Composite Janus particle

Abstract

The invention provides a composite Janus particle. The composite Janus particle disclosed by the invention can be used for treating the dentin hypersensitivity, not only can be accurately oriented on the surface of the dentin, but also has the effects of inducing mineralization and inhibiting bacteria on the two sides respectively, and has great application potential for treating the dentin hypersensitivity and preventing decayed teeth.

Description

Technical Field

[0001] The invention relates to composite Janus particles and belongs to the field of composite materials. Background Art

[0002] Dentin hypersensitivity (DH) is a common oral health problem worldwide, which is caused by the exposure of dentin and dentinal tubules. The strategy for treating dentine hypersensitivity is to block the dentinal tubules or reduce the activity of dentinal sensory nerve fibers, usually using two methods: home care and clinical desensitization. Home care usually uses anti-sensitivity toothpaste or mouthwash, which patients use twice a day for 4-8 weeks, which can greatly relieve dentine sensitivity. Anti-sensitivity toothpaste usually contains potassium salts, stannous fluoride, calcium complexes, bioactive glass, etc., which can effectively relieve dentine sensitivity. When home care is ineffective, professional intervention can be considered, including local drug desensitization therapy and laser treatment. Local drug desensitization treatment can use desensitizers with similar ingredients to home care products to relieve dentin sensitivity, or use resins and adhesives to block dentinal tubules.

[0003] However, desensitizing drugs usually have the following problems: (1) Anti-sensitive materials other than fluoride have no antibacterial effect, which can easily cause plaque to adhere to the surface of the hard tissue of the tooth, further aggravate the demineralization of the hard tissue, and expose the dentinal tubules. (2) Home desensitizers need to be used for a long time, have a slow onset of action, and a short duration of effect. Once discontinued, there is a risk of recurrence. (3) The obstruction material or anti-sensitizer that blocks the dentinal tubules is not acid-resistant and can be easily worn away by friction or saliva in the oral environment. This makes it impossible to maintain a stable long-term bond, and patients cannot afford the trouble of repeated visits to the doctor. (4) Some desensitizers have certain cytotoxicity and cause damage to human oral cells. For example, the Gluma desensitizer commonly used in clinical practice has glutaraldehyde and β-hydroxyethyl methacrylate (HEMA) as its main components. The coexistence of these two substances will cause cytotoxicity to dental pulp cells and other cells, and has poor biocompatibility.

[0004] Markwitz and Pashely proposed a novel treatment strategy that mimics the natural desensitization process of dentin, allowing the dentinal tubules to spontaneously mineralize and close over time, thereby improving the treated dentin's resistance to mechanical and chemical stresses. Therefore, the ideal treatment approach would be to remineralize the dentin and induce mineral formation. During this process, oral saliva provides calcium and phosphate ions, forming calcium-phosphate-sialoglycoprotein aggregates that occlude the superficial layers of the dentinal tubules, sealing the tubules and blocking external stimuli. Currently used biomimetic molecules include polyacrylic acid (PAA), polyvinylphosphonic acid (PVPA), synthetic peptides, casein phosphopeptide-amorphous calcium phosphate complexes (CPP-ACP), and polydopamine coatings. However, these materials require liquid culture medium for remineralization, and their concentration and duration are critical, making them difficult to use in clinical practice.

[0005] In 1991, renowned French scientist de Gennes first used the term "Janus" in his Nobel Prize acceptance speech to describe Janus particles, particles with dual properties. Over the past 30 years, Janus materials have experienced rapid development, demonstrating numerous novel properties and promising applications. These particles possess two distinct, strictly compartmentalized chemical compositions on their surfaces. Furthermore, the diverse array of reactive chemical groups on Janus particles makes them potentially capable of functionalization. By modifying the particles to respond to magnetic, optical, or thermal factors, the application of Janus materials can be expanded. Janus materials hold broad potential in applications such as solid emulsifiers, interfacial compatibilization, interfacial catalysis, functional coatings, and cell diagnostics and therapy. Summary of the Invention

[0006] Problems to be solved by the invention

[0007] The materials currently used for dentin remineralization include polyacrylic acid (PAA), polyvinylphosphonic acid (PVPA), synthetic peptides, etc., but these materials require liquid culture medium to complete remineralization, and have requirements on concentration and time, making them difficult to put into clinical use.

[0008] Therefore, an object of the present invention is to provide composite Janus particles that can be used to treat dentin hypersensitivity.

[0009] Solutions for solving problems

[0010] The inventors discovered during their research that Janus particles have unique properties in structure and performance. Utilizing these unique properties, the present invention modified the Janus particles so that one side was grafted with a catechol polymer and the other side was grafted with a quaternary ammonium salt polymer. The resulting Janus particles can be used to treat dentin hypersensitivity. Not only can they be precisely oriented on the dentin surface, but both sides can also induce mineralization and inhibit bacteria, respectively. Therefore, they have great application potential for treating dentin hypersensitivity and preventing dental caries, thus completing the present invention.

[0011] That is, the present invention is as follows.

[0012] [1] A composite Janus particle, wherein the surface of the composite Janus particle has a smooth partition and a rough partition, the smooth partition is grafted with a catechol polymer, and the rough partition is grafted with a quaternary ammonium salt polymer.

[0013] [2] The composite Janus particle according to [1], wherein the composite Janus particle body is silicon oxide,

[0014] The composite Janus particles are smooth partitioned silicone-containing catechol polymers,

[0015] The coarsely partitioned organosilicon of the composite Janus particles contains a quaternary ammonium salt polymer.

[0016] [3] The composite Janus particle according to [1] or [2], wherein the composite Janus particle has a diameter of 200 nm or more and 1000 nm or less.

