Composite particle, preparation method thereof and buccal product

Abstract

The invention discloses a composite particle, a preparation method thereof and a buccal product, the composite particle comprises a load structure and a plurality of functional substances, and the functional substances comprise an active substance and a flavoring agent; the loading structure comprises a plurality of loading layers, and the plurality of loading layers at least comprise an active substance loading layer loaded with an active substance and a flavoring agent loading layer loaded with a flavoring agent. According to the invention, layered loading is carried out on different functional substances, so that interference among molecules of the functional substances can be avoided, and the consistency and stability of the product are improved.

Description

Technical Field

[0001] The present application relates to the field of food or medical technology, and in particular to a composite particle, a preparation method thereof, and an oral product. Background Art

[0002] Oral products come in various forms, including sachets, films, powders, and chewing gum. These are placed in the mouth or other areas of the mouth, where they dissolve and release functional substances such as nicotine or its derivatives, which are then absorbed through the mucous membranes. They offer advantages such as precise dosage, rapid onset of action, and portability.

[0003] Nicotine oral products typically contain an active substance (nicotine or its derivatives), a carrier, and, to improve taste, other functional substances such as sweeteners, flavorings, and cooling agents. Currently, nicotine products are typically prepared by mixing various components, including nicotine and sweeteners, with a carrier.

[0004] However, direct mixing of multiple components is prone to intermolecular competitive adsorption or mutual interference, resulting in poor product consistency and poor stability of functional substances. Summary of the Invention

[0005] The present application provides a composite particle and a preparation method thereof, and an oral product, which are used to solve the problems of poor product consistency and stability caused by direct mixing of components in existing nicotine products.

[0006] The present application discloses a composite particle, which includes a loading structure and multiple functional substances, wherein the functional substances include active substances and flavorings; the loading structure includes multiple loading layers, and the multiple loading layers include at least an active substance loading layer loaded with active substances and a flavoring loading layer loaded with flavorings.

[0007] In one implementation of the present application, the multiple load layers include a core and a first shell layer that at least partially covers the core; or, the multiple load layers include a core, a first shell layer that at least partially covers the core, and a second shell layer that at least partially covers the first shell layer.

[0008] In one implementation of the present application, the release rate of the functional substance in the first shell layer is greater than the release rate of the functional substance in the core; and / or the release rate of the functional substance in the second shell layer is greater than the release rate of the functional substance in the first shell layer.

[0009] In one implementation of the present application, the functional substance in the inner core is a substance released by pH response, the functional substance in the first shell layer is a substance released by temperature response, and the functional substance in the second shell layer is a substance released by water solubility; and / or, the carrier of the inner core includes at least one of the following: attapulgite, chitosan and sodium tripolyphosphate; and / or, the carrier of the first shell layer includes β-cyclodextrin; and / or, the carrier of the second shell layer includes gelatin; and / or, the second shell layer also includes sodium alginate and calcium chloride.

[0010] In one implementation of the present application, the particle size of the composite particles is 250 nm to 500 nm; and / or the particle size of the core is 100 nm to 200 nm; and / or the thickness of the first shell is 50 nm to 80 nm;

[0011] And / or, the thickness of the second shell layer is 30 nm to 60 nm.

[0012] In one implementation of the present application, the Bloom value of the gelatin is less than or equal to 100; and / or, the composite particles, by weight, include: 1 to 30 parts of the active substance, 20 to 65 parts of the carrier of the core, 0.1 to 10 parts of the cooling agent, 5 to 20 parts of the carrier of the first shell layer, 0.5 to 12 parts of the flavoring substance, and 10 to 45 parts of the carrier of the second shell layer; and / or, the composite particles, by weight, The invention relates to a novel flavoring agent comprising: 1 to 30 parts of the active substance, 5 to 20 parts of the attapulgite, 10 to 40 parts of the chitosan, 0.5 to 3 parts of the sodium tripolyphosphate, 0.1 to 10 parts of the cooling agent, 5 to 20 parts of the beta-cyclodextrin, 0.05 to 2 parts of the sweetener, 0.5 to 10 parts of the fragrance, 10 to 30 parts of the gelatin, 2 to 10 parts of the sodium alginate, and 0.5 to 5 parts of the calcium chloride.

[0013] In one implementation of the present application, the active substance includes at least one of nicotine and nicotine derivatives, the flavoring includes at least one of a flavoring substance and a cooling agent, and the flavoring includes at least one of a sweetener and an aromatic.

[0014] In one implementation of the present application, the core is the active substance loading layer, and the first shell layer is the flavoring agent loading layer; or, the core is the active substance loading layer, the first shell layer loads the cooling agent, and the second shell layer loads the flavoring agent.

