CN116531321A - Hydrogel composite material, preparation method thereof and eye medicine - Google Patents
Hydrogel composite material, preparation method thereof and eye medicine Download PDFInfo
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- CN116531321A CN116531321A CN202310631719.4A CN202310631719A CN116531321A CN 116531321 A CN116531321 A CN 116531321A CN 202310631719 A CN202310631719 A CN 202310631719A CN 116531321 A CN116531321 A CN 116531321A
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- 239000003814 drug Substances 0.000 title abstract description 18
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- XNCNNYXFGGTEMT-BYPYZUCNSA-N (4s)-4-propan-2-yl-1,3-oxazolidine-2,5-dione Chemical compound CC(C)[C@@H]1NC(=O)OC1=O XNCNNYXFGGTEMT-BYPYZUCNSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Ophthalmology & Optometry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Medicinal Preparation (AREA)
Abstract
The application relates to the technical field of medical hydrogel materials, in particular to a hydrogel composite material, a preparation method thereof and an eye medicine. The hydrogel composite material comprises hydrogel and EGCG loaded on the hydrogel; the hydrogel comprises methoxypolyethylene glycol amine and L-tyrosine-NCA. The hydrogel composite material provided by the application has no toxic or side effect and has longer retention time on the ocular surface.
Description
Technical Field
The application relates to the technical field of medical hydrogel materials, in particular to a hydrogel composite material, a preparation method thereof and an eye medicine.
Background
Dry eye is a complex ocular surface multiple disease causing multiple clinical symptoms such as dry feel, foreign body feel, burning feel and the like, which affect the work and life quality of patients. Because of the relatively complex mechanism and long treatment period of dry eye, it is becoming an important direction of ophthalmic drug research. The clinical application at the present stage mainly comprises anti-inflammatory drugs and auxiliary therapeutic drugs for promoting the wetting of the ocular surface.
Current drugs for the relief and treatment of dry eye mainly include: artificial tears (PEG and polysaccharides such as hyaluronic acid and carboxymethyl cellulose, etc.) and inhibitors/antagonists of biological function (immune cell or lymphocyte inhibitors/antagonists). However, the artificial tear has short residence time in the ocular surface and needs to be frequently used; while inhibition/antagonism of biological function can cause systemic toxic side effects on the human body after long-term use.
Disclosure of Invention
Based on the above, it is necessary to provide a hydrogel composite material capable of increasing retention time of ocular surface, and free from toxic and side effects, a preparation method thereof and an ocular drug.
In a first aspect, the present application provides a hydrogel composite material comprising a hydrogel and EGCG supported on the hydrogel;
the hydrogel comprises methoxy polyethylene glycol amine and L-tyrosine-NCA.
In some embodiments, the concentration of EGCG in the hydrogel is from 0.25mg/mL to 1.25mg/mL.
In some embodiments, the mass ratio of the methoxypolyethylene glycol amine to the L-tyrosine-NCA is 1: (6-40);
and/or the number average molecular weight of the methoxy polyethylene glycol amine is 2000-5000.
In a second aspect, the present application also provides a method for preparing the hydrogel composite material according to the first aspect, comprising the steps of:
preparing the hydrogel and EGCG solution;
and mixing the hydrogel with the EGCG solution to prepare the hydrogel composite material.
In some embodiments, the mass ratio of EGCG in the EGCG solution to the hydrogel is 1: (1-9);
and/or the concentration of the EGCG solution is 0.25 mg/mL-1.25 mg/mL.
In some embodiments, the step of preparing the hydrogel comprises:
dissolving the methoxy polyethylene glycol amine and the L-tyrosine-NCA in an organic solvent, and carrying out ring-opening polymerization reaction under the atmosphere of protective gas to prepare a block copolymer;
mixing the block copolymer with a precipitator to prepare a precipitate, and freeze-drying the precipitate to prepare gel powder;
the gel powder is dissolved in water to prepare the hydrogel.
In some embodiments, the organic solvent comprises one or more of N, N-dimethylformamide and an alkane solvent;
and/or the precipitant comprises anhydrous diethyl ether and/or petroleum ether.
In some embodiments, the concentration of the gel powder is 10mg/mL to 30mg/mL in water.
