US20180243211A1 - A pharmaceutical composition for reducing local fat and uses thereof - Google Patents

A pharmaceutical composition for reducing local fat and uses thereof Download PDF

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US20180243211A1
US20180243211A1 US15/754,363 US201615754363A US2018243211A1 US 20180243211 A1 US20180243211 A1 US 20180243211A1 US 201615754363 A US201615754363 A US 201615754363A US 2018243211 A1 US2018243211 A1 US 2018243211A1
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resveratrol
pharmaceutical composition
drug
weight
green tea
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Yu-Fang LING
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Caliway Biopharmaceuticals Co Ltd
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Caliway Biopharmaceuticals Co Ltd
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Priority claimed from PCT/CN2015/088340 external-priority patent/WO2016029870A1/fr
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    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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Definitions

  • the present invention relates to a pharmaceutical composition for reducing localized fat, specifically, relates to a pharmaceutical composition comprising drug-containing micelles and resveratrol encapsulated in the micelles, and the pharmaceutical composition is for localized fat reduction.
  • liposuction is the most prevalent technology to reduce localized fat.
  • the procedure of liposuction causes severe damages to the nerves, blood vessels, and other tissues.
  • Liposuction also comes with risks of infections, severe bleeding, prolonged anesthesia, and unpredictable life-threatening conditions such as fat embolism and allergic reactions to anesthesia.
  • the present invention provides a pharmaceutical composition for reducing localized fat.
  • the pharmaceutical composition comprises drug-containing micelles made of surfactants, and resveratrol encapsulated in said drug-containing micelles.
  • the pharmaceutical composition for reducing localized fat can reduce fat at the administration site, and has the advantages of high stability, high fat tissue bioavailability, few side effects, and sustained release.
  • the present invention can promote apoptosis of the adipocytes at the administration site, thereby achieving the goal of localized fat reduction at the administration site.
  • the present invention dramatically solves the problems of prior arts, including adverse reactions and side effects such as necrosis of the surrounding cells and inflammation reactions, and its efficacy on localized fat reduction is significantly superior to other non-surgical pharmaceutical compositions for localized fat reduction.
  • the present invention is suitable for administration at sites requiring subcutaneous fat reduction by direct injection, subcutaneous implantation, implanted infusion, or skin absorption ways, e.g. cream or patch application, without the need for surgery or the help with equipment. Preferably, it is subcutaneously injected into the localized subcutaneous fat layer at the administration site.
  • the formulations for injection of the pharmaceutical composition in the present invention include, but are not limited to, powder for injection, or powder for solution for injection.
  • the “localized fat” in the present invention includes but is not limited to the waist, abdomen, legs, arms, chin, and face, etc.
  • resveratrol refers to resveratrol extracted from natural plants or commercially available resveratrol.
  • the purity of resveratrol is 90% to 100%.
  • green tea extract refers to green tea ingredient mixture extracted by any solvent with any extraction method, commercially available green tea extract, any mixture with at least 45% (wt %) of epigallocatechin gallate (EGCG), or commercially available epigallocatechin gallate (EGCG).
  • EGCG epigallocatechin gallate
  • EGCG epigallocatechin gallate
  • the term “micelle” refers to a microstructure formed by surfactants, wherein each of the surfactants has a hydrophilic end and a hydrophobic (lipophilic) end, and the surfactants are arranged in a way that the hydrophilic ends face outward and the hydrophobic (lipophilic) ends face inward to form the microstructure.
  • the microstructure is a spherical structure, a spherical-like structure, or other micro structural structures.
  • drug-containing micelles refer to micelles containing resveratrol; that is, the term “drug-containing micelles” refer to micelles encapsulating or containing resveratrol.
  • second lipophilic drug-containing micelles refer to micelles containing any lipophilic drugs expect resveratrol. That is, the term “second lipophilic drug-containing micelles” refer to micelles encapsulating or containing other lipophilic drugs.
  • other lipophilic drugs refer to at least one of curcumin, quercetin, puerarin, and other lipophilic drugs except resveratrol, or combination thereof; or, the term “other lipophilic drugs” refer to lipophilic drugs other than resveratrol.
  • hydrophilic drugs refer to at least one of green tea extract, epigallocatechin gallate, epicatechin, epicatechin gallate, epigallocatechin, gallocatechin gallate, gallocatechin, catechin gallate, catechin, epigallocatechin gallate (EGCG), caffeine, carnitine, L-carnitine, synephrine, chlorogenic acid, and other hydrophilic drugs, or combination thereof.
  • the term “state without precipitation”, as used herein, refers to a state wherein no precipitation can be observed with the naked eye, that is, without the need by the assistance of artificial instruments.
  • the present invention provides a pharmaceutical composition for reducing localized fat, comprising:
  • the drug-containing micelle is a microstructure formed by a pharmaceutically acceptable surfactant, and the hydrophilic-lipophilic balance value (HLB value) of the surfactantis greater than 10.
  • HLB value hydrophilic-lipophilic balance value
  • the diameter of the drug-containing micelles is 3 ⁇ 250 nm.
  • the diameter of the drug-containing micelles is 5 ⁇ 50 nm.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable aqueous solution, and the drug-containing micelles are evenly distributed in said pharmaceutically acceptable aqueous solution.
  • the pharmaceutically acceptable aqueous solution is water for injection, an aqueous solution for injection, or normal saline.
  • the surfactant is a non-ionic surfactant.
  • the non-ionic surfactant is at least one of polysorbate 80 (tween 80), 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15), polyoxyethylene castor oil derivatives, and other non-ionic surfactants, or combination thereof.
  • the polyoxyethylene castor oil derivatives are at least one of Kolliphor ELP (also known as cremophor ELP), cremophor RH 40, and other polyoxyethylene castor oil derivatives, or combination thereof.
  • the weight ratio of resveratrol to the surfactant is 1:4 to 1:500.
  • the weight ratio of resveratrol to the surfactant is 1:5 to 1:200.
  • the weight ratio of resveratrol to the surfactant is 1:8 to 1:80.
  • the pharmaceutical composition maintains at a state without precipitation for at least 24 hours when it is subjected to accelerated stability test at 25° C. ⁇ 2° C., relative humidity 60% ⁇ 5%, and in the absence of direct light.
  • the pharmaceutical composition maintains at a state without precipitation for at least 6 months when it is subjected to accelerated stability test at 25° C. ⁇ 2° C., relative humidity 60% ⁇ 5%, and in the absence of direct light.
  • the concentration of resveratrol in the pharmaceutical composition is 0.2 ⁇ 166.7 mg/mL.
  • the concentration of resveratrol in the pharmaceutical composition is 2.5 ⁇ 60 mg/mL.
  • the pharmaceutical composition further comprises 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 ingredient wherein said first green tea extract ingredient is epigallocatechin gallate (EGCG).
  • EGCG epigallocatechin gallate
  • the concentration of epigallocatechin gallate (EGCG) in the pharmaceutical composition is 0.25 ⁇ 300 mg/mL.
  • the concentration of epigallocatechin gallate (EGCG) in the pharmaceutical composition is 1 ⁇ 200 mg/mL.
  • the content of epigallocatechin gallate (EGCG) is 45 ⁇ 100% by weight (wt %), based on 100% by weight of the total green tea extract.
  • the weight ratio of the resveratrol to the green tea extract is 30:1 to 1:30.
  • the weight ratio of the resveratrol to the green tea extract is 20:1 to 1:20.
  • the weight ratio of the resveratrol to the green tea extract is 10:1 to 1:10.
  • the amount of the surfactant is 0.24 ⁇ 70 parts by weight, based on 1 part by weight of the total amount of resveratrol and green tea extract; or, the weight ratio of the total weight of the resveratrol and the green tea extract to the surfactant is 4:1 to 1:70.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable aqueous solution and a second lipophilic drug-containing micelle, wherein the second lipophilic drug-containing micelles are evenly distributed in the pharmaceutically acceptable aqueous solution.
  • the second lipophilic drug-containing micelle is another microstructure formed by a second surfactant, and an other lipophilic drug (or second lipophilic drug) is encapsulated in said second lipophilic drug-containing micelle.
  • the hydrophilic-lipophilic balance value (HLB value) of the second surfactant is greater than 10.
  • the second surfactant is a non-ionic surfactant.
  • the non-ionic surfactant is at least one of polysorbate 80 (tween 80), 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15), polyoxyethylene castor oil derivatives, and other non-ionic surfactants, or combination thereof.
  • the polyoxyethylene castor oil derivatives are at least one of cremophor ELP, cremophor RH 40, and other polyoxyethylene castor oil derivatives, or combination thereof.
  • the lipophilic drug is at least one of quercetin, synephrine, puerarin, curcumin, and other lipophilic drugs except resveratrol, or combination thereof.
  • the weight ratio of the resveratrol to the second lipophilic drug is 30:1 ⁇ 1:20.
  • the weight ratio of the resveratrol to the second lipophilic drug is 20:1 ⁇ 1:15.
  • the weight ratio of the resveratrol to the second lipophilic drug is 15:1 ⁇ 1:10.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable aqueous solution and a hydrophilic drug.
  • the hydrophilic drug is at least one of green tea extract, epigallocatechin gallate, epicatechin, epicatechin gallate, epigallocatechin, gallocatechin gallate, gallocatechin, catechin gallate, catechin, epigallocatechin gallate (EGCG), caffeine, carnitine, L-carnitine, synephrine, chlorogenic acid, and other hydrophilic drugs, or combination thereof.
  • green tea extract epigallocatechin gallate, epicatechin, epicatechin gallate, epigallocatechin, gallocatechin gallate, gallocatechin, catechin gallate, catechin, epigallocatechin gallate (EGCG), caffeine, carnitine, L-carnitine, synephrine, chlorogenic acid, and other hydrophilic drugs, or combination thereof.
  • the weight ratio of the resveratrol to the hydrophilic drug is 20:1 ⁇ 1:30.
  • the weight ratio of the resveratrol to the hydrophilic drug is 15:1 ⁇ 1:20.
  • the weight ratio of the resveratrol to the hydrophilic drug is 10:1 ⁇ 1:15.
  • the hydrophilic drugs is gallocatechin gallate
  • the concentration of gallocatechin gallate in the pharmaceutical composition is 0.25 ⁇ 300 mg/mL.
  • the hydrophilic drugs is gallocatechin gallate, and the concentration of gallocatechin gallate in the pharmaceutical composition is 1 ⁇ 200 mg/mL.
  • the hydrophilic drugs is green tea extract, and the weight ratio of the resveratrol to the green tea extract is 30:1 to 1:30.
  • the hydrophilic drugs is green tea extract, and the weight ratio of the resveratrol to the green tea extract is 20:1 to 1:20.
  • the hydrophilic drugs is green tea extract
  • the weight ratio of the resveratrol to the green tea extract is 10:1 to
  • the pharmaceutical composition further comprises a cosolvent to enhance the solubility of the drug.
  • the cosolvent is at least one of polyethylene glycol, propylene glycol, ethanol, and other cosolvent, or combination thereof.
  • the polyethylene glycol is at least one of PEG 200, PEG 400, PEG 600, and other polyethylene glycol, or combination thereof.
  • the pharmaceutical composition further comprises a suspending agent to decrease the sedimentation rate of the drug or micelles.
  • the suspending agent is at least one of sodium alginate, glycerol, carboxymethylcellulose sodium, mannitol, and other suspending agent, or combination thereof.
  • the pharmaceutical composition further comprises an oil phase excipient to enhance the stability of the pharmaceutical composition and the solubility of the drug.
  • the oil phase excipient is at least one of unsaturated fatty acid, glycerol, triglyceride, and other oil phase excipient, or combination thereof.
  • the unsaturated fatty acid is at least one of oleic acid, castor oil, sesame oil, cottonseed oil, soybean oil, safflower oil, corn oil, and other unsaturated fatty acid, or combination thereof.
  • the triglyceride is at least one of medium chain triglycerides and other triglyceride, or combination thereof.
