Drug-loaded hydrogel powder as well as preparation method and application thereof

Abstract

The invention discloses drug-loaded hydrogel powder as well as a preparation method and application thereof, and the drug-loaded hydrogel powder is prepared from the following raw materials: sodium alginate, 3-aminophenylboronic acid, N-(3-dimethylaminopropyl)-N '-ethylcarbodiimide hydrochloride, N-hydroxysuccinimide, MES monohydrate, 2, 3-epoxypropyltrimethylammonium chloride, dimethyl sulfoxide, dopamine hydrochloride and lidocaine hydrochloride. Dexamethasone acetate; the preparation method comprises the following steps: firstly, synthesizing Alg-QA through a ring-opening reaction of 2, 3-epoxypropyl trimethyl ammonium chloride and sodium alginate; further synthesizing the carboxyl phenylboronic acid and the sodium alginate-quaternary ammonium salt into Alg-QA-PBA through an amidation reaction; meanwhile, through an amidation reaction, dopamine and sodium alginate-quaternary ammonium salt are synthesized into Alg-QA-DA; then mixing the freeze-dried sponge of the Alg-QA-PBA and the freeze-dried sponge of the Alg-QA-DA according to a certain proportion, and crushing the mixture into uniform powder by using a flour mill; the preparation process is simple; the drug-loaded hydrogel powder is used as a rapid spray gel powder (SRPG) and is applied to oral ulcer, so that the performance of the hydrogel is improved, and the use experience of a patient is optimized.

Description

Technical Field

[0001] The invention relates to the technical field of polymer materials, and in particular to a drug-loaded hydrogel powder, a preparation method and application thereof. Background Art

[0002] Recurrent aphthous ulcer (RAU) is a common inflammatory disease of the oral mucosa with many pathogenic factors. Almost 10% to 20% of people worldwide are suffering from it, and the number of patients in China alone accounts for nearly one-fifth of them. These ulcers mainly exist on some moist dynamic interfaces, such as the oral floor, the lateral and sublingual surfaces of the tongue, the cheeks or the throat. Therefore, patients usually experience a burning sensation on the wound surface due to facial movements caused by talking or chewing, or by eating spicy or hot foods. Therefore, it is very important to effectively and continuously relieve the pain of patients during the ulcer period and promote the healing of oral ulcer wounds in a timely manner.

[0003] At present, clinical treatment measures usually use commercially available films, tablets, mouthwashes or pastes loaded with anesthetic drugs and corticosteroids to relieve pain or promote healing. However, due to the flushing of saliva in the mouth, these methods can usually only maintain relief for 10-30 minutes, and then they will completely dissolve. Therefore, patients have the trouble of needing to take the medicine repeatedly. At the same time, solid tablets will also cause a foreign body sensation in the mouth and the phenomenon of rapid peeling of the wound mucosa during daily talking or eating. Therefore, finding a comfortable film that can continuously retain drugs on the moist oral interface and release them is still an urgent clinical need.

[0004] Author: Wenjie Zhan et al., title: "Promoting Oral Mucosal Wound Healing with a Hydrogel Adhesive Based on a Phototriggered S-Nitrosylation Coupling Reaction", source: Adv. Mater. 2021, 33, 2105667, technical solution: This study proposed a photo-cross-linked hydrogel for the treatment of oral ulcers, which solidifies the hydrogel through light of a specific wavelength to prolong its residence time in the oral cavity. However, since the hydrogel requires additional light irradiation equipment to cut the precursor solution, it is easy to flow, which limits the convenient use of patients and increases the difficulty and cost of use for patients.

[0005] To address these limitations, the scientific community has shown great interest in adhesive hydrogels, especially the application of prefabricated hydrogel films and in situ cross-linked hydrogels. However, there are still some problems with the thickness of the prefabricated hydrogel films in the existing technology and the difficulty of the liquid hydrogel to stay on complex curved surfaces before cross-linking, which makes the existing hydrogel dressings have significant limitations in clinical applications and difficult to achieve commercial transformation. Summary of the invention

[0006] In order to overcome the shortcomings of the above-mentioned prior art, the object of the present invention is to provide a drug-loaded hydrogel powder, a preparation method and an application thereof. First, a sodium alginate-quaternary ammonium salt (Alg-QA) is synthesized by a ring-opening reaction of 2,3-epoxypropyltrimethylammonium chloride (QA) and sodium alginate (Alg), and then carboxyphenylboric acid and sodium alginate-quaternary ammonium salt are synthesized into sodium alginate-quaternary ammonium salt-phenylboric acid (Alg-QA-PBA) by an amidation reaction, and then freeze-dried; at the same time, dopamine and sodium alginate-quaternary ammonium salt are synthesized into sodium alginate-quaternary ammonium salt-polyboric acid by an amidation reaction. Dopamine (Alg-QA-DA), freeze-dried, and then the freeze-dried sponges of Alg-QA-PBA and Alg-QA-DA were mixed in a certain proportion and crushed into a uniform drug-loaded hydrogel powder using a grinder; the drug-loaded hydrogel powder was used as a rapid spray gel powder (SRPG) for oral ulcers, which improved the performance of the hydrogel, optimized the patient's experience, effectively relieved the patient's wound pain and promoted healing. SRPG can be used as a wide range of drug-loading platforms for mass production, storage and transportation, and can be used with a powder spraying device for patients to conveniently administer the drug themselves.

[0007] In order to achieve the above object, the technical solution adopted by the present invention is:

[0008] A drug-loaded hydrogel powder, the raw materials of the drug-loaded hydrogel powder include:

[0009] Sodium alginate (Mw = 20-50 kDa): 10 g-50 g;

[0010] 3-Aminophenylboronic acid, abbreviated as PBA: 200mg-400mg;

[0011] N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, abbreviated as EDC: 600mg-800mg;

[0012] N-hydroxysuccinimide, abbreviated as NHS: 400mg-600mg;

[0013] MES monohydrate, abbreviated as MES: 0.05M-0.2M;

[0014] 2,3-Epoxypropyltrimethylammonium chloride, abbreviated as QA: 600mg-800mg;

[0015] Dimethyl sulfoxide, abbreviated as DMSO: 2mL-5mL;

[0016] Dopamine hydrochloride: 400mg-600mg;

[0017] Lidocaine hydrochloride: 5g-10g;

[0018] Dexamethasone acetate: 25mg-50mg.

