WO2016008440A1 - 含有13种甘油酯的薏苡仁油、制剂及其应用 - Google Patents
含有13种甘油酯的薏苡仁油、制剂及其应用 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/231—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having one or two double bonds
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- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/899—Poaceae or Gramineae (Grass family), e.g. bamboo, corn or sugar cane
- A61K36/8994—Coix (Job's tears)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids
Definitions
- the invention relates to the field of pharmacy, in particular to a coix seed oil, a preparation, a preparation method thereof and application thereof in preparing an antitumor drug.
- Coix seed is a mature dry seed of Coix lacryma-jobi L.var ma-yuen (Roman.) Stapf. It is a diuretic drug for a long time. Modern research has found that Coix seed has pharmacological effects such as analgesic, anti-inflammatory, immune regulation, anti-ulcer, hypolipidemic and weight loss. In recent years, domestic and foreign scholars have studied the chemical constituents of Coix seed by TLC, HPLC-MS, GC and other methods, and found that it contains a variety of active ingredients, including coix seed esters, triglycerides, fatty acids, lactams. Compounds such as terpenoids, saccharides, sterols, and triterpenoids.
- esters are the first to be found to have anti-tumor activity, and are also the most reported chemical components.
- Kanglaite injection which is currently used as an active ingredient in Chinese herbal medicine, has been widely used, its use of coix seed oil is complicated, and contains triglyceride and diglyceride in addition to triglyceride. And fatty acid esters, etc., which will inevitably pose great challenges to quality control and clinical drug safety in the actual production process.
- the invention uses the hazelnut powder as a raw material, adopts the steps of supercritical carbon dioxide extraction, alkalization, neutral alumina and kaolin purification to obtain an effective part of coix seed oil; by separating and identifying the active components thereof, it is determined.
- the composition is mainly composed of eight triglyceride components and five diglyceride components; and further physical and chemical constants are determined, and the optimal acid value, iodine value, saponification value, refractive index and relative density are determined.
- the use of the coix seed oil of the invention is determined by the composition and composition, and the quality stability between batches in industrial production is ensured.
- the object of the present invention is to provide a coix seed oil extracted from coix seed, which is characterized in that the coix seed oil contains five kinds of diglyceride components and eight triglyceride components in the following mass percentages: 1,3-dioleic acid diglyceride 0.40-0.58%, 1-linoleic acid-3-oleic acid diglyceride 0.91 ⁇ 1.31%, 1,2-dioleic acid diglyceride 0.24 ⁇ 0.35%, 1- Oleic acid-2-linoleic acid diglyceride 0.66-0.95%, 1,2-dilinoleic acid glyceride 0.33-0.47%, trilinoleic acid glyceride 4.87-6.99%, 1-oleic acid-2,3- Dilinoleic acid glyceride 13.00 ⁇ 18.69%, 1-palmitic acid-2,3-dilinoleic acid glyceride 5.25 ⁇ 7.54%, 1,3-dioleic acid-2-linoleic acid gly
- the mass percentage of the above five diglyceride components and eight triglyceride components is: 1,3-dioleic acid diglyceride 0.45-0.55%, 1-linoleic acid-3-oleic acid glycerol Diester 1.03 to 1.25%, 1,2-dioleic acid diglyceride 0.27 to 0.33%, 1-oleic acid-2-linoleic acid diglyceride 0.75 to 0.91%, 1,2-dilinoleic acid glyceride 0.37-0.45%, linoleic acid glyceride 5.47-6.69%, 1-oleic acid-2,3-dilinoleic acid glyceride 14.63 ⁇ 17.88%, 1-palmitic acid-2,3-dilinoleic acid glyceride 5.9 to 7.21%, 1,3-dioleic acid-2-linoleic acid glyceride 14.88 to 18.19%, 1-palmitic acid-2-linoleic acid-3-
- the mass percentage of the above five diglyceride components and eight triglyceride components is: 1,3-dioleic acid diglyceride 0.49 to 0.51%, 1-linoleic acid-3-oleic acid Diglyceride 1.12 ⁇ 1.16%, 1,2-dioleic acid diglyceride 0.29 ⁇ 0.31%, 1-oleic acid-2-linoleic acid diglyceride 0.81 ⁇ 0.85%, 1,2-dilinoleic acid glycerin Ester 0.40 ⁇ 0.42%, trilinoleic acid glyceride 5.96 ⁇ 6.20%, 1-oleic acid-2,3-dilinoleic acid glyceride 15.93 ⁇ 16.58%, 1-palmitic acid-2,3-dilinoleic acid glycerin Ester 6.43 ⁇ 6.69%, 1,3-dioleic acid-2-linoleic acid glyceride 16.20 ⁇ 16.87%, 1-palmitic acid-2-linoleic acid-3-ole
- the above content refers to the mass percentage of the diglyceride or triglyceride compound in the coix seed oil, according to the present invention.
- the coix seed oil prepared by the method is used as a raw material, and five diglyceride monomer compounds and eight triglyceride monomer compounds are obtained by preparative chromatography, and weighed and calculated. It can also be derived according to conventional analytical methods in the art.
- the physicochemical constant of the eucalyptus oil is as follows: a relative density of 0.916 to 0.920 at 20 ° C, a refractive index of 1.471 to 1.474 at 20 ° C, an acid value of ⁇ 0.2, an iodine value of 100 to 106, and a saponification value of 186 to 195;
- the coix seed oil of the present invention is obtained by the following method:
- Supercritical carbon dioxide extraction the coix seed is pulverized into 10 mesh to 80 mesh, and extracted by a 600 L ⁇ 2 supercritical CO 2 extractor.
- the coix seed powder is charged into the extraction kettle, and the CO 2 preheater is heated by a jacketed circulating hot water.
- the extraction kettle and the separation column are such that the extraction temperature and the separation temperature are respectively 33 to 45 ° C and 30 to 45 ° C, and the outlet temperatures of the first stage analytical reactor and the secondary analytical reactor are maintained at 20 to 50 ° C and 15 to 35 ° C, respectively;
- the CO 2 fluid enters the separation column, and the pressure of the separation column is controlled to be 7-10 Mpa, and the coix seed oil is separated.
- the CO 2 gas from the separation column enters the primary and secondary analytical reactors, respectively, and the pressure is maintained at 5-7 Mpa and 4-6 Mpa respectively. Discarding the impurities such as moisture obtained by analysis, the CO 2 gas is converted into liquid CO 2 through a condenser, recycled, and continuously extracted for 2 to 3 hours to obtain coix seed oil;
- Refining Take the coix seed oil obtained by supercritical CO 2 extraction, add 60% of the oil weight of 60 ° C ⁇ 90 ° C petroleum ether, and then add the oil weight 36% ⁇ 56% of 2% NaOH solution according to the acid value, after stirring for 10 min After standing for 18 to 24 hours, the lower layer of soap is removed, and the upper layer is washed with purified water, and after standing for 18 to 24 hours, the lower layer of wastewater is removed; the upper layer is taken for the second water washing, and after standing for 40 to 50 hours, the lower layer of wastewater is removed.
- the lower layer of wastewater is removed; the upper layer of oil is heated under reduced pressure and dried under reduced pressure, and then the activated neutral alumina is added with an oil weight of 8% to 12%, stirred, placed in a cold place, filtered, and filtered. Under nitrogen-filled conditions, it is concentrated under heating and reduced pressure, and then dried at 160-170 ° C under reduced pressure.
- the bacteria are 1-2 hours, cooled and filtered through a 0.2 ⁇ m microporous membrane, and dispensed into a 500 ml glass infusion bottle, filled with nitrogen, sealed, and obtained;
- the refining step is as follows:
- the coix seed oil obtained by supercritical CO 2 extraction is added with 60% of oil weight 60 ° C ⁇ 90 ° C petroleum ether, and then according to the acid value, adding oil weight 36% ⁇ 56% 2% NaOH solution, stirring for 10 min, then static After 20h, the lower layer of soap was removed, and the upper layer was washed with purified water. After standing for 22 hours, the lower layer of wastewater was removed. The upper layer was taken for the second water washing. After standing for 46 hours, the lower layer of wastewater was removed. The upper layer was refilled by 70%.
- the coix seed oil of the invention is a pale yellow clear liquid with slight gas and mild taste; it is very soluble in petroleum ether or chloroform, soluble in acetone, slightly soluble in ethanol, and insoluble in water.
- the coix seed oil prepared according to the method of the present invention is tested according to an appendix method of the Chinese Pharmacopoeia 2010 edition, and the physical and chemical constants thereof are: relative density of 0.916 to 0.920 at 20 ° C, and refractive index of 1.471 to 1.474 at 20 ° C, acid The value is ⁇ 0.2, the iodine value is 100 to 106, and the saponification value is 186 to 195.
