Persistent antibacterial composite tooth socket for drug loading and preparation method thereof

Abstract

The invention relates to the field of oral cavities, and particularly discloses a lasting antibacterial type composite tooth socket for medicine carrying and a preparation method thereof.The lasting antibacterial type composite tooth socket comprises an adsorption layer and an antibacterial membrane layer, the adsorption layer is used for adsorbing oral cavity treatment liquid medicine, and the antibacterial membrane layer comprises a nano-silver antibacterial layer and a chitosan antibacterial layer; the preparation method comprises the following steps: mixing a tea polyphenol-polylactic acid composite solution, a nano-silver-carboxylation modified cellulose compound and a polyvinyl alcohol solution, and carrying out electrostatic spinning to prepare a nano-silver antibacterial fiber membrane, so as to form the nano-silver antibacterial layer; mixing chitosan with hot water, adding cinnamyl aldehyde, glycerol and boric acid, stirring to obtain a mixed solution, coating one side of the nano-silver antibacterial layer with the mixed solution, and curing to form a chitosan antibacterial layer; the adsorption layer is attached to the side, away from the chitosan antibacterial layer, of the nano-silver antibacterial layer, and then the lasting antibacterial type composite tooth socket for carrying the medicine is prepared through hot-pressing compounding. The drug-loaded composite tooth socket has the characteristic of further improving the antibacterial property and the antibacterial durability of the drug-loaded composite tooth socket.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of oral cavity, more particularly, it relates to a long-lasting antibacterial composite mouthpiece for drug loading and a preparation method thereof. BACKGROUND

[0002] Traditional mouthpieces are mainly used for tooth correction, guiding tooth movement by applying continuous and stable correction force to achieve the purpose of improving tooth arrangement and occlusal relationship. However, the traditional mouthpiece has limitations in function and cannot directly treat oral diseases such as oral ulcer, periodontitis, halitosis, etc. In addition, during the period of wearing the mouthpiece, due to the close fit of the mouthpiece and the teeth, the difficulty of oral cleaning increases, and bacteria are easily bred, further aggravating the oral problems.

[0003] With the improvement of oral health awareness, people's demand for tooth treatment and health care is increasing. Traditional tooth treatment methods such as mouthwash and local medication have the problems of short drug retention time in the oral cavity, slow efficacy, and difficulty in accurately acting on the lesion site. Especially during the period of wearing the mouthpiece, due to the obstruction of the mouthpiece, the difficulty of local medication increases, and the drug is difficult to directly act on the lesion site, limiting the treatment effect.

[0004] As an innovative tooth correction technology, invisible aligners are rapidly popularizing worldwide due to their aesthetic, comfortable and convenient features. However, the existing invisible aligners mainly focus on the correction function of teeth, and the treatment and health care function of teeth is relatively limited. Some aligners or appliances with drug loading function still have deficiencies in antibacterial performance and wearing comfort.

[0005] For example, a new drug-loaded composite appliance film is disclosed in the related art, which includes a body and a tooth groove formed on the body. The body is composed of an inner film layer, a middle drug-loading layer and an outer film layer. The inner film layer is provided with micropores, the middle drug-loading layer is adsorbed with drugs, the middle drug-loading layer is made of a material with slow-release function, and the outer film layer is a dense and airtight structure. However, this appliance film has deficiencies in antibacterial performance, antibacterial durability and stability.

[0006] Therefore, it is of great significance to develop a drug-loaded composite mouthpiece with good antibacterial performance and antibacterial durability to meet market demand. SUMMARY

[0007] In order to further improve the antibacterial and antibacterial durability of the drug-loaded composite mouthpiece, the present application provides a long-lasting antibacterial composite mouthpiece for drug loading and a preparation method thereof.

[0008] In a first aspect, the present application provides a long-lasting antibacterial composite mouthpiece for drug loading, which adopts the following technical solution: The application discloses a long-acting antibacterial composite dental cover for drug loading, which comprises an adsorption layer for adsorbing a therapeutic oral liquid and an antibacterial film layer, wherein the adsorption layer is in contact with the oral cavity, and the antibacterial film layer comprises a nanosilver antibacterial layer and a chitosan antibacterial layer, and the nanosilver antibacterial layer is between the chitosan antibacterial layer and the adsorption layer. The nanosilver antibacterial layer is prepared by electrospinning a nanosilver antibacterial fiber film prepared by mixing a tea polyphenol-polylactic acid composite solution, a nanosilver-carboxymethylated cellulose compound and a polyvinyl alcohol solution. The chitosan antibacterial layer is prepared by coating and solidifying a mixture of chitosan, cinnamyl aldehyde, glycerol and boric acid on the nanosilver antibacterial layer.

[0009] By adopting the technical scheme, the adsorption layer realizes slow release of the drug through physical adsorption or chemical bonding, and on this basis, the antibacterial film layer in the application is prepared by electrospinning a fiber film, so that a porous structure with a high specific surface area is formed, which can realize further adsorption and slow release of the drug, and on the other hand, it is helpful for the release of nanosilver and tea polyphenol to play an antibacterial role, and at the same time, a physical barrier is provided to prevent bacterial adhesion. In the chitosan antibacterial layer, the synergistic effect of chitosan and cinnamyl aldehyde is utilized to realize spectrum antibiosis by destroying bacterial cell membranes and inhibiting bacterial metabolism, boric acid is used as a crosslinking agent to form a stable network structure, so as to prolong the durability of the antibacterial layer, and in addition, chitosan not only has excellent biocompatibility, but also can enhance the adhesion of the dental cover to the oral tissue, so as to reduce the risk of falling off.

