WO2013032206A1 - Controlled-release oral composition containing itopride hydrochloride, and preparation method thereof - Google Patents

Abstract

The present invention relates to a preparation method of an extended release tablet containing itopride hydrochloride as an active ingredient, and more specifically, the present invention provides an extended release tablet in which dissolution is extended for enabling administration of one dose per day, thereby improving administration convenience and compliance when compared to existing commercial preparations which are taken three times a day. The itopride extended release tablet according to the present invention can effectively control the release of itopride hydrochloride with a velocity close to zero order for 24 hours without the deviation of dissolution, and thus the inconvenience of taking three doses per day can be solved by taking only one dose per day. In addition, since the weight per tablet is 450 mg and the size of a tablet is small, the compliance of a patient is high, thereby preventing the loss of efficacy or the worsening of symptoms.

Description

Compositions of Controlled Release Oral Formulations Containing Itopride Hydrochloride and Methods for Making the Same

The present invention relates to a method for producing a sustained-release tablet containing itopride hydrochloride as an active substance, specifically, the convenience of taking and compared to conventional commercial preparations to be extended three times a day so that it can be taken once a day Provide sustained-release tablets to improve medication compliance.

Itopride hydrochloride (N-[[4- (2-dimethylaminoethoxy) phenyl] methyl] -3,4-dimethoxybenzamide) inhibits acetylcholine esterase and antagonizes dopamine D2 receptor By increasing the amount of acetylcholine, the acetylcholine promotes gastrointestinal peristalsis, and is a drug used for digestive symptoms such as bloating, epigastric pain, anorexia, chest pain, and vomiting due to functional dyspepsia. This drug is suitable for long-term use because peripheral dopamine D2 antagonism shows little side effects such as gynecomastia and milk secretion, which is a side effect of gastrointestinal function improving agents such as domperidone.

Itopride Hydrochloride (N-[[4- (2-Dimethylaminoethoxy) phenyl] methyl] -3,4-dimethoxybenzamide) has an action time of 30 minutes oral administration and reaches a peak blood concentration of about 0.5 ~ 1.5 hours, duration is about 12 hours. It is known that about 80% of etopriide is excreted in the urine upon oral administration, and the excretion rate (half life) is about 6 hours.

Patients who take long-term use of Itopride formulations have not been developed as a dosage form that can be taken once a day, even though they have to take long-term doses due to frequent symptoms caused by stress due to the characteristics of patients with poor digestion. Inconvenience in medication guidance and medication compliance may result. The present invention can help to prevent the loss of medication or worsening of symptoms by forgetting to take the patient by the sustained release of the dosage form of itopride hydrochloride three times a day.

The technical problem to be achieved by the present invention is characterized by a matrix tablet with an active ingredient of itopride hydrochloride, the drug that was administered three times a day 50mg each day by 150mg once a day dose of about 150 hours without dissolution variation The present invention provides sustained-release tablets containing itopride hydrochloride that effectively release the drug to sustain it, thereby increasing the therapeutic effect and simplifying the formulation therapy of patients with gastrointestinal diseases, thereby improving patient convenience and dosage compliance.

According to a preferred embodiment of the present invention, in the sustained release of itofride hydrochloride comprising an itopride hydrochloride, a water-soluble additive, a disintegrant, a filler, a release controlling polymer and a lubricant, the release controlling polymer is hydroxypropylmethylcellulose. It is characterized in that the sustained release of itopride hydrochloride.

According to another suitable embodiment of the present invention, the weight ratio of the hydroxypropyl methyl cellulose is preferably 10% to 45% of the total weight.

