Oral anti-inflammatory toothpaste and preparation method thereof

Abstract

The invention particularly relates to oral cavity anti-inflammatory toothpaste and a preparation method thereof. Comprising the following components in parts by weight: 20-30 parts of a friction agent, 1-2 parts of a surfactant, 1-2 parts of a thickening agent, 20-30 parts of a humectant, 0.1-0.55 part of a sweetening agent, 0.1-0.3 part of a preservative, 3-5 parts of an anti-inflammatory nano-composite, 0.3-0.35 part of lysozyme, a pH regulator for maintaining the pH value of the toothpaste to be 6.5-7.4, and the balance of water added to 100 parts. The anti-inflammatory nano compound is a nano compound formed by encapsulating patchouli alcohol, magnolol and a Zn-chlorogenic acid complex by using Eudragit E100 / chitosan. The intelligent pH response core-shell structure Eudragit E100 / chitosan is adopted, anti-inflammatory active ingredients can be accurately released at the oral inflammation part, the targeted delivery effect of efficient release of the inflammation part is achieved, a lysozyme pH response nano system is combined, the antibacterial spectrum is enhanced while targeted release is achieved, and the anti-inflammatory effect is achieved. The patchouli alcohol (antibacterial), the magnolol (anti-inflammatory) and the Zn-chlorogenic acid complex (repair promoting) form a composite efficacy system, and experiments prove that the inhibition rate on inflammatory factors such as TNF-alpha and IL-6 is about 70%.

Description

Technical Field

[0001] The present invention relates to the technical field of oral care, and in particular to an oral anti-inflammatory toothpaste and a preparation method thereof. Background Art

[0002] Oral inflammation is a common oral health problem, mainly including gingivitis, periodontitis, oral ulcers, angular cheilitis, etc. Its typical symptoms are red, swollen and bleeding gums, oral mucosal damage, pain, bad breath and decreased local pH. These inflammations are mainly caused by bacterial infection (such as Porphyromonas gingivalis, Streptococcus), abnormal immune response or mechanical stimulation (such as friction of dental braces). If not intervened in time, it may develop into chronic periodontal disease and even affect systemic health (such as cardiovascular disease, diabetes, etc.).

[0003] At present, commercially available anti-inflammatory toothpastes mainly rely on broad-spectrum antibacterial agents (such as chlorhexidine, triclosan) or natural extracts (such as peppermint oil, tea tree oil) to inhibit bacteria, but the following key problems still exist: conventional toothpaste ingredients are evenly released in the mouth and cannot act precisely on the site of inflammation, resulting in low utilization of effective ingredients and may disrupt the balance of normal oral flora. pH mismatch: The microenvironment of the oral inflammation area is weakly acidic (pH 5.0-6.5), while the pH of most toothpastes is neutral or weakly alkaline (7.0-8.0), which cannot respond to the acidic environment of the inflammation site to trigger drug release. Existing products mostly focus on antibacterial, ignoring the synergistic effects of anti-inflammation, mucosal repair and immune regulation, making it difficult to fully relieve inflammatory symptoms and lacking synergy. Some active ingredients (such as phenolic compounds) are easily oxidized and inactivated, or react with the toothpaste matrix (such as fluoride, abrasives), resulting in decreased efficacy and insufficient stability.

[0004] In response to the above problems, although some studies have attempted to apply nanocarriers (such as liposomes and polymer micelles) to toothpaste in recent years, most carriers tend to release drugs prematurely in the complex environment of the oral cavity (saliva flushing, mechanical friction), or have difficulty penetrating the mucosa and being retained in the inflammatory site. In addition, there is still a lack of carrier systems that are pH responsive, have high drug loading and process compatibility. Therefore, there is an urgent need to develop a new oral anti-inflammatory toothpaste, the core of which is to have an intelligent delivery system and multi-effect synergistic controlled release. Summary of the Invention

[0005] In response to the problems existing in the prior art, the present invention aims to provide an oral anti-inflammatory toothpaste and a preparation method thereof. The oral anti-inflammatory toothpaste of the present invention is an intelligent delivery system, which achieves targeted release at the inflammatory site through pH-responsive materials (such as Eudragit E100 / chitosan), reducing interference with normal tissues; combines antibacterial (patchouli alcohol), anti-inflammatory (magnolia bark phenol) and pro-repair (Zn-chlorogenic acid complex) ingredients, and synergistically covers the entire inflammation process; ensures the stability and release controllability of the carrier in the toothpaste matrix (high abrasive content, long-term storage).

