HK1107257B - Film coated tablet having plural coats - Google Patents

Description

Film-coated tablet having multiple coating layers

Technical Field

The present invention relates to film-coated tablets containing 4-amino-5-chloro-2-ethoxy-N- [ [4- (4-fluorobenzyl) -2-morpholinyl ] methyl ] benzamide or a physiologically acceptable salt thereof.

Background

(±) -4-amino-5-chloro-2-ethoxy-N- [ [4- (4-fluorobenzyl) -2-morpholinyl ] methyl ] benzamide (hereinafter sometimes referred to as mosapride) is a selective serotonin 4 receptor agonist and shows a good gastrointestinal activity promoting effect (see US patent No.4,870,074). In addition, mosapride and its physiologically acceptable salts are useful as medicaments for the treatment of gastroesophageal reflux disease, post-gastrectomy syndrome, and other gastrointestinal symptoms.

As a solid formulation containing mosapride, a tablet containing mosapride citrate is described in example 245 of US patent No.4,870,074. Specifically, disclosed is a solid preparation comprising mosapride citrate, corn starch, lactose, crystalline cellulose, hydroxypropylcellulose, light anhydrous silicic acid and magnesium stearate.

Furthermore, mosapride citrate dihydrate has been used in practice to improve gastrointestinal symptoms associated with chronic gastritis. In Japan, tablets (1.72mg or 3.44mg of mosapride) containing 2.5mg or 5mg of mosapride citrate (anhydrous) have been sold under the trade name "Gasmotin". Since mosapride is a bitter drug, this tablet is a film-coated tablet. The tablets are aluminum-packed to prevent the production of by-products and discoloration during long-term storage.

Disclosure of Invention

It is an object of the present invention to provide a rapidly dissolving film-coated tablet superior in storage stability, even without an aluminum package, which contains mosapride or a physiologically acceptable salt thereof.

The present inventors have conducted various studies in an attempt to obtain a rapidly dissolving solid formulation containing mosapride or a physiologically acceptable salt thereof, which is superior in storage stability even without aluminum packaging. In the course of this, they have found that the particular pharmaceutical excipients considered necessary to form the coating layer of the film-coated tablet promote the decomposition of mosapride. Therefore, they tried to prepare film-coated tablets using a coating composition without specific pharmaceutical excipients. As a result, they have newly found that the use of a composition for forming a coating layer causes difficulty in the preparation of the preparation. However, they have found that when a film-coated tablet containing mosapride and a pharmaceutical excipient is prepared without contact between the following two components, rapid dissolution properties can be maintained, no difficulty is caused in the preparation, decomposition of mosapride is suppressed during long-term storage even without aluminum packaging, and discoloration of the formulation can be suppressed, which led to the completion of the present invention.

Accordingly, the present invention provides a fast-dissolving film-coated tablet containing 4-amino-5-chloro-2-ethoxy-N- [ [4- (4-fluorobenzyl) -2-morpholinyl ] methyl ] benzamide (hereinafter referred to as "compound a") or a physiologically acceptable salt thereof, wherein the film-coated tablet contains a specific pharmaceutical excipient, compound a or a physiologically acceptable salt thereof is not in contact with the specific pharmaceutical excipient, in particular, the fast-dissolving film-coated tablet has two or more coating layers on the surface of the uncoated tablet, wherein the first layer formed on the uncoated tablet is substantially free of the specific pharmaceutical excipient, and at least one of the second and subsequent layers contains the specific pharmaceutical excipient.

More specifically, the present invention provides the following inventions.

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

wherein the film-coated tablet comprises at least one pharmaceutical excipient (hereinafter referred to as "component B") selected from polyethylene glycol, poloxamer, polyoxyethylene hydrogenated castor oil, polysorbate, and glycerol, and

the tablet has a structure in which compound a or a physiologically acceptable salt thereof is not in contact with component B.

[2]: [1] a film-coated tablet of (a), comprising: (a) uncoated tablets containing Compound A or a physiologically acceptable salt thereof, and

(b) two or more coating layers formed on the surface of the uncoated tablet,

wherein the first layer formed on the uncoated tablet is substantially free of component B and

at least one of the second and subsequent layers contains component B.

[3]: [2] the film-coated tablet of (1), wherein at least one of the second and subsequent layers comprises component B at a concentration of about 5 to about 98 wt%.

[4]: [2] the film-coated tablet of [1] or [3], wherein the outermost coating layer comprises component B.

[5]: [1] the film-coated tablet of any one of [1] to [4], wherein the component B is polyethylene glycol.

[6]: [2] the film-coated tablet of (1), wherein the coating layer comprises a first layer and a second layer, wherein the second layer comprises component B.

[7]：[6]The film-coated tablet of (1), wherein the first layer covers from about 0.5 to about 10mg/cm²Uncoated tablet surface.

[8]：[6]Or [ 7]]The film-coated tablet of (1), wherein the second layer covers from about 0.1 to about 20mg/cm²Of the first layer surface.

[9]: [2] the film-coated tablet of (a), wherein the first layer comprises one or more film-coating agents.

[10]: [1] the film-coated tablet of any one of to [9], wherein the compound a or a physiologically acceptable salt thereof is a citrate dihydrate of the compound a.

