Coprocessing additive

Abstract

To provide a coprocessing additive for producing tablets that have good fluidity, suppress spreading caused by mixing of tableted powder, suppress delay in disintegration, reduction in formability and hardness, and improve content uniformity, and tablets using the same. A particulate composition containing a lubricant, a low-solubility saccharide, and calcium hydrogen phosphate anhydrous.

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 described above, the problem in the preparation of tablet powder lies in the addition of lubricants. Generally, after mixing and granulating pharmaceutical additive components other than lubricants, the lubricant is added and mixed immediately before tableting. Since lubricants cause spreading during the mixing of tablet powder and during the flow in the hopper or turntable during tableting, the addition condition is adjusted according to individual mixers and tablet presses. The effect of the lubricant is to improve the peelability between the tableted tablets and the mortar and pestle and to eliminate tableting obstacles. Although the lubricant exhibits its lubricating effect when present on the surface of the tablet, only the disadvantages such as a decrease in formability, a delay in disintegration due to a decrease in water conductivity, and a decrease in the dissolution of the active ingredient are present for the portion inside the tablet. Also, as a method of adding the lubricant, there is a method of using an external lubrication device to make the lubricant present only on the surface of the tablet, but a special device is required, and it is necessary to be able to retrofit the external lubrication device from the design stage of the tablet press. Without the device, it cannot be easily used. Therefore, suppression of the spreading of the lubricant inside the tablet is required.

[0005] In new drug development, it is often necessary to change the formulation and manufacturing method in preclinical, early clinical, and late clinical stages. Each time a change is made, it is necessary to confirm the equivalence between the formulation before the change and the formulation after the change, and a lot of development time and costs are spent. Therefore, there is a need for a tablet design that can be manufactured simply by mixing directly with the drug and is less affected by scale-up.

[0006] A coprocess additive (all-in-one coprocess additive) is a combination of two or more additives obtained by physical coprocessing (cocombining), and it is known to exhibit functions that cannot be achieved by simple mixing of individual additives. However, no report has been made on those that can sufficiently solve the above problems. Therefore, there is a need for an excipient, disintegrant, lubricant, and other pharmaceutical additive components that have drug content uniformity, stability, appropriate disintegration properties and formability, suppress the influence of the mixing time of tablet powder and machinery, and enable the production of tablets only by mixing and tableting the drug and the coprocess additive, and a coprocess additive prepared in advance.

[0007] Previously, the applicant has proposed spherical co-process additives containing calcium hydrogen phosphate anhydrous, lactose, and a disintegrant. For example, a spherical co-process additive obtained by spray-drying mannitol, calcium hydrogen phosphate anhydrous, lactose, and a disintegrant (Patent Document 1), a spherical co-process additive obtained by spray-drying calcium hydrogen phosphate anhydrous, lactose, and a disintegrant (Patent Document 2), a spherical co-process additive obtained by spray-drying calcium hydrogen phosphate anhydrous, lactose, and crospovidone (Patent Document 3), and a granulated product containing saccharides, a disintegrant, an excipient, and, if necessary, an inorganic powder, which is prepared separately from the active ingredient (Patent Document 4). However, in these inventions, the lubricant is mixed with the co-process additive during tableting and does not contain a lubricant in the co-process additive.

[0008] In recent years, as all-in-one co-process additives containing a lubricant, there are commercially available a spherical composition having an average particle diameter of about 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 having an average particle diameter of about 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

Patent Document 2

Patent Document 3

Patent Document 4

Non-Patent Documents

[0010]

Non-Patent Document 1

Non-Patent Document 2

Summary of the Invention

Problems 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 spreading caused by mixing of tableted powder, suppress delayed disintegration, reduced formability and hardness, and are excellent in content uniformity with a drug, and tablets using the same.

Means for Solving the Problems

[0012] As a result of investigations to solve the above problems, the present inventors have found that a particulate composition containing a lubricant, a low-solubility saccharide, and calcium hydrogen phosphate anhydrous has suppressed spreadability, good tableting properties, excellent content uniformity with a drug, and is useful as a co-process additive for producing tablets that are excellent in disintegratability and formability only by mixing and tableting with a drug.