[0006] In order to achieve the above object, the technical solution of the present invention is achieved as follows:

[0007] An oral anti-inflammatory toothpaste comprises the following components by weight: 20-30 parts of an abrasive, 1-2 parts of a surfactant, 1-2 parts of a thickener, 20-30 parts of a moisturizer, 0.1-0.55 parts of a sweetener, 0.1-0.3 parts of a preservative, 3-5 parts of an anti-inflammatory nanocomposite, 0.3-0.35 parts of a lysozyme, a pH regulator to maintain the pH of the toothpaste at 6.5-7.4, and water as the balance to 100 parts; the anti-inflammatory nanocomposite is a nanocomposite of Eudragit E100 / chitosan encapsulating patchouli alcohol, magnolol, and a Zn-chlorogenic acid complex.

[0008] Furthermore, the abrasive is hydroxyapatite or hydrated silica; the surfactant is one or more of sodium N-lauroyl sarcosinate, sodium lauroyl glutamate, sodium cocoyl glutamate and sodium lauryl sulfate; the thickener is glucomannan and xanthan gum or carboxymethyl cellulose; the preservative is sodium benzoate, potassium sorbate or paraben; the humectant is glycerin or sorbitol; and the sweetener is xylitol or erythritol.

[0009] Furthermore, the anti-inflammatory nanocomplex is a core-shell structure with a particle size of 150-300 nm; the shell layer is Eudragit E100, and the core layer is a complex of chitosan, patchouli alcohol, magnolol and Zn-chlorogenic acid complex.

[0010] Furthermore, the mass ratio of chitosan to Eudragit E100 in the anti-inflammatory nanocomposite is 1:1-2; the mass ratio of patchouli alcohol, magnolol and Zn-chlorogenic acid complex to chitosan and Eudragit E100 is 0.5:0.3-0.5:0.3-0.5:1:1-2.

[0011] Furthermore, the preparation method of the above-mentioned oral anti-inflammatory toothpaste comprises the following steps:

[0012] (1) Dissolve the pH regulator and thickener in 8-12 times the mass of water, add the moisturizer and stir at 45-70°C until transparent, add the premixed solution of surfactant, sweetener and the remaining water, add the anti-inflammatory nanocomposite and stir evenly;

[0013] (2) adding a friction agent to step (1) and stirring at a low speed; adding lysozyme and preservative after cooling to 30°C;

[0014] Vacuum degassing and packaging as finished product.

[0015] Furthermore, the preparation method of the anti-inflammatory nanocomposite comprises the following steps:

[0016] S1: dissolving chlorogenic acid in a mixed solution of 50-60% ethanol or methanol with water at a pH of 6, adding zinc salt to the mixed solution in a molar ratio of chlorogenic acid to zinc salt of 2-3:1, stirring in a water bath at 40-60°C in the dark for 1-2 hours; cooling to room temperature, adding pure ethanol or methanol until the ethanol or methanol content is greater than 85%, collecting the precipitate, washing with alcohol, and drying to prepare a Zn-chlorogenic acid complex;

[0017] S2: dissolving the Zn-chlorogenic acid complex in step S1 in an aqueous solution with a pH of 6.0 to avoid precipitation to obtain an aqueous solution of the Zn-chlorogenic acid complex; dissolving patchouli alcohol and magnolol in anhydrous ethanol to obtain an oil phase;

[0018] S3: Dissolve chitosan in 1-1.5% acetic acid solution, add surfactants poloxamer 188 and SDS to completely dissolve into the aqueous phase; slowly add the oil phase in step S2 dropwise to the aqueous phase, stir to form a coarse emulsion, and then finely emulsify by ultrasonication; add sodium tripolyphosphate aqueous solution dropwise, continue stirring and reacting, and obtain a chitosan / patchouli alcohol and magnolol composite nanoemulsion;

[0019] S4: adding the Zn-chlorogenic acid complex aqueous solution of step S2 to step S3, stirring for 1-2 hours in the dark, to obtain a Zn-chlorogenic acid / chitosan / patchouli alcohol and magnolol composite nanoemulsion;

[0020] S5: Dissolve Eudragit E100 in ethanol solution and slowly add it dropwise to the emulsion in step S4; homogenize under high pressure to form a uniform core-shell structure; and rotary evaporate and freeze-dry to prepare an anti-inflammatory nanocomplex.

