Drug-loaded hydrogel powder, preparation method and application thereof

Abstract

The application relates to a drug-loaded hydrogel powder, a preparation method and application thereof, wherein raw materials of the drug-loaded hydrogel powder comprise sodium alginate, 3-aminophenyl boronic acid, N-(3-dimethylaminopropyl)-N'-ethyl carbodiimide hydrochloride, N-hydroxysuccinimide, MES monohydrate, 2,3-epoxypropyl trimethyl ammonium chloride, dimethyl sulfoxide, dopamine hydrochloride, lidocaine hydrochloride and dexamethasone acetate; Alg-QA is synthesized by ring-opening reaction of 2,3-epoxypropyl trimethyl ammonium chloride and sodium alginate; carboxyl phenyl boronic acid and sodium alginate-quaternary ammonium salt are further synthesized into Alg-QA-PBA through amidation reaction; meanwhile, dopamine and sodium alginate-quaternary ammonium salt are synthesized into Alg-QA-DA through amidation reaction; the freeze-dried sponge of Alg-QA-PBA and Alg-QA-DA is mixed in a certain proportion and crushed into uniform powder by a pulverizer; the preparation process is simple; the drug-loaded hydrogel powder is applied to oral ulcers as a rapid spray gel powder (SRPG), the performance of the hydrogel is improved, and the use experience of patients is optimized.

Description

Technical Field

[0001] This invention relates to the field of polymer materials technology, specifically to a drug-loaded hydrogel powder, its preparation method, and its application. Background Technology

[0002] Recurrent aphthous ulceration (RAU) is a common inflammatory disease of the oral mucosa with multiple contributing factors. It affects approximately 10% to 20% of the global population, with nearly one-fifth of cases occurring in China alone. These ulcers primarily occur on moist, dynamic surfaces such as the base of the mouth, the sides and sublingual surfaces of the tongue, the cheeks, or the throat. Therefore, patients often experience burning pain due to facial movements during speaking or chewing, or from consuming spicy or hot foods. Effective and sustained pain relief during ulceration and timely promotion of oral ulcer healing are therefore crucial.

[0003] Current clinical treatments typically involve using commercially available films, tablets, mouthwashes, or ointments loaded with anesthetic drugs and corticosteroids to relieve pain or promote healing. However, these methods usually only provide relief for 10-30 minutes due to saliva rinsing in the mouth, after which they completely dissolve. This leads to the inconvenience of repeated medication administration for patients. Furthermore, solid tablets can cause a foreign body sensation in the mouth and rapid peeling of the wound mucosa during daily speaking or eating. Therefore, finding a comfortable, sustained-release patch that can remain on a moist oral surface remains a pressing clinical need.

[0004] The authors, Wenjie Zhan et al., published an article titled "Promoting Oral Mucosal Wound Healing with a Hydrogel Adhesive Based on a Phototriggered S-Nitrosylation Coupling Reaction," in Adv. Mater. 2021, 33, 2105667. The technical solution described is as follows: This study proposes a photocrosslinked hydrogel for the treatment of oral ulcers. The hydrogel is solidified by irradiation with light of a specific wavelength to prolong its residence time in the oral cavity. However, the hydrogel requires additional light irradiation equipment, and the precursor solution is prone to flow, limiting its ease of use for patients and increasing the difficulty and cost of its application.

[0005] To address these limitations, the scientific community has shown great interest in adhesive hydrogels, particularly the application of pre-fabricated hydrogel films and in-situ crosslinked hydrogels. However, existing technologies still present challenges, such as the thickness of pre-fabricated hydrogel films and the difficulty in maintaining the pre-crosslinked liquid hydrogel on complex curved surfaces. These limitations significantly restrict the clinical application of current hydrogel dressings and hinder their commercialization. Summary of the Invention