- the acid value in the pharmacopoeia refers to the weight (mg) of potassium hydroxide required to neutralize the free fatty acid contained in 1 gram of fat, fatty oil or the like. In the quality study of oil and fat products, the acid value is an important evaluation index.
- the acid value is less than 0.2, that is, the purification process by supercritical extraction parameters and alkalization in the preparation process.
- the prepared hazelnut oil has the following advantages: on the one hand, the free fatty acid content as an impurity is extremely low, and the finished product quality is good; on the other hand, a large amount of active components of diglyceride and triglyceride are enriched, and the purity is high. And wherein the diglyceride and triglyceride components are clear in type and stable in content.
- the preparation method of the invention has high yield, low cost, stable product, is suitable for industrial production, and is safe and controllable.
- the pharmaceutically acceptable carrier includes conventional diluents, excipients, fillers, emulsifiers, binders, lubricants, absorption enhancers, surfactants, disintegrants, lubricants or An antioxidant, if necessary, a flavoring agent, a sweetener, a preservative or a coloring agent.
- the pharmaceutically acceptable carrier may be selected from the group consisting of: mannitol, sorbitol, sodium metabisulfite, sodium hydrogen sulfite, sodium thiosulfate, cysteine hydrochloride, thioglycolic acid, methionine, soybean phospholipid, vitamin C, vitamin E , EDTA disodium, EDTA calcium sodium, monovalent alkali metal carbonate, acetate, phosphate or its aqueous solution, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acid, sodium chloride, potassium chloride, sodium lactate, hydroxybenzene Ethyl ester solution, benzoic acid, potassium sorbate, chlorhexidine acetate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivatives, cellulose and Derivatives, alginate, gelatin, polyvin
- the pharmaceutical preparation may be an oral solid preparation, an oral liquid preparation or an injection.
- the oral solid preparation is selected from the group consisting of a capsule, a tablet, a dropping pill, a granule, and a concentrated pill;
- the oral liquid preparation is selected from an aqueous or oily suspension, a solution, an emulsion, a syrup or an elixir, or It is a dry product which can be formulated with water or other suitable carrier before use;
- the injection is selected from one of a nanosuspension, a liposome, an emulsion, a lyophilized powder injection and an aqueous injection.
- the injection comprises the following components: 50-350 g of the coix seed oil of the invention, 10-40 g of soybean phospholipid for injection or soybean lecithin for injection, glycerol for injection or 15-50 g of glycerin for injection, and water for injection is added. 1000ml.
- coix seed oil the oil ester and the water phase are separately heated to 60-70 ° C, and then placed in a high-pressure homogenizer for high-pressure emulsification.
- the emulsifier homogenizer low pressure is 5 to 12 MPa
- the high pressure is 25 to 50 MPa.
- the recycling homogenization 3 to 6 times, to 2 ⁇ m or less particles should be not less than 95%, particles above 5 ⁇ m should not be detected, if necessary, adjust the pH to 4.8 ⁇ 8.5, preferably 6.8 ⁇ 7.0, most preferably 6.8 with NaOH or HCl ;
- the uniform emulsion nitrogen gas is pressurized and filtered through a microporous filter cartridge of 3 ⁇ m or less, sterilized by nitrogen filling, and cooled.
- the capsule comprises the following components: 200 to 800 g of coix seed oil, 0.20 to 0.60 g of an antioxidant and/or an emulsifier, and 1000 capsules.
- Preparation of glue Weigh the appropriate amount of gelatin, purified water, glycerin and preservative according to the weight ratio of 1:0.6 ⁇ 1.2:0.3 ⁇ 0.8:0.0001 ⁇ 0.01; glycerin, purified water and preservative (selected from 10% hydroxybenzene) Ethyl ester solution, one of benzoic acid, potassium sorbate and chlorhexidine acetate) is added to a plastic can, heated to 70 ° C ⁇ 90 ° C, then add gelatin, stir constantly, vacuum until gelatin is completely dissolved, will Glue filtration, stored at 56 ⁇ 62 ° C, spare;
- Preparation of liquid medicine Add the formula amount of coix seed oil, antioxidant and/or emulsifier (antioxidant is vitamin E, emulsifier is Tween 80) into the batching tank, and stir constantly until it is evenly mixed;
- antioxidant is vitamin E
- emulsifier is Tween 80
- Pressure capsule select the appropriate pellet mold according to the size of the capsule, and enter at 15 ⁇ 30°C and relative humidity less than 35%. After the pressure pellets are shaped, the pellets are dried, the pellets are removed, and the pellets are washed with 95% medicinal ethanol, and then dried until the water content is less than 12%. The unqualified capsules are removed by visual inspection, printed, and packaged.
- the invention shows through the pharmacodynamic experiment that the coix seed oil and its preparation have different degrees of inhibition effects on various human tumor cell lines, and can be used as a medicine for treating tumor diseases.
- the object of the present invention is to provide a above-mentioned coix seed oil, a pharmaceutical preparation alone or in combination with platinum, an alkylating agent, a difluoronucleoside, an antibiotic, a cytotoxic or a hormonal chemical antitumor drug. Application in anti-tumor or inflammatory drugs.
- the platinum is preferably cisplatin or carboplatin
- the alkylating agent is preferably cyclophosphamide
- the difluoronucleoside is preferably gemcitabine hydrochloride
- the antibiotics are preferably mitoxantrone, mitomycin, cytotoxic
- the class is docetaxel, paclitaxel
- the hormone is preferably leuprolide acetate
- the tumor refers to early, middle or advanced lung cancer, liver cancer, pancreatic cancer, prostate cancer, ovarian cancer, breast cancer, sarcomatoid carcinoma Or carcinosarcoma
- the inflammation refers to benign prostatic hyperplasia.
- compositions of the invention and their formulations in combating tumors or treating inflammation are illustrated below by experimental data.
- Cell lines PANC-1 (human pancreatic cancer cells), SKOV3 (human ovarian cancer cells), MCF-7 (human breast cancer cells), Bcap-37 (human breast cancer cells), SMMC-7721 (human liver cancer) Cells), HepG-2 (human liver cancer cells), A549 (human lung cancer cells), H460 (human lung cancer cells), the above cell lines were preserved by the Shanghai Pharmaceutical Industry Research Pharmacological Evaluation Research Center and maintained.
- DMEM complete medium 10% newborn calf serum (GIBCO BRL), double antibody was added.
- Trypsin purchased from Invitrogen, stored at -20 °C.
- PBS Phosphate buffer
- MTT (AMRESCO) solution A solution of 5 mg/ml was prepared with PBS.
- Dissolving solution 10 ml of SDS, 5 ml of isobutanol and 0.1 ml of concentrated hydrochloric acid per 100 ml of deionized double distilled water.
- the inhibitory effect of the sample on the above cell line was measured by the MTT method.
- Cell culture 1 The cells were taken out from liquid nitrogen, rapidly thawed in a 37 ° C water bath, and the cells were transferred to a 10 ml sterile centrifuge tube in a sterile table to add 6 ml of the cell culture medium, and centrifuged at 1000 rpm for 5 minutes. Discard the supernatant, add 5-6 ml of cell culture medium to the pellet, pipette it to suspend it, transfer it to the cell culture flask, and place it in a 37 °C cell culture incubator.
- the cells are trypsinized and washed, suspended in a medium containing 10% calf serum, counted by the trypan blue staining method, and the cell suspension is adjusted.
- the density is 2 x 10 5 cells/ml.
- Human lung cancer A549 cell line frozen in liquid nitrogen was collected and cultured at 37 ° C and 5% CO 2 after resuscitation. After subculture, the cells in logarithmic growth phase were prepared into a cell suspension of (1 ⁇ 2) ⁇ 10 7 cell / ml concentration with physiological saline, and inoculated into BALB / C nude mice (SPF grade, 18 ⁇ 20g, 6 weeks old, male) right subcutaneous. Under sterile conditions, the tumor tissue of the second generation xenograft model of human lung cancer A549, which grew vigorously in vivo, was cut into uniform pieces of 1 to 2 mm 3 size, and a trocar was used to inoculate a piece of the right sac of each nude mouse. .
- the applied feed, litter, cage and contact equipment should be used after autoclaving, and the nude mice should be placed in a laminar flow rack. And began to dynamically observe and test tumor size and animal weight. The animals in each group were sacrificed in about three weeks, and the tumors were weighed.
