Sustained-release pellet particles containing gamma-aminobutyric acid and preparation method of sustained-release pellet particles

Abstract

The invention provides a sustained-release pellet containing gamma-aminobutyric acid, the sustained-release pellet comprises a pellet core and a coating layer wrapping the pellet core, the pellet core contains a physiologically active substance, and the physiologically active substance is gamma-aminobutyric acid; the pellet core comprises the following components in parts by weight: 15-40 parts of gamma-aminobutyric acid, 30-55 parts of a filling agent, 1-30 parts of a lubricating agent and 0.5-5 parts of an anti-caking agent; the filling agent comprises at least one of microcrystalline cellulose, powdery cellulose, starch and derivatives thereof, hydroxypropyl cellulose, hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, sugar or sugar alcohol and fruit and vegetable powder; the lubricant comprises at least one of talcum powder, magnesium stearate, stearic acid, glycerol and leucine; the anti-caking agent comprises at least one of magnesium carbonate, tricalcium phosphate, calcium hydrophosphate and silicon dioxide.

Description

Technical Field

[0001] This invention belongs to the field of dietary supplement technology, specifically relating to a sustained-release microsphere containing γ-aminobutyric acid and its preparation method. Background Technology

[0002] GABA (γ-aminobutyric acid) is an important inhibitory neurotransmitter in the human central nervous system. It has sedative, anti-anxiety, and sleep-improving effects. It can also participate in physiological processes such as regulating blood pressure and lowering blood ammonia levels. It is widely used in the fields of medicine and health food.

[0003] To prolong the duration of action of GABA in vivo, improve drug compliance, and achieve stable blood drug concentrations, developing it into an oral sustained-release formulation is an important technological direction. Among them, multi-unit drug delivery systems (such as sustained-release microgranules) are considered an ideal dosage form choice because they can avoid the "burst release" risk that may exist in single-unit formulations (such as tablets), and have advantages such as less impact from gastrointestinal emptying and relatively stable bioavailability.

[0004] However, successfully preparing high-quality sustained-release microspheres from GABA faces a series of severe technical challenges, mainly due to the physicochemical properties of the GABA raw material itself: First, strong hygroscopicity and poor flowability. GABA has strong hygroscopicity and easily absorbs moisture from the air, causing it to clump together, resulting in a large angle of repose and extremely poor flowability. This not only causes uneven mixing with excipients but also easily leads to bridging and clogging problems in subsequent feeding and conveying processes, seriously affecting the continuity of production and the accuracy of dosage. Second, adhesion and molding difficulties: GABA powder has a certain degree of viscosity, and during wet granulation or extrusion, it easily adheres to the inner wall of the equipment, the sieve plate, and the surface of the spherical pan. This often leads to extrusion strip breakage, poor soft material conveying, severe agglomeration of microspheres during sphericalization, or the generation of excessive fine powder, ultimately resulting in poor sphericity, wide particle size distribution, and low yield of microspheres. Third, heat sensitivity: GABA may degrade at higher temperatures, while the drying and coating processes in microsphere preparation inevitably involve heating. Improper process control, especially excessively high local temperatures in the material, may lead to GABA deactivation, affecting the efficacy of the final product.

[0005] Existing microsphere preparation technologies, such as the traditional extrusion-spheronization method, often fail to achieve satisfactory results when applied to GABA. Conventional extrusion processes for GABA are prone to problems with extrudate formation. Furthermore, the use of a single rotation speed for both extrusion and spheronization in the extrusion-spheronization process makes it difficult to precisely control the plastic deformation process of the microspheres from strips to spheres. This easily leads to a large span of microsphere size distribution and uneven sphericity, which in turn affects the uniformity of the subsequent coating film and the consistency of drug release in the final product. Summary of the Invention

[0006] To address the problems and shortcomings of existing technologies, this invention provides sustained-release microspheres containing γ-aminobutyric acid (GABA) and their preparation method. By rationally designing the ratio of each component, the sustained-release microspheres effectively solve the problems of GABA's easy agglomeration and difficulty in forming, significantly improving the formability and uniformity of the formulation. This overcomes the disadvantage of easy agglomeration in traditional sustained-release formulations during the forming process, which is conducive to ensuring the stable release and effective absorption of GABA, and improving the bioavailability and efficacy of the drug.

[0007] According to a first aspect of the present invention, a sustained-release microsphere containing γ-aminobutyric acid (GABA) is provided, comprising a core and a coating layer surrounding the core. The core contains a physiologically active substance, namely γ-aminobutyric acid. The core, by weight, comprises the following components: 15-40 parts of γ-aminobutyric acid, 30-55 parts of filler, 1-30 parts of lubricant, and 0.5-5 parts of anti-caking agent. 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 alcohol, and fruit and vegetable solid beverages. The lubricant comprises at least one of talc, magnesium stearate, stearic acid, glycerin, and leucine. The anti-caking agent comprises at least one of magnesium carbonate, tricalcium phosphate, calcium hydrogen phosphate, and silicon dioxide. In the above-mentioned pellet core, γ-aminobutyric acid can be, for example, 15 parts, 17 parts, 20 parts, 22 parts, 25 parts, 28 parts, 30 parts, 32 parts, 35 parts, 38 parts, or 40 parts; filler can be, for example, 30 parts, 32 parts, 35 parts, 38 parts, 40 parts, 42 parts, 45 parts, 48 ​​parts, 50 parts, 52 parts, or 55 parts; lubricant can be, for example, 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; and anti-caking agent can be, for example, 0.5 parts, 0.9 parts, 1 part, 2 parts, 3 parts, 3.5 parts, 4 parts, or 5 parts. The above-mentioned raw materials are not limited to the listed values, and other unlisted values ​​within the range are also applicable. Regarding fruit and vegetable solid beverages, the definition is based on GB / T 29602-2013 Solid Beverages, section 4.2: Powdered fruit / vegetable beverages: solid beverages made from fruits and / or vegetables (including edible roots, stems, leaves, flowers, and fruits) or their products as the main raw materials, with or without the addition of other food raw materials and food additives.

