Nintedanib ethanesulfonate-containing capsule preparation

Abstract

To provide a capsule preparation and a method for producing the capsule preparation, having excellent elution properties of nintedanib ethanesulfonate and capable of retaining nintedanib ethanesulfonate in a stable form condition over an extended period.SOLUTION: Provided is a capsule preparation comprising a capsule content solution coated with a capsule shell, the capsule content solution containing nintedanib ethanesulfonate, medium chain fatty acid triglycerides, hard fat, and a specific surfactant.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a capsule formulation containing nintedanib ethanesulfonate, and more specifically, to a capsule formulation in which a capsule content liquid containing nintedanib ethanesulfonate, a medium-chain fatty acid triglyceride, hard fat, and a surfactant is encapsulated in a capsule shell. [Background technology]

[0002] Nintedanib ethanesulfonate was approved by the U.S. Food and Drug Administration (FDA) in 2014 as the first drug for the treatment of idiopathic pulmonary fibrosis (IPF).

[0003] Formulations containing nintedanib ethanesulfonate include formulations containing a suspension of nintedanib ethanesulfonate (see, for example, Patent Document 1), pharmaceutical dosage forms that provide an immediate release profile in which 70% or more of nintedanib ethanesulfonate dissolves within 60 minutes in vitro (see, for example, Patent Document 2), and pharmaceutical dosage forms that are involved in angiogenesis and contain nintedanib ethanesulfonate, medium-chain triglycerides, soy lecithin, cholesterol, glycerin, benzalkonium chloride, and vitamin E. and a pharmaceutical composition comprising (1) nintedanib, or (2) nintedanib and an agent selected from the group consisting of an antimetabolite selected from the group consisting of mitomycin C, 5-fluorouracil, and thiotepa, for use in inducing pterygium regression from the visual axis / center of the cornea in an affected eye, stabilizing pterygium in an affected eye, or reducing the rate of pterygium growth in an affected eye (see, for example, Patent Document 4). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Special Publication No. 2011-522812 [Patent Document 2] Special Publication No. 2011-522010 [Patent Document 3] Special Publication No. 2019-534870 [Patent Document 4] Patent No. 6868014 Summary of the Invention [Problem to be solved by the invention]

[0005] The object of the present invention is to provide a capsule formulation that has excellent dissolution properties of nintedanib ethanesulfonate and can contain nintedanib ethanesulfonate in a stable state for a long period of time, and a method for producing such a capsule formulation.

[0006] As a result of extensive research aimed at solving the above problems, the inventors discovered that by using a specific surfactant, it is possible to produce a capsule formulation which has excellent dissolution properties and contains nintedanib ethanesulfonate in a stable state for a long period of time, and thus completed the present invention.

[0007] That is, the present invention is as follows. [1] A capsule formulation in which the capsule content liquid containing nintedanib ethanesulfonate, medium-chain triglyceride, hard fat, and a surfactant is coated with a capsule shell. [2] The capsule formulation according to [1] above, wherein the surfactant is one or more selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polysorbate, polyoxyl stearate, and sorbitan sesquioleate. [3] The capsule formulation according to [1] or [2] above, in which the dissolution rate of nintedanib ethanesulfonate is 93% or more after 30 minutes. [4] The capsule formulation according to [1] or [2] above, in which the dissolution rate of nintedanib ethanesulfonate is 94% or more after 10 minutes. [5] A capsule formulation according to the above [1] or [2], in which the dissolution rate of nintedanib ethanesulfonate is 95% or more after 5 minutes.

[0008] The present invention is also as follows. [6] A method for producing a capsule comprising the following steps (a) to (d). (a) mixing a medium chain triglyceride, a hard fat, and a surfactant to prepare an additive mixture; (b) allowing the additive mixture to cool; (c) adding nintedanib ethanesulfonate to the cooled additive mixture and stirring to prepare a capsule content; (d) encapsulating the capsule content liquid into the capsule shell; Effect of the Invention

[0009] According to the capsule formulation of the present invention, nintedanib ethanesulfonate has excellent dissolution properties and can be stored in a stable state for a long period of time. [Brief description of the drawings]

