KR101045508B1 - Film-coated tablet - Google Patents

Abstract

4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide (hereinafter referred to as "Compound A") or its physiology A film-coated tablet containing a salt that is acceptable to a scholar, wherein the film-coated tablet having a fast dissolving property, which is excellent in storage stability, comprises (a) a compound containing Compound A or a physiologically acceptable salt thereof, and ( b) A fast dissolving film coating having a coating layer containing at least one plasticizer (eg, triacetin) selected from the group consisting of a compound substantially free of a plasticizer or having an ester bond on the predetermined surface thereof. tablet.

Film coated tablet

Description

Film Coating Tablet {FILM-COATED TABLET}

The present invention relates to 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide or a physiologically acceptable salt thereof. It is related with the film coating tablet containing.

(±) -4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide (hereinafter referred to as "mosafride" Is a selective serotonin 4 receptor agonist and has a good digestive motility promoting action (US Pat. No. 4,870,074). In addition, mosapride or its physiologically acceptable salt is also useful as a therapeutic drug for reflux esophagitis, gastrectomy syndrome, and other digestive symptoms.

As solid preparations containing mosaprides, Example 245 of US Pat. No. 4,870,074 describes tablets without film coatings containing citric acid mosaprides. The tablet is a solid preparation containing citric acid sulfide, corn starch, lactose, crystalline cellulose, hydroxypropyl cellulose, hard silicic anhydride, and magnesium stearate.

Citrate mosapride dihydrate has already been put to practical use for the purpose of improving digestive symptoms associated with chronic gastritis. Tablets containing 2.5 mg or 5 mg (1.72 mg or 3.44 mg as mosapride) as citric acid sulfide (anhydride) are commercially available under the trade name "gasmotin" in Japan. Commercially available tablets take the form of a film-coated tablet in that mosapride is a chemical having a bitter taste, and aluminum packaging is applied to prevent the formation and coloring of by-products under long-term storage.

DISCLOSURE OF INVENTION

SUMMARY OF THE INVENTION An object of the present invention is to provide a fast-soluble film-coated tablet having excellent storage stability in a film-coated tablet containing mosapride or a physiologically acceptable salt thereof, even without carrying out protective packaging such as aluminum packaging. It is to offer.

MEANS TO SOLVE THE PROBLEM As a result of earnestly examining in order to solve such a subject, the present inventors accelerate | stimulate decomposition | disassembly of a mosapride according to the kind of specific plasticizer considered to be necessary when forming a coating layer in a film coating tablet, and decomposition | disassembly of a mosapride. It was found that there is something that suppresses (or does not affect degradation).

Therefore, first, as a result of attempting to produce a film-coated tablet using the film coating composition from which the plasticizer has been removed, undesirably, even if the aluminum packaging is not carried out even in long-term storage, the decomposition of the mosapride is suppressed, It discovered that coloring was suppressed and completed this invention.

As a result of the inventors' studies, when formulated using a film coating composition containing a specific formulation component that can inhibit the decomposition of the mosapride or does not affect the decomposition, there is no problem in manufacturing. Also, even in the case of long-term storage, it was found that even if the aluminum packaging was not carried out, the decomposition of the mosapride was suppressed and the coloring of the formulation was suppressed, thereby completing the present invention.

That is, the present invention, 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide or its physiologically acceptable A fast-soluble film-coated tablet containing a salt, which is coated with a coating layer substantially free of a plasticizer or containing a specific formulation component, is provided.

More specifically, the following invention is provided.

Item 1: 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide (hereinafter referred to as "compound A") Or as a fast dissolving film-coated tablet containing the physiologically acceptable salt thereof,

(a) a predetermined amount containing Compound A or a physiologically acceptable salt thereof, and

(b) The predetermined surface is substantially free of a plasticizer or triacetin, diethyl phthalate, dibutyl sebacate, tributyl citrate, diethyl sebacate, glycerin fatty acid ester, and acetylated monoglycelide Acetyl triethyl citrate, acetyl tributyl citrate, monostearin, sorbitan monolaurate, dioctyl phthalate, butyl phthalyl butyl glycolate and medium chain fatty acid triglycerides. 1 type coating layer

Film coated tablet having a.

Item 2: The film-coated tablet according to item 1, having a coating layer substantially free of a plasticizer.

