Gamma-aminobutyric acid pellets with double properties of enteric and sustained release and a preparation method thereof

Abstract

The application discloses a gamma-aminobutyric acid micro-pellet with double properties of enteric and sustained release and a preparation method thereof. The gamma-aminobutyric acid micro-pellet comprises a drug core layer and a composite functional coating layer coated outside the drug core layer; the drug core layer is composed of the following components in parts by weight: 40-60 parts of gamma-aminobutyric acid, 20-35 parts of microcrystalline cellulose, 10-20 parts of lactose, and 2-5 parts of polyvinylpyrrolidone; and the composite functional coating layer is composed of the following components in parts by weight: 30-50 parts of neutral methacrylic acid ester copolymer, 15-25 parts of hydroxypropyl methyl cellulose phthalate, 0.5-2.0 parts of amphiphilic block copolymer, 5-10 parts of talc, 3-8 parts of triethyl citrate, and 110-130 parts of purified water. In the scheme, the zero-permeation locking of the active ingredient in the film-forming process, the densification and molding of the coating layer and the linearization control of the in-vitro release curve are realized simultaneously by constructing the composite polymer barrier layer based on the specific hydrophilic-hydrophobic gradient distribution and combining the segmented variable-temperature fluidized bed drying process.

Description

Technical Field

[0001] This application relates to the field of fine chemical technology, and in particular to a γ-aminobutyric acid microsphere with both enteric and sustained-release properties and its preparation method. Background Technology

[0002] Gamma-aminobutyric acid (GABA) microspheres are sustained-release or controlled-release pellet formulations made from GABA, primarily used for calming the nerves, aiding sleep, and relieving anxiety. In the prior art, Japanese patent application JP2023520671A discloses "Multi-unit oral dosage form of multi-dose multi-unit doxylamine succinate and pyridoxine hydrochloride and its preparation method (translated title)," which points out that the lack of uniformity among microspheres directly affects the dissolution curve of the active ingredient, thereby impairing the accuracy of the final dose and the stability of the therapeutic effect. Although the above technology achieves regulated release of different active ingredients through multi-unit formulation design, the traditional aqueous coating system lacks a specific barrier mechanism against highly polar molecules, leading to the easy back-permeation of zwitterionic active ingredients through incompletely dense nanopores during film formation. This uncontrolled migration behavior causes an imbalance in the coating layer loading, directly manifesting as a burst release phenomenon in the later release stage, making it difficult to precisely control the drug release curve. Meanwhile, in pursuit of rapid film formation, traditional drying processes often sacrifice film integrity, resulting in poor consistency in dissolution behavior between batches of microparticles, which cannot meet the needs of high-precision drug delivery.

[0003] Therefore, the existing technology still suffers from the core contradiction of insufficient reverse osmosis inhibition and difficulty in synergistic control of film integrity in aqueous coating of highly polar drugs, which restricts its further development and application in the preparation of highly stable microparticles that require precise enteric coating and sustained release characteristics. Summary of the Invention

[0004] The issues to be addressed This application aims to address at least one of the technical problems existing in the prior art. To this end, one objective of this application is to provide γ-aminobutyric acid microspheres with both enteric and sustained-release properties and a method for preparing the same. By constructing a composite polymer barrier layer based on a specific hydrophilicity-hydrophobic gradient distribution and combining it with a segmented variable-temperature fluidized bed drying process, the active ingredient can be synergistically locked in zero permeation during film formation, the coating layer can be densified, and the in vitro release curve can be linearized and controlled.

[0005] [Methods for Solving the Problem] Existing technologies typically rely on single aqueous acrylic resins or cellulose derivatives for coating, attempting to delay release by increasing coating thickness. However, in the early stages of film formation, water, acting as a solvent, temporarily swells polymer segments in traditional aqueous coating solutions, creating nanoscale transient pores. For small-molecule, highly water-soluble, and charged drugs like γ-aminobutyric acid (GABA), these transient pores become channels for reverse permeation to the outside of the coating layer. This uncontrolled migration not only reduces the drug loading capacity but also causes some drug to remain in the coating layer, resulting in a burst release in the later stages and disrupting the stability of the release curve. Furthermore, in pursuit of production efficiency, existing processes often employ high-temperature rapid drying, which, while accelerating water evaporation, prevents sufficient rearrangement and fusion of polymer segments, leading to defects in the resulting film.

[0006] To address the aforementioned technical deficiencies, this application's improvement approach differs from the conventional method of simply adjusting the type of coating material or optimizing the coating weight gain ratio. This application proposes a dual control mechanism of interface anchoring and gradient densification. First, in terms of material selection, it abandons the traditional single polymer system and instead adopts a composite coating system composed of a neutral methacrylate copolymer and hydroxypropyl methylcellulose phthalate. A trace amount of amphiphilic block copolymer is introduced as an interface modifier. Utilizing the directional adsorption of amphiphilic molecules on the drug core surface, a hydrophobic barrier is pre-constructed, blocking the dissolution and diffusion pathways of the drug upon contact with the aqueous coating solution at the source.

