Aspirin anhydrous swallowable granules, and preparation method and application thereof

Abstract

This invention relates to anhydrous aspirin granules, their preparation method, and applications, belonging to the field of biomedical technology. The aim is to provide an aspirin granule more suitable for emergency treatment of acute myocardial infarction or acute coronary syndrome, enabling anhydrous swallowing. The anhydrous aspirin granules have a non-blocking taste-masking coating structure, composed of a combination of immediate-release drug-loaded granules A and flavoring granules B. Immediate-release drug-loaded granules A include: aspirin, a first diluent, and a flow aid and microenvironment moisture regulator; flavoring granules B include: a second diluent, an acidity regulator, a sweetener, a flavoring agent, and a flow aid and microenvironment moisture regulator. This invention achieves a balance between anhydrous, swallowable aspirin formulation, rapid gastric release, long-term stability, and uniform dispensing, significantly improving the accuracy of administration, ease of operation, and patient compliance in emergency situations.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and in particular to anhydrous aspirin granules, their preparation method, and their applications. Background Technology

[0002] Acute myocardial infarction (AMI) is a critical emergency caused by acute occlusion of the coronary arteries, leading to myocardial ischemia and necrosis. It is characterized by sudden onset, rapid progression, high risk of death and disability, and a narrow treatment window. In clinical treatment, early administration of adequate doses of antiplatelet drugs during the pre-hospital emergency stage to block platelet cascade activation and thrombus progression is crucial for reducing infarct size, lowering mortality, and improving prognosis. Therefore, developing early antiplatelet intervention agents suitable for out-of-hospital emergencies, with rapid administration and accurate dosage, has significant clinical and public health value.

[0003] Aspirin, as a cornerstone drug for antiplatelet therapy, holds an irreplaceable position in the field of cardiovascular emergency care. Its pharmacological mechanism is well-defined; it primarily exerts a rapid and sustained antiplatelet aggregation effect by irreversibly acetyling cyclooxygenase-1 (COX-1) within platelets, blocking the conversion of arachidonic acid (ARA) to thromboxane A2 (TXA2). Multiple large-scale evidence-based medicine studies have confirmed that early administration of a 300mg loading dose in suspected acute myocardial infarction significantly reduces early mortality and the risk of non-fatal re-infarction. Based on its proven efficacy and rapid onset of action, authoritative guidelines from the American College of Cardiology, the European Society of Cardiology, and the Chinese Society of Cardiology unanimously recommend 300 mg aspirin as the first-line first-line emergency drug for suspected myocardial infarction and acute coronary syndrome.

[0004] However, existing commercially available aspirin formulations are insufficient to fully meet the specific requirements of "rapid, accurate, and easy-to-use" in emergency situations for acute myocardial infarction. Currently, clinical emergency treatment often uses 100mg enteric-coated aspirin tablets, requiring patients to chew three tablets at once to physically break the enteric coating and promote early drug release and absorption. However, this off-label method of administration has significant drawbacks: First, patients experiencing acute myocardial infarction often experience severe chest pain, weakness, or altered consciousness, leading to low compliance with the need to find and chew multiple tablets; second, aspirin itself has a strong astringent taste, and the coating fragments and gritty sensation produced during chewing can easily induce nausea and vomiting, affecting dosage accuracy and potentially increasing myocardial oxygen consumption, even inducing serious arrhythmias; third, swallowing chewed fragments relies on drinking water, which can severely delay treatment in emergency situations where water is unavailable or the patient is unconscious. Summary of the Invention

[0005] Based on the above analysis, this invention provides anhydrous aspirin granules, their preparation method, and applications. The purpose is to provide an aspirin granule that is more suitable for emergency treatment of acute myocardial infarction or acute coronary syndrome, and can be swallowed without water.

[0006] On one hand, the present invention provides anhydrous aspirin granules. The anhydrous aspirin granules have a non-blocking taste-masking coating structure and are composed of an immediate-release drug-loaded granule A and a flavoring granule B. The immediate-release drug-loaded granule A includes: aspirin, a first diluent, and a flow aid and microenvironment moisture regulator; the flavoring granule B includes: a second diluent, an acidity regulator, a sweetener, a flavoring, and a flow aid and microenvironment moisture regulator.

[0007] Furthermore, by weight, the immediate-release drug-loaded particles A comprise: 50-150 parts aspirin, 75-200 parts a first diluent, 0.5-20 parts a flow aid and microenvironment moisture regulator, and 0-8 parts a lubricant.

[0008] Furthermore, the immediate-release drug-loaded particle A also includes a lubricant, with ≤8 parts of lubricant.

[0009] Further, by weight, flavoring granules B comprise: 50-120 parts of a second diluent, 8-30 parts of an acidity regulator, 0.5-6 parts of a sweetener, 5-30 parts of a flavoring agent, and 0.5-10 parts of a flow aid and microenvironment moisture regulator.

[0010] Furthermore, the mass ratio of immediate-release drug-loaded granules A to flavored granules B is 1.0~8.0:1.

[0011] Furthermore, the flow aids and microenvironment moisture regulators in the immediate-release drug-loaded particles A and flavoring particles B respectively include one or more of the following: silica, colloidal silica, and porous silica.

[0012] Furthermore, the mass ratio of the flow aid and microenvironment moisture regulator to the total mass of anhydrous aspirin granules is 0.005~0.05:1.

[0013] Furthermore, the first diluent and the second diluent respectively include one or more of mannitol, erythritol, isomaltitol, and xylitol.

[0014] Furthermore, the lubricant includes one or more of sodium stearate fumarate, polyethylene glycol, sodium lauryl sulfate, and sodium benzoate.

[0015] Furthermore, the acidity regulator is a composition of anhydrous organic acids and organic acid salts, including: anhydrous citric acid and sodium citrate or sodium citrate, anhydrous tartaric acid and sodium tartrate, and anhydrous malic acid and sodium malate.

[0016] Furthermore, the average particle size of aspirin and / or the first diluent is 80-120 mesh; and / or the average particle size of the second diluent is 40-80 mesh; and / or the overall particle size distribution of the anhydrous aspirin granules meets the following conditions: the mass percentage of particles larger than 40 mesh is ≤40%, the mass percentage of particles between 40 and 80 mesh is 40%-90%, and the mass percentage of particles smaller than 80 mesh is ≤15%.

[0017] On the other hand, the present invention also provides a method for preparing anhydrous aspirin granules, for preparing the above-mentioned anhydrous aspirin granules, the preparation method comprising: S1, aspirin, the first diluent, and the flow aid and microenvironment moisture regulator are directly mixed by dry method or granulated by dry method to obtain immediate-release drug-loaded particles A. S2, the second diluent, acidity regulator, sweetener, flavoring, and flow aid and microenvironment moisture regulator are directly dry-mixed or dry-granulated to obtain flavored granules B; S3, mix the immediate-release drug-loaded granules A and flavoring granules B evenly to obtain the total mixed granules; S4. Dispense the total mixed granules into single doses to obtain anhydrous aspirin granules.

[0018] On the other hand, the present invention also provides the application of the above-mentioned anhydrous aspirin granules or the anhydrous aspirin granules prepared by the above preparation method in the preparation of emergency drugs for acute myocardial infarction, acute coronary syndrome or thromboembolic diseases, wherein the preferred specification of the anhydrous aspirin granules is 300mg.

[0019] This invention can achieve at least one of the following beneficial effects: 1. The aspirin of the present invention adopts an anhydrous granule form, which enables the formulation to be administered rapidly in a single dose without the need for drinking water or chewing. It can be swallowed without water, improving the convenience and compliance of patients in emergency situations, and is more suitable for emergency treatment of acute myocardial infarction or acute coronary syndrome.

[0020] 2. This invention addresses the technical challenge of ensuring the chemical stability of aspirin in anhydrous swallowable granules. It employs a phase-separated compounding process of immediate-release drug-loaded granules A and flavor-enhancing granules B. Through functional granule phase separation design, phase A primarily undertakes the functions of drug loading and rapid release, while phase B primarily undertakes the functions of flavor enhancement, saliva secretion promotion, and improved swallowing experience. This design reduces direct contact between aspirin and complex components such as acidulants, flavorings, and sweeteners, lowering the risk of degradation due to local pH changes, moisture absorption, or excipient interactions. Simultaneously, dispersing flow aids and microenvironment moisture regulators within the granules allows for the physical adsorption of trace amounts of moisture that may intrude during preparation, packaging, and storage, reducing the hydrolytic effect of moisture on the ester bonds of aspirin. This achieves long-term granule stability, avoids component segregation, and improves the uniformity of aspirin content.

[0021] 3. Aspirin has a distinctly sour and astringent taste and causes oral irritation. Conventional coating techniques for masking taste conflict with the requirements for rapid release of emergency medications. Therefore, the anhydrous aspirin granules of this invention do not employ conventional polymer coating techniques to mask taste, thus avoiding the delaying effect of the coating film on particle wetting, disintegration, and dissolution. Because no blocking coating layer is formed on the surface of the aspirin granules, the drug can quickly contact gastric juice and disperse and release rapidly after entering the stomach, meeting the requirements for rapid onset of action of early loading administration in acute cardiovascular events. Furthermore, to address the sour and astringent taste, powdery feel, and throat irritation caused by aspirin, this invention uses a phase-by-phase compounding of flavor-correcting granules B and rapid-release drug-loaded granules A, and employs acid modifiers, sweeteners, and flavorings to synergistically improve palatability, achieving a balance between the anhydrous, swallow-friendly nature of the aspirin formulation and rapid gastric release.

