Multilayer particle structure for promoting absorption of functional ingredients and method for manufacturing thereof

Abstract

The present invention relates to a multilayer particle structure for promoting the absorption of functional raw materials and a method for manufacturing the same, and more specifically, to a method for manufacturing a three-layer structure particle of a core layer, a coat layer, and a functional layer that simultaneously achieves improved release and bioavailability through the control of water activity. The manufacturing method of the present invention comprises: a core layer forming step of mixing a functional raw material and an excipient to form core particles with an average particle size of 50 micrometers to 300 micrometers and adjusting the water activity to 0.35 or less; a step of forming a coat layer by spraying a first coating solution containing a hydrophilic polymer and a water activity regulator onto the core particles using a fluid bed coating method; an intermediate drying step of drying the particles with the formed coat layer in stages to adjust the water activity to 0.35 to 0.55; a step of forming a functional layer by spraying a second coating solution containing an absorption promoter or a release control agent; and a step of stabilizing the water activity of the multilayer particle structure to a range of 0.35 to 0.55 and adjusting the final moisture content to 3 weight percent to 8 weight percent through final drying and aging.

Description

Technology Field

[0001] The following examples relate to a multilayer particle structure for promoting the absorption of functional raw materials and a method for manufacturing the same. Background Technology

[0002] Various technologies have been developed to enhance the bioavailability of functional ingredients in the fields of health functional foods and cosmetics. In particular, multilayer particle structure technology is being widely studied as an effective method for protecting active ingredients and controlling their release rates. Conventional multilayer particle technologies are primarily based on core-shell structures, and manufacturing methods such as layer-by-layer stacking, temperature-controlled mixing, and fluidized bed coating have been utilized.

[0003] U.S. Patent No. 7939103 discloses multilayer coated particles ranging in size from 100 nm to 100 μm, and U.S. Patent No. 11123291 presents a method for forming a multilayer structure through temperature-controlled mixing. Additionally, U.S. Patent No. 10624858 discloses a release control technology using a transfer coating, and U.S. Patent No. 6911217 discloses bead-shaped particles with a four-layer structure. In Korea, Korean Published Patent No. 2014-0112979 presents a coating technology using pectin and maltodextrin.

[0004] However, most of these existing technologies focus on protecting active ingredients and achieving sustained-release, which limits their ability to simultaneously achieve immediate release and improved bioavailability. In particular, existing technologies are limited to the simple formation of physical coating layers, and there is a lack of approaches that optimize dissolution rates by actively controlling physicochemical parameters such as water activity. Furthermore, since most prior art is specialized for the pharmaceutical field, there are limitations in applying it universally to various formulations, such as health functional foods or cosmetics.

[0005] In the health functional food market, there is a growing trend among consumers to prioritize rapid absorption and tangible effects. In particular, there is increasing demand for technologies capable of delivering immediate effects, such as oral disintegration within 3 seconds and the release of active ingredients within 30 seconds, across various formulations including orally disintegrating films, tablets, soft capsules, and powders. To meet these market demands, a new approach is required to precisely control dissolution speed and absorption efficiency starting from the particle structure design stage. Prior art literature

[0006] Korean Registered Patent 10-1468796 Korean Registered Patent 10-0771426 Korean Published Patent 10-2006-0063476 Korean Registered Patent 10-1445957 The problem to be solved

[0007] The first problem that this invention aims to solve is to overcome the issue where existing multilayer particle technology focuses on simple protection or sustained-release, failing to simultaneously achieve immediate release and improved bioavailability. Existing technology controls the release rate by relying solely on the thickness of the coating layer or the selection of materials; however, this is unsuitable for applications in health functional foods and cosmetics that require immediate dissolution and absorption.

[0008] The second challenge is the lack of a mechanism to actively control water activity. Although water activity is a parameter that critically influences the storage stability and solubility characteristics of particles, prior art has not presented a method for systematically controlling it. In particular, there is a need for technology to control water activity within a critical range that can induce explosive hydration upon contact with bodily fluids while ensuring stability during storage.

[0009] The third challenge is that the functional differentiation of multilayer structures is unclear. In existing technologies, the role of each layer in multilayer structures was often unclear or functioned merely as a physical barrier. Optimization of each layer was difficult because a clear functional separation—such as protecting active ingredients in the core layer, controlling water activity in the coat layer, and promoting absorption or controlling release in the functional layer—was not achieved.

[0010] The fourth challenge is the lack of formulation versatility. Existing multilayer particle technology had structural limitations, either being applicable only to specific formulations or making it difficult to integrate across various final forms ranging from tablets to liquid suspensions. The health functional food industry needs to provide the same functional ingredient in various formulations—such as tablets, capsules, powders, orally dissolving films, and liquids—but existing technology required separate technological development for each formulation.

[0011] The fifth challenge is the lack of quantitative proof of effectiveness. There is no established manufacturing method that can quantitatively present clear performance indicators that consumers can perceive, such as oral disintegration time, the release rate of active ingredients, and the bioavailability enhancement ratio, and that can reproducibly implement these.

[0012] Therefore, the present invention aims to provide a method for manufacturing a multilayer particle structure that simultaneously achieves improved release and bioavailability through a three-layer functional differentiation structure with water activity control as the core mechanism, is universally applicable to various formulations, and can reproducibly implement quantitative effects. means of solving the problem

[0013] The present invention relates to a method for manufacturing a multilayer particle structure for promoting the absorption of functional raw materials, comprising forming a core layer, forming a coat layer containing a hydrophilic polymer, forming a functional layer containing an absorption promoter or a release control agent, and drying to adjust water activity.

[0014] At this time, the method comprises: (a) a core layer forming step of forming core particles with an average particle size of 50 μm to 300 μm by mixing and aggregating a functional raw material and an excipient, and drying the core particles to adjust the water activity to 0.35 or less; (b) a step of forming a coat layer by spraying a first coating solution containing a hydrophilic polymer onto the core particles using a fluid bed coating method; (c) an intermediate drying step of drying the particles with the formed coat layer to adjust the water activity to 0.35 to 0.55; (d) a step of forming a functional layer by spraying a second coating solution containing an absorption promoter or a release control agent onto the particles that have undergone the intermediate drying step; and (e) a step of finally drying the particles with the formed functional layer to maintain the water activity of the multilayer particle structure in the range of 0.35 to 0.55.

[0015] At this time, step (a) is a step of mixing 10 to 60 parts by weight of a functional raw material and 40 to 90 parts by weight of a core-forming excipient, adding 10 to 40 parts by weight of a binder to wet granulate, then performing primary drying at 40°C to 60°C and secondary drying at 50°C to 70°C to adjust the water activity to 0.25 to 0.35, and cooling and sieving to form core particles with an average particle size of 50μm to 300μm, and step (b) is a step of preparing a first coating solution having a solid content concentration of 5% to 25% by weight by dissolving a hydrophilic polymer and a water activity regulator, fluid bed coating under conditions of an inlet air temperature of 35°C to 50°C and a spray speed of 0.5g / min to 5g / min to form a coat layer with a weight increase rate of 5% to 25% by weight relative to the weight of the core particles, and post-drying. Step (c) is a step of adjusting the water activity of the particles with the formed coat layer to 0.35 to 0.55 by performing a first intermediate drying at an inlet air temperature of 30°C to 40°C, a second intermediate drying at 40°C to 50°C, and a third intermediate drying at 45°C to 55°C in stages, and stabilizing the coat layer structure by slow cooling to 20°C to 30°C; Step (d) is a step of preparing a second coating solution having a solid content concentration of 3% to 20% by weight containing 1% to 10% by weight of an absorption promoter or 3% to 15% by weight of a release control agent, fluid bed coating under conditions of an inlet air temperature of 30°C to 55°C and a spray rate of 0.3g / min to 4g / min to form a functional layer with a weight increase rate of 2% to 25% by weight and post-drying; and Step (e) is a step in which the inlet air temperature First final drying at 35°C to 45°C, second final drying at 40°C to 50°C, and third final drying at 45°C to 55°C are performed to obtain a water activity of 0.35 to 0.The step involves stabilizing at 55°C, cooling to 20°C to 30°C, and then aging for 12 to 48 hours at 20°C to 25°C and a relative humidity of 40% to 60% to adjust the final moisture content to 3% to 8% by weight.

[0016] At this time, the above step (a) comprises: (a1) a step of preparing a preliminary mixture by mixing 10 to 60 parts by weight of a functional raw material and 40 to 90 parts by weight of a core-forming excipient, wherein the core-forming excipient is one or more selected from the group consisting of microcrystalline cellulose, mannitol, lactose, starch, and sugar globules, in a mixer at a rotational speed of 100 rpm to 500 rpm for 5 to 20 minutes; (a2) a step of forming primary granules by wet granulating in a temperature range of 15°C to 35°C while spray-adding to the preliminary mixture, in an amount of 10 to 40 parts by weight per 100 parts by weight of the preliminary mixture, a binding solution comprising purified water, an aqueous ethanol solution, or an aqueous binder solution, having a viscosity of 5 cP to 50 cP and a pH adjusted to 4.0 to 7.0; (a3) a step of first drying the primary granules in a fluidized bed dryer for 10 to 30 minutes under conditions of an inlet air temperature of 40°C to 60°C and an air flow rate of 30 m³ / h to 80 m³ / h to preferentially remove surface moisture and adjust the water activity to 0.40 to 0.50 after the first drying; (a4) a step of second drying the primary dried granules for 20 to 60 minutes under conditions of an inlet air temperature of 50°C to 70°C and an air flow rate of 20 m³ / h to 50 m³ / h to gradually control internal moisture and adjust the water activity to 0.25 to 0.35 after the second drying; (a5) a step of cooling the secondary dried granules to 20°C to 30°C to stabilize the particle surface; and (a6) a step of sieving the cooled granules with a vibrating sieve to select core particles with an average particle size of 50 μm to 300 μm; is included.

[0017] At this time, the above step (b) comprises: (b1) a step of preparing a first coating solution in which the hydrophilic polymer is one or more selected from the group consisting of hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, modified starch, and pullulan, and the water activity regulator is one or more selected from the group consisting of trehalose, maltodextrin, sorbitol, erythritol, and mannitol, and the hydrophilic polymer is dissolved in purified water or an aqueous ethanol solution, and the water activity regulator is additionally dissolved in an amount of 10 to 80 parts by weight per 100 parts by weight of the hydrophilic polymer, thereby having a combined solid content concentration of the hydrophilic polymer and the water activity regulator of 5% to 25% by weight; (b2) a step of introducing the core particles into a fluidized bed coating machine, setting the inlet air temperature to 35°C to 50°C and the air flow rate to 40 m³ / h to 100 m³ / h to make the core particles into a fluidized state; (b3) a step of initiating spraying of the first coating liquid through a spray nozzle at an initial spraying speed of 0.5 g / min to 1.9 g / min when the surface temperature of the core particles in the fluidized state reaches 25°C to 35°C; (b4) a step of proceeding with coating by increasing the spraying speed to an intermediate spraying speed of 2 g / min to 5 g / min when it is confirmed that the first coating liquid is uniformly attached to the surface of the core particles after the spraying starts, such that the cumulative spraying amount of the first coating liquid relative to the total weight of the core particles reaches 1 weight% to 3 weight%; (b5) forming a coat layer by maintaining the spray pressure at 1.0 bar to 2.0 bar while continuing the spray until the weight increase rate of the core particles, based on the total weight of the core particles before the start of spraying, reaches 5% to 25% by weight; and (b6) stopping the spraying when the target weight increase rate is reached and stabilizing the surface of the coat layer by post-drying for 5 to 15 minutes while maintaining the inlet air temperature at 35°C to 50°C;

[0018] At this time, the above step (c) comprises: (c1) a step of first intermediate drying the particles having the coating layer formed thereon in a fluidized bed dryer for 5 to 15 minutes under conditions of an inlet air temperature of 30°C to 40°C and an air flow rate of 30 m³ / h to 70 m³ / h to preferentially remove free water on the surface of the coating layer; (c2) a step of measuring the water activity of the particles that were first intermediate dried, and after confirming that the water activity is in the range of 0.50 to 0.60, raising the inlet air temperature to 40°C to 50°C and decreasing the air flow rate to 20 m³ / h to 50 m³ / h to perform second intermediate drying for 10 to 25 minutes to control the bound water inside the coating layer in stages; (c3) a step of re-measuring the water activity of the second intermediate dried particles and, when the water activity reaches the range of 0.40 to 0.50, adjusting the water activity to 0.35 to 0.55 by performing a third intermediate drying for 5 to 15 minutes while controlling the inlet air temperature to 45°C to 55°C; (c4) a step of finally confirming whether the water activity of the third intermediate dried particles is within the range of 0.35 to 0.55 and terminating the drying when the target range is reached; and (c5) a step of stabilizing the structure of the coat layer by slowly cooling the particles after drying to 20°C to 30°C while reducing the air flow rate to 10 m³ / h to 30 m³ / h in a fluidized bed dryer;

[0019] At this time, the above step (d) comprises: (d1) when forming an absorption-promoting functional layer, the absorption promoter comprises one or more selected from the group consisting of chitosan, chitosan derivatives, cationic gelatin, polysorbate, poloxamer, and sodium lauryl sulfate in an amount of 1% to 10% by weight relative to the total weight of the second coating solution, and when forming a release-controlled functional layer, the release control agent comprises one or more selected from the group consisting of Eudragit L100-55, Eudragit L, Eudragit S, hydroxypropylmethylcellulose acetate succinate, and hydroxypropylmethylcellulose phthalate in an amount of 3% to 15% by weight relative to the total weight of the second coating solution, and dissolving or dispersing the absorption promoter or release control agent in purified water, an aqueous ethanol solution, or an organic solvent to prepare a second coating solution having a solid content concentration of 3% to 20% by weight; (d2) reintroducing the particles that have undergone step (c) into a fluid bed coating machine, and setting the inlet air temperature to 30°C to 45°C when forming an absorption-promoting functional layer, and setting the inlet air temperature to 40°C to 55°C when forming a release-controlled functional layer, thereby making the particles into a fluid state; (d3) when the surface temperature of the particles in the fluid state reaches the set temperature range, initiating spraying of the second coating solution at an initial low-speed spray of 0.3g / min to 1.5g / min to form a uniform primer layer on the surface of the particles; (d4) after forming the primer layer, increasing the spray speed to a medium-speed spray of 1.5g / min to 4g / min and maintaining the spray pressure at 0.8bar to 1.5bar, and continuously spraying until the weight increase rate of the particles after the completion of step (c) reaches 2% to 10% by weight for the absorption-promoting type and 10% to 25% by weight for the release-controlled type to form a functional layer; (d5) Spray rate 0 during the last 5 minutes before reaching the target weight increase rate.The method includes: a step of densely finishing the surface of the functional layer by reducing the final low-speed spray to 5 g / min to 1 g / min; and (d6) a step of stabilizing the functional layer by post-drying at an air flow rate of 30 m³ / h to 70 m³ / h for 3 minutes to 10 minutes while maintaining the inlet air temperature after the spraying is finished.

[0020] At this time, the above step (e) comprises: (e1) a step of removing free water from the surface of the functional layer by performing a first final drying of the particles formed with the functional layer in a fluidized bed dryer for 10 to 20 minutes under conditions of an inlet air temperature of 35°C to 45°C and an air flow rate of 40 m³ / h to 80 m³ / h; (e2) a step of measuring the water activity of the particles that were first finally dried, and if the measured water activity is within the range of 0.45 to 0.60, a step of controlling the moisture of the entire particle in stages by raising the inlet air temperature to 40°C to 50°C and decreasing the air flow rate to 30 m³ / h to 60 m³ / h to perform a second final drying for 15 to 30 minutes; (e3) a step of measuring the water activity at intervals of 3 to 7 minutes during the second final drying and confirming the point in time when the measured water activity reaches the range of 0.35 to 0.55; (e4) When the water activity reaches the range of 0.35 to 0.55, perform a third final drying for 5 to 15 minutes while maintaining the inlet air temperature at 45°C to 55°C and reducing the air flow rate to 20 m³ / h to 40 m³ / h to stabilize the water activity within the range of 0.35 to 0.55; (e5) Cool the particles that have been thirdly dried in a fluidized bed dryer for 10 to 25 minutes while reducing the inlet air temperature to 30°C to 40°C and maintaining the air flow rate to 10 m³ / h to 30 m³ / h to control the temperature of the particles to 20°C to 30°C; (e6) a step of transferring the cooled particles to a sealed container and aging them for 12 to 48 hours under conditions of 20°C to 25°C and relative humidity of 40% to 60% to homogenize the moisture distribution inside the particles; and (e7) a step of measuring the final moisture activity of the aged particles to confirm whether it is within the range of 0.35 to 0.55 and confirming that the final moisture content is 3% to 8% by weight;

[0021] A device according to one embodiment may be combined with hardware and controlled by a computer program stored on a medium to execute the method of any one of the methods described above. Effects of the invention

[0022] The present invention can simultaneously secure storage stability and immediate dissolution characteristics by precisely controlling the water activity to a range of 0.35 to 0.55. In this critical water activity range, free water is minimized, thereby inhibiting microbial growth and chemical decomposition, while at the same time, the osmotic driving force is maximized upon contact with body fluids, resulting in explosive hydration. Although powder aggregation due to over-drying occurs when the water activity is below 0.35 and storage stability decreases when it exceeds 0.55, these problems are effectively resolved within the scope of the present invention.

[0023] Furthermore, the present invention can optimize the role of each layer through a three-layer functional differentiation structure consisting of a core layer, a coat layer, and a functional layer. The core layer stably protects the functional raw material and forms an appropriate release base, the coat layer determines solubility characteristics through a hydrophilic polymer and a water activity regulator, and the functional layer imparts final performance suitable for the product purpose through an absorption promoter or a release control agent. This clear functional separation enables independent optimization of each layer, thereby maximizing the performance of the entire system.

[0024] In addition, the present invention can precisely control the water activity of each layer through a stepwise drying process. By performing a first drying step to adjust the water activity to 0.25 to 0.35 after forming a core, an intermediate drying step to adjust it to 0.35 to 0.55 after forming a coat layer, and a final drying and aging step to stabilize the final water activity to a range of 0.35 to 0.55 after forming a functional layer, both structural stability and functional performance of each layer can be secured.

[0025] In addition, the present invention achieves a disintegration initiation time that is 5 to 10 times faster than conventional simple coating technology. The particle structure according to the present invention initiates disintegration within 2 to 3 seconds after being inserted into the oral cavity, and more than 80 percent of the functional raw material is released within 30 seconds in an aqueous solution at 37°C. This is a significantly superior performance compared to the disintegration time of 10 to 30 seconds and the 30-second release rate of 40 to 60 percent of conventional technology.

[0026] Furthermore, the present invention can improve bioavailability by more than 150 percent. When an absorption-promoting functional layer is applied, cationic polymers such as chitosan or surfactants increase mucosal permeability and open tight junctions, thereby dramatically increasing the efficiency of absorption of active ingredients into the body. This provides a difference in effect that consumers can directly experience.

[0027] In addition, the present invention can be universally applied to various final formulations, such as tablets, hard capsules, soft capsules, powders, granules, oral dissolving films, and liquid suspensions. Since products can be diversified by changing only the formulation based on the same multilayer particle structure, manufacturing efficiency is high and quality control is easy. This enables health functional food companies to build a diverse product lineup with a single core technology.

[0028] Furthermore, the present invention enables highly reproducible manufacturing by systematically optimizing the process conditions of a fluidized bed coating method. By precisely controlling parameters such as inlet air temperature, spray speed, spray pressure, and air flow rate at each stage, quality variations between batches can be minimized, and consistent performance can be ensured even during mass production.

[0029] In addition, the present invention can improve long-term storage stability by homogenizing the moisture distribution inside the particles through an aging process. When aging is performed for 12 to 48 hours under conditions of 20 to 25 degrees Celsius and a relative humidity of 40 percent to 60 percent, the moisture activity of the surface and the interior is equilibrium, thereby minimizing changes in physical properties over time. Specific details for implementing the invention

[0030] Embodiments are described in detail below. However, various modifications may be made to the embodiments, and thus the scope of the patent application is not limited or restricted by these embodiments. It should be understood that all modifications, equivalents, and substitutions to the embodiments are included within the scope of the rights.

[0031] Specific structural or functional descriptions of the embodiments are disclosed for illustrative purposes only and may be modified and implemented in various forms. Accordingly, the embodiments are not limited to the specific disclosed forms, and the scope of this specification includes modifications, equivalents, or substitutions that fall within the technical concept.

[0032] Terms such as "first" or "second" may be used to describe various components, but these terms should be interpreted solely for the purpose of distinguishing one component from another. For example, the first component may be named the second component, and similarly, the second component may be named the first component.

[0033] When it is stated that a component is "connected" to another component, it should be understood that it may be directly connected to or coupled with that other component, or that there may be other components in between.

[0034] The terms used in the embodiments are for illustrative purposes only and should not be interpreted as intended to be limiting. Singular expressions include plural expressions unless the context clearly indicates otherwise. In this specification, terms such as "comprising" or "having" are intended to indicate the existence of the features, numbers, steps, actions, components, parts, or combinations thereof described in the specification, and should be understood as not precluding the existence or addition of one or more other features, numbers, steps, actions, components, parts, or combinations thereof.

[0035] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as generally understood by those skilled in the art to which the embodiments pertain. Terms such as those defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology, and should not be interpreted in an ideal or overly formal sense unless explicitly defined in this application.

[0036] The advantages and features of the present invention and the methods for achieving them will become clear by referring to the embodiments described in detail below. However, the present invention is not limited to the embodiments disclosed below but may be implemented in various different forms. These embodiments are provided merely to ensure that the disclosure of the present invention is complete and to fully inform those skilled in the art of the scope of the invention, and the present invention is defined only by the scope of the claims.

[0037] In the embodiments of the present invention, unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as generally understood by those skilled in the art to which the present invention pertains. Terms such as those defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology, and should not be interpreted in an ideal or overly formal sense unless explicitly defined in the embodiments of the present invention.

[0038] The shapes, sizes, ratios, angles, numbers, etc. disclosed to describe embodiments of the present invention are exemplary and are not limited to the disclosed matters. Furthermore, in describing the present invention, if it is determined that a detailed description of related known technology may unnecessarily obscure the essence of the present invention, such detailed description is omitted. Where terms such as "comprising," "having," or "consisting of" are used in this specification, other parts may be added unless "only" is used. Where a component is expressed in the singular, it includes cases where it includes the plural unless specifically stated otherwise.

[0039] In interpreting the components, they are interpreted to include a margin of error even in the absence of a separate explicit statement.

[0040] The size and thickness of each disclosed component are disclosed for convenience of explanation and the present invention is not necessarily limited to the size and thickness of the disclosed components.

[0041] The features of each of the various embodiments of the present invention may be combined or combined with one another, either partially or wholly, and as will be fully understood by those skilled in the art, various technical interlocking and operation are possible, and each embodiment may be implemented independently of one another or together in an interlocking relationship.

[0042] The present invention relates to a method for manufacturing a multilayer particle structure for promoting the absorption of functional raw materials, comprising forming a core layer, forming a coat layer containing a hydrophilic polymer, forming a functional layer containing an absorption promoter or a release control agent, and drying to adjust water activity.

