KR20190000661A - Once a day oral dosage sustained-release formulation comprising mosapride - Google Patents

Abstract

The present invention relates to an oral administration type sustained-release two-layered medication containing mosapride or a salt thereof. To simultaneously satisfy conditions for quick pharmacological activity expression and 24-hour pharmacological activity maintenance, the two-layered medication comprises: an immediate-release layer for making medicine quickly eluted; and a sustained-release layer for making medicine gradually eluted. To indicate optimal elution, many kinds of elution control agents having different elution properties depending on the degree of substitution are used as a discharge controller, and an elution rate in each gastrointestinal tract with a different pH and retention time in each gastrointestinal tract are controlled. Moreover, to be applied to a patient, having slow digestion or a degraded digestive system due to diseases, while increasing administrative compliance of the patient, the sustained-release two-layer medication is made to last longer than for general patients.

Description

{ONCE A DAY ORAL DOSAGE SUSTAINED-RELEASE FORMULATION COMPRISING MOSAPRIDE}

The present invention relates to a pharmaceutical composition for oral administration, which is prepared by mixing two kinds of hydroxypropylmethylcellulose having different degree of substitution and precisely adjusting the elution pattern thereof, To a sustained-release two-layer tablet and a manufacturing method thereof.

BACKGROUND ART Mosapride (4-amino-5-chloro-2-ethoxy-N- 4- (4-fluorobenzyl) -2-morpholinyl] methyl benzamide is a known compound having the structural formula And its physiologically acceptable salts are selective serotonin 5-HT4 receptors present in the sarcomere plexus as selective serotonin 5-hydroxytryptamine 4 (hereinafter referred to as '5-HT4') receptor agonist And accelerates the release of acetylcholine at the nerve endings. This acetylcholine contracts the smooth muscle of the digestive tract and promotes digestive tract movement, resulting in diabetic gastropathy, dyspepsia, gastritis gastritis, gastroesophageal reflux disease, and the like. Mossafrid has no fear of arrhythmia or cardiogenic death due to the prolongation of QT interval in the non-selective 5-HT4 receptor agonist Sissaflide, and has no dopamine-2 (D-2) receptor antagonism, CNS) side effects (extrapyramidal symptoms), hyperprolactinemia (lactation, feminized breast), and other side effects.

[Chemical Formula 1]

Mossafrid has a digestive tract absorption rate of 93% or more and is distributed at a concentration more than 10 times higher than plasma concentration in the liver, small intestine, stomach, kidney, and adrenal glands. It is distributed at high concentration in the spleen and low in the brain and eyeball, about half of the blood concentration. Mossafrid exhibits a time of about 0.5 to 1.4 hours to reach the peak plasma concentration when administered orally.

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

In the case of a general slow-release tablet, it takes a long time to reach an effective blood concentration at an early stage. In addition, it is difficult to maintain effective pharmacological activity for 24 hours by expressing rapid pharmacological activity after oral administration.

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

DISCLOSURE OF THE INVENTION The present invention has been conceived to solve the problems described above. The applicant of the present invention has found that by analyzing the elution pattern during 24 hours of the simulated free two-layer structure consisting of a conventional and a continuous layer, The inventors of the present invention have realized an excellent effect and an optimal dissolution profile for achieving the same.

Further, the present invention provides a sustained-release double-layered tablet containing a simulated frit which satisfies simultaneous expression of a pharmacological activity and sustained long-term pharmacological activity lasting more than 24 hours, and a method for producing the same.

The present invention relates to a once-daily oral sustained-release two-layer tablet containing moscafide or a salt thereof as an active ingredient, which comprises an immediate-release layer containing an active ingredient, a filler, a disintegrating agent and an additive and an active ingredient, a filler, , A release modifier and an additive, wherein the release modifier comprises 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 Hydroxypropylmethylcellulose having a degree of substitution of 27.0 to 35.0% and a degree of hydroxypropoxyl group substitution of 5.0 to 16.0%

The 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 release modifier is 65 to 80% by weight, the methoxyl group substitution degree is 27.0 to 35.0% And 20 to 35% by weight of hydroxypropylmethylcellulose having a hydroxypropoxyl group substitution degree of 5.0 to 16.0%.

