CN105267197B - Pharmaceutical composition, preparation and application thereof containing 13 kinds of glyceride - Google Patents
Pharmaceutical composition, preparation and application thereof containing 13 kinds of glyceride Download PDFInfo
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- CN105267197B CN105267197B CN201410342799.2A CN201410342799A CN105267197B CN 105267197 B CN105267197 B CN 105267197B CN 201410342799 A CN201410342799 A CN 201410342799A CN 105267197 B CN105267197 B CN 105267197B
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 24
- 239000000825 pharmaceutical preparation Substances 0.000 title claims description 12
- BVDRUCCQKHGCRX-UHFFFAOYSA-N 2,3-dihydroxypropyl formate Chemical compound OCC(O)COC=O BVDRUCCQKHGCRX-UHFFFAOYSA-N 0.000 title abstract description 23
- 238000002360 preparation method Methods 0.000 claims abstract description 50
- 239000003814 drug Substances 0.000 claims abstract description 40
- 230000036039 immunity Effects 0.000 claims abstract description 8
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims description 129
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 117
- 239000007924 injection Substances 0.000 claims description 98
- 238000002347 injection Methods 0.000 claims description 97
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 94
- 229910052757 nitrogen Inorganic materials 0.000 claims description 47
- 239000000243 solution Substances 0.000 claims description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 40
- 239000002775 capsule Substances 0.000 claims description 39
- 235000011187 glycerol Nutrition 0.000 claims description 39
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- 239000007788 liquid Substances 0.000 claims description 33
- 239000003921 oil Substances 0.000 claims description 32
- 108010010803 Gelatin Proteins 0.000 claims description 29
- 239000008273 gelatin Substances 0.000 claims description 29
- 229920000159 gelatin Polymers 0.000 claims description 29
- 235000019322 gelatine Nutrition 0.000 claims description 29
- 235000011852 gelatine desserts Nutrition 0.000 claims description 29
- 239000003292 glue Substances 0.000 claims description 27
- 239000008347 soybean phospholipid Substances 0.000 claims description 24
- 239000008187 granular material Substances 0.000 claims description 20
- 230000001804 emulsifying Effects 0.000 claims description 19
- 239000008215 water for injection Substances 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- 239000008213 purified water Substances 0.000 claims description 17
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 16
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 229940079593 drugs Drugs 0.000 claims description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 14
- 206010028980 Neoplasm Diseases 0.000 claims description 13
- 239000000839 emulsion Substances 0.000 claims description 13
- 239000007787 solid Substances 0.000 claims description 13
- 238000005406 washing Methods 0.000 claims description 12
- 229930003427 Vitamin E Natural products 0.000 claims description 11
- 229940046009 Vitamin E Drugs 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000012467 final product Substances 0.000 claims description 11
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 11
- 235000019165 vitamin E Nutrition 0.000 claims description 11
- 239000011709 vitamin E Substances 0.000 claims description 11
- 150000003712 vitamin E derivatives Chemical class 0.000 claims description 11
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 10
- 229920000053 polysorbate 80 Polymers 0.000 claims description 10
- 239000008346 aqueous phase Substances 0.000 claims description 9
- 230000002950 deficient Effects 0.000 claims description 9
- 239000006185 dispersion Substances 0.000 claims description 9
- 238000000465 moulding Methods 0.000 claims description 9
- 238000010008 shearing Methods 0.000 claims description 9
- 238000004513 sizing Methods 0.000 claims description 9
- 230000001954 sterilising Effects 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- 239000005711 Benzoic acid Substances 0.000 claims description 8
- 229940069338 Potassium Sorbate Drugs 0.000 claims description 8
- CHHHXKFHOYLYRE-STWYSWDKSA-M Potassium sorbate Chemical compound [K+].C\C=C\C=C\C([O-])=O CHHHXKFHOYLYRE-STWYSWDKSA-M 0.000 claims description 8
- 239000003963 antioxidant agent Substances 0.000 claims description 8
- 235000010233 benzoic acid Nutrition 0.000 claims description 8
- 238000004945 emulsification Methods 0.000 claims description 8
- 235000010241 potassium sorbate Nutrition 0.000 claims description 8
- 239000004302 potassium sorbate Substances 0.000 claims description 8
- -1 Pulvis Talci Substances 0.000 claims description 7
- 230000000259 anti-tumor Effects 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 239000003995 emulsifying agent Substances 0.000 claims description 7
- 239000004519 grease Substances 0.000 claims description 7
- 239000003755 preservative agent Substances 0.000 claims description 7
- 239000011780 sodium chloride Substances 0.000 claims description 7
- 235000002639 sodium chloride Nutrition 0.000 claims description 7
- GYCKQBWUSACYIF-UHFFFAOYSA-N Ethyl salicylate Chemical compound CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 claims description 6
- 210000003810 Killer Cells, Lymphokine-Activated Anatomy 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 229960002152 Chlorhexidine Acetate Drugs 0.000 claims description 5
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Exidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 claims description 5
- 230000002335 preservative Effects 0.000 claims description 5
- 239000000725 suspension Substances 0.000 claims description 5
- BJHIKXHVCXFQLS-UYFOZJQFSA-N Fructose Natural products OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO BJHIKXHVCXFQLS-UYFOZJQFSA-N 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- GUBGYTABKSRVRQ-YOLKTULGSA-N Maltose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)O[C@H]1CO)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 GUBGYTABKSRVRQ-YOLKTULGSA-N 0.000 claims description 4
- 229940023488 Pill Drugs 0.000 claims description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L Sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 4
- 230000003078 antioxidant Effects 0.000 claims description 4
- 235000006708 antioxidants Nutrition 0.000 claims description 4
- 201000008275 breast carcinoma Diseases 0.000 claims description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- 238000009472 formulation Methods 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 239000006187 pill Substances 0.000 claims description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 4
- 239000004094 surface-active agent Substances 0.000 claims description 4
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 claims description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 3
- 206010033128 Ovarian cancer Diseases 0.000 claims description 3
- 210000000496 Pancreas Anatomy 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 201000011510 cancer Diseases 0.000 claims description 3
- 235000009508 confectionery Nutrition 0.000 claims description 3
- 230000002708 enhancing Effects 0.000 claims description 3
- 235000011167 hydrochloric acid Nutrition 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 229920001817 Agar Polymers 0.000 claims description 2
- 239000005995 Aluminium silicate Substances 0.000 claims description 2
- PZZYQPZGQPZBDN-UHFFFAOYSA-N Aluminium silicate Chemical compound O=[Al]O[Si](=O)O[Al]=O PZZYQPZGQPZBDN-UHFFFAOYSA-N 0.000 claims description 2
- 229960003563 Calcium Carbonate Drugs 0.000 claims description 2
- NKWPZUCBCARRDP-UHFFFAOYSA-L Calcium bicarbonate Chemical compound [Ca+2].OC([O-])=O.OC([O-])=O NKWPZUCBCARRDP-UHFFFAOYSA-L 0.000 claims description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L Calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 2
- 229920000858 Cyclodextrin Polymers 0.000 claims description 2
- 229960001305 Cysteine Hydrochloride Drugs 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
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- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 claims description 2
- 206010027336 Menstruation delayed Diseases 0.000 claims description 2
- 229940005581 Sodium Lactate Drugs 0.000 claims description 2
- NGSFWBMYFKHRBD-UHFFFAOYSA-M Sodium lactate Chemical compound [Na+].CC(O)C([O-])=O NGSFWBMYFKHRBD-UHFFFAOYSA-M 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- 229930003268 Vitamin C Natural products 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N Xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 229960002675 Xylitol Drugs 0.000 claims description 2
- QIJRTFXNRTXDIP-JIZZDEOASA-N [(1R)-1-carboxy-2-sulfanylethyl]azanium;chloride;hydrate Chemical compound O.Cl.SC[C@H](N)C(O)=O QIJRTFXNRTXDIP-JIZZDEOASA-N 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
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- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
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- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
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- 235000001014 amino acid Nutrition 0.000 claims description 2
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- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 claims description 2
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Abstract
nullThe present invention relates to a kind of pharmaceutical composition containing glyceride，Specifically it is made up of following 13 kinds of compounds: 1,3 two Oleic acid diglycerides、1 linoleic acid 3 Oleic acid diglyceride、1,2 two Oleic acid diglycerides、1 oleic acid 2 linoleic acid diester、1,2 dilinoleic acid glyceride、Trilinoleyl glyceride、1 oleic acid 2,3 dilinoleic acid glyceride、1 Palmic acid 2,3 dilinoleic acid glyceride、1,3 two oleic acid 2 glyceryl linoleates、1 Palmic acid 2 linoleic acid 3 olein、1,3 two Palmic acid 2 glyceryl linoleates、Glycerol trioleate、1 Palmic acid 2,3 glyceryl dioleate，Present invention additionally comprises the preparation of aforementioned pharmaceutical compositions、Preparation method and as antitumor drug and the application that improves in body's immunity medicine.
Description
Technical field
The present invention relates to pharmaceutical field, specifically, the present invention relates to the pharmaceutical composition containing 13 kinds of glyceride, system
Agent, preparation method and the application in preparing antitumor and raising body's immunity medicine thereof.
Background technology
Semen Coicis is grass family Coix plant Semen Coicis Coix lacryma-jobi L.var ma-yuen (Roman.)
The maturation of Stapf is dried kernel, for damp-clearing drug, is medicine-food two-purpose kind for a long time.Modern study finds Semen Coicis tool
There are the pharmacological actions such as antalgic and inflammation relieving, immunomodulating, antiulcer, blood fat reducing and fat-reducing.In recent years, Chinese scholars by TLC,
The chemical composition of Semen Coicis is studied by the methods such as HPLC-MS, GC, finds that it contains various active composition, mainly includes
The compounds such as coixenolide, triglyceride, fatty acid, lactams, Semen Coicis lactone, saccharide, sterols, triterpenes.
