JP2020033303A - Orally quick disintegrating tablet containing lanthanum carbonate and being stable - Google Patents

Abstract

To provide an orally quick disintegrating tablet containing lanthanum carbonate or hydrate thereof that is compact and easy to take, and resists changes in its properties even under test conditions of severe tests and is stable.SOLUTION: A tablet contains lanthanum carbonate or hydrate thereof, and sugar alcohol.SELECTED DRAWING: None

Description

  TECHNICAL FIELD The present invention relates to a tablet containing lanthanum carbonate, and more particularly to a tablet containing lanthanum carbonate and having excellent stability and excellent disintegration in the oral cavity.

  Lanthanum carbonate has been used as a therapeutic agent for hyperphosphatemia. Orally administered lanthanum carbonate binds tightly with the phosphoric acid ingested in the intestine to form extremely insoluble lanthanum phosphate, which is excreted into the feces without dissociation, and Is suppressed and the serum phosphorus concentration is reduced.

  Hyperphosphatemia is a disease that occurs in many patients with chronic kidney disease (CKD) during dialysis or in the preservation phase due to decreased excretion of phosphorus from the kidneys and increased levels of phosphorus in the blood. If the condition continues, calcification tends to occur around organs and joints. In particular, it has been pointed out that calcification on the blood vessel wall causes arteriosclerosis, thereby increasing the risk of developing myocardial infarction and angina. Therefore, in CKD patients, it is important to control the serum phosphorus concentration in an appropriate range.

Examples of lanthanum carbonate-containing preparations include foslenol chewable tablets 250 mg and 500 mg marketed by Bayer Yakuhin, and foslenol granule packaged 250 mg and 500 mg.
In the treatment of CKD patients, since water management is also important, a dosage form taken without water is strongly desired. Therefore, chewable tablets are preferable to granules in this regard.
The conventional hoslenol chewable tablets marketed by Bayer AG have the dosage forms described in Table 1 below.

  As can be seen from Table 1, among the foslenol chewable tablets, a 250 mg tablet containing 250 mg of lanthanum carbonate as lanthanum has a diameter of 13 m and a weight of 1042 mg, and a 500 mg tablet containing 500 mg of lanthanum carbonate as lanthanum has a diameter of 18 mm. Weighing 2084 mg, each tablet is large and difficult to chew and take. In addition, if taken without chewing, all tablets are hard to disintegrate and dissolve easily, causing intestinal perforation and ileus.Therefore, there are cases where foslenol chewable tablets 250 mg and 500 mg are included in the package insert. Precautions for use '' include, `` This drug is difficult to dissolve when taken without chewing, and some cases of intestinal perforation and ileus have not chewed, so chew enough in the mouth, saliva or It should be instructed to swallow with a small amount of water, and it is desirable to pulverize and administer this drug to patients (elderly people, etc.) who have difficulty chewing. ]]] ".

The above-mentioned conventional hoslenol chewable tablets are large in size, hard to disintegrate and hard to dissolve, and therefore, it is necessary to pay attention to the above points when taking them.
In addition, this tablet shows discoloration during long-term storage at a high temperature, and prolongs the disintegration time during storage.
Therefore, it is a tablet that is small in size but has sufficient hardness as a tablet, dissolves easily in the mouth, and can be easily chewed in the mouth, and suppresses property changes even under test conditions such as severe tests. Thus, there has been a demand for the development of a stable tablet containing lanthanum carbonate.

  The present inventors have conducted intensive studies to solve the above-described problems, and found that by blending a sugar alcohol with a lanthanum carbonate-containing tablet, the problems of the conventional lanthanum carbonate-containing tablets can be solved. The present invention has been completed.

