CN101314622A - Salicylic-g-chitosan oligosaccharide grafts and synthesizing process - Google Patents
Salicylic-g-chitosan oligosaccharide grafts and synthesizing process Download PDFInfo
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- CN101314622A CN101314622A CNA2008100626486A CN200810062648A CN101314622A CN 101314622 A CN101314622 A CN 101314622A CN A2008100626486 A CNA2008100626486 A CN A2008100626486A CN 200810062648 A CN200810062648 A CN 200810062648A CN 101314622 A CN101314622 A CN 101314622A
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Abstract
The invention discloses salicylic acid-g-chitosan oligosaccharide graft and the synthetic method thereof. The salicylic acid-g-chitosan oligosaccharide graft, the general structure of which is shown in formula (I), is prepared from alicylic acid and chitosan oligosaccharide by graft polymerization. The molecular weight of chitosan oligosaccharide is 1-100kDa and the deacetylation degree thereof is 70%-100%. A part of amino groups on chitosan oligosaccharide chain in the salicylic acid-g-chitosan oligosaccharide graft are replaced by salicyl, and the substitution degree of the amino group is 1%-80%. The synthetic method is simple and convenient for post-treatment. The prepared salicylic acid-g-chitosan oligosaccharide graft employs hydrotropic compound salicylic acid as the hydrophobic part and chitosan oligosaccharide as the hydrophilic part to form salicylic acid-g-chitosan oligosaccharide micelle as an insoluble drug carrier in an aqueous medium by self-aggregation, thereby the administering means is greatly enriched and the curative effect is improved.
Description
(1) technical field
The present invention relates to salicylic-g-chitosan oligosaccharide grafts and synthetic method thereof.
(2) background technology
The amphipathy macromolecule polymer micelle is a new tool that was used to improve insoluble drug solubleness in recent years as the insoluble drug solid support material.Polymer micelle is by amphiphilic group spontaneous nuclear-shell-like structure that forms in solvent, compares with tensio-active agent commonly used, has lower micelle-forming concentration and stable space structure, can embody distinctive biologically stable.By selection and modification, can give polymer micelle different characteristics, to satisfy the requirement of different pharmaceutical structure and medicine-feeding part to hydrophilic, hydrophobic two part groups.The polymer micelle of nano-scale also has " strengthen infiltration and delay effect ", for neoplasm targeted therapy Special Significance is arranged.
Chitosan is naturally occurring, cationic polysaccharide.Biodegradable, have excellent biological compatibility.Because chitosan has a series of special chemistry and biological property, is suitable as the control slow-released carrier of medicine, is widely used in preparation research.Yet, because chitosan is high molecular, high viscosity and high acetylize, make it be insoluble to general organic solvent and water, this is very big difficulty for its widespread use has caused.In order to improve its solvability, people have carried out many modification work to it, and low molecule oligochitosan wherein molten through peracid and that enzymolysis obtains has kept the advantage of chitosan, has improved its shortcoming, is ideal wetting ability framework material, can be used for the structure of polymer micelle.By regulation and control, can realize the artificial control of micella particle diameter to the oligochitosan molecular weight; It has the ability of opening the cytolemma gap, helps the transhipment that polymer micelle is striden film; A large amount of free free amino groups on the sugar chain are for micella grafting hydrophobic group or other functional groups provide possibility.
Whitfield's ointment is hydrotropisms's compound that insoluble drug solubleness can be improved, and it is slightly soluble in water, and chemical structure is to have adjacent a carboxyl and a hydroxyl on the phenyl ring.It not only contains the π key, and is to exist with the benzene ring structure that insoluble drug mostly has.It mainly is that phenyl ring by π key and insoluble drug interacts, increased and insoluble drug between reactive force, thereby improved the solubleness of insoluble drug in water, also increase the stability after insoluble drug enters water-soluble medium simultaneously.Studies show that the solubleness of taxol in the 3.5M sodium salicylate aqueous solution is 5.543mg/ml, this compares with the solubleness (0.3 μ g/ml) of taxol in pure water, has increased about 18,000 times.In fact, sodium salicylate is widely known by the people and is used for the lyotropy of insoluble drug, and it often is added in the release in vitro medium and builds sink conditions.But as micromolecular compound, sodium salicylate enters cell with medicine, toxigenicity during as pharmaceutical carrier easily.Therefore, need become macromolecular compound as drug carrier material with other compound grafting or block copolymerization Whitfield's ointment.