Wherein, esters is the composition with anti-tumor activity being first found, and is also to report chemical composition the most of greatest concern.Though
The most current KANGLAITE injection on Chinese Clinical with Semen Coicis oil as effective ingredient is widely used, but about its thing
Matter basis and the research of anticancer active constituent rarely have report, to the quick grade of intelligence [CHINA JOURNAL OF CHINESE MATERIA MEDICA, 2005,30 (18): 1436-
1438] only with Liquid Chromatography/Mass Spectrometry, three lactone component in Semen Coicis oil have been carried out qualitative analysis, 12 kinds of glycerol three of earlier assumptions
Ester composition: Trilinoleyl glyceride, dilinoleic acid olein, Palmic acid dilinoleic acid glyceride, linoleic acid two oleic acid are sweet
Grease, Palmic acid linoleic acid oil acid glyceride, two Palmic acid glyceryl linoleates, glycerol trioleate, Oleic Linoleic are stearic
Acid glyceride, Palmic acid glyceryl dioleate, Palmic acid linoleic acid tristerin, two palmitic acid oil acid glycerides and two oil
Acid tristerin, but particular chemical and pharmacologically active to each composition is not furtherd investigate.And Semen Coicis oil
In do not contain only outside above-mentioned triglyceride composition, possibly together with monoglyceride, diglyceride and fatty acid ester etc..As can be seen here, the heart of a lotus seed
The complexity of Semen Coicis lubricant component, it is the biggest that this will necessarily make the quality control in actual production process and clinical drug safety face
Challenge.
Therefore, develop a kind of safely, effectively, controlled treatment tumor and improve the medicine of body's immunity and become this
The focus that invention is paid close attention to.It is true that the present invention has carried out separation, structure one by one to diglyceride in Semen Coicis oil and triglyceride composition
The screening of card, drug activity, have chosen 13 kinds and has notable antitumor and strengthen the glyceride monomers of immunologic function, by it according to not
Combine in proportion, carry out test of pesticide effectiveness research, obtained pharmaceutical composition of the present invention, preparation and in antitumor and increasing
Application in strong immunocompetence.Using compositions medication of the present invention, composition and composition determine, energy effective guarantee is each in producing
The stability of batch end product quality, it is to avoid the poison caused because complicated component is unclear because directly using coarse oil from coix seed to be used as medicine is secondary anti-
Should.
Summary of the invention
It is an object of the invention to provide a kind of pharmaceutical composition containing glyceride, specifically by following weight/mass percentage composition
13 kinds of one-tenth be grouped into:
Preferably, the weight/mass percentage composition of above-mentioned 13 kinds of compositions is:
It is furthermore preferred that the weight/mass percentage composition of above-mentioned 13 kinds of compositions is:
Wherein, described 13 kinds of glyceride compositions can be separated by method as described in the present embodiment of the invention and obtain, it is also possible to
This area conventional synthesis process preparation or direct market is used to buy.
A further object of the present invention is to provide a kind of pharmaceutical preparation containing glyceride, specifically includes medicine of the present invention
Compositions and one or more pharmaceutically acceptable carriers.
Wherein, described pharmaceutically acceptable carrier includes the diluent of pharmaceutical field routine, excipient, filler, breast
Agent, binding agent, lubricant, absorption enhancer, surfactant, disintegrating agent, lubricant or antioxidant, it may also be necessary to
Add flavouring agent, sweeting agent, preservative or coloring agent.
Described pharmaceutically acceptable carrier can be selected from: mannitol, sorbitol, sodium pyrosulfite, sodium sulfite, sulfur
Sodium thiosulfate, cysteine hydrochloride, TGA, methionine, soybean phospholipid, vitamin C, vitamin E, EDETATE SODIUM, EDTA
Calcium sodium, the alkali-metal carbonate of monovalence, acetate, phosphate or its aqueous solution, hydrochloric acid, acetic acid, sulphuric acid, phosphoric acid, aminoacid, chlorine
Change sodium, potassium chloride, sodium lactate, ethyl hydroxybenzoate solution, benzoic acid, potassium sorbate, chlorhexidine acetate, xylitol, maltose, Fructus Vitis viniferae
Sugar, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivative, cellulose and its derivates, algae
Hydrochlorate, gelatin, polyvinylpyrrolidone, glycerol, Tween 80, agar, calcium carbonate, calcium bicarbonate, surfactant, poly-second two
Alcohol, cyclodextrin, beta-schardinger dextrin-, phospholipid material, Kaolin, Pulvis Talci, calcium stearate or magnesium stearate.
Described pharmaceutical preparation can be oral solid formulation, oral liquid or injection.
Preferably,
Described oral solid formulation one in capsule, tablet, drop pill, granule, concentrated pill；Described oral liquid
Body preparation be selected from aqueous or oily suspensions, solution, Emulsion, syrup or elixir, or one available water before use or its
The dry products that its suitable carrier is compounding；Described injection selected from nano suspension, liposome, Emulsion, lyophilized injectable powder and
One in aqueous injection.
It is furthermore preferred that
Described injection includes following composition: pharmaceutical composition 50～350g of the present invention, injection soybean phospholipid or
Can injection soybean phospholipid 10～40g, glycerol for injection or be available for glycerol for injection 15～50g, water for injection adds to
1000ml。
It can be prepared via a method which:
Weigh prescription amount of preparation injection soybean phospholipid or can injection soybean phospholipid, add appropriate water for injection
After, be dispersed to without block and granular solids with high-shearing dispersion emulsifying machine, add the glycerol for injection weighed by formula ratio or
It is available for glycerol for injection, and injects water to ormal weight, stir standby；
Separately weigh the pharmaceutical composition containing 13 kinds of active component, the grease weighed and aqueous phase are separately heated to 60～70
After DEG C, putting high pressure homogenizer and carry out high-pressure emulsification, during emulsifying, homogenizer low pressure is 5～12MPa, and high pressure is 25～50MPa, then follows
Ring homogenizing 3～6 times, should be no less than 95% to the 2 following granules of μm, and the 5 above granules of μm must not detect, if desired with NaOH or HCl
Regulation pH to 4.8～8.5, preferably 6.8～7.0, most preferably 6.8；
Being forced through the microporous element filter filtration less than or equal to 3 μm by preparing uniform Emulsion nitrogen, nitrogen charging fill is gone out
Bacterium, cools down and get final product.
Described capsule includes following composition: the pharmaceutical composition 200～800g containing 13 kinds of active component, antioxidant
And/or emulsifying agent 0.20～0.60g, make 1000.
It can be prepared via a method which:
Glue is prepared: by weight weighing appropriate amounts of gelatin, purification for 1:0.6～1.2:0.3～0.8:0.0001～0.01
Water, glycerol and preservative；Successively by glycerol, purified water, preservative (selected from 10% ethyl hydroxybenzoate solution, benzoic acid, potassium sorbate
With the one in chlorhexidine acetate) in additionization glue tank, after being heated to 70 DEG C～90 DEG C, add gelatin be stirred continuously, take out true
Sky, until gelatin is completely dissolved, filters glue, deposits at 56～62 DEG C, standby；
Drug solution preparing: by the pharmaceutical composition of formula ratio, antioxidant and/or emulsifying agent (antioxidant is vitamin E,
Emulsifying agent is Tween 80) add in material-compound tank, it is stirred continuously, until mix homogeneously；
Moulding capsule: select suitable pelleting mould according to capsule size, 15～30 DEG C, relative humidity is less than 35% condition
Under carry out being dried after pelleting sizing, reject big piller, then after washing ball with 95% medicinal alcohol, continue to be dried to water content and be less than
12%, defective capsule, lettering are rejected in visual inspection, pack and get final product.
The present invention is shown by effect experiment, and multiple human tumor cell line is all had not by described pharmaceutical composition and preparation thereof
With the inhibitory action of degree, can be as treatment tumor disease medicine.
Therefore, the present invention also aims to provide a kind of aforementioned pharmaceutical compositions, pharmaceutical preparation preparing antineoplastic agent
Application in thing.And aforementioned pharmaceutical compositions improves the application in body's immunity medicine in preparation, and with LAK cell
The combination of (Tumor-infiltrating lymphocytes) application in preparing antitumor drug.
Wherein, described tumor refer in early days, mid-term or the pulmonary carcinoma in late period, hepatocarcinoma, cancer of pancreas, carcinoma of prostate, ovarian cancer or
Breast carcinoma.
Illustrate that compositions of the present invention and preparation thereof at antitumor and improve immunity of organism merit below by way of experimental data
Beneficial effect in terms of Neng.
One, external mtt assay measures pharmaceutical composition and the preparation inhibitory action to 8 kinds of human tumor cell lines thereof
1, experiment material and preparation
(1) cell strain: PANC-1 (human pancreatic cancer cell), SKOV3 (Proliferation of Human Ovarian Cell), (human breast carcinoma is thin for MCF-7
Born of the same parents), Bcap-37 (human breast cancer cell), SMMC-7721 (human liver cancer cell), HepG-2 (human liver cancer cell), A549 (people's lung
Cancerous cell), H460 (human lung carcinoma cell), above-mentioned cell strain by Shanghai medical industry research Pharmacological Evaluation research center preserve, pass
In generation, maintains.
(2) DMEM complete medium: add 10% new-born calf serum (GIBCO BRL), dual anti-.
(3) 0.25% trypsin solutions (Trypsin): purchased from Invitrogen company ,-20 DEG C of preservations.
(4) phosphate buffer (PBS): NaCl8g, KCl0.2g, Na2HPO41.15g, KH2PO40.2g, is dissolved in the double steaming of 1L
Water, 121 DEG C of autoclave sterilization 20min, 4 DEG C of preservations.
(5) MTT (AMRESCO) solution: be made into 5mg/ml solution with PBS.
(6) lysate: every 100ml deionization distilled water is containing SDS10g, isobutanol 5ml, concentrated hydrochloric acid 0.1ml.
2, experimental technique
The inhibitory action of above-mentioned cell strain is recorded by sample by mtt assay.
Specifically comprise the following steps that
(1) cell is cultivated: 1. being taken out from liquid nitrogen by cell, thaw rapidly in 37 DEG C of water-baths, cell is in sterile working
Moving in platform in 10ml sterile centrifugation tube and add 6ml cell culture medium, 1000 revs/min are centrifuged 5 minutes.Abandoning supernatant, precipitation
Middle addition 5～6ml cell culture medium, dropper piping and druming moves in Tissue Culture Flask after making it suspend, puts in 37 DEG C of cell culture incubators.