That is, the present invention provides the following.
[1] A tablet containing lanthanum carbonate or a hydrate thereof, and a sugar alcohol.
[2] The tablet according to [1], wherein the sugar alcohol is selected from the group consisting of mannitol, erythritol, and xylitol.
[3] The tablet according to [1], wherein the sugar alcohol is mannitol.
[4] The tablet according to any one of [1] to [3], which contains 3 to 40% by weight of a sugar alcohol.
[5] The tablet according to any one of [1] to [4], which does not contain sugar.
[6] The tablet according to any one of [1] to [5], which is a chewable tablet.
[7] The tablet according to any one of [1] to [5], which is a rapidly disintegrating tablet in the oral cavity.
[8] The tablet according to any one of [1] to [7], wherein the oral disintegration time is 20 to 30 seconds.
[9] The tablet according to any one of [1] to [8], wherein the tablet has a hardness of 60 N or more.

According to the present invention, there is provided a stable tablet containing lanthanum carbonate or a hydrate thereof, which is small in size, easy to take, and whose property change is suppressed even under test conditions such as a severe test.
The tablet provided by the present invention has a sufficient hardness as a tablet while being small, is easily dissolved in the mouth, and can be easily chewed in the mouth. Therefore, it is also possible to obtain an easily and / or stable oral rapidly disintegrating tablet or chewable tablet containing lanthanum carbonate or a hydrate thereof.

In one embodiment of the present invention, there is provided a tablet comprising lanthanum carbonate or a hydrate thereof and a sugar alcohol.
As lanthanum carbonate or a hydrate thereof used in the present invention, any lanthanum carbonate or hydrate thereof that is permitted to be used as a medicament can be used without particular limitation. The hydrate of is preferably used.
In the present specification, lanthanum carbonate and hydrates thereof may be collectively referred to simply as "lanthanum carbonate", unless technically apparently inappropriate.
Lanthanum carbonate or its hydrate is usually
General formula: La ₂ (CO ₃ ) ₃ .xH ₂ O
It is represented by X in the formula generally has a value from 0 to 10. In the present invention, x preferably has a value of 2 to 8, x preferably has a value of 4 to 8, x is particularly preferably 4 or 8, and lanthanum carbonate octahydrate is used. Is most preferred. In the pharmaceutical package insert of Bayer's foslenol chewable tablets, lanthanum carbonate hydrate as an active ingredient is described as “x = mainly 4” in the above formula, and x is mainly used as a carbonate. The hydration degree of lanthanum may be indicated, or the average of the hydration degree of lanthanum carbonate may be indicated. The degree of hydration of lanthanum carbonate can be measured by a method well known in the art, such as thermal analysis (TGA) or X-ray powder diffraction (XRPD).

  The particle size of lanthanum carbonate or a hydrate thereof used in the present invention is not particularly limited as long as the tablet of the present invention can be produced. The particle size of lanthanum carbonate or a hydrate thereof can be changed by a measuring method, and is usually measured as a particle size distribution, so that it is often represented by an average particle size. Therefore, when specific numerical values of the average particle diameter are exemplified in this specification, the numerical values may be, for example, laser diffraction values such as those of Microtrack MT330II of Nikkiso Co., Ltd., unless otherwise specified. It means the average particle size measured by a scattering type particle size distribution device.

  The diameter that the tablet of the present invention should have is not particularly limited as long as the object of the present invention can be achieved, while having sufficient hardness as a tablet, it is easily melted in the mouth, In order to achieve the object of the present invention, which can be easily chewed with a tablet, the diameter of the tablet is preferably 8 to 17 mm, more preferably 9 to 16 mm, and particularly preferably 10 to 15 mm.

As the sugar alcohol used in the present invention, those usually used for pharmaceuticals and those which can achieve the object of the present invention can be used without any particular limitation.
In one preferred embodiment of the present invention, the sugar alcohol is at least one selected from the group consisting of mannitol, erythritol, and xylitol. In particular, mannitol is the most preferable since a tablet having good moldability and good disintegration properties can be obtained.
The blending amount of the sugar alcohol is not particularly limited as long as the effects of the present invention are exerted, but is preferably 3 to 40% by weight, more preferably 5 to 25% by weight, particularly preferably 10 to 15% by weight per tablet. It is preferred that the content be contained by weight. If the amount is less than 3% by weight, the moldability may decrease. If the amount is more than 40% by weight, the tablet may become large and the ingestibility may decrease.