[0008] In the sustained-release microgranules containing γ-aminobutyric acid provided by this invention, targeted excipients are designed for the physiologically active ingredient γ-aminobutyric acid, namely, the specific excipient combination of "filler + lubricant + anti-caking agent" is selected, which effectively solves the problems of easy aggregation and difficult molding of GABA, significantly improves the formability and uniformity of the formulation, and is conducive to promoting the stable release and effective absorption of GABA.

[0009] Specifically, controlling the GABA content as described above ensures an effective dosage and avoids difficulties in molding and a decrease in strength caused by excessive active ingredients. This facilitates the production of dense, smooth pellet cores, providing an ideal substrate for the subsequent uniform coating of the sustained-release coating layer and ensuring the integrity of the coating film and the uniformity of drug release behavior.

[0010] The selected cellulose and cellulose derivatives, starch and starch derivatives, etc., are used as fillers. After wetting, they produce moderate viscosity and plasticity, acting as endogenous binders. This gives the prepared soft material good cohesion and extrudability, thus providing good moldability. Furthermore, the filler content is controlled as described above to ensure sufficient filler to construct a stable core skeleton, providing the necessary mechanical strength (low brittleness) to withstand subsequent drying, coating, and transportation processes.

[0011] The selected lubricant forms a lubricating layer between the material and the metal surface of the equipment, precisely controlling the adhesion force and effectively preventing the soft material from sticking to the screen plate and spheroidizing pan during extrusion, thus avoiding broken strips, blocked holes, and agglomeration of core particles. Moreover, a specific amount of lubricant can work synergistically with the filler, enabling the successful production of round core particles through the extrusion spheroidizing process even without the addition of traditional binders.

[0012] The selected anti-caking agent can further improve the overall flowability of the mixture and effectively mitigate the agglomeration problem of GABA, enabling it to meet the requirements of subsequent uniform mixing and precise metering. Furthermore, a specific dosage of the anti-caking agent can synergistically enhance the overall process stability by working with the lubricant.

[0013] Ultimately, the overall system composed of the four components—γ-aminobutyric acid, filler, lubricant, and anti-caking agent—within the specified weight range exhibits excellent material flowability, controllable adhesion, and high overall process stability under the synergistic effect of each raw material. This results in high sphericity of the final microsphere core, concentrated particle size distribution, and low brittleness, possessing excellent powder properties. Consequently, it helps ensure the stable release and effective absorption of GABA, thereby improving the bioavailability and efficacy of the drug.

[0014] Specifically, the sphericity of the micro-pellet cores (cores) prepared in this invention is characterized by the following: with the maximum and minimum diameters of the cores being D1 and D2 respectively, the proportion of core particles satisfying D1 / D2≤1.5 is W1, and W1≥90%. Firstly, this ensures that each micro-pellet core has a similar geometric shape and surface area. During subsequent sustained-release coating, this provides an ideal physical basis for the coating material to form a uniform, continuous, and dense film on the core surface, thus ensuring a highly consistent release rate of GABA from each micro-pellet. This fundamentally avoids fluctuations in drug release behavior caused by differences in particle shape, improving the reliability and predictability of the sustained-release effect. Secondly, spherical or near-spherical particles have optimal flowability. This characteristic allows the micro-pellet cores to flow smoothly and uniformly during subsequent coating or packaging processes, reducing blockages and stratification during production, and improving production efficiency and dosage accuracy.

[0015] The microcapsule cores prepared by this invention exhibit a particle size distribution characterized by a range ≤2.0 mm. This highly concentrated particle size distribution facilitates a more uniform coating thickness during fluidized bed coating, ensuring consistent drug release behavior for each microcapsule and even the entire batch, significantly improving the stability and reproducibility of the sustained-release effect. Furthermore, the narrow particle size distribution further enhances flowability, facilitating transport, metering, and filling during production.

[0016] The micro-pellet cores (pellet cores) prepared by this invention exhibit low friability, ≤1.5%, indicating good mechanical strength and structural density. This allows them to effectively resist mechanical stress and friction generated during subsequent coating, packaging, and transportation, preventing the formation of fine powder due to breakage. This not only ensures the yield and appearance of the final product but, more importantly, prevents problems such as uneven dosage and coating defects (fine powder may adhere and damage the coating film) caused by fine powder, facilitating industrial production and long-term storage stability.

[0017] Furthermore, the sustained-release microgranule formulation system composed of the above-mentioned four types of components—γ-aminobutyric acid, filler, lubricant, and anti-caking agent—can eliminate or reduce the use of high-temperature sensitive binders, and the entire system is beneficial for protecting the activity of GABA in subsequent drying and coating processes.

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

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

[0020] In one embodiment, the core pellet includes 40-55 parts by weight of filler. In another embodiment, the core pellet includes 45-55 parts by weight of filler. In yet another embodiment, the core pellet includes 50-55 parts by weight of filler.

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

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

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

[0024] In one embodiment, the filler includes at least one of microcrystalline cellulose, mannitol, and honey pear powder; and / or, the lubricant includes at least one of talc and stearic acid; and the anti-caking agent includes at least one of dicalcium phosphate and silica. Selecting the above materials as fillers not only effectively ensures the sustained-release microspheres have high mechanical strength, but also effectively improves the adhesion and molding problems of GABA, which is more conducive to preparing microsphere cores with high sphericity, concentrated particle size distribution, and excellent mechanical properties. Furthermore, their overall compatibility helps protect GABA activity in the subsequent low-temperature coating process, ensuring the reliable and efficient release of the microspheres.

