KR101620856B1 - Mosapride citrate sustained-release matrix formulation dispersed by pellet, and preparing the method thereof - Google Patents

Abstract

In the case of the capsule preparation containing the simfried citrate of the present invention, there is no fear of arrhythmia and cardiogenic sudden death, and there is no side effects such as central nervous system side effect and hyperprolactinemia, so that it can be safely used.
In addition, as compared with the conventional sustained-release matrix preparation, the elution time can be controlled relatively accurately, and the elution pattern exhibits a pattern similar to a zero order.

Description

TECHNICAL FIELD [0001] The present invention relates to a sustained release matrix formulation containing a mash-free citrate-dispersed pellet in a matrix and a method for preparing the same,

The present invention relates to a sustained-release matrix preparation in which pellets containing a mosaic pride citrate are uniformly dispersed in a matrix containing a mosaapride citrate, and a method for producing the same.

Recent developments in the industry have led to the greatest interest in human food and the westernization of eating habits in this most affluent eating season has led to the development of gastric reflux symptoms such as chest pain through GERD and acid reflux Diseases characterized have become one of the most common diseases. The anti-secretory and the like; (PPIs Proton pump inhibitors); a method of treating gastroesophageal reflux disease (GERD) is Pro kinetic agents (Prokinetic agent), histamine H ₂ receptor antagonist (H ₂ receptor antagonists H ₂ RAs) and a proton pump inhibitor Is used. Among these, prokinetic agents are more effective in treating esophagitis than other drugs, such as H ₂ receptor antagonists (H ₂ RAs), and exhibit symptom relief and drug persistence over a long period of time.

The most representative drug for prokinetic agents is Mosapride, which is a 4-amino-5-chloro-2-epoxy-N- [4- (4-fluorobenzyl) -2-morpholinyl] methylbenzamide) is a compound having the formula below, the selective 5HT ₄ receptor (5-hydroxytrypatamine ₄ receptor) agonists, and promoting only the serotonin 5HT ₄ receptor on muscle nerve layer optionally an acetyl choline in nerve endings (acetylcholine), and this acetylcholine contracts smooth muscle of the digestive tract and promotes digestive tract movement, leading to diabetic gastropathy, dyspepsia, gastritis, gastroesophageal reflux disease reflux disease). Mossafrid has no fear of arrhythmia and cardiogenic sudden death due to the prolongation of QT interval in the non-selective 5-HT ₄ receptor agonist Cisapride and has no dopamine-2 (D-2) Central Nervous System (CNS) Side effects (extrapyramidal symptoms), hyperprolactinemia (milk secretion, feminized breast)

Gt; Structure of the simulated fly

Mossafrid has a digestive tract absorption rate of more than 93%, and is distributed at concentrations more than 10 times higher than the plasma concentration in the liver, small intestine, stomach, kidney, and adrenal gland, and also in the lung, submandibular gland, pituitary gland, thyroid gland, It is distributed at a high concentration, and it is distributed as low as 1/2 of blood concentration in the brain and eyeballs. Mossafrid exhibits a time of about 0.5 to 1.4 hours to reach the peak plasma concentration when administered orally, and exhibits a fast-acting time.

Since the half-life is as short as 1.3 to 2 hours, the drug is rapidly absorbed into the body and disappears rapidly, so that the initial efficacy release time and the duration of drug efficacy are relatively short. Mossafrid is currently being developed and marketed in the form of tablets, and the initial efficacy release time and duration of drug efficacy are short enough that 5mg should be administered once a day three times a day.

The present invention is a sustained-release matrix formulation which is advantageous in that it can adjust the dissolution rate of a drug relatively accurately, unlike the conventional matrix-type drug formulation, and disperses drug-containing pellets in a matrix to form drug- .

Thus, in order to simultaneously satisfy the control of the elution rate and the drug elution pattern of the zero-order type, the pellet composed of the active ingredient and the low-viscosity hydroxypropyl methylcellulose is dispersed in the matrix composed of the active ingredient and the high viscosity hydroxypropylmethylcellulose Type matrix preparation was prepared, and a dissolution pattern similar to the zero-order form was confirmed and the present invention was completed.

