JP7429061B2 - Pharmaceutical composition containing lanthanum carbonate - Google Patents

Description

TECHNICAL FIELD The present invention relates to a pharmaceutical composition containing lanthanum carbonate or a pharmaceutically acceptable salt thereof, and particularly to an intraorally rapidly disintegrating tablet containing lanthanum carbonate or a pharmaceutically acceptable salt thereof.

Lanthanum carbonate is used as a hyperphosphatemia treatment. In the intestinal tract, orally administered lanthanum carbonate strongly binds with phosphoric acid ingested through meals to form extremely poorly soluble lanthanum phosphate, which is excreted into the feces without dissociating. Phosphorus absorption from the bloodstream is inhibited, reducing serum phosphorus levels.

Hyperphosphatemia is a disease that occurs in many patients with chronic kidney disease (CKD) on dialysis or in the non-dialytic phase, when phosphorus excretion from the kidneys decreases and blood phosphorus levels increase. If the phosphatemic state persists, calcification tends to occur around organs and joints. In particular, it has been pointed out that calcification on blood vessel walls causes arteriosclerosis, which increases the risk of developing myocardial infarction and angina pectoris. Therefore, in CKD patients, it is important to control the serum phosphorus concentration within an appropriate range.

Conventionally used therapeutic agents for hyperphosphatemia include Fosrenol chewable tablets 250 mg and 500 mg, and Fosrenol granule sachets 250 mg and 500 mg, manufactured by Bayer Yakuhin Co., Ltd. Furthermore, in 2017, the company launched Fosrenol OD tablets 250 mg and 500 mg, which are formulations that can be taken without water and can be disintegrated in the oral cavity with saliva or a small amount of water for oral administration.

As can be seen from Table 1, the content of lanthanum carbonate hydrate in one tablet is 46% to 79% in orally rapidly disintegrating tablets (OD tablets) compared to chewable tablets, and the tablets are smaller. has been made into Furthermore, the rapidly disintegrating tablet in the oral cavity disintegrates instantly even with a small amount of saliva in the oral cavity, making it easy to take and suitable for elderly people and children who have difficulty swallowing ordinary tablets. In particular, orally rapidly disintegrating tablets are the most suitable dosage form for CKD patients, as it is necessary to minimize the intake of water.

The single dose of lanthanum carbonate-containing preparations is very high at 250 to 500 mg of lanthanum (542 to 1084 mg in terms of lanthanum carbonate octahydrate, 477 to 954 mg in terms of lanthanum carbonate tetrahydrate), and it has an excellent feeling of administration. In order to obtain a tablet that rapidly disintegrates in the oral cavity, for example, Patent Document 1 states that it is necessary to increase the content of lanthanum carbonate or a pharmaceutically acceptable salt thereof in the formulation. Furthermore, in order to obtain a high-quality tablet that quickly disintegrates in the oral cavity containing lanthanum carbonate, both rapid disintegration and high hardness are required.

Japanese Patent Application Publication No. 2017-66119

The present inventor aimed to develop a pharmaceutical composition containing lanthanum carbonate or a pharmaceutically acceptable salt thereof, which has rapid disintegration properties, high hardness, and is excellent in feeling when taken. That is, an object of the present invention is to produce a pharmaceutical composition containing lanthanum carbonate or a pharmaceutically acceptable salt thereof, which has rapid disintegration properties and high hardness and is excellent in feeling when taken, especially a tablet that quickly disintegrates in the oral cavity. The goal is to establish a method.

As a result of intensive studies to solve the above problems, the inventors of the present invention unexpectedly found that by incorporating a small amount of a disintegrant into a pharmaceutical composition, a carbonated drug with rapid disintegration, high hardness, and excellent feel on administration. The present inventors have discovered that it is possible to produce a pharmaceutical composition containing lanthanum or a pharmaceutically acceptable salt thereof, and have completed the present invention.