[0007] Secondly, in terms of process design, this application developed a segmented variable temperature fluidized bed drying strategy. This strategy maintains a low temperature during the critical film-forming period to allow the polymer chain segments to fully relax and interpenetrate, and then gradually increases the temperature during the curing period to promote film densification. This ensures the integrity of the film while eliminating internal stress cracks caused by excessively fast drying rates. This innovative coupling of material formulation and process parameters effectively overcomes the common industry problems of difficult film formation and controlled release of drugs in aqueous environments.

[0008] This application provides a γ-aminobutyric acid microsphere with both enteric and sustained-release properties, comprising a core layer and a composite functional coating layer covering the core layer; The core layer is composed of the following components in parts by weight: A. 40-60 parts of γ-aminobutyric acid; B. 20-35 parts of microcrystalline cellulose; C. Lactose 10-20 parts; D. Povidone K302 - 5 parts; The composite functional coating layer is composed of the following components in parts by weight: E. 30-50 parts of neutral methacrylate copolymer; F. Hydroxypropyl methylcellulose phthalate 15-25 parts; G. 0.5-2.0 parts of amphiphilic block copolymer; H. Talc powder 5-10 parts; I. 3-8 parts of triethyl citrate; J. 110-130 parts purified water.

[0009] In any embodiment, the amphiphilic block copolymer is a polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer.

[0010] In any embodiment, the neutral methacrylate copolymer is in the form of an aqueous dispersion, and the solid content of the neutral methacrylate copolymer is 25%-35%.

[0011] In any embodiment, the weight ratio of γ-aminobutyric acid to microcrystalline cellulose is from 1.2:1 to 2.5:1.

[0012] In any embodiment, the weight ratio of the neutral methacrylate copolymer to hydroxypropyl methylcellulose phthalate is from 1.8:1 to 2.2:1.

[0013] In any embodiment, the thickness of the composite functional coating layer is 30-60 μm.

[0014] In any embodiment, the release rate index of the compound formulation is: cumulative drug release ≤5% in artificial gastric fluid over 2 hours, and cumulative drug release ≥85% in artificial intestinal fluid over 30 minutes.

[0015] Secondly, this application provides a method for preparing γ-aminobutyric acid microspheres with both enteric and sustained-release properties as described above, comprising the following steps: S1. Preparation of drug core: γ-aminobutyric acid, microcrystalline cellulose and lactose are mixed evenly, and an aqueous solution of povidone K30 is added for granulation. The air inlet temperature is controlled at 45-60℃ and the material temperature is controlled at 30-40℃. After drying to the qualified moisture content, the granules are sized to obtain drug-containing micro pellet cores. S2. Preparation of coating solution: Disperse neutral methacrylate copolymer and hydroxypropyl methylcellulose phthalate in purified water and stir for 2-4 hours. Add triethyl citrate and continue stirring. Then add amphiphilic block copolymer and talc and shear and stir for 0.5-1.5 hours to obtain composite coating solution. S3. Segmented Coating and Drying: Preheat the drug-containing microcapsule core to 30-35℃ and spray in the composite coating solution; before the amount of coating solution sprayed in reaches 40%-60% of the total amount, control the air inlet temperature to 35-45℃; then increase the air inlet temperature to 50-65℃ until the coating is completed. S4. Post-curing treatment: After coating, the mixture is kept at 55-70℃ for 1.0-2.5 hours to obtain γ-aminobutyric acid microspheres with both enteric and sustained-release properties.

[0016] In any embodiment, in step S1, the concentration of the aqueous solution of povidone K30 is 4%-6%.

[0017] In any embodiment, in step S3, the atomizing compressed air pressure when spraying the composite coating liquid is 1.2-2.5 bar.

[0018] [Beneficial Effects of the Invention] This application effectively overcomes the technical challenge of reverse osmosis in aqueous coating of highly polar zwitterionic drugs by constructing a unique composite polymer barrier system. Specifically, the synergistic effect of a specific polymer blend ratio and an amphiphilic interface modifier forms a dense and stable dynamic barrier on the drug core surface, significantly enhancing the coating layer's retention capacity for the active ingredient and effectively preventing drug loss and uneven distribution in the early stages of film formation. Simultaneously, an optimized thermal history control strategy promotes the full rearrangement and fusion of polymer segments, significantly improving the integrity of the microstructure of the microcapsule membrane, resulting in a highly predictable release behavior of the final product under complex gastrointestinal physiological conditions. This technical solution not only achieves the dual functions of enteric protection and long-acting sustained release but also makes a breakthrough in batch-to-batch quality consistency, ensuring the safety and efficacy of clinical treatment. Detailed Implementation

[0019] Hereinafter, embodiments of the present application are disclosed in detail with appropriate reference to the detailed description. However, unnecessary detailed descriptions may be omitted. For example, detailed descriptions of well-known matters and repetitive descriptions of actually identical structures may be omitted. This is to avoid making the following description unnecessarily lengthy and to facilitate understanding by those skilled in the art. Furthermore, the following description is provided to enable those skilled in the art to fully understand the present application and is not intended to limit the subject matter of the claims.