[0010] Finally, the mutual cooperation of the double-layer antibacterial structure in the application, especially the cooperation between the electrospun fiber film layer and the coating layer, on the one hand, reduces the loss of antibacterial components and improves the long-term effective release of the antibacterial components, and on the other hand, the high specific surface area and porosity of the electrospun fiber film can increase the contact area of nanosilver and bacteria, so as to improve the bacteriostatic effect, and the antibacterial components in the chitosan antibacterial layer can also play an antibacterial effect through the pore structure, finally, the composite dental cover prepared in the application can release the drug through the adsorption layer, and at the same time, the antibacterial film layer has a higher bacteriostatic rate and a more durable bacteriostatic effect.

[0011] Optionally, the nanosilver-carboxymethylated cellulose compound is prepared by the following method: 1) carboxymethyl cellulose is dissolved in water, a silver nitrate solution with a mass concentration of 15-20wt% is added, ascorbic acid is added after stirring and mixing, and then the mixture is stirred and reacted at 50-60 DEG C for 2-3h, and then the mixture is cooled, filtered, washed with water and dried to obtain nanosilver-loaded carboxymethyl cellulose; 2) chitosan oligosaccharide is dissolved in hot water at 50-60℃, mixed and stirred, then heated to 70-80℃, then add the carboxymethyl cellulose loaded with nano-silver, then stir, add ammonium persulfate, stir for 2-3h, then filter, dry, and prepare nano-silver-carboxylated modified cellulose composite.

[0012] By adopting the above technical scheme, after the carboxymethyl cellulose is dissolved in water, the silver nitrate solution is added, the silver nitrate ions are uniformly dispersed in the solution, ascorbic acid is added as a reducing agent to reduce the silver ions into nano-silver particles, and due to the negative charge on the surface of the carboxymethyl cellulose, the system is stable by electrostatic repulsion, and the nano-silver particles are uniformly dispersed on the carboxymethyl cellulose system, so that the carboxymethyl cellulose with uniformly dispersed nano-silver is obtained. Then the carboxymethyl cellulose is further modified by chitosan oligosaccharide, and under the action of ammonium persulfate as an initiator, the amino and hydroxyl functional groups on the chitosan oligosaccharide form chemical bonds with the carboxyl functional groups on the carboxymethyl cellulose, and the chitosan oligosaccharide is grafted onto the carboxymethyl cellulose to form a nano-silver-carboxylated modified cellulose composite.

[0013] The post-modification of chitosan oligosaccharide not only synergistically enhances the antibacterial effect of silver nanoparticles, but more importantly, the chitosan oligosaccharide is grafted onto the carboxymethyl cellulose to form a stable chemical bonding structure, which has a certain effect on slowing down the release speed of the nano-silver loaded on the carboxymethyl cellulose. It forms an antibacterial protective film on the surface, continuously inhibits the growth and reproduction of bacteria, prolongs the antibacterial time, and improves the antibacterial durability. At the same time, it increases the interaction force between the molecular chains, and the molecular chains of carboxymethyl cellulose and chitosan oligosaccharide are intertwined and crosslinked to form a more compact network structure, improving the strength and toughness of the composite dental cover, which is not easy to break or deform during use, and has better mechanical properties.

[0014] Optionally, during the preparation of the nano-silver-carboxylated modified cellulose composite, In step 1), the mass ratio of carboxymethyl cellulose to water is 1:(4-5), and the mass ratio of carboxymethyl cellulose to silver nitrate is 1:(0.6-0.8), and the amount of ascorbic acid added is 3-5wt% of silver nitrate; In step 2), the mass ratio of chitosan oligosaccharide to hot water is 1:(2-3), and the amount of chitosan oligosaccharide added is 5-8wt% of the carboxymethyl cellulose loaded with nano-silver, and the amount of ammonium persulfate added is 2-5wt% of chitosan oligosaccharide.

[0015] By adopting the above technical scheme, when the above amount is selected, the comprehensive performance of the antibacterial performance and mechanical properties of the finally prepared composite dental cover is better.

[0016] Optionally, in the preparation process of the nanosilver-carboxymethylated cellulose composite, in step 1), silver nitrate solution is added, and zinc nitrate solution and cerium nitrate solution are also added, the mass concentration of zinc nitrate in the zinc nitrate solution is 3-5 wt%, the mass concentration of cerium nitrate in the cerium nitrate solution is 1-3 wt%, and the mass ratio of zinc nitrate, cerium nitrate and silver nitrate is 1:(0.4-0.5):(2.5-3). And ascorbic acid is added, and sodium borohydride is also added, the amount of sodium borohydride added is 0.5-1.5 wt% of silver nitrate.

[0017] By adopting the above technical solution, when the nanosilver is loaded on the carboxymethyl cellulose, zinc nitrate solution and cerium nitrate solution are also added, in the process of reducing the nanosilver, zinc ions are partially reduced and doped into the nanosilver lattice, changing the electronic structure of the nanosilver and improving its antibacterial activity, it is found that the nanosilver doped with zinc has more spectral antibacterial performance, and in the process of reducing and doping the nanosilver, cerium ions can participate in electron transfer to promote the formation of nanosilver and the doping of zinc, thereby further improving the antibacterial activity.

[0018] Optionally, the nanosilver antibacterial layer is prepared by the following method: Preparation of tea polyphenol-polylactic acid composite solution: poly-lactic acid is mixed with dichloromethane and N,N-dimethylformamide to obtain a polylactic acid solution, then tea polyphenol is added and stirred to obtain a tea polyphenol-polylactic acid composite solution; Preparation of spinning solution: polyvinyl alcohol is mixed with water to obtain a polyvinyl alcohol solution, then the polyvinyl alcohol solution is mixed with the tea polyphenol-polylactic acid composite solution and the nanosilver-carboxymethylated cellulose composite, and polysorbate is added, then stirred to obtain a spinning solution; Electrospinning: the prepared spinning solution is deposited by electrospinning to form a nanosilver antibacterial fiber membrane.