Item 3: triacetin, diethyl phthalate, dibutyl sebacate, tributyl citrate, diethyl sebacate, glycerin fatty acid ester, acetylated monoglycelide, acetyl triethyl citrate, acetyl tributyl citrate, monostearine, sorbitan The film-coated tablet of Claim 1 which has a coating layer containing at least 1 type of specific formulation components selected from the group which consists of a monolaurate, dioctyl phthalate, butylphthalyl butyl glycolate, and a heavy chain fatty acid triglyceride.

Item 4: Specific formulation ingredients include triacetin, diethyl phthalate, dibutyl sebacate, tributyl citrate, diethyl sebacate, glycerin fatty acid esters, acetylated monoglylides, acetyltriethyl citrate and acetyltributyl citrate. The film-coated tablet according to item 3, which is selected from the group consisting of.

Item 5: The film-coated tablet according to item 3, wherein the specific formulation component is selected from the group consisting of triacetin, diethyl phthalate, dibutyl sebacate and tributyl citrate.

Item 6: The film-coated tablet according to item 3, wherein the specific formulation component is triacetin.

Item 7: The film-coated tablet according to item 3, wherein the content of the specific formulation component is about 0.1 to about 30% by weight in the coating layer.

Item 8: The film-coated tablet according to any one of items 1 to 7, wherein the physiologically acceptable salt of compound A is a dihydrate of citrate of compound A.

Item 9: The film-coated tablet according to any one of Items 1 to 8, wherein the content of Compound A or its physiologically acceptable salt is about 0.5 to about 70% by weight in terms of Compound A.

Item 10: When the film-coated tablet is stored for 6 months in a container at 40 ° C under a plug of 75% RH, the proportion of the amount of the compound A produced by the flexible substance is determined by high performance liquid chromatography. The film-coated tablet according to any one of items 1 to 9, which is about 1% or less in the measured area percentage.

Item 11: A commercial package comprising the film-coated tablet according to item 1 and a substrate related to the film-coated tablet, wherein the film-coated tablet is used for promoting digestive tract motor function, improving symptoms after gastrectomy, or preventing or treating gastroesophageal reflux. A commercial package comprising a substrate on or within a package that can be used or should be used.

Since the film-coated tablet of this invention has the said characteristic, even if it does not carry out protective packaging, such as aluminum packaging, Compound A or its physiologically acceptable salt does not decompose well, and can be preserve | saved in a stable state. And when taking the film coating tablet of this invention, it does not feel a bitter taste.

BRIEF DESCRIPTION OF THE DRAWINGS It is a graph which shows the result of the contact test of the citrate of the compound A-a (racemic body of the compound A) of this invention with various components.

2 is a graph showing the results of stability tests of the formulations obtained in Example 1 and Comparative Example 1. FIG.

3 is a graph showing the results of stability tests of the formulations obtained in Example 1 and Comparative Example 1. FIG.

4 is a graph showing the results of stability tests of the formulations obtained in Example 2 and Comparative Example 2. FIG.

5 is a graph showing the results of stability tests of the formulations obtained in Example 2 and Comparative Example 2. FIG.

Carrying out the invention  Best form for

A first aspect of the present invention is a fast-soluble film-coated tablet having a coating containing Compound A or a physiologically acceptable salt thereof and a coating layer substantially free of a plasticizer on the predetermined surface. The film-coated tablets exhibit an effect of inhibiting decomposition of Compound A as an active ingredient and suppressing coloration of the formulation even when long-term storage is not carried out by protective packaging such as aluminum packaging.

Film-coated tablets coated with a film usually contain a plasticizer in the coating layer (coating layer), and the plasticizer has been considered not to react with the active ingredient. However, when the present inventors have contacted certain plasticizers, specifically, polyethylene glycol, poloxamer, polysorbate, polyoxyethylene cured castor oil, glycerin, and the like, Compound A or a physiologically acceptable salt thereof, It was found that the decomposition of A was promoted. Specifically, as shown in the following Reference Examples, it was found that a large amount of decomposition products (flexible materials) were produced by contacting Compound A or a physiologically acceptable salt with the above components in the present invention. On the other hand, it has also been found that there is a plasticizer that inhibits decomposition of Compound A.

Thus, it has been found that when the coating layer is coated with a coating layer substantially free of the plasticizer to be contained in the coating layer, the decomposition of Compound A is suppressed even in long term storage.