2. next day, in incubator, take out cell, discard cell culture medium in cell bottle, add 5～6ml cell culture mediums, put 37 DEG C
In cell culture incubator.3., the next day, in incubator, take out cell, discard cell culture medium in cell bottle, add PBS (pH7.4) 2
～3ml rocks cleaning, repeat after outwelling PBS solution and once clean.3～5 0.25% trypsin are added in culture bottle
Solution rocks uniformly, adds a cover and is placed in 37 DEG C of cell culture incubators about 3 minutes, finds that cell is from culture bottle in basis of microscopic observation
Depart from wall, add cell culture medium 2ml, after dropper piping and druming makes cell completely disengage from bottle wall, move into 2 clean culture bottles respectively
In, add cell culture medium 5～6ml piping and druming uniformly, be placed in 37 DEG C of cell culture incubators.4., the next day, 3. step is repeated.Whole
In incubation, attached cell does not allows to grow overstocked, and suspension cell remains exponential phase.(2) sample and reference substance
Preparation: weigh appropriate amount of drug composition sample and be dissolved in DMSO, obtain the solution that concentration is 10mg/ml.Gradient is made again with PBS
Dilution, obtains concentration 10mg/ml, 5000 μ g/ml, 2500 μ g/ml, 1250 μ g/ml, 625 μ g/ml, the dilution of 312.5 μ g/ml
Sample.
(3) sample diluted is added in flat 96 orifice plates, every hole 10 μ l, makees two parallel testings at every.By DMSO
Add after making gradient dilution accordingly in plate, as comparison.
(4) taking and be in the cell of exponential phase, cell is suspended in containing 10% calf serum through trypsinization and after washing
Culture medium in, dye exclusive method meter viable count through trypan blu e, and regulate cell suspending liquid density to 2 × 105Individual cell/
ml。
(5) flat 96 orifice plates of cell will be added at 37 DEG C, 5%CO2Cell culture incubator is cultivated 48 hours.
(6) every hole adds the 5mg/ml MTT solution of 20 μ l, continues to be incubated 3～4 hours in incubator.
(7) every hole adds 100 μ l lysates, continues incubated overnight in incubator, and the first crystal making generation is the most molten
Solve.Measure 570nm absorbance value.
(8) inhibitory rate of cell growth of each sample concentration group is calculated according to absorbance value.Computing formula is as follows:
(1-experimental port average light absorption value/control wells average light absorption value) × 100%
3, experimental result
The table 1 variable concentrations sample growth inhibition ratio (%) to 8 kinds of cell strains
Table 2 sample IC to 8 kinds of cell strains in vitro50(μg/ml)
4, conclusion
Above-mentioned 8 kinds of human tumor cell lines are had in various degree by the present composition of variable concentrations and preparation in vitro thereof
Inhibitory action.
Two, injection of the present invention is measured on the impact on immune function of mice
1, animal and material
1.1 animal
Kunming mouse, male, 18～22g, Shanghai Institute of Pharmaceutical Industry's Animal House provides, Shanghai dynamic circuit connector card word 107.
C57BL/6 mice, male, 18～20g, Shanghai Experimental Animal Center provides.
DBA/6 mice, male, 18～20g, Shanghai Experimental Animal Center provides, and Guan Hui 005 moves in middle section.
1.2 material
Injection of the present invention: provided by Zhejiang Prov. Hospital of Traditional Chinese Medicine, prepares according to the method for the invention.
Coordinative solvent: provided by Zhejiang Prov. Hospital of Traditional Chinese Medicine, as blank in this experiment.
Lentinan: Meifeng Pharmaceutical Factory Fuzhou City produces, lot number 911026, every 2ml 4mg Han lentinan, makees in this experiment
For positive control.
Culture fluid: RPMI1640, U.S.'s Difco product, include 15% calf serum, mercaptoethanol, Hepes etc..
3H-TdR: Shanghai nuclear research institute, radioactive concentration 1mci/ml.
Con A (ConA): Sigma product, 50 μ g/ml.
YAC-1 cell, L1210 cell, ctll cell, this laboratory is standby.
2, method and result
The impact of 2.1 injection of the present invention ConA outer on Mice Body induction spleen lymphocyte proliferation
C57BL/6 mice, takes spleen, separating Morr. cell, adjusts with RPMI1640+15%FCS culture fluid thin under aseptic condition
Born of the same parents' concentration is 1 × 107Individual/ml, medicine group respectively sets four dosage groups, and on 96 well culture plates, hole adds cell 100 μ l, various
Variable concentrations medicinal liquid 100 μ l, ConA50 μ l, with lentinan as positive controls, sets coordinative solvent matched group and cultivation simultaneously
The white matched group of liquid air, each group is all provided with three wells, 37 DEG C, 5%CO2Under the conditions of cultivate 48 hours, add3H-TdR0.5 μ ci/ hole, continues
Continuous cultivation 20 hours, collects cell and surveys CPM value on liquid scintillation instrument and compare with matched group.The results are shown in Table 3, injection of the present invention with
Lentinan is the same, all can have obvious facilitation by spleen lymphocyte proliferation outer to Mice Body, and in concentration linear relationship.
The impact of table 3 injection of the present invention spleen lymphocyte proliferation outer on Mice Body
* P < 0.01, compares with coordinative solvent and culture fluid matched group.
The impact on tumor animal splenic lymphocytes of 2.2 injection of the present invention
DBA/2 mice 60, every Mus subcutaneous vaccination L1210 mouse leukemia cell 1 × 104Individual, rise next day and be randomly divided into 6
Group, organizes 10, i.e. lentinan 20mg/kg, injection 6.25ml/kg, 12.5ml/kg, 25ml/kg of the present invention and the most molten
Agent matched group, saline control group, iv × 7, it is administered after terminating and puts to death animal, under aseptic condition, take spleen, count splenocyte, and
Adjusting cell concentration is 1 × 107Individual/ml, adds cell 100 μ l, culture fluid 100 μ l on 96 orifice plates, and each group is all provided with three wells, and 37
DEG C, 5%CO2Under the conditions of cultivate after 48 hours, add3H-TdR0.5 μ ci/ hole, continues to cultivate 20 hours, collects cell and surveys CPM value
And compare with matched group, the results are shown in Table 4.Injection of the present invention is improved spleen lymphocyte proliferation and makees lotus tumor (L1210) animal
With, and strengthening immunologic enhancement increasing with dosage, lentinan also presents immunologic enhancement.
The impact on lotus L1210 leukemia mouse splenic lymphocytes of table 4 injection of the present invention
* P < 0.01, compares with coordinative solvent group or normal saline group.△ P > 0.1, compares with normal saline group.
The impact of 2.3 injection of the present invention natural killer cell (NK cell) outer on Mice Body activity
With3H-TdR mixes suppression detection method and measures mice NK activity.
C57BL/6 mice, takes spleen under aseptic condition, is made into 1 × 106Individual/ml cell concentration, action effect cell, separately take
Cultivate the YAC-1 cell of 24 hours, be also adjusted to 1 × 104Individual/ml cell concentration, as target cell, detection sample is with 1:1
Dilution, is added on 96 well culture plates with the ratio cell as 100:1 and the sample imitating target, separately adds3H-TdR0.5 μ ci/ hole, 37 DEG C,
5%CO2Under the conditions of cultivate after 24 hours, collect cell, survey CPM value, calculate specificity inhibition percentage (Pi) expression NK cell
Activity, with lentinan as positive control, coordinative solvent and culture fluid are blank group.Pi computing formula is as follows:
The results are shown in Table 5, injection of the present invention as lentinan all can activation Mice Body in various degree outer NK activity,
Illustrate that injection of the present invention has Immunestimulatory effect.
The impact of table 5 injection of the present invention NK cytoactive outer on Mice Body
* P < 0.01, compares with effect group of solvents and culture fluid matched group.
The impact on tumor animal NK cytoactive of 2.4 injection of the present invention
DBA/2 mice 60, every Mus axil subcutaneous vaccination L1210 mouse leukemia 1 × 104Individual, rise next day and be randomly divided into 6
Group, often group 10, i.e. positive control lentinan 20mg/kg, injection 6.25ml/kg, 12.5ml/kg, 25ml/kg of the present invention
And coordinative solvent matched group, saline control group, it is iv × 7, is administered after terminating, takes spleen under aseptic condition, prepare spleen thin
Born of the same parents, adjusting cell concentration is 1 × 106Individual/ml, uses3H-TdR mixes suppression method detection method and measures mice NK activity, i.e. in 96 holes
Adding splenocyte 100 μ l (effector lymphocyte) on plate, (target cell concentration is 1 × 10 to YAC-1 cell4Individual/ml) 100 μ l,3H-
TdR0.5 μ ci/ hole, group is all provided with three wells, 37 DEG C, 5%CO2Under the conditions of cultivate after 24 hours, collect cell, survey CPM value, count
Calculate specificity inhibition percentage (Pi) and represent NK cytoactive (computing formula is the same).
The results are shown in Table 6, injection of the present invention all can have activation to tumor animal NK activity as lentinan, says
Bright have Immunestimulatory effect.
The impact on tumor animal NK cytoactive of table 6 injection of the present invention
* P<0.01, compares △ P>0.1 with coordinative solvent and saline control group, compares with saline control group
2.5 injection of the present invention produce the impact of IL-2 to tumor-bearing mice
DBA/2 mice 60, every Mus axil subcutaneous vaccination L1210 mouse leukemia 1 × 104Individual, rise next day and be randomly divided into 6
Group, organizes 10, i.e. lentinan 20mg/kg, injection 6.25ml/kg, 12.5ml/kg, 25ml/kg of the present invention and suspension
Matched group and saline control group, be iv × 7, is administered after terminating, puts to death animal, aseptically take spleen, prepare spleen
Cell, adjusting cell concentration is 1 × 107Individual/ml, on 24 porocyte culture plates, every hole adds 2ml and Con A5 μ g/ml, 37 DEG C,
5%CO2Under the conditions of cultivate and collect supernatant after 24 hours, with IL-2 dependent cell strain CTLL with3H-TdR incorporation methods measures IL-
2 activity.
The results are shown in Table 7, injection of the present invention has the effect promoting to produce IL-2 to tumor animal, and at tried third gear dosage
In be remarkably reinforced with dosage increasing action.
