A surface-modified bioactive glass oral desensitizing ointment and its preparation method

Abstract

This invention discloses a surface-modified bioactive glass oral desensitizing paste and its preparation method, relating to the technical field of oral desensitizing pastes. The surface-modified bioactive glass oral desensitizing paste comprises the following raw materials in parts by weight: 5-15 parts bioactive glass, 3-6 parts modifier, 3-5 parts silica, 20-30 parts humectant, 0.5-1 part sweetener, 0.5-1.5 parts foaming agent, 0.5-2 parts thickener, and 60-120 parts deionized water. The surface-modified bioactive glass oral desensitizing paste prepared by this invention exhibits excellent antibacterial properties and dentinal tubule sealing effects.

Description

Technical Field

[0001] This invention relates to the field of oral desensitizing ointment technology, specifically to a surface-modified bioactive glass oral desensitizing ointment and its preparation method. Background Technology

[0002] Dentin hypersensitivity is a common oral sensitivity disorder, primarily characterized by brief, sharp pain in teeth when exposed to external stimuli such as hot, cold, sweet, sour, or mechanical friction. The root cause lies in the exposure of dentinal tubules after enamel wear or gingival recession, allowing stimuli to be transmitted through the fluid within these tubules to the dental pulp nerve. Currently, commonly used desensitizing products include fluoride preparations, potassium salt preparations, resin sealants, and bioactive glass materials. Among these, bioactive glass, due to its excellent biocompatibility and mineralization induction ability, is widely researched and applied in the prevention and treatment of dentin hypersensitivity. In saliva or a water environment, bioactive glass can react with ions to release calcium... 2+ PO4 3- Plasma is used to form a hydroxyapatite layer on the dentin surface, effectively sealing dentinal tubules and reducing allergy symptoms. However, traditional bioactive glass still has limitations such as limited antibacterial properties, low tubule sealing rate, and easy detachment. Therefore, it is crucial to develop a surface-modified bioactive glass oral desensitizing paste that combines good antibacterial properties with dentinal tubule sealing performance.

[0003] Chinese invention patent CN120549781A discloses an oral care desensitizing paste and its preparation method. The oral care desensitizing paste comprises the following components: bioactive glass, strontium chloride, sodium chloride, silicon dioxide, sodium carboxymethyl cellulose, polyethylene glycol 400, xanthan gum solution, sodium lauryl sulfate, sodium lauroyl sarcosinate, titanium dioxide, β-glucan, sodium saccharin, sorbitol, methylparaben, propylparaben, edible flavoring, and water. This oral care desensitizing paste can be used to seal dentinal tubules and treat tooth sensitivity; it can also be used to treat plaque-induced gingivitis, relieve and reduce gingival bleeding, and inhibit and reduce dental plaque; it also reduces the risk of accidental swallowing during use, but its antibacterial properties are still insufficient. Summary of the Invention

[0004] To address the shortcomings of existing technologies, the purpose of this invention is to provide a surface-modified bioactive glass oral desensitizing ointment and its preparation method.

[0005] To achieve the above objectives, the present invention provides the following technical solution:

[0006] A surface-modified bioactive glass oral desensitizing cream, comprising the following raw materials in parts by weight:

[0007] 5-15 parts bioactive glass, 3-6 parts modifier, 3-5 parts silica, 20-30 parts humectant, 0.5-1 part sweetener, 0.5-1.5 parts foaming agent, 0.5-2 parts thickener, and 60-120 parts deionized water;

[0008] The modifier is prepared by the following method:

[0009] S1: N-Dodecylethanolamine reacts with 1-chloro-(E,Z,Z)-4,7,10-hexadecanetriene to generate intermediate 1, as shown in the following schematic equation:

[0010]

[0011] S2: Intermediate 1 reacts with L-lysine to generate intermediate 2, and the reaction equation is shown below:

[0012]

[0013] S3: Intermediate 2 is converted into intermediate 3 under the action of m-chloroperoxybenzoic acid. The reaction equation is shown below:

[0014]

[0015] S4: Intermediate 3 reacts with mercaptopropyltrimethoxysilane to generate intermediate 4, and the reaction equation is shown below:

[0016]

[0017] S5: Intermediate 4 reacts with guanidinoacetic acid to generate a modifier. The reaction equation is shown below:

[0018]

[0019] In step S1, the molar ratio of N-dodecylethanolamine to 1-chloro-(E,Z,Z)-4,7,10-hexadecanetriene is 1:(1.01-1.05).

[0020] In step S2, the molar ratio of intermediate 1 to L-lysine is 1:(2.05-2.1).

[0021] In step S3, the molar ratio of intermediate 2 to m-chloroperoxybenzoic acid is 1:(3.3-3.9).

[0022] In step S4, the molar ratio of intermediate 3 to mercaptopropyltrimethoxysilane is 1:(3.05-3.1).

[0023] In step S5, the molar ratio of intermediate 4 to guanidinoacetic acid is 1:(3.1-3.2).

[0024] The moisturizer is glycerin.

[0025] The sweetener is stevia.

[0026] The foaming agent is sodium lauroyl sarcosinate; the thickener is xanthan gum.

