Delayed-release micropellet particles containing γ-aminobutyric acid

Abstract

Delayed-release micropellet particles containing γ-aminobutyric acid, characterized in that it comprises a pellet core and a coating layer surrounding the pellet core, wherein the pellet core contains a physiologically active substance, the physiologically active substance being gamma-aminobutyric acid; the pellet core comprises, calculated in parts by weight, the following components: 15 to 40 parts of gamma-aminobutyric acid, 30 to 55 parts of a filler, 1 to 30 parts of a lubricant, 0.5 to 5 parts of an anti-caking agent; wherein the filler comprises at least one of microcrystalline cellulose, powdered cellulose, starch and its derivatives, hydroxypropyl cellulose, hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, sugar or sugar alcohols and solid fruit and vegetable drinks; wherein the lubricant comprises at least one of talc, magnesium stearate, stearic acid, glycerol and leucine; wherein the anti-caking agent comprises at least one of magnesium carbonate, tricalcium phosphate, dicalcium phosphate and silicon dioxide.

Description

Technical field

[0001] The present invention falls within the technical field of food supplements and specifically relates to a delayed-release micro-pellet particle containing γ-aminobutyric acid. State of the art

[0002] GABA (gamma-aminobutyric acid) is an important inhibitory neurotransmitter in the central nervous system of the human body. It has a calming, anxiolytic, and sleep-inducing effect. At the same time, it can participate in physiological processes such as the regulation of blood pressure and the reduction of blood ammonia, and is widely used in the fields of pharmaceuticals and functional foods.

[0003] To prolong the duration of action of GABA in the body, improve adherence to dosage, and achieve stable plasma concentrations, the development of an oral, sustained-release formulation is an important technical direction. Among these, the multi-component drug-release system (such as delayed-release micropellets) is considered the ideal dosage form due to its ability to avoid the risk of "sudden release" that can occur with single-component preparations (e.g., tablets), as well as its lower impact on gastrointestinal emptying and its relatively stable bioavailability.

[0004] The successful production of high-quality, delayed-release micropellets from GABA, however, faces a number of significant technical challenges, primarily stemming from the physicochemical properties of the GABA feedstock itself: First, its high hygroscopicity and poor flowability. GABA is highly hygroscopic, tending to absorb moisture from the air and clump, resulting in a large angle of repose and extremely poor flowability. This not only leads to uneven mixing with additives but also easily causes bridging and blockages in subsequent process steps such as feeding and conveying, significantly impacting production continuity and dosing accuracy. Second, adhesion and shaping issues: GABA powder exhibits a degree of stickiness.During wet granulation or extrusion processes, it has a strong tendency to adhere to the inner walls of equipment, screen plates, and the surface of the spheronization vessel. This frequently leads to breakage of the extrusion strands, problems with the transport of the soft material, and, during spheronization, to severe agglomeration of the micropellets or the formation of excessive amounts of fine dust, ultimately resulting in poor micropellet roundness, a wide particle size distribution, and low product yield. Thirdly, temperature or heat sensitivity: GABA can decompose at elevated temperatures, and process steps such as drying and coating in micropellet production inevitably involve heating. If the process is not properly controlled, particularly if locally excessive material temperatures occur, this can lead to GABA inactivation and impair the efficacy of the final product.

[0005] Existing micropellet manufacturing techniques, such as the conventional extrusion-spheronization process, often prove ineffective when applied to GABA. Conventional extrusion techniques, when applied to GABA, frequently lead to problems with extrudate shape. During the extrusion-spheronization process, using a single rotational speed for both extrusion and spheronization makes precise control of the micropellets' plastic deformation from a strand-like to a spherical shape difficult. This easily results in a wide particle size distribution (high span value) and uneven micropellet roundness, which in turn negatively impacts the uniformity of the subsequent coating membrane and the consistency of the drug release in the final product. The invention and its advantages

[0006] To overcome the problems and shortcomings of the prior art, the present invention provides a delayed-release micro-pellet containing gamma-aminobutyric acid (GABA). This delayed-release micro-pellet effectively solves the problems of GABA's easy agglomeration and difficult shaping through a rational design of the mixing ratio of the individual components, significantly improves the moldability and uniformity of the preparation, overcomes the disadvantage of the easy agglomeration of traditional delayed-release preparations during the shaping process, promotes the assurance of stable release and effective absorption of GABA, and increases the bioavailability and efficacy of the active ingredient.

[0007] According to a first aspect of the present invention, a delayed-release micropellet particle containing γ-aminobutyric acid is provided, comprising a pellet core and a coating layer surrounding the pellet core, wherein the pellet core contains a physiologically active substance, the physiologically active substance being gamma-aminobutyric acid; the pellet core comprises, calculated in parts by weight, the following components: 15 to 40 parts gamma-aminobutyric acid, 30 to 55 parts of a filler, 1 to 30 parts of a lubricant, 0.5 to 5 parts of an anti-caking agent; wherein the filler comprises at least one of microcrystalline cellulose, powdered cellulose, starch and its derivatives, hydroxypropyl cellulose, hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, sugar or sugar alcohols, and solid fruit and vegetable beverages;wherein the lubricant comprises at least one of talc, magnesium stearate, stearic acid, glycerol, and leucine; wherein the anti-caking agent comprises at least one of magnesium carbonate, tricalcium phosphate, dicalcium phosphate, and silicon dioxide. In the pellet core described above, the gamma-aminobutyric acid may, for example, be in 15, 17, 20, 22, 25, 28, 30, 32, 35, 38, or 40 parts; the filler may, for example, be in 30, 32, 35, 38, 40, 42, 45, 48, 50, 52, or 55 parts; The lubricant may, for example, be in the proportion of 1 part, 3 parts, 5 parts, 8 parts, 10 parts, 12 parts, 15 parts, 18 parts, 20 parts, 22 parts, 25 parts, 28 parts, or 30 parts; the anti-caking agent may, for example, be in the proportion of 0.5 parts, 0.9 parts, 1 part, 2 parts, 3 parts, 3.5 parts, 4 parts, or 5 parts;The raw materials mentioned above are not limited to the listed numerical values; other, unlisted numerical values ​​within the ranges are equally applicable. Regarding solid fruit and vegetable drinks, their definition refers to GB / T 29602-2013 Solid Beverages, Section 4.2 Solid Fruit / Vegetable Drinks: a solid beverage produced mainly from fruit and / or vegetables (including edible roots, stems, leaves, flowers, fruits) or their products as the main raw material, with or without the addition of other food raw materials and food additives.

