KR20190029355A - Once a day oral dosage sustained-release formulation comprising itopride - Google Patents

Abstract

An oral administration sustained-release two-layer tablet comprising itopride hydrochloride of the present invention, to satisfy both rapid pharmacological activity expression and sustained pharmacological activity for 24 hours, comprises: a quick-release layer which enables the drug to be dissolved in a rapid manner; and a sustained-release layer which enables the drug to be dissolved in a sustained manner. To exhibit an optimal release, hydroxypropyl methylcellulose having dissolution control properties depending on a certain degree of substitution and viscosity is used as a release regulator. The dissolution rate in gastrointestinal tracts with differing pH and residence time in gastrointestinal tracts are controlled. In addition, in the present invention, provided is a method for manufacturing an oral administration sustained-release two-layer tablet comprising itopride hydrochloride which is designed to increase patient′s adaptation to medication, prevent side effects caused by excessive release of early phase active ingredients, and maintain a constant dissolution rate.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention [0001] The present invention relates to an itopride hydrochloride-containing sustained-

The present invention is based on the finding that by using hydroxypropylmethylcellulose having specific degrees of substitution and viscosity as a release modifier and precisely adjusting the dissolution profile thereof, it is possible to obtain an oral dosage form containing itopride hydrochloride which exhibits an optimal dissolution profile once a day, And a manufacturing method thereof.

Itopride hydrochloride (N - [[4- (2-dimethylaminoethoxy) phenyl] methyl] -3,4-dimethoxybenzamide) has abdominal bloating due to functional dyspepsia, abdominal pain, anorexia, chest pain, , Vomiting, and the like, and has the following chemical formula.

Itopride hydrochloride blocks the dopamine D2 receptor and inhibits acetylcholinesterase, thereby increasing the concentration of acetylcholine in the body. Increased acetylcholine further enhances gastrointestinal motility, increases the pressure of the lower esophageal sphincter, accelerates gastric emptying, improves gastric and duodenal coordination, improves digestive function deterioration, and relieves abdominal pain .

In addition, itopride hydrochloride has advantages such as long-term use because it does not show side effects such as gynecomastia and lactic acid secretion, which are side effects of gastrointestinal function-improving agents such as domperidone.

Itopride hydrochloride is usually administered orally within 30 minutes, and the time to reach the peak plasma concentration is about 0.5 to 1.5 hours and the duration is about 12 hours. About 80% of the active ingredient is known to be excreted in the urine, and the excretion rate (half-life) is known to be about 6 hours.

In general, patients suffering from poor digestive function frequently develop symptoms due to stress and are required to take a long term. As described above, itopride hydrochloride should be taken regularly three times a day due to its short half-life . This leads to inconvenience in the guidance of medication for long - term patients, and also in compliance with medication.

In order to solve such a problem, Korean Patent No. 10-1485421 discloses a slow release tablet containing itopride once a day, but the slow release tablet is obtained by applying a release delay matrix to a single tablet containing itopride hydrochloride, And there is a disadvantage in that the efficacy is deteriorated because the elution is gradually made after administration.

The present invention provides a sustained-release bi-layer tablet comprising a herbicidal layer and a sustained-release layer containing itopride hydrochloride, and the sustained-release bi-layer tablet according to the present invention achieves sufficient pharmacological activity only once per day, And exhibits excellent effects.

Korean Patent No. 10-1485421

DISCLOSURE OF THE INVENTION The present invention has been conceived to solve the above-mentioned problems. The applicant of the present invention analyzed the 24 hour release pattern of the itopride hydrochloride sustained-release tablet, which is a conventional single-schedule tablet, to solve the problem, and found that hydroxypropylmethylcellulose The inventors have realized an oral administration sustained-release double-layer tablet containing itopride hydrochloride having excellent efficacy and an optimal elution profile for achieving the same, compared with the prior art, reflecting the dissolution characteristics depending on the viscosity and degree of substitution.

The present invention provides once-daily orally-administered sustained-release or controlled-release double-layer tablets containing itopride hydrochloride as an active ingredient.