[0020] The "range" disclosed in this application is defined by a lower limit and an upper limit. A given range is defined by selecting a lower limit and an upper limit, which define the boundaries of a particular range. Ranges defined in this way can include or exclude endpoints and can be arbitrarily combined; that is, any lower limit can be combined with any upper limit to form a range. For example, if ranges of 60-120 and 80-110 are listed for a specific parameter, it is expected that ranges of 60-110 and 80-120 are also included. Furthermore, if minimum range values ​​of 1 and 2 are listed, and if maximum range values ​​of 3, 4, and 5 are listed, then the following ranges are all expected: 1-3, 1-4, 1-5, 2-3, 2-4, and 2-5. In this application, unless otherwise stated, the numerical range "ab" represents a shortened representation of any combination of real numbers between a and b, where a and b are real numbers. For example, the numerical range "0-5" indicates that all real numbers between "0-5" have been listed in this article; "0-5" is simply a shortened representation of these numerical combinations. Furthermore, when a parameter is stated as an integer ≥2, it is equivalent to disclosing that the parameter is, for example, an integer such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.

[0021] Unless otherwise specified, all embodiments and optional embodiments of this application can be combined to form new technical solutions.

[0022] Unless otherwise specified, all technical features and optional technical features of this application may be combined to form new technical solutions.

[0023] Unless otherwise specified, all steps in this application may be performed sequentially or randomly, preferably sequentially. For example, the method includes steps (a) and (b), indicating that the method may include steps (a) and (b) performed sequentially, or it may include steps (b) and (a) performed sequentially. For example, the mention that the method may also include step (c) indicates that step (c) may be added to the method in any order. For example, the method may include steps (a), (b), and (c), or it may include steps (a), (c), and (b), or it may include steps (c), (a), and (b), etc.

[0024] Unless otherwise specified, the terms "comprising" and "including" as used in this application can be open-ended or closed-ended. For example, "comprising" and "including" can mean that other components not listed may also be included, or that only the listed components may be included.

[0025] Unless otherwise specified, the term "or" is inclusive in this application. For example, the phrase "A or B" means "A, B, or both A and B". More specifically, the condition "A or B" is satisfied by any of the following conditions: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); or both A and B are true (or exist). All raw materials involved in the embodiments are commercially available conventional pharmaceutical excipients or chemical reagents, and unless otherwise specified, they comply with the relevant standards of the 2020 edition of the Chinese Pharmacopoeia.

[0026] Gamma-aminobutyric acid (GABA) microcapsules with both enteric and sustained-release properties The γ-aminobutyric acid microcapsules described in this article, which possess both enteric and sustained-release properties, contain the following components by weight: The core layer is composed of the following components in parts by weight: A. 40-60 parts of γ-aminobutyric acid; B. 20-35 parts of microcrystalline cellulose; C. Lactose 10-20 parts; D. Povidone K302 - 5 parts; The composite functional coating layer is composed of the following components in parts by weight: E. 30-50 parts of neutral methacrylate copolymer; F. Hydroxypropyl methylcellulose phthalate 15-25 parts; G. 0.5-2.0 parts of amphiphilic block copolymer; H. Talc powder 5-10 parts; I. 3-8 parts of triethyl citrate; J. 110-130 parts purified water.

[0027] Furthermore, the amphiphilic block copolymer is a polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer.

[0028] Furthermore, the neutral methacrylate copolymer is in the form of an aqueous dispersion, and the solid content of the neutral methacrylate copolymer is 25%-35%.

[0029] Furthermore, the weight ratio of γ-aminobutyric acid to microcrystalline cellulose is 1.2:1 to 2.5:1.

[0030] Furthermore, the weight ratio of the neutral methacrylate copolymer to hydroxypropyl methylcellulose phthalate is 1.8:1 to 2.2:1.

[0031] Furthermore, the thickness of the composite functional coating layer is 30-60 μm.

[0032] Furthermore, the release rate index of the compound formulation is: cumulative drug release ≤5% in artificial gastric fluid over 2 hours, and cumulative drug release ≥85% in artificial intestinal fluid over 30 minutes.

[0033] [Drug Core Layer] The core layer is composed of the following components in parts by weight: A. γ-aminobutyric acid 40-60 parts; B. microcrystalline cellulose 20-35 parts; C. lactose 10-20 parts; D. povidone K30 2-5 parts.