- the tumor inhibition rate was calculated according to the following formula:
- Tumor inhibition rate% [(control group average tumor weight-average tumor weight of administration group)/control group average tumor weight] ⁇ 100% effect of combined medication Q value was calculated according to the formula of Jin:
- E a+b is the tumor inhibition rate of the combined drug
- E a and E b are the tumor inhibition rates of drug A and drug B, respectively.
- the Q value of 0.85-1.15 is additive (+), and greater than 1.15 is enhanced (++).
- the dosage of the injection of the invention is 25ml/kg, 12.5ml/kg, 6.25ml/kg, and is administered according to the iv ⁇ 10qd regimen, and the growth of human lung cancer A549 transplanted into nude mice is significantly inhibited.
- the anti-tumor effect of the injection of the invention combined with cisplatin on human lung cancer A549 transplanted into nude mice is obviously stronger than that of the injection of the invention and cisplatin alone, and has obvious additive effect.
- the human tumor liver cancer QGY cell line frozen in liquid nitrogen was taken and cultured at 37 ° C and 5% CO 2 after resuscitation. Others are the same as "two, two.”
- the dosage of the injection of the invention is 25ml/kg, 12.5ml/kg, 6.25ml/kg, and is administered according to the iv ⁇ 10qd regimen, and the growth of human liver cancer QGY transplanted into nude mice is obviously inhibited.
- the anti-tumor effect of the injection of the present invention combined with doxorubicin on human liver cancer QGY transplanted into nude mice is significantly stronger than that of the injection of the present invention and doxorubicin alone.
- the human tumor liver cancer LM-3 cell line frozen in liquid nitrogen was taken and cultured under the condition of 37 ° C and 5% CO 2 after resuscitation. Others are the same as "two, two.”
- the dosage of the injection of the invention is 25ml/kg, 12.5ml/kg, 6.25ml/kg, and is administered according to the iv ⁇ 10qd regimen, and the growth of human liver cancer LM-3 transplanted into nude mice is obviously inhibited.
- the anti-tumor effect of the injection of the invention combined with cyclophosphamide on human liver cancer LM-3 transplanted into nude mice is obviously stronger than that of the injection of the invention and cyclophosphamide alone, and has obvious additive effect.
- the human tumor liver cancer SMMC-7721 cell line frozen in liquid nitrogen was taken and cultured at 37 ° C and 5% CO 2 after resuscitation. Others are the same as "two, two.”
- the dosage of the injection of the invention is 25ml/kg, 12.5ml/kg, 6.25ml/kg, and is administered according to the iv ⁇ 10qd regimen.
- the growth of human liver cancer SMMC-7721 in nude mice was significantly inhibited.
- Injection of the invention (specification: 100ml: 10g), cyclophosphamide (CTX), imitoril (DHAD), mitomycin (MMC), physiological saline;
- CX cyclophosphamide
- DHAD imitoril
- MMC mitomycin
- the well-grown S180 ascites was prepared and diluted with physiological saline 1:4 to prepare a cell suspension of about (1-2) ⁇ 10 7 cells/ml.
- Each mouse was inoculated with 0.2 ml subcutaneously and randomly grouped as shown in Table 7. The dose is administered from the next day. The animals were sacrificed by cervical dislocation 10 days after inoculation, and the tumor masses were dissected. The tumor weights of each dose group were compared and the inhibition rate was calculated.
- W256 carcinosarcoma inoculated in Wistar rats, 50-60g, female;
- the vigorously-grown rat W256 ascites was prepared and diluted with physiological saline to prepare a cell suspension of about (1-2) ⁇ 10 7 cells/ml, which was inoculated subcutaneously into the right ankle of the rat, 0.2 ml/mouse, after inoculation.
- the rats were randomly divided into groups and started to be administered. Two weeks later, the animals were dissected, and the tumors were weighed. The difference between the experimental group and the control group was compared, and the tumor weight inhibition rate was calculated.
- the anti-tumor effect of the injection of the invention combined with CTX is obviously stronger than that of the injection of the invention and chemotherapy alone, and has obvious additive effect.
- PENC-1 human pancreatic cancer cells inoculated in BALB/C nude mice, 16-18 g, female;
- the well-grown PENC-1 human pancreatic cancer tumors were harvested and subcutaneously inoculated into 4 weeks old female BALB/C nude mice.
- the mice were randomly divided into groups and started to be administered.
- the mice were sacrificed 1 week after the administration was stopped, and the tumors were weighed.
- the tumor weight inhibition rate was calculated by the difference from the control group.
- the anti-tumor effect of the injection of the invention combined with gemcitabine hydrochloride is obviously stronger than that of the injection of the invention and chemotherapy alone, and has obvious additive effect.
- FC-3M human prostate cancer inoculated in BALB/C nude mice, 17-21 g, male;
- FC-3M tumors were prepared and homogenized with 1:4 saline. Each mouse was inoculated with 0.2 ml subcutaneously, randomly divided into groups and administered on the next day. The mice were sacrificed 21 days after inoculation. Weighing, comparing the difference between the experimental group and the control group, calculating the tumor weight inhibition rate.
- the anti-tumor effect of the injection of the invention combined with Lupron is obviously stronger than that of the injection of the invention and chemotherapy alone, and has obvious additive effect.
- Injection of the invention (specification: 100ml: 10g), docetaxel injection (Taxotere, specification: 20mg/bottle), physiological saline
- Human breast cancer Bcap-37 inoculated in BALB/C nude mice (SPF grade), 18-20 g, female;
- a well-grown Bcap-37 tumor mass was prepared and homogenized with physiological saline to prepare a cell suspension of (1-2) ⁇ 10 7 cell/ml concentration.
- Each mouse was inoculated with 0.2 ml of the right iliac crest, randomly divided into groups and inoculated. After the 7th day of administration, the mice were sacrificed 20 days after inoculation, and the tumors were weighed. The difference between the experimental group and the control group was compared, and the tumor weight inhibition rate and the effect Q value of the combined drug were calculated.
- Human breast cancer MDA-MB-435 inoculated in BALB/C nude mice (SPF grade), 18-20 g, female;
- the well-grown MDA-MB-435 tumor pieces were prepared and homogenized with physiological saline to prepare cell suspensions at a concentration of (1-2) ⁇ 10 7 c ell/ml.
- Each mouse was inoculated with 0.2 ml of right sac, and randomly divided into groups. The mice were administered on the 7th day after inoculation. The mice were sacrificed on the 18th day after inoculation, and the tumors were weighed. The difference between the experimental group and the control group was compared, and the tumor weight inhibition rate and the effect Q value of the combined drug were calculated.
- the anti-tumor effect of the injection of the invention combined with paclitaxel injection on human breast cancer MDA-MB-435 transplanted into nude mice is obviously stronger than that of the injection of the present invention and paclitaxel injection, and the experiment proves that the injection of the invention is combined with paclitaxel injection.
- the liquid has a distinct additive effect.
- 58 patients with advanced ovarian cancer were randomly divided into the present invention group and the control group, wherein 30 patients in the present invention group were treated with the TC regimen (paclitaxel + carboplatin) in combination with the capsule of the present invention, and 28 patients in the control group, only using the TC regimen, two Baseline data were balanced in the group (p>0.05).
- Paclitaxel 175 mg/m 2 Day 1
- 6 capsules of the present invention 3 times/d, continued Take it until the condition progresses or an intolerable toxic side effect occurs.
- Efficacy and disease control rate The short-term efficacy evaluation was performed once every 2 cycles of chemotherapy, and analyzed by RECIST criteria, which were divided into complete remission (CR), partial remission (PR), stable (SD) and progression (PD). CR+PR calculates the effective rate (RR) and calculates the disease control rate (DCR) by CR+PR+SD. All CR and PR patients were confirmed for efficacy after 4 weeks.
- the efficiency and disease control rate of the present invention group were significantly higher than those of the control group.
- Toxic side effects 58 patients were evaluated for toxicity and side effects. The most common side effects were gastrointestinal reactions, myelosuppression, neurotoxicity, and muscle and joint pain. The incidence of 3/4 degree myelosuppression in the present invention group and the control group was 42.5% and 54%, respectively, and the incidence of 3/4 degree febrile neutropenia/infection was 12% and 19%, respectively. There were no deaths; nausea, vomiting, neurotoxicity, and muscle and joint pain were more common in the control group; the fatigue of the present invention was significantly lower than that of the control group.
- the capsule of the invention combined with paclitaxel and carboplatin has high efficiency in treating advanced ovarian cancer, and the toxicity and side effects of chemotherapy are light, which can effectively improve the quality of life of patients.
