KR20240115574A - Novel Pharmaceutical Composition with Improved Stability Comprising Ramosetron, or Pharmaceutically Acceptable Salt Thereof - Google Patents

Abstract

The present invention relates to a novel pharmaceutical composition with improved stability containing Ramosetron or a pharmaceutically acceptable salt thereof and a method for preparing the same.
The pharmaceutical composition containing ramosetron's pharmaceutically acceptable salt according to the present invention as an active ingredient not only exhibits excellent ramosetron content and content uniformity, but also has the effect of minimizing loss on drying.

Description

Novel Pharmaceutical Composition with Improved Stability Comprising Ramosetron, or Pharmaceutically Acceptable Salt Thereof}

The present invention relates to a novel pharmaceutical composition with improved stability containing Ramosetron, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and a method for manufacturing the same.

Ramosetron has the structure of Chemical Formula 1, (-)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl]-4,5,6,7- It is a tetrahydrobenzimidazole derivative with the compound name of tetrahydro-1H-benzimidazole, and has the function of a serotonin 5-HT₃ receptor antagonist.

Currently, Ramosetron is used for a variety of purposes, including the prevention and treatment of diarrhea-type irritable bowel syndrome in men and women, prevention of digestive symptoms such as nausea and vomiting caused by the administration of anticancer drugs such as cisplatin, and prevention of nausea and vomiting after surgery. there is.

[Formula 1]

Pharmaceutical formulations containing ramosetron as an active ingredient are used in the form of tablets and injections. In the case of tablet formulations, the content of ramosetron is contained in a very small amount (less than 5 ㎍), making it very difficult to control the uniformity of the content. , Furthermore, there is a problem of high loss on drying (LOD).

Furthermore, when manufacturing tablets using the existing wet granulation method containing ramosetron as an active ingredient, not only does the process take a long time, but there is also the problem of low yield.

Accordingly, there is still an urgent need for a pharmaceutical composition containing ramosetron as an active ingredient with high retention uniformity and low loss on drying, a formulation containing the same, and a method for manufacturing the same.

Under this background, the purpose of the present invention is to provide a pharmaceutical composition with high content uniformity of ramosetron or a pharmaceutically acceptable salt thereof and low loss on drying, a pharmaceutical formulation containing the same, and a method for manufacturing the same.

In order to solve the above problems, the present inventors tried to develop a pharmaceutical composition containing ramosetron or a pharmaceutically acceptable salt thereof with high content uniformity and low loss on drying, and a pharmaceutical formulation containing the same. As a result, Ramosetron When microcrystalline cellulose and lactose or their hydrates are included as excipients (diluents) in a composition containing ramosetron or a pharmaceutically acceptable salt thereof, not only is the content uniformity of ramosetron significantly improved, but weight loss on drying is also allowed. The present invention was completed by confirming that there was a significant improvement within the range.

Accordingly, the present invention provides a pharmaceutical composition containing ramosetron or a pharmaceutically acceptable salt thereof as an active ingredient and microcrystalline cellulose and lactose or a hydrate thereof as an excipient, and a pharmaceutical formulation, especially a tablet, containing the pharmaceutical composition. Provides a dosage form.

In addition, the present invention provides a pharmaceutical composition containing ramosetron with improved stability, a pharmaceutically acceptable salt thereof as an active ingredient, and a method for producing a pharmaceutical formulation containing the same.

The pharmaceutical composition containing ramosetron or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient and the pharmaceutical formulation containing the same exhibit excellent stability with significantly improved content uniformity and loss on drying.

Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by a person skilled in the art to which the present invention pertains. In general, the nomenclature used herein is well known and commonly used in the art.

In one aspect, the present invention provides a pharmaceutical composition containing ramosetron or a pharmaceutically acceptable salt thereof, microcrystalline cellulose and lactose or a hydrate thereof, and a pharmaceutical formulation containing the same.

