KR102467265B1 - Sustained-release formulation comprising mosapride having a broad molecular weight distribution - Google Patents

Abstract

The sustained-release bi-layer tablet containing Mosapride citric acid according to the present invention has very excellent dissolution control properties, and the dissolution is maintained constant and stable for a long time from the beginning of oral administration, so that it is easy to vomit or vomit due to a rapid increase in the concentration of the active ingredient in the blood after administration. It is suitable for sensitive patients who feel dizzy.

Description

Mosapride-containing sustained-release preparation with controlled molecular weight distribution {SUSTAINED-RELEASE FORMULATION COMPRISING MOSAPRIDE HAVING A BROAD MOLECULAR WEIGHT DISTRIBUTION}

The present invention relates to a once-a-day oral sustained-release bi-layer tablet containing Mosapride whose bioavailability is improved by controlling the molecular weight distribution of a controlled release agent and a method for preparing the same.

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 improved the disadvantages by analyzing the dissolution pattern of the conventional two-layer Mosapride tablet consisting of an immediate-release layer and a sustained-release layer for 24 hours, and dissolution control by controlling the properties in a novel method. Provided is a sustained-release bi-layer tablet of Mosapride showing excellent effects using a base and a manufacturing method thereof.

The present invention is a sustained-release or controlled-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, and fillers. , A disintegrant, a release-modifying agent, and a sustained-release layer containing additives, wherein the release-modifying agent is hydroxypropylmethylcellulose having a viscosity of 11,250 to 21,000 mPa.s, and hydroxypropylmethylcellulose having a viscosity of 3,000 to 5,600 mPa.s. Cellulose and hydroxypropylmethylcellulose having a viscosity of 75,000 to 140,000 mPa.s are mixed and used, and 60 to 80% by weight of hydroxypropylmethylcellulose having a viscosity of 11,250 to 21,000 mPa.s with respect to the total weight of the release controlling agent Mosapride characterized by containing 10 to 20% by weight of hydroxypropylmethylcellulose having a viscosity of 3,000 to 5,600 mPa.s and 10 to 20% by weight of hydroxypropylmethylcellulose having a viscosity of 75,000 to 140,000 mPa.s. Provided is a sustained-release bi-layer tablet for oral administration containing

When the amount of hydroxypropylmethylcellulose having a viscosity of 11,250 to 21,000 mPa.s is less than 60% by weight, the uniform dissolution control effect of the active ingredient is reduced, and when it exceeds 80% by weight, the sustained release property is deteriorated.

Hydroxypropylmethylcellulose having a viscosity of 3,000 to 5,600 mPa.s and hydroxypropylmethylcellulose having a viscosity of 75,000 to 140,000 mPa.s increase the molecular weight distribution of the release-controlling agent to control dissolution characteristics.

When less than 10% by weight of hydroxypropylmethylcellulose having a viscosity of 3,000 to 5,600 mPa.s or a viscosity of 75,000 to 140,000 mPa.s is included, the molecular weight distribution value is not sufficiently increased, and the dissolution delay effect is deteriorated. On the other hand, if the viscosity of 3,000 to 5,600 mPa.s hydroxypropylmethylcellulose exceeds 20% by weight, there is a concern that the initial dissolution rate will be too high, and the degree of hydroxypropylmethylcellulose with a degree of 75,000 to 140,000mPa.s exceeds 20% by weight In this case, sufficient elution may not be achieved, and the pharmacological effect may be reduced.

The controlled-release agent according to the present invention preferably has a molecular weight distribution of 2.6 to 3.2, more preferably 2.7 to 3.0. If it is less than 2.6, the sustained-release improvement effect of the controlled-release agent according to the present invention does not appear, and if it exceeds 3.2, the dissolution rate of the active ingredient per hour is not sufficient, so the pharmacological effect is reduced.

The sustained-release bi-layer tablet according to the present invention contains an active ingredient in the immediate-release layer or the sustained-release layer, respectively. The active ingredient in the immediate-release layer is 3 to 5% by weight based on the total weight of the immediate-release layer. It is characterized in that it is included in 6 to 10% by weight based on the total weight of.

If the active ingredient of the immediate-release layer is less than 3% by weight or the active ingredient of the sustained-release layer is less than 6% by weight, sufficient therapeutic effect cannot be obtained, and if the active ingredient of the immediate-release layer exceeds 5% by weight or the active ingredient of the sustained-release layer exceeds 10% by weight, blood concentration Too much can cause side effects.

