Compound oral care composition as well as preparation method and application thereof

Abstract

The invention relates to the technical field of oral care products, and particularly discloses a compound oral care composition as well as a preparation method and application thereof. The compound oral care composition is prepared from the following raw materials in percentage by total weight of the compound oral care composition: 0.01 to 0.1 percent of cetylpyridinium chloride, 0.01 to 2 percent of sodium gualenate, 0.1 to 15 percent of L-glutamine derivatives and 0.001 to 0.05 percent of domiphen. According to the compound oral care composition, through a sterilization-bacteriostasis-anti-inflammatory-repair quaternary synergistic system, three-dimensional and full-chain intervention on oral etiology is achieved, the compound oral care composition has the advantages of efficient sterilization, long-acting bacteriostasis, rapid anti-inflammatory, mucosa repair acceleration and rapid pain relief, and the market requirement is met.

Description

Technical Field

[0001] This application relates to the field of oral care products technology, and more specifically, to a compound oral care composition and its preparation method and application. Background Technology

[0002] The oral cavity, as an important physiological organ, is the starting point of the digestive system and also an important site for microbial colonization. The oral cavity contains a large number of bacteria, fungi, and other microorganisms. When the oral mucosal barrier is damaged, the flora is imbalanced, or the body's immunity is weakened, various oral diseases such as oral ulcers, gingivitis, periodontitis, and stomatitis can easily occur, seriously affecting people's quality of life.

[0003] Currently, the market offers a wide variety of oral care and treatment products, but most have limited functionality. For example, antibacterial oral care products often contain cetylpyridinium chloride as their active ingredient, which provides immediate and broad-spectrum bactericidal activity but is less effective in anti-inflammation and tissue repair. Anti-inflammatory oral care products typically contain azulene sulfonate, which has anti-inflammatory and tissue-regenerating effects, but its bactericidal and tissue-repairing capabilities are also limited. Repairing oral care products often contain glutamine, which provides nutrition to mucosal cells but lacks sufficient bactericidal and anti-inflammatory capabilities. Some researchers have proposed compound oral care products, such as compound glutamine granules, which combine anti-inflammatory and nutritional repair components but lack potent and immediate bactericidal effects, resulting in slow treatment outcomes and a high recurrence rate. Therefore, developing a compound oral care composition that is highly effective in bactericidal activity, provides rapid anti-inflammation, and accelerates mucosal repair is of great significance for improving the prevention and treatment of oral diseases and meeting people's oral care needs. Summary of the Invention

[0004] In order to improve the killing rate and reduce the pain relief time and healing time, this application provides a compound oral care composition, its preparation method and application.

[0005] In a first aspect, this application provides a compound oral care composition, which adopts the following technical solution: A compound oral care composition, based on the total weight of the composition, comprises the following ingredients: cetylpyridinium chloride 0.05-0.1%, sodium azulene sulfonate 0.01-2%, L-glutamine derivative 0.1-15%, and domiphen 0.001-0.05%. The compound oral care composition of this application achieves a three-dimensional, full-chain intervention on the causes of oral diseases through a four-element synergistic system of "bactericidal-bacteriostatic-anti-inflammatory-repair". It has the advantages of highly efficient sterilization, rapid anti-inflammatory effect and accelerated mucosal repair, with a kill log value of >3 in 1 minute, a kill rate of ≥99.9% in 1 minute, pain relief time of ≤2.5 days and healing time of ≤3.5 days, which meets market demand.

[0006] The compound oral care composition of this application contains cetylpyridinium chloride, which provides instantaneous and broad-spectrum bactericidal activity. Sodium azulene sulfonate has bactericidal, anti-inflammatory, and tissue-regenerating effects. Domiphen not only provides long-lasting antibacterial action but also alters cell membrane permeability, promoting the penetration of cetylpyridinium chloride and sodium azulene sulfonate into deeper tissues, resulting in synergistic bactericidal and anti-inflammatory effects. The addition of an L-glutamine derivative to the raw materials, along with the introduction of a 3-pyridinecarboxamide fragment and a glycine tert-butyl ester fragment onto L-glutamine, not only provides nutritional support to mucosal cells but also effectively promotes cell proliferation and differentiation, inhibits the release of inflammatory factors, reduces redness and swelling of ulcer wounds, relieves pain, promotes collagen synthesis, promotes mucosal repair, enhances the mucosal barrier after repair, and reduces pain relief time and healing time, thus shortening the course of the disease.

