CN104013969A - Bestatin glycol chitosan and preparation method thereof - Google Patents
Bestatin glycol chitosan and preparation method thereof Download PDFInfo
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- CN104013969A CN104013969A CN201410260315.XA CN201410260315A CN104013969A CN 104013969 A CN104013969 A CN 104013969A CN 201410260315 A CN201410260315 A CN 201410260315A CN 104013969 A CN104013969 A CN 104013969A
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Abstract
The invention belongs to the technical field of a pharmaceutical adjuvant, and discloses glycol chitosan having an aminopeptidase inhibitory activity and a preparation method thereof. The bestatin glycol chitosan is generated through a reaction of bestatin and glycol chitosan under a catalysis condition. In structural formula of the bestatin glycol chitosan, R represents either CH3CO- or H, n is equal to or greater than 20 and equal to or less than 320, and m/(m+n)=0.2-0.8. Physical and chemical indicators of the compound are as follows: the compound is represented as light yellow to white powdery solid which is dissolvable in water, and molecular weight is 80-250KD. By introducing the bestatin to a molecular carbohydrate chain of the glycol chitosan, the compound has a significant inhibitory activity to aminopeptidase. The bestatin glycol chitosan can inhibit aminopeptidase's degradation on small peptide protein, and can serve as a multifunctional adjuvant component in a pharmaceutical process.
Description
Technical field
The present invention relates to a kind of glycol-chitosan derivant of bestatin grafting, belong to the technical field of pharmaceutic adjuvant.
Background technology
In recent years, more and more there is bioactive protein and peptide drugs and be found, because its high efficiency and specificity in physiological function is widely used in treatment various diseases.But because it is easily degraded in vivo, and biological half-life is short, its application is restricted, so exploitation protein and peptide drugs drug-supplying system is a study hotspot.At present, this research is mainly concentrated both ways: the one, to peptide medicament itself improve, modification, embedding etc., to change its physicochemical property; The 2nd, change drug absorption environment, as used enzyme inhibitor, absorption enhancer etc.
Glycol-chitosan is by 6 hydroxyls of chitosan, by ethylene glycol, to be replaced the water-soluble cationic alkaline polysaccharide of gained.Glycol-chitosan has plurality of advantages, as the function of good biological degradability, biocompatibility and promotion drug absorption, and due to ethylene glycol and amino existence, this material can be dissolved in acidity, neutrality and alkaline aqueous solution, in field extensive uses such as food industry and pharmaceutical industries.Amino peptidase is extensively present in intestinal wall absorptive cell surface, be one of main source of degraded in protein peptide class medicine intestinal, and glycol-chitosan itself does not have amino peptidase enzyme inhibit feature.Bestatin is clear and definite as aminopeptidase inhibitor mechanism, active high.Yet bestatin is insoluble in water, under physiological environment pH condition, (as intestinal) easily precipitates, and is therefore difficult to give full play to its effect.
The present invention prepares bestatin glycol-chitosan by chemical modification, the medicines such as Thymopentin, thymus tetrapeptide and thymus tripeptide of take are amino peptidase substrate model, bestatin glycol-chitosan has been carried out to enzyme inhibition activity research, drawn the Cot curve of model drug, respond well, be not reported.
Summary of the invention
The object of the invention is to research and develop and a kind ofly there is amino peptidase and suppress active glycol-chitosan derivant, can be used as the multi-functional auxiliary material component in pharmacy procedure.
Another object of the present invention is to provide above-mentioned glycol-chitosan derivant---the preparation method of bestatin glycol-chitosan.
The structure of bestatin glycol-chitosan of the present invention is:
Wherein, R=CH
3cO-or H; 320>=n>=20; M/ (m+n)=0.2～0.8.
On glycol-chitosan molecule, introduce after bestatin, it is active that this compound has obvious inhibition to amino peptidase.The physical and chemical indexes of this compound: light yellow to white powder solid, be dissolved in acidity, neutrality and alkaline aqueous solution, molecular weight is 80～250KD.
