CN1508176A - Elemene nydroxy propyl-beta-cyclodextrin clathrate and preparation and preparing method thereof - Google Patents
Elemene nydroxy propyl-beta-cyclodextrin clathrate and preparation and preparing method thereof Download PDFInfo
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- CN1508176A CN1508176A CNA021449414A CN02144941A CN1508176A CN 1508176 A CN1508176 A CN 1508176A CN A021449414 A CNA021449414 A CN A021449414A CN 02144941 A CN02144941 A CN 02144941A CN 1508176 A CN1508176 A CN 1508176A
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Abstract
The invention relates to an elemene hydroxylpropyl-beta- cyclodextrin inclusion compound, the preparation and the preparing method. The weight ratio of elemene : hydroxylpropyl-beta- cyclodextrin =1:1-100; it adds the elemene dissolving in organic menstruum to the hydroxylpropyl-beta-cyclodextrin water solution for mixing, then freeze-dries to form water-soluble inclusion compound; and then makes ultrafiltration and 0.22mum-aperture film filtration on the water solution to freeze-dry to make freeze-dried powder injection. The inclusion compound, mixed with other assistant material, can be made into suppository, ointment, tablet and capsule.
Description
Affiliated technical field
The present invention relates to hydroxypropyl-beta-cyclodextrin inclusion and the preparation and the preparation method of Elemenum, this bag and thing can be used to injection, oral, external application, have antiviral, anticancer effect.
Background technology
Elemenum is the effective ingredients in plant from zingiberaceous plant zddoary Curcuma phaeocaulis Valeton. or Guangxi zedoary Curcuma kwangsiensis S.G.Lee et C.F. or RADIX CURCUMAE CurcumaWenyujin Y.H.chen et C.Ling or Herba Cymbopogonis Citrari extraction, English Elemene by name, chemistry 1-methyl isophthalic acid-vinyl-2 by name, 4-diisopropenyl hexanaphthene, molecular formula are C
15H
24Contain multiple isomer in the Elemenum, mainly contain α-Elemenum, beta-elemene, γ-Elemenum, δ-Elemenum, and contain curcumene, cloves alkene, Elemenum has effects such as anticancer, antiviral, the emulsified injection made from Elemenum has been widely used in clinically, has obtained curative effect preferably in the clinical application.The preparation method of Elemenum has more bibliographical information, generally extracts from above-mentioned plant and makes with extra care, or directly separate from zedoary turmeric oil, as among Chinese patent CN1060038 and the Chinese patent CN1200266 description being arranged all.
Elemenum is a fat-soluble component, be insoluble in water, the injection liquid that is made generally in emulsion clinically or is added with solubility promoter is used, as the Elemenum Emulsion injection that has gone on the market by the preparation of Chinese patent CN1060038 method, the said preparation less stable, easily layering, particle is big, brings potential danger to clinical application.Also there are some bibliographical informations to adopt some tensio-active agent hydrotropies, as tween etc.In Chinese patent CN1076613A, describe and adopt polyoxyethylene ricinolein 35 hydrotropies to be prepared into injection liquid, adopt these tensio-active agent hydrotropies to prepare injection liquid and have weakness such as pungency is big, instability, haemolysis, easy allergy usually, limited the application of Elemenum.Bibliographical information (Wang Lijun, herbal medicine 2001.4.314.316 were once arranged; Chen Xingcan, herbal medicine 1990-8 11-18), adopt beta-cyclodextrin, the zedoary turmeric oil that contains Elemenum is carried out inclusion, obtained success, the zedoary turmeric oil inclusion compound water soluble behind the inclusion, stability improves, and improved bioavailability, but beta-cyclodextrin has hemolytic reaction, and injection is not easy to do.Also once describing zedoary turmeric oil in Chinese patent application 02109680.5 in addition can be by the hydroxypropyl-beta-cyclodextrin inclusion, and the inclusion compound of formation is very easily water-soluble.The all undeclared whether inclusion Elemenum of these documents and patent, retrieval is other documents and patent both at home and abroad, finds no about Elemenum to adopt hydroxypropyl-beta-cyclodextrin Elemenum to be carried out the patent and the document of inclusion.
