JP2017066119A - Pharmaceutical composition containing lanthanum compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical composition that contains lanthanum carbonate or pharmaceutically acceptable salt thereof, is effective in improving hyperphosphatemia in a chronic renal disease patient, and orally administered by disintegrating in an oral cavity by saliva or a small amount of water.SOLUTION: In a pharmaceutical composition, lanthanum carbonate or pharmaceutically acceptable salt thereof, disintegrator such as crospovidone and hydroxypropyl cellulose, fluidizing agent such as silicic acid anhydride, lubricant such as magnesium stearate, and sweetener such as aspartame are blended, tablet hardness is 100 newtons or more, and friability is less than 0.5%.SELECTED DRAWING: None

Description

  The present invention relates to a pharmaceutical composition containing lanthanum carbonate or a pharmaceutically acceptable salt thereof.

  Lanthanum carbonate is known to be effective in improving hyperphosphatemia in patients with chronic kidney disease, and its high safety is known.

  As preparations containing lanthanum carbonate, Phoslenol® chewable tablets and Phoslenol® granule sachets are commercially available, but patients with chronic kidney disease usually have severely restricted water intake. Since many patients have difficulty in chewing and swallowing, development of a preparation that can be easily taken without water is desired.

  As a preparation that can be easily taken without water, an orally disintegrating preparation (also referred to as an OD preparation) that is orally administered after being disintegrated in the oral cavity with saliva or a small amount of water is known. Many of these dosage forms are tablets and films. Particularly in general-purpose dosage forms, that is, orally disintegrating tablets (also referred to as OD tablets), there are conflicting formulation characteristics such as rapid disintegration and high hardness. A wide variety of formulation technologies and related products are publicly available. For example, JP-A-5-271054 discloses an orally disintegrating tablet obtained by tableting a mixture containing a medicinal ingredient, a saccharide, and a water content that moistens the surface of the saccharide particles. International Publication No. 95/20380 pamphlet describes an orally disintegrating compression-molded product containing a saccharide having a low moldability and a saccharide having a high moldability and rapidly disintegrating in the oral cavity. Furthermore, in recent years, premix-type additives have also become available in which lubricants are added after mixing with medicinal ingredients and OD tablets can be easily obtained by direct powder compression (direct compression). Specific examples include GRANFILLER-D (registered trademark), SmartEx (registered trademark), Ludflash (registered trademark), and the like.

In Japanese Patent Application Laid-Open No. 11-503119, in a pharmaceutical composition containing lanthanum carbonate, lanthanum carbonate represented by La ₂ (CO ₃ ) ₃ xH ₂ O has x of 3.8-4. When the value is 5, it is described that phosphoric acid bonds are most efficiently performed and removed as phosphates. XRD analysis of lanthanum carbonate 4H ₂ O is also shown.

  In addition, JP 2013-544267 A discloses an invention of an oral pharmaceutical capsule containing a gelatin shell encapsulating lanthanum carbonate or lanthanum carbonate hydrate and a lubricant such as talc. There is no description about the lock.

  JP-T-2015-504878 discloses valsartans or pharmaceutically acceptable salts, disintegrants, and fluidizing agents that are orally disintegrated in the oral cavity with saliva or an amount of water equivalent to saliva. And a tablet comprising a pharmaceutical composition containing a lubricant. However, the examples specifically described are limited to OD tablets having a two-layer structure consisting of an inner core whose hardness cannot be satisfactorily obtained and an outer layer protecting it.

Japanese Patent Laid-Open No. 5-271054 International Publication No. 95/20380 Pamphlet Japanese National Patent Publication No. 11-503119 Special table 2013-544267 gazette JP-T-2015-504878

  When the inventors examined, when lanthanum carbonate was used as a medicinal ingredient, the above-mentioned Patent Document 1, Patent Document 2, and a known method including the premix type additive, even if an OD tablet was produced, It has become clear that the rapid disintegration, high hardness and low friability cannot be achieved, making it unsuitable for use.

  First, as a method for producing a pharmaceutical composition containing lanthanum carbonate as a medicinal ingredient, a method involving water is inappropriate. Since lanthanum carbonate forms various numbers of hydrates and is known to have different physical properties and stability, it should not be used, humidified, or dried in the manufacturing process of the formulation. In Patent Document 1, a wet granule mainly composed of a saccharide containing a small amount of water is compression-molded and then dried to produce a tablet. In Patent Document 2, humidification and drying are performed after tableting at low pressure. It is difficult to control the hydration state of lanthanum carbonate after these production steps.

