TW201717949A - Tablet containing fexofenadine as an active ingredient - Google Patents

Abstract

The present invention provides a miniaturized fexofenadine tablet. The present invention provides a fexofenadine tablet having a high content of fexofenadine as an active ingredient and a reduced size by using carmellose calcium as a disintegrating agent. Since the fexofenadine tablet is small, it is easy for oral administration, and its dissolution rate is also appropriate, so it is highly useful in the treatment and prevention of allergy.

Description

Lozenges containing fexofenadine as an active ingredient

The present invention relates to a tablet for use as an anti-allergic agent, which comprises fexofenadine as an active ingredient (hereinafter referred to as "fexofenadine"), and more particularly, to miniaturize a tablet. It is easy to take the fexofenadine ingot.

A tablet of a general pharmaceutical product is produced by adding an additive such as an excipient to a drug which is an active ingredient, granulating, further adding a lubricant or the like, and ingot. However, in the case of a drug having a large amount of administration, the amount of the additive for tableting treatment tends to increase with the amount of the drug, and as a result, the size of the tablet becomes large, and it becomes difficult to take it. problem.

Fexofenadine is a second-generation antihistamine with H1 receptor antagonistic activity. It is often used as a drug for central nervous system depression, such as almost no drowsiness or cognitive decline, and is the first choice for rhinorrhea allergic rhinitis/hay fever. Fenofenadine is marketed in Japan as an oral lozenge with its hydrochloride as an active ingredient and an intraoral collapse tablet. Its indications are allergic rhinitis, urticaria and itching associated with skin diseases.

The standard dose per dose of febufenadine in adults is 60 mg for fexofenadine hydrochloride. The original product, which is sold in Japan, is a 50 mg ingot (manufactured by Sanofi Co., Ltd., Allegra [registered trademark] ingot 60 mg) having an ellipse having a major axis of 12.1 mm, a short diameter of 5.6 mm, and a thickness of 4.1 mm. Shape, weight 210mg. In addition, among the general-purpose drugs for the 60 mg ingot of fexinadine hydrochloride sold in Japan, the smallest tablet (manufactured by Tosho Pharmaceutical Co., Ltd., 60 mg "Towa" of fexofenadine hydrochloride ingot) is The circle is 8.1 mm in diameter and 3.7 mm in thickness and weighs 186 mg. The smaller each tablet, the easier it is to take, and the higher the convenience, especially for patients with weak swallowing ability such as elderly people or patients who have to take a plurality of tablets. Therefore, in the range of easy handling, smaller tablets are sought.

However, if the additive is reduced and the entire weight and size are made smaller than those of the previous fexofenadine, it is difficult to obtain a tablet having the same dissolution properties as the existing fexofenadine. Since the availability/safety data of the existing fexofenadine can be utilized, it is not suitable to significantly differ in the dissolution rate of the active ingredient compared to the existing fexofenadine. Therefore, it has been desired to develop a tablet having the same dissolution properties as that of the existing fexofenadine and which can be miniaturized.

Regarding tablets containing fexofenadine as an active ingredient or lozenges containing carboxymethylcellulose calcium, a prescription has been made in several prior art documents. For example, in Patent Document 1, a formulation containing L-glutamic acid and magnesium metasilicate aluminate, and a tablet containing carboxymethylcellulose calcium, lactose, and methylcellulose is disclosed, and the formulation of the prescription is shown. Good disintegration. Further, in Patent Document 2, it is disclosed that fexofenadine hydrochloride (4-[4-[4-(hydroxyl) Diphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetic acid hydrochloride), containing croscarmellose sodium, microcrystalline cellulose Formulations of lozenges and capsules of lactose, alpha-starch, gelatin and magnesium stearate, and revealing that the formulation of the formulation improves bioavailability. Further, Patent Document 3 discloses diphenhydramine hydrochloride containing an antihistamine, and contains carboxymethylcellulose calcium, crystalline cellulose, lactose, hydroxypropylcellulose, and magnesium stearate. The formulation of the tablet is disclosed, and it is revealed that the formulation of the prescription can suppress the decrease in the initial content of diphenhydramine hydrochloride at the time of manufacture. However, by viewing Patent Documents 1 to 3 or other related prior documents, it has not been disclosed to disclose a doxofibine ingot which is miniaturized in size using carboxymethylcellulose calcium as a disintegrating agent while exhibiting an appropriate dissolution behavior.