The term "substantially free of a plasticizer" in the present embodiment means that not only the plasticizer having the action of promoting the decomposition of the compound A when it comes into contact with the compound A, but also inhibits (or does not affect) the decomposition of the compound A. It does not contain a plasticizer. Here, as the plasticizer, poloxamer, polysorbate, propylene glycol, polyethylene glycol, glycerin, polyoxyethylene cured castor oil, triacetin, diethyl phthalate, dibutyl sebacate, tributyl citrate, diethyl sebacate, glycerin Fatty acid ester, acetylated monoglycelide, acetyl triethyl citrate, acetyl tributyl citrate, monostearin, sorbitan monolaurate, dioctyl phthalate, butyl phthalyl butyl glycolate, heavy chain fatty acid triglyceride, etc. are mentioned. .

A second aspect of the present invention is a fast-soluble film-coated tablet having a coating containing Compound A or a physiologically acceptable salt thereof, and a coating layer containing at least one specific formulation component on the predetermined surface thereof. In the film-coated tablet, the coating process proceeds smoothly by incorporating a specific formulation component into the coating layer, and even in long-term storage, the decomposition of compound A, which is an active ingredient, is not promoted or degradation is inhibited even when protective packaging such as aluminum packaging is not performed. It also shows the effect that the coloring of the formulation is suppressed. Moreover, even in manufacture, it does not cause trouble.

Specific formulation ingredients

Examples of the "specific formulation component" in this embodiment include triacetin, diethyl phthalate, dibutyl sebacate, tributyl citrate, diethyl sebacate, glycerin fatty acid esters, acetylated monoglycerides, acetyl triethyl citrate, Acetyl tributyl citrate, monostearin, sorbitan monolaurate, dioctyl phthalate, butyl phthalyl butyl glycolate and heavy chain fatty acid triglycerides. These compounds are generally mix | blended with a formulation as a plasticizer. In addition, some of these compounds may be blended into the formulation as a dispersant, brightening agent, stabilizer, surfactant, or the like.

Therefore, at least one of the specific formulation components, specifically, triacetin, diethyl phthalate, dibutyl sebacate, tributyl citrate, diethyl sebacate, glycerin fatty acid ester, acetylated monoglycerides, acetyl triethyl citrate , At least one component selected from the group consisting of acetyl tributyl citrate, monostearin, sorbitan monolaurate, dioctyl phthalate, butyl phthalyl butyl glycolate and heavy chain fatty acid triglycerides is preferably blended into the coating layer. . Thereby, decomposition | disassembly of compound A is further suppressed, a coating layer becomes stronger, and the slipperiness | lubricacy (including fluidity | liquidity) of a tablet may also be sufficient. Preferably, they are triacetin, diethyl phthalate, dibutyl sebacate, tributyl citrate, diethyl sebacate, glycerin fatty acid ester, acetylated monoglycelide, acetyl triethyl citrate and acetyl tributyl citrate, more preferred. Preferably triacetin, diethyl phthalate, dibutyl sebacate and tributyl citrate.

Content of these specific formulation components is about 0.1 to about 30 weight% in a coating layer, Preferably it is about 2 to about 25 weight%, Especially about 7 to about 20 weight% is preferable.

Hereinafter, the features and components common to the first and second aspects of the present invention will be described.

The "fast solubility" of the film-coated tablet according to the present invention means the dissolution rate after 30 minutes in the dissolution test (37 ° C., paddle method, 50 revolutions / minute, water of 900 ml of solvent) described in the 14th revised Japanese Pharmacy Room. It means more than%. The dissolution rate is preferably 90% or more, and more preferably 95% or more.

Compound A or its physiologically acceptable salts

Compound A related to the present invention, that is, 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide, is represented by the following formula :

It is a compound represented by, and has a good digestive motility promoting action as a selective serotonin 4 receptor agonist. Although the compound A which concerns on this invention may be a racemate, or one optically active substance, a racemate is preferable.

In addition, the compound A may be a free body and its physiologically acceptable salt may be sufficient as it. As the salt, acid addition salts are preferable. For example, as addition salts of organic acids, formate, acetate, lactate, adipic acid salts, citrate, tartarate salts, fumarate salts, methanesulfonate salts, maleate salts, etc. , Hydrochloride, sulfate, nitrate, phosphate and the like can be exemplified. Among these, citrate is especially preferable. The compound A or its physiologically acceptable salt may be a solvate or a hydrate or a non-hydrate. Preferably, the citrate hydrate is preferable, and citrate dihydrate is particularly preferable.

