Oral solid composition

Abstract

To provide a technology for suppressing aggregation of fine powdered drug substances and improving their flowability.SOLUTION: An oral solid composition according to one embodiment of the present invention comprises eltrombopag olamine and one or more additives, wherein the eltrombopag olamine particles have a D90 of less than 9 μm and an average particle size of less than 4 μm, and the one or more additives comprise anhydrous calcium hydrogen phosphate particles having a circularity of 0.80 or more, the surfaces of which are coated with hardened oil.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to oral solid compositions. [Background technology]

[0002] There is a need to use finely divided drug substances as drug substances to be added to oral solid compositions. For example, Patent Document 1 describes a pharmaceutical tablet containing drug particles in which about 90% of the drug particles have a particle size larger than 10 microns but smaller than 90 microns. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2008 / 136843 Summary of the Invention [Problem to be solved by the invention]

[0004] However, finely divided drug substances tend to be easily aggregated and have poor flowability.

[0005] An object of one aspect of the present invention is to provide a technology for suppressing aggregation and improving flowability of a finely powdered drug substance of eltrombopag olamine. [Means for solving the problem]

[0006] In order to solve the above problems, an oral solid composition according to one aspect of the present invention is an oral solid composition comprising eltrombopag olamine and one or more additives, wherein the eltrombopag olamine particles have a D 90 The one or more additives include anhydrous calcium hydrogen phosphate particles having a circularity of 0.80 or more and a surface of the particles being coated with hardened oil. Effect of the Invention

[0007] According to one aspect of the present invention, a technique for suppressing aggregation of a finely powdered drug substance and improving the flowability can be provided. [Brief description of the drawings]

[0008] [Figure 1] FIG. 1 is a diagram for explaining an outline of a method for producing hardened oil-coated anhydrous calcium hydrogen phosphate particles according to one embodiment of the present invention. [Diagram 2] FIG. 1 shows the results of an example, and is a diagram showing the comparison results of the dissolution profile between Formulation 1, Formulation 2, and Revolade (registered trademark) Tablets 25 mg (an oral solid composition containing eltrombopag olamine, manufactured by Novartis Pharma KK). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] An embodiment of the present invention will be described in detail below. In this specification, unless otherwise specified, "A to B" indicating a numerical range means "A or more and B or less."

[0010] <1. Oral solid composition> An oral solid composition according to one embodiment of the present invention is an oral solid composition comprising eltrombopag olamine and one or more additives, wherein the eltrombopag olamine particles have a D 90 The one or more additives include anhydrous calcium hydrogen phosphate particles having a circularity of 0.80 or more and a surface of the anhydrous calcium hydrogen phosphate particles coated with hardened oil (hereinafter, also referred to as "hardened oil-coated anhydrous calcium hydrogen phosphate particles").

[0011] (Eltrombopag olamine) The oral solid composition according to one embodiment of the present invention contains eltrombopag olamine as an active ingredient. Eltrombopag olamine has the chemical name 3'-{(2Z)-2-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylate bis(2-aminoethanol) and the molecular formula C 25 H 22 It is a compound represented by the formula N4O4·2(C2H7NO). In this specification, eltrombopag olamine is sometimes referred to as the drug substance.

[0012] Eltrombopag olamine can be produced by known methods, such as the production method described in WO 03 / 098992.

[0013] Eltrombopag olamine is an agonist of the thrombopoietin (TPO) receptor, and is particularly useful in promoting platelet production (see Patent Document 1). Eltrombopag olamine is commercially available as Revolade (registered trademark) (manufactured by Novartis Pharma KK; hereinafter, referred to as "commercially available formulation").

[0014] (D of Eltrombopag Olamine Particles 90 and average particle size) In the oral solid composition according to one embodiment of the present invention, the eltrombopag olamine particles have a D 90 is less than 9 μm and the average particle size is less than 4 μm.

[0015] As used herein, the D 90 is the cumulative 90% diameter of the volume-based particle size distribution, and is a value measured by a wet method.