In some embodiments, the temperature at which the gel powder is dissolved in water is from 4 ℃ to 37 ℃;
and/or, after mixing the block copolymer with a precipitant, further comprising the step of dialyzing the mixed product with a dialysis bag to filter the precipitate.
In a third aspect, the present application further provides an ophthalmic drug comprising the hydrogel composite of the first aspect.
The hydrogel composite material provided by the application adopts methoxy polyethylene glycol amine (mPEG-NH) 2 ) And L-tyrosine-NCA is used as a raw material to form hydrogel, and epigallocatechin gallate (EGCG) is loaded in the hydrogel to prepare the hydrogel composite material which can be used for xerophthalmia and has no toxic or side effect and long retention time on the ocular surface. The polyamino acid hydrogel containing the PEG chain segment has excellent biocompatibility, can provide good moisturizing effect, and provides hydration protection for the ocular surface microenvironment. And compared with emulsion or water agent, the gel preparation can further improve the retention of the medicine on the ocular surfaceAnd (3) the room(s).
And EGCG with antioxidant effect can be used for repairing ocular surface injury. The biological cause of dry eye is mainly chronic inflammation under the action of oxidative stress, thereby causing ocular surface damage. The introduction of EGCG can radically avoid the generation of oxidative stress, thereby reducing the formation of inflammation and repairing the damage of the ocular surface. And the pure EGCG has poor oxidation resistance due to the existence of phenol structure. The hydrogel is used as a carrier of the antioxidant EGCG, namely intermolecular hydrogen bonding action and pi-pi acting force can be formed between a phenol structure in the L-tyrosine-NCA and a phenol structure in the EGCG, so that a stable and firm loading action can be formed between the hydrogel and the EGCG, and the effect that the EGCG can stably apply medicines is realized. And the introduction of EGCG can reduce the gel forming concentration of the hydrogel, enhance the gel forming property of the hydrogel and improve the residence time of the hydrogel composite material on the ocular surface.
Drawings
In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings that are needed in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present application, and other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 shows amino acids and mPEG-NH in examples 1 to 7 2 H-NMR spectrum of the block copolymer formed;
FIG. 2 is a graph showing the results of rheological property tests of the hydrogel composite materials prepared in examples 3 to 5 and comparative example 1;
FIG. 3 is a graph showing cytotoxicity evaluation results of a pure EGCG solution at a cellular level and a hydrogel composite material prepared in example 3;
FIG. 4 is a graph showing the cytotoxicity evaluation results of the hydrogel (PY 15) obtained in example 3;
FIG. 5 is a graph showing the results of the biocompatibility test of the hydrogel composite material prepared in example 3 during the use of the ocular surface;
FIG. 6 is a graph showing the result of the repairing effect of the hydrogel composite material prepared in example 3 on the corneal injury;
fig. 7 is a graph showing the therapeutic effect of the hydrogel composite material prepared in example 3 on ocular surface damage in dry eye.
Detailed Description
In order to facilitate an understanding of the present application, a more complete description of the present application will now be provided with reference to the relevant figures. Preferred embodiments of the present application are shown in the accompanying drawings. This application may, however, be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein in the description of the application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.
Herein, the structural formulas of L-tyrosine-NCA and EGCG are shown in the following formulas I and II, respectively:
the traditional medicine for xerophthalmia has the defects of short residence time, frequent use and systemic toxic and side effects on human bodies caused by long-term use. Therefore, the application provides the hydrogel composite material which can increase the retention time of the ocular surface and has no toxic or side effect, the preparation method thereof and the ocular medicament.
In a first aspect, the present application provides a hydrogel composite material comprising a hydrogel and EGCG supported on the hydrogel;
the hydrogel comprises methoxy polyethylene glycol amine and L-tyrosine-NCA.
The hydrogel composite material provided by the application adopts methoxy polyethylene glycol amine (mPEG-NH) 2 ) Andthe L-tyrosine-NCA is used as a raw material to form hydrogel, and epigallocatechin gallate (EGCG) is loaded in the hydrogel to prepare the hydrogel composite material which can be used for xerophthalmia and has no toxic or side effect and long retention time on the ocular surface. The polyamino acid hydrogel containing the PEG chain segment has excellent biocompatibility, can provide good moisturizing effect, and provides hydration protection for the ocular surface microenvironment. And compared with emulsion, water, etc., the gel form can further improve the residence time of the medicine on the ocular surface.