[0006] To overcome the shortcomings of the prior art, the present invention aims to provide a drug-loaded hydrogel powder, its preparation method, and its application. First, a sodium alginate-quaternary ammonium salt (Alg-QA) is synthesized via a ring-opening reaction of 2,3-epoxypropyltrimethylammonium chloride (QA) and sodium alginate (Alg). Further, carboxyphenylboronic acid and sodium alginate-quaternary ammonium salt are synthesized via an amidation reaction to form sodium alginate-quaternary ammonium salt-phenylboronic acid (Alg-QA-PBA), followed by freeze-drying. Simultaneously, dopamine and sodium alginate-quaternary ammonium salt are synthesized via an amidation reaction to form sodium alginate-quaternary ammonium salt-phenylboronic acid. Dopamine (Alg-QA-DA) is freeze-dried, and then the freeze-dried sponges of Alg-QA-PBA and Alg-QA-DA are mixed in a certain proportion and pulverized into a uniform drug-loaded hydrogel powder using a grinder. The drug-loaded hydrogel powder is used as a rapid spray gel powder (SRPG) for oral ulcers, which improves the performance of the hydrogel, optimizes the patient's user experience, effectively relieves the patient's wound pain and promotes healing. SRPG can be used as a broad drug delivery platform for mass production, storage and transportation. At the same time, when combined with a powder spraying device, it allows patients to conveniently administer the drug themselves.

[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

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

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

[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 a drug-loaded hydrogel powder, the specific steps of which are as follows:

[0020] Step 1: A ring-opening reaction is carried out between QA and sodium alginate to synthesize quaternary ammonium salt-grafted sodium alginate, abbreviated as Alg-QA.

[0021] Step 2: The PBA group is attached to Alg-QA obtained in Step 1 by 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: Synthesize sodium alginate grafted with quaternary ammonium salt group and dopamine group, abbreviated as Alg-QA-DA;

[0023] Step 4: Mix Alg-QA-PBA and Alg-QA-DA at a mass ratio of 2:1 to 5:1, and then grind them into powder using a pulverizer to obtain mixed powder;

[0024] Step 5: Dissolve 5g-10g of the mixed powder obtained in Step 4 quantitatively in double-distilled water (dd H2O) to form a 1% solution. Add 25mg-50mg of dexamethasone sodium acetate and 5g-10g of lidocaine hydrochloride to form a mixed drug-loaded precursor solution. Adjust the pH of the mixed drug-loaded precursor solution to 7 using an alkaline reagent. Then freeze-dry and grind the powder to form a drug-loaded hydrogel powder.

[0025] The specific method for step one is as follows:

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

[0027] Step 1.2: Add QA to the sodium alginate solution obtained in Step 1.1 according to the molar ratio of sodium alginate solution to QA n(Alg) = 3:1-5:1 to obtain a mixed solution of sodium alginate and QA.

[0028] Step 1.3: The mixed solution obtained in step 1.2 is subjected to a ring-opening reaction at 40℃-60℃ for 4-8 hours to obtain the reaction product;

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

[0030] Step 1.5: After dialysis, the sample is freeze-dried to obtain Alg-QA.

[0031] The specific method for step two is as follows:

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

[0033] Step 2.2: Add 600mg-800mg of EDC and 400mg-600mg of NHS to the Alg-QA solution obtained in Step 2.1, mix thoroughly, and obtain mixed solution two;

[0034] Step 2.3: Dissolve 200mg-400mg of PBA in 2mL-5mL of dimethyl sulfoxide (DMSO), and then add it dropwise to mixed solution two at a rate of 1mL-3mL / min to obtain mixed solution three; use an acidic reagent to ensure that the pH of mixed solution three is maintained between 4.5 and 5.5 for 18-26 hours to obtain mixed solution four;

[0035] Step 2.4: Transfer the mixed solution into a dialysis bag with a molecular weight cutoff of 3500 Da-8000 Da, maintain the pH of the solution between 5 and 6, and perform dialysis for 5-7 days to remove unreacted PBA.

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

[0037] The specific method for synthesizing Alg-QA-DA in step three is as follows:

[0038] Step 3.1: Dissolve 1g-5g of Alg-QA obtained in Step 1 in an aqueous solution of 0.05M-0.2M MES monohydrate to form a 1%-5% (w / w) Alg-QA solution.

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

[0040] Step 3.3: Subsequently, 400 mg-600 mg of dopamine hydrochloride is added to the resulting mixed solution five until it is completely dissolved, thus obtaining mixed solution six.

[0041] Step 3.4: The mixed solution obtained in step 3.3 is subjected to EDC / NHS reaction at room temperature of 20-25℃ for 20-30 hours. During the reaction, the pH value is maintained between 4.0 and 5.0 by using an alkaline reagent.