- the capsule of the invention Pharmatech tablets (specification: pollen extract P5 70mg, EA10 4mg), sodium chloride injection (specification 250ml: 2.25g, 250ml / bottle), sodium pentobarbital, olive oil, penicillin sodium for injection (specification 800,000 units / support).
- urogenital sinus sexual mature ICR mice, 20 females, 10 males, weighing 25 ⁇ 30g, male and female 2: l cage, every morning to check the yin, open the vulva with a small scorpion, such as seeing mating
- the day of the fetus is the first day of pregnancy
- the female rats were sacrificed for 16 days
- the 16-day-old fetus was taken out under sterile conditions.
- the urogenital sinus is placed in a glass dish containing saline for later use.
- Modeling Sexually mature ICR male mice, 60, weighing 25-30 g, intraperitoneal injection of pentobarbital sodium anesthesia, abdominal incision under sterile conditions, carefully separating the ventral prostate, implanting 3 in the prostate ventral lobe The urogenital sinus tissue of the 16d gestational age of the same fetal rat, 10 of which were only puncture and not implanted as a sham operation group. After intraperitoneal injection of 20,000 units of penicillin for 3 consecutive days.
- Group administration no abnormalities were found in group 3 days after operation, which were sham operation group, model group, positive control group (siniton 60 mg/kg), high-dose group (9 g/kg) of the present invention. Dose group (3 g/kg) and low dose group (1 g/kg). The rats were administered by continuous intragastric administration for 28 days at a dose of 0.1 ml/l0 g, and the sham-operated group and the model group were intragastrically administered with the same amount of olive oil.
- Test indicators 1 body weight, 2 ventral prostate wet weight and prostate index (prostate wet weight / mouse weight), 3 ventral prostate tissue pathological changes (see Table 13 for scoring criteria).
- the capsule of the invention 1 ⁇ 9g/kg administered by intragastric administration for 28 days can significantly reduce the wet weight of the ventral lobe and the prostate index of the ventral lobe in mice with benign prostatic hyperplasia induced by urogenital sinus implantation; significantly improve the urogenital sinus implantation Pathological changes of fibroblast proliferation, glandular enlargement, glandular epithelial hyperplasia and glandular endocrine secretion in the prostatic hyperplasia of benign prostatic hyperplasia mice; significantly reduce uterine genital sinus implantation-induced benign prostatic hyperplasia mouse ventral prostate Glandular area and glandular epithelial height. It can be seen that the capsule of the invention has a significant therapeutic effect on prostatic hyperplasia induced by urogenital sinus implantation in mice.
- the present invention has a certain inhibitory effect on the growth of human lung cancer A549, liver cancer QGY, LM-3, SMMC-7721, S180 sarcoma, W256 carcinosarcoma, etc. transplanted in nude mice, the injection of the present invention and Capsules combined with low-dose cisplatin, cyclophosphamide, gemcitabine hydrochloride, imiprazole, mitomycin, Lupron, docetaxel, paclitaxel and carboplatin, human lung cancer A549, human liver cancer LM-3, SMMC-7721
- the growth inhibition of S180 sarcoma, W256 carcinosarcoma, pancreatic cancer, prostate cancer, breast cancer and ovarian cancer has obvious additive effects, and has a combined drug effect.
- the capsule of the invention has a significant therapeutic effect on prostate hyperplasia in mice.
- Supercritical carbon dioxide extraction the coix seed is pulverized into 60 mesh, extracted by a 600L ⁇ 2 supercritical CO 2 extractor, and the coix seed powder is charged into the extraction kettle, and the CO 2 preheater and the extraction kettle are heated by the jacketed circulating hot water.
- the extraction temperature and separation temperature are respectively 40 ° C and 45 ° C, maintaining the outlet temperature of the first stage analytical reactor and the secondary analytical reactor are 50 ° C and 35 ° C respectively;
- liquid CO 2 is added by high pressure pump at a flow rate of 2 t / h Pressed into the CO 2 preheater to become a fluid in supercritical state, enter the extraction kettle, maintain the pressure of 20Mpa, extract the coix seed oil;
- the CO 2 fluid dissolved in the coix seed oil enters the separation column, controls the separation column pressure 7Mpa, and separates Coix seed oil;
- the CO 2 gas from the separation column enters the primary and secondary analytical reactors, respectively, and maintains the pressures of 7Mpa and 6Mpa respectively, discards the impurities such as water obtained by analysis, and the CO 2 gas becomes liquid CO 2 through the condenser. , recycling, continuous extraction for 2.5h, to obtain coix seed oil;
- Supercritical carbon dioxide extraction the coix seed is pulverized into 80 mesh, extracted with a 600L ⁇ 2 supercritical CO 2 extractor, and the coix seed powder is charged into the extraction kettle, and the CO 2 preheater and the extraction kettle are heated by the jacketed circulating hot water.
- the extraction temperature and separation temperature are respectively 40 ° C and 40 ° C, maintaining the outlet temperature of the first stage analytical reactor and the secondary analytical reactor are 20 ° C and 15 ° C respectively;
- liquid CO 2 is pumped at a flow rate of 1 t / h by high pressure pump Pressed into the CO 2 preheater, became the fluid in the supercritical state, entered the extraction kettle, maintained the pressure of 22Mpa, extracted the coix seed oil;
- the CO 2 fluid dissolved in the coix seed oil entered the separation column, controlled the separation column pressure 8Mpa, and separated Coix seed oil;
- CO 2 gas from the separation column enters the first-stage and second-stage analytical reactors, respectively, and maintains the pressures of 6Mpa and 5Mpa respectively, discards the impurities such as water obtained by analysis, and the CO 2 gas becomes liquid CO 2 through the condenser. , recycling, continuous extraction for 2h, to obtain coix seed oil;
- the lower layer of waste acetone was removed; the upper layer of the oil solution was taken, and the activated neutral alumina with an oil weight of 8% was added, stirred for 30 minutes, and then filtered; after the filtrate was heated, the activated kaolin was added with an oil weight of 6%, and stirred.
- the filtrate was recovered under reduced pressure, and then purified water was added for washing.
- the lower layer of wastewater was removed; the upper layer of oil was dried under reduced pressure with nitrogen, and then re-gripped at 8%.
- the activated neutral alumina is stirred, placed in a cold place, and filtered.
- the filtered oil is concentrated under heating and decompression under nitrogen-filling conditions, and then dried and sterilized by dry heat at 170 ° C for 1.5 h.
- ⁇ m microporous membrane filtration divided into 500ml glass
- nitrogen is filled and sealed, that is, the coix seed oil is obtained, the yield is 4.9%;
- the physical and chemical constant is determined as follows: the relative density is 0.920 at 20 ° C, the refractive index is 1.473 at 20 ° C, the acid value is 0.19, the iodine value is 104, and the saponification value is 186.
- Supercritical carbon dioxide extraction the coix seed is pulverized into 10 mesh, extracted with a 600L ⁇ 2 supercritical CO 2 extractor, and the coix seed powder is charged into the extraction kettle, and the CO 2 preheater and the extraction kettle are heated by the jacketed circulating hot water.
- the extraction temperature and separation temperature were respectively 33 ° C and 39 ° C, maintaining the outlet temperature of the first stage analytical reactor and the secondary analytical reactor were 30 ° C and 20 ° C respectively;
- the liquid CO 2 was pumped at a flow rate of 3 t / h by high pressure pump Pressed into the CO 2 preheater to become a fluid in supercritical state, enter the extraction kettle, maintain the pressure of 19Mpa, extract the coix seed oil;
- the CO 2 fluid dissolved in the coix seed oil enters the separation column, controls the separation column pressure 9Mpa, and separates Coix seed oil;
- CO 2 gas coming out of the separation column enters the primary and secondary analytical reactors, respectively, maintaining the pressures of 5Mpa and 4Mpa, discarding the impurities such as water obtained by analysis, and the CO 2 gas is changed into liquid CO 2 through the condenser. , recycling, continuous extraction for 3h, to obtain coix seed oil;
- the filtered oil is concentrated under heating and decompression under nitrogen-filling conditions, and then dried and sterilized by dry heat at 160 ° C for 2 h, and after cooling for 0.2 ⁇ m.
- Microporous membrane filtration divided into 500ml glass In the liquid bottle, nitrogen is filled and sealed, that is, the coix seed oil is obtained, the yield is 4.7%; the physical and chemical constant is determined as follows: the relative density is 0.918 at 20 ° C, the refractive index is 1.474 at 20 ° C, the acid value is 0.15, the iodine value is 100, and the saponification value is 194.
