
被包覆在所述含药微胞中的白藜芦醇 (resveratrol);
其中， 所述含药微胞为医药上可接受的一非离子表面活性剂所形成的一微形结构， 且 该非离子表面活性剂的亲水亲油性平衡值 (hydrophilic-lipophilic balance value, HLB值；)大 于 ιο。
于一较佳实施例中， 该些含药微胞的粒径为 3 250 nm。
于一较佳实施例中， 该些含药微胞的粒径为 5~50 nm。
于一较佳实施例中， 该非离子性表面活性剂为聚山梨醇酯 80(Tween 80)、 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15)、 聚氧乙烯蓖麻油衍生物 (polyoxyethylene castor oil derivatives；)、 及其他非离子性表面活性剂中的至少一者或其组 合。
于一较佳实施例中，该聚氧乙烯蓖麻油衍生物为聚氧乙烯 35蓖麻油 (Cremophor ELP；)、 聚氧乙烯 40氢化蓖麻油 (Cremophor RH 40)、 及其他聚氧乙烯蓖麻油衍生物中的至少一者 或其组合。
于一较佳实施例中， 白藜芦醇与该非离子表面活性剂的重量比为 1 : 4至 1 : 500。 于一较佳实施例中， 白藜芦醇在该医药组成物中的浓度为 0.2〜 166.7 mg/mL。
于一较佳实施例中，该医药组成物中更包含一医药上可接受的水溶液以及一第二脂溶 性药物微胞， 该第二脂溶性药物微胞为均匀分布在该医药上可接受的水溶液中； 其中， 该 第二脂溶性药物微胞为第二非离子性表面活性剂所形成的另一微形结构，且一第二脂溶性 药物被包覆在所述第二脂溶性药物微胞中。 于一较佳实施例中， 该第二非离子性表面活性剂的亲水亲油性平衡值 (hydrophilic-lipophilic balance value, HLB值)大于 10。
于一较佳实施例中， 该第二非离子性表面活性剂为聚山梨醇酯 80(Tween 80)、 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15)、 聚氧乙烯蓖麻油衍生物 (polyoxyethylene castor oil derivatives；)、 及其他非离子性表面活性剂中的至少一者或其组 合。
于一较佳实施例中， 该第二非离子性表面活性剂为聚氧乙烯 35 蓖麻油 (Cremophor ELP)^ 聚氧乙烯 40氢化蓖麻油 (Cremophor RH 40)、 及其他聚氧乙烯蓖麻油衍生物中的至 少一者或其组合。
于一较佳实施例中， 该第二脂溶性药物为槲皮素 (quercetin)、 辛弗林 (synephrine)、 葛 根素 Cpuerarin)、 姜黄色素类物质 (curcuminoid)及其他白藜芦醇 (resveratrol)以外的脂溶性药 物中的至少一者或其组合。
于一较佳实施例中， 该白藜芦醇与该第二脂溶性药物的重量比为 30: 1 - 1： 20。 于一较佳实施例中，该医药组成物中更包含一医药上可接受的水溶液以及一水溶性药 物。
于一较佳实施例中， 该水溶性药物为绿茶萃取物、 表没食子儿茶素没食子酸酯 (Epigallocatechin gallate)、表儿茶素 (Epicatechin)、表儿茶素没食子酸酯 (Epicatechin gallate)、 表没食子儿茶素 (Epigallocatechin)、 没食子儿茶素没食子酸酯 (Gallocatechin gallate)、 没食 子儿茶素 (Gallocatechin；)、 儿茶素没食子酸酯 (Catechin gallate；)、 儿茶素 (Catechin；)、 表没食 子儿茶素没食子酸酉旨 (epigallocatechin gallate, EGCG；)、 咖啡因 (Caffeine；)、 肉碱 (Carnitine; 又称为卡尼丁或卡尼汀)、左旋肉碱 (L-carnitine；)、辛内弗林 (Synephrine；)、绿原酸（Chlorogenic acid) 、 及其他水溶性药物中的至少一者或其组合。
于一较佳实施例中， 该白藜芦醇与该水溶性药物的重量比为 20: 1 - 1： 30。
于一较佳实施例中， 该水溶性药物为表没食子儿茶素没食子酸酯， 且表没食子儿茶素 没食子酸酯在该皮下脂肪层注射针剂或皮下注射针剂中的浓度为 0.25~300mg/mL。
于一较佳实施例中， 该水溶性药物为绿茶萃取物， 且该白藜芦醇与该绿茶萃取物的重 量比为 30: 1至 1 : 30。
于一较佳实施例中， 以该白藜芦醇与该绿茶萃取物的总重量为一个重量单位计之， 该 非离子表面活性剂的重量为 0.24 70个重量单位； 抑或是， 该白藜芦醇与该绿茶萃取物的 总重量与该非离子表面活性剂的重量比为 4: 1至 1 : 70。
于一较佳实施例中， 该药物或皮下注射剂中包含治疗有效量的该医药组成物。
于一较佳实施例中， 治疗有效量为每平方公分局部部位施用 0.2〜 20毫克该医药组成 于一较佳实施例中， 治疗有效量为每公斤体重施用 0.2 40毫克该医药组成物。
于一较佳实施例中， 该药物或皮下注射剂的施用频率为每间隔 1天至 30天施予该施 用部位 1次至 12次。
于一较佳实施例中， 该个体为一动物。
于一较佳实施例中， 为在该个体的该局部部位注射该药物或皮下注射剂； 抑或是， 在 该个体的该局部部位涂抹 (apply)该药物。
于一较佳实施例中，该医药组成物中更包含一助溶剂 (cosolvent；)、一助悬剂 (suspending agent ) , 以及一油相赋形剂 (oil phase excipients；)的至少一者或其组合。
于一较佳实施例中， 该油相赋形剂及 /或助溶剂与该非离子性表面活性剂共同形成该 微形结构。 附图说明
图 1A: 无微胞的白藜芦醇皮下注射液及无微胞的绿茶萃取物皮下注射液对大鼠皮下 脂肪量影响的长条图。
图 1B: 无微胞的白藜芦醇皮下注射液及无微胞的绿茶萃取物皮下注射液对大鼠相对 总增重影响的长条图。
图 2A: 利用不同赋形剂制备出的白藜芦醇皮下注射针剂， 对大鼠局部皮下脂肪量影 响的长条图。
图 2B: 利用不同赋形剂制备出的白藜芦醇皮下注射针剂， 对大鼠相对总增重影响的 长条图。
图 3 : 白藜芦醇医药组成物对大鼠皮下脂肪量影响的长条图。
图 4A: 白藜芦醇复方医药组成物对大鼠皮下脂肪量影响的长条图。
图 4B: 白藜芦醇复方医药组成物对大鼠相对总增重影响的长条图。
图 5 : 白藜芦醇 -其他脂溶性药物复方医药组成物对成熟脂肪细胞进行细胞凋亡的影 响。
图 6: 白藜芦醇 -其他水溶性药物复方医药组成物对成熟脂肪细胞进行细胞凋亡的影 响。 具体实施方式
白藜芦醇 (resveratrol)为一种多酚类化合物， 主要存在于红葡萄皮、 虎杖、 或红酒中。 由于白藜芦醇难溶于水溶液、 容易在体内快速代谢成葡萄糖醛酸与硫酸盐代谢物、 会快速 经由尿液及粪便排出、 以及其身体可利用率极差等原因， 利用白藜芦醇开发减少局部脂肪 的医药组成物会面临相当程度的困难。发明人在开发此医药组成物的初期，即面临此困境。
实验一： 白藜芦醇及绿茶萃取物皮下注射液对大鼠皮下脂肪量及体重的影响 配制绿茶萃取物皮下注射液： 利用注射用水 (water for injection)将绿茶萃取物配制成 5 mg/mL水溶液。 以 0.2 μιη滤膜过滤， 即为本实验所述的 5 mg/mL绿茶萃取物皮下注射液。 须避光保存于 4°C冰箱。 配制白藜芦醇皮下注射液：利用习知常用于非水溶性药物注射剂的赋形剂聚山梨醇酯 80 (polysorbate 80, Tween 80)、 溶媒乙醇、 以及注射用水将白藜芦醇配制成 5 mg/mL溶液。 详细配制方法如下： 将 0.5 g白藜芦醇与适量溶媒乙醇混合， 使白藜芦醇完全溶解后， 再 加入 0.1 g聚山梨醇酯 80 (Tween 80)， 使聚山梨醇酯完全溶解； 抽气挥发 2 ~ 4小时， 使乙 醇挥发； 待乙醇完全挥发后， 加入注射用水， 使总体积为 100 mL; 搅拌均匀后， 再以 0.2 μιη滤膜过滤， 即为本实验所述的 5 mg/mL的白藜芦醇皮下注射液。 须避光保存于 4°C冰 箱。
使用 7周龄 SD品系雄性大鼠 (male Sprague-Dawley rat)进行实验。 首先， 以高脂饲料 (high-fat diet, 厂牌为 Research Diets, Inc.; 型号为 #1)12492；)喂食 18只大鼠诱导皮下脂肪增 力 B， 连续喂食至大鼠体重达 330±10 g后， 将大鼠随机分成 3组， 分别为高脂对照组、 白 藜芦醇组、 及绿茶萃取物组， 每组 6只大鼠， 使各组大鼠的体重无统计差异。 记录每只大 鼠的体重， 定义为每只大鼠的 "试验前体重" 。 然后， 以下列方式给予药物。
将 5 mg/mL的白藜芦醇皮下注射液， 注射至白藜芦醇组大鼠的下腹股沟的皮下脂肪 层，每次注射量为每公斤体重注射 8 mg (8 mg/kg)白藜芦醇；亦即，每公斤体重注射 1.6 mL 上述 5 mg/mL的白藜芦醇皮下注射液。 将 5 mg/mL的绿茶萃取物皮下注射液， 注射至绿 茶萃取物组大鼠的下腹股沟的皮下脂肪层， 每次注射量为每公斤体重注射 8 mg (8 mg/kg) 绿茶萃取物； 亦即， 每公斤体重注射 1.6 mL上述 5 mg/mL的绿茶萃取物皮下注射液。 高 脂对照组则以上述同样注射方式给予同体积注射用水。
上述注射部位为大鼠下腹股沟脂肪处， 平均注射于左、 右两侧， 于试验第 1、 3、 5日 各注射 1次。试验期间持续给予高脂饲料，并每日记录体重变化，每周记录饮水摄食一次， 于试验第 20天禁食， 第 21天以二氧化碳牺牲大鼠。
记录每只大鼠的体重， 定义为每只大鼠的 "试验后体重"。 将每只大鼠的 "试验后体 重"扣除 "试验前体重"， 得到 "总增重" 。 将各组大鼠的总增重除以高脂对照组大鼠的 总增重， 得到 "相对总增重" 。
取大鼠左右两侧下腹股沟的脂肪进行秤重， 并计算各组下腹股沟的脂肪量。 以平均值
±SD方式呈现数据， 并以单因子变异数分析 （one-way ANOVA) 进行统计。 统计结果以 符号或英文字母表示， 不同符号或字母表示组间具有统计差异 (p< 0.05)， 相同符号或字母 则表示组间不具有统计差异 (p> 0.05)。
请参阅图 1A以及图 1B， 图 1 A为无微胞的白藜芦醇皮下注射液及无微胞的绿茶萃取 物皮下注射液对大鼠皮下脂肪量影响的长条图。 图 1B为无微胞的白藜芦醇皮下注射液及 无微胞的绿茶萃取物皮下注射液对大鼠相对总增重影响的长条图。其中， 所述下腹股沟脂 肪量为左右两侧下腹股沟脂肪量的总和。
图 1A结果显示， 经 3次皮下脂肪注射给药后， 与高脂对照组相比， 白藜芦醇组和绿 茶萃取物组注射部位局部脂肪量都没有显著减少 (p> 0.05), 显示直接将溶解后的白藜芦醇 或绿茶萃取物注射到皮下脂肪层， 无法减少注射部位的局部脂肪。 图 IB结果显示， 经 3次皮下脂肪注射给药后， 与高脂对照组相比， 白藜芦醇组和绿 茶萃取物组大鼠的体重都没有显著减少 (p> 0.05), 显示直接将溶解后的白藜芦醇或绿茶萃 取物注射到皮下脂肪层， 无法减少体重。
其中， 绿茶萃取物为水溶性极佳的成分， 先前的细胞实验研究发现， 其可促进脂肪细 胞凋亡， 但将绿茶萃取物溶解后直接注射于皮下脂肪处， 竟无法减少其局部皮下脂肪， 也 无法减少体重。 由本实验可知， 直接将白藜芦醇或绿茶萃取物溶解后注射到皮下脂肪层， 不足以减少局部脂肪及体重。发明人为了克服此问题， 进一步研究开发出本发明包含白藜 芦醇的医药组成物。
实验二： 不同种类的白藜芦醇皮下注射针剂对大鼠皮下脂肪量及体重的影响 以下列方式配制白藜芦醇生理食盐水溶液、 白藜芦醇 PEG溶液、 以及白藜芦醇 ELP 溶液。
白藜芦醇生理食盐水溶液的配制方法：
将 500mg白藜芦醇与适量的注射用生理食盐水混合， 使最终体积达 100mL。 搅拌均 匀， 使白藜芦醇完全溶解， 即可得到白藜芦醇生理食盐水溶液， 且所述白藜芦醇生理食盐 水溶液中的白藜芦醇浓度为 5mg/mL。
白藜芦醇 PEG溶液的配制方法：
将 15 g 聚乙二醇 400 (polyethylene glycol 400， 简称为 PEG400)、 15 g甘油 (glycerol)、 以及适量的注射用生理食盐水混合， 使最终体积达 100 mL。 搅拌均匀， 使聚乙二醇 400 及甘油完全溶解， 得到聚乙二醇暨甘油混合液。 将 450 mg白藜芦醇与适量的聚乙二醇暨 甘油混合液混合， 使最终体积达 90 ml。 搅拌均匀， 使白藜芦醇完全溶解， 即可得到白藜 芦醇 PEG溶液。 所述白藜芦醇 PEG溶液中的白藜芦醇浓度为 5mg/mL。
白藜芦醇 ELP溶液的配制方法：
将 500 mg 白藜芦醇与 100 160 mL 二氯甲垸 (dichloromethane)混合， 于室温下以 150~500rpm搅伴至白藜芦醇完全溶解。 加入 20 g聚氧乙烯 35蓖麻油 (Kolliphor ELP, 简 称为 ELP)， 在转速 100 300 rpm条件下搅拌均匀， 使二氯甲垸挥发。 待二氯甲垸完全挥 发后， 缓慢加入注射用生理食盐水， 使最终体积达 100 mL, 搅拌均匀， 即可得到白藜芦 醇 ELP溶液。 所述白藜芦醇 ELP溶液中的白藜芦醇浓度为 5mg/mL、 聚氧乙烯 35蓖麻油 (ELP)的浓度约为 20% (重量百分比；)、 且白藜芦醇与聚氧乙烯 35蓖麻油的重量比为 1 : 40。
使用 6周龄 SD品系雄性大鼠 (male Sprague-Dawley rat)进行实验。 首先， 以高脂饲料 (high-fat diet, 厂牌为 Research Diets, Inc.; 型号为 #D12492)喂食 20只大鼠诱导皮下脂肪增 力口， 连续喂食至大鼠体重达 330±10 g后， 将大鼠随机分成 4组， 分别为控制组、 生理食 盐水组、 PEG组及 ELP组， 每组 5只大鼠， 使各组大鼠的体重无统计差异。 记录每只大 鼠的体重， 定义为每只大鼠的 "试验前体重" 。 然后， 以下列方式给予药物。
将白藜芦醇生理食盐水溶液、 白藜芦醇 PEG溶液、 以及白藜芦醇 ELP溶液， 分别注 射至生理食盐水组、 PEG组及 ELP组大鼠的下腹股沟的皮下脂肪层， 每次注射量为每公 斤体重注射 4 mL(4mL/kg), 使得每次注射剂量都是每公斤体重施予 20 mg白藜芦醇 （20 mg/kg; 计算方式为 4mL/kg χ 5 mg/mL = 20 mg/kg), 控制组则以上述同样注射方式给予同 体积注射用生理食盐水。
上述注射部位为大鼠下腹股沟脂肪处， 平均注射于左、 右两侧， 于试验第 1、 2、 3、 4 日各注射 1次。 试验期间持续给予高脂饲料， 并每日记录体重变化， 每周记录饮水摄食一 次， 试验共进行 14天， 于第 15天以二氧化碳牺牲大鼠。
记录每只大鼠的体重， 定义为每只大鼠的 "试验后体重"。 将每只大鼠的 "试验后体 重"扣除 "试验前体重"， 得到 "总增重" 。 将各组大鼠的总增重除以控制组大鼠的总增 重， 得到 "相对总增重" 。
取大鼠左右两侧下腹股沟的皮下脂肪进行秤重，并将左右两侧下腹股沟皮下脂肪量加 总， 以计算出下腹股沟皮下脂肪量。将各组大鼠的下腹股沟皮下脂肪量除以控制组大鼠的 下腹股沟皮下脂肪量， 得到 "下腹股沟皮下脂肪相对重量" 。
以平均值±80方式呈现数据， 并以单因子变异数分析 （ one-way ANOVA) 进行统计。 统计结果以符号或英文字母表示， 不同符号或字母表示组间具有统计差异 (p< 0.05)， 相同 符号或字母则表示组间不具有统计差异 (p> 0.05)。
请参阅图 2A及图 2B。 图 2A是利用不同赋形剂制备出的白藜芦醇皮下注射针剂， 对 大鼠局部皮下脂肪量影响的长条图。 图 2B是利用不同赋形剂制备出的白藜芦醇皮下注射 针剂， 对大鼠相对总增重影响的长条图。