[0019] By adopting the above technical solution, in the preparation process of the nanosilver antibacterial layer in the present application, polyvinyl alcohol is used as a substrate to promote the formation of a fiber membrane, tea polyphenol has antioxidant and antibacterial activity, and nanosilver has spectral antibacterial properties, tea polyphenol has antibacterial effect by inhibiting bacterial enzyme activity or destroying cell walls, nanosilver destroys bacterial cell membranes and DNA by releasing silver ions, and inhibits bacterial reproduction, the above-mentioned tea polyphenol and nanosilver are compounded and applied to significantly improve the antibacterial effect, and the combination of tea polyphenol and polylactic acid can enhance biocompatibility while significantly improving the mechanical properties, and the addition of carboxymethylated cellulose can improve the dispersibility and stability of nanosilver and reduce agglomeration.

[0020] The polyvinyl alcohol solution is mixed with the tea polyphenol-polylactic acid composite solution and the nano-silver-carboxymethylated cellulose composite, and then poly sorbate is added. The molecular chains of the polyvinyl alcohol and the polylactic acid are intertwined, the nano-silver-carboxymethylated cellulose composite and the polymer solution form interaction to form a uniform system, and the flowability and spinnability of the system are improved by adding the poly sorbate, so that the raw materials are fully dispersed and mixed, a spinning solution is prepared, and then an electrospinning process is performed to form a fiber membrane with a certain pore structure, which is helpful to the antibacterial effect and has a certain slow-release effect on the fiber membrane structure, thereby improving the antibacterial durability.

[0021] Optionally, in the preparation process of the nano-silver antibacterial layer, in the step of preparing the tea polyphenol-polylactic acid composite solution, the mass ratio of polylactic acid to dichloromethane and N,N-dimethylformamide is 1: (1.2-1.5): (0.6-0.8), and the mass ratio of tea polyphenol to polylactic acid is 1: (3-4). In the step of preparing the spinning solution, the mass ratio of polyvinyl alcohol to water is 1: (2-3), and the mass ratio of polyvinyl alcohol, tea polyphenol-polylactic acid composite solution and nano-silver-carboxymethylated cellulose composite is 1: (0.6-0.8): (0.8-1), and the poly sorbate is added in an amount of 3-5 wt% of the polyvinyl alcohol.

[0022] By using the above technical solution, the nano-silver antibacterial layer prepared by the above ratio has better antibacterial durability.

[0023] Optionally, in the preparation process of the nano-silver antibacterial layer, the electrospinning parameters are as follows: the spinning voltage is 15-20 kV, the spinning distance is 15-18 cm, and the spinning speed is 0.5-0.9 ml / h.

[0024] Optionally, the raw materials in the chitosan antibacterial layer are added in the following weight parts: 10-15 parts of chitosan, 3-5 parts of cinnamaldehyde, 8-15 parts of glycerol and 1-3 parts of boric acid.

[0025] In a second aspect, the application provides a preparation method of a drug-loaded durable antibacterial composite dental cover, which uses the following technical solution: A preparation method of a drug-loaded durable antibacterial composite dental cover, comprising the following steps: S1. mixing a tea polyphenol-polylactic acid composite solution and a nano-silver-carboxymethylated cellulose composite with a polyvinyl alcohol solution, and then electrospinning to prepare a nano-silver antibacterial fiber membrane and form a nano-silver antibacterial layer; S2. mixing chitosan with hot water at 50-60℃ in a mass ratio of 1: (2-3), then adding cinnamaldehyde, glycerol and boric acid, and stirring to prepare a mixed solution, coating the mixed solution on one side of the nano-silver antibacterial layer, and then performing solidification treatment at 70-90℃ to form a chitosan antibacterial layer. S3, adhere the adsorption layer to the side of the nanosilver antibacterial layer away from the chitosan antibacterial layer, and then hot-press to obtain the long-lasting antibacterial composite dental cover for drug loading.

[0026] Optionally, the hot-pressing parameters are as follows: hot-pressing temperature is 140-180℃, pressure is 2-4MPa, and time is 10-30min.

[0027] In summary, the present application has the following beneficial effects: 1. In the present application, the mutual cooperation of the double-layer antibacterial structure, especially the structural cooperation between the electrospun fiber membrane layer and the coating layer, on the one hand reduces the loss of antibacterial components and improves the long-term effective release of the antibacterial components, and on the other hand, the high specific surface area and porosity of the electrospun fiber membrane can increase the contact area of the nanosilver and bacteria and improve the bacteriostatic effect, and the antibacterial components in the chitosan antibacterial layer can also play an antibacterial effect through the pore structure, and finally the composite dental cover prepared in the present application can release drugs through the adsorption layer, and the antibacterial membrane layer has a higher bacteriostatic rate and a more durable bacteriostatic effect. 2. In the present application, the post-modification of chitooligosaccharide on the one hand synergistically enhances the antibacterial effect of silver nanoparticles, and more importantly, the chitooligosaccharide is grafted onto the carboxymethyl cellulose to form a stable chemical bonding structure, which has a certain effect on slowing down the release speed of the nanosilver loaded on the carboxymethyl cellulose. It forms an antibacterial protective film on the surface, continuously inhibits the growth and reproduction of bacteria, prolongs the antibacterial time, and improves the antibacterial durability, and at the same time, it increases the interaction force between the molecular chains, and the molecular chains of carboxymethyl cellulose and chitooligosaccharide are intertwined and crosslinked to form a more compact network structure, improving the strength and toughness of the composite dental cover, which is not easy to break or deform during use, and has better mechanical properties. DETAILED DESCRIPTION

[0028] The present application is further described in detail below in conjunction with the examples, and it is particularly pointed out that: in the following examples, the specific conditions are not specified, and the conventional conditions or the conditions recommended by the manufacturer are used, and the raw materials used in the following examples can be obtained from ordinary market sources unless otherwise specified.

