Temperature-sensitive slow-release medical auxiliary material and preparation method thereof

Abstract

The invention discloses a temperature-sensitive slow-release medical auxiliary material and a preparation method of the temperature-sensitive slow-release medical auxiliary material, and belongs to the technical field of medical auxiliary materials. Comprising the following components: 1-2% w / v of acrylamide hydroxyethyl chitosan, 5-15% w / v of polyethylene glycol diacrylate, 1-6% w / v of N-methyl acrylate caprolactam, 0.05-2% w / v of an initiator, 0.01-0.5% w / v of a cross-linking agent and the balance of a PBS (Phosphate Buffer Solution), the acrylamide hydroxyethyl chitosan is modified by chitosan hydroxyl group and ethyl group; the N-methyl acrylate caprolactam monomer provided by the invention effectively improves the temperature sensitivity of the temperature-sensitive polymer auxiliary material; the acrylamide hydroxyethyl chitosan can reduce the swelling ratio and slow down the drug release; the polyethylene glycol diacrylate can be a crosslinking monomer of the temperature-sensitive polymer auxiliary material, meanwhile, an ether bond is introduced to improve the biocompatibility of the temperature-sensitive polymer auxiliary material, and the temperature-sensitive slow-release medical auxiliary material which is low in drug slow-release rate and responds to the temperature of a human body is prepared by combining the polyethylene glycol diacrylate, the ether bond and the temperature-sensitive polymer auxiliary material.

Description

Technical Field

[0001] The present invention relates to the technical field of medical excipients, in particular to a temperature-sensitive sustained-release medical excipient and a preparation method thereof. Background Art

[0002] Wound healing is a dynamic and complex process, in which the microenvironment at the wound site plays a crucial role. Medical excipients, as commonly used materials for wound healing, can maintain a moist wound environment, accelerate wound healing, and prevent external wound infection. Hydrogels, polymers composed of hydrophilic segments with a three-dimensional network structure, have advantages such as high water content, good biocompatibility, and tunable physical and chemical properties, making them a hot topic in wound dressing research. Smart hydrogel excipients have attracted widespread attention due to their excellent environmental responsiveness. Thermosensitive hydrogels, as intelligent polymer hydrogels, can respond to slight temperature changes in the environment. Below the gel transition temperature, such as room temperature, they are in a flowable sol state. At the gel transition temperature, such as body temperature, they rapidly transform into a semi-solid gel, enabling controlled drug release and on-demand drug delivery in a controlled manner. These intelligent hydrogel excipients are ideal for wound applications and should exhibit antibacterial or anti-inflammatory properties, biocompatibility, temperature responsiveness, and appropriate adhesion and mechanical properties. The natural polysaccharide chitosan has good biocompatibility and antibacterial properties, but its thermosensitive response properties are poor, and the prepared hydrogel is loose and porous, resulting in a fast drug release rate. Summary of the Invention

[0003] To overcome the shortcomings of the aforementioned prior art, the present invention provides a temperature-sensitive sustained-release medical excipient and a method for preparing the same. The temperature-sensitive sustained-release medical excipient comprises a hydrogel network formed by copolymerizing N-methyl acrylate caprolactam (NVC), modified acryloylated hydroxyethyl chitosan (EtCS), and polyethylene glycol diacrylate. N-methyl acrylate caprolactam (NVC) imparts excellent temperature sensitivity to the gel; ethyl groups are modified on the hydroxyl groups of chitosan to moderately increase hydrophobicity and reduce drug release rate; and polyethylene glycol diacrylate serves as a crosslinker, while ether bonds are introduced to enhance the biocompatibility of the polymer.

[0004] The purpose of the present invention is to provide a temperature-sensitive sustained-release medical excipient and a preparation method thereof.

[0005] The present invention is achieved through the following technical solutions:

[0006] A temperature-sensitive sustained-release medical excipient comprises the following components, calculated by mass in a solution: 1-2% w / v of acrylamidated hydroxyethyl chitosan, 5-15% w / v of polyethylene glycol diacrylate, 1-6% w / v of N-methyl acrylate caprolactam, 0.05-2% w / v of an initiator, 0.01-0.5% w / v of a cross-linking agent, and the balance being PBS solution.