It is an object of the present invention to provide a sustained-release matrix formulation in which a pellet comprising a mosapride citrate as an active ingredient is dispersed in a matrix containing a mofarf citrate as an active ingredient, Another object of the present invention is to provide a sustained-release matrix formulation containing a simulated fried citrate in which the pellet showing a dissolution pattern similar to the zero-order form is dispersed in the matrix for 24 hours by taking it once a day.

It is another object of the present invention to provide a method for preparing a sustained-release matrix formulation containing a simulated fried citrate wherein the pellets are dispersed in a matrix.

In one embodiment, the present invention provides a sustained release matrix formulation comprising a simulated fried citrate wherein the pellets are dispersed in a matrix.

In the present invention, the above-mentioned simaflid citrate is a typical prokinetic agent, which accelerates gastric emptying throughout human gastrointestinal tract and has excellent efficacy in the treatment of gastritis, reflux esophagitis, functional dyspepsia and irritable bowel syndrome.

In the present invention, the matrix preparation is a structure in which the drug and the excipient are uniformly present in the preparation, does not require strict production control as compared with the sustained-release coating-type preparation, Production is possible. Therefore, high productivity is expected, and even when a high-dose preparation of a drug is manufactured, the preparation of the preparation is easy and its size can be avoided. Therefore, the sustained-release matrix formulation is more useful than the sustained-release coating formulation in view of high productivity and downsizing of the formulation.

Also, in the present invention, the total weight ratio of the pellets can be variously adjusted regardless of the size of the preparation, and the release pattern can be changed according to the weight ratio, which is the most important component of the present invention.

In another embodiment, the present invention provides a method for preparing a sustained release matrix formulation comprising a simulated free citrate salt wherein the pellets are dispersed in a matrix.

In order to prepare the matrix preparation of the present invention, a combination and granulation process is performed after mixing the mashafide citrate, the excipient and the disintegrant, the binder is added, and the pellet is prepared by mixing and pelletizing the lubricant after drying and sizing . Thereafter, the matrix and the disintegrant are mixed with each other, and the binder and the pellet prepared above are then added, and the combined and granulated process is performed. After the drying and sizing, the lubricant is mixed and the tablet is prepared to prepare a matrix preparation.

Specifically,

(a) preparing a pellet association by adding povidone dissolved in an appropriate amount of ethanol prepared in advance to a pellet in a high-speed reciprocating machine, mixing the simfurf citrate, the excipient and the disintegrant;

(b) drying and sizing the pellet association of (a) and adding and mixing the glidant to produce a pellet;

(c) mixing the matrix fried citrate, the excipient, and the disintegrant in a high-speed coalescer, mixing the prepared matrix conjugate with povidone dissolved in an appropriate amount of ethanol prepared in advance, as a binder;

(d) drying and granulating the matrix material of (c) to prepare a mixture after adding and mixing the pellets of the lubricant and the (b);

(e) pressing the mixture of (d) using a tablet machine to produce a tablet; And

(f) a step of adding opaque to the tablet of (e) and coating the pellet, wherein the pellet is dispersed in the matrix, to prepare a sustained release matrix formulation containing the simfried citrate.

In the present invention, the above-mentioned simulated free citrate is contained in at least one of the pellet and the matrix, and is preferably contained in an amount of 10 to 20% by weight based on the weight of the matrix preparation. If the amount is less than 10% by weight, the pharmacological effect is poor. If the amount is more than 20% by weight, side effects such as Yanbyeon, diarrhea and dry mouth may occur.

The excipient serves to increase the volume so that pellets of a desired size can be produced. The excipient is not limited as long as it is pharmaceutically acceptable and includes lactose, starch, white sugar, mannitol, sorbitol, microcrystalline cellulose, hydroxypropyl methylcellulose And the like. Lactose hydrate, microcrystalline cellulose, hydroxypropylmethylcellulose or a mixture thereof.

The disintegrant is used to absorb water and promote disintegration of the formulation to improve dissolution of the simfried citrate. Examples of disintegrants that can be used in the formulation of the present invention include croscarmellose sodium, sodium Sodium starch glycolate, microcrystalline cellulose, crospovidone (cross-linked povidine) and other commercially available polyvinylpyrrolidone (PVP), low-substituted hydroxypropylcellulose One or a mixture thereof selected from the group consisting of hydroxypropylcellulose, low substituted alginic acid, powdered cellulose, starch and sodium alginate can be used. Preferably, the disintegrant is effective when low-substituted hydroxypropylcellulose, crospovidone and the like are used, and the disintegrant can be added additionally in a pharmaceutically acceptable manner in addition to the oral solid preparation, Additional secondary disintegrants may be used for faster release. The disintegrant is preferably used in an amount of 10 to 30% by weight, and most preferably 20 to 30% by weight, based on the total weight of the disintegrant.

