Buccal product and preparation method thereof

Abstract

The invention discloses a buccal product and a preparation method thereof, the buccal product comprises a composite particle, the composite particle comprises an inner core, a middle layer and an outer layer, the inner core comprises an active component and a first carrier, the middle layer comprises the active component and a second carrier, and the outer layer comprises the active component and a third carrier, the initial release rate of the active ingredients in different layers meets the condition that the outer layer > the middle layer > the inner core. According to the buccal product disclosed by the invention, the active ingredients have a gradient release effect, so that the buccal product can take effect quickly and continuously.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of oral functional products, in particular to an oral product and a preparation method thereof. BACKGROUND

[0002] Oral functional products, such as oral caffeine, oral nicotine products, etc., refer to products that are placed in the oral cavity or swallowed through the oral cavity for use to absorb active substances and achieve a specific function.

[0003] With the acceleration of modern life, caffeine, as a widely used stimulating ingredient, is commonly found in coffee, energy drinks and oral products. However, traditional caffeine intake methods (such as coffee or energy drinks) usually cause rapid release of caffeine in a short period of time, which may cause side effects such as palpitations, anxiety, etc., and the effect lasts for a short time, so it needs to be taken multiple times to maintain the effect. The existing caffeine slow-release technology (such as slow-release tablets or caffeine microcapsules) has a single release rate, which cannot meet the needs of instant stimulation and long-acting slow release at the same time.

[0004] Therefore, there is an urgent need for a functional product that can have the dual functions of rapid onset and long-acting effect. SUMMARY

[0005] Based on the above problems, the present application provides an oral product and a preparation method thereof.

[0006] The present application discloses an oral product, comprising a composite particle, the composite particle comprising a core, an intermediate layer and an outer layer, the core comprising an active ingredient and a first carrier, the intermediate layer comprising an active ingredient and a second carrier, and the outer layer comprising an active ingredient and a third carrier, wherein the initial release rate of the active ingredient in different regions after water absorption satisfies: outer layer > intermediate layer > core.

[0007] In an implementation manner of the present application, the active ingredient comprises caffeine.

[0008] In an implementation manner of the present application, the caffeine is caffeine nanocrystal; and / or, the active ingredient further comprises L-theanine.

[0009] In an implementation manner of the present application, the first carrier is configured to form a gel network structure after water absorption; and / or, the second carrier is configured to form a structure with pores after water absorption; and / or, the third carrier is configured to disintegrate after water absorption.

[0010] In an implementation form of the application, the first carrier comprises at least one of chitosan, carboxymethyl chitosan, sodium alginate, polyvinyl acetate-povidone, ethyl acrylate-methyl methacrylate copolymer, pectin-zinc cross-linking material; and / or, the second carrier comprises at least one of polylactic acid-glycolic acid copolymer, polylactic acid and chitosan-citrate complex; and / or, the third carrier comprises at least one of nanocellulose, cross-linked sodium carboxymethyl cellulose and low-substituted hydroxypropyl cellulose.

[0011] In an implementation form of the application, the ratio of the particle size of the inner core, the thickness of the intermediate layer and the thickness of the outer layer is 30-50:10-30:20-40; and / or, the particle size of the composite particle is 45-350 μm; and / or, the particle size of the inner core is 15-100 μm; and / or, the thickness of the intermediate layer is 5-30 μm; and / or, the thickness of the outer layer is 10-80 μm.

[0012] In an implementation form of the application, in the inner core, the mass ratio of the first carrier to the active ingredient is 80-95:5-20; and / or, in the intermediate layer, the mass ratio of the second carrier to the active ingredient is 85-95:5-15; and / or, in the outer layer, the mass ratio of the third carrier to the active ingredient is 4-5:3-4; and / or, the mass ratio of the active ingredient in the outer layer, the intermediate layer and the inner core is 2-3:2-3:1-2.

[0013] In an implementation form of the application, the outer layer further comprises at least one of a sweetener, an aroma, a cooling agent, an antioxidant, a preservative, a pH regulator.

