KR102294186B1 - Once a day oral dosage sustained-release formulation comprising mosapride - Google Patents

Abstract

Orally administered sustained-release double-layer tablet containing Mosapride or a salt thereof of the present invention, in order to satisfy the rapid expression of pharmacological activity and the continuation of pharmacological activity for 24 hours at the same time, the immediate-release layer for rapid dissolution of the drug and the slow dissolution As a sustained-release double-layer tablet consisting of a sustained-release layer, in order to show an optimal dissolution pattern, several types of dissolution-controlling agents with different dissolution properties depending on the degree of substitution are used as release control agents, 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 provides a method for preparing an oral sustained-release double-layer tablet containing Mosapride designed to prevent side effects due to excessive release of the initial active ingredient while increasing the patient's medication compliance.

Description

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

The present invention relates to a sustained-release double-layer tablet containing Mosapride that exhibits an optimal dissolution profile by mixing two types of hydroxypropylmethylcellulose with different degrees of substitution to precisely control the dissolution profile, and a sustained-release double-layer tablet administered once a day and a manufacturing method thereof. it's about

Mosapride (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 Mosapride And physiologically acceptable salts thereof are selective serotonin 5-hydroxytryptamine 4 (hereinafter, referred to as '5-HT4') receptor agonists, which selectively select only the serotonin 5-HT4 receptor present in the intestinal muscle plexus. It promotes the release of acetylcholine from nerve endings, and this acetylcholine contracts the smooth muscle of the digestive tract and promotes digestive tract movement. It is a drug that shows excellent efficacy in the treatment of gastritis and gastroesphageal reflux disease. Mosapride does not have the risk of arrhythmia and sudden cardiac death due to QT interval prolongation, which was seen with cisapride, a non-selective 5-HT4 receptor agonist, and does not have dopamine-2 (D-2) receptor antagonism. It is a safe drug without side effects such as CNS) side effects (extrapyramidal symptoms) and hyperprolactinemia (milk secretion, feminised breast).

[Formula 1]

When administered orally, Mosapride has a digestive tract absorption rate of 93% or more, and is distributed in the liver, small intestine, stomach, kidney, and adrenal glands at a concentration 10 times higher than the plasma concentration. It is distributed at a high concentration in the spleen, etc., and is distributed as low as 1/2 of the blood concentration in the brain and eyes. When administered orally, Mosapride exhibits a rapid onset of drug effect with a time of 0.5 to 1.4 hours to reach peak plasma concentration.

Because Mosapride has a short half-life of 1.3 to 2 hours, the drug is quickly lost after absorption into the body, and the duration of the drug is short, so it has to be taken several times a day. Mosapride is currently being 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 a general sustained-release tablet, there is a disadvantage that it takes a long time to initially reach an effective blood concentration. In addition, if rapid pharmacological activity is expressed after oral administration, it is difficult to sustain 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 problem, and the present applicant analyzed the dissolution pattern for 24 hours of a conventional two-layered Mosapride tablet consisting of an immediate-release layer and a sustained-release layer to improve the shortcomings, and to improve the degree of substitution of the dissolution control mechanism. By paying attention to the dissolution characteristics of the present invention, an optimal dissolution profile was implemented for achieving an excellent effect compared to the prior art.

In addition, the present invention provides a sustained-release double-layer tablet containing Mosapride that simultaneously satisfies rapid expression of pharmacological activity and continuation of pharmacological activity for 24 hours, and a method for manufacturing the same, and uniform dissolution while suppressing initial excessive release that may cause side effects It is characterized by the appearance.

The present invention is a sustained-release double-layer tablet for oral administration once a day, containing Mosapride or a salt thereof as an active ingredient, an immediate-release layer comprising an active ingredient, a filler, a disintegrant and an additive, an active ingredient, a filler, and a disintegrant , a sustained-release layer comprising a release controlling agent and an additive, wherein the release controlling agent is 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% and a methoxyl group substitution degree 27.0 to 35.0%, hydroxypropylmethylcellulose having a hydroxypropoxyl group substitution degree of 5.0 to 16.0% is mixed and used,

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

When 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% with respect to the total weight of the release controlling agent is less than 20 wt%, the sustained-release effect is remarkably reduced, and 35 wt% If it exceeds, dissolution in the body is excessively delayed, so it is difficult to obtain sufficient pharmacological effect.