[0021] Furthermore, in step S1, the zinc salt is one or more of zinc acetate, zinc sulfate, zinc bromide, zinc citrate, zinc chloride, zinc nitrate, zinc tartrate, zinc D-lactate, zinc L-lactate, zinc pyrophosphate, zinc gluconate and zinc glycerophosphate.

[0022] Furthermore, in step S3, the concentration of chitosan in the acetic acid solution is 0.5% w / v; the mass ratio of poloxamer 188 to SDS is 2-4:1; and the total concentration of poloxamer 188 and SDS in the acetic acid solution is 0.5-1% w / v.

[0023] Furthermore, the conditions for ultrasonic microemulsification in step S3 are: power 200-300 W, ultrasonic 2 seconds / interval 2 seconds, total 5 minutes; the mass ratio of chitosan to sodium tripolyphosphate is 5:1, and the stirring reaction time is continued for 30 minutes.

[0024] Furthermore, the high-pressure homogenization conditions in step S5 are 5000-10000 rpm, 3-5 min.

[0025] Patchouli alcohol inhibits the TLR4 / NF-κB pathway and is hydrophobic (sesquiterpene alcohol, fat-soluble, requires ethanol / oil solubility); when the three extracts are used in combination, patchouli alcohol may synergize through multiple targets, and reduce IL-6.

[0026] Beneficial effects of the present invention:

[0027] 1. The present invention provides an oral anti-inflammatory toothpaste and a preparation method thereof, which achieves targeted release at the inflammatory site through pH-responsive materials (such as Eudragit E100 / chitosan) to reduce interference with normal tissues; in addition, nano-encapsulation technology improves the stability and action time of the anti-inflammatory components; lysozyme is combined with an anti-inflammatory nanocomplex, namely, antibacterial patchouli alcohol, anti-inflammatory magnolol and a pro-repair Zn-chlorogenic acid complex, to synergistically cover the entire inflammation process; ensure the stability and release controllability of the carrier during long-term storage in a toothpaste matrix with a high abrasive content; the zinc-chlorogenic acid complex is realized through a metal ion coordination reaction, which can not only enhance the stability of polyphenols, but also improve the bioavailability of zinc and enhance the anti-inflammatory activity of the toothpaste.

[0028] 2. Experimental verification shows that the toothpaste of this invention inhibits inflammatory factors such as TNF-α and IL-6 by approximately 70%. The innovative combination of lysozyme and a pH-responsive nanosystem allows for targeted release while enhancing the antimicrobial spectrum. The preparation process is simple and suitable for industrial production. The resulting toothpaste maintains conventional cleaning properties while exhibiting significantly superior anti-inflammatory and tooth-protecting effects than commercially available products. This technology is particularly suitable for individuals susceptible to oral inflammation. DETAILED DESCRIPTION

[0029] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0030] Example 1

[0031] The present embodiment provides a method for preparing an oral anti-inflammatory toothpaste, comprising the following steps:

[0032] (1) Preparation of anti-inflammatory nanocomplexes:

[0033] ① Accurately weigh 0.1g of chlorogenic acid and dissolve it in 50ml of 60% ethanol aqueous solution, adjust the pH to 6, accurately weigh a certain amount of zinc chloride and dissolve it in water according to the molar ratio of chlorogenic acid to zinc chloride 2:1, mix it with the chlorogenic acid solution, place it in a round-bottom flask, stir and react in a 40℃ water bath in the dark for 2h, cool to room temperature, add anhydrous ethanol to adjust the alcohol content to 90%, precipitate the complex at room temperature, recover the solvent to obtain a light yellow complex, wash with ethanol until no Cl is detected in the filtrate with AgNO3, and then add CaCl2O3. 2+ Dry in a desiccator under vacuum to constant weight.

[0034] ② The Zn-chlorogenic acid complex prepared in step ① was dissolved in water and the pH was adjusted to 6.0 to avoid precipitation to obtain an aqueous solution of the Zn-chlorogenic acid complex; patchouli alcohol and magnolol were dissolved in anhydrous ethanol to obtain an oil phase;