图 2A的结果显示， 控制组大鼠的下腹股沟皮下脂肪相对重量为 100±27.6%， 生理食 盐水组大鼠的下腹股沟皮下脂肪相对重量为 108.2±24.7%， PEG组大鼠的下腹股沟皮下脂 肪相对重量为 114.0±4.4%， ELP组大鼠的下腹股沟皮下脂肪相对重量为 72.5±0.0%。 生理 食盐水组大鼠的下腹股沟皮下脂肪相对重量与控制组大鼠之间无显著差异，显示直接将白 藜芦醇注射至施用部位的皮下脂肪层， 无法减少施用部位的脂肪 (局部脂肪；)。 PEG组大鼠 的下腹股沟皮下脂肪相对重量与控制组大鼠之间无显著差异； ELP组大鼠的下腹股沟皮下 脂肪相对重量与控制组大鼠之间则有显著差异 (p<0.05)， 且 ELP组大鼠的下腹股沟皮下脂 肪相对重量减少 27.5%。
图 2B的结果显示， 控制组大鼠的相对总增重为 100.0±30.8 %， 生理食盐水组大鼠的 相对总增重为 128.3±16.9%， PEG组大鼠的相对总增重为 120.8±18.2%， ELP组大鼠的相 对总增重为 101.3±22.0%， 四组之间无显著差异 (p> 0.05)。
由上述实验可知， 直接将白藜芦醇注射至施用部位的皮下脂肪层， 无法减少施用部位 的脂肪 (局部脂肪；)， 也无法减少体重。 将添加赋形剂 PEG (—般常见的助溶剂;)的白藜芦醇 组合物注射至施用部位的皮下脂肪层， 无法减少施用部位的脂肪 (局部脂肪；)， 也无法减少 体重， 但将添加非离子性表面活性剂 ELP 的白藜芦醇组合物注射至施用部位的皮下脂肪 层， 却能够显著减少施用部位的脂肪 (局部脂肪；)。 因此， 需要进一步探讨白藜芦醇组合物 是否必须含有非离子性表面活性剂，才能减少施用部位的皮下脂肪 (局部脂肪)、减少体重。 进一步分析发现上述施用的白藜芦醇 PEG溶液中没有微胞， 白藜芦醇 ELP溶液中则 具有微胞， 且白藜芦醇是被包覆在 ELP 形成的微胞中。 因此， 更需要进一步探讨微胞对 减少局部脂肪及减少体重的影响。
实验三：包含微胞的白藜芦醇单方组成物皮下注射针剂对大鼠皮下脂肪量及体重的影 响
以下列方式配制白藜芦醇 ELP部分微胞剂型、 白藜芦醇 HS-15部分微胞剂型、 白藜 芦醇 ELP微胞剂型、 以及白藜芦醇 HS-15微胞剂型。
白藜芦醇 ELP部分微胞剂型的配制方法： 将 20 g聚氧乙烯 35蓖麻油 (即 ELP)与适量 的注射用生理食盐水混合，使最终重量达 100 go搅拌均匀，使聚氧乙烯 35蓖麻油 (即 ELP) 完全溶解， 获得 20% ELP溶液。将 400 mg白藜芦醇与适量的 20% ELP溶液混合， 使最终 重量达 80 g。搅拌均匀， 使白藜芦醇完全溶解， 即可得到白藜芦醇 ELP部分微胞剂型。所 述白藜芦醇 ELP部分微胞剂型中的白藜芦醇浓度约为 5mg/mL、 聚氧乙烯 35蓖麻油 (ELP) 的浓度约为 20% (重量百分比；)、 且白藜芦醇与聚氧乙烯 35蓖麻油的重量比约为 1 : 40。
白藜芦醇 HS-15部分微胞剂型的配制方法:将 20 g聚乙二醇硬脂酸酯 15 (Kolliphor HS 15， 简称为 HS-15)与适量的注射用生理食盐水混合， 使最终重量达 100 g。 搅拌均匀， 使 聚乙二醇硬脂酸酯 15 (BP HS-15;)完全溶解， 获得 20% HS-15溶液。 将 400 mg白藜芦醇与 适量的 20% HS-15溶液混合， 使最终重量达 80 g。搅拌均匀， 使白藜芦醇完全溶解， 即可 得到白藜芦醇 HS-15部分微胞剂型。所述白藜芦醇 HS-15部分微胞剂型中的白藜芦醇浓度 约为 5mg/mL、 聚乙二醇硬脂酸酯 15 (即 HS-15)的浓度约为 20% (重量百分比)、 且白藜芦 醇与聚乙二醇硬脂酸酯 15 (即 HS-15)的重量比约为 1 : 40。
白藜芦醇 ELP微胞剂型的配制方法： 与实验二中的白藜芦醇 ELP溶液的配制方法相 同。
白藜芦醇 HS-15微胞剂型的配制方法： 将 500 mg的白藜芦醇与 80 140 mL的二氯甲 垸混合， 于室温下以 150~500rpm搅拌至白藜芦醇完全溶解。 加入 20 g聚乙二醇硬脂酸酯 15 (Kolliphor HS 15, 简称为 HS-15), 在转速 100 ~300 rpm条件下搅拌均匀， 使二氯甲垸 挥发。 待二氯甲垸完全挥发后， 缓慢加入注射用生理食盐水， 使最终体积达 100 g， 搅拌 均匀， 以形成多个含药微胞， 即可得到白藜芦醇 HS-15 微胞剂型。 所述白藜芦醇 HS-15 微胞剂型中的白藜芦醇浓度约为 5mg/g、聚乙二醇硬脂酸酯 15 (HS-15)的浓度为 20% (重量 百分比；)、 且白藜芦醇与聚乙二醇硬脂酸酯 15 (HS-15)的重量比为 1 : 40。
利用粒径分析仪 (particle size analyzer)测定白藜芦醇 ELP 部分微胞剂型、 白藜芦醇
HS-15部分微胞剂型、 白藜芦醇 ELP微胞剂型、 以及白藜芦醇 HS-15微胞剂型中是否含有 微胞 (micelle), 并测量微胞的粒径大小。
结果显示， 白藜芦醇 ELP部分微胞剂型、 以及白藜芦醇 HS-15部分微胞剂型中都含 有大量沉淀物， 且含药微胞的数量较少。 白藜芦醇 ELP微胞剂型、 以及白藜芦醇 HS-15 微胞剂型则为澄清无分层， 且含药微胞的数量较多。 由此可知， 虽然白藜芦醇 ELP部分微胞剂型、 以及白藜芦醇 HS-15部分微胞剂型中 都含有大量沉淀物， 但上清液中仍含有微胞， 因此， 白藜芦醇 ELP 部分微胞剂型、 白藜 芦醇 HS-15部分微胞剂型、 白藜芦醇 ELP微胞剂型、 以及白藜芦醇 HS-15微胞剂型都是 本发明的医药组成物。
使用 6周龄 SD品系雄性大鼠 (male Sprague-Dawley rat)进行实验。 首先， 以高脂饲料
(high-fat diet, 厂牌为 Research Diets, Inc.; 型号为 #D 12492)喂食 20只大鼠诱导皮下脂肪增 力口， 连续喂食至大鼠体重达 330±10 g后， 将大鼠随机分成 5组， 分别为控制组、 ELP部 分微胞组、 HS-15部分微胞组、 ELP微胞组、 以及 HS-15微胞组， 每组 4只大鼠， 使各组 大鼠的体重无统计差异。记录每只大鼠的体重， 定义为每只大鼠的"试验前体重"。然后， 以下列方式给予药物。
将白藜芦醇 ELP部分微胞剂型、 白藜芦醇 HS-15部分微胞剂型、 白藜芦醇 ELP微胞 剂型、 以及白藜芦醇 HS-15微胞剂型分别混合均匀后 (使部分微胞剂型中的沉淀物均匀悬 浮；)， 分别注射至 ELP部分微胞组、 HS-15部分微胞组、 ELP微胞组、 以及 HS-15微胞组 大鼠的下腹股沟的皮下脂肪层，每次注射量为每公斤体重注射 4 mL(4mL/kg)，使得每次注 射剂量都是每公斤体重施予 20 mg白藜芦醇 C20 mg/kg; 计算方式为 4mL/kg χ 5 mg/mL = 20 mg/kg), 控制组则以上述同样注射方式给予同体积注射用生理食盐水。
上述注射部位为大鼠下腹股沟脂肪处， 平均注射于左、右两侧， 于试验第 1、 2、 3、 4、 5、 6日各注射 1次。试验期间持续给予高脂饲料， 并每日记录体重变化， 每周记录饮水摄 食一次， 试验共进行 14天， 于第 15天以二氧化碳牺牲大鼠。
记录每只大鼠的体重， 定义为每只大鼠的 "试验后体重"。 将每只大鼠的 "试验后体 重"扣除 "试验前体重"， 得到 "总增重" 。 将各组大鼠的总增重除以控制组大鼠的总增 重， 得到 "相对总增重" 。
取大鼠左右两侧下腹股沟的皮下脂肪进行秤重，并将左右两侧下腹股沟皮下脂肪量加 总， 以计算出下腹股沟皮下脂肪量。将各组大鼠的下腹股沟皮下脂肪量除以控制组大鼠的 下腹股沟皮下脂肪量， 得到 "下腹股沟皮下脂肪相对重量" 。
以平均值±80方式呈现数据， 并以单因子变异数分析 （one-way ANOVA)进行统计。 统计结果以符号或英文字母表示， 不同符号或字母表示组间具有统计差异 (p< 0.05)， 相同 符号或字母则表示组间不具有统计差异 (p> 0.05)。
由上述的剂型配制方法以及粒径分析结果可知， 白藜芦醇 ELP 部分微胞剂型及白藜 芦醇 ELP微胞剂型中的 ELP浓度、 白藜芦醇浓度都一致， 仅含药微胞的数量具有差异。 因此， 与白藜芦醇 ELP部分微胞剂型相比， 若是白藜芦醇 ELP微胞剂型使得施用部位局 部脂肪显著减少，代表形成含药微胞是白藜芦醇组成物能显著减少施用部位局部脂肪的关 键因子； 若是白藜芦醇 ELP微胞剂型使得体重显著减少， 代表形成含药微胞是白藜芦醇 组成物能显著减少体重的关键因子。
同样地， 白藜芦醇 HS-15部分微胞剂型及白藜芦醇 HS-15微胞剂型中的 HS-15浓度、 白藜芦醇浓度都一致， 仅含药微胞的数量具有差异。 因此， 与白藜芦醇 HS-15部分微胞剂 型相比， 若是白藜芦醇 HS-15微胞剂型使得施用部位局部脂肪显著减少， 代表形成含药微 胞是白藜芦醇组成物能显著减少施用部位局部脂肪的关键因子；若是白藜芦醇 HS-15微胞 剂型使得体重显著减少， 代表形成含药微胞是白藜芦醇组成物能显著减少体重的关键因 子。
实验结果显示， 将白藜芦醇 ELP部分微胞剂型、 或白藜芦醇 HS-15部分微胞剂型注 射至施用部位的皮下脂肪层， 都能减少施用部位脂肪 (局部脂肪)。 另一方面， 将白藜芦醇 ELP微胞剂型、或白藜芦醇 HS-15微胞剂型注射至施用部位的皮下脂肪层， 也能减少施用 部位脂肪 (局部脂肪)。 四种剂型之间， 以白藜芦醇 ELP微胞剂型的局部溶脂效果最好。
与白藜芦醇 ELP部分微胞剂型相比， 白藜芦醇 ELP微胞剂型能显著减少局部脂肪。 与白藜芦醇 HS-15部分微胞剂型相比， 白藜芦醇 HS-15微胞剂型能显著减少局部脂肪。
由此可知， 形成微胞是白藜芦醇组成物能显著减少施用部位局部脂肪的关键因子， 且 以含有聚氧乙烯蓖麻油衍生物 (例如 ELP)所形成的含药微胞的局部溶脂效果最好。
实验结果显示， 将白藜芦醇 ELP部分微胞剂型、 或白藜芦醇 HS-15部分微胞剂型注 射至施用部位的皮下脂肪层， 都能减少体重。 另一方面， 将白藜芦醇 ELP微胞剂型、 或 白藜芦醇 HS-15微胞剂型注射至施用部位的皮下脂肪层， 也能减少体重。 四种剂型之间， 以白藜芦醇 ELP微胞剂型的减重效果最好。
由本实验可知， 形成微胞是白藜芦醇组成物能显著减少体重的关键因子， 且以含有聚 氧乙烯蓖麻油衍生物 (例如 ELP)所形成的含药微胞的减重效果最好。
实验四： 制备用于减少局部脂肪的医药组成物
本实验利用白藜芦醇制备第一医药组成物，并利用白藜芦醇及绿茶萃取物制备第二医 药组成物。
制备第一医药组成物的步骤如下：
(a)将第一重量的白藜芦醇与溶媒混合，于室温下以 200~500rpm搅拌至白藜芦醇完全 溶解；
(b) 加入第二重量的医药上可接受的一表面活性剂， 在转速 100 300 rpm条件下搅拌 均匀，使溶媒挥发， 其中， 该表面活性剂的亲水亲油性平衡值 (hydrophilic-lipophilic balance value, HLB值)大于 10;
(c) 待溶媒完全挥发后， 缓慢加入第三重量的医药上可接受的水溶液， 搅拌均匀， 获 得多个含药微胞； 以及
(d) 以 0.2 μιη滤膜过滤后， 将含有含药微胞的滤液避光冷藏保存；
其中， 步骤 (c)中， 该含药微胞为表面活性剂所形成的一微形结构， 且白藜芦醇被包覆 在所述含药微胞中。
较佳者， 第三重量为大于或等于 0g。
较佳者， 步骤 (a)中， 溶媒的沸点小于纯水的沸点。 较佳者， 步骤 (a)中， 溶媒为亲水性溶媒。
较佳者，该亲水性溶媒为甲醇、乙醇、丙酮及其他亲水性溶媒中的至少一者或其组合。 较佳者， 步骤 (a)中的溶媒为亲脂性溶媒。
较佳者， 该亲脂性溶媒为乙醚、 苯、 氯仿、 乙酸乙酯、 二氯甲垸、 己垸及其他亲脂性 溶媒中的至少一者或其组合。
较佳者， 步骤 (b)中， 该表面活性剂为非离子性表面活性剂。
较佳者， 该非离子性表面活性剂为聚山梨醇酯 80(Tween 80)、 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15)、 聚氧乙炼蓖麻油衍生物 (polyoxyethylene castor oil derivatives) ^ 及其他非离子性表面活性剂中的至少一者或其组合。
较佳者， 该聚氧乙烯蓖麻油衍生物为聚氧乙烯 35蓖麻油 (Crem0ph0r ELP)、 聚氧乙烯
40氢化蓖麻油 (Cremophor RH 40)、 及其他聚氧乙烯蓖麻油衍生物中的至少一者或其组合。
较佳者， 步骤 (a)及 (b)中， 该第一重量的白藜芦醇与该第二重量的表面活性剂的重量 比为 1 : 4至 1 : 500。
较佳者，步骤 (a)及 (c)中，该第一重量的白藜芦醇与该第三重量的医药上可接受的水溶 液的重量比为 1 : 400至 3 : 50。
较佳者， 步骤 (c)中， 该该医药上可接受的水溶液为注射用水、 注射用水溶液、 或生理 食盐水。
较佳者， 步骤 (c)中， 该医药上可接受的水溶液中包含局部麻醉剂。
较佳者， 该局部麻醉剂为酰胺类、 对氨基苯甲胺脂类、 及胺基醚类中的至少一者或其 组合。
较佳者， 该酰胺类为待布卡因 (Dibucaine；)、 利多卡因 (Lidocaine；)、 甲哌卡因盐酸盐 (Mepivacaine HC1) 、 布比卡因盐酸盐 （ Bupivacine HC1 ) 、 吡咯卡因盐酸盐 （Pyrrocaine HC1 ) 、 丙胺卡因盐酸盐 （Prilocaine HC1) 、 Digammacaine、 及奥昔卡因 （Oxethazaine) 中的至少一者或其组合。
较佳者， 该对氨基苯甲胺脂类为布他卡因 (Butacaine；)、 二甲卡因 (Dimethocaine；)、 及图 托卡因 (Tutocaine)的至少一者或其组合。
较佳者， 该胺基醚类为奎尼卡因 (Quinisocaine；)、 及普莫卡因 (Pramocaine)的至少一者 或其组合。
较佳者， 步骤 (c)中， 该医药上可接受的水溶液中包含抗氧化剂。
较佳者，该抗氧化剂为 β-胡萝卜素 (beta-carotene；)、叶黄素 (lutein；)、番茄红素 (lycopene；)、 胆红素 (bilirubin；)、维生素 A(vitamin K)、维生素 C (vitamin C;又称为抗坏血酸，即 ascorbic acid)、维生素 E (vitamin E)、尿酸 (uric acid)、一氧化氮 (nitric oxide)、硝基氧 (nitroxide)、 丙酮酸盐 (pyruvate) 、 过氧化氢酶 (catalase)、 超氧化物歧化酶 (superoxide dismutase)、 谷 胱甘肽过氧化物酶 (glutathione peroxidases；)、 N-乙酰半胱氨酸 (N-acetyl cysteine；)、 及柚皮素 (naringenin)中的至少一者或其组合。 制备第二医药组成物的步骤如下：
(al)将第四重量的白藜芦醇与溶媒混合， 于室温下以 200~500rpm搅拌至白藜芦醇完 全溶解；
(bl) 加入第五重量的医药上可接受的一表面活性剂， 在转速 100 -300 rpm条件下搅 拌均匀， 使溶媒挥发， 其中， 该表面活性剂的亲水亲油性平衡值 (hydrophilic-lipophilic balance value, HLB值)大于 10;
(cl) 待溶媒完全挥发后， 缓慢加入第六重量的第一医药上可接受的水溶液， 在转速 100 300 rpm条件下搅拌均匀， 以形成多个含药微胞； 以及
(dl) 以 0.2 μιη滤膜过滤后， 将含有含药微胞的滤液避光冷藏保存；
其中， 该第一医药上可接受的水溶液中包含第七重量的绿茶萃取物； 该绿茶萃取物包 含一第一绿茶萃取成分， 所述第一绿茶萃取成分为表没食子儿茶素没食子酸酯。
较佳者， 步骤 (al)中， 溶媒的沸点小于纯水的沸点。
较佳者， 步骤 (al)中， 溶媒为亲水性溶媒。
较佳者，该亲水性溶媒为甲醇、乙醇、丙酮及其他亲水性溶媒中的至少一者或其组合。 较佳者， 步骤 (al)中的溶媒为亲脂性溶媒。
较佳者， 该亲脂性溶媒为乙醚、 苯、 氯仿、 乙酸乙酯、 二氯甲垸、 己垸及其他亲脂性 溶媒中的至少一者或其组合。