[0014] The application also discloses a preparation method of the oral product, for preparing the oral product as described above, the preparation method comprising: obtaining a first mixed solution containing a first carrier, a second mixed solution containing a second carrier, and a third mixed solution containing a third carrier; forming a to-be-molded inner core by the first mixed solution and an active ingredient through a microfluidic process, adding a cross-linking solution to the to-be-molded inner core for solidification treatment to obtain an inner core; forming an intermediate layer on the surface of the inner core by the second mixed solution and the active ingredient through the microfluidic process; forming an outer layer on the surface of the intermediate layer by the third mixed solution and the active ingredient through the microfluidic process to obtain a multi-layer structure particle; and obtaining the composite particle through a purification step and a drying step; wherein the composite particle comprises the inner core, the intermediate layer and the outer layer, the inner core comprises the active ingredient and the first carrier, the intermediate layer comprises the active ingredient and the second carrier, and the outer layer comprises the active ingredient and the third carrier, and the initial release rate of the active ingredient in different regions after water absorption satisfies: outer layer > intermediate layer > inner core.

[0015] In an implementation manner of the application, the active ingredient comprises caffeine; and / or, in the microfluidic process, the flow rate of the first mixed solution is 0.5-1 mL / min, the flow rate of the second mixed solution is 0.3-0.6 mL / min, and the flow rate of the third mixed solution is 0.2-0.4 mL / min; and / or, the solidification treatment is low-temperature cross-linking solidification, and the temperature of the cross-linking solution is 4-10 DEG C; and / or, the cross-linking solution is a calcium chloride solution; and / or, the cross-linking solution is a calcium chloride solution with a mass fraction of 1-1.5%; and / or, the solidification treatment lasts for 30-60 minutes; and / or, the purification step comprises cleaning and centrifugal collection of precipitates; and / or, the drying step comprises drying at a temperature of 20-40 DEG C.

[0016] The application has the following beneficial effects:

[0017] The oral product of the application has the following beneficial effects: BRIEF DESCRIPTION OF DRAWINGS

[0018] Figure 1 is a caffeine dissolution curve of the composite particles with different formulations involved in the embodiments of the application.

[0019] Figure 2 The caffeine dissolution curve of the composite particles and the common particles involved in the embodiments of the present application. DETAILED DESCRIPTION

[0020] The application will be described in further detail below with specific reference to the drawings. In the following embodiments, many specific details are described in order to provide a thorough understanding of the application. However, it will be apparent to one skilled in the art that the specific features described in some cases can be omitted in other cases, or can be substituted by other features, without departing from the scope of the application. In some cases, some operations related to the application are not shown or described in the specification in order to avoid the core part of the application being overwhelmed by too much description, and it is not necessary for those skilled in the art to describe these related operations in detail according to the description in the specification and the general technical knowledge in the art.

[0021] In addition, the features, operations or characteristics described in the specification can be combined in any appropriate manner to form various embodiments. At the same time, the steps or actions in the method description can also be sequentially adjusted or adjusted in a manner that is obvious to those skilled in the art. Therefore, the various sequences in the specification and the drawings are only for the purpose of clearly describing a certain embodiment, and do not mean that the sequence is necessary, unless otherwise stated that a certain sequence must be followed.

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

[0023] With the acceleration of modern life, caffeine, as a widely used stimulant ingredient, is commonly found in coffee, energy drinks and oral products. However, traditional caffeine intake methods (such as coffee or energy drinks) usually cause rapid release of caffeine in a short period of time, which may cause side effects such as palpitations and anxiety, and the effect lasts for a short time, so it needs to be taken multiple times to maintain the effect. The existing caffeine slow-release technology (such as slow-release tablets) has the following problems: (1) The release rate is single, which cannot meet the needs of instant stimulation and long-acting slow release at the same time. (2) Insufficient stability: some caffeine composite particles are prone to breakage during storage or use, resulting in premature release of caffeine. (3) Poor taste: some slow-release technologies affect the solubility and taste of the product, reducing user experience. Therefore, there is an urgent need for a new caffeine delivery system that can precisely control the release rate while taking into account stability, taste and long-acting effect.

[0024] In view of this, the present application develops a caffeine sustained-release system with gradient release characteristics through an innovative multi-layer structure combined with nanotechnology and new carrier materials. Through the multi-layer structure, the active ingredient is released in stages, achieving a release effect of rapid onset and sustained effect; the multi-layer coating technology is adopted to prevent breakage during storage or transportation, thereby improving the stability of caffeine; the production process is also simple, and high-precision, scalable production is achieved through microfluidic technology; importantly, the side effects of caffeine can be reduced, and the safety of use can be improved.

[0025] The present application relates to a mouthpiece and a method for making the same.

[0026] In an embodiment, the mouthpiece can include a composite particle.

[0027] In an embodiment, the composite particle can include an inner core, an intermediate layer, and an outer layer.