The compound A or a physiologically acceptable salt thereof can be prepared, for example, by the method described in US Pat. No. 4870074 or a method similar thereto.

Prescribed

The "predetermined" may be Compound A or its physiologically acceptable salt alone, but in general, it is formed by blending other formulation components. These other formulation components have no problem even if they are blended, and any of them may be used as long as there is a need for blending. For example, binders, excipients, glidants, disintegrating agents and the like can be given as examples.

The content of Compound A or its physiologically acceptable salt is about 0.01 to about 90% by weight, preferably about 0.5 to about 70% by weight, and more preferably about 0.5 to about 50% by weight, in terms of Compound A. %, More preferably about 0.5 to about 30% by weight.

Binder

Specific examples of the binder include gum arabic, starch paste, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, pullulan, gelatin, ethyl cellulose, methyl cellulose, sodium carmellose, dextrin, povidone and the like. have. Preferably, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, etc. are mentioned. The amount of the binder may be an amount that maintains the hardness of the tablet and does not interfere with disintegration in the digestive tract, and is usually about 0.5 to about 10% by weight, preferably about 1 to about 7% by weight.

Excipient

Specific examples of the excipient include lactose, starch, mannitol, crystalline cellulose, sucrose, erythritol, trehalose, anhydrous calcium phosphate, calcium sulfate and the like, and lactose, starch, mannitol, crystalline cellulose and the like are preferable. The compounding quantity is about 5 to about 97 weight% normally, Preferably it is about 10 to about 80 weight%.

Glidants

Specific examples of the fluidizing agent include hard silicic anhydride, magnesium metasilicate aluminate, and the like, and hard silicic anhydride is preferable. The compounding quantity is about 0.01 to about 10 weight% normally, Preferably it is about 0.1 to about 5 weight%.

Disintegrant

Examples of the disintegrating agent include low-substituted hydroxypropyl cellulose, calcium carmellose, croscarmellose sodium, crospovidone and the like. Among these, in the low-substituted hydroxypropyl cellulose, the hydroxypropoxy group content is usually about 5 to about 16% by weight, preferably about 7 to about 16% by weight, more preferably about 10 to about 16% by weight is used. The compounding amount of the disintegrating agent is usually about 2 to about 30% by weight, preferably about 5 to about 25% by weight.

In addition, you may mix | blend formulation components, such as glidants, such as magnesium stearate, zinc stearate, and calcium stearate, as needed.

Predetermination can be manufactured by compression-molding according to a conventional method, combining suitably the said formulation component. Among these components, it is preferable to select lactose and starch as excipients, hydroxypropyl cellulose as a binder, hard silicic anhydride as a fluidizing agent, low-substituted hydroxypropyl cellulose as a disintegrating agent, and magnesium stearate as a lubricant.

Coating layer

The following are mentioned as a component contained in a coating layer other than the said specific formulation component.

Film base

Examples of the film base include cellulose derivatives such as hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), methyl cellulose (MC) and ethyl cellulose (EC), polyvinyl alcohol (PVA), and polyvinylpyrrolidone. Vinyl polymers, such as (PVP), acrylic polymers, such as a methacrylic acid copolymer, etc. can be illustrated. Preferably, HPMC can be illustrated. The concentration of the film base in the coating layer is preferably about 5 to about 100% by weight, preferably about 30 to about 100% by weight, particularly about 50 to about 98% by weight, in the case of the coating layer containing no plasticizer. Also, for coating layers containing certain formulation components, about 5 to about 99.9 weight percent, preferably about 30 to about 98 weight percent, especially about 50 to about 93 weight percent.

As a component which may be added to coating layers other than the said film base and the said specific formulation component, for example, coloring agents, such as titanium oxide and iron oxide 32 (content in a coating layer: about 0.1 to about 50 weight%), anti-sticking agents, such as talc, (Content in the coating layer: about 0.1 to about 50% by weight), a polishing agent such as hard silicic anhydride (content in the coating layer: about 0.1 to about 10% by weight) and the like. In addition, you may mix | blend a formulation component suitably as needed.

The step of forming the coating layer is prepared by selecting one or two or more film bases (or film bases and specific formulation components) of the substrate and dissolving or suspending them in an organic solvent such as water or ethanol, preferably water. It can carry out by spraying a liquid composition (coating liquid) on a predetermined top. Moreover, you may mix | blend the said coloring agent, anti-sticking agent, a brightening agent, etc. with a coating liquid as needed.