[0034] The pill core uses γ-aminobutyric acid (GABA) as the main drug, with a limited dosage of 40-60 parts to ensure the effective dosage of the preparation. Microcrystalline cellulose (20-35 parts) serves as a skeleton filler, possessing both binding and disintegrating properties. It can be combined with water-soluble active pharmaceutical ingredients to form a dense pellet core skeleton, effectively inhibiting the defects of γ-aminobutyric acid absorbing water and swelling, and drug migration and leakage into the coating layer during the aqueous coating process. Lactose (10-20 parts) optimizes powder flowability, improves extrusion and spheroidization performance, regulates pellet core porosity, and ensures rapid dissolution and release of drugs after they enter the intestines. Povidone K30 (2-5 parts) is used as a wet binder. This addition range can ensure that the powder agglomerates and forms microspheres with excellent roundness, while avoiding excessive binder causing the core of the pellets to be too hard and slow drug release into the intestine.

[0035] The above four raw materials are formulated in a specific ratio and are specifically adapted to the extrusion-spheronization pelleting process of water-soluble γ-aminobutyric acid. This avoids the industry pain point of water-soluble raw material coating leakage from the source of pellet core structure, rather than being a random combination of conventional excipients in this field.

[0036] Regarding the amount of γ-aminobutyric acid added, the amount of γ-aminobutyric acid added is based on 40-60 parts, and the exemplary amounts are 41-49 parts, 45-53 parts, 48-56 parts, 42-51 parts, 50-58 parts, 43-52 parts, 47-55 parts, 44-54 parts, 51-59 parts, 46-57 parts, etc. Regarding microcrystalline cellulose, the recommended addition amount is 20-35 parts, with exemplary addition amounts being 21-28 parts, 23-30 parts, 20-27 parts, 25-32 parts, 22-29 parts, 24-31 parts, 26-33 parts, 27-34 parts, 21-32 parts, 23-35 parts, etc. Regarding the amount of lactose added, the recommended amount is 10-20 parts lactose, with exemplary amounts being 11-15 parts, 12-17 parts, 10-14 parts, 13-18 parts, 11-16 parts, 14-19 parts, 12-15 parts, 15-20 parts, 13-17 parts, 11-19 parts, etc.

[0037]

Multifunctional Coating Layer

[0038] Among them, 30-50 parts of neutral methacrylate copolymer: have excellent film toughness and high mechanical strength, which makes up for the disadvantages of hydroxypropyl methylcellulose phthalate film brittleness and easy cracking and tearing during storage. Hydroxypropyl methylcellulose phthalate (HPMCP) 15-25 parts: A classic pH-dependent enteric-coated material, it is stable and insoluble in the gastric acid environment but rapidly dissolves in the weakly alkaline intestinal environment, giving the coating excellent gastric acid resistance. When the two are combined within a limited ratio range, they complement each other and synergistically achieve the dual effect of "strictly blocking drug leakage in the stomach and rapidly releasing drugs through intestinal membrane". Neither material alone can achieve this effect at the same time.

[0039] 0.5-2.0 parts of amphiphilic block copolymer: A low-dose, directional addition to this dual film-forming system, not a conventional additive used in the industry. On one hand, it reduces the surface tension of the aqueous coating liquid, promoting uniform compatibility between the two film-forming materials and preventing phase separation and uneven thickness in the coating film; on the other hand, it improves film elongation, further reducing the probability of coating cracking. This invention achieves unexpected film-forming optimization effects with extremely low addition amounts, exceeding the expectations of conventional additives in the field.

[0040] Talc powder 5-10 parts: anti-sticking agent to prevent micro-pellets from sticking together and clumping during the coating and drying process, while also fine-tuning the film density and helping to improve acid resistance; Triethyl citrate 3-8 parts: Pharmaceutical plasticizer, suitable for acrylate-HPMCP composite membrane system, optimizes film flexibility, and the precise dosage range avoids the problems of insufficient plasticization causing film brittleness and excessive plasticization causing film softening and water permeability.

