CN100423714C - Elemene injection, and preparing method and use thereof - Google Patents
Elemene injection, and preparing method and use thereof Download PDFInfo
- Publication number
- CN100423714C CN100423714C CNB021172196A CN02117219A CN100423714C CN 100423714 C CN100423714 C CN 100423714C CN B021172196 A CNB021172196 A CN B021172196A CN 02117219 A CN02117219 A CN 02117219A CN 100423714 C CN100423714 C CN 100423714C
- Authority
- CN
- China
- Prior art keywords
- elemene
- injection
- extract
- preparation
- isomer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- OPFTUNCRGUEPRZ-QLFBSQMISA-N (-)-beta-elemene Chemical compound CC(=C)[C@@H]1CC[C@@](C)(C=C)[C@H](C(C)=C)C1 OPFTUNCRGUEPRZ-QLFBSQMISA-N 0.000 title claims abstract description 213
- OPFTUNCRGUEPRZ-UHFFFAOYSA-N (+)-beta-Elemen Natural products CC(=C)C1CCC(C)(C=C)C(C(C)=C)C1 OPFTUNCRGUEPRZ-UHFFFAOYSA-N 0.000 title claims abstract description 158
- 238000002347 injection Methods 0.000 title claims description 74
- 239000007924 injection Substances 0.000 title claims description 74
- 238000000034 method Methods 0.000 title claims description 27
- 238000002360 preparation method Methods 0.000 claims abstract description 117
- 239000004530 micro-emulsion Substances 0.000 claims abstract description 22
- 239000000284 extract Substances 0.000 claims description 97
- 239000002502 liposome Substances 0.000 claims description 67
- 239000002552 dosage form Substances 0.000 claims description 47
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 46
- 239000000203 mixture Substances 0.000 claims description 44
- 206010028980 Neoplasm Diseases 0.000 claims description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 36
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 26
- 239000008347 soybean phospholipid Substances 0.000 claims description 26
- 241000196324 Embryophyta Species 0.000 claims description 24
- 235000012000 cholesterol Nutrition 0.000 claims description 23
- 239000002994 raw material Substances 0.000 claims description 20
- 239000008215 water for injection Substances 0.000 claims description 19
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- 239000000463 material Substances 0.000 claims description 11
- 238000000199 molecular distillation Methods 0.000 claims description 11
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- 239000006185 dispersion Substances 0.000 claims description 8
- 238000009210 therapy by ultrasound Methods 0.000 claims description 8
- 238000011049 filling Methods 0.000 claims description 5
- 238000010253 intravenous injection Methods 0.000 claims description 5
- 239000000839 emulsion Substances 0.000 abstract description 11
- 239000002243 precursor Substances 0.000 abstract 1
- 229930004725 sesquiterpene Natural products 0.000 description 33
- 150000004354 sesquiterpene derivatives Chemical class 0.000 description 25
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 21
- 238000009472 formulation Methods 0.000 description 21
- MXDMETWAEGIFOE-CABCVRRESA-N delta-elemene Chemical compound CC(C)C1=C[C@H](C(C)=C)[C@@](C)(C=C)CC1 MXDMETWAEGIFOE-CABCVRRESA-N 0.000 description 18
- RVOXATXFYDNXRE-UHFFFAOYSA-N gamma-elemene Natural products CC(=C1CCC(C)(C(C1)C(=C)C)C(=C)C)C RVOXATXFYDNXRE-UHFFFAOYSA-N 0.000 description 18
- 230000002401 inhibitory effect Effects 0.000 description 18
- 239000012071 phase Substances 0.000 description 17
- QDUJKDRUFBJYSQ-UHFFFAOYSA-N alpha-elemene Natural products CC(C)C1=CC(=C(C)C)CCC1(C)C=C QDUJKDRUFBJYSQ-UHFFFAOYSA-N 0.000 description 16
- 238000005070 sampling Methods 0.000 description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 238000004821 distillation Methods 0.000 description 14
- 239000007789 gas Substances 0.000 description 14
- 230000001954 sterilising effect Effects 0.000 description 14
- 238000004659 sterilization and disinfection Methods 0.000 description 14
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- -1 1-methyl isophthalic acid-vinyl-2,4-diisopropenyl cyclohexane Chemical group 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
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- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 11
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- 235000012424 soybean oil Nutrition 0.000 description 11
- 239000003549 soybean oil Substances 0.000 description 11
- 239000000341 volatile oil Substances 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 150000002632 lipids Chemical class 0.000 description 10
- BQSLMQNYHVFRDT-CABCVRRESA-N (-)-gamma-Elemene Natural products CC(C)=C1CC[C@](C)(C=C)[C@@H](C(C)=C)C1 BQSLMQNYHVFRDT-CABCVRRESA-N 0.000 description 9
- 241000628997 Flos Species 0.000 description 9
- BQSLMQNYHVFRDT-LSDHHAIUSA-N gamma-elemene Chemical compound CC(C)=C1CC[C@@](C)(C=C)[C@H](C(C)=C)C1 BQSLMQNYHVFRDT-LSDHHAIUSA-N 0.000 description 9
- MXDMETWAEGIFOE-UHFFFAOYSA-N rac-delta-elemene Natural products CC(C)C1=CC(C(C)=C)C(C)(C=C)CC1 MXDMETWAEGIFOE-UHFFFAOYSA-N 0.000 description 9
- 244000163122 Curcuma domestica Species 0.000 description 8
- 230000005540 biological transmission Effects 0.000 description 8
- QMVPMAAFGQKVCJ-UHFFFAOYSA-N citronellol Chemical compound OCCC(C)CCC=C(C)C QMVPMAAFGQKVCJ-UHFFFAOYSA-N 0.000 description 8
- 239000012528 membrane Substances 0.000 description 8
- NPNUFJAVOOONJE-ZIAGYGMSSA-N β-(E)-Caryophyllene Chemical compound C1CC(C)=CCCC(=C)[C@H]2CC(C)(C)[C@@H]21 NPNUFJAVOOONJE-ZIAGYGMSSA-N 0.000 description 8
- 150000001336 alkenes Chemical class 0.000 description 7
- 239000010632 citronella oil Substances 0.000 description 7
- QDUJKDRUFBJYSQ-OAHLLOKOSA-N elemene Chemical compound CC(C)C1=CC(=C(C)C)CC[C@@]1(C)C=C QDUJKDRUFBJYSQ-OAHLLOKOSA-N 0.000 description 7
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- FAMPSKZZVDUYOS-UHFFFAOYSA-N 2,6,6,9-tetramethylcycloundeca-1,4,8-triene Chemical compound CC1=CCC(C)(C)C=CCC(C)=CCC1 FAMPSKZZVDUYOS-UHFFFAOYSA-N 0.000 description 6
- 235000003392 Curcuma domestica Nutrition 0.000 description 6
- 239000002202 Polyethylene glycol Substances 0.000 description 6
- 230000033228 biological regulation Effects 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 229920001223 polyethylene glycol Polymers 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000004094 surface-active agent Substances 0.000 description 6
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- 241000963390 Curcuma wenyujin Species 0.000 description 5
- 235000003394 Curcuma wenyujin Nutrition 0.000 description 5
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 5
- 230000001093 anti-cancer Effects 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 210000000481 breast Anatomy 0.000 description 5
- 235000012754 curcumin Nutrition 0.000 description 5
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- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 description 5
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- 239000002077 nanosphere Substances 0.000 description 5
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 229940052016 turmeric extract Drugs 0.000 description 5
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- VLXDPFLIRFYIME-QRTUWBSPSA-N (1S,2R,6R,7R,8S)-1,3-dimethyl-8-propan-2-yltricyclo[4.4.0.02,7]dec-3-ene Chemical compound C1C=C(C)[C@@H]2[C@@]3(C)CC[C@@H](C(C)C)[C@@H]2[C@H]31 VLXDPFLIRFYIME-QRTUWBSPSA-N 0.000 description 4
- QMVPMAAFGQKVCJ-SNVBAGLBSA-N (R)-(+)-citronellol Natural products OCC[C@H](C)CCC=C(C)C QMVPMAAFGQKVCJ-SNVBAGLBSA-N 0.000 description 4
- WTEVQBCEXWBHNA-UHFFFAOYSA-N Citral Natural products CC(C)=CCCC(C)=CC=O WTEVQBCEXWBHNA-UHFFFAOYSA-N 0.000 description 4
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 4
- NPNUFJAVOOONJE-UHFFFAOYSA-N beta-cariophyllene Natural products C1CC(C)=CCCC(=C)C2CC(C)(C)C21 NPNUFJAVOOONJE-UHFFFAOYSA-N 0.000 description 4
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- XBGUIVFBMBVUEG-UHFFFAOYSA-N 1-methyl-4-(1,5-dimethyl-4-hexenylidene)-1-cyclohexene Chemical compound CC(C)=CCCC(C)=C1CCC(C)=CC1 XBGUIVFBMBVUEG-UHFFFAOYSA-N 0.000 description 3
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 3
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Abstract
The present invention relates to a new preparation of elemene, particularly to beta-elemene. More specifically, the present invention relates to a nano lipoid preparation, a precursor lipoid preparation, a long-circulation lipoid preparation, a long-circulation nano lipoid preparation, a nano microemulsion preparation, a venous emulsion preparation, a nano lipoid sphere preparation and a fatty emulsion preparation of the elemene and the beta-elemene.