[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 calcium hydrogen phosphate anhydrous. 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 diameter of 20 μm or less. 4) The composition according to 1) or 2), having an average particle diameter of 50 to 200 μm, a static bulk specific volume of 1 to 5 mL / cm 2 , or a Hausner ratio of 1 to 1.45. 5) The composition according to 1) or 2), wherein the rate of decrease in tablet hardness due to the mixing time when mixed with a drug and tableted is 30% or less at 10 minutes and / or 40% or less at 60 minutes with respect to 0 minutes of mixing time. 6) The composition according to 1) or 2), wherein the composition contains 99% by mass of the composition according to claim 1 or 2 and 1% by mass of the drug, and the determination value of content uniformity in the content uniformity test according to the 18th revised Japanese Pharmacopoeia for tablets is 15 or less. 7) The composition according to 1) or 2), wherein the lubricant is at least one selected from magnesium stearate, calcium stearate, glycerin fatty acid ester, stearic acid, sodium stearyl fumarate, and sucrose fatty acid ester. 8) The composition according to 1) or 2), wherein the lubricant is at least one 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 the lubricant with respect to 100 parts by mass of the particle composition. 10) The composition according to 1) or 2), wherein the average particle diameter 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 with respect to 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 with respect to 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 diameter of 0.1 to 5 μm. 14) The composition according to 1) or 2), wherein the low-solubility saccharides are saccharides or sugar alcohols 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 saccharides are lactose, mannitol, or erythritol. 16) The composition according to 1) or 2), which contains 50 to 85 parts by mass of the low-solubility saccharides with respect to 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 saccharides with respect to 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 at least one 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 the disintegrant with respect to 100 parts by mass of the particulate composition. 22) The composition according to 2), which contains 3 to 10 parts by mass of the disintegrant with respect to 100 parts by mass of the whole particulate composition. 23) A method for producing the particulate composition according to 1), comprising a step of dissolving or dispersing a lubricant, a low-solubility saccharide, and calcium hydrogen phosphate anhydrous in a solvent to prepare a slurry, and a step of removing the solvent from the slurry. 24) A method for producing the particulate composition according to 2), comprising a step of dissolving or dispersing a lubricant, a low-solubility saccharide, calcium hydrogen phosphate anhydrous, and a disintegrant in a solvent to prepare a slurry, and a step of removing the solvent from the slurry. 25) The production 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 compression molding the composition according to 1) or 2) and a drug.

Advantages of the Invention

[0014] As a co-process additive, the particulate composition of the present invention can produce a tablet with suppressed disintegration delay, formability, hardness reduction, and spreadability and excellent content uniformity with the drug only by mixing and tableting with the drug.

Brief Description of the Drawings

[0015] [Figure 1] SEM photograph of the particulate composition of Example 1. [Figure 2] SEM-BEX photograph of the inside of the particulate composition of Example 1. [Figure 3] SEM-BEX photograph of the inside of the particulate composition of Example 1. [Figure 4] SEM photograph of the raw material magnesium stearate. [Figure 5] Tableting evaluation: mixing time - hardness. [Figure 6] Tableting evaluation: mixing time - disintegration time. [Figure 7] SEM-BEX photograph of the cross-section of a tablet obtained by tableting the particulate composition of Example 1. [Figure 8] SEM-BEX photograph of the cross-section of a tablet obtained by tableting the particulate composition of Comparative Example 1 and magnesium stearate.

Mode for Carrying Out the Invention

[0016] Hereinafter, the present invention will be described in detail. Unless otherwise specified in the present invention, the uses of each pharmaceutical additive are based on the uses of pharmaceutical additives in the Dictionary of Pharmaceutical Additives.

