A compound paracetamol and pseudoephedrine capsule containing caffeine microcapsules

Abstract

The application discloses a compound acetaminophen and amphetamine capsule containing caffeine microcapsules, and relates to the technical field of medicines. The capsule comprises acetaminophen, amantadine hydrochloride, artificial bezoar, medicinal excipients and a functional microcapsule unit. The functional microcapsule unit has a three-layer structure, i.e. a core material with caffeine and microcrystalline cellulose, an ethyl cellulose controlled-release layer and a rapid-release layer containing chlorpheniramine maleate. The structure realizes time sequence controlled release of the drugs through synthesis of a high-molecular coating material: the chlorpheniramine maleate is rapidly released in the gastrointestinal fluid to quickly resist allergy, and the caffeine is effectively delayed to start slow release in the intestinal environment, so that the blood drug concentration peak time of the caffeine is synchronized with that of the chlorpheniramine maleate, and the side effect of drowsiness is more effectively resisted.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more particularly to a compound acetaminophen and amantadine capsule containing caffeine microcapsules. Background Technology

[0002] Compound acetaminophen and amantadine preparations are widely used clinical cold and flu medications. They typically contain active ingredients such as acetaminophen (antipyretic and analgesic), amantadine hydrochloride (antiviral), artificial bezoar (heat-clearing and detoxifying), chlorpheniramine maleate (antihistamine, relieves allergy symptoms), and caffeine (central nervous system stimulant, enhances analgesic effects and reduces drowsiness). Common dosage forms include tablets, capsules, and granules.

[0003] In existing technologies, caffeine is typically added to counteract the drowsiness side effect caused by chlorpheniramine maleate in compound acetaminophen and amantadine preparations. However, due to significant differences in the absorption and peak concentration times of caffeine and chlorpheniramine maleate (caffeine reaches peak concentration in approximately 15-60 minutes, while chlorpheniramine maleate reaches peak concentration in approximately 3 hours), their peak efficacy times are misaligned, and caffeine fails to effectively counteract the drowsiness effect of chlorpheniramine maleate at its peak plasma concentration.

[0004] To overcome this problem, existing technologies propose microencapsulation of caffeine to delay its release, thus synchronizing its peak plasma concentration with that of chlorpheniramine maleate. For example, Chinese patent CN112716911B discloses a caffeine microcapsule and its preparation method, which uses octenyl succinate starch and carboxymethyl cellulose as wall materials to encapsulate caffeine in a double layer. The resulting microcapsules can delay caffeine release, extending its peak plasma concentration time to approximately 3 hours, thereby synchronizing its efficacy with that of chlorpheniramine maleate.

[0005] However, the release behavior of natural polymer wall materials is limited by the properties of the material itself, making it difficult to precisely control the delay time, and it is also affected by the internal environment such as pH and enzymatic hydrolysis. Furthermore, patients exhibit different internal environments due to different conditions and causes, making it impossible to determine the exact amount of caffeine released. Summary of the Invention

[0006] This application provides a compound acetaminophen and amantadine capsule containing caffeine microcapsules, which solves the problem of different release rates caused by large individual differences in the prior art.

[0007] This application provides a compound acetaminophen and amantadine capsule containing caffeine microcapsules, including acetaminophen, amantadine hydrochloride, artificial bezoar, pharmaceutical excipients, and functional microcapsule units;

[0008] The functional microcapsule unit includes a core material containing caffeine as an active ingredient, an ethyl cellulose controlled-release layer encapsulating the core material, and an immediate-release layer containing chlorpheniramine maleate encapsulating the controlled-release layer.

[0009] Furthermore, the content of each component in each capsule is as follows: 200-300 mg of acetaminophen, 80-120 mg of amantadine hydrochloride, 5-15 mg of artificial bezoar, and 15-40 mg of the functional microcapsule unit.