In the present invention, ramosetron is a substance having the structure of formula (1), and in the present invention, the pharmaceutically acceptable salt of ramosetron is known in the art as a pharmaceutically acceptable salt of ramosetron. Any salt present can be used without limitation, including ramosetron hydrochloride, sodium salt, p-toluenesulfonate, fumarate, citrate, succinate, salicylate, oxalate, bromate, phosphate, methanesulfonate, Examples include, but are not limited to, tartrate, maleate, and mandelic acid, and ramosetron hydrochloride having the structure of formula (2) is preferred.

[Formula 2]

In the pharmaceutical composition according to the present invention, the amount of ramosetron or a pharmaceutically acceptable salt thereof is 0.1 to 20 μg, preferably 0.5 to 15 μg, more preferably 1 to 10 μg, based on the weight of ramosetron. It may be included, most preferably 1.5 to 8 ㎍, but is not limited thereto.

In addition, in the pharmaceutical composition according to the present invention, microcrystalline cellulose is contained in an amount of 1 to 50 mg, preferably 5 to 30 mg, more preferably 10 to 25 mg, and most preferably 15 to 20 mg, and lactose or its The hydrate may contain 10 to 300 mg, preferably 20 to 200 mg, more preferably 30 to 120 mg, and most preferably 50 to 80 mg.

In addition, in the pharmaceutical composition according to the present invention, the content ratio of microcrystalline cellulose and lactose or its hydrate is 4:1 to 1:4 by weight, preferably 2:1 to 1:4, more preferably 1:1 to 1:4. It may be 1:4, but is not limited to this.

The pharmaceutical composition according to the present invention may additionally contain one or more pharmaceutically acceptable excipients, including excipients (diluents or fillers), disintegrants, binders, lubricants, preservatives, and oxidizing agents. One or more selected from the group consisting of preventive agents, buffering agents, chelating agents, solubilizers, and sweeteners may be used. Preferably, the pharmaceutical composition according to the present invention contains one or more additives selected from the group consisting of binders, disintegrants, and lubricants.

As a non-limiting example, excipients included in the pharmaceutical composition according to the present invention include mannitol, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, and Fructose, lactitol, lactose anhydrous, sorbitol, starch, pregelatinized starch, sucrose, talc, xylitol ), maltose, one or more selected from the group consisting of maltodextrin and maltitol may be used, but are not limited thereto.

As a non-limiting example, the disintegrant included in the pharmaceutical composition according to the present invention is crospovidone, sodium starch glycolate, croscarmellose sodium, hydroxypropyl cellulose, alginic acid, carbon dioxide, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium. , powdered cellulose, crospovidone, sodium docusate, guar gum, methylcellulose, polacrilin potassium, poloxamer, povidone, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate, sodium starch glycolate, starch. And one or more selected from the group consisting of pregelatinized starch may be used, but is not limited thereto.

As a non-limiting example, the binder included in the pharmaceutical composition according to the present invention is polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hyplomellose), cobopidone, hydroxyethyl cellulose, and Acacia musil. Acacia mucilage, alginic acid, carbomer, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, powdered cellulose, ethyl cellulose, gelatin, liquid glucose, guar gum, maltodextrin, methylcellulose, polydex. One or more selected from the group consisting of trose, polyethylene oxide, and sodium alginate may be used, but are not limited thereto.

As a non-limiting example, lubricants included in the pharmaceutical composition according to the present invention include magnesium stearate, zinc stearate, calcium stearate, stearic acid, talc, paraffins, lead, glyceryl behanate, sodium stearyl fumarate, Stearyl fumarate, colloidal silicon dioxide, polyethylene glycol 4000, polyethylene glycol 6000, sodium lauryl sulfate, starch, glyceryl behenate, hydrogenated castor oil, glyceryl palmitostearate, glyceryl monostearate. One or more selected from the group consisting of starch, calcium silicate, powdered cellulose, and starch may be used, but are not limited thereto.

The pharmaceutical composition according to the present invention is prepared by mixing microcrystalline cellulose, lactose or its hydrate, and one or more additives selected from the group consisting of binders, disintegrants, and lubricants in a high speed mixer, and then preparing an additive mixture. It is characterized in that it is prepared by adding an aqueous solution containing mostron to the additive mixture.

