KR101984892B1 - Sustained-release formulation comprising mosapride using parameters for release control - Google Patents

Abstract

The orally administrable sustained release double-layer tablets containing the simulated fibrids or salts thereof of the present invention can be administered orally or parenterally in order to simultaneously elicit rapid pharmacological activity and sustained pharmacological activity for 24 hours, A sustained-release bi-layer tablet consisting of a sustained-release layer, characterized by controlling the dissolution rate and residence time in the gastrointestinal tract using an optimal release modifier.
The present invention also provides a new factor for predicting the dissolution profile of the body to provide a customized composition according to the sickness characteristics of a patient and provides a novel pharmaceutical composition for oral administration of sustained release sustained- And a manufacturing method thereof.

Description

SUSTAINED-RELEASE FORMULATION COMPRISING MOSAPRIDE USING PARAMETERS FOR RELEASE CONTROL USING NEW DELIVERY PARAMETERS [0002]

The present invention relates to once-daily oral sustained-release double-layered tablets containing a simulated fry which precisely adjusts the elution pattern using novel elution parameters 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, leading to 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. Thus, 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

SUMMARY OF THE INVENTION The present invention has been conceived in order to solve the above-mentioned problems, and it is an object of the present invention to provide a method for preparing a drug composition, To provide a sustained-release two-ply tablet.

Further, according to the unique dissolution characteristics of the sustained-release sustained-release tablets made up of the immediate-release layer and the sustained-release layer, the present invention divides the total elution interval into three sections to derive a new elution factor for obtaining optimal pharmacological activity efficiency, The present invention provides a sustained release double-layered tablet containing a simaflid citrate, which satisfies both of active expression and sustained long-term pharmacological activity for more than 24 hours, and a process for preparing the same, and a novel elution factor for the elution control is provided.

The present invention relates to a once-daily sustained-release sustained-release or controlled-release double-layered tablet containing moscafide or a salt thereof as an active ingredient, which comprises an immediate-release layer containing an effective ingredient, a filler, a disintegrant and an additive, A release modifier and an additive, wherein the release modifier is a mixture of hydroxypropylmethylcellulose having a viscosity of from 75,000 to 140,000 mPa.s and hydroxypropylmethylcellulose having a viscosity of from 3,000 to 5,600 mPa.s use.

The sustained-release sustained-release two-ply tablets of the present invention may contain 20 to 35% by weight of the hydroxypropylmethylcellulose having a viscosity of 75,000 to 140,000 mPa · s, And 65 to 80% by weight of hydroxypropylmethylcellulose having 5,600 mPa · s.

If the hydroxypropylmethylcellulose having a viscosity of 75,000 to 140,000 mPa · s is less than 20% by weight, elution does not continue for more than 24 hours. If it exceeds 35% by weight, the initial elution is delayed and the pharmacological activity is slow. If the viscosity of the hydroxypropylmethylcellulose having a viscosity of 3,000 to 5,600 mPa · s is less than 65% by weight, the effective concentration of the active ingredient may not sufficiently rise to lower the therapeutic effect. When the content exceeds 35% by weight, So that side effects may occur.

Meanwhile, the present invention provides a linear dissolution slope as a new parameter according to the following formula (1) to control the dissolution profile of the active ingredient.

[Equation 1]

The sustained-release double-layered tablet containing the simulated fried powder according to the present invention has a linear elution gradient according to Equation 1 in the range from 0 to 0.5 hours in the case of the pH 1.2 eluate, from 66 to 73, from 0.5 to 18 hours In the third section from 11 to 28 hours, and from 36 to 45, 0.5 to 18 hours in the first section from 0 to 0.5 hours in the case of the pH 6.8 eluate. Time is 1.4 to 1.5 in the second section, and 0.2 to 0.3 in the third section from 18 to 24 hours.

The sustained-release sustained-release two-layer tablet containing the simulated preparation of the present invention may contain 2 to 4% by weight of the active ingredient based on the total weight of the immediate-release layer in the case of the immediate-release layer, 5 to 7% .