较佳者， 步骤 (bl)中， 该表面活性剂为非离子性表面活性剂。
较佳者， 该非离子性表面活性剂系聚山梨醇酯 80(Tween 80)、 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15)、 聚氧乙炼蓖麻油衍生物 (polyoxyethylene castor oil derivatives) ^ 及其他非离子性表面活性剂中的至少一者或其组合。
较佳者， 该聚氧乙烯蓖麻油衍生物为聚氧乙烯 35蓖麻油 (Crem0ph0r ELP)、 聚氧乙烯 40氢化蓖麻油 (Cremophor RH 40)、 及其他聚氧乙烯蓖麻油衍生物中的至少一者或其组合。
较佳者， 在步骤 (cl)与步骤 (dl)之间， 更包含步骤：
(cl l) 加入第八重量的第二医药上可接受的水溶液， 搅拌均匀， 使第二医药上可接受 的水溶液完全溶解。
较佳者， 该绿茶萃取物为溶解在该第一医药上可接受的水溶液中， 该含药微胞为表面 活性剂所形成的一微形结构， 且白藜芦醇被包覆在所述含药微胞中。
较佳者， 该第一医药上可接受的水溶液中的绿茶萃取物中， 表没食子儿茶素没食子酸 酯的含量， 以该绿茶萃取物的总重量为 100重量百分比计之， 为 45 ~ 100 %。
较佳者，步骤 (al)及 (cl)中，该第四重量的白藜芦醇与该第七重量的绿茶萃取物的重量 比为 30: 1至 1 : 30 。
较佳者， 步骤 (al)~(cl)中， 以该第四重量的白藜芦醇与该第七重量的绿茶萃取物的总 重量为一个重量单位计之， 该第五重量的表面活性剂的重量为 0.24 70个重量单位； 抑或 是， 该白藜芦醇与该绿茶萃取物的总重量与该表面活性剂的重量比为 4: 1至 1 : 70。 较佳者， 步骤 (al)、 (cl), 及 (cl l)中， 以该第四重量的白藜芦醇与该第七重量的绿茶 萃取物的总重量为一个重量单位计之，该第六重量的第一医药上可接受的水溶液与该第八 重量的第二医药上可接受的水溶液的总重量为 16 400个重量单位； 抑或是， 该第四重量 与该第七重量的总和： 该第六重量与该第八重量的总和为 1 :400 3:50。
该白藜芦醇与该绿茶萃取物的总重量为一个重量单位计之，该第一医药上可接受的水 溶液与该第二医药上可接受的水溶液的总重量为 10 1000个重量单位； 抑或是， 该白藜芦 醇与该绿茶萃取物的总重量：该第一医药上可接受的水溶液与该第二医药上可接受的水溶 液的总重量为 1 : 1000 - 1： 10。
较佳者， 步骤 (cl)及 (cl l)中， 该第一医药上可接受的水溶液及该第二医药上可接受的 水溶液为注射用水、 注射用水溶液、 或生理食盐水。
较佳者， 步骤 (cl)中， 该第一医药上可接受的水溶液中包含局部麻醉剂。
较佳者， 该局部麻醉剂为酰胺类、 对氨基苯甲胺脂类、 及胺基醚类中的至少一者或其 组合。
较佳者， 该酰胺类为待布卡因 (Dibucaine；)、 利多卡因 (Lidocaine；)、 甲哌卡因盐酸盐 (Mepivacaine HC1) 、 布比卡因盐酸盐 （ Bupivacine HC1 ) 、 吡咯卡因盐酸盐 （Pyrrocaine HC1 ) 、 丙胺卡因盐酸盐 （Prilocaine HC1) 、 Digammacaine、 及奥昔卡因 （Oxethazaine) 中的至少一者或其组合。
较佳者， 该对氨基苯甲胺脂类为布他卡因 (Butacaine；)、 二甲卡因 (Dimethocaine；)、 及图 托卡因 (Tutocaine)的至少一者或其组合。
较佳者， 该胺基醚类为奎尼卡因 (Quinisocaine；)、 及普莫卡因 (Pramocaine)的至少一者 或其组合。
较佳者， 步骤 (cl)中， 该医药上可接受的水溶液中包含抗氧化剂。
较佳者，该抗氧化剂为 β-胡萝卜素 (beta-carotene)、叶黄素 Clutein)、番茄红素 Clycopene)、 胆红素 (bilirubin；)、维生素 A(vitamin K)、维生素 C (vitamin C;又称为抗坏血酸，即 ascorbic acid)、维生素 E (vitamin E)、尿酸 (uric acid)、一氧化氮 (nitric oxide)、硝基氧 (nitroxide)、 丙酮酸盐 (pyruvate) 、 过氧化氢酶 (catalase)、 超氧化物歧化酶 (superoxide dismutase)、 谷 胱甘肽过氧化物酶 (glutathione peroxidases；)、 N-乙酰半胱氨酸 (N-acetyl cysteine；)、 及柚皮素 (naringenin)中的至少一者或其组合。
本实验利用白藜芦醇及水溶性药物制备第三医药组成物，并利用白藜芦醇及其他脂溶 性药物制备第四医药组成物以及第五医药组成物。
制备第三医药组成物的步骤如下：
(a2)将白藜芦醇与溶媒混合， 于室温下以 200~500rpm搅拌至白藜芦醇完全溶解； (b2) 加入医药上可接受的一表面活性剂， 在转速 100 -300 rpm条件下搅拌均匀， 使 溶媒挥发， 其中， 该表面活性剂的亲水亲油性平衡值 Chydrophilic-lipophilic balance value, HLB值；)大于 10; (c2)待溶媒完全挥发后， 缓慢加入第一医药上可接受的水溶液， 在转速 100 300 rpm 条件下搅拌均匀， 以形成多个含药微胞； 以及
(d2) 以 0.2 μιη滤膜过滤后， 将含有含药微胞的滤液避光冷藏保存；
其中， 该第一医药上可接受的水溶液中包含水溶性药物。
较佳者， 该第一医药上可接受的水溶液中包含局部麻醉剂。
较佳者， 该局部麻醉剂为酰胺类、 对氨基苯甲胺脂类、 及胺基醚类中的至少一者或其 组合。
较佳者， 该酰胺类为待布卡因 (Dibucaine；)、 利多卡因 (Lidocaine；)、 甲哌卡因盐酸盐 (Mepivacaine HC1) 、 布比卡因盐酸盐 （ Bupivacine HC1 ) 、 吡咯卡因盐酸盐 （Pyrrocaine HC1 ) 、 丙胺卡因盐酸盐 （Prilocaine HC1) 、 Digammacaine、 及奥昔卡因 （Oxethazaine) 中的至少一者或其组合。
较佳者， 该对氨基苯甲胺脂类为布他卡因 (Butacaine；)、 二甲卡因 (Dimethocaine；)、 及图 托卡因 (Tutocaine)的至少一者或其组合。
较佳者， 该胺基醚类为奎尼卡因 (Quinisocaine；)、 及普莫卡因 (Pramocaine)的至少一者 或其组合。
较佳者， 该医药上可接受的水溶液中包含抗氧化剂。
较佳者，该抗氧化剂为 β-胡萝卜素 (beta-carotene)、叶黄素 (lutein)、番茄红素 (lycopene)、 胆红素 (bilirubin；)、维生素 A(vitamin K)、维生素 C (vitamin C;又称为抗坏血酸，即 ascorbic acid)、维生素 E (vitamin E)、尿酸 (uric acid)、一氧化氮 (nitric oxide)、硝基氧 (nitroxide)、 丙酮酸盐 （pyruvate) 、 过氧化氢酶 (catalase)、 超氧化物歧化酶 (superoxide dismutase)、 谷 胱甘肽过氧化物酶 (glutathione peroxidases；)、 N-乙酰半胱氨酸 (N-acetyl cysteine；)、 及柚皮素 (naringenin)中的至少一者或其组合。
较佳者， 步骤 (a2)中， 溶媒的沸点小于纯水的沸点。
较佳者， 步骤 (a2)中， 溶媒为亲水性溶媒。
较佳者，该亲水性溶媒为甲醇、乙醇、丙酮及其他亲水性溶媒中的至少一者或其组合。 较佳者， 步骤 (a2)中的溶媒为亲脂性溶媒。
较佳者， 该亲脂性溶媒为乙醚、 苯、 氯仿、 乙酸乙酯、 二氯甲垸、 己垸及其他亲脂性 溶媒中的至少一者或其组合。
较佳者， 步骤 (b2)中， 该表面活性剂为非离子性表面活性剂。
较佳者， 该非离子性表面活性剂为聚山梨醇酯 80(Tween 80)、 2-hydroxyethyl
12-hydroxyoctadecanoate (solutol HS 15)、 聚氧乙炼蓖麻油衍生物 (polyoxyethylene castor oil derivatives) ^ 及其他非离子性表面活性剂中的至少一者或其组合。
较佳者， 该聚氧乙烯蓖麻油衍生物系聚氧乙烯 35蓖麻油 (Crem0ph0r ELP)、 聚氧乙烯 40氢化蓖麻油 (Cremophor RH 40)、 及其他聚氧乙烯蓖麻油衍生物中的至少一者或其组合。
较佳者， 在步骤 (c2)与步骤 (d2)之间， 更包含步骤： (c21) 加入第二医药上可接受的水溶液， 搅拌均匀， 使第二医药上可接受的水溶液完 全溶解。
较佳者， 该水溶性药物溶解在该第一医药上可接受的水溶液中， 该含药微胞为表面活 性剂所形成的一微形结构， 且白藜芦醇被包覆在所述含药微胞中。
较佳者， 该第一医药上可接受的水溶液中的水溶性药物， 为绿茶萃取物、 表没食子儿 茶素没食子酸酯 (Epigallocatechin gallate)、 表儿茶素 (Epicatechin)、 表儿茶素没食子酸酯 (Epicatechin gallate)、 表没食子儿茶素 (Epigallocatechin)、 没食子儿茶素没食子酸酯 (Gallocatechin gallate)、 没食子儿茶素 (Gallocatechin)、 儿茶素没食子酸酯 (Catechin gallate)、 儿茶素 (Catechin；)、 表没食子儿茶素没食子酸酯 (epigallocatechin gallate, EGCG)^ 咖啡因 (Caffeine；)、 肉碱 (Carnitine; 又称为卡尼丁或卡尼汀）、 左旋肉碱 (L-carnitine；)、 辛内弗林 (Synephrine)^ 绿原酸 （ Chi orogenic acid) 、 及其他水溶性药物中的至少一者或其组合。
较佳者， 步骤 (a2)及 (c2)中， 该白藜芦醇与该水溶性药物的重量比为 30: 1至 1 : 30。 较佳者， 步骤 (a2)~(c2)中， 以该白藜芦醇与该水溶性药物的总重量为一个重量单位计 之， 该表面活性剂的重量为 0.24 70个重量单位； 抑或是， 该白藜芦醇与该水溶性药物的 总重量与该表面活性剂的重量比为 4: 1至 1 : 70。
较佳者， 步骤 (a2)、 (c2), 及 (c21)中， 以该白藜芦醇与该水溶性药物的总重量为一个 重量单位计之，该第一医药上可接受的水溶液与该第二医药上可接受的水溶液的总重量为 16-400 个重量单位； 抑或是， 该第四重量与该第七重量的总和： 该第六重量与该第八重 量的总和为 1 :400~3 :50。
较佳者， 步骤 (c2)及 (c21)中， 该第一医药上可接受的水溶液及该第二医药上可接受的 水溶液为注射用水、 注射用水溶液、 或生理食盐水。
制备第四医药组成物的步骤如下：
(A) 制备含药微胞次组合物的步骤， 用以制备一含药微胞次组合物；
(B ) 制备第二脂溶性药物微胞次组合物的步骤， 用以制备一第二脂溶性药物微胞次 组合物： 以及
( C ) 将该含药微胞次组合物与该第二脂溶性药物微胞次组合物混合， 以制备出该第 四医药组成物；
其中， 该制备含药微胞次组合物的步骤 (A)包含下列步骤 (a3)~(d3):
(a3) 将白藜芦醇与第一溶媒混合，于室温下以 200~500rpm搅拌至白藜芦醇完全溶解； (b3) 加入医药上可接受的第一表面活性剂， 在转速 100 -300 rpm条件下搅拌均匀， 使第一溶媒挥发， 其中， 该第一表面活性剂的亲水亲油性平衡值 (hydrophilic-lipophilic balance value, HLB值)大于 10;
(c3) 待第一溶媒完全挥发后， 缓慢加入医药上可接受的水溶液， 搅拌均匀， 以形成多 个含药微胞； 以及
(d3) 以 0.2 μιη滤膜过滤后， 滤液即为含有含药微胞的该含药微胞次组合物； 而且， 该制备第二脂溶性药物微胞次组合物的步骤 (B)包含下列步骤 (a4)~(d4):
(a4)将一其他脂溶性药物与第二溶媒混合， 于室温下以 200~500rpm搅拌至使该其他 脂溶性药物完全溶解；
(b4) 加入医药上可接受的第二表面活性剂， 在转速 100 -300 rpm条件下搅拌均匀， 使第二溶媒挥发， 其中， 该第二表面活性剂的亲水亲油性平衡值 (hydrophilic-lipophilic balance value, HLB值)大于 10;
(c4)待第二溶媒完全挥发后， 缓慢加入医药上可接受的水溶液， 搅拌均匀， 以形成多 个第二脂溶性药物微胞； 以及
(d4) 以 0.2 μιη滤膜过滤后， 滤液即为含有第二脂溶性药物微胞的该第二脂溶性药物 微胞次组合物。
其中， 步骤 (c3)中， 该含药微胞为第一表面活性剂所形成的一微形结构， 且白藜芦醇 被包覆在所述含药微胞中。 步骤 (c4)中， 该第二脂溶性药物微胞为第二表面活性剂所形成 的一微形结构， 且该其他脂溶性药物被包覆在所述第二脂溶性药物微胞中。
较佳者， 该脂溶性药物为姜黄素 (Curcumin)、 槲皮素 (quercetin)、 葛根素 (puerarin)、 及 其他白藜芦醇以外的脂溶性药物的至少一者或其组合。
较佳者， 步骤 (a3)或 /及步骤 (a4)中， 第一溶媒或 /及第二溶媒的沸点小于纯水的沸点。 较佳者， 步骤 (a3)或 /及步骤 (a4)中， 第一溶媒或 /及第二溶媒为亲水性溶媒。
较佳者，该亲水性溶媒为甲醇、乙醇、丙酮及其他亲水性溶媒中的至少一者或其组合。 较佳者， 步骤 (a3)或 /及 (a4)中的第一溶媒或 /及第二溶媒为亲脂性溶媒。
较佳者， 该亲脂性溶媒为乙醚、 苯、 氯仿、 乙酸乙酯、 二氯甲垸、 己垸及其他亲脂性 溶媒中的至少一者或其组合。
较佳者， 步骤 (b3)或 /及 (b4)中， 该第一表面活性剂或 /及第二表面活性剂为非离子性表 面活性剂。
较佳者， 该非离子性表面活性剂为聚山梨醇酯 80(Tween 80)、 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15)、 聚氧乙炼蓖麻油衍生物 (polyoxyethylene castor oil derivatives) ^ 及其他非离子性表面活性剂中的至少一者或其组合。
较佳者， 该聚氧乙烯蓖麻油衍生物为聚氧乙烯 35蓖麻油 (Crem0ph0r ELP)、 聚氧乙烯 40氢化蓖麻油 (Cremophor RH 40)、 及其他聚氧乙烯蓖麻油衍生物中的至少一者或其组合。
较佳者， 步骤 (a3)及 (b3)中， 该白藜芦醇与该第一表面活性剂的重量比为 1 : 4至 1 : 500。
较佳者， 步骤 (a4)及 (b4)中， 该其他脂溶性药物与该第二表面活性剂的重量比为 1 : 4 至 1 : 500。
较佳者，步骤 (a3)及 (c3)中，该白藜芦醇与该医药上可接受的水溶液的重量比为 1 : 400 至 3 : 50。
较佳者，步骤 (a4)及 (c4)中，该其他脂溶性药物与该医药上可接受的水溶液的重量比为 1： 400至 3 : 50。
较佳者， 步骤 (c3)或 /及 (c4)中， 该医药上可接受的水溶液为注射用水、 注射用水溶液、 或生理食盐水。
较佳者， 步骤 (c3)或 /及 (c4)中， 该医药上可接受的水溶液中包含局部麻醉剂。
较佳者， 该局部麻醉剂为酰胺类、 对氨基苯甲胺脂类、 及胺基醚类中的至少一者或其 组合。
较佳者， 该酰胺类为待布卡因 (Dibucaine；)、 利多卡因 (Lidocaine；)、 甲哌卡因盐酸盐 (Mepivacaine HC1) 、 布比卡因盐酸盐 （ Bupivacine HC1 ) 、 吡咯卡因盐酸盐 （Pyrrocaine HC1 ) 、 丙胺卡因盐酸盐 （Prilocaine HC1) 、 Digammacaine、 及奥昔卡因 （Oxethazaine) 中的至少一者或其组合。
