CN1650846B - Elemene liposome and its preparation method - Google Patents
Elemene liposome and its preparation method Download PDFInfo
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- CN1650846B CN1650846B CN 200410082866 CN200410082866A CN1650846B CN 1650846 B CN1650846 B CN 1650846B CN 200410082866 CN200410082866 CN 200410082866 CN 200410082866 A CN200410082866 A CN 200410082866A CN 1650846 B CN1650846 B CN 1650846B
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Abstract
A novel elemene lipid in the form of oral liquid, injection, perfusion, aerosol, or solid is prepared from the plant extract containing element isomer, phosphoride and cholesterol by alcohol injection method, reverse-phase distilling method, extruding method, or mechanical method. Its advantages are high distribution in liver, low distribution in kidney, high biologic utilization rate, and high target effect.
Description
Technical field: the invention belongs to medical technical field, exactly it is fat-soluble medicine elemene lipidosome and preparation method thereof.
Background technology:
Elemene is to extract the sesquiterpene mixture that obtains from Chinese medicine or certain plants, and Latin is called elemenum, English elemene by name.Elemene is for containing the mixture of a small amount of other sesquiterpenes (α-elemene, γ-elemene, δ-elemene) with beta-elemene for advocating peace.The chemical constitution of beta-elemene is 1-methyl isophthalic acid-vinyl-2,4-diisopropenyl cyclohexane extraction, and molecular formula is C
15H
24, volatility is arranged, fat-soluble strong.Elemene is used for the treatment of carcinous breast, ascites clinically, multiple cancers such as hepatocarcinoma, cervical cancer, cerebroma, pulmonary carcinoma, esophageal carcinoma.It does not damage normal cell when killing and wounding cancerous cell.A large amount of clinical researches show that during its treatment cancerous ascites pleural fluid, effect significantly is better than cisplatin.Pharmacological research shows that elemene has the effect of microcirculation improvement, leukocyte increasing level, human body immunity improving power.Elemene is a cancer therapy drug that application prospect is arranged very much.
Elemene can extract from kind of Chinese medicine surplus RADIX CURCUMAE (Curcuma Wenyujin Y.H.Chen et C.Ling also is warm Rhizoma Curcumae), Herba Cymbopogonis Citrari (Cymbopoqon Citratus (DC.) Stapt), Radix Ginseng, the Rhizoma Atractylodis Macrocephalae, Rhizoma Curcumae, Herba Pogostemonis, Myrrha, Flos Caryophylli, Atractylodes lancea (Thunb.) DC., Fructus Cnidii, Radix Saposhnikoviae, the Magnolia sieboldii etc. 60 and plant and obtain.Wherein RADIX CURCUMAE, Herba Cymbopogonis Citrari is in the china natural resources abundance, and is cheap and easy to get.
In recent years, the Anticancer Activities of natural drug more and more comes into one's own.In 1977, Oleum Curcumae just was written into Pharmacopoeia of People's Republic of China as cancer therapy drug.Nineteen eighty-three, Guo Yong etc. extract from warm Rhizoma Curcumae first and obtain elemene, and reported first elemenes such as the broom that continues in the time of afterwards have active anticancer.Elemene is strong liposoluble constituent, and is water insoluble, generally all is clinically to be made into Emulsion to use.
Patent is arranged, and (publication number: CN1076613A) relate to elemene emulsion injection and preparation method thereof, the injection that obtains is an Emulsion, and particle diameter is bigger, and mean diameter generally is no more than 15 μ m, particularly is no more than 2 μ m.Particle diameter is bigger, has vein irritating and produces pain.
Patent is arranged, and (publication number: CN1507857A) relate to elemene fat emulsion injection and preparation method, obtain fat emulsion injection, particle diameter is bigger, and pH value is higher, reaches as high as pH10, surpasses intravenous injection pH allowed band.