[0016] <Wet method> A predetermined amount of eltrombopag olamine particles is dispersed in a predetermined liquid to prepare a dispersion. The obtained dispersion is subjected to wet particle size distribution measurement using a laser diffraction particle size distribution measuring device to obtain a volume-based cumulative particle size distribution curve. In the obtained cumulative particle size distribution curve, the particle size value at 90% accumulation from the population is defined as the 90% cumulative volume particle size D90 (μm). As the laser diffraction particle size distribution measuring device, for example, a particle size distribution measuring device (Spectris, Inc., Mastersizer 3000) can be used.

[0017] In this specification, the average particle size is a value measured by a wet method. For example, about 0.1 g of eltrombopag olamine is weighed out and suspended in a saturated solution of eltrombopag olamine in hexane (1→1000) with a span of 80, and a suitable amount of this suspension is stirred while measuring the particle size distribution by a wet method.

[0018] Eltrombopag olamine particle D 90 By making the diameter of the particles of eltrombopag olamine less than 9 μm, the specific surface area is increased, improving the solubility and bioabsorption. In addition, a sharp distribution can be obtained, stabilizing the quality (for example, suppressing the variation in dissolution). 90 From the viewpoint of dissolution property and dissolution rate, the upper limit of is preferably less than 9 μm, 8.5 μm or less, 8.0 μm or less, 7.5 μm or less, 7.0 μm or less, 6.5 μm or less, 6.0 μm or less, 5.5 μm or less, or 5.0 μm or less. 90 The lower limit is not particularly limited, but from the viewpoint of particle aggregation, it is preferably 0.1 μm or more, 0.2 μm or more, 0.3 μm or more, 0.4 μm or more, 0.5 μm or more, 0.6 μm or more, or 0.7 μm or more.

[0019] In addition, the average particle size of eltrombopag olamine particles is less than 4 μm, so that the specific surface area is increased, and the solubility and bioabsorbability are improved.The upper limit of the average particle size of eltrombopag olamine particles is preferably less than 4 μm, 3.5 μm or less, 3.0 μm or less, 2.5 μm or less, 2.0 μm or less, 1.5 μm or less, or 1.0 μm or less, from the viewpoint of dissolution and dissolution rate.In addition, the lower limit of the average particle size of eltrombopag olamine particles is not particularly limited, but from the viewpoint of particle aggregation, it is preferably 0.1 μm or more, 0.2 μm or more, 0.3 μm or more, 0.4 μm or more, 0.5 μm or more, 0.6 μm or more, or 0.7 μm or more.

[0020] (Eltrombopag olamine content) The content of eltrombopag olamine contained in the oral solid composition according to one embodiment of the present invention is not particularly limited and can be appropriately set. For example, the content of eltrombopag olamine can be 5% by mass or more and 18% by mass or less based on the total mass of the oral solid composition.

[0021] (Additives) The oral solid composition according to one embodiment of the present invention includes one or more additives. The additives may be pharma-ceutically acceptable pharmaceutical additives. Examples of such additives include excipients, binders, disintegrants, lubricants, coating agents, surfactants, etc. The excipients are also called diluents.

[0022] In the oral solid composition according to one embodiment of the present invention, the one or more additives include hydrogenated oil-coated anhydrous calcium hydrogen phosphate particles. By including hydrogenated oil-coated anhydrous calcium hydrogen phosphate particles as an additive, it is possible to suppress aggregation of the fine powdered drug substance and improve the flowability.

[0023] (Hydrogenated oil-coated anhydrous calcium hydrogen phosphate particles) The hardened oil-coated anhydrous calcium hydrogen phosphate particles are anhydrous calcium hydrogen phosphate particles having a circularity of 0.80 or more, the surfaces of which are coated with hardened oil.

[0024] In the hardened oil-coated anhydrous calcium hydrogen phosphate particles, the coverage rate with hardened oil is not particularly limited, but in order to maintain a good angle of repose, for example, it is more preferable that 80% or more of the surface area of ​​the anhydrous calcium hydrogen phosphate particles is covered with hardened oil, and it is even more preferable that 90% or more of the surface area of ​​the anhydrous calcium hydrogen phosphate particles is covered with hardened oil. The coverage rate of the surface of the anhydrous calcium hydrogen phosphate particles with hardened oil can be confirmed by image analysis of the surface of the anhydrous calcium hydrogen phosphate particles using an electron microscope and elemental analysis.

