CN100434066C - Curcuma longa extract injection, and preparing process and use thereof - Google Patents
Curcuma longa extract injection, and preparing process and use thereof Download PDFInfo
- Publication number
- CN100434066C CN100434066C CNB02117217XA CN02117217A CN100434066C CN 100434066 C CN100434066 C CN 100434066C CN B02117217X A CNB02117217X A CN B02117217XA CN 02117217 A CN02117217 A CN 02117217A CN 100434066 C CN100434066 C CN 100434066C
- Authority
- CN
- China
- Prior art keywords
- injection
- extract
- preparation
- dosage form
- liposome
- 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
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Images
Abstract
The present invention relates to a novel injection of curcuma longa extracts, particularly to a nanometer liposome injection, a proliposome injection, a long circulating liposome injection, a long circulating nanometer liposome injection, the nanometer slight emulsion, the vein emulsion, a lipid nanosphere injection and the fat emulsion of the curcuma longa extracts.
Description
Technical field:
The present invention relates to the new injection type of Rhizoma Curcumae Longae extract, 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.
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, 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 curcuma longa extract injection, it contains: the extract with total sesquiterpene alkene class content 〉=70wt% that extracts from curcuma plant, surfactant, and water-bearing media, this injection is a kind of aqueous dispersion, the mean diameter of decentralized photo≤1 micron, the amount of surfactant is the 1-5wt% of total injection, the concentration of total sesquiterpene alkene class (active component) is 1-10mg/ml in injection.More preferably, this water-bearing media is a water.
Another object of the present invention provides the new injection type of Rhizoma Curcumae Longae extract, liposome dosage form more specifically to this extract, 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.
The invention provides the novel form of these medicines.Be prepared into its nanometer liposome dosage form with Rhizoma Curcumae Longae extract respectively as raw material, 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 bisabolene isomer body 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 various raw materials that are 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 and 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 the present invention as specific embodiment, with RADIX CURCUMAE Curcuma wenyujin Y.H.Chen et C.Ling volatile oil, citronella oil Cymbopoqon citratus (DC.) Stapt submember (citronella oil is removed the remaining afterwards mixing grease of citral, citronellol) is raw material, makes with extra care out elemene through material filling type vacuum rectifying apparatus or molecular distillation instrument.
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 for example 30 meters long capillary gas chromatograph-mass spectrometer (GC-MS) (chromatographs: Bio-Rad FTS-65A of the higher chromatographic apparatus of sensitivity, HP5890II, chromatographic column: BP-5) 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, Rhizoma Curcumae Longae extract refers to that Rhizoma Curcumae Longae volatile oil 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, detects through GC-MS, and Rhizoma Curcumae Longae extract contains sesquiterpene and a spot of curcumin of main amount.
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 raw material is a Rhizoma Curcumae Longae extract, and its total sesquiterpene alkene class content 〉=70wt% it is desirable to 75wt%, and is preferred 〉=80wt%, more preferably 〉=and 85wt%, preferred 〉=90wt%, more preferred 〉=95wt% especially.This extract contains≤curcumin of 28wt%, contain ideally≤curcumin of 15wt%, and preferably contain≤curcumin of 10wt%, more preferably contain≤curcumin of 5wt%.
Use 30 meters long capillary gas chromatograph-mass spectrometer (GC-MS) Detection and Extraction things described here, contain 〉=extract of 70wt% sesquiterpene just can be used among the present invention.Employed Rhizoma Curcumae Longae extract 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 be as required oneself preparation, for the preparation method of Rhizoma Curcumae Longae extract referring to preparation example.
Employed Rhizoma Curcumae Longae extract raw material, reagent have no particular limits among the application, as long as this extract is to extract from the natural plants Rhizoma Curcumae Longae and total sesquiterpene alkene class purity 〉=70wt% just can use in the present invention, better is, this purity 〉=75wt%, better 〉=80wt%, preferably 〉=85wt%, preferred 〉=90wt% especially.
