KR102465629B1 - Once a day oral dosage sustained-release formulation comprising mosapride - Google Patents

Abstract

The oral sustained-release bi-layer tablet containing Mosapride or a salt thereof according to the present invention has an immediate-release layer for rapidly dissolving the drug and a slow-release layer for rapid pharmacological activity and sustained pharmacological activity for 24 hours at the same time. As a sustained-release bi-layer tablet composed of a sustained-release layer, several types of release-controlling agents with different dissolution characteristics depending on the degree of substitution are used as release-controlling agents in order to show the optimal dissolution pattern, and the dissolution rate at each site in the gastrointestinal tract with different pH and controlling the residence time in the gastrointestinal tract.
In addition, the present invention is an oral sustained-release formulation containing Mosapride designed to maintain the effect over a longer period of time than normal patients for administration to patients with reduced digestive system function or slow digestion due to disease while increasing patient compliance with medication. A method for preparing a bilayer tablet is provided.

Description

Mosapride-containing sustained-release formulation for oral administration once a day {ONCE A DAY ORAL DOSAGE SUSTAINED-RELEASE FORMULATION COMPRISING MOSAPRIDE}

In the present invention, by mixing two types of hydroxypropylmethylcellulose with different degrees of substitution and precisely adjusting the dissolution form, the once-a-day oral administration of Mosapride, which shows an optimal dissolution profile, especially for patients with significantly reduced digestive function It relates to a sustained-release bi-layer tablet and a manufacturing method thereof.

Mosapride (4-amino-5-chloro-2-ethoxy-N- [4- (4-fluorobenzyl) -2-morpholinyl] methyl benzamide) is a known compound having the structural formula of Formula 1 below. and physiologically acceptable salts thereof are selective serotonin 5-hydroxytryptamine 4 (hereinafter referred to as '5-HT4') receptor agonists, selective only for serotonin 5-HT4 receptors present in the enteric muscle plexus. , which promotes the release of acetylcholine from the nerve terminals, and this acetylcholine contracts the smooth muscles of the digestive tract and promotes the movement of the digestive tract, leading to diabetic gastropathy, dyspepsia, gastritis It is a drug that shows excellent efficacy in the treatment of gastritis and gastroesphageal reflux disease. Mosapride does not have the concerns of arrhythmia and sudden cardiac death due to QT interval prolongation, which was seen in Cisapride, a non-selective 5-HT4 receptor agonist, and does not have dopamine-2 (D-2) receptor antagonism. It is a safe drug with no side effects such as CNS) side effects (extrapyramidal symptoms) and hyperprolactinemia (lactation, feminized breast).

[Formula 1]

Mosapride has a digestive tract absorption rate of more than 93% when administered orally, and is distributed in the liver, small intestine, stomach, kidney, and adrenal gland at a concentration more than 10 times higher than the concentration in plasma, and is It is also distributed in high concentrations in the spleen, etc., and is distributed in the brain and eyes at a low concentration of about half of the blood concentration. When administered orally, Mosapride takes about 0.5 to 1.4 hours to reach its highest blood concentration, showing a rapid onset of efficacy.

Mosapride has a short half-life of 1.3 to 2 hours, so the drug is quickly lost after being absorbed into the body, so the duration of the drug's effect is short, so it has to be taken several times a day. Mosapride is currently developed and marketed in the form of a tablet, and one tablet containing 5 mg of Mosapride is administered three times a day. Therefore, it is necessary to increase the patient's medication compliance by reducing the number of doses and to continuously maintain the drug efficacy by continuously maintaining the blood concentration of the drug.

In the case of general sustained-release tablets, there is a disadvantage in that it takes a long time to reach an effective blood concentration in the initial stage. In addition, when rapid pharmacological activity is expressed after oral administration, it is difficult to maintain effective pharmacological activity for 24 hours.

Korean Patent Registration No. 10-1190708 Korean Patent Registration No. 10-1612931

The present invention was devised to solve the above problems, and the present applicant analyzed the dissolution pattern for 24 hours of the conventional two-layer tablet of Mosapride consisting of an immediate-release layer and a sustained-release layer to improve the disadvantages and improve the degree of substitution of the dissolution control mechanism. Focusing on the elution characteristics of the above, we implemented an optimal elution profile for superior effect and achievement compared to the prior art.

In addition, the present invention provides a sustained-release bi-layer tablet containing Mosapride that simultaneously satisfies rapid pharmacological activity and long-term pharmacological activity lasting for more than 24 hours and a manufacturing method thereof.

