An indole compound direct-taking granule and a preparation method thereof

Abstract

This invention provides indole compound direct-release granules, comprising immediate-release granules and sustained-release granules. The immediate-release granules comprise an active pharmaceutical ingredient, a blank pellet core, a binder, and an anti-adhesion agent. The sustained-release granules comprise a drug-loaded layer and a sustained-release layer. The drug-loaded layer comprises the active pharmaceutical ingredient, a blank pellet core, a binder, and an anti-adhesion agent. The sustained-release layer comprises a sustained-release material, a plasticizer, and an anti-adhesion agent. The structural formula of the active pharmaceutical ingredient is shown below. This invention, by selecting blank pellet cores with smaller particle sizes, controlling the weight ratio of the active pharmaceutical ingredient to the blank pellet core, and increasing the weight gain of the sustained-release layer coating, obtains indole-based direct-release granules with better palatability, better sustained-release effect, and convenient administration.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to an indole compound direct-administered granule and its preparation method. Background Technology

[0002] Indole compounds, chemically named N-acetyl-5-methoxytryptamine, have the structural formula shown in compound I below: Indole is one of the hormones secreted by the pineal gland in the brain. It plays a variety of roles in the human body, including regulating the biological clock, improving sleep quality, and relieving symptoms of depression and anxiety. At the same time, the secretion of indole compounds has a circadian rhythm, and the level of indole compounds at night directly affects the quality of sleep.

[0003] Childhood neurodevelopmental disorders are a group of chronic developmental brain dysfunctions caused by various genetic or acquired factors. While their clinical manifestations vary, a very high proportion of these disorders are accompanied by sleep disturbances. Sleep disorders significantly impair children with neurodevelopmental disorders across multiple domains, including cognition, emotion, social development, and behavior, and can even severely impact the sleep quality and quality of life of their families. Therefore, prioritizing and actively treating sleep disorders in children with developmental disorders can help improve their daytime behavior and learning abilities and should be considered an important component of their comprehensive treatment.

[0004] Currently, medication should be considered for children with particularly severe sleep disorders, or those who do not respond well to behavioral management therapy, especially when the sleep disorder has significantly impacted their daytime functioning or family functioning. Existing medications include antipsychotics, anticonvulsants, and antihistamines with sedative effects, as well as the aforementioned indole compounds.

[0005] Currently, the EU has marketed sustained-release microtablets, which are 3mm in size. However, these microtablets should not be broken or chewed; they must be swallowed whole, posing a significant inconvenience for children. Although the microtablets are much smaller than regular tablets, children of different ages have varying swallowing abilities. For younger children, the acceptability and swallowing ability of microtablets, as well as the potential for choking or other safety issues during administration, need to be fully evaluated through clinical trial data. Furthermore, sustained-release microtablets do not release the drug quickly after administration, making them less effective in addressing difficulty falling asleep.

[0006] Direct-swallowing granules are a special granule dosage form that can be swallowed directly without dissolving. Compared to microtablets, they can further improve children's medication adherence and reduce the risk of medication being chewed. Through taste masking and flavor-correcting technologies, direct-swallowing granules can effectively improve the unpleasant taste of the medication, increasing children's compliance. In addition, since they do not require water, they also improve the convenience of administration.

[0007] However, developing indole compounds into direct-acting granules faces a key technical challenge: due to the small size of the active ingredient, it is prone to uneven mixing during formulation production, which in turn affects the uniformity of content and may ultimately affect the safety and efficacy of the drug.

[0008] Therefore, developing a sustained-release formulation of indole compounds that is more suitable for children and can more effectively improve sleep quality has significant clinical value and application prospects. Summary of the Invention

[0009] To address the technical problems in existing technologies, such as poor patient compliance, difficulty swallowing, unsatisfactory sustained-release effects, and difficulty in ensuring the uniformity of small-sized drug mixtures, this invention successfully obtained indole compound direct-taken granules with significantly improved palatability, excellent sustained-release effects, convenient administration, and satisfactory content uniformity by synergistically controlling the particle size of blank pellets, the weight ratio of active pharmaceutical ingredients to blank pellets, and the weight gain of the sustained-release coating.