[0015] The present application also discloses a method for preparing composite particles, comprising: providing a loading structure and a plurality of functional substances, and preparing the loading structure and the functional substances into composite particles, wherein: the functional substances include active substances and flavoring agents; the loading structure includes a plurality of loading layers, and the plurality of loading layers include at least an active substance loading layer loaded with active substances and a flavoring agent loading layer loaded with flavoring agents.

[0016] In one implementation of the present application, the preparation method includes: preparing core particles: mixing a first carrier and the active substance to obtain the core particles; coating the first shell layer: mixing the core particles with a mixed liquid containing a second carrier and a cooling agent to obtain intermediate particles in which the first shell layer at least partially coats the core particles; coating the second shell layer: mixing the intermediate particles with a mixed liquid containing a third carrier and a flavoring substance, and drying to obtain the composite particles in which the second shell layer at least partially coats the first shell layer.

[0017] The present application also discloses an oral product, comprising a permeable bag and the composite particles as described above encapsulated in the permeable bag; or, the oral product further comprises a filler, and the composite particles are at least partially adsorbed on the filler.

[0018] The beneficial effects of this application are:

[0019] The composite particles of the present application can help avoid interference between functional substance molecules and improve product consistency and stability by layering different functional substances. DETAILED DESCRIPTION

[0020] The present invention is described in further detail below by specific embodiments. In the following embodiments, many details are described in order to make the present application better understood. However, those skilled in the art can easily recognize that some of the features can be omitted in different situations, or can be replaced by other materials or methods. In some cases, some operations related to the present application are not shown or described in the specification. This is to avoid the core part of the present application being overwhelmed by too much description, and for those skilled in the art, it is not necessary to describe these related operations in detail. They can fully understand the related operations based on the description in the specification and the general technical knowledge in this area.

[0021] In addition, the features, operations, or characteristics described in this specification may be combined in any appropriate manner to form various embodiments. Furthermore, the steps or actions in the method description may be reordered or adjusted in a manner readily apparent to those skilled in the art. Therefore, the various sequences in this specification are provided solely for the purpose of clearly describing an embodiment and are not intended to be mandatory, unless otherwise specified.

[0022] The serial numbers assigned to the components in this document, such as "first", "second", etc., are only used to distinguish the objects described and do not have any order or technical meaning.

[0023] Oral preparations in related technologies have the following problems: (1) Uneven release and uncontrolled volatilization: In the traditional preparation method of direct mixing of multiple components, the release rates of each component in the oral cavity are inconsistent, and nicotine, sweeteners or cooling agents may be released too quickly and instantly, resulting in an abrupt taste; (2) Poor product consistency: It is difficult to control the preparation process parameters between batches, resulting in large fluctuations in the concentration of each active ingredient, particle size and release curve; (3) Difficulty in controlling taste: Due to the different physical and chemical properties of each component, traditional preparation methods are difficult to simultaneously meet the requirements of long-term sustained release and immediate flavor experience. At present, the commonly used technical means mainly include: (1) polymer encapsulation technology: nicotine and cooling agents are encapsulated using high molecular materials such as polylactic acid and polycaprolactone, but there are problems such as uneven coating and short sustained release time; (2) microemulsion method: microemulsion is prepared and then solidified into microcapsules, but this method is easily affected by environmental factors, and the preparation process is complicated, making it difficult to ensure the consistency of each batch of products; (3) blended microspheres: multiple components are directly mixed and then encapsulated to form microspheres, but intermolecular competitive adsorption is prone to occur, resulting in sudden release or sustained release failure.

[0024] In light of this, this application creatively proposes a composite particle, its preparation method, and oral product. In this application, a layered loading design effectively mitigates mutual interference between functional substances and improves component stability. A step-by-step release design effectively achieves precise regulation and stable sustained release of functional components, for example, immediate release of flavorings, gradual release of cooling agents to maintain a cooling sensation, and long-lasting sustained release of the functional substance nicotine.

[0025] The present application firstly relates to a composite particle.

[0026] In one embodiment, the composite particles include a supporting structure and a plurality of functional substances. The functional substances may be supported in the supporting structure.

[0027] In a specific embodiment, the load structure is a multi-layer structure, and different layers correspond to different load layers.

[0028] In a specific embodiment, the load structure has multiple load layers, and the multiple load layers can be independent of each other.

[0029] In a specific embodiment, different functional substances can be loaded by different loading layers. It should be noted that, generally speaking, different loading layers can be understood as containing different functional substances, but in actual situations, a small amount or part of the functional substance molecules may migrate to other loading layers.