  • the pharmaceutically acceptable aqueous solution comprises a local anesthetic.
  • the local anesthetic is at least one of amides, para-aminobenzoic acid esters, and amino ethers, or combination thereof.
  • the amides are at least one of dibucaine, lidocaine, mepivacaine HCl, bupivacine HCl, pyrrocaine HCl, prilocaine HCl, digammacaine, and oxethazaine, or combination thereof.
  • para-aminobenzoic acid esters are at least one of butacaine, dimethocaine, and tutocaine, or combinations thereof.
  • the amino ethers are at least one of quinisocaine and pramocaine, or combination thereof.
  • the pharmaceutically acceptable aqueous solution comprises an antioxidant.
  • the antioxidant is at least one of beta-carotene, lutein, lycopene, bilirubin, vitamin A, vitamin C (ascorbic acid), vitamin E, uric acid, nitric oxide, nitroxide, pyruvate, catalase, superoxide dismutase, glutathione peroxidases, N-acetyl cysteine, and naringenin, or combination thereof.
  • the present invention further provides a formulation for subcutaneous fat layer injection or a formulation for subcutaneous injection for reducing the amount of localized subcutaneous fat, comprising:
  • said drug-containing micelle is a microstructure formed by a pharmaceutically acceptable surfactant, and the hydrophilic-lipophilic balance value (HLB value) of the pharmaceutically acceptable surfactant is greater than 10.
  • said amount of localized subcutaneous fat is the amount of subcutaneous fat at the administration site.
  • the diameter of the drug-containing micelles is 3 ⁇ 250 nm.
  • the diameter of the drug-containing micelles is 5 ⁇ 50 nm.
  • the pharmaceutically acceptable aqueous solution is water for injection, aqueous solutions for injection, or normal saline.
  • the surfactant is a non-ionic surfactant.
  • the non-ionic surfactant is at least one of polysorbate 80 (tween 80), 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15), polyoxyethylene castor oil derivatives, and other non-ionic surfactants, or combination thereof.
  • the polyoxyethylene castor oil derivatives are at least one of cremophor ELP, cremophor RH 40, and other polyoxyethylene castor oil derivatives, or combination thereof.
  • the weight ratio of resveratrol to the surfactant is 1:4 to 1:500.
  • the weight ratio of resveratrol to the surfactant is 1:5 to 1:200.
  • the weight ratio of resveratrol to the surfactant is 1:8 to 1:80.
  • the concentration of resveratrol in the formulation for subcutaneous fat layer injection or the formulation for subcutaneous injection is 0.2 ⁇ 166.7 mg/mL.
  • the concentration of resveratrol in the formulation for subcutaneous fat layer injection or the formulation for subcutaneous injection is 2.5 ⁇ 60 mg/mL.
  • the formulation for subcutaneous fat layer injection or the formulation for subcutaneous injection further comprises 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 ingredient wherein said first green tea extract ingredient is epigallocatechin gallate (EGCG).
  • EGCG epigallocatechin gallate
  • the concentration of epigallocatechin gallate (EGCG) in the formulation for subcutaneous fat layer injection or the formulation for subcutaneous injection is 0.25 ⁇ 300 mg/mL.
  • the concentration of epigallocatechin gallate (EGCG) in the formulation for subcutaneous fat layer injection or the formulation for subcutaneous injection is 1 ⁇ 200 mg/mL.
  • the content of epigallocatechin gallate (EGCG) is 45 ⁇ 100% by weight (wt %) based on 100% by weight of the total green tea extract.
  • the weight ratio of the resveratrol to the green tea extract is 30:1 to 1:30.
  • the weight ratio of the resveratrol to the green tea extract is 20:1 to 1:20.
  • the weight ratio of the resveratrol to the green tea extract is 10:1 to 1:10.
  • the amount of the surfactant is 0.24 ⁇ 70 parts by weight, based on 1 part by weight of the total amount of resveratrol and green tea extract; or, the weight ratio of the total weight of the resveratrol and the green tea extract to the surfactant is 4:1 to 1:70.
  • the administered dosage be injected at the administration site is 0.2 ⁇ 20 mg/cm 2 .
  • the administered dosage be injected at the administration site is 0.4 ⁇ 12 mg/cm 2 .
  • the administered dosage is 0.2 ⁇ 40 mg/kg at the administration site.
  • the administered dosage is 0.4 ⁇ 20 mg/kg at the administration site.
  • the dosing frequency is 1 to 12 times every other day to every 30 days.
  • the dosing frequency is 1 to 8 times every other day to every 21 days.
  • the formulation for subcutaneous fat layer injection or a formulation for subcutaneous injection further comprises a second lipophilic drug-containing micelle, and the second lipophilic drug-containing micelles are evenly distributed in the pharmaceutically acceptable aqueous solution.
  • the second lipophilic drug-containing micelle is a microstructure formed by another surfactant, and the other lipophilic drug is encapsulated in said second lipophilic drug-containing micelle.
  • the hydrophilic-lipophilic balance value (HLB value) of the other surfactant is greater than 10.
  • the other surfactant is a non-ionic surfactant.
  • the non-ionic surfactant is at least one of polysorbate 80 (tween 80), 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15), polyoxyethylene castor oil derivatives, and other non-ionic surfactants, or combination thereof.
  • the polyoxyethylene castor oil derivatives are at least one of cremophor ELP, cremophor RH 40, and other polyoxyethylene castor oil derivatives, or combination thereof.
  • the lipophilic drug is at least one of curcumin, quercetin, puerarin, and other lipophilic drugs except resveratrol, or combination thereof.
  • the pharmaceutically acceptable aqueous solution further comprises a hydrophilic drug.
  • the hydrophilic drug is at least one of green tea extract, epigallocatechin gallate, epicatechin, epicatechin gallate, epigallocatechin, gallocatechin gallate, gallocatechin, catechin gallate, catechin, epigallocatechin gallate (EGCG), caffeine, carnitine, L-carnitine, synephrine, chlorogenic acid, and other hydrophilic drugs, or combination thereof.
  • green tea extract epigallocatechin gallate, epicatechin, epicatechin gallate, epigallocatechin, gallocatechin gallate, gallocatechin, catechin gallate, catechin, epigallocatechin gallate (EGCG), caffeine, carnitine, L-carnitine, synephrine, chlorogenic acid, and other hydrophilic drugs, or combination thereof.
  • the pharmaceutically acceptable aqueous solution comprises a local anesthetic.
  • the local anesthetic is at least one of amides, para-aminobenzoic acid esters, amino ethers, or combination thereof.
  • the amides are at least one of dibucaine, lidocaine, mepivacaine HCl, bupivacine HCl, pyrrocaine HCl, prilocaine HCl, digammacaine, and oxethazaine, or combination thereof.
  • para-aminobenzoic acid esters are at least one of butacaine, dimethocaine, and tutocaine, or combination thereof.
  • the amino ethers are at least one of quinisocaine and pramocaine, or combination thereof.
  • the pharmaceutically acceptable aqueous solution comprises an antioxidant.
  • the antioxidant is at least one of beta-carotene, lutein, lycopene, bilirubin, vitamin A, vitamin C (ascorbic acid), vitamin E, uric acid, nitric oxide, nitroxide, pyruvate, catalase, superoxide dismutase, glutathione peroxidases, N-acetyl cysteine, and naringenin, or combination thereof.
  • the present invention provides a method for reducing the amount of localized subcutaneous fat of a subject, comprising a step of administering a pharmaceutical composition to the local site of the subject, wherein the pharmaceutical composition comprising:
  • the diameter of the drug-containing micelles is 3 ⁇ 250 nm.
  • the diameter of the drug-containing micelles is 5 ⁇ 50 nm.
  • the surfactant is a non-ionic surfactant.
  • the non-ionic surfactant is at least one of polysorbate 80 (tween 80), 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15), polyoxyethylene castor oil derivatives, and other non-ionic surfactants, or combination thereof.
  • the polyoxyethylene castor oil derivatives are at least one of cremophor ELP, cremophor RH 40, and other polyoxyethylene castor oil derivatives, or combination thereof.
  • the weight ratio of resveratrol to the surfactant is 1:4 to 1:500.
  • the weight ratio of resveratrol to the surfactant is 1:5 to 1:200.
  • the weight ratio of resveratrol to the surfactant is 1:8 to 1:80.
  • the concentration of resveratrol in the pharmaceutical composition is 0.2 ⁇ 166.7 mg/mL.
  • the concentration of resveratrol in the pharmaceutical composition is 2.5 ⁇ 60 mg/mL.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable aqueous solution and a second lipophilic drug-containing micelle, wherein the second lipophilic drug-containing micelles are evenly distributed in the pharmaceutically acceptable aqueous solution; the second lipophilic drug-containing micelle is another microstructure formed by a second non-ionic surfactant, and a second lipophilic drug is encapsulated in said second lipophilic drug-containing micelle.
  • the hydrophilic-lipophilic balance value (HLB value) of the second non-ionic surfactant is greater than 10.
  • the second non-ionic surfactant is at least one of polysorbate 80 (tween 80), 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15), polyoxyethylene castor oil derivatives, and other non-ionic surfactants, or combination thereof.
  • the second non-ionic surfactant is at least one of cremophor ELP, cremophor RH 40, and other polyoxyethylene castor oil derivatives, or combination thereof.
  • the second lipophilic drug is at least one of quercetin, synephrine, puerarin, curcuminoid, curcumin, and other lipophilic drugs except resveratrol, or combination thereof.
  • the weight ratio of resveratrol to the second lipophilic drug is 30:1 to 1:20.
  • the weight ratio of resveratrol to the second lipophilic drug is 20:1 to 1:15.
  • the weight ratio of resveratrol to the second lipophilic drug is 15:1 to 1:10.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable aqueous solution and a hydrophilic drug.
  • the hydrophilic drug is at least one of green tea extract, epigallocatechin gallate, epicatechin, epicatechin gallate, epigallocatechin, gallocatechin gallate, gallocatechin, catechin gallate, catechin, epigallocatechin gallate (EGCG), caffeine, carnitine, L-carnitine, synephrine, chlorogenic acid, and other hydrophilic drugs, or combination thereof.
  • green tea extract epigallocatechin gallate, epicatechin, epicatechin gallate, epigallocatechin, gallocatechin gallate, gallocatechin, catechin gallate, catechin, epigallocatechin gallate (EGCG), caffeine, carnitine, L-carnitine, synephrine, chlorogenic acid, and other hydrophilic drugs, or combination thereof.
  • the weight ratio of resveratrol to the hydrophilic drugs is 20:1 to 1:30.
  • the weight ratio of resveratrol to the hydrophilic drugs is 15:1 to 1:20.
  • the weight ratio of resveratrol to the hydrophilic drugs is 10:1 to 1:15.
  • the hydrophilic drug is gallocatechin gallate
  • the concentration of gallocatechin gallate in the pharmaceutical composition is 0.25 ⁇ 300 mg/mL.
  • the hydrophilic drug is gallocatechin gallate
  • the concentration of gallocatechin gallate in the pharmaceutical composition is 1 ⁇ 200 mg/mL.
  • the hydrophilic drug is green tea extract
  • the weight ratio of resveratrol to the green tea extract is 30:1 to 1:30.
  • the hydrophilic drug is green tea extract
  • the weight ratio of resveratrol to the green tea extract is 20:1 to 1:20.
  • the hydrophilic drug is green tea extract
  • the weight ratio of resveratrol to the green tea extract is 10:1 to 1:10.
  • the amount of the surfactant is 0.24 ⁇ 70 parts by weight, based on 1 part by weight of the total amount of resveratrol and green tea extract; or, the weight ratio of the total weight of the resveratrol and the green tea extract to the surfactant is 4:1 to 1:70.
  • the administered dosage of the pharmaceutical composition to be injected at the local site is 0.2 ⁇ 20 mg/cm 2 .
  • the administered dosage of the pharmaceutical composition to be injected at the local site is 0.4 ⁇ 12 mg/cm 2 .
