Co-processing additive

Abstract

Provided are: a co-processing additive which has good fluidity, suppresses elongation caused by mixing of tableting powder, suppresses disintegration delay, decreases in moldability and hardness, and improves content uniformity; and a tablet which uses the co-processing additive. The present invention is a particulate composition comprising a lubricant, a low solubility saccharide, and anhydrous calcium hydrogen phosphate.

Description

Technical Field

[0001] This invention relates to a co-processing additive with excellent disintegration and tableting properties, inhibits extensibility, and is suitable for direct tableting; a method for manufacturing the additive; and tablets containing the additive. Background Technology

[0002] Methods for manufacturing tablets include: granulation compression, where the active ingredient is wet-granulated or dry-granulated, additives are added, and the mixture is then compressed into tablets; and direct compression, where no granulation step is performed on the active ingredient, and all ingredients are mixed before compression. Direct compression has advantages over granulation compression: fewer manufacturing steps, such as granulation, reduce manufacturing costs; and the absence of water or heating steps makes it suitable for active ingredients intolerant to water or heat. However, it has disadvantages such as difficulty in designing uniformity of content, formability, and dissolution.

[0003] In addition, there are batch manufacturing and continuous manufacturing methods for tablets. Batch manufacturing involves mixing or granulating additives using the aforementioned granulation or direct compression methods, preparing tablet powder for each batch, and then compressing the powder. This method has been widely used. Continuous manufacturing involves continuously mixing or granulating additives using the aforementioned granulation or direct compression methods to prepare tablet powder, and then continuously compressing the powder. Batch manufacturing allows for sequential verification of each step, making the design of the manufacturing steps easier. However, when scaling up from pilot production to mass production, changes in batch size require verification of mixability, etc. In contrast, continuous manufacturing, because it involves continuous mixing or granulation of each component, while making the design of the manufacturing steps more difficult, offers the following advantages: changes in batch size only require changes in manufacturing time, without the obstacle of scale-up, and it can better control manufacturing costs compared to batch manufacturing in commercial production.

[0004] As mentioned above, the problem in tablet powder preparation lies in the addition of lubricants. Generally, after mixing and granulating the pharmaceutical additives other than the lubricant, the lubricant is added and mixed before tableting. The lubricant spreads during mixing the tablet powder and during tableting in the hopper or rotary table; therefore, the addition method must be adjusted according to each mixer or tableting machine. The effect of adding lubricant is to improve the separation of the tablet from the mortar and pestle, eliminating tableting resistance. The lubricant only exerts its lubricating effect when present on the tablet surface; the portion present inside the tablet only has disadvantages such as delayed disintegration or reduced dissolution of the active ingredient due to decreased formability and water conductivity. Another method of adding lubricant is to use an external lubrication device, ensuring the lubricant is only present on the tablet surface. However, this requires special equipment and must be pre-designed from the tableting machine's design stage to allow for subsequent installation of an external lubrication device; otherwise, it cannot be used simply. Therefore, it is necessary to suppress the spread of lubricant inside the tablet.

[0005] In new drug development, changes to the formulation or manufacturing method are often made in the preclinical, early clinical, and late clinical stages. Each change requires verification of the equivalence between the original and revised formulations, which consumes development time and costs. Therefore, there is a need for a tablet design that can be manufactured simply by mixing with the drug and directly compressing it, and is not easily affected by scale-up.

[0006] Co-processing additives (integrated co-processing additives) are known to be combinations of two or more additives obtained through physical co-processing. They exhibit functions that cannot be achieved by simply mixing individual additives, but no reports have been found that can fully solve the above problems.

[0007] Therefore, there is a need for a pre-prepared co-processing additive that provides uniform drug content, stability, moderate disintegration and formability, suppresses the effects of mixing time or mechanical processes on the tableting powder, contains pharmaceutical additives such as excipients, disintegrants and lubricants that can be used to manufacture tablets by mixing and compressing the drug with the co-processing additive.

[0008] Previously, the applicant has proposed a spherical co-processed additive containing anhydrous dicalcium phosphate, lactose, and a disintegrant. Examples include: a spherical co-processed additive obtained by spray drying mannitol, anhydrous dicalcium phosphate, lactose, and a disintegrant (Patent Document 1); a spherical co-processed additive obtained by spray drying anhydrous dicalcium phosphate, lactose, and a disintegrant (Patent Document 2); a spherical co-processed additive obtained by spray drying anhydrous dicalcium phosphate, lactose, and crospovidone (Patent Document 3); and granules containing sugars, disintegrants, excipients, and, if desired, inorganic powders, prepared separately from the active ingredient (Patent Document 4). However, in these inventions, the lubricant is mixed with the co-processed additive during tableting, and the co-processed additive does not contain a lubricant.