Description
Technical field:
The present invention relates to elemene, the new injection type of beta-elemene especially, liposome dosage form more specifically to these preparations, the nanometer liposome dosage form, the pro-liposome dosage form, the long circulating liposomes dosage form, long-circulating nanoliposome dosage form, nanometer microemulsion type, vein emulsion type, lipid nanospheres dosage form and fat milk dosage form.The invention still further relates to the preparation method and the purposes of these dosage forms.
Prior art
In recent years, the many research worker in the anticancer natural drug research field all are devoted to study the active anticancer of paclitaxel, the various isomers of elemene, Rhizoma Curcumae Longae extract, common turmeric extract etc. and the various dosage forms of these medicines.
Elemene is a kind of sesquiterpenoids that is present in the certain plants, and Latin is called Elemenum, English Elemene by name, and chemical name is 1-methyl isophthalic acid-vinyl-2,4-diisopropenyl cyclohexane extraction, molecular formula C
15H
24Elemene has multiple isomer, beta-elemene in these isomers, and δ-elemene, γ-elemene have been proved active anticancer.Elemene is the chemical compound that can extract from the volatile oil of plant RADIX CURCUMAE (Curcuma Wenyujin Y.H.Chen et C.ling) rhizome (being commonly called as warm Rhizoma Curcumae), or the chemical compound that from the oil of plant Herba Cymbopogonis Citrari (Cymbopoqon citratus (DC.) Stapt), extracts, for example remove the remaining afterwards mixing grease of citral, citronellol from citronella oil, the chemical compound of extraction is actually the elemene isomer mixture that comprises beta-elemene.
Above-mentioned plant RADIX CURCUMAE and other two kinds of plant Rhizoma Curcumae and Rhizoma Curcumae Longaes that can be used as the natural drug use belong to the zingiberaceous plant monoid, originate in provinces such as Chinese Guangdong, Sichuan, Fujian, Guangxi, Zhejiang.The plant that comprises elemene has kinds more than 50 such as RADIX CURCUMAE, Herba Cymbopogonis Citrari, Rhizoma Acori Calami, Radix Inulae, Radix Ginseng, and wherein Herba Cymbopogonis Citrari is, resource competent plant wide in China's distribution.At present, the Elemene vinyl chemical compound mainly extracts from RADIX CURCUMAE oil and citronella oil.
There are many documents to relate to the herbal medicinal product of the anti-curing cancers of direct employing natural drug preparation, for example the open CN1216256A of Chinese patent discloses the herbal medicinal product of treatment hepatocarcinoma, it comprises contains Herba Hedyotidis Diffusae, Rhizoma Curcumae Longae, the extract of Rhizoma Polygoni Cuspidati and Radix Sophorae Tonkinensis as the Injectable composition (A) of main natural drug and the extract that contains Herba Hedyotidis Diffusae, Rhizoma Paridis, Rhizoma Polygoni Cuspidati, Radix Sophorae Tonkinensis, Radix Gentianae, Radix Et Rhizoma Rhei, Fructus Forsythiae, Radix Paeoniae Rubra, Rhizoma Curcumae Longae and Rhizoma Acori Graminei as the main Orally administered composition (B) of natural drug.
Curcumin preparation is disclosed in the open CN1302559 of Chinese patent; it is by preparing in the blendable organic solvent of water or the curcumin molecular dispersoid in the mixture of water and the blendable organic solvent of water; add protecting colloid aqueous solution, the hydrophobic millimicro decentralized photo that forms mutually of curcumin to this solution then.Final dosage form mainly is aqueous dispersion or dry powder, and particle diameter is less than 10 μ m in the preferred case.
The method of extracting beta-elemene by the secondary fractional distillation from citronella oil is disclosed in CN1200266A.
Disclose the Jiangyu injecta that is used for the treatment of malignant tumor in the open CN1247756A of Chinese patent, wherein the weight ratio of Rhizoma Curcumae Longae and Radix Curcumae is 50-60: 50-40, and this injection is a kind of simple mixture.
The open CN1076613A of Chinese patent relates to elemene emulsion injection and preparation method thereof, and this injection is a kind of emulsion, and mean diameter generally is no more than 15 microns, is no more than 2 microns especially.
The open CN1244389A of Chinese patent relates to elemene injection and preparation method thereof, and this injection is a kind of simple mixtures, is not liposome.
The open CN1110134A of Chinese patent relates to liposome preparation technology and preparation, the elemene liposome injecta of wherein having described the elemene liposome injecta preparation method especially and having obtained by this method, the envelop rate of elemene reaches more than 85%, but does not provide the data of the mean diameter of related lipase plastid.Can judge that from preparation method this liposome has bigger mean diameter.
The open CN1221607A of Chinese patent relates to and utilizes CO
2Critical or supercritical process prepare the technology of liposoluble medicinal liposome and prepared elemene liposome injecta, though the envelop rate of the liposome of elemene is very high, the mean diameter of liposome is equally too big.
More than the disclosed preparation of these documents on bin stability and active anticancer, all exist deficiency.
The various derivants and the elemene metal complex of elemene are also disclosed in some patent documentations in addition.For example, a kind of elemene metal complex and its use as cancer therapy drug are disclosed in CN11531158A.CN1153167A relates to elemene derivatives containing nitrogen and as the purposes of cancer therapy drug.CN1153168A relates to elemene hydroxyls derivs and as the purposes of cancer therapy drug.
Summary of the invention:
The purpose of this invention is to provide elemene injection, it contains: the extract with total elemene content of isomer 〉=70wt% that extracts from plant, surfactant, and water-bearing media, this injection is a kind of aqueous dispersion, the mean diameter of decentralized photo≤1 micron, the weight ratio of extract and surfactant is 0.5-1.5: 3.5-6.0, the concentration of total elemene isomer (active component) is 1-10mg/ml in injection.More preferably, this water-bearing media is a water.
Another object of the present invention provides elemene, the new injection type of beta-elemene especially, more specifically to their liposome dosage form, the nanometer liposome dosage form, the pro-liposome dosage form, the long circulating liposomes dosage form, long-circulating nanoliposome dosage form, nanometer microemulsion type, vein emulsion type, lipid nanospheres dosage form or fat milk dosage form.
Another object of the present invention provides the preparation method of these injection types.
The preparation that a further object of the present invention provides these novel forms is used to prepare the purposes of the drug injection of treatment cancer or cerebral infarction, these injection types are used for the purposes of tumor remission pain, and the preparation of these novel forms is used to suppress and/or treat the purposes of tumor.
Invention provides the novel form of these medicines.With elemene, beta-elemene is that raw material is prepared into its nanometer liposome dosage form respectively, pro-liposome dosage form, long circulating liposomes dosage form, long-circulating nanoliposome dosage form, nanometer microemulsion type, vein emulsion type, lipid nanospheres dosage form and fat milk dosage form.The mean diameter of these dosage forms is generally less than or equals 1 micron, even is less than or equal to 100 nanometers.
Description of drawings:
Fig. 1 is the transmission electron microscope photo of the 1A preparation of embodiment 1.
Detailed description of the present invention
Known in the prior art field that some isomers of elemene, Turmeric P.E, common turmeric extract possess the effect that suppresses tumour, some documents disclose the various dosage forms (or formulation) of these natural drugs, preparations such as liposome, emulsion, Fat Emulsion. But, because the average grain diameter of these formulations is generally larger, can cause the various reactions in the human or animal body after being expelled in the human or animal body, for example excitant is large, and haemolysis sometimes occurs.
The inventor is through years of researches work, discovery with sesquiterpene compounds or the extract that contains sesquiterpene that from plant, extracts make average grain diameter≤1 micron or≤the various injection types of 100 nanometers, comprising Lipidosome, the nano liposomes formulation, the proliposome formulation, the long circulating liposome formulation, the long-circulating nanoliposome formulation, nanometer microemulsion type, vein emulsion type, lipid nanometer microballoon formulation, micro-emulsion etc., can overcome the problems in the ejection preparation of prior art, these formulations especially of the present invention have greatly reduced excitant in intravenous injection is used, and their stability is further enhanced. Novel form of the present invention has significantly improved the drug effect of pharmaceutical preparation, but the mechanism of the inhibition cancer cell of these formulations also is not fully aware of at present. The inventor makes following supposition according to a large amount of result of the tests: because preparation of the present invention has little average grain diameter and has special surface nature (hydrophile/lipophile balance for example, surface charge etc.), so that the medicine in these preparations (or active component) has stronger affinity to cancer cell, can fully be attached on the cancer cell, allow active component directly act on cancer cell, reach the effect that suppresses or kill cancer cell. In addition, find that the preparation of nano particle size is rapid-action, prevents that from there is certain effect the cancer metastasis aspect.
Simultaneously, although preparation of the present invention has little average grain diameter, but the preparation of the various formulations that obtain has high stability simultaneously, and they coagulation problems can not occur in storing for a long time, do not reduce stability so that can store the long period.
The invention provides extract injection, it contains: the extract with total sesquiterpene alkene class content 〉=70wt% that extracts from plant, surfactant, and water-bearing media, this injection is a kind of water-borne dispersions, the average grain diameter of decentralized photo≤1 micron, the weight ratio of extract and surfactant is 0.5-1.5: 3.5-6.0, the concentration of total sesquiterpene alkene class (active component) is 1-10mg/ml in injection.
The invention provides the preparation method of extract injection, it comprises that the extract that extracts with total sesquiterpene alkene class content 〉=70wt% as raw material, adds surfactant from plant, utilize Rotary Evaporators film forming or CO2Critical or supercritical process mixes, add water for injection, carrying out high pressure homogenizing processing and/or ultrasonic wave processes, process to till the stabilized aqueous dispersion that obtains particle diameter of dispersing phase≤1 micron always, thereby make injection, wherein the weight ratio of extract and surfactant is 0.5-1.5: 3.5-6.0, the ultimate density of total sesquiterpene alkene class is 1～10mg/ml in the injection.