On the other hand, when hydroxypropylmethylcellulose having a methoxyl group substitution degree of 27.0 to 35.0% and a hydroxypropoxyl group substitution degree of 5.0 to 16.0% with respect to the total weight of the release controlling agent is less than 65% by weight, sufficient dissolution occurs in the initial stage after oral administration It does not lose, and when it exceeds 80% by weight, the dissolution pattern may change rapidly.

The sustained-release double-layer tablet of the present invention contains active ingredients in the immediate-release layer and the sustained-release layer, respectively. do.

If the content of the active ingredient in the immediate-release layer relative to the total weight of the immediate-release layer is less than 5% by weight, or the active ingredient in the sustained-release layer is less than 12% by weight relative to the total weight of the sustained-release layer, sufficient pharmacological effect does not appear, and the immediate-release layer is effective relative to the total weight of the immediate-release layer When the component content exceeds 10% by weight or when the active ingredient in the sustained-release layer exceeds 17% by weight relative to the total weight of the sustained-release layer, the concentration of the active ingredient in the blood is excessively high, which may cause various side effects.

In the dissolution test under the buffer solution conditions of pH 1.2 and pH 6.8, the oral sustained-release double-layer tablet according to the present invention showed a relative activity according to Equation 1 below: 1.84 to 1.9 after 15 minutes of dissolution, 1.74 to 1.98, 18 after 3 hours It is characterized in that it is 2.23 to 2.53 after hours.

[Equation 1]

The relative activity makes it possible to predict the dissolution pattern of the active ingredient that is simultaneously eluted in the immediate-release layer and the sustained-release layer. 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 double-layer tablet according to the present invention contains 12 to 17% by weight of mosapride citrate, 25 to 35% by weight of the release controlling agent, 10 to 20% by weight of lactose hydrate, based on the total weight of the total sustained-release layer, It is characterized in that it contains 1 to 4% 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 double-layer tablet according to the present invention exhibits an optimal dissolution pattern in the body. 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 oral sustained-release double-layer tablet containing Mosapride of the present invention has a total weight of 130 to 170 mg, which enables easy oral administration even for patients with bronchial disease. However, if the total weight is less than 130 mg, stability problems may occur during the tableting process And, if it exceeds 170mg, the patient's medication compliance may be different.

The oral sustained-release double-layer tablet containing Mosapride of the present invention may be prepared in various forms, but the thickness of the dosage form is preferably 2 to 5 mm. If the thickness is less than 2mm, the tablet may crack or collapse during tableting, resulting in a drop in yield and poor stability of the finished tablet, which may cause the formulation to break even with a small impact. Depending on the constitution, age, disease, etc., it may feel difficult.

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

preparing sustained-release granules by compressing the mosapride citrate granules, a release controlling agent, a filler, a disintegrant and an additive;

Mosapride citrate granules, a filler, a disintegrant, a release controlling agent and the step of pressing the additive to prepare an immediate-release layer granules;

Compressing the immediate-release granules and the sustained-release granules with a force of 2.0 to 5.0 kgf per unit area of 1 cm 2 to prepare a single tablet;

At this time, the sustained-release granules preferably have a particle diameter of 350 to 450 μm. When the particle diameter of the granules is less than 350 μm, the dissolution pattern of the active ingredient is uneven due to poor stability, and when it exceeds 450 μm, disintegration is delayed for 24 hours. The dissolution of the active ingredient is not performed sufficiently.

The compression force in the single tablet manufacturing step is preferably 2 to 5 kgf/cm2, more preferably 3 to 4.5 kgf/cm2, but if it is less than 2 kgf/cm2, the sustained-release matrix structure by the release controlling agent is easily collapsed, resulting in initial excessive dissolution. Due to this, the sustained-release effect is extremely reduced, and when it exceeds 5 kgf/cm 2 , dissolution is excessively delayed, making it difficult to maintain a continuous concentration of the active ingredient.

The Mosapride sustained-release double-layer tablet according to the present invention preferably has a hardness of 10 to 25 kg/cm 2 , more preferably 13 to 23 kg/cm 2 .

If the hardness is less than 10kgf/cm2, the sustained-release layer partially disintegrates at the beginning and the drug is eluted, which may cause excessive dissolution and deterioration of the sustained performance of the drug. appear slowly.

The sustained-release double-layer tablet of the present invention is characterized in that it uses a release control agent obtained by mixing two types of hydroxypropylmethyl cellulose having different substitution degree characteristics in a specific mixing ratio, so that it has excellent sustained-release properties and uniform dissolution pattern.