[0008] In the delayed-release micro-pellet particles containing γ-aminobutyric acid provided by the present invention, a targeted excipient design for the physiologically active ingredient gamma-aminobutyric acid was implemented, namely the selection of the specific excipient combination "filler + lubricant + anti-caking agent" as described above. This effectively solves the problems of the easy agglomeration and difficult shaping of GABA, significantly improves the formability and uniformity of the preparation, and promotes the stable release and effective absorption of GABA.

[0009] Specifically, the aforementioned control of the GABA content ensures effective dosing and avoids shaping problems and loss of strength that could be caused by an excessively high active ingredient content. This facilitates the production of a pellet core with a dense structure and smooth surface, providing an ideal base for the subsequent uniform coating with the sustained-release layer, thus ensuring the integrity of the coating membrane and the consistency of the release behavior.

[0010] The selected celluloses, as well as cellulose derivatives, starches, and starch derivatives, etc., act as fillers and develop appropriate stickiness and plasticity upon moistening. They function as an endogenous binder, giving the resulting soft material good cohesion and extrudability, i.e., good formability. Furthermore, the aforementioned control of the filler content ensures that the filler is sufficient to build a stable pellet core structure and provide the necessary mechanical strength (low brittleness) to withstand subsequent processing steps such as drying, coating, and transport.

[0011] The selected lubricants can form a lubricating layer between the material and the metal surface of the equipment, precisely controlling the adhesive force and effectively preventing the soft material from sticking to the screen plates and the spheronization vessel during the extrusion process. This avoids strand breakage, pore clogging, and agglomeration of pellet core particles. Furthermore, the lubricant, in the specified quantity, can act synergistically with the filler, enabling the successful production of round pellet core particles using extrusion spheronization technology even without the addition of conventional binders.

[0012] The selected anti-caking agents can further improve the overall flowability of the mixture and effectively address the problem of slight GABA agglomeration, thus meeting the process engineering requirements for uniform mixing and precise dosing for subsequent steps. Furthermore, the anti-caking agent, in the specific quantity, can act synergistically with the lubricant and increase the stability of the entire process.

[0013] Ultimately, the overall system, comprised of four components—gamma-aminobutyric acid, filler, lubricant, and anti-caking agent—in the specified weight proportions, ensures good material flowability, controllable adhesion, and high stability throughout the entire manufacturing process through the synergistic interaction of the individual raw materials. This results in micropellet cores with high roundness, a narrow particle size distribution, and low brittleness, exhibiting excellent powder-technological properties. This, in turn, promotes the stable release and effective absorption of GABA and increases the bioavailability and efficacy of the active ingredient.

[0014] Specifically, the rounding of the micropellet core (pellet core) produced according to the present invention is as follows: If the maximum and minimum diameters of the pellet core are defined as D1 and D2, respectively, then the proportion W1 of the pellet cores that meet D1 / D2 ≤ 1.5 is W1 ≥ 90%. Firstly, this ensures that each micropellet core has a similar geometric shape and surface. When a delayed-release coating is subsequently applied, this provides an ideal physical basis for the formation of a uniformly thick, continuous, and dense coating membrane on the pellet core surface. This ensures that the release rate of GABA from each micropellet particle is highly consistent, thereby fundamentally avoiding release variations due to particle shape differences and improving the reliability and predictability of the delayed-release effect.Secondly, spherical or near-spherical particles exhibit the best flowability. This property allows the micropellet cores to flow evenly and smoothly in subsequent process steps such as coating or filling, reducing blockages and segregation during production and thus increasing production efficiency and dosing accuracy.

[0015] The narrow particle size distribution of the micropellet core (pellet core) produced according to the present invention is characterized by a particle size distribution range of ≤ 2.0. The high uniformity of the pellet core size facilitates achieving a more uniform coating membrane thickness during the fluidized bed coating process. This ensures that the drug release behavior of each individual micropellet particle, and even of the entire batch, is highly consistent, significantly improving the stability and reproducibility of the delayed-release effect. Simultaneously, a narrow particle size distribution can further enhance the bulk material flowability, facilitating transport, dosing, and filling during the production process.

[0016] The low brittleness of the micropellet core (pellet core) produced according to the present invention is demonstrated by a brittleness of ≤ 1.5%. This indicates that the pellet core possesses good mechanical strength and a dense structure, enabling it to effectively withstand the mechanical stresses and friction that arise during subsequent processes such as encapsulation, packaging, and transport, thus preventing the generation of fine dust due to breakage. This not only ensures the yield and appealing appearance of the final product but, more importantly, prevents problems such as dosing inconsistencies or encapsulation defects (fine dust can adhere and damage the encapsulation membrane) that can be caused by the generation of fine dust. This facilitates industrial production and long-term storage stability.

[0017] Furthermore, the formulation system for the delayed-release micropellet particles, consisting of four components—gamma-aminobutyric acid, filler, lubricant, and anti-caking agent—allows for the elimination or reduction of the use of temperature- or heat-sensitive binders. The entire system also helps to protect the activity of GABA during subsequent drying and coating processes.