And EGCG with antioxidant effect can be used for repairing ocular surface injury. The biological cause of dry eye is mainly chronic inflammation under the action of oxidative stress, thereby causing ocular surface damage. The introduction of EGCG can radically avoid the generation of oxidative stress, thereby reducing the formation of inflammation and repairing the damage of the ocular surface. And the pure EGCG has poor oxidation resistance due to the existence of phenol structure. The hydrogel is used as a carrier of the antioxidant EGCG, namely intermolecular hydrogen bonding action and pi-pi acting force can be formed between a phenol structure in the L-tyrosine-NCA and a phenol structure in the EGCG, so that a stable and firm loading action can be formed between the hydrogel and the EGCG, and the effect that the EGCG can stably apply medicines is realized. And the introduction of EGCG can reduce the gel forming concentration of the hydrogel, enhance the gel forming property of the hydrogel and improve the residence time of the hydrogel composite material on the ocular surface.
In some embodiments, the concentration of EGCG in the hydrogel is 0.25 mg/mL-1.25 mg/mL, e.g., 0.30mg/mL, 0.35mg/mL, 0.40mg/mL, 0.45mg/mL, 0.50mg/mL, 0.55mg/mL, 0.60mg/mL, 0.65mg/mL, 0.70mg/mL, 0.75mg/mL, 0.80mg/mL, 0.85mg/mL, 0.90mg/mL, 0.95mg/mL, 1.00mg/mL. The concentration of EGCG is regulated within the range, so that the problem that the oxidation resistance effect cannot be achieved due to low concentration of EGCG can be avoided, and precipitation caused by overhigh concentration of EGCG can be avoided. Preferably, the concentration of EGCG is 1.25mg/mL.
In the present application, the number average molecular weight of methoxypolyethylene glycol amine is not limited, and methoxypolyethylene glycol amine which is commercially available and has any number average molecular weight known in the art may be used. In some embodiments, the methoxypolyethylene glycol amine has a number average molecular weight of 2000 to 5000, e.g., 2000 or 5000. The methoxypolyethylene glycol amine preferably has a number average molecular weight of 2000, based on economic principles.
In some embodiments, the mass ratio of the methoxypolyethylene glycol amine to the L-tyrosine-NCA is 1: (6-40), for example, 1:6, 1:10, 1:15, 1:30, 1:40. The block length of L-tyrosine-NCA was determined based on the segment length of methoxypolyethylene glycol amine. Preferably, the mass ratio of methoxy polyethylene glycol amine to L-tyrosine-NCA is 1:15.
In a second aspect, the present application further provides a method for preparing the hydrogel composite material according to the first aspect, including steps S100 to S200:
step S100: the hydrogel and EGCG solution were prepared.
In some embodiments, the step of preparing the hydrogel comprises steps S101-S103:
step S101: and dissolving the methoxy polyethylene glycol amine and the L-tyrosine-NCA in an organic solvent, and carrying out ring-opening polymerization reaction under the atmosphere of protective gas to prepare the block copolymer.
In the present application, the choice of the organic solvent is not limited, and an organic solvent commonly used in the field of hydrogel preparation is selected so as to be capable of completely dissolving the methoxypolyethylene glycol amine and the L-tyrosine-NCA. In some embodiments, the organic solvent comprises one or more of N, N-Dimethylformamide (DMF) and an alkane solvent, preferably DMF. Wherein the alkane solvent comprises dichloromethane and/or chloroform.
In the present application, the shielding gas is not limited either, and inert gas and/or nitrogen may be selected. Wherein the inert gas comprises helium and/or argon.
It is understood that the temperature of the ring-opening polymerization reaction may be room temperature and the time may be 70 to 80 hours.
Step S102: mixing the block copolymer with a precipitant to prepare a precipitate, and lyophilizing the precipitate to prepare gel powder.
In the application, the type of the precipitant and the mass ratio of the block copolymer to the precipitant are not limited, and solvents commonly used in the field of precipitation are selected so as to be capable of completely precipitating and separating the block copolymer. In some embodiments, the precipitating agent comprises anhydrous diethyl ether and/or petroleum ether, preferably anhydrous diethyl ether.