[11]: [1] the film-coated tablet of any one of to [10], wherein the uncoated tablet comprises compound a or a physiologically acceptable salt thereof in a proportion of about 0.5 to about 70 wt% based on compound a.

[12]: [1] the film-coated tablet of any one of to [11], wherein the proportion of related substances of compound a produced when the tablet is placed in a container and stored at 40 ℃ and 75% RH for 6 months under unsealed conditions is not more than about 1%.

[13]: [6] the film-coated tablet of (1), wherein the uncoated tablet comprises citrate dihydrate of Compound A in a proportion of about 0.5 to about 50 wt% based on Compound A,

the first layer comprises one or more film-coating agents and covers about 0.7 to 5mg/cm²Of uncoated tablets, and

the second layer covers about 0.5 to 10mg/cm²Of the first layer surface.

[14]: [13] the film-coated tablet of (1), wherein the film-coating agent is selected from the group consisting of Hydroxypropylmethylcellulose (HPMC), Hydroxypropylcellulose (HPC), Methylcellulose (MC), Ethylcellulose (EC), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), and methacrylic acid copolymer.

[15]: [13] the film-coated tablet of (1), wherein component B is polyethylene glycol.

[16]: [6] the film-coated tablet of (1), wherein the uncoated tablet comprises citrate dihydrate of Compound A in a proportion of about 0.5 to about 30 wt% based on Compound A,

the first layer comprises hydroxypropyl methylcellulose and covers about 1.5 to 3mg/cm²The surface of the uncoated tablet of (a),

the second layer comprises polyethylene glycol 6000 and covers about 1 to 5mg/cm²A first layer surface of, and

when the tablets were placed in a container and stored for 6 months under unsealed conditions at 40 ℃ and 75% RH, a proportion of related substances of compound a of not more than about 0.6% was produced.

[17]: a commercial package comprising the film-coated tablet of [1] and written matter associated therewith, wherein instructions for use of the film-coated tablet in or on the package that may or should be used to promote gastrointestinal motility, ameliorate post gastrectomy syndrome, or prevent or treat gastroesophageal reflux (GERD) are included on or in the written matter of the package.

Since the film-coated tablet of the present invention has the above-described characteristics, compound a and a physiologically acceptable salt thereof are not easily decomposed even without a protective package such as an aluminum package or the like, and can be stored in a stable state. Moreover, no difficulties are caused during the preparation. Furthermore, no bitter taste was noted during the administration.

Drawings

FIG. 1 is a graph showing the results of incompatibility test between the citrate salt of Compound A-a (racemate of Compound A) of the present invention and each component B.

Fig. 2 is a graph showing the results of stability tests of the formulations obtained in examples 1 to 5 and comparative example 1.

Fig. 3 is a graph showing the results of stability tests of the formulations obtained in examples 1 to 5 and comparative example 1.

Fig. 4 is a graph showing the results of stability tests of the formulations obtained in examples 6 to 8 and comparative example 2.

Fig. 5 is a graph showing the results of stability tests of the formulations obtained in examples 6 to 8 and comparative example 2.

Detailed Description

The "fast dissolution property" of the film-coated tablet of the present invention means a dissolution rate of not less than about 85%, preferably not less than 90%, more preferably not less than 95% after 30 minutes in a dissolution test (37 ℃, stirring method, 50rpm, separation medium 900ml of water) described in japanese pharmacopoeia 14 th edition.

Compound A or a physiologically acceptable salt thereof

Compound a of the present invention, 4-amino-5-chloro-2-ethoxy-N- [ [4- (4-fluorobenzyl) -2-morpholinyl ] methyl ] benzamide, is a compound represented by the formula:

the compound A has good gastrointestinal activity promoting effect as a selective serotonin 4 receptor agonist. In the present invention, compound a may be a racemic modification or an optically active modification, and a racemic modification is preferred.

In the present invention, compound a may be in the free state or a physiologically acceptable salt thereof. For salts, acid addition salts are preferred. Examples of addition salts with organic acids include formate, acetate, lactate, adipate, citrate, tartrate, fumarate, methanesulfonate, maleate, and the like. Examples of the addition salts with inorganic acids include hydrochloride, sulfate, nitrate, phosphate and the like. Among these, citrate is particularly preferable. Compound a or a physiologically acceptable salt thereof may be a solvate, hydrate or non-hydrate. Hydrates of citrate salts are preferred, and citrate dihydrate is particularly preferred.

The above-mentioned compound a and physiologically acceptable salts thereof can be prepared, for example, by the method described in U.S. patent No.4870074 or a similar method thereto.

Component B

Examples of the pharmaceutical excipient (component B) which is the main component of the film-coated tablet of the present invention and is not present in contact with compound a or a physiologically acceptable salt thereof include polyethylene glycol, poloxamer, polysorbate, polyoxyethylene hydrogenated castor oil and glycerol. Since the contact of compound a with component B promotes the decomposition of compound a, component B does not come into contact with compound a in the present invention.

Component B is considered necessary for the preparation of film-coated tablets. For example, the absence of component B in the film component can lead to film formation problems such as brittle films, reduced slip properties (including flow), loss of gloss, and the like. When component B is not present, problems such as picking occur during industrial production, making preparation very difficult. Acquisition refers to the delamination of the film layer at the contact points between tablets or between tablets and device during the film coating step.