The binder used is polyvinylpyrrolidone (commonly known as povidone, which has a molecular weight of 30 and povidone K-30 is used) and is a synthetic water-soluble polymer that can be dissolved in an organic solvent and serves to increase the binding force of the preparation. The binder is preferably added in an amount of 3 to 10% by weight of the capsule preparation, and when the binder is added in an amount of less than 3% by weight, the binding force is weak and it is difficult to tablet the pellet. When the binder is added in an amount exceeding 10% It becomes difficult to control.

The lubricant improves the fluidity of the powder and increases the filling of the die, which is the lower part of the tablet machine. The friction between the powder and the punch-die, which is the upper part of the powder and granulator, To facilitate compression and release of the tablet. The lubricant in the present invention is characterized by being a mixture of at least one selected from the group consisting of silicon dioxide, talc, stearic acid and magnesium stearate, preferably a mixture of silicon dioxide, talc, stearic acid and magnesium stearate . The lubricant is preferably added in an amount of 1 to 5% by weight based on the weight of the capsule preparation. When the lubricant is added in an amount of less than 1% by weight, tableting of the tablet becomes difficult. When the lubricant is added in an amount of more than 5% by weight, This phenomenon affects the dissolution profile of the tablet.

In the case of the capsule preparation containing the mosaaphide citrate of the present invention, there is no fear of arrhythmia and cardiogenic sudden death due to the extension of the QT interval in the cisapride, and there is no dopamine-2 (D-2) There are no side effects such as central nervous system (CNS) side effects (extrapyramidal symptoms), hyperprolactinemia (milk secretion, feminized breast) and can be safely used.

In addition, as compared with the conventional sustained-release matrix preparation, the elution time can be controlled relatively accurately, and the elution pattern exhibits a pattern similar to a zero order.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic diagram of a matrix preparation containing a simulated fried citrate matrix in which the pellets according to the present invention are dispersed in a matrix.
Figure 2 shows the dissolution rates at 5 mg eluate pH 4.0 of the matrix formulation prepared in Examples 2 to 4 according to the present invention.
Figure 3 shows the dissolution rates at 5 mg eluate pH 4.0 of the matrix formulation prepared in Examples 5-7 according to the present invention.

Hereinafter, the present invention will be described in more detail with reference to examples. It will be apparent to those skilled in the art that these embodiments are for illustrative purposes only and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention.

Example 1: Preparation of a sustained-release matrix formulation containing a simulated fried citrate in which pellets are dispersed in a matrix

1-1. Manufacture of pellets containing simfried citrate

(4,000 cps HPMC 2910), lactose hydrate and low-substituted hydroxypropylcellulose (L-HPC) were mixed with a povidone K-30 solution previously dissolved in ethanol. Granulated and dried in a cabinet dryer at 50 to 60 for 30 to 40 minutes (LOD 2% or less). After sizing, silicon dioxide and magnesium stearate are added and mixed to produce pellets.

1-2. Manufacture of a matrix formulation containing a morphine-free citrate with dispersed pellets

(100,000 cps, HPMC 2208) and low-substituted hydroxypropyl cellulose (L-HPC) were mixed with microfine citrate, microcrystalline cellulose, lactose hydrate, high viscosity hydroxypropyl methylcellulose Coagulated and granulated, and dried in a cabinet dryer at 50 to 60 DEG C for 30 to 40 minutes (LOD 2% or less). After the formulation, silicon dioxide and magnesium stearate were added and mixed, and the mixture was compressed by a tablet machine, followed by addition of Opadyl to prepare a sustained-release matrix formulation containing the pellets dispersed in the matrix.