Wherein the sustained release or controlled release two-ply tablets comprise a sustained layer comprising an active ingredient, a filler, a binder, a disintegrant, and a sustained release layer comprising an active ingredient, a filler, a binder, a disintegrant and a release modifier, Hydroxypropylmethylcellulose having a methoxyl group substitution degree of 19 to 24%, a hydroxypropoxyl group substitution degree of 7 to 12% and a viscosity of 11,250 to 21,000 mPa.s is used.

When the degree of substitution of the methoxyl group of the release modifier is out of the above range, the characteristics of the release modifier are not uniform and the stability of the release control matrix according to the present invention is degraded.

When the viscosity of the release controlling agent is less than 11,250 mPa.s, the active ingredient may be excessively eluted at the initial stage, resulting in adverse effects. If the viscosity is more than 21,000 mPa.s, the elution of the active ingredient may be delayed excessively, .

The sustained-release bi-layered tablet according to the present invention is characterized in that the active ingredient is contained in each of the immediate-release layer and the sustained-release layer, and the content of each effective ingredient is 20 to 60 mg for the immediate-release layer and 90 to 130 mg for the extended- .

If the effective amount of the immediate-release layer is less than 20 mg or the effective amount of the sustained-release layer is less than 90 mg, a sufficient therapeutic effect is not obtained. If the effective amount of the immediate-release layer exceeds 60 mg or the effective amount of the sustained-release layer exceeds 130 mg, the blood concentration may excessively increase and side effects may occur .

The sustained-release layer composition of the sustained-release bi-layer tablet according to the present invention comprises 30 to 45% by weight of itopride hydrochloride, 15 to 25% by weight of release modifying agent, 2 to 2% by weight of low-substituted hydroxypropyl cellulose, To 5% by weight, and 2 to 5% by weight of Povidone K-30.

When the content of the release modifying agent is out of the above range, excessive dissolution occurs in the initial stage of administration or the dissolution is delayed excessively, It is preferred that the low-substituted propyl cellulose as the disintegrant and the povidone K-30 as the binder also affect the dissolution rate, so that they do not deviate from the above range.

The total weight of the sustained-release sustained-release double-layer tablet containing itopride hydrochloride of the present invention is 400 to 500 mg. If the total weight is less than 400 mg, there may be a problem with the stability of the sustained-release preparation, and if it exceeds 500 mg, Can fall.

The itopride hydrochloride-containing orally administrable sustained release bi-layer tablet of the present invention can be prepared in various forms, but the thickness of the formulation is preferably 4 to 9 mm. When the thickness is less than 4 mm, cracks are formed or collapsed in the tablets during tableting, resulting in poor yield. The stability of the finished tablets may be poor and the formulations may be broken even under small impact. When the tablet is over 9 mm, It can be felt difficult depending on the condition such as constitution, age, disease and the like.

Meanwhile, the itopride hydrochloride-containing sustained-release double-layer tablet once orally administered once daily according to the present invention,

Mixing itopride hydrochloride granules, release modifiers, fillers, binders and disintegrants to produce sustained-release granules;

Mixing the itopride hydrochloride granule, the filler, the binder and the disintegrant to produce a granule of the immediate layer;

And compressing the granules of the immediate-release layer and the granules of the sustained-release layer at a force of 3.0 to 8.0 kgf per unit area of 1 cm 2 to prepare a single tablet.

At this time, it is preferable that the grain size of the sustained-release layer is in the range of 350 to 450 탆. When the granular particle size is less than 350 탆, stability is inferior and the dissolution profile of the active ingredient is uneven. When it exceeds 450 탆, The elution of the active ingredient is not sufficiently performed.

Preferably, the force for pressing in the single tablet production step is 3 to 8 kgf / cm 2, more preferably 4 to 6 kgf / cm 2. When the pressure is less than 3 kgf / cm 2, the sustained release matrix structure by the release modifier easily collapses, If the concentration exceeds 8 kgf / cm < 2 >, the elution is excessively delayed, which makes it difficult to maintain the concentration of the active ingredient continuously.