[0028] In an embodiment, the outer layer at least partially coats the intermediate layer, and the intermediate layer at least partially coats the inner core. The inner core can include an active ingredient and a first carrier. In the inner core, the active ingredient can be adsorbed to the first carrier. The intermediate layer can include the active ingredient and a second carrier. In the intermediate layer, the active ingredient can be adsorbed to the second carrier. The outer layer can include the active ingredient and a third carrier. In the outer layer, the active ingredient can be adsorbed to the third carrier. The first carrier, the second carrier, and the third carrier are at least partially different from each other in composition, so that the release rates of the active ingredient in different layers are different.

[0029] In an embodiment, the active ingredient can include caffeine.

[0030] In an embodiment, the caffeine can be caffeine nanocrystals. It should be noted that caffeine nanocrystals have a size in the nanometer range (<1 μm) and a large specific surface area, which can significantly improve the solubility and dissolution efficiency of the substance. The use of caffeine nanocrystals can improve bioavailability. In an embodiment, the particle size of the caffeine nanocrystals is <200 nm.

[0031] In an embodiment, the active ingredient can also be selected from other substances with medical or other specific purposes. For example, nicotine, nicotine derivatives, vitamins, capsaicin, etc., to meet the needs of different users.

[0032] In an embodiment, the active ingredient can also include L-theanine. L-theanine has the benefits of promoting relaxation and reducing anxiety, improving cognitive function, supporting cardiovascular health, and enhancing immune function.

[0033] In one embodiment, the first carrier is configured to have a structure of a gel network after absorbing water. The active ingredient can be carried in the first carrier by a mesh capture effect. In this case, by forming a gel barrier, the matrix of the material is thick, and the active ingredient is adsorbed by the mesh capture principle, so that the diffusion and release of the active ingredient can be inhibited. Thus, the active ingredient in the core has a slower release rate.

[0034] In one embodiment, the first carrier can include at least one of chitosan, carboxymethyl chitosan, sodium alginate, polyvinyl acetate-povidone, ethyl acrylate-methyl methacrylate copolymer, pectin-zinc crosslinker. Preferably, the first carrier includes carboxymethyl chitosan. Unmodified chitosan is only soluble in acidic solutions, and carboxymethylation treatment can improve the solubility of chitosan while maintaining its properties as a sustained-release material.

[0035] In one embodiment, the second carrier is configured to have a structure with pores after absorbing water. The active ingredient can be carried in the second carrier by adsorption. In this case, the release rate of the active ingredient can be limited by the pore size of the pore structure of the second carrier. Thus, the active ingredient in the intermediate layer has a slower release rate.

[0036] In one embodiment, the second carrier can include at least one of polylactic acid-glycolic acid copolymer (PLGA), polylactic acid (PLA), and chitosan-citrate complex.

[0037] In one embodiment, the third carrier is configured to have a structure that can disintegrate after absorbing water. In this case, the third carrier can disintegrate and release the active ingredient after absorbing water. Thus, the active ingredient in the outer layer has a faster release rate.

[0038] In one embodiment, the third carrier includes at least one of nanocellulose (NFC), cross-linked sodium carboxymethyl cellulose (CCNa), and low-substituted hydroxypropyl cellulose (L-HPC).

[0039] In one embodiment, the sustained-release ability of the first carrier, the second carrier, and the third carrier for the active ingredient decreases in turn. It should be noted that it can mean that under the same test conditions, the sustained-release ability of the first carrier, the second carrier, and the third carrier for the active ingredient decreases in turn (for example, the first carrier, the second carrier, and the third carrier carrying the same amount of active ingredient are respectively placed in the same solution, the release time of the active ingredient in the first carrier > the release time of the active ingredient in the second carrier > the release time of the active ingredient in the third carrier).

[0040] In one specific embodiment, after the composite particles absorb water, the initial release rate of the active ingredient in different regions satisfies the following order: outer layer > middle layer > core. It should be noted that this can mean that under the same test conditions, the initial release rate of the active ingredient in different regions satisfies the following order: outer layer > middle layer > core (for example, if the outer layer, middle layer, and core are placed in the same solution, the initial release rate of the active ingredient in the outer layer > the initial release rate of the active ingredient in the middle layer > the initial release rate of the active ingredient in the core).

[0041] In one specific embodiment, the composite particles have a three-layer progressive release structure (release rate: outer layer > middle layer > core), achieving gradient release of the active ingredient.

[0042] In one specific embodiment, the particle size of the core, the thickness of the intermediate layer, and the thickness of the outer layer can be 30–50: 10–30: 20–40. This allows the outer layer to carry a larger amount of active ingredient and release it through rapid disintegration, meeting the user's immediate needs; and enables the active ingredient in the oral product to have a gradient release effect of fast, medium, and slow.

