A chewable effervescent tablet capable of self-providing nitric oxide and its preparation method and application

Abstract

This invention provides a self-generating nitric oxide chewable effervescent tablet, its preparation method, and its application. The self-generating nitric oxide chewable effervescent tablet comprises, by weight, 0.5-8 parts of active material, 10-30 parts of acid source, 20-40 parts of alkali source, 1-3 parts of surfactant, 2-6 parts of lubricant, and 35-50 parts of filler; wherein the active material includes L-arginine, vitamin C, and an exogenous nitric oxide donor. The self-generating nitric oxide chewable effervescent tablet of this invention combines the active material, acid source, alkali source, surfactant, lubricant, and filler in a specific weight ratio, rapidly generating a large amount of nitric oxide gas during chewing. The generated gas remains in the oral cavity in foam form in every tooth and gum corner, providing comprehensive antibacterial effects and maintaining oral hygiene. Furthermore, the chewable effervescent tablet has a smooth surface, is not easily stuck, and has a low breakage rate.

Description

Technical Field

[0001] The invention belongs to the technical field of oral care, and in particular relates to a chewable effervescent tablet capable of self-providing nitric oxide, a preparation method and an application thereof. Background Art

[0002] The oral cavity is a warm, moist, irregular cavity that is directly connected to the outside world. The temperature, humidity, and easy retention of food residues in the oral cavity are suitable for the growth and reproduction of microorganisms, causing oral uncleanliness and even oral diseases such as local oral inflammation and ulcers. Oral care refers to the process of taking certain methods and choosing appropriate oral care products to achieve the purpose of cleaning the oral cavity, removing plaque, and preventing and treating oral inflammation.

[0003] Nitric oxide is an effective broad-spectrum antibacterial and antifungal agent, widely present in various tissues and cells of the human body, and has physiological functions such as vasodilation and inhibition of platelet aggregation. Nitric oxide is a free radical gas molecule with an extremely short half-life, so it is not easy to produce drug resistance and toxic side effects during its action.

[0004] Oral care products include toothpaste, mouthwash, chewing gum, etc. Toothpaste is a traditional oral cleaning and care product that needs to be used with a toothbrush. It is usually only suitable for oral care at home and is not convenient to carry outside. Although mouthwash is more convenient to use than toothpaste, it is in liquid form and the container is large, which limits the carrying of mouthwash when taking public transportation, and it is usually not convenient for multiple people to share. Although chewing gum does not have the above defects and is very convenient to use and carry, the colloid product after use is difficult to handle and easily affects the environment, and it has no killing effect on dental bacteria.

[0005] In contrast, oral care products in tablet form have the functions of cleaning teeth, eliminating bad breath, and killing bacteria. They are also easy to carry, and their solid form prevents leakage and wetting of other items, thus overcoming the above-mentioned defects.

[0006] However, existing tablet products have the following defects:

[0007] CN101254201B discloses a synergistic nystatin-menthol composition, which has nystatin and menthol as main active ingredients, and the nystatin component contained therein is used to prevent and treat oral fungal infections. The nystatin used in the preparation is a broad-spectrum antifungal drug, which is commonly used to treat oral fungal infections. Long-term daily use will cause an imbalance in the oral flora, and it cannot be used for daily oral cleaning and care.

[0008] CN101185613B and CN1306814A provide a mouthwash tablet that can simultaneously inhibit bacteria, clean the oral cavity, remove bad breath, and prevent dental caries. The antibacterial agent contained in the mouthwash tablet is selected from common disinfectants: 2,4,4'-trichloro-2'-hydroxydiphenyl ether (triclosan), metronidazole, chlorhexidine acetate, cetylpyridinium chloride, and benzalkonium bromide. Once these disinfectants enter the human body in excessive amounts, they will produce potential toxic effects.

[0009] At present, among the oral cleaning products on the market, liquid products such as mouthwash are inconvenient to carry and easy to leak and soak other items; products such as chewing gum are difficult to handle after use; tablet products often contain medicinal ingredients such as antibiotics or disinfectant ingredients such as chlorhexidine acetate, which have potential toxic effects. How to further improve the portability and ease of use, and reduce the potential toxic effects of oral care products, is an urgent problem to be solved. Summary of the invention

[0010] In view of the deficiencies in the prior art, the object of the present invention is to provide an oral chewable tablet and a preparation method and application thereof, and in particular to provide a chewable effervescent tablet that can self-provide nitric oxide and a preparation method and application thereof.

[0011] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0012] In a first aspect, the present invention provides a chewable effervescent tablet that can self-provide nitric oxide, wherein the chewable effervescent tablet that can self-provide nitric oxide comprises, by weight, 0.5-8 parts of active material, 10-30 parts of acid source, 20-40 parts of alkali source, 1-3 parts of surfactant, 2-6 parts of lubricant and 35-50 parts of filler; wherein the active material comprises L-arginine, vitamin C and an exogenous nitric oxide donor.

[0013] The present invention creatively applies nitric oxide donors to chewable effervescent tablet products to prepare a chewable effervescent tablet product that can provide nitric oxide by itself. In its formula, the acid source ionizes hydrogen ions after being chewed and meets water, and the alkali source ionizes carbonate or bicarbonate ions after meeting water. The acid source and the alkali source undergo double decomposition reaction in the oral cavity to produce a large amount of carbon dioxide, causing the tablet to disintegrate rapidly. As the effervescent process proceeds, the surfactant can significantly change the interface state of the solution system in the oral cavity, promoting the generation of a large amount of foam. The generated nitric oxide gas remains in the form of foam in every corner of the teeth and gums in the oral cavity, exerting an antibacterial effect without dead corners. After adding a lubricant, the surface of the tablet product is smooth, not easy to stick, and not damaged. The filler in the formula does not react with other substances, and plays a role in improving the comprehensive performance of tableting and reducing sticking; more importantly, the active material in the chewable effervescent tablet is a specific selection of a combination of L-arginine, vitamin C and an exogenous nitric oxide donor. The exogenous nitric oxide donor enters the oral environment and is rapidly degraded and releases nitric oxide when it encounters water, while L-arginine and vitamin C can cooperate with the exogenous nitric oxide donor to promote the exogenous nitric oxide donor to continuously release nitric oxide, with a release amount of 1000-3000ppb, which can have a good antibacterial effect. In addition, the strong alkaline amino acid arginine, in addition to being an endogenous nitric oxide donor, can also be used as an efficient alkaline regulator. If the system does not contain arginine, the simple alkaline source must not only adjust the pH, but also participate in the neutralization reaction of the acid source. In order to achieve a slightly alkaline environment, a larger amount of alkaline source is required, which will lead to a worse effervescent effect and taste. However, adding a small amount of arginine to the reaction system can promote an increase in pH. Combined with an appropriate amount of alkaline source, it is easy to achieve an alkaline reaction environment, which is beneficial to simultaneously ensure a good effervescent effect, taste and a higher release of nitric oxide.

