Ondansetron water-free swallowing particle

Abstract

The invention provides an ondansetron water-free swallowing granule which comprises an ondansetron granule and a flavoring granule, the ondansetron granule sequentially comprises a pill core, a drug-containing layer, an isolating layer and a smooth layer from inside to outside, and the ondansetron granule and the flavoring granule are mixed and filled in a two-channel filling mode. The ondansetron water-free swallowing granules are beneficial to rapid swallowing in the oral cavity, good taste of the preparation is ensured in the whole process, the technical characteristics of water-free swallowing are realized, the taking compliance of a patient is improved, the stability of the raw material medicines is also improved, the problem of ondansetron degradation of ondansetron or a salt preparation thereof is solved, and the ondansetron water-free swallowing granules are suitable for being used in oral administration. The growth of related substances is effectively reduced, and the stability and safety of the preparation are ensured.

Description

[0001] This application is a divisional application of the Chinese invention patent application with the application date of July 18, 2016, application number: 2016105651830, and invention name: A kind of ondansetron anhydrous swallowing granules. Technical Field

[0002] The present invention provides a new pharmaceutical dosage form of ondansetron hydrochloride, specifically, anhydrous ondansetron swallowable granules. The anhydrous ondansetron swallowable granules stimulate saliva secretion in the oral cavity, facilitating rapid swallowing. The granules also maintain a good taste throughout the entire process, achieving the technical advantage of anhydrous swallowing and improving patient compliance. Background Art

[0003] Ondansetron is a selective 5-HT3 receptor antagonist used for the preventive treatment of nausea and vomiting caused by cancer chemotherapy, and nausea and / or vomiting after radiotherapy and surgery. Existing ondansetron preparations mainly include ordinary tablets, orally disintegrating tablets and injections. The conventional process is to granulate and tablet the raw materials and excipients of ondansetron or to prepare the API into a solution for injection. The use of conventional processes to prepare oral tablets cannot effectively solve the bitter and numb taste of the API ondansetron, which makes it inconvenient for patients to take it. Preparing ondansetron into an injection solves the problem of oral taste, but the production cost and storage conditions of the injection are relatively high, and the route and method of administration of this dosage form cause great pain and inconvenience to patients. Summary of the Invention

[0004] The present invention provides a novel ondansetron pharmaceutical preparation to solve the adaptability problem of ondansetron oral preparations.

[0005] The technical solutions of the present invention are as follows:

[0006] The invention provides ondansetron anhydrous swallowable granules, comprising ondansetron granules and flavor-correcting granules. The ondansetron granules are characterized in that they are composed of a core, a drug-containing layer, an isolation layer and a smooth layer from the inside out.

[0007] The above-mentioned ondansetron anhydrous swallowing granules, wherein the pellet core is selected from sucrose pellet core, microcrystalline cellulose pellet core, etc.

[0008] The above-mentioned ondansetron anhydrous swallowable granules, wherein the drug-containing layer comprises ondansetron or its salt (preferably ondansetron hydrochloride), a binder (for example, selected from hydroxypropyl cellulose, povidone, hydroxypropyl methylcellulose, etc.), an anti-adhesive (for example, talc, titanium dioxide, etc.)

[0009] The above-mentioned ondansetron anhydrous swallowable granules, wherein the isolation layer includes a binder (for example, selected from hydroxypropyl cellulose, povidone, hydroxypropyl methylcellulose, etc.), an anti-adhesive (for example, talc, titanium dioxide, etc.)

[0010] In the above-mentioned ondansetron anhydrous swallowable granules, the smoothing layer includes a binder (e.g., selected from Eudragit, hydroxypropyl cellulose, povidone), a lubricant (e.g., selected from carbomer, sodium carboxymethyl cellulose, ethyl cellulose, etc.), a buffer (e.g., selected from sodium bicarbonate, calcium bicarbonate, etc.), and an anti-adhesive agent (e.g., talc, titanium dioxide, etc.).

[0011] In the above-mentioned ondansetron anhydrous swallowable granules, preferably, the weight gain of the isolation layer coating is 5%-10%; preferably, the weight gain of the smooth layer coating is 7%-15%.