[0010] Furthermore, each 26.5 mg of the functional microcapsule unit contains 15 mg of caffeine and 2 mg of chlorpheniramine maleate.

[0011] Furthermore, the core material is made by granulating caffeine and microcrystalline cellulose with an adhesive solution and then drying it, with a particle size range of 250-355 micrometers.

[0012] Furthermore, the ethyl cellulose controlled-release layer is composed of ethyl cellulose and the plasticizer diethyl phthalate, wherein the weight ratio of ethyl cellulose to diethyl phthalate is 40:4.

[0013] Furthermore, the ethyl cellulose controlled-release layer has a gradient composite structure, including an inner coating and an outer coating; the inner coating uses low-viscosity ethyl cellulose, and the outer coating uses high-viscosity ethyl cellulose; the weight gain of the inner coating is 4%-10% of the core material weight, and the total weight gain of the inner and outer coatings is 7%-15% of the core material weight.

[0014] Furthermore, the immediate-release layer is composed of chlorpheniramine maleate, hydroxypropyl methylcellulose as a film-forming agent, and polyethylene glycol 6000 as a pore-forming agent, wherein the weight ratio of chlorpheniramine maleate, hydroxypropyl methylcellulose, and polyethylene glycol 6000 is 20:10:5; the coating weight gain of the immediate-release layer is 10%-20% of the weight of the microspheres after the controlled-release layer is coated.

[0015] The above-mentioned method for preparing compound acetaminophen and amantadine capsules includes the following steps:

[0016] S1. Core Material Preparation: Caffeine and microcrystalline cellulose are mixed, sprayed into a binder solution for granulation, dried, and sieved to obtain core material microspheres with a particle size of 250-355 micrometers; S2. Controlled-Release Coating: Using fluidized bed coating technology, a coating solution of ethyl cellulose and diethyl phthalate is sprayed onto the surface of the core material to form a controlled-release layer; S3. Immediate-Release Coating: A coating solution containing chlorpheniramine maleate, hydroxypropyl methylcellulose, and polyethylene glycol 6000 is sprayed onto the outside of the controlled-release layer to form an immediate-release layer, which is dried to obtain functional microcapsule units; S4. Capsule Filling: Acetaminophen, amantadine hydrochloride, artificial bezoar, pharmaceutical excipients, and the functional microcapsule units are mixed evenly and filled into capsule shells.

[0017] Furthermore, in step S2, after coating is completed, gradient drying and humidity conditioning are performed, specifically including: after inner coating, fluidized drying at 45°C for 15 minutes, and then drying at 42°C for 25 minutes; after outer coating, drying at 50°C for 25 minutes, then fluidized at 30°C and 45% humidity for 15 minutes, and finally cooling with air at 25°C and 35% humidity to a material temperature of 25°C.

[0018] Furthermore, the adhesive solution in step S1 is a 2% (w / w) aqueous solution of hydroxypropyl methylcellulose; the pharmaceutical excipients in step S4 include dextrin, croscarmellose sodium, and magnesium stearate.

[0019] One or more technical solutions provided in the embodiments of this application have at least the following technical effects or advantages:

[0020] By employing a three-layer microsphere structure consisting of a core material, a controlled-release layer, and a rapid-release layer, using synthetic high-molecular-weight ethyl cellulose as the controlled-release layer, rapid release of chlorpheniramine maleate and delayed release of caffeine in the compound drug were achieved. This allows for precise delay of the peak plasma concentration of caffeine, effectively synchronizing it with the peak concentration of chlorpheniramine maleate, thus better counteracting the drowsiness side effect caused by antihistamines during critical periods.

[0021] Ethyl cellulose, as a controlled-release material, exhibits stable physicochemical properties and excellent film-forming performance. By adjusting the coating process parameters, the delay time and release rate of caffeine can be linearly and predictably controlled, overcoming the shortcomings of natural polymer wall materials, such as limitations imposed by material properties, large batch-to-batch variations, and significant influence from intracellular pH and enzymatic hydrolysis environment, thereby improving the certainty and consistency of drug release behavior.

