CN113980303B - Hyaluronic acid and biodegradable polymer modified material and preparation method thereof - Google Patents
Hyaluronic acid and biodegradable polymer modified material and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a hyaluronic acid and biodegradable polymer modified material and a preparation method thereof, belonging to the technical field of polymer material modification. Modifying hyaluronic acid by using starch to obtain modified hyaluronic acid, enabling sulfhydryl and carboxyl in the modified hyaluronic acid to have a crosslinking reaction with groups in the biodegradable material under the action of a curing agent, pre-radiating a crosslinked product under the aerobic condition, and heating and drying to obtain the hyaluronic acid and biodegradable polymer modified material. Raw materials such as raw materials starch, hyaluronic acid and biodegradable materials in the preparation process are safe and nontoxic, do not harm human bodies, and the preparation process is simple, high in yield, high in degradation rate and good in biocompatibility, can be applied to the medical field as a drug carrier, and achieves the purpose of rapid drug release.
Description
Technical Field
The invention relates to a hyaluronic acid and biodegradable polymer modified material and a preparation method thereof, belonging to the technical field of polymer material modification.
Background
Polymer materials are widely used in various fields, but with this, waste polymer materials cause serious pollution to the environment, and biodegradable materials have been proposed in order to reduce pollution to the human environment. Biodegradable materials degrade due to respiration or chemical energy synthesis of natural microorganisms such as fungi and bacteria, and finally decompose into carbon dioxide and water, and such materials are widely used in agriculture, forestry, packaging industry, textile industry and medical field at present, wherein in order to meet the medical performance requirement, the biodegradable materials used in the medical field must have good biocompatibility, specific degradation rate and mechanical performance, and the materials and degradation products thereof should have no toxic or side effect on the matrix.
The biodegradable material is used as a drug controlled release carrier, which is a hot spot of current research, and the drug is released to a designated part according to a predetermined speed in a designated time by utilizing the degradability of the biodegradable material in vivo, but the release speed of the drug can be reduced along with the concentration reduction of the drug in the carrier under the influence of the degradation speed of the material in the drug release process, so that the drug can not act on the designated part in time under the condition of needing quick drug release or extremely small drug loading, thereby failing to achieve the therapeutic effect. Therefore, it is necessary to provide a novel biopolymer modified material which has high degradation rate and excellent biocompatibility and mechanical properties.
Disclosure of Invention
In order to solve the technical problems, the invention provides a hyaluronic acid and biodegradable polymer modified material and a preparation method thereof, wherein the hyaluronic acid is used for modifying the biodegradable material, so that the prepared modified material has the characteristics of high degradation rate, good biocompatibility and excellent mechanical property, and can be applied to the medical field as a drug carrier to enable a drug to be quickly released, thereby achieving the purpose of treatment.
In order to achieve the above object, the present invention provides the following solutions:
the invention provides a modified material of hyaluronic acid and biodegradable polymer, which is prepared by modifying hyaluronic acid with starch to obtain modified hyaluronic acid, enabling sulfhydryl and carboxyl in the modified hyaluronic acid to have a crosslinking reaction with groups in the biodegradable material under the action of a curing agent, pre-radiating a crosslinked product under the aerobic condition, and heating and drying to obtain the modified material of hyaluronic acid and biodegradable polymer.
Further, the biodegradable material is one or more of cellulose, chitosan, polylactic acid, polyphosphate, polyanhydride and polycarbonate.
Further, the curing agent is one or more of hexahydrophthalic anhydride, triethylenetetramine, dimethylaminopropylamine, diethylaminopropylamine, glutaraldehyde, epichlorohydrin and divinyl sulfoxide.
The invention also provides a preparation method of the hyaluronic acid and biodegradable polymer modified material, which comprises the following steps:
(1) Modification of hyaluronic acid: dissolving hyaluronic acid and starch in distilled water, then adding sodium carbonate, dropwise adding epichlorohydrin, stirring for reaction, then adding phosphoric acid, centrifuging, washing, drying and grinding to 150 meshes to obtain modified hyaluronic acid;
(2) Dissolving the modified hyaluronic acid and the biodegradable material obtained in the step (1) in acetone, adding a curing agent, stirring and reacting, and washing with ethanol with the mass concentration of 55% to obtain a crosslinked product;
(3) And (3) dissolving the crosslinked product obtained in the step (2) in supercritical carbon dioxide solution, irradiating with ultraviolet rays under the aerobic condition, performing graft copolymerization reaction, and then taking out reactants, washing and drying to obtain the hyaluronic acid and biodegradable polymer modified material.
