KR101645313B1 - Sustained release formulation comprising mosapride citrate in matrix and coating layer - Google Patents

Abstract

The present invention relates to a method for preparing a sustained-release sustained-release matrix formulation containing a simulated fry that shows the effect of improving gastrointestinal tract diseases.
The present invention relates to a sustained-release sustained-release formulation comprising a coating layer comprising an active ingredient and a coating agent on the surface of a matrix formulation comprising an active ingredient, an excipient, a disintegrant, a sustained-release agent and an additive, Matrix formulation.
The present invention has the advantage that the coating layer and the matrix can exhibit the effects of the immediate layer and the extended layer, respectively, because the matrix contains the active ingredient and various additives.

Description

[0001] The present invention relates to a sustained-release matrix composition for treating gastrointestinal diseases, which comprises a matrix and a coating layer, and a preparation method thereof,

The present invention relates to a sustained-release sustained-release matrix formulation containing a mosapride, which comprises a matrix containing an active ingredient and various additives, unlike an existing matrix, so that the coating layer and the matrix each contain a pharmacologically active ingredient To a method for producing a drug containing a simulated free drug.

Due to the development of the industry, various stresses and dietary habits of modern people are being exposed to diseases of digestive system unknown due to westernization. Functional dyspepsia is not life-threatening, but it can have a major impact on quality of life if chronic symptoms are repeated. Digestive system diseases include reflux esophagitis (GERD), chest pain through acid reflux Diseases characterized by symptoms became one of the most common diseases.

In Korea, the main symptom is genital soreness and depression. Examples of gastrointestinal stimulants include anti-dopamine drugs (Mexoron, domperidone, levopride, itopride), 5-hydroxytryptamine4 (5-HT4) receptor agonists, and erythromycin acting on motilin receptors. A method of treating gastroesophageal reflux (GERD) is Pro kinetic agents (Prokinetic agent), histamine H ₂ receptor antagonist, anti the like;; (PPIs Proton pump inhibitors) (H 2 receptor antagonists H 2 RAs) and a proton pump inhibitor Secretory compounds and the like. Among these, gastrointestinal stimulants are the most commonly used drugs in combination with gastric acid secretion inhibitors in the treatment of functional dyspepsia. As a drug, it differs according to its functional group. Mosafride, a 5-hydroxytryptamine4 (5-HT4) receptor agonist, is a typical drug. Mosapride (4-amino-5-chloro-2- fluorobenzyl) -2-morpholinyl] methylbenzamide) is a compound having the following chemical structural formula and is disclosed as a digestive tract exercise promoter.

Gt; Structure of the simulated fly

Mossafrid is a selective 5-HT, 5-hydroxytryptamine receptor agonist that acts selectively on the serotonin (5-HT) receptors on the digestive tract's cholinergic neurons to stimulate the secretion of acetylcholine and stimulate strong gastrointestinal motility . (Cisapride), a non-selective 5-HT4 receptor agonist, has no fear of arrhythmia and cardiogenic death due to prolongation of the QT interval and has no dopamine-2 (D-2) Nervous System, CNS) It is a safe drug without side effects such as side effects (extrapyramidal symptoms), hyperprolactinemia (milk secretion, feminized breast).

Mossafrid can be taken both before meals and after meals, and it is administered 3 times a day with 1 tablet of 5mg once a day. The drug efficacy after administration is rapid, and the administration of about 2 weeks gives a high improvement effect of symptoms of digestive dysfunction. It exhibits a short biological half-life of about 1.4 to 2.0 hours and disappears rapidly after the drug is absorbed into the body, Duration is short. Since the physiochemical properties of the simulated freedoms are rapidly metabolized and disappear when they are absorbed into the body, there is a problem in that the duration of the blood and the duration of the drug action of the rapid-type or quasi-drug formulations commercially available are short.

The sustained-release matrix formulation is uniformly present in drug and sustained release formulations and does not require strict production control as compared to sustained release coating formulations and can be produced through the same manufacturing operations as conventional fast-release formulations . Therefore, high productivity is expected, and even when a high-dose preparation of a drug is manufactured, it is easy to manufacture a preparation 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.