When the content 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 release modifier is less than 65% by weight, effective drug elution can not be continued for 24 hours, When it exceeds 80% by weight, elution in the body is excessively delayed, so that it is difficult to obtain a 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% based on the total weight of the release modifier is less than 20% by weight, the dissolution profile after oral administration is not uniform If it is more than 35% by weight, the initial stability may be deteriorated and excessive initial elution can be achieved.

The sustained-release two-ply tablets of the present invention contain the active ingredient in the immediate layer and the sustained-release layer, respectively. In the case of the immediate-release layer, 2 to 4% by weight based on the total weight and 5 to 7% do.

If the immediate layer active ingredient content relative to the total weight of the immediate layer is less than 2% by weight, or if the open-wall effective ingredient content is less than 5% by weight based on the total weight of the release layer, sufficient pharmacological effect is not exhibited, When the ingredient content exceeds 4% by weight or the effective amount of the sustained-release layer to the total weight of the sustained-release layer exceeds 7% by weight, the concentration of the effective ingredient in the blood becomes excessively high and various side effects may be caused.

In the elution test under the conditions of the buffer solution of pH 1.2 and pH 6.8, the relative activity by the following formula (1) was 1.75 to 1.85 after 15 minutes of elution and 1.45 to 1.70, 3 hours after 3 hours of elution And is 1.90 to 2.25 after the lapse of time.

[Equation 1]

The relative activity is a very desirable indicator that can predict the dissolution profile of the active ingredient that is simultaneously eluted from the immediate and extended layers in the immediate and extended layers so that the effect of the two-layer tablet can be verified before oral administration, If it is designed to deviate from the above range, the elution may be delayed too much or the elution time may be shortened.

The sustained-release layer of the sustained-release bi-layer tablet according to the present invention comprises 5 to 7% by weight of the simfurf citrate, 25 to 35% by weight of the release modifier, 10 to 20% by weight of lactose, 15 to 30% by weight of low-substituted hydroxypropylcellulose, and 3 to 10% by weight of Povidone K-30.

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

The total weight of the sustained-release sustained-release two-ply tablets of the present invention is 330 to 370 mg. When the total weight is less than 330 mg, there is a problem in stability during the tabletting process. When the tablet is more than 370 mg, It is becoming bigger and less adherence to medication.

The sustained-release sustained-release two-ply tablets of the present invention can be prepared in various forms, but the thickness of the formulation is preferably from 2 to 7 mm. When the thickness is less than 2 mm, cracks are formed or collapsed in the tablets during tableting, resulting in poor yield. The stability of the finished tablets may be poor and the formulations may be broken even with small impact. When the thickness exceeds 7 mm, It can be felt difficult depending on the condition such as constitution, age, disease and the like.

Meanwhile, the sustained-release double-layered tablet containing the simulated fibrin, which is orally administered once a day according to the present invention,

Pressurizing the simulated pride citrate granules, the release modifier, the filler, the disintegrant, and the additive to produce a sustained-release granule;

Pressurizing the simulated pride citrate granules, the filler, the disintegrant, the release modifier and the additive to produce the immediate layer granule;

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

At this time, it is preferable that the granules of the sustained-release layer have a particle diameter of 350 to 450 mu. When the granule size is less than 350 mu m, the stability is poor and the dissolution profile of the active ingredient is uneven. When it exceeds 450 mu m, The elution of the active ingredient becomes insufficient.

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

The sustained-release sustained-release two-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.

 When the hardness is less than 7.0 kgf / cm 2, the dissolution of the drug in the early phase may occur due to the partial disintegration of the slow release layer in the early stage. .

The sustained-release bi-layered tablet of the present invention is characterized in that release stability is more excellent than that of the conventional sustained-release tablet by using a release modifier in which two types of hydroxypropylmethylcellulose having different substitution characteristics are mixed, and the dissolution profile is uniform. In particular, since the duration of the effect is longer than that of the conventional sustained-release formulation, it is suitable for patients suffering from digestive system diseases and having poor digestive function or slow digestion.