[0009] In recent years, as an integrated co-processing additive containing lubricant, the following compositions have been commercially available: a spherical composition with an average particle size of about 150 μm containing 87% lactose, 9% crospovidone, 3% polyethylene glycol-polyvinyl alcohol graft polymer and 1% sodium stearate fumarate (Non-Patent Literature 1); and a composition with an average particle size of about 160 μm containing 96% microcrystalline cellulose, 1.2% sodium starch glycolate, 2% silica and 0.8% sodium stearate fumarate (Non-Patent Literature 2).

[0010] Existing technical documents Patent documents Patent Document 1: International Publication No. 2005 / 037254 Patent Document 2: Japanese Patent Application Publication No. 2011-157348 Patent Document 3: International Publication No. 1999 / 055373 Patent Document 4: Japanese Patent Application Publication No. 2015-78182 Non-patent literature Non-patent document 1: Kollitab (registered trademark) DC87L Technical Information Specification Non-patent document 2: PROSOLV (registered trademark) EASYtab SP instruction manual Summary of the Invention

[0011] The problem that the invention aims to solve This invention relates to a co-processing additive that provides good compressibility, inhibits the stretching caused by mixing of tableting powders, and is used to manufacture tablets in which disintegration delay, moldability and hardness reduction are inhibited and the content uniformity with the drug is excellent, as well as tablets using the same.

[0012] Technical solutions for solving the problem In order to solve the above-mentioned problems, the inventors conducted research and found that a granular composition containing a lubricant, a low-solubility sugar and anhydrous calcium hydrogen phosphate can be used as a co-processing additive for manufacturing tablets with suppressed extensibility, good compressibility, excellent uniformity of drug content, and excellent disintegration and formability simply by mixing with the drug and compressing.

[0013] That is, the present invention relates to the following 1) to 27).

[0014] 1) A particulate composition comprising a lubricant, a low-solubility sugar, and anhydrous dicalcium phosphate.

[0015] 2) The composition as described in 1) contains a disintegrant.

[0016] 3) The composition as described in 1) or 2) is formed by dispersing the lubricant in the composition in the form of lubricant particles with a particle size of less than 20 μm.

[0017] 4) The composition as described in 1) or 2) has an average particle size of 50–200 μm and a static bulk volume of 1–5 mL / cm³. 2 , or Hausner ratio is 1 to 1.45.

[0018] 5) The composition as described in 1) or 2) wherein, when mixed with the drug and compressed into tablets, the reduction rate of tablet hardness relative to the mixing time of 0 minutes is less than 30% at 10 minutes and / or less than 40% at 60 minutes.

[0019] 6) The composition as described in claim 1 or 2, wherein the tablet comprising 99% by mass of the composition as described in claim 1 or 2 and 1% of the drug has a content uniformity determination value of 15 or less in the content uniformity test according to the 18th revision of the Japanese Pharmacopoeia.

[0020] 7) The composition as described in 1) or 2), wherein the lubricant is one or more selected from magnesium stearate, calcium stearate, glycerol fatty acid ester, stearic acid, sodium stearate fumarate and sucrose fatty acid ester.

[0021] 8) The composition as described in 1) or 2), wherein the lubricant is selected from one or more of magnesium stearate, calcium stearate and sodium stearate fumarate.

[0022] 9) The composition as described in 1) or 2) contains 0.1 to 5 parts by weight of lubricant relative to 100 parts by weight of the particulate composition.

[0023] 10) The composition as described in 1) or 2), wherein the average particle size of the lubricant is 2 to 20 μm.

[0024] 11) The composition as described in 1) or 2) contains 10 to 40 parts by weight of anhydrous dicalcium phosphate relative to 100 parts by weight of the particulate composition.

[0025] 12) The composition as described in 1) or 2) contains 25 to 35 parts by weight of anhydrous dicalcium phosphate relative to 100 parts by weight of the particulate composition.

[0026] 13) The composition as described in 1) or 2), wherein the anhydrous dicalcium phosphate consists of primary particles with an average particle size of 0.1 to 5 μm.

[0027] 14) The composition as described in 1) or 2), wherein the low-solubility sugar is a sugar or sugar alcohol with a solubility of less than 50 g relative to 100 g of water at 25°C.

[0028] 15) The composition as described in 1) or 2), wherein the low-soluble sugar is lactose, mannitol or erythritol.

[0029] 16) The composition as described in 1) or 2) contains 50 to 85 parts by weight of low-soluble sugars relative to 100 parts by weight of the particulate composition.