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 the employed gas chromatograph of chromatography in this application is: Bio-Rad FTS-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, 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, 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: the preparation of Rhizoma Curcumae Longae extract
Preparation method A: the molecular distillation of Rhizoma Curcumae Longae volatile oil
With the Rhizoma Curcumae Longae volatile oil is raw material, 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, 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 distillation respectively and are heated up in a steamer excess, the secondary that obtains is heated up in a steamer excess run up to q.s, 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, 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 (utilize the detections of 30 meters long capillary gas chromatograph-mass spectrometer (GC-MS) gas chromatograpies with gas chromatograph, chromatograph: Bio-Rad FTS-65A, HP5890II, chromatographic column: when BP-5) detecting till total sesquiterpene alkene content 〉=75wt%.This extract detects through above-mentioned gas chromatograph, also contains about 1/20 the curcumin that is equivalent to whole sesquiterpene gross weights.Formulate for the detection finger printing with gas chromatography.This products known as Rhizoma Curcumae Longae extract A.
Preparation method B: material filling type rectification under vacuum
With Rhizoma Curcumae Longae volatile oil through the rectification of material filling type vacuum rectifying apparatus; the material filling type vacuum rectifying apparatus is by the still of dress Rhizoma Curcumae Longae volatile oil; stuffing rectification column; return channel; vacuum pump constitutes; design by new packing technology development center of Shanghai Chemical Research Inst; filler is Dixon filler (a Q net ring filler); vacuum is 1-3mmHg; collect the above fraction of 82 ℃/3mmHg; (utilize 30 meters long capillary gas chromatograph-mass spectrometer (GC-MS) gas chromatograpies to detect through gas chromatograph; chromatograph: Bio-Rad FTS-65A; HP5890II, chromatographic column: BP-5) analyzing is sesquiterpenoid.Total sesquiterpene alkene content 〉=75wt% also contains about 1/20 the curcumin that is equivalent to whole sesquiterpene gross weights.Formulate for the detection finger printing with gas chromatography.This products known as Rhizoma Curcumae Longae extract B.
In addition, with Rhizoma Curcumae Longae through CO
2The slag that the volatile oil that supercritical extraction obtains stays adds methanol, and the heating extracting obtained yellow viscous solution in 3 hours, methanol is distilled, obtain pale brown color paste,, obtain the curcumin product of purity 〉=90wt% with the chloroform eluting these pastes preparation of silica gel chromatogram purification.Above-mentioned product A and product B are mixed with 50: 50 weight ratios, formed mixture is mixed in the ratio of 20: 1 (weight) with this curcumin product and obtain another kind of mixture, be called extract C.
Embodiment 1: the preparation of the nano-lipid body injection of Rhizoma Curcumae Longae extract
Program 1A: with the product A and the refining soybean phospholipid of preparation example, 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 is 5 ± 0.10mg/ml with the ultimate density that gas chromatography (utilizing 30 meters long capillary gas chromatograph-mass spectrometer (GC-MS) gas chromatograpies) records active component (weight (mg) of total sesquiterpene alkene active component/volumes of formulation (ml)).
Detect envelop rate with sieve method, promptly, utilize Sephadex G25 tomographic system that the extract nano-liposome preparation is divided into two stream parts, promptly extract nano-liposome stream part and free extract flow part are detected the extractive content that contains in two stream parts through gas chromatograph.Envelop rate surpasses 85%.The extractive content ÷ of envelop rate computing formula=extract nano-liposome stream part [extractive content+free extract amount of extract nano-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 product A of preparation example with the product B of preparation example.Microscope, transmission electron microscope detect, and confirm that preparation is a nanometer liposome.The concentration of total sesquiterpene alkene class 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 Rhizoma Curcumae Longae extract
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.Envelop rate is higher than 85%.Said preparation added injection water before injection is used be 5 ± 0.10mg/ml to reach final active component (total sesquiterpene alkene class) concentration.
2B: repeating above-mentioned 2A, just replace the product A of preparation example with the B product of preparation example, 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 (mg) of total sesquiterpene alkene class/volumes of formulation (ml)).
Embodiment 3: the preparation of the long-circulating nanoliposome of Rhizoma Curcumae Longae extract
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: Rhizoma Curcumae Longae extract A: 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 sesquiterpene alkene class is 5 ± 0.10mg/ml in the preparation.Envelop rate is higher than 85%.