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

The procedure for preparing the sustained release double-layered tablet of the simulated free citrate salt of the two-layer structure according to the present invention is as follows.

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

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

Hereinafter, one specific example of the preparation method of the sustained release double-layer tablet of the simulated free citric acid salt according to the present invention will be described in detail.

Manufacturing method of the suspended layer granule

A pharmacologically active ingredient as a pharmacologically active ingredient with respect to the total weight of the sustained-release layer is 5 to 7% by weight of simfurf citrate, 10 to 15% by weight of lactose, a suitable amount of microcrystalline cellulose, a degree of methoxyl substitution of 18.0 to 26.0%, a degree of hydroxypropoxyl group substitution of 2.0 To 14.0% of hydroxypropylmethylcellulose, 25 to 35% by weight of a mixed release modifier comprising 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% And 15 to 30% by weight of low-substituted hydroxypropylcellulose is mixed as a release agent. 3 to 10% by weight of povidone dissolved in an appropriate amount of ethanol is added to the binding solution, which is then combined and granulated, and then dried and sieved to a LOD of 4% or less at a temperature of 60 DEG C in a fluidized bed dryer. Followed by mixing a suitable amount of gliding agents to form a sustained-release layer granule.

In this case, the mixed release modifier may contain 65 to 80% by weight 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 modifier, And 20 to 35% by weight of hydroxypropylmethylcellulose having a silyl group substitution degree of 27.0 to 35.0% and a hydroxypropoxyl group substitution degree of 5.0 to 16.0%.

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

Manufacturing method of granule

2 to 4% by weight of simulated pride citrate as a total weight of the immediate layer is mixed with 15 to 30% by weight of lactose, an appropriate amount of microcrystalline cellulose and 25 to 35% by weight of low-substituted hydroxypropylcellulose and then dissolved in an appropriate amount of ethanol 5 to 10% by weight of povidone K-30 is added to the binding solution, followed by coalescence and granulation, and dried and sieved to a LOD of 4% or less at a temperature of 60 ° C in a fluidized bed dryer. Afterwards, an appropriate amount of lubricant flux is mixed to produce the immediate-layer granules.

Manufacturing method of sustained release double layer tablet

The above-prepared sustained-release granules and the pre-granulated granules are tableted at a speed of 33 rpm using a rotary tablet press with a pressure of preferably 3 to 8 kgf / cm 2, more preferably 4 to 6 kgf / cm 2.

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

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

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

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

Examples 1 to 4 and Comparative Examples 1 to 2

The sustained release double-layer tablets of Examples 1 to 4 and Comparative Examples 1 and 2 containing the simulated fresh citrate were prepared according to the ingredients in Table 1 below.

Modified Fried two layer formulation (Unit: mg) division Classification ingredient Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Comparative Example 2 book
room
layer chief ingredient Sima pride citrate
Hydrate 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 baggage 27.00 27.00 27.00 27.00 27.00 27.00 Release
Modulator The methoxyl group substitution degree was 29%
Hydroxypropoxylcellulose having a hydroxypropoxyl group substitution degree of 6% 17.50 15.00 12.50 10.00 25.00 35.00 Release
Modulator A methoxyl group substitution degree of 22%
Hydroxypropoxylcellulose having a hydroxypropoxyl group substitution degree of 8% 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 Disintegration Low-substituted propyl cellulose 35.00 35.00 35.00 35.00 35.00 35.00 Lubricant Light anhydrous silicic acid 0.80 0.80 0.80 0.80 0.80 0.80 Lubricant Magnesium stearate 1.50 1.50 1.50 1.50 1.50 1.50 Subtotal (mg / tablet) 175 mg genus
room
layer chief ingredient Sima pride citrate
Hydrate 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 baggage 45.00 45.00 45.00 45.00 45.00 45.00 Disintegration 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 Lubricant Light anhydrous silicic acid 0.80 0.80 0.80 0.80 0.80 0.80 Lubricant Magnesium stearate 1.50 1.50 1.50 1.50 1.50 1.50 Subtotal (mg / tablet) 175 mg Coating agent Opa Dry 0Y-C-7000A 5 mg Total (mg / tablet) 355 mg

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

Immediate layer  Manufacture of granules

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

The microfibrillated citrate, microcrystalline cellulose, lactose hydrate and low-substituted hydroxypropylcellulose were mixed for 3 minutes in a speed mixer, and the resulting solution was mixed for 3 minutes for 3 minutes each time, .