In addition, the present invention provides a sustained-release double-layer tablet containing Mosapride that simultaneously satisfies rapid expression of pharmacological activity and continuation of pharmacological activity for 24 hours, and a method for manufacturing the same. It is characterized in that it shows a uniform dissolution pattern while suppressing excessive release.

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

The manufacturing sequence of the sustained-release double-layer tablet of mosapride citrate having a double-layered structure according to the present invention is as follows.

The sustained-release layer and the immediate-release layer containing mosapride citrate are each prepared into granules through mixing, kneading and granulation processes. Then, a sustained-release double-layer tablet is prepared by first preparing a tablet in any one of the sustained-release layer and the immediate-release layer made of granules, and then filling the granules of the other layer on the tablet and tableting.

In addition, unlike the above method, the sustained-release 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 tabletting the tablet.

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

Method for producing sustained-release granules

5 to 7% by weight of mosapride citrate, 10 to 15% by weight of lactose, an appropriate amount of microcrystalline cellulose as a pharmacologically active ingredient relative to the total weight of the sustained-release layer, 18.0 to 26.0% of methoxyl group substitution, hydroxypropoxyl group substitution degree 25 to 35 wt% of a mixed release controlling agent comprising hydroxypropylmethylcellulose of 2.0 to 14.0% and hydroxypropylmethylcellulose having a degree of substitution of a methoxyl group of 27.0 to 35.0% and a degree of substitution of a hydroxypropoxyl group of 5.0 to 16.0%, 1 to 4 wt% of low-substituted hydroxypropyl cellulose is mixed as a disintegrant. Here, 3 to 10 wt% of povidone K-30 dissolved in an appropriate amount of ethanol is added as a binding solution, kneaded and granulated, and then dried and granulated at a temperature of 60°C in a fluidized bed dryer to a loss on drying (LOD) of 4% or less. After that, an appropriate amount of lubricant is mixed to prepare sustained-release granules.

In this case, the mixed release controlling agent contains 20 to 35 wt% of 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%, based on the total weight of the mixed release controlling agent, methoxy It contains 65 to 80% by weight of hydroxypropylmethylcellulose having a degree of substitution of 27.0 to 35.0% of an actual group, and a degree of substitution of a hydroxypropoxyl group of 5.0 to 16.0%.

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

Manufacturing method of immediate-release granules

2 to 4% by weight of mosapride citrate based on the total weight of the immediate-release layer was mixed 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, and then dissolved in an appropriate amount of ethanol in advance. 5 to 10% by weight of povidone K-30 was added as a binding solution, kneaded and granulated, and dried and granulated at a temperature of 60° C. in a fluidized bed dryer to an LOD of 4% or less. After that, an appropriate amount of lubricant is mixed to prepare granules for the immediate-release layer.

Manufacturing method of sustained-release double-layer tablet

The sustained-release granules and immediate-release granules prepared above are compressed using a rotary tablet press at a speed of 33 rpm while applying a pressure of preferably 2 to 5 kgf/cm 2 , more preferably 3 to 4.5 kgf/cm 2 .

The sustained-release double-layer tablet according to the present invention may be manufactured in the order of first tableting the sustained-release layer granules into tablets, then filling the immediate-release layer granules thereon to perform secondary tableting. The tableting of the immediate-release layer does not have to be performed, and the tableting of the immediate-release layer is preferentially performed, and it is also possible to fill the granules of the sustained-release layer to tabletting. In addition, it is also possible to perform single tableting by filling the immediate-release layer and the sustained-release layer, respectively, sequentially or in reverse order.

The total weight of the completed sustained-release double-layer tablet is 130 to 170 mg, and in order to improve patient compliance, the thickness of the tablet is preferably 2 to 5 mm, more preferably 3 to 4 mm.

In addition, the hardness of the sustained-release double-layer tablet according to the present invention is preferably 10 to 25 kg/cm 2 , more preferably 13 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 content of Table 1 below, the sustained-release double-layer tablets of Examples 1 to 4 and Comparative Examples 1 to 2 containing mosapride citrate were prepared.

