TWI488622B - A film-coating tablet with reduced discoloration and smell - Google Patents

Description

Film-coated ingots that inhibit discoloration and odor

The present invention relates to a film-coated tablet containing tranexamic acid, vitamin C and L-cysteine, the discoloration of the preparation is not easy to occur, and the odor generated from the preparation is suppressed.

As an anti-cytoplasmic agent, tranexamic acid has anti-hemorrhagic, anti-allergic, anti-inflammatory effects, etc., and is widely used as a medical drug, and is also mixed with OTC pharmaceuticals. In 1979, after administration of tranexamic acid to patients with chronic urticaria, accidentally, the disappearance of the liver spot was reported, and since then, the acid was prescribed for the treatment of liver spot (refer to, for example, Non-Patent Document 1) .

It is known that vitamin C inhibits the production of melanin and inhibits pigmentation by decomposing the accumulated melanin. In the case of OTC pharmaceuticals, the preparation of vitamin C as the main drug is approved. In the case, pigment deposition due to spots, freckles, sun, and macules is recognized (see Non-Patent Document 2).

Further, a preparation for treating a pigmentation disease containing tranexamic acid and vitamin C has been disclosed, and it has been reported that the improvement of the pigmentation disease is better than the administration of a single agent of tranexamic acid or a single dose of vitamin C (see Patent Document 1). Further, it has been revealed that a whitening composition containing tranexamic acid, vitamin C, and L-cysteine is further suppressed by the use of tranexamic acid and vitamin C (see Patent Document 2).

On the other hand, in the solid preparation of L-cysteine, the scent of cysteine itself is strong and it is difficult to take it directly. Further, a general method of masking a pungent odor is to apply a water-soluble polymer such as hydroxypropylcellulose, hypromellose or polyvinylpyrrolidone as a base in a solid preparation. The method of film coating failed to prevent the smell of cysteine, which was previously prevented by the application of sugar coating. However, the sugar coating step has a drawback that it takes a long time and the preparation becomes large, which affects the stability or appearance of the active ingredient, etc. (refer to Patent Document 3 above).

As a simple technique for masking the pungent odor of L-cysteine and miniaturizing the tablet, (I) a film-coated tablet containing a partial saponified product of polyvinyl alcohol (Patent Document 3) (II) A film-coated tablet of mixed carboxymethylcellulose (Patent Document 4).

On the other hand, the present inventors have actually found that the tablet containing the tranexamic acid, the vitamin C, and the L-cysteine in Patent Document 2 has been found to be stored for a long period of time (temperature 40 ° C, relative humidity 75%). Under the accelerated test, it gradually changed color (reddened), and it was further confirmed that it had a coating which caused a problem of the smell of cysteine.

Moreover, it was found during the study that even with the techniques of (I) and (II) above, it is difficult to simultaneously suppress discoloration (reddening) of a preparation containing tranexamic acid, vitamin C, and L-cysteine. Cysteine smell.

Further, the polyvinyl alcohol copolymer (PVA copolymer) is a copolymer of polyvinyl alcohol and a polymerizable vinyl monomer, and has been used as a gelatin capsule material since it was caused by bovine spongiform encephalopathy (BSE). For example, Patent Document 5). For the medical use of a PVA copolymer other than a capsule, there is disclosed a coating agent (Patent Document 6) or a binder for a tablet or a granule (Patent Document 7).

Further, it has not been known so far as an active ingredient containing tranexamic acid, vitamin C and L-cysteine as carboxymethyl cellulose, polyvinyl alcohol, polyvinyl alcohol partial saponified product, polyethylene as an additive. The alcohol copolymer is applied to a lozenge of the film coat.