[0043] In one specific embodiment, the particle size of the composite particles can be 45 μm to 350 μm. For example, the particle size of the composite particles can be 45 μm, 50 μm, 100 μm, 150 μm, 200 μm, 250 μm or 350 μm.

[0044] In one specific embodiment, the kernel particle size can be 15μm to 100μm. For example, the kernel particle size can be 15μm, 20μm, 30μm, 40μm, 50μm, 60μm, 70μm, 80μm, 90μm or 100μm.

[0045] In one specific embodiment, the thickness of the intermediate layer can be 5 μm to 30 μm. For example, the thickness of the intermediate layer can be 5 μm, 10 μm, 15 μm, 20 μm, 25 μm or 30 μm.

[0046] In one specific embodiment, the thickness of the outer layer can be from 10 μm to 80 μm. For example, the thickness of the outer layer can be 10 μm, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm or 80 μm.

[0047] In one specific embodiment, the core may include, by weight, 80 to 95 parts of a first carrier and 5 to 20 parts of an active ingredient. In other words, the mass ratio of the first carrier to the active ingredient in the core may be 80 to 95: 5 to 20.

[0048] In one specific embodiment, the intermediate layer may include, by weight, 85 to 95 parts of a second carrier and 5 to 15 parts of an active ingredient. In other words, the mass ratio of the second carrier to the active ingredient in the intermediate layer may be 85 to 95: 5 to 15.

[0049] In one specific embodiment, the outer layer may include, by weight, 40 to 50 parts of a third carrier and 30 to 40 parts of an active ingredient. In other words, the mass ratio of the third carrier to the active ingredient in the outer layer may be 4 to 5: 3 to 4.

[0050] In one specific embodiment, the mass fractions of active ingredients in the outer layer, middle layer, and core of the composite particles can be 10-15 parts, 10-15 parts, and 5-10 parts, respectively. For example, the mass fractions of active ingredients in the outer layer, middle layer, and core of the composite particles can be 15 parts, 10 parts, and 5 parts, respectively. Thus, the active ingredients can be preferentially released primarily through the outer layer, meeting the user's immediate needs.

[0051] In one specific embodiment, the mass ratio of the active ingredients in the outer layer, intermediate layer, and core is 2–3:2–3:1–2. For example, the mass ratio of the active ingredients in the outer layer, intermediate layer, and core can be 3:2:1.5.

[0052] In one specific embodiment, the composite particles may further include at least one of a sweetener, flavoring agent, cooling agent, antioxidant, preservative, and pH adjuster. In another specific embodiment, the outer layer, middle layer, and core of the composite particles may independently include at least one of a sweetener, flavoring agent, cooling agent, antioxidant, preservative, and pH adjuster. For example, the outer layer may contain a sweetener, flavoring agent, and antioxidant; the middle layer may contain a cooling agent; and the core may contain a sweetener and flavoring agent.

[0053] In one specific embodiment, the outer layer may further include at least one of sweeteners, flavorings, cooling agents, antioxidants, preservatives, and pH adjusters. Thus, the flavor substances (such as sweeteners, flavorings, and cooling agents) in the outer layer can provide a better mouthfeel for the oral product, enhancing the user experience; the antioxidants in the outer layer can protect the active ingredients and improve the stability of the oral product.

[0054] In one specific embodiment, the sweetener may include at least one selected from xylitol, sorbitol, mannitol, iodine, lactitol, maltitol, isomaltitol, hydrogenated starch hydrolysate, erythritol, maltodextrin, aspartame, acesulfame potassium, sodium saccharin, sucralose, neotame, cyclamate, alitane, steviol glycosides, arabinitol, and monk fruit sweetener. Other edible-grade substances may also be selected, which will not be detailed here.

[0055] In one specific embodiment, the flavoring agent may include at least one of fragrance, natural essential oil, and natural extract. The fragrance is an edible fragrance, which may include at least one of latte flavor, bergamot flavor, eucalyptus flavor, citrus flavor, lemon flavor, peppermint flavor, peppermint flavor, menthol, licorice flavor, wintergreen flavor, tobacco flavor, coffee flavor, vanilla flavor, lime flavor, apple flavor, peach flavor, mango flavor, cherry flavor, blueberry flavor, strawberry flavor, cola flavor, cinnamon flavor, vanilla flavor, and watermelon flavor. Other types of edible fragrances may also be included, which will not be detailed here.