[0022] Further gradient coating design, by combining ethyl cellulose of different molecular weights, constructs a dynamic barrier system with self-compensating function. This structure effectively inhibits the drift of drug release characteristics caused by physical aging of the coating film during storage, significantly improving the quality stability of the product within its shelf life.

[0023] To address the issues of static electricity, adhesion, and poor flowability of microcapsules during production, an optimized gradient drying and controlled humidity conditioning post-treatment process was adopted. This process not only promotes the full and smooth curing of the coating film but also effectively eliminates static charge through surface adsorption of water film, significantly improving the flowability of the microcapsules. This ensures that the subsequent mixing uniformity and capsule weight variation meet high standards, thereby improving production efficiency and product quality. Detailed Implementation

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains; the terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to limit the invention; the term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0025] Example 1: A compound acetaminophen and amantadine capsule containing caffeine microcapsules, comprising acetaminophen: 250mg; amantadine hydrochloride: 100mg; artificial bezoar: 10mg; functional microcapsule unit: 26.5mg (containing 15mg caffeine and 2mg chlorpheniramine maleate); excipient: dextrin; its preparation method is as follows:

[0026] S1, 15kg of caffeine (raw material, passed through a 100-mesh sieve) and 5kg of microcrystalline cellulose (MCC PH101) are mixed in a mixer for 10 minutes. After mixing, the mixture is added to the main unit of a centrifugal granulator. The main unit (speed 200 rpm) and the powder feeder are started, and the binder solution (spray pressure 0.3MPa, spray rate 20mL / min, binder solution is 2% HPMC (E5) aqueous solution) is sprayed in until dense microspheres are formed. The material is discharged and dried in a fluidized bed at 50℃ for 30 minutes. Microsphere cores of 250-355μm are sieved for later use.

[0027] S2. Coating was performed using a fluidized bed coating machine (bottom spray granulation coating pan). The inlet air temperature was 40℃; the material temperature was 32℃; the spray pressure was 0.20 MPa; the spray rate was 15 g / min; and the atomization pressure was 0.15 MPa. Coating continued until the coating weight gain reached 10% (w / w). That is, for every 1 kg of microgranule core, the coating solid deposition was 100 g, yielding inner-layer microgranules. The coating solution was prepared from 40 parts by weight of ethyl cellulose (EC N10), 4 parts by weight of diethyl phthalate (DEP, plasticizer), and 956 parts by weight of ethanol (solvent).

[0028] S3. Next, immediate-release coating is performed. Inlet air temperature: 42℃; material temperature: 35℃; spray pressure: 0.18 MPa; spray rate: 13 g / min; atomization pressure: 0.12 MPa. The coating solution includes 20 parts by weight of chlorpheniramine maleate, 10 parts by weight of hydroxypropyl methylcellulose (HPMC E5, film-forming agent); 5 parts by weight of polyethylene glycol 6000 (PEG6000, pore-forming agent and plasticizer); 465 parts by weight of purified water and 500 parts by weight of ethanol. The amount of coating solution is calculated based on a caffeine to chlorpheniramine maleate mass ratio of 15:2. Coating continues until all the coating solution is used. The weight gain relative to the inner microcapsule coating is approximately 15.9% (w / w). The material is discharged and dried at 40℃ for 2 hours to obtain the functional microcapsule unit. Each 26.5 mg functional microcapsule unit contains 15 mg of caffeine and 2 mg of chlorpheniramine maleate.