[0007] Optionally, the raw materials of the compound oral care composition, by total weight, include 0.01-0.1% cetirizine chloride, 0.01-2% sodium azulene sulfonate, 0.1-8% L-glutamine derivative, and 0.001-0.05% domiphen.

[0008] Optionally, the raw materials of the compound oral care composition include cetylpyridinium chloride 0.05-0.1%, sodium azulene sulfonate 0.03-0.5%, L-glutamine derivative 0.5-8%, and domiphen 0.003-0.01%. Optionally, the L-glutamine derivative is prepared using the following method: S1. At a temperature of 30-40℃, N,N-dimethylformamide and L-glutamine are mixed, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride is added, and the mixture is stirred for 20-40 min. Then, 3-pyridineformamide is added, and the mixture is stirred for 4-6 h. Next, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and N,N-diisopropylethylamine are mixed, and glycine tert-butyl ester is added. The mixture is stirred for 23-27 h, and then concentrated under reduced pressure to obtain the reaction mixture. S2. Adjust the pH of the reaction mixture to 6-7, add water and mix, cool to 1-5℃, precipitate solid, filter, wash, dry, and obtain L-glutamine derivative.

[0009] Optionally, the weight ratio of L-glutamine, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 3-pyridinecarboxamide, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, N,N-diisopropylethylamine, and glycine tert-butyl ester is 10:(13-15):(8-10):(32-34):(18-20):(9-11).

[0010] By employing the above technical solution, L-glutamine contains amino and carboxyl groups. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride serves as a condensing agent, allowing L-glutamine and 3-pyridinecarboxamide to fully contact and react in its presence. 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate serves as a condensing agent, and N,N-diisopropylethylamine serves as an organic base; in their presence, L-glutamine and glycine tert-butyl ester fully contact and react. Using step S1, 3-pyridinecarboxamide and glycine tert-butyl ester are simultaneously grafted onto L-glutamine. Then, the pH is adjusted, water is added, and the temperature is lowered to 1-5°C, causing solid precipitation. This solid is filtered, washed, and the L-glutamine derivative is obtained. Step S2 is used to separate and purify the L-glutamine derivative. The preparation method described in this application not only enables the preparation of L-glutamine derivatives, but also ensures that the purity of the L-glutamine derivatives is ≥99.8%, i.e., the mass concentration of the L-glutamine derivatives is ≥99.8%, thus guaranteeing the quality and efficacy of the L-glutamine derivatives.

[0011] Optionally, in step S1, the volume is concentrated under reduced pressure to 1 / 5 to 1 / 2 of the original volume.

[0012] In several implementations, in step S1, the volume is concentrated to 1 / 3 of the original volume under reduced pressure. It can also be concentrated to 1 / 5, 1 / 4, 1 / 2, etc., as needed, but it is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0013] Optionally, the weight ratio of L-glutamine, N,N-dimethylformamide in step S1, and water in step S2 is 1:(17-23):(27-33).

[0014] In several implementations, the weight ratio of L-glutamine, N,N-dimethylformamide in step S1, and water in step S2 is 1:20:30. However, the weight ratio can also be set to 1:17:27, 1:17:30, 1:17:33, 1:20:27, 1:20:33, 1:23:27, 1:23:30, 1:23:33, etc., as needed. But it is not limited to the values ​​listed, and other unlisted values ​​within this range are also applicable.

[0015] Optionally, in step S2, the acid used to adjust the pH value is an aqueous solution of hydrochloric acid, with a mass concentration of 5-20%. The alkali used to adjust the pH value is an aqueous solution of sodium hydroxide, with a mass concentration of 5-20%.