In the dissolution test of the sustained-release bilayer tablet for oral administration containing Mosapride according to the present invention, under buffer conditions of pH 1.2 and pH 6.8,

It is characterized in that the relative activity according to Equation 1 below is 1.83 to 2.05 after 15 minutes of dissolution, 1.70 to 1.80 after 3 hours, and 2.35 to 2.45 after 18 hours.

[Equation 1]

The relative activity makes it possible to predict the dissolution pattern of the active ingredient simultaneously eluted from the immediate-release layer and the sustained-release layer, and is a very desirable index that can verify the effect of the two-layer tablet in advance before oral administration, and the relative activity is outside the above range. If designed to do so, dissolution will be excessively delayed or the dissolution duration will be shortened.

The composition of the sustained-release layer of the sustained-release bi-layer tablet according to the present invention is based on the total weight of the sustained-release layer, Mosapride citrate. 6 to 10% by weight, release controlling agent 25 to 35% by weight, 10 to 20% by weight of lactose hydrate, 5 to 10% by weight of low-substituted hydroxypropyl cellulose, and 5 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 230 to 270 mg. If the total weight is less than 230 mg, stability problems may occur during the tableting process, and if the total weight exceeds 270 mg, the size of the dosage form As the size increases, medication compliance may decrease.

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 2.0 to 7.0 kgf per unit area of 1 cm2.

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

The compressive force in the single tablet manufacturing step is preferably 2 to 7 kgf/cm 2 , more preferably 3 to 5 kgf/cm 2 , but if it is less than 2 kgf/cm 2 , the sustained-release matrix structure by the release-modifying agent is easily collapsed due to excessive dissolution at the initial stage. The sustained-release effect is extremely reduced, and when the concentration exceeds 7 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 8 to 27 kg/cm 2 , more preferably 13 to 20 kg/cm 2 .

If the hardness is less than 8kgf/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. appear slower.

The sustained-release bi-layer tablet containing Mosapride citric acid according to the present invention has very excellent dissolution control properties, and the dissolution is maintained constant and stable for a long time from the beginning of oral administration, so that it is easy to vomit or vomit due to a rapid increase in the concentration of the active ingredient in the blood after administration. It is suitable for sensitive patients who feel dizzy.

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.

Commercially available hydroxypropylmethylcellulose, which is mainly used as a release control agent in sustained-release preparations, has different viscosity characteristics depending on its type.

Among them, when hydroxypropylmethylcellulose having a viscosity of 11,250 to 21,000 mPa.s is used as a release-modifying agent, it has the advantage of maintaining a uniform and stable amount of elution over time in the body after administration of the formulation.

However, when hydroxypropylmethylcellulose having a viscosity of 11,250 to 21,000 mPa.s is used alone as a release controlling agent, the duration does not exceed 12 hours, so it is not suitable for use in the preparation of sustained-release preparations administered once a day Inappropriate.

After repeated research, the present applicant added one or two or more hydroxypropylmethylcelluloses of a specific viscosity having different viscosities to hydroxypropylmethylcellulose having a viscosity of 11,250 to 21,000 mPa.s in a constant ratio to determine the molecular weight of the release controlling agent By changing the distribution value, a method of increasing the dissolution duration while maintaining the uniform and stable dissolution control characteristics of hydroxypropylmethylcellulose having a viscosity of 11,250 to 21,000 mPa.s was derived.

The oral sustained-release bi-layer tablet containing Mosapride according to the present invention contains hydroxypropylmethylcellulose having a viscosity of 3,000 to 5,600 mPa.s and hydroxypropylmethylcellulose having a viscosity of 75,000 Hydroxypropylmethylcellulose with a viscosity of 11,250 to 21,000 mPa.s is used as a release control agent by adding hydroxypropylmethylcellulose with a viscosity of 11,250 to 21,000 mPa.s at a constant rate, while maintaining the release control properties of hydroxypropylmethylcellulose with a viscosity of 11,250 to 21,000 mPa.s. Unlike, it was confirmed that the dissolution of the active ingredient continued for more than 18 hours, more preferably more than 24 hours.