[0010] [Figure 1] This graph shows the results of a dissolution test on a hard capsule filled with a capsule content liquid containing 43% nintedanib ethanesulfonate as the active ingredient, 38.26% medium-chain triglyceride, 18.17% hard fat, and 0.56% each of the following surfactants: polyoxyl 35 castor oil (A1), polyoxyethylene hydrogenated castor oil 60 (B1), polysorbate 60 (C1), and sorbitan sesquioleate (M1), compared with existing products containing lecithin. [Diagram 2] This graph shows the results of a dissolution test for capsules filled into hard capsules with a capsule content liquid containing 43% nintedanib ethanesulfonate as the active ingredient, medium chain fatty acid triglyceride, and hard fat in the proportions shown in Table 3, and 0.56% ((A1) and (A'1)) or 2.71% ((A5) and (A'5)) polyoxyl 35 castor oil as a surfactant. [Diagram 3]This graph shows the results of a dissolution test for capsules filled into hard capsules with a capsule content liquid containing 43% nintedanib ethanesulfonate as the active ingredient, medium-chain fatty acid triglyceride, and hard fat in the proportions shown in Table 4, and 0.56% (B1 and B'1) or 2.71% (B5 and B'5) of polyoxyethylene hydrogenated castor oil 60 as a surfactant. [Figure 4] This graph shows a comparison of the results of dissolution tests on capsules filled with capsule content liquid containing 43% nintedanib ethanesulfonate as the active ingredient, medium-chain fatty acid triglycerides, and hard fats in the proportions shown in Table 5, and 0.56% (C1 and C'1) or 2.71% (C5 and C'5) of polysorbate 60 as a surfactant, with existing products containing lecithin. [Diagram 5] This graph shows the results of a dissolution test for a hard capsule filled with a capsule content liquid containing 43% nintedanib ethanesulfonate as the active ingredient, 37.05% medium-chain triglyceride, 17.45% hard fat, and 2.49% each of polysorbate 80 (D5), polyoxyl 40 stearate (E5), sorbitan sesquioleate (M5), glyceryl monostearate (O5), Sunfat GDO-DV (P5), and lauromacrogol (G5) as surfactants. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The capsule formulation of the present invention is not particularly limited as long as it is a capsule formulation in which a capsule content liquid containing nintedanib ethanesulfonate, a medium-chain fatty acid triglyceride, hard fat, and a surfactant is encapsulated in a capsule shell, and the above capsule formulation, using nintedanib ethanesulfonate as an active ingredient, can be used for purposes such as the treatment of interstitial lung disease accompanied by progressive fibrosis, idiopathic pulmonary fibrosis, and interstitial lung disease accompanied by systemic sclerosis.

[0012] Nintedanib Ethanesulfonate in the present invention, i.e., Methyl(3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate monoethanesulfonate, is the first compound approved as a drug for the treatment of idiopathic pulmonary fibrosis (IPF), and can be prepared by known methods or can be obtained by purchasing a commercially available product.

[0013] The content of nintedanib ethanesulfonate in the capsule content liquid is not particularly limited, but may be, for example, 30 to 80% by mass, preferably 35 to 70% by mass, and more preferably 40 to 60% by mass in the capsule content liquid.

[0014] The surfactant is not particularly limited as long as it can achieve the effects of the present invention, and preferred examples include nonionic surfactants such as polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polysorbate, polyoxyl stearate, sorbitan sesquioleate, etc. The blending ratio of these surfactants in the capsule content liquid is usually 0.3% to 5%.

[0015] The polyoxyethylene castor oil is a nonionic surfactant obtained by addition polymerization of ethylene oxide to castor oil, and may be a pale yellow to yellow viscous liquid, or a vaseline-like or wax-like substance. A preferred example is polyoxyl 35 castor oil, which has an average molar number of ethylene oxide added of about 35.

[0016] The blending ratio of the polyoxyl castor oil in the capsule content liquid can be 0.3 to 5 mass %, for example, 0.4 to 4 mass %, and more preferably 0.5 to 3.5 mass %.

