CN1302769C - Curcuma oil extract injection aqueous solution and preparation method and application thereof - Google Patents
Curcuma oil extract injection aqueous solution and preparation method and application thereof Download PDFInfo
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- CN1302769C CN1302769C CN 03153226 CN03153226A CN1302769C CN 1302769 C CN1302769 C CN 1302769C CN 03153226 CN03153226 CN 03153226 CN 03153226 A CN03153226 A CN 03153226A CN 1302769 C CN1302769 C CN 1302769C
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- turmerone
- turmeric oil
- oil extract
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- Medicines Containing Plant Substances (AREA)
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Abstract
The present invention relates to an injection solution of curcuma oil extract containing arylturmerone, turmerone and/or arylturmerone derivative. It is prepared from curcuma oil extract containing active components, surfactant and aqueous medium.
Description
Technical field:
The present invention relates to contain the water injection of the turmeric oil extract of active component.The invention still further relates to the preparation method and the purposes of these dosage forms.
Background technology:
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, turmeric oil extract, common turmeric extract etc. and the various dosage forms of these medicines.
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.
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.
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.
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 turmeric oil extract homogeneous phase injection is water injection, it is with containing turmeric oil extract, surfactant and the water-bearing media of active component as feedstock production, this turmeric oil extract that contains active component be from turmeric oil separate obtain and comprise aryl turmerone at least about 25wt% as active component, this surfactant is medicinal non-ionic surface active agent, and the concentration of aryl turmerone is 0.02～4wt% in the water injection.More preferably, this water-bearing media is a water.
Another object of the present invention provides the preparation method of these water injections.
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 water injections are used for the purposes of tumor remission pain, and these preparations are used to suppress and/or treat the purposes of tumor.Water injection of the present invention increases the effect of bile secretion in addition.
Description of drawings:
Fig. 1 is the dactylogram of measuring immediately after the preparation of turmeric oil extract.
Fig. 2 is the dactylogram of measuring after turmeric oil extract preparation back is placed 3 months.
Detailed description of the present invention:
Known in the prior art field that some isomers of elemene, curcuma oil extract, 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, for the effect of the inhibition tumour of specific sesquiterpene ketone, people solve seldom, the report of relevant this respect is seldom in the document.
The inventor has carried out years of researches to the cancer suppressing action of curcuma oil extract emulsion dosage form, has been found that the sesquiterpenoid (C in the curcuma oil15H
24) zingiberene, curcumene, ar-curcumene have close tumor-suppression activity as elemene. We find again to belong in the curcuma oil that the compound turmerone, ar-turmerone etc. of sesquiterpene ketone are prepared into the injection breast through pharmacological testing, confirm that its tumor-suppression activity improves 15%～25% than Elemenum Emulsion, extremely have exploitation to be worth. We are to turmerone, ar-turmerone in the curcuma oil extract, contain oxygen tumor-suppression activity composition and develop clear and bright parenteral solution, cosolvent adopts respectively Tween-80 (Polyasorbate-80 (Tween-80), tween-80), polyoxyethylene glycerine three castor oil acid esters 35 (cremophorEL castor oil APEO), rilanit special APEO and propane diols. Prepare curcuma oil extract (sesquiterpene ketone) Tween-80 parenteral solution, curcuma oil extract (Tween-80) glucose injection and curcuma oil extract (sesquiterpene ketone) castor oil polyoxyethylene ether (polyoxyethylene glycerine three castor oil acid esters cremophorEL), rilanit special APEO (cremophorRH40, cremophorRH60) propane diols parenteral solution, curcuma oil extract (cremophor) glucose infusion liquid. The physical features of these six kinds of parenteral solutions all is the homogeneous phase parenteral solutions that are clear and bright.
Curcuma oil extract used in the present invention is the extract that contains ar-turmerone, turmerone and ar-turmerone derivative that extracts from the essential oil (or being called volatile oil or curcuma oil) that turmeric obtains, and wherein the content of ar-turmerone is approximately more than the 25wt%.
The inventor utilizes the high efficiency chromatography post of long (more than 25 meters or 25 meters), adopt chromatograph mass spectrometer successfully to disassemble specific several sesquiterpene ketone of turmeric oil, the function of tumor inhibition of finding them is better than sesquiterpene, and has produced water injection from this turmeric oil extract.This water injection should comprise the injection of smaller dose and heavy dose of transfusion in a broad sense.As the injection of smaller dose, contain higher concentration promptly up to the active component (referring to described ketone) of 4wt%, and, contain the active component (referring to described ketone) that is low to moderate 0.02wt% as heavy dose of transfusion.Here, water injection, injection and injection can exchange use.
The invention provides turmeric oil extract water injection, as feedstock production, this turmeric oil extract that contains active component comprises the aryl turmerone at least about 25wt% as active component with the turmeric oil extract, surfactant and the water-bearing media that contain active component for it.Under normal circumstances, if do not cut branch in chromatographic isolation, this turmeric oil extract that contains active component also comprises the aryl turmerone derivant at least about turmerone and the 0-20wt% of 20wt% as active component.Wherein the aryl turmerone derivant contains the isomer of following general formula I:
The present invention also provides the preparation method of turmeric oil extract water injection, it comprises mixes turmeric oil extract, surfactant and the water-bearing media that contains active component, and this turmeric oil extract that contains active component comprises the aryl turmerone at least about 25wt% as active component.