[0029] The following preparation example is a preparation example of a nanosilver-carboxymethyl cellulose composite.

[0030] Preparation Example 1 A preparation method of a nanosilver-carboxymethyl cellulose composite, comprising the following steps: 1) carboxymethyl cellulose is dissolved in 4.5 times the amount of water by mass, then a silver nitrate solution with a mass concentration of 18wt% is added, after stirring and mixing, ascorbic acid is added, after stirring and reacting at 55℃ for 2.5h, it is cooled, filtered, washed with water, and dried to obtain carboxymethyl cellulose loaded with nano-silver; The mass ratio of carboxymethyl cellulose to silver nitrate is 1:0.7, and the amount of ascorbic acid added is 4wt% of the silver nitrate. 2) chitooligosaccharide is dissolved in 2.5 times the amount of hot water by mass at 55℃, after stirring and mixing, it is heated to 75℃, then the carboxymethyl cellulose loaded with nano-silver prepared in step 1) is added and stirred, ammonium persulfate is added, after stirring and reacting for 2.5h, it is filtered and dried to obtain a nano-silver-carboxymodified cellulose composite, the amount of chitooligosaccharide added is 6wt% of the carboxymethyl cellulose loaded with nano-silver, and the amount of ammonium persulfate added is 3wt% of the chitooligosaccharide.

[0031] Preparation Example 2 A method for preparing a nano-silver-carboxymodified cellulose composite, comprising the following steps: 1) carboxymethyl cellulose is dissolved in 4 times the amount of water by mass, then a silver nitrate solution with a mass concentration of 15wt% is added, after stirring and mixing, ascorbic acid is added, after stirring and reacting at 50℃ for 3h, it is cooled, filtered, washed with water, and dried to obtain carboxymethyl cellulose loaded with nano-silver; The mass ratio of carboxymethyl cellulose to silver nitrate is 1:0.6, and the amount of ascorbic acid added is 3wt% of the silver nitrate. 2) chitooligosaccharide is dissolved in 3 times the amount of hot water by mass at 50℃, after stirring and mixing, it is heated to 70℃, then the carboxymethyl cellulose loaded with nano-silver prepared in step 1) is added and stirred, ammonium persulfate is added, after stirring and reacting for 3h, it is filtered and dried to obtain a nano-silver-carboxymodified cellulose composite, the amount of chitooligosaccharide added is 5wt% of the carboxymethyl cellulose loaded with nano-silver, and the amount of ammonium persulfate added is 2wt% of the chitooligosaccharide.

[0032] Preparation Example 3 A method for preparing a nano-silver-carboxymodified cellulose composite, comprising the following steps: 1) carboxymethyl cellulose is dissolved in 5 times the amount of water by mass, then a silver nitrate solution with a mass concentration of 20wt% is added, after stirring and mixing, ascorbic acid is added, after stirring and reacting at 60℃ for 2h, it is cooled, filtered, washed with water, and dried to obtain carboxymethyl cellulose loaded with nano-silver; The mass ratio of carboxymethyl cellulose to silver nitrate is 1:0.8, and the amount of ascorbic acid added is 5wt% of the silver nitrate. 2) chitosan oligosaccharide is dissolved in 3 times of 60℃ hot water, mixed and stirred, then heated to 80℃, then carboxymethyl cellulose loaded with nano-silver prepared in step 1) is added and stirred, ammonium persulfate is added, stirred for 2h, then filtered, dried, to prepare a nano-silver-carboxymethyl cellulose composite, the amount of chitosan oligosaccharide is 8wt% of the carboxymethyl cellulose loaded with nano-silver, and the amount of ammonium persulfate is 5wt% of the chitosan oligosaccharide.

[0033] Preparation Example 4 A method for preparing a nano-silver-carboxymethyl cellulose composite, which is prepared according to the method in Preparation Example 1, except that in step 1), silver nitrate solution is added together with zinc nitrate solution and cerium nitrate solution, the mass concentration of zinc nitrate in zinc nitrate solution is 4wt%, the mass concentration of cerium nitrate in cerium nitrate solution is 2wt%, and the mass ratio of zinc nitrate, cerium nitrate and silver nitrate is 1:0.45:2.8. Ascorbic acid is added together with sodium borohydride, and the amount of sodium borohydride is 1wt% of silver nitrate.

[0034] Preparation Example 5 A method for preparing a nano-silver-carboxymethyl cellulose composite, which is prepared according to the method in Preparation Example 1, except that in step 1), silver nitrate solution is added together with zinc nitrate solution and cerium nitrate solution, the mass concentration of zinc nitrate in zinc nitrate solution is 3wt%, the mass concentration of cerium nitrate in cerium nitrate solution is 1wt%, and the mass ratio of zinc nitrate, cerium nitrate and silver nitrate is 1:0.4:2.5. Ascorbic acid is added together with sodium borohydride, and the amount of sodium borohydride is 0.5wt% of silver nitrate.

[0035] Preparation Example 6 A method for preparing a nano-silver-carboxymethyl cellulose composite, which is prepared according to the method in Preparation Example 1, except that in step 1), silver nitrate solution is added together with zinc nitrate solution and cerium nitrate solution, the mass concentration of zinc nitrate in zinc nitrate solution is 5wt%, the mass concentration of cerium nitrate in cerium nitrate solution is 3wt%, and the mass ratio of zinc nitrate, cerium nitrate and silver nitrate is 1:0.5:3. Ascorbic acid is added together with sodium borohydride, and the amount of sodium borohydride is 1.5wt% of silver nitrate.