The present invention is a sustained-release bi-layer tablet for oral administration once a day containing Mosapride or a salt thereof as an active ingredient, comprising an immediate-release layer containing active ingredients, fillers, disintegrants, and excipients, active ingredients, fillers, and disintegrants. , A release-controlling agent and a sustained-release layer containing additives, wherein the release-controlling agent is hydroxypropylmethylcellulose having a methoxyl group substitution of 18.0 to 26.0% and a hydroxypropoxyl group substitution of 2.0 to 14.0% and a methoxyl group substitution degree 27.0 to 35.0%, hydroxypropylmethylcellulose having a degree of substitution of 5.0 to 16.0% of hydroxypropoxyl group is mixed and used,

Based on the total weight of the release controlling agent, 65 to 80% by weight of hydroxypropylmethylcellulose having a degree of substitution of 18.0 to 26.0% of a methoxyl group and 2.0 to 14.0% of a degree of substitution of a hydroxypropoxyl group, a degree of substitution of a methoxyl group of 27.0 to 35.0%, It is characterized in that it contains 20 to 35% by weight of hydroxypropylmethylcellulose having a degree of substitution of hydroxypropoxyl groups of 5.0 to 16.0%.

When the amount of hydroxypropylmethylcellulose having a degree of substitution of 18.0 to 26.0% of a methoxyl group and a degree of substitution of a hydroxypropoxyl group of 2.0 to 14.0% with respect to the total weight of the controlled-release agent is less than 65% by weight, effective drug dissolution does not last for 24 hours, When it exceeds 80% by weight, dissolution in the body is excessively delayed, making it difficult to obtain sufficient pharmacological effects.

On the other hand, when the amount of hydroxypropylmethylcellulose having a degree of methoxyl group substitution of 27.0 to 35.0% and a hydroxypropoxyl group substitution of 5.0 to 16.0% relative to the total weight of the controlled-release agent is less than 20% by weight, the dissolution pattern immediately after oral administration is not uniform. When it exceeds 35% by weight, the stability is poor and excessive elution may occur in the early stage.

The sustained-release bi-layer tablet of the present invention contains an active ingredient in an immediate-release layer and a sustained-release layer, respectively. do.

If the active ingredient content of the immediate-release layer is less than 2% by weight relative to the total weight of the immediate-release layer or less than 5% by weight of the active ingredient in the sustained-release layer relative to the total weight of the immediate-release layer, sufficient pharmacological effects are not exhibited, and the effective immediate-release layer is effective relative to the total weight of the immediate-release layer. If the component content exceeds 4% by weight or the active ingredient in the sustained-release layer exceeds 7% by weight relative to the total weight of the sustained-release layer, the concentration of the active ingredient in the blood becomes excessively high, which may cause various side effects.

The oral sustained-release bi-layer tablet according to the present invention, when dissolution was tested under buffer conditions of pH 1.2 and pH 6.8, the relative activity according to Equation 1 below was 1.80 to 2.15 after 15 minutes of dissolution and 1.60 to 1.70 after 3 hours, 18 Characterized in that it is 2.00 to 2.25 after hours.

[Equation 1]

The relative activity is a very desirable index that can predict the dissolution pattern of the active ingredient simultaneously eluted from the immediate-release layer and the sustained-release layer, thereby verifying the effect of the two-layer tablet in advance before oral administration, and the relative activity If the design is out of the above range, the dissolution is excessively delayed or the dissolution duration is shortened.

The sustained-release layer of the sustained-release bi-layer tablet according to the present invention contains 5 to 7% by weight of mosapride citrate, 25 to 35% by weight of the controlled-release agent, 10 to 20% by weight of lactose hydrate, based on the total weight of the sustained-release layer. It is characterized by including 15 to 30% by weight of low-substituted hydroxypropyl cellulose and 3 to 10% by weight of povidone K-30.

The content ratio is devised so that the sustained-release bi-layer tablet according to the present invention exhibits an optimal dissolution pattern in the body. If the content of the controlled-release agent is out of the above range, excessive dissolution occurs at the beginning of administration or dissolution is excessively delayed, Since the disintegrant, 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.

The total weight of the oral sustained-release bi-layer tablet containing Mosapride of the present invention is characterized in that the total weight is 330 to 370 mg. If the total weight is less than 330 mg, stability problems may occur during the tableting process, and if the total weight exceeds 370 mg, the dosage form may be excessively Increased medication compliance.