[0056] In one specific embodiment, the cooling agent may include at least one of menthol, menthol derivatives, WS-3, and WS-23.

[0057] In one specific embodiment, the antioxidant may include silica. Furthermore, silica can also act as an anti-caking agent, flow aid, or adsorbent, helping to maintain the free flow of powdered or granular foods, preventing clumping, and improving the texture and stability of the product.

[0058] In one specific embodiment, the pH adjuster may include at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and magnesium carbonate.

[0059] In one specific embodiment, the preservative (or antibacterial agent) may be selected from at least one of the following substances: ethylparaben, benzoic acid, sodium benzoate, potassium sorbate, and benzalkonium chloride. The antibacterial agent may also be selected from other edible-grade antibacterial substances, which will not be elaborated upon herein.

[0060] In one embodiment, the oral article may further include a bag. The composite particles may be placed within the bag. The bag may be saliva-permeable. The bag may have pores to allow saliva to enter the bag.

[0061] This application also relates to a method for preparing an oral product.

[0062] In one specific embodiment, the preparation method is used to prepare the oral product as described above, the oral product comprising composite particles.

[0063] In one specific embodiment, the preparation method may include: obtaining a first mixture containing a first carrier, a second mixture containing a second carrier, and a third mixture containing a third carrier; forming a core to be formed by the first mixture and an active ingredient through a microfluidic process; adding a crosslinking liquid to the core to be formed and performing a curing treatment to obtain the core; forming an intermediate layer on the surface of the core by the second mixture and an active ingredient through a microfluidic process; forming an outer layer on the surface of the intermediate layer by the third mixture and an active ingredient through a microfluidic process to obtain multilayer structured particles; and obtaining composite particles by purifying and drying the multilayer structured particles.

[0064] In one specific embodiment, in the microfluidic process, the flow rate of the first mixture is 0.5–1 mL / min. The flow rate of the second mixture is 0.3–0.6 mL / min. The flow rate of the third mixture is 0.2–0.4 mL / min.

[0065] In one specific embodiment, the curing process is low-temperature crosslinking curing, and the temperature of the crosslinking liquid is 4°C to 10°C.

[0066] In one specific embodiment, the first carrier may include sodium alginate, and the crosslinking solution may be a calcium chloride solution.

[0067] In one specific embodiment, the first carrier may include sodium alginate and chitosan, and the crosslinking solution may be a solution of calcium chloride and sodium citrate. Therefore, sodium citrate can lower the pH of the crosslinking solution, thereby inhibiting the ionization of chitosan and interfering with the reaction between chitosan and calcium chloride. 2+ Cross-linking is beneficial for Ca 2+ It acts directly on sodium alginate.

[0068] In one specific embodiment, the crosslinking solution may include 1% to 1.5% calcium chloride by mass.

[0069] In one specific embodiment, the crosslinking solution may include 0.1M sodium citrate.

[0070] In one specific embodiment, the crosslinking solution may include 0.1M sodium citrate and 1%–1.5% calcium chloride by mass. This facilitates the formation of a core with a gel network structure after water absorption.

[0071] In one specific embodiment, the curing time is 30 to 60 minutes.

[0072] In one specific embodiment, the purification step may include washing and centrifuging to collect the precipitate. Washing may be performed using deionized water. Centrifugation conditions may be: 8000–12000 rpm, 30 minutes.

[0073] In one specific embodiment, the drying step may include drying at a temperature of 20°C to 40°C.

[0074] In one specific embodiment, the drying step is carried out under conditions of 8–10 MPa.

[0075] In one specific embodiment, the drying step may employ supercritical CO2 drying technology.

[0076] It should be noted that the process can ensure uniform and controllable thickness of each functional layer by precisely controlling the flow rate and curing conditions of each layer, thus realizing the characteristic of gradient release of active ingredients.

[0077] The present application will be further described in detail below through specific experimental procedures and experimental data examples. The following examples are for further illustration only and should not be construed as limiting the present application. In these examples, unless otherwise specified, all reagents and instruments used are commercially available, and all experimental operations are performed in accordance with product instructions and standard experimental procedures.

[0078] Example

[0079] (1) Process steps:

[0080] Preparation of caffeine nanocrystals: Caffeine was dissolved in ethanol (caffeine concentration 5%~10%), and then rapidly injected with 5 times the volume of ultrapure water. The mixture was ultrasonically treated (200W, 10 minutes) and spray-dried to obtain caffeine nanocrystal powder (particle size <200nm).

