WO2022142383A1 - 一种含透明质酸的口腔用品及其制备方法 - Google Patents

一种含透明质酸的口腔用品及其制备方法 Download PDF

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WO2022142383A1
WO2022142383A1 PCT/CN2021/113404 CN2021113404W WO2022142383A1 WO 2022142383 A1 WO2022142383 A1 WO 2022142383A1 CN 2021113404 W CN2021113404 W CN 2021113404W WO 2022142383 A1 WO2022142383 A1 WO 2022142383A1
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hyaluronic acid
fluoride
oral product
composition
oral
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PCT/CN2021/113404
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English (en)
French (fr)
Inventor
张红
陈凤
张旻
邓全富
舒盈盈
宫敬禹
邓嵘
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重庆登康口腔护理用品股份有限公司
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Publication of WO2022142383A1 publication Critical patent/WO2022142383A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/20—Halogens; Compounds thereof
    • A61K8/21—Fluorides; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/24—Phosphorous; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/59—Mixtures
    • A61K2800/592—Mixtures of compounds complementing their respective functions
    • A61K2800/5922—At least two compounds being classified in the same subclass of A61K8/18

Definitions

  • the invention relates to the technical field of oral products, in particular to a hyaluronic acid-containing oral product and a preparation method thereof.
  • Dental caries is a progressive lesion of the tooth hard tissue caused by a combination of factors in the oral cavity, manifested as demineralization of inorganic matter and decomposition of organic matter.
  • Dental caries is a bacterial disease, so it can be secondary to pulpitis and apical periodontitis, and even cause inflammation of the alveolar and jaw bones.
  • the secondary infection of dental caries can form lesions and cause or add to other systemic diseases such as arthritis, periostitis, chronic kidney disease and various eye diseases.
  • Fluoride is one of the trace elements needed by the human body. Studies have shown that an appropriate amount of fluoride can prevent caries and promote tooth remineralization. The anti-caries mechanism of fluoride is reflected in reducing the solubility of enamel, promoting enamel remineralization, inhibiting bacterial metabolism and plaque formation, and affecting tooth morphology.
  • the present invention is intended to provide a hyaluronic acid-containing oral product and a preparation method thereof, so as to solve the problems of strong astringency and irritation to the oral cavity and poor taste of the oral product when using fluoride to prepare an anti-caries oral product in the prior art.
  • a composition containing hyaluronic acid comprising a hyaluronic acid composition and a fluoride
  • the hyaluronic acid composition comprises small molecule hyaluronic acid, medium molecular Macromolecular hyaluronic acid, or including small molecular hyaluronate, medium molecular hyaluronate and macromolecular hyaluronate.
  • fluoride is widely used in the field of anti-caries, and the principle of fluoride to prevent caries is: 1.
  • Fluoride can form calcium fluoride (CaF 2 ) deposition layer on the surface of tooth enamel.
  • F - in CaF 2 can combine with Ca 2+ and PO 4 - dissolved on the surface of apatite crystal to form fluorohydroxyapatite, which recrystallizes to the surface of apatite in enamel, so that enamel remineralization can occur.
  • fluoride can inhibit bacterial acid production. When the local pH of the oral cavity drops, F - and H - in the oral cavity combine to form hydrofluoric acid (HF), and HF carries H - into the cytoplasm, inhibiting the outward transport of H - from the cell membrane, reducing the pH value in the cytoplasm, and destroying acid-producing bacteria.
  • HF hydrofluoric acid
  • fluoride can inhibit the uptake, transformation and utilization of glucose by Streptococcus mutans, affecting the synthesis of extracellular polysaccharides, the storage of intracellular polysaccharides, and interfere with the accumulation of bacteria and plaque on the tooth surface and adhesion.
  • fluoride a relatively large amount of fluoride ions are released and accumulated near the teeth and periodontal, which has a relatively strong effect on the periodontal tissue and oral mucosa.
  • Hyaluronic acid or a mixture of hyaluronic acid salts the fluoride ions released by fluoride will attach to the hyaluronic acid film, slowly release into the tooth surface through the hyaluronic acid film, and gradually exert its anti-caries and remineralization properties At the same time, it can also avoid the transfer and absorption of fluoride ions by periodontal tissue and oral mucosa, and reduce irritation.
  • the hyaluronic acid in this technical solution is preferably macromolecular hyaluronic acid, medium molecular hyaluronic acid and small molecular hyaluronic acid or macromolecular hyaluronic acid salt, medium molecular hyaluronic acid salt and small molecular hyaluronic acid salt.
  • the mass ratio of the hyaluronic acid composition to the fluoride is 0.05-5:0.01-0.15.
  • the hyaluronic acid composition and the compound can achieve synergistic effect while the respective functions of the hyaluronic acid composition and the compound are exerted, thereby improving the oral cavity.
  • the effects of product taste, caries prevention and remineralization promotion can not only significantly improve the effective rate of treating oral ulcers, but also reduce the recurrence rate.
  • the fluoride is one or more of sodium fluoride, sodium monofluorophosphate, stannous fluoride, and olafluor; in the hyaluronic acid composition, small molecule hyaluronic acid or small Molecular hyaluronate accounts for 30%-40%, medium molecular hyaluronic acid or medium molecular hyaluronate accounts for 30%-50%, and macromolecular hyaluronic acid or macromolecular hyaluronate accounts for 20%-30%.
  • sodium fluoride, sodium monofluorophosphate, stannous fluoride, and olafluoride all have better ability to prevent caries and promote tooth remineralization
  • stannous fluoride is a kind of good effect.
  • stannous ions have a certain bactericidal effect, and they are both effective in preventing caries, but they have a specific bitter and astringent taste, and stannous fluoride has been hydrolyzed and oxidized, so that the effect is weakened and the stability is relatively low. Difference.
  • the oral product is toothpaste, mouthwash, gel, tooth powder or oral spray.
  • the above-mentioned types of oral care products are commonly used products in people's daily life, and the application of the composition of this solution to the above-mentioned products can have a good effect on preventing caries and promoting tooth remineralization. .
  • the oral product includes the following raw materials in parts by mass: hyaluronic acid composition, fluoride, and additives, and the additives are moisturizing agents, adhesives, flavoring agents, surfactants, friction agents, and thickening agents , one or more of stabilizers, preservatives, pH adjusters.
  • the above-mentioned raw materials can be used to prepare oral products with multiple functions of preventing dental caries, promoting tooth mineralization and treating oral ulcers.
  • the oral product is toothpaste
  • the toothpaste includes the following raw materials in parts by mass: hyaluronic acid composition, fluoride, moisturizing agent, adhesive, flavoring agent, surfactant, and friction agent.
  • the above-mentioned raw materials can be used to prepare a toothpaste product with multiple functions, and the properties of each component in the toothpaste are stable, and the toothpaste has a remarkable effect of preventing dental caries and promoting tooth mineralization.