The oral sustained-release bi-layer tablet containing Mosapride of the present invention may be manufactured in various forms, but the thickness of the dosage form is preferably 2 to 7 mm. If the thickness is less than 2mm, the tablet may crack or collapse during tableting, resulting in a drop in yield and the stability of the finished tablet, which may cause the formulation to break even with a small impact. If the thickness exceeds 7mm, the patient's body shape, Depending on your constitution, age, disease, etc., you may experience difficulties.

On the other hand, the sustained-release bi-layer tablet containing Mosapride, which is administered orally once a day according to the present invention,

Preparing sustained-release layer granules by compressing Mosapride citrate granules, a release controlling agent, a filler, a disintegrant, and additives;

Preparing granules for an immediate release layer by compressing Mosapride citrate granules, a filler, a disintegrant, a release controlling agent, and additives;

Preparing a single tablet by 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 cm2.

At this time, the sustained-release layer granules preferably have a particle diameter of 350 to 450 μm. If the particle diameter of the granules is less than 350 μm, the stability is poor and the dissolution pattern of the active ingredient is non-uniform. During this time, the active ingredient is not sufficiently eluted.

The compression force in the single tablet manufacturing step is preferably 3 to 8 kgf/cm2, more preferably 4 to 6 kgf/cm2. The sustained-release effect is extremely reduced, and when it exceeds 8 kgf/cm 2 , elution is excessively delayed, making it difficult to maintain a continuous concentration of the active ingredient.

The Mosapride sustained-release bi-layer tablet according to the present invention preferably has a hardness of 7 to 30 kg/cm 2 , more preferably 9.0 to 23.0 kg/cm 2 .

If the hardness is less than 7.0kgf/cm2, the sustained-release layer is partially disintegrated at the beginning and the drug is eluted, which may cause over-dissolution and deterioration in the efficacy of the drug. will appear slowly.

The sustained-release bi-layer tablet of the present invention uses a release controlling agent in which two types of hydroxypropylmethylcellulose having different degrees of substitution are mixed, and is characterized in that the sustained-release tablet exhibits uniform dissolution while exhibiting superior sustained-release properties compared to conventional sustained-release tablets. In particular, since the duration of the effect is longer than that of conventional sustained-release tablets, it is suitable for patients with reduced digestive function due to digestive system diseases or slow digestion.

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

The manufacturing sequence of the sustained-release bi-layer tablet of Mosapride citrate according to the present invention is as follows.

The slow-release layer and the fast-release layer containing Mosapride citrate are prepared into granules through mixing, kneading, and granulation processes, respectively. Thereafter, a sustained-release two-layer tablet is prepared by first preparing one layer of the slow-release layer and the fast-release layer made of granules into tablets, and then filling the granules of the other layer thereon and tableting them.

In addition, unlike the above method, the sustained-release double-layer tablet of the present invention may be prepared by separately preparing the sustained-release layer tablet and the immediate-release layer tablet, and then overlapping the tablets of each layer and tableting.

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

Method for producing sustained-release layer granules

Mosapride citrate 5 to 7% by weight, lactose 10 to 15% by weight, appropriate amount of microcrystalline cellulose, methoxyl group substitution 18.0 to 26.0%, hydroxypropoxyl group substitution 2.0 25 to 35% by weight of a mixed release-controlling agent containing hydroxypropylmethylcellulose of 14.0%, 27.0 to 35.0% of methoxyl group substitution, and 5.0 to 16.0% of hydroxypropylmethylcellulose of 5.0 to 16.0% of hydroxypropoxyl group substitution, As a release, 15 to 30% by weight of low-substituted hydroxypropyl cellulose is mixed. Here, 3 to 10% by weight of povidone dissolved in an appropriate amount of ethanol is added as a binding solution to knead and granulate, and then dried and sized in a fluidized bed dryer at a temperature of 60 ° C with a loss on drying (LOD) of 4% or less. After that, an appropriate amount of lubricants are mixed to prepare sustained-release layer granules.

At this time, the mixed release-controlling agent is 65 to 80% by weight of hydroxypropylmethylcellulose having a methoxyl group substitution of 18.0 to 26.0% and a hydroxypropoxyl group substitution of 2.0 to 14.0% with respect to the total weight of the mixed release-controlling agent, methoxy 20 to 35% by weight of hydroxypropylmethylcellulose having an actual group substitution degree of 27.0 to 35.0% and a hydroxypropoxyl group substitution degree of 5.0 to 16.0%.

