Co-processed excipient

Abstract

To provide a co-processed excipient for producing a tablet that has good fluidity, suppresses spreading caused by mixing of tableting powder, suppresses a delay in disintegration and deterioration in moldability and hardness, and has improved content uniformity, and to provide a tablet using the same.SOLUTION: The present invention provides a particulate composition comprising a lubricant, a low-solubility saccharide, and anhydrous calcium hydrogen phosphate.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a co-processed additive that has excellent disintegration and tabletability, suppresses spreadability, and is suitable for direct compression, a method for producing the additive, and a tablet containing the additive. [Background technology]

[0002] Tablet manufacturing methods include the granule compression method, in which active ingredients are wet granulated or dry granulated, then additives are added, mixed, and then tableted, and the direct compression method, in which all ingredients are mixed and then tableted without the granulation step of the active ingredients. The direct compression method has the advantage of having fewer manufacturing steps, such as a granulation step, than the granule compression method, thereby reducing manufacturing costs, and the advantage of not using water or heating, making it useful for active ingredients that are sensitive to water or heat, but has the disadvantage of making it difficult to design content uniformity, moldability, and dissolution properties.

[0003] Tablet manufacturing methods include batch and continuous manufacturing. Batch manufacturing is a manufacturing method in which additives are mixed and granulated using the granule compression method or direct compression method to prepare tablet powder for each batch, which is then compressed into tablets. This method has been widely used. Continuous manufacturing is a manufacturing method in which additives are continuously mixed and granulated using the granule compression method or direct compression method to prepare tablet powder, which is then continuously compressed into tablets. Batch manufacturing is easy to set up because each step can be checked sequentially, but when changing batch size, such as from pilot scale to actual scale, it is necessary to check mixability, etc. In contrast, continuous manufacturing involves continuous mixing and granulation of each ingredient, which makes manufacturing process design difficult. However, continuous manufacturing has the advantage of reducing manufacturing costs compared to batch manufacturing, as changes in lot size are achieved by simply changing the production time, eliminating the obstacles to scale-up and reducing manufacturing costs during commercial production.

[0004] As mentioned above, one issue in the preparation of tableting powders is the addition of lubricants. Generally, after mixing and granulating pharmaceutical additives other than the lubricant, the lubricant is added and mixed immediately before tableting. Lubricants cause spreading during mixing of the tableting powders and during flow in the hopper and turntable during tableting, so the amount added must be adjusted to suit the individual mixer and tablet press. Lubricants are added to improve the release of the compressed tablet from the dies and punches, eliminating tableting problems. While lubricants exert their lubricating effect when present on the tablet surface, those present inside the tablet only have disadvantages, such as reduced compactibility, delayed disintegration due to reduced water conductivity, and reduced active ingredient release. Another method of adding lubricant is to use an external lubricating device to lubricate the tablet surface only, but this requires specialized equipment and requires the tablet press to be designed for retrofitting; otherwise, it is difficult to use. Therefore, there is a need to prevent the lubricant from spreading inside the tablet.

[0005] In new drug development, changes to formulations and manufacturing methods are often made during preclinical, early clinical, and late clinical trials, and each time a change is made, it is necessary to confirm the equivalence of the formulation before and after the change, which consumes development time and money. Therefore, there is a demand for tablet designs that can be manufactured simply by mixing with the drug and compressing directly, and that are not affected by scale-up.

[0006] Co-processed additives (all-in-one co-processed additives) are combinations of two or more additives obtained by physical co-processing, and are known to exhibit functions that cannot be achieved by simply mixing individual additives. However, no additives that can fully solve the above-mentioned problems have been reported. Therefore, there is a demand for pre-prepared co-processed excipients that have uniformity and stability of drug content, appropriate disintegration and compactibility, suppress the influence of mixing time and machinery on tableting powders, and contain pharmaceutical additives such as excipients, disintegrants, and lubricants that allow tablets to be manufactured simply by mixing the drug and co-processed excipients and tableting.

[0007] The present applicant has previously proposed spherical co-processed excipients containing anhydrous calcium hydrogen phosphate, lactose, and a disintegrant. Examples include a spherical co-processed excipient obtained by spray-drying mannitol, anhydrous calcium hydrogen phosphate, lactose, and a disintegrant (Patent Document 1), a spherical co-processed excipient obtained by spray-drying anhydrous calcium hydrogen phosphate, lactose, and a disintegrant (Patent Document 2), a spherical co-processed excipient obtained by spray-drying anhydrous calcium hydrogen phosphate, lactose, and crospovidone (Patent Document 3), and a granule prepared separately from the active ingredient, which contains a sugar, a disintegrant, an excipient, and, if necessary, an inorganic powder (Patent Document 4). However, in these inventions, the lubricant is mixed with the co-processed excipient during tableting, and the co-processed excipient does not contain a lubricant.