[0012] The above-mentioned ondansetron anhydrous swallowable granules, wherein the flavored granules include a flavoring agent (for example, selected from sorbitol, maltodextrin, sodium carboxymethyl cellulose, etc.), a sweetener (for example, selected from aspartame, sucralose, etc.), an acidulant (for example, selected from citric acid, malic acid, fruit acid, etc.), an auxiliary sweetener (for example, selected from fruit flavors such as orange flavor), and a glidant (for example, selected from talc, silicon dioxide, etc.).

[0013] In the above-mentioned ondansetron anhydrous swallowable granules, the ondansetron granules and the flavor-correcting granules are filled in a double-channel filling manner.

[0014] As another object of the present invention, a method for preparing the above-mentioned ondansetron anhydrous swallowable granules is also provided, which comprises the following steps:

[0015] (1) drug application to the pill core: preparing the drug-containing suspension by adding the raw materials and excipients of the drug-containing layer to the pill core with a solvent, and applying the drug to the pill core to obtain the drug-containing pill core;

[0016] (2) Seal layer coating: the isolation layer excipient is prepared into an isolation layer coating suspension with a solvent, and the drug-containing pellet cores prepared in step (1) are subjected to isolation layer coating to obtain isolation layer coated drug-containing pellet cores;

[0017] (3) Smooth layer coating: the smooth layer excipients are prepared into a smooth layer coating suspension with a solvent, and the pill cores coated with the isolation layer prepared in step (2) are subjected to smooth layer coating to prepare ondansetron granules;

[0018] (4) Preparation of flavoring granules: Mix the other flavoring excipients except the fruit essence, wet granulate, dry and mix with the fruit essence to prepare the flavoring granules;

[0019] (5) Filling: The ondansetron granules prepared in step (3) and the flavor-correcting granules prepared in step (4) are filled in a double-channel filling manner to obtain ondansetron anhydrous swallowable granules.

[0020] In the above-mentioned method, the pill core coating, isolation layer coating or smooth layer coating is carried out using a fluidized bed.

[0021] The ondansetron anhydrous swallowable granules of the present invention contain ondansetron in an amount of 1.8% to 2.3% per unit dosage form, preferably 1.8% to 2%.

[0022] The diameter of the pellet core is preferably 0.4-0.7 mm, more preferably 0.6-0.7 mm; the weight of the pellet core is 20%-30%, preferably 20%-25%.

[0023] The above-mentioned ondansetron anhydrous swallowable granules have a drug-containing coating weight gain of 18%-23%, preferably 19%-22%.

[0024] In the above-mentioned ondansetron anhydrous swallowable granules, the amount of excipients in the isolation layer is 3%-10%, preferably 5%-10%;

[0025] In the above-mentioned ondansetron anhydrous swallowable granules, the amount of excipients in the smooth layer is 5%-15%, preferably 7%-15%;

[0026] In the above-mentioned ondansetron anhydrous swallowable granules, the ratio of ondansetron granules to flavor-correcting granules is 1:3, preferably 1:2;

[0027] In the method for preparing the ondansetron anhydrous swallowable granules of the present invention, the solvent used in the preparation of the drug-containing suspension or coating suspension in the drug-coating of the pellet core, the isolation layer coating, or the smooth layer coating can be water or ethanol solution, preferably ethanol solution.

[0028] In the method for preparing the ondansetron anhydrous swallowable granules of the present invention, the drug application on the pellet core, the isolation layer coating or the smooth layer coating is preferably carried out by a fluidized bed drug application or coating process. Preferably, the material temperature is controlled at 35°C-50°C, preferably 35°C-45°C.

[0029] In the method for preparing the ondansetron anhydrous swallowable granules of the present invention, during the drug application on the pellet core, the isolation layer coating or the smooth layer coating, the pellet cores or granules are preferably sieved between 20-30 meshes for later use.

[0030] In the method for preparing the ondansetron anhydrous swallowable granules of the present invention, preferably a wet granulation process is used to prepare the flavored granules, and the solvent can be water or an ethanol solution, preferably purified water; after granulation, preferably granules between 20 and 30 mesh are taken out, dried at a temperature of 40° C. to 50° C., preferably 45° C. to 50° C., and then fruit essence is added and mixed to obtain a flavored granule composition.

[0031] In the method for preparing the ondansetron anhydrous swallowable granules of the present invention, a double-channel filling method is preferably used for filling into stick packs.