[0042] Step 3.5: Dialyze 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, the pH value is maintained at 5.5-6.5 using an alkaline reagent, and then freeze-dried to obtain Alg-QA-DA.

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

[0045] In steps 2.5 and 5, the freeze-drying temperature is -20°C to -80°C, the vacuum degree is controlled to not exceed 0.1 bar, and the freeze-drying time is 3-5 days.

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

[0047] The acidic reagents include HCl reagents, acetic acid reagents, or phosphoric acid reagents.

[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 as follows:

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

[0051] 2. This invention utilizes the dynamic properties of borate ester bonds, enabling the hydrogel to self-heal in the oral cavity, adapt to changes in the dynamic environment, significantly extend its service life and improve its functional stability, and solve the problem of easy breakage of existing hydrogels.

[0052] 3. This invention optimizes adhesion properties by adjusting the proportion of dopamine groups, enabling the hydrogel to form a stable adhesion barrier in humid environments. This ensures continuous drug release and effective protection, thereby improving therapeutic efficacy and prolonging drug retention time at the ulcer site. Simultaneously, the introduced quaternary ammonium groups enhance the antibacterial properties of the hydrogel, reducing the risk of infection and providing a favorable microenvironment for ulcer healing.

[0053] 4. The preparation process of this invention is simple and easy to operate, and the spray application method allows patients to spray it from multiple angles, greatly facilitating its use. Through these innovations, this invention not only improves the performance of the hydrogel but also optimizes the patient's user experience, meeting the urgent needs of patients with oral ulcers.

[0054] 5. The drug-loaded hydrogel powder prepared in this invention, when applied as a rapid-spray gel powder (SRPG) for oral ulcers, rapidly undergoes a significant biomechanical transformation into an elastic, adhesive hydrogel barrier upon contact with saliva. This barrier's biomechanical properties allow it to remain effective for over 12 hours, resisting challenges such as saliva penetration and biomechanical stresses associated with oral activity, while ensuring sustained drug release. In a rat oral ulcer model, the composite drug-loaded gel powder characterized by lidocaine hydrochloride and dexamethasone sodium phosphate exhibited anti-inflammatory effects at the ulcer site, accelerating wound healing and shortening the healing time to 2–4 days. The biomechanical effectiveness and ease of use of SRPG were further biomechanically validated in a preclinical pig model, highlighting its biomechanical potential as a clinical hydrogel dressing for oral ulcers.

[0055] In summary, compared with the prior art, this invention mixes Alg-QA-PBA and Alg-QA-DA freeze-dried sponges in a certain proportion and pulverizes them into uniform powder using a grinder; the preparation process is simple; the drug-loaded hydrogel powder, as a rapid spray gel powder (SRPG), is applied to oral ulcers, improving the performance of the hydrogel; when combined with a powder spraying device, it allows patients to conveniently administer the medication themselves, optimizing the patient's user experience, effectively relieving wound pain and promoting healing; it also has the advantages of stable adhesion, good safety, and high reliability. Attached Figure Description

[0056] Figure 1 This describes the process for using the drug-loaded hydrogel powder of the present invention.

[0057] Figure 2 This invention describes the gelation process of drug-loaded hydrogel powder. Detailed Implementation

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

[0059] Example 1

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

[0061] Step 1: Synthesize Alg-QA by reacting 2,3-epoxypropyltrimethylammonium chloride (QA) with sodium alginate via a ring-opening reaction (the ring structure of sodium alginate is attacked by the functional groups of the quaternary ammonium salt, thus opening its ring structure):

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

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

[0064] Step 1.3: The sodium alginate obtained in Step 1.2 and the QA mixture solution were subjected to a ring-opening reaction at 40°C for 6 hours to obtain the reaction product;

[0065] Step 1.4: Dialyze 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 dialysis, the sample is freeze-dried to obtain Alg-QA. The freeze-drying temperature is -80°C, the vacuum degree is controlled at 1 bar, and the freeze-drying time is 3 days.

[0067] Step 2: The phenylboronic acid (PBA) group is attached to the Alg-QA obtained in Step 1 by the EDC / NHS reaction (EDC and NHS act together between the carboxyl and amino groups to promote the formation of a stable amide bond), thus synthesizing Alg-QA-PBA.