[0010] This invention provides a direct-release granule of an indole compound, comprising immediate-release granules and sustained-release granules. The immediate-release granules comprise an active pharmaceutical ingredient, a blank pellet core, a binder, and an anti-adhesion agent. The sustained-release granules comprise a drug-loaded layer and a sustained-release layer. The drug-loaded layer comprises an active pharmaceutical ingredient, a blank pellet core, a binder, and an anti-adhesion agent. The sustained-release layer comprises a sustained-release material, a plasticizer, and an anti-adhesion agent. The structural formula of the active pharmaceutical ingredient is shown below: .

[0011] In some embodiments, the blank pellet core has a particle size of 20-75 μm.

[0012] In some embodiments, the blank pellet core has a particle size of 20–75 μm; preferably 30–60 μm; more preferably 40–50 μm.

[0013] Using blank pellet cores with smaller particle size has the following beneficial effects: First, the resulting direct-acting granules have a smaller particle size, which is beneficial for swallowing in young children and improves medication compliance; second, the smaller particle cores have a larger specific surface area, which is conducive to the uniform loading of active pharmaceutical ingredients and improves drug delivery uniformity; third, it can reduce the gritty feeling during medication administration and improve oral tactile sensation; fourth, the smaller particle cores are more likely to form a uniform and continuous sustained-release layer during the coating process, which helps to obtain a stable in vitro release curve.

[0014] In some embodiments, the weight ratio of the active pharmaceutical ingredient to the blank pellet core in the immediate-release granules and the sustained-release granule drug-loaded layer is 0.5–8 : 90–60; preferably 1–6 : 85–70; more preferably 2–4 : 80–75.

[0015] This weight ratio is a parameter affecting the key quality attributes of the formulation: if the proportion of the active pharmaceutical ingredient is too high, it can easily lead to uneven drug loading, resulting in substandard content uniformity, and may also cause drug accumulation on the particle surface, affecting the integrity of subsequent sustained-release coating; if the proportion of the active pharmaceutical ingredient is too low, the drug loading per particle is insufficient, requiring an increase in the number of particles to be taken to achieve the target dose, reducing the convenience of medication for children. This invention, by controlling the weight ratio within the above range, can achieve suitable drug loading and excellent sustained-release effect while ensuring content uniformity.

[0016] In some embodiments, the weight ratio of active ingredients in the immediate-release granules and the sustained-release granules is 2:1 to 1:4.

[0017] In some embodiments, the weight ratio of anti-adhesive to sustained-release material in the sustained-release layer is 1:10 to 1:20.

[0018] In some embodiments, the weight gain of the sustained-release layer in the sustained-release particles ranges from 10% to 27%.

[0019] In some embodiments, the blank pellet core includes one or more of the following: sucrose pellet core, microcrystalline cellulose pellet core, silica pellet core, starch pellet core, tartaric acid pellet core, and mannitol pellet core.

[0020] In some embodiments, the adhesive includes one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, and polyvinyl alcohol.

[0021] In some embodiments, the anti-adhesion agent includes one or more of talc, silica, magnesium stearate, micronized silica gel, and sodium dodecyl sulfate.

[0022] Anti-adhesion agents can prevent adhesion between particles and between particles and equipment walls during the preparation process, ensuring the smooth progress of fluidized bed granulation or coating processes; at the same time, in the sustained-release layer, anti-adhesion agents can also adjust the density and permeability of the sustained-release membrane, affecting the drug release rate.

[0023] In some embodiments, the sustained-release material includes one or more of ethyl cellulose, Eutec RS-PO, and Eutec RL-PO.

[0024] In some embodiments, the plasticizer includes one or more of triethyl citrate, polyethylene glycol, phthalate, and castor oil.

[0025] Plasticizers can lower the glass transition temperature of slow-release materials, promote the continuity of the film-forming process, prevent the coating film from cracking, and ensure the stability of the slow-release effect.