When the active ingredient content of the immediate layer is less than 2% by weight or the active ingredient content of the slow layer is less than 5% by weight, sufficient pharmacological activity can not be obtained and the active ingredient content of the immediate layer exceeds 4% When the active ingredient content of the active ingredient is more than 7% by weight, side effects such as vomiting and dizziness may occur as the blood concentration of the active ingredient increases sharply.

The present invention provides, as a parameter for controlling the elution of the active ingredient,

&Quot; (2) "

The sustained-release sustained-release bi-layered tablet containing the simulated fried tablet according to the present invention is characterized in that the interval elution change rate according to Equation 2 is 5.5 to 6.5% in the pH 1.2 eluate and 3.0 to 4.0% in the pH 6.8 eluate in the first section, And 20 to 26% in the pH 1.2 aqueous buffer solution and 15 to 22% in the pH 6.8 eluate for the second section.

The sustained-release sustained-release two-layered tablet according to the present invention is characterized in that the sustained-release layer of the sustained-release sustained-release two-layer tablet contains 5 to 7% by weight of simaflid citrate, 25 to 35% by weight of the release modifier, To 30% by weight, 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 preferable that the binder povidone K-30 also does not deviate from the above range because it affects the dissolution rate.

The sustained-release sustained-release two-ply tablets of the present invention are characterized in that the total weight is limited to 330 to 370 mg in consideration of the stability of the tablet. When the total weight is less than 330 mg, there is a problem in stability during tableting or oral administration If the dose is more than 370 mg, there may be a problem in compliance.

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 2 to 7 mm, more preferably 3 to 5 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, release modifiers, fillers and additives 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 grain size of the sustained-release layer is in the range of 350 to 450 탆. When the granular particle size is less than 350 탆, stability is inferior and the dissolution profile of the active ingredient is uneven. When it exceeds 450 탆, The elution of the active ingredient is not sufficiently performed.

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 13 to 25 kg / cm 2.

 When the hardness is less than 7 kgf / cm 2, the dissolution of the drug in the early phase may occur due to the partial dissolution of the slow release layer, which may result in the initial overdissolution and deterioration of the drug efficacy. If the hardness exceeds 30 kgf / It appears to be slow.

The sustained-release two-layer tablet of the present invention is characterized in that a pharmacological effect is rapidly exhibited by using a release modifier in which two kinds of hydroxypropylmethylcellulose having different viscosity characteristics are mixed, and the long-term effect is sustained.

The present invention also provides a new elution parameter that allows more elaborate control of dissolution.

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 hydroxypropylmethylcellulose having a pharmacologically active ingredient as a pharmacologically active ingredient with respect to the total weight of the sustained-release layer in an amount of 5 to 7% by weight, a lactose of 20 to 30% by weight and a viscosity of 75,000 to 140,000 mPa · s and a viscosity of 3,000 to 5,600 mPa 20 to 35% by weight of a release modifier comprising hydroxypropylmethylcellulose, and an appropriate amount of microcrystalline cellulose. 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 50 to 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 may be hydroxypropylmethylcellulose having a viscosity of 75,000 to 140,000 mPa · s and 20 to 35% by weight of a hydroxypropylmethylcellulose, and a viscosity of 3,000 to 5,600 mPa · s, based on the total weight of the release modifier 65 to 80% by weight.