[0025] The addition of hydrogenated oil-coated anhydrous calcium hydrogen phosphate particles has the following advantages. By adding hydrogenated oil as an additive, the aggregation of the finely powdered drug substance can be suppressed and the dispersibility of the finely powdered drug substance in the solvent can be improved. In addition, hydrogenated oil has low fluidity because of its irregular particle shape, particle size, etc. Therefore, when hydrogenated oil is added, the fluidity of the finely powdered drug substance tends to decrease. On the other hand, by forming a wax matrix in which the anhydrous calcium hydrogen phosphate particles are used as the core and the surface is covered with hydrogenated oil, the particle size becomes large and a lubricating effect is also obtained, so that the fluidity is improved compared to when hydrogenated oil is added. By adding this wax matrix, the aggregation of the finely powdered drug substance is suppressed in the mixed powder of this wax matrix and the finely powdered drug substance due to the lubricating effect of the wax matrix, the interaction between particles, etc., and as a result, the fluidity of the mixed powder is improved.

[0026] In this embodiment, an example in which the core of the wax matrix is ​​anhydrous calcium hydrogen phosphate particles has been described, but particles other than anhydrous calcium hydrogen phosphate particles may be used as the core of the wax matrix. Also, an additive containing a coordination metal other than anhydrous calcium hydrogen phosphate may be included as the core of the wax matrix. However, the anhydrous calcium hydrogen phosphate particles used in the present invention are porous, and hardened oil enters the pores during preparation, and they tend to be crushed during granulation and not become a powder with a broad particle size distribution, so they can be preferably used as the core of the wax matrix.

[0027] (anhydrous calcium hydrogen phosphate particles) Examples of anhydrous calcium hydrogen phosphate particles that can be used for the hardened oil-coated anhydrous calcium hydrogen phosphate particles include conventionally known anhydrous calcium hydrogen phosphate particles, which are spherical particles used as pharmaceutically acceptable pharmaceutical additives. Such anhydrous calcium hydrogen phosphate particles, which are spherical particles, have a circularity of 0.80 or more, preferably 0.85 or more, more preferably 0.90 or more, and can be, for example, those commercially available under the product name "Fujicalin" (manufactured by Fuji Chemical Industry Co., Ltd.). In this specification, the circularity is determined by measuring the minor axis and major axis of about 10 random particles from an image taken using a microscope (VHX-100, manufactured by Keyence Corporation), and averaging the values ​​derived from the ratio of minor axis / major axis. The anhydrous calcium hydrogen phosphate particles may be, for example, spherical granules obtained by spray drying anhydrous calcium hydrogen phosphate, but are not limited thereto. When the anhydrous calcium hydrogen phosphate particles are spherical particles with a circularity of 0.80 or more, the flowability of the fine powder drug substance is improved.

[0028] The anhydrous calcium hydrogen phosphate particles that can be used for the hardened oil-coated anhydrous calcium hydrogen phosphate particles may be spherical particles and may be porous. If the content of fine powdered drug substance in the oral solid composition is high, handling is poor in the formulation process, and there is a risk of tableting trouble occurring in the tableting process. The anhydrous calcium hydrogen phosphate particles are spherical particles with a roundness of 0.80 or more, and are porous, thereby improving moldability. The oral solid composition according to one embodiment of the present invention contains a predetermined amount of hardened oil-coated anhydrous calcium hydrogen phosphate particles as at least a part of the excipient, thereby reducing the risk of poor handling in the formulation process and tableting trouble occurring in the tableting process due to the inclusion of fine powdered drug substance.

[0029] (hardened oil) The hardened oil may be any of the hardened oils known in the art that are used as pharma- ceutically acceptable pharmaceutical additives. Examples of such hardened oils include hydrogenated castor oil (hydrogenated castor oil), hydrogenated rapeseed oil, and hydrogenated soybean oil. One type of hardened oil may be used alone, or two or more types may be used in combination. In addition, denaturation of the hardened oil due to high ambient temperatures is considered. In order to ensure the quality of pharmaceuticals, it is preferable to use hardened oils with as high a melting point as possible. Among these hardened oils, hydrogenated castor oil is preferable. As the hardened oil, for example, commercially available products such as "Lubriwax-101" (manufactured by Freund Corporation, hydrogenated castor oil) can be used.