[0018] In one embodiment, the pellet core, calculated as mass percent, comprises the following components: 15 to 40% gamma-aminobutyric acid (GABA), 30 to 55% filler, 1 to 30% lubricant, and 0.5 to 5% anti-caking agent. In the pellet core described above, the GABA content may be, for example, 15%, 17%, 20%, 22%, 25%, 28%, 30%, 32%, 35%, 38%, or 40%; the filler may be, for example, 30%, 32%, 35%, 38%, 40%, 42%, 45%, 48%, 50%, 52%, or 55%; the lubricant may be, for example, 1%, 3%, 5%, 8%, 10%, 12%, 15%, 18%, 20%, 22%, 25%, 28%, or 30%. The anti-caking agent can be, for example, 0.5%, 0.9%, 1%, 2%, 3%, 3.5%, 4%, or 5%; the raw materials mentioned above are not limited to the listed numerical values, other, unlisted numerical values ​​within the numerical ranges are equally applicable.

[0019] In one embodiment, the pellet core comprises 25 to 40 parts of gamma-aminobutyric acid, calculated in parts by weight. In another embodiment, the pellet core comprises 28 to 35 parts of gamma-aminobutyric acid, calculated in parts by weight.

[0020] In one embodiment, the pellet core comprises 40 to 55 parts of filler, calculated in parts by weight. In another embodiment, the pellet core comprises 45 to 55 parts of filler, calculated in parts by weight. In yet another embodiment, the pellet core comprises 50 to 55 parts of filler, calculated in parts by weight.

[0021] In one embodiment, the pellet core comprises 10 to 30 parts of lubricant, calculated in parts by weight. In another embodiment, the pellet core comprises 15 to 25 parts of lubricant, calculated in parts by weight.

[0022] In one embodiment, the pellet core comprises, calculated in parts by weight, 0.5 to 4 parts of anti-caking agent. In another embodiment, the pellet core comprises, calculated in parts by weight, 0.9 to 3.5 parts of anti-caking agent.

[0023] In one embodiment, the filler comprises at least one sugar or sugar alcohol consisting of erythritol, lactose, sorbitol, isomalt, mannitol, stachyose and xylitol; and / or the fruit and vegetable powder comprises at least one sweet orange powder, dragon fruit powder and honey pear powder.

[0024] In one embodiment, the filler comprises at least one of microcrystalline cellulose, mannitol, and honey pear powder; and / or the lubricant comprises at least one of talc and stearic acid; the anti-caking agent comprises at least one of dicalcium phosphate and silicon dioxide. The selection of the above-mentioned materials as fillers can not only effectively ensure that the delayed-release micropellet particles exhibit high mechanical strength, but also effectively improve the adhesion and shape retention of GABA. This further facilitates the production of micropellet cores with high roundness, a narrow particle size distribution, and excellent mechanical properties. Moreover, the overall composition promotes the protection of GABA activity during the subsequent low-temperature coating process, thus ensuring the reliability and efficacy of the delayed-release micropellet particles.

[0025] In one embodiment, the filler is selected from at least one of microcrystalline cellulose and mannitol; the lubricant is selected from at least one of talc and stearic acid; the anti-caking agent comprises dicalcium phosphate and / or silicon dioxide. In another embodiment, the filler comprises microcrystalline cellulose and mannitol; the lubricant comprises talc and stearic acid; the anti-caking agent comprises dicalcium phosphate and / or silicon dioxide. Furthermore, the separate selection of the aforementioned materials for filler, lubricant, and anti-caking agent is advantageous for the functional complementarity and synergistic effect of the individual components. This therefore promotes a more effective improvement of problems such as adhesion, pore clogging, and agglomeration of the GABA-soft material in the subsequent, crucial steps of heat-generated extrusion and spheronization.It ensures the continuity of the process and the roundness of the micro-pellet particles, further promotes the optimization of the retardation properties, the uniformity and stability of the preparation, and improves the clinical application effect and the range of application of the preparation.

[0026] In one embodiment, the delayed-release micro-pellet particle further comprises a binder, wherein the binder comprises hydroxypropyl methylcellulose.

[0027] The roundness of the pellet core in the present invention is further demonstrated by the fact that the proportion of approximately spherical or spherical particles is ≥ 85%. Approximately spherical particles are defined as particles that are approximately circular.

[0028] Furthermore, in the present invention, the pellet core exhibits not only extremely high roundness but also very high surface smoothness, specifically demonstrated by the fact that the proportion of surface-smooth particles in the pellet core is ≥ 85%. Surface-smooth particles are defined as particles without any discernible elevations or depressions on their surface.

[0029] Thus, further improving the aforementioned roundness and surface smoothness enhances the stability of subsequent process steps, such as the coating of the pellet core, ensures a uniform and stable coating layer, and can thereby further optimize the stability and reproducibility of the delayed-release effect of the micropellet particles. At the same time, the smooth surface further increases the flowability of the particles, which improves the production efficiency of subsequent processes that require high flowability.

[0030] Furthermore, the particle size distribution range of the pellet core according to the present invention can reach ≤ 1.0, it can also reach ≤ 0.55, and even ≤ 0.5. Therefore, the particle size distribution range of the pellet core in the present invention can reach an extremely low value, which further facilitates subsequent process steps such as coating, packaging, and transport.

[0031] Furthermore, the brittleness of the coated pellet (i.e., the ultimately produced, gamma-aminobutyric acid-containing, delayed-release micropellet particle) of the present invention can reach ≤ 1.3% and can also reach ≤ 1.0%.

[0032] Furthermore, the repose angle of the pellet core of the present invention can reach ≤ 40° and can also reach ≤ 32°. The repose angle, also referred to as the angle of rest, is the minimum angle between an inclined surface and a horizontal surface at which an object placed thereon enters the critical state of incipient slippage along the incline (i.e., as the angle of inclination increases, the slippage of the object on the inclined surface becomes easier; when the object reaches the state of incipient slippage, this critical angle is referred to as the repose angle).