Further, the mass ratio of hyaluronic acid to starch in the step (1) is 5: (1-2), wherein the mass ratio of the hyaluronic acid to the sodium carbonate is 1: (0.01-1), the amount of the epoxy chloropropane is 0.5-1 times of the volume of the hyaluronic acid and the starch which are dissolved in distilled water and added with sodium carbonate.
Further, the temperature of the stirring reaction in the step (1) is 50-62 ℃ and the time is 1-2h.
Further, phosphoric acid with a concentration of 1mol/L is added in the step (1) for adjusting the pH value to 5-7.
Further, the mass ratio of the modified hyaluronic acid to the biodegradable material in the step (2) is (0.1-2): (1-2), wherein the mass ratio of the curing agent to the biodegradable material is (0.05-0.5): 1.
further, the temperature of the stirring reaction in the step (2) is 55-65 ℃, and the reaction time is 1.5-4h.
Further, the power of the ultraviolet rays in the step (3) is 150-350W, the irradiation time is 0.5-3h, and the irradiation distance is 0.3-1.5m.
Further, the temperature of the drying in the step (3) is 100-200 ℃ and the time is 0.5-2h.
The invention discloses the following technical effects:
1) According to the invention, the modified hyaluronic acid and the biodegradable material are crosslinked through the curing agent, so that the mercapto and carboxyl in the modified hyaluronic acid react with the groups in the biodegradable material under the action of the curing agent, and the prepared hyaluronic acid and the biodegradable polymer modified material have crosslinking and grafting structures at the same time by utilizing the radiation grafting technology, so that the mechanical property of the modified hyaluronic acid is enhanced.
2) The hyaluronic acid is used as an extracellular matrix, has better biocompatibility and higher degradation rate, the starch is used for modifying the hyaluronic acid, the modified hyaluronic acid reacts with the biodegradable material, and the addition of the hyaluronic acid can enable the prepared hyaluronic acid to have higher biocompatibility with the biodegradable polymer modified material and further improve the degradation rate of the biodegradable material.
3) The invention only adds curing agent in the cross-linking reaction process, has no other by-products, uses supercritical carbon dioxide as solvent in the grafting reaction process, can lead the cross-linking product to exist stably under the irradiation of ultraviolet rays due to chemical inertness, reduces the generation of the by-products, and has safe and nontoxic reaction process.
4) The raw materials such as starch, hyaluronic acid, biodegradable materials and the like used in the preparation of the hyaluronic acid and biodegradable polymer modified material are safe and nontoxic, do not harm human bodies, have simple preparation process, high yield and high degradation rate, have good biocompatibility, can be applied to the medical field as a drug carrier, and realize the purpose of rapid drug release.
Detailed Description
Various exemplary embodiments of the invention will now be described in detail, which should not be considered as limiting the invention, but rather as more detailed descriptions of certain aspects, features and embodiments of the invention.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. In addition, for numerical ranges in this disclosure, it is understood that each intermediate value between the upper and lower limits of the ranges is also specifically disclosed. Every smaller range between any stated value or stated range, and any other stated value or intermediate value within the stated range, is also encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless otherwise defined, 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 invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.
It will be apparent to those skilled in the art that various modifications and variations can be made in the specific embodiments of the invention described herein without departing from the scope or spirit of the invention. Other embodiments will be apparent to those skilled in the art from consideration of the specification of the present invention. The specification and examples of the present invention are exemplary only.
As used herein, the terms "comprising," "including," "having," "containing," and the like are intended to be inclusive and mean an inclusion, but not limited to.
The raw materials used in the examples of the present invention were all commercially available, in which the weight average molecular weight of hyaluronic acid was 9000.