[Previous Technical Literature] [Patent Literature]

[Patent Document 1] Japanese Patent Laid-Open No. Hei 11-302200

[Patent Document 2] Japanese Patent Publication No. 11-501028

[Patent Document 3] Japanese Patent Laid-Open Publication No. 2009-1520

The present invention provides a fexofenadine tablet in which the content of fexofenadine which is an active ingredient is high, and it is easy to take by miniaturization, and an appropriate dissolution rate is exhibited.

The inventors have made it easy to take by miniaturization, and at the same time As a result of intensive research on a non-sofinatine ingot having an appropriate dissolution, it was found to be a disintegrating agent called a super-disintegrating agent without croscarmellose sodium or crospovidone. In the case of a tablet containing an appropriate amount of calcium carboxymethylcellulose, a desired fexofenadine tablet can be obtained, and the present invention has been completed.

That is, the present invention relates to the following: (1) a tablet containing fexofenadine or a pharmaceutically acceptable salt thereof as an active ingredient, and carboxymethylcellulose calcium; (2) The tablet according to the above (1), wherein the active ingredient is fexofenadine hydrochloride; (3) the tablet according to the above (1) or (2), wherein each tablet is fexofenadine Or a pharmaceutically acceptable salt thereof, in an amount of 35 to 60% by weight; (4) a tablet according to the above (1) or (2), wherein each tablet is fexofenadine or pharmaceutically acceptable thereof The tablet of any one of the above-mentioned (1) to (4), wherein the amount of the carboxymethylcellulose calcium per tablet is from 10 to 50% by weight. (6) The tablet according to any one of the above (1) to (4) wherein the amount of carboxymethylcellulose calcium per tablet is from 15 to 25% by weight; (7) as The tablet according to any one of the above (1), further comprising an excipient; (8) the tablet according to the above (7), wherein the excipient is crystalline cellulose; (9) The tablet according to the above (8), wherein the amount of crystalline cellulose per tablet is 20 to 40 % Amount; (10) to (8) described in the above-mentioned lozenges, wherein the lozenges of each crystal fiber (11) The tablet according to any one of the above (8) to (10), wherein the aspect ratio of the average particle diameter of the crystalline cellulose is (L/D) The tablet according to any one of the above (8), wherein the average particle diameter of the crystalline cellulose has a long diameter to diameter ratio (L/D) of 2.8 to 4.0; (13) The tablet according to the above (7), wherein the excipient is a sucrose fatty acid ester; (14) the tablet according to the above (13), wherein the sucrose fatty acid ester content per tablet is 0.5 (15) The tablet according to the above (13), wherein the content of the sucrose fatty acid ester per tablet is from 1 to 3% by weight; (16) as in the above (1) to (15) The tablet according to any one of the above (16), wherein the binder is hypromellose; (18) the tablet according to (17) above, The amount of hypromellose per one tablet is from 1 to 5% by weight; (19) The tablet according to the above (17), wherein the amount of hypromellose per tablet is 2 to 4 (20) A lozenge according to any one of the above (17) to (19), which is used as a binder The lozenge of any one of the above-mentioned (1) to (20), wherein the lozenge is a film-coated tablet; (22) The lozenge according to any one of the above (1) to (21), which is in one tablet (23) The tablet according to the above (22), which has a diameter of 5.0 mm to 6.0 mm and a thickness of 2.5 mm to 3.5 mm; (24) as described above (22) The lozenge according to any one of the above (22) to (24), wherein the tablet has a weight of 5.3 mm to 5.8 mm and a thickness of 2.8 mm to 3.3 mm; The lozenge according to any one of the above (22) to (24), wherein the lozenge has a weight of 60 to 72 mg; (27) as in any one of the above (1) to (21) The lozenge according to the above-mentioned item (27), which has a long diameter of 9 mm to 12 mm and a short diameter of 3.5 mm, wherein the tablet contains 60 mg of fexofenadine hydrochloride. (29) The tablet according to the above (27), which has a long diameter of from 10.5 mm to 11.5 mm, a short diameter of from 4.0 mm to 5.0 mm, and a thickness of from 3.3 mm to 3.8. (30) The tablet according to the above (27), which has a major axis of 10.8 mm to 11.3 mm, a short diameter of 4.3 mm to 4.8 mm, and a thickness of 3.3 mm to 3.8 mm; (31) as described above (27) The lozenge according to any one of the above-mentioned (27) to (30), wherein the lozenge according to any one of the above (27) to (30), wherein The tablet has a weight of 120 to 140 mg; (33) a tablet which is a tablet containing fexofenadine hydrochloride as an active ingredient, and is characterized in that the dissolution rate of the active ingredient from the tablet is in accordance with The second method of the dissolution test method in the general test method of the Japanese Pharmacopoeia In the dissolution test of the method, 900 mL of a test solution having a liquid temperature of 37 ° C was used, and when the elution test was performed at 50 rotations per minute, the elution rate in water was 80% by weight or more after 15 minutes, and 85 weights after 30 minutes. The dissolution rate in the first liquid is 60% by weight or more after 30 minutes, and is 80% by weight or more after 60 minutes.