Conventional technical literature Patent literature:

Patent Document 1 Japanese Patent Laid-Open No. 4-243825

Patent Document 2 Japanese Patent Laid-Open Publication No. 2004-217655

Patent Document 3 Japanese Patent Publication No. 2008-201711

Patent Document 4 Japanese Patent Laid-Open Publication No. 2005-162619

Patent Document 5 Japanese Patent Laid-Open Publication No. 2007-091670

Patent Document 6 Japanese Patent Laid-Open Publication No. 2007-022938

Patent Document 7 International Publication No. 2005/019286

Non-patent literature

Non-Patent Document 1 FARUMASHIA Vol.44 No.5 2008 p.437-442

Non-Patent Document 2 "General Pharmaceutical Manufacturing (Input) Recognition Standard" JHO 2008 Edition

An object of the present invention is to provide a tablet containing a tranexamic acid, vitamin C, and L-cysteine, which is a solid preparation which is discolored (reddened), has little odor, and has excellent stability.

When a partially saponified or polyvinyl alcohol copolymer of polyvinyl alcohol is used for the film coating, the tablet is in the form of a tablet when it is dried due to the strong adhesion of the saponified portion of the polyvinyl alcohol or the physical property of the polyvinyl alcohol copolymer. The problem of attachment is easy to occur.

When a partially saponified polyvinyl alcohol or a polyvinyl alcohol copolymer is used for the film coating, in order to prevent adhesion between the tablets, the coating step is lowered as compared with the film coating agent such as hypromellose used in the prior art. The amount of spray in can also be considered.

However, when the amount of the coating agent is reduced, it is difficult to secure a sufficient thickness of the film to exhibit the effect of the coating, and it is difficult to produce a film coating agent having excellent stability.

Therefore, if a film coating method can be developed, it is possible to ensure the thickness of the film coating of the stable tablet even if the amount of the coating agent is reduced.

Further, by controlling the thickness of the film coat, even if the drying time is shortened, the adhesion between the tablets is less likely to occur, and the step time can be shortened.

The present inventors have solved the above problems, and which technology is most helpful for the stability of the preparation, and has been repeatedly tested and failed over the years.

The result was found to be: a tablet containing tranexamic acid, vitamin C and L-cysteine, etc.

(1) using a polyvinyl alcohol copolymer as a film coating agent;

(2) The shape of the tablet is processed to obtain the effect of the coating (the discoloration (reddening) of the contact surface (interface) between the tablet and the film coat is suppressed, and the discoloration (red) of the ingot (internal) is preserved for a long period of time. The present invention has also been completed by suppressing the further odor and suppressing the excellent film coat.

That is, the present invention is as follows:

(1): A film-coated tablet in which a film containing a polyvinyl alcohol copolymer is applied to a tablet containing a tranexamic acid, a vitamin C, and an L-cysteine.

(2) The film-coated ingot according to (1), which has a film thickness of 60 μm or more.

(3) The film coating ingot according to (1), which has a film thickness of 70 μm or more.

(4) The film-coated ingot according to any one of (1) to (3), wherein the thickness/diameter value is 0.50 or more.

(5) The film-coated ingot according to any one of (1) to (3), which has a thickness/diameter value of 0.60 or more.

(6) The film-coated tablet according to any one of (1) to (5), which is capable of suppressing the occurrence of odor in addition to suppressing discoloration at the interface between the film coating layer and the ingot.

(7) The film-coated ingot according to any one of (1) to (6) which has a spherical crown height/diameter value of 0.15 or more.

(8) The film-coated ingot according to any one of (1) to (6) which has a spherical crown height/diameter value of 0.18 or more.

The tablet according to the present invention contains tranexamic acid, vitamin C, and L-cysteine, and the discoloration (reddening) of the contact surface between the tablet and the film coat is suppressed, and the ingot is preserved for a long period of time (internal). The discoloration (reddening) is also suppressed, and further odor is suppressed and thus useful.

Further, according to the present invention, even if the drying time is shortened, the adhesion between the tablets is less likely to occur, and a film coating agent having a short processing time can be produced.

[Materials used, etc.]

"Traditional Acid" and "Vitamin C" are included in the "15th Correction of the Japanese Drug Administration".

"L-cysteine" and "polyvinyl alcohol partial saponification" are included in "Pharmaceutical Additive Specification 2003", for example.