[0027] A method for preparing a surface-modified bioactive glass oral desensitizing ointment includes the following steps:

[0028] (1) Weigh out the following by weight: 5-15 parts of bioactive glass, 3-6 parts of modifier, 3-5 parts of silica, 20-30 parts of humectant, 0.5-1 part of sweetener, 0.5-1.5 parts of foaming agent, 0.5-2 parts of thickener, and 60-120 parts of deionized water;

[0029] (2) Mix one-third of the deionized water, bioactive glass, and modifier, and heat to react to obtain modified bioactive glass; stir the remaining two-thirds of the deionized water, humectant, sweetener, foaming agent, and thickener, add silica and modified bioactive glass, shear at high speed, degas under vacuum, and let stand to obtain surface-modified bioactive glass oral desensitizing ointment.

[0030] Due to the adoption of the above technical solutions, the beneficial effects of the present invention include:

[0031] The surface-modified bioactive glass oral desensitizing paste prepared by this invention has excellent antibacterial properties and dentinal tubule sealing effect. The siloxane structure in the added modifier can be hydrolyzed to generate silanol, which forms a strong Si-O-Si covalent bond with the silanol on the surface of the bioactive glass to achieve surface modification of the bioactive glass. The antibacterial properties and dentinal tubule sealing rate of the surface-modified bioactive glass oral desensitizing paste are improved by the synergistic effect of quaternary ammonium salt, guanidine group, long-chain alkyl group and multiple amino groups. Attached Figure Description

[0032] Figure 1 The proton NMR spectrum of intermediate 1 prepared in Example 1;

[0033] Figure 2 High-resolution mass spectrum of intermediate 1 prepared in Example 1;

[0034] Figure 3 The proton NMR spectrum of intermediate 2 prepared in Example 1;

[0035] Figure 4 High-resolution mass spectrum of intermediate 2 prepared in Example 1;

[0036] Figure 5 The proton NMR spectrum of intermediate 3 prepared in Example 1;

[0037] Figure 6 High-resolution mass spectrum of intermediate 3 prepared in Example 1;

[0038] Figure 7 The proton NMR spectrum of intermediate 4 prepared in Example 1;

[0039] Figure 8 High-resolution mass spectrum of intermediate 4 prepared in Example 1;

[0040] Figure 9 The proton NMR spectrum of the modifier prepared in Example 1;

[0041] Figure 10 The high-resolution mass spectrum of the modifier prepared in Example 1 is shown. Detailed Implementation

[0042] The following description, in conjunction with specific embodiments, provides further details, but the present invention is not limited to these embodiments.

[0043] Example 1: Preparation of the modifier:

[0044] S1: 250 ml of anhydrous ethanol, 0.1 mol of N-dodecylethanolamine, and 0.101 mol of 1-chloro-(E,Z,Z)-4,7,10-hexadecanetriene were stirred and mixed thoroughly. The mixture was heated to reflux and reacted for 24 h. After cooling to room temperature, it was distilled under reduced pressure at 50 °C for 3 h. The mixture was recrystallized from 250 ml of ethyl acetate / anhydrous ethanol (ethyl acetate / anhydrous ethanol V:V = 8:2) and dried under vacuum at 60 °C for 12 h to obtain intermediate 1 (liquid phase purity 99.2%). Its proton NMR spectrum is shown below. Figure 1 As shown, the proton NMR data are as follows: 1 H NMR (400 MHz, Chloroform- d δ 5.54 (d, J = 6.3 Hz, 2H), 5.40-5.30 (m, 4H), 3.93 (t, J = 5.0Hz, 2H), 3.76 (d, J = 5.0 Hz, 4H), 3.50-3.40 (m, 8H), 2.76 (d, J = 0.9 Hz, 4H), 2.19-2.14 (m, 2H), 2.03 (t, J = 0.9 Hz, 2H), 1.90 (q, J = 12.4 Hz, 4H), 1.42 (s, 2H), 1.35-1.25 (m, 22H), 0.90 (s, 6H); its carbon NMR data are as follows: 13 C NMR (400 MHz, Chloroform- dδ 131.81, 130.93, 129.68, 129.01, 128.79, 61.65, 59.68, 57.16, 31.53, 31.07, 30.07, 29.32, 29.28, 29.20, 29.13, 28.85, 28.73, 28.69, 28.27, 27.09, 26.96, 24.97, 24.76, 22.72, 22.61, 14.03; its high-resolution mass spectrum is as follows: Figure 2 As shown, the mass spectrometry data are as follows: HRMS (m / z): 492.4771 [M-Cl] + ;