According to the present invention, in the case of a tablet having a fexofenadine hydrochloride content of 60 mg in one tablet, when the total weight of the tablet is 150 mg or less, the long diameter of the tablet diameter is 12 mm or less and the short diameter is 5.5. When the thickness is less than mm and the thickness is 4.0 mm or less, the weight ratio is reduced by about 40% as compared with the previous product (original product). Moreover, even if the weight ratio is reduced by about 30%, it is easy to take, compared with the minimum amount of fexofenadine hydrochloride ingot 60mg "Towa" which is currently sold in the market. Small non-sofopadine ingots.

Fig. 1 is a view showing the dissolution mode of the tablet of the present invention (containing 60 mg of fexofenadine hydrochloride tablet) shown in Example 1 in accordance with the dissolution test method in the general test method of the Japanese Pharmacopoeia. A graph of the results measured by the 2 method (paddle method, water, and 60 minutes after the start of dissolution). The vertical axis represents the dissolution rate of fexofenadine hydrochloride, and the horizontal axis represents the time after the start of dissolution.

Fig. 2 is a view showing the dissolution mode of the tablet of the present invention (containing 60 mg of fexofenadine hydrochloride tablet) shown in Example 1 in accordance with the dissolution test method of the general test method of the Japanese Pharmacopoeia. A graph of the results of the 2 method (paddle method, pH 1.2, after the start of dissolution to 120 minutes). Vertical axis The dissolution rate of phenaldine hydrochloride, and the horizontal axis indicates the time after the start of dissolution.

[Used to implement the aspect of the invention]

The present invention is characterized in that in a tablet containing fexofenadine as an active ingredient, calcium carboxymethylcellulose is contained as an additive for promoting the collapse of the preparation.

The tablet of the present invention contains fexofenadine as an active ingredient, but may be a pharmaceutically acceptable salt thereof. With regard to fexofenadine, it is not particularly limited as long as a pharmaceutically acceptable acid-addition salt is used, and examples thereof include hydrochloride, sulfate, nitrate, phosphate, hydrofluoride, and hydrobromide. Inorganic acid or acetate, tartrate, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, besylate, tosylate, naphthalenesulfonic acid An organic acid salt such as salt or camphor sulfonate. It is particularly preferred to use fexofenadine hydrochloride which is widely used clinically as an antiallergic drug. Further, a stereoisomer or a hydrate or a solvate of fexofenadine is also contained in fexofenadine which can be an active ingredient of the tablet of the present invention.

The content of fexofenadine or a pharmaceutically acceptable salt thereof in the tablet of the present invention is not particularly limited, and may be appropriately selected depending on the size of the tablet, etc., but is 20 to 70% by weight based on 100% by weight of the tablet. Preferably, it is 35 to 60% by weight, more preferably 40 to 50% by weight. Further, the content of the carboxymethylcellulose calcium in the tablet of the present invention is not particularly limited, but is 5 to 40% by weight, preferably 10 to 30% by weight, and more preferably 15% by weight based on 100% by weight of the tablet. ~25% by weight.