[0017] [4] The method for preparing composite Janus particles according to any one of [1] to [3], wherein the method comprises:

[0018] Step A: Mixing raw material Janus particles, a first organic base and a first halogen-containing compound to obtain Janus particles grafted with the halogen-containing compound;

[0019] Step B: mixing the Janus particles grafted with the halogen-containing compound with a quaternary ammonium salt monomer to obtain Janus particles grafted with the quaternary ammonium salt polymer in rough partitions;

[0020] Step C: mixing the Janus particles with the quaternary ammonium salt polymer grafted onto the rough partitions, a second organic base, and a second halogen-containing compound to obtain Janus particles with the halogen-containing compound grafted onto the smooth partitions and the quaternary ammonium salt polymer grafted onto the rough partitions; and

[0021] Step D: mixing the Janus particles in which the smooth partitions are grafted with the halogen-containing compound and the rough partitions are grafted with the quaternary ammonium salt polymer with catechol monomer to obtain composite Janus particles in which the rough partitions are grafted with the quaternary ammonium salt polymer and the smooth partitions are grafted with the catechol polymer.

[0022] [5] The preparation method according to [4], wherein the step A satisfies at least one of the following conditions:

[0023] (a) the raw material Janus particles are ternary strawberry-shaped Janus particles;

[0024] (b) the first organic base comprises an amine compound or a nitrogen-containing heterocyclic compound;

[0025] (c) the first organic base comprises triethylamine, dimethylamine or pyridine;

[0026] (d) the first halogen-containing compound comprises 2-bromoisobutyryl bromide, N-bromosuccinimide, arsenic chloride or cuprous bromide;

[0027] (e) the mass ratio of the first organic base to the raw material Janus particles is 3:1 to 9:1;

[0028] The mass ratio of the first halogen-containing compound to the raw material Janus particles is 15:1 to 20:1.

[0029] [6] The preparation method according to [4], wherein, in step B, the mass ratio of the quaternary ammonium salt monomer to the Janus particles grafted with the halogen-containing compound is 2:1 to 6:1.

[0030] [7] The preparation method according to [4], wherein the step C satisfies at least one of the following conditions:

[0031] (f) the second organic base comprises an amine compound or a nitrogen-containing heterocyclic compound;

[0032] (g) the second organic base comprises triethylamine, dimethylamine or pyridine;

[0033] (h) the second halogen-containing compound comprises 2-bromoisobutyryl bromide, N-bromosuccinimide, arsenic chloride or cuprous bromide;

[0034] (i) the mass ratio of the second organic base to the Janus particles of the rough partitioned grafted quaternary ammonium salt polymer is 3:1 to 9:1;

[0035] (j) The mass ratio of the second halogen-containing compound to the Janus particles of the rough partitioned grafted quaternary ammonium salt polymer is 15:1 to 20:1.

[0036] [8] The preparation method according to [4], wherein in step D, the mass ratio of the catechol monomer to the Janus particles having the acyl halide compound grafted to the smooth partition and the quaternary ammonium salt polymer grafted to the rough partition is 2:1 to 6:1.

[0037] [9]. A composition comprising the composite Janus particles according to any one of [1] to [3].

[0038]

[10] Use of the composite Janus particles according to any one of [1] to [3] in the preparation of a composition for treating dentin hypersensitivity.

[0039] Effects of the Invention

[0040] This invention addresses the challenges of existing treatments for dentin hypersensitivity, which require repeated use or visits to a doctor, have a short onset of action, and lack antibacterial properties. By developing an in-situ mineralized dentin hypersensitivity treatment technology based on ternary strawberry-shaped Janus particles, the application of Janus particles enables this technology to achieve the following:

[0041] (1) Long-lasting and stable antibacterial performance: The rough surface of Janus particles is grafted with quaternary ammonium polymers. Quaternary ammonium polymers are cationic polymers with broad-spectrum antibacterial activity. Their antibacterial mechanism is to attract bacteria with negatively charged cell membranes through electrostatic effects. The hydrophobic alkyl chains of the polymers take this opportunity to penetrate the cell membranes and induce bacterial cell rupture. This process is a contact sterilization process. While achieving antibacterial effects, it prevents the active components from diffusing into the oral environment, which is beneficial to the long-term antibacterial effect. At the same time, the nanoscale roughness of Janus particles makes the dentin surface coated with them superhydrophobic, which can effectively inhibit bacterial adhesion and further inhibit the formation of biofilms.

[0042] In addition, the quaternary ammonium salt groups grafted onto the rough surface of Janus particles can prevent plaque from adhering to the surface of hard tooth tissue, thereby further improving the phenomenon of tooth demineralization.

[0043] (2) Long-term stable bonding with dentin: The flat surface of the Janus particles is grafted with catechol polymers. The catechol groups help the particles adhere strongly to the substrate even in high humidity environments. In the moist environment of the oral cavity, the catechol polymers can form hydrogen bonds, metal coordination, and other non-covalent interactions with the substrate surface, thereby tightly binding to the substrate surface.

[0044] In addition, the catechol group can also enrich calcium ions and phosphorus ions, thereby promoting the mineralization of dentin and making it more resistant to mechanical and chemical effects. At the same time, the Janus particles of the present invention are nanometer-sized and can play a physical sealing role. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 This is a scanning electron microscope image of the composite Janus particles prepared according to Example 1.

[0046] Figure 2 TEM image of the composite Janus particles prepared according to Example 1.

[0047] Figure 3 This is a scanning electron micrograph of dentin treated with ethanol (blank group) 14 days later.

[0048] Figure 4 This is a scanning electron micrograph of dentin treated with the composite Janus particles prepared in Example 1 after 14 days. DETAILED DESCRIPTION

[0049] Various exemplary embodiments, features, and aspects of the present invention will be described in detail below. The word "exemplary" is used herein to mean "serving as an example, embodiment, or illustration." Any embodiment described herein as "exemplary" is not necessarily to be construed as superior or preferred over other embodiments.

[0050] In addition, numerous specific details are provided in the following detailed description to better illustrate the present invention. Those skilled in the art will appreciate that the present invention can be practiced without certain specific details. In other instances, methods, means, equipment, and steps well known to those skilled in the art are not described in detail in order to highlight the main points of the present invention.