[0030] When the oral solid composition according to one embodiment of the present invention contains a predetermined amount of hydrogenated oil as at least a part of the lubricant, aggregation of the finely powdered drug substance can be suppressed and the dispersibility of the finely powdered drug substance in a solvent can be improved.

[0031] (Content of anhydrous calcium hydrogen phosphate particles and hardened oil) The content of the anhydrous calcium hydrogen phosphate particles in the oral solid composition according to one embodiment of the present invention is not particularly limited, but from the viewpoint of reducing the risk of tableting failure during the tableting step, it is preferably 2% by mass or more, more preferably 3% by mass or more, and more preferably 10% by mass or less.

[0032] The content of the hardened oil in the oral solid composition according to one embodiment of the present invention is not particularly limited, but from the viewpoint of suppressing aggregation of the fine powdered drug substance, it is preferably 3.5% by mass or more, more preferably 6% by mass or more, and more preferably 60% by mass or less.

[0033] The oral solid composition according to one embodiment of the present invention may contain hardened oil and anhydrous calcium hydrogen phosphate particles that do not form hardened oil-coated anhydrous calcium hydrogen phosphate particles. The total content of the hardened oil and anhydrous calcium hydrogen phosphate particles that do not form hardened oil-coated anhydrous calcium hydrogen phosphate particles is preferably 20% by mass or less.

[0034] (Ratio of anhydrous calcium hydrogen phosphate particles to hardened oil) The ratio of the content of anhydrous calcium hydrogen phosphate particles to the content of hardened oil in the oral solid composition according to one embodiment of the present invention can be appropriately adjusted and is not particularly limited. The amount of anhydrous calcium hydrogen phosphate particles coated with hardened oil is preferably 80% or more, and the ratio of the content of anhydrous calcium hydrogen phosphate particles to the content of hardened oil in the oral solid composition according to one embodiment of the present invention is preferably 1:1.75 or more by mass ratio, more preferably 1:2 or more. In addition, if the content of hardened oil is too high relative to the content of anhydrous calcium hydrogen phosphate particles, the amount of wax matrix that does not have anhydrous calcium hydrogen phosphate particles in the core increases, so that the hydrophobic properties of the tablet are too high, water conduction to the tablet is poor, and the medicinal effect is reduced. Therefore, the ratio of the content of anhydrous calcium hydrogen phosphate particles to the content of hardened oil in the oral solid composition according to one embodiment of the present invention is preferably 1:6 or less by mass ratio, more preferably 1:4 or less.

[0035] (Method for preparing hardened oil-coated anhydrous calcium hydrogen phosphate particles) A method for producing hardened oil-coated anhydrous calcium hydrogen phosphate particles according to one embodiment of the present invention will be described below with reference to Fig. 1. Fig. 1 is a diagram for explaining an outline of a method for producing hardened oil-coated anhydrous calcium hydrogen phosphate particles according to one embodiment of the present invention. In Fig. 1, only one anhydrous calcium hydrogen phosphate particle 1 out of a plurality of anhydrous calcium hydrogen phosphate particles 1 is given a reference number, and the reference numbers of the other anhydrous calcium hydrogen phosphate particles 1 are omitted. The same applies to hardened oil 2 and hardened oil-coated anhydrous calcium hydrogen phosphate particles 10.

[0036] A predetermined amount of anhydrous calcium hydrogen phosphate particles 1 and a predetermined amount of hardened oil 2 are mixed and the resulting mixture is heat-treated to obtain hardened oil-coated anhydrous calcium hydrogen phosphate particles 10 in which the surfaces of the anhydrous calcium hydrogen phosphate particles 1 are covered with hardened oil 2. The heat treatment of the mixture can be carried out using a conventionally known shelf dryer or vacuum dryer. The heat treatment conditions can be appropriately set as long as the temperature is equal to or higher than the melting point of the hardened oil. For example, hydrogenated castor oil-coated anhydrous calcium hydrogen phosphate particles 10 can be obtained by heat treatment at 110°C for 60 minutes.

[0037] (Other additives)

[0038] The oral solid composition according to one embodiment of the present invention may contain additives other than the hydrogenated oil and the hydrogenated oil-coated anhydrous calcium hydrogen phosphate particles, if necessary, within a range that does not impair the effects of the present invention.