  In one preferred embodiment of the invention, the tablets of the invention do not contain sugar. Here, the term “sugar” has the same meaning as the term “sugar” commonly used in the field of organic chemistry, and such a saccharide usually has a six-membered ring structure (pyranose) or a five-membered ring structure (furanose). have. When sugar is contained, the effect of the present invention may be reduced. Furthermore, when sugars such as dextran, lactose, refined sucrose, glucose and the like are included in the tablets, when subjected to a severe test for testing the stability, a change in properties (discoloration) occurs.

In a preferred embodiment of the tablet of the present invention, the tablet of the present invention is a chewable tablet because it has sufficient hardness as a tablet but can be easily chewed in the mouth. Since the tablet of the present invention easily dissolves in the mouth, even if it is a chewable tablet, it can be immediately dissolved in the mouth after chewing.
In another preferred embodiment of the tablet of the present invention, the tablet of the present invention is a rapidly disintegrating tablet in the mouth because it has sufficient hardness as a tablet but is easily dissolved in the mouth. An orally rapidly disintegrating tablet is a tablet that disintegrates quickly when it is contained in the mouth.
The disintegration time may be any one that satisfies the disintegration time as approved as a pharmaceutical product as a rapidly disintegrating buccal tablet, and is not particularly limited as long as the object of the present invention can be achieved. It is 20 to 30 seconds, preferably 15 to 25 seconds, more preferably 10 to 20 seconds. Even in the case of chewable tablets, it is preferable to dissolve within the above disintegration time after putting in the mouth and chewing.
The above-mentioned disintegration time in the oral cavity can be measured by a method known in the art, such as measurement using a commercially available orally disintegrating tablet tester. Specifically, the oral disintegration time described in this specification is measured by the disintegration test method (test liquid: water) of the Japanese Pharmacopoeia general test method.

  The hardness of the tablet of the present invention is not particularly limited as long as it is easily melted in the mouth, and can be easily chewed in the mouth, and has sufficient hardness during transportation and storage. It is preferably at least 60N, more preferably at least 80N, even more preferably at least 100N. In consideration of chewing in the oral cavity, the upper limit of the hardness is preferably 250 N or less, more preferably 200 N or less, and even more preferably 150 N or less.

  If desired, the tablet of the present invention may further contain a substance acceptable as a pharmaceutical additive as long as the object of the present invention can be achieved. Such additives include, for example, disintegrants, binders, flow agents, sweeteners, lubricants, coloring agents, and the like, other than sugar alcohols.

  The disintegrant is not particularly limited, and examples thereof include carmellose calcium, croscarmellose sodium, sodium starch glycolate, crospovidone, and any combination thereof. Preferred disintegrants are at least one selected from carmellose calcium, croscarmellose sodium, sodium starch glycolate and crospovidone. A particularly preferred disintegrant is crospovidone from the viewpoint of taking feeling. The blending amount of the disintegrant is not particularly limited as long as the tablet of the present invention can achieve the object of the present invention. It is 3% by weight, preferably 0.5 to 2% by weight, particularly preferably 1 to 1.5% by weight.

  Examples of the binder include gum arabic, sodium alginate, carboxyvinyl polymer, gelatin, dextrin, pectin, sodium polyacrylate, pullulan, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, and polyvinylpyrrolidone. Any combination is possible.

  Examples of the fluidizing agent include hydrated silicon dioxide, light anhydrous silicic acid, talc, and any combination of any of these.

  Examples of the sweetener include saccharin sodium, saccharin, aspartame, acesulfame potassium, stevia, thaumatin, and any combination thereof.

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

Examples of the lubricant include magnesium stearate, calcium stearate, macrogol, glycerin fatty acid ester, sodium stearyl fumarate, sodium lauryl sulfate, talc, and any combination thereof.
A particularly preferred lubricant is talc, since the use of talc does not increase the disintegration time in the oral cavity. The amount of talc is not particularly limited as long as the object of the present invention can be achieved, but is usually 1 to 5% by weight, preferably 1 to 4% by weight, more preferably 1 to 3% by weight in one tablet. It is. If the amount of talc is more than 5% by weight, tableting trouble such as capping may occur at the time of compression molding, and if less than 1% by weight, tableting trouble such as sticking may occur.