In the present application, the conditions of lyophilization are not limited either, as long as the water in the precipitate can be removed and a uniformly dispersed powder can be formed. In some embodiments, the conditions of lyophilization include:
the freeze-drying temperature is-40 ℃ to-50 ℃ and the time is 40h to 60h.
It will be appreciated that in order to remove unreacted small molecules or solvent, after mixing the block copolymer with the precipitant, a step of dialyzing the mixed product using a dialysis bag to filter the precipitate is further included. Wherein the molecular weight cut-off of the dialysis bag can be 3000Da, and the dialysis time can be 24-48 hours.
Step S103: the gel powder is dissolved in water to prepare the hydrogel.
In the present application, the method for observing whether the hydrogel is successfully gelled is not limited, and a method commonly used in the art may be selected, for example, a vial inversion method may be used to observe the gelling condition of the hydrogel.
In some embodiments, the concentration of the gel powder in water is 10mg/mL to 30mg/mL, e.g., 12mg/mL, 15mg/mL, 20mg/mL, 22mg/mL, 25mg/mL. The concentration of the gel powder is regulated within the range, so that the gel state of the hydrogel can be further ensured, and the hydrogel has stronger gel forming property. Furthermore, after EGCG is introduced, the concentration of gel powder can be reduced on the basis of improving the gel forming property of the hydrogel, and preferably, the concentration of the gel powder is 20mg/mL.
In some embodiments, the temperature at which the gel powder is dissolved in water is 4 ℃ to 37 ℃, e.g., 4 ℃, room temperature (25 ℃), 37 ℃; preferably, the temperature at which the gel powder is dissolved in water is 37 ℃.
It is understood that the solvent in the EGCG solution may be water. After the hydrogel is mixed with the EGCG solution, stable and firm loading effect is formed between the hydrogel and the EGCG under intermolecular hydrogen bond action and pi-pi acting force between a phenol structure in the L-tyrosine-NCA and a phenol structure in the EGCG.
In some embodiments, the concentration of EGCG solution is from 0.25mg/mL to 1.25mg/mL.
Step S200: and mixing the hydrogel with the EGCG solution to prepare the hydrogel composite material.
In some embodiments, the mass ratio of EGCG in the EGCG solution to the hydrogel is 1: (1-9). Preferably, the mass ratio of EGCG to hydrogel is 1:3.
According to a specific embodiment, the method for preparing the hydrogel composite material comprises the following steps:
step 1): dissolving the methoxy polyethylene glycol amine and the L-tyrosine-NCA in an organic solvent, and carrying out ring-opening polymerization reaction under the atmosphere of protective gas to prepare a block copolymer;
step 2): mixing the block copolymer with a precipitating agent, dialyzing to prepare a precipitate, and freeze-drying the precipitate to prepare gel powder;
step 3): dissolving the gel powder in water to prepare the hydrogel;
step 4): dissolving EGCG in water to prepare EGCG solution; and
step 5): and mixing the hydrogel with an EGCG solution to prepare the hydrogel composite material.
In a third aspect, the present application further provides an ophthalmic drug comprising the hydrogel composite of the first aspect.
In this application, the ophthalmic drug may specifically be a drug for treating dry eye, such as an eye drop.
The present application is described in further detail below in connection with specific embodiments.
Example 1
Step 1): methoxy polyethylene glycol amine (mPEG-NH) with molecular weight of 2000 2 ) The mass ratio of the L-tyrosine-NCA to the L-tyrosine-NCA is 1:10 in N' N-Dimethylformamide (DMF) and ring-opening polymerization was carried out at room temperature under nitrogen atmosphere for 72 h. Subsequently, anhydrous diethyl ether was added for precipitation, and then dialysis was performed for 48 hours with a dialysis bag having a molecular weight of 3000 Da. Then freeze-drying for 24 hours at the temperature of-80 ℃ to obtain a powder product;
step 2): dissolving the powder product obtained in the step 1) in water, and forming hydrogel with the concentration of 30mg/mL at 37 ℃, which is marked as PY10;
step 3): and dissolving the EGCG in water to form EGCG solution. Then according to the mass ratio of EGCG to PY10 of 1:3 to form a hydrogel loaded with EGCG, designated EGCG@PY10. Wherein the final concentration of EGCG loaded in the hydrogel is 1.25mg/mL. The gel transition temperature is reduced after EGCG is added by observing a vial inversion method, which shows that the interaction between EGCG and hydrogel increases the internal acting force of the hydrogel.