For these turmeric oil extracts, require it to comprise as the pact of the active component aryl turmerone of 25wt% at least, other is turmerone and turmerone derivant, also has sesquiterpene and a small amount of other natural component (comprising natural components such as monoterpene, two terpenes, curcumin) that promptly is lower than 5wt%.Ideally, this turmeric oil extract comprises 30wt% at least as active component, more preferably 45wt% even more preferably 60wt%, more preferably 70wt%, further more preferably 80wt%, preferred especially 85wt% at least, the aryl turmerone of 95wt% at least most preferably at least at least more at least.The content of other natural component is to be lower than 4wt%, preferably be lower than 3.5wt%, more preferably less than 3wt%, again more preferably less than 2.5wt%, even more preferably less than 2wt% with especially preferably be lower than 1.5wt%, more especially preferably be lower than 0.5wt% and most preferably be lower than 0.01wt%.Owing to adopted long high efficiency chromatography post, make it possible to isolate aryl turmerone respectively with high-purity, turmerone, with the aryl turmerone derivant, occur according to from left to right order in the fingerprint spectrogram that the three provides successively in the accompanying drawings as three main peaks, as can be seen, three peaks of these three kinds of materials can separate from accompanying drawing for this, and intercepting these three kinds of compositions respectively is to realize easily.Certainly, each composition of cutting branch is further carried out chromatographic isolation, it also is possible obtaining higher purity (concentration).Because turmerone, the aryl turmerone derivant also has good effect, so, aryl turmerone, turmerone and aryl turmerone derivant three are sometimes seemed and there is no need further the separation, promptly needn't be split.
In addition, (FeCl3) carries out chromogenic assay with ferric chloride, shows that the aryl turmerone derivant exists phenolic hydroxyl group or enol-type structure.
It is to be noted, the turmeric oil extract for preparing water injection as initiation material of the present invention can use the product that is purchased in the present invention, as aryl turmerone as described in containing, the turmeric oil extract of turmerone and/or aryl turmerone derivant is purchased product, and the turmeric oil extract product that extracts from the volatile oil (or quintessence oil or turmeric oil) of curcuma plant (preferably its rhizome) according to method described in the prior or described here method.If need oneself these extract of preparation in this application, the various volatile oil (or quintessence oil) that are used to prepare these extracts can use and be purchased product, also can use the volatile oil that obtains from plant (for example plant rhizome) by common steam distillation or CO2 super critical extraction.Each extract can be used as initiation material of the present invention, and the volatile oil of RADIX CURCUMAE can be as the raw material that obtains extract.It is pointed out that also active component in this application specifically comprises a kind of, two or three ketone in aryl turmerone, turmerone and the aryl turmerone derivant, but aryl turmerone must have.
In principle, that extracts from plant contains 〉=25wt%, preferably 〉=30wt%, more preferably 〉=45wt%, more more preferably 〉=all extracts of the active component of 60wt% even more preferably 〉=65wt%, most preferably 〉=70wt% all can be used as raw material and are used to prepare water injection of the present invention.In some cases, the turmeric oil extract contains 〉=60wt%, better 〉=65wt%, preferably 〉=70wt%, especially preferably 〉=75wt%, very particularly preferably 〉=80wt%, further especially preferably 〉=85wt%, most preferably 〉=and the active component of 95wt%, promptly be selected from aryl turmerone, a kind of, two or three ketone in turmerone and the aryl turmerone derivant.Other composition in the turmeric oil extract is sesquiterpene and other natural component (comprising monoterpene, two terpenes, curcumin etc.) that promptly is lower than 5wt% on a small quantity.Ideally, the content of other natural component is to be lower than 4wt%, preferably is lower than 3.5wt%, more preferably less than 3wt%, again more preferably less than 2.5wt%, even more preferably less than 2wt% with especially preferably be lower than 1.5wt%, more especially preferably be lower than 0.5wt% and most preferably be lower than 0.01wt%.Under unusual ideal situation, other natural component content should be lower than 0.0001wt%.The content of various compositions be with 25 meters left and right sides length capillary column gas chromatography-GC-MS (be about 25 meters long capillary gas chromatograph-mass spectrometer (GC-MS)s: Bio-Rad FTS-65A, HP5890II, chromatographic column: BP-5) the Detection and Extraction thing is obtained.The raw material for preparing usefulness as water injection, contain 70wt%, preferred 75wt%, more preferably the turmeric oil extract of the above active component of 80wt% is ideal, it is preferred containing the above extraction of active ingredients thing of 85wt%, it is preferred containing the above extraction of active ingredients thing of 90wt%, and it is particularly preferred containing the above extraction of active ingredients thing of 95wt%.