A preparation method for bestatin glycol-chitosan compound, its step is as follows:
1) glycol-chitosan is soluble in water, add bestatin, the mass ratio of glycol-chitosan and bestatin is 1～12.5: 1, pH is adjusted to 5.0～6.8, obtains step 1) solution;
2) in step 1) add 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and N-hydroxy-succinamide in solution, or add their pH value and step 1) solution phase with aqueous solution; Adding water to 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride ultimate density is 0.1～0.4M, and the ultimate density of N-hydroxy-succinamide is 0.005～0.02M, obtains step 2) solution; 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride consumption is 1.9～7.7 times of glycol-chitosan by mass;
3) by step 2) solution lucifuge, stirring at room reaction 3～24 hours, obtains step 3) solution;
4) by step 3) to transfer to molecular cut off be in 8000～14000 daltonian bag filters to solution, take 0.05M hydrochloric acid as dialysis solution dialysis, then take deionized water as dialysis solution dialysis, obtains step 4) solution;
5) by the step 4 in bag filter) solution lyophilization, obtain bestatin glycol-chitosan.
Described dialysis, condition is: lucifuge stirs, and 4 ℃, hydrochloric acid and deionized water are respectively dialysed 36～48 hours, within every 4 hours, changes a dialysis solution.
Described lyophilization, can be by the step 4 in bag filter) solution is transferred to clean beaker or minute installs in clean cillin bottle ,-80 ℃ of pre-freezes 12 hours, then vacuum lyophilization 12～36 hours under-60 ℃ of conditions.
In each above-mentioned step, as long as within the scope of given process conditions, such as: the pH value scope of solution, the molar concentration scope of solution, the time range of stirring at room reaction, the molecular cut off scope of bag filter etc., all can implement the present invention, and products therefrom all has good inhibition activity to amino peptidase.
The present invention also asks for protection bestatin glycol-chitosan and applies in pharmaceutical industry as amino peptidase being had to the active pharmaceutic adjuvant of inhibition.
The present invention is grafted to bestatin on glycol-chitosan strand, obtains bestatin glycol-chitosan.This design can give biomaterial glycol-chitosan enzyme inhibit feature on the one hand; can significantly improve the water solublity of bestatin on the other hand; and utilize the bioadhesion effect help bestatin of glycol-chitosan in local microenvironment (as absorptive cell,intestinal surface) performance enzyme inhibition, thereby just can avoid degraded by protected protein peptide medicament in the situation that bestatin consumption is lower.
The present invention is incorporated into bestatin the novel glycol-chitosan derivant (bestatin glycol-chitosan) of preparing on glycol-chitosan molecule amino peptidase is had to good inhibition activity, can be used as the functional adjuvant in pharmacy procedure.
Accompanying drawing explanation
Fig. 1 is the structural formula figure of bestatin glycol-chitosan of the present invention.
Fig. 2 is the infrared spectrogram of existing glycol-chitosan.
Fig. 3 is the infrared spectrogram of the bestatin glycol-chitosan prepared of the present invention.
Fig. 4 is the uv absorption spectra of glycol-chitosan and bestatin glycol-chitosan of the present invention.
Fig. 5 is glycol-chitosan and the inhibitory action figure of bestatin glycol-chitosan of the present invention to amino peptidase degraded Thymopentin.
Fig. 6 is glycol-chitosan and the inhibitory action figure of bestatin glycol-chitosan of the present invention to amino peptidase degraded thymus tetrapeptide.
Fig. 7 is glycol-chitosan and the inhibitory action figure of bestatin glycol-chitosan of the present invention to amino peptidase degraded thymus tripeptide.
The specific embodiment
Embodiment 1:
Taking 1g glycol-chitosan and add in beaker, add 90ml deionized water, is 6.0 with 5M salt acid for adjusting pH value, adds bestatin 0.08g, and mix homogeneously adds appropriate amount of deionized water to make total liquid volume reach 100ml.Take 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride 1.917g, take N-hydroxy-succinamide 0.058g, together join in aforementioned solution, lucifuge stirring at room 12 hours.After reaction finishes, it is to dialyse in 10000 daltonian bag filters that reactant liquor is transferred to molecular cut off, under 4 ℃ of conditions, take 0.05M HCl as dialysis medium in 5L dialysis solution, dialyse, within every 4 hours, change dialysis solution once, continue dialysis 48 hours, the deionized water of take is dialysed as dialysis medium in 5L dialysis solution, within every 4 hours, change dialysis solution once, continue dialysis 48 hours.Shift dialysis solution in beaker ,-80 ℃ of pre-freezes 12 hours ,-60 ℃ of lyophilizations 24 hours, obtain synthetic product bestatin glycol-chitosan.Gained synthetic product is-20 ℃ of condition lower seal lucifuge kept dry.