[0045] S2: Under nitrogen protection, 300 ml of anhydrous DMF, 0.205 mol L-lysine, and 0.5 mol triethylamine were mixed and stirred thoroughly. At 0°C, 500 ml of anhydrous DMF solution containing 108.6 g of fluorenyl chloroformate was slowly added dropwise over 4 hours, and the mixture was stirred at 25°C for 4 hours. Then, 0.1 mol of intermediate 1, 0.21 mol of dicyclohexylcarbodiimide, and 0.04 mol of 4-dimethylaminopyridine were added, and the mixture was reacted at 25°C for 18 hours. The reaction solution was then poured into 800 ml of an ice-water mixture (containing 90 ml of 1 M HCl), stirred for 30 minutes, and the triethylamine was neutralized. The mixture was extracted with ethyl acetate (3 × 400 ml), and the combined organic phases were washed with 400 ml of saturated brine. The mixture was dried over 2 hours with 30 g of anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure at 50°C for 1 hour to obtain a concentrated solution. The concentrated solution was then added to 300 ml of... In a mixed solution of DMF and piperidine (DMF to piperidine volume ratio 4:1), the mixture was stirred at 25°C for 35 min to deprotect it. Then, 400 ml of 0.1 M HCl solution at 0°C was added, and the mixture was stirred to precipitate the precipitate. The precipitate was filtered and washed successively with 200 ml of cold water, 150 ml of saturated sodium bicarbonate solution, and 200 ml of cold water. The precipitate was then dried under vacuum at 60°C for 12 h to obtain intermediate 2 (liquid phase purity 99.4%). Its 1H NMR spectrum is shown below. Figure 3 As shown, the proton NMR data are as follows: 1 H NMR (400 MHz, Chloroform- d) δ 5.54 (d, J = 6.3 Hz, 2H), 5.40-5.29 (m,4H), 4.42 (s, 4H), 3.72 (d, J = 12.4 Hz, 2H), 3.69-3.61 (m, 4H), 3.50 (d, J =0.5 Hz, 2H), 3.48-3.41 (m, 4H), 3.26 (d, J = 0.5 Hz, 2H), 2.77-2.63 (m, 8H), 2.16 (dt, J = 6.5, 1.0 Hz, 2H), 2.03 (dt, J = 1.8, 1.0 Hz, 2H), 1.95-1.77 (m,8H), 1.75 (d, J = 0.7 Hz (4H), 1.51–1.25 (m, 32H), 0.90 (s, 6H); its carbon NMR data are as follows: 13 C NMR (400 MHz, Chloroform- d δ 172.50, 131.81, 130.93, 129.68, 129.01, 128.79, 62.38, 60.31, 59.87, 55.27, 54.35, 41.09, 31.53, 31.07, 30.40, 29.92, 29.30, 29.20, 29.13, 28.85, 28.73, 28.69, 28.27, 27.09, 26.96, 24.98, 24.20, 22.72, 22.61, 14.03; its high-resolution mass spectrum is as follows. Figure 4 As shown, the mass spectrometry data are as follows: HRMS (m / z): 748.6679 [M-Cl] + ;

[0046] S3: Mix 650 ml of anhydrous dichloromethane and 0.1 mol of intermediate 2 thoroughly. Under ice bath conditions, add 0.33 mol of m-chloroperoxybenzoic acid. Stir for 30 min, then heat to 25 °C and react for 4 h. Wash the reaction solution successively with 200 ml of saturated sodium sulfite solution and 200 ml of saturated sodium bicarbonate solution. Dry with 30 g of anhydrous magnesium sulfate for 1 h, filter, and rotary evaporate at 35 °C for 1 h to obtain intermediate 3 (liquid phase purity 99.1%). Its 1H NMR spectrum is shown below. Figure 5 As shown, the proton NMR data are as follows: 1 H NMR (400 MHz, DMSO- d 6δ 4.41 (d, J = 0.6 Hz, 4H), 4.06 (d, J = 0.5 Hz, 2H), 3.77-3.61 (m, 12H), 3.52 (d, J = 9.1 Hz, 2H), 3.46 (s, 4H), 2.77-2.65 (m, 4H), 2.15 (dd, J = 12.4, 1.5Hz, 2H), 1.99-1.87 (m, 4H), 1.86-1.24 (m, 46H), 0.89 (s, 6H); its carbon NMR data are as follows: 13 C NMR (400 MHz, DMSO- d 6 δ 172.08, 62.65, 60.06, 59.77, 56.83, 56.61, 55.65, 55.57, 55.52, 54.84, 54.82, 54.42, 40.42, 35.82, 31.78, 31.22, 30.95, 30.89, 30.13, 28.96, 28.94, 28.86, 28.43, 27.81, 25.25, 24.65, 23.91, 22.84, 22.38, 22.19, 13.80; its high-resolution mass spectrum is as follows: Figure 6 The mass spectrometry data are as follows: HRMS (m / z): 796.6514 [M-Cl] + ;

[0047] S4: Under nitrogen protection, 850 ml of anhydrous DMF, 0.1 mol of intermediate 3, 0.305 mol of mercaptopropyltrimethoxysilane, and 0.31 mol of triethylamine were stirred and mixed. The mixture was heated to 40 °C and reacted for 5 h. After cooling to room temperature, the mixture was distilled under reduced pressure at 60 °C for 2 h. 500 ml of anhydrous ethyl acetate was added to the reaction solution, and the mixture was stirred for 30 min. The mixture was filtered, and 600 ml of cold anhydrous n-hexane was added to the filtrate. The precipitate was precipitated, filtered, and the filter cake was washed with cold anhydrous n-hexane (3 × 250 ml). The precipitate was dried under vacuum at 60 °C for 12 h to obtain intermediate 4 (liquid phase purity 99.6%). Its proton NMR spectrum is shown below. Figure 7 As shown, the proton NMR data are as follows: 1 H NMR (400 MHz, Chloroform- d) δ 4.92-4.47 (m, 3H), 4.41 (d, J = 0.6 Hz, 4H), 4.06 (d, J = 0.5 Hz, 2H), 3.75 (s, 2H), 3.73-3.59 (m, 9H), 3.52 (s, 27H), 3.49-3.41 (m, 4H), 3.09-2.90(m, 3H), 2.77-2.65 (m, 4H), 2.59-2.44 (m, 6H), 1.93 (dt, J = 19.8, 0.6 Hz,4H), 1.88-1.25 (m, 54H), 1.16 (d, J = 1.7 Hz, 6H), 0.89 (s, 6H); its carbon NMR data are as follows: 13 C NMR (400 MHz, DMSO- d 6 ) δ 172.08, 71.59, 71.32, 71.27, 62.65,60.06, 59.77, 54.84, 54.42, 53.01, 49.81, 48.60, 48.35, 40.42, 34.57, 34.53,34.03, 33.39, 33.08, 31.22, 30.82, 30.13, 28.96, 28.94, 28.86, 28.43, 27.81,26.84, 25.49, 24.65, 23.91, 22.73, 22.38, 22.18, 13.80, 9.78; its high-resolution mass spectrum is as follows Figure 8 As shown, the mass spectrometry data are as follows: HRMS (m / z): 1384.8294 [M-Cl] + ;