The "polyvinyl alcohol copolymer" can be produced according to the method described in WO2005/19286 or WO2002/17848, and is a polyvinyl alcohol copolymer which is a partially saponified polyvinyl alcohol having an average polymerization degree of 100 to 2,000 and at least one or more. The polymerizable vinyl monomer is copolymerized by copolymerization at a weight ratio of 6:4 to 9:1, and the viscosity of the copolymer in a 2% by weight solution at 20 ° C is 10 to 300 mPa ‧ s.

As the polyvinyl alcohol copolymer, a partially saponified polyvinyl alcohol having an average polymerization degree of 150 to 1000 and at least one kind of "polymerizable vinyl monomer" are preferably used in a weight ratio of 6:4 to 9:1. A copolymer obtained by proportional copolymerization, and a copolymer of the copolymer having a viscosity of 10 to 250 mPa·s at a viscosity of 2% by weight at 20 ° C.

As the polymerizable vinyl monomer to be used, acrylic acid, methacrylic acid, polyethylene glycol (Macrogol) or the like is preferred.

Further, a copolymer of polyvinyl alcohol and polyethylene glycol is also preferred as the polyvinyl alcohol copolymer used in the present invention.

The polyvinyl alcohol copolymer used in the present invention is commercially available, for example, under the trade name "POVACOAT" (Nisshin Chemical Co., Ltd.) and the trade name "Kollicoat IR" (BASF). easy to get.

The content of the tranexamic acid, the vitamin C, the L-cysteine, and the polyvinyl alcohol copolymer or the polyvinyl alcohol partial saponified compound used in the present invention is 0.01 to 10 per 1 part by weight of the tranexamic acid. The weight is 0.01 to 10 parts by weight, and 0.001 to 1 part by weight, preferably 0.1 to 2 parts by weight, 0.1 to 2 parts by weight, and 0.01 to 1 part by weight.

[About the shape of the tablet]

The shape of the tablet of the present invention is not particularly limited. For example, when viewed from the upper portion, it is usually a circular shape, an elliptical shape, a so-called couplet shape, a rhombic shape, or the like, and a circular shape is preferred.

The cross section of the tablet of the present invention is formed by an R surface (upper or lower surface) and an O surface (side surface or belt portion) as shown in Figs. 1 and 2 .

The term "diameter" refers to the length of the O surface from the O side to the other side in the cross-sectional view (1 in Fig. 1). Further, when the shape of the tablet is not circular, for example, a considerable diameter (= 4X ingot projected area/ingot circumference) or the like can be used.

The "radius of curvature" refers to the radius of curvature of the R surface (2 in Fig. 1). However, if the tablet or the shape of the upper and lower 2 R faces is not circular, the arithmetic mean radius of curvature or the like can be used.

The term "ball crown height" refers to the maximum value (3) of the length from the line to the R surface when the line is drawn at the uppermost portion of the O surface in Fig. 2 (1). The same applies to the case where the shape of the tablet is not circular.

The term "film coat thickness" means the thickness of the film coat on the O side.

The term "thickness/diameter" refers to the thickness of the prime ingot (the longest distance from the R surface on one side to the R surface on the other side in the cross-sectional view)/diameter.

The term "prime" refers to a tablet before application of a film coat.

The term "ball crown height/diameter" refers to the value of dividing the above "ball crown height" by the above "diameter".

By applying a film coat to the ingot, it is possible to manufacture a customizing agent which inhibits discoloration (reddening) and pungent odor.

The film coat is preferably 60 μm or more and 400 μm or less, more preferably 70 μm or more and 300 μm or less.

When the "thickness/diameter" is large, it is possible to apply a thick film coat with a small amount of film. In order to achieve the effect of the present invention, the effect of suppressing the occurrence of discoloration and odor is exhibited, and the value of "thickness/diameter" is usually 0.5 or more, preferably 0.60 or more and 1.0 or less, more preferably 0.70 or more and 0.9 or less.