Wu Xuefen etc. have proposed a kind of chitosan-g-Whitfield's ointment and synthetic method [synthetic chemistry, 2005 the 13rd the 5th phases of volume, 461-463 page or leaf], this method is to be raw material with high molecular chitosan and Whitfield's ointment, pass through to stir or griding reaction at a certain temperature with in the solvent-free or an amount of solvent, make amino and the automatic adsorption dewatering of salicylic carboxyl on the chitosan make chitosan-g-Whitfield's ointment, but this method product postprocessing is cumbersome.And this method is because to adopt high molecular chitosan be raw material, thus on the also inevitable area of the chitosan that makes-g-Whitfield's ointment some defectives of chitosan itself, not good etc. as solubility property, on application, be restricted.
Chinese patent application 200510107271.8 discloses a kind of Whitfield's ointment and chitin-2-, 6 6-bit grafts and preparation method thereof, the structure of its grafts is a grafting Whitfield's ointment on 2 free amino group of chitosan glycogen not only, and on 6 methoxyl groups of chitosan glycogen also grafting Whitfield's ointment.Wherein based on 6 6-bit grafts.
(3) summary of the invention
The technical problem to be solved in the present invention is to provide a kind of salicylic-g-chitosan oligosaccharide grafts and synthetic method, this salicylic-g-chitosan oligosaccharide grafts is in aqueous medium, form the salicylic-g-chitosan oligosaccharide micelle by self aggregation, can be used as the carrier micelle of poorly water soluble drugs.
Salicylic-g-chitosan oligosaccharide grafts of the present invention, its general structure is as follows:
Wherein
Described salicylic-g-chitosan oligosaccharide grafts obtains by oligochitosan and Whitfield's ointment graft polymerization; the molecular weight of described oligochitosan is 1～100kDa; deacetylation is 70～100%; part free amino group on the described salicylic-g-chitosan oligosaccharide grafts mesochite oligonucleotide chain is replaced by salicyloyl, and amino group substitution degree is 1～80%.
The present invention also provides a kind of preparation method of salicylic-g-chitosan oligosaccharide grafts, it is characterized in that described preparation method is: choosing molecular weight is that 1～100kDa, deacetylation are 70～100% oligochitosan, use water dissolution, at 5～95 ℃ of addings Whitfield's ointment of organic solvent dissolution and the solution of carbodiimide, 5～95 ℃ of reactions 2～80 hours, reaction solution got the salicylic-g-chitosan oligosaccharide grafts of structure shown in general formula (I) through separation and purification;
Described organic solvent can dissolve Whitfield's ointment and carbodiimide, also can dissolve each other with the solvent of dissolving oligochitosan, and can be ethanol, acetonitrile etc., preferred alcohol.
The reactant of the present invention amount of substance that feeds intake is gone up the free amino group numbers than 2 in oligochitosan glycogen: Whitfield's ointment: carbodiimide is 1: 0.01-1: 1-20.
Described separation and purification can be taked following steps: reaction solution is through the dialysis purifying, solution lyophilize after the dialysis obtains the salicylic-g-chitosan oligosaccharide grafts crude product, the salicylic-g-chitosan oligosaccharide grafts crude product is soluble in water, supersound process, centrifugal, get the supernatant liquor lyophilize and obtain the pure product of salicylic-g-chitosan oligosaccharide grafts.Described dialysis employing retaining molecular weight is 3500 dialysis membrane, and described supersound process adopts probe ultrasonic.
Oligochitosan of the present invention can be prepared as follows: choose deacetylation and be 70～100% chitosan, under 40-60 ℃ and pH4.0-6.0 condition, add cellulase in cellulase and chitosan ratio 0.1-5: 100 (w/w), degrade chitosan is with the palliating degradation degree of viscosimetry control chitosan, the degradation solution of gained chitosan, remove impurity after filtration, select suitable ultra-filtration membrane ultrafiltration classification, the ultrafiltrated lyophilize gets described oligochitosan.