[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; and the anti-caking agent includes dicalcium phosphate and / or silica. In another embodiment, the filler includes microcrystalline cellulose and mannitol; the lubricant includes talc and stearic acid; and the anti-caking agent includes dicalcium phosphate and / or silica. Furthermore, selecting the above-mentioned materials for the filler, lubricant, and anti-caking agent is more conducive to the functional complementarity and synergistic effect of each component. Therefore, it is more beneficial to more effectively improve the adhesion, pore blockage, and agglomeration problems of GABA soft material in the key steps of exothermic extrusion and spheroidization in the back kitchen, ensuring the continuity of the process and the sphericity of the microspheres. This is also more conducive to optimizing the sustained-release performance, uniformity, and stability of the formulation, and improving the clinical efficacy and applicability of the formulation.

[0026] In one embodiment, the sustained-release microspheres further include a binder comprising hydroxypropyl methylcellulose.

[0027] Furthermore, the roundness of the pellet core in this invention is further characterized by the proportion of near-spherical or spherical particles being ≥85%. Near-spherical particles are defined as particles that are nearly perfectly round.

[0028] Furthermore, the pellet core in this invention not only has extremely high roundness, but also high surface smoothness. Specifically, the proportion of smooth-surfaced particles in the pellet core is ≥85%. Particles without obvious protrusions or depressions on the surface are considered to be smooth-surfaced particles.

[0029] Therefore, the further improvement in sphericity and surface smoothness is more conducive to the stability of subsequent processes such as core coating, ensuring a uniform and stable coating layer, and thus further optimizing the stability and reproducibility of the sustained-release effect of the microcapsules. At the same time, surface smoothness also further improves the flowability of the particles, which is beneficial to improving the production efficiency of subsequent processes that require high flowability.

[0030] Furthermore, the particle size distribution range of the pellet core in this invention can reach ≤1.0, ≤0.55, or even ≤0.5. Therefore, the particle size distribution range of the pellet core in this invention can reach extremely low values, which is more beneficial for subsequent coating, packaging, transportation and other processes.

[0031] Furthermore, the friability of the core-coated pellets of the present invention (i.e., the sustained-release micro-particles containing γ-aminobutyric acid that are finally prepared) can reach ≤1.3% or ≤1.0%.

[0032] Furthermore, the angle of repose of the pellet core of the present invention can reach ≤40° or ≤32°. The angle of repose, also known as the angle of rest, is the smallest angle between the inclined plane and the horizontal surface when the inclined plane is in a critical state of sliding down the inclined plane (that is, as the angle of inclination increases, the object on the inclined plane will slide down more easily; the angle of the critical state when the object begins to slide down is called the angle of repose).

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

[0034] Furthermore, setting a coating weight gain of 15% to 35% ensures the formation of a coating layer of moderate thickness and dense structure, thereby achieving a stable, continuous, and complete release of GABA and reaching an ideal sustained-release kinetic curve. Moreover, the selected coating material has good film-forming properties and adhesion to the pellet core, which is more conducive to ensuring that the sustained-release microspheres have more suitable in vitro release behavior and in vivo pharmacokinetic characteristics.

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

[0036] According to a second aspect of the present invention, a method for preparing any of the above-mentioned sustained-release microspheres containing γ-aminobutyric acid is provided, comprising the following steps: S1. Preparing a soft material: after uniformly mixing γ-aminobutyric acid, a filler, a lubricant and an anti-caking agent, a wetting agent is added to the obtained mixture to form a wet mass, thereby obtaining a soft material; S2. Extrusion and spheroidizing treatment: the soft material is extruded through a sieve to obtain an extrusion strip; the extrusion strip is first cut at a speed of 600~1000 rpm, and then spheroidized at a speed of 250~350 rpm for 2~20 min to obtain a pellet core; S3. Coating: the pellet core is coated with a coating solution containing a coating material to obtain sustained-release microspheres. In step 2 above, the cutting speed can be, for example, 600 rpm, 650 Rpm, 700 Rpm, 750 Rpm, 800 Rpm, 850 Rpm, 900 Rpm, 950 Rpm, or 1000 Rpm; the rolling speed can be, for example, 250 Rpm, 280 Rpm, 300 Rpm, 320 Rpm, or 350 Rpm; and the rolling time can be, for example, 2 min, 4 min, 6 min, 8 min, 10 min, 12 min, 15 min, 18 min, or 20 min. However, the above process parameters are not limited to the listed values, and other unlisted values ​​within the range are also applicable.

[0037] In the preparation method of sustained-release microspheres containing γ-aminobutyric acid provided by this invention, step S2 is the key step, which involves staged extrusion and rounding. First, relatively high-speed cutting ensures that the extruded strip is quickly and uniformly divided into starting materials of consistent length, which is a prerequisite for obtaining pellet cores with a uniform particle size distribution. Subsequently, relatively low-speed rounding provides these short strips with controllable plastic deformation energy and time, allowing them to gradually be shaped into spherical shapes through friction and rolling. Under this parameter combination, pellet cores with high sphericity, concentrated particle size distribution (small Span value), and good mechanical strength (low brittleness) can be obtained, effectively solving the problems of uneven particle size and poor sphericity caused by rounding at a single rotation speed, and providing an ideal substrate for subsequent coating.