[0008] In recent years, commercially available all-in-one co-processed excipients containing lubricants include a spherical composition with an average particle size of approximately 150 μm containing 87% lactose, 9% crospovidone, 3% polyethylene glycol-polyvinyl alcohol graft polymer, and 1% sodium stearyl fumarate (Non-Patent Document 1), and a composition with an average particle size of approximately 160 μm containing 96% microcrystalline cellulose, 1.2% sodium starch glycolate, 2% silicon dioxide, and 0.8% sodium stearyl fumarate (Non-Patent Document 2). [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2005 / 037254 [Patent Document 2] Japanese Patent Application Laid-Open No. 2011-157348 [Patent Document 3] International Publication No. 1999 / 055373 [Patent Document 4] Japanese Patent Application Laid-Open No. 2015-78182 [Non-patent literature]

[0010] [Non-Patent Document 1] Kollitab® DC87L Technical Information Brochure [Non-patent document 2] PROSOLV® EASYtab SP Brochure Summary of the Invention [Problem to be solved by the invention]

[0011] The present invention relates to a co-process additive for producing tablets that have good tableting properties, suppress spread caused by mixing of tableting powders, suppress delayed disintegration, and suppress decreases in moldability and hardness, and have excellent content uniformity with a drug, and to provide tablets using the same. [Means for solving the problem]

[0012] As a result of investigations aimed at solving the above-mentioned problems, the present inventors have found that a particulate composition containing a lubricant, a low-solubility saccharide, and anhydrous calcium hydrogen phosphate has reduced spreadability, good tabletability, and excellent content uniformity with a drug, and is useful as a co-process additive for producing tablets with excellent disintegration and moldability by simply mixing with a drug and tableting.

[0013] That is, the present invention relates to the following 1) to 27). 1) A particulate composition comprising a lubricant, a low-solubility saccharide, and anhydrous calcium hydrogen phosphate. 2) The composition according to 1), which contains a disintegrant. 3) The composition according to 1) or 2), wherein the lubricant is dispersed in the composition as lubricant particles having a particle size of 20 μm or less. 4) Average particle size: 50-200 μm, static bulk volume: 1-5 mL / cm 2 or the Hausner ratio is 1 to 1.45. 5) The composition according to 1) or 2), wherein when mixed with a drug and compressed into tablets, the rate of decrease in tablet hardness with mixing time is 30% or less after 10 minutes and / or 40% or less after 60 minutes compared to 0 minutes of mixing time. 6) The composition according to 1) or 2), wherein a tablet containing 99% by mass of the composition according to 1) or 2) and 1% of the drug has a content uniformity rating of 15 or less in a content uniformity test according to the 18th edition of the Japanese Pharmacopoeia. 7) The composition according to 1) or 2), wherein the lubricant is one or more selected from magnesium stearate, calcium stearate, glycerin fatty acid esters, stearic acid, sodium stearyl fumarate, and sucrose fatty acid esters. 8) The composition according to 1) or 2), wherein the lubricant is one or more selected from magnesium stearate, calcium stearate, and sodium stearyl fumarate. 9) The composition according to 1) or 2), which contains 0.1 to 5 parts by mass of a lubricant per 100 parts by mass of the particulate composition. 10) The composition according to 1) or 2), wherein the average particle size of the lubricant is 2 to 20 μm. 11) The composition according to 1) or 2), which contains 10 to 40 parts by mass of anhydrous calcium hydrogen phosphate per 100 parts by mass of the particle composition. 12) The composition according to 1) or 2), which contains 25 to 35 parts by mass of anhydrous calcium hydrogen phosphate per 100 parts by mass of the particle composition. 13) The composition according to 1) or 2), wherein the anhydrous calcium hydrogen phosphate is composed of primary particles having an average particle size of 0.1 to 5 μm. 14) The composition according to 1) or 2), wherein the low-solubility saccharide is a sugar or sugar alcohol having a solubility of 50 g or less per 100 g of water at 25°C. 15) The composition according to 1) or 2), wherein the low-solubility saccharide is lactose, mannitol, or erythritol. 16) The composition according to 1) or 2), which contains 50 to 85 parts by mass of the low-solubility saccharide per 100 parts by mass of the particle composition. 17) The composition according to 1) or 2), which contains 60 to 70 parts by mass of the low-solubility saccharide per 100 parts by mass of the particle composition. 18) The composition according to 15), wherein the mass ratio of lactose to anhydrous calcium hydrogen phosphate is 50:50 to 80:20. 19) The composition according to 2), wherein the disintegrant is a swelling disintegrant. 20) The composition according to 2), wherein the disintegrant is one or more selected from sodium carboxymethyl starch, croscarmellose sodium, crospovidone, and low-substituted hydroxypropyl cellulose. 21) The composition according to 2), which contains 2 to 20 parts by mass of a disintegrant per 100 parts by mass of the particulate composition. 22) The composition according to 2), which contains 3 to 10 parts by mass of a disintegrant per 100 parts by mass of the total particulate composition. 23) A method for producing the particulate composition described in 1), comprising the steps of dissolving or dispersing a lubricant, a low-solubility saccharide, and anhydrous calcium hydrogen phosphate in a solvent to prepare a slurry, and removing the solvent from the slurry. 24) A method for producing the particulate composition described in 2), comprising the steps of dissolving or dispersing a lubricant, a low-solubility saccharide, anhydrous calcium hydrogen phosphate, and a disintegrant in a solvent to prepare a slurry, and removing the solvent from the slurry. 25) The manufacturing method according to 23) or 24), wherein the lubricant is uniformly dispersed in the slurry. 26) A tablet comprising the composition according to 1) or 2) and a drug. 27) A method for producing tablets by mixing and compressing the composition according to 1) or 2) and a drug. [Effects of the Invention]

