WO2018037384A1 - 用于減少体重的皮下注射剂及其用途 - Google Patents

用于減少体重的皮下注射剂及其用途 Download PDF

Info

Publication number
WO2018037384A1
WO2018037384A1 PCT/IB2017/055129 IB2017055129W WO2018037384A1 WO 2018037384 A1 WO2018037384 A1 WO 2018037384A1 IB 2017055129 W IB2017055129 W IB 2017055129W WO 2018037384 A1 WO2018037384 A1 WO 2018037384A1
Authority
WO
WIPO (PCT)
Prior art keywords
drug
curcumin
group
weight
castor oil
Prior art date
Application number
PCT/IB2017/055129
Other languages
English (en)
French (fr)
Inventor
凌玉芳
Original Assignee
康霈生技股份有限公司
康霈（美国）股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/IB2016/055102 external-priority patent/WO2017037594A2/zh
Application filed by 康霈生技股份有限公司, 康霈（美国）股份有限公司 filed Critical 康霈生技股份有限公司
Priority to US16/327,466 priority Critical patent/US10716824B2/en
Priority to JP2019510854A priority patent/JP2019528297A/ja
Priority to KR1020197008320A priority patent/KR20190040305A/ko
Priority to EP17843043.5A priority patent/EP3505168A1/en
Priority to CN201780050055.5A priority patent/CN109640969A/zh
Priority to RU2019108198A priority patent/RU2753507C2/ru
Priority to CA3033041A priority patent/CA3033041A1/en
Publication of WO2018037384A1 publication Critical patent/WO2018037384A1/zh
Priority to US16/926,631 priority patent/US20200338152A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/82—Theaceae (Tea family), e.g. camellia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/11—Encapsulated compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A61K8/347—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/86—Polyethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/06—Preparations for care of the skin for countering cellulitis