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

Manufacturing method of immediate-release layer granules

After mixing 2 to 4% by weight of Mosapride citrate with 15 to 30% by weight of lactose, an appropriate amount of microcrystalline cellulose and 25 to 35% by weight of low-substituted hydroxypropyl cellulose, based on the total weight of the sok-release layer, the mixture was dissolved in an appropriate amount of ethanol in advance. 5 to 10% by weight of povidone K-30 is added as a binding solution, kneaded and granulated, and dried and sized to an LOD of 4% or less in a fluidized bed dryer at 60 ° C. After that, an appropriate amount of lubricants are mixed to prepare the granules of the immediate release layer.

Manufacturing method of sustained-release bi-layer tablet

The sustained-release layer granules and immediate-release layer granules prepared above are tableted at a speed of 33 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 double-layer tablet according to the present invention may be prepared by first compressing the granules of the sustained-release layer into tablets and then filling the granules of the immediate-release layer thereon to perform secondary tableting. It is not necessary to tablet the immediate-release layer, and it is also possible to tablet the immediate-release layer by first filling it with granules of the sustained-release layer. In addition, it is also possible to compress the fast-release layer and the slow-release layer sequentially or in the reverse order, respectively, and tablet once.

The total weight of the finished sustained-release bi-layer tablet is 330 to 370 mg, and in order to improve patient compliance, the thickness of the tablet is preferably 2 to 7 mm, more preferably 3 to 5 mm.

In addition, the hardness of the sustained-release bi-layer tablet according to the present invention is preferably 7 to 30 kg/cm 2 , more preferably 9 to 23 kg/cm 2 .

Hereinafter, a preferred implementation method of the present invention will be described in detail. In the following examples, specific components and specific factors for implementation according to the present invention are described, which are provided to help the 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 shown in Table 1 below, the sustained-release bi-layer tablets of Examples 1 to 4 and Comparative Examples 1 to 2 containing Mosapride citrate were prepared.

Composition of Mosapride double-layer tablet (unit: mg) division classification ingredient Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Comparative Example 2 west
room
floor chief ingredient Mosapride citrate
luggage 10.58 10.58 10.58 10.58 10.58 10.58 excipient microcrystalline cellulose 38.12 38.12 38.12 38.12 38.12 38.12 excipient lactose hydrate 27.00 27.00 27.00 27.00 27.00 27.00 Release
regulator methoxyl group substitution 29%,
Hydroxypropylmethylcellulose with a degree of hydroxypropoxyl group substitution of 6% 17.50 15.00 12.50 10.00 25.00 35.00 Release
regulator methoxyl group substitution 22%,
Hydroxypropylmethylcellulose with 8% degree of hydroxypropoxyl group substitution 32.50 35.00 37.50 40.00 25.00 15.00 binder Povidone K-30 12.00 12.00 12.00 12.00 12.00 12.00 disintegrant Low-substituted propyl cellulose 35.00 35.00 35.00 35.00 35.00 35.00 glidant light anhydrous silicic acid 0.80 0.80 0.80 0.80 0.80 0.80 glidant Magnesium Stearate 1.50 1.50 1.50 1.50 1.50 1.50 Subtotal (mg/tablet) 175mg inside
room
floor chief ingredient Mosapride citrate
luggage 5.29 5.29 5.29 5.29 5.29 5.29 excipient microcrystalline cellulose 51.91 51.91 51.91 51.91 51.91 51.91 excipient lactose hydrate 45.00 45.00 45.00 45.00 45.00 45.00 disintegrant Low-substituted propyl cellulose 58.30 58.30 58.30 58.30 58.30 58.30 binder Povidone K-30 12.20 12.20 12.20 12.20 12.20 12.20 glidant light anhydrous silicic acid 0.80 0.80 0.80 0.80 0.80 0.80 glidant Magnesium Stearate 1.50 1.50 1.50 1.50 1.50 1.50 Subtotal (mg/tablet) 175mg coating agent Opadry 0Y-C-7000A 5mg Total (mg/tablet) 355mg

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

immediate release layer Preparation of granules

While slowly adding povidone K-30 to an ethanol solvent, stirring was performed for 30 minutes at an air pressure of 3 kg/cm 2 to prepare a binder solution.