[0014] The particulate composition of the present invention can be used as a co-process additive to produce tablets with excellent drug content uniformity by simply mixing with a drug and tableting, thereby suppressing delay in disintegration, reduction in compactibility and hardness, and spreadability. [Brief explanation of the drawings]

[0015] [Figure 1] 1 is an SEM photograph of the particulate composition of Example 1. [Figure 2] 1 is a SEM-BEX photograph of the interior of the particulate composition of Example 1. [Figure 3] 1 is a SEM-BEX photograph of the interior of the particulate composition of Example 1. [Figure 4] SEM photo of the raw material magnesium stearate. [Figure 5] Blending and tableting evaluation: Blending time - Hardness. [Figure 6] Mixing and tableting evaluation: Mixing time - Disintegration time. [Figure 7] 1 is an SEM-BEX photograph of a cross section of a tablet obtained by tableting the particulate composition of Example 1. [Figure 8] 1 is a SEM-BEX photograph of a cross section of a tablet obtained by compressing the particulate composition of Comparative Example 1 and magnesium stearate. DETAILED DESCRIPTION OF THE INVENTION

[0016] The present invention will be described in detail below. Unless otherwise specified, the use of each pharmaceutical additive in the present invention is in accordance with the use of pharmaceutical additives in the Pharmaceutical Additives Dictionary.

[0017] (Particulate composition) The particulate composition of the present invention is a spherical composition containing a lubricant, a low-solubility saccharide, and anhydrous calcium hydrogen phosphate.

[0018] The lubricant in the particulate composition of the present invention can be either an organic lubricant or an inorganic lubricant, but it is preferable to use an organic lubricant. Examples of organic lubricants include magnesium stearate, calcium stearate, sucrose fatty acid esters, glycerin fatty acid esters, stearic acid, and sodium stearyl fumarate, and the like. Preferred are magnesium stearate, calcium stearate, and sodium stearyl fumarate, and more preferably magnesium stearate. The average particle size of the lubricant is preferably 20 μm or less, more preferably 2 to 20 μm, more preferably 2 to 20 μm, even more preferably 3 to 15 μm, and most preferably 3 to 10 μm.

[0019] The low-solubility saccharide in the particulate composition of the present invention is a sugar or sugar alcohol that has low solubility in water, for example, a solubility of 50 g or less in 100 mL of water at 25°C. Specifically, it is lactose, mannitol, or erythritol, preferably lactose or mannitol, more preferably lactose. When the particulate composition of the present invention is used to produce ordinary tablets, lactose is most preferred in terms of availability and price, while when used to produce intraorally rapidly disintegrating tablets, mannitol is most preferred in terms of taste and texture.

[0020] Low-solubility saccharides are blended to function as excipients and binders. Low-solubility saccharides contain crystalline and amorphous portions, and it is believed that the crystalline portion acts as an excipient, while the amorphous portion acts as a binder that binds the various components together and acts as an excipient.

[0021] The anhydrous calcium hydrogen phosphate in the particulate composition of the present invention can be anhydrous calcium hydrogen phosphate as described in the Japanese Pharmacopoeia, but it is preferable to use one with good moldability. Particles having an average primary particle diameter of 0.05 to 10 μm, preferably 0.1 to 5 μm, and an anhydrous calcium hydrogen phosphate having a crystallinity of 0.3 to 0.9, preferably 0.4 to 0.8, can be used. The crystallinity is the ratio to the highest peak in XRD, using an anhydrous calcium hydrogen phosphate commercially available as a reagent with an average crystalline particle diameter of 50 μm or more as a standard. Specific commercially available products include Fujicalin (registered trademark) (manufactured by Fuji Chemical Industry Co., Ltd.), GS, and GSH (Kyowa Chemical Industry Co., Ltd.), with Fujicalin being preferred.