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

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

West floor  Manufacture of granules

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

And hydroxypropylmethylcellulose having a methoxyl group substitution degree of 22% and a hydroxypropoxyl group substitution degree of 8%, a methoxyl group substitution degree of 29% and a hydroxypropoxyl group substitution degree of 6% Hydroxypropylmethylcellulose and low-substituted hydroxypropylcellulose (L-HPC) were mixed in a speed mixer for 3 minutes, and then the above-prepared binding solution was added thereto and mixed three times for 3 minutes each time To prepare a combined solution.

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

 The granules thus formed were dried in a fluid bed drier at a temperature of 60 ° C for 35 minutes (LOD 2% or less), and the dried granules were formulated with a power mill for 20 minutes. Then, a lubricant was added thereto, For 20 minutes to prepare a sustained-release layer granule.

Preparation of sustained release double layer tablet

The granules of the late layer granules and the inner granules prepared in the above step were compressed at a speed of 33 rpm while applying a pressure of 5 kgf / cm 2 using a rotary tablet press.

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

The two-layered tablets were demineralized using a refining quench, and then coated with Opadry-OY-C-7000A (Colorcon Co.) for 120 minutes at a pump pressure of 3.0 bar and an air pressure of 2.5 bar using a 60- Coated with a coating agent, and then dried at 70 ° 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 the active ingredient of simfurf citrate in one tablet.

To increase patient compliance, the thickness of the slow-release bi-layer tablet was limited to 5 mm, the hardness was 20.4 kg / cm 2, and the total weight of the completed two-layer tablets was 355 mg.

Invitro (In-vitro) elution test

The dissolution rate of the active ingredient of the simulated free citric acid salt was measured with respect to the formulations of each of the examples and the comparative examples with the lapse of time under the conditions of the Korean Pharmacopoeia dissolution test liquid to confirm the dissolution profile.

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

Specimen: Mossafrid citric acid salt according to Examples and Comparative Examples Sustained release double-layered tablets

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

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

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

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

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

Test result

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

Elution rate at pH 1.2 division Dissolution rate (%) 15 minutes 30 minutes 60 minutes 90 minutes 120 minutes 180 minutes 300 minutes 360 minutes 480 minutes 600 minutes 720 minutes 1080 minutes 1440 minutes Example 1 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

Elution rate at pH 4.0 division Dissolution rate (%) 15 minutes 30 minutes 60 minutes 90 minutes 120 minutes 180 minutes 300 minutes 360 minutes 480 minutes 600 minutes 720 minutes 1080 minutes 1440 minutes Example 1 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

Elution rate at pH 6.8 division Dissolution rate (%) 15 minutes 30 minutes 60 minutes 90 minutes 120 minutes 180 minutes 300 minutes 360 minutes 480 minutes 600 minutes 720 minutes 1080 minutes 1440 minutes Example 1 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

Elution rate in water division Dissolution rate (%) 15 minutes 30 minutes 60 minutes 90 minutes 120 minutes 180 minutes 300 minutes 360 minutes 480 minutes 600 minutes 720 minutes 1080 minutes 1440 minutes Example 1 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

It can be seen that Examples 1 to 4 exhibit a constant dissolution rate for a longer period of time than the conventional sustained-release tablet, and the long-term effect continues. On the other hand, in the case of Comparative Examples 1 and 2, it was found that the effective ingredient eluted too early and almost no elution after 10 hours.

Relative activity  Factors and Significance

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

 [Equation 1]

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

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

Therefore, the relative activity factor of the dissolution rate in the pH 1.2 environment in which the active ingredient of the immediate layer of the two-layer tablet is eluted and the dissolution rate in the pH 6.8 environment in which the active ingredient of the slow-release layer is gradually eluted gradually, So that the effect of the two-layer tablet can be highly verified before oral administration.