Mosapride citrate, microcrystalline cellulose, lactose hydrate, and low-substituted hydroxypropyl cellulose were mixed in a speed mixer for 3 minutes, and then mixed 3 times for 3 minutes each time while adding the binder solution prepared above. was manufactured.

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

The formed granules were dried for 40 minutes at 55 ° C. in a fluidized bed dryer (LOD 2% or less), and after sizing the dried granules for 20 minutes with a power mill, a lubricant was added and 24 rpm in a 40 mesh stencil drum mixer Sokbang layer granules were prepared by mixing for 20 minutes at a speed of.

Western layer Preparation of granules

While slowly adding povidone K-30 to an ethanol solvent, stirring was performed for 30 minutes at an air pressure of 3 kg/cm 2 to prepare a binding solution.

Mosapride citrate, microcrystalline cellulose, lactose hydrate, 22% methoxyl group substitution, 8% hydropropoxyl group substitution, hydroxypropylmethylcellulose, 29% methoxyl group substitution, 6% hydroxypropoxyl group substitution Hydroxypropylmethylcellulose and low-substituted hydroxypropylcellulose (L-HPC) were mixed in a speed mixer for 3 minutes, and then mixed 3 times for 3 minutes each time while adding the binder solution prepared above. A joint solution was prepared.

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

The formed granules were dried for 35 minutes at 60 ° C. in a fluidized bed dryer (LOD 2% or less), and the dried granules were regulated by a power mill for 20 minutes, and then a lubricant was added and 40 mesh stencil drum mixer at 24 rpm The slow-release layer granules were prepared by mixing for 20 minutes at a speed of .

Manufacture of sustained-release bi-layer tablet

The sustained-release layer granules and immediate-release layer granules prepared in the above step were compressed into tablets at a speed of 33 rpm while applying a pressure of 5 kgf/cm 2 using a rotary tablet press.

First, the granules of the slow-release layer were first compressed into tablets, and the granules of the immediate-release layer were filled thereon to form a second tablet, thereby preparing a two-layer tablet.

After dedusting the two-layer tablet using a tablet dehydrator, a 60-mesh film-coating pan was used for 120 minutes at a pump pressure of 3.0 bar and an air gun pressure of 2.5 bar. Opadry-OY-C-7000A (Colorcon) After coating with a coating base, drying was performed at 70° C. at a speed of 1 rpm for 10 minutes to prepare a sustained-release bi-layer tablet of the present invention containing 15 mg of Mosapride citrate active ingredient per tablet.

In order to improve patient compliance, the thickness of the sustained-release bi-layer tablet was limited to 5 mm, the hardness was set to 20.4 kg/cm 2 , and the total weight of the completed bi-layer tablet was 355 mg.

in vitro (In-vitro) dissolution test

The dissolution rate of the active ingredient of Mosapride citrate for the formulations of each of the Examples and Comparative Examples was measured over time under the dissolution test solution conditions of the Korean Pharmacopoeia, and the dissolution pattern was confirmed.

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

Sample: Mosapride citrate sustained-release bi-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

Elution amount: 900 ㎖, test temperature: 37 ± 0.5 ℃

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

Sampling: Take 10mL of the eluate at each sampling time, filter it with a 0.45㎛ filter, and use the sample solution.

Analysis equipment: UV 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 31.9 34.8 39.6 44.5 48.6 53.2 58.7 64.6 71.4 78.3 85.9 92.4 99.8 Example 2 30.5 33.7 38.5 42.7 46.5 51.7 56.4 62.1 68.5 76.2 83.2 89.6 95.6 Example 3 30.8 33.9 37.5 41.8 44.6 49.8 55.7 59.4 65.7 72.4 79.5 85.7 92.3 Example 4 31.2 34.2 36.7 39.5 42.6 47.3 52.1 56.4 62.1 68.4 74.5 79.4 85.6 Comparative Example 1 32.4 37.2 42.7 47.1 51.6 56.9 62.3 68.9 75.9 83.4 91.4 98.9 100.3 Comparative Example 2 31.5 38.9 44.6 50.7 57.4 64.3 71.2 77.8 84.6 91.5 98.9 99.8 100.5