The sustained release double-layered tablets containing itopride hydrochloride according to the present invention preferably have a hardness of 10 to 25 kg / cm 2, more preferably 15 to 20 kg / cm 2.

When the hardness is less than 10 kgf / cm 2, the dissolution of the drug in the early phase may occur due to some disintegration of the slow release layer. It appears to be slow.

The present invention provides an oral administration sustained-release double-layer tablet containing itopride hydrochloride, which improves patient compliance and prevents adverse effects due to excessive release of the initial active ingredient and maintains a uniform dissolution rate.

Fig. 1 shows the dissolution rates in the pH 1.2 eluant for the preparations prepared in each of the examples and the comparative examples.
Fig. 2 shows the dissolution rate in the pH 4.0 eluant for the preparations prepared in each of the examples and the comparative examples.
Figure 3 shows the dissolution rate in the pH 6.8 eluant for the preparations prepared in each of the Examples and Comparative Examples.
Figure 4 shows the dissolution rate in water for the formulations prepared in each of the Examples and Comparative Examples.

The preparation procedure of the two-layer structured Itopride hydrochloride sustained-release two-layer tablet according to the present invention is as follows.

The middle layer and the inner layer, including itopride hydrochloride, are mixed, combined and granulated to form granules. Then, the sustained-release bi-layer tablet is prepared by first preparing one of the middle layer and the middle layer, which is made of granules, and then filling the granules of the other layer with the granules.

Further, unlike the above-mentioned method, the sustained-release two-layer tablets of the present invention can also be prepared by separately preparing the slow-layer tablet and the inner layer tablet, and then tableting the tablets of each layer.

Hereinafter, one embodiment of the preparation method of the itopride hydrochloride sustained-release two-layer tablet according to the present invention will be described in detail.

Manufacturing method of the suspended layer granule

30 to 45% by weight of itopride hydrochloride and 30 to 50% by weight of microcrystalline cellulose as a pharmacologically active ingredient with respect to the total weight of the sustained-release layer, a degree of substitution of methoxyl group of 19 to 24% as a release controlling agent, a degree of substitution of hydroxypropoxyl group 15 to 25% by weight of hydroxypropylmethylcellulose having a viscosity of 7 to 12%, a viscosity of 11,250 to 21,000 mPa.s, and 2 to 5% by weight of a low-substituted hydroxypropylcellulose as a disintegrant. 2 to 5% by weight of povidone dissolved in an appropriate amount of ethanol is added to the binding solution, which is then combined and granulated, and then dried and sieved to a LOD of 4% or less at a temperature of 60 DEG C in a fluidized bed dryer. Followed by mixing a suitable amount of gliding agents to form a sustained-release layer granule.

The granule size of the sustained-release layer produced through the above process is 350 to 450 탆.

Manufacturing method of granule

15 to 40% by weight of itopride hydrochloride relative to the total weight of the immediate-release layer is mixed with 20 to 50% by weight of lactose, an appropriate amount of microcrystalline cellulose and 2 to 5% by weight of croscarmellose sodium and then povidone is dissolved in an appropriate amount of ethanol Weight% is added to the binding liquid, followed by coalescence and granulation, and dried and sieved to a LOD of 4% or less at a temperature of 60 DEG C in a fluidized bed dryer. Afterwards, an appropriate amount of lubricant flux is mixed to produce the immediate-layer granules.

Manufacturing method of sustained release double layer tablet

The above-prepared sustained-release granules and the pre-granulated granules are tableted at a rate of 30 to 40 rpm using a rotary tablet press with a pressure of preferably 3 to 8 kgf / cm 2, more preferably 4 to 6 kgf / cm 2.

The sustained-release bi-layer tablet according to the present invention can be prepared by first tableting the slow-layer granules with the tablet first, filling the granules with the granules, and then performing secondary tableting. However, It is not necessary that tableting of the immediate layer is performed, but tableting of the immediate layer is preferentially performed, and it is also possible to fill the granules of the sustained-release layer. Further, it is also possible to fill the inner layer and the middle layer sequentially or in reverse order, and to fix them once.

