Co-processed excipient

Abstract

Provided are: a co-processed excipient for producing a tablet that has good fluidity, suppresses spreading caused by mixing of tableting powder, suppresses disintegration delay and degradation of moldability and hardness, and has improved content uniformity; and a tablet using same.　This particulate composition comprises a lubricant, a low-solubility saccharide, and anhydrous calcium hydrogen phosphate.

Description

Co-processed excipients

[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.

[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 spread 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 tablets 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 formability, 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 ensure that the lubricant is present only on the tablet surface, but this requires specialized equipment and requires the tablet press to be designed for retrofitting; without such equipment, it is not easily implemented. 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 excipients (all-in-one co-processed excipients) are combinations of two or more excipients obtained by physical co-processing, and are known to exhibit functions that cannot be achieved by simply mixing the individual excipients. However, no excipients that can fully solve the above-mentioned problems have been reported. Therefore, there is a need for pre-prepared co-processed excipients that have drug content uniformity and stability, appropriate disintegration and compactibility, suppress the effects of mixing time and machinery on tableting powders, and contain pharmaceutical additives such as excipients, disintegrants, and lubricants that allow tablets to be produced 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 containing sugars, disintegrants, excipients, and optionally inorganic powders, prepared separately from the active ingredient (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 the lubricant.

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

[0009] International Publication No. 2005 / 037254 Japanese Patent Application Laid-Open No. 2011-157348 International Publication No. 1999 / 055373 Japanese Patent Application Laid-Open No. 2015-78182

[0010] Kollitab (registered trademark) DC87L Technical Information Brochure PROSOLV (registered trademark) EASYtab SP Brochure

[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.

[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 suppressed 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 simply by mixing with a drug and tableting.

[0013] That is, the present invention relates to the following 1) to 27). 1) A particulate composition containing 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), in which the lubricant is dispersed in the composition as lubricant particles having a particle diameter of 20 μm or less. 4) A composition having an average particle diameter of 50 to 200 μm and a static bulk volume of 1 to 5 mL / cm. ２or a Hausner ratio of 1 to 1.45. 5) The composition of 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 at 10 minutes and / or 40% or less at 60 minutes compared to 0 minutes of mixing time. 6) The composition of 1) or 2), wherein a tablet containing 99% by mass of the composition of claim 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 of 1) or 2), wherein the lubricant is one or more selected from magnesium stearate, calcium stearate, glycerin fatty acid ester, stearic acid, sodium stearyl fumarate, and sucrose fatty acid ester. 8) The composition of 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), containing a lubricant in an amount of 0.1 to 5 parts by mass relative to 100 parts by mass of the particulate composition. 10) The composition according to 1) or 2), wherein the lubricant has an average particle size of 2 to 20 μm. 11) The composition according to 1) or 2), containing anhydrous calcium hydrogen phosphate in an amount of 10 to 40 parts by mass relative to 100 parts by mass of the particulate composition. 12) The composition according to 1) or 2), containing anhydrous calcium hydrogen phosphate in an amount of 25 to 35 parts by mass relative to 100 parts by mass of the particulate 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 in 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), wherein the low-solubility saccharide is contained in an amount of 50 to 85 parts by mass relative to 100 parts by mass of the particulate composition. 17) The composition according to 1) or 2), wherein the low-solubility saccharide is contained in an amount of 60 to 70 parts by mass relative to 100 parts by mass of the particulate 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 carboxymethyl starch sodium, croscarmellose sodium, crospovidone, and low-substituted hydroxypropyl cellulose. 21) The composition according to 2), wherein the disintegrant is contained in an amount of 2 to 20 parts by mass per 100 parts by mass of the particulate composition. 22) The composition according to 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) A method for producing a particulate composition according to 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 a particulate composition according to 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 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 a tablet by mixing and compressing the composition according to 1) or 2) and a drug.

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

[0015] SEM photograph of the particulate composition of Example 1. SEM-BEX photograph of the interior of the particulate composition of Example 1. SEM-BEX photograph of the interior of the particulate composition of Example 1. SEM photograph of the raw material magnesium stearate. Mixing and tableting evaluation: mixing time - hardness. Mixing and tableting evaluation: mixing time - disintegration time. SEM-BEX photograph of the cross section of a tablet obtained by tableting the particulate composition of Example 1. SEM-BEX photograph of the cross section of a tablet obtained by tableting the particulate composition of Comparative Example 1 and magnesium stearate.