[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] As the lubricant in the particulate composition of the present invention, either an organic lubricant or an inorganic lubricant can be used, but it is preferable to use an organic lubricant. Examples of the organic lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, glycerin fatty acid ester, and stearic acid and sodium stearyl fumarate. Preferably, they are magnesium stearate, calcium stearate, and sodium stearyl fumarate, and more preferably magnesium stearate. The average particle diameter of the lubricant is preferably 20 μm or less, more preferably 2 - 20 μm, still more preferably 2 - 20 μm, further preferably 3 - 15 μm, and most preferably 3 - 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 with 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, calcium carboxymethylcellulose, carboxymethylcellulose, croscarmellose, sodium croscarmellose, low-substituted hydroxypropylcellulose, corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, sodium carboxymethyl starch, and the like. The disintegrant is preferably crospovidone, carboxymethylcellulose, croscarmellose, low-substituted hydroxypropylcellulose, or the like, and more preferably crospovidone. These disintegrants can be used alone or in combination of two or more.

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

[0024] The content ratio 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 with respect to 100 parts by mass of the composition. The content ratio of calcium hydrogen phosphate anhydrous 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 with respect to 100 parts by mass of the composition. The content ratio of low water-soluble saccharides 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 with respect to 100 parts by mass of the composition. In the particulate composition of the present invention, for example, the mass ratio of lactose to calcium phosphate anhydrous is 50:50 to 80:20, preferably 60:40 to 75:25. When a disintegrant is blended, the content ratio 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 with respect to 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, indicating the volume (mL) per 1 g, which is a value obtained by measuring the volume and mass and dividing the volume by the mass. The bulk density of the Japanese Pharmacopoeia can be measured by the same method.

[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 measured by a nitrogen adsorption isotherm using BELSORP-miniII manufactured by MicrotracBEL Corporation and analyzed and calculated by BELMaster Ver6.3.2.1.

[0027] The average particle diameter 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 diameter is the median diameter (D50) based on volume, and can be measured using a dry laser diffraction / scattering particle size distribution measuring device. Specific measurement conditions can be those described in the examples below.

[0028] The Hausner ratio of the particulate composition of the present invention is 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 of the Japanese Pharmacopoeia.

[0029] The particulate composition of the present invention preferably has a particulate structure in which components such as a lubricant, a disintegrant, anhydrous calcium hydrogen phosphate, and crystalline low-solubility saccharide particles are uniformly dispersed without uneven distribution on the surface and inside of the particulate composition and are crosslinked and bonded by the low-solubility saccharide. By the disintegrant, anhydrous calcium hydrogen phosphate, and crystalline low-solubility saccharide particles constituting such a structure inside the particulate composition, it is considered to be excellent in tableting properties, disintegration properties during tableting, and moldability. Further, the lubricant is uniformly dispersed without uneven distribution, particularly uniformly dispersed on the surface of the particulate composition in the same manner as inside, and preferably has a particle size of 20 μm or less, more preferably 10 μm or less, and even more preferably 5 μm or less. The particle size of these lubricants can be confirmed by SEM photographs and / or cross-sectional SEM photographs of the particulate composition of the present invention. During the mixing of the tableting powder or in the tableting machine, it is considered that spreading is suppressed because a part of the surface of the lubricant is exposed, and sufficient moldability is obtained between the tablet and the mortar during tableting. Further, when the tableting pressure is high, the particulate composition at the contact portion between the outer periphery of the tablet and the mortar may be broken and the internal lubricant may have a lubricating effect.

[0030] Here, "uneven distribution" refers to a state where (1) a constituent component such as a lubricant has a layered structure inside or on the outer periphery of the particle and is contained in a specific layer, and (2) aggregates of the average particle size derived from the raw material of the constituent component such as a lubricant are included. On the other hand, "uniformly dispersed" means a state in which there is no such uneven distribution, and each constituent component is dispersed or crosslinked in the low-solubility saccharide by removing the solvent while maintaining the size at which each constituent particle was dispersed in the solution during production in the particulate composition. For example, in the case of anhydrous calcium hydrogen phosphate, it does not have an average particle size of about 120 μm of the raw material, but mainly has a particle size of about 10 to 40 μm, and in the case of a disintegrant, it refers to a state in which 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 mapping elements with SEM photographs and SEM-BEX photographs, etc.