Embodiment 2:
Taking 1g glycol-chitosan and add in beaker, add 45ml deionized water, is 6.0 with 5M salt acid for adjusting pH value, adds bestatin 0.3g, mix homogeneously.Taking respectively 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride 1.917g and N-hydroxy-succinamide 0.058g adds in beaker, add 45ml deionized water, with 5M salt acid for adjusting pH value, be 6.0, then merge this solution in the aforementioned solution that contains glycol-chitosan and bestatin, add appropriate amount of deionized water to make total liquid volume reach 100ml, make lucifuge stirring at room 12 hours.After reaction finishes, it is to dialyse in 10000 daltonian bag filters that reactant liquor is transferred to molecular cut off, under 4 ℃ of conditions, take 0.05M HCl as dialysis medium in 5L dialysis solution, dialyse, within every 4 hours, change dialysis solution once, continue dialysis 48 hours, the deionized water of take is dialysed as dialysis medium in 5L dialysis solution, within every 4 hours, change dialysis solution once, continue dialysis 48 hours.Shift dialysis solution in beaker ,-80 ℃ of pre-freezes 12 hours ,-60 ℃ of lyophilizations 24 hours, obtain synthetic product bestatin glycol-chitosan.Gained synthetic product is-20 ℃ of condition lower seal lucifuge kept dry.
Analysis chart 2 and Fig. 3 two width infrared spectrums are visible, in glycol-chitosan infared spectrum, 1664cm-1 place is amido link carbonyl C=O base stretching vibration peak, 1600cm-1 place is amino N-H deformation vibration peak, 2871cm-1 place is C-H stretching vibration peak, 3374cm-1 place is O-H stretching vibration peak and N-H stretching vibration peak in glycol-chitosan molecule, the vibration peak that 1062cm-1 place produces for C-OH; In product, 1066cm-1 place is C-OH vibration peak; 1633cm-1 place is the stack at amido link carbonyl C=O base stretching vibration peak and phenyl ring skeletal vibration peak; peak obviously strengthens with respect to the C-OH vibration peak at 1066cm-1 place by force; 1525cm-1 place is phenyl ring skeletal vibration peak, can know bestatin by inference and mainly on the amino of glycol-chitosan, acylation reaction occur.
Fig. 4, for take deionized water as solvent, makes the solution that concentration is 1mg/ml, the uv absorption spectra recording by glycol-chitosan and bestatin glycol-chitosan.Wherein, 1 uv absorption spectra that is glycol-chitosan, 2 is the uv absorption spectra of bestatin glycol-chitosan.As can be seen from Figure 4, bestatin is connected on glycol-chitosan molecule, due to the impact of phenyl ring chromophore, there are distinctive five absworption peaks in glycol-chitosan derivant between 240～280nm, and wherein maximum peak is positioned at by force 254nm place.
Embodiment 3:
Taking 1g glycol-chitosan and add in beaker, add 45ml deionized water, is 6.0 with 5M salt acid for adjusting pH value, adds bestatin 1g, mix homogeneously.Taking respectively 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride 7.668g and N-hydroxy-succinamide 0.232g adds in beaker, add 45ml deionized water, with 5M salt acid for adjusting pH value, be 6.0, then merge this solution in the aforementioned solution that contains glycol-chitosan and bestatin, add appropriate amount of deionized water to make total liquid volume reach 100ml, make lucifuge stirring at room 12 hours.After reaction finishes, it is to dialyse in 10000 daltonian bag filters that reactant liquor is transferred to molecular cut off, under 4 ℃ of conditions, take 0.05M HCl as dialysis medium in 5L dialysis solution, dialyse, within every 4 hours, change dialysis solution once, continue dialysis 48 hours, the deionized water of take is dialysed as dialysis medium in 5L dialysis solution, within every 4 hours, change dialysis solution once, continue dialysis 48 hours.Shift dialysis solution in beaker ,-80 ℃ of pre-freezes 12 hours ,-60 ℃ of lyophilizations 24 hours both synthetic product bestatin glycol-chitosan.Gained synthetic product is-20 ℃ of condition lower seal lucifuge kept dry.
The inhibitory effect of embodiment 4 embodiment of the present invention 2 products therefroms to amino peptidase degraded Thymopentin.