[0038] In one embodiment, in step S1, before mixing the raw materials, γ-aminobutyric acid, filler, lubricant, and anti-caking agent are sieved through an 80-mesh standard sieve; and / or, in step S1, the wetting agent includes at least one of water, an aqueous ethanol solution, or an aqueous solution containing a binder. The aqueous solution containing a binder includes a 0.5-1.0% hydroxypropyl methylcellulose solution. The mass fraction of the hydroxypropyl methylcellulose solution can be, for example, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1.0%, but is not limited to the listed values; other unlisted values ​​within the range are also applicable.

[0039] The purpose of sieving γ-aminobutyric acid, filler, lubricant and anti-caking agent through an 80-mesh standard sieve is to remove lumps, impurities and large particles from the raw materials to ensure that the particle size of each component is uniform (≤180μm).

[0040] In one embodiment, the specific operation of forming a wet agglomerate in step S1 is as follows: Wetting agent is added to the mixture while water is added and stirred continuously for 1-5 minutes until a wet agglomerate is formed. The stirring time can be, for example, 1 minute, 2 minutes, 3 minutes, 4 minutes, or 5 minutes, but is not limited to the listed values; other unlisted values ​​within the range are also applicable. The endpoint judgment criteria for the soft material are: the wet agglomerate can naturally clump together when squeezed in the hand, without any loose fine powder falling off; when the agglomerate is gently pressed with a finger, it can be easily dispersed into uniform particles, without a hard core or sticky adhesion, ensuring that the soft material has good plasticity and extrusion molding properties.

[0041] In one embodiment, in step S2, the soft material is extruded through a sieve with an aperture of 0.7~0.9mm at a rotation speed of 12~20 r / min to obtain an extruded strip; and / or, in step S2, during the rounding process, the temperature of the rounding chamber is 10~35℃ and the relative humidity is 30~75%. The sieve aperture can be, for example, 0.7mm, 0.8mm, or 0.9mm; the extrusion speed can be, for example, 12rpm, 14rpm, 16rpm, 18rpm, or 20rpm; the temperature of the rounding chamber can be, for example, 10℃, 12℃, 15℃, 18℃, 20℃, 22℃, 25℃, 28℃, 30℃, or 35℃; and the relative humidity can be, for example, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%. The above process parameters are not limited to the listed values; other unlisted values ​​within the range are also applicable.

[0042] In step S2, the control of the extrusion parameters, namely a screen aperture of 0.7~0.9mm and an extrusion speed of 12~20 rpm, achieves an optimal match between the extrusion speed and the rheological properties of the soft material. Specifically, the aperture range ensures that the extruded strip has an initial diameter suitable for subsequent spheroidization. Simultaneously, the matching extrusion speed ensures that the soft material passes through the screen aperture under moderate shear force, forming continuous, dense, and uniformly sized cylindrical strips. This avoids the loose and easily broken structure of the strips due to excessive speed, or the low production efficiency and material retention in the equipment due to excessively slow speed. It provides high-quality starting material for the spheroidization process and is the primary process guarantee for obtaining uniformly sized microsphere cores. Controlling the spheroidization chamber temperature to 10~35℃ and the relative humidity to 30%~75% serves two purposes. First, the temperature is controlled within a relatively low range. This prevents GABA from degrading due to localized overheating. Second, it avoids the excessively rapid evaporation of the wetting agent (such as water) due to excessively high temperature, which would harden the surface of the soft material and make it difficult to spheroidize. Secondly, humidity control within the aforementioned range ensures that the pellet cores maintain suitable humidity and viscoelasticity during the critical plastic deformation period of spheroidization. This prevents premature drying and excessive fine powder production due to excessively low humidity, while also avoiding excessive particle adhesion and agglomeration due to excessively high humidity. This environmental parameter control creates stable and controllable external conditions for the effective implementation of the "staged spheroidization" process.

[0043] In one embodiment, after the rounding process in step S2, a drying process is further included. The drying adopts a fluidized bed drying method, controlling the inlet air temperature at 35~80℃ and the material temperature at 30~45℃, drying until the moisture content of the pellet core is ≤5%. Preferably, the drying time is 5~30min. The inlet air temperature can be, for example, 35℃, 40℃, 45℃, 50℃, 55℃, 60℃, 65℃, 70℃, 75℃, or 80℃; the material temperature can be, for example, 30℃, 32℃, 35℃, 38℃, 40℃, 42℃, or 45℃; the moisture content of the pellet core can be, for example, 0.5%, 1%, 2%, 3%, 4%, or 5%; and the drying time can be, for example, 5min, 10min, 15min, 20min, 25min, or 30min. The above process parameters are not limited to the listed values, and other unlisted values ​​within the range are also applicable.

[0044] In one embodiment, in step S3, the coating is fluidized bed coating, and the material temperature is controlled at 30~45℃ during the coating process; and / or, in step S3, the coating liquid is atomized and sprayed at a flow rate of 1.5~10 rpm. In one embodiment, in step S3, the fluidized bed coating is bottom spray coating. During the coating process, the material temperature can be, for example, 30℃, 32℃, 35℃, 38℃, 40℃, 42℃, or 45℃, and the atomization and spraying flow rate of the coating liquid can be, for example, 1.5 rpm, 2 rpm, 3 rpm, 4 rpm, 5 rpm, 6 rpm, 7 rpm, 8 rpm, 9 rpm, or 10 rpm; the above process parameters are not limited to the listed values, and other unlisted values ​​within the range are also applicable.

[0045] The coating process controls the material temperature to 30-45℃, which minimizes the thermal degradation of GABA during coating, ensuring the bioactivity of the final product. It also provides ideal drying and film-forming conditions for the coating solution (usually a polymer solution), allowing the solvent (such as water or ethanol) to evaporate appropriately, promoting effective migration and entanglement of polymer chains, thereby forming a continuous, dense, and defect-free slow-release coating film. Controlling the coating solution to atomize and spray at a flow rate of 1.5-10 rpm achieves uniform atomization and controllable weight gain, resulting in a uniform, dense, and continuous coating layer.