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 6 to 10% by weight, lactose 10 to 20% by weight, microcrystalline cellulose in an appropriate amount, hydroxypropylmethylcellulose having a viscosity of 11,250 to 21,000 mPa.s, viscosity as pharmacologically active ingredients relative to the total weight of the sustained-release layer Low-substituted hydroxypropyl cellulose as a disintegrant, 25 to 35% by weight of a controlled-release agent mixed with hydroxypropylmethylcellulose having a viscosity of 75,000 to 140,000 mPa.s and hydroxypropylmethylcellulose having a viscosity of 3,000 to 5,600 mPa.s 5 to 10% by weight of is mixed. Here, 5 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 release-controlling agent in which three types of hydroxypropylmethylcellulose having different viscosities are mixed is 60 to 80% by weight of hydroxypropylmethylcellulose having a viscosity of 11,250 to 21,000 mPa.s relative to the total weight of the release-controlling agent %, 10 to 20% by weight of hydroxypropylmethylcellulose having a viscosity of 75,000 to 140,000 mPa.s and 10 to 20% by weight of hydroxypropylmethylcellulose having a viscosity of 3,000 to 5,600 mPa.s are used. do.

On the other hand, the grain size of the sustained-release layer prepared through the above process is 350 to 450㎛.

Manufacturing method of immediate-release layer granules

After mixing 3 to 5% by weight of Mosapride citrate relative to the total weight of the fast-release layer with 20 to 30% by weight of lactose, an appropriate amount of microcrystalline cellulose, and 30 to 40% by weight of low-substituted hydroxypropyl cellulose, the mixture was dissolved in an appropriate amount of ethanol in advance. 5 to 10% by weight of povidone is added as a binding solution to kneading and granulating, and drying and sizing 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 using a rotary tablet press at a speed of 30 to 40 rpm while applying a pressure of preferably 2 to 7 kgf/cm 2 , more preferably 3 to 5 kgf/cm 2 .

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 230 to 270 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 8 to 27 kg/cm 2 , more preferably 13 to 20 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 Example 1

According to the component contents shown in Table 1 below, the sustained-release bi-layer tablets of Examples 1 to 4 and Comparative Example 1 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 west
room
floor chief ingredient Mosapride citrate
luggage 10.58 10.58 10.58 10.58 10.58 excipient microcrystalline cellulose 33.00 33.00 33.00 33.00 33.00 excipient lactose hydrate 20.72 20.72 20.72 20.72 20.72 controlled release agent Hypromellose 2910
(HPMC 4000 mPa.s) 8.00 4.00 8.00 4.00 0.00 controlled release agent Hypromellose 2208
(HPMC 100000 mPa.s) 8.00 8.00 4.00 4.00 0.00 controlled release agent Hypromellose 2208
(HPMC 15000 mPa.s) 24.00 28.00 28.00 32.00 40.00 binder Povidone K-30 9.00 9.00 9.00 9.00 9.00 disintegrant Low-substituted propyl cellulose 10.00 10.00 10.00 10.00 10.00 glidant light anhydrous silicic acid 0.60 0.60 0.60 0.60 0.60 glidant Magnesium Stearate 1.10 1.10 1.10 1.10 1.10 Subtotal (mg/tablet) 125mg inside
room
floor chief ingredient Mosapride citrate
luggage 5.29 5.29 5.29 5.29 5.29 excipient microcrystalline cellulose 36.00 36.00 36.00 36.00 36.00 excipient lactose hydrate 32.51 32.51 32.51 32.51 32.51 disintegrant Low-substituted propyl cellulose 41.00 41.00 41.00 41.00 41.00 binder Povidone K-30 8.50 8.50 8.50 8.50 8.50 glidant light anhydrous silicic acid 0.60 0.60 0.60 0.60 0.60 glidant Magnesium Stearate 1.10 1.10 1.10 1.10 1.10 Subtotal (mg/tablet) 125mg coating agent Opadry 0Y-C-7000A 5mg Total (mg/tablet) 255mg

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

Preparation of immediate-release layer 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.

After mixing Mosapride citrate, microcrystalline cellulose, lactose hydrate, and low-substituted hydroxypropyl cellulose in a speed mixer for 3 minutes, mixing and kneading 3 times for 3 minutes each time while adding the binder solution prepared above, Consortium was prepared.

The mixed mixture was put into a rotary granulator and granulated into 1.2 nets to form granules.

The formed granules were dried at a temperature of 60 ° C in a fluidized bed dryer (LOD 2% or less), and the dried granules were sized in a power mill with a 1.2 net for 20 minutes, and then apples were added through a 40 mesh stencil and a lubricant was added, Sok-release layer granules were prepared by mixing for 20 minutes at a speed of 24 rpm in a drum mixer.