Accordingly, the present invention provides the following summary.
[1] Contains lanthanum carbonate or a pharmaceutically acceptable salt thereof and 0.2 to 4% by mass of a disintegrant, which is characterized by being disintegrated in the oral cavity with saliva or a small amount of water and then administered orally. A pharmaceutical composition.
[2] The pharmaceutical composition according to [1], wherein the disintegrant includes at least one selected from the group consisting of sodium carboxymethyl starch, croscarmellose sodium, crospovidone, and low-substituted hydroxypropyl cellulose.
[3] The pharmaceutical composition according to [1] or [2], wherein the disintegrant contains crospovidone.
[4] Lanthanum carbonate has the general formula La ₂ (CO ₃ ) ₃ ·xH ₂ O (where x is 3 to 9)
The pharmaceutical composition according to any one of [1] to [3], which is represented by:
[5] The pharmaceutical composition according to [4], wherein x is 8 to 9.
[6] The pharmaceutical composition according to any one of [1] to [5], which contains 91 to 99% by mass of lanthanum carbonate or a pharmaceutically acceptable salt thereof.
[7] The pharmaceutical composition according to any one of [1] to [6], which is a tablet.
[8] The pharmaceutical composition according to any one of [1] to [7], wherein the content of magnesium stearate is 1.5% by mass or less.
[9] The pharmaceutical composition according to any one of [1] to [8], wherein the talc content is 5% by mass or less.
[10] The pharmaceutical composition according to any one of [1] to [9], wherein the content of light silicic anhydride is 3% by mass or less.

According to the present invention, lanthanum carbonate or a pharmaceutically acceptable salt thereof, which has rapid disintegration and high hardness and is excellent in feeling when taken, even if the content of the disintegrant is 0.2 to 4% by mass. A pharmaceutical composition containing the following is obtained.
That is, the present invention is a direct tabletting method in which lanthanum carbonate or a pharmaceutically acceptable salt thereof is blended with a small amount of a disintegrant, and if necessary, a lubricant, a fluidizing agent, a sweetener, etc. are blended. By dry granulation or by tabletting after dry granulation, it becomes possible to produce intraorally rapidly disintegrating tablets containing lanthanum carbonate or a pharmaceutically acceptable salt thereof.

In one embodiment of the present invention, 0.2 to 4% by mass of lanthanum carbonate or a pharmaceutically acceptable salt thereof, which is disintegrated in the oral cavity with saliva or a small amount of water and then administered orally, is provided. A disintegrant is provided.

As the disintegrant used in the present invention, any disintegrant commonly used in pharmaceuticals can be used without any particular restriction as long as it can achieve the purpose of the present invention. The content of the disintegrant in the pharmaceutical composition is preferably about 0.2 to about 4% by weight, more preferably about 0.3 to about 3.5% by weight, and even more preferably about 0.5% by weight. ~3% by mass. If it is less than 0.2% by mass, the desired disintegrability may not be obtained.

In a preferred embodiment of the present invention, the disintegrant includes at least one selected from the group consisting of carboxymethyl starch sodium, croscarmellose sodium, crospovidone, and low-substituted hydroxypropylcellulose, and preferably carboxymethyl starch sodium. It contains at least one selected from the group consisting of starch sodium, croscarmellose sodium, and crospovidone.

In a further preferred embodiment of the invention, the disintegrant comprises comfy crospovidone.

The term "lanthanum carbonate" as used herein shall also include lanthanum carbonate hydrate, unless it is technically inappropriate.

Lanthanum carbonate or a pharmaceutically acceptable salt thereof used in the present invention is not particularly limited as long as it can achieve the purpose of the present invention.

In a preferred embodiment of the invention, the lanthanum carbonate has the general formula La ₂ (CO ₃ ) _{3.xH 2} O, where x is from 3 to 9.
Preferably, x is 8 to 9.

The content of lanthanum carbonate or its pharmaceutically acceptable salt in the pharmaceutical composition is not particularly limited as long as the object of the present invention can be achieved.

In a preferred embodiment of the invention, the content of lanthanum carbonate or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is from about 40 to about 99% by weight, preferably from about 70 to about 99% by weight. , more preferably about 91 to about 99% by weight.

The particle size of lanthanum carbonate or its pharmaceutically acceptable salt is not particularly limited as long as the pharmaceutical composition of the present invention can be produced. The particle size of lanthanum carbonate or its pharmaceutically acceptable salt can vary depending on the measurement method, and is usually measured as a particle size distribution, so it is often expressed as an average particle size. . Therefore, when a specific numerical value of the average particle diameter is exemplified in this specification, unless otherwise specified, the numerical value is, for example, based on the laser diffraction analysis of Nikkiso Co., Ltd.'s Microtrack MT330II, etc. - Means the average particle diameter measured by a scattering particle size distribution device.