  • the administered dosage of the pharmaceutical composition to be administered at the local site is 0.2 ⁇ 40 mg/kg.
  • the administered dosage of the pharmaceutical composition to be administered at the local site is 0.4 ⁇ 20 mg/kg.
  • the dosing frequency of the pharmaceutical composition is 1 to 12 times every other day to every 30 days.
  • the dosing frequency of the pharmaceutical composition is 1 to 8 times every other day to every 21 days.
  • the subject is an animal or a human.
  • the step is to inject or apply the pharmaceutical composition to the local site of the subject.
  • the pharmaceutical composition further comprises at least one of a cosolvent, a suspending agent, and an oil phase excipient, or combination thereof.
  • the microstructure is co-formed by the non-ionic surfactant and the oil phase excipient and/or the cosolvent.
  • the present invention provides a use of a pharmaceutical composition in preparing a drug or a subcutaneous injection formulation for reducing the amount of localized subcutaneous fat of a subject; the pharmaceutical composition comprising:
  • the diameter of the drug-containing micelles is 3 ⁇ 250 nm.
  • the diameter of the drug-containing micelles is 5 ⁇ 50 nm.
  • the non-ionic surfactant is at least one of polysorbate 80 (tween 80), 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15), polyoxyethylene castor oil derivatives, and other non-ionic surfactants, or combination thereof.
  • the polyoxyethylene castor oil derivatives are at least one of cremophor ELP, cremophor RH 40, and other polyoxyethylene castor oil derivatives, or combination thereof.
  • the weight ratio of resveratrol to the non-ionic surfactant is 1:4 to 1:500.
  • the concentration of resveratrol in the pharmaceutical composition is 0.2 ⁇ 166.7 mg/mL.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable aqueous solution and a second lipophilic drug-containing micelle, wherein the second lipophilic drug-containing micelles are evenly distributed in the pharmaceutically acceptable aqueous solution; the second lipophilic drug-containing micelle is another microstructure formed by a second non-ionic surfactant, and a second lipophilic drug is encapsulated in said second lipophilic drug-containing micelle.
  • the hydrophilic-lipophilic balance value (HLB value) of the second non-ionic surfactant is greater than 10.
  • the second non-ionic surfactant is at least one of polysorbate 80 (tween 80), 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15), polyoxyethylene castor oil derivatives, and other non-ionic surfactants, or combination thereof.
  • the second non-ionic surfactant is at least one of cremophor ELP, cremophor RH 40, and other polyoxyethylene castor oil derivatives, or combination thereof.
  • the second lipophilic drug is at least one of quercetin, synephrine, puerarin, curcuminoid, and other lipophilic drugs except resveratrol, or combination thereof.
  • the weight ratio of resveratrol to the second lipophilic drug is 30:1 to 1:20.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable aqueous solution and a hydrophilic drug.
  • the hydrophilic drug is at least one of green tea extract, epigallocatechin gallate, epicatechin, epicatechin gallate, epigallocatechin, gallocatechin gallate, gallocatechin, catechin gallate, catechin, epigallocatechin gallate (EGCG), caffeine, carnitine, L-carnitine, synephrine, chlorogenic acid, and other hydrophilic drugs, or combination thereof.
  • green tea extract epigallocatechin gallate, epicatechin, epicatechin gallate, epigallocatechin, gallocatechin gallate, gallocatechin, catechin gallate, catechin, epigallocatechin gallate (EGCG), caffeine, carnitine, L-carnitine, synephrine, chlorogenic acid, and other hydrophilic drugs, or combination thereof.
  • the weight ratio of resveratrol to the hydrophilic drugs is 20:1 to 1:30.
  • the hydrophilic drug is gallocatechin gallate
  • the concentration of gallocatechin gallate in the pharmaceutical composition for the formulation for subcutaneous fat layer injection or a formulation for subcutaneous injection is 0.25 ⁇ 300 mg/mL.
  • the hydrophilic drug is green tea extract
  • the weight ratio of resveratrol to the green tea extract is 30:1 to 1:30.
  • the amount of the surfactant is 0.24 ⁇ 70 parts by weight, based on 1 part by weight of the total amount of resveratrol and green tea extract; or, the weight ratio of the total weight of the resveratrol and the green tea extract to the surfactant is 4:1 to 1:70.
  • the drug or subcutaneous injection formulation comprises a treatment effective amount of the pharmaceutical composition.
  • the treatment effective amount is to administrate 0.2 ⁇ 20 mg the pharmaceutical composition per cm 2 at the local site.
  • the treatment effective amount is to administrate 0.2 ⁇ 40 mg the pharmaceutical composition per kg of the body weight.
  • the dosing frequency of the drug or subcutaneous injection formulation is 1 to 12 times every other day to every 30 days.
  • the subject is an animal or a human.
  • the step is to inject the drug or subcutaneous injection formulation to the local site of the subject; or apply the drug to the local site of the subject.
  • the pharmaceutical composition further comprises at least one of a cosolvent, a suspending agent, and an oil phase excipient, or combination thereof.
  • the microstructure is co-formed by the non-ionic surfactant and the oil phase excipient and/or the cosolvent.
  • FIG. 1A A bar graph showing the effects of the non-micellar resveratrol solution for subcutaneous injection and the non-micellar green tea extract solution for subcutaneous injection on the amount of subcutaneous fat of rats
  • FIG. 1B A bar graph showing the effects of the non-micellar resveratrol solution for subcutaneous injection and the non-micellar green tea extract solution for subcutaneous injection on the relative weight gain of rats.
  • FIG. 2A A bar graph showing the effects of resveratrol subcutaneous injection formulations prepared with different excipients on the amount of localized subcutaneous fat of rats.
  • FIG. 2B A bar graph showing the effects of resveratrol subcutaneous injection formulations prepared with different excipients on the relative weight gain of rats.
  • FIG. 3 A bar graph showing the effects of the resveratrol pharmaceutical composition on the amount of subcutaneous fat of rats.
  • FIG. 4A A bar graph showing the effects of the resveratrol complex pharmaceutical composition on the amount of subcutaneous fat of rats.
  • FIG. 4B A bar graph showing the effects of the resveratrol complex pharmaceutical composition on the relative weight gain of rats.
  • FIG. 5 The effects of the resveratrol-other lipophilic drug complex pharmaceutical composition on the apoptosis of the mature adipocytes.
  • FIG. 6 The effects of the resveratrol-other hydrophilic drug complex pharmaceutical composition on the apoptosis of the mature adipocytes.
  • Resveratrol is a polyphenol commonly found in the skin of red grapes, Japanese knotweed, or red wine. Because resveratrol has low solubility in aqueous solutions, it is easily to be rapidly metabolized into glucuronide metabolites and sulfate metabolites in the body, it is rapidly excreted via urine and feces, and it is extremely poor bioavailability, development of resveratrol-based pharmaceutical compositions faces a certain degree of difficulties. The inventor also faced these obstacles at the early stage of developing this pharmaceutical composition.
  • a green tea extract solution for subcutaneous injection a 5 mg/mL green tea extract aqueous solution was prepared with water for injection and green tea extract. The green tea extract aqueous solution was filtered through a 0.2 ⁇ m filter to obtain the 5 mg/mL green tea extract solution for subcutaneous injection in the present experiment. The green tea extract solution for subcutaneous injection had to be stored in dark at 4° C.
  • a resveratrol solution for subcutaneous injection a 5 mg/mL resveratrol solution was prepared with polysorbate 80 (tween 80), which is an excipient commonly used by prior arts for non-hydrophilic drug formulations for injection, ethanol, water for injection, and resveratrol.
  • polysorbate 80 tween 80
  • the detailed preparation method is as follows: 0.5 g of resveratrol was mixed with an appropriate amount of ethanol.
  • the rats were randomly assigned into three groups: a high-fat diet control group, a resveratrol group, and a green tea extract group, with 6 rats in each group such that there was no statistical difference in the body weight between groups.
  • drugs were administrated as follows:
  • the 5 mg/mL resveratrol solution for subcutaneous injection was injected into the lower inguinal subcutaneous fat layer of rats in the resveratrol group.
  • Each injected dosage was 8 mg of resveratrol per kilogram (8 mg/kg) of body weight; that is, 1.6 mL of the aforementioned 5 mg/mL resveratrol solution for subcutaneous injection was injected per kilogram of body weight.
  • the 5 mg/mL green tea extract solution for subcutaneous injection was injected into the lower inguinal subcutaneous fat layer of rats in the green tea extract group.
  • Each injected dosage was 8 mg of green tea extract per kilogram (8 mg/kg) of body weight; that is, 1.6 mL of the aforementioned 5 mg/mL green tea extract solution for subcutaneous injection was injected per kilogram of body weight.
  • Rats in the high-fat diet control group were injected with the same volume of water for injection in the same manner described above.
  • the aforementioned injection sites were the lower inguinal fat pads of rats. Bilateral injections were performed evenly at the injection sites once a day on day 1, 3, and 5 of the experiment. The rats were fed with high-fat diet during the entire duration of the experiment. Their weight change was recorded daily, and their water and food consumption was recorded weekly. Rats were fasted on day 20 and euthanized by CO 2 on day 21.
  • the body weight of each rat was recorded and defined as its “post-experimental body weight”.
  • the “total body weight gain” of each rat was obtained by subtracting its “pre-experimental body weight” from its “post-experimental body weight”.
  • the “relative weight gain” was obtained by dividing the total body weight gain of each group by the total body weight gain of the high-fat diet control group.
  • the bilateral inguinal fat pads of rats were dissected and weighed, and the amount of the lower inguinal fat of each group was calculated.
  • the data were presented as mean ⁇ SD and analyzed by one-way ANOVA.
  • Statistical analysis results were presented as symbols or letters. Different symbols or letters indicate statistical difference (p ⁇ 0.05), and identical symbols or letters indicate no statistical difference (p>0.05).
  • FIG. 1A is a bar graph showing the effects of the non-micellar resveratrol solution for subcutaneous injection and the non-micellar green tea extract solution for subcutaneous injection on the relative weight of lower inguinal subcutaneous fat of rats.
  • FIG. 1B is a bar graph showing the effects of the non-micellar resveratrol solution for subcutaneous injection and the non-micellar green tea extract solution for subcutaneous injection on the relative weight gain of rats.
  • said amount of lower inguinal fat is the total amount of bilateral lower inguinal fat.
  • green tea extract is an ingredient with very high solubility in water, and previous studies have shown that it promotes adipocyte apoptosis in cell-based experiments.
  • direct injection of dissolved green tea extract to the subcutaneous fat layer surprisingly can reduce neither the localized subcutaneous fat nor the body weight.
  • This experiment demonstrated that direct injection of dissolved resveratrol or green tea extract to the subcutaneous fat layer cannot reduce the localized fat and body weight.
  • the inventor conducted further studies to develop the resveratrol-containing pharmaceutical composition in the present invention.
  • Resveratrol normal saline solution resveratrol PEG solution, and resveratrol ELP solution were prepared as follows:
  • mice Six-week-old male Sprague-Dawley rats were used for the experiment. First, 20 rats were fed with high-fat diet (Research Diets, Inc.; Cat #D12492) to induce the accumulation of subcutaneous fat. Feeding was continued until each rat weighed 330 ⁇ 10 g, and the rats were randomly assigned into four groups: a control group, a normal saline group, a PEG group, and an ELP group, with 5 rats in each group such that there was no statistical difference in the body weight between groups. The body weight of each rat was recorded and defined as the “pre-experimental body weight”. Then, drugs were administrated as follows:
  • the resveratrol normal saline solution, the resveratrol PEG solution, and the resveratrol ELP solution were injected to the lower inguinal subcutaneous fat pads of rats in the normal saline group, the PEG group, and the ELP group, respectively.
  • Rats in the control group were injected with the same volume of normal saline in the same manner mentioned above.
  • the injection sites mentioned above were the lower inguinal fat pads of rats. Bilateral injections were administrated evenly once a day on day 1, 2, 3, and 4 of the experiment. The rats were fed with high-fat diet for the entire duration of the experiment. Their weight changes were recorded daily, and food and water consumption was recorded weekly. The experiment lasted for 14 days, and the rats were euthanized by CO 2 on day 15.