[0030] 17) The composition as described in 1) or 2) contains 60 to 70 parts by weight of low-soluble sugars relative to 100 parts by weight of the particulate composition.

[0031] 18) The composition as described in 15), wherein the mass ratio of lactose to anhydrous dicalcium phosphate is 50:50 to 80:20.

[0032] 19) The composition as described in 2), wherein the disintegrant is a swelling disintegrant.

[0033] 20) The composition as described in 2), wherein the disintegrant is one or more selected from sodium carboxymethyl starch, croscarmellose sodium, croscarmellose and low-substituted hydroxypropyl cellulose.

[0034] 21) The composition as described in 2) contains 2 to 20 parts by weight of disintegrant relative to 100 parts by weight of the particulate composition.

[0035] 22) The composition as described in 2) contains 3 to 10 parts by weight of disintegrant relative to 100 parts by weight of the total particulate composition.

[0036] 23) A method for manufacturing a particulate composition as described in 1), comprising: a step of dissolving or dispersing a lubricant, a low-solubility sugar and anhydrous calcium hydrogen phosphate in a solvent to prepare a slurry, and a step of removing the solvent from the slurry.

[0037] 24) A method for manufacturing a particulate composition as described in 2), comprising: a step of dissolving or dispersing a lubricant, a low-solubility sugar, anhydrous dicalcium phosphate and a disintegrant in a solvent to prepare a slurry, and a step of removing the solvent from the slurry.

[0038] 25) The manufacturing method as described in 23) or 24), wherein the lubricant is uniformly dispersed in the slurry.

[0039] 26) A tablet comprising the composition and drug as described in 1) or 2).

[0040] 27) A method for manufacturing a tablet, comprising mixing and compressing the composition and the drug as described in 1) or 2).

[0041] Invention Effects The granular composition of the present invention can be used as a co-processing additive. By simply mixing with a drug and compressing it, tablets with delayed disintegration, reduced formability and hardness, and inhibited extensibility can be manufactured, and the content of the drug is highly uniform. Attached Figure Description

[0042] Figure 1 This is a SEM image of the particulate composition of Example 1.

[0043] Figure 2 This is a SEM-BEX image of the interior of the particulate composition of Example 1.

[0044] Figure 3 This is a SEM-BEX image of the interior of the particulate composition of Example 1.

[0045] Figure 4 SEM image of magnesium stearate as raw material.

[0046] Figure 5 Evaluation of mixed tableting: mixing time - hardness.

[0047] Figure 6 Evaluation of mixed compression: mixing time - disintegration time.

[0048] Figure 7 SEM-BEX image of a cross section of a tablet obtained by compressing the granular composition of Example 1.

[0049] Figure 8 SEM-BEX image of a cross section of a tablet obtained by compressing the granular composition of Comparative Example 1 with magnesium stearate. Detailed Implementation

[0050] The present invention will now be described in detail. Unless otherwise expressly stated, the uses of each pharmaceutical additive in this invention are as described in the pharmaceutical additives dictionary.

[0051] (Particulate composition) The granular composition of the present invention is a spherical composition containing a lubricant, a low-solubility sugar, and anhydrous calcium hydrogen phosphate.

[0052] The lubricant in the particulate composition of the present invention can be any one of an organic lubricant or an inorganic lubricant, preferably an organic lubricant. Examples of organic lubricants include magnesium stearate, calcium stearate, sucrose fatty acid esters, glycerol fatty acid esters, and sodium stearate and fumarate, with magnesium stearate, calcium stearate, and sodium stearate and fumarate being preferred, and magnesium stearate being more preferred. The average particle size of the lubricant is preferably 20 μm or less, more preferably 2 to 20 μm, even more preferably 2 to 20 μm, further preferably 3 to 15 μm, and most preferably 3 to 10 μm.

[0053] The low-soluble sugars in the granular composition of the present invention are sugars or sugar alcohols with low solubility in water, for example, those with a solubility of less than 50 g relative to 100 mL of water at 25°C. Specifically, these are lactose, mannitol, and erythritol, preferably lactose or mannitol, and more preferably lactose. When the granular composition of the present invention is used in the manufacture of conventional tablets, lactose is most preferred in terms of ease of acquisition or price; when used in the manufacture of intraorally disintegrating tablets, mannitol is most preferred in terms of taste and palatability.

[0054] Low-solubility sugars are prepared to function as excipients and binders. They contain both crystalline and amorphous portions. The crystalline portion is considered to have excipient properties, while the majority of the amorphous portion acts as a binder and excipient, binding the components together.