The curcuma that is used to extract aryl turmerone, turmerone, aryl turmerone derivant comprises the Rhizoma Curcumae Longae that the southern china each province produces, and especially the Rhizoma Curcumae Longae that produces of Guangdong mainly obtains turmeric oil from rhizome, prepares the turmeric oil extract from turmeric oil again.About the description of these plants and contained composition sesquiterpene ketone referring to " Acta Pharmaceutica Sinica (ACTAPHARMACEUTICA SINICA) ", " research of China curcuma ", Vol.XVII, No.6 (the 17th the 6th phase of volume), June nineteen eighty-two.Describe the composition and the content of Curcuma five kind of plant rhizome volatile oil in this article in detail, the document is incorporated herein for reference with full content.
The explanation of term:
In this application, the turmeric oil extract refers to from curcuma plant, and especially the volatile oil that obtains from the curcuma plant rhizome (or quintessence oil or turmeric oil) is through the smart distilled component of vacuum material filling type rectifier unit or the component made from extra care out through the molecular distillation instrument.Through GC-MS (gas chromatograph-mass spectrometer (GC-MS)) detection level.
Purity is meant percent purity by weight in this application, except as otherwise noted.
Employed raw material is that the turmeric oil extract has no particular limits among the application, as long as this extract is to extract from natural plants and comprise 〉=aryl turmerone of 25wt%, other is turmerone and aryl turmerone derivant, a small amount of sesquiterpene and a small amount of other natural component that promptly is lower than 5wt% that promptly is lower than 10wt% (comprises monoterpene, two terpenes, curcumin etc.), and aryl turmerone, turmerone and aryl turmerone derivant are considered to active component here, then this extract just can use in the present invention, better is, this purity 〉=30wt%, better 〉=45wt%, preferably 〉=60wt%, especially preferably 〉=65wt%, very particularly preferably 〉=70wt%.Certainly, more the extract of high activity composition purity is ideal, since the purity height, the corresponding minimizing of extract consumption when the preparation water injection.So, can adopt active component (aryl turmerone, turmerone and/or aryl turmerone derivant) purity 〉=70wt% sometimes, better 〉=75wt%, preferably 〉=80wt%, especially preferably 〉=85wt%, very particularly preferably 〉=88wt%, the turmeric oil extract of more preferred 〉=95wt%.Described active component refers to, is selected from aryl turmerone, a kind of, two or three ketone in turmerone and the aryl turmerone derivant, but aryl turmerone must have.Wherein aryl turmerone, turmerone also should comprise whole separately isomers, if any.In addition, the turmeric oil extract can contain the aryl turmerone that 90wt% is above or 95wt% is above, and can think that it is an one-component this moment.
Except as otherwise noted, otherwise other composition such as the ethanol that use in the present invention, propylene glycol or glycerol, non-ionic surface active agents etc. are general to require to meet national medicinal standard, and these are mainly for the consideration of emulsifiability and healthy aspect.
Except as otherwise noted, otherwise the employed gas chromatograph-mass spectrometer (GC-MS) of chromatography in this application is: Bio-Rad FTS-65A, HP5890II, capillary chromatographic column (30m * 0.25mm * 0.25 μ m) is: DB1 (fixative is a polydimethylsiloxane), (fixative is poly-(5% phenyl) dimethyl siloxane for BP-5 or DB5.
Water injection of the present invention is clear and bright or is half clear and bright, should half clear and bright state be considered to mercerising shape, homogenizing, and the visible lights of the overwhelming majority can see through.This water injection can be used for the treatment of purpose with intravenous injection, topical mode.Water injection of the present invention is a kind of homogeneous phase injection.
The preferred embodiments of the invention
The preferred embodiments of the invention high level overview is as follows:
1. turmeric oil extract water injection, it is with containing turmeric oil extract, surfactant and the water-bearing media of active component as feedstock production, this turmeric oil extract that contains active component be from turmeric oil separate obtain and comprise aryl turmerone at least about 25wt% as active component, this surfactant is medicinal non-ionic surface active agent, and the concentration of aryl turmerone is 0.02～4wt% in the water injection.
2. according to 1 water injection, wherein this turmeric oil extract that contains active component comprises the aryl turmerone at least about 30wt% as active component.
3. according to 1 water injection, wherein this turmeric oil extract that contains active component comprises the aryl turmerone at least about 45wt% as active component, or preferred 60wt% at least, more preferably at least about 70wt%, more preferably 80wt% at least again, even more preferably 85wt% at least, most preferably at least about the aryl turmerone of 95wt%-99wt%.When the turmeric oil extract comprises aryl turmerone at least about 95wt%, can think that said preparation is a Western medicine preparation.
4. according to 1 or 3 water injection, wherein this turmeric oil extract that contains active component comprises the aryl turmerone at least about 95wt% as active component.
5. according to each water injection among the 1-4, wherein the concentration of aryl turmerone described in the water injection is 0.03～4wt%.
6. according to each water injection among the 1-4, wherein the concentration of aryl turmerone described in the water injection is 0.03～3wt%.
7. according to 1 water injection, wherein this turmeric oil extract that contains active component also further comprise as active component at least about the turmerone of 20wt% with at least about the aryl turmerone derivant of 18wt%, and aryl turmerone, turmerone and aryl turmerone derivant three's total concentration is 0.03～4wt% in the water injection, preferred 0.04～4wt%, more preferably 0.04-3.5wt%, more preferably 0.04-3wt% again.This moment, it was a kind of Chinese medicine preparation.
