KR102189191B1 - Once a day oral dosage sustained-release formulation comprising itopride - Google Patents

Abstract

The sustained-release double-layer tablet for oral administration containing itopride hydrochloride of the present invention is composed of an immediate-release layer for rapid dissolution of drugs and a sustained-release layer for slow dissolution in order to simultaneously achieve rapid pharmacological activity and sustain pharmacological activity for 24 hours. As a sustained-release two-layer tablet made, in order to show an optimal dissolution pattern, hydroxypropyl methylcellulose having a dissolution control characteristic according to a specific degree of substitution and viscosity is used as a release control agent, and the dissolution rate at each gastrointestinal tract with a different pH And controlling the residence time in the gastrointestinal tract.
In addition, the present invention provides a method of manufacturing a sustained-release double-layer tablet containing itopride hydrochloride, which is designed to prevent side effects due to over-release of the initial active ingredient, and maintain a uniform dissolution rate while increasing patient compliance.

Description

Sustained release formulation containing itopride hydrochloride administered orally once a day {ONCE A DAY ORAL DOSAGE SUSTAINED-RELEASE FORMULATION COMPRISING ITOPRIDE}

The present invention uses hydroxypropyl methylcellulose having a specific degree of substitution and viscosity characteristics as a release control agent to precisely adjust the dissolution form, thereby containing itopride hydrochloride showing the optimum dissolution profile once a day orally administered sustained-release two-layer tablet And it relates to the manufacturing method.

Itopride hydrochloride (N-[[4-(2-dimethylaminoethoxy)phenyl]methyl]-3,4-dimethoxybenzamide) is a functional indigestion-induced abdominal bloating, epigastric pain, loss of appetite, chest pain, nausea , As a pharmacologically active substance mainly used to improve digestive symptoms such as vomiting, it has a structure as shown in the following formula.

Itopride hydrochloride increases the concentration of acetylcholine in the body by blocking dopamine D2 receptor and inhibiting acetylcholinesterase. Increased acetylcholine further promotes gastrointestinal peristalsis, increases the pressure of the lower esophageal sphincter, accelerates the excretion of the stomach contents, improves the cooperation between the stomach and the duodenum, improves digestive function and reduces abdominal pain. There is.

In addition, itopride hydrochloride has an advantage that is suitable for long-term administration because it hardly shows side effects such as gynecomastia and milk secretion, which are side effects of gastrointestinal function improving agents such as domperidone.

When itopride hydrochloride is administered orally, the onset of action is generally within 30 minutes, the time to reach the maximum blood concentration is about 0.5 to 1.5 hours, and the duration is about 12 hours. It is known that about 80% of the active ingredients are excreted in urine, and the excretion rate (half-life) is known to be about 6 hours.

In general, patients with poor digestive function often develop symptoms due to stress and require a long-term use. As described above, itopride hydrochloride should be taken regularly three times a day due to a short half-life. . Due to this, there is inconvenience in the guidance of medication for long-term patients, and there is a problem in that medication compliance is also poor.

In order to solve this problem, Korean Patent Registration No. 10-1485421 discloses a sustained-release tablet containing itopride taken once a day, but the sustained-release tablet is a single tablet containing itopride hydrochloride. There is a disadvantage in that the immediate effect is inferior since the dissolution occurs slowly after administration.

The present invention provides a sustained-release two-layer tablet consisting of an immediate-release layer and a sustained-release layer containing itopride hydrochloride, and the sustained-release two-layer tablet according to the present invention achieves sufficient pharmacological activity only once a day, while the effect appears quickly. It shows an excellent effect.

Korean Patent Registration No. 10-1485421

The present invention was conceived to solve the above problem, and the present applicant improved the problem by analyzing the dissolution pattern of itopride hydrochloride sustained-release tablet consisting of a conventional single tablet for 24 hours, and hydroxypropyl methylcellulose as a sustained-release control base. By reflecting the dissolution characteristics according to the viscosity and degree of substitution of, the oral administration sustained-release two-layer tablet containing itopride hydrochloride having an optimal dissolution profile for achieving superior effect and achieving the same compared to the prior art was implemented.