According to another suitable embodiment of the present invention, the disintegrant is Croscarcamellose Sodium, Sodium Starch Glycolate, Pregelatinized Starch (Starch 1500 or Premojel) , Microcrystalline cellulose, crospovidone (cross-linked povidone), polyvinylpyrrolidone (PVP, Povidone), hydroxypropylcellulose (low substituted), alginic acid (alginic) acid, calcium and sodium salts of Carboxymethylcellulose, fumed silica, colloidal silica, guar gum, Magnesium aluminum silicate, methylcellulose, One or two selected from the group consisting of powdered cellulose, starch and sodium alginate And more thereof, wherein the filler is one or a mixture of two or more selected from microcrystalline cellulose, gyeoljil silicic acid anhydride, the group consisting of before the gelling starch and lactose and the lubricant is magnesium stearate (magnesium stearate), silica oxide (SiO ₂₎ , A colloidal silicon dioxide, colloidal silica, and talc (talc) is one or a mixture of two or more kinds.

According to another suitable embodiment of the present invention, it is preferable that the dissolution rate of the sustained-release tablets is 10 to 30% at 1 hour, 55 to 75% at 12 hours and 85% or more at 24 hours.

Itopride sustained-release tablet according to the present invention can effectively control the release of etopriide hydrochloride for 24 hours at a rate close to zero order without dissolution deviation, thereby solving the inconvenience of eating three times a day by eating once a day In addition, since the tablet weight is 450mg per tablet, the patient's medication compliance is high due to the small tablet size, which can prevent the loss of efficacy and the worsening of symptoms.

1 shows the results of the dissolution test (eluate: purified water) of the formulations described in Examples 1 to 10 of the present invention.

Figure 2 shows the results of the dissolution test (eluate: purified water) of the formulations described in Comparative Examples 1 and 2 and Example 10 of the present invention.

Figure 3 shows the results of the wear and tear test of the formulations described in Examples 1 to 10 of the present invention.

Figure 4 shows the results of the hardness test of the formulations described in Examples 1 to 10 of the present invention.

Hereinafter, the present invention will be described in detail through Examples and Comparative Examples. However, embodiments according to the present invention may be modified in various forms, the scope of the present invention is not limited to the embodiments described below. Embodiments of the present invention are provided to more fully explain the present invention to those skilled in the art.

The present invention is an oral composition formulated with itopride hydrochloride (N-[[4- (2-dimethylaminoethoxy) phenyl] methyl] -3,4-dimethoxybenzamide), which is a very useful drug for treating digestive disorders. In more detail, the present invention relates to an oral sustained-release composition in which etopride hydrochloride is eluted at a constant rate for 24 hours to give a sufficient therapeutic effect by taking a daily dose, and to reduce the weight of tablets to increase ease of taking.

Itopride hydrochloride sustained-release tablet of the present invention has the advantage of slowly releasing the active ingredient at the release rate almost similar to the 0th order with the same biological activity but once a day as compared to the conventionally taken drug three times a day Have

The composition of the sustained-release tablet according to the present invention is 30% by weight of the pharmacological active ingredient itopride hydrochloride, 45% by weight of hydroxypropylmethylcellulose, 5% by weight of microcrystalline cellulose, 6% by weight of lactose, 5% by weight of low-substituted hydroxypropyl cellulose It is an isopride hydrochloride sustained-release tablet composition containing%, povidone 3% by weight, lubricant 1% by weight.

In the composition of the present invention, the sustained-release agent should form a hydrogel matrix to effectively control the release of itopride hydrochloride having a very high water solubility, and should have an appropriate viscosity range. In addition, the 24 hour release control means that the pH of the patient's body goes through different organs, so the sustained release agent should have little change in viscosity or release pattern with pH. Hydroxypropylmethylcellulose is suitable as a sustained-release base that satisfies the above conditions and has a long dissolution time and is capable of relatively constant dissolution rate control. In the composition of the present invention, when hydroxypropyl cellulose is made into a 2% by weight aqueous solution and the viscosity is measured at 20 ° C., when the viscosity is 80,000 cps or less, the highly soluble diphosphide hydrochloride is effectively released for 24 hours. It is not controllable, and when 120,000 cps or more, hydroxypropyl methyl cellulose having a viscosity in the range of 80,000 cps to 120,000 cps is suitable because the initial gel hydration time is delayed to increase the elution deviation.