  In consideration of continuous tableting for a long time during compression molding, such tableting is possible only by using talc, but it is easy to add a stamp to tablets, since usually tablets are often marked. Due to its properties, it is often desirable to use magnesium stearate in combination. However, when magnesium stearate is used, if the amount is too large, the disintegration time in the oral cavity may be prolonged. Therefore, in the present invention, it is preferable to add a small amount of magnesium stearate. The amount of magnesium stearate is 0.1 to 0.75% by weight, preferably 0.2 to 0.75% by weight, particularly preferably 0.2 to 0.5% by weight, per tablet. The combined use of magnesium stearate in this range enables continuous tableting for a longer time than when only talc is used, while avoiding prolongation of the disintegration time.

The method for producing the tablet of the present invention is not particularly limited as long as a tablet having the desired properties of the present invention is obtained, and the degree of hydration and average particle size of lanthanum carbonate or its hydrate to be used, and the type of sugar alcohol An appropriate method may be selected according to specific conditions such as the contents of these components.
For example, when using lanthanum carbonate or a hydrate thereof having a small average particle diameter of about 10 μm, lanthanum carbonate or a hydrate thereof, a sugar alcohol, and other additives as necessary. It is preferable that a tableting powder is produced by granulation by dry granulation or wet granulation while mixing the mixture, and then compression-molded to obtain a tablet. However, even when the average particle diameter of lanthanum carbonate or a hydrate thereof is about 10 μm, lanthanum carbonate or a hydrate thereof pulverized by an impact-type pulverizer such as a jet mizer has very strong cohesiveness of the pulverized product. For this reason, since agglomerates having good fluidity can be obtained by mixing with a mixer such as a V-type mixer, the aggregates can be mixed with a sugar alcohol as required without performing dry granulation or wet granulation. It is possible to perform compression molding by adding other additives.
In addition, for example, when lanthanum carbonate or a hydrate thereof having a large average particle size of about 30 to 50 μm is used, lanthanum carbonate or a hydrate thereof, a sugar alcohol, and other And then compression-molded into a tablet without granulation.

  Hereinafter, the present invention will be described in detail 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 was measured by a laser diffraction / scattering type particle size distribution device.
The diameter of the tablet (tablet diameter) was measured with a caliper.
The tablet hardness was measured by a tablet hardness tester (Load cell type tablet hardness tester PC-30, manufactured by Okada Seiko Co., Ltd.).
The oral disintegration time was measured by the disintegration test method (test solution: water) of the Japanese Pharmacopoeia general test method.
The severe test was stored at 60 ° C. for 20 days.
The property change after the severe test was visually observed.

[Example 1]
542 g of lanthanum carbonate octahydrate (average particle size: 3.66 μm), 61 g of mannitol (PARTEC (registered trademark) M200, manufactured by Merck Ltd.), 61 g of carmellose calcium (ECG-505, manufactured by Gotoku Pharmaceutical Co., Ltd.) ) And 9 g of magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.) for 10 minutes by a mixer (S-3, Tsutsui Rikagiki Co., Ltd.) for 10 minutes, and then dry granulator (TF-Labo, Freund Corporation) ). After sizing with a granulator (TC-Labo, Fukae Powtech Co., Ltd.), tablets with a tablet diameter of 10 mm and a weight of 630 mg per tablet were obtained with a tableting machine (VELA5, Kikusui Seisakusho Co., Ltd.).

[Example 2]
Tablets were obtained in the same manner as in Example 1, except that mannitol in Example 1 was replaced with erythritol (manufactured by San-Eihara FFI Co., Ltd.).

[Example 3]
Tablets were obtained in the same manner as in Example 1, except that mannitol in Example 1 was replaced with xylitol (Xylit, manufactured by Mitsubishi Foodtech Corporation).

[Comparative Example 1]
Tablets were obtained in the same manner as in Example 1 except that mannitol in Example 1 was replaced with dextrate (manufactured by Retten Myers Japan KK).