[0026] In some embodiments, the immediate-release particles further include a solvent comprising ethanol and water in a weight ratio of 7:3 to 1:1.

[0027] An appropriate ratio of ethanol-water mixed solvent can effectively dissolve the active pharmaceutical ingredients and binders, while controlling the drying rate to avoid excessive solvent evaporation that could lead to drug migration or pellet aggregation.

[0028] In some embodiments, the sustained-release layer further includes a solvent comprising ethanol and water in a weight ratio of 4:1 to 7:3.

[0029] Considering the differences in solubility of active pharmaceutical ingredients and sustained-release coating materials in different solvents, the solvent system needs to be comprehensively optimized. A higher proportion of ethanol helps dissolve hydrophobic sustained-release materials such as ethyl cellulose, while reducing the penetration and dissolution of the drug-loaded layer and protecting its integrity.

[0030] Because the active pharmaceutical ingredient and the sustained-release coating material have different solubilities in solvents, the solvent system used needs to be considered comprehensively.

[0031] In some embodiments, the direct-acting granules contain flavoring excipients, including one or more of sucrose, lactose, glucose, sorbitol, mannitol, sucralose, strawberry flavoring, sweet orange flavoring, and milk flavoring.

[0032] Adding flavoring excipients can effectively mask any unpleasant bitterness or odor that may be present in the active ingredients of a drug, significantly improving children's acceptance and compliance with medication. Flavoring excipients can be physically mixed with immediate-release and sustained-release granules before filling, avoiding the destruction of flavorings during the high-temperature granulation process.

[0033] In some embodiments, the direct-release granules include immediate-release granules and sustained-release granules. The immediate-release granules comprise 0.5-8 parts of the active pharmaceutical ingredient, 60-90 parts of blank pellet core, 1.5-3.5 parts of binder, and 5-10 parts of anti-adhesion agent. The sustained-release granules comprise a drug-loaded layer and a sustained-release layer. The drug-loaded layer comprises 0.5-8 parts of the active pharmaceutical ingredient, 60-90 parts of blank pellet core, 1.5-3.5 parts of binder, and 5-10 parts of anti-adhesion agent. The sustained-release layer comprises 8-23 parts of sustained-release material, 0.2-1.2 parts of plasticizer, and 0.4-2.3 parts of anti-adhesion agent. Preferably, the direct-release granules include immediate-release granules and sustained-release granules. The immediate-release granules include 0.5-8 parts of the active pharmaceutical ingredient, 60-90 parts of blank pellet core, 1.5-3.5 parts of hydroxypropyl methylcellulose, and 5-10 parts of talc. The sustained-release granules include a drug-loaded layer and a sustained-release layer. The drug-loaded layer includes 0.5-8 parts of the active pharmaceutical ingredient, 60-90 parts of blank pellet core, 1.5-3.5 parts of hydroxypropyl methylcellulose, and 5-10 parts of talc. The sustained-release layer includes 8-23 parts of ethylcellulose, 0.2-1.2 parts of triethyl citrate, and 0.4-2.3 parts of talc.

[0034] Another aspect of the present invention provides a method for preparing direct-acting granules, characterized by comprising the following steps: Step 1: Dissolve the active pharmaceutical ingredient in a solvent, then mix it with an adhesive and an anti-adhesion agent to obtain a drug-applying solution; Step 2: Using blank pellet cores as substrates, the drug-coating solution is atomized and sprayed onto the blank pellet cores through a fluidized bed powder coating process to obtain drug-loaded particles in immediate-release and sustained-release granules. Step 3: Mix the sustained-release material with the solvent to obtain the sustained-release coating solution; Step 4: Using drug-loaded particles as a substrate, the release coating liquid is atomized and sprayed onto the drug-loaded particles through a fluidized bed powder coating process for sustained-release coating. After coating, the particles are dried to obtain sustained-release particles. Step 5: Mix the immediate-release granules and the sustained-release granules, and then add any optional flavoring excipients.

