CN113527657B - Polyethylene glycol modified cystine amide derivative, preparation and application thereof - Google Patents
Polyethylene glycol modified cystine amide derivative, preparation and application thereof Download PDFInfo
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- CN113527657B CN113527657B CN202110808607.2A CN202110808607A CN113527657B CN 113527657 B CN113527657 B CN 113527657B CN 202110808607 A CN202110808607 A CN 202110808607A CN 113527657 B CN113527657 B CN 113527657B
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- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/334—Polymers modified by chemical after-treatment with organic compounds containing sulfur
- C08G65/3348—Polymers modified by chemical after-treatment with organic compounds containing sulfur containing nitrogen in addition to sulfur
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
Abstract
The invention belongs to the technical field of drug polymer materials and chemical drugs, and in particular relates to a polyethylene glycol modified cystine amide derivative, and preparation and application thereof. The derivative has a general formula shown in a formula (I):
in the formula (I), R 1 And R is 2 Each independently is a C6-C30 monocyclic or polycyclic aromatic acid or aromatic heterocyclic acid linked to the amino group of cystine through an amide bond; mPEG represents polyethylene glycol, wherein the single end of the polyethylene glycol is blocked by an inert group, and the other end is connected with X 1 And X 2 The groups are respectively connected with two carboxyl groups of cystine; x is X 1 And X 2 Each independently is an amino group or a hydrazide. The polyethylene glycol modified cystine amide derivative provided by the invention is used as a novel Gemini amino acid surfactant, has low critical micelle concentration, is safe and nontoxic, has no stimulation and good biodegradability, and can be used as a carrier of a water-insoluble and fat-soluble drug delivery system.
Description
Technical Field
The invention belongs to the technical field of drug polymer materials and chemical drugs, and in particular relates to a polyethylene glycol modified cystine amide derivative, and preparation and application thereof.
Background
The Gemini surfactant has a molecular structure containing two molecular monomer surfactants which are connected at an ion head group through chemical bond, and has novel structure and higher performance than the traditional monomer surfactant, but has higher price, and at present, the Gemini surfactant cannot be industrially produced on a large scale.
Amino acid surfactants are surfactants which use amino acid or short peptide groups as hydrophilic groups, have basic properties such as surfactant wetting, washing, foaming, solubilization, emulsification and the like, and have the advantages of low irritation, low toxicity, good surface activity, biodegradability, environmental compatibility and the like, so that the amino acid surfactants are widely paid attention to and applied to the industries of foods, medicines and cosmetics.
The cystine has two amino groups and carboxyl groups, and the structure is similar to disulfide bonds to connect the two cysteines, so that hydrophobic groups are introduced to the two amino groups of the cystine, and hydrophilic long chains are introduced to the two carboxyl groups to synthesize the Gemini surfactant. The common quaternary ammonium salt type cystine cationic Gemini surfactant and carboxylate type cystine anionic Gemini surfactant are researched very well, but the cystine nonionic Gemini surfactant which is safe, nontoxic, non-irritating and good in biodegradability is very rare.
Liu Bing and the like, wherein L-cystine and alkyl acyl chlorides with different carbon chain lengths are used for synthesizing long-chain alkyl cystine derivatives, the cystine Gemini surfactant, cholesterol, span80 and Tween80 are mixed according to a certain proportion, chlorophyll is used as a model medicament, and the chlorophyll cystine Gemini surfactant vesicles are prepared by a film dispersion ultrasonic method, so that the obtained four kinds of cystine Gemini surfactants have higher surface activity, and the surface activity of the four kinds of cystine Gemini surfactants is reduced along with the extension of double carbon chains; the CMC value of the four synthesized products is 10 - 5 The CMC value is higher in g/mL, the drug encapsulation efficiency and encapsulation stability are poor when the CMC value is used for drug delivery, the hemolysis is obviously enhanced when the concentration exceeds the critical micelle concentration, and the risk of hemolysis is higher.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a polyethylene glycol modified cystine amide derivative, and preparation and application thereof, wherein two amino groups of cystine are respectively connected with aromatic acid or aromatic heterocyclic acid through amide bonds, and simultaneously two carboxyl groups of cystine are respectively modified by polyethylene glycol to synthesize a Gemini surfactant which is used for a drug delivery system carrier, so that the technical problems of low safety, higher CMC value, low drug encapsulation rate, poor stability and the like of the application of the cystine-based Gemini surfactant in the drug delivery system carrier in the prior art are solved.