较佳者， 该对氨基苯甲胺脂类为布他卡因 (Butacaine；)、 二甲卡因 (Dimethocaine；)、 及图 托卡因 (Tutocaine)的至少一者或其组合。
较佳者， 该胺基醚类为奎尼卡因 (Quinisocaine；)、 及普莫卡因 (Pramocaine)的至少一者 或其组合。
较佳者， 步骤 (c3)或 /及 (c4)中， 该医药上可接受的水溶液中包含抗氧化剂。
较佳者，该抗氧化剂为 β-胡萝卜素 (beta-carotene)、叶黄素 (lutein)、番茄红素 (lycopene)、 胆红素 (bilirubin；)、维生素 A(vitamin K)、维生素 C (vitamin C;又称为抗坏血酸，即 ascorbic acid)、维生素 E (vitamin E)、尿酸 (uric acid)、一氧化氮 (nitric oxide)、硝基氧 (nitroxide)、 丙酮酸盐 (pyruvate) 、 过氧化氢酶 (catalase)、 超氧化物歧化酶 (superoxide dismutase)、 谷 胱甘肽过氧化物酶 (glutathione peroxidases；)、 N-乙酰半胱氨酸 (N-acetyl cysteine；)、 及柚皮素 (naringenin)中的至少一者或其组合。
制备第五医药组成物的步骤如下：
(a5)将白藜芦醇以及其他脂溶性药物与溶媒混合， 于室温下以 200~500rpm搅拌至完 全溶解；
(b5) 加入医药上可接受的一表面活性剂， 在转速 100 -300 rpm条件下搅拌均匀， 使 溶媒挥发， 其中， 该表面活性剂的亲水亲油性平衡值 Chydrophilic-lipophilic balance value, HLB值；)大于 10;
(c5)待溶媒完全挥发后， 缓慢加入医药上可接受的水溶液， 搅拌均匀， 以形成多个含 药微胞以及多个第二脂溶性药物微胞； 以及
(d5) 以 0.2 μιη滤膜过滤后， 将含有含药微胞以及多个第二脂溶性药物微胞的滤液避 光冷藏保存。
第五医药组成物中使用的溶媒、 表面活性剂、 医药上可接受的水溶液、 以及其他脂溶 性药物的种类范围与第四医药组成物均相同。而且， 第五医药组成物中的各成分间的比例 关系范围， 也与第四医药组成物相同。
较佳者， 该医药上可接受的水溶液中包含局部麻醉剂或 /及抗氧化剂。 较佳者， 第五医药组成物中使用的局部麻醉剂或 /及抗氧化剂的种类范围与第四医药 组成物均相同。
实验五： 测定医药组成物的品质
实验 5-1 组成份分析
将医药组成物静置至少 20分钟， 若未发生分层现象， 则进一步利用粒径分析仪测试。 利用粒径分析仪 (particle size analyzer)测定医药组成物中是否含有微胞 (micelle)。 若医 药组成物经粒径分析仪分析后， 测得的粒径小于 250nm、 PDI值小于 0.4、 以肉眼观察发 现医药组成物中的溶液为澄清透明、且使用激光照射溶液后能观察到光径， 则代表医药组 成物中具有微胞。
若医药组成物具有微胞，则所制备出的组成物即为本发明的可用于减少局部脂肪的医 药组成物。
若医药组成物静置后未分层且具有微胞，则所制备出的组成物即为本发明的可用于减 少局部脂肪的较佳医药组成物。
实验 5-2 利用粒径分布状况分析医药组成物的稳定性
利用粒径分析仪 (particle size analyzer) (购自 Malvern)测定粒径的分布状况及多分散性 指数 (polydispersity index; PDI), 若多分散性指数小于 0.4， 则代表医药组成物的稳定性佳， 也就是医药组成物中的微胞能稳定地存在。
实验 5-3 利用加速稳定性试验测定医药组成物的稳定性。
本发明的医药组成物的储存条件为 2~8°C。 为了测试医药组成物的稳定性， 发明人将 医药组成物放置在相对高温度且高湿度的环境 (温度 25°C ±2°C、 相对湿度 RH60%±5%)， 观察医药组成物中的微胞在相对高温的状态下，能稳定存在多久，以推算医药组成物在 2~8 °C 的状态下能保存多久。
若医药组成物在 25°C条件下可以储存 n个月，则该医药组成物在 5°C条件下可以储存 的时间长度为 n个月的 2((25—5)/1Q)倍。 亦即， 该医药组成物在 5°C条件下可以储存的时间长 度为 n个月的 22倍， 也就是 4倍。
举例而言， 若医药组成物在 25°C条件下可以储存 6个月， 则该医药组成物在 5°C条件 下可以储存的时间长度为 24个月 (6个月 X 4倍 =24个月）。
较佳者， 在温度摄氏 25±2度 (25±2°C；)、 相对湿度 RH60%±5%、 避免光线直射的条件 下进行加速试验时， 该医药组成物仍维持于无沉淀物产生的状态至少达 24小时。
较佳者， 在温度摄氏 25±2度、 相对湿度 RH60%±5%、 避免光线直射的条件下进行加 速试验时， 该医药组成物仍维持于无沉淀物产生的状态至少达 6个月。
较佳者， 在温度 2~8°C条件下， 该医药组成物仍维持于无沉淀物产生的状态至少达 24 个月。
实验六： 各种非离子性表面活性剂形成的含药微胞的最大载药量
由于含药微胞的最大载药量直接影响注射体积， 对局部皮下脂肪层 (例如脸部的皮下 脂肪层)单次须容纳的药物体积、 副作用、 及负担影响甚巨。 因此， 本实验将探讨各种非 离子性表面活性剂形成的含药微胞的最大载药量， 以评估哪一种非离子性表面活性剂为制 备本发明医药组成物的最佳赋形剂。
选用 4种非离子性表面活性剂进行本实验。所述 4种非离子性表面活性剂为聚氧乙烯 35蓖麻油 (即 ELP)、聚乙二醇硬脂酸酯 15 (即 HS-15)、聚氧乙烯 40氢化蓖麻油 (Cremophor RH 40， 简称为 RH 40)、 以及聚山梨醇酯 80(即 Tween 80)。
实验分为 4组， 分别为 ELP组、 HS-15组、 RH40组、 以及 Tween 80组。
实验步骤：
(a') 将 2.0 g (第一重量的示例）白藜芦醇与 300 500 mL 二氯甲垸混合， 于室温下以 150~500rpm搅拌至白藜芦醇完全溶解；
(b') 加入 18.0 g (第二重量的示例)单一种上述非离子性表面活性剂， 在转速 100 -300 rpm条件下搅拌均匀， 使二氯甲垸挥发； 以及
(C)待溶媒完全挥发后， 获得一组成物， 共 20 g; 取 2 g该组成物， 缓慢加入 8 g (第 三重量的示例；)注射用生理食盐水， 搅拌均匀， 获得待检测组成物。 该待检测组成物中的 白藜芦醇浓度为 20 mg/g， 且非离子性表面活性剂的浓度为 18%。
将 ELP组、 HS-15组、 RH40组、 以及 Tween 80组的待检测组成物静置至少 20分钟， 观察是否发生分层现象。若发生分层现象， 代表白藜芦醇浓度太高而使第一阶段组成物中 的微胞破裂， 亦即， 利用该非离子性表面活性剂无法制备出白藜芦醇浓度为 20 mg/g的本 发明医药组成物。
评估各种赋形剂 (ELP、 HS-15 , RH40、 以及 Tween 80)是否具有毒性， 依各国药典
(pharmacopoeia)规范的赋形剂注射浓度限制， 推算各种赋形剂形成的含药微胞的载药量上 限。
为了得知 ELP的最大载药限制， 发明人进行后续实验七， 得知 ELP的最大载药量为 大于或等于 166.7 mg/g (白藜芦醇与 ELP的比例为 1 :5时，制备出的医药组成物中含有 166.7 mg/g白藜芦醇；)。
实验结果显示， ELP是制备本发明医药组成物的最佳赋形剂。 利用 ELP制备出的医 药组成物中， 白藜芦醇浓度可达 166.7 mg/g。
实验七： 利用聚氧乙烯 35蓖麻油 (ELP)制备医药组成物
本实验利用白藜芦醇及聚氧乙烯 35蓖麻油 (ELP)的比例变化， 制备出一系列的本发明 医药组成物， 并进行稳定性分析， 以得知白藜芦醇及聚氧乙烯 35蓖麻油 (ELP)的适当比例 以及利用 ELP制备本发明医药组成物时的最大载药量。
实验共分为 9组， 即第 1~9组， 各组医药组成物的配制方法与实验六的实验步骤大致 相同， 仅白藜芦醇的重量 (步骤 (a')中的第一重量；)、 ELP的重量 (步骤 (b')中的第二重量；)、注 射用生理食盐水的重量 (步骤 (c')中的第三重量；)不同。 本实验中， 白藜芦醇的重量 (第一重 量；)、 ELP的重量 (第二重量；)、注射用生理食盐水的重量 (第三重量)的添加原则如表一所示。 本实验中， 第 1~9组的白藜芦醇与 ELP比例 (重量比)依序为一比一 (1 : 1)、 一比二点 五 (1 : 2.5)、 一比五 (1 : 5)、 一比八 (1 : 8)、 一比十 (1 : 10)、 一比四十 (1 : 40)、 一比八十 (1 : 80)、 一比两百 (1 : 200)、 以及一比五百 (1 : 500)， 且第 1~9组配制出的医药组成物中， 白 藜芦醇终浓度依序为 1000 mg/g、 285.71 mg/g、 166. 7 mg/g、 60 mg/g、 30 mg/g、 7.5 mg/g、 3.75 mg/g, 0.5 mg/g、 0.2 mg/g。 亦即， 第 1~9组医药组成物的配制方法中， 步骤 (a')中的 白藜芦醇与步骤 (b')中的 ELP 的重量比 (第一重量与第二重量的比例；)依序为一比一、 一比 二点五、 一比五、 一比八、 一比十、 一比四十、 一比八十、 一比两百、 以及一比五百， 且 在步骤 (c')加入第三重量注射用生理食盐水后， 将依序配制出白藜芦醇终浓度为 1000 mg/g、 285.71 mg/g、 166.7 mg/g、 60 mg/g、 30 mg/g、 7.5 mg/g、 3.75 mg/g、 0.5 mg/g、 以 及 0.2 mg/g的医药组成物。 其中， 药物终浓度以 mg/g表示时， 代表每克医药组成物中含 有的白藜芦醇毫克数。
利用粒径分析仪 (particle size analyzer)测定医药组成物中是否含有微胞 (micelle), 并测 量微胞的粒径大小。
利用粒径分析仪 (particle size analyzer)测定粒径的分布状况及多分散性指数 (polydispersity index; PDI)， 以评估医药组成物的稳定性。 利用高效能液相色谱仪 (high performance liquid chromatography, HPLC; 例如 HPLC-UV)分析微胞中的白藜芦醇含量， 定义为 "起始药物含量" 。
利用加速稳定性试验观察医药组成物在高温储存条件 (摄氏 25±2度；)下 3个月是否发生 分层现象， 并利用高效能液相色谱仪 (； high performance liquid chromatography, HPLC; 例 如 HPLC-UV)分析微胞中的药物含量， 定义为 "加速实验后的药物含量" 。 将 "加速实验 后的药物含量"除以 "起始药物含量"， 得到 "药物含量百分比" 。 若药物含量百分比大 于或等于 95%， 代表医药组成物的稳定性极佳。 表一 利用 ELP配制医药组成物的样品配制表
白藜芦醇与 ELP比例 医药组成物中的白藜
Figure imgf000031_0001
(重量比；） 芦醇终浓度 (mg/g)
1 1 : 1 1000
2 1 :2.5 285.71
3 1 :5 166.7
4 1 :8 60 1:40
1:80 3.75
1:200
1:500 0.2
请参见表二， 表二为医药组成物的安定性分析结果。 表二显示， 白藜芦醇与 ELP 的 重量比为 1: 5至 1: 500时，各组医药组成物中都具有微胞，测得的微胞粒径为 10 250 nm， 因此， 白藜芦醇与 ELP比例为 1: 5至 1: 500所制备出的医药组成物， 都是本发明可用 于减少局部脂肪的医药组成物。
在稳定性方面， 白藜芦醇与 ELP的比例为 1: 5至 1: 500时， PDI均小于 0.4。 因此， 若要制备稳定性较佳的本发明可用于减少局部脂肪的医药组成物， 以白藜芦醇的重量为 1 个重量单位计之， ELP的重量应大于或等于 5个重量单位。 较佳者， 以白藜芦醇的重量为 1个重量单位计之， ELP的重量为 5 500个重量单位。 较佳者， 以白藜芦醇的重量为 1个 重量单位计之， ELP的重量为 10 80个重量单位。 较佳者， 以白藜芦醇的重量为 1个重量 单位计之， ELP的重量为 8~80个重量单位。 表二 医药组成物的稳定性分析
加速实验后 白藜芦醇与 ELP 微胞 加速实验后
PDI 的药物含量 比例 (重量比） 粒径 (nm) 的外观
百分比 C¼)
1:1 404.13 ± 64.70 1.00 ± 0.00
1:2. 787.07 ± 186.84 0.71 ± 0.50
240.63 ± 9.49 0.189 ± 0.06 澄清无分层 97.41 ±0.17
30 1 : 8 174 ± 1.97 0.15 ± 0.05
1 : 10 15.61 ± 0.39 0.180 ± 0.01 澄清无分层 98.32 ± 0.23
1 :40 13.66 ± 0.49 0.237 ± 0.03 澄青无分层 95.76 ± 0.66
1 : 80 12.22 ± 0.13 0.181 ± 0.0 澄清无分层 95.54 ± 0.03
1 :200 12.84 ± 0.29 0.17 ± 0.02
1 : 500 12.08 ± 0.96 0.15 ± 0.09 上表中， 空白的栏位代表未进行分析。 由表二的数据可知， 将第 3、 5~7组医药组成物储存在摄氏 25度的环境下 3个月， 各 组样品的白藜芦醇药物含量百分比皆大于 95%， 且与起始药物含量相比无明显下降趋势。 由该结果可知， 所述医药组成物具有良好的稳定性， 且依据加速实验的经验法则推估， 该 些医药组成物在 2~8 °C冷藏的状态下， 至少可储存 24个月。
实验八： 利用聚氧乙烯 35蓖麻油制备医药组成物对局部溶脂及减重的影响
实施例 1 : 利用聚氧乙烯 35蓖麻油及白藜芦醇制备白藜芦醇医药组成物
(a') 将 0.4 g (第一重量的示例）白藜芦醇与 20 70 mL 乙醇混合， 于室温下以 200~500rpm搅拌至白藜芦醇完全溶解；
(b') 加入 4 g (第二重量的示例)聚氧乙烯 35蓖麻油， 在转速 100 -300 rpm条件下搅拌 均匀， 使乙醇挥发；
(C) 待乙醇完全挥发后， 缓慢加入注射用生理食盐水， 使注射用生理食盐水的重量达 80 g (第三重量的示例；)， 搅拌均匀， 以形成多个含药微胞； 以及
(d') 以 0.2 μιη滤膜过滤后， 滤液即为含有含药微胞的白藜芦醇医药组成物。 避光冷 藏保存。
在此具体实施例中， 注射用生理食盐水的比重为 l g/mL。 因此， 80 g注射用生理食盐 水的体积为 80 mLo据此， 该白藜芦醇医药组成物中的白藜芦醇的浓度约为 5 mg/mL (0.4g ÷ 80 mL = 0.005 g/mL = 5 mg/mL)0
在此具体实施例中， 第一重量的白藜芦醇与第二重量的聚氧乙烯 35蓖麻油 (表面活性 剂)的重量比为 0.4: 4， 亦即， 重量比为 1 : 10。
在此具体实施例中，第一重量的白藜芦醇与第三重量的注射用生理食盐水的重量比为 0.4： 80， 亦即， 重量比为 1 : 200ο
实施例 2:利用聚氧乙烯 35蓖麻油、 白藜芦醇及绿茶萃取物制备白藜芦醇复方医药组 成物
(al') 将 0.36 g (第四重量的示例）白藜芦醇与 20~70 mL乙醇混合，于室温下以 200~500 rpm搅拌至白藜芦醇完全溶解；
(bl') 加入 4 g (第五重量的示例)聚氧乙烯 35蓖麻油， 在转速 100 -300 rpm条件下搅 拌均匀， 使乙醇挥发；
(cl') 待乙醇完全挥发后， 缓慢加入第六重量的第一注射用生理食盐水， 在转速 100 ~300 rpm条件下搅拌均匀， 以形成多个含药微胞， 其中， 该第一注射用生理食盐水中包含 0.04 g (第七重量的示例)绿茶萃取物， 且该绿茶萃取物的组成分中包含表没食子儿茶素没 食子酸酯；