  • the oral product is mouthwash
  • the mouthwash includes the following raw materials by mass: hyaluronic acid composition, fluoride, moisturizing agent, thickening agent, flavoring agent, stabilizer, preservative, pH adjustment agent.
  • the above-mentioned raw materials can be used to prepare a mouthwash product with multiple functions, and the properties of each component in the mouthwash are stable, and the mouthwash has a significant effect on preventing dental caries and promoting tooth mineralization.
  • the fluoride in the toothpaste is sodium monofluorophosphate
  • the fluoride in the mouthwash is stannous fluoride
  • sodium monofluorophosphate has good stability, and also has good stability in toothpaste. After compounding the hyaluronic acid composition, it can slowly and continuously release fluoride ions to play an anti-caries and remineralization effect; Stannous compound has poor stability and needs to be used with stabilizer in the formula. In mouthwash, fluoride ion and stannous ion can be dissociated at the same time, and the anti-caries effect is more prominent.
  • the oral product is toothpaste
  • the preparation method of the oral product comprises the following steps:
  • S1 add a moisturizing agent and a binder, stir to homogenize, add flavoring agent, hyaluronic acid composition, sodium monofluorophosphate, and surfactant again, and stir evenly;
  • the oral product is mouthwash
  • the preparation method of the oral product comprises the following steps:
  • S1 add water, humectant, solubilizer and stir evenly, then add flavoring agent, hyaluronic acid composition, stannous fluoride, tin stabilizer, pH value adjuster and stir evenly, then add preservative and stir evenly;
  • a mouthwash product with multiple functions of preventing dental caries, promoting tooth mineralization and treating oral ulcers can be obtained.
  • S1 through the adsorption and slow release effect of the hyaluronic acid film, the bitterness and astringency of stannous fluoride are better neutralized and the taste is improved; in addition, the formation of the hyaluronic acid film can also affect the Tin plays a better stabilizing role.
  • Example 1 to Example 10 are the preparation examples of the mouthwash of the present invention
  • Comparative Example 1 to Comparative Example 9 are the comparative examples of the preparation of the mouthwash. (unit: g, the total amount of raw materials in each example and comparative example is calculated as 100 g).
  • glycerin is a moisturizing agent
  • sorbitol is a solubilizer
  • sodium saccharin is a flavoring agent
  • poloxamer is a solubilizing agent
  • stannous chloride is a tin stabilizer
  • the essence is peppermint essence
  • the hyaluronic acid composition in the ratio 1-comparative example 3 is the sodium hyaluronate composition, and is the volume ratio mixing of small molecular sodium hyaluronate, medium molecular sodium hyaluronate, macromolecular sodium hyaluronate
  • the sodium hyaluronate composition in comparative example 6 is respectively small molecule sodium hyaluronate, medium molecular sodium hyaluronate and macromolecular sodium hyaluronate
  • the sodium hyaluronate composition in comparative example 7 is small molecule Sodium hyaluronate and medium molecular weight sodium hy
  • the mouthwashes prepared by the above examples and comparative examples were verified by efficacy experiments.
  • the efficacy experiments included the clinical trials of mouthfeel and stability, clinical anti-caries effect, remineralization performance, and oral ulcers. The details are as follows.
  • the mouthwashes of Examples 1-10 and Comparative Examples 1-9 were subjected to sensory evaluation, mainly to evaluate their bitterness; the mouthwashes prepared by each Example and Comparative Example were placed in a high temperature (45°C) environment to observe the stability, and each time Three parallel experiments were set up for each treatment group to observe the stratification of mouthwash after 7 days, 15 days, 1 month, 2 months, and 3 months, respectively. The results are shown in Table 2.
  • Table 2 In this example, by adjusting the addition ratio between the sodium hyaluronate composition and the fluoride, the bitterness of the fluoride can be reduced. Except for Example 3 and Example 6, the stability of the mouthwash can be ensured, so that the Store at high temperature for 3 months without delamination.
  • the mouthwashes prepared in each example and comparative example were clinically tested for preventing permanent tooth caries, with 40 people in each group. All subjects received 3 routine oral examinations and dental caries surface examinations, and recorded. Use a fiber optic mouth mirror with its own light source and a special oral probe. Uniform inspection equipment was used for each inspection; the inspection was fixed by two strictly trained physicians, and a standard consistency test was performed before the inspection, and the Kappa value was 0.85. During each inspection, 10% of the subjects were randomly selected by the organizer for repeated inspection, and the coincidence rate of the two inspections was 93% to 95%. Rinse the mouth with mouthwash once in the morning, noon and in the evening. The control group rinsed with water for 1 min or more each time. After 12 months and 24 months, the patients were reexamined. The caries surface was recorded according to the above method, and the reduction rate of caries was calculated. , statistical analysis was performed, and the results are shown in Table 3.
  • Example 9 By comparing Example 9 and Comparative Examples 4-9, it can be seen that when the sodium hyaluronate composition is compounded by small molecular weight sodium hyaluronate, medium molecular weight sodium hyaluronate, and high molecular weight sodium hyaluronate, the The caries effect is significantly higher than the single molecular weight sodium hyaluronate alone and the combination of two molecular weight sodium hyaluronates.
  • Freshly extracted isolated bovine teeth (within 1 month of extraction time, the crowns are required to be intact without cracks and caries), and the enamel surface was fully cleaned.
  • a low-speed precision cutting machine was used to obtain a flat enamel sheet with a thickness of about 5 mm ⁇ 5 mm and a thickness of about 2 mm.
  • the samples were polished with silicon carbide sandpaper (600 mesh, 1000 mesh, and 2000 mesh in sequence) under the condition of water perfusion using a grinder and polishing machine to form a uniform, flat and smooth surface, and ultrasonically cleaned with deionized water for 3 times, 10 min each time.
  • the bovine tooth samples were etched with 40% orthophosphoric acid for 20 min to remove the blurred layer.
  • the samples were placed on a shaker and shaken back and forth slightly. Then rinsed with deionized water, slightly corroded with 5.0% NaOCl for 5 min, and then ultrasonically cleaned with deionized water for 20 min. After acid etching and demineralization, the enamel slices were observed with a mirror microscope, and the specimens with uniform appearance were selected and soaked in artificial saliva.
  • the microhardness tester selected enamel slices with a microhardness value (KNH) of 150 ⁇ , 3 slices in each group, soaked in mouthwash for 3 minutes in the morning, noon and night, and treated for 7 days.
  • KNH microhardness value
  • One enamel sheet was randomly selected from each group before and after treatment. Under the condition of positive pressure of 50 g (about 50 N) for 15 s, three points were randomly selected to test the surface microhardness value of the glaze sheet and calculate the increase rate before and after.
  • One enamel slice was randomly selected from each group after treatment and after acid etching again, and the surface pores and surface morphology changes of the enamel slice were observed under scanning electron microscope. Each enamel slice was randomly measured in 3 fields of 25 ⁇ m 2 , and the micropore area in the field of view was measured by image analysis software, and the reduction rate was calculated. The results are shown in Table 4.