[0055] The anhydrous dicalcium phosphate in the granular composition of the present invention can be the anhydrous dicalcium phosphate described in the Japanese Pharmacopoeia, but is preferably the one with good formability. The primary granules are composed of granules with an average particle size of 0.05 to 10 μm, preferably 0.1 to 5 μm, and the anhydrous dicalcium phosphate with a crystallinity of 0.3 to 0.9, preferably 0.4 to 0.8, can be used. Crystallinity is the ratio of the highest peak of XRD to the average particle size of crystalline dicalcium phosphate with an average particle size of 50 μm or more, sold as a reagent and used as a standard. Specific commercially available products include Fujiicalin (registered trademark) (manufactured by Fuji Chemical Industry Co., Ltd.), GS, and GSH (Kyowa Chemical Industry Co., Ltd.), with Fujiicalin being preferred.

[0056] In the particulate composition of the present invention, a disintegrant may be included inside the particles as needed.

[0057] The disintegrant is not particularly limited, but examples include: crospovidone, calcium carboxymethyl cellulose, carboxymethyl cellulose, crospovidone carboxymethyl cellulose, sodium crospovidone carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, corn starch, potato starch, wheat starch, rice starch, partially α-starch, α-starch, sodium carboxymethyl starch, etc. The preferred disintegrants are crospovidone, carboxymethyl cellulose, crospovidone carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, etc., and more preferably crospovidone. One or more of these disintegrants may be used.

[0058] Furthermore, the particulate composition of the present invention may contain appropriate amounts of additives and active ingredients commonly used in pharmaceuticals. These may be used alone or in combination with two or more ingredients. Examples of additives include, for instance, excipients, binders, coating agents, gloss agents, colorants, flavoring agents, sweeteners, and fragrances.

[0059] The lubricant content in the particulate composition of the present invention is 0.1 to 5 parts by weight relative to 100 parts by weight of the composition, preferably 0.2 to 4 parts by weight, more preferably 0.3 to 3 parts by weight, and even more preferably 0.5 to 2 parts by weight.

[0060] The anhydrous dicalcium phosphate content in the granular composition of the present invention is 10 to 40 parts by weight relative to 100 parts by weight of the composition, preferably 20 to 40 parts by weight, and more preferably 25 to 35 parts by weight.

[0061] The proportion of low water-soluble sugars in the granular composition of the present invention is 50 to 85 parts by weight relative to 100 parts by weight of the composition, preferably 54 to 75 parts by weight, and more preferably 60 to 70 parts by weight.

[0062] In the granular composition of the present invention, for example, the mass ratio of lactose to anhydrous calcium phosphate is 50:50 to 80:20, preferably 60:40 to 75:25.

[0063] In addition, when preparing a disintegrant, the content of the disintegrant is 2 to 20 parts by mass relative to 100 parts by mass of the composition, preferably 3 to 15 parts by mass, and more preferably 3 to 10 parts by mass.

[0064] The static bulk density of the particulate composition of the present invention is 1 to 5 mL / g, preferably 1.5 to 2.5 mL / g.

[0065] The static saturated volume is the reciprocal of the apparent density, representing the volume (mL) per 1 g. It is the value obtained by measuring the volume and mass and dividing the volume by the mass. The apparent density in the Japanese Pharmacopoeia can be determined using the same method.

[0066] The BET specific surface area of ​​the particulate composition of the present invention is 1 to 5 m². 2 / g, preferably 1.5–3 m 2 / g.

[0067] The specific surface area and pore volume of BET can be determined using the BELSORP-miniII manufactured by MicrotracBEL Inc. to measure the nitrogen adsorption isotherm, and then analyzed and calculated using BELMaster Ver6.3.2.1.

[0068] The average particle size of the particulate composition of the present invention is 40-300 μm, preferably 50-200 μm, and more preferably 60-150 μm.

[0069] In this invention, the average particle size is the median particle size (D50) based on volume, which can be measured using a dry laser diffraction-scattering particle size distribution measuring device. Detailed measurement conditions are as described in the examples described later.

[0070] The hauschnauzzi ratio of the particulate composition of the present invention is 1.00 to 1.45, preferably 1.08 to 1.34. More preferably 1.10 to 1.25.

[0071] Hausnerby is the value obtained by dividing the static sonic volume by the dynamic sonic volume, and can be determined according to the Hausnerby determination method in the Japanese Pharmacopoeia.