Table 7 injection of the present invention produces the impact of IL-2 to L1210 leukemia mouse
* P<0.01, compares △ P>0.1 with normal saline group, compares with normal saline group
The impact on macrophage phagocytosis of mice of 2.6 injection of the present invention
Take the healthy Kunming mouse of body weight 18-22g, be randomly divided into administration group and matched group, with coordinative solvent for comparison
Group, continuous 7 days intraperitoneal administrations, after last administration, every Mus lumbar injection 2% chicken erythrocyte suspension 1ml, is spaced 30 minutes, neck
Vertebra dislocation is put to death, and faces upward position and is fixed on Mus plate.Abdominal cavity skin is cut off in center, through abdominal cavity saline injection 2ml, rotates Mus plate 1
Minute, then sucking-off abdominal cavity washing liquid 1ml, average mark drips on two panels microscope slide, puts people and is lined with in the enamel box of wet gauze, moves to
37 DEG C of incubators are cultivated 30 minutes.Rinse in normal saline after taking-up.To remove non-paster cell, dry, acetone-methanol
(1:1) solution is fixed.4% (v/v) Giemsa-phosphate buffer dyes 3 minutes, clean with distilled water drift, dries.
Count macrophage under oil mirror, every 100, be calculated as follows phagocytic percentage and phagocytic index.
The results are shown in Table 8, injection abdominal cavity of the present invention is injected 7 times continuously, has bright when 12.5ml/kg, 6.25ml/kg dosage
The function of aobvious promotion Turnover of Mouse Peritoneal Macrophages phagocytic activity.
Table 8 injection of the present invention is to mouse peritoneal phagocytic function activation
* P < 0.01, compares with matched group
3, conclusion
Injection of the present invention has facilitation to mouse lymphocyte propagation, has activation to make to mice with tumor NK cytoactive
With；Tumor-bearing mice is had the effect that promotion IL-2 produce；There is the function being obviously promoted Turnover of Mouse Peritoneal Macrophages phagocytic activity.
Illustrate that injection of the present invention can improve body's immunity, play more preferable antitumor action.
Three, the injection of the present invention impact on LAK cell curative effect is measured
1, materials and methods
1.1 sample
Injection of the present invention is provided (lot number: 930924) by drug research room, Zhejiang Prov. Hospital of Traditional Chinese Medicine, stores in 4 DEG C of refrigerators standby
With.
1.2 target cell
K562 cell, Daudi cell is introduced by National Cancer Center Research Institute.
1.3 activating solution
People AB type serum+2mM paddy ammonia amine+100U/ml penicillin+100 μ g/ of RPMI1640 culture fluid+10% inactivation
Ml streptomycin+rIL-2, for the induction of LAK cell.
1.4 culture fluid
PRMI1640 culture fluid+10% new born bovine blood (NBS)+2mM paddy ammonia amine+100U/ml penicillin+100 μ g/ml
Streptomycin, for target cell cultivation etc..
The induction of 1.5LAK cell
Take healthy blood donor peripheral blood, add lymphocyte separation medium, centrifugal, take mononuclearcell, wash 2 with Hanks liquid
With 1 × 10 after secondary6The concentration of/ml is suspended in LAK cell activation liquid.Activating solution contains RPMI1640, penicillin, streptomycin, paddy
Glutamine, people's AB type serum of inactivation and rIL-2.Cell is cultivated 10 days, gained cell centrifugation 15 minutes, then washes through Hanks liquid
After washing 2 times, it is suspended in the normal saline solution containing 5% normal human serum albumin and rIL-2.
NK activity is that the killing activity of the mononuclearcell by healthy blood donor peripheral blood isolated represents.
1.6 injection of the present invention process tumor cell
Use tumor cell K562 cell sensitive to NK and the cell strain Daudi cell to NK cell tolerance.By tumor
Cell modulation is 1 × 105The concentration of/ml, then add with the injection of the present invention of RPMI1640 culture fluid 1:8 dilution, cell hangs
Liquid: injection=1:1 of the present invention, acts on 2 hours as target cell.
1.7 cell killing activity tests
Effector lymphocyte is washed 3 times with RPMI1640 culture fluid, then allows cell suspension, and inject 96 together with target cell
Few cells plate hole at the bottom of the U of hole, the ratio making effect target is 15.Every hole adds 0.5 μ ci3H-TdR l0 μ l, terminates after starting to cultivate 18 hours
Reaction.CPM is measured with liquid scintillation instrument.It is calculated as follows killing activity:
A: effector lymphocyte and the CPM of target cell mixing culture hole.
B: the CPM in effector lymphocyte's single culture hole.
C: the CPM in target cell single culture hole.
2, result
2.1NK it is active
The K562 cell processed through 2 hours injection of the present invention is not changed in by NK killing activity, and to Daudi cell by
4.9% rises to 11.0% (P < 0.01).
2.2LAK it is active
LAK cytoactive is also same, is not changed in the cell K562 processed, and to Daudi cell by
31.1% rises to 43.2% (P < 0.01).
3, discuss
This experimental result shows, LAK cell significantly carries for the killing activity of tumor cell Daudi processed by the invention
Height, NK activity also rises.The injection of the present invention drug combination as clinical LAK therapy is described.
In sum, the present composition and preparation thereof are in vitro to cancer of pancreas, ovarian cancer, breast carcinoma, hepatocarcinoma, pulmonary carcinoma etc.
Cell strain all has certain inhibitory action；Injection of the present invention can enhancing human body immunity function, have simultaneously and merge with LAK therapy
Medication effect.
Being confirmed by test, the glyceride composition of other content of the present invention and preparation thereof all can reach above-mentioned
Effect described in test example.
The present invention further illustrates the present invention by embodiment in detail below, but not as the restriction of the present invention.
Detailed description of the invention
The preparation of embodiment 1 Semen Coicis oil
The Semen Coicis 1000g of water intaking point≤10% is ground into 100 mesh, uses supercritical carbon dioxide extraction, extraction temperature
50 DEG C, extracting pressure 22Mpa, separation temperature 40 DEG C, separating pressure 8Mpa, carbon dioxide flow 500L/h, continuous extraction 3 is little
Time, isolated coarse oil from coix seed；Add the petroleum ether of coarse oil from coix seed weight 46%, and the aqueous solution of the sodium hydroxide of 1%
Alkali refining；Taking organic facies after separatory, the activated neutral alumina being firstly added 5% filters, and filtrate is heated to 45 DEG C, adds again 4%
Activated Filtration of Kaolin Clay, decompression, except solvent, adds 10% activated neutral alumina, filters, 170 DEG C of xeothermic going out of reducing pressure
Bacterium, cold filtration, obtain Semen Coicis oil.
Embodiment 2
Semen Coicis oil 8000mg adds 10ml normal hexane ultrasonic dissolution, then is configured to the heart of a lotus seed of 50mg/mL with flowing phase acetone
Semen Coicis oil solution.CHEETAH-HP100 high performance liquid preparative chromatography instrument is utilized to separate；Flowing phase: normal hexane: acetone=
94:6(v/v)；Separate sample size: 15ml every time；Chromatographic column: Venusil XBP silica (20*250mm, 10 μm)；Flow velocity:
18mL/min；ELSD detector: drift tube temperature 45 DEG C, flow rate of carrier gas 2.0L/min.Collecting retention time is the color of 15.8min
Spectral peak flow point, receives liquid and transfers to nitrogen ambient temperature under nitrogen in 10ml sample bottle at 30 DEG C after concentrating under reduced pressure and dry up, obtain 1,
3-bis-Oleic acid diglyceride.
Under room temperature, colorless oil；
Q-TOF/MS: quasi-molecular ion peak [M+Na]+=m/z643.5277 (Calcd.=643.5272, C39H72O5Na),
Degree of unsaturation=4,
1H H NMR spectroscopy and13C H NMR spectroscopy is shown in Table 9.
Table 91H NMR and13C H NMR spectroscopy data (CDCl3)
Embodiment 3
Semen Coicis oil 8000mg adds 10ml normal hexane ultrasonic dissolution, then is configured to the heart of a lotus seed of 50mg/mL with flowing phase acetone
Semen Coicis oil solution.CHEETAH-HP100 high performance liquid preparative chromatography instrument is utilized to separate；Flowing phase: normal hexane: acetone=
94:6(v/v)；Separate sample size: 15ml every time；Chromatographic column: Venusil XBP silica (20*250mm, 10 μm)；Flow velocity:
18mL/min.ELSD detector: drift tube temperature 45 DEG C, flow rate of carrier gas 2.0L/min.Collecting retention time is the chromatograph of 17min
Peak flow point, reception liquid is transferred to nitrogen ambient temperature under nitrogen in 10ml sample bottle at 30 DEG C and is dried up, obtains 1-sub-after concentrating under reduced pressure
Oleic acid-3-Oleic acid diglyceride.
Under room temperature, colorless oil；
Q-TOF/MS: quasi-molecular ion peak [M+Na]+=m/z641.5121 (Calcd.=641.5115, C39H70O5Na),
Degree of unsaturation=5；
1H H NMR spectroscopy and13C H NMR spectroscopy is shown in Table 10.
Table 101H NMR and13C H NMR spectroscopy data (CDCl3)
Embodiment 4
Semen Coicis oil 8000mg adds 10ml normal hexane ultrasonic dissolution, then is configured to the heart of a lotus seed of 50mg/mL with flowing phase acetone
Semen Coicis oil solution.CHEETAH-HP100 high performance liquid preparative chromatography instrument is utilized to separate；Flowing phase: normal hexane: acetone=
94:6(v/v)；Separate sample size: 15ml every time；Chromatographic column: Venusil XBP silica (20*250mm, 10 μm)；Flow velocity:
18mL/min.ELSD detector: drift tube temperature 45 DEG C, flow rate of carrier gas 2.0L/min.Collecting retention time is the chromatograph of 23min
Peak flow point, reception liquid is transferred to nitrogen ambient temperature under nitrogen in 10ml sample bottle at 30 DEG C and is dried up, obtains 1,2-after concentrating under reduced pressure
Glyceryl dioleate.
Under room temperature, colorless oil；
Q-TOF/MS: quasi-molecular ion peak [M+Na]+=m/z643.5277 (Calcd.=643.5272, C39H72O5Na),
Degree of unsaturation=4；
1H H NMR spectroscopy and13C H NMR spectroscopy is shown in Table 11.
Table 111H NMR and13C H NMR spectroscopy data (CDCl3)
Embodiment 5
Semen Coicis oil 8000mg adds 10ml normal hexane ultrasonic dissolution, then is configured to the heart of a lotus seed of 50mg/mL with flowing phase acetone
Semen Coicis oil solution.CHEETAH-HP100 high performance liquid preparative chromatography instrument is utilized to separate；Flowing phase: normal hexane: acetone=
94:6(v/v)；Separate sample size: 15ml every time；Chromatographic column: Venusil XBP silica (20*250mm, 10 μm)；Flow velocity:
18mL/min.ELSD detector: drift tube temperature 45 DEG C, flow rate of carrier gas 2.0L/min.Collecting retention time is the color of 24.5min
Spectral peak flow point, reception liquid is transferred to nitrogen ambient temperature under nitrogen in 10ml sample bottle at 30 DEG C and is dried up, obtains 1-after concentrating under reduced pressure
Oleic acid-2-linoleic acid diester.