[0017] The polyoxyethylene hydrogenated castor oil can be a nonionic surfactant obtained by addition polymerization of ethylene oxide to hydrogenated castor oil obtained by adding hydrogen to castor oil. Various commercially available products are provided according to the average degree of polymerization of ethylene oxide, such as polyoxyethylene (20) hydrogenated castor oil (NIKKOL HCO-20), polyoxyethylene (40) hydrogenated castor oil (NIKKOL HCO-40), polyoxyethylene (50) hydrogenated castor oil (NIKKOL HCO-50), polyoxyethylene (60) hydrogenated castor oil (NIKKOL HCO-60), and polyoxyethylene (100) hydrogenated castor oil (NIKKOL HCO-100) (all manufactured by Nikko Chemicals Co., Ltd.), with polyoxyethylene (60) hydrogenated castor oil (hereinafter also referred to as "polyoxyethylene hydrogenated castor oil 60") being preferred.

[0018] The blending ratio of the polyoxyethylene hydrogenated castor oil in the capsule content liquid can be 0.3% to 5%, for example, 0.4 to 4 mass%, preferably 0.5 to 3.5 mass%, more preferably 1.5 to 3.25 mass%, and particularly preferably 2.3 to 3.0 mass%.

[0019] The polysorbate may be a nonionic surfactant obtained by reacting a sorbitan fatty acid ester with ethylene oxide, and examples thereof include polysorbate 60 (polyoxyethylene sorbitan monostearate (Tween (registered trademark) 60)), polysorbate 80 (polyoxyethylene sorbitan oleate (Tween (registered trademark) 80)), polysorbate 85 (polyoxyethylene sorbitan trioleate (20E.O.)), etc., with polysorbate 60 and polysorbate 80 being preferred, and polysorbate 60 being particularly preferred.

[0020] The blending ratio of the polysorbate in the capsule content liquid can be 0.3% to 5%, for example, 0.4 to 4 mass %, preferably 0.5 to 3.5 mass %, more preferably 1.5 to 3.25 mass %, and particularly preferably 2.3 to 3.0 mass %.

[0021] The polyoxyl 40 stearate is a monoester obtained by esterifying stearic acid with ethylene oxide (40 moles), and examples of such surfactants include those classified as ethylene oxide condensed polyoxyethylene fatty acid esters.

[0022] The blending ratio of the polyoxyl 40 stearate in the capsule content liquid is 1.5 to 3.5% by mass, for example, and more preferably 2.3 to 3.0% by mass.

[0023] The sorbitan sesquioleate esters are sorbitan fatty acid esters obtained by esterifying some of the hydroxyl groups of sorbitol anhydride with oleic acid, and include nonionic surfactants which are mixtures of monoesters and diesters.

[0024] The blending ratio of the sorbitan sesquioleate in the capsule content liquid is, for example, 1.5 to 3.5% by mass, and more preferably 2.3 to 3.0% by mass.

[0025] Medium chain triglycerides (MCT) include triglycerides in which one molecule of glycerol is ester-bonded with three molecules of medium chain fatty acid, and the medium chain fatty acid includes saturated fatty acids having 6 to 12 carbon atoms, preferably 8 to 12 carbon atoms, such as caprylic acid, capric acid, and lauric acid. Examples of the medium chain triglycerides include caprylic acid triglyceride, capric acid triglyceride, a mixture of triglycerides of caprylic acid and capric acid, and a mixture of triglycerides of caprylic acid, capric acid, and lauric acid, and particularly preferably tri(caprylic acid / capric acid)glyceryl.

[0026] The blending ratio of the medium-chain fatty acid triglyceride in the capsule content liquid is, for example, 30 to 50% by mass, and preferably 35 to 40% by mass.

[0027] The hard fat may be a triglyceride of saturated fatty acid [CH3(CH2)nCOOH, n is 6 to 18] or a mixture thereof, which is a white to pale yellow waxy solid at room temperature. Grades including monoglycerides and diglycerides may also be used, and a suitable example of the hard fat is tri(caprylic acid / capric acid / myristic acid / stearic acid)glyceryl.

[0028] The blending ratio of the hard fat in the capsule content liquid is, for example, 8% to 20% by mass, more preferably 9 to 19% by mass, further preferably 9.5 to 18% by mass, and particularly preferably 10 to 12% by mass.