Definitions

  • the present invention relates to a subcutaneous injection for administration to an overweight or obese individual to reduce the body weight of the individual, and more particularly to a curcuminoid comprising a plurality of drug-containing micelles and coated in the drug-containing micelles Subcutaneous injection, and the subcutaneous injection is used to reduce body weight. Background technique
  • Obesity is a state of the body that has accumulated too much body fat and has a negative impact on health, which may lead to shortened life and various health problems.
  • body mass index (BMI) greater than 25 is defined as overweight (overweight;)
  • BMI greater than 30 is defined as obesity
  • some East Asian countries adopt more stringent standards, such as Taiwan health.
  • Taiwan health In April 2002, the Ministry of Welfare announced that BMI ⁇ 27 in Taiwanese adults was obese, and 24 ⁇ BMI ⁇ 27 was overweight.
  • Obesity is currently a health issue that is highly valued around the world. Studies have pointed out that the causes of obesity are very complex and there are multiple factors involved. A growing body of evidence also shows that obesity is not a simple problem that can be improved by self-control, but rather a complex symptom of appetite regulation and energy metabolism in the body, and a disease of metabolic imbalance in the body. Obesity not only causes an increase in mortality and a huge medical burden, but also affects the quality of life of human beings. Although the cause of obesity is not fully established, it is thought to be related to genetic, metabolic, biochemical, cultural and spiritual social factors.
  • appetite suppression is the main mechanism of past and current market-based weight-loss drugs.
  • These drugs include Sibutramine, Lorcaserin, Qsymia and Contrave, which have serious side effects and a certain degree of cardiovascular risk.
  • Sibutramine a previously-obtained weight-loss drug, as an example, its market share has reached 70%, but it has been confirmed to increase the risk of cardiovascular disease. Therefore, the EU, the US, Australia, Taiwan, etc. have announced in 2010
  • the diet pills containing Sibutramine ingredients are taken off the shelf.
  • a weight-loss drug that blocks partial absorption of fat in food by the intestine is Orlistat, a specific and reversible gastrointestinal lipolytic enzyme inhibitor that inhibits pancreatic and intestinal fat-digesting enzymes. , and reduce the intestinal absorption of the absorbed fat by 25 to 30%.
  • Orlistat's main mode of action is to block the absorption of oil, there may be side effects such as oily stools, increased frequency of bowel movements, bloating, and other gastrointestinal side effects during medication, which may also interfere with the absorption of fat-soluble vitamins. Cases of serious side effects such as gallstones.
  • the present invention provides a pharmaceutical composition for reducing body weight, comprising a plurality of drug-containing micelles formed by a polyoxyethylene castor oil derivative, and coated on the drug-containing micelle The curcuminoids in the medium.
  • the pharmaceutical composition for reducing body weight can reduce body weight, and has the advantages of low dose, high stability, low side effects, and sustained release.
  • the invention can promote the apoptotic reaction of the systemic fat cells after administration, thereby achieving the purpose of reducing body weight.
  • the invention can greatly improve the problems of high dosage and high side effects of the prior art, and the effect of reducing body weight is significantly better than oral diet pills.
  • the invention is suitable for administration to an overweight or obese individual by subcutaneous injection or subcutaneous fat layer injection without the intervention or assistance of any surgical or instrumentation.
  • overweight refers to an adult having a body mass index of 24 or more and less than 27: Obesity refers to a body mass index of 27 or more. Preferably, overweight refers to an adult's body mass index greater than 25; fat refers to a body mass index greater than 30.
  • the turmeric extract refers to a turmeric ingredient mixture extracted by any solvent and any extraction method, and a commercially available turmeric extract, at least 75% by weight; A mixture of curcumin, any mixture comprising at least 75% by weight of curcuminoi d, or commercially available curcumin.
  • resveratrol refers to resveratrol obtained from natural plant extract or commercially available.
  • the resveratrol has a purity of from 90% to 100% by weight.
  • the green tea extract refers to a mixture of green tea ingredients extracted from any solvent and any extraction method or a commercially available green tea extract, preferably, at least 45% ( Percent by weight;) a mixture of epigallocatechin gallate, EGCG), any mixture comprising at least 90% (by weight;) total catechins, or commercially available table galls Catechin gallate.
  • a micelle refers to a micro-structure formed of a polyoxyethylene castor oil derivative having a hydrophilic end and a lipophilic end (lipophilic end). ;), and the polyoxyethylene castor oil derivative forms the microstructure with the hydrophilic end outward and the lipophilic end (lipophilic end;) inward.
  • the microstructure is a spherical, spheroidal, or other microstructured structure.
  • the drug-containing microsphere refers to a microcell containing a curcuminoid.
  • the drug-containing microsphere refers to a microcapsule containing curcumin; that is, a drug-containing microparticle
  • the cell refers to a microcapsule coated or containing a curcuminoid substance.
  • the drug-containing microcapsule refers to a microcapsule coated or containing curcumin.
  • the drug-containing micelles are uniformly distributed in the pharmaceutical composition.
  • the total concentration of the curcuminoids coated in the drug-containing micelles when expressed in mg/g, it represents the curcumin in all the drug-containing micelles contained per gram of the pharmaceutical composition. The total number of milligrams of the substance.
  • the total concentration of the curcuminoids coated in the drug-containing micelles may be measured by, for example, the following steps:
  • the pharmaceutical composition was filtered through a 0.2 ⁇ filter to obtain a filtrate and a precipitate of curcuminoids not coated with the drug-containing microcapsules;
  • the total concentration of the curcuminoids contained in the drug-containing cells in the pharmaceutical composition was calculated from the concentration of the curcumin substance in the sample solution.
  • the first drug-containing microsphere refers to a microcapsule containing a curcuminoid substance
  • the drug-containing microsphere refers to a microcapsule containing curcumin; that is, the first drug-containing microsphere finger It is a microcapsule coated or containing a curcuminoid substance.
  • the first drug-containing microcapsule refers to a microcapsule coated or containing curcumin.
  • the second drug-containing microsphere refers to a resveratrol-containing micelle. That is, the second drug-containing microsphere refers to a microcapsule coated or containing resveratrol.
  • the curcuminoid is curcumin; demethoxycurcumin
  • the total catechin Ccatechins is Epigall ocatechin gallate ⁇ Epicatechin; Epicatechin gallate ⁇ Epidermis Epigallocatechin; Gallocatechin gallate; Gallocatechin; Catechin gallate; Catechin .
  • state without precipitation is used to mean any precipitate which is not visible to the human eye, that is, without the use of artificial means.
  • the pharmaceutically acceptable aqueous solution is at least one or a combination of water for injection, aqueous solution for injection, physiological saline, and other pharmaceutically acceptable aqueous solutions.
  • the local anesthetic is at least one of an amide, a p-aminobenzamide, an aminoether, and other local anesthetics or a combination thereof.
  • the amide is dibucaine; Lidocaine, mepivacaine hydrochloride (Bepivacaine HC1), bupivacine HCl (Bupivacine HC1), pyrrole. At least one of or a combination of hydrochloride (Pyrrocaine HCl), prilocaine HCl (Prilocaine HC1), Digammacaine, and Oxethazaine.
  • the p-aminobenzamide is at least one or a combination of butacaine; dimethocaine; and tutocaine.
  • the amino ether is at least one of quinicin (Quinisocaine;) and pramocaine or a combination thereof.
  • the antioxidants are beta-carotene; lutein; lycopene, bilirubin, vitamin A, vitamin C (vitamin A), vitamin C (vitamin A), vitamin C (vitamin A), vitamin C (vitamin A), vitamin C (vitamin A) Vitamin C; also known as ascorbic acid, vitamin E, uric acid, nitric oxide, nitroxide, pyruvate, peroxidation Catalase, superoxide dismutase, glutathione peroxidases, At least one of N-acetyl cysteine; naringenin; and other antioxidants or a combination thereof.
  • the pharmaceutical composition when the pharmaceutical composition is subjected to an accelerated stability test under the conditions of a temperature of 25 ° C ⁇ 2 ° C, a relative humidity of RH 60% ⁇ 5%, and direct light avoidance, the pharmaceutical composition is maintained in the absence of sediment.
  • the state is at least 24 hours.
  • the pharmaceutical composition when the pharmaceutical composition is subjected to an accelerated stability test under the conditions of a temperature of 25 ° C ⁇ 2 ° C, a relative humidity of RH 60% ⁇ 5%, and direct light avoidance, the pharmaceutical composition is maintained in the absence of sediment.
  • the status is at least 6 months.
  • the concentration of polyoxyethylene 35 castor oil represents the number of grams of polyoxyethylene 35 castor oil per 100 ml of the solution.
  • the present invention provides a use of a pharmaceutical composition for preparing a subcutaneous injection for administration to a body which is overweight or obese to reduce the body weight of the individual; the pharmaceutical composition comprising:
  • the drug-containing micelles are pharmaceutically acceptable polyoxyethylene castor oil derivatives a micro-structure formed, and the polyoxyethylene castor oil derivative has a hydrophilic-lipophilic balance value (HLB value) greater than 10;
  • the total concentration of the curcuminoids encapsulated in the drug-containing micelles is 0.2120 mg/g.
  • the pharmaceutically acceptable aqueous solution further comprises a total catechin component.
  • the total concentration of the curcuminoids in the drug-containing micelles is 0.4167 mg/g; or the total concentration of the curcuminoids in the drug-containing micelles is 0.511 1 mg/ g; or, the total concentration of curcuminoids in the drug-containing micelles is 2 to 91 mg/g.
  • the total catechin component concentration is 0.04 835 mg/g o
  • the total catechin component concentration is 0.15 733 mg/g.
  • the total catechin component is Epigallocatechin gallate (Epicatechin;), epicatechin gallate (Epicatechin gallate) ⁇ Table gallnut At least one of Epigallocatechin; Gallocatechin gallate; Gallocatechin; Calcatechin gallate; Catechin gallate; Catechin One or a combination thereof.
  • the weight ratio of the curcuminoid to the total catechin component in the pharmaceutical composition is from 50:1 to 1:20.
  • the weight ratio of the curcumin substance to the total catechin component in the pharmaceutical composition is 30:1.
  • the weight ratio of the curcuminoid to the total catechin component in the pharmaceutical composition is
  • the weight ratio of the curcuminoid to the total catechin component in the pharmaceutical composition is from 7:1 to 1:4.
  • the drug-containing micelles have a particle size of 3 to 50 nm.
  • the drug-containing micelles have a particle size of 5 to 20 nm.
  • the subcutaneous injection is administered at a dose of 0.15 40 mg per kg.
  • the subcutaneous injection is administered at a dose of 0.25 25 mg per kg.
  • the subcutaneous injection is administered at a frequency of from 1 to 6 times per 1 to 90 days at the application site.
  • a subcutaneous injection of greater than or equal to 1 needle is administered each time the site of administration is administered.
  • the weight ratio of the curcuminoid to the polyoxyethylene castor oil derivative is 1: 5 to 1:
  • the weight ratio of the curcuminoid to the polyoxyethylene castor oil derivative is from 1:20 to 1:150.
  • the polyoxyethylene castor oil derivative is in the form of polyoxyethylene 35 castor oil (Crem 0 phor ELP), polyoxyethylene 40 hydrogenated castor oil (Cremophor RH 40), and other polyoxyethylene castor oil derivatives. At least one or a combination thereof.
  • the pharmaceutical composition further comprises at least one of a cosolvent, a suspending agent, and an oil phase excipients, or a combination thereof.
  • At least one of the oil phase excipient and the cosolvent together with the polyoxyethylene castor oil derivative form the microstructure.
  • the curcuminoid is curcumin ( CU r CU min).
  • the present invention further provides the use of a pharmaceutical composition for preparing a subcutaneous injection for administration to a body which is overweight or obese to reduce the body weight of the individual; the pharmaceutical composition comprising:
  • the first drug-containing micelles are formed by a pharmaceutically acceptable polyoxyethylene castor oil derivative a micro-structure, and the polyoxyethylene castor oil derivative has a hydrophilic-lipophilic balance value (HLB value;) greater than 10;
  • HLB value hydrophilic-lipophilic balance value
  • the total concentration of the curcuminoids encapsulated in the first drug-containing micelles is 0.2167 mg/g.
  • the total concentration of resveratrol coated in the second drug-containing micelles is 0.2 733 mg/g.
  • the total concentration of the curcuminoids encapsulated in the first drug-containing micelles and the total concentration of resveratrol coated in the second drug-containing micelles is 0.4900.
  • the total weight of the curcuminoids coated in the first drug-containing micelles is coated with the The ratio of the total weight of resveratrol in the drug-containing micelles is from 50:1 to 1:30.
  • the total weight of the curcumin substance coated in the first drug-containing micelles is: 30% of the total weight of the resveratrol coated in the drug-containing micelles. : 1 to 1: 10.
  • the total weight of the curcumin substance coated in the first drug-containing micelles is: 20% of the total weight of the resveratrol coated in the drug-containing micelles. : 1 to 1:20.
  • the total weight of the curcumin substance coated in the first drug-containing micelles is: 20% of the total weight of the resveratrol coated in the drug-containing micelles. : 1 to 1: 8.
  • the subcutaneous injection is administered at a dose of 0.15 40 mg per kg.
  • the application agent of the subcutaneous injection 0.25 25 mg per kg injection.
  • the application agent for the injection of the dermal injection is 0.4 to 25 mg per kg.
  • the application agent of the subcutaneous injection is: 0.5 to 20 mg per kg injection.
  • the application agent for the subcutaneous injection is: 0.02 to 20 mg per square centimeter.
  • the application agent of the subcutaneous injection is: 0.04 to 16 mg per square centimeter.
  • the subcutaneous injection is applied at a frequency of from 1 to 12 times per 1 to 90 days.
  • the subcutaneous injection is applied to the application site 1 to 6 times every 1 to 90 days.
  • the application frequency of the subcutaneous injection is 1 to 6 times per 1 to 60 days.
  • the ratio of the total weight of the curcuminoids coated in the first drug-containing micelles to the total weight of the polyoxyethylene ricinoleic acid derivative is 1:5 to 1:750.
  • the pharmaceutical composition further comprises at least one of a cosolvent, a suspending agent, and an oil phase excipients, or a combination thereof.
  • At least one of the oil phase excipient and the cosolvent together with the polyoxyethylene castor oil derivative form the microstructure.
  • the second drug-containing microsphere is a second micro-shaped structure formed by a pharmaceutically acceptable polyoxy ethylene castor oil derivative, and the second polyoxygen
  • the vinyl castor oil derivative has a hydrophilic-lipophilic balance value (HLB value) of more than 10.
  • the polyoxyethylene castor oil derivative is in the form of polyoxyethylene 35 castor oil (Crem 0 phor ELP), polyoxyethylene 40 hydrogenated castor oil (Cremophor RH 40), and other polyoxyethylene castor oil derivatives. At least one or a combination thereof; or the second polyoxyethylene castor oil derivative is a polyoxyethylene 35 castor oil (Cremophor ELP), polyoxyethylene 40 hydrogenated castor oil (Cremophor RH 40), and other polyoxyethylene At least one of castor oil derivatives or a combination thereof.
  • the curcuminoid is curcumin (c UrCU min).
  • the pharmaceutical composition further comprises a cosolvent for increasing the solubility of the drug.
  • a cosolvent for increasing the solubility of the drug.
  • the solubilizing flush the I! Is polyethylene glycol (polyethylene glycol), propylene glycol (propylene glycol), ethanol (eth an0 l), or a combination thereof and at least one other co-solvents.
  • the polyethylene glycol is at least one of polyethylene glycol 200 (PEG 200), polyethylene glycol 400 (PEG 400), polyethylene glycol 600 (PEG 600), and other polyethylene glycols. kind or a combination thereof.
  • the pharmaceutical composition further comprises a suspending agent (also known as a suspending agent) for reducing the rate of sedimentation of the drug or the micelle.
  • a suspending agent also known as a suspending agent
  • the suspending agent is at least one of sodium alginate, glycerol, carboxymethylcellulose sodium, mannitol, and other suspending agents. kind or a combination thereof.
  • the pharmaceutical composition further comprises oil phase excipients; to increase the stability of the pharmaceutical composition and the solubility of the drug.
  • the oil phase vehicle is at least one or a combination of an unsaturated fatty acid, glycerol, triglyceride, and other oil phase excipients.
  • the unsaturated fatty acid is oleic acid, castor oil, sesame oil, cottonseed oil, soybean oil, safflower oil (safflower) At least one of oil), corn oil, and other unsaturated fatty acids, or a combination thereof.
  • the triglyceride is at least one of a medium chain triglycerides; and other triglycerides or a combination thereof.
  • the pharmaceutically acceptable aqueous solution comprises a local anesthetic.
  • the pharmaceutically acceptable aqueous solution contains an antioxidant.
  • the present invention further provides a method of reducing the body weight of an overweight or obese individual comprising administering a subcutaneous injection to the overweight or obese individual, wherein the subcutaneous injection comprises:
  • the drug-containing micelles are pharmaceutically acceptable polyoxyethylene castor oil derivatives a micro-structure formed, and the polyoxyethylene castor oil derivative has a hydrophilic-lipophilic balance value (HLB value) greater than 10;
  • the pharmaceutically acceptable aqueous solution further comprises a total catechin component.
  • the weight ratio of the curcuminoid to the total catechin component in the subcutaneous injection is from 50:1 to 1:20.
  • the weight ratio of the curcumin substance to the total catechin component in the subcutaneous injection is 30:1.
  • the weight ratio of the curcumin substance to the total catechin component in the subcutaneous injection is 10:1 to 1:4; or is the curcumin substance in the subcutaneous injection and the The total catechin ingredient weight ratio is from 7:1 to 1:4.
  • the invention further provides a method of reducing the body weight of an overweight or obese individual comprising administering a subcutaneous injection to the overweight or obese individual, wherein the subcutaneous injection comprises:
  • the first drug-containing micelles are formed by a pharmaceutically acceptable polyoxyethylene castor oil derivative a micro-structure, and the polyoxyethylene castor oil derivative has a hydrophilic-lipophilic balance value (HLB value;) greater than 10;
  • HLB value hydrophilic-lipophilic balance value
  • the total concentration of the curcuminoids encapsulated in the first drug-containing micelles is 0.2167 mg/g.
  • Figure 1A Bar graph of the effect of the curcumin-green tea extract compound medicinal composition on the relative total weight gain of rats in different ways.
  • Figure 1B Bar graph of the effect of a combination of curcumin-green tea extract compound medicinal composition on the relative weight of visceral fat in rats.
  • Figure 2A Bar graph of the effect of the ratio of curcumin to green tea extract on relative total weight gain in rats.
  • Figure 2B Bar graph of the effect of the ratio of curcumin to green tea extract on the relative weight of visceral fat in rats.
  • Figure 3A A bar graph of the effect of the dose of curcumin-green tea compound medicinal composition on relative total weight gain in rats.
  • Figure 3B Bar graph of the effect of the dose of curcumin-green tea compound medicinal composition on the relative weight of visceral fat in rats.
  • Figure 4A Bar graph of the effect of the frequency of administration of the curcumin-green tea complex medicinal composition on the relative total weight gain of the rat.
  • Figure 4B Bar graph of the effect of the frequency of administration of the curcumin-green tea compound medicinal composition on the relative weight of visceral fat in rats.
  • Figure 5A Bar graph of the effect of the ratio of curcumin to resveratrol on relative total weight gain in rats.
  • Figure 5B Bar graph of the effect of the ratio of curcumin to resveratrol on the relative weight of visceral fat in rats.
  • Figure 6A Bar graph of the effect of the dose of curcumin-resveratrol combination medicinal composition on relative total weight gain in rats.
  • Figure 6B Bar graph of the effect of the dose of curcumin-resveratrol combination medicinal composition on the relative weight of visceral fat in rats.
  • Figure 7A Bar graph of the effect of the frequency of application of curcumin-resveratrol combination medicinal composition on relative total weight gain in rats.
  • Figure 7B Bar graph of the frequency of application of the curcumin-resveratrol combination pharmaceutical composition on the relative weight of visceral fat in rats. detailed description
  • a pharmaceutical composition containing a low dose of curcuminoids can be established, which can reduce the body weight and visceral fat of the individual, and has high stability. High adipose tissue bioavailability, low side effects, and sustained release.
  • the green tea extract refers to a mixture comprising at least 45% by weight of epigallocatechin gallate (EGCG), or any one of at least 90% by weight. a mixture of total catechins.
  • EGCG epigallocatechin gallate
  • Experiment 1 Effect of low-dose pharmaceutical composition administered by different administration routes on body weight and visceral fat mass in rats
  • Preparation method of curcumin-green tea extract oral liquid Add appropriate amount of curcumin and green tea extract to an appropriate amount of sterile reverse osmosis water, and stir evenly, that is, curcumin-green tea extract oral solution.
  • the total concentration of curcumin and green tea extract is 100 mg/mL
  • the weight ratio of curcumin to green tea extract is 4:1.
  • Preparation method of curcumin-green tea extract compound pharmaceutical composition 0.8 g of curcumin and 150 200 mL of dichloromethane are mixed, and stirred at 150 500 rpm at room temperature until the curcumin is completely dissolved. Add 30 g of polyoxyethylene 35 castor oil (!0)1 ⁇ 110 £0>, abbreviated as ELP;), stir evenly at 100-300 rpm to volatilize. After the dichloromethane was completely evaporated, the physiological saline for injection was slowly added to a final volume of 200 mL, wherein 0.2 g of the green tea extract was contained in the physiological saline for injection. Stir well to obtain a curative composition of curcumin-green tea extract containing ELP.
  • ELP polyoxyethylene 35 castor oil
  • the curcumin-green tea extract compound medicine composition containing ELP contains drug-containing micelles, the total concentration of curcumin and green tea extract is 5 mg/mL, and the weight ratio of curcumin to green tea extract is 4:1. And the concentration of polyoxyethylene 35 castor oil is about 15%.
  • mice were fed with normal diet (Research Diets, Inc.) for a week to weigh approximately 175 200 g, followed by high-fat diet (Research Diets, Inc.; Model #D12492) After feeding 14 angel rats to be induced into an obese animal model and increasing body weight to 400 450 g, the rats were randomly divided into 5 groups, respectively Control group, oral group (PO group;), intraperitoneal injection group (IP group;), subcutaneous injection group (SC group;), and subcutaneous fat injection group (IA group;), no statistical difference in body weight of each group of rats .
  • PO group oral group
  • IP group intraperitoneal injection group
  • SC group subcutaneous injection group
  • IA group subcutaneous fat injection group
  • control group contained 8 rats
  • oral group contained 8 rats
  • intraperitoneal injection group contained 4 rats
  • subcutaneous injection group contained 4 rats.
  • body weight of each rat was recorded before the test and defined as the "pre-test body weight" of each rat.
  • Subcutaneous injection group (SC group;): The curcumin-green tea extract compound pharmaceutical composition was administered to the rats by subcutaneous injection, and the injection site was behind the back of the rat, above the shoulder and cheekbone, or under the shoulder and cheekbones. On the 1st, 3rd, 5th, 7th, 9th, and 11th day of the experiment, the drug was administered once, and the drug was administered 6 times. Each dose was 4 mL (4 mL/kg) per kilogram of body weight, so that each dose was 16 mg of curcumin and 4 mg of green tea extract were administered per kg of body weight.
  • Subcutaneous fat injection group (IA group;): The curcumin-green tea extract compound pharmaceutical composition was administered to rats by subcutaneous fat injection, and the injection site was the left and right inferior inguinal fat position of the rat, and the test was first. On the 3rd, 5th, 7th, 9th, and 1st, each dose was administered once, and the total dose was 6 times. Each dose was 4 mL (4 mL/kg) per kilogram of body weight, so that each dose was per kilogram of body weight. 16 mg of curcumin and 4 mg of green tea extract were administered.
  • Control group The control group was further divided into oral control group and injection control group, 4 rats each.
  • the rats in the oral control group were given sterile reverse osmosis water by oral administration.
  • the daily feeding was given once, and the amount of each tube was 2 mL (2 mL/kg) per kilogram of body weight tube, and the continuous tube was fed for 14 days.
  • the rats in the injection control group were injected with physiological saline by injection, and each injection was given once on the 1st, 3rd, 5th, 7th, 9th, and 11th day of the test, and a total of 6 injections per kilogram of body weight per injection. Inject 4 mL (4 mL/kg). The test results showed that there was no significant difference between the oral control group and the injection control group, so the two groups of data were combined into a control group.
  • the "post-test weight” of each rat was subtracted from the “pre-test weight” to obtain “total weight gain”.
  • the total weight gain of each group of rats was divided by the total weight gain of the control group rats to obtain "relative total weight gain”.
  • the rat fat, perirenal fat and mesenteric fat were weighed separately, and the total weight of the visceral fat was added.
  • the visceral fat weight of each group of rats was divided by the visceral fat weight of the control group rats to obtain "relative visceral fat weight”.
  • Fig. 1A is a bar graph of the effect of the curcumin-green tea extract compound pharmaceutical composition on the relative total weight gain of rats in different ways.
  • Fig. 1B is a bar graph of the effect of the curcumin-green tea extract compound pharmaceutical composition on the relative visceral fat weight of rats in different ways.
  • the relative visceral fat amount of the control group rats was not significantly different from that of the oral group rats, indicating that the curcumin-green tea extract compound medicine composition was administered orally, and the visceral fat of the rats could not be reduced; the intraperitoneal injection group was large.
  • the relative visceral fat weight of the rats was significantly different from that of the control group ( ⁇ 0.05), but the relative visceral fat weight of the rats in the intraperitoneal injection group was only reduced by 20.3%.
  • the relative visceral fat weight of the rats in the subcutaneous fat injection group was There was a significant difference between the control group ( ⁇ 0.05), and the relative visceral fat weight of the rats in the subcutaneous fat group decreased by 28.9%; the relative visceral fat weight of the rats in the subcutaneous injection group and the control group rats There was a significant difference (p ⁇ 0.05), and the relative visceral fat weight of the rats in the subcutaneous injection group was reduced by 43.5%.
  • the intraperitoneal injection method enables the drug to reach various parts of the body of the rat more quickly than the subcutaneous injection method, thereby achieving, for example, a systemic effect of reducing weight or reducing visceral fat.
  • the administration of a low dose of the pharmaceutical composition of the present invention to an overweight or obese rat by subcutaneous injection is more effective in reducing weight and reducing visceral fat. ⁇ 0.05) That is, administration of a low dose of the pharmaceutical composition of the present invention by subcutaneous injection has an unpredictable effect.
  • Experiment 2 Effect of curcumin-green tea extract compound pharmaceutical composition on different ethnic groups
  • the curcumin-green tea extract compound pharmaceutical composition was separately applied to normal and obese rats to evaluate the effects of the curcumin-green tea extract compound pharmaceutical composition on different ethnic groups of rats.
  • Method for arranging curcumin-green tea extract compound medicinal composition Mix 0.6 g of curcumin and 150 200 mL of dichloromethane, and stir at 150 500 rpm at room temperature until the curcumin is completely dissolved. Add 30 g of polyoxyethylene 35 castor oil (!0)1 ⁇ 110 £0>, abbreviated as ELP;), stir evenly at 100-300 rpm to volatilize. After the dichloromethane was completely evaporated, the physiological saline for injection was slowly added to a final volume of 200 mL, wherein 0.4 g of green tea extract was contained in the physiological saline for injection. Stir well to obtain a curative composition of curcumin-green tea extract containing ELP.
  • ELP polyoxyethylene 35 castor oil
  • the curcumin-green tea extract compound medicine composition containing ELP contains drug-containing micelles, the total concentration of curcumin and green tea extract is 5 mg/mL, and the weight ratio of curcumin to green tea extract is 3:2. And the concentration of polyoxyethylene 35 castor oil is about 15%.
  • mice were fed with normal diet for about 175-200 g for one week, the rats were divided into 4 groups, namely normal feed control group, high fat diet control group, normal feed-green tea extract compound medicine composition group. And a high-fat feed-green tea extract compound pharmaceutical composition group. Then, the rats in the normal feed control group and the normal feed-green tea extract compound medicine composition group were fed with normal feed for 14 days, and the high fat diet control group and the high fat feed-green tea extract were fed with the high fat diet. Rats in the compound pharmaceutical composition group were induced for 14 days in the high-fat diet control group and the high-fat diet-green tea extract compound pharmaceutical composition group to induce an obese animal model and increase the body weight to 400 450 go. , subcutaneous injection in the following manner.
  • Normal feed control group and high-fat diet control group Rats were administered with physiological saline by subcutaneous injection. The injection site was behind the back of the rat, above the shoulder and cheekbones, or under the shoulder and cheekbones. On the 3rd, 5th, 7th, 9th, and 11th, each injection was given 6 times, and each injection was 4 mL (4 mL/kg) per kilogram of body weight.
  • Normal feed-green tea extract compound medicine composition group and high fat feed-green tea extract compound medicine composition group The curcumin-green tea extract compound medicine composition is administered to rats by subcutaneous injection, and the injection site is rat.
  • the normal feed was continuously supplied to the normal feed control group and the normal feed-green tea extract compound medicine composition group, and the high fat diet was supplied to the high fat diet control group and the high fat feed-green tea extract compound medicine composition.
  • Group of rats The test was carried out for 20 days, and the rats were sacrificed with carbon dioxide on the 21st day.
  • the experimental results showed that the relative total weight gain and relative visceral fat weight of the normal feed-green tea extract compound pharmaceutical composition group were not significantly lower than those of the normal feed control group, indicating that the pharmaceutical composition of the present invention could not be obtained. Reducing the body weight of normal rats also does not reduce the visceral fat weight of normal rats. Compared with the high fat diet control group, the relative total weight gain and relative visceral fat weight of the high fat diet-green tea extract compound pharmaceutical composition group were significantly decreased (p ⁇ 0.05), indicating the pharmaceutical composition of the present invention. The ability to reduce the body weight of overweight or obese rats also reduces the visceral fat weight of overweight or obese rats.
  • the pharmaceutical composition of the present invention has an effect of reducing body weight and reducing visceral fat only for a specific ethnic group, that is, it can exert effects of reducing body weight and reducing visceral fat only for an overweight or obese group.
  • Experiment 3 Preparation of the pharmaceutical composition of the present invention
  • the filtrate containing the drug-containing microcapsules is stored in the dark, and wherein the drug-containing micelle is a micro-structure formed by the surfactant in the step (c), and The curcuminoid is encapsulated in the drug-containing micelle; the third weight is greater than or equal to 0 g.
  • the step of the step (c) is: after the solvent is completely evaporated, the third weight of the medicine is slowly added. An acceptable aqueous solution is stirred to form a plurality of drug-containing micelles.
  • the boiling point of the solvent is less than the boiling point of pure water.
  • the solvent is a hydrophilic solvent.
  • the hydrophilic solvent is at least one of methanol, ethanol, acetone, and other hydrophilic solvents, or a combination thereof.
  • the solvent in step (a) is a lipophilic solvent.
  • the lipophilic solvent is at least one of diethyl ether, benzene, chloroform, ethyl acetate, chloroform, hexamethylene and other lipophilic vehicles or a combination thereof.
  • the surfactant is a nonionic surfactant.
  • the nonionic surfactant is polysorbate 80CT ween 80), 2-hydroxyethyl
  • At least one or a combination of 12-hydroxyoctadecanoate (solutol HS 15), polyoxyethylene castor oil derivatives, and other nonionic surfactants.
  • the polyoxyethylene castor oil derivative is at least one of Cremophor ELP, Cremophor RH 40, and other polyoxyethylene castor oil derivatives. Or a combination thereof.
  • the weight ratio of the first weight of the curcuminoid to the second weight of the surfactant is from 1:5 to 1:500.
  • the weight ratio of the first weight of the curcuminoid to the second weight of the surfactant is from 1:20 to 1:150.
  • the weight ratio of the first weight of the curcuminoid to the third weight of the pharmaceutically acceptable aqueous solution is from 1:400 to 3:50.
  • the pharmaceutically acceptable aqueous solution is water for injection, aqueous solution for injection, or physiological saline.
  • the pharmaceutically acceptable aqueous solution comprises a local anesthetic.
  • the pharmaceutically acceptable aqueous solution contains an antioxidant.
  • the present invention provides a first method for preparing a curcuminoid-other fat-soluble drug compound pharmaceutical composition, the curcuminoid-other fat-soluble drug compound pharmaceutical composition comprising a plurality of drug-containing micelles and a second The fat-soluble drug microcapsule; the first step of preparing the curcuminoid-other fat-soluble drug compound pharmaceutical composition is as follows:
  • step (A) of preparing the drug-containing micro-cell composition comprises the following step (a2 (d2) :
  • the step ( ⁇ ) of preparing the second lipophilic drug microcapsule composition comprises the following Step (a3) d3):
  • HLB value hydrophilic-lipophilic balance value
  • the filtrate is the second liposoluble drug microcapsule composition containing the second fat-soluble drug micelle.
  • the drug-containing micelle is a micro-structure formed by the first surfactant, and the turmeric pigment-like substance is coated in the drug-containing micelle.
  • the second fat-soluble drug micelle is a micro-structure formed by the second surfactant, and the second fat-soluble drug is coated in the second fat-soluble drug cell.
  • the step (c2) is carried out as follows: After the first solvent is completely volatilized, the pharmaceutically acceptable aqueous solution is slowly added and stirred uniformly to form a plurality of drug-containing micelles.
  • the step (c3) is carried out as follows: After the second solvent is completely volatilized, the pharmaceutically acceptable aqueous solution is slowly added and stirred uniformly to form a plurality of second fat-soluble drug micelles.
  • the second fat-soluble drug is qi erce tin, sy ne phri ne , puerarin, resveratrol, and curcumin. At least one or a combination of the fat-soluble drugs.
  • the boiling point of the first solvent or / and the second solvent is less than the boiling point of the pure water.
  • the first solvent or/and the second solvent are hydrophilic solvents.
  • the hydrophilic solvent is at least one of methanol, ethanol, acetone, and other hydrophilic solvents, or a combination thereof.
  • the first solvent or / and the second solvent in the step (a2) or / and (a3) are lipophilic solvents.
  • the lipophilic solvent is at least one of diethyl ether, benzene, chloroform, ethyl acetate, chloroform, hexamethylene and other lipophilic vehicles or a combination thereof.
  • the first surfactant or / and the second surfactant are nonionic surfactants.
  • the nonionic surfactant is polysorbate 80CT ween 80), 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15), polyoxyethylene castor oil derivatives ⁇ and other non- At least one or a combination of ionic surfactants.
  • the polyoxyethylene castor oil derivative is at least one of Cremophor ELP, Cremophor RH 40, and other polyoxyethylene castor oil derivatives. Or a combination thereof.
  • the weight ratio of the curcuminoid to the second fat-soluble drug is from 30:1 to 1:10.
  • the weight ratio of the curcuminoid to the first surfactant is 1:
  • the weight ratio of the second fat-soluble drug to the second surfactant is from 1:4 to 1:500.
  • the pharmaceutically acceptable aqueous solution is water for injection, water for injection, or physiological saline.
  • the pharmaceutically acceptable aqueous solution comprises a local anesthetic.
  • the local anesthetic is at least one of an amide, a p-aminobenzamide, and an amino ether, or a combination thereof.
  • the amide is dibucaine; Lidocaine; mepivacaine hydrochloride (Bepivacaine HCl), bupivacine HCl (Bupivacine HC1), pyrrole At least one or a combination of pyrrocaine HCl, prilocaine HCl, Digammacaine, and Oxethazaine.
  • the para-aminobenzamide is at least one of or a combination of butacaine (Butacaine;), dimethocaine (Dmethocaine), and Tutocaine.
  • the amino ether is at least one of quinacine (Quinisocaine;) and pramocaine or a combination thereof.
  • the pharmaceutically acceptable aqueous solution contains an antioxidant.
  • the antioxidant is ⁇ -carotene Cb eta-carotene), lutein, lycopene (lycopene), bilirubin, vitamin A, vitamin C (also known as ascorbic acid), vitamin E, uric acid, nitric oxide ( nitric oxide), nitroxide, pyruvate, catalase, superoxide dismutase, glutathione peroxidases N - at least one of acetylcysteine (N-acetyl cysteine;) and naringenin or a combination thereof.
  • the present invention provides a second method for preparing a curcuminoid-other fat-soluble pharmaceutical compound pharmaceutical composition, and the second curcuminoid-other fat-soluble pharmaceutical compound pharmaceutical composition is prepared by the first method of curcumin
  • the second type of curcumin substance - a solvent, a surfactant, a pharmaceutically acceptable aqueous solution, and a second fat-soluble drug used in the preparation method of the other fat-soluble drug compound pharmaceutical composition, and the first type of turmeric
  • the pigments are the same as those used in the preparation of other fat-soluble pharmaceutical compound pharmaceutical compositions.
  • the ratio of the ratio between the components in the preparation method of the second curcumin substance-other fat-soluble drug compound pharmaceutical composition is also the same as the first curcumin substance-other fat-soluble drug compound pharmaceutical composition.
  • the preparation method is the same.
  • the pharmaceutically acceptable aqueous solution comprises a local anesthetic or/and an antioxidant.
  • the second anthraquinone substance-other fat-soluble drug combination pharmaceutical composition is used in a method for preparing a local anesthetic agent and/or an antioxidant, and the first curcumin substance-other fat-soluble property The same applies to the preparation method of the pharmaceutical compound pharmaceutical composition.
  • the first pharmaceutically acceptable aqueous solution comprises a local anesthetic.
  • the local anesthetic is at least one of an amide, a p-aminobenzamide, and an amino ether, or a combination thereof.
  • the amide is dibucaine; Lidocaine; mepivacaine hydrochloride (Bepivacaine HCl), bupivacine hydrochloride (Bupivacine HC1), At least one of pyrrocaine HC1, prilocaine HCl, Digammacaine, and Oxethazaine, or a combination thereof.
  • the para-aminobenzamide is at least one of or a combination of butacaine (Butacaine;), dimethocaine (Dmethocaine), and Tutocaine.
  • the amino ether is at least one of quinacine (Quinisocaine;) and pramocaine or a combination thereof.
  • the first pharmaceutically acceptable aqueous solution comprises an antioxidant.
  • the antioxidant is ⁇ -carotene Cb eta-carotene), lutein, lycopene, bilirubin, vitamin A, vitamin C C; also known as ascorbic acid, namely, vitamin E, uric acid, nitric oxide, nitroxide, pyruvate; Catalase; superoxide dismutase, glutathione peroxidases, N-acetyl cysteine, and naringenin At least one of naringenin) or a combination thereof.
  • the boiling point of the solvent is smaller than the boiling point of the pure water.
  • the solvent is a hydrophilic solvent.
  • the hydrophilic solvent is at least one of methanol, ethanol, acetone, and other hydrophilic solvents, or a combination thereof.
  • the solvent in step (a5) is a lipophilic solvent.
  • the lipophilic solvent is at least one of diethyl ether, benzene, chloroform, ethyl acetate, chloroform, hexamethylene and other lipophilic vehicles or a combination thereof.
  • the surfactant is a nonionic surfactant.
  • the nonionic surfactant is polysorbate 80CT ween 80), 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15), polyoxyethylene castor oil derivative (polyoxyethylene) Castor oil derivatives) and at least one or a combination of other nonionic surfactants.
  • the polyoxyethylene castor oil derivative is at least one of Cremophor ELP, Cremophor RH 40, and other polyoxyethylene castor oil derivatives. Or a combination thereof.
  • step (c5) the method further comprises the steps of:
  • the water-soluble drug is dissolved in the first pharmaceutically acceptable aqueous solution
  • the drug-containing microcell is a micro-structure formed by a surfactant
  • the curcumin substance is coated in the In the drug-containing micelles.
  • the water-soluble drug in the first pharmaceutically acceptable aqueous solution is green tea extract, epigallocatechin gallate, epicatechin, epicatechin Epicatechin gallate ⁇ Epigallocatechin; Gallocatechin gallate; Gallocatechin; Calecate gallate , Catechin, Caffeine, Carnitine (also known as Carnitine or Carnitine), L-carnitine, Synephrine, Green At least one or a combination of an acid ( Chi orogenic acid), and other water soluble drugs.
  • the weight ratio of the curcuminoid to the water-soluble drug is from 30:1 to 1:10.
  • the weight of the curcumin substance and the water-soluble drug is one weight unit, and the weight of the surfactant is 0.24 70 weight units;
  • the weight ratio of the total weight of the curcuminoid to the water-soluble drug to the surfactant is from 4:1 to 1:70.
  • the first pharmaceutically acceptable aqueous solution is based on the total weight of the curcumin substance and the water-soluble drug in one weight unit.