[0007] In a specific embodiment, the preparation method of N-methyl acrylate caprolactam (NVC) comprises the following steps:

[0008] Under a nitrogen atmosphere, methyl 3-bromoacrylate, caprolactam, an inorganic base, and a ligand Ruphos are placed in a dry container, a catalyst Pd2(dba)3 is added, and the temperature is raised to 80-100°C. The reaction is stirred for 12-24 hours to complete the reaction. The reaction mixture is cooled to room temperature and purified to obtain the product N-methyl acrylate caprolactam.

[0009] In a specific embodiment, the amount of methyl 3-bromoacrylate is 1-1.5 equivalents of caprolactam; the inorganic base is one of potassium phosphate or cesium carbonate; and the amount of the ligand Ruphos is 0.1-0.5 wt % of caprolactam.

[0010] In a specific embodiment, the preparation method of the acryloyl hydroxyethyl chitosan (EtCS) comprises the following steps:

[0011] S1. Chitosan was dissolved in 1% acetic acid solution and adjusted to an appropriate pH by adding triethylamine; phthalic anhydride was added and the reaction was heated for 12 hours; after the reaction, the mixture was dialyzed with deionized water (MWCO 3500Da, 2-3 days) and freeze-dried to obtain phthalylated chitosan;

[0012] S2. Under a nitrogen atmosphere, anhydrous DMF was added to a 250 mL three-necked flask containing phthalylated chitosan and stirred at room temperature to dissolve. Dry inorganic base powder (6 equivalents / hydroxyl group) was added and stirred for 0.5 hours to activate the hydroxyl groups. An alkyl halide, such as ethyl iodide, was added and the reaction was heated for 7 hours. After the reaction, the mixture was filtered and the filtrate was poured into ice water (containing 1% acetic acid) for precipitation. The solid was collected by centrifugation and purified by washing with ethanol. The mixture was dialyzed (MWCO 3500 Da, water / methanol mixed solvent) and freeze-dried to obtain phthalylated hydroxyethyl chitosan.

[0013] S3. 80% hydrazine hydrate (excess) and an ethanol / water mixed solvent were added to the ethylated phthalate chitosan and reacted at 60°C; the reaction was purified by dialysis and freeze-dried to obtain hydroxyethyl chitosan;

[0014] S4. Under a nitrogen atmosphere, hydroxyethyl chitosan was dissolved in anhydrous THF and stirred in an ice bath for 30 minutes. A mixture of acryloyl chloride and triethylamine (0.8 equivalent) was slowly added dropwise, and the mixture was reacted at 0°C for 2 hours. After the reaction, glacial ether was poured into the reaction mixture, and the precipitate was filtered, dialyzed (MWCO 3500Da), and lyophilized to obtain acrylamidated hydroxyethyl chitosan.

[0015] In a specific embodiment, the pH in step S1 is 4-6, the amount of phthalic anhydride used is 1-1.5 equivalents of chitosan, and the temperature is 40-60°C.

[0016] In a specific embodiment, the inorganic base in step S2 is one of potassium hydroxide, potassium carbonate, cesium carbonate or potassium phosphate, the amount of the inorganic base is 3-6 equivalents of the hydroxyl groups contained in the phthalated chitosan, the alkyl halide is one of iodomethane, iodoethane or iodopropane, the amount of the alkyl halide is 1-1.1 equivalents of the hydroxyl groups contained in the phthalated chitosan, and the temperature is 40-60°C.

[0017] In a specific embodiment, the reaction time in step S3 is 24-48 hours.

[0018] In a specific embodiment, the amount of acryloyl chloride used in step S4 is 0.8-1.2 equivalents of hydroxyethyl chitosan, and the amount of triethylamine used is 0.5-1 equivalents.