[0022] The particulate composition of the present invention may contain a disintegrant inside the particles, if necessary. The disintegrant is not particularly limited, and examples thereof include crospovidone, carmellose calcium, carmellose, croscarmellose, croscarmellose sodium, low-substituted hydroxypropyl cellulose, corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, and carboxymethyl starch sodium. The disintegrant is preferably crospovidone, carmellose, croscarmellose, low-substituted hydroxypropyl cellulose, and more preferably crospovidone. These disintegrants may be used alone or in combination.

[0023] In addition, the particulate composition of the present invention can contain an appropriate amount of additives and medicinal ingredients commonly used in pharmaceuticals. These can be used alone or in combination of two or more. Here, examples of additives include excipients, binders, coating agents, glossing agents, colorants, flavoring agents, sweeteners, and fragrances.

[0024] The content of the lubricant in the particulate composition of the present invention is 0.1 to 5 parts by mass, preferably 0.2 to 4 parts by mass, more preferably 0.3 to 3 parts by mass, and even more preferably 0.5 to 2 parts by mass, per 100 parts by mass of the composition. The content of anhydrous calcium hydrogen phosphate in the particulate composition of the present invention is 10 to 40 parts by mass, preferably 20 to 40 parts by mass, and more preferably 25 to 35 parts by mass, per 100 parts by mass of the composition. The content of the poorly water-soluble saccharide in the particulate composition of the present invention is 50 to 85 parts by mass, preferably 54 to 75 parts by mass, and more preferably 60 to 70 parts by mass, per 100 parts by mass of the composition. In the particulate composition of the present invention, for example, the mass ratio of lactose to anhydrous calcium phosphate is 50:50 to 80:20, and preferably 60:40 to 75:25. When a disintegrant is added, the content of the disintegrant is 2 to 20 parts by mass, preferably 3 to 15 parts by mass, and more preferably 3 to 10 parts by mass, per 100 parts by mass of the composition.

[0025] The particulate composition of the present invention has a static bulk specific volume of 1 to 5 mL / g, preferably 1.5 to 2.5 mL / g. Static bulk specific volume is the reciprocal of bulk density, and indicates the volume (mL) per 1g. It is calculated by measuring the volume and mass and dividing the volume by the mass. The bulk density in the Japanese Pharmacopoeia can be measured in the same way.

[0026] The BET specific surface area of ​​the particulate composition of the present invention is 1 to 5 m 2 / g, preferably 1.5 to 3 m 2 / g. The BET specific surface area and pore volume can be calculated by measuring the nitrogen adsorption isotherm using a BELSORP-miniII manufactured by Microtrac-Bell Corporation, and analyzing the result using BELMaster Ver. 6.3.2.1.

[0027] The average particle size of the particulate composition of the present invention is 40 to 300 μm, preferably 50 to 200 μm, and more preferably 60 to 150 μm. In the present invention, the average particle size is a volume-based median diameter (D50) and can be measured using a dry laser diffraction / scattering particle size distribution analyzer. Detailed measurement conditions can be found in the Examples section below.

[0028] The particulate composition of the present invention has a Hausner ratio of 1.00 to 1.45, preferably 1.08 to 1.34, and more preferably 1.10 to 1.25. The Hausner ratio is a value obtained by dividing the static bulk specific volume by the dynamic bulk specific volume, and can be determined according to the Hausner ratio measurement method in the Japanese Pharmacopoeia.

[0029] The particulate composition of the present invention preferably has a particle structure in which components such as lubricant, disintegrant, anhydrous calcium hydrogen phosphate, and crystalline low-solubility saccharide particles are uniformly dispersed on and inside the particulate composition without uneven distribution, and are cross-linked and bonded by the low-solubility saccharide. It is believed that the disintegrant, anhydrous calcium hydrogen phosphate, and crystalline low-solubility saccharide particles forming such a structure inside the particulate composition contributes to excellent tableting properties, disintegration properties, and compactibility when tableted. Furthermore, the lubricant is uniformly dispersed without uneven distribution, particularly on the surface of the particulate composition as uniformly as inside, and preferably has a particle diameter of 20 μm or less, preferably 10 μm or less, and more preferably 5 μm or less. The particle diameter of these lubricants can be confirmed by SEM photographs and / or cross-sectional SEM photographs of the particulate composition of the present invention. It is believed that the lubricant is partially exposed on the surface during mixing of the tableting powder or in a tablet press, thereby suppressing spreading and providing sufficient compactibility between the tablet and the mortar and pestle during tableting. Furthermore, if the tableting pressure is too high, the particulate composition at the contact points between the outer periphery of the tablet and the mortar and pestle may be destroyed, and the internal lubricant may have a lubricating effect.