[0014] The mass fraction of the active material can be selected to be 0.5, 2, 3, 4, 5, 6, 7 or 8, etc.

[0015] The weight percentage of the acid source can be 10 parts, 12 parts, 14 parts, 16 parts, 18 parts, 20 parts, 22 parts, 24 parts, 26 parts, 28 parts or 30 parts.

[0016] The mass fraction of the alkali source can be selected from 20 parts, 22 parts, 24 parts, 26 parts, 28 parts, 30 parts, 32 parts, 34 parts, 36 parts, 38 parts or 40 parts, etc.

[0017] The mass fraction of the surfactant can be selected from 1 part, 1.2 parts, 1.4 parts, 1.6 parts, 1.8 parts, 2 parts, 2.2 parts, 2.4 parts, 2.6 parts, 2.8 parts or 3 parts, etc.

[0018] The mass fraction of the lubricant can be selected from 2 parts, 2.4 parts, 2.8 parts, 3.2 parts, 3.6 parts, 4 parts, 4.4 parts, 4.8 parts, 5.2 parts, 5.6 parts or 6 parts, etc.

[0019] The mass fraction of the filler can be selected to be 35 parts, 37 parts, 39 parts, 41 parts, 43 parts, 45 parts, 47 parts, 49 parts or 50 parts, etc.

[0020] Other specific point values ​​within the above numerical ranges can be selected and will not be described in detail here.

[0021] Preferably, the exogenous nitric oxide donor includes any one of S-nitrosoglutathione, S-nitroso-N-acetylpenicillamine or S-nitroso-N-acetylcysteine, S-nitrosotriphenylmethyl mercaptan, S-nitrosotriphenylmethyl mercaptan, S-nitrosocysteine, S-nitrosothioglycerol, S-nitrosomethic acid, S-nitrosothioethylamine, S-nitroso-3-mercaptopropionic acid, and S-nitroso-D-thioglucose, or a combination of at least two thereof. The combination of at least two thereof includes, for example, a combination of S-nitrosoglutathione and S-nitroso-N-acetylpenicillamine, a combination of S-nitrosoglutathione and S-nitroso-N-acetylcysteine, a combination of S-nitroso-N-acetylpenicillamine and S-nitroso-N-acetylcysteine, and the like. Any other combinations may be selected, and they will not be described one by one here.

[0022] It is well known to those skilled in the art that S-nitrosoglutathione, S-nitroso-N-acetylpenicillamine or S-nitroso-N-acetylcysteine, S-nitrosotriphenylmethyl mercaptan, S-nitrosotriphenylmethyl mercaptan, S-nitrosocysteine, S-nitrosothioglycerol, S-nitrosomethicone, S-nitrosothioethylamine, S-nitroso-3-mercaptopropionic acid, and S-nitroso-D-thioglucose are commonly used nitric oxide donors and can react in a variety of systems to supply nitric oxide.

[0023] Preferably, the exogenous nitric oxide donor comprises S-nitrosoglutathione and / or S-nitroso-N-acetylcysteine.

[0024] Preferably, the exogenous nitric oxide donor is a combination of S-nitrosoglutathione and S-nitroso-N-acetylcysteine.

[0025] Preferably, the molar ratio of S-nitrosoglutathione to S-nitroso-N-acetylcysteine ​​is (1-3):1.

[0026] The present invention also creatively finds that when the exogenous nitric oxide donor selects S-nitrosoglutathione and / or S-nitroso-N-acetylcysteine, especially the combination of S-nitrosoglutathione and S-nitroso-N-acetylcysteine, the nitric oxide release shows a rapid increase followed by a slow decrease and then a stable release behavior, and the rapid release behavior in a short period of time can destroy the bacterial biofilm, further improving the antibacterial effect of the chewable effervescent tablet that can self-provide nitric oxide. When the molar ratio of S-nitrosoglutathione to S-nitroso-N-acetylcysteine ​​is further limited to (1-3):1, the nitric oxide release is faster and the oral antibacterial effect is stronger.

[0027] The specific numerical values ​​in (1-3) can be selected from 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 or 3, and other specific point values ​​within the above numerical ranges can be selected, which will not be repeated here.

[0028] Preferably, the mass ratio of L-arginine, vitamin C and exogenous nitric oxide donor is (4-10):1:(1-4).

[0029] When the mass ratio of L-arginine, vitamin C and exogenous nitric oxide donor in the active material of the present invention is (4-10):1:(1-4), the short-term release of nitric oxide is higher and the antibacterial effect is stronger. Moreover, L-arginine, as an endogenous nitric oxide donor, can maintain the long-term release of nitric oxide, inhibit the formation of bacterial biofilm, and achieve a long-term antibacterial effect.

[0030] The specific numerical values ​​in (4-10) can be selected as 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 or 10, etc. Other specific point values ​​within the above numerical ranges can be selected, and they will not be described one by one here.

[0031] The specific numerical values ​​in (1-4) can be selected as 1, 1.3, 1.6, 1.9, 2.2, 2.5, 2.7, 3, 3.3, 3.6 or 4, etc. Other specific point values ​​within the above numerical ranges can be selected and will not be described in detail here.

[0032] Preferably, the acid source includes any one of citric acid, tartaric acid, fumaric acid or malic acid, or a combination of at least two of them. The combination of at least two includes, for example, a combination of citric acid and tartaric acid, a combination of citric acid and fumaric acid, a combination of tartaric acid and malic acid, etc. Any other combinations may be selected and will not be described here one by one.

[0033] Preferably, the acid source comprises malic acid and / or citric acid.

