Pharmaceutical composition

Abstract

To improve dissolution properties under near-neutral conditions in a pharmaceutical composition containing an active ingredient comprising lenvatinib or a salt thereof or a solvate thereof.SOLUTION: According to one embodiment of the present invention, the pharmaceutical composition contains an active ingredient comprising lenvatinib or a salt thereof or a solvate thereof, and exhibits a pH of 6.0-8.0 when suspended in 15 mL of water. According to one embodiment of the present invention, the pharmaceutical composition may further contain a pH adjuster such that a 5%(W / W) aqueous solution or suspension thereof has a pH of 7.0 or more and less than 8.0.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] One embodiment of the present invention relates to a pharmaceutical composition comprising an active ingredient consisting of lenvatinib, a salt thereof, or a solvate thereof. [Background technology]

[0002] Lenvatinib is an anti-cancer drug that has been recognized as effective as a preventive and therapeutic agent for various tumors, including thyroid cancer, hepatocellular carcinoma, thymic cancer, uterine cancer, and renal cell cancer, as well as an agent to suppress the metastasis of these tumors. Lenvima (registered trademark) Capsules is a drug product containing lenvatinib as an active ingredient.

[0003] Lenvatinib is susceptible to degradation under humidified and heated storage conditions, and furthermore, gelation easily occurs on the surface of pharmaceutical compositions containing it. Therefore, when lenvatinib is stored under humidified and heated storage conditions, moisture absorption can cause delays in the dissolution of the active ingredient.

[0004] Previously, a pharmaceutical composition containing lenvatinib as an active ingredient has been reported in which the stability of the pharmaceutical composition has been improved by using additives and silicic acids having a pH of 8 or higher, thereby suppressing gelation and improving dissolution delay (Patent Document 1). Another pharmaceutical composition containing lenvatinib as an active ingredient has been reported in which the use of an alkaline earth metal carbonate salt has resulted in excellent dissolution properties of lenvatinib and stability even after long-term storage (Patent Document 2). Furthermore, it has been reported that lenvatinib mesylate gels when dispersed in a 0.1 M HCl (pH 1.0) aqueous solution, and that gelation is accelerated in low pH solutions (Non-Patent Document 1).

[0005] However, while Patent Document 1, Patent Document 2, and Non-Patent Document 1 disclose that pharmaceutical compositions containing lenvatinib as a medicinal ingredient and using additives with a pH of 8 or higher have excellent dissolution properties under acidic conditions of about pH 1.2, there is no description of dissolution properties in water or under near-neutral conditions of about pH 6.8. The inventors have now revealed that dissolution properties are significantly reduced in water or under near-neutral conditions of about pH 6.8. When humans ingest medicinal ingredients, absorption in the small intestine, etc. must be taken into consideration. Because the pH of the small intestine, etc. is near-neutral, if dissolution properties under near-neutral conditions are low, sufficient absorption cannot be achieved, raising concerns that an appropriate therapeutic effect may not be achieved. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Patent No. 4834553 [Patent Document 2] Patent No. 5048871 [Non-patent literature]

[0007] [Non-Patent Document 1] “International Journal of Pharmaceutics,Volume 607,(2021),121019” Summary of the Invention [Problem to be solved by the invention]

[0008] The present invention solves the above problems, and one of its objects is to maintain sufficient dissolution properties of a pharmaceutical composition containing an active ingredient consisting of lenvatinib, a salt thereof, or a solvate thereof, even under near-neutral conditions. [Means for solving the problem]

[0009] According to one embodiment of the present invention, the pharmaceutical composition comprises an active ingredient consisting of lenvatinib or a salt thereof, or a solvate thereof, and the pharmaceutical composition has a pH of 6.0 to 8.0 when suspended in 15 mL of water.

[0010] According to one embodiment of the present invention, the pharmaceutical composition may further comprise one or more pH adjusting agents such that the pH of the 5% (W / W) aqueous solution or suspension is between 7.0 and 8.0.

[0011] The pH adjuster may be one or more selected from the group consisting of sodium chloride, calcium gluconate hydrate, sodium L-glutamate, disodium succinate hydrate, sodium tartrate, calcium lactate hydrate, dried aluminum hydroxide gel, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, sodium alginate, sodium lauryl sulfate, titanium oxide, calcium hydrogen phosphate granules, hydrogenated oil, and calcium sulfate hydrate.