[0016] In several embodiments, the hydrochloric acid aqueous solution has a mass concentration of 10%, but it can also be set to 5%, 8%, 13%, 15%, 18%, 20%, etc., as needed, but is not limited to the listed values; other unlisted values ​​within this range are also applicable. Similarly, in several embodiments, the sodium hydroxide aqueous solution has a mass concentration of 10%, but it can also be set to 5%, 8%, 13%, 15%, 18%, 20%, etc., as needed, but is not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0017] Optionally, the dosage form of the compound oral care composition is one of mouthwash, oral spray, lozenge, oral patch, oral dissolving film, or gel care solution.

[0018] By adopting the above technical solutions, the compound oral care composition can be made into mouthwash, oral spray, lozenge, oral patch, oral dissolving film, and gel care solution, providing multiple routes of administration to meet the needs of different oral problems and usage scenarios.

[0019] Optionally, the raw materials of the compound oral care composition may further include 5-30 wt% of a moisturizing stabilizer, wherein the moisturizing stabilizer is selected from one or more of glycerin, propylene glycol, sorbitol, and xylitol.

[0020] Preferably, the raw materials of the compound oral care composition further include 5-20 wt% of a moisturizing stabilizer.

[0021] By adopting the above technical solution, a moisturizing stabilizer is added to the raw materials of the compound oral care composition, which can ensure the solubility and chemical stability of ingredients such as sodium azulene sulfonate and extend the shelf life.

[0022] Optionally, the compound oral care composition is in the form of an oral spray, and its raw materials further include 0.01-3 wt% of a flavoring agent, 0.05-1 wt% of a pH adjuster, and the balance being water.

[0023] By adopting the above technical solution, flavoring agents and pH adjusters are added to the raw materials. Flavoring agents can improve the taste, while pH adjusters can reduce irritation and increase tolerance.

[0024] Secondly, this application provides a method for preparing the aforementioned compound oral care composition, employing the following technical solution: A method for preparing the compound oral care composition includes the following steps: Mix some water, moisturizing stabilizer, and fragrance, add L-glutamine derivative, sodium azulene sulfonate, and domiphen, add cetirizine chloride, add pH adjuster, add the remaining water, filter to sterilize, and fill to obtain a compound oral care composition.

[0025] By adopting the above technical solution, the raw materials are fully mixed, ensuring the quality and effectiveness of the compound oral care composition.

[0026] Thirdly, this application provides the use of the compound oral care composition described above in the preparation of oral care products for the prevention and / or treatment of stomatitis, pharyngitis, oral ulcers, periodontitis, and gingivitis.

[0027] Fourthly, this application provides the use of the compound oral care composition described above in the preparation of products for pre-operative disinfection of oral surgery or for daily oral health care.

[0028] In summary, this application has at least the following beneficial effects: 1. The compound oral care composition of this application achieves three-dimensional and full-chain intervention on the causes of oral diseases through a four-element synergistic system of "bactericidal-bacteriostatic-anti-inflammatory-repair". It has the advantages of highly efficient bactericidal effect, long-lasting antibacterial effect, rapid anti-inflammatory effect, accelerated mucosal repair and rapid pain relief. The kill rate is ≥99.9% in 1 minute, the pain disappearance time is ≤2.5 days and the healing time is ≤3.5 days, which meets market demand.

[0029] 2. The compound oral care composition of this application provides cetylpyridinium chloride with instantaneous and broad-spectrum bactericidal ability, while domiphen not only has long-lasting antibacterial effects but also alters cell membrane permeability, promoting the penetration of cetylpyridinium chloride and sodium azulene sulfonate into deeper tissues, producing synergistic bactericidal and anti-inflammatory effects. Sodium azulene sulfonate has bactericidal, anti-inflammatory, and tissue-regenerating effects, while L-glutamine derivatives provide nutritional support to mucosal cells, promote cell proliferation and differentiation, inhibit the release of inflammatory factors, reduce redness and swelling of ulcer wounds, relieve pain, promote collagen synthesis, promote mucosal repair, reduce pain relief time and healing time, and help shorten the course of the disease. Detailed Implementation

[0030] The present application will be further described in detail below with reference to the embodiments.