The polyethylene glycol is prepared from H (OCH)₂CH₂)_nOH (n is not less than 4), and has a molecular weight of about 200 to 9000. For example, polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000 and the like are known. The numbers indicated after "polyethylene glycol" refer to the average molecular weight.

Poloxamers are block copolymers of α -hydrogen- ω -hydroxy poly (oxyethylene) -poly (oxypropylene) -poly (oxyethylene), having a molecular weight of about 2000 to 20000, and are known to be nonionic surfactants. Examples of poloxamers include poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, and the like. Specifically, for example, those sold under the trade name pluronic (pluronic) or the like can be used.

Polysorbates are polyoxyethylene sorbitol esters and are nonionic surfactants. As commercially available compounds, polysorbate 80 (tween 80) and the like are known.

The polyoxyethylene hydrogenated castor oil is prepared as follows: hydrogen was added to castor oil to give hydrogenated castor oil, which was then subjected to addition polymerization with various amounts of ethylene oxide. Several products with different degrees of polymerization are commercially available, such as NIKKOLHCO-20, NIKKOL HCO-40, NIKKOL HCO-50, NIKKOLHCO-60, and the like.

The glycerol is prepared from CH₂(OH)CH(OH)CH₂A compound represented by OH.

Preferred component B for preparing the film-coated tablets of the invention is polyethylene glycol, more preferably polyethylene glycol 4000 or 6000, especially polyethylene glycol 6000.

Contactless structure

As shown in the following reference examples, the present inventors have first found that when compound a or a physiologically acceptable salt of the present invention is contacted with the above-mentioned component B, a large amount of decomposition products (related substances) of compound a are produced.

As the "contactless structure", for example, a structure including: an uncoated tablet comprising compound a or a physiologically acceptable salt, a first layer made of a composition substantially free of the above-mentioned component B, which covers the uncoated tablet, and at least one of a second and subsequent layer made of a composition comprising component B. This embodiment is specifically explained below.

Uncoated tablets

An "uncoated tablet" may comprise compound a or a physiologically acceptable salt thereof alone, and typically it further comprises a pharmaceutical excipient other than component B above.

The "other pharmaceutical excipient" may be any substance provided that it does not cause inconvenience due to mixing and is necessary. Examples thereof include binders, diluents, glidants, and disintegrants.

In an uncoated tablet, compound a or a physiologically acceptable salt thereof is contained in a proportion of about 0.01 to about 90 wt%, preferably about 0.5 to about 70 wt%, more preferably about 0.5 to about 50 wt%, still more preferably about 0.5 to about 30 wt%, based on compound a.

Adhesive agent

Specific examples of the binder include gum arabic, starch paste, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl alcohol, pullulan, gelatin, ethyl cellulose, methyl cellulose, sodium carboxymethylcellulose, dextrin, polyvinylpyrrolidone and the like. Preferred are hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone and the like. The content of the binder may be any amount as long as it can maintain the hardness of the tablet and does not interfere with the decomposition in the gastrointestinal tract. Typically, in uncoated tablets, the binder is included in a proportion of about 0.5 to about 10 wt%, preferably about 1 to about 7 wt%.

Diluent

Specific examples of the diluent include lactose, starch, mannitol, crystalline cellulose, sucrose, erythritol, trehalose, anhydrous calcium hydrogen phosphate, calcium sulfate and the like, and lactose, starch, mannitol, crystalline cellulose and the like are preferable. In uncoated tablets, it is generally included in a proportion of about 5 to about 97 wt%, preferably about 10 to about 80 wt%.

Glidants

Specific examples of the glidant include light anhydrous silicic acid, magnesium aluminum metasilicate and the like, and light anhydrous silicic acid is preferred. In uncoated tablets, it is generally included in a proportion of about 0.01 to about 10% by weight, preferably about 0.1 to about 5% by weight.

Disintegrating agent

Examples of the disintegrant include low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, and the like. Of these, low-substituted hydroxypropylcellulose having a hydroxypropyl content of 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. In uncoated tablets, disintegrants are generally included in a proportion of about 2 to about 30 wt%, preferably about 5 to about 25 wt%.

In addition, pharmaceutical excipients such as lubricants (e.g., magnesium stearate, zinc stearate, calcium stearate, etc.) and the like may be added as necessary.

Uncoated tablets may be prepared by conventional means by suitably mixing the above-mentioned pharmaceutical excipients and compression moulding. Preferably, lactose and starch are chosen among the above excipients as diluents, hydroxypropylcellulose as binder, light anhydrous silicic acid as glidant, low-substituted hydroxypropylcellulose as disintegrant and magnesium stearate as lubricant.

Coating layer

The film-coated tablets of the present invention have at least two coating layers. The layer directly overlying the uncoated tablet is referred to as the first layer, and from the first layer outward, the layers are referred to sequentially as the second layer, the third layer (if present), and so on. According to the invention, the first layer is substantially free of component B and at least one of the second and subsequent layers comprises component B.