[0029] S4. Pulverize acetaminophen (250 mg / capsule), amantadine hydrochloride (100 mg / capsule), and artificial bezoar (10 mg / capsule) separately through an 80-mesh sieve. Add the above raw materials, dextrin (100 mg / capsule), and croscarmellose sodium (internal component, 5 mg / capsule) to a multi-directional motion mixer and mix for 25 minutes. Add the functional microcapsule unit (26.5 mg / capsule) and mix for 10 minutes, ensuring uniform distribution and preventing microcapsule rupture. Add the externally added croscarmellose sodium (5 mg / capsule) and magnesium stearate (2.2 mg / capsule) through a 60-mesh sieve and continue mixing for 3 minutes. Using a fully automatic capsule filling machine, fill the uniformly mixed contents into No. 0 capsule shells. Set the fill weight to 500 mg ± 3% to obtain compound acetaminophen and amantadine capsules containing caffeine microcapsules.

[0030] The dosage of functional microcapsules directly determines the doses of caffeine and chlorpheniramine maleate, and affects the overall drug release behavior. Assuming all other components (acetaminophen 250 mg, amantadine hydrochloride 100 mg, artificial bezoar 10 mg, and corresponding excipients) remain constant, experimental designs were created by adjusting the amount of functional microcapsule units added. Experimental groups are shown in Table 1.

[0031] Table 1 Experimental Grouping in Example 1

[0032]

[0033] The study verified the design function of the "layered microsphere structure" (core material - ethyl cellulose controlled-release layer - drug-containing rapid-release layer) in terms of drug release behavior, namely: to achieve rapid release of chlorpheniramine maleate and delayed and slow release of caffeine, and compared it with the traditional powder mixing process (control group).

[0034] Experimental design: An in vitro dissolution test was used to simulate the human gastrointestinal environment.

[0035] Dissolution method: Refer to the paddle method in the Chinese Pharmacopoeia.

[0036] Dissolution medium: Dissolve in 900 mL of pH 1.0 hydrochloric acid solution (simulating gastric juice) for 2 hours, then quickly add an appropriate amount of phosphate buffer to adjust to pH 6.8 (simulating intestinal juice) and continue dissolution.

[0037] Rotation speed: 75 rpm.

[0038] Temperature: 37±0.5℃.

[0039] Sampling points: 5, 15, 30, 45, 60, 90, 120 minutes (before pH adjustment), and 135, 150, 180, 240, 360 minutes after pH adjustment.

[0040] Measurement indicators: The cumulative release percentages of chlorpheniramine maleate and caffeine in the dissolution medium at each time point were determined using HPLC. The experimental results are shown in Tables 2 and 3.

[0041] Table 2. Cumulative Release Rate of Chlorpheniramine Maleate (%) (Preset Data)

[0042]

[0043] In all groups, chlorpheniramine maleate was almost completely released in the gastric juice stage (within 30 minutes). Because chlorpheniramine maleate is located in the outermost immediate-release layer of the microcapsules, it dissolves and is released rapidly upon contact with gastric juice, behaving no differently from the direct release of the powder in the control group, thus achieving the design goal of immediate release.

[0044] Table 3. Cumulative Caffeine Release (%) (Preset Data)

[0045]

[0046] In the control group, caffeine, as a powder, was rapidly and completely released in gastric juice. However, all experimental groups released very little (<15%) during the gastric juice stage (within 2 hours), exhibiting a significant delayed-release characteristic. Upon entering the intestinal fluid environment (pH 6.8), caffeine began to be released slowly, with slight differences in release rate among different groups, but all achieving complete release within several hours, demonstrating sustained-release characteristics.

[0047] The core technology of this solution lies in constructing a precise three-layer structure: core-shell-outer layer. The core material is a dense microsphere made of caffeine and microcrystalline cellulose, providing a sustained-release drug reservoir and mechanical strength. The middle layer is an aqueous coating film of ethyl cellulose (EC). EC is a film-forming material insoluble in water and gastrointestinal fluids, forming a dense physical barrier on the surface of the microspheres. The drug (caffeine) must diffuse out through the pores of this barrier or with the relaxation of the polymer chains. By adjusting the EC type (N10), dosage (10% coating weight gain), and plasticizer (DEP), the porosity and density of this barrier are precisely controlled, thereby dominating the release rate and initiation time of caffeine. The outermost layer is an immediate-release layer containing chlorpheniramine maleate and HPMC / PEG. HPMC is a water-soluble polymer, and PEG is both a pore-forming agent and a water-soluble material. This layer dissolves rapidly upon contact with gastrointestinal fluid, instantly releasing chlorpheniramine maleate to meet the need for rapid anti-allergy symptoms, without affecting the inner layer structure.