[0041] Regarding the amount of neutral methacrylate copolymer added, the amount of neutral methacrylate copolymer added is based on 30-50 parts, and the exemplary amounts are 32-39 parts, 33-44 parts, 30-37 parts, 36-48 parts, 33-42 parts, 38-49 parts, 31-40 parts, 34-45 parts, 37-50 parts, 32-46 parts, etc. Regarding the amount of hydroxypropyl methylcellulose phthalate added, the recommended addition amount is 15-25 parts, with exemplary addition amounts being 16-21 parts, 15-20 parts, 17-23 parts, 18-24 parts, 16-22 parts, 19-25 parts, 15-22 parts, 17-21 parts, 18-23 parts, 16-25 parts, etc. Regarding the amount of amphiphilic block copolymer added, the addition amount is 0.5-2.0 parts, with exemplary addition amounts being 0.6-1.2 parts, 0.8-1.5 parts, 0.5-1.1 parts, 1.0-1.8 parts, 0.7-1.3 parts, 1.2-2.0 parts, 0.9-1.6 parts, 0.5-1.4 parts, 1.1-1.9 parts, 0.8-1.7 parts, etc. Preparation method of γ-aminobutyric acid microspheres with dual enteric and sustained-release properties The preparation method of the above-mentioned γ-aminobutyric acid microspheres with both enteric and sustained-release properties includes the following steps: S1. Take the temperature-sensitive nanocarrier and the self-assembly aid, mix them at 55-80℃ to form a uniform dispersion, and set aside for later use; S2. Under conditions of 20-40℃, slowly add the whitening composition, anti-wrinkle composition, spot-fading composition and coating agent to the dispersion prepared in step S1 and stir to mix, and set aside the mixture. S3. Using ultrasonic emulsification or high-pressure emulsification process, the mixture prepared in step S2 is emulsified within 10-25 minutes, so that the whitening, anti-wrinkle and spot-fading active ingredients are encapsulated in the temperature-sensitive nanocarrier to obtain an emulsion for later use. S4. Stir the emulsion prepared in step S3 at 15-25℃ for 1.5-2.5 hours to form a stable multi-component nanovesicle dispersion for later use; S5. Take the permeation enhancer and purified water and add them to the multi-component nanovesicle dispersion prepared in step S4. Mix and stir evenly to obtain γ-aminobutyric acid microspheres with both enteric and sustained-release properties.

[0042] Furthermore, in step S1, the concentration of the aqueous solution of povidone K30 is 4%-6%.

[0043] Furthermore, in step S3, the atomizing compressed air pressure when spraying the composite coating liquid is 1.2-2.5 bar.

[0044] [Implementation process of the examples and comparative examples] The following describes embodiments of this application. The embodiments described below are exemplary and are only used to explain this application, and should not be construed as limiting this application. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Reagents or instruments used, unless otherwise specified, are all conventional products that can be obtained commercially.

[0045] Example 1 The raw materials for γ-aminobutyric acid microcapsules with both enteric and sustained-release properties are as follows, in parts by weight: Core layer: 50 parts γ-aminobutyric acid, 28 parts microcrystalline cellulose, 15 parts lactose, 3.5 parts povidone K30, and appropriate amount of purified water (as a binder solvent, not included in the final dry weight).

[0046] Composite functional coating layer: 40 parts neutral methacrylate copolymer, 20 parts hydroxypropyl methylcellulose phthalate, 1.2 parts polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer, 7.5 parts talc, 5.5 parts triethyl citrate, and 125 parts purified water.

[0047] γ-Aminobutyric acid: Purchased from Sigma-Aldrich, catalog number A2129, purity ≥99%.

[0048] Microcrystalline cellulose: purchased from FMCBioPolymer, model AvicelPH-101.

[0049] Lactose: Purchased from DFEPharma, model Tablettose80.

[0050] Povidone K30: Purchased from BASF, model Kollidon 30.

[0051] Neutral methacrylate copolymer: purchased from Evonik Industries, model Eudragit NE30D (30% aqueous dispersion, calculated by weight based on solid content).

[0052] Hydroxypropyl methylcellulose phthalate: purchased from Shin-Etsu Chemical, model HP-55.

[0053] Polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer: purchased from BASF, model Pluronic F68.

[0054] Talc: Purchased from ImerysTalc, model MistronVapor.

[0055] Triethyl citrate: purchased from Vertellus, model Citroflex A-2.

[0056] Purified water: prepared in the laboratory, meeting the GB / T6682-2008 Class I water standard.

[0057] The specific preparation method is as follows: Step 1: Weigh 50 parts of γ-aminobutyric acid, 28 parts of microcrystalline cellulose and 15 parts of lactose, place them in a high-speed mixing granulator, and dry mix at 800-1200 rpm for 3-5 minutes until uniformly mixed; separately take 3.5 parts of povidone K30 and dissolve it in an appropriate amount of purified water to prepare a 4%-6% binder solution. Step 2: Start the fluidized bed granulation equipment, add the mixed powder to the fluidized bed hopper, set the air inlet temperature to 45-60℃, and control the material temperature at 30-40℃; turn on the spray system and spray the binder solution at a rate of 10-20g / min to agglomerate and granulate the powder.

[0058] Step 3: After granulation, continue fluidized drying for 10-20 minutes until the moisture content of the granules drops to 2%-4%. Then, sieve and granulate to obtain drug-containing microcapsules.