[0022] 4. This invention uses low-moisture, low-hygroscopic sugar alcohol diluents to construct the formulation framework, avoiding the use of high-moisture excipients at the formulation level and reducing the source of free water inside the formulation; at the same time, the flow aids and microenvironment moisture regulators dispersed in the particles physically adsorb the trace amounts of moisture that intrude during preparation, dispensing and storage, reducing the hydrolytic effect of moisture on the ester bonds of aspirin, thereby further ensuring the long-term stability of aspirin.

[0023] 5. This invention constructs an acidity adjustment system using anhydrous organic acids and organic acid salts, which can form a suitable acidic microenvironment after the particles come into contact with a small amount of saliva or aqueous medium. The common ion effect is used to further inhibit the hydrolysis reaction of aspirin, thus achieving a balance between the stability and palatability of aspirin.

[0024] 6. By controlling the particle size of raw materials and excipients as well as the overall particle size, this invention can reduce the possibility of segregation and agglomeration, ensuring good content uniformity of anhydrous swallowable granules. On the other hand, it can also take into account the swallowing taste, making it neither gritty nor powdery, resulting in better patient compliance.

[0025] 7. This invention employs a completely non-aqueous dry process, eliminating aspirin degradation caused by moisture introduction at the source of operation, reducing the impact of water vapor on raw materials and intermediates during preparation, and ensuring the chemical stability of the formulation. Single-dose packaging improves the mixing uniformity and filling consistency of high-drug-load particles. Furthermore, the synergistic effect of the completely non-aqueous, low-humidity process, functional phase separation, low-hygroscopic framework, and microenvironment regulation effectively solves the technical challenge of easy hydrolysis in high-drug-load aspirin uncoated systems, significantly improving the stability of the formulation during preparation, storage, and use.

[0026] In this invention, the above-described technical solutions can be combined with each other to achieve more preferred combinations. Other features and advantages of this invention will be set forth in the following description, and some advantages may become apparent from the description or be learned by practicing the invention. The objects and other advantages of this invention can be realized and obtained from what is particularly pointed out in the description and drawings. Attached Figure Description

[0027] The accompanying drawings are for illustrative purposes only and are not intended to limit the invention. Throughout the drawings, the same reference numerals denote the same parts.

[0028] Figure 1 The above are in vitro dissolution curves of various embodiments and comparative examples according to the present invention; Figure 2 This is a pharmacokinetic curve of the present invention (Example 1) and the reference formulation in a beagle dog. Figure 3 The figure shows the pharmacokinetic simulation results in the human body according to Example 1 of the present invention. Detailed Implementation

[0029] To make the objectives, technical solutions, and advantages of the present invention clearer, exemplary embodiments of the present invention will be described below in conjunction with the accompanying drawings. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. For clarity and brevity, not all features of actual embodiments are described in the specification.

[0030] An embodiment of the present invention provides anhydrous aspirin granules, which have a non-blocking taste-masking coating structure and are composed of immediate-release drug-loaded granules A and flavoring granules B. The immediate-release drug-loaded granules A include aspirin, a first diluent, and a flow aid and microenvironment moisture regulator; the flavoring granules B include a second diluent, an acidity regulator, a sweetener, a flavoring, and a flow aid and microenvironment moisture regulator.

[0031] Anhydrous granules are a class of oral solid dosage forms that can be swallowed directly or with the aid of a small amount of saliva. They are characterized by single-dose packaging, no need for chewing, no need for drinking water or pre-dissolving, easy portability, and rapid on-site administration. The aspirin of this invention uses this anhydrous granule formulation, enabling rapid single-dose administration without the need for drinking water or chewing, thus improving patient convenience and compliance in emergency situations. It is particularly suitable for emergency treatment of acute myocardial infarction or acute coronary syndrome.

[0032] However, achieving anhydrous aspirin administration presents a technical challenge: ensuring the chemical stability of aspirin within the anhydrous granules. On one hand, the aspirin molecule contains unstable ester bonds, making it highly sensitive to moisture and humid conditions. Conventional coating processes often introduce moisture or solvents, which can easily induce aspirin hydrolysis to salicylic acid, leading to excessive impurities and reduced efficacy in the formulation. On the other hand, sweeteners, flavorings, and acidulants added to improve palatability are hygroscopic, introducing moisture into the microenvironment. When mixed with aspirin, these components can easily cause aspirin degradation, resulting in reduced drug content in single-dose formulations, excessive impurities, and decreased efficacy.

[0033] To address this, the present invention employs a phase-separated compounding of immediate-release drug-loaded particles A and flavor-enhancing particles B. Through functional particle phase separation design, phase A primarily undertakes the functions of drug loading and rapid release, while phase B primarily undertakes the functions of flavor enhancement, saliva production stimulation, and improved swallowing experience. This design reduces direct contact between aspirin and complex components such as acidulants, flavorings, and sweeteners, lowering the risk of degradation due to local pH changes, moisture absorption, or excipient interactions. Simultaneously, dispersing flow aids and microenvironment moisture regulators within the particles allows for the physical adsorption of trace amounts of moisture that may intrude during preparation, dispensing, and storage, reducing the hydrolytic effect of moisture on the aspirin ester bonds. This achieves long-term particle stability, avoids component segregation, and improves the uniformity of aspirin content.

[0034] Furthermore, the functional phase separation design allows for the separate adjustment of particle size, flowability, mouthfeel, and hygroscopicity of phases A and B, and single-dose dispensing through total mixing, which helps improve the mixing uniformity, filling consistency, and industrial controllability of high drug-load particles.

[0035] Aspirin has a distinctly astringent taste and causes oral irritation. To achieve anhydrous aspirin swallowing, it is necessary to effectively improve the taste of anhydrous aspirin granules. However, conventional taste-masking techniques conflict with the requirement for rapid release. Conventional polymer coating taste-masking techniques tend to form a release barrier on the surface of drug granules, delaying the dispersion and dissolution of granules in the stomach, which contradicts the rapid release required for emergency administration.

[0036] Therefore, the anhydrous aspirin granules of this invention do not employ conventional polymer-masked coating technology to avoid the delaying effect of the coating film on particle wetting, disintegration, and dissolution. Because no blocking coating layer is formed on the surface of the aspirin granules, the drug can quickly contact gastric juice and disperse and release rapidly after entering the stomach, meeting the requirements for early loading administration in acute cardiovascular events for rapid onset of action. Furthermore, to address the sour taste, powdery feel, and throat irritation caused by aspirin, this invention uses a phase-by-phase compounding of flavor-correcting granules B and fast-release drug-loaded granules A, and employs acidity modifiers, sweeteners, and flavorings to synergistically improve palatability, achieving anhydrous, swallow-friendly aspirin formulation with rapid gastric release.

[0037] In summary, based on comprehensive considerations of aspirin stability, palatability adjustment, and rapid release, the anhydrous aspirin granules of this invention, through functional particle phase separation design and uncoated particle structure, achieve a balance between anhydrous swallowability, rapid gastric release, long-term stability, and uniform content of aspirin formulations. This significantly improves the accuracy of administration, ease of operation, and patient compliance in emergency situations. The formulation of this invention is specifically designed for the emergency load administration needs of acute myocardial infarction or acute coronary syndrome. The particle structure and formulation are specially designed so that the prepared anhydrous swallowable granules can effectively mask the taste without the need for a blocking taste-masking coating, and are instantly dispersed and released in saliva or the stomach. This significantly improves the patient's emergency administration experience and solves the technical contradictions of existing enteric-coated tablets, such as inconvenience of chewing, delayed onset of action, poor patient compliance, and the difficulty in simultaneously achieving palatability, rapid release, stability, and uniform dispensing. It provides clinical practice with an aspirin emergency administration regimen that balances palatability, rapid onset of action, good stability, and accurate dosage.

[0038] According to some embodiments of the present invention, the immediate-release drug-loaded particles A, by weight, comprise: 50-150 parts of aspirin, 75-200 parts of a first diluent, and 0.5-20 parts of a flow aid and microenvironment moisture regulator. For example, the aspirin is in the following quantities: 50 parts, 55 parts, 60 parts, 65 parts, 70 parts, 75 parts, 80 parts, 85 parts, 90 parts, 95 parts, 100 parts, 105 parts, 110 parts, 115 parts, 120 parts, 125 parts, 130 parts, 135 parts, 140 parts, 145 parts, and 150 parts. The first diluent is available in concentrations of 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, and 200 parts. The flow aid and microenvironment moisture regulator are available in concentrations of 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 parts.

[0039] Optionally, the immediate-release drug-loaded particle A further includes a lubricant, wherein the lubricant is ≤8 parts. For example, the lubricant may be 0.1 parts, 0.5 parts, 1 part, 1.5 parts, 2 parts, 2.5 parts, 3 parts, 3.5 parts, 4 parts, 4.5 parts, 5 parts, 5.5 parts, 6 parts, 6.5 parts, 7 parts, 7.5 parts, or 8 parts. It should be noted that the immediate-release drug-loaded particle A in this embodiment of the invention may or may not contain a lubricant.

[0040] It should be noted that the immediate-release drug-loaded particle A is the main drug-containing and releasing unit. The design of the dosage range of each component is based on the principles of meeting the aspirin loading dose, good stability, and achieving rapid release. The aspirin dosage is used to meet the emergency loading dose requirements; the primary diluent is used to disperse the active pharmaceutical ingredient and improve processing performance; the flow aid and microenvironment moisture regulator are used to improve the flowability, anti-caking properties, and trace moisture control of the high drug loading system, but excessive dosage should be avoided to prevent increased powderiness or localized hygroscopicity; the lubricant is used to reduce friction and adhesion during mixing, dry granulation, and dispensing, while the dosage needs to be controlled to avoid affecting gastric wetting and rapid release. Therefore, the setting of the proportions of each component is the result of balancing stability, process adaptability, and immediate-release performance while ensuring accurate single-dose aspirin administration.