Example 2
The preparation method of example 2 is substantially the same as that of example 1, except that: in step 1), mPEG-NH 2 The mass ratio of the L-tyrosine-NCA to the L-tyrosine-NCA is 1:30; in step 2), the concentration of the hydrogel was 10mg/mL. The method comprises the following specific steps:
step 1): mPEG-NH with molecular weight of 2000 2 And L-tyrosine-NCA are dissolved in N' N-Dimethylformamide (DMF) according to the mass ratio of 1:30, and ring-opening polymerization reaction is carried out at room temperature under the atmosphere of nitrogen for 72 hours. Subsequently, anhydrous diethyl ether was added for precipitation, and then dialysis was performed for 48 hours with a dialysis bag having a molecular weight of 3000 Da. Then freeze-drying for 60 hours at the temperature of-45 ℃ to obtain a powder product;
step 2): dissolving the powder product obtained in the step 1) in water to form PY30. Experiments prove that the powder product has poor solubility in water and cannot form hydrogel.
Example 3
The preparation method of example 3 is substantially the same as that of example 1, except that: in step 1), mPEG-NH 2 The mass ratio of the L-tyrosine-NCA to the L-tyrosine-NCA is 1:15; in step 2), the concentration of the hydrogel was 20mg/mL. The method comprises the following specific steps:
step 1): mPEG-NH with molecular weight of 2000 2 The compound and L-tyrosine-NCA are dissolved in N' N-Dimethylformamide (DMF) according to the mass ratio of 1:15, and ring-opening polymerization reaction is carried out at room temperature under the atmosphere of nitrogen for 72 hours. Subsequently, anhydrous diethyl ether was added for precipitation, and then dialysis was performed for 48 hours with a dialysis bag having a molecular weight of 3000 Da. Then freeze-drying for 60 hours at the temperature of-45 ℃ to obtain a powder product;
step 2): dissolving the powder product obtained in the step 1) in water, and forming hydrogel with the concentration of 20mg/mL at 37 ℃, which is marked as PY15;
step 3): and dissolving the EGCG in water to form EGCG solution. Then according to the mass ratio of EGCG to PY15 of 1:3 to form a hydrogel loaded with EGCG, designated EGCG@PY15. Wherein the final concentration of EGCG loaded in the hydrogel is 1.25mg/mL.
Example 4
The preparation method of example 4 is substantially the same as that of example 3, except that: in step 3), the final concentration of EGCG loaded in the hydrogel was 0.25mg/mL.
Example 5
The preparation method of example 5 is substantially the same as that of example 3, except that: in step 3), the final concentration of EGCG loaded in the hydrogel was 0.75mg/mL.
Example 6
The preparation method of example 6 was substantially the same as that of example 1, except that: in step 1), mPEG-NH 2 The mass ratio of the L-tyrosine-NCA to the L-tyrosine-NCA is 1:6; dissolving the powder product obtained in the step 1) in water to form PY6.PY6 has almost no viscosity and can not be glued.
Example 7
The preparation method of example 7 is substantially the same as that of example 1, except that: in step 1), mPEG-NH 2 The mass ratio of the L-tyrosine-NCA to the L-tyrosine-NCA is 1:40; dissolving the powder product obtained in the step 1) in water to form PY40. Experiments prove that the powder product has poor solubility in water and cannot form hydrogel.
Example 8
The preparation method of example 8 was substantially the same as that of example 1, except that: in step 2), the hydrogel-forming temperature was 0 ℃.
Example 9
The preparation method of example 9 was substantially the same as that of example 1, except that: in step 2), the hydrogel-forming temperature was room temperature (25 ℃).
Comparative example 1
The preparation method of comparative example 1 was substantially the same as that of example 3, except that: step 3) was not performed, i.e. the hydrogel was not loaded with EGCG (final concentration of loaded EGCG in the hydrogel was 0).
Comparative example 2
The preparation method of comparative example 2 was substantially the same as that of example 3, except that: L-phenylalanine-NCA was used in place of L-tyrosine-NCA.