[0036] Preparation Example 7 A preparation method of a nano-silver-carboxymodified cellulose composite, which is prepared according to the method in Preparation Example 1, except that in the preparation process of the nano-silver-carboxymodified cellulose composite, in step 1), silver nitrate solution is added, and at the same time, zinc nitrate solution is also added, the mass concentration of zinc nitrate in the zinc nitrate solution is 3-5wt%, and the mass ratio of zinc nitrate to silver nitrate added is 1:2.8; And ascorbic acid is added at the same time, and sodium borohydride is also added, the amount of sodium borohydride added is 1wt% of silver nitrate.

[0037] Preparation Example 8 A preparation method of a nano-silver-carboxymodified cellulose composite, which is prepared according to the method in Preparation Example 1, except that in the preparation process of the nano-silver-carboxymodified cellulose composite, in step 1), silver nitrate solution is added, and at the same time, cerium nitrate solution is also added, the mass concentration of cerium nitrate in the cerium nitrate solution is 2wt%, and the mass ratio of cerium nitrate to silver nitrate added is 0.45:2.8; And ascorbic acid is added at the same time, and sodium borohydride is also added, the amount of sodium borohydride added is 1wt% of silver nitrate.

[0038] Comparative Preparation Example 1 A preparation method of a nano-silver-carboxymodified cellulose composite, which is prepared according to the method in Preparation Example 1, except that step 2) is not performed, and the carboxymethyl cellulose loaded with nano-silver prepared in step 1) is the nano-silver-carboxymodified cellulose composite.

[0039] The adsorption layer in the following examples is a hydrophilic polymer for adsorbing oral cavity treatment liquid, and the drug molecules are fixed through physical adsorption or chemical action to treat oral cavity diseases. In the following examples, the adsorption layer is specifically polyacrylamide gel. In this application, the composite mouthpiece is soaked to allow the liquid medicine to enter the adsorption layer for treatment.

[0040] Example 1

[0041] A preparation method of a drug-loaded long-acting antibacterial composite mouthpiece, comprising the following steps: S1, the specific operation comprises the following steps: S1-1, preparing a tea polyphenol-polylactic acid composite solution: mixing polylactic acid, dichloromethane and N,N-dimethylformamide according to a mass ratio of 1:1.3:0.7 to obtain a polylactic acid solution, then adding tea polyphenol and stirring to obtain a tea polyphenol-polylactic acid composite solution, the mass ratio of tea polyphenol to polylactic acid added is 1:3.5; S1-2, preparing a spinning solution: polyvinyl alcohol and water are mixed in a mass ratio of 1:2.5 to prepare a polyvinyl alcohol solution, then the polyvinyl alcohol solution is mixed with a tea polyphenol-polylactic acid composite solution and a nanosilver-carboxymethylated cellulose composite prepared in Preparation Example 1, and polysorbate 80 is added, the amount of polysorbate 80 added is 4wt% of the polyvinyl alcohol, and the mass ratio of the polyvinyl alcohol, the tea polyphenol-polylactic acid composite solution, and the nanosilver-carboxymethylated cellulose composite is 1:0.7:0.9, then the mixture is stirred to prepare a spinning solution; S1-3, electrospinning: the prepared spinning solution is deposited by electrospinning to form a nanosilver antibacterial fiber membrane, and the thickness of the nanosilver antibacterial layer is 60μm; and the electrospinning parameters are a spinning voltage of 18kV, a spinning distance of 15cm, and a spinning speed of 0.6ml / h; S2, specifically comprising the following steps: S2-1, material preparation: the materials are prepared according to the following amounts: 12g of chitosan, 4g of cinnamaldehyde, 12g of glycerol, and 2g of boric acid; S2-2, preparation: chitosan is mixed with hot water at 55℃ in a mass ratio of 1:2.5, then cinnamaldehyde, glycerol, and boric acid are added, and a mixed solution is prepared by stirring, the mixed solution is coated on one side of the nanosilver antibacterial layer, and then solidified at 70℃ to form a chitosan antibacterial layer with a thickness of 20μm; S3, the adsorption layer is attached to the side of the nanosilver antibacterial layer away from the chitosan antibacterial layer, and then hot-pressed to prepare a durable antibacterial composite mouthpiece for drug loading, and the hot-pressing parameters are a hot-pressing temperature of 160℃, a pressure of 3MPa, and a time of 20min.