[0034] When malic acid and / or citric acid are selected as the acid source involved in the present invention, the chewable effervescent tablet capable of self-providing nitric oxide has better water solubility, rapid effervescence and better taste.

[0035] Preferably, the alkali source includes any one of sodium bicarbonate, potassium bicarbonate or sodium carbonate, or a combination of at least two of them. The combination of at least two includes, for example, a combination of sodium bicarbonate and potassium bicarbonate, a combination of sodium bicarbonate and sodium carbonate, a combination of potassium bicarbonate and sodium carbonate, etc. Other arbitrary combinations can be selected and will not be described one by one here.

[0036] Preferably, the alkali source comprises sodium bicarbonate and / or sodium carbonate.

[0037] The alkali source of the present invention is selected from any one of sodium bicarbonate, sodium carbonate or potassium bicarbonate or a combination of at least two thereof. While exerting the original foaming effect of sodium bicarbonate, sodium carbonate or potassium bicarbonate, the pH of the reaction system can also be adjusted to a state of partial alkalinity. In an alkaline environment, the release effect of the nitric oxide donor is enhanced, and a better antibacterial effect can be achieved. In particular, when the alkali source is selected from sodium bicarbonate and / or sodium carbonate, the two will not produce too much potassium ions compared with potassium bicarbonate to affect the potassium ion balance of the body, and sodium bicarbonate and / or sodium carbonate are purer.

[0038] Preferably, the surfactant includes any one of sodium dodecyl sulfate, magnesium dodecyl sulfate or Tween-80, or a combination of at least two of them. The combination of at least two includes, for example, a combination of sodium dodecyl sulfate and magnesium dodecyl sulfate, a combination of sodium dodecyl sulfate and Tween-80, a combination of magnesium dodecyl sulfate and Tween-80, etc. Any other combinations may be selected and will not be described in detail here.

[0039] Preferably, the surfactant comprises sodium dodecyl sulfate and / or Tween-80.

[0040] Preferably, the surfactant is a combination of sodium lauryl sulfate and Tween-80.

[0041] When the surfactant of the present invention is sodium dodecyl sulfate and / or Tween-80, especially when a combination of sodium dodecyl sulfate and Tween-80 is selected, the chewable effervescent tablet capable of self-providing nitric oxide has a better foaming effect, a longer foaming duration, and a better user experience.

[0042] Preferably, the lubricant includes any one of polyethylene glycol 4000, polyethylene glycol 6000, magnesium stearate, L-leucine or magnesium dodecyl sulfate, or a combination of at least two thereof. The combination of at least two thereof includes, for example, a combination of polyethylene glycol 4000 and polyethylene glycol 6000, a combination of polyethylene glycol 4000 and magnesium stearate, a combination of polyethylene glycol 6000 and magnesium stearate, etc. Any other combinations may be selected and will not be described herein one by one.

[0043] Preferably, the lubricant comprises polyethylene glycol 6000 and / or magnesium stearate.

[0044] Preferably, the lubricant is a combination of polyethylene glycol 6000 and magnesium stearate.

[0045] Preferably, the mass ratio of polyethylene glycol 6000 to magnesium stearate is (1-5):1.

[0046] The lubricant of the present invention is selected from polyethylene glycol 6000 and / or magnesium stearate, especially when a combination of polyethylene glycol 6000 and magnesium stearate is selected, the chewable effervescent tablet capable of self-providing nitric oxide has a smoother surface and is less prone to sticking and breakage. When the mass ratio of polyethylene glycol 6000 to magnesium stearate is selected to be (1-5):1, the probability of sticking and breakage is lower.

[0047] The specific numerical values ​​in (1-5) can be selected as 1, 1.4, 1.8, 2.2, 2.6, 3, 3.4, 3.8, 4.2, 4.6 or 5, etc. Other specific point values ​​within the above numerical ranges can be selected and will not be described in detail here.

[0048] Preferably, the filler includes any one of starch, mannitol, microcrystalline cellulose, dextrin, lactose or glucose, or a combination of at least two of them. The combination of at least two includes, for example, a combination of starch and microcrystalline cellulose, a combination of starch and mannitol, a combination of mannitol and microcrystalline cellulose, etc. Any other combination can be selected and will not be described here one by one.

[0049] Preferably, the filler comprises lactose and / or mannitol.

[0050] Preferably, the filler is a combination of lactose and mannitol.

[0051] Preferably, the mass ratio of lactose to mannitol is (6-12):1.

[0052] When lactose and / or mannitol are selected as fillers, especially when a combination of lactose and mannitol is selected, the chewable effervescent tablet capable of self-providing nitric oxide has better comprehensive performance and is less prone to sticking and breakage. When the mass ratio of lactose to mannitol is specifically selected to be (6-12):1, the probability of sticking and breakage is even lower.

[0053] The specific numerical values ​​in (6-12) can be selected as 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 10, 10.5, 11, 11.5 or 12, etc. Other specific point values ​​within the above numerical ranges can be selected, and they will not be described one by one here.

[0054] Preferably, the chewable effervescent tablet capable of self-supplying nitric oxide further comprises a sweetener.

[0055] Preferably, the sweetener includes any one or a combination of two of sucralose, aspartame or stevioside. The combination of at least two includes, for example, a combination of sucralose and aspartame, a combination of aspartame and stevioside, a combination of sucralose and stevioside, and the like. Any other combinations may be selected and will not be described in detail here.

[0056] In a second aspect, the present invention provides a method for preparing a chewable effervescent tablet that can self-provide nitric oxide as described in the first aspect, the preparation method comprising: crushing an acid source, a portion of a lubricant and L-arginine, sieving for a first time to obtain a mixture; mixing the mixture with an alkali source, a surfactant, a filler, the remaining lubricant, an exogenous nitric oxide donor and vitamin C, sieving for a second time, and pressing and granulating to obtain the chewable effervescent tablet that can self-provide nitric oxide.

[0057] The present invention relates to a method for preparing a chewable effervescent tablet capable of self-providing nitric oxide as described in the first aspect, which does not require the acid source and the alkali source to be added with adhesives to prepare soft materials, sieve, dry, granulate, and then mix and compress the tablets, thereby reducing the energy consumption of the preparation process and being easy to operate. In the case of omitting the adhesive, the effervescent chewable tablet can be prepared by mixing in a one-step method, and the preparation method also has the characteristics of reducing the hygroscopicity of the material and the sticking rate. In addition, the preparation method is simple to operate and suitable for industrial scale-up.