The measurement and calculation of clearance rate: take krebs-Ringer phosphate buffer as solvent, glycol-chitosan solution and the bestatin glycol-chitosan solution of configuration different quality mark.Add the little peptide of thymus (the present embodiment is Thymopentin), the concentration that makes the little peptide of thymus is 0.1mM, and then mix homogeneously adds amino peptidase (EC3.4.11.2), and making amino peptidase concentration is 0.01U/ml.Sample mix is even, is placed in 37 ℃ of waters bath with thermostatic control, respectively after adding amino peptidase 2,6,12,20,30,40,50,60min sampling cessation reaction, the residual concentration of the little peptide of high effective liquid chromatography for measuring thymus.Draw the little peptide residual concentration of thymus time graph, calculate the corresponding area under curve of each time point and the little peptide total degradation of thymus amount, calculate clearance rate:
∑ M=CL
remove* AUC
Wherein ∑ M is the little peptide degradation amount of thymus, and AUC is area under each time point drug level time graph, CL
removebe clearance rate.
The results are shown in Table 1.
Table 1
As a comparison, table 1 also provides the inhibitory effect of glycol-chitosan to amino peptidase degraded Thymopentin.
Embodiment 5: the inhibitory effect of the embodiment of the present invention 2 products therefroms to amino peptidase degraded thymus tetrapeptide.
The measurement and calculation of clearance rate: the little peptide of thymus is thymus tetrapeptide in the present embodiment, and all the other are with embodiment 4.
The results are shown in Table 2.
Table 2
As a comparison, table 2 also provides the inhibitory effect of glycol-chitosan to amino peptidase degraded thymus tetrapeptide.
Embodiment 6: the inhibitory effect of the embodiment of the present invention 2 products therefroms to amino peptidase degraded thymus tripeptide.
The measurement and calculation of clearance rate: the little peptide of thymus is thymus tripeptide in the present embodiment, and all the other are with embodiment 4.
The results are shown in Table 3.
Table 3
As a comparison, table 3 also provides the inhibitory effect of glycol-chitosan to amino peptidase degraded thymus tripeptide.
The amino peptidase of embodiment 7 embodiment of the present invention 2 products therefroms suppresses experiment
Amino peptidase suppresses experimental technique: take krebs-Ringer phosphate buffer as solvent, glycol-chitosan solution and the bestatin glycol-chitosan solution of configuration different quality mark.Add the little peptide of thymus (being respectively Thymopentin, thymus tetrapeptide and thymus tripeptide in the present embodiment), the concentration that makes the little peptide of thymus is 0.1mM, and then mix homogeneously adds amino peptidase (EC3.4.11.2), and making amino peptidase concentration is 0.01U/ml.Sample mix is even, is placed in 37 ℃ of waters bath with thermostatic control, respectively after adding amino peptidase 2,6,12,20,30,40,50,60min sampling cessation reaction, the residual concentration of the little peptide of high effective liquid chromatography for measuring thymus.Thymopentin group, glycol-chitosan and bestatin glycol-chitosan concentration are 2mg/ml; Thymus tetrapeptide group, glycol-chitosan and bestatin glycol-chitosan concentration are 1mg/ml; Thymus tripeptide group, glycol-chitosan and bestatin glycol-chitosan concentration are 1mg/ml.All matched groups are not containing glycol-chitosan and bestatin glycol-chitosan.Concentration during the little peptide 0min of the thymus of take is 100%, calculates the little peptide of thymus in the residual percentage of each time point.The Thymopentin of drawing, the residual concentration time graph of thymus tetrapeptide and thymus tripeptide is as Fig. 5, Fig. 6 and Fig. 7.
Fig. 5 is glycol-chitosan and the inhibitory action curve of bestatin glycol-chitosan to amino peptidase degraded Thymopentin.As can be known from Fig. 5, glycol-chitosan itself does not suppress the effect of amino peptidase degraded Thymopentin, and each time point and Thymopentin matched group do not have significant difference.And bestatin glycol-chitosan is all significantly higher than matched group at all time points, and residual concentration during 30min is about for 43% when initial, therefore show that bestatin glycol-chitosan has inhibitory action significantly to amino peptidase degraded Thymopentin.
Fig. 6 is glycol-chitosan and the inhibitory action curve of bestatin glycol-chitosan to amino peptidase degraded thymus tetrapeptide.As we know from the figure, glycol-chitosan itself does not suppress the effect of amino peptidase degraded thymus tetrapeptide, presents on the contrary certain facilitation.And bestatin glycol-chitosan is all significantly higher than matched group at all time points, and residual concentration during 20min is about for 24% when initial, therefore show that bestatin glycol-chitosan has inhibitory action significantly to amino peptidase degraded thymus tetrapeptide.