In a preferred embodiment of the invention, the pharmaceutical composition of the invention is a tablet.

In a more preferred embodiment of the present invention, the pharmaceutical composition of the present invention is a chewable tablet because it has sufficient hardness as a tablet and can be easily chewed in the mouth. Since the pharmaceutical composition of the present invention easily dissolves in the mouth, even chewable tablets can be quickly dissolved in the mouth after being chewed.
In a more preferred embodiment of the present invention, the pharmaceutical composition of the present invention is a rapidly disintegrating tablet in the oral cavity, since it has sufficient hardness as a tablet but easily dissolves in the mouth. Orally rapidly disintegrating tablets are tablets that quickly disintegrate when placed in the mouth.
The disintegration time is not particularly limited as long as it satisfies the disintegration time approved as a pharmaceutical for rapidly disintegrating tablets in the oral cavity, and is not particularly limited as long as the purpose of the present invention can be achieved. Within about 60 seconds, preferably within about 45 seconds, and more preferably within about 30 seconds. Even when it is made into a chewable tablet, it is preferable that it disintegrates within the above-mentioned disintegration time after being put in the mouth and chewed.
For the oral disintegration time, a well-known measuring method such as measurement using a commercially available oral disintegration tester can be used. Specifically, the oral disintegration time described herein is measured by the disintegration test method (test liquid: water) of the Japanese Pharmacopoeia General Test Methods.

When the pharmaceutical composition of the present invention is a tablet, the diameter that the tablet should have is not particularly limited as long as it can achieve the purpose of the present invention, but while having sufficient hardness as a tablet, The diameter of the tablet is preferably about 8 to about 15 mm, more preferably about 9 to about 15 mm, in order to achieve the object of the present invention that it is easy to dissolve in the mouth and can be easily chewed in the mouth. The length is about 14 mm, more preferably about 10 to about 13 mm.

When the pharmaceutical composition of the present invention is a tablet, the tablet hardness is particularly determined as long as it is easy to dissolve in the mouth, can be easily chewed in the mouth, and has sufficient hardness during transportation and storage. Although not limited, it is preferably about 40N or more, more preferably about 50N or more, even more preferably about 60N or more, and the upper limit is preferably about 200N or less, More preferably, it is about 150N or less.

The pharmaceutical composition of the present invention may contain a sugar alcohol, if necessary, as long as the purpose of the present invention can be achieved. By incorporating a sugar alcohol, it is possible to obtain a stable pharmaceutical composition in which changes in properties are suppressed even under test conditions such as severe tests.
Examples of the sugar alcohol include, but are not limited to, mannitol, erythritol, xylitol, and the like. In particular, mannitol is most preferred because it provides a pharmaceutical composition with good moldability and good disintegration properties.

If necessary, the pharmaceutical composition of the present invention may further contain additives that can be blended as pharmaceutical additives, as long as the purpose of the present invention can be achieved. Such additives include, for example, lubricants, flow agents, binders, sweeteners, colorants, and the like.

Examples of lubricants include, but are not limited to, stearates (magnesium stearate, calcium stearate, etc.), macrogol, glycerin fatty acid esters, sodium stearyl fumarate, sodium lauryl sulfate, talc, and the like. Although any combination thereof may be mentioned, stearate or talc is preferred, and magnesium stearate or talc is more preferred.

Since stearate has a strong lubricating effect, the effect can be obtained even with a small amount of addition, and a tablet that rapidly disintegrates in the oral cavity with a fast disintegration time and high hardness can be obtained. However, if the amount of stearate is too large, the disintegration time in the oral cavity may be prolonged and the disintegration may be prolonged in the storage stability test. Therefore, the content of stearate in the pharmaceutical composition is preferably about 1.5% by mass or less, and the lower limit is preferably about 0.1% by mass or more. Methods for suppressing the content of stearate in pharmaceutical compositions to about 1.5% by mass or less include (1) using an external lubricating device during compression molding, and (2) prolonging the disintegration time of talc, etc. It may be effective to blend a lubricant free of silica and/or (3) blend a fluidizing agent such as light anhydrous silicic acid.