[0072] The granular composition of the present invention preferably has the following particle structure: lubricant, disintegrant, anhydrous dicalcium phosphate, and crystalline low-solubility sugar particles are uniformly dispersed on the surface and inside of the granular composition without any agglomeration, and are formed by cross-linking and bonding through the low-solubility sugars. It is believed that this structure, formed by the disintegrant, anhydrous dicalcium phosphate, and crystalline low-solubility sugar particles within the granular composition, results in excellent tableting properties, disintegration properties when formed into tablets, and formability. Furthermore, the lubricant is preferably uniformly dispersed without agglomeration, especially uniformly dispersed on the surface and inside the granular composition, with a particle size of 20 μm or less, preferably 10 μm or less, and more preferably 5 μm or less. The particle size of these lubricants can be confirmed using SEM images and / or cross-sectional SEM images of the granular composition of the present invention. It is believed that during tableting powder mixing or in the tableting machine, a portion of the lubricant is exposed on the surface, thus suppressing stretching and ensuring sufficient formability between the tablet and the mortar during tableting. In addition, if the pressure is high during tablet compression, the following situation may occur: the particulate composition at the contact area between the tablet periphery and the pestle is destroyed, thus allowing the internal lubricant to have a lubricating effect.

[0073] Here, "existence of partial aggregates" refers to the following states: (1) the constituent components such as lubricants have a layered structure inside or around the particles and are contained in specific layers; (2) aggregates containing the constituent components such as lubricants with an average particle size derived from the raw materials. On the other hand, "uniform dispersion" refers to the absence of such partial aggregates, where each constituent component in the particulate composition maintains the same size as the constituent particles after dispersion treatment in the solution during manufacturing, and is dispersed or cross-linked in sugars with low solubility by removing the solvent. For example, in the case of anhydrous dicalcium phosphate, it means that it does not exist with an average particle size of about 120 μm as the raw material, but exists with a particle size mainly of about 10 to 40 μm. In the case of disintegrants, it means that the particle size derived from the raw material remains unchanged. Here, the particle size of each component in the particulate composition can be confirmed by imagery of elements using SEM images and SEM-BEX images.

[0074] The granular composition of the present invention suppresses the extensibility caused by the lubricant when mixed with a drug and compressed into tablets. As an effect of suppressing extensibility, the reduction rate of tablet hardness relative to the tablet hardness at a mixing time of 0 minutes is 30% or less at a mixing time of 10 minutes and / or 40% or less at a mixing time of 60 minutes, preferably 30% or less at a mixing time of 10 minutes and / or 40% or less at a mixing time of 60 minutes. Although it varies depending on the drug to be mixed or the equipment, the amount of mixing powder added relative to the capacity of the mixer under the measurement conditions is only required to be within a mixable range, for example, 20 to 60% by volume, preferably 20 to 40% by volume. Specific conditions are shown in the examples described later. The reduction in tablet disintegration time resulting from the mixing time varies depending on the set hardness; relative to a set hardness of 50 N and a mixing time of 0 minutes, it is 15 N or less at a mixing time of 10 minutes and / or 20 N or less at a mixing time of 60 minutes, preferably 10 N or less at a mixing time of 10 minutes and / or 15 N or less at a mixing time of 60 minutes.

[0075] Furthermore, when the granular composition of the present invention is mixed with a drug and compressed into tablets, tablets with excellent content uniformity and no drug segregation between the drug and the granular composition can be obtained. When the drug content relative to the tablet weight is 5% by mass or less, especially 1% by mass or less, content uniformity problems can easily occur, particularly in direct compression. However, if the granular composition of the present invention is used, this problem can be suppressed.

[0076] Regarding the content uniformity when the granular composition is mixed with the drug and compressed into tablets, for example, for tablets manufactured by mixing 99% by mass of the granular composition with 1% by mass of the drug, the judgment value measured according to the content uniformity test method of the 18th revised edition of the Japanese Pharmacopoeia is 15 or less, preferably 10 or less, more preferably 8 or less, and even more preferably 6 or less.

[0077] Here, the judgment value refers to the value obtained according to the judgment value calculation formula of the content uniformity test in the 18th revised edition of the Japanese Pharmacopoeia, as shown in Formula (1). X is the average value of each content expressed as a percentage of the quantification value, k is the judgment coefficient, which is 2.4 when the number of samples is 10, s is the standard deviation, and M = X when M is 98.5 ≤ X ≤ 101.5.

[0078] (Number 1) Judgment value = |M - X| + ks (Method for manufacturing particulate composition) The method for manufacturing the particulate composition of the present invention includes the steps of preparing a slurry by dissolving or dispersing a lubricant, a sugar with low solubility and anhydrous calcium hydrogen phosphate in a solvent, and the step of removing the solvent from the slurry.

[0079] Specifically, the particulate composition of the present invention is prepared by dissolving / dispersing a lubricant, a low-soluble sugar, anhydrous dicalcium phosphate, and other pharmaceutical additives as needed in a solvent to form a spray liquid (slurry), which is then sprayed into an airflow to instantly remove the solvent and form spherical particles.