Patent (publication number: CN1221607A) liposoluble medicinal liposome production technology and elemene liposome injecta is arranged.Raw material after dissolving under the critical or postcritical carbon dioxide, release of carbon dioxide and add dispersion liquid lentamente then.The microporous filter membrane of crossing 1 μ m at last obtains into multilamellar liposome, and granularity is still very big
Patent (publication number: CN1244389A) relate to elemene injection and preparation method is arranged.With propylene glycol and Cremphor
EL (polyoxyethylene ricinoleidin 35) dissolving elemene obtains clear and bright solution, but propylene glycol, Cremphor
The EL consumption is all excessive, and the two consumption is respectively 7.5-14 a times of elemene amount, and 9-16 doubly.Cremphor
The EL consumption is excessive, can produce anaphylaxis (Allen Zhang J.et al.Development and characterization of a novel C remphor
EL free liposome-basedpaclitaxel (LEP-ETU) formulation.European journal of pharmaceutics andbiopharmaceutics.xx (2004) 1-11).
Patent (publication number: CN1508176A) relate to hydroxypropyl clathrate and the preparation and the preparation method of elemene is arranged, obtain the clathrate lyophilization and prepare freeze-dried powder, but lyophilization length consuming time, elemene has volatility again, and long-time vacuum freeze-drying can cause a large amount of losses of raw material.
Patent (publication number: CN1451377 A) relate to elemene injection and preparation method and purposes is arranged.Rotary Evaporators film forming and carbon dioxide are critical to be prepared with supercritical process but utilize.The former does not have the possibility of industrialized great production, and uses deleterious organic solvent such as chloroform, handles with freeze drying process equally in the preparation pro-liposome, is not suitable for elemene.
All there is deficiency in the disclosed preparation of above patent documentation at the zest and the aspects such as anaphylaxis, active anticancer of storage-stable, clinical practice.
Summary of the invention:
The purpose of this invention is to provide the new injection type of a kind of elemene, peroral dosage form, transfusion dosage form, aerosol-type is elemene lipidosome and preparation method thereof, and poor to improve the elemene oral absorption, bioavailability is low; The defective of elemene injection poor stability.Simultaneously, as the phospholipid of film material, itself is nontoxic, and can strengthen body immunity, has many health cares.Studies have shown that in a large number, phospholipid can reduce serum cholesterol, content of triglyceride, also can clean blood vessel makes its softness in the prevention of arterial sclerosis,------reperfusion injury degree is removed the risk factor of the multiple chronic pathological changes such as cardiovascular and cerebrovascular disease that arteriosclerosis causes significantly to alleviate arteriosclerosis and myocardial ischemia.Therefore phospholipid has positive prophylactic treatment effect to cardiovascular and cerebrovascular disease.
The required raw material of preparation that is used to prepare the various dosage forms of liposome among the present invention can use commercially available elemene product (elemene extract), beta-elemene product (beta-elemene extract), the Herba Cymbopogonis Citrari extract, common turmeric extract, Rhizoma Curcumae Longae extract, Rhizoma Atractylodis Macrocephalae extract, and Flos Caryophylli, Myrrha, Atractylodes lancea (Thunb.) DC., Atractylodes lancea (Thunb.) DC., Fructus Cnidii, Radix Saposhnikoviae, the extraction product of kind of plant surplus the Magnolia sieboldii etc. 60, it also can be beta-elemene, α-elemene, γ-elemene, the monomer of δ-elemene or any several mixture among them can also be the elemene and the derivant thereof of chemosynthesis.Elemene lipidosome contains the extract with total elemene content of isomer 〉=75% that extracts from plant, adjuvants such as elemene and phospholipid, cholesterol are prepared into liposome, the mean diameter≤500nm of decentralized photo.The present invention prepares the phospholipid of liposome, can be soybean lecithin, hydrogenated soya phosphatide, also can be synthetic phospholipid, and its composition comprises: elemene, phospholipid, cholesterol.The weight ratio of phospholipid and elemene is 0.4: 1～40: 1, and the weight ratio of C/PL is 0～4: 1.The ultimate density of total elemene isomer is 1～10mg/ml in the preparation.The envelop rate of liposome 〉=85%:.The dosage form that is specifically related to is elemene lipidosome, elemene sterically stabilized liposome, elemene thermal sensitive liposome, elemene thermosensitive long circulation liposome, elemene nanometer liposome, elemene long-circulating nanoliposome, elemene temperature-sensitive nanometer liposome, elemene temperature-sensitive long-circulating nanoliposome.Preparation method can adopt can industrialized great production alcohol injection, reverse phase evaporation, extrusion molding, Mechanical Method (comprising that various operating machine such as homogenizer, dispersing emulsification machine prepares the method for liposome) etc.The employed disperse medium of preparation liposome can be water, phosphate buffer, Tris buffer, carbonate buffer solution, 5% D/W etc.Can make dosage forms such as injection, transfusion, oral liquid, aerosol and solid preparation with elemene lipidosome.