As the excipient which is an additive of the tablet of the present invention, crystalline cellulose, sucrose fatty acid ester, lactose, D-mannitol, calcium hydrogen phosphate, corn starch, potato starch or the like can be used, but it is particularly preferred to be crystalline cellulose and Sucrose fatty acid ester. Crystalline cellulose is purified by partial depolymerization of α-cellulose obtained from the formation of pulp from fibrous plants, and can be purchased from commercially available products, and can be used in the Japanese Pharmacopoeia (sixteenth correction). By. Further, although there are various grades in the crystalline cellulose, it is preferred to use a high formability crystalline cellulose having a long diameter to diameter ratio (L/D) of an average particle diameter of 1.5 to 4.0. More preferably, the long diameter to diameter ratio (L/D) of the average particle diameter is 2.8 to 4.0. The content of the crystalline cellulose in the tablet of the present invention is not particularly limited, but is preferably 20 to 40% by weight, more preferably 25 to 35% by weight based on 100% by weight of the tablet. On the other hand, the sucrose fatty acid ester is a surfactant which is ester-bonded to a fatty acid of a sucrose, and can be purchased from a commercial product, and can be used in "Pharmaceutical Additive Specification 2013" (issued by Nippon Pharmaceutical Daily). Receiver. The content of the sucrose fatty acid ester in the tablet of the present invention is not particularly limited, but is preferably 0.5 to 5% by weight, more preferably 1 to 3% by weight based on 100% by weight of the tablet.

In the tablet of the present invention, in addition to the above components, when the binder is blended, the physical quality is improved and it is more preferable. That is, the tablet of the present invention must have an appropriate strength, however, only carboxymethylcellulose calcium and an excipient as an additive have insufficient hardness or wear or capping (the tablet is in the form of a slide) The phenomenon of splitting occurs. Therefore, it is preferred to prepare a preparation having an appropriate hardness by adding a binder. For the binder used in the tablet of the present invention, hypromellose (hydroxypropylmethylcellulose) can be used. Or hydroxypropylcellulose, povidone, pullulan, etc., but particularly preferred is hypromellose. The content of hypromellose in the tablet of the present invention is not particularly limited, and is usually about 1 to 5% by weight, more preferably 2 to 4% by weight based on 100% by weight of the tablet.

The tablet of the present invention may generally contain various additives used in the production of tablets, in addition to the above, insofar as the effects of the invention are not impaired. In the case of such an additive, excipients and binders other than those exemplified above may be exemplified by disintegrating agents, flavoring agents, foaming agents, perfumes, lubricants, coloring agents, etc., which may be appropriately added according to the purpose. . Further, the above-mentioned tablet may be coated as needed. By coating, the tablet becomes less susceptible to damage/wear and is convenient for transport or packaging.

[Examples]

The present invention will be specifically described below by way of examples, but the present invention is not limited thereto.

Example 1

11.535 kg of fexofenadine hydrochloride, 5.268 kg of crystalline cellulose, 0.462 kg of sucrose fatty acid ester, 1.154 kg of carboxymethylcellulose calcium and 0.037 kg were taken according to the conditions shown in Table 1. Hypromellose. The adhesive solution was stirred by stirring 0.425 kg of hypromellose and adding it to 8.075 kg of water. The powder thus weighed was passed through a 1.18 mm sieve, put into a stirring granulator (YC-SMG-150, YENCHEN MACHINERY CO., LTD), and premixed at a mixer speed of 120 rpm and a chopper speed of 3500 rpm for 5 minutes. Add 8.50 kg to 3 minutes A 5% hypromellose solution was stirred and granulated, and dried using a fluidized bed dryer (YC-FBDG-60, YENCHEN MACHINERY CO., LTD) for about 2 hours. The granules were granulated using a granulator (YC-OG-2, YENCHEN MACHINERY CO., LTD, sieve hole 0.6 mm) to obtain 18.88 kg of granules. Then, the second stirring granulation was carried out in the same manner, and the mixture was dried using a fluidized bed dryer for about 2 hours. The granules were granulated using the above granulator to obtain 18.42 kg of granules. To the obtained granules, 6.713 kg of carboxymethylcellulose calcium and 4.923 kg of crystalline cellulose were added and placed in a mixer (YC-TM-100, YENCHEN MACHINERY CO., LTD) at 28 rotations/min. Mix for 5 minutes at speed. 0.224 kg of magnesium stearate was added and mixed at a speed of 28 rotations/min for 3 minutes to obtain pellets for tableting.