Mosapride double-layer tablet composition (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 20.52 20.52 20.52 20.52 20.52 20.52 excipient lactose hydrate 11.00 11.00 11.00 11.00 11.00 11.00 dissolution
modifier 29% of methoxyl group substitution,
Hydroxypropylmethylcellulose having a degree of hydroxypropyl group substitution of 6% 16.25 17.50 18.75 20.00 12.50 7.50 dissolution
modifier Methoxyl group substitution degree 22%,
Hydroxypropylmethylcellulose having a hydroxypropyl group substitution degree of 8% 8.75 7.50 6.25 5.00 12.50 17.50 binder Povidone K-30 5.00 5.00 5.00 5.00 5.00 5.00 disintegrant Low-substituted propyl cellulose 2.00 2.00 2.00 2.00 2.00 2.00 lubricant Light anhydrous silicic acid 0.30 0.30 0.30 0.30 0.30 0.30 lubricant magnesium stearate 0.60 0.60 0.60 0.60 0.60 0.60 Subtotal (mg/tablet) 75mg inside
room
floor chief ingredient Mosapride Citrate
luggage 5.29 5.29 5.29 5.29 5.29 5.29 excipient Microcrystalline Cellulose 21.00 21.00 21.00 21.00 21.00 21.00 excipient lactose hydrate 18.81 18.81 18.81 18.81 18.81 18.81 disintegrant Low-substituted propyl cellulose 24.00 24.00 24.00 24.00 24.00 24.00 binder Povidone K-30 5.00 5.00 5.00 5.00 5.00 5.00 lubricant Light anhydrous silicic acid 0.30 0.30 0.30 0.30 0.30 0.30 lubricant magnesium stearate 0.60 0.60 0.60 0.60 0.60 0.60 Subtotal (mg/tablet) 75mg coating agent Opadry 0Y-C-7000A 5mg Total (mg/tablet) 155mg

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

A binding solution was prepared by slowly adding povidone K-30 to an ethanol solvent and stirring at an air pressure of 3 kg/cm 2 for 30 minutes.

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 prepared.

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

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

Western tier Preparation of granules

A binding solution was prepared by slowly adding povidone K-30 to an ethanol solvent and stirring at an air pressure of 3 kg/cm 2 for 30 minutes.

Mosapride citrate and microcrystalline cellulose, lactose hydrate, hydroxypropyl methylcellulose with methoxyl group substitution of 22%, hydroxypropyl group substitution degree of 8%, methoxyl group substitution degree of 29%, hydroxypropyl group substitution degree of 6% After mixing hydroxypropylmethyl cellulose and low-substituted hydroxypropyl cellulose (L-HPC) in a speed mixer for 3 minutes, the binder solution prepared above is added thereto, mixing 3 times for 3 minutes each, and kneading. liquid was prepared.

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

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

Production of sustained-release double-layered tablets

The sustained-release granules and immediate-release granules prepared in the above step were compressed at a speed of 33 rpm while applying a pressure of 4.5 kgf/cm 2 using a rotary tablet press.

First, the sustained-release granules were first compressed into tablets, and the immediate-release granules were filled thereon, followed by secondary tableting to prepare a double-layer tablet.

After the two-layer tablet was demineralized using a tablet demineralization method, 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 at 70° C. at a speed of 1 rpm for 10 minutes to prepare a sustained-release double-layer tablet of the present invention containing 15 mg of mosapride citrate active ingredient per tablet.

To increase patient compliance, the thickness of the sustained-release bilayer tablet was limited to 4 mm, the hardness was 16.2 kg/cm 2 , and the total weight of the completed bilayer tablet was 155 mg.

in vitro (In-vitro) dissolution test

The dissolution pattern was confirmed by measuring the dissolution rate of the active ingredient mosapride citrate for the formulations of each of the Examples and Comparative Examples over time in the conditions of the dissolution test solution of the Korean Pharmacopoeia.

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

Sample: Mosapride citrate 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

Eluate 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 every sampling time, filter it through a 0.45㎛ filter, and use it as the sample solution. After taking the eluate, adjust the same amount of the new eluate.