The preparation of the drug-carrying system in the invention is a common technical means in the field, and is not an invention point of the invention, so the preparation is not repeated.
The technical scheme of the invention is further described by the following examples.
Example 1
(1) Modification of hyaluronic acid: dissolving 500g of hyaluronic acid and 100g of starch in 1L of distilled water, then adding 10g of sodium carbonate, dropwise adding epichlorohydrin with the same volume as that of the hyaluronic acid and the starch which are dissolved in the distilled water and added with sodium carbonate, stirring at 50 ℃ for 2 hours, adding 1mol/L of phosphoric acid, adjusting the pH value to 7, centrifuging at 3500r/min for 30min, washing, drying and grinding to 150 meshes to obtain modified hyaluronic acid;
(2) Dissolving 100g of modified hyaluronic acid obtained in the step (1) and 1000g of polyphosphate in 500mL of acetone, adding 50g of divinyl sulfoxide, stirring at 55 ℃ for reaction for 3 hours, and washing with ethanol with the mass concentration of 55%, thus obtaining a crosslinked product; the crosslinking rate was 48.2% as measured according to ASTM-D2765-2011.
(3) Dissolving the crosslinked product obtained in the step (2) in 500mL of supercritical carbon dioxide solution, irradiating with ultraviolet rays with the power of 350W for 2h under the aerobic condition, performing graft copolymerization reaction at the irradiation distance of 1m, and then taking out reactants to wash at 200 ℃ and drying for 2h to obtain the hyaluronic acid and biodegradable polymer modified material; and carrying out ATR-IR, XPS and element analysis on the obtained hyaluronic acid and the biodegradable polymer modified material, wherein the analysis result shows that the modified hyaluronic acid is grafted into the polyphosphate, and the total grafting rate is 85.6%.
Example 2
(1) Modification of hyaluronic acid: dissolving 500g of hyaluronic acid and 50g of starch in 1L of distilled water, then adding 5g of sodium carbonate, dropwise adding hyaluronic acid, dissolving starch in distilled water, adding epichlorohydrin with the volume being 0.5 times that of sodium carbonate, stirring at 62 ℃ for reaction for 1.2 hours, then adding 1mol/L of phosphoric acid, adjusting the pH value to be 5, centrifuging at 3500r/min for 30min, washing, drying and grinding to 150 meshes to obtain modified hyaluronic acid;
(2) Dissolving 100g of modified hyaluronic acid obtained in the step (1) and 2000g of cellulose in 500mL of acetone, adding 1000g of epichlorohydrin, stirring at 65 ℃ for reaction for 4 hours, and washing with ethanol with the mass concentration of 55%, thus obtaining a crosslinked product; the crosslinking rate was 46.3% as measured according to ASTM-D2765-2011.
(3) And (3) dissolving the crosslinked product obtained in the step (2) in 500mL of supercritical carbon dioxide solution, irradiating with ultraviolet rays with the power of 300W for 0.5h under the aerobic condition, performing graft copolymerization reaction at the irradiation distance of 0.3m, and then taking out the reactant to wash at 200 ℃ and drying for 2h to obtain the hyaluronic acid and biodegradable polymer modified material. And carrying out ATR-IR, XPS and element analysis on the obtained hyaluronic acid and the biodegradable polymer modified material, wherein the analysis result shows that the modified hyaluronic acid is grafted into cellulose, and the total grafting rate is 83.9%.
Example 3
(1) Modification of hyaluronic acid: dissolving 500g of hyaluronic acid and 1g of starch in 1L of distilled water, then adding 500g of sodium carbonate, dropwise adding hyaluronic acid, dissolving starch in distilled water, adding epichlorohydrin with the volume being 0.6 times that of sodium carbonate, stirring at 55 ℃ for 2 hours, adding 1mol/L phosphoric acid, adjusting the pH value to be 6, centrifuging at 3500r/min for 30min, washing, drying and grinding to 150 meshes to obtain modified hyaluronic acid;
(2) Dissolving 100g of modified hyaluronic acid obtained in the step (1) and 50g of polylactic acid in 500mL of acetone, adding 25g of diethylaminopropylamine, stirring at 55 ℃ for reaction for 4 hours, and washing with ethanol with the mass concentration of 55%, thus obtaining a crosslinked product; the crosslinking rate was 40.9% as measured according to ASTM-D2765-2011.