To achieve the above object, the present invention provides a polyethylene glycol modified cystine amide derivative (Ar-cys-mPEG) having a general formula as shown in formula (I):
in the formula (I), R 1 And R is 2 Each independently is a C6-C30 monocyclic or polycyclic aromatic acid or aromatic heterocyclic acid linked to the amino group of cystine through an amide bond;
mPEG represents polyethylene glycol, wherein the single end of the polyethylene glycol is blocked by an inert group, and the other end is connected with X 1 And X 2 The group is respectively connected with two carboxyl groups of cystine; x is X 1 And X 2 Each independently is an amino (-NH) 2 ) Or hydrazide (-NH-NH-).
In a preferred embodiment, R 1 And R is 2 Each independently is a benzene ring-containing amino acid or a benzene ring-containing dipeptide linked to the amino group of cystine through an amide bond.
In a preferred embodiment, R 1 And R is 2 Each independently is phenylalanine or tyrosine linked to the amino group of cystine through an amide bond.
In a preferred embodiment, R 1 And R is 2 Each independently is niacin, cinnamic acid, mandelic acid or ferulic acid linked to the amino group of cystine by an amide bond.
In a preferred embodiment, the inert group is methoxy or methyl.
In a preferred embodiment, the polyethylene glycol has a molecular weight of 500 to 10000.
Preferably, the polyethylene glycol is PEG1000, PEG1500, PEG2000, PEG3000, PEG4000, PEG5000, PEG6000, PEG8000.
Further preferably, the polyethylene glycol is PEG2000, PEG4000, PEG5000.
According to another aspect of the present invention, there is provided a process for the preparation of said derivative comprising the steps of:
(1) Carrying out amidation reaction on aromatic acid chloride or aromatic heterocyclic acid chloride and cystine to obtain cystine amide derivative;
(2) And (3) reacting the cystine amide derivative obtained in the step (1) with polyethylene glycol with tail end modified amino or hydrazide groups in the presence of EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) and under an acidic condition to obtain the polyethylene glycol modified cystine amide derivative.
In a preferred embodiment, the pH of the composition is between 4.5 and 5 under acidic conditions.
According to another aspect of the present invention there is provided the use of said polyethylene glycol modified cystine amide derivatives as solubilisers, absorption enhancers, emulsifiers or carriers for poorly water-soluble/fat-soluble drug delivery systems.
According to another aspect of the present invention there is provided a nanomicelle comprising the polyethylene glycol modified cystine amide derivative.
Preferably, the nano micelle is prepared from the polyethylene glycol modified cystine amide derivative by a direct dissolution method, a fusion method, a solvent evaporation method or a dialysis method and the like.
According to another aspect of the present invention, there is provided a poorly water-soluble and/or fat-soluble drug delivery system comprising a drug and the nano-micelle, wherein the nano-micelle is used as a drug delivery system carrier.
Preferably, the particle size of the nano micelle is 5-1000 nm.
In general, the above technical solutions conceived by the present invention have the following beneficial effects compared with the prior art:
(1) The invention provides a polyethylene glycol modified cystine amide derivative (Ar-cys-mPEG for short), which is prepared by respectively connecting two amino groups of cystine with aromatic acid or aromatic heterocyclic acid through amide bonds, and simultaneously respectively modifying two carboxyl groups of cystine with polyethylene glycol. Most of indissolvable drugs have complex aromatic structures, poor water solubility limits the application of the indissolvable drugs in clinic, and pi-pi accumulation effect between the polyethylene glycol modified cystine amide derivative and the indissolvable drugs with the aromatic structures is carried out, so that pi-pi conjugation effect between aromatic ring electron clouds of the indissolvable drugs is greatly enhanced in fat solubility compared with fatty acid, and meanwhile, excellent synergistic effect can be shown with other surfactants, so that a new scheme is provided for the transmission of indissolvable drugs in clinic.
(2) According to the polyethylene glycol modified cystine amide derivative Ar-cys-mPEG provided by the invention, two carboxyl groups of cystine are respectively modified by polyethylene glycol, so that the solubility and the hardness resistance of the cystine amide derivative Ar-cys-mPEG serving as a surfactant are greatly improved, and the defects of carboxylate surfactants are overcome.