  • Example 1 30.7 66.4
  • Example 2 35.5 73.5
  • Example 3 39.9 78.2
  • Example 4 33.5 69.8
  • Example 5 39.3 77.1
  • Example 6 41.1 80.6 Example 7 37.6 73.2 Example 8 42.7 80.6 Example 9 46.4 84.9 Example 10 47.6 85.0 Comparative Example 1 1.5 0.9 Comparative Example 2 38.0 76.9 Comparative Example 3 1.7 1.1 Comparative Example 4 39.4 78.1 Comparative Example 5 38.9 78.4 Comparative Example 6 40.1 79.3 Comparative Example 7 41.6 81.1 Comparative Example 8 41.9 81.8 Comparative Example 9 42.4 82.4
  • Example 9 Continuing to increase the amount of the sodium hyaluronate composition on the mass fraction of the sodium hyaluronate composition and stannous fluoride composition in Example 9 has no obvious effect on the increase of the microhardness value and the decrease of the micropore area. Therefore, in this example, the raw material ratio of Example 9 is the best.
  • Example 9 By comparing Example 9 and Comparative Examples 4-9, it can be seen that when the sodium hyaluronate mixture is compounded by small molecular weight sodium hyaluronate, medium molecular weight sodium hyaluronate, and high molecular weight sodium hyaluronate, the raw material is effective for enamel sheets.
  • the remineralization effect is significantly higher than the single molecular weight sodium hyaluronate alone and the combination of two molecular weight sodium hyaluronates.
  • the mouthwashes prepared in each example and the comparative example were clinically tested for the treatment of oral ulcers, with 33 persons in each group. All subjects underwent routine oral examination, and subjects had one or more shallow ulcers of 2-15mm in diameter, round or oval, with neat margins and a slightly concave surface, and recorded. Evaluation criteria: cured—the ulcer was completely healed, and the pain disappeared; improved—the ulcer surface was reduced or the ulcer was reduced, and the pain was relieved; ineffective—the ulcer was not healed, and the pain existed. Both cure and improvement were effective, and all tests were performed by the same investigator.
  • the control group rinsed their mouths with water.
  • Example 1-10 and Comparative Example 1-3 gargle with mouthwash once in the morning, in the middle and in the evening, each time for 1 min or more, check again after 3 days, and record according to the above evaluation criteria, the results are shown in Table 5 (average number).
  • the sodium hyaluronate composition is compounded with stannous fluoride, and it can be considered that the sodium hyaluronate composition can reduce the irritation of stannous fluoride to the oral mucosa.
  • Example 9 By comparing Example 9 and Comparative Examples 4-9, it can be seen that when the sodium hyaluronate mixture is compounded by small molecular weight sodium hyaluronate, medium molecular weight sodium hyaluronate, and high molecular weight sodium hyaluronate, the The effects of ulceration and recurrence prevention are significantly higher than those of single molecular weight sodium hyaluronate alone and the combination of two molecular weight sodium hyaluronates.
  • Embodiment 11-Embodiment 13 is the preparation example of toothpaste of the present invention
  • comparative example 1-comparative example 9 is the comparative example of toothpaste preparation, in each embodiment and comparative example, raw material kind and addition amount are as shown in table 6 (unit: g, the total amount of raw materials in each example and comparative example is based on 100 g).
  • sodium hyaluronate compositions in Example 11-Example 13 and Comparative Example 1-Comparative Example 3 are sodium hyaluronate compositions, and are small molecular sodium hyaluronate, medium molecular sodium hyaluronate, and macromolecular transparent Sodium hyaluronate is mixed in equal volume ratio; the sodium hyaluronate composition in comparative example 4-comparative example 6 is respectively small molecular sodium hyaluronate, medium molecular sodium hyaluronate and macromolecular sodium hyaluronate; in comparative example 7 The composition of sodium hyaluronate is mixed with equal
  • S1 glycerin and cellulose gum are stirred and homogenized, and then 48g sorbitol, 0.5g sodium saccharin, 0.01g sodium hyaluronate composition (small molecular sodium hyaluronate, medium molecular sodium hyaluronate, macromolecular hyaluronic acid) are added. Sodium equal volume mixing), 1.1g sodium monofluorophosphate, 1.5g sodium 120,000 base sulfate, and uniformly stir to obtain system I;
  • the toothpastes prepared in each example and the comparative example were clinically tested for the prevention of permanent tooth caries, with 40 people in each group. All subjects received 3 routine oral examinations and dental caries surface examinations, and recorded. Use a fiber optic mouth mirror with its own light source and a special oral probe to check. Uniform inspection equipment was used for each inspection; the inspection was fixed by two strictly trained physicians, and a standard consistency test was performed before the inspection, and the Kappa value was 0.85. During each inspection, 10% of the subjects were randomly selected by the organizer for repeated inspection, and the coincidence rate of the two inspections was 93% to 95%.
  • Comparative example 1 was used as a control group, and as a toothpaste without sodium monofluorophosphate and sodium hyaluronate, subjects brushed their teeth with the toothpaste made in the example and the comparative example, once in the morning, in the middle and in the evening, and brushed their teeth each time 3min, 12 months, 24 months later, the caries surface was recorded according to the above method, the caries reduction rate was calculated, and statistical analysis was performed. The results are shown in Table 7.
  • Example 13 By comparing Example 13 and Comparative Examples 1-9, it can be seen that when the sodium hyaluronate composition is compounded by small molecular weight sodium hyaluronate, medium molecular weight sodium hyaluronate, and high molecular weight sodium hyaluronate, the The caries effect is higher than the single molecular weight sodium hyaluronate alone and the combination of two molecular weight sodium hyaluronates.
  • Freshly extracted isolated bovine teeth (within 1 month of extraction time, the crowns are required to be intact without cracks and caries), and the enamel surface was fully cleaned.
  • a low-speed precision cutting machine was used to obtain a flat enamel sheet with a thickness of about 5 mm ⁇ 5 mm and a thickness of about 2 mm.
  • the samples were polished with silicon carbide sandpaper (600 mesh, 1000 mesh, and 2000 mesh in sequence) under the condition of water perfusion using a grinder and polishing machine to form a uniform, flat and smooth surface, and ultrasonically cleaned with deionized water for 3 times, 10 min each time.
  • the bovine tooth samples were etched with 40% orthophosphoric acid for 20 min to remove the blurred layer.
  • the samples were placed on a shaker and shaken back and forth slightly. After that, rinse with deionized water, lightly corrode with 5.0% NaOCl for 5 min, and then ultrasonically clean with deionized water for 20 min. After acid etching and demineralization, the enamel slices were observed with a mirror microscope, and the specimens with uniform appearance were selected and soaked in artificial saliva.
  • the microhardness tester selects enamel slices with a microhardness value (KNH) of 150 ⁇ , 3 slices for each group, soaked in toothpaste solution for 3 minutes in the morning, middle and evening, and treated for 7 days.