(cir) 加入第八重量的第二注射用生理食盐水， 使注射用生理食盐水的总体积为 so mL (亦即， 第六重量的第一注射用生理食盐水及第八重量的第二注射用生理食盐水的总体 积为 80 mL)， 搅拌均匀， 使第二注射用生理食盐水完全溶解。
(dl') 以 0.2 μιη滤膜过滤后， 含有含药微胞的滤液即为白藜芦醇复方医药组成物。 避 光冷藏保存。
在此具体实施例中，此白藜芦醇复方医药组成物中的白藜芦醇暨绿茶萃取物的浓度约 为 5 mg/mL [(0.36g + 0.04g) ÷ 80mL = 0.4g ÷ 80 mL = 0.005 g/mL = 5 mg/mL]。
在此具体实施例中，若以该绿茶萃取物的总重量 (0.04 g)为 100重量百分比计之， 该绿 茶萃取物中表没食子儿茶素没食子酸酯的含量为 95 %
在此具体实施例中， 第四重量的白藜芦醇与第七重量的绿茶萃取物的重量比为 0.36: 0.04， 亦即， 重量比为 9: 1。
在此具体实施例中， 以该第四重量的白藜芦醇与该第七重量的绿茶萃取物的总重量 (0.36g + 0.04g = 0.4g)为一个重量单位计之， 该第五重量的表面活性剂的重量为 10个重量 单位 (4g ÷ 0.4g = 10)。
在此具体实施例中， 注射用生理食盐水的比重为 l g/mL。 因此， 在本具体实施例中第 六重量的第一注射用生理食盐水及第八重量的第二生理食盐水的总体积为 80 mL 的示例 下， 该些生理食盐水的总重量为 80 g。
据此， 以该第四重量的白藜芦醇与该第七重量的绿茶萃取物的总重量 (0.36g + 0.04g = o.4g)为一个重量单位计之，该第六重量的第一注射用生理食盐水与该第八重量的第二注射 用生理食盐水的总重量 (80 g)为 200个重量单位 (80g ÷ 0.4g = 200)。
实施例 3 : 白藜芦醇医药组成物的溶脂效果
使用 6周龄 SD品系雄性大鼠 (male Sprague-Dawley rat)进行实验。 首先， 以高脂饲料 喂食 15只大鼠诱导皮下脂肪增加， 连续喂食至大鼠体重达 330±10 g后， 将大鼠随机分成 3组， 分别为高脂对照组、 白藜芦醇低剂量组、 及白藜芦醇高剂量组， 每组 5只大鼠， 使 各组大鼠的体重无统计差异。
将上述实施例 1的 5 mg/mL白藜芦醇医药组成物注射至白藜芦醇低剂量组大鼠的下腹 股沟的皮下脂肪层， 每次注射量为每公斤体重注射 10 mg (10 mg/kg)白藜芦醇； 亦即， 每 公斤体重注射 2 mL上述实施例 1的 5 mg/mL白藜芦醇医药组成物。 将上述实施例 1的 5 mg/mL白藜芦醇医药组成物注射至白藜芦醇高剂量组大鼠的下腹股沟的皮下脂肪层，每次 注射量为每公斤体重注射 20 mg (20 mg/kg)白藜芦醇； 亦即， 每公斤体重注射 4 mL上述实 施例 1的 5 mg/mL白藜芦醇医药组成物。高脂对照组则以上述同样注射方式给予同体积注 射用生理食盐水。
上述注射部位为大鼠下腹股沟脂肪处， 平均注射于左、 右两侧， 于试验第 1、 2、 3、 4 日各注射 1次。 试验期间持续给予高脂饲料， 并每日记录体重变化， 每周记录饮水摄食一 次， 于试验第 14天禁食， 第 15天以二氧化碳牺牲大鼠。
取大鼠左右两侧下腹股沟的脂肪进行秤重， 并计算各组下腹股沟的脂肪量。 以平均值 ±SD方式呈现数据， 并以单因子变异数分析 （one-way ANOVA) 进行统计。 统计结果以 符号或英文字母表示， 不同符号或字母表示组间具有统计差异 (p< 0.05)， 相同符号或字母 则表示组间不具有统计差异 (p> 0.05)。
请参阅图 3及表三。 图 3为白藜芦醇医药组成物对大鼠皮下脂肪量影响的长条图。表 三为白藜芦醇医药组成物使大鼠皮下脂肪量减少的程度。其中， 下腹股沟皮下脂肪量为左 右两侧脂肪重量的总和。
实验结果显示， 与高脂对照组相比， 白藜芦醇低剂量组 (给药剂量为 10 mg/kg)大鼠的 下腹股沟皮下脂肪量已有减少趋势，局部脂肪减少百分比为 5.6%;而白藜芦醇高剂量组 (给 药剂量为 20 mg/kg)大鼠的下腹股沟皮下脂肪量与高脂对照组相比则呈现显著下降的结果 (p<0.05), 其局部脂肪的减少百分比达到 18.1%。 表三、 白藜芦醇医药组成物使大鼠皮下脂肪量减少的程度
下腹股沟皮下脂肪量 (g) 脂肪减少百分比
Figure imgf000035_0001
Mean士 SD (%) 高脂对照组 .4± 0.8 白藜芦醇低剂量组 .1± 0.4 .6% 白藜芦醇高剂量组 4.4± 0.8 18.1%
依发明人的经验，适用于大鼠的给药频率为 4次时，适用于人类的给药频率即为 1~12 次。 较佳者， 施用于人类的给药频率为每间隔 1天至 30天施予药物 1~12次。 较佳者， 施 用于人类的给药频率为每间隔 1天至 30天施予药物 1~6次。
依发明人的经验， 适用于大鼠的给药剂量为 10mg/kg ~ 20mg/kg时， 适用于人类的给 药剂量即为 0.2 40 mg/kg。
较佳者， 施用于人类的给药剂量为 0.4 20 mg/kg。
较佳者， 施用于人类的剂量为每平方公分注射 0.2~ 20毫克。
较佳者， 施用于人类的剂量为每平方公分注射 0.4 ~ 12毫克。
实施例 4: 白藜芦醇复方医药组成物的溶脂及减重效果
配制绿茶萃取物组成物： 利用注射用生理食盐水将绿茶萃取物溶解， 以配制 5 mg/mL 的绿茶萃取物组成物。
使用 6周龄 SD品系雄性大鼠 (male Sprague-Dawley rat)进行实验。 首先， 以高脂饲料 喂食 20只大鼠诱导皮下脂肪增加， 连续喂食至大鼠体重达 330±10 g后， 将大鼠随机分成 4组， 分别为高脂对照组、 绿茶萃取物组、 白藜芦醇组、 及白藜芦醇-绿茶萃取物复方组， 每组 5只大鼠， 使各组大鼠的体重无统计差异。 记录每只大鼠的体重， 定义为每只大鼠的 "试验前体重" 。 然后， 以下列方式给予药物。
将本实施例的 5 mg/mL绿茶萃取物组成物注射至绿茶萃取物组大鼠的下腹股沟的皮 下脂肪层， 每次注射量为每公斤体重注射 10 mg (10 mg/kg)绿茶萃取物； 亦即， 每公斤体 重注射 2 mL本实施例的 5 mg/mL绿茶萃取物组成物。将上述实施例 1的 5 mg/mL白藜芦 醇医药组成物注射至白藜芦醇组大鼠的下腹股沟的皮下脂肪层，每次注射量为每公斤体重 注射 10 mg (10 mg/kg)白藜芦醇； 亦即， 每公斤体重注射 2 mL上述实施例 1的 5 mg/mL 白藜芦醇医药组成物。将上述实施例 2的 5 mg/mL白藜芦醇复方医药组成物注射至白藜芦 醇-绿茶萃取物复方组大鼠的下腹股沟的皮下脂肪层，每次注射量为每公斤体重注射 10 mg (10 mg/kg)白藜芦醇暨绿茶； 亦即，每公斤体重注射 2 mL上述实施例 2的 5 mg/mL白藜芦 醇复方医药组成物。 高脂对照组则以上述同样注射方式给予同体积注射用生理食盐水。
上述注射部位为大鼠下腹股沟脂肪处， 平均注射于左、 右两侧， 于试验第 1、 2、 3、 4 日各注射 1次。 试验期间持续给予高脂饲料， 并每日记录体重变化， 每周记录饮水摄食一 次， 于试验第 14天禁食， 第 15天以二氧化碳牺牲大鼠。
记录每只大鼠的体重， 定义为每只大鼠的 "试验后体重"。 将每只大鼠的 "试验后体 重"扣除 "试验前体重"， 得到 "总增重" 。 将各组大鼠的总增重除以高脂对照组大鼠的 总增重， 得到 "相对总增重" 。
取大鼠左右两侧下腹股沟的脂肪进行秤重， 并计算各组下腹股沟的脂肪量。 以平均值 ±SD方式呈现数据， 并以单因子变异数分析 （one-way ANOVA) 进行统计。 统计结果以 符号或英文字母表示， 不同符号或字母表示组间具有统计差异 (p< 0.05)， 相同符号或字母 则表示组间不具有统计差异 (p> 0.05)。
由于每组每一次都是施予 10 mg/kg的药物， 白藜芦醇-绿茶萃取物复方组大鼠的局部 溶脂效果应介于白藜芦醇组及绿茶萃取物组之间。 若白藜芦醇-绿茶萃取物复方组大鼠的 局部溶脂效果比白藜芦醇及绿茶萃取物组佳， 代表白藜芦醇-复方医药组成物中的白藜芦 醇及绿茶萃取物在局部溶脂的功效上具有协同效应 (synergy)。
请参阅图 4A及表四。 图 4A为白藜芦醇复方医药组成物对大鼠皮下脂肪量影响的长 条图。 表四为白藜芦醇复方医药组成物使大鼠皮下脂肪量减少程度。 其中， 下腹股沟皮下 脂肪量为左右两侧脂肪重量的总和。
图 4A实验结果显示， 与高脂对照组相比， 绿茶萃取物组大鼠的注射部位皮下脂肪并 没有减少 (给药剂量为每公斤体重给予 10 mg绿茶萃取物)。 白藜芦醇组大鼠的注射部位皮 下脂肪量与高脂对照组相比虽无统计差异， 但已呈现减少趋势， 其局部脂肪减少百分比为 5.6% (给药剂量为每公斤体重给予 10 mg白藜芦醇)。 白藜芦醇 -绿茶萃取物复方组大鼠的 注射部位皮下脂肪量则呈现显著下降的结果 (p<0.05)， 其局部脂肪减少百分比达到 18.9% (给药剂量为每公斤体重给予 10 mg白藜芦醇暨绿茶萃取物；)。 亦即， 白藜芦醇复方医药组 成物更能显著达到减少局部脂肪的效果， 所述效果为白藜芦醇医药组成物效果的 3.4倍。
本实施例显示本发明的白藜芦醇加上绿茶萃取物的复方医药组合物，较相同剂量的白 藜芦醇单方具有更佳的局部溶脂效果。
比较白藜芦醇组、 绿茶萃取物组、 以及白藜芦醇-绿茶萃取物复方组大鼠的局部溶脂 效果可知， 白藜芦醇复方医药组成物中的白藜芦醇及绿茶萃取物在局部溶脂的功效上具有 协同效应 (synergy)。 表四、 白藜芦醇复方医药组成物使大鼠皮下脂肪量减少程度
下腹股沟皮下脂肪量 (g) 脂肪减少百分比 组别
Mean士 SD (%) 高脂对照组 5.4± 0.8 - 绿茶萃取物组 5.4士 0.9 0% 白藜芦醇组 5.1± 0.4 5.6% 白藜芦醇 -绿茶
4.4士 0.6 18.9% 萃取物复方组 请参见图 4B 以及表五。 图 4B为白藜芦醇复方医药组成物对大鼠相对总增重影响的 长条图。 表五为白藜芦醇复方医药组成物使大鼠减重的程度。
图 4B实验结果显示， 与高脂对照组相比， 绿茶萃取物组大鼠的相对总增重并没有减 少 (给药剂量为每公斤体重给予 10 mg绿茶萃取物；)。 白藜芦醇组大鼠的相对总增重与高脂 对照组相比虽无统计差异， 但呈现减少趋势， 其局部脂肪减少百分比为 7.4% (给药剂量为 每公斤体重给予 10 mg白藜芦醇；)。 与高脂对照组相比， 白藜芦醇-绿茶萃取物复方组大鼠 的相对总增重减少百分比达到 15.9% (给药剂量为每公斤体重给予 10 mg白藜芦醇暨绿茶 萃取物；)， 虽然仍未具有显著差异， 但效果比白藜芦醇组更佳。 依据发明人的经验， 只要 将给药剂量或频率提高， 利用本发明制备出的白藜芦醇单方医药组成物及白藜芦醇 -绿茶 萃取物复方医药组即可达到显著的减重效果。 表五、 白藜芦醇复方医药组成物使大鼠减重的程度
体重减少百分比 组别 相对总增重(％)
(%) 高脂对照组 100.0± 16.3 - 绿茶萃取物组 103.7± 21.8 0% 白藜芦醇组 92.6士 17.8 7.4% 白藜芦醇-绿茶萃取
84.1± 0.6 15.9%
物复方组 实验九： 白藜芦醇与其他脂溶性药物形成的复方医药组成物对溶脂的影响
本实验利用白藜芦醇及其以外的其它脂溶性药物配制成复方医药组成物， 以评估各种 脂溶性复方医药组成物对成熟脂肪细胞的溶脂效果。
本实验选用葛根素 (puerarin)、 以及槲皮素 (quercetin)制备各种脂溶性复方医药组成物。 实验 9-1 细胞毒性测试
利用细胞存活率实验 (MTT assay)评估 50 ppm的白藜芦醇、 葛根素 (puerarin)、 或槲皮 素 (quercetin)是否对脂肪细胞以外的其他细胞具有毒性， 若不具毒性， 才进行溶脂测试。
实验结果显示， 50 ppm的白藜芦醇、 葛根素 Cpuerarin)、 及槲皮素 (quercetin)对大鼠脂 肪细胞以外的一般体细胞 (somatic cells)不具细胞毒性， 因此此剂量不会对一般体细胞造成 影响。
实验 9-2 成熟脂肪细胞溶脂效果
以下列方式配制 DMSO控制组细胞培养液、 白藜芦醇细胞培养液、 葛根素细胞培养 液、 槲皮素细胞培养液、 白藜芦醇 -葛根素复方细胞培养液、 以及白藜芦醇-槲皮素复方细 胞培养液液。 DMSO控制组细胞培养液： 将 DMSO与适量的无菌水混合， 以配制出 0.5% DMSO 溶液。 将 0.5% DMSO溶液与细胞培养液 (；产品名称为 Dulbecco's Modified Eagle Medium, 购自 Gibco)混合， 以配制出 DMSO控制组细胞培养液， 其中， 0.5% DMSO溶液与细胞培 养液的体积比为 1 : 1000。
白藜芦醇细胞培养液： 将白藜芦醇与适量的 0.5% DMSO溶液混合， 以配制出白藜芦 醇溶液。 将白藜芦醇溶液与细胞培养液 (产品名称为 Dulbecco's Modified Eagle Medium ， 购自 Gibco)混合， 以配制出含有 50 ppm白藜芦醇的白藜芦醇细胞培养液， 其中， 白藜芦 醇溶液与细胞培养液的体积比为 1： 1000。
葛根素细胞培养液： 将葛根素 (购自 Sigma-Aldrich)与适量的 0.5% DMSO溶液混合， 以配制出葛根素溶液。 将葛根素溶液与细胞培养液混合， 以配制出含有 50 ppm葛根素的 葛根素细胞培养液， 其中， 葛根素溶液与细胞培养液的体积比为 1 : 1000。
槲皮素细胞培养液： 将槲皮素 (购自 Sigma-Aldrich)与适量的 0.5% DMSO溶液混合， 以配制出槲皮素溶液。 将槲皮素溶液与细胞培养液混合， 以配制出含有 50 ppm槲皮素的 槲皮素细胞培养液， 其中， 葛根素溶液与细胞培养液的体积比为 1 : 1000。
白藜芦醇 -葛根素复方细胞培养液： 将白藜芦醇、 葛根素、 以及适量的 0.5% DMSO溶 液混合， 以配制出白藜芦醇 -葛根素复方溶液。 其中， 白藜芦醇与葛根素的重量比为 2: 3。 将白藜芦醇-葛根素复方溶液与细胞培养液混合，以配制出含有 50 ppm白藜芦醇-葛根素复 方药物的细胞培养液， 其中， 白藜芦醇的浓度为 20 ppm， 葛根素的浓度为 30 ppm， 且白 藜芦醇-葛根素复方溶液与细胞培养液的体积比为 1 : 1000。
白藜芦醇 -槲皮素复方细胞培养液： 将白藜芦醇、 槲皮素、 以及适量的 0.5% DMSO溶 液混合， 以配制出白藜芦醇 -槲皮素复方溶液。 其中， 白藜芦醇与槲皮素的重量比为 2: 3。 将白藜芦醇-槲皮素复方溶液与细胞培养液混合，以配制出含有 50 ppm白藜芦醇-槲皮素复 方药物的细胞培养液， 其中， 白藜芦醇的浓度为 20 ppm， 槲皮素的浓度为 30 ppm， 且白 藜芦醇-槲皮素复方溶液与细胞培养液的体积比为 1 : 1000。
成熟脂肪细胞溶脂效果的实验步骤：
将 3T3-L1前驱脂肪细胞 (购自台湾食品工业发展研究所，简称为 BCRC)接种在 12 well plate中， 使每 well中含有 1 X 105 个细胞。 培养 2天后， 利用细胞诱导分化培养液 (DMI medium); 其中含有 0.5 μΜ ΙΒΜΧ (购自 Sigma-Aldrich), 0.1 μΜ Dexamethasone (购自 Sigma-Aldrich), 以及 5 μ^ιηΐ Insulin (购自 Humunlin R.))培养 2天。 然后， 利用含 5 μ^ιηΐ 胰岛素 (Insulin)的培养液培养 6天， 待细胞型态由纺锤状变为球形且细胞内堆积许多脂肪 油滴 (lipo droplets)时， 表示已分化为成熟脂肪细胞 (Mature adipocytes；)。
将成熟脂肪细胞分成 6组， 分别为 DMSO控制组、 白藜芦醇组、 葛根素组、 槲皮素 组、 白藜芦醇-葛根素复方组、 以及白藜芦醇-槲皮素复方组。
以 DMSO控制组细胞培养液、 白藜芦醇细胞培养液、 葛根素细胞培养液、 槲皮素细 胞培养液、 白藜芦醇 -葛根素复方细胞培养液、 以及白藜芦醇 -槲皮素复方细胞培养液， 分 别培养 DMSO控制组、 白藜芦醇组、 葛根素组、 槲皮素组、 白藜芦醇-葛根素复方组、 以 及白藜芦醇 -槲皮素复方组中的成熟脂肪细胞 24小时。