Fig. 7 is glycol-chitosan and the inhibitory action curve of bestatin glycol-chitosan to amino peptidase degraded thymus tripeptide.As we know from the figure, glycol-chitosan itself does not suppress the effect of amino peptidase degraded thymus tripeptide, and each time point and thymus tripeptide matched group do not have significant difference.And bestatin glycol-chitosan is all significantly higher than matched group at all time points, and residual concentration during 40min is about for 38% when initial, therefore show that bestatin glycol-chitosan has inhibitory action significantly to amino peptidase degraded thymus tripeptide.
Comprehensive above-mentioned product of the present invention suppresses experiment to inhibitory effect and the amino peptidase of the little peptide of amino peptidase degraded thymus, can illustrate: bestatin glycol-chitosan is applied in pharmaceutical industry as amino peptidase being had to the active pharmaceutic adjuvant of inhibition.
Those of ordinary skill in the art can understand, and in protection scope of the present invention, for above-described embodiment, modifies, and it is all possible adding and replacing, and it does not all exceed protection scope of the present invention.
Claims (6)
1. a bestatin glycol-chitosan, structure is:
Wherein, R=CH
3cO-or H; 320>=n>=20; M/m+n=0.2～0.8.
2. bestatin glycol-chitosan according to claim 1, is characterized in that, described bestatin glycol-chitosan, and for light yellow, to white powder solid, molecular weight is 80～250KD.
3. a preparation method for the bestatin glycol-chitosan of claim 1, its step is as follows:
1) glycol-chitosan is soluble in water, add bestatin, the mass ratio of glycol-chitosan and bestatin is 1～12.5: 1, pH is adjusted to 5.0～6.8, obtains step 1) solution;
2) in step 1) add 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and N-hydroxy-succinamide in solution, or add their pH value and step 1) solution phase with aqueous solution; Adding water to 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride ultimate density is 0.1～0.4M, and the ultimate density of N-hydroxy-succinamide is 0.005～0.02M, obtains step 2) solution; 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride consumption is 1.9～7.7 times of glycol-chitosan by mass;
3) by step 2) solution lucifuge, stirring at room reaction 3～24 hours, obtains step 3) solution;
4) by step 3) to transfer to molecular cut off be in 8000～14000 daltonian bag filters to solution, take 0.05M hydrochloric acid as dialysis solution dialysis, then take deionized water as dialysis solution dialysis, obtains step 4) solution;
5) by the step 4 in bag filter) solution lyophilization, obtain bestatin glycol-chitosan.
4. the preparation method of bestatin glycol-chitosan according to claim 3, is characterized in that, described dialysis, and condition is: lucifuge stirs, and 4 ℃, hydrochloric acid and deionized water are respectively dialysed 36～48 hours, within every 4 hours, changes a dialysis solution.
5. according to the preparation method of the bestatin glycol-chitosan described in claim 3 or 4, it is characterized in that, described lyophilization, by the step 4 in bag filter) solution is transferred to beaker or minute installs in cillin bottle,-80 ℃ of pre-freezes 12 hours, then vacuum lyophilization 12～36 hours under-60 ℃ of conditions.
6. a purposes for the bestatin glycol-chitosan of claim 1, bestatin glycol-chitosan is with doing that amino peptidase is had to the pharmaceutic adjuvant that suppresses active.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060040850A1 (en) * | 2002-03-15 | 2006-02-23 | Siegfried Ansorge | Use of enzyme inhibitors with aminopeptidase n and/or dipeptidylpeptidase IV activities and pharmaceutical preparations produced therefrom for the therapy and prevention of dermatological diseases with seborrhoeic hyperproliferation and altered differentiation states |
| CN101829338A (en) * | 2010-04-23 | 2010-09-15 | 武汉理工大学 | Novel amphiphilic macromolecular prodrug based on thiopurine medicine and preparation method thereof |
| CN102988999A (en) * | 2012-05-09 | 2013-03-27 | 中国药科大学 | Curcumin-polysaccharide conjugate as well as preparation method and application thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060040850A1 (en) * | 2002-03-15 | 2006-02-23 | Siegfried Ansorge | Use of enzyme inhibitors with aminopeptidase n and/or dipeptidylpeptidase IV activities and pharmaceutical preparations produced therefrom for the therapy and prevention of dermatological diseases with seborrhoeic hyperproliferation and altered differentiation states |
| CN101829338A (en) * | 2010-04-23 | 2010-09-15 | 武汉理工大学 | Novel amphiphilic macromolecular prodrug based on thiopurine medicine and preparation method thereof |
| CN102988999A (en) * | 2012-05-09 | 2013-03-27 | 中国药科大学 | Curcumin-polysaccharide conjugate as well as preparation method and application thereof |
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