[0051] Unless otherwise stated, the units used in this specification are international standard units, and the numerical values and numerical ranges appearing in the present invention should be understood to include the inevitable systematic errors in industrial production.

[0052] In this specification, the use of "may" includes both the meaning of performing a certain process and the meaning of not performing a certain process.

[0053] In this specification, references to "some specific / preferred embodiments," "other specific / preferred embodiments," "embodiments," etc., mean that the specific elements (e.g., features, structures, properties, and / or characteristics) described in connection with the embodiments are included in at least one embodiment described herein, and may or may not be present in other embodiments. In addition, it should be understood that the elements may be combined in various embodiments in any suitable manner.

[0054] In this specification, the numerical range expressed using "a numerical value A to a numerical value B" means a range including the endpoints A and B.

[0055] <Compound Janus Particles>

[0056] One object of the present invention is to provide a composite Janus particle, wherein the surface of the composite Janus particle has a smooth partition and a rough partition, the smooth partition is grafted with a catechol polymer, and the rough partition is grafted with a quaternary ammonium salt polymer.

[0057] The term "Janus particle" refers to a particle having two or more chemical species in a spatial orientation. Different chemical species are assigned to different compartments (e.g., hemispheres), with each compartment varying in composition, polarity, hydrophobicity, or other chemical or physical properties. For example, a Janus particle can comprise a hydrophobic surface and a hydrophilic surface, or alternatively, separate surfaces or a combination of separate surfaces having chemical species capable of binding separate ligands.

[0058] The present invention utilizes the amphiphilicity of Janus particles to simultaneously graft quaternary ammonium salt polymers and catechol polymers on both sides of the Janus particles. The composite Janus particles thus obtained can be used to treat dentin hypersensitivity.

[0059] In the present invention, the smooth partition (smooth surface) of the composite Janus particles is grafted with a catechol polymer, which forms a long-term stable bond with the dental implant or enamel surface through metal chelation, hydrogen bonding and other forces, induces dentin mineralization, and forms a strong and wear-resistant coating.

[0060] The roughened surfaces of the composite Janus particles are grafted with quaternary ammonium polymers. Quaternary ammonium polymers are cationic polymers with broad-spectrum antimicrobial activity. They adhere to negatively charged bacterial cell membranes through electrostatic interactions, causing them to lose their membrane potential and induce cell rupture. This unique contact antibacterial mechanism imparts stable and long-lasting antimicrobial properties to the Janus particles.

[0061] Furthermore, the nanoscale dimensions of the composite Janus particles of the present invention not only physically seal dentinal tubules, promoting particle-dentine bonding, but also impart superhydrophobicity to the coating, preventing bacterial adhesion and further enhancing antibacterial properties. The composite Janus particles of the present invention offer long-lasting antibacterial properties, long-term stable bonding with dentin, and excellent cytocompatibility for the treatment of dentin hypersensitivity, demonstrating significant clinical potential.

[0062] In the present invention, the composite Janus particles have a size in the nanometer range. In some preferred embodiments, the composite Janus particles preferably have a diameter of 1 to 900 nm. In some specific embodiments, the composite Janus particles have a diameter of 1 nm, 10 nm, 50 nm, 100 nm, 200 nm, 250 nm, 300 nm, 400 nm, 500 nm, 600 nm, 700 nm, 800 nm, or 900 nm.

[0063] In the present invention, the composite Janus particles are mainly composed of silicon oxide, the smooth regions of the composite Janus particles contain silanol groups, and the rough regions contain amine groups. The presence of silanol groups and amine groups makes it possible to modify the functionality of the Janus particles.

[0064] In the present invention, the smooth partitions of the composite Janus particles are grafted with catechol polymers. The catechol groups help them adhere strongly to the substrate even in high humidity environments. In the moist environment of the oral cavity, the catechol polymer forms a long-term, stable, and tight bond with the substrate surface (e.g., dental implants or tooth enamel surfaces) through forces such as hydrogen bonding, metal chelation, and other non-covalent interactions. In addition, the catechol groups can also enrich calcium and phosphate ions, thereby promoting the mineralization of dentin, making it more resistant to mechanical and chemical effects, and forming a strong, wear-resistant coating.

[0065] In some preferred embodiments, the catechol polymer is formed from a catechol monomer. The catechol monomer is preferably obtained by the following steps: dissolving sodium borate decahydrate and sodium bicarbonate in water to form an aqueous phase, dissolving methacrylic anhydride in tetrahydrofuran (THF) and adding the resulting solution dropwise to the aqueous phase, simultaneously adding dopamine hydrochloride, adjusting the pH of the system to alkaline using sodium hydroxide, stirring at room temperature for 24 hours, and connecting the solution to a nitrogen balloon to obtain the catechol monomer.

[0066] In the present invention, the roughened sections of the composite Janus particles are grafted with a quaternary ammonium polymer. Quaternary ammonium polymers are cationic polymers with broad-spectrum antimicrobial activity. Their antimicrobial mechanism involves electrostatic attraction to negatively charged bacteria. The hydrophobic alkyl chains of the polymer then penetrate the cell membrane, causing the bacterial cells to rupture. This process, a contact sterilization process, achieves antimicrobial efficacy while preventing the active ingredient from diffusing into the oral environment, contributing to the long-lasting antimicrobial effect.

[0067] Examples of the quaternary ammonium salt polymer include polymers that are soluble in water and have one or more quaternary ammonium salt structures in the chain of repeating units constituting the polymer.