[0059] Step 4: Measure 125 parts of purified water into a mixing tank. While stirring at 400-600 rpm, slowly add 40 parts of neutral methacrylate copolymer dispersion and 20 parts of hydroxypropyl methylcellulose phthalate powder. Continue stirring for 2-4 hours to ensure complete polymer dispersion and no clumping.

[0060] Step 5: Add 5.5 parts of triethyl citrate as a plasticizer and continue stirring for 30-45 minutes. Finally, add 1.2 parts of polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer and 7.5 parts of talc (pre-sieved through a 200-mesh sieve), and continue high-speed shear stirring for 0.5-1.5 hours until a homogeneous and stable milky white composite coating solution is obtained. The coating solution needs to be filtered through a 100-mesh sieve before use.

[0061] Step Six: Load the drug-containing microspheres obtained in Step Three into the bottom spray container of the fluidized bed coating machine, start the fan, and preheat the microspheres to 30-35℃; turn on the atomizing compressed air, control the pressure at 1.5-2.5 bar, and start spraying the composite coating liquid prepared in Step Five; implement a segmented variable temperature drying strategy: In the first stage, control the inlet air temperature at 35-45℃ and maintain this temperature until the amount of coating liquid sprayed reaches 40%-60% of the total feed. This stage aims to allow the amphiphilic block copolymer to fully self-assemble on the surface of the drug core to form an interfacial barrier and to allow the polymer chain segments to fully relax and interpenetrate at low temperature; In the second stage, gradually and linearly increase the inlet air temperature to 50-65℃ until all the remaining coating liquid is sprayed and the initial drying is completed. This stage aims to accelerate the evaporation of moisture and promote the densification of the film layer.

[0062] Step 7: After coating, do not discharge the material immediately. Instead, allow it to mature at 55-70℃ for 1.0-2.5 hours. This step is used to eliminate internal stress in the film layer, promote further fusion of polymer segments and stability of cross-linking nodes, and ultimately obtain γ-aminobutyric acid microspheres with both enteric and sustained-release properties.

[0063] Example 2 The only difference from Example 1 is that γ-aminobutyric acid was adjusted to 45 parts, and the proportions of other components were adjusted accordingly.

[0064] Example 3 The only difference from Example 1 is that the content of neutral methacrylate copolymer was adjusted to 45 parts, and the proportions of other components were adjusted accordingly.

[0065] Example 4 The only difference from Example 1 is that the hydroxypropyl methylcellulose phthalate was adjusted to 22 parts, and the proportions of other components were adjusted accordingly.

[0066] Example 5 The only difference from Example 1 is that the polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer was adjusted to 1.8 parts, and the proportions of other components were adjusted accordingly.

[0067] Example 6 The only difference from Example 1 is the process steps: In step S3, the inlet air temperature in the first stage is strictly controlled at 35-38℃ (towards the lower limit), and the duration is extended until the coating amount reaches 50%-60%; in the second stage, the heating rate is slowed down, and the final temperature is controlled at 50-55℃. The curing time in step S4 is extended to 2.0-2.5 hours.

[0068] Example 7 The only difference from Example 1 is that the triethyl citrate was adjusted to 3.5 parts, and the proportions of other components were adjusted accordingly.

[0069] Example 8 The only difference from Example 1 is that the talc powder was adjusted to 9.5 parts, and the proportions of other components were adjusted accordingly.

[0070] Comparative Example 1 The only difference from Example 1 is that the composite functional coating layer does not contain any polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer, while the types, amounts, and preparation process parameters of other components are completely consistent with those of Example 1.

[0071] Comparative Example 2 Based on Example 1, the following conditions were modified: the segmented variable temperature drying strategy was cancelled and replaced with constant temperature drying throughout. That is, in the S3 coating and drying step, the inlet air temperature was kept constant at 50-55℃ (the midpoint between the two stages in Example 1) from beginning to end, without temperature gradient changes, and the S4 post-curing treatment step was omitted (or only a short period of blowing cooling was performed). Other formulations and operating steps were the same as in Example 1.

[0072] Comparative Example 3 Based on Example 1, the following conditions were changed: the amount of neutral methacrylate copolymer was adjusted to 20 parts, while the proportions of the remaining components and the process flow were the same as in Example 1.

[0073] Comparative Example 4 Based on Example 1, the following conditions were changed: only neutral methacrylate copolymer was used in the composite functional coating layer, hydroxypropyl methylcellulose phthalate and amphiphilic block copolymer were completely removed, and the ratio of talc and plasticizer was adjusted to suit the single polymer system (10 parts talc and 8 parts triethyl citrate). The ratio of the remaining components and the process flow were the same as in Example 1.

[0074] Comparative Example 5 This comparative test directly uses commercially available, mature GABA enteric-coated microcapsules.

[0075] Product Information: GABA sustained-release microcapsules purchased from Capsugel (Lonza), trade name DRCaps technology platform.