  • KNH microhardness value
  • One enamel sheet was randomly selected from each group before and after treatment. Under the condition of positive pressure of 50 g (about 50 N) for 15 s, three points were randomly selected to test the surface microhardness value of the glaze sheet and calculate the increase rate before and after.
  • One enamel slice was randomly selected from each group after treatment and after acid etching again, and the surface pores and surface morphology changes of the enamel slice were observed under scanning electron microscope. Each enamel slice was randomly measured in 3 fields of 25 ⁇ m 2 , and the micropore area in the field of view was measured by image analysis software, and the reduction rate was calculated. The results are shown in Table 8.
  • the sodium hyaluronate composition is compounded with sodium monofluorophosphate, and with the increase of the dosage of the sodium hyaluronate composition, it has a good synergistic effect on the increase of the microhardness value and the reduction of the micropore area.
  • Example 13 By comparing Example 13 and Comparative Examples 1-9, it can be seen that when the sodium hyaluronate composition is composed of small molecular weight sodium hyaluronate, medium molecular weight sodium hyaluronate, and high molecular weight sodium hyaluronate, the The remineralization effect of the flakes is significantly higher than the single molecular weight sodium hyaluronate alone and the combination of two molecular weight sodium hyaluronates.
  • the toothpastes prepared from each example and the comparative example were clinically tested for the treatment of oral ulcers, with 35 people in each group. All subjects underwent routine oral examination, and subjects had one or more shallow ulcers of 2-15mm in diameter, round or oval, with neat margins and a slightly concave surface, and recorded.
  • Comparative example 1 was used as a control group, and as a toothpaste without sodium monofluorophosphate and sodium hyaluronate, the subjects brushed their teeth with the toothpaste made in the example and the comparative example, once in the morning, in the middle and in the evening, and brushed their teeth each time 3min, recheck after 3 days, record according to the above evaluation criteria, the results are shown in Table 9 (average).
  • the sodium hyaluronate composition is compounded with sodium monofluorophosphate, and it can be considered that the sodium hyaluronate composition can reduce the irritation of sodium monofluorophosphate to oral mucosa.
  • Example 13 In addition, by comparing Example 13 and Comparative Examples 1-9, it can be seen that when the sodium hyaluronate composition is compounded by small molecular weight sodium hyaluronate, medium molecular weight sodium hyaluronate, and high molecular weight sodium hyaluronate, the The effects of oral ulcers and recurrence prevention are significantly higher than those of single molecular weight sodium hyaluronate alone and the combination of two molecular weight sodium hyaluronates.