[0032] As a specific embodiment of the present invention, an ondansetron anhydrous swallowable granule and a preparation method thereof are provided as follows:

[0033] In unit preparation:

[0034]

[0035]

[0036] 1. Drug application on pill cores - Raw materials and excipients include: ondansetron hydrochloride, hydroxypropyl cellulose, talcum powder, and ethanol, which are prepared into a drug-containing suspension for drug application on pill cores.

[0037] Preparation of drug-containing suspension:

[0038]

[0039] Procedure: Ondansetron-containing pellet cores are prepared using a fluidized bed drug application process. The material temperature is controlled at 35-40°C. After preparation, pellet cores between 20-30 mesh sieves are taken for later use to obtain drug-containing pellet cores.

[0040] 2. Isolation layer coating - the raw materials include: hydroxypropyl methylcellulose, talc, purified water, which are prepared into an isolation layer suspension for isolation layer coating.

[0041] Preparation of isolation layer coating suspension:

[0042]

[0043] Procedure: Ondansetron-containing pellet cores are prepared using a fluidized bed drug application process. The material temperature is controlled at 40-45°C. After preparation, pellet cores between 20-30 mesh sieves are taken for later use to obtain the drug-containing pellet cores wrapped in an isolation layer.

[0044] 3. Smooth layer coating - Raw materials include: Eudragit, talc, carbomer, sodium bicarbonate, and ethanol. Prepare the smooth layer coating suspension for smooth layer coating.

[0045]

[0046] Procedure: Ondansetron pellet cores are prepared using a fluidized bed drug application process. The material temperature is controlled at 35-40°C. After preparation, the pellet cores between 20-30 mesh sieves are taken for later use to obtain ondansetron granules.

[0047] 4. Preparation of flavoring auxiliary material granules - raw materials include: sorbitol, maltodextrin, citric acid, aspartame, sodium carboxymethyl cellulose, fruit essence, talc

[0048] Processing of raw and auxiliary materials: sorbitol is sieved through a 60-mesh sieve, and citric acid is crushed and sieved through a 60-mesh sieve.

[0049] Procedure: Mix sorbitol, citric acid, and aspartame in a wet granulator for 5 minutes, add purified water by spraying, granulate through a 20-mesh sieve, and dry at 50°C. Add an appropriate amount of orange flavor to obtain a flavoring composition, and prepare flavoring granules.

[0050] 5. Filling: The ondansetron granules prepared in step (3) and the flavor-correcting granules prepared in step (4) are filled using a dual-channel filling method to obtain ondansetron anhydrous swallowable granules. Ensure product specifications and sample uniformity. Fill the granules into stick packs using a dual-channel filling method. Shake well before taking and pour into the mouth.

[0051] The ondansetron anhydrous swallowable granules provided by this invention address the bitter taste of traditional oral ondansetron preparations by encapsulating the pill core with a specific isolation layer and a smoothing layer. This solution also makes it easier for patients to swallow the preparation. Furthermore, the flavor-correcting granule composition adjusts the sample's taste, allowing the entire preparation to achieve the technical advantage of anhydrous swallowing and improving patient adaptability. The ondansetron anhydrous swallowable granules of the present invention fill a domestic gap. Through their unique formulation and process, they address the inconvenience and high production cost of ondansetron preparations prepared using conventional prescriptions and processes, providing users with a more optimal preparation option, expanding the applicable population, and changing the traditional dosage form to make it more convenient for patients to carry and take.

[0052] The ondansetron anhydrous swallowable granules of the present invention not only eliminate the bitter taste of the raw material ondansetron or its salt, but also achieve the technical feature of anhydrous swallowing by forming a gel through the wetting of saliva in the mouth, thereby achieving a smooth effect. This solves the problems of unpleasant mouthfeel and inconvenience in taking common ondansetron preparations, and further improves the stability of the raw material, solves the problem of ondansetron degradation in ondansetron or its salt preparations, effectively reduces the growth of related substances, and ensures the stability and safety of the preparation. DETAILED DESCRIPTION

[0053] The following examples or comparative examples are intended to better explain or illustrate the ondansetron anhydrous swallowable granules of the present invention, but do not limit or restrict the scope of protection of this application.

[0054] Example 1

[0055] Ondansetron granules in the amount of 6000 units of preparation:

[0056]

[0057]

[0058] Preparation process:

[0059] 1. Drug application on pill cores - Raw materials and excipients include: ondansetron hydrochloride, hydroxypropyl cellulose, talcum powder, and ethanol, which are prepared into a drug-containing suspension for drug application on pill cores.