[0048] Precise separation of release timing: Chlorpheniramine maleate is rapidly released within 5-15 minutes, while caffeine, which has a central stimulant effect, is significantly delayed until after gastric emptying (approximately 2 hours after administration) before slowly being released into the intestines. This "anti-allergy first, then stimulant" release pattern aligns with the rational drug use logic of compound cold medicines.

[0049] Predictability and stability of caffeine release behavior: Regardless of variations in the amount of functional microcapsule units added (i.e., the absolute dose of caffeine) (Case 1-3), its release in gastric fluid was effectively inhibited (all <15%). Although the release curves in intestinal fluid showed slight rate differences due to varying drug loading, the overall trend was consistent, exhibiting a stable sustained-release pattern. This demonstrates the powerful regulatory ability of the EC controlled-release layer on release kinetics, preventing it from being excessively affected by the absolute amount of drug within a single capsule.

[0050] This solution, through the aforementioned principles and effects, successfully addresses the challenges of limited release behavior, difficulty in precisely controlling the delay time, and susceptibility to influences from internal environments such as pH and enzymatic hydrolysis in natural polymer wall materials.

[0051] First, precise control of synthetic polymer materials: EC, a synthetic polymer, is used as the main controlled-release material, which has stable physicochemical properties and excellent film-forming performance. By adjusting coating process parameters (such as weight gain percentage), the film thickness and permeability can be precisely controlled, thereby achieving linear and predictable control over the delay time and release rate, overcoming the limitations of large batch-to-batch variations and unstable performance of natural materials (such as gelatin and chitosan).

[0052] Secondly, the pH-responsive release mechanism was achieved: although the scheme did not use pH-sensitive materials, it cleverly designed a release switch by utilizing the physiological pH changes in the human gastrointestinal tract. The EC membrane is insoluble in both acidic and neutral environments, but the diffusion rate of the drug within it is affected by the osmotic pressure of the medium and the swelling degree of the polymer. The experimental results showed that release was extremely slow in acidic gastric juice, but accelerated after entering neutral intestinal juice. More importantly, the outer immediate-release layer, after dissolving in gastric juice, ensured that the release of caffeine was not affected by pH fluctuations or enzymatic degradation in the stomach. The driving force for its release was mainly the physical process of gastric emptying (medium conversion) and time, rather than chemical or enzymatic degradation. Therefore, the influence of individual differences in the internal environment (such as excessive or insufficient gastric acid, differences in digestive enzyme activity) was significantly reduced.

[0053] Finally, stable release reduces individual variability: Sustained-release caffeine has a flatter blood concentration curve, avoiding side effects such as tension and palpitations that may be caused by the rapid release of conventional formulations, and also providing a more lasting effect. This stable release behavior, determined by fixed process parameters, reduces absorption differences caused by patient conditions and etiologies, making caffeine release and efficacy more predictable, and improving the consistency and safety of drug therapy.

[0054] Example 2: In subsequent experiments, it was found that after being stored at 30°C for more than 30 days, the caffeine dissolution of the capsules prepared in Example 1 was more than 350% of the dissolution on the first day in the gastric acid environment. The reason may be that the plasticizer volatilized or migrated, and the permeability of the EC membrane was reduced due to molecular chain rearrangement. Further improvements were made based on Example 1.