In the present invention, mixing in the high-speed mixer is performed when the agitator and chopper rotation speed is 100 to 1,000 rpm, preferably 150 to 500 rpm, more preferably 200 to 400 rpm, 1 It may be performed for 10 to 10 minutes, preferably 1.5 to 8 minutes, and more preferably 2 to 5 minutes, but is not limited thereto.

The aqueous solution containing ramosetron is characterized in that it does not contain a binder, and preferably contains a stabilizer. The stabilizer may be used without limitation as long as it is capable of stabilizing ramosetron, and is preferably one selected from the group consisting of citric acid, succinic acid, L-glutamic acid, L-malic acid, boric acid, tartaric acid, lactic acid, and fumaric acid. It may be more than this, but it is not limited to this.

Preferably, the pharmaceutical composition according to the present invention contains 50 to 80% by weight of excipient (diluent), 5 to 10% by weight of disintegrant, 0.1 to 1.0% by weight of stabilizer, and 1.0 to 5.0% by weight, based on the weight of the entire composition. % of binder and 0.1 to 1% by weight of lubricant, but is not limited thereto.

The pharmaceutical composition according to the present invention may have a Loss on Drying of 3.5% or less, more preferably 3.0% or less, even more preferably 2.6% or less, and even more preferably 2% or less.

Additionally, the present invention provides a pharmaceutical formulation comprising the pharmaceutical composition according to the present invention. The pharmaceutical formulation containing the pharmaceutical composition according to the present invention is preferably, but not limited to, a capsule, pellet, or tablet, and the tablet is more preferably a film-coated tablet including a film coating layer.

The film coating layer is selected from the group consisting of polyvinyl alcohol, copolymer of polyvinyl alcohol and polyethylene, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, methacrylic acid copolymer, polyethylene oxide, and xanthan gum. It can be formed using one or more coating bases, and accordingly, the film coating layer is made of polyvinyl alcohol, a copolymer of polyvinyl alcohol and polyethylene, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, and meta. It may include, but is not limited to, one or more film coating bases selected from the group consisting of acrylic acid copolymer, polyethylene oxide, and xanthan gum.

Polyvinyl alcohol and copolymers of polyvinyl alcohol and polyethylene that may be included in the film coating base may have a weight average molecular weight of about 2,500 to 1,000,000, preferably about 2,500 to 500,000, and xanthan gum may have a weight average molecular weight of Approximately 2,000,000 may be used, but is not limited thereto.

Illustratively, commercially available water-soluble film coating bases such as Opadry II ^TM , Opadry AMB ^TM (Calacon, USA), and Colicoat IR ^TM (BASF, Germany) may be used, but are not limited thereto. The content of the water-soluble film coating base may be 0.5 to 10% by weight, preferably 0.8 to 7% by weight, and more preferably 1 to 5% by weight, based on the total weight of the formulation, but is not limited thereto.

The pharmaceutical formulation according to the present invention, preferably a film-coated tablet, is an immediate-release formulation characterized by a disintegration time of less than 10 minutes, preferably less than 5 minutes.

The present invention also provides a method for producing the pharmaceutical composition according to the present invention.

The method for producing the pharmaceutical composition according to the present invention is:

(1) Preparing an additive mixture by mixing microcrystalline cellulose, lactose or its hydrate, and one or more additives selected from the group consisting of binders, disintegrants, and lubricants in a high speed mixer; and

(2) adding an aqueous solution containing ramosetron to the additive mixture and combining to obtain a final mixture;

It is characterized by including.

Preferably, the method for producing a pharmaceutical composition according to the present invention may additionally include, after step (2), the step of drying the obtained final mixture through a dryer and/or the step of sieving. The drying may be performed at 20 to 70 ℃, preferably 30 to 60 ℃, more preferably 35 to 50 ℃, and the sieving is 200 to 2,000 ㎛, preferably 500 to 1,000 ㎛, more preferably It may be performed using a sieve of 600 to 900 μm, but is not limited thereto.

The final mixture, or the final mixture that has been dried and/or sieved, can be filled into capsules as is, or manufactured into pellet form and filled into capsules, and can be manufactured into tablets through a tableting process, etc. The final mixture is preferably in granule form, but is not limited thereto.