  • the body weight of each rat was recorded and defined as its “post-experimental body weight”.
  • the “total body weight gain” of each rat was obtained by subtracting its “pre-experimental body weight” from its “post-experimental body weight”.
  • the “relative weight gain” was obtained by dividing the total body weight gain of each group by the total body weight gain of the control group.
  • the bilateral lower inguinal subcutaneous fat pads of rats were dissected and weighed, and the weights of the bilateral lower inguinal subcutaneous fat pads were summed to calculate the amount of lower inguinal subcutaneous fat.
  • the amount of lower inguinal subcutaneous fat of each group was divided by the amount of lower inguinal subcutaneous fat of the control group to obtain the “relative weight of lower inguinal subcutaneous fat”.
  • FIG. 2A is a bar graph showing the effects of resveratrol subcutaneous injection formulations prepared with different excipients on the amount of localized subcutaneous fat of rats.
  • FIG. 2B is a bar graph showing the effect of resveratrol subcutaneous injection formulations prepared with different excipients on the relative weight gain of rats
  • the relative weight of lower inguinal subcutaneous fat of rats in the control group was 100 ⁇ 27.6%
  • the relative weight of lower inguinal subcutaneous fat of rats in the normal saline group was 108.2 ⁇ 24.7%
  • the relative weight of lower inguinal subcutaneous fat of rats in the PEG group was 114.0 ⁇ 4.4%
  • the relative weight of lower inguinal subcutaneous fat of rats in the ELP group was 72.5 ⁇ 0.0%.
  • the relative weight gain of rats in the control group was 100.0 ⁇ 30.8%
  • the relative weight gain of rats in the normal saline group was 128.3 ⁇ 16.9%
  • the relative weight gain of rats in the PEG group is 120.8 ⁇ 18.2%
  • the relative weight gain of rats in the ELP group was 101.3 ⁇ 22.0%. There was no significant difference between the four groups (p>0.05).
  • Resveratrol ELP partial micellar formulation resveratrol HS-15 partial micellar formulation, resveratrol ELP micellar formulation, and resveratrol HS-15 micellar formulation were prepared as follows:
  • resveratrol ELP partial micellar formulation 20 g of Kolliphor ELP (also known as Cremophor ELP, abbreviated as ELP) was mixed with an appropriate amount of normal saline for injection to make the total weight become 100 g. The solution was stirred well to completely dissolve Kolliphor ELP (also known as ELP) to obtain a 20% ELP solution. 400 mg of resveratrol was mixed with an appropriate amount of the 20% ELP solution to make the total weight become 80 g. The solution was stirred well to completely dissolve resveratrol to obtain the resveratrol ELP partial micellar formulation.
  • Kolliphor ELP also known as Cremophor ELP, abbreviated as ELP
  • the concentration of resveratrol was approximately 5 mg/mL
  • the concentration of ELP was approximately 20% (wt %)
  • the weight ratio of resveratrol to ELP was approximately 1:40.
  • resveratrol HS-15 partial micellar formulation 20 g of Kolliphor HS-15 (abbreviated as HS-15) was mixed with an appropriate amount of normal saline for injection to make the total weight become 100 g. The solution was stirred well to completely dissolve HS-15 to obtain a 20% HS-15 solution. 400 mg of resveratrol was mixed with an appropriate amount of the 20% HS-15 solution to make the total weight become 80 g. The solution was stirred well to completely dissolve resveratrol to obtain the resveratrol HS-15 partial micellar formulation.
  • HS-15 Kolliphor HS-15
  • the concentration of resveratrol was approximately 5 mg/mL
  • the concentration of HS-15 was approximately 20% (wt %)
  • the weight ratio of resveratrol to HS-15 was approximately 1:40.
  • resveratrol HS-15 micellar formulation 500 mg of resveratrol was mixed with 80 ⁇ 140 mL of dichloromethane and stirred at 150 ⁇ 500 rpm at room temperature until resveratrol dissolved completely. 20 g of Kolliphor HS-15 (abbreviated as HS-15) was added and stirred at 100 ⁇ 300 rpm to volatize dichloromethane. Once dichloromethane volatized completely, normal saline for injection was slowly added to make the total weight become 100 g. The solution was stirred well to form drug-containing micelles to obtain the resveratrol HS-15 micellar formulation.
  • Kolliphor HS-15 abbreviated as HS-15 micellar formulation
  • the concentration of resveratrol was approximately 5 mg/g
  • the concentration of HS-15 was approximately 20% (wt %)
  • the weight ratio of resveratrol to HS-15 was approximately 1:40.
  • the resveratrol ELP partial micellar formulation, the resveratrol HS-15 partial micellar formulation, the resveratrol ELP micellar formulation, and the resveratrol HS-15 micellar formulation were analyzed by a particle size analyzer to determine if micelles were present therein, and determine the diameter of micelles was measured.
  • micellar group Six-week-old male Sprague-Dawley rats were used for the experiment. First, 20 rats were fed with high-fat diet (Research Diets, Inc.; Cat #D12492) to induce the accumulation of subcutaneous fat. Feeding was continued until each rat weighed 330 ⁇ 10 g, and the rats were randomly assigned into 5 groups: a control group, an ELP partial micellar group, an HS-15 partial micellar group, an ELP micellar group, and an HS-15 micellar group, with 4 rats in each group such that there was no statistical difference in the body weight between groups. The body weight of each rat was recorded and defined as the “pre-experimental body weight”. Then, drugs were administrated as follows:
  • the resveratrol ELP partial micellar formulation, the resveratrol HS-15 partial micellar formulation, the resveratrol ELP micellar formulation, and the resveratrol HS-15 micellar formulation were each mixed well (to evenly suspend the precipitates in the partial micellar formulations), and were injected into the lower inguinal subcutaneous fat layer of rats in the ELP partial micellar group, the HS-15 partial micellar group, the ELP micellar group, and the HS-15 micellar group, respectively.
  • Rats in the control group were injected with the same volume of normal saline in the same manner mentioned above.
  • the injection sites mentioned above were the lower inguinal fat pads of rats. Bilateral injections were administrated evenly once a day on day 1, 2, 3, 4, 5, and 6 of the experiment. The rats were fed with high-fat diet for the entire duration of the experiment. Their weight changes were recorded daily, and food and water consumption was recorded weekly. The experiment lasted for 14 days, and the rats were euthanized with CO 2 on day 15.
  • the body weight of each rat was recorded and defined as its “post-experimental body weight”.
  • the “total body weight gain” of each rat was obtained by subtracting its “pre-experimental body weight” from its “post-experimental body weight”.
  • the “relative weight gain” was obtained by dividing the total body weight gain of each group by the total body weight gain of the control group.
  • the bilateral lower inguinal subcutaneous fat pads of rats were dissected and weighed, and the weights of the bilateral lower inguinal subcutaneous fat pads were summed to calculate the amount of lower inguinal subcutaneous fat.
  • the amount of lower inguinal subcutaneous fat of each group was divided by the amount of lower inguinal subcutaneous fat of the control group to obtain the “relative weight of lower inguinal subcutaneous fat”.
  • the concentration of ELP and the concentration of resveratrol in the resveratrol ELP partial micellar formulation were identical to those of the resveratrol ELP micellar formulation, only the number of drug-containing micelles differed.
  • resveratrol ELP micellar formulation can significantly reduce the localized fat at the administration site, this indicates that formation of drug-containing micelles is the critical factor of resveratrol compositions to significantly reduce the localized fat at the administration site; if the resveratrol ELP micellar formulation can significantly reduce the body weight, this indicates that formation of drug-containing micelles is the critical factor of resveratrol compositions to significantly reduce the body weight.
  • the concentration of HS-15 and the concentration of resveratrol in the resveratrol HS-15 partial micellar formulation were identical to those of the resveratrol HS-15 micellar formulation, only the number of drug-containing micelles differed.
  • resveratrol HS-15 micellar formulation can significantly reduce the localized fat at the administration site, this indicates that formation of drug-containing micelles is the critical factor of resveratrol compositions to significantly reduce the localized fat at the administration site; if the resveratrol HS-15 micellar formulation can significantly reduce the body weight, this indicates that formation of drug-containing micelles is the critical factor of resveratrol compositions to significantly reduce the body weight.
  • the resveratrol ELP micellar formulation can reduce the localized fat significantly. Comparing to resveratrol HS-15 partial micellar formulation, resveratrol HS-15 micellar formulation can reduce the localized fat significantly.
  • This experiment prepared a first pharmaceutical composition with resveratrol, and prepared a second pharmaceutical composition with resveratrol and green tea extract.
  • the drug-containing micelle is a microstructure formed by the surfactant, and resveratrol is encapsulated in said drug-containing micelle.
  • the third weight is heavier than or equal to 0 g.
  • the boiling point of the solvent is lower than that 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 combination thereof.
  • the solvent in step (a) is a lipophilic solvent.
  • the lipophilic solvent is at least one of ether, benzene, chloroform, ethyl acetate, dichloromethane, hexane, and other lipophilic solvents, or combination thereof.
  • the surfactant is a non-ionic surfactant.
  • the non-ionic surfactant is at least one of polysorbate 80 (tween 80), 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15), polyoxyethylene castor oil derivatives, and other non-ionic surfactants, or combination thereof.
  • the polyoxyethylene castor oil derivatives are at least one of cremophor ELP, cremophor RH 40, and other polyoxyethylene castor oil derivatives, or combination thereof.
  • the weight ratio of the first weight of resveratrol and the second weight of surfactant is 1:4 to 1:500.
  • the weight ratio of the first weight of resveratrol and the third weight of pharmaceutically acceptable aqueous solution is 1:400 to 3:50.
  • the pharmaceutically acceptable aqueous solution is water for injection, aqueous solution for injection, or normal saline.
  • the pharmaceutically acceptable solution comprises a local anesthetic.
  • the local anesthetic is at least one of amides, para-aminobenzoic acid esters, and amino ethers, or combination thereof.
  • the amides are at least one of dibucaine, lidocaine, mepivacaine HCl, bupivacine HCl, pyrrocaine HCl, prilocaine HCl, digammacaine, and oxethazaine, or combination thereof.
  • the para-aminobenzoic acid esters are at least one of butacaine, dimethocaine, and tutocaine, or combination thereof.
  • the amino ethers are at least one of quinisocaine and pramocaine, or combination thereof.
  • the pharmaceutically acceptable aqueous solution comprises an antioxidant.
  • the antioxidant is at least one of beta-carotene, lutein, lycopene, bilirubin, vitamin A, vitamin C (ascorbic acid), vitamin E, uric acid, nitric oxide, nitroxide, pyruvate, catalase, superoxide dismutase, glutathione peroxidases, N-acetyl cysteine, and naringenin, or combination thereof.
  • the first pharmaceutically acceptable aqueous solution comprises a seventh weight of green tea extract; the green tea extract comprises a first green tea extract ingredient, and said first green tea extract ingredient is epigallocatechin gallate.
  • the boiling point of the solvent is lower than that 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 combination thereof.
  • the solvent in step (a1) is a lipophilic solvent.
  • the lipophilic solvent is at least one of ether, benzene, chloroform, ethyl acetate, dichloromethane, hexane, and other lipophilic solvents, or combination thereof.
  • the surfactant is a non-ionic surfactant.
  • the non-ionic surfactant is at least one of polysorbate 80 (tween 80), 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15), polyoxyethylene castor oil derivatives, and other non-ionic surfactants, or combination thereof.
  • the polyoxyethylene castor oil derivatives are at least one of cremophor ELP, cremophor RH 40, and other polyoxyethylene castor oil derivatives, or combination thereof.
  • step (c1) further comprising a step:
  • the green tea extract is dissolved in the first pharmaceutically acceptable aqueous solution, and the drug-containing micelle is a microstructure formed by the surfactant, wherein resveratrol is encapsulated in said drug-containing micelle.