Under room temperature, colorless oil；
Q-TOF/MS: quasi-molecular ion peak [M+Na]+=m/z641.5121 (Calcd.=641.5115, C39H70O5Na),
Degree of unsaturation=5；
1H H NMR spectroscopy and13C H NMR spectroscopy is shown in Table 12.
Table 121H NMR and13C H NMR spectroscopy data (CDCl3)
Embodiment 6
Semen Coicis oil 8000mg adds 10ml normal hexane ultrasonic dissolution, then is configured to the heart of a lotus seed of 50mg/mL with flowing phase acetone
Semen Coicis oil solution.CHEETAH-HP100 high performance liquid preparative chromatography instrument is utilized to separate；Flowing phase: normal hexane: acetone=
94:6(v/v)；Separate sample size: 15ml every time；Chromatographic column: Venusil XBP silica (20*250mm, 10 μm)；Flow velocity:
18mL/min.ELSD detector: drift tube temperature 45 DEG C, flow rate of carrier gas 2.0L/min.Collecting retention time is the chromatograph of 27min
Peak flow point, reception liquid is transferred to nitrogen ambient temperature under nitrogen in 10ml sample bottle at 30 DEG C and is dried up, obtains 1,2-after concentrating under reduced pressure
Dilinoleic acid glyceride.
Under room temperature, colorless oil；
Q-TOF/MS: quasi-molecular ion peak [M+Na]+=m/z639.4964 (Calcd.=639.4959, C39H68O5Na),
Degree of unsaturation=6；
1H H NMR spectroscopy and13C H NMR spectroscopy is shown in Table 13.
Table 131H NMR and13C H NMR spectroscopy data (CDCl3)
The preparation of embodiment 7 Trilinoleyl glyceride
P3000A high performance liquid preparative chromatography instrument is utilized to separate, mobile phase A: acetonitrile, Mobile phase B: acetonitrile-tetrahydrochysene furan
Mutter (1:1), is configured to the Semen Coicis oil solution of 50mg/mL by Mobile phase B, separates sampling volume 1.5mL every time；Chromatographic column:
Superstar BenetnachTM C18(20mm × 150mm, 5 μm)；Gradient condition: Mobile phase B: 0～27min:50%～
60%, 27～35min:90%, 35～45min:100%；Flow velocity: 18mL/min；Ultraviolet detection wavelength: 208nm；Collect and retain
Time is the chromatographic peak flow point of 12.6～14.2min, uses Rotary Evaporators concentrating under reduced pressure, turn with chloroform under the protection of nitrogen
Moving to 10mL bottle, in vacuum drying oven after 35 DEG C of dry 6h, be filled with nitrogen, dried sample is freezing in refrigerator to be protected
Deposit, obtain Trilinoleyl glyceride.
HR-EI-MS:m/z=878.7344 (Calcd.=878.7363, C57H98O6), degree of unsaturation=9.
IR (KBr film): 1746,1170,1098；2928、2856、724；3008,1655 (weak) cm-1。
1H-NMR data are shown in Table 14.
13C-NMR data are shown in Table 15.
Compound described in table 14 embodiment 7-141H-NMR spectrum data
Wherein, A: Trilinoleyl glyceride, B:1-oleic acid-2,3-dilinoleic acid glyceride, C:1-Palmic acid-2,3-bis-is sub-
Olein, D:1,3-bis-oleic acid-2-glyceryl linoleate, E:1-Palmic acid-2-linoleic acid-3-olein, F:1,
3-bis-Palmic acid-2-glyceryl linoleate, G: glycerol trioleate, H:1-Palmic acid-2,3-glyceryl dioleate.
Compound described in table 15 embodiment 7-1413C-NMR spectrum data
Wherein, A: Trilinoleyl glyceride, B:1-oleic acid-2,3-dilinoleic acid glyceride, C:1-Palmic acid-2,3-bis-is sub-
Olein, D:1,3-bis-oleic acid-2-glyceryl linoleate, E:1-Palmic acid-2-linoleic acid-3-olein, F:1,
3-bis-Palmic acid-2-glyceryl linoleate, G: glycerol trioleate, H:1-Palmic acid-2,3-glyceryl dioleate.
The preparation of embodiment 8 1-oleic acid-2,3-dilinoleic acid glyceride
P3000A high performance liquid preparative chromatography instrument is utilized to separate, mobile phase A: acetonitrile, Mobile phase B: acetonitrile-tetrahydrochysene furan
Mutter (1:1), is configured to the Semen Coicis oil solution of 50mg/mL by Mobile phase B, separates sampling volume 1.5mL every time；Chromatographic column:
Superstar BenetnachTM C18(20mm × 150mm, 5 μm)；Gradient condition: Mobile phase B: 0～27min:50%～
60%, 27～35min:90%, 35～45min:100%；Flow velocity: 18mL/min；Ultraviolet detection wavelength: 208nm；Collect and retain
Time is the chromatographic peak flow point of 15.4～17.3min, uses Rotary Evaporators concentrating under reduced pressure, turn with chloroform under the protection of nitrogen
Moving to 10mL bottle, in vacuum drying oven after 35 DEG C of dry 6h, be filled with nitrogen, dried sample is freezing in refrigerator to be protected
Deposit, obtain 1-oleic acid-2,3-dilinoleic acid glyceride.
HR-EI-MS:m/z=880.7518 (Calcd.=880.7520, C55H98O6), degree of unsaturation=7.
IR (KBr film): 1747,1164,1098；2925,2854,723；3008,1655 (weak) cm-1。
1H-NMR data are shown in Table 14.
13C-NMR data are shown in Table 15.
The preparation of embodiment 9 1-Palmic acid-2,3-dilinoleic acid glyceride
P3000A high performance liquid preparative chromatography instrument is utilized to carry out initial gross separation, mobile phase A: acetonitrile, Mobile phase B: acetonitrile-four
Hydrogen furan (1:1), is configured to the Semen Coicis oil solution of 50mg/mL by Mobile phase B, separates sampling volume 1.5mL every time；Chromatograph
Post: Superstar BenetnachTM C18(20mm × 150mm, 5 μm)；Gradient condition: Mobile phase B: 0～27min:50%～
60%, 27～35min:90%, 35～45min:100%；Flow velocity: 18mL/min；Ultraviolet detection wavelength: 208nm；Collect and retain
Time is the chromatographic peak flow point of 17.4～18.1min, uses Rotary Evaporators concentrating under reduced pressure, obtain crude product under the protection of nitrogen.
Mobile phase A time secondarily purified: acetonitrile, Mobile phase B: acetonitrile-oxolane (1:1), by above-mentioned crude product Mobile phase B
It is configured to the solution of 20mg/mL, separates sampling volume 1.5mL every time；Chromatographic column: Superstar BenetnachTM C18
(10mm×250mm,5μm)；Gradient condition: Mobile phase B: 0～23min:50%～60%, 32～43min:60%～90%,
43～60min:100%；Flow velocity: 3mL/min；Ultraviolet detection wavelength: 208nm, collecting retention time is 31.2～34.7min
Chromatographic peak flow point, uses Rotary Evaporators concentrating under reduced pressure under the protection of nitrogen, is transferred to 10mL bottle with chloroform, do in vacuum
In dry case after 35 DEG C of dry 6h, it is filled with nitrogen, dried sample freezen protective in refrigerator, obtains 1-Palmic acid-2,3-bis-
Glyceryl linoleate monomer.
HR-EI-MS:m/z=854.7370 (Calcd.=854.7363, C55H98O6), degree of unsaturation=7.
IR (KBr Flim): 1746,1165,1095；2926,2854,722；3009,1648cm-1(weak).
1H-NMR data are shown in Table 14.
13C-NMR data are shown in Table 15.
The preparation of embodiment 10 1,3-bis-oleic acid-2-glyceryl linoleate
P3000A high performance liquid preparative chromatography instrument is utilized to separate, mobile phase A: acetonitrile, Mobile phase B: acetonitrile-tetrahydrochysene furan
Mutter (1:1), is configured to the Semen Coicis oil solution of 50mg/mL by Mobile phase B, separates sampling volume 1.5mL every time；Chromatographic column:
Superstar BenetnachTM C18(20mm × 150mm, 5 μm)；Gradient condition: Mobile phase B: 0～27min:50%～
60%, 27～35min:90%, 35～45min:100%；Flow velocity: 18mL/min；Ultraviolet detection wavelength: 208nm；Collect and retain
Time is the chromatographic peak flow point of 18.4～20.2min, uses Rotary Evaporators concentrating under reduced pressure, turn with chloroform under the protection of nitrogen
Moving to 10mL bottle, in vacuum drying oven after 35 DEG C of dry 6h, be filled with nitrogen, dried sample is freezing in refrigerator to be protected
Deposit, obtain 1-oleic acid-2,3-dilinoleic acid glyceride.
HR-EI-MS:m/z=882.7678 (Calcd.=882.7672, C57H102O6), degree of unsaturation=7.
IR (KBr Flim): 1747,1163,1097；2925、2855、723；3007、1655cm-1(weak).
1H-NMR data are shown in Table 14.
13C-NMR data are shown in Table 15.
The preparation of embodiment 11 1-Palmic acid-2-linoleic acid-3-olein
P3000A high performance liquid preparative chromatography instrument is utilized to carry out initial gross separation.Mobile phase A: acetonitrile, Mobile phase B: acetonitrile-four
Hydrogen furan (1:1), is configured to the Semen Coicis oil solution of 50mg/mL by Mobile phase B, separates sampling volume 1.5mL every time；Chromatograph
Post: Superstar BenetnachTM C18(20mm × 150mm, 5 μm)；Gradient condition: Mobile phase B: 0～27min:50%～
60%, 27～35min:90%, 35～45min:100%；Flow velocity: 18mL/min；Ultraviolet detection wavelength: 208nm；Collect and retain
Time is the chromatographic peak flow point of 20.3～21.4min, uses Rotary Evaporators concentrating under reduced pressure, turn with chloroform under the protection of nitrogen
Moving to 10mL bottle, in vacuum drying oven after 35 DEG C of dry 6h, be filled with nitrogen, dried sample is freezing in refrigerator to be protected
Deposit, obtain 1-Palmic acid-2-linoleic acid-3-olein.