3B: repeat above-mentioned 3A, just replace the product A of preparation example with the product B of preparation example.The injection that is obtained is called for short 3B.Mean diameter≤100nm.The ultimate density of total sesquiterpene alkene class 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 Rhizoma Curcumae Longae extract
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 sesquiterpene alkene class 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: extract A: 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 sesquiterpene alkene class 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 product A of preparation example with the product B of preparation example.The ultimate density that sampling records total sesquiterpene alkene class 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 product A of preparation example with the product B of preparation example.The ultimate density that sampling records total sesquiterpene alkene class 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 Rhizoma Curcumae Longae extract
5A: the extract A of getting preparation example 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: extract 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 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 sesquiterpene alkene class 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 product A of preparation example with the product B of preparation example.Mean diameter≤the 100nm of lipid ball.The ultimate density that chromatography records total sesquiterpene alkene class 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 Rhizoma Curcumae Longae extract
6A: the Rhizoma Curcumae Longae extract A of preparation example, 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 Rhizoma Curcumae Longae extract vein breast, the ultimate density that sampling records total sesquiterpene alkene class is 5 ± 0.10mg/ml.This injection is called for short 6A.
6B: repeat above 6A, just replace the product A of preparation example with the product B of preparation example.Check particle diameter less than 1 micron with the Coulter instrument.The ultimate density of total sesquiterpene alkene class is 5 ± 0.10mg/ml in the preparation.The injection that is obtained is called for short 6B.
Embodiment 7: the preparation of Rhizoma Curcumae Longae extract fat milk
7A: product A and the soybean phospholipid of getting preparation example 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: extract A 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 sesquiterpene alkene class 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 product A of preparation example with the product B of preparation example.The ultimate density that records total sesquiterpene alkene class 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 extract A adding of soybean phospholipid and preparation example is wherein mixed (extract A: 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≤1 of liposome micron (being called liposome), or as required, ultrasonic Treatment is until till particle diameter of dispersing phase≤100 nanometers (being called nanometer liposome).Then liposome is regulated PH with 1M biphosphate sodium water solution, 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 sesquiterpene alkene class.Envelop rate is higher than 88%.
8B: repeat above-mentioned 8A, just replace the product A of preparation example, make liposome with the product B of preparation example.The ultimate density that records total sesquiterpene alkene class in preparation is 5 ± 0.10mg/ml.The injection that is obtained is called for short 8B.Envelop rate is higher than 88%.