[0030] Here, "uneven distribution" refers to (1) a layered structure of components such as lubricants within or on the periphery of particles, and the components are contained in a specific layer, or (2) aggregates of the average particle size of the lubricant or other components derived from the raw materials are present. On the other hand, "uniform dispersion" refers to a state in which there is no such uneven distribution, and each component is dispersed or crosslinked in the low-solubility saccharide after removal of the solvent, while maintaining the size of each component particle dispersed in the solution during production. For example, in the case of anhydrous calcium hydrogen phosphate, the average particle size of the raw material is not approximately 120 μm, but the particle size is mainly present in the range of 10 to 40 μm, and in the case of a disintegrant, the particle size derived from the raw material is maintained. Here, the particle size of each component in the particulate composition can be confirmed by element mapping using SEM photographs, SEM-BEX photographs, etc.

[0031] The particulate composition of the present invention exhibits suppressed spreadability due to the lubricant when mixed with a drug and compressed into tablets. The spreadability suppression effect is such that the reduction in tablet hardness relative to the tablet hardness at 0 minutes of mixing is 30% or less after 10 minutes of mixing and / or 40% or less after 60 minutes of mixing, preferably 30% or less after 10 minutes of mixing and / or 40% or less after 60 minutes of mixing. The amount of mixed powder added relative to the volume of the mixer under measurement conditions may be within a range that allows mixing, although this varies depending on the drug being mixed and the mixing equipment used. For example, the amount is 20 to 60% by volume, preferably 20 to 40% by volume. Specific conditions are shown in the Examples below. The decrease in tablet disintegration time due to mixing time varies depending on the set hardness, but is 15 N or less after 10 minutes of mixing and / or 20 N or less after 60 minutes of mixing, relative to a set hardness of 50 N and a mixing time of 0 minutes, preferably 10 N or less after 10 minutes of mixing and / or 15 N or less after 60 minutes of mixing.

[0032] Furthermore, when the particulate composition of the present invention is mixed with a drug and compressed into tablets, the drug and the particulate composition do not segregate, making it possible to obtain tablets with excellent content uniformity. When the drug content is 5% by mass or less, particularly 1% by mass or less, relative to the tablet weight, problems with content uniformity are likely to occur, which is particularly problematic in the case of direct compression, but the use of the particulate composition of the present invention can prevent such problems from occurring. The content uniformity when the particulate composition and drug are mixed and compressed into tablets is, for example, a judgment value of 15 or less, preferably 10 or less, more preferably 8 or less, and even more preferably 6 or less, when measured according to the content uniformity test method of the 18th Edition of the Japanese Pharmacopoeia, for a tablet produced by mixing 99% by mass of the particulate composition and 1% by mass of the drug. Here, the judgment value is the value obtained by the judgment value calculation formula for content uniformity testing in the 18th edition of the Japanese Pharmacopoeia, shown below (Equation 1). X is the average of the individual contents expressed as a percentage of the quantitative value, k is the judgment coefficient, which is 2.4 when the number of samples is 10, s is the standard deviation, and M is M=X when 98.5≦X≦101.5.

[0033] (Number 1) Judgment value = |MX|+ks

[0034] (Method of producing particulate composition) The method for producing the particulate composition of the present invention includes the steps of dissolving or dispersing a lubricant, a low-solubility saccharide, and anhydrous calcium hydrogen phosphate in a solvent to prepare a slurry, and removing the solvent from the slurry. Specifically, the particulate composition of the present invention is produced as spherical particles by preparing a spray liquid (slurry) by dissolving / dispersing a lubricant, a low-solubility saccharide, anhydrous calcium hydrogen phosphate, and, if necessary, other pharmaceutical additives in a solvent, and then spraying the slurry into an air stream to instantly remove the solvent.

[0035] As the production equipment, spray drying, fluidized bed, or tumbling bed can be used, and spray drying is preferred because it allows for continuous mass production. If further drying is required after granulation, the granules can be dried to the desired moisture content by a conventional drying method such as tray drying or fluidized bed drying. After drying, the particle size can be adjusted by sizing or crushing.

[0036] As the solvent, a water-soluble solvent can be used, for example, water, ethanol, methanol, propanol, or acetone, preferably water.