[0058] Preferably, the sieve used for the first screening is 60-100 mesh, for example, 60 mesh, 65 mesh, 70 mesh, 75 mesh, 80 mesh, 85 mesh, 90 mesh, 95 mesh or 100 mesh, etc. Other specific point values ​​within the above numerical ranges can be selected, and they will not be described one by one here.

[0059] When the mesh of the first screening involved in the present invention is specifically selected to be 60-100 mesh, the particle distribution of L-arginine is more uniform, and the lubricant polyethylene glycol 6000 can maximize the internal lubrication effect. If the mesh number is too large, exceeding 100 mesh, the particles will be too fine, and finally the mixture will float on the surface and cannot be evenly mixed with other materials. If the mesh number is too small, less than 60 mesh, the particle size will be too large, and the original function of the material cannot be maximized.

[0060] Preferably, the sieve used for the second screening is 10-30 mesh, for example, 10 mesh, 12 mesh, 14 mesh, 16 mesh, 18 mesh, 20 mesh, 22 mesh, 24 mesh, 26 mesh, 28 mesh or 30 mesh, etc. Other specific point values ​​within the above numerical ranges can be selected, and they will not be described one by one here.

[0061] In a third aspect, the present invention provides use of the chewable effervescent tablet capable of self-providing nitric oxide as described in the first aspect in the preparation of an oral care product.

[0062] The oral care product involved in the present invention may be, for example, an oral chewable tablet, an oral rinse tablet or a chewing gum.

[0063] Compared with the prior art, the present invention has the following beneficial effects:

[0064] 1. The chewable effervescent tablet that can provide nitric oxide by itself according to the present invention uses active materials, acid sources, alkaline sources, surfactants, lubricants and fillers in a specific mass ratio, and the chewable effervescent tablet can quickly produce a large amount of nitric oxide gas during chewing by adjusting the acidity and alkalinity of the tablet. The generated nitric oxide gas is retained in the oral cavity in the form of foam in every corner of the teeth and gums, playing a role in inhibiting bacteria without dead angles and maintaining the cleanliness of the oral environment. The chewable effervescent tablet has a smooth surface, is not easy to stick and has a low breakage rate.

[0065] 2. The preparation method of the chewable effervescent tablet that can self-provide nitric oxide according to the present invention does not need to add adhesives to acid source and alkali source to prepare soft materials, sieve, dry, granulate, and then mix and compress the tablets, which reduces the energy consumption of the preparation process and is easy to operate. In the case of omitting the adhesive, the effervescent chewable tablet can be prepared by mixing in a one-step method, and the preparation method also has the characteristics of reducing the hygroscopicity of the material and the viscosity. In addition, the preparation method is simple to operate and suitable for industrial scale-up. BRIEF DESCRIPTION OF THE DRAWINGS

[0066] Figure 1 This is the appearance picture of the chewable effervescent tablet sample that can self-provide nitric oxide prepared in Example 1.

[0067] Figure 2 This is the appearance picture of the chewable effervescent tablet sample that can self-provide nitric oxide prepared in Example 8.

[0068] Figure 3 This is the disintegration condition of the chewable effervescent tablet sample capable of self-providing nitric oxide prepared in Example 1.

[0069] Figure 4 This is a graph showing the antibacterial performance test results of the chewable effervescent tablet sample that can self-provide nitric oxide prepared in Example 1.

[0070] Figure 5 This is the result graph corresponding to the blank group in the antibacterial performance test. DETAILED DESCRIPTION

[0071] The technical solution of the present invention is further described below by specific implementation methods. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0072] Example 1

[0073] In this embodiment, a chewable effervescent tablet capable of self-providing nitric oxide is prepared. The preparation method is as follows: 2.5 parts of malic acid, 20 parts of citric acid, 1.5 parts of L-arginine, and 2 parts of polyethylene glycol 6000 are put into a pulverizer and pulverized. The pulverization time program is to pause for 20 seconds after every 10 seconds, the pulverization speed is 30000rpm, and the pulverization is performed 3 times in total. The pulverized mixture is sieved through an 80-mesh screen, put into a clean plastic bag and sealed for standby use; then the mixture is mixed with 0.39 parts of S-nitrosoglutathione, 0.11 parts of S-nitroso-N-acetylcysteine, 0.25 parts of vitamin C, 30 parts of sodium bicarbonate, 36 parts of lactose, 4 parts of mannitol, 0.5 parts of sucralose, 1 part of sodium lauryl sulfate, 1 part of Tween-80, and 1 part of magnesium stearate, and the mixture is evenly mixed and sieved through a 20-mesh screen, and the tablets are pressed and granulated to obtain the chewable effervescent tablet capable of self-providing nitric oxide. The product appearance is shown in the figure below. Figure 1 shown.

[0074] Example 2

[0075] In this embodiment, a chewable effervescent tablet capable of self-providing nitric oxide is prepared, and the preparation method thereof is as follows: 2.5 parts of tartaric acid, 20 parts of citric acid, 1.5 parts of L-arginine, and 2 parts of polyethylene glycol 6000 are put into a pulverizing machine for pulverization, the pulverization time program is to pause for 20 seconds after every 10 seconds, the pulverization speed is 20000rpm, and the pulverization is performed 3 times in total. The pulverized mixture is sieved through a 70-mesh sieve, put into a clean plastic bag and sealed for standby use; then the mixture is mixed with 0.32 parts of S-nitrosoglutathione, 0.18 parts of S-nitroso-N-acetylcysteine, 0.25 parts of vitamin C, 30 parts of sodium carbonate, 34.3 parts of lactose, 5.7 parts of mannitol, 0.5 parts of aspartame, 1 part of sodium lauryl sulfate, 1 part of Tween-80, and 1 part of magnesium stearate, and the mixture is evenly mixed through a 25-mesh sieve, and the mixture is pressed into tablets and granulated to obtain the chewable effervescent tablet capable of self-providing nitric oxide.