A bare ingot of 30 mg ingot was made into a male and female mold (杵臼) having a diameter of 5.5 mm, and a bare ingot of 8.50 kg was produced by a tableting machine (JC-DSH-39B, Chin Yi MACHINERY CO., LTD). Regarding the bare ingot of 60 mg ingot, a male ingot of 11 mm × 4.5 mm was also used, and a bare ingot of 37.17 kg was produced in the same manner.

0.075 kg of hypromellose was added to 1.060 kg of water, stirred and dissolved. Weigh 0.007 kg of Macrogol 400 and 0.0115 kg of titanium oxide, stir and disperse. A film coating liquid was formed through a 0.18 mm sieve. The coating of the bare ingot of 30 mg ingot was carried out in 2 portions. A bare ingot of 4.25 kg of a 30 mg ingot was placed in a coating machine (YC-SC-40F, YENCHEN MACHINERY CO., LTD), and the coating was applied to a prescribed amount at a spray rate of 10 g/min and an exhaust gas temperature of about 45 °C. After drying, a film ingot containing 30 mg of fexofenadine hydrochloride in one tablet (weight 65 to 70 mg, diameter 5.56 to 5.59 mm, thickness 2.87 to 3.02 mm) was obtained. A 4.25 kg bare ingot was again weighed in the same manner to obtain a film ingot.

0.537 kg of hypromellose was added to 7.631 kg of water, and stirred and dissolved. Weigh 0.053 kg of Macrogol 400 and 0.082 kg of titanium oxide, stir and disperse. A film coating liquid was formed through a 0.18 mm sieve. A bare bark of 37.17 kg of 60 mg ingot was placed in a coating machine (YC-SC-100F, YENCHEN MACHINERY CO., LTD), and the coating was applied to the formulation at a spray rate of 12 ± 10 g/min and an exhaust temperature of about 45 ° C. the amount. After drying, a film ingot containing 60 mg of fexofenadine hydrochloride (weight: 131 to 137 mg, long diameter 11.11 to 11.15 mm, short diameter 4.56 to 4.58 mm, thickness 3.47 to 3.58 mm) was obtained in one tablet.

Observing the master mold (臼)/mold mold (杵) of the tableting machine and the tablet after the tableting, the addition of the sucrose fatty acid ester does not cause adhesion (the powder adheres to the male mold), and the tableting property becomes good.

When the granules for tableting were obtained, they were originally sized by a sieve hole of 0.8 mm. However, when the obtained granules were tableted, many of the particles which were hard to be broken were formed, which was problematic in terms of elution properties. Then, the amount of the hypromellose solution added when the granulated granules were stirred was adjusted, and the moisture content was adjusted to 30% by weight, and the sieve hole was changed to 0.6 mm at the time of granulation to obtain a lozenge having improved dissolution property. .

Four kinds of fexofenadine ingots using carboxymethylcellulose calcium, croscarmellose sodium, crospovidone or gelatinized starch as disintegrating agents were put into a dissolution tester (test liquid: water, paddle) In the container of the method, 50 rotations per minute, the collapse was observed for 30 minutes. As a result, a tablet using carboxymethylcellulose calcium showed the best disintegration.

Test Example (1): Dissolution test

For the fexofenadine ingot prepared in the above examples (the dosage of fexofenadine hydrochloride is 60 mg), according to the second method of the dissolution test method in the general test method of the Japanese Pharmacopoeia (paddle) The method of the method was carried out for the dissolution test. Further, the test solution was subjected to the dissolution test first solution (pH 1.2) and water in the general test method of the Japanese Pharmacopoeia.

One test tablet was placed in 900 mL of each test solution at a liquid temperature of 37 ± 0.5 ° C, and the elution test was started after 50 rotations per minute. Then, 10 mL of the elution solution was taken at each predetermined time, and the membrane was filtered through a membrane having a pore diameter of 0.45 μm. The filter was filtered, 4 mL of the initial filtrate was discarded, 5 mL of the obtained filtrate was taken out correctly, and water was added and adjusted to 10 mL correctly as a sample solution. The standard solution was precisely weighed 30 mg of fexofenadine hydrochloride (day), added 5 mL of methanol, irradiated with ultrasonic waves to dissolve, and water was adjusted to 100 mL correctly. 10 mL of this solution was accurately weighed, water was added and properly adjusted to 100 mL as a standard solution.