[0033] In one embodiment, the mass of the coating layer is 15 to 35% of the mass of the pellet core (i.e., a weight increase of 15 to 35% relative to the pellet core); and / or the coating layer comprises at least one of ethylcellulose, acrylic resin, shellac, and hydroxypropyl methylcellulose. Based on the pellet core, the coating weight increase can be, for example, 15%, 17%, 20%, 22%, 25%, 28%, 30%, 32%, or 35%, but is not limited to the values ​​listed; other values ​​within the range are equally applicable.

[0034] Furthermore, adjusting the coating weight by 15% to 35% ensures the formation of a coating layer with adequate thickness and dense structure, thus achieving a uniform, sustained, and complete release of GABA, resulting in an ideal sustained-release kinetic curve. The selected coating materials exhibit good film-forming ability and adhesion to the pellet core, further facilitating a more suitable in vitro release behavior and in vivo pharmacokinetic profile of the delayed-release micropellets.

[0035] In one embodiment, the coating layer is selected from at least one of ethylcellulose, acrylic resin and hydroxypropyl methylcellulose.

[0036] In summary, the technical solution provided by the present invention achieves the following technical effects: (1) By selecting ‘lubricant + anti-caking agent + filler’ as basic excipients, the present invention effectively solves the problems of the easy agglomeration and difficult shaping of GABA, significantly improves the malleability and uniformity of the preparation and overcomes the disadvantage of the easy agglomeration of traditional sustained-release preparations during the shaping process. (2) The sustained-release micropellet particle composition of the present invention not only improves the stability and uniformity of the preparation, but also enhances the sustained-release properties and bioavailability of the active ingredient, thus offering new therapeutic options for the treatment of various diseases. Description of the exemplary implementations

[0037] To facilitate the understanding of those skilled in the art regarding the solutions of the present invention, the technical solutions in the examples of the present invention are described clearly and completely below. Obviously, the described examples of the invention represent only a subset of the examples of the present invention and not all of them. Invention examples 1 to 12, comparative examples 1 to 12

[0038] Table 1 (Table 1-1, Table 1-2, Table 1-3, Table 1-4) shows the formulations of the respective delayed-release micropellet particles containing gamma-aminobutyric acid (GABA) in the following examples of the invention and comparative examples.

[0039] Furthermore, the process for producing the delayed-release micropellet particles with gamma-aminobutyric acid (GABA) in the respective examples of the invention and comparative examples in Table 1 comprised the following steps: S1. Production of a soft material: S11. The functional component gamma-aminobutyric acid (GABA), the food-grade lubricant, the anti-caking agent, and the filler were each sieved using an 80-mesh standard sieve to remove clumps, impurities, and coarse particles from the raw materials and to ensure a uniform particle size (≤180 µm) for each component; after sieving, all materials were placed in a mixer and mixed for 2 to 5 minutes, resulting in a homogeneous mixture. S12. A wetting agent (such as purified water, an ethanol-water solution, or an aqueous solution containing a binder, e.g., a 0.5% to 1.0% hydroxypropyl methylcellulose solution, selected according to the shaping requirements) was gradually added to the mixture. Stirring was carried out during the addition of the water and continued for 1 to 5 minutes until a uniform moist lump formed. The criterion for the endpoint of the soft material was: the moist lump could be naturally formed into a ball in the hand without any loose fine dust particles being released; when light pressure was applied to the lump with a finger, it easily broke apart into uniform particles, without a hard core and without any sticky adhesion phenomena, thus ensuring that the soft material had good plasticity and extrudability. S2. Extrusion spheronization treatment: S21. Extrusion Formation: The produced soft material was fed into the feed hopper of a screw extrusion machine. The extrusion machine's screen hole diameter was set to 0.8 mm and the extrusion speed to 16 rpm, with the feed rate adjusted to the extrusion speed (to avoid die clogging due to excessively fast feeding or strand breakage due to excessively slow feeding). The extrusion machine was started, and the soft material was forced through the screen holes, forming cylindrical extrusion strands of uniform diameter, continuous and dense under the thrust. It was ensured that the extrusion strands were free of bubbles and cavities to provide a high-quality base material for subsequent spheronization; this process step was to be carried out 2 to 3 times per cycle. S22. Multi-stage spheronization: The continuously extruded cylindrical strands (extrusion strands) were transferred directly into the spheronization chamber of the spheronization machine. Using a multi-stage process of "cutting - preliminary spheronization - fine spheronization," the micro-pellet shape was precisely controlled. First stage (cutting phase): The speed of the spherionizing machine was set to 600 to 1000 rpm (preferably 800 rpm). The rapidly rotating cutting blades cut the extruded strands into short strands of equal length. Second stage (preliminary spheronization): Maintaining a chamber temperature of 10 to 35 °C and a relative humidity of 30 to 75%, the rotational speed was set to 300 rpm. Spheronization was continued for 1 to 10 minutes, during which the cut short strands were gradually rounded under the influence of centrifugal and frictional forces, edges were removed, and preliminary, approximately spherical particles were formed. Third stage (fine spheronization): While maintaining 300 rpm, the spheronization was continued for a further 1 to 5 min to further optimize the particle shape, so that the micropellets had a smooth, burr-free surface and an almost circular profile (at this point the undried, uncoated pellets were obtained). S3. Fluidized bed drying and coating S31. Low-temperature drying: The wet, spheronized micropellets were transferred to the drying chamber of a fluidized bed dryer. The supply air temperature was set to 35–80 °C, while the material temperature was strictly controlled to 30–45 °C (to avoid inactivation of thermolabile components such as GABA). Using fluidized bed drying (i.e., the fluidized bed drying process), the micropellets were completely fluidized and uniformly heated in the hot air stream. The drying time was 5–30 minutes. The moisture content of the micropellets was monitored in real time. Once the residual moisture content of the micropellets was ≤ 5% (wet base), the drying process was stopped, resulting in dry, loose, free-flowing, uncoated micropellets (at this point, the dried, uncoated pellets were obtained). S32. Bottom Atomization Coating: After drying was complete, the fluidized state of the material in the fluidized bed was maintained, and the bottom atomization coating system was activated. The preset coating solution (e.g., an aqueous solution of a film coating premix, corresponding to the coating material in Table 1) was delivered to the bottom atomization nozzle head via a peristaltic pump. The flow rate of the coating solution was set to 1.5 to 10 rpm (adjusted to the fluidized state of the micropellets to prevent clumping at excessively high speeds or uneven coating at excessively low speeds), thereby atomizing the coating solution into fine droplets and spraying them evenly onto the fluidized micropellet surfaces.During the coating process, the material temperature was maintained at 30 to 45 °C to ensure rapid film formation of the coating solution and the development of a continuous, smooth, and dense coating layer. Following completion of the coating process, a further fluidized bed drying was performed for 5 to 10 minutes to cure the coating layer. Finally, the finished GABA-containing micropellets (i.e., delayed-release micropellet particles containing gamma-aminobutyric acid) were obtained with a flat surface, uniform coating, and good stability.