The film-coated tablets of the present invention characteristically retain fast-dissolving properties. Typically, tablets having two or more film coating layers are extended release or enteric coated tablets. Fast dissolving tablets generally do not have two or more film coating layers. Thus, the present inventors found that the presence of the above component B attempted to prepare a film-coated tablet having a layer containing no component B. However, in view of the actual production situation, problems such as collection occur during industrial production, and the production is difficult. Therefore, it was determined that the above-mentioned component B should be added to the coating layer, and that the compound A or a physiologically acceptable salt thereof and the above-mentioned component B should not contact each other. Specifically, uncoated tablets containing compound a or a physiologically acceptable salt thereof are coated with a film layer not containing component B, and then further coated with a film layer containing component B. The tablet having such a structure maintains the rapid dissolution property, shows the inhibition of the decomposition of compound a and the inhibition of the discoloration of the formulation even under long-term storage, and shows the inhibition of collection and the like during industrial production.

For example, the first coating layer comprises the film coating agents shown below. The concentration of the film coating agents of the first layer is from about 5 to about 100 wt%, preferably from about 30 to about 100 wt%, particularly preferably from about 50 to about 98 wt%.

Controlling the coating amount of the first layer to 1cm²The surface area of the uncoated tablets is from about 0.5 to about 10mg, preferably from about 0.7 to about 5 mg. For this amount, when the composition comprising component B is further applied as shown below, compound a or a physiologically acceptable salt thereof is not contacted with component B. More preferably, every 1cm²The surface area of the uncoated tablet of (a), the amount of coating of the first layer is from about 1.5 to about 3 mg.

After the first layer described above is formed, a composition comprising component B is applied at any stage. For example, a composition comprising component B may be applied as a second layer, or a composition without component B may be applied to form one to several layers, and a composition comprising component B may be applied last. Further, two or more layers containing component B may be formed.

Component B is contained in a proportion of about 5 to about 98 wt.%, preferably about 7.5 to about 90 wt.%, particularly preferably about 10 to about 50 wt.%, in the layer containing component B.

The number of coating layers is preferably 2. In this case, the number of coatings of the second layer was adjusted to 1cm per layer²From about 0.1 to about 20mg, preferably from about 0.5 to about 10mg, of the surface area of the first layer. With respect to the coating amount, decomposition of the compound A and the like caused by the above-mentioned component B can be completely suppressed. More preferably, every 1cm²The surface area of the first layer, and the amount of coating of the second layer is from about 1 to about 5 mg.

Although the weight ratio of the first layer to the second layer is not particularly limited, the second layer is, for example, about 0.1 to about 10 parts by weight, preferably about 0.5 to about 5 parts by weight, per 1 part by weight of the first layer.

The ingredients contained in each coating layer are as follows.

Film coated reagents

Examples of the film-coating agent include cellulose derivatives such as Hydroxypropylmethylcellulose (HPMC), Hydroxypropylcellulose (HPC), Methylcellulose (MC), Ethylcellulose (EC) and the like, vinyl polymers such as polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP) and the like, acrylic polymers such as methacrylic acid copolymers and the like, and HPMC is preferable.

Examples of the ingredients that may be contained in the coating layer, in addition to the above-mentioned film-coating agent and the above-mentioned component B, include colorants such as titanium dioxide and ferric oxide (amount in each layer: 0.1 to 50 wt%), anti-binders such as talc (amount in each layer: 0.1 to 50 wt%), gloss agents such as light anhydrous silicic acid (amount in each layer: 0.1 to 10 wt%), and the like.

The first layer may be prepared as follows: one or more of the above-described film-coating agents are selected, the film-coating agent is dissolved or suspended in water or an organic solvent such as ethanol or the like, preferably water, to obtain a liquid composition (coating liquid), and the composition is sprayed on the uncoated tablet. The coating liquid may contain the above-mentioned coloring agent, anti-adhesive agent, gloss agent, etc., as necessary.

The layer comprising component B can be prepared as follows: component B is selected, dissolved or suspended in water or an organic solvent such as ethanol or the like, preferably water, to give a liquid composition, and the composition is sprayed. If necessary, the composition may contain the above-mentioned film coating agent, the above-mentioned coloring agent, anti-adhesive agent, gloss agent, and the like.

The other layer not containing component B may be formed by a step similar to the step of forming the first layer.

The film-coated tablets of the present invention are stable even during long-term storage. Thus, when, for example, the film-coated tablet of the present invention is placed in a container, stored under unsealed conditions at 40 ℃ and 75% RH for 6 months and the produced amount of the relevant substance (total amount of the relevant substance) is determined by high performance liquid chromatography, the proportion of the area percentage of all the relevant substances is not more than about 1%. Preferably not greater than about 0.6%.

The amount of the relevant substance produced (total amount of the relevant substance) is the total amount of the decomposition product of compound a, an intermediate during the production, an impurity during the production, and the like, which means the total amount detectable under the measurement conditions of high performance liquid chromatography described below. The area percentage means a number percentage representing the ratio of the total peak area to the total peak area of the relevant substance obtained by the high performance liquid chromatography described below.

The measurement conditions of the high performance liquid chromatography are as described in examples.

The film-coated tablet of the present invention is preferably used for promoting gastrointestinal motility, ameliorating postgastrectomy syndrome, or preventing or treating gastroesophageal reflux disease (GERD).

Examples

The invention is explained in more detail below by means of examples, which are not to be construed as limiting. In the following examples, the racemate of compound a was defined as compound a-a, the citrate dihydrate of compound a-a as a-b, and a-b used was prepared by Dainippon Pharmaceutical co.ltd. (average particle size about 7 μm).