- Supercritical carbon dioxide extraction the coix seed is pulverized into 50 mesh, extracted by a 600L ⁇ 2 supercritical CO 2 extractor, and the coix seed powder is charged into the extraction kettle, and the CO 2 preheater and the extraction kettle are heated by the jacketed circulating hot water.
- the extraction temperature and separation temperature are respectively 35 ° C and 42 ° C, maintaining the outlet temperature of the first stage analytical reactor and the secondary analytical reactor are respectively 40 ° C and 30 ° C;
- liquid CO 2 is passed through the high pressure pump at a flow rate of 1.5 t / h Pressurized into the CO 2 preheater, become the fluid in the supercritical state, enter the extraction kettle, maintain the pressure 21Mpa, extract the coix seed oil;
- the CO 2 fluid dissolved in the coix seed oil enters the separation column, and controls the separation column pressure 10Mpa, separation
- separation The coix seed oil is obtained;
- the CO 2 gas coming out of the separation column enters the primary and secondary analytical reactors successively, and the pressures are maintained at 7 MPa and 5 MPa, respectively, and the impurities such as water obtained by the analysis are discarded, and the CO 2 gas is turned into a liquid CO through the condenser. 2 , recycling, continuous extraction for 2h, to obtain coix seed oil;
- Refining Take the coix seed oil extracted by supercritical CO 2 , add 70% petroleum oil with 60% oil weight, add 50% 2% NaOH solution according to the acid value, stir for 10 min, and let stand for 19 h. The lower layer of soap was removed, and the upper layer was washed with purified water. After standing for 21 hours, the lower layer of wastewater was removed. The upper layer was taken for the second time, and after standing for 50 hours, the lower layer of wastewater was removed. The upper layer was re-emulsified by 85% acetone.
- the filtered oil is concentrated under heating and decompression under nitrogen-filling conditions, and then dried under vacuum at 162 ° C for 2 h. After cooling, 0.2 ⁇ m is passed.
- Microporous membrane filtration divided into 500ml glass In the liquid bottle, nitrogen is filled and sealed, that is, the coix seed oil is obtained, the yield is 4.0%; the physicochemical constant is determined as follows: the relative density is 0.920 at 20 ° C, the refractive index is 1.071 at 20 ° C, the acid value is 0.16, the iodine value is 105, and the saponification value is 192.
- Supercritical carbon dioxide extraction the coix seed is pulverized into 30 mesh, extracted by a 600L ⁇ 2 supercritical CO 2 extractor, and the coix seed powder is charged into the extraction kettle, and the CO 2 preheater and the extraction kettle are heated by the jacketed circulating hot water.
- the column was separated so that the extraction temperature and the separation temperature were 42 ° C and 45 ° C, respectively, and the outlet temperatures of the first stage analytical reactor and the second stage analytical reactor were 35 ° C and 25 ° C, respectively; the liquid CO 2 was passed through the high pressure pump at a flow rate of 2.5 t / h.
- the activated neutral alumina is stirred, placed in a cold place, filtered, and the filtered oil is concentrated under heating and depressurization under nitrogen-filled conditions, and then dried under reduced pressure at 165 ° C for 1.5 h. Filtered through a 0.2 ⁇ m microporous membrane and dispensed in 500ml glass Infusion bottle, filled with nitrogen, sealed, that is; lotus seed oil, yield 4.3%; determination of its physical and chemical constant: relative density of 0.916 at 20 ° C, refractive index of 1.473 at 20 ° C, acid value of 0.14, iodine value of 101, saponification The value is 192.
- the chromatographic peak fraction with a retention time of 15.8 min was collected, and the receiving solution was concentrated under reduced pressure at 30 ° C, transferred to a 10 ml sample vial, and nitrogen-dried at room temperature under nitrogen to obtain 1,3-dioleic acid diglyceride.
- the chromatographic peak fraction with a retention time of 27 min was collected, and the receiving solution was concentrated under reduced pressure at 30 ° C, transferred to a 10 ml sample vial, and nitrogen-dried at room temperature under nitrogen to obtain 1,2-dilinoleic acid glyceride.
- mobile phase A acetonitrile
- mobile phase B acetonitrile-tetrahydrofuran (1:1)
- Mobile phase B 0 to 27 min: 50% to 60%, 27 to 35 min: 90%, 35 to 45 min: 100%
- Flow rate 18 mL/min
- UV detection wavelength 208 nm
- collected chromatographic peak fraction with retention time of 12.6 to 14.2 min concentrated under reduced pressure with a rotary evaporator under a nitrogen atmosphere, transferred to a 10 mL vial with chloroform, and dried under vacuum After drying in a box at 35 ° C for 6 h, it was filled with nitrogen gas, and the dried sample was stored in a freezer in a refrigerator to obtain tri oleic acid glyceride
- A tri linoleic acid glyceride
- B 1-oleic acid-2,3-dilinoleic acid glyceride
- C 1-palmitic acid-2,3-dilinoleic acid glyceride
- D 1, 3-Dioleic acid-2-linoleic acid glyceride
- E 1-palmitic acid-2-linoleic acid-3-oleic acid glyceride
- F 1,3-dipalmitate-2-linoleic acid glycerin Ester
- G triolein
- H 1-palmitic acid-2,3-dioleate.
- A tri linoleic acid glyceride
- B 1-oleic acid-2,3-dilinoleic acid glyceride
- C 1-palmitic acid-2,3-dilinoleic acid glyceride
- D 1, 3-Dioleic acid-2-linoleic acid glyceride
- E 1-palmitic acid-2-linoleic acid-3-oleic acid glyceride
- F 1,3-dipalmitate-2-linoleic acid glycerin Ester
- G triolein
- H 1-palmitic acid-2,3-dioleate.
- Preliminary separation was carried out by P3000A high performance liquid chromatography, mobile phase A: acetonitrile, mobile phase B: acetonitrile-tetrahydrofuran (1:1), and mobile phase B was prepared into 50 mg/mL hazelnut oil solution, each time separated.
- the mobile phase A acetonitrile
- mobile phase B acetonitrile-tetrahydrofuran (1:1)
- the above crude product was prepared into a 20 mg/mL solution using mobile phase B, and the injection volume was 1.5 mL each time;
- Superstar Benetnach TM C 18 (10 mm ⁇ 250 mm, 5 ⁇ m);
- Gradient conditions Mobile phase B: 0 to 23 min: 50% to 60%, 32 to 43 min: 60% to 90%, 43 to 60 min: 100%; flow rate: 3 mL /min; UV detection wavelength: 208nm, collect the chromatographic peak fraction with retention time of 31.2 ⁇ 34.7min, concentrate under reduced pressure with nitrogen under the protection of nitrogen, transfer to 10mL vial with chloroform, 35°C in vacuum drying oven After drying for 6 hours, nitrogen was charged, and the dried sample was stored in a freezer in a refrigerator to obtain 1-palmitic acid-2,3-dilinoleic acid glyceride monomer.
- Preliminary separation was carried out by P3000A high performance liquid chromatography, mobile phase A: acetonitrile, mobile phase B: acetonitrile-tetrahydrofuran (1:1), and mobile phase B was prepared into 50 mg/mL hazelnut oil solution, each time separated.
- Preliminary separation was carried out by P3000A high performance liquid chromatography, mobile phase A: acetonitrile, mobile phase B: acetonitrile-tetrahydrofuran (1:1), and mobile phase B was prepared into 50 mg/mL hazelnut oil solution, each time separated.
- Preliminary separation was carried out by P3000A high performance liquid chromatography, mobile phase A: acetonitrile, mobile phase B: acetonitrile-tetrahydrofuran (1:1), and mobile phase B was prepared into 50 mg/mL hazelnut oil solution, each time separated.
- the mobile phase A acetonitrile
- mobile phase B acetonitrile-tetrahydrofuran (1:1)
- the above crude product was prepared into a 20 mg/mL solution using mobile phase B, and the injection volume was 1.5 mL each time;
- Superstar Benetnach TM C 18 (10 mm ⁇ 250 mm, 5 ⁇ m);
- Gradient conditions Mobile phase B: 0 to 23 min: 50% to 60%, 32 to 43 min: 60% to 90%, 43 to 60 min: 100%; flow rate: 3 mL /min; UV detection wavelength: 208nm, collect the chromatographic peak fraction with retention time of 32.9 ⁇ 35.1min, concentrate under reduced pressure with nitrogen under the protection of nitrogen, transfer to 10mL vial with chloroform, 35°C in vacuum drying oven After drying for 6 hours, nitrogen was charged, and the dried sample was stored in a freezer in a refrigerator to obtain 1-palmitic acid-2,3-dioleate.