[0019] In a specific embodiment, the initiator is selected from ammonium persulfate (APS); the cross-linking agent is selected from N,N,N',N'-tetramethylethylenediamine (TEMED).

[0020] Another object of the present invention is to provide a method for preparing a temperature-sensitive sustained-release medical excipient, comprising the following steps:

[0021] S1. Preparation of pregel solution: The specific steps are as follows: 1. Pass acrylamidated hydroxyethyl chitosan powder through an 80-mesh sieve to remove agglomerated particles; 2. Dissolve acrylamidated hydroxyethyl chitosan in preheated PBS solution and stir magnetically until completely dissolved; 3. Add polyethylene glycol diacrylate to the solution and stir thoroughly; 4. Add N-methyl acrylate caprolactam dissolved in a small amount of DMSO to the solution and stir in the dark; 5. Add initiator and stir, then add TEMED and mix rapidly.

[0022] S2. Thermally initiated polymerization: The specific steps are as follows:

[0023] The pre-gel solution is injected into a mold, which is a silicone cylindrical mold in a specific embodiment, and lightly shaken to remove air bubbles; covered with a sealing film and reacted in a 37° C. water bath for 30-60 minutes;

[0024] S3. Post-processing: The specific steps are as follows:

[0025] After the reaction is completed, the gel is formed and rinsed three times with PBS to remove unreacted monomers; the hydrogel is then immersed in a phosphate buffer solution (PBS) containing 10% ethanol, and the water is changed every 12 hours for 72 hours to remove the organic solvents DMSO and TEMED and the inorganic salt APS; the ethanol is removed by vacuum drying to obtain a dry gel sample, thereby preparing a temperature-sensitive sustained-release medical excipient.

[0026] Beneficial effects

[0027] The present invention provides a thermosensitive sustained-release medical excipient and a preparation method thereof. The thermosensitive sustained-release medical excipient is prepared by dissolving three components, namely, acrylamidated hydroxyethyl chitosan, polyethylene glycol diacrylate, and N-methyl acrylate caprolactam, in a PBS solution. Under initiator conditions, free radical polymerization, crosslinking, and purification are carried out to form a hydrogel, thereby obtaining the thermosensitive sustained-release medical excipient. N-methyl acrylate caprolactam (NVC) imparts excellent thermosensitivity to the gel, allowing the hydrogel to maintain a sol state at room temperature. When applied as an excipient on a wound, it can present a semi-cured gel that adheres to the skin and releases drugs. The chitosan hydroxyl group is modified with an alkane, such as an ethyl group, to appropriately increase hydrophobicity, reduce swelling properties, and reduce pores, thereby effectively reducing the drug release rate and prolonging the drug action time. Polyethylene glycol diacrylate acts as a crosslinking agent to promote copolymerization of the three components, while introducing ether bonds to increase the biocompatibility of the polymer for application in organisms. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 It is the synthetic route of temperature-sensitive medical excipients;

[0029] Figure 2 is the H NMR spectrum of N-methyl acrylate caprolactam;

[0030] Figure 3 These are the infrared spectra of pure chitosan, acrylamidated hydroxyethyl chitosan and thermosensitive medical excipient polymer. DETAILED DESCRIPTION

[0031] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts shall fall within the scope of protection of the present invention.

[0032] In the examples, the experimental methods used are conventional methods unless otherwise specified, and the materials, reagents, etc. used are all commercially available unless otherwise specified.

[0033] The raw materials used in the embodiments and comparative examples are now described as follows:

[0034] Caprolactam: 99.5%, product number B02025199, purchased from Shanghai Anaiji Chemical Co., Ltd.

[0035] Methyl 3-bromoacrylate: 95%, product number BD306828, purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd.

[0036] Catalyst: tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), 98%, product number BD21135, purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd.

[0037] Ligand: 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (Ruphos), 97%, product number BD74362, purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd.;

[0038] Chitosan: deacetylation degree ≥95%, MW50000-60000, product number C766421, purchased from Shanghai MacLean Biochemical Technology Co., Ltd.