  • the content of epigallocatechin gallate is 45 ⁇ 100% by weight, based on 100% by weight of the total green tea extract.
  • the weight ratio of the fourth weight of resveratrol and the seventh weight of green tea extract is 30:1 to 1:30.
  • the amount of the fifth weight of surfactant is 0.24 ⁇ 70 parts by weight, based on 1 part by weight of the total amount of the fourth weight of resveratrol and the seventh weight of the green tea extract; or, the weight ratio of the total weight of the resveratrol and the green tea extract to the surfactant is 4:1 to 1:70.
  • the total amount 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 parts by weight, based on 1 part by weight of the total amount of the fourth weight of resveratrol and the seventh weight of the green tea extract; or, the ratio of the sum of the fourth weight and the seventh weight to the sum of the sixth weight and the eighth weight is 1:400 ⁇ 3:50.
  • the total amount of the first pharmaceutically acceptable aqueous solution and the second pharmaceutically acceptable aqueous solution is 10 ⁇ 1000 parts by weight, based on 1 part by weight of the total amount of resveratrol and green tea extract; or, the ratio of the total weight of the resveratrol and the green tea extract to the total weight of the first pharmaceutically acceptable aqueous solution and the second pharmaceutically acceptable solution is 1:1000 ⁇ 1:10.
  • the first pharmaceutically acceptable aqueous solution and the second pharmaceutically acceptable aqueous solution are water for injection, aqueous solution for injection, or normal saline.
  • the first pharmaceutically acceptable aqueous solution comprises a local anesthetic.
  • the local anesthetic is at least one of amides, para-aminobenzoic acid esters, and amino ethers, or combination thereof.
  • the amides are at least one of dibucaine, lidocaine, mepivacaine HCl, bupivacine HCl, pyrrocaine HCl, prilocaine HCl, digammacaine, and oxethazaine, or combination thereof.
  • the para-aminobenzoic acid esters are at least one of butacaine, dimethocaine, and tutocaine, or combination thereof.
  • the amino ethers are at least one of quinisocaine and pramocaine, or combination thereof.
  • the first pharmaceutically acceptable aqueous solution comprises an antioxidant.
  • the antioxidant is at least one of beta-carotene, lutein, lycopene, bilirubin, vitamin A, vitamin C (ascorbic acid), vitamin E, uric acid, nitric oxide, nitroxide, pyruvate, catalase, superoxide dismutase, glutathione peroxidases, N-acetyl cysteine, and naringenin, or combination thereof.
  • This experiment prepared a third pharmaceutical composition with resveratrol and a hydrophilic drug, and prepared a fourth pharmaceutical composition and a fifth pharmaceutical composition with resveratrol and other lipophilic drugs.
  • the first pharmaceutically acceptable aqueous solution comprises a hydrophilic drug.
  • the first pharmaceutically acceptable aqueous solution comprises a local anesthetic.
  • the local anesthetic is at least one of amides, para-aminobenzoic acid esters, and amino ethers, or combination thereof.
  • the amides are at least one of dibucaine, lidocaine, mepivacaine HCl, bupivacine HCl, pyrrocaine HCl, prilocaine HCl, digammacaine, and oxethazaine, or combination thereof.
  • the para-aminobenzoic acid esters are at least one of butacaine, dimethocaine, and tutocaine, or combination thereof.
  • the amino ethers are at least one of quinisocaine and pramocaine, or combination thereof.
  • the first pharmaceutically acceptable aqueous solution comprises an antioxidant.
  • the antioxidant is at least one of beta-carotene, lutein, lycopene, bilirubin, vitamin A, vitamin C (ascorbic acid), vitamin E, uric acid, nitric oxide, nitroxide, pyruvate, catalase, superoxide dismutase, glutathione peroxidases, N-acetyl cysteine, and naringenin, or combination thereof.
  • the boiling point of the solvent is lower than that 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 combination thereof.
  • the solvent in step (a2) is a lipophilic solvent.
  • the lipophilic solvent is at least one of ether, benzene, chloroform, ethyl acetate, dichloromethane, hexane, and other lipophilic solvents, or combination thereof.
  • the surfactant is a non-ionic surfactant.
  • the non-ionic surfactant is at least one of polysorbate 80 (tween 80), 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15), polyoxyethylene castor oil derivatives, and other non-ionic surfactants, or combination thereof.
  • the polyoxyethylene castor oil derivatives are at least one of cremophor ELP, cremophor RH 40, and other polyoxyethylene castor oil derivatives, or combination thereof.
  • steps (c2) and (d2) further comprising a step:
  • the hydrophilic drug is dissolved in the first pharmaceutically acceptable aqueous solution, and the drug-containing micelle is a microstructure formed by the surfactant, and resveratrol is encapsulated in said drug-containing micelle.
  • the hydrophilic drug in the first pharmaceutically acceptable aqueous solution is at least one of green tea extract, epigallocatechin gallate, epicatechin, epicatechin gallate, epigallocatechin, gallocatechin gallate, gallocatechin, catechin gallate, catechin, epigallocatechin gallate (EGCG), caffeine, carnitine, L-carnitine, synephrine, chlorogenic acid, and other hydrophilic drugs, or combination thereof.
  • green tea extract epigallocatechin gallate, epicatechin, epicatechin gallate, epigallocatechin, gallocatechin gallate, gallocatechin, catechin gallate, catechin, epigallocatechin gallate (EGCG), caffeine, carnitine, L-carnitine, synephrine, chlorogenic acid, and other hydrophilic drugs, or combination thereof.
  • the weight ratio of the resveratrol to the hydrophilic drug is 30:1 to 1:30.
  • the amount of the surfactant is 0.24 ⁇ 70 parts by weight, based on 1 part by weight of the total amount of resveratrol and the hydrophilic drug; or, the weight ratio of the total weight of the resveratrol and the hydrophilic drug to the surfactant is 4:1 to 1:70.
  • the total amount of the first pharmaceutically acceptable aqueous solution and the second pharmaceutically acceptable solution is 16 ⁇ 400 parts by weight, based on 1 part by weight of the total amount of resveratrol and the hydrophilic drug; or, the ratio of the sum of the fourth weight and the seventh weight to 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 normal saline.
  • the drug-containing micelle is a microstructure formed by the first surfactant, and resveratrol is encapsulated in said drug-containing micelle.
  • the second lipophilic drug-containing micelle is a microstructure formed by the second surfactant, and the other lipophilic drug is encapsulated in said second lipophilic drug-containing micelle.
  • the lipophilic drug is at least one of curcumin, quercetin, puerarin, and other lipophilic drugs except resveratrol, or combination thereof.
  • the boiling point(s) of the first solvent and/or the second solvent are/is lower than that of pure water.
  • the first solvent and/or the second solvent are/is (a) hydrophilic solvent(s).
  • the hydrophilic solvent is at least one of methanol, ethanol, acetone, and other hydrophilic solvents, or combination thereof.
  • the first solvent and/or the second solvent in steps (a3) and/or (a4) are/is (a) lipophilic solvent(s).
  • the lipophilic solvent is at least one of ether, benzene, chloroform, ethyl acetate, dichloromethane, hexane, and other lipophilic solvents, or combination thereof.
  • the first surfactant and/or the second surfactant are/is (a) non-ionic surfactant(s).
  • the non-ionic surfactant is at least one of polysorbate 80 (tween 80), 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15), polyoxyethylene castor oil derivatives, and other non-ionic surfactants, or combination thereof.
  • the polyoxyethylene castor oil derivatives are at least one of cremophor ELP, cremophor RH 40, and other polyoxyethylene castor oil derivatives, or combination thereof.
  • the weight ratio of the resveratrol to the first surfactant is 1:4 to 1:500.
  • the weight ratio of the other lipophilic drug to the second surfactant is 1:4 to 1:500.
  • the weight ratio of the resveratrol to the pharmaceutically acceptable aqueous solution is 1:400 to 3:50.
  • the weight ratio of the other lipophilic 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 normal saline.
  • the pharmaceutically acceptable aqueous solution comprises a local anesthetic.
  • the local anesthetic is at least one of amides, para-aminobenzoic acid esters, and amino ethers, or combination thereof.
  • the amides are at least one of dibucaine, lidocaine, mepivacaine HCl, bupivacine HCl, pyrrocaine HCl, prilocaine HCl, digammacaine, and oxethazaine, or combination thereof.
  • the para-aminobenzoic acid esters are at least one of butacaine, dimethocaine, and tutocaine, or combination thereof.
  • the amino ethers are at least one of quinisocaine and pramocaine, or combination thereof.
  • the pharmaceutically acceptable aqueous solution comprises an antioxidant.
  • the antioxidant is at least one of beta-carotene, lutein, lycopene, bilirubin, vitamin A, vitamin C (ascorbic acid), vitamin E, uric acid, nitric oxide, nitroxide, pyruvate, catalase, superoxide dismutase, glutathione peroxidases, N-acetyl cysteine, and naringenin, or combination thereof.
  • the types and ranges of the solvents, surfactants, pharmaceutically acceptable aqueous solutions, and other lipophilic drugs used in the fifth pharmaceutical composition are the same as those used in the fourth pharmaceutical composition. Additionally, the ranges of relative ratios of the ingredients used in the fifth pharmaceutical composition are also the same as those used in the fourth pharmaceutical composition.
  • the pharmaceutically acceptable aqueous solution comprises a local anesthetic and/or an antioxidant.
  • the types and ranges of the local anesthetic and/or antioxidant used in the fifth pharmaceutical composition are the same as those used in the fourth pharmaceutical composition.
  • the pharmaceutical composition stand for at least 20 minutes. If the composition does not separate into layers, further analyzing it by a particle analyzer.
  • the pharmaceutical composition comprises micelles by a particle size analyzer. If the particle diameter of the pharmaceutical composition, after being analyzed by a particle analyzer, is smaller than 250 nm, the PDI value is less than 0.4, the solution of the pharmaceutical composition is deemed clear and transparent when observed by the naked eye, and the light beam can be observed when the solution of the pharmaceutical composition is shined by a laser, then it indicates that the pharmaceutical composition comprises micelles.
  • the prepared composition is the pharmaceutical composition for reducing localized fat in the present invention
  • the prepared pharmaceutical composition is the preferable pharmaceutical composition for reducing localized fat in the present invention.
  • PDI polydispersity index
  • the storage condition of the pharmaceutical composition in the present invention is 2 ⁇ 8° C.
  • the inventor placed the pharmaceutical compositions in an environment of relatively high temperature and relatively high humidity (temperature 25° C. ⁇ 2° C., relative humidity 60% ⁇ 5%), observed how long the micelles in the pharmaceutical composition can stably exist in a condition of relatively high temperature, to reckon the shelf life of the pharmaceutical composition at 2 ⁇ 8° C.
  • the shelf life of the pharmaceutical composition at a condition of 25° C. is 2 ((25-5)/10) folds of n months. That is, the shelf life of the pharmaceutical composition at a condition of 5° C. is 2 2 folds of n months, that is, 4 folds.
  • the shelf life of the pharmaceutical composition is 6 months at a condition of 25° C.
  • the pharmaceutical composition maintains at a state without precipitation for at least 24 hours when it is subjected to accelerated stability test at a condition of temperature of 25° C. ⁇ 2° C., relatively humidity of 60% ⁇ 5%, and in the absence of direct light.
  • the pharmaceutical composition maintains at a state without precipitation for at least 6 months when it is subjected to accelerated stability test at a condition of temperature of 25° C. ⁇ 2° C., relatively humidity of 60% ⁇ 5%, and in the absence of direct light.
  • the pharmaceutical composition maintains at a state without precipitation for at least 24 months at a condition of temperature of 2 ⁇ 8° C.
  • non-ionic surfactants Four non-ionic surfactants were selected for this experiment.
  • the five non-ionic surfactants were Kolliphor ELP (also known as Cremophor ELP, abbreviated as ELP), Kolliphor HS-15 (HS-15), Cremophor RH 40 (abbreviated as RH 40), and polysorbate 80 (also known as Tween 80).