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 30.5 33.5 38.5 43.5 47.5 52.4 58.4 64.5 71.9 78.4 86.1 93.4 100.2 Example 2 30.4 32.4 37.4 41.5 45.2 50.8 55.9 61.8 67.3 74.8 82.1 88.7 94.8 Example 3 31.2 34.8 36.5 41.5 43.8 49.5 54.5 58.7 64.9 71.2 78.2 84.6 91.8 Example 4 30.2 33.8 36.4 38.8 43.2 46.8 51.7 55.9 61.8 67.7 73.4 78.2 84.2 Comparative Example 1 31.7 36.5 41.8 46.9 50.8 55.7 61.8 67.8 74.2 82.4 91.3 99.5 100.2 Comparative Example 2 36.3 39.5 45.2 51.2 57.9 65.2 71.4 77.3 84.3 91.8 99.9 100.2 100.4

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 17.2 24.8 27.4 28.9 30.4 31.9 33.7 35.2 36.9 38.7 40.2 41.2 41.8 Example 2 16.8 23.2 26.4 28.1 29.4 30.7 32.4 34.5 35.8 37.2 39.4 40.8 40.5 Example 3 15.4 22.4 25.6 28.2 28.9 30.4 31.7 33.2 34.6 36.8 38.4 39.6 39.6 Example 4 14.8 22.1 24.9 27.9 28.4 29.4 30.4 32.4 33.9 35.4 37.2 38.4 38.9 Comparative Example 1 18.4 25.6 28.4 29.5 30.8 32.4 33.9 36.1 37.4 39.2 41.4 41.8 42.6 Comparative Example 2 18.9 26.4 29.2 31.2 32.4 34.2 35.4 37.2 38.2 40.6 42.1 42.2 42.9

Dissolution 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 31.2 34.2 39.7 44.8 49.1 53.7 59.6 65.1 71.4 78.9 86.7 94.2 99.5 Example 2 31.4 34.7 38.6 42.1 44.6 49.5 54.1 60.7 66.4 73.2 81.4 87.5 93.2 Example 3 32.1 33.4 36.4 40.8 42.7 48.4 53.1 57.4 63.2 70.8 77.4 83.2 89.6 Example 4 30.5 34.2 35.4 37.9 41.8 46.8 51.4 54.8 60.8 66.4 72.8 78.1 83.4 Comparative Example 1 32.1 36.4 41.5 46.2 51.9 56.7 61.8 68.4 74.5 81.7 90.7 98.4 99.9 Comparative Example 2 31.8 40.2 44.5 50.9 56.9 64.5 70.8 77.4 85.5 92.1 97.5 99.8 99.9

In the case of Examples 1 to 4, it can be seen that a constant dissolution rate is exhibited for a longer time than the conventional sustained-release tablet, and the long-term effect is maintained. On the other hand, in the case of Comparative Examples 1 and 2, it was found that the active ingredient was eluted too quickly and hardly eluted after 10 hours.

relative activity factor and significance

The present applicant is a significant criterion for predicting and determining whether the sustained-release double-layer tablet according to the present invention can exhibit a long-lasting effect by sequentially passing through the stomach and intestinal environment when orally administered to a patient, according to Equation 1 below A relative activity factor was derived.

[Equation 1]

In the case of a sustained-release double-layer tablet consisting of an immediate-release layer and a sustained-release layer, the active ingredient in the immediate-release layer that dissolves quickly after oral administration and the active ingredient in the sustained-release layer that dissolves slowly over a long period of time are simultaneously absorbed in the body and maintain a constant concentration. The relative ratio between the dissolution rate of the active ingredient and the dissolution rate of the active ingredient in the sustained-release layer for sustained effects is very important.

Regarding the active ingredient in the immediate release layer, if the active ingredient in the sustained-release layer is excessively eluted at the beginning, the blood concentration of the active ingredient rises rapidly and side effects such as vomiting and dizziness may occur. This is because the effect rapidly deteriorates from the point at which the effect of the active ingredient in the eluted immediate-release layer is stopped.

Therefore, the relative activity factor of the dissolution rate in the pH 1.2 environment where the active ingredient in 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 is continuously and slowly dissolved is the active ingredient simultaneously eluted in the immediate-release layer and the sustained-release layer. It is a very desirable index to verify the effect of the double-layer tablet in advance before oral administration by enabling the prediction of the dissolution pattern.

Accordingly, the present applicant calculated the relative activity of each Example and Comparative Example according to Equation 1, and showed them in Table 6 below.