  • Example 13 is obviously better than Example 11 in the healing effect of oral ulcers, so it is selected to implement The raw material ratio of Example 13 is the best.
  • the hyaluronic acid composition in this embodiment is described by taking the sodium hyaluronate composition as an example, and can be replaced with hyaluronic acid compositions of different molecular weights or other hyaluronic acid salts in practical application.

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Abstract

本发明涉及口腔用品技术领域，公开了一种含透明质酸的口腔用品及其制备方法，其中一种含透明质酸的组合物，包括透明质酸组合物和氟化物，透明质酸组合物包括小分子透明质酸、中分子透明质酸和大分子透明质酸，或包括小分子透明质酸盐、中分子透明质酸盐和大分子透明质酸盐；制备而成的口腔用品为牙膏、漱口水、凝胶、牙粉或口腔喷雾。本发明中氟化物释放的氟离子会附着在透明质酸薄膜上，透过透明质酸薄膜缓释到牙齿表面中，并逐步发挥其防龋和再矿化作用，延长其作用时间和增强作用效果；同时，可避免牙周组织、口腔黏膜对氟离子的转移和吸收，降低刺激性。

Description

一种含透明质酸的口腔用品及其制备方法 技术领域
本发明涉及口腔用品技术领域，具体涉及一种含透明质酸的口腔用品及其制备方法。
背景技术
龋齿是一种由口腔中多种因素复合如作用所导致的牙齿硬组织进行性病损，表现为无机质脱矿和有机质分解，随病程发展而从色泽改变到形成实质性病损的演变过程。龋齿是细菌性疾病，因此它可以继发牙髓炎和根尖周炎，甚至能引起牙槽骨和颌骨炎症。龋齿的继发感染可以形成病灶，致成或加得关节炎、心骨膜炎、慢性肾为和多种眼病等全身其他疾病，因此防龋齿越来越受到人们的重视。
氟是人体所需的微量元素之一，研究表明适量的氟可预防龋病，促进牙齿再矿化。氟化物的防龋机制体现在降低釉质溶解度，促进釉质再矿化，抑制细菌代谢和菌斑形成，影响牙体形态等方面。但是利用氟化物制备防龋口腔用品时发现，过量的氟可引起成釉细胞内钙超载，诱导成釉细胞凋亡，对口腔黏膜有一定的收敛刺激作用；相对较为大量的氟离子释放会聚集在牙齿及牙周附近，对牙周组织及口腔黏膜产生较为强烈的作用。若长期多次地使用上述口腔护理用品，对牙周组织及口腔黏膜易造成一定的损伤，且氟化物制备而成的口腔用品口感也较差。
发明内容
本发明意在提供一种含透明质酸的口腔用品及其制备方法，以解决现有技术中利用氟化物制备防龋齿口腔用品时存在的口腔用品对口腔收敛刺激性强、口感差的问题。
为达到上述目的，本发明采用如下技术方案：一种含透明质酸的组合物，包括透明质酸组合物和氟化物，透明质酸组合物包括小分子透明质酸、中分子透明质酸和大分子透明质酸，或包括小分子透明质酸盐、中分子透明质酸盐和大分子透明质酸盐。
本方案的原理及优点是：氟化物在防龋领域内广泛应用，氟化物防龋的原理为：1、首先抑制牙釉质溶解度：龋齿的形成的一个重要因素是牙斑菌，在进食的过程中牙斑菌和食物中的糖分和淀粉充分接触并发生化学反应，这些化学反应会释放出有机酸，这些有机酸能 够长时间地跟牙齿表面密切接触，使得羟基磷灰石溶解。2、促进牙釉质再矿化：氟化物可在牙釉质表面形成氟化钙(CaF 2)沉积层。CaF 2中的F －可与磷灰石晶体表面溶解的Ca 2+和PO 4-结合为氟羟基磷灰石，再结晶到釉质中的磷灰石表面，使得牙釉质再矿化得以发生。3、抑制细菌代谢和菌斑形成：首先，氟化物可以抑制细菌产酸。在口腔局部pH下降时，口腔中的F -与H -结合成氢氟酸(HF)，HF携带H -进入细胞质，抑制细胞膜向外转运H -，降低细胞质内的pH值，破坏产酸菌细胞酶发挥活性的环境；其次，氟化物可以抑制变异链球菌等对葡萄糖的摄取、转化和利用，影响胞外多糖的合成、胞内多糖的储存，干扰细菌和菌斑在牙面上的堆积和黏附。氟化物在使用时，相对较为大量的氟离子释放聚集在牙齿及牙周附近，对牙周组织及口腔黏膜产生较为强烈的作用，本技术方案中，引入了透明质酸组合物(为不同分子量的透明质酸或透明质酸盐的混合物)，氟化物释放的氟离子会附着在透明质酸薄膜上，透过透明质酸薄膜缓释到牙齿表面中，并逐步发挥其防龋和再矿化作用，延长其作用时间和增强作用效果；同时，亦可避免牙周组织、口腔黏膜对氟离子的转移和吸收，降低刺激性。此外，本技术方案中的透明质酸优选为大分子透明质酸、中分子透明质酸及小分子透明质酸或大分子透明质酸盐、中分子透明质酸盐及小分子透明质酸盐混合而成的混合物，经过试验验证，相较于单独使用其中一种或两者分子量的透明质酸或透明质酸盐而言，防龋齿及再矿化的效果显著增强，具有突出的协同加强效果。
优选的，作为一种改进，透明质酸组合物与氟化物(以氟计)的质量比为0.05-5:0.01-0.15。
本技术方案中，通过对透明质酸组合物及氟化物之间添加比例的优化，可以使得在透明质酸组合物以及复合物各自发挥功效的同时，达到协同增效的作用，起到改善口腔用品口感、防龋齿及促进再矿化的作用，不仅能够显著提高治疗口腔溃疡的有效率，而且还可降低复发率。
优选的，作为一种改进，氟化物为氟化钠、单氟磷酸钠、氟化亚锡、奥拉氟中的一种或多种；透明质酸组合物中，小分子透明质酸或小分子透明质酸盐占30％-40％，中分子透明质酸或中分子透明质酸盐占30％-50％，大分子透明质酸或大分子透明质酸盐占20％-30％。
本技术方案中，氟化钠、单氟磷酸钠、氟化亚锡、奥拉氟均具有较好的预防龋病，促进牙齿再矿化的能力，其中氟化亚锡是一种效果很好的氟剂，除了含氟以外，亚锡离子还有一 定的杀菌功效，防龋方面双管齐下，但其有特定的苦涩味，且氟化亚锡已水解及氧化，从而使作用减弱，稳定性较差。本技术方案研究发现，通过透明质酸薄膜的吸附缓释作用，对氟化亚锡的苦涩味亦有较好的中和作用，使口感得到改善；实验中，发明人还发现透明质酸薄膜的形成还可对氟化亚锡起到较好的稳定作用。
优选的，作为一种改进，口腔用品为牙膏、漱口水、凝胶、牙粉或口腔喷雾。
本技术方案中，上述类型的口腔护理用品为人们日常生活中常用到的产品，将本方案的组合物应用到上述产品中，可以对预防龋病，促进牙齿再矿化起到很好的效果。
优选的，作为一种改进，口腔用品包括如下质量份的原料：透明质酸组合物、氟化物、添加剂，添加剂为保湿剂、粘合剂、调味剂、表面活性剂、摩擦剂、增稠剂、稳定剂、防腐剂、pH调节剂中的一种或多种。
本技术方案中，采用上述原料可以制备而成兼具预防龋齿及促进牙齿矿化、治疗口腔溃疡的多功效的口腔用品。