8C: repeat above-mentioned 8A, just replace the product A of preparation example, make liposome with the extract C of preparation example.The ultimate density that records total sesquiterpene alkene class in preparation is 5 ± 0.10mg/ml.The injection that is obtained is called for short 8C.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 (sesquiterpene)/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 | 30.6％ | 40 | 39.3％ | 80 | 45.6％ |
| 1B | 20 | 30.0％ | 40 | 39.1％ | 80 | 45.0％ |
| 2A | 20 | 30.1％ | 40 | 37.4％ | 80 | 44.0％ |
| 2B | 20 | 30.0％ | 40 | 38.4％ | 80 | 43.2％ |
| 3A | 20 | 29.2％ | 40 | 39.2％ | 80 | 44.4％ |
| 3B | 20 | 29.8％ | 40 | 38.2％ | 80 | 44.5％ |
| 4A-1 | 20 | 30.5％ | 40 | 38.4％ | 80 | 46.0％ |
| 4A-2 | 20 | 31.2％ | 40 | 37.9％ | 80 | 46.6％ |
| 4B-1 | 20 | 30.6％ | 40 | 37.5％ | 80 | 45.3％ |
| 4B-2 | 20 | 29.5％ | 40 | 38.2％ | 80 | 44.9％ |
| 5A | 20 | 29.3％ | 40 | 38.7％ | 80 | 44.3％ |
| 5B | 20 | 29.4％ | 40 | 38.2％ | 80 | 44.4％ |
| 6A | 20 | 29.8％ | 40 | 37.8％ | 80 | 43.6％ |
| 6B | 20 | 29.5％ | 40 | 37.9％ | 80 | 43.4％ |
| 7A | 20 | 29.6％ | 40 | 37.5％ | 80 | 44.0％ |
| 7B | 20 | 29.2％ | 40 | 37.6％ | 80 | 43.6％ |
| 8A | 20 | 29.5％ | 40 | 37.5％ | 80 | 44.0％ |
| 8B | 20 | 29.6％ | 40 | 37.6％ | 80 | 43.6％ |
| 8C | 20 | 29.5％ | 40 | 37.2％ | 80 | 44.6％ |
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 | 45.6％ |
| 1B | 20 | 29.1％ | 40 | 39.1％ | 80 | 45.0％ |
| 2A | 20 | 29.3％ | 40 | 37.4％ | 80 | 44.0％ |
| 2B | 20 | 28.5％ | 40 | 38.4％ | 80 | 43.2％ |
| 3A | 20 | 29.1％ | 40 | 39.2％ | 80 | 44.4％ |
| 3B | 20 | 29.0％ | 40 | 38.2％ | 80 | 44.5％ |
| 4A-1 | 20 | 29.5％ | 40 | 38.4％ | 80 | 46.0％ |
| 4A-2 | 20 | 29.4％ | 40 | 37.9％ | 80 | 46.6％ |
| 4B-1 | 20 | 28.8％ | 40 | 37.5％ | 80 | 45.3％ |
| 4B-2 | 20 | 28.3％ | 40 | 38.2％ | 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 | 47.2％ | 40 | 59.4％ | 80 | 68.6％ |
| 1B | 20 | 46.8％ | 40 | 59.6％ | 80 | 68.4％ |
| 2A | 20 | 47.6％ | 40 | 57.2％ | 80 | 64.0％ |
| 2B | 20 | 48.6％ | 40 | 56.3％ | 80 | 63.2％ |
| 3A | 20 | 49.4％ | 40 | 59.2％ | 80 | 67.4％ |
| 3B | 20 | 48.5％ | 40 | 58.3％ | 80 | 66.5％ |
| 4A-1 | 20 | 49.3％ | 40 | 58.5％ | 80 | 67.0％ |
| 4A-2 | 20 | 49.5％ | 40 | 57.7％ | 80 | 67.6％ |
| 4B-1 | 20 | 48.2％ | 40 | 57.6％ | 80 | 66.3％ |
| 4B-2 | 20 | 49.3％ | 40 | 58.5％ | 80 | 67.9％ |
| 5A | 20 | 49.8％ | 40 | 58.7％ | 80 | 68.3％ |
| 5B | 20 | 47.8％ | 40 | 58.3％ | 80 | 65.4％ |
| 6A | 20 | 47.2％ | 40 | 56.8％ | 80 | 63.6％ |
| 6B | 20 | 46.9％ | 40 | 56.9％ | 80 | 63.4％ |
| 7A | 20 | 48.6％ | 40 | 56.5％ | 80 | 66.0％ |
| 7B | 20 | 46.8％ | 40 | 56.6％ | 80 | 63.6％ |
Table 4: to the curative effect (tumour inhibiting rate) of subcutaneous vaccination mice cerebroma G422 model.
| Injection | Dosage | Tumour inhibiting rate | Dosage | Tumour inhibiting rate | Dosage | Tumour inhibiting rate |
| (mg/kg) | (mg/kg) | (mg/kg) | ||||
| 1A | 20 | 23.1％ | 40 | 29.8％ | 80 | 35.5％ |
| 1B | 20 | 23.0％ | 40 | 29.2％ | 80 | 35.6％ |
| 2A | 20 | 22.8％ | 40 | 27.8％ | 80 | 34.0％ |
| 2B | 20 | 22.8％ | 40 | 28.4％ | 80 | 33.3％ |
| 3A | 20 | 22.9％ | 40 | 29.8％ | 80 | 34.6％ |
| 3B | 20 | 23.0％ | 40 | 28.7％ | 80 | 34.8％ |
| 4A-1 | 20 | 24.6％ | 40 | 28.1％ | 80 | 36.6％ |
| 4A-2 | 20 | 24.5％ | 40 | 27.9％ | 80 | 36.6％ |
| 4B-1 | 20 | 23.2％ | 40 | 27.8％ | 80 | 35.6％ |
| 4B-2 | 20 | 23.6％ | 40 | 28.7％ | 80 | 34.5％ |
| 5A | 20 | 23.5％ | 40 | 28.7％ | 80 | 34.8％ |
| 5B | 20 | 24.1％ | 40 | 28.2％ | 80 | 34.4％ |
| 6A | 20 | 22.5％ | 40 | 27.9％ | 80 | 33.6％ |
| 6B | 20 | 22.2％ | 40 | 27.8％ | 80 | 33.5％ |
| 7A | 20 | 22.5％ | 40 | 27.4％ | 80 | 34.1％ |
| 7B | 20 | 22.6％ | 40 | 27.3％ | 80 | 33.2％ |
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 1.5～1.45 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 1.5～1.45.
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.