[0031] Preparation Example Preparation Example 1 An L-glutamine derivative, prepared by the following method: S1. At a rotation speed of 500 r / min and a temperature of 35℃, 10 g of L-glutamine was added to 200 g of N,N-dimethylformamide, and the mixture was stirred for 5 min. Then, 14.3 g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride was added, and the mixture was stirred for 30 min. Next, 9.2 g of 3-pyridinecarboxamide was added, and the mixture was stirred for 5 h. Then, 33.2 g of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and 19.3 g of N,N-diisopropylethylamine were added, and the mixture was stirred for 5 min. Finally, 10 g of glycine tert-butyl ester was added, and the mixture was stirred for 25 h. The mixture was then concentrated under reduced pressure to 1 / 3 of its original volume to obtain the reaction mixture.

[0032] S2. Adjust the pH of the reaction mixture obtained in step S1 to 6 at a rotation speed of 500 r / min. Add 300 g of water and stir for 10 min. Cool to 3℃ to precipitate a solid, which is then filtered. Wash five times with 100 g of water at 3℃ each time. Then dry at 50℃ to obtain the L-glutamine derivative, with a purity ≥99.8%.

[0033] The acid used to adjust the pH value is hydrochloric acid aqueous solution with a mass concentration of 10%, and the alkali used to adjust the pH value is sodium hydroxide aqueous solution with a mass concentration of 10%.

[0034] Preparation Example 2 An L-glutamine derivative, prepared by the following method: S1. At a rotation speed of 500 r / min and a temperature of 35℃, 10 g of L-glutamine was added to 200 g of N,N-dimethylformamide, and the mixture was stirred for 5 min. Then, 13 g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride was added, and the mixture was stirred for 30 min. Next, 8 g of 3-pyridinecarboxamide was added, and the mixture was stirred for 4 h. Then, 34 g of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and 20 g of N,N-diisopropylethylamine were added, and the mixture was stirred for 5 min. Finally, 11 g of glycine tert-butyl ester was added, and the mixture was stirred for 27 h. The mixture was then concentrated under reduced pressure to 1 / 3 of its original volume to obtain the reaction mixture.

[0035] S2. Adjust the pH of the reaction mixture obtained in step S1 to 6 at a rotation speed of 500 r / min. Add 300 g of water and stir for 10 min. Cool to 3℃ to precipitate a solid, which is then filtered. Wash five times with 100 g of water at 3℃ each time. Then dry at 50℃ to obtain the L-glutamine derivative, with a purity ≥99.8%.

[0036] The acid used to adjust the pH value is hydrochloric acid aqueous solution with a mass concentration of 10%, and the alkali used to adjust the pH value is sodium hydroxide aqueous solution with a mass concentration of 10%.

[0037] Preparation Example 3 An L-glutamine derivative, prepared by the following method: S1. At a rotation speed of 500 r / min and a temperature of 35℃, 10 g of L-glutamine was added to 200 g of N,N-dimethylformamide, and the mixture was stirred for 5 min. Then, 15 g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride was added, and the mixture was stirred for 30 min. Next, 10 g of 3-pyridinecarboxamide was added, and the mixture was stirred for 6 h. Then, 32 g of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and 18 g of N,N-diisopropylethylamine were added, and the mixture was stirred for 5 min. Finally, 9 g of glycine tert-butyl ester was added, and the mixture was stirred for 23 h. The mixture was then concentrated under reduced pressure to 1 / 3 of its original volume to obtain the reaction mixture.

[0038] S2. Adjust the pH of the reaction mixture obtained in step S1 to 6 at a rotation speed of 500 r / min. Add 300 g of water and stir for 10 min. Cool to 3℃ to precipitate a solid, which is then filtered. Wash five times with 100 g of water at 3℃ each time. Then dry at 50℃ to obtain the L-glutamine derivative, with a purity ≥99.8%.

[0039] The acid used to adjust the pH value is hydrochloric acid aqueous solution with a mass concentration of 10%, and the alkali used to adjust the pH value is sodium hydroxide aqueous solution with a mass concentration of 10%.

[0040] Example

[0041] Table 1. Raw material dosage of compound oral care composition (unit: g)

[0042] Example 1 A compound oral care composition, the dosage form of which is an oral spray, and its raw materials and raw material ratios are shown in Table 1.