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 20 to 30% by weight of lactose, 25 to 35% by weight of low-substituted hydroxypropyl cellulose and an appropriate amount of microcrystalline cellulose, and then dissolved in an appropriate amount of ethanol 3 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 rate of 30 to 40 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 10 to 25 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 two-layered 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 50.02 50.02 50.02 50.02 50.02 50.02 Excipient Lactose baggage 45.00 45.00 45.00 45.00 45.00 45.00 Release modifier Hypromellose 2910
(HPMC 4000 mPa s) 35.75 38.50 41.25 44.00 27.50 16.50 Release modifier Hypromellose 2208
(HPMC 100000 mPa s) 19.25 16.50 13.75 11.00 27.50 38.50 Binder Povidone K-30 12.00 12.00 12.00 12.00 12.00 12.00 Lubricant Light anhydrous silicic acid 0.80 0.80 0.80 0.80 0.80 0.80 Lubricant Magnesium stearate 1.60 1.60 1.60 1.60 1.60 1.60 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 51.31 51.31 51.31 51.31 51.31 51.31 Excipient Lactose baggage 45.00 45.00 45.00 45.00 45.00 45.00 Disintegration Low-substituted propyl cellulose 59.00 59.00 59.00 59.00 59.00 59.00 Binder Povidone K-30 12.00 12.00 12.00 12.00 12.00 12.00 Lubricant Light anhydrous silicic acid 0.80 0.80 0.80 0.80 0.80 0.80 Lubricant Magnesium stearate 1.60 1.60 1.60 1.60 1.60 1.60 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.

(HPMC 2208) having a viscosity of 100,000 mPa · s and hydroxypropylmethylcellulose (HPMC 2910) having a viscosity of 4,000 mPa · s were mixed in a speed mixer for 3 minutes After mixing, the combined solution prepared above was added thereto and mixed three times for 3 minutes per one 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 DEG 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 active ingredient as a simulated pride citrate in one tablet.

In order to increase patient compliance, the thickness of the slow-release bilayer tablets was limited to 5 mm, the hardness was set to 22.3 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 30.8 34.1 36.5 38.9 42.4 47.2 53.2 60.3 66.6 72.5 78.2 84.6 90.4 Example 2 29.6 33.4 36.8 39.6 44.5 51.8 57.6 64.2 70.5 76.6 82.5 87.4 93.2 Example 3 31.2 35.8 38.5 42.1 48.5 54.2 60.4 66.4 73.2 79.5 85.4 92.1 97.8 Example 4 32.3 36.2 40.6 45.2 51.2 56.9 63.1 69.2 76.5 82.9 89.1 94.5 100.3 Comparative Example 1 31.5 32.6 35.6 37.6 39.6 43.5 48.5 54.2 59.6 65.7 72.6 79.4 86.4 Comparative Example 2 31.5 32.7 35.6 37.6 39.6 42.2 45.6 50.1 54.6 60.3 67.4 74.6 81.6

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 30.5 34.3 35.4 38.2 41.6 46.8 52.5 59.4 65.2 71.5 77.5 83.6 91.2 Example 2 30.6 34.9 37.2 40.2 44.9 52.4 58.6 65.1 70.2 76.2 82.9 88.1 93.4 Example 3 32.4 34.8 39.2 41.2 47.9 53.9 59.2 65.7 72.1 78.9 84.2 91.2 97.2 Example 4 31.8 35.9 39.8 44.8 51.1 56.4 62.9 68.9 76.2 82.5 88.8 94.2 99.8 Comparative Example 1 30.2 33.8 34.8 36.8 38.2 42.4 47.6 53.9 58.4 64.8 71.2 78.8 85.9 Comparative Example 2 31.4 33.5 34.7 35.9 38.7 41.8 44.7 49.9 53.8 59.7 66.9 73.5 80.4

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 14.2 18.4 21.6 23.8 26.2 28.4 30.3 31.4 32.5 33.9 34.8 36.8 38.5 Example 2 14.2 19.5 22.4 25.1 27.2 28.9 31.2 32.1 33.5 34.5 35.8 37.9 39.4 Example 3 15.6 20.1 24.5 26.7 28.5 30.2 31.5 33.6 34.8 35.6 37.2 38.9 40.8 Example 4 15.4 22.4 26.5 27.9 29.6 31.5 33.4 35.2 36.4 37.1 38.9 40.1 41.5 Comparative Example 1 13.8 16.8 19.9 22.4 24.6 26.9 28.6 30.1 31.2 32.8 33.9 35.9 37.5 Comparative Example 2 14.1 15.9 18.5 20.8 22.9 24.8 26.9 28.7 30.1 31.7 32.8 34.8 36.8