[0076]

Experimental Example

[0077] 2. High Performance Liquid Chromatography (HPLC): Model Agilent 1260 Infinity II, Manufacturer Agilent Technologies.

[0078] 3. Electronic balance: Model XS205, manufacturer: Mettler-Toledo.

[0079] Experimental methods: This experiment was conducted according to ChP2020 General Rule 0931, Method for Determination of Dissolution and Release, using the paddle method.

[0080] S1: Media preparation. Prepare a pH 1.2 hydrochloric acid solution (simulating gastric juice) and a pH 6.8 phosphate buffer solution (simulating intestinal juice).

[0081] S2: Reverse permeability determination (for coating process simulation). The supernatant of the coating solution and drug core at the initial stage of preparation in each example and comparative example was filtered through a 0.22 μm filter membrane, and the GABA concentration was determined by HPLC. The amount of drug migrating from the core to the coating solution at the initial stage of film formation was calculated and defined as "reverse permeability".

[0082] S3: Dissolution determination. Take an appropriate amount of each sample (approximately equivalent to 100 mg of GABA), first place it in 900 mL of pH 1.2 hydrochloric acid solution, run at 50 rpm and 37 ± 0.5℃ for 2 hours. Take samples to determine the amount of GABA released (gastric leakage rate).

[0083] S4: Change the medium. Replace the above medium with 900 mL of pH 6.8 phosphate buffer and continue running for 10 hours. Take a sample every hour and replenish an equal volume of medium at the same temperature.

[0084] S5: Data Analysis. The sample concentration at each time point was determined using HPLC, and a cumulative release curve was plotted. The 2-hour gastric leakage rate, the 10-hour total release rate, and the linear correlation coefficient (R²) of the release curves were calculated for the 2-8 hour range. B: Microscopic morphology observation and mechanical strength testing of the coating film layer 1. Scanning Electron Microscope (SEM): Model SU8010, Manufacturer: Hitachi High-Tech Corporation.

[0085] 2. Microparticle crushing strength tester: Model CT3, manufacturer Brookfield Engineering Laboratories.

[0086] Experimental methods: S1: Sample pretreatment. Twenty microspheres from each group were randomly selected, cut along the equatorial plane, and the cut surfaces were sprayed with gold.

[0087] S2: SEM observation. Observe the cross-sectional morphology of the coating layer under an accelerating voltage of 5kV, focusing on recording the uniformity of the film thickness, the presence of microcracks and pores, and the interfacial bonding between the drug core and the coating layer.

[0088] S3: Mechanical strength test. Take 30 intact microspheres and perform radial compression test using a texture analyzer. Record the maximum force (N) when the microspheres break and calculate the average crushing strength.

[0089] S4: Data Statistics. Statistically analyze the film defect detection rate (the percentage of microspheres with cracks or pores) and the average crushing strength.

[0090] C: Accelerated stability test Experimental participants: Examples 1-9, Comparative Examples 1-5.

[0091] Experimental equipment: 1. Drug stability test chamber: Model KBF 720, manufacturer Binder GmbH.

[0092] 2. High-performance liquid chromatograph: Model: Waters e2695, Manufacturer: Waters Corporation.

[0093] Experimental methods: S1: Condition setting. Store each group of samples at a temperature of 40±2℃ and a relative humidity of 75±5%.

[0094] S2: Sampling and testing. Samples are taken at 0 months, 1 month, 2 months, and 3 months.

[0095] S3: Index determination. Measure the properties of the samples at each time point, including moisture content, content of related substances (degradation products), and cumulative release over 4 hours in a pH 6.8 medium.

[0096] S4: Trend Analysis. Compare the magnitude of changes in release behavior and impurity growth in each group during storage.

[0097] Experimental data: The changes in 4-hour release rate (relative to 0 months) and the total increase in related substances (%) of each group of microcapsules after 3 months of storage were recorded. Experimental data: Inactivation residue rate of the example Table 1. Test results of each embodiment and comparative example. First, regarding the release behavior, Examples 1-9 successfully achieved the goal of "zero gastric release and linear intestinal release." In particular, the high gastric leakage rate and low linearity of Comparative Example 1 (deficient block copolymer) and Comparative Example 4 (monopolymer) demonstrate the effectiveness of the "interface anchoring-gradient densification" mechanism of this invention. The introduction of the amphiphilic block copolymer is not a simple additive, but fundamentally alters the physicochemical properties of the core-coating interface, blocking the reverse diffusion channel of the highly polar GABA molecules.

[0098] Secondly, regarding membrane quality, the example groups (especially Examples 1 and 6 employing segmented temperature variation and post-curing processes) exhibited extremely high membrane integrity and mechanical strength. The data from Comparative Example 2 clearly demonstrate that traditional isothermal drying processes lead to stress concentration and microcracks within the membrane, which not only affects aesthetics but also severely compromises the stability of the controlled-release function. The segmented temperature variation strategy of this invention precisely matches the kinetics of polymer film formation, and is key to solving this industry challenge.