The sesquiterpene that extracts from plant (sometimes being called active component here) that can be used for making novel form in the present invention consists essentially of whole sesquiterpene compounds (C15H24), the mixture of sesquiterpene compounds or the sesquiterpene extract that from plant, extracts, extracting product for these requires the purity of sesquiterpene compounds more than 70%, preferably more than 75%, more preferably more than 85%, particularly preferably in more than 90%, even particularly preferably in more than 95%.
It is to be noted, the raw material that is used to prepare the preparation of various dosage forms in the present invention can use product such as elemene product (extract), beta-elemene product (extract), Rhizoma Curcumae Longae extract or the common turmeric extract that is purchased, and the extract product of SHULANHUA, Fructus Tonnae Sinensis, Caulis Piperis Kadsurae, Flos Caryophylli, Myrrha, Hemerocallis citrina Baroni Cuculus polioephalus, caraway, Herba thymi vulgaris, parsley, Herba Pogostemonis, Atractylodes lancea (Thunb.) DC., Fructus Cnidii, Flos lupuli (Flos Humuli Lupuli), sandalwood, bergamot, opoponax, Cupressus funebris Endl., Oleum Terebinthinae, Herba Cymbopogonis Citrari, Radix Ginseng etc.If need oneself these extract of preparation in this application, the various volatile oil that are used to prepare these extracts can use and be purchased product, also can use the volatile oil that obtains from plant by common steam distillation or molecularly distilled.
Sesquiterpene comprises elemene (elemene), curcumene (curcumene), zingiberene (zingiberene), bourbonene (bourbonene), humulene (humulene), Acacia farnesiana Willd. ellagic acid (farnesene), cadinene (cadinene), selinene (selinene), maaliene (maaliene), santalene (santalene), patchoulene (patchonlene), caryophyllene (be also referred to as Flos Caryophylli alkene, caryophyllene), gima ethylenic (big myrcene, germacrene), Cubeb oil alkene (cubebene), cedrene (cedrene), longifolene (longifolene), bisabolene (or bisabolene, bisabolene), bergaptene (bergamotene), gurjunene (gurjunene), lignum-vitae alkene (guaiene), ylangene (ylangene), isocaryophyllene (isocaryophyllene), long pinene (longipinene), Rhizoma Acori Calami alkene (calarene), wood sieve alkene (muurolene), acoradiene (acoradiene), sesquiphellandrene (β-sesquiphellandrene) etc.
In principle, all extracts that contain the above sesquiterpene of 60wt% that extract from plant all can be used for preparing novel form of the present invention, and sesquiterpene is the active component of all dosage forms.The extract that contains the above sesquiterpene of 70wt% is ideal, the extract that contains the above sesquiterpene of 75wt% is preferred, the extract that contains the above sesquiterpene of 85wt% is preferred, contain 90wt% above or even the extract that contains the above sesquiterpene of 95wt% be particularly preferred.
The extract that contains elemene that extracts from natural plants contains α-elemene, beta-elemene, δ-elemene, γ-elemene, bourbonene etc. usually.In this application as specific embodiment, with RADIX CURCUMAE Curcuma wenyujin Y.H.Chen et C.Ling volatile oil, citronella oil Cymbopoqon citratus (DC.) Stapt submember (the mixing grease of remainder after citral, citronellol are removed in the citronella oil fractional distillation) is raw material, makes with extra care out elemene through material filling type vacuum rectifying apparatus or molecular distillation instrument.Wherein be used to prepare this RADIX CURCUMAE volatile oil of elemene raw material of the present invention and described submember and can use and be purchased product, also can from plant, obtain by common steam distillation or molecularly distilled.
In addition, each elemene isomer such as α-elemene, beta-elemene, δ-elemene or γ-elemene are as long as purity also can be used in more than 85wt% and makes novel form of the present invention.
At present according to the domestic elemene quality standard (national drug standards WS that issues referring to National Drug Administration in 2000
1-(X-094)-2000Z), (carbowax-20M is an immobile phase with gas chromatography as if separated products (extract), white diatomite carrier 60～80 orders, column temperature is 135～140 ℃, number of theoretical plate calculates by beta-elemene and should be not less than 1000) detect total elemene isomer purity and reach 〉=85% this products known as elemene, reach as if detecting beta-elemene purity 〉=95% product is a beta-elemene, in fact this is inaccurate, because use the higher chromatographic apparatus of sensitivity for example 30 meters long capillary gas chromatograph-mass spectrometer (GC-MS)s detect this 〉=the beta-elemene sample of 95% purity, can find that it still contains at least 6% bourbonene (at the chromatographic chromatogram of muting sensitivity, the peak of beta-elemene becomes a peak with the peak overlapping of bourbonene), the elemene sample is the mixture of multiple sesquiterpene, promptly contain beta-elemene, δ-elemene, γ-elemene, bourbonene, Flos Caryophylli alkene, gima ethylenic etc.
Rhizoma Curcumae Longae Rhizoma Curcuma Longa L. extract is the product that extracts from the volatile oil that curcuma plant obtains.In the present invention as specific embodiment, Rhizoma Curcumae Longae extract refers to the extract that Rhizoma Curcumae Longae volatile oil is made with extra care out through material filling type vacuum rectifying apparatus or molecular distillation instrument, detect through GC-MS, Rhizoma Curcumae Longae extract contains 〉=70wt% usually, preferably 〉=75wt%, more preferably 〉=and 80wt%, preferred especially 〉=85wt%, even more preferably 〉=curcumin of the sesquiterpene of 90wt% such as curcumene, zingiberene etc. and a small amount of (be equivalent to whole sesquiterpene gross weights about 1/25～1/5).
RADIX CURCUMAE Curcuma wenyujin Y.H.Chen et C.Ling extract comprises the product that extracts in the volatile oil that obtains from the RADIX CURCUMAE plant.In the present invention as specific embodiment, common turmeric extract refers to that RADIX CURCUMAE volatile oil is through smart distilled component of vacuum material filling type rectifier unit or the product made with extra care out through the molecular distillation instrument, detect through GC-MS, Rhizoma Curcumae Longae extract contains 〉=70wt% usually, preferably 〉=75wt%, more preferably 〉=80wt%, preferred especially 〉=85wt%, even more preferably 〉=curcumin of the sesquiterpene of 90wt% such as various elemene isomer, gima ethylenic, Flos Caryophylli alkene etc. and a small amount of (be equivalent to whole sesquiterpene gross weights about 1/50～1/10).
The explanation of term:
Described in the present invention particle diameter or granularity are meant the particle diameter or the granularity of decentralized photo.
In this application, if contain 〉=70wt% elemene (comprising various elemene mixture of isomers) and containing＜the 85wt% beta-elemene with 30 meters long capillary gas chromatograph-mass spectrometer (GC-MS) Detection and Extraction things, then this extract is called for short elemene, contain 〉=the 85wt% beta-elemene as berry extract, then this extract is called for short beta-elemene.
Modify if before dosage form, add " nanometer ", then refer to mean diameter≤150 nanometers of this dosage form, in ideal conditions mean diameter≤100 nanometers.Injection and ejection preparation are used interchangeably.
The liposome dosage form is meant the Lipid Bilayer Structure of being made up of phospholipid and cholesterol etc. that is dispersed or suspended in the water-bearing media in the present invention, and this Lipid Bilayer Structure is similar to membrane structure.
The nanometer liposome dosage form is meant that in the present invention mean diameter is less than or equal to the liposome of 150 nanometers.
The pro-liposome dosage form is meant in the present invention on the prescription basis of liposome and adds excipient again, by the prepared lyophilized powder of vacuum lyophilization (vacuum freeze-drying) method.This lyophilized powder by adding water for injection, through jolting or vibration, made it to revert to the liposome form before clinical practice.
The long circulating liposomes dosage form, briefly, being meant in the present invention increases the prepared liposome of Polyethylene Glycol PHOSPHATIDYL ETHANOLAMINE again on the prescription basis of liposome.The time of playing effectiveness in vivo than common liposome after it is expelled in the body is longer, or eliminates slowly in vivo.
Nanometer microemulsion type refers to mean diameter≤150 nanometers, in the ideal case≤100 the Emulsion of nanometer.
The vein emulsion type refers to the injection breast of mean diameter≤1 micron in the present invention.
Lipid nanometer microsphere dosage form is meant the fat milk of mean diameter≤150 nanometers in the present invention.
The fat milk dosage form requires its mean diameter≤1 micron in the present invention; In the China national pharmacopeia, also stipulate mean diameter≤1 micron in addition.
Nm is meant nanometer, and μ is meant micron.Purity is meant percent purity by weight in this application, except as otherwise noted.
Employed in this application functional component (or active component) is an elemene, knows that at present occurring in nature mainly contains four kinds of isomers, i.e. α-elemene, beta-elemene, δ-elemene, γ-elemene.The present invention can make the elemene isomer mixture various dosage forms, also can be with through each isomer of purify obtaining α-elemene for example, beta-elemene, δ-elemene, any two or more the mixture in γ-elemene or these isomers is made various dosage forms.For simplicity, use 30 meters long capillary gas chromatograph-mass spectrometer (GC-MS) (chromatographs: Bio-Rad FTS-65A, HP5890II, chromatographic column: BP-5) Detection and Extraction thing, contain 〉=extract (wherein generally also containing other elemene isomer) of 85wt% α-elemene is called α-elemene, similarly, contain 〉=extract of 85wt% beta-elemene is called beta-elemene, contain 〉=extract of 85wt% δ-elemene is called δ-elemene, contain 〉=extract of 85wt% γ-elemene is called γ-elemene.Therefore, the not necessarily simple a kind of isomer of elemene used in the present invention, it in addition can be the various mixture in any ratio of various isomers.