  When a tablet is produced by a direct compression method using a premix-type additive, it can be produced without water, but increasing the content and reducing the size are problems. The clinical dose of lanthanum carbonate is as high as 250 to 750 mg of lanthanum per dose (477 to 1431 mg in terms of lanthanum carbonate tetrahydrate). The content of lanthanum carbonate or a pharmaceutically acceptable salt thereof (hereinafter referred to as the drug substance) in the preparation must be approximately 70% by mass or more. However, the inventors have examined that tablets prepared using the premix-type additive have both rapid disintegration, high hardness, and low friability at such high drug substance content. I could not. Note that increasing the content and reducing the size is a common problem in manufacturing processes involving water.

  Further, a common problem in any known technique is quantitative evaluation of a small amount of impurities and decomposition products derived from lanthanum carbonate. In general, OD preparations are easy to absorb moisture due to their formulation characteristics, and there is concern about chemical stability as well as changes in physical properties. In order to ensure high quality, it is essential to establish a highly sensitive purity test method. However, since lanthanum carbonate is an inorganic compound, it must be performed by a powder X-ray diffraction method. On the other hand, saccharides (sugars or sugar alcohols) widely used in the formulation of OD tablets have both a sharp powder X-ray diffraction peak, and a small amount of impurities and decompositions derived from lanthanum carbonate in order to achieve both disintegration and hardness. The detection sensitivity of objects is significantly reduced. In fact, in Patent Document 1 and Patent Document 2, the use of saccharides is essential, and GRANFILLER-D (registered trademark), SmartEx (registered trademark) and Ludiflash (registered trademark) listed as specific examples of the premix-type additive. In any case, D-mannitol is the main component.

  Thus, according to the conventional method, lanthanum carbonate is a medicinal ingredient, and it is excellent in taking feeling and is a high quality OD preparation, that is, to obtain an OD tablet having both rapid disintegration, high hardness and low friability. It was difficult.

  According to the present invention, it is possible to obtain a high-quality OD preparation having lanthanum carbonate as a medicinal ingredient and excellent in feeling of administration. The OD preparation has both rapid disintegration, high hardness, and low friability, enables quantitative evaluation of trace impurities and decomposition products derived from lanthanum carbonate, and is stable in a normal packaging form.

  As described above, there are many problems to be solved in order to obtain a high-quality OD preparation having lanthanum carbonate as a medicinal ingredient and excellent in feeling of taking. As shown, we found that all these issues could be solved.

  The present invention provides a pharmaceutical composition which can be easily administered orally and contains lanthanum carbonate as an active ingredient. Specifically, the present invention provides a pharmaceutical composition containing lanthanum carbonate or a pharmaceutically acceptable salt thereof that is orally administered after being disintegrated in the oral cavity with saliva or a small amount of water.

  The pharmaceutical composition of the present invention is preferably a tablet or sachet (granule, fine granule, powder) having an accurate dose, and particularly preferably a tablet which is not bulky when carried.

  One form of the present invention is the pharmaceutical composition which is a tablet.

The lanthanum carbonate used in the pharmaceutical composition of the present invention has a general formula La ₂ (CO ₃ ) ₃ · xH ₂ O (wherein x = 3 to 8) having known physical, chemical and biological properties. ) Is preferable, and x = 4 to 5 is particularly preferable. As described above, the content of the lanthanum carbonate or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is preferably 70% by mass or more in order to achieve both a high clinical dose and an excellent feeling of administration. In order to obtain the tablet characteristics (rapid disintegration, high hardness, low friability), the range of 70 to 90% by mass is particularly preferable.

One aspect of the present invention is the pharmaceutical composition, wherein the lanthanum carbonate is represented by the general formula La ₂ (CO ₃ ) ₃ · xH ₂ O (wherein x is 3 to 8).

  One form of this invention is the said pharmaceutical composition whose said x is 4-5.

  One aspect of the present invention is the pharmaceutical composition, wherein the content of the lanthanum carbonate or a pharmaceutically acceptable salt thereof is 70 to 90% by mass.