[0041] According to some embodiments of the present invention, the flavoring granules B, by weight, comprise: 50-120 parts of a second diluent, 8-30 parts of an acidity regulator, 0.5-6 parts of a sweetener, 5-30 parts of a flavoring agent, and 0.5-10 parts of a flow aid and microenvironment moisture regulator.

[0042] For example, the second diluent is in the quantities of 50 parts, 55 parts, 60 parts, 65 parts, 70 parts, 75 parts, 80 parts, 85 parts, 90 parts, 95 parts, 100 parts, 105 parts, 110 parts, 115 parts, and 120 parts. The acidity regulator is in the quantities of 8 parts, 10 parts, 12 parts, 14 parts, 15 parts, 16 parts, 18 parts, 20 parts, 22 parts, 24 parts, 25 parts, 26 parts, 28 parts, and 30 parts. The sweetener is in the quantities of 0.5 parts, 1 part, 1.5 parts, 2 parts, 2.5 parts, 3 parts, 3.5 parts, 4 parts, 4.5 parts, 5 parts, 5.5 parts, and 6 parts. The flavoring is in the quantities of 5 parts, 8 parts, 10 parts, 12 parts, 15 parts, 18 parts, 20 parts, 22 parts, 25 parts, 28 parts, and 30 parts. The flow aid and microenvironment moisture regulator are available in concentrations of 0.5 parts, 1 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, and 10 parts.

[0043] It should be noted that flavoring granules B are used to improve taste, wetting, and swallowing compliance during anhydrous swallowing. Their dosage must balance flavor intensity, moisture absorption risk, and repackaging performance. The second diluent, acting as the B-phase framework, carries and disperses acidity modifiers, sweeteners, and flavorings, improving granule taste and ingestion dispersibility. Acidity modifiers harmonize the astringent taste of aspirin and promote saliva secretion. Simultaneously, an appropriate amount of acidity modifier can create a suitable acidic microenvironment after the granules come into contact with a small amount of saliva or aqueous medium, further inhibiting the hydrolysis of aspirin through the common ion effect. Sweeteners and flavorings improve taste and olfactory acceptance. Flow aids and microenvironment moisture regulators improve the dispersibility and anti-caking properties of the flavoring components and reduce the adverse effects of moisture absorption by acidity modifiers, flavorings, and other components on granule stability and flowability. When the dosage of each component is too low, it is difficult to guarantee the taste and swallowing experience; when it is too high, it may increase the risks of moisture absorption, clumping, single dose volume and stability. Therefore, it is necessary to limit it within an appropriate range.

[0044] According to some embodiments of the present invention, the mass ratio of immediate-release drug-loaded granules A to flavored granules B is 1.0 to 8.0:1, for example, 1.0:1, 1.2:1, 1.5:1, 1.8:1, 2.0:1, 2.5:1, 3.0:1, 3.5:1, 4.0:1, 4.5:1, 5.0:1, 5.5:1, 6.0:1, 6.5:1, 7.0:1, 7.5:1, 8.0:1.

[0045] The mass ratio of immediate-release drug-loaded granules A to flavoring granules B directly affects the masking effect, swallowing volume, and mixing uniformity. If the proportion of granules A is too high, the flavoring component of granules B will be insufficient, making it difficult to effectively improve the astringent taste and swallowing discomfort when administering high doses of aspirin. If the proportion of granules B is too high, it will increase the swallowing volume, potentially exceeding the limited wetting capacity of saliva in emergency situations, and increasing the burden of excipient hygroscopicity and dispensing. Simultaneously, controlling the mass ratio of the two phases within an appropriate range can reduce differences in powder kinetics during mixing, effectively avoiding powder segregation during total mixing, and ensuring the content uniformity of single-dose strip packaging.

[0046] According to some embodiments of the present invention, both the first diluent and the second diluent are low-moisture, low-hygroscopic sugar alcohol diluents. The first diluent includes one or more of mannitol, erythritol, isomaltitol, and xylitol; the second diluent includes one or more of mannitol, erythritol, isomaltitol, and xylitol.

[0047] The diluent selection in this invention abandons traditional diluents with high moisture content or easy hygroscopicity, and innovatively selects sugar alcohols with extremely low water content and virtually no hygroscopicity as the first and second diluents. This design cuts off the introduction of internal free water at the source, reducing the threat of hydrolysis of aspirin ester bonds by the skeleton material. At the same time, the sugar alcohol excipients have an endothermic effect when dissolved, which can produce a cooling taste when swallowed without water. Combined with the acidity regulators, sweeteners and flavorings in flavoring granules B, they can synergistically enhance the taste masking effect, significantly improving the palatability and patient compliance of swallowing without water.

[0048] Preferably, the first diluent is a combination of mannitol and erythritol. The mass ratio of mannitol to erythritol is 0.5 to 4:1, for example, 0.5:1, 0.8:1, 1:1, 1.2:1, 1.5:1, 1.8:1, 2:1, 2.2:1, 2.5:1, 2.8:1, 3:1, 3.2:1, 3.5:1, 3.8:1, or 4:1.

[0049] Preferably, the second diluent is erythritol.

[0050] In the embodiments of the present invention, the diluent in the immediate-release drug-loaded particles A is preferably a combination of mannitol and erythritol. Mannitol has excellent powder processability, compressibility and flowability, while erythritol can provide excellent refreshing taste and rapid dissolution characteristics. The above-mentioned combination can give full play to the synergistic advantages of the two sugar alcohols in powder rheology and sensory experience, overcome the performance shortcomings of single excipients, and help to achieve the stability, palatability and immediate release of the formulation.

[0051] According to some embodiments of the present invention, the flow aid and microenvironment moisture regulator in the immediate-release drug-loaded particles A and the flavoring particles B respectively include one or more of silica, colloidal silica, and porous silica.

[0052] This invention selects silica-based substances as flow aids and microenvironment moisture regulators, primarily based on the multiple physical properties imparted by their nanoscale mesoporous structure and extremely large specific surface area. On one hand, the high drug loading of aspirin conflicts with powder processing. If a dry powder mixing method is used to avoid moisture, a high proportion of aspirin raw material can easily lead to problems such as static electricity, agglomeration, and poor flowability. This invention, by adding silica-based substances, can effectively eliminate static electricity generated during the mixing process of high-drug-loading particles, reduce agglomeration, and improve powder flowability and mixing uniformity. On the other hand, its mesoporous structure can also adsorb trace amounts of moisture that intrude during preparation, packaging, and storage, protecting aspirin from hydrolysis. Simultaneously, it also helps improve particle surface dispersibility, reduce fine powder agglomeration upon ingestion, dry powder sensation, and throat irritation, and improve the smoothness of anhydrous swallowing.

[0053] Preferably, the mass ratio of the total mass of the flow aid and microenvironment moisture regulator in the immediate-release drug-loaded granules A and the flavoring granules B to the total mass of the anhydrous aspirin granules is 0.005~0.05:1, for example, 0.005:1, 0.008:1, 0.01:1, 0.015:1, 0.02:1, 0.025:1, 0.03:1, 0.035:1, 0.04:1, 0.045:1, 0.05:1.

[0054] The dosage of the flow aid and microenvironment moisture regulator components needs to be controlled within a reasonable range. If the dosage is too low, it will be difficult to exert sufficient flow aid, water control and mouthfeel improvement effects. If the dosage is too high, it may lead to local moisture enrichment due to capillary condensation effect, increase the risk of hydrolysis, and bring a dry mouthfeel and powder residue. This dosage design achieves a good balance between powder processing performance, chemical stability and mouthfeel when swallowed anhydrous.

[0055] According to some embodiments of the present invention, the lubricant is a hydrophilic or low-hydrophobic lubricant, including one or more of sodium stearate fumarate, polyethylene glycol, sodium dodecyl sulfate, and sodium benzoate.

[0056] This invention balances lubrication efficiency, rapid release, and palatability in the selection of lubricants. While traditional strong hydrophobic lubricants such as magnesium stearate provide good lubrication, they tend to form a hydrophobic layer on the particle surface, reducing the wetting speed of small amounts of saliva or gastric juice, leading to difficulty swallowing, increased oral residue, and delayed aspirin release. This invention selects hydrophilic or low-hydrophobic lubricants and controls their usage within a low range. This reduces the risks of friction, adhesion, and static electricity during dry granulation, mixing, and packaging, while avoiding the formation of a significant hydrophobic barrier. This allows the particles to be more easily wetted by saliva in the mouth, making swallowing smoother, and ensuring rapid dispersion and release after entering the stomach.

[0057] According to some embodiments of the present invention, the acidity regulator is a composition of anhydrous organic acids and organic acid salts, including: anhydrous citric acid and sodium citrate or sodium citrate, anhydrous tartaric acid and sodium tartrate, and anhydrous malic acid and sodium malate.

[0058] Preferably, the mass ratio of anhydrous organic acid to organic acid salt in the acidity regulator is 0.5 to 2:1, for example, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2.0:1.

[0059] Preferably, the mass ratio of the acidity modifier to the total mass of anhydrous aspirin granules is 0.01 to 0.08:1, for example, 0.01:1, 0.015:1, 0.02:1, 0.025:1, 0.03:1, 0.035:1, 0.04:1, 0.045:1, 0.05:1, 0.06:1, 0.07:1, or 0.08:1.