[0035] The indole compounds described in this invention have the following advantages; 1. This invention prepares indole compound direct-taken granules by selecting blank pellet cores with smaller particle size (preferably 20–75 μm). The resulting granules are small and uniform in size, with a delicate texture, and no significant gritty feeling when taken, providing a pleasant oral experience. They are particularly suitable for children with weaker swallowing abilities, as they can be swallowed directly without water, significantly improving medication adherence. 2. This invention effectively solves the technical problem of uneven mixing of small-sized drugs during formulation by precisely controlling the weight ratio of the active pharmaceutical ingredient to the blank pellet core (preferably 0.5–8 : 90–60). This ensures a uniform loading of the active pharmaceutical ingredient on the pellet core surface, making the content uniformity of the formulation meet requirements, thereby guaranteeing the safety and efficacy of the drug. 3. This invention achieves stable release behavior and eliminates the risk of burst release by applying a sustained-release coating to the drug-loaded layer and optimizing the control of the coating weight gain. This sustained-release layer design allows for stable drug release in the body, avoiding excessive fluctuations in blood drug concentration. This ensures both rapid improvement in difficulty falling asleep and sustained improvement in sleep quality. Furthermore, reducing the frequency of medication administration further enhances the convenience and compliance of medication use in children. Detailed Implementation

[0036] Numerous specific details are set forth in the following description to provide a full understanding of the invention. However, the invention can be practiced in many other ways different from those described herein, and similar modifications can be made by those skilled in the art without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0037] 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 in this specification is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0038] Examples 1-5 Table 1. Prescriptions for Examples 1-5 and Comparative Examples 1-2

[0039] Preparation method (the content of other excipients is the same in all embodiments): ①Preparation of drug-loaded layer: Preparation of ethanol solution for indole compounds: Add the indole compound to 50 times its prescribed amount of 95% ethanol solution, stir until dissolved, and set aside. Hydroxypropyl methylcellulose aqueous solution: Disperse hydroxypropyl methylcellulose in hot water (70℃~90℃) at 50 times the amount of indole compound in the prescription, stir to dissolve, and set aside for later use; Mix the ethanol solution of indole compounds with the aqueous solution of hydroxypropyl methylcellulose and stir until homogeneous; continue to add talc powder and apply high shear for at least 5 minutes to obtain the drug solution. Using microcrystalline cellulose blank pellet cores as substrates, a fluidized bed powder coating process is used to control the material temperature at 30℃~45℃. The drug-loaded solution is atomized and sprayed onto the blank pellet cores to obtain drug-loaded particles.

[0040] ②Preparation of sustained-release layer: A sustained-release coating solution with ethyl cellulose ethanol aqueous solution as the main component was prepared, wherein the mass ratio of ethanol to water was 4:1. Continue using the powder coating process, control the material temperature at 25℃~40℃, atomize the sustained-release coating liquid and spray it onto the drug-loaded particles prepared in the first step for sustained-release coating; after coating, dry to obtain sustained-release particles.

[0041] ③ Total Mixing: The drug-loaded particles and sustained-release particles are mixed and then packaged.

[0042] Table 2. Results of content uniformity testing of formulations prepared in Examples 1-5 and Comparative Examples 1-2

[0043] Results analysis: Comparison of the content uniformity of the preparations prepared in Examples 1-5 and Comparative Examples 1-2 shows that the content uniformity of the preparations is good when the weight ratio of active ingredient to blank pellet core is in the range of 0.5-8:90-60.

[0044] Examples 6-8 Table 3. Prescriptions for Examples 6-8 and Comparative Examples 3-4

[0045] The preparation method is the same as in Examples 1-5.

[0046] The direct-release granules prepared in Examples 6-8 and Comparative Examples 3-4 (with an API weight ratio of 1:1 between immediate-release and sustained-release granules) were tested according to the Dissolution and Release Determination Method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II), using 900 ml of pH 6.8 phosphate buffer solution as the dissolution medium, and the chromatographic conditions under the Assay section were followed. The results are as follows.