[0060] Preparation of drug-containing suspension:

[0061]

[0062] Procedure: Ondansetron-containing pellet cores are prepared using a fluidized bed drug application process. The material temperature is controlled at 35-40°C. After preparation, pellet cores between 20-30 mesh sieves are taken for later use to obtain drug-containing pellet cores.

[0063] 2. Isolation layer coating - the raw materials include: hydroxypropyl methylcellulose, talc, purified water, which are prepared into an isolation layer suspension for isolation layer coating.

[0064] Preparation of isolation layer coating suspension:

[0065]

[0066] Procedure: Ondansetron-containing pellet cores are prepared using a fluidized bed drug application process. The material temperature is controlled at 40-45°C. After preparation, pellet cores between 20-30 mesh sieves are taken for later use to obtain the drug-containing pellet cores wrapped in an isolation layer.

[0067] 3. Smooth layer coating - Raw materials include: Eudragit, talc, carbomer, sodium bicarbonate, and ethanol. Prepare the smooth layer coating suspension for smooth layer coating.

[0068]

[0069] Procedure: Ondansetron pellet cores are prepared using a fluidized bed drug application process. The material temperature is controlled at 35-40°C. After preparation, the pellet cores between 20-30 mesh sieves are taken for later use to obtain ondansetron granules.

[0070] Composition of flavoring granules:

[0071] name Dosage Sorbitol P60W 247.5mg Maltodextrin 19D 104.4mg Sodium carboxymethyl cellulose 7H4XF 19.3mg Aspartame 1.93mg Citric acid 9.6mg Orange flavor 2.3mg talcum powder 0.7mg purified water 19.9mg

[0072] Preparation process:

[0073] The excipients except flavor and talcum powder are mixed in a wet granulator, water is added as a wetting agent by spraying, and the mixture is stirred and granulated. The mixture is sieved through a 20-mesh sieve, dried at 50° C. to obtain a moisture content of 1%-3%, sieved through a 20-mesh sieve, and flavor and talcum powder are added to mix the flavoring excipient granules to complete the preparation.

[0074] Filling: Mix the prepared flavor-correcting granules and ondansetron granules in a ratio of 1:1, 2:1, or 3:1, respectively. Use a dual-channel filling process, placing the ondansetron granules and flavor-correcting granules into separate aluminum bags according to their respective filling amounts. Filling is complete. Mix well before use and pour into mouth.

[0075] result:

[0076] 1. Taste: With the increase of the proportion of flavoring excipients, the swallowing effect of the sample is significantly improved.

[0077] 2. The mixing ratio of flavor-correcting granules and ondansetron granules is 2:1, which has a better taste and a moderate filling volume, making it easier to scale up production.

[0078] 3. The sample content, dissolution rate and related substance results all meet the requirements.

[0079] 4. The mixing method of ondansetron granules and flavor correction granules, compared with the direct mixing method, which results in the sample mixing uniformity failing to meet the requirements, adopts a dual-channel filling process to solve the mixing uniformity problem and ensure the stability of the sample content.

[0080] Example 2

[0081] Effects of weight gain of isolation gowns (4%, 6%, 10%) on sample dissolution and related substances

[0082]

[0083] The preparation process is the same as that of Example 1

[0084] Dissolution results of isolation gown weight gain test samples:

[0085] 5min 15min 30min 4％ 54.9％ 80.3％ 94.4％ 6％ 52.1％ 81.3％ 93.2％ 10％ 51.6％ 82.1％ 93.8％

[0086] Conclusion: The weight gain of isolation gowns between 4% and 6% has no significant effect on the dissolution rate of the sample.

[0087] The influence of different weight gain of isolation gowns on the growth trend of related substances in samples was investigated. The samples were placed at 40℃ and 75%Rh for 60 days. Sampling was carried out at 0 day, 15 day, 30 day and 60 day respectively to compare the change trend of related substances in samples.

[0088] Here are the results:

[0089]

[0090] in conclusion:

[0091] 1. Comparing the different weight gain ranges of the sample isolation gowns, the change trend of the relevant substances under accelerated conditions shows that as the weight gain of the sample isolation gowns increases, the change of the sample related substances tends to slow down. Between 6% and 10%, the sample related substances are relatively stable and meet the impurity limit requirements. (Impurity content is less than 1%, and single impurity content is less than 0.2%)

[0092] 2. The weight gain of the sample isolation gown was between 4% and 6%, and the sample dissolution and stability results were good.