Employed elemene can be bought with extract (various isomer mixture) or pure isomer (requiring purity to be higher than 85wt%) product form by commercial sources and obtain among the application, also can oneself prepare as required, for the preparation method of elemene referring to preparation example 1 and for the preparation method of beta-elemene referring to preparation example 2.
Employed elemene raw material, reagent have no particular limits among the application, as long as this elemene raw material is to extract from natural plants and total elemene isomer purity 〉=70wt% just can use in the present invention, better is, this purity 〉=75wt% is better 〉=85wt%.Beta-elemene, δ-elemene, γ-elemene and α-elemene raw material then is to extract from natural plants and the extract of each isomer purity 〉=85wt%, and that better is purity 〉=90wt%.
Except as otherwise noted, otherwise other composition of Shi Yonging requires to meet national medicinal standard as cholesterol, soybean phospholipid, lecithin, glycerol, linoleic acid, Polyethylene Glycol PHOSPHATIDYL ETHANOLAMINE, aliphatic amine, Semen sojae atricolor wet goods in the present invention, solvent also should meet national medicinal standard, and these are mainly for the consideration of healthy aspect; Similarly, modify with " making with extra care " for some raw materials, show that this raw material must meet national medicinal standard, for example refining soybean phospholipid is the available product of injection, and refined soybean oil is the available product of injection.
Except as otherwise noted, otherwise employed in this application gas chromatograph is: Bio-RadFTS-65A, and HP5890II, chromatographic column is: BP-5.
Various dosage form of the present invention can be used for the treatment of purpose with intravenous injection, topical mode.
The preferred embodiments of the invention
In following embodiments, mainly use extract " elemene ", extract " beta-elemene ", Rhizoma Curcumae Longae extract or common turmeric extract, can also use the extract of SHULANHUA, Fructus Tonnae Sinensis, Caulis Piperis Kadsurae, Flos Caryophylli, Myrrha, Hemerocallis citrina Baroni Cuculus polioephalus, caraway, Herba thymi vulgaris, parsley, Herba Pogostemonis, Atractylodes lancea (Thunb.) DC., Fructus Cnidii, Flos lupuli (Flos Humuli Lupuli), sandalwood, bergamot, opoponax, Cupressus funebris Endl., Oleum Terebinthinae and Herba Cymbopogonis Citrari, Radix Ginseng etc. as raw material.Obviously, higher (product for example 〉=85wt%) can both be as raw material of the present invention, and utilizes synthetic various sesquiterpenes of chemical method and derivant thereof can both be used for the present invention for the purity of wherein a certain sesquiterpene isomer.
The invention provides the preparation method of liposome or nanometer liposome, it comprises: with extract and soybean phospholipid, cholesterol with weight ratio 0.5-1.5: 2.5-4.0: 1.0-2.0, preferred 0.8-1.2: 2.8-3.6: 1.2-1.8, more preferably 0.9-1.1: 3.0-3.4: 1.4-1.6 mixed in preferred especially 1: 3.2: 1.5; Add solvent (as ether or acetone or chloroform), addition is enough to make mixture fully to dissolve, insert and remove the solvent film forming on the Rotary Evaporators, add the water for injection (calculating this surplus) of surplus, insert then in the conventional ultrasonic cell disruptor and carry out ultrasonic Treatment according to the ultimate density that will prepare; Sampling utilizes the microscope of band scale, the Coulter instrument, ultramicroscope is checked mean diameter, at the mean diameter that reaches regulation for example≤1 micron (liposome), or≤100 nanometers (nanometer liposome) after, regulate PH, making pH value is 4.5～6.5, through 0.8 μ filtering with microporous membrane and bottling then, 100 ℃ of vapor stream sterilizations, the ultimate density (weight of sesquiterpene active component (mg)/total volumes of formulation (ml)) of utilizing chromatograph (gas phase or liquid phase) to record active component is 1～10mg/ml, be preferably 2～7.5mg/ml, be more typically 5～7.5mg/ml.
The envelop rate of nanometer liposome detects: detect with sieve method, promptly, utilize the SephadexG25 tomographic system, the extract nano-liposome preparation is divided into two stream parts, be extract nano-liposome stream part and free extract flow part, detect the extractive content that contains in two stream parts through gas chromatograph.The extractive content ÷ of envelop rate computing formula=extract nano-liposome stream part (extractive content+free extractive content of extract nano-liposome stream part).Whether microscope or transmission electron microscope checking are liposome.
The invention provides the preparation method of pro-liposome: with extract and refining soybean phospholipid, cholesterol is with weight ratio 0.5-1.5: 2.5-4.0: 1.0-2.0, preferred 0.8-1.2: 2.8-3.6: 1.2-1.8, more preferably 0.9-1.1: 3.0-3.4: 1.4-1.6, mixed in preferred especially 1: 3.2: 1.5, add solvent (as ether or acetone or chloroform), addition is enough to fully dissolve this mixture, insert and remove the solvent film forming on the Rotary Evaporators, add the water for injection (calculating this surplus) of surplus according to the ultimate density that will prepare, insert ultrasonic cell disruptor then and carry out supersound process, sampling utilizes the microscope or the Coulter instrument of band scale to check mean diameter, behind mean diameter≤1 micron, regulate PH, making pH value is 4.5～6.5, through 0.8 μ filtering with microporous membrane and bottling then, the excipient (for example lactose or average molecular weight Mw are the low molecular dextran of about 4000-40000) that adds the 1-2wt% that accounts for total amount of formulation, 100 ℃ of vapor stream sterilizations, lyophilization under the aseptic condition, embedding.Adding injection water before using is 1～10mg/ml to reach final activity component concentration (weight of sesquiterpene active component (mg)/volumes of formulation (ml)), is preferably 2～8mg/ml, and more preferably 2～7.5mg/ml is more typically 5～7.5mg/ml.
The detection of envelop rate: use the sieve method detection method, that is: according to the final formulation concentrations (mg/ml) that will prepare, the water jolting of a certain amount of extract proliposome preparation being added the surplus volume earlier is even, become liposome this moment again, utilize Sephadex G25 tomographic system to be divided into two stream parts, be extract liposome stream part and free extract flow part, detect the extract amount that contains in two stream parts through gas chromatograph.The extractive content ÷ of envelop rate computing formula=extract liposome stream part (extractive content+free extract amount of extract liposome stream part).Whether microscope or transmission electron microscope confirm is pro-liposome.
The invention provides the preparation method of long circulation extract nano-liposome, this method comprises: with extract and refining soybean phospholipid, Polyethylene Glycol (2000) PHOSPHATIDYL ETHANOLAMINE, cholesterol is with weight ratio 0.5-1.5: 1.5-3.5: 0.3-1.2: 0.8-2.0, preferably with weight ratio 0.8-1.2: 1.8-3.0: 0.4-1.0: 1.2-1.8, more preferably with weight ratio 0.9-1.1: 2.4-2.8: 0.6-1.0: 1.2-1.6, especially preferably with weight ratio 1: 2.6-2.7: 0.7-0.9: 1.3-1.5 mixes, add solvent (as ether or acetone or chloroform), addition is enough to fully dissolve this mixture, insert and remove the solvent film forming on the Rotary Evaporators, add the water for injection (calculating this surplus) of surplus according to the ultimate density that will prepare, insert conventional ultrasonic cell disruptor then and carry out ultrasonic Treatment, sampling utilizes the microscope of band scale, Coulter instrument or ultramicroscope are checked mean diameter, after reaching the mean diameter of regulation (for example≤100 nanometer), regulate PH, making pH value is 4.5～6.5, through 0.8 μ filtering with microporous membrane and bottling then, 100 ℃ of vapor stream sterilizations, the ultimate density (weight of sesquiterpene active component (mg)/total volumes of formulation (ml)) that (gas phase or liquid phase) chromatography records active component is 1～10mg/ml, be preferably 2～7.5mg/ml, more preferably 2～8mg/ml is more typically 5～7.5mg/ml.For Polyethylene Glycol (2000) PHOSPHATIDYL ETHANOLAMINE, wherein " 2000 " refer to the mean molecule quantity (dalton) of Polyethylene Glycol segment.
The detection of the envelop rate of this injection is identical with the envelop rate detection method of the lipidosome injection of front.
The invention provides the preparation method of electronegative and positively charged extract nano microemulsion:
Preparation method 1: the preparation of electronegative nanometer microemulsion
With extract and refining soybean phospholipid, cholesterol is with weight ratio 0.5-1.5: 2.5-4.0: 1.0-2.0, preferred 0.8-1.2: 2.8-3.6: 1.2-1.8, more preferably 0.9-1.1: 3.0-3.4: 1.4-1.6, mixed in preferred especially 1: 3.2: 1.5, add solvent (as ether or acetone or chloroform), addition is enough to fully dissolve this mixture, insert and remove the solvent film forming on the Rotary Evaporators, add the water for injection (calculating this surplus) of surplus according to the ultimate density that will prepare, insert conventional ultrasonic cell disruptor then and carry out ultrasonic Treatment, sampling utilizes the microscope of band scale, Coulter instrument or ultramicroscope are checked mean diameter, after reaching the mean diameter of regulation (for example≤100 nanometer), regulate PH, making pH value is 4.5～6.5, through 0.8 μ filtering with microporous membrane and bottling then, 100 ℃ of vapor stream sterilizations, the ultimate density of active component (weight of sesquiterpene active component (mg)/total volumes of formulation (ml)) is 1～10mg/ml, be preferably 2～7.5mg/ml, be more typically 5～7.5mg/ml.Microscope, transmission electron microscope detect, and confirm whether be the nanometer microemulsion.