[0048] S5: Under nitrogen protection, 600 ml of anhydrous DMF, 0.1 mol of intermediate 4, and 0.48 mol of triethylamine were mixed thoroughly. At 0°C, 400 ml of anhydrous DMF solution containing 103.5 g of fluorenyl chloroformate was slowly added dropwise (over 3 hours), and the mixture was stirred at 25°C for 4 hours. Then, 0.31 mol of guanidinoacetic acid, 0.32 mol of dicyclohexylcarbodiimide, and 0.06 mol of triethylamine were added. 4-Dimethylaminopyridine was reacted at 25°C for 18 hours. The reaction solution was poured into a mixed solution consisting of 800 ml of cold anhydrous diethyl ether and 200 ml of saturated ammonium chloride solution, stirred for 30 minutes, filtered, and concentrated under reduced pressure at 60°C for 2 hours to obtain a concentrated solution. The concentrated solution was added to a mixed solution of anhydrous DMF and piperidine (DMF to piperidine volume ratio of 4:1), stirred at 25°C for 35 minutes to deprotect the solution. The deprotected reaction solution was concentrated under reduced pressure at 60°C for 2 hours to obtain an oily substance. The oily substance was redissolved in 700 ml of anhydrous dichloromethane, and then slowly added to 800 ml of cold anhydrous diethyl ether with stirring to precipitate the precipitate. The precipitate was filtered, washed with 500 ml of cold anhydrous diethyl ether, and dried under vacuum at 60°C for 12 hours to obtain the modifier (liquid phase purity 99.8%). Its proton NMR spectrum is shown below. Figure 9 As shown, the proton NMR data are as follows: 1 H NMR (400MHz, Chloroform- d ) δ 7.73 (s, 3H), 7.48 (d, J = 0.6 Hz, 3H), 6.41 (d, J =18.7 Hz, 6H), 4.89-4.77 (m, 3H), 4.41 (d, J = 0.6 Hz, 4H), 4.06 (d, J = 0.5Hz, 2H), 4.03-3.90 (m, 6H), 3.74 (dd, J = 1.5, 1.0 Hz, 2H), 3.72 (d, J = 0.6Hz, 3H), 3.68-3.61 (m, 3H), 3.52 (s, 27H), 3.44 (d, J = 14.6 Hz, 4H), 3.10-2.83 (m, 3H), 2.77-1.07 (m, 74H), 0.89 (s, 6H); its carbon NMR data are as follows: 13 C NMR (400 MHz, DMSO-) d 6) δ 172.08, 169.44, 156.70, 74.81, 74.44, 74.32, 62.65,60.58, 60.33, 54.83, 54.42, 50.08, 49.81, 48.19, 47.76, 44.29, 40.42, 33.59,33.35, 33.13, 33.03, 32.83, 31.22, 30.82, 30.13, 29.11, 28.96, 28.94, 28.86,28.43, 27.81, 26.99, 25.93, 25.90, 24.65, 23.91, 22.93, 22.38, 22.12, 13.80, 9.78; its high-resolution mass spectrum is as follows: Figure 10 As shown, the mass spectrometry data are as follows: HRMS (m / z): 1681.9579 [M-Cl] + .

[0049] Example 2: Preparation of the modifier:

[0050] S1: 250 ml of anhydrous ethanol, 0.1 mol of N-dodecylethanolamine, and 0.103 mol of 1-chloro-(E,Z,Z)-4,7,10-hexadecanetriene were stirred and mixed, heated to reflux, and reacted for 24 h. After cooling to room temperature, the mixture was distilled under reduced pressure at 50 °C for 3 h. The mixture was recrystallized from 250 ml of ethyl acetate / anhydrous ethanol (ethyl acetate / anhydrous ethanol V:V=8:2) and dried under vacuum at 60 °C for 12 h to obtain intermediate 1.

[0051] S2: Under nitrogen protection, 300 ml of anhydrous DMF, 0.208 mol L-lysine, and 0.5 mol triethylamine were mixed and stirred. At 0°C, 500 ml of anhydrous DMF solution containing 108.6 g fluorenyl chloroformate was slowly added dropwise (over 4 hours), and the mixture was stirred at 25°C for 4 hours. Then, 0.1 mol intermediate 1, 0.21 mol dicyclohexylcarbodiimide, and 0.04 mol 4-dimethylaminopyridine were added, and the reaction was carried out at 25°C for 17 hours. The reaction solution was then poured into 800 ml of an ice-water mixture (containing 90 ml of 1 M HCl), stirred for 30 minutes, and the triethylamine was neutralized. The mixture was extracted with ethyl acetate (3 × 400 ml), and the combined organic phases were washed with 400 ml of saturated brine. The mixture was dried over 2 hours with 30 g of anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure at 50°C for 1 hour to obtain a concentrated solution. The concentrated solution was then added to 300 ml of... In a mixed solution of DMF and piperidine (DMF to piperidine volume ratio of 4:1), the mixture was stirred at 25°C for 35 min to remove protection. Then, 400 ml of 0.1 M HCl solution at 0°C was added, and the mixture was stirred to precipitate the precipitate. The precipitate was filtered and washed successively with 200 ml of cold water, 150 ml of saturated sodium bicarbonate solution, and 200 ml of cold water. The precipitate was then dried under vacuum at 60°C for 12 h to obtain intermediate 2.