[0029] The capsule content liquid in the present invention may further contain other substances such as taste-imparting agents such as sweeteners, flavorings, dissolution aids, and viscosity adjusters.

[0030] The method for preparing the capsule content liquid includes first mixing a medium-chain fatty acid triglyceride, a hard fat, and a surfactant, and heating the mixture to 60 to 80°C, preferably 65 to 75°C, and more preferably 68 to 72°C; or mixing a medium-chain fatty acid triglyceride and a hard fat, and heating the mixture to 60 to 80°C, preferably 65 to 75°C, and more preferably 68 to 72°C to prepare a heated mixture, and adding a surfactant to the heated mixture and stirring the mixture; to prepare an additive mixture. Next, any of the additive mixtures described above is allowed to cool to room temperature, and the capsule content liquid can be prepared by adding nintedanib ethanesulfonate, which is the drug substance (active ingredient), and stirring the mixture.

[0031] The capsule formulation of the present invention is a pharmaceutical formulation in which the dissolution of the active ingredient nintedanib ethanesulfonate from the capsule formulation in gastric juice is promoted. For example, when a dissolution test is conducted using a method conforming to the general test dissolution test of the 18th Edition of the Japanese Pharmacopoeia, the dissolution rate of nintedanib ethanesulfonate is preferably 95% or more 30 minutes after the start of the test, more preferably 98% or more after 30 minutes, even more preferably 95% or more after 10 minutes, and particularly preferably 95% or more after 5 minutes.

[0032] The dissolution rate of the capsule formulation of the present invention is not particularly limited as long as it is calculated by a method for testing the dissolution of the main ingredient with the aim of ensuring a certain level of quality of the solid formulation for internal use, and examples thereof include a method for calculating the dissolution rate of nintedanib ethanesulfonate in a test solution using an ultraviolet-visible spectrophotometer or liquid chromatography, and specific examples thereof include the paddle method of dissolution test in the general test method of the Japanese Pharmacopoeia, 18th Edition, and the European Pharmacopoeia 6.2.

[0033] The method of calculating the dissolution rate according to the paddle method of the Japanese Pharmacopoeia Dissolution Test, 18th Edition, can be performed in 900 mL of 0.1 mol / L hydrochloric acid at 37±0.5° C. with a paddle rotation speed of 50 rpm to 200 rpm, etc., and a sinker can be used if the sample floats. The dissolution rate of the capsule formulation of the present invention can be evaluated by sampling at 5 minutes, 10 minutes, 15 minutes, 30 minutes, and 60 minutes, calculating the dissolution rate of nintedanib ethanesulfonate at each sampling time when a dissolution test is performed, and comparing the dissolution rates of each test sample.

[0034] The outline of the dissolution test according to European Pharmacopoeia 6.2 is as follows: It can be carried out using an additive-free dissolution medium of 0.1 M HCl, pH 1.0, 37°C, using European Pharmacopoeia 6.2 Apparatus 2 (paddle), optionally using a sinker, optionally in the presence of surfactants and / or enzymes, optionally in the presence of organic solvents, or using normal simulated intestinal or gastric fluid, using European Pharmacopoeia 6.2 Apparatus 1 or 2, pH 1 to 6.8, dissolution medium having a volume of 500 to 2000 mL, at a stirring speed of 50 rpm to 150 rpm.

[0035] An example of a method for producing the capsule formulation of the present invention includes the following steps. (a) mixing MCT, hard fat and a surfactant and heating to prepare an additive mixture; (b) allowing the additive mixture to cool; (c) adding nintedanib ethanesulfonate to the cooled additive mixture and stirring to prepare a capsule content; (d) encapsulating the capsule content liquid into the capsule shell;

[0036] Alternatively, as described below, MCT and hard fat can be heated to prepare a heated mixture, and then a surfactant can be added to the heated mixture to prepare an additive mixture. (a) preparing a heated mixture by heating MCT and hard fat; (b) adding a surfactant to the heated mixture to form an additive mixture; (c) allowing the additive mixture to cool; (d) adding nintedanib ethanesulfonate to the cooled additive mixture and stirring to prepare a capsule content; (e) encapsulating the capsule content liquid into the capsule shell;

[0037] When the capsule formulation according to the present invention is a hard capsule formulation, the capsule content liquid can be enclosed in the capsule shell by filling the capsule content liquid into the body of a preformed capsule body and sealing it with a cap, which can be performed using a liquid hard capsule filling machine. Also, sealing can be performed after sealing the body with a cap to prevent leakage of the content liquid.