The total weight of the completed sustained-release bi-layer tablet is 400 to 500 mg. In order to improve the patient compliance with the medicament, the thickness of the tablets is preferably 4 to 9 mm, more preferably 5 to 7 mm.

The hardness of the sustained-release two-layer tablet according to the present invention is preferably 10 to 25 kg / cm 2, more preferably 15 to 20 kg / cm 2.

Hereinafter, preferred embodiments of the present invention will be described in detail. In the following Examples, specific components and specific factors for the practice of the present invention are described. However, the present invention is not limited by the following Examples. .

Examples 1 to 4 and Comparative Examples 1 to 2

According to the ingredient contents in the following Table 1, sustained release double-layer tablets of Examples 1 to 4 and Comparative Examples 1 to 2 containing itopride hydrochloride were prepared.

Itopride hydrochloride-containing two-layer tablet composition (unit: mg) division Classification ingredient Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Compare to 2 book
room
layer available
ingredient Itopride hydrochloride 110 110 110 120 110 110 Release
Modulator Hypromellose
(Degree of methoxyl group substitution of 22%, degree of hydroxypropoxyl group substitution of 8%, viscosity of 15.000 mPa.s) 43.5 72.5 72.5 72.5 29 130.5 Excipient Pending
cellulose 111.5 82.5 82.5 72.5 126 24.5 Binder Povidone K-30 10 10 10 10 10 10 Disintegration Low-substituted propyl cellulose 10 10 10 10 10 10 Lubricant Stearic acid
magnesium 5 5 5 5 5 5 Gross Weight 290 genus
room
layer available
ingredient Itopride hydrochloride 40 40 40 30 40 40 Excipient Lactose baggage 50 50 50 50 50 50 Excipient Pending
cellulose 40 40 40 40 40 40 Binder Povidone K-30 5 5 5 5 5 5 Disintegration Croscarmellose sodium 4 4 4 4 4 4 Lubricant Stearic acid
magnesium One One One One One One Gross weight 140 Coating layer Coating agent Opa Dry 0Y-C-7000A 15 Tablet weight 445

Detailed preparation steps of the respective examples and comparative examples based on the ingredient contents in Table 1 are as follows.

Immediate layer  Manufacture of granules

The povidone K-30 was gradually added to the ethanol solvent while stirring at an air pressure of 3 kg / cm < 2 > for 30 minutes to prepare a binding solution.

Ito-Pride hydrochloride and lactose hydrate, microcrystalline cellulose and croscarmellose sodium were mixed for 3 minutes in a speed mixer, and the resulting solution was added and mixed three times for 3 minutes each time, Respectively.

The combined liquid was put into a rotary granulator and granulated for 20 minutes to form granules.

 The granules thus formed were dried in a fluid bed drier at 55 ° C for 40 minutes (LOD 2% or less), and the dried granules were formulated with a power mill for 20 minutes, then glidant was added and the mixture was stirred at 24 rpm in a drum mixer of 40 mesh stencil For 20 minutes to prepare the immediate-layer granules.

West floor  Manufacture of granules

The povidone K-30 was gradually added to the ethanol solvent while stirring at an air pressure of 3 kg / cm < 2 > for 30 minutes to prepare a binding solution.

Hydroxypropylmethylcellulose and low-substituted hydroxypropylcellulose (L-HPC) having a methoxy group substitution degree of 22%, a hydroxypropyl group substitution degree of 8%, and a viscosity of 15,000 mPa.s were mixed with itopride hydrochloride and microcrystalline cellulose, Speed mixer for 3 minutes, and then the above-prepared binding solution was added thereto and mixed three times for 3 minutes per one time to prepare a combined solution.

The resultant liquid mixture was put into a rotary granulator and granulated for 20 minutes to form granules.

 The granules thus formed were dried in a fluid bed drier at a temperature of 60 ° C. for 30 minutes (LOD 2% or less), and the dried granules were formulated with a power mill for 20 minutes. Then, a glidant was added thereto and the mixture was stirred in a drum mixer of 40 mesh stencil at 24 rpm For 20 minutes to prepare a sustained-release layer granule.