Further, when the film thickness is the same, the larger the value of the "ball crown height/diameter" is, the more the discoloration inside the tablet can be suppressed. In order to achieve the effect of the present invention, the effect of suppressing the occurrence of discoloration and odor is exhibited, and the value of "spherical height/diameter" is preferably 0.15 or more, more preferably 0.18 or more.

Further, the correlation between the film thickness of the O surface and the discoloration rate has been confirmed, and it can be expressed by the relationship of y=ae ^bx (x: film thickness of the O surface, y: discoloration rate of the tablet, a and b: constant). At this time, the coefficient R ^{2 is} determined to be preferably 0.8 or more, and more preferably 0.85. Further, the constant a is preferably 800 or more and 805 or less; and the constant b is preferably -0.03 or more and -0.05 or less.

The film-coated tablet of the present invention can further add an additive by mixing tranexamic acid, vitamin C and L-cysteine, and other medicinal ingredients as necessary, and classify the particles for granulation as necessary, and After the tableting is carried out to produce a tablet, the film coat is applied and manufactured.

Example

In order to explain the present invention in more detail, the examples and comparative examples are described below. Test Example 1: Comparison test of the contact surface (interface) between the tablet and the film coat

Preparation of tablets (1) Modulation of Prime Ingot 1

A pellet: In a fluidized bed granulator, 2403.8 g of tranexamic acid, 769.2 g of L-cysteine, 118.6 g of calcium pantothenate, 19.2 g of pyridoxine hydrochloride, and an appropriate amount of crystalline cellulose were mixed and sprayed. An aqueous solution of hypromellose which is a binder to prepare a granulated powder and thereby use it as an A particle.

B particles: In a fluidized layer granulator, 961.5 g of vitamin C, an appropriate amount of crystalline cellulose, and an aqueous solution of hypromellose as a binder were sprayed to prepare a granular powder and used as a B particle.

Ingot 1: Into 3651.3g of granule powder mixed with A particles and B particles, 205.1 g of crystalline cellulose, 102.6 g of croscarmellose sodium, 41.0 g of magnesium stearate, and diameter After 9.5mm, the radius of curvature is 11.0mm, and the upper 2R surface is 3.8mm. The ingot is a single ingot of 390mg and 5.6mm thick.

(2) Modulation of plain ingot 2

A granule: In a fluidized bed granulator, 2403.8 g of tranexamic acid, 118.6 g of calcium pantothenate, and an appropriate amount of crystalline cellulose are mixed, and an aqueous solution of hypromellose as a binder is sprayed to prepare granule powder. For A particles.

B particles: In the fluidized layer granulator, put and mix vitamin C961.5g, L-cysteine 769.2g, pyridoxine hydrochloride 19.2g, appropriate amount of crystalline cellulose, and spray as a binder of hydroxypropyl An aqueous solution of cellulose is used to prepare a granular powder and thereby use it as a B particle.

Ingot 2: Into 3651.3 g of granule powder mixed with A particles and B particles, 205.1 g of crystalline cellulose, 102.6 g of croscarmellose sodium, 41.0 g of magnesium stearate, and a diameter of After 9.5 mm, the radius of curvature is 11.0 mm, and the upper 2R surface is 3.8 mm. The ingot is 1 ingot of mass 390 mg and 5.6 mm thick.

(3) Modulation of Prime Ingot 3

A granules: 410.2 g of tranexamic acid, 15.2 g of calcium pantothenate, 16.4 g of nicotinic decylamine, and 50% of spray-dried powder of Tocopherol acetate were added to a fluidized layer granulator. 24.6 g of the body, an appropriate amount of crystalline vitamins, and an aqueous solution of hypromellose was sprayed to prepare a granular powder and used as the A particles.

B particles: In a fluidized layer granulator, 255.5 g of vitamin C, 204.4 g of L-cysteine, 10.2 g of pyridoxine hydrochloride, an appropriate amount of crystalline cellulose, and an aqueous solution of hypromellose were sprayed. The granule powder is prepared and used as the B granule.