[0035] ③ Chitosan was dissolved in 50 ml of 1% acetic acid solution at a concentration of 0.5% w / v, and poloxamer 188 and SDS were added in a mass ratio of 3:1 to completely dissolve the chitosan in the aqueous phase; the concentration of the surfactant was 0.8% w / v, and the oil phase in step S2 was slowly added dropwise to the aqueous phase. The mass ratio of patchouli alcohol, magnolol and chitosan was 0.5:0.3:1; stirred to form a coarse emulsion, and then ultrasonically finely emulsified at a power of 200-300 W, ultrasonically for 2 seconds / interval of 2 seconds, for a total of 5 minutes; sodium tripolyphosphate aqueous solution was added dropwise to promote chitosan cross-linking. The mass ratio of chitosan to sodium tripolyphosphate was 5:1. The stirring reaction was continued for 30 minutes to obtain a chitosan / patchouli alcohol and magnolol composite nanoemulsion;

[0036] ④ Add the Zn-chlorogenic acid complex aqueous solution of step S2 to step S3, the mass ratio of Zn-chlorogenic acid complex to chitosan is 0.4:1; stir in the dark for 1 hour, when the pH is close to neutral, the benzene ring structure of chlorogenic acid interacts with the acetyl group or hydrophobic region of chitosan through van der Waals force, so that the Zn-chlorogenic acid complex is adsorbed on the surface of the chitosan / patchouli alcohol and magnolol composite nanoemulsion, and a Zn-chlorogenic acid / chitosan / patchouli alcohol and magnolol composite nanoemulsion is obtained;

[0037] ⑤ Dissolve Eudragit E100 in ethanol solution and slowly add it dropwise to the emulsion in step S4; the mass ratio of chitosan to Eudragit E100 is 1:1.5, and high-pressure homogenization is performed at 5000 rpm for 5 min to form a uniform core-shell structure; rotary evaporation and freeze-drying are performed to prepare an anti-inflammatory nanocomposite of Eudragit E100 / chitosan encapsulating patchouli alcohol, magnolol, and Zn-chlorogenic acid complex, with a particle size of 150-300 nm as determined by dynamic light scattering (DLS);

[0038] (2) The pH of the solution was adjusted to 7.0 by PBS, and 2 parts of the thickener glucomannan were dissolved in 8 times the mass of water.

[0039] Add 25 parts of moisturizing agent glycerin and stir until transparent at 45-70℃, add 2 parts of surfactant sodium lauroyl sarcosinate, 0.3 parts of sweetener xylitol and the remaining water premix solution, add 3-5 parts of anti-inflammatory nanocomplex and stir evenly;

[0040] (3) Add 25 parts of hydrated silica as a friction agent to step (1) and stir evenly at a low speed of 400 r / min; after cooling to 30° C., add 0.3 parts of lysozyme and 0.2 parts of sodium benzoate as a preservative; vacuum degassing and packaging as a finished product.

[0041] Example 2

[0042] The present embodiment provides a method for preparing an oral anti-inflammatory toothpaste, comprising the following steps:

[0043] (1) Preparation of anti-inflammatory nanocomplexes:

[0044] ① Accurately weigh 0.1 g of chlorogenic acid and dissolve it in 50 ml of 60% ethanol aqueous solution, adjust the pH to 6, accurately weigh a certain amount of zinc sulfate and dissolve it in water according to the molar ratio of chlorogenic acid to zinc sulfate 3:1, mix it with the chlorogenic acid solution, place it in a round-bottom flask, stir and react in a 40 ° C water bath in the dark for 2 hours, cool to room temperature, add anhydrous ethanol to adjust the alcohol content to 90%, precipitate the complex at room temperature, recover the solvent to obtain the Zn-chlorogenic acid complex, wash with ethanol, and then vacuum dry to constant weight for use;

[0045] ② The Zn-chlorogenic acid complex prepared in step ① was dissolved in water and the pH was adjusted to 6.0 to avoid precipitation to obtain an aqueous solution of the Zn-chlorogenic acid complex; patchouli alcohol and magnolol were dissolved in anhydrous ethanol to obtain an oil phase;

[0046] ③ Chitosan was dissolved in 50 ml of 1% acetic acid solution at a concentration of 0.5% w / v, and poloxamer 188 and SDS were added in a mass ratio of 3:1 to completely dissolve the chitosan in the aqueous phase; the concentration of the surfactant was 0.5% w / v, and the oil phase in step S2 was slowly added dropwise to the aqueous phase. The mass ratio of patchouli alcohol, magnolol and chitosan was 0.5:0.3:1; stirred to form a coarse emulsion, and then ultrasonically finely emulsified at a power of 200 W, ultrasonication for 2 seconds / interval of 2 seconds, for a total of 5 minutes; sodium tripolyphosphate aqueous solution was added dropwise to promote chitosan cross-linking. The mass ratio of chitosan to sodium tripolyphosphate was 5:1. The stirring reaction was continued for 30 minutes to obtain a chitosan / patchouli alcohol and magnolol composite nanoemulsion;