[0019] A method for preparing drug-loaded hydrogel powder, the specific steps are as follows:

[0020] Step 1: Through the ring-opening reaction between QA and sodium alginate, sodium alginate grafted with quaternary ammonium salt groups is synthesized, which is abbreviated as Alg-QA:

[0021] Step 2: Connect the PBA group to the Alg-QA obtained in step 1 through EDC / NHS reaction to synthesize sodium alginate grafted with quaternary ammonium salt group and phenylboronic acid group, abbreviated as Alg-QA-PBA;

[0022] Step 3: synthesizing sodium alginate grafted with quaternary ammonium salt group and dopamine group, abbreviated as Alg-QA-DA;

[0023] Step 4: Alg-QA-PBA and Alg-QA-DA are mixed in a mass ratio of 2:1-5:1, and then ground using a grinder to obtain a mixed powder;

[0024] Step 5: 5g-10g of the mixed powder obtained in step 4 is quantitatively dissolved in double distilled water (dd H2O) to form a 1% solution, and 25mg-50mg of dexamethasone sodium phosphate acetate and 5g-10g of lidocaine hydrochloride are added respectively to form a mixed drug-loaded precursor solution, and the pH of the mixed drug-loaded precursor solution is adjusted to 7 by an alkaline reagent; then freeze-dried and powdered to form a drug-loaded hydrogel powder.

[0025] The specific method of step 1 is:

[0026] Step 1.1, fully dissolving 10 g to 50 g of sodium alginate (Mw = 20-50 kDa) in double distilled water (dd H2O) to prepare a sodium alginate solution with a concentration of 0.5% to 2% (w / w);

[0027] Step 1.2, adding QA to the sodium alginate solution prepared in step 1.1 at a molar ratio of sodium alginate solution to QA of n(Alg)=3:1-5:1, to obtain a mixed solution of sodium alginate and QA;

[0028] Step 1.3, subjecting the mixed solution obtained in step 1.2 to a ring-opening reaction at 40° C. to 60° C. for 4 to 8 hours to obtain a reaction product;

[0029] Step 1.4, dialyzing the reaction product obtained in step 1.3 using a dialysis bag with a molecular weight cutoff of 3500Da-8000Da for 5-7 days to remove unreacted QA;

[0030] Step 1.5, after the dialysis is completed, freeze-drying is performed to obtain Alg-QA.

[0031] The specific method of step 2 is:

[0032] Step 2.1, dissolving 1 g to 5 g of the Alg-QA obtained in step 1.5 in a 0.05 M to 0.2 M aqueous solution of MES monohydrate to prepare a 1% to 5% (w / w) Alg-QA solution; adjusting the pH value of the obtained Alg-QA solution to 4.5 to 5.5 using an alkaline reagent;

[0033] Step 2.2, adding 600 mg-800 mg of EDC and 400 mg-600 mg of NHS to the Alg-QA solution obtained in step 2.1, and mixing thoroughly to obtain a mixed solution II;

[0034] Step 2.3, dissolving 200 mg-400 mg of PBA in 2 mL-5 mL of dimethyl sulfoxide (DMSO), and then adding the mixture to the mixed solution 2 at a rate of 1 mL-3 mL / min to obtain a mixed solution 3; using an acidic reagent to ensure that the pH of the mixed solution 3 is always maintained between 4.5 and 5.5 for 18-26 hours to obtain a mixed solution 4;

[0035] Step 2.4, the mixed solution is transferred into a dialysis bag with a molecular weight cutoff of 3500Da-8000Da, the pH value of the solution is maintained between 5-6, and dialyzed for 5-7 days to remove unreacted PBA;

[0036] Step 2.5, after the dialysis is completed, the pH of the solution is adjusted to 7.0 by an alkaline reagent, and then freeze-dried to finally obtain Alg-QA-PBA.

[0037] Step 3 The specific method for synthesizing Alg-QA-DA is:

[0038] Step 3.1, dissolving 1 g to 5 g of the Alg-QA obtained in step 1 in a 0.05 M to 0.2 M aqueous solution of MES monohydrate to form a 1% to 5% (w / w) Alg-QA solution;

[0039] Step 3.2, then, add 600 mg-800 mg of EDC and 300 mg-400 mg of NHS to the Alg-QA solution obtained in step 3.1, and mix thoroughly to obtain a mixed solution V;

[0040] Step 3.3, then, add 400 mg to 600 mg of dopamine hydrochloride to the obtained mixed solution 5 until it is completely dissolved to obtain a mixed solution 6;

[0041] Step 3.4, subjecting the mixed solution obtained in step 3.3 to an EDC / NHS reaction at room temperature of 20-25° C. for 20-30 hours, and during the reaction, an alkaline reagent is used to maintain the pH value between 4.0 and 5.0;

[0042] Step 3.5, dialyzing the reaction product obtained in step 3.4 for 5-7 days using a dialysis bag with a molecular weight cutoff of 3500Da-8000Da to remove unreacted DA;

[0043] Step 3.6, after dialysis is completed, the pH value is maintained at 5.5-6.5 by using an alkaline reagent, and then freeze-dried to obtain Alg-QA-DA.

[0044] The freeze-drying temperature in step 1.5 and step 3.6 is: minus 20°C to minus 80°C, the vacuum degree is controlled at no more than 1 bar, and the freeze-drying time is 3-5 days.

[0045] The freeze-drying temperature in step 2.5 and step 5 is -20°C to -80°C, the vacuum degree is controlled to be no more than 0.1 bar, and the freeze-drying time is 3-5 days.

[0046] The alkaline reagent includes NaOH reagent, KOH reagent or Na2CO3 reagent.

[0047] The acidic reagent includes HCL reagent, acetic acid reagent or phosphoric acid reagent.