  • the total weight of the second pharmaceutically acceptable aqueous solution is 16,400 weight units.
  • the first pharmaceutically acceptable aqueous solution and the second pharmaceutically acceptable aqueous solution are water for injection, aqueous solution for injection, or physiological saline.
  • the pharmaceutical composition was allowed to stand for at least 20 minutes, and if delamination did not occur, it was further tested by a particle size analyzer.
  • Whether or not a microcapsule (micelle;) is contained in the pharmaceutical composition is measured by a particle size analyzer. If the pharmaceutical composition is analyzed by a particle size analyzer, the measured particle size is less than 250 nm, and the medical group is observed by naked eyes.
  • the solution in the product is clear and transparent, and when the solution is observed by using a laser to irradiate the solution in the pharmaceutical composition, it means that the medical composition has micelles.
  • the prepared pharmaceutical composition is the pharmaceutical composition of the present invention which can be used for reducing body weight and body fat.
  • the prepared pharmaceutical composition is a preferred pharmaceutical composition of the present invention.
  • the particle size distribution (purchased from Malvern) was used to determine the distribution of particle size and polydispersity index (PDI). If the polydispersity index is less than 0.4, it represents the stability of the pharmaceutical composition. That is, the micelles in the pharmaceutical composition can exist stably.
  • the pharmaceutical composition of the present invention has a storage condition of 2 to 8 ° C.
  • the inventors placed the pharmaceutical composition in a relatively high temperature and high humidity environment (temperature 25 ° C ⁇ 2 ° C, relative humidity RH 60% ⁇ 5%) for accelerated stability test, observed How long the cells in the pharmaceutical composition can be stably stored at a relatively high temperature, and how long the medical composition can be stored at 2 to 8 ° C in accordance with the accelerated stability formula, as explained below.
  • the pharmaceutical composition can be stored for n months at 25 ° C, the pharmaceutical composition can be stored at 5 ° C for a period of time of 2 ((25 - 5) / 1Q) times n months. That is, the pharmaceutical composition can be stored at a temperature of 5 ° C for a length of 22 times, that is, 4 times.
  • the pharmaceutical composition is maintained at least in the form of no precipitate generation. Up to 24 hours.
  • the pharmaceutical composition is maintained at a state where no precipitate is generated at least 6 months.
  • the pharmaceutical composition is maintained in a state free of precipitates for at least 24 months at a temperature of 2 to 8 °C.
  • Experiment 5 Maximum drug loading of drug-containing micelles formed by various nonionic surfactants
  • the experiment was divided into 4 groups, namely ELP group, HS-15 group, RH40 group, and Tween 80 group.
  • composition 8 g (Example of the third weight)
  • the physiological saline solution for injection was uniformly stirred to obtain a composition to be detected.
  • the curcumin concentration in the composition to be tested was 20 mg/g, and the concentration of the nonionic surfactant was 18%.
  • the components to be tested in the ELP group, the HS-15 group, the RH40 group, and the Tween 80 group were allowed to stand for at least 20 minutes to observe whether stratification occurred. If delamination occurs, the concentration of curcumin is too high to rupture the micelles in the composition to be tested, that is, the pharmaceutical of the present invention having a curcumin concentration of 20 mg/g cannot be prepared by using the nonionic surfactant.
  • Composition Composition.
  • the experimental results showed that the components to be tested in the HS-15 group and the RH40 group were stratified, and only the ELP group and the Tween 80 group had no stratification. It can be seen that the drug-containing micelles formed by HS-15 and RH40 have a maximum drug loading of curcumin per gram of pharmaceutical composition less than 20 mg o ELP and Tween 80 formed drug-containing micelles per gram of medicine The maximum drug loading of curcumin in the composition is greater than or equal to 20 mg.
  • Tween 80 is toxic, the national pharmacopoeia (; pharmacopoeia) limits the injection concentration of Tween 80 to less than 0.4%, so as to avoid adverse reactions or toxicity, so the drug-containing micelles formed by Tween 80 are in each gram of pharmaceutical composition.
  • the inventors conducted subsequent experiments and found that the maximum drug loading of ELP is greater than or equal to 167 mg of curcumin per gram of pharmaceutical composition.
  • ELP is an optimal excipient for preparing the pharmaceutical composition of the present invention.
  • the drug-containing microspheres formed by ELP can have a maximum drug loading of curcumin per gram of pharmaceutical composition up to 167 mg.
  • the other drug-containing microvesicles formed by nonionic surfactants are curcumin per gram of pharmaceutical composition.
  • the maximum drug loading is less than 20 mg/g (see Table 1;).
  • the inventors further utilized the non-ionics.
  • Sexual surface The agent was used to prepare a pharmaceutical composition of the present invention having a curcumin concentration of 10 mg/g.
  • the results showed that ELP, HS-15, RH40, and Tween 80 all prepared the pharmaceutical composition of the present invention having a curcumin concentration of 10 mg/g, and the curcumin concentration of 10 mg/g of the pharmaceutical composition of the present invention.
  • the prepared pharmaceutical composition has a PDI of more than 0.4, which is inconsistent with the stability of the micelle in the pharmaceutical composition. definition. From this, it is known that among the nonionic surfactants selected in this experiment, HS-15 has the lowest drug loading limit (see Table 1). Table 1 Maximum drug loading of drug-containing micelles formed by various nonionic surfactants
  • compositions of the present invention were prepared by using a ratio change of curcumin and polyoxyethylene 35 castor oil (ELP), and stability analysis was carried out to know curcumin and polyoxyethylene 35 castor oil (ELP).
  • ELP polyoxyethylene 35 castor oil
  • the experiment was divided into 9 groups, namely groups 1 to 9.
  • the preparation method of the pharmaceutical composition of each group was substantially the same as the experimental procedure of experiment 5, only the weight of curcumin (the first weight in step (a'); The weight of the ELP (the second weight in the step (b');), the weight of the physiological saline for injection (the third weight in the step (c');) is different.
  • the principle of addition of curcumin weight first weight;
  • weight of ELP second weight;
  • weight of physiological saline for injection third weight
  • Table 2 Sample Preparation Table for Formulating Pharmaceutical Compositions Using ELP
  • Curcumin and ELP ratio Curcumin final group in pharmaceutical composition are Curcumin and ELP ratio Curcumin final group in pharmaceutical composition
  • the ratio of curcumin to ELP in the 1st to 9th groups is one to four (1: 4), one to five (1: 5), one to eight (1: 8), One to ten (1:10), one to twenty (1:20), one to forty (1:40), one to one hundred (1:100), and one to one hundred and fifty (1:150) One to five hundred (1:500), and the final concentration of curcumin in the pharmaceutical composition prepared in groups 1 to 9 is 200 mg/g, 167 mg/g, lll mg/g, 91 mg/ g, 47.62 mg/g, 7.5 mg/g, 3 mg/g, 2 mg/g, 0.5 mg/g.
  • the weight ratio of the curcumin in the step (a') to the ELP in the step (b') (the ratio of the first weight to the second weight;
  • the order is one to four, one to five, one to eight, one to ten, one to twenty, one to forty, one to one hundred, one to one hundred five, and one to five hundred, and in the step (c ')
  • the final concentrations of curcumin are 200 mg/g, 167 mg/g, lll mg/g, 91 mg/g, 47.62 mg/g, 7.5 mg. /g, 3 mg/g, 2 mg/g, and 0.5 mg/g of pharmaceutical composition.
  • the final concentration of the drug is expressed in mg/g, it represents that each gram of the pharmaceutical composition is contained Some milligrams of curcumin.
  • the particle size analyzer was used to determine whether or not the micelle was contained in the medicinal composition, and the particle size of the micelle was measured.
  • the particle size distribution and the polydispersity index (PDI) were measured using a particle size analyzer to evaluate the stability of the pharmaceutical composition.
  • the curcumin content in the micelles was analyzed by high performance liquid chromatography (HPLC; for example, HPLC-UV) and defined as "initial drug content”.
  • the accelerated stability test was used to observe whether the medicinal composition was stratified under high temperature storage conditions (25 ⁇ 2 °C) for 3 months, and high performance liquid chromatography (HPLC); for example, HPLC-UV
  • HPLC high performance liquid chromatography
  • the analysis of the drug content in the micelles is defined as "the drug content after the accelerated experiment”. Divide “drug content after accelerated experiment” by “starting drug content” to get “percentage of drug content”. If the percentage of the drug content is greater than or equal to 95%, it represents an excellent stability of the pharmaceutical composition.
  • Table 3 for the stability analysis results of the stable pharmaceutical composition.
  • Table 3 shows that the pharmaceutical compositions of Groups 2 to 9 all have micelles. Therefore, the pharmaceutical compositions prepared by the ratio of curcumin to ELP of 1:5 to 1:500 are all useful for reducing body weight and Medicinal composition of visceral fat.
  • the ratio of curcumin to ELP should be less than one-fifth (1/5). That is, to prepare a medical composition having a better stability, the weight of the ELP should be more than 5 units by weight based on the weight of the curcumin.
  • the weight of the curcumin is 1 weight unit, and the weight of the ELP is 8 500 weight units.
  • the weight of the curcumin is 1 weight unit, and the weight of the ELP is 20 150 weight units.
  • the pharmaceutical composition of Groups 5-8 was stored at 25 °C for 3 months, and the percentage of curcumin drug content of each sample was greater than 95%, and compared with the initial drug content. Significant downward trend. From the results, it is understood that the pharmaceutical composition has good stability, and the pharmaceutical compositions can be stored for at least 24 months under refrigeration at 2 to 8 ° C according to an accelerated experimental formula.
  • the inventors believe that the concentration of the drug-containing micelles may affect the stability, weight-reducing efficacy, and safety of the pharmaceutical composition of the present invention. Therefore, in this experiment, a series of pharmaceutical compositions having different concentrations of drug-containing micelles were prepared by the same preparation method, and the stability, weight-reducing efficacy, and safety of the pharmaceutical compositions were determined (whether the application site would An ulcer occurs;).
  • the pharmaceutical composition of this experiment is divided into 12 tubes, namely tubes 1 to 12.
  • the first tube pharmaceutical composition is prepared by mixing 18 mg (example of the first weight) of curcumin with 80 140 mL of Dichloromethane and stirring at 150 500 rpm until the curcumin is completely completed at room temperature. Dissolved. Add 90 mg (example of the second weight) of polyoxyethylene 35 castor oil 0111 110 ELP, abbreviated as ELP;), stir evenly at 100-300 rpm to volatilize methylene chloride.
  • the physiological saline solution for injection is slowly added to make a final volume of 180 mL to form a plurality of drug-containing micelles, and the first tube pharmaceutical composition of the experiment can be obtained.
  • the pharmaceutical composition just prepared in this way does not cause the precipitation of curcumin, and the proportion of the pharmaceutical composition is about 1
  • the preparation method of the second to the 12th tube medical composition is substantially the same as the method of preparing the first tube medical composition, and only the weight of the curcumin (the first weight) and the weight of the ELP (the second weight) are different, but the curcumin and the poly
  • the weight ratio of oxyethylene 35 castor oil is 1:5.
  • Table 4 Sample preparation table for preparing pharmaceutical composition using ELP
  • Ginger in a pharmaceutical composition, a ginger coated in a drug-containing cell, and another IJ
  • a particle size analyzer was used to determine whether or not a micelle was contained in the pharmaceutical composition, and the particle size of the micelle was measured.
  • Particle size distribution and polydispersity index were determined using a particle size analyzer
  • PDI polydispersity index
  • the accelerated stability test was used to observe whether the medicinal composition was stratified under high temperature storage conditions (25 ⁇ 2 °C) for 3 months, and high performance liquid chromatography (HPLC); for example, HPLC-UV
  • HPLC high performance liquid chromatography
  • the analysis of the drug content in the micelles is defined as "the drug content after the accelerated experiment”. Divide “drug content after accelerated experiment” by “starting drug content” to get “percentage of drug content”. If the percentage of the drug content is greater than or equal to 95%, it represents an excellent stability of the pharmaceutical composition.
  • the measured particle size was less than 250 nm, and the PDI value was less than 0.4.
  • the solution in the pharmaceutical composition was visually observed to be clear and transparent, and was not separated after standing.
  • the layer is free of precipitates, and the light path can be observed after laser irradiation of the solution in the pharmaceutical composition, and the precipitation can be maintained at a temperature of 25 ° C ⁇ 2 ° C and a relative humidity of RH 60% ⁇ 5%.
  • the status is at least 24 hours. From this, it is understood that the pharmaceutical composition has stability when the total concentration of curcumin contained in the drug-containing micelles is in the range of 0.1 167 mg/g.
  • the PDI value of the 12th tube pharmaceutical composition of the experiment was greater than 0.4. From this, it was found that the pharmaceutical composition was not stable when the total concentration of curcumin coated in the drug-containing micelles was 175 mg/g.
  • Rats Forty-two rats were weighed to approximately 175 200 g a week and fed with high fat diet, and the 52 rats were induced to be obese animal models. Rats were divided into 13 groups, namely, control group, group 1, group 2, group 3, group 4, group 5, group 6, group 7, group 8, group 9, number 10 Groups, Group 11, and Group 12, 4 rats in each group, showed no statistical difference in body weight of each group of rats. Then, subcutaneous injection was performed in the following manner.
  • Groups 1 ⁇ 12 The first to 12th tube medicinal compositions of Experiment 7-1 were administered to the rats of Groups 1 to 12 by subcutaneous injection, and the injection site was the back of the rat's back, above the shoulder and cheekbone, Or under the cheekbones.
  • Control group The physiological saline solution for injection was administered to the control group by subcutaneous injection, and the injection site was large. The back of the mouse, the top of the shoulder and cheekbones, or the lower cheekbones.
  • the high-fat diet was continuously administered during the test, and the test was carried out for 20 days.
  • the rats were sacrificed with carbon dioxide on the 21st day.
  • the ulceration of the site where the medicinal composition was injected was observed, and the "relative total weight gain” and "relative visceral fat weight” of each group of rats were calculated.
  • the curcumin-green tea extract compound medicine composition of the experiment is divided into 12 tubes, namely, curcumin tube, green tea extract tube, Dijon ⁇ 4' tube, 6' ⁇ 7' tube, 9' tube, and The first ⁇ 13' tube, the arrangement method of each tube is almost the same as that of the experiment one, only the ratio of curcumin to green tea extract is different, and the concentration of polyoxyethylene 35 castor oil is 15%.
  • the ratio of curcumin to green tea extract is shown in Table 6.
  • Curcumin - Green tea extract compound pharmaceutical composition the weight ratio of curcumin to green tea extract is the total concentration of curcumin and green tea extract of curcumin and green tea extract
  • 13' 3:2 5 Experiments were performed using 6-week old SD strain male rats (male Sprague-Dawley rat). 52 rats were fed with normal diet. The weight of the 3 angels was about 175 200 g. After feeding 21 angels with high fat diet and induced into obese animal model and increasing the body weight to 400-450 g, the rats were randomly divided into 13 groups. The high-fat control group, the curcumin group, the green tea extract group, the OIG1 OIG4 group, the OIG6 OIG7 group, the OIG9 group, and the OIG1 l ⁇ OIG13 group, each group of 4 rats, the weight of each group of rats There are no statistical differences. Then, the drug is administered in the following manner.
  • High-fat control group The rats were administered with physiological saline by subcutaneous injection, and the injection site was the back of the ear, the upper part of the shoulder and cheekbone, or the lower part of the shoulder and cheekbones.
  • One injection was given on the first, third, fifth, seventh, ninth, and eleventh days of the trial, and a total of six injections were given, each injection of 4 mL (4 mL/kg) per kilogram of body weight.
  • the pharmaceutical composition was administered to the curcumin group, the green tea extract group, the OIG1 OIG4 group, the OIG6 OIG7 group, the OIG9 group, and the OIG1 l ⁇ OIG13 group, and the injection site was the back of the rat, shoulder.
  • each dose was administered on the first, third, fifth, seventh, ninth, and eleventh days of the trial, and the total dose was 6 times.
  • the high-fat diet was continuously administered during the test, and the test was carried out for 20 days.
  • the rats were sacrificed with carbon dioxide on the 21st day.
  • the "relative total weight gain” and "relative visceral fat weight” of each group of rats were calculated.
  • the results in Fig. 2A show that the relative total weight gain of the rats in the high-fat control group was 100.0 ⁇ 18.5%, and the relative total weight gain in the curcumin group was 92.1 ⁇ 11.3%, and the relative total weight gain in the green tea extract group.
  • the relative total weight gain of the rats in the OIG1 OIG4 group, the OIG6 OIG7 group, the OIG9 group, and the OIG1 l ⁇ OIG13 group was 85.1 ⁇ 13.6%, 68.4 ⁇ 3.1%, and 61.0 ⁇ 5.6. %, 62.3 ⁇ 3.3%, 59.3 ⁇ 5.4%, 64.4 ⁇ 4.8%, 63.5 ⁇ 8.1%, 67.7 ⁇ 5.3%, 80.8 ⁇ 7.9%, and 49.4 ⁇ 14.3%.
  • the relative total weight gain of the curcumin group and the green tea extract group was not significantly decreased (p>0.05), indicating that if only curcumin or green tea extract was provided, the conditions in this experiment The weight of the rats could not be significantly reduced (p>0.05).
  • the relative total weight gain of the OIG1 OIG4 group, the OIG6 OIG7 group, the OIG9 group, and the OIG1 l ⁇ OIG13 group was significantly lower (p ⁇ 0.05), showing When the ratio of curcumin to green tea extract is in the range of 50:1 to 1:20, the body weight of the rats can be significantly reduced.
  • the relative total weight gain of the OIG2 OIG4 group, the OIG6 OIG7 group, the OIG9 group, the OIG1 1 group, and the OIG13 group was significantly lower than that of the curcumin group or the green tea extract group (p ⁇ 0.05), showing that the ratio of curcumin to green tea extract has a synergistic effect (sy nerg y) in the range of 30:1 - 1:10 .
  • the ratio of curcumin to green tea extract has a better synergy in the range of 10:1 - 1:4.
  • Fig. 2B show that the relative visceral fat weight of the high fat control group was 100.0 ⁇ 33.4%, the relative visceral fat weight of the curcumin group was 89.7 ⁇ 19.9%, and the relative visceral fat weight of the green tea extract group.
  • the relative visceral fat weight of the rats in the OIG1 ⁇ OIG4 group, the OIG6 ⁇ OIG7 group, the OIG9 group, and the OIG1 l ⁇ OIG13 group was 84.3 ⁇ 26.1%, 61.9 ⁇ 14.2%, 63.5, which was 93.7 ⁇ 15.2%.
  • the relative visceral fat weight of the OIG2 OIG4 group, the OIG6 OIG7 group, the OIG9 group, and the OIG11 group and the OIG13 group were significantly lower ( ⁇ 0.05). It shows that the ratio of curcumin to green tea extract can significantly reduce visceral fat in rats in the range of 30:1 - 1:10.
  • the preparation method of the curcumin-green tea extract compound medicine composition of the experiment is the same as the procedure of the experiment No. 13th tube, that is, the ratio of curcumin to green tea extract is 3:2 and the polyoxyethylene 35 castor oil is used. The concentration is 15%.
  • the normal control group and the high-fat control group the physiological saline solution for injection was administered to the normal control group and the high-fat control group by subcutaneous injection, and the injection site was the back of the rat's back, the upper cheekbone, or the shoulder and cheekbones.
  • One injection was given on the first, third, fifth, seventh, ninth, and eleventh days of the trial, and a total of six injections were given, each injection of 8 mL (8 mL/kg) per kilogram of body weight.
  • the curcumin-green tea extract compound pharmaceutical composition of the experiment was administered to the rats by subcutaneous injection, and the injection site was the back of the rat's back, the upper part of the shoulder and cheekbone, or the lower side of the shoulder and cheekbones. 1, 3, 5, 7, 9, 1 1 each dose of medicine, a total of 6 times, each dose is 2 mL (2 mL / kg) per kilogram of body weight, so that each dose is per kilogram Body weight 6 mg curcumin and 4 mg green tea extract.
  • Middle dose group The mode and frequency of administration were the same as those of the low dose group, and only the dose was different. Each dose was injected 4 mL (4 mL/kg) per kilogram of body weight, so that each dose was administered with 12 mg of curcumin and 8 mg of green tea extract per kilogram of body weight.
  • High-dose group The mode and frequency of administration were the same as those in the low-dose group, and only the dose was different. Each dose was injected 8 mL (8 mL/kg) per kilogram of body weight, so that each dose was administered with 24 mg of curcumin and 16 mg of green tea extract per kilogram of body weight.
  • the high-fat diet was continuously administered during the test, and the test was carried out for 20 days.
  • the rats were sacrificed with carbon dioxide on the 21st day.
  • the "relative total weight gain” and "relative visceral fat weight” of each group of rats were calculated.
  • Fig. 3B show that the relative visceral fat weight of the normal control group was 37.0 ⁇ 5.2%, and the relative visceral fat weight of the high fat control group was 100.0 ⁇ 32.2%, the low dose group, the middle dose group, and the high dose.
  • the relative visceral fat weight of the rats in the group was 66.8 ⁇ 18.0%, 68.0 ⁇ 21.0%, and 55.2 ⁇ 26.1%, respectively.
  • the relative visceral fat weight of the low-dose group, the middle-dose group, and the high-dose group was significantly lower (p ⁇ 0.05), indicating different doses of curcumin-green tea extract compound medicine
  • the composition can significantly reduce the amount of visceral fat in rats, and the effect is best in the high dose group.
  • the curcumin-green tea extract compound pharmaceutical composition has a significant weight loss and a reduction in visceral fat at a dose of 10 mg/kg, and the higher the dose, the more remarkable the effect.
  • the dose for humans when administered at a dose of 10 mg/kg to 40 mg/kg, is 0.1 80 mg/kg.
  • the dosage administered to humans is 10 40 mg/kg.
  • the dose applied to humans is 0.02 to 20 mg per square centimeter.
  • the dose applied to humans is 0.04 to 16 mg per square centimeter.
  • the dose applied to humans is 0.2 to 12 mg per square centimeter.
  • the dose applied to humans is 0.4 to 8 mg per square centimeter.
  • the dose applied to humans is 0.01 to 40 mg per kg.
  • the dose applied to humans is 0.4 to 40 mg per kg.
  • the dose applied to humans is 0.8 to 20 milligrams per kilogram.
  • the preparation method of the curcumin-green tea extract compound medicine composition of the experiment is the same as the procedure of the experiment No. 13th tube, that is, the ratio of curcumin to green tea extract is 3:2 and the polyoxyethylene 35 castor oil is used. The concentration is 15%.
  • the normal control group and the high-fat control group the physiological saline solution for injection was administered to the normal control group and the high-fat control group by subcutaneous injection, and the injection site was the back of the rat's back, the upper cheekbone, or the shoulder and cheekbones.
  • the injection site was the back of the rat's back, the upper cheekbone, or the shoulder and cheekbones.
  • each injection was performed 8 times, and each injection volume was 4 mL (4 mL/kg) per kilogram of body weight.
  • the curcumin-green tea extract compound pharmaceutical composition of the experiment was applied by subcutaneous injection. To the rats, the injection site was behind the back of the rat, above the shoulder and cheekbone, or under the shoulder and cheekbones. The drug was administered once on the first, third, fifth, and seventh days of the test, and the drug was administered four times. 4 mL (4 mL/kg) was injected per kilogram of body weight, so that each dose was administered with 12 mg of curcumin and 8 mg of green tea extract per kilogram of body weight.
  • Medium frequency group The dosage mode and the dose of each dose are the same as those of the low frequency group, and only the frequency of administration is different. On the 1st, 3rd, 5th, 7th, 9th and 11th day of the experiment, the drug was administered once, and the drug was administered 6 times.
  • High frequency group The dosage mode and the dose of each dose are the same as those of the low frequency group, and only the frequency of administration is different. On the 1st, 3rd, 5th, 7th, 9th, 11th, 13th and 15th day of the experiment, the drug was administered once, and the drug was administered 8 times.
  • the high-fat diet was continuously administered during the test, and the test was carried out for 20 days.
  • the rats were sacrificed with carbon dioxide on the 21st day.
  • the "relative total weight gain” and "relative visceral fat weight” of each group of rats were calculated.
  • the application frequency of the curcumin-green tea extract compound pharmaceutical composition has a significant weight loss and a reduction in visceral fat at four times, and the higher the application frequency, the more remarkable the effect.
  • the frequency of administration for humans is 1 to 16 times.
  • the frequency of administration to humans is from 1 to 6 times.
  • the frequency of administration to humans is 1 to 12 times per 1 to 90 days.
  • the frequency of application to humans is 1 to 6 times per 1 to 90 days.
  • the frequency of application to humans is 3 to 60 times every 1 to 90 days; preferably, the frequency of application to humans is 6 to 42 times every 1 to 60 days.
  • curcumin-resveratrol compound pharmaceutical composition was applied to rats fed normal diet and high fat diet to evaluate the effects of curcumin-resveratrol compound pharmaceutical composition on different ethnic groups of rats. .
  • Method for arranging curcumin-resveratrol compound medicinal composition Mix 0.8 g of curcumin, 0.2 g of resveratrol, and 150 to 200 mL of dichloromethane, and stir at room temperature at 150-500 rpm until turmeric The hormone is completely dissolved. Add 30 g of polyoxyethylene 35 castor oil (Kolliphor ELP, referred to as ELP;), stir at 100-300 rpm Mix well and let the methylene chloride volatize. After the dichloromethane is completely evaporated, the physiological saline solution for injection is slowly added to make the final volume up to 200 mL, and the mixture is stirred uniformly to obtain a curcumin-resveratrol compound solution containing ELP.
  • ELP polyoxyethylene 35 castor oil
  • the curcumin-resveratrol compound pharmaceutical composition containing ELP contains the first drug-containing cell and the second drug-containing cell, the curcumin concentration is 4 mg/mL, and the resveratrol concentration is 1 mg/
  • the concentration of mL, polyoxyethylene castor oil (ELP) is about 15% (% by weight;), and the weight ratio of curcumin, resveratrol, and polyoxyethylene castor oil is 4:1:200.
  • Rats were fed with normal diet for a week to achieve a body weight of approximately 175-200 g.
  • the rats were divided into 4 groups, namely normal feed control group, high-fat diet control group, and normal feed-resveratrol compound pharmaceutical composition. Group, and high fat feed-resveratrol compound pharmaceutical composition group. Then, the rats in the normal diet control group and the normal feed-resveratrol compound pharmaceutical composition group were fed with normal feed for 14 days, and the high fat diet control group and the high fat diet-white peony were fed with the high fat diet.
  • Rats in the ruthenium compound pharmaceutical composition group were induced for 14 days in the high fat diet control group and the high fat diet-resveratrol compound pharmaceutical composition group to induce an obese animal model and increase the body weight to 400. 450 go Then, subcutaneous injection is performed in the following manner.
  • Rats were administered with physiological saline by subcutaneous injection. The injection site was behind the back of the rat, above the shoulder and cheekbones, or under the shoulder and cheekbones. On the 3rd, 5th, 7th, 9th, and 11th, each injection was given 6 times, and each injection was 4 mL (4 mL/kg) per kilogram of body weight.
  • Normal feed-resveratrol compound pharmaceutical composition group and high-fat diet-resveratrol compound medicine composition group The curcumin-resveratrol compound medicine composition is administered to rats by subcutaneous injection, the injection site For the back of the ear, above the cheekbone, or under the cheekbone of the rat, the drug was administered once on the first, third, fifth, seventh, ninth, and eleventh days of the test, and the drug was administered six times, each time for each dose. Inject 4 mL (4 mL/kg) into kilograms of body weight, so that each dose is administered with 16 mg of curcumin and 4 mg of resveratrol per kg of body weight (curcumin and resveratrol administered per kg of body weight).
  • 5 X 4 16 mg
  • the normal feed was continuously supplied to the normal feed control group and the normal feed-resveratrol compound pharmaceutical composition group, and the high fat diet was supplied to the high fat diet control group and the high fat diet-resveratrol compound medicine.
  • Composition group of rats The test was carried out for 20 days, and the rats were sacrificed with carbon dioxide on the 21st day.
  • the pharmaceutical composition of the present invention has reduced body weight and reduced internal organs only for a specific ethnic group.
  • the effect of fat that is, the ability to reduce body weight and reduce visceral fat only for overweight or obese people.
  • Experiment 12 Effects of different proportions of curcumin-resveratrol combination on body weight and visceral fat weight in rats
  • the curcumin-resveratrol compound medicine composition of this experiment is divided into 12 tubes, namely, curcumin tube, resveratrol tube, and first " ⁇ 10" tube, and the configuration method of each tube and experiment 11
  • the experimental procedure was approximately the same, only the ratio of curcumin to resveratrol was different, and the concentration of polyoxyethylene 35 castor oil was 15%.
  • the ratio of curcumin to resveratrol is shown in Table 7.
  • Table 7 Weight ratio and total concentration of curcumin and resveratrol in curcumin-resveratrol compound pharmaceutical composition
  • Curcumin and resveratrol with curcumin and resveratrol with curcumin and resveratrol
  • High-fat control group The normal saline injection was administered to the high-fat control rats by subcutaneous injection.
  • the injection site was behind the back of the rat, above the shoulder and cheekbone, or below the shoulder and cheekbones.
  • the curcumin group, the resveratrol group, and the OIR1 OIR10 group were administered to the curcumin group by subcutaneous injection.
  • the injection site was behind the back of the rat, above the shoulder and cheekbone, or below the shoulder and cheekbones, in the first, third, fifth, seventh, ninth, and eleventh trials.
  • Each dose was administered once a day, and a total of 6 doses were administered.
  • Each dose was injected 4 mL (4 mL/kg) per kilogram of body weight, so that each dose was administered with 20 mg of drug per kilogram of body weight (per kilogram of body weight per dose).
  • the high-fat diet was continuously administered during the test, and the test was carried out for 20 days.
  • the rats were sacrificed with carbon dioxide on the 21st day.
  • the "relative total weight gain” and "relative visceral fat weight” of each group of rats were calculated.
  • the relative total weight gain of the curcumin group and the resveratrol group did not significantly decrease (p>0.05), indicating that if only curcumin or resveratrol is provided, Rat body weight could not be significantly reduced under experimental conditions.
  • the relative total weight gain of the OIR2 OIR9 group was significantly lower (p ⁇ 0.05), indicating that the ratio of curcumin to resveratrol was in the range of 20:1 ⁇ 1:20. , can significantly reduce the weight of rats.
  • the relative total weight gain of the OIR2 OIR9 group was significantly lower (p ⁇ 0.05), indicating that the ratio of curcumin to resveratrol was 20:1 ⁇ Synergism in the 1:20 range.
  • the ratio of curcumin to resveratrol is 4:1 with better synergy.
  • Fig. 5B show that the relative visceral fat weight of the high-fat control group was 100.0 ⁇ 24.2%, and the relative visceral fat weight of the curcumin group was 122.2 ⁇ 25.2%.
  • the weight of the relative visceral fat in the OIR1 ⁇ OIR10 group was 105.8 ⁇ 15.4%, 83.6 ⁇ 17.1 0 / 0 , 79.4 ⁇ 14 0 / 0 , 76.9 ⁇ 1 1 0 / 0 , 60.5.
  • the preparation method of the curcumin-resveratrol compound medicine composition of the experiment is the same as the step of the experiment No. 12th 5th tube, that is, the ratio of curcumin to resveratrol is 4:1 and polyoxyethylene 35
  • the concentration of castor oil is 15%.
  • the normal control group and the high-fat control group the physiological saline solution for injection was administered to the normal control group and the high-fat control group by subcutaneous injection, and the injection site was the back of the rat's back, the upper cheekbone, or the shoulder and cheekbones.
  • each injection was given 6 times, and each injection volume was 8 mL (8 mL/kg) per kg body weight.
  • the curcumin-resveratrol compound pharmaceutical composition of this experiment was administered to rats by subcutaneous injection, and the injection site was the back of the rat's back, the upper part of the shoulder and cheekbone, or the lower part of the shoulder and cheekbones.
  • each dose was administered once, and the total dose was 6 times.
  • Each dose was 2 mL (2 mL/kg) per kilogram of body weight, so that each dose was administered per dose. 8 mg of curcumin and 2 mg of resveratrol were administered at a body weight of kg.
  • Middle dose group The mode and frequency of administration were the same as those of the low dose group, and only the dose was different. Each dose was injected 4 mL (4 mL/kg) per kilogram of body weight, so that each dose was administered with 16 mg of curcumin and 4 mg of resveratrol per kilogram of body weight.
  • High-dose group The mode and frequency of administration were the same as those in the low-dose group, and only the dose was different. Each dose was injected 8 mL (8 mL/kg) per kilogram of body weight, so that each dose was administered with 32 mg of curcumin and 8 mg of resveratrol per kilogram of body weight.
  • the high-fat diet was continuously administered during the test, and the test was carried out for 20 days.
  • the rats were sacrificed with carbon dioxide on the 21st day.
  • the "relative total weight gain” and "relative visceral fat weight” of each group of rats were calculated.
  • Fig. 6A show that the relative total weight gain of the rats in the normal control group was 57.4 ⁇ 8.6%, and the relative total weight gain in the high-fat control group was 100.0 ⁇ 1 1.2%.
  • the relative total weight gain of the rats in the group was 76.2 ⁇ 6.7%, 62.4 ⁇ 9.1%, and 48.7 ⁇ 10.1%.
  • low dose The relative total weight gain of the rats in the middle, middle dose, and high dose groups was significantly lower (p ⁇ 0.05), indicating that different doses of curcumin-resveratrol compound pharmaceutical composition can significantly reduce the body weight of rats.
  • the weight loss effect is the best.
  • Fig. 6B show that the relative visceral fat weight of the normal control group was 37.0 ⁇ 5.2%, and the relative visceral fat weight of the high fat control group was 100.0 ⁇ 32.2%, the low dose group, the middle dose group, and the high dose.
  • the relative visceral fat weight of the rats in the group was 68.1 ⁇ 15.2%, 56.0 ⁇ 15.7%, and 46.9 ⁇ 7.2%.
  • the relative visceral fat weight of the low-dose group, the middle-dose group, and the high-dose group was significantly lower (p ⁇ 0.05), indicating different doses of curcumin-resveratrol combination.
  • the pharmaceutical composition can effectively reduce the weight of visceral fat in rats, and the high dose group is the best.
  • curcumin-resveratrol compound pharmaceutical composition has a significant weight loss and a reduction in visceral fat at a dose of 10 mg/kg, and the higher the dose, the more remarkable the effect.
  • the dose for humans when administered at a dose of 10 mg/kg to 40 mg/kg, is 0.1 80 mg/kg.
  • the dosage administered to humans is 10 40 mg/kg.
  • the dose applied to humans is 0.02 to 20 mg per square centimeter.
  • the dose applied to humans is 0.04 to 16 mg per square centimeter.
  • the dose applied to humans is 0.2 to 12 mg per square centimeter.
  • the dose applied to humans is 0.4 to 8 mg per square centimeter.
  • the dose applied to humans is 0.01 to 40 mg per kg.
  • the dose applied to humans is 0.4 to 40 mg per kg.
  • the dose applied to humans is 0.8 to 20 milligrams per kilogram.
  • the preparation method of the curcumin-resveratrol compound medicine composition of the experiment is the same as the step of the experiment No. 12th 5th tube, that is, the ratio of curcumin to resveratrol is 4:1 and polyoxyethylene 35
  • the concentration of castor oil is 15%.
  • mice Twenty rats 3 angels weighed approximately 175-200 g, and the rats were divided into 5 groups, namely normal control group, high-fat control group, low-frequency group, medium-frequency group, and high-frequency group. Then, the rats in the normal control group were continued to feed the normal control for 21 days, and the high-fat control group, the low-frequency group, the medium-frequency group, and the high-frequency group were fed with the high-fat diet for 21 days to make the high fat. Rats in the control, low frequency, medium frequency, and high frequency groups were induced to an obese animal model and gained weight to 400 450 g. Then, subcutaneous injection was performed in the following manner.
  • the normal control group and the high-fat control group the physiological saline solution for injection was administered to the normal control group and the high-fat control group by subcutaneous injection, and the injection site was the back of the rat's back, the upper cheekbone, or the shoulder and cheekbones.
  • the injection site was the back of the rat's back, the upper cheekbone, or the shoulder and cheekbones.
  • the curcumin-resveratrol compound pharmaceutical composition of the experiment was administered to the rats by subcutaneous injection, and the injection site was the back of the ear, the upper part of the shoulder and cheekbone, or the lower part of the shoulder and cheekbones.
  • the drug was administered once, and the drug was administered 4 times.
  • Each dose was 4 mL (4 mL/kg) per kilogram of body weight, so that each dose was administered per kilogram of body weight.
  • Medium frequency group The dosage mode and the dose of each dose are the same as those of the low frequency group, and only the frequency of administration is different. On the 1st, 3rd, 5th, 7th, 9th and 11th day of the experiment, the drug was administered once, and the drug was administered 6 times.
  • High frequency group The dosage mode and the dose of each dose are the same as those of the low frequency group, and only the frequency of administration is different. On the 1st, 3rd, 5th, 7th, 9th, 11th, 13th and 15th day of the experiment, the drug was administered once, and the drug was administered 8 times.
  • the high-fat diet was continuously administered during the test, and the test was carried out for 20 days.
  • the rats were sacrificed with carbon dioxide on the 21st day.
  • the "relative total weight gain” and "relative visceral fat weight” of each group of rats were calculated.
  • Fig. 7B show that the relative visceral fat weight of the normal control group was 38.7 ⁇ 7.4%, and the relative visceral fat weight of the high fat control group was 100.0 ⁇ 16.2%, low frequency group, medium frequency group, and high frequency.
  • the relative visceral fat weight of the rats in the group was 72.2 ⁇ 13.7%, 66.8 ⁇ 4.5%, and 58.6 ⁇ 10.0%.
  • the relative visceral fat weight of the low-frequency group, the middle-frequency group, and the high-frequency group was significantly lower ( ⁇ 0.05), indicating that different administration frequencies can significantly reduce rat visceral fat.
  • the quantity which is the best in the high frequency group.
  • the application frequency of the curcumin-resveratrol compound pharmaceutical composition has a remarkable effect of reducing visceral fat at four times, and the effect of significant weight loss can be achieved at the application frequency of eight times.
  • the frequency of administration to rats is 4 to 8 times
  • the frequency of administration to humans is 1 to 16 times.
  • the frequency of administration to humans is from 1 to 6 times.
  • the frequency of administration to humans is 1 to 12 times per 1 to 90 days.
  • the frequency of application to humans is 1 to 6 times per 1 to 90 days.
  • the frequency of application to humans is 3 to 60 times every 1 to 90 days; preferably, the frequency of application to humans is 6 to 42 times every 1 to 60 days.
  • the curcumin single-medical composition, curcumin-resveratrol compound pharmaceutical composition, curcumin-green tea extract compound medicine composition, curcumin-other fat-soluble drug compound medicine provided by the present invention are known.
  • the composition, the curcumin-water-soluble drug compound pharmaceutical composition, and other pharmaceutical compositions provided by the present invention can reduce body weight and visceral fat mass.
  • curcumin single-medical composition provided by the present invention, Curcumin-resveratrol compound medicine composition, curcumin-green tea extract compound medicine composition, curcumin-other fat-soluble drug compound medicine composition, curcumin-water-soluble medicine compound medicine composition, and the present invention
  • Other pharmaceutical compositions provided for the preparation of subcutaneous implants, subcutaneous implants, implantable infusions, ointments, or patches, which can be implanted subcutaneously, implanted, ointment or paste A cloth or the like is applied to the individual to reduce the body weight or body fat of the individual.
  • the curcumin single-medical composition, curcumin-resveratrol compound pharmaceutical composition, curcumin-green tea extract compound medicine composition, curcumin-other fat-soluble drug compound medicine composition, And the curcumin-water-soluble drug compound pharmaceutical composition and the other pharmaceutical composition provided by the present invention can reduce the body weight or body fat of the individual by subcutaneous injection or subcutaneous fat injection.
  • the curcumin single-medical composition, curcumin-resveratrol compound pharmaceutical composition, curcumin-green tea extract compound medicine composition, curcumin-other fat-soluble drug compound medicine composition, and turmeric provided by the present invention
  • the pharmaceutically-soluble drug compound medicinal composition, and other pharmaceutical compositions provided by the present invention can be used for preparing a subcutaneous fat layer injection or a hypodermic injection for reducing body weight or body fat.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dermatology (AREA)
  • Birds (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dispersion Chemistry (AREA)
  • Medical Informatics (AREA)
  • Botany (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Mycology (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Child & Adolescent Psychology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Emergency Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