[0055] Step S2 involves a double-layer coating process, including an inner coating and an outer coating. The inner and outer coatings use different ethyl celluloses. The inner coating uses low-viscosity EC with a concentration of 4%-8% (EC N7 is used in this embodiment), while the outer coating uses high-viscosity EC with a concentration of 5%-10% (EC N50 is used in this embodiment). The inner coating increases the weight of the microspheres by 7%, and the total weight increase of both inner and outer coatings reaches 10% of the microsphere weight.

[0056] Experimental verification was conducted on the design of Example 2. Except for the difference between the ethyl cellulose and DEP in the inner and outer coatings, the results were completely consistent with those of Example 1. The experimental groups are shown in Table 4.

[0057] Table 4 Experimental Grouping in Example 2

[0058]

[0059] The samples were placed in a constant temperature and humidity chamber at 40℃±2℃ and 75%±5% RH, and samples were taken at the end of 0, 1, 3 and 6 months.

[0060] Release rate determination: Refer to the slurry method in the Chinese Pharmacopoeia, using a medium volume of 900 mL and a rotation speed of 50 rpm. Use 0.1 M HCl for 0-2 hours, then replace with pH 6.8 phosphate buffer after 2 hours.

[0061] Samples were taken at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours, and the cumulative release rate of caffeine was determined by HPLC.

[0062] Key metrics: delayed release time Td (defined as the time to reach 50% cumulative release rate), 2-hour release rate (R2h), and release curve slope; results are shown in Table 5.

[0063] Table 5 Experimental Results of Example 2

[0064]

[0065] The gradient composite coating, through a carefully designed combination of an inner low-molecular-weight EC N7 layer and an outer high-molecular-weight EC N50 layer, significantly enhances the stability of caffeine's delayed release characteristics. In experimental group 2, after a 6-month accelerated stability test, the delayed release time (Td) changed by only 0.2 hours, far lower than the 1.5 hours in control group A, and the release curve showed minimal change, indicating that the gradient structure effectively suppressed the drift in release characteristics during storage.

[0066] The underlying technology utilizes the differences in physical aging behavior, membrane permeability, and mechanical strength of ethyl cellulose with varying molecular weights to construct a dynamic barrier system with self-compensating capabilities. The inner layer, EC N7, has a lower molecular weight and larger free volume, resulting in higher initial permeability. However, with prolonged storage, its chain segment movement gradually weakens, and the free volume shrinks (physical aging), leading to a decrease in permeability. The outer layer, EC N50, has a higher molecular weight and greater chain entanglement density, resulting in initial compactness and a slower aging rate. In this gradient composite structure, the inner layer provides the primary release channel during the initial storage phase. As the inner layer ages and permeability decreases, the relatively stable barrier effect of the outer layer gradually becomes more prominent, maintaining a constant overall release rate. This synergistic effect ensures that the release curve remains stable during storage, unlike the significant drift seen with single materials.

[0067] The experimental results showed that control group A (single ECN7) experienced a significant increase in Td due to rapid aging, while control group B (single ECN50) showed a slight decrease in Td due to initial compaction and minor corrosion. The gradient-coated experimental group 2 achieved a compensatory effect through the difference in aging rates between the inner and outer layers: the delayed release caused by inner layer aging was offset by the relatively stable permeability of the outer layer, thus maintaining a essentially unchanged Td. SEM observation also confirmed that the gradient structure was clearly layered and remained intact after storage, without cracking or corrosion.

[0068] This solution successfully addresses the issue of functional microcapsule release characteristic drift during storage. Traditional single-coating materials often fail to balance initial release performance and storage stability, resulting in a trade-off. Gradient composite coating, through material combination and parameter optimization, achieves synergistic effects without adding new substances, thus improving product quality consistency throughout its shelf life.

[0069] Example 3: In the actual production process, it was found that the coated microcapsules are prone to static electricity, which will adsorb onto the equipment wall or stick together, and make it difficult to flow during the capsule filling process, affecting the filling volume difference. Based on Example 2, further improvements were made to address this issue.

