CN1274704C - Beta-cyclodextrin inclusion composite - Google Patents
Beta-cyclodextrin inclusion composite Download PDFInfo
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- CN1274704C CN1274704C CN 03135996 CN03135996A CN1274704C CN 1274704 C CN1274704 C CN 1274704C CN 03135996 CN03135996 CN 03135996 CN 03135996 A CN03135996 A CN 03135996A CN 1274704 C CN1274704 C CN 1274704C
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Abstract
The present invention relates to a beta-cyclodextrin compound, particularly to an inclusion compound composed of branch chain beta-cyclodextrin or chemically modified beta-cyclodextrin and sialic acid and a preparing method for the inclusion compound. The present invention also relates to a method using a multi-crystal step to purify non-branch beta-cyclodextrin from water solution.
Description
The affiliated field of invention
The present invention relates to the beta-cyclodextrin mixture, particularly relate to by what the beta-cyclodextrin of branched chain beta-cyclodextrin or chemically modified and sialic acid constituted and forgive mixture and preparation method thereof, the invention still further relates to the method for using the non-branch of many crystallisation steps purifying from aqueous solution beta-cyclodextrin.
Background of invention
Cyclodextrin is the cyclic oligomeric thing that the dewatered grape sugar monomer is formed by connecting by α-1,4 glycosidic link.According to the number of monomers purpose difference of forming the ring-type oligosaccharides, cyclodextrin divides for the alpha-cylodextrin be made up of 6 monomers again, the beta-cyclodextrin of being made up of 7 monomers and the γ-Huan Hujing of being made up of 8 monomers.
Branching cd comprises the ring texture of the anhydroglucose that is formed by connecting by α-1,4 glycosidic link, and by it tell-individual or a plurality of dewatered grape sugar monomers that connect by α-1,6 glycosidic link.Branch itself comprises more than one dewatered grape sugar monomer, so said branch can be oligomer or polymer.These additional dehydration glucose monomers that constitute branched structure are to connect by α-1,4 key.Compare with non-branch beta-cyclodextrin, branch's beta-cyclodextrin is more soluble in water relatively.Specifically, the solubleness of non-branch beta-cyclodextrin is about 2%, and branch's beta-cyclodextrin then has about 50% or higher solubleness.
Cyclodextrin is under suitable pH and temperature condition, uses Maltose 4-glucosyltransferase (CGT) processing starch or liquefying starch to produce.The starch that is used to produce cyclodextrin can be the various plants source, for example can be W-Gum, wheat starch, sorghum starch, sweet corn starch and yam starch etc.The CGT enzyme is then by microorganisms such as bacillus megaterium, annular genus bacillus.Reaction parameter between CGT and the starch is well known by persons skilled in the art.
In order to prepare beta-cyclodextrin, can at first starch be made concentration about 35% (V/V) aqueous slurries.Use enzyme (particularly α-Dian Fenmei) or acid treatment slurry to make starch gel gel or liquefaction to sugared equivalent be approximately 1-5 then.Then in the slurry of gelation and liquefaction, adding CGT under suitable pH and the temperature condition.Generally speaking, the pH during the enzymatic reaction is about 4.5-8.5, and temperature range is 25-75 ℃.Reaction times approximately needs 10 hours to several days.The generation of beta-cyclodextrin will depend on reaction conditions and employed certain enzyme in the enzymatic reaction.Can use ordinary methods such as crystallization, precipitation or filtration from the thick digestion product of starch, to isolate beta-cyclodextrin.
In order to improve the production of beta-cyclodextrin, can during CGT and liquefying starch slurry reaction, add appropriate solvent, so as to increasing the output of beta-cyclodextrin.Typical solvent comprises toluene and p-Xylol.Because such solvent can form mixture and throw out with cyclodextrin, be also referred to as the cyclodextrin recombiner.Can heated and boiled compound beta-cyclodextrin solution to isolate solvent.And then use ordinary methods such as precipitation, crystallization or filtration from then on to isolate cyclodextrin in the solution.
Be the ring compound that a class contains the cavity on the cyclodextrin structure, have the character that forms the mixture of specific type with other molecules.It is to constitute molecular compound by the another kind of composition as " object " of the composition parcel of wherein a kind of conduct " main body " that formed this quasi-molecule is forgiven mixture.
The almost completely different original character with main body or object composition of the character of master/object mixture.For example, under many situations, the total water dissolubility of object may be than its water-soluble obvious raising under combined state not.
The external structure of cyclodextrin molecular is hydrophilic nmature, and its interior void then has very strong hydrophobicity.In theory, strong hydrophilicity molecule and strong hydration and ionogen almost can not be compound each other, and have only hydrophobic relatively in nature molecule just compound easily.Therefore, the stability of the mixture that is formed between subject and object comes down to the hydrophobic proterties of guest molecule or its part closely-related.In fact, the guest molecule with good recombination property generally all is water-soluble poor.