[0042] Example 2

[0043] A method for preparing a durable antibacterial composite mouthpiece for drug loading, comprising the following steps: S1, specifically comprising the following steps: S1-1, preparing a tea polyphenol-polylactic acid composite solution: polylactic acid is mixed with dichloromethane and N,N-dimethylformamide in a mass ratio of 1:1.2:0.6 to obtain a polylactic acid solution, then tea polyphenol is added and stirred to prepare a tea polyphenol-polylactic acid composite solution, and the mass ratio of tea polyphenol to polylactic acid is 1:3; S1-2, preparing a spinning solution: polyvinyl alcohol and water are mixed in a mass ratio of 1:2 to prepare a polyvinyl alcohol solution, then the polyvinyl alcohol solution is mixed with the tea polyphenol-polylactic acid composite solution and the nanosilver-carboxymethylated cellulose composite prepared in Preparation Example 2, and polysorbate 80 is added, the amount of polysorbate 80 added is 3wt% of the polyvinyl alcohol, and the mass ratio of the polyvinyl alcohol, the tea polyphenol-polylactic acid composite solution and the nanosilver-carboxymethylated cellulose composite is 1:0.6:0.8, then the spinning solution is prepared after stirring and mixing; S1-3, electrospinning: the prepared spinning solution is deposited by electrospinning to form a nanosilver antibacterial fiber membrane, and the thickness of the nanosilver antibacterial layer is 60μm; and the electrospinning parameters are a spinning voltage of 15kV, a spinning distance of 15cm, and a spinning speed of 0.5ml / h; S2, specifically comprising the following steps: S2-1, preparing materials: preparing materials according to the following raw material addition amount: 10g of chitosan, 3g of cinnamaldehyde, 8g of glycerol and 1g of boric acid; S2-2, preparation: chitosan is mixed with hot water at 50℃ in a mass ratio of 1:2, then cinnamaldehyde, glycerol and boric acid are added, and a mixed solution is prepared by stirring, the mixed solution is coated on one side of the nanosilver antibacterial layer, and then solidified at 60℃ to form a chitosan antibacterial layer with a thickness of 20μm; S3, the adsorption layer is attached to the side of the nanosilver antibacterial layer away from the chitosan antibacterial layer, and then hot-pressed to prepare a durable antibacterial composite mouthpiece for drug loading, and the hot-pressing parameters are a hot-pressing temperature of 140℃, a pressure of 2MPa, and a time of 30min.

[0044] Example 3

[0045] A method for preparing a durable antibacterial composite mouthpiece for drug loading, comprising the following steps: S1, the specific operation comprises the following steps: S1-1, preparing a tea polyphenol-polylactic acid composite solution: polylactic acid is mixed with dichloromethane and N,N-dimethylformamide in a mass ratio of 1:1.5:0.8 to obtain a polylactic acid solution, then tea polyphenol is added and stirred to prepare a tea polyphenol-polylactic acid composite solution, and the mass ratio of tea polyphenol to polylactic acid is 1:4; S1-2, preparing a spinning solution: polyvinyl alcohol and water were mixed in a mass ratio of 1:3 to prepare a polyvinyl alcohol solution, then the polyvinyl alcohol solution was mixed with a tea polyphenol-polylactic acid composite solution and a nanosilver-carboxymethylated cellulose composite prepared in Preparation Example 3, and polysorbate 80 was added, the amount of polysorbate 80 being 5wt% of the polyvinyl alcohol, and the mass ratio of the polyvinyl alcohol, the tea polyphenol-polylactic acid composite solution and the nanosilver-carboxymethylated cellulose composite being 1:0.8:1, then the mixture was stirred to prepare a spinning solution; S1-03, electrospinning: the prepared spinning solution was deposited by electrospinning to form a nanosilver antibacterial fiber membrane, and the thickness of the nanosilver antibacterial layer was 60μm; and the electrospinning parameters were a spinning voltage of 20kV, a spinning distance of 18cm, and a spinning speed of 0.5ml / h; S2, specifically comprising the following steps: S2-1, preparing materials: the materials were prepared according to the following amounts: 15g of chitosan, 5g of cinnamaldehyde, 15g of glycerol and 3g of boric acid; S2-2, preparing: chitosan was mixed with hot water at 60℃ in a mass ratio of 1:3, then cinnamaldehyde, glycerol and boric acid were added, and a mixed solution was prepared by stirring, the mixed solution was coated on one side of the nanosilver antibacterial layer, and then solidification treatment was carried out at 80℃ to form a chitosan antibacterial layer with a thickness of 20μm; S3, the adsorption layer was attached to the side of the nanosilver antibacterial layer away from the chitosan antibacterial layer, and then hot pressing was carried out to prepare a durable antibacterial composite mouthpiece for drug loading, and the hot pressing parameters were a hot pressing temperature of 180℃, a pressure of 4MPa and a time of 10min.

[0046] Examples 4-8 A method for preparing a durable antibacterial composite mouthpiece for drug loading was carried out according to the method in Example 1, except that the nanosilver-carboxymethylated cellulose composite in step S1-2 was selected from the nanosilver-carboxymethylated cellulose composite prepared in Preparation Examples 4-8.

[0047] Comparative Example 1 A method for preparing a durable antibacterial composite mouthpiece for drug loading was carried out according to the method in Example 1, except that the nanosilver-carboxymethylated cellulose composite in step S1-2 was selected from the nanosilver-carboxymethylated cellulose composite prepared in Comparative Preparation Example 1.

[0048] Comparative Example 2 A preparation method of a drug-loaded long-lasting antibacterial composite mouthpiece, which is prepared according to the method in Example 1, except that in step S1-2, the nanosilver-carboxymethylated cellulose composite is replaced by an equal amount of a mixture of nanosilver and carboxymethyl cellulose, and the mass ratio of nanosilver to carboxymethyl cellulose is 1:0.9.

[0049] Comparative Example 3 A preparation method of a drug-loaded long-lasting antibacterial composite mouthpiece, which is prepared according to the method in Example 1, except that in step S1, the tea polyphenol-polylactic acid composite solution is replaced by an equal amount of polylactic acid solution without adding tea polyphenol.

[0050] Comparative Example 4 A preparation method of a drug-loaded long-lasting antibacterial composite mouthpiece, which is prepared according to the method in Example 1, except that in step S1, 60 g of polyvinyl alcohol, 14 g of tea polyphenol, 49 g of polylactic acid, and 55 g of the nanosilver-carboxymethylated cellulose composite prepared in Preparation Example 1 are directly mixed and then extruded and granulated (extrusion temperature is 200°C), and then the nanosilver antibacterial layer with the same thickness is prepared by extrusion molding in a tenter at 200°C.