  The pharmaceutical composition of the present invention may contain a disintegrant, such as sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, wheat starch, rice starch, low-substituted hydroxypropylcellulose, corn starch , Preferably at least one selected from the group consisting of potato starch and partially pregelatinized starch, and for superior tablet properties (rapid disintegration, high hardness, low friability), at least crospovidone It is more preferable to include at least crospovidone and low-substituted hydroxypropylcellulose. The content of crospovidone in the pharmaceutical composition is preferably in the range of 5 to 12% by mass, and the content of the low-substituted hydroxypropylcellulose in the pharmaceutical composition is preferably in the range of 1 to 12% by mass. When the disintegrant is only crospovidone, the content is preferably in the range of 10 to 15% by mass. When the disintegrant is only low-substituted hydroxypropylcellulose, the content is in the range of 10 to 25% by mass. The inside is preferable.

  One aspect of the present invention is the pharmaceutical composition containing a disintegrant.

  In one form of the present invention, the disintegrant is a carboxymethyl starch sodium, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, wheat starch, rice starch, low-substituted hydroxypropylcellulose, corn starch, potato starch and Said pharmaceutical composition comprising at least one selected from the group consisting of partially pregelatinized starch.

  One aspect of the present invention is the pharmaceutical composition, wherein the disintegrant includes at least crospovidone.

  One form of the present invention is the pharmaceutical composition, wherein the disintegrant comprises at least crospovidone and low-substituted hydroxypropylcellulose.

  One form of this invention is the said pharmaceutical composition characterized by the content rate in the pharmaceutical composition of the said crospovidone being 5-12 mass%.

  One form of this invention is the said pharmaceutical composition characterized by the content rate in the pharmaceutical composition of the said low substituted hydroxypropyl cellulose being 1-12 mass%.

  The pharmaceutical composition of the present invention may contain a fluidizing agent, including hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium magnesium hydroxide, stearic acid, calcium stearate, stearic acid It is preferable to include at least one selected from the group consisting of magnesium, talc and magnesium aluminate metasilicate, and it is particularly preferable to include at least light anhydrous silicic acid. The content of the fluidizing agent in the pharmaceutical composition is preferably in the range of 0.5 to 2.0% by mass.

  One aspect of the present invention is the pharmaceutical composition containing a fluidizing agent.

  In one aspect of the present invention, the fluidizing agent comprises hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium magnesium hydroxide, stearic acid, calcium stearate, magnesium stearate, talc and The pharmaceutical composition comprising at least one selected from the group consisting of magnesium aluminate metasilicate.

  One aspect of the present invention is the pharmaceutical composition, wherein the fluidizing agent includes at least light anhydrous silicic acid.

  One form of this invention is the said pharmaceutical composition characterized by the content rate in the pharmaceutical composition of the said fluidizing agent being 0.5-2.0 mass%.

  The pharmaceutical composition of the present invention may contain a lubricant, such as carnauba wax, hydrous silicon dioxide, hydrous amorphous silicon oxide, dry aluminum hydroxide gel, magnesium silicate, light anhydrous silicic acid, synthetic aluminum silicate, oxidation Magnesium, heavy silicic acid anhydride, sucrose fatty acid ester, aluminum hydroxide gel, stearyl alcohol, stearic acid, calcium stearate, magnesium stearate, cetanol, talc, magnesium carbonate, precipitated calcium carbonate, sodium stearyl fumarate, silicic anhydride It is preferable to include at least one selected from the group consisting of hydrated products and magnesium aluminate metasilicate, and particularly preferable to include at least magnesium stearate. The content of the lubricant in the pharmaceutical composition is preferably in the range of 0.5 to 2.0% by mass.

  One aspect of the present invention is the pharmaceutical composition containing a lubricant.

  In one embodiment of the present invention, the lubricant comprises carnauba wax, hydrous silicon dioxide, hydrous amorphous silicon oxide, dry aluminum hydroxide gel, magnesium silicate, light anhydrous silicic acid, synthetic aluminum silicate, magnesium oxide, heavy Silicic anhydride, sucrose fatty acid ester, aluminum hydroxide gel, stearyl alcohol, stearic acid, calcium stearate, magnesium stearate, cetanol, talc, magnesium carbonate, precipitated calcium carbonate, sodium stearyl fumarate, anhydrous silicic acid hydrate and The pharmaceutical composition comprising at least one selected from the group consisting of magnesium aluminate metasilicate.

  One form of the present invention is the pharmaceutical composition, wherein the lubricant comprises at least magnesium stearate.

  One form of this invention is the said pharmaceutical composition characterized by the content rate in the pharmaceutical composition of the said lubricant being 0.5-2.0 mass%.