Preparation of sustained-release layer 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, hydroxypropylmethylcellulose (HPMC 2208) with a viscosity of 100,000 mPa.s, hydroxypropylmethylcellulose (HPMC 2208) with a viscosity of 15,000 mPa.s, and a viscosity of 4,000 mPa. After mixing s-hydroxypropylmethylcellulose (HPMC 2910) and low-substituted hydroxypropylcellulose (L-HPC, 1/2) for 3 minutes in a speed mixer, while adding the binder solution prepared above, The mixture was prepared by mixing three times for 3 minutes each time.

The mixed mixture was put into a rotary granulator and granulated into 1.2 nets to form granules.

The formed granules were dried at a temperature of 60 ° C in a fluidized bed dryer (LOD 2% or less), sized for 20 minutes with a 1.2 mesh, and then appled with hydroxypropyl cellulose (L-HPC, 1/2) and a 40 mesh stencil. A lubricant was added and mixed for 20 minutes at a speed of 24 rpm in a drum mixer to prepare sustained-release layer granules.

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 4 kgf/cm 2 using a double tablet 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 average hardness was 16.8 kg/cm 2 , and the average weight of the completed bi-layer tablet was 255 mg.

Measurement of molecular weight distribution of release-modifying agent

On the other hand, the controlled-release agent according to the present invention is one in which the molecular weight distribution value is changed by adding two types of hydroxypropylmethylcellulose having different viscosities in a certain ratio to hydroxypropylmethylcellulose having a viscosity of 11,250 to 21,000 mPa.s. Molecular weight distributions of the mixed release-controlling agents used in Examples and Comparative Examples were calculated through GPC (Gel Permeation Chromatography) separation method and are shown in Table 2 below.

Example 1 Example 2 Example 3 Example 4 Comparative Example 1 molecular weight distribution 3.2 3.0 2.7 2.6 2.1

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 in-vitro dissolution test results are shown in Tables 3 to 6 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 31.4 34.2 40.2 45.4 49.6 54.2 59.5 65.4 72.6 79.2 86.9 94.2 100.2 Example 2 30.4 34.2 38.6 42.8 46.2 50.7 55.7 62.4 68.7 75.8 82.9 89.4 96.8 Example 3 31.5 36.4 42.5 48.2 52.7 57.8 63.5 70.8 77.4 84.8 92.6 99.8 100 Example 4 31.4 35.6 41.6 46.2 50.5 55.4 60.8 67.5 74.2 82.6 89.4 97.2 100.1 Comparative Example 1 32.8 41.2 48.9 55.7 62.5 68.9 75.4 82.1 88.7 95.4 99.8 100.1 100.2

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 31.5 34.5 39.2 44.4 48.5 53.1 58.6 64.5 71.2 78.4 85.8 93.1 100.1 Example 2 30.8 33.9 37.5 41.8 44.6 49.8 55.7 61.2 67.2 74.3 81.2 88.4 95.8 Example 3 31.8 36.8 41.5 47.1 51.6 56.9 62.3 68.9 75.9 83.4 91.4 98.9 100.3 Example 4 31.2 35.2 40.6 45.2 49.6 54.8 59.8 66.7 73.4 81.4 88.6 96.2 100.2 Comparative Example 1 32.4 40.7 47.6 54.7 61.2 67.8 74.2 80.6 87.4 94.8 99.6 100.1 100.3

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 15.4 22.4 25.6 27.8 29.2 30.9 32.1 33.6 35.1 36.8 38.4 39.6 40.5 Example 2 14.8 22.1 24.9 26.9 28.1 29.4 30.6 31.9 33.4 34.9 36.5 37.8 38.9 Example 3 17.2 24.8 27.6 29.5 30.8 32.4 34.1 35.8 37.2 38.7 40.2 41.2 42.1 Example 4 16.8 23.6 26.8 28.4 30.1 31.8 33.2 34.9 36.1 37.8 39.4 40.8 41.2 Comparative Example 1 18.4 25.6 29.3 31.2 32.9 34.9 36.5 38.2 39.5 40.9 42.2 43.2 43.9