[0030] In one embodiment, the functional substance includes an active substance and a flavoring agent.

[0031] In a specific embodiment, the loading structure includes a plurality of loading layers, and the plurality of loading layers include at least an active substance loading layer loaded with an active substance and a flavoring agent loading layer loaded with a flavoring agent.

[0032] In one embodiment, in the composite particles, a portion of the loading layer is loaded with an active substance, i.e., a portion of the loading layer is an active substance loading layer, and another portion of the loading layer is loaded with a flavoring agent, i.e., another portion of the loading layer is a flavoring agent loading layer. For example, the loading structure includes two independent loading layers, one of which is loaded with an active substance and the other is loaded with a flavoring agent.

[0033] In one embodiment, the active substance includes nicotine and / or nicotine derivatives.

[0034] In a specific embodiment, nicotine includes natural nicotine and synthetic nicotine. Nicotine derivatives may include one or more of nicotine salts, nicotine in a matrix such as a sugar matrix or an organometallic complex, a nicotine-resin combination, a nicotine inclusion complex, and non-covalently bound nicotine. Non-covalently bound nicotine includes nicotine lactate, nicotine malate, nicotine salicylate, nicotine cyclodextrin inclusion complex, nicotine hydrochloride, nicotine dihydrochloride, nicotine tartrate, nicotine tartrate dihydrate, nicotine sulfate, nicotine zinc chloride, nicotine benzoate, and the like. Nicotine derivatives also include nicotine containing substituents, such as hexamethyl nicotine, hexamethyl nicotine lactate, hexamethyl nicotine malate, hexamethyl nicotine salicylate, hexamethyl nicotine cyclodextrin embedded complex, hexamethyl nicotine hydrochloride, hexamethyl nicotine dihydrochloride, hexamethyl nicotine tartrate, hexamethyl nicotine tartrate dihydrate, hexamethyl nicotine sulfate, hexamethyl nicotine zinc chloride, and hexamethyl nicotine benzoate. One or more mixtures thereof.

[0035] In a specific embodiment, the functional substance may also be selected from other substances with medical or other specific uses, such as vitamins, capsaicin, caffeine, etc., to meet the needs of different users.

[0036] In a specific embodiment, the functional substance can also be selected from other alkaloids or amino acids, for example, alkaloids such as tobacco, coffee, and tea.

[0037] In a specific embodiment, the flavoring agent includes at least one of a flavoring substance and a cooling agent.

[0038] In a specific embodiment, in the composite particles, part of the loading layer is loaded with active substances, part of the loading layer is loaded with cooling agents, and the remaining loading layer is loaded with flavor substances.

[0039] In a specific embodiment, the flavoring substance includes at least one of a sweetener and an aromatic.

[0040] In a specific embodiment, the sweetener may include at least one of xylitol, sorbitol, mannitol, iglesia, lactitol, maltitol, isomalt, hydrogenated starch hydrolysate, erythritol, maltotriitol, aspartame, acesulfame potassium, saccharin sodium, sucralose, neotame, cyclamate, alitame, steviol glycosides, arabitol, and monk fruit sweetener. The sweetener may also be selected from other edible-grade substances, which will not be detailed here.

[0041] In a specific embodiment, the fragrance can include at least one of bergamot essence, eucalyptus essence, citrus essence, lemon essence, peppermint essence, mint essence, menthol, licorice essence, wintergreen essence, tobacco essence, coffee essence, vanilla essence, lime essence, apple essence, peach essence, mango essence, cherry essence, blueberry essence, strawberry essence, cola essence, cinnamon essence, pandan essence, and watermelon essence. The fragrance can also be other types of edible flavors, which will not be detailed here.

[0042] In a specific embodiment, the cooling agent may include at least one of menthol, menthol derivatives, WS-3, and WS-23.

[0043] In a specific embodiment, the composite particles further include other excipients, for example, a pH regulator, a preservative (or an antibacterial agent). The pH regulator can be used to adjust the acidity or alkalinity of the oral product. The pH regulator can be acidic, such as citric acid, or alkaline, such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, or magnesium carbonate. The antibacterial agent can be selected from at least one of the following substances: ethyl paraben, benzoic acid, sodium benzoate, potassium sorbate, benzalkonium chloride. The antibacterial agent can also be selected from other edible-grade antibacterial substances, which will not be described in detail herein.