[0038] When the capsule formulation of the present invention is a hard capsule formulation, the base material constituting the hard capsule can be a known one, and examples thereof include one or more selected from vegetable polysaccharides such as pullulan and carrageenan, cellulose derivatives such as cellulose and hydroxypropylmethylcellulose (HPMC), gelatins such as gelatin, alkali-treated gelatin, and acid-treated gelatin, etc. The shape of the hard capsule is not particularly limited, and examples thereof include known shapes composed of a body and a cap.

[0039] When the capsule preparation of the present invention is a soft capsule preparation, the capsule shell enclosing the capsule content liquid is preferably a capsule membrane, which may be either a hydrophobic membrane or a hydrophilic membrane, but is preferably a hydrophilic membrane.

[0040] The base material constituting the hydrophilic coating is not particularly limited as long as it is one that is commonly used as a coating for soft capsule preparations, and examples thereof include gelatins such as gelatin, succinylated gelatin, acid-treated gelatin, and alkali-treated gelatin, carrageenan, agar, sodium alginate, pullulan, glucomannan, gum arabic, furcellaran, Eucheuma algae, gellan gum, guar gum, locust bean gum, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, and starches such as starch, modified starch, processed starch, and starch hydrolysates, and a combination of two or more of these hydrophilic polymers are preferred.

[0041] In addition to the base, the components of the hydrophilic coating may further include plasticizers such as glycerin, sorbitol, propylene glycol, and polyethylene glycol, light-shielding agents such as titanium dioxide, pH adjusters such as sodium phosphate, chelating agents such as trisodium citrate and sodium metaphosphate, gelation promoters such as calcium lactate and potassium chloride, surfactants such as polyglycerol fatty acid esters and lecithin, tasters, sweeteners, fragrances, preservatives, colorants, pH adjusters, dissolution aids, and the like.

[0042] When the capsule formulation of the present invention is a soft capsule formulation, the method for encapsulating the capsule content liquid in a capsule shell can be a method for covering the capsule content liquid with a membrane. Examples of the method for covering the capsule content liquid with a membrane include a known method such as a flat plate method, a rotary die method in which the content liquid is filled between two membrane sheets while being molded and punched out, and a seamless method in which a seamless capsule is produced by a dropping method using a nozzle.

[0043] The present invention will be specifically described below by way of examples, but the present invention is not limited to these examples in any way. EXAMPLES

[0044] [Example 1] [Preparation of capsule contents] (Test materials and abbreviations) Nintedanib ethanesulfonate (Glenmark Life Sciences) was used as the drug substance. The raw materials used for the formulation study of the capsule content liquid containing the drug substance are shown in Table 1 below.

[0045] [Table 1]

[0046] [Dissolution rate study 1] (Preparation of Capsule Contents 1) As shown in Table 2, Miglyol (registered trademark) 812N, an ester oil in which a mixed fatty acid of caprylic acid and capric acid is combined with glycerin, was used as a medium chain triglyceride (MCT) and added to a final concentration of 38.26%, and Sotfisan-378 was used as a hard fat and added to a final concentration of 18.17 mass%, and a heated mixture was prepared by heating and mixing on a hot plate set at 70 ° C. As surfactants, polyoxyl 35 castor oil (A1), polyoxyethylene hydrogenated castor oil 60 (B1), polysorbate 60 (C1), and sorbitan sesquioleate (M1) were each added to the above heated mixture to a final concentration of 0.56%, and heated and mixed at 70 ° C. to prepare an additive mixture. The additive mixture was allowed to cool, and then the drug substance nintedanib ethanesulfonate was added to the additive mixture so that the final concentration was 43%, and the mixture was stirred to prepare four types of capsule content solutions for investigation, as shown in Table 2 below. Note that the blending ratio (%) here is by mass%.