The film coated tablet of this invention is stable also in long term storage. Therefore, when the film-coated tablet of the present invention is stored in a container and stored for 6 months under the condition of opening the stopper of 40 ° C and 75% RH in the container, the amount of flexible substance (total amount of flexible substance) is converted into a high-performance liquid chromatography method. Is measured, the ratio of the total amount of flexible material in the area percentage is about 1% or less. It is preferably about 0.6% or less. The amount of formation of the flexible substance (total amount of flexible substance) is the total amount of the decomposition product of Compound A, the intermediate in preparation, the impurity in preparation, etc., and means the total amount detectable under the measurement conditions by high-speed liquid chromatography method described later. An area percentage means the number which represented the ratio of the total peak area of the flexible substance to the total peak area obtained by the high performance liquid chromatography method mentioned later in%.

The measurement conditions in the said high performance liquid chromatography method are as having described in the Example. The film coating agent of the present invention is preferably used for promoting digestive tract motor function, improving symptoms after gastrectomy or preventing or treating gastroesophageal reflux (GERD).

Although an Example is given to the following and this invention is more concretely demonstrated to it, this invention is not limited to these Examples.

In the following Examples etc., the racemate of the compound A was defined as the compound Aa, the citrate dihydrate of the compound Aa was defined as the compound Ab, and Ab was used by Dainippon Pharmaceutical Co., Ltd. ( Average particle diameter of about 7 μm).

Polyethylene glycol 1500 is "polyethylene glycol 1500" by Nakarai Task Co., Ltd. polyethylene glycol 400 is "macrogol 400" of Maruishi Pharmaceutical Co., Ltd., polyethylene glycol 6000 is "macrogol 6000" by Nippon Yushi Corporation Polysorbate 80 refers to `` polyoxyethylene sorbitan monooleate '' manufactured by Nakarai Task Co., Ltd., and poloxamer 188 refers to `` Pluronic PE6800 '' manufactured by BASF Japan. The thing of the product made by Wako Pure Chemical Industries Ltd., the thing made by Nakarai Tesque Co., Ltd. make, and the thing of the product made by Wako Pure Chemical Industries Ltd. were used for the sorbitan monolaurate. In addition, the mono stearin used the thing made by Nakarai Tesque Co., Ltd., and the triacetin used the thing made by the organic synthetic chemical industry.

Lactose used "Pharmatose ^R 200mesh" by DMV. Starch used "corn starch" made by Nippon Food & Drink Processing Co., Ltd. As the hard silicic anhydride, "Aerosil (registered trademark) 200" manufactured by Nippon Aerosol Co., Ltd. was used. As hydroxypropyl cellulose, "Nisso HPC L" by Nippon Soda Corporation was used. As the low-substituted hydroxypropyl cellulose, Shin-Etsu Chemical Co., Ltd. L-HPC (LH-11) '' was used. As magnesium stearate, "magnesium stearate" derived from a plant manufactured by Taihei Chemical Industries, Ltd. was used. As hydroxypropyl methyl cellulose, "TC-5RW" manufactured by Shin-Etsu Chemical Co., Ltd. was used. Titanium oxide used "titanium oxide" by Ishihara Industrial Co., Ltd. was used. Talc used the Nippon-Talk Corporation make.

Reference Example

Compound change test of compound Ab and various components (polyethylene glycol 6000, polyethylene glycol 1500, polyethylene glycol 400, polysorbate 80, poloxomer 188, glycerin, sorbitan monolaurate, diethyl phthalate, monostearine, triacetin) Was carried out. That is, the compound A-b and various components were mix | blended in the ratio of 1: 1 to a glass container by weight ratio, the stopper was sealed, and the preservation test was done for 60 months and 1 month. When it did not melt | dissolve at the time of compounding, it was left in suspension or contact state. As a comparative example, only Compound A-b was put into a glass container, the stopper was sealed, and the storage test of 60 degreeC and 1 month was similarly performed. After 1 month, the amount of flexible substance (total amount of flexible substance) was measured. The amount of analog produced was measured by high performance liquid chromatography (area percentage). In addition, the total amount of flexible substances means the total amount of the decomposition product of Compound A-a, the intermediate in production, the impurities in production, and the like. Preparation of the sample was performed by adding water: methanol in a ratio of 1: 9 to the glass container, shaking the mixture for 20 minutes, and centrifuging to obtain a supernatant. The column used was Deverosil ODS-7 (Nomura Chemical), and the mobile phase used sodium citrate buffer (pH 3.4) / methanol / acetonitrile liquid mixture (24: 9: 7). The measurement wavelength was 274 nm.