[0076] Example 3

[0077] In this embodiment, a chewable effervescent tablet capable of self-providing nitric oxide is prepared, and the preparation method thereof is as follows: 25 parts of citric acid, 1.5 parts of L-arginine, and 2 parts of polyethylene glycol 6000 are put into a pulverizing machine for pulverization, the pulverization time program is to pause for 20 seconds after every 10 seconds, the pulverization speed is 25000rpm, and the pulverization is performed 3 times in total. The pulverized mixture is sieved through a 90-mesh screen, put into a clean plastic bag, and sealed for standby use; then the mixture is mixed with 0.42 parts of S-nitrosoglutathione, 0.08 parts of S-nitroso-N-acetylcysteine, 0.25 parts of vitamin C, 30 parts of sodium carbonate, 36 parts of lactose, 3 parts of mannitol, 1 part of sucralose, 2 parts of sodium lauryl sulfate, 1 part of Tween-80, and 1 part of magnesium stearate, and the mixture is evenly mixed with a 15-mesh screen, sieved, and granulated to obtain the chewable effervescent tablet capable of self-providing nitric oxide.

[0078] Example 4

[0079] In this example, a chewable effervescent tablet capable of self-providing nitric oxide is prepared. The preparation method thereof is different from that in Example 1 only in that 0.39 parts of S-nitrosoglutathione and 0.11 parts of S-nitroso-N-acetylcysteine ​​in the raw materials are replaced with a single component having an equimolar total amount of S-nitrosoglutathione, and the rest is the same as in Example 1.

[0080] Example 5

[0081] In this example, a chewable effervescent tablet capable of self-providing nitric oxide is prepared. The preparation method thereof is different from that in Example 1 only in that 0.39 parts of S-nitrosoglutathione and 0.11 parts of S-nitroso-N-acetylcysteine ​​in the raw materials are replaced with a single component having an equimolar total amount of S-nitroso-N-acetylcysteine, and the rest is the same as in Example 1.

[0082] Example 6

[0083] In this embodiment, a chewable effervescent tablet capable of self-providing nitric oxide is prepared. The preparation method thereof is different from that in Example 1 only in that 1 part of sodium dodecyl sulfate and 1 part of Tween-80 in the raw materials are replaced with 2 parts of sodium dodecyl sulfate, and the rest is the same as in Example 1.

[0084] Example 7

[0085] In this embodiment, a chewable effervescent tablet capable of self-providing nitric oxide is prepared. The preparation method thereof is different from that in Example 1 only in that 1 part of sodium dodecyl sulfate and 1 part of Tween-80 in the raw materials are replaced with 2 parts of Tween-80, and the rest is the same as in Example 1.

[0086] Example 8

[0087] This example prepares a chewable effervescent tablet that can self-provide nitric oxide. The difference between the preparation method and that of Example 1 is that 2 parts of polyethylene glycol 6000 and 1 part of magnesium stearate in the raw materials are replaced with 3 parts of magnesium stearate. The rest is the same as that of Example 1. The appearance of the product is shown in FIG. Figure 2 shown.

[0088] Example 9

[0089] In this embodiment, a chewable effervescent tablet capable of self-providing nitric oxide is prepared. The preparation method thereof is different from that in Example 1 only in that 2 parts of polyethylene glycol 6000 and 1 part of magnesium stearate in the raw materials are replaced with 3 parts of polyethylene glycol 6000, and the rest is the same as in Example 1.

[0090] Example 10

[0091] This embodiment prepares a chewable effervescent tablet that can self-provide nitric oxide. The preparation method thereof is different from that of Example 1 only in that 36 parts of lactose and 4 parts of mannitol in the raw materials are replaced with 40 parts of mannitol, and the rest is the same as that of Example 1.

[0092] Embodiment 11

[0093] This embodiment prepares a chewable effervescent tablet that can self-provide nitric oxide. The preparation method thereof is different from that of Example 1 only in that 36 parts of lactose and 4 parts of mannitol in the raw materials are replaced with 40 parts of lactose, and the rest is the same as that of Example 1.

[0094] Example 12

[0095] In this embodiment, a chewable effervescent tablet capable of self-providing nitric oxide is prepared. The preparation method thereof is different from that in Example 1 only in that 1.5 parts of L-arginine and 0.25 parts of vitamin C (in a ratio of 6:1) in the raw materials are replaced with 1.17 parts of L-arginine and 0.58 parts of vitamin C (adjusted to a ratio of 2:1), and the rest are the same as in Example 1.

[0096] Embodiment 13

[0097] In this embodiment, a chewable effervescent tablet capable of self-providing nitric oxide is prepared. The preparation method thereof is different from that in Example 1 only in that 1.5 parts of L-arginine and 0.25 parts of vitamin C (in a ratio of 6:1) in the raw materials are replaced with 1.62 parts of L-arginine and 0.13 parts of vitamin C (adjusted to a ratio of 12.5:1), and the rest are the same as in Example 1.

[0098] Embodiment 14

[0099] This embodiment prepares a chewable effervescent tablet that can self-provide nitric oxide. The preparation method thereof is different from that of Example 1 only in that the mesh size of the sieve used for the first screening is replaced with 55 meshes, and the rest is the same as that of Example 1.

[0100] Embodiment 15

[0101] This embodiment prepares a chewable effervescent tablet that can self-provide nitric oxide. The preparation method thereof is different from that of Example 1 only in that the mesh size of the sieve used for the first screening is replaced with 110 meshes, and the rest is the same as that of Example 1.

[0102] Comparative Example 1

[0103] In this comparative example, a chewable effervescent tablet capable of self-providing nitric oxide is prepared. The preparation method thereof is the same as that of Example 1 except that 1.5 parts of L-arginine and 0.25 parts of vitamin C in the raw materials are replaced with 1.75 parts of vitamin C.

[0104] Comparative Example 2

[0105] In this comparative example, a chewable effervescent tablet capable of self-providing nitric oxide is prepared. The preparation method thereof is the same as that of Example 1 except that 1.5 parts of L-arginine and 0.25 parts of vitamin C in the raw materials are replaced with 1.75 parts of L-arginine.