The object composition is retained in the composite structure of cyclodextrin and promoting agent formation with three different space keys (key of the key of two C-H groups and a glucosides oxygen) by non-covalent bonding force.These keys collaborative structured the formation and formed a nonpolar relatively microenvironment at the binding site place.Yet this combination of being controlled by intrinsic kinetic balance originally can not be lasting, because kinetic balance depends primarily on geometry and space suitability between main body/object composition, and the solubleness of object composition in medium.After these two kinds of strength of power of dissociating between the subject and object composition and bonding force interact and reach balance, can make mixture be in a stable combined state.
No matter the subject and object composition is in solution state or solid state, all can take place compound between the two.Heating liquid state or solid mixt can increase the solubleness of cyclodextrin and object.After object comprises under the situation of stretching out the charged group outside the cavity, be compound is to form soluble complex mostly.Because the object composition shows different solubleness in water, and compound action depends on the amount of the object that is added, and (as methyl alcohol and ethanol etc.) fully dissolve the object composition so need with an organic solvent sometimes.
The cyclodextrin of chemically modified and the cyclodextrin of unmodified have visibly different physicochemical property and forgive behavior.For example, the solubleness of hydroxypropyl beta cyclodextrin in water approximately increases by 60% than the cyclodextrin of unmodified.Equally, for example succinylation cyclodextrin and cyclodextrin tetradecasulfate all have well water-soluble other modified cyclodextrin.
The purpose of invention
An object of the present invention is to provide the mixture of forgiving that forms between the beta-cyclodextrin of a kind of branched chain beta-cyclodextrin or chemically modified and the sialic acid.
According to a preferred embodiment of the invention, wherein forming the main body composition of forgiving mixture is the beta-cyclodextrin of branched chain beta-cyclodextrin or chemically modified.
According to a preferred embodiment of the invention, wherein said branched chain beta-cyclodextrin is to use crystallization method to obtain behind the non-branched chain beta-cyclodextrin by removing in the solution that contains cyclodextrin.
According to a preferred embodiment of the invention, wherein the beta-cyclodextrin of said chemically modified is selected from hydroxyethyl beta-cyclodextrin, hydroxypropyl, sulfation beta-cyclodextrin and uncle's aminocarboxylic methyl beta-cyclodextrin.
According to a preferred embodiment of the invention, wherein forming the object composition of forgiving mixture is sialic acid.
According to a preferred embodiment of the invention, the wherein said mixture of forgiving can make sialic solubleness bring up to about 10% from about 0.4%.
According to a preferred embodiment of the invention, use therein solvent is a water.
According to a preferred embodiment of the invention, said branched chain beta-cyclodextrin/sialic acid mixture contains about 5-10% sialic acid, approximately 60-75% branched chain beta-cyclodextrin and about 50% water.
The detailed description of invention
Cyclodextrin is the ring molecule that has the cavity, center in a kind of its structure.Can utilize this constitutional features of cyclodextrin molecular to form and forgive mixture, make one or more guest molecules be retained in also combination stably with it in the cavity, center of cyclodextrin molecular.When mixture was forgiven in formation, the molecule number ratio of guest molecule and host molecule generally was 1: 1.Yet,, may need more than one guest molecule to combine with cyclodextrin if the molecular weight of guest molecule is less.On the contrary, if the molecular weight of object is bigger, then needs more than one cyclodextrin molecular and form mixture with it.
The cyclodextrin that is used to form mixture is preferably by the branched chain beta-cyclodextrin with higher water solubility of purifying in the solution that contains cyclodextrin, perhaps the cyclodextrin of chemically modified.
Can use periodic crystallisation intermediate processing of the present invention,, collect the supernatant that not crystallization is separated out then by removing in the cyclodextrin soln containing of heat treated as sedimentary non-branched chain beta-cyclodextrin.Concentrate also and promptly obtain highly purified branched chain beta-cyclodextrin behind the dry said supernatant.
When the cyclodextrin that uses deutero-or modification prepares cyclodextrin and forgives mixture, be to use the molecule outer surface part to have hydroxyl or hydroxyalkyl mostly and obviously changed the cyclodextrin of inherent nature, for example hydroxyethyl-, hydroxypropyl-, the amino carboxymethyl-beta-cyclodextrin of uncle etc.
In general, the solubleness with the mixture of branched chain or modified cyclodextrin formation is significantly higher than the not solubleness of the guest compound of combined state.Therefore, use
BranchThe relatively poor compound formation of the beta-cyclodextrin of chain or modification and solubleness is forgiven mixture, is to improve some a kind of effective ways as the solubleness of the compound of object.The invention provides the compound method of a kind of beta-cyclodextrin that uses branched chain beta-cyclodextrin or modification and some guest molecule with the solubleness that improves these objects.Method of the present invention is particularly suitable for enlarging the range of application of some medicinal compound.