[0037] Specific conditions for spray drying are, for example, a heat input of 100 to 240° C. and a heat exhaust of 70 to 140° C. A pressure nozzle or rotary atomizer can be used as the spraying device, and the pressure conditions and rotation speed can be set in a conventional manner depending on the desired particle diameter.

[0038] The particulate composition of the present invention requires uniform dispersion of the lubricant, anhydrous calcium phosphate, lactose, and disintegrant, and is prepared by appropriately setting the dispersion, stirring speed, temperature, time, and concentration of the spray liquid under conditions in particular that the lubricant is dispersed but not liberated. The viscosity of the spray liquid is within a sprayable range, and a higher viscosity is preferred because it improves the dispersibility of insoluble matters such as the lubricant and reduces the energy required for solvent removal.

[0039] (Tablets using particulate composition) The granular composition of the present invention can be produced by mixing with an active ingredient (drug) alone and tableting. The amount of active ingredient can be appropriately set depending on the properties of the active ingredient; for example, the active ingredient is 0.0001 to 90 parts by mass per 100 parts by mass of tablet formulation. When the active ingredient is 3 parts by mass or less, it can be triturated with the granular composition of the present invention, and then further mixed with the granular composition of the present invention before tableting. The tablets may be uncoated or film-coated. The tablets produced in this way have excellent moldability, inhibited delayed disintegration, and inhibited loss of tablet hardness.

[0040] To provide the desired properties, the particulate composition of the present invention can be mixed with commonly used pharmaceutical additives other than the active ingredient and compressed into tablets, such as colorants, light-blocking agents, sweeteners, stabilizers, disintegrants, etc.

[0041] Examples of coloring agents include Food Blue No. 1, Food Blue No. 2, Food Yellow No. 4, Food Red No. 2, Food Red No. 3, Food Blue No. 1 Aluminum Lake, Food Blue No. 2 Aluminum Lake, Food Red No. 2 Aluminum Lake, ferric oxide (red), titanium oxide, yellow ferric oxide, caramel, talc, etc.

[0042] Examples of light-blocking agents include titanium oxide, calcium carbonate, zinc oxide, talc, iron oxides such as yellow ferric oxide, ferric oxide, and black ferric oxide, Food Yellow No. 5, Food Red No. 102, and the like, and preferably titanium oxide and calcium carbonate are used.

[0043] Examples of sweeteners include one or more sweeteners selected from sugar, oligosaccharides, maltitol, erythritol, sorbitol, xylitol, aspartame, acesulfame potassium, sucralose, and stevia.

[0044] Examples of disintegrants include starches such as corn starch and potato starch, partially pregelatinized starch, carboxymethyl starch sodium, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, crystalline cellulose, and hydroxypropyl starch.

[0045] Examples of the fluidizing agent include talc, hydrous silicon dioxide, light anhydrous silicic acid, magnesium aluminometasilicate, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, calcium stearate, and magnesium stearate. [Example]

[0046] The present invention will be described in more detail below with reference to Examples, Comparative Examples and Test Examples, but the present invention is not limited to these. The samples obtained in the Examples were evaluated by the following methods. 1. The average particle size was measured using a laser analysis / scattering particle size distribution analyzer MT3300EXII manufactured by Microtrac-Bell Co., Ltd., and analyzed using a DMS2 Ver11.1.0-257F2 manufactured by Microtrac-Bell Co., Ltd. The measurement conditions were: particle transmittance = transmission, particle refractive index = 1.81, particle shape = aspherical, solvent = nitrogen, solvent refractive index = 1.00. 2. The static bulk specific volume was calculated by inserting a glass tube into a 100 ml measuring cylinder, using a funnel to add the sample to the glass tube so that the volume was 90-100 ml, and then gently pulling out the glass tube to flatten the surface of the sample. The volume V0 and the weight W of the sample were calculated as V0 / W. 3. The Hausner ratio is the ratio of static bulk specific volume V0 to dynamic bulk specific volume V f Measure V0 / V f The dynamic bulk specific volume V f is the volume V when the sample whose static bulk specific volume was calculated is tapped at a height of 4 cm at a rate of 100 times / 250 seconds. f From V f / W. 4. Content uniformity was determined according to the content uniformity test of the 18th edition of the Japanese Pharmacopoeia, using the coefficient of judgment when the number of samples (n) was 10.

[0047] Example 1 [Production of particulate composition] A spray liquid was prepared by dissolving / mixing 1 part by mass of magnesium stearate, 30 parts by mass of anhydrous calcium hydrogen phosphate, 70 parts by mass of lactose hydrate, and 8 parts by mass of crospovidone in purified water at room temperature (20 to 25° C.). This spray liquid was spray-dried using a spray dryer to obtain a particulate composition with an average particle size of approximately 100 μm, a static bulk specific volume of 1.71 mL / g, and a Hausner ratio of 1.18.