[0093] Example 3

[0094] Effect of weight gain of the smooth layer (7%, 10%, 15%) on sample dissolution and related substances

[0095]

[0096] The preparation process is the same as that of Example 1

[0097] The dissolution results of the samples were investigated by weight gain of the smooth layer:

[0098] 5min 15min 30min 7％ 55.9％ 83.3％ 93.4％ 10％ 53.1％ 81.3％ 95.2％ 15％ 51.5％ 85.1％ 94.8％

[0099] Conclusion: 1. The weight gain of the sample smooth layer is between 7% and 15%, which has no obvious effect on the dissolution rate of the sample.

[0100] 2. The weight gain of the smooth layer of the comparative sample is between 7% and 15%. The mouthfeel of the sample after swallowing is improved as the weight gain of the smooth layer increases.

[0101] 3. The weight gain of the sample smooth layer is between 7% and 15%, and the sample dissolution and swallowing effects are good.

[0102] Comparative Example 1

[0103] Ondansetron granules were prepared by wet granulation process.

[0104] prescription:

[0105] name Dosage Ondansetron hydrochloride 4.0g sorbitol 200.0g Maltodextrin 19D 60.0g 50% ethanol 35.0g

[0106] Preparation process:

[0107] Ondansetron hydrochloride, sorbitol, and maltodextrin 19D were mixed, and 50% ethanol was added for wet granulation. The granules were sieved through a 20-mesh sieve and dried in an oven at 50°C.

[0108] Results: There was no special smell during the preparation process, the material was dusty, and the particles were large after drying. I tried the bitter numbness, but it could not be swallowed directly.

[0109] Comparative Example 2

[0110] Sweeteners are added to the wet granulation formula and some excipients are mixed in.

[0111] prescription:

[0112]

[0113] Preparation process:

[0114] Mix ondansetron hydrochloride, sorbitol, maltodextrin 19D, and aspartame in a wet granulator. Add 50% ethanol to make a soft material. Sieve through a 20-mesh sieve. After drying, control the moisture content to 1%-3%. Sieve through a 20-mesh sieve. Add sorbitol, sodium carboxymethylcellulose, citric acid, and fruit flavoring and mix for 5 minutes.

[0115] Results: There were no abnormalities during the preparation process and the sample dissolved quickly in the mouth. However, the sample tasted bitter and could not be swallowed normally. In addition, ondansetron was unstable under acid, alkali, wet and hot conditions, and the preparation was not stable.

[0116] Comparative Example 3

[0117] The drug-loaded pill cores are prepared by extrusion and spheronization. In order to solve the bitter and numbing taste of the drug, the drug is prepared into drug-containing particles and coated on the outside of the particles. This can isolate the drug from contact with taste buds during swallowing, thereby solving the problem of bitterness and numbing when swallowing the raw material drug. It can also improve the taste and have a smooth effect, making it easier to swallow the pill cores.

[0118] prescription:

[0119]

[0120] Preparation method:

[0121] 1) Soft materials made of materials

[0122] The raw and auxiliary materials are mixed in a wet granulator, and water is added in a spraying manner to prepare a soft material.

[0123] 2) Extrusion and rounding process:

[0124] Use screw extruder to extrude soft materials, shot blasting parameters:

[0125] 500rpm(90s)→1000rpm(60s)→1500rpm(120s)

[0126] 3) Results: The material was made into a soft material as white granules. During the extrusion process, the material generated heat under the action of the screw. The technical drug was unstable under hot and humid conditions. Therefore, the extruded material did not turn pink and the appearance changed significantly. There was a risk to the stability of the sample. The related substances in the sample were determined to have 3 new impurities, and the total impurities exceeded 1%.

[0127] Comparative Example 4

[0128] The core drug-loading process is used to prepare the drug-loaded pill core particles, and the relevant functional excipients are wrapped around the particles to play the role of isolating and masking the taste to assist swallowing.

[0129] prescription:

[0130]

[0131]

[0132] Preparation process:

[0133] Preparation of drug suspension:

[0134]

[0135] The ondansetron-loaded pellet cores were prepared by a fluidized bed pellet core loading process, and the pellet cores were selected to have a mesh size of 20-30.