[0046] In one embodiment, step S3, after coating, further includes a fluidized bed drying process. This step is used to solidify the coating layer. During the fluidized bed drying process, the material temperature is controlled at 30~45℃, and the drying time is 5~10min. The material temperature can be, for example, 30℃, 32℃, 35℃, 38℃, 40℃, 42℃, or 45℃, and the drying time can be, for example, 5min, 6min, 7min, 8min, 9min, or 10min; the above process parameters are not limited to the listed values, and other unlisted values ​​within the range are also applicable.

[0047] In summary, the technical solution provided by this invention achieves the following technical effects: (1) By selecting “lubricant + anti-caking agent + filler” as the basic excipients, this invention effectively solves the problems of easy aggregation and difficult molding of GABA, significantly improves the formability and uniformity of the formulation, and overcomes the disadvantage of easy aggregation of traditional sustained-release formulations during the molding process; (2) The present invention adopts a staged extrusion and rounding process, optimizes the extrusion parameters and rounding process, ensures the uniformity of particle size and roundness of micro pellets, and solves the problem of particle size fluctuation caused by single rotation speed rounding. (3) By rationally designing the ratio of each component and the staged rolling process, this invention achieves stable release and effective absorption of GABA, thereby improving the bioavailability and efficacy of the drug. (4) The present invention adopts fluidized bed coating process, precisely controls coating parameters, avoids GABA degradation caused by high temperature, and ensures that the coating liquid uniformly covers the surface of microspheres, thus achieving a stable sustained release effect; (5) The sustained-release microparticle composition of the present invention not only improves the stability and uniformity of the formulation, but also enhances the sustained-release performance and bioavailability of the drug, providing a new treatment option for treating various diseases. Detailed Implementation

[0048] To enable those skilled in the art to better understand the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments.

[0049] Examples 1-12, Comparative Examples 1-12 Table 1 (Table 1-1, Table 1-2, Table 1-3, Table 1-4) shows the formulations of sustained-release microgranules containing γ-aminobutyric acid (GABA) in the following examples and comparative examples.

[0050] Furthermore, the preparation methods of the sustained-release microspheres containing γ-aminobutyric acid (GABA) in the various examples and comparative examples in Table 1 include the following steps: S1. Preparation of soft material: S11. The functional ingredient γ-aminobutyric acid (GABA), food-grade lubricant, anti-caking agent and filler are sieved through an 80-mesh standard sieve to remove lumps, impurities and large particles from the raw materials to ensure that the particle size of each component is uniform (≤180μm); after sieving, all materials are put into a mixer and mixed for 2~5 minutes to obtain a homogeneous mixture. S12. Gradually add a wetting agent (such as purified water, ethanol aqueous solution, or aqueous solution containing binder, such as 0.5%~1.0% hydroxypropyl methylcellulose solution, selected according to molding requirements) to the mixture while stirring. Continue stirring for 1~5 minutes until a uniform wet mass is formed. The endpoint judgment criteria for the soft material are: the wet mass can be formed into a ball naturally when squeezed by hand, without loose fine powder falling off; when the mass is gently pressed with a finger, it can be easily dispersed into uniform particles, without a hard core or sticky adhesion, ensuring that the soft material has good plasticity and extrusion molding properties. S2. Extrusion and rounding process: S21. Extrusion Molding: The prepared soft material is fed into the feed hopper of the screw extruder. The extruder screen diameter is set to 0.8 mm, and the extrusion speed is 16 r / min. The feed rate is matched with the extrusion speed (to avoid die blockage due to excessive feed or strip breakage due to excessive feed). The extruder is started, and the soft material passes through the screen under the pushing force to form a uniform, continuous, and dense cylindrical extruded strip. This ensures that the extruded strip is free of air bubbles and hollows, providing a high-quality substrate for subsequent rounding. This process requires 2-3 cycles of extrusion. S22. Staged Rounding: The continuously extruded cylindrical strips (extruded strips) are immediately fed into the rounding chamber of the rounding machine, and a staged process of "cutting-preliminary rounding-fine rounding" is adopted to precisely control the morphology of the micro-pellets. First stage (cutting stage): Set the rolling machine speed to 600~1000rpm (preferably 800rpm), and cut the extruded strip into short strips of uniform length by a high-speed rotating cutting blade; Second stage (preliminary rounding): Maintain the temperature of the rounding chamber at 10~35℃ and the relative humidity at 30~75%, adjust the rotation speed to 300rpm, and continue to round for 1~10min. Under the action of centrifugal force and friction, the cut strips are gradually rounded, the sharp edges are removed, and preliminary spherical particles are formed. The third stage (fine rounding): Continue rounding at 300 rpm for 1 to 5 minutes to further optimize the particle morphology, making the surface of the microspheres smooth and burr-free, and the outline close to a perfect circle (at this time, the obtained particles are undried raw particles). S3. Fluidized bed drying and coating S31. Low-temperature drying: The rounded wet microspheres are fed into the drying chamber of a fluidized bed dryer. The inlet air temperature is set to 35~80℃, and the material temperature is strictly controlled at 30~45℃ (to avoid deactivation of heat-sensitive components such as GABA). The boiling drying method (i.e., fluidized bed drying) is adopted to ensure that the microspheres are fully fluidized and uniformly heated in the hot air flow. The drying time is 5~30 minutes. The moisture content of the microspheres is monitored in real time. When the residual moisture content of the microspheres is ≤5% (wet basis), the drying is stopped, and dry, loose, and free-flowing blank microspheres are obtained (at this time, the dried raw particles are obtained). S32. Bottom Spray Coating: After drying, maintain the fluidized state of the material in the fluidized bed and turn on the bottom spray coating system; deliver the pre-formulated coating solution (such as the aqueous solution of the film coating premix, corresponding to the coating materials in Table 1) to the bottom spray atomizing nozzle through a peristaltic pump, set the coating solution flow rate to 1.5~10 rpm (adjust according to the fluidization state of the microparticles to avoid excessive flow rate causing microparticle adhesion or excessive flow rate causing uneven coating), so that the coating solution is atomized into fine droplets and evenly sprayed on the surface of the fluidized microparticles; maintain the material temperature at 30~45℃ during the coating process to ensure that the coating solution forms a film quickly, forming a continuous, smooth, and dense coating layer; after coating, continue fluidized drying for 5~10 minutes to solidify the coating layer, and finally obtain a finished product containing GABA microparticles (i.e., slow-release microparticles containing γ-aminobutyric acid) with a smooth surface, uniform coating, and good stability.