[0080] As a manufacturing apparatus, spray drying, fluidized bed drying, and rolling bed drying can be used. For the purpose of large-scale continuous manufacturing, spray drying is preferred. When drying is required after granulation, conventional drying methods such as cabinet drying and fluidized bed drying can be used to achieve the desired moisture content. After drying, granulation or crushing can be performed to adjust the particle size.

[0081] Water-soluble solvents can be used, such as water, ethanol, methanol, propanol, acetone, with water being preferred.

[0082] Specific conditions for spray drying include, for example, a heat input of 100–240°C and a heat discharge of 70–140°C. As for the spraying device, a pressurized nozzle or a rotary atomizer can be used. The pressurization conditions and rotation speed can be set using conventional methods according to the required particle size.

[0083] The particulate composition of the present invention requires the uniform dispersion of the lubricant, anhydrous calcium phosphate, lactose, and disintegrant. In particular, the dispersion, stirring speed, temperature, time, and concentration are appropriately set to prepare the spray solution under conditions where the lubricant is dispersed and does not become free. The viscosity of the spray solution is within the sprayable viscosity range; a higher viscosity is preferred in terms of increased dispersibility of insoluble substances such as lubricants and lower energy required for solvent removal.

[0084] (Tablets using granular compositions) The granular composition of the present invention can be manufactured by mixing with a single active ingredient (drug) and compressing it into tablets. The amount of active ingredient prepared can be appropriately set according to the characteristics of the active ingredient, for example, 0.0001 to 90 parts by weight of the active ingredient relative to 100 parts by weight of the tablet formulation. When the amount of active ingredient is 3 parts by weight or less, it can be dispersed in the granular composition of the present invention, then mixed with the granular composition of the present invention, and then compressed into tablets. The tablets can remain in their uncoated state or be made into film-coated tablets. In this way, the resulting tablets have excellent formability, disintegration delay is suppressed, and the reduction of tablet hardness can also be suppressed.

[0085] To achieve the desired properties, the particulate composition of the present invention can be mixed with conventionally usable pharmaceutical additives other than the active ingredient and then compressed into tablets. Examples of pharmaceutical additives include, for instance, colorants, opacifiers, sweeteners, stabilizers, disintegrants, etc.

[0086] Examples of coloring agents include: food coloring blue 1, food coloring blue 2, food coloring yellow 4, food coloring red 2, food coloring red 3, food coloring blue 1 aluminum lake, food coloring blue 2 aluminum lake, food coloring red 2 aluminum lake, ferric oxide (red), titanium dioxide, yellow ferric oxide, caramel, talc, etc.

[0087] Examples of opaque agents include titanium dioxide, calcium carbonate, zinc oxide, talc, yellow ferric oxide, ferric oxide, iron oxide black, etc., food coloring yellow No. 5, food coloring red No. 102, etc., with titanium dioxide and calcium carbonate being preferred.

[0088] As a sweetener, examples include one or more sweeteners selected from sugar, oligosaccharides, maltitol, erythritol, sorbitol, xylitol, aspartame, acesulfame potassium, sucralose, and stevia.

[0089] Examples of disintegrants include: corn starch or potato starch, partially α-starch, sodium carboxymethyl starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, croscarmellose, low-substituted hydroxypropyl cellulose, crystalline cellulose, hydroxypropyl starch, etc.

[0090] Examples of lubricants include: talc, hydrated silica, light anhydrous silica, magnesium aluminum silicate, synthetic aluminum silicate, heavy anhydrous silicate, magnesium aluminum hydroxide, stearic acid, calcium stearate, and magnesium stearate.

[0091] Example The present invention will now be described in more detail through examples, comparative examples, and test examples, but the present invention is not limited thereto. The evaluation of the samples obtained in the examples was performed using the following methods.

[0092] 1. The average particle size was measured using a MicrotracBEL MT3300EXII laser absorptivity-scattering particle size distribution analyzer, and analyzed using a MicrotracBEL DMS2 Ver11.1.0-257F2. The measurement conditions were: particle permeability set to transparent, particle refractive index set to 1.81, particle shape set to non-spherical, solvent set to nitrogen, and solvent refractive index set to 1.00.

[0093] 2. The static loose volume is calculated by inserting a glass tube into a 100 mL graduated cylinder to achieve a volume of 90-100 mL, placing the sample into the glass tube using a funnel, and then gently pulling out the glass tube. The volume V0 when the sample surface is flat and the weight W of the sample are used to calculate the volume V0 / W.

