CN100560134C - A kind of elemene inclusion complex, its preparation and preparation method - Google Patents
A kind of elemene inclusion complex, its preparation and preparation method Download PDFInfo
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- CN100560134C CN100560134C CNB2005101352193A CN200510135219A CN100560134C CN 100560134 C CN100560134 C CN 100560134C CN B2005101352193 A CNB2005101352193 A CN B2005101352193A CN 200510135219 A CN200510135219 A CN 200510135219A CN 100560134 C CN100560134 C CN 100560134C
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Abstract
The present invention relates to a kind of elemene inclusion complex, its preparation and their preparation method with antiviral, antitumaous effect.In this elemene inclusion complex, elemene: enclose material=1: 1-100, wherein the enclose material is selected from any or its any mixture in beta-schardinger dextrin-, microcrystalline Cellulose, Powderd cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, the methylcellulose.Elemene inclusion complex of the present invention is soluble in water, and its stability, bioavailability are very high, have no irritating odor.
Description
Technical field
The present invention relates to a kind of medicine, particularly relate to a kind of elemene inclusion complex, its preparation and their preparation method with antiviral, antitumaous effect.
Background technology
Elemene is the effective ingredient from zingiberaceous plant Rhizoma Curcumae Curcuma phaeocalis Valeton. or Guangxi zedoary Curcumakwangsiensis S.G.Lee et C.F. or warm Rhizoma Curcumae Curcuma Wenyujin Y.H.chen et C.Ling or other plant extraction, English Elemene by name, chemical name: 1-methyl isophthalic acid-vinyl-2,4 diisopropenyl cyclohexane extraction, molecular formula: C
15H
24Contain multiple isomer in the elemene, mainly contain α-elemene, beta-elemene, γ-elemene, δ-elemene, curcumene, Flos Caryophylli alkene.Extract purified method about elemene, more bibliographical information has been arranged, as among Chinese patent CN1060038 and the Chinese patent CN1200266 description being arranged all.
Elemene has antiviral, anticancer effect.Pharmacological testing proves: elemene has the obvious suppression effect to multiple animal transplanting tumor; Animal experiment all shows with clinical trial: demonstrate the effect that significantly kills and wounds and suppress growth of tumour cell when elemene directly contacts with tumor cell.
Dalian medical science institute in 1996 and Jingang Pharmaceutical Co., Ltd., Dalian's joint research and development be used for the treatment of ascites pleural fluid tumor disease ' elemene emulsion injection ' list marketings such as (local applications).Because determined curative effect, side effect such as no bone marrow depression are applied clinically very soon.Clinical practice for many years proves: this medicine is very effective to treatment tumor of cervix, lymphoma, skin carcinoma, the carotid artery injection for curing cerebral tumor, femoral arteriography treatment hepatocarcinoma.
Calendar year 2001 Dalian medical science institute and Jingang Pharmaceutical Co., Ltd., Dalian's joint research and development be used for the treatment of esophageal carcinoma, gastric cancer ' the oral breast of elemene ' beginning list marketing, the treatment digestive tract tumor all receive good curative effect.
Because elemi olefinic volatile oil, be liposoluble constituent, be insoluble in water, and has the strong impulse abnormal smells from the patient, so these commercially available elemene formulations are generally all made oil-in-water Emulsion or are added with cosolvent at present, the adjuvant that uses is refining soybean phospholipid, soybean oil, lecithin, cholesterol, also having with other vegetable oil is adjuvant, its production technology is common Liposomal formulation production technology, therefore this technology can not wrap elemene fully, can't cover the uncomfortable sense of taste of elemene medicine, when patient smells this penetrating odor or when oral, can cause vomiting, therefore cause product can't effectively promote clinically so far.
Chinese patent application CN1060038 has disclosed a kind of Elemenum Emulsion injection, and it also has following shortcoming except the defective with penetrating odor: have as distribute undesirable, uniform particles degree of the targeting of carrier and be difficult to control, less stable, easily irritated.