The area percentage was calculated | required by the calculation formula of (total peak area / total peak area of a flexible material) * 100.

The results are shown in FIG. When compound A-b, poloxamer 188, polyethyleneglycols, polysorbate 80 or glycerin are mixed, it has been found that a flexible substance is formed and decomposition is promoted. On the other hand, when compound A-b and sorbitan monolaurate, diethyl phthalate, monostearine, or triacetin were mixed, it was found that decomposition was suppressed more than that of compound A-b alone or preserved alone.

Example 1 Preparation of Film Coated Tablets

(1) predetermined production

Predetermination of film coated tablet ingredient Quantity of 1 political party Compound A-b 5.29mg Lactose 61.66mg Starch 32.5mg Low Substitution Hydroxypropyl Cellulose 26.0mg Hydroxypropylcellulose 2.6mg Magnesium stearate 1.3mg Hard silicic anhydride 0.65mg Prescribed 130.Omg

According to the prescription shown in Table 1, the predetermined | prescribed product containing 3.43 mg of single-party compound A-a was manufactured (130 mg of single tablets, round tablet, diameter 7.0mm).

(2) Formation of coating layer

Coating Components of Film-Coated Tablets ingredient 1 layer of coating layer Hydroxypropylmethylcellulose 4.30mg Titanium oxide 0.50mg Talc 0.15mg Hard silicic anhydride 0.05mg Purified water 45mg Coating solution 50 mg Coating amount 5mg

Titanium oxide, talc, and hard silicic anhydride are added to the purified water, and then suspended. Then, a 10 wt% hydroxypropylmethylcellulose aqueous solution prepared in advance is added and dispersed, passed through a sieve through a sieve (No. 80) to prepare a coating solution. It was.

The predetermined 400g (about 3100 tablets) obtained by said (1) was put into the high coater (HC-LAB0 type, Freund Industries), and it coat | covered so that the coating amount after spraying and drying the coating liquid might be 5.00 mg per one. After the completion of coating, drying was carried out in a high coater to obtain a desired film-coated tablet.

Comparative Example 1

The film-coated tablet which gave the coating | coated of Table 1 per 1 predetermined | prescribed in Example 1 (1) was manufactured by the following method.

Coating Components of Film-Coated Tablets ingredient 1 layer of coating layer Hydroxypropylmethylcellulose 3.60mg Polyethylene Glycol 6000 0.70mg Titanium oxide 0.50mg Talc 0.15mg Hard silicic anhydride 0.05mg Purified water 45.0mg Coating solution 50.0 mg Coating amount 5.00mg

Suspended by adding polyethylene glycol 6000, titanium oxide, talc, and hard silicic anhydride to purified water, and then dispersing by adding 10 wt% hydroxypropylmethylcellulose aqueous solution prepared in advance and passing through a sieve (No. 80). And the coating liquid was prepared.

Predetermined 400 g (about 3100 tablets) obtained in Example 1 (1) were put into a high coater (HC-LABO type, Freund Industries), and the coating liquid was sprayed and dried to coat a coating amount of 5.00 mg per one. After the coating was completed, drying was performed in a high coater.

Test Example 1 Stability Test

The tablets obtained in Example 1 and Comparative Example 1 were stored (1) in a glass bottle cap for 6 months at 40 ° C 75% RH, or (2) in a glass bottle cap for 6 months at 40 ° C 75% RH. The amount of flexible material produced (total amount of flexible material) and the color change were examined at regular time intervals. The amount of the flexible substance was added to 1 tablet of water and 9 ml of methanol, to prepare a sample by the method described in the reference example, and measured by high-performance liquid chromatography method (area percentage) described in the reference example. The change was judged by visual observation.

The results are shown in Fig. 2 (opening the vial stopper) and Fig. 3 (opening the vial stopper) and Table 4 (opening the vial stopper) and Table 5 (opening the vial stopper).

Color Changes of Preserved Seals Vial Caps At the start 40 ℃ 75% RH 6 months Example 1 White White Comparative Example 1 White White

Color Changes of Preserved Products with Glass Bottle Caps Opened At the start 40 ℃ 75% RH 6 months Example 1 White White Comparative Example 1 White Brownish

As a result, in the film-coated tablet of the present invention, even after storing for 6 months, the amount of flexible substance (total amount of flexible substance) was equal to or less than the reference value (1%) under any of the conditions in which the cap was opened and the cap was sealed. In addition, color change was not recognized and was stable.