本发明提供一种用于减少体重的皮下注射剂，包含聚氧乙烯蓖麻油衍生物所形成的多个含药微胞、以及被包覆在所述含药微胞中的姜黄色素类物质。所述用于减少体重的皮下注射剂可减少过重或肥胖个体的体重及内脏脂肪，且具有剂量低、高稳定性、高度脂肪组织生物利用率、低副作用、以及缓释等优点。

Description

用于减少体重的皮下注射剂及其用途 技术领域
本发明是关于一种施用于过重或肥胖个体以减少该个体的体重的皮下注射剂， 特别 是关于一种包含多个含药微胞以及被包覆在含药微胞中的姜黄色素类物质的皮下注射 剂， 且该皮下注射剂用于减少体重。 背景技术
肥胖（Obesity)是指体脂肪累积过多而对健康造成负面影响的身体状态， 可能导致寿 命减短及各种健康问题。 根据世界卫生组织对肥胖的定义， 以身体质量指数 (Body mass index, BMI)大于 25定义为过重 (overweight；)， BMI大于 30定义为肥胖， 一些东亚国家采用 更严格的标准， 例如台湾卫生福利部于 2002年 4月公布台湾成人的 BMI^27 即为肥胖， 24≤BMI<27 则为过重。
统计资料指出 2014年全球体重过重与肥胖的人口已经超过 27亿人， 其中大约有 13% 人口为肥胖人口， 而这些肥胖的人罹患心血管疾病、 高血脂症、 糖尿病、 癌症等相关疾 病的机率也比一般人大幅增高。 世界卫生组织的研究报告也指出， 全球引起死亡风险的 疾病中， 过重和肥胖排名第 6。 研究资料显示， 2013年至少有超过 340万成人死于过重或 肥胖所引起的慢性病， 其中有 44%的糖尿病及 23%的缺血性心脏病医疗负担可归因于肥 胖。 而且， 肥胖者的年龄有逐渐下降的趋势， 依据世界卫生组织的资料显示， 2011 年全 世界约有 4000 多万 5 岁以下儿童过重。 美国约翰霍普金斯大学彭博公共卫生学院 (JohnsHopkins Bloomberg School of Public Health)在 2007年的报告指出， 预计 2015年全美 将有 75%成人体重过重， 其中 41%人口属于肥胖， 且随着发展中国家的兴起， 将使全球 肥胖人口快速扩增， 成为主要的流行病之一。 美国 CDC疾病管制局指出美国成人肥胖人 口超过 7200万人， 而在全球肥胖人口中亚太地区就占 40%， 中国成年人过重和肥胖比率 从 2002年的 25%大幅上升到 2010年的 38.5%， 预计在 2015年， 中国将会有 50%至 57% 的人口体重过重。
肥胖目前是全球都非常重视的健康问题， 研究指出导致肥胖的原因非常复杂， 有多 重因素牵涉其中。 越来越多的证据也显示肥胖不是自我控制就能改善的简单问题， 而是 涉及体内食欲调节与能量代谢的复杂症状， 也是一种体内代谢失衡的疾病。 肥胖不仅造 成死亡率提高及庞大医疗负担， 也影响了人类的生活品质。 虽然肥胖的病因并未完全被 确立， 但认为与遗传、 代谢、 生化、 文化与精神社会的因素有关。 研究显示人类有许多 死因与肥胖有关， 包括恶性肿瘤、 心血管疾病、 脑血管疾病、 糖尿病、 慢性下呼吸道疾 病、 慢性肝病及肝硬化、 高血压性疾病、 肾脏疾病等， 显示肥胖问题已成为全球皆极须 重视的问题。 近年来肥胖的盛行率愈来愈高， 而肥胖通常会伴随高血压、 高血糖、 胰岛 素阻抗、 及血脂异常等代谢异常现象而导致代谢症候群， 很容易演变成糖尿病、 心血管 疾病、 动脉粥状硬化、 脑血管疾病及癌症等疾病， 造成中风或心肌梗塞， 甚至死亡。
目前用于减重的合成药物的作用机制主要可分为两大类， 分别为抑制食欲及阻断肠 道对于食物中的脂肪的部分吸收二大类。 其中， 抑制食欲是过去及目前市售减肥药物的 主要机转， 这一类药物包含 Sibutramine (诺美婷）、 Lorcaserin、 Qsymia及 Contrave等药 物， 副作用严重且具有一定程度的心血管风险。 以之前下架的减肥药 Sibutramine (诺美婷) 为例， 其市场占有率曾高达 7 成， 却被证实会增加心血管疾病风险， 因此欧盟、 美国、 澳洲、 台湾等已在 2010年宣布将含 Sibutramine成分的减肥药下架。
通过阻断肠道对于食物中的脂肪的部分吸收的减肥药物则为 Orlistat, 它是一种具有 专一性及可逆性的肠胃道脂肪分解酶抑制剂， 通过抑制胰脏和肠道脂肪消化酶， 而减少 肠道对所摄食脂肪的吸收达 25至 30%。 由于 Orlistat的主要作用方式是阻断油脂吸收， 因 此在服药期间可能会出现油便、 排便次数增加、 胃胀气等胃肠道方面的副作用， 也会干 扰脂溶性维生素吸收， 国外亦有造成肝损伤， 胆结石等严重副作用的案例。
由此可见， 目前用于减肥的合成药物仍存在程度不一的心血管风险与安全性疑虑， 市场上仍需要一种安全性更高、 副作用低、 无心血管风险疑虑且同时可有效减轻体重与 体脂肪， 并能降低心血管危险的减肥药品。
Mohsen Meydani等人发表的文献" Dietary Polyphenols and Obesity"揭露了可透过口服 姜黄素 (Curcumin)的方式减少大鼠体重总增重。 然而， 该篇文献透过口服方式施用姜黄素 时的施用剂量高达 250〜 10000 mg/kg, 且减重效果非常有限。
因此， 市场上仍极欠缺一种能有效减少体重、 剂量低、 副作用低、 安全性佳的减重 医药组成物。 在消费者与医师皆有高度需求的情况下， 开发足以突破目前技术限制的减 重医药组成物将是迫切需要被探讨及解决的课题。
【非专利文献 1】
Mohsen Meydani et al,"Dietary Polyphenols and Obesity", Nutrients, 2010, 2:735-751. 发明内容
鉴于习知技术的缺陷， 本发明提供一种用于减少体重的医药组成物， 包含聚 氧乙烯蓖麻油衍生物所形成的多个含药微胞、 以及被包覆在所述含药微胞中的姜黄 色素类物质。所述用于减少体重的医药组成物可减少体重， 且具有低剂量、 高稳定 性、 低副作用、 以及缓释等优点。
本发明能促使施用后的全身脂肪细胞进行细胞凋亡反应 (apoptosis)，达到减少体 重的目的。 本发明能大幅改善习知技术剂量高及副作用高的问题， 且减少体重的效 果显著优于口服减肥药。 本发明适用于以皮下注射方式或皮下脂肪层注射方式施用 于过重或肥胖个体，而无须任何外科手术或仪器的介入或辅助。较佳者，施用于 BMI ^ 24的个体； 较佳者， 施用于 BMI>25的个体； 较佳者， 施用于 BMI ^ 27的个体； 较 佳者， 施用于 BMI>30的个体。
本发明中， 过重指的是成人的身体质量指数大于等于 24且小于 27: 肥胖指的是 身体质量指数大于等于 27。 较佳者， 过重指的是成人的身体质量指数大于 25 ; 肥脬 指的是身体质量指数大于 30。
本发明中， 姜黄萃取物指的是以任一种溶剂及任一种萃取方式所提取出的姜黄 成分混合物、 商业上可取得的姜黄萃取物、 任一种至少包含 75 % (重量百分比；)姜黄 素（curcumin)的混合物、 任一种至少包含 75% (重量百分比；)姜黄色素类物质 (curcuminoi d)的混合物、 或商业上可取得的姜黄素。
本发明中，白藜芦醇指的是自天然植物萃取所取得或商业上可取得的白藜芦醇。 较佳者， 白藜芦醇的纯度为 90%至 100% (重量百分比；)。
本发明中， 绿茶萃取物指的是以任一种溶剂及任一种萃取方式所提取出的绿茶 成分混合物或商业上可取得的绿茶萃取物， 较佳者， 指的是至少包含 45 % (重量百 分比;)表没食子儿茶素没食子酸酯 Cepigallocatechin gallate, EGCG)的混合物、 任一种 至少包含 90 % (重量百分比;)总儿茶素 (catechins)的混合物、或商业上可取得的表没食 子儿茶素没食子酸酯。
本发明中， 微胞 (micelle)指的是由聚氧乙烯蓖麻油衍生物所形成的一微形结构， 该聚氧乙烯蓖麻油衍生物具有一亲水端以及一亲脂端 (亲油端；)， 且该聚氧乙烯蓖麻 油衍生物以该亲水端向外， 亲脂端 (亲油端；)向内而形成该微形结构。 较佳者， 该微 形结构为球形、 类球形、 或其他微形结构的结构。
本发明中， 含药微胞指的是含姜黄色素类物质 (curcuminoid)的微胞， 较佳者， 含药微胞指的是含姜黄素 (curcumin)的微胞； 亦即， 含药微胞指的是包覆或包含姜黄 色素类物质的微胞， 较佳者， 含药微胞指的是包覆或包含姜黄素的微胞。
较佳者， 含药微胞均匀分布在医药组成物中。
本发明的医药组成物中， 包覆在含药微胞中的姜黄色素类物质的总浓度以 mg/g 表示时， 代表每克医药组成物所包含的所有的含药微胞中， 姜黄色素类物质的总毫 克数。
本发明的医药组成物中， 包覆在含药微胞中的姜黄色素类物质的总浓度的测量 方式可以是例如下列步骤：
以 0.2 μιη滤膜过滤医药组成物， 获得一滤液以及未被含药微胞包覆的姜黄色素 类物质沉淀物；
以 DMSO稀释该滤液后获得一样品溶液， 使该滤液中的含药微胞被 DMSO溶解， 进而使原本包覆在含药微胞中的姜黄色素类物质释放至该样品溶液中； 利用高效能液相色谱仪（high performance liquid chromatography, HPLC); 例如 HPLC-UV)测量该样品溶液中的姜黄色素类物质浓度； 以及
利用该样品溶液中的姜黄色素类物质浓度计算 "医药组成物中， 包覆在含药微 胞中的姜黄色素类物质的总浓度" 。
本发明中， 第一含药微胞指的是含姜黄色素类物质的微胞， 较佳者， 含药微胞 指的是含姜黄素的微胞； 亦即， 第一含药微胞指的是包覆或包含姜黄色素类物质的 微胞， 较佳者， 第一含药微胞指的是包覆或包含姜黄素的微胞。
本发明中， 第二含药微胞指的是含白藜芦醇 (resveratrol)的微胞。 亦即， 第二含 药微胞指的是包覆或包含白藜芦醇的微胞。
本发明中， 姜黄色素类物质 Ccurcuminoid)为姜黄素 (curcumin；)、 去甲氧基姜黄素
(demethoxycurcumin) 以及双去甲氧基姜黄素 (bisdemethoxycurcumin)的总称。
本发明中， 总儿茶素 Ccatechins)为表没食子儿茶素没食子酸酯 (Epigall ocatechin gall ate) ^ 表儿茶素 (Epicatechin；)、 表儿茶素没食子酸酯 (Epicatechin gall ate) ^ 表没食 子儿茶素 (Epigallocatechin；)、 没食子儿茶素没食子酸酯（Gallocatechin gallate；)、 没食 子儿茶素 (Gallocatechin；)、 儿茶素没食子酸酯（Catechin gallate；)、 儿茶素 (Catechin)的 总称。
本发明中， 所用的 "无沉淀物产生的状态" 一词指不含人类肉眼可看到的任何 沉淀物， 亦即， 无需藉助人工装置。
本发明中， 医药上可接受的水溶液为注射用水、 注射用水溶液、 生理食盐水、 及其他医药上可接受的水溶液中的至少一种或其组合。
本发明中， 局部麻醉剂为酰胺类、 对氨基苯甲胺脂类、 胺基醚类、 以及其他局 部麻醉剂中的至少一种或其组合。 较佳者， 该酰胺类为待布卡因 (Dibucaine；)、 利多 卡因（Lidocaine)、 甲哌卡因盐酸盐（Mepivacaine HC1 )、布比卡因盐酸盐（Bupivacine HC1 ) 、 吡咯卡因盐酸盐 （Pyrrocaine HCl ) 、 丙胺卡因盐酸盐 （Prilocaine HC1 ) 、 Digammacaine、 及奥昔卡因 （ Oxethazaine) 中的至少一种或其组合。 较佳者， 该对 氨基苯甲胺脂类为布他卡因（Butacaine；)、 二甲卡因（Dimethocaine；)、 及图托卡因 (Tutocaine)中的至少一种或其组合。 较佳者， 该胺基醚类为奎尼卡因（Quinisocaine；)、 及普莫卡因 (Pramocaine)中的至少一种或其组合。
本发明中， 抗氧化剂为 β-胡萝 卜素 (beta-carotene；)、 叶黄素 (lutein；)、 番茄红素 (lycopene)、 胆红素 (bilirubin)、 维生素 A(vitamin A)、 维生素 C ( vitamin C; 又称为 抗坏血酸， 即 ascorbic acid)、维生素 E (vitamin E)、尿酸 ( uric acid)、一氧化氮 ( nitric oxide) 、 硝基氧 ( nitroxide) 、 丙酮酸盐 ( pyruvate) 、 过氧化氢酶 (catalase)、 超氧 化物歧化酶（superoxide dismutase)、 谷胱甘肽过氧化物酶（glutathione peroxidases)、 N-乙酰半胱氨酸 (N-acetyl cysteine；)、 柚皮素 (naringenin；)、 以及其他抗氧化剂中的至 少一种或其组合。
本发明中， 该医药组成物在温度 25 °C ± 2 °C、 相对湿度 RH60%±5%、 避免光线 直射的条件下进行加速稳定性试验时， 该医药组成物仍维持于无沉淀物产生的状态 至少达 24小时。
抑或是， 该医药组成物在温度 25 °C ± 2 °C、 相对湿度 RH60%±5%、 避免光线直 射的条件下进行加速稳定性试验时， 该医药组成物仍维持于无沉淀物产生的状态至 少达 6个月。
本发明中， 聚氧乙烯 35蓖麻油的浓度以百分比表示时，代表每 100毫升的溶液中 含有的聚氧乙烯 35蓖麻油的克数。
本发明提供一种医药组成物的用途， 其用于制备施用于过重或肥胖的一个体以 减少该个体的体重的皮下注射剂； 该医药组成物包含：
一医药上可接受的水溶液；
多个含药微胞 (micelle), 为均匀分散在该医药上可接受的水溶液中； 其中， 该 含药微胞为医药上可接受的一聚氧乙烯蓖麻油衍生物 (polyoxyethylene castor oil derivatives)所形成的一微形结构， 且该聚氧乙烯蓖麻油衍生物的亲水亲油性平衡值 (hydrophilic-lipophilic balance value, HLB值)大于 10; 以及
被包覆在所述含药微胞中的姜黄色素类物质 (curcuminoid);
其中， 包覆在该些含药微胞中的姜黄色素类物质的总浓度为 0.2 120 mg/g。 较佳者， 医药上可接受的水溶液中更包含一总儿茶素成份。
较佳者， 该些含药微胞中的姜黄色素类物质的总浓度为 0.4 167 mg/g; 抑或是， 该些含药微胞中的姜黄色素类物质的总浓度为 0.5 11 1 mg/g; 抑或是， 该些含药微 胞中的姜黄色素类物质的总浓度为 2~91 mg/g。
较佳者， 该总儿茶素成份的浓度为 0.04 835 mg/g o
较佳者， 该总儿茶素成份的浓度为 0.15 733 mg/g。
较佳者， 该总儿茶素成份为表没食子儿茶素没食子酸酯 (Epigallocatechin gall ate) ^ 表儿茶素 (Epicatechin；)、 表儿茶素没食子酸酯 (Epicatechin gall ate) ^ 表没食 子儿茶素 (Epigallocatechin；)、 没食子儿茶素没食子酸酯（Gallocatechin gallate；)、 没食 子儿茶素 (Gallocatechin；)、 儿茶素没食子酸酯（Catechin gallate；)、 儿茶素 (Catechin)中 的至少一种或其组合。
较佳者， 该医药组成物中的姜黄色素类物质与该总儿茶素成份的重量比为 50: 1 至 1 :20。
较佳者， 该医药组成物中的姜黄色素类物质与该总儿茶素成份的重量比为 30: 1 至 1 : 10; 抑或是， 该医药组成物中的姜黄色素类物质与该总儿茶素成份的重量比为
10: 1至 1 :4; 抑或是， 该医药组成物中的姜黄色素类物质与该总儿茶素成份的重量比 为 7: 1至 1 :4。
较佳者， 该些含药微胞的粒径为 3 ~ 50 nm。
较佳者， 该些含药微胞的粒径为 5 ~ 20 nm。
较佳者， 该皮下注射剂的施用剂量为每公斤注射 0.15 40毫克。
较佳者， 该皮下注射剂的施用剂量为每公斤注射 0.25 25毫克。
较佳者， 该皮下注射剂的施用频率为每 1~90天施用于施用部位 1~6次。
较佳者， 每次施用于该施用部位时， 施用大于或等于 1针的皮下注射剂。
较佳者， 该姜黄色素类物质与该聚氧乙烯蓖麻油衍生物的重量比为 1 : 5 〜 1：
750。
较佳者，该姜黄色素类物质与聚氧乙烯蓖麻油衍生物的重量比为 1 : 20 〜 1： 150。 较佳者， 该聚氧乙烯蓖麻油衍生物为聚氧乙烯 35蓖麻油 (Crem0phor ELP)、 聚氧 乙烯 40氢化蓖麻油 (Cremophor RH 40)、 及其他聚氧乙烯蓖麻油衍生物中的至少一种 或其组合。
较佳者， 该医药组成物中更包含一助溶剂（cosolvent；)、 一助悬剂（suspending agent )、 以及一油相赋形剂 (oil phase excipients)中的至少一种或其组合。
较佳者， 该油相赋形剂以及该助溶剂中的至少一种与该聚氧乙烯蓖麻油衍生物 共同形成该微形结构。
较佳者， 该姜黄色素类物质为姜黄素 (CUrCUmin)。
本发明再提供一种医药组成物的用途， 其用于制备施用于过重或肥胖的一个体 以减少该个体的体重的皮下注射剂； 该医药组成物包含：
多个第一含药微胞 (micelle)以及多个第二含药微胞；该第一含药微胞为医药上可接受 的一聚氧乙烯蓖麻油衍生物 (polyoxyethylene castor oil derivatives)所形成的一微形结构， 且该聚氧乙烯蓖麻油衍生物的亲水亲油性平衡值 (hydrophilic-lipophilic balance value, HLB值；)大于 10;
被包覆在所述第一含药微胞中的姜黄色素类物质 (curcuminoid); 以及
被包覆在所述第二含药微胞中的白藜芦醇；
其中， 包覆在该些第一含药微胞中的姜黄色素类物质的总浓度为 0.2 167 mg/g。 较佳者， 包覆在该些第二含药微胞中的白藜芦醇的总浓度为 0.2 733 mg/g。 较佳者， 包覆在该些第一含药微胞中的姜黄色素类物质的总浓度以及包覆在该 些第二含药微胞中的白藜芦醇的总浓度的总和为 0.4 900 mg/g o
较佳者， 包覆在该些第一含药微胞中的姜黄色素类物质的总重量与包覆在该些 ：含药微胞中的白藜芦醇的总重量的比例为 50: 1至 1 :30。
较佳者， 包覆在该些第一含药微胞中的姜黄色素类物质的总重: ：与包覆在该些 ：含药微胞中的白藜芦醇的总重量的比例为 30: 1至 1 : 10。
较佳者， 包覆在该些第一含药微胞中的姜黄色素类物质的总重: ：与包覆在该些 ：含药微胞中的白藜芦醇的总重量的比例为 20: 1至 1 :20。
较佳者， 包覆在该些第一含药微胞中的姜黄色素类物质的总重: ：与包覆在该些 ：含药微胞中的白藜芦醇的总重量的比例为 20: 1至 1 : 8。
较佳者， 该皮下注射剂的施用剂量为每公斤注射 0.15 40毫克。
较佳者: 该皮下注射剂的施用剂： ：为每公斤注射 0.25 25毫克。
较较佳佳者者:， 该该皮皮下下注注射射剂剂的的施施用用剂剂：量为每公斤注射 0.4 ~ 25毫克。
较佳者: 该皮下注射剂的施用剂： ：为每公斤注射 0.5~20毫克。
较佳者: 该皮下注射剂的施用剂： ：为每平方公分注射 0.02 〜 20毫克。
较佳者: 该皮下注射剂的施用剂： ：为每平方公分注射 0.04 ~ 16毫克。
较佳者: 该皮下注射剂的施用频率为每 1~90天施用于该施用部位 1~12次。
较较佳佳者者:， 该皮下注射剂的施用频率为每 1~90天施用于该施用部位 1~6次。
较佳者: 该皮下注射剂的施用频率为每 1~60天施用于该施用部位 1~6次。
较佳者: 包覆在该些第一含药微胞中的姜黄色素类物质的总重量与聚氧乙烯蓖 麻油衍生物的总重量的比例为 1 : 5 〜 1 :750。
较佳者， 该医药组成物中更包含一助溶剂（cosolvent；)、 一助悬剂（suspending agent )、 以及一油相赋形剂 (oil phase excipients)中的至少一种或其组合。
较佳者， 该油相赋形剂以及该助溶剂中的至少一种与该聚氧乙烯蓖麻油衍生物 共同形成该微形结构。
较佳者， 该第二含药微胞为医药上可接受的一第二聚氧乙烯蓖麻油衍生物 (polyoxy ethylene castor oil derivatives)所形成的一第二微形结构， 且该第二聚氧乙烯 蓖麻油衍生物的亲水亲油性平衡值 (hydrophilic-lipophilic balance value, HLB值）大于 10。
较佳者， 该聚氧乙烯蓖麻油衍生物为聚氧乙烯 35蓖麻油 (Crem0phor ELP)、 聚氧 乙烯 40氢化蓖麻油 (Cremophor RH 40)、 及其他聚氧乙烯蓖麻油衍生物中的至少一种 或其组合； 抑或是， 该第二聚氧乙烯蓖麻油衍生物为聚氧乙烯 35蓖麻油 (Cremophor ELP), 聚氧乙烯 40氢化蓖麻油 (Cremophor RH 40)、 及其他聚氧乙烯蓖麻油衍生物中 的至少一种或其组合。
较佳者， 该姜黄色素类物质为姜黄素 (cUrCUmin)。
较佳者， 该医药组成物中更包含助溶剂 (Cosolvent ), 用以增加药物溶解度。 较佳者， 该助溶齐 I!为聚乙二醇 (polyethylene glycol)、 丙二醇 (propylene glycol)、 乙醇 (ethan0l)、 以及其他助溶剂中的至少一种或其组合。
较佳者， 该聚乙二醇为聚乙二醇 200 (PEG 200)、 聚乙二醇 400 (PEG 400)、 聚乙 二醇 600 (PEG 600)、 及其他聚乙二醇中的至少一种或其组合。
较佳者， 该医药组成物中更包含助悬剂 (又称为悬浮剂； suspending agent), 用 以降低药物或微胞的沉降速度。
较佳者， 该助悬剂为海藻酸钠 (Sodium alginate；)、 甘油 (glycerol；)、 羟甲基纤维素 钠（carboxymethylcellulose sodium)、 甘露醇（mannitol)、 以及其他助悬剂中的至少一 种或其组合。
较佳者， 该医药组成物中更包含油相赋形剂 (oil phase excipients；)， 用以增加医 药组成物的稳定性及药物的溶解度。
较佳者，油相赋形剂为不饱和脂肪酸、甘油 (glycerol)、三酸甘油脂 (triglyceride；)、 及其他油相赋形剂中的至少一种或其组合。
较佳者， 该不饱和脂肪酸为油酸 (oleic acid)、 蓖麻油（castor oil)、 芝麻油（sesame oil)、 棉子油（cottonseed oil)、 大豆油（soybean oil)、 红花子油（safflower oil)、 玉米油 (corn oil)^ 以及其他不饱和脂肪酸中的至少一种或其组合。
较佳者， 该三酸甘油脂为中链三酸甘油酯 (medium chain triglycerides；)、 及其他 三酸甘油脂中的至少一种或其组合。
较佳者， 该医药上可接受的水溶液中包含局部麻醉剂。
较佳者， 该医药上可接受的水溶液中包含抗氧化剂。
本发明更提供一种减少过重或肥胖个体体重的方法， 包括在该过重或肥胖个体 施用一皮下注射剂， 其中， 该皮下注射剂包含：
一医药上可接受的水溶液；
多个含药微胞 (micelle), 为均匀分散在该医药上可接受的水溶液中； 其中， 该 含药微胞为医药上可接受的一聚氧乙烯蓖麻油衍生物 (polyoxyethylene castor oil derivatives)所形成的一微形结构， 且该聚氧乙烯蓖麻油衍生物的亲水亲油性平衡值 (hydrophilic-lipophilic balance value, HLB值)大于 10; 以及
被包覆在所述含药微胞中的姜黄色素类物质 (curcuminoid);
其中， 包覆在该些含药微胞中的姜黄色素类物质的总浓度为 0.2 167 mg/g。 较佳者， 该医药上可接受的水溶液中更包含一总儿茶素成份。
较佳者， 该皮下注射剂中的姜黄色素类物质与该总儿茶素成份的重量比为 50: 1 至 1 :20。
较佳者， 该皮下注射剂中的姜黄色素类物质与该总儿茶素成份的重量比为 30: 1 至 1 : 10; 抑或是， 该皮下注射剂中的姜黄色素类物质与该总儿茶素成份的重量比为 10: 1至 1 :4; 抑或是， 该皮下注射剂中的姜黄色素类物质与该总儿茶素成份的重量比 为 7: 1至 1 :4。
本发明又提供一种减少过重或肥胖个体体重的方法， 包括在该过重或肥胖个体 施用一皮下注射剂， 其中， 该皮下注射剂包含：
多个第一含药微胞 (micelle)以及多个第二含药微胞；该第一含药微胞为医药上可接受 的一聚氧乙烯蓖麻油衍生物 (polyoxyethylene castor oil derivatives)所形成的一微形结构， 且该聚氧乙烯蓖麻油衍生物的亲水亲油性平衡值 (hydrophilic-lipophilic balance value， HLB值；)大于 10;
被包覆在所述第一含药微胞中的姜黄色素类物质 (curcuminoid); 以及
被包覆在所述第二含药微胞中的白藜芦醇；
其中， 包覆在该些第一含药微胞中的姜黄色素类物质的总浓度为 0.2 167 mg/g。 附图说明
图 1A: 以不同方式施予姜黄素-绿茶萃取物复方医药组成物， 对大鼠相对总增重 影响的长条图。
图 1B : 以不同方式施予姜黄素-绿茶萃取物复方医药组成物， 对大鼠内脏脂肪相 对重量影响的长条图。
图 2A: 姜黄素与绿茶萃取物的比例对大鼠相对总增重影响的长条图。
图 2B : 姜黄素与绿茶萃取物的比例对大鼠内脏脂肪相对重量影响的长条图。 图 3A: 姜黄素-绿茶萃取物复方医药组成物的剂量对大鼠相对总增重影响的长条 图。
图 3B : 姜黄素-绿茶萃取物复方医药组成物的剂量对大鼠内脏脂肪相对重量影响 的长条图。
图 4A: 姜黄素-绿茶萃取物复方医药组成物的施用频率对大鼠相对总增重影响的 长条图。
图 4B : 姜黄素-绿茶萃取物复方医药组成物的施用频率对大鼠内脏脂肪相对重量 影响的长条图。
图 5A: 姜黄素与白藜芦醇的比例对大鼠相对总增重影响的长条图。
图 5B: 姜黄素与白藜芦醇的比例对大鼠内脏脂肪相对重量影响的长条图。
图 6A:姜黄素 -白藜芦醇复方医药组成物的剂量对大鼠相对总增重影响的长条图。 图 6B : 姜黄素-白藜芦醇复方医药组成物的剂量对大鼠内脏脂肪相对重量影响的 长条图。 图 7A: 姜黄素-白藜芦醇复方医药组成物的施用频率对大鼠相对总增重影响的长 条图。
图 7B : 姜黄素-白藜芦醇复方医药组成物的施用频率对大鼠内脏脂肪相对重量影 响的长条图。 具体实施方式
鉴于习知技术的缺陷， 发明人依据多年的研究成果及经验， 认为应能建立一种包 含低剂量的姜黄色素类物质的医药组成物， 可以减少个体的体重及内脏脂肪， 且具有 高稳定性、 高度脂肪组织生物利用率、 低副作用、 以及缓释等优点。
以下为利用本发明的实施例的详细说明， 以及本发明的技术、 特点。 然本实施例 并非用以限定本发明，任何本领域普通技术人员在不脱离本发明的精神和范围内所作 的各种更动、 润饰， 均应包含在本发明的申请专利范围内。
以下具体实施例中，绿茶萃取物指的是至少包含 45 % (重量百分比；)表没食子儿茶 素没食子酸酯 (epigallocatechin gallate, EGCG)的混合物、 或任一种至少包含 90 % (重 量百分比)总儿茶素 (catechins)的混合物。 实验一： 以不同给药途径施予低剂量医药组成物， 对大鼠体重及内脏脂肪量的影 响
姜黄素 -绿茶萃取物口服液的配制方法： 将适量的姜黄素与绿茶萃取物加入适量 的无菌反渗透水中， 搅拌均匀， 即为姜黄素-绿茶萃取物口服液。 其中， 姜黄素与绿 茶萃取物的总浓度为 100 mg/mL， 且姜黄素与绿茶萃取物的重量比为 4: 1。