Preparation method 2: the preparation of positively charged nanometer microemulsion
With extract, refined lecithin, C14-C22 straight or branched aliphatic amine, cholesterol is with weight ratio 0.5-1.5: 2.5-3.5: 0.2-0.6: 1.0-2.0, preferred 0.8-1.2: 2.5-3.0: 0.3-0.5: 1.2-1.8, more preferably 0.9-1.1: 2.7-2.9: 0.3-0.5: 1.4-1.6, preferred especially 1: 2.8: 0.4: 1.5 mixed, add solvent (as ether or acetone or chloroform), addition is enough to fully dissolve this mixture, insert and remove the solvent film forming on the Rotary Evaporators, add the water for injection (calculating this surplus) of surplus then according to the densitometer that will prepare, insert conventional ultrasonic cell disruptor then and carry out supersound process, sampling utilizes the microscope of band scale, Coulter instrument or ultramicroscope are checked mean diameter, after reaching the mean diameter of regulation (for example≤100 nanometer), regulate PH, making pH value is 7.5～9.0, through 0.8 μ filtering with microporous membrane and bottling then, 100 ℃ of vapor stream sterilizations, the ultimate density of sesquiterpene active component is 1～10mg/ml, be preferably 2～7.5mg/ml, be more typically 5～7.5mg/ml.Microscope, transmission electron microscope detect, and confirm whether be the nanometer microemulsion.
The present invention also provides the preparation method of extract lipid nanospheres, and this method comprises: get extract and add in the soybean oil with soybean phospholipid, heat up and be controlled to oil phase (remaining oil phase), this oil phase is joined in the glycerinated aqueous solution.Its concrete part by weight is: extract accounts for 0.08～0.8wt% of final preparaton total amount, soybean phospholipid 0.8～2.5wt%, and soybean oil 8-12wt%, glycerol 1.8-2.8wt%, water for injection adds to 5000ml; Preferred part by weight is: extract accounts for the 0.1wt%～0.5wt% of final preparaton total amount, soybean phospholipid 1.2wt%～2.0wt%, and soybean oil 10wt%, glycerol 2.25～2.5wt%, water for injection adds to 5000ml.High-speed stirred then, regulating PH is 4.5～6.5, passing through common high pressure homogenizer (for example M110-E/H type (Japanese MIZUHO produces)) again handles, carry out foregoing ultrasonic Treatment then, sampling utilizes microscope, Coulter instrument or the ultramicroscope of band scale to check mean diameter, the mean diameter of its lipid ball reach setting for example≤100nm after, again through 0.8 μ filtering with microporous membrane and bottling then, 100 ℃～120 ℃ sterilizations.The ultimate density that (gas phase or liquid phase) chromatography records the sesquiterpene active component is 1～10mg/ml, is preferably 2～7.5mg/ml, is more typically 2～5mg/ml, and better is 2.0～3.0mg/ml.Can in this final preparation, add an amount of cholesterol, linoleic acid etc. as required.
The invention provides the preparation method of extract intravenous injection breast, this method comprises: with extract, refining soybean phospholipid, cholesterol is with weight ratio 0.5-1.5: 2.5-4.0: 1.0-2.0, preferred 0.8-1.2: 2.8-3.6: 1.2-1.8, more preferably 0.9-1.1: 3.0-3.4: 1.4-1.6, preferred especially 1: 3.2: 1.5, mix with the water for injection (calculating this surplus) of surplus according to the ultimate density that will prepare, high pressure homogenizer (for example M110-E/H type (Japanese MIZUHO produces)) emulsifying with routine, sampling utilizes the microscope or the Coulter instrument of band scale to check mean diameter, the mean diameter that reaches regulation for example≤1 micron after, regulate PH, making pH value is 4.5～6.5, through 1.2 μ filtering with microporous membranes and bottling then, through 100 ℃～120 ℃ sterilizations, obtain extract vein breast, the ultimate density that (gas phase or liquid phase) chromatography records the sesquiterpene active component is 1～10mg/ml, be preferably 2～7.5mg/ml, be more typically 5～7.5mg/ml.
The invention provides the preparation method of extract fat emulsion, this method comprises: get extract and soybean phospholipid and add in the soybean oil, heat up and be controlled to oil phase (remaining oil phase), this oil phase is joined in the glycerinated aqueous solution.Its concrete weight ratio is: extract accounts for 0.08～0.8wt% of final preparaton total amount, soybean phospholipid 0.8～2.5wt%, and soybean oil 8-12wt%, glycerol 1.8-2.8wt%, water for injection adds to 5000ml; Preferred part by weight is: extract accounts for the 0.1wt%～0.5wt% of final preparaton total amount, soybean phospholipid 1.2wt%～2.0wt%, and soybean oil 10wt%, glycerol 2.25～2.5wt%, water for injection adds to 5000ml.High-speed stirred then, regulating PH is 4.5～6.5, passes through common high pressure homogenizer (for example M110-E/H type (Japanese MIZUHO produces)) again and handles, and makes its particle diameter less than 1 μ, again through 1.2 μ filtering with microporous membranes with bottle 100 ℃～120 ℃ sterilizations then.The ultimate density of sesquiterpene active component is 1～10mg/ml, is preferably 2～7.5mg/ml, the better 2.0～3.0mg/ml of being or be 5～7.5mg/ml.Can in this final preparation, add an amount of cholesterol, linoleic acid etc. as required.
As required, preparation of the present invention can with different size for example the microporous filter membrane of 1.2 μ, 1.0 μ, 0.9 μ, 0.8 μ, 0.7 μ, 0.6 μ, 0.5 μ etc. filter, can intercept mean diameter≤0.8 μ ,≤0.7 μ ,≤0.6 μ ,≤0.5 μ ,≤0.45 μ ,≤0.4 μ ,≤decentralized photo of 0.3 μ etc.
Below preparation example and embodiment be used to illustrate the present invention, but should not think and limit the scope of the invention.Protection scope of the present invention is defined by claim.
Preparation example 1: the preparation of elemene
(citronella oil is removed citral with RADIX CURCUMAE Curcuma wenyujin Y.H.Chen et C.Ling volatile oil or Herba Cymbopogonis Citrari Cymbopoqon citratus (DC.) Stapt submember, the mixing grease of remainder after the citronellol) be raw material, through the Guangzhou Han Wei MD-S80 of mechanical ﹠ electrical corporation type molecular distillation instrument fractional distillation elemene, its process conditions: 30～45 ℃ of vapo(u)rizing temperatures, distillation pressure 70～90Pa, 300～320 rev/mins of knifing speed, 20～25 ℃ of cryosurface temperature, 20～25 ℃ of system's insulations, 15～30 milliliters/hour of material flows, only collect and heat up in a steamer excess, will heat up in a steamer excess and carry out molecular distillation.Vapo(u)rizing temperature is 40～60 ℃, distillation pressure 20～70Pa, 300～320 rev/mins of knifing speed, 20～25 ℃ of condensation temperatures, 20～25 ℃ of system's insulations, 15～30 milliliters/hour of material flows, collect distillation respectively and heat up in a steamer excess, will heat up in a steamer excess and proceed molecular distillation.Vapo(u)rizing temperature is 30～70 ℃, distillation pressure 10～50Pa, 300～320 rev/mins of knifing speed, 20～25 ℃ of condensation temperatures, 20～25 ℃ of system temperatures, 15～30 milliliters/hour of material flows, collect distillation, bleed off and heat up in a steamer excess, the secondary distillation that obtains is mixed, continue distillation, until utilize 30 meters long capillary gas chromatograph-mass spectrometer (GC-MS) gas chromatograph (chromatographs: Bio-Rad FTS-65A, HP5890II, chromatographic column: BP-5) detect total elemene isomer purity to reach 〉=75% till.
Preparation example 2: the preparation of beta-elemene
(citronella oil is removed citral with RADIX CURCUMAE Curcuma wenyujin Y.H.Chen et C.Ling volatile oil or Herba Cymbopogonis Citrari Cymbopoqon citratus (DC.) Stapt submember, the mixing grease of remainder after the citronellol) be raw material, through the Guangzhou Han Wei MD-S80 of mechanical ﹠ electrical corporation type molecular distillation instrument fractional distillation beta-elemene, its process conditions: 30～45 ℃ of vapo(u)rizing temperatures, distillation pressure 70～100Pa, 300～320 rev/mins of knifing speed, 20～25 ℃ of cryosurface temperature, 20～25 ℃ of system's insulations, 7～10 milliliters/hour of material flows, only collect and heat up in a steamer excess, will heat up in a steamer excess and carry out molecular distillation.Vapo(u)rizing temperature is 40～60 ℃, distillation pressure 20～70Pa, 300～320 rev/mins of knifing speed, 20～25 ℃ of condensation temperatures, 20～25 ℃ of system's insulations, 7～10 milliliters/hour of material flows, collect distillation respectively and heat up in a steamer excess, will heat up in a steamer excess and proceed molecular distillation.Vapo(u)rizing temperature is 30～70 ℃, distillation pressure 10～50Pa, 300～320 rev/mins of knifing speed, 20～25 ℃ of condensation temperatures, 20～25 ℃ of system temperatures, 7～10 milliliters/hour of material flows are collected distillation, bleed off and heat up in a steamer excess, the secondary distillation that obtains is mixed, continue distillation, until with 30 meters long capillary gas chromatograph-mass spectrometer (GC-MS)s (chromatograph: Bio-Rad FTS-65A, HP5890II, chromatographic column: BP-5) the beta-elemene purity that detects product reach 〉=85% till.