Comparative example 3
The preparation method of comparative example 3 was substantially the same as that of example 3, except that: L-valine-NCA was used instead of L-tyrosine-NCA.
The following table 1 shows the parameters such as raw materials and proportions in the preparation methods of examples 1 to 9 and comparative examples 1 to 3:
TABLE 1
The hydrogel composites prepared in examples 1 to 9 and comparative examples 1 to 3 were subjected to the relevant performance test.
1) Test examples 1 to 3, 6 and 7 amino acids and mPEG-NH 2 The H-NMR spectrum of the block copolymer formed was shown in FIG. 1. As can be seen from FIG. 1, mPEG-NH is utilized 2 The ring-opening polymerization reaction of the amino group and the lactone structure of the L-tyrosine-NCA can be carried out to obtain a block copolymerA polymer. And the amino acids having different segments are used, showing different assembling ability, according to the segment length of PEG. In addition, with the addition of EGCG, the acting force between EGCG and the hydrogel carrier enhances the stability of a polymerization system. Meanwhile, by means of pi-pi acting force and intermolecular hydrogen bonding action between L-tyrosine-NCA and benzene rings in EGCG, the EGCG can be stably loaded in a poly-tyrosine network.
2) The hydrogel composites prepared in examples 3 to 5 and comparative example 1 were subjected to rheological test, and the test results are shown in fig. 2. As can be seen from fig. 2, as EGCG increases, the storage modulus (G') of the drug-loaded gel increases, and intermolecular forces increase, thereby increasing the strength of the hydrogel.
3) The hydrogel composite materials prepared in examples 3-5 and comparative example 1 and the pure EGCG solution (EGCG concentration is 1.25 mg/mL) are tested, and the test results show that the hydrogel loaded with EGCG has a significantly better treatment effect on xerophthalmia than the pure EGCG aqueous solution and the hydrogel material prepared in comparative example 1. By regulating the final concentration of the EGCG loaded in the hydrogel, the expected therapeutic effect cannot be achieved if the final concentration of the EGCG loaded in the hydrogel is too low, and precipitation can be caused if the concentration is too high. The final EGCG load concentration is preferably 1.25mg/mL. At the concentration, the hydrogel composite material has higher safety and slow release property, slower oxidation rate, better EGCG load stability, lower gel forming concentration required by the hydrogel, enhanced gel forming performance and longer ocular surface residence time.
4) At the cellular level, cytotoxicity was evaluated on pure EGCG solution (EGCG concentration of 1.25 mg/mL) and the hydrogel composite material prepared in example 3, and the test results are shown in FIG. 3. EGCG is used as a polyphenol antioxidant, and can complete the biological effects of oxidation resistance and inflammation resistance by means of polyphenol; meanwhile, the polyphenol structure is easily oxidized to become quinone with biotoxicity, so that the patent medicine of EGCG is limited. As can be seen from fig. 3, the hydrogel composite material loaded with EGCG provided by the present application not only can complete hydration of eyes by means of PEG and increase wettability of eye surfaces, but also can effectively combine with EGCG to realize stable loading and loading of EGCG. The hydrogel composite material provided by the application has excellent biocompatibility.
5) Cytotoxicity evaluation was carried out on the hydrogel (PY 15) obtained in example 3, and the test results are shown in FIG. 4. As can be seen from FIG. 4, due to mPEG-NH 2 Both the included PEG segments and amino acids are biological materials with good biocompatibility, and still exhibit low cytotoxicity after polymerization to form hydrogel systems.
6) Animal experiments were performed to evaluate the biocompatibility of the hydrogel composite material (example 3), pure EGCG and pure hydrogel PY15 provided in the present application in the use process of the ocular surface, and the specific steps are as follows:
taking 8-week-old C57BL female mice as a study object, respectively dripping sodium fluorescein solution, PY15, EGCG water solution and EGCG@PY15 into eyes of the female mice, and observing retention conditions of different substances in eyes under a slit lamp at 0min, 5min, 10min, 20min and 30min after dripping. The test results are shown in fig. 5. As can be seen from fig. 5, pure hydrogel PY15 and egcg@py15 loaded with EGCG have no significant toxicity to the ocular surface and do not cause damage to the cornea. Meanwhile, by means of spot dyeing of sodium fluorescein, the EGCG@PY15 can be judged to be capable of increasing the residence time of EGCG on the ocular surface (20 min is increased), and more convenient conditions are provided for increasing the efficacy of the medicine.