[0051] Furthermore, the sphericity, particle size distribution span (Span value), friability, and surface morphology of the blank microspheres (cores) after fluidized bed drying in S31 were tested. The friability of the coated microspheres in S32 was further evaluated. The test results are shown in Table 1 (Tables 1-1 to 1-4), and the relevant test methods are as follows: I. Roundness 1. Preparations before testing (1) Instruments and materials Core tools: Transmitting and reflecting polarizing microscope, glass slide, pointed tweezers, standard shape template; Sample requirements: Randomly select freshly prepared sample particles (avoid moisture absorption / sticking).

[0052] (2) Standard shape template

[0053] 2. Testing Methods Step 1: Sample Preparation Gently pick up the sample particles with tweezers, disperse them on a glass slide (without overlapping), and place them under a microscope.

[0054] Step 2: Observation and Comparison Adjust the eyepiece, align it with the particle, observe its outline and shape, compare it with the "standard shape template", and determine the roundness level of each particle one by one: Grade 1 (Excellent): The particle outline is uniform, with no obvious difference in length and short diameter, and there is no "angularity" when rotating; Grade 2 (Good): The particles are slightly flat, but there are no obvious protrusions, and the visual difference between the major and minor axes is small; Grade 3 (Qualified): The particles have some differences in length and short diameter, but no sharp edges or corners, and the shape is relatively regular; Grade 4 (Unqualified): Particles are obviously deformed, have sharp edges, or the long diameter is much larger than the short diameter.

[0055] Step 3: Results Statistics Record the quantity and percentage of particles of each grade: roundness grade, number of particles, percentage (%) II. Particle size distribution span (Span value) Particle size distribution span is a core parameter describing the breadth of particle size distribution and a key indicator for process control and quality evaluation. It can assess the particle size uniformity of extruded and rounded granules, ensuring flowability, content uniformity, and dissolution performance.

[0056] 1. Preparations before testing (1) Preparation of instruments and materials Core equipment: a set of standard test sieves (20 mesh, 40 mesh, 60 mesh, 80 mesh, conforming to ISO3310-1 metal wire mesh standard).

[0057] Auxiliary equipment: electronic balance (accuracy 0.001g, traceable calibration), sample spoon, brush (soft bristles to avoid scratching the screen), and sealing bag.

[0058] Sample requirements: Take a representative sample. If it is a clump of dry powder, it should be gently crushed (to avoid breaking the particles), pre-sieved (e.g., 1mm sieve) to remove large impurities, and sealed for later use.

[0059] (2) Screen inspection Check each screen layer for damage or blockage, and clean any remaining particles with a soft brush.

[0060] 2. Practical steps Step 1: Screen layer assembly Stack the sieve frames in order of increasing aperture size: place the receiving tray at the bottom, and stack the sieve layers in sequence: 850μm (20 mesh), 425μm (40 mesh), 250μm (60 mesh), and 180μm (80 mesh). Place the sieve cover at the top (ensure that the sieve layers are well sealed and there are no gaps for powder leakage).

[0061] Step 2: Sample weighing and feeding Weigh the empty weighing dish using an electronic balance (recorded as m0), then weigh the pretreated sample (recorded as m_total, with a total mass of 100g, ensuring that each sieve layer has a detectable amount of residue to avoid errors caused by excessively low mass). Slowly pour the sample into the top sieve and gently scrape it level with a sample spoon to avoid the sample concentrating on one side of the sieve.

[0062] Step 3: Vibrating Screening Manual sieving (without equipment): Hold the sieve pile with both hands and gently vibrate and tap it horizontally at a frequency of about 20 times / minute for 5 minutes. During this period, invert the sieve layer and tap it twice every 2 minutes to prevent particles from clogging the sieve holes.

[0063] Step 4: Collection and weighing of residual particles After screening, carefully remove each sieve layer (from the top to the bottom, to avoid residual particles falling between sieve layers). Use a soft brush to gently remove any residual particles from each sieve layer and collect them all into the corresponding weighing dish (Note: the brush should only clean the inside of the sieve to avoid impurities from the outside from getting in). Weigh each weighing dish and the total mass of the residual particles using an electronic balance (denoted as m1, m2, m3..., corresponding to the pore size of each sieve layer from largest to smallest), and calculate the mass of the residual particles in each sieve layer: m1 = m_i(total) - m0.