[0052] S3: Mix 650 ml of anhydrous dichloromethane and 0.1 mol of intermediate 2. Under ice bath conditions, add 0.36 mol of m-chloroperoxybenzoic acid. Stir for 30 min and then heat to 30 °C for 3 h. Wash the reaction solution successively with 200 ml of saturated sodium sulfite solution and 200 ml of saturated sodium bicarbonate solution. Dry with 30 g of anhydrous magnesium sulfate for 1 h, filter, and rotary evaporate at 35 °C for 1 h to obtain intermediate 3.

[0053] S4: Under nitrogen protection, 850 ml of anhydrous DMF, 0.1 mol of intermediate 3, 0.308 mol of mercaptopropyltrimethoxysilane, and 0.31 mol of triethylamine were stirred and mixed. The mixture was heated to 45 °C and reacted for 4 h. After cooling to room temperature, the mixture was distilled under reduced pressure at 60 °C for 2 h. 500 ml of anhydrous ethyl acetate was added to the reaction solution and stirred for 30 min. The mixture was filtered, and 600 ml of cold anhydrous n-hexane was added to the filtrate and stirred to precipitate the precipitate. The precipitate was filtered, and the filter cake was washed with cold anhydrous n-hexane (3 × 250 ml). The mixture was dried under vacuum at 60 °C for 12 h to obtain intermediate 4.

[0054] S5: Under nitrogen protection, 600 ml of anhydrous DMF, 0.1 mol of intermediate 4, and 0.48 mol of triethylamine were stirred and mixed thoroughly. At 0°C, 400 ml of anhydrous DMF solution containing 103.5 g of fluorenyl chloroformate was slowly added dropwise (over 3 hours), and the mixture was stirred at 25°C for 4 hours. Then, 0.315 mol of guanidinoacetic acid, 0.32 mol of dicyclohexylcarbodiimide, and 0.06 mol of triethylamine were added. 4-Dimethylaminopyridine was reacted at 25°C for 17 hours. The reaction solution was poured into a mixed solution consisting of 800 ml of cold anhydrous diethyl ether and 200 ml of saturated ammonium chloride solution, stirred for 30 minutes, filtered, and concentrated under reduced pressure at 60°C for 2 hours to obtain a concentrated solution. The concentrated solution was added to a mixed solution of anhydrous DMF and piperidine (the volume ratio of DMF to piperidine was 4:1), stirred at 25°C for 35 minutes to deprotect the solution, and concentrated under reduced pressure at 60°C for 2 hours to obtain an oily substance. The oily substance was redissolved in 700 ml of anhydrous dichloromethane, and then slowly added to 800 ml of cold anhydrous diethyl ether. The mixture was stirred to precipitate the precipitate, filtered, and the filter cake was washed with 500 ml of cold anhydrous diethyl ether and dried under vacuum at 60°C for 12 hours to obtain the modifier.

[0055] Example 3: Preparation of the modifier:

[0056] S1: 250 ml of anhydrous ethanol, 0.1 mol of N-dodecylethanolamine, and 0.105 mol of 1-chloro-(E,Z,Z)-4,7,10-hexadecanetriene were stirred and mixed, heated to reflux, and reacted for 24 h. After cooling to room temperature, the mixture was distilled under reduced pressure at 50 °C for 3 h. The mixture was recrystallized from 250 ml of ethyl acetate / anhydrous ethanol (ethyl acetate / anhydrous ethanol V:V=8:2) and dried under vacuum at 60 °C for 12 h to obtain intermediate 1.

[0057] S2: Under nitrogen protection, 300 ml of anhydrous DMF, 0.21 mol L-lysine, and 0.5 mol triethylamine were stirred and mixed thoroughly. At 0°C, 500 ml of anhydrous DMF solution containing 108.6 g fluorenyl chloroformate was slowly added dropwise (over 4 hours), and the mixture was stirred at 25°C for 4 hours. Then, 0.1 mol intermediate 1, 0.21 mol dicyclohexylcarbodiimide, and 0.04 mol 4-dimethylaminopyridine were added, and the mixture was reacted at 30°C for 16 hours. The reaction solution was then poured into 800 ml of an ice-water mixture (containing 90 ml of 1 M HCl), stirred for 30 minutes, and the triethylamine was neutralized. The mixture was extracted with ethyl acetate (3 × 400 ml), and the combined organic phases were washed with 400 ml of saturated brine. The mixture was dried over 2 hours with 30 g of anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure at 50°C for 1 hour to obtain a concentrated solution. The concentrated solution was then added to 300 ml of... In a mixed solution of DMF and piperidine (DMF to piperidine volume ratio of 4:1), the mixture was stirred at 25°C for 35 min to remove protection. Then, 400 ml of 0.1 M HCl solution at 0°C was added, and the mixture was stirred to precipitate the precipitate. The precipitate was filtered and washed successively with 200 ml of cold water, 150 ml of saturated sodium bicarbonate solution, and 200 ml of cold water. The precipitate was then dried under vacuum at 60°C for 12 h to obtain intermediate 2.