[0060] The acidity modifier of this invention uses a combination of anhydrous organic acids and organic acid salts, based on a comprehensive consideration of taste correction, saliva secretion stimulation, and aspirin stability. Using an anhydrous form reduces the risk of hydrolysis caused by the introduction of free water into the formulation; the specific ratio of acid salts creates a milder acidity modifier system, rapidly stimulating saliva secretion and effectively masking the aspirin odor, avoiding excessive acidity or increased oral irritation caused by using organic acids alone. Simultaneously, it can rapidly create a slightly acidic microenvironment when the powder comes into local contact with trace amounts of moisture or saliva, utilizing the common ion effect to inhibit aspirin hydrolysis, thus achieving a balance between taste optimization and chemical stability.

[0061] According to some embodiments of the present invention, the sweetener includes one or more of sucralose, aspartame, acesulfame potassium, steviol glycosides, neotame, and sodium saccharin.

[0062] According to some embodiments of the present invention, the flavoring includes one or more of orange flavoring, pomegranate flavoring, lemon flavoring, and berry flavoring.

[0063] This invention utilizes a high-intensity sweetener and a compound fruit flavoring, primarily to achieve a powerful taste masking effect under the limited volume of a single dose in emergency situations. High-drug-load formulations are extremely sensitive to volumetric load, while the high-intensity sweetener achieves a powerful sweetening and bitter-masking effect with very low dosage. Combined with the fruit flavoring, it enhances the overall taste through both olfactory and gustatory effects, significantly improving swallowing compliance in emergency situations.

[0064] According to some embodiments of the present invention, the average particle size of aspirin can be 80-120 mesh; the average particle size of the first diluent can be 80-120 mesh; and the average particle size of the second diluent can be 40-80 mesh.

[0065] In the embodiments of this invention, the particle size range of each component is determined comprehensively based on dissolution, content uniformity, taste, and pharmacopoeia requirements for granules. Both aspirin raw material and the first diluent are controlled at 80-120 mesh, which ensures that the particle sizes of the A-phase main and excipients are similar, reducing the risk of segregation and agglomeration during dry mixing or dry granulation, and is beneficial for content uniformity and packaging consistency. The second diluent is controlled at 40-80 mesh, which improves the flowability and mouthfeel of the B-phase flavoring granules, and reduces the powdery feel and the risk of moisture absorption and clumping caused by fine powder.

[0066] According to some embodiments of the present invention, the overall particle size distribution of the anhydrous aspirin granules satisfies the following conditions: the mass percentage of particles larger than 40 mesh is ≤40% (e.g., 40%, 30%, 20%, 10%, 5%, etc.), the mass percentage of particles between 40 and 80 mesh is 40% to 90% (e.g., 40%, 50%, 60%, 70%, 80%, 90%), and the mass percentage of particles smaller than 80 mesh is ≤15% (e.g., 15%, 12%, 10%, 8%, 6%, 5%, 2%).

[0067] The aspirin anhydrous granules of this invention have a main distribution range of 40-80 mesh, which can balance the taste, flowability, and rapid release in the stomach when swallowed anhydrously. A higher proportion of coarse particles can easily affect the taste and increase packaging fluctuations, while a higher proportion of fine particles can easily generate static electricity, dust, agglomeration, and segregation. Controlling the fine powder passing through an 80-mesh sieve to no more than 15% also helps to meet the pharmacopoeia's requirements for controlling the proportion of fine powder in granules and ensures the stability of industrial packaging of the formulation.

[0068] According to some embodiments of the present invention, flavoring granules B may further include an oral moistening and clump-forming agent, which can cause the fine powder to slightly aggregate into a more suitable granular structure, reducing the dusty feeling and choking risk that may occur when swallowed without water. The oral moistening and clump-forming agent accounts for 0 to 20 parts by weight of flavoring granules B. Specifically, the oral moistening and clump-forming agent includes one or more of carbomer, poloxamer, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and xanthan gum.

[0069] According to some embodiments of the present invention, flavoring particles B may further include a hydrophilic or hypohydrophobic lubricant to improve the flowability and anti-adhesion properties of the B-phase powder without affecting the particle's rapid release characteristics. The lubricant comprises 0-8 parts by weight of flavoring particles B. Specifically, the lubricant includes one or more of sodium stearate fumarate, polyethylene glycol, sodium dodecyl sulfate, and sodium benzoate.

[0070] According to some embodiments of the present invention, the aspirin content in the anhydrous swallowable granules is preferably 300 mg, i.e., the drug loading is 300 mg.

[0071] It should be noted that the anhydrous aspirin granules of this invention have a non-blocking taste-masking coating structure, which can effectively mask the taste and rapidly disperse and release the aspirin in a small amount of saliva or after entering the gastric juice. This invention does not employ a blocking taste-masking coating based on a comprehensive consideration of aspirin stability and the need for rapid release in emergency situations. Conventional taste-masking coating processes require dissolving the coating material in water or an organic solvent, followed by spray coating and drying. The moisture and humid heat introduced in this process can easily lead to the hydrolysis of aspirin ester bonds, affecting the stability of the formulation. Simultaneously, blocking taste-masking coatings form a physical barrier on the granule surface, which, while reducing oral irritation, may delay the wetting, dispersion, and release of the granules, which is not conducive to the clinical need for rapid early onset of action in acute myocardial infarction. This invention achieves a good taste by functional phase separation, combined with the refreshing taste of the sugar alcohol skeleton of the diluent, and the flavoring effect of the acidity regulator, high sweetener and flavoring. Under the premise of avoiding the risks of water-based coating and humid heat, it can ensure both the chemical stability of aspirin and the instantaneous dispersion and rapid release of particles in saliva or gastric juice.

[0072] The present invention also provides a method for preparing anhydrous aspirin granules, which is used to prepare the above-mentioned anhydrous aspirin granules. The preparation method includes: S1, aspirin, the first diluent, and the flow aid and microenvironment moisture regulator are directly mixed by dry method or granulated by dry method to obtain immediate-release drug-loaded particles A; S2, the second diluent, acidity regulator, sweetener, flavoring, and flow aid and microenvironment moisture regulator are directly dry-mixed or dry-granulated to obtain flavored granules B; S3, mix the immediate-release drug-loaded particles A and flavoring particles B evenly (for example, using a three-dimensional motion mixer or a V-type mixer) to obtain the total mixed particles; S4. Dispense the total mixed granules into single doses to obtain anhydrous aspirin granules.

[0073] The preparation method of this invention adopts a fully non-aqueous dry process, which constructs a complete water-hydrolysis barrier, eliminating aspirin degradation caused by moisture introduction from the source of operation. Through the synergistic effect of the above-mentioned fully non-aqueous dry process, the functional phase separation of drug loading and flavoring, the low hygroscopic skeleton of the diluent, and the microenvironment moisture regulator, this invention effectively solves the technical problem of easy hydrolysis of high drug loading aspirin uncoated system, and significantly improves the stability of the formulation during preparation, storage and use.

[0074] In S4, the total mixed granules are packaged according to the specification of a single dose containing 300mg of aspirin. The embodiments of the present invention use the above-mentioned packaging specification, which simplifies the existing clinical administration method of "urgently chewing three 100mg enteric-coated tablets" to "one packet for immediate administration." Patients suspected of having an acute myocardial infarction or acute coronary syndrome can administer the medication without needing to identify the specification, count the tablets, or chew or drink water. This administration method effectively avoids potential risks such as insufficient chewing, difficulty swallowing fragments, nausea and vomiting, and inconsistent dosage, improving the accuracy, convenience, and patient compliance of early loading administration in emergency situations.

[0075] Preferably, all operations in steps S1 to S4 are carried out in a low-humidity environment with a relative humidity (RH) of ≤40%. This invention strictly controls the relative humidity of the production and packaging environment to ≤40%. A low-humidity production environment reduces the contact between airborne water vapor and raw materials and intermediates from the source, minimizing the impact of water vapor on raw materials and intermediates during the preparation process, effectively inhibiting hydrolysis reactions, and ensuring the chemical stability of the formulation preparation process.

[0076] Preferably, in step S4, the anhydrous aspirin granules are individually sealed in pharmaceutical high-barrier moisture-proof packaging material. Pharmaceutical high-barrier moisture-proof packaging material includes one or more of the following: aluminum-plastic composite film, aluminum foil composite film, pharmaceutical high-barrier composite film, strip packaging material, or rod packaging material. This embodiment of the invention uses high-barrier moisture-proof packaging, which can prevent external moisture penetration during product storage and transportation, ensuring the chemical stability of the formulation throughout its entire life cycle. The combination of dry processing and packaging conditions not only meets the stability requirements of aspirin but also facilitates industrial-scale production, providing an important guarantee for the long-term stability and clinical safety of anhydrous aspirin granules.

[0077] Embodiments of the present invention also provide the application of the above-described anhydrous aspirin granules or the anhydrous aspirin granules prepared by the above preparation method in the preparation of emergency drugs for acute myocardial infarction, cardiovascular emergencies, acute coronary syndrome or thromboembolic diseases.

[0078] The anhydrous aspirin granules of this invention are used to replace the existing emergency load administration method of chewing 3 100mg enteric-coated aspirin tablets, and are particularly suitable for pre-hospital emergency patients in situations where they are elderly, have difficulty swallowing, or lack water.