将 Annexin V 蛋白 (；购自 eBioscience)以及 Propidium iodide 染剂 (；简称为 PI; 购自 eBioscience)与各组细胞混合一段时间后， 利用流式细胞仪 (flow cytometry)分析各组细胞被 Annexin V 蛋白以及 PI 染剂标定 (label)的比例， 藉以评估成熟脂肪细胞进行细胞凋亡 (apoptosis)的比例。 其中， 同时被 Annexin V蛋白以及 PI染剂标定的成熟脂肪细胞， 代表 已进入细胞凋亡程序； 越多成熟脂肪细胞进行细胞凋亡， 代表所施予的药物的溶脂效果越 好， 且代表溶脂是透过细胞凋亡程序而非使细胞坏死 (necrosis；)。
以平均值±80方式呈现数据， 并以单因子变异数分析 （one-way ANOVA) 进行统计。 统计结果以符号或英文字母表示， 不同符号或字母表示组间具有统计差异 (p< 0.05)， 相同 符号或字母则表示组间不具有统计差异 (p> 0.05)。
由于每组施予药物的总剂量都是 50 ppm， 白藜芦醇 -葛根素复方组的细胞凋亡效果应 介于白藜芦醇组以及葛根素组之间。 若白藜芦醇 -葛根素复方组的细胞凋亡效果比白藜芦 醇组以及葛根素组佳， 代表白藜芦醇-葛根素复方医药组成物中的白藜芦醇及葛根素在溶 脂的功效上具有协同效应 (Synergy)。 同样地， 白藜芦醇-槲皮素复方组的细胞凋亡效果应介 于白藜芦醇组以及槲皮素组之间。 若白藜芦醇-槲皮素复方组的细胞凋亡效果比白藜芦醇 组以及槲皮素组佳， 代表白藜芦醇 -槲皮素复方医药组成物中的白藜芦醇及槲皮素在溶脂 的功效上具有协同效应 (synergy)。
请参阅图 5。图 5是白藜芦醇-其他脂溶性药物复方对成熟脂肪细胞进行细胞凋亡的影 响。
图 5结果显示， DMSO控制组细胞凋亡百分比为 4.9±2.5%， 白藜芦醇组细胞凋亡百 分比为 19.0±1.1%， 葛根素组细胞凋亡百分比为 7.2±3.7%， 槲皮素组细胞凋亡百分比为 5.9±2.6%， 白藜芦醇 -葛根素复方组细胞凋亡百分比为 50.6±3.8%， 白藜芦醇-槲皮素复方组 细胞凋亡百分比为 12.1±2.7%。
比较白藜芦醇组、 葛根素组、 以及白藜芦醇-葛根素复方组的细胞凋亡效果可知， 白 藜芦醇 -葛根素复方医药组成物在溶脂的功效上具有协同效应 (synergy)。
由此可知， 白藜芦醇与各种脂溶性药物形成的复方医药组成物都能够达到溶脂效果， 且白藜芦醇与各种脂溶性药物在溶脂的功效上具有协同效应 (synergy)。 因此， 本发明利用 白藜芦醇与各种脂溶性药物制备出含药微胞及第二脂溶性药物微胞，进而制备出白藜芦醇 -其他脂溶性药物复方医药组成物， 可作为局部溶脂及减重的医药组成物。
实验十： 白藜芦醇与水溶性药物形成的复方医药组成物对溶脂的影响
本实验利用绿茶萃取物以外的其它水溶性药物以及白藜芦醇配制成复方医药组成物， 以评估各种白藜芦醇-水溶性药物复方医药组成物对成熟脂肪细胞的溶脂效果。
本实验选用咖啡因 (caffeine；)、 以及左旋肉碱 (L-camitine)制备各种白藜芦醇-水溶性药 物复方医药组成物。 实验 10-1 细胞毒性测试
利用细胞存活率实验 (MTT assay)评估 50 ppm 的咖啡因 (caffeine；)、 以及左旋肉碱 (L-camitine)是否对脂肪细胞以外的其他细胞具有毒性， 若不具毒性， 才进行溶脂测试。
实验结果显示， 50 ppm的咖啡因 (caffeine；)、 以及左旋肉碱 (L-carnitine)对大鼠脂肪细胞 以外的一般体细胞不具细胞毒性， 因此此剂量不会对一般体细胞造成影响。
实验 10-2 成熟脂肪细胞溶脂效果
以下列方式配制无菌水控制组细胞培养液、白藜芦醇细胞培养液、咖啡因细胞培养液、 左旋肉碱细胞培养液、 白藜芦醇 -咖啡因复方细胞培养液、 以及白藜芦醇-左旋肉碱复方细 胞培养液。
无菌水控制组细胞培养液： 将无菌水 (sterile water)与细胞培养液混合， 以配制出无菌 水控制组细胞培养液。 其中， 无菌水与细胞培养液的体积比为 1 : 1000。
白藜芦醇细胞培养液： 与实验 9-2中的白藜芦醇细胞培养液的配制方法相同。
咖啡因细胞培养液： 将咖啡因 (购自 Sigma-Aldrich)与适量的无菌水混合， 以配制出咖 啡因溶液。 将咖啡因溶液与细胞培养液混合， 以配制出含有 50 ppm咖啡因的咖啡因细胞 培养液， 其中， 咖啡因溶液与细胞培养液的体积比为 1 : 1000。
左旋肉碱细胞培养液： 将左旋肉碱 (购自 Sigma-Aldrich)与适量的无菌水混合， 以配制 出左旋肉碱溶液。 将左旋肉碱溶液与细胞培养液混合， 以配制出含有 50 ppm左旋肉碱的 左旋肉碱细胞培养液， 其中， 左旋肉碱溶液与细胞培养液的体积比为 1 : 1000。
白藜芦醇 -咖啡因复方细胞培养液： 将白藜芦醇、 咖啡因、 以及适量的无菌水混合， 以配制出白藜芦醇 -咖啡因复方溶液。 其中， 白藜芦醇与咖啡因的重量比为 2: 3。 将白藜 芦醇-咖啡因复方溶液与细胞培养液混合，以配制出含有 50 ppm白藜芦醇-咖啡因复方药物 的细胞培养液， 其中， 白藜芦醇的浓度为 20 ppm， 咖啡因的浓度为 30 ppm， 且白藜芦醇- 咖啡因复方溶液与细胞培养液的体积比为 1 : 1000。
白藜芦醇-左旋肉碱复方细胞培养液： 将白藜芦醇、 左旋肉碱、 以及适量的无菌水混 合， 以配制出白藜芦醇-左旋肉碱复方溶液。 其中， 白藜芦醇与左旋肉碱的重量比为 2: 3。 将白藜芦醇 -左旋肉碱复方溶液与细胞培养液混合，以配制出含有 50 ppm白藜芦醇-左旋肉 碱复方药物的细胞培养液， 其中， 白藜芦醇的浓度为 20 ppm， 左旋肉碱的浓度为 30 ppm， 且白藜芦醇-左旋肉碱复方溶液与细胞培养液的体积比为 1 : 1000。
制备成熟脂肪细胞的方法与实验 9-2相同。
将成熟脂肪细胞分成 6组， 分别为无菌水控制组、 白藜芦醇组、 咖啡因组、 左旋肉碱 组、 白藜芦醇-咖啡因复方组、 以及白藜芦醇 -左旋肉碱复方组。
以无菌水控制组细胞培养液、 白藜芦醇细胞培养液、 咖啡因细胞培养液、 左旋肉碱细 胞培养液、 白藜芦醇 -咖啡因复方细胞培养液、 以及白藜芦醇-左旋肉碱复方细胞培养液， 分别培养无菌水控制组、 白藜芦醇组、 咖啡因组、 左旋肉碱组、 白藜芦醇-咖啡因复方组、 以及白藜芦醇-左旋肉碱复方组中的成熟脂肪细胞 24小时。 将 Annexin V 蛋白（购自 eBioscience)以及 Propidium iodide 染剂（简称 PI; 购自 eBioscience)与各组细胞混合一段时间后， 利用流式细胞仪 (flow cytometry)分析各组细胞被 Annexin V 蛋白以及 PI 染剂标定 (label)的比例， 藉以评估成熟脂肪细胞进行细胞凋亡 (apoptosis)的比例。 其中， 同时被 Annexin V蛋白以及 PI染剂标定的成熟脂肪细胞， 代表 已进入细胞凋亡程序； 越多成熟脂肪细胞进行细胞凋亡， 代表所施予的药物的溶脂效果越 好， 且代表溶脂是透过细胞凋亡程序而非使细胞坏死 (necrosis；)。
由于每组施予药物的总剂量都是 50 ppm，且白藜芦醇的比例占 40%而咖啡因占 60%， 因此， 白藜芦醇-咖啡因复方组的细胞凋亡效果应趋近于白藜芦醇组以及咖啡因组的平均 值。 若白藜芦醇素-咖啡因复方组的细胞凋亡效果显著优于白藜芦醇组以及咖啡因组的平 均值， 代表白藜芦醇 -咖啡因复方医药组成物中的白藜芦醇及咖啡因在溶脂的功效上具有 协同效应 (synergy)。 同样地， 由于每组施予药物的总剂量都是 50 ppm， 且白藜芦醇的比例 占 40%而左旋肉碱占 60%， 因此， 白藜芦醇-左旋肉碱复方组的细胞凋亡效果应趋近于白 藜芦醇组以及左旋肉碱组的平均值。 若白藜芦醇 -左旋肉碱复方组的细胞凋亡效果显著优 于白藜芦醇组以及左旋肉碱组的平均值， 代表白藜芦醇 -左旋肉碱复方医药组成物中的白 藜芦醇及左旋肉碱在溶脂的功效上具有协同效应 (Synergy)。
请参阅图 6。图 6是白藜芦醇-其他水溶性药物复方医药组成物对成熟脂肪细胞进行凋 亡的影响。
图 6结果显示，无菌水控制组细胞凋亡百分比为 9.6±1.5%， 白藜芦醇组细胞凋亡百分 比为 19.0±1.1%， 咖啡因组细胞凋亡百分比为 6.9±1.1%， 左旋肉碱组细胞凋亡百分比为 5.2±1.2%， 白藜芦醇-咖啡因复方组细胞凋亡百分比为 43.1±4.5%， 白藜芦醇-左旋肉碱复方 组细胞凋亡百分比为 19.3±0.5%。
比较白藜芦醇组、 咖啡因组、 以及白藜芦醇-咖啡因复方组的细胞凋亡效果可知， 白 藜芦醇-咖啡因复方医药组成物中的白藜芦醇及咖啡因在溶脂的功效上具有协同效应
(synergy)
比较白藜芦醇组、 左旋肉碱组、 以及白藜芦醇 -左旋肉碱复方组的细胞凋亡效果可知， 白藜芦醇-左旋肉碱复方医药组成物中的白藜芦醇及左旋肉碱在溶脂的功效上具有协同效 应 (synergy)。
由此可知， 白藜芦醇与各种水溶性药物形成的复方医药组成物都能够达到溶脂效果， 且白藜芦醇与各种水溶性药物在溶脂的功效上具有协同效应 (synergy)。 因此， 本发明利用 白藜芦醇与各种水溶性药物制备出包含含药微胞的白藜芦醇 -水溶性药物复方医药组成 物， 可作为局部溶脂及减重的医药组成物。
由本发明的实施例可知， 本发明提供的第一医药组成物、 第二医药组成物、 第三医药 组成物、 第四医药组成物、 第五医药组成物、 以及本发明提供的其他医药组成物， 均可使 得局部脂肪量减少。 因此， 本发明提供的第一医药组成物、 第二医药组成物、 第三医药组 成物、 第四医药组成物、 第五医药组成物、 以及本发明提供的其他医药组成物， 可用于制 备皮下植入装置、 皮下植入物、 埋植式输注液、 软膏 (ointment或 salve)、 或贴布， 而能透 过皮下植入、 埋植式输注、 涂抹 (apply)或贴布等经皮吸收方式施用于需要减少皮下脂肪的 部位。
较佳者， 本发明提供的第一医药组成物、 第二医药组成物、 第三医药组成物、 第四医 药组成物、 第五医药组成物、 以及本发明提供的其他医药组成物， 可透过皮下脂肪注射方 式， 使施用部位的脂肪减少。 因此， 本发明提供的第一医药组成物、 第二医药组成物、 第 三医药组成物、 第四医药组成物、 第五医药组成物、 以及本发明提供的其他医药组成物， 可用于制备用于减少局部皮下脂肪的皮下脂肪层注射针剂或皮下注射针剂。
以上所述仅为本发明的较佳实施例， 并非用以限定本发明的权利要求， 因此凡其它未 脱离本发明所揭示的精神下所完成的各种更动或润饰等， 均应包含于本发明的权利要求 内。

Claims

权利要求
1、 一种用于减少局部脂肪的医药组成物， 包含：
多个含药微胞 (micelle); 以及
被包覆在所述含药微胞中的白藜芦醇 (resveratrol);
其中， 所述含药微胞为医药上可接受的一聚氧乙烯蓖麻油衍生物 (polyoxyethylene castor oil derivatives)所形成的一微形结构， 且该聚氧乙烯蓖麻油衍生物的亲水亲油性平衡 值 (hydrophilic-lipophilic balance value, HLB值)大于 10。
2、 如权利要求 1所述的医药组成物， 该些含药微胞的粒径为 3 250 nm。
3、如权利要求 1所述的医药组成物，该聚氧乙烯蓖麻油衍生物为聚氧乙烯 35蓖麻油 (Cremophor ELP)^ 聚氧乙烯 40氢化蓖麻油 (Cremophor RH 40)、及其他聚氧乙烯蓖麻油衍 生物中的至少一种或其组合。
4、 如权利要求 1所述的医药组成物， 其中， 该白藜芦醇与该表面活性剂的重量比为 1： 4至 1 : 500。
5、 如权利要求 4所述的医药组成物， 其中， 该白藜芦醇与该表面活性剂的重量比为 1 : 5至 1 : 80。
6、 如权利要求 1所述的医药组成物， 其中， 该白藜芦醇在该医药组成物中的浓度为 0.2~166.7 mg/mL。
7、 如权利要求 6所述的医药组成物， 其中， 该白藜芦醇在该医药组成物中的浓度为 2.5〜 60 mg/mL。
8、 如权利要求 1所述的医药组成物， 该医药组成物中更包含一医药上可接受的水溶 液。
9、 如权利要求 1或 8所述的医药组成物， 该医药组成物中更包含一第二脂溶性药物 微胞；该第二脂溶性药物微胞为第二聚氧乙烯蓖麻油衍生物所形成的另一微形结构，且一 第二脂溶性药物被包覆在该第二脂溶性药物微胞中。
10、 如权利要求 9所述的医药组成物， 该第二聚氧乙烯蓖麻油衍生物为聚氧乙烯 35 蓖麻油 (Cremophor ELP；)、 聚氧乙烯 40氢化蓖麻油 (Cremophor RH 40)、及其他聚氧乙烯蓖 麻油衍生物中的至少一种或其组合。
11、 如权利要求 9所述的医药组成物， 该第二脂溶性药物为槲皮素 (qUercetin)、 辛弗 林 (synephrine)、葛根素 (pUerarin)、姜黄素、 以及白藜芦醇以外的其他脂溶性药物中的至少 一种或其组合。
12、 如权利要求 11所述的医药组成物， 该白藜芦醇与该第二脂溶性药物的重量比为 30： 1 〜 1： 20 ο
13、 如权利要求 1或 8所述的医药组成物， 该医药组成物更包含一水溶性药物。
14、 如权利要求 13所述的医药组成物， 该水溶性药物为绿茶萃取物、 表没食子儿茶 素没食子酸酯 (Epigallocatechin gallate)、 表儿茶素 (Epicatechin)、 表儿茶素没食子酸酯 (Epicatechin gallate)、 表没食子儿茶素 (Epigallocatechin)、 没食子儿茶素没食子酸酯 (Gallocatechin gallate)、没食子儿茶素 (Gallocatechin)、儿茶素没食子酸酯 (Catechin gallate)、 儿茶素 CCatechin；)、 表没食子儿茶素没食子酸酯 (epigallocatechin gallate, EGCG)^ 咖啡因 (Caffeine；)、 肉碱 (Carnitine; 又称为卡尼丁或卡尼汀）、 左旋肉碱 (L-carnitine；)、 辛内弗林 (Synephrine；)、 绿原酸 （ Chi orogenic acid) 、 及其他水溶性药物中的至少一种或其组合。
15、 如权利要求 14所述的医药组成物， 该白藜芦醇与该水溶性药物的重量比为 20:
1 〜 1： 30。
16、 如权利要求 14所述的医药组成物， 其中， 该水溶性药物为表没食子儿茶素没食 子酸酯， 且表没食子儿茶素没食子酸酯在该医药组成物中的浓度为 0.25 ~300mg/mL。
17、 如权利要求 14所述的医药组成物， 该水溶性药物为绿茶萃取物， 且该白藜芦醇 与该绿茶萃取物的重量比为 30: 1至 1 : 30。
18、一种减少个体局部部位的皮下脂肪量的方法，包括在该个体的该局部部位施用一 医药组成物， 其中， 该医药组成物包含：
多个含药微胞 (micelle); 以及
被包覆在所述含药微胞中的白藜芦醇 (resveratrol);
其中， 所述含药微胞为医药上可接受的一非离子性表面活性剂所形成的一微形结构， 且该非离子性表面活性剂的亲水亲油性平衡值 Chydrophilic-lipophilic balance value, HLB 值)大于 10。
19、 如权利要求 18所述的方法， 该些含药微胞的粒径为 3 250 nm。
20、如权利要求 18所述的方法， 该非离子性表面活性剂为聚山梨醇酯 80(Tween 80)、 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15)、 聚氧乙烯蓖麻油衍生物
(polyoxyethylene castor oil derivatives；)、 及其他非离子性表面活性剂中的至少一种或其组 合。