Ingot 3: In the 688.0 g of granular powder mixed with A particles and B particles, 77.7 g of crystalline cellulose, 22.3 g of croscarmellose sodium, 12.0 g of magnesium stearate, and a diameter of 9.5 mm were mixed. After that, the R surface of the radius of curvature of 7.6 mm is used, and the ingot is a single ingot 3 having a mass of 350 mg and a thickness of 5.6 mm.

(Comparative Example 1)

19.5 g of hypromellose and 3.0 g of talc were dispersed and dissolved in 240 g of pure water to prepare a coating solution. The ingot 1 (250 g, about 640 spindles) was filled in a coating pan (Hicoater mini, Freund Corporation), and each of the tablets was sprayed with a film coating liquid to 410 mg to obtain a film-coated tablet.

(Comparative Example 2)

22.5 g of a film-coating base (trade name: Ou Baide II) containing a polyvinyl alcohol partial saponified product was dispersed and dissolved in 240 g of pure water to prepare a film coating liquid. The ingot 1 (250 g, about 640 ingots) was filled in the above-mentioned film coat pan, and each of the ingots was sprayed with a film coating liquid to 410 mg to obtain a film-coated tablet.

(Comparative Example 3)

22.5 g of a film-coating base (trade name: Oubad AMB) containing a polyvinyl alcohol partial saponified product was dispersed and dissolved in 240 g of pure water to prepare a film coating liquid. The ingot 1 (250 g, about 640 ingots) was filled in the above-mentioned film coat pan, and each of the ingots was sprayed with a film coating liquid to 410 mg to obtain a film-coated tablet.

(Comparative Example 4)

19.5 g of hypromellose, 1.0 g of sodium carboxymethylcellulose, and 2.0 g of talc were dispersed and dissolved in 240 g of pure water to prepare a film coating liquid. The ingot 1 (250 g, about 640 spindles) was filled in a film coat pan, and each of the tablets was sprayed with a film coating liquid to 410 mg to obtain a film-coated tablet.

(Comparative Example 5)

Using a plain ingot 2, a film ingot was obtained in the same manner as in Comparative Example 1.

(Comparative Example 6)

A film ingot was obtained in the same manner as in Comparative Example 2 using Prime Ingot 2.

(Comparative Example 7)

Using a plain ingot 2, a film ingot was obtained in the same manner as in Comparative Example 3.

(Comparative Example 8)

Using a plain ingot 2, a film ingot was obtained in the same manner as in Comparative Example 4.

(Comparative Example 9)

Using a plain ingot 3, a film ingot was obtained in the same manner as in Comparative Example 1.

(Comparative Example 10)

A film ingot was obtained in the same manner as in Comparative Example 2 using Prime Ingot 3.

(Example 1)

19.5 g of a polyvinyl alcohol copolymer (trade name "Pobart") and 3.0 g of talc were dispersed and dissolved in 240 g of pure water to prepare a film coating liquid. Ingot 1 (250 g, about 640 spindles) was filled in the coat pan, and each of the tablets was sprayed to 408 mg with a film coating liquid to obtain a film-coated tablet.

(Example 2)

A film ingot was obtained in the same manner as in Example 1 using the ingot 2.

(Example 3)

A film ingot was obtained in the same manner as in Example 1 using the ingot 3.

2. Test method

60 ingots of Comparative Examples 1-10 and Examples 1-3 were filled and sealed in a glass bottle (6k size bottle). After 2 days of storage at 50 ° C, the tablet was broken and the discoloration (reddening) of the tablet was evaluated and the odor immediately after opening.

(1) Benchmark of evaluation [Visual evaluation (coloring)]

The evaluation was carried out in four stages of A: no discoloration, B: slight discoloration, C: discoloration, and D: significant discoloration.

[odor]

It was evaluated in four stages: A: odorless, B: slightly odor, C: odor, D: significant odor.

3. Test results

The test results are shown in Table 1. According to the results of Table 1, it was found that when the film coating was applied with a polyvinyl alcohol copolymer, the discoloration (reddening) and the occurrence of cysteine odor at the interface between the film coat and the ingot were suppressed.