(3) And (3) dissolving the crosslinked product obtained in the step (2) in 500mL of supercritical carbon dioxide solution, irradiating with ultraviolet rays with the power of 350W for 3h under the aerobic condition, performing graft copolymerization reaction at the irradiation distance of 1.5m, and then taking out the reactant, washing at 150 ℃ and drying for 1h to obtain the hyaluronic acid and biodegradable polymer modified material. And carrying out ATR-IR, XPS and element analysis on the obtained hyaluronic acid and the biodegradable polymer modified material, wherein the analysis result shows that the modified hyaluronic acid is grafted into polylactic acid, and the total grafting rate is 81.6%.
Example 4
(1) Modification of hyaluronic acid: dissolving 500g of hyaluronic acid and 20g of starch in 1L of distilled water, then adding 200g of sodium carbonate, dropwise adding hyaluronic acid, dissolving starch in distilled water, adding epichlorohydrin with the volume being 0.5 times that of sodium carbonate, stirring at 50 ℃ for reaction for 1h, adding 1mol/L of phosphoric acid, adjusting the pH value to be 5, centrifuging at 3500r/min for 30min, washing, drying and grinding to 150 meshes to obtain modified hyaluronic acid;
(2) Dissolving 100g of modified hyaluronic acid obtained in the step (1) and 100g of polycarbonate in 500mL of acetone, adding 50g of glutaraldehyde, stirring at 65 ℃ for reaction for 1.5h, and washing with ethanol with the mass concentration of 55%, thus obtaining a crosslinked product; the crosslinking rate was 41.5% as measured according to ASTM-D2765-2011.
(3) And (3) dissolving the crosslinked product obtained in the step (2) in 500mL of supercritical carbon dioxide solution, irradiating with ultraviolet rays with the power of 150W for 3h under the aerobic condition, performing graft copolymerization reaction at the irradiation distance of 1.5m, and then taking out the reactant to wash at 200 ℃ and drying for 0.5h to obtain the hyaluronic acid and biodegradable polymer modified material. And carrying out ATR-IR, XPS and element analysis on the obtained hyaluronic acid and the biodegradable polymer modified material, wherein the analysis result shows that the modified hyaluronic acid is grafted into polycarbonate, and the total grafting rate is 82.1%.
Example 5
(1) Modification of hyaluronic acid: dissolving 500g of hyaluronic acid and 65g of corn starch in 1L of distilled water, then adding 10g of sodium carbonate, dropwise adding hyaluronic acid, adding epoxy chloropropane with the volume being 0.6 times that of the sodium carbonate, stirring at 60 ℃ for reaction for 2 hours, adding 1mol/L phosphoric acid, adjusting the pH value to 7, centrifuging at 3500r/min for 30min, washing, drying and grinding to 150 meshes to obtain modified hyaluronic acid;
(2) Dissolving 100g of modified hyaluronic acid obtained in the step (1) and 80g of polyanhydride in 500mL of acetone, adding 4g of hexahydrophthalic anhydride, stirring at 60 ℃ for reaction for 2 hours, and washing with ethanol with the mass concentration of 55%, thus obtaining a crosslinked product; the crosslinking rate was measured according to ASTM-D2765-2011 to be 42.6%.
(3) And (3) dissolving the crosslinked product obtained in the step (2) in 500mL of supercritical carbon dioxide solution, irradiating with ultraviolet rays with the power of 300W for 3h under the aerobic condition, performing graft copolymerization reaction at the irradiation distance of 0.3m, and then taking out the reactant to wash at 100 ℃ and drying for 0.5h to obtain the hyaluronic acid and biodegradable polymer modified material. And carrying out ATR-IR, XPS and element analysis on the obtained hyaluronic acid and the biodegradable polymer modified material, wherein the analysis result shows that the modified hyaluronic acid is grafted into the polyanhydride, and the total grafting rate is 81.1%.