8. according to 1 water injection, wherein water-bearing media is a water.
9. according to 1 water injection, it is clear and bright or is half clear and bright.
10. according to 1 water injection, wherein the content of non-ionic surface active agent is about 10%-40wt%.
11. according to 1 water injection, wherein surfactant is the non-ionic surface active agent of Polysorbate type (for example tween 80) and/or polyoxyethylene-type.
12. according to 1 or 11 water injection, wherein surfactant is castor oil polyoxyethylene ether and/or castor oil hydrogenated polyoxyethylene ether, for example Cremophor EL and Cremphor RH.
13. according to 1 or 11 water injection, it also contains the ethanol that is selected from of 5-28wt%, and 1,2-propylene glycol, 1, one or more alcohols in ammediol and the glycerol.
14. the preparation method of turmeric oil extract water injection, it comprises the turmeric oil extract that contain active component of mixing as raw material, surfactant and water-bearing media, this turmeric oil extract that contains active component be from turmeric oil separate obtain and comprise aryl turmerone at least about 25wt% as active component, this surfactant is medicinal non-ionic surface active agent, the consumption of non-ionic surface active agent is that the basis is about 10%-40wt% in final water injection weight, this turmeric oil extract that contains active component is so that the concentration of aryl turmerone is 0.02～4wt% in this water injection, be preferably 0.03～4wt%, more preferably that consumption of 0.03～3wt% uses.
15. according to 14 preparation method, wherein water-bearing media is a water.
16. preparation method according to 14, wherein this turmeric oil extract that contains active component comprises the aryl turmerone at least about 45wt% as active component, or preferred 60wt% at least, more preferably at least about 70wt%, more preferably 80wt% at least again, even more preferably 85wt% at least, most preferably at least about the aryl turmerone of 95wt%.
17. preparation method according to 14, wherein this turmeric oil extract that contains active component also comprise as active component at least about the turmerone of 20wt% with at least about the aryl turmerone derivant of 18wt%, make that aryl turmerone in this water injection, turmerone and aryl turmerone derivant three's total concentration is 0.04～4wt%.
18. according to 14 preparation method, also mixed the ethanol that is selected from as raw material, 1, the 2-propylene glycol, 1, one or more alcohols in ammediol and the glycerol, its consumption make water injection contain these one or more alcohols of 5-28wt%.
19. the water injection of any one is used for suppressing and/or the treatment tumor in the above 1-13 item, is used for anticancer and shifts, and is used for tumor remission pain, is used for prevention or treatment cerebral infarction, or is used to increase the purposes of bile secretion.
20. the purposes that the water injection of any one is used to prepare the medicine of inhibition or treatment cancer or is used to prepare the medicine that increases bile secretion in the above 1-13 item.
21. water injection by the method preparation of any one in the above 14-18 item.
When water-bearing media was water, this water injection contained the ethanol that is selected from of 5-28wt%, and 1, the 2-propylene glycol, 1, one or more alcohols (lower alcohols) in ammediol and the glycerol, this alcohol are to add as raw material in the preparation of water injection.When water-bearing media is the ethanol that is selected from that for example contains 10-40wt%, 1, the 2-propylene glycol, 1, during the aqueous solution of one or more alcohols in ammediol and the glycerol, then no longer add this alcohols as raw material.Certainly, use some surfactant for example during castor oil hydrogenated polyoxyethylene ether (Cremophor RH40 or Cremophor RH60), can not use this lower alcohols or use more a spot of this lower alcohols, because these surfactants are very strong to the emulsifying capacity of active component.
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.
Obtain volatile oil by common steam distillation or CO2 supercritical process from the Rhizoma Curcumae Longae rhizome.Following preparation example adopts these volatile oil.
Preparation example 1:
The preparation method of turmeric oil extract (sesquiterpene ketone)
(aryl turmerone, turmerone and aryl turmerone derivant three's content 〉=15wt%) is raw material with the 1000ml Rhizoma Curcumae Longae volatile oil, refining through the Guangzhou Han Wei MD-S80 of mechanical ﹠ electrical corporation type molecular distillation instrument, its process conditions: 35～45 ℃ of vapo(u)rizing temperatures, distillation pressure 70～90Pa, 300-320 rev/min of knifing speed, 20～25 ℃ of cryosurface temperature, 20～25 ℃ of system's insulations, 15～30 milliliters/hour of material flows, obtain distillation, only collect and heat up in a steamer excess, run up to q.s (about 450ml), proceed molecular distillation.45～60 ℃ of vapo(u)rizing temperatures, distillation pressure 30～70Pa, 300-320 rev/min of knifing speed, 20～25 ℃ of cryosurface temperature, 20～25 ℃ of system's insulations, 15～30 milliliters/hour of this fraction flow velocitys are collected the 150ml distillation respectively and are heated up in a steamer excess with about 300ml, the secondary that obtains is heated up in a steamer excess run up to q.s (750ml), proceed molecular distillation.30～70 ℃ of vapo(u)rizing temperatures, distillation pressure 10～50Pa, 300-320 rev/min of knifing speed, 20～25 ℃ of cryosurface temperature, 20～25 ℃ of system's insulations, 15～30 milliliters/hour of this fraction flow velocitys, collect distillation (320ml), bleed off and heat up in a steamer excess, add to again and continue to repeat distillation in the molecular distillation instrument slipping out thing until (be about 25 meters long capillary gas chromatograph-mass spectrometer (GC-MS): Bio-RadFTS-65A with gas chromatograph, HP5890II, chromatographic column: till gross activity component content 〉=75wt%, obtain 150ml turmeric oil extract when BP-5) detecting.This extract detects through above-mentioned gas chromatograph, contains the active component of 75.5wt%, i.e. aryl turmerone, turmerone and aryl turmerone derivant.Formulate for the detection finger printing with gas chromatography.It is to contain the fraction that carbonyl is the master that DB1, BP5 or DB5 capillary chromatographic column detect, and fixative is that capillary column chromatography has three main peaks when gathering (5% phenyl) dimethyl siloxane, from left to right corresponds respectively to aryl turmerone, turmerone and aryl turmerone derivant.This extract is used for the following examples.