[0068] Specific examples of quaternary ammonium salt polymers include poly(2-hydroxy-3-methacryloyloxypropyltrimethylammonium chloride), poly(2-hydroxy-3-methacryloyloxypropyltriethylammonium chloride), poly(2-hydroxy-3-acryloyloxypropyltrimethylammonium chloride), poly(2-hydroxy-3-acryloyloxypropyltriethylammonium chloride), poly(2-methacryloyloxyethyltrimethylammonium chloride), poly(2-methacryloyloxyethyltriethylammonium chloride), poly(2-acryloyloxyethyltrimethylammonium chloride), poly( 2-acryloyloxyethyltriethylammonium chloride), salts of poly(dimethylaminoethyl methacrylate), salts of poly(diethylaminoethyl methacrylate), salts of poly(diethylaminoethyl acrylate), salts of poly(dimethylaminoethyl methacrylate), salts of poly(dimethylaminoethyl acrylate), poly(4-vinyl-N-methylpyridinium chloride), N,N-dimethyl-substituted 3,5-methylpiperidinium chloride resin, poly(dimethyldiallylammonium chloride) and poly(diethyldiallylammonium chloride) polyethyleneimine hydrochloride, etc.

[0069] In some preferred embodiments, the quaternary ammonium salt polymer is formed from a quaternary ammonium salt monomer. The quaternary ammonium salt monomer is preferably obtained by the following steps: dissolving N,N-dimethylaminoethyl methacrylate (DMAEMA) and 1-bromododecane in isopropanol, stirring at 40° C. for 24 hours, rotary evaporating the resulting solution and allowing it to stand to obtain snowflake-like crystals, which are then washed and freeze-dried in a vacuum to obtain the quaternary ammonium salt monomer.

[0070] <Method for Preparing Composite Janus Particles>

[0071] Another object of the present invention is to provide a method for preparing composite Janus particles, comprising:

[0072] Step A: Mixing raw material Janus particles, a first organic base and a first halogen-containing compound to obtain Janus particles grafted with the halogen-containing compound;

[0073] Step B: mixing the Janus particles grafted with the halogen-containing compound with a quaternary ammonium salt monomer to obtain Janus particles grafted with a quaternary ammonium salt polymer in rough partitions;

[0074] Step C: mixing the Janus particles having the rough partitions grafted with the quaternary ammonium salt polymer, a second organic base, and a second halogen-containing compound to obtain Janus particles having the smooth partitions grafted with the halogen-containing compound and the rough partitions grafted with the quaternary ammonium salt polymer; and

[0075] Step D: Mixing the Janus particles in which the smooth partitions are grafted with the halogen-containing compound and the rough partitions are grafted with the quaternary ammonium salt polymer with catechol monomer to obtain composite Janus particles in which the rough partitions are grafted with the quaternary ammonium salt polymer and the smooth partitions are grafted with the catechol polymer.

[0076] Process A

[0077] The raw material Janus particles used in the present invention can be prepared by methods known in the art.

[0078] In one embodiment, the method for preparing composite Janus particles of the present invention further comprises the step of preparing raw material Janus particles.

[0079] In some preferred embodiments, the raw material Janus particles are ternary strawberry-shaped Janus particles.

[0080] The ternary strawberry-shaped Janus particles are prepared by a soft-templating-based emulsion interface self-assembly method. Specifically, a surfactant is used to form an oil-in-water emulsion. Multiple silanes undergo a sol-gel process at the emulsion interface. Simultaneously, the surfactant induces phase separation, forming a patchy structure at the interface. Ultimately, these particles form hemispherical particles with weak interconnections. These connections are easily disrupted by ultrasound, ultimately disintegrating into individual hemispherical particles. These particles have a rough, porous, amino-modified hemispherical hydrophilic end and a flat, hydrophobic end.

[0081] In some preferred embodiments, the steps of preparing raw Janus particles include:

[0082] Step S1: dissolving the binary surfactant in deionized water and adjusting the pH with hydrochloric acid to form an aqueous phase;

[0083] Step S2: dissolving three silane coupling agents in toluene to form an oil phase;

[0084] Step S3: uniformly mixing the water phase containing the biphasic surfactant and the oil phase containing the three silane compounds, reacting them, and causing phase separation to obtain raw material Janus particles.

[0085] (Process S1)

[0086] Examples of the binary surfactant include cationic surfactants such as amine salts such as N,N-dimethyloctadecylamine hydrochloride, octadecylamine hydrochloride, distearylamine hydrochloride, dodecyltrimethylammonium bromide, octadecyltrimethylammonium chloride, and hexadecyltrimethylammonium chloride; anionic surfactants such as sodium lauryl sulfate, sodium lauryl alcohol polyoxyethylene ether sulfate, sodium lauryl sulfonate, sodium secondary alkyl sulfonate, dodecylammonium sulfate, sodium fatty alcohol isethionate, dodecylbenzenesulfonic acid, sodium dodecylbenzenesulfonate, and phosphate salts such as triethanolamine lauryl phosphate, dodecyl phosphate, and potassium lauryl phosphate; and nonionic surfactants such as Tween 80, Span 80, ethyl orthosilicate, octylphenol polyoxyethylene ether, nonylphenol polyoxyethylene ether, dodecyl alcohol polyoxyethylene ether, and fatty alcohol polyoxyethylene ether such as hydroxyl alcohol polyoxyethylene ether.

[0087] In the present invention, the seed emulsion is preferably acidic. In some preferred embodiments, hydrochloric acid is used to adjust the pH to 2-3, and the pH value of the seed emulsion is 2-3.

[0088] In some preferred embodiments, the above components are dispersed in water under dynamic action. There is no particular limitation on the manner in which the dynamic action is applied; for example, mechanical stirring, oscillation, vortexing, ultrasound, electric field, magnetic field, etc. may be applied. In the present invention, the pressure in this step may be any of atmospheric pressure, pressurization, and reduced pressure, but atmospheric pressure is preferred for ease of operation.

[0089] (Step S2)

[0090] In the present invention, the silane coupling agent includes tetraethyl orthosilicate (TEOS), 3-aminopropyltriethoxysilane (APTES) and phenyltriethoxysilane (PTEOS).

[0091] In some preferred embodiments, from the viewpoint of more easily obtaining raw material Janus particles, the mass ratio of tetraethyl orthosilicate (TEOS), 3-aminopropyltriethoxysilane (APTES), and phenyltriethoxysilane (PTEOS) is preferably 1:1:1.