In addition, in the composition of the present invention, when hydroxypropylmethylcellulose is included in less than 10% by weight of the total composition, it is also not possible to effectively control the release of itopride hydrochloride having a very high water solubility for 24 hours, more than 45% by weight When it is enacted, since poor compression and capping problems may occur, it is preferable to include 10 to 45% by weight of the total composition.

In the composition of the present invention, it is preferable to use a binder in order to make tablets desirable. In particular, in order to reduce the size and weight of the final sustained-release tablet to improve patient compliance, it is very important to use a binder having an appropriate binding force because it is necessary to minimize the amount of excipient added to the tablet. In the present invention, polyvinylpyrrolidone (common name is povidone and povidone K-30 having a molecular weight of 30 is used), which preferably adds 3 to 5% by weight of the tablet weight, and the binder is less than 3% by weight. When added as it is difficult to establish a sustained-release tablet due to the weak binding force, if the addition of more than 5% by weight of the initial dissolution rate of the drug is lowered, it is difficult to expect a fast drug after dosing.

In the compositions of the present invention, disintegrants are used to absorb moisture to promote initial disintegration of the formulation, to facilitate dissolution of the itopride hydrochloride, and examples of disintegrants that can be used in the formulation of the present invention are croscarmellose. Sodium (Croscamellose Sodium), Sodium Starch Glycolate, Pregelatinized Starch (Starch 1500 or Premojel), Microcrystalline cellulose, Crospovidone, cross-linked povidone) and other commercially available polyvinylpyrrolidones (PVP, Povidone) and one or more mixtures selected from the group consisting of low substituted hydroxypropylcellulose (Low substituted).

Preferably, the disintegrant includes at least one selected from the group consisting of croscarmellose sodium, sodium starch glycolate, pregelatinized starch, microcrystalline cellulose, crospovidone, and commercially available low-substituted hydroxypropylcellulose. Mixtures.

The glidants in the present invention are characterized in that one or two or more kinds selected from the group consisting of silicon dioxide, stearic acid and magnesium stearate, and preferably magnesium stearate can be used. The glidant improves the fluidity of the powder to be tableted to increase the filling ability of the tableting machine into the die, and improves the friction between the powders and the punch-die which is the upper part of the powder and the tongue. Reduction to facilitate compression of the tablets. It is preferable to add 1 to 3% by weight of the lubricant, and it is difficult to tablet tablets when the lubricant is added in an amount less than 1% by weight, and the coating phenomenon of the lubricant granules when added in excess of 3% by weight This affects the dissolution pattern of the main component.

In the present invention, one or more excipients selected from the group consisting of lactose, glucose, mannitol, white sugar, sorbitol, microcrystalline cellulose, calcium phosphate, calcium dihydrogen phosphate, and dextrin may be added in a daily amount and used as described above. Coating bases can be used to prevent the appearance of the active ingredients, sustained-release agents, binders, glidants and to improve the appearance. Additives commonly used in the pharmaceutical art, such as surfactants, stabilizers, preservatives, may also be added. However, the addition of other excipients increases the volume of the final formulation and decreases the patient's ease of taking, which is an advantage of sustained-release preparations, so that the previously described active ingredients, sustained-release agents, binders, glidants and excipients, minimal amounts of coating agents Ideally, nothing else is added.

Method for preparing an oral preparation of sustained-release tablet of etopriide according to the present invention comprises the steps of: (1) mixing the topride hydrochloride with microcrystalline cellulose and lactose and hydroxypropylmethylcellulose as a pharmacologically active ingredient; (2) a granulation step of preparing wet sustained-release granules by adding a liquid solvent in which a binder is dissolved to the mixture obtained in the mixing step; (3) milling the ground granules; (4) tableting after mixing the lubricants; (5) It consists of a coating step of coating with a suitable coating base. All of the above steps can be easily formulated using equipments such as mixers, grinders, tablets, etc., which are conventionally used, so that there is no additional equipment cost and can be easily formulated with high productivity. There is this.