Further, under 40-60 ℃ and pH4.0-6.0 condition, preferably earlier make the abundant swelling of chitosan, add cellulase then and carry out DeR by stirring.
Compared with prior art, usefulness of the present invention is mainly reflected in:
A) to select molecular weight for use be that 1～100kDa, the metastable oligochitosan of physico-chemical property are as raw material in the present invention, studies show that, molecular weight possesses the good aqueous solubility under higher pH environment less than the oligochitosan of 200kDa, and cytotoxicity significantly reduces with the decline of molecular weight.Therefore, the salicylic-g-chitosan oligosaccharide grafts that the present invention prepares, with hydrotropisms's compound Whitfield's ointment is hydrophobic parts, with the oligochitosan is hydrophilic parts, in aqueous medium, can form the salicylic-g-chitosan oligosaccharide micelle by self aggregation, can be used as the carrier of poorly water soluble drugs (as some cancer therapy drugs), will greatly enrich means of administration, improve curative effect.
B) synthetic method of salicylic-g-chitosan oligosaccharide grafts of the present invention is simple, and aftertreatment is easy.
(4) description of drawings
Fig. 1 is the oligochitosan that embodiment 1 makes
1The H-NMR spectrogram.
Fig. 2 is salicylic
1The H-NMR spectrogram.
Fig. 3 is the salicylic-g-chitosan oligosaccharide that embodiment 1 makes
1The H-NMR spectrogram.
(5) embodiment
Come technical scheme of the present invention is further described with specific embodiment below, but protection scope of the present invention is not limited thereto:
(1) preparation of oligochitosan
Get the chitosan that commercially available molecular weight is 550kDa (70% deacetylation), under 55 ℃ and pH5.0 condition, stirred 2 hours, after making the abundant swelling of chitosan, add cellulase (Shanghai uncle bio tech ltd production difficult to understand), degrade chitosan in cellulase and chitosan ratio 0.5: 100 (w/w).Palliating degradation degree with viscosimetry control chitosan.The degradation solution of gained chitosan is removed impurity after filtration, uses molecular weight to carry out the ultrafiltration classification as the ultra-filtration membrane of 10kDa and 30kDa.Get the ultrafiltrated lyophilize of molecular weight between 10kDa and 30kDa, deacetylation be 70%, the oligochitosan of molecular weight 18.0kDa.
(2) preparation of salicylic-g-chitosan oligosaccharide grafts
Precision takes by weighing 0.2756g carbodiimide (EDC) and 0.0397g Whitfield's ointment (Salicycleacid, SA) place the dehydrated alcohol (A liquid) of 3ml, the accurate then oligochitosan (CSO) that takes by weighing 0.1g places the distilled water (DW) (B liquid) of 6ml, in the time of 25 ℃, the A drop is added in the B liquid, and 25 ℃ are reacted 53hr down.After the cooling, change dialysis tubing (MWCO=3500) dialysis over to after 24 hours, pre-freeze, freeze-drying promptly gets thick product.Thick product is dissolved in a certain amount of water, pop one's head in ultrasonic (400w, ultrasonic 2s, interval 3s, 40 times), the centrifugal 10min of 4000rmp gets supernatant liquor pre-freeze, and freeze-drying promptly gets the solid support material behind the purifying.Employing hydrogen spectrum nucleus magnetic resonance (
1H-NMR) structure of affirmation CSO-g-SA.
Embodiment 2-5
The synthetic prescription listed according to table 1 prepares salicylic-g-chitosan oligosaccharide grafts, and other conditions are with embodiment 1.
