KR101587140B1 - Capsule containing mini-tablets comprising mosapride citrate for sustained-releasing formulation improving gastrointestinal disease 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, the manufacturing process is simple as compared with the conventional biodegradable or capsule preparation, and the active ingredient is filled in the capsule unlike ordinary tablets, so that there is little risk of contamination and deterioration by microorganisms and the like. It has the effect of having a pattern similar to the dissolution profile shown in the double column.

Description

Technical Field [0001] The present invention relates to a sustained-release capsule formulation containing a mosapride citrate mini tablet for the treatment of gastrointestinal diseases, and a method for preparing the same,

The present invention relates to a sustained-release capsule preparation comprising a mosapride citrate for the treatment of gastrointestinal diseases, characterized by a granular sustained-release preparation and a sustained-release formulation in the form of a mini-tablet, and a process for its preparation.

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 maximum blood concentration at the time of oral administration.

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 relates to a sustained-release capsule preparation containing mini-tablets which simultaneously contains a sustained-release preparation exhibiting a drug efficacy immediately after the active ingredient is injected into the body and a sustained-release sustained drug efficacy for more than 24 hours. The manufacturing process is relatively simple and the dissolution profile of the conventional tablet is similar to that of the conventional tablet and the dissolution profile is similar to that of the conventional tablet.

Accordingly, the present inventors prepared capsule preparations in which both mini-tablets and granules were simultaneously injected in order to simplify the manufacturing process and simultaneously satisfy a dissolution profile similar to the double-tablet, and confirmed the dissolution pattern similar to double-tablet and confirmed the present invention.

It is an object of the present invention to provide a sustained-release capsule preparation containing mini-tablets prepared by preparing mini-tablets and granules containing moscafide citrate as an active ingredient and putting them into capsules, The present invention also provides a sustained-release capsule preparation containing a mini-tablet, which comprises a mosafide citrate as an active ingredient, which can easily produce a capsule preparation that satisfies the above-mentioned conditions and simultaneously exhibits an elution pattern similar to that of a double tablet.

Another object of the present invention is to provide a method for producing a sustained-release capsules formulation containing mini-tablet comprising as an active ingredient morpha-fred citrate.

In one embodiment, the present invention provides a sustained release capsule formulation comprising mini-tablets comprising moscafide citrate for the treatment of gastrointestinal disorders.

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 sustained release is a slowly releasing system as a sustained drug release system, and is a system used for chronic diseases by being administered once or twice daily, by keeping the drug concentration constant for a predetermined time or more.

In the present invention, the mini-tablet refers to a tablet made by compressing a medicine in a predetermined shape as in the case of a tablet, but it is possible to vary the diameter of the mini-tablet differently from ordinary tablets having no change in diameter, The number of mini tablets which can be injected into the capsule increases. The capsule preparation may be prepared by filling a capsule into a capsule in the form of a liquid, a tablet, a powder, a granule, a mini tablet, or a pellet or by capsulating with a capsule base. A method of charging the capsules simultaneously in the form of mini-tablets, or encapsulating the capsules with a capsule base was used.

The gastrointestinal disorder may be referred to as various names such as chronic dyspepsia, non-ulcerative dyspepsia, chronic diarrhea, irritable bowel, irritable bowelitis, chronic gastritis, chronic abdominal pain, neurogenic gastroenteritis and gastrointestinal pain, constipation, diarrhea, vomiting It is a disease that has various symptoms repeatedly. Examples include various symptoms occurring in the gastrointestinal tract, but the type is not limited thereto.

In another embodiment, the present invention provides a method for preparing a sustained-release capsules formulation comprising mini-tablet comprising moscafide citrate for the treatment of gastrointestinal disorders.

In order to prepare the sustained-release capsule preparation containing the micro-purified citrate salt of the present invention, the mini-tablet and the granule are mixed, combined and granulated, respectively. The mini-tablet is then tableted and the granule and the mini-tablet are encapsulated .