Preparation of sustained release double layer tablet

The granules of the late layer granules and the inner granules prepared in the above step were compressed at a speed of 33 rpm while applying a pressure of 5.5 kgf / cm 2 using a rotary tablet press.

First, the granules of the middle layer were firstly tableted to prepare tablets. Secondary tablets were filled with the granules of the inner layer to prepare tablets.

The two-layered tablets were demineralized using a refining quench, and then coated with Opadry-OY-C-7000A (Colorcon Co.) for 120 minutes at a pump pressure of 3.0 bar and an air pressure of 2.5 bar using a 60- Coated with a coating agent, and then dried at 70 DEG C at a speed of 1 rpm for 10 minutes to prepare a sustained release bi-layer tablet of the present invention containing the active ingredient of itopride hydrochloride in one tablet.

To increase patient compliance, the thickness of the slow-release bi-layer tablet was limited to 6 mm, the hardness was 18.7 kg / cm 2, and the total weight of the completed two-layer tablets was 445 mg.

Invitro (In-vitro) elution test

The elution rate of itopride hydrochloride active ingredient in each of the formulations of the above Examples and Comparative Examples over time under the conditions of the Korean Pharmacopoeia dissolution test was measured to confirm the dissolution profile.

The test conditions used for the dissolution test are as follows.

Specimen: Itopride hydrochloride according to the examples and comparative examples Sustained-release two-layer tablets

Elution test solution: pH 1.2, pH 4.0, pH 6.8 and water

Amount of eluent: 900 ml, Test temperature: 37 ± 0.5 ° C

Test method: Korean Pharmacopoeia dissolution test No. 2 (paddle method), 50 rotations per minute

Sampling: 10 mL of the eluate is sampled every sampling time, filtered with a 0.45 μm filter to prepare the sample solution, and the eluate is sampled.

Analysis equipment: Ultraviolet spectrophotometer (UV-Vis), absorbance 273 nm

Test result

The results of the In-Vitro elution test are shown in Tables 2 to 5 and Figs. 1 to 4.

Elution rate at pH 1.2 division Dissolution rate (%) 15 minutes 30 minutes 60 minutes 90 minutes 120 minutes 180 minutes 300 minutes 360 minutes 480 minutes 600 minutes 720 minutes 1080 minutes 1440 minutes Example 1 22.1 27.9 36.5 41.2 45.5 53.7 65.6 69.1 77.8 82.6 89.7 96.5 99.2 Example 2 24.5 30.1 37.4 44.4 48.4 55.1 65.4 71.2 78.8 83.2 89.7 98.6 100.1 Example 3 21.9 28.5 35.7 42.4 46.1 54.7 63.8 68.1 75.4 81.2 84.5 96.7 99.9 Example 4 20.1 22.8 31.4 35.4 41.3 44.8 55.1 58.8 71.4 85.8 93.1 94.5 97.8 Comparative Example 1 21.1 22.4 40.8 54.2 61.7 74.3 85.1 92.1 94.4 95.5 95.7 95.7 95.2 Comparative Example 2 20.1 28.7 40.2 43.7 50.6 54.8 56.2 62.2 64.0 66.9 70.3 73.6 75.6

Elution rate at pH 4.0 division Dissolution rate (%) 15 minutes 30 minutes 60 minutes 90 minutes 120 minutes 180 minutes 300 minutes 360 minutes 480 minutes 600 minutes 720 minutes 1080 minutes 1440 minutes Example 1 21.8 30.6 37.7 43.1 48.1 56.1 67.4 71.3 81.9 86.6 93.6 98.4 99.6 Example 2 22.8 27.6 36.5 45.6 49.8 57.7 68.6 71.3 81.6 88.7 94.2 98.8 100.2 Example 3 21.1 29.3 39.1 42.4 49.1 56.7 66.1 70.1 82.8 87.9 92.6 97.6 99.7 Example 4 19.8 22.4 31.2 32.1 41.2 45.5 56.8 57.2 68.8 84.3 95.5 96.3 98.2 Comparative Example 1 20.5 22.3 41.6 52.7 63.8 75.1 83.1 89.2 94.9 95.9 96.8 97.5 97.8 Comparative Example 2 17.7 24.4 40.1 44.8 48.8 50.3 52.8 56.6 61.1 65.6 69.7 74.8 77.6