[0081] Carrier solution preparation: Nanocellulose (NFC) powder was dispersed in deionized water and magnetically stirred (600 rpm, 1 hour) to form a homogeneous suspension, i.e., NFC dispersion. PLGA (50:50, i.e., 50% lactic acid units and 50% glycolic acid units) was dissolved in dichloromethane and heated in a 40°C water bath with stirring until completely dissolved, yielding a 10% (w / w) PLGA solution. Carboxymethyl chitosan was dissolved in a 1% acetic acid solution and magnetically stirred (500 rpm, 2 hours) to obtain a 6% (w / w) carboxymethyl chitosan solution.

[0082] Core preparation: Caffeine nanocrystals, chitosan solution and sodium alginate were granulated using a microfluidic process at a flow rate of 0.2-0.4 mL / min to obtain core particles.

[0083] Low-temperature crosslinking curing: drip CaCl2 crosslinking solution (concentration 1-1.5%) at 4-10℃ into the core particles and cure for 30-60 minutes.

[0084] Microfluidic multilayer coating: Cross-linked and cured core particles and intermediate layer reagents (caffeine nanocrystals + PLGA solution) are granulated using a microfluidic process at a flow rate of 0.3-0.6 mL / min, coating the core surface to obtain an intermediate layer. Then, it is granulated again with an outer layer reagent (caffeine nanocrystals + NFC dispersion) using a microfluidic process at a flow rate of 0.5-1 mL / min, resulting in multilayered particles with a three-layer structure.

[0085] Centrifugal purification: Centrifuge and collect (8000-12000 rpm, 30 minutes), wash 3 times with deionized water.

[0086] Drying: The powder is dried using supercritical CO2 drying technology at 35℃ and 8-10MPa to obtain a dry powder with good flowability.

[0087] Additive mixing: The cooling agent, L-theanine, steviol glycosides, silicon dioxide and dry powder are mixed evenly to obtain the composite particles of this embodiment.

[0088] Packaging: Dispensed in 200mg / bag (containing 40mg caffeine) into water-permeable non-woven bags, with a built-in moisture-proof oxygen absorber.

[0089] (2) The four carrier materials used in this embodiment (nanocellulose, PLGA, carboxymethyl chitosan, and sodium alginate) have different sustained-release effects due to their polymer adsorption and network capture principles. By adjusting the ratio of different carrier materials, six formulations were set up, namely four caffeine sustained-release formulations (A, B, C, and D) and two functional sustained-release formulations (E and F):

[0090] Formula A:

[0091]

[0092] Formula B:

[0093]

[0094]

[0095] Formula C:

[0096]

[0097] Formula D:

[0098]

[0099]

[0100] Formula E:

[0101]

[0102] Formula F:

[0103]

[0104]

[0105] (3) Drug loading rate detection:

[0106] The drug loading rate of caffeine bags with different formulations was tested: 1 mg of sample was incubated in a water bath at 40℃ for 30 min, centrifuged, and the supernatant was filtered through a 0.22 μm filter membrane to obtain the free caffeine test solution, which was then analyzed by HPLC. Based on the HPLC method, an Agilent HC-C18 column (250 mm × 4.6 mm, 5 μm) was used, with a detection wavelength of 273 nm, a flow rate of 1.0 mL / min, a mobile phase of methanol-water (70:30), a column temperature of 30℃, and isocratic elution. The drug loading rate was measured using 1 g of composite particles, and the average value was taken. The HPLC experimental conditions were 25℃, 40% RH, and n = 3 independent batches. Drug loading rate = (mass of caffeine in composite particles / total mass of composite particles) * 100%. The results are shown in the table below:

[0107]

[0108] (4) Encapsulation efficiency test:

[0109] Encapsulation efficiency refers to the percentage of drug successfully encapsulated in the composite particles out of the total drug dosage, reflecting the capability of the preparation process. Take 1 mL of the composite particle suspension, centrifuge at 12000 rpm for 10 min, collect the supernatant, and filter through a 0.22 μm filter membrane to obtain the free caffeine test solution. Take another 1 mL of the suspension, add 5 mL of methanol, sonicate for 10 min (power 200W), centrifuge, collect the supernatant, and filter through a 0.22 μm filter membrane to obtain the total caffeine test solution. Similar to the drug loading rate detection, HPLC was used for analysis. Encapsulation amount = total drug amount - free drug amount, encapsulation efficiency = (total drug amount - free drug amount) / total drug amount * 100%. The results showed that the encapsulation efficiency was 92.3 ± 1.8% (n = 3), which meets the process requirements for sustained-release systems (>90%).