[0068] Step 2.1: Dissolve 1g of Alg-QA obtained in Step 1 in a 0.1M aqueous solution of MES monohydrate to form a 1% (w / w) Alg-QA solution; adjust the pH of the Alg-QA solution to 5.5 using NaOH reagent.

[0069] Step 2.2: Add 700 mg EDC and 500 mg NHS to the Alg-QA solution obtained in Step 2.1, mix thoroughly, and obtain mixed solution two;

[0070] Step 2.3: Dissolve 300 mg of 3-aminophenylboronic acid (PBA) in 3 mL of dimethyl sulfoxide (DMSO), and then add it dropwise to mixed solution two at a rate of 1 mL / min to obtain mixed solution three; use a pH meter to detect the pH value of mixed solution three and use HCl reagent to ensure that the pH value is 5.5, maintain it for 18 hours, and obtain mixed solution four;

[0071] Step 2.4: Transfer the mixed solution into a dialysis bag with a molecular weight cutoff of 4000 Da, maintain the pH of the solution at 5.5, and dialyze for 6 days to remove unreacted PBA.

[0072] Step 2.5: After dialysis, the pH of the solution was adjusted to 7.0 with NaOH reagent, and then freeze-dried to obtain Alg-QA-PBA. The freeze-drying temperature was -40℃, the vacuum degree was controlled at 0.1 bar, and the freeze-drying time was 4 days.

[0073] Step 3: Synthesize Alg-QA-DA.

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

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

[0076] Step 3.3: Subsequently, 400 mg of dopamine hydrochloride was added to the resulting mixed solution five and completely dissolved to obtain mixed solution six.

[0077] Step 3.4: The resulting mixed solution VI was subjected to an EDC / NHS reaction at room temperature (25°C) for 26 hours, with the pH value maintained at 5 using NaOH reagent during the reaction.

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

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

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

[0081] Step 5: Dissolve 10g of the mixed powder obtained in Step 4 quantitatively in double-distilled water (dd H2O) to form a 1% solution. Add 25mg of dexamethasone sodium acetate and 5g of lidocaine hydrochloride to form a mixed drug-loaded precursor solution. Adjust the pH of the mixed drug-loaded precursor solution to 7 using NaOH reagent. Freeze-dry and grind into powder to form a drug-loaded hydrogel powder. The freeze-drying temperature is -20℃, the vacuum degree is 0.1 bar, and the freeze-drying time is 3 days.

[0082] Example 2

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

[0084] Step 1: Synthesize Alg-QA by reacting 2,3-epoxypropyltrimethylammonium chloride (QA) with sodium alginate via a ring-opening reaction.

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

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

[0087] Step 1.3: The sodium alginate obtained in Step 1.2 and the QA mixture solution were subjected to a ring-opening reaction at 60°C for 4 hours to obtain the 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 4000 Da for 5 days to remove unreacted QA.

[0089] Step 1.5: After dialysis, the sample is freeze-dried to obtain Alg-QA. The freeze-drying temperature is -60°C, the vacuum degree is controlled at 0.5 bar, and the freeze-drying time is 5 days.

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

[0091] Step 2.1: Dissolve 1g of Alg-QA obtained in Step 1 in a 0.05M aqueous solution of MES monohydrate to form a 1% (w / w) Alg-QA solution; adjust the pH of the Alg-QA solution to 5.5 using NaOH reagent.

[0092] Step 2.2: Add 600 mg EDC and 400 mg NHS to the Alg-QA solution obtained in Step 2.1, mix thoroughly, and obtain mixed solution two;

[0093] Step 2.3: Dissolve 300 mg of 3-aminophenylboronic acid (PBA) in 2 mL of dimethyl sulfoxide (DMSO), and then add it dropwise to mixed solution two at a rate of 1 mL / min to obtain mixed solution three; use a pH meter to detect the pH value of mixed solution three and use HCl reagent to ensure that the pH value is 5, and maintain it for 20 hours to obtain mixed solution four;

[0094] Step 2.4: Transfer the mixed solution into a dialysis bag with a molecular weight cutoff of 3500 Da, maintain the pH of the solution at 5.5, and dialyze for 5 days to remove unreacted PBA.

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

[0096] Step 3: Synthesize Alg-QA-DA.

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

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

[0099] Step 3.3: Subsequently, 500 mg of dopamine hydrochloride was added to the resulting mixed solution five and completely dissolved to obtain mixed solution six.