[0039] Phthalic anhydride: 99.7%, product number P816733, purchased from Shanghai MacLean Biochemical Technology Co., Ltd.;

[0040] Acetic acid: 99.5%, product number A801295, purchased from Shanghai MacLean Biochemical Technology Co., Ltd.;

[0041] Triethylamine: 99.5%, product number T818774, purchased from Shanghai MacLean Biochemical Technology Co., Ltd.;

[0042] N,N-dimethylformamide: 99.8%, product number N821474, purchased from Shanghai MacLean Biochemical Technology Co., Ltd.;

[0043] Ethyl iodide: 99%, product number I811648, purchased from Shanghai MacLean Biochemical Technology Co., Ltd.;

[0044] Hydrazine hydrate: Product No. C19671, purchased from Shanghai Anaiji Chemical Co., Ltd.

[0045] Acryloyl chloride: 96%, product number A800376, purchased from Shanghai MacLean Biochemical Technology Co., Ltd.;

[0046] Initiator: ammonium persulfate, 99.99%, Shanghai Aladdin Biochemical Technology Co., Ltd.

[0047] N,N,N,N-Tetramethylethylenediamine (TEMED): 99%, product number N818999, purchased from Shanghai MacLean Biochemical Technology Co., Ltd.;

[0048] PBS solution: pH 7.4, product number P787575, purchased from Shanghai MacLean Biochemical Technology Co., Ltd.;

[0049] Polyethylene glycol-based double-end cross-linking monomer: polyethylene glycol diacrylate (PEGDA); Mn700, product number P816111, purchased from Shanghai MacLean Biochemical Technology Co., Ltd.;

[0050] Adriamycin (DOX): 97%, product number A864033, purchased from Shanghai MacLean Biochemical Technology Co., Ltd.;

[0051] N-methyl acrylate caprolactam (NVC): Homemade, prepared as follows: Under a nitrogen atmosphere, methyl 3-bromoacrylate (1.1 equivalents), caprolactam (1 equivalent), potassium phosphate (5 equivalents), and ligand Ruphos (0.1 wt%) were placed in a dry 10 mL Schlenk tube and bubbling was performed for 30 minutes; the catalyst Pd2(dba)3 was added and bubbling was performed for another 10 minutes, and the temperature was raised to 100°C and stirred for 24 hours to complete the reaction; the reaction mixture was cooled to room temperature, diluted with dichloromethane, filtered, and the filtrate was concentrated and purified by flash chromatography on a short silica gel column (dichloromethane / n-hexane) to obtain the product N-methyl acrylate caprolactam;

[0052] Acryloylation of hydroxyethyl chitosan (EtCS): homemade, the preparation method is as follows:

[0053] S1. Chitosan (1 g) was dissolved in 1% acetic acid solution (100 mL) and triethylamine was added to adjust the pH to 4-6. Phthalic anhydride (1.5 equivalents, dissolved in a small amount of acetone) was added and reacted at 60°C for 12 hours. After the reaction, the mixture was dialyzed against deionized water (MWCO 3500 Da, 2-3 days) and freeze-dried to obtain phthalylated chitosan.

[0054] S2. Under a nitrogen atmosphere, anhydrous DMF was added to a 250 mL three-necked flask containing phthalylated chitosan and stirred at room temperature to dissolve. Dry potassium hydroxide powder (6 equivalents / hydroxyl group) was added and stirred for 0.5 hours to activate the hydroxyl groups. Ethyl iodide (1.1 equivalents / hydroxyl group) was added and reacted at 45°C for 7 hours. After the reaction, the mixture was filtered and the filtrate was poured into ice water (containing 1% acetic acid) for precipitation. The solid was collected by centrifugation and purified by washing with ethanol. The phthalylated hydroxyethyl chitosan was obtained by dialysis (MWCO 3500 Da, water / methanol mixed solvent) and freeze-dried.