[0040] Furthermore, the uncoated micropellets (pellet cores) obtained by fluidized bed drying according to S31 were tested for roundness, particle size distribution range (span value), brittleness, and surface morphology. Subsequently, the micropellets coated according to S32 were subjected to a brittleness test. The test results are shown in Table 1, and the relevant test methods were as follows: I. Roundness 1. Preparation before the test (1) Instruments and materials

[0041] Main tools: Transmitted / reflected light polarizing microscope, microscope slide, pointed tweezers, standard shape template.

[0042] Sample request: Freshly produced sample particles were randomly selected (to avoid moisture absorption / clumping). (2) Standard shape template Degree of roundness Description of the standard form Visual reference Level 1 (Excellent) Approximately circular: contour without discernible elevations / depressions, very little difference between longitudinal and short diameters. Similar to a pea, a small marble. Level 2 (Good) Ellipsoidal: ratio of longitudinal diameter to short diameter 1.0 to 1.2, contour approximately circular. Similar to an olive (slightly flattened). Level 3 (Acceptable) Approximately round: ratio of longitudinal diameter to short diameter 1.2 to 1.5, shape relatively regular. Similar to an almond (without distinct edges). Level 4 (Unacceptable) Irregular shape: ratio of longitudinal diameter to short diameter > 1.5, and / or with deformed edges. Similar to broken rice, irregular lumps. 2. Test Method Step 1: Sample Preparation

[0043] The sample particles were carefully picked up with tweezers, placed on a microscope slide (without overlapping the particles) and put under the microscope. Step 2: Observation and comparison

[0044] The eyepiece was adjusted to focus on the particles, and their contour shape was observed. By comparison with the "standard shape template," the degree of roundness of each individual particle was determined. Level 1 (Excellent): The particle contour was uniform, with no discernible difference between longitudinal and short diameters; no “edge feeling” was perceptible during rotation. Level 2 (Good): The particles were slightly flattened, but without any discernible elevations; the visual difference between longitudinal and short diameters was small. Level 3 (Acceptable): The particles showed some difference between longitudinal and short diameters, but without sharp edges; the shape was relatively regular. Level 4 (Not acceptable): The particles were clearly deformed, had sharp edges, or the longitudinal diameter was significantly larger than the short diameter. Step 3: Results evaluation

[0045] The number and percentage of particles in each roundness grade were recorded: Roundness grade, number of particles (pieces), percentage. II. Range of particle size distribution (span value)

[0046] The range of the particle size distribution (particle size distribution) is a key parameter for describing the width of the particle size distribution and a crucial indicator for process control and quality assessment. It serves to evaluate the particle size homogeneity of extrusion spheronization particles and ensures their flowability, consistency of content, and solubility. 1. Preparation before the test(1) Preparation of equipment and materials

[0047] Main unit: A set of standard sieves (20 mesh, 40 mesh, 60 mesh, 80 mesh, according to the ISO 3310-1 standard for metal wire mesh).

[0048] Auxiliary equipment: Electronic balance (accuracy 0.001 g, traceable calibration), sample scoop, brush (soft bristles to avoid damage to the sieve mesh), sealable bag.

[0049] Sample request: A representative sample was taken. If it was lumpy dry powder, it was carefully crushed (avoiding particle breakage), passed through a pre-sieve (e.g., 1 mm sieve) to remove coarse impurities, and then sealed for later use. (2) Sieve control

[0050] Each sieve layer was checked for damage or blockages in the sieve mesh. Any remaining particles were cleaned with a soft brush. 2. Practical Implementation Steps Step 1: Assembling the Screen Layers

[0051] The sieve frames were stacked on top of each other in order of increasing mesh size: The collection tray was placed at the bottom, followed by the sieves with 850 µm (20 mesh), 425 µm (40 mesh), 250 µm (60 mesh), and 180 µm (80 mesh) mesh. The sieve lid was placed on top (ensuring that the sieve layers were well sealed and no powder could escape). Step 2: Sample weighing and loading

[0052] The mass of an empty weighing vessel was determined using an electronic balance (noted as m0). Subsequently, the pretreated sample was weighed (noted as m_total, total mass 100 g, to ensure that a detectable amount of residue was present on each sieve layer and to avoid errors due to insufficient mass).

[0053] The sample was slowly placed in the top sieve and carefully distributed evenly using the sample scoop to avoid accumulation of the sample on only one side of the sieve. Step 3: Sieving process (vibrating sieving)

[0054] Manual sieving (when a sieving machine is unavailable): The sieve stack was held with both hands and gently shaken and tapped horizontally at a frequency of approximately 20 times per minute for 5 minutes. The sieve stack was turned over every 2 minutes and lightly tapped twice to prevent clogging of the sieve mesh by particles. Step 4: Collecting and weighing the residue particles

[0055] After the sieving was completed, the individual sieve layers were carefully removed (from top to bottom to avoid any particles remaining between the layers falling down).