[0043] The moisturizing stabilizer is selected from glycerin, propylene glycol, and xylitol, with a weight ratio of 5:5:1; the fragrance is selected from menthol; the pH adjuster is selected from sodium citrate; and the L-glutamine derivative is prepared using the method described in Preparation Example 1.

[0044] A method for preparing a compound oral care composition includes the following steps: At a rotation speed of 500 rpm, a moisturizing stabilizer and a fragrance were added to a portion of the water, and the mixture was stirred for 5 minutes. L-glutamine derivative, sodium azulene sulfonate, and domiphen were added, and the mixture was stirred for 10 minutes. Cetylpyridinium chloride was added, and the mixture was stirred for 10 minutes. A pH adjuster was added, and the mixture was stirred for 5 minutes. The remaining water was added, and the mixture was stirred for 3 minutes. The mixture was then filtered through a 0.22 μm microporous membrane for sterilization. Finally, it was filled in a Class 100,000 cleanroom to obtain the compound oral care composition.

[0045] The weight ratio of some water to the remaining water is 4:6.

[0046] Example 2 A compound oral care composition differs from Example 1 in that the raw material ratios of the compound oral care composition are different, and the raw material ratios of the compound oral care composition are shown in Table 1.

[0047] Example 3 A compound oral care composition differs from Example 1 in that the raw material ratios of the compound oral care composition are different, and the raw material ratios of the compound oral care composition are shown in Table 1.

[0048] Example 4 A compound oral care composition differs from Example 1 in that the raw material ratios of the compound oral care composition are different, and the raw material ratios of the compound oral care composition are shown in Table 1.

[0049] Example 5 A compound oral care composition differs from Example 1 in that the raw material ratios of the compound oral care composition are different, and the raw material ratios of the compound oral care composition are shown in Table 1.

[0050] Example 6 A compound oral care composition differs from Example 1 in that the L-glutamine derivative in the raw materials of the compound oral care composition has a different source, and the L-glutamine derivative is prepared by the method of Preparation Example 2.

[0051] Example 7 A compound oral care composition differs from Example 1 in that the L-glutamine derivative in the raw materials of the compound oral care composition has a different source, and the L-glutamine derivative is prepared by the method of Preparation Example 3.

[0052] Example 8 A compound oral care composition, in the form of a mouthwash, is made from the following ingredients: 0.05g cetylpyridinium chloride, 0.3g sodium azulene sulfonate, 5g L-glutamine derivative, 0.01g domiphen, 13g moisturizing stabilizer, 0.5g polysorbate, 0.05g flavoring agent, 1g pH adjuster, and 80.09g water.

[0053] Among them, the moisturizing stabilizer is selected from glycerin and sorbitol, with a weight ratio of glycerin to sorbitol of 10:3; polysorbate is selected from polysorbate 80; the fragrance is selected from peppermint fragrance; the pH adjuster is selected from sodium bicarbonate; and the L-glutamine derivative is prepared by the method of Preparation Example 1.

[0054] A method for preparing a compound oral care composition includes the following steps: At a rotation speed of 500 rpm, a moisturizing stabilizer, polysorbate, and flavoring agent were added to a portion of the water, and the mixture was stirred for 5 minutes. L-glutamine derivative, sodium azulene sulfonate, and domiphen were added, and the mixture was stirred for 10 minutes. Cetylpyridinium chloride was added, and the mixture was stirred for 10 minutes. A pH adjuster was added, and the mixture was stirred for 5 minutes. The remaining water was added, and the mixture was stirred for 3 minutes. The mixture was then filtered through a 0.22 μm microporous membrane for sterilization. Finally, it was filled in a Class 100,000 cleanroom to obtain the compound oral care composition.

[0055] The weight ratio of some water to the remaining water is 4:6.

[0056] Comparative Example Comparative Example 1 A compound oral care composition differs from Example 1 in that, in the raw materials of the compound oral care composition, an equal amount of water is used to replace sodium azulene sulfonate, L-glutamine derivative, and domiphen.

[0057] Comparative Example 2 A compound oral care composition differs from Example 1 in that, in the raw materials of the compound oral care composition, an equal amount of water is used to replace cetylpyridinium chloride, sodium azulene sulfonate, and L-glutamine derivative.