Chinese patent application CN1076613 has disclosed a kind of elemene formulation, owing to adopted polyoxyethylene castor oil as the surface activity cosolvent, makes that the zest of elemene formulation of preparation is big, easy haemolysis, easily irritated.
Itself is not only volatile oil elemene, and has the strong impulse abnormal smells from the patient.Existing elemene injection or mouth are reported the supplementary product kind of newborn use many, are involved great expense, and have improved the cost of product, and its production technology can not wrap elemene fully simultaneously, can't solve the flavor problem of smelling of elemene, so can't use clinically.
Be reported in how to solve elemene abnormal smells from the patient and water solublity problem in the elemene pharmaceutical preparation in the prior art as yet, keep the stable of elemene pharmaceutical preparation simultaneously, make it to be fit to clinical practice.
Summary of the invention
Purpose of the present invention is exactly to overcome the defective that is not suitable for sense of taste that existing elemene pharmaceutical preparation exists, adopt specific adjuvant and proportioning with the elemene enclose, make elemene inclusion complex and preparation, thereby elemene abnormal smells from the patient and water solublity problem have been solved, it has good stable simultaneously, water solublity and having no irritating odor makes it to be fit to clinical practice.
An object of the present invention is to provide a kind of elemene inclusion complex.
Another object of the present invention provides a kind of method for preparing described elemene inclusion complex.
A further object of the present invention provides a kind of pharmaceutical preparation that contains described elemene inclusion complex.
The objective of the invention is to be achieved through the following technical solutions:
A kind of elemene inclusion complex, it comprises the elemene and the enclose material of following part by weight:
Elemene: enclose material=1: 1-100.
Preferably, in the elemene inclusion complex of the present invention, the part by weight of elemene and enclose material is elemene: enclose material=1: 2-50; More preferably, elemene: enclose material=1: 4-7.
The term elemene of the present invention meaning is meant α-elemene, beta-elemene, γ-elemene, δ-elemene and curcumene, Flos Caryophylli alkene monomer or its mixture arbitrarily.
The used enclose material of the present invention is selected from any or its any mixture in beta-schardinger dextrin-, microcrystalline Cellulose, Powderd cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, the methylcellulose.The enclose material that the present invention selects can form stable clathrate with elemene enclose well, makes the clathrate of formation soluble in water simultaneously, and dissolubility can reach more than 10%.
In the elemene inclusion complex of the present invention, the weight ratio of elemene and enclose material is generally 1: 1-100, and wherein with 1: the 2-50 ratio serves as preferred, and this moment, the dissolubility of clathrate was bigger, and inclusion rate is higher, and content is the most suitable, and the enclose material usage is less; Particularly when both weight ratios be 1: during 4-7, inclusion rate is the highest, and content is the highest, and inclusion rate can reach more than 95%, and content is 22%-23%.
The invention provides first kind of method for preparing described elemene inclusion complex, it may further comprise the steps:
A. be 1 by the weight of elemene and the volume ratio of organic solvent: 5-10 is dissolved in elemene in the organic solvent, gets elemene solution;
B. be 1 by the weight of enclose material and the volume ratio of water: 2-50 is soluble in water with the enclose material, slowly drips elemene solution, all adds the back and stirs 0.5-24 hour;
C. use filtering with microporous membrane, the filtrate lyophilization, the white powder that must loosen is elemene inclusion complex, and the clathrate that obtains also can adopt the ether washing, to remove the not elemene of enclose.
The present invention also provides second kind of method for preparing described elemene inclusion complex, and it may further comprise the steps:
A. be 1 by the weight of elemene and the volume ratio of organic solvent: 5-10 is dissolved in elemene in the organic solvent, gets elemene solution;
B. be 1 by the weight of enclose material and the volume ratio of water: 2-50 is soluble in water with the enclose material, behind the adding elemene solution, places supersonic generator, carries out ultrasonic concussion;
C. use filtering with microporous membrane, the filtrate lyophilization, the white powder that must loosen is elemene inclusion complex.