[0100] Step 3.4: The resulting mixed solution VI was subjected to an EDC / NHS reaction at room temperature (20°C) for 24 hours, with the pH value maintained at 4.5 using NaOH reagent during the reaction.

[0101] Step 3.5: After the reaction is complete, the reaction product obtained in step 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, the pH is adjusted to 6 using an alkaline reagent, and then freeze-dried to obtain Alg-QA-DA. The freeze-drying temperature is -20°C, the vacuum degree is controlled at 0.5 bar, and the freeze-drying time is 3 days.

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

[0104] Step 5: Dissolve 5g of the mixed powder obtained in Step 4 quantitatively in double-distilled water (dd H2O) to form a 1% solution. Add 30mg of dexamethasone sodium acetate and 6g of lidocaine hydrochloride to form a mixed drug-loaded precursor solution. Adjust the pH of the mixed drug-loaded precursor solution to 7 using NaOH reagent. Freeze-dry and grind into powder to form a drug-loaded hydrogel powder. The freeze-drying temperature is -40℃, the vacuum degree is 0.08 bar, and the freeze-drying time is 5 days.

[0105] Example 3

[0106] Step 1: Synthesize Alg-QA by reacting 2,3-epoxypropyltrimethylammonium chloride (QA) with sodium alginate via a ring-opening reaction.

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

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

[0109] Step 1.3: The sodium alginate obtained in Step 1.2 and the QA mixture solution were subjected to a ring-opening reaction at 60°C for 8 hours to obtain the reaction product;

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

[0111] Step 1.5: After dialysis, the sample is freeze-dried to obtain Alg-QA. The freeze-drying temperature is -80°C, the vacuum degree is controlled at 0.8 bar, and the freeze-drying time is 5 days.

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

[0113] Step 2.1: Dissolve 5g of Alg-QA obtained in Step 1 in a 0.1M aqueous solution of MES monohydrate to form a 3% (w / w) Alg-QA solution; adjust the pH of the Alg-QA solution to 5 using NaOH reagent.

[0114] Step 2.2: Add 800 mg EDC and 600 mg NHS to the Alg-QA solution obtained in Step 2.1, mix thoroughly, and obtain mixed solution two;

[0115] Step 2.3: Dissolve 400 mg of 3-aminophenylboronic acid (PBA) in 3 mL of dimethyl sulfoxide (DMSO), and then add it dropwise to mixed solution two at a rate of 1 mL / min to obtain mixed solution three; use a pH meter to detect the pH value of mixed solution three and use HCl reagent to ensure that the pH value is 4.5, maintain it for 26 hours, and obtain mixed solution four;

[0116] Step 2.4: Transfer the mixed solution into a dialysis bag with a molecular weight cutoff of 8000 Da, maintain the pH of the solution at 6, and perform dialysis for 6 days to remove unreacted PBA.

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

[0118] Step 3: Synthesize Alg-QA-DA.

[0119] Step 3.1: Dissolve 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 EDC and 400 mg NHS to the Alg-QA solution obtained in 3.1, and mix thoroughly to obtain mixed solution five;

[0121] Step 3.3: Subsequently, 600 mg of dopamine hydrochloride was added to the resulting mixed solution five and completely dissolved to obtain mixed solution six.

[0122] Step 3.4: The resulting mixed solution VI was subjected to an EDC / NHS reaction at room temperature (25°C) for 30 hours, with the pH value maintained at 5.0 using NaOH reagent during the reaction.

[0123] Step 3.5: After the reaction is complete, the reaction product obtained in step 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, the pH is adjusted to 6.5 using an alkaline reagent, and then freeze-dried to obtain Alg-QA-DA. The freeze-drying temperature is -20°C, the vacuum degree is controlled at 0.8 bar, and the freeze-drying time is 5 days.

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

[0126] Step 5: Dissolve 5g of the mixed powder obtained in Step 4 quantitatively in double-distilled water (dd H2O) to form a 1% solution. Add 50mg of dexamethasone sodium acetate and 5g of lidocaine hydrochloride to form a mixed drug-loaded precursor solution. Adjust the pH of the mixed drug-loaded precursor solution to 7 using NaOH reagent. Freeze-dry and grind into powder to form a drug-loaded hydrogel powder. The freeze-drying temperature is -20℃, the vacuum degree is 0.05 bar, and the freeze-drying time is 3 days.