优选的，作为一种改进，口腔用品为牙膏，牙膏包括如下质量份的原料：透明质酸组合物、氟化物、保湿剂、粘合剂、调味剂、表面活性剂、摩擦剂。
本技术方案中，采用上述原料可以制备获得具有多重功效的牙膏产品，且牙膏中各成分性质稳定，经检测牙膏预防龋齿及促进牙齿矿化效果显著。
优选的，作为一种改进，口腔用品为漱口水，漱口水包括如下质量份的原料：透明质酸组合物、氟化物、保湿剂、增稠剂、调味剂、稳定剂、防腐剂、pH调节剂。
本技术方案中，采用上述原料可以制备获得具有多重功效的漱口水产品，且漱口水中各成分性质稳定，经检测该漱口水预防龋齿及促进牙齿矿化效果显著。
优选的，作为一种改进，牙膏中的氟化物为单氟磷酸钠，漱口水中的氟化物为氟化亚锡。
本技术方案中，单氟磷酸钠稳定性较好，在牙膏中亦具有较好的稳定性，复配透明质酸组合物后能缓慢持续释放出氟离子发挥防龋及再矿化作用；氟化亚锡稳定性较差，配方中需搭配稳定剂使用，在漱口水中可同时解离出氟离子及亚锡离子，防龋效果更为突出。
优选的，作为一种改进，口腔用品为牙膏，口腔用品的制备方法，包括如下步骤：
S1：加入保湿剂、粘合剂，搅拌均质，再一次加入调味剂、透明质酸组合物、单氟磷酸钠、表面活性剂，搅拌均匀；
S2：加入摩擦剂后抽真空，搅拌均匀；
S3：加入香精，搅拌均质后脱气，牙膏制备完成。
本采用上述制备方法，可以获得具有兼具预防龋齿及促进牙齿矿化、治疗口腔溃疡的多功效的牙膏产品，在S1中透明质酸组合物与单氟磷酸钠协同加强效果显著。
优选的，作为一种改进，口腔用品为漱口水，口腔用品的制备方法，包括如下步骤：
S1：加入水、保湿剂、增溶剂搅拌均匀，再加入调味剂、透明质酸组合物、氟化亚锡、锡稳定剂、pH值调节剂搅拌均匀，再加入防腐剂搅拌均匀；
S2：加入香精搅拌均匀，漱口水制备完成。
本技术方案中，可以获得具有兼具预防龋齿及促进牙齿矿化、治疗口腔溃疡的多功效的漱口水产品。在S1中，通过透明质酸薄膜的吸附缓释作用，对氟化亚锡的苦涩味有较好的中和作用，使口感得到改善；此外，透明质酸薄膜的形成还可对氟化亚锡起到较好的稳定作用。
具体实施方式
下面通过具体实施方式进一步详细说明：
实施例1-实施例10为本发明漱口水的制备实施例，对比例1-对比例9为漱口水制备的对比例，各实施例及对比例中的原料种类及添加量如表1所示(单位：g，每个实施例及对比例的原料总量按100g计)。其中，甘油为保湿剂，山梨醇为增溶剂，糖精钠为调味剂，泊洛沙姆为增溶剂，氯化亚锡为锡稳定剂，香精为薄荷香精；实施例1-实施例10以及对比例1-对比例3中的透明质酸组合物为透明质酸钠组合物，且为小分子透明质酸钠、中分子透明质酸钠、大分子透明质酸钠等体积比混合；对比例4-对比例6中的透明质酸钠组合物分别为小分子透明质酸钠、中分子透明质酸钠和大分子透明质酸钠；对比例7中的透明质酸钠组合物为小分子透明质酸钠与中分子透明质酸钠等体积比混合；对比例8中的透明质酸钠组合物为小分子透明质酸钠与大分子透明质酸钠等体积比混合；对比例9中的透明质酸钠组合物为中分子透明质酸钠与大分子透明质酸钠等体积比混合。
表1
Figure PCTCN2021113404-appb-000001
Figure PCTCN2021113404-appb-000002
以实施例1为例详细叙述漱口水的制备方法，包括如下步骤：
S1：将水、甘油5g、山梨醇13g、泊洛沙姆1.2g搅拌均匀，再加入糖精钠0.5g、透明质酸钠组合物(本实施例中的透明质酸钠组合物为小分子量透明质酸钠、中分子量透明质酸钠、大分子量透明质酸钠等体积比混合而成)0.01g、氟化亚锡0.11g、氯化亚锡0.5g混合均匀，加入羟苯甲酯0.1g搅拌均匀成水相；
S2：再加入薄荷香精0.5g混合均匀，搅拌过程中慢慢加入水相，过滤分装，漱口水制备完成。
对上述各实施例及对比例制备而成的漱口水进行功效性实验验证，功效性实验包括口感及稳定性、临床防龋效果、再矿化性能、口腔溃疡的临床试验，详细如下。
实验一：1、口感及稳定性考察
对实施例1-10及对比例1-9的漱口水进行感官评价，主要评价其苦味；将各个实施例及对比例制备而成的漱口水放置于高温(45℃)环境观察稳定性，每个处理组设置三个平行试验，分别观察7天、15天、1个月、2个月、3个月后的漱口水的分层情况，结果如表2所示。本实施例中，通过对透明质酸钠组合物与氟化物之间添加比例的调整，可降低氟化物的苦味，除实施例3、实施例6外，能够保证漱口水的稳定性，使其在高温下存储3个月不分层。
表2
Figure PCTCN2021113404-appb-000003
实验二：临床防龋效果
对各实施例及对比例制备而成的漱口水进行预防恒牙龋的临床测试，每组40人。所有受试者均接受3次常规口腔检查和牙齿龋面检查，并记录。使用自带光源的光纤口镜和口腔 专用探针检查。每次检查都使用统一的检查器械；固定由两名经过严格培训好医师进行检查，检查前做标准一致性试验，Kappa值为0.85。在每次检查过程中，由组织者安排随机抽出10％的受试者作重复检查，两次检查的符合率为93％～95％。用漱口水漱口早、中、晚各一次，对照组用清水漱口，每次保持在1min及以上，12个月、24个月后复查，按照上述方法记录龋面，计算龋病减少率，进行统计学分析，结果如表3所示。
表3
Figure PCTCN2021113404-appb-000004
由表3可知，从实施例1-9可以发现，增加氟化亚锡用量，防龋效果明显提升，氟化亚锡到0.41份后防龋效果到最佳。随着透明质酸钠组合物用量的增加，防龋效果有较大程度提升，可见透明质酸钠组合物复配氟化亚锡在防龋效果方面有较好的增效作用。
在实施例9的透明质酸钠组合物、氟化亚锡质量份数上继续增加透明质酸钠组合物的量， 其防龋效果变化不再显著增加。因此，综合成本考虑，本实施例中，实施例9的原料配比最佳。
通过比较实施例9及对比例4-9，可知透明质酸钠组合物由小分子量透明质酸钠、中分子量透明质酸钠、大分子量透明质酸钠复配而成时，该原料的防龋效果显著高于单独使用单一分子量的透明质酸钠以及使用其中两种分子量的透明质酸钠的组合。
实验三：再矿化性能测试
选取新鲜拔除的离体牛牙(拔牙时间在1个月内，要求牙冠完整无裂纹、无龋坏)，充分清洁釉质表面。用低速精密切割机处理得到约为5mm×5mm，厚度控制在2mm左右的平坦釉质片。样本使用磨抛机在水灌注情况下使用碳化硅砂纸(依次使用600目、1000目、2000目)抛光形成均一、平整、光滑的表面，去离子水超声波清洗3次，每次10min。用40％的正磷酸腐蚀牛牙样本20min去除模糊层，腐蚀过程中将样本置于摇床进行轻微来回震荡。后用去离子水冲洗，用5.0％NaOCl轻度腐蚀5min，再用去离子水超声清洗20min。釉质片酸蚀脱矿后用镜相显微镜观察，挑选出外观均一的标本片浸泡于人工唾液中。显微硬度测量仪选取显微硬度值(KNH)为150±的釉质片，每组选用3片，早、中、晚各用漱口水泡3min，处理7天。
各组在处理前后随机选取1个釉质片，在正压力50g(约50N)持续时间15s的条件下，随机选择3个点，测试釉片表面显微硬度值并计算前后增加率。各组在处理后和再次酸蚀处理后均随机选取1个釉质片，用扫描电镜下观察釉质片表面孔隙及表面形态变化情况。每个釉质片随机测量25μm 2视野3个，用图像分析软件测定视野内微孔隙面积，计算减少率，结果如表4所示。