[0043] At this time, the method comprises: (a) a core layer forming step in which a core particle with an average particle size of 50 μm to 300 μm is formed by mixing and aggregating a functional raw material and an excipient, and the core particle is dried to adjust the water activity to 0.35 or less; (b) a step in which a first coating solution containing a hydrophilic polymer is sprayed onto the core particle using a fluid bed coating method to form a coat layer; (c) an intermediate drying step in which the particle with the coat layer formed is dried to adjust the water activity to 0.35 to 0.55; (d) a step in which a second coating solution containing an absorption promoter or a release control agent is sprayed onto the particle that has undergone the intermediate drying step to form a functional layer; and (e) a step in which the particle with the functional layer formed is finally dried to maintain the water activity of the multilayer particle structure in the range of 0.35 to 0.55.

[0044] At this time, step (a) is a step of mixing 10 to 60 parts by weight of a functional raw material and 40 to 90 parts by weight of a core-forming excipient, adding 10 to 40 parts by weight of a binder to wet granulate, then performing primary drying at 40°C to 60°C and secondary drying at 50°C to 70°C to adjust the water activity to 0.25 to 0.35, and cooling and sieving to form core particles with an average particle size of 50μm to 300μm, and step (b) is a step of preparing a first coating solution having a solid content concentration of 5% to 25% by weight by dissolving a hydrophilic polymer and a water activity regulator, fluid bed coating under conditions of an inlet air temperature of 35°C to 50°C and a spray speed of 0.5g / min to 5g / min to form a coat layer with a weight increase rate of 5% to 25% by weight relative to the weight of the core particles, and post-drying. Step (c) is a step of adjusting the water activity of the particles with the formed coat layer to 0.35 to 0.55 by performing a first intermediate drying at an inlet air temperature of 30°C to 40°C, a second intermediate drying at 40°C to 50°C, and a third intermediate drying at 45°C to 55°C in stages, and stabilizing the coat layer structure by slow cooling to 20°C to 30°C; Step (d) is a step of preparing a second coating solution having a solid content concentration of 3% to 20% by weight containing 1% to 10% by weight of an absorption promoter or 3% to 15% by weight of a release control agent, fluid bed coating under conditions of an inlet air temperature of 30°C to 55°C and a spray rate of 0.3g / min to 4g / min to form a functional layer with a weight increase rate of 2% to 25% by weight and post-drying; and Step (e) is a step in which the inlet air temperature First final drying at 35°C to 45°C, second final drying at 40°C to 50°C, and third final drying at 45°C to 55°C are performed to obtain a water activity of 0.35 to 0.The step involves stabilizing at 55°C, cooling to 20°C to 30°C, and then aging for 12 to 48 hours at 20°C to 25°C and a relative humidity of 40% to 60% to adjust the final moisture content to 3% to 8% by weight.

[0045] At this time, the above step (a) comprises: (a1) a step of preparing a preliminary mixture by mixing 10 to 60 parts by weight of a functional raw material and 40 to 90 parts by weight of a core-forming excipient, wherein the core-forming excipient is one or more selected from the group consisting of microcrystalline cellulose, mannitol, lactose, starch, and sugar spheres, in a mixer at a rotational speed of 100 rpm to 500 rpm for 5 to 20 minutes; (a2) a step of forming primary granules by wet granulating the mixture in a temperature range of 15°C to 35°C while spray-adding to the preliminary mixture, in an amount of 10 to 40 parts by weight per 100 parts by weight of the preliminary mixture, a binding solution composed of purified water, an aqueous ethanol solution, or an aqueous binder solution, having a viscosity of 5 cP to 50 cP and a pH adjusted to 4.0 to 7.0; and (a3) ​​a step of drying the primary granules in a fluidized bed dryer at an inlet air temperature of 40°C to A step of first drying for 10 to 30 minutes under conditions of 60°C and an air flow rate of 30 m³ / h to 80 m³ / h to preferentially remove surface moisture and adjust the water activity to 0.40 to 0.50 after the first drying; (a4) a step of second drying the first-dried granules for 20 to 60 minutes under conditions of an inlet air temperature of 50°C to 70°C and an air flow rate of 20 m³ / h to 50 m³ / h to gradually control internal moisture and adjust the water activity to 0.25 to 0.35 after the second drying; (a5) a step of cooling the second-dried granules to 20°C to 30°C to stabilize the particle surface; and (a6) a step of sieving the cooled granules with a vibrating sieve to select core particles with an average particle size of 50 μm to 300 μm. It is accomplished.

[0046] At this time, the above step (b) comprises: (b1) preparing a first coating solution in which the hydrophilic polymer is one or more selected from the group consisting of hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, modified starch, and pullulan, and the water activity regulator is one or more selected from the group consisting of trehalose, maltodextrin, sorbitol, erythritol, and mannitol, and the hydrophilic polymer is dissolved in purified water or an aqueous ethanol solution, and the water activity regulator is additionally dissolved in an amount of 10 to 80 parts by weight per 100 parts by weight of the hydrophilic polymer, thereby having a combined solid content concentration of the hydrophilic polymer and the water activity regulator of 5% to 25% by weight; and (b2) introducing the core particles into a fluidized bed coating machine, setting the inlet air temperature to 35°C to 50°C, and setting the air flow rate to 40 m³ / h to 100 m³ / h so that the core particles flow A step of making the core particle in the fluid state into a state; (b3) a step of initiating spraying of the first coating liquid through a spray nozzle at an initial spraying speed of 0.5 g / min to 1.9 g / min when the surface temperature of the core particle in the fluid state reaches 25°C to 35°C; (b4) a step of proceeding with coating by increasing the spraying speed to an intermediate spraying speed of 2 g / min to 5 g / min when it is confirmed that the first coating liquid is uniformly attached to the surface of the core particle after the spraying starts, such that the cumulative spraying amount of the first coating liquid relative to the total weight of the core particle reaches 1 weight% to 3 weight%; (b5) a step of forming a coat layer by maintaining the spraying pressure at 1.0 bar to 2.0 bar while continuing spraying until the weight increase rate of the core particle relative to the total weight of the core particle before the spraying starts reaches 5 weight% to 25 weight%; and (b6) stopping spraying when the target weight increase rate is reached, and for 5 to 15 minutes while maintaining the inlet air temperature at 35°C to 50°C It consists of a step of drying to stabilize the surface of the coat layer.

[0047] At this time, the above step (c) comprises: (c1) a step of first intermediate drying the particles with the formed coat layer in a fluidized bed dryer for 5 to 15 minutes under conditions of an inlet air temperature of 30°C to 40°C and an air flow rate of 30 m³ / h to 70 m³ / h to preferentially remove free water from the surface of the coat layer; (c2) a step of measuring the water activity of the particles that were first intermediate dried, and after confirming that the water activity is in the range of 0.50 to 0.60, raising the inlet air temperature to 40°C to 50°C and decreasing the air flow rate to 20 m³ / h to 50 m³ / h to perform second intermediate drying for 10 to 25 minutes to control the bound water inside the coat layer in stages; and (c3) a step of re-measuring the water activity of the particles that were second intermediate dried, and when the water activity reaches the range of 0.40 to 0.50, raising the inlet air temperature to 45°C to The method comprises the steps of: (c4) adjusting the water activity to 0.35 to 0.55 by performing a third intermediate drying for 5 to 15 minutes while controlling the temperature to 55°C; (c4) finally confirming whether the water activity of the particles that were subjected to the third intermediate drying is within the range of 0.35 to 0.55, and terminating the drying when the target range is reached; and (c5) slowly cooling the particles that were subjected to drying in a fluidized bed dryer to 20°C to 30°C while reducing the air flow rate to 10 m³ / h to 30 m³ / h to stabilize the structure of the coat layer.

[0048] At this time, the above step (d) comprises: (d1) when forming an absorption-promoting functional layer, the absorption promoter comprises one or more selected from the group consisting of chitosan, chitosan derivatives, cationic gelatin, polysorbate, poloxamer, and sodium lauryl sulfate in an amount of 1% to 10% by weight relative to the total weight of the second coating solution, and when forming a release-controlled functional layer, the release control agent comprises one or more selected from the group consisting of Eudragit L100-55, Eudragit L, Eudragit S, hydroxypropylmethylcellulose acetate succinate, and hydroxypropylmethylcellulose phthalate in an amount of 3% to 15% by weight relative to the total weight of the second coating solution, and dissolving or dispersing the absorption promoter or release control agent in purified water, an aqueous ethanol solution, or an organic solvent to prepare a second coating solution having a solid content concentration of 3% to 20% by weight; and (d2) the particles that have undergone the above step (c) are placed in a fluid bed coating machine A step of re-introducing and setting the inlet air temperature to 30°C to 45°C when forming an absorption-promoting functional layer, and setting the inlet air temperature to 40°C to 55°C when forming a release-controlled functional layer, to make the particles into a fluid state; (d3) when the surface temperature of the particles in the fluid state reaches the set temperature range, initiating spraying of the second coating solution at an initial low-speed spray of 0.3g / min to 1.5g / min to form a uniform primer layer on the surface of the particles; (d4) after forming the primer layer, increasing the spray speed to a medium-speed spray of 1.5g / min to 4g / min and maintaining the spray pressure at 0.8bar to 1.5bar, and continuously spraying until the weight increase rate of the particles reaches 2% to 10% in the case of an absorption-promoting type and 10% to 25% in the case of a release-controlled type after the completion of step (c) to form a functional layer; and (d5) during the last 5 minutes before reaching the target weight increase rate, the spray speed 0.The process comprises the step of densely finishing the surface of the functional layer by reducing the final low-speed spray to 5 g / min to 1 g / min, and (d6) the step of stabilizing the functional layer by post-drying at an air flow rate of 30 m³ / h to 70 m³ / h for 3 minutes to 10 minutes while maintaining the inlet air temperature after the spraying is finished.

[0049] At this time, the above step (e) comprises: (e1) a step of removing free water from the surface of the functional layer by performing a first final drying of the particles formed with the functional layer in a fluidized bed dryer for 10 to 20 minutes under conditions of an inlet air temperature of 35°C to 45°C and an air flow rate of 40 m³ / h to 80 m³ / h; (e2) a step of controlling the moisture of the entire particle in stages by measuring the water activity of the particles that were first finally dried, and if the measured water activity is within the range of 0.45 to 0.60, raising the inlet air temperature to 40°C to 50°C and decreasing the air flow rate to 30 m³ / h to 60 m³ / h to perform a second final drying for 15 to 30 minutes; and (e3) measuring the water activity at intervals of 3 to 7 minutes during the second final drying and confirming the point at which the measured water activity reaches the range of 0.35 to 0.55. Steps: (e4) when the water activity reaches the range of 0.35 to 0.55, perform a third final drying for 5 to 15 minutes while maintaining the inlet air temperature at 45°C to 55°C and reducing the air flow rate to 20 m³ / h to 40 m³ / h to stabilize the water activity within the range of 0.35 to 0.55; (e5) cool the particles that have been thirdly dried in a fluidized bed dryer for 10 to 25 minutes while reducing the inlet air temperature to 30°C to 40°C and maintaining the air flow rate to 10 m³ / h to 30 m³ / h to control the temperature of the particles to 20°C to 30°C; and (e6) transfer the cooled particles to a sealed container and age them for 12 to 48 hours under conditions of 20°C to 25°C and relative humidity of 40% to 60% to... The method comprises the steps of: (e7) measuring the final moisture activity of the aged particles to determine if it is within the range of 0.35 to 0.55, and determining that the final moisture content is 3% by weight to 8% by weight.

[0050] Specific implementation method of the core layer formation step

[0051] Core layer formation step (a) Overall overview

[0052] The core layer formation step involves manufacturing core particles that possess physical properties suitable for a subsequent coating process while stably protecting the functional raw material. In this step, the functional raw material and excipients are mixed in appropriate proportions, and particles are formed through wet granulation using a binder. Subsequently, the particles undergo stepwise drying to reach a target water activity. Finally, uniform core particles with an average particle size ranging from 50 micrometers to 300 micrometers are obtained, and these particles are adjusted to a water activity of 0.35 or less to ensure storage stability. Lowering the water activity of the core layer to 0.35 or less is intended to ensure long-term stability by suppressing degradation reactions of the functional raw material, such as oxidation, hydrolysis, and microbial growth. Additionally, the appropriate particle size range is intended to guarantee fluidity during the fluid bed coating process and maintain a size suitable for oral administration when applied to the final formulation.

[0053] Preliminary mixture preparation step (a1)

[0054] One or more excipients selected from the group consisting of microcrystalline cellulose, mannitol, lactose, starch, and sugar spheres are used for core formation. Microcrystalline cellulose provides excellent compressibility and binding properties and is suitable for forming the structural framework of granules due to its insolubility. Mannitol is a water-soluble sugar alcohol that provides a pleasant sweetness and cooling sensation, and its low hygroscopicity is advantageous for storage stability. Lactose is a representative excipient that provides a mild sweetness and excellent fluidity. Starch is a natural polymer that provides both binding and disintegration properties. Sugar spheres serve as spherical, inert cores that provide an ideal surface for layered coatings. These excipients may be used individually or in combination depending on the characteristics of the functional raw material, the target formulation, and the required physical properties.

[0055] The functional ingredient is blended in a ratio of 10 to 60 parts by weight and a core-forming excipient in a ratio of 40 to 90 parts by weight. If the content of the functional ingredient is less than 10 parts by weight, the content of the active ingredient in the final product becomes excessively low, making it difficult to exhibit the desired efficacy. Conversely, if it exceeds 60 parts by weight, the amount of excipient is relatively insufficient, resulting in poor granule formation and reduced mechanical strength, and problems such as particle breakage or aggregation may occur during the subsequent coating process. Preferably, a ratio of 20 to 50 parts by weight of the functional ingredient and 50 to 80 parts by weight of the excipient is used, and more preferably, a ratio of 30 to 40 parts by weight of the functional ingredient and 60 to 70 parts by weight of the excipient is used.

[0056] Various types of mixers suitable for powder mixing, such as high-shear mixers, V-type mixers, double cone mixers, and ribbon blenders, can be used. The rotational speed of the mixer is set to a range of 100 rpm to 500 rpm. If the rotational speed is less than 100 rpm, mixing is insufficient, resulting in uneven dispersion of components, which leads to variations in particle content within the batch. If the rotational speed exceeds 500 rpm, excessive shear force may damage functional raw materials or cause the powder to adhere strongly to the walls of the mixer, which may actually reduce mixing efficiency. The preferred rotational speed is 150 rpm to 400 rpm, and more preferably 200 rpm to 300 rpm.

[0057] The mixing time is set to between 5 and 20 minutes. A mixing time of less than 5 minutes is insufficient to achieve uniform dispersion of the ingredients. Mixing exceeding 20 minutes reduces economic efficiency by increasing process time while providing only minimal additional improvement in uniformity. Furthermore, prolonged mixing generates frictional heat, which may damage heat-sensitive functional ingredients. The preferred mixing time is between 7 and 15 minutes, and more preferably between 10 and 12 minutes. The completion of mixing can be confirmed through visual observation or a content uniformity test via sampling. Mixing is deemed complete when the variation in the content of functional ingredients within the mixture is within 5 percent.

[0058] It is desirable to perform the mixing process in a temperature-controlled environment. In particular, when using heat-sensitive functional raw materials, the temperature during the mixing process should be managed so that it does not exceed 30°C. If necessary, a cooling jacket may be attached to the mixer, or the indoor temperature may be controlled through an air conditioning system. After the mixing is complete, the resulting preliminary mixture should be immediately transferred to the next step, or if unavoidable, stored in a sealed container and preferably used within 24 hours.

[0059] Wet granulation step (a2)

[0060] In the wet granulation step, a binder is added to the premix to aggregate the powder particles and form granules. Purified water, an aqueous ethanol solution, or an aqueous binder solution is used as the binder. Purified water is the most economical and safe binder, but it can be problematic if some functional raw materials are sensitive to moisture. The aqueous ethanol solution generally has a composition of 10 to 50 weight percent ethanol and 50 to 90 weight percent purified water; the higher the ethanol content, the faster the drying speed and the more advantageous it is for raw materials sensitive to moisture. The aqueous binder solution is prepared by dissolving water-soluble polymers such as polyvinylpyrrolidone, hydroxypropylcellulose, and hydroxypropylmethylcellulose in purified water at a concentration of 0.5 to 5 weight percent, which has the effect of strengthening the binding force of the granules.

[0061] The viscosity of the binder is adjusted to a range of 5 cP to 50 cP. If the viscosity is excessively low, below 5 cP, the binder does not distribute uniformly on the powder surface and penetrates rapidly, which may result in localized over-wetting. If the viscosity exceeds 50 cP, spraying and dispersion of the binder become difficult, and an uneven coating is formed on the granule surface, degrading the quality of the granules. The preferred viscosity range is 10 cP to 40 cP, and more preferably 15 cP to 30 cP. The viscosity is based on the value measured at 25°C using a rotational viscometer.

[0062] The pH of the binding solution is adjusted to 4.0 to 7.0. Under acidic conditions with a pH below 4.0, some functional ingredients or excipients may decompose or discolor. Under alkaline conditions with a pH above 7.0, the stability of specific functional ingredients may be reduced or a reaction with excipients may occur. A preferred pH range is 5.0 to 6.5, and more preferably 5.5 to 6.0. pH adjustment can be performed using food-grade pH adjusters such as citric acid, phosphoric acid, sodium hydroxide, or potassium hydroxide.

[0063] The amount of binder added is 10 to 40 parts by weight per 100 parts by weight of the premix. If the amount of binder is less than 10 parts by weight, there is insufficient moisture for granule formation, resulting in a large amount of ungranulated powder remaining and granules that are small and non-uniform. If the amount of binder exceeds 40 parts by weight, excessive moisture causes the granules to be excessively large and soft, lumps to form, and the drying time to become excessively long. The preferred amount is 15 to 35 parts by weight, and more preferably 20 to 30 parts by weight. Since the optimal amount of binder may vary depending on the type and ratio of excipients, the characteristics of the functional raw material, the apparent density of the mixture, etc., it is desirable to determine it through preliminary experiments.

[0064] Spray addition is used as the method for adding the binder. Spray addition is a method of creating fine droplets of the binder and dispersing them uniformly over the powder surface; this is advantageous for preventing localized over-wetting and forming uniform granules. Two-fluid nozzles, pressure nozzles, ultrasonic nozzles, etc., can be used as spray nozzles. The spray pressure is generally set in the range of 1.0 bar to 3.0 bar, and the spray speed is adjusted according to the amount of the premix and the capacity of the mixer. Generally, spraying is performed at a rate of 10 to 50 milliliters per minute per kilogram of premix. If the spraying is too fast, localized over-wetting occurs, and if it is too slow, the process time is unnecessarily extended.

[0065] During the wet granulation process, the temperature is maintained within the range of 15°C to 35°C. If the temperature is below 15°C, the viscosity of the binder increases and miscibility with the powder decreases, resulting in poor granule formation. If the temperature exceeds 35°C, the surface of the granules dries prematurely due to the rapid evaporation of moisture, forming non-uniform granules that are wet inside but dry on the surface. Additionally, heat-sensitive functional raw materials may be damaged. The preferred temperature range is 18°C ​​to 30°C, and more preferably 20°C to 25°C. Temperature control can be achieved through an air conditioning system or jacket cooling of the mixer.

[0066] High-shear mixers, fluidized bed granulators, and extruded spheroids can be used as wet granulation equipment. High-shear mixers are the most widely used because they can produce dense, nearly spherical granules in a short time through the high-speed rotation of the impeller and chopper. The impeller speed is generally set in the range of 200 rpm to 800 rpm, and the chopper speed is set in the range of 1,000 rpm to 3,000 rpm. Fluidized bed granulators use an upward airflow to flow the powder while spraying a binder, and have the advantage of being able to perform drying and granulation simultaneously. Extruded spheroids extrude the wet mass through a screen and then form it into spherical granules in a spheroidizing device, allowing for the production of uniform granules with a relatively large particle size.

[0067] The granulation endpoint is determined by observing the physical properties of the granules. When properly granulated, the granules have a strength such that they clump together when lightly squeezed by hand but break easily with a finger. When a sample of the granules is taken and observed under a microscope, individual particles are aggregated by the binding solution, and generally round granules are observed rather than irregular clumps. Additionally, the appropriate binding strength can be confirmed by the fact that the granules do not disintegrate rapidly and maintain their shape for a certain period of time when placed in a small amount of purified water. The primary granules obtained after the completion of wet granulation are immediately transferred to the drying stage.

[0068] 1st drying step (a3)

[0069] The first drying step is a step to preferentially remove free water present on the surface of the granules immediately after wet granulation. By rapidly removing surface moisture, aggregation between granules is prevented, and a foundation is laid to effectively remove internal moisture in the subsequent second drying step. Drying is performed for 10 to 30 minutes using a fluidized bed dryer under conditions of an inlet air temperature of 40 to 60 degrees Celsius and an air flow rate of 30 cubic meters per hour to 80 cubic meters per hour.

[0070] A fluidized bed dryer is equipment that dries granules by suspending them with heated air supplied upward from the bottom. It enables rapid and uniform drying due to the large contact area between the granules and the drying air and high heat transfer efficiency. Fluidized bed dryers come in various forms, including vertical fluidized beds, horizontal fluidized beds, and vibrating fluidized beds, all of which can be used in this invention. In the case of a batch-type fluidized bed dryer, equipment of an appropriate capacity is selected based on the amount of granules that can be processed at once. In the case of a continuous-type fluidized bed dryer, the desired degree of drying can be achieved by adjusting the residence time.

[0071] The inlet air temperature is set to between 40°C and 60°C. If the inlet air temperature is below 40°C, the drying speed becomes excessively slow, resulting in an excessively long process time; furthermore, a wet state is maintained for an extended period, which may cause aggregation between granules. If the inlet air temperature exceeds 60°C, rapid drying of the granule surface may lead to the formation of a dense film, causing a case hardening phenomenon where the movement of internal moisture is hindered. Additionally, there is a risk of damage to heat-sensitive functional raw materials. The preferred inlet air temperature is between 45°C and 55°C, and more preferably between 48°C and 52°C. The inlet air temperature is monitored by a temperature sensor installed at the dryer inlet, and the heater output is automatically controlled to maintain the set temperature.

[0072] The air flow rate is set within the range of 30 cubic meters per hour to 80 cubic meters per hour. If the air flow rate is less than 30 cubic meters per hour, the granules cannot be sufficiently flowed, resulting in uneven drying and aggregation between granules. If the air flow rate exceeds 80 cubic meters per hour, excessive flow causes the granules to break or wear down, generating fine particles, and increases drift losses where granules fly into the exhaust filter. The preferred air flow rate is 40 cubic meters per hour to 70 cubic meters per hour, and more preferably 50 cubic meters per hour to 60 cubic meters per hour. Since the appropriate air flow rate depends on the size, density, and shape of the granules, conditions that allow the granules to flow smoothly while minimizing drift are determined experimentally.

[0073] The first drying time is set to 10 to 30 minutes. If the drying time is less than 10 minutes, surface moisture is not sufficiently removed, leading to aggregation between granules and potentially causing problems during the subsequent second drying. If the drying time exceeds 30 minutes, the functional raw material may be damaged due to unnecessary prolonged exposure to heat, and the granule surface becomes excessively dry, resulting in a larger moisture gradient between the surface and the interior. The preferred first drying time is 12 to 25 minutes, and more preferably 15 to 20 minutes. Since the optimal drying time depends on the initial moisture content of the granules, the size and quantity of the granules, and drying conditions, it is adjusted while monitoring the product temperature and the humidity of the exhaust air.