[0047] Table 4. In vitro dissolution data of Examples 6-8 and Comparative Examples 3-4

[0048] Results Analysis: It was observed that the dissolution behavior of Comparative Example 3 was not significantly different from the control formulation of indole compound particles (trade name: Manlajing, specification: 2mg), with over 90% dissolution achieved in vitro within 5 minutes. Examples 6-8 all achieved a significant sustained-release effect in in vitro dissolution behavior compared to the control formulation, improving sleep maintenance difficulties through the slow release of indole compounds. As the sustained-release layer weight gain increased, the dissolution rate showed a significant decreasing trend. When the sustained-release weight gain increased to 40%, the endpoint dissolution amount was already below 80%, indicating that the formulation released too slowly. Therefore, a sustained-release weight gain range of 10%–27% resulted in relatively ideal sustained-release behavior in vitro.

[0049] Example 9: Selection of Solvent Ratio The direct-acting granules of this invention are prepared using a spray-application process. The indole compound active pharmaceutical ingredient is slightly soluble in water but has good solubility in ethanol; however, the binder hydroxypropyl methylcellulose needs to be dissolved in water, therefore, an ethanol-water mixture is selected as the solvent for the drug-loaded layer. Considering the flammability and explosiveness of ethanol, a lower ethanol ratio is preferred for coating in production; therefore, the ethanol-water ratio was investigated. Results show that when the ethanol-water ratio is reduced to below 1:1, the indole compound active pharmaceutical ingredient is difficult to fully dissolve in the drug-loaded coating solution; while when the ethanol ratio is too high (e.g., above 7:3), although it is beneficial for the dissolution of the active pharmaceutical ingredient, the rapid evaporation of ethanol can easily lead to spray gun clogging and increase production safety hazards. Based on the balance between solubility and process safety, the preferred weight ratio of ethanol to water in the drug-loaded coating solution is 7:3 to 1:1.

[0050] In the sustained-release coating solution, the sustained-release material is ethyl cellulose, which is soluble in ethanol but insoluble in water. Therefore, the sustained-release coating solution also uses an ethanol-water mixture, and the ethanol ratio should not be too low. Experiments have shown that when the ethanol-water ratio decreases to below 7:3, the ethyl cellulose in the mixed solution will precipitate and cannot form a film; while when the ethanol ratio is too high (e.g., above 4:1), although it can ensure the stable dissolution of ethyl cellulose, the excessively polar solvent may cause percolation of the drug-loaded layer, and the drying load and production cost will increase. Therefore, the preferred weight ratio of ethanol to water in the sustained-release coating solution is 4:1 to 7:3.

[0051] Examples 10-13: Investigation of the API ratio in immediate-release and sustained-release granules The indole compound direct-release granules of this invention comprise two parts: immediate-release granules and sustained-release granules. The API in the immediate-release granules is rapidly released to take effect, thereby improving difficulty falling asleep. The API in the sustained-release granules is released slowly, maintaining a continuous and stable blood drug concentration during nighttime sleep to maintain healthy sleep and the circadian rhythm, further improving sleep quality. Therefore, the ratio between immediate-release and sustained-release granules is crucial.

[0052] Table 5 Summary of API weight ratios in formulations prepared in Examples 10-13

[0053] The other formulations and preparation methods of the immediate-release granules and sustained-release granules are the same as in Example 7 (the weight ratio of API is controlled by taking different weights of immediate-release granules and sustained-release granules). The direct-release granules prepared in Examples 10-13 and Comparative Examples 5-6 were taken and the dissolution and release were determined according to the method of determination of dissolution and release (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II), using 900 ml of pH 6.8 phosphate buffer solution as the dissolution medium, and the chromatographic conditions under the content determination section were followed. The results are as follows.