Hereinafter, the present invention will be described in more detail with reference to test examples, examples, and comparative examples. However, these examples do not limit the scope of the present invention.

<Test Example 1>

The following tests were carried out to confirm the interaction and suitability of the itopride hydrochloride and excipients.

After mixing 150 mg of etopri hydrochloride and each of the excipients and accelerated test at room temperature for 1hr, the content test after 1 month in the environment of temperature 45 ℃, 75% humidity, the results are shown in Table 1.

Table 1 Excipient Initial content test Content test after accelerated test standard result Judgment standard result Judgment Microcrystalline cellulose 95-105% 99.7% fitness 95-105% 99.4% fitness Lactose Monohydrate 95-105% 99.1% fitness 95-105% 99.2% fitness Sorbitol 95-105% 99.8% fitness 95-105% 99.7% fitness Pregelatinized Starch 95-105% 99.3% fitness 95-105% 99.1% fitness PVP K-30 95-105% 99.1% fitness 95-105% 99.3% fitness Hydroxypropyl cellulose 95-105% 99.5% fitness 95-105% 99.4% fitness Crospovidone 95-105% 99.7% fitness 95-105% 99.8% fitness Croscarmellose sodium 95-105% 99.7% fitness 95-105% 99.9% fitness Low-substituted 95-105% 99.3% fitness 95-105% 99.4% fitness Methocel K4M 95-105% 99.2% fitness 95-105% 99.1% fitness Methocel K15M 95-105% 99.8% fitness 95-105% 99.2% fitness Methocel K100M 95-105% 99.9% fitness 95-105% 99.3% fitness Sodium Starch Glycolate 95-105% 99.2% fitness 95-105% 99.7% fitness Magnesium stearate 95-105% 99.4% fitness 95-105% 99.9% fitness Stearic acid 95-105% 99.2% fitness 95-105% 99.4% fitness SiO ₂ 95-105% 99.4% fitness 95-105% 99.0% fitness

<Example 1>

To the sustained-release tablet of itopride hydrochloride with the components and contents shown in Table 2 below. After mixing the itopride hydrochloride with microcrystalline cellulose, lactose and hydroxypropylmethylcellulose, povidone K-30 solution dissolved in ethanol is added to form and coalesce the mixture, and dried in a fluidized bed dryer at 50 ° C for 1 hour. After granulating the obtained granules, the namiji lubricating agent was mixed, tableted, and coated with Opadry-OY-C-7000A (trade name of Colorcon, Inc.). Make. The weight percent of the components are shown in Table 2.

TABLE 2 Classification ingredient Weight (mg) weight% Pharmacologically active ingredient Itopride HCI 150 32.6 Excipient MCC pH102 100 21.7 Excipient Lactose monohydrate 120 26.1 Emission Control Polymer HPMC (Methcel K100M) 35 7.6 Disintegrant L-HPC 25 5.4 Binder PVP K-30 15 3.3 Lubricant St-mg 5 1.1 Coating Opadry OY-C-7000A 10 2.2 Sum 460 100.0

<Example 2>

It is the same as Example 1 except the weight of each component is the same as Table 3.

TABLE 3 Classification ingredient Weight (mg) weight% Pharmacologically active ingredient Itoride HCI 150 32.6 Excipient MCC pH102 100 21.7 Excipient Lactose monohydrate 110 23.9 Emission Control Polymer HPMC (Methcel K100M) 45 9.8 Disintegrant L-HPC 25 5.4 Binder PVP K-30 15 3.3 Lubricant St-mg 50 1.1 Coating Opadry OY-C-7000A 10 2.2 Sum 460 100.0

<Example 3>

It is the same as Example 1 except the weight ratio of each component is as Table 4.