[0058] Comparative Example 3 A compound oral care composition differs from Example 1 in that, in the raw materials of the compound oral care composition, an equal amount of water is used to replace cetirizine chloride, L-glutamine derivative, and domiphen.

[0059] Comparative Example 4 A compound oral care composition differs from Example 1 in that an equal amount of water is used to replace the L-glutamine derivative in the raw materials of the compound oral care composition.

[0060] Comparative Example 5 A compound oral care composition differs from Example 1 in that an equal amount of L-glutamine is used to replace an L-glutamine derivative in the raw materials of the compound oral care composition.

[0061] Comparative Example 6 A compound oral care composition differs from Example 1 in that the source of the L-glutamine derivative in the raw materials of the compound oral care composition is different, and the L-glutamine derivative is prepared by the following method: S1. At a rotation speed of 500 r / min and a temperature of 35℃, 10 g of L-glutamine was added to 200 g of N,N-dimethylformamide, and the mixture was stirred for 5 min. Then, 14.3 g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride was added, and the mixture was stirred for 30 min. Finally, 9.2 g of 3-pyridinecarboxamide was added, and the mixture was stirred for 5 h to obtain the reaction mixture.

[0062] S2. Adjust the pH of the reaction mixture obtained in step S1 to 2 at a rotation speed of 500 r / min. Add 300 g of water and stir for 10 min. Cool to 3°C to precipitate a solid, which is then filtered. Wash three times with 100 g of water at 3°C ​​each time. Finally, dry at 50°C to obtain the L-glutamine derivative.

[0063] The acid used to adjust the pH value is hydrochloric acid aqueous solution with a mass concentration of 10%, and the alkali used to adjust the pH value is sodium hydroxide aqueous solution with a mass concentration of 10%.

[0064] Comparative Example 7 A compound oral care composition differs from Example 1 in that the source of the L-glutamine derivative in the raw materials of the compound oral care composition is different, and the L-glutamine derivative is prepared by the following method: S1. At a rotation speed of 500 r / min and a temperature of 35℃, 10 g of L-glutamine was added to 200 g of N,N-dimethylformamide, and the mixture was stirred for 5 min. Then, 33.2 g of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and 19.3 g of N,N-diisopropylethylamine were added, and the mixture was stirred for 5 min. Finally, 10 g of glycine tert-butyl ester was added, and the mixture was stirred for 25 h. The mixture was then concentrated under reduced pressure to 1 / 3 of its original volume to obtain the reaction mixture.

[0065] S2. Adjust the pH of the reaction mixture obtained in step S1 to 6 at a rotation speed of 500 r / min. Add 300 g of water and stir for 10 min. Cool to 3°C to precipitate a solid, which is then filtered. Wash three times with 100 g of water at 3°C ​​each time. Then dry at 50°C to obtain the L-glutamine derivative.

[0066] The acid used to adjust the pH value is hydrochloric acid aqueous solution with a mass concentration of 10%, and the alkali used to adjust the pH value is sodium hydroxide aqueous solution with a mass concentration of 10%.

[0067] Performance testing (1) The compound oral care compositions obtained in Examples 1-7 were taken as samples, and toxicological safety, microbiological and chemical residue tests were conducted on the compound oral care compositions obtained in Examples 1-7 in accordance with the "Biological Evaluation of Medical Devices" and "Cosmetic Safety Technical Specifications" (2015 edition). After the tests, the compound oral care compositions of Examples 1-7 showed no irritation in the oral mucosa irritation test, no sensitization in the skin sensitization test, no symptoms of poisoning in the acute oral toxicity test, no symptoms of poisoning in the subchronic oral toxicity test, a total bacterial count ≤100 CFU / mL, a total mold and yeast count ≤10 CFU / mL, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Candida albicans were not detected, cadmium, arsenic, and mercury were not detected, the N,N-dimethylformamide content was ≤300 mg / kg, and the ethanol content was ≤0.05 wt%. The compound oral care compositions of Examples 1-7 have good safety.