[0055] S3. To the ethylated phthalate chitosan was added 80% hydrazine hydrate (excess), ethanol / water mixed solvent, refluxed for 4 hours; the reaction was completed by dialysis purification, freeze-dried to give hydroxyethyl chitosan;

[0056] S4. Under a nitrogen atmosphere, hydroxyethyl chitosan (1 equivalent) was dissolved in anhydrous THF and stirred on ice for 30 minutes. A mixture of acryloyl chloride (1.1 equivalents) and triethylamine (0.8 equivalents) was slowly added dropwise, and the mixture was allowed to react at 0°C for 2 hours. After the reaction, glacial ether was added to the reaction solution, and the precipitate was filtered, dialyzed (MWCO 3500 Da), and freeze-dried to obtain acrylamidated hydroxyethyl chitosan. The degree of acrylamidation (DS) ranged from 70% to 90%, and the yield was between 85% and 90%. The results are shown below.

[0057] Table 1 Synthesis results of EtCS

[0058] Sample name molar ratio Degree of substitution / % (DS) Yield / % EtCS-1 0.81 70 86 EtCS-2 0.96 85 89 EtCS-3 1.06 90 85

[0059] Examples and Comparative Examples

[0060] A thermosensitive sustained-release medical excipient: homemade, the preparation method is as follows:

[0061] S1. Preparation of pregel solution: The specific steps are as follows: pass acrylamidated hydroxyethyl chitosan powder through an 80-mesh sieve to remove agglomerated particles; dissolve acrylamidated hydroxyethyl chitosan (1.17% w / v) in 86 mL of preheated PBS (37°C) solution and stir magnetically for 2-4 hours until completely dissolved; add polyethylene glycol diacrylate (10% w / v) to the solution and stir for 30 minutes until uniform; then add N-methyl acrylate caprolactam (2.75% w / v) dissolved in a small amount of DMSO to the above solution and stir in the dark for 20 minutes; first add APS (e.g., 0.05% w / v) and stir for 5 minutes, then add TEMED (0.05% w / v) and mix quickly;

[0062] S2. Thermally initiated polymerization: The specific steps are as follows:

[0063] Pour the pregel solution into a silicone cylindrical mold and shake gently to remove bubbles; cover with a sealing film and react in a 37°C water bath for 30-60 minutes;

[0064] S3. Post-processing: The specific steps are as follows:

[0065] After the reaction is completed, the gel is washed three times with PBS to remove unreacted monomers. The hydrogel is then immersed in a phosphate buffered saline (PBS) solution containing 10% ethanol, with the water changed every 12 hours for 72 hours to remove the organic solvents DMSO and TEMED and the inorganic salt APS. The ethanol is then removed by vacuum drying to obtain a PNVC-EtCS-PEGDA dry gel sample, which is a temperature-sensitive sustained-release medical excipient.

[0066] A thermosensitive drug-loaded hydrogel acrylamidated hydroxyethyl chitosan, polyethylene glycol diacrylate, and N-methyl acrylate caprolactam hydrogel (DOX-PNVC-EtCS-PEGDA) was prepared in-house. The preparation method is as follows:

[0067] The preparation method is different from that of pure hydrogel in that 1 g of drug such as doxorubicin (DOX) is added to PBS solution in S1 to prepare the hydrogel.

[0068] Unless otherwise specified, the components and raw materials used in the examples and comparative examples of the present invention are all commercially available raw materials, and the components and raw materials used in each parallel experiment are all of the same kind.

[0069] Table 2 Thermosensitive sustained-release medical excipients (mass percentage, supplemented with PBS to 100g)

[0070]

[0071]

[0072] The following performance tests were performed on a temperature-sensitive sustained-release medical excipient prepared in the examples and comparative examples. The results are shown in the accompanying drawings and Table 2, respectively.

[0073] 1. Nuclear magnetic resonance spectrum: The synthesized N-methyl acrylate caprolactam sample was dissolved in deuterated chloroform to prepare a solution with a concentration of 1.0 wt%. The nuclear magnetic resonance spectrum of the sample was measured by a hydrogen nuclear magnetic resonance spectrometer at 400 MHz. The results are as follows: Figure 2 shown.