表4
组别 KNH增加率(％) 微孔隙面积减少率(％)
实施例1 30.7 66.4
实施例2 35.5 73.5
实施例3 39.9 78.2
实施例4 33.5 69.8
实施例5 39.3 77.1
实施例6 41.1 80.6
实施例7 37.6 73.2
实施例8 42.7 80.6
实施例9 46.4 84.9
实施例10 47.6 85.0
对比例1 1.5 0.9
对比例2 38.0 76.9
对比例3 1.7 1.1
对比例4 39.4 78.1
对比例5 38.9 78.4
对比例6 40.1 79.3
对比例7 41.6 81.1
对比例8 41.9 81.8
对比例9 42.4 82.4
从实施例1-9可以发现，氟化亚锡增加，显微硬度值明显增加，微孔隙面积显著减少，氟化亚锡到0.22份达到最佳。透明质酸钠组合物复配氟化亚锡，随着透明质酸钠组合物用量的增加，对显微硬度值增加及微孔隙面积减少均有较好的增效作用。
在实施例9的透明质酸钠组合物、氟化亚锡质量份数上继续增加透明质酸钠组合物的量，对显微硬度值增加及微孔隙面积减少没有明显影响。因此，本实施例中，实施例9的原料配比最佳。
通过比较实施例9及对比例4-9，可知透明质酸钠混合物由小分子量透明质酸钠、中分子量透明质酸钠、大分子量透明质酸钠复配而成时，该原料对釉质片再矿化效果显著高于单独使用单一分子量的透明质酸钠以及使用其中两种分子量的透明质酸钠的组合。
实验四：口腔溃疡的临床试验
对各实施例及对比例制备而成的漱口水进行治疗口腔溃疡方面的临床测试，每组33人。所有受试者均接受常规口腔检查，受试者有一个或多个2-15mm的圆形或椭圆形，边缘整齐，表面微凹的浅溃疡，并记录。评价标准：治愈——溃疡完全治愈，疼痛消失；好转——溃疡面减小或溃疡减少，疼痛减轻；无效——溃疡未愈合，疼痛存在。治愈和好转均为有效，所 有检测均由同一名研究者进行。对照组用清水漱口。实施例1-10和对比例1-3用漱口水漱口早、中、晚各一次，每次保持在1min及以上，3天后复查，按照上述评价标准记录，结果如表5所示(平均数)。
表5
组别 有效率(％) 3个月后复发率(％)
对照组 23.5 28.9
实施例1 39.8 16.5
实施例2 40.1 15.6
实施例3 40.7 15.2
实施例4 75.6 8.8
实施例5 77.1 9.4
实施例6 76.4 10.6
实施例7 83.1 5.4
实施例8 84.7 5.0
实施例9 85.2 5.6
实施例10 87.1 4.1
对比例1 30.4 20.6
对比例2 22.6 26.1
对比例3 85.5 5.2
对比例4 72.8 11.3
对比例5 73.4 10.7
对比例6 73.9 9.9
对比例7 78.3 7.6
对比例8 78.9 8.1
对比例9 78.6 7.1
由上表可知，从实施例1-9可以发现，增加透明质酸钠组合物用量，有效率明显提升，透明质酸钠到0.2份后有效率到最佳。透明质酸钠组合物复配氟化亚锡，随着氟化亚锡用量的增加，对缓解口腔溃疡方面没有显著影响。
通过对比例2与对照组比较还发现，当配方中有氟化亚锡，没有透明质酸钠组合物时，有效率降低，复发率升高。由此，透明质酸钠组合物复配氟化亚锡，可认为透明质酸钠组合物可降低氟化亚锡对口腔黏膜的刺激性。
此外，通过比较实施例9及对比例4-9，可知透明质酸钠混合物由小分子量透明质酸钠、中分子量透明质酸钠、大分子量透明质酸钠复配而成时，对缓解口腔溃疡及防止复发效果显著高于单独使用单一分子量的透明质酸钠以及使用其中两种分子量的透明质酸钠的组合。
实施例11-实施例13为本发明牙膏的制备实施例，对比例1-对比例9为牙膏制备的对比例，各实施例及对比例中原料种类及添加量如表6所示(单位：g，每个实施例及对比例的原料总量按100g计)。其中，二氧化硅为摩擦剂，甘油为保湿剂，山梨醇为增溶剂，糖精钠为调味剂，纤维素胶为粘合剂，十二万基硫酸钠为表面活性剂，香精为薄荷香精，实施例11-实施例13以及对比例1-对比例3中的透明质酸钠组合物为透明质酸钠组合物，且为小分子透明质酸钠、中分子透明质酸钠、大分子透明质酸钠等体积比混合；对比例4-对比例6中的透明质酸钠组合物分别为小分子透明质酸钠、中分子透明质酸钠和大分子透明质酸钠；对比例7中的透明质酸钠组合物为小分子透明质酸钠与中分子透明质酸钠等体积比混合；对比例8中的透明质酸钠组合物为小分子透明质酸钠与大分子透明质酸钠等体积比混合；对比例9中的透明质酸钠组合物为中分子透明质酸钠与大分子透明质酸钠等体积比混合。
表6
Figure PCTCN2021113404-appb-000005
Figure PCTCN2021113404-appb-000006
以实施例11为例叙述牙膏的制备方法，包括如下步骤：
S1：甘油和纤维素胶搅拌均质，再加入48g山梨醇、0.5g糖精钠、0.01g透明质酸钠组合物(小分子透明质酸钠、中分子透明质酸钠、大分子透明质酸钠等体积混合)、1.1g单氟磷酸钠、1.5g十二万基硫酸钠，并均匀搅拌，得体系Ⅰ；
S2：在体系Ⅰ中加入23g二氧化硅后抽真空，搅拌均匀，得体系Ⅱ；
S3：在体系Ⅱ中加入1g薄荷香精，搅拌均质并脱气，得牙膏。
实验一：临床防龋效果
对各实施例及对比例制备而成的牙膏进行预防恒牙龋的临床测试，每组40人。所有受试者均接受3次常规口腔检查和牙齿龋面检查，并记录。使用自带光源的光纤口镜和口腔专用探针检查。每次检查都使用统一的检查器械；固定由两名经过严格培训好医师进行检查，检查前做标准一致性试验，Kappa值为0.85。在每次检查过程中，由组织者安排随机抽出10％的受试者作重复检查，两次检查的符合率为93％～95％。将对比例1作为对照组，作为不添加单氟磷酸钠和透明质酸钠的牙膏，受试者用实施例和对比例制作而成的牙膏刷牙，早、中、 晚各一次，每次刷牙3min，12个月、24个月后复查，按照上述方法记录龋面，计算龋病减少率，进行统计学分析，结果如表7所示。
表7
Figure PCTCN2021113404-appb-000007
由表7可知，从实施例11-13可以发现，增加单氟磷酸钠用量，防龋效果明显提升。从实施例11-13和对比例1-9可以看出，增加透明质酸钠添加量，牙膏防龋效果有较大提升，说明透明质酸钠组合物复配单氟磷酸钠在防龋效果方面有较好的增效作用。
通过比较实施例13及对比例1-9，可知透明质酸钠组合物由小分子量透明质酸钠、中分子量透明质酸钠、大分子量透明质酸钠复配而成时，该原料的防龋效果高于单独使用单一分子量的透明质酸钠以及使用其中两种分子量的透明质酸钠的组合。
实验二：再矿化性能测试
选取新鲜拔除的离体牛牙(拔牙时间在1个月内，要求牙冠完整无裂纹、无龋坏)，充分清洁釉质表面。用低速精密切割机处理得到约为5mm×5mm，厚度控制在2mm左右的平坦釉质片。样本使用磨抛机在水灌注情况下使用碳化硅砂纸(依次使用600目、1000目、2000目)抛光形成均一、平整、光滑的表面，去离子水超声波清洗3次，每次10min。用40％的正磷酸腐蚀牛牙样本20min去除模糊层，腐蚀过程中将样本置于摇床进行轻微来回震荡。后 用去离子水冲洗，用5.0％NaOCl轻度腐蚀5min，再用去离子水超声清洗20min。釉质片酸蚀脱矿后用镜相显微镜观察，挑选出外观均一的标本片浸泡于人工唾液中。显微硬度测量仪选取显微硬度值(KNH)为150±的釉质片，每组选用3片，早、中、晚各用牙膏溶液泡3min，处理7天。