Table 4 Classification ingredient Weight (mg) weight% Pharmacologically active ingredient Itoride HCI 150 32.6 Excipient MCC pH102 100 21.7 Excipient Lactose monohydrate 100 21.7 Emission Control Polymer HPMC (Methcel K100M) 55 12.0 Disintegrant L-HPC 25 5.4 Binder PVP K-30 15 3.3 Lubricant St-mg 5 1.1 Coating Opadry OY-C-7000A 10 2.2 Sum 460 100.0

<Example 4>

It is the same as Example 1 except the weight ratio of each component is the same as Table 5.

Table 5 Classification ingredient Weight (mg) weight% Pharmacologically active ingredient Itoride HCI 150 32.6 Excipient MCC pH102 100 21.7 Excipient Lactose monohydrate 90 19.6 Emission Control Polymer HPMC (Methcel K100M) 65 14.1 Disintegrant L-HPC 25 5.4 Binder PVP K-30 15 3.3 Lubricant St-mg 5 1.1 Coating Opadry OY-C-7000A 10 2.2 Sum 460 100.0

Example 5

It is the same as Example 1 except the weight ratio of each component is the same as Table 6.

Table 6 Classification ingredient Weight (mg) weight% Pharmacologically active ingredient Itoride HCI 150 32.6 Excipient MCC pH102 100 21.7 Excipient Lactose monohydrate 75 16.3 Emission Control Polymer HPMC (Methcel K100M) 80 17.4 Disintegrant L-HPC 25 5.4 Binder PVP K-30 15 3.3 Lubricant St-mg 5 1.1 Coating Opadry OY-C-7000A 10 2.2 Sum 460 100.0

<Example 6>

Except that the weight ratio of each component is shown in Table 7 is the same as in Example 1.

TABLE 7 Classification ingredient Weight (mg) weight% Pharmacologically active ingredient Itoride HCI 150 32.6 Excipient MCC pH102 100 21.7 Excipient Lactose monohydrate 65 14.1 Emission Control Polymer HPMC (Methcel K100M) 90 19.6 Disintegrant L-HPC 25 5.4 Binder PVP K-30 15 3.3 Lubricant St-mg 5 1.1 Coating Opadry OY-C-7000A 10 2.2 Sum 460 100.0

<Example 7>

Except that the weight ratio of each component is the same as in Table 8.

Table 8 Classification ingredient Weight (mg) weight% Pharmacologically active ingredient Itoride HCI 150 32.6 Excipient MCC pH102 100 21.7 Excipient Lactose monohydrate 35 7.6 Emission Control Polymer HPMC (Methcel K100M) 120 26.1 Disintegrant L-HPC 25 5.4 Binder PVP K-30 15 3.3 Lubricant St-mg 5 1.1 Coating Opadry OY-C-7000A 10 2.2 Sum 460 100.0

<Example 8>

It is the same as Example 1 except the weight ratio of each component is the same as Table 9.

Table 9 Classification ingredient Weight (mg) weight% Pharmacologically active ingredient Itoride HCI 150 32.6 Excipient MCC pH102 100 21.7 Excipient Lactose monohydrate 15 3.3 Emission Control Polymer HPMC (Methcel K100M) 140 30.4 Disintegrant L-HPC 25 5.4 Binder PVP K-30 15 3.3 Lubricant St-mg 5 1.1 Coating Opadry OY-C-7000A 10 2.2 Sum 460 100.0

Example 9

It is the same as Example 1 except the weight ratio of each component is the same as Table 10.

Table 10 Classification ingredient Weight (mg) weight% Pharmacologically active ingredient Itoride HCI 150 32.6 Excipient MCC pH102 45 9.8 Excipient Lactose monohydrate 30 6.5 Emission Control Polymer HPMC (Methcel K100M) 180 39.1 Disintegrant L-HPC 25 5.4 Binder PVP K-30 15 3.3 Lubricant St-mg 5 1.1 Coating Opadry OY-C-7000A 10 2.2 Sum 460 100.0

<Example 10>

It is the same as Example 1 except the weight ratio of each component is shown in Table 11.