[0047] ④ Add the Zn-chlorogenic acid complex aqueous solution of step S2 to step S3, with the mass ratio of Zn-chlorogenic acid complex to chitosan being 0.5:1; stir in the dark for 1 hour to obtain a Zn-chlorogenic acid / chitosan / patchouli alcohol and magnolol composite nanoemulsion;

[0048] ⑤ Dissolve Eudragit E100 in ethanol solution and slowly add it dropwise to the emulsion in step S4; the mass ratio of chitosan to Eudragit E100 is 1:2, and high-pressure homogenization is performed at 7000 rpm for 5 min to form a uniform core-shell structure; rotary evaporation and freeze-drying are performed to prepare an anti-inflammatory nanocomposite of Eudragit E100 / chitosan encapsulating patchouli alcohol, magnolol, and Zn-chlorogenic acid complex with a particle size of 300 nm;

[0049] (2) The pH of the solution was adjusted to 7.4 by PBS as a pH adjuster, and 2 parts of glucomannan and carboxymethyl cellulose (with a mass ratio of 1:1) as thickeners were dissolved in 10 times the mass of water. 30 parts of sorbitol as a moisturizer were added at 70°C and stirred until transparent. A premixed solution of 1 part of sodium lauryl sulfate as a surfactant, 0.1 part of xylitol as a sweetener, and the remaining water was added. 3 parts of the anti-inflammatory nanocomplex were added and stirred evenly.

[0050] (3) Add 20 parts of friction agent hydroxyapatite to step (1), stir evenly at a low speed of 500r / min; cool to 30℃

[0051] Then, 0.3 parts of lysozyme and 0.3 parts of preservative potassium sorbate were added; vacuum degassing was carried out, and the product was packaged.

[0052] Example 3

[0053] The present embodiment provides a method for preparing an oral anti-inflammatory toothpaste, comprising the following steps:

[0054] (1) Preparation of anti-inflammatory nanocomplexes:

[0055] ① Accurately weigh 0.1 g of chlorogenic acid and dissolve it in 50 ml of 60% ethanol aqueous solution, adjust the pH to 6, accurately weigh a certain amount of zinc chloride and dissolve it in water according to the molar ratio of chlorogenic acid to zinc nitrate of 2.5:1, mix it with the chlorogenic acid solution, place it in a round-bottom flask, stir in a 40 ° C water bath in the dark for 2 hours, cool to room temperature, add anhydrous ethanol to adjust the alcohol content to 90%, precipitate the complex at room temperature, recover the solvent to obtain a light yellow complex, and vacuum dry to constant weight;

[0056] ② The Zn-chlorogenic acid complex prepared in step ① was dissolved in water and the pH was adjusted to 6.0 to avoid precipitation to obtain an aqueous solution of the Zn-chlorogenic acid complex; patchouli alcohol and magnolol were dissolved in anhydrous ethanol to obtain an oil phase;

[0057] ③ Chitosan was dissolved in 50 ml of 1.5% acetic acid solution to a concentration of 0.5% w / v, and poloxamer 188 and SDS were added in a mass ratio of 2:1 to completely dissolve the chitosan in the aqueous phase; the concentration of the surfactant was 1% w / v, and the oil phase in step S2 was slowly added dropwise to the aqueous phase, with the mass ratio of patchouli alcohol, magnolol and chitosan being 0.5:0.5:1; stirred to form a coarse emulsion, and then ultrasonically finely emulsified at a power of 300 W, ultrasonically for 2 seconds / interval of 2 seconds, for a total of 5 minutes; sodium tripolyphosphate aqueous solution was added dropwise to promote chitosan cross-linking, with the mass ratio of chitosan to sodium tripolyphosphate being 5:1, and the stirring reaction was continued for 30 minutes to obtain a chitosan / patchouli alcohol and magnolol composite nanoemulsion;

[0058] ④ Add the Zn-chlorogenic acid complex aqueous solution of step S2 to step S3, with the mass ratio of Zn-chlorogenic acid complex to chitosan being 0.3:1; stir in the dark for 1 hour to obtain a Zn-chlorogenic acid / chitosan / patchouli alcohol and magnolol composite nanoemulsion;