[0079] The anhydrous aspirin granules of the present invention have the following advantages: (1) It adopts a non-blocking taste-masking coating structure, which takes into account both palatability and rapid release in the stomach: This invention does not employ conventional polymer-masking coating technology, thus avoiding the delaying effect of the coating film on particle wetting, disintegration, and dissolution. Addressing the astringent taste, powdery feel, and throat irritation associated with 300mg high-load aspirin, a phase-separated compounding of flavor-correcting particles B and immediate-release drug-loaded particles A is used. An anhydrous organic acid / organic acid salt acidity adjustment system, a high-intensity sweetener, a complex flavoring, and a low-moisture, low-hygroscopic sugar alcohol backbone are employed to synergistically improve palatability. The cooling sensation of the sugar alcohol, the mild salivation-promoting effect of the acidity adjustment system, and the synergistic flavor-correcting effect of the sweetener and flavoring harmonize the astringent and irritating sensation of aspirin, improving oral acceptability. Furthermore, appropriate raw material particle size, total particle size distribution, microenvironment moisture regulator dosage, and a hydrophilic lubrication system ensure that the particles can be quickly wetted and dispersed upon contact with a small amount of saliva, reducing the dry powdery feel, foreign body sensation, and the risk of choking. Meanwhile, because no blocking coating layer is formed on the surface of aspirin particles, the drug can quickly come into contact with gastric juice and be rapidly dispersed and released after entering the stomach. Its in vitro dissolution curve and in vivo pharmacokinetic characteristics meet the stringent requirements for onset speed of early loading administration in acute cardiovascular events.

[0080] (2) The risk of aspirin hydrolysis is reduced synergistically through "non-aqueous low-humidity process - functional phase separation - low hygroscopic framework - microenvironment moisture and acidity regulation": To address the issue of aspirin ester bonds being sensitive to moisture and humid conditions, and easily hydrolyzing to form salicylic acid, this invention constructs a systematic anti-degradation system: ① Fully non-aqueous process and low humidity environment control: The entire preparation process adopts a non-aqueous dry process to avoid contact between aspirin and any liquid water or organic solvents. At the same time, the relative humidity of the production and packaging environment is strictly controlled at a low level, thereby eliminating the risk of aspirin degradation caused by solvent introduction at the source of production; ② Functional phase separation design: The immediate-release drug-loaded phase (phase A) and the flavoring phase (phase B) are physically isolated and premixed, effectively reducing the risk of incompatibility degradation caused by long-term direct contact between aspirin and hygroscopic components such as acidulants and fragrances; ③ Low hygroscopic matrix: The entire formulation uses a low-moisture, low-hygroscopic sugar alcohol diluent as the basic matrix, cutting off the introduction of internal free water and the absorption of external environmental moisture at the formulation matrix level; ④ Microenvironment moisture regulation: The microenvironment moisture regulator dispersed in the formulation can actively adsorb trace amounts of free water that invade during preparation or storage, protecting aspirin molecules from moisture erosion; ⑤ Microenvironment acidity regulation: The acidic buffer system composed of anhydrous organic acids and organic acid salts can maintain suitable acidic conditions in the microenvironment when in contact with trace amounts of moisture or saliva, further inhibiting the hydrolysis reaction of aspirin through the common ion effect, thereby significantly improving the long-term stability of the formulation throughout its entire life cycle.

[0081] (3) Ensure content accuracy and uniformity under high drug loading conditions: To address the challenges of powder segregation and process degradation that are prone to occur during the all-dry processing of 300mg high-load aspirin, this invention significantly reduces the differences in powder kinetics between the main and auxiliary materials by employing appropriate raw material and excipient particle sizes and total mixed particle size distribution, suitable silica flow aids, and A / B functional phase separation design. This overcomes powder stratification during dry mixing and ensures excellent content uniformity in single-dose packaging. Simultaneously, relying on a completely non-aqueous process, a low-hygroscopic sugar alcohol diluent framework, and a microenvironment water control strategy, it blocks the hydrolysis of the active pharmaceutical ingredient induced by free water intrusion at the source, ensuring long-term stability of the formulation content. This multi-dimensional synergistic design effectively guarantees the dosage accuracy, content stability, and industrial packaging consistency of high-load aspirin anhydrous swallowable granules.

[0082] (4) Reasonably limit the dosage of silica-based flow aids and / or microenvironment moisture regulators to balance flow aid, water control, and taste: This invention utilizes silica, colloidal silica, or porous silica as a flow aid and microenvironment moisture regulator, and limits its suitable dosage range. Within this range, it exerts excellent powder flow aid properties, eliminating the risk of electrostatic agglomeration in high-load aspirin and improving mixing and dispensing efficiency. Simultaneously, it provides appropriate microenvironment water-locking function, effectively preventing strong capillary reverse humidification caused by excessive use by setting strict dosage limits, thus avoiding accelerated drug hydrolysis due to excessive local moisture accumulation in the particles. Furthermore, an appropriate amount of silica-like substances can improve the particle surface dispersion, reduce local fine powder agglomeration and dry powder accumulation in the mouth, helping to reduce oral powderiness, stickiness, and throat irritation, and improving smoothness and acceptability when swallowed anhydrous.

[0083] (5) Provides a specific aspirin formulation regimen suitable for early loading administration in cardiovascular emergencies: This invention systematically addresses the challenges of simultaneously achieving high drug loading, anhydrous swallowability in single-dose formulations, rapid gastric release, long-term stability, and uniform packaging of aspirin from three aspects: dosage form structure, formulation composition, and preparation process. Compared with existing chewable enteric-coated aspirin tablets, wet-process granules, polymer-coated taste-masked granules, or direct-mixing solutions of ordinary powders, this invention offers comprehensive advantages in terms of administration convenience, early rapid release, stability, taste, and industrial controllability. It provides a more suitable formulation for early antiplatelet loading administration in cardiovascular emergencies such as acute myocardial infarction or acute coronary syndrome, demonstrating clear clinical application value and industrialization prospects.

[0084] The technical solution of the present invention will be further illustrated below with specific embodiments. The parts by weight in the present invention represent the proportional relationship of each substance, and are not absolute values.

[0085] Examples 1-11 Examples 1-11 each provide anhydrous aspirin granules, and the composition of the anhydrous aspirin granules in each example is shown in Table 1.

[0086] Table 1. Composition of the anhydrous aspirin granules in each embodiment

[0087] In Examples 1-6 and 8-11, the preparation method of anhydrous aspirin granules includes: S1, Preparation of immediate-release drug-loaded particles A: The prescribed amount of aspirin, first diluent, flow aid, and microenvironment moisture regulator are passed through a 60-mesh sieve and then mixed in a three-dimensional mixer for 10 minutes. A lubricant is then added and mixing continues for 5 minutes to obtain phase A premix. The above phase A premix is ​​transferred to a dry roller granulator for dry granulation. The roller pressure is 5.0 MPa, the roller speed is 8 rpm, and the roller gap is 1 mm. The resulting flake-like material is then pulverized and granulated using a 20-40 mesh sieve. Particles distributed in the 40-80 mesh range are collected to obtain immediate-release drug-loaded particles A.

[0088] S2, Preparation of Flavoring Granules B: Pass the second diluent through a 40-mesh sieve, and pass the acidity regulator, sweetener, flavoring, and flow aid and / or microenvironment moisture regulator through an 80-mesh sieve respectively. First, premix the acidity regulator, sweetener, flavoring, flow aid and / or microenvironment moisture regulator with an equal volume of the second diluent in a small mixer for 5 minutes; then add them together with the remaining second diluent to a three-dimensional mixer and mix for 12 minutes to obtain flavoring granules B.

[0089] S3, Total Mixing: Add immediate-release drug-loaded granules A and flavoring granules B into a three-dimensional motion mixer and mix for 10 minutes to obtain total mixed granules.

[0090] S4, Packaging: The total mixed granules are transferred to a high-speed strip packaging machine and packaged into single-dose 300mg aspirin granules. The granules are then sealed with a pharmaceutical high-barrier aluminum-plastic composite moisture-proof film to obtain anhydrous aspirin granules.

[0091] Example 7 In addition to the ingredients listed in Table 1, the aspirin anhydrous swallowable granules of this embodiment also contain 8g of the wetting and flocculating agent poloxamer 188 and 2g of the lubricant sodium stearate fumarate.

[0092] In addition, in the preparation method of the aspirin anhydrous swallowable granules in this embodiment, steps S2 to S4 are similar to those in Example 1. The difference is that the A-phase premix in step S1 is no longer dry granulated, and the whole powder is directly mixed to obtain the immediate-release drug-loaded granules A.

[0093] Comparative Example 1 The formulation and preparation method of this comparative example are similar to those of Example 1, except that wet granulation is used in step S1. Aspirin is mixed with mannitol and erythritol, and then an appropriate amount of 5% hydroxypropyl methylcellulose aqueous solution is added. The soft material is prepared in a wet granulator, and the soft material is granulated by passing it through a 20-mesh sieve. Then the particles are placed in a fluidized bed and dried until the moisture content is <1.0%. The dried particles are mixed with porous silica and sodium stearate fumarate to obtain immediate-release drug-loaded particles A.

[0094] Comparative Example 2 The formulation and preparation method of this comparative example are similar to those of Example 1, except that the functional phase separation design and isolation premixing of immediate-release drug-loaded particles A and flavoring particles B are not performed. After sieving all raw and excipient materials in the formulation, they are directly put into a three-dimensional mixer for one-time total mixing. After mixing for 25 minutes, the mixture is discharged and packaged into single-dose strips.

[0095] Comparative Example 3 The formulation and preparation method of this comparative example are similar to those of Example 1. The difference is that the particle size of each phase of raw and auxiliary materials is not differentiated during the preparation process, and raw and auxiliary materials that have not been screened or adjusted in particle size are directly fed into the feed.

[0096] Comparative Example 4 The formulation and preparation method of this comparative example are similar to those of Example 1, except that porous silica is not added to the immediate-release drug-loaded particles A and the flavored particles B.