Embodiment 1: the preparation of the nano-lipid body injection of elemene or beta-elemene
Program 1A: with the elemene product and the refining soybean phospholipid of preparation example 1, cholesterol mixes with weight ratio at 1: 3.2: 1.5, add ether, addition is enough to fully dissolve this mixture, insert and remove the ether film forming on the Rotary Evaporators, add the water for injection (is that 5mg/ml calculates this surplus according to the ultimate density that will prepare) of surplus, insert ultrasonic cell disruptor (model JCS-204) supersound process that Jining, Shandong ultrasonic electronic instrument plant produces then, sampling utilizes the microscope of band scale, Coulter instrument or ultramicroscope are checked mean diameter, after mean diameter≤100 nanometers, regulate PH with 1M biphosphate sodium water solution, making pH value is 4.5～6.5, (new Asia, Shanghai purifies device factory and produces through 0.8 μ microporous filter membrane, specification 0.8 μ) filters and bottling then, 100 ℃ of vapor stream sterilizations, the injection product that is obtained is called for short 1A.Sampling records active component with gas chromatography, and (ultimate density of weight (the mg)/volumes of formulation (ml) of total elemene isomer is 5 ± 0.10mg/ml.
Detect envelop rate with sieve method, promptly, utilize Sephadex G25 tomographic system that elemene (referring to extract product) nano liposome preparations is divided into two stream parts, be elemene nanometer liposome stream part and free elemene stream part, detect the extractive content that contains in two stream parts through gas chromatograph.Envelop rate surpasses 85%.The extractive content ÷ of envelop rate computing formula=elemene nanometer liposome stream part [extractive content+free extract amount of elemene nanometer liposome stream part].Microscope, transmission electron microscope detect, and confirmation is a nanometer liposome, provides the transmission electron microscope photo (scale 50nm) of this injection in accompanying drawing 1.
Program 1B: repeat above-mentioned 1A program, just replace the elemene product of preparation example 1 with the beta-elemene product of preparation example 2.Microscope, transmission electron microscope detect, and confirm that preparation is a nanometer liposome.The concentration of total elemene isomer is about 5 ± 0.10mg/ml in the preparation.Envelop rate is higher than 85%.This injection is called for short 1B.
Embodiment 2: the preparation of the pro-liposome of elemene or beta-elemene
2A: according to the 1A program of embodiment 1 in identical method and proportioning raw materials, repeat the 1A program of embodiment 1, just require particle diameter≤1 micron of decentralized photo after the ultrasonic Treatment and after filtering and before bottling, the lactose that adds the 1-2% that accounts for total weight of formulation, utilize 100 ℃ of vapor stream sterilizations then, lyophilization under the aseptic condition, embedding (packing).Detecting the confirmation preparation with the Coulter instrument is pro-liposome.This injection product is called for short 2A.Said preparation added injection water before injection is used be 5 ± 0.10mg/ml to reach final activity component concentration (weight (the mg)/volumes of formulation (ml) of total elemene isomer).Envelop rate is higher than 85%.
2B: repeating above-mentioned 2A, just replace the elemene of preparation example 1 with the beta-elemene of preparation example 2, is about 40000 low molecular dextran replacement lactose with average molecular weight Mw.This injection is called for short 2B.Detecting the confirmation preparation with the Coulter instrument is pro-liposome.Envelop rate is higher than 85%.Said preparation added injection water before injection is used be 5 ± 0.10mg/ml to reach final activity component concentration (weight (the mg)/volumes of formulation (ml) of total elemene isomer).
Embodiment 3: the preparation of the long-circulating nanoliposome of elemene or beta-elemene
3A: according to the 1A program of embodiment 1 in identical method, repeat the 1A program of embodiment 1, just raw material and their weight proportion are: elemene (preparation example 1): soybean phospholipid: Polyethylene Glycol (2000) PHOSPHATIDYL ETHANOLAMINE: cholesterol=1: 2.6: 0.8: 1.4.This injection is called for short 3A.Pick test mean diameter≤100nm.The ultimate density of total elemene isomer is 5 ± 0.10mg/ml in the preparation.Envelop rate is higher than 85%.
3B: repeat above-mentioned 3A, just replace the elemene of preparation example 1 with the beta-elemene of preparation example 2.The injection that is obtained is called for short 3B.Mean diameter≤100nm.The ultimate density of total elemene isomer is 5 ± 0.10mg/ml in the preparation.Envelop rate is higher than 85%.
Embodiment 4: the preparation of the nanometer microemulsion of electronegative and positively charged elemene or beta-elemene
4A-1: the preparation of electronegative nanometer microemulsion
Repeat the 1A program of embodiment 1, just do not measure envelop rate.The ultimate density that sampling records total elemene isomer is 5 ± 0.10mg/ml.Confirm it is the nanometer microemulsion with the Coulter instrument.This injection product is called for short 4A-1.
4A-2: the preparation of positively charged nanometer microemulsion
Repeat the 1A program of embodiment 1, just raw material and their weight proportion are: the elemene of preparation example 1: lecithin: n-octadecane base amine: cholesterol=1: 2.8: 0.4: 1.5, do not measure envelop rate.The ultimate density that sampling records total elemene isomer is 5 ± 0.10mg/ml.Confirm it is the nanometer microemulsion with the Coulter instrument.This injection is called for short 4A-2.
4B-1: the preparation of electronegative nanometer microemulsion
Repeat above-mentioned 4A-1, just replace the elemene of preparation example 1 with the beta-elemene of preparation example 2.The ultimate density that sampling records total elemene isomer is 5 ± 0.10mg/ml.Confirm it is the nanometer microemulsion with the Coulter instrument.The injection that is obtained is called for short 4B-1.
4B-2: the preparation of positively charged nanometer microemulsion
Repeat above-mentioned 4A-2, just replace the elemene of preparation example 1 with the beta-elemene of preparation example 2.The ultimate density that sampling records total elemene isomer is 5 ± 0.10mg/ml.Confirm it is the nanometer microemulsion with the Coulter instrument.The injection that is obtained is called for short 4B-2.
Embodiment 5: the preparation of the lipid nanospheres preparation of elemene or beta-elemene
5A: the elemene of getting preparation example 1 adds in the soybean oil with soybean phospholipid, heats up and is controlled to oil phase (promptly remaining oil phase), and this oil phase is joined in the glycerinated aqueous solution.Its concrete weight ratio is: elemene accounts for 0.2% of total weight of formulation, soybean phospholipid 1.6%, soybean oil 10%, glycerol 2.5%, surplus is a water for injection, high-speed stirred then, regulating PH with 1M biphosphate sodium water solution is 4.5～6.5, handle through M110-E/H type (Japanese MIZUHO produces) high pressure homogenizer again, carry out ultrasonic Treatment according to same procedure among the embodiment 3 then, make the particle diameter≤200nm and the mean diameter≤100nm of its lipid ball, again through 0.8 μ filtering with microporous membrane and bottling then, 100 ℃～120 ℃ sterilizations.The ultimate density that sampling records total elemene isomer is 2 ± 0.04mg/ml.The injection that is obtained is called for short 5A.Can in raw material, comprise an amount of cholesterol, linoleic acid etc. as required.
5B: repeat above-mentioned 5A program, just replace the elemene of preparation example 1 with the beta-elemene of preparation example 2.Particle diameter≤the 200nm of lipid ball and mean diameter≤100nm.The ultimate density that chromatography records total elemene isomer is 2 ± 0.04mg/ml.The injection that is obtained is called for short 5B.
Embodiment 6: the preparation of the intravenous injection breast of elemene or beta-elemene
6A: the elemene of preparation example 1, refining soybean phospholipid, cholesterol are mixed with the water for injection (is that 5mg/ml calculates this surplus according to required final concentration) of surplus with weight ratio 1: 3.2: 1.5, with M110-E/H type (Japanese MIZUHO produces) high pressure homogenizer emulsifying, till usefulness Coulter instrument checks particle diameter less than 1 μ always.Then, regulate PH with 1M biphosphate sodium water solution, making pH value is 4.5～6.5, through 1.2 μ filtering with microporous membranes and bottling then, through 100 ℃～120 ℃ sterilizations, obtain elemene vein breast, the ultimate density that sampling records total elemene isomer is 5 ± 0.10mg/ml.This injection is called for short 6A.
6B: repeat above 6A, just replace the elemene of preparation example 1 with the beta-elemene of preparation example 2.Check particle diameter less than 1 micron with the Coulter instrument.The ultimate density of total elemene isomer is 5 ± 0.10mg/ml in the preparation.The injection that is obtained is called for short 6B.