As the above result shows, the film-coated tablet of this invention was excellent in stability under the conditions of 40 degreeC and 75% RH. Therefore, the film-coated tablet of this invention can also preserve | save a fixed amount in the state which is not individually packed (for example, PTP packaging etc.), so-called virtue packaging is also possible. Therefore, the film-coated tablet of the present invention can be prescribed to the patient in the form of a package (for example, packaged with glassine paper, medicine wrapping paper, etc.) in a convenient form, or in a one-dos package form in a bundle at every dose.

Test Example 2 Bitter Masking Test

The bitterness masking test of the tablet obtained in the said Example 1 was done. That is, compared with compound A-b, it tested by three panelists whether there was a shielding effect of an unpleasant taste. As a result, the tablet of the Example reliably had a shielding effect, and no unpleasant taste was felt at all.

Example 2 Film Coated Tablets

According to the prescription shown in Table 6, a predetermined amount containing 1.72 mg of a single compound Aa was prepared (80 mg per round, round tablet, diameter 6.5 mm), and a coating liquid comprising the composition shown in Table 7 was used as in Example 1. Coating to prepare the desired film-coated tablets.

Predetermination of film coated tablet ingredient Quantity of 1 political party Compound A-b 2.65mg Lactose 38.55mg Starch 20.0 mg Low Substitution Hydroxypropyl Cellulose 16.0mg Hydroxypropylcellulose 1.6mg Magnesium stearate 0.80mg Hard silicic anhydride 0.40mg Prescribed 80.0mg

Coating Components of Film-Coated Tablets ingredient 1 layer of coating layer Hydroxypropylmethylcellulose 2.58mg Titanium oxide 0.30mg Talc 0.09mg Hard silicic anhydride 0.03mg Purified water 27.0mg Coating solution 30mg Coating amount 3mg

Comparative Example 2

The coating obtained in Example 2 was coated with a composition shown in Table 8 per party to prepare a film-coated tablet.

Coating Components of Film-Coated Tablets ingredient 1 layer of coating layer Hydroxypropylmethylcellulose 2.16mg Polyethylene Glycol 6000 0.42mg Titanium oxide 0.30mg Talc 0.09mg Hard silicic anhydride 0.03mg Purified water 27.0mg Coating solution 30.0 mg Coating amount 3.00mg

Suspended by adding polyethylene glycol 6000, titanium oxide, talc, and hard silicic anhydride to purified water, and then dispersing by adding 10 wt% hydroxypropylmethylcellulose aqueous solution prepared in advance and passing through a sieve (No. 80). And the coating liquid was prepared.

The predetermined 400 g (about 5000 tablets) obtained in Example 2 was put into the high coater (HC-LAB0 type, Freund Industries), and it coat | covered so that the coating amount after spraying and drying the coating liquid might be 3.00 mg per unit. After the coating was completed, drying was performed in a high coater.

Test Example 3 Stability Test

The tablets obtained in Example 2 and Comparative Example 2 were stored (1) in a glass bottle cap for 6 months at 40 ° C 75% RH, or (2) with a glass bottle cap open at 40 ° C 75% RH for 6 months. The amount of flexible material produced (total amount of flexible material) and the color change were examined at regular time intervals. The amount of formation of the flexible substance was measured in the same manner as in Test Example 1, and the color change was determined by visual observation.

The results are shown in Fig. 4 (opening the vial stopper) and Fig. 5 (opening the vial stopper) and Table 9 (opening the vial stopper) and Table 10 (opening the vial stopper).

As a result, in the film-coated tablet of the present invention, even after storing for 6 months, the amount of flexible substance (total amount of flexible substance) was equal to or less than the reference value (1%) under any of the conditions in which the cap was opened and the cap was sealed. In addition, color change was not recognized and was stable.

Color Changes of Preserved Seals Vial Caps At the start 40 ℃ 75% RH 6 months Example 2 White White Comparative Example 2 White White

Color Changes of Preserved Products with Glass Bottle Caps Opened At the start 40 ℃ 75% RH 6 months Example 2 White White Comparative Example 2 White Brownish

Example 3

The film-coated tablet which gave the coating | coating of Table 1 of 1 prescribed | prescribed in Example 1 (1) by the following method was manufactured by the following method.