[0068] (2) The compound oral care compositions obtained in Examples 1-7 and Comparative Examples 1-3 were used as samples, and the logarithmic and effusive killing values ​​of the compound oral care compositions were tested using the Time-Kill method. The test results are shown in Table 2. At the same time, a negative control group was set up. The negative control group used physiological saline.

[0069] In the sterilization test, the bacterial species was Staphylococcus aureus (ATCC25923), and the bacterial count of Staphylococcus aureus in the working bacterial solution used was 4 × 10⁻⁶. 6 CFU / mL, meaning the initial bacterial concentration was 4 × 10⁻⁶. 6 CFU / mL. The volume ratio of the compound oral care composition to the working bacterial solution is 9:1, and the volume ratio of physiological saline to the working bacterial solution is 9:1.

[0070] Kill logarithmic value = lg(initial bacterial concentration) - lg(bacterial concentration after 1 min of action). Kill rate (%) = (initial bacterial concentration - bacterial concentration after 1 min of action) / initial bacterial concentration × 100%.

[0071] (3) The compound oral care compositions obtained in Example 1 and Comparative Examples 4-7 were used as samples, and a rat oral ulcer model was established. The rats were divided into groups, and the pain disappearance time and healing time were measured. The results are shown in Table 2. Simultaneously, a negative control group, a positive control group 1, and a positive control group 2 were established. The negative control group used physiological saline. Positive control group 1 used commercially available compound glutamine granules, dissolved in water, and prepared as a compound glutamine aqueous solution with a glutamine content of 0.1 g / mL. Positive control group 2 used commercially available cetylpyridinium chloride oral spray, with a cetylpyridinium chloride mass concentration of 0.05%.

[0072] In the test of oral ulcer healing time, SPF-grade SD rats weighing 200-250g were used. Ulcers were created in the rats' mouths using a chemical cauterization method, with an area of ​​3-4 mm. A spray was applied directly to the ulcers at a rate of 0.1 mL twice daily.

[0073] The time for pain to subside was defined as the time it took for the rat to resume normal eating, stop licking behavior, and regain weight. The time for healing was defined as the time it took for the ulcer to become completely epithelialized, for there to be no redness or swelling, for the pseudomembrane to slough off, and for the mucosa to return to normal.

[0074] Table 2 Test Results

[0075] As shown in Table 2, the compound oral care composition of this application has a high 1-minute kill log value and 1-minute kill rate, with a 1-minute kill log value > 3 and a 1-minute kill rate ≥ 99.9%, demonstrating a high kill rate. Furthermore, it also exhibits low pain relief time and healing time, with a pain relief time ≤ 2.5 days and a healing time ≤ 3.5 days, demonstrating good pain relief and high ulcer healing promotion effects. In other words, the compound oral care composition of this application, through the synergistic effect of its raw materials, possesses the advantages of highly efficient sterilization and anti-inflammation, rapid promotion of mucosal repair, and pain relief, meeting market demands.

[0076] Comparative Examples 1-3 and Example 1 were compared. The compound oral care composition of Comparative Example 1 contained cetylpyridinium chloride; the compound oral care composition of Comparative Example 2 contained domiphen; the compound oral care composition of Comparative Example 3 contained sodium azulene sulfonate; and the compound oral care composition of Example 1 contained cetylpyridinium chloride, sodium azulene sulfonate, and domiphen. It can be seen that adding cetylpyridinium chloride alone, sodium azulene sulfonate alone, or domiphen alone to the raw materials results in limited bactericidal rates. However, the simultaneous addition of cetylpyridinium chloride, sodium azulene sulfonate, and domiphen can completely kill bacteria within 1 minute. The bactericidal speed is significantly faster than adding cetylpyridinium chloride alone, significantly faster than adding sodium azulene sulfonate alone, and significantly faster than adding domiphen alone. The combination of cetylpyridinium chloride, sodium azulene sulfonate, and domiphen produces a significant synergistic effect, effectively improving the 1-minute bactericidal rate.

