KR20190000660A - Release controlled oral dosage form comprising mosapride - Google Patents

Abstract

An oral administration type sustained-release bilayer tablet containing mosapride and salt thereof of the present invention relate to a sustained-release bilayer tablet comprising an immediate release layer which makes a drug quickly eluted and a sustained-release layer which makes a drug slowly eluted to satisfy rapid pharmacological activity expression and pharmacological activity lasting for 24 hours at the same time. To show an optimum elution condition, the present invention uses a release controller, prepared by mixing three types of hydroxypropyl methylcelluloses which have different viscosities and controls an elution rate at each part in a gastrointestinal tract, having a different pH, and a residence time in the gastrointestinal tract. Also, the present invention provides a method for manufacturing oral administration type sustained-release bilayer tablet containing mosapride which increases drug compliance of a patient and ensures superior effects as mentioned above.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention [0001] The present invention relates to an oral dosage form for oral administration,

The present invention relates to a once-a-day sustained-release sustained-release double-layer tablet with a simulated preparation which is prepared by precisely adjusting the elution pattern using three kinds of hydroxypropylmethylcellulose whose dissolution characteristics differ according to the viscosity, and a method for producing the same.

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 Technical Problem Accordingly, the present invention has been made to solve the above-mentioned problems, and it is an object of the present invention to further improve the conventional sustained-release technology to precisely adjust the elution amount of the active ingredient per hour while simultaneously satisfying both the rapid pharmacological activity and 24- A sustained release double-layered tablet containing a simulated preparation exhibiting excellent pharmacological activity and a process for producing the same.

The present invention provides a once-daily oral sustained-release or controlled-release double-layer tablet containing moscafide or a salt thereof as an active ingredient.

Wherein the sustained release or controlled release two-ply tablet comprises a continuous layer comprising an active ingredient, a filler, a disintegrant and an additive, and a sustained release layer comprising an active ingredient, a filler, a disintegrant, a release modifier and an additive, Is used in combination with three types of hydroxypropylmethylcellulose having different viscosities, and the viscosity of each hydroxypropylmethylcellulose is 75,000 to 140,000 mPa.s, 11,250 to 21,000 mPa.s and 3,000 to 5,600 mPa.s, respectively use.

The content of each hydroxypropylmethylcellulose in the release controlling agent is 40 to 50% by weight, and the viscosity is 11,250 to 21,000 mPa.s, in the case of hydroxypropylmethylcellulose having a viscosity of 75,000 to 140,000 mPa.s, The hydroxypropylmethylcellulose contains 20% by weight of hydroxypropylmethylcellulose and 40 to 50% by weight of hydroxypropylmethylcellulose having a viscosity of 3,000 to 5,600 mPa.s.

When the hydroxypropylmethylcellulose having a viscosity of 75,000 to 140,000 mPa.s is less than 40% by weight, sufficient sustained-release can not be attained. When the amount of hydroxypropylmethylcellulose exceeds 50% by weight, sufficient amount of effective drug is not eluted per hour, .

On the other hand, when the content of hydroxypropylmethylcellulose having a viscosity of 3,000 to 5,600 mPa.s is less than 40% by weight, elution of sufficient effective drug is not achieved in the early stage, and when it exceeds 50% by weight, Fall off.

Hydroxypropylmethylcellulose having a viscosity of 11,250 to 21,000 mPa.s serves to uniformly and precisely control the elution amount of an active ingredient for a long period of time. When the content is less than 10% by weight, elution pattern with time does not appear uniformly, If it exceeds 20% by weight, the sustained-release effect decreases.

 The sustained-release bi-layered tablet according to the present invention contains the active ingredient in the immediate layer or the sustained-release layer, and the content of each effective ingredient is 2 to 4% by weight based on the total weight of the immediate layer in the case of the immediate layer, And 5 to 7% by weight based on the total weight of the layer.

When the active ingredient of the immediate-release layer is less than 2% by weight or the active ingredient of the slow-release layer is less than 5% by weight, the sufficient therapeutic effect is not obtained. When the effective ingredient of the immediate- May go too far and cause side effects.

The sustained-release sustained-release double-layered tablets containing the simulated fibrils according to the present invention exhibited, in the elution test under the buffer solution conditions of pH 1.2 and pH 6.8,

Relative activity according to the following formula 1 is 2.25 to 2.45 after 15 minutes of elution, 2.15 to 2.25 after 3 hours, and 2.75 to 2.95 after 18 hours.

[Equation 1]

The relative activity is a very desirable indicator that can predict the dissolution profile of the active ingredient eluted simultaneously in the immediate layer and the extended layer so that the effect of the two-layer tablet can be verified before oral administration, The elution may be delayed excessively or the dissolution duration may be shortened.

The sustained-release layer composition 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 release modifier, 10 to 20% by weight of lactose hydrate, 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 two-layered tablet for oral administration made up of the immediate-release layer and the sustained-release layer produced according to the present invention can be controlled to elute the dissolution rate of the drug using a pharmaceutically acceptable release-controlling agent and have the same biological activity , The effective immediate-treatment blood concentration reaches to the immediate gastro-intestinal tract, thereby improving the gastrointestinal motility disorder. The active active ingredient and the active metabolite are continuously maintained in the plasma for a considerable period of time. Therefore, it is very useful because it improves the convenience of taking a single tablet while reducing the number of doses compared to the existing drug, thereby increasing the drug adaptability to the patients and improving the dosage compliance.