[0039] Examples of excipients other than the hardened oil-coated anhydrous calcium hydrogen phosphate particles include conventionally known excipients used as pharma-ceutically acceptable pharmaceutical additives. Examples of such excipients include crystalline cellulose, D-mannitol, lactose hydrate, and corn starch. The excipients other than the hardened oil-coated anhydrous calcium hydrogen phosphate particles may be used alone or in combination of two or more. The content of the excipients other than the hardened oil-coated anhydrous calcium hydrogen phosphate particles contained in the oral solid composition according to one embodiment of the present invention is not particularly limited and can be set appropriately. As an example, the content of the excipients other than the hardened oil-coated anhydrous calcium hydrogen phosphate particles can be 10% by mass or more and 80% by mass or less with respect to the total mass of the oral solid composition.

[0040] Examples of the binder include conventionally known binders used as pharmaceutical additives. Examples of such binders include polyvinylpyrrolidone (povidone), hydroxypropyl cellulose, hypromellose, methylcellulose, etc. The binder may be used alone or in combination of two or more. The content of the binder contained in the oral solid composition according to one embodiment of the present invention is not particularly limited and can be set appropriately. As an example, the content of the binder can be 0.5% by mass or more and 10% by mass or less with respect to the total mass of the oral solid composition.

[0041] The disintegrant may be a conventionally known disintegrant used as a pharmaceutical additive. Examples of such disintegrants include sodium starch glycolate, crospovidone, croscarmellose sodium, and carmellose calcium. The disintegrant may be used alone or in combination of two or more. The content of the disintegrant contained in the oral solid composition according to one embodiment of the present invention is not particularly limited and may be appropriately set. As an example, the content of the disintegrant may be 3% by mass or more and 12% by mass or less with respect to the total mass of the oral solid composition.

[0042] Examples of lubricants other than hydrogenated oil include conventional lubricants used as pharmaceutical additives. Examples of such lubricants include magnesium stearate, stearic acid, and sodium fumarate. The lubricants other than hydrogenated oil may be used alone or in combination of two or more. The content of the lubricant other than hydrogenated oil contained in the oral solid composition according to one embodiment of the present invention is not particularly limited and can be appropriately set. As an example, the content of the lubricant other than hydrogenated oil can be 0.5% by mass or more and 2% by mass or less with respect to the total mass of the oral solid composition.

[0043] Examples of the coating agent include conventionally known coating agents used as pharma- ceutically acceptable pharmaceutical additives. Examples of such coating agents include OPADRY (registered trademark) WHITE, hypromellose, and the like. The coating agent may be used alone or in combination of two or more. In addition to the coating base material, additives such as colorants, plasticizers, and surfactants that are usually blended into film coating agents may be included.

[0044] (Use of oral solid composition) The oral solid composition according to one embodiment of the present invention is a pharmaceutical composition. Since the oral solid composition according to one embodiment of the present invention contains eltrombopag olamine as an active ingredient, it is useful as an oral solid composition for treating thrombocytopenia, for example.

[0045] (Oral solid composition dosage form) The form (dosage form) of the oral solid composition according to one embodiment of the present invention is not particularly limited. Examples of oral solid compositions include tablets, granules, powders, etc. Among these, tablets are preferred. The tablets may be coated with a conventionally known coating agent. These may have ingredients, shapes, and sizes that are normally used in the pharmaceutical field, and there is no particular limit to the form.

[0046] (Method of producing oral solid composition) The method for producing the oral solid composition according to one embodiment of the present invention is not particularly limited. A method suitable for obtaining a desired dosage form can be selected from among conventionally known production methods in the art. For example, the oral solid composition according to one embodiment of the present invention is prepared by mixing the raw materials of the oral solid composition in a known mixer to obtain a mixture. Thereafter, the oral solid composition can be produced by directly compressing the mixture or compressing granules into tablets.

[0047] Since the drug substance is a fine powder, if it is used as it is, the content uniformity may decrease, so the method of compressing the granules into tablets is preferable. The method of producing the granules can be selected from known production methods such as dry granulation and wet granulation.