  The pharmaceutical composition of the present invention can contain a sweetening agent to improve the feeling of administration, and aspartame, erythritol, fructose, xylitol, brown sugar, saccharin, saccharin sodium hydrate, sucralose, purified sucrose, purified sucrose It preferably contains at least one selected from the group consisting of spherical granules, D-sorbitol, dextranate, lactose hydrate, sucrose, glucose, maltitol, maltose hydrate, D-mannitol and thaumatin, and at least aspartame It is particularly preferable to include it. The sweetener is preferably in a powder form rather than a granule form in order to prevent variation in sweetness between dosage units. Here, “granular” and “powder” are, for example, when the particle size is measured using a vacuum suction type sieving machine typified by Alpine air jet sieve, the former is generally about 90% by mass or more. The latter remains on a sieve having an opening of 250 μm, and the latter passes through a sieve having an opening of 250 μm in general by 90% by mass or more. The content of the sweetener in the pharmaceutical composition is preferably in the range of 0.5 to 2.0% by mass.

  One aspect of the present invention is the pharmaceutical composition containing a sweetener.

  In one form of the present invention, the sweetener is aspartame, erythritol, fructose, xylitol, brown sugar, saccharin, saccharin sodium hydrate, sucralose, purified sucrose, purified sucrose spherical granules, D-sorbitol, dextreate, lactose hydration A sucrose, glucose, maltitol, maltose hydrate, D-mannitol and at least one selected from the group consisting of thaumatin.

  One form of the present invention is the pharmaceutical composition, wherein the sweetener comprises at least aspartame.

  One aspect of the present invention is the pharmaceutical composition, wherein the sweetener is in a powder form.

  One form of this invention is the said pharmaceutical composition characterized by the content rate in the pharmaceutical composition of the said sweetener being 0.5-2.0 mass%.

  In addition, what is particularly important in using lanthanum carbonate as a medicinal component is quantitative evaluation of a small amount of impurities and decomposition products derived from lanthanum carbonate. As described above, in general, OD formulations are easily hygroscopic due to their formulation characteristics, and there is concern about chemical stability as well as changes in physical properties. In order to ensure high quality, it is essential to establish a highly sensitive purity test method. However, since lanthanum carbonate is an inorganic compound, it must be performed by a powder X-ray diffraction method. Therefore, the prescription components of the pharmaceutical composition should not interfere with high sensitivity analysis by powder X-ray diffraction measurement.

  Since the pharmaceutical composition of the present invention can ensure high quality including stability during storage, the content in the pharmaceutical composition is 2 except for lanthanum carbonate or a pharmaceutically acceptable salt thereof. It is preferable that the additive exceeding 0.0 mass% is composed only of components having no clear powder X-ray diffraction peak. Here, “having no clear powder X-ray diffraction peak” is a phenomenon known to those skilled in the art, but is almost synonymous with “showing a halo pattern”, and most of the structure or Since it is entirely amorphous or glass-like, it means a phenomenon that does not have a clear diffraction peak over the entire measurement range (2θ) and sometimes shows a halo-like pattern with a wide intensity distribution. By configuring a pharmaceutical composition only with components having these characteristics, it is possible to quantitatively evaluate trace amounts of impurities and degradation products derived from lanthanum carbonate, and to ensure high quality including stability during storage. It becomes possible.

  In one embodiment of the present invention, except for lanthanum carbonate or a pharmaceutically acceptable salt thereof, any compounding component whose content in the pharmaceutical composition exceeds 2.0% by mass exhibits a clear powder X-ray diffraction peak. It is the said pharmaceutical composition characterized by not having.

  When the pharmaceutical composition of the present invention is an OD tablet, the disintegration must be rapid. Here, “promptly” refers to, for example, within 60 seconds with an auxiliary board and within 30 seconds without an auxiliary board when testing using purified water in accordance with the disintegration test method (Japan General Test Method). . Also, for example, when the tablet is placed between the tongue and upper jaw and lightly pressed, the time taken for the tablet to completely disintegrate by sucking saliva and feel no lumps is taken as the oral disintegration time, the tongue is moved. Within 60 seconds when there is no, and within 30 seconds when the tongue is moved.

  It is also important to have a certain strength as a tablet. Some commercially available OD tablets disintegrate quickly but easily break or chip. Such tablets are very difficult to handle, and it is questionable whether it can be said that they are generally more convenient than ordinary tablets. The “high” hardness that can be handled in the same manner as a normal tablet is, for example, 100 N or more when measured using a tablet hardness meter. The “low” friability is, for example, less than 0.5% (no obvious cracks, cracks, or chips) when the test is performed according to the tablet friability test method (JP Reference Information).