[0054] Table 6. In vitro dissolution data of the formulations prepared in Examples 10-13 and Comparative Examples 5-6

[0055] The results showed that the in vitro dissolution rate gradually slowed down as the proportion of API in sustained-release granules increased. When the proportion of API in sustained-release granules was too high (as in Comparative Example 6), the drug release was too slow, resulting in a low endpoint dissolution volume and incomplete API release, which may make it difficult to effectively maintain sleep duration in clinical applications. Conversely, when the proportion of API in immediate-release granules was too high (as in Comparative Example 5), the drug release was too fast, and the blood drug concentration may experience an early peak followed by a rapid decline, making it difficult to achieve a sustained effect in improving sleep disorders. Therefore, the weight ratio of API in immediate-release and sustained-release granules needs to be controlled within a reasonable range (2:1~1:4) to ensure rapid onset of action while maintaining a stable drug release behavior, thereby achieving the dual therapeutic effects of sleep induction and sleep maintenance.

[0056] Examples 14-15: Selection of Adhesive Type The direct-administered granule preparation process of this invention requires dissolving the active pharmaceutical ingredient in a solvent, then mixing it with a binder and other components to obtain a drug-loaded solution. In this embodiment of the invention, several commonly used binders for oral solid dosage forms (other excipients are the same as in Example 7) were screened, and process feasibility was used as the evaluation index. The results are as follows: Table 7 Results of the study on different adhesives

[0057] Examples 16-17 Selection of Anti-adhesive Types The direct-acting granule preparation process described in this invention involves powder coating. Powder coating processes commonly exhibit electrostatic phenomena, which can easily lead to material adhesion, nozzle blockage, and even experimental failure. Therefore, an anti-adhesion agent needs to be added to the coating solution to reduce electrostatic phenomena during the coating process and ensure the smoothness of the process. In this embodiment of the invention, several commonly used anti-adhesion agents in oral solid dosage forms were screened (other excipients are the same as in Example 7). Process feasibility was used as the evaluation index, and the results are as follows: Table 8 Results of the study on different anti-adhesion agents

[0058] Examples 18-19 Selection of Anti-adhesive Dosage The direct-release granules of this invention are prepared using a powder coating process. An anti-adhesion agent, such as talc, is added to the coating solution to suppress static electricity and ensure process smoothness. Simultaneously, the anti-adhesion agent also acts as a pore-forming agent in the coating solution, affecting the density and continuity of the sustained-release film. In this invention, using talc as an example (other excipients are the same as in Example 7, and the amount of ethyl cellulose remains unchanged), the feasibility of the process and the formulation release behavior under different amounts of anti-adhesion agent were investigated. The results are as follows: Table 9 Results of the study on the dosage of anti-adhesive

[0059] Table 10 In vitro dissolution data of the formulations prepared in Examples 18-19 and Comparative Example 8

[0060] Experimental results show that the amount of talc used as an anti-adhesion agent affects the coating process and drug release behavior. When the amount of talc is too small, electrostatic phenomena are severe during the coating process, resulting in poor powder flowability and poor process feasibility, making stable coating impossible. Conversely, when the amount of talc is too large, its pore-forming effect is significantly enhanced, reducing the controlled-release capacity of the sustained-release layer, causing the drug to be released too quickly, and making it difficult to achieve the expected sustained-release effect. Considering both process feasibility and in vitro drug release behavior, the preferred weight ratio of the anti-adhesion agent to the sustained-release material in this invention is 1:10 to 1:20.

[0061] Examples 20-24: Selection of Plasticizer Type and Dosage The direct-acting granules of this invention are prepared using a powder coating process. A plasticizer is added to the coating solution, enabling the coating solution to form a continuous film with a certain degree of toughness after drying. In this embodiment, the effects of different types and amounts of plasticizers on film formation were investigated (other excipients were the same as in Example 7), and the results are as follows: Table 11 Results of the Investigation on Plasticizer Types and Dosage

[0062] In this invention, the preferred amount of plasticizer is 0.2 to 1.2 parts, which can form a continuous and complete coating film.