[0044] In a specific embodiment, the composite particles may include a core and a first shell that at least partially covers the core. In other words, the composite particles may have a double-layer structure, and the loading layer includes the core and the first shell. The release rate of the functional substance in the first shell may be greater than the release rate of the functional substance in the core. The functional substance is located in the core, and the flavoring is located in the first shell. Thus, composite particles can be obtained in which the functional substance and the flavoring are loaded in layers, and the functional substance is released more slowly and the flavoring is released more quickly. The core loads the active substance, and the first shell loads the flavoring. Thus, composite particles can be obtained in which the active substance and the flavoring are loaded in layers. It should be noted that the release rate refers to the rate at which the functional substance dissolves into the water after the composite particles come into contact with water.

[0045] In a specific embodiment, the composite particles may include a core, a first shell layer that at least partially covers the core, and a second shell layer that at least covers the first shell layer. In other words, the composite particles may be a three-layer structure, and the load layer includes a core, a first shell layer, and a second shell layer. The release rate of the functional substance in the first shell layer may be greater than the release rate of the functional substance in the core, and the release rate of the functional substance in the second shell layer is greater than the release rate of the functional substance in the first shell layer. The active substance is loaded on the core, and the other functional substances are loaded on the first shell layer and the second shell layer respectively. For example, the cooling agent can be loaded on the first shell layer, and the flavoring substance can be loaded on the second shell layer. In this way, composite particles can be obtained in which the functional substances are loaded in layers, and the functional substances are released more slowly, the cooling agent is released at a medium speed, and the flavoring substance is released quickly.

[0046] In a specific embodiment, the functional substance in the core can be a substance released by pH response. In the first shell layer. The functional substance can be a substance released by temperature response. The functional substance in the second shell layer can be a substance released by water solubility. It should be noted that it can only be released through a response under specific conditions, thereby reducing the abrupt taste caused by instantaneous release too quickly. Among them, when the composite particles in the oral product enter the oral cavity, the release mechanism or process is as follows: saliva dissolves the second shell layer, and the functional substances in the second shell layer (such as sweeteners and fragrances) are quickly released to provide a good taste and flavor experience; as the temperature rises to body temperature, the first shell layer gradually releases its loaded functional substances (such as cooling agents) to maintain a cool feeling; then, the core slowly releases the functional substances (such as nicotine) in the weakly alkaline environment of the oral cavity.

[0047] In a specific embodiment, the carrier of the inner core (also referred to as the first carrier) may include at least one of the following: attapulgite, chitosan and sodium tripolyphosphate. It should be noted that attapulgite (Attapulgite) is a natural hydrous magnesium silicate clay mineral with a large specific surface area and a unique layered structure. It has good adsorption properties, chemical stability and mechanical strength. In addition, attapulgite particles can be used as excipients and as the main mechanical skeleton of the inner core of the composite particles. TPP (sodium tripolyphosphate) is a commonly used cross-linking agent that can undergo ionic cross-linking reactions with positively charged chitosan molecules to form a stable three-dimensional network structure. This cross-linking not only enhances the mechanical strength of the material, but also improves its encapsulation efficiency and controlled release performance for active ingredients. Chitosan is a weakly alkaline polysaccharide that will only be protonated (–NH3 + ) and has a certain degree of water solubility. The oral pH is typically between 6.5 and 7.4 (neutral or slightly alkaline). At this pH, chitosan is not easily dissolved and only swells to form a hydrogel structure. Chitosan forms a gel network in the mouth, and nicotine is slowly released primarily through diffusion from this cross-linked network. Furthermore, both chitosan and attapulgite are naturally derived materials with excellent biocompatibility.

[0048] In one embodiment, attapulgite and chitosan may be combined with each other through the interaction of physical and / or chemical groups.

[0049] In one embodiment, the attapulgite may be acidified. For example, the attapulgite may be mixed with an acetic acid solution for acidification. Acidification can help remove impurities (such as calcium carbonate and other metal oxides) from the attapulgite, increase the number of surface active sites, improve the specific surface area and porosity of the attapulgite, and enhance its adsorption properties.

[0050] In one embodiment, the functional substance (eg, nicotine) is loaded into a composite carrier formed by attapulgite, chitosan, and sodium tripolyphosphate.

[0051] In a specific embodiment, the carrier of the first shell (which may also be referred to as the second carrier) may include β-cyclodextrin. The cooling agent is encapsulated by a hydrophobic cavity. It should be noted that a cylindrical hydrophobic cavity is formed inside the β-cyclodextrin, which can accommodate hydrophobic molecules or hydrophobic parts of various sizes. This phenomenon is called inclusion complexation. Due to the lack of polar groups inside it, it exhibits a strong affinity for non-polar or hydrophobic substances. In this application, cooling agents such as menthol, most of which are non-polar bonds in their molecules, are hydrophobic. Therefore, the cooling agent can be loaded by entering the internal cavity of β-cyclodextrin. When the oral temperature (about 37°C) is reached, the expansion of the β-cyclodextrin cavity can be triggered, and the cooling agent is gradually released.