Regarding the sample solution and the standard solution, the amount of dissolution of fexofenadine was determined by liquid chromatography.

Hereinafter, the test conditions of the liquid chromatography method used for the analysis of the sample solution and the standard solution are shown.

Detector: UV spectrophotometer (measuring wavelength: 220 nm)

Pipe column: octadecyl decyl phthalocyanine for liquid chromatography with 5 μm filling in a stainless steel tube with an inner diameter of 4.6 mm and a length of 10 cm.

Column temperature: constant temperature of about 25 ° C

Mobile phase: Dissolve 1.8 g of sodium dihydrogen phosphate, 0.5 mL of phosphoric acid and 0.8 g of sodium perchlorate in 500 mL of water, and add 500 mL of acetonitrile for liquid chromatography.

An example of the results of the elution test (water) after elution to 60 minutes is shown in the graphs of Table 2 and Figure 1, and the dissolution test was carried out using the tablet manufactured in Example 1. In the figure, the vertical axis represents the dissolution rate of fexofenadine hydrochloride, and the horizontal axis represents the time after the start of the dissolution test.

An example of the results of the dissolution test (pH 1.2) after the start of elution to 120 minutes is shown in the graphs of Tables 3 and 2, and the dissolution test was carried out using the tablet manufactured in Example 1. In the figure, the vertical axis represents the dissolution rate of fexofenadine hydrochloride, and the horizontal axis represents the time after the start of the dissolution test.

From the results, it is apparent that in the fexofenadine ingot produced in Example 1, 80% by weight or more of the active ingredient of fexofenadine is soluble in water within 15 minutes from the start of the test; In the first liquid, it was dissolved within 60 minutes from the start of the test. This is with the existing Equivalent results for fexofenadine. Therefore, compared with the prior preparation, the fexofenadine ingot according to the present invention is clearly a preparation which exhibits an appropriate dissolution rate regardless of whether the content of the active ingredient fexofenadine is high or not.

[Industrial availability]

As described above, the fexofenadine ingot of the present invention is easy to take because it is small. Further, the fexofenadine ingot of the present invention exhibits an appropriate dissolution behavior in the dissolution test and is highly useful.

The picture in this case is experimental data, not the representative figure of this case. Therefore, there is no designated representative map in this case.

Claims (17)

A tablet containing fexofenadine or a pharmaceutically acceptable salt thereof as an active ingredient, and calcium carboxymethylcellulose. The tablet according to claim 1, wherein the active ingredient is fexofenadine hydrochloride. The tablet according to claim 1 or 2, wherein the amount of fexofenadine or a pharmaceutically acceptable salt thereof per tablet is from 35 to 60% by weight. The tablet according to claim 1 or 2, wherein the amount of fexofenadine or a pharmaceutically acceptable salt thereof per tablet is 40 to 50% by weight. The tablet according to any one of claims 1 to 4, wherein the amount of carboxymethylcellulose calcium per tablet is from 10 to 30% by weight. The tablet according to any one of claims 1 to 4, wherein the amount of carboxymethylcellulose calcium per tablet is from 15 to 25% by weight. The tablet according to any one of claims 1 to 6, which further contains an excipient. The tablet according to claim 7, wherein the excipient is crystalline cellulose. The tablet according to claim 8, wherein the amount of crystalline cellulose per tablet is from 20 to 40% by weight. The lozenge according to item 8 of the patent application, wherein each lozenge The content of crystalline cellulose is from 25 to 35% by weight. The tablet according to any one of claims 1 to 10, wherein the tablet is a film ingot. The tablet according to any one of claims 1 to 11, wherein one tablet contains 30 mg of fexofenadine hydrochloride. The tablet according to claim 12, which has a diameter of 5.0 mm to 6.0 mm and a thickness of 2.5 mm to 3.5 mm. The tablet of claim 12, wherein the tablet has a weight of 50 to 80 mg. A lozenge according to any one of claims 1 to 11, wherein 60 mg of fexofenadine hydrochloride is contained in one tablet. The tablet according to claim 15, which has a long diameter of 9 mm to 12 mm, a short diameter of 3.5 mm to 5.5 mm, and a thickness of 3.0 mm to 4.0 mm. The tablet according to claim 15 or 16, wherein the tablet has a weight of 110 to 150 mg.