[0074] During the first drying process, the product temperature of the granules is monitored in real time using a temperature probe inserted inside the dryer. Initially, due to the evaporative cooling effect, the product temperature remains significantly lower than the inlet air temperature, but it gradually rises as surface moisture is removed. When the product temperature stabilizes within the range of 35 to 45 degrees Celsius, it can be determined that most of the surface moisture has been removed. The relative humidity of the exhaust air is also an important indicator; it initially shows high humidity but gradually decreases once the removal of surface moisture is complete.

[0075] After the first drying, the water activity of the granules is adjusted to 0.40 to 0.50. If the water activity is less than 0.40, it indicates that drying has proceeded excessively during the first drying stage, and the moisture gradient between the surface and the interior becomes excessively large, which may cause cracking in the granules during the second drying process. If the water activity exceeds 0.50, surface moisture is not sufficiently removed, and aggregation between granules may occur when transitioning to the second drying. The preferred water activity after the first drying is 0.42 to 0.48, and more preferably 0.44 to 0.46. The water activity is measured using a water activity meter, and the measurement is taken after the granule sample reaches equilibrium at 25°C.

[0076] Once the first drying is complete, the granules can be immediately transferred to the second drying stage while being maintained in a fluidized bed dryer, or temporarily transferred to a sealed container for storage. When storing, it is preferable to temper the granules at a temperature of 20°C to 25°C for 1 to 3 hours to achieve equilibrium between the surface and internal moisture of the granules. Tempering homogenizes the moisture distribution within the granules, thereby increasing the efficiency of the second drying stage and improving the quality of the final product.

[0077] Second drying step (a4)

[0078] The second drying step is a step in which bound water inside the granules that was not removed in the first drying step is removed while controlling it step by step. Since this is performed with most of the surface moisture removed, the risk of aggregation between granules is low, but because the movement speed of internal moisture is slow, sufficient time and appropriate temperature conditions are required. Drying is performed in a fluidized bed dryer for 20 to 60 minutes under conditions of an inlet air temperature of 50 to 70 degrees Celsius and an air flow rate of 20 cubic meters per hour to 50 cubic meters per hour.

[0079] The inlet air temperature is set to 50°C to 70°C. The reason for using a higher temperature than the first drying step is to remove surface moisture, thereby reducing the risk of case hardening, and to increase the diffusion rate of internal moisture. If the inlet air temperature is below 50°C, the rate of internal moisture removal is excessively slow, resulting in an excessively long drying time. If the inlet air temperature exceeds 70°C, rapid moisture evaporation causes vapor pressure to form inside the granules, which may cause the granules to expand or rupture, and increases the risk of decomposition of heat-sensitive functional ingredients. The preferred inlet air temperature is 55°C to 65°C, and more preferably 58°C to 62°C.

[0080] The air flow rate is set to 20 cubic meters per hour to 50 cubic meters per hour. The reason for using a flow rate lower than that for primary drying is that the surface is dried, making the granules lighter and more prone to scattering, and vigorous flow is not required. If the air flow rate is less than 20 cubic meters per hour, the flow of the granules is insufficient, resulting in uneven drying, and some granules may stagnate at the bottom of the dryer and overheat. If the air flow rate exceeds 50 cubic meters per hour, wear and breakage of the granules increase, and scattering losses become greater. The preferred air flow rate is 25 cubic meters per hour to 45 cubic meters per hour, and more preferably 30 cubic meters per hour to 40 cubic meters per hour.

[0081] The secondary drying time is set to 20 to 60 minutes. If the drying time is less than 20 minutes, internal moisture is not sufficiently removed, failing to reach the target water activity, and quality changes may occur due to moisture migration during storage. If the drying time exceeds 60 minutes, over-drying causes the granules to become excessively hard or brittle, and increases the risk of damage to heat-sensitive functional ingredients. The preferred secondary drying time is 25 to 50 minutes, and more preferably 30 to 45 minutes. Since the optimal drying time depends on the size and density of the granules, the moisture status after primary drying, and drying conditions, it is determined while continuously monitoring the product temperature and exhaust air humidity.

[0082] During the secondary drying process, the product temperature of the granules gradually rises and approaches the inlet air temperature. When the product temperature stabilizes within the range of 45°C to 55°C, it can be determined that the removal of internal moisture has progressed significantly. The relative humidity of the exhaust air gradually decreases as internal moisture is removed, and when it decreases below a certain level and stabilizes, it can be considered that the drying process has approached completion. To determine the point of drying completion, small samples can be taken at regular intervals to measure water activity.

[0083] After secondary drying, the water activity of the granules is adjusted to 0.25 to 0.35. This range is intended to satisfy the target water activity of the core layer, which is 0.35 or less, while preventing over-drying. If the water activity is less than 0.25, the granules are in an over-dried state, becoming excessively hard and brittle, making them prone to breakage during the subsequent coating process. Additionally, excessively dried granules tend to rapidly absorb moisture from the surrounding environment, which may lead to problems with moisture reabsorption during storage. If the water activity exceeds 0.35, storage stability decreases, and the risk of microbial growth and chemical decomposition reactions increases. The preferred water activity after secondary drying is 0.27 to 0.33, and more preferably 0.29 to 0.31.

[0084] In the second drying process, a modified example of gradually increasing the temperature may be applied. For instance, the initial 10 to 15 minutes start with an inlet air temperature of 50 to 55 degrees Celsius to induce moisture movement within the granules, the middle 10 to 20 minutes raise the inlet air temperature to 55 to 60 degrees Celsius to increase the drying speed, and the final 5 to 15 minutes raise the inlet air temperature to 60 to 70 degrees Celsius to completely remove residual moisture. This stepwise temperature increase method can achieve efficient drying while preventing granule damage caused by rapid moisture evaporation.

[0085] Once the second drying is complete, the granules are immediately transferred to the cooling stage within the dryer. Since discharging the granules to the outside while they are in a high-temperature state can cause cracking in the granules due to rapid temperature changes or increase water activity by absorbing moisture from the surrounding air, it is desirable to cool them under controlled conditions within the dryer.

[0086] Cooling step (a5)

[0087] The cooling step is a step in which the high-temperature granules, after secondary drying is completed, are cooled to near room temperature to stabilize the particle surface. By cooling the granules to 20 to 30 degrees Celsius, thermal stress is relieved, and quality changes caused by temperature fluctuations during subsequent processes or storage are prevented. Cooling is most efficient when performed inside a fluidized bed dryer, and is carried out by stopping the heating of the inlet air and continuously supplying cooling air or room-temperature air.

[0088] The target cooling temperature is 20°C to 30°C. If the granule temperature is excessively cooled to below 20°C, there is a risk of condensation occurring or moisture absorption after discharge due to the temperature difference with the surrounding environment. If discharged when the granule temperature exceeds 30°C, some functional raw materials may continue to deteriorate due to residual heat, and moisture redistribution may occur within the packaging container. The preferred target cooling temperature is 22°C to 28°C, and more preferably 23°C to 27°C. The optimal cooling temperature can be adjusted according to the temperature and humidity of the working environment and is generally set to a level 2°C to 5°C higher than room temperature.

[0089] The flow rate of the cooling air is set to a range of 10 cubic meters per hour to 40 cubic meters per hour. If the flow rate is excessively low, the cooling time becomes excessively long, and if the flow rate is excessively high, the loss of airborne dried granules increases. The preferred cooling air flow rate is 15 cubic meters per hour to 35 cubic meters per hour, and more preferably 20 cubic meters per hour to 30 cubic meters per hour. The cooling air may use indoor air directly or air with its temperature and humidity controlled through an air conditioning system. It is desirable to maintain the relative humidity of the cooling air in the range of 30 percent to 60 percent, as using excessively humid air may cause the granules to absorb moisture during cooling.

[0090] The cooling time varies depending on the amount of granules, the initial temperature, and the cooling air conditions, but generally takes 10 to 30 minutes. During the cooling process, the temperature of the granules is continuously monitored by a temperature probe inserted inside the dryer, and cooling is terminated when the target temperature is reached. Once cooling is complete, the granules are discharged through the outlet at the bottom of the fluidized bed dryer into a sealed container or a drum equipped with a vinyl liner. To minimize contact with external air during the discharge process, it is advisable to seal the outlet and the receiving container tightly or connect them with a flexible hose.

[0091] Once cooling is complete, the surface of the granules stabilizes, significantly reducing the tendency for aggregation or caking. The fluidity of the granules is also improved, allowing the subsequent sieving process to proceed smoothly. After cooling is complete, the water activity of the granules must be maintained within the range of 0.25 to 0.35, the same as before cooling. If the water activity exceeds 0.35 due to moisture absorption during cooling, it indicates that the humidity of the cooling air was excessively high or the cooling time was excessively long, so the conditions must be readjusted.

[0092] Constitution and screening stage (a6)

[0093] The sieving and screening step is a step of selecting core particles corresponding to the target particle size range from granules after cooling is complete. Granules that have undergone wet granulation and drying processes are not uniform in size and contain excessively large lumps or fine powder. By selecting only core particles with an average particle size range of 50 micrometers to 300 micrometers, uniform coating is possible in the subsequent fluidized bed coating process, and the quality of the final product can be maintained consistently.

[0094] A vibrating sieve is used as the sieving equipment. A vibrating sieve is a device that separates granules by size by vibrating a horizontal or inclined screen, offering high throughput and classification efficiency. Types of vibrating sieves include circular vibrating sieves, linear vibrating sieves, and ultrasonic vibrating sieves, all of which can be used in this invention. The vibration frequency of the vibrating sieve is generally set within the range of 1,000 rpm to 3,000 rpm, and the amplitude is adjusted according to the size and density of the granules. If the vibration is too weak, the sieving efficiency is low and clogging occurs; if the vibration is too strong, the granules are damaged or fine particles are generated.

[0095] The screen used for sieving utilizes a combination of two or more meshes. The upper screen uses a mesh of 300 to 500 micrometers to remove excessively large granules and lumps. The lower screen uses a mesh of 50 to 100 micrometers to remove fine powder. The intermediate fraction passing between the two screens becomes core particles with an average particle size of 50 to 300 micrometers, which is the target particle size range. Stainless steel wire mesh or polyester screens may be used as the screen material, and the material must be suitable for food contact.

[0096] During the sieving process, coarse granules remaining on the upper screen can be recovered by crushing them to an appropriate size using a grinder and sieving them again. Pin mills, hammer mills, roller mills, etc., can be used as grinders, and they should be operated at a low speed to prevent excessive breakage of the granules. Fine powder passing through the lower screen can be discarded or partially recycled during the wet granulation stage of a new batch. However, when recycling fine powder, it must be used only for batches of the same functional raw material and the same composition to prevent cross-contamination between batches.

[0097] The particle size distribution of the sieved core particles is measured using laser diffraction or microscopy. If the average particle size is in the range of 50 micrometers to 300 micrometers and the standard deviation of the particle size distribution is within 30 percent of the average particle size, the core particles are determined to be uniform. If the particle size distribution is excessively wide, additional sieving may be performed or the mesh size of the screen may be adjusted to select a narrower range. The preferred average particle size range is 80 micrometers to 250 micrometers, and more preferably 100 micrometers to 200 micrometers.

[0098] The core particles, once sieving is complete, are stored in a sealed container. Polyethylene bags, aluminum laminated film bags, stainless steel drums, etc., may be used as storage containers, and they must be made of a material capable of blocking the penetration of moisture and oxygen. It is desirable to maintain the storage environment at a temperature of 20 to 25 degrees Celsius and a relative humidity of 40 to 60 percent. Since the water activity of the core particles is adjusted to be low at 0.35 or lower, they are drier than the surrounding environment and may gradually absorb moisture during long-term storage. Therefore, it is desirable to introduce the core particles into the coating process as soon as possible after manufacturing, and if storage is unavoidable, the storage period should not exceed one to two weeks.

[0099] The quality of the core particles is verified by inspecting the following items. The average particle size and particle size distribution are measured by laser diffraction as previously mentioned. Water activity is measured at 25°C using a water activity meter and must be in the range of 0.25 to 0.35. Moisture content is measured by Karl Fischer titration or the loss-on-drying method and is generally in the range of 2 to 6 weight percent. The content of functional raw materials is quantified by high-performance liquid chromatography or an appropriate analytical method and must be in the range of 90 to 110 percent of the design content. Apparent density and tap density are indicators for evaluating the fluidity of the powder, and fluidity is considered good if the Hausner ratio is 1.5 or less. Only core particles that have passed these quality inspections are fed into the next step, the coating layer formation process.

[0100] Specific implementation method of the coat layer formation step

[0101] Coat layer formation step (b) Overall overview

[0102] The coat layer formation step is a step of forming a uniform coat layer by applying a first coating solution containing a hydrophilic polymer and a water activity regulator to the surface of the manufactured core particles using a fluid bed coating method. The coat layer is a layer that plays a key role in the multilayer particle structure and is responsible for the function of inducing rapid hydration and disintegration upon contact with body fluids while ensuring stability during storage by precisely controlling the water activity to a range of 0.35 to 0.55. The thickness of the coat layer is generally formed in the range of 5 micrometers to 30 micrometers and is controlled at a weight increase rate of 5 weight percent to 25 weight percent relative to the weight of the core particles.

[0103] The fluidized bed coating method is a technique that sprays a coating liquid while suspending core particles with heated air supplied upward from below, and is the most efficient method for forming a uniform coating layer on the entire surface of the particles. In particular, the present invention uses a three-stage approach in which the spraying speed is adjusted stepwise to form a primer layer at a low speed initially, proceed with coating at a medium speed in the middle stage, and stabilize the coating layer through post-drying. Through this, efficient adhesion of the coating liquid and the formation of a uniform layer can be achieved simultaneously.

[0104] The hydrophilic polymer used in the coating layer induces rapid hydration upon contact with body fluids, enabling rapid disintegration and release. The water activity regulator is a key component that ensures both storage stability and release by precisely adjusting the water activity of the coating layer to a target range. By appropriately controlling parameters such as the solid content concentration of the first coating solution, spray rate, and process temperature, it is possible to form a highly reproducible coating layer.

[0105] Step 1 of preparing the coating solution (b1)

[0106] In the first coating solution preparation step, a hydrophilic polymer and a water activity regulator are dissolved in a suitable solvent to prepare a coating solution having properties suitable for fluid bed coating. As the hydrophilic polymer, one or more selected from the group consisting of hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, modified starch, and pullulan are used.

[0107] Hydroxypropylmethylcellulose is a cellulose ether derivative that possesses excellent water solubility and film-forming ability, and various options are available depending on the viscosity grade. Generally, low-viscosity grades ranging from 3 to 15 cP or medium-viscosity grades ranging from 5 to 50 cP are used. Since hydroxypropylmethylcellulose is non-ionic, it has minimal interaction with other components, allowing for the preparation of a stable coating solution. Polyvinylpyrrolidone is a synthetic water-soluble polymer with strong bonding strength and excellent film-forming ability; it is classified by K-value according to molecular weight, and generally, K25 to K30 grades are used. Polyvinyl alcohol is a hydrolysis product of polyvinyl acetate that provides excellent film-forming ability and mechanical strength, and products with a saponification degree ranging from 87 percent to 99 percent can be used. Modified starch is produced by chemically or physically modifying natural starch, including hydroxypropyl starch and acetylated starch, and is utilized as a hydrophilic polymer based on natural materials. Pullulan is a natural polysaccharide produced by microbial fermentation that has excellent film-forming ability and oxygen barrier properties, and products with a molecular weight in the range of 100,000 to 200,000 are generally used.

[0108] These hydrophilic polymers can be used individually or in combination of two or more. When used in combination, synergistic effects can be obtained by utilizing the advantages of each polymer. For example, mixing hydroxypropylmethylcellulose and polyvinylpyrrolidone in a weight ratio of 3:1 to 1:1 can simultaneously obtain excellent film-forming ability and strong bonding strength. The selection of a preferred hydrophilic polymer is determined by the characteristics of the functional raw material, the target dissolution profile, and the type of formulation.

[0109] As water activity regulators, one or more selected from the group consisting of trehalose, maltodextrin, sorbitol, erythritol, and mannitol are used. Trehalose is a non-reducing disaccharide that possesses excellent moisturizing and protein-stabilizing effects, and imparts a soft texture to the product while lowering water activity. Maltodextrin is a partial hydrolysis product of starch and comes in various grades depending on the dextrose equivalent; generally, products with a DE value in the range of 10 to 20 are used. Sorbitol is a hexose sugar alcohol that possesses excellent moisturizing and sweetness properties and is effective for controlling water activity due to its relatively high hygroscopicity. Erythritol is a tetraose sugar alcohol that has very low hygroscopicity, provides a cooling sensation, and has low-calorie characteristics. Mannitol is a hexose sugar alcohol that has low hygroscopicity and good crystallinity, making it advantageous for improving storage stability.

[0110] A water activity modifier is added in an amount of 10 to 80 parts by weight per 100 parts by weight of the hydrophilic polymer. If the amount of the water activity modifier is less than 10 parts by weight, the water activity control effect is insufficient, making it difficult to reach the target range of 0.35 to 0.55. If the amount of the water activity modifier exceeds 80 parts by weight, the viscosity of the coating solution becomes excessively high, or it becomes difficult to control the solid content concentration, and the coating layer may become excessively brittle or powdered. The preferred amount added is 20 to 60 parts by weight, and more preferably 30 to 50 parts by weight. The optimal ratio is determined through preliminary experiments based on the type of hydrophilic polymer and water activity modifier used, and the target water activity value.

[0111] Purified water or an aqueous ethanol solution is used as the solvent for the coating solution. Purified water is the most economical and safest solvent and can effectively dissolve most hydrophilic polymers and water activity regulators. The aqueous ethanol solution has a composition of 5 to 30 weight percent ethanol and 70 to 95 weight percent purified water; adding ethanol accelerates the dissolution rate and promotes rapid drying during the coating process, thereby shortening the process time. It also has the effect of improving the solubility of some hydrophilic polymers. However, caution is required because if the ethanol content is excessively high, the solubility of some polymers, such as polyvinyl alcohol, may decrease.

[0112] The procedure for preparing the first coating solution is as follows. First, a solvent, such as purified water or an aqueous ethanol solution, is placed into a stirring vessel, and a stirrer is operated. The stirring speed is set to a range of 100 rpm to 500 rpm. The temperature of the solvent is controlled to a range of 20°C to 40°C; while higher temperatures accelerate the dissolution of the polymer, excessively high temperatures may cause some components to denature. The preferred solvent temperature is 25°C to 35°C. The hydrophilic polymer is gradually dispersed while stirring the solvent. Since adding the polymer all at once results in the formation of clumps and uneven dissolution, it is added in small amounts or dispersed through a sieve. Stirring is continued for 30 minutes to 2 hours to ensure complete dissolution of the hydrophilic polymer. The point of complete dissolution is determined when, upon visual inspection, no insoluble particles are visible and a uniform solution that is transparent or translucent is formed.

[0113] Once the dissolution of the hydrophilic polymer is complete, a water activity modifier is added. Since the water activity modifier generally has high solubility, it dissolves faster than the hydrophilic polymer. The water activity modifier is slowly added to the polymer solution being stirred and stirred for 10 to 30 minutes to ensure complete dissolution. After the dissolution of the water activity modifier is complete, the coating solution is diluted with purified water or an aqueous ethanol solution or concentrated so that the total solid content concentration of the coating solution is in the range of 5% to 25% by weight. If the solid content concentration is less than 5% by weight, the coating efficiency is low and excessive time is required to form the coat layer; if the solid content concentration exceeds 25% by weight, the viscosity of the coating solution becomes excessively high, making spraying difficult and uniform coating difficult. A preferred solid content concentration is 8% to 20% by weight, and more preferably 10% to 15% by weight.

[0114] The viscosity of the first coating solution, once prepared, is generally in the range of 5 to 100 cP when measured at 25°C using a rotational viscometer. If the viscosity is excessively low, it flows down from the surface of the core particles, making uniform coating difficult; if the viscosity is excessively high, the spray nozzle becomes clogged or the size of the spray droplets becomes excessively large. A preferred viscosity range is 10 to 80 cP, and more preferably 20 to 60 cP. The pH of the coating solution is generally adjusted to a range of 4.5 to 7.0, and can be acidified with citric acid or phosphoric acid, or neutralized with sodium hydroxide, if necessary. The prepared coating solution is filtered through a filtration device to remove insoluble particles or foreign matter before use. A stainless steel screen or cartridge filter with a mesh size of 100 to 200 is generally used for filtration. The filtered coating solution is stored in a sealed container, and it is preferable to use it within 24 hours of preparation. Since microbial contamination or precipitation of ingredients may occur during prolonged storage, stir again immediately before use to check uniformity.

[0115] Core particle fluidization step (b2)

[0116] The core particle fluidization step involves introducing the manufactured core particles into a fluidized bed coater and supplying air at an appropriate temperature and flow rate to bring the core particles into a fluidized state. A fluidized state refers to a condition where particles are suspended by an upward airflow and circulate smoothly; in this state, spraying the coating solution allows for uniform application to the surface of all particles.

[0117] Fluidized bed coating machines are broadly classified into top spray, bottom spray, and tangential spray types. The top spray type is the most traditional form, characterized by spraying the coating liquid downward from the top of the particle layer. The bottom spray type sprays upward from the bottom of the particle layer, enabling uniform coating and efficient drying; the Würster coating method is a representative example. The tangential spray type sprays tangentially from the side of the particle layer and is also known as the rotary coating method. In this invention, all of these types of fluidized bed coating machines can be used, but the bottom spray type is the most preferred.

[0118] The amount of core particles fed into the fluid bed coater is determined by the capacity of the coater. Generally, it is appropriate to fill 10 percent to 40 percent of the capacity of the coater chamber. If the amount fed is too small, the particles flow excessively violently, causing wear and breakage; if the amount fed is too large, the particle layer becomes excessively high, making uniform flow difficult and causing coating deviation between the upper and lower parts. The preferred amount fed is 15 percent to 35 percent of the chamber capacity, and more preferably 20 percent to 30 percent.

[0119] The inlet air temperature is set to 35°C to 50°C. If the inlet air temperature is below 35°C, the drying speed of the sprayed coating liquid is slow, causing the particle surface to become over-wet and resulting in aggregation between particles. If the inlet air temperature exceeds 50°C, the coating liquid dries prematurely in the spray nozzle or in the air, reducing spraying efficiency and potentially damaging heat-sensitive functional materials. The preferred inlet air temperature is 38°C to 48°C, and more preferably 40°C to 45°C. The inlet air temperature is controlled by adjusting the heater output and maintaining the set value while monitoring in real-time with a temperature sensor.

[0120] The air flow rate is set to between 40 cubic meters per hour and 100 cubic meters per hour. If the air flow rate is less than 40 cubic meters per hour, the core particles cannot be sufficiently flowed, resulting in the formation of stagnant regions at the bottom of the particle layer and an uneven coating. If the air flow rate exceeds 100 cubic meters per hour, excessive flow causes particle wear and breakage, generates fine particles, and increases drift losses where particles fly to the exhaust filter. The preferred air flow rate is between 50 cubic meters per hour and 90 cubic meters per hour, and more preferably between 60 cubic meters per hour and 80 cubic meters per hour. Since the optimal air flow rate depends on the size, density, and shape of the core particles, conditions are found through preliminary experiments where particles flow smoothly while drift is minimized.