[0059] ⑤ Dissolve Eudragit E100 in ethanol solution and slowly add it dropwise to the emulsion in step S4; the mass ratio of chitosan to Eudragit E100 is 1:1, and high-pressure homogenization is performed at 10,000 rpm for 3 minutes to form a uniform core-shell structure; rotary evaporation and freeze-drying are performed to prepare an anti-inflammatory nanocomposite of Eudragit E100 / chitosan encapsulating patchouli alcohol, magnolol, and Zn-chlorogenic acid complex with a particle size of 150 nm;

[0060] (2) The pH of the solution was adjusted to 6.8 by PBS as a pH regulator, and 1 part of glucomannan and xanthan gum (a thickener) with a mass ratio of 1:0.5 was dissolved in 12 times the mass of water. 20 parts of humectant glycerol were added at 45°C and stirred until transparent. A premixed solution of 2 parts of surfactant sodium lauroyl glutamate, 0.55 parts of sweetener erythritol and the remaining water was added, and 5 parts of the anti-inflammatory nanocomplex was added and stirred evenly.

[0061] (3) Add 30 parts of hydrated silica as a friction agent to step (1) and stir evenly at a low speed of 200 r / min; after cooling to 30° C., add 0.35 parts of lysozyme and 0.1 parts of preservative paraben; vacuum degassing and packaging as a finished product.

[0062] Comparative Example 1

[0063] This comparative example provides a toothpaste, which is different from Example 1 in that the toothpaste provided in this comparative example does not prepare an anti-inflammatory nanocomposite, and the Zn-chlorogenic acid complex, patchouli alcohol and magnolol are added to the toothpaste as raw materials, and the effective content is the same as in Example 1, wherein the preparation method of the Zn-chlorogenic acid complex is the same as step ①.

[0064] Comparative Example 2

[0065] This comparative example provides a toothpaste, which is different from Example 1 in that the anti-inflammatory nanocomposite in the toothpaste provided in this comparative example does not contain the Zn-chlorogenic acid complex described in Example 1, and the sum of the amounts of patchouli alcohol and magnolol is the same as the sum of the three components in Example 1; the remaining steps and formula are the same as Example 1.

[0066] Comparative Example 3

[0067] This comparative example provides a toothpaste, which is different from Example 1 in that the anti-inflammatory nanocomposite of the toothpaste provided in this comparative example does not contain Zn-chlorogenic acid complex and patchouli alcohol, but only magnolol; the amount of magnolol in this comparative example is equal to the sum of the above three components in Example 1; the remaining steps are the same as Example 1.

[0068] Comparative Example 4

[0069] This comparative example provides a toothpaste, which is different from Example 1 in that lysozyme is not added to the toothpaste provided in this comparative example, and the remaining steps are the same as Example 1.

[0070] Comparative Example 5

[0071] Commercially available toothpaste claims to contain the anti-inflammatory ingredient triclosan.

[0072] Experimental Example 1: pH-responsive release experiment

[0073] In vitro release test:

[0074] To simulate the oral environment, different pH buffer solutions (pH 5.5, 6.5, 7.4) were set.

[0075] The toothpaste samples of Example 1 of the present invention and Comparative Examples 1-3 were dispersed in a medium and shaken at 37°C.

[0076] Samples were taken at regular intervals and the cumulative release rates of patchouli alcohol, magnolol and chlorogenic acid were detected by HPLC.

[0077]

[0078] Experimental results: At pH 5.5, pH 6.5, and pH 7.4, the 4h release rates are shown in Table 1:

[0079] Table 1:

[0080] Simulated oral environment Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 pH 5.5 80％ 95％ 81％ 83％ pH 6.5 50％ 96％ 48％ 45％ pH 7.4 30％ 97％ 33％ 27％

[0081] As shown in Table 1, the anti-inflammatory nanocomplex prepared by the present invention has targeting, selectively releases highly in the microenvironment of pH 5.5 at the inflammation site, releases less in the normal oral environment, avoids the influence of beneficial bacteria in the oral cavity, and has controllable release performance.

[0082] Experimental Example 2: Antibacterial and anti-inflammatory synergistic experiment

[0083] Antibacterial testing:

[0084] The minimum inhibitory concentration (MIC) of common oral pathogens (such as Streptococcus mutans S.mutans and Porphyromonas gingivalis P.gingivalis) was determined.

[0085]

[0086] step:

[0087] Equal amounts of the toothpastes of Example 1 of the present invention and Comparative Examples 2, 3, 4 and 5 and chlorhexidine (dissolved in PBS and sterilized by filtration) were taken and a two-fold gradient dilution (0.5-256 μg / mL) was performed.