Summary of the invention
The hydroxypropyl-beta-cyclodextrin inclusion and freeze-dried powder and preparation method and other formulation preparing methods that the purpose of this invention is to provide a kind of Elemenum.This method is utilized cyclodextrin encapsulated effect, with the Elemenum inclusion, forms stable inclusion compound, makes it soluble in water.
Elemenum among the present invention can be beta-elemene, γ-Elemenum, the δ-Elemenum mixture that meets Chinese Western medicine quality standard WS-048 (X-040)-96, it can be the mixture of α-Elemenum, beta-elemene, γ-Elemenum, δ-Elemenum and curcumene, cloves alkene etc., it also can be the Elemenum monomeric compound, or α-Elemenum, or beta-elemene, or γ-Elemenum, or δ-Elemenum, or curcumene, or cloves alkene.
Hydroxypropyl-beta-cyclodextrin (HPCD) is the derivative of beta-cyclodextrin, has the tubular molecular structure, and molecular weight is 1540, and is very easily water-soluble, and the inclusion amount is big, no hemolytic reaction, and toxicity is low, can be applicable to injection.Because Elemenum is the ring molecule that has than small molecular weight, analyze hydroxypropyl-beta-cyclodextrin easily with its inclusion.Through test, Elemenum and hydroxypropyl-beta-cyclodextrin (HPCD) are by behind certain weight ratio inclusion, and solubleness can reach more than 10%, reaches soluble in water by water insoluble, and stability also improves a lot.After lyophilize, become solid state by liquid state.
The objective of the invention is to be achieved through the following technical solutions:
It is made of by weight following raw material:
Elemenum: hydroxypropyl-beta-cyclodextrin=1: 1-100
Preparation method of the present invention is:
Selection meets Elemenum or the Elemenum monomer of Chinese Western medicine quality standard WS-048 (X-040)-96, to be dissolved in by the Elemenum that above-mentioned weight is made a gesture of measuring in an amount of organic solvent, be generally methyl alcohol, ethanol, acetone etc., add-on (the monomeric weight of Elemenum or Elemenum: the volume of organic solvent) be about 1: 1-5 or more in the multiregion; To be dissolved in the distilled water by the hydroxypropyl-beta-cyclodextrin (HPCD) of above-mentioned weight ratio, the water add-on press HPCD calculate (weight of HPCD: the volume of water), 1: in the 5-50 scope; The aqueous solution violent stirring that will contain HPCD, slowly drip Elemenum solution, after all adding, continue to stir 0.5-24 hour, in hundred grades of workshops of cleanliness factor, use 0.45 μ m or 0.22 μ m filtering with microporous membrane, the filtrate lyophilize, the white powder that must loosen is the hydroxypropyl-beta-cyclodextrin inclusion of Elemenum.The inclusion compound that obtains also can adopt the ether washing, to remove the not Elemenum of inclusion.
Inclusion compound of the present invention also can adopt the preparation of other method, as supersonic method, be about to above-mentioned contain Elemenum solution and be added to HPCD solution after, place ultrasonic generator, as Ultrasonic Cleaners, in the vibrating machine etc., carry out sonic oscillation and replace above-mentioned stirring, also can obtain inclusion compound.Or the employing polishing, be about to Elemenum solution and add among the HPCD, add suitable quantity of water and grind all, cryodrying gets inclusion compound.Its drying means also can adopt the spray drying process preparation.
Elemenum and HPCD weight ratio are 1 in the inclusion compound among the present invention: 1-100, and wherein with 1: 2-5 ratio solubleness is bigger, and inclusion rate is higher, and content is the highest, and the hydroxypropyl-beta-cyclodextrin consumption is minimum.And both weight ratios are 1: 1 o'clock, promptly have inclusion compound to form, and wherein suitable with 1: 5 inclusion rate, content, inclusion rate can reach more than 95%, and content is 19%.