[0121] The flow state is verified through visual observation or an observation window. Under proper flow conditions, the particle layer exhibits a circulation pattern where it rises from the center like a fountain and descends toward the periphery, and the surface of the particle layer appears to ripple smoothly. It must be confirmed that no stagnant regions or channeling are observed within the particle layer, and that all particles are moving continuously. An expansion ratio of the particle layer should be approximately 1.5 to 3 times the height of the stationary layer. If the expansion ratio is excessively low, the flow is insufficient, while if it is excessively high, the residence time of the particles is shortened and scattering increases.

[0122] After establishing a fluid state, preheating is continued until the surface temperature of the core particles reaches 25°C to 35°C. The surface temperature can be measured using a temperature probe inserted into the particle layer or non-contactly using an infrared thermometer. It generally takes 5 to 15 minutes for the surface temperature of the core particles to reach the target range. If coating is started when the surface temperature is below 25°C, the drying of the coating solution is excessively slow, causing aggregation; if coating is started when the surface temperature exceeds 35°C, the coating solution dries prematurely, making it difficult to form a uniform film. The preferred surface temperature range is 27°C to 33°C, and more preferably 28°C to 32°C. Once the surface temperature stably reaches the target range, preparations are complete to begin spraying the coating solution.

[0123] Initial spraying step (b3)

[0124] The initial spraying step is a step of forming an initial layer of the first coating liquid on the surface of the core particle, and the purpose is to uniformly attach the primer layer through low-speed spraying. When the surface temperature of the core particle in a fluid state reaches 25°C to 35°C, the first coating liquid is sprayed through a spray nozzle at an initial spraying speed of 0.5 grams per minute to 1.9 grams per minute.

[0125] A two-fluid nozzle is generally used for spraying. The two-fluid nozzle generates fine droplets by mixing a liquid coating solution with gaseous compressed air for spraying, allowing for easy control of droplet size and the attainment of a uniform spray pattern. The nozzle orifice diameter is typically in the range of 0.8 to 1.5 millimeters and is selected based on the viscosity of the coating solution and the target spray velocity. The spray nozzle is positioned inside or below the particle layer; in the case of the Würster coating method, the nozzle is located below the center of the particle layer to spray upward.

[0126] The initial spray rate is set to 0.5 grams per minute to 1.9 grams per minute. If the initial spray rate is less than 0.5 grams per minute, the coating efficiency is excessively low, resulting in an excessively long process time, and the sprayed droplets dry before reaching the surface of the core particles, thereby reducing coating efficiency. If the initial spray rate exceeds 1.9 grams per minute, the surface of the core particles becomes rapidly wetted, causing aggregation between particles and forming an uneven primer layer. The preferred initial spray rate is 0.8 grams per minute to 1.5 grams per minute, and more preferably 1.0 grams per minute to 1.3 grams per minute. The initial spray rate is controlled by adjusting the speed of the coating liquid supply pump and is monitored in real time using a flow meter.

[0127] The spray pressure is generally set in the range of 0.8 bar to 1.5 bar. If the spray pressure is excessively low, the droplet size is large and the spray pattern is uneven; if the spray pressure is excessively high, the droplet size becomes excessively small, causing it to dry prematurely in the air or be lost to the exhaust. The preferred spray pressure is 1.0 bar to 1.3 bar. The compressed air used for spraying must be clean air from which moisture and oil have been removed, and it is purified through an air filter and a dryer.

[0128] The initial spraying step is continued until the cumulative spraying amount of the first coating liquid relative to the total weight of the core particles reaches 1 to 3 weight percent. If the cumulative spraying amount is less than 1 weight percent, the formation of the primer layer is insufficient, resulting in uneven adhesion of the coating liquid during the subsequent intermediate spraying. If low-speed spraying is continued to exceed the cumulative spraying amount of 3 weight percent, the process time is unnecessarily extended, thereby reducing economic efficiency. The preferred cumulative spraying amount is 1.5 to 2.5 weight percent, and more preferably 1.8 to 2.2 weight percent. The cumulative spraying amount is calculated through the weight loss of the coating liquid supply tank or the cumulative value of the flow meter.

[0129] The uniform adhesion of the primer layer is confirmed through the visual observation of the particle layer and the visual inspection of the particle sample. When the primer layer is properly formed, the particle surface is slightly moist and glossy, and the particles flow freely without aggregation. When a small amount of particle sample is taken and touched by hand, a degree of slight tackiness is appropriate if it does not stick to the fingers. When observing the particle layer through an observation window, if the particles circulate smoothly and no clumps or aggregates are visible, it is determined that the primer layer has been uniformly attached.

[0130] During the initial spraying process, the product temperature is continuously monitored. During the wet coating process, the product temperature tends to drop slightly due to the evaporative cooling effect, but it is generally maintained within the set surface temperature range of 25°C to 35°C. If the product temperature drops below 25°C, the inlet air temperature is increased by 2°C to 5°C to compensate, and if the product temperature exceeds 35°C, the spraying speed is increased or the inlet air temperature is lowered. The relative humidity of the exhaust air is also an important indicator; if the exhaust humidity rises after the start of spraying the coating liquid and stabilizes at a certain level, it indicates that the coating and drying are in equilibrium.

[0131] Once the primer layer formation is complete, immediately proceed to the intermediate spraying stage. Ensure that unnecessary interruptions do not occur between the initial and intermediate spraying; if an interruption is unavoidable, resume within a short period while maintaining the flow of the particle layer.

[0132] Mid-stage spraying phase (b4)

[0133] The intermediate spraying stage is a stage for accumulating a coating layer on core particles on which a primer layer has been formed, and the purpose is to increase coating efficiency by increasing the spraying speed while maintaining a uniform layer formation. Once it is confirmed that the first coating liquid has been uniformly attached to the surface of the core particles in the initial spraying stage, the coating is carried out by increasing the spraying speed to an intermediate spraying speed of 2 grams per minute to 5 grams per minute.

[0134] The intermediate spraying speed is increased to approximately 1.5 to 4 times the initial spraying speed. If the spraying speed is less than 2 grams per minute, the coating efficiency is low, and an excessive amount of time is required to reach the target weight increase rate. If the spraying speed exceeds 5 grams per minute, the supply volume of the coating liquid exceeds the drying capacity, resulting in an over-wet state of the particle surfaces and the occurrence of aggregation between particles. The preferred intermediate spraying speed is 2.5 to 4.5 grams per minute, and more preferably 3 to 4 grams per minute. Since the optimal spraying speed depends on the drying capacity of the fluid bed coater, the amount of core particles, and the solid content concentration of the coating liquid, it is adjusted while monitoring the product temperature and exhaust humidity.

[0135] It is desirable to increase the spray rate in stages. For example, if the initial spray rate is 1.2 grams per minute, rather than immediately increasing it to 4 grams per minute upon the start of intermediate spraying, it is preferable to first increase it to 2 grams per minute and maintain it for 2 to 5 minutes, then increase it to 3 grams per minute and maintain it for 2 to 5 minutes, and finally increase it to 4 grams per minute. This method prevents rapid wetting of the particle surface and enables stable coating. At each stage, the product temperature and the flow state of the particle layer are checked to ensure there are no signs of aggregation or abnormalities before proceeding to the next stage.

[0136] During the intermediate spraying process, the inlet air temperature should be maintained within the range of 35°C to 50°C, but may be increased by 2°C to 5°C as the spraying speed increases. This is because an increase in spraying speed increases the supply volume of the coating liquid, and consequently, the amount of heat required to dry it must also increase. However, care must be taken not to exceed 50°C, as excessively high inlet air temperatures may damage heat-sensitive components. The product temperature is generally maintained within the range of 28°C to 38°C, and within this range, a proper balance is achieved between coating and drying.

[0137] The spray pressure is maintained in the range of 1.0 bar to 2.0 bar. As the spray speed increases, the spray pressure may also be slightly increased to effectively atomize the increased liquid flow rate. The preferred spray pressure is 1.2 bar to 1.8 bar, and more preferably 1.3 bar to 1.6 bar. The spray pattern is periodically visually inspected to check whether a uniform conical spray is maintained. If the spray pattern becomes asymmetrical or the droplet size becomes uneven due to clogging or wear of the spray nozzle, the nozzle is cleaned or replaced immediately.

[0138] The air flow rate should be maintained within the initial setting range of 40 cubic meters per hour to 100 cubic meters per hour, but can be increased by approximately 10 to 20 cubic meters per hour if necessary. Since increasing the spray speed increases the wetness of the particle surface and thus increases the tendency for particles to stick together, aggregation can be prevented by slightly increasing the air flow rate to induce more vigorous flow. However, caution is required as increasing the air flow rate excessively increases particle abrasion and scattering.

[0139] The intermediate spraying stage is continued until the weight increase rate, based on the total weight of the core particles before the start of spraying, reaches 5% to 25% by weight. The weight increase rate is calculated by measuring the weight of the core particles before coating and the weight of the particles after coating, and is estimated during the process using the integrated value of the coating liquid supply amount and the solid content concentration. If the weight increase rate is less than 5% by weight, the thickness of the coating layer is insufficient, making it difficult to achieve the target water activity control effect and solubility characteristics. If the weight increase rate exceeds 25% by weight, the coating layer becomes excessively thick, reducing release properties and prolonging the disintegration time. A preferred weight increase rate is 8% to 20% by weight, and more preferably 10% to 15% by weight.

[0140] It is desirable to gradually reduce the spray speed as the target weight increase rate approaches. For example, if the target weight increase rate is 15 weight percent, the spray speed is reduced from 4 grams per minute to 3 grams per minute when the weight increase rate reaches 13 weight percent, reduced to 2 grams per minute when it reaches 14 weight percent, and spraying is stopped when it reaches exactly 15 weight percent. This gradual deceleration helps to accurately match the target weight and achieve a smooth finish on the surface of the coat layer.

[0141] During the intermediate spraying process, particle samples are periodically collected to check the coating status. Generally, small samples are taken at weight gains of 5 wt percent, 10 wt percent, and 15 wt percent to perform visual inspection and microscopic observation. Properly coated particles have a smooth surface and a uniform coating layer, with minimal variation in particle size. Under microscopic observation, the boundary between the core and the coating layer is clearly distinguished, and the thickness of the coating layer appears uniform across the entire particle. If the coating is uneven or aggregates are detected, the process conditions are adjusted.

[0142] Coat layer completion stage (b5)

[0143] The coat layer completion stage is a stage in which intermediate spraying is continued to accurately reach the target weight increase rate, and the final coat layer is completed by maintaining the spray pressure appropriately. The coat layer is formed by maintaining the spray pressure at 1.0 bar to 2.0 bar while continuing spraying until the weight increase rate based on the total weight of the core particles before the start of spraying reaches 5 weight percent to 25 weight percent.

[0144] The target weight gain rate is determined based on the function required for the coating layer and the intended use of the final product. For immediate-release products requiring rapid disintegration and dissolution, the weight gain rate is set low to form a thin coating layer, generally using a range of 5 to 12 weight percent. When appropriate water activity control and storage stability are required, the weight gain rate is set to a moderate level, generally using a range of 10 to 18 weight percent. If additional protective effects are required, the weight gain rate may be set higher, but should not exceed 25 weight percent.

[0145] The spray pressure is maintained within the range of 1.0 bar to 2.0 bar. If the spray pressure is less than 1.0 bar, the droplet size is large and the spray pattern is uneven, resulting in a rough and irregular surface of the coat layer. If the spray pressure exceeds 2.0 bar, the droplet size becomes excessively small, leading to premature drying in the air or loss during exhaust, and economic efficiency is reduced due to excessive use of compressed air. The preferred spray pressure is 1.2 bar to 1.8 bar, and more preferably 1.3 bar to 1.6 bar. The spray pressure is set via a pressure regulator and continuously monitored using a pressure gauge.

[0146] Sufficient coating time is required to ensure uniformity of the coating layer during the coating process. The more times each core particle passes through the spray area, the more uniform the coating layer becomes. Generally, since 2 to 5 minutes of coating time are required per 1 weight percent increase in weight, 30 to 75 minutes of coating time is required to achieve a total weight increase of 15 weight percent. If the coating time is excessively short, some particles will not receive enough coating liquid, while others will receive too much, resulting in significant variation between particles. To ensure sufficient coating time, it is important to maintain the spray speed at an appropriate level without increasing it excessively.

[0147] During the coating process, the presence of particle aggregation or clumping is continuously monitored. The particle layer is observed through an observation window, or small samples are periodically taken and checked. If aggregation is observed, spraying is stopped immediately, and drying is promoted by raising the inlet air temperature by 5 to 10 degrees Celsius or increasing the air flow rate. Spraying is resumed once it is confirmed that the aggregates have disintegrated and are flowing freely. If aggregation occurs repeatedly, measures such as lowering the spray speed or reducing the solid content concentration of the coating solution are required.

[0148] When the target weight increase rate is reached, the spraying of the coating solution is stopped immediately. The spraying stop signal simultaneously stops the coating solution supply pump and cuts off the compressed air for spraying, ensuring that droplets are no longer ejected from the nozzle. Even after the spraying is stopped, the particles remain in a flowing state, and the process immediately transitions to the post-drying stage. It is important to minimize the delay time between the spraying stop and post-drying, and generally, the transition to post-drying conditions is performed within 10 seconds.

[0149] Post-drying and stabilization step (b6)

[0150] The post-drying and stabilization step is a step to remove residual moisture on the surface of the coated particles and stabilize the structure of the coat layer. When the target weight increase rate is reached, spraying is stopped, and the surface of the coat layer is stabilized by post-drying for 5 to 15 minutes while maintaining the inlet air temperature at 35 to 50 degrees.

[0151] Post-drying is an important process that dries and solidifies the wet coat layer formed during the coating process. Immediately after spraying, the coat layer contains free water on its surface and the polymer chains are not yet fully stabilized, making it prone to inter-particle adhesion or aggregation. Through post-drying, surface moisture is removed, allowing the polymer chains to align and bond to form a strong film. Additionally, mutual diffusion occurs at the interface between the coat layer and the core layer, improving interlayer adhesion.

[0152] The inlet air temperature is maintained within the same range of 35°C to 50°C as the temperature used during coating. If the inlet air temperature is excessively high during post-drying, cracks may occur in the coat layer due to rapid moisture evaporation, or delamination may occur at the interface between the coat layer and the core layer. Conversely, if the inlet air temperature is too low, drying is insufficient, and the purpose of post-drying is not achieved. The preferred inlet air temperature is 38°C to 48°C, and more preferably 40°C to 45°C. If the inlet air temperature was raised during coating, it is desirable to lower it back to the initial set temperature during post-drying.

[0153] The air flow rate can be maintained or slightly reduced during coating. Generally, it is maintained in the range of 30 cubic meters per hour to 80 cubic meters per hour. If the air flow rate is maintained at an excessively high level, particle abrasion increases, and if it is maintained at an excessively low level, particle flow is insufficient, resulting in uneven drying. The preferred air flow rate is 40 cubic meters per hour to 70 cubic meters per hour.

[0154] The post-drying time is set to 5 to 15 minutes. If the post-drying time is less than 5 minutes, moisture on the surface of the coating layer is not sufficiently removed, which may lead to particle aggregation or caking after discharge. If the post-drying time exceeds 15 minutes, the additional drying effect is minimal, while functional raw materials may be damaged due to unnecessary heat exposure, and economic efficiency is reduced as only the process time is extended. The preferred post-drying time is 7 to 12 minutes, and more preferably 8 to 10 minutes. The optimal post-drying time may vary depending on the thickness of the coating layer, the solid content concentration of the coating solution, and the type of hydrophilic polymer.

[0155] During the post-drying process, the product temperature gradually rises and approaches the inlet air temperature. When the product temperature stabilizes within the range of 32°C to 42°C, it can be determined that most of the surface moisture has been removed. The relative humidity of the exhaust air remains high during the initial stages of post-drying and then gradually decreases; when it drops below a certain level and stabilizes, it can be considered that the drying process is approaching completion. Post-drying can be terminated when the exhaust humidity decreases to a level similar to the humidity of the surrounding environment.

[0156] To determine the completion of post-drying, a small sample of particles can be taken to check their tactile sensation. Properly post-dried particles have a dry and smooth surface that does not stick to fingers. When the particles are lightly squeezed by hand, they flow freely without clumping. When observed under a microscope, the surface of the coating layer is uniform and smooth, free of cracks or defects.

[0157] Once post-drying is complete, the particles are cooled. Cooling is most efficient when performed inside the fluidized bed coater; the heating of the inlet air is stopped, and cooling air or ambient air is continuously supplied. The target cooling temperature is 20 to 30 degrees Celsius, and the cooling time generally takes 10 to 20 minutes. Once cooling is complete, the coated particles are discharged from the fluidized bed coater and collected in a sealed container. During the discharge process, contact with external air is minimized to prevent moisture absorption.

[0158] Particles that have completed the coating layer formation stage undergo the following quality inspections. The weight gain is verified by measuring the weight before and after coating, and must be within the range of 95 percent to 105 percent of the target value. The thickness of the coating layer is measured by observing the cross-section of the particles under a microscope and is generally in the range of 5 micrometers to 30 micrometers. Water activity may not yet reach the target range at this stage and is adjusted to the range of 0.35 to 0.55 through a subsequent intermediate drying stage. Moisture content is measured by the Karl Fischer titration method and is generally in the range of 5 weight percent to 12 weight percent. Particle size distribution is measured by laser diffraction to confirm that the average particle size has increased compared to before coating and that the particle size distribution remains uniform. Coated particles that pass these quality inspections are fed into the next stage, the intermediate drying process.

[0159] Specific implementation method of the intermediate drying step

[0160] Intermediate drying stage (c) Overall overview

[0161] The intermediate drying step is a step of precisely adjusting the water activity of the particles formed with the coating layer to a critical range of 0.35 to 0.55, which is a key critical range of the present invention. Immediately after the formation of the coating layer, the particles have a high water activity due to the sprayed first coating liquid, and if they are not dried properly, microbial growth and chemical decomposition may occur during storage. However, since excessive drying can damage the structure of the coating layer and degrade immediate properties, a stepwise and controlled drying process is essential.

[0162] The water activity range of 0.35 to 0.55 targeted in this invention has critical significance in that it minimizes free water to ensure storage stability, while maximizing the osmotic driving force upon contact with body fluids to induce explosive hydration. Below a water activity of 0.35, the coating layer becomes excessively dry, which reduces the hydration capacity of hydrophilic polymers and may cause microcracks in the coating film. Conversely, if the water activity exceeds 0.55, the risk of microbial growth increases, and hydrophilic polymers within the coating layer may partially dissolve, leading to aggregation between particles.

[0163] The intermediate drying stage consists of three steps: first, second, and third intermediate drying. In each step, the temperature and air flow rate are gradually adjusted to sequentially remove free water from the surface of the coat layer, control internal bound water, and adjust the final water activity. Between each drying step, the drying progress is monitored by measuring water activity; once the target range is reached, the process proceeds to the next step or terminating. Finally, the structure of the coat layer is stabilized through a slow cooling step, maintaining a state suitable for the subsequent functional layer formation process.

[0164] 1st intermediate drying stage (c1)

[0165] The first intermediate drying step is a step for preferentially removing free water present on the particle surface immediately after the formation of the coat layer. Although the first coating liquid sprayed during the coating process dries rapidly on the particle surface, a significant amount of free water remains on the surface even after the coating is finished. If this free water is not removed quickly, aggregation between particles may occur or the coat layer may be formed unevenly. The particles are dried in a fluidized bed dryer for 5 to 15 minutes under conditions of an inlet air temperature of 30 to 40 degrees Celsius and an air flow rate of 30 to 70 cubic meters per hour.

[0166] The inlet air temperature is set to 30°C to 40°C. This is a lower temperature compared to core layer drying or secondary intermediate drying, intended to prevent structural damage caused by rapid drying while the coat layer is not yet completely solidified. If the inlet air temperature is below 30°C, the evaporation rate of free surface water is excessively slow, resulting in an excessively long drying time, during which aggregation may occur due to liquid cross-linking between particles. If the inlet air temperature exceeds 40°C, the hydrophilic polymer on the surface of the coat layer may rapidly dehydrate, forming a dense skin layer on the surface and hindering the movement of internal moisture, which may lead to a case hardening phenomenon. The preferred inlet air temperature is 32°C to 38°C, and more preferably 34°C to 36°C.

[0167] The air flow rate is set to 30 cubic meters per hour to 70 cubic meters per hour. Since the surface of the particles is wet immediately after coating, it is important to maintain a sufficient air flow rate to keep the particles float so that they do not come into contact with each other. If the air flow rate is less than 30 cubic meters per hour, the flow of particles is insufficient, causing contact and aggregation between particles, and some particles become stagnant at the bottom of the dryer, resulting in uneven drying. If the air flow rate exceeds 70 cubic meters per hour, the coat layer, which does not yet have sufficient strength, may be damaged or peeled off by the shear force of the air, and undried particles are scattered into the exhaust filter, increasing losses. The preferred air flow rate is 40 cubic meters per hour to 60 cubic meters per hour, and more preferably 45 cubic meters per hour to 55 cubic meters per hour.

[0168] The first intermediate drying time is set to 5 to 15 minutes. If the drying time is less than 5 minutes, surface free water is not sufficiently removed, which may cause particle aggregation problems when transitioning to the second intermediate drying. If the drying time exceeds 15 minutes, surface drying proceeds excessively, increasing the moisture gradient between the surface and the interior; this may induce stress in the coat layer during the subsequent drying stage, potentially causing cracking. The preferred first intermediate drying time is 7 to 13 minutes, and more preferably 8 to 12 minutes. Since the optimal drying time depends on the solid content concentration of the coating liquid, the coating weight increase rate, the thickness of the coat layer, etc., it is adjusted while monitoring the product temperature and the humidity of the exhaust air.

[0169] During the first intermediate drying process, the product temperature of the particles is monitored in real time using a temperature probe inserted inside the dryer. Initially, due to the evaporative cooling effect of the coating solution, the product temperature remains significantly lower than the inlet air temperature, but it gradually rises as free surface water is removed. When the product temperature stabilizes within the range of 25°C to 32°C, it can be determined that most of the free surface water has been removed. The relative humidity of the exhaust air is also an important indicator; it initially shows high humidity but gradually decreases as surface moisture removal progresses. The point at which the relative humidity of the exhaust air stabilizes can be used as an indicator of the completion of the first intermediate drying.

[0170] Once the first intermediate drying is completed, a small sample is taken to measure water activity. Water activity is measured using a water activity meter; the sample is placed in a measuring chamber at 25°C and allowed to stand until equilibrium is reached before measurement. Generally, it takes 10 to 30 minutes to reach equilibrium. The conditions for the second intermediate drying are determined by verifying whether the measured water activity is within a suitable range for proceeding to the next step. The water activity at the time of completion of the first intermediate drying is generally in the range of 0.55 to 0.70, which means that while most of the surface free water has been removed, a significant amount of moisture still remains within the coat layer.

[0171] 2nd intermediate drying stage (c2)

[0172] The second intermediate drying step is a step of controlling the bound water inside the coat layer step by step after confirming the water activity measured in the first intermediate drying step. After confirming that the water activity of the particles dried in the first intermediate drying step is in the range of 0.50 to 0.60, the process proceeds to the next step. If the water activity exceeds 0.60, the first intermediate drying step is insufficient, so additional drying is performed under the conditions of the first intermediate drying step. Conversely, if the water activity is less than 0.50, the first intermediate drying step is excessive, so the conditions for the second intermediate drying step are relaxed and applied.