[0058] S3: Mix 650 ml of anhydrous dichloromethane and 0.1 mol of intermediate 2. Under ice bath conditions, add 0.39 mol of m-chloroperoxybenzoic acid. Stir for 30 min and then heat to 35 °C for 2 h. Wash the reaction solution successively with 200 ml of saturated sodium sulfite solution and 200 ml of saturated sodium bicarbonate solution. Dry with 30 g of anhydrous magnesium sulfate for 1 h, filter, and rotary evaporate at 35 °C for 1 h to obtain intermediate 3.

[0059] S4: Under nitrogen protection, 850 ml of anhydrous DMF, 0.1 mol of intermediate 3, 0.31 mol of mercaptopropyltrimethoxysilane, and 0.31 mol of triethylamine were stirred and mixed. The mixture was heated to 50 °C and reacted for 3 h. After cooling to room temperature, the mixture was distilled under reduced pressure at 60 °C for 2 h. 500 ml of anhydrous ethyl acetate was added to the reaction solution and stirred for 30 min. The mixture was filtered, and 600 ml of cold anhydrous n-hexane was added to the filtrate and stirred to precipitate the precipitate. The precipitate was filtered, and the filter cake was washed with cold anhydrous n-hexane (3 × 250 ml). The mixture was dried under vacuum at 60 °C for 12 h to obtain intermediate 4.

[0060] S5: Under nitrogen protection, 600 ml of anhydrous DMF, 0.1 mol of intermediate 4, and 0.48 mol of triethylamine were mixed thoroughly. At 0°C, 400 ml of anhydrous DMF solution containing 103.5 g of fluorenyl chloroformate was slowly added dropwise (over 3 hours), and the mixture was stirred at 25°C for 4 hours. Then, 0.32 mol of guanidinoacetic acid, 0.34 mol of dicyclohexylcarbodiimide, and 0.06 mol of triethylamine were added. 4-Dimethylaminopyridine was reacted at 30°C for 16 hours. The reaction solution was poured into a mixed solution consisting of 800 ml of cold anhydrous diethyl ether and 200 ml of saturated ammonium chloride solution, stirred for 30 minutes, filtered, and concentrated under reduced pressure at 60°C for 2 hours to obtain a concentrated solution. The concentrated solution was added to a mixed solution of anhydrous DMF and piperidine (the volume ratio of DMF to piperidine was 4:1), stirred at 25°C for 35 minutes to deprotect the solution. The deprotected reaction solution was concentrated under reduced pressure at 60°C for 2 hours to obtain an oily substance. The oily substance was redissolved in 700 ml of anhydrous dichloromethane, and then slowly added to 800 ml of cold anhydrous diethyl ether. The precipitate was stirred to precipitate, filtered, and the filter cake was washed with 500 ml of cold anhydrous diethyl ether and dried under vacuum at 60°C for 12 hours to obtain the modifier.

[0061] Example 4: Preparation of surface-modified bioactive glass oral desensitizing ointment:

[0062] (1) Weigh the following by weight: 5g of bioactive glass, 3g of modifier (prepared in Example 1), 3g of silica, 20g of humectant (glycerin), 0.5g of sweetener (stevia), 0.5g of foaming agent (sodium lauroyl sarcosinate), 0.5g of thickener (xanthan gum), and 60g of deionized water;

[0063] (2) Mix 20g of deionized water, bioactive glass and modifier, heat to 70℃ and react for 6h, cool naturally to room temperature, filter, wash three times with anhydrous ethanol (15ml each time), and vacuum dry at 80℃ for 12h to obtain modified bioactive glass; mix 40g of deionized water, humectant, sweetener, foaming agent and thickener, stir at 500rpm for 30min, add silica and modified bioactive glass, place in a high shear emulsifier, shear at 10000rpm for 20min, vacuum degas (-0.08MPa, 25℃) for 20min, and let stand for 24h to obtain surface modified bioactive glass oral desensitizing ointment.

[0064] Example 5: Preparation of surface-modified bioactive glass oral desensitizing ointment:

[0065] (1) Weigh the following by weight: 10g of bioactive glass, 4.5g of modifier (prepared in Example 2), 4g of silica, 25g of humectant (glycerin), 0.8g of sweetener (stevia), 0.8g of foaming agent (sodium lauroyl sarcosinate), 1.2g of thickener (xanthan gum), and 90g of deionized water;

[0066] (2) Mix 30g of deionized water, bioactive glass and modifier, heat to 70℃ and react for 6h, cool naturally to room temperature, filter, wash three times with anhydrous ethanol (25ml each time), and vacuum dry at 80℃ for 12h to obtain modified bioactive glass; mix 60g of deionized water, humectant, sweetener, foaming agent and thickener, stir at 500rpm for 30min, add silica and modified bioactive glass, place in a high shear emulsifier, shear at 10000rpm for 20min, vacuum degas (-0.08MPa, 25℃) for 20min, and let stand for 24h to obtain surface modified bioactive glass oral desensitizing ointment.

[0067] Example 6: Preparation of surface-modified bioactive glass oral desensitizing ointment:

[0068] (1) Weigh the following by weight: 15g of bioactive glass, 6g of modifier (prepared in Example 3), 5g of silica, 30g of humectant (glycerin), 1g of sweetener (stevia), 1.5g of foaming agent (sodium lauroyl sarcosinate), 2g of thickener (xanthan gum), and 120g of deionized water.