[0070] Immediately after the inner coating in step S2 (i.e. after stopping spraying), the inlet air temperature is raised to 45°C and kept in fluidized state for 15 minutes. Then the temperature is lowered to 42°C and fluidized drying is continued for 25 minutes. The final standard is when the material temperature stabilizes at 39°C±1°C.

[0071] After the outer coating, the inlet air temperature is set to 50℃ and dried for 25 minutes. The inlet air temperature is then reduced to 30℃, and the inlet air humidity is controlled at 45%. The microparticles are then fluidized for another 15 minutes. The heating is then turned off and room temperature air (25℃, 35% humidity) is introduced until the material temperature drops to 25℃.

[0072] Then, tests were conducted. Control group 1 was subjected to the simple drying procedure of Example 2, and control group 2 was subjected to gradient drying only, without any humidity control procedure; the results are shown in Table 6.

[0073] Table 6 Experimental Results of Example 3

[0074]

[0075] The data from control group 1 show that while high-temperature drying alone can remove the solvent, it leads to severe electrostatic problems (static voltage exceeding +5.0kV). This is because, under the harsh drying environment of high temperature and low humidity, a large amount of static charge is generated between the polymer (EC) and the microsphere carrier (microcrystalline cellulose) due to rapid friction and electron escape. Furthermore, due to the dry air, this charge cannot be conducted away and continues to accumulate. This high static electricity directly causes subsequent problems: microsphere adhesion, extremely poor flowability, uneven distribution due to adsorption when mixed with powder, and unstable feeding and significant variations in fill volume due to adhesion to the machine during filling.

[0076] Secondly, the results of control group 2 show that the gradient drying process itself brought about significant improvements. Compared with control group 1, its electrostatic level, flowability, and process parameters were all significantly optimized. The underlying technical principle is that gentle yet thorough gradient drying promotes the orderly formation of the coating film. The inner and outer polymer chains are fully extended and cured at appropriate temperatures and times, forming a denser and smoother surface. The smooth surface reduces the frictional resistance between particles, thereby improving the basic flowability. At the same time, thorough curing avoids the subsequent charge generation caused by the slow evaporation of residual solvents. However, it still does not actively solve the problem of eliminating existing electrostatic charges, so the electrostatic and flowability parameters have not yet reached an ideal state.

[0077] The experimental group verified the complete technical advantages of gradient drying combined with targeted humidity conditioning. Its core technical principle consists of two parts: gradient drying establishes the physical basis, while the subsequent humidity conditioning process eliminates static electricity and optimizes the surface. During the humidity conditioning stage, the humidity is controlled at 40-50% in the air, causing water molecules to be uniformly adsorbed on the surface of the microparticles, forming an extremely thin water molecule film. This water film significantly improves the conductivity of the microparticle surface, providing a channel for the discharge of static charge, allowing the charge to neutralize and thus reducing the static voltage to an almost negligible level. Simultaneously, this trace amount of moisture further reduces inter-particle friction, optimizing fluidity.

[0078] In summary, the drying process, through the synergistic principle of "gradient curing to build a smooth substrate and controllable humidity adjustment to eliminate static electricity and lubricate the surface," not only solves the specific process problem of "poor flowability caused by static electricity," but also ensures the dosage accuracy and quality uniformity of the entire compound capsule by ensuring the physical stability of the microcapsules.

[0079] In summary, this compound acetaminophen and amantadine capsule containing caffeine microcapsules, through an innovative layered microparticle structure design and synthetic polymer coating technology, achieves time-controlled release of the two components. It not only solves the problems of imprecise regulation and significant environmental influence in traditional natural material sustained-release technologies, but also optimizes the efficacy and safety of compound drugs, demonstrating the powerful capabilities of modern formulation technology in improving drug performance.