[0056] The particles remaining on each sieve layer were carefully brushed off with a soft brush and completely transferred to the appropriate weighing vessel (Note: The brush was only used to clean the inside of the sieve mesh to avoid contamination by external contaminants).

[0057] For each weighing vessel, including the collected residue particles, the total mass was determined using an electronic balance (noted as m1, m2, m3... corresponding to the sieve layers in descending order of mesh size). The mass of the residue particles on each sieve layer was calculated: m_i = m_i(total) - m0. Step 5: Data collection and validation

[0058] The mesh size of each sieve layer and the corresponding residue particle mass m_i were recorded. The cumulative residue mass (Σm_i) and the recovery rate were calculated: Recovery rate = (Σm_i / mtotal) × 100%.

[0059] The validation criterion was: The recovery rate had to be between 95% and 105%. If it was below 95%, this could indicate powder loss or clogged sieve meshes, and the test had to be repeated. If it was above 105%, this could indicate weighing errors or moisture absorption by the sample, which required calibration of the balance and re-pretreatment of the sample. III. Calculation of the range of the particle size distribution 1. Calculation of the cumulative mass fraction for each sieve layer

[0060] The sieve layers were sorted in order of increasing mesh size. For each sieve layer, the cumulative residue mass (Σm≤d, i.e., the total mass of particles smaller than or equal to that mesh size) was calculated.

[0061] The cumulative mass fraction w(≤d) was calculated as follows: w(≤d) = (Σm≤d / m_total) × 100 %. 2. Determination of D 10 , D 50 and D 90by interpolation

[0062] D 10 : The particle size that corresponds to a cumulative mass fraction of 10% (10% of the particles are smaller than this size).

[0063] D 50 : The particle size that corresponds to a cumulative mass fraction of 50% (median particle size).

[0064] D 90 : The particle size that corresponds to a cumulative mass fraction of 90% (90% of the particles are smaller than this size). 3. Calculation of the range of the particle size distribution

[0065] Formula: Span = (D 90 - D 10 ) / D 50 ; the result was rounded to two significant figures.

[0066] 4. Evaluation standard: Typically, a span < 1 indicates a narrow distribution, 1 to 2 a medium distribution, and > 2 a wide distribution. IV. Fragility 1. Preparation before the test Instruments and materials

[0067] Main device: Particle brittleness tester (or a modified brittleness tester with a transparent, tightly closing rotary cylinder, speed 25 to 30 rpm, cylinder inner diameter 286 mm, length 143 mm), 80-mesh sieve (mesh size typically 180 µm).

[0068] Auxiliary equipment: Electronic scale (accuracy 0.001 g, traceable calibration), weighing vessel, soft brush, sealable bag.

[0069] Sample request: A representative particle sample was taken. If clumps were present, they were carefully broken up (avoiding damage to the particles through excessive force), passed through a pre-sieve (e.g., 1 mm sieve) to remove coarse impurities, and, after thorough mixing, set aside for further use. 2. Specific Implementation Steps Step 1: Sample Weighing and Sieve Pretreatment

[0070] The mass of an empty weighing vessel was determined using an electronic balance (noted as m0). Subsequently, the pretreated particle sample was weighed (noted as m1, mass 20 g, to ensure that the amount of fine dust produced after the test is detectable).

[0071] The weighed sample was placed in the selected standard sieve (e.g., 180 µm) and gently sieved for 1 minute (only to remove any existing fine dust, not to break up the particles). The particles remaining on the sieve were collected and weighed again (recorded as m², i.e., the sample mass after removal of the initial fine dust). Step 2: Test with the brittleness tester

[0072] The particle brittleness tester was opened. All particles remaining on the sieve (mass m2) were placed in the transparent rotating cylinder of the device, and the cylinder lid was closed (ensuring a tight seal to prevent particles from falling out).

[0073] The test parameters were set as follows: rotational speed 25 rpm, test duration 10 minutes.

[0074] The device was started, the cylinder began to rotate, and the particles collided and rubbed against each other inside, creating fine dust. Step 3: Sieving and weighing after the test

[0075] After the test was completed, the device was switched off. All particles in the cylinder (including the fine dust) were carefully removed and placed in the identical standard sieve (180 µm) used in step 1.

[0076] The sieve mesh was lightly brushed and sifted with a soft brush for 2 minutes. The particles remaining on the sieve (unbroken, intact particles) were collected and placed in the weighing container.

[0077] The total mass of the weighing vessel together with the particles suspended from the sieve was determined using an electronic balance (noted as m³). The net mass of the particles suspended from the sieve was calculated: m⁴ = m³ - m⁰.

[0078] Step 4: Calculating the fragility Brittleness(%)=[(m2−m4) / m2]×100%

[0079] Explanation: m2 - m4 corresponds to the mass of the fine dust generated during the test. The proportion of this mass to the initial particle mass (m2) determines the brittleness. V. Surface Morphology 1. Preparation before the test Instruments and materials

[0080] Main tool: Transmitted / reflected light polarizing microscope.

[0081] Tools required: microscope slides, sample spoons.

[0082] Sample request: Freshly produced extrusion spheronization particles were taken. 2. Specific Implementation Steps Step 1: Sample Preparation

[0083] Using a sample spoon, an appropriate amount of particles was carefully taken and placed on a microscope slide (the particles did not overlap to avoid mutual obscuration). Step 2: Setting the observation conditions

[0084] The slide was placed on the microscope and adjusted until the surface details of the particles were clearly visible. Step 3: Observation and documentation of surface morphology

[0085] Each particle was observed sequentially according to the following dimensions and its characteristic features were recorded: a. Surface smoothness:

[0086] Classification: Smooth (no visible bumps / depressions), slightly rough (few fine pores), rough (many pores / ridges). b. Formal regularity:

[0087] Classification: Approximately spherical, ellipsoidal, irregular shape (glued / deformed). c. Defect situation:

[0088] The inspection included checking for cracks, depressions, stuck particles (several particles adhering to each other) or surface adhesions (such as unevenly distributed additives). Step 4: Results analysis and evaluation

[0089] The proportion of each characteristic among 20 observed particles was determined (e.g., "proportion of surface-smooth particles: 90%").