The table abbreviations are as follows.

HP: hypromellose, PVAP: PVA partial saponification,

CNa: sodium carboxymethyl cellulose, PVAC: PVA copolymer,

MC: polyethylene glycol, SL: soy lecithin, TO: titanium oxide,

TA: Talc

Discoloration: visual discoloration evaluation

Odor: evaluation of cysteine smell

Test Example 2: Comparative test of film-coated tablets 1. Modulation of plain ingots (1) Modulation of ingot powder (a) Ingot powder a

A pellet: In a fluidized bed granulator, 2403.8 g of tranexamic acid, 769.2 g of L-cysteine, 118.6 g of calcium pantothenate, 19.2 g of pyridoxine hydrochloride, and an appropriate amount of crystalline cellulose were mixed and sprayed. It is an aqueous solution of hypromellose which is a binder to prepare a granular powder and is used as the A particle.

B particles: In a fluidized layer granulator, 961.5 g of vitamin C, an appropriate amount of crystalline cellulose, and an aqueous solution of hypromellose as a binder were sprayed to prepare a granular powder and used as a B particle.

Ingot powder a: Into 3651.3g of granule powder mixed with A granules and B granules, 205.1 g of crystalline cellulose, 102.6 g of croscarmellose sodium, and 41.0 g of magnesium stearate were charged and mixed. Ingot powder a.

(b) Ingot powder b

A granule: In a fluidized bed granulator, 2403.8 g of tranexamic acid, 118.6 g of calcium pantothenate, and an appropriate amount of crystalline cellulose are mixed, and an aqueous solution of hypromellose as a binder is sprayed to prepare granule powder. For A particles.

B granules: In a fluidized layer granulator, 961.5 g of vitamin C, 769.2 g of L-cysteine, 19.2 g of pyridoxine hydrochloride, an appropriate amount of crystalline cellulose, and a hydroxypropyl group as a binder were sprayed and mixed. An aqueous solution of cellulose is used to prepare a granular powder and thereby use it as a B particle.

Ingot powder b: Into 3651.3 g of granule powder mixed with A particles and B particles, 205.1 g of crystalline cellulose, 102.6 g of croscarmellose sodium, and 41.0 g of magnesium stearate were charged and mixed. Ingot powder b.

(c) Ingot powder c

A granules: 432.5 g of tranexamic acid, 16.0 g of calcium pantothenate, 17.3 g of nicotine decylamine, an appropriate amount of crystalline cellulose, and an aqueous solution of hypromellose were sprayed in a fluidized bed granulator to prepare granule powder. This is the A particle.

B particles: In a fluidized layer granulator, 255.5 g of vitamin C, 204.4 g of L-cysteine, 10.2 g of pyridoxine hydrochloride, an appropriate amount of crystalline cellulose, and an aqueous solution of hypromellose were sprayed. The granule powder is prepared and used as the B granule.

Ingot powder c: 744.9 g of granular powder mixed with A particles and B particles, mixed with vitamin E succinate 12.8 g, crystalline cellulose 202.1 g, croscarmellose sodium 25.0 g, stearic acid Magnesium oxide 15.2g, the ingot powder c was obtained.

(d) Ingot powder d

A pellet: 573.8 g of tranexamic acid, 21.2 g of calcium pantothenate, 23.0 g of nicotine decylamine, 50% of vitamin E acetate (acetate vitamin E) spray dried powder 34.4 g were placed in a fluidized bed granulator. An appropriate amount of crystalline cellulose is sprayed, and an aqueous solution of hypromellose is sprayed to prepare a granular powder and used as the A particle.

B particles: In a fluidized layer granulator, 255.5 g of vitamin C, 204.4 g of L-cysteine, 10.2 g of pyridoxine hydrochloride, an appropriate amount of crystalline cellulose, and an aqueous solution of hypromellose were sprayed. The granule powder is prepared and used as the B granule.

Ingot powder d: In 1003.9 g of granular powder mixed with A particles and B particles, 243.9 g of crystalline cellulose, 32.5 g of croscarmellose sodium, and 19.7 g of magnesium stearate were mixed. Powder d.