[0097] Comparative Example 5 The formulation and preparation method of this comparative example are similar to those of Example 1, except that the porous silica in the immediate-release drug-loaded particles A is 60g.

[0098] Comparative Example 6 The formulation and preparation method of this comparative example are similar to those of Example 1, except that the mannitol and erythritol used in the flavor granules B are all replaced with an equal amount of sorbitol, which has high moisture content and high hygroscopicity.

[0099] Comparative Example 7 The formulation and preparation method of this comparative example are similar to those of Example 1, except that the lubricant sodium stearate used in the immediate-release drug-loaded particles A is replaced with an equal amount of hydrophobic magnesium stearate.

[0100] Comparative Example 8 The formulation and preparation method of this comparative example are similar to those of Example 1, except that only anhydrous citric acid is used as an acidity regulator, and its dosage is increased to 35 mg.

[0101] Comparative Example 9 The formulation and preparation method of this comparative example are similar to those of Example 1, except that the amount of each component of the flavoring granule B is reduced by 3 times.

[0102] Comparative Example 10 The formulation and preparation method of this comparative example are similar to those of Example 1, except that the amount of each component of the flavoring granule B is increased by 4 times.

[0103] Comparative Example 11 The difference between this comparative example and Example 1 is that a polymer coating technology is used for taste masking. The prescribed amount of aspirin and an appropriate amount of hydroxypropyl methylcellulose are dissolved in water to prepare a pharmaceutical solution. This solution is then uniformly sprayed onto the surface of a blank microcrystalline cellulose pellet core via a fluidized bed, and dried to obtain an aspirin-containing pellet core. Eudragit, a gastrointestinal soluble acrylic resin, is used... ® EPO, appropriate amounts of triethyl citrate and talc are dispersed in water to prepare a coating solution. This coating solution is then uniformly sprayed onto the surface of the drug-containing pellet core in a fluidized bed, resulting in a coating weight gain of 5%–50%. After drying, polymer-masked flavor-coated granules are obtained. These flavor-coated granules are then mixed with flavor-correcting granules B in a mixer for 8–20 minutes, and subsequently packaged as a single-dose 300mg aspirin.

[0104] Comparative Example 12 The formulation and preparation method of this comparative example are similar to those of Example 1. The difference is that in step S1, after the immediate-release drug-loaded particles A are dry-granulated, a 12-mesh sieve is used during granulation to make the resulting total mixed particles mainly coarse particles.

[0105] Comparative Example 13 The formulation and preparation method of this comparative example are similar to those of Example 1. The difference is that in step S1, after the immediate-release drug-loaded particles A are dry-granulated, an 80-mesh sieve is used during granulation, resulting in an excessively high proportion of fine powder in the total mixed particles.

[0106] Experimental Example 1: Flowability and Packaging Adaptability To investigate the flowability and repackaging suitability of the anhydrous aspirin granules of this invention, the following study was conducted using powder properties (angle of repose, Carr index, and particle size distribution) as indicators.

[0107] Angle of repose: Determined using the fixed funnel method, as described in Section IV, General Chapter 0993, Determination of Powder Properties, of the 2025 edition of the Chinese Pharmacopoeia. The funnel was vertically fixed above a horizontal test platform, allowing the particles to flow naturally down the inner wall of the funnel to form a cone. The height H and base diameter D of the cone were measured, and the angle of repose θ was calculated using the formula tanθ = H / (D / 2). The results are shown in Table 2.

[0108] Carr index: Calculated using loose density and tapped density, according to the method described in Section IV, General Chapter 0993, Determination of Powder Properties, of the 2025 edition of the Chinese Pharmacopoeia. Weigh 50.0 g of the total mixed granular sample, gently place it into a graduated cylinder, and read the volume V0. Calculate the loose density ρ0 = m / V0. Then place the graduated cylinder on a tapped density meter, tap it at the specified frequency and number of times, and read the volume V. Calculate the tapped density ρ = m / V. Calculate the Carr index using the formula Carr index = (ρ - ρ0) / ρ × 100%. The results are shown in Table 2.

[0109] Particle size distribution: The particle size distribution was determined by sieving, following the method described in Section IV, General Chapter 0982, "Determination of Particle Size and Distribution," of the 2025 edition of the Chinese Pharmacopoeia. Accurately weigh 100.0 g of the total mixed particle sample and place it in a stack of standard sieves arranged in descending order of aperture (from top to bottom: 40-mesh sieve, 80-mesh sieve, and bottom receiving tray). Shake the sieves as specified, weigh each sieve layer and the mass of the material passing through the sieve, and calculate the mass percentage of each particle size range. The results are shown in Table 2.

[0110] Table 2 Results of Powder Properties Testing

[0111] Table 2 shows that the particles obtained in Examples 1-6 and 8-11 have good flowability, with an angle of repose ≤35° and a Carr index ≤20%. The 40-80 mesh particle size is the main distribution range, and the proportion of fine powder is controllable, indicating good flowability and packaging adaptability. In Example 7, because both phases A and B were directly mixed and the dosage was close to the upper limit, the flowability and fine powder control were slightly worse, but still within acceptable limits. Comparative Example 2 did not perform functional phase separation of A and B; aspirin was directly mixed with trace flavoring components, which easily led to local enrichment and segregation. Comparative Example 3 did not control the particle size of raw materials and excipients, resulting in increased differences in particle size and density, leading to stratification during mixing and feeding. Comparative Example 4 lacked silica to aid flow, increasing the risk of powder adhesion, electrostatic aggregation, and agglomeration. Comparative Example 13 had too much fine powder, easily generating dust, agglomeration, and bridging, all of which led to decreased flowability and increased packaging fluctuations. When the particle size of the finished products in Comparative Examples 11 and 12 was too large, although the flowability was not necessarily significantly reduced, it easily led to uneven particle distribution, feeding fluctuations, and a gritty feeling in the mouth, affecting the packaging stability and the experience of swallowing without water. The above results indicate that the functional phase separation of A and B, the appropriate amount of silica-like substances to aid flow, and the control of the particle size of raw materials, excipients, and total mixed particles are the key factors to ensure the powder properties of the high drug loading particles of this invention and the consistency of industrial packaging.

[0112] Experimental Example 2: Content Accuracy and Single-Dose Uniformity To investigate the accuracy of the aspirin content and the uniformity of single doses in the anhydrous swallowable granules of this invention, the following study was conducted using content and content uniformity as indicators.

[0113] Content: The method is described in Section IV, General Chapter 0512 of the 2025 edition of the Chinese Pharmacopoeia. Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase; acetonitrile-tetrahydrofuran-glacial acetic acid-water (20:5:5:70) was used as the mobile phase; the flow rate was 1.0 mL / min; and the detection wavelength was 276 nm. The results are shown in Table 3.

[0114] Content uniformity: The method is described in General Chapter 0941, Part IV, Chinese Pharmacopoeia 2025 Edition. Ten single-dose packets were randomly selected, and the contents of each packet were accurately weighed. The content of each packet was determined according to the content assay method. The percentage content of each single-dose product was calculated, and the relative standard deviation (RSD%) was calculated. The results are shown in Table 3.

[0115] Table 3. Results of content and content uniformity tests

[0116] As shown in Table 3, Examples 1-11 all achieved good aspirin content (98%~102%) and content uniformity (RSD≤5.0%), indicating that the formulation and process of this invention can effectively guarantee the accuracy of single-dose administration. Compared with Example 1, in Comparative Example 2, the active pharmaceutical ingredient and trace flavoring components were directly mixed without phase separation, which easily led to local enrichment due to differences in particle size, density, and dosage, resulting in an increase in RSD. Comparative Example 3 did not control particle size, and the particle size of the finished products in Comparative Examples 12 and 13 was too large or too small, which increased the risk of stratification or fine powder agglomeration during mixing, transfer, and packaging, affecting the content uniformity. Comparative Example 4 did not add SiO2, resulting in insufficient powder flowability and anti-caking ability, increased packaging fluctuations, and the lack of microenvironment water control made aspirin more prone to hydrolysis. Comparative Example 6 used a high-moisture / high-hygroscopic skeleton, and Comparative Example 11 used polymer coating to mask the taste, which led to a decrease in content due to the moisture absorption of excipients or the introduction of humid heat conditions during the coating process. The above results indicate that the synergistic effects of the functional phase separation design of A and B, the low-moisture sugar alcohol framework, the appropriate amount of silica-like substances, the control of particle size of raw materials and excipients and total mixed particles, and the non-aqueous process can effectively ensure the accuracy, stability and uniformity of the high drug loading particles of the present invention.

[0117] Experiment Example 3: Rapid Release Feature To evaluate the early and rapid release characteristics of the anhydrous aspirin granules of this invention in emergency drug administration scenarios, the following study was conducted using in vitro dissolution as an indicator.

[0118] Dissolution: The method is as described in Section IV, General Chapter 0931, Method II of the 2025 edition of the Chinese Pharmacopoeia. 1000 mL of 0.1 mol / L hydrochloric acid solution was used as the dissolution medium. The dissolution speed was 100 r / min. Samples were taken at 5, 10, 15, and 30 min, filtered, and the contents of aspirin and salicylic acid were determined by high-performance liquid chromatography (HPLC). The salicylic acid content was multiplied by 1.304 and added to the aspirin content to calculate the cumulative dissolution percentage. Commercially available 100 mg enteric-coated aspirin tablets (trade name: Bayer Aspirin) were used. ® The particles were ground to simulate clinical chewing, then sieved through a 20-mesh sieve. The particles that passed through the sieve were collected to simulate the particle size after human chewing. The particle weight of 3 enteric-coated tablets was used as a reference preparation. The results are shown in Table 4. Figure 1 .