  • compositions to be tested from the ELP group, HS-15 group, RH40 group, and Tween 80 group were let stand for at least 20 minutes to observe if stratification occurs. If stratification occurs, it indicates that the concentration of resveratrol is too high, causing the micelles in the stage I composition to burst. That is, the non-ionic surfactant cannot be used to prepare the pharmaceutical compositions in the present invention which comprise as high as 20 mg/g of resveratrol.
  • the inventor further performed Experiment 7 and determined that the maximum drug loading of ELP is greater than or equal to 166.7 mg/g. (As the ratio of resveratrol to ELP is 1:5, the prepared pharmaceutical composition contains 166.7 mg/g of resveratrol.)
  • ELP is the best excipient to prepare the pharmaceutical compositions in the present invention.
  • concentration of resveratrol can reach 166.7 mg/g in the pharmaceutical compositions prepared with ELP.
  • the ratios of resveratrol to ELP (weight ratio) in the first group to the ninth group were 1:1, 1:2.5, 1:5, 1:8, 1:10. 1:40, 1:80, 1:200, 1:500, respectively, and the final concentrations of resveratrol in the pharmaceutical compositions prepared in the first to the ninth group were 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, respectively.
  • the preparation of pharmaceutical composition in the first to the ninth group the weight ratios of resveratrol in step (a′) to ELP in step (b′) (the ratios of the first weight to the second weight) were 1:1, 1:2.5, 1:5, 1:8, 1:10. 1:40, 1:80, 1:200, 1:500, respectively, and after adding the third weight of normal saline for injection in step (c′), the final concentrations of resveratrol in the prepared pharmaceutical compositions were 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, respectively. Wherein, when the final concentrations of drug was presented as mg/g, this indicates the number of milligrams of resveratrol per gram of pharmaceutical composition.
  • Particle size analyzer was utilized to determine if micelles were present in the pharmaceutical compositions, and the particle diameter of the micelles was measured.
  • the distribution of particle diameters and the polydispersity index (PDI) were determined by a particle size analyzer.
  • the resveratrol content in the micelles was analyzed by high performance liquid chromatography (HPLC; e.g., HPLC-UV) and defined as the “initial drug content”.
  • the pharmaceutical compositions were subjected to accelerated stability test to observe if stratification occurred when the pharmaceutical compositions were stored at high temperature storage condition (25 ⁇ 2° C.) for 3 months.
  • the drug content in the micelles was determined by high performance liquid chromatography (HPLC; e.g., HPLC-UV), and defined as the “drug content after accelerated stability test”.
  • HPLC high performance liquid chromatography
  • the “percentage of drug content” was calculated by dividing the “drug content after accelerated stability test” by the “initial drug content”. If the percentage of drug content is greater than or equal to 95%, it indicates the stability of the pharmaceutical composition was excellent.
  • Table 2 is the stability analysis result of the pharmaceutical compositions.
  • the weight ratio of resveratrol to ELP is 1:5 to 1:500, as shown in Table 2, micelles are present in different pharmaceutical composition, and the measured particle diameter of the micelles was 10 ⁇ 250 nm. Therefore, the pharmaceutical compositions, in which the weight ratio of resveratrol to ELP is 1:5 to 1:500, are all pharmaceutical compositions for reducing localized fat in the present invention.
  • the weight of ELP should be greater than or equal to 5 weight units.
  • the weight of ELP is 5 ⁇ 500 weight units.
  • the weight of ELP is 10 ⁇ 80 weight units.
  • the weight of ELP is 8 ⁇ 80 weight units.
  • the density of normal saline for injection is 1 g/mL.
  • the volume of 80 g of normal saline for injection is 80 mL.
  • the weight ratio of the first weight of resveratrol to the second weight of Cremophor ELP (surfactant) is 0.4:4. That is, the weight ratio is 1:10.
  • the weight ratio of the first weight of resveratrol to the third weight of normal saline for injection is 0.4:80. That is, the weight ratio is 1:200.
  • 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 green tea extract is 0.36:0.04. That is, the weight ratio is 9:1.
  • the density of normal saline for injection is 1 g/mL.
  • the total volume of the sixth weight of the first normal saline for injection and the eighth weight of the second normal saline for injection is 80 mL, as an example, the total weight of normal saline for injection is 80 g.
  • mice Six-week-old male Sprague-Dawley rats were used for the experiment. First, 15 rats were fed with high-fat diet to induce accumulation of subcutaneous fat. Feeding was continued until each rat weighed 330 ⁇ 10 g. The rats were randomly assigned into three groups: a high-fat diet control group, a low dosage resveratrol group, and a high dosage resveratrol group, with 5 rats in each group such that there was no statistical difference in the body weight between groups.
  • the 5 mg/mL resveratrol pharmaceutical composition prepared in Example 1 was injected into the lower inguinal subcutaneous fat layer of rats in the low dosage resveratrol group.
  • Each injected dosage was 10 mg of resveratrol per kilogram of body weight (10 mg/kg); that is, 2 mL of the 5 mg/mL resveratrol pharmaceutical composition prepared in Example 1 was injected per kilogram body weight.
  • the 5 mg/mL resveratrol pharmaceutical composition prepared in Example 1 was injected into the lower inguinal subcutaneous fat layer of rats in the high dosage resveratrol group.
  • Each injected dosage was 20 mg of resveratrol per kilogram of body weight (20 mg/kg); that is, 4 mL of the 5 mg/mL resveratrol pharmaceutical composition prepared in Example 1 was injected per kilogram body weight.
  • Rats in the high-fat diet control group were injected with the same volume of normal saline for injection in the same manner mentioned above.
  • the aforementioned injection sites were the lower inguinal fat pads of rats. Bilateral injections were performed evenly at the injection sites once a day on day 1, 2, 3, and 4 of the experiment. The rats were fed with high-fat diet during the entire duration of the experiment. Their weight change was recorded daily, and their water and food consumption was recorded weekly. The rats were fasted on day 14 and euthanized with CO 2 on day 15.
  • the bilateral inguinal fat pads of rats were dissected and weighed, and the amount of lower inguinal fat of each group was calculated.
  • the data were presented as mean ⁇ SD and analyzed by one-way ANOVA.
  • Statistical analysis results were presented as symbols or letters. Different symbols or letters indicate statistical difference (p ⁇ 0.05), and identical symbols or letters indicate no statistical difference (p>0.05).
  • FIG. 3 is a bar graph showing the effects of the resveratrol pharmaceutical composition on the amount of subcutaneous fat of rats.
  • Table 3 shows the degree of subcutaneous fat reduction in rats caused by the resveratrol pharmaceutical composition.
  • the amount of lower inguinal subcutaneous fat is the total weight of bilateral lower inguinal fat pads.
  • the suitable dosing frequency to be administered to rats is 4 times
  • the suitable dosing frequency to be administered to human is 1 to 12 times.
  • the dosing frequency to be administered to human is 1 to 12 times every other day to every 30 days.
  • the dosing frequency to be administered to human is 1 to 6 times every other day to every 30 days.
  • the suitable dosage to be administered to rats is 10 mg/kg ⁇ 20 mg/kg
  • the suitable dosage to be administered to human is 0.2 ⁇ 40 mg/kg.
  • the injected dosage to be administered to human is 0.4 ⁇ 20 mg/kg.
  • the administered dosage to be injected to human is 0.2 ⁇ 20 mg/cm 2 .
  • the administered dosage to be injected to human is 0.4 ⁇ 12 mg/cm 2 .
  • green tea extract composition a 5 mg/mL green tea extract composition was prepared by dissolving green tea extract in normal saline for injection.
  • mice Six-week-old male Sprague-Dawley rats were used for the experiment. First, 20 rats were fed with high-fat diet to induce accumulation of subcutaneous fat. Feeding was continued until each rat weighed 330 ⁇ 10 g. The rats were randomly assigned into four groups: a high-fat diet control group, a green tea extract group, a resveratrol group, and a resveratrol-green tea extract complex group, with 5 rats in each group such that there was no statistical difference in the body weight between groups. The body weight of each rat was recorded and defined as its “pre-experimental body weight”. Then, drugs were administrated as follows:
  • the 5 mg/mL green tea extract composition prepared in this example was injected into the lower inguinal subcutaneous fat layer of rats in the green tea extract group. Each injected dosage was 10 mg of green tea extract per kilogram of body weight (10 mg/kg); that is, 2 mL of the 5 mg/mL green tea extract composition prepared in this example was injected per kilogram body weight.
  • the 5 mg/mL resveratrol pharmaceutical composition prepared in Example 1 was injected into the lower inguinal subcutaneous fat layer of rats in the resveratrol group. Each injected dosage was 10 mg of resveratrol per kilogram of body weight (10 mg/kg); that is, 2 mL of the 5 mg/mL resveratrol pharmaceutical composition prepared in Example 1 was injected per kilogram body weight.
  • the 5 mg/mL resveratrol complex pharmaceutical composition prepared in Example 2 was injected into the lower inguinal subcutaneous fat layer of rats in the resveratrol-green tea extract complex group. Each injected dosage was 10 mg of resveratrol-green tea extract per kilogram of body weight (10 mg/kg); that is, 2 mL of the 5 mg/mL resveratrol complex pharmaceutical composition prepared in Example 2 was injected per kilogram body weight. Rats in the high-fat diet control group were injected with the same volume of normal saline for injection in the same manner mentioned above.
  • the aforementioned injection sites were the lower inguinal fat pads of rats. Bilateral injections were performed evenly at the injection sites once a day on day 1, 2, 3, and 4 of the experiment. The rats were fed with high-fat diet during the entire duration of the experiment. Their weight change was recorded daily, and their water and food consumption was recorded weekly. The rats were fasted on day 14 and euthanized with CO 2 on day 15.
  • the body weight of each rat was recorded and defined as its “post-experimental body weight”.
  • the “total body weight gain” of each rat was obtained by subtracting its “pre-experimental body weight” from its “post-experimental body weight”.
  • the “relative weight gain” was obtained by dividing the total body weight gain of each group by the total body weight gain of the high fat diet control group.
  • the bilateral inguinal fat pads of rats were dissected and weighed, and the amount of lower inguinal fat of each group was calculated.
  • the data were presented as mean ⁇ SD and analyzed by one-way ANOVA.
  • Statistical analysis results were presented as symbols or letters. Different symbols or letters indicate statistical difference (p ⁇ 0.05), and identical symbols or letters indicate no statistical difference (p>0.05).
  • each dosage to be administered to the rats in each group is 10 mg/kg
  • the efficacy in reducing localized fat shown in the resveratrol-green tea extract complex group should be between the efficacy shown in the resveratrol group and the green tea extract group. If the efficacy in reducing localized fat shown in the resveratrol-green tea extract complex group is better than that in the resveratrol group and the green tea extract group, it indicates that resveratrol and green tea extract in the resveratrol-green tea extract pharmaceutical composition manifest synergy in localized fat reduction efficacy.
  • FIG. 4A is a bar graph showing the effects of the resveratrol complex pharmaceutical composition on the amount of subcutaneous fat of rats.
  • Table 4 shows the degree of subcutaneous fat reduction in rats caused by the resveratrol complex pharmaceutical composition.
  • the amount of lower inguinal subcutaneous fat is the total weight of bilateral lower inguinal fat pads.
  • the experimental results demonstrated in FIG. 4A show that comparing to the high-fat diet control group, the subcutaneous fat at the injection site of rats in the green tea extract group (wherein the dosage was 10 mg of green tea extract per kilogram of body weight) was not reduced.
  • the amount of subcutaneous fat at the injection site of rats in the resveratrol group did not reach statistical difference comparing to that of the high-fat diet control group, it has shown a tendency of reduction, and the localized fat was reduced by 5.6% (wherein the dosage was 10 mg of resveratrol per kilogram of body weight.)