[0069] (2) Mix 40g of deionized water, bioactive glass and modifier, heat to 70℃ and react for 6h, cool naturally to room temperature, filter, wash three times with anhydrous ethanol (35ml each time), and vacuum dry at 80℃ for 12h to obtain modified bioactive glass; mix 80g of deionized water, humectant, sweetener, foaming agent and thickener, stir at 500rpm for 30min, add silica and modified bioactive glass, place in a high shear emulsifier, shear at 10000rpm for 20min, vacuum degas (-0.08MPa, 25℃) for 20min, and let stand for 24h to obtain surface modified bioactive glass oral desensitizing ointment.

[0070] Comparative Example 1

[0071] The raw material composition and preparation method of the surface-modified bioactive glass oral desensitizing ointment are basically the same as those in Example 5, except that the modifier (prepared in Example 2) is replaced with an equal weight of the modifier prepared by the following method:

[0072] The preparation method of the modifier is basically the same as that in Example 2, except that N-dodecylethanolamine in step S1 is replaced with an equimolar amount of N-ethyldiethanolamine.

[0073] Comparative Example 2

[0074] The raw material composition and preparation method of the surface-modified bioactive glass oral desensitizing ointment are basically the same as those in Example 5, except that the modifier (prepared in Example 2) is replaced with an equal weight of the modifier prepared by the following method:

[0075] The preparation method of the modifier is basically the same as that in Example 2, except that 1-chloro-(E,Z,Z)-4,7,10-hexadecanetriene in step S1 is replaced with an equimolar amount of (Z)-1-chloro-9-octadecene; the amount of intermediate chloroperoxybenzoic acid in step S3 is replaced with 0.12 mol; the amount of mercaptopropyltrimethoxysilane in step S4 is replaced with 0.108 mol and the amount of triethylamine is replaced with 0.11 mol; and the amount of guanidinoacetic acid in step S5 is replaced with 0.115 mol and the amount of triethylamine is replaced with 0.14 mol.

[0076] Comparative Example 3

[0077] The raw material composition and preparation method of the surface-modified bioactive glass oral desensitizing ointment are basically the same as those in Example 5, except that the modifier (prepared in Example 2) is replaced with an equal weight of the modifier prepared by the following method:

[0078] The preparation method of the modifier is basically the same as that in Example 2, except that L-lysine in step S2 is replaced with an equimolar amount of 6-aminohexanoic acid.

[0079] Comparative Example 4

[0080] The raw material composition and preparation method of the surface-modified bioactive glass oral desensitizing ointment are basically the same as those in Example 5, except that the modifier (prepared in Example 2) is replaced with an equal weight of the modifier prepared by the following method:

[0081] The preparation method of the modifier is basically the same as that in Example 2, except that the guanidinoacetic acid in step S5 is replaced with an equimolar amount of ureaacetic acid (also known as hydantoin, CAS No.: 462-60-2).

[0082] The bioactive glass used in the embodiments and comparative examples of this application is medical-grade HQ-BG45s-D1, manufactured by Kunshan Huaqiao Science and Technology New Materials Co., Ltd.; the xanthan gum is KELTROL. ® CG-T; the silica is designated as SM-C, with a particle size of 50nm, and is produced by Nanjing Dongna Biotechnology Co., Ltd.; the CAS number of 1-chloro-(E,Z,Z)-4,7,10-hexadecanetriene is 75315-88-7; the CAS number of (Z)-1-chloro-9-octadecene is 16507-61-2; the CAS number of guanidinoacetic acid is 352-97-6; and the CAS number of stevia is 57817-89-7.

[0083] The surface-modified bioactive glass oral desensitizing ointments prepared in Examples 4-6 and Comparative Examples 1-4 were tested for antibacterial properties and dentinal tubule sealing effects. The test results are shown in Table 1.

[0084] Antibacterial performance test: A sterile cotton swab was used to absorb a concentration of 5×10 5 A CFU / ml suspension of the test bacteria (Streptococcus mutans (ATCC25175)) was evenly spread three times on the surface of a nutrient agar plate. The plate was rotated 60° after each spread. Finally, a cotton swab was used to swab around the edge of the plate, and the plate was covered. The surface-modified bioactive glass oral desensitizing ointment prepared in Examples 4-6 and Comparative Examples 1-4 was spread into a 5mm diameter, 2mm thick disc in the center of the agar plate. After spreading, the disc was gently pressed with sterile forceps to ensure it adhered tightly to the plate surface. The plate was then covered and placed in a 37°C biochemical incubator for constant temperature incubation. After 24 hours, the plate was removed to observe bacterial growth and record the size of the inhibition zone.

[0085] Dentin tubule sealing rate test: First, 42 healthy and intact bovine premolars were taken and divided into 7 groups of 6 teeth each. The enamel on the occlusal surface was removed with a diamond needle to expose the dentin. The roots were then removed, and the teeth were placed in an ultrasonic cleaner to remove debris from the dentinal tubules. Then, the surface-modified bioactive glass oral desensitizing ointment prepared in Examples 4-6 and Comparative Examples 1-4 was evenly applied to the moist bovine teeth with exposed dentinal tubules at a dosage of 2 g / cm³. 2 After standing for 5 minutes, rinse with distilled water until no residue remains. Repeat this process every 2 hours for a total of 15 times, then rinse with water. Allow the treated samples to air dry for 24 hours, then plate with gold using an ion sputtering apparatus. Analyze the sealing of dentinal tubules in each group using a scanning electron microscope at 500x magnification, and use the following formula: (N1: Area of ​​unsealed dentinal tubules; N2: Total area of ​​dentinal tubules) Calculate the dentinal tubule sealing rate, and take the average value of 6 tests for each group.