The dosage and administration interval of the pharmaceutical composition according to the present invention and the pharmaceutical formulation containing the same may be adjusted depending on the disease state of the subject requiring treatment, and are preferably administered twice a day or once a day. It may be possible, but it is not limited to this.

Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention, and it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as limited by these examples.

[Example]

Example 1. Yield improvement and process time reduction effect due to use of high-speed mixer

Previously, granules of ramosetron or its pharmaceutically acceptable salt were manufactured using a fluidized bed granulator. However, due to the nature of the fluidized bed granulator, which manufactures granules by floating the mixture with air and spraying the main ingredient from the top and bottom, the process time This process takes a long time (about 3 to 4 hours), and there is a possibility that the main ingredient (active ingredient) may be lost during air supply and exhaust, resulting in a low yield (about 92%), which has the disadvantage that excessive input of the main ingredient is inevitable.

Operating conditions of high speed mixer process steps Rotation speed (rpm) Process time (minutes) agitator chopper additive mixing 300 2,000 3 Union 300 2,000 3

However, surprisingly, in the present invention, when granules containing ramosetron as an active ingredient are manufactured using a high-speed mixer according to the operating conditions shown in Table 1, the process time is shortened (30 minutes to 1 hour) as shown in Table 2. It was confirmed that improvement in yield (about 97%) and yield (approximately 97%) were possible.

Changes in process time and yield due to use of high-speed mixer equipment used Yield (based on 10,000 Ramosetron 5㎍ tablets) Process time (hours) theoretical weight final weight transference number fluid bed granulator 1,000.05g 924.16g 92.41% 3~4 High speed mixer 1,000.05g 973.80g 97.38% 0.5~1

Example 2. Improvement of the content and content uniformity of ramosetron depending on whether a binder is included in the aqueous solution containing ramosetron

In the case of the existing manufacturing method, especially the process of producing granules containing ramosetron using a fluidized bed granulator, the granules were manufactured by dissolving the binder and ramosetron together. In this case, due to the increase in viscosity due to the binder, ramosetron There was a problem that not only did the content of Tron decrease, but there was also a high possibility that non-uniformity in the content would occur.

Accordingly, in the present invention, the effect of improving content and content uniformity was confirmed by separately dissolving ramosetron in a solution containing no binder and then mixing the binder with other additives in a high-speed mixer to produce granules.

Specifically,

(1) Dissolve a fixed amount of citric acid hydrate, a stabilizer, in distilled water for more than 1 hour,

(2) After confirming that citric acid hydrate is dissolved, add a fixed amount of ramosetron hydrochloride, the main ingredient, into the stabilizing solution containing the stabilizer and dissolve it for 10 to 15 minutes,

(3) Add the excipients microcrystalline cellulose, lactose hydrate, hydroxypropyl cellulose as a binder, and low-density hydroxypropyl cellulose as a disintegrant in a high speed mixer and mix for 3 to 5 minutes,

(4) After the mixing of the additives was completed, the stabilizing solution containing ramosetron hydrochloride was added little by little to a high speed mixer and mixed with the additives for 3 to 5 minutes.

Additionally, after the above process is completed, the ramosetron hydrochloride granules are dried at 40°C for about 24 hours through a dryer, and after the drying process is completed, the apples are dried using a mesh with an eye size of 700um to 800um. did.

As a result, as shown in Table 3, according to the present invention, ramosetron or a pharmaceutically acceptable salt thereof is separately dissolved in a solution containing no binder, and then the binder is mixed with other additives in a high-speed mixer. When producing granules, the ramosetron content was found to be about 98% or more regardless of the sampling location in the mixer, whereas when producing by the existing method, it varies depending on the sampling location, but is about 78 to 80%. % Ramosetron content was shown.

Accordingly, it was confirmed that the ramosetron content in the granules prepared by the production method according to the present invention was significantly increased, that is, improved, by more than about 20%.