[0119] Table 4. Results of in vitro dissolution test

[0120] From Table 4 and Figure 1 It can be seen that Examples 1-11 all achieved approximately 80% early rapid release within 5 minutes, nearly complete dissolution within 10 minutes, and reached peak release within 15 minutes. This indicates that the formulation prepared by this patent can rapidly disperse and release aspirin in the stomach. A slight decrease in dissolution rate at 30 minutes is consistent with the characteristic of aspirin undergoing hydrolysis over time in acidic aqueous media. The overall release rate of Examples 1-11 is faster than that of the reference formulation after clinical chewing of 3 enteric-coated tablets, meeting the need for rapid onset of action in emergency situations. Comparative Example 11 used polymer coating to mask the taste, and the early dissolution rate decreased significantly, indicating that the blocking coating forms a significant dissolution barrier. Comparative Example 7 used a hydrophobic lubricant, and the dissolution rate decreased significantly from 5 to 10 minutes, suggesting that the hydrophobic lubricating layer delays gastric juice wetting. Comparative Example 4's formulation did not contain SiO2, and the early dissolution showed a delayed trend. SiO2 can reduce the formation of water-repellent agglomerates on the liquid surface due to static electricity. If the amount is too low, it can lead to slowed release due to agglomeration or insufficient wetting and dispersion. In Comparative Example 12, the coarser particle size resulted in a smaller specific surface area insufficient to support rapid release. In Comparative Example 13, while finer particle size improved early dissolution, it easily led to a heavy powdery feel and potential uniformity issues. These results demonstrate that the present invention achieves rapid particle dispersion and release through an uncoated structure, hydrophilic lubricant, appropriate amounts of silica-like substances, and the limitation of the particle size range of raw materials and aggregates.

[0121] Experiment Example 4: Stability To investigate the stability of the anhydrous aspirin granules of this invention, an accelerated stability study (40°C, 75% RH) was conducted, using appearance, free salicylic acid, and related substances as indicators. The study methods are as follows.

[0122] Free salicylic acid: The method is described in Section IV, General Chapter 0512 of the 2025 edition of the Chinese Pharmacopoeia. Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase, with acetonitrile-tetrahydrofuran-glacial acetic acid-water (20:5:5:70) as the mobile phase, and the flow rate was 1.0 mL / min; the detection wavelength was 303 nm. The accelerated stability test results are shown in Table 6.

[0123] Related substances (total impurities): The method is described in General Chapter 0512 of Part IV of the 2025 edition of the Chinese Pharmacopoeia. Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase. Acetonitrile-tetrahydrofuran-glacial acetic acid-water (20:5:5:70) was used as mobile phase A, and acetonitrile was used as mobile phase B. Gradient elution was performed according to Table 5 at a flow rate of 1.0 mL / min. The detection wavelength was 276 nm. Accelerated stability test results are shown in Table 6.

[0124] Table 5 Gradient elution procedure for aspirin-related substances

[0125] Table 6 Results of Accelerated Stability Study

[0126] Table 6 shows that after 3 months of accelerated processing, the free salicylic acid content and total impurity growth in Examples 1-11 were controlled at low levels (free salicylic acid ≤ 1.5%, total impurities ≤ 2.0%), and the formulations exhibited stable appearance and good chemical stability. In Comparative Example 1 (wet granulation) and Comparative Example 11 (polymer flavor-masking coating), moisture, solvents, or humid heat conditions were introduced during the preparation process, resulting in significant increases in both initial and storage-period impurities. Comparative Example 2 (no phase separation) and Comparative Example 10 (excessive flavor-correcting phase ratio) increased contact between aspirin and hygroscopic or microenvironment-affecting components such as flavorings and acidulants, leading to significant impurity growth. Comparative Example 6 used a high-moisture / high-hygroscopic diluent framework, which increased the risk of moisture absorption, resulting in increased impurities. These results indicate that a completely non-aqueous, low-humidity process, a low-hygroscopic sugar alcohol framework, and physical phase separation are prerequisites for cutting off hydrolysis pathways and compatibility degradation at the source. Comparative Example 4, lacking SiO2, lacked microenvironmental water control, while Comparative Example 5, with excessive SiO2, experienced localized moisture accumulation due to its strong hygroscopic capacity. Both resulted in significant increases in impurities during day 0 and the acceleration period, indicating that an appropriate amount of microenvironmental moisture regulator is crucial for maintaining formulation stability. Comparative Example 8, lacking an organic salt buffer pair and exhibiting excessively high acidity of its single acid, was highly susceptible to hygroscopicity, ultimately leading to accelerated exceeding of limits. This demonstrates that a suitable anhydrous organic acid / organic acid salt buffer system is essential for maintaining the local acidic microenvironment of the formulation and inhibiting aspirin hydrolysis. The above results indicate that the design of the low-humidity non-aqueous process, functional phase separation of particles A / B, low-hygroscopic sugar alcohol skeleton, appropriate SiO2 dosage, and anhydrous acidic buffer system in this invention are all key technical means to ensure the preparation and long-term stability of anhydrous aspirin granules.

[0127] Experiment Example 5: Compliance with Anhydrous Swallowing and Patient Acceptance To evaluate the compliance and patient acceptance of the anhydrous aspirin granules of the present invention with anhydrous swallowing, the following study was conducted using simulated oral wetting time and taste evaluation as indicators.

[0128] Simulated oral wetting time: 1.5 mL of 37°C artificial saliva was added to the center of a dry culture dish. A single-dose granule (containing 300 mg of aspirin) was poured steadily and centrally into the center of the culture dish from a height of 1 cm. The time it took for the granule to be completely wetted without any obvious dry powder clumps was immediately recorded using a stopwatch, while the wetting state was observed. The results are shown in Table 7.

[0129] Table 7 Results of simulated oral cavity wetting time study

[0130] As shown in Table 7, the particle wetting time in Examples 1-11 was ≤15s, indicating that the particles could be rapidly wetted and uniformly dispersed in the simulated oral environment, meeting the clinical requirements for anhydrous swallowing. In Comparative Example 1, the wet granulation process resulted in reduced particle porosity and slower hydration due to the introduction of moisture, demonstrating that the dry process is the fundamental prerequisite for maintaining high particle porosity and rapid capillary water absorption capacity. Comparative Example 3, lacking control over the particle size of raw materials and excipients, resulted in uneven particle size and localized dry powder residue. Comparative Example 12 showed excessively large particle size distribution, leading to a gritty feel and uneven wetting. Comparative Example 13 showed excessively small particle size, resulting in rapid wetting but with fine powder floating and a noticeable choking sensation. This indicates that raw materials and excipients within a suitable particle size range, along with the total mixed particles, are the core guarantee for the instantaneous uniform hydration of anhydrous swallowing particles and the elimination of the foreign body sensation in the throat. In Comparative Example 4, the particles were insufficiently wetted without SiO2, while in Comparative Example 5, excessive SiO2 increased the powdery feel, indicating that appropriate amounts of flow aids and microenvironment moisture regulators are key to balancing powder flowability and oral wetting performance. Comparative Example 7, using magnesium stearate, and Comparative Example 11, using polymer film coating, exhibited significant water repellency, indicating that hydrophobic lubricants and barrier coatings form a hydrophobic barrier, hindering rapid wetting with limited saliva. In Comparative Example 9, insufficient content of component B in the flavor-enhancing granules weakened the wetting and flavor-enhancing effects. In Comparative Example 10, excessively high content of component B in the flavor-enhancing granules increased the total powder volume and prolonged the complete wetting time, demonstrating that an appropriate A / B phase mass ratio is crucial for balancing high drug loading, oral wetting, flavor enhancement, and swallowing volume. These results indicate that the present invention, through the synergistic design of a non-aqueous dry process, appropriate particle size control, suitable SiO2, hydrophilic lubricant, and a reasonable A / B phase ratio, achieves rapid wetting, low powderiness, and good swallowing adaptability of anhydrous aspirin granules under limited saliva conditions.

[0131] Taste evaluation: Ten volunteers, without drinking water, directly poured a single-dose granule (containing 300mg aspirin) onto their tongues and used their own saliva to hold, moisten, and swallow it. Each test sample was spaced at least 15 minutes apart. Volunteers rated the taste on a 10-point scale in a blinded state. The rating dimensions comprehensively considered "masking of sour, astringent, and bitter tastes," "gritty and powdery sensations," "smoothness of swallowing," "throat irritation," and "taste acceptability," and sensory descriptions were recorded. An average score ≥8.0 was considered to have a good taste and meet the needs of emergency use. The results are shown in Table 8.