It is an object of the present invention to provide a method for producing a sustained-release matrix formulation having the advantage that the form of the matrix comprising the simulated fried citrate and the form of the formulation constituting the coating layer can exhibit the effects of the immediate layer and the extended layer, respectively.

The present invention provides a sustained-release matrix formulation for the treatment of gastrointestinal diseases, comprising a mosaaphride citrate.

In the present invention, the mosaaphride citrate accelerates gastric emptying throughout the human gastrointestinal tract and has excellent efficacy in the treatment of gastritis, reflux esophagitis, functional dyspepsia and irritable bowel syndrome.

According to the above object, unlike a matrix-type preparation in which an active ingredient is not contained in an existing matrix, the present invention contains an active ingredient and various additives in the matrix.

The present invention includes a cosmetic preparation as an active ingredient, and the matrix preparation is composed of an active ingredient, an excipient, a disintegrant, a sustained-release base, and an additive, and the coating layer is composed of an effective ingredient and a coating agent. The formulation form of the preparation is composed of a matrix preparation which constitutes a coating layer containing the active ingredient on the surface of the matrix.

In the present invention, it is preferable that the simpia fructure citrate is contained in an amount of 10 to 20 wt% based on the weight of the sustained release form. If it is contained in an amount less than 10% by weight, the pharmacological effect is deteriorated. If it is contained in an amount exceeding 20% by weight, side effects such as Yanbyeon, diarrhea and dryness may occur.

Disintegrants used in the formulations of the present invention are used to absorb water and promote disintegration of the formulation to enhance dissolution of the simfried citrate salt. Examples of disintegrants that may be used in the formulations of the present invention include croscarmellose sodium Croscamellose sodium, sodium starch glycolate, microcrystalline cellulose, crospovidone, cross-linked povidone and other commercially available polyvinylpyrrolidone, PVP, Povidone One or a mixture thereof selected from the group consisting of hydroxypropylcellulose, low substituted hydroxypropylcellulose, 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.

Polyvinylpyrrolidone (povidone, povidone K-30 having a molecular weight of 30 is used) was used as a binder used in the preparation of the present invention. It is a synthetic water-soluble polymer and can be dissolved in an organic solvent, . The binder is preferably added in an amount of 3 to 10% by weight of the formulation, 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 formulate the preparation. When the binder is added in an amount exceeding 10% Becomes difficult.

Further, the lubricant used in the formulation of the present invention can improve the fluidity of the powder particles, thereby increasing the filling property of the die, which is the lower part of the tablet machine, and improving the punching ability of the powder particles, thereby reducing the friction between the dies and facilitating the compression and release of the formulation. 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 preparation. When the lubricant is added in an amount of less than 1% by weight, it is difficult to formulate the formulation. When the lubricant is added in an amount exceeding 5% Which affects the dissolution profile of the formulation.

Examples of the coating agent used in the formulation of the present invention include natural and synthetic starch, natural and synthetic cellulose, acryl, resin, methacrylate, shellac, ammonia methacrylate copolymer (Eudragit RS), ammonia methacrylate copolymer (Eudragit L), methacrylic acid copolymer (Eudragit L), methacrylic acid copolymer (Eudragit E), ethyl acrylate and methyl methacrylate copolymer (Eudragit NE), methacrylic acid copolymer (Eudragit S).

The formulation is preferably contained in an amount of about 5 to 40% by weight based on the weight of the matrix preparation, more preferably about 10 to 30% by weight based on the weight of the matrix preparation.

The present invention relates to a coating layer containing an effective ingredient and a matrix preparation, which not only exhibits an immediate gastrointestinal motility disorder improvement effect, but also differs from a conventional technique in terms of structure, and contains an active ingredient and various additives in the matrix, And it is very useful because it has the advantage of showing the effect of the extended layer.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a schematic view of a matrix preparation containing an active ingredient and a coating layer, showing an example of a formulation according to the present invention. Fig.
FIG. 2 shows the dissolution rates of the matrix prepared in Examples 1 to 3 according to the present invention and the sustained-release matrix preparation for treating gastrointestinal diseases containing the mosaic pride in the coating layer according to the active ingredient in the pH 4.0 condition of the eluate.