[0047] [Table 2]

[0048] (Filling capsule contents) The capsule contents for each study were filled by filling 0.2 g of each content into Japanese Pharmacopoeia hard capsules (gelatin) No. 3 (Kobayashi Capsules) to obtain four types of test capsule formulations. Each test capsule formulation was subjected to a dissolution test according to the procedure described below. The results are shown in Figure 1.

[0049] (Dissolution test) From here on, for each test formulation used in the study of dissolution rate, the dissolution rate of nintedanib ethanesulfonate from each test formulation was calculated according to the following procedure.

[0050] According to the paddle method of the dissolution test of the Japanese Pharmacopoeia, 18th Edition, each test capsule formulation was placed in a sinker and submerged in the test liquid (900 mL of 0.1 mol / L hydrochloric acid), and the dissolution test was initiated by stirring at 37°C with a paddle rotation speed of 100 rpm.

[0051] After the start of the dissolution test, the sample solution corresponding to each test capsule was sampled 5, 10, 15, 30, and 60 minutes later. At each sampling time, about 10 mL of sample solution was collected from each vessel. The sample solution collected was filtered using a 0.45 μm pore size RC or PTFE syringe filter, the initial flow of 3 mL was discarded, and the remaining liquid was taken exactly 1 mL, and the test liquid was added to make exactly 10 mL, and each 10 mL of sample solution for measurement was used.

[0052] Separately, approximately 19.2 mg of nintedanib ethanesulfonate was precisely weighed out and dissolved in the test solution to make exactly 20 mL. 2 mL of this solution was precisely taken and the test solution was added to make exactly 200 mL to prepare the standard solution.

[0053] Each measurement sample solution and the above standard solution were used as specimens, and the absorption spectrum was measured at wavelengths of 200-600 nm and then 300-400 nm using an ultraviolet-visible spectrophotometer, and it was confirmed that the absorption maximum was observed around 386.5 nm. The concentration of nintedanib ethanesulfonate in the measurement sample solution was calculated from the absorbance at 386.5 nm of each measurement sample solution and the above standard solution, and the dissolution rate at each sampling point was calculated using the theoretical content per capsule. The results are shown in Figure 1.

[0054] (result) As is clear from Fig. 1, the hard capsule preparations containing the capsule content liquid containing polyoxyl 35 castor oil (A1), polyoxyethylene hydrogenated castor oil 60 (B1), or polysorbate 60 (C1) showed good dissolution rates, reaching nearly 100% after 30 minutes, and among them, the dissolution rate of polyoxyl 35 castor oil (A1) was high. On the other hand, the dissolution rate of the capsule preparation (M1) containing the capsule content liquid containing sorbitan sesquioleate after 30 minutes was low at 50%.

[0055] [Dissolution rate study 2] (Preparation of Capsule Contents 2) Polyoxyl 35 castor oil, which had given good results in Example 1 above, was selected as the surfactant, and the blending ratio was changed for further investigation.

[0056] As shown in Table 3, the above Miglyol 812N was added to the additive mixture at a final concentration of 38.26% (A1), 36.81% (A5), 45.15% (A'1) or 43.43% (A'5), and the above Sotfisan-378 was added to the heated mixture at a final concentration of 18.17% (A1), 17.48% (A5), 11.29% (A'1) or 10.86% (A'5), and heated and mixed at 70 ° C to prepare an additive mixture. The above polyoxyl 35 castor oil was added to the heated mixture at a final concentration of 0.56% (A1 and A'1) or 2.71% (A5 and A'5), and heated and mixed at 70 ° C to prepare an additive mixture. Four types of capsule content liquids for examination were prepared by adding nintedanib ethanesulfonate to the additive mixture in the same manner as in the preparation 1 of the capsule content liquid. In addition, in A1 and A5, the MCT:hard fat ratio was approximately 2.1:1, and in A'1 and A'5, the MCT:hard fat ratio was approximately 4:1.

[0057] [Table 3]

[0058] (Filling capsule contents) The above four types of capsule content liquids for investigation were filled into hard capsules in the same manner as in Example 1 to obtain four types of test capsule formulations. Each test capsule formulation was subjected to a dissolution test in accordance with the above procedure. The results are shown in Figure 2, and the values ​​of the dissolution rates after 30 minutes are shown in Table 4.