The inclusion compound that obtains by the present invention is characterized as and contains Elemenum and hydroxypropyl-beta-cyclodextrin chemical ingredients, and soluble in water.Its thin-layer chromatography collection of illustrative plates, comprise Elemenum, the elemene inclusion complex alcohol extract, Elemenum bag and thing ether extract sample, spot shows after launching, and Elemenum and Elemenum bag and thing alcohol extract spot (chemical ingredients) are in full accord, and Elemenum bag and thing ether extract do not show above-mentioned spot composition, illustrate that Elemenum and HPCD have formed inclusion compound, and contain the Elemenum all the components in the inclusion compound; Its infrared spectra (IR spectrum) elemene inclusion complex IR spectrum is different from hydroxypropyl-beta-cyclodextrin and Elemenum and Elemenum and HPCD miscellany IR spectrum; Its DSC differential scanning collection of illustrative plates, the HPCD miscellany of the hydroxypropyl-beta-cyclodextrin inclusion of Elemenum and Elemenum and Elemenum and HPCD are obviously different; The phase solubility method confirms that along with HPCD concentration improves, Elemenum solubleness increases.
Inclusion compound of the present invention hundred grades of cleaning shops, removes thermal source and sterile filtration (0.22 μ m) through ultrafiltration, through after the lyophilize, can be made into freeze-dried powder.Inclusion compound of the present invention can add an amount of auxiliary material, is prepared into suppository, ointment and eye drops, tablet, capsule etc.Hydroxypropyl-beta-cyclodextrin can adopt beta-cyclodextrin to substitute in the inclusion compound of the present invention, makes oral tablet, capsule, suppository etc.
The invention has the advantages that hydroxypropyl-beta-cyclodextrin bag and thing that a kind of Elemenum soluble in water is provided, can improve its stability simultaneously, improve its bioavailability, the Elemenum and the freeze-dried powder preparation method that provide injectable to use.Its preparation is very easily water-soluble, and good stability does not have hemolytic reaction, and is non-stimulated, and is not irritated, uses easily clinically.
Inclusion compound among the present invention proves by the following method mainly one adopts its inclusion compound of tlc determination whether to form.Its method is for getting Elemenum ethanolic soln (1 → 1ml), elemene inclusion complex ethanolic soln (1 → 1ml), elemene inclusion complex petroleum ether solution (1 → 3ml), difference point sample 1-5 μ l, on silica gel G-CMC plate, launch, developping agent is sherwood oil-acetone-ethyl acetate (94: 5: 1), developer is 5% Vanillin Glacial acetic acid-perchloric acid (5: 1) solution, the result, thin-layer chromatogram demonstration Elemenum and elemene inclusion complex ethanolic soln spot are in full accord, and Elemenum petroleum ether solution immaculate illustrates that Elemenum HPCD has formed inclusion compound.Its two pairs of elemene inclusion complexes, Elemenum and HPCD miscellany and HPCD, Elemenum has been done infrared spectra (IR spectrum), adopt pellet technique, Elemenum adopts coating method, proofreaies and correct with polystyrene film, carries out above-mentioned IR spectrum relatively, find that elemene inclusion complex IR spectrum is different from Elemenum and HPCD miscellany IR spectrum, illustrates the inclusion compound that has formed Elemenum HPCD.The above-mentioned sample of its three couple has been done differential scanning and has been analyzed DSC, finds that elemene inclusion complex DSC spectrum is different from Elemenum and HPCD miscellany DSC spectrum, judges to have formed inclusion compound.Its four, adopt the phase solubility method to measure its inclusion compound and form, its method is for getting the 0.1g Elemenum, be added in the HPCD solution of different concns, stirred 24 hours, 0.45 μ m membrane filtration, the sherwood oil flush away is inclusion oils not, adopts the GC vapor-phase chromatography, is reference substance with the beta-elemene, measure its concentration, HPCD concentration is figure, get solubility curve with beta-elemene concentration, curve display, along with the concentration increasing of HPCD, Elemenum concentration increases, and proves to have formed inclusion compound.
Elemenum content analysis measuring method in the Elemenum adopts vapor-phase chromatography, with reference to Chinese Western medicine quality standard WS-048 (X-040)-96, with the beta-elemene is reference substance (Chinese Pharmacopoeia reference substance), with external standard method, its condition determination is a stationary phase for poly-ethanol 20M (PEG20M), and coating concentration is 10%, shimalit W carrier, the 60-80 order, 135 ℃-140 ℃ of column temperatures, number of theoretical plate calculate by the beta-elemene peak and are not less than 1000.