  • the amount of subcutaneous fat at the injection site of rats in the resveratrol-green tea complex group was reduced significantly (p ⁇ 0.05), and the localized fat was reduced by 18.9% (wherein the dosage was 10 mg of resveratrol-green tea extract per kilogram of body weight.) That is, the resveratrol complex pharmaceutical composition showed a significantly superior efficacy in reducing localized fat, and the efficacy was 3.4-fold of that of
  • FIG. 4B is a bar graph showing the effects of the resveratrol complex pharmaceutical composition on the relative weight gain of rats.
  • Table 5 shows the degree of weight reduction in rats caused by the resveratrol complex pharmaceutical composition.
  • Resveratrol and other lipophilic drugs except resveratrol were used in this experiment to prepare complex pharmaceutical compositions in order to assess the lipolysis efficacy of various lipophilic complex pharmaceutical compositions on mature adipocytes.
  • puerarin and quercetin were chosen to prepare various lipophilic complex pharmaceutical compositions.
  • a DMSO control group cell culture medium, a resveratrol cell culture medium, a puerarin cell culture medium, a quercetin cell culture medium, a resveratrol-puerarin complex cell culture medium, and a resveratrol-quercetin complex cell culture medium were prepared as follows:
  • the DMSO control group cell culture medium DMSO was mixed with an appropriate amount of sterile water to obtain a 0.5% DMSO solution.
  • the 0.5% DMSO solution was mixed with a cell culture medium (product name: Dulbecco's Modified Eagle Medium, purchased from Gibco) to prepare the DMSO control group cell culture medium, wherein, the volume ratio between the 0.5% DMSO solution and the cell culture medium is 1:1000.
  • the resveratrol cell culture medium resveratrol was mixed with an appropriate amount of 0.5% DMSO solution to obtain a resveratrol solution.
  • the resveratrol solution was mixed with a cell culture medium (product name: Dulbecco's Modified Eagle Medium, purchased from Gibco) to prepare the resveratrol cell culture medium containing 50 ppm of resveratrol, wherein, the volume ratio between the resveratrol solution and the cell culture medium is 1:1000.
  • puerarin cell culture medium puerarin (purchased from Sigma-Aldrich) was mixed with an appropriate amount of 0.5% DMSO solution to obtain a puerarin solution.
  • the puerarin solution was mixed with a cell culture medium to prepare the puerarin cell culture medium containing 50 ppm of puerarin, wherein, the volume ratio between the puerarin solution and the cell culture medium is 1:1000.
  • the quercetin cell culture medium quercetin (purchased from Sigma-Aldrich) was mixed with an appropriate amount of 0.5% DMSO solution to obtain a quercetin solution.
  • the quercetin solution was mixed with a cell culture medium to prepare the quercetin cell culture medium containing 50 ppm of quercetin, wherein, the volume ratio between the puerarin solution and the cell culture medium is 1:1000.
  • the resveratrol-puerarin complex cell culture medium resveratrol and puerarin were mixed with an appropriate amount of 0.5% DMSO solution to obtain a resveratrol-puerarin complex solution.
  • the weight ratio between resveratrol and puerarin was 2:3.
  • the resveratrol-puerarin complex solution was mixed with a cell culture medium to prepare the resveratrol-puerarin complex cell culture medium containing 50 ppm of resveratrol-puerarin complex drug, wherein, the concentration of resveratrol was 20 ppm, the concentration of puerarin was 30 ppm, and the volume ratio between the resveratrol-puerarin complex solution and the cell culture medium was 1:1000.
  • the resveratrol-quercetin complex cell culture medium resveratrol and quercetin were mixed with an appropriate amount of 0.5% DMSO solution to obtain a resveratrol-quercetin complex solution.
  • the weight ratio between resveratrol and quercetin was 2:3.
  • the resveratrol-quercetin complex solution was mixed with a cell culture medium to prepare the resveratrol-quercetin complex cell culture medium containing 50 ppm of resveratrol-quercetin complex drug, wherein, the concentration of resveratrol was 20 ppm, the concentration of quercetin was 30 ppm, and the volume ratio between the resveratrol-quercetin complex solution and the cell culture medium was 1:1000.
  • the adipocyte precursors 3T3-L1 cells (purchased from the Food Industry Research and Development Institute, Taiwan; abbreviated as BCRC) were seeded in 12-well plates, such that each well contained 1 ⁇ 10 5 cells. After two days of culture, the cells were cultured for another two days in a differentiation induction media (DMI medium, wherein contains 0.5 ⁇ M of IBMX (purchased from Sigma-Aldrich), 0.1 ⁇ M of dexamethasone (purchased from Sigma-Aldrich), and 5 ⁇ g/ml of insulin (purchased from Humulin R.)) Then, the cells were cultured in a medium containing 5 ⁇ g/ml of insulin for six days. Once the cell morphology changed from spindle-shaped to spherical and many lipid droplets were accumulated in the cells, it indicates that the cells have differentiated into mature adipocytes.
  • DMI medium wherein contains 0.5 ⁇ M of IBMX (purchased from Sigma-Aldrich), 0.1
  • the mature adipocytes were divided into 6 groups, which are a DMSO control group, a resveratrol group, a puerarin group, a quercetin group, a resveratrol-puerarin complex group, and a resveratrol-quercetin complex group.
  • the mature adipocytes in the DMSO control group, the resveratrol group, the puerarin group, the quercetin group, the resveratrol-puerarin complex group, and the resveratrol-quercetin complex group were respectively cultured in the DMSO control group cell culture medium, the resveratrol cell culture medium, the puerarin cell culture medium, the quercetin cell culture medium, the resveratrol-puerarin complex cell culture medium, and the resveratrol-quercetin complex cell culture medium for 24 hours.
  • Annexin V protein (purchased from eBioscience) and propidium iodide (PI; purchased from eBioscience) were mixed with the cells in each group for a period of time, and then the percentage of cells labeled by annexin V protein and PI in each group was analyzed by flow cytometry to assess the percentage of mature adipocytes undergoing apoptosis.
  • PI propidium iodide
  • a mature adipocyte when labeled by both annexin V protein and PI, it indicates that the cell is undergoing apoptosis; when more mature adipocytes are undergoing apoptosis, it indicates that the lipolysis efficacy of the administered drug is better, and it also indicates that lipolysis is mediated through apoptosis but not necrosis.
  • the apoptosis efficacy of the resveratrol-puerarin complex group should be between the efficacy of the resveratrol group and the puerarin group. If the apoptosis efficacy of the resveratrol-puerarin complex group is better than that of the resveratrol group and the puerarin group, it indicates that resveratrol and puerarin in the resveratrol-puerarin complex pharmaceutical composition manifests synergy in lipolysis efficacy.
  • the apoptosis efficacy of the resveratrol-quercetin complex group should be between the efficacy of the resveratrol group and the quercetin group. If the apoptosis efficacy of the resveratrol-quercetin complex group is better than that of the resveratrol group and the quercetin group, it indicates that resveratrol and quercetin in the resveratrol-quercetin complex pharmaceutical composition manifests synergy in lipolysis efficacy.
  • FIG. 5 is a bar graph showing the effects of the resveratrol-other lipophilic drug complex pharmaceutical composition on the apoptosis of mature adipocytes.
  • results in FIG. 5 showed that the percentage of apoptotic cells in the DMSO control group was 4.9 ⁇ 2.5%, the percentage of apoptotic cells in the resveratrol group was 19.1 ⁇ 1.1%, the percentage of apoptotic cells in the puerarin group was 7.2 ⁇ 3.7%, the percentage of apoptotic cells in the quercetin group was5.9 ⁇ 2.6%, the percentage of apoptotic cells in the resveratrol-puerarin complex group was 50.6 ⁇ 3.8%, and the percentage of apoptotic cells in the resveratrol-quercetin complex group was 12.1 ⁇ 2.7%.
  • complex pharmaceutical compositions formed by resveratrol and various lipophilic drugs can all achieve lipolysis, and there are synergies between resveratrol and various lipophilic drugs in lipolysis efficacy.
  • the present invention uses resveratrol and various lipophilic drugs to prepare drug-containing micelles and a second lipophilic drug-containing micelles, and further prepares the resveratrol-other lipophilic drug complex pharmaceutical composition, which is a pharmaceutical composition capable to be used for localized lipolysis and weight reduction.
  • Hydrophilic drug other than green-tea extract and resveratrol were used in this experiment to prepare complex pharmaceutical compositions in order to assess the lipolysis efficacy of various resveratrol-hydrophilic drug complex pharmaceutical compositions on mature adipocytes.
  • This experiment uses caffeine and L-carnitine to prepare various resveratrol-hydrophilic drug complex pharmaceutical compositions.
  • a sterile water control group cell culture medium, a resveratrol cell culture medium, a caffeine cell culture medium, a L-carnitine cell culture medium, a resveratrol-caffeine complex cell culture medium, and a resveratrol-L-carnitine complex cell culture medium were prepared as follows:
  • the sterile water control group cell culture medium Sterile water was mixed with a cell culture medium to prepare the sterile water control group cell culture medium, wherein, the volume ratio between the sterile water and the cell culture medium is 1:1000.
  • the caffeine cell culture medium caffeine (purchased from Sigma-Aldrich) was mixed with an appropriate amount of sterile water to obtain a caffeine solution.
  • the caffeine solution was mixed with a cell culture medium to prepare the caffeine cell culture medium containing 50 ppm of caffeine, wherein, the volume ratio between the caffeine solution and the cell culture medium is 1:1000.
  • the L-carnitine cell culture medium L-carnitine (purchased from Sigma-Aldrich) was mixed with an appropriate amount of sterile water to obtain a L-carnitine solution.
  • the L-carnitine solution was mixed with a cell culture medium to prepare the L-carnitine cell culture medium containing 50 ppm of L-carnitine, wherein, the volume ratio between the L-carnitine solution and the cell culture medium is 1:1000.
  • the resveratrol-caffeine complex cell culture medium resveratrol, caffeine, and an appropriate amount of sterile water were mixed to obtain a resveratrol-caffeine complex solution.
  • the weight ratio between resveratrol and caffeine was 2:3.
  • the resveratrol-caffeine complex solution was mixed with a cell culture medium to prepare the resveratrol-caffeine complex cell culture medium containing 50 ppm of resveratrol-caffeine complex drug, wherein, the concentration of resveratrol was 20 ppm, the concentration of caffeine was 30 ppm, and the volume ratio between the resveratrol-caffeine complex solution and the cell culture medium was 1:1000.
  • the resveratrol-L-carnitine complex cell culture medium resveratrol, L-carnitine, and an appropriate amount of sterile water were mixed to obtain a resveratrol-L-carnitine complex solution.
  • the weight ratio between resveratrol and L-carnitine was 2:3.
  • the resveratrol-L-carnitine complex solution was mixed with a cell culture medium to prepare the resveratrol-L-carnitine complex cell culture medium containing 50 ppm of resveratrol-L-carnitine complex drug, wherein, the concentration of resveratrol was 20 ppm, the concentration of L-carnitine was 30 ppm, and the volume ratio between the resveratrol-L-carnitine complex solution and the cell culture medium was 1:1000.
  • the preparation of mature adipocytes is the same method as that in Experiment 9-2.
  • the mature adipocytes were divided into 6 groups, which are a sterile water control group, a resveratrol group, a caffeine group, a L-carnitine group, a resveratrol-caffeine complex group, and a resveratrol-L-carnitine complex group.
  • the mature adipocytes in the sterile water control group, the resveratrol group, the caffeine group, the L-carnitine group, the resveratrol-caffeine complex group, and the resveratrol-L-carnitine complex group were respectively cultured in the sterile water control group cell culture medium, the resveratrol cell culture medium, the caffeine cell culture medium, the L-carnitine cell culture medium, the resveratrol-caffeine complex cell culture medium, and the resveratrol-L-carnitine complex cell culture medium for 24 hours.
  • Annexin V protein (purchased from eBioscience) and propidium iodide (PI; purchased from eBioscience) were mixed with the cells in each group for a period of time, and then the percentage of cells labeled by annexin V protein and PI in each group was analyzed by flow cytometry to assess the percentage of mature adipocytes undergoing apoptosis.