[0127] Example 4

[0128] Step 1: Synthesize Alg-QA by reacting 2,3-epoxypropyltrimethylammonium chloride (QA) with sodium alginate via a ring-opening reaction.

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

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

[0131] Step 1.3: The sodium alginate obtained in Step 1.2 and the QA mixture solution were subjected to a ring-opening reaction at 50°C for 5 hours to obtain the 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 7000 Da for 6 days to remove unreacted QA.

[0133] Step 1.5: After dialysis, the sample is freeze-dried to obtain Alg-QA. The freeze-drying temperature is -30°C, the vacuum degree is controlled at 1 bar, and the freeze-drying time is 4 days.

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

[0135] Step 2.1: Dissolve 3g of Alg-QA obtained in Step 1 in a 0.05M aqueous solution of MES monohydrate to form a 3% (w / w) Alg-QA solution; adjust the pH of the Alg-QA solution to 5 using NaOH reagent.

[0136] Step 2.2: Add 650 mg EDC and 450 mg NHS to the Alg-QA solution obtained in Step 2.1, mix thoroughly, and obtain mixed solution two;

[0137] Step 2.3: Dissolve 300 mg of 3-aminophenylboronic acid (PBA) in 2.5 mL of dimethyl sulfoxide (DMSO), and then add it dropwise to mixed solution two at a rate of 1 mL / min to obtain mixed solution three; use a pH meter to detect the pH value of mixed solution three and use HCl reagent to ensure that the pH value is 3, and maintain it for 24 hours to obtain mixed solution four;

[0138] Step 2.4: Transfer the mixed solution into a dialysis bag with a molecular weight cutoff of 4000 Da, maintain the pH of the solution at 6, and dialyze for 5 days to remove unreacted PBA.

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

[0140] Step 3: Synthesize Alg-QA-DA.

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

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

[0143] Step 3.3: Subsequently, 450 mg of dopamine hydrochloride was added to the resulting mixed solution five and completely dissolved to obtain mixed solution six.

[0144] Step 3.4: The resulting mixed solution VI was subjected to an EDC / NHS reaction at room temperature (23°C) for 24 hours, with the pH value maintained at 4.5 using NaOH reagent during the reaction.

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

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

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

[0148] Step 5: Dissolve 6g of the mixed powder obtained in Step 4 quantitatively in double-distilled water (dd H2O) to form a 1% solution. Add 30mg of dexamethasone sodium acetate and 7g of lidocaine hydrochloride to form a mixed drug-loaded precursor solution. Adjust the pH of the mixed drug-loaded precursor solution to 7 using NaOH reagent. Freeze-dry and grind into powder to form a drug-loaded hydrogel powder. The freeze-drying temperature is -40℃, the vacuum degree is 0.1 bar, and the freeze-drying time is 4 days.

[0149] Example 5

[0150] Step 1: Synthesize Alg-QA by reacting 2,3-epoxypropyltrimethylammonium chloride (QA) with sodium alginate via a ring-opening reaction.

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

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

[0153] Step 1.3: The sodium alginate obtained in Step 1.2 and the QA mixture solution were subjected to a ring-opening reaction at 45°C for 5.5 hours to obtain the reaction product;

[0154] Step 1.4: Dialyze 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 dialysis, the sample is freeze-dried to obtain Alg-QA. The freeze-drying temperature is -25°C, the vacuum degree is controlled at 0.6 bar, and the freeze-drying time is 7 days.

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

[0157] Step 2.1: Dissolve 2.5g of Alg-QA obtained in Step 1 in a 0.15M aqueous solution of MES monohydrate to form a 1% (w / w) Alg-QA solution; adjust the pH of the Alg-QA solution to 5.2 using NaOH reagent.

[0158] Step 2.2: Add 670 mg EDC and 430 mg NHS to the Alg-QA solution obtained in Step 2.1, mix thoroughly, and obtain mixed solution two;

[0159] Step 2.3: Dissolve 310 mg of 3-aminophenylboronic acid (PBA) in 2 mL of dimethyl sulfoxide (DMSO), and then add it dropwise to mixed solution two at a rate of 1.2 mL / min to obtain mixed solution three; use a pH meter to detect the pH value of mixed solution three and use HCl reagent to ensure that the pH value is 5, and maintain it for 16.5 hours to obtain mixed solution four;

[0160] Step 2.4: Transfer the mixed solution into a dialysis bag with a molecular weight cutoff of 5500 Da, maintain the pH of the solution at 5.5, and dialyze for 5 days to remove unreacted PBA.