[0048] An SEM photograph of the particulate composition is shown in Figure 1, an SEM-BEX photograph of the interior of the particulate composition is shown in Figure 2, the Mg distribution in the SEM-BEX photograph is shown in Figure 3, and an SEM photograph of the raw material magnesium stearate is shown in Figure 4. While agglomerated particles of 10 to 40 μm can be seen in the raw material magnesium stearate, the Mg distribution in the SEM-BEX photograph shows that the magnesium stearate does not form agglomerates or specific layers, i.e., it is not unevenly distributed but is uniformly dispersed, with particles no larger than 20 μm. The anhydrous calcium hydrogen phosphate used was Fujicalin (registered trademark) SG (a granulated anhydrous calcium phosphate with a primary particle size of 0.1 to 5 μm) manufactured by Fuji Chemical Industry Co., Ltd.

[0049] Example 2 A particulate composition was obtained under the same conditions as in Example 1, except that the lubricant was changed to sodium stearyl fumarate.

[0050] (Comparative Example 1) A particulate composition was obtained under the same conditions as in Example 1, except that magnesium stearate was omitted.

[0051] [Mixing and tableting evaluation] The granules of Examples 1 and 2, 99.1% of the granules of Comparative Example 1, and 0.9% magnesium stearate (3 kg as mixed powder) were charged into a 20 L tumbler Miniser and mixed for 60 minutes, after which they were compressed into tablets using a rotary tablet press (Kikusui Seisakusho, VIRGO 0518SS) with a diameter of 8Φ12R, a rotation speed of 10 rpm, a set hardness of 5 N, and a tablet weight of 200 mg. The results are shown in Tables 1, 2, 3, and Figures 5 and 6.

[0052] [Table 1]

[0053] [Table 2]

[0054] [Table 3]

[0055] The tablets produced using the particulate compositions of Examples 1 and 2 showed no change in disintegration time with mixing time and suppressed a decrease in tablet hardness, whereas the tablets prepared in Comparative Example 1 showed a delay in disintegration time and a large decrease in hardness. That is, the particulate composition of the present invention showed sufficiently suppressed spreadability and good tableting properties.

[0056] Figures 7 and 8 show SEM-BEX and SEM-BEX (Mg) photographs of the cross sections of a tablet obtained from the granules of Example 1 (Tablet of Example 1) and a tablet obtained from 99.1% granules of Comparative Example 1 and 0.9% magnesium stearate (Tablet of Comparative Example 1). The size of the lubricant on the surface of the granules in the cross section of the tablet of Example 1 was at most 20 μm or less. The cross section of the tablet of Comparative Example 1, i.e., the surface of the granules of Comparative Example 1, contained more magnesium stearate than the surface of the granules of Example 1, and the particle size was larger. This is thought to be because there was originally a lot of magnesium stearate on the particle surface, and it adhered to the surface at a size almost identical to that of the raw material.

[0057] (Comparative Example 2) The granules of Comparative Example 1 were compressed into tablets using a rotary tablet press (VIRGO 0518SS, manufactured by Kikusui Seisakusho Co., Ltd.) with settings of 8Φ12R, rotation speed 10 rpm, set hardness 5N, and tablet weight 200 mg. Sticking occurred in the mortar and pestle, and sufficient tablets could not be obtained.

[0058] Examples 3 to 6 According to the method of Example 1, a particulate composition was obtained using magnesium stearate, anhydrous calcium hydrogen phosphate, lactose hydrate, and crospovidone in the amounts shown in Table 4. The physical properties of the particulate composition are shown in Table 5, and the results of hardness and disintegration time are shown in Table 6.

[0059] [Table 4]

[0060] [Table 5]

[0061] [Table 6]

[0062] The particulate compositions of the present invention in Examples 3 to 6 have sufficiently good hardness and disintegrability for the production of tablets.

[0063] (Examples 7 to 8) 99% by mass of the particulate composition of Example 1 and 1% by mass of rebamipide or 1% by mass of loxoprofen sodium hydrate were mixed and then tableted using a rotary tablet press with settings of 8φR12, set hardness of 5N, rotation speed of 30 rpm, and tablet weight of 200 mg. The results of content uniformity, hardness, and disintegration are shown in Table 7.

[0064] [Table 7]

[0065] Tablets containing the particulate composition of the present invention and an active ingredient had sufficiently good hardness and disintegration properties. Furthermore, the content uniformity was judged to be acceptable, with a value of 15.0 or less, and the particulate composition of the present invention had excellent content uniformity, despite the drug content being as low as 1%.