In addition, the sustained-release bi-layer tablet of the present invention is characterized in that the dissolution characteristics are controlled more precisely than the conventional sustained-release tablet using a release modifier in which three kinds of hydroxypropylmethylcellulose having different viscosities are mixed, It is possible to elute the active ingredient uniformly for a long time while suppressing the initial excessive release in the body.

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

Hydroxypropylmethylcellulose having 5 to 7% by weight of simfurf citrate, 10 to 15% by weight of lactose, an appropriate amount of microcrystalline cellulose and a viscosity of 75,000 to 140,000 mPa.s as a pharmacologically active ingredient, Of hydroxypropylmethylcellulose having a viscosity of 11,250 to 21,000 mPa.s and a mixed release modifier of hydroxypropylmethylcellulose having a viscosity of 3,000 to 5,600 mPa.s as a disintegrant, and a low-substituted hydroxypropylcellulose Is mixed in an amount of 15 to 30% by weight. 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.

At this time, the release modifier mixed with the three kinds of hydroxypropylmethylcellulose having different viscosities, the hydroxypropylmethylcellulose having a viscosity of 75,000 to 140,000 mPa.s relative to the total weight of the release modifier is 40 to 50 %, 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 at a content ratio of 40 to 50% by weight do.

Meanwhile, 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 hydroxypropyl cellulose and dissolved in an appropriate amount of ethanol 3 to 10% by weight of povidone 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 DEG 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 9.0 to 23.0 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 3 and Comparative Examples 1 to 2

The sustained release double-layer tablets of Examples 1 to 3 and Comparative Examples 1 to 2 containing the simulated fresh citrate were prepared according to the ingredient contents shown in Table 1 below.

Modified two-layered formulation (Unit: mg) division Classification ingredient Example 1 Example 2 Example 3 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 Excipient Microcrystalline cellulose 38.42 38.42 38.42 38.42 38.42 Excipient Lactose baggage 24.00 24.00 24.00 24.00 24.00 Release modifier Hypromellose 2910
(HPMC 4000 mPa.s) 21.00 21.00 26.25 26.25 18.375 Release modifier Hypromellose 2208
(HPMC 15000 mPa.s) 5.25 10.50 5.25 0.00 15.750 Release modifier Hypromellose 2208
(HPMC 100000 mPa.s) 26.25 21.00 21.00 26.25 18.375 Binder Povidone K-30 12.20 12.20 12.20 12.20 12.20 Disintegration Low-substituted propyl cellulose 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 Lubricant Magnesium stearate 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 Excipient Microcrystalline cellulose 51.91 51.91 51.91 51.91 51.91 Excipient Lactose baggage 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 Binder Povidone K-30 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 Lubricant Magnesium stearate 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.

Manufacture of granules 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 in a speed mixer for 3 minutes, and the combined solution prepared above was mixed and mixed three times for 3 minutes each time, The association product was prepared.

The mixed material thus obtained was put into a rotary granulator and granulated with 1.2 mesh to form granules.

 The dried granules were dried in a fluid bed drier at 60 DEG C (LOD 2% or less), and the dried granules were dried for 20 minutes in a 1.2 mm mesh in a power mill. The dried granules were added to a 40 mesh stencil, Were mixed in a drum mixer at a speed of 24 rpm for 20 minutes to prepare a granule of the immediate layer.

Manufacture of Sustained Layer 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.

(HPMC 2208) having a viscosity of 100,000 mPa.s, hydroxypropylmethylcellulose (HPMC 2208) having a viscosity of 15,000 mPa.s, a viscosity of 4,000 mPa · s, and a viscosity of 5,000 mPa · s. hydroxypropylmethylcellulose (HPMC 2910) and low-substituted hydroxypropylcellulose (L-HPC, 1/2) were mixed in a speed mixer for 3 minutes. To the resulting mixture was added 1 The blend was prepared by mixing three times for 3 minutes each time.

The mixed material thus obtained was put into a rotary granulator and granulated with 1.2 mesh to form granules.

 The formed granules were dried in a fluidized bed drier at 60 ° C (LOD 2% or less), and were sieved in 1.2 mesh for 20 minutes. The granules were then dipped in a solution of hydroxypropylcellulose (L-HPC, 1/2) and a 40 mesh stencil The lubricant was added and mixed in a drum mixer at a speed of 24 rpm for 20 minutes to produce a sustained-release granule.

Preparation of sustained release double layer tablet

The sustained-release granules and the pre-granulated 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 double-row 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.

In order to increase patient compliance, the thickness of the slow-release bilayer tablets was limited to 5 mm, the average hardness was set to 18.5 kg / cm 2, and the average 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 below.