[0094] 3. Hausnerby used this method to determine the static Somne volume V0 and the dynamic Somne volume V. f via V0 / V f And thus, the dynamic loose volume V is obtained. f To determine the volume V of a sample whose static loose volume is calculated, which is then subjected to 100 impacts per 250 seconds from a height of 4 cm. f via V f / W is used to find the answer.

[0095] 4. Content uniformity is determined according to the content uniformity test of the 18th revised edition of the Japanese Pharmacopoeia, using the determination coefficient when the number of samples n is 10.

[0096] (Example 1) [Preparation of the particulate composition] One part by weight of magnesium stearate, 30 parts by weight of anhydrous dicalcium phosphate, 70 parts by weight of lactose hydrate, and 8 parts by weight of crospovidone were dissolved / mixed with purified water to prepare a spray solution at room temperature (20–25°C). The spray solution was spray-dried using a spray dryer to obtain a particulate composition with an average particle size of approximately 100 μm, a static bulk density of 1.71 mL / g, and a Hausner ratio of 1.18.

[0097] SEM images of the particulate composition are shown below. Figure 1 SEM-BEX images of the interior of the particulate composition are shown below. Figure 2 The Mg distribution in the SEM-BEX images is shown in... Figure 3 SEM images of magnesium stearate from the raw material are shown below. Figure 4Magnesium stearate from the raw material can be identified as aggregated particles of 10–40 μm. In contrast, based on the Mg distribution in the SEM-BEX images, it can be seen that magnesium stearate does not form aggregates or specific layers, that is, it is uniformly dispersed rather than segregated, with a maximum size of less than 20 μm.

[0098] Anhydrous dicalcium phosphate is produced using Fujichemical Industrial Co., Ltd.'s (registered trademark) Fujiicalin SG (a granulated product of anhydrous calcium phosphate with a primary particle size of 0.1 to 5 μm).

[0099] (Example 2) Except for changing the lubricant to sodium stearate fumarate, a particulate composition was obtained under the conditions of Example 1.

[0100] (Comparative Example 1) Except for the removal of magnesium stearate, a particulate composition was obtained under the conditions of Example 1.

[0101] [Evaluation of Mixing and Tableting] The granules from Examples 1 and 2, 99.1% of the granules from Comparative Example 1, and 0.9% magnesium stearate were added as a 3 kg mixed powder to a 20 L drum mixer and mixed for 60 minutes. Tableting was then performed using a rotary tableting machine (Kikusui Seisakusho, VIRGO 0518SS) at 8 ϕ 12 R, 10 rpm, a set hardness of 5 N, and a tablet weight of 200 mg. The results are shown in Tables 1, 2, and 3. Figure 5 , 6 .

[0102] [Table 1] Mixing time and hardness The numerical value represents hardness [N]. [Table 2] Mixing time and hardness reduction rate The reduction rate [%] when the hardness is set to 100 at a mixing time of 0 minutes. [Table 3] Mixing time and disintegration time The value is in seconds. The tablets manufactured using the granular compositions of Examples 1 and 2 do not exhibit changes in tablet disintegration time due to mixing time, and the reduction in tablet hardness is suppressed. In contrast, the tablets prepared in Comparative Example 1 showed a delayed disintegration time and a greater reduction in hardness. That is, the extensibility of the granular compositions of the present invention is sufficiently suppressed, and the tableting properties are also good.

[0103] SEM-BEX images and SEM-BEX (Mg) images of cross-sections of tablets obtained from the granulation of Example 1 (Example 1 tablets) and tablets obtained from 99.1% granulation of Comparative Example 1 and 0.9% magnesium stearate (Comparative Example 1 tablets) are shown below. Figure 7 , 8 In Example 1, the lubricant on the surface of the granulated material in the tablet cross-section had a maximum size of less than 20 μm. The surface of the granulated material in Comparative Example 1, compared to the surface of the granulated material in Example 1, contained more magnesium stearate and had a larger particle size. This is believed to be because the original particle surface contained a large amount of magnesium stearate, which adhered to the surface while maintaining almost the same size as the raw material.

[0104] (Comparative Example 2) The granules of Comparative Example 1 were tableted using a rotary tableting machine (manufactured by Kikusui Seisakusho, VIRGO 0518SS) at 8ϕ12R, 10 rpm, a set hardness of 5 N, and a tablet weight of 200 mg. The pestle adhered, and insufficient tablets were obtained.

[0105] (Examples 3-6) Following the method of Example 1, a particulate composition was obtained using magnesium stearate, anhydrous calcium hydrogen phosphate, lactose hydrate, and crospovidone, according to the preparation amounts in Table 4. The physical property evaluation of the particulate composition is shown in Table 5, and the results for hardness and disintegration time are shown in Table 6.