The present invention provides a sustained-release or controlled-release two-layer tablet containing itopride hydrochloride as an active ingredient, orally administered once a day.

The sustained-release or controlled-release two-layer tablet consists of an immediate-release layer containing an active ingredient, a filler, a binder, and a disintegrant, and a sustained-release layer containing an active ingredient, a filler, a binder, a disintegrant and a release controlling agent. Uses hydroxypropyl methylcellulose 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.

When the degree of substitution of the methoxyl group of the release-controlling agent is out of the above range, the properties of the release-controlling agent are not uniform and the stability of the release control matrix according to the present invention is deteriorated.

In addition, when the viscosity of the release-controlling agent is less than 11,250 mPa.s, the active ingredient is initially over-eluted and side effects may occur, and when it exceeds 21,000 mPa.s, the dissolution of the active ingredient is excessively delayed, so that sufficient effects may not be exhibited. .

The sustained-release two-layer tablet according to the present invention contains active ingredients in the immediate-release layer or the sustained-release layer, respectively, and the content of each active ingredient is characterized in that it contains 20 to 60 mg for the immediate-release layer and 90 to 130 mg for the sustained-release layer. .

If the active ingredient in the immediate-release layer is less than 20mg or the active ingredient in the sustained-release layer is less than 90mg, sufficient therapeutic effects may not be obtained.If the active ingredient in the immediate-release layer exceeds 60mg or the active ingredient in the sustained-release layer exceeds 130mg, the blood concentration may rise excessively and side effects may occur. .

The sustained-release layer composition of the sustained-release two-layer tablet according to the present invention includes 30 to 45% by weight of itopride hydrochloride, 15 to 25% by weight of a release control agent, and 2 low-substituted hydroxypropyl cellulose based on the total weight of the sustained-release layer. It is characterized in that it comprises from to 5% by weight, and 2 to 5% by weight of povidone K-30.

The content ratio is that the sustained-release two-layer tablet according to the present invention has been devised to exhibit an optimal dissolution pattern in the body, and when the content of the release controlling agent is outside the above range, excessive dissolution at the beginning of administration or dissolution is excessively delayed, Since the disintegrating agent, low-substituted propyl cellulose and the binder, povidone K-30, also affect the dissolution rate, it is preferable not to deviate from the above range.

It is characterized in that the total weight of the 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 in the stability of the sustained-release tablet, and if it exceeds 500 mg, This can fall.

The oral administration sustained-release bilayer tablet containing itopride hydrochloride of the present invention may be prepared in various forms, but the thickness of the formulation is preferably 4 to 9mm. If the thickness is less than 4mm, the tablet may crack or collapse during tableting, resulting in a decrease in yield.The stability of the finished tablet may be poor, and the formulation may break even with a small impact.If the thickness exceeds 9mm, the patient's body shape, when administered orally, You may feel difficult depending on your constitution, age, or disease.

Meanwhile, the sustained-release bilayer tablet containing itopride hydrochloride, administered orally once a day according to the present invention,

Mixing itopride hydrochloride granules, a release controlling agent, a filler, a binder, and a disintegrant to prepare a sustained-release layer granules;

Mixing itopride hydrochloride granules, a filler, a binder, and a disintegrant to prepare immediate-release granules;

The immediate-release layer granules and the sustained-release layer granules are compressed with a force of 3.0 to 8.0 kgf per unit area of 1 cm 2 to produce a single tablet.

At this time, it is preferable that the slow-release granules have a particle diameter of 350 to 450 μm, but if the particle diameter of the granules is less than 350 μm, stability is poor and the elution pattern of the active ingredient appears uneven. If the particle size exceeds 450 μm, disintegration is delayed for 24 hours. The active ingredient is not sufficiently eluted.