[0048] The drug-loaded hydrogel powder prepared above is used as a rapid spray gel powder (SRPG) for spraying oral ulcers.

[0049] Compared with the prior art, the beneficial effects of the present invention are:

[0050] 1. The present invention uses natural alginate as the main component, which enhances the biocompatibility and biodegradability of the product, avoids the safety issues that may be caused by synthetic polymers, and thus improves safety and acceptability.

[0051] 2. The present invention utilizes the dynamic characteristics of borate bonds to enable the hydrogel to self-heal in the oral cavity and adapt to changes in the dynamic environment, thereby significantly extending the service life and improving functional stability, and solving the problem of easy breakage of existing hydrogels.

[0052] 3. The present invention optimizes the adhesion performance by adjusting the ratio of dopamine groups, so that it forms a stable adhesion barrier in a humid environment, ensures the sustained release and effective protection of the drug, thereby improving the therapeutic effect and prolonging the retention time of the drug in the ulcer site. At the same time, the introduced quaternary ammonium salt group enhances the antibacterial property of the hydrogel, reduces the risk of infection, and provides a favorable microenvironment for ulcer healing.

[0053] 4. The preparation process of the present invention is simple and easy to operate, and the spray application method enables patients to spray themselves at multiple angles, which greatly facilitates use. Through these innovations, the present invention not only improves the performance of the hydrogel, but also optimizes the patient's experience of use, meeting the urgent needs of patients with oral ulcers.

[0054] 5. The drug-loaded hydrogel powder prepared by the present invention is applied to oral ulcers as a rapid spray gel powder (SRPG). After contact with saliva, SPRG can quickly undergo a significant biomechanical transformation into an elastic adhesive hydrogel barrier. The biomechanical properties of the barrier enable it to remain effective for more than 12 hours, resisting challenges such as salivary penetration and biomechanical pressure associated with oral activities, while ensuring the sustained release of the drug. In a rat oral ulcer model, a composite drug-loaded gel powder characterized by lidocaine hydrochloride and dexamethasone sodium phosphate exhibited anti-inflammatory effects at the ulcer site, accelerated wound healing, and shortened the healing time to 2 to 4 days. The biomechanical effectiveness and ease of use of SRPG were further biomechanically verified in a preclinical model of pigs, emphasizing its biomechanical potential as a clinical hydrogel dressing for oral ulcers.

[0055] In summary, compared with the prior art, the present invention mixes freeze-dried sponges of Alg-QA-PBA and Alg-QA-DA in a certain proportion and grinds them into uniform powder using a grinder; the preparation process is simple; the drug-loaded hydrogel powder is used as a rapid spray gel powder (SRPG) for oral ulcers, which improves the performance of the hydrogel, and the powder spraying device allows patients to conveniently administer the drug themselves, optimizes the patient's use experience, effectively relieves the patient's wound pain and promotes healing; and has the advantages of stable adhesion, good safety and high reliability. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1 The present invention provides a process for using the drug-loaded hydrogel powder.

[0057] Figure 2 This is the gelling process of the drug-loaded hydrogel powder of the present invention. DETAILED DESCRIPTION

[0058] The present invention is further described in detail below with reference to the embodiments.

[0059] Example 1

[0060] A method for preparing drug-loaded hydrogel powder, the specific steps are as follows:

[0061] Step 1: Alg-QA is synthesized by a ring-opening reaction between 2,3-epoxypropyltrimethylammonium chloride (QA) and sodium alginate (the ring structure of sodium alginate is attacked by the functional group of the quaternary ammonium salt, thereby opening its ring structure):

[0062] Step 1.1, dissolving 10 g of sodium alginate (Mw=20 kDa) in double distilled water (dd H2O) to prepare a sodium alginate solution with a concentration of 1% (w / w);

[0063] Step 1.2, adding QA to the sodium alginate solution prepared in step 1.1 at a molar ratio of n(Alg)=3:1 to obtain a mixed solution of sodium alginate and QA;

[0064] Step 1.3, subjecting the mixed solution of sodium alginate obtained in step 1.2 and QA to a ring-opening reaction at 40° C. for 6 hours to obtain a reaction product;

[0065] Step 1.4, dialyzing the reaction product obtained in step 1.3 using a dialysis bag with a molecular weight cutoff of 3500 Da for 6 days to remove unreacted QA;

[0066] Step 1.5, after the dialysis is completed, freeze drying is performed to finally obtain Alg-QA; the freeze drying temperature is minus 80°C, the vacuum degree is controlled at 1 bar, and the freeze drying time is 3 days;

[0067] Step 2: Connecting the phenylboronic acid (PBA) group to the Alg-QA obtained in step 1 through an EDC / NHS reaction (EDC and NHS act together between the carboxyl group and the amino group to promote the formation of a stable amide bond) to synthesize Alg-QA-PBA;

[0068] Step 2.1, dissolving 1 g of Alg-QA obtained in step 1 in a 0.1 M aqueous solution of MES monohydrate to form a 1% (w / w) Alg-QA solution; adjusting the pH value of the obtained Alg-QA solution to 5.5 using a NaOH reagent;

[0069] Step 2.2, add 700 mg of EDC and 500 mg of NHS to the Alg-QA solution obtained in step 2.1, mix thoroughly, and obtain a mixed solution II;

[0070] Step 2.3, dissolving 300 mg of 3-aminophenylboronic acid (PBA) in 3 mL of dimethyl sulfoxide (DMSO), and then adding the mixture dropwise to the mixed solution 2 at a rate of 1 mL / min to obtain a mixed solution 3; using a pH meter to detect, using HCl reagent to ensure that the pH value of the mixed solution 3 is 5.5, and maintaining for 18 hours to obtain a mixed solution 4;

[0071] Step 2.4, the mixed solution was transferred into a dialysis bag with a molecular weight cutoff of 4000 Da, the pH of the solution was maintained at 5.5, and dialyzed for 6 days to remove unreacted PBA;

[0072] Step 2.5, after dialysis is completed, the pH of the solution is adjusted to 7.0 with NaOH reagent, and then freeze-dried to finally obtain Alg-QA-PBA; the freeze-drying temperature is minus 40° C., the vacuum degree is controlled at 0.1 bar, and the freeze-drying time is 4 days.