[0074] 2. Infrared Spectroscopy: N-methyl acrylate caprolactam, acrylamidated hydroxyethyl chitosan, and post-polymerization xerogel were mixed with potassium bromide at a ratio of 1:50 to form a pellet. This test was performed using an Avatar 380 spectrometer. The sample was pressed into a potassium bromide pellet. Before the test, a blank background was scanned, and then the pellet sample was placed in the test. The scanning range was 500-4000 cm -1 , the results are as follows Figure 3 shown.

[0075] 3. Rheological test: The rheological properties of the hydrogel were tested by a rotational rheometer, and the model of the rotational rheometer used was RS6000. The hydrogel sample was placed between parallel plates with a diameter of 20 mm, and the plate spacing was adjusted to 1.0 mm. First, the sample was dissolved in PBS buffer to prepare a PNVC-EtCS-PDGA solution (5wt%). The relationship between the storage modulus (G') and the loss modulus (G") with temperature change (5-50°C) was measured. The test conditions were a frequency of 1 Hz and a strain of 0.1%. The intersection of the G' and G" curves was T gel .

[0076] 4. Swelling properties: Swelling properties are related to the degree of cross-linking and hydrophobicity / hydrophilicity. Appropriate swelling properties are beneficial for drug loading and application in organisms. The swelling properties of the hydrogel were measured by weighing. First, a certain mass (Wd) of PNVC-EtCS-PDGA dry gel was weighed, then immersed in PBS solution, placed at 37°C for a period of time, and then taken out. The PBS solution on the surface of the gel was removed and weighed (Wt). The swelling ratio (SR) of the hydrogel was calculated as shown below:

[0077]

[0078] 5. Encapsulation efficiency (EE%) test: The prepared drug-loaded hydrogel was centrifuged using a TDZ4-WS low-speed automatic balance centrifuge (3,000 rpm, 15 min). The supernatant was collected and the free drug concentration C was tested by HPLC. free , combined with the initial drug concentration C0. The encapsulation efficiency is calculated by the following formula:

[0079]

[0080] 6. Drug release performance test: UV-Vis was used to test the in vitro drug release performance of the hydrogel for doxorubicin. Under 4°C conditions, the drug hydrogel (5.0wt%) was dissolved in 30mL PBS buffer, and the DOX-PNVC-EtCS-PEGDA drug-loaded gel was obtained after dissolution. It was placed in a constant temperature water bath oscillator at 37°C and cultured at an oscillation speed of 20r / min. At the predetermined time, 1mL PBS solution was drawn into a small test tube, and 2mL fresh PBS solution was added at the same time, and an equal volume of fresh PBS solution was supplemented. Finally, the drug concentration in the drawn 1mL PBS solution was measured by HPLC, and the total concentration in the 30mL PBS solution was calculated to test the release rate of the drug on the 5th day. The cumulative drug release rate (Ar) can be calculated by the following formula:

[0081]

[0082] Where V0 is the total volume of PBS; c t is the concentration of doxorubicin in PBS measured at a certain time point; V is the volume of PBS aspirated each time; and m is the initial drug loading capacity of DOX-PNVC-EtCS-PEGDA hydrogel.

[0083] Table 3 Performance test results of thermosensitive sustained-release hydrogel

[0084]

[0085] From the attached Figure 2From the H-NMR spectrum, we can see that the integral is consistent with the number of hydrogen atoms in the molecule, and the displacement of each hydrogen atom in the spectrum is consistent with the chemical environment, indicating that the target compound N-methyl acrylate caprolactam was successfully synthesized.