[0106] Comparative Example 3

[0107] In this comparative example, a chewable effervescent tablet capable of self-providing nitric oxide is prepared. The preparation method thereof is the same as that in Example 1, the 1.5 parts of L-arginine, 0.25 parts of vitamin C, 0.39 parts of S-nitrosoglutathione, and 0.11 parts of S-nitroso-N-acetylcysteine ​​(the molar ratio of S-nitrosoglutathione to S-nitroso-N-acetylcysteine ​​is 2:1) in the raw materials are replaced with 1.76 parts of S-nitrosoglutathione and 0.49 parts of S-nitroso-N-acetylcysteine ​​(the molar ratio of S-nitrosoglutathione to S-nitroso-N-acetylcysteine ​​is 2:1). The rest are the same as those in Example 1.

[0108] Test Example 1

[0109] The tablet performance of the products prepared in Examples 1-15 and Comparative Examples 1-3 was investigated. The specific evaluation method is as follows: 20 tablets of the products prepared in Examples 1-15 and Comparative Examples 1-3 were taken, and 10 volunteers jointly evaluated the color uniformity, surface finish and surface integrity of the tablets, and the average score of the tablet products of each embodiment was calculated. In addition, the tablets were accurately weighed respectively to calculate the average tablet weight, and then the amount of each tablet was weighed, and the tablet weight difference was calculated according to the calculation formula: tablet weight difference = (single tablet weight - average tablet weight) / average tablet weight × 100%.

[0110] Color uniformity, surface finish and surface integrity were scored according to the scoring criteria in Table 1, and the embodiments in Table 2 were evaluated based on the scores.

[0111] Table 1

[0112] Fraction Color uniformity Surface finish Surface integrity 3 Very uniform color overall Very smooth surface The surface is very complete 2 Local uneven color Partial surface roughness Partial surface imperfection 1 Uneven color overall The overall surface is not smooth The surface is not complete

[0113] Table 2

[0114]

[0115]

[0116] S-nitrosoglutathione is a pink solid powder, so the uneven mixing of the ingredients in the tablet can be reflected by the color uniformity. From the data in Table 2, it can be seen that when the mesh number of the first screening screen in Example 14 is 55 meshes, the color uniformity of the tablets is worse than that in Example 1, which shows that selecting the mesh number of the first screening screen of 60-100 meshes in the product preparation method of the present invention can promote more uniform mixing of the product.

[0117] During tablet preparation, the added lubricant, filler and first sieving mesh size will affect the tablet surface finish, surface integrity and tablet weight variation. It can be seen from the data in Table 2 that when magnesium stearate or polyethylene glycol 6000 is used as a lubricant in Examples 8 and 9, the surface smoothness and integrity of the tablets are worse than those in Example 1, and the difference in tablet weight is greater than that in Example 1, which indicates that when the lubricant in the product preparation method of the present invention is a combination of polyethylene glycol 6000 and magnesium stearate, the probability of sticking and breakage of the product is low; when mannitol or lactose is used as a filler in Examples 10 and 11, the surface smoothness and integrity of the tablets are worse than those in Example 1, and the difference in tablet weight is greater than that in Example 1, which indicates that when the filler in the product preparation method of the present invention is a combination of mannitol and lactose, the probability of sticking and breakage of the product is low; when the mesh number of the first sieving screen in Example 14 is 55 meshes, the surface smoothness and integrity of the tablets are worse than those in Example 1, and the difference in tablet weight is greater than that in Example 1, which indicates that when the mesh number of the first sieving screen in the product preparation method of the present invention is selected as 60-100 meshes, the product particle size is more suitable and the overall performance of the tablet is better.

[0118] Test Example 2

[0119] The disintegration performance of the obtained products was investigated. The specific evaluation method is: take 6 random tablets of the products obtained in Examples 1-15 and Comparative Examples 1-3, place them in a 250ml beaker (containing 200ml of water at a temperature of 20°C ± 5°C), start timing when placing them in the beaker, and a large number of bubbles will immediately emerge. When the gas around the tablets or fragments stops escaping, the tablets should be dissolved or dispersed in the water, and no aggregated particles will remain. At this time, stop timing, and the timing time is the disintegration time. Each tablet disintegrated within 5 minutes, and the disintegration phenomenon of the product of Example 1 is shown in the figure below. Figure 3 shown.

[0120] Test Example 3

[0121] The products prepared in Examples 1-15 and Comparative Examples 1-3 were tested for nitric oxide release performance. The specific evaluation method is as follows: take the products prepared in Examples 1-15 and Comparative Examples 1-3, randomly take 10 tablets from each embodiment on the day of preparation, put them into a two-necked round-bottomed glass bottle filled with 15 mL of pure water, one neck is an air inlet (air flow rate 0.5 L / min), and the other neck is an air outlet connected to a Thremo sampling tube, and timing is started at the same time when effervescence begins, and the nitric oxide release concentration (ppb) at 0 min, 1 min, 2 min, 3 min, 4 min, 5 min, 8 min, 10 min, 13 min, 16 min, and 20 min is measured respectively, and the average value of the nitric oxide release concentration of each embodiment at different times is calculated.

[0122] Differences in product raw material composition and tablet performance will result in differences in nitric oxide release. Table 3.1 shows the changes in nitric oxide release over time for the products prepared in Examples 1, 4, 5, 12, 13 and Comparative Examples 1-3; Table 3.2 shows the changes in nitric oxide release over time for the products prepared in Examples 2-3 and Examples 6-15.

[0123] Table 3.1

[0124]

[0125] Table 3.2

[0126]

[0127]

[0128] The only difference between the examples and comparative examples in Table 3.1 and Example 1 is the active material composition. The active material composition ratios of each example in Table 3.2 are all optimal ratios. The difference in nitric oxide release is mainly affected by the difference in tablet performance.

[0129] It can be seen from the data in Table 3.1 that when the active materials used in Comparative Examples 1, 2, and 3 are vitamin C and an exogenous nitric oxide donor, L-arginine and an exogenous nitric oxide donor, and an exogenous nitric oxide donor, respectively, the peak value of nitric oxide release is lower than that in Example 1, and the time when the highest point of nitric oxide release occurs is later than that in Example 1, indicating that vitamin C and L-arginine cooperate with the exogenous nitric oxide donor to exert a stronger short-term release effect of nitric oxide.