[0092] (Process S3)

[0093] In the present invention, the aqueous phase and the oil phase are mixed together under dynamic action to form an oil-in-water emulsion. The method of applying the dynamic action is not particularly limited; for example, mechanical stirring, oscillation, vortexing, ultrasound, electric field, or magnetic field may be applied. In the present invention, a preferred method is to shear the mixture at 13,000 rpm for 3 minutes using a high-speed shearing machine.

[0094] In some preferred embodiments, the reaction temperature is preferably 50-85° C., more preferably 60-80° C.; the reaction time is preferably 6-24 h, more preferably 10-14 h.

[0095] In some preferred embodiments, ternary strawberry-shaped Janus particles are prepared using a soft template-based emulsion interface self-assembly method. These ternary strawberry-shaped Janus particles utilize the aforementioned surfactants to form an oil-in-water emulsion. Multiple silane coupling agents with double bonds undergo a sol-gel process at the emulsion interface. The surfactants induce phase separation, forming a patchy structure at the interface and ultimately forming hemispherical particles with weak connections. These connections are easily disrupted by ultrasound, ultimately breaking the particles into individual hemispherical particles.

[0096] In some specific embodiments, the ternary strawberry-shaped Janus particles are preferably obtained by the following steps: mixing an acidic aqueous phase containing a surfactant and an oil phase containing a silane coupling agent with double bonds, shearing the mixture with a high-speed shearing machine to form an oil-in-water emulsion; and subjecting the oil-in-water emulsion to polymerization at high temperature to obtain the ternary strawberry-shaped Janus particles. The surfactant and silane coupling agent with double bonds can be those described above. The polymerization reaction temperature is preferably 50-85°C, more preferably 60-80°C; and the reaction time is preferably 6-24 hours, more preferably 10-14 hours.

[0097] In step A, the first organic base preferably comprises an amine compound or a nitrogen-containing heterocyclic compound.

[0098] In some preferred embodiments, the amine compound preferably comprises triethylamine or dimethylamine, etc. The nitrogen-containing heterocyclic compound preferably comprises pyridine, etc.

[0099] In step A, the first halogen-containing compound comprises an acyl halide compound, a bromoamide compound, or a halide.

[0100] In some preferred embodiments, the acyl halide compound comprises 2-bromoisobutyryl bromide, the bromoamide compound comprises N-bromosuccinimide (NBS), the halide compound comprises arsenic chloride, cuprous bromide, and the like.

[0101] In some preferred embodiments, the mass ratio of the first organic base to the raw material Janus particles is 3:1 to 9:1. In some specific embodiments, the mass ratio of the first organic base to the raw material Janus particles is 3:1, 4:1, 5:1, 6:1, 7:1, 8:1 or 9:1.

[0102] In some preferred embodiments, the mass ratio of the first halogen-containing compound to the raw material Janus particles is 15:1 to 20:1. In some specific embodiments, the mass ratio of the first halogen-containing compound to the raw material Janus particles is 15:1, 16:1, 17:1, 18:1, 19:1 or 20:1.

[0103] In some preferred embodiments, the reaction temperature for obtaining Janus particles grafted with halogen-containing compounds in step A is preferably 15-30° C., more preferably 20-25° C.; the reaction time is preferably 18-30 h, more preferably 23-25 h.

[0104] Process B

[0105] In some preferred embodiments, the quaternary ammonium salt monomer is preferably obtained by the following steps: dissolving N,N-dimethylaminoethyl methacrylate (DMAEMA) and 1-bromododecane in isopropanol and stirring at 40° C. for 24 hours; rotary evaporating the resulting solution and allowing it to stand to obtain snowflake-like crystals, which are then washed and freeze-dried in a vacuum to obtain the quaternary ammonium salt monomer.

[0106] In some preferred embodiments, the mass ratio of the quaternary ammonium salt monomer to the Janus particles grafted with the halogen-containing compound is 2:1 to 6:1. In some specific embodiments, the mass ratio of the quaternary ammonium salt monomer to the Janus particles grafted with the halogen-containing compound is 2:1, 3:1, 4:1, 5:1 or 6:1.

[0107] In some preferred embodiments, the reaction temperature is preferably 60-80° C., more preferably 70-75° C.; the reaction time is preferably 18-30 h, more preferably 23-25 h.

[0108] Process C

[0109] In some preferred embodiments, the second organic base preferably comprises an amine compound or a nitrogen-containing heterocyclic compound.

[0110] In some preferred embodiments, the amine compound preferably comprises triethylamine or dimethylamine, etc. The nitrogen-containing heterocyclic compound preferably comprises pyridine, etc.

[0111] In some preferred embodiments, the second halogen-containing compound comprises an acyl halide compound, a bromoamide compound, or a halide.

[0112] In some preferred embodiments, the acyl halide compound comprises 2-bromoisobutyryl bromide, the bromoamide compound comprises N-bromosuccinimide (NBS), the halide compound comprises arsenic chloride, cuprous bromide, and the like.

[0113] In some preferred embodiments, the mass ratio of the second organic base to the Janus particles of the rough partitioned grafted quaternary ammonium salt polymer is 3:1 to 9:1. In some specific embodiments, the mass ratio of the second organic base to the Janus particles of the rough partitioned grafted quaternary ammonium salt polymer is 3:1, 4:1, 5:1, 6:1, 7:1, 8:1 or 9:1.

[0114] In some preferred embodiments, the mass ratio of the second halogen-containing compound to the Janus particles of the rough partitioned grafted quaternary ammonium salt polymer is 15:1 to 20:1. In some specific embodiments, the mass ratio of the first halogen-containing compound to the raw material Janus particles is 15:1, 16:1, 17:1, 18:1, 19:1, or 20:1.

[0115] In some preferred embodiments, the reaction temperature is preferably 15 to 30° C., more preferably 20 to 25° C.; the reaction time is preferably 18 to 30 h, more preferably 23 to 25 h.