  One aspect of the present invention is the pharmaceutical composition, wherein the tablet hardness is 100 Newtons or more.

  One form of the present invention is the pharmaceutical composition, characterized in that the friability is less than 0.5%.

  The pharmaceutical composition of the present invention must also ensure stability during a certain distribution period. “Stable” means, for example, that there is no clear change in quality for at least 3 months in an environment of 30 ° C./65% relative humidity in the PTP package after opening the original seal. Further, for example, in a final packaging form of PTP / aluminum pillow packaging, there is no clear change in quality for at least 6 months in an environment of 40 ° C./75% relative humidity. “A clear quality change” is defined by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceutical Use for Pharmaceutical Use, a stability test defined by the ICH. That is, in general, when the content has changed by 5% or more from the start of the test, when a specific degradation product exceeds the criterion, appearance, physical items, and functionality tests deviate from the criterion (eg, color , Hardness, dissolution test).

  The pharmaceutical composition of the present invention can be filled into PTP molded using a film made of polyvinyl chloride or polypropylene in order to ensure stability in a certain distribution period. If necessary, the moisture-proof property can be enhanced by using a film in which polychlorotrifluoroethylene is laminated on either of them. Furthermore, it can be filled in an aluminum bag.

  In one embodiment of the present invention, a PTP (Press Through Package) formed using polyvinyl chloride, polypropylene, or a film in which polychlorotrifluoroethylene is laminated on either is filled at 30 ° C./65% relative humidity. The pharmaceutical composition is characterized in that there is no clear change in quality for at least 3 months under the above environment.

  In one embodiment of the present invention, polyvinyl chloride, polypropylene, or PTP formed by using a film in which polychlorotrifluoroethylene is laminated on either one of them is filled, and further filled in an aluminum bag to obtain 40 ° C./relative humidity. Said pharmaceutical composition characterized in that there is no clear quality change for at least 6 months under 75% environment.

Powder X-ray diffraction pattern (Drug substance, Comparative Example 1) Powder X-ray diffraction pattern (Drug substance, Comparative Example 7) Powder X-ray diffraction pattern (Drug substance, Comparative Example 8) Powder X-ray diffraction pattern (Drug substance, Example 2)

  EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, this invention is not limited to an Example.

[Formulation method]
Drug substances (for example, 70 to 90% by mass of lanthanum carbonate hydrate), disintegrants (for example, 5 to 12% by mass of crospovidone, 1 to 12% by mass of low-substituted hydroxypropylcellulose), sweeteners (for example, 0.1% by mass). 5 to 2.0% by weight of aspartame) and a fluidizing agent (for example, 0.5 to 2.0% by weight of light anhydrous silicic acid), and further a lubricant (for example, 0.5 to 2.0% by weight). Add magnesium stearate) and mix. Each raw material is preferably sized in advance using a sieve having an appropriate pore size. The type of the mixer is not limited as long as it can be mixed uniformly. A container-rotating mixer such as a general-purpose V-type mixer is sufficient. Next, using a rotary tableting machine or the like, a tablet having a predetermined mass is produced by a direct compression method (direct compression method) at a compression pressure at which appropriate hardness is obtained. The tablets avoid moisture absorption and are immediately packed in PTP, then aluminum pillow, and stored. As the PTP film, commonly used polyvinyl chloride or polypropylene can be used. If necessary, a film in which highly moisture-proof polychlorotrifluoroethylene (Aclar (registered trademark)) is laminated can be used. A desiccant can be included in the aluminum pillow.

[Evaluation method]
The thickness of the tablet was measured using a dial thickness gauge.

  The hardness of the tablet was measured using a Schleuniger hardness meter. The target quality of tablet hardness was set to 100 N or more with the aim of handling the same as that of a normal tablet.

  The friability was tested according to the tablet friability test method (JP Reference Information). The target quality of the friability was set to less than 0.5% (no obvious cracks, cracks, or chipping) aiming for the same handling as a normal tablet.

  The JP disintegration time was tested using purified water according to the disintegration test method (JP General Test Method) (with / without auxiliary panel). The target quality of the JP disintegration time was set to within 60 seconds with an auxiliary board and within 30 seconds without an auxiliary board.