"polyethylene glycol 6000" manufactured by NOF Corporation was used as polyethylene glycol 6000. "polyethylene glycol 1500" prepared by Nacalai Tesque was used as polyethylene glycol 1500, "polyethylene glycol 400" prepared by Maruishi Pharmaceutical co.ltd. was used as polyethylene glycol 400, "polyoxyethylene sorbitan monooleate" prepared by Nacalai Tesque was used as polysorbate 80, "pluronic PE 6800" prepared by BASF JAPAN ltd. was used as poloxamer 188, and glycerol prepared by Wako Pure chemical industries, ltd.

For lactose, "Pharmatose (trademark) 200 mesh" prepared by DMV was used. For starch, "corn starch" prepared by Nihon Shoku hin Kako co. For light anhydrous silicic acid, "AEROSIL (trade mark) 200" prepared by NIPPON AEROSIL was used. For hydroxypropyl cellulose, "NISSO HPC L" prepared by NIPPON Soda co. For the low-substituted hydroxypropylcellulose, "L-HPC (LH-11)" prepared by Shin-Etsu chemical Co., Ltd. As the magnesium stearate, "magnesium stearate" of vegetable origin prepared by Taihei Chemical Industrial co. For the hydroxypropylmethylcellulose, "TC-5 RW" manufactured by Shin-Etsu Chemical Co., Ltd. For titanium dioxide, "titanium dioxide" prepared by Ishihara Sangyo Kaisha, ltd. For Talc, one prepared by Nippon Talc co.

Reference examples

Incompatibility tests were performed on compounds a-B and various "component B" (polyethylene glycol 6000, polyethylene glycol 1500, polyethylene glycol 400, polysorbate 80, poloxamer 188, glycerol). Specifically, the compounds A-B were mixed with each component B in a weight ratio of 1: 1 in a glass container, the container was hermetically sealed, and a storage test was conducted at 60 ℃ for one month. When they are not dissolved at the time of mixing, they are prepared as a suspension or left in a contact state. For the comparative example, compounds a-b were placed individually in glass containers, the containers were hermetically sealed, and storage tests were performed at 60 ℃ for one month in the same manner. One month after hermetic sealing, the amount of the relevant substance produced (total amount of the relevant substance) was measured. The amount (area percentage) of the substance concerned produced was determined by high performance liquid chromatography. The total amount of the relevant substances means the total amount of decomposition products of the compound A-a, intermediates during the production, impurities during the production, and the like. The sample was prepared by adding water to methanol (1: 9) to the above glass container, stirring the mixture for 20 minutes, centrifuging the mixture, and obtaining a supernatant. The column used was Deverosil ODS-7(Nomura Chemical Co., Ltd.) and for the mobile phase a mixture of sodium citrate buffer (pH 3.4)/methanol/acetonitrile (24: 9: 7) was used. The measurement wavelength was 274n m. The results are shown in FIG. 1. It has been clarified that when compound A-b is mixed with poloxamer, polyethylene glycol, polysorbate or glycerol, a larger amount of the relevant substance is produced than when compound A-b is stored alone.

Example 1

(1) Preparation of uncoated tablets

Uncoated tablets each containing 3.43m g Compound A-a were prepared according to the formulation shown in Table 1. (130 mg per tablet, round tablet, diameter 7.0mm, surface area: 115.5mm²)。

TABLE 1

Component (A)	Uncoated tablet dosage/tablet
		Compounds A-b	5.29mg
Lactose	61.66mg
		Starch	32.5mg
Low-substituted hydroxypropyl cellulose	26.0mg
		Hydroxypropyl cellulose	2.6mg
Magnesium stearate	1.3mg
		Light anhydrous silicic acid	0.65mg
Uncoated tablets	130.0mg

(2) Forming a coating layer

The respective coating liquids were prepared to form respective coating layers each having the composition described in table 2. That is, titanium dioxide and talc were added to purified water to obtain a suspension, a 10 wt% hydroxypropylmethylcellulose aqueous solution prepared in advance was added thereto to obtain a dispersion, and the dispersion was passed through a sieve (No.80) to obtain a coating liquid of the first layer. Further, polyethylene glycol 6000 and light anhydrous silicic acid were added to purified water to obtain a suspension, and the suspension was passed through a sieve (No.80) to obtain a coating liquid of the second layer.

TABLE 2

The uncoated tablets (400g, about 3100 tablets) obtained in the above (1) were placed in a Hicoater (HC-LABO, Freund Corporation) and the coating liquid of the first layer was sprayed thereon so that the coating amount after drying became 4.25mg per tablet.

Subsequently, a second layer of coating liquid was sprayed thereon so that the coating amount after drying became 0.75mg per tablet. After coating was completed, the tablets were dried in a Hicoater to obtain the target film-coated tablets.

Example 2

Uncoated tablets (400g, about 3100 tablets) obtained in example 1(1) were each coated with two layers described in table 3 below in the same manner as in example 1(2) except that talc was removed from the coating liquid of the first layer and talc was added to the coating liquid of the second layer to obtain film-coated tablets.

TABLE 3

Example 3

The uncoated tablets obtained in example 1(1) were each coated with two layers described in table 4 to give film-coated tablets as shown below.

TABLE 4

That is, titanium dioxide and talc were added to purified water to obtain a suspension, a 10 wt% hydroxypropylmethylcellulose aqueous solution prepared in advance was added thereto to obtain a dispersion, and the dispersion was passed through a sieve (No.80) to obtain a coating liquid of the first layer.