[0073] Step 3: Synthesis of Alg-QA-DA.

[0074] Step 3.1, dissolving 1 g of Alg-QA obtained in step 1 in a 0.1 M aqueous solution of MES monohydrate to form a 2% (w / w) Alg-QA solution;

[0075] Step 3.2, then, add 700 mg of EDC and 350 mg of NHS to the Alg-QA solution obtained in 3.1, and mix thoroughly to obtain a mixed solution V;

[0076] Step 3.3, then, add 400 mg of dopamine hydrochloride to the obtained mixed solution 5 and completely dissolve it to obtain a mixed solution 6;

[0077] Step 3.4, subjecting the obtained mixed solution VI to EDC / NHS reaction at room temperature (25°C) for 26 hours, and maintaining the pH value at 5 by using NaOH reagent during the reaction;

[0078] Step 3.5, after the reaction is completed, the reaction product obtained in 3.4 is dialyzed for 5 days using a dialysis bag with a molecular weight cutoff of 4000Da to remove unreacted DA;

[0079] Step 3.6, after dialysis is completed, the pH is adjusted to 6 by using an alkaline reagent, and then freeze-dried to obtain Alg-QA-DA; the freeze-drying temperature is minus 20° C., the vacuum degree is controlled at 0.8 bar, and the freeze-drying time is 3 days.

[0080] Step 4: Mix the freeze-dried sponges of Alg-QA-PBA and Alg-QA-DA at a mass ratio of 2:1, and then grind them using a grinder to obtain a mixed powder.

[0081] Step 5: 10 g of the mixed powder obtained in step 4 is quantitatively dissolved in double distilled water (dd H2O) to form a 1% solution, 25 mg of dexamethasone sodium phosphate acetate and 5 g of lidocaine hydrochloride are added respectively to form a mixed drug-loaded precursor solution, and the pH of the mixed drug-loaded precursor solution is adjusted to 7 by NaOH reagent; freeze-dried and ground into powder to form a drug-loaded hydrogel powder; the freeze-drying treatment temperature is minus 20°C, the vacuum degree is 0.1 bar, and the freeze-drying time is 3 days.

[0082] Example 2

[0083] A method for preparing drug-loaded hydrogel powder, the specific steps are as follows:

[0084] Step 1: Alg-QA is synthesized by ring-opening reaction of 2,3-epoxypropyltrimethylammonium chloride (QA) and sodium alginate:

[0085] Step 1.1, dissolving 20 g of sodium alginate (Mw=30 kDa) in double distilled water (dd H2O) to prepare a sodium alginate solution with a concentration of 0.5% (w / w);

[0086] Step 1.2, adding QA to the sodium alginate solution prepared in step 1.1 at a molar ratio of n(Alg)=4:1 to obtain a mixed solution of sodium alginate and QA;

[0087] Step 1.3, subjecting the mixed solution of sodium alginate obtained in step 1.2 and QA to a ring-opening reaction at 60° C. for 4 hours to obtain a reaction product;

[0088] Step 1.4, dialyze the reaction product obtained in step 1.3 using a dialysis bag with a molecular weight cutoff of 4000Da for 5 days to remove unreacted QA;

[0089] Step 1.5, after the dialysis is completed, freeze drying is performed to finally obtain Alg-QA; the freeze drying temperature is minus 60°C, the vacuum degree is controlled at 0.5 bar, and the freeze drying time is 5 days;

[0090] Step 2: Connecting the phenylboronic acid (PBA) group to the Alg-QA obtained in step 1 by EDC / NHS reaction to synthesize Alg-QA-PBA;

[0091] Step 2.1, dissolving 1 g of Alg-QA obtained in step 1 in a 0.05 M aqueous solution of MES monohydrate to form a 1% (w / w) Alg-QA solution; adjusting the pH value of the obtained Alg-QA solution to 5.5 using a NaOH reagent;

[0092] Step 2.2, add 600 mg of EDC and 400 mg of NHS to the Alg-QA solution obtained in step 2.1, mix thoroughly, and obtain a mixed solution II;

[0093] Step 2.3, dissolving 300 mg of 3-aminophenylboronic acid (PBA) in 2 mL of dimethyl sulfoxide (DMSO), and then dropping the mixture into the mixed solution 2 at a rate of 1 mL / min to obtain a mixed solution 3; using a pH meter to detect, using HCl reagent to ensure that the pH value of the mixed solution 3 is 5, and maintaining it for 20 hours to obtain a mixed solution 4;

[0094] Step 2.4, the mixed solution was transferred into a dialysis bag with a molecular weight cutoff of 3500 Da, the pH of the solution was maintained at 5.5, and dialyzed for 5 days to remove unreacted PBA;

[0095] Step 2.5, after dialysis is completed, the pH of the solution is adjusted to 7.0 with NaOH reagent, and then freeze-dried to finally obtain Alg-QA-PBA; the freeze-drying temperature is minus 20° C., the vacuum degree is controlled at 0.08 bar, and the freeze-drying time is 5 days.

[0096] Step 3: Synthesis of Alg-QA-DA.

[0097] Step 3.1, dissolving 1 g of Alg-QA obtained in step 1 in a 0.3 M aqueous solution of MES monohydrate to form a 1% (w / w) Alg-QA solution;

[0098] Step 3.2, then, add 700 mg of EDC and 300 mg of NHS to the Alg-QA solution obtained in 3.1, and mix thoroughly to obtain a mixed solution V;

[0099] Step 3.3, then, add 500 mg of dopamine hydrochloride to the obtained mixed solution 5 and completely dissolve it to obtain a mixed solution 6;

[0100] Step 3.4, subjecting the obtained mixed solution VI to EDC / NHS reaction at room temperature (20°C) for 24 hours, and maintaining the pH value at 4.5 by using NaOH reagent during the reaction;

[0101] Step 3.5, after the reaction is completed, the reaction product obtained in 3.4 is dialyzed for 6 days using a dialysis bag with a molecular weight cutoff of 3500 Da to remove unreacted DA;

[0102] Step 3.6, after dialysis is completed, the pH is adjusted to 6 by using an alkaline reagent, and then freeze-dried to obtain Alg-QA-DA; the freeze-drying temperature is minus 20° C., the vacuum degree is controlled at 0.5 bar, and the freeze-drying time is 3 days.