Comparative example 1
The procedure is as in example 1, except that step (1) is omitted, 100g of hyaluronic acid, 1000g of polyphosphate are directly dissolved in 500mL of acetone, and 50g of divinyl sulfoxide is added for the subsequent reaction. The crosslinking rate was 32.1% as measured according to ASTM-D2765-2011. And carrying out ATR-IR, XPS and element analysis on the obtained hyaluronic acid and the biodegradable polymer modified material, wherein the analysis result shows that the hyaluronic acid is partially grafted into the polyanhydride, and the total grafting rate is 28.6%.
Comparative example 2
The difference with example 1 is that in the step (1), 500g of hyaluronic acid and 200g of starch are dissolved in 1L of distilled water, then 4g of sodium carbonate is added, the same volume of epichlorohydrin is added dropwise, stirring reaction is carried out at 50 ℃ for 2 hours, then 1mol/L of phosphoric acid is added, the pH value is regulated to 9, centrifugation is carried out for 30min at 3500r/min, washing is carried out, and drying and grinding are carried out until 150 meshes are reached, thus obtaining the modified hyaluronic acid. The crosslinking rate was 28.7% as measured according to ASTM-D2765-2011. And carrying out ATR-IR, XPS and element analysis on the obtained hyaluronic acid and the biodegradable polymer modified material, wherein the analysis result shows that the modified hyaluronic acid is partially grafted into the polyanhydride, and the total grafting rate is 42.3%.
Comparative example 3
The difference is that in the step (2), 100g of the modified hyaluronic acid obtained in the step (1) and 200g of polyphosphate are dissolved in 500mL of acetone, 2g of divinyl sulfoxide is added, and the mixture is stirred and reacted for 3 hours at 30 ℃ and then washed with ethanol with the mass concentration of 55%, so that a crosslinked product is obtained. The crosslinking rate was 30.1% as measured according to ASTM-D2765-2011. And carrying out ATR-IR, XPS and element analysis on the obtained hyaluronic acid and the biodegradable polymer modified material, wherein the analysis result shows that the modified hyaluronic acid is partially grafted into the polyanhydride, and the total grafting rate is 36.3%.
Comparative example 4
The difference is that the step (3) is that the crosslinked product obtained in the step (2) is dissolved in 500mL of supercritical carbon dioxide solution, irradiated with ultraviolet rays with the power of 450W for 2 hours under the aerobic condition and the irradiation distance of 2m, and subjected to graft copolymerization, and then the reactants are taken out to wash at 250 ℃ and dried for 2 hours, so that the hyaluronic acid and biodegradable polymer modified material is obtained. And carrying out ATR-IR, XPS and element analysis on the obtained hyaluronic acid and the biodegradable polymer modified material, wherein the analysis result shows that the modified hyaluronic acid is partially grafted into the polyanhydride, and the total grafting rate is 36.3%.
Comparative example 5
The only difference from example 1 is that acetone is used instead of supercritical carbon dioxide solution in step (3). And carrying out ATR-IR, XPS and element analysis on the obtained hyaluronic acid and the biodegradable polymer modified material, wherein the analysis result shows that the modified hyaluronic acid is partially grafted into the polyanhydride, and the total grafting rate is 25.9%.
Comparative example 6
The only difference from example 1 is that step (3) is omitted.
Performance testing
The modified materials obtained in examples 1 to 5 and comparative examples 1 to 6 were prepared to obtain drug-carrying systems, the drug-carrying was ketoprofen, and the drug-carrying rate and drug release properties of each group of drug-carrying systems were measured by absorbance photometry, and the results are shown in Table 1.