Table 11 Classification ingredient Weight (mg) weight% Pharmacologically active ingredient Itoride HCI 150 32.6 Excipient MCC pH102 25 5.4 Excipient Lactose monohydrate 30 6.5 Emission Control Polymer HPMC (Methcel K100M) 200 43.5 Disintegrant L-HPC 25 5.4 Binder PVP K-30 15 3.3 Lubricant St-mg 5 1.1 Coating Opadry OY-C-7000A 10 2.2 Sum 460 100.0

Comparative Example 1

Comparative Examples were prepared with the ingredients and contents shown in Table 12 below. After mixing itopride hydrochloride, lactose, carboxymethyl cellulose, and colloidal silicon dioxide, corn starch solution dissolved in purified water is added, and then granulated and granulated, and dried in a fluidized bed dryer at 50 ° C. for 6 hours. After granulating the obtained granules, the remaining colloidal silicon dioxide and magnesium stearate were mixed and tableted, and then coated with Opadry-OY-C-7000A (trade name of Colorcon, Inc.), Ito containing 50 mg of itopride hydrochloride in one tablet. Fried hydrochloride makes regular tablets. The weight percentages of the components are shown in Table 12.

Table 12 Classification ingredient Weight (mg) weight% Pharmacologically active ingredient Itopride HCI 50.0 38.5 Excipient Lactose 35.0 26.9 Binder Corn starch 15.0 11.5 Disintegrant Carboxymethyl Cellulose 20.0 15.4 Disintegrant Colloidal silicon dioxide 4.0 3.1 Lubricant St-mg 1.0 0.8 Coating Opadry OY-C-7000A 5.0 3.8 Sum 130.00 100.0

Comparative Example 2

It is the same as Example 1 except the viscosity unit of the hydroxypropyl methylcellulose used as a sustained-release base is different. The weight percentages of the components are shown in Table 13.

Table 13 Classification ingredient Weight (mg) weight% Pharmacologically active ingredient Itoride HCI 150 32.6 Excipient MCC pH102 25 5.4 Excipient Lactose monohydrate 30 6.5 Emission Control Polymer HPMC (Methcel K4M) 200 43.5 Disintegrant L-HPC 25 5.4 Binder PVP K-30 15 3.3 Lubricant St-mg 5 1.1 Coating Opadry OY-C-7000A 10 2.2 Sum 460 100.0

Comparative Example 3

It is the same as Example 1 except the viscosity unit of the hydroxypropyl methylcellulose used as a sustained-release base is different. The weight percentages of the components are shown in Table 14.

Table 14 Classification ingredient Weight (mg) weight% Pharmacologically active ingredient Itoride HCI 150 32.6 Excipient MCC pH102 25 5.4 Excipient Lactose monohydrate 30 6.5 Emission Control Polymer HPMC (Methcel K15M) 200 43.5 Disintegrant L-HPC 25 5.4 Binder PVP K-30 15 3.3 Lubricant St-mg 5 1.1 Coating Opadry OY-C-7000A 10 2.2 Sum 460 100.0

Dissolution Test

The elution test of the itopride hydrochloride was carried out as follows.

▶ Temperature: 37 ± 0.5 ℃

▶ Elution method: Method 2 of the Korean Pharmacopoeia Dissolution Test (Paddle method)

▶ Eluent: Purified Water, 900mL

Stirring Speed: 50rpm

Analysis method: The eluate was collected at the time after the start of the dissolution test, and the absorbed liquid was measured at 266 nm using an ultraviolet-visible absorbance spectrophotometer using an ultraviolet-visible absorption spectrophotometer.