(3) According to the invention, the Ar-cys-mPEG enhances the hydrophobicity and hydrophilicity of different coupling groups of cystine, and the Ar-cys-mPEG surfactant is closely arranged on an interface, so that aggregation and micelle formation tend to occur, the adsorption area of molecules at the interface is greatly reduced, the molecular adsorption weight is not easy to reach a saturated state, and higher surface activity and lower critical micelle concentration are displayed.
(4) The polyethylene glycol modified cystine amide derivative provided by the invention is a gemini star-type surfactant, and the particle size of the prepared nano particle is 10-300 nm. The derivative can be used as a solubilizer, an absorption promoter, an emulsifier and a water-insoluble and fat-soluble drug delivery system carrier in preparation research. The Ar-cys-mPEG provided by the invention is a nonionic amino acid surfactant, is subjected to enzymatic degradation in vivo, is safe and nontoxic, has no stimulation, has good biodegradability, and can be used as a carrier of a water-insoluble and fat-soluble drug delivery system.
Drawings
FIG. 1 is a synthetic route diagram of phenylalanine-cystine-mPEG according to example 1 of the present invention.
FIG. 2 is a synthetic route pattern for tyrosine-cystine-mPEG of example 2 of the invention.
FIG. 3 is a synthetic route pattern for niacin-cystine-mPEG of example 3 of the present invention.
FIG. 4 is a graph of particle size of phenylalanine-cystine-mPEG 4000 entrapped poorly soluble drug micelle solution.
FIG. 5 is an electron microscope image of docetaxel-Tyr-cys-mPEG 2000 nano-micelle.
Detailed Description
The present invention will be described in further detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
Most of insoluble drugs have complex aromatic structures, poor water solubility limits the clinical application of the drugs, and pi-pi accumulation effect between polyethylene glycol modified cystine amide derivatives and insoluble drugs provided by the invention is used for entrapment, so that a new scheme is provided for the clinical delivery of insoluble drugs. The polyethylene glycol modified cystine amide derivative provided by the invention is used as a novel Gemini amino acid surfactant, has the advantages of novel structure, low critical micelle concentration, high surface activity, synergistic effect, safety, no toxicity, no stimulation and good biodegradability, and can be used as a carrier of a water-insoluble and fat-soluble drug delivery system.
The following are specific examples:
example 1
Synthesis of phenylalanine-cystine-mPEG
19.38g of Fmoc-D-phenylalanine, 20mL of chloroform and 6.0mL of thionyl chloride are weighed respectively, added into a 100mL flask, reacted for 2.0h at 60 ℃, distilled off chloroform and thionyl chloride under reduced pressure, and then recrystallized by petroleum ether to obtain white crystal Fmoc-D-phenylalanine acyl chloride. Weighing 20.23g of Fmoc-D-phenylalanine acyl chloride, dissolving with 25mL of acetone for later use, adding 12.01-g L-cystine and 10mL of acetone into a 100mL flask, slowly dropwise adding the Fmoc-D-phenylalanine acyl chloride acetone solution under ice bath and magnetic stirring, heating to room temperature after dropwise adding, stirring for reaction for 4 hours, decompressing and distilling off the acetone, and separating out solids, filtering, washing and drying to obtain the Fmoc-D-phenylalanine-L-cystine.
2.1g of Fmoc-D-phenylalanine-L-cystine and mPEG were weighed out separately 2000 -NH 2 24g is dissolved by 300mL of anhydrous dichloromethane, 1.5g of DCC is added, stirring reaction is carried out for 48 hours, excessive cold diethyl ether is used for precipitation, suction filtration and washing are carried out, 200mL of anhydrous dichloromethane is dissolved, 20mL of pyridine is added, stirring reaction is carried out for 1 hour, excessive cold diethyl ether is used for precipitation, suction filtration, washing and drying are carried out, and D-phenylalanine-L-cystine-mPEG is obtained 2000 (Phe-cys-mPEG 2000) and the synthetic route is shown in FIG. 1.