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

[0162] Step 3: Synthesize Alg-QA-DA.

[0163] Step 3.1: Dissolve 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 EDC and 330 mg NHS to the Alg-QA solution obtained in 3.1, and mix thoroughly to obtain mixed solution five;

[0165] Step 3.3: Subsequently, 510 mg of dopamine hydrochloride was added to the resulting mixed solution five and completely dissolved to obtain mixed solution six.

[0166] Step 3.4: The resulting mixed solution VI was subjected to an EDC / NHS reaction at room temperature (25°C) for 23 hours, with the pH value maintained at 4.5 using NaOH reagent during the reaction.

[0167] Step 3.5: After the reaction is complete, the reaction product obtained in step 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, the pH is adjusted to 6 using an alkaline reagent, and then freeze-dried to obtain Alg-QA-DA. The freeze-drying temperature is -20°C, the vacuum degree is controlled at 0.6 bar, and the freeze-drying time is 3 days.

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

[0170] Step 5: Dissolve 5g of the mixed powder obtained in Step 4 quantitatively in double-distilled water (dd H2O) to form a 1% solution. Add 25mg of dexamethasone acetate sodium phosphate and 5g of lidocaine hydrochloride to form a mixed drug-loaded precursor solution. Adjust the pH of the mixed drug-loaded precursor solution to 7 using NaOH reagent. Freeze-dry and grind into powder to form a drug-loaded hydrogel powder. The freeze-drying temperature is -60℃, the vacuum degree is 0.05 bar, and the freeze-drying time is 5 days.

[0171] See Figure 1 , Figure 2 Through experiments, the mechanical properties, adhesion, resistance to fluid erosion, and self-healing ability of the hydrogel powder prepared according to this invention were tested. The gel formed by this invention forms a tight fusion with the tissue surface, and simulations of saliva erosion, tissue torsion, and stretching in the oral cavity all showed that the gel adhered tightly to the tissue surface. The self-healing performance of this invention was also well demonstrated; by attaching two separate gels together, a complete gel can be formed.

[0172] Furthermore, the hydrogel powder prepared by this invention can achieve a density of 0.5 mg / cm³. 2 —6mg / cm 2 Within the gelation zone, the liquid on the tissue surface is rapidly absorbed and gelled. As shown in the gel healing curve, the gelation speed is less than 3 seconds. Compared to existing photocrosslinking technologies, no additional lighting equipment is needed to gel the precursor solution, significantly improving the cost-effectiveness and convenience 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 needs of different parts of the oral cavity.

[0174] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any modifications, equivalent substitutions, and improvements made by those skilled in the art within the scope of the technology disclosed in the present invention, and within the spirit and principles of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A drug-loaded hydrogel powder, characterized in that, The drug-loaded hydrogel powder raw material comprises: Sodium alginate Mw=20-50kDa: 10g-50g; 3-aminophenyl boronic 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, 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 sodium phosphate: 25mg-50mg; The preparation method of the drug-loaded hydrogel powder, and the specific steps are as follows: Step one: through the ring-opening reaction of QA and sodium alginate, quaternary ammonium salt group grafted sodium alginate, abbreviated as Alg-QA, is synthesized: Step two: PBA groups are connected to Alg-QA obtained in step one through EDC / NHS reaction, and quaternary ammonium salt group and phenylboronic acid group grafted sodium alginate, abbreviated as Alg-QA-PBA, is synthesized; Step three: quaternary ammonium salt group and dopamine group grafted sodium alginate, abbreviated as Alg-QA-DA, is synthesized; Step four: Alg-QA-PBA and Alg-QA-DA are mixed in a mass ratio of 2:1-5:1, and then a powder is obtained by using a powder mill; Step five: 5g-10g of the mixed powder obtained in step four is quantitatively dissolved into a 1% solution using double distilled water dd H2O, 25mg-50mg of dexamethasone acetate sodium phosphate 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 through an alkaline reagent; then freeze-drying and powdering are performed to form a drug-loaded hydrogel powder.