Example 2-4: Preparation of a matrix preparation according to the active ingredient content ratio of pellets and matrix

In order to compare the properties of the matrix preparations with the contents of the pellets and the matrix of the simfurf citrate, the content ratio of the simfried citrate in the matrix preparation prepared in Example 1 was changed so that the contents of the components were as shown in Table 1 below To prepare a matrix preparation.

division Classification ingredient Example 2 Example 3 Example 4 Pellets chief ingredient Mosaic pride citrate 5.0 10.0 12.0 Excipient Low viscosity hydroxypropyl methylcellulose (HPMC 2910) 22.0 17.0 15.0 Excipient Lactose baggage 20.0 20.0 20.0 Disintegration Low-substituted propyl cellulose 24.0 24.0 24.0 Binder Povidone K-30 6.0 6.0 6.0 Lubricant Silicon dioxide 1.4 1.4 1.4 Lubricant Magnesium stearate 1.6 1.6 1.6 Total (mg / tablet) 80.0 80.0 80.0 matrix chief ingredient Mosaic pride citrate 10.0 5.0 3.0 Excipient Microcrystalline cellulose 22.0 27.0 29.0 Excipient Lactose baggage 20.0 20.0 20.0 Excipient High viscosity hydroxypropyl methylcellulose (HPMC 2208) 21.0 21.0 21.0 Binder Povidone K-30 6.0 6.0 6.0 Disintegration Low-substituted propyl cellulose 15.0 15.0 15.0 Lubricant Silicon dioxide 0.4 0.4 0.4 Lubricant Magnesium stearate 0.6 0.6 0.6 Coating agent Opa Dry OY-C-7000A 5.0 5.0 5.0 Total (mg / tablet) 100.0 100.0 100.0 Total (mg / tablet) 180.0 180.0 180.0

Example 5-7: Preparation of matrix formulation according to weight ratio of pellets and matrix

In order to compare the properties of the matrix preparation according to the weight ratio between the pellets and the matrix, the weight ratio of the pellets to the matrix in the matrix preparation prepared in Example 2 was varied, .

division Classification ingredient Example 5 Example 6 Example 7 Pellets chief ingredient Mosaic pride citrate 5.0 5.0 5.0 Excipient Low viscosity hydroxypropyl methylcellulose (HPMC 2910) 22.0 27.0 32.0 Excipient Lactose baggage 20.0 20.0 20.0 Disintegration Low-substituted propyl cellulose 24.0 24.0 24.0 Binder Povidone K-30 6.0 6.0 6.0 Lubricant Silicon dioxide 1.4 1.4 1.4 Lubricant Magnesium stearate 1.6 1.6 1.6 Total (mg / tablet) 80.0 85.0 90.0 matrix chief ingredient Mosaic pride citrate 10.0 10.0 10.0 Excipient Microcrystalline cellulose 22.0 22.0 22.0 Excipient Lactose baggage 20.0 20.0 20.0 Excipient High viscosity hydroxypropyl methylcellulose (HPMC 2208) 21.0 16.0 11.0 Binder Povidone K-30 6.0 6.0 6.0 Disintegration Low-substituted propyl cellulose 15.0 15.0 15.0 Lubricant Silicon dioxide 0.4 0.4 0.4 Lubricant Magnesium stearate 0.6 0.6 0.6 Coating agent Opa Dry OY-C-7000A 5.0 5.0 5.0 Total (mg / tablet) 100.0 95.0 90.0 Total (mg / tablet) 180.0 180.0 180.0

Example 8: Elution rate test

The dissolution profile of the matrix preparation in the in-vitro state of the sustained-release matrix formulation containing the simulated free citrate in which the pellets prepared above were dispersed in the matrix was tested to confirm the dissolution profile of the matrix preparation under the pH 4.0 condition. 3 and Figures 2 and 3, respectively.

The controlled-release preparation comprising the capsule preparation of the present invention is prepared by dissolving the drug selectively in the elution time desired by the inventor for 24 hours, The dissolution rate after 8 hours was 56 to 81%, the dissolution rate after 16 hours was 81 to 95%, the dissolution rate after 2 hours was 18 to 52%, the dissolution rate after 4 hours was 35 to 66% The inventors have observed a relatively predictable dissolution pattern as desired.