[0066] Example 9 After mixing 90 parts by weight of the particulate composition of Example 1 and 10 parts by weight of acetaminophen, the mixture was tableted using a rotary tablet press with settings of 8φR12, set hardness of 5N, rotation speed of 30 rpm, and tablet weight of 200 mg to obtain tablets with a tablet hardness of 45.0N and a disintegration time of 88.0 seconds.

Claims

1. A particulate composition comprising a lubricant, a low-solubility saccharide, and anhydrous calcium hydrogen phosphate.

2. The composition of claim 1 , further comprising a disintegrant.

3. 3. The composition according to claim 1, wherein the lubricant is dispersed on the surface and inside of the composition as lubricant particles having a particle size of 20 μm or less.

4. 3. The composition according to claim 1, having an average particle size of 50 to 200 μm, a static bulk specific volume of 1 to 5 mL / g, or a Hausner ratio of 1 to 1.

45.

5. 3. The composition according to claim 1, wherein the rate of decrease in tablet hardness with mixing time when mixed with a drug and compressed into tablets is 30% or less after 10 minutes and / or 40% or less after 60 minutes compared to 0 minutes of mixing time.

6. 3. The composition according to claim 1 or 2, wherein a tablet containing 99% by mass of the composition according to claim 1 or 2 and 1% of a drug has a content uniformity rating of 15 or less in a content uniformity test according to the 18th edition of the Japanese Pharmacopoeia.

7. 3. The composition according to claim 1, wherein the lubricant is one or more selected from the group consisting of magnesium stearate, calcium stearate, glycerin fatty acid esters, stearic acid, sodium stearyl fumarate, and sucrose fatty acid esters.

8. 3. The composition according to claim 1, wherein the lubricant is one or more selected from magnesium stearate, calcium stearate and sodium stearyl fumarate.

9. 3. The composition according to claim 1, further comprising a lubricant in an amount of 0.1 to 5 parts by mass per 100 parts by mass of the particulate composition.

10. 3. The composition according to claim 1, wherein the lubricant has an average particle size of 2 to 20 μm.

11. 3. The composition according to claim 1, comprising 10 to 40 parts by mass of anhydrous calcium hydrogen phosphate per 100 parts by mass of the particulate composition.

12. 3. The composition according to claim 1, wherein the anhydrous calcium hydrogen phosphate is contained in an amount of 25 to 35 parts by mass per 100 parts by mass of the particulate composition.

13. 3. The composition according to claim 1, wherein the anhydrous calcium hydrogen phosphate is composed of primary particles having an average particle size of 0.1 to 5 μm.

14. 3. The composition according to claim 1, wherein the low-solubility saccharide is a sugar or sugar alcohol having a solubility of 50 g or less per 100 g of water at 25°C.

15. 3. The composition according to claim 1, wherein the low-solubility saccharide is lactose, mannitol, or erythritol.

16. 3. The composition according to claim 1, comprising 50 to 85 parts by mass of the low-solubility saccharide per 100 parts by mass of the particulate composition.

17. 3. The composition according to claim 1, comprising 60 to 70 parts by mass of the low-solubility saccharide per 100 parts by mass of the particulate composition.

18. The composition according to claim 15, wherein the mass ratio of lactose to anhydrous calcium hydrogen phosphate is 50:50 to 80:

20.

19. The composition according to claim 2, wherein the disintegrant is a swelling disintegrant.

20. The composition according to claim 2, wherein the disintegrant is one or more selected from the group consisting of sodium carboxymethyl starch, croscarmellose sodium, crospovidone, and low-substituted hydroxypropyl cellulose.

21. The composition according to claim 2, wherein the disintegrant is contained in an amount of 2 to 20 parts by weight per 100 parts by weight of the particulate composition.

22. The composition according to claim 2, wherein the disintegrant is contained in an amount of 3 to 10 parts by mass per 100 parts by mass of the total particulate composition.

23. 2. A method for producing the particulate composition according to claim 1, comprising the steps of dissolving or dispersing a lubricant, a low-solubility saccharide, and anhydrous calcium hydrogen phosphate in a solvent to prepare a slurry, and removing the solvent from the slurry.

24. 3. A method for producing a particulate composition according to claim 2, comprising the steps of dissolving or dispersing a lubricant, a low-solubility saccharide, anhydrous calcium hydrogen phosphate and a disintegrant in a solvent to prepare a slurry, and removing the solvent from the slurry.

25. 25. The method of claim 23 or 24, wherein the lubricant is uniformly dispersed in the slurry.

26. A tablet comprising the composition of claim 1 or 2 and a drug.

27. A method for producing tablets, comprising mixing and compressing the composition according to claim 1 or 2 and a drug.

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