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 29.4 33.2 35.4 38.9 41.8 46.8 52.8 59.1 65.4 71.8 77.5 82.6 89.5 Example 2 31.2 35.6 37.8 40.8 45.6 50.8 56.7 63.8 69.2 75.1 81.5 86.8 92.8 Example 3 32.3 34.5 37.9 41.9 47.5 53.8 59.8 65.4 72.8 78.4 86.2 90.4 96.4 Example 4 31.9 35.4 40.9 44.2 50.8 56.2 62.8 68.7 75.9 82.4 88.9 94.5 100.3 Comparative Example 1 29.5 33.5 36.5 38.9 40.2 43.6 47.5 53.1 59.1 65.7 71.8 78.5 84.2 Comparative Example 2 31.5 34.1 35.6 37.6 39.6 42.2 45.6 50.1 54.6 59.8 66.5 72.6 78.9

Linear gradient and rate of change

The dissolution rate of the simulated free-standing two-ply tablets of pH 1.2, pH 4.0, pH 6.8 and water shown in Tables 2 to 5 was divided into three sections based on the time of rapid change of the dissolution rate, 1 to 4, respectively. The characteristics of the elution profile were analyzed and the elution interval for 24 hours was divided into three sections as shown in Table 6 below.

division Time (h) Characteristics start End Section 1 0 0.5 In the section where the active ingredient of the immediate-release layer rapidly dissolves The second section 0.5 12 In the section where the elution of the inner layer is terminated and the release layer is eluted Section 3 12 24 The section where the elution of the active ingredient ends

In order to quantify the dissolution characteristics of each section of Table 6, the dissolution rate difference at both ends of the section is divided by the change with time, and the linear dissolution slope according to Equation 1 is derived.

[Equation 1]

Since the active ingredient is simultaneously eluted from the immediate layer and the slow layer in the simulated free sustained-release two-layer tablet according to the present invention, it is very important that the effective ingredient eluted simultaneously in each layer maintains an appropriate blood concentration for a long time.

That is, a sufficient amount of the active ingredient should be eluted so as to exhibit the pharmacologically active effect, but an excessive amount of the effective ingredient should not be eluted in order to prevent side effects due to the rapid increase in the blood concentration.

In order to achieve the above object, the applicant of the present invention divides the total elution section into 24 hours, which is the elution section, and the elongation section, the elongation section and the elongation section of the elongation layer, The elution characteristics of the section were quantified by the linear elution gradient according to Equation (1).

However, since there is a limit to simultaneously grasp the active ingredient eluted simultaneously in the immediate layer and the sustained-release layer only by the linear dissolution slope, the Applicant has found that the ratio of the elution outgrowth according to the following formula (2) Respectively.

&Quot; (2) "

The linear dissolution slope of Equation (1) and the dissolution rate of dissolution rate of Equation (2) were calculated on the basis of the dissolution rate measured in the eluate of pH 1.2 and pH 6.8, and are shown in Table 7 and Table 8, respectively.

The elution slope at pH 1.2 pH 1.2
Eluent Linear elution gradient by section Percent change in fraction elution (%) Section 1
(0 to 0.5h) 2 sections
(0.5 to 12 h) 3 sections
(12h to 24h) Section 1 2 sections Example 1 68.2 3.8 1.0 5.6 26.5 Example 2 66.8 4.3 0.9 6.4 20.9 Example 3 71.6 4.3 1.0 6.0 24.0 Example 4 72.4 4.6 0.9 6.4 20.3 Comparative Example 1 65.2 3.3 1.2 5.1 34.4 Comparative Example 2 65.5 2.9 1.2 4.4 40.9

The elution slope at pH 6.8 pH 6.8
Eluent Linear elution gradient by section Percent change in fraction elution (%) Section 1
(0 to 0.5h) 2 sections
(0.5 to 12 h) 3 sections
(12h to 24h) Section 1 2 sections Example 1 36.8 1.4 0.3 3.9 21.6 Example 2 39.0 1.4 0.3 3.6 21.2 Example 3 40.2 1.5 0.3 3.7 20.2 Example 4 44.8 1.4 0.2 3.2 15.1 Comparative Example 1 33.6 1.7 0.3 4.4 20.2 Comparative Example 2 31.8 1.5 0.3 4.6 22.7