Talc is the only lubricant for which no such extension of the disintegration time was observed, whereas when other lubricants were mixed and subjected to severe tests, an extension of the disintegration time was observed. Generally, by adding talc, the disintegration time tends to be shortened, but the hardness of the tablet tends to decrease. The content of talc in the pharmaceutical composition is preferably about 5% by mass or less, more preferably about 4% by mass or less, even more preferably about 3% by mass or less, and the lower limit is preferably It is about 0.2% by mass or more. If it exceeds 5% by mass, tabletting problems such as capping may be observed during compression molding.

Examples of the fluidizing agent include hydrated silicon dioxide, light anhydrous silicic acid, talc, and any combination of these, but preferably light anhydrous silicic acid. By adding a fluidizing agent, the hardness of the tablet can be increased and the disintegration time can be shortened.
The content of the fluidizing agent in the pharmaceutical composition is usually preferably about 3% by mass or less, more preferably about 2.5% by mass or less, still more preferably about 2% by mass or less, The lower limit is preferably about 0.05% by mass or more. If it exceeds 3% by mass, tabletting problems such as capping may be observed during compression molding.

Examples of the binder include gum arabic, sodium alginate, carboxyvinyl polymer, gelatin, dextrin, pectin, sodium polyacrylate, pullulan, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and any of these. Any combination may be mentioned.

Examples of sweeteners include sodium saccharin, saccharin, aspartame, acesulfame potassium, stevia, thaumatin, sucralose, and any combination of these.

Examples of the coloring agent include food pigments such as Food Yellow No. 5, Food Red No. 2, and Food Blue No. 2.

When the pharmaceutical composition of the present invention is a tablet, the method for manufacturing the tablet includes, for example, when using lanthanum carbonate or a pharmaceutically acceptable salt thereof having an average particle size of about 30 to 50 μm, a disintegrant, Sugar alcohols, lubricants, fluidizers, sweeteners, and the like are mixed in a mixer and compression molded to produce tablets that quickly disintegrate in the oral cavity. When the particle size of lanthanum carbonate or a pharmaceutically acceptable salt thereof is about 10 μm, it can be compressed after producing a tablet powder by dry granulation or wet granulation, for example. In addition, even if the particle size is about 10 μm or less, agglomerated granules with good fluidity can be obtained by mixing impact type pulverized products such as jet miser with a V-type mixer etc. It is possible to mix a disintegrant, a sugar alcohol, a lubricant, a sweetener, etc. and compression mold the mixture.

The present invention will be explained in detail below with reference to Examples, but the present invention should not be limited to the embodiments shown in these Examples.

Common Items The average particle size of lanthanum carbonate octahydrate and lanthanum carbonate tetrahydrate was measured using a laser diffraction/scattering particle size distribution device.
The diameter of the tablet (tablet diameter) was measured using a caliper.
The hardness of the tablet was measured using a tablet hardness meter (load cell type tablet hardness meter PC-30, manufactured by Okada Seiko Co., Ltd.).
The oral disintegration time was measured by the disintegration test method (test liquid: water) of the Japanese Pharmacopoeia General Test Methods.

[Comparative Examples 1 to 4, Example 1]
Lanthanum carbonate octahydrate (average particle size: 50 μm), mannitol (Partek (registered trademark) M200, manufactured by Merck & Co., Ltd.), crospovidone (manufactured by ISP Japan Co., Ltd.), in the amounts listed in Table 2, Light anhydrous silicic acid (Aerosil 200, manufactured by Nippon Aerosil Co., Ltd.), talc (manufactured by Matsumura Sangyo Co., Ltd.), and magnesium stearate (manufactured by Taihei Kagaku Sangyo Co., Ltd.) were mixed in a mixer (Model S-3, Tsutsui Rikagaku Kiki Co., Ltd.). ) for 10 minutes, tablets with a diameter of 10 mm were obtained using a tablet press (VELA5, Kikusui Seisakusho Co., Ltd.).

<Test Example 1>
The tablet characteristics of the tablets manufactured in Comparative Examples 1 to 4 and Example 1 were evaluated. The results are shown in Table 3.

<Results>
Table 3 shows that when talc or light anhydrous silicic acid is added to Comparative Example 1, the disintegration time tends to become faster (Comparative Examples 2 and 3), and when 0.94% by mass of crospovidone is added, the disintegration time becomes faster. It took less than 1 minute (Example 1). On the other hand, the hardness tended to increase when the amount of light silicic anhydride or magnesium stearate was reduced.