[0173] The inlet air temperature is raised to 40°C to 50°C. The reason for applying a higher temperature than the first intermediate drying is that surface free water is removed, reducing the risk of case hardening, and a higher temperature is required to remove bound water inside the coat layer. If the inlet air temperature is below 40°C, the diffusion rate of internal bound water is excessively slow, resulting in an excessively long drying time. If the inlet air temperature exceeds 50°C, the hydrophilic polymers in the coat layer are excessively dehydrated, causing structural changes, and heat-sensitive water activity regulators may decompose or crystallize. The preferred inlet air temperature is 42°C to 48°C, and more preferably 44°C to 46°C.

[0174] The air flow rate is reduced to 20 cubic meters per hour or 50 cubic meters per hour. The reason for using a flow rate lower than that of the first intermediate drying is that the surface is dried, reducing the risk of aggregation between particles; the particles become lighter due to the temperature rise, making them prone to scattering; and for the removal of internal moisture, an appropriate residence time is more important than vigorous flow. If the air flow rate is less than 20 cubic meters per hour, the flow of particles is insufficient, resulting in uneven drying, and some particles may stagnate at the bottom of the dryer and overheat. If the air flow rate exceeds 50 cubic meters per hour, particle wear and breakage increase, and scattering losses become greater. The preferred air flow rate is 25 cubic meters per hour to 45 cubic meters per hour, and more preferably 30 cubic meters per hour to 40 cubic meters per hour.

[0175] The second intermediate drying time is set to 10 to 25 minutes. If the drying time is less than 10 minutes, the bound water inside the coat layer is not sufficiently removed, making it difficult to reach the target water activity. If the drying time exceeds 25 minutes, the structure of the coat layer may be damaged due to over-drying, and the hydration ability of the hydrophilic polymer may be reduced. The preferred second intermediate drying time is 12 to 22 minutes, and more preferably 15 to 20 minutes. Since the optimal drying time depends on the moisture status after the first intermediate drying, the composition and thickness of the coat layer, and drying conditions, it is determined while continuously monitoring the product temperature and exhaust air humidity.

[0176] During the second intermediate drying process, the product temperature of the particles gradually rises and approaches the inlet air temperature. When the product temperature stabilizes within the range of 35°C to 42°C, it can be determined that the removal of internal bound water has progressed significantly. The relative humidity of the exhaust air gradually decreases as internal moisture is removed, and when it decreases below a certain level and stabilizes, it can be considered that the drying process is approaching completion. To accurately assess the drying progress, small samples can be taken at regular intervals to measure water activity.

[0177] In the second intermediate drying process, a variation in which the temperature is gradually increased may be applied. For instance, the initial 5 to 8 minutes start with an inlet air temperature of 40 to 43 degrees Celsius to induce moisture movement within the coat layer, the intermediate 5 to 10 minutes raise the inlet air temperature to 43 to 46 degrees Celsius to increase the drying speed, and the final 3 to 7 minutes raise the inlet air temperature to 46 to 50 degrees Celsius to effectively remove residual bound water. This stepwise temperature increase method can achieve efficient drying while minimizing thermal stress applied to the coat layer.

[0178] Once the second intermediate drying is completed, a small sample is taken again to re-measure the water activity. It is checked whether the measured water activity has reached the range of 0.40 to 0.50; if it has, the process proceeds to the third intermediate drying. If the water activity exceeds 0.50, the second intermediate drying is extended to perform additional drying. If the water activity is less than 0.40, it is already close to the target range, so the conditions for the third intermediate drying are relaxed or the drying time is shortened. A water activity of 0.40 to 0.50 at the completion of the second intermediate drying indicates that the structure of the coat layer has generally stabilized, but additional drying is required to reach the final target range.

[0179] 3rd intermediate drying stage (c3)

[0180] The third intermediate drying step is a step of finally adjusting the water activity to a range of 0.35 to 0.55 after confirming the water activity measured in the second intermediate drying step. This is a step for achieving the critical range of the present invention, and requires precise control. Drying is performed for 5 to 15 minutes while controlling the inlet air temperature to 45°C to 55°C.

[0181] The inlet air temperature is set to 45°C to 55°C. This is the highest temperature during the intermediate drying stage, intended to finally remove residual moisture and reach the target water activity. If the inlet air temperature is below 45°C, the rate of residual moisture removal is slow, resulting in an excessive amount of time required to reach the target water activity. If the inlet air temperature exceeds 55°C, there is a risk that the coating layer will be excessively dehydrated, causing the water activity to drop below 0.35, and structural changes in the hydrophilic polymer or degradation of the water activity regulator may occur. The preferred inlet air temperature is 47°C to 53°C, and more preferably 49°C to 51°C.

[0182] The air flow rate is maintained in the range of 20 cubic meters per hour to 50 cubic meters per hour, which is similar to the level of the second intermediate drying. Since the temperature is high at this stage, applying an excessive flow rate may increase particle scattering losses. The preferred air flow rate is 25 cubic meters per hour to 45 cubic meters per hour, and more preferably 30 cubic meters per hour to 40 cubic meters per hour. The air flow rate is adjusted while visually observing the fluidity of the particles, maintaining conditions where particles flow smoothly while scattering is minimized.

[0183] The third intermediate drying time is set to 5 to 15 minutes. Since the water activity has already reached the range of 0.40 to 0.50 through the second intermediate drying, the third intermediate drying takes a relatively short time as a final adjustment step. If the drying time is less than 5 minutes, it is difficult to fine-tune the water activity and the target range may not be accurately reached. If the drying time exceeds 15 minutes, the water activity may drop below 0.35 or the quality of the coat layer may deteriorate due to over-drying. The preferred third intermediate drying time is 7 to 13 minutes, and more preferably 8 to 12 minutes.

[0184] Changes in water activity must be closely monitored during the third intermediate drying process. Small samples are taken at intervals of 3 to 5 minutes after the start of drying to measure water activity, and drying conditions are fine-tuned when the measured value approaches the target range of 0.35 to 0.55. For example, if a rapid decrease in water activity from 0.40 to 0.38 is observed, the drying speed is slowed down by lowering the inlet air temperature by 2 to 3 degrees Celsius or reducing the air flow rate. Conversely, if the rate of decrease in water activity is excessively slow, the inlet air temperature is slightly increased or the drying time is extended.

[0185] During the third intermediate drying process, the product temperature reaches a range of 40 to 48 degrees Celsius. If the product temperature becomes excessively high, the cooling effect is enhanced by lowering the inlet air temperature or increasing the airflow velocity. The relative humidity of the exhaust air stabilizes at a very low level, which indicates that the moisture within the particles has reached near equilibrium. Since the drying speed slows down during the third intermediate drying process, it is important to continue drying patiently until the target moisture activity is accurately reached.

[0186] The end point of the third intermediate drying is determined when the measured water activity is stably located within the range of 0.35 to 0.55. Preferably, the water activity is in the range of 0.38 to 0.52, and more preferably, in the range of 0.40 to 0.50. It is most ideal for the water activity to be located near the median value of the target range, which allows it to remain within an acceptable range even if there are slight changes in moisture during subsequent processes or storage.

[0187] Final verification step (c4)

[0188] The final verification step is a step of finally confirming whether the water activity of the third intermediate dried particles is within the target range of 0.35 to 0.55, and terminating drying when the target range is reached. In this step, the uniformity of the entire batch is confirmed by taking multiple samples and measuring the water activity.

[0189] Sampling is performed at different locations in the dryer. Generally, samples are taken from the top, middle, and bottom sections of the dryer to check the variation in water activity according to location. Samples taken from each location are measured using a water activity meter, and all measured values ​​must be within the range of 0.35 to 0.55. If the deviation between measured values ​​is within 0.03, it is determined that uniform drying has been achieved. If the sample at a specific location falls outside the target range, additional drying is performed or the drying conditions are adjusted.

[0190] If a sample with a water activity of less than 0.35 is found, it indicates that over-drying has occurred, so humidification treatment may be considered. Humidification treatment is a method of supplying air at a low speed with a relative humidity of 60 to 80 percent while monitoring the water activity to raise it to the target range. However, since precise control is difficult with humidification treatment, it is desirable to manage the process to prevent over-drying as much as possible. If a sample with a water activity exceeding 0.55 is found, additional drying is required, and the measurement is taken again after performing additional drying for 5 to 10 minutes under third intermediate drying conditions.

[0191] Drying is terminated once it is confirmed that the water activity of all samples is within the target range. At the end of drying, heating of the inlet air is stopped, and airflow is continued to prepare the particles for cooling. Accurate recording of the drying end time is important for process control and ensuring reproducibility. The drying start time, time required for each stage, temperature and flow rate setpoints for each stage, and measured water activity values ​​are recorded in detail.

[0192] In the final verification stage, other quality indicators may be measured in addition to water activity. Moisture content is measured by the Karl Fischer titration method or the drying loss method, and is generally in the range of 4 to 10 weight percent. Although water activity and moisture content are related, they are not the same concept, and in this invention, water activity is the key indicator. Particle size distribution is measured by laser diffraction to verify whether particle breakage or aggregation occurred during the drying process. Fluidity is evaluated through the measurement of apparent density, tap density, and angle of repose, and it is determined to have good fluidity if the Hausner ratio is 1.5 or less.

[0193] Slow cooling stage (c5)

[0194] The slow cooling step is a step in which the particles, after drying is complete, are gradually cooled without rapid temperature changes to stabilize the structure of the coat layer. Cooling is performed from 20°C to 30°C while reducing the air flow rate in a fluidized bed dryer from 10 cubic meters per hour to 30 cubic meters per hour. Slow cooling is important to ensure that the hydrophilic polymer structure of the coat layer solidifies into a stable form without excessive thermal stress and to maintain a state suitable for the subsequent functional layer formation process.

[0195] The air flow rate is reduced to between 10 cubic meters per hour and 30 cubic meters per hour. The reason for using a flow rate significantly lower than that of the drying stage is that vigorous flow is not required during the cooling process, and gentle cooling is achieved through low-speed flow. If the air flow rate is less than 10 cubic meters per hour, the flow of particles almost stops, causing uneven cooling, and some particles may stagnate at the bottom of the dryer, delaying cooling. If the air flow rate exceeds 30 cubic meters per hour, the cooling speed becomes excessively fast, causing thermal stress due to rapid cooling and potentially leading to microcracks in the coat layer. The preferred air flow rate is between 15 cubic meters per hour and 25 cubic meters per hour, and more preferably between 18 cubic meters per hour and 22 cubic meters per hour.

[0196] The target cooling temperature is 20 to 30 degrees Celsius. This is within the general room temperature range, and cooling the particles to this temperature minimizes the temperature difference with the surrounding environment after discharge. If the particle temperature is excessively cooled to below 20 degrees Celsius, there is a risk of condensation or moisture absorption after discharge due to the temperature difference with the surrounding environment. If the particles are discharged while the temperature exceeds 30 degrees Celsius, quality changes due to residual heat may persist, and moisture redistribution may occur internally when stored in a sealed container. The preferred target cooling temperature is 22 to 28 degrees Celsius, and more preferably 23 to 27 degrees Celsius. The optimal cooling temperature is adjusted according to the temperature and humidity of the working environment and is generally set to a level 2 to 5 degrees Celsius higher than room temperature.

[0197] The conditions of the cooling air affect cooling efficiency and quality. Indoor air may be used directly for cooling, or air with controlled temperature and humidity through an air conditioning system may be used. The temperature of the cooling air is preferably in the range of 15 to 25 degrees Celsius, and the relative humidity is preferably in the range of 30 to 60 percent. Caution is required because if the relative humidity of the cooling air is excessively high, particles may absorb moisture during cooling, causing an increase in water activity. If necessary, the relative humidity can be lowered by dehumidifying the cooling air.

[0198] The slow cooling time varies depending on the amount of particles, the initial temperature, and the cooling air conditions, but generally takes 15 to 40 minutes. Unlike rapid cooling, slow cooling aims for a gradual temperature drop, so it is important to ensure sufficient time. If the cooling time is less than 15 minutes, thermal stress may be applied to the coating layer due to rapid temperature changes. If the cooling time exceeds 40 minutes, process efficiency decreases, and particle wear may occur during prolonged flow. The preferred slow cooling time is 20 to 35 minutes, and more preferably 25 to 30 minutes.

[0199] During the cooling process, the temperature of the particles is continuously monitored using a temperature probe inserted inside the dryer. Initially, the temperature decreases relatively rapidly, but the rate of decrease slows as it approaches room temperature. Slow cooling is terminated when the product temperature reaches the target temperature. Even after slow cooling is complete, air supply is maintained for an additional 5 to 10 minutes to ensure that the entire particle reaches a uniform temperature. This process is called tempering, and through tempering, temperature equilibrium is achieved between the surface and the interior of the particles, thereby enhancing quality stability after discharge.

[0200] After slow cooling is complete, the structure of the coating layer of the particles is stabilized, improving mechanical strength and minimizing the tendency to aggregate. The hydrophilic polymer within the coating layer forms a robust network structure while maintaining an appropriate hydration state, and the water activity regulator is uniformly dispersed to stably maintain the target water activity. After slow cooling is complete, the water activity of the particles is measured once again to verify that it is maintained within the range of 0.35 to 0.55. There should be almost no change in water activity during the slow cooling process; if a significant change is observed, it indicates that the humidity of the cooling air was inappropriate.

[0201] Once slow cooling is complete, the particles are discharged into a sealed container through an outlet at the bottom of the fluidized bed dryer. To minimize contact with external air during the discharge process, the outlet and the receiving container are sealed tightly or connected via a flexible hose. Stainless steel drums with built-in polyethylene bags or aluminum laminated film bags are used as receiving containers. The discharged particles are quickly sealed for storage or immediately fed into the next step, the functional layer formation process.

[0202] The particles that have completed the intermediate drying step have a coating layer precisely adjusted to a target water activity range of 0.35 to 0.55, and are in an optimal state satisfying both storage stability and immediate characteristics. These particles possess surface characteristics and mechanical strength suitable for receiving additional coating in the subsequent functional layer formation process, and serve as the basis for ensuring the excellent performance of the final product. The precise execution of the intermediate drying step is an essential element for achieving the critical range of the present invention, and highly reproducible manufacturing is possible through systematic control and continuous monitoring of the conditions at each step.

[0203] Specific implementation method of the functional layer formation step

[0204] Functional layer formation step (d) Overall overview

[0205] The functional layer formation step is a step in which a functional coating is finally applied to particles that have undergone an intermediate drying step to form a coating layer with a water activity adjusted to 0.35 to 0.55. Depending on the purpose of the product, the functional layer is classified into an absorption-promoting type or a release-controlled type, and different materials and coating conditions are applied to each. The absorption-promoting functional layer aims to increase mucosal permeability and improve bioavailability by using absorption promoters such as chitosan and surfactants. The release-controlled functional layer aims to protect the functional raw material from gastric acid and enable its release in the small intestine by using enteric polymers such as Eudrajit series or hydroxypropylmethylcellulose derivatives.

[0206] For the absorption-promoting type, the functional layer is formed relatively thin to ensure it exhibits an absorption-promoting effect without hindering dissolution, while for the release-controlled type, it is formed with sufficient thickness to prevent dissolution in an acidic environment. This step proceeds in the following order: preparation of the second coating solution, re-introduction into and preheating of the fluidized bed coating machine, initial low-speed spraying for the formation of the primer layer, medium-speed spraying for the main coating, final low-speed spraying for surface finishing, and stabilization through post-drying. At each stage, process parameters such as temperature, spray speed, spray pressure, and air flow rate are precisely controlled to form a uniform and defect-free functional layer.

[0207] Step 2 of preparing the coating solution (d1)

[0208] The second coating solution is prepared using an absorption promoter or a release control agent as the main component, depending on the type of functional layer. When forming an absorption-promoting functional layer, one or more selected from the group consisting of chitosan, chitosan derivatives, cationic gelatin, polysorbate, poloxamer, and sodium lauryl sulfate are used as absorption promoters. Chitosan is a cationic polymer that improves mucosal adhesion through electrostatic interactions with anionic substances on the mucosal surface and promotes absorption through intercellular pathways by temporarily opening tight junctions. Chitosan derivatives include carboxymethyl chitosan, thiolated chitosan, and quaternary ammonium chitosan, which have the advantage of improved water solubility and mucosal permeability promotion effects compared to chitosan.

[0209] Cationic gelatin is produced by replacing the carboxyl groups of gelatin with amine groups to impart a positive charge, promoting absorption through a mechanism similar to that of chitosan. Polysorbates are nonionic surfactants, such as polysorbate 20 and polysorbate 80, which are used to improve particle wettability and facilitate penetration into the mucus layer on the mucosal surface. Poloxamers are block copolymers of polyoxyethylene and polyoxypropylene, such as poloxamer 188 and poloxamer 407, which are used for their excellent surfactant effects and high biocompatibility. Sodium lauryl sulfate is an anionic surfactant that exhibits strong wetting and penetration effects; however, since excessive use may cause mucosal irritation, its usage amount should be limited.

[0210] The absorption promoter is included in an amount of 1 to 10 weight percent based on the total weight of the second coating solution. If the content of the absorption promoter is less than 1 weight percent, the viscosity of the coating solution becomes excessively low, making it difficult to achieve a uniform coating, and the thickness of the formed functional layer is thin, resulting in insufficient absorption-promoting effects. If the content of the absorption promoter exceeds 10 weight percent, the viscosity of the coating solution becomes excessively high, making spraying difficult, and the formed functional layer becomes excessively thick, which may hinder the dissolution rate. The preferred content of the absorption promoter is 2 to 8 weight percent, and more preferably 3 to 6 weight percent. The optimal content of the absorption promoter is determined by considering the type of material used, the target absorption-promoting effect, and the characteristics of the functional raw material.

[0211] When forming a controlled-release functional layer, one or more selected from the group consisting of Eudrajit L100-55, Eudrajit L, Eudrajit S, hydroxypropylmethylcellulose acetate succinate, and hydroxypropylmethylcellulose phthalate are used as the control agents. Eudrajit L100-55 is a copolymer of methacrylic acid and ethyl acrylate that dissolves at pH 5.5 or higher, does not dissolve in gastric acid, and begins to dissolve in the upper duodenum. Eudrajit L dissolves at pH 6.0 or higher and is released in the lower duodenum and upper jejunum. Eudrajit S is a delayed-release polymer that dissolves at pH 7.0 or higher and is released in the ileum and large intestine.

[0212] Hydroxypropylmethylcellulose acetate succinate is a cellulose derivative whose dissolution pH varies depending on the degree of substitution of acetyl and succinyl groups, and generally dissolves at pH 5.5 to 6.5. Hydroxypropylmethylcellulose phthalate is a cellulose derivative with introduced phthalic groups that begins to dissolve at pH 5.0 to 5.5. These enteric polymers do not dissolve in the gastric acid environment of pH 1.2 to 2.0, thereby protecting the functional ingredients, and dissolve in the neutral or slightly alkaline environment of the small intestine to release the functional ingredients. Depending on the target release site, a polymer with an appropriate dissolution pH can be selected, or polymers with different dissolution pH values ​​can be combined and used.

[0213] The release control agent is included in an amount of 3 to 15 weight percent based on the total weight of the second coating solution. If the content of the release control agent is less than 3 weight percent, the viscosity of the coating solution is low and the thickness of the formed functional layer is thin, so it does not provide sufficient protection against stomach acid. If the content of the release control agent exceeds 15 weight percent, the viscosity of the coating solution becomes excessively high, making spraying and coating difficult, and the stability of the coating solution is reduced, which may lead to precipitation or gelation. The preferred content of the release control agent is 5 to 12 weight percent, and more preferably 6 to 10 weight percent. The optimal content of the release control agent is determined by considering the target coating thickness, required stomach acid resistance, release rate profile, etc.

[0214] Purified water, an aqueous ethanol solution, or an organic solvent is used as the solvent for the second coating solution. Since chitosan and chitosan derivatives among the absorption promoters are soluble in weakly acidic aqueous solutions, a solution adjusted to a pH of 4.0 to 5.5 by adding a small amount of food-grade organic acid, such as acetic acid, citric acid, or lactic acid, to purified water is generally used. Cationic gelatin can be directly dissolved in purified water. Polysorbate, poloxamer, and sodium lauryl sulfate are water-soluble, so they are dissolved in purified water. Among the release control agents, Eudragit-based polymers are soluble in organic solvents such as ethanol, acetone, and isopropanol, or in a mixed solvent of these and purified water. Generally, a mixed solvent of 50 to 90 weight percent ethanol and 10 to 50 weight percent purified water is used.

[0215] Hydroxypropylmethylcellulose acetate succinate and hydroxypropylmethylcellulose phthalate are soluble in aqueous solutions of ethanol, acetone, and methanol. While the use of organic solvents offers the advantages of faster drying speeds and improved coating layer density, it requires management of solvent residue and safety. When applied to health functional foods and cosmetics, sufficient drying time must be ensured to meet residual solvent standards. Whenever possible, using aqueous coating solutions is advantageous in terms of safety and environmental impact.

[0216] The solid content concentration of the second coating solution is prepared to be 3 weight percent to 20 weight percent. If the solid content concentration is less than 3 weight percent, the coating solution is excessively diluted, requiring an excessive amount of coating solution to be sprayed to reach the target coating thickness. This extends the process time and causes the particles to undergo excessive wetting-drying cycles, which may degrade the quality. If the solid content concentration exceeds 20 weight percent, the viscosity of the coating solution is excessively high, making it difficult to spray through a spray nozzle. Furthermore, it is not uniformly dispersed on the surface of the particles, resulting in non-uniform quality of the coating layer. A preferred solid content concentration is 5 weight percent to 18 weight percent, and more preferably 8 weight percent to 15 weight percent.

[0217] The preparation of the second coating solution is performed as follows. First, the solvent is placed in a stirring-capable container and heated to a constant temperature. The absorption promoter or release control agent is slowly added to the solvent while stirring with a stirrer. The stirring speed is set within the range of 100 rpm to 500 rpm, selecting conditions where vortices are formed while minimizing air incorporation. For substances that take time to dissolve, such as chitosan, stirring is performed for 1 to 3 hours to ensure complete dissolution. The dissolution temperature is adjusted according to the characteristics of the substance and is generally performed within the range of 20°C to 50°C. Once dissolution is complete, insoluble impurities are removed through a filtration process. A filter with a mesh size of 5 micrometers to 20 micrometers is used for filtration.

[0218] If necessary, a plasticizer may be added to the second coating solution. The plasticizer serves to improve the flexibility of the coating layer and prevent cracking. Triethyl citrate, triacetin, polyethylene glycol, etc. are used as plasticizers, and 5 to 30 parts by weight are added per 100 parts by weight of release control agent. In addition, a small amount of talc, glyceryl monostearate, etc., may be added as a lubricant to improve the sprayability of the coating solution. The second coating solution, once prepared, is stored in a sealed container and stirred again before use to ensure there are no settled components. It is preferable to use the coating solution within 24 hours of preparation, as microbial growth or component degradation may occur during long-term storage.

[0219] Particle reintroduction and preheating step (d2)

[0220] Particles that have undergone an intermediate drying step are reintroduced into the fluid bed coating machine. If the particles are in the same fluid bed coating machine used in the coat layer formation step, the process can proceed continuously to the next step; if the particles have been temporarily discharged and stored, they are reintroduced into the fluid bed coating machine. Bottom spray, top spray, and tangential spray methods can be used as fluid bed coating machines, and the Würster coating machine, a bottom spray method, is the most widely used for functional layer coating. The Würster coating machine is structured to spray upward from the bottom center, allowing particles to circulate around the nozzle and achieve a uniform coating.