[0116] Process D

[0117] In some preferred embodiments, the catechol monomer is preferably obtained by the following steps: sodium borate decahydrate and sodium bicarbonate are dissolved in water to form an aqueous phase, methacrylic anhydride is dissolved in tetrahydrofuran (THF) and added to the aqueous phase, dopamine hydrochloride is added at the same time, and the pH of the system is adjusted to alkaline (for example, pH 8 or above) using sodium hydroxide, stirred at room temperature for 24 hours, and connected to a nitrogen balloon to obtain the catechol monomer.

[0118] In some preferred embodiments, the mass ratio of the catechol monomer to the Janus particles having an acyl halide compound grafted onto smooth partitions and a quaternary ammonium salt polymer grafted onto rough partitions is 2:1 to 6:1. In some specific embodiments, the mass ratio of the catechol monomer to the Janus particles having an acyl halide compound grafted onto smooth partitions and a quaternary ammonium salt polymer grafted onto rough partitions is 2:1, 3:1, 4:1, 5:1, or 6:1.

[0119] In some preferred embodiments, the reaction temperature is preferably 60-80° C., more preferably 70-75° C.; the reaction time is preferably 18-30 h, more preferably 23-25 h.

[0120] <Purpose>

[0121] The present invention also provides use of the composite Janus particles according to the present invention in preparing a composition for treating dentin hypersensitivity.

[0122] Example

[0123] The embodiments of the present invention will be described in detail below with reference to the examples, but it will be understood by those skilled in the art that the following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention. Where specific conditions are not specified in the examples, the methods were performed according to conventional conditions or the conditions recommended by the manufacturer. Where the manufacturers of the reagents or instruments are not specified, they are all conventional products that can be obtained commercially.

[0124] Example 1

[0125] Synthesis of ternary strawberry-shaped Janus particles:

[0126] 1.0 g of Tween-80 and 10 mL of 10% wt hydrolyzed styrene-maleic anhydride (HSMA) were dissolved in 75 mL of deionized water, and the pH was adjusted to 2.5 with 2.2 mol / L hydrochloric acid to prepare an aqueous phase.

[0127] 500 mg of tetraethyl orthosilicate (TEOS), 500 mg of (3-aminopropyl)triethoxysilane (APTES), and 500 mg of phenyltriethoxysilane (PTEOS) were dissolved in 5 mL of toluene to prepare an oil phase.

[0128] After mixing the aqueous and oil phases, the mixture was sheared at 13,000 rpm for 5 minutes to form an oil-in-water emulsion. The mixture was then reacted at 70°C for 12 hours. After cooling to room temperature, the mixture was centrifuged at 11,000 rpm and washed three times with ethanol to obtain a white precipitate, i.e., strawberry-shaped Janus particles. The mixture was then vacuum-dried at room temperature overnight to obtain a white powder. This white powder exhibited a strawberry-like structure under an electron microscope.

[0129] Using ternary strawberry-shaped Janus particles as raw materials, quaternary ammonium salt polymers were grafted onto their rough surfaces:

[0130] (1) Grafting 2-bromoisobutyryl bromide onto the amino end

[0131] Disperse 100 mg of the ternary strawberry-shaped Janus particles obtained above in 50 mL of dry dichloromethane and add 0.6 mL of triethylamine. Place the system in an ice-water bath, maintaining the system at 0°C, and add 1.0 mL of 2-bromoisobutyryl bromide dropwise with stirring. Continue stirring for 1 hour after the addition is complete. Then, stir at room temperature for 24 hours. The resulting dispersion is centrifuged at 6000 rpm and washed three times with dichloromethane. The precipitate is dried under vacuum at room temperature overnight to obtain a light brown powder, i.e., Janus particles with 2-bromoisobutyryl bromide grafted onto their rough surfaces.

[0132] (2) Synthesis of quaternary ammonium salt monomer

[0133] Dissolve 10 mL (9.43 g, 60 mmol) of N,N-dimethylaminoethyl methacrylate (DMAEMA) and 14.95 g (60 mmol) of 1-bromododecane in 30 mL of isopropanol and stir at 40°C for 24 hours. Rotary evaporate the resulting solution at room temperature (23-25°C) until no distillate remains. Allow the remaining liquid to stand for 48 hours to yield transparent, snowflake-like crystals. Add 30 mL of petroleum ether to the remaining liquid while stirring, and centrifuge at 6000 rpm to yield a white precipitate. Wash three times with petroleum ether, discarding the upper, transparent, colloid-like material each time. Freeze-dry the remaining white precipitate in a vacuum overnight to yield a white, flaky powder.

[0134] (3) Grafting quaternary ammonium salt polymer onto the amino end of the hemispherical rough surface

[0135] 60 mg of Janus particles with roughened surfaces grafted with 2-bromoisobutyryl bromide were dispersed in 5 mL of isopropanol. 180 mg of the quaternary ammonium salt monomer synthesized above was added and dissolved. Then, 18 mg of cuprous bromide and 20 μL of pentamethyldiethylenetriamine (PMDETA) were quickly added, and a magnetic stirrer was added. The dispersion was dark blue. Eight freeze-thaw cycles were performed using a Schlenk line to deoxygenate the system. The procedure was as follows: the reactants were placed in a Schlenk flask. After closing the flask's vent valve, the Schlenk line was connected and the flask was placed in liquid nitrogen, ensuring that the liquid nitrogen level submerged the reaction mixture. After the reaction mixture solidified, the vacuum pump and valves leading to the flask were opened to evacuate the air. After several minutes, the valves and vacuum pump were closed, and the flask was placed in a cold water bath to thaw. After thawing, bubbles were observed emerging from the reaction mixture due to the escape of dissolved gases in the liquid phase. After the bubbles disappeared, the flask was placed in liquid nitrogen again and frozen. This cycle was repeated eight times. After the final thawing, the reaction system was allowed to cool to room temperature and then stirred at 70°C for 24 hours.

[0136] The system was centrifuged at 8000 rpm to obtain a yellow-green precipitate. After washing with toluene and methanol three times respectively, the yellow precipitate was dried in vacuum at room temperature overnight to obtain a light yellow powder, namely, Janus particles with rough surfaces grafted with quaternary ammonium salt polymers.