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 32.9 36.5 41.6 46.9 51.8 57.9 63.2 69.5 75.9 81.4 87.6 93.4 100.3 Example 2 33.2 38.6 43.5 50.3 56.8 61.3 66.4 71.6 79.6 85.6 91.2 97.5 100.8 Example 3 33.9 39.5 47.3 52.6 59.3 63.8 71.2 75.6 82.9 88.6 94.5 100.5 100.7 Comparative Example 1 33.2 36.5 42.6 51.5 55.3 61.2 67.2 73.5 79.6 86.1 91.2 98.8 100.1 Comparative Example 2 37.5 43.2 52.6 59.6 65.8 74.0 77.5 83.6 89.6 92.4 98.6 100.1 100.6

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 31.2 35.8 40.6 45.7 50.4 55.9 62.4 67.3 74.4 80.1 85.5 92.3 99.5 Example 2 32.5 36.9 42.6 49.6 54.5 59.6 65.1 70.5 77.6 83.5 89.6 96.8 99.8 Example 3 33.8 38.6 46.2 51.6 58.9 62.5 69.4 74.5 81.5 87.6 93.5 99.6 100.2 Comparative Example 1 32.4 37.4 43.5 50.6 56.4 60.4 66.6 72.1 78.4 84.5 90.4 97.9 100.1 Comparative Example 2 36.9 44.9 52.3 58.9 64.9 69.6 76.4 79.5 85.4 91.8 97.6 99.6 101.2

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 13.9 17.1 20.2 22.9 24.6 25.8 27.1 29.1 29.2 30.9 31.2 32.4 33.5 Example 2 14.2 18.5 21.6 23.4 26.2 27.5 28.6 30.4 31.2 32.5 33.5 34.2 35.6 Example 3 14.5 18.4 22.9 25.5 27.9 28.6 29.4 31.6 31.5 33.2 34.5 35.6 37.6 Comparative Example 1 15.6 18.5 22.4 24.6 27.5 29.5 30.1 31.6 32.5 33.5 34.6 36.2 37.2 Comparative Example 2 14.6 20.1 24.9 27.6 29.6 31.5 32.5 33.2 34.5 35.9 36.5 37.5 38.2

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 30.8 34.6 39.5 44.6 50.2 55.6 61.5 67.9 73.2 79.8 85.3 92.6 98.9 Example 2 31.2 35.4 41.5 48.6 53.2 58.6 64.7 69.5 76.2 82.5 88.6 95.7 99.5 Example 3 33.5 39.6 45.7 50.2 56.6 61.2 68.2 73.6 79.5 85.2 91.5 96.5 98.6 Comparative Example 1 31.9 35.6 42.5 48.9 54.6 59.5 65.4 70.5 76.5 81.5 87.5 94.5 98.9 Comparative Example 2 35.8 43.2 51.9 56.8 62.5 67.5 74.2 77.9 83.4 89.5 95.6 97.5 99.7

The dissolution profiles shown in the above table are shown in the graphs of FIGS. 1 to 4, and the dissolution profiles are analyzed. In Examples 1 to 3, elution was maintained constantly for 24 hours while exhibiting a highly preferable dissolution profile, and in Comparative Examples 1 and 2, almost no elution was observed after 9 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.

division 15 minutes 3h 18h Example 1 2.37 2.24 2.88 Example 2 2.34 2.23 2.85 Example 3 2.34 2.23 2.82 Comparative Example 1 2.13 2.07 2.73 Comparative Example 2 2.57 2.35 2.67

Review

In Examples 1 to 3, release modifiers prepared by mixing three kinds of HPMCs having different viscosities were used. With the optimum content ratio, it was possible to control the elution more precisely, and the dissolution rate in Tables 2 to 5 and the dissolution rate As shown in the graph of FIG. 4, even after 30 minutes of elution of most of the immediate-release active ingredients, the effective drug elution rate was very favorable for 24 hours.

As shown in Table 6, relative activity in the stomach and intestines was calculated from the dissolution rate at pH 1.2 and pH 6.8, which was 2.25 to 2.45 after 15 minutes, 2.15 to 2.25 after 3 hours, and 18 hours after Is 2.75 to 2.95, 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 FIGS.

Claims (9)

A once-a-day oral sustained-release or controlled-release double-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 viscosity of 75,000 to 140,000 mPa.s,
Hydroxypropylmethylcellulose having a viscosity of 11,250 to 21,000 mPa.s and
And hydroxypropylmethylcellulose having a viscosity of 3,000 to 5,600 mPa.s are mixed and used,
Relative to the total weight of the release modifier
The hydroxypropylmethylcellulose having a viscosity of 75,000 to 140,000 mPa.s is contained in an amount of 40 to 50% by weight,
The hydroxypropylmethylcellulose having a viscosity of 11,250 to 21,000 mPa.s is contained in an amount of 10 to 20% by weight,
Wherein the hydroxypropylmethylcellulose having a viscosity of 3,000 to 5,600 mPa.s is contained in an amount of 40 to 50% by weight.
The method according to claim 1,
Wherein the effective ingredient of the immediate-release layer comprises 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% Sex 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 from 2.25 to 2.45 after 15 minutes of elution, from 2.15 to 2.25 after 3 hours, and from 2.75 to 2.95 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,
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 >.

Images