Embodiment
Embodiment 1
Get Elemenum 0.1g, be dissolved in the 0.5ml ethanol, get hydroxypropyl-beta-cyclodextrin 0.5g, be dissolved in the 20ml water for injection, the Elemenum ethanolic soln is dropwise added in the HPCD solution, room temperature magnetic agitation 3 hours, use 0.45 μ m filtering with microporous membrane freezing, get the white loose powder, confirm, formed Elemenum and hydroxypropyl-beta-cyclodextrin inclusion through thin-layer chromatography.Gas Chromatographic Determination, inclusion rate are 95%.
Embodiment 2
With the inclusion compound powder that example 1 obtains,, wave most ether and get white inclusion compound powder with the ether washing.
Embodiment 3
Other changes the magnetic agitation method into the sonic oscillation method with example 1, and room temperature was vibrated 20 minutes, through 0.45 μ m filtering with microporous membrane, the filtrate lyophilize gets the white loose powder, confirms through thin-layer chromatography with solution behind the inclusion, formed inclusion compound, through gas Chromatographic Determination, inclusion rate is 90%.
Embodiment 4
Other changes the magnetic agitation method into polishing with example 1, grind all after, ether is washed, and waves most ether, the low-temperature reduced-pressure drying, white powder, confirm that through thin-layer chromatography formed inclusion compound, through gas Chromatographic Determination, inclusion rate is 62%.
Embodiment 5
With the filtrate that example 1 obtains, carry out spraying drying, obtain inclusion compound.
Embodiment 6
From example 1, solution is behind 0.45 μ m filtering with microporous membrane behind the inclusion, adopt ultrafiltration process, with carrying the filter membrane ultrafiltration of staying molecular weight 5000-10000, after the depyrogenation, through 0.22 μ m membrane filtration degerming, it is aseptic subpackaged hundred grades of cleaning shops to obtain filtrate again, and lyophilize obtains injection Elemenum freeze-dried powder.
Embodiment 7
Change magnetic agitation method in the example 1 into the ultrasonic pinane 20 minutes of shaking, other is with example 6.
Embodiment 8
Change ultrafiltration depyrogenation method in the example 6 into activated carbon method, other is with example 6.
Embodiment 9
Change hydroxypropyl-beta-cyclodextrin 0.5g in the example 1 into 0.1g, other are with example 1, and through gas Chromatographic Determination, inclusion rate is 70%.
Embodiment 10
Change hydroxypropyl-beta-cyclodextrin 0.5g in the example 1 into 10g, other are with example 1, and through gas Chromatographic Determination, inclusion rate is 98, content 1.0%.
Embodiment 11
Inclusion compound with example 1 obtains adds appropriate amount of auxiliary materials, regulates osmotic pressure, is made into eye drops.
Embodiment 12
Inclusion compound with example 1 obtains adds an amount of auxiliary material, makes instant sublingual tablet.
Embodiment 13
Inclusion compound with example 1 obtains adds an amount of auxiliary material, makes capsule, suppository.
Embodiment 14
Hydroxypropyl-beta-cyclodextrin in the example 1 is replaced with beta-cyclodextrin, and other make inclusion compound with example 1, add an amount of auxiliary material, make tablet, capsule, suppository.
Claims (10)
1, a kind of hydroxypropyl-beta-cyclodextrin inclusion of Elemenum, it is made of by weight following raw material: Elemenum: hydroxypropyl-beta-cyclodextrin=1: 1-100); Join in the aqueous solution that contains hydroxypropyl-beta-cyclodextrin by the Elemenum that will be dissolved in organic solvent, after the stirring, drying forms inclusion compound soluble in water; Described Elemenum can be beta-elemene, γ-Elemenum, the δ-Elemenum mixture that meets Chinese Western medicine quality standard WS-048 (X-040)-96, it can be the mixture of α-Elemenum, beta-elemene, γ-Elemenum, δ-Elemenum and curcumene, cloves alkene, also can be the Elemenum monomeric compound, or α-Elemenum or beta-elemene or γ-Elemenum or δ-Elemenum or curcumene or cloves alkene; Described organic solvent is an ethanol, also can be methyl alcohol, acetone.