- coix seed oil contains the following ingredients:
- soy lecithin for injection add appropriate amount of water for injection, disperse it to a block-free and granular solid with a high-shear dispersing emulsifier, add glycerin for injection, which is weighed according to the formula, and add water for injection. To the specified amount, stir evenly;
- Another name is the coix seed oil, the weighed oil and water are separately heated to 60 ° C, and then placed in a high-pressure homogenizer for high-pressure emulsification, the homogenizer low pressure is 6MPa, the high pressure is 30MPa, the recycling is homogeneous 4 times , the particles below 2 ⁇ m should be not less than 95%, particles above 5 ⁇ m should not be detected, if necessary, adjust the pH to 8.5 with NaOH or HCl;
- the uniform emulsion nitrogen gas is pressurized and filtered through a microporous filter filter of ⁇ 3 ⁇ m, sterilized by nitrogen filling, and cooled.
- coix seed oil contains the following ingredients:
- soy lecithin for injection add appropriate amount of water for injection, disperse it to a block-free and granular solid with a high-shear dispersing emulsifier, add glycerin for injection, which is weighed according to the formula, and add water for injection. Stir to the specified amount Evenly spare;
- coix seed oil the oil ester and the water phase are separately heated to 70 ° C, and then placed in a high-pressure homogenizer for high-pressure emulsification, the homogenizer low pressure is 12 MPa, the high pressure is 45 MPa, and the recycling is uniform. All the particles below 2 ⁇ m should be not less than 95%, particles above 5 ⁇ m should not be detected, if necessary, adjust the pH to 7.1 with NaOH or HCl;
- the uniform emulsion nitrogen gas is pressurized and filtered through a microporous filter filter of ⁇ 3 ⁇ m, sterilized by nitrogen filling, and cooled.
- Soybean phospholipid for injection 25g
- coix seed oil contains the following ingredients:
- soy lecithin for injection add appropriate amount of water for injection, disperse it to a block-free and granular solid with a high-shear dispersing emulsifier, add glycerin for injection, which is weighed according to the formula, and add water for injection. To the specified amount, stir evenly;
- coix seed oil the oil ester and the water phase are separately heated to 65 ° C, and then placed in a high-pressure homogenizer for high-pressure emulsification.
- the emulsifier homogenizer low pressure is 10 MPa
- the high pressure is 30 MPa
- the recirculation is homogeneous 5 All the particles below 2 ⁇ m should be not less than 95%, particles above 5 ⁇ m should not be detected, if necessary, adjust the pH to 4.8 with NaOH or HCl;
- the uniform emulsion nitrogen gas is pressurized and filtered through a microporous filter filter of ⁇ 3 ⁇ m, sterilized by nitrogen filling, and cooled.
- coix seed oil contains the following ingredients:
- soy lecithin for injection add appropriate amount of water for injection, disperse it to a block-free and granular solid with a high-shear dispersing emulsifier, add glycerin for injection, which is weighed according to the formula, and add water for injection. To the specified amount, stir evenly;
- coix seed oil the oil ester and the water phase are separately heated to 68 ° C, and then placed in a high-pressure homogenizer for high-pressure emulsification.
- the emulsifier homogenizer low pressure is 7 MPa
- the high pressure is 35 MPa
- the recirculation is homogeneous 3 All the particles below 2 ⁇ m should be not less than 95%, particles above 5 ⁇ m should not be detected, if necessary, adjust the pH to 6.8 with NaOH or HCl;
- the uniform emulsion nitrogen gas is pressurized and filtered through a microporous filter filter of ⁇ 3 ⁇ m, sterilized by nitrogen filling, and cooled.
- coix seed oil contains the following ingredients:
- Preparation of glue Weigh the appropriate amount of gelatin, purified water, glycerin and 10% hydroxyethyl ester solution according to the weight ratio of 1:1.2:0.8:0.01; add glycerin, purified water and 10% hydroxyethyl ester solution to the rubber In the tank, after heating to 70 ° C, add gelatin and stir constantly, vacuum until the gelatin is completely dissolved, filter the glue, store at 60 ° C, and set aside;
- Preparation of liquid medicine Add the formula amount of coix seed oil and vitamin E into the ingredient tank, and stir constantly until it is evenly mixed;
- Capsule Select the appropriate pellets according to the size of the capsules, and then dry at 18 °C and relative humidity ⁇ 35%. After the pellets are dried, the pellets are removed, and the pellets are washed with 95% medicinal ethanol. The amount of water is less than 12%. The unqualified capsules are removed by visual inspection, printed and packaged.
- coix seed oil contains the following ingredients:
- 1,3-dioleic acid diglyceride 0.55%
- Preparation of glue Weigh the appropriate amount of gelatin, purified water, glycerin and benzoic acid at a weight ratio of 1:1.2:0.8:0.01; add glycerin, purified water and benzoic acid to the gelatin tank in turn, heat to 90 °C, then Add gelatin and stir constantly, vacuum until the gelatin is completely dissolved, filter the glue, store at 56 ° C, and set aside;
- Preparation of liquid medicine Add the formula amount of coix seed oil and Tween 80 into the ingredient tank, and stir constantly until it is evenly mixed;
- Pressure capsule Select the appropriate pellet mold according to the size of the capsule, and then dry it at 26 ° C and relative humidity ⁇ 35%, then remove the size pellets, and then wash the pellets with 95% medicinal ethanol, then continue to dry to contain The amount of water is less than 12%. The unqualified capsules are removed by visual inspection, printed and packaged.
- coix seed oil contains the following ingredients:
- Preparation of glue Weigh the appropriate amount of gelatin, purified water, glycerin and potassium sorbate according to the weight ratio of 1:0.9:0.6:0.005; add glycerin, purified water and potassium sorbate to the gelatin tank in turn, and heat to 80 °C. Then add gelatin and stir constantly, vacuum, until the gelatin is completely dissolved, filter the glue, store at 62 ° C, and set aside;
- Preparation of liquid medicine Add the formula amount of coix seed oil and vitamin E into the ingredient tank, and stir constantly until it is evenly mixed;
- Pressure capsule select the appropriate pellet mold according to the size of the capsule, and then dry it at 28 ° C and relative humidity ⁇ 35%, then remove the size pellets, then wash the pellets with 95% medicinal ethanol, and continue to dry until The amount of water is less than 12%.
- the unqualified capsules are removed by visual inspection, printed and packaged.
- coix seed oil contains the following ingredients:
- Preparation of glue Weigh the appropriate amount of gelatin, purified water, glycerin and chlorhexidine acetate according to the weight ratio of 1:1.0:0.5:0.008; add glycerin, purified water and chlorhexidine acetate to the gelatin tank in turn, and heat to 85 After °C, add gelatin and stir constantly, vacuum until the gelatin is completely dissolved, filter the glue, store at 56 °C, and set aside;
- Preparation of liquid medicine Add the formula amount of coix seed oil and Tween 80 into the ingredient tank, and stir constantly until it is evenly mixed;
- Pressure capsule select the appropriate pellet mold according to the size of the capsule, dry it at 30 ° C, relative humidity ⁇ 35%, and then remove the size pellets, then wash the pellets with 95% medicinal ethanol, and continue to dry until The amount of water is less than 12%.
- the unqualified capsules are removed by visual inspection, printed and packaged.
- coix seed oil contains the following ingredients:
- 1,3-dioleic acid-2-linoleic acid glyceride 15.01%
- soy lecithin for injection add appropriate amount of water for injection, disperse it to a block-free and granular solid with a high-shear dispersing emulsifier, add glycerin for injection, which is weighed according to the formula, and add water for injection. To the specified amount, stir evenly;
- the coix seed oil the oil and the water phase are separately heated to 60 ° C, and then placed in a high-pressure homogenizer for high-pressure emulsification.
- the homogenizer has a low pressure of 7 MPa, a high pressure of 26 MPa, and a recycling homogenization of 5 times.
- the particles below 2 ⁇ m should be not less than 95%, particles above 5 ⁇ m should not be detected, if necessary, adjust the pH to 6.8 with NaOH or HCl;
- the uniform emulsion nitrogen gas is pressurized and filtered through a microporous filter filter of ⁇ 3 ⁇ m, sterilized by nitrogen filling, and cooled.
- coix seed oil contains the following ingredients:
- soy lecithin for injection add appropriate amount of water for injection, disperse it to a block-free and granular solid with a high-shear dispersing emulsifier, add glycerin for injection, which is weighed according to the formula, and add water for injection. To the specified amount, stir evenly;
- coix seed oil the oil and the water phase are separately heated to 70 ° C, and then placed in a high-pressure homogenizer for high-pressure emulsification.