[0130] In Example 12, the L-arginine: vitamin C ratio of 6:1 was replaced by L-arginine: vitamin C at a ratio of 2:1, and in Example 13, the L-arginine: vitamin C ratio of 6:1 was replaced by L-arginine: vitamin C at a ratio of 12.5:1. The peak nitric oxide release of Examples 12 and 13 was higher than that of Comparative Examples 1, 2, and 3, and lower than that of Example 1. The time when the highest point of nitric oxide release occurred was earlier than that of Comparative Examples 2 and 3, and later than that of Example 1. This shows that when the mass ratio of L-arginine: vitamin C is (4-10):1, the short-term release of nitric oxide is high, which is beneficial to the cleansing effect.

[0131] When Examples 4 and 5 respectively use single components of equimolar total amounts of S-nitrosoglutathione and S-nitroso-N-acetylcysteine, the peak value of nitric oxide release is lower than that of Example 1, and the peak time of nitric oxide release occurs later, which indicates that when S-nitrosoglutathione and S-nitroso-N-acetylcysteine ​​are used in combination, they can synergistically enhance the short-term release of nitric oxide.

[0132] It can be seen from the data in Table 3.2 that the active material composition ratios of each embodiment in the table are all optimal ratios, and each group of samples releases nitric oxide over time and basically reaches a peak at around 3 minutes. When Examples 8 and 9 respectively use magnesium stearate or polyethylene glycol 6000 as lubricants alone, the tablet surface smoothness and integrity are worse than those in Example 1, and the tablet weight difference is greater than that in Example 1, resulting in a lower nitric oxide release peak than in Example 1, which indicates that when the lubricant described in the preparation method of the product of the present invention is a combination of polyethylene glycol 6000 and magnesium stearate, the product breakage rate is low and the nitric oxide release capacity is stronger; when Examples 10 and 11 respectively use mannitol or lactose as fillers alone, the tablet surface smoothness and integrity are worse than those in Example 1, and the tablet weight difference is greater than that in Example 1, resulting in a lower nitric oxide release peak than in Example 1, which indicates that the product preparation method of the present invention When the filler described in the preparation method is a combination of mannitol and lactose, the probability of the product sticking and breaking is low, which is more conducive to promoting the release of nitric oxide; Example 14 uses a 55-mesh screen for the first screening, which will cause the first screening particles to be coarse, which is not conducive to the contact reaction of various components in the tablet, and will cause the time when the highest point of nitric oxide release appears later than Example 1 and the peak value is lower than Example 1; Example 15 uses a 110-mesh screen for the first screening, which will cause the first screening particles to be too fine, and finally float on the surface after mixing, and cannot be mixed evenly with other materials, and will also cause insufficient contact reaction of various components in the tablet, and its peak value is lower than Example 1. This shows that when the mesh number of the first screening screen in the product preparation method of the present invention is selected as 60-100 mesh, the product particle size is more suitable, the contact reaction of various components in the tablet is more sufficient, and it is more conducive to enhancing the release of nitric oxide.

[0133] Test Example 4

[0134] The antibacterial performance of the products obtained in Examples 1-15 and Comparative Examples 1-3 was tested. The specific evaluation method was as follows: (1) prepare a 10 12 CFU / mL of Staphylococcus aureus suspension; (2) Add 5mL of sterile water to a sterile beaker; (3) Add 100μL of the bacterial suspension in (1) to each beaker, mix well, and obtain mixed solution 1; (4) Randomly take one piece of the sample prepared in Examples 1-15 and Comparative Examples 1-3 from the sample group, put it into mixed solution 1, start timing, and after 10 minutes, draw 200μL, evenly spread it on the surface of the solid culture medium, turn the plate over and culture at 37℃ for 24 hours, and count the colonies; (5) The blank group directly takes mixed solution 1, starts timing at the same time as the sample group, and after 10 minutes, draw 200μL, evenly spread it on the surface of the solid culture medium, turn the plate over and culture at 37℃ for 24 hours, and count the colonies. The percentage of (blank group colony count-sample group colony count) / blank group colony count is recorded as the antibacterial rate. The antibacterial performance test results of the chewable effervescent tablet sample that can self-provide nitric oxide prepared in Example 1 are shown in the figure below. Figure 4 As shown; the antibacterial performance test results of the blank group are shown in Figure 5 shown.

[0135] Table 4

[0136] Antibacterial rate (%) Example 1 90.2％ Example 2 89.7％ Example 3 90％ Example 4 89.0％ Example 5 85.0％ Example 6 88.8％ Example 7 89.0％ Example 8 86.8％ Example 9 85.2％ Example 10 85.2％ Embodiment 11 85.9％ Example 12 86.6％ Example 13 86.2％ Embodiment 14 79.1％ Embodiment 15 85.3％ Comparative Example 1 70.2％ Comparative Example 2 62.7％ Comparative Example 3 67.4％

[0137] From the data analysis of Table 4, it can be seen that when the active materials used in Comparative Examples 1, 2, and 3 are vitamin C and an exogenous nitric oxide donor, L-arginine and an exogenous nitric oxide donor, and an exogenous nitric oxide donor, respectively, the antibacterial effect is worse than that in Example 1, indicating that vitamin C and L-arginine cooperate with the exogenous nitric oxide donor to exert a stronger nitric oxide release effect and achieve a stronger antibacterial effect.

[0138] In Example 12, the L-arginine: vitamin C ratio of 6:1 was replaced by L-arginine: vitamin C at a ratio of 2:1, and in Example 13, the L-arginine: vitamin C ratio of 6:1 was replaced by L-arginine: vitamin C at a ratio of 12.5:1. The antibacterial rates of Examples 12 and 13 were higher than those of Comparative Examples 1, 2, and 3, and lower than those of Example 1. This indicates that when the mass ratio of L-arginine: vitamin C is (4-10):1, the short-term release of nitric oxide is high and the antibacterial rate is high, which is beneficial to enhancing the cleaning effect of the oral cavity.