[0064] Step 5: Data Recording and Verification Record the pore size and residual particle mass m_i of each sieve layer, and calculate the cumulative residual mass (Σm_i) and recovery rate: Recovery rate = (Σm_i / m_total) × 100%; Verification criteria: The recovery rate should be between 95% and 105%. If it is below 95%, it may be due to powder leakage or particles clogging the sieve holes, and the test needs to be repeated. If it is above 105%, it may be due to weighing error or sample moisture absorption, and the balance needs to be calibrated and the sample needs to be re-pretreated.

[0065] III. Calculation of Particle Size Distribution Span 1. Calculate the cumulative mass fraction of each sieve layer. Sort the sieve layers by aperture size from smallest to largest, and calculate the cumulative residual mass (Σm_≤d, i.e., the total mass of particles less than or equal to that aperture size) for each sieve layer. The cumulative quality score w(≤d) = (Σm_≤d / m_total) × 100%.

[0066] 2. Using interpolation to determine D10, D50, and D90 D10: The particle size corresponding to a cumulative mass fraction of 10% (10% of particles are smaller than this particle size); D50: The particle size (median particle size) corresponding to a cumulative mass fraction of 50%. D90: The particle size corresponding to a cumulative mass fraction of 90% (90% of the particles are smaller than this particle size).

[0067] 3. Calculate the particle size distribution span Formula: Span = (D90 - D10) / D50; retain 2 significant figures; 4. Standard: Generally, Span < 1 belongs to narrow distribution, 1~2 belongs to medium distribution, and > 2 belongs to wide distribution.

[0068] IV. Crispness 1. Preparations before testing Instruments and Materials Core equipment: Particle friability tester (or improved friability tester with transparent sealed drum, rotation speed 25~30r / min, drum inner diameter 286mm, length 143mm), 80 mesh sieve (aperture usually 180μm). Auxiliary equipment: electronic balance (accuracy 0.001g, traceable calibration), weighing dish, soft brush, and sealing bag.

[0069] Sample requirements: Take a representative particle sample. If there are clumps, crush them gently (avoid damaging the particles with force). Pass the sample through a pre-sieve (such as a 1mm sieve) to remove large impurities. Mix well before use.

[0070] 2. Specific operating steps Step 1: Sample weighing and sieving pretreatment Weigh the empty weighing dish using an electronic balance (record as m0), then weigh the pretreated particle sample (record as m1, mass 20g, to ensure that the amount of fine powder can be detected after testing). Pour the weighed sample into the selected standard sieve (e.g., 180μm) and sieve gently for 1 minute (to remove only the original fine powder and avoid particle breakage). Collect the particles remaining on the sieve and weigh them again (record as m2, which is the sample mass after removing the initial fine powder).

[0071] Step 2: Friability tester test Turn on the particle friability tester, pour all the remaining particles (mass m2) on the sieve into the transparent drum of the instrument, and close the drum cover (ensure it is sealed to prevent particles from falling out). Set the test parameters: rotation speed 25 r / min, test time 10 minutes; When the instrument is started, the drum begins to tumble, and the particles collide and rub against each other inside the drum, producing fine powder.

[0072] Step 3: Post-test sieving and weighing After the test, turn off the instrument, carefully remove all particles (including fine powder) from the drum, and pour them into the same standard sieve (180μm) used in step 1. Gently brush the sieve with a soft brush and sieve for 2 minutes. Collect the remaining particles (unbroken whole particles) on the sieve and put them into a weighing dish. Weigh the weighing dish and the total mass of the particles remaining on the sieve using an electronic balance (denoted as m3). Calculate the net mass of the particles remaining on the sieve: m4 = m3 - m0.

[0073] Step 4: Calculation of Friability Formula: Friability (%) = [(m2-m4) / m2] × 100% Note: m2-m4 represents the mass of fine powder produced after the test, and the proportion of this fine powder to the initial particle mass (m2) is the degree of friability.

[0074] V. Surface Morphology 1. Preparations before testing Instruments and Materials Core tool: Transmitting and reflecting polarizing microscope; Auxiliary tools: glass slide, sampling spoon; Sample requirements: Take freshly prepared extruded and rounded granules.

[0075] 2. Specific operating steps Step 1: Sample Preparation Gently take an appropriate amount of particles with a sampling spoon and place them scattered on a glass slide (the particles should not overlap to avoid obstruction). Step 2: Setting Observation Conditions Place the slide on the microscope to clearly see the details on the surface of the particles.

[0076] Step 3: Surface morphology observation and recording Observe each particle individually according to the following dimensions and record its typical characteristics: a. Surface smoothness: Grading: Smooth (no obvious bumps / depressions), Slightly rough (few small pores), Rough (numerous pores / burrs); b. Shape regularity: Grading: Near-spherical, ellipsoidal, irregular (adhesive / deformed); c. Defect details: Observe for cracks, dents, stuck particles (multiple particles stuck together), and surface deposits (such as unevenly mixed excipients); Step 4: Results Statistics and Evaluation Calculate the percentage of each characteristic among the 20 particles (e.g., "90% of the particles have smooth surfaces"). Based on the process requirements, the evaluation requires that "near-spherical proportions be ≥85%, smooth surface proportions be ≥85%, and there be no obvious defects".

[0077] Table 1-1 Formulations and related test results of the examples and comparative examples

[0078] Table 1-2 Formulations and related test results of the examples and comparative examples

[0079] Table 1-3 Formulations and related test results of the examples and comparative examples

[0080] Table 1-4 Formulations and related test results of the examples and comparative examples

[0081] As can be seen from Examples 1-12 in Table 1 above, this invention effectively improves the problems of GABA's easy agglomeration and molding difficulties by selecting "lubricant + anti-caking agent + filler" as the basic excipients and strictly controlling the proportions of GABA, lubricant, anti-caking agent and filler within a specific range. This allows for the production of uniform, continuous and dense cylindrical extrusion strips with no air bubbles or hollows, and normal rounding process. Ultimately, it yields pellet cores (plain pellets) with extremely high sphericity, small particle size distribution span (Span value), high proportion of spherical or near-spherical particles, and high proportion of smooth-surfaced particles. This provides an ideal substrate for the subsequent uniform coating of the sustained-release coating layer, ensuring the integrity of the coating film and the uniformity of drug release behavior. This is beneficial for ensuring the stable release and effective absorption of GABA, improving the bioavailability and efficacy of the drug, and also reducing the brittleness of the pellet core coated pellets (i.e., the final sustained-release micro-pellets) and improving mechanical stability.