[0103] Step 4: Mix the freeze-dried sponges of Alg-QA-PBA and Alg-QA-DA at a mass ratio of 3:1, and then grind them using a grinder to obtain a mixed powder.

[0104] Step 5: 5 g of the mixed powder obtained in step 4 is quantitatively dissolved in double distilled water (dd H2O) to form a 1% solution, 30 mg of dexamethasone sodium phosphate acetate and 6 g of lidocaine hydrochloride are added respectively to form a mixed drug-loaded precursor solution, and the pH of the mixed drug-loaded precursor solution is adjusted to 7 by NaOH reagent; freeze-dried and ground into powder to form a drug-loaded hydrogel powder; the freeze-drying treatment temperature is minus 40°C, the vacuum degree is 0.08 bar, and the freeze-drying time is 5 days.

[0105] Example 3

[0106] Step 1: Alg-QA is synthesized by ring-opening reaction of 2,3-epoxypropyltrimethylammonium chloride (QA) and sodium alginate:

[0107] Step 1.1, dissolving 30 g of sodium alginate (Mw=40 kDa) in double distilled water (dd H2O) to prepare a sodium alginate solution with a concentration of 1.5% (w / w);

[0108] Step 1.2, adding QA to the sodium alginate solution prepared in step 1.1 at a molar ratio of n(Alg)=3:1 to obtain a mixed solution of sodium alginate and QA;

[0109] Step 1.3, subjecting the mixed solution of sodium alginate obtained in step 1.2 and QA to a ring-opening reaction at 60° C. for 8 hours to obtain a reaction product;

[0110] Step 1.4, dialyzing the reaction product obtained in step 1.3 using a dialysis bag with a molecular weight cutoff of 8000Da for 7 days to remove unreacted QA;

[0111] Step 1.5, after the dialysis is completed, freeze drying is performed to finally obtain Alg-QA; the freeze drying temperature is minus 80°C, the vacuum degree is controlled at 0.8 bar, and the freeze drying time is 5 days;

[0112] Step 2: Connecting the phenylboronic acid (PBA) group to the Alg-QA obtained in step 1 by EDC / NHS reaction to synthesize Alg-QA-PBA;

[0113] Step 2.1, dissolving 5 g of Alg-QA obtained in step 1 in a 0.1 M aqueous solution of MES monohydrate to form a 3% (w / w) Alg-QA solution; adjusting the pH value of the obtained Alg-QA solution to 5 using a NaOH reagent;

[0114] Step 2.2, add 800 mg of EDC and 600 mg of NHS to the Alg-QA solution obtained in step 2.1, mix thoroughly, and obtain a mixed solution II;

[0115] Step 2.3, dissolving 400 mg of 3-aminophenylboronic acid (PBA) in 3 mL of dimethyl sulfoxide (DMSO), and then dropping the mixture into the mixed solution 2 at a rate of 1 mL / min to obtain a mixed solution 3; using a pH meter to detect, using HCl reagent to ensure that the pH value of the mixed solution 3 is 4.5, and maintaining it for 26 hours to obtain a mixed solution 4;

[0116] Step 2.4, the mixed solution was transferred into a dialysis bag with a molecular weight cutoff of 8000Da, the pH of the solution was maintained at 6, and dialyzed for 6 days to remove unreacted PBA;

[0117] Step 2.5, after dialysis is completed, the pH of the solution is adjusted to 7.0 with NaOH reagent, and then freeze-dried to finally obtain Alg-QA-PBA; the freeze-drying temperature is minus 30° C., the vacuum degree is controlled at 0.05 bar, and the freeze-drying time is 4 days.

[0118] Step 3: Synthesis of Alg-QA-DA.

[0119] Step 3.1, dissolving 1 g of Alg-QA obtained in step 1 in a 0.2 M aqueous solution of MES monohydrate to form a 2% (w / w) Alg-QA solution;

[0120] Step 3.2, then, add 800 mg of EDC and 400 mg of NHS to the Alg-QA solution obtained in 3.1, and mix thoroughly to obtain a mixed solution V;

[0121] Step 3.3, then, add 600 mg of dopamine hydrochloride to the obtained mixed solution 5 and completely dissolve it to obtain a mixed solution 6;

[0122] Step 3.4, subjecting the obtained mixed solution VI to EDC / NHS reaction at room temperature (25°C) for 30 hours, and maintaining the pH value at 5.0 by using NaOH reagent during the reaction;

[0123] Step 3.5, after the reaction is completed, the reaction product obtained in 3.4 is dialyzed for 7 days using a dialysis bag with a molecular weight cutoff of 3500 Da to remove unreacted DA;

[0124] Step 3.6, after dialysis is completed, the pH is adjusted to 6.5 by using an alkaline reagent, and then freeze-dried to obtain Alg-QA-DA; the freeze-drying temperature is minus 20° C., the vacuum degree is controlled at 0.8 bar, and the freeze-drying time is 5 days.

[0125] Step 4: Mix the freeze-dried sponges of Alg-QA-PBA and Alg-QA-DA at a mass ratio of 5:1, and then grind them using a grinder to obtain a mixed powder.

[0126] Step 5: 5 g of the mixed powder obtained in step 4 is quantitatively dissolved in double distilled water (dd H2O) to form a 1% solution, 50 mg of dexamethasone acetate sodium phosphate and 5 g of lidocaine hydrochloride are added respectively to form a mixed drug-loaded precursor solution, and the pH of the mixed drug-loaded precursor solution is adjusted to 7 by NaOH reagent; freeze-dried and ground into powder to form a drug-loaded hydrogel powder; the freeze-drying treatment temperature is minus 20°C, the vacuum degree is 0.05 bar, and the freeze-drying time is 3 days.