[0086] Table 1

[0087]

[0088] As can be seen from Table 1, the surface-modified bioactive glass oral desensitizing ointment prepared in Examples 4-6 of this application has excellent antibacterial properties and a high dentinal tubule sealing rate, mainly due to the addition of modifiers containing siloxanes, quaternary ammonium salts, guanidine groups, long-chain alkyl groups, and multiple amino groups. The siloxane structure in the modifier can form strong covalent bonds with the silanol groups on the surface of bioactive glass, achieving surface modification of the bioactive glass. The quaternary ammonium salt structure and guanidine group carry positive charges and can disrupt the structure and stability of the cell membrane through electrostatic interactions with phospholipid molecules on the bacterial cell membrane, increasing cell membrane permeability and causing leakage of intracellular substances, thereby achieving bactericidal effects. Long-chain alkyl groups enhance hydrophobic interactions with the bacterial cell membrane, assisting the quaternary ammonium salt structure and guanidine group in disrupting the cell membrane and improving antibacterial efficiency. The presence of multiple amino groups, as well as the quaternary ammonium salt structure and guanidine group, gives the entire surface-modified bioactive glass a large positive charge, which can electrostatically interact with the negatively charged collagen fibers in exposed dentinal tubules, attracting them to the tubule openings and interior for targeted deposition, thus improving the dentinal tubule sealing effect. The synergistic effect of the various groups in the modifier improves the antibacterial properties and dentinal tubule sealing effect of the surface-modified bioactive glass oral desensitizing paste. The modifier used in Comparative Example 2 had fewer guanidine groups than the one used in the Example, which weakened its ability to damage cell membranes and reduced the number of positive charges on the surface-modified bioactive glass, resulting in poor antibacterial properties and dentinal tubule sealing effect of the oral desensitizing paste.

[0089] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. However, any modifications, alterations, and variations made by those skilled in the art without departing from the scope of the present invention based on the disclosed technical content are equivalent embodiments of the present invention. Furthermore, any modifications, alterations, and variations made to the above embodiments based on the essential technology of the present invention are still within the protection scope of the present invention.

Claims

1. A surface-modified bioactive glass oral desensitizing ointment, characterized in that, The ingredients include the following parts by weight: 5-15 parts bioactive glass, 3-6 parts modifier, 3-5 parts silica, 20-30 parts humectant, 0.5-1 part sweetener, 0.5-1.5 parts foaming agent, 0.5-2 parts thickener, and 60-120 parts deionized water; The modifier is prepared by the following method: S1: N-Dodecylethanolamine reacts with 1-chloro-(E,Z,Z)-4,7,10-hexadecanetriene to generate intermediate 1. S2: Intermediate 1 reacts with L-lysine to generate intermediate 2. S3: Intermediate 2 is converted into intermediate 3 under the action of m-chloroperoxybenzoic acid. S4: Intermediate 3 reacts with mercaptopropyltrimethoxysilane to generate intermediate 4. S5: Intermediate 4 reacts with guanidinoacetic acid to generate a modifier, the chemical structure of which is as follows: 。 2. The surface-modified bioactive glass oral desensitizing ointment according to claim 1, characterized in that, In step S1, the molar ratio of N-dodecylethanolamine to 1-chloro-(E,Z,Z)-4,7,10-hexadecanetriene is 1:(1.01-1.05).

3. The surface-modified bioactive glass oral desensitizing ointment according to claim 1, characterized in that, In step S2, the molar ratio of intermediate 1 to L-lysine is 1:(2.05-2.1).

4. The surface-modified bioactive glass oral desensitizing ointment according to claim 1, characterized in that, In step S3, the molar ratio of intermediate 2 to m-chloroperoxybenzoic acid is 1:(3.3-3.9).

5. The surface-modified bioactive glass oral desensitizing ointment according to claim 1, characterized in that, In step S4, the molar ratio of intermediate 3 to mercaptopropyltrimethoxysilane is 1:(3.05-3.1).

6. The surface-modified bioactive glass oral desensitizing ointment according to claim 1, characterized in that, In step S5, the molar ratio of intermediate 4 to guanidinoacetic acid is 1:(3.1-3.2).

7. The surface-modified bioactive glass oral desensitizing ointment according to claim 1, characterized in that, The moisturizer is glycerin.

8. The surface-modified bioactive glass oral desensitizing ointment according to claim 1, characterized in that, The sweetener is stevia.

9. The surface-modified bioactive glass oral desensitizing ointment according to claim 1, characterized in that, The foaming agent is sodium lauroyl sarcosinate; the thickener is xanthan gum.

10. A method for preparing a surface-modified bioactive glass oral desensitizing ointment as described in any one of claims 1-9, characterized in that, Includes the following steps: (1) Weigh out the following by weight: 5-15 parts of bioactive glass, 3-6 parts of modifier, 3-5 parts of silica, 20-30 parts of humectant, 0.5-1 part of sweetener, 0.5-1.5 parts of foaming agent, 0.5-2 parts of thickener, and 60-120 parts of deionized water; (2) Mix one-third of the deionized water, bioactive glass, and modifier, and heat to react to obtain modified bioactive glass; stir the remaining two-thirds of the deionized water, humectant, sweetener, foaming agent, and thickener, add silica and modified bioactive glass, shear at high speed, degas under vacuum, and let stand to obtain surface-modified bioactive glass oral desensitizing ointment.

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