Specifically, sialic acid solubleness in water is approximately 0.3% under the room temperature.Because sialic water solubility is very low, mostly is emulsion greatly so contain the regular dosage form of sialic acid preparation, at first utilizes organic solvent to prepare sialic solution when perhaps producing preparation.The solubleness of the mixture that hydroxypropyl-beta-cyclodextrin and sialic acid form is about 60%.Be approximately 6-7% with the solubleness of solid sialic acid in water and compare, this solubleness has improved about 20 times.
In solution, constitute the main body of mixture: the object ratio can be 1: 1,1: 2,2: 1 or 2: 2.The ratio of subject and object molecule depends primarily on the size and the shape of guest molecule.Separated from one another and be comprised in the cavity of cyclodextrin molecular both ratios preferably 1: 1 in order to ensure guest molecule.But according to the size and the shape of guest molecule, and object/main body combination/dissociation equilibrium between the two, this ratio also can be 1: 2,2: 1 or 2: 2.
As previously mentioned, constituting the host molecule that the present invention forgives mixture can be to remove the branched chain powder-beta-dextrin that obtains behind the non-branched chain powder-beta-dextrin with the periodic crystallisation method from contain cyclodextrin soln, also can be that (β-CD) is hydroxyethyl β-CD, hydroxypropyl beta-CD, sulfation β-CD and uncle's aminocarboxylic methyl β-CD etc. for example for the beta-cyclodextrin of chemically modified.
What also should particularly point out is that methyl hydroxybenzoate, ethyl phenoxy and many other biocides also can be made into to forgive mixture, and improve its solubleness by this method.In addition, though preferred solvent is a water in the method for the present invention, also can use other organic solvents such as methyl alcohol, ethanol and propyl alcohol.
Embodiment
Embodiment 1:
BranchThe preparation of chain beta-cyclodextrin
Through about 20 hours,
To contain 250gThe crude product that obtains with the CGT amyloclastic is cooled to 25 ℃ by 90 ℃, directly to obtain cyclodextrin soln.Use this solution of filter paper vacuum filtration then, in 100 ℃ of baking boxs, obtain about 95g cyclodextrin after the drying.Stir and in the filter cake of collecting, add 400ml distilled water down and be heated to 95 ℃ to form first solution.Then this first solution is cooled to 20 ℃ and placed 16 hours.Filter and collect supernatant liquor (1) and solid sediment (1).Dissolution precipitation thing in kind
(1)Obtain second solution.Handle second solution with quadrat method then, filter and collect supernatant liquor (2) and discard solid sediment (2).
Concentrate, dry and with after supernatant liquor (1) and (2) merging, obtain highly purified branched chain beta-cyclodextrin.
High pressure liquid chromatography (HPLC) (HPLC) analytical results shows, through obtaining pure basically branched chain beta-cyclodextrin after two step crystallization.
Embodiment 2: comprise the preparation of sialic highly water-soluble branched chain beta-cyclodextrin mixture
Under 50 ℃ of mechanical stirring, the branched chain beta-cyclodextrin that 50g is as above made mixes with the 30ml deionized water, adds the 5g sialic acid then in the aqueous solution of cyclodextrin.Promptly obtain clarifying thick liquid mixture after stirring.
Embodiment 3: comprise the preparation of sialic highly water-soluble hydroxyethyl beta-cyclodextrin mixture
The 60g hydroxyethyl-is added to 35ml preheats in 50 ℃ the deionized water, stir then and in resulting cyclodextrin aqueous solution, add the 5g sialic acid down.After stirring, obtain the yellow complex solution of translucent syrupy shape.
Claims (4)
1, a kind of by the mixture of forgiving that forms between branched chain beta-cyclodextrin or hydroxyethyl beta-cyclodextrin and the sialic acid.
2, according to the mixture of forgiving of claim 1, the wherein said main body composition of forgiving mixture is branched chain beta-cyclodextrin or hydroxyethyl beta-cyclodextrin.
3, according to the mixture of forgiving of claim 1, wherein said branched chain beta-cyclodextrin is to use crystallization method to obtain behind the non-branched chain beta-cyclodextrin by removing in the solution that contains cyclodextrin.
4, according to the mixture of forgiving of claim 1, wherein forming the object composition of forgiving mixture is sialic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03135996 CN1274704C (en) | 2003-09-29 | 2003-09-29 | Beta-cyclodextrin inclusion composite |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03135996 CN1274704C (en) | 2003-09-29 | 2003-09-29 | Beta-cyclodextrin inclusion composite |
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| Publication Number | Publication Date |
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| CN1603330A CN1603330A (en) | 2005-04-06 |
| CN1274704C true CN1274704C (en) | 2006-09-13 |
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| CN 03135996 Expired - Fee Related CN1274704C (en) | 2003-09-29 | 2003-09-29 | Beta-cyclodextrin inclusion composite |
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| CN118178673B (en) * | 2024-04-07 | 2024-11-05 | 铭畅生物医药南通有限公司 | Sialic acid ester cyclodextrin inclusion compound and preparation method and application thereof |
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