[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, among others. 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, and when it is 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 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 crystal 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 can contain a disintegrant inside the particles, if necessary. The disintegrant is not particularly limited, but 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 can 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 the 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 even 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 even 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 static bulk specific volume of the particulate composition of the present invention is 1 to 5 mL / g, preferably 1.5 to 2.5 mL / g. The static bulk specific volume is the reciprocal of the bulk density, and indicates the volume (mL) per 1 g, obtained 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 manner.

[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 The BET specific surface area and pore volume can be calculated by measuring a nitrogen adsorption isotherm using a BELSORP-mini II 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 the 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 of 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 results in excellent tableting properties, disintegration properties, and moldability 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 moldability 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 tablet periphery and the mortar and pestle may be destroyed, and the internal lubricant may have a lubricating effect.

[0030] Here, "uneven distribution" refers to a state in which (1) a component such as a lubricant has a layered structure inside or on the periphery of a particle and is contained in a specific layer, or (2) aggregates of an average particle size derived from the raw material of the component such as a lubricant are contained. On the other hand, "uniformly dispersed" refers to a state in which there is no such uneven distribution, and each component is dispersed or crosslinked in a low-solubility saccharide by removing the solvent while maintaining the size of each component particle dispersed in the solution during production in the particulate composition. For example, in the case of anhydrous calcium hydrogen phosphate, the particle size is not the average particle size of the raw material, which is about 120 μm, but is mainly present in a particle size of about 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 and 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 at 10 minutes of mixing and / or 40% or less at 60 minutes of mixing, preferably 30% or less at 10 minutes of mixing and / or 40% or less at 60 minutes of mixing. The amount of mixed powder added relative to the volume of the mixing vessel under measurement conditions may vary depending on the drug being mixed and the mixing equipment, as long as it is within a range that allows mixing; for example, 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 with mixing time varies depending on the set hardness, but is 15 N or less at 10 minutes of mixing and / or 20 N or less at 60 minutes of mixing, relative to a set hardness of 50 N and 0 minutes of mixing, preferably 10 N or less at 10 minutes of mixing and / or 15 N or less at 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, allowing tablets with excellent content uniformity to be obtained. When the drug content is 5% by mass or less, particularly 1% by mass or less, relative to the tablet weight, content uniformity problems are likely to occur, particularly in the case of direct compression, but the use of the particulate composition of the present invention can prevent such problems from occurring. When the particulate composition and a drug are mixed and compressed into tablets, for example, for a tablet produced by mixing 99% by mass of the particulate composition and 1% by mass of the drug, the content uniformity test value measured according to the content uniformity test method of the Japanese Pharmacopoeia, 18th Edition, is 15 or less, preferably 10 or less, more preferably 8 or less, and even more preferably 6 or less. Here, the judgment value is the value obtained by the judgment value calculation formula for the content uniformity test of the Japanese Pharmacopoeia, 18th Edition, shown as the following formula (Mathematical Formula 1): X is the average of the individual contents expressed as a percentage of the quantitative value, k is the coefficient of determination 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] (Equation 1) Judgment value = |M-X| + ks

[0034] (Method for 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 by dissolving / dispersing a lubricant, a low-solubility saccharide, anhydrous calcium hydrogen phosphate, and, if necessary, other pharmaceutical additives in a solvent to prepare a spray liquid (slurry), which is then sprayed into an air stream, thereby instantly removing the solvent and producing spherical particles.

[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 a 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 particulate 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, 0.0001 to 90 parts by mass of the active ingredient 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 particulate composition of the present invention, and then further mixed with the particulate composition of the present invention before tableting. The tablets may be plain or film-coated. The tablets produced in this way have excellent moldability, inhibited delayed disintegration, and inhibited reduction in 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 coloring agents, 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, and the like.

[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.