[0077] Comparative Examples 4-5 and Example 1 were compared. The compound oral care composition of Comparative Example 4 did not contain L-glutamine or any L-glutamine derivatives; the compound oral care composition of Comparative Example 5 contained L-glutamine; and the compound oral care composition of Example 1 contained an L-glutamine derivative. This shows that both L-glutamine and L-glutamine derivatives can reduce pain relief time and healing time, and have the effects of promoting mucosal repair and relieving pain. However, the effect of L-glutamine is not as good as that of L-glutamine derivatives.

[0078] Comparative Examples 6-7 and Example 1 were compared. Comparative Example 6 featured an L-glutamine derivative grafted with 3-pyridinecarboxamide; Comparative Example 7 featured an L-glutamine derivative grafted with glycine tert-butyl ester; and Example 1 featured an L-glutamine derivative grafted with both 3-pyridinecarboxamide and glycine tert-butyl ester. This demonstrates that, compared to grafting 3-pyridinecarboxamide or glycine tert-butyl ester alone onto L-glutamine, simultaneously grafting both 3-pyridinecarboxamide and glycine tert-butyl ester onto L-glutamine, and utilizing their synergistic effect, can effectively promote epithelial cell proliferation and mucosal barrier repair, further shortening the healing cycle.

[0079] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. A compound oral care composition, characterized in that: Based on the total weight of the compound oral care composition, the raw materials of the compound oral care composition include cetylpyridinium chloride 0.01-0.1%, sodium azulene sulfonate 0.01-2%, L-glutamine derivative 0.1-15%, and domiphen 0.001-0.05%.

2. The compound oral care composition according to claim 1, characterized in that: The ingredients of the compound oral care composition include cetylpyridinium chloride 0.05-0.1%, sodium azulene sulfonate 0.03-0.5%, L-glutamine derivative 0.5-8%, and domiphen 0.003-0.01%.

3. The compound oral care composition according to claim 1, characterized in that: The L-glutamine derivative was prepared using the following method: S1. At a temperature of 30-40℃, N,N-dimethylformamide and L-glutamine are mixed, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride is added, and the mixture is stirred for 20-40 min. Then, 3-pyridineformamide is added, and the mixture is stirred for 4-6 h. Next, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and N,N-diisopropylethylamine are mixed, and glycine tert-butyl ester is added. The mixture is stirred for 23-27 h, and then concentrated under reduced pressure to obtain the reaction mixture. S2. Adjust the pH of the reaction mixture to 6-7, add water and mix, cool to 1-5℃, precipitate solid, filter, wash, dry, and obtain L-glutamine derivative.

4. The compound oral care composition according to claim 3, characterized in that: The weight ratio of L-glutamine, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 3-pyridinecarboxamide, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, N,N-diisopropylethylamine, and glycine tert-butyl ester is 10:(13-15):(8-10):(32-34):(18-20):(9-11).

5. The compound oral care composition according to claim 1, characterized in that: The dosage form of the compound oral care composition is one of the following: mouthwash, oral spray, lozenge, oral patch, oral dissolving film, and gel care solution.

6. The compound oral care composition according to claim 1, characterized in that: The raw materials of the compound oral care composition also include 5-30 wt% of a moisturizing stabilizer, which is selected from one or more of glycerin, propylene glycol, sorbitol, and xylitol.

7. A compound oral care composition according to claim 6, characterized in that: The compound oral care composition is in the form of an oral spray, and its raw materials also include 0.01-3 wt% of flavoring agent, 0.05-1 wt% of pH adjuster, and the balance being water.

8. A method for preparing the compound oral care composition as described in claim 7, characterized in that: Includes the following steps: Mix a portion of water, a moisturizing stabilizer, and a fragrance agent. Add L-glutamine derivative, sodium azulene sulfonate, and domiphen, then add cetirizine chloride and mix. Add a pH adjuster and mix. Add the remaining water and mix. Filter to sterilize, then fill into a container to obtain a compound oral care composition.

9. The use of a compound oral care composition as described in any one of claims 1-6 in the preparation of an oral care product for the prevention and / or treatment of stomatitis, pharyngitis, oral ulcers, periodontitis, and gingivitis.

10. The use of a compound oral care composition as described in any one of claims 1-6 in the preparation of products for preoperative disinfection of oral surgery or for daily oral care.

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