Advantage of the present invention is: the distribution height of preparation in liver, and the distribution in kidney is few, the targeting effect obviously is better than the normal injection of patent 03114984.7 preparation, is beneficial to treatment of diseases.Also proved the effect of preparation by pharmacodynamics test.
The specific embodiment:
Concrete preparation method of the present invention is illustrated by following embodiment, but protection scope of the present invention is not limited to this.
Embodiment 1: get the 0.4g soybean phospholipid, 0.1g cholesterol, 0.05g elemene, an amount of V
EWith ether injection method or alcohol injection, be injected in the pH 8 Tris buffer of 10ml, promptly get elemene lipidosome.
Embodiment 2: get 0.75g soybean phospholipid, 0.25g cholesterol, 0.075g elemene, an amount of V
EWith 40ml chloroform-ether (1: 1) dissolving, place the 500ml flask, the film forming that reduces pressure on rotary film evaporator also eliminates organic solvent, adds the phosphate buffer aquation of 25ml pH7.4, gets elemene lipidosome
Embodiment 3: take by weighing 0.60g soybean phospholipid, 0.2g cholesterol, 0.075g elemene, an amount of V
EAdd the dissolving of 10ml chloroform, place the 150ml eggplant-shape bottle, the reduction vaporization chloroform forms one deck lipid membrane at the bottle inwall.Add the 5ml chloroform, the 10ml ether, add then in the phosphate buffer (pH7.4) of 15ml elemene, the bath formula made and forms the homogeneous single_phase system in ultrasonic 3 minutes, evaporation under reduced pressure removed chloroform ether is to gel formation, continued reduction vaporization 5～10 minutes, it is that liposome forms that spiral vibrates to aqueous suspension.
Embodiment 4: take by weighing 0.60g soybean phospholipid, 0.2g cholesterol, 0.1g Polyethylene Glycol
2000PHOSPHATIDYL ETHANOLAMINE, 0.05g elemene promptly get the elemene sterically stabilized liposome.
Embodiment 5: take by weighing the 0.50g synthetic phospholipid and be dipalmitoyl phosphatidyl choline DPPC and two palmityl phosphatidyl glycerol DPPG mixture (DPPC: DPPG=7: 3molar), 0.17g cholesterol, 0.03g elemene, promptly get the elemene thermal sensitive liposome.
Embodiment 6: take by weighing the 0.40g synthetic phospholipid and be dipalmitoyl phosphatidyl choline DPPC and two palmityl phosphatidyl glycerol DPPG mixture (DPPC: DPPG=7: 3molar), 0.05g cholesterol, 0.1g Polyethylene Glycol
2000PHOSPHATIDYL ETHANOLAMINE, the 0.04g elemene promptly gets the elemene thermosensitive long circulation liposome.
Embodiment 7: various elemene lipidosomes are crossed the sterilization of 0.22 μ m microporous filter membrane, fill N
2, embedding gets various elemene liposome injectas.
Embodiment 8: various elemene lipidosomes are crossed the sterilization of 100nm microporous filter membrane, fill N
2, embedding gets various elemene nanometer liposome injection.
Embodiment 9: various elemene lipidosomes are crossed the sterilization of 0.22 μ m microporous filter membrane, fill N
2, embedding gets various elemene lipidosome aerosols.
The foregoing description 3, embodiment 10, embodiment 15 samples were stablized 1 year at least 4 ℃ of placements.