Elution rate at pH 6.8 division Dissolution rate (%) 15 minutes 30 minutes 60 minutes 90 minutes 120 minutes 180 minutes 300 minutes 360 minutes 480 minutes 600 minutes 720 minutes 1080 minutes 1440 minutes Example 1 22.1 30.2 37.3 42.2 46.2 55.2 62.2 66.1 73.2 77.8 82.0 95.9 99.5 Example 2 22.5 30.4 39.1 45.4 49.4 56.1 65.4 70.8 76.8 77.2 83.3 96.7 99.1 Example 3 21.2 30.3 35.6 44.3 48.5 57.3 66.2 67.7 77.9 79.5 84.4 95.1 98.7 Example 4 18.4 24.1 29.9 30.1 41.4 49.3 59.7 62.3 68.8 71.6 87.7 91.1 93.4 Comparative Example 1 18.5 22.2 27.8 33.4 42.2 66.8 79.3 87.1 94.1 95.4 95.7 96.2 96.7 Comparative Example 2 17.5 21.4 37.4 41.2 44.3 47.4 51.2 55.4 60.7 64.1 67.2 72.6 75.5

Elution rate in water division Dissolution rate (%) 15 minutes 30 minutes 60 minutes 90 minutes 120 minutes 180 minutes 300 minutes 360 minutes 480 minutes 600 minutes 720 minutes 1080 minutes 1440 minutes Example 1 21.6 29.7 36.1 44.2 48.1 57.8 66.6 74.3 81.4 85.5 92.4 96.7 99.7 Example 2 22.1 28.2 37.3 46.6 48.2 58.8 67.1 73.5 83.6 86.9 92.4 98.3 99.8 Example 3 21.1 29.1 38.1 45.3 51.1 58.5 67.7 76.5 81.2 88.3 94.6 96.6 100.2 Example 4 18.2 24.3 31.3 33.4 41.5 45.8 58.2 64.2 70.1 72.3 86.6 92.3 96.8 Comparative Example 1 16.4 21.4 27.7 35.2 46.3 65.7 79.5 89.2 93.1 94.9 95.4 95.6 95.5 Comparative Example 2 17.7 22.2 38.2 43.2 46.1 51.4 58.8 65.2 68.9 71.2 74.6 76.3 80.8

In the case of Examples 1 to 4, it shows a constant dissolution rate constant over time, and it is predicted that the long-term effect will continue.

In particular, in the case of Example 2, the active ingredient was completely eluted with a constant dissolution profile for 24 hours, and the most suitable formulation appeared.

On the other hand, in the case of Comparative Example 1, complete dissolution was completed in about 8 hours, and the sustained release properties did not appear properly. In Comparative Example 2, the dissolution was too slow,

Relative activity  Factors and Significance

The Applicant has found that when a sustained-release biodegradable tablet according to the present invention is orally administered to a patient, it is a meaningful criterion that can predict and discriminate whether or not a sustained effect can be exhibited through the stomach and intestinal environment sequentially, Relative activity factors were derived.

 [Equation 1]

In the case of the sustained-release two-layer formulation consisting of the immediate-release layer and the sustained-release layer, the effective ingredient of the rapidly eluting immediate-release layer after oral administration and the effective ingredient of the sustained-release sustained release layer are simultaneously absorbed in the body, The relative ratio of the effective ingredient dissolution rate of the active ingredient to the active ingredient dissolution rate of the sustained-release layer for the continuous effect is very important.

When the effective amount of the active ingredient in the immediate-release layer is excessively eluted at an early stage with respect to the effective ingredient in the immediate-release layer where the active ingredient elutes immediately, the blood concentration of the active ingredient may rapidly rise to cause side effects such as vomiting and dizziness. This is because the effect is rapidly lowered from the point of time when the effect of the eluted immediate-layer effective ingredient is stopped.