[0086] From the attached Figure 3 It can be seen that in the spectrum, the peak appears at 1720-1755cm -1 The peaks are at 1640-1680 cm-1, which are attributed to the stretching vibration of C=O on the ester carbonyl and amide carbonyl groups. -1 It is attributed to C=C vibration. In the spectrum of modified chitosan, the peak appears at 1750cm -1 It is attributed to the stretching vibration of C=O on the amide group, with a peak at 1680 cm -1 It is attributed to the stretching vibration of the C=C double bond of acrylate, and the peak appears at 1596 cm -1 The stretching vibration attributed to the amino group disappeared, indicating that the acrylate was successfully connected to the chitosan amino group; at the same time, the peak appeared at 2972-2872 cm -1 The new absorption peaks attributable to the upper methyl and methylene groups of the inserted ethyl groups indicate that the hydroxyl groups have been successfully replaced by ethyl groups. In the spectrum of the hydrogel, the peaks are at 1640-1680 cm -1 The peak attributed to C=C vibration disappeared, and the characteristic groups of the three monomers were present, proving that the PNVC-EtCS-PEGDA polymer had been successfully copolymerized to prepare the hydrogel.

[0087] As can be seen from Table 3, with the increase of cross-linking degree, T gel It shows a downward trend, indicating that PNVC-EtCS-PEGDA is thermosensitive. The temperature in Example 4 is close to the temperature of human skin. When applied to human skin, in situ gelation occurs to form a wound protection layer, which is suitable for biomedical applications. When there is no thermosensitive monomer, as shown in Comparative Example 2, the hydrogel shows almost no thermosensitivity, and due to the high cross-linking density, it is difficult to completely release the drug.

[0088] As can be seen from Table 3, the encapsulation efficiency of the prepared hydrogels ranged from 41% to 97%. For the drug-loaded hydrogels with a high degree of cross-linking, Examples 4 and 5 were above 80%, indicating that the prepared hydrogels were suitable for drug sustained-release carriers.

[0089] It can also be seen from Table 3 that the release time of doxorubicin can reach 5 days, and when equilibrium is reached, the release rate is generally above 65%, indicating that PNVC-EtCS-PEGDA hydrogel has the effect of slowing down drug release and is an excellent temperature-sensitive sustained-release drug carrier.

[0090] The preferred embodiments of the present invention disclosed above are intended only to help illustrate the present invention. These preferred embodiments do not exhaustively describe all details, nor do they limit the present invention to the specific embodiments described. Obviously, many modifications and variations are possible based on the content of this specification. These embodiments are selected and described in detail in this specification to better explain the principles and practical applications of the present invention, thereby enabling those skilled in the art to better understand and utilize the present invention. The present invention is limited only by the claims and their full scope and equivalents.

Claims

1. A temperature-sensitive sustained-release medical excipient, characterized in that: The invention comprises the following components by mass percentage: 1-2% w / v acrylamidated hydroxyethyl chitosan, 5-15% w / v polyethylene glycol diacrylate, 1-6% w / v N-methyl acrylate caprolactam, 0.05-2% w / v initiator, 0.01-0.5% w / v crosslinking agent, and the balance is PBS solution.

2. A temperature-sensitive sustained-release medical excipient according to claim 1, characterized in that: The preparation method of the N-methyl acrylate caprolactam comprises the following steps: Under a nitrogen atmosphere, methyl 3-bromoacrylate, caprolactam, an inorganic base, and a ligand Ruphos are placed in a dry container, a catalyst Pd2(dba)3 is added, and the temperature is raised to 80-100°C. The reaction is stirred for 12-24 hours to complete the reaction. The reaction mixture is cooled to room temperature and purified to obtain the product N-methyl acrylate caprolactam.

3. A temperature-sensitive sustained-release medical excipient according to claim 2, characterized in that: The amount of (Z)-3-bromoacrylate is 1-1.5 equivalents of caprolactam; the inorganic base is one of potassium phosphate and cesium carbonate; and the amount of ligand Ruphos is 0.1-0.5 wt % of caprolactam.