Example 2
Synthesis of tyrosine-cystine-mPEG
12.01g Fmoc-L-tyrosine, 20mL chloroform and 6.0mL thionyl chloride are respectively weighed and added into a 100mL flask, the mixture is reacted for 2.0h at 60 ℃, the chloroform and the thionyl chloride are distilled off under reduced pressure, and then petroleum ether is recrystallized, so that white crystal Fmoc-L-tyrosine acyl chloride is obtained. 21.14g of Fmoc-L-tyrosine acyl chloride is weighed and dissolved in 25mL of DMF for standby, 12.01-g L-cystine, 20mL of concentrated ammonia water and 15mL of DMF are added into a 100mL flask, under the ice bath and magnetic stirring conditions, the Fmoc-L-tyrosine acyl chloride DMF solution is slowly added dropwise, the temperature is raised to room temperature after the dropwise addition, the stirring reaction is carried out for 4 hours, the DMF is distilled off under reduced pressure, and the Fmoc-L-tyrosine-L-cystine is obtained by recrystallization by ethanol/water/ethyl acetate. 2.4g of Fmoc-L-tyrosine-L-cystine and mPEG are respectively weighed 4000 -NH 2 40g is dissolved by 400mL of anhydrous dichloromethane, 1.5g of DCC is added, stirring reaction is carried out for 48 hours, excessive cold diethyl ether is used for precipitation, suction filtration and washing are carried out, 200mL of anhydrous dichloromethane is dissolved, 20mL of pyridine is added, stirring reaction is carried out for 1 hour, excessive cold diethyl ether is used for precipitation, suction filtration, washing and drying are carried out, and L-tyrosine-L-cystine-mPEG is obtained 4000 (Tyr-cys-mPEG 4000) and the synthetic route is shown in FIG. 2.
Example 3
Synthesis of Niacin-cystine-mPEG
5.56g of nicotinic acid, 20mL of chloroform and 6.0mL of thionyl chloride are respectively weighed and added into a 100mL flask, the mixture is reacted for 2.0h at 60 ℃, the chloroform and the thionyl chloride are distilled off under reduced pressure, and then petroleum ether is recrystallized, so that white crystal nicotinic acid chloride is obtained. Weighing 7.12g of nicotinic acid acyl chloride, dissolving with 25mL of acetone for later use, adding 12.01-g L-cystine, 25.0mL of sodium hydroxide solution (2.5 mol/L) and 10mL of acetone into a 100mL flask, slowly dropwise adding the nicotinic acid acyl chloride acetone solution and 5.0mL of sodium hydroxide solution (0.5 mol/L) under ice bath and magnetic stirring conditions, heating to room temperature after dropwise adding, stirring for reacting for 4h, decompressing and distilling acetone, dropwise adding dilute sulfuric acid solution until the solution is weakly acidic, precipitating solids, filtering, washing and drying to obtain nicotinic acid-L-cystine. 2.0g of nicotinic acid-L-cystine and mPEG are respectively weighed 5000 -NHNH 2 60g of the extract is dissolved by 500mL of anhydrous dichloromethane, 2.0g of EDC is added, the mixture is stirred and reacted for 48 hours, excessive cold diethyl ether is used for precipitation, suction filtration, washing and drying are carried out, and nicotinic acid-L-cystine-mPEG is obtained 5000 (VPP-cys-mPEG 5000), the synthetic route is shown in FIG. 3.
Example 4
Determination of phenylalanine-cystine-mPEG 2000 Critical micelle concentration
The surface tension of phenylalanine-cystine-mPEG 1000 aqueous solution at each concentration at 25 ℃ is measured by using a Williammi hanging tablet method, and the method is as follows: accurately weighing 10mg Phe-cys-mPEG 2000, placing in a 100mL volumetric flask, dissolving with deionized water, and fixing volume to obtain 1X 10 -4 g/mL Phe-cys-mPEG 2000 standard aqueous solution; after standing stably, transferring 50mL of the solution to a 100mL volumetric flask by using a pipette, and fixing the volume to obtain 5X 10 -5 g/mL of Phe-cys-mPEG 2000 aqueous solution was diluted in the same way and in different proportions, each 1X 10 was prepared -5 g/mL、5*10 -6 g/mL、1*10 -6 g/mL、5*10 -7 g/mL、1*10 -7 g/mL of Phe-cys-mPEG 2000 aqueous solution; accurately weighing Phe-cys-mPEG 2000, placing in a 100mL volumetric flask, dissolving with deionized water, and fixing volume to obtain 1X 10 -2 g/mL、1*10 -3 g/mL Phe-cys-mPEG 2000 standard aqueous solution. The surface tension of deionized water at 25 ℃ is measured by experiments, and after the solution is stabilized, the solution is respectivelyThe surface tension of each concentration of Phe-cys-mPEG 2000 solution was determined at 25 ℃. The experiment shows that the critical micelle concentration of Phe-cys-mPEG 2000 is 9.32 x 10 -7 g/mL。
Example 5
Preparation of docetaxel-Phe-cys-mPEG 2000 nano-micelle
Docetaxel 20.0mg and Phe-cys-mPEG 2000.0 mg were weighed, fully dissolved with 2mL of dichloromethane, removed by rotary evaporation to form a film, and added with 4mL of deionized water to dissolve the film to form a docetaxel-Phe-cys-mPEG 2000 nano-micelle aqueous solution. And measuring indexes such as particle size and particle size distribution, morphology, encapsulation efficiency, stability and the like. The average particle size of the micelle solution is 16nm, the particle size is uniform, and the encapsulation rate of the docetaxel is 96.4%. The micelle solution is still clear and free from turbidity after being placed in a stability test box at 40 ℃ for 1 month, and the encapsulation rate of the docetaxel is measured to be 95.8%. 5% of sucrose is added as a freeze-drying protective agent, and freeze-drying is carried out to prepare a freeze-dried preparation, wherein an electron microscopic image of freeze-dried powder is shown in figure 5, and the powder has moderate roundness and uniform size.