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 34.3 38.9 44.1 48.2 52.8 58.4 64.3 70.9 78.2 85.6 92.9 99.9 Example 2 30.6 33.5 37.2 41.5 45.2 49.5 54.8 60.2 66.8 73.2 80.3 88.2 94.8 Example 3 31.5 36.2 41.2 46.8 51.4 56.5 62.1 68.7 75.7 83.1 91.2 98.7 100.1 Example 4 31.3 34.9 40.4 44.9 49.5 54.5 60.1 66.4 73.2 81.2 88.4 96.1 100.1 Comparative Example 1 31.5 39.8 46.5 53.5 60.8 66.7 73.2 79.5 86.4 93.4 98.2 99.5 100.2

The dissolution profile shown in the table above is shown in the graphs of FIGS. 1 to 4. In the case of Examples 1 to 4, the dissolution is maintained constantly for 24 hours while showing a very desirable dissolution pattern, and in the case of Comparative Example 1, the dissolution is completely completed around 12 hours, and it can be seen that no more dissolution occurs.

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 a sustained effect 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 of the active ingredient in the eluted immediate-release layer is rapidly reduced from the point of time when the effect 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 7 below.

Relative activity in pH 1.2 eluate relative to pH 6.8 division 0.25h 3h 18h Example 1 2.04 1.75 2.38 Example 2 2.05 1.72 2.37 Example 3 1.83 1.78 2.42 Example 4 1.87 1.74 2.38 Comparative Example 1 1.78 1.97 2.32

Review

In Examples 1 to 4, two types of hydroxypropylmethylcellulose having different viscosities were added at a certain ratio to hydroxypropylmethylcellulose having a viscosity of 150,000 mPa.s to change the molecular weight distribution of the release controlling agent while maintaining the viscosity characteristics, The change in dissolution rate according to each Example and Comparative Example was measured.

As shown in the dissolution rates of Tables 3 to 6 and the graphs of FIGS. 1 to 4 showing them, the case of Example 2 showed an optimal dissolution profile, whereby the molecular weight distribution range is preferably 2.6 to 3.2, more preferably. It was found that the active ingredient dissolution rate was most excellent when it was 2.7 to 3.0.

In addition, as shown in Table 7, when calculating the relative activity in the stomach and intestinal environment through the dissolution rates at pH 1.2 and pH 6.8, it was 1.83 to 2.05 after 15 minutes of dissolution, 1.70 to 1.80 after 3 hours, and 1.70 to 1.80 after 18 hours. It can be seen that when it appears as 2.35 to 2.45, it shows the optimal dissolution activity as in Examples 1 to 4.

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 FIGS. 1 to 4 .

Claims (10)

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,
the active ingredient 6 to 10% by weight, the release controlling agent 25 to 35% by weight, 10 to 20% by weight of lactose hydrate, 5 to 10% by weight of low-substituted hydroxypropyl cellulose, and 5 to 10% by weight of povidone K-30,
The release controlling agent,
Hydroxypropylmethylcellulose having a viscosity of 11,250 to 21,000 mPa.s,
Hydroxypropylmethylcellulose having a viscosity of 3,000 to 5,600 mPa.s, and
Hydroxypropylmethylcellulose having a viscosity of 75,000 to 140,000 mPa.s is mixed and used,
With respect to the total weight of the release-controlling agent
Hydroxypropylmethylcellulose having a viscosity of 11,250 to 21,000 mPa.s is 60 to 80% by weight,
Hydroxypropylmethylcellulose having a viscosity of 3,000 to 5,600 mPa.s is 10 to 20% by weight,
10 to 20% by weight of hydroxypropylmethylcellulose having a viscosity of 75,000 to 140,000 mPa.s,
The release controlling agent has a molecular weight distribution of 2.6 to 3.2,
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 1.83 to 2.05 after 15 minutes of dissolution, 1.70 to 1.80 after 3 hours, and 2.35 to 2.45 after 18 hours.
[Equation 1]

delete According to claim 1,
The sustained-release bi-layer tablet, characterized in that the active ingredient of the fast-release layer is contained in 3 to 5% 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 230 to 270mg.
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 bilayer 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 sok-release layer granules by compressing Mosapride citrate granules, fillers, disintegrants, release controlling agents and additives;
Preparing a single tablet by compressing the fast-release layer granules and the slow-release layer granules with a force of 2.0 to 7.0 kgf per unit area of 1 cm2;
According to claim 8,
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 8,
The single tablet is a method for producing a sustained-release bi-layer tablet, characterized in that the hardness is 8 to 27kg / ㎠.

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