[0059] [Table 4]

[0060] (result) As is clear from Table 4 and Figure 2, the dissolution rate after 30 minutes was 93% or more in all the test capsule formulations, which showed good dissolution rates. Among them, the dissolution rate of A'1, which contains 0.56% polyoxyl 35 castor oil, 45.15% MCT, and 11.29% hard fat, was 80% or more after 10 minutes.

[0061] [Dissolution rate study 3] (Preparation of Capsule Contents 3) Polyoxyethylene hydrogenated castor oil 60, which had given good results in Example 1 above, was selected as the surfactant, and the blending ratio was changed for investigation.

[0062] As shown in Table 5, the above Miglyol 812N was added to the above mixture so that the final concentration was 38.26% (B1), 36.81% (B5), 45.15% (B'1) or 43.43% (B'5), and the above Sotfisan-378 was added to the above mixture so that the final concentration was 18.17% (B1), 17.48% (B5), 11.29% (B'1) or 10.86% (B'5), and heated and mixed at 70 ° C to obtain an additive mixture. Polyoxyethylene hydrogenated castor oil 60 was added to the above mixture so that the final concentration was 0.56% (B1 and B'1) or 2.71% (B5 and B'5), and heated and mixed at 70 ° C to obtain an additive mixture. Nintedanib ethanesulfonate was added to the above mixture in the same manner as in the preparation 1 of the capsule content liquid to prepare four types of capsule content liquid for examination. In addition, in B1 and B5, the MCT:hard fat ratio was approximately 2.1:1, and in B'1 and B'5, the MCT:hard fat ratio was approximately 4:1.

[0063] [Table 5]

[0064] (Filling capsule contents) The above four types of capsule content liquids for investigation were filled into hard capsules in the same manner as in Example 1 to prepare four types of test capsule formulations. Each test capsule formulation was subjected to a dissolution test according to the above procedure. The results are shown in Figure 3.

[0065] (result) As is clear from Figure 3, the dissolution rate after 30 minutes was nearly 100% in all test capsule formulations B1, B5, B'1, and B'5, showing good dissolution rates. Among them, the dissolution rate of B'5, which contains 2.71% polyoxyethylene hydrogenated castor oil 60, 43.43% MCT, and 10.86% hard fat, was 94.19% after 10 minutes.

[0066] [Dissolution rate study 4] (Preparation of Capsule Contents 4) Polysorbate 60, which had given good results in Example 1 above, was selected as the surfactant, and the blending ratio was changed for investigation.

[0067] As shown in Table 6, the above Miglyol 812N was added to a final concentration of 38.26% (C1), 36.81% (C5), 45.15% (C'1) or 43.43% (C'5), the above Sotfisan-378 was added to a final concentration of 18.17% (C1), 17.48% (C5), 11.29% (C'1) or 10.86% (C'5), and polysorbate 60 was added to the above heated mixture to a final concentration of 0.56% (C1 and C'1) or 2.71% (C5 and C'5), and heated and mixed at 70 ° C. to prepare an additive mixture. Four types of capsule content liquids for investigation were prepared by adding nintedanib ethanesulfonate to the above additive mixture in the same manner as in Preparation 1 of the above capsule content liquid. In addition, in C1 and C5, the MCT:hard fat ratio was approximately 2.1:1, and in C'1 and C'5, the MCT:hard fat ratio was approximately 4:1.

[0068] [Table 6]

[0069] (Filling capsule contents) The above four types of capsule content liquids for investigation were filled into hard capsules in the same manner as in Example 1 to obtain four types of test capsule formulations. Each test capsule formulation was subjected to a dissolution test in accordance with the above procedure. The results are shown in Figure 4. The dissolution rates of C5 and C'5 are shown in Table 7 below.

[0070] [Table 7]

[0071] (result) As is clear from FIG. 4 and Table 7, the dissolution rate after 30 minutes was close to 100% in all the test capsule formulations C1, C5, C'1, and C'5, showing good dissolution rates. Among them, the dissolution rate of C'5, which contains 2.71% polysorbate 60, 43.43% MCT, and 10.86% hard fat, was 98.25% after 5 minutes, showing a significantly good dissolution rate. In addition, the dissolution rate of C5, which contains 2.71% polysorbate 60, 36.81% MCT, and 17.48% hard fat, was 97.29% after 10 minutes.