  The oral disintegration time was defined as the oral disintegration time, which was taken by placing the tablet between the tongue and the upper jaw, pressing it lightly, and the tablet sucked saliva and completely disintegrated, and no lumps were felt. The case where the tongue is not moved is static, and the case where the tongue is moved is dynamic. The target quality of the oral disintegration time was set to be static within 60 seconds and dynamic within 30 seconds.

  For powder X-ray diffraction, the tablets were made into fine powders using an agate pestle and mortar, and the test was performed according to the powder X-ray diffraction measurement method (Japan General Test Method). The target quality of the powder X-ray diffraction method was that quantitative evaluation of trace impurities and decomposition products derived from lanthanum carbonate was possible.

[OD formulation using premix type additive]
Table 1 shows the results of studies using GRANFILLER-D (registered trademark), which is said to be suitable for high content and downsizing among commercially available premix-type additives.

  The drug substance, premix, and fluidizing agent that have been sized using a sieve with an appropriate pore size are mixed together, and then a lubricant that has been sized using an sieve with an appropriate pore size is added. And mixed. A tablet with a diameter of 10 mm containing 477 mg of lanthanum carbonate hydrate per tablet (corresponding to 250 mg of lanthanum) was obtained by a direct compression method using a rotary tableting machine (Comparative Example 1).

  According to the tableting pressure, the tablet hardness was high and the friability was low, but at the same time, the disintegration time (in Japan, oral cavity) was prolonged. Further, in the friability test, clear cracks, cracks and chips were observed at a high ratio. Thus, at least at the high drug substance content of 70% by mass or more as intended, it was impossible to achieve both rapid disintegration, high hardness, and low friability. In addition, many strong peaks different from the drug substance were detected in the powder X-ray diffraction pattern of this product (FIG. 1). Although it is thought that it originates from the sugar alcohol and D-mannitol contained in GRANFILLER-D (trademark), it is impossible to evaluate the trace amount impurity and decomposition product derived from lanthanum carbonate from such a pattern.

[OD formulation using super disintegrant]
Table 2 shows the results of studies using carboxymethyl starch sodium, croscarmellose sodium, crospovidone or low-substituted hydroxypropylcellulose, which are so-called super disintegrants.

  The drug substance, disintegrant, excipient, and fluidizing agent, each of which has been sized using a sieve with an appropriate pore size, are mixed, and then the size is adjusted using a sieve with an appropriate pore size. A mixture was added and mixed. Using a rotary tableting machine, tablets with a diameter of 10 mm containing 477 mg of lanthanum carbonate hydrate (corresponding to 250 mg of lanthanum) per tablet were obtained by a direct compression method (Comparative Examples 2 to 6).

  In the absence of disintegrant, the tablet did not disintegrate at all (Comparative Example 2). Only tablets containing crospovidone reached the target quality for disintegration time (in Japan, in the oral cavity) at a blending ratio of up to 10.0% by weight. (Comparative Example 5). However, in the friability test, clear cracks, cracks and chips were observed at a high ratio. In addition, all the formulations are blended at a high ratio of 19.9% by mass (29.9% in Comparative Example 2 containing no disintegrant) using dextranate having a powder X-ray diffraction peak as an excipient. Therefore, it was difficult to evaluate a trace amount of impurities and decomposition products derived from lanthanum carbonate.

[OD formulation capable of quantitative evaluation of trace impurities and decomposition products derived from lanthanum carbonate]
Table 3 shows the results of improvement studies based on the formulation of Comparative Example 5 (Table 2), in which the disintegration time (date and mouth) was relatively good.

  The drug substance, disintegrant, excipient, sweetener and fluidizing agent that have been sized using a sieve with an appropriate pore size are mixed in advance, and further sized using a sieve with an appropriate pore size. Oita lubricant was added and mixed. Using a rotary tableting machine, tablets with a diameter of 10 mm containing 477 mg of lanthanum carbonate hydrate (corresponding to 250 mg of lanthanum) per tablet were obtained by a direct compression method (Comparative Examples 7-8, Examples 1-6). .

  The formulation in which dextranate was replaced with the most commonly used excipient D-mannitol in OD tablets showed almost the same tablet physical properties as before the change (Comparative Example 7), but sharper than when using dextranate. It was impossible to evaluate a trace amount of impurities and decomposition products derived from lanthanum carbonate having a contamination peak of powder X-ray diffraction (FIG. 2). The formulation in which half the amount of dextranate was replaced with crystalline cellulose having no powder X-ray diffraction peak showed physical property values equal to or higher (tablet hardness, friability) (Comparative Example 8), but derived from dextranate. Even when the powder X-ray diffraction peak was lowered to this blending ratio (9.9%), it was still at a level that affected the evaluation (FIG. 3).