Further, polyethylene glycol 6000, titanium dioxide, talc and light anhydrous silicic acid were added to purified water to obtain a suspension, a 10 wt% hydroxypropylmethylcellulose aqueous solution was added thereto to obtain a dispersion, and the dispersion was passed through a sieve (No.80) to obtain a coating liquid of the second layer.

The uncoated tablets (400g, about 3100 tablets) obtained in example 1(1) above were placed in a Hicoater (HC-LABO, Freund Corporation) and the coating liquid of the first layer was sprayed thereon so that the coating amount after drying became 3.00mg per tablet.

Subsequently, a second layer of coating liquid was sprayed thereon so that the amount of coating after drying became 2.00mg per tablet. After coating, the tablets were dried in a Hicoater.

Example 4

In the same manner as in example 3, each tablet was coated with the uncoated tablet (400g, about 3100 tablets) obtained in example 1(1) using two kinds of layers described in table 5 to obtain a film-coated tablet.

TABLE 5

Example 5

Uncoated tablets (400g, approximately 3100 tablets) obtained in example 1(1) were each coated with two kinds of layers described in the following table 6 in the same manner as in example 3 except that titanium dioxide was not added to the coating liquid of the first layer to obtain film-coated tablets.

TABLE 6

Comparative example 1

As shown below, film-coated tablets were prepared in which each of the tablet coating layers (1 layer) described in table 7 was formed on the surface of the uncoated tablet obtained in example 1 (1).

TABLE 7

Component (A)	Coating (1 layer) amount/tablet
		Hydroxypropyl methylcellulose	3.60mg
Polyethylene glycol 6000	0.70mg
		Titanium dioxide	0.50mg
Talc	0.15mg
		Light anhydrous silicic acid	0.05mg
Purified water	45.0mg
		Coating liquid	50.0mg
Number of coats	5.00mg

Component (A)	Coating (1 layer) amount/tablet
		Number of coatings per unit area	4.33mg/cm

Polyethylene glycol 6000, titanium dioxide, talc and light anhydrous silicic acid were added to purified water to obtain a suspension, a 10 wt% hydroxypropylmethylcellulose aqueous solution prepared in advance was added thereto to obtain a dispersion, and the dispersion was passed through a sieve (No.80) to obtain a coating liquid.

The uncoated tablets (400g, about 3100 tablets) obtained in example 1(1) above were placed in a Hicoater (HC-LABO, Freund Corporation) and a coating liquid was sprayed thereon so that the coating amount after drying became 5.00mg per tablet. After coating, the tablets were dried in a Hicoater.

Experimental example 1: stability test

The tablets obtained in examples 1 to 5 and comparative example 1 were stored in (1) a glass bottle (hermetically sealed) at 40 ℃ and 75% RH for 6 months, or in (2) a glass bottle (unsealed) at 40 ℃ and 75% RH for 6 months, and examined for changes in the amount of production (total amount of relevant substance) and color tone of the relevant substance over a given period of time. The amount of the related substance produced was determined as follows: samples were prepared according to the method described in the reference example, in which water (1ml) and methanol (9ml) were added to two tablets, and subjected to high performance liquid chromatography (area percentage) described in the reference example, and visually evaluated for changes in hue.

The results are shown in fig. 2 (hermetically sealed glass bottle) and fig. 3 (unsealed glass bottle) and table 8 (hermetically sealed glass bottle) and table 9 (unsealed glass bottle).

TABLE 8

TABLE 9

As a result, even after 6 months of storage, the film-coated tablet of the present invention showed: the amount of the relevant substance produced (total amount of the relevant substance) does not exceed the standard value (1%) for unsealed and hermetically sealed. Furthermore, there was no change in hue and the sample was stable.

As shown by the above results, the film-coated tablet of the present invention is superior in stability at 40 ℃ and 75% RH. Thus, the film-coated tablets of the invention may also be stored in a given quantity without separate packaging (e.g. PTP packaging etc.), so-called bulk packaging. Thus, the film-coated tablets of the present invention may be prescribed to patients in simple packaging (e.g., cellophane, medical paper, etc.) or may be packaged in a single dose for each administration.

Experimental example 2: bitterness screening test

The tablets obtained in examples 1 to 5 above were subjected to a bitterness masking test. That is, the unpleasant taste masking effect compared to compounds a-b was examined by 3 panelists. As a result, all tablets clearly showed a masking effect, which completely prevented the unpleasant taste.

Examples 6 to 8: film-coated tablet

Uncoated tablets each containing 1.72mg of Compound A-a (80 mg per tablet, circular tablet, diameter 6.5mm, surface area: 83.6 mm) were prepared according to the formulation shown in Table 10²) And a coating layer was formed on the obtained uncoated tablet according to the formulation shown in table 11 in the same manner as in examples 1 to 5 to obtain a film-coated tablet.

Watch 10

Component (A)	Uncoated tablet dosage/tablet
		Compounds A-b	2.65mg
Lactose	38.55mg
		Starch	20.0mg
Low-substituted hydroxypropyl cellulose	16.0mg
		Hydroxypropyl cellulose	1.6mg

Component (A)	Uncoated tablet dosage/tablet
		Magnesium stearate	0.80mg
Light anhydrous silicic acid	0.40mg
		Uncoated tablets	80.0mg

Comparative example 2

Film-coated tablets in which the coating layer (1 layer) of each tablet described in table 12 was formed on the surface of the uncoated tablet obtained in example 6 were prepared as shown below.