The present invention also provides the third to prepare the method for described elemene inclusion complex, and it may further comprise the steps:
A. be 1 by the weight of elemene and the volume ratio of organic solvent: 5-10 is dissolved in elemene in the organic solvent, gets elemene solution;
B. be 1 by the weight of enclose material and the volume ratio of water: 2-50 is soluble in water with the enclose material, behind the adding elemene solution, places dismembyator, grinds well, and cold drying obtains elemene inclusion complex.
Organic solvent described in the said method is methanol, ethanol, acetone etc.Prepared clathrate also can adopt the ether washing, to remove the not elemene of enclose.
The present invention also can adopt conventional spray drying method to prepare elemene inclusion complex.
The present invention also provides a kind of pharmaceutical preparation, and it comprises described elemene inclusion complex and pharmaceutic adjuvant.Described pharmaceutic adjuvant can be any suitable pharmaceutic adjuvant of this area routine, comprises diluent, disintegrating agent, binding agent, lubricant, fluidizer etc.Pharmaceutical preparation of the present invention can be dosage forms such as tablet, eye drop, suppository, capsule.
Whether adopt following method to detect elemene inclusion complex of the present invention forms, first method is: get elemene alcoholic solution (1 → 1ml), elemene inclusion complex petroleum ether solution (1 → 3ml), difference point sample 1-5ul, point is developing solvent with petroleum ether-acetone-ethyl acetate (94: 5: 1), after the expansion on same silica gel G F lamellae, dry, developer is 5% vanillin glacial acetic acid-perchloric acid (5: 1) solution.The result, the elemene inclusion complex alcohol extract sample that thin-layer chromatogram shows and elemene reference substance the speckle of apparent color and position and reference substance solution identical, and the elemene inclusion complex ether extract does not show above-mentioned speckle composition, illustrates that elemene and enclose material have formed clathrate.Second method: to elemene inclusion complex, elemene and enclose material blends and enclose material, elemene has been made infrared spectrum (IR), adopt pellet technique, elemene adopts coating method, proofreaies and correct with polystyrene film, carries out above-mentioned IR spectrum relatively, find that clathrate IR spectrum is different from enclose material and elemene and enclose material blends IR spectrum, illustrates that elemene and enclose material have formed clathrate.The third method: above-mentioned sample has been made differential scanning analyzed DSC, the clathrate of discovery elemene is obviously different with the DSC spectrum of the enclose material blends of elemene and elemene and enclose material, illustrates that elemene and enclose material have formed clathrate.Whether the 4th kind of method adopts the phase solubility method to measure its clathrate and forms, and its method is for getting the 0.1g elemene, be added in the enclose material solution of variable concentrations, stirred the 0.45um membrane filtration 24 hours, the petroleum ether flush away is enclose oils not, adopt the GC gas chromatography, HPMCP concentration is figure, obtain solubility curve with the enclose material concentration, curve display, along with HPMCP concentration improves, the elemene dissolubility increases, and illustrates that elemene and enclose material have formed clathrate.
The present invention makes the elemene inclusion complex that makes soluble in water owing to adopted specific enclose material and selected specific proportioning, improves its stability simultaneously, improves its bioavailability, has no irritating odor.The pharmaceutical preparation that comprises elemene inclusion complex provided by the invention is also very easily water-soluble, good stability, and the bioavailability height has no irritating odor, and uses easily clinically.
Elemene inclusion complex preparation of the present invention is compared with other dosage form also has following outstanding advantage: product appearance is good, mouthfeel is good, rapid-action, absorb fully, human bioavailability is high, easy to use, good stability is convenient to the storage transportation, be difficult for microbiological contamination, quality guarantee rate height, take safer; The concentration height is convenient to patient's clinical application.
The specific embodiment
Below adopt embodiment to specify elemene inclusion complex of the present invention and preparation method thereof.
1 one kinds of elemene Benexate Hydrochlorides of embodiment
Get the 10g elemene, be dissolved in the 30ml ethanol, get beta-schardinger dextrin-30g, be dissolved in the 120ml water for injection, the elemene alcoholic solution is added drop-wise to gradually in the aqueous solution of beta-schardinger dextrin-, the room temperature lower magnetic force stirred 3 hours, used the 0.45um filtering with microporous membrane, the filtrate lyophilization, white powder must loosen, be the Benexate Hydrochloride of elemene, through gas chromatography determination, inclusion rate is 96%.