HR-EI-MS:m/z=856.7519, (Calcd.=856.7513, C55H100O6), degree of unsaturation=6.
IR (KBr Flim): 1747,1164,1098；2925、2854、723；3008、1655cm-1(weak).
1H-NMR data are shown in Table 14.
13C-NMR data are shown in Table 15.
The preparation of embodiment 12 1,3-bis-Palmic acid-2-glyceryl linoleate
P3000A high performance liquid preparative chromatography instrument is utilized to carry out initial gross separation, mobile phase A: acetonitrile, Mobile phase B: acetonitrile-four
Hydrogen furan (1:1), is configured to the Semen Coicis oil solution of 50mg/mL by Mobile phase B, separates sampling volume 1.5mL every time；Chromatograph
Post: Superstar BenetnachTM C18(20mm × 150mm, 5 μm)；Gradient condition: Mobile phase B: 0～27min:50%～
60%, 27～35min:90%, 35～45min:100%；Flow velocity: 18mL/min；Ultraviolet detection wavelength: 208nm；Collect and retain
Time is the chromatographic peak flow point of 25.7～26.2min, uses Rotary Evaporators concentrating under reduced pressure, turn with chloroform under the protection of nitrogen
Moving to 10mL bottle, in vacuum drying oven after 35 DEG C of dry 6h, be filled with nitrogen, dried sample is freezing in refrigerator to be protected
Deposit, obtain 1,3-bis-Palmic acid-2-glyceryl linoleate.
HR-EI-MS:m/z=830.7371 (Calcd.=830.7363, C53H98O6), degree of unsaturation=5.
IR (KBr film): 1747,1164,1098；2925、2854、723；3008、1655cm-1(weak).
1H-NMR data are shown in Table 14.
13C-NMR data are shown in Table 15.
The preparation of embodiment 13 glycerol trioleate
P3000A high performance liquid preparative chromatography instrument is utilized to carry out initial gross separation, mobile phase A: acetonitrile, Mobile phase B: acetonitrile-four
Hydrogen furan (1:1), is configured to the Semen Coicis oil solution of 50mg/mL by Mobile phase B, separates sampling volume 1.5mL every time；Chromatograph
Post: Superstar BenetnachTM C18(20mm × 150mm, 5 μm)；Gradient condition: Mobile phase B: 0～27min:50%～
60%, 27～35min:90%, 35～45min:100%；Flow velocity: 18mL/min；Ultraviolet detection wavelength: 208nm；Collect and retain
Time is the chromatographic peak flow point of 26.6～27.7min, uses Rotary Evaporators concentrating under reduced pressure, turn with chloroform under the protection of nitrogen
Moving to 10mL bottle, in vacuum drying oven after 35 DEG C of dry 6h, be filled with nitrogen, dried sample is freezing in refrigerator to be protected
Deposit, obtain glycerol trioleate.
HR-EI-MS:m/z=884.7851 (Calcd.=884.7833, C57H104O6), degree of unsaturation=6.
IR (KBr film): 1749,1165,1095；2925,2854,723；3004,1654cm-1(weak).
1H-NMR data are shown in Table 14.
13C-NMR data are shown in Table 15.
The preparation of embodiment 14 1-Palmic acid-2,3-glyceryl dioleate
P3000A high performance liquid preparative chromatography instrument is utilized to carry out initial gross separation, mobile phase A: acetonitrile, Mobile phase B: acetonitrile-four
Hydrogen furan (1:1), is configured to the Semen Coicis oil solution of 50mg/mL by Mobile phase B, separates sampling volume 1.5mL every time；Chromatograph
Post: Superstar BenetnachTM C18(20mm × 150mm, 5 μm)；Gradient condition: Mobile phase B: 0～27min:50%～
60%, 27～35min:90%, 35～45min:100%；Flow velocity: 18mL/min；Ultraviolet detection wavelength: 208nm；Collect and retain
Time is the chromatographic peak flow point of 28.2～29.3min, uses Rotary Evaporators concentrating under reduced pressure, obtain crude product under the protection of nitrogen.
Mobile phase A time secondarily purified: acetonitrile, Mobile phase B: acetonitrile-oxolane (1:1), by above-mentioned crude product Mobile phase B
It is configured to the solution of 20mg/mL, separates sampling volume 1.5mL every time；Chromatographic column: Superstar BenetnachTM C18
(10mm×250mm,5μm)；Gradient condition: Mobile phase B: 0～23min:50%～60%, 32～43min:60%～90%,
43～60min:100%；Flow velocity: 3mL/min；Ultraviolet detection wavelength: 208nm, collecting retention time is 32.9～35.1min
Chromatographic peak flow point, uses Rotary Evaporators concentrating under reduced pressure under the protection of nitrogen, is transferred to 10mL bottle with chloroform, do in vacuum
In dry case after 35 DEG C of dry 6h, it is filled with nitrogen, dried sample freezen protective in refrigerator, obtains 1-Palmic acid-2,3-bis-
Olein.
HR-EI-MS:m/z=858.7672 (Calcd.=858.7676, C55H102O6), degree of unsaturation=5.
IR (KBr film): 1747,1166,1095；2926,2854,722；3003,1654cm-1(weak).
1H-NMR data are shown in Table 14.
13C-NMR data are shown in Table 15.
The preparation of embodiment 15 medicine composition injection of the present invention
The weight/mass percentage composition (%) of each composition in compositions:
Prescription:
Above-mentioned composition 100g
Injection soybean phospholipid 10g
Glycerol for injection 15g
Water for injection adds to 1000ml
Technique:
Weigh the injection soybean phospholipid of prescription amount of preparation, after adding appropriate water for injection, use high-shearing dispersion emulsifying machine
It is dispersed to, without block and granular solids, add the glycerol for injection weighed by formula ratio, and inject water to ormal weight, stir
Mix the most standby；
Separately claim above-mentioned composition, after the grease weighed and aqueous phase are separately heated to 60 DEG C, put high pressure homogenizer and carry out height
Pressure emulsifying, during emulsifying, homogenizer low pressure is 5MPa, and high pressure is 25MPa, recirculation homogenizing 6 times, should be no less than to the 2 following granules of μm
95%, the 5 above granules of μm must not detect, and regulates pH to 8.5 with NaOH or HCl if desired；
By prepare uniform Emulsion nitrogen be forced through≤microporous element filter of 3 μm filters, nitrogen charging fill sterilizing, cooling
Obtain.
The preparation of embodiment 16 medicine composition injection of the present invention
The weight/mass percentage composition (%) of each composition in compositions:
Prescription:
Above-mentioned composition 300g
Can injection soybean phospholipid 40g
It is available for glycerol for injection 50g
Water for injection adds to 1000ml
Technique:
Weigh the injection soybean phospholipid of prescription amount of preparation, after adding appropriate water for injection, use high-shearing dispersion emulsifying machine
It is dispersed to, without block and granular solids, add the glycerol for injection weighed by formula ratio, and inject water to ormal weight, stir
Mix the most standby；
Separately weigh above-mentioned composition, after the grease weighed and aqueous phase are separately heated to 70 DEG C, put high pressure homogenizer and carry out
High-pressure emulsification, during emulsifying, homogenizer low pressure is 10MPa, and high pressure is 50MPa, recirculation homogenizing 3 times, should not to the 2 following granules of μm
Less than 95%, the 5 above granules of μm must not detect, and regulates pH to 7.1 with NaOH or HCl if desired；
By prepare uniform Emulsion nitrogen be forced through≤microporous element filter of 3 μm filters, nitrogen charging fill sterilizing, cooling
Obtain.
The preparation of embodiment 17 medicine composition injection of the present invention
The weight/mass percentage composition (%) of each composition in compositions:
Prescription:
Above-mentioned composition 200g
Injection soybean phospholipid 25g
It is available for glycerol for injection 30g
Water for injection adds to 1000ml
Technique:
Weigh the injection soybean phospholipid of prescription amount of preparation, after adding appropriate water for injection, use high-shearing dispersion emulsifying machine
It is dispersed to, without block and granular solids, add the glycerol for injection weighed by formula ratio, and inject water to ormal weight, stir
Mix the most standby；
Separately weigh above-mentioned composition, after the grease weighed and aqueous phase are separately heated to 65 DEG C, put high pressure homogenizer and carry out
High-pressure emulsification, during emulsifying, homogenizer low pressure is 9MPa, and high pressure is 35MPa, recirculation homogenizing 4 times, should be many to the 2 following granules of μm
In 95%, the 5 above granules of μm must not detect, and regulates pH to 4.8 with NaOH or HCl if desired；
By prepare uniform Emulsion nitrogen be forced through≤microporous element filter of 3 μm filters, nitrogen charging fill sterilizing, cooling
Obtain.
The preparation of embodiment 18 medicine composition injection of the present invention
The weight/mass percentage composition (%) of each composition in compositions:
Prescription:
Above-mentioned composition 150g
Can injection soybean phospholipid 35g
Glycerol for injection or 30g
Water for injection adds to 1000ml
Technique:
Weigh the injection soybean phospholipid of prescription amount of preparation, after adding appropriate water for injection, use high-shearing dispersion emulsifying machine
It is dispersed to, without block and granular solids, add the glycerol for injection weighed by formula ratio, and inject water to ormal weight, stir
Mix the most standby；
Separately weigh above-mentioned composition, after the grease weighed and aqueous phase are separately heated to 68 DEG C, put high pressure homogenizer and carry out
High-pressure emulsification, during emulsifying, homogenizer low pressure is 8MPa, and high pressure is 40MPa, recirculation homogenizing 5 times, should be many to the 2 following granules of μm
In 95%, the 5 above granules of μm must not detect, and regulates pH to 6.8 with NaOH or HCl if desired；
By prepare uniform Emulsion nitrogen be forced through≤microporous element filter of 3 μm filters, nitrogen charging fill sterilizing, cooling
Obtain.