[0137] The product after grafting 2-bromoisobutyryl bromide was determined by Fourier infrared spectroscopy at 1780 cm -1 A distinct absorption peak at the quaternary ammonium salt region is identified, indicating the carbonyl stretching absorption peak of the acyl bromide, indicating that 2-bromoisobutyryl bromide has been grafted onto the Janus particle surface. The zeta potential of the particles increased by an average of 16.3 mV after grafting the quaternary ammonium salt polymer. This is because the addition of the quaternary ammonium salt introduces a positive charge to the particles, confirming the successful grafting of the quaternary ammonium salt polymer.

[0138] To graft catechol polymer onto the other side of the Janus particles grafted with quaternary ammonium salt:

[0139] (1) Replace the flat end of the Janus particle with an amino group and graft 2-bromoisobutyryl bromide

[0140] 100 mg of the rough-surfaced Janus particles grafted with a quaternary ammonium salt polymer were dispersed in 75 mL of ethanol. 50 mg of (3-aminopropyl)triethoxysilane (APTES) was added dropwise while stirring. The dispersion was stirred at 60°C for 12 hours. After centrifugation at 6000 rpm, the mixture was washed three times with toluene and the precipitate was dried overnight under vacuum at room temperature to obtain a light yellow powder, i.e., Janus particles with amino groups on their flat surfaces.

[0141] Disperse 100 mg of the Janus particles with amino groups on their flat surfaces obtained above in 50 mL of dry dichloromethane, and add 0.6 mL of triethylamine. Place the mixture in an ice-water bath, and add 1.0 mL of 2-bromoisobutyryl bromide dropwise at 0°C with stirring. Stirring is continued for 1 hour after the addition is complete, followed by a further 24 hours at room temperature. The resulting dispersion is centrifuged at 6000 rpm and washed three times with dichloromethane. The precipitate is then vacuum-dried overnight at room temperature to obtain a light yellow powder, i.e., Janus particles grafted with 2-bromoisobutyryl bromide on their flat surfaces and a quaternary ammonium salt polymer on their rough surfaces.

[0142] (2) Synthesis of catechol monomer

[0143] 5.0 g of sodium borate decahydrate and 2.0 g of sodium bicarbonate were dissolved in 50 mL of water to form the aqueous phase, and nitrogen was bubbled through the system for 20 minutes. 2.35 mL of methacrylic anhydride was dissolved in 12.5 mL of tetrahydrofuran (THF) and added dropwise to the aqueous phase. While continuing the nitrogen flow, 2.5 g of dopamine hydrochloride was added, and the pH of the system was adjusted to above 8 with 1 M NaOH. The system was stirred at room temperature for 24 hours while connected to a nitrogen balloon. The resulting white slurry was filtered to remove undissolved sodium salts. The resulting solution was washed twice with 20 mL of ethyl acetate to remove residual methacrylic anhydride. The system was acidified to pH = 2 with 6 M HCl. Extracted three times with 20 mL of ethyl acetate, the transparent brown organic layer was retained and dried over magnesium sulfate. The organic phase was filtered to remove the magnesium sulfate, and the solution volume was reduced to approximately 10 mL using a rotary evaporator. The remaining solution was added to 100 mL of hexane under vigorous stirring to obtain a suspension of precipitated brown solid. The resulting suspension was refrigerated at 4°C for 12 hours to allow the product to recrystallize. A gray precipitate was obtained by filtration, dissolved in 10 mL of ethyl acetate, and precipitated again in 100 mL of hexane. The suspension was refrigerated at 4°C overnight. The precipitate was finally filtered and dried under vacuum at room temperature for 48 hours to obtain a gray powder, the catechol monomer.

[0144] (3) Grafting catechol polymer onto the amino end of the flat surface

[0145] 60 mg of the Janus particles obtained above, with 2-bromoisobutyryl bromide grafted onto the flat surface and a quaternary ammonium salt polymer grafted onto the rough surface, were dispersed in 5 mL of isopropanol. 180 mg of the catechol monomer obtained above was added and dissolved. Then, 18 mg of cuprous bromide and 20 μL of pentamethyldiethylenetriamine (PMDETA) were quickly added, and a magnetic stirrer was added. The dispersion was now dark blue. Eight freeze-thaw cycles were performed using a Schlenk line to deoxygenate the system. After the final thaw, the reaction system was allowed to cool to room temperature and then stirred at 70°C for 24 hours.

[0146] The system was centrifuged at 8000 rpm to obtain a brown precipitate. After washing with toluene and methanol three times respectively, the brown precipitate was dried in vacuum at room temperature overnight to obtain a light brown powder, namely Janus particles with catechol polymer grafted on the flat side and quaternary ammonium salt polymer grafted on the rough side.

[0147] The element distribution of Janus particles before and after catechol grafting was characterized. The results showed that after catechol grafting, the oxygen content of the particles increased significantly, corresponding to the catechol groups with higher oxygen content, proving that catechol had been successfully grafted.

[0148] Figure 1 A scanning electron micrograph of composite Janus particles prepared according to Example 1 is shown. Figure 2 A transmission electron micrograph of the composite Janus particles prepared according to Example 1 is shown.

[0149] Example 2

[0150] Composite Janus particles were prepared in the same manner as in Example 1 except that the step (1) grafting 2-bromoisobutyryl bromide onto the amino end was replaced by the following step (1).

[0151] (1) Grafting 2-bromoisobutyryl bromide onto the amino end

[0152] Disperse 300 mg of the ternary strawberry-shaped Janus particles obtained above in 150 mL of dry dichloromethane and add 1.8 mL of triethylamine. Subsequently, add 3.0 mL of 2-bromoisobutyryl bromide dropwise at 0°C. Stir for 1 hour after the addition is complete. Then, stir at room temperature for 24 hours. The resulting dispersion is centrifuged at 6000 rpm and washed three times with dichloromethane. The precipitate is dried under vacuum at room temperature overnight to obtain a light brown powder, which is the Janus particle with 2-bromoisobutyryl bromide grafted onto its rough surface.