[0063] Examples 25-26: Selection of Sustained-Release Material Types The sustained-release granules of this invention utilize a powder coating process to uniformly coat the surface of immediate-release granules with a solvent containing the sustained-release material, thereby forming a dense sustained-release layer on the surface of the immediate-release granules. This layer blocks the entry of external solvents, achieving a slow drug release effect. This invention provides formulations prepared from commonly used sustained-release materials in oral solid dosage forms (other excipients are the same as in Example 6), and dissolution tests have demonstrated that they all achieve good in vitro sustained-release effects.

[0064] Table 12 Examination of Types of Sustained-Release Materials

[0065] Table 13 In vitro dissolution data of the formulations prepared in Examples 25-26

[0066] Examples 27-28: Examples of different specifications Table 14 Prescription Tables for Examples 2 and 27-28

[0067] The preparation method is the same as in Examples 1-5. Add the excipients during the final mixing.

[0068] Table 15 Dissolution data for Examples 2 and 27-28

[0069] The formulations prepared in Examples 2 and 27-28 of this invention have been shown in dissolution tests to achieve good in vitro sustained-release effects.

[0070] Example 29 Taste Evaluation Experiment Without disclosing the product details, the palatability and taste of the direct-taken granules prepared in Examples 6-8 and Comparative Examples 9-10 (the preparation method and formulation of Comparative Examples 9-10 were the same as those in Example 6, but the particle size of the blank pellets was 100 μm and 125 μm, respectively) were evaluated in adult volunteers. The results are as follows: Table 16. Taste evaluation of the direct-acting particles prepared in Examples 6-8 and Comparative Examples 9-10

[0071] Taste evaluation scoring criteria: Taste: 1. Sweet, widely accepted 2. No bitterness, relatively widely accepted 3. Slightly bitter, acceptable 4. Bitter, acceptable 5. Very bitter, difficult to accept; Aftertaste: 1. Suitable aftertaste, highly acceptable 2. Fairly suitable aftertaste, relatively acceptable 3. Slightly unpleasant aftertaste, acceptable 4. Unpleasant aftertaste, but still acceptable 5. Strong aftertaste, unpleasant, difficult to accept; Odor: 1. Pleasant odor, no odor, high acceptance 2. Pleasant odor, no odor, relatively high acceptance 3. Slight odor, acceptable 4. Odor present, acceptable 5. Strong odor, unacceptable; Texture: (gritty texture) 1. Very smooth, no gritty texture 2. Smooth with a slight gritty texture 3. Slightly less smooth, with a gritty texture 4. Poor smoothness, noticeable gritty texture 5. Very poor smoothness, very noticeable gritty texture; Overall rating: 1. Very good 2. Good 3. Average 4. Poor 5. Very poor

[0072] All volunteers reported that the direct-taken granules prepared in Examples 6-8 met the requirements for drug swallowing in terms of saliva secretion volume and rate after entering the oral cavity, allowing for smooth waterless swallowing without any unpleasant taste and a good mouthfeel. In contrast, the direct-taken granules prepared in Comparative Examples 9-10 had a heavier gritty feel, affecting the mouthfeel.

Claims

1. A type of indole compound granule for direct administration, characterized in that, The direct-release granules include immediate-release granules and sustained-release granules. The immediate-release granules include a pharmaceutical active ingredient, a blank pellet core, a binder, and an anti-adhesion agent. The sustained-release granules include a drug-loaded layer and a sustained-release layer. The drug-loaded layer includes a pharmaceutical active ingredient, a blank pellet core, a binder, and an anti-adhesion agent. The sustained-release layer includes a sustained-release material, a plasticizer, and an anti-adhesion agent. The structural formula of the pharmaceutical active ingredient is shown below: 。 2. The direct-acting granules according to claim 1, characterized in that, The blank pellet core has a particle size of 20-75 μm.

3. The direct-acting granules according to claim 1, characterized in that, The weight ratio of active ingredients in the immediate-release granules and the sustained-release granules is 2:1 to 1:

4.

4. The direct-acting granules according to claim 1, characterized in that, The weight ratio of the active pharmaceutical ingredient to the blank pellet core in the drug-loaded layer of immediate-release and sustained-release granules is 0.5-8:90-60.