Claims (12)
1. curcuma longa extract injection, it contains: the Rhizoma Curcumae Longae extract that extracts from curcuma plant, surfactant and water-bearing media is characterized in that: described Rhizoma Curcumae Longae extract contains 〉=and the extract of 80wt% sesquiterpene and sesquiterpene gross weight 1/25～1/5 curcumin;
Described injection is a kind of aqueous dispersion, the mean diameter of decentralized photo≤100 nanometers, and 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.
2. according to the curcuma longa extract injection of claim 1, it is characterized in that: the dosage form of described injection is the liposome dosage form, and the concentration of the total sesquiterpene alkene class of this injection is 2-7.5mg/ml, the envelop rate of preparation 〉=80%; Or the vein emulsion type, the concentration of the total sesquiterpene alkene class of this injection is 2-7.5mg/ml.
3. according to the curcuma longa extract injection of claim 2, it is characterized in that: described liposome dosage form is the long circulating liposomes dosage form, and described vein emulsion type is the lipid nanospheres dosage form.
4. according to the injection of claim 2, it is characterized in that: envelop rate when dosage form is liposome 〉=85%; Wherein surfactant is phospholipid and/or cholesterol.
5. according to the injection of claim 3, it is characterized in that: the concentration of the total sesquiterpene alkene class of lipid nanospheres dosage form injection is 2.0-3.0mg/ml.
6. according to the injection of claim 1 or 3, it is characterized in that: wherein injection also contains the glycerol of the penetrating agent such as oily or conduct that are selected from vegetable oil and animal oil.
7. according to the injection of claim 1 or 3, it is characterized in that: wherein when surfactant was lecithin, injection also contained C
14-C
22The straight or branched aliphatic amine.
8. the preparation method of a curcuma longa extract injection as claimed in claim 1, it may further comprise the steps:
(1), from Rhizoma Curcumae Longae volatile oil, extracts and contain 〉=Rhizoma Curcumae Longae extract of 80wt% sesquiterpene and sesquiterpene gross weight 1/25～1/5 curcumin through the rectification of material filling type vacuum rectifying apparatus or molecular distillation instrument;
(2), the Rhizoma Curcumae Longae extract that obtains with step (1) is raw material, adds surfactant, utilizes Rotary Evaporators film forming or CO
2Critical or supercritical process comes mix homogeneously, add water for injection, carry out 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 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.
9. preparation method according to Claim 8, it is characterized in that: the dosage form of described injection is the liposome dosage form, the concentration of the total sesquiterpene alkene class of this injection is 2-7.5mg/ml, the envelop rate of preparation 〉=80%; Or the vein emulsion type, the concentration of the total sesquiterpene alkene class of this injection is 2-7.5mg/ml.
10. according to the preparation method of claim 9, it is characterized in that: described liposome dosage form is the long circulating liposomes dosage form, and described vein emulsion type is the lipid nanospheres dosage form.
11. wherein also add according to Claim 8 or 10 preparation method, the glycerol of penetrating agent such as the oil that is selected from vegetable oil and animal oil or conduct with surfactant.
12. the application of the described curcuma longa extract injection of arbitrary claim in preparation inhibition or treatment cancer drug among the claim 1-7.
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| CN103040914A (en) * | 2013-01-22 | 2013-04-17 | 湖南奇异生物科技有限公司 | Preparation method of eucommia ulmoides seed oil nano emulsion injection |
| CN110051649B (en) * | 2018-01-19 | 2021-08-17 | 深圳大学 | Method for preparing lipid nanoparticles by supercritical carbon dioxide expansion solution crystallization |
Citations (4)
| 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 |
| 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 |
| CN1244389A (en) * | 1998-08-12 | 2000-02-16 | 大连科宇药业科技开发有限公司 | Elemi olefine injecta and its preparation |
| CN1062733C (en) * | 1994-07-30 | 2001-03-07 | 大连市医药科学研究所 | Liposome preparing technology and preparation thereof |
-
2002
- 2002-04-17 CN CNB02117217XA patent/CN100434066C/en not_active Expired - Lifetime
Patent Citations (4)
| 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 |
| CN1062733C (en) * | 1994-07-30 | 2001-03-07 | 大连市医药科学研究所 | Liposome preparing technology and preparation thereof |
| CN1244389A (en) * | 1998-08-12 | 2000-02-16 | 大连科宇药业科技开发有限公司 | Elemi olefine injecta and its preparation |
| 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 |
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