Specifically,

(a) mixing simfurf citrate and an excipient, lactose hydrate, in a high-speed aliquot and mixing the resulting mixture with povidone dissolved in an appropriate amount of ethanol prepared beforehand to prepare a granular association product;

(b) granulating the granular material of (a) to produce granules;

(c) preparing a mini tablet association product by adding povidone dissolved in an appropriate amount of ethanol prepared in advance into a high-speed compounding machine, mixing the simfurf citrate and the excipient, the sustained-release agent and the disintegrant into a high-

(d) drying and sizing the mini-tablet association (c), adding a lubricant and mixing, and then preparing a mini-tablet mixture;

(e) preparing a mini tablet preparation by tableting the mini tablet mixture of (d) using a tableting machine; And

(f) filling the capsules with the granules of (b) and the mini-tablet of (e), and coating the capsules with opaques; and The method comprising:

In the present invention, it is preferable that the simulated free citrate is contained in an amount of 10 to 20% by weight based on the weight of the capsule 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 as to make granules and mini tablets of a desired size. Any type of pharmaceutical excipient may be used as long as it is pharmaceutically acceptable. Examples of such excipients include lactose, starch, sandalwood, mannitol, sorbitol and microcrystalline cellulose . Lactose hydrate, microcrystalline cellulose 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 addition, the present invention relates to a method for preparing a pharmaceutical composition comprising the steps of: mixing a high-viscosity hydroxypropylmethylcellulose and a low-viscosity hydroxypropylmethylcellulose in a weight ratio of 10: 1 to 1: 1, .

In the case of the sustained-release capsule preparation containing the mosaaphide citrate of the present invention, there was no fear of arrhythmia and cardiogenic death due to the prolongation of the QT interval in the cisapride, and the dopamine-2 (D-2) receptor Because there is no antagonism, there is no side effects such as central nervous system (CNS) side effects (extrapyramidal symptoms), hyperprolactinemia (milk secretion, feminized breast).

In addition, the manufacturing process is simple as compared with the conventional biodegradable or capsule preparation, and the active ingredient is filled in the capsule unlike ordinary tablets, so that there is little risk of contamination and deterioration by microorganisms and the like. It has the advantage of having a pattern similar to the dissolution profile shown in the double column.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic diagram of a capsule preparation containing mini-tablets containing a mosaic pride citrate according to the present invention.
Figure 2 shows the dissolution rates at 5 mg of the capsule preparation prepared in Examples 2 to 5 and pH 4.0 of the eluate 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 capsules containing mini-tablets containing moscafide citrate

1-1. Manufacture of Granules Containing Modified Fried Citrate

The mashafrid citrate and lactose hydrate were mixed and kneaded in a high-speed coater, and granules were prepared by co-and granulation process by adding povidone K-30 solution previously dissolved in ethanol.

1-2. Preparation of Mini Tablets Containing Modified Fried Citrate

HPC 2910), high viscosity hydroxypropyl methylcellulose (100,000 cps, HPMC 2208), low-substituted hydroxypropylcellulose (L-HPC), low viscosity hydroxypropyl methylcellulose ) Are mixed and granulated by previously adding povidone K-30 solution dissolved in ethanol, and dried in a cabinet dryer at 50 to 60 for 30 to 40 minutes (LOD 2% or less). After the preparation, silicon dioxide and magnesium stearate are added and mixed to prepare a mini tablet.

1-3. Preparation of capsule preparation

The granules and mini tablets prepared above were filled into capsules using a capsule filling machine and coated with methanol as a solvent to prepare a capsule preparation.

Example 2-5: Preparation of capsules containing mini-tablets according to the content of active ingredient

In order to compare the properties of the capsules containing the mini-tablets according to the differences in the content of the monoflip citrate, the content of the monoflip citrate in the capsule preparation prepared in Example 1 was varied so that the contents of the components were as shown in Table 1 A capsule preparation containing a mini tablet was prepared.

division Classification ingredient Example 2 Example 3 Example 4 Example 5 Granule chief ingredient Mosaic pride citrate 5 8 10 13 Excipient Lactose baggage 65 62 60 57 Binder Povidone K-30 5 5 5 5 Total (mg / tablet) 75 75 75 75 mini
refine chief ingredient Mosaic pride citrate 10 7 5 2 Excipient Microcrystalline cellulose 13 16 18 21 Lactose baggage 10 10 10 10 Westernization
Mechanism Low viscosity hydroxypropyl methylcellulose (HPMC 2910) 6 6 6 6 High viscosity hydroxypropyl methylcellulose (HPMC 2208) 16 16 16 16 Binder Povidone K-30 5 5 5 5 Disintegration Low-substituted propyl cellulose 14 14 14 14 Lubricant Silicon dioxide 0.4 0.4 0.4 0.4 Magnesium stearate 0.6 0.6 0.6 0.6 menstruum Methanol 170 170 170 170 Coating agent Opa Dry 5 5 5 5 Total (mg / tablet) 155 155 155 155