[0051] Comparative Example 5 A preparation method of a drug-loaded long-lasting antibacterial composite mouthpiece, which is prepared according to the method in Example 1, except that step S1 is not performed, and in step S3, the adsorption layer is directly attached to the 80 μm thick chitosan antibacterial layer and then subjected to heat pressing and compounding.

[0052] Comparative Example 6 A preparation method of a drug-loaded long-lasting antibacterial composite mouthpiece, which is prepared according to the method in Example 1, except that step S2 is not performed, and in step S3, the adsorption layer is attached to the 80 μm thick nanosilver antibacterial layer and then subjected to heat pressing and compounding.

[0053] Performance detection The antibacterial film layer obtained after step S2 in the above examples and comparative examples is first subjected to antibacterial performance detection, which is cutting the antibacterial film layer into 1 cm x 1 cm thin pieces. 20 μL of bacterial LB suspension with a concentration of 10 6 CFU / mL is added to the surface, 1 cm x 1 cm polypropylene film is covered on the surface to evenly spread the bacterial (Candida albicans, Streptococcus sanguis, and Streptococcus mutans) suspension on the surface of the thin piece, the sample is incubated at 37°C for 12 h, and then ultrasonic bacterial detachment and plate bacterial culture method are used to determine the antibacterial rate of the sample, and the detection results are shown in Table 1.

[0054] In addition, the antibacterial film layers obtained after step S2 in the above examples and comparative examples were placed in an environment of 55°C and 80 RH% humidity, and after slight rubbing and cleaning treatment every day, the antibacterial rate of the antibacterial film layers after 20 days of treatment was determined according to the above method, and the antibacterial attenuation rate after aging treatment was calculated as ((initial antibacterial rate - antibacterial rate after aging treatment) / initial antibacterial rate) x 100%. The detection results are shown in Table 2.

[0055] Table 1:

[0056] Table 2:

[0057] Referring to the detection results in Tables 1 and 2, the antibacterial film layers prepared in the examples of the present application have excellent antibacterial performance and antibacterial durability. In combination with the detection results of Example 1 and Examples 4-6, when silver nitrate is added to the preparation of the nanosilver-carboxymethylated cellulose composite, and zinc and cerium elements are also added, the antibacterial rate and antibacterial durability of the nanosilver-carboxymethylated cellulose composite against Streptococcus sanguis and Streptococcus mutans are significantly improved. In combination with the detection results of Example 7 and Example 8, when only zinc element is added in Example 7, the antibacterial rate is reduced, and the zinc doping helps to improve the antibacterial effect. In combination with the detection results of Example 8, when only cerium element is added, the antibacterial rate is also significantly reduced compared with Example 4. Although cerium element can also play a synergistic antibacterial effect, when it is combined with zinc, it can promote the doping of zinc and thus significantly improve the antibacterial effect.

[0058] Referring to the detection results of Example 1 and Comparative Example 1, the antibacterial durability of the nanosilver-carboxymethylated cellulose composite in Comparative Example 1 is significantly improved when it is not modified by chitooligosaccharide. In combination with the detection results of Comparative Example 2, when nanosilver and carboxymethyl cellulose are simply mixed and added in the nanosilver antibacterial layer in Comparative Example 2, the antibacterial performance and antibacterial durability are significantly reduced. After the nanosilver is loaded on the carboxymethyl cellulose and treated, on the one hand, it is important for the uniform distribution of the nanosilver, and on the other hand, it helps to achieve slow release and improve the antibacterial durability. In Comparative Example 3, when tea polyphenol is not added in the chitosan antibacterial layer, the antibacterial rate and antibacterial durability against Streptococcus sanguis and Streptococcus mutans are reduced. In combination with the detection results of Comparative Example 4, when the intermediate layer is prepared by extrusion molding, the antibacterial durability is significantly reduced compared with the electrospinning molding method in Example 1. In combination with the detection results of Comparative Examples 5 and 6, when a single antibacterial layer is selected for the antibacterial film layer, the antibacterial performance and antibacterial durability are significantly reduced. The antibacterial film layer prepared by the specific molding method, film layer structure and film layer formula in the examples of the present application has better comprehensive performance in antibacterial performance and antibacterial durability.

[0059] In addition, the tensile strength of the antibacterial film layers prepared in Embodiment 1, Comparative Example 1 and Comparative Examples 5-6 of the present application was detected according to GB / T528-1998, and the abrasion rate was detected according to GB / T3960, and the results are shown in Table 3 below.

[0060] Table 3:

[0061] In combination with the detection results in Table 3 above, the antibacterial film layers prepared in the present application have good tensile strength and abrasion rate, which meet the requirements. When it is necessary to further improve the mechanical properties and abrasion properties thereof, inorganic fillers such as diamond can be added to the antibacterial film layers by using the methods commonly used in the art to further improve the mechanical properties thereof.

[0062] The specific embodiments are merely illustrative of the present application, and are not intended to limit the present application. Those skilled in the art can make modifications to the embodiments without creative contribution after reading the present specification, and the modifications are protected by the patent law as long as they are within the scope of the claims of the present application.

Claims

1. A durable antibacterial composite dental crown for drug delivery, comprising an adsorption layer for adsorbing oral medication and an antibacterial film layer, wherein the adsorption layer is in contact with the oral cavity, characterized in that, The antibacterial membrane layer includes a nano-silver antibacterial layer and a chitosan antibacterial layer, with the nano-silver antibacterial layer located between the chitosan antibacterial layer and the adsorption layer; The nano-silver antibacterial layer is a nano-silver antibacterial fiber membrane prepared by electrospinning a mixture of tea polyphenol-polylactic acid composite solution, nano-silver-carboxylated modified cellulose composite and polyvinyl alcohol solution. The chitosan antibacterial layer is prepared by coating a mixture of chitosan, cinnamaldehyde, glycerol, and boric acid onto a nano-silver antibacterial layer and then curing it.