[0088] Inoculate the above cultured bacterial solution (~10 5 CFU / mL) and cultured anaerobically for 24-48h.

[0089] The lowest concentration at which no visible growth was observed (MIC);

[0090] Minimum bactericidal concentration (MBC) determination: Take bacterial solution with MIC or above concentration, spread it on agar plate, and calculate the concentration that kills 99.9% of the bacteria.

[0091] The minimum inhibitory concentration and minimum bactericidal concentration are shown in Table 2 (MIC / MBC μg / ml):

[0092] Table 2:

[0093]

[0094] Compared with the comparative example, the toothpaste prepared by the present invention is effective against both S. mutans (caries) and P. gingivalis (periodontitis), and the MIC is significantly lower than that of the comparative example and commercially available products.

[0095] Experimental Example 3: Anti-inflammatory Test

[0096] RAW 264.7 cells were cultured with DMEM+10% FBS+1% double antibody at 37°C and 5% CO2. Cells were passaged (digested with 0.25% trypsin) when the cell density reached 80%.

[0097] The cells were plated at 5 × 10 4 cells / well were seeded into 96-well plates (200 μL / well) and cultured for 24 h until adherence.

[0098] Drug pretreatment and LPS stimulation: Group treatment (6 replicates per group):

[0099] Blank group: DMEM (without LPS, without drugs); LPS model group: DMEM + LPS (1 μg / mL);

[0100] Experimental group: LPS+Example 1, Comparative Example 1, 3, 4 or 5.

[0101] Drugs were added for pretreatment for 1 h, and then LPS was added for stimulation for 24 h.

[0102] TNF-α and IL-6 were detected by ELISA, and the supernatant was collected and centrifuged (1000 rpm, 5 min). The supernatant was taken and stored at -80°C for future use.

[0103] ELISA operation (according to the kit instructions): coating antibody → adding standard / sample → incubation → washing plate → adding detection antibody → color development → measuring OD 450 nm.

[0104] Calculation of inflammatory factor concentrations: Calculate the inflammatory factor inhibition rate by fitting the TNF-α / IL-6 concentration (pg / mL) according to the standard curve, as shown in Table 3:

[0105] Table 3:

[0106]

[0107]

[0108]

[0109] Experimental Example 4: Accelerated Stability Test

[0110] Stability comparison test: The toothpastes prepared in Example 1 and Comparative Examples 1-4 were stored under simulated normal storage conditions (25°C, relative humidity 60%, protected from light) and accelerated aging conditions (37°C, relative humidity 70%, protected from light) for a certain period of time (6 months and 3 months, respectively), and their anti-inflammatory activity, pH value, appearance and other indicators were regularly tested for changes. Under normal storage conditions, after 6 months, all indicators of the toothpaste of Example 1 remained stable, and there was no significant decrease in pH response release performance and anti-inflammatory activity; the antibacterial activity of Comparative Example 1 decreased by about 25%, and slight discoloration occurred, and the pH value exceeded the normal range; the antibacterial activity of Comparative Example 5 decreased by about 15%, and the pH value fluctuated slightly. This shows that the oral anti-inflammatory toothpaste of the present invention is also superior to the prior art products in terms of stability.

[0111] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. An oral anti-inflammatory toothpaste, characterized in that: The toothpaste comprises the following components by weight: 20-30 parts of abrasive, 1-2 parts of surfactant, 1-2 parts of thickener, 20-30 parts of moisturizer, 0.1-0.55 parts of sweetener, 0.1-0.3 parts of preservative, 3-5 parts of anti-inflammatory nanocomposite, 0.3-0.35 parts of lysozyme, a pH regulator to maintain the pH of the toothpaste at 6.5-7.4, and the balance is water added to 100 parts; the anti-inflammatory nanocomposite is a nanocomposite of Eudragit E100 / chitosan encapsulating patchouli alcohol, magnolol and Zn-chlorogenic acid complex.

2. The oral anti-inflammatory toothpaste according to claim 1, characterized in that: The abrasive is hydroxyapatite or hydrated silica; the surfactant is one or more of sodium N-lauroyl sarcosinate, sodium lauroyl glutamate, sodium cocoyl glutamate and sodium lauryl sulfate; the thickener is one or more of glucomannan, xanthan gum or carboxymethyl cellulose; the preservative is one or more of sodium benzoate, potassium sorbate and paraben; the humectant is glycerol or sorbitol; and the sweetener is xylitol or erythritol.