Table 1: the synthetic prescription of the Whitfield's ointment-oligochitosan of different molecular weight and percentage of grafting (SA-g-CSO)
| Embodiment | Oligochitosan | Whitfield's ointment | EDC(g) | Whitfield's ointment | Ethanol | Oligochitosan | Distilled water |
| Molecular weight (kDa) | Theoretical substitution value | (g) | (ml) | (g) | (ml) | ||
| |
1,8000 | 50％ | 0.2756 | 0.0397 | 3 | 0.1 | 6 |
| |
2,8000 | 15％ | 0.0826 | 0.0119 | 1 | 0.1 | 6 |
| Embodiment 3 | 2,8000 | 50％ | 0.2756 | 0.0397 | 3 | 0.1 | 6 |
| Embodiment 4 | 2,8000 | 100％ | 0.5512 | 0.0794 | 6 | 0.1 | 6 |
| Embodiment 5 | 4,4000 | 50％ | 0.2756 | 0.0397 | 3 | 0.1 | 6 |
Embodiment 6: the physical and chemical property determining of salicylic-g-chitosan oligosaccharide grafts
The salicylic-g-chitosan oligosaccharide grafts that makes with embodiment 1-5 is as tested object respectively.
A. adopt the trinitro-benzene-sulfonic acid method, measure the amino group substitution degree of gained salicylic-g-chitosan oligosaccharide grafts.
Get Different Weight certain molecular weight oligochitosan (0.5～9mg), accurate claim surely, be dissolved in respectively in the distilled water of 2ml, add the trinitro-benzene-sulfonic acid 2ml of the sodium hydrogen carbonate solution 2ml and 0.1% (w/v) of 4% (w/v), hatch 2h for 37 ℃.Add 2N hydrochloric acid 2ml, shake up, the ultrasonic bubble of driving away is measured absorbance (A) at 344nm wavelength place, obtains the amino group substitution degree typical curve of this molecular weight oligochitosan.The Whitfield's ointment grafts 4mg that takes by weighing an amount of this molecular weight oligochitosan is dissolved in the 2ml redistilled water, with the method operation, measures the absorption value at 344nm wavelength place, presses the amino group substitution degree that typical curve calculates oligochitosan-Whitfield's ointment grafting.
Method of calculation: amino group substitution degree SD=N/X.
Wherein X contains free NH on every molCSO
2Number, N is the substituted NH of every molCSO
2Number, and A sugar/A carrier=[(m sugar/M sugar)/(m carrier/M carrier)] * [X/ (X-N)]
B. adopt the pyrene fluorescence spectrometry, the critical micelle concentration of salicylic-g-chitosan oligosaccharide grafts.
Get 0.5ml 0.0012mg/ml pyrene and put into the test tube of 10ml, put into 50 ℃ of baking ovens and volatilize pyrene (about 6hr).The blank carrier soln 5ml of preparation 0.05mg/ml～500mg/ml different concns joins the blank carrier soln of these each concentration of 5ml in the test tube that volatilizes pyrene, and the final concentration that makes pyrene is 7 * 10
-7MolL
-1Jolting is spent the night in 37 ℃ shaking table.Measure fluorescence.Excitation spectrum is fixed on 339nm, the slit stuck-at-0nm of excitation spectrum, the slit of emmission spectrum is fixed on 2.5nm, and sweep velocity is 1500nm/min, exciting voltage is a 400V. scanning 350-450nm emmission spectrum, measures the fluorescence intensity of pyrene at 374nm, 384nm place.The I that obtains according to mensuration
374/ I
384Calculate critical micelle concentration.
C. measure the particle diameter and the Zeta potential of salicylic-g-chitosan oligosaccharide grafts micelle.
Get Whitfield's ointment-g-chitosan oligosaccharide grafts 10mg, the accurate title, decide, and is dissolved in distilled water, pops one's head in ultrasonic 20 times (500w, work 2s stops 3s), is settled to 10ml, the salicylic-g-chitosan oligosaccharide grafts micelle solution of preparation 1mg/ml.The particle diameter and the Zeta potential of Zetasizer 3000HS analysis-e/or determining oligochitosan-Whitfield's ointment grafts micelle.