[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 measuring device MT3300EXII manufactured by Microtrac-Bell Co., Ltd., and analyzed using a DMS2 Ver. 11.1.0-257F2 manufactured by Microtrac-Bell Co., Ltd. The measurement conditions were: particle transmittance = transmission, particle refractive index = 1.81, particle shape = aspherical, solvent = nitrogen, and solvent refractive index = 1.00. 2. The static bulk specific volume was measured by inserting a glass tube into a 100 ml graduated cylinder, adding a sample to the glass tube with a funnel so that the volume was 90 to 100 ml, gently pulling out the glass tube, and flattening the surface of the sample to determine the volume V ０and the weight of the sample W, V ０ 3. The Hausner ratio is calculated by the static bulk specific volume V ０ and dynamic bulk specific volume V ｆ Measure V ０ / V ｆ The dynamic bulk specific volume V ｆ is the volume V when the sample for which the static bulk specific volume was determined was tapped at a height of 4 cm at a rate of 100 times / 250 seconds. ｆ From V ｆ 4. Content uniformity was determined in accordance with the content uniformity test of the Japanese Pharmacopoeia, 18th Edition, 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 having 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 were observed in the raw material magnesium stearate, the Mg distribution in the SEM-BEX photograph showed that the magnesium stearate did not form agglomerates or specific layers, i.e., it was not unevenly distributed but was uniformly dispersed, with particles no larger than 20 μm. Fujicalin (registered trademark) SG (a granulated product of anhydrous calcium phosphate with a primary particle size of 0.1 to 5 μm) manufactured by Fuji Chemical Industry Co., Ltd. was used as the anhydrous calcium hydrogen phosphate.

[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, and then tableted using a rotary tablet press (manufactured by Kikusui Seisakusho, VIRGO 0518SS) with settings of 8Φ12R, rotation speed of 10 rpm, set hardness of 5 N, and tablet weight of 200 mg. The results are shown in Tables 1, 2, 3, and Figures 5 and 6.

[0052]

[0053]

[0054]

[0055] The tablets produced using the particulate compositions of Examples 1 and 2 showed no change in tablet 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 tableted 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, particulate compositions were 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 compositions are shown in Table 5, and the results of hardness and disintegration time are shown in Table 6.

[0059]

[0060]

[0061]

[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 and 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]

[0065] The tablets containing the particulate composition of the present invention and the active ingredient had sufficiently good hardness and disintegration properties. Furthermore, the content uniformity was judged to be acceptable, with a judgement 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) 90 parts by mass of the particulate composition of Example 1 and 10 parts by mass of acetaminophen were mixed, and then tableted using a rotary tablet press with settings of 8φR12, set hardness 5N, rotation speed 30 rpm, and tablet weight 200 mg to obtain tablets with a tablet hardness of 45.0 N 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. The composition according to claim 1 or 2, 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. The composition according to claim 1 or 2, having an average particle size of 50 to 200 μm, a static bulk volume of 1 to 5 mL / g, or a Hausner ratio of 1 to 1.

45.

5. The composition according to claim 1 or 2, in which 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. The composition according to claim 1 or 2, wherein a tablet containing 99% by weight of the composition according to claim 1 or 2 and 1% of a drug has a content uniformity judgment value of 15 or less in a content uniformity test according to the 18th Edition of the Japanese Pharmacopoeia.

7. The composition according to claim 1 or 2, wherein the lubricant is one or more selected from magnesium stearate, calcium stearate, glycerol fatty acid esters, stearic acid, sodium stearyl fumarate and sucrose fatty acid esters.

8. The composition according to claim 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 claim 1 or 2, which contains a lubricant in an amount of 0.1 to 5 parts by weight per 100 parts by weight of the particulate composition.

10. The composition according to claim 1 or 2, wherein the average particle size of the lubricant is 2 to 20 μm.

11. The composition according to claim 1 or 2, which contains 10 to 40 parts by weight of anhydrous calcium hydrogen phosphate per 100 parts by weight of the particulate composition.

12. The composition according to claim 1 or 2, which contains 25 to 35 parts by weight of anhydrous calcium hydrogen phosphate per 100 parts by weight of the particulate composition.

13. The composition according to claim 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 claim 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 claim 1 or 2, wherein the low-solubility sugar is lactose, mannitol or erythritol.

16. The composition according to claim 1 or 2, which contains 50 to 85 parts by mass of a low-solubility saccharide per 100 parts by mass of the particulate composition.

17. The composition according to claim 1 or 2, which contains 60 to 70 parts by mass of a 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 from 50:50 to 80:

20.

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

20. The composition of claim 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 claim 2, comprising a disintegrant 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, which contains a disintegrant in an amount of 3 to 10 parts by weight per 100 parts by weight of the total particulate composition.

23. A method for producing a 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. 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. The method of claim 23 or 24, wherein a 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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