[0082] In Comparative Examples 1-12, the amounts of GABA, and / or fillers, and / or lubricants, and / or anti-caking agents were outside the specific dosage range, resulting in problems such as extrusion strips being unable to form, and / or being unable to be rounded, and / or having very low roundness. Therefore, these results also indicate that only when GABA, fillers, lubricants, and anti-caking agents are within the specific dosage range can the micro-pellet cores have good forming effect, high roundness, Span value, and other properties during the preparation process, as well as low brittleness of the core-coated pellets. This, in turn, can further ensure the stability and uniformity of the formulation, and achieve stable release and effective absorption of GABA.

[0083] The above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention, but such modifications or substitutions are all within the scope of protection of the present invention.

Claims

1. A sustained-release microgranule containing γ-aminobutyric acid, characterized in that, It includes a pellet core and a coating layer surrounding the pellet core, wherein the pellet core contains a physiologically active substance, namely γ-aminobutyric acid; The pellet core, by weight, comprises the following components: The composition includes 15-40 parts of γ-aminobutyric acid, 30-55 parts of filler, 1-30 parts of lubricant, and 0.5-5 parts of anti-caking agent. The filler includes at least one of microcrystalline cellulose, powdered cellulose, starch and its derivatives, hydroxypropyl cellulose, hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, sugar or sugar alcohol, and fruit and vegetable solid beverages. The lubricant includes at least one of talc, magnesium stearate, stearic acid, glycerin, and leucine. The anti-caking agent includes at least one of magnesium carbonate, tricalcium phosphate, dicalcium phosphate, and silicon dioxide.

2. The sustained-release microgranules containing γ-aminobutyric acid as described in claim 1, characterized in that: In the filler, the sugar or sugar alcohol includes at least one of erythritol, lactose, sorbitol, isomaltitol, mannitol, stachyose, and xylitol; And / or, the fruit and vegetable solid beverage includes at least one of sweet orange powder, dragon fruit powder, and honey pear powder.

3. The sustained-release microgranules containing γ-aminobutyric acid as described in claim 2, characterized in that: The filler includes at least one of the microcrystalline cellulose, mannitol, and honey pear powder; And / or, the lubricant includes at least one of the talc powder and the stearic acid; And / or, the anti-caking agent includes at least one of the dicalcium phosphate and the silicon dioxide.

4. The sustained-release microgranules containing γ-aminobutyric acid as described in claim 3, characterized in that: The filler is selected from at least one of the microcrystalline cellulose and the mannitol; the lubricant is selected from at least one of the talc and the stearic acid; the anti-caking agent includes the dicalcium phosphate and / or the silicon dioxide.

5. The sustained-release microgranules containing γ-aminobutyric acid as described in claim 4, characterized in that: The filler includes the microcrystalline cellulose and the mannitol; the lubricant includes the talc and the stearic acid; and the anti-caking agent includes the dicalcium phosphate and / or the silicon dioxide.

6. The sustained-release microgranules containing γ-aminobutyric acid as described in claim 1, characterized in that: The mass of the coating layer is 15-35% of the mass of the pellet core; And / or, the coating layer includes at least one of ethyl cellulose, acrylic resin, shellac, and hydroxypropyl methylcellulose.

7. A method for preparing sustained-release microgranules containing γ-aminobutyric acid as described in any one of claims 1 to 6, characterized in that, Includes the following steps: S1. Preparation of soft material: After the γ-aminobutyric acid, the filler, the lubricant and the anti-caking agent are mixed evenly, a wetting agent is added to the obtained mixture to form a wet mass, thereby obtaining a soft material; S2. Extrusion and rounding process: The soft material is extruded through a screen to obtain an extruded strip; the extruded strip is first cut at a speed of 600~1000 rpm, and then rounded at a speed of 250~350 rpm for 2~20 minutes to obtain the pellet core; S3. Coating: The pellet core is coated with a coating solution containing a coating material to obtain the sustained-release microparticles.

8. The method for preparing sustained-release microspheres containing γ-aminobutyric acid as described in claim 7, characterized in that: In step S1, before mixing the raw materials, the γ-aminobutyric acid, the filler, the lubricant and the anti-caking agent are sieved through an 80-mesh standard sieve. And / or, in step S1, the wetting agent includes at least one of water, an aqueous ethanol solution, or an aqueous solution containing an adhesive.

9. The method for preparing sustained-release microspheres containing γ-aminobutyric acid as described in claim 7, characterized in that: In step S2, the soft material is extruded through a sieve with a pore size of 0.7~0.9mm at a rotation speed of 12~20 r / min to obtain the extruded strip; And / or, in step S2, during the spherical rolling process, the temperature of the spherical rolling chamber is 10~35℃ and the relative humidity is 30~75%.

10. The method for preparing sustained-release microspheres containing γ-aminobutyric acid as described in claim 7, characterized in that: In step S3, the coating is a fluidized bed coating, and the material temperature is controlled at 30~45℃ during the coating process; And / or, in step S3, the coating liquid is atomized and sprayed at a flow rate of 1.5~10 rpm.

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