姜黄素 -绿茶萃取物复方医药组成物的配制方法：将 0.8 g姜黄素、以及 150 200 mL 二氯甲垸混合， 于室温下以 150 500 rpm搅拌至姜黄素完全溶解。 加入 30 g聚氧乙烯 35蓖麻油(!0)1^110 £0>， 简称为 ELP；)， 在转速 100 ~300 rpm条件下搅拌均匀， 使二氯 甲垸挥发。 待二氯甲垸完全挥发后， 缓慢加入注射用生理食盐水， 使最终体积达 200 mL， 其中， 注射用生理食盐水中含有 0.2 g绿茶萃取物。 搅拌均匀， 即可得到含有 ELP 的姜黄素-绿茶萃取物复方医药组成物。 所述含有 ELP的姜黄素-绿茶萃取物复方医药 组成物中含有含药微胞， 姜黄素与绿茶萃取物的总浓度为 5 mg/mL， 姜黄素与绿茶萃 取物的重量比为 4: 1， 且聚氧乙烯 35蓖麻油的浓度约为 15%。
使用 6周龄 SD品系雄性大鼠（male Sprague-Dawley rat)进行实验。 以正常饲料 (normal diet, 厂牌为 Research Diets, Inc.)喂食 24只大鼠一周使体重约达 175 200 g， 再 以高脂饲料 (high-fat diet, 厂牌为 Research Diets, Inc. ; 型号为 #D12492)喂食 14天使大 鼠被诱导为肥胖动物模式并使体重增加至 400 450 g后， 将大鼠随机分成 5组， 分别为 控制组、 口服组 (PO组；)、 腹腔注射组 (IP组；)、 皮下注射组 (SC组；)、 以及皮下脂肪注射 组 (IA组；)， 使各组大鼠的体重无统计差异。 其中， 控制组包含 8只大鼠， 口服组、 腹 腔注射组、 皮下注射组、 以及皮下脂肪注射组则各包含 4只大鼠。 试验前记录每只大 鼠的体重， 定义为每只大鼠的 "试验前体重" 。
口服组 (PO组；)： 于试验第一天开始以管喂方式给予大鼠姜黄素-绿茶萃取物口服 液，每日投药一次，连续投药 14天，每次投药量为每公斤体重管喂给予 2 mL(2 mL/kg), 使得每次投药剂量都是每公斤体重施予 160 mg 姜黄素以及 40 mg绿茶萃取物 (每公斤 体重施予的姜黄素与绿茶萃取物的总浓度为 2 mL/kg X 100 mg/mL = 200 mg/kg，其中， 姜黄素与绿茶萃取物的重量比为 4 : 1， 因此每公斤体重施予的姜黄素为 200 mg/kg ÷ 5 4 = 160 mg, 每公斤体重施予的绿茶萃取物为 200 mg/kg ÷ 5 χ 1 =40 mg)。
腹腔注射组 (IP组；)： 以腹腔注射方式将姜黄素-绿茶萃取物复方医药组成物施用予 大鼠， 注射部位为大鼠右侧腹腔， 于试验第 1、 3、 5、 7、 9、 1 1日各投药 1次， 共投药 6次， 每次投药量为每公斤体重注射 4 mL(4 mL/kg)， 使得每次投药剂量都是每公斤体 重施予 16 mg 姜黄素以及 4 mg绿茶萃取物 (每公斤体重施予的姜黄素与绿茶萃取物的 总浓度为 4 mL/kg X 5 mg/mL = 20 mg/kg,其中，姜黄素与绿茶萃取物的重量比为 4 : 1， 因此每公斤体重施予的姜黄素为 20 mg/kg ÷ 5 X 4 = 16 mg， 每公斤体重施予的绿茶萃 取物为 20 mg/kg ÷ 5 X 1 =4 mg)。
皮下注射组 (SC组；)： 以皮下注射方式将姜黄素 -绿茶萃取物复方医药组成物施用 予大鼠， 注射部位为大鼠背部耳后、 肩颊骨上方、 或肩颊骨下方， 于试验第 1、 3、 5、 7、 9、 1 1日各投药 1次， 共投药 6次， 每次投药量为每公斤体重注射 4 mL(4 mL/kg)， 使得每次投药剂量都是每公斤体重施予 16 mg 姜黄素以及 4 mg绿茶萃取物。
皮下脂肪注射组 (IA组；)：以皮下脂肪注射方式将姜黄素 -绿茶萃取物复方医药组成 物施用予大鼠， 注射部位为大鼠左、 右两侧下腹股沟脂肪位置， 于试验第 1、 3、 5、 7、 9、 1 1日各投药 1次， 共投药 6次， 每次投药量为每公斤体重注射 4 mL(4 mL/kg)， 使得 每次投药剂量都是每公斤体重施予 16 mg 姜黄素以及 4 mg绿茶萃取物。
控制组： 控制组中又分为口服控制组及注射控制组， 各 4只大鼠。 以口服管喂方 式给予口服控制组大鼠无菌反渗透水， 每日管喂给予一次， 每次管喂量为每公斤体重 管喂 2 mL(2 mL/kg)， 连续管喂给予 14天； 以注射方式给予注射控制组大鼠注射用生 理食盐水， 于试验第 1、 3、 5、 7、 9、 1 1日各注射 1次， 共注射 6次， 每次注射量为每 公斤体重注射 4 mL(4 mL/kg)。 试验结果显示口服控制组与注射控制组的数据无显著 差异， 故将两组数据合并为控制组。
试验期间持续给予高脂饲料， 并每日记录体重变化， 每周记录饮水摄食一次， 试 验共进行 20天， 于第 21天以二氧化碳牺牲大鼠。 然后， 记录每只大鼠的体重， 定义为 每只大鼠的 "试验后体重" 。
将每只大鼠的 "试验后体重"扣除 "试验前体重" ， 得到 "总增重" 。 将各组大 鼠的总增重除以控制组大鼠的总增重， 得到 "相对总增重" 。
将大鼠附睪脂肪、 肾周脂肪及肠系膜脂肪分别取下秤重， 加总后即为内脏脂肪重 量。 将各组大鼠的内脏脂肪重量除以控制组大鼠的内脏脂肪重量， 得到 "相对内脏脂 肪重量" 。
以平均值±80方式呈现数据， 并以单因子变异数分析（one-way ANOVA)进行统 计。 统计结果以英文字母表示， 不同字母符号表示组间具有统计差异 (p< 0.05)， 相同 字母符号则表示组间不具有统计差异 (p> 0.05)。
请参阅图 1A及图 1B。 图 1A是以不同方式施予姜黄素 -绿茶萃取物复方医药组成 物， 对大鼠相对总增重影响的长条图。 图 1B是以不同方式施予姜黄素-绿茶萃取物复 方医药组成物， 对大鼠相对内脏脂肪重量影响的长条图。
图 1A结果显示， 控制组大鼠的相对总增重为 100.1±9.4%， 口服组大鼠的相对总 增重为 96.2± 12.4%， 腹腔注射组大鼠的相对总增重为 97.8± 10.1%， 皮下脂肪注射组大 鼠的相对总增重为 80.8±6.5%， 皮下注射组大鼠的相对总增重为 72.9±10.6%。 其中， 口服组大鼠的相对总增重与控制组大鼠的相对总增重之间无显著差异，显示将姜黄素 -绿茶萃取物复方医药组成物以口服方式给予， 无法减少大鼠体重； 腹腔注射组大鼠 的相对总增重与控制组大鼠之间无显著差异， 显示将姜黄素-绿茶萃取物复方医药组 成物以腹腔注射方式给予， 亦无法减少大鼠体重； 皮下脂肪注射组大鼠的相对总增重 与控制组大鼠之间则有显著差异 (ρ<0.05)， 且皮下脂肪注射组大鼠的相对总增重减少 19.3%； 皮下注射组大鼠的相对总增重与控制组大鼠之间有显著差异 (ρ<0.05)， 且皮 下注射组大鼠的相对总增重减少 27.2%。 结果显示以皮下脂肪注射或皮下注射方式给 予低剂量姜黄素-绿茶萃取物复方医药组成物都可有效减少过重或肥胖的大鼠的体 重， 且以皮下注射方式的效果最好。
图 1B结果显示， 控制组大鼠的相对内脏脂肪重量为 100.0±18.8 %， 口服组大鼠的 相对内脏脂肪重量为 88.3±5.9%， 腹腔注射组大鼠的相对内脏脂肪重量为 79.7±10.1%， 皮下脂肪注射组大鼠的相对内脏脂肪重量为 71.1±1 1.0%，皮下注射组大鼠的相对内脏 脂肪重量为 56.5±13.1%。 其中， 控制组大鼠的相对内脏脂肪量与口服组大鼠之间无显 著差异， 显示将姜黄素 -绿茶萃取物复方医药组成物以口服方式给予， 无法减少大鼠 内脏脂肪； 腹腔注射组大鼠的相对内脏脂肪重量与控制组大鼠之间有显著差异 (ρ<0.05) , 但腹腔注射组大鼠的相对内脏脂肪重量只减少 20.3% ; 皮下脂肪注射组大 鼠的相对内脏脂肪重量与控制组大鼠之间有显著差异 (ρ<0.05)， 且皮下脂肪组大鼠的 相对内脏脂肪重量减少 28.9%; 皮下注射组大鼠的相对内脏脂肪重量与控制组大鼠之 间有显著差异 (p<0.05)， 且皮下注射组大鼠的相对内脏脂肪重量减少 43.5%。 结果显 示， 以腹腔注射、 皮下脂肪注射、 或皮下注射及方式给予低剂量姜黄素 -绿茶萃取物 复方医药组成物皆可减少过重或肥胖的大鼠的相对内脏脂肪重量， 其中， 以皮下脂肪 注射及皮下注射方式的效果为较佳，且皮下注射方式达到的减脂幅度甚至显著高于腹 腔注射方式 (p<0.05)。
一般而言， 腹腔注射方式比皮下注射方式更能使药物快速到达大鼠身体各部位， 进而达到例如减重或减少内脏脂肪的全身性效果。 然而， 由本实验的结果可知， 对比 于腹腔注射方式，透过皮下注射方式将低剂量的本发明医药组成物施予过重或肥胖大 鼠更能显著达到减重及减少内脏脂肪的效果 (p<0.05)， 亦即， 透过皮下注射方式施予 低剂量的本发明医药组成物具有无法预期的效果。 实验二： 姜黄素-绿茶萃取物复方医药组成物施用于不同族群的影响
本实验将姜黄素 -绿茶萃取物复方医药组成物分别施用于正常及肥胖的大鼠， 藉 以评估姜黄素-绿茶萃取物复方医药组成物对于不同族群大鼠的影响。
姜黄素-绿茶萃取物复方医药组成物的配置方法：将 0.6 g姜黄素、以及 150 200 mL 二氯甲垸混合， 于室温下以 150 500 rpm搅拌至姜黄素完全溶解。 加入 30 g聚氧乙烯 35蓖麻油(!0)1^110 £0>， 简称为 ELP；)， 在转速 100 ~300 rpm条件下搅拌均匀， 使二氯 甲垸挥发。 待二氯甲垸完全挥发后， 缓慢加入注射用生理食盐水， 使最终体积达 200 mL， 其中， 注射用生理食盐水中含有 0.4 g绿茶萃取物。 搅拌均匀， 即可得到含有 ELP 的姜黄素-绿茶萃取物复方医药组成物。 所述含有 ELP的姜黄素-绿茶萃取物复方医药 组成物中含有含药微胞， 姜黄素与绿茶萃取物的总浓度为 5 mg/mL， 姜黄素与绿茶萃 取物的重量比为 3 : 2， 且聚氧乙烯 35蓖麻油的浓度约为 15%。
使用 6周龄 SD品系雄性大鼠进行实验。 以正常饲料喂食 16只大鼠一周使体重约达 175-200 g后， 将大鼠分为 4组， 即正常饲料对照组、 高脂饲料对照组、 正常饲料-绿 茶萃取物复方医药组成物组、 以及高脂饲料 -绿茶萃取物复方医药组成物组。 然后， 以正常饲料继续喂食正常饲料对照组与正常饲料-绿茶萃取物复方医药组成物组中的 大鼠 14天， 同时， 以高脂饲料喂食高脂饲料对照组与高脂饲料-绿茶萃取物复方医药 组成物组中的大鼠 14天， 使高脂饲料对照组与高脂饲料-绿茶萃取物复方医药组成物 组中的大鼠被诱导为肥胖动物模式并使体重增加至 400 450 g o 然后， 以下列方式进 行皮下注射。
正常饲料对照组及高脂饲料对照组：以皮下注射方式将注射用生理食盐水施用予 大鼠， 注射部位为大鼠背部耳后、 肩颊骨上方、 或肩颊骨下方， 于试验第 1、 3、 5、 7、 9、 1 1日各注射 1次， 共注射 6次， 每次注射量为每公斤体重注射 4 mL(4 mL/kg)。 正常饲料-绿茶萃取物复方医药组成物组及高脂饲料 -绿茶萃取物复方医药组成 物组： 以皮下注射方式将姜黄素-绿茶萃取物复方医药组成物施用予大鼠， 注射部位 为大鼠背部耳后、 肩颊骨上方、 或肩颊骨下方， 于试验第 1、 3、 5、 7、 9、 1 1日各投 药 1次， 共投药 6次， 每次投药量为每公斤体重注射 4 mL(4 mL/kg), 使得每次投药剂 量都是每公斤体重施予 12 mg 姜黄素以及 8 mg绿茶萃取物 (每公斤体重施予的姜黄素 与绿茶萃取物的总浓度为 4 mL/kg x 5 mg/mL = 20 mg/kg， 其中， 姜黄素与绿茶萃取物 的重量比为 3 : 2， 因此每公斤体重施予的姜黄素为 20 mg/kg ÷ 5 X 3 = 12mg， 每公斤 体重施予的绿茶萃取物为 20 mg/kg ÷ 5 2 = 8 mg；)。
试验期间持续提供正常饲料予正常饲料对照组及正常饲料-绿茶萃取物复方医药 组成物组的大鼠， 并提供高脂饲料予高脂饲料对照组及高脂饲料 -绿茶萃取物复方医 药组成物组的大鼠。 试验共进行 20天， 于第 21天以二氧化碳牺牲大鼠。
实验结果显示， 与正常饲料对照组大鼠相比， 正常饲料-绿茶萃取物复方医药组 成物组大鼠的相对总增重和相对内脏脂肪重量均未显著降低，显示本发明的医药组成 物无法减少正常大鼠的体重， 也无法减少正常大鼠的内脏脂肪重量。与高脂饲料对照 组大鼠相比， 高脂饲料 -绿茶萃取物复方医药组成物组大鼠的相对总增重和相对内脏 脂肪重量均显著下降 (p<0.05)， 显示本发明的医药组成物能够减少过重或肥胖大鼠的 体重， 也能够减少过重或肥胖大鼠的内脏脂肪重量。
由上述实验可知，本发明的医药组成物仅对于特定族群具有减少体重及减少内脏 脂肪的效果， 亦即， 仅能针对过重或肥胖族群发挥减少体重及减少内脏脂肪的功效。 实验三： 制备本发明的医药组成物
实验 3-1 : 制备姜黄色素类物质单方医药组成物
(a) 将第一重量的姜黄色素类物质（curcuminoid)与溶媒混合， 于室温下以 150-500 rpm搅拌至姜黄素完全溶解；
(b) 加入第二重量的医药上可接受的一表面活性剂， 在转速 100 -300 rpm条 件下搅拌均匀， 使溶媒挥发， 其中， 该表面活性剂的亲水亲油性平衡值 (hydrophilic-lipophilic balance value, HLB值)大于 10; 以及
(c) 待溶媒完全挥发后， 缓慢加入第三重量的医药上可接受的水溶液， 获得 多个含药微胞； 以及
(d) 以 0.2 μιη滤膜过滤后， 将含有含药微胞的滤液避光冷藏保存； 其中， 步骤 (c)中， 该含药微胞为表面活性剂所形成的一微形结构， 且姜黄色素 类物质被包覆在所述含药微胞中； 第三重量为大于或等于 0g。
较佳者， 步骤 (c)的操作步骤为： 待溶媒完全挥发后， 缓慢加入第三重量的医药 上可接受的水溶液， 搅拌均匀， 以形成多个含药微胞。
较佳者， 步骤 (a)中， 溶媒的沸点小于纯水的沸点。
较佳者， 步骤 (a)中， 溶媒为亲水性溶媒。
较佳者， 该亲水性溶媒为甲醇、 乙醇、 丙酮及其他亲水性溶媒中的至少一者或其 组合。
较佳者， 步骤 (a)中的溶媒为亲脂性溶媒。
较佳者， 该亲脂性溶媒为乙醚、 苯、 氯仿、 乙酸乙酯、 二氯甲垸、 己垸及其他亲 脂性溶媒中的至少一者或其组合。
较佳者， 步骤 (b)中， 该表面活性剂为非离子性表面活性剂。
较佳者， 该非离子性表面活性剂为聚山梨醇酯 80CT ween 80)、 2-hydroxyethyl
12-hydroxyoctadecanoate (solutol HS 15)、 聚氧乙烯蓖麻油衍生物（polyoxyethylene castor oil derivatives) ^ 及其他非离子性表面活性剂中的至少一者或其组合。
较佳者， 该聚氧乙烯蓖麻油衍生物为聚氧乙烯 35蓖麻油 (Cremophor ELP)、 聚氧 乙烯 40氢化蓖麻油 (Cremophor RH 40)、 及其他聚氧乙烯蓖麻油衍生物中的至少一者 或其组合。
较佳者， 步骤 (a)及 (b)中， 该第一重量的姜黄色素类物质与该第二重量的表面活 性剂的重量比为 1 : 5至 1 : 500。
较佳者， 步骤 (a)及 (b)中， 该第一重量的姜黄色素类物质与该第二重量的表面活 性剂的重量比为 1 :20至 1 : 150。
较佳者， 步骤 (a)及 (c)中， 该第一重量的姜黄色素类物质与该第三重量的医药上 可接受的水溶液的重量比为 1 : 400至 3 : 50。
较佳者， 步骤 (c)中， 该该医药上可接受的水溶液为注射用水、 注射用水溶液、 或生理食盐水。
较佳者， 步骤 (c)中， 该医药上可接受的水溶液中包含局部麻醉剂。
较佳者， 步骤 (c)中， 该医药上可接受的水溶液中包含抗氧化剂。
实验 3-2: 制备姜黄色素类物质 -其他脂溶性药物复方医药组成物
本发明提供第一种制备姜黄色素类物质-其他脂溶性药物复方医药组成物的方 法， 该姜黄色素类物质-其他脂溶性药物复方医药组成物包含多个含药微胞 (micelle) 以及第二脂溶性药物微胞； 第一种制备姜黄色素类物质-其他脂溶性药物复方医药组 成物的步骤如下：
( A) 制备含药微胞次组合物的步骤， 用以制备一含药微胞次组合物；
( B ) 制备第二脂溶性药物微胞次组合物的步骤， 用以制备一第二脂溶性药物微 胞次组合物： 以及 ( C) 将该含药微胞次组合物与该第二脂溶性药物微胞次组合物混合， 以制备出 该姜黄色素类物质-其他脂溶性药物复方医药组成物；
其中， 该制备含药微胞次组合物的步骤 (A)包含下列步骤 (a2 (d2):
(a2) 将姜黄色素类物质与第一溶媒混合， 于室温下以 150~500 rpm搅拌至姜 黄色素类物质完全溶解；
(b2) 加入医药上可接受的第一表面活性剂， 在转速 100 ~300 rpm条件下搅拌 均匀， 使第一溶媒挥发， 其中， 该第一表面活性剂的亲水亲油性平衡值 (hydrophilic-lipophilic balance value, HLB值)大于 10;
(c2) 待第一溶媒完全挥发后， 获得多个含药微胞； 以及
(d2) 以 0.2 μιη滤膜过滤后， 滤液即为含有含药微胞的该含药微胞次组合物； 而且， 该制备第二脂溶性药物微胞次组合物的步骤 (Β)包含下列步骤 (a3) d3):
(a3) 将一第二脂溶性药物与第二溶媒混合， 于室温下以 200 500 rpm搅拌至 使该第二脂溶性药物完全溶解；
(b3) 加入医药上可接受的第二表面活性剂， 在转速 100 ~300 rpm条件下搅拌 均匀， 使第二溶媒挥发， 其中， 该第二表面活性剂的亲水亲油性平衡值
(hydrophilic-lipophilic balance value, HLB值)大于 10;
(c3) 待第二溶媒完全挥发后， 获得多个第二脂溶性药物微胞； 以及
(d3) 以 0.2 μιη滤膜过滤后，滤液即为含有第二脂溶性药物微胞的该第二脂溶 性药物微胞次组合物。
其中， 步骤 (c2)中， 该含药微胞为第一表面活性剂所形成的一微形结构， 且姜黄 色素类物质被包覆在所述含药微胞中。 步骤 (c3)中， 该第二脂溶性药物微胞为第二表 面活性剂所形成的一微形结构，且该第二脂溶性药物被包覆在所述第二脂溶性药物微 胞中。
较佳者， 步骤 (c2)的操作步骤为： 待第一溶媒完全挥发后， 缓慢加入医药上可接 受的水溶液， 搅拌均匀， 以形成多个含药微胞。
较佳者， 步骤 (c3)的操作步骤为： 待第二溶媒完全挥发后， 缓慢加入医药上可接 受的水溶液， 搅拌均匀， 以形成多个第二脂溶性药物微胞。
较佳者， 该第二脂溶性药物为槲皮素 (qUercetin)、 辛弗林 (synephrine)、 葛根素 (puerarin)、 白藜芦醇 (resveratrol)、及姜黄素以外的其他脂溶性药物中的至少一者或其 组合。
较佳者， 步骤 (a2)或 /及步骤 (a3)中， 第一溶媒或 /及第二溶媒的沸点小于纯水的沸 点。
较佳者， 步骤 (a2)或 /及步骤 (a3)中， 第一溶媒或 /及第二溶媒为亲水性溶媒。 较佳者， 该亲水性溶媒为甲醇、 乙醇、 丙酮及其他亲水性溶媒中的至少一者或其 组合。
较佳者， 步骤 (a2)或 /及 (a3)中的第一溶媒或 /及第二溶媒为亲脂性溶媒。
较佳者， 该亲脂性溶媒为乙醚、 苯、 氯仿、 乙酸乙酯、 二氯甲垸、 己垸及其他亲 脂性溶媒中的至少一者或其组合。
较佳者， 步骤 (b2)或 /及 (b3)中， 该第一表面活性剂或 /及第二表面活性剂为非离子 性表面活性剂。
较佳者， 该非离子性表面活性剂为聚山梨醇酯 80CT ween 80)、 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15)、 聚氧乙烯蓖麻油衍生物（polyoxyethylene castor oil derivatives) ^ 及其他非离子性表面活性剂中的至少一者或其组合。
较佳者， 该聚氧乙烯蓖麻油衍生物为聚氧乙烯 35蓖麻油 (Cremophor ELP)、 聚氧 乙烯 40氢化蓖麻油 (Cremophor RH 40)、 及其他聚氧乙烯蓖麻油衍生物中的至少一者 或其组合。
较佳者， 姜黄色素类物质与该第二脂溶性药物的重量比为 30: 1 - 1： 10。
较佳者，步骤 (a2)及 (b2)中，该姜黄色素类物质与该第一表面活性剂的重量比为 1 :
4至 1 : 500。
较佳者，步骤 (a3)及 (b3)中，该第二脂溶性药物与该第二表面活性剂的重量比为 1 : 4至 1 : 500。
较佳者， 步骤 (c2)或 /及 (c3)中， 该医药上可接受的水溶液为注射用水、 注射用水 溶液、 或生理食盐水。
较佳者， 步骤 (c2)或 /及 (c3)中， 该医药上可接受的水溶液中包含局部麻醉剂。 较佳者， 该局部麻醉剂为酰胺类、 对氨基苯甲胺脂类、 及胺基醚类中的至少一者 或其组合。
较佳者， 该酰胺类为待布卡因 (Dibucaine；)、 利多卡因 (Lidocaine；)、 甲哌卡因盐酸盐 (Mepivacaine HCl) 、 布比卡因盐酸盐 （ Bupivacine HC1 ) 、 吡咯卡因盐酸盐 （Pyrrocaine HCl ) 、 丙胺卡因盐酸盐 （Prilocaine HCl) 、 Digammacaine、 及奥昔卡因 （Oxethazaine) 中的至少一者或其组合。
较佳者， 该对氨基苯甲胺脂类为布他卡因 (Butacaine；)、 二甲卡因 (Dimethocaine；)、 及图托卡因 (Tutocaine)中的至少一者或其组合。
较佳者， 该胺基醚类为奎尼卡因（Quinisocaine；)、 及普莫卡因 (Pramocaine)中的至 少一者或其组合。
较佳者， 步骤 (c2)或 /及 (c3)中， 该医药上可接受的水溶液中包含抗氧化剂。
较佳者， 该抗氧化剂为 β-胡萝 卜素 Cb eta-carotene)、 叶黄素 (lutein)、 番茄红素 (lycopene)、 胆红素 (bilirubin)、 维生素 A(vitamin A)、 维生素 C ( vitamin C; 又称为抗 坏血酸， 即 ascorbic acid)、 维生素 E (vitamin E)、 尿酸 ( uric acid) 、 一氧化氮 ( nitric oxide) 、 硝基氧 （nitroxide) 、 丙酮酸盐 （pyruvate) 、 过氧化氢酶 (catalase)、 超氧 化物歧化酶（superoxide dismutase)、 谷胱甘肽过氧化物酶（glutathione peroxidases) N- 乙酰半胱氨酸 (N-acetyl cysteine；)、 及柚皮素 (naringenin)中的至少一者或其组合。
本发明提供第二种制备姜黄色素类物质-其他脂溶性药物复方医药组成物的方 法， 且该第二种姜黄色素类物质-其他脂溶性药物复方医药组成物的制备方法较第一 种姜黄色素类物质 -其他脂溶性药物复方医药组成物的制备方法更精简； 该第二种制 备姜黄色素类物质 -其他脂溶性药物复方医药组成物的步骤如下：
(a4) 将姜黄色素类物质、 第二脂溶性药物、 以及溶媒混合， 于室温下以
200-500 rpm搅拌至姜黄色素类物质完全溶解；
(b4) 加入医药上可接受的一表面活性剂， 在转速 100 ~300 rpm条件下搅拌均 匀， 使溶媒挥发， 其中， 该表面活性剂的亲水亲油性平衡值 (hydrophilic-lipophilic balance value, HLB值）大于 10;
(c4) 待溶媒完全挥发后， 缓慢加入医药上可接受的水溶液， 搅拌均匀， 以 形成多个含药微胞以及多个第二脂溶性药物微胞； 以及
(d4) 以 0.2 μιη滤膜过滤后，将含有多个含药微胞以及多个第二脂溶性药物微 胞的滤液避光冷藏保存。
该第二种姜黄色素类物质 -其他脂溶性药物复方医药组成物的制备方法中使用的 溶媒、 表面活性剂、 医药上可接受的水溶液、 以及第二脂溶性药物的种类范围与第一 种姜黄色素类物质-其他脂溶性药物复方医药组成物的制备方法中使用的均相同。 而 且， 该第二种姜黄色素类物质 -其他脂溶性药物复方医药组成物的制备方法中的各成 分间的比例关系范围， 也与第一种姜黄色素类物质 -其他脂溶性药物复方医药组成物 的制备方法相同。
较佳者， 该医药上可接受的水溶液中包含局部麻醉剂或 /及抗氧化剂。
较佳者， 该第二种姜黄色素类物质-其他脂溶性药物复方医药组成物的制备方法 中使用的局部麻醉剂或 /及抗氧化剂的种类范围与该第一种姜黄色素类物质-其他脂 溶性药物复方医药组成物的制备方法中使用的均相同。
实验 3-3 : 制备姜黄色素类物质-水溶性药物复方医药组成物
(a5) 将姜黄色素类物质与溶媒混合， 于室温下以 150 500 rpm搅拌至姜黄色 素类物质完全溶解；
(b5) 加入医药上可接受的一表面活性剂， 在转速 100 ~300 rpm条件下搅拌均 匀， 使溶媒挥发， 其中， 该表面活性剂的亲水亲油性平衡值 (hydrophilic-lipophilic balance value, HLB值）大于 10;
(c5) 待溶媒完全挥发后， 缓慢加入第一医药上可接受的水溶液， 在转速 100 ~300 rpm条件下搅拌均匀， 以形成多个含药微胞； 以及
(d5) 以 0.2 μιη滤膜过滤后， 将含有含药微胞的滤液避光冷藏保存； 其中， 该第一医药上可接受的水溶液中包含水溶性药物。
较佳者， 该第一医药上可接受的水溶液中包含局部麻醉剂。
较佳者， 该局部麻醉剂为酰胺类、 对氨基苯甲胺脂类、 及胺基醚类中的至少一者 或其组合。
较佳者， 该酰胺类为待布卡因 (Dibucaine；)、 利多卡因 (Lidocaine；)、 甲哌卡因盐酸 盐 (Mepivacaine HCl)、 布比卡因盐酸盐 (Bupivacine HC1)、 普鲁卡因（Pyrrocaine HC1)、 丙胺卡因（Prilocaine HC1)、 Digammacaine、 及奥昔卡因（Oxethazaine)中的至少一者或 其组合。
较佳者， 该对氨基苯甲胺脂类为布他卡因 (Butacaine；)、 二甲卡因 (Dimethocaine；)、 及图托卡因 (Tutocaine)中的至少一者或其组合。
较佳者， 该胺基醚类为奎尼卡因（Quinisocaine；)、 及普莫卡因 (Pramocaine)中的至 少一者或其组合。
较佳者， 该第一医药上可接受的水溶液中包含抗氧化剂。
较佳者， 该抗氧化剂为 β-胡萝 卜素 Cb eta-carotene)、 叶黄素 (lutein)、 番茄红素 (lycopene)、 胆红素 (bilirubin)、 维生素 A(vitamin A)、 维生素 C ( vitamin C; 又称为抗 坏血酸，即 ascorbic acid)、维生素 E (vitamin E)、尿酸 (uric acid)、一氧化氮 (nitric oxide)、 硝基氧（nitroxide；)、 丙酮酸盐（pyruvate；)、 过氧化氢酶（catalase；)、 超氧化物歧化酶 (superoxide dismutase)、 谷胱甘肽过氧化物酶 (glutathione peroxidases)、 N-乙酰半胱氨 酸 (N-acetyl cysteine)、 及柚皮素（naringenin)中的至少一者或其组合。
较佳者， 步骤 (a5)中， 溶媒的沸点小于纯水的沸点。
较佳者， 步骤 (a5)中， 溶媒为亲水性溶媒。
较佳者， 该亲水性溶媒为甲醇、 乙醇、 丙酮及其他亲水性溶媒中的至少一者或其 组合。
较佳者， 步骤 (a5)中的溶媒为亲脂性溶媒。
较佳者， 该亲脂性溶媒为乙醚、 苯、 氯仿、 乙酸乙酯、 二氯甲垸、 己垸及其他亲 脂性溶媒中的至少一者或其组合。
较佳者， 步骤 (b5)中， 该表面活性剂为非离子性表面活性剂。
较佳者， 该非离子性表面活性剂为聚山梨醇酯 80CT ween 80)、 2-hydroxyethyl 12-hydroxyoctadecanoate (solutol HS 15)、 聚氧乙烯蓖麻油衍生物（polyoxyethylene castor oil derivatives) ^ 及其他非离子性表面活性剂中的至少一者或其组合。
较佳者， 该聚氧乙烯蓖麻油衍生物为聚氧乙烯 35蓖麻油 (Cremophor ELP)、 聚氧 乙烯 40氢化蓖麻油 (Cremophor RH 40)、 及其他聚氧乙烯蓖麻油衍生物中的至少一者 或其组合。
较佳者， 在步骤 (c5)与步骤 (d5)之间， 更包含步骤：
(c51) 加入第二医药上可接受的水溶液， 搅拌均匀， 使第二医药上可接受的 水溶液完全溶解。