21、 如权利要求 20 所述的方法， 该聚氧乙烯蓖麻油衍生物为聚氧乙烯 35 蓖麻油 (Cremophor ELP)^ 聚氧乙烯 40氢化蓖麻油 (Cremophor RH 40)、及其他聚氧乙烯蓖麻油衍 生物中的至少一种或其组合。
22、 如权利要求 18所述的方法， 其中， 该白藜芦醇与该非离子表面活性剂的重量比 为 1 : 4至 1 : 500。
23、 如权利要求 18所述的方法， 其中， 该白藜芦醇在该医药组成物中的浓度为 0.2 ~ 166.7 mg/mL。
24、 如权利要求 18所述的方法， 该医药组成物中更包含一医药上可接受的水溶液。
25、如权利要求 18或 24所述的方法，该医药组成物中更包含一第二脂溶性药物微胞； 其中，该第二脂溶性药物微胞为第二非离子性表面活性剂所形成的另一微形结构，且一第 二脂溶性药物被包覆在所述第二脂溶性药物微胞中。
26、 如权利要求 25 所述的方法， 该第二非离子性表面活性剂的亲水亲油性平衡值 (hydrophilic-lipophilic balance value, HLB值)大于 10。
27、 如权利要求 26所述的方法， 该第二非离子性表面活性剂为聚山梨醇酯 80(Tween 80)、 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15)、 聚氧乙烯蓖麻油衍生物
(polyoxyethylene castor oil derivatives；)、 及其他非离子性表面活性剂中的至少一种或其组 合。
28、 如权利要求 27所述的方法， 该第二非离子性表面活性剂为聚氧乙烯 35蓖麻油 (Cremophor ELP)^ 聚氧乙烯 40氢化蓖麻油 (Cremophor RH 40)、及其他聚氧乙烯蓖麻油衍 生物中的至少一种或其组合。
29、 如权利要求 25 所述的方法， 该第二脂溶性药物为槲皮素 (qUercetin)、 辛弗林 (synephrine)、 葛根素 (puerarin)、 姜黄色素类物质 (curcuminoid)及其他白藜卢醇 (resveratrol) 以外的脂溶性药物至少一种或其组合。
30、如权利要求 29所述的方法， 该白藜芦醇与该第二脂溶性药物的重量比为 30: 1 ~ 1： 20。
31、 如权利要求 18或 24所述的方法， 该医药组成物中更包含一水溶性药物。
32、 如权利要求 31所述的方法， 该水溶性药物为绿茶萃取物、 表没食子儿茶素没食 子酸酯 (Epigallocatechin gallate；)、 表儿茶素 (Epicatechin；)、 表儿茶素没食子酸酯 (Epicatechin gallate)、 表没食子儿茶素 (Epigallocatechin)、 没食子儿茶素没食子酸酯（Gallocatechin gallate；)、 没食子儿茶素（Gallocatechin；)、 儿茶素没食子酸酯（Catechin gallate；)、 儿茶素 (Catechin)^表没食子儿茶素没食子酸酯 (epigallocatechin gallate, EGCG；)、咖啡因 (Caffeine；)、 肉碱 (Carnitine; 又称为卡尼丁或卡尼汀)、 左旋肉碱 (L-camitine；)、 辛内弗林 (Synephrine；)、 绿原酸 （ Chi orogenic acid) 、 及其他水溶性药物中的至少一种或其组合。
33、 如权利要求 32所述的方法， 该白藜芦醇与该水溶性药物的重量比为 20: 1 - 1： 30。
34、如权利要求 32所述的方法， 其中， 该水溶性药物为表没食子儿茶素没食子酸酯， 且表没食子儿茶素没食子酸酯在该医药组成物中的浓度为 0.25~300mg/mL。
35、 如权利要求 32所述的方法， 该水溶性药物为绿茶萃取物， 且该白藜芦醇与该绿 茶萃取物的重量比为 30: 1至 1 : 30。
36、 如权利要求 35所述的方法， 以该白藜芦醇与该绿茶萃取物的总重量为一个重量 单位计之， 该非离子性表面活性剂的重量为 0.24 70个重量单位； 抑或是， 该白藜芦醇与 该绿茶萃取物的总重量与该非离子性表面活性剂的重量比为 4: 1至 1 : 70。
37、 如权利要求 18所述的方法， 在该局部部位施用该医药组成物的剂量为每平方公 分注射 0.2 ~ 20毫克。
38、 如权利要求 18所述的方法， 在该局部部位施用该医药组成物的剂量为每公斤注 射 0.2~40毫克。
39、如权利要求 18所述的方法，施用该医药组成物的频率为每间隔 1天至 30天施予 该施用部位 1次至 12次。
40、 如权利要求 18所述的方法， 该个体为一动物或一人类。
41、 如权利要求 18所述的方法， 为在该个体的该局部部位注射、 或涂抹 (apply)该医 药组成物。
42、如权利要求 18所述的方法， 该医药组成物中更包含一助溶剂 (cosolvent；)、一助悬 剂 (suspending agent；)、 以及一油相赋形剂 (oil phase excipients；)的至少一种或其组合。
43、 如权利要求 42所述的方法， 该油相赋形剂以及该助溶剂的至少一种与该非离子 性表面活性剂共同形成该微形结构。
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017037593A3 (zh) * 2015-08-28 2018-08-23 康霈生技股份有限公司 用于减少局部脂肪的医药组成物及其用途
CN113730650A (zh) * 2021-10-13 2021-12-03 哈尔滨泽润医疗机构管理有限公司 一种碳水溶酶组合物及其制备方法和应用
US11318110B2 (en) 2015-08-28 2022-05-03 Caliway Biopharmaceuticals Co., Ltd. Pharmaceutical composition for reducing local fat and uses thereof
WO2023192259A1 (en) * 2022-03-28 2023-10-05 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Synergy for increasing insulin sensitivity
WO2023221945A1 (en) * 2022-05-16 2023-11-23 Caliway Biopharmaceuticals Co., Ltd. Compositions and methods for alleviating conditions caused by abnormal subcutaneous deposit of adipose tissue or fat

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10537548B2 (en) 2014-08-28 2020-01-21 Caliway Biopharmaceuticals Co., Ltd. Composition and medical product for reducing body weight and body fat, and use of said product
EP3505168A1 (en) 2016-08-26 2019-07-03 Caliway Biopharmaceuticals Co., Ltd. Subcutaneous injection for reducing body weight and application thereof
EP3541815A4 (en) 2016-11-18 2020-07-15 Pacira Pharmaceuticals, Inc. ZINC MELXICAM COMPLEX MICROPARTICLE MULTIVESICULAR LIPOSOME FORMULATIONS AND METHODS OF MAKING THE SAME
JP2020515552A (ja) * 2017-03-28 2020-05-28 カリウェイ バイオファーマシューティカルズ カンパニー リミテッド 体重と体脂肪減少に用いられる組成物又は医薬品及びその用途
PH12021551764A1 (en) * 2019-02-11 2022-05-23 Joseph Halstead Therapeutically administrable high dose non-aqueous curcuminoid solutions
US20220184170A1 (en) * 2019-03-24 2022-06-16 NaishadhKumar Ramubhai Patel Formulation to enhance the bioavailibity and stability of curcuminoids and/or its derivatives thereof
CN110934827B (zh) * 2019-11-08 2021-03-19 江西中医药大学 一种口服葛根素混合胶束制剂、制备方法及应用
KR102691705B1 (ko) * 2021-10-25 2024-08-06 주식회사 지엘케이인터내셔날 지방 분해용 조성물
US12111372B2 (en) 2022-04-25 2024-10-08 GE Precision Healthcare LLC Wireless coil adaptor for a magnetic resonance imaging system
KR20250111120A (ko) * 2022-11-22 2025-07-22 칼리웨이 바이오파마슈티칼스 코., 엘티디. 부종성 섬유경화성 피하지방병의 치료 및/또는 예방 방법
WO2025231431A1 (en) * 2024-05-03 2025-11-06 Amalfi Bio, Inc. Methods for reducing fatty infiltration

Family Cites Families (76)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6048736A (en) * 1998-04-29 2000-04-11 Kosak; Kenneth M. Cyclodextrin polymers for carrying and releasing drugs
HK1040062A1 (zh) * 1999-03-03 2002-05-24 Eli Lilly And Company 含有成胶束表面活性剂的棘白菌素药物配方
EP1077211B1 (en) * 1999-08-16 2006-11-22 DSM IP Assets B.V. Process for the production of epigallocatechin gallate
US6475530B1 (en) * 2000-05-31 2002-11-05 Eric H. Kuhrts Methods and compositions for producing weight loss
US6383482B1 (en) * 2000-08-24 2002-05-07 Vitacost.Com, Inc. Weight loss composition containing green tea, hydroxycitric acid, 5-hydroxytryptophan, glucomannan, picolinate and lactobacillus
US20040071799A1 (en) 2001-02-12 2004-04-15 Xiurong Xu Herbal compositions and methods for effecting weight loss in humans
JP4179494B2 (ja) 2001-10-23 2008-11-12 株式会社カネカ ペルオキシソーム増殖剤応答性受容体リガンド剤
US20040146539A1 (en) 2003-01-24 2004-07-29 Gupta Shyam K. Topical Nutraceutical Compositions with Selective Body Slimming and Tone Firming Antiaging Benefits
CN1809288A (zh) * 2003-06-04 2006-07-26 雀巢技术公司 体重管理饮料
CN100539988C (zh) * 2003-06-27 2009-09-16 株式会社太平洋 含有生理活性成分的自聚集聚合物纳米颗粒和含有该纳米颗粒的外用搽剂
AU2004312072B2 (en) 2003-12-29 2011-06-23 President And Fellows Of Harvard College Compositions for treating or preventing obesity and insulin resistance disorders
US20050232974A1 (en) * 2004-04-19 2005-10-20 Gore Makarand P System and a method for pharmaceutical dosage preparation using jettable microemulsions
US20050267221A1 (en) 2004-05-14 2005-12-01 Research Development Foundation Use of curcumin and analogues thereof as inhibitors of ACC2
CN100486567C (zh) * 2004-08-12 2009-05-13 山东绿叶天然药物研究开发有限公司 姜黄素乳剂及其制备方法
WO2006074278A2 (en) 2005-01-05 2006-07-13 Mitsunori Ono Compositions for treating diabetes or obesity
US8268792B2 (en) 2005-02-04 2012-09-18 Peter Heger Use of an active ingredient combination that contains hydroxystilbene for preventing and/or treating diseases
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
ES2384641T3 (es) 2005-07-14 2012-07-10 Lithera, Inc. Formulación lipolítica que potencia la liberación mantenida para el tratamiento localizado del tejido adiposo
JP2007063137A (ja) * 2005-08-29 2007-03-15 Daicho Kikaku:Kk 抗肥満薬
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
CN100367951C (zh) * 2005-12-16 2008-02-13 石药集团恩必普药业有限公司 丁苯酞静脉乳剂及其应用
EP1993365B1 (en) * 2006-03-06 2013-05-08 The Regents of the University of California Bioavailable curcuminoid formulations for treating alzheimer's disease and other age-related disorders
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