Example 6
Preparation of paclitaxel-Tyr-cys-mPEG 4000 nano micelle
Weighing 20.0mg of paclitaxel, 60.0mg of Tyr-cys-mPEG, fully dissolving the paclitaxel and the Tyr-cys-mPEG with 2mL of absolute ethyl alcohol, pouring the mixed solution into a dialysis bag, dialyzing the solution for 24h with 1L of deionized water, and filtering the solution after dialysis to form the paclitaxel-Tyr-cys-mPEG 4000 nano micelle aqueous solution. And measuring indexes such as particle size and particle size distribution, morphology, encapsulation efficiency, stability and the like. The drug-loaded nano micelle has the advantages of 24nm of flat particle diameter, uniform particle size, narrow distribution and good micelle formation. The encapsulation efficiency of the paclitaxel is 94.3%. The micelle solution is still clear and free from turbidity after being placed in a stability test box at 40 ℃ for 1 month, and the encapsulation rate of the paclitaxel is measured to be 94.0%.
Example 7
Preparation of voriconazole-VPP-cys-mPEG 5000 nano micelle
20.0mg of voriconazole and 5000.0 mg of VPP-cys-mPEG are weighed, stirred with 4mL of deionized water for 4 hours at room temperature, and filtered to form a voriconazole-VPP-cys-mPEG 5000 nano-micelle aqueous solution. And measuring indexes such as particle size and particle size distribution, morphology, encapsulation efficiency, stability and the like. The average particle size of the micelle solution is 20nm, the particle size is uniform, and the encapsulation rate of the docetaxel is 93.3%. The micelle solution is still clear and free from turbidity after being placed in a stability test box at 40 ℃ for 1 month, and the encapsulation rate of the docetaxel is measured to be 92.6 percent.
Determining Critical Micelle Concentration (CMC) values of polyethylene glycol modified cystine amide derivatives, wherein CMC values are less than 10 as shown in table 1 -5 g/mL, indicating good surface activity.
TABLE 1 critical micelle concentration of polyethylene glycol modified cystine amide derivatives
| Cystine amide derivatives | Critical micelle concentration (g/mL) |
| Phe-cys-mPEG 2000 | 9.32*10 -7 |
| Phe-cys- |
2.06*10 -6 |
| Phe-cys-mPEG 5000 | 2.41*10 -6 |
| Tyr-cys-mPEG 2000 | 1.85*10 -6 |
| Tyr-cys- |
3.17*10 -6 |
| Tyr-cys-mPEG 5000 | 3.76*10 -6 |
| VPP-cys-mPEG 2000 | 6.02*10 -6 |
| VPP-cys- |
7.63*10 -6 |
| VPP-cys-mPEG 5000 | 8.54*10 -6 |
The prepared different cystine amide derivatives are used as delivery system carriers of different medicines, the performance of the different cystine amide derivatives is tested according to the method of the embodiment, and the test results are shown in table 2.
FIG. 4 is a graph showing particle size of phenylalanine-cystine-mPEG 4000 entrapped different poorly soluble drug micelle solutions. From fig. 4 and table 2, it can be seen that different polyethylene glycol modified cystine amide derivatives prepared in the embodiment of the invention can be used as carriers of drug delivery systems, the encapsulation rate is greater than 93%, the drug loading rate is greater than 20%, the dispersion coefficient of drug loading micelles is small, the particle size distribution is narrower, and the micelle formation is good.