  Next, a formulation in which excipients (dextrate, D-mannitol, etc., all sugar / sugar alcohol) were completely eliminated was examined. Since these excipients also have aspects as sweeteners, separately, aspartame having a sweetness 200 times that of sucrose was blended to a ratio not affecting powder X-ray diffraction measurement.

Sufficient sweetness was obtained with 1.8% by mass of aspartame (Example 2), and the powder X-ray diffraction pattern almost coincided with the drug substance itself (FIG. 4). As described above, since there is no contaminating peak derived from the additive, it is possible to quantitatively evaluate a trace amount of impurities and decomposition products derived from lanthanum carbonate. On the other hand, when powdered aspartame was used, the disintegration time was extended depending on the blending amount, but there was no variation in the sweetness of each tablet (Examples 1 and 2). When granular aspartame was used, the disintegration time was improved, but the powdered aspartame was superior in the sweetness variation between tablets (Examples 3 and 4). The formulation that returned to powdered aspartame and replaced the disintegrant crospovidone with a large amount (21.8% by mass) of low-substituted hydroxypropylcellulose, the JP disintegration time met the target quality, but the oral disintegration time Extended (Example 5). The combination of disintegrant crospovidone and croscarmellose sodium was also the same (Example 6).

[OD formulation combining multiple disintegrants]
Tables 4 and 5 show the results of improvement studies based on the formulation of Example 2 (Table 3), which satisfy the target quality other than the JP disintegration time.

  Lubricants that have been preliminarily sized using a sieve with an appropriate pore size, mixed with the drug substance, disintegrant, sweetener, and fluidizing agent that have been sized using a sieve with an appropriate pore size. The agent was added and mixed. Using a rotary tableting machine, tablets having a diameter of 10 mm or 13 mm containing 477 mg of lanthanum carbonate hydrate (corresponding to 250 mg of lanthanum) or 954 mg of lanthanum carbonate hydrate (corresponding to 500 mg of lanthanum) per tablet by a direct compression method Obtained (Examples 7 to 18).

By combining crospovidone and low-substituted hydroxypropylcellulose at a specific ratio as a disintegrant, all target qualities (tablet hardness, friability, disintegration time (in Japan, oral), evaluation of trace impurities and degradation products) )

[Stability]
A pocket formed using a polypropylene film having a thickness of 300 μm was filled with the tablets prepared in Examples 7, 8, 13, 16, 17, and 18, and sealed with aluminum foil to obtain a PTP packaged product. The target quality of the PTP packaged product was determined to have no clear quality change for at least 3 months in an environment of 30 ° C./65% relative humidity.

  The PTP packaged product was further filled in an aluminum bag and packed with silica gel. This was heat-sealed to obtain a PTP / aluminum pillow package. The target quality of the PTP / aluminum pillow package was determined to have no clear quality change for at least 6 months in an environment of 40 ° C./75% relative humidity.

PTP packaged products stored at 30 ° C / 65% relative humidity for 3 months and PTP / aluminum pillow packages stored at 40 ° C / 75% relative humidity for 6 months in a constant temperature and humidity chamber for chemical and physical stability Sex was evaluated. As a result, under any prescription / storage conditions, no clear change was observed from the beginning, and the conditions were stable (Table 6).

Claims (29)