[0052] In a specific embodiment, the carrier of the second shell layer (also referred to as the third carrier) may include gelatin.

[0053] In a specific embodiment, the gelatin is soluble gelatin, which may have a low Bloom value (≤100). It can dissolve and disperse within a few seconds to tens of seconds under the action of oral temperature and saliva. It should be noted that the Bloom value is an indicator of gelatin gel strength. A high Bloom value means that the gelatin has a stronger gel-forming ability, and the gel formed is harder and more elastic. A low Bloom value indicates that the gelatin gel strength is weaker, and the gel formed is softer and easier to deform.

[0054] In a specific embodiment, the carrier of the second shell layer (also referred to as the third carrier) may further include sodium alginate and calcium chloride. It should be noted that the sodium alginate gel after calcium chloride cross-linking has higher mechanical strength, which helps to protect the internally encapsulated material from the influence of the external environment and maintain its integrity. In this application, by adding sodium alginate, the film-forming property is strong, the release is faster under neutral alkaline conditions, and the taste is also better.

[0055] In one embodiment, in the second shell layer, the carrier loads the sweetener and the flavoring agent through electrostatic adsorption.

[0056] In one specific embodiment, after the composite particles come into contact with saliva, the second shell layer dissolves preferentially, releasing 70% or more of the sweetener or fragrance within 10 minutes; the first shell layer gradually releases the cooling agent, releasing more than 60% of the cooling agent within 30 minutes; the core slowly releases the functional substance, releasing no more than 40% of the functional substance within 30 minutes and releasing more than 80% of the functional substance within 120 minutes.

[0057] In a specific embodiment, the particle size of the composite particles may be 250 nm to 500 nm. For example, the particle size of the composite particles may be 250 nm, 300 nm, 350 nm, 400 nm, 450 nm, or 500 nm.

[0058] In a specific embodiment, the particle size of the core can be 100nm to 200nm. For example, the particle size of the core can be 100nm, 150nm or 200nm.

[0059] In a specific embodiment, the thickness of the first shell layer may be 50 nm to 80 nm. For example, the thickness of the first shell layer may be 50 nm, 60 nm, 70 nm, or 80 nm.

[0060] In a specific embodiment, the thickness of the second shell layer may be 30 nm to 60 nm. For example, the thickness of the second shell layer may be 30 nm, 40 nm, 50 nm, or 60 nm.

[0061] In a specific embodiment, the composite particles may include at least one of the following by weight: 1 to 30 parts of active substances, 20 to 65 parts of core carriers, 0.1 to 10 parts of cooling agents, 5 to 20 parts of first shell carriers, 0.5 to 12 parts of flavoring substances, and 10 to 45 parts of second shell carriers.

[0062] In a specific embodiment, in a specific embodiment, the composite particles may include at least one of the following, by weight: 1 to 30 parts of active substances, 5 to 20 parts of attapulgite, 10 to 40 parts of chitosan, 0.5 to 3 parts of sodium tripolyphosphate, 0.1 to 10 parts of cooling agents, 5 to 20 parts of β-cyclodextrin, 0.05 to 2 parts of sweeteners, 0.5 to 10 parts of flavoring agents, 10 to 30 parts of gelatin, 2 to 10 parts of sodium alginate, and 0.5 to 5 parts of calcium chloride.

[0063] This application also relates to a method for preparing composite particles. The method may include providing a load structure and multiple functional substances, and then preparing the load structure and functional substances into composite particles. The load structure, functional substances, and composite particles involved in the preparation method may be the same as those described above.

[0064] In a specific embodiment, the preparation method of the composite particles may specifically include: preparing core particles: mixing a first carrier and an active substance to obtain the core particles (step S100); coating the first shell layer: mixing the core particles with a mixed liquid containing a second carrier and a cooling agent to obtain intermediate particles in which the first shell layer at least partially coats the core particles (step S200); coating the second shell layer: mixing the intermediate particles with a mixed liquid containing a third carrier and a flavoring substance, and drying to obtain composite particles in which the second shell layer at least partially coats the first shell layer (step S300).

[0065] In a specific embodiment, step S100 includes: mixing a solvent, attapulgite, chitosan, sodium tripolyphosphate and an active substance to obtain core particles.