[0048] In the method for producing an oral solid composition according to one embodiment of the present invention, the hardened oil-coated anhydrous calcium hydrogen phosphate particles may be added at the stage of granulation (also called "internal addition"), or may be added at the stage of mixing with the granulated granules (also called "external addition").

[0049] The obtained granules can be compressed and tableted using a conventionally known tablet press (e.g., VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.) to produce a solid preparation. The oral solid composition according to one embodiment of the present invention contains hardened oil-coated anhydrous calcium hydrogen phosphate particles as an additive, which can suppress aggregation of the fine powdered drug substance and improve flowability. This can reduce the risk of tableting problems during the tableting process.

[0050] (Preferred Formulation of Oral Solid Composition) An oral solid composition according to one embodiment of the present invention comprises eltrombopag olamine and one or more additives, and the eltrombopag olamine particles have a D 90 Preferably, the oral solid composition has a mean particle size of less than 9 μm and a mean particle size of less than 4 μm, and the one or more additives comprise hardened oil-coated anhydrous calcium hydrogen phosphate particles. a) 5% or more and 18% or less by weight of eltrombopag olamine; b) 3.5% by mass or more and 60% by mass or less of hydrogenated oil; c) 2% by weight or more and 10% by weight or less of anhydrous calcium hydrogen phosphate particles; It is preferred that the compound contains

[0051] In addition, the one or more additives in the oral solid composition may further comprise: d) 10% by mass or more and 80% by mass or less of excipients other than the hydrogenated oil-coated anhydrous calcium hydrogen phosphate particles; e) 0.5% by weight or more and 10% by weight or less of a binder; f) 0.5% by weight or more and 2% by weight or less of a lubricant other than the hydrogenated oil; or g) 3% to 12% by mass of disintegrant The additives d) to g) may be included alone or in combination of two or more.

[0052] The present invention is not limited to the above-described embodiments, and various modifications are possible within the scope of the claims. Embodiments obtained by appropriately combining the technical means disclosed in the respective embodiments are also included in the technical scope of the present invention. EXAMPLES

[0053] [1. Raw materials] <Active ingredient> Eltrombopagulamine (Compound name: 3'-{(2Z)-2-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid bis(2-aminoethanol), D90: 4μm, average particle size: 2μm)

[0054] <Excipients> D-mannitol (Mitsubishi Corporation Life Sciences Co., Ltd., Mannit P) Crystalline cellulose (Asahi Kasei Corporation, PH-102) Crystalline cellulose (KG-802, Asahi Kasei Corporation) Anhydrous calcium hydrogen phosphate (Fuji Chemical Industry Co., Ltd., Fujicalin, porous spherical granules, roundness: 0.90)

[0055] <Binding agent> Povidone K30 (Iifutact, manufactured by Daiichi Kogyo Seiyaku Co., Ltd.)

[0056] <Disintegrant> Sodium starch glycolate (Primogel, manufactured by DFE Pharma Co., Ltd.)

[0057] <Lubricant> Hydrogenated castor oil (Freund Corporation, Lubriwax-101) Magnesium stearate (Magnesium stearate-S, manufactured by NOF Corporation)

[0058] <Film Coating (FC)) OPADRY (registered trademark) WHITE (manufactured by Japan Colorcon LLC)

[0059] 2. Preparation of hydrogenated castor oil-coated anhydrous calcium hydrogen phosphate particles Anhydrous calcium hydrogen phosphate particles covered with hydrogenated castor oil (see hydrogenated castor oil-coated anhydrous calcium hydrogen phosphate particles 10 in FIG. 1) were obtained by a heat melting method at 110° C. for about 1 hour using a dryer (VAC-200PR, manufactured by Espec Corporation). In this embodiment, the mixture of hydrogenated castor oil and anhydrous calcium hydrogen phosphate particles before heat treatment is sometimes referred to as the "wax matrix before heat treatment", and the anhydrous calcium hydrogen phosphate particles covered with hydrogenated castor oil after heat treatment is sometimes referred to as the "wax matrix after heat treatment" or simply as the "wax matrix".

[0060] [3. Particle size distribution measurement] <Preparation of test samples> Approximately 31.8 mg of the drug substance (eltrombopag olamine) was taken and dispersed in the second fluid for the dissolution test to prepare a dispersion liquid for Sample 1. In addition, approximately 31.8 mg of the drug substance (eltrombopag olamine) was taken and mixed with approximately 24 mg of hydrogenated castor oil, and dispersed in the second fluid for the dissolution test to prepare a dispersion liquid for Sample 2.