3. The oral anti-inflammatory toothpaste according to claim 1, characterized in that: The anti-inflammatory nanocomposite is a core-shell structure with a particle size of 150-300 nm; the shell layer is Eudragit E100, and the core layer is a complex of chitosan, patchouli alcohol, magnolol and Zn-chlorogenic acid complex.

4. The oral anti-inflammatory toothpaste according to claim 3, characterized in that: The mass ratio of chitosan to Eudragit E100 in the anti-inflammatory nanocomposite is 1:1-2; the mass ratio of the patchouli alcohol, magnolol and Zn-chlorogenic acid complex to chitosan and Eudragit E100 is 0.5:0.3-0.5:0.3-0.5:1:1-2.

5. The method for preparing the oral anti-inflammatory toothpaste according to any one of claims 1 to 4, characterized in that: The steps include: (1) Dissolve the pH regulator and thickener in 8-12 times the mass of water, add the moisturizer and stir at 45-70°C until transparent, add the premixed solution of surfactant, sweetener and the remaining water, add the anti-inflammatory nanocomposite and stir evenly; (2) adding a friction agent to step (1) and stirring at a low speed; adding lysozyme and a preservative after cooling to 30° C.; vacuum degassing, and packaging as a finished product.

6. The method for preparing the oral anti-inflammatory toothpaste according to claim 5, wherein: The preparation method of the anti-inflammatory nanocomposite comprises the following steps: S1: dissolving chlorogenic acid in a mixed solution of 50-60% ethanol or methanol with water at a pH of 6, adding zinc salt to the mixed solution in a molar ratio of chlorogenic acid to zinc salt of 2-3:1, stirring in a water bath at 40-60°C in the dark for 1-2 hours; cooling to room temperature, adding pure ethanol or methanol until the ethanol or methanol content is greater than 85%, collecting the precipitate, washing with alcohol, and drying to prepare a Zn-chlorogenic acid complex; S2: dissolving the Zn-chlorogenic acid complex in step S1 in an aqueous solution with a pH of 6.0 to avoid precipitation to obtain an aqueous solution of the Zn-chlorogenic acid complex; dissolving patchouli alcohol and magnolol in anhydrous ethanol to obtain an oil phase; S3: Dissolve chitosan in 1-1.5% acetic acid solution, add surfactants poloxamer 188 and SDS to completely dissolve into the aqueous phase; slowly add the oil phase in step S2 dropwise to the aqueous phase, stir to form a coarse emulsion, and then finely emulsify by ultrasonication; add sodium tripolyphosphate aqueous solution dropwise, continue stirring and reacting, and obtain a chitosan / patchouli alcohol and magnolol composite nanoemulsion; S4: adding the Zn-chlorogenic acid complex aqueous solution of step S2 to step S3, stirring for 1-2 hours in the dark, to obtain a Zn-chlorogenic acid / chitosan / patchouli alcohol and magnolol composite nanoemulsion; S5: Dissolve Eudragit E100 in ethanol solution and slowly add it dropwise to the emulsion in step S4; homogenize under high pressure to form a uniform core-shell structure; and rotary evaporate and freeze-dry to prepare an anti-inflammatory nanocomplex.

7. The method for preparing the oral anti-inflammatory toothpaste according to claim 5, wherein: The zinc salt in step S1 is one or more of zinc acetate, zinc sulfate, zinc bromide, zinc citrate, zinc chloride, zinc nitrate, zinc tartrate, zinc D-lactate, zinc L-lactate, zinc pyrophosphate, zinc gluconate and zinc glycerophosphate.

8. The method for preparing the oral anti-inflammatory toothpaste according to claim 5, wherein: In step S3, the concentration of chitosan in the acetic acid solution is 0.5% w / v; the mass ratio of poloxamer 188 to SDS is 2-4:1; and the total concentration of poloxamer 188 and SDS in the acetic acid solution is 0.5-1% w / v.

9. The method for preparing the oral anti-inflammatory toothpaste according to claim 5, wherein: The conditions for ultrasonic microemulsification in step S3 are: power 200-300 W, ultrasonic 2 seconds / interval 2 seconds, total 5 minutes; the mass ratio of chitosan to sodium tripolyphosphate is 5:1, and the stirring reaction time is continued for 30 minutes.

10. The method for preparing the oral anti-inflammatory toothpaste according to claim 6, wherein: The conditions for high pressure homogenization in step S5 are 5000-10000 rpm for 3-5 min.

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