[Comparative Example 2]
Tablets were obtained in the same manner as in Example 1 except that mannitol in Example 1 was replaced with lactose hydrate (manufactured by San-Eihara FFI Co., Ltd.).

[Comparative Example 3]
Tablets were obtained in the same manner as in Example 1 except that mannitol in Example 1 was replaced with purified sucrose (manufactured by Merck Ltd.).

[Comparative Example 4]
A tablet was obtained in the same manner as in Example 1, except that glucose in Example 1 (manufactured by Sanei Saccharification Co., Ltd.) was used.

<Test Example 1>
The tablets produced in Examples 1 to 3 and Comparative Examples 1 to 4 and the commercially available 250 mg and 500 mg of foslenol chewable tablets (manufactured by Bayer Yakuhin, Ltd.) were subjected to a severe test to determine their properties and disintegration time (disintegration in the oral cavity). Time) was measured. The results are shown in Table 2.

<Result>
From Table 2 (the results of Test Example 1), it is understood that the tablet of the present invention is a tablet excellent in solubility in the mouth (short disintegration time in the oral cavity) while maintaining hardness as a tablet. In the severe test, the conventional products, foslenol chewable tablets 250 mg and 500 mg, and the comparative examples 1 (using dextrates containing the foslenol chewable tablets) and comparative examples 2 to 4 were subjected to the severe test. While the tablet changed its property to yellow, no property change was observed in the tablets of Examples 1 to 3 of the present invention. In particular, in the tablet of Example 1 using mannitol as the sugar alcohol, the best results were obtained in all of the hardness, the oral disintegration time, and the property change as compared with the case where erythritol or xylitol was used.

[Examples 4 to 9]
Carmellose calcium of Example 1 was replaced with crospovidone (manufactured by ASP Japan Co., Ltd.), and talc (manufactured by Matsumura Sangyo Co., Ltd.) was further blended. Then, a tableting powder was produced, and a tablet was produced with a tableting machine (HT-P22A, Hata Ironworks Co., Ltd.). Examples 4 to 6 and 8 were tablets having a tablet diameter of 10.5 mm and a tablet weight of 630 mg, and Examples 7 and 9 were tablets having a tablet diameter of 15 mm and a tablet weight of 1260 mg.

<Test Example 2>
Examples 4 to 9 A severe test was performed on the manufactured tablets, and the property change and disintegration time (oral disintegration time) after the severe test were measured. Table 4 shows the results.

<Result>
From Table 4 (results of Test Example 2), Test Examples 4 and 5 in which talc was mixed, and Test Examples 6 and 7 in which 0.24% by weight of magnesium stearate was added in addition to talc, disintegrated in the oral cavity after the severe test. No extension of time was allowed. However, in Examples 8 and 9 in which 1.4% by weight of magnesium stearate was added, although the disintegration time in the oral cavity was almost the same as that in Test Examples 4 to 7 before the severe test, the disintegration time in the oral cavity after the severe test was confirmed. Was significantly extended. Therefore, it was found that the incorporation of a large amount of magnesium stearate causes a significant increase in the oral disintegration time after the severe test. That is, when the amount of magnesium stearate added is about 0.24% by weight, no increase in the disintegration time is observed regardless of the presence or absence of a severe test. No prolongation of the time was observed, but a noticeable prolongation of the disintegration time was observed after the severe test.

[Example 10]
5420 g of lanthanum carbonate octahydrate (average particle diameter: 50 μm), 640 g of mannitol (PARTEC (registered trademark) M200, manufactured by Merck Co., Ltd.), and 180 g of talc (manufactured by Matsumura Sangyo Co., Ltd.) were mixed with a V-type mixer (V-200 stock). After mixing for 20 minutes with a Co., Ltd. Dalton), 60 g of crospovidone (manufactured by IS Japan Co., Ltd.) was added, and a tablet machine (HT-P22A, Hata Ironworks Co., Ltd.) had a tablet diameter of 15 mm and a tablet weight of 1260 mg. For 90 minutes. Tableting was possible without tableting trouble such as sticking.