较佳者， 该水溶性药物为溶解在该第一医药上可接受的水溶液中， 该含药微胞为 表面活性剂所形成的一微形结构， 且姜黄色素类物质被包覆在所述含药微胞中。
较佳者， 该第一医药上可接受的水溶液中的水溶性药物， 为绿茶萃取物、 表没食 子儿茶素没食子酸酯 (Epigallocatechin gallate) ^ 表儿茶素 (Epicatechin；)、 表儿茶素没食 子酸酯 (Epicatechin gallate) ^ 表没食子儿茶素 (Epigallocatechin；)、 没食子儿茶素没食子 酸酯（Gallocatechin gallate；)、没食子儿茶素 (Gallocatechin；)、儿茶素没食子酸酯（Catechin gallate)、 儿茶素 (Catechin)、 咖啡因（Caffeine)、 肉碱 (Carnitine; 又称为卡尼丁或卡尼 汀）、 左旋肉碱 (L-carnitine)、 辛内弗林（Synephrine)、 绿原酸 （ Chi orogenic acid) 、 及 其他水溶性药物中的至少一者或其组合。
较佳者， 步骤 (a5)及 (c5)中， 该姜黄色素类物质与该水溶性药物的重量比为 30: 1 至 1 : 10。
较佳者， 步骤 (a5)~(c5)中， 以该姜黄色素类物质与该水溶性药物的总重量为一个 重量单位计之， 该表面活性剂的重量为 0.24 70个重量单位； 抑或是， 该姜黄色素类 物质与该水溶性药物的总重量与该表面活性剂的重量比为 4: 1至 1 : 70。
较佳者， 步骤 (a5)、 （c5)、 及 (c51)中， 以该姜黄色素类物质与该水溶性药物的总 重量为一个重量单位计之，该第一医药上可接受的水溶液与该第二医药上可接受的水 溶液的总重量为 16 400个重量单位。
较佳者， 步骤 (c5)及 (c51)中， 该第一医药上可接受的水溶液及该第二医药上可接 受的水溶液为注射用水、 注射用水溶液、 或生理食盐水。 实验四： 测定医药组成物的品质
实验 4-1 组成份分析
将医药组成物静置至少 20分钟， 若未发生分层现象， 则进一步利用粒径分析仪测 试。
利用粒径分析仪 (particle size analyzer)测定医药组成物中是否含有微胞 (micelle；)。 若医药组成物经粒径分析仪分析后，测得的粒径小于 250 nm、 以肉眼观察发现医药组 成物中的溶液为澄清透明、且使用激光照射医药组成物中的溶液后能观察到光径， 则 代表医药组成物中具有微胞。
若医药组成物具有微胞，则所制备出的医药组成物即为本发明的可用于减少体重 及体脂肪的医药组成物。
较佳者， 若医药组成物静置后未分层且不含沉淀物， 则所制备出的医药组成物即 为本发明较佳的医药组成物。
实验 4-2 利用粒径分布状况分析医药组成物的稳定性
利用粒径分析仪 (particle size analyzer) (；购自 Malvern)测定粒径的分布状况及多分 散性指数 (polydispersity index; PDI) , 若多分散性指数小于 0.4， 代表医药组成物的稳 定性佳， 也就是医药组成物中的微胞能稳定地存在。
实验 4-3 利用加速稳定性试验测定医药组成物的稳定性。
本发明的医药组成物的储存条件为摄氏 2~8 °C。 为了测试医药组成物的稳定性， 发明人将医药组成物放置在相对高温度且高湿度的环境 (温度 25 °C ±2 °C、 相对湿度 RH60%±5%)进行加速稳定性试验， 观察医药组成物中的微胞在相对高温的状态下， 能稳定存在多久， 以依据加速稳定性公式推算医药组成物在摄氏 2~8 °C的状态下能保 存多久， 说明如下。
若医药组成物在 25 °C条件下可以储存 n个月，则该医药组成物在 5 °C条件下可以储 存的时间长度为 n个月的 2((25—5)/1Q)倍。 亦即， 该医药组成物在 5 °C条件下可以储存的时 间长度为 n个月的 22倍， 也就是 4倍。
举例而言， 若医药组成物在 25 °C条件下可以储存 6个月， 则该医药组成物在 5 °C条 件下可以储存的时间长度为 24个月（6个月 χ4倍 =24个月）。
在较佳者， 在温度 25 °C ±2 °C、 相对湿度 RH60%±5%、 避免光线直射的条件下进 行加速稳定性试验时， 该医药组成物仍维持于无沉淀物产生的状态至少达 24小时。
较佳者， 在温度 25 °C ±2 °C、 相对湿度 RH60%±5%、 避免光线直射的条件下进行 加速稳定性试验时， 该医药组成物仍维持于无沉淀物产生的状态至少达 6个月。
较佳者， 在温度 2~8 °C条件下， 该医药组成物仍维持于无沉淀物产生的状态至少 达 24个月。 实验五： 各种非离子性表面活性剂形成的含药微胞的最大载药量
由于每单位医药组成物中， 含药微胞的最大载药量直接影响注射体积， 对局部皮 下位置单次须容纳的药物体积、 副作用、 及负担影响甚巨。 因此， 本实验将探讨各种 非离子性表面活性剂形成的含药微胞在每单位医药组成物中对姜黄素的最大载药量， 以评估哪一种非离子性表面活性剂为制备本发明医药组成物的最佳赋形剂。 选用 4种非离子性表面活性剂进行本实验。所述 4种非离子性表面活性剂为聚氧乙 烯 35蓖麻油（即 ELP)、 聚乙二醇硬脂酸酯 15 (即 HS-15)、 聚氧乙烯 40氢化蓖麻油 (Cremophor RH 40， 简称为 RH 40)以及聚山梨醇酉旨 80(即 Tween 80)。
实验分为 4组， 分别为 ELP组、 HS-15组、 RH40组、 以及 Tween 80组。
实验步骤:
(a') 将 2.0 g (第一重量的示例）姜黄素与 300~500 mL二氯甲垸混合， 于室温下 以 150 500 rpm搅拌至姜黄素完全溶解；
(b') 加入 18.0 g (第二重量的示例)单一种上述的非离子性表面活性剂， 在转 速 100 300 rpm条件下搅拌均匀， 使二氯甲垸挥发； 以及
(c') 待溶媒完全挥发后， 获得一组成物， 共 20 g; 取 2 g该组成物， 缓慢加入
8 g (第三重量的示例)注射用生理食盐水， 搅拌均匀， 获得待检测组成物。 该待检 测组成物中的姜黄素浓度为 20 mg/g， 且非离子性表面活性剂的浓度为 18%。 将 ELP组、 HS-15组、 RH40组、 以及 Tween 80组的待检测组成物静置至少 20分钟， 观察是否发生分层现象。若发生分层现象， 代表姜黄素浓度太高而使待检测组成物中 的微胞破裂， 亦即， 利用该非离子性表面活性剂无法制备出姜黄素浓度为 20 mg/g的 本发明医药组成物。
实验结果显示， HS-15组、 以及 RH40组的待检测组成物都发生分层现象， 仅 ELP 组以及 Tween 80组的待检测组成物未发生分层现象。 由此可知， HS-15、 以及 RH40 形成的含药微胞在每克医药组成物中对姜黄素的最大载药量均小于 20 mg o ELP以及 Tween 80形成的含药微胞在每克医药组成物中对姜黄素的最大载药量均大于或等于 20 mg。
然而， 由于 Tween 80具有毒性， 各国药典 (； pharmacopoeia)都限制 Tween 80的注射 浓度应小于 0.4%， 以免造成不良反应或毒性， 故 Tween 80形成的含药微胞在每克医药 组成物中对姜黄素的的载药量上限应为 0.44 mg (计算方式： 20mg χ (0.4%/ 18%)= 0.44 mg。
为了得知 ELP的最大载药限制， 发明人进行后续实验， 得知 ELP的最大载药量为 每克医药组成物中含有大于或等于 167 mg的姜黄素。
由上述结果可知， ELP是制备本发明医药组成物的最佳赋形剂。 ELP形成的含药 微胞在每克医药组成物中对姜黄素的最大载药量可达 167 mg，其他非离子性表面活性 剂形成的含药微胞在每克医药组成物中对姜黄素的最大载药量均小于 20 mg/g (请参 见表一；)。
为了得知 HS-15以及 RH40中，哪一种非离子性表面活性剂所形成的含药微胞在每 单位医药组成物中对姜黄素的载药上限最低，发明人进一步利用该些非离子性表面活 性剂制备姜黄素浓度为 10 mg/g的本发明医药组成物。结果显示， ELP、 HS-15 , RH40、 以及 Tween 80都能制备出姜黄素浓度为 10 mg/g的本发明医药组成物， 且所述姜黄素 浓度为 10 mg/g的本发明医药组成物均为澄清无分层， 粒径依序为 15.95±0.24 nm、 88.23±1 16.06 nm、 21.63±9.34 nm、 11.37±0.13 nm， PDI值依序为 0.32±0.02、 0.48±0.27、 0.26±0.09、 0.33±0.04。
其中， 利用 HS-15制备本发明姜黄素浓度为 10 mg/g的医药组成物时， 所制备出的 医药组成物的 PDI大于 0.4， 不符合本发明对医药组成物中微胞具备稳定性的定义。 由 此可知， 在本实验选用的非离子性表面活性剂中， HS-15的载药上限最低 (请参见表 一)。 表一 各种非离子性表面活性剂形成的含药微胞的最大载药量
每克医药组成物中， 微胞对姜黄 每克医药组成物中，身体可容许 素的最大载药量 (mg) 的微胞剂量的载药上限 (mg)
ELP组 167 167
HS-15组 < 10 < 10 RH40组 <20； ≥ 10 <20； ≥ 10 Tween 80组 20 0.44
实验六： 利用聚氧乙烯 35蓖麻油 (ELP)制备医药组成物
本实验利用姜黄素及聚氧乙烯 35蓖麻油 (ELP)的比例变化， 制备出一系列的本发 明医药组成物， 并进行稳定性分析， 以得知姜黄素及聚氧乙烯 35蓖麻油 (ELP)的适当 比例以及利用 ELP制备本发明医药组成物时的最大载药量。
实验共分为 9组， 即第 1~9组， 各组医药组成物的配制方法与实验五的实验步骤大 致相同， 仅姜黄素的重量 (步骤 (a')中的第一重量；)、 ELP的重量 (步骤 (b')中的第二重 量；)、 注射用生理食盐水的重量 (步骤 (c')中的第三重量;)不同。 本实验中， 姜黄素的重 量 (第一重量；)、 ELP的重量 (第二重量；)、 注射用生理食盐水的重量 (第三重量)的添加原 则如表二所示。 表二 利用 ELP配制医药组成物的样品配制表
姜黄素与 ELP比例 医药组成物中的姜黄素终 组别
(重量比） 浓度 (mg/g)
1 1:4 200
2 1:5 167
3 1:8 111
4 1:10 91
5 1:20 47.62
6 1:40 7.5
7 1:100 3
8 1:150 2
9 1:500 0.5
本实验中， 第 1~9组的姜黄素与 ELP比例 (重量比；)依序为一比四（1: 4)、 一比五 (1: 5)、 一比八（1: 8)、 一比十（1: 10)、 一比二十（1: 20)、 一比四十（1: 40)、 一比一百（1: 100)、 以及一比一百五（1: 150)、 一比五百（1: 500)， 且第 1~9组配制出的医药组成物 中，姜黄素终浓度依序为 200 mg/g、167 mg/g、lll mg/g、91 mg/g、 47.62 mg/g、7.5 mg/g, 3 mg/g、 2 mg/g, 0.5 mg/g。 亦即， 第 1~9组医药组成物的配制方法中， 步骤 (a')中的 姜黄素与步骤 (b')中的 ELP的重量比 (第一重量与第二重量的比例；)依序为一比四、一比 五、 一比八、 一比十、 一比二十、 一比四十、 一比一百、 一比一百五、 以及一比五百， 且在步骤 (c')加入第三重量注射用生理食盐水后， 将依序配制出姜黄素终浓度为 200 mg/g、 167 mg/g、 lll mg/g、 91 mg/g、 47.62 mg/g、 7.5 mg/g、 3 mg/g、 2 mg/g、 以及 0.5 mg/g的医药组成物。 其中， 药物终浓度以 mg/g表示时， 代表每克医药组成物中含 有的姜黄素毫克数。
利用粒径分析仪 (particle size analyzer)测定医药组成物中是否含有微胞 (micelle；)， 并测量微胞的粒径大小。
利用粒径分析仪 (particle size analyzer)测定粒径的分布状况及多分散性指数 (polydispersity index; PDI), 以评估医药组成物的稳定性。利用高效能液相色谱仪 (high performance liquid chromatography, HPLC ;例如 HPLC-UV)分析微胞中的姜黄素含量， 定义为 "起始药物含量" 。
利用加速稳定性试验观察医药组成物在高温储存条件 (25 ± 2 °C )下 3个月是否发 生分层现象， 并利用高效能液相色谱仪（high performance liquid chromatography, HPLC; 例如 HPLC-UV)分析微胞中的药物含量， 定义为 "加速实验后的药物含量" 。 将 "加速实验后的药物含量" 除以 "起始药物含量" ， 得到 "药物含量百分比" 。 若 药物含量百分比大于或等于 95%， 代表医药组成物的稳定性极佳。
请参见表三， 表三稳医药组成物的稳定性分析结果。 表三显示， 第 2~9组医药组 成物中都具有微胞， 因此， 姜黄素与 ELP比例为 1 : 5至 1 : 500所制备出的医药组成物， 都是本发明可用于减少体重及内脏脂肪的医药组成物。 表三 医药组成物的稳定性分析
加速实验后的药 姜黄素与 ELP 加速实验后
别 微胞粒径 (nm) PDI 物含量百分比 的外观
(%)
1 :4 772.5 ± 198.92 0.79 ± 0.36
153.97 ± 40.17 0.41 ± 0.13
1 :8 13.17 ± 0.21 0.2 ± 0.02
1 : 10 12.47 ± 0.23 0.17 ± 0.01
1 :20 12.57 ± 0.12 0.137 ± 0.03 澄清无分层 103.82 ± 2.07
1 :40 1 1.59 ± 0.27 0.174 ± 0.0 澄清无分层 100.78 ± 0.51 1 : 100 12.26 ± 0.12 0.096 ± 0.07 澄青无分层 100.62 ± 0.21 1 : 150 12.93 ± 0.29 0.197 ± 0.02 澄青无分层 102.45 ± 0.05 1 :500 12.66 ± 0.14 0.16 ± 0.01 上表中， 空白的栏位代表未进行分析。 在稳定性方面， 姜黄素与 ELP的比例为 1 : 4及 1 : 5时， PDI均大于 0.4; 姜黄素与 ELP的比例为 1 : 8至 1 : 500时， PDI均小于 0.4。 因此， 若要制备稳定性较佳的医药组 成物， 姜黄素与 ELP的比值应小于五分之一 (1/5)。 亦即， 若要制备稳定性较佳的医药 组成物， 以姜黄素的重量为 1个重量单位计之， ELP的重量应大于 5个重量单位。 较佳 者， 以姜黄素的重量为 1个重量单位计之， ELP的重量为 8 500个重量单位。 较佳者， 以姜黄素的重量为 1个重量单位计之， ELP的重量为 20 150个重量单位。
由表三的数据可知，将第 5~8组医药组成物储存在 25 °C的环境下 3个月， 各样品的 姜黄素药物含量百分比皆大于 95%， 且与起始药物含量相比无明显下降趋势。 由该结 果可知， 所述医药组成物具有良好的稳定性， 且依据加速实验公式计算， 该些医药组 成物在 2~8 °C冷藏的状态下， 至少可储存 24个月。
实验七： 含药微胞的浓度对医药组成物的稳定性及减重功效的影响
依据发明人在台湾专利申请案号 105127451的发明内容， 发明人认为含药微胞的 浓度可能会影响本发明医药组成物的稳定性、 减重功效、 以及安全性。 因此， 本实验 以相同的制备方法制备出含药微胞浓度各不相同的一系列医药组成物，并测定该些医 药组成物的稳定性、 减重功效、 以及安全性测定 (施用部位是否会发生溃疡；)。
实验 7-1 : 制备医药组成物
本实验的医药组成物共分为 12管， 即第 1~12管。第 1管医药组成物的配制方法为： 将 18 mg (第一重量的示例）的姜黄素与 80 140 mL的二氯甲垸 (Dichloromethane)混 合， 于室温下以 150 500 rpm搅拌至姜黄素完全溶解。 加入 90 mg (第二重量的示例）的 聚氧乙烯 35蓖麻油 0111 110 ELP，简称为 ELP；)，在转速 100 -300 rpm条件下搅拌均匀， 使二氯甲垸挥发。 待二氯甲垸完全挥发后， 缓慢加入注射用生理食盐水， 使最终体积 达 180 mL， 以形成多个含药微胞， 即可得到本实验第 1管医药组成物。 以此方法刚配 制出的医药组成物都不会发生姜黄素沉淀的情形， 且医药组成物的比重约为 1 mg/mL, 因此所述第 1管医药组成物中， 包覆在含药微胞中的姜黄素的总浓度为 0.1 mg/mL(18 mg ÷ 180 g = 0.1 mg/g)。
第 2~12管医药组成物的配制方法与第 1管医药组成物的配制方法大致相同， 仅姜 黄素的重量 (第一重量)及 ELP的重量 (第二重量)不同， 但姜黄素与聚氧乙烯 35蓖麻油 的重量比都是 1 : 5。 配制第 1~12管医药组成物时使用的姜黄素重量 (第一重量)及 ELP 重量 (第二重量)的添加原则如表四所示。 表四 利用 ELP配制医药组成物的样品配制表
医药组成物中的姜 医药组成物中的 包覆在含药微胞中的姜 管另 IJ
ELP重量 (g) 黄素的总浓度 (mg/g)
1 0.018 0.09 0.1
2 0.045 0.225 0.25
3 0.072 0.36 0.4
4 0.09 0.45 0.5
5 0.36 1.8 2
6 0.54 2.7 3
7 1.35 6.75 7.5
8 8.5716 42.858 47.62
9 16.38 81.9 91
10 19.98 99.9 1 1 1
1 1 30.06 150.3 167 12 31. 157. 175
实验 7-2: 医药组成物的稳定性分析
利用粒径分析仪 (particle size analyzer)测定医药组成物中是否含有微胞 (micelle), 并测量微胞的粒径大小。
利用粒径分析仪 (particle size analyzer)测定粒径的分布状况及多分散性指数
(polydispersity index; PDI), 以评估医药组成物的稳定性。利用高效能液相色谱仪 (high performance liquid chromatography, HPLC ;例如 HPLC-UV)分析微胞中的姜黄素含量， 定义为 "起始药物含量" 。
利用加速稳定性试验观察医药组成物在高温储存条件 (25 ± 2 °C )下 3个月是否发 生分层现象， 并利用高效能液相色谱仪（high performance liquid chromatography, HPLC; 例如 HPLC-UV)分析微胞中的药物含量， 定义为 "加速实验后的药物含量" 。 将 "加速实验后的药物含量" 除以 "起始药物含量" ， 得到 "药物含量百分比" 。 若 药物含量百分比大于或等于 95%， 代表医药组成物的稳定性极佳。
医药组成物的稳定性分析结果请参见表五。
本实验第 1~11管医药组成物经粒径分析仪分析后， 测得的粒径小于 250nm、 PDI 值小于 0.4、 以肉眼观察发现医药组成物中的溶液为澄清透明、 静置后未分层且不含 沉淀物、 使用激光照射医药组成物中的溶液后能观察到光径、 且在温度 25 °C ± 2°C及 相对湿度 RH60%±5%条件下能维持无沉淀物产生的状态至少达 24小时。 由此可知，包 覆在含药微胞中的姜黄素的总浓度在 0.1 167 mg/g范围时， 医药组成物具有稳定性。 然而， 以粒径分析仪分析后， 发现本实验第 12管医药组成物的 PDI值大于 0.4。 由此可 知， 包覆在含药微胞中的姜黄素的总浓度在 175 mg/g时， 医药组成物不具有稳定性。
实验 7-3 : 医药组成物的减重效果
使用 6周龄 SD品系雄性大鼠 (male Sprague-Dawley rat)进行实验。 以正常饲料喂食
52只大鼠一周使体重约达 175 200 g， 再以高脂饲料喂食， 使所述 52只大鼠都被诱导 为肥胖动物模式。 将大鼠分为 13组， 即控制组、 第 1组、 第 2组、 第 3组、 第 4组、 第 5 组、 第 6组、 第 7组、 第 8组、 第 9组、 第 10组、 第 11组、 以及第 12组， 每组 4只大鼠， 使各组大鼠的体重无统计差异。 然后， 以下列方式进行皮下注射。
第 1~12组： 以皮下注射方式将实验 7-1的第 1~12管医药组成物分别施用予第 1~12 组的大鼠， 注射部位为大鼠背部耳后、 肩颊骨上方、 或肩颊骨下方。
控制组： 以皮下注射方式将注射用生理食盐水施用予控制组大鼠， 注射部位为大 鼠背部耳后、 肩颊骨上方、 或肩颊骨下方。
试验期间持续给予高脂饲料， 试验共进行 20天， 于第 21天以二氧化碳牺牲大鼠。 观察大鼠被注射医药组成物的部位是否发生溃疡情形， 并计算各组大鼠的"相对总增 重" 以及 "相对内脏脂肪重量" 。
医药组成物的减重效果请参见表五。 表五 不同浓度医药组成物的减重功效及微胞稳定性结果
包覆在含药微胞中的姜
组别 减重功效 微胞稳定性 黄素的总浓度 (mg/g)
1 0. 1 X V
2 0.25 X V
3 0.4 V V
4 0.5 V V
5 2 V V
6 3 V V
7 7.5 V V
8 47.62 V V
9 91 V V
10 1 1 1 V V
1 1 167 V V 12 175 V X
实验结果显示， 与控制组相比， 第 1组大鼠的 "相对总增重" 及 "相对内脏脂肪 重量"都未显著下降 (p>0.05)， 且第 2组大鼠的"相对总增重"及"相对内脏脂肪重量" 也未显著下降 (p>0.05)， 然而， 第 3组〜第 12组大鼠的 "相对总增重" 及 "相对内脏脂 肪重量" 均显著下降 (p<0.05)。 由此可知， 医药组成物中， 包覆在含药微胞中的姜黄 素的总浓度在 0.4 200 mg/g范围时可以达到减少大鼠体重及内脏脂肪的效果。
由上述结果可知， 医药组成物中， 包覆在含药微胞中的姜黄素的总浓度大于等于 0.4 mg/g时， 能够达到减少大鼠体重及内脏脂肪的效果， 另一方面， 包覆在含药微胞 中的姜黄素的总浓度小于等于 167 mg/g时， 能够维持微胞的稳定性。 由此可知， 本发 明医药组成物中， 包覆在含药微胞中的姜黄素的总浓度在 0.4 167 mg/g范围时， 能够 兼具稳定性及减重功效。 较佳者， 本发明医药组成物中， 包覆在含药微胞中的姜黄素 的总浓度为 0.4 1 1 1 mg/g o 实验八： 不同比例的姜黄素-绿茶萃取物复方医药组成物对大鼠体重及内脏脂肪 重量的影响
本实验的姜黄素-绿茶萃取物复方医药组成物共分为 12管， 即姜黄素管、 绿茶萃 取物管、 第 Γ~4'管、 第 6'~7'管、 第 9'管、 以及第 1 Γ~13 '管， 各管的配置方法与实验 一的实验步骤大致相同， 仅姜黄素与绿茶萃取物的比例不同， 而且， 聚氧乙烯 35蓖麻 油的浓度为 15%。 姜黄素与绿茶萃取物的比例如表六所示。
表六 姜黄素 -绿茶萃取物复方医药组成物中，姜黄素与绿茶萃取物的重量比以 总浓度 管别 姜黄素与绿茶萃取物的 姜黄素与绿茶萃取物的
比例 (重量比） 总浓度 (mg/mL) 謹 1:0 5 绿茶萃取物 0:1 5
Γ 50:1 5
2' 30:1 5
3' 10:1 5
4' 7:1 5
6' 4:1 5
T 1:1 5
9' 1:4 5
11' 1:10 5
12' 1:20 5
13' 3:2 5 使用 6周龄 SD品系雄性大鼠 (male Sprague-Dawley rat)进行实验。 以正常饲料喂食 52只大鼠 3天使体重约达 175 200 g， 再以高脂饲料喂食 21天使被诱导为肥胖动物模式 并使体重增加至 400~450g后， 将大鼠随机分成 13组， 分别为高脂对照组、 姜黄素组、 绿茶萃取物组、第 OIG1 OIG4组、第 OIG6 OIG7组、第 OIG9组、 以及第 OIG1 l~OIG13 组， 每组 4只大鼠， 各组大鼠的体重无统计差异。 然后， 以下列方式给予药物。
高脂对照组： 以皮下注射方式将注射用生理食盐水施用予大鼠， 注射部位为大鼠 背部耳后、 肩颊骨上方、 或肩颊骨下方。 于试验第 1、 3、 5、 7、 9、 11日各注射 1次， 共注射 6次， 每次注射量为每公斤体重注射 4 mL(4 mL/kg)。
姜黄素组、 绿茶萃取物组、 第 OIG1 OIG4组、 第 OIG6 OIG7组、 第 OIG9组、 以 及第 OIG11 OIG13组： 以皮下注射方式分别将姜黄素管、 绿茶萃取物管、 第 Γ~4'管、 第 6'~7'管、 第 9'管、 以及第 1 Γ~13 '管中的医药组成物施用予姜黄素组、 绿茶萃取物 组、 第 OIG1 OIG4组、 第 OIG6 OIG7组、 第 OIG9组、 以及第 OIG1 l~OIG13组的大鼠， 注射部位为大鼠背部耳后、 肩颊骨上方、 或肩颊骨下方， 于试验第 1、 3、 5、 7、 9、 11日各投药 1次， 共投药 6次， 每次投药量为每公斤体重注射 4 mL(4 mL/kg)， 使得每 次投药剂量都是每公斤体重施予 20 mg的药物 (每公斤体重施予的姜黄素与绿茶萃取 物的总浓度为 4 mL/kg 5 mg/mL = 20 mg/kg)。
试验期间持续给予高脂饲料， 试验共进行 20天， 于第 21天以二氧化碳牺牲大鼠。 计算各组大鼠的 "相对总增重" 以及 "相对内脏脂肪重量" 。
图 2A的结果显示， 高脂对照组大鼠的相对总增重为 100.0±18.5%， 姜黄素组大鼠 的相对总增重为 92.1±11.3%， 绿茶萃取物组大鼠的相对总增重为 95.4±5.6%， 第 OIG1 OIG4组、 第 OIG6 OIG7组、 第 OIG9组、 以及第 OIG1 l~OIG13组大鼠的相对总 增重依序为 85.1±13.6%、 68.4±3.1%、 61.0±5.6%、 62.3±3.3%、 59.3±5.4%、 64.4±4.8%、 63.5±8.1%、 67.7±5.3%、 80.8±7.9%、 以及 49.4±14.3%。 其中， 与高脂对照组相比， 姜 黄素组和绿茶萃取物组大鼠的相对总增重未显著降低 (p>0.05)， 显示若是仅提供姜黄 素或绿茶萃取物， 在本实验的条件下无法显著减少大鼠体重 (p>0.05)。 然而， 与高脂 对照组大鼠相比，第 OIG1 OIG4组、第 OIG6 OIG7组、第 OIG9组、以及第 OIG1 l~OIG13 组大鼠的相对总增重皆显著降低 (p<0.05)， 显示姜黄素与绿茶萃取物的比例在 50: 1 ~ 1： 20范围时， 能显著减少大鼠体重。 此外， 与姜黄素组或绿茶萃取物组相比， 第 OIG2 OIG4组、 第 OIG6 OIG7组、 第 OIG9组、 第 OIG1 1组、 以及第 OIG13组大鼠的相 对总增重皆显著降低 (p<0.05)， 显示姜黄素与绿茶萃取物的比例在 30: 1 - 1： 10范围 时具有协同效应 (synergy)。 较佳者， 姜黄素与绿茶萃取物的比例在 10: 1 - 1： 4范围 时具有更佳的协同效应 (synergy)。
图 2B的结果显示， 高脂对照组大鼠的相对内脏脂肪重量为 100.0±33.4%， 姜黄素 组大鼠的相对内脏脂肪重量为 89.7±19.9%，绿茶萃取物组大鼠的相对内脏脂肪重量为 93.7±15.2%， 第 OIGl~OIG4组、 第 OIG6~OIG7组、 第 OIG9组、 以及第 OIG1 l~OIG13 组大鼠的相对内脏脂肪重量依序为 84.3±26.1%、 61.9±14.2%、 63.5±7.5%、 50.1±5.0%、 56.0±9.6%、 64.5±13.6%、 58.9±15.6%、 57.6±15.6%、 77.4±10.1%、 以及 52.8±9.1%。 其中， 与高脂对照组相比， 姜黄素组和绿茶萃取物组大鼠的相对内脏脂肪重量未显著 降低 (ρ>0.05)， 显示若是仅提供姜黄素或绿茶萃取物， 在本实验的条件下无法显著减 少大鼠内脏脂肪 (ρ>0.05)。 然而， 与高脂对照组大鼠相比， 第 OIG2 OIG4组、 第 OIG6 OIG7组、 第 OIG9组、 以及第 OIG11组、 第 OIG13组大鼠的相对内脏脂肪重量皆 显著降低 (ρ<0.05)， 显示姜黄素与绿茶萃取物的比例在 30: 1 - 1： 10范围时， 能显著 减少大鼠内脏脂肪。 此外， 与姜黄素组或绿茶萃取物组相比， 第 OIG2组、 第 OIG4组、 第 OIG6组、 第 OIG9组、 第 OIG11组、 以及第 OIG13组大鼠的相对内脏脂肪重量皆显著 降低 (p<0.05)， 显示姜黄素与绿茶萃取物的比例在 30: 1 - 1： 10范围时具有协同效应 (synergy) 较佳者， 姜黄素与绿茶萃取物的比例为 7: 1 - 1： 1。 实验九： 不同剂量的姜黄素-绿茶萃取物复方医药组成物对大鼠体重及内脏脂肪 重量的影响