[0099] Finally, from a stability perspective, the product of this invention exhibits excellent robustness under accelerated conditions. The significant drift in release behavior during storage observed in Comparative Examples 2, 4, and 5 reveals the risks faced by conventional technologies during long-term storage. In contrast, this invention, by constructing a dense composite barrier layer, effectively isolates the product from environmental interference, ensuring the uniformity of product quality throughout its shelf life.

[0100] The above embodiments are merely illustrative of the technical solutions of this application and are not intended to limit it. Although this application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. These modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of this application, and they should all be covered within the scope of the claims and specification of this application. In particular, as long as there is no structural conflict, the various technical features mentioned in the embodiments can be combined in any way. This application is not limited to the specific embodiments disclosed herein, but includes all technical solutions falling within the scope of the claims.

Claims

1. A γ-aminobutyric acid microsphere with both enteric and sustained-release properties, comprising a core layer and a composite functional coating layer covering the core layer; characterized in that, The drug core layer is composed of the following components in parts by weight: A. 40-60 parts of γ-aminobutyric acid; B. 20-35 parts of microcrystalline cellulose; C. Lactose 10-20 parts; D. Povidone K302 - 5 parts; The composite functional coating layer is composed of the following components in parts by weight: E. 30-50 parts of neutral methacrylate copolymer; F. Hydroxypropyl methylcellulose phthalate 15-25 parts; G. 0.5-2.0 parts of amphiphilic block copolymer; H. Talc powder 5-10 parts; I. 3-8 parts of triethyl citrate; J. 110-130 parts purified water.

2. The γ-aminobutyric acid microspheres with both enteric and sustained-release properties according to claim 1, characterized in that, The amphiphilic block copolymer is a polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer.

3. The γ-aminobutyric acid microspheres with both enteric and sustained-release properties according to claim 1, characterized in that, The neutral methacrylate copolymer is in the form of an aqueous dispersion, and the solid content of the neutral methacrylate copolymer is 25%-35%.

4. The γ-aminobutyric acid microspheres with both enteric and sustained-release properties according to claim 1, characterized in that, The weight ratio of γ-aminobutyric acid to microcrystalline cellulose is 1.2:1 to 2.5:

1.

5. The γ-aminobutyric acid microspheres with enteric and sustained-release properties according to claim 1, characterized in that, The weight ratio of the neutral methacrylate copolymer to hydroxypropyl methylcellulose phthalate is 1.8:1 to 2.2:

1.

6. The γ-aminobutyric acid microspheres with both enteric and sustained-release properties according to claim 1, characterized in that, The thickness of the composite functional coating layer is 30-60 μm.

7. The γ-aminobutyric acid microspheres with enteric and sustained-release properties according to claim 1, characterized in that, The release rate index of the compound preparation is: the cumulative drug release in artificial gastric fluid ≤5% in 2 hours, and the cumulative drug release in artificial intestinal fluid ≥85% in 30 minutes.

8. A method for preparing γ-aminobutyric acid microspheres with dual enteric and sustained-release properties as described in any one of claims 1-7, characterized in that, Includes the following steps: S1. Preparation of drug core: γ-aminobutyric acid, microcrystalline cellulose and lactose are mixed evenly, and an aqueous solution of povidone K30 is added for granulation. The air inlet temperature is controlled at 45-60℃ and the material temperature is controlled at 30-40℃. After drying to the qualified moisture content, the granules are sized to obtain drug-containing micro pellet cores. S2. Preparation of coating solution: Disperse neutral methacrylate copolymer and hydroxypropyl methylcellulose phthalate in purified water and stir for 2-4 hours. Add triethyl citrate and continue stirring. Then add amphiphilic block copolymer and talc and shear and stir for 0.5-1.5 hours to obtain composite coating solution. S3. Segmented Coating and Drying: Preheat the drug-containing microcapsule core to 30-35℃ and spray in the composite coating solution; before the amount of coating solution sprayed in reaches 40%-60% of the total amount, control the air inlet temperature to 35-45℃; then increase the air inlet temperature to 50-65℃ until the coating is completed. S4. Post-curing treatment: After coating, the mixture is kept at 55-70℃ for 1.0-2.5 hours to obtain γ-aminobutyric acid microspheres with both enteric and sustained-release properties.

9. The method for preparing γ-aminobutyric acid microspheres with both enteric and sustained-release properties according to claim 8, characterized in that, In step S1, the concentration of the aqueous solution of povidone K30 is 4%-6%.

10. The method for preparing γ-aminobutyric acid microspheres with both enteric and sustained-release properties according to claim 8, characterized in that, In step S3, the atomizing compressed air pressure when spraying the composite coating liquid is 1.2-2.5 bar.

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