  A pharmaceutical composition comprising lanthanum carbonate or a pharmaceutically acceptable salt thereof, wherein the composition is orally administered after being disintegrated in the oral cavity with saliva or a small amount of water.   The pharmaceutical composition according to claim 1, which is a tablet. The lanthanum carbonate has the general formula _{La 2 (CO 3) 3 ·} xH 2 O ( wherein, x is 3 to 8) represented by the pharmaceutical composition according to claim 1 or 2.   The pharmaceutical composition according to claim 3, wherein x is 4-5.   The pharmaceutical composition according to any one of claims 1 to 4, wherein the content of the lanthanum carbonate or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 70 to 90% by mass. .   The pharmaceutical composition according to any one of claims 1 to 5, comprising a disintegrant.   The disintegrant is a group consisting of sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, wheat starch, rice starch, low-substituted hydroxypropylcellulose, corn starch, potato starch and partially pregelatinized starch The pharmaceutical composition according to any one of claims 1 to 6, comprising at least one more selected.   The pharmaceutical composition according to any one of claims 1 to 7, wherein the disintegrant comprises at least crospovidone.   The pharmaceutical composition according to any one of claims 1 to 8, wherein the disintegrant comprises at least crospovidone and low-substituted hydroxypropylcellulose.   The pharmaceutical composition according to any one of claims 1 to 9, wherein the content of the crospovidone in the pharmaceutical composition is 5 to 12% by mass.   The pharmaceutical composition according to any one of claims 1 to 10, wherein the content of the low-substituted hydroxypropylcellulose in the pharmaceutical composition is 1 to 12% by mass.   The pharmaceutical composition according to any one of claims 1 to 11, comprising a fluidizing agent.   The fluidizing agent comprises hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium hydroxide alumina, stearic acid, calcium stearate, magnesium stearate, talc and magnesium aluminate metasilicate. The pharmaceutical composition according to any one of claims 1 to 12, comprising at least one selected from the group.   The pharmaceutical composition according to any one of claims 1 to 13, wherein the fluidizing agent comprises at least light anhydrous silicic acid.   The content rate in the pharmaceutical composition of the said fluidizing agent is 0.5-2.0 mass%, The pharmaceutical composition as described in any one of Claims 1-14 characterized by the above-mentioned.   The pharmaceutical composition according to any one of claims 1 to 15, comprising a lubricant.   The lubricant is carnauba wax, hydrous silicon dioxide, hydrous amorphous silicon oxide, dry aluminum hydroxide gel, magnesium silicate, light anhydrous silicic acid, synthetic aluminum silicate, magnesium oxide, heavy anhydrous silicic acid, sucrose fatty acid. Esters, aluminum hydroxide gel, stearyl alcohol, stearic acid, calcium stearate, magnesium stearate, cetanol, talc, magnesium carbonate, precipitated calcium carbonate, sodium stearyl fumarate, anhydrous silicate hydrate and magnesium metasilicate aluminate The pharmaceutical composition according to any one of claims 1 to 16, comprising at least one selected from the group.   The pharmaceutical composition according to any one of claims 1 to 17, wherein the lubricant comprises at least magnesium stearate.   The pharmaceutical composition according to any one of claims 1 to 18, wherein the content of the lubricant in the pharmaceutical composition is 0.5 to 2.0 mass%.   The pharmaceutical composition according to any one of claims 1 to 19, comprising a sweetening agent.   The sweetener is aspartame, erythritol, fructose, xylitol, brown sugar, saccharin, saccharin sodium hydrate, sucralose, purified white sugar, purified white sugar spherical granules, D-sorbitol, dextrate, lactose hydrate, white sugar, glucose, multi 21. The pharmaceutical composition according to any one of claims 1 to 20, comprising at least one selected from the group consisting of tall, maltose hydrate, D-mannitol and thaumatin.   The pharmaceutical composition according to any one of claims 1 to 21, wherein the sweetener comprises at least aspartame.   The pharmaceutical composition according to any one of claims 1 to 22, wherein the sweetening agent is in a powder form.   The pharmaceutical composition according to any one of claims 1 to 23, wherein the content of the sweetener in the pharmaceutical composition is 0.5 to 2.0 mass%.   Except for lanthanum carbonate or a pharmaceutically acceptable salt thereof, none of the compounding components whose content in the pharmaceutical composition exceeds 2.0% by mass has a clear powder X-ray diffraction peak. The pharmaceutical composition according to any one of claims 1 to 24.   The pharmaceutical composition according to any one of claims 2 to 25, wherein the tablet hardness is 100 Newtons or more.   27. Pharmaceutical composition according to any one of claims 2 to 26, characterized in that the friability is less than 0.5%.   At least 3 months in an environment of 30 ° C / 65% relative humidity by filling PTP (Press Through Package) molded using polyvinyl chloride, polypropylene, or a film of polychlorotrifluoroethylene laminated on either. 28. The pharmaceutical composition according to any one of claims 1 to 27, characterized in that there is no clear quality change.   Filling a PTP formed using a film in which polyvinyl chloride, polypropylene or a polychlorotrifluoroethylene is laminated on either, and then filling an aluminum bag, at least in an environment of 40 ° C./75% relative humidity. 29. Pharmaceutical composition according to any one of claims 1 to 28, characterized in that there is no clear quality change for 6 months.

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