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

Relative activity in pH 1.2 eluate to pH 6.8 division 15 minutes 3h 18h Example 1 1.85 1.67 2.24 Example 2 1.77 1.62 2.17 Example 3 1.79 1.56 2.08 Example 4 1.81 1.48 1.93 Comparative Example 1 1.88 1.78 2.40 Comparative Example 2 1.92 2.02 2.42

Review

In Examples 1 to 4, a release controlling agent comprising two kinds of hydroxypropylmethylcellulose having different degrees of substitution was used. Due to the optimum content ratio, elution continued for a longer period of time, As shown in the dissolution rate of 2 to 5 and the graph of FIG. 1 to 4 showing this, even after 30 minutes of elution of most of the immediate-layer active ingredients, the effective drug dissolution rate continued to be uniformly eluted until after 24 hours.

Further, as shown in Table 6, relative activity in the stomach and intestine was calculated from the dissolution rate at pH 1.2 and pH 6.8, and it was 1.75 to 1.85 after 15 minutes of elution, 1.45 to 1.70 after 3 hours, 1.90 to 1.90 after 18 hours 2.25, it can be seen that the optimum elution activity is shown as in Examples 1 to 3 above.

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

Claims (9)

A once-daily oral sustained-release two-layer tablet containing moscafide or a salt thereof as an active ingredient,
An active ingredient, a filler, a disintegrant and an additive;
An active ingredient, a filler, a disintegrant, a release modifier and an additive,
Wherein the release modifier comprises:
Hydroxypropylmethylcellulose having a degree of methoxyl group substitution of 18.0 to 26.0% and a degree of substitution of hydroxypropoxyl group of 2.0 to 14.0%
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 mixed and used,
With respect to the total weight of the release modifier,
65 to 80% by weight 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%
Wherein the hydroxypropylmethylcellulose has a methoxyl group substitution degree of 27.0 to 35.0% and a hydroxypropoxyl group substitution degree of 5.0 to 16.0%, and 20 to 35% by weight of hydroxypropylmethylcellulose.
The method according to claim 1,
Wherein the effective ingredient of the immediate-release layer is contained in an amount of 2 to 4% by weight based on the total weight of the immediate-release layer, and the effective ingredient of the sustained-release layer is contained in an amount of 5 to 7% Double layer tablet.
The method according to claim 1,
The above sustained-release sustained-release two-layer tablets containing the simulated frit exhibited, in the elution test under the buffer solution conditions of pH 1.2 and pH 6.8,
Wherein the relative activity according to Equation (1) is 1.75 to 1.85 after 15 minutes of elution, 1.45 to 1.70 after 3 hours, and 1.90 to 2.25 after 18 hours.
[Equation 1]

The method according to claim 1,
The sustained release layer comprises, based on the total sustained release layer total weight,
5 to 7% by weight of simfurf citrate, 25 to 35% by weight of the release modifier, 10 to 20% by weight of lactose hydrate, 15 to 30% by weight of low-substituted hydroxypropylcellulose, and 3 to 10 Wherein the sustained-release two-ply tablets of the present invention are characterized in that the tablets have a weight-average molecular weight of about 5,000 to about 10,000.
The method according to claim 1,
Wherein the total weight of the sustained-release sustained-release two-layer tablets containing the simulated prions is 330 to 370 mg.
The method according to claim 1,
Wherein the thickness of the sustained-release sustained-release two-layer tablet containing the simulated fried is 2 to 7 mm.
A method for producing a sustained-release double-layered tablet containing a simulated preparation, which is orally administered once a day according to claim 1,
Pressurizing the simulated pride citrate granules, the release modifier, the filler, the disintegrant, and the additive to produce a sustained-release granule;
Pressurizing the simulated pride citrate granules, the filler, the disintegrant, the release modifier and the additive to produce the immediate layer granule;
The granules of the immediate-release layer and the granules of the sustained-release layer are compressed at a force of 3.0 to 8.0 kgf per unit area of 1 cm 2 to prepare a single tablet. Way.
8. The method of claim 7,
Wherein the immediate-granule granules have a diameter of 350 to 450 mu.
8. The method of claim 7,
Wherein the single tablet has a hardness of 7 to 30 kg / cm < 2 >.

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