Therefore, the relative activity factor of the dissolution rate in the pH 1.2 environment in which the active ingredient of the immediate layer of the two-layer tablet is eluted and the dissolution rate in the pH 6.8 environment in which the active ingredient of the slow-release layer slowly elutes slowly, And the effect of the two-layer tablet can be verified in advance before oral administration, which is a very desirable index.

Accordingly, Applicant calculates the relative activity of each Example and Comparative Example according to Equation (1) above, and is shown in Table 6 below.

Relative activity in pH 1.2 eluate to pH 6.8 division 15 minutes 3h 18h Example 1 One 0.97 1.01 Example 2 1.09 0.98 1.02 Example 3 1.03 0.95 1.02 Example 4 1.09 0.91 1.04 Comparative Example 1 1.14 1.11 1.01 Comparative Example 2 1.15 1.16 1.01

Review

In Examples 1 to 4, a release controlling agent comprising two kinds of hydroxypropylmethylcellulose having different degree of substitution was used, and elution was continued for 24 hours due to the optimum content ratio, and precise elution control And as shown in the dissolution rate of Tables 2 to 5 and the graph of FIGS. 1 to 4 thereof, the effective drug dissolution rate even after 30 minutes of elution of most of the active ingredients of the immediate-morning layer was very preferable for 24 hours.

Further, as shown in Table 6, the relative activity in stomach and intestines was calculated from the dissolution rate at pH 1.2 and pH 6.8. The activity was 1.0 to 1.1 after 15 minutes, 0.9 to 1.0 hours after 3 hours, 1.1, the optimal elution activity is shown as in Examples 1 to 4 above.

In the case of the sustained-release bi-layer tablet according to the present invention, when the relative activity is out of the above range, elution is delayed or the duration is shortened as shown in the comparative examples of FIGS. 1 to 4.

Claims (8)

A once-daily oral sustained-release two-layer tablet containing itopride hydrochloride as an active ingredient,
An active ingredient, a filler, a binder, a disintegrant,
An active ingredient, a filler, a binder, a disintegrating agent and a release modifier,
Wherein the release modifier is hydroxypropylmethylcellulose having a methoxyl group substitution degree of 19 to 24%, a hydroxypropoxyl group substitution degree of 7 to 12%, and a viscosity of 11,250 to 21,000 mPa.s. Orally administrable sustained release double layered tablet.
The method according to claim 1,
Wherein the immediate-release layer contains 20 to 60 mg of active ingredient, and the sustained-release layer contains 90 to 130 mg of active ingredient.
The method according to claim 1,
The sustained release layer comprises, based on the total sustained release layer total weight,
Characterized in that it comprises 30 to 45% by weight of itopride hydrochloride, 15 to 25% by weight of the release modifier, 2 to 5% by weight of low-substituted hydroxypropyl cellulose and 2 to 5% by weight of povidone K-30 Orally administered sustained-release double-layer tablet containing itopride hydrochloride.
The method according to claim 1,
Wherein the total weight of the isopride hydrochloride-containing oral administration sustained-release two-layer tablet is 400 to 500 mg.
The method according to claim 1,
And the thickness of the sustained-release sustained-release two-layer tablet containing itopride hydrochloride is 4 to 9 mm. The sustained-release sustained release double-layer tablet containing itopride hydrochloride.
A process for producing itopride hydrochloride-containing sustained release double layered tablet according to claim 1,
Mixing itopride hydrochloride granules, release modifiers, fillers, binders and disintegrants to produce sustained-release granules;
Mixing the itopride hydrochloride granule, the filler, the binder and the disintegrant to produce a granule of the immediate layer;
Wherein the sustained-release sustained-release double-layer tablet containing itopride hydrochloride is prepared by compressing the granules of the immediate-release layer and the granules of the sustained-release layer with a force of 3.0 to 8.0 kgf per unit area of 1 cm 2. Gt;
The method according to claim 6,
Wherein the immediate-granule granules have a diameter of 350 to 450 mu m.
The method according to claim 6,
Wherein the single tablet has a hardness of 10 to 25 kg / cm < 2 >.

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