Claims (3)
1. elemene lipidosome is characterized in that: get the 0.4g soybean phospholipid, 0.1g cholesterol, 0.05g elemene, an amount of V
EWith ether injection method or alcohol injection, be injected in the pH 8 Tris buffer of 10ml, get elemene lipidosome.
2. elemene lipidosome is characterized in that: get 0.75g soybean phospholipid, 0.25g cholesterol, 0.075g elemene, an amount of V
EWith the dissolving in 1: 1 of 40ml chloroform-ether, place the 500ml flask, the film forming that reduces pressure on rotary film evaporator also eliminates organic solvent, adds the phosphate buffer aquation of 25ml pH7.4, gets elemene lipidosome.
3. elemene lipidosome is characterized in that: get 0.60g soybean phospholipid, 0.2g cholesterol, 0.075g elemene, an amount of V
EAdd the dissolving of 10ml chloroform, place the 150ml eggplant-shape bottle, the reduction vaporization chloroform forms one deck lipid membrane at the bottle inwall; Add the 5ml chloroform, the 10ml ether, add then in the pH7.4 phosphate buffer of 15ml elemene, the bath formula made and forms the homogeneous single_phase system in ultrasonic 3 minutes, evaporation under reduced pressure removed chloroform ether is to gel formation, continued reduction vaporization 5～10 minutes, it is that liposome forms that spiral vibrates to aqueous suspension.
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| CN 200410082866 CN1650846B (en) | 2004-12-07 | 2004-12-07 | Elemene liposome and its preparation method |
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| CN 200410082866 CN1650846B (en) | 2004-12-07 | 2004-12-07 | Elemene liposome and its preparation method |
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| CN1650846A CN1650846A (en) | 2005-08-10 |
| CN1650846B true CN1650846B (en) | 2011-11-16 |
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Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102871965A (en) * | 2011-07-13 | 2013-01-16 | 郭增平 | Preparation method of tumor treatment medicine spray |
| CN105311031A (en) * | 2015-12-07 | 2016-02-10 | 南京海澳斯生物医药科技有限公司 | Composition and application thereof in medicine for increasing leukocyte |
| CN105779563A (en) * | 2016-04-29 | 2016-07-20 | 大连华立金港药业有限公司 | Detection reagent kit and method of heat-resistant microorganisms in elemene lipidosome injection semi-finished products |
| CN108309940B (en) * | 2018-04-04 | 2020-07-24 | 南通大学 | β -elemene and platinum drug co-carried liposome and its preparation method |
| CN109438166B (en) * | 2018-11-08 | 2021-06-04 | 石药集团远大(大连)制药有限公司 | (1S,2S,4S) -beta-elemene and preparation method and application thereof |
| CN109330994A (en) * | 2018-11-28 | 2019-02-15 | 杭州普施康生物科技有限公司 | A kind of elemene solid lipid nano granule and preparation method thereof |
| CN111358757A (en) * | 2020-03-13 | 2020-07-03 | 石药集团远大(大连)制药有限公司 | Elemene nano liposome and preparation method thereof |
| CN113476317A (en) * | 2021-06-30 | 2021-10-08 | 花安堂生物科技集团有限公司 | Antioxidant liposome and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1110134A (en) * | 1994-07-30 | 1995-10-18 | 大连市医药科学研究所 | Liposome preparing technology and preparation 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 |
| CN1413577A (en) * | 2002-10-18 | 2003-04-30 | 沈阳药科大学 | Thermosensitive long circulation liposome preparation |
| CN1451377A (en) * | 2002-04-17 | 2003-10-29 | 大连医大安鹏生物医药技术有限公司 | Elemene injection, and preparing method and use thereof |
-
2004
- 2004-12-07 CN CN 200410082866 patent/CN1650846B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1110134A (en) * | 1994-07-30 | 1995-10-18 | 大连市医药科学研究所 | Liposome preparing technology and preparation 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 |
| CN1451377A (en) * | 2002-04-17 | 2003-10-29 | 大连医大安鹏生物医药技术有限公司 | Elemene injection, and preparing method and use thereof |
| CN1413577A (en) * | 2002-10-18 | 2003-04-30 | 沈阳药科大学 | Thermosensitive long circulation liposome preparation |
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