[0031] The particulate composition of the present invention has its extensibility by a lubricant suppressed when mixed with a drug and tableted. As the extensibility suppressing effect, the rate of decrease in tablet hardness with respect 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 conditions such as the drug to be mixed and the apparatus, the amount of the mixed powder added with respect to the capacity of the mixer under the measurement conditions may be within the mixable range. For example, it is mixed at 20 to 60% by volume, preferably 20 to 40% by volume. Specific conditions are shown in the examples described later. The decrease in the disintegration time of the tablet due to the mixing time varies depending on the set hardness, but with respect 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.

[0032] Also, when the particulate composition of the present invention is mixed and tableted with a drug, segregation of the drug and the particulate composition does not occur, and a tablet with excellent content uniformity can be obtained. When the content of the drug is 5% by mass or less, particularly 1% by mass or less, with respect to the tablet weight, problems of content uniformity are likely to occur, especially in the case of direct compression, which becomes an issue. However, when the particulate composition of the present invention is used, the occurrence of such problems can be suppressed. The content uniformity when the particulate composition and the drug are mixed and tableted is, for example, for a tablet produced by mixing 99% by mass of the particulate composition and 1% by mass of the drug, the determination value measured according to the content uniformity test method of the 18th revised Japanese Pharmacopoeia is 15 or less, preferably 10 or less, more preferably 8 or less, and even more preferably 6 or less. Here, the determination value is a value obtained by the determination value calculation formula of the content uniformity test of the 18th revised Japanese Pharmacopoeia shown by the following formula (Equation 1). X is the average of the individual contents expressed as a percentage with respect to the quantitative value, k is the determination coefficient which is 2.4 when the number of samples is 10, s is the standard deviation, and M = X when 98.5 ≤ X ≤ 101.5.

[0033] (Equation 1) Determination value = |M - X| + ks

[0034] (Method for producing the 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 particulate composition of the present invention can be produced by mixing and tableting with the active ingredient (drug) alone. Depending on the properties of the active ingredient, the blending amount of the active ingredient can be appropriately set. For example, with respect to 100 parts by mass of the tablet formulation, the active ingredient is 0.0001 to 90 parts by mass. When the active ingredient is 3 parts by mass or less, after trituration with the particulate composition of the present invention, the particulate composition of the present invention can be further mixed and then tableted. The tablet may be in the form of a plain tablet or film-coated. Thus, the produced tablet is excellent in moldability, has suppressed delayed disintegration, and also has suppressed reduction in tablet hardness.

[0040] To have desired properties, the particulate composition of the present invention can be mixed with pharmaceutically acceptable additive components that can be normally used in addition to the active ingredient and then tableted. Examples of the pharmaceutically acceptable additive components include coloring agents, light-shielding agents, sweeteners, stabilizers, disintegrants and the like.

[0041] Examples of the coloring agent 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 sesquioxide (red), Titanium oxide, Yellow ferric sesquioxide, Caramel, Talc and the like.

[0042] Examples of the light-shielding agent include Titanium oxide, Calcium carbonate, Zinc oxide, Talc, Yellow ferric sesquioxide, Ferric oxides such as Ferric sesquioxide and Black ferric oxide, Food Yellow No. 5, Food Red No. 102 and the like, and preferably Titanium oxide and Calcium carbonate.

[0043] Examples of the sweetener include one or more sweeteners selected from sugar, oligosaccharide, 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. EXAMPLES

[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. The content uniformity was determined using the coefficient of determination when the number of samples n was 10, in accordance with the content uniformity test of the 18th revised Japanese Pharmacopoeia.

[0047] (Example 1) [Production of particulate composition] 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 were dissolved / mixed with purified water to prepare a spray solution at room temperature (20 - 25°C). This spray solution was spray-dried using a spray dryer to obtain a particulate composition with an average particle diameter of about 100 μm, a static bulk specific volume of 1.71 mL / g, and a Hausner ratio of 1.18.