[0127] Example 4

[0128] Step 1: Alg-QA is synthesized by ring-opening reaction of 2,3-epoxypropyltrimethylammonium chloride (QA) and sodium alginate:

[0129] Step 1.1, dissolving 50 g of sodium alginate (Mw=50 kDa) in double distilled water (dd H2O) to prepare a sodium alginate solution with a concentration of 2% (w / w);

[0130] Step 1.2, adding QA to the sodium alginate solution prepared in step 1.1 at a molar ratio of n(Alg)=5:1 to obtain a mixed solution of sodium alginate and QA;

[0131] Step 1.3, subjecting the mixed solution of sodium alginate obtained in step 1.2 and QA to a ring-opening reaction at 50° C. for 5 hours to obtain a reaction product;

[0132] Step 1.4, dialyze the reaction product obtained in step 1.3 using a dialysis bag with a molecular weight cutoff of 7000Da for 6 days to remove unreacted QA;

[0133] Step 1.5, after the dialysis is completed, freeze drying is performed to finally obtain Alg-QA; the freeze drying temperature is minus 30°C, the vacuum degree is controlled at 1 bar, and the freeze drying time is 4 days;

[0134] Step 2: Connecting the phenylboronic acid (PBA) group to the Alg-QA obtained in step 1 by EDC / NHS reaction to synthesize Alg-QA-PBA;

[0135] Step 2.1, dissolving 3 g of Alg-QA obtained in step 1 in a 0.05 M aqueous solution of MES monohydrate to form a 3% (w / w) Alg-QA solution; adjusting the pH value of the obtained Alg-QA solution to 5 using NaOH reagent;

[0136] Step 2.2, add 650 mg of EDC and 450 mg of NHS to the Alg-QA solution obtained in step 2.1, mix thoroughly, and obtain a mixed solution II;

[0137] Step 2.3, dissolving 300 mg of 3-aminophenylboronic acid (PBA) in 2.5 mL of dimethyl sulfoxide (DMSO), and then dropping the mixture into the mixed solution 2 at a rate of 1 mL / min to obtain a mixed solution 3; using a pH meter to detect, using HCl reagent to ensure that the pH value of the mixed solution 3 is 3, and maintaining it for 24 hours to obtain a mixed solution 4;

[0138] Step 2.4, the mixed solution was transferred into a dialysis bag with a molecular weight cutoff of 4000 Da, the pH of the solution was maintained at 6, and dialyzed for 5 days to remove unreacted PBA;

[0139] Step 2.5, after dialysis is completed, the pH of the solution is adjusted to 7.0 with NaOH reagent, and then freeze-dried to finally obtain Alg-QA-PBA; the freeze-drying temperature is minus 20° C., the vacuum degree is controlled at 0.1 bar, and the freeze-drying time is 4 days.

[0140] Step 3: Synthesis of Alg-QA-DA.

[0141] Step 3.1, dissolving 3 g of Alg-QA obtained in step 1 in a 0.1 M aqueous solution of MES monohydrate to form a 3% (w / w) Alg-QA solution;

[0142] Step 3.2, then, add 650 mg of EDC and 350 mg of NHS to the Alg-QA solution obtained in 3.1, and mix thoroughly to obtain a mixed solution V;

[0143] Step 3.3, then, add 450 mg of dopamine hydrochloride to the obtained mixed solution 5 and completely dissolve it to obtain a mixed solution 6;

[0144] Step 3.4, subjecting the obtained mixed solution VI to EDC / NHS reaction at room temperature (23°C) for 24 hours, and maintaining the pH value at 4.5 by using NaOH reagent during the reaction;

[0145] Step 3.5, after the reaction is completed, the reaction product obtained in 3.4 is dialyzed for 5-7 days using a dialysis bag with a molecular weight cutoff of 3500Da to remove unreacted DA;

[0146] Step 3.6, after dialysis is completed, the pH is adjusted to 6 by using an alkaline reagent, and then freeze-dried to obtain Alg-QA-DA; the freeze-drying temperature is minus 40° C., the vacuum degree is controlled at 1 bar, and the freeze-drying time is 3 days.

[0147] Step 4: Mix the freeze-dried sponges of Alg-QA-PBA and Alg-QA-DA at a mass ratio of 4:1, and then grind them using a grinder to obtain a mixed powder.

[0148] Step 5: 6 g of the mixed powder obtained in step 4 is quantitatively dissolved in double distilled water (dd H2O) to form a 1% solution, 30 mg of dexamethasone acetate sodium phosphate and 7 g of lidocaine hydrochloride are added respectively to form a mixed drug-loaded precursor solution, and the pH of the mixed drug-loaded precursor solution is adjusted to 7 by NaOH reagent; freeze-dried and ground into powder to form a drug-loaded hydrogel powder; the freeze-drying treatment temperature is minus 40°C, the vacuum degree is 0.1 bar, and the freeze-drying time is 4 days.

[0149] Example 5

[0150] Step 1: Alg-QA is synthesized by ring-opening reaction of 2,3-epoxypropyltrimethylammonium chloride (QA) and sodium alginate:

[0151] Step 1.1, dissolving 20 g of sodium alginate (Mw=30 kDa) in double distilled water (dd H2O) to prepare a sodium alginate solution with a concentration of 1% (w / w);

[0152] Step 1.2, adding QA to the sodium alginate solution prepared in step 1.1 at a molar ratio of n(Alg)=2:1 to obtain a mixed solution of sodium alginate and QA;

[0153] Step 1.3, subjecting the mixed solution of sodium alginate obtained in step 1.2 and QA to a ring-opening reaction at 45° C. for 5.5 hours to obtain a reaction product;

[0154] Step 1.4, dialyzing the reaction product obtained in step 1.3 using a dialysis bag with a molecular weight cutoff of 4000 Da for 6 days to remove unreacted QA;

[0155] Step 1.5, after the dialysis is completed, freeze drying is performed to finally obtain Alg-QA; the freeze drying temperature is minus 25°C, the vacuum degree is controlled at 0.6 bar, and the freeze drying time is 7 days;