  • PI propidium iodide
  • a mature adipocyte when labeled by both annexin V protein and PI, it indicates that the cell is undergoing apoptosis; when more mature adipocytes are undergoing apoptosis, it indicates that the lipolysis efficacy of the administered drug is better, and it also indicates that lipolysis is mediated through apoptosis but not necrosis.
  • the apoptosis efficacy of the resveratrol-caffeine complex group should approximate the average of the efficacy of the resveratrol group and the caffeine group. If the apoptosis efficacy of the resveratrol-caffeine complex group is better than the average of that of the resveratrol group and the caffeine group, it indicates that resveratrol and caffeine in the resveratrol-caffeine complex pharmaceutical composition manifests synergy in lipolysis efficacy.
  • the ratio of resveratrol thereof was 40%, and the ratio of L-carnitine thereof was 60%; therefore, the apoptosis efficacy of the resveratrol-L-carnitine complex group should approximate the average of the efficacy of the resveratrol group and the L-carnitine group.
  • apoptosis efficacy of the resveratrol-L-carnitine complex group is better than the average of that of the resveratrol group and the L-carnitine group, it indicates that resveratrol and L-carnitine in the resveratrol-L-carnitine complex pharmaceutical composition manifests synergy on lipolysis efficacy.
  • FIG. 6 shows the effects of resveratrol-other hydrophilic drug complex pharmaceutical compositions on the apoptosis of the mature adipocytes.
  • results in FIG. 6 showed that the percentage of apoptotic cells in the sterile water control group was 9.6 ⁇ 1.5%, the percentage of apoptotic cells in the resveratrol group was 19.0 ⁇ 1.1%, the percentage of apoptotic cells in the caffeine group was 6.9 ⁇ 1.1%, the percentage of apoptotic cells in the L-carnitine group was 5.2 ⁇ 1.2%, the percentage of apoptotic cells in the resveratrol-caffeine complex group was 43.1 ⁇ 4.5%, and the percentage of apoptotic cells in the resveratrol-L-carnitine complex group was 19.3 ⁇ 0.5%.
  • complex pharmaceutical compositions formed by resveratrol and various hydrophilic drugs can all achieve lipolysis, and there are synergies between resveratrol and various hydrophilic drugs in lipolysis efficacy.
  • the present invention uses resveratrol and various hydrophilic drugs to prepare the resveratrol-hydrophilic drug complex pharmaceutical composition comprising drug-containing micelles, which is a pharmaceutical composition capable to be used for localized lipolysis and weight reduction.
  • the first pharmaceutical composition, the second pharmaceutical composition, the third pharmaceutical composition, the fourth pharmaceutical composition, the fifth pharmaceutical composition, and other pharmaceutical compositions in the present invention can all reduce the localized fat. 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 in the present invention can be used to prepare subcutaneous implanted devices, subcutaneous implants, solutions for implanted infusion, ointment (or salve), or patches, which is capable to be administered by subcutaneous implantation, implanted infusion, or skin absorption ways, such as applying ointment (or salve) or wearing patches.
  • the first pharmaceutical composition, the second pharmaceutical composition, the third pharmaceutical composition, the fourth pharmaceutical composition, the fifth pharmaceutical composition, and other pharmaceutical compositions in the present invention can reduce the localized fat at the administration site by subcutaneous fat layer injection. 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 in the present invention can be used to prepare formulation for subcutaneous fat layer injection or formulation for subcutaneous injection for reducing localized fat.

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11318110B2 (en) 2015-08-28 2022-05-03 Caliway Biopharmaceuticals Co., Ltd. Pharmaceutical composition for reducing local fat and uses thereof
US11433034B2 (en) 2015-08-28 2022-09-06 Caliway Biopharmaceuticals Co., Ltd. Pharmaceutical composition for reducing local fat and uses thereof

Families Citing this family (9)

* 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
WO2018037384A1 (fr) 2016-08-26 2018-03-01 康霈生技股份有限公司 Injection sous-cutanée pour réduire le poids corporel et application associée
EP3541815A4 (fr) 2016-11-18 2020-07-15 Pacira Pharmaceuticals, Inc. Formulations de liposomes multivésiculaires à microparticules de complexe de méloxicam de zinc et leurs procédés de fabrication
AU2018241639B2 (en) * 2017-03-28 2020-10-15 Caliway Biopharmaceuticals Co., Ltd. Composition for reducing weight and reducing body fat and pharmaceutical product and application thereof
EP3946407A4 (fr) * 2019-03-24 2022-12-28 Patel, Naishadhkumar Ramubhai Formulation pour améliorer la biodisponibilité et la stabilité de curcuminoïdes et/ou de dérivés de ceux-ci
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
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 (fr) * 2022-03-28 2023-10-05 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Synergie pour augmenter la sensibilité à l'insuline
WO2023221945A1 (fr) * 2022-05-16 2023-11-23 Caliway Biopharmaceuticals Co., Ltd. Compositions et procédés pour soulager des états provoqués par un dépôt sous-cutané anormal de tissu adipeux ou de graisse

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1077211A2 (fr) * 1999-08-16 2001-02-21 F. Hoffmann-La Roche Ag Procédé de production d'épigallocatéchine gallate
US20100129304A1 (en) * 2008-11-25 2010-05-27 Oy Granula Ab Ltd Method for preparing a composition comprising a compound mixture and a carrier agent
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
US20120088829A1 (en) * 2010-09-29 2012-04-12 MyCell Holdings Limited Formulations of Ubiquinol and Resveratrol Esters
US20130245118A1 (en) * 2010-07-02 2013-09-19 Eric H. Kuhrts Stable fatty acid-containing formulations

Family Cites Families (71)

* 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
WO2000051564A1 (fr) * 1999-03-03 2000-09-08 Eli Lilly And Company Formulations pharmaceutiques d'echinocandine contenant des tensioactifs formant des micelles
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
ATE440509T1 (de) 2003-06-04 2009-09-15 Nestec Sa Getränk zur gewichtskontrolle
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
US20050171027A1 (en) 2003-12-29 2005-08-04 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 (fr) 2005-01-05 2006-07-13 Mitsunori Ono Compositions pour traiter un diabete ou une obesite
AU2006210114B2 (en) 2005-02-04 2011-11-17 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 (fr) 2005-09-29 2007-04-12 New Chapter, Inc. Methodes permettant de moduler l'apoptose, la croissance cellulaire et l'expression des proteines au moyen de compositions a base de plantes
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
US9192644B2 (en) * 2006-03-06 2015-11-24 The Regents Of The University Of California Bioavailable curcuminoid formulations for treating Alzheimer's disease and other age-related disorders
WO2007112996A2 (fr) 2006-03-31 2007-10-11 Dsm Ip Assets B.V. Nouvelle utilisation de composés et de combinaisons de composés pour améliorer l'aspect physique
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 (fr) * 2006-04-04 2007-10-11 Dsm Ip Assets B.V. Récipients opaques contenant des aliments, des produits pharmaceutiques ou une ou plusieurs herbes médicinales
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 (fr) * 2007-11-22 2009-05-28 Ganga Raju Gokaraju Nouvelle composition phytochimique synergique pour le traitement de l'obésité
WO2009089011A2 (fr) * 2008-01-08 2009-07-16 Sirtris Pharmaceuticals, Inc. Formulations de resvératrol
CA2721665C (fr) 2008-04-18 2017-01-24 Reata Pharmaceuticals, Inc. Composes comprenant un pharmacore anti-inflammatoire et procedes d'utilisation
JP2011525921A (ja) * 2008-06-25 2011-09-29 イーエルシー マネージメント エルエルシー 皮膚および身体の外観を改善するための方法および組成物
AU2009307753A1 (en) 2008-10-22 2010-04-29 Metaproteomics, Llc Novel mitochondrial uncoupling methods and compositions for enhancing adipocyte thermogenesis
KR20110096132A (ko) * 2008-11-26 2011-08-29 리포프로틴 테크놀로지스, 인코포레이티드 레스베라트롤의 향상된 생활성 제제
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
CA2792601C (fr) * 2010-03-10 2015-09-29 Abbott Laboratories Compositions solides d'inhibiteurs de vhc amorphes
US8835509B2 (en) 2010-05-31 2014-09-16 Arbro Pharmaceuticals Ltd. Self emulsifying drug delivery system for a curcuminoid based composition
SI2588101T1 (sl) 2010-07-02 2015-01-30 Helix Biomedix, Inc. Derivati N-acil amino kisline za zdravljenje koĹľnih stanj, kot je celulitis
KR101640258B1 (ko) * 2010-07-05 2016-07-15 주식회사 엘지생활건강 적포도 추출물, 녹차 추출물, 대두 추출물 및 ｌ－카르니틴을 유효성분으로 함유하는 항비만 조성물
WO2012007560A1 (fr) 2010-07-16 2012-01-19 Merz Pharma Gmbh & Co. Kgaa Utilisation d'un médicament amphiphile cationique pour la préparation d'une formulation destinée à la réduction du tissu adipeux sous-cutané
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
WO2013108254A1 (fr) * 2012-01-19 2013-07-25 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Formulation et méthode destinées à augmenter la biodisponibilité orale de médicaments
US8496979B1 (en) 2012-02-02 2013-07-30 Reliv International, Inc. Caffeine-free dietary supplements for increasing energy and methods of administering the same
CA2863710A1 (fr) 2012-02-29 2013-09-06 Avon Products, Inc. Utilisation de modulateurs de cpt-1 et de compositions associees
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
WO2014025672A1 (fr) 2012-08-04 2014-02-13 Eric Hauser Kuhrts Formulations de composés naturels lipophiles hydrosolubles
WO2014028607A1 (fr) * 2012-08-14 2014-02-20 Abbott Laboratories Compositions nutritives à faible indice glycémique pour conserver la masse musculaire et améliorer la composition corporelle chez les diabétiques
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 (fr) 2013-03-07 2014-09-12 Topokine Therapeutics, Inc. Procédés et compositions pour la réduction de la graisse corporelle et des 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
US10226413B2 (en) 2013-11-15 2019-03-12 Damy Chemical Co., Ltd. Solution solubilization composition of insoluble material and method for solubilizing insoluble material using same
AU2014354599A1 (en) * 2013-11-27 2016-06-09 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 Caliway Biomedical Co Ltd 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
KR101859345B1 (ko) * 2014-08-28 2018-05-18 칼리웨이 바이오파마슈티칼스 코., 엘티디. 국소 지방 및 체중 감소용 조성물 및 그의 제약 및 용도
JP6446552B2 (ja) * 2014-08-28 2018-12-26 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およびその医薬品と使用
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
TWI630922B (zh) 2015-08-28 2018-08-01 康霈生技股份有限公司 用於減少局部脂肪的醫藥組成物及其用途
US11318110B2 (en) 2015-08-28 2022-05-03 Caliway Biopharmaceuticals Co., Ltd. Pharmaceutical composition for reducing local fat and uses thereof
WO2018037384A1 (fr) 2016-08-26 2018-03-01 康霈生技股份有限公司 Injection sous-cutanée pour réduire le poids corporel et application associée

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1077211A2 (fr) * 1999-08-16 2001-02-21 F. Hoffmann-La Roche Ag Procédé de production d'épigallocatéchine gallate
US20100129304A1 (en) * 2008-11-25 2010-05-27 Oy Granula Ab Ltd Method for preparing a composition comprising a compound mixture and a carrier agent
US20130245118A1 (en) * 2010-07-02 2013-09-19 Eric H. Kuhrts Stable fatty acid-containing formulations
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

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11318110B2 (en) 2015-08-28 2022-05-03 Caliway Biopharmaceuticals Co., Ltd. Pharmaceutical composition for reducing local fat and uses thereof
US11433034B2 (en) 2015-08-28 2022-09-06 Caliway Biopharmaceuticals Co., Ltd. Pharmaceutical composition for reducing local fat and uses thereof

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