本实验的姜黄素-绿茶萃取物复方医药组成物的配制方法与实验八第 13'管的步 骤相同， 亦即， 姜黄素与绿茶萃取物的比例为 3 : 2且聚氧乙烯 35蓖麻油的浓度为 15%。
使用 6周龄 SD品系雄性大鼠 (male Sprague-Dawley rat)进行实验。 以正常饲料喂食 20只大鼠 3天使体重约达 175~200 g后， 将大鼠分为 5组， 即正常对照组、 高脂对照组、 低剂量组、 中剂量组、 以及高剂量组。 然后， 以正常饲料继续喂食正常对照组中的大 鼠 21天， 同时， 以高脂饲料喂食高脂对照组、 低剂量组、 中剂量组、 以及高剂量组中 的大鼠 21天， 使高脂对照组、 低剂量组、 中剂量组、 以及高剂量组中的大鼠被诱导为 肥胖动物模式并使体重增加至 400~450g。 然后， 以下列方式进行皮下注射。
正常对照组以及高脂对照组：以皮下注射方式将注射用生理食盐水施用予正常对 照组以及高脂对照组大鼠， 注射部位为大鼠背部耳后、 肩颊骨上方、 或肩颊骨下方。 于试验第 1、 3、 5、 7、 9、 11日各注射 1次， 共注射 6次， 每次注射量为每公斤体重注 射 8 mL(8 mL/kg)。
低剂量组： 以皮下注射方式将本实验的姜黄素 -绿茶萃取物复方医药组成物施用 予大鼠， 注射部位为大鼠背部耳后、 肩颊骨上方、 或肩颊骨下方， 于试验第 1、 3、 5、 7、 9、 1 1日各投药 1次， 共投药 6次， 每次投药量为每公斤体重注射 2 mL(2 mL/kg)， 使得每次投药剂量都是每公斤体重施予 6 mg 姜黄素以及 4 mg绿茶萃取物。
中剂量组： 投药方式及频率都与低剂量组相同， 仅投药量不同。 每次投药量为每 公斤体重注射 4 mL(4 mL/kg)， 使得每次投药剂量都是每公斤体重施予 12 mg 姜黄素 以及 8 mg绿茶萃取物。
高剂量组： 投药方式及频率都与低剂量组相同， 仅投药量不同。 每次投药量为每 公斤体重注射 8 mL(8 mL/kg), 使得每次投药剂量都是每公斤体重施予 24 mg 姜黄素 以及 16 mg绿茶萃取物。
试验期间持续给予高脂饲料， 试验共进行 20天， 于第 21天以二氧化碳牺牲大鼠。 计算各组大鼠的 "相对总增重" 以及 "相对内脏脂肪重量" 。
图 3A的结果显示， 正常对照组大鼠的相对总增重为 57.4±8.6%， 高脂对照组大鼠 的相对总增重为 100.0±11.2%， 低剂量组、 中剂量组、 以及高剂量组大鼠的相对总增 重依序为 81.0±10.6%、 72.7±13.4%、 以及 59.6±12.1%。 其中， 与高脂对照组相比， 低 剂量组、 中剂量组、 以及高剂量组大鼠的相对总增重皆显著降低 (p<0.05)， 显示不同 剂量的姜黄素 -绿茶萃取物复方医药组成物都能显著减少大鼠体重， 其中又以高剂量 组的减重效果最佳。
图 3B的结果显示， 正常对照组大鼠的相对内脏脂肪重量为 37.0±5.2%， 高脂对照 组大鼠的相对内脏脂肪重量为 100.0±32.2%， 低剂量组、 中剂量组、 以及高剂量组大 鼠的相对内脏脂肪重量依序为 66.8±18.0%、 68.0±21.0%、 以及 55.2±26.1%。 其中， 与 高脂对照组相比， 低剂量组、 中剂量组、 以及高剂量组大鼠的相对内脏脂肪重量皆显 著降低 (p<0.05)，显示不同剂量的姜黄素-绿茶萃取物复方医药组成物都能显著减少大 鼠内脏脂肪量， 其中又以高剂量组的效果最佳。
由此上述实验结果可知， 姜黄素-绿茶萃取物复方医药组成物在剂量 10 mg/kg时 即具有显著的减重及减少内脏脂肪的效果， 且剂量越高， 效果越显著。
依发明人的经验， 适用于大鼠的给药剂量为 10 mg/kg ~ 40 mg/kg时， 适用于人类 的给药剂量即为 0.1 80 mg/kg。 较佳者， 施用于人类的给药剂量为 10 40 mg/kg。
较佳者， 施用于人类的剂量为每平方公分注射 0.02 ~ 20毫克。 较佳者， 施用于人 类的剂量为每平方公分注射 0.04 ~ 16毫克。 较佳者， 施用于人类的剂量为每平方公分 注射 0.2 ~ 12毫克。 较佳者， 施用于人类的剂量为每平方公分注射 0.4 ~ 8毫克。
较佳者， 施用于人类的剂量为每公斤注射 0.01 ~ 40毫克。 较佳者， 施用于人类的 剂量为每公斤注射 0.4 ~ 40毫克。 较佳者， 施用于人类的剂量为每公斤注射 0.8 ~ 20毫 克。 实验十： 姜黄素-绿茶萃取物复方医药组成物的施用频率对大鼠体重及内脏脂肪 重量的影响
本实验的姜黄素-绿茶萃取物复方医药组成物的配制方法与实验八第 13'管的步 骤相同， 亦即， 姜黄素与绿茶萃取物的比例为 3 : 2且聚氧乙烯 35蓖麻油的浓度为 15%。
使用 6周龄 SD品系雄性大鼠 (male Sprague-Dawley rat)进行实验。 以正常饲料喂食 20只大鼠 3天使体重约达 175~200 g后， 将大鼠分为 5组， 即正常对照组、 高脂对照组、 低频率组、 中频率组、 以及高频率组。 然后， 以正常饲料继续喂食正常对照组中的大 鼠 21天， 同时， 以高脂饲料喂食高脂对照组、 低频率组、 中频率组、 以及高频率组中 的大鼠 21天， 使高脂对照组、 低频率组、 中频率组、 以及高频率组中的大鼠被诱导为 肥胖动物模式并使体重增加至 400~450g。 然后， 以下列方式进行皮下注射。
正常对照组以及高脂对照组：以皮下注射方式将注射用生理食盐水施用予正常对 照组以及高脂对照组大鼠， 注射部位为大鼠背部耳后、 肩颊骨上方、 或肩颊骨下方。 于试验第 1、 3、 5、 7、 9、 11、 13、 15日各注射 1次， 共注射 8次， 每次注射量为每公 斤体重注射 4 mL(4 mL/kg)o
低频率组： 以皮下注射方式将本实验的姜黄素 -绿茶萃取物复方医药组成物施用 予大鼠， 注射部位为大鼠背部耳后、 肩颊骨上方、 或肩颊骨下方， 于试验第 1、 3、 5、 7日各投药 1次， 共投药 4次， 每次投药量为每公斤体重注射 4 mL(4 mL/kg)， 使得每次 投药剂量都是每公斤体重施予 12 mg 姜黄素以及 8 mg绿茶萃取物。
中频率组： 投药方式及每次的投药剂量都与低频率组相同， 仅投药频率不同。 于 试验第 1、 3、 5、 7、 9、 11日各投药 1次， 共投药 6次。
高频率组： 投药方式及每次的投药剂量都与低频率组相同， 仅投药频率不同。 于 试验第 1、 3、 5、 7、 9、 11、 13、 15日各投药 1次， 共投药 8次。
试验期间持续给予高脂饲料， 试验共进行 20天， 于第 21天以二氧化碳牺牲大鼠。 计算各组大鼠的 "相对总增重" 以及 "相对内脏脂肪重量" 。
图 4A的结果显示， 正常对照组大鼠的相对总增重为 57.6±12.1%， 高脂对照组大 鼠的相对总增重为 100.0±9.2%， 低频率组、 中频率组、 以及高频率组大鼠的相对总增 重依序为 82.1±12.3%、 75.7±20.9%、 以及 54.7±13.4%。 其中， 与高脂对照组相比， 低 频率组、 中频率组、 以及高频率组大鼠的相对总增重皆显著降低 (p<0.05)， 显示不同 施用频率都能显著减少大鼠体重， 其中又以高频率组的减重效果最佳。
图 4B的结果显示， 正常对照组大鼠的相对内脏脂肪重量为 38.7±7.4%， 高脂对照 组大鼠的相对内脏脂肪重量为 100.0±16.2%， 低频率组、 中频率组、 以及高频率组大 鼠的相对内脏脂肪重量依序为 75.9±18.5%、 69.0±6.2%、 以及 55.8±10.9%。 其中， 与 高脂对照组相比， 低频率组、 中频率组、 以及高频率组大鼠的相对内脏脂肪重量皆显 著降低 (p<0.05)， 显示不同施用频率都能显著减少大鼠内脏脂肪量， 其中又以高频率 组的效果最佳。
由此上述实验结果可知，姜黄素-绿茶萃取物复方医药组成物的施用频率在 4次时 即具有显著的减重及减少内脏脂肪的效果， 且施用频率越高， 效果越显著。
依发明人的经验， 适用于大鼠的给药频率为 4~8次时， 适用于人类的给药频率即 为 1-16次。 较佳者， 施用于人类的给药频率为 1~6次。
较佳者， 施用于人类的频率为每 1~90天施用 1~12次。较佳者， 施用于人类的频率 为每 1~90天施用 1~6次。抑或是， 较佳者， 施用于人类的频率为每 1~90天施用 3~60次； 较佳者， 施用于人类的频率为每 1~60天施用 6~42次。 实验十一： 姜黄素-白藜芦醇复方医药组成物施用于不同族群的影响
本实验将姜黄素-白藜芦醇复方医药组成物分别施用于喂食正常饲料及高脂饲料 的族群的大鼠，藉以评估姜黄素 -白藜芦醇复方医药组成物对于不同族群大鼠的影响。
姜黄素 -白藜芦醇复方医药组成物的配置方法： 将 0.8 g姜黄素、 0.2 g白藜芦醇、 以及 150~200 mL二氯甲垸混合， 于室温下以 150~500 rpm搅拌至姜黄素完全溶解。 加 入 30 g聚氧乙烯 35蓖麻油 (Kolliphor ELP, 简称为 ELP；)， 在转速 100 ~300 rpm条件下搅 拌均匀， 使二氯甲垸挥发。 待二氯甲垸完全挥发后， 缓慢加入注射用生理食盐水， 使 最终体积达 200 mL， 搅拌均匀， 即可得到含有 ELP的姜黄素-白藜芦醇复方溶液。 所 述含有 ELP的姜黄素 -白藜芦醇复方医药组成物中含有第一含药微胞及第二含药微 胞， 姜黄素浓度为 4 mg/mL、 白藜芦醇浓度为 1 mg/mL、 聚氧乙烯蓖麻油 (ELP)的浓度 约为 15% (重量百分比；)、 且姜黄素、 白藜芦醇、 与聚氧乙烯蓖麻油的重量比为 4: 1 :200。
使用 6周龄 SD品系雄性大鼠 (male Sprague-Dawley rat)进行实验。 以正常饲料喂食 16只大鼠一周使体重约达 175~200 g后， 将大鼠分为 4组， 即正常饲料对照组、 高脂饲 料对照组、 正常饲料-白藜芦醇复方医药组成物组、 以及高脂饲料 -白藜芦醇复方医药 组成物组。 然后， 以正常饲料继续喂食正常饲料对照组与正常饲料-白藜芦醇复方医 药组成物组中的大鼠 14天， 同时， 以高脂饲料喂食高脂饲料对照组与高脂饲料 -白藜 芦醇复方医药组成物组中的大鼠 14天， 使高脂饲料对照组与高脂饲料-白藜芦醇复方 医药组成物组中的大鼠被诱导为肥胖动物模式并使体重增加至 400 450 g o 然后， 以 下列方式进行皮下注射。
正常饲料对照组及高脂饲料对照组：以皮下注射方式将注射用生理食盐水施用予 大鼠， 注射部位为大鼠背部耳后、 肩颊骨上方、 或肩颊骨下方， 于试验第 1、 3、 5、 7、 9、 1 1日各注射 1次， 共注射 6次， 每次注射量为每公斤体重注射 4 mL(4 mL/kg)。
正常饲料-白藜芦醇复方医药组成物组及高脂饲料-白藜芦醇复方医药组成物组： 以皮下注射方式将姜黄素 -白藜芦醇复方医药组成物施用予大鼠， 注射部位为大鼠背 部耳后、 肩颊骨上方、 或肩颊骨下方， 于试验第 1、 3、 5、 7、 9、 1 1日各投药 1次， 共 投药 6次， 每次投药量为每公斤体重注射 4 mL(4 mL/kg)， 使得每次投药剂量都是每公 斤体重施予 16 mg 姜黄素以及 4 mg白藜芦醇 (每公斤体重施予的姜黄素与白藜芦醇的 总浓度为 4 mL/kg X 5 mg/mL = 20 mg/kg， 其中， 姜黄素与白藜芦醇的重量比为 4: 1， 因此每公斤体重施予的姜黄素为 20 mg/kg ÷ 5 X 4 = 16 mg，每公斤体重施予的白藜 芦醇为 20 mg/kg ÷ 5 X l =4 mg)。
试验期间持续提供正常饲料予正常饲料对照组及正常饲料-白藜芦醇复方医药组 成物组的大鼠， 并提供高脂饲料予高脂饲料对照组及高脂饲料-白藜芦醇复方医药组 成物组的大鼠。 试验共进行 20天， 于第 21天以二氧化碳牺牲大鼠。
实验结果显示， 与正常饲料对照组相比， 正常饲料-白藜芦醇复方医药组成物组 大鼠的相对总增重和相对内脏脂肪重量均未显著降低，显示本发明医药组成物无法减 少正常大鼠的体重， 也无法减少正常大鼠的内脏脂肪重量。 与高脂饲料对照组相比， 高脂饲料 -白藜芦醇复方医药组成物组大鼠的相对总增重和相对内脏脂肪重量均显著 下降 (ρ<0.05)， 显示本发明的医药组成物能够减少过重或肥胖大鼠的体重， 也能够减 少过重或肥胖大鼠的内脏脂肪重量。
由上述实验可知，本发明的医药组成物仅对于特定族群具有减少体重及减少内脏 脂肪的效果， 亦即， 仅能针对过重或肥胖族群发挥减少体重及减少内脏脂肪的功效。 实验十二： 不同比例的姜黄素-白藜芦醇复方组成物对大鼠体重及内脏脂肪重量 的影响
本实验的姜黄素 -白藜芦醇复方医药组成物共分为 12管， 即姜黄素管、 白藜芦醇 管、 以及第 1"~10"管， 各管的配置方法与实验十一的实验步骤大致相同， 仅姜黄素 与白藜芦醇的比例不同， 而且， 聚氧乙烯 35蓖麻油的浓度为 15%。 姜黄素与白藜芦醇 的比例如表七所示。 表七 姜黄素-白藜芦醇复方医药组成物中，姜黄素与白藜芦醇的重量比以及总浓 度
姜黄素与白藜芦醇的 姜黄素与白藜芦醇的
比例（重量比） 总浓度 (mg/mL) 姜館 1:0 白藜芦醇 0:1
1" 50:1 5
2" 20:1 5
3" 15:1 5
4" 8:1 5
5" 4:1 5
6" 1:1 5
7" 1:4 5
8" 1:10 5
9" 1:20 5
10" 1:30 5 使用 6周龄 SD品系雄性大鼠 (male Sprague-Dawley rat)进行实验。 以正常饲料喂食 52只大鼠 3天使体重约达 175 200 g， 再以高脂饲料喂食 21天使大鼠被诱导为肥胖动物 模式并使体重增加至 400 450 g后， 将大鼠随机分成 13组， 分别为高脂对照组、 姜黄 素组、 白藜芦醇组、 以及第 OIR1 OIR10组， 每组 4只大鼠， 各组大鼠的体重无统计差 异。 然后， 以下列方式给予药物。
高脂对照组： 以皮下注射方式将注射用生理食盐水施用予高脂对照大鼠， 注射部 位为大鼠背部耳后、 肩颊骨上方、 或肩颊骨下方， 于试验第 1、 3、 5、 7、 9、 11日各 注射 1次， 共注射 6次， 每次注射量为每公斤体重注射 4 mL(4 mL/kg)。
姜黄素组、 白藜芦醇组、 以及第 OIR1 OIR10组： 以皮下注射方式分别将姜黄素 管、 白藜芦醇管、 以及第 r'~io"管中的医药组成物施用予姜黄素组、 白藜芦醇组、 以及第 OIR1 OIR10组的大鼠， 注射部位为大鼠背部耳后、 肩颊骨上方、 或肩颊骨下 方， 于试验第 1、 3、 5、 7、 9、 11日各投药 1次， 共投药 6次， 每次投药量为每公斤体 重注射 4 mL(4 mL/kg)，使得每次投药剂量都是每公斤体重施予 20 mg的药物 (每公斤体 重施予的姜黄素与白藜芦醇的总浓度为 4 mL/kg 5 mg/mL = 20 mg/kg；)。
试验期间持续给予高脂饲料， 试验共进行 20天， 于第 21天以二氧化碳牺牲大鼠。 计算各组大鼠的 "相对总增重" 以及 "相对内脏脂肪重量" 。
图 5A的结果显示， 高脂对照组大鼠的相对总增重为 100.0±11.1%， 姜黄素组大鼠 的相对总增重为 102.4±13%， 白藜芦醇组大鼠的相对总增重为 96.3±3.2%， 第 OIR1 OIR10组大鼠的相对总增重依序为为 104.4±9.7%、 81.7±7.6%、 74.2±13.4%、 73.7±11.2%、 60.4±6.3%、 75.4±6.1%、 80.2±7.1%、 79.5±7.5%、 80.9±1 1.2%、 以及 86.3±2.8%。 其中， 与高脂对照组相比， 姜黄素组和白藜芦醇组大鼠的相对总增重未 显著降低差异 (p>0.05)， 显示若是仅提供姜黄素或白藜芦醇， 在本实验的条件下无法 显著减少大鼠体重。 然而， 与高脂对照组相比， 第 OIR2 OIR9组大鼠的相对总增重皆 显著降低 (p<0.05)， 显示姜黄素与白藜芦醇的比例在 20: 1~1 :20范围时， 能显著减少大 鼠体重。 此外， 与姜黄素组或白藜芦醇组相比， 第 OIR2 OIR9组大鼠的相对总增重皆 显著降低 (p<0.05)， 显示姜黄素与白藜芦醇的比例在 20: 1~1 :20范围时具有协同效应 (synergy) 较佳者， 姜黄素与白藜芦醇的比例为 4: 1时具有更佳的协同效应 (synergy)。
图 5B的结果显示， 高脂对照组大鼠的相对内脏脂肪重量为 100.0±24.2%， 姜黄素 组大鼠的相对内脏脂肪重量为 122.2±25.2%， 白藜芦醇组大鼠的相对内脏脂肪重量为 92.5±41.7%， 第 OIR1~OIR10组大鼠的相对内脏脂肪重量依序为 105.8±15.4%、 83.6±17.10/0、 79.4±140/0、 76.9±1 10/0、 60.5±18.2ο/ο、 72.7±10.40/0、 73±12.10/0、 68.4±5.20/0、 86.1±17.1%、 以及 75.8±6.3%。 其中， 与高脂对照组相比， 姜黄素组和白藜芦醇组大 鼠的相对内脏脂肪重量都未显著降低 (p>0.05)， 显示若是仅提供姜黄素或白藜芦醇， 在本实验的条件下无法有效减少大鼠内脏脂肪。然而，与姜黄素组及白藜芦醇组相比， 第 OIR2~OIR10组大鼠的相对内脏脂肪重量已有更降低的趋势， 显示在相同的总药物 浓度下， 将姜黄素与白藜芦醇共同施用于大鼠更能达到减少大鼠内脏脂肪量的效果。 实验十三： 不同剂量的姜黄素-白藜芦醇复方组成物对大鼠体重及内脏脂肪重量 的影响
本实验的姜黄素-白藜芦醇复方医药组成物的配制方法与实验十二第 5"管的步骤 相同， 亦即， 姜黄素与白藜芦醇的比例为 4: 1且聚氧乙烯 35蓖麻油的浓度为 15%。
使用 6周龄 SD品系雄性大鼠 (male Sprague-Dawley rat)进行实验。 以正常饲料喂食 20只大鼠 3天使体重约达 175~200 g， 将大鼠分为 5组， 即正常对照组、 高脂对照组、 低剂量组、 中剂量组、 以及高剂量组。 然后以正常饲料继续喂食正常对照组中的大鼠 21天， 同时， 以高脂饲料喂食高脂对照组、 低剂量组、 中剂量组、 以及高剂量组中的 大鼠 21天， 使高脂对照组、 低剂量组、 中剂量组、 以及高剂量组的大鼠被诱导为肥胖 动物模式并使体重增加至 400 450 g。 然后， 以下列方式进行皮下注射。
正常对照组以及高脂对照组：以皮下注射方式将注射用生理食盐水施用予正常对 照组以及高脂对照组大鼠， 注射部位为大鼠背部耳后、 肩颊骨上方、 或肩颊骨下方， 于试验第 1、 3、 5、 7、 9、 1 1日各注射 1次， 共注射 6次， 每次注射量为每公斤体重注 射 8 mL(8 mL/kg)。
低剂量组： 以皮下注射方式将本实验的姜黄素 -白藜芦醇复方医药组成物施用予 大鼠， 注射部位为大鼠背部耳后、 肩颊骨上方、 或肩颊骨下方， 于试验第 1、 3、 5、 7、 9、 1 1日各投药 1次， 共投药 6次， 每次投药量为每公斤体重注射 2 mL(2 mL/kg)， 使得 每次投药剂量都是每公斤体重施予 8 mg 姜黄素以及 2 mg白藜芦醇。
中剂量组： 投药方式及频率都与低剂量组相同， 仅投药量不同。 每次投药量为每 公斤体重注射 4 mL(4 mL/kg)， 使得每次投药剂量都是每公斤体重施予 16 mg 姜黄素 以及 4 mg白藜芦醇。
高剂量组： 投药方式及频率都与低剂量组相同， 仅投药量不同。 每次投药量为每 公斤体重注射 8 mL(8 mL/kg), 使得每次投药剂量都是每公斤体重施予 32 mg 姜黄素 以及 8 mg白藜芦醇。
试验期间持续给予高脂饲料， 试验共进行 20天， 于第 21天以二氧化碳牺牲大鼠。 计算各组大鼠的 "相对总增重" 以及 "相对内脏脂肪重量" 。
图 6A的结果显示， 正常对照组大鼠的相对总增重为 57.4±8.6%， 高脂对照组大鼠 的相对总增重为 100.0± 1 1.2%， 低剂量组、 中剂量组以及高剂量组大鼠的相对总增重 依序为 76.2±6.7%、 62.4±9.1%、 以及 48.7±10.1%。 其中， 与高脂对照组相比， 低剂量 组、 中剂量组、 以及高剂量组大鼠的相对总增重皆显著降低 (p<0.05)， 显示不同剂量 的姜黄素-白藜芦醇复方医药组成物都能显著减少大鼠体重， 其中又以高剂量组的减 重效果最佳。
图 6B的结果显示， 正常对照组大鼠的相对内脏脂肪重量为 37.0±5.2%， 高脂对照 组大鼠的相对内脏脂肪重量为 100.0±32.2%， 低剂量组、 中剂量组、 以及高剂量组大 鼠的相对内脏脂肪重量依序为 68.1±15.2%、 56.0±15.7%、 以及 46.9±7.2%。 其中， 与 高脂对照组相比， 低剂量组、 中剂量组、 以及高剂量组大鼠的相对内脏脂肪重量皆显 著降低 (p<0.05)，显示不同剂量的姜黄素-白藜芦醇复方医药组成物都能有效减少大鼠 内脏脂肪重量， 其中又以高剂量组的效果最佳。
由上述实验结果可知， 姜黄素 -白藜芦醇复方医药组成物在剂量 10 mg/kg时即具 有显著的减重及减少内脏脂肪的效果， 且剂量越高， 效果越显著。
依发明人的经验， 适用于大鼠的给药剂量为 10 mg/kg ~ 40 mg/kg时， 适用于人类 的给药剂量即为 0.1 80 mg/kg。 较佳者， 施用于人类的给药剂量为 10 40 mg/kg。
较佳者， 施用于人类的剂量为每平方公分注射 0.02 ~ 20毫克。 较佳者， 施用于人 类的剂量为每平方公分注射 0.04 ~ 16毫克。 较佳者， 施用于人类的剂量为每平方公分 注射 0.2 ~ 12毫克。 较佳者， 施用于人类的剂量为每平方公分注射 0.4 ~ 8毫克。
较佳者， 施用于人类的剂量为每公斤注射 0.01 ~ 40毫克。 较佳者， 施用于人类的 剂量为每公斤注射 0.4 ~ 40毫克。 较佳者， 施用于人类的剂量为每公斤注射 0.8 ~ 20毫 克。 实验十四： 姜黄素 -白藜芦醇复方组成物的施用频率对大鼠体重及内脏脂肪重量 的影响
本实验的姜黄素-白藜芦醇复方医药组成物的配制方法与实验十二第 5"管的步骤 相同， 亦即， 姜黄素与白藜芦醇的比例为 4: 1且聚氧乙烯 35蓖麻油的浓度为 15%。
使用 6周龄 SD品系雄性大鼠 (male Sprague-Dawley rat)进行实验。 以正常饲料喂食
20只大鼠 3天使体重约达 175~200 g， 将大鼠分为 5组， 即正常对照组、 高脂对照组、 低频率组、 中频率组、 以及高频率组。 然后， 以正常饲料继续喂食正常对照组中的大 鼠 21天， 同时， 以高脂饲料喂食高脂对照组、 低频率组、 中频率组、 以及高频率组的 大鼠 21天， 使高脂对照组、 低频率组、 中频率组、 以及高频率组中的大鼠被诱导为肥 胖动物模式并使体重增加至 400 450 g后。 然后， 以下列方式进行皮下注射。
正常对照组以及高脂对照组：以皮下注射方式将注射用生理食盐水施用予正常对 照组以及高脂对照组大鼠， 注射部位为大鼠背部耳后、 肩颊骨上方、 或肩颊骨下方。 于试验第 1、 3、 5、 7、 9、 11、 13、 15日各注射 1次， 共注射 8次， 每次注射量为每公 斤体重注射 4 mL(4 mL/kg)o
低频率组： 以皮下注射方式将本实验的姜黄素 -白藜芦醇复方医药组成物施用予 大鼠， 注射部位为大鼠背部耳后、 肩颊骨上方、 或肩颊骨下方， 于试验第 1、 3、 5、 7 日各投药 1次， 共投药 4次， 每次投药量为每公斤体重注射 4 mL(4 mL/kg), 使得每次 投药剂量都是每公斤体重施予 16 mg 姜黄素以及 4 mg白藜芦醇。
中频率组： 投药方式及每次的投药剂量都与低频率组相同， 仅投药频率不同。 于 试验第 1、 3、 5、 7、 9、 1 1日各投药 1次， 共投药 6次。
高频率组： 投药方式及每次的投药剂量都与低频率组相同， 仅投药频率不同。 于 试验第 1、 3、 5、 7、 9、 1 1、 13、 15日各投药 1次， 共投药 8次。
试验期间持续给予高脂饲料， 试验共进行 20天， 于第 21天以二氧化碳牺牲大鼠。 计算各组大鼠的 "相对总增重" 以及 "相对内脏脂肪重量" 。
图 7A的结果显示， 正常对照组大鼠的相对总增重为 57.6± 12.1%， 高脂对照组大 鼠的相对总增重为 100.0±9.2%， 低频率、 中频率组、 以及高频率组大鼠的相对总增重 依序为 87.5± 15.8%、 66.2±13.0%、 以及 53.7±1 1.7%。 其中， 与高脂对照组相比， 高频 率组大鼠的相对总增重显著降低 (p<0.05)， 显示投药频率为 8次时能显著减少大鼠体 重。
图 7B的结果显示， 正常对照组大鼠的相对内脏脂肪重量为 38.7±7.4%， 高脂对照 组大鼠的相对内脏脂肪重量为 100.0± 16.2%， 低频率组、 中频率组、 以及高频率组大 鼠的相对内脏脂肪重量依序为 72.2± 13.7%、 66.8±4.5%、 以及 58.6± 10.0%。 其中， 与 高脂对照组相比， 低频率组、 中频率组、 以及高频率组大鼠的相对内脏脂肪重量皆显 著降低 (ρ<0.05)， 显示不同施用频率都能显著减少大鼠内脏脂肪量， 其中又以高频率 组的效果最佳。
由上述实验结果可知，姜黄素 -白藜芦醇复方医药组成物的施用频率在 4次时即具 有显著减少内脏脂肪的效果， 施用频率在 8次时能达到显著减重的效果。
依发明人的经验， 适用于大鼠的给药频率为 4~8次时， 适用于人类的给药频率即 为 1 -16次。 较佳者， 施用于人类的给药频率为 1~6次。
较佳者， 施用于人类的频率为每 1~90天施用 1~12次。较佳者， 施用于人类的频率 为每 1~90天施用 1~6次。抑或是， 较佳者， 施用于人类的频率为每 1~90天施用 3~60次； 较佳者， 施用于人类的频率为每 1~60天施用 6~42次。
由本发明的实施例可知， 本发明提供的姜黄素单方医药组成物、 姜黄素-白藜芦 醇复方医药组成物、 姜黄素-绿茶萃取物复方医药组成物、 姜黄素 -其他脂溶性药物复 方医药组成物、 以及姜黄素-水溶性药物复方医药组成物、 以及本发明提供的其他医 药组成物，均可减少体重及内脏脂肪量。因此，本发明提供的姜黄素单方医药组成物、 姜黄素-白藜芦醇复方医药组成物、姜黄素-绿茶萃取物复方医药组成物、姜黄素 -其他 脂溶性药物复方医药组成物、 以及姜黄素-水溶性药物复方医药组成物、 以及本发明 提供的其他医药组成物， 可用于制备皮下植入装置、 皮下植入物、 埋植式输注液、 软 膏、 或贴布， 而能透过皮下植入、 埋植式输注、 软膏或贴布等方式施用于个体， 以减 少个体的体重或体脂肪。
较佳者， 本发明提供的姜黄素单方医药组成物、 姜黄素-白藜芦醇复方医药组成 物、 姜黄素-绿茶萃取物复方医药组成物、 姜黄素-其他脂溶性药物复方医药组成物、 以及姜黄素-水溶性药物复方医药组成物、 以及本发明提供的其他医药组成物， 可透 过皮下注射方式或皮下脂肪注射方式， 使个体的体重或体脂肪减少。 因此， 本发明提 供的姜黄素单方医药组成物、 姜黄素-白藜芦醇复方医药组成物、 姜黄素 -绿茶萃取物 复方医药组成物、 姜黄素-其他脂溶性药物复方医药组成物、 以及姜黄素 -水溶性药物 复方医药组成物、 以及本发明提供的其他医药组成物， 可用于制备用于减少体重或体 脂肪的皮下脂肪层注射针剂或皮下注射针剂。
以上所述仅为本发明的较佳实施例， 并非用以限定本发明的权利要求范围， 因此 凡其它未脱离本发明所揭示的精神下所完成的各种更动或润饰等，均应包含于本发明 的权利要求范围内。