7) Drug efficacy evaluation: the repair effect of the hydrogel composite material prepared in example 3 on cornea damage and the treatment effect on ocular surface damage in dry eye are verified by using benzalkonium chloride (BAC) induced dry eye 8-week-old C57BL female mice as an experimental model. The specific method comprises the following steps:
scopolamine hydrobromide, 2.5mg/mL, was subcutaneously injected in female rats three times a day for 7 days to form a dry eye model. Physiological saline, xiidra, aqueous EGCG and egcg@py15 were administered three times daily for 4 days, slit lamp shots were taken on day 0, day 2 and day 4 of treatment, respectively, and the cornea was observed and scored for sodium fluorescein spot staining, and the test results are shown in fig. 6 and 7. As can be seen from fig. 6, the hydrogel composite material provided by the present application has a more efficient and safer repairing effect than the clinically known drug (ritodlast (Xiidra)). As can be seen from fig. 7, the hydrogel composite material prepared in example 3 has an optimal therapeutic effect by comparing the hydrogel composite material with the control group, the physiological saline group and the free EGCG.
9) Rheological tests are carried out on the materials prepared in the example 1 and the comparative examples 2-3, and the test results show that other amino acids cannot form stable loading effect with EGCG, and the retention time of the ocular surface is difficult to improve.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples merely represent a few embodiments of the present application, which are described in more detail and are not to be construed as limiting the scope of the invention. It should be noted that it would be apparent to those skilled in the art that various modifications and improvements could be made without departing from the spirit of the present application, which would be within the scope of the present application. The scope of the patent application is therefore intended to be covered by the appended claims, which description and drawings should be construed in view of the scope of the claims.
Claims (10)
1. A hydrogel composite material, which is characterized by comprising hydrogel and EGCG loaded on the hydrogel;
the hydrogel comprises methoxy polyethylene glycol amine and L-tyrosine-NCA.
2. The hydrogel composite of claim 1, wherein the concentration of EGCG in the hydrogel is between 0.25mg/mL and 1.25mg/mL.
3. The hydrogel composite of claim 1 or 2, wherein the mass ratio of methoxypolyethylene glycol amine to L-tyrosine-NCA is 1: (6-40);
and/or the number average molecular weight of the methoxy polyethylene glycol amine is 2000-5000.
4. A method of preparing a hydrogel composite material according to any one of claims 1 to 3, comprising the steps of:
preparing the hydrogel and EGCG solution;
and mixing the hydrogel with the EGCG solution to prepare the hydrogel composite material.
5. The method of claim 4, wherein the mass ratio of EGCG in the EGCG solution to the hydrogel is 1: (1-9);
and/or the concentration of the EGCG solution is 0.25 mg/mL-1.25 mg/mL.
6. The method of preparing as claimed in claim 4, wherein the step of preparing the hydrogel comprises:
dissolving the methoxy polyethylene glycol amine and the L-tyrosine-NCA in an organic solvent, and carrying out ring-opening polymerization reaction under the atmosphere of protective gas to prepare a block copolymer;
mixing the block copolymer with a precipitator to prepare a precipitate, and freeze-drying the precipitate to prepare gel powder;
the gel powder is dissolved in water to prepare the hydrogel.
7. The method of claim 6, wherein the organic solvent comprises one or more of N, N-dimethylformamide and an alkane solvent;
and/or the precipitant comprises anhydrous diethyl ether and/or petroleum ether.
8. The method according to claim 6, wherein the concentration of the gel powder in water is 10mg/mL to 30mg/mL.
9. The method according to any one of claims 6 to 8, wherein the temperature at which the gel powder is dissolved in water is 4 ℃ to 37 ℃;
and/or, after mixing the block copolymer with a precipitant, further comprising the step of dialyzing the mixed product with a dialysis bag to filter the precipitate.
10. An ophthalmic drug comprising the hydrogel composite of any one of claims 1-3.
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| CN117618655B (en) * | 2024-01-03 | 2024-09-03 | 中国医学科学院放射医学研究所 | Immune regulation hydrogel and preparation method thereof |
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