- the homogenizer low pressure is 11 MPa
- the high pressure is 48 MPa
- the recycling is homogenized 6 times.
- the particles below 2 ⁇ m should be not less than 95%
- particles above 5 ⁇ m should not be detected, if necessary, adjust the pH to 7.5 with NaOH or HCl;
- the uniform emulsion nitrogen gas is pressurized and filtered through a microporous filter filter of ⁇ 3 ⁇ m, sterilized by nitrogen filling, and cooled.
- Soybean phospholipid for injection 25g
- coix seed oil contains the following ingredients:
- soy lecithin for injection add appropriate amount of water for injection, disperse it to a block-free and granular solid with a high-shear dispersing emulsifier, add glycerin for injection, which is weighed according to the formula, and add water for injection. To the specified amount, stir evenly;
- coix seed oil the oil and the water phase are separately heated to 65 ° C, and then placed in a high-pressure homogenizer for high-pressure emulsification.
- the emulsifier homogenizer low pressure is 8 MPa
- the high pressure is 40 MPa
- the recirculation is homogeneous 4 times.
- the particles below 2 ⁇ m should be not less than 95%
- particles above 5 ⁇ m should not be detected, if necessary, adjust the pH to 6.5 with NaOH or HCl;
- the uniform emulsion nitrogen gas is pressurized and filtered through a microporous filter filter of ⁇ 3 ⁇ m, sterilized by nitrogen filling, and cooled.
- coix seed oil contains the following ingredients:
- Preparation of glue Weigh the appropriate amount of gelatin, purified water, glycerin and 10% hydroxyethyl ester solution according to the weight ratio of 1:1.2:0.8:0.01; add glycerin, purified water and 10% hydroxyethyl ester solution to the rubber In the tank, after heating to 70 ° C, add gelatin and stir constantly, vacuum until the gelatin is completely dissolved, filter the glue, store at 59 ° C, and set aside;
- Preparation of liquid medicine Add the formula amount of coix seed oil and vitamin E into the ingredient tank, and stir constantly until it is evenly mixed;
- Pressure capsule select the appropriate pellet mold according to the size of the capsule, dry it at 16 °C and relative humidity ⁇ 35%, then remove the size pellets, then wash the pellets with 95% medicinal ethanol, and continue to dry until The amount of water is less than 12%.
- the unqualified capsules are removed by visual inspection, printed and packaged.
- coix seed oil contains the following ingredients:
- 1,3-dioleic acid-2-linoleic acid glyceride 18.50%
- Preparation of glue Weigh the appropriate amount of gelatin, purified water, glycerin and benzoic acid at a weight ratio of 1:1.2:0.8:0.01; add glycerin, purified water and benzoic acid to the gelatin tank in turn, heat to 90 °C, then Add gelatin and stir constantly, vacuum until the gelatin is completely dissolved, filter the glue, store at 60 ° C, and set aside;
- Preparation of liquid medicine Add the formula amount of coix seed oil and Tween 80 into the ingredient tank, and stir constantly until it is evenly mixed;
- Pressure capsule Select the appropriate pellet mold according to the size of the capsule, and then dry it at 26 ° C and relative humidity ⁇ 35%, then remove the size pellets, and then wash the pellets with 95% medicinal ethanol, then continue to dry to contain The amount of water is less than 12%. The unqualified capsules are removed by visual inspection, printed and packaged.
- coix seed oil contains the following ingredients:
- Preparation of glue Weigh the appropriate amount of gelatin, purified water, glycerin and potassium sorbate according to the weight ratio of 1:0.9:0.6:0.005; add glycerin, purified water and potassium sorbate to the gelatin tank in turn, and heat to 80 °C. Then add gelatin and stir constantly, vacuum, until the gelatin is completely dissolved, filter the glue, store at 62 ° C, and set aside;
- Preparation of liquid medicine Add the formula amount of coix seed oil and vitamin E into the ingredient tank, and stir constantly until it is evenly mixed;
- Capsule Select the appropriate pellets according to the size of the capsules, and then dry at 20 °C and relative humidity ⁇ 35%, then remove the pellets, then wash the pellets with 95% medicinal ethanol, and continue to dry until The amount of water is less than 12%. The unqualified capsules are removed by visual inspection, printed and packaged.
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Abstract
Description
Claims (10)
- 一种薏苡仁油,其特征在于:该薏苡仁油中含有如下质量百分含量的5种甘油二酯类成分和8种甘油三酯类成分:1,3-二油酸甘油二酯0.40~0.58%、1-亚油酸-3-油酸甘油二酯0.91~1.31%、1,2-二油酸甘油二酯0.24~0.35%、1-油酸-2-亚油酸甘油二酯0.66~0.95%、1,2-二亚油酸甘油酯0.33~0.47%、三亚油酸甘油酯4.87~6.99%、1-油酸-2,3-二亚油酸甘油酯13.00~18.69%、1-棕榈酸-2,3-二亚油酸甘油酯5.25~7.54%、1,3-二油酸-2-亚油酸甘油酯13.23~19.02%、1-棕榈酸-2-亚油酸-3-油酸甘油酯10.26~14.75%、1,3-二棕榈酸-2-亚油酸甘油酯2.28~3.28%、三油酸甘油酯14.44~20.76%和1-棕榈酸-2,3-二油酸甘油酯8.06~11.58%。