[0110]

[0111] (5) Caffeine dissolution curve:

[0112] ① Caffeine dissolution curves of different formulation compound particles: Tested using a Distek 2100C dissolution meter, method: USPII paddle method, rotation speed: 50 rpm, temperature: 37℃. Medium: 900 mL PBS (pH 6.8) containing 0.5% SDS. Filter membrane: 0.2 μm. Sampling volume: 5 mL, replenished with an equal volume of fresh medium. Dissolution curves are shown below. Figure 1 , Figure 1 These are the caffeine dissolution curves of the different formulations of composite particles involved in the embodiments of this application. The caffeine dissolution data at different time points are shown in the table below:

[0113]

[0114]

[0115] As can be seen, the composite particles in this embodiment generally have a longer sustained-release time, with the dissolution curve gradually flattening out, thus balancing rapid release and long-lasting sustained release. Formulation A achieves near-complete release within 180 minutes, suitable for short-duration, high-intensity applications. Formulation B retains 15.7% unreleased in the final stage. Formulation D is a high-load formulation, but this does not affect its final release rate. Formulation F (low-side-effect type) has a higher L-theanine content, resulting in a 15% reduction in the overall release rate and a more stable blood drug concentration.

[0116] ② Caffeine dissolution curves of composite granules and ordinary granules in this embodiment: The test method is the same as above. Ordinary granules refer to those that do not use the sustained-release carrier materials—carboxymethyl chitosan and sodium alginate—nor calcium chloride cross-linking. Other materials, proportions, processes, etc., are the same as in formulation A. Dissolution curves are shown below. Figure 2 , Figure 2 These are the caffeine dissolution curves of the composite particles and ordinary particles involved in the embodiments of this application. The caffeine dissolution data at different time points are shown in the table below:

[0117]

[0118] As can be seen, caffeine from ordinary particles exhibits rapid burst release (>80% release within 50 minutes), while the composite particles in this embodiment, due to their gradient release design (synergistic effect of rapid release / intermediate release / slow release layers), significantly extend the duration of action to 180 minutes.

[0119] (6) Product stability testing:

[0120] An accelerated environmental test was conducted using a programmable temperature and humidity chamber to simulate air and sea transport conditions and the environmental conditions of the host country. The environmental test conditions were set as follows: temperature 50℃, humidity 90%, and placement time 6 days. The samples were sealed and stored in the chamber.

[0121] An Agilent C18 column was used with a mobile phase of methanol-water (70:30) at a flow rate of 1.0 mL / min and a detection wavelength of 273 nm. 10 mg of the composite particles were ultrasonically broken down with methanol, and the supernatant was filtered (0.22 μm) after centrifugation and injected into the sample.

[0122] Before and after environmental testing, environmental factors had little impact on the caffeine content of the composite particles, indicating that the composite particles effectively protected the caffeine. The multi-chamber structure of the composite particles effectively isolates oxygen, moisture, and light, inhibiting caffeine degradation.

[0123]

[0124] Color change after composite particle ring testing: Detected using a colorimeter (HunterLab ColorFlex). A control group was set up. Parameters: L* (brightness), a* (red-green value), b* (yellow-blue value). Standard: Using the initial sample as a baseline (ΔE<3 is acceptable), pure caffeine powder was used as the color baseline group, and blank particles (caffeine-free) were used to eliminate carrier interference. Combining the yellow characteristics of caffeine itself and the protective effect of the composite particles, the color change after an accelerated test (40℃ / 75%RH, 6 days) was simulated. The test data are as follows:

[0125] Sample Group ΔΕ (Color Difference) Visual Observation Conclusion Pure Caffeine Powder ΔΕ = 12.2 Significantly Darker Yellow, Slightly Caked Blank Granules ΔΕ = 1.1 No Change Formula A ΔΕ = 2.6 Almost No Change Formula B ΔΕ = 2.3 Almost No Change Formula C ΔΕ = 2.3 Almost No Change Formula D ΔΕ = 2.2 Almost No Change Formula E ΔΕ = 2.5 Almost No Change Formula F ΔΕ = 2.8 Slightly Yellowed

[0126] In summary, the composite particles of this application, based on a three-layer progressive release structure design and employing differentiated carrier materials (each layer using carriers with specific solubility properties), achieve a gradient release effect (immediate release + intermediate release + sustained release), which helps avoid a sudden increase in blood drug concentration and reduces side effects such as palpitations and anxiety. It enables precise release and long-lasting effect; the rapid release can be used for emergency alertness, such as before exercise, while the sustained release can be used for prolonged focus during overtime work or study. It exhibits good stability; environmental tests and accelerated experiments show that the caffeine content retention rate is greater than 90%, and there is no visible change in color. The microfluidic three-step encapsulation method can improve drug loading.