2. by the hydroxypropyl-beta-cyclodextrin inclusion of the described Elemenum of claim 1, it is made of by weight following raw material: Elemenum: hydroxypropyl-beta-cyclodextrin=1: 2-5.
3. the preparation method of the hydroxypropyl-beta-cyclodextrin inclusion of an Elemenum, it by following raw material by weight forming: Elemenum: hydroxypropyl-beta-cyclodextrin=1: 1-100; By above-mentioned weight ratio Elemenum is dissolved in the 1-5 organic solvent doubly, hydroxypropyl-beta-cyclodextrin is dissolved in the distilled water of 5-50 by above-mentioned weight ratio, the aqueous solution violent stirring that will contain hydroxypropyl-beta-cyclodextrin, slowly drip Elemenum solution, after all adding, continue to stir 0.5-24 hour, use filtering with microporous membrane, the filtrate lyophilize, the white powder that must loosen is the hydroxypropyl-beta-cyclodextrin inclusion of Elemenum.
4. press the preparation method of the hydroxypropyl-beta-cyclodextrin inclusion of the described Elemenum of claim 3, also can adopt supersonic method, be about to above-mentioned contain Elemenum solution and be added to hydroxypropyl-beta-cyclodextrin solution after, place ultrasonic generator, carry out sonic oscillation and replace above-mentioned stirring, also can obtain inclusion compound.
5. press the preparation method of the hydroxypropyl-beta-cyclodextrin inclusion of the described Elemenum of claim 3, can also adopt polishing, be about to Elemenum solution and add in the hydroxypropyl-beta-cyclodextrin, add suitable quantity of water and grind all, cryodrying gets inclusion compound.
6. press the preparation method of the hydroxypropyl-beta-cyclodextrin inclusion preparation of the described Elemenum of claim 3, the hydroxypropyl-beta-cyclodextrin inclusion of described Elemenum, solution is through filtering with microporous membrane behind the inclusion, after the depyrogenation, again through the membrane filtration degerming, it is aseptic subpackaged hundred grades of cleaning shops to obtain filtrate, and lyophilize obtains injection Elemenum freeze-dried powder.
7. by the hydroxypropyl-beta-cyclodextrin inclusion of claim 1 or 2 described Elemenums,, add auxiliary material, regulate osmotic pressure, be made into eye drops described inclusion compound.
8. by the hydroxypropyl-beta-cyclodextrin inclusion of claim 1 or 2 described Elemenums,, add auxiliary material, make instant sublingual tablet described inclusion compound.
9. by the hydroxypropyl-beta-cyclodextrin inclusion of claim 1 or 2 described Elemenums,, add auxiliary material, make suppository, capsule described inclusion compound.
10. by the hydroxypropyl-beta-cyclodextrin inclusion of claim 8 or 9 described Elemenums, hydroxypropyl-beta-cyclodextrin can substitute with beta-cyclodextrin.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02144941 CN1290914C (en) | 2002-12-18 | 2002-12-18 | Elemene nydroxy propyl-beta-cyclodextrin clathrate and preparation and preparing method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 02144941 CN1290914C (en) | 2002-12-18 | 2002-12-18 | Elemene nydroxy propyl-beta-cyclodextrin clathrate and preparation and preparing method thereof |
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| CN1508176A true CN1508176A (en) | 2004-06-30 |
| CN1290914C CN1290914C (en) | 2006-12-20 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101810593A (en) * | 2010-05-10 | 2010-08-25 | 杭州法善医药有限公司 | Elemene sustained-release tablets |
-
2002
- 2002-12-18 CN CN 02144941 patent/CN1290914C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101810593A (en) * | 2010-05-10 | 2010-08-25 | 杭州法善医药有限公司 | Elemene sustained-release tablets |
| WO2011140872A1 (en) | 2010-05-10 | 2011-11-17 | Xie Tian | Slow release tablet of elemene anti-tumor plant medicine |
| 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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| CN1290914C (en) | 2006-12-20 |
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