2. The drug-loaded hydrogel powder of claim 1, wherein, The specific method of step one is: Step 1.1, 10g-50g of sodium alginate is fully dissolved in double distilled water dd H2O to prepare a sodium alginate solution with a concentration of 0.5%-2% (w / w); Step 1.2, according to the molar ratio of sodium alginate solution to QA of 3:1-5:1, QA is added to the sodium alginate solution prepared in step 1.1 to obtain a mixed solution one of sodium alginate and QA; Step 1.3, the mixed solution one obtained in step 1.2 is subjected to ring-opening reaction at 40℃-60℃ for 4-8 hours to obtain a reaction product; Step 1.4, the reaction product obtained in step 1.3 is subjected to dialysis using a dialysis bag with a molecular weight cut-off of 3500Da-8000Da for 5-7 days to remove unreacted QA; Step 1.5, after dialysis, freeze-drying treatment is performed to obtain Alg-QA.

3. The drug-loaded hydrogel powder of claim 2, wherein, The specific method of step two is: Step 2.1, dissolve Alg-QA 1g-5g obtained in step 1.5 in 0.05M-0.2M MES monohydrate aqueous solution to form 1%-5%(w / w) Alg-QA solution; adjust the pH of the obtained Alg-QA solution to 4.5-5.5 using basic reagent; Step 2.2, add 600mg-800mg EDC and 400mg-600mg NHS to the Alg-QA solution obtained in step 2.1 and mix well to obtain mixed solution two; Step 2.3, dissolve 200mg-400mg PBA in 2mL-5mL dimethyl sulfoxide (DMSO), then add it into the mixed solution two at a speed of 1mL-3mL / min to obtain mixed solution three; use acidic reagent to ensure that the pH of the mixed solution three is maintained at 4.5-5.5 for 18-26 hours to obtain mixed solution four; Step 2.4, transfer the mixed solution four into a dialysis bag with a molecular weight cut-off of 3500Da-8000Da, and dialyze for 5-7 days to remove unreacted PBA while maintaining the solution pH at 5-6; Step 2.5, after dialysis, adjust the pH of the solution to 7.0 by using basic reagent, then freeze-dry to obtain Alg-QA-PBA.

4. The drug-loaded hydrogel powder of claim 1, wherein, Step three, the specific method for synthesizing Alg-QA-DA is as follows: Step 3.1, dissolve Alg-QA 1g-5g obtained in step one in 0.05M-0.2M MES monohydrate aqueous solution to form 1%-5%(w / w) Alg-QA solution; Step 3.2, then add 600mg-800mg EDC and 300mg-400mg NHS to the Alg-QA solution obtained in step 3.1 and mix well to obtain mixed solution five; Step 3.3, then add 400mg-600mg dopamine hydrochloride to the mixed solution five until it is completely dissolved to obtain mixed solution six; Step 3.4, carry out EDC / NHS reaction on the mixed solution six obtained in step 3.3 at room temperature of 20-25℃ for 20-30 hours, and maintain the pH at 4.0-5.0 during the reaction by using basic reagent; Step 3.5, dialyze the reaction product obtained in step 3.4 using a dialysis bag with a molecular weight cut-off of 3500Da-8000Da for 5-7 days to remove unreacted dopamine hydrochloride; Step 3.6, after dialysis, maintain the pH at 5.5-6.5 by using basic reagent, then freeze-dry to obtain Alg-QA-DA.

5. The drug-loaded hydrogel powder according to claim 2 or 4, wherein, The temperature for freeze-drying in step 1.5 and step 3.6 is -20℃ to -80℃, the vacuum degree is controlled to be not more than 1bar, and the freeze-drying time is 3-5 days.

6. The drug-loaded hydrogel powder according to claim 1 or 3, wherein, The temperature for freeze-drying in step 2.5 and step five is -20℃ to -80℃, the vacuum degree is controlled to be not more than 0.1bar, and the freeze-drying time is 3-5 days.

7. The drug-loaded hydrogel powder of claim 1, wherein, The basic agent includes NaOH agent, KOH agent or Na2CO3 agent.

8. The drug-loaded hydrogel powder of claim 3, wherein, The acidic agent includes HCL agent, acetic acid agent or phosphoric acid agent.

9. The drug-loaded hydrogel powder of claim 1, wherein, As a fast spray gel powder SRPG, it is applied to spray mouth ulcers.

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