Table 15 Elution time (hr) 0.25 0.5 One 1.5 2 3 5 6 8 10 12 24 Dissolution rate (%) Example 1 8.1 13.5 21.0 27.2 32.6 43.7 60.1 67.3 84.3 93.7 97.2 98.8 Example 2 8.1 13.1 20.3 26.6 31.3 41.3 56.6 63.0 74.1 83.4 91.7 98.8 Example 3 8.1 13.0 19.9 26.1 31.2 41.1 56.0 62.3 73.3 82.6 90.3 98.1 Example 4 8.6 13.6 20.8 26.6 31.6 40.6 53.3 59.2 70.3 78.4 86.2 104.1 Example 5 8.8 13.7 21.2 26.7 32.0 41.0 58.3 65.4 75.0 82.9 88.1 103.5 Example 6 8.2 12.7 19.2 24.3 29.2 37.3 57.2 64.1 73.9 83.4 89.1 103.0 Example 7 8.1 12.1 18.2 23.3 27.8 35.2 47.9 53.9 63.6 73.1 81.5 103.8 Example 8 7.8 11.4 17.0 21.6 25.8 32.6 44.2 50.2 59.0 68.5 76.6 101.6 Example 9 7.3 10.7 15.8 20.3 24.3 31.5 43.0 48.8 58.8 68.0 76.9 101.1 Example 10 6.8 9.9 14.6 18.8 22.7 29.2 40.2 45.5 54.9 64.1 72.5 101.7

Table 16 Elution time (hr) 0.25 0.5 One 1.5 2 3 5 6 8 10 12 24 Dissolution rate (%) Comparative Example 1 12.5 21.2 32.6 45.5 52.9 65.1 71.3 79.8 85.2 90.6 98.4 99.5 Comparative Example 2 8.5 12.5 20.1 30.1 38.9 45.1 52.5 60.1 69.8 75.9 81.5 99.8 Example 10 6.8 9.9 14.6 18.8 22.7 29.2 40.2 45.5 54.9 64.1 72.5 101.7

<Property test>

Samples prepared in Examples 1 to 10 and Comparative Examples 1 to 3 were put into a hardness tester (Pharmatest, Germany) six times for each sample, and the tablet hardness, thickness, and diameter were measured, and the wear and tear rate was measured using a wear tester. The average and standard deviation of the measurement results are shown in Table 17 below.

Table 17 Furtherance Diameter (mm) Thickness (mm) Hardness (㎏ / ㎠) Wear and tear (%) Weight change (mg) Example 1 10.64 ± 0.03 5.49 ± 0.02 10.6 ± 0.25 0.96 451.6 ± 2.3 Example 2 10.67 ± 0.02 5.47 ± 0.05 11.2 ± 0.43 0.91 452.1 ± 3.5 Example 3 10.71 ± 0.04 5.46 ± 0.04 11.9 ± 0.65 0.85 453.2 ± 4.1 Example 4 10.69 ± 0.06 5.47 ± 0.06 12.8 ± 0.47 0.78 449.3 ± 2.3 Example 5 10.62 ± 0.04 5.48 ± 0.03 13.2 ± 0.21 0.74 452.4 ± 4.9 Example 6 10.65 ± 0.05 5.51 ± 0.06 13.7 ± 0.81 0.65 451.6 ± 5.1 Example 7 10.69 ± 0.07 5.45 ± 0.04 14.2 ± 0.36 0.62 453.1 ± 4.8 Example 8 10.67 ± 0.03 5.47 ± 0.09 14.9 ± 0.42 0.54 449.4 ± 3.6 Example 9 10.63 ± 0.02 5.46 ± 0.03 15.3 ± 0.51 0.31 456.3 ± 4.3 Example 10 10.62 ± 0.09 5.48 ± 0.07 16.7 ± 0.64 0.21 452.1 ± 3.4

<Stability Test>

The stability test of the itopride hydrochloride was carried out under the conditions of 1-4.