- 根据权利要求1所述的薏苡仁油,其特征在于:所述薏苡仁油按脂肪油检测理化常数为:20℃时相对密度0.916~0.920,20℃时折光率1.471~1.474,酸值<0.2,碘值100~106,皂化值186~195;所述甘油二酯成分和甘油三酯成分的质量百分含量为:1,3-二油酸甘油二酯0.45~0.55%、1-亚油酸-3-油酸甘油二酯1.03~1.25%、1,2-二油酸甘油二酯0.27~0.33%、1-油酸-2-亚油酸甘油二酯0.75~0.91%、1,2-二亚油酸甘油酯0.37~0.45%、三亚油酸甘油酯5.47~6.69%、1-油酸-2,3-二亚油酸甘油酯14.63~17.88%、1-棕榈酸-2,3-二亚油酸甘油酯5.9~7.21%、1,3-二油酸-2-亚油酸甘油酯14.88~18.19%、1-棕榈酸-2-亚油酸-3-油酸甘油酯11.55~14.11%、1,3-二棕榈酸-2-亚油酸甘油酯2.57~3.14%、三油酸甘油酯16.25~19.86%和1-棕榈酸-2,3-二油酸甘油酯9.07~11.08%;优选地,所述甘油二酯成分和甘油三酯成分的质量百分含量为:1,3-二油酸甘油二酯0.49~0.51%、1-亚油酸-3-油酸甘油二酯1.12~1.16%、1,2-二油酸甘油二酯0.29~0.31%、1-油酸-2-亚油酸甘油二酯0.81~0.85%、1,2-二亚油酸甘油酯0.40~0.42%、三亚油酸甘油酯5.96~6.20%、1-油酸-2,3-二亚油酸甘油酯15.93~16.58%、1-棕榈酸-2,3-二亚油酸甘油酯6.43~6.69%、1,3-二油酸-2-亚油酸甘油酯16.20~16.87%、1-棕榈酸-2-亚油酸-3-油酸甘油酯12.57~13.09%、1,3-二棕榈酸-2-亚油酸甘油酯2.79~2.91%、三油酸甘油酯17.69~18.42%和1-棕榈酸-2,3-二油酸甘油酯9.87~10.27%。
- 一种权利要求1所述薏苡仁油的制备方法,具体包括如下步骤:超临界二氧化碳萃取:取薏苡仁粉碎成10目~80目,采用600L×2超临界CO2萃取器萃取,将薏苡仁粉装入萃取釜,用夹套循环热水加热CO2预热器、萃取釜和分离柱,使萃取温度和分离温度分别达到33~45℃和30~45℃,保持一级解析釜和二级解析釜出口温度分别为20~50℃和15~35℃;液态CO2以1~3t/h的流量经高压泵加压进入CO2预热器,成为超临界状态下的流体,进入萃取釜,保持压力19~23Mpa,萃取薏苡仁油;溶有薏苡仁油的CO2流体进入分离柱,控制分离柱压力7~10Mpa,分离得到薏苡仁油;从分离柱出来的CO2气体先后进入一级、二级解析釜,分别保持压力为5~7Mpa和4~6Mpa,弃去解析得到的水分等杂质,CO2气体经冷凝器变成液态CO2,循环使用,连续萃取2~3h,得到薏苡仁油;精制:取超临界CO2萃取得到的薏苡仁油,加入油重量60%的60℃~90℃石油醚,再根据酸值,加入油重36%~56%的2%NaOH溶液,搅拌10min后,静置18~24h后,除去下层皂脚,取上层用纯化水进行水洗,静置18~24h后,除去下层废水;取上层进行第二次水洗,静置40~50h后,除去下层废水;取上层加油重70%~90%丙酮破乳,静置2~4h后,除去下层废丙酮;取上层油溶液,加入3~8%的经活化的中性氧化铝,搅拌30min后,过滤;滤液加热后,加入油重2%~6%经活化的高岭土,搅拌,在40~50℃下保温30min,过滤;滤液减压回收溶剂后,再加纯化水进行水洗,静置1~2h后,除去下层废水;上层油在充氮条件下,加热减压干燥,再加入油重8%~12%经活化的中性氧化铝,搅拌,置冷处静置,过滤,过滤后的油在充氮条件 下,加热减压浓缩,再经160~170℃减压干热灭菌1~2h,冷却后经0.2μm微孔滤膜过滤,分装于500ml玻璃输液瓶中,充氮,密封,即得;优选地,所述精制步骤如下:取超临界CO2萃取得到的薏苡仁油,加入油重量60%的60℃~90℃石油醚,再根据酸值,加入油重36%~56%的2%NaOH溶液,搅拌10min后,静置20h后,除去下层皂脚,取上层用纯化水进行水洗,静置22h后,除去下层废水;取上层进行第二次水洗,静置46h后,除去下层废水;取上层加油重70%~90%丙酮破乳,静置3h后,除去下层废丙酮;取上层油溶液,加入油重5%的经活化的中性氧化铝,搅拌30min后,过滤;滤液加热后,加入油重4%经活化的高岭土,搅拌,在40~50℃下保温30min,过滤;滤液减压回收溶剂后,再加纯化水进行水洗,静置1h后,除去下层废水;上层油在充氮条件下,加热减压干燥,再加入油重8%~12%经活化的中性氧化铝,搅拌,置冷处静置,过滤,过滤后的油在充氮条件下,加热减压浓缩,再经160~170℃减压干热灭菌2h,冷却后经0.2μm微孔滤膜过滤,分装于500ml玻璃输液瓶中,充氮,密封,即得。
- 一种药物制剂,其特征在于含有治疗有效量的权利要求1~3任一所述的薏苡仁油及一种或几种药学上可接受的载体,其中所述药学上可接受的载体包括药学领域常规的稀释剂、赋形剂、填充剂、乳化剂、粘合剂、润滑剂、吸收促进剂、表面活性剂、崩解剂、润滑剂或抗氧化剂,必要时还可以加入香味剂、甜味剂、防腐剂或着色剂;其中,所述药学上可接受的载体可以选自:甘露醇、山梨醇、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、盐酸半胱氨酸、巯基乙酸、蛋氨酸、大豆磷脂、维生素C、维生素E、EDTA二钠、EDTA钙钠,一价碱金属的碳酸盐、醋酸盐、磷酸盐或其水溶液、盐酸、醋酸、硫酸、磷酸、氨基酸、氯化钠、氯化钾、乳酸钠、羟苯乙酯溶液、苯甲酸、山梨酸钾、醋酸氯己定、木糖醇、麦芽糖、葡萄糖、果糖、右旋糖苷、甘氨酸、淀粉、蔗糖、乳糖、甘露糖醇、硅衍生物、纤维素及其衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、吐温80、琼脂、碳酸钙、碳酸氢钙、表面活性剂、聚乙二醇、环糊精、β-环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙或硬脂酸镁。
- 根据权利要求4所述药物制剂,其可以是口服固体制剂、口服液体制剂或注射剂;其中,所述口服固体制剂选自胶囊剂、片剂、滴丸、颗粒剂、浓缩丸中的任何一种;所述口服液体制剂选自水性或油性悬浮液、溶液、乳剂、糖浆剂或酏剂,或是一种在使用前可用水或其它适宜的载体复配的干燥产品;所述注射剂选自纳米混悬剂、脂质体、乳剂、冻干粉针剂和水针剂中的任何一种。
- 根据权利要求5所述药物制剂,其特征在于所述注射剂包含如下成分:薏苡仁油 50~350g注射用大豆磷脂或可供注射用大豆磷脂 10~40g注射用甘油或可供注射用甘油 15~50g注射用水加至 1000ml。
- 根据权利要求6所述药物制剂的制备方法,其特征在于包括如下步骤:称取处方配制量的注射用大豆磷脂或可供注射用大豆磷脂,加适量的注射用水后,用高剪切分散乳化机分散至无块状及颗粒状固体,加入按配方量称取的注射用甘油或可供注射用甘油,并加注射用水至规定量,搅拌均匀备用;另称取薏苡仁油,将称取的油酯与水相分别加热至60~70℃后,置高压均质机进行高压乳 化,乳化时均质机低压为5~12MPa,高压为25~50MPa,再循环均质3~6遍,至2μm以下颗粒应不少于95%,5μm以上颗粒不得检出,必要时用NaOH或HCl调节pH至4.8~8.5,优选6.8~7,最优选为6.8;将制得均匀乳剂氮气加压通过小于等于3μm的微孔滤芯过滤器过滤,充氮灌装灭菌,冷却即得。
- 根据权利要求5所述药物制剂,其特征在于所述胶囊剂包含如下成分:薏苡仁油 200~800g抗氧化剂和/或乳化剂 0.20~0.60g制成 1000粒。
- 根据权利要求8所述药物制剂的制备方法,其特征在于包括如下步骤:胶液配制:按重量比为1:0.6~1.2:0.3~0.8:0.0001~0.01称取适量明胶、纯化水、甘油和防腐剂;依次将甘油、纯化水、防腐剂加入化胶罐内,加热至70℃~90℃后,再加入明胶不断搅拌、抽真空,直至明胶完全溶解,将胶液过滤,在56℃~62℃下存放,备用;药液配制:将配方量的薏苡仁油、抗氧化剂和/或乳化剂加入配料罐内,不断搅拌,直至混合均匀;压胶囊:根据胶囊大小选择合适的压丸模具,在15℃~30℃、相对湿度小于35%条件下进行压丸定型后干燥,剔除大小丸,再用95%药用乙醇洗丸后,继续干燥至含水量小于12%,目检剔除不合格胶囊,印字,包装即得;其中,所述防腐剂选自10%羟苯乙酯溶液、苯甲酸、山梨酸钾和醋酸氯己定中的一种;所述抗氧化剂为维生素E,乳化剂为吐温80。
- 根据权利要求1所述薏苡仁油在制备抗肿瘤或治疗炎症药物中的应用,其中,所述抗肿瘤药物可以是薏苡仁油与铂类、烷化剂类、二氟核苷类、抗生素类、细胞毒类和/或激素类化学药物的组合;优选为薏苡仁油与顺铂、卡铂、环磷酰胺、盐酸吉西他滨、米托蒽醌、丝裂霉素、醋酸亮丙瑞林、多西他赛和/或紫杉醇等化学药物的组合;所述肿瘤是指早期、中期或晚期的肺癌、肝癌、胰腺癌、前列腺癌、卵巢癌、乳腺癌、肉瘤样癌或癌肉瘤;所述炎症是指前列腺炎或前列腺增生。
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Publication number | Publication date |
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CA2954688C (en) | 2019-10-29 |
CN105267776A (zh) | 2016-01-27 |
EP3153164B1 (en) | 2019-05-22 |
KR101893812B1 (ko) | 2018-09-04 |
PL3153164T3 (pl) | 2019-11-29 |
JP6473802B2 (ja) | 2019-02-20 |
CA2954688A1 (en) | 2016-01-21 |
US9585929B2 (en) | 2017-03-07 |
AP2017009705A0 (en) | 2017-01-31 |
EA033751B1 (ru) | 2019-11-21 |
EP3153164A1 (en) | 2017-04-12 |
AU2015291529B2 (en) | 2018-04-19 |
US20160015769A1 (en) | 2016-01-21 |
AU2015291529A1 (en) | 2016-12-08 |
JP2017524047A (ja) | 2017-08-24 |
SG11201700120XA (en) | 2017-02-27 |
EP3153164A4 (en) | 2017-05-03 |
EA201790116A1 (ru) | 2017-07-31 |
NZ726577A (en) | 2018-06-29 |
KR20170014005A (ko) | 2017-02-07 |
DK3153164T3 (da) | 2019-08-26 |
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