[0090] An evaluation was carried out in comparison with the process requirements: The requirements were “proportion of approximately spherical particles ≥ 85%, proportion of surface-smooth particles ≥ 85%, no recognizable defects”. Table 1-1 Formulations and associated test results of the invention examples and comparative examples Component (percent) Invention example 1 Invention example 2 Invention example 3 Invention example 4 Invention example 5 Invention example 6 Invention example 7 Active ingredient GABA 29.75% 32.00% 35.00% 28.00% 30.00% 33.00% 29.00% Filler Microcrystalline cellulose 49.50% 45.00% 3.00% 48.00% 45.00% / 50.00% Honey-pear powder / 3.00% / / 5.00% 2.00% / Mannitol / / 42.00% 4.00% / 40.00% / lubricant talc 19.80% / 17.00% 17.00% / 22.00% / Stearic acid / 18.00% / 2.00% 18.00% / 18.00% Anti-caking agent Dicalcium phosphate / 2.00% / / 2.00% / 2.00% silicon dioxide 0.95% / 3.00% 1.00% / 3.00% 1.00% Wrapping material Ethylcellulose; weight gain 30% Acrylic resin; weight increase 25% Hydroxypropylmethylcellulose; weight gain 28% Ethylcellulose; weight gain 30% Acrylic resin; weight increase 26% Hydroxypropylmethylcellulose; weight gain 27% Ethylcellulose; weight gain 30% Extrusion situation Uniform diameter, continuous, dense cylindrical extrusion strands, bubble-free, Uniform diameter, continuous, dense cylindrical extrusion strands, bubble-free, Uniform diameter, continuous, dense cylindrical extrusion Uniform diameter, continuous, dense cylindrical extrusion strands, bubble-free, without cavities Uniform diameter, continuous, dense cylindrical extrusion strands, bubble-free, Uniform diameter, continuous, dense cylindrical extrusion strands, bubble-free, Uniform diameter, continuous, dense cylindrical extrusion strands, bubble-free, Component (percent) Invention example 1 Invention example 2 Invention example 3 Invention example 4 Invention example 5 Invention example 6 Invention example 7 without cavities without cavities strands, bubble-free, without cavities without cavities without cavities without cavities Spheronization situation Normal Normal Normal Normal Normal Normal Normal Roundness level (proportion of levels 1+2+3) 92% 92% 91% 94% 90% 91% 93% Span value 0.48 0.51 0.50 0.47 0.53 0.52 0.49 Proportion of spherical or near-spherical particles 85% 88% 89% 92% 87% 88% 91% Proportion of surface smooth particles 92% 92% 94% 96% 90% 93% 95% brittleness 1.0% 1.2% 1.1% 0.9% 1.3% 1.2% 1.0% Table 1-2: Formulations and associated test results of the invention examples and comparative examples Component (percent) Invention example 8 Invention example 9 Invention example 10 Invention example 11 Invention example 12 Comparative example 1 Comparative example 2 Active ingredient GABA 31.00% 34.00% 15.50% 32.50% 32.50% 42.0% 13.0% Filler Microcrystalline cellulose 2.00% 44.00% 50.00% 45.00% 3.00% 25.01 % 54.01% Honey-pear powder / 2.00% / 4.00% / / / Mannitol 43.00% / 5.00% / 41.00% / / lubricant talc 21.00% / 27.00% / 20.00% / / Stearic acid / 17.00% 1.50% 16.00% / 32.0% 32.0% Anti-caking agent Dicalcium phosphate 3.00% / 1.00% / 3.50% / / silicon dioxide / 3.00% / 2.50% / 0.99% 0.99% Wrapping material Acrylic resin; weight Hydroxypropylmethylcellulose Ethylcellulose; Acrylic resin; weight Hydroxypropylmethylcell / / Component (percent) Invention example 8 Invention example 9 Invention example 10 Invention example 11 Invention example 12 Comparative example 1 Comparative example 2 ahme 29% loose; weight gain 28% Weight gain 31% ahme 26% ulose; weight gain 27% Extrusion situation Uniform diameter, continuous, dense cylindrical extrusion strands, bubble-free, without cavities Uniform diameter, continuous, dense cylindrical extrusion strands, bubble-free, without cavities Uniform diameter, continuous, dense cylindrical extrusion strands, bubble-free, without cavities Uniform diameter, continuous, dense cylindrical extrusion strands, bubble-free, without cavities Uniform diameter, continuous, dense cylindrical extrusion strands, bubble-free, without cavities The extruded strands could not be formed and fell apart in a granular fashion. The extruded strands could not be formed and fell apart in a granular fashion. Spheronization situation Normal Normal Normal Normal Normal Did not meet the sample requirements, therefore no procedure was carried out. Did not meet the sample requirements, therefore no procedure was carried out. Roundness level (proportion of levels 1+2+3) 90% 92% 93% 91% 90% Not measured Not measured Span value 0.51 0.50 0.48 0.52 0.53 Not measured Not measured Proportion of spherical or near-spherical particles 89% 90% 92% 88% 87% Not measured Not measured Proportion of surface smooth particles 92% 94% 96% 93% 91% Not measured Not measured Component (percent) Invention example 8 Invention example 9 Invention example 10 Invention example 11 Invention example 12 Comparative example 1 Comparative example 2 brittleness 1.2% 1.1% 0.9% 1.2% 1.3% Not measured Not measured Table 1-3: Formulations and associated test results of the invention examples and comparative examples Component (percent) Comparative example 3 Comparative example 4 Comparative example 5 Comparative example 6 Comparative example 7 Comparative example 8 Comparative example 9 Active ingredient GABA 42.0% 13.0% 42.0% 13.0% 22.21% 51.21% 29.75% Filler Microcrystalline cellulose 38.0% 61.2% 37.21% / / 28.0% 37.26% Honey-pear powder / / / 16.21% / / / Mannitol / / / 50.00% 57.0% / / lubricant talc 14.0% 19.80% 19.80% 19.80% 19.80% 19.80% / Stearic acid / / / / / / 32.0% Anti-caking agent Dicalcium phosphate 6.0% 6.0% / / / / / silicon dioxide / / 0.99% 0.99% 0.99% 0.99% 0.99% Wrapping material / / / / / / / Component (percent) Comparative example 3 Comparative example 4 Comparative example 5 Comparative example 6 Comparative example 7 Comparative example 8 Comparative example 9 Extrusion situation Insufficient moisture content led to the tearing of the sieve fabric; Insufficient moisture content led to the sieve fabric tearing; Uniform diameter, continuous, dense cylindrical extrusion strands, bubble-free, without cavities Uniform diameter, continuous, dense cylindrical extrusion strands, bubble-free, without cavities Uniform diameter, continuous, dense cylindrical extrusion strands, bubble-free, without cavities The extruded strands could not be formed and fell apart in a granular fashion. The extruded strands could not be formed and fell apart in a granular fashion. Spheronization situation Did not meet the sample requirements, therefore no procedure was carried out. Did not meet the sample requirements, therefore no procedure was carried out. During spheronization, the particles became increasingly larger and moister; they clumped together to form agglomerates. During spheronization, the particles became increasingly larger and moister; they clumped together to form agglomerates. During spheronization, the particles became increasingly larger and moister; they clumped together to form agglomerates. Did not meet the sample requirements, therefore no procedure was carried out. Did not meet the sample requirements, therefore no procedure was carried out. Roundness level (proportion of levels 1+2+3) Not measured Not measured Percentage of unacceptable level 4: 100% Percentage of unacceptable level 4: 100% Percentage of unacceptable level 4: 100% Not measured Not measured Span value Not measured Not measured Not measured Not measured Not measured Not measured Not measured Component (percent) Comparative example 3 Comparative example 4 Comparative example 5 Comparative example 6 Comparative example 7 Comparative example 8 Comparative example 9 Proportion of spherical or near-spherical particles Not measured Not measured Not measured Not measured Not measured Not measured Not measured Proportion of surface smooth particles Not measured Not measured Not measured Not measured Not measured Not measured Not measured brittleness Not measured Not measured Not measured Not measured Not measured Not measured Not measured Table 1-4: Formulations and associated test results of the invention examples and comparative examples Component (percent) Comparative example 10 Comparative example 11 Comparative example 12 Active ingredient GABA 29.75% 29.75% 29.75% Filler Microcrystalline cellulose 68.46% 44.45% 50.05% Honey-pear powder / / / Mannitol / / / lubricant talc 0.8% 19.80% 19.80% Stearic acid / / / Anti-caking agent Dicalcium phosphate / 6.0% / silicon dioxide 0.99% / 0.4% Wrapping material / / / Extrusion situation Uniform diameter, continuous, dense cylindrical extrusion strands, bubble-free, without cavities Insufficient moisture content led to the tearing of the sieve fabric; Uniform diameter, continuous, dense cylindrical extrusion strands, bubble-free, without cavities Spheronization situation During spheronization, the particles became increasingly larger and moister; they clumped together to form agglomerates. Did not meet the sample requirements, therefore no sample was taken. Normal Roundness level (proportion of levels 1+2+3) Percentage of unacceptable level 4: 100% Not measured Percentage of levels 1+2+3: 65%; Percentage of unacceptable level 4: 35% Component (percent) Comparative example 10 Comparative example 11 Comparative example 12 Span value Not measured Not measured Not measured Proportion of spherical or near-spherical particles Not measured Not measured Not measured Proportion of surface smooth particles Not measured Not measured Not measured brittleness Not measured Not measured Not measured