Claims

权利要求
1、 一种减少过重或肥胖个体体重的方法， 包括在该过重或肥胖个体施用一皮下注射 剂， 其中， 该皮下注射剂包含：
一医药上可接受的水溶液；
多个含药微胞 (micelle), 为均匀分散在该医药上可接受的水溶液中； 其中， 该含 药微胞为医药上可接受的一聚氧乙烯蓖麻油衍生物（polyoxyethylene castor oil derivatives)所形成的一微形结构， 且该聚氧乙烯蓖麻油衍生物的亲水亲油性平衡值 (hydrophilic-lipophilic balance value, HLB值)大于 10; 以及
被包覆在所述含药微胞中的姜黄色素类物质 (curcuminoid);
其中， 包覆在该些含药微胞中的姜黄色素类物质的总浓度为 0.2 167 mg/g。
2、 如权利要求 1所述的方法， 该医药上可接受的水溶液中更包含一总儿茶素成份。
3、 如权利要求 1所述的方法， 其中， 该些含药微胞中的姜黄色素类物质的总浓度为 0.4-167 mg/g; 抑或是， 该些含药微胞中的姜黄色素类物质的总浓度为 0.5 111 mg/g; 抑 或是， 该些含药微胞中的姜黄色素类物质的总浓度为 2~91 mg/g。
4、 如权利要求 2所述的方法， 其中， 该总儿茶素成份的浓度为 0.04 835 mg/g。
5、 如权利要求 4所述的方法， 其中， 该总儿茶素成份的浓度为 0.15 733 mg/g。
6、 如权利要求 2所述的方法， 该总儿茶素成份为表没食子儿茶素没食子酸酯 (Epigallocatechin gallate)、表儿茶素 (Epicatechin)、表儿茶素没食子酸酯 (Epicatechin gallate)、 表没食子儿茶素 (Epigallocatechin)、 没食子儿茶素没食子酸酯 (Gallocatechin gallate)、 没食 子儿茶素 (Gallocatechin)、 儿茶素没食子酸酯 (Catechin gallate)、 儿茶素 (Catechin)中的至少 一种或其组合。
7、如权利要求 2所述的方法，该皮下注射剂中的姜黄色素类物质与该总儿茶素成份的 重量比为 50: 1至 1 :20。
8、如权利要求 7所述的方法，该皮下注射剂中的姜黄色素类物质与该总儿茶素成份的 重量比为 30: 1至 1 : 10; 抑或是， 该皮下注射剂中的姜黄色素类物质与该总儿茶素成份的重 量比为 10: 1至 1 :4; 抑或是， 该皮下注射剂中的姜黄色素类物质与该总儿茶素成份的重量 比为 7: 1至 1 :4。
9、 如权利要求 1所述的方法， 该皮下注射剂的施用剂量为每公斤注射 0.15 40 毫克。
10、 如权利要求 9所述的方法， 该皮下注射剂的施用剂量为每公斤注射 0.25 25 毫克。
11、如权利要求 1所述的方法， 该皮下注射剂的施用频率为每 1~90天施用于施用 部位 1~6次。
12、 如权利要求 1所述的方法， 其中， 该姜黄色素类物质与聚氧乙烯蓖麻油衍生 物的重量比为 1 : 5~ 1： 750。
13、 如权利要求 1所述的方法， 该聚氧乙烯蓖麻油衍生物为聚氧乙烯 35蓖麻油 (Cremophor ELP)^ 聚氧乙烯 40氢化蓖麻油（Cremophor RH 40)、 及其他聚氧乙烯蓖麻 油衍生物中的至少一种或其组合。
14、 如权利要求 1所述的方法， 该皮下注射剂中更包含一助溶剂 (cosolvent)、 一 助悬剂（suspending agent；)、 以及一油相赋形剂（oil phase excipients)中的至少一种或其 组合。
15、 如权利要求 14所述的方法， 该油相赋形剂以及该助溶剂中的至少一种与该 聚氧乙烯蓖麻油衍生物共同形成该微形结构。
16、 如权利要求 1所述的方法， 该姜黄色素类物质为姜黄素 (cUrCUmin)。
17、 一种减少过重或肥胖个体体重的方法， 包括在该过重或肥胖个体施用一皮 下注射剂， 其中， 该皮下注射剂包含：
多个第一含药微胞 (micelle)以及多个第二含药微胞； 该第一含药微胞为医药上可接受 的一聚氧乙烯蓖麻油衍生物 (polyoxyethylene castor oil derivatives)所形成的一微形结构，且 该聚氧乙烯蓖麻油衍生物的亲水亲油性平衡值 (hydrophilic-lipophilic balance value, HLB 值；)大于 ιο;
被包覆在所述第一含药微胞中的姜黄色素类物质 (curcuminoid); 以及
被包覆在所述第二含药微胞中的白藜芦醇；
其中， 包覆在该些第一含药微胞中的姜黄色素类物质的总浓度为 0.2 167 mg/g。
18、如权利要求 17所述的方法， 其中， 包覆在该些第二含药微胞中的白藜芦醇的总浓 度为 0.2~733 mg/g。
19、如权利要求 17所述的方法，包覆在该些第一含药微胞中的姜黄色素类物质的总浓 度以及包覆在该些第二含药微胞中的白藜芦醇的总浓度的总和为 0.4 900 mg/g。
20、如权利要求 17所述的方法， 其中， 包覆在该些第一含药微胞中的姜黄色素类物质 的总重量与包覆在该些第二含药微胞中的白藜芦醇的总重量的比例为 50: 1至 1 :30。
21、如权利要求 20所述的方法， 其中， 包覆在该些第一含药微胞中的姜黄色素类物质 的总重量与包覆在该些第二含药微胞中的白藜芦醇的总重量的比例为 20: 1至 1 :20。
22、 如权利要求 17所述的方法， 该皮下注射剂的施用剂量为每公斤注射 0.15 40 毫克。
23、 如权利要求 17所述的方法， 该皮下注射剂的施用剂量为每公斤注射 0.25 25
24、 如权利要求 17所述的方法， 该皮下注射剂的施用频率为每 1~90天施用于施 用部位 1~6次。
25、 如权利要求 17所述的方法， 其中， 包覆在该些第一含药微胞中的姜黄色素 类物质的总重量与聚氧乙烯蓖麻油衍生物的总重量的比例为 1 :5 ~ 1 :750。
26、 如权利要求 17所述的方法， 该皮下注射剂中更包含一助溶剂 (cosolvent)、 一 助悬齐 ij (suspending agent )、 以及一油相赋开剂（oil phase excipients)中的至少一种或其 组合。
27、 如权利要求 26所述的方法， 该油相赋形剂以及该助溶剂中的至少一种与该 聚氧乙烯蓖麻油衍生物共同形成该微形结构。
28、 如权利要求 17所述的方法， 该第二含药微胞为医药上可接受的一第二聚氧 乙烯蓖麻油衍生物 (polyoxy ethylene castor oil derivatives)所形成的一第二微形结构， 且该第二聚氧乙烯蓖麻油衍生物的亲水亲油性平衡值 (hydrophilic-lipophilic balance value, HLB值；)大于 10。
29、 如权利要求 17或 28所述的方法， 其中， 该聚氧乙烯蓖麻油衍生物为聚氧乙 烯 35蓖麻油（Cremophor ELP)、 聚氧乙烯 40氢化蓖麻油（Cremophor RH 40)、 及其他聚 氧乙烯蓖麻油衍生物中的至少一种或其组合； 抑或是， 该第二聚氧乙烯蓖麻油衍生 物为聚氧乙烯 35蓖麻油（Cremophor ELP) ^ 聚氧乙烯 40氢化蓖麻油（Cremophor RH 40)、 及其他聚氧乙烯蓖麻油衍生物中的至少一种或其组合。
30、 如权利要求 17所述的方法， 该姜黄色素类物质为姜黄素 (CUrCUmin)。
PCT/IB2017/055129 2015-11-20 2017-08-25 用于減少体重的皮下注射剂及其用途 WO2018037384A1 (zh)

Priority Applications (8)

Application Number Priority Date Filing Date Title
US16/327,466 US10716824B2 (en) 2016-08-26 2017-08-25 Subcutaneous injection formulation for reducing body weight and uses thereof
JP2019510854A JP2019528297A (ja) 2015-11-20 2017-08-25 体重減少に用いられる皮下注射製剤およびその用途
KR1020197008320A KR20190040305A (ko) 2016-08-26 2017-08-25 체중 감소를 위한 피하 주사제 및 그의 용도
EP17843043.5A EP3505168A1 (en) 2016-08-26 2017-08-25 Subcutaneous injection for reducing body weight and application thereof
CN201780050055.5A CN109640969A (zh) 2016-08-26 2017-08-25 用于減少体重的皮下注射剂及其用途
RU2019108198A RU2753507C2 (ru) 2015-11-20 2017-08-25 Композиция подкожной инъекции для снижения массы тела и ее применения
CA3033041A CA3033041A1 (en) 2016-08-26 2017-08-25 A subcutaneous injection formulation for reducing body weight and uses thereof
US16/926,631 US20200338152A1 (en) 2016-08-26 2020-07-10 Subcutaneous injection formulation for reducing body weight and uses thereof

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IBPCT/IB2016/055102 2016-08-26
PCT/IB2016/055102 WO2017037594A2 (zh) 2015-08-28 2016-08-26 用于减少局部脂肪的医药组成物及其用途
IBPCT/IB2016/055101 2016-08-26
PCT/IB2016/055101 WO2017037593A2 (zh) 2015-08-28 2016-08-26 用于减少局部脂肪的医药组成物及其用途

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US16/327,466 A-371-Of-International US10716824B2 (en) 2016-08-26 2017-08-25 Subcutaneous injection formulation for reducing body weight and uses thereof
US16/926,631 Continuation US20200338152A1 (en) 2016-08-26 2020-07-10 Subcutaneous injection formulation for reducing body weight and uses thereof

Publications (1)

Publication Number Publication Date
WO2018037384A1 true WO2018037384A1 (zh) 2018-03-01

Family

ID=66641545

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2017/055129 WO2018037384A1 (zh) 2015-11-20 2017-08-25 用于減少体重的皮下注射剂及其用途

Country Status (6)

Country Link
US (2) US10716824B2 (zh)
EP (1) EP3505168A1 (zh)
KR (1) KR20190040305A (zh)
CN (1) CN109640969A (zh)
CA (1) CA3033041A1 (zh)
WO (1) WO2018037384A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023221945A1 (en) * 2022-05-16 2023-11-23 Caliway Biopharmaceuticals Co., Ltd. Compositions and methods for alleviating conditions caused by abnormal subcutaneous deposit of adipose tissue or fat

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2018002462A (es) 2015-08-28 2018-06-19 Caliway Biopharmaceuticals Co Ltd Una composicion farmaceutica para reducir la grasa localizada y sus usos.
US11318110B2 (en) 2015-08-28 2022-05-03 Caliway Biopharmaceuticals Co., Ltd. Pharmaceutical composition for reducing local fat and uses thereof

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6475530B1 (en) * 2000-05-31 2002-11-05 Eric H. Kuhrts Methods and compositions for producing weight loss
US20030147979A1 (en) * 2001-10-23 2003-08-07 Tatsumasa Mae Ligand for peroxisome proliferator-activated receptor
US20040071799A1 (en) * 2001-02-12 2004-04-15 Xiurong Xu Herbal compositions and methods for effecting weight loss in humans
US20050267221A1 (en) * 2004-05-14 2005-12-01 Research Development Foundation Use of curcumin and analogues thereof as inhibitors of ACC2
US20060188590A1 (en) * 2005-01-05 2006-08-24 Mitsunori Ono Compositions for treating diabetes or obesity
US20090324703A1 (en) * 2006-03-06 2009-12-31 Frautschy Sally A Bioavailable curcuminoid formulations for treating alzheimer's disease and other age-related disorders
WO2015081319A2 (en) * 2013-11-27 2015-06-04 Research Foundation Of The City University Of New York Activity enhancing curcumin compositions and methods of use
US20170157195A1 (en) * 2014-08-28 2017-06-08 Caliway Biopharmaceuticals Co., Ltd. Plant extract composition for reducing topical fat and promoting weight loss as well as applications thereof

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1895239B (zh) * 2006-06-20 2010-05-12 中国人民解放军第二军医大学 一种姜黄素制剂及其制备方法
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
CN103054807A (zh) * 2011-12-22 2013-04-24 苏州雷纳药物研发有限公司 一种肌内或皮下注射用姜黄素微粉组合物及其制备方法和用途
WO2014138426A2 (en) * 2013-03-07 2014-09-12 Topokine Therapeutics, Inc. Methods and compositions for reducing body fat and adipocytes
CN103285401A (zh) * 2013-05-27 2013-09-11 沈阳药科大学 一种能提高难溶性药物溶解性和生物利用度的组合物
JP6473505B2 (ja) * 2014-08-28 2019-02-20 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 局所の脂肪と体重の減少に用いられる組成物およびその医薬品と使用
MX2018002462A (es) 2015-08-28 2018-06-19 Caliway Biopharmaceuticals Co Ltd Una composicion farmaceutica para reducir la grasa localizada y sus usos.

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6475530B1 (en) * 2000-05-31 2002-11-05 Eric H. Kuhrts Methods and compositions for producing weight loss
US20040071799A1 (en) * 2001-02-12 2004-04-15 Xiurong Xu Herbal compositions and methods for effecting weight loss in humans
US20030147979A1 (en) * 2001-10-23 2003-08-07 Tatsumasa Mae Ligand for peroxisome proliferator-activated receptor
US20050267221A1 (en) * 2004-05-14 2005-12-01 Research Development Foundation Use of curcumin and analogues thereof as inhibitors of ACC2
US20060188590A1 (en) * 2005-01-05 2006-08-24 Mitsunori Ono Compositions for treating diabetes or obesity
US20090324703A1 (en) * 2006-03-06 2009-12-31 Frautschy Sally A Bioavailable curcuminoid formulations for treating alzheimer's disease and other age-related disorders
WO2015081319A2 (en) * 2013-11-27 2015-06-04 Research Foundation Of The City University Of New York Activity enhancing curcumin compositions and methods of use
US20170157195A1 (en) * 2014-08-28 2017-06-08 Caliway Biopharmaceuticals Co., Ltd. Plant extract composition for reducing topical fat and promoting weight loss as well as applications thereof

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
"Kolliphor ELP", O-BASF, March 2012 (2012-03-01), pages 1 - 7, XP055584413 *
"Kolliphor RH 40", O-BASF, December 2011 (2011-12-01), pages 1 - 9, XP055584417 *
HU: "Enhancement of Oral Bioavailability of Curcumin by a Novel Solid Dispersion System", AAPS, vol. 16, no. 6, 25 March 2015 (2015-03-25), pages 1327 - 1334, XP035566124 *
KISS LÓRÁND, ET AL.: "Kinetic Analysis of the Toxicity of Pharmaceutical Excipients Cremophor EL and RH40 on Endothelial and Epithelial Cells", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 102, no. 4, 29 January 2013 (2013-01-29), pages 1173 - 1181, XP055584406 *
MOHSEN MEYDANI ET AL.: "Dietary Polyphenols and Obesity", NUTRIENTS, vol. 2, 2010, pages 735 - 751
NAKSURIYA, CURCUMIN NANOFORMULATIONS: A REVIEW OF PHARMACEUTICAL PROPERTIES AND PRECLINICAL STUDIES AND CLINICAL DATA RELATED TO CANCER TREATMENT, 15 January 2014 (2014-01-15), XP028822063 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023221945A1 (en) * 2022-05-16 2023-11-23 Caliway Biopharmaceuticals Co., Ltd. Compositions and methods for alleviating conditions caused by abnormal subcutaneous deposit of adipose tissue or fat

Also Published As

Publication number Publication date
CN109640969A (zh) 2019-04-16
CA3033041A1 (en) 2018-03-01
EP3505168A1 (en) 2019-07-03
KR20190040305A (ko) 2019-04-17
US20200338152A1 (en) 2020-10-29
US10716824B2 (en) 2020-07-21
US20190167753A1 (en) 2019-06-06

Similar Documents

Publication Publication Date Title
TWI667044B (zh) 用於減少體重的皮下注射劑及其用途
JP2018531220A6 (ja) 局所脂肪減少に用いられる医薬組成物及びその用途
US20200338152A1 (en) Subcutaneous injection formulation for reducing body weight and uses thereof
US11318110B2 (en) Pharmaceutical composition for reducing local fat and uses thereof

Legal Events

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

Ref document number: 17843043

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3033041

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2019510854

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 20197008320

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2017843043

Country of ref document: EP

Effective date: 20190326