The compression force in the single tablet manufacturing step is preferably 3 to 8kgf/cm2, and more preferably 4 to 6kgf/cm2, but if it is less than 3kgf/cm2, the sustained-release matrix structure by the release control agent is easily collapsed, due to the initial excessive elution. The sustained-release effect is extremely deteriorated, and if it exceeds 8kgf/cm2, the elution is excessively delayed, making it difficult to maintain a continuous concentration of the active ingredient.

The sustained-release two-layer tablet containing itopride hydrochloride according to the present invention preferably has a hardness of 10 to 25 kg/cm 2, and more preferably 15 to 20 kg/cm 2.

If the hardness is less than 10kgf/㎠, the sustained-release layer partially disintegrates and the drug is eluted, resulting in over-dissolution and deterioration of the sustained efficacy of the drug. If it exceeds 25kgf/cm2, the disintegration time of the tablet is delayed and the effect is reduced. It will appear slowly.

The present invention provides an oral sustained-release double-layer tablet containing itopride hydrochloride that increases patient compliance, prevents side effects due to over-release of an initial active ingredient, and maintains a uniform dissolution rate.

1 shows the dissolution rate in the pH 1.2 eluate for the formulations prepared in each Example and Comparative Example.
Figure 2 shows the dissolution rate in the pH 4.0 eluate for the formulations prepared in each Example and Comparative Example.
Figure 3 shows the dissolution rate in the pH 6.8 eluate for the formulations prepared in each Example and Comparative Example.
4 shows the dissolution rate in water for the formulations prepared in each Example and Comparative Example.

The production sequence of the sustained-release double-layer tablet of itopride hydrochloride according to the present invention is as follows.

The sustained-release layer portion and the immediate-release layer portion containing itopride hydrochloride are prepared into granules through mixing, association and granulation processes, respectively. Then, one of the sustained-release layer and the immediate-release layer made of granules is first prepared as a tablet, and then the other layer of granules is filled thereon and tableted to prepare a sustained-release two-layer tablet.

In addition, unlike the above method, the sustained-release tablet and the immediate-release tablet may be separately prepared, and then tablets of each layer may be stacked and compressed to prepare the sustained-release two-layer tablet of the present invention.

Hereinafter, one specific example of the manufacturing method for the sustained-release double-layer tablet of itopride hydrochloride according to the present invention will be described in detail.

Method for producing slow-release granules

As a pharmacologically active ingredient of the total weight of the sustained release layer, 30 to 45% by weight of itopride hydrochloride, 30 to 50% by weight of microcrystalline cellulose, 19 to 24% of methoxyl group substitution degree as a release control agent, and hydroxypropoxyl group substitution degree 15 to 25% by weight of hydroxypropylmethylcellulose having a viscosity of 7 to 12% and a viscosity of 11,250 to 21,000 mPa·s, and 2 to 5% by weight of low-substituted hydroxypropyl cellulose as a disintegrant are mixed. Here, 2 to 5% by weight of povidone dissolved in an appropriate amount of ethanol is added as a binding solution to coalesce and granulate, followed by drying and sizing at a temperature of 60°C in a fluid bed dryer to less than 4% of loss on drying (LOD). After that, an appropriate amount of lubricant is mixed to prepare slow-release granules.

The particle size of the granules of the sustained-release layer prepared through the above process is 350 to 450 μm.

Method for producing immediate-release granules

After mixing 15 to 40% by weight of itopride hydrochloride relative to the total weight of the immediate release layer with 20 to 50% by weight of lactose, an appropriate amount of microcrystalline cellulose, and 2 to 5% by weight of croscarmellose sodium, 2 to 5 povidone dissolved in an appropriate amount of ethanol in advance Combined and granulated by adding wt% as a binding solution, and dried and sieved at a temperature of 60°C in a fluid bed dryer to less than 4% LOD. After that, an appropriate amount of lubricant is mixed to prepare immediate-release granules.

Manufacturing method of sustained-release two-layer tablet

The sustained-release layer granules and the immediate-release layer granules prepared above are tableted at a speed of 30 to 40 rpm while applying a pressure of preferably 3 to 8 kgf/cm 2, more preferably 4 to 6 kgf/cm 2 using a rotary tablet press.