Table 18 standard Week 0 2 weeks 4 Weeks 6 Weeks Properties White fitness fitness fitness fitness Confirmation test IR fitness fitness fitness fitness HPLC fitness fitness fitness fitness Dissolution test (purified water) 180 minutes 20.2%-40.0% 97.0% 97.6% 97.1% 96.8% 720min55.0%-75.0% 71.0% 71.5% 72.1% 72.8% 1440 minutes 80.0% or more 99.4% 99.5% 98.2% 99.5% Content test 90-1105 100.2% 101.3% 99.6% 99.9%

▶ Condition 1: Circulate from minus 20 ℃ to 40 ℃ and confirm for 6 weeks

Table 19 standard Week 0 2 months 4 months Properties White fitness fitness fitness Confirmation test IR fitness fitness fitness HPLC fitness fitness fitness Dissolution test (purified water) 180 minutes 20.0 ~ 40.0% 97.0% 97.2% 96.9% 720min55.0 ~ 75.0% 71.0% 72.0% 70.0% 1440 minutes 80.0% or more 99.4% 99.8% 98.5% Content test 90-110% 100.2% 101.5% 99.8%

Condition 2: Validated for 4 months at 4 ° C / RH 60%

Table 20 standard Week 0 2 months 4 months Properties White fitness fitness fitness Confirmation test IR fitness fitness fitness HPLC fitness fitness fitness Dissolution test (purified water) 180 minutes 20.0 ~ 40.0% 97.0% 96.2% 95.4% 720min55.0 ~ 75.0% 71.0% 73.1% 72.5% 1440 minutes 80.0% or more 99.4% 98.2% 97.5% Content test 90-110% 100.2% 100.1% 99.8%

Condition 3: Validated for 4 months at 25 ° C / RH 60%

Table 21 standard Week 0 2 months 4 months Properties White fitness fitness fitness Confirmation test IR fitness fitness fitness HPLC fitness fitness fitness Dissolution test (purified water) 180 minutes 20.0 ~ 40.0% 97.0% 96.8% 96.4% 720min55.0 ~ 75.0% 71.0% 72.2% 71.5% 1440 minutes 80.0% or more 99.4% 99.2% 98.3% Content test 90-110% 100.2% 100.2% 99.5%

Condition 4: Validated for 4 months at 40 ° C / RH 75%

Claims (4)

In a sustained-release tablet of itofride hydrochloride comprising an itopride hydrochloride, a water-soluble additive, a disintegrant, a filler, a release controlling polymer and a lubricant, The release control polymer is sustained release of itopride hydrochloride, characterized in that the hydroxypropyl methyl cellulose. The method according to claim 1, Itopride hydrochloride sustained-release tablet, characterized in that the weight ratio of the hydroxypropyl methyl cellulose is 10% to 45% relative to the total weight. The method according to claim 1, The disintegrant is Croscarcamellose Sodium, Sodium Starch Glycolate, Pregelatinized Starch (Starch 1500 or Premojel), Microcrystalline cellulose, Cross Povidone (Crospovidone, cross-linked povidone), Polyvinylpyrrolidone (PVP, Povidone), Low substituted hydroxypropylcellulose (Low substituted), Alginic acid, Carboxymethylcellulose (Calcium) Salts and sodium salts, colloidal silica, colloidal silica, guar gum, magnesium aluminum silicate, methylcellulose, powdered cellulose, starch and sodium alginate (sodium alginate) is one or a mixture of two or more selected from the group consisting of, The filler is one or a mixture of two or more selected from the group consisting of microcrystalline cellulose, crystalline silicic anhydride, pregelatinized starch and lactose, The lubricant is one or two or more mixtures selected from the group consisting of magnesium stearate, silica oxide (SiO ₂ ), colloidal silicon dioxide, colloidal silica and talc (talc) Hydrochloride sustained-release tablet. The method according to claim 1, Itopride hydrochloride sustained-release tablet showing the dissolution rate of the sustained-release tablet 10 to 30% at 1 hour, 55 to 75% at 12 hours and 85% or more at 24 hours.

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