[0072] [Dissolution rate study 5] (Preparation of Capsule Contents 5) Further investigations were carried out using various surfactants.

[0073] As shown in Table 8, the above-mentioned Miglyol 812N was added to a final concentration of 37.05%, the above-mentioned Sotfisan-378 was added to a final concentration of 17.45%, and polysorbate 80 (D5), polyoxyl 40 stearate (E5), sorbitan sesquioleate (M5), glycerin monostearate (O5), Sanfat GDO-DV (P5), and lauromacrogol (G5) were added to the above-mentioned heated mixture to a final concentration of 2.49%, and heated and mixed at 70 ° C. to prepare an additive mixture. Six types of capsule content liquids for investigation were prepared by adding nintedanib ethanesulfonate to the above-mentioned additive mixture in the same manner as in the preparation 1 of the above-mentioned capsule content liquid.

[0074] [Table 8]

[0075] (Filling capsule contents) The six types of capsule contents for investigation were filled into hard capsules in the same manner as in Example 1 to prepare six types of test capsule formulations. Each test capsule formulation was subjected to a dissolution test in accordance with the above procedure. The results are shown in Figure 5, and the values ​​of the dissolution rates after 30 minutes are shown in Table 9.

[0076] [Table 9]

[0077] (result) As is clear from Figure 5 and Table 9, when polysorbate 80 (D5), polyoxyl 40 stearate (E5), or sorbitan sesquioleate (M5) was used as the surfactant, the dissolution rate after 30 minutes was nearly 100%, which was a good dissolution rate. On the other hand, when glycerin monostearate (O5), Sunfat GDO-DV (P5), or lauromacrogol (G5) was used, the dissolution rate after 30 minutes was less than 70%, which was not excellent.

[0078] From the above considerations, the following points were confirmed: 1) The dissolution rate of C'5, which contained 2.71% polysorbate 60, 43.43% MCT, and 10.86% hard fat, was approximately 100% after 5 minutes, and the dissolution rate of C'5 was extremely excellent. 2) The dissolution rate of B'5, which contains 2.71% polyoxyethylene hydrogenated castor oil 60, 43.43% MCT, and 10.86% hard fat, was 94% or more after 10 minutes, demonstrating an excellent dissolution rate. 3) On the other hand, the dissolution rate of C1, which contained 0.56% polysorbate 60, 38.26% MCT, and 18.17% hard fat, after 5 minutes was less than 30%, suggesting that the surfactant ratio is important. 4) From the above 1) and 3), the dissolution rate is considered to be high when the tablet contains 2.71% surfactant, 43.43% MCT, 10.86% hard fat, and 43% drug substance. [Industrial Applicability]

[0079] The capsule formulation of the present invention can be used in the fields of medicines, quasi-drugs, etc. as a capsule formulation that allows nintedanib ethanesulfonate to be used efficiently and can be maintained in a stable state for a long period of time.

Claims

1. A capsule formulation in which a capsule content liquid containing nintedanib ethanesulfonate, a medium-chain fatty acid triglyceride, hard fat, and a surfactant is coated with a capsule shell.

2. 2. The capsule according to claim 1, wherein the surfactant is one or more selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polysorbate, polyoxyl stearate, and sorbitan sesquioleate.

3. 3. A capsule according to claim 1 or 2, in which the dissolution rate of nintedanib ethanesulfonate is 93% or more after 30 minutes.

4. 3. A capsule according to claim 1 or 2, in which the dissolution rate of nintedanib ethanesulfonate is 94% or more after 10 minutes.

5. 3. A capsule according to claim 1 or 2, in which the dissolution rate of nintedanib ethanesulfonate is 95% or more after 5 minutes.

6. A method for producing a capsule comprising the following steps (a) to (d). (a) preparing an additive mixture by mixing a medium chain triglyceride, a hard fat, and a surfactant; (b) allowing the additive mixture to cool; (c) adding nintedanib ethanesulfonate to the cooled additive mixture and stirring to prepare a capsule content; (d) encapsulating the capsule content liquid into the capsule shell;

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