Example 6: Test for dissolution rate

The dissolution profile of the capsule preparation containing the mosaaphide citrate salt was confirmed by in vitro dissolution test of the capsule preparation containing the mosaaphride citrate salt prepared as described above to confirm the dissolution profile of the capsule preparation containing the mosaaphide citrate mini tablet at pH 4.0, Are shown in Table 2 and Fig.

The sustained-release preparation made of the capsule preparation containing the mini-tablet of the present invention is characterized in that the drug is continuously eluted at a constant concentration for 24 hours, and the elution test is carried out for 1 hour The elution rate after 30 minutes was 30 to 42%, the elution rate after 4 hours was 46 to 75%, the elution rate after 8 hours was 65 to 89%, and the elution rate after 16 hours was 91 to 100% .

- pH 4.0 The dissolution rate test

Sample: Mini-tablet-containing capsule preparation containing simulated free citrate salt of Examples 2 to 5

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

Test temperature: 37.5 ℃

Elution method: Korean Pharmacopoeia dissolution test Method 2 (paddle method), 50 rotations per minute

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 42.1 60.4 75.4 81.7 89.0 92.7 95.7 99.4 100 Example 3 36.4 55.7 66.7 75.4 80.0 85.4 91.0 95.4 97.5 Example 4 32.8 45.7 54.7 62.8 71.8 80.9 88.7 92.4 94.2 Example 5 30.1 38.7 46.8 55.9 65.7 75.9 86.4 91.2 94.0

Claims (6)

Wherein the mordant fried or salt thereof is used as an active ingredient,
Granules comprising the active ingredient, the excipient and the binder, and
A sustained-release capsule preparation comprising the above-mentioned active ingredient, an excipient, a sustained release agent-binding agent, a disintegrant and a lubricant,
The sustained release agent may be prepared by mixing hydroxypropylmethylcellulose having a high viscosity and low viscosity in a weight ratio of 10: 1 to 1: 1,
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)
Sustained release capsule formulation:
After 1 hour, the dissolution rate was 30 to 42%, the dissolution rate after 8 hours was 65 to 89%, and the dissolution rate after 16 hours was 91 to 100%.
The method according to claim 1,
Wherein the active ingredient comprises 10 to 20% by weight of the total weight of the capsule preparation, 20 to 56% by weight of an excipient, 10 to 30% by weight of a disintegrant, 3 to 10% by weight of a binder and 1 to 5% sign,
Sustained release capsule formulation.
3. The method of claim 2,
The active ingredient preferably comprises 11 to 18% by weight, more preferably 30 to 39% by weight, disintegrant 20 to 29% by weight, binder 4 to 8% by weight and lubricant 2 to 3% by weight based on the total weight of the capsule preparation ≪ / RTI >
Sustained release capsule formulation.
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, sandalwood, mannitol, sorbitol and microcrystalline cellulose.
Sustained release capsule formulation.
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, or a mixture thereof. In fact,
Sustained release capsule formulation.
(a) mixing simfurf citrate and an excipient, lactose hydrate, in a high-speed aliquot and mixing the resulting mixture with povidone dissolved in an appropriate amount of ethanol prepared beforehand to prepare a granular association product;
(b) granulating the granular material of (a) to produce granules;
(c) preparing a mini tablet association product by adding povidone dissolved in an appropriate amount of ethanol prepared in advance into a high-speed compounding machine, mixing the simfurf citrate and the excipient, the sustained-release agent and the disintegrant into a high-
(d) drying and sizing the mini-tablet association (c), adding a lubricant and mixing, and then preparing a mini-tablet mixture;
(e) preparing a mini tablet preparation by tableting the mini tablet mixture of (d) using a tableting machine; And
(f) filling the capsules with the granules of (b) and the mini-tablet of (e), and coating the capsules with opaques.
≪ / RTI >

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