Coating Components of Film-Coated Tablets ingredient 1 layer of coating layer Hydroxypropylmethylcellulose 3.60mg Triacetin 0.70mg Titanium oxide 0.50mg Talc 0.15mg Hard silicic anhydride 0.05mg Purified water 45.0mg Coating solution 50.0 mg Coating amount 5.00mg

Suspended by adding triacetin, titanium oxide, talc, and hard silicic anhydride to purified water, and then adding and dispersing 10% by weight aqueous solution of hydroxypropylmethylcellulose prepared in advance, passing through a sieve (No. 80), The coating solution was prepared.

The predetermined 400g (about 3100 tablets) obtained in Example 1 (1) was put into the high coater (HC-LAB0 type, Freund Industries), and it coat | covered so that the coating amount after spraying and drying the coating liquid might be 5.00 mg per one. After the coating was completed, drying was performed in a high coater.

Test Example 4 Stability Test

The tablet obtained in Example 3 (1) was sealed in a glass bottle cap and stored at 40 ° C 75% RH for 1 month, and the amount of flexible substance (total amount of flexible substance) was measured in the same manner as in Test Example 1. As a result, both tablets were stable.

Test Example 5 Dissolution Test

Using the tablet of Example 1, the dissolution test was carried out according to the dissolution test (37 ° C., paddle method, 50 revolutions / minute, solvent 900 ml of water) described in the 14th revised Japanese Pharmacy Room. As a result, the dissolution rate after 30 minutes was 98.5%.

According to the film-coated tablet of the present invention, Compound A or its physiologically acceptable salts are not decomposed well and can be stored in a stable state even without protective packaging such as aluminum packaging. In addition, there is no problem in production. Furthermore, I do not feel bitter taste at the time of taking.

While some of the specific embodiments of the present invention have been described in detail above, those skilled in the art can make various modifications and changes to the specific embodiments disclosed without departing substantially from the teachings and advantages of the present invention. Accordingly, all such modifications and changes are intended to be included within the spirit and scope of the invention as claimed in the following claims.

This application is based on the patent application 2004-220864 (filed in July 28, 2004) which was applied in Japan, The content is contained in this specification.

Claims (14)

4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide (hereinafter referred to as "Compound A") or its physiology As a fast dissolving film-coated tablet containing a salt acceptable scientifically, (a) certain compounds containing Compound A or a physiologically acceptable salt thereof (b) Coating layer which does not contain plasticizer or contains triacetin on the predetermined surface Film coated tablet having a. The method of claim 1, A film coated tablet having a coating layer free of plasticizers. delete delete delete delete The method of claim 1, The film-coated tablet whose content of triacetin is 0.1-30 weight% in a coating layer. The method according to any one of claims 1, 2 or 7, A film coated tablet wherein the physiologically acceptable salt of Compound A is a dihydrate of Citrate of Compound A. The method according to any one of claims 1, 2 or 7, A film-coated tablet having a content of Compound A or a physiologically acceptable salt thereof in an amount of 0.5 to 70% by weight in terms of Compound A. The method according to any one of claims 1, 2 or 7, The area | region where the ratio of the amount of formation of the soft substance of the compound A when the said film-coated tablet was preserve | saved for 6 months under the conditions which opened 40 degreeC and 75% RH stopper in the container was the area measured by the high performance liquid chromatography method. Film coated tablets of 1% or less in percentage. A commercial package comprising the film-coated tablet according to claim 1 and a substrate relating to the film-coated tablet, wherein the film-coated tablet is used for promoting digestive tract motor function, improving symptoms after gastrectomy, or preventing or treating gastroesophageal reflux. A commercial package comprising a substrate that can or should be used in a substrate on or within the package. The method of claim 8, A film-coated tablet having a content of Compound A or a physiologically acceptable salt thereof in an amount of 0.5 to 70% by weight in terms of Compound A. The method of claim 8, The area | region where the ratio of the amount of formation of the soft substance of the compound A when the said film-coated tablet was preserve | saved for 6 months under the conditions which opened 40 degreeC and 75% RH stopper in the container was the area measured by the high performance liquid chromatography method. Film coated tablets of 1% or less in percentage. The method of claim 9, The area | region where the ratio of the amount of formation of the soft substance of the compound A when the said film-coated tablet was preserve | saved for 6 months under the conditions which opened 40 degreeC and 75% RH stopper in the container was the area measured by the high performance liquid chromatography method. Film coated tablets of 1% or less in percentage.

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