[0066] In a specific embodiment, step S100 includes: preparing a chitosan solution: dissolving chitosan in an acetic acid aqueous solution to obtain a chitosan solution; compounding attapulgite: adding attapulgite to the chitosan solution and mixing to obtain a chitosan-attapulgite composite suspension; loading the active substance: adding a nicotine (and / or nicotine salt) solution to the chitosan-attapulgite composite suspension for loading; and TPP cross-linking: slowly dripping the chitosan-attapulgite composite suspension loaded with the active substance into the TPP solution for cross-linking to obtain core particles, which can be collected by centrifugation.

[0067] In a specific embodiment, step S200 includes: mixing the core particles with a mixture containing β-cyclodextrin and a cooling agent to obtain intermediate particles in which the first shell layer at least partially covers the core particles.

[0068] In one embodiment, step S200 includes: stirring β-cyclodextrin and a cooling agent to load the cooling agent onto the β-cyclodextrin; adding core particles to adsorb the β-cyclodextrin and the cooling agent onto the core particles to form a first shell layer; and collecting the mixture by centrifugation to obtain double-layer composite particles, also known as intermediate particles.

[0069] In a specific embodiment, step S300 includes: mixing the intermediate particles with a mixed solution containing gelatin and flavoring substances, and drying to obtain composite particles in which the second shell layer at least partially covers the first shell layer.

[0070] In one embodiment, step S300 includes: mixing gelatin, sodium alginate, a sweetener, and flavoring to form a gelatin coating solution; slowly adding the double-layer composite particles to the gelatin solution for coating; and dropwise adding a calcium chloride solution to form three-layer composite particles. After drying, the composite particles of the present application are obtained.

[0071] The present application also relates to an oral product. The oral product includes the composite particles described above and an osmotic bag. The composite particles are encapsulated in the osmotic bag, which is a small bag permeable to saliva.

[0072] In a specific embodiment, the oral preparation may further include a filler.

[0073] In one embodiment, the composite particles may be at least partially adsorbed onto the filler.

[0074] In a specific embodiment, the filler may include microcrystalline cellulose, which may include microcrystalline cellulose 101, 102, 112, 301, 200, and other types.

[0075] In a specific embodiment, the filler may include a sugar alcohol, which may include at least one of xylitol, sorbitol, mannitol, lactitol, isomalt, and erythritol.

[0076] In a specific embodiment, the oral preparation may include 20 to 90 parts by weight of filler, for example, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 parts by weight of filler.

[0077] In a specific embodiment, the oral preparation may include 10 to 80 parts by weight of the composite particles, for example, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 parts by weight of the composite particles.

[0078] In a specific embodiment, the oral product may further include an adhesive.

[0079] In a specific embodiment, the binder may include at least one of the following: povidone K30, sodium alginate, hydroxypropyl methylcellulose, and carboxymethyl cellulose.

[0080] In a specific embodiment, the oral preparation may include 0 to 10 parts by weight of a binder, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 parts by weight of a binder.

[0081] The present application also relates to a method for preparing the oral product.

[0082] In a specific embodiment, the preparation method of the oral product may include: mixing the composite particles and the filler, granulating to obtain oral particles, and bagging the oral particles.

[0083] In a specific embodiment, the particle size of the orally contained particles is 70 μm to 600 μm.

[0084] In a specific embodiment, the preparation method of the oral product may include: mixing the composite particles and a filler so that the composite particles can be at least partially adsorbed on the filler; and bagging.

[0085] In a specific embodiment, the preparation method of the oral product may include: mixing the composite particles and the filler in a wet granulator, adding 1% povidone K30 and 70% alcohol solution to granulate, then fluidizing and drying (45°C, 30 min), sieving to obtain 70μm to 600μm particles, and then bagging.

[0086] The present invention is further described in detail below by specific experimental process and experimental data examples. The following examples are only used to further illustrate the present invention and should not be construed as limiting the present invention. In the present embodiment, unless otherwise specified, the reagents and instruments used are all commercially available, and the experimental operations are all carried out in accordance with the product specifications and conventional experimental specifications.

[0087] Example 1:

[0088] (1) Preparation of the core

[0089] Preparation of chitosan solution: Weigh 2 g of chitosan (degree of deacetylation ≥ 85%) and dissolve it in 100 mL of 0.5% (w / v) acetic acid aqueous solution. Stir magnetically at room temperature for 2 hours to obtain a clear and uniform chitosan solution. Filter it through a 0.45 μm filter membrane to remove impurities and set aside.