[0156] Step 2: Connecting the phenylboronic acid (PBA) group to the Alg-QA obtained in step 1 by EDC / NHS reaction to synthesize Alg-QA-PBA;

[0157] Step 2.1, dissolving 2.5 g of Alg-QA obtained in step 1 in a 0.15 M aqueous solution of MES monohydrate to form a 1% (w / w) Alg-QA solution; adjusting the pH value of the obtained Alg-QA solution to 5.2 using a NaOH reagent;

[0158] Step 2.2, add 670 mg of EDC and 430 mg of NHS to the Alg-QA solution obtained in step 2.1, mix thoroughly, and obtain a mixed solution II;

[0159] Step 2.3, dissolving 310 mg of 3-aminophenylboronic acid (PBA) in 2 mL of dimethyl sulfoxide (DMSO), and then dropping the mixture into the mixed solution 2 at a rate of 1.2 mL / min to obtain a mixed solution 3; using a pH meter to detect, using HCl reagent to ensure that the pH value of the mixed solution 3 is 5, and maintaining it for 16.5 hours to obtain a mixed solution 4;

[0160] Step 2.4, the mixed solution was transferred into a dialysis bag with a molecular weight cutoff of 5500 Da, the pH of the solution was maintained at 5.5, and dialyzed for 5 days to remove unreacted PBA;

[0161] Step 2.5, after dialysis is completed, the pH of the solution is adjusted to 7.0 with NaOH reagent, and then freeze-dried to finally obtain Alg-QA-PBA; the freeze-drying temperature is minus 25° C., the vacuum degree is controlled at 0.05 bar, and the freeze-drying time is 5.5 days.

[0162] Step 3: Synthesis of Alg-QA-DA.

[0163] Step 3.1, dissolving 1 g of Alg-QA obtained in step 1 in a 0.1 M aqueous solution of MES monohydrate to form a 1% (w / w) Alg-QA solution;

[0164] Step 3.2, then, add 670 mg of EDC and 330 mg of NHS to the Alg-QA solution obtained in 3.1, and mix thoroughly to obtain a mixed solution V;

[0165] Step 3.3, then, add 510 mg of dopamine hydrochloride to the obtained mixed solution 5 and completely dissolve it to obtain a mixed solution 6;

[0166] Step 3.4, subjecting the obtained mixed solution VI to EDC / NHS reaction at room temperature (25°C) for 23 hours, and maintaining the pH value at 4.5 by using NaOH reagent during the reaction;

[0167] Step 3.5, after the reaction is completed, the reaction product obtained in 3.4 is dialyzed for 5.5 days using a dialysis bag with a molecular weight cutoff of 3500 Da to remove unreacted DA;

[0168] Step 3.6, after dialysis is completed, the pH is adjusted to 6 by using an alkaline reagent, and then freeze-dried to obtain Alg-QA-DA; the freeze-drying temperature is minus 20° C., the vacuum degree is controlled at 0.6 bar, and the freeze-drying time is 3 days.

[0169] Step 4: Mix the freeze-dried sponges of Alg-QA-PBA and Alg-QA-DA at a mass ratio of 2.3:1, and then grind them using a grinder to obtain a mixed powder.

[0170] Step 5: 5 g of the mixed powder obtained in step 4 is quantitatively dissolved in double distilled water (dd H2O) to form a 1% solution, 25 mg of dexamethasone acetate sodium phosphate and 5 g of lidocaine hydrochloride are added respectively to form a mixed drug-loaded precursor solution, and the pH of the mixed drug-loaded precursor solution is adjusted to 7 by NaOH reagent; freeze-dried and ground into powder to form a drug-loaded hydrogel powder; the freeze-drying treatment temperature is minus 60°C, the vacuum degree is 0.05 bar, and the freeze-drying time is 5 days.

[0171] See also Figure 1 , Figure 2 Through experiments on the mechanical properties, adhesion, fluid scouring resistance and self-healing ability of the hydrogel powder prepared by the present invention, the gel formed by the present invention forms a tight fusion with the tissue surface, and by simulating saliva scouring, tissue twisting and stretching in the oral cavity, it is found that the gel is tightly adhered to the tissue surface. The self-healing performance of the present invention is also well demonstrated, and a complete gel can be formed by attaching two independent gels together.

[0172] In addition, the hydrogel powder prepared by the present invention can be 2 —6mg / cm 2 The liquid on the tissue surface is quickly absorbed and gelled in the area. The gel healing curve shows that the gelling speed is less than 3S. Compared with the existing photo-crosslinking technology, there is no need to use additional lighting equipment to illuminate the precursor solution for gelling, which greatly improves the cost and convenience of use for patients.

[0173] In addition, the hydrogel powder of the present invention can achieve different shear fracture strengths by adjusting the proportion, and can be customized according to the mechanical requirements of different parts of the oral cavity.

[0174] The above description is only a specific implementation mode of the present invention, but the protection scope of the present invention is not limited thereto. Any modifications, equivalent substitutions and improvements made by any technician familiar with the technical field within the technical scope disclosed by the present invention and within the spirit and principle of the present invention should be covered by the protection scope of the present invention.

Claims

1. A drug-loaded hydrogel powder, characterized in that: The raw materials of drug-loaded hydrogel powder include: Sodium alginate (Mw = 20-50 kDa): 10 g-50 g; 3-Aminophenylboronic acid, abbreviated as PBA: 200mg-400mg; N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, abbreviated as EDC: 600mg-800mg; N-hydroxysuccinimide, abbreviated as NHS: 400mg-600mg; MES monohydrate, abbreviated as MES: 0.05M-0.2M; 2,3-Epoxypropyltrimethylammonium chloride, abbreviated as QA: 600mg-800mg; Dimethyl sulfoxide, abbreviated as DMSO: 2mL-5mL; Dopamine hydrochloride: 400mg-600mg; Lidocaine hydrochloride: 5g-10g; Dexamethasone acetate: 25mg-50mg.