(2) Modulation of prime ingot

Using the ingot powder a-d, the tableting was carried out by a rotary tableting machine, and the following specifications of the ingots 1-4 were prepared.

Plain ingot: a plain ingot with a diameter of 9.5 mm, a radius of curvature of 7.6 mm and a mass of 390 mg (at this time (thickness/diameter) = 0.64, (ball crown height/diameter) = 0.18)

Plain ingot B: a fine ingot having a diameter of 9.0 mm, a radius of curvature of 7.2 mm and a mass of 390 mg (at this time (thickness/diameter) = 0.71, (spherical crown height/diameter) = 0.18)

Prime ingot: a plain ingot with a diameter of 9.5 mm, a radius of curvature of 3.8, 11.0 mm, and a mass of 390 mg (at this time (thickness/diameter) = 0.60, (spherical crown height/diameter) = 0.16)

Plain ingot: a fine ingot having a diameter of 9.5 mm, a radius of curvature of 11.4 mm, and a mass of 390 mg (at this time (thickness/diameter) = 0.57, (spherical crown height/diameter) = 0.11)

2. Modulation of film coating liquid (1) polyvinyl alcohol copolymer film coating liquid

1121.0 g of a polyvinyl alcohol copolymer (Bobate), 455.0 g of talc, and 320.0 g of titanium oxide were dispersed and dissolved in a mixed liquid of 9685.0 g of pure water and 2419.0 g of ethanol to prepare a film coating liquid (hereinafter, also referred to as "copolymer").

(2) polyvinyl alcohol partial saponified film coating solution 1

100 g of a film-coating base (trade name: "Oubaid II") containing a polyvinyl alcohol partial saponified product was dispersed and dissolved in 750 g of pure water as a film coating liquid (hereinafter, also referred to as "partial suspension 1" ").

(3) polyvinyl alcohol partial saponified film coating solution 2

100 g of a film-coating base (trade name: "Oubad AMB") containing a polyvinyl alcohol partial saponified product was dispersed and dissolved in 750 g of pure water as a film coating liquid (hereinafter, also referred to as "partial suspension 2" ").

(Comparative Example 2-1)

The ingot powder b is used to prepare the ingot.

(Comparative Example 2-2)

The ingot tablet b is used to prepare the ingot B.

(Comparative Example 2-3)

The ingots prepared by using the ingot powder b were filled in the above-mentioned film coat pan, and each ingot was coated with a polyvinyl alcohol copolymer film coating liquid (copolymer) to 405 mg. The film thickness (O surface) at this time was 45.1 μm.

(Comparative Example 2-4)

The ingot B prepared by using the tableting powder b was filled in the above-mentioned film coating pan, and each ingot was added to 416 mg with a polyvinyl alcohol partial saponified film coating liquid 1 (partial suspension 1). The film thickness (O surface) at this time was 75.1 μm.

(Comparative Example 2-5)

The ingot B prepared by using the tableting powder b was filled in the above-mentioned film coating pan, and each ingot was added to 416 mg with a polyvinyl alcohol partial saponified film coating liquid 2 (partial suspension 2). At this time, the film thickness (O surface) was 72.2 μm.

(Comparative Example 2-6)

The ingot powder c is used to prepare the ingot.

(Comparative Example 2-7)

The ingot powder d is used to prepare the ingot.

(Example 2-1)

The ingots prepared by using the ingot powder b were filled in the above-mentioned film coat pan, and each ingot was sprayed with a copolymer to 416 mg for coating. At this time, the film thickness (O surface) was 64.7 μm.

(Example 2-2)

The ingots prepared by using the ingot powder b were filled in the above-mentioned film coat pan, and each ingot was sprayed with a copolymer to 427 mg for coating. The film thickness (O surface) at this time was 96.4 μm.

(Example 2-3)

The ingot B prepared by using the ingot powder b was filled in the above-mentioned film coat pan, and each ingot was sprayed with a copolymer to 405 mg for coating. The film thickness (O surface) at this time was 61.6 μm.