[0090] Composite preparation of attapulgite: 1 g of attapulgite (montmorillonite) was weighed and ultrasonically dispersed in 10 L of distilled water for 10 minutes, then slowly added to the chitosan solution and stirred for 1 hour to obtain a chitosan-attapulgite composite suspension.

[0091] Nicotine loading: Add nicotine solution dropwise to the above composite suspension, controlling the added amount to 50 mg, and stir for 30 minutes in a sealed, light-proof environment. The temperature is controlled at 25±2°C to allow nicotine to be fully adsorbed into the composite carrier.

[0092] TPP cross-linking nucleation: Prepare 100 mL of a 0.1% (w / v) sodium tripolyphosphate (TPP) solution; add the nicotine-loaded chitosan / attapulgite mixture dropwise to the TPP solution at a rate of 2 mL / min with stirring (300 rpm). The cross-linking reaction lasts for 1 hour to form cross-linked core particles.

[0093] Washing and collection: The particles were collected by centrifugation at 4000 rpm for 10 minutes, washed twice with deionized water, and resuspended in a small amount of deionized water for later use.

[0094] (2) Preparation of the intermediate layer

[0095] 2 g of β-cyclodextrin was placed in 20 mL of distilled water at 40°C, 0.1 g of menthol was added, and the mixture was stirred for 2 hours to form an inclusion complex solution.

[0096] The core particles prepared in step (1) above are added to the inclusion solution and slowly stirred at room temperature for 30 minutes to allow the cooling agent and its carrier in the middle layer to be adsorbed to the particle surface to form double-layer composite particles.

[0097] Washing and collection: The particles were collected by centrifugation at 4000 rpm for 10 minutes, washed twice with deionized water, and resuspended in a small amount of deionized water for later use.

[0098] (3) Preparation of outer layer

[0099] Weigh 2g of sodium alginate and 5g of low Bloom value (≤100) soluble gelatin and add them to 50mL of 40℃ warm water and stir until a transparent solution is obtained. Add 0.1g of sucralose and 0.2g of flavor and stir to dissolve to form a gelatin coating solution.

[0100] The double-layer composite particles were slowly added to the above gelatin solution at a ratio of 1:1 (volume ratio), and then 2-3 mL of 0.1 M CaCl2 solution was added dropwise. The stirring rate was maintained at 400 rpm, and the coating reaction time was 20 minutes.

[0101] The coated three-layer composite particle suspension is formed by spray drying. The spray drying conditions are: inlet air temperature 110-120°C, outlet air temperature 65-75°C, spray rate 5 mL / min, atomizing gas flow rate 600 L / h, and the collected particles are composite particles.

[0102] Comparative Example 1:

[0103] Chitosan and TPP are cross-linked to form an ion gel. The remaining materials (attapulgite, β-cyclodextrin, gelatin, chitosan, nicotine, flavoring, sucralose, menthol, etc.) are the same as those in Example 1, and the amounts of each material are also the same as in Example 1. However, in Comparative Example 1, all materials are mixed by physical mixing to obtain a granular material.

[0104] Performance testing:

[0105] (1) Component compatibility test

[0106] Method: An accelerated stability test (40° C., 75% RH (relative humidity), 30 days) was conducted to detect the degradation rate of the sweetener and the volatility of the fragrance (flavor) in the composite particles prepared in Example 1 and Comparative Example 1.

[0107] result:

[0108] Group Sweetener retention rate (%) Fragrance retention rate (%) Comparative Example 1 60±5 45±6 Example 1 95±3 85±4

[0109] It can be seen that the composite particles and functional substances of the present application have better stability.

[0110] (2) Multi-component synergistic release homogeneity test

[0111] Methods: The composite particles prepared in Example 1 were placed in saliva in a simulated oral environment (37°C, pH 7.0, saliva flow rate 0.5 mL / min). Samples were taken at different time points, and the concentrations of each component were detected by HPLC / GC-MS.

[0112] result:

[0113]

[0114] It can be seen that the composite particles of the present application have a step-by-step release characteristic. After contact with the oral cavity, the outer shell preferentially degrades to release sweeteners and flavors (within 10 minutes), the middle layer gradually releases the cooling agent as the saliva temperature rises (15-30 minutes), and the inner core slowly releases nicotine in a weakly alkaline environment (lasting 1-2 hours).

[0115] The composite particles of the present application have a synergistic release effect: the sweetener and flavor are quickly released to improve palatability, the cooling agent maintains a refreshing feeling, and nicotine is released for a long time; they have high ingredient stability: layered loading avoids intermolecular interference, and the ingredient stability is above 85%.