4. The temperature-sensitive sustained-release medical excipient according to claim 1, characterized in that: The preparation method of the acryloyl hydroxyethyl chitosan comprises the following steps: S1. Chitosan was dissolved in acetic acid solution, triethylamine was added to adjust the pH to 4-6; phthalic anhydride was added, and the reaction temperature was raised for 10-20 hours; the reaction was dialyzed with deionized water and freeze-dried to obtain phthalylated chitosan; S2. Under a nitrogen atmosphere, anhydrous DMF was added to the phthalated chitosan and stirred at room temperature to dissolve; 4-8 equivalents / hydroxyl of dry inorganic base powder was added and stirred to activate the hydroxyl groups; an alkyl halide was added and the temperature was raised to react for 5-10 hours; after the reaction was completed, the filtrate was filtered and poured into ice water containing acetic acid for precipitation, the solid was collected by centrifugation, and purified by washing with ethanol; dialyzed and freeze-dried to obtain phthalated hydroxyethyl chitosan; S3. Excess hydrazine hydrate and an ethanol / water mixed solvent were added to the ethylated phthalate chitosan and the reaction was carried out at 60-75°C; after the reaction, the chitosan was purified by dialysis and freeze-dried to obtain hydroxyethyl chitosan; S4. Under a nitrogen atmosphere, hydroxyethyl chitosan was dissolved in anhydrous THF and stirred in an ice bath. A mixture of acryloyl chloride and triethylamine was slowly added dropwise and reacted at 0-5°C for 2 hours. After the reaction, glacial ether was poured into the reaction solution, and the precipitate was filtered, dialyzed, and freeze-dried to obtain acrylamidated hydroxyethyl chitosan.

5. The temperature-sensitive sustained-release medical excipient according to claim 4, characterized in that: In step S1, the amount of phthalic anhydride used is 1-1.5 equivalents of chitosan, and the reaction temperature is 40-60°C.

6. The temperature-sensitive sustained-release medical excipient according to claim 4, characterized in that: The inorganic base in step S2 is selected from one or more of potassium hydroxide, potassium carbonate, cesium carbonate and potassium phosphate, the amount of the inorganic base is 3-6 equivalents of the hydroxyl groups contained in the phthalated chitosan, the alkyl halide is selected from one or more of iodomethane, iodoethane and iodopropane, the amount of the alkyl halide is 1-1.1 equivalents of the hydroxyl groups contained in the phthalated chitosan, and the temperature is 40-60°C.

7. The temperature-sensitive sustained-release medical excipient according to claim 4, characterized in that: The reaction time in step S3 is 24-48 hours; the amount of acryloyl chloride used in step S4 is 0.8-1.2 equivalents of hydroxyethyl chitosan, and the amount of triethylamine used is 0.5-1 equivalents.

8. A temperature-sensitive sustained-release medical excipient as claimed in claim 1, characterized in that: The initiator is selected from ammonium persulfate; the cross-linking agent is selected from N,N,N',N'-tetramethylethylenediamine.

9. The method for preparing a temperature-sensitive sustained-release medical excipient according to any one of claims 1 to 8, characterized in that: The following steps are involved: S1. Preparation of pregel solution: The specific steps are as follows:

1. Pass acrylamidated hydroxyethyl chitosan powder through an 80-mesh sieve to remove agglomerated particles; 2. Dissolve acrylamidated hydroxyethyl chitosan in preheated PBS solution and stir magnetically until completely dissolved; 3. Add polyethylene glycol diacrylate to the solution and stir thoroughly; 4. Add N-methyl acrylate caprolactam dissolved in a small amount of DMSO to the solution and stir in the dark; 5. Add an initiator and then a crosslinker and mix rapidly. S2. Thermally initiated polymerization: The specific steps are as follows: Pour the pregel solution into the mold and shake gently to remove bubbles; cover with a sealing film and react in a 37°C water bath for 30-60 minutes; S3. Post-processing: The specific steps are as follows: After the reaction is completed, the gel is formed and washed with PBS to remove unreacted monomers; the hydrogel is then immersed in a phosphate buffer solution (PBS) containing 10% ethanol, and a dry gel sample is obtained after purification to prepare a temperature-sensitive sustained-release medical excipient.

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