WO2007113008A2 (en) * 2006-04-04 2007-10-11 Dsm Ip Assets B.V. Opaque container comprising food or pharmaceutical products or herbal(s)
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
US7923026B2 (en) * 2006-10-20 2011-04-12 Solvay Pharmaceuticals B.V. Embedded micellar nanoparticles
KR101069502B1 (ko) * 2006-10-31 2011-09-30 (주)아모레퍼시픽 비만 및 당뇨병 개선용 경구용 조성물
JP2008133272A (ja) * 2006-10-31 2008-06-12 Ito En Ltd Ｃｐｔ活性亢進剤及び飲食物
CN101310718A (zh) * 2007-05-23 2008-11-26 中国科学院上海生命科学研究院 减肥降血脂的含儿茶素的组合物及其用途
CN102357226B (zh) 2007-08-07 2013-07-10 北京北大维信生物科技有限公司 中草药姜黄的醇提取物在制备具有脂肪酶活性抑制作用的药物中的应用
WO2009066303A2 (en) * 2007-11-22 2009-05-28 Ganga Raju Gokaraju New synergistic phytochemical composition for the treatment of obesity
US20110009496A1 (en) * 2008-01-08 2011-01-13 Sirtris Pharmaceuticas, Inc. Resveratrol formulations
CN103588678A (zh) 2008-04-18 2014-02-19 里亚塔医药公司 包含抗炎症药效团的化合物以及使用方法
KR101372658B1 (ko) * 2008-06-25 2014-03-14 이엘씨 매니지먼트 엘엘씨 피부 및 신체 외관 개선 방법 및 조성물
US20100215782A1 (en) 2008-10-22 2010-08-26 Metaproteomics, Llc Novel mitochondrial uncoupling methods and compositions for enhancing adipocyte thermogenesis
US8496974B2 (en) * 2008-11-25 2013-07-30 Oy Granula Ab Ltd Method for preparing a composition comprising a compound mixture and a carrier agent
CA2748344A1 (en) 2008-11-26 2010-06-03 Lipoprotein Technologies, Inc. Enhanced bioactive formulations of resveratrol
MA33220B1 (fr) * 2009-03-20 2012-04-02 Bioxtract S A Composition pharmaceutique a proprietes anti-inflammatoires
CN101874763A (zh) * 2009-04-29 2010-11-03 上海家化联合股份有限公司 一种白藜芦醇柔性脂质体及其制备方法
KR20100124519A (ko) * 2009-05-19 2010-11-29 (주)아모레퍼시픽 녹차 추출물을 함유하는 조성물
CN101632655B (zh) 2009-08-04 2011-12-07 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
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
NZ602288A (en) * 2010-03-10 2014-02-28 Abbvie Bahamas Ltd Solid compositions comprising amorphous (2r,6s,13as,14ar,16as,z)-n-(cyclopropylsulfonyl)-6-(5-methylpyrazine-2-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide
US8835509B2 (en) 2010-05-31 2014-09-16 Arbro Pharmaceuticals Ltd. Self emulsifying drug delivery system for a curcuminoid based composition
KR101639196B1 (ko) 2010-07-02 2016-07-14 헬릭스 바이오메딕스, 인코포레이티드 셀룰라이트와 같은 피부 질환을 치료하는 ｎ―아실 아미노산 유도체
WO2012003515A2 (en) * 2010-07-02 2012-01-05 Eric Hauser Kuhrts Stable fatty acid-containing formulations
KR101640258B1 (ko) * 2010-07-05 2016-07-15 주식회사 엘지생활건강 적포도 추출물, 녹차 추출물, 대두 추출물 및 ｌ－카르니틴을 유효성분으로 함유하는 항비만 조성물
EP2593093A1 (en) 2010-07-16 2013-05-22 Merz Pharma GmbH & Co. KGaA Use of a cationic amphiphilic drug for the preparation of a formulation for the reduction of subcutaneous adipose tissue
US20120088829A1 (en) * 2010-09-29 2012-04-12 MyCell Holdings Limited Formulations of Ubiquinol and Resveratrol Esters
CN102106816A (zh) 2010-12-16 2011-06-29 天津迈迪瑞康生物医药科技有限公司 一种白藜芦醇纳米制剂及其制备方法
US8815310B2 (en) 2011-01-10 2014-08-26 Morteza Naghavi Compositions for boosting metabolism, assisting weight loss, and promoting cardiovascular health
CN102512404B (zh) 2011-11-18 2014-05-07 上海交通大学 一种姜黄素类化合物肺靶向制剂及其制备方法与应用
US9745279B2 (en) 2011-12-27 2017-08-29 Tokiwa Phytochemical Co., Ltd. Sirtuin activator
DK2804587T3 (da) * 2012-01-19 2019-08-12 Yissum Res Dev Co Of Hebrew Univ Jerusalem Ltd Formulering og fremgangsmåde til øgning af lægemidlers biotilgængelighed
US8496979B1 (en) 2012-02-02 2013-07-30 Reliv International, Inc. Caffeine-free dietary supplements for increasing energy and methods of administering the same
MX2014009308A (es) 2012-02-29 2014-10-14 Avon Prod Inc Uso de moduladores de cpt-1 y composiciones de los mismos.
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
US9731015B2 (en) 2012-08-04 2017-08-15 Eric Hauser Kuhrts Water-soluble lipophilic natural compound formulations
WO2014028607A1 (en) * 2012-08-14 2014-02-20 Abbott Laboratories Low glycemic index nutritional compositions for preserving muscle mass and improving body composition in diabetics
US9211298B2 (en) 2012-11-16 2015-12-15 Song Gao Compositions containing enriched natural crocin and/or crocetin, and their therapeutic or nutraceutical uses
DE202012012130U1 (de) * 2012-12-19 2014-03-21 Aquanova Ag Curcuminsolubilisat
WO2014138426A2 (en) * 2013-03-07 2014-09-12 Topokine Therapeutics, Inc. Methods and compositions for reducing body fat and adipocytes
CN103285401A (zh) * 2013-05-27 2013-09-11 沈阳药科大学 一种能提高难溶性药物溶解性和生物利用度的组合物
US9458086B1 (en) * 2013-07-03 2016-10-04 University Of South Florida (A Florida Non-Profit Corporation) Compositions and methods for adipocyte modulation
WO2015072602A1 (ko) 2013-11-15 2015-05-21 (주)다미화학 난용성 물질의 수용액 가용화 조성물 및 이를 이용한 난용성 물질의 수용액 가용방법
WO2015081319A2 (en) * 2013-11-27 2015-06-04 Research Foundation Of The City University Of New York Activity enhancing curcumin compositions and methods of use
TW201540294A (zh) * 2014-04-25 2015-11-01 康立為生醫科技股份有限公司 用於抑制脂肪細胞、降低體脂肪、減少體重或促進脂肪代謝之植物萃取組成物及其醫藥組合物與用途
CN103989659B (zh) * 2014-05-26 2016-09-07 重庆医科大学 姜黄素纳米结构脂质载体及其制备方法
HUE059878T2 (hu) * 2014-08-28 2023-01-28 Caliway Biopharmaceuticals Co Ltd Készítmény és gyógyszerek lokális zsír és testtömeg csökkentésére és ezek alkalmazása
US10226503B2 (en) 2014-08-28 2019-03-12 Caliway Biopharmaceuticals Co., Ltd. Plant extract composition for reducing topical fat and promoting weight loss as well as applications thereof
MX2017002584A (es) 2014-08-28 2017-05-25 Caliway Biopharmaceuticals Co Ltd Composicion y producto medicinal para reducir peso corporal y grasa corporal, y uso del producto.
WO2017037594A2 (zh) * 2015-08-28 2017-03-09 康霈生技股份有限公司 用于减少局部脂肪的医药组成物及其用途
US11318110B2 (en) 2015-08-28 2022-05-03 Caliway Biopharmaceuticals Co., Ltd. Pharmaceutical composition for reducing local fat and uses thereof
EP3505168A1 (en) 2016-08-26 2019-07-03 Caliway Biopharmaceuticals Co., Ltd. Subcutaneous injection for reducing body weight and application thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017037593A3 (zh) * 2015-08-28 2018-08-23 康霈生技股份有限公司 用于减少局部脂肪的医药组成物及其用途
WO2017037594A3 (zh) * 2015-08-28 2018-08-23 康霈生技股份有限公司 用于减少局部脂肪的医药组成物及其用途
US10610496B2 (en) 2015-08-28 2020-04-07 Caliway Biopharmaceuticals Co., Ltd. Pharmaceutical composition for reducing local fat and uses thereof
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
CN113730650A (zh) * 2021-10-13 2021-12-03 哈尔滨泽润医疗机构管理有限公司 一种碳水溶酶组合物及其制备方法和应用
CN113730650B (zh) * 2021-10-13 2022-11-01 哈尔滨泽润医疗机构管理有限公司 一种碳水溶酶组合物及其制备方法和应用
WO2023192259A1 (en) * 2022-03-28 2023-10-05 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Synergy for increasing insulin sensitivity
WO2023221945A1 (en) * 2022-05-16 2023-11-23 Caliway Biopharmaceuticals Co., Ltd. Compositions and methods for alleviating conditions caused by abnormal subcutaneous deposit of adipose tissue or fat
TWI864754B (zh) * 2022-05-16 2024-12-01 康霈生技股份有限公司 用於緩解由脂肪組織或脂肪的異常皮下沉積所引起的病狀之組合物及方法

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