[0116] The above content is a further detailed description of the present application in conjunction with specific implementation methods, and the specific implementation of the present application cannot be considered to be limited to these descriptions. For ordinary technicians in the technical field to which the present application belongs, several simple deductions or substitutions can be made without departing from the concept of the present application.

Claims

1. A composite particle, characterized in that The composite particles include a loading structure and a plurality of functional substances, wherein the functional substances include active substances and flavoring agents; The loading structure includes a plurality of loading layers, and the plurality of loading layers at least include an active substance loading layer loaded with an active substance and a flavoring agent loading layer loaded with a flavoring agent.

2. The composite particles according to claim 1, characterized in that The plurality of supporting layers include an inner core, a first shell layer at least partially encapsulating the inner core; Alternatively, the plurality of supporting layers include a core, a first shell layer at least partially covering the core, and a second shell layer at least partially covering the first shell layer.

3. The composite particles according to claim 2, characterized in that The release rate of the functional substance in the first shell is greater than the release rate of the functional substance in the core; And / or, the release rate of the functional substance in the second shell layer is greater than the release rate of the functional substance in the first shell layer.

4. The composite particles according to claim 2, characterized in that The functional substance in the core is a substance released by pH response, the functional substance in the first shell is a substance released by temperature response, and the functional substance in the second shell is a substance released by water solubility; and / or, the carrier of the inner core comprises at least one of the following: attapulgite, chitosan and sodium tripolyphosphate; and / or, the carrier of the first shell layer comprises β-cyclodextrin; and / or, the carrier of the second shell layer comprises gelatin; And / or, the second shell layer further comprises sodium alginate and calcium chloride.

5. The composite particles according to claim 2, characterized in that The particle size of the composite particles is 250nm to 500nm; and / or, the particle size of the core is 100 nm to 200 nm; and / or, the thickness of the first shell layer is 50 nm to 80 nm; And / or, the thickness of the second shell layer is 30 nm to 60 nm.

6. The composite particles according to claim 4, characterized in that The Bloom value of the gelatin is less than or equal to 100; And / or, the composite particles comprise, by weight: 1 to 30 parts of the active substance, 20 to 65 parts of the carrier of the core, 0.1 to 10 parts of a cooling agent, 5 to 20 parts of the carrier of the first shell layer, 0.5 to 12 parts of a flavoring substance, and 10 to 45 parts of the carrier of the second shell layer; And / or, the composite particles include, by weight: 1 to 30 parts of the active substance, 5 to 20 parts of attapulgite, 10 to 40 parts of chitosan, 0.5 to 3 parts of sodium tripolyphosphate, 0.1 to 10 parts of a cooling agent, 5 to 20 parts of β-cyclodextrin, 0.05 to 2 parts of a sweetener, 0.5 to 10 parts of a fragrance, 10 to 30 parts of gelatin, 2 to 10 parts of sodium alginate, and 0.5 to 5 parts of calcium chloride.

7. The composite particles according to any one of claims 2 to 6, characterized in that The active substance includes at least one of nicotine and nicotine derivatives, the flavoring agent includes at least one of a flavoring agent and a cooling agent, and the flavoring agent includes at least one of a sweetener and an aromatic agent.

8. The composite particles according to claim 7, characterized in that The inner core is the active substance loading layer, and the first shell is the flavoring agent loading layer; Alternatively, the inner core is the active substance-carrying layer, the first shell layer carries the cooling agent, and the second shell layer carries the flavoring substance.

9. A method for preparing composite particles, characterized in that: include: A loading structure and a plurality of functional substances are provided, and the loading structure and the functional substances are used to prepare composite particles, wherein: the functional substances include active substances and flavoring agents; the loading structure includes a plurality of loading layers, and the plurality of loading layers include at least an active substance loading layer loaded with the active substance and a flavoring agent loading layer loaded with the flavoring agent.

10. The preparation method according to claim 9, characterized in that The preparation method comprises: Preparing core particles: mixing the first carrier and the active substance to obtain the core particles; Coating with the first shell layer: mixing the core particles with a mixed solution containing a second carrier and a cooling agent to obtain intermediate particles in which the first shell layer at least partially coats the core particles; Coating with the second shell layer: mixing the intermediate particles with a mixed solution containing a third carrier and flavoring substances, and drying to obtain the composite particles in which the second shell layer at least partially covers the first shell layer.

11. An oral product, characterized in that: A device comprising a permeable bag and the composite particles according to any one of claims 1 to 8 encapsulated in the permeable bag; Alternatively, the oral product further comprises a filler, and the composite particles are at least partially adsorbed on the filler.

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