[0139] When the single components of Examples 4 and 5 are used in equal molar total amounts of S-nitrosoglutathione and S-nitroso-N-acetylcysteine, the antibacterial rate is lower than that of Example 1, which indicates that when S-nitrosoglutathione and S-nitroso-N-acetylcysteine ​​are used in combination, the antibacterial effect of the product can be synergistically enhanced. It can also be obtained from the data in Table 4 that when the mesh number of the first sieving screen is 55 meshes in Example 14, the antibacterial effect is worse than that of Example 1, indicating that larger particles are not conducive to the original role of each component in the product, resulting in the inability to fully exert the antibacterial active ingredients; when the mesh number of the first sieving screen is 110 meshes in Example 15, the antibacterial effect is worse than that of Example 1, indicating that finer particles are easily mixed and floated on the surface, and cannot be mixed evenly with other materials, resulting in the inability to fully exert the antibacterial effect.

[0140] Test Example 5

[0141] The foaming performance of the products prepared in Examples 1, 6, and 7 was tested. The specific evaluation method was as follows: 10 volunteers chewed the tablets in each example and scored according to the amount of foam, with the scoring criteria being (1) moderate foam, 3 points; (2) little foam, 2 points; (3) almost no foam, 1 point; and the average value was calculated based on the scoring results.

[0142] Table 5

[0143] Foaming performance scoring Example 1 2.8 Example 6 1.8 Example 7 2.4

[0144] It can be seen from the data in Table 5 that when Examples 6 and 7 respectively use single components of sodium dodecyl sulfate and Tween-80, the foaming performance is poorer than that of Example 1, indicating that the combined use of sodium dodecyl sulfate and Tween-80 can achieve a significant foaming effect.

[0145] The applicant declares that the present invention illustrates the process method of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned process steps, that is, it does not mean that the present invention must rely on the above-mentioned process steps to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of the raw materials selected by the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A chewable effervescent tablet capable of self-providing nitric oxide, characterized in that: The chewable effervescent tablet capable of self-providing nitric oxide comprises, by weight, 0.5-8 parts of active material, 10-30 parts of acid source, 20-40 parts of alkali source, 1-3 parts of surfactant, 2-6 parts of lubricant and 35-50 parts of filler; Wherein, the active material comprises L-arginine, vitamin C and an exogenous nitric oxide donor; the mass ratio of L-arginine, vitamin C and exogenous nitric oxide donor is (4-10):1:(1-4); The surfactant is a combination of sodium lauryl sulfate and Tween-80; The lubricant is a combination of polyethylene glycol 6000 and magnesium stearate; The filler is a combination of lactose and mannitol; The chewable effervescent tablet capable of self-providing nitric oxide is prepared by the following method, which comprises: crushing an acid source, a part of a lubricant and L-arginine, sieving for the first time to obtain a mixture; mixing the mixture with an alkali source, a surfactant, a filler, the remaining lubricant, an exogenous nitric oxide donor and vitamin C, sieving for the second time, and tableting and granulating to obtain the chewable effervescent tablet capable of self-providing nitric oxide; The first screening process uses a sieve with a mesh size of 60-100.

2. The chewable effervescent tablet capable of self-providing nitric oxide according to claim 1, characterized in that: The exogenous nitric oxide donor includes any one of S-nitrosoglutathione, S-nitroso-N-acetylpenicillamine or S-nitroso-N-acetylcysteine, S-nitrosotriphenylmethylmercaptan, S-nitrosocysteine, S-nitrosothioglycerol, S-nitrosomethicone, S-nitrosothioethylamine, S-nitroso-3-mercaptopropionic acid, and S-nitroso-D-thioglucose, or a combination of at least two thereof.

3. The chewable effervescent tablet capable of self-providing nitric oxide according to claim 2, characterized in that: The exogenous nitric oxide donor includes S-nitrosoglutathione and / or S-nitroso-N-acetylcysteine.

4. The chewable effervescent tablet capable of self-providing nitric oxide according to claim 3, characterized in that: The exogenous nitric oxide donor is a combination of S-nitrosoglutathione and S-nitroso-N-acetylcysteine.

5. The chewable effervescent tablet capable of self-providing nitric oxide according to claim 4, characterized in that: The molar ratio of S-nitrosoglutathione to S-nitroso-N-acetylcysteine ​​is (1-3):

1.

6. The chewable effervescent tablet capable of self-providing nitric oxide according to claim 1, characterized in that: The acid source includes any one of citric acid, tartaric acid, fumaric acid or malic acid, or a combination of at least two of them.

7. The chewable effervescent tablet capable of self-providing nitric oxide according to claim 6, characterized in that: The acid source includes malic acid and / or citric acid.

8. The chewable effervescent tablet capable of self-providing nitric oxide according to claim 1, characterized in that: The alkali source includes any one of sodium bicarbonate, potassium bicarbonate or sodium carbonate, or a combination of at least two of them.

9. The chewable effervescent tablet capable of self-providing nitric oxide according to claim 8, characterized in that: The alkali source includes sodium bicarbonate and / or sodium carbonate.

10. The chewable effervescent tablet capable of self-providing nitric oxide according to claim 1, characterized in that: The mass ratio of polyethylene glycol 6000 to magnesium stearate is (1-5):

1.

11. The chewable effervescent tablet capable of self-providing nitric oxide according to claim 1, characterized in that: The mass ratio of lactose to mannitol is (6-12):

1.

12. The chewable effervescent tablet capable of self-providing nitric oxide according to claim 1, characterized in that: The chewable effervescent tablet capable of self-supplying nitric oxide further comprises a sweetener.

13. The chewable effervescent tablet capable of self-providing nitric oxide according to claim 12, characterized in that: The sweetener includes any one of sucralose, aspartame or stevioside, or a combination of at least two of them.

14. The method for preparing a chewable effervescent tablet capable of self-providing nitric oxide according to any one of claims 1 to 13, characterized in that: The preparation method comprises: The acid source, part of the lubricant and L-arginine are crushed and sieved for the first time to obtain a mixture; the mixture is mixed with an alkali source, a surfactant, a filler, the remaining lubricant, an exogenous nitric oxide donor and vitamin C, sieved for a second time, and tableted and granulated to obtain the chewable effervescent tablet capable of self-providing nitric oxide; The first screening process uses a sieve with a mesh size of 60-100.

15. The method for preparing the chewable effervescent tablet capable of self-providing nitric oxide according to claim 14, characterized in that: The second screening process uses a sieve with mesh size of 10-30.

16. Use of the chewable effervescent tablet capable of self-providing nitric oxide according to any one of claims 1 to 13 in the preparation of oral care products.

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