[0221] After introducing the particles into a fluid bed coating machine, the inlet air temperature is set according to the type of functional layer. When forming an absorption-promoting functional layer, the inlet air temperature is set to 30°C to 45°C. Among the absorption promoters, chitosan, chitosan derivatives, cationic gelatin, etc., are relatively sensitive to heat, and a decrease in molecular weight or denaturation may occur at excessive temperatures. In addition, since the absorption-promoting functional layer is formed thinly to avoid hindering the dissolution rate, sufficient drying is possible even at relatively low temperatures. If the inlet air temperature is below 30°C, the drying speed of the coating solution is excessively slow, so the coating solution sprayed on the particle surface is not sufficiently dried, and aggregation between particles may occur. If the inlet air temperature exceeds 45°C, there is a risk of denaturation of the absorption promoter. The preferred inlet air temperature is 32°C to 42°C, and more preferably 35°C to 40°C.

[0222] When forming a release-controlled functional layer, the inlet air temperature is set to 40°C to 55°C. The release control agent is a polymer material with relatively high thermal stability, and when using a coating solution containing an organic solvent, a relatively high temperature is required to ensure a sufficient drying speed. Additionally, since the release-controlled functional layer is formed thickly, a large amount of coating solution is sprayed, and a high temperature is advantageous for effectively drying it. If the inlet air temperature is below 40°C, the drying speed of the organic solvent is slow, causing aggregation between particles and a decrease in the density of the coating layer. If the inlet air temperature exceeds 55°C, rapid drying of the coating layer surface may cause microcracks to form, or bubble formation may occur due to excessive evaporation of the solvent. The preferred inlet air temperature is 43°C to 52°C, and more preferably 45°C to 50°C.

[0223] After setting the inlet air temperature, the air flow rate is adjusted to bring the particles into a fluid state. The air flow rate is adjusted according to the particle size, density, and volume, and is generally set within the range of 40 cubic meters per hour to 100 cubic meters per hour. An appropriate fluid state is one in which the particles circulate smoothly and pass around the nozzle. If the flow rate is excessively low, some particles become stagnant at the bottom of the dryer, resulting in an uneven coating; if the flow rate is excessively high, the particles move too violently, causing breakage or increased scattering losses. The flow pattern can be visually inspected through a transparent observation window or monitored by measuring pressure drop.

[0224] After bringing the particles into a fluid state, they are preheated for a certain period. The preheating time is generally 5 to 15 minutes and continues until the particle temperature approaches the inlet air temperature and stabilizes. If the coating solution is sprayed before sufficient preheating, the solution condenses on the cold particle surface, forming an uneven coating. The particle surface temperature is monitored in real time using a temperature probe inserted inside the dryer. For the absorption-promoting type, spraying can begin when the particle surface temperature reaches between 25°C and 35°C. For the release-controlled type, spraying can begin when the particle surface temperature reaches between 35°C and 45°C. Once the particle surface temperature reaches the set temperature range and stabilizes, the next step, spraying the coating solution, begins.

[0225] Initial primer layer formation step (d3)

[0226] When the particle surface temperature reaches a set temperature range, spraying of the second coating solution is initiated. The initial spraying is performed at a low speed of 0.3 grams per minute to 1.5 grams per minute. The purpose of the initial low-speed spraying is to form a thin, uniform primer layer on the particle surface. The primer layer improves the adhesion between the coat layer and the functional layer and provides a basis for the coating solution to be uniformly dispersed during the subsequent main coating process. If the spraying speed is less than 0.3 grams per minute, the spray volume is excessively low, causing the nozzle to clog or the spraying to be intermittent, resulting in an uneven coating. If the spraying speed exceeds 1.5 grams per minute, excessive wetting occurs during the initial stage, which may cause the coating solution to aggregate on the particle surface or adhesion between particles. A preferred initial spraying speed is 0.5 grams per minute to 1.2 grams per minute, and more preferably 0.7 grams per minute to 1.0 grams per minute.

[0227] Initial low-speed spraying is performed until the coating solution adheres uniformly to the particle surface and a primer layer is formed. The time required for primer layer formation varies depending on the particle volume, surface area, and spraying speed, but generally takes 2 to 10 minutes. Whether a primer layer has formed can be determined by visual observation, changes in particle color, and changes in surface gloss. If the particle surface becomes generally wet and gloss appears, and the relative humidity of the exhaust air rises compared to the initial level, it can be considered that the primer layer has begun to form. If a thin coating layer is formed on the surface when a sample of particles is observed under a microscope, it is determined that the primer layer has been properly formed.

[0228] During the initial spraying process, the spray pressure is maintained in the range of 0.8 bar to 1.5 bar. If the spray pressure is less than 0.8 bar, the atomization of the coating liquid is insufficient, resulting in the formation of large droplets, which adhere unevenly to the particle surface and cause a stained coating. If the spray pressure exceeds 1.5 bar, the coating liquid is sprayed as an excessively fine mist, increasing the loss of adhesion to the dryer walls or exhaust filter and reducing the amount of coating liquid reaching the particle surface. The preferred spray pressure is 1.0 bar to 1.3 bar, and more preferably 1.1 bar to 1.2 bar. The spray pressure can be adjusted according to the viscosity of the coating liquid, the solid content concentration, and the type of nozzle.

[0229] During the initial spraying process, the product temperature of the particles and the humidity of the exhaust air are continuously monitored. If the product temperature rises excessively, the inlet air temperature can be slightly lowered or the spray rate increased to utilize the evaporative cooling effect. If the product temperature drops excessively, the spray rate is reduced or the inlet air temperature is slightly increased. If the relative humidity of the exhaust air exceeds 70 percent, it is an over-humid state, so the spray rate is reduced or the inlet air temperature is increased. If the relative humidity of the exhaust air is less than 30 percent, it is an over-dry state, so the spray rate can be increased. The appropriate relative humidity of the exhaust air is in the range of 40 percent to 60 percent.

[0230] Once the primer layer is formed, the process proceeds to the next step, the main coating. While it is common to proceed continuously without a separate drying step between the primer layer and the main coating, if necessary, the spraying can be stopped for 1 to 3 minutes to perform only drying, thereby stabilizing the primer layer. This intermediate drying strengthens the adhesion of the primer layer and improves stability during the main coating process.

[0231] Main coating step (d4)

[0232] After forming the primer layer, the spraying speed is increased to a medium-speed spray of 1.5 grams per minute to 4 grams per minute. This coating step is a critical step that determines the efficiency of the process and the quality of the coating layer, as it involves spraying most of the coating liquid to achieve the target coating thickness. If the spraying speed is less than 1.5 grams per minute, the time required to reach the target weight increase rate becomes excessively long, and the particles may be exposed to heat for an extended period, potentially damaging functional raw materials or absorption promoters. If the spraying speed exceeds 4 grams per minute, the amount of coating liquid sprayed onto the particle surface exceeds the drying capacity, resulting in over-wetting and increased aggregation between particles or non-uniformity of the coating layer. The preferred coating spraying speed is 2.0 grams per minute to 3.5 grams per minute, and more preferably 2.5 grams per minute to 3.0 grams per minute.

[0233] During the coating process, the spray pressure is maintained within the range of 0.8 bar to 1.5 bar. This is the same range as the initial spray, and maintaining a consistent spray pressure ensures uniformity of droplet size and maintains consistent quality of the coating layer. Abrupt changes in spray pressure must be avoided, as they cause changes in droplet size and affect the density and thickness of the coating layer. If the viscosity of the coating solution changes over time, the spray pressure can be fine-tuned to maintain a consistent spray pattern.

[0234] The coating is performed continuously after the completion of the intermediate drying step until the weight increase rate of the particles reaches a target value. When forming an absorption-promoting functional layer, the target weight increase rate is 2 weight percent to 10 weight percent. If the weight increase rate is less than 2 weight percent, the thickness of the functional layer is excessively thin, resulting in insufficient absorption-promoting effects. If the weight increase rate exceeds 10 weight percent, the functional layer becomes excessively thick, hindering the dissolution rate and impairing the immediate release properties that are the objective of the present invention. The preferred absorption-promoting weight increase rate is 3 weight percent to 8 weight percent, and more preferably 4 weight percent to 6 weight percent.

[0235] When forming a controlled-release functional layer, the target weight gain is 10 to 25 weight percent. If the weight gain is less than 10 weight percent, the thickness of the functional layer is insufficient, so the functional ingredient cannot be completely protected in the gastric acid environment, and some premature release may occur. If the weight gain exceeds 25 weight percent, the functional layer becomes excessively thick, which delays dissolution even in the small intestine environment and may result in incomplete release of the functional ingredient. In addition, excessive coating significantly increases the particle size, making it difficult to apply to the final formulation. The preferred controlled-release weight gain is 12 to 22 weight percent, and more preferably 15 to 20 weight percent.

[0236] The weight growth rate is monitored periodically during the coating process. If a load cell is installed in the fluid bed coater, the weight of the particles can be measured in real time. If a load cell is not installed, a small sample is taken at regular intervals to measure its weight, and the weight growth rate is estimated by comparing this with the total amount of sprayed coating liquid. The calculation of the weight growth rate is as follows: The percentage of weight growth is calculated by subtracting the initial weight of the particles after the completion of the intermediate drying stage from the total weight of the particles after coating, dividing the result by the initial weight of the particles after the completion of the intermediate drying stage, and multiplying by 100. As the target weight growth rate approaches, the spraying speed is gradually reduced to prevent excessive coating.

[0237] During the coating process, the inlet air temperature is controlled to maintain the product temperature of the particles within the range of 25 to 35°C for the absorption-promoting type and within the range of 35 to 45°C for the release-controlled type. If the product temperature rises excessively, rapid drying of the coating layer surface may cause microcracks or reduce the flexibility of the coating layer. If the product temperature drops excessively, insufficient drying of the coating solution may lead to aggregation between particles. Stable maintenance of the product temperature is essential for the formation of a uniform and high-quality coating layer.

[0238] During the coating process, small sample sizes are periodically sampled to check the coating status. Samples are observed under a microscope to verify whether the coating layer is formed uniformly and to check for any defects or non-uniformities on the surface. If necessary, the thickness and density of the coating layer can be evaluated by cutting the sample and observing the cross-section. If problems are detected in the coating layer, process conditions are adjusted immediately. For example, if bubbles or cracks are observed in the coating layer, the inlet air temperature is lowered or the spray velocity is reduced. If the coating layer is formed non-uniformly, the air flow rate is adjusted to improve the particle flow pattern.

[0239] Finishing coating step (d5)

[0240] During the last 5 minutes immediately prior to reaching the target weight increase rate, the spray speed is reduced to a final low-speed spray of 0.5 gram-per-minute to 1 gram-per-minute. The purpose of the finishing coating step is to densely finish the surface of the functional layer, minimize defects in the coating layer, and reduce surface roughness. Although the coating layer formed by medium-speed spraying in this coating step is efficient, fine irregularities or non-uniformities may exist on the surface. Through the final low-speed spraying, these non-uniformities can be mitigated and the surface can be finished smoothly.

[0241] The starting point for the finishing coating is when the weight gain rate reaches 90 to 95 percent of the target value. For example, if the target weight gain rate for the absorption-promoting type is 5 weight percent, the spray speed is switched to the final low speed when the weight gain rate reaches 4.5 to 4.75 weight percent. If the target weight gain rate for the release-controlled type is 15 weight percent, the spray speed is switched when the weight gain rate reaches 13.5 to 14.25 weight percent. The uniformity of the coating layer is maintained by gradually decreasing the spray speed over 1 to 2 minutes rather than switching it abruptly.

[0242] If the final low-speed spray rate is less than 0.5 grams per minute, the spray volume is excessively low, causing nozzle clogging or unstable spraying. If the final low-speed spray rate exceeds 1 gram per minute, the finishing effect is insufficient and the improvement in surface quality is limited. The preferred final low-speed spray rate is 0.6 to 0.9 grams per minute, and more preferably 0.7 to 0.8 grams per minute. If the finishing coating time is less than 5 minutes, the finishing effect is insufficient, and if it exceeds 5 minutes, the process time is unnecessarily extended and the target weight increase rate may be exceeded due to excessive coating.

[0243] During the final coating process, conditions such as spray pressure, inlet air temperature, and air flow rate are maintained identically to those of the main coating. Maintaining consistent process conditions is crucial for ensuring uniformity in the quality of the coating layer. During the final coating, a gradual decrease in the relative humidity of the exhaust air can be observed; this is because the drying load is reduced as the volume of sprayed coating liquid decreases. Once the target weight gain is precisely reached, spraying is immediately stopped, and the process transitions to the post-drying stage.

[0244] Particles with completed finishing coatings have a smooth and glossy surface, and a uniform and dense coating layer is formed upon microscopic observation. For absorption-promoting functional layers, the coating layer thickness is generally in the range of 2 micrometers to 10 micrometers, and for release-controlling functional layers, it is in the range of 10 micrometers to 50 micrometers. The thickness of the coating layer can be measured by observing the cross-section of the particle using a scanning electron microscope. A uniform coating layer is defined as having a thickness variation of within 20 percent across the entire surface of the particle.

[0245] Post-drying step (d6)

[0246] Once the spraying of the coating solution is completed, post-drying is performed for 3 to 10 minutes while maintaining the inlet air temperature and adjusting the air flow rate to a range of 30 cubic meters per hour to 70 cubic meters per hour. The purpose of post-drying is to remove residual solvent from the coating layer, stabilize the coating layer, and separate any weak adhesions between particles. Immediately after the end of spraying, the surface of the coating layer is not yet completely dry, and residual solvent is present, particularly when organic solvents are used. By removing this residual solvent through post-drying, product safety is ensured and the mechanical strength of the coating layer is improved.

[0247] The inlet air temperature is maintained at the same level as the temperature set during the spraying process. For the absorption-promoting type, this is 30 to 45°C, and for the release-controlled type, it is 40 to 55°C. By maintaining a constant temperature, shrinkage or cracking of the coating layer caused by sudden temperature changes is prevented. In some variations, the spray temperature may be maintained during the initial post-drying stage, and then increased by 5 to 10°C in the later stages to facilitate the removal of residual solvent. However, care must be taken to avoid thermal damage to the coating layer or functional raw materials when the temperature is increased.

[0248] The air flow rate is set to 30 cubic meters per hour to 70 cubic meters per hour. It is generally set slightly lower than the flow rate used during the spraying process, because after the spraying is finished, the moisture content of the particles decreases, making them lighter and more prone to scattering. If the air flow rate is less than 30 cubic meters per hour, the flow of particles is insufficient, resulting in uneven drying and the stagnation of some particles, which may lead to overheating. If the air flow rate exceeds 70 cubic meters per hour, particle scattering losses increase, and wear on the surface of the coating layer may occur. The preferred air flow rate is 40 cubic meters per hour to 60 cubic meters per hour, and more preferably 45 cubic meters per hour to 55 cubic meters per hour.

[0249] The post-drying time is set to 3 to 10 minutes. If the post-drying time is less than 3 minutes, residual solvent is not sufficiently removed and the stabilization of the coating layer is incomplete. If the post-drying time exceeds 10 minutes, the additional drying effect is negligible, while the process time is extended and the risk of quality degradation due to heat increases. The preferred post-drying time is 4 to 8 minutes, and more preferably 5 to 7 minutes. Since the optimal post-drying time varies depending on the type of coating solution, the solvent used, the thickness of the coating layer, drying conditions, etc., it must be verified through residual solvent analysis.

[0250] During the post-drying process, the relative humidity of the exhaust air gradually decreases until it drops to less than half of its initial level. Once the exhaust air humidity stabilizes below a certain level, the removal of residual solvent can be considered complete. The product temperature of the particles gradually rises during the post-drying process and approaches the inlet air temperature. Post-drying can be terminated when the product temperature stabilizes and the exhaust humidity remains low.

[0251] The particles, having completed post-drying, proceed to the cooling stage within the dryer. Similar to the cooling in the core layer formation stage, the heating of the inlet air is stopped, and cooling air or ambient air is supplied to cool the particles to 20°C to 30°C. The cooling time generally takes 10 to 30 minutes. Once cooling is complete, the particles are discharged into a sealed container through the outlet at the bottom of the fluidized bed coater. During the discharge process, contact with external air is minimized to prevent moisture absorption.

[0252] Multilayer particles with a completed functional layer can undergo quality inspection before being transferred to the final drying and aging stage. Inspection items include average particle size and particle size distribution, weight gain rate, appearance observation, and evaluation of coating layer uniformity by microscopic observation. If necessary, a dissolution test is performed to verify the performance of the functional layer. For absorption-promoting types, rapid disintegration and dissolution must be demonstrated in the dissolution test, while for release-controlled types, dissolution of 10 percent or less over 2 hours in a solution with pH 1.2 and rapid dissolution in a solution with pH 6.8 must be demonstrated. Only particles that pass these quality inspections are fed into the next stage, the final drying and aging stage.

[0253] Specific implementation method for the final drying and aging steps

[0254] Final drying stage (e) Overall overview

[0255] The final drying step is a step for precisely adjusting the water activity of the multilayer particles, upon completion of the functional layer formation, to the core range of 0.35 to 0.55 of the present invention. This step goes beyond simple drying and is one of the most critical processes for determining the storage stability and solubility characteristics of the entire multilayer particle structure. The water activity range of 0.35 to 0.55 is a critical range that minimizes free water during storage to inhibit microbial growth and chemical decomposition, while maximizing osmotic driving force upon contact with bodily fluids to induce explosive hydration. This step consists of a three-stage drying process—first, second, and third final drying—and a cooling and aging process. In each stage, the temperature, air flow rate, and time are precisely controlled to achieve the target water activity. In particular, by adopting a stepwise drying method, structural damage caused by rapid moisture removal is prevented, and the moisture distribution of the entire particle, from the core layer to the functional layer, can be uniformly controlled.

[0256] 1st final drying stage (e1)

[0257] The first final drying step is a step to preferentially remove free water present on the particle surface immediately after the formation of the functional layer. Although the second coating liquid is sprayed and post-drying is performed during the functional layer coating process, a certain amount of free water still remains on the particle surface, and rapidly removing this is essential to prevent aggregation between particles and improve the efficiency of subsequent drying. Drying is performed for 10 to 20 minutes in a fluidized bed dryer under conditions of an inlet air temperature of 35 to 45 degrees Celsius and an air flow rate of 40 cubic meters per hour to 80 cubic meters per hour.

[0258] The inlet air temperature is set to 35°C to 45°C. This is a level slightly higher than or similar to the temperature used in the functional layer coating process, representing a range where surface moisture can be effectively removed without causing thermal damage to the functional layer structure. If the inlet air temperature is below 35°C, the drying speed is excessively slow, resulting in insufficient removal of free water from the particle surface; this causes aggregation between particles and reduces subsequent drying efficiency. If the inlet air temperature exceeds 45°C, rapid surface drying may cause microcracks on the surface of the functional layer or the surface to become excessively dense, hindering the movement of internal moisture. In particular, if a heat-sensitive polymer such as chitosan is used as an absorption promoter, excessive temperature can degrade its functionality. The preferred inlet air temperature is 37°C to 43°C, and more preferably 38°C to 42°C.

[0259] The air flow rate is set within the range of 40 cubic meters per hour to 80 cubic meters per hour. The reason for using a relatively high air flow rate is that particles with a formed functional layer have a tendency to aggregate because their surfaces are in a wet state; therefore, sufficient flow is provided to ensure that the particles remain separated while drying. If the air flow rate is less than 40 cubic meters per hour, the flow of particles is insufficient, causing some particles to stick together and form clumps, which leads to uneven drying and quality degradation. If the air flow rate exceeds 80 cubic meters per hour, excessive flow causes particles to collide strongly with the dryer walls, which may damage or peel off the functional layer, and also increases the generation of fine particles and scattering losses. The preferred air flow rate is 45 cubic meters per hour to 75 cubic meters per hour, and more preferably 50 cubic meters per hour to 70 cubic meters per hour.

[0260] The first final drying time is set to 10 to 20 minutes. If the drying time is less than 10 minutes, free water on the surface of the functional layer is not sufficiently removed, leading to particle aggregation and potentially causing problems during the subsequent second final drying. If the drying time exceeds 20 minutes, the functional components of the functional layer may be damaged due to unnecessary prolonged exposure to heat while the surface free water has already been removed. The preferred first final drying time is 12 to 18 minutes, and more preferably 13 to 17 minutes. Since the optimal drying time varies depending on the type and thickness of the functional layer, the amount of residual moisture after coating, and drying conditions, it is adjusted while monitoring the product temperature and the humidity of the exhaust air.

[0261] During the first final drying process, the product temperature of the particles is monitored in real time using a temperature probe inserted inside the dryer. Initially, the product temperature remains lower than the inlet air temperature due to the evaporative cooling effect of surface moisture, but it gradually rises as free surface water is removed. When the product temperature stabilizes within the range of 30 to 38 degrees Celsius, it can be determined that most of the free surface water has been removed. The relative humidity of the exhaust air is also an important indicator; it initially exhibits high humidity but gradually decreases and stabilizes once the removal of surface moisture is complete. When the rate of change in exhaust air humidity decreases to less than 5 percent per hour, the first final drying can be considered to be nearing completion.

[0262] Once the first final drying is completed, free water is removed from the surface of the particles, improving fluidity and significantly reducing the tendency to aggregate. However, a significant amount of moisture still remains inside the particles, which is removed in stages during the second final drying. At the completion of the first final drying, a small sample can be taken to perform visual observation and fluidity tests. If the particles are separated individually and possess sufficient fluidity to flow easily by hand, the first final drying is deemed to have been performed properly.

[0263] 2nd final drying stage (e2)

[0264] The second final drying stage is a step in which moisture inside the particles that was not removed during the first final drying is removed while being controlled in stages. In this stage, moisture is balanced across the core layer, coat layer, and functional layer to bring the water activity of the entire multilayer particle structure closer to the target range. Before starting the second final drying, the water activity of the particles dried in the first final drying stage is measured to verify the drying status.

[0265] Water activity is measured by taking a small amount of particle sample from the dryer and using a water activity meter. The measurement temperature is standardized to 25°C, and the measurement value is recorded after waiting until the sample reaches equilibrium within the measurement chamber. Generally, it takes 5 to 15 minutes to reach equilibrium. It is checked whether the measured water activity is within the range of 0.45 to 0.60. If the water activity is less than 0.45, it indicates that the first final drying was excessive, and the conditions for the second final drying must be relaxed or the time shortened. If the water activity exceeds 0.60, it indicates that the first final drying was insufficient, and the first final drying time must be extended or the temperature slightly increased.

[0266] If the measured water activity is within the range of 0.45 to 0.60, a second final drying step is performed. The inlet air temperature is raised to 40°C to 50°C. The reason for raising the temperature compared to the first final drying step is to remove surface free water, thereby reducing the risk of case hardening, and to improve drying efficiency by increasing the diffusion rate of internal moisture. If the inlet air temperature is below 40°C, the rate of internal moisture removal is excessively slow, resulting in an excessively long drying time. If the inlet air temperature exceeds 50°C, rapid moisture evaporation causes internal stress in the multilayer structure, which may lead to interlayer delamination or cracking, and accelerates the deterioration of functional raw materials. The preferred inlet air temperature is 42°C to 48°C, and more preferably 44°C to 46°C.