[0048] The SEM photograph of the particulate composition is shown in Figure 1, the SEM-BEX photograph of the inside of the particulate composition is shown in Figure 2, the Mg distribution of the SEM-BEX photograph is shown in Figure 3, and the SEM photograph of the raw material magnesium stearate is shown in Figure 4. Aggregated particles of 10 - 40 μm can be confirmed in the raw material magnesium stearate, whereas from the Mg distribution of the SEM-BEX photograph, it was found that magnesium stearate does not form aggregated lumps or specific layers, that is, it is not unevenly distributed, but is uniformly dispersed and at most 20 μm or less in size. Anhydrous calcium hydrogen phosphate used was Fujicalin (registered trademark) SG manufactured by Fuji Chemical Industry Co., Ltd. (granulated particulate product of anhydrous calcium phosphate with a primary particle diameter of 0.1 - 5 μm).

[0049] (Example 2) A particulate composition was obtained under the conditions of Example 1 except that the lubricant was changed to sodium stearyl fumarate.

[0050] (Comparative Example 1) A particulate composition was obtained under the conditions of Example 1 except that magnesium stearate was removed.

[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 co-process additive composition comprising a lubricant, a low-solubility saccharide, and calcium hydrogen phosphate anhydrous, wherein the lubricant is dispersed on the surface and inside of the composition as lubricant particles having a particle diameter of 20 μm or less, and 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.

2. The composition according to claim 1, comprising a disintegrant.

3. The composition according to claim 1 or 2, having an average particle diameter 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.

4. The composition according to claim 1 or 2, wherein the rate of decrease in tablet hardness due to the mixing time when mixed with a drug and tabletted is 30% or less at 10 minutes and / or 40% or less at 60 minutes with respect to 0 minutes of mixing time.

5. The composition according to claim 1 or 2, wherein the determination value of content uniformity in the content uniformity test according to the 18th revised Japanese Pharmacopoeia for a tablet containing 99% by mass of the composition according to claim 1 or 2 and 1% by mass of a drug is 15 or less.

6. The composition according to claim 1 or 2, wherein the lubricant is at least one selected from magnesium stearate, calcium stearate, glycerin fatty acid ester, stearic acid, sodium stearyl fumarate, and sucrose fatty acid ester.

7. The composition according to claim 1 or 2, wherein the lubricant is at least one selected from magnesium stearate, calcium stearate, and sodium stearyl fumarate.

8. The composition according to claim 1 or 2, containing 0.1 to 5 parts by mass of the lubricant with respect to 100 parts by mass of the particle composition.

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

10. The composition according to claim 1 or 2, containing 10 to 40 parts by mass of calcium hydrogen phosphate anhydrous with respect to 100 parts by mass of the particle composition.

11. The composition according to claim 1 or 2, containing 25 to 35 parts by mass of calcium hydrogen phosphate anhydrous with respect to 100 parts by mass of the particle composition.

12. The composition according to claim 1 or 2, wherein the calcium hydrogen phosphate anhydrous is composed of primary particles having an average particle diameter of 0.1 to 5 μm.

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

14. The composition according to claim 1 or 2, containing 50 to 85 parts by mass of the low-solubility saccharide with respect to 100 parts by mass of the particle composition.

15. The composition according to claim 1 or 2, which contains 60 to 70 parts by mass of a low-solubility saccharide with respect to 100 parts by mass of the particle composition.

16. The composition according to claim 13, wherein the mass ratio of lactose to calcium hydrogen phosphate anhydrous is 50:50 to 80:

20.

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

18. The composition according to claim 2, wherein the disintegrant is at least one selected from sodium carboxymethyl starch, croscarmellose sodium, crospovidone, and low-substituted hydroxypropyl cellulose.

19. The composition according to claim 2, which contains 2 to 20 parts by mass of a disintegrant with respect to 100 parts by mass of the particle composition.

20. The composition according to claim 2, which contains 3 to 10 parts by mass of a disintegrant with respect to 100 parts by mass of the whole particle composition.

21. The method for producing the particulate co-process additive composition according to claim 1, comprising a step of dissolving or dispersing a lubricant, a low-solubility saccharide, and calcium hydrogen phosphate anhydrous in a solvent to prepare a slurry, and a step of removing the solvent from the slurry.

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

23. The production method according to claim 21 or 22, wherein the lubricant is uniformly dispersed in the slurry.

24. A tablet comprising the composition according to claim 1 or 2 and a drug.

25. The method for producing a tablet by mixing and compression molding the composition according to claim 1 or 2 and a drug.

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