After measured, the physico-chemical property of oligochitosan-Whitfield's ointment grafts sees Table 2
The physico-chemical property (n=3) of table 2. oligochitosan-Whitfield's ointment grafts
| Embodiment | Oligochitosan molecular weight (kDa) | Salicylic theoretical substitution value | Amino group substitution degree (%) | Critical micelle concentration (μ g/ml) | The equal particle diameter of Z (nm) | Zeta potential (mV) |
| |
1,8000 | 50％ | 12.41±0.47 | 454.79 | 481.0 | 39.9±38.3 |
| |
2,8000 | 15％ | 8.94±1.31 | 368.89 | 513.2 | 51.9±22.9 |
| Embodiment 3 | 2,8000 | 50％ | 11.44±1.75 | 163.98 | 461.8 | 48.6±9.9 |
| Embodiment 4 | 2,8000 | 100％ | 23.39±2.63 | 78.90 | 440.8 | 44.1±1.6 |
| Embodiment 5 | 4,4000 | 50％ | 4.26±0.47 | 78.89 | 12209.4 | 51.5±1.6 |
Claims (9)
1, a kind of salicylic-g-chitosan oligosaccharide grafts, its general structure is as follows:
Wherein
Described salicylic-g-chitosan oligosaccharide grafts obtains by oligochitosan and Whitfield's ointment graft polymerization; the molecular weight of described oligochitosan is 1～100kDa; deacetylation is 70～100%; part amino on the described salicylic-g-chitosan oligosaccharide grafts mesochite oligonucleotide chain is replaced by salicyloyl, and amino group substitution degree is 1～80%.
2, a kind of preparation method of salicylic-g-chitosan oligosaccharide grafts as claimed in claim 1, it is characterized in that described preparation method is: choosing molecular weight is that 1～100kDa, deacetylation are 70～100% oligochitosan, use water dissolution, at 5～95 ℃ of addings Whitfield's ointment of organic solvent dissolution and the solution of carbodiimide, 5～95 ℃ of reactions 2～80 hours, reaction solution got described salicylic-g-chitosan oligosaccharide grafts through separation and purification.
3, the preparation method of salicylic-g-chitosan oligosaccharide grafts as claimed in claim 2, it is characterized in that the described reactant amount of substance that feeds intake goes up the free amino group numbers than 2 in oligochitosan glycogen: Whitfield's ointment: carbodiimide is 1: 0.01-1: 1-20.
4, the preparation method of salicylic-g-chitosan oligosaccharide grafts as claimed in claim 2, it is characterized in that described separation and purification is: reaction solution is through the dialysis purifying, solution lyophilize after the dialysis obtains the salicylic-g-chitosan oligosaccharide grafts crude product, the salicylic-g-chitosan oligosaccharide grafts crude product is soluble in water, supersound process, centrifugal, get the supernatant liquor lyophilize and obtain the pure product of salicylic-g-chitosan oligosaccharide grafts.
5, the preparation method of salicylic-g-chitosan oligosaccharide grafts as claimed in claim 2 is characterized in that described organic solvent is ethanol or acetonitrile.
6, the preparation method of salicylic-g-chitosan oligosaccharide grafts as claimed in claim 4 is characterized in that described dialysis employing retaining molecular weight is 3500 dialysis membrane.
7, the preparation method of salicylic-g-chitosan oligosaccharide grafts as claimed in claim 4 is characterized in that described supersound process adopts probe ultrasonic.
8, as the preparation method of the described salicylic-g-chitosan oligosaccharide grafts of one of claim 2～7, it is characterized in that described oligochitosan is prepared as follows: choose deacetylation and be 70～100% chitosan, under 40-60 ℃ and pH4.0-6.0 condition, add cellulase in cellulase and chitosan ratio 0.1-5: 100 (w/w), degrade chitosan, palliating degradation degree with viscosimetry control chitosan, the degradation solution of gained chitosan, remove impurity after filtration, select suitable ultra-filtration membrane ultrafiltration classification, the ultrafiltrated lyophilize gets described oligochitosan.
9, the preparation method of salicylic-g-chitosan oligosaccharide grafts as claimed in claim 8 is characterized in that stirring and making the abundant swelling of chitosan under 40-60 ℃ and pH4.0-6.0 condition, adds cellulase then and carries out DeR.
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