TABLE 12

Component (A)	Coating (1 layer) amount/tablet
		Hydroxypropyl methylcellulose	2.16mg
Polyethylene glycol 6000	0.42mg
		Titanium dioxide	0.30mg
Talc	0.09mg
		Light anhydrous silicic acid	0.03mg
Purified water	27.0mg
		Coating liquid	30.0mg
Number of coats	3.00mg
		Number of coatings per unit area	3.59mg/cm

Polyethylene glycol 6000, titanium dioxide, talc and light anhydrous silicic acid were added to purified water to obtain a suspension, a 10 wt% hydroxypropylmethylcellulose aqueous solution prepared in advance was added thereto to obtain a dispersion, and the dispersion was passed through a sieve (No.80) to obtain a coating liquid.

The uncoated tablets (400g, about 5000 tablets) obtained in example 6 were placed in a Hicoater (HC-LABO, Freund Corporation) and a coating liquid was sprayed thereon so that the coating amount after drying became 3.00mg per tablet. After coating, the tablets were dried in a Hicoater.

Experimental example 3: stability test

The tablets obtained in examples 6 to 8 and comparative example 2 were stored in (1) a glass bottle (hermetically sealed) at 40 ℃ and 75% RH for 6 months or in (2) a glass bottle (unsealed) at 40 ℃ and 75% RH for 6 months, and examined for changes in the amount of the related substance produced (the total amount of the related substance) and the color tone over a given period of time. The amount of the related substance produced (area percentage) was measured by high performance liquid chromatography in the same manner as in experimental example 1, and the change in hue was visually evaluated.

The results are shown in fig. 4 (hermetically sealed glass bottle) and fig. 5 (unsealed glass bottle) and table 13 (hermetically sealed glass bottle) and table 14 (unsealed glass bottle).

As a result, even after 6 months of storage, the film-coated tablet of the present invention showed: the amount of the relevant substance produced (total amount of the relevant substance) does not exceed the standard value (1%) for the unsealed and airtight seal.

Watch 13

TABLE 14

Example 9

Film-coated tablets were prepared as shown below, in which two coating layers of each tablet described in table 15 were formed on the surface of the uncoated tablet obtained in example 1 (1).

Watch 15

Each coating liquid was prepared. That is, titanium dioxide and talc were added to purified water to obtain a suspension, a 10 wt% hydroxypropylmethylcellulose aqueous solution prepared in advance was added thereto to obtain a dispersion, and the dispersion was passed through a sieve (No.80) to obtain a coating liquid of the first layer.

Further, poloxamer 188, titanium dioxide, talc and light anhydrous silicic acid were added to purified water to obtain a suspension, a 10 wt% aqueous solution containing hydroxypropylmethylcellulose was added thereto to obtain a dispersion, and the suspension was passed through a sieve (No.80) to obtain a coating liquid of the second layer.

The uncoated tablets (400g, about 3100 tablets) obtained in example 1(1) above were placed in a Hicoater (HC-LABO, Freund Corporation) and the coating liquid of the first layer was sprayed thereon so that the coating amount after drying became 3.00mg per tablet.

Subsequently, a second layer of coating liquid was sprayed thereon so that the amount of coating after drying became 2.00mg per tablet. After coating, the tablets were dried in a Hicoater.

Experimental example 4: stability test

The tablets obtained in example 9 were stored in (1) a glass bottle (not sealed) at 40 ℃ and 75% RH for 1 month, and the amount of the related substance produced (total amount of the related substance) was measured in the same manner as in experimental example 1. As a result, all tablets were stable.

Experimental example 5: dissolution test

The dissolution test was carried out according to the dissolution test (37 ℃, stirring method, 50rpm, separation medium 900ml of water) described in japanese pharmacopoeia 14 th edition using the tablet of example 4. As a result, the dissolution ratio after 30 minutes was 102.7%.

Industrial applicability

According to the film-coated tablet of the present invention, compound a and a physiologically acceptable salt thereof do not readily decompose and can be stored in a stable state even without a protective package such as an aluminum package or the like. Furthermore, no difficulties are caused during the preparation. Furthermore, no bitter taste was noted during the administration.

The present application is based on the patent application No. 2004-.

Claims (30)

1. A fast dissolving film-coated tablet comprising 4-amino-5-chloro-2-ethoxy-N- [ [4- (4-fluorobenzyl) -2-morpholinyl ] methyl ] benzamide, compound A or a physiologically acceptable salt thereof,

wherein the film-coated tablet comprises at least one pharmaceutical excipient component B, said excipient being selected from the group consisting of polyethylene glycol, poloxamer, polyoxyethylene hydrogenated castor oil, polysorbate, and glycerol, and

the tablet has a structure in which compound a or a physiologically acceptable salt thereof is not in contact with component B.

2. The film-coated tablet of claim 1, comprising:

(a) uncoated tablets containing Compound A or a physiologically acceptable salt thereof, and

(b) two or more coating layers formed on the surface of the uncoated tablet,

wherein the first layer formed on the uncoated tablet is substantially free of component B and

at least one of the second and subsequent layers contains component B.