[0267] The air flow rate is reduced to between 30 cubic meters per hour and 60 cubic meters per hour. The reason for using a flow rate lower than that of the first final drying is that the surface is dried, reducing the risk of aggregation between particles, and to provide sufficient time for internal moisture to move to the surface and be removed under a gentle flow state rather than a vigorous flow. If the air flow rate is less than 30 cubic meters per hour, the flow of particles is insufficient, resulting in uneven drying, and some particles may stagnate at the bottom of the dryer and overheat. If the air flow rate exceeds 60 cubic meters per hour, particle abrasion and damage to the functional layer increase, and scattering losses also increase. The preferred air flow rate is between 35 cubic meters per hour and 55 cubic meters per hour, and more preferably between 40 cubic meters per hour and 50 cubic meters per hour.

[0268] The second final drying time is set to 15 to 30 minutes. If the drying time is less than 15 minutes, internal moisture is not sufficiently removed, failing to reach the target water activity, and quality changes may occur due to moisture migration during storage. If the drying time exceeds 30 minutes, over-drying causes the particles to become excessively hard and brittle, and there is a concern about damage to functional components due to prolonged heat exposure. The preferred second final drying time is 18 to 27 minutes, and more preferably 20 to 25 minutes.

[0269] During the second final drying process, the product temperature of the particles gradually rises and approaches the inlet air temperature. When the product temperature stabilizes within the range of 35°C to 43°C, it can be determined that the removal of internal moisture has progressed significantly. As internal moisture is removed, the relative humidity of the exhaust air gradually decreases, and the rate of decrease slows down, showing a tendency to stabilize at a certain level. Since it is important to regularly monitor the moisture status of the particles during the second final drying process, this is carried out in conjunction with the next step, the water activity measurement and monitoring stage.

[0270] Water activity monitoring step (e3)

[0271] The water activity monitoring step involves regularly measuring the water activity of the particles during the second final drying to accurately determine when the target range of 0.35 to 0.55 is reached. This is essential for preventing over-drying or under-drying and for determining the optimal drying end point. Water activity is measured at intervals of 3 to 7 minutes during the second final drying.

[0272] The measurement interval is set to 3 to 7 minutes. If the measurement interval is shorter than 3 minutes, the process is interrupted more frequently due to overly frequent sampling, sample loss increases, and the increase in actual information acquisition is minimal. If the measurement interval exceeds 7 minutes, there is a risk of over-drying beyond the target range because changes in water activity cannot be detected in a timely manner. The preferred measurement interval is 4 to 6 minutes, and more preferably, 5 minutes. In the actual process, measurements may be omitted for the first 5 to 10 minutes after the start of the second final drying, and regular measurements may begin thereafter.

[0273] Sample collection for water activity measurement is performed through the sampling port of the dryer. The sampling port is installed on the side of the dryer and designed to allow a small amount of sample to be collected without interrupting the process. The amount of sample collected is the minimum required for water activity measurement, and generally, 5 to 10 grams is sufficient. The collected sample is immediately transferred to a measuring container, and the lid is closed to prevent contact with outside air. If the sample temperature differs significantly from the standard measurement temperature of 25°C, the sample is left at room temperature for 5 to 10 minutes to allow the temperature to equilibrate before measurement.

[0274] Water activity meters can utilize equipment based on various principles, such as capacitive, dew point, and optical methods. It is advisable to use equipment with a measurement accuracy of plus or minus 0.01 or higher, and calibration should be performed using a standard salt solution prior to measurement. The sample is placed in the measurement chamber and waited until equilibrium is reached, which generally takes 5 to 15 minutes. Modern measuring equipment automatically detects the arrival of equilibrium and displays the measurement value.

[0275] The measured water activity values ​​are recorded, and the trend of change over time is monitored. At the beginning of the second final drying, the water activity starts in the range of 0.55 to 0.60 and gradually decreases as time progresses. The rate of decrease in water activity tends to be fast at the beginning and gradually slows down. The point at which the measured water activity reaches the range of 0.35 to 0.55 is identified. This is the target water activity range of the present invention, and is a critical range that simultaneously satisfies storage stability and immediate characteristics.

[0276] When the water activity reaches the range of 0.35 to 0.55, the secondary final drying is terminated, and the process immediately proceeds to the tertiary final drying. If the water activity decreases excessively to below 0.35, it indicates an over-drying state; therefore, in subsequent batches, the secondary final drying time must be shortened or the temperature lowered. If the water activity remains above 0.55, the secondary final drying time is extended or the temperature is slightly increased to accelerate drying. Water activity monitoring data is stored as batch records and utilized as process control and quality control data.

[0277] 3rd final drying stage (e4)

[0278] The third final drying step is a step for stabilizing particles that have reached a water activity in the range of 0.35 to 0.55 within this range. The purpose of this step is not to remove moisture further, but to maintain the achieved water activity uniformly and to equilibrate the moisture distribution within the particles. Drying is performed for 5 to 15 minutes while maintaining the inlet air temperature at 45 to 55 degrees Celsius and reducing the air flow rate from 20 cubic meters per hour to 40 cubic meters per hour.

[0279] The inlet air temperature is maintained between 45°C and 55°C. The reason for using a temperature slightly higher than that of the second final drying step is to minimize the moisture gradient between the particle surface and the interior, and to completely remove any remaining trace amounts of free water. However, since the purpose of this stage is not additional moisture removal, an excessively high temperature is not used. If the inlet air temperature is below 45°C, the rate of moisture equilibration is slow, making it difficult to obtain a sufficient stabilization effect. If the inlet air temperature exceeds 55°C, exposure to excessive heat after the target water activity has already been reached may damage functional components or cause unintended additional drying. The preferred inlet air temperature is between 47°C and 53°C, and more preferably between 48°C and 52°C.

[0280] The air flow rate is reduced to between 20 cubic meters per hour and 40 cubic meters per hour. The reason for using a low flow rate is to induce moisture equilibrium by supplying heat while gently processing the particles under mild flow conditions at this stage. If the air flow rate is less than 20 cubic meters per hour, the flow of particles is reduced excessively, which may cause some particles to stagnate and result in uneven processing. If the air flow rate exceeds 40 cubic meters per hour, particle damage and energy waste occur due to unnecessarily strong flow. The preferred air flow rate is between 25 cubic meters per hour and 35 cubic meters per hour, and more preferably between 28 cubic meters per hour and 32 cubic meters per hour.

[0281] The third final drying time is set to 5 to 15 minutes. If the drying time is less than 5 minutes, moisture equilibration is insufficient, and a moisture gradient may remain between the surface and the interior of the particles, which causes moisture redistribution during storage. If the drying time exceeds 15 minutes, particles that have already reached equilibrium are unnecessarily exposed to heat, resulting in quality degradation and energy waste. The preferred third final drying time is 7 to 13 minutes, and more preferably 8 to 12 minutes.

[0282] During the third final drying process, the product temperature of the particles is maintained very close to the inlet air temperature. It is confirmed that the product temperature is stably maintained within the range of 40°C to 48°C. The relative humidity of the exhaust air maintains a very low and stable value with almost no change over time. This means that no further significant moisture removal occurs. Upon completion of the third final drying, a small sample is taken to measure the water activity, and it is confirmed that it is stably maintained within the range of 0.35 to 0.55.

[0283] The third final drying not only stabilizes the moisture state of the particles but also has the effect of strengthening interlayer bonding by heat-treating the entire multilayer structure. In particular, as the polymers used in the coating layer and functional layer soften at an appropriate temperature, they adhere more densely to the particle surface and form a solid coating layer after cooling. This contributes to improving the mechanical strength of the coating layer and preventing delamination during storage and transportation.

[0284] Cooling stage (e5)

[0285] The cooling step is a step in which the high-temperature particles, after the third final drying is completed, are cooled to near room temperature to stabilize the temperature of the particles. By cooling the particles to 20°C to 30°C, thermal stress is relieved, and temperature changes during subsequent aging or packaging processes are minimized. Cooling is most efficient when performed in a fluidized bed dryer, and the inlet air temperature is reduced to 30°C to 40°C, and the air flow rate is maintained at 10 cubic meters per hour to 30 cubic meters per hour while cooling for 10 to 25 minutes.

[0286] The inlet air temperature is reduced to 30 to 40 degrees Celsius. This is a level significantly lower than the inlet air temperature of the third final drying stage, intended to gradually cool the particles. If the inlet air temperature is excessively low (below 30 degrees Celsius), the rapid temperature change can cause thermal stress in the multilayer structure, potentially leading to delamination or cracking. Additionally, if the temperature difference between the cooling air and the particles is excessive, condensation may form on the particle surface, posing a risk of increased water activity. If the inlet air temperature exceeds 40 degrees Celsius, the cooling rate becomes excessively slow, resulting in an excessively long cooling time. The preferred inlet air temperature is 32 to 38 degrees Celsius, and more preferably 33 to 37 degrees Celsius. A stepwise cooling method may also be applied, using a slightly higher temperature during the initial cooling phase and gradually lowering it.

[0287] The air flow rate is maintained at 10 cubic meters per hour to 30 cubic meters per hour. During the cooling stage, a low flow rate is used to gently process the particles while ensuring sufficient heat exchange with the cooling air. If the air flow rate is less than 10 cubic meters per hour, the flow of particles almost stops, resulting in uneven cooling; particles at the bottom of the dryer may be excessively cooled, while particles at the top may not be sufficiently cooled. If the air flow rate exceeds 30 cubic meters per hour, particle damage and scattering losses may occur due to unnecessarily strong flow. The preferred air flow rate is 12 cubic meters per hour to 28 cubic meters per hour, and more preferably 15 cubic meters per hour to 25 cubic meters per hour.

[0288] The cooling time is set to between 10 and 25 minutes. If the cooling time is less than 10 minutes, the particles are not sufficiently cooled and fail to reach the target temperature; furthermore, problems may arise due to the rapid temperature difference with the surrounding air when discharged in a high-temperature state. If the cooling time exceeds 25 minutes, particles that have already reached the target temperature are unnecessarily circulated for a long period, resulting in particle wear and energy waste. The preferred cooling time is between 12 and 23 minutes, and more preferably between 15 and 20 minutes. Since the optimal cooling time depends on the amount of particles, the initial temperature, and the temperature and flow rate of the cooling air, it is determined while continuously monitoring the product temperature.

[0289] The target cooling temperature is 20°C to 30°C. If the particle temperature is excessively cooled to below 20°C, there is a risk that condensation will form on the particle surface or moisture will be absorbed due to the temperature difference with the surrounding environment after discharge. If the particle is discharged when the temperature exceeds 30°C, unintended additional drying may occur at the beginning of the aging process due to residual heat, or moisture redistribution may occur within the sealed container. The preferred target cooling temperature is 22°C to 28°C, and more preferably 23°C to 27°C. It is desirable to set the optimal cooling temperature to be similar to the temperature of the environment where aging is to be performed, and generally, it is set to a level 2°C to 5°C higher than the aging temperature.

[0290] During the cooling process, the product temperature of the particles is continuously monitored using a temperature probe inside the dryer. Cooling is terminated when the product temperature gradually decreases and reaches the target range. The relative humidity of the cooling air is also monitored to ensure that excessively humid air is not used. It is desirable to maintain the relative humidity of the cooling air within the range of 30 to 60 percent, and a dehumidification device or an air conditioning system may be used for this purpose.

[0291] Once cooling is complete, the particles are discharged into a sealed container through the outlet at the bottom of the fluidized bed dryer. To minimize contact with external air during the discharge process, it is advisable to seal the outlet and the receiving container tightly or connect them with a flexible hose. The discharged particles are immediately placed in a sealed container with a lid to isolate them from the external environment. After cooling, the particles have a stabilized surface, excellent fluidity, and no tendency toward aggregation or caking. The particles have a smooth, glossy surface and are evenly coated with a functional layer.

[0292] Aging stage (e6)

[0293] The aging step is a stage in which the moisture distribution within the particles is homogenized while storing the cooled particles in a sealed container. Particles that have undergone the drying and cooling process may have fine moisture gradients between the surface and the interior, and between the core layer, the coat layer, and the functional layer. Aging is an important process that equilibrates these moisture gradients to make the water activity of the entire particle uniform and improves long-term storage stability. The particles transferred to a sealed container are aged for 12 to 48 hours under conditions of 20 to 25°C and a relative humidity of 40 percent to 60 percent.

[0294] The aging container should be made of a material that can effectively block the penetration of moisture and oxygen. High-density polyethylene drums, stainless steel containers, and aluminum laminated film bags may be used. The size of the container should be selected appropriately according to the amount of particles, but it is desirable to fill 60 to 80 percent of the container's volume with particles. If the container is filled with too many particles, moisture equilibrium during aging is hindered, and if it is filled with too few, the headspace inside the container becomes excessive, which may affect moisture redistribution. The container should be sealed immediately after adding the particles using a lid or sealant.

[0295] The aging temperature is set to 20°C to 25°C. This falls within the general room temperature range and is intended to prevent condensation or evaporation caused by temperature fluctuations during aging and to induce stable moisture equilibrium. If the aging temperature is below 20°C, the low temperature slows down the rate of moisture diffusion, requiring an excessively long time to reach equilibrium. If the aging temperature exceeds 25°C, the stability of certain functional ingredients may be compromised due to the temperature rise, and the risk of condensation occurring inside the container increases during temperature fluctuations. The preferred aging temperature is 21°C to 24°C, and more preferably 22°C to 23°C. The aging space utilizes a constant temperature room equipped with temperature control functions or an indoor environment equipped with an air conditioning system.

[0296] The relative humidity of the aging environment is set to 40 percent to 60 percent. This is the humidity range that equilibrates with the target water activity of the particles, which is 0.35 to 0.55. If the relative humidity is excessively low (below 40 percent) and the container seal is incomplete, there is a risk that the particles will lose moisture and become over-dried. If the relative humidity exceeds 60 percent and the container seal is incomplete, there is a risk that the particles will absorb moisture and the water activity will increase. The preferred relative humidity is 45 percent to 55 percent, and more preferably 48 percent to 52 percent. Humidity control is performed using a dehumidifier, a humidifier, or an air conditioning system.

[0297] The aging time is set to 12 to 48 hours. If the aging time is less than 12 hours, moisture diffusion within the particles does not proceed sufficiently, leaving a moisture gradient between the surface and the interior, which causes continuous moisture redistribution during storage. If the aging time exceeds 48 hours, the additional moisture equilibration effect is negligible, while the process time increases, leading to reduced economic efficiency. The preferred aging time is 18 to 42 hours, and more preferably 24 to 36 hours. The optimal aging time may vary depending on the particle size and structure, as well as the initial moisture distribution state.

[0298] During the aging process, the particles are kept stationary within the container. If necessary, the container may be gently rotated or inverted during aging to reposition the particles, but this is an optional operation. Generally, sufficient moisture equilibrium is achieved by aging in a stationary state within a sealed container alone. The aging space should be selected to avoid direct sunlight and minimize vibration.

[0299] The physicochemical mechanism of aging is as follows. Immediately after drying and cooling, the surface water activity of the particles is slightly lower than that of the interior. As time passes in a sealed environment, internal moisture moves to the surface by diffusion, and the water activity of the surface and the interior reaches equilibrium. Simultaneously, moisture redistribution occurs within each layer—the core layer, the coat layer, and the functional layer—resulting in a uniform water activity across all layers. This moisture equilibration improves the physical stability of the particles and prevents structural changes or performance degradation caused by moisture migration during storage.

[0300] During aging, physicochemical changes other than moisture equilibration can occur in the particles. The polymers in the coating and functional layers rearrange at the molecular level to form a more stable structure and strengthen interlayer bonding. The interactions between functional ingredients and excipients also reach equilibrium, stabilizing the crystalline or amorphous state. All of these changes have a positive impact on the quality and stability of the final product.

[0301] Final quality verification step (e7)

[0302] The final quality verification step involves measuring the water activity and moisture content of the aged particles to confirm whether the manufacturing process has been successfully completed. This is an essential step for product quality assurance and batch record management. The final water activity of the aged particles is measured to ensure it is within the range of 0.35 to 0.55, and the final moisture content is confirmed to be between 3 weight percent and 8 weight percent.

[0303] To measure the final water activity, a representative sample is taken from the aging container. A sample representative of the entire batch is obtained by taking small amounts from the top, middle, and bottom of the container and mixing them. A total sample volume of 5 to 10 grams is sufficient for measuring water activity. The collected sample is immediately transferred to a measuring container, and the lid is closed to prevent contact with outside air.

[0304] Water activity is measured using a water activity meter at 25°C. The sample is placed in the measurement chamber and allowed to stand until equilibrium is reached, which typically takes 5 to 15 minutes. Verify that the measured water activity value falls within the range of 0.35 to 0.55. If the water activity is below 0.35, the sample is over-dried; the particles are excessively hard and brittle, and tend to rapidly absorb moisture from the surrounding environment. Such batches may be reworked by relaxing the final drying conditions or adjusting the aging conditions. If the water activity exceeds 0.55, storage stability is reduced, and the risk of microbial growth and chemical degradation increases. Such batches must undergo additional drying to adjust the water activity to the target range.

[0305] The preferred final water activity range is 0.38 to 0.52, and more preferably 0.40 to 0.50. Within this range, both storage stability and immediate characteristics are optimized. The results of the water activity measurement are recorded in the batch record and included in the quality certificate at the time of product shipment.

[0306] The final moisture content is measured using the Karl Fischer titration method or the loss-on-drying method. The Karl Fischer titration method is the most accurate method for quantitatively measuring moisture, electrochemically measuring the moisture content by reacting the sample with the Karl Fischer reagent. The loss-on-drying method calculates the moisture content by drying the sample at a constant temperature and calculating the weight loss; while simple, it may also measure volatile components other than moisture. In this invention, it is preferable to use the Karl Fischer titration method.

[0307] It is checked whether the measured final moisture content is within the range of 3% to 8% by weight. If the moisture content is less than 3% by weight, it is in an over-dry state, and the physical properties of the particles become excessively hardened and brittleness increases. If the moisture content exceeds 8% by weight, there is a high risk of problems such as microbial growth, chemical decomposition, and caking occurring during storage. The preferred final moisture content is 4% to 7% by weight, and more preferably 5% to 6% by weight.

[0308] Water activity and moisture content are related but are not identical concepts. Water activity is a thermodynamic parameter representing the activity of free water within particles; it is directly related to microbial growth and chemical reactions and serves as a key management indicator for this invention. Moisture content is a physical parameter representing the total amount of moisture within particles and affects the product's weight and distribution characteristics. Since water activity can vary depending on the binding state of water even at the same moisture content, it is important to measure and manage both parameters.

[0309] In the final quality verification stage, other quality characteristics can be evaluated in addition to water activity and moisture content. Particle size distribution is measured by laser diffraction to verify whether the average particle size remains within the target range even after coating. The average particle size of multilayer particles is generally in the range of 60 micrometers to 350 micrometers, and increases slightly compared to core particles due to the coating. The content of functional raw materials is quantified using high-performance liquid chromatography or an appropriate analytical method to verify that it is within the range of 90 percent to 110 percent of the design content.

[0310] The quality of the coating layer can be evaluated through microscopic observation. By embedding a portion of the particles in epoxy resin to create a cross-section and observing it with an optical microscope or scanning electron microscope, the structure of the core layer, coat layer, and functional layer can be confirmed. It is confirmed that each layer is clearly distinguishable and formed with a uniform thickness, and that there is no delamination or cracking between layers. The thickness of the coat layer is generally in the range of 5 micrometers to 30 micrometers, and the thickness of the functional layer is in the range of 2 micrometers to 10 micrometers for the absorption-promoting type and 10 micrometers to 50 micrometers for the emission-controlled type.

[0311] Solubility characteristics must be evaluated as a key performance indicator of the present invention. The oral disintegration test involves introducing the particles into an oral simulator or artificial saliva and measuring the time at which disintegration begins. The multilayer particles of the present invention must begin disintegrating within 3 seconds. The dissolution test is performed in an aqueous solution at 37°C according to the USP or KP dissolution test method, and confirms whether at least 80 percent of the functional ingredient is dissolved within 30 seconds. These solubility characteristics are achievable only within a water activity range of 0.35 to 0.55, and this is important data proving the technical effects of the present invention.

[0312] Flowability is evaluated using indicators such as angle of repose, compressibility, and Hausner ratio. Excellent flowability ensures fillability and uniformity in subsequent formulation processes. Since the multilayer particles of the present invention have a coated surface and their water activity is adjusted to be low, they generally exhibit excellent flowability. It is preferable that the angle of repose be 35 degrees or less and the Hausner ratio be 1.25 or less.

[0313] Storage stability can be evaluated through accelerated stability testing. Particles are stored for 1 to 3 months under conditions of 40°C and 75 percent relative humidity, and the content of functional ingredients, water activity, appearance, solubility characteristics, etc., are measured periodically. Particles manufactured within the water activity range of the present invention exhibit excellent storage stability, and changes in quality are minimized even under accelerated conditions.

[0314] If the results of all quality verification tests satisfy the specifications, the batch is deemed acceptable and transferred to the next process, the formulation stage, or stored under appropriate conditions. If the results of the quality verification tests do not satisfy the specifications, the reason for non-conformity is analyzed, and quality is improved by performing rework if possible. For example, if water activity falls outside the target range, it can be adjusted through additional drying or wetting treatments. If rework is not possible, the batch is discarded.

[0315] The multilayer particles that have been finally approved are packaged in a sealed container and stored under conditions of a temperature of 20 to 25 degrees Celsius and a relative humidity of 40 to 60 percent. For long-term storage, the particles are vacuum-packed in aluminum laminated film bags or nitrogen-exchanged packaging to minimize the penetration of oxygen and moisture. Under appropriate storage conditions, the multilayer particles of the present invention can maintain their quality for at least 12 months. Information such as the manufacturing date, batch number, water activity, and functional ingredient content is displayed on the product to facilitate traceability management.

[0316] In addition, the present invention relates to a multilayer particle structure for promoting the absorption of a functional ingredient, wherein the multilayer particle structure for promoting the absorption of the functional ingredient is manufactured by a method for manufacturing the multilayer particle structure.

[0317] Hereinafter, the structure of the present invention and the resulting effects will be explained in more detail through specific embodiments and comparative examples. However, these embodiments are intended to explain the present invention more specifically, and the scope of the present invention is not limited to these embodiments.

[0318] Design of Examples and Comparative Examples

[0319] Example 1

[0320] A multilayer particle structure was prepared using Vitamin C as a functional ingredient. First, to form a core layer, a preliminary mixture was prepared by mixing 30 parts by weight of Vitamin C, 50 parts by weight of microcrystalline cellulose, and 20 parts by weight of mannitol in a mixer at 250 rpm for 10 minutes. Primary granules were formed by wet granulating at 25°C while spray-adding 25 parts by weight of purified water to 100 parts by weight of this preliminary mixture. The primary granules were first dried in a fluidized bed dryer for 20 minutes under conditions of an inlet air temperature of 50°C and an air flow rate of 50 cubic meters per hour, and secondarily dried for 40 minutes under conditions of an inlet air temperature of 60°C and an air flow rate of 35 cubic meters per hour to adjust the water activity to 0.30. The dried granules were cooled to 25°C and sieved using a vibrating sieve to select core particles with an average particle size of 150 micrometers.