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

Test result

The in-vitro dissolution test results 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 31.2 34.8 38.9 42.1 45.8 50.7 55.2 60.4 66.4 72.8 78.2 83.6 88.9 Example 2 30.8 35.2 39.7 43.2 47.6 52.9 57.6 63.8 69.8 75.9 80.7 85.4 91.6 Example 3 31.4 35.4 40.2 44.6 49.2 54.1 59.7 65.8 72.5 78.5 84.2 89.6 95.4 Example 4 30.2 37.2 42.6 47.5 52.4 57.9 63.4 69.4 76.5 82.9 88.7 94.8 100.2 Comparative Example 1 28.4 35.7 38.5 41.7 44.2 48.6 53.4 58.2 63.4 69.4 75.2 80.4 85.7 Comparative Example 2 31.5 34.2 37.4 40.8 42.8 46.4 51.2 55.7 61.7 66.5 72.8 77.4 83.4

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 30.8 33.5 38.2 41.9 44.8 49.9 54.8 60.5 66.7 72.1 77.6 83.2 89.7 Example 2 31.1 34.8 38.9 44.2 47.9 52.8 57.8 63.8 69.8 75.8 81.6 86.7 92.8 Example 3 32 35.4 39.8 45.8 50.4 55.7 60.8 66.7 73.4 79.8 85.4 90.8 96.4 Example 4 31.4 36.7 41.8 46.8 51.8 57.1 62.9 68.8 75.4 82.4 88.1 93.8 99.9 Comparative Example 1 31.5 33.7 37.8 41.1 43.5 47.8 52.9 57.8 62.9 68.7 74.8 79.8 85.4 Comparative Example 2 30.4 32.9 36.8 39.7 41.5 45.8 50.9 55.1 60.9 65.8 72.1 76.8 82.9

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 16.4 23.2 25.4 26.2 27.5 29.2 31.2 32.5 33.4 34.8 35.8 37.5 38.5 Example 2 15.8 22.1 24.8 26.4 28.2 29.8 32.1 33.5 34.2 35.8 36.7 38.8 39.8 Example 3 16.1 22.4 25.1 27.5 29.1 30.9 33.2 34.6 35.4 36.9 37.9 39.2 40.5 Example 4 16.5 23.4 26.8 28.9 30.4 32.4 34.8 36.2 37.2 38.2 39.6 40.8 41.2 Comparative Example 1 15.7 21.8 23.5 25.1 26.4 27.8 30.1 31.2 32.1 33.8 34.5 36.2 37.8 Comparative Example 2 15.4 21.5 22.8 24.4 25.9 27.1 28.9 30.1 31.5 32.5 33.8 35.8 36.9

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 31.4 33.7 37.8 41.5 45.9 49.2 54.9 60.1 65.8 71.9 77.2 83.2 90.1 Example 2 30.9 34.5 39.8 44.9 47.5 52.4 57.9 62.8 69.2 74.9 80.9 85.9 92.4 Example 3 31.8 34.8 40.1 45.7 50.2 54.9 59.8 65.2 72.7 79.1 84.8 89.9 95.8 Example 4 31.2 35.9 40.9 46.1 51.2 56.9 62.2 67.9 74.6 81.8 87.5 94.8 100.3 Comparative Example 1 30.4 33.9 36.5 39.8 42.9 47.2 51.9 56.8 63.1 68.9 74.5 80.4 86.4 Comparative Example 2 31.4 34.5 37.5 39.2 42.5 45.8 49.5 54.9 59.8 65.7 71.8 76.8 82.9

In the case of Examples 1 to 4, it continuously shows a constant dissolution rate with the lapse of time, and thus it can be predicted that the effect will be sustained for a long time.

In particular, in the case of Example 4, all the active ingredients were eluted while showing a constant dissolution pattern for 24 hours, indicating the most suitable formulation.

On the other hand, in the case of Comparative Examples 1 and 2, it can be seen that the active ingredient is not sufficiently eluted even after a considerable amount of time has elapsed, or the active ingredient is eluted too quickly.

relative activity factor and significance

Applicants of the present invention, as a meaningful criterion for predicting and determining whether the sustained-release double-layer tablet according to the present invention can be orally administered to a patient, can exhibit a long-lasting effect through the stomach and intestine environment sequentially, according to the following Equation 1 Relative activity factors were 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, which dissolves quickly after oral administration, and the active ingredient in the sustained-release layer, which dissolves slowly for a long period of time after oral administration, are simultaneously absorbed in the body and maintain a constant concentration. The relative ratio of the dissolution rate of the active ingredient of the sustained-release layer and the dissolution rate of the active ingredient in the sustained-release layer is very important.

If the active ingredient in the sustained-release layer is excessively eluted in the early stage for the active ingredient in the immediate-release layer, which is immediately released, the blood concentration of the active ingredient rises rapidly and side effects such as vomiting and dizziness may occur. This is because the effect of the active ingredient in the immediate-release layer is rapidly reduced from the point when the effect of the eluted active ingredient is stopped.