2. A method for preparing a drug-loaded hydrogel powder, characterized in that: The specific steps are as follows: Step 1: Through the ring-opening reaction between QA and sodium alginate, sodium alginate grafted with quaternary ammonium salt groups is synthesized, which is abbreviated as Alg-QA: Step 2: Connect the PBA group to the Alg-QA obtained in step 1 through EDC / NHS reaction to synthesize sodium alginate grafted with quaternary ammonium salt group and phenylboronic acid group, abbreviated as Alg-QA-PBA; Step 3: synthesizing sodium alginate grafted with quaternary ammonium salt group and dopamine group, abbreviated as Alg-QA-DA; Step 4: Alg-QA-PBA and Alg-QA-DA are mixed in a mass ratio of 2:1-5:1, and then ground using a grinder to obtain a mixed powder; Step 5: 5g-10g of the mixed powder obtained in step 4 is quantitatively dissolved in double distilled water (dd H2O) to form a 1% solution, and 25mg-50mg of dexamethasone sodium phosphate acetate and 5g-10g of lidocaine hydrochloride are added respectively to form a mixed drug-loaded precursor solution, and the pH of the mixed drug-loaded precursor solution is adjusted to 7 by an alkaline reagent; then freeze-dried and powdered to form a drug-loaded hydrogel powder.

3. The method for preparing a drug-loaded hydrogel powder according to claim 2, characterized in that: The specific method of step 1 is: Step 1.1, fully dissolving 10 g to 50 g of sodium alginate (Mw = 20-50 kDa) in double distilled water (dd H2O) to prepare a sodium alginate solution with a concentration of 0.5% to 2% (w / w); Step 1.2, adding QA to the sodium alginate solution prepared in step 1.1 at a molar ratio of sodium alginate solution to QA of n(Alg)=3:1-5:1, to obtain a mixed solution of sodium alginate and QA; Step 1.3, subjecting the mixed solution obtained in step 1.2 to a ring-opening reaction at 40° C. to 60° C. for 4 to 8 hours to obtain a reaction product; Step 1.4, dialyzing the reaction product obtained in step 1.3 using a dialysis bag with a molecular weight cutoff of 3500Da-8000Da for 5-7 days to remove unreacted QA; Step 1.5, after the dialysis is completed, freeze-drying is performed to obtain Alg-QA.

4. The method for preparing a drug-loaded hydrogel powder according to claim 2, characterized in that: The specific method of step 2 is: Step 2.1, dissolving 1 g to 5 g of the Alg-QA obtained in step 1.5 in a 0.05 M to 0.2 M aqueous solution of MES monohydrate to prepare a 1% to 5% (w / w) Alg-QA solution; adjusting the pH value of the obtained Alg-QA solution to 4.5 to 5.5 using an alkaline reagent; Step 2.2, adding 600 mg-800 mg of EDC and 400 mg-600 mg of NHS to the Alg-QA solution obtained in step 2.1, and mixing thoroughly to obtain a mixed solution II; Step 2.3, dissolving 200 mg-400 mg of PBA in 2 mL-5 mL of dimethyl sulfoxide (DMSO), and then adding the mixture to the mixed solution 2 at a rate of 1 mL-3 mL / min to obtain a mixed solution 3; using an acidic reagent to ensure that the pH of the mixed solution 3 is always maintained between 4.5 and 5.5 for 18-26 hours to obtain a mixed solution 4; Step 2.4, the mixed solution is transferred into a dialysis bag with a molecular weight cutoff of 3500Da-8000Da, the pH value of the solution is maintained between 5-6, and dialyzed for 5-7 days to remove unreacted PBA; Step 2.5, after the dialysis is completed, the pH of the solution is adjusted to 7.0 by an alkaline reagent, and then freeze-dried to finally obtain Alg-QA-PBA.

5. The method for preparing a drug-loaded hydrogel powder according to claim 2, characterized in that: Step 3 The specific method for synthesizing Alg-QA-DA is: Step 3.1, dissolving 1 g to 5 g of the Alg-QA obtained in step 1 in a 0.05 M to 0.2 M aqueous solution of MES monohydrate to form a 1% to 5% (w / w) Alg-QA solution; Step 3.2, then, add 600 mg-800 mg of EDC and 300 mg-400 mg of NHS to the Alg-QA solution obtained in step 3.1, and mix thoroughly to obtain a mixed solution V; Step 3.3, then, add 400 mg to 600 mg of dopamine hydrochloride to the obtained mixed solution 5 until it is completely dissolved to obtain a mixed solution 6; Step 3.4, subjecting the mixed solution obtained in step 3.3 to an EDC / NHS reaction at room temperature of 20-25° C. for 20-30 hours, and during the reaction, an alkaline reagent is used to maintain the pH value between 4.0 and 5.0; Step 3.5, dialyzing the reaction product obtained in step 3.4 for 5-7 days using a dialysis bag with a molecular weight cutoff of 3500Da-8000Da to remove unreacted DA; Step 3.6, after dialysis is completed, the pH value is maintained at 5.5-6.5 by using an alkaline reagent, and then freeze-dried to obtain Alg-QA-DA.

6. The method for preparing a drug-loaded hydrogel powder according to claim 3 or 5, characterized in that: The freeze-drying temperature in step 1.5 and step 3.6 is: minus 20°C to minus 80°C, the vacuum degree is controlled at no more than 1 bar, and the freeze-drying time is 3-5 days.

7. The method for preparing a drug-loaded hydrogel powder according to claim 2 or 4, characterized in that: The freeze-drying temperature in step 2.5 and step 5 is -20°C to -80°C, the vacuum degree is controlled to be no more than 0.1 bar, and the freeze-drying time is 3-5 days.

8. The method for preparing a drug-loaded hydrogel powder according to claim 2, characterized in that: The alkaline reagent includes NaOH reagent, KOH reagent or Na2CO3 reagent.

9. The method for preparing a drug-loaded hydrogel powder according to claim 2, characterized in that: The acidic reagent includes HCL reagent, acetic acid reagent or phosphoric acid reagent.

10. The drug-loaded hydrogel powder prepared based on the raw material of claim 1 and the preparation method of claims 2 to 5, characterized in that: As a rapid spray gel powder (SRPG), it is used for spraying oral ulcers.

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