[0106] [Table 4] Preparation amount of each component [Table 5] Physical property evaluation of particulate compositions [Table 6] Evaluation of hardness and compressibility The granular compositions of the present invention in Examples 3-6 have sufficiently good hardness and disintegration properties in the manufacture of tablets.

[0107] (Examples 7-8) The granular composition of Example 1 (99% by mass) was mixed with either rebamipide (1% by mass) or loxoprofen sodium hydrate (1% by mass), and then tableted using a rotary tableting machine at settings of 8 ϕR12, hardness of 5 N, rotation speed of 30 rpm, and tablet weight of 200 mg. The results for content uniformity, hardness, and disintegration are shown in Table 7.

[0108] [Table 7] Formulation evaluation Tablets containing the granular composition and active ingredient of the present invention have sufficiently good hardness and disintegration properties. Furthermore, regarding content uniformity, a value of 15.0 or less is considered suitable; although the drug content is as low as 1%, the granular composition of the present invention exhibits excellent content uniformity.

[0109] (Example 9) After mixing 90 parts by weight of the granular composition of Example 1 and 10 parts by weight of acetamide phenol, the mixture was compressed using a rotary tablet press at 8ϕR12, a set hardness of 5 N, a rotation speed of 30 rpm, and a tablet weight of 200 mg to obtain tablets with a hardness of 45.0 N and a disintegration time of 88.0 seconds.

Claims

1. A particulate composition comprising a lubricant, a low-solubility sugar, and anhydrous dicalcium phosphate.

2. The composition of claim 1, wherein it comprises a disintegrant.

3. The composition according to claim 1 or 2, wherein the lubricant is dispersed on the surface and inside the composition in the form of lubricant particles with a particle size of less than 20 μm.

4. The composition according to claim 1 or 2, wherein the average particle size is 50 to 200 μm, the static bulk density is 1 to 5 mL / g, or the Hauss-Na ratio is 1 to 1.

45.

5. The composition of claim 1 or 2, wherein, when mixed with the drug and compressed into tablets, the rate of decrease in tablet hardness relative to the mixing time is less than 30% at 10 minutes and / or less than 40% at 60 minutes.

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

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

8. The composition of claim 1 or 2, wherein the lubricant is selected from one or more of magnesium stearate, calcium stearate and sodium stearate fumarate.

9. The composition according to claim 1 or 2, wherein it contains 0.1 to 5 parts by weight of lubricant relative to 100 parts by weight of the particulate composition.

10. The composition of 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, wherein it contains 10 to 40 parts by weight of anhydrous dicalcium phosphate relative to 100 parts by weight of the particulate composition.

12. The composition according to claim 1 or 2, wherein it contains 25 to 35 parts by weight of anhydrous dicalcium phosphate relative to 100 parts by weight of the particulate composition.

13. The composition of claim 1 or 2, wherein the anhydrous dicalcium phosphate is composed of primary particles with an average particle size of 0.1 to 5 μm.

14. The composition of claim 1 or 2, wherein the low-solubility sugar is a sugar or sugar alcohol with a solubility of less than 50 g relative to 100 g of water at 25°C.

15. The composition of claim 1 or 2, wherein the low-soluble sugar is lactose, mannitol or erythritol.

16. The composition of claim 1 or 2, wherein it contains 50 to 85 parts by weight of low-soluble sugars relative to 100 parts by weight of the particulate composition.

17. The composition of claim 1 or 2, wherein it contains 60 to 70 parts by weight of low-soluble sugars relative to 100 parts by weight of the particulate composition.

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

20.

19. The composition of 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, croscarmellose and low-substituted hydroxypropyl cellulose.

21. The composition of claim 2, wherein it contains 2 to 20 parts by weight of disintegrant relative to 100 parts by weight of the particulate composition.

22. The composition of claim 2, wherein it contains 3 to 10 parts by weight of disintegrant relative to 100 parts by weight of the total particulate composition.

23. A method for manufacturing the particulate composition of claim 1, comprising: The steps of preparing a slurry by dissolving or dispersing a lubricant, a sugar with low solubility, and anhydrous calcium hydrogen phosphate in a solvent, and the steps of removing the solvent from the slurry.

24. A method for manufacturing the particulate composition of claim 2, comprising: The steps of preparing a slurry by dissolving or dispersing a lubricant, a sugar with low solubility, anhydrous dicalcium phosphate, and a disintegrant in a solvent, and the steps of removing the solvent from the slurry.

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

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

27. A method for manufacturing a tablet, comprising mixing and compressing the composition and the drug as described in claim 1 or 2.

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