[0132] Table 8. Results of Taste Evaluation

[0133] As shown in Table 8, the granules from Examples 1 to 11 all scored above 8.0 in taste, exhibiting a refreshing fruity aroma, good flavor masking, and smooth swallowing. Comparative Example 1, prepared by wet granulation, produced granules that were relatively hard, wetting slowly, and exhibiting a noticeable granular texture in the mouth. This indicates that this product is better suited for a non-aqueous dry granulation process to maintain suitable granule pore structure and rapid wetting characteristics. Comparative Example 3 did not control the particle size of the raw materials, resulting in uneven granule size and a coexisting powdery and gritty texture. Comparative Example 12 produced granules that were too coarse, with a noticeable gritty and foreign body sensation. Comparative Example 13 produced granules that were too fine, with a strong powdery texture and a tendency to cause choking. This demonstrates that appropriate particle size control is crucial for ensuring uniform taste and swallowing comfort of anhydrous granules. Comparative Example 4 showed poor powder dispersion upon ingestion without SiO2. In Comparative Example 5, excessive SiO2 increased oral dryness and residual powderiness, indicating that controlling the dosage of flow aids and microenvironment moisture regulators can balance rapid powder dispersion and prevent localized drying. Comparative Example 7, using a hydrophobic lubricant, exhibited poor wetting and less smooth swallowing, suggesting that hydrophilic lubricants are more suitable for the rapid wetting and anhydrous swallowing requirements of this invention. Comparative Example 8 had a sharp, pungent taste, indicating that an appropriate amount of anhydrous buffered hydrochloric acid flavor-modifying system helps reduce mucosal irritation while promoting saliva secretion. In Comparative Example 9, insufficient proportion of flavor-modifying particles (B) resulted in inadequate masking of the aspirin's astringent taste. In Comparative Example 10, excessively high proportion of flavor-modifying particles (B) led to powder overload, demonstrating that a suitable A / B phase mass ratio is crucial for balancing flavor enhancement and anhydrous swallowing volume. The above results indicate that, through the synergistic design of a non-aqueous dry process throughout the entire process, appropriate particle size control of raw materials and mixed particles, appropriate amount of microenvironment moisture regulator, hydrophilic lubricant, reasonable A / B phase mass ratio, and an anhydrous organic acid / organic acid salt buffer system, this invention can improve the sour taste, powdery feel, foreign body sensation in the throat, and dust cough of high-dose aspirin administration without using a blocking taste-masking coating, and improve the palatability of anhydrous swallowing.

[0134] Experimental Example 6: Pharmacokinetics Using the anhydrous aspirin granules from Example 1 as the subject of investigation, commercially available 100mg enteric-coated aspirin tablets (trade name: Bayer Aspirin) were compared with those of Bayer Aspirin. ® After grinding, the particles were passed through a 20-mesh sieve. Three tablets (equivalent to 300 mg of aspirin) of the sieve were taken as the reference preparation. The pharmacokinetic differences between Example 1 and the reference preparation in beagle dogs were compared.

[0135] Eight healthy adult beagle dogs were randomly divided into two groups. They were fasted for 12 hours before the experiment, and water was withheld one hour before administration to simulate oral dryness during emergency treatment. A two-way crossover design was used. In the first cycle, either the granules from Example 1 or the reference formulation was administered once. After a one-week washout period, the dosage was switched in the second cycle. The granules were poured directly onto the base of the beagle's tongue to induce swallowing, without water. The dosage was 300 mg. Blood samples were collected from the forelimb veins before administration (0 h) and at 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, and 8 h after administration. Plasma was separated by centrifugation, and the concentration of aspirin in the plasma was determined using a validated LC-MS / MS method. The peak concentration (C) of the two formulations was calculated and compared using a non-compartmental model. max ), area under the plasma concentration-time curve (AUC), time to peak concentration (T) max The in vivo absorption characteristics of the granules of this invention under conditions requiring no drinking water and no chewing were evaluated and compared with the administration method of simulated chewable enteric-coated tablets to verify the ability of the formulation of this invention to achieve rapid absorption in emergency situations. Results are shown below. Figure 2 See Table 9.

[0136] Table 9 Results of pharmacokinetic studies in beagle dogs

[0137] 1 AUC value is AUC 0-t The value of the ratio. 2 For anhydrous swallowable granules and enteric-coated tablets with simulated chewing, Bayer aspirin ® The ratio of .

[0138] Depend on Figure 2 As shown in Table 9, compared with simulated chewing enteric-coated aspirin tablets, the Tg of the particles of this invention is significantly higher. max No significant change, C max The increase of approximately 15% with a substantially equivalent AUC indicates that the anhydrous swallowable granules of this invention can achieve a total in vivo exposure comparable to the chewable reference formulation under anhydrous swallowing conditions, while also achieving a higher peak concentration. These pharmacokinetic characteristics demonstrate that the anhydrous swallowable granules of this invention, while reducing the complexity of administration and improving dosage accuracy, do not reduce the in vivo absorption of aspirin, and are beneficial for meeting the requirements of rapid absorption and convenient administration in emergency situations.

[0139] Simultaneously, this invention utilizes the physicochemical properties of aspirin, as well as absorption, distribution, metabolism, and elimination data obtained from in vitro and in vivo experiments, to construct a physiological pharmacokinetic (PBPK) model of aspirin. Furthermore, it employs a single oral administration of commercially available enteric-coated aspirin tablets (trade name: Bayer Aspirin) to healthy subjects under fasting and postprandial conditions.® The measured pharmacokinetic curves and their main pharmacokinetic parameters C after the experiment max AUC, T max The model was validated. Then, using the validated PBPK model, dissolution data of anhydrous aspirin granules in in vitro media were integrated to predict the pharmacokinetic characteristics of anhydrous aspirin granules in the Chinese population, providing a basis for assessing the absorption rate, extent of absorption, and relative bioavailability of anhydrous aspirin granules. The predicted pharmacokinetic (PBPK) simulation results of anhydrous aspirin granules in humans are as follows: Figure 3 As shown, its main pharmacokinetic parameters are shown in Table 10.

[0140] Table 10 Simulation results of PBPK model

[0141] 1 AUC value is AUC 0-t The value of the ratio. 2 For hydrophobic granules and chewable enteric-coated tablets, use aspirin. ® The ratio of .

[0142] The PBPK model prediction results are consistent with the pharmacokinetic results in beagle dogs. As shown in Table 10, the Tp of the particles of this invention... max C max The AUC values ​​are essentially the same as those of chewable enteric-coated tablets. These results suggest that the anhydrous swallowable granules of this invention, while simplifying administration, avoiding chewing, and reducing reliance on water, maintain overall exposure comparable to clinically chewable enteric-coated aspirin tablets, better meeting the clinical needs for rapid, accurate, and easy-to-use early loading administration in acute myocardial infarction or acute coronary syndrome.

[0143] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any changes or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention.

Claims

1. Anhydrous aspirin granules, characterized in that, The non-blocking taste-masking coating structure of the aspirin anhydrous swallowable granules is composed of fast-release drug-loaded granules A and taste-masking granules B. The immediate-release drug-loaded particles A include: aspirin, a first diluent, and a flow aid and microenvironment moisture regulator; The flavoring granules B include: a second diluent, an acidity regulator, a sweetener, a flavoring agent, and a flow aid and microenvironment moisture regulator.

2. The anhydrous aspirin granules according to claim 1, characterized in that, According to the weight parts, the immediate-release drug-loaded particles A include: 50-150 parts of aspirin, 75-200 parts of the first diluent, and 0.5-20 parts of a flow aid and microenvironment moisture regulator; And / or, the immediate-release drug-loaded particles A further include a lubricant, wherein the lubricant is ≤8 parts.

3. The anhydrous aspirin granules according to claim 1, characterized in that, By weight, the flavoring granules B comprise: 50-120 parts of a second diluent, 8-30 parts of an acidity regulator, 0.5-6 parts of a sweetener, 5-30 parts of a flavoring agent, and 0.5-10 parts of a flow aid and microenvironment moisture regulator.

4. The anhydrous aspirin granules according to claim 1, characterized in that, The mass ratio of the immediate-release drug-loaded granules A to the flavored granules B is 1.0~8.0:

1.

5. The anhydrous aspirin granules according to claim 1, characterized in that, The flow aids and microenvironment moisture regulators in the immediate-release drug-loaded particles A and flavoring particles B respectively include one or more of the following: silica, colloidal silica, and porous silica. And / or, the mass ratio of the flow aid and microenvironment moisture regulator to the total mass of the anhydrous aspirin granules is 0.005~0.05:

1.

6. The anhydrous aspirin granules according to claim 1, characterized in that, The first diluent and the second diluent each comprise one or more of mannitol, erythritol, isomaltitol, and xylitol. And / or, the lubricant includes one or more of sodium stearate fumarate, polyethylene glycol, sodium dodecyl sulfate, and sodium benzoate.

7. The anhydrous aspirin granules according to claim 1, characterized in that, The acidity regulator is a composition of anhydrous organic acids and organic acid salts, including: anhydrous citric acid and sodium citrate or sodium citrate, anhydrous tartaric acid and sodium tartrate, and anhydrous malic acid and sodium malate.

8. The anhydrous aspirin granules according to claim 1, characterized in that, The aspirin and / or the first diluent have an average particle size of 80-120 mesh. And / or, the average particle size of the second diluent is 40-80 mesh; And / or, the overall particle size distribution of the aspirin anhydrous granules meets the following conditions: the mass percentage of particles larger than 40 mesh is ≤40%, the mass percentage of particles between 40 and 80 mesh is 40% to 90%, and the mass percentage of particles smaller than 80 mesh is ≤15%.

9. A method for preparing anhydrous aspirin granules, characterized in that, The method for preparing anhydrous aspirin granules according to any one of claims 1-8 comprises: S1, aspirin, the first diluent, and the flow aid and microenvironment moisture regulator are directly mixed by dry method or granulated by dry method to obtain immediate-release drug-loaded particles A. S2, the second diluent, acidity regulator, sweetener, flavoring, and flow aid and microenvironment moisture regulator are directly dry-mixed or dry-granulated to obtain flavored granules B; S3, mix the immediate-release drug-loaded particles A and flavoring particles B evenly to obtain total mixed particles; S4, the total mixed granules are packaged into single doses to obtain anhydrous aspirin granules.

10. The use of anhydrous aspirin granules according to any one of claims 1-8 or anhydrous aspirin granules prepared by the preparation method according to claim 9 in the preparation of emergency drugs for acute myocardial infarction, acute coronary syndrome or thromboembolic diseases, wherein the preferred specification of the anhydrous aspirin granules is 300 mg.

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