[0321] To form a coating layer, 15 parts by weight of hydroxypropylmethylcellulose and 45 parts by weight of trehalose were dissolved in purified water to prepare a first coating solution with a solid content concentration of 15% by weight. 100 grams of core particles were fed into a fluid bed coater, and the first coating solution was sprayed at a spraying rate of 3.5 grams per minute under conditions of an inlet air temperature of 42°C and an air flow rate of 60 cubic meters per hour to form a coating layer with a weight increase rate of 15% by weight. After the spraying was finished, the particles were post-dried for 10 minutes at an inlet air temperature of 42°C. The particles with the formed coating layer were subjected to a first intermediate drying for 10 minutes under conditions of an inlet air temperature of 35°C and an air flow rate of 50 cubic meters per hour, a second intermediate drying for 18 minutes under conditions of an inlet air temperature of 45°C and an air flow rate of 35 cubic meters per hour, and a third intermediate drying for 10 minutes under conditions of an inlet air temperature of 50°C to adjust the water activity to 0.45. After drying, it was slowly cooled to 25°C.

[0322] To form a functional layer, a second coating solution was prepared with a solid content concentration of 10 wt% containing 5 wt% chitosan. Intermediately dried particles were reintroduced into a fluid bed coater, and the second coating solution was sprayed at a spray rate of 2.5 grams per minute under conditions of an inlet air temperature of 38°C and an air flow rate of 55 cubic meters per hour to form an absorption-promoting functional layer with a weight increase rate of 6 wt%. After the spraying was finished, the particles were post-dried for 7 minutes at an inlet air temperature of 38°C.

[0323] For final drying, the particles with the formed functional layer were subjected to a first final drying step in a fluidized bed dryer for 15 minutes under conditions of an inlet air temperature of 40°C and an air flow rate of 60 cubic meters per hour. Subsequently, a second final drying step was performed for 22 minutes under conditions of an inlet air temperature of 45°C and an air flow rate of 45 cubic meters per hour; during this process, the water activity was measured at 5-minute intervals and confirmed to have reached 0.45. A third final drying step was performed for 10 minutes under conditions of an inlet air temperature of 50°C and an air flow rate of 30 cubic meters per hour to stabilize the water activity at 0.45. The particles were cooled for 18 minutes under conditions of an inlet air temperature of 35°C and an air flow rate of 20 cubic meters per hour to adjust the particle temperature to 25°C.

[0324] The cooled particles were transferred to a sealed container and aged for 24 hours at a temperature of 23°C and a relative humidity of 50 percent. After the aging process was completed, the final water activity was measured to be 0.45, and the final moisture content was 5.2 weight percent.

[0325] Example 2

[0326] The core layer and coat layer were formed in the same manner as in Example 1, but the water activity was lowered to 0.35 by adjusting the intermediate drying conditions. Specifically, the first intermediate drying was performed for 12 minutes at an inlet air temperature of 35°C, the second intermediate drying for 25 minutes at an inlet air temperature of 48°C and an air flow rate of 30 cubic meters per hour, and the third intermediate drying for 12 minutes at an inlet air temperature of 52°C. The formation of the functional layer and post-drying were performed in the same manner as in Example 1.

[0327] During the final drying process, a second final drying was performed for 28 minutes under conditions of an inlet air temperature of 48°C and an air flow rate of 40 cubic meters per hour to adjust the water activity to 0.35. A third final drying was performed for 12 minutes under conditions of an inlet air temperature of 52°C and an air flow rate of 28 cubic meters per hour. Cooling and aging were performed in the same manner as in Example 1. After the completion of aging, the final water activity was 0.35, and the final moisture content was 4.1 weight percent.

[0328] Example 3

[0329] The core layer and coat layer were formed in the same manner as in Example 1, but the water activity was maintained at 0.55 by adjusting the intermediate drying conditions. Specifically, the first intermediate drying was performed for 8 minutes at an inlet air temperature of 33°C, the second intermediate drying for 15 minutes at an inlet air temperature of 42°C and an air flow rate of 40 cubic meters per hour, and the third intermediate drying for 8 minutes at an inlet air temperature of 45°C. The formation of the functional layer and post-drying were performed in the same manner as in Example 1.

[0330] During the final drying process, a second final drying was performed for 18 minutes under conditions of an inlet air temperature of 42°C and an air flow rate of 48 cubic meters per hour to adjust the water activity to 0.55. A third final drying was performed for 8 minutes under conditions of an inlet air temperature of 46°C and an air flow rate of 32 cubic meters per hour. Cooling and aging were performed in the same manner as in Example 1. After the completion of aging, the final water activity was 0.55, and the final moisture content was 6.5 weight percent.

[0331] Comparative Example 1

[0332] The core layer and coat layer were formed in the same manner as in Example 1, but the water activity was lowered to 0.25 by strengthening the intermediate drying conditions. Specifically, the first intermediate drying was performed for 15 minutes at an inlet air temperature of 38°C, the second intermediate drying for 35 minutes at an inlet air temperature of 52°C and an air flow rate of 25 cubic meters per hour, and the third intermediate drying for 15 minutes at an inlet air temperature of 58°C. The formation of the functional layer and post-drying were performed in the same manner as in Example 1.

[0333] During the final drying process, a second final drying was performed for 35 minutes under conditions of an inlet air temperature of 50°C and an air flow rate of 38 cubic meters per hour to adjust the water activity to 0.25. A third final drying was performed for 15 minutes under conditions of an inlet air temperature of 54°C and an air flow rate of 26 cubic meters per hour. Cooling and aging were performed in the same manner as in Example 1. After the completion of aging, the final water activity was 0.25, and the final moisture content was 2.8 weight percent.

[0334] Comparative Example 2

[0335] The core layer and coat layer were formed in the same manner as in Example 1, but the intermediate drying conditions were relaxed to maintain the water activity at 0.60. Specifically, the first intermediate drying was performed for 6 minutes at an inlet air temperature of 32°C, the second intermediate drying for 12 minutes at an inlet air temperature of 38°C and an air flow rate of 45 cubic meters per hour, and the third intermediate drying for 5 minutes at an inlet air temperature of 40°C. The formation of the functional layer and post-drying were performed in the same manner as in Example 1.

[0336] During the final drying process, a second final drying was performed for 12 minutes under conditions of an inlet air temperature of 38°C and an air flow rate of 50 cubic meters per hour to adjust the water activity to 0.60. A third final drying was performed for 5 minutes under conditions of an inlet air temperature of 42°C and an air flow rate of 35 cubic meters per hour. Cooling and aging were performed in the same manner as in Example 1. After the completion of aging, the final water activity was 0.60, and the final moisture content was 7.8 wt percent.

[0337] Comparative Example 3

[0338] The core layer and coat layer were formed in the same manner as in Example 1, but the intermediate drying conditions were further relaxed to maintain the water activity at 0.70. Specifically, the first intermediate drying was performed for 5 minutes at an inlet air temperature of 30°C, the second intermediate drying for 8 minutes at an inlet air temperature of 35°C and an air flow rate of 48 cubic meters per hour, and the third intermediate drying for 3 minutes at an inlet air temperature of 38°C. The formation of the functional layer and post-drying were performed in the same manner as in Example 1.

[0339] During the final drying process, a second final drying was performed for 8 minutes at an inlet air temperature of 35°C and an air flow rate of 52 cubic meters per hour to adjust the water activity to 0.70. A third final drying was performed for 3 minutes at an inlet air temperature of 38°C and an air flow rate of 38 cubic meters per hour. Cooling and aging were performed in the same manner as in Example 1. After the completion of aging, the final water activity was 0.70, and the final moisture content was 9.2 weight percent.

[0340] Comparative Example 4

[0341] A single-layer particle was prepared in which only the core layer was formed and the coat layer and functional layer were not formed. The core particle was prepared using the same method as in Example 1, but the drying conditions were adjusted to adjust the final water activity to 0.45. The core particle was stored in a sealed container as is without a coating process.

[0342] Water activity measurement and disintegration test

[0343] Experimental method

[0344] Water activity measurement

[0345] Water activity was measured for each of the multilayer particles prepared in Examples 1 to 3 and Comparative Examples 1 to 4. Approximately 5 grams of each sample was placed in the measurement chamber of a water activity meter and allowed to stand at 25°C until equilibrium was reached, after which the water activity value was recorded. The measurement was repeated three times for each sample, and the average value was calculated.

[0346] Disintegration test

[0347] To evaluate oral disintegration characteristics, a disintegration test was performed using artificial saliva. The artificial saliva was prepared by dissolving 0.4 grams of sodium chloride, 0.4 grams of potassium chloride, 0.795 grams of calcium chloride, 0.78 grams of sodium dihydrogen phosphate, and 0.005 grams of disodium hydrogen phosphate in 1 liter of purified water and adjusting the pH to 6.8. 200 milliliters of artificial saliva were placed in a beaker and maintained at 37°C. 1 gram of multilayer particles of each sample was added to the artificial saliva, and a timer was started. While gently stirring with a glass rod, the disintegration onset time was recorded by visually observing when the particles began to disintegrate. Disintegration onset was defined as the point at which the outer layer of the particles separates and the contents begin to disperse. The experiment was repeated five times for each sample, and the average value was calculated.

[0348] Experimental results

[0349] division Water activity Disintegration onset time (seconds) Example 1 0.45 2.4 Example 2 0.35 2.8 Example 3 0.55 2.6 Comparative Example 1 0.25 14.2 Comparative Example 2 0.60 4.8 Comparative Example 3 0.70 7.5 Comparative Example 4 0.45 18.5

[0350] Analysis results

[0351] As a result of measuring water activity, it was confirmed that Examples 1 to 3 were all accurately controlled within the target range of 0.35 to 0.55. On the other hand, Comparative Example 1 was 0.25, which was lower than the target range, and Comparative Examples 2 and 3 exceeded the target range with values ​​of 0.60 and 0.70, respectively. Comparative Example 4 had an appropriate water activity of 0.45, but it was a single-layer particle without a multilayer structure.

[0352] As a result of the disintegration test, all of Examples 1 to 3 began to disintegrate within 3 seconds; specifically, Example 1 showed a disintegration initiation time of 2.4 seconds, Example 2 2.8 seconds, and Example 3 2.6 seconds. This demonstrates that multilayer particles prepared within a water activity range of 0.35 to 0.55 rapidly disintegrate upon contact with body fluids when administered into the oral cavity, causing explosive hydration. Although the slight differences in disintegration times between the examples appear to be due to slight differences in water activity, all satisfied the goal of being within 3 seconds.

[0353] Comparative Example 1 exhibited a long disintegration time of 14.2 seconds due to an excessively low water activity of 0.25. This was because the particles became excessively hard and dense due to over-drying, which delayed the penetration of body fluids. Additionally, the over-dried particles showed a slow rate of water penetration from the surface to the interior, and the hydration rate was significantly reduced due to a weak osmotic driving force resulting from extremely low free water content inside. When observed visually, the particles of Comparative Example 1 appeared to have a very hard surface and powder aggregation, which is a typical over-drying phenomenon observed at a water activity of less than 0.35.

[0354] Comparative Example 2 had a water activity of 0.60, which slightly exceeded the target range, and the disintegration onset time was 4.8 seconds, which was slightly slower than the Examples but faster than Comparative Example 1. At a water activity of 0.60, the amount of free water within the particles increases, causing aggregation or caking between particles to begin during storage, which is believed to delay disintegration. Additionally, it appears that the rate of body fluid penetration decreased slightly due to structural changes in the coat layer caused by the high water activity.

[0355] Comparative Example 3 exhibited an excessively high water activity of 0.70, resulting in a disintegration time of 7.5 seconds. This is because more pronounced caking and structural changes occurred compared to Comparative Example 2. At a water activity level of 0.70, the risk of microbial growth increases, and chemical decomposition reactions are accelerated, significantly reducing storage stability. When observed visually, the particles of Comparative Example 3 showed a tendency for the surface to be slightly sticky, and partial fusion between particles was observed.

[0356] Comparative Example 4 had a water activity of 0.45, identical to Example 1, but exhibited a very long disintegration time of 18.5 seconds as a single-layer structure without a coat layer or a functional layer. This clearly demonstrates that the multilayer structure of the present invention is essential for improving disintegration characteristics. In a single-layer structure, even if the water activity is appropriate, rapid hydration does not occur upon contact with body fluids due to the absence of a coat layer composed of a hydrophilic polymer, and there is no effect of increasing mucosal permeability due to the absence of a functional layer containing an absorption promoter. The results of Comparative Example 4 show that controlling water activity alone is insufficient and that a three-layer functional differentiation structure is essential.

[0357] Through a comparison of Examples 1 to 3 and Comparative Examples 1 to 3, it was clearly proven that a range of water activity of 0.35 to 0.55 has critical significance. If the water activity falls outside this range, the disintegration time increases rapidly, making it impossible to achieve the target disintegration within 3 seconds. In particular, problems caused by excessive drying occur at a water activity below 0.35, and problems caused by excessive wetting occur at a water activity above 0.55, both of which degrade disintegration performance. Although Examples 1 to 3 all exhibited excellent disintegration characteristics, it is determined that the water activity of 0.45 in Example 1 provides the most stable results as an intermediate value.

[0358] Dissolution test

[0359] Experimental method

[0360] A dissolution test was performed on each of the multilayer particles prepared in Examples 1 to 3 and Comparative Examples 1 to 4. A pH 6.8 phosphate buffer solution was used as the test solution and maintained at 37°C. 900 milliliters of the test solution were placed in a beaker and stirred at 100 rpm using a magnetic stirrer. An amount of the multilayer particles of each sample equivalent to 100 milligrams of Vitamin C was accurately weighed and added to the test solution, and a timer was started. At 30 seconds, 1 minute, 2 minutes, 5 minutes, and 10 minutes after addition, 5 milliliters of the test solution were collected, and an equal amount of fresh test solution was immediately added. The collected samples were filtered, and the Vitamin C concentration was quantified by measuring the absorbance at 265 nanometers using a UV spectrophotometer. The dissolution rate was calculated using a previously prepared calibration curve. The experiment was repeated three times for each sample, and the average value was calculated.

[0361] Experimental results

[0362] division 30-second dissolution rate (%) 1-minute dissolution rate (%) 2-minute dissolution rate (%) 5-minute dissolution rate (%) 10-minute dissolution rate (%) Example 1 87.5 94.2 98.5 99.8 99.9 Example 2 82.3 91.8 97.2 99.5 99.9 Example 3 85.1 93.5 98.1 99.7 99.9 Comparative Example 1 43.2 65.8 82.5 95.3 98.8 Comparative Example 2 76.8 88.5 95.2 98.9 99.7 Comparative Example 3 64.5 81.2 91.8 97.5 99.2 Comparative Example 4 38.5 58.2 75.8 91.5 97.2

[0363] Analysis results

[0364] As a result of the dissolution test, Examples 1 to 3 all achieved a dissolution rate of 80 percent or more within 30 seconds; specifically, Example 1 showed a 30-second dissolution rate of 87.5 percent, Example 2 82.3 percent, and Example 3 85.1 percent. This result satisfies the objective of the present invention, which is to achieve a dissolution rate of 80 percent or more within 30 seconds. The examples showed a dissolution rate of 90 percent or more at the 1-minute mark and 97 percent or more at the 2-minute mark, demonstrating a very rapid and complete dissolution profile. It is believed that Example 1 exhibiting the highest 30-second dissolution rate is due to the fact that a water activity of 0.45 is the intermediate value that optimizes the hydration and disintegration rates of the coat layer.

[0365] The rapid dissolution of the examples is directly related to the explosive hydration phenomenon achieved within a water activity range of 0.35 to 0.55. When the multilayer particles come into contact with the test solution, the hydrophilic polymer of the coating layer rapidly hydrates and swells; during this process, an osmotic driving force acts to rapidly disintegrate the particles. Simultaneously with disintegration, Vitamin C from the core layer is released, and the chitosan of the functional layer provides the effect of increasing mucosal permeability. This complex mechanism results in an excellent dissolution rate of over 80 percent within 30 seconds.

[0366] Comparative Example 1 showed a dissolution rate of only 43.2 percent at 30 seconds, remaining at half the level of the Examples. This is because, in an over-dried state with a water activity of 0.25, the coating layer was excessively dense and hard, delaying the penetration of the test solution and significantly reducing the hydration rate. Comparative Example 1 showed a dissolution rate of 82.5 percent even at the 2-minute mark, exhibiting a dissolution rate more than four times slower than that of the Examples. Over-dried particles form a dense film on their surface, which limits the rate at which internal Vitamin C diffuses to the outside; this is expected to lead to a decrease in the absorption rate in vivo.

[0367] Comparative Example 2 had a 30-second dissolution rate of 76.8 percent, which was lower than that of the Examples but significantly higher than that of Comparative Example 1. At a water activity of 0.60, the large amount of free water within the particles causes structural changes during storage, which is believed to cause a slight decrease in the dissolution rate. However, since the hydrophilicity remains high and hydration occurs relatively quickly, the dissolution is not extremely slow. The problem with Comparative Example 2 lies in storage stability and the risk of microbial growth rather than the dissolution rate.

[0368] Comparative Example 3 had a 30-second dissolution rate of 64.5 percent, which was lower than that of Comparative Example 2. In a highly wet state with a water activity of 0.70, inter-particle aggregation and caking are intensified, and the particles tend to maintain a lumpy state when introduced into the test solution; this reduces the surface area and delays dissolution. Additionally, it appears that further hydration swelling is limited because the polymers in the coating layer are already partially plasticized due to the high moisture content.

[0369] Comparative Example 4 had the lowest 30-second dissolution rate at 38.5 percent, which once again demonstrates the importance of the multilayer structure. Even if the water activity is adequate, single-layer core particles have a slow hydration rate due to the absence of a hydrophilic coating layer and a limited dissolution rate due to the absence of an absorption-promoting functional layer. Comparative Example 4 only reached a dissolution rate of 97.2 percent at the 10-minute mark, which was much longer than the time taken to reach complete dissolution in the Examples.

[0370] When comprehensively comparing the elution profiles of Examples 1 to 3 and Comparative Examples, it is clear that the goal of eluting more than 80 percent within 30 seconds can be achieved only when both a water activity range of 0.35 to 0.55 and a three-layer structure are satisfied. If the water activity falls outside this range or if there is no multi-layer structure, the elution rate decreases significantly. Although the minor differences between the examples are attributed to minor differences in water activity, all exhibited excellent performance satisfying the target. In particular, the water activity of 0.45 in Example 1 provided the highest 30-second elution rate and was determined to be the optimal value; Examples 2 and 3 also showed excellent performance within the range, proving that the entire water activity range of the present invention is valid.

[0371] The results of the dissolution test showed a high correlation with the results of the disintegration test. Samples that disintegrated faster also exhibited faster dissolution, suggesting that disintegration is the rate-limiting step of dissolution. The multilayer particles of the present invention form a large surface area through rapid disintegration, and Vitamin C is rapidly released from therefrom, which is expected to provide rapid absorption and high bioavailability in vivo.

Claims

Claim 1 A method for manufacturing a multilayer particle structure for promoting the absorption of functional raw materials comprises forming a core layer, forming a coat layer containing a hydrophilic polymer, forming a functional layer containing an absorption promoter, and drying to adjust water activity; wherein the formation of the core layer involves mixing 10 to 60 parts by weight of a functional raw material with 40 to 90 parts by weight of a core-forming excipient composed of microcrystalline cellulose and mannitol, wet-granulating the mixture, and then drying to adjust the water activity to 0.25 to 0.35; wherein the hydrophilic polymer is hydroxypropylmethylcellulose; wherein the formation of the coat layer involves preparing a first coating solution by dissolving the hydroxypropylmethylcellulose and trehalose, which is a water activity regulator, such that the combined solid content concentration thereof is 5% to 25% by weight, and performing fluid bed coating thereof; wherein the absorption promoter is chitosan; and wherein the formation of the functional layer involves 1% to 10% by weight of the chitosan relative to the total weight of the second coating solution. A method for manufacturing a multilayer particle structure, wherein the water activity adjustment drying comprises: a step of first final drying the particles formed with the functional layer under conditions of an inlet air temperature of 35°C to 45°C; a step of measuring the water activity of the particles that were first final dried, and if the measured water activity is within the range of 0.45 to 0.60, raising the inlet air temperature to 40°C to 50°C to perform second final drying; a step of measuring the water activity at intervals of 3 to 7 minutes during the second final drying; and a step of third final drying while maintaining the inlet air temperature at 45°C to 55°C when the measured water activity reaches the range of 0.35 to 0.55; thereby adjusting the water activity of the multilayer particle structure to a range of 0.35 to 0.

55. Claim 2 A method for manufacturing a multilayer particle structure according to claim 1, comprising: (a) a core layer forming step of forming core particles with an average particle size of 50 μm to 300 μm by mixing and granulating a functional raw material and an excipient, and drying the core particles to adjust the water activity to 0.35 or less; (b) a step of forming a coat layer by spraying a first coating solution containing a hydrophilic polymer onto the core particles using a fluid bed coating method; (c) an intermediate drying step of drying the particles with the formed coat layer to adjust the water activity to 0.35 to 0.55; (d) a step of forming a functional layer by spraying a second coating solution containing an absorption promoter onto the particles that have undergone the intermediate drying step; and (e) a step of finally drying the particles with the formed functional layer to maintain the water activity of the multilayer particle structure in the range of 0.35 to 0.

55. Claim 3 In paragraph 2, the above step (a) is a step of mixing 10 to 60 parts by weight of a functional raw material and 40 to 90 parts by weight of a core-forming excipient, adding 10 to 40 parts by weight of a binder, wet granulating, then first drying at 40°C to 60°C and second drying at 50°C to 70°C to adjust the water activity to 0.25 to 0.35, and cooling and sieving to form core particles with an average particle size of 50μm to 300μm, and the above step (b) is a step of preparing a first coating solution having a solid content concentration of 5% to 25% by weight based on the combined weight of the hydrophilic polymer and the water activity regulator by dissolving a hydrophilic polymer and a water activity regulator, and fluid bed coating under conditions of an inlet air temperature of 35°C to 50°C and a spray speed of 0.5g / min to 5g / min to form a total of core particles before the start of spraying. The step of forming a coat layer with a weight increase rate of 5% to 25% by weight based on weight and post-drying; the step (c) is a step of adjusting the water activity of the particles with the formed coat layer to 0.35 to 0.55 by performing a first intermediate drying at an inlet air temperature of 30°C to 40°C, a second intermediate drying at 40°C to 50°C, and a third intermediate drying at 45°C to 55°C in stages, and stabilizing the coat layer structure by slow cooling to 20°C to 30°C; the step (d) is a step of preparing a second coating solution containing 1% to 10% by weight of an absorption promoter based on the total weight of the second coating solution and having a solid content concentration of 3% to 20% by weight based on the total weight of the second coating solution, an inlet air temperature of 30°C to 55°C, and a spray rate of 0.A method for manufacturing a multilayer particle structure, characterized in that the method comprises: a step of forming a functional layer with a weight increase rate of 2% to 25% based on particle weight after completing step (c) by fluid bed coating under conditions of 3g / min to 4g / min, and post-drying; and the step (e) comprises performing a first final drying at an inlet air temperature of 35°C to 45°C, a second final drying at 40°C to 50°C, and a third final drying at 45°C to 55°C to stabilize the water activity to 0.35 to 0.55, cooling to 20°C to 30°C, and then aging for 12 to 48 hours at 20°C to 25°C and relative humidity of 40% to 60% to adjust the final moisture content to 3% to 8% by weight.

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