Therefore, the relative activity factors of the dissolution rate in the pH 1.2 environment where the active ingredient in the immediate-release layer of the double-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 elutes are the active ingredients that are simultaneously eluted in the immediate-release layer and the sustained-release layer. It is a very desirable indicator that can predict the dissolution pattern of the bilayer 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.

division 15 minutes 3h 18h Example 1 1.90 1.74 2.23 Example 2 1.88 1.81 2.28 Example 3 1.91 1.85 2.39 Example 4 1.84 1.98 2.53 Comparative Example 1 1.81 1.66 2.14 Comparative Example 2 1.92 1.59 2.06

Review

In Examples 1 to 4, a release controlling agent mixed with two types of hydroxypropylmethyl cellulose having different degrees of substitution was used, and the dissolution was maintained for 24 hours due to the optimal content ratio, and the dissolution was precisely controlled while suppressing the initial excessive dissolution. This was made 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 preferable for 24 hours even after 30 minutes of dissolution of most of the immediate-release layer active ingredients.

In addition, as shown in Table 6, when the relative activity in the stomach and intestinal environment is calculated through the dissolution rates at pH 1.2 and pH 6.8, 1.84 to 1.9 after 15 minutes of dissolution, 1.74 to 1.98 after 3 hours, and 2.23 to after 18 hours When it is shown as 2.53, it can be seen that the optimal dissolution activity is exhibited as in Examples 1 to 3.

In the case of the sustained-release double-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 double-layer tablet containing Mosapride or a salt thereof as an active ingredient, administered orally once a day,
An immediate-release layer comprising an active ingredient, a filler, a disintegrant and an additive;
Including a sustained-release layer comprising an active ingredient, a filler, a disintegrant, a release controlling agent and an additive,
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%,
A mixture of hydroxypropylmethylcellulose having a methoxyl group substitution degree of 27.0 to 35.0% and a hydroxypropoxyl group substitution degree of 5.0 to 16.0% is used,
With respect to the total weight of the release controlling agent,
20 to 35% by weight 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%,
65 to 80% by weight of hydroxypropylmethylcellulose having a methoxyl group substitution degree of 27.0 to 35.0% and a hydroxypropoxyl group substitution degree of 5.0 to 16.0%,
The sustained-release layer is based on the total weight of the entire sustained-release layer,
12 to 17% by weight of mosapride citrate, 25 to 35% by weight of the release controlling agent, 10 to 20% by weight of lactose hydrate, 1 to 4% by weight of low-substituted hydroxypropyl cellulose, and 3 to 10% by weight of povidone K-30 % by weight,
During the dissolution test under the buffer solution conditions of pH 1.2 and pH 6.8,
A two-layer tablet, characterized in that the relative activity according to the following formula (1) is 1.84 to 1.9 after 15 minutes of dissolution, 1.74 to 1.98 after 3 hours, and 2.23 to 2.53 after 18 hours.
[Equation 1]

The method of claim 1,
The active ingredient of the immediate-release layer is 5 to 10% by weight based on the total weight of the immediate-release layer, and the active ingredient of the sustained-release layer is 12 to 17% by weight based on the total weight of the sustained-release layer.
delete delete According to claim 1,
A double-layer tablet, characterized in that the total weight of the bi-layer tablet is 130 to 170 mg.
According to claim 1,
A double-layer tablet, characterized in that the thickness of the bi-layer tablet is 2 to 5 mm.
In the method for manufacturing the double-layer tablet according to claim 1,
preparing sustained-release granules by compressing the mosapride citrate granules, a release controlling agent, a filler, a disintegrant and an additive;
Mosapride citrate granules, a filler, a disintegrant, a release controlling agent and the step of pressing the additive to prepare an immediate-release layer granules;
manufacturing a single tablet by compressing the immediate-release granules and the sustained-release granules with a force of 2.0 to 5.0 kgf per unit area of 1 cm 2 .
8. The method of claim 7,
The method for producing a double-layer tablet, characterized in that the granules in the immediate-release layer have a particle diameter of 350 to 450 μm.
8. The method of claim 7,
The single tablet is a method of manufacturing a double-layer tablet, characterized in that the hardness of 10 to 25 kg / ㎠.

Images