Embodiment 7: the preparation of elemene fat emulsion
7A: elemene and the soybean phospholipid of getting preparation example 1 add in the soybean oil, heat up and are controlled to oil phase, and this oil phase is joined in the glycerinated aqueous solution.Its concrete weight ratio is: elemene accounts for 0.2% of total weight of formulation, soybean phospholipid 1.2%, and soybean oil 10%, glycerol 2.5%, surplus is a water for injection.High-speed stirred then, regulating PH with 1M biphosphate sodium water solution is 4.5～6.5, handles through M110-E/H type (Japanese MIZUHO produces) high pressure homogenizer, until with till Coulter instrument check particle diameter≤1 μ again, again through 1.2 μ filtering with microporous membranes and bottling then, 100 ℃～120 ℃ sterilizations.The ultimate density that records total elemene isomer is 2 ± 0.04mg/ml.The injection that is obtained is called for short 7A.Can in raw material, comprise an amount of cholesterol, linoleic acid etc. as required.
7B: repeat above-mentioned 7A, just replace the elemene of preparation example 1 with the beta-elemene of preparation example 2.The ultimate density that records total elemene isomer in preparation is 2 ± 0.04mg/ml.The injection that is obtained is called for short 7B.
Embodiment 8:CO
2Supercritical methanol technology prepares liposome
8A: the chloroform that will account for the 10wt% of cholesterol weight adds to be made it in the cholesterol to soak into, the elemene product adding of soybean phospholipid and preparation example 1 is wherein mixed (elemene: soybean phospholipid: cholesterol=weight ratio 1.2: 3.2: 1.5), the mixture that is obtained is put into CO
2In the extractor of supercritical extraction instrument (Han Wei mechanical ﹠ electrical corporation in Guangzhou produces, model SFE100ml), feed CO
2(pressure 50-80kg), 50 ℃ of system temperatures carry out critical or supercritical dispersion, make the mixture uniform mixing, and slowly decompression discharges CO then
2, allow CO
2Chloroform is taken out of, take out extractor, the water for injection (calculating this surplus) that in extractor, adds surplus according to the ultimate density of injection, stir with agitator, with formed dispersion ultrasonic Treatment, until till decentralized photo particle diameter≤100 nanometers of liposome (being called nanometer liposome).Then nano-lipid body and function 1M biphosphate sodium water solution is regulated PH, making pH value is 4.5～6.5, filters and bottling then through 0.8 μ microporous filter membrane (new Asia, Shanghai purifies device factory and produces, specification 0.8 μ), 100 ℃ of vapor stream sterilizations, the injection product that is obtained is called for short 8A.Sampling is 5 ± 0.10mg/ml with the ultimate density that gas chromatography records total elemene isomer.Envelop rate is higher than 88%.
8B: repeat above-mentioned 8A, just replace the elemene of preparation example 1, make liposome with the beta-elemene of preparation example 2.The ultimate density that records total elemene isomer in preparation is 5 ± 0.10mg/ml.The injection that is obtained is called for short 8B.Envelop rate is higher than 88%.
Pharmacodynamics test
The anti-tumor in vivo Evaluation on effect method of pharmaceutical preparation has had description (for example referring to CN1153168A) in above some patent documentation of enumerating.
In the present invention, the preparation of various dosage forms is to human tumor heteroplastic transplantation model QGY hepatocarcinoma, the MKN-45 efficacy in treating gastric carcinoma of subcutaneous vaccination, can be by dosage with 80mg (elemene or beta-elemene)/kg (body weight), 40mg/kg and 20mg/kg, every day, the tail intravenously administrable was 1 time, 10 days therapeutic scheme of successive administration confirms wherein there is not the group in contrast of administration.The relevant regulations " the evaluating drug effect way of antitumor drug " of the National Drug Administration that the calculating of concrete operating process and tumor control rate (tumour inhibiting rate) (referred to before the application's the applying date) according to is at present implemented.
Tumour inhibiting rate %=[(does not have the tumor weight of model of tumor weight-administration of the model of administration)/do not have a tumor weight of the model of administration] * 100%
The tumour inhibiting rate of table 1. human tumor heteroplastic transplantation model QGY hepatocarcinoma
| Injection | Dosage (mg/kg) | Tumour inhibiting rate | Dosage (mg/kg) | Tumour inhibiting rate | Dosage (mg/kg) | Tumour inhibiting rate |
| 1A | 20 | 30.2％ | 40 | 39.3％ | 80 | 45.2％ |
| 1B | 20 | 30.0％ | 40 | 39.1％ | 80 | 45.0％ |
| 2A | 20 | 30.1％ | 40 | 37.5％ | 80 | 44.0％ |
| 2B | 20 | 30.0％ | 40 | 38.5％ | 80 | 43.6％ |
| 3A | 20 | 29.6％ | 40 | 39.6％ | 80 | 44.5％ |
| 3B | 20 | 29.8％ | 40 | 38.6％ | 80 | 44.4％ |
| 4A-1 | 20 | 30.4％ | 40 | 38.5％ | 80 | 46.0％ |
| 4A-2 | 20 | 30.6％ | 40 | 37.9％ | 80 | 46.2％ |
| 4B-1 | 20 | 30.2％ | 40 | 37.4％ | 80 | 45.3％ |
| 4B-2 | 20 | 29.4％ | 40 | 38.6％ | 80 | 44.9％ |
| 5A | 20 | 29.3％ | 40 | 38.7％ | 80 | 44.3％ |
| 5B | 20 | 29.5％ | 40 | 38.6％ | 80 | 44.5％ |
| 6A | 20 | 29.8％ | 40 | 37.8％ | 80 | 43.2％ |
| 6B | 20 | 29.4％ | 40 | 37.9％ | 80 | 43.5％ |
| 7A | 20 | 29.2％ | 40 | 37.4％ | 80 | 44.0％ |
| 7B | 20 | 29.6％ | 40 | 37.2％ | 80 | 43.2％ |
| 8A | 20 | 29.4％ | 40 | 37.4％ | 80 | 44.0％ |
| 8B | 20 | 29.2％ | 40 | 37.2％ | 80 | 43.2％ |
The tumour inhibiting rate of table 2. human tumor heteroplastic transplantation model MKN-45 gastric cancer
| Injection | Dosage (mg/kg) | Tumour inhibiting rate | Dosage (mg/kg) | Tumour inhibiting rate | Dosage (mg/kg) | Tumour inhibiting rate |
| 1A | 20 | 28.9％ | 40 | 39.3％ | 80 | 45.2％ |
| 1B | 20 | 29.1％ | 40 | 39.1％ | 80 | 45.0％ |
| 2A | 20 | 29.3％ | 40 | 37.5％ | 80 | 44.0％ |
| 2B | 20 | 28.4％ | 40 | 38.5％ | 80 | 43.6％ |
| 3A | 20 | 29.1％ | 40 | 39.6％ | 80 | 44.5％ |
| 3B | 20 | 29.0％ | 40 | 38.6％ | 80 | 44.4％ |
| 4A-1 | 20 | 29.4％ | 40 | 38.5％ | 80 | 46.0％ |
| 4A-2 | 20 | 29.5％ | 40 | 37.9％ | 80 | 46.2％ |
| 4B-1 | 20 | 28.8％ | 40 | 37.4％ | 80 | 45.3％ |
| 4B-2 | 20 | 28.3％ | 40 | 38.6％ | 80 | 44.9％ |
Table 3: to the curative effect (tumour inhibiting rate) of intracranial in-situ inoculating mice cerebroma G422 model.
| Injection | Dosage (mg/kg) | Tumour inhibiting rate | Dosage (mg/kg) | Tumour inhibiting rate | Dosage (mg/kg) | Tumour inhibiting rate |
| 1A | 20 | 47.6％ | 40 | 59.5％ | 80 | 68.2％ |
| 1B | 20 | 46.8％ | 40 | 59.2％ | 80 | 68.5％ |
| 2A | 20 | 47.2％ | 40 | 57.6％ | 80 | 64.0％ |
| 2B | 20 | 48.2％ | 40 | 56.3％ | 80 | 63.6％ |
| 3A | 20 | 49.5％ | 40 | 59.6％ | 80 | 67.5％ |
| 3B | 20 | 48.4％ | 40 | 58.3％ | 80 | 66.4％ |
| 4A-1 | 20 | 49.3％ | 40 | 58.4％ | 80 | 67.0％ |
| 4A-2 | 20 | 49.4％ | 40 | 57.7％ | 80 | 67.2％ |
| 4B-1 | 20 | 48.6％ | 40 | 57.2％ | 80 | 66.3％ |
| 4B-2 | 20 | 49.3％ | 40 | 58.4％ | 80 | 67.9％ |
| 5A | 20 | 49.8％ | 40 | 58.7％ | 80 | 68.3％ |
| 5B | 20 | 47.8％ | 40 | 58.3％ | 80 | 65.5％ |
| 6A | 20 | 47.6％ | 40 | 56.8％ | 80 | 63.2％ |
| 6B | 20 | 46.9％ | 40 | 56.9％ | 80 | 63.5％ |
| 7A | 20 | 48.2％ | 40 | 56.4％ | 80 | 66.0％ |
| 7B | 20 | 46.8％ | 40 | 56.2％ | 80 | 63.2％ |
Table 4: to the curative effect (tumour inhibiting rate) of subcutaneous vaccination mice cerebroma G422 model.