Table 2 determination of polyethylene glycol modified cystine amide derivatives Properties
It will be readily appreciated by those skilled in the art that the foregoing description is merely a preferred embodiment of the invention and is not intended to limit the invention, but any modifications, equivalents, improvements or alternatives falling within the spirit and principles of the invention are intended to be included within the scope of the invention.
Claims (10)
1. A polyethylene glycol modified cystine amide derivative, which is characterized by having a general formula shown in formula (one):
first, the first is
In the formula (I), R 1 And R is 2 Each independently is a residue obtained by amidation reaction of a C6-C30 monocyclic or polycyclic aromatic acid or aromatic heterocyclic acid with cystine;
mPEG represents polyethylene glycol, wherein the single end of the polyethylene glycol is blocked by an inert group, and the other end is connected with X 1 And X 2 The group is respectively connected with two carboxyl groups of cystine; x is X 1 And X 2 Each independently is an amino group or a hydrazide.
2. The derivative of claim 1, wherein R 1 And R is 2 Each independently is a residue after amidation reaction of a benzene ring-containing amino acid or a benzene ring-containing dipeptide with cystine.
3. The derivative of claim 1, wherein R 1 And R is 2 Each independently is a residue after amidation of phenylalanine or tyrosine with cystine.
4. The derivative of claim 1, wherein R 1 And R is 2 Each independently is a residue after amidation reaction of nicotinic acid, cinnamic acid, mandelic acid or ferulic acid with cystine.
5. The derivative of claim 1, wherein the inert group is methoxy or methyl.
6. The derivative according to claim 1, wherein the polyethylene glycol has a molecular weight of 500 to 10000.
7. A process for the preparation of a derivative according to claim 1, comprising the steps of:
(1) Carrying out amidation reaction on aromatic acid chloride or aromatic heterocyclic acid chloride and cystine to obtain cystine amide derivative;
(2) And (3) reacting the cystine amide derivative obtained in the step (1) with polyethylene glycol with tail end modified amino or hydrazide groups in the presence of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, and obtaining the polyethylene glycol modified cystine amide derivative under an acidic condition.
8. Use of a polyethylene glycol modified cystine amide derivative according to any one of claims 1 to 6 as a solubiliser, absorption enhancer, emulsifier or as a carrier for the preparation of poorly water soluble/fat soluble drug delivery systems.
9. Nanomicelle comprising a polyethylene glycol modified cystine amide derivative according to any one of claims 1 to 6.
10. A poorly water-soluble and/or fat-soluble drug delivery system, comprising a drug and the nano-micelle according to claim 9, wherein the nano-micelle is used as a drug delivery system carrier.
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Citations (4)
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| CN1837191A (en) * | 2005-03-23 | 2006-09-27 | 于勇海 | N-acetyl cysteine derivatives and use thereof |
| CN106883404A (en) * | 2017-01-17 | 2017-06-23 | 沈阳药科大学 | TPGS derivative and its preparation method and application |
| CN110386890A (en) * | 2018-04-12 | 2019-10-29 | 沈阳药科大学 | A kind of medicament-carried nano hydrogel and preparation method thereof based on cystyl amine derivative |
| WO2021050009A2 (en) * | 2019-09-13 | 2021-03-18 | National Science And Technology Development Agency | Composition of renaturation buffer solution for dimeric proteins and method of renaturation dimeric proteins using the composition thereof |
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| CA2346700A1 (en) * | 1998-10-09 | 2000-04-20 | Ajinomoto Co., Inc. | Cysteine derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1837191A (en) * | 2005-03-23 | 2006-09-27 | 于勇海 | N-acetyl cysteine derivatives and use thereof |
| CN106883404A (en) * | 2017-01-17 | 2017-06-23 | 沈阳药科大学 | TPGS derivative and its preparation method and application |
| CN110386890A (en) * | 2018-04-12 | 2019-10-29 | 沈阳药科大学 | A kind of medicament-carried nano hydrogel and preparation method thereof based on cystyl amine derivative |
| WO2021050009A2 (en) * | 2019-09-13 | 2021-03-18 | National Science And Technology Development Agency | Composition of renaturation buffer solution for dimeric proteins and method of renaturation dimeric proteins using the composition thereof |
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