Relative activity in pH 1.2 eluate relative to pH 6.8 division 15 minutes 3h 18h Example 1 1.85 1.67 2.24 Example 2 1.82 1.68 2.20 Example 3 2.00 1.64 2.16 Example 4 2.11 1.61 2.07 Comparative Example 1 1.76 1.76 2.37 Comparative Example 2 1.67 1.88 2.36

Review

In Examples 1 to 4, a release controlling agent in which two types of hydroxypropylmethylcellulose having different degrees of substitution were mixed was used, and due to the optimal content ratio, precise dissolution control was possible while dissolution lasted for a longer time, and the above table As shown in the dissolution rate of 2 to 5 and the graphs of FIGS. 1 to 4 showing this, even after 30 minutes when most of the active ingredients in the immediate release layer were dissolved, the effective drug dissolution rate continued uniformly until after 24 hours.

In addition, as shown in Table 6, when calculating the relative activity in the stomach and intestinal environment through the dissolution rate at pH 1.2 and pH 6.8, it was 1.80 to 2.15 after 15 minutes of dissolution, 1.60 to 1.70 after 3 hours, and 2.00 to 1.70 after 18 hours. In the case of 2.25, it can be seen that the optimal dissolution activity is shown as in Examples 1 to 3.

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, dissolution is excessively delayed or the duration is shortened, as shown in Comparative Examples of FIGS. 1 to 4 .

Claims (9)

A sustained-release bi-layer tablet for oral administration once a day containing mosapride citrate as an active ingredient,
An immediate release layer containing active ingredients, fillers, disintegrants and additives;
Including a sustained-release layer containing active ingredients, fillers, disintegrants, release control agents and additives,
The western layer is based on the total weight of the western layer,
5 to 7% by weight of the active ingredient, 25 to 35% by weight of the controlled-release agent, 10 to 20% by weight of lactose hydrate, 15 to 30% by weight of low-substituted hydroxypropyl cellulose, and 3% by weight of povidone K-30 to 10% by weight,
The release controlling agent,
Hydroxypropylmethylcellulose having a methoxyl group substitution degree of 18.0 to 26.0% and a hydroxypropoxyl group substitution degree of 2.0 to 14.0%
Hydroxypropylmethylcellulose having a degree of substitution of methoxyl group of 27.0 to 35.0% and a degree of substitution of hydroxypropoxyl group of 5.0 to 16.0% is mixed and used,
With respect to the total weight of the release-controlling agent,
65 to 80% by weight of hydroxypropylmethylcellulose having a degree of substitution of the methoxyl group of 18.0 to 26.0% and a degree of substitution of the hydroxypropoxyl group of 2.0 to 14.0%,
20 to 35% by weight of hydroxypropylmethylcellulose having a degree of substitution of the methoxyl group of 27.0 to 35.0% and a degree of substitution of the hydroxypropoxyl group of 5.0 to 16.0%,
The sustained-release double-layer tablet was tested for dissolution under buffer conditions of pH 1.2 and pH 6.8.
A sustained-release double-layer tablet characterized in that the relative activity according to Equation 1 below is 1.80 to 2.15 after 15 minutes of dissolution, 1.60 to 1.70 after 3 hours, and 2.00 to 2.25 after 18 hours.
[Equation 1]

According to claim 1,
The sustained-release bi-layer tablet, characterized in that the active ingredient of the fast-release layer is contained in 2 to 4% by weight based on the total weight of the fast-release layer.
delete delete According to claim 1,
Sustained-release bi-layer tablet, characterized in that the total weight of the sustained-release bi-layer tablet is 330 to 370mg.
According to claim 1,
Sustained-release bi-layer tablet, characterized in that the thickness of the sustained-release bi-layer tablet is 2 to 7mm.
In the manufacturing method of the sustained-release bi-layer tablet administered orally once a day according to claim 1,
Preparing sustained-release layer granules by compressing Mosapride citrate granules, a release controlling agent, a filler, a disintegrant, and additives;
Preparing granules for an immediate release layer by compressing Mosapride citrate granules, a filler, a disintegrant, a release controlling agent, and additives;
Preparing a single tablet by compressing the fast-release layer granules and the sustained-release layer granules with a force of 3.0 to 8.0 kgf per unit area of 1 cm2; Method for producing a sustained-release bi-layer tablet comprising the.
According to claim 7,
The sustained-release layer granules are a method for producing a sustained-release bi-layer tablet, characterized in that the particle size is 350 to 450㎛.
According to claim 7,
The method for producing a sustained-release bi-layer tablet, characterized in that the single tablet has a hardness of 7 to 30 kg / cm 2 .

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