5. The direct-acting granules according to claim 1, characterized in that, The weight ratio of anti-adhesive to sustained-release material in the sustained-release layer is 1:10 to 1:

20.

6. The direct-acting granules according to claim 1, characterized in that, The weight gain of the sustained-release layer in the sustained-release particles ranges from 10% to 27%.

7. The direct-acting granules according to claim 1, characterized in that, The blank pellet core includes one or more of sucrose pellet core, microcrystalline cellulose pellet core, silica pellet core, starch pellet core, tartaric acid pellet core, and mannitol pellet core; and / or the adhesive includes one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, and polyvinyl alcohol; and / or the anti-adhesive includes one or more of talc, silica, magnesium stearate, micronized silica gel, and sodium lauryl sulfate; and / or the sustained-release material includes one or more of ethyl cellulose, Eutec RS-PO, and Eutec RL-PO; and / or the plasticizer includes one or more of triethyl citrate, polyethylene glycol, phthalate, and castor oil.

8. The direct-acting granules according to claim 1, characterized in that, The immediate-release granules also include a solvent comprising ethanol and water in a weight ratio of 7:3 to 1:1; the sustained-release layer also includes a solvent comprising ethanol and water in a weight ratio of 4:1 to 7:

3.

9. The direct-acting granules according to claim 1, characterized in that, The direct-acting granules contain flavoring excipients mixed in, including one or more of sucrose, lactose, glucose, sorbitol, mannitol, sucralose, strawberry flavoring, sweet orange flavoring, and milk flavoring.

10. The direct-acting granules according to claim 1, characterized in that, The direct-release granules include immediate-release granules and sustained-release granules. The immediate-release granules comprise 0.5-8 parts of the active pharmaceutical ingredient, 60-90 parts of blank pellet core, 1.5-3.5 parts of binder, and 5-10 parts of anti-adhesion agent. The sustained-release granules comprise a drug-loaded layer and a sustained-release layer. The drug-loaded layer comprises 0.5-8 parts of the active pharmaceutical ingredient, 60-90 parts of blank pellet core, 1.5-3.5 parts of binder, and 5-10 parts of anti-adhesion agent. The sustained-release layer comprises 8-23 parts of sustained-release material, 0.2-1.2 parts of plasticizer, and 0.4-2.3 parts of anti-adhesion agent. Preferably, the direct-release granules include immediate-release granules and sustained-release granules. The immediate-release granules include 0.5-8 parts of the active pharmaceutical ingredient, 60-90 parts of blank pellet core, 1.5-3.5 parts of hydroxypropyl methylcellulose, and 5-10 parts of talc. The sustained-release granules include a drug-loaded layer and a sustained-release layer. The drug-loaded layer includes 0.5-8 parts of the active pharmaceutical ingredient, 60-90 parts of blank pellet core, 1.5-3.5 parts of hydroxypropyl methylcellulose, and 5-10 parts of talc. The sustained-release layer includes 8-23 parts of ethylcellulose, 0.2-1.2 parts of triethyl citrate, and 0.4-2.3 parts of talc.

11. A method for preparing the direct-acting granules according to any one of claims 1-10, characterized in that, Includes the following steps: Step 1: Dissolve the active pharmaceutical ingredient in a solvent, then mix it with an adhesive and an anti-adhesion agent to obtain a drug-applying solution; Step 2: Using blank pellet cores as substrates, the drug-coating solution is atomized and sprayed onto the blank pellet cores through a fluidized bed powder coating process to obtain drug-loaded particles in immediate-release and sustained-release granules. Step 3: Mix the sustained-release material with the solvent to obtain the sustained-release coating solution; Step 4: Using drug-loaded particles as a substrate, the release coating liquid is atomized and sprayed onto the drug-loaded particles through a fluidized bed powder coating process for sustained-release coating. After coating, the particles are dried to obtain sustained-release particles. Step 5: Mix the immediate-release granules and the sustained-release granules, and then add any optional flavoring excipients.

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