[0136] Preparation of isolation gown suspension:

[0137]

[0138] The fluidized bed coating process is used to prepare the isolation coating pellets, and the pellets are between 20-30 mesh.

[0139] in conclusion:

[0140] 1. Each process can be operated normally, and after wrapping the isolation gown, it has a certain effect on covering up the bitter and numb taste of the raw materials in the pill core.

[0141] 2. The pill core sticks to the mouth and cannot be swallowed smoothly.

Claims

1. An ondansetron anhydrous swallowable granule, comprising ondansetron granules and flavor-correcting granules, characterized in that The ondansetron granules are composed of a core, a drug-containing layer, an isolation layer and a smooth layer from the inside to the outside.

2. The ondansetron anhydrous swallowable granules according to claim 1, wherein The pellet core is selected from sucrose pellet core, microcrystalline cellulose, etc.; preferably, the diameter of the pellet core is 0.4-0.7 mm.

3. The ondansetron anhydrous swallowable granules according to claim 1-2, wherein: The drug-containing layer comprises ondansetron or its salt (preferably ondansetron hydrochloride), a binder (such as hydroxypropyl cellulose, povidone, hydroxypropyl methylcellulose, etc.) and an anti-adhesive (such as talc, titanium dioxide, etc.).

4. The ondansetron anhydrous swallowable granules according to claims 1-3, wherein: The isolation layer includes an adhesive (such as hydroxypropyl cellulose, povidone, hydroxypropyl methylcellulose, etc.) and an anti-adhesive (such as talc, titanium dioxide, etc.).

5. The ondansetron anhydrous swallowable granules according to claims 1-4, wherein: The smooth layer includes an adhesive (e.g., selected from Eudragit, hydroxypropyl cellulose, povidone), a smoothing agent (e.g., selected from carbomer, sodium carboxymethyl cellulose, ethyl cellulose, etc.), a buffer (e.g., selected from sodium bicarbonate, calcium bicarbonate, etc.) and an anti-sticking agent (e.g., talc, titanium dioxide, etc.).

6. The ondansetron anhydrous swallowable granules according to claims 1-5, wherein: Preferably, the weight gain of the isolation layer coating is 5%-10%; preferably, the weight gain of the smooth layer coating is 7%-15%.

7. The ondansetron anhydrous swallowable granules according to claims 1-6, wherein: The flavoring particles include flavoring agents (for example, selected from sorbitol, maltodextrin, sodium carboxymethyl cellulose, etc.), sweeteners (for example, selected from aspartame, sucralose, etc.), acidulants (for example, selected from citric acid, malic acid, fruit acid, etc.), auxiliary sweeteners (for example, selected from fruit flavors such as orange flavor), and glidants (for example, selected from talc, silicon dioxide, etc.).

8. The ondansetron anhydrous swallowable granules according to claims 1-7, wherein: The ondansetron granules and the flavor-correcting granules are filled in a double-channel filling manner.

9. The method for preparing the ondansetron anhydrous swallowable granules according to claims 1 to 8, comprising the following steps: (1) drug application to the pill core: preparing the drug-containing suspension by adding the raw materials and excipients of the drug-containing layer to the pill core with a solvent, and applying the drug to the pill core to obtain the drug-containing pill core; (2) Seal layer coating: the isolation layer excipient is prepared into an isolation layer coating suspension with a solvent, and the drug-containing pellet cores prepared in step (1) are subjected to isolation layer coating to obtain isolation layer coated drug-containing pellet cores; (3) Smooth layer coating: the smooth layer excipients are prepared into a smooth layer coating suspension with a solvent, and the pill cores coated with the isolation layer prepared in step (2) are subjected to smooth layer coating to prepare ondansetron granules; (4) Preparation of flavoring granules: Mix the other flavoring excipients except the fruit essence, wet granulate, dry and mix with the fruit essence to prepare the flavoring granules; (5) Filling: The ondansetron granules prepared in step (3) and the flavor-correcting granules prepared in step (4) are filled in a double-channel filling manner to obtain ondansetron anhydrous swallowable granules.

10. The method according to claim 9, wherein the pill core coating, isolation layer coating or smooth layer coating is carried out using a fluidized bed.

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