3. The film-coated tablet according to claim 2, wherein at least one of the second and subsequent layers comprises component B in a concentration of 5 to 98 wt%.

4. The film-coated tablet according to claim 2, wherein the outermost coating layer comprises component B.

5. The film-coated tablet according to claim 3, wherein the outermost coating layer comprises component B.

6. The film-coated tablet according to any one of claims 1 to 5, wherein component B is polyethylene glycol.

7. The film-coated tablet according to claim 2, wherein the coating layer comprises a first layer and a second layer, wherein the second layer comprises component B.

8. The film-coated tablet according to claim 7, wherein the first layer covers 0.5 to 10mg/cm²Of uncoated tablets.

9. The film-coated tablet according to claim 7, wherein the second layer covers 0.1 to 20mg/cm²Of the first layer.

10. The film-coated tablet according to claim 8, wherein the second layer covers 0.1 to 20mg/cm²Of the first layer.

11. The film-coated tablet of claim 2, wherein the first layer comprises one or more film-coating agents.

12. The film-coated tablet according to any one of claims 1 to 5 and 7 to 11, wherein compound a or a physiologically acceptable salt thereof is citrate dihydrate of compound a.

13. The film-coated tablet according to claim 6, wherein Compound A or a physiologically acceptable salt thereof is citrate dihydrate of Compound A.

14. The film-coated tablet according to any one of claims 1 to 5 and 7 to 11, wherein the uncoated tablet comprises compound a or a physiologically acceptable salt thereof in a proportion of 0.5 to 70 wt% based on compound a.

15. The film-coated tablet according to claim 6, wherein the uncoated tablet comprises Compound A or a physiologically acceptable salt thereof in a proportion of 0.5 to 70% by weight based on Compound A.

16. The film-coated tablet according to claim 12, wherein the uncoated tablet comprises compound a or a physiologically acceptable salt thereof in a proportion of 0.5 to 70 wt% based on compound a.

17. The film-coated tablet according to claim 13, wherein the uncoated tablet comprises compound a or a physiologically acceptable salt thereof in a proportion of 0.5 to 70 wt% based on compound a.

18. The film-coated tablet according to any one of claims 1 to 5 and 7 to 11, wherein the related substance proportion of compound a produced when the tablet is placed in a container and stored under unsealed conditions at 40 ℃ and 75% RH for 6 months is not more than 1%.

19. The film-coated tablet according to claim 6, wherein the proportion of related substances of Compound A produced when the tablet is placed in a container and stored under unsealed conditions at 40 ℃ and 75% RH for 6 months is not more than 1%.

20. The film-coated tablet according to claim 12, wherein the proportion of related substances of compound a produced when the tablet is placed in a container and stored under unsealed conditions at 40 ℃ and 75% RH for 6 months is not more than 1%.

21. The film-coated tablet according to claim 13, wherein the proportion of related substances of compound a produced when the tablet is placed in a container and stored under unsealed conditions at 40 ℃ and 75% RH for 6 months is not more than 1%.

22. The film-coated tablet according to claim 14, wherein the proportion of related substances of compound a produced when the tablet is placed in a container and stored under unsealed conditions at 40 ℃ and 75% RH for 6 months is not more than 1%.

23. The film-coated tablet according to claim 15, wherein the proportion of related substances of compound a produced when the tablet is placed in a container and stored under unsealed conditions at 40 ℃ and 75% RH for 6 months is not more than 1%.

24. The film-coated tablet according to claim 16, wherein the proportion of related substances of compound a produced when the tablet is placed in a container and stored under unsealed conditions at 40 ℃ and 75% RH for 6 months is not more than 1%.

25. The film-coated tablet according to claim 17, wherein the proportion of related substances of compound a produced when the tablet is placed in a container and stored under unsealed conditions at 40 ℃ and 75% RH for 6 months is not more than 1%.

26. The film-coated tablet according to claim 7, wherein the uncoated tablet comprises citrate dihydrate of Compound A in a proportion of 0.5 to 50 wt% based on Compound A,

the first layer comprises one or more film coating agents and covers 0.7 to 5mg/cm²Of uncoated tablets, and

the second layer covers 0.5-10 mg/cm²Of the first layer.

27. The film-coated tablet of claim 26, wherein the film-coating agent is selected from the group consisting of: hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), Methylcellulose (MC), Ethylcellulose (EC), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), and methacrylic acid copolymers.

28. The film-coated tablet of claim 26, wherein component B is polyethylene glycol.

29. The film-coated tablet according to claim 7, wherein the uncoated tablet comprises citrate dihydrate of Compound A in a proportion of 0.5 to 30 wt% based on Compound A,

the first layer comprises hydroxypropyl methylcellulose and covers 1.5-3 mg/cm²The surface of the uncoated tablet of (a),

the second layer contains polyethylene glycol 6000 and covers 1-5 mg/cm²Of the first layer of (a), and

when the tablets were placed in a container and stored for 6 months under unsealed conditions at 40 ℃ and 75% RH, a proportion of related substances of compound a of not more than 0.6% was produced.

30. A commercial package comprising the film-coated tablet of claim 1 and written matter associated therewith, wherein instructions on or in the package that the film-coated tablet can or should be used to promote gastrointestinal motility, ameliorate post-gastrectomy syndrome, or prevent or treat gastroesophageal reflux (GERD) are contained.