[0153] Fourier transform infrared spectroscopy of the above product showed an obvious absorption peak at 1780 cm-1, which was judged to be the carbonyl stretching absorption peak of the acyl bromide, indicating that 2-bromoisobutyryl bromide had been grafted onto the surface of the Janus particles.

[0154] <Evaluation>

[0155] 2 mg of the composite Janus particles prepared in Example 1 were dispersed in 1 mL of ethanol and ultrasonically treated for 20 min to uniformly disperse the particles, thereby obtaining an ethanol dispersion of the composite Janus particles.

[0156] Dentin slices were smeared with ethanol and the ethanol dispersion of the composite Janus particles prepared above using a microbrush, forming a composite Janus particle group and a blank group. Dentin slices from the composite Janus particle group and the blank group were then immersed in artificial saliva at 37°C, with the artificial saliva replaced every two days. After 14 days, the dentin slices from both groups were removed and allowed to air dry at room temperature. Their morphology was characterized using scanning electron microscopy.

[0157] Figure 3 This is a scanning electron micrograph of dentin treated with ethanol (blank group) 14 days later. Figure 4 This is a scanning electron micrograph of dentin treated with the composite Janus particles prepared in Example 1 after 14 days.

[0158] like Figure 4 As shown, the dentin treated with the composite Janus particles prepared in Example 1 has a rough surface, and the dentinal tubules therein have been basically covered by newly formed minerals, indicating that the composite Janus particles have a good repairing effect on the dentinal tubules.

[0159] In contrast, Figure 3 As shown in the figure, the dentin treated with ethanol (blank group) showed some mineralization after 14 days, but the dentinal tubules were still exposed.

[0160] It should be noted that, although the technical solutions of the present invention are described with specific examples, those skilled in the art will appreciate that the present invention should not be limited thereto.

[0161] While various embodiments of the present invention have been described above, the above descriptions are intended to be illustrative, non-exhaustive, and not limited to the disclosed embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments. The terminology used herein is selected to best explain the principles of the embodiments, their practical applications, or technological improvements in the marketplace, or to enable others skilled in the art to understand the embodiments disclosed herein.

Claims

1. A composite Janus particle, characterized in that: The surface of the composite Janus particle has a smooth partition and a rough partition, the smooth partition is grafted with a catechol polymer, and the rough partition is grafted with a quaternary ammonium salt polymer.

2. The composite Janus particle according to claim 1, characterized in that The composite Janus particles are mainly composed of silicon oxide. The composite Janus particles are smooth partitioned silicone-containing catechol polymers, The coarsely partitioned organosilicon of the composite Janus particles contains a quaternary ammonium salt polymer.

3. The composite Janus particle according to claim 1 or 2, characterized in that The composite Janus particles have a diameter of 200 nm or more and 1000 nm or less.

4. The method for preparing composite Janus particles according to any one of claims 1 to 3, characterized in that: The preparation method comprises: Step A: Mixing raw material Janus particles, a first organic base and a first halogen-containing compound to obtain Janus particles grafted with the halogen-containing compound; Step B: mixing the Janus particles grafted with the halogen-containing compound with a quaternary ammonium salt monomer to obtain Janus particles grafted with the quaternary ammonium salt polymer in rough partitions; Step C: mixing the Janus particles with the quaternary ammonium salt polymer grafted onto the rough partitions, a second organic base, and a second halogen-containing compound to obtain Janus particles with the halogen-containing compound grafted onto the smooth partitions and the quaternary ammonium salt polymer grafted onto the rough partitions; and Step D: mixing the Janus particles in which the smooth partitions are grafted with the halogen-containing compound and the rough partitions are grafted with the quaternary ammonium salt polymer with catechol monomer to obtain composite Janus particles in which the rough partitions are grafted with the quaternary ammonium salt polymer and the smooth partitions are grafted with the catechol polymer.

5. The preparation method according to claim 4, characterized in that The process A satisfies at least one of the following conditions: (a) the raw material Janus particles are ternary strawberry-shaped Janus particles; (b) the first organic base comprises an amine compound or a nitrogen-containing heterocyclic compound; (c) the first organic base comprises triethylamine, dimethylamine or pyridine; (d) the first halogen-containing compound comprises 2-bromoisobutyryl bromide, N-bromosuccinimide, arsenic chloride or cuprous bromide; (e) the mass ratio of the first organic base to the raw material Janus particles is 3:1 to 9:1; The mass ratio of the first halogen-containing compound to the raw material Janus particles is 15:1 to 20:

1.

6. The preparation method according to claim 4, characterized in that In the step B, the mass ratio of the quaternary ammonium salt monomer to the Janus particles grafted with the halogen-containing compound is 2:1 to 6:

1.

7. The preparation method according to claim 4, characterized in that The process C satisfies at least one of the following conditions: (f) the second organic base comprises an amine compound or a nitrogen-containing heterocyclic compound; (g) the second organic base comprises triethylamine, dimethylamine or pyridine; (h) the second halogen-containing compound comprises 2-bromoisobutyryl bromide, N-bromosuccinimide, arsenic chloride or cuprous bromide; (i) the mass ratio of the second organic base to the Janus particles of the rough partitioned grafted quaternary ammonium salt polymer is 3:1 to 9:1; (j) The mass ratio of the second halogen-containing compound to the Janus particles of the rough partitioned grafted quaternary ammonium salt polymer is 15:1 to 20:

1.

8. The preparation method according to claim 4, characterized in that In the step D, the mass ratio of the catechol monomer to the Janus particles having the smooth partitions grafted with the acyl halide compound and the rough partitions grafted with the quaternary ammonium salt polymer is 2:1 to 6:

1.

9. A composition, characterized in that The composition comprises the composite Janus particles according to any one of claims 1 to 3.

10. Use of the composite Janus particles according to any one of claims 1 to 3 in preparing a composition for treating dentin hypersensitivity.

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