2 one kinds of elemene microcrystalline Cellulose of embodiment clathrate
Get the 10g elemene, be dissolved in the 30ml ethanol, get microcrystalline Cellulose 30g, be dissolved in the 120ml water for injection, the elemene alcoholic solution is added drop-wise to gradually in the aqueous solution of microcrystalline Cellulose, the room temperature lower magnetic force stirred 3 hours, used the 0.45um filtering with microporous membrane, the filtrate lyophilization, white powder must loosen, be the microcrystalline Cellulose clathrate of elemene, through gas chromatography determination, inclusion rate is 99%.
3 one kinds of elemene carboxymethyl starch sodium of embodiment clathrate
Get the 10g elemene, be dissolved in the 40ml ethanol, get carboxymethyl starch sodium 50g, be dissolved in the 120ml water for injection, the elemene alcoholic solution is added drop-wise to gradually in the aqueous solution of carboxymethyl starch sodium, places ultrasonic generator, room temperature sonic oscillation 20 minutes, use the 0.45um filtering with microporous membrane, the filtrate lyophilization, the white powder that must loosen is the carboxymethyl starch sodium clathrate of elemene, through gas chromatography determination, inclusion rate is 97%.
4 one kinds of elemene hydroxypropyl celluloses of embodiment clathrate
Get the 10g elemene, be dissolved in the 50ml ethanol, get hydroxypropyl cellulose 20g, be dissolved in the 120ml water for injection, the elemene alcoholic solution is added drop-wise to gradually in the aqueous solution of hydroxypropyl cellulose, the room temperature lower magnetic force stirred 3 hours, used the 0.45um filtering with microporous membrane, and filtrate is carried out spray drying, white powder must loosen, be the hydroxypropyl cellulose clathrate of elemene, through gas chromatography determination, inclusion rate is 96%.
5 one kinds of elemene methylcellulose of embodiment clathrate
Get the 10g elemene, be dissolved in the 30ml ethanol, get methylcellulose 30g, be dissolved in the 120ml water for injection, the elemene alcoholic solution is added drop-wise to gradually in the aqueous solution of methyl fiber rope, the room temperature lower magnetic force stirred 3 hours, used the 0.45um filtering with microporous membrane, the filtrate lyophilization, white powder must loosen, be the methylcellulose clathrate of elemene, through gas chromatography determination, inclusion rate is 97%.
6 one kinds of elemene Powderd celluloses of embodiment clathrate
Get the 10g elemene, be dissolved in the 30ml ethanol, get Powderd cellulose 30g, be dissolved in the 200ml water for injection, the elemene alcoholic solution is added drop-wise to gradually in the aqueous solution of Powderd cellulose, the room temperature lower magnetic force stirred 4 hours, used the 0.45um filtering with microporous membrane, the filtrate lyophilization, white powder must loosen, be the Powderd cellulose clathrate of elemene, through gas chromatography determination, inclusion rate is 98%.
7 one kinds of elemene cross-linking sodium carboxymethyl celluloses of embodiment clathrate
Get the 10g elemene, be dissolved in the 30ml ethanol, get cross-linking sodium carboxymethyl cellulose 30g, be dissolved in the 120ml water for injection, the elemene alcoholic solution is added drop-wise to gradually in the aqueous solution of cross-linking sodium carboxymethyl cellulose, places ultrasonic generator, room temperature sonic oscillation 20 minutes, use the 0.45um filtering with microporous membrane, the filtrate lyophilization, the white powder that must loosen is the Benexate Hydrochloride of elemene, through gas chromatography determination, inclusion rate is 96%.
8 one kinds of elemene hydroxyethyl-celluloses of embodiment clathrate
Get the 10g elemene, be dissolved in the 40ml ethanol, get hydroxyethyl-cellulose 30g, be dissolved in the 150ml water for injection, the elemene alcoholic solution is added drop-wise to gradually in the aqueous solution of hydroxyethyl-cellulose, the room temperature lower magnetic force stirred 3 hours, used the 0.45um filtering with microporous membrane, the filtrate lyophilization, white powder must loosen, be the hydroxyethyl-cellulose clathrate of elemene, through gas chromatography determination, inclusion rate is 97%.