Preparation example 2: use with preparation example in identical raw material be Rhizoma Curcumae Longae volatile oil, according to the same procedure in the preparation example 1, be only to cut branch at the peak of aryl turmerone, obtained containing the turmeric oil extract of 95.5wt% aryl turmerone of having an appointment.In order to prepare the Western medicine injection, can use the turmeric oil extract of preparation example 2, identical among the preparation method of injection and the following embodiment.
In accompanying drawing 1, provided the dactylogram of the turmeric oil extract of preparation example 1.The turmeric oil extract that has provided preparation example 1 in accompanying drawing 2 is having the dactylogram after depositing 3 months in the presence of the air.Capillary chromatography fixative title wherein: polydimethylsiloxane or poly-(5% phenyl) dimethyl siloxane, commodity post title DB1, DB-5 or BP5 etc.The variation of the peak heights in two dactylograms has reflected that turmerone is partially converted to more stable aryl turmerone.And, regulate pH value to acid or alkaline, can quicken this conversion.
The employed gas chromatograph-mass spectrometer (GC-MS) of chromatography in this application is: Bio-Rad FTS-65A, HP5890II, capillary chromatographic column (30 * 0.25mm * 0.25 μ m) is: DB1 (fixative is a polydimethylsiloxane), (fixative is poly-(5% phenyl) dimethyl siloxane for BP-5 or DB5.
The GC/MC parameter:
(GC)
Col.：DB-1MS(30m×0.25mm×0.25μm)；Col.Temp.：100℃(2min)--8℃/min--200℃(2min)
Inj.Temp.：230℃；Inj.Mode：split(10∶1)；Inj.Volume：10μl；Carrier gas：He；Column flow：1ml/min
(EIMS)70eV
Mass Range：33-500 Scan Rate：1000amu/s
Interface Temp.：230℃ Solvent：CHCl
3
Solvent Cut Time：4.0min Start time：4.2min
Detector：1.00Kv
Chromatographic peak in its dactylogram formation is resolved through gas chromatography mass spectrometry, finds to have aryl turmerone:
Turmerone:
With the aryl turmerone derivant that contains enol or phenolic hydroxyl structure.
It is worthy of note that as can be seen, three peaks obviously separate from accompanying drawing, can intercept each main component respectively basically, or intercepting two kinds of main components wherein.
Owing to find the effect that their threes have the good restraining tumor in the present invention,, operate and seem simpler, more easily so the three is split.
The preparation method of embodiment 1. turmeric oil extract (tween 80) injection
Take by weighing turmeric oil extract 200g and be dissolved in the 2000g tween 80 (Tween-80), be stirred to evenly.Add 30 ℃～60 ℃ pharmaceutical purpose distilled water to 20 then, 000ml, the limit edged stirs, and is dissolved in the distilled water fully up to turmeric oil extract, tween 80 mixture.Use filtering with microporous membrane, fill in the peace bottle of nitrogen with the filling apparatus branch 20ml that packs into, steam sterilization is 30 minutes under 112 ℃～115 ℃ conditions, and cooling is after jolting makes it clear and bright.Yet, randomly, through pyrogen test, lamp inspection, the turmeric oil extractive content (every bottle of about 0.2g turmeric oil extract, by Rhizoma Curcumae Longae extract, down with) after check is all qualified, warehouse-in.
The preparation method of embodiment 2. turmeric oil extract (tween 80) glucose infusion liquids
Get 200g turmeric oil extract and mix with 2000g Tween 80 (Tween-80), make it mixing, then 30 ℃～60 ℃ of it addings are supplied in the pharmaceutical purpose distilled water, the limit edged stirs and makes final volume is 125,000ml.
Cofabrication 10% glucose solution 125,000ml mixes two solution stirring, and through filtering with microporous membrane, in the 250ml infusion bottle through filling nitrogen of packing into, through 110 ℃～115 ℃ sterilizations 40 minutes, sterilization back jolting was placed into clear and bright.Then, randomly, through pyrogen, content (every bottle of 0.2g turmeric oil extract, glucose 12.5g), clarity, it is qualified that particulate matter detects, warehouse-in.