- pH 4.0 The dissolution rate test

Specimen: A sustained-release matrix formulation containing a simulated pride citrate in which the pellets of Examples 2 to 7 were dispersed in a matrix

Elution Test Solution: 900 ml of the Korean Pharmacopoeia Disintegration Test (pH 4.0)

Test temperature: 37 ± 0.5 ℃

Elution method: Korean Pharmacopoeia dissolution test Method 2 (paddle method), 50 rpm

Test solution
(pH 4.0) Average dissolution rate (%) 1 hours 2 hours 4 hours 6 hours 8 hours 10 hours 12 hours 16 hours 24 hours Example 2 11.8 19.7 36.5 48.7 57.8 66.1 73.4 82.7 97.6 Example 3 25.4 36.1 50.1 58.6 67.5 74.8 80.9 89.1 98.7 Example 4 35.2 49.5 63.7 70.7 78.9 83.9 87.8 93.7 100.0 Example 5 10.7 18.6 35.4 47.6 56.7 65.0 72.3 81.6 96.5 Example 6 26.5 37.2 51.2 59.7 68.6 75.9 82.0 90.2 99.7 Example 7 38.7 52.7 66.1 73.2 81.0 86.5 90.2 95.5 100.0

Claims (6)

Wherein the mordant fried or salt thereof is used as an active ingredient,
Wherein the pellet comprising the active ingredient and a pharmaceutically acceptable carrier is dispersed in a matrix,
Wherein the pellet comprising an excipient, a disintegrant, a binder and a glidant is dispersed in the matrix comprising an excipient, a disintegrant, a binder and a glidant,
Wherein the pellet comprises low viscosity hydroxypropyl methylcellulose,
Wherein the matrix comprises high viscosity hydroxypropyl methylcellulose,
Which satisfies the following dissolution profile in a pH 4.0 aqueous solution at 37 占 폚 according to the Korean Pharmacopoeia dissolution assay method 2 (paddle method)
A sustained-release matrix formulation comprising a simulated frit in which pellets are dispersed in a matrix:
After 1 hour, the dissolution rate was 10 to 38%, the dissolution rate after 18 hours was 18 to 52%, the dissolution rate after 4 hours was 35 to 66%, the dissolution rate after 8 hours was 56 to 81%, the dissolution rate after 16 hours was 81 to 95% Eluted.
The method according to claim 1,
The active ingredient is present in an amount of from 10 to 20% by weight based on the total weight of the matrix formulation, from 20 to 56% by weight of excipients, from 10 to 30% by weight of disintegrant, from 3 to 10% by weight of binders, from 1 to 5% 32 wt%.
A sustained-release matrix formulation comprising a simulated frit in which pellets are dispersed in a matrix.
3. The method of claim 2,
The active ingredient is present in an amount of 11 to 18% by weight based on the total weight of the matrix preparation, 30 to 39% by weight of an excipient, 20 to 29% by weight of a disintegrant, 4 to 8% by weight of a binder, 2 to 3% 31% by weight.
A sustained-release matrix formulation comprising a simulated frit in which pellets are dispersed in a matrix.
4. The method according to any one of claims 1 to 3,
Wherein the excipient is at least one selected from the group consisting of lactose, starch, white sugar, mannitol, sorbitol and microcrystalline cellulose.
A sustained-release matrix formulation comprising a simulated frit in which pellets are dispersed in a matrix.
4. The method according to any one of claims 1 to 3,
The disintegrant may be selected from the group consisting of Croscamellose sodium, Sodium starch glycolate, microcrystalline cellulose, Crospovidone, cross-linked povidine, Polyvinylpyrrolidone (PVP), hydroxypropylcellulose (low substituted), alginic acid, powdered cellulose, starch, and sodium alginate.
A sustained-release matrix formulation comprising a simulated frit in which pellets are dispersed in a matrix.
(a) preparing a pellet association by adding povidone dissolved in an appropriate amount of ethanol prepared in advance to a pellet in a high-speed reciprocating machine, mixing the simfurf citrate, the excipient and the disintegrant;
(b) drying and sizing the pellet association of (a) and adding and mixing the glidant to produce a pellet;
(c) mixing the matrix fried citrate, the excipient, and the disintegrant in a high-speed coalescer, mixing the prepared matrix conjugate with povidone dissolved in an appropriate amount of ethanol prepared in advance, as a binder;
(d) drying and granulating the matrix material of (c) to prepare a mixture after adding and mixing the pellets of the lubricant and the (b);
(e) pressing the mixture of (d) using a tablet machine to produce a tablet; And
(f) a step of adding opaque to the tablet of (e) and coating the pellet, wherein the pellet is dispersed in the matrix.

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