各组在处理前后随机选取1个釉质片，在正压力50g(约50N)持续时间15s的条件下，随机选择3个点，测试釉片表面显微硬度值并计算前后增加率。各组在处理后和再次酸蚀处理后均随机选取1个釉质片，用扫描电镜下观察釉质片表面孔隙及表面形态变化情况。每个釉质片随机测量25μm 2视野3个，用图像分析软件测定视野内微孔隙面积，计算减少率，结果如表8所示。
表8
组别 KNH增加率(％) 微孔隙面积减少率(％)
实施例11 44.7 82.6
实施例12 30.6 67.8
实施例13 43.9 81.8
对比例1 5.9 7.5
对比例2 18.2 47.1
对比例3 28.7 60.6
对比例4 32.3 65.7
对比例5 32.9 66.5
对比例6 33.3 67.5
对比例7 38.8 72.4
对比例8 39.2 73.4
对比例9 39.6 73.7
从实施例11-13可以发现，单氟磷酸钠增加，显微硬度值明显增加，微孔隙面积显著减少。透明质酸钠组合物复配单氟磷酸钠，随着透明质酸钠组合物用量的增加，对显微硬度值增加及微孔隙面积减少均有较好的增效作用。
通过比较实施例13及对比例1-9，可知透明质酸钠组合物由小分子量透明质酸钠、中分 子量透明质酸钠、大分子量透明质酸钠复配而成时，该原料对釉质片再矿化效果显著高于单独使用单一分子量的透明质酸钠以及使用其中两种分子量的透明质酸钠的组合。
实验三：口腔溃疡的临床试验
对各实施例及对比例制备而成的牙膏进行治疗口腔溃疡方面的临床测试，每组35人。所有受试者均接受常规口腔检查，受试者有一个或多个2-15mm的圆形或椭圆形，边缘整齐，表面微凹的浅溃疡，并记录。
评价标准：治愈——溃疡完全治愈，疼痛消失；好转——溃疡面减小或溃疡减少，疼痛减轻；无效——溃疡未愈合，疼痛存在。治愈和好转均为有效，所有检测均由同一名研究者进行。将对比例1作为对照组，作为不添加单氟磷酸钠和透明质酸钠的牙膏，受试者用实施例和对比例制作而成的牙膏刷牙，早、中、晚各一次，每次刷牙3min，3天后复查，按照上述评价标准记录，结果如表9所示(平均数)。
表9
组别 有效率(％) 3个月后复发率(％)
实施例11 27.8 24.9
实施例12 55.7 17.8
实施例13 83.1 6.4
对比例1 20.5 25.3
对比例2 82.4 7.2
对比例3 15.6 32.3
对比例4 68.8 13.4
对比例5 69.1 13.6
对比例6 70.0 12.9
对比例7 75.9 8.3
对比例8 76.3 8.9
对比例9 77.2 7.2
由上表可知，从实施例11-13可以发现，增加透明质酸钠组合物用量，口腔溃疡有效率明显提升，透明质酸钠组合物到5份后有效率到最佳。透明质酸钠组合物复配单氟磷酸钠，随着单氟磷酸钠用量的增加，对缓解口腔溃疡方面没有显著影响。
通过对比例1和3比较还发现，当配方中有单氟磷酸钠，没有透明质酸钠组合物时，有效率降低，复发率升高。由此，透明质酸钠组合物复配单氟磷酸钠，可认为透明质酸钠组合 物可降低单氟磷酸钠对口腔黏膜的刺激性。
此外，通过比较实施例13及对比例1-9，可知透明质酸钠组合物由小分子量透明质酸钠、中分子量透明质酸钠、大分子量透明质酸钠复配而成时，对缓解口腔溃疡及防止复发效果显著高于单独使用单一分子量的透明质酸钠以及使用其中两种分子量的透明质酸钠的组合。
综合以上实验，由于实施例11和13的防龋效果、显微硬度值增加以及微孔隙面积减少效果相差不大，但在口腔溃疡治愈效果中实施例13明显优于实施例11，故选择实施例13的原料配比最佳。
本实施例中的透明质酸组合物是以透明质酸钠组合物为例叙述，实际应用时可替换为不同分子量的透明质酸组合物或其他透明质酸盐。
以上所述的仅是本发明的实施例，方案中公知的具体技术方案和/或特性等常识在此未作过多描述。应当指出，对于本领域的技术人员来说，在不脱离本发明技术方案的前提下，还可以作出若干变形和改进，这些也应该视为本发明的保护范围，这些都不会影响本发明实施的效果和专利的实用性。本申请要求的保护范围应当以其权利要求的内容为准，说明书中的具体实施方式等记载可以用于解释权利要求的内容。

Claims (10)

  1. 一种含透明质酸的组合物，其特征在于，包括透明质酸组合物和氟化物，所述透明质酸组合物包括小分子透明质酸、中分子透明质酸和大分子透明质酸，或包括小分子透明质酸盐、中分子透明质酸盐和大分子透明质酸盐。
  2. 根据权利要求1所述的一种含透明质酸的组合物，其特征在于：所述透明质酸组合物与氟化物(以氟计)的质量比为0.05-5:0.01-0.15。
  3. 根据权利要求2所述的一种含透明质酸的组合物，其特征在于：所述氟化物为氟化钠、单氟磷酸钠、氟化亚锡、奥拉氟中的一种或多种；所述透明质酸组合物中，小分子透明质酸或小分子透明质酸盐占30％-40％，中分子透明质酸或中分子透明质酸盐占30％-50％，大分子透明质酸或大分子透明质酸盐占20％-30％。
  4. 一种含透明质酸的口腔用品，其特征在于：所述口腔用品为牙膏、漱口水、凝胶、牙粉或口腔喷雾。
  5. 根据权利要求4所述的一种含透明质酸的口腔用品，其特征在于：所述口腔用品包括如下质量份的原料：透明质酸组合物、氟化物、添加剂，所述添加剂为保湿剂、粘合剂、调味剂、表面活性剂、摩擦剂、增稠剂、稳定剂、防腐剂、pH调节剂中的一种或多种。
  6. 根据权利要求5所述的一种含透明质酸的口腔用品，其特征在于：所述口腔用品为牙膏，牙膏包括如下原料：透明质酸组合物、氟化物、保湿剂、粘合剂、调味剂、表面活性剂、摩擦剂。
  7. 根据权利要求5所述的一种含透明质酸的口腔用品，其特征在于：所述口腔用品为漱口水，漱口水包括如下质量份的原料：透明质酸组合物、氟化物份、保湿剂、增稠剂、调味剂、稳定剂、防腐剂、pH调节剂。
  8. 根据权利要求6或7所述的一种含透明质酸的口腔用品，其特征在于：所述牙膏中的氟化物为单氟磷酸钠，所述漱口水中的氟化物为氟化亚锡。
  9. 一种含透明质酸的口腔用品的制备方法，其特征在于：所述口腔用品为牙膏，口腔用品的制备方法包括如下步骤：
    S1：加入保湿剂、粘合剂，搅拌均质，再一次加入调味剂、透明质酸组合物、单氟磷酸钠、表面活性剂，搅拌均匀；
    S2：加入摩擦剂后抽真空，搅拌均匀；
    S3：加入香精，搅拌均质后脱气，牙膏制备完成。
  10. 一种含透明质酸的口腔用品的制备方法，其特征在于：所述口腔用品为漱口水，口腔用品的制备方法包括如下步骤：
    S1：加入水、保湿剂、增溶剂搅拌均匀，再加入调味剂、透明质酸组合物、氟化亚锡、锡稳定剂、pH值调节剂搅拌均匀，再加入防腐剂搅拌均匀；
    S2：加入香精搅拌均匀，漱口水制备完成。
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