The preparation method of embodiment 3. turmeric oil extract (tween 80) glucose infusion liquids
Get 200g turmeric oil extract and mix with 2000g tween 80 (Tween-80), make it mixing, then 30 ℃～60 ℃ of it addings are supplied in the pharmaceutical purpose distilled water, the limit edged stirs and makes final volume is 250,000ml.
Cofabrication 10% glucose solution 250,000ml mixes two solution stirring, through filtering with microporous membrane, in the 250ml infusion bottle of packing into, through 110 ℃～115 ℃ sterilizations 40 minutes through filling nitrogen, sterilization back jolting, be placed into clear and bright, through pyrogen, content (every bottle of 0.1g turmeric oil extract, glucose 12.5g), clarity, it is qualified that particulate matter detects, warehouse-in.
The preparation method of embodiment 4. turmeric oil extracts (cremophor EL propylene glycol) injection.
Getting the cremophorEL that 200g turmeric oil extract and 1800g be heated to 50-60 ℃ mixes, fully stir, adding 1600g propylene glycol (proportion is 1) then is stirred to clear and bright fully, add again and be preheated to 50～60 ℃ of waters for injection to 10,000ml, be stirred to homogenizer clear and bright, filtering with microporous membrane.Yet randomly, embedding is in filling nitrogen 10ml peace bottle, and 100 ℃ were rotated steam sterilization 30 minutes, through pyrogen, and content (approximately 2wt% turmeric oil extract), clarity is up to the standards, warehouse-in.
The preparation method of embodiment 5. turmeric oil extracts (cremophor EL, cremophor RH40 propylene glycol) injection:
Get 200g turmeric oil extract and mix, fully stir, add 600ml propylene glycol (proportion 1), be stirred to clear and bright fully with the cremophor EL (1600g) and the cremophor RH40 (1600g) that are heated to 60 ℃.Add again and be preheated to 50～60 ℃ of waters for injection to 10,000ml, be stirred to homogenizer half clear and bright, filtering with microporous membrane.Then, embedding is in filling nitrogen 10ml peace bottle, and 100 ℃ were rotated steam sterilization 30 minutes, through pyrogen, and content (about 2wt% turmeric oil extract), clarity is up to the standards, warehouse-in.
Embodiment 6. turmeric oil extracts (cremophor RH40, cremophorRH60) preparation method of injection:
Mix in getting 200g turmeric oil extract (sesquiterpene ketone chemical compound) and all being heated to 60 ℃ 1700g cremophor RH40 and 1700g cremophor RH60, be stirred well to half clear and bright.Add and be preheated to 50～60 ℃ of waters for injection to 10,000ml is stirred to clear and bright or half clear and bright with homogenizer, filtering with microporous membrane.Embedding is in filling nitrogen 10ml peace bottle, and 100 ℃ were rotated steam sterilization 30 minutes, through pyrogen, and content, clarity is up to the standards, warehouse-in.
The preparation method of embodiment 7. turmeric oil extracts (cremophor EL) glucose infusion liquid:
Get 200g turmeric oil extract (sesquiterpene ketone chemical compound) and mix, fully stir, add the 1600g propylene glycol then, be stirred well to partly clear and bright with the 1800g cremophor EL that all has been heated to 60 ℃.Add and be preheated to 50～60 ℃ of waters for injection to 50,000ml is stirred to clear and bright or half clear and bright with homogenizer, mixes filtering with microporous membrane with the 50000ml D/W that contains 10% glucose.Embedding in filling nitrogen 250ml infusion bottle, 112-115 ℃ of rotation steam sterilization 40 minutes, through pyrogen, content (0.2% turmeric oil extract, 12.5g glucose, promptly 5%), clarity is up to the standards, warehouse-in.
The preparation method of embodiment 8. turmeric oil extracts (cremophor EL)-ethanol injection liquid:
According to embodiment 4, just the ethanol with equivalent replaces propylene glycol.Can prepare turmeric oil extract (cremophorEL)-ethanol injection liquid.
Anaphylaxis appears when indivedual allergic constitution patients use this medicine, use this medicine before, should do skin test or an amount of hormone to alleviate anaphylaxis.
The test of pesticide effectiveness :-turmeric oil extract injection antitumor curative effect test
The cancer resistant effect of turmeric oil extract (tween 80) injection and turmeric oil extract glucose infusion liquid:
The turmeric oil extract injection with intravenous route with 40,20 and 10mg/kg (high, medium and low dosage) administration, once a day, continuous 10 days dosage regimen, in the body human tumor heteroplastic transplantation model antitumor curative effect is tested: to the curative effect of human body glioma brain tumour SHG-44 (axil subcutaneous vaccination), the result shows, the suppression ratio of high dose group is 41.30-45.60%, and the suppression ratio of middle dosage group is 35.87-39.78%, and the suppression ratio of low dose group also can reach 28.26～33.33%.40mg/kg treats with same approach with reference to the comparable group Elemenum Emulsion, and its suppression ratio is 36.41～41.33%.To the curative effect of human body adenocarcinoma of lung LAX (intravenous inoculation), the suppression ratio of high dose group is 40.00～44.94% in the body, and middle dosage group is 29.92～32.40%, low dose group 22.63～24.75%.Elemenum Emulsion 40mg/kg with reference to comparable group treats with same approach, and its suppression ratio is than test group low 10%.