[0080] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. For those skilled in the art, the present invention can have various modifications and variations. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A compound acetaminophen and amantadine capsule containing caffeine microcapsules, characterized in that, Including acetaminophen, amantadine hydrochloride, artificial bezoar, pharmaceutical excipients, and functional microcapsule units; The functional microcapsule unit includes a core material containing caffeine as an active ingredient, an ethyl cellulose controlled-release layer encapsulating the core material, and an immediate-release layer containing chlorpheniramine maleate encapsulating the controlled-release layer. The core material is made by granulating caffeine and microcrystalline cellulose with an adhesive solution and then drying it, with a particle size range of 250-355 micrometers. The ethyl cellulose controlled-release layer has a gradient composite structure, composed of ethyl cellulose and the plasticizer diethyl phthalate, including an inner coating and an outer coating; the inner coating uses low-viscosity ethyl cellulose, and the outer coating uses high-viscosity ethyl cellulose; the weight gain of the inner coating is 4%-10% of the core material weight, and the total weight gain of the inner and outer coatings is 7%-15% of the core material weight, wherein the weight ratio of ethyl cellulose to diethyl phthalate is 40:4; The immediate-release layer is composed of chlorpheniramine maleate, hydroxypropyl methylcellulose as a film-forming agent, and polyethylene glycol 6000 as a pore-forming agent, wherein the weight ratio of chlorpheniramine maleate, hydroxypropyl methylcellulose, and polyethylene glycol 6000 is 20:10:5; the coating weight gain of the immediate-release layer is 10%-20% of the weight of the microspheres after the controlled-release layer is coated. The preparation method of compound acetaminophen and amantadine capsules includes: S1. Preparation of core material; S2. Fluidized bed coating technology is used to coat the controlled-release layer; S3, coating immediate-release layer; S4, capsule filling; In step S2, after coating, gradient drying and humidity conditioning are performed, specifically including: after inner coating, fluidized drying at 45°C for 15 minutes, and then drying at 42°C for 25 minutes; after outer coating, drying at 50°C for 25 minutes, then fluidized at 30°C and 45% humidity for 15 minutes, and finally cooling with air at 25°C and 35% humidity to a material temperature of 25°C.

2. The compound acetaminophen and amantadine capsules as described in claim 1, characterized in that, The contents of each component in each capsule are as follows: 200-300 mg of acetaminophen, 80-120 mg of amantadine hydrochloride, 5-15 mg of artificial bezoar, and 15-40 mg of the functional microcapsule unit.

3. The compound acetaminophen and amantadine capsules as described in claim 2, characterized in that, Each 26.5 mg functional microcapsule unit contains 15 mg of caffeine and 2 mg of chlorpheniramine maleate.

4. A method for preparing compound acetaminophen and amantadine capsules as described in any one of claims 1-3, characterized in that, Includes the following steps: S1. Preparation of core material: Caffeine and microcrystalline cellulose are mixed, sprayed into an adhesive solution for granulation, dried and sieved to obtain core material pellets with a particle size of 250-355 micrometers. S2. Controlled-release coating layer: Using fluidized bed coating technology, the coating solution of ethyl cellulose and diethyl phthalate is sprayed onto the surface of the core material to form a controlled-release layer; S3, Immediate-Release Coating Layer: A coating solution containing chlorpheniramine maleate, hydroxypropyl methylcellulose and polyethylene glycol 6000 is sprayed on the outside of the controlled-release layer to form an immediate-release layer. After drying, functional microcapsule units are obtained. S4. Capsule filling: Mix acetaminophen, amantadine hydrochloride, artificial bezoar, pharmaceutical excipients and the functional microcapsule unit evenly, and fill the capsule shell.

5. The method as described in claim 4, characterized in that, The adhesive solution in step S1 is a 2% (w / w) aqueous solution of hydroxypropyl methylcellulose; the pharmaceutical excipients in step S4 include dextrin, croscarmellose sodium, and magnesium stearate.

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