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 1-3: Preparation of sustained-release matrix formulation according to the active ingredient content

In order to compare the properties of the matrix preparation according to the difference in the content of the simulated frit, the sustained-release matrix formulation was prepared by varying the content of the active ingredient so that each component had the content shown in Table 1 below. I will explain in more detail. 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.

division Classification ingredient Example 1 Example 2 Example 3 That is,
(mg / tablet) chief ingredient Mosaic pride citrate 5.0 10.0 12.0 Coating agent Eudragit 0.5 0.5 0.5 menstruum ethanol 94.5 85.0 87.5 Total (mg / tablet) 100.0 100.0 100.0 Sustainable
(mg / tablet) chief ingredient Mosaic pride citrate 10.0 5.0 3.0 Excipient Lactose baggage 5.0 10.0 12.0 Excipient Microcrystalline cellulose 40.0 40.0 40.0 Binder Hydroxypropylcellulose 5.0 5.0 5.0 Sustainable fire system Hydroxypropylmethylcellulose 4000 cps 27.0 27.0 27.0 Sustainable fire system Hydroxypropyl methylcellulose (high viscosity) 9.0 9.0 9.0 Lubricant Light anhydrous silicic acid 1.5 1.5 1.5 Lubricant Magnesium stearate 2.5 2.5 2.5 Total (mg / tablet) 100.0 100.0 100.0 Total (mg / tablet) 200.0 200.0 200.0

Example 4: Elution rate test

In order to compare the dissolution rates according to the contents of the active ingredients of Examples 1 to 3, the dissolution rate test was carried out at pH 4.0 under the conditions of pH 4.0 and pH below.

The sustained-release matrix preparation to which the active ingredient of the present invention was added exhibited a dissolution pattern similar to that of the conventional two-layer tablet preparation for 24 hours, and the dissolution test was carried out under this pH condition as the reference dissolution at pH 4.0 After 1 hour, the dissolution rate after 29 hours was 29 to 35%, the dissolution rate after 2 hours was 39 to 49%, the dissolution rate after 4 hours was 44 to 57%, the dissolution rate after 8 hours was 61 to 71% 100%, indicating that the initial elution time exhibited a relatively predictable dissolution pattern as desired by the inventor.

- pH 4.0 The dissolution rate test

Specimen: The simulated free citrate sustained-release preparation of Examples 2 to 4

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 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 1 29.1 39.2 44.3 53.4 61.5 70.3 78.8 84.2 89.7 Example 2 32.5 42.7 49.5 56.7 64.7 73.2 81.9 87.5 95.3 Example 3 35.3 49.2 57.9 63.1 71.4 78.0 87.6 94.4 100

Claims (4)

Comprising a mosaic fly as an active ingredient,
A matrix comprising the active ingredient, the excipient, the disintegrant, the sustained-release base, and the excipient,
A coating layer comprising the active ingredient and the coating base,
Wherein the sustained release matrix formulation comprises 10 to 20% by weight of the active ingredient, 20 to 60% by weight of excipient, 10 to 30% by weight of disintegrant, 3 to 10% by weight of binder and 1 to 5%
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. ,
The sustained-release sustained-release matrix preparation for the treatment of gastrointestinal diseases, which satisfies the following dissolution profile at a temperature of 37 DEG C and pH 4.0 in accordance with Method 2 of the Korean Pharmacopoeia (Paddle Method)
In the pH 4.0 eluent condition, the contained active ingredient was eluted from 29 to 35.3% after 1 hour, from 61 to 71.4% after 8 hours, and from 89 to 100% after 24 hours.
delete The method according to claim 1,
Wherein the excipient is at least one selected from the group consisting of lactose and microcrystalline cellulose.
delete

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