The preparation of embodiment 19 medicament composition capsule of the present invention agent
The weight/mass percentage composition (%) of each composition in compositions:
Prescription:
Above-mentioned composition 200g
Vitamin E 0.20g
Make 1000
Technique:
Glue is prepared: by weight weighing appropriate amounts of gelatin, purified water, glycerol and 10% oxybenzene second for 1:1.2:0.8:0.01
Ester solution；Successively by glycerol, purified water, 10% ethyl hydroxybenzoate solution additionization glue tank, after being heated to 70 DEG C, add gelatin
Be stirred continuously, evacuation, until gelatin is completely dissolved, by glue filter, deposit at 58 DEG C, standby；
Drug solution preparing: the above-mentioned composition of formula ratio, vitamin E are added in material-compound tank, be stirred continuously, until mixing is all
Even；
Moulding capsule: select suitable pelleting mould according to capsule size, 25 DEG C, relative humidity < carries out under the conditions of 35%
It is dried after pelleting sizing, rejects big piller, then after washing ball with 95% medicinal alcohol, continue to be dried to water content and be less than 12%, mesh
Defective capsule, lettering are rejected in inspection, pack and get final product.
The preparation of embodiment 20 medicament composition capsule of the present invention agent
The weight/mass percentage composition (%) of each composition in compositions:
Prescription:
Above-mentioned composition 800g
Tween 80 0.60g
Make 1000
Technique:
Glue is prepared: by weight weighing appropriate amounts of gelatin, purified water, glycerol and benzoic acid for 1:1.2:0.8:0.01；Depend on
Secondary by glycerol, purified water, benzoic acid additionization glue tank, after being heated to 90 DEG C, add gelatin be stirred continuously, evacuation, directly
It is completely dissolved to gelatin, glue is filtered, deposits at 56 DEG C, standby；
Drug solution preparing: the above-mentioned composition of formula ratio, Tween 80 are added in material-compound tank, be stirred continuously, until mixing is all
Even；
Moulding capsule: select suitable pelleting mould according to capsule size, 20 DEG C, relative humidity < carries out under the conditions of 35%
It is dried after pelleting sizing, rejects big piller, then after washing ball with 95% medicinal alcohol, continue to be dried to water content and be less than 12%, mesh
Defective capsule, lettering are rejected in inspection, pack and get final product.
The preparation of embodiment 21 medicament composition capsule of the present invention agent
The weight/mass percentage composition (%) of each composition in compositions:
Prescription:
Above-mentioned composition 500g
Vitamin E 0.40g
Make 1000
Technique:
Glue is prepared: by weight weighing appropriate amounts of gelatin, purified water, glycerol and potassium sorbate for 1:0.9:0.6:0.005；
Successively by glycerol, purified water, potassium sorbate additionization glue tank, after being heated to 80 DEG C, add gelatin and be stirred continuously, take out very
Sky, until gelatin is completely dissolved, filters glue, deposits at 62 DEG C, standby；
Drug solution preparing: the above-mentioned composition of formula ratio, vitamin E are added in material-compound tank, be stirred continuously, until mixing is all
Even；
Moulding capsule: select suitable pelleting mould according to capsule size, 30 DEG C, relative humidity < carries out under the conditions of 35%
It is dried after pelleting sizing, rejects big piller, then after washing ball with 95% medicinal alcohol, continue to be dried to water content and be less than 12%, mesh
Defective capsule, lettering are rejected in inspection, pack and get final product.
The preparation of embodiment 22 medicament composition capsule of the present invention agent
The weight/mass percentage composition (%) of each composition in compositions:
Prescription:
Above-mentioned composition 600g
Tween 80 0.3g
Make 1000
Technique:
Glue is prepared: own by weight weighing appropriate amounts of gelatin, purified water, glycerol and acetic acid chlorine for 1:1.0:0.5:0.008
Fixed；Successively by glycerol, purified water, chlorhexidine acetate additionization glue tank, after being heated to 85 DEG C, add gelatin be stirred continuously,
Evacuation, until gelatin is completely dissolved, filters glue, deposits at 56 DEG C, standby；
Drug solution preparing: the above-mentioned composition of formula ratio, Tween 80 are added in material-compound tank, be stirred continuously, until mixing is all
Even；
Moulding capsule: select suitable pelleting mould according to capsule size, 18 DEG C, relative humidity < carries out under the conditions of 35%
It is dried after pelleting sizing, rejects big piller, then after washing ball with 95% medicinal alcohol, continue to be dried to water content and be less than 12%, mesh
Defective capsule, lettering are rejected in inspection, pack and get final product.
The preparation of embodiment 23 medicine composition injection of the present invention
The weight/mass percentage composition (%) of each composition in compositions:
Prescription:
Above-mentioned composition 100g
Injection soybean phospholipid 10g
Glycerol for injection 15g
Water for injection adds to 1000ml
Technique:
Weigh the injection soybean phospholipid of prescription amount of preparation, after adding appropriate water for injection, use high-shearing dispersion emulsifying machine
It is dispersed to, without block and granular solids, add the glycerol for injection weighed by formula ratio, and inject water to ormal weight, stir
Mix the most standby；
Separately weigh above-mentioned composition, after itself and aqueous phase are separately heated to 60 DEG C, put high pressure homogenizer and carry out high-pressure emulsification,
During emulsifying, homogenizer low pressure is 6MPa, and high pressure is 28MPa, recirculation homogenizing 4 times, should be no less than 95% to the 2 following granules of μm, 5 μ
More than m granule must not detect, and regulates pH6.8 with NaOH or HCl if desired；
By prepare uniform Emulsion nitrogen be forced through≤microporous element filter of 3 μm filters, nitrogen charging fill sterilizing, cooling
Obtain.
The preparation of embodiment 24 medicine composition injection of the present invention
The weight/mass percentage composition (%) of each composition in compositions:
Prescription:
Above-mentioned composition 300g
Can injection soybean phospholipid 40g
It is available for glycerol for injection 50g
Water for injection adds to 1000ml
Technique:
Weigh the injection soybean phospholipid of prescription amount of preparation, after adding appropriate water for injection, use high-shearing dispersion emulsifying machine
It is dispersed to, without block and granular solids, add the glycerol for injection weighed by formula ratio, and inject water to ormal weight, stir
Mix the most standby；
Separately weigh above-mentioned composition, after itself and aqueous phase are separately heated to 70 DEG C, put high pressure homogenizer and carry out high-pressure emulsification,
During emulsifying, homogenizer low pressure is 11MPa, and high pressure is 46MPa, recirculation homogenizing 56 times, should be no less than 95% to the 2 following granules of μm,
The 5 above granules of μm must not detect, and regulates pH to 7.5 with NaOH or HCl if desired；
By prepare uniform Emulsion nitrogen be forced through≤microporous element filter of 3 μm filters, nitrogen charging fill sterilizing, cooling
Obtain.
The preparation of embodiment 25 medicine composition injection of the present invention
The weight/mass percentage composition (%) of each composition in compositions:
Prescription:
Above-mentioned composition 200g
Injection soybean phospholipid 25g
It is available for glycerol for injection 30g
Water for injection adds to 1000ml
Technique:
Weigh the injection soybean phospholipid of prescription amount of preparation, after adding appropriate water for injection, use high-shearing dispersion emulsifying machine
It is dispersed to, without block and granular solids, add the glycerol for injection weighed by formula ratio, and inject water to ormal weight, stir
Mix the most standby；
Separately weigh above-mentioned composition, after itself and aqueous phase are separately heated to 65 DEG C, put high pressure homogenizer and carry out high-pressure emulsification,
During emulsifying, homogenizer low pressure is 9MPa, and high pressure is 36MPa, recirculation homogenizing 3 times, should be no less than 95% to the 2 following granules of μm, 5 μ
More than m granule must not detect, and regulates pH to 6.5 with NaOH or HCl if desired；
By prepare uniform Emulsion nitrogen be forced through≤microporous element filter of 3 μm filters, nitrogen charging fill sterilizing, cooling
Obtain.
The preparation of embodiment 26 medicament composition capsule of the present invention agent
The weight/mass percentage composition (%) of each composition in compositions:
Prescription:
Above-mentioned composition 200g
Vitamin E 0.20g
Make 1000
Technique:
Glue is prepared: by weight weighing appropriate amounts of gelatin, purified water, glycerol and 10% oxybenzene second for 1:1.2:0.8:0.01
Ester solution；Successively by glycerol, purified water, 10% ethyl hydroxybenzoate solution additionization glue tank, after being heated to 70 DEG C, add gelatin
Be stirred continuously, evacuation, until gelatin is completely dissolved, by glue filter, deposit at 60 DEG C, standby；Above-mentioned composition, dimension are raw
Element E adds in material-compound tank, is stirred continuously, until mix homogeneously；
Moulding capsule: select suitable pelleting mould according to capsule size, 28 DEG C, relative humidity < carries out under the conditions of 35%
It is dried after pelleting sizing, rejects big piller, then after washing ball with 95% medicinal alcohol, continue to be dried to water content and be less than 12%, mesh
Defective capsule, lettering are rejected in inspection, pack and get final product.
The preparation of embodiment 27 medicament composition capsule of the present invention agent
The weight/mass percentage composition (%) of each composition in compositions:
Prescription:
Above-mentioned composition 800g
Tween 80 0.60g
Make 1000
Technique:
Glue is prepared: by weight weighing appropriate amounts of gelatin, purified water, glycerol and benzoic acid for 1:1.2:0.8:0.01；Depend on
Secondary by glycerol, purified water, benzoic acid additionization glue tank, after being heated to 90 DEG C, add gelatin be stirred continuously, evacuation, directly
It is completely dissolved to gelatin, glue is filtered, deposits at 56 DEG C, standby；
Drug solution preparing: the above-mentioned composition of formula ratio, Tween 80 are added in material-compound tank, be stirred continuously, until mixing is all
Even；
Moulding capsule: select suitable pelleting mould according to capsule size, 16 DEG C, relative humidity < carries out under the conditions of 35%
It is dried after pelleting sizing, rejects big piller, then after washing ball with 95% medicinal alcohol, continue to be dried to water content and be less than 12%, mesh
Defective capsule, lettering are rejected in inspection, pack and get final product.
The preparation of embodiment 28 medicament composition capsule of the present invention agent
The weight/mass percentage composition (%) of each composition in compositions:
Prescription:
Above-mentioned composition 500g
Vitamin E 0.40g
Make 1000
Technique:
Glue is prepared: by weight weighing appropriate amounts of gelatin, purified water, glycerol and potassium sorbate for 1:0.9:0.6:0.005；
Successively by glycerol, purified water, potassium sorbate additionization glue tank, after being heated to 80 DEG C, add gelatin and be stirred continuously, take out very
Sky, until gelatin is completely dissolved, filters glue, deposits at 61 DEG C, standby；
Drug solution preparing: the above-mentioned composition of formula ratio, vitamin E are added in material-compound tank, be stirred continuously, until mixing is all
Even；
Moulding capsule: select suitable pelleting mould according to capsule size, 22 DEG C, relative humidity < carries out under the conditions of 35%
It is dried after pelleting sizing, rejects big piller, then after washing ball with 95% medicinal alcohol, continue to be dried to water content and be less than 12%, mesh
Defective capsule, lettering are rejected in inspection, pack and get final product.