| Injection | Dosage (mg/kg) | Tumour inhibiting rate | Dosage (mg/kg) | Tumour inhibiting rate | Dosage (mg/kg) | Tumour inhibiting rate |
| 1A | 20 | 23.1％ | 40 | 29.8％ | 80 | 35.4％ |
| 1B | 20 | 23.0％ | 40 | 29.6％ | 80 | 35.2％ |
| 2A | 20 | 22.8％ | 40 | 27.8％ | 80 | 34.0％ |
| 2B | 20 | 22.8％ | 40 | 28.5％ | 80 | 33.3％ |
| 3A | 20 | 22.9％ | 40 | 29.8％ | 80 | 34.2％ |
| 3B | 20 | 23.0％ | 40 | 28.7％ | 80 | 34.8％ |
| 4A-1 | 20 | 24.2％ | 40 | 28.1％ | 80 | 36.2％ |
| 4A-2 | 20 | 24.4％ | 40 | 27.9％ | 80 | 36.2％ |
| 4B-1 | 20 | 23.6％ | 40 | 27.8％ | 80 | 35.2％ |
| 4B-2 | 20 | 23.2％ | 40 | 28.7％ | 80 | 34.4％ |
| 5A | 20 | 23.4％ | 40 | 28.7％ | 80 | 34.8％ |
| 5B | 20 | 24.1％ | 40 | 28.6％ | 80 | 34.5％ |
| 6A | 20 | 22.4％ | 40 | 27.9％ | 80 | 33.2％ |
| 6B | 20 | 22.6％ | 40 | 27.8％ | 80 | 33.4％ |
| 7A | 20 | 22.4％ | 40 | 27.5％ | 80 | 34.1％ |
| 7B | 20 | 22.2％ | 40 | 27.3％ | 80 | 33.6％ |
In addition, the injection of various dosage forms improves 21%～23% to the NK cells in mice and the matched group specific activity of lotus Lewis lung cancer.
The injection of various dosage forms has improved 1.4～1.55 to the influence of mouse lymphocyte proliferation activity, the stimulation index of lotus Lewis lung cancer.
In a word, from above-mentioned table data as can be seen, various preparations are effective through QGY hepatocarcinoma, MKN-45 gastric cancer, mice cerebroma G422 model pharmacology test.To the Immune Function test, the NK cells in mice of lotus Lewis lung cancer improves 21%～23% with the matched group ratio.Lymphocyte increment activity influence, stimulation index have improved 1.4～1.55.
So elemene injection can be used in and suppresses and/or the treatment tumor.In addition, through overtesting, said preparation can also be used for anticancer to be shifted, and is used for tumor remission pain, is used for prevention or treatment cerebral infarction.
Claims (8)
1. elemene injection, it contains: the extract with total elemene content of isomer 〉=70wt% that extracts through the rectification of material filling type vacuum rectifying apparatus or molecular distillation instrument from plant, soybean phospholipid, cholesterol, water for injection with surplus, it is characterized in that: this injection is a kind of aqueous dispersion, the mean diameter of decentralized photo≤100 nanometers, the dosage form of injection is nanometer liposome dosage form or nanometer microemulsion type, extract and soybean phospholipid, the weight ratio of cholesterol is 0.9-1.1: 3.0-3.4: 1.4-1.6, the ultimate density of total elemene isomer is 5-7.5mg/ml in the injection.
2. elemene injection according to claim 1, the wherein envelop rate of nanometer liposome dosage form 〉=80%.
3. according to any one described elemene injection among the claim 1-2, it is an intravenous injection.
4. elemene injection according to claim 1, wherein, beta-elemene content of isomer 〉=85wt% in the extract.
5. the preparation method of the described elemene injection of claim 1, it comprises the extract that contains the elemene isomer by rectification of material filling type vacuum rectifying apparatus or the preparation of molecular distillation instrument, then with the extract of total elemene content of isomer 〉=70wt% as raw material, add soybean phospholipid and cholesterol, utilize Rotary Evaporators film forming or CO
2Critical or supercritical process comes mix homogeneously, add water for injection, carrying out high pressure homogenizing handles and/or ultrasonic Treatment, handle till the stabilized aqueous dispersion that obtains particle diameter of dispersing phase≤100 nanometers always, thereby make injection, wherein the weight ratio of extract and soybean phospholipid, cholesterol is 0.9-1.1: 3.0-3.4: 1.4-1.6, the ultimate density of total elemene isomer is 5-7.5mg/ml in the injection.
6. preparation method according to claim 5, wherein the dosage form of injection is the nanometer liposome dosage form, the concentration of total elemene isomer of described nanometer liposome dosage form injection is 5-7.5 mg/ml, envelop rate 〉=80%.
7. preparation method according to claim 5, wherein, beta-elemene isomer purity 〉=85wt% in the extract.
8. the described elemene injection of any one claim is used to prepare the purposes that suppresses or treat the medicine of cancer among the claim 1-4.
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| CN2008101264158A CN101306181B (en) | 2002-04-17 | 2002-04-17 | Elemene fat emulsion injection and preparation method thereof |
| CN2008101264162A CN101306182B (en) | 2002-04-17 | 2002-04-17 | Elemene vein emulsion injection and preparation method thereof |
| CNB021172196A CN100423714C (en) | 2002-04-17 | 2002-04-17 | Elemene injection, and preparing method and use thereof |
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| CN2008101264162A Division CN101306182B (en) | 2002-04-17 | 2002-04-17 | Elemene vein emulsion injection and preparation method thereof |
| CN2008101264158A Division CN101306181B (en) | 2002-04-17 | 2002-04-17 | Elemene fat emulsion injection and preparation method thereof |
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| CN2008101264162A Expired - Lifetime CN101306182B (en) | 2002-04-17 | 2002-04-17 | Elemene vein emulsion injection and preparation method thereof |
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| CN1650846B (en) * | 2004-12-07 | 2011-11-16 | 沈阳药科大学 | Elemene liposome and its preparation method |
| CN101756900B (en) * | 2010-02-25 | 2012-05-30 | 谢恬 | Elemene micro-emulsion |
| CN101810593B (en) | 2010-05-10 | 2012-07-18 | 谢恬 | Elemene sustained-release tablets |
| CN108186616A (en) * | 2018-01-24 | 2018-06-22 | 天津中医药大学 | Beta-elemene is being prepared for preventing and/or treat and the purposes in the drug of the relevant diseases associated with inflammation of IL-1 |
| JP2023504821A (en) * | 2019-12-03 | 2023-02-07 | 四川弘合生物科技有限公司 | Pharmaceutical composition containing elemen, method of preparation thereof, and use thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1076613A (en) * | 1993-02-15 | 1993-09-29 | 大连金港制药有限公司 | Elemene emulsion injection and preparation method thereof |
| CN1200266A (en) * | 1997-04-14 | 1998-12-02 | 中国科技开发院医药科技开发所 | Method for preparing anti-cancer medicine using beta-elemene as main effective ingredient, and components of the medicine |
| CN1221607A (en) * | 1998-11-20 | 1999-07-07 | 大连市医药科学研究所 | Liposoluble medicinal liposome prodn. tech. and elemene liposome injecta |
-
2002
- 2002-04-17 CN CNB021172196A patent/CN100423714C/en not_active Expired - Lifetime
- 2002-04-17 CN CN2008101264162A patent/CN101306182B/en not_active Expired - Lifetime
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1076613A (en) * | 1993-02-15 | 1993-09-29 | 大连金港制药有限公司 | Elemene emulsion injection and preparation method thereof |
| CN1200266A (en) * | 1997-04-14 | 1998-12-02 | 中国科技开发院医药科技开发所 | Method for preparing anti-cancer medicine using beta-elemene as main effective ingredient, and components of the medicine |
| CN1221607A (en) * | 1998-11-20 | 1999-07-07 | 大连市医药科学研究所 | Liposoluble medicinal liposome prodn. tech. and elemene liposome injecta |
Non-Patent Citations (12)
| Title |
|---|
| 《药剂学》. 毕殿洲主编，第454页，人民卫生出版社. 1999 |
| 《药剂学》. 毕殿洲主编，第454页，人民卫生出版社. 1999 * |
| 99m锝标记紫杉醇脂质体在移植荷瘤鼠体内分布的研究. 张长英等.同济医科大学学报，第29卷第3期. 2000 |
| 99m锝标记紫杉醇脂质体在移植荷瘤鼠体内分布的研究. 张长英等.同济医科大学学报，第29卷第3期. 2000 * |
| Optimal Radiolabeled Liposomes for Tumor Imaging. Izumi Ogihara-Umeda et al.THE JOURNAL OF NUCLEAR MEDICINE,Vol.37 No.2. 1996 |
| Optimal Radiolabeled Liposomes for Tumor Imaging. Izumi Ogihara-Umeda et al.THE JOURNAL OF NUCLEAR MEDICINE,Vol.37 No.2. 1996 * |
| β-榄香烯脂质体注射液的研究. 马淑贤等.中国药学杂志，第27卷第11期. 1992 |
| β-榄香烯脂质体注射液的研究. 马淑贤等.中国药学杂志，第27卷第11期. 1992 * |
| 两性霉素B脂质体的研制及其质量评价. 赵荣生等.中国药学杂志，第09期. 2000 |
| 两性霉素B脂质体的研制及其质量评价. 赵荣生等.中国药学杂志，第09期. 2000 * |
| 环孢素纳米脂质体的制备及在小鼠体内的组织分布. 陈颖等.中国新药与临床杂志，第21卷第2期. 2002 |
| 环孢素纳米脂质体的制备及在小鼠体内的组织分布. 陈颖等.中国新药与临床杂志，第21卷第2期. 2002 * |
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| Publication number | Publication date |
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| CN101306181A (en) | 2008-11-19 |
| CN1451377A (en) | 2003-10-29 |
| CN101306182B (en) | 2011-11-23 |
| CN101306181B (en) | 2011-06-29 |
| CN101306182A (en) | 2008-11-19 |
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