Content improvement effect due to separate use of ramosetron and binder Detail The binder is added to the stabilizing solution along with ramosetron.
When manufacturing granules After mixing the binder with other additives in a high-speed mixer,
When manufacturing granules sampling
location content(%) 1_Prize 77.9 98.96 2_middle 78.6 97.88 3_low 79.7 97.40 4_Left 80.7 97.85 5_Right 80.3 98.21

In addition, as a result of comparing the content and content uniformity between samples of granules manufactured by the method according to the present invention and granules manufactured by a method using a conventional fluid bed granulator, as shown in Table 4, the binder was used as a solid When producing granules using a high-speed mixer after mixing with other additives, the standard deviation and content uniformity of the sample content were similar when compared to the case manufactured in a fluidized bed granulator, while the standard deviation and content uniformity were similar to those of the existing method. , when granules were manufactured by dissolving ramosetron or a pharmaceutically acceptable salt thereof with a binder, not only was the content very low, but the content uniformity was also found to be inadequate.

Therefore, when granules are prepared by dissolving ramosetron or a pharmaceutically acceptable salt thereof in a separate solution from the binder according to the present invention, the content and content uniformity of ramosetron or a pharmaceutically acceptable salt thereof are significantly reduced. It was confirmed that not only can this be improved, but the process efficiency (time required) is significantly reduced compared to the case of manufacturing in a conventional fluid bed granulator.

Effect of improving content and content uniformity by using a high-speed mixer item Lot No. content
average(%) standard
Deviation Content uniformity judgment value (%) Judgment result fluidized bed
granulator sample #One 100.7 2.05 4.9 fitness
(Judgement value ≤ 15.0%) #2 100.6 1.76 4.2 #3 102.8 2.31 6.9 High speed mixer sample Main ingredient + binding solution
manufacturing 77.1 5.28 incongruity 1) Main ingredient+
Stabilizing solution preparation
2) Binder + Additive 99.6 0.73 2.4 fitness
(Judgement value ≤ 15.0%)

In summary, when the main ingredient, ramosetron or a pharmaceutically acceptable salt thereof, is dissolved in a solution that does not contain a binder, the binder is mixed in a solid state with other additives, and granules are manufactured using a high-speed mixer. , it was confirmed that the content uniformity of ramosetron or its pharmaceutically acceptable salt could also be significantly improved.

Example 3. LOD evaluation according to the composition ratio of MCC (microcrystalline cellulose) and lactose hydrate

The manufacturing process of the pharmaceutical composition containing ramosetron or a pharmaceutically acceptable salt thereof according to the present invention requires a separate drying process due to the use of a high-speed mixer, and it is necessary to adjust the LOD (3.0% or less) suitable for wet granules. To this end, a study was conducted to improve LOD according to the combination of raw materials and additives.

As a result, it was confirmed that when microcrystalline cellulose and lactose hydrate were used in a weight ratio of 1:1 to 1:4, the LOD was reduced below the standard value.

LOD changes according to MCC and lactose hydrate content ratio item Additive name LOD (%) microcrystalline cellulose lactose monohydrate additive
ratio 100% 0% About 4.7% 80% 20% About 3.5% 50% 50% About 2.6% 20% 80% About 1.9%

Example 4. Actual tablet manufacturing example

Film-coated tablets having the formulations shown in Tables 6 and 7 were prepared using granules prepared by the method according to the invention described in the previous examples. Specifically, tableting was performed using the granules prepared in the previous example, and then tablets were manufactured by coating them with Opadry AMB II yellow dissolved in purified water.

Ramosetron 5 μg film coated tablets Raw materials and dosage (104.005 mg per tablet) Formulation Purpose Raw material name Quantity (mg) ratio(%) chief ingredient Ramosetron hydrochloride 0.005 0.005 excipient microcrystalline cellulose 17.20 16.5 excipient lactose hydrate 68.80 66.2 disintegrant Low-substituted hydroxypropyl cellulose 10.00 9.6 binder Hydroxypropylcellulose 3.00 2.9 stabilizer citric acid monohydrate 0.50 0.5 lubricant Magnesium Stearate 0.50 0.5 Coating mechanism Opadry AMB2 Yellow (88A220016) 4.00 3.8 Sum 104.005