The sustained-release two-layer tablet according to the present invention may be prepared in the order of first tableting the sustained-release layer granules into tablets, and then filling the immediate-release layer granules thereon to perform secondary tableting, but must be performed after the sustained-release layer is tableted. The tableting of the immediate-release layer is not required, and the tableting of the immediate-release layer is made preferentially, and it is also possible to tablet by filling the granules of the sustained-release layer. In addition, it is also possible to single tableting by filling the immediate-release layer and the sustained-release layer sequentially or in reverse order.

The total weight of the completed sustained-release two-layer tablet is 400 to 500 mg, and in order to improve patient compliance, the thickness of the tablet is preferably 4 to 9 mm, and more preferably 5 to 7 mm.

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

Hereinafter, a preferred implementation method of the present invention will be described in detail. In the following examples, specific elements and specific factors for implementation according to the present invention are described, which are provided to aid in an overall understanding of the present invention, and the present invention is not limited by the examples. .

Examples 1 to 4 and Comparative Examples 1 to 2

According to the component contents of Table 1 below, sustained-release two-layer tablets of Examples 1 to 4 and Comparative Examples 1 to 2 containing itopride hydrochloride were prepared.

Composition of two-layer tablet containing itopride hydrochloride (unit: mg) division Classification ingredient Example 1 Example 2 Example 3 Example 4 Comparative Example 1 In comparison 2 book
room
layer available
ingredient Itopride hydrochloride 110 110 110 120 110 110 Release
Modulator Hypromellose
(Methoxyl group substitution degree 22%, hydroxypropoxyl group substitution degree 8%, viscosity 15.000mPa.s) 43.5 72.5 72.5 72.5 29 130.5 Excipient Undecided
cellulose 111.5 82.5 82.5 72.5 126 24.5 Binder Povidone K-30 10 10 10 10 10 10 Disintegrant Low-substituted propyl cellulose 10 10 10 10 10 10 Lubricant Stearic acid
magnesium 5 5 5 5 5 5 Total weight of the western layer 290 genus
room
layer available
ingredient Itopride hydrochloride 40 40 40 30 40 40 Excipient Lactose hydrate 50 50 50 50 50 50 Excipient Undecided
cellulose 40 40 40 40 40 40 Binder Povidone K-30 5 5 5 5 5 5 Disintegrant Croscarmellose Sodium 4 4 4 4 4 4 Lubricant Stearic acid
magnesium One One One One One One Total weight of the immediate release layer 140 Coating layer Coating agent Opadry 0Y-C-7000A 15 Total tablet weight 445

Detailed manufacturing steps of each of the Examples and Comparative Examples according to the component content of Table 1 are as follows.

Immediate release Preparation of granules

Povidone K-30 was slowly added to the ethanol solvent and stirred for 30 minutes at an air pressure of 3 kg/cm 2 to prepare a binding solution.

After mixing itopride hydrochloride, lactose hydrate, microcrystalline cellulose, and croscarmellose sodium for 3 minutes in a speed mixer, mixing and combining three times for 3 minutes at a time while adding the above-prepared binding solution to prepare a combined solution I did.

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

The formed granules were dried in a fluid bed dryer at 55° C. for 40 minutes (LOD 2% or less), and the dried granules were sized for 20 minutes with a power mill, and then a lubricant was added and a 40 mesh stencil drum mixer at 24 rpm Mixing for 20 minutes at a rate of to prepare immediate-release granules.

Western Preparation of granules

Povidone K-30 was slowly added to the ethanol solvent and stirred for 30 minutes at an air pressure of 3 kg/cm 2 to prepare a binding solution.

Itopride hydrochloride and microcrystalline cellulose, hydroxypropyl methylcellulose with a degree of substitution of 22% methoxyl group, 8% of hydroxypropyl group substitution, and a viscosity of 15,000 mPa.s, low-substituted hydroxypropyl cellulose (L-HPC) After mixing for 3 minutes in a speed mixer, a combined solution was prepared by mixing three times for 3 minutes each time while adding the binding solution prepared above thereto.