[Example 11]
5420 g of lanthanum carbonate octahydrate (average particle diameter: 4.18 μm) was mixed with a V-type mixer (V-200 Dalton Co., Ltd.) for 30 minutes to form an agglomerated granulated product, and then mannitol (PARTEC (registered trademark) M200, 625 g of Merck Co., Ltd., 180 g of talc (manufactured by Matsumura Sangyo Co., Ltd.), and 15 g of magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.) were mixed with a V-type mixer (V-200 Dalton Co., Ltd.) for 20 minutes. Furthermore, 60 g of crospovidone (manufactured by ISP Japan Co., Ltd.) was added, and tableting was performed with a tableting machine (HT-P22A, Hata Iron Works) at a tablet diameter of 10.5 mm and a tablet weight of 630 mg for 120 minutes. did. Tableting was possible without tableting trouble such as sticking.

[Examples 12 to 17 and Comparative Examples 5 to 6]
OD tablets (orally disintegrating tablets) were produced using a tableting machine (HT-P22A, Hata Ironworks Co., Ltd.) in the same manner as in Example 1 using the compounding amounts shown in Table 5.

<Test Example 3>
A severe test was performed on the OD tablets manufactured in Examples 12 to 17 and Comparative Examples 5 and 6, and the property change and disintegration time (oral disintegration time) after the severe test were measured. Table 6 shows the results.

<Result>
From Table 6 (the results of Test Example 3), when the blending amount of mannitol was 3 to 40% by weight (Examples 12 to 17), the tablet hardness was 70 to 102 N and the oral disintegration time was 20 to 30 seconds. However, when the blending amount of mannitol was 1.5% (Comparative Example 5), the hardness was reduced to 35N, the oral disintegration time was increased to 40 to 50 seconds, and the blending amount of mannitol was 46% by weight (Comparative Example 6). Then, the disintegration time in the oral cavity was 20 to 30 seconds, which was not different from Examples 12 to 17, but the hardness was reduced to 30N. Therefore, when mannitol is compounded, it is considered that the compounding amount is preferably 3 to 40% by weight.

[Examples 18 to 20 and Comparative Examples 7 to 8]
Chewable tablets were produced using a tableting machine (HT-P22A, Hata Ironworks Co., Ltd.) in the same manner as in Example 1 using the compounding amounts shown in Table 7.

<Test Example 4>
A severe test was performed on the chewable tablets produced in Examples 18 to 20 and Comparative Examples 7 and 8, and the property change and disintegration time (oral disintegration time) after the severe test were measured. Table 8 shows the results.

<Result>
From Table 8 (the results of Test Example 4), when the blending amount of mannitol was 3 to 40% by weight (Examples 18 to 20), the tablet hardness was 60 to 80 N and the oral disintegration time was 20 to 30 seconds. However, when the blending amount of mannitol was 1.5% (Comparative Example 7), the hardness was reduced to 30N, the oral disintegration time was increased to 50 to 60 seconds, and the blending amount of mannitol was 46% by weight (Comparative Example 8). Then, the disintegration time in the oral cavity was 20 to 30 seconds, and although there was no difference from Examples 18 to 20, the hardness was reduced to 25N. Therefore, when mannitol is compounded, it is considered that the compounding amount is preferably 3 to 40% by weight.

Claims (9)

  A tablet containing lanthanum carbonate or a hydrate thereof, and a sugar alcohol.   The tablet of claim 1, wherein the sugar alcohol is selected from the group consisting of mannitol, erythritol, and xylitol.   The tablet according to claim 1, wherein the sugar alcohol is mannitol.   The tablet according to any one of claims 1 to 3, comprising 3 to 40% by weight of a sugar alcohol.   The tablet according to any one of claims 1 to 4, which does not contain sugar.   The tablet according to any one of claims 1 to 5, which is a chewable tablet.   The tablet according to any one of claims 1 to 5, which is a rapidly disintegrating tablet in the oral cavity.   The tablet according to any one of claims 1 to 7, wherein the oral disintegration time is 20 to 30 seconds.   The tablet according to any one of claims 1 to 8, wherein the tablet has a hardness of 60 N or more.