Ramosetron 2.5 μg film coated tablets Raw materials and dosage (104.0025mg per tablet) Formulation Purpose Raw material name Quantity (mg) ratio(%) chief ingredient Ramosetron hydrochloride 0.0025 0.0025 excipient microcrystalline cellulose 17.20 16.5 excipient lactose hydrate 68.80 66.2 disintegrant Low-substituted hydroxypropyl cellulose 10.00 9.6 binder Hydroxypropylcellulose 3.00 2.9 stabilizer citric acid monohydrate 0.50 0.5 lubricant Magnesium Stearate 0.50 0.5 Coating mechanism Opadry AMB2 Yellow (88A220016) 4.00 3.8 Sum 104.0025

As a result of checking the disintegration time of the tablets prepared according to the above example in water at a temperature of 37 ± 2 ℃, it was confirmed that the tablets were completely disintegrated within 5 minutes (n = 6).

So far, the present invention has been examined focusing on its preferred embodiments. A person skilled in the art to which the present invention pertains will understand that the present invention can be implemented in a modified form without departing from the essential characteristics of the present invention.

Therefore, the above-described embodiments should be considered from an illustrative rather than a restrictive perspective. The scope of the present invention is indicated in the claims rather than the foregoing description, and all differences within the equivalent scope should be construed as being included in the present invention.

Claims (18)

A pharmaceutical composition comprising ramosetron or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, and lactose or a hydrate thereof.
The pharmaceutical composition according to claim 1, wherein the content ratio of microcrystalline cellulose and lactose or its hydrate is 4:1 to 1:4 by weight.
The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt of ramosetron is ramosetron hydrochloride.
The pharmaceutical composition according to claim 1, further comprising one or more additives selected from the group consisting of binders, disintegrants, and lubricants.
The method of claim 4, wherein an additive mixture is prepared by mixing microcrystalline cellulose, lactose or its hydrate, and one or more additives selected from the group consisting of a binder, a disintegrant, and a lubricant in a high speed mixer, A pharmaceutical composition, characterized in that it is prepared by adding an aqueous solution containing tron to the additive mixture.
The pharmaceutical composition according to claim 5, wherein the aqueous solution containing ramosetron does not contain a binder.
The pharmaceutical composition according to claim 5, wherein the aqueous solution containing ramosetron contains a stabilizer.
The pharmaceutical composition according to claim 7, wherein the stabilizer is at least one selected from the group consisting of citric acid, succinic acid, L-glutamic acid, L-malic acid, boric acid, tartaric acid, lactic acid, and fumaric acid.
The pharmaceutical composition according to claim 4, wherein the binder is at least one selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, and hypromellose.
The pharmaceutical composition according to claim 4, wherein the disintegrant is at least one selected from the group consisting of crospovidone, sodium starch glycolate, croscarmellose sodium, and hydroxypropyl cellulose (HPC).
The method of claim 4, wherein the lubricant is one selected from the group consisting of magnesium stearate, zinc stearate, calcium stearate, stearic acid, talc, paraffins, lead, glyceryl behanate, sodium stearyl fumarate, and stearyl fumarate. A pharmaceutical composition characterized by the above.
The pharmaceutical composition according to claim 1, wherein the loss on drying is 3.0% or less.
5. The method of claim 4, wherein, based on the weight of the total composition, 50 to 80% by weight of excipient, 5 to 10% by weight of disintegrant, 0.1 to 1.0% by weight of stabilizer, 1.0 to 5.0% by weight of binder, and 0.1 to 1.0% by weight of binder. A pharmaceutical composition comprising 1% by weight of a lubricant.
A pharmaceutical formulation comprising the pharmaceutical composition according to any one of claims 1 to 13.
15. The pharmaceutical formulation according to claim 14, which is a tablet, film-coated tablet or capsule.
16. The pharmaceutical formulation according to claim 15, wherein the disintegration time is less than 10 minutes.
(1) Preparing an additive mixture by mixing microcrystalline cellulose, lactose or its hydrate, and one or more additives selected from the group consisting of binders, disintegrants, and lubricants in a high speed mixer; and
(2) adding an aqueous solution containing ramosetron to the additive mixture and combining to obtain a final mixture;
A method for producing a pharmaceutical composition containing ramosetron, comprising:
The method of claim 17, wherein after step (2), the final mixture obtained further comprises the steps of drying through a dryer and sieving.