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

The formed granules were dried in a fluid bed dryer at 60°C for 30 minutes (LOD 2% or less), and after sizing the dried granules for 20 minutes with a power mill, a lubricant was added and a 40 mesh stencil drum mixer at 24 rpm By mixing for 20 minutes at the speed of the sustained-release layer granules were prepared.

Preparation of sustained-release two-layer tablet

The sustained-release layer granules and the immediate-release layer granules prepared in the above step were tableted at a speed of 33 rpm while applying a pressure of 5.5 kgf/cm 2 using a rotary tablet press.

First, the sustained-release layer granules were first tableted to form tablets, and the immediate-release layer granules were filled thereon to perform secondary tableting to prepare a two-layer tablet.

After de-dividing the two-layer tablet using a tablet deduster, Opadry-OY-C-7000A (Colorcon) for 120 minutes at a pump pressure of 3.0 bar and an air gun pressure of 2.5 bar using a 60 mesh film coating pan. After coating with a coating base, it was dried for 10 minutes at 70° C. at a speed of 1 rpm to prepare a sustained-release two-layer tablet of the present invention containing an active ingredient of itopride hydrochloride in one tablet.

To increase patient compliance, the thickness of the sustained-release two-layer tablet was limited to 6mm, the hardness was 18.7kg/cm2, and the total weight of the finished two-layer tablet was 445mg.

In vitro (In-vitro) dissolution test

In the conditions of the dissolution test solution of the Korean Pharmacopoeia, the dissolution rate of the active ingredient of itopride hydrochloride for the formulations of Examples and Comparative Examples was measured over time to confirm the dissolution pattern.

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

Specimen: Itopride hydrochloride sustained-release double-layer tablet according to Examples and Comparative Examples

Dissolution test solution: pH 1.2, pH 4.0, pH 6.8 and water in the dissolution test method of the Korean Pharmacopoeia

Eluent volume: 900 ml, Test temperature: 37 ±0.5℃

Test method: Korean Pharmacopoeia dissolution test method 2 (paddle method), 50 rotations per minute

Sampling: Take 10 mL of the eluate at each sampling time, filter it with a 0.45㎛ filter, and make the sample solution. After taking the eluate, correct the same amount of the new eluate.

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

Test result

The results of the In-Vitro dissolution test are shown in Tables 2 to 5 and FIGS. 1 to 4 below.

Dissolution 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

Dissolution 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

Dissolution 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 can be predicted that the dissolution rate will continue to be constant over time, and thus the effect will continue for a long time.

In particular, in the case of Example 2, all the active ingredients were eluted while showing a constant dissolution pattern for 24 hours, resulting in the most suitable formulation.

On the other hand, in the case of Comparative Example 1, the dissolution was completely completed in about 8 hours, so that the sustained-release property was not properly displayed, and in the case of Comparative Example 1, the dissolution was too slow, so that sufficient medicinal effects were not observed.

Relative activity Argument and significance

The applicant of the present invention is a meaningful criterion for predicting and discriminating whether or not the sustained-release double-layer tablet according to the present invention can be administered orally to a patient, passing through the gastric and intestinal environments sequentially and exhibiting a long-lasting effect. The relative activity factor was derived.

[Equation 1]

In the case of a sustained-release two-layer tablet consisting of an immediate-release layer and a sustained-release layer, the active ingredient of the immediate-release layer that dissolves quickly after oral administration and the active ingredient of the sustained-release layer that slowly elutes for a long time must be absorbed in the body at the same time and maintain a constant concentration. The relative ratio of the active ingredient dissolution rate of the sustained-release layer and the active ingredient dissolution rate of the sustained-release layer is very important.

When the active ingredient in the sustained-release layer is initially excessively eluted with respect to the active ingredient in the immediate-release layer, side effects such as vomiting and dizziness may occur due to a rapid increase in the concentration of the active ingredient in the blood. This is because the effect rapidly deteriorates from the point when the effect of the eluted immediate-release active ingredient ceases.