Table 1 results of drug loading rates and drug release properties of each group of drug loading systems
| Drug loading rate | Drug loading is released in 24h accumulation | |
| Example 1 | 75.2％ | 86.3％ |
| Example 2 | 65.9％ | 84.1％ |
| Example 3 | 68.6％ | 82.6％ |
| Example 4 | 70.3％ | 83.9％ |
| Example 5 | 69.1％ | 83.6％ |
| Comparative example 1 | 70.5％ | 45.2％ |
| Comparative example 2 | 72.3％ | 62.3％ |
| Comparative example 3 | 73.9％ | 61.3％ |
| Comparative example 4 | 72.1％ | 58.6％ |
| Comparative example 5 | 68.9％ | 60.9％ |
| Comparative example 6 | 72.3％ | 58.6％ |
As can be seen from the data in Table 1, under the condition that the drug loading rates of the drug loading systems prepared by the materials in examples 1-5 and comparative examples 1-6 are relatively close, the drug release of examples 1-5 is obviously faster than that of the drug loading system prepared by the material in comparative example, which indicates that the hyaluronic acid and the biodegradable polymer modified material prepared by the invention have high degradation efficiency, and can realize rapid drug release in specific positions.
The mechanical properties and antibacterial properties of the modified materials prepared in examples 1 to 5 and comparative examples 1 to 6 were tested according to GB/T1040-2006 method and QB/T2591-2003, and the test results are shown in Table 2.
TABLE 2 mechanical Properties and antibacterial Property test results
As can be seen from the data in Table 2, the modified material prepared by the embodiment of the invention has good mechanical properties and is safe and sterile.
The above embodiments are only illustrative of the preferred embodiments of the present invention and are not intended to limit the scope of the present invention, and various modifications and improvements made by those skilled in the art to the technical solutions of the present invention should fall within the protection scope defined by the claims of the present invention without departing from the design spirit of the present invention.
Claims (2)
1. The modified hyaluronic acid is obtained by modifying hyaluronic acid with starch, so that sulfhydryl and carboxyl in the modified hyaluronic acid are subjected to crosslinking reaction with groups in the biodegradable material under the action of a curing agent, and a crosslinked product is subjected to pre-irradiation under the aerobic condition, and is heated and dried to obtain the modified hyaluronic acid and biodegradable polymer material;
the biodegradable material is cellulose, chitosan, polylactic acid, polyphosphate, polyanhydride or polycarbonate;
the curing agent is one or more of hexahydrophthalic anhydride, triethylenetetramine, dimethylaminopropylamine, diethylaminopropylamine, glutaraldehyde, epichlorohydrin and divinyl sulfoxide;
the preparation method of the hyaluronic acid and biodegradable polymer modified material comprises the following steps:
(1) Modification of hyaluronic acid: dissolving hyaluronic acid and starch in distilled water, then adding sodium carbonate, dropwise adding epichlorohydrin, stirring for reaction, then adding phosphoric acid, centrifuging, washing, drying and grinding to obtain modified hyaluronic acid;
(2) Dissolving the modified hyaluronic acid and the biodegradable material obtained in the step (1) in acetone, adding a curing agent, stirring and reacting, and washing with ethanol to obtain a crosslinked product;
(3) Irradiating the crosslinked product obtained in the step (2) with ultraviolet rays under the aerobic condition, and washing and drying to obtain the hyaluronic acid and biodegradable polymer modified material;
the mass ratio of the hyaluronic acid to the starch in the step (1) is 5: (1-2), wherein the mass ratio of the hyaluronic acid to the sodium carbonate is 1: (0.01-1), wherein the amount of the epoxy chloropropane is 0.5-1 time of the volume of the hyaluronic acid and the starch which are dissolved in distilled water and added with sodium carbonate;
the temperature of the stirring reaction in the step (1) is 50-62 ℃ and the time is 1-2h;
the concentration of phosphoric acid is 1mol/L in the step (1) and is used for adjusting the pH value to 5-7;
the mass ratio of the modified hyaluronic acid to the biodegradable material in the step (2) is (0.1-2): (1-2), wherein the mass ratio of the curing agent to the biodegradable material is (0.05-0.5): 1, a step of;
the temperature of the stirring reaction in the step (2) is 55-65 ℃ and the reaction time is 1.5-4h;
the power of the ultraviolet rays in the step (3) is 150-350W, the irradiation time is 0.5-3h, and the irradiation distance is 0.3-1.5m.
2. The modified hyaluronic acid and biodegradable polymer material according to claim 1, wherein the temperature of drying in step (3) is 100-200 ℃ for 0.5-2 hours.
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