2. The durable antibacterial composite dental crown for drug delivery according to claim 1, characterized in that: The nano-silver-carboxylated modified cellulose composite was prepared by the following method: 1) After dissolving carboxymethyl cellulose in water, add silver nitrate solution with a mass concentration of 15-20wt%, stir and mix, then add ascorbic acid, stir and react at 50-60℃ for 2-3 hours, cool, filter, wash with water, and dry to obtain carboxymethyl cellulose loaded with nano silver. 2) Dissolve chitosan oligosaccharide in hot water at 50-60℃, mix and stir, then heat to 70-80℃, add carboxymethyl cellulose loaded with nano-silver and stir, add ammonium persulfate, stir and react for 2-3 hours, then filter and dry to obtain nano-silver-carboxylated modified cellulose complex.

3. A durable antibacterial composite dental crown for drug delivery according to claim 2, characterized in that: During the preparation of the nano-silver-carboxylated modified cellulose composite, In step 1), the mass ratio of carboxymethyl cellulose to water is 1:(4-5), the mass ratio of carboxymethyl cellulose to silver nitrate is 1:(0.6-0.8), and the amount of ascorbic acid added is 3-5 wt% of silver nitrate. In step 2), the mass ratio of chitosan oligosaccharide to hot water is 1:(2-3), and the amount of chitosan oligosaccharide added is 5-8 wt% of carboxymethyl cellulose loaded with nano-silver, while the amount of ammonium persulfate added is 2-5 wt% of chitosan oligosaccharide.

4. A durable antibacterial composite dental crown for drug delivery according to claim 2, characterized in that: In the preparation of nano-silver-carboxylated modified cellulose composite, in step 1), zinc nitrate solution and cerium nitrate solution are added along with silver nitrate solution. The mass concentration of zinc nitrate in zinc nitrate solution is 3-5 wt%, and the mass concentration of cerium nitrate in cerium nitrate solution is 1-3 wt%. The mass ratio of zinc nitrate, cerium nitrate and silver nitrate is 1:(0.4-0.5):(2.5-3). In addition to ascorbic acid, sodium borohydride is also added, with the amount of sodium borohydride added being 0.5-1.5 wt% of silver nitrate.

5. A durable antibacterial composite dental crown for drug delivery according to claim 1, characterized in that: The nano-silver antibacterial layer was prepared by the following method: Preparation of tea polyphenol-polylactic acid composite solution: Polylactic acid is mixed with dichloromethane and N,N-dimethylformamide to obtain a polylactic acid solution, and then tea polyphenols are added and stirred to obtain a tea polyphenol-polylactic acid composite solution. Preparation of spinning solution: Polyvinyl alcohol is mixed with water to prepare a polyvinyl alcohol solution. Then, polyvinyl alcohol solution is mixed with tea polyphenol-polylactic acid composite solution and nano silver-carboxylated modified cellulose composite, and polysorbate is added. After stirring and mixing, the spinning solution is obtained. Electrospinning: The prepared spinning solution is deposited by electrospinning to form a nano-silver antibacterial fiber membrane.

6. A durable antibacterial composite dental crown for drug delivery according to claim 5, characterized in that: In the preparation of the nano-silver antibacterial layer, in the step of preparing the tea polyphenol-polylactic acid composite solution, the mass ratio of polylactic acid to dichloromethane and N,N-dimethylformamide is 1:(1.2-1.5):(0.6-0.8), and the mass ratio of tea polyphenols to polylactic acid is 1:(3-4). In the step of preparing the spinning solution, the mass ratio of polyvinyl alcohol to water is 1:(2-3), and the mass ratio of polyvinyl alcohol, tea polyphenol-polylactic acid composite solution and nano silver-carboxylated modified cellulose composite is 1:(0.6-0.8):(0.8-1), and the amount of polysorbate added is 3-5 wt% of polyvinyl alcohol.

7. A durable antibacterial composite dental crown for drug delivery according to claim 5, characterized in that: During the preparation of the nano-silver antibacterial layer, the electrospinning parameters are as follows: spinning voltage is 15-20kV, spinning distance is 15-18cm, and spinning speed is 0.5-0.9ml / h.

8. A durable antibacterial composite dental crown for drug delivery according to claim 1, characterized in that: The ingredients in the chitosan antibacterial layer are added in the following proportions by weight: 10-15 parts chitosan, 3-5 parts cinnamaldehyde, 8-15 parts glycerol and 1-3 parts boric acid.

9. A method for preparing a drug-loaded, durable antibacterial composite dental crown as described in any one of claims 1-8, characterized in that: Includes the following steps: S1. A nano-silver antibacterial fiber membrane is prepared by electrospinning a mixture of tea polyphenol-polylactic acid composite solution, nano-silver-carboxylated modified cellulose composite and polyvinyl alcohol solution to form a nano-silver antibacterial layer. S2. Mix chitosan with hot water at 50-60℃ in a mass ratio of 1:(2-3), then add cinnamaldehyde, glycerol and boric acid, stir to prepare a mixed solution, coat the mixed solution on one side of the nano silver antibacterial layer, and then cure at 60-80℃ for 30-40 minutes to form a chitosan antibacterial layer. S3. The adsorption layer is attached to the side of the nano-silver antibacterial layer away from the chitosan antibacterial layer, and then hot-pressed to obtain a durable antibacterial composite dental crown for drug loading.

10. A method for preparing a drug-loaded, long-lasting antibacterial composite dental crown according to claim 9, characterized in that: The hot-pressing composite parameters are: hot-pressing temperature 140-180℃, pressure 2-4MPa, and time 10-30min.

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