Therefore, the relative activity factors of the dissolution rate in the pH 1.2 environment in which the active ingredient of the immediate-release layer of the two-layer tablet is eluted and the dissolution rate in the pH 6.8 environment in which the active ingredient in the sustained-release layer continuously elutes slowly are the active ingredients that are simultaneously eluted in the immediate-release layer and the sustained-release layer It makes it possible to easily predict the dissolution pattern according to the pH environment of, and is a very desirable index to verify the effect of the double-layer tablet before oral administration.

Accordingly, the present applicant calculated the relative activity of each Example and Comparative Example according to Equation 1, 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 in which two types of hydroxypropyl methylcellulose having different degrees of substitution were mixed was used, and the elution was continued for 24 hours due to the optimum content ratio, and precise dissolution was controlled while suppressing initial excessive elution. This became possible, and as shown in the dissolution rates of Tables 2 to 5 and the graphs of FIGS. 1 to 4 showing the same, the effective drug dissolution rate was very desirable for 24 hours even after 30 minutes when most of the immediate release layer active ingredients were eluted.

In addition, as shown in Table 6, when calculating the relative activity in the gastric and intestinal environment through the dissolution rates at pH 1.2 and pH 6.8, 1.0 to 1.1 after 15 minutes of elution, 0.9 to 1.0 after 3 hours, 1.0 to 1.0 after 18 hours In the case of 1.1, it can be seen that the optimal elution activity is shown as in Examples 1 to 4.

In the case of the sustained-release two-layer tablet according to the present invention, when the relative activity is out of the above range, the dissolution is excessively delayed or the duration is shortened as shown in Comparative Examples of FIGS. 1 to 4.

Claims (8)

As a sustained-release bilayer tablet administered orally once a day, containing itopride hydrochloride as an active ingredient,
An immediate release layer comprising an active ingredient, a filler, a binder, and a disintegrant,
It includes a sustained-release layer containing an active ingredient, a filler, a binder, a disintegrant and a release controlling agent,
The release controlling agent uses hydroxypropyl methylcellulose 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, and
The immediate-release layer contains 20 to 60 mg of an active ingredient, and the sustained-release layer contains 90 to 130 mg of an active ingredient,
The sustained-release layer is based on the total weight of the total sustained-release layer,
30 to 45% by weight of itopride hydrochloride, 15 to 25% by weight of the release control agent, 2 to 5% by weight of low-substituted hydroxypropylcellulose as a disintegrant, and 2 to 5% by weight of povidone K-30 as a binder Orally administered sustained-release bilayer tablet containing itopride hydrochloride, characterized in that it comprises a.
delete delete The method of claim 1,
The oral administration sustained-release bi-layer tablet containing itopride hydrochloride, characterized in that the total weight of the oral administration sustained-release bi-layer tablet containing itopride hydrochloride is 400 to 500mg.
The method of claim 1,
The oral administration sustained-release bilayer tablet containing itopride hydrochloride, characterized in that the thickness of the oral administration sustained-release bilayer tablet containing itopride hydrochloride is 4 to 9mm.
In the method for producing a sustained-release two-layer tablet containing itopride hydrochloride according to claim 1,
Mixing itopride hydrochloride granules, a release controlling agent, a filler, a binder, and a disintegrant to prepare a sustained-release layer granules;
Mixing itopride hydrochloride granules, a filler, a binder, and a disintegrant to prepare immediate-release granules;
Compressing the immediate-release layer granules and the sustained-release layer granules with a force of 3.0 to 8.0 kgf per unit area of 1 cm 2 to prepare a single tablet; Manufacturing method.
The method of claim 6,
The immediate-release layer granules have a diameter of 350 to 450㎛, characterized in that the method for producing a sustained-release bilayer tablet for oral administration containing itopride hydrochloride.
The method of claim 6,
The single tablet has a hardness of 10 to 25kg/cm2, characterized in that itopride hydrochloride-containing oral administration sustained-release two-layer tablet manufacturing method.

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