9. 1 kinds of elemene eye drop of embodiment
Get the elemene Benexate Hydrochloride 100g that embodiment 1 makes, add adjuvants such as 500ml-5000ml water for injection, make eye drop.
10. 1 kinds of instant Sublingual tablets of elemene of embodiment
Get the elemene microcrystalline Cellulose clathrate 100g that embodiment 2 makes, add the adjuvants such as dried starch of 200g-9000g, be made into instant Sublingual tablet.
11. 1 kinds of elemene capsules of embodiment
Get the elemene Benexate Hydrochloride 100g that embodiment 1 makes, can directly fill, make capsule.
Claims (6)
1. elemene inclusion complex, it comprises the elemene and the enclose material of following part by weight:
Elemene: enclose material=1: 4-7,
Wherein the enclose material is selected from any or its any mixture in microcrystalline Cellulose, Powderd cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, the methylcellulose.
2. according to the elemene inclusion complex of claim 1, wherein elemene is selected from α-elemene, beta-elemene, γ-elemene, δ-elemene, curcumene or Flos Caryophylli alkene monomer.
3. pharmaceutical preparation, it comprises claim 1 or 2 described elemene inclusion complex and pharmaceutic adjuvants, and it is made into tablet, eye drop, suppository or capsule formulation.
4. prepare the method for elemene inclusion complex according to claim 1 and 2, it may further comprise the steps:
A. be 1 by the weight of elemene and the volume ratio of organic solvent: 5-10 is dissolved in elemene in the organic solvent, gets elemene solution;
B. be 1 by the weight of enclose material and the volume ratio of water: 2-50 is soluble in water with the enclose material, slowly drips elemene solution, all adds the back and stirs 0.5-24 hour;
C. use filtering with microporous membrane, the filtrate lyophilization, the white powder that must loosen is elemene inclusion complex.
5. prepare the method for elemene inclusion complex according to claim 1 and 2, it may further comprise the steps:
A. be 1 by the weight of elemene and the volume ratio of organic solvent: 5-10 is dissolved in elemene in the organic solvent, gets elemene solution;
B. be 1 by the weight of enclose material and the volume ratio of water: 2-50 is soluble in water with the enclose material, behind the adding elemene solution, places supersonic generator, carries out ultrasonic concussion;
C. use filtering with microporous membrane, the filtrate lyophilization, the white powder that must loosen is elemene inclusion complex.
6. prepare the method for elemene inclusion complex according to claim 1 and 2, it may further comprise the steps:
A. be 1 by the weight of elemene and the volume ratio of organic solvent: 5-10 is dissolved in elemene in the organic solvent, gets elemene solution;
B. be 1 by the weight of enclose material and the volume ratio of water: 2-50 is soluble in water with the enclose material, behind the adding elemene solution, places dismembyator, grinds well, and cold drying obtains elemene inclusion complex.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2570121A1 (en) * | 2010-05-10 | 2013-03-20 | Xie, Tian | Slow release tablet of elemene anti-tumor plant medicine |
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2005
- 2005-12-29 CN CNB2005101352193A patent/CN100560134C/en not_active Expired - Fee Related
Non-Patent Citations (2)
| Title |
|---|
| β-环糊精包合莪术挥发油的工艺研究. 李丹等.中药材，第27卷第11期. 2004 |
| β-环糊精包合莪术挥发油的工艺研究. 李丹等.中药材，第27卷第11期. 2004 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2570121A1 (en) * | 2010-05-10 | 2013-03-20 | Xie, Tian | Slow release tablet of elemene anti-tumor plant medicine |
| EP2570121A4 (en) * | 2010-05-10 | 2014-06-25 | Xie Tian | Slow release tablet of elemene anti-tumor plant medicine |
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| CN1990047A (en) | 2007-07-04 |
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