[Examples 2 to 8]
Lanthanum carbonate octahydrate (average particle size: 50 μm), mannitol (Partek (registered trademark) M200, manufactured by Merck Co., Ltd.), crospovidone (manufactured by ISP Japan Co., Ltd.), in the amounts listed in Table 4, Sucralose (manufactured by Saneihara FFI Co., Ltd.), light silicic anhydride (Aerosil 200, manufactured by Nippon Aerosil Co., Ltd.), talc (manufactured by Matsumura Sangyo Co., Ltd.), and magnesium stearate (manufactured by Taihei Kagaku Sangyo Co., Ltd.). After mixing for 10 minutes using a mixer (Model S-3, Tsutsui Rikagaku Kiki Co., Ltd.), the mixture was granulated using a dry granulator (TF-Labo, Freund Sangyo Co., Ltd.). After sizing using a sizing machine (TC-Labo, Fukae Powtec Co., Ltd.), tablets with a diameter of 10 mm were obtained using a tablet press (VELA5, Kikusui Seisakusho Co., Ltd.).

<Test Example 2>
The tablet properties of the tablets produced in Examples 2 to 8 were evaluated. The results are shown in Table 5.

<Results>
From Table 5, when containing 0.5 to 3% by mass of crospovidone, tablets with high hardness and rapid disintegration in the oral cavity with a disintegration time of 1 minute or less were obtained (Examples 2 to 8).
Furthermore, from Examples 2 to 4, the disintegration time became shorter as the content of crospovidone increased.

[Examples 9 to 15]
Tablets with a tablet diameter of 10 mm were obtained in the same manner as in Examples 2 to 8, except that lanthanum carbonate octahydrate was replaced with lanthanum carbonate tetrahydrate (average particle size: 10 μm) and the blending amounts were as shown in Table 6.

<Test Example 3>
Tablet properties of the tablets produced in Examples 9 to 15 were evaluated. The results are shown in Table 7.

<Results>
From Table 7, similarly to lanthanum carbonate octahydrate, even when lanthanum carbonate tetrahydrate was used, a tablet that rapidly disintegrated in the oral cavity was obtained which had high hardness and a disintegration time of less than 1 minute (Example 9 ~15).
Furthermore, from Examples 9 to 11, the disintegration time became shorter as the content of crospovidone increased.

[Examples 16 to 19]
Lanthanum carbonate octahydrate (average particle size: 50 μm), mannitol (Partek (registered trademark) M200, manufactured by Merck & Co., Ltd.), disintegrant, sucralose (Saneihara F.F.I.) in the amounts listed in Table 8. Co., Ltd.), light silicic anhydride (Aerosil 200, Nippon Aerosil Co., Ltd.), talc (Matsumura Sangyo Co., Ltd.), and magnesium stearate (Taihei Kagaku Sangyo Co., Ltd.) in a mixer (S-3 type, After mixing for 10 minutes using a tablet machine (VELA5, Kikusui Seisakusho Co., Ltd.) (Tsutsui Rikagaku Kiki Co., Ltd.), tablets with a diameter of 12 mm were obtained.
The following disintegrants were used.
・Crospovidone (manufactured by ISP Japan Co., Ltd.)
・Sodium carboxymethyl starch (GLYCOLYS, manufactured by Rocket Japan Co., Ltd.)
・Crosscarmellose sodium (Kitucolate ND-2HS, manufactured by Asahi Kasei Corporation)
・Low-substituted hydroxypropyl cellulose (L-HPC NBD-022, manufactured by Shin-Etsu Chemical Co., Ltd.)

<Test Example 4>
Tablet properties of the tablets produced in Examples 16 to 19 were evaluated. The results are shown in Table 9.

<Results>
Table 9 shows that no matter which disintegrant was used, tablets with high hardness and a disintegration time of 1 minute or less were obtained.

Claims (2)

It is characterized by being disintegrated in the oral cavity with saliva or a small amount of water and administered orally,
70 to 99% by mass of lanthanum carbonate or a pharmaceutically acceptable salt thereof,
0.1-1.5% by mass of magnesium stearate,
0.2 to 4% by mass of talc,
0.05 to 2% by mass of light silicic anhydride,
0.5-3% by mass of crospovidone,
mannitol, and
Sucralose
A tablet containing. The tablet according to claim 1, which is a rapidly disintegrating tablet in the oral cavity.