[0061] (Dissolution test second fluid) Water <100% by mass Disodium hydrogen phosphate 0.18% by mass Potassium dihydrogen phosphate 0.17% by mass <Test Method> For each dispersion, the particle size distribution (D 10 , D50 , D 90 ) was measured by a wet method using a particle size distribution measuring device (Mastersizer 3000, manufactured by Spectris Corporation).

[0062] The results are shown in Table 1. As shown in Table 1, in sample 1, which contains only the drug substance, the original D 90 4μm drug substance in solvent D 90 In contrast, sample 2, which contained hydrogenated castor oil, had a particle size of about 870 μm. 90 The particle size was approximately 316 μm. It was found that the addition of hydrogenated castor oil suppressed aggregation of the active pharmaceutical ingredient. [Table 1]

[0063] [4. Fluidity test] The angle of repose was measured as an index of flowability.

[0064] <Preparation of test samples> Only hydrogenated castor oil was used, which was designated as Sample 3. 100g of anhydrous calcium hydrogen phosphate was taken, 200g of hydrogenated castor oil was added, and mixed to prepare powder for Sample 4. Also, 100g of anhydrous calcium hydrogen phosphate was taken, 200g of hydrogenated castor oil was added, and the mixture was heated and melted at 110°C for about 1 hour using a dryer (Espec Corporation, VAC-200PR), and then granulated to prepare powder for Sample 5.

[0065] <Test Method> The angle of repose of each powder was measured using a powder tester (PT-R, manufactured by Hosokawa Micron Corporation).

[0066] The results are shown in Table 2. The angle of repose is an index of fluidity. As shown in Table 2, by adding the wax matrix after heat treatment, the angle of repose of the powder became 35°, which indicates that the fluidity was improved. [Table 2]

[0067] Formulations 1 and 2 were produced on a 500 g scale according to the following manufacturing method. 5. Formulations and Preparations (Formulation 1) Formulation 1 was prepared according to Formulation 1 shown in Table 3. In Formulation 1, a wax matrix was added during granulation. Specifically, hydrogenated castor oil and anhydrous calcium hydrogen phosphate were mixed, heated and melted at 110°C for about 1 hour using a dryer (VAC-200PR, manufactured by Espec Corporation), and then allowed to stand at room temperature to solidify. The solidified wax matrix was crushed by granulation to obtain a wax matrix. Next, crystalline cellulose (PH-102), D-mannitol (Mannit-P), povidone K30 (Eiftact) and the wax matrix were charged into a high-speed stirring granulator (LFS-GS-1J, manufactured by Fukae Kogyo Co., Ltd.) and premixed. Next, eltrombopag olamine was added as the drug substance and mixed. Furthermore, 12% purified water was added relative to the mass of the internal additive, and wet granulation was performed and discharged. The obtained granules were dried at 70°C for about 1 hour using a fluidized bed dryer (Powrex FD-MP-01), and then sized using a granulator (NARA MACHINERY MFG. CO., LTD. SAMF:10V1TYPE). Then, crystalline cellulose (PH-102), crystalline cellulose (KG-802), and sodium starch glycolate (Primogel) were added and mixed. Finally, magnesium stearate was added and mixed to obtain tablet powder. The obtained tablet powder was compressed using a tablet press to obtain uncoated tablets. The obtained uncoated tablets were film-coated to obtain FC tablets.

[0068] (Formulation 2) Formulation 2 was prepared according to Formulation 2 shown in Table 3. In Formulation 2, the wax matrix prepared by the method described in Formulation 1 was added externally. Specifically, crystalline cellulose (PH-102), D-mannitol (Mannit-P), and povidone K30 (Eiftact) were charged into a high-speed stirring granulator (Fukae Kogyo Co., Ltd. LFS-GS-1J) and premixed. Next, eltrombopag olamine was added as the drug substance and mixed. Furthermore, 18% purified water was added to the mass of the internally added additives, and wet granulation was performed and discharged. The obtained granulated granules were dried at 70 ° C. for about 1 hour using a fluidized bed dryer (Powrex Corporation FD-MP-01), and then granulated using a granulator (NARA Machinery Manufacturing Co., Ltd. SAMF: 10V1 TYPE). Then, crystalline cellulose (PH-102), crystalline cellulose (KG-802), sodium starch glycolate (Primogel) and the wax matrix were added and mixed. Finally, magnesium stearate was added and mixed to obtain tablet powder. The obtained tablet powder was compressed using a tablet press to obtain uncoated tablets. The obtained uncoated tablets were then film-coated to obtain FC tablets. [Table 3]