[0091] From the exemplary embodiments 1 to 12 in Table 1 mentioned above, it can be seen that the present invention, by selecting "lubricant + anti-caking agent + filler" as the basic additives and by strictly controlling the proportions of these four substances – GABA, lubricant, anti-caking agent, and filler – within specific ranges, effectively improves the problems of the easy agglomeration and difficult shaping of GABA. This resulted in cylindrical extrusion strands with a uniform diameter, continuous and dense, free of bubbles and cavities, being obtained during the extrusion process. The spheronization process proceeded normally, and pellet cores (uncoated pellets) with extremely high roundness, a low particle size distribution (chip value), a high proportion of spherical or nearly spherical particles, and a high proportion of smooth-surfaced particles were ultimately obtained.This provided an ideal base for the subsequent uniform coating with the sustained-release coating layer, ensuring the integrity of the coating membrane and the consistency of the release behavior, promoting the stable release and effective absorption of GABA, and increasing the bioavailability and efficacy of the active ingredient. At the same time, the brittleness of the coated pellets (i.e., the final sustained-release micropellet particles) was reduced and their mechanical stability increased.

[0092] In contrast, in comparison examples 1 to 12, the amounts of GABA and / or the filler and / or the lubricant and / or the anti-caking agent were not within the specified ranges. This led to problems such as the inability to produce dimensionally stable extruded strands, the impossibility of spheronization, and / or very low roundness. These results also demonstrate that only when GABA, filler, lubricant, and anti-caking agent are within the specified ranges can good shaping and high roundness of the micropellet cores be ensured during the manufacturing process, along with performance parameters such as chip removal and low brittleness of the coated pellets. This, in turn, is a prerequisite for ensuring the stability and uniformity of the preparation and thus achieving stable release and effective absorption of GABA.