(Example 2-4)

The ingot B prepared by using the tableting powder b was filled in the above-mentioned film coating pan, and each ingot was sprayed with a copolymer to 416 mg for coating. The film thickness (O surface) at this time was 71.4 μm.

(Example 2-5)

The ingot B prepared by using the tableting powder b was filled in the above-mentioned film coating pan, and each ingot was sprayed to 427 mg with a copolymer to be added. At this time, the film thickness (O surface) was 119.5 μm.

(Example 2-6)

The primed tablets prepared by using the ingot powder b were filled in the above-mentioned film coat pan, and each of the ingots was sprayed with a copolymer to 413 mg for coating. The film thickness at this time was 90.0 μm.

(Examples 2-7)

The ingots prepared by using the ingot powder b were filled in the above-mentioned film coat pan, and each ingot was sprayed to 427 mg with a copolymer to be added. The film thickness at this time was 86.1 μm.

(Examples 2-8)

The plain powder prepared by using the ingot powder c was filled in the above-mentioned film coat pan, and each of the ingots was sprayed with a copolymer to 425 mg for coating. The film coat thickness at this time was 94.1 μm.

(Examples 2-9)

The primed tablets prepared by using the ingot powder d were filled in the above-mentioned coat pan, and each ingot was sprayed with a copolymer to 425 mg for coating. The film thickness at this time was 94.4 μm.

3. Test method

120 samples of Comparative Examples 2-1 to 2-7 and Examples 2-1 to 2-9 were filled and sealed in a glass bottle (6k size bottle). After storage at 60 ° C for 1 week and storage at 50 ° C for 8 weeks, the odor and the discoloration (redness) of the ingot (internal) immediately after the opening of the bottle were evaluated.

(1) Method of evaluation

60 ingots were filled and sealed in a glass bottle (6 k size bottle). After 2 days of storage at 50 ° C, the tablet was broken up and the discoloration (coloring, redness) and cysteine odor at the tablet interface were evaluated.

(2) Benchmark of evaluation [discoloration]

Regarding the discoloration (reddening) of the ingot (internal), 100 tablets of the tablet were broken, and the number of tablets of discoloration (reddening) was calculated and evaluated by the relative percentage of the number of tests (100 spindles).

The evaluation was carried out in four stages of A: no discoloration, B: slight discoloration, C: discoloration, and D: significant discoloration.

[odor]

It was evaluated in four stages: A: odorless, B: slightly odor, C: odor, D: significant odor.

Further, the film thickness of the film coat was evaluated based on the average of the number of tests (n = 20) by the image analysis method by a microscope.

4. Test results

The results are shown in Table 2 and Table 3. It is known that when a film coat is applied by a polyvinyl alcohol copolymer (copolymer), the discoloration (reddening) of the ingot (internal) is significantly suppressed when the film coat is applied with a polyvinyl alcohol partial saponified product. Cysteine smell.

1‧‧‧diameter (ingot diameter)

2‧‧‧ radius of curvature

3‧‧‧High crown

4‧‧‧ Center

R‧‧‧R face

O‧‧‧O face (side (belt) part)

Fig. 1 is a cross-sectional view showing a film ingot of the present invention.

Fig. 2 is a cross-sectional view showing a film ingot of the present invention.

Claims (5)

A film-coated tablet in which a film ingot containing a film of a polyvinyl alcohol copolymer is applied to a tablet containing tranexamic acid, vitamin C and L-cysteine, and the film thickness is 60 μm or more, and the value of the crown height/diameter is 0.15 or more. The film coating ingot of claim 1 has a film thickness of 70 μm or more. For example, the film ingot of the second application of the patent scope has a spherical crown height/diameter value of 0.18 or more. For example, the film-coated ingot of claim 1 has a spherical crown height/diameter value of 0.18 or more. The film-coated tablet of any one of claims 1 to 4, which suppresses the discoloration of the interface between the film coating layer and the ingot, and suppresses the occurrence of odor.