Test shows in the turmeric oil extract injection body all has certain antitumor curative effect to human tumor heteroplastic transplantation model SHG-44, LAX, more responsive to the former, and has certain dose-effect relationship, and the clinical experimental data that provides is provided.
Table 1: turmeric oil extract (tween 80) injection (the injection product of embodiment 1) to the clinical trial of SHG-44 human body glioma brain tumour (subcutaneous vaccination) it
| Sample | Dosage mg/kg | Dosage regimen | Number of animals beginning/end (only) | Suppression ratio % |
| The turmeric oil extract injection | 40 | iv×10 | 6/6 | 45.42 |
| The turmeric | 20 | iv×10 | 6/6 | 39.23 |
| The turmeric | 10 | iv×10 | 6/6 | 32.12 |
| Matched group | Coordinative solvent | iv×10 | 12/12 |
Table 2: turmeric oil extract (cremophor EL propylene glycol) injection (product of embodiment 4) is to two of the clinical trial of SHG-44 human body glioma brain tumour (subcutaneous vaccination):
| Sample | Dosage mg/kg | Dosage regimen | Number of animals beginning/end (only) | Suppression ratio % |
| The turmeric oil extract injection | 40 | iv×10 | 6/6 | 45.58 |
| The turmeric | 20 | iv×10 | 6/6 | 38.46 |
| The turmeric | 10 | iv×10 | 6/6 | 32.10 |
| Matched group | Coordinative solvent | iv×10 | 12/12 |
Table 3: turmeric oil extract (cremophor EL propylene glycol) injection (product of embodiment 4) is to one of clinical trial of LAX human body adenocarcinoma of lung (intravenous inoculation):
| Sample | Dosage mg/kg | Dosage regimen | Number of animals beginning/end (only) | Suppression ratio % |
| The turmeric oil extract injection | 40 | iv×10 | 6/6 | 41.36 |
| The turmeric |
20 | iv×10 | 6/6 | 32.46 |
| The turmeric |
10 | iv×10 | 6/6 | 24.64 |
| Matched group | Coordinative solvent | iv×10 | 12/12 |
Table 4: turmeric oil extract (tween 80) glucose injection (product of embodiment 2) shifts the clinical trial result to murine melanoma B16 experiment lung:
| Sample | Dosage mg/kg | Dosage regimen | Number of animals beginning/end (only) | Suppression ratio % |
| The turmeric oil extract injection | 40 | iv×10 | 10/10 | 57.22 |
| The turmeric | 20 | iv×10 | 10/10 | 44.84 |
| The turmeric | 10 | iv×10 | 10/10 | 40.32 |
Table 5: Rhizoma Curcumae Longae extract (Cremophor EL propylene glycol) injection (product of embodiment 4) is to testing the excretory influence of rat bile (intravenously administrable):
| Sample | Dosage mg/kg | Dosage regimen | Number of animals beginning/end (only) | Secretion increment rate % |
| The turmeric oil extract injection | 35 | iv×10 | 6/6 | 30.46 |
| The turmeric oil extract injection | 25 | iv×10 | 6/6 | 25.33 |
| The turmeric oil extract injection | 15 | iv×10 | 6/6 | 5.54 |
| Matched group (sodium dehydrocholate) | iv×10 | 12/12 | 30.81 |
Table 6: Rhizoma Curcumae Longae extract (Cremophor EL propylene glycol) injection (product of embodiment 4) is to testing the excretory influence of rat bile (duodenal administration):
| Sample | Dosage mg/kg | Dosage regimen | Number of animals beginning/end (only) | Secretion increment rate % |
| The turmeric oil extract injection | 35 | 10 days | 6/6 | 40.68 |
| The turmeric oil extract injection | 25 | 10 days | 6/6 | 31.16 |
| The turmeric oil extract injection | 15 | 10 days | 6/6 | 17.23 |
| Matched group (sodium dehydrocholate) | 10 |
12/12 | 33.36 |
Note:
In the present invention, injection adopts the anti-tumor experiment method of pharmacological room of Shanghai Institute of Pharmaceutical Industry (the application's most experimental result entrusts them to finish) to estimate to the antitumor curative effect of tumor models such as B16 murine melanoma experiment lung transfer, this method is the method (method of National Drug Administration's regulation) of generally acknowledging in the domestic field of antineoplastic medicaments of China at present, and method is specific as follows carries out:
Get the B16 murine melanoma cultured cell of In vitro culture exponential phase under the aseptic condition, be prepared into 2.5 * 10
5/ ml cell suspension is from the every Mus (5 * 10 of C57BL/6 mouse tail vein inoculation 0.2ml/
4Individual cell), press the experimental program administration after 24 hours; Each treated animal of three week of test back execution cuts open and gets each treated animal lungs, and the colony number that the every Mus lungs of instrumentation are shifted with the average colony number of each group tumor, calculates tumor control rate by following formula:
The average colony number of the tumor control rate %=[(matched group-average colony number of administration group)/the average colony number of matched group] * 100
The tumor source: mice B16 melanoma cell goes down to posterity by pharmacological room of Shanghai Institute of Pharmaceutical Industry and keeps.