Claims (17)
1. a pharmaceutical composition, it is characterised in that be grouped into by 13 kinds of one-tenth of following weight/mass percentage composition:
Pharmaceutical composition the most according to claim 1, it is characterised in that the weight/mass percentage composition of described 13 kinds of compositions is:
3. a pharmaceutical preparation, it is characterised in that containing the pharmaceutical composition described in claim 1 and one or more pharmaceutically
Acceptable carrier, wherein said pharmaceutically acceptable carrier includes the diluent of pharmaceutical field routine, excipient, filling
Agent, emulsifying agent, binding agent, lubricant, absorption enhancer, surfactant, disintegrating agent or antioxidant.
Pharmaceutical preparation the most according to claim 3, it is characterised in that described pharmaceutically acceptable carrier can also include
Flavouring agent, sweeting agent, preservative or coloring agent.
Pharmaceutical preparation the most according to claim 3, it is characterised in that described pharmaceutically acceptable carrier can be selected from: sweet
Dew alcohol, sorbitol, sodium pyrosulfite, sodium sulfite, sodium thiosulfate, cysteine hydrochloride, TGA, soybean phospholipid,
Vitamin C, vitamin E, EDETATE SODIUM, Ethylenediaminetetraacetic Acid Calcium Salt, the alkali-metal carbonate of monovalence, acetate, phosphate or its aqueous solution,
Hydrochloric acid, acetic acid, sulphuric acid, phosphoric acid, aminoacid, sodium chloride, potassium chloride, sodium lactate, ethyl hydroxybenzoate solution, benzoic acid, potassium sorbate,
Chlorhexidine acetate, xylitol, maltose, glucose, fructose, dextran, starch, sucrose, lactose, mannitol, silicon are derivative
Thing, cellulose and its derivates, alginate, gelatin, polyvinylpyrrolidone, glycerol, Tween 80, agar, calcium carbonate, bicarbonate
Calcium, surfactant, Polyethylene Glycol, cyclodextrin, phospholipid material, Kaolin, Pulvis Talci, calcium stearate or magnesium stearate.
The most according to claim 3, pharmaceutical preparation, it can be oral solid formulation, oral liquid or injection.
Pharmaceutical preparation the most according to claim 6, it is characterised in that:
Described oral solid formulation is selected from any one of capsule, tablet, drop pill, granule, concentrated pill；
Described oral liquid is selected from aqueous or oily suspensions, solution, Emulsion, syrup or elixir, or one makes
With the compounding dry products of front available water or other suitable carrier；
Described injection is selected from any one of nano suspension, liposome, Emulsion, lyophilized injectable powder and aqueous injection.
Pharmaceutical preparation the most according to claim 6, it is characterised in that described injection is made up of following composition:
The pharmaceutical composition 50～350g of 13 kinds of active component
Injection soybean phospholipid or can injection soybean phospholipid 10～40g
Glycerol for injection or be available for glycerol for injection 15～50g
Water for injection adds to 1000ml.
The preparation method of injection the most according to claim 8, it is characterised in that comprise the steps:
Weigh prescription amount of preparation injection soybean phospholipid or can injection soybean phospholipid, after adding appropriate water for injection, use
High-shearing dispersion emulsifying machine is dispersed to, without block and granular solids, add the glycerol for injection weighed by formula ratio or be available for note
Penetrate and use glycerol, and inject water to ormal weight, stir standby；
Separately weigh the pharmaceutical composition of 13 kinds of active component, after the grease weighed and aqueous phase are separately heated to 60～70 DEG C, put
High pressure homogenizer carries out high-pressure emulsification, and during emulsifying, homogenizer low pressure is 5～12MPa, and high pressure is 25～50MPa, recirculation homogenizing 3
～6 times, should be no less than 95% to the 2 following granules of μm, the 5 above granules of μm must not detect, and regulates pH to 4.8 with NaOH or HCl
～8.5；
Prepared uniform Emulsion nitrogen is forced through and filters less than or equal to the microporous element filter of 3 μm, nitrogen charging fill sterilizing, cold
But and get final product.
The preparation method of injection the most according to claim 9, it is characterised in that described NaOH or HCl regulates pH to 6.8
～7.
The preparation method of 11. injections according to claim 9, it is characterised in that described NaOH or HCl regulates pH to 6.8.
12. pharmaceutical preparatioies according to claim 7, it is characterised in that described capsule is made up of following composition:
The pharmaceutical composition 200～800g of 13 kinds of active component
Antioxidant and/or emulsifying agent 0.20～0.60g
Make 1000.
13. according to the preparation method of capsule described in claim 12, it is characterised in that comprise the steps:
Glue is prepared: weigh appropriate amounts of gelatin, purified water, sweet by weight for 1:0.6～1.2:0.3～0.8:0.0001～0.01
Oil and preservative；Successively by glycerol, purified water, preservative additionization glue tank, after being heated to 70 DEG C～90 DEG C, add gelatin
Be stirred continuously, evacuation, until gelatin is completely dissolved, by glue filter, deposit at 56～62 DEG C, standby；
Drug solution preparing: the pharmaceutical composition of formula ratio, antioxidant and/or emulsifying agent are added in material-compound tank, is stirred continuously, directly
To mix homogeneously；
Moulding capsule: select suitable pelleting mould according to capsule size, 15～30 DEG C, relative humidity is less than entering under the conditions of 35%
It is dried after the sizing of row pelleting, rejects big piller, then after washing ball with 95% medicinal alcohol, continue to be dried to water content and be less than 12%,
Defective capsule, lettering are rejected in visual inspection, pack and get final product.
14. according to method described in claim 13, it is characterised in that:
Described preservative one in 10% ethyl hydroxybenzoate solution, benzoic acid, potassium sorbate and chlorhexidine acetate；
Described antioxidant is vitamin E, and emulsifying agent is Tween 80.
15. pharmaceutical composition is being prepared antitumor or is being improved the application in body's immunity medicine according to claim 1.
16. the combination of pharmaceutical composition and LAK cell application in preparing antitumor drug according to claim 1.
17. application according to claim 15, it is characterised in that described tumor refers in early days, mid-term or the pulmonary carcinoma in late period,
Hepatocarcinoma, cancer of pancreas, carcinoma of prostate, ovarian cancer or breast carcinoma.
Priority Applications (14)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410342799.2A CN105267197B (en) | 2014-07-18 | Pharmaceutical composition, preparation and application thereof containing 13 kinds of glyceride | |
| US14/733,098 US9585858B2 (en) | 2014-07-18 | 2015-06-08 | Pharmaceutical composition containing 13 triglycerides, and preparations and use thereof |
| EA201790117A EA033077B1 (en) | 2014-07-18 | 2015-07-17 | Pharmaceutical composition containing 13 triglycerides, and preparations and use thereof |
| SG11201700122TA SG11201700122TA (en) | 2014-07-18 | 2015-07-17 | Pharmaceutical compound comprising 13 glycerides, formulation and application thereof |
| KR1020177001303A KR20170031146A (en) | 2014-07-18 | 2015-07-17 | Pharmaceutical compound comprising 13 glycerides, formulation and application thereof |
| JP2017503156A JP6473801B2 (en) | 2014-07-18 | 2015-07-17 | Pharmaceutical composition comprising 13 glycerides, formulation and application thereof |
| EP15821314.0A EP3153163B1 (en) | 2014-07-18 | 2015-07-17 | Pharmaceutical compound comprising 13 glycerides, formulation and application thereof |
| AP2017009706A AP2017009706A0 (en) | 2014-07-18 | 2015-07-17 | Pharmaceutical compound comprising 13 glycerides, formulation and application thereof |
| PL15821314T PL3153163T3 (en) | 2014-07-18 | 2015-07-17 | Pharmaceutical compound comprising 13 glycerides, formulation and application thereof |
| DK15821314.0T DK3153163T3 (en) | 2014-07-18 | 2015-07-17 | PHARMACEUTICAL COMPOUND CONTAINING 13 GLYCERIDES, FORMULATION AND USE THEREOF |
| PCT/CN2015/084295 WO2016008441A1 (en) | 2014-07-18 | 2015-07-17 | Pharmaceutical compound comprising 13 glycerides, formulation and application thereof |
| NZ726582A NZ726582A (en) | 2014-07-18 | 2015-07-17 | Pharmaceutical composition containing 13 glycerides, and preparations and use thereof |
| CA2954792A CA2954792C (en) | 2014-07-18 | 2015-07-17 | Pharmaceutical compound comprising 13 glycerides, formulation and application thereof |
| AU2015291530A AU2015291530B2 (en) | 2014-07-18 | 2015-07-17 | Pharmaceutical composition containing 13 glycerides, and preparations and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410342799.2A CN105267197B (en) | 2014-07-18 | Pharmaceutical composition, preparation and application thereof containing 13 kinds of glyceride |
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| Publication Number | Publication Date |
|---|---|
| CN105267197A CN105267197A (en) | 2016-01-27 |
| CN105267197B true CN105267197B (en) | 2016-11-30 |
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| PB01 | Publication | ||
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| TR01 | Transfer of patent right |
Effective date of registration: 20171010 Address after: 310018 No. 11 road, Xiasha economic and Technological Development Zone, Hangzhou, Zhejiang Patentee after: ZHEJIANG KANGLAITE PHARMACEUTICAL CO., LTD. Address before: 310018 No. 16 Road, Xiasha economic and Technological Development Zone, Hangzhou, Zhejiang Co-patentee before: ZHEJIANG KANGLAITE PHARMACEUTICAL CO., LTD. Patentee before: Zhejiang Kanglaite Group Co., Ltd. |
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| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20160127 Assignee: Zhejiang Kanglaite Group Co., Ltd. Assignor: ZHEJIANG KANGLAITE PHARMACEUTICAL CO., LTD. Contract record no.: 2017330000138 Denomination of invention: Pharmaceutical composition containing 13 glycerides, and preparation and application thereof Granted publication date: 20161130 License type: Common License Record date: 20171025 |