[0127] The above description, in conjunction with specific embodiments, provides a further detailed explanation of this application and should not be construed as limiting the specific implementation of this application to these descriptions. Those skilled in the art to which this application pertains can make several simple deductions or substitutions without departing from the concept of this application.

Claims

1. A mouth-held product, characterized in that, The invention includes composite particles, which comprise a core, an intermediate layer, and an outer layer. The core comprises an active ingredient and a first carrier, the intermediate layer comprises an active ingredient and a second carrier, and the outer layer comprises an active ingredient and a third carrier. After water absorption, the initial release rate of the active ingredient in different regions satisfies the following order: outer layer > intermediate layer > core.

2. The oral article according to claim 1, characterized in that, The active ingredient includes caffeine.

3. The oral article according to claim 2, characterized in that, The caffeine is caffeine nanocrystals; And / or, the active ingredient also includes L-theanine.

4. The oral article according to claim 1, characterized in that, The first carrier is configured to have a gel network structure after absorbing water; And / or, the second carrier is configured to have a porous structure after absorbing water; And / or, the third carrier is configured to disintegrate upon absorbing water.

5. The oral article according to any one of claims 1 to 4, characterized in that, The first carrier includes at least one of chitosan, carboxymethyl chitosan, sodium alginate, polyvinyl acetate-polyvinyl ketone, ethyl acrylate-methacrylate copolymer, and pectin-zinc crosslinker; And / or, the second carrier comprises at least one of polylactic acid-glycolic acid copolymer, polylactic acid, and chitosan-citrate complex; And / or, the third carrier includes at least one of nanocellulose, cross-linked sodium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose.

6. The oral article according to claim 1, characterized in that, The ratio of the particle size of the core, the thickness of the intermediate layer, and the thickness of the outer layer is 30-50:10-30:20-40; And / or, the particle size of the composite particles is 45 μm to 350 μm; And / or, the particle size of the core is 15 μm to 100 μm; And / or, the thickness of the intermediate layer is 5 μm to 30 μm; And / or, the thickness of the outer layer is 10 μm to 80 μm.

7. The oral article according to claim 1, characterized in that, In the core, the mass ratio of the first carrier to the active ingredient is 80-95:5-20; And / or, in the intermediate layer, the mass ratio of the second carrier to the active ingredient is 85-95:5-15; And / or, in the outer layer, the mass ratio of the third carrier to the active ingredient is 4-5:3-4; And / or, the mass ratio of the active ingredients in the outer layer, the intermediate layer and the core is 2-3:2-3:1-2.

8. The oral article according to claim 1, characterized in that, The outer layer also includes at least one of sweeteners, flavorings, cooling agents, antioxidants, preservatives, and pH adjusters.

9. A method for preparing a mouth-held product, characterized in that, For preparing a mouth-held product as described in any one of claims 1 to 8, the mouth-held product comprising composite particles, the preparation method comprising: obtaining a first mixture containing a first carrier, a second mixture containing a second carrier, and a third mixture containing a third carrier; forming a core to be formed by microfluidic technology with the first mixture and an active ingredient; adding a crosslinking liquid to the core to be formed and performing a curing treatment to obtain the core; forming an intermediate layer on the surface of the core with the second mixture and the active ingredient by microfluidic technology; forming an outer layer on the surface of the intermediate layer with the third mixture and the active ingredient by microfluidic technology to obtain multilayer structured particles; and obtaining the composite particles by purification and drying steps. The composite particles comprise a core, an intermediate layer, and an outer layer. The core comprises the active ingredient and the first carrier. The intermediate layer comprises the active ingredient and the second carrier. The outer layer comprises the active ingredient and the third carrier. After absorbing water, the initial release rate of the active ingredient in different regions satisfies the following order: outer layer > intermediate layer > core.

10. The preparation method according to claim 9, characterized in that, The active ingredient includes caffeine; And / or, in the microfluidic process, the flow rate of the first mixture is 0.5–1 mL / min, the flow rate of the second mixture is 0.3–0.6 mL / min, and the flow rate of the third mixture is 0.2–0.4 mL / min; And / or, the curing process is low-temperature crosslinking curing, and the temperature of the crosslinking liquid is 4℃~10℃; And / or, the crosslinking solution is a calcium chloride solution.

Images