Review

In Examples 1 to 4, a release controlling agent obtained by mixing two kinds of hydroxypropylmethylcellulose having different viscosities was used. Due to the optimum content ratio, elution continued for a longer time, As shown in the dissolution rate of 5 and the graphs of FIGS. 1 to 4 showing the same, the effective drug dissolution rate continued to be uniformly eluted until after 24 hours even after 30 minutes after elution of the most effective ingredients of the immediate-release layer.

In the simulated free sustained-release two-layer tablet according to the present invention, the value of the linear elution gradient according to the formula (1) is 66 to 73 in the first section, 3.8 to 4.6 in the second section, 0.9 to 1.0 And in the pH 6.8 eluate, the optimum dissolution profile is shown when the ratio is 36 to 45 in the first section, 1.4 to 1.5 in the second section and 0.2 to 0.3 in the third section.

The sustained-release sustained-release biodegradable tablet according to the present invention is characterized in that when the interval elution change ratio according to the formula (2) is in a range of 1 to 5.5% to 6.5% in the pH 1.2 eluate and 3.0 to 4.0% in the pH 6.8 eluate, 20 to 27% in the eluate, and 15 to 22% in the eluate of pH 6.8.

If the linear elution gradient or the elution change rate of the elution out of the range is out of the above range, the dissolution duration is shortened or the elution is excessively delayed as shown in the comparative example of FIGS.

Claims (9)

As a once-daily oral administration 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 release modifier and an additive,
Wherein the release modifier comprises:
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 are mixed and used,
With respect to the total weight of the release modifier,
Hydroxypropylmethylcellulose having a viscosity of 75,000 to 140,000 mPa · s is 20 to 35% by weight, hydroxypropylmethylcellulose having a viscosity of 3,000 to 5,600 mPa · s is contained in an amount of 65 to 80% by weight,
The sustained release layer comprises, based on the total weight of the sustained release layer,
10.58 mg of simaflid citrate, 55 mg of the release modifier, 45 mg of lactose hydrate and 12 mg of povidone K-30,
The linear elution gradient according to the following formula (1)
In the pH 1.2 eluate,
66 to 73 in the first section from 0 hour to 0.5 hour,
3.8 to 4.6 in the second section from 0.5 hour to 12 hours,
0.9 to 1.0 in the third section from 12 hours to 24 hours,
In the pH 6.8 eluate,
36 to 45 in the first section from 0 hour to 0.5 hour,
1.4 to 1.5 in the second section from 0.5 hour to 12 hours,
0.2 to 0.3 in the third section from 12 hours to 24 hours,
The rate of change of the elution rate of the elution according to the following formula (2)
5.5 to 6.5% in the pH 1.2 aqueous buffer solution for the first section, 3.0 to 4.0% in the pH 6.8 aqueous buffer solution,
Wherein the second section is from 20 to 27% in a pH 1.2 aqueous buffer solution and from 15 to 22% in a pH 6.9 aqueous buffer solution environment.
[Equation 1]

&Quot; (2) "

The method according to claim 1,
Wherein the effective ingredient of the immediate-release layer comprises 2 to 4 wt% based on the total weight of the immediate-release layer, and the effective ingredient of the sustained-release layer comprises 5 to 7 wt% Sustained release double layer tablet.
delete delete 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 preparation containing the simulated fried is 2 to 7 mm.
A method for producing a simulated pre-citric acid salt-containing sustained release double-layer tablet according to claim 1,
Pressurizing the simulated pride citrate granules, release modifiers, fillers and additives 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-layer granules have a diameter of 350 to 450 mu m.
8. The method of claim 7,
Wherein the single tablet has a hardness of 7 to 30 kg / cm < 2 >.

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