Laboratory animal: C57BL/6 and Kunming mouse are provided by Shanghai Chinese Academy of Sciences Experimental Animal Center, the quality certification number: No. the 107th, the moving quality certification in Shanghai.Body weight: 18-20 gram.Male and female all can, same sex is used in every batch of experiment.Every group 10.
Dosage regimen: intravenously administrable, every day 1 time, continuous 10 days.Matched group gives blank Emulsion, and it is the injection that does not contain active component corresponding to each injection.
So 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, and promotes bile secretion.
Claims (13)
1. turmeric oil extract water injection, it is with the turmeric oil extract that contains active component, surfactant and water-bearing media are as feedstock production, this turmeric oil extract that contains active component be through the rectifier unit rectification of vacuum material filling type or molecular distillation instrument refining from turmeric oil separate obtain and comprise 〉=aryl turmerone and turmerone and the aryl turmerone derivant of 70wt%, the HPLC collection of illustrative plates of aryl turmerone derivant that wherein contains enol or phenolic hydroxyl structure is shown in accompanying drawing 1 collection of illustrative plates, this surfactant is medicinal non-ionic surface active agent, aryl turmerone in the injection, turmerone and aryl turmerone derivant three's total concentration is 0.03～4wt%, and the content of non-ionic surface active agent is 10%-40wt%.
2. according to the water injection of claim 1, wherein the concentration of aryl turmerone described in the injection is 0.03～3wt%.
3. according to the water injection of claim 1, wherein this turmeric oil extract that contains active component comprises the aryl turmerone as active component of 95wt% at least.
4. according to the water injection of claim 1, wherein water-bearing media is a water.
5. according to the water injection of claim 1, it is clear and bright or is half clear and bright.
6. according to each water injection in the claim 1,5 and 6, the turmeric oil extract that wherein contains active component be from turmeric oil separate obtain and comprise the aryl turmerone of 95wt% at least as active component.
7. according to the water injection of claim 1, wherein surfactant is the non-ionic surface active agent of Polysorbate type and/or polyoxyethylene-type.
8. according to the water injection of claim 1 or 8, wherein surfactant is castor oil polyoxyethylene ether and/or castor oil hydrogenated polyoxyethylene ether.
9. according to the water injection of claim 1 or 8, it also contains the ethanol that is selected from of 5-28wt%, and 1,2-propylene glycol, 1, one or more alcohols in ammediol and the glycerol.
10. the preparation method of turmeric oil extract water injection, it comprises the turmeric oil extract that contain active component of mixing as raw material, surfactant and water-bearing media, this turmeric oil extract that contains active component be through the rectifier unit rectification of vacuum material filling type or molecular distillation instrument refining from turmeric oil separate obtain and comprise 〉=aryl turmerone and the turmerone of 70wt%, this surfactant is medicinal non-ionic surface active agent, the consumption of non-ionic surface active agent is that the basis is about 10%-40wt% in final injection weight, and this turmeric oil extract that contains active component is so that the concentration of aryl turmerone is that consumption use of 0.02～4wt% in this injection.
11. according to the preparation method of claim 11, wherein water-bearing media is a water.
12. according to the preparation method of claim 11, also mixed the ethanol that is selected from as raw material, 1,2-propylene glycol, 1, one or more alcohols in ammediol and the glycerol.
13. the purposes that the water injection of any one is used to prepare the medicine of inhibition or treatment cancer or is used to prepare the medicine that increases bile secretion among the claim 1-10.
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| CN 03153226 CN1302769C (en) | 2003-08-08 | 2003-08-08 | Curcuma oil extract injection aqueous solution and preparation method and application thereof |
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| CN 03153226 CN1302769C (en) | 2003-08-08 | 2003-08-08 | Curcuma oil extract injection aqueous solution and preparation method and application thereof |
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| CN1302769C true CN1302769C (en) | 2007-03-07 |
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| PT1890546T (en) | 2005-05-30 | 2019-01-23 | Antony Benny | Method for improving the bioavailability of curcumin |
| US12053438B2 (en) | 2005-05-30 | 2024-08-06 | Arjuna Natural Private Limited | Formulation of curcuminoids with enhanced bioavailability of curcumin, demethoxycurcumin, bisdemethoxycurcumin and method of preparation and uses thereof |
| US10543277B2 (en) | 2005-05-30 | 2020-01-28 | Arjuna Natural Private Limited | Formulation of curcumin with enhanced bioavailability of curcumin and method of preparation and treatment thereof |
| US10286027B2 (en) | 2005-05-30 | 2019-05-14 | Arjuna Natural Extracts, Ltd. | Sustained release formulations of curcuminoids and method of preparation thereof |
| JP5578822B2 (en) * | 2009-09-25 | 2014-08-27 | 株式会社ピカソ美化学研究所 | Acetylcholinesterase inhibitor |
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