[0069] [6. Comparison of dissolution behavior] The dissolution profiles of Formulations 1 and 2 were compared with that of a commercially available 25 mg formulation (Revolade (registered trademark) tablets 25 mg).

[0070] <Test Method> The test was performed using 900 mL of test solution (0.5% polysorbate 80 dissolution test second solution (pH 6.8)) by the paddle method at the specified paddle rotation speed (50 rpm). One formulation 1 was taken and the test was started. At the specified time, 10 mL of the dissolution solution was taken and filtered through a hydrophilic PTFE membrane filter unit with a pore size of 0.45 μm. The first 5 mL of filtrate was removed and the next filtrate was used as the sample solution. Separately, about 18 mg of eltrombopag olamine for quantitative analysis was precisely weighed and dissolved in methanol to make exactly 100 mL. 10 mL of this solution was precisely weighed and the test solution was added to make exactly 50 mL to use as the standard solution. The sample solution and standard solution were tested by ultraviolet-visible absorbance measurement under the following conditions, and the absorbance A of eltrombopag in each solution was measured. T and A S was measured.

[0071] <Test conditions> UV-visible spectrophotometer (measurement wavelength: 420nm) Cell length: 1cm Cell capacity: 1.5~3.0mL Control solvent: Test solution The equivalent amount of eltrombopag was calculated using the following formula. Eltrombopag equivalent amount (mg) = Weighed amount of eltrombopagolamine (mg) × (100 - 2-aminoethanol content (%)) / 100

[0072] In addition, eltrombopag (C 25 H 22 The concentration of N4O4 was calculated using the following formula (1): Eltrombopag (C 25 H 22 Concentration of N4O4 (μg / mL) = M S ×A T / A S / 500 ··· (1) M S :Equivalent amount of eltrombopag (mg)

[0073] In addition, Eltrombopag (C 25 H 22The elution rate of N4O4) relative to the indicated amount was calculated using the following formula (2).

number

[0074] The results of the above test, and the results of measurements when Formulation 2 and the commercially available 25 mg formulation were used instead of Formulation 1 in the above test method, are shown in Table 4 and Figure 2. Figure 2 shows the results of a comparison of the dissolution profiles of Formulation 1, Formulation 2 and the commercially available 25 mg formulation. [Table 4]

[0075] As shown in Table 4 and FIG. 2, the dissolution profiles of Formulations 1 and 2 were comparable to those of the commercially available formulation 25 mg. [Industrial Applicability]

[0076] The present invention can provide a technique for suppressing aggregation of a finely powdered drug substance and improving the flowability. [Explanation of symbols]

[0077] 1. Anhydrous calcium hydrogen phosphate particles 2 Hydrogenated oil 10. Hardened oil-coated anhydrous calcium hydrogen phosphate particles

Claims

1. An oral solid composition comprising eltrombopag olamine and one or more excipients, The eltrombopag olamine particles are ９０ is less than 9 μm and the average particle size is less than 4 μm; The oral solid composition, wherein the one or more additives include anhydrous calcium hydrogen phosphate particles having a circularity of 0.80 or more and the surface of the particles is coated with hardened oil.

2. The one or more additives are 10% by mass or more and 80% by mass or less of anhydrous calcium hydrogen phosphate particles having a circularity of 0.80 or more, other than particles the surfaces of which are coated with hardened oil; 0.5% by weight or more and 10% by weight or less of a binder; 0.5% by mass or more and 2% by mass or less of a lubricant other than the hydrogenated oil; and 3% by mass or more and 12% by mass or less of a disintegrant 2. The oral solid composition of claim 1, wherein the oral solid composition is one or more selected from the group consisting of:

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