[0012] The pharmaceutical composition of the present invention comprises a granulated product containing the active ingredient, and the pH adjuster comprises a first pH adjuster, and the first pH adjuster may be contained in the granulated product.

[0013] The pharmaceutical composition of the present invention may further comprise an additive other than the granules, and the pH adjuster may further comprise a second pH adjuster, and the second pH adjuster may be contained in the additives.

[0014] The first pH adjuster and the second pH adjuster may be one or more selected from the group consisting of sodium chloride, calcium gluconate hydrate, sodium L-glutamate, disodium succinate hydrate, sodium tartrate, calcium lactate hydrate, dry aluminum hydroxide gel, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, sodium alginate, sodium lauryl sulfate, titanium oxide, calcium hydrogen phosphate granules, hydrogenated oil, and calcium sulfate hydrate.

[0015] The first pH adjuster and the second pH adjuster may be one or more selected from the group consisting of sodium chloride, sodium tartrate, calcium lactate hydrate, dry aluminum hydroxide gel, anhydrous calcium hydrogen phosphate, and calcium hydrogen phosphate hydrate. [Effects of the Invention]

[0016] According to one embodiment of the present invention, there is provided a pharmaceutical composition comprising an active ingredient consisting of lenvatinib or a salt thereof, or a solvate of the same, which has sufficient dissolution properties even under near-neutral conditions. [Brief explanation of the drawings]

[0017] [Figure 1] 1 is a graph showing the results of dissolution tests of an example of the present invention and a comparative example. [Figure 2] 1 is a graph showing the results of dissolution tests of an example of the present invention and a comparative example. [Figure 3] 1 is a graph showing the results of dissolution tests of an example of the present invention and a comparative example. [Figure 4] 1 is a graph showing the results of dissolution tests of an example of the present invention and a comparative example. [Figure 5] 1 is a graph showing the results of dissolution tests of an example of the present invention and a comparative example. [Figure 6] 1 is a graph showing the results of dissolution tests of an example of the present invention and a comparative example. [Figure 7] 1 is a graph showing the results of dissolution tests of an example of the present invention and a comparative example. [Figure 8] 1 is a graph showing the results of dissolution tests of an example of the present invention and a comparative example. [Figure 9] 1 is a graph showing the results of dissolution tests of an example of the present invention and a comparative example. [Figure 10] 1 is a graph showing the results of dissolution tests of an example of the present invention and a comparative example. [Figure 11] 1 is a graph showing the results of dissolution tests of an example of the present invention and a comparative example. DETAILED DESCRIPTION OF THE INVENTION

[0018] The pharmaceutical composition according to the present invention will be described in detail below. However, the pharmaceutical composition of the present invention should not be construed as being limited to the description of the following embodiments and examples.

[0019] As used herein, the dosage form of a pharmaceutical composition refers to solid preparations such as granules, fine granules, tablets, capsules, etc. Preferably, it refers to tablets and capsules filled with these fine granules or granules.

[0020] Patent Document 1 describes that delayed dissolution is improved by adding silicic acid or a salt thereof, or a solvate of either to inhibit gelation of the surface of a pharmaceutical composition containing lenvatinib. Patent Document 2 describes that, for example, a pharmaceutical composition containing lenvatinib using an alkaline earth metal salt of carbonate or talc as an additive at a pH of 8 or higher causes lenvatinib to be rapidly dissolved under acidic conditions. Non-Patent Document 1 describes that lenvatinib mesylate gels when dispersed in an acidic environment (pH 1) or in water, and that gelation is promoted on the acidic side.

[0021]

[0003] One of the reasons for the low dissolution of pharmaceutical compositions containing a medicinal ingredient consisting of lenvatinib, a salt thereof, or a solvate thereof is thought to be related to the fact that the microenvironment into which lenvatinib is taken becomes acidic during dissolution of lenvatinib, a salt thereof, or a solvate thereof, promoting gelation, and that lenvatinib is poorly soluble under basic conditions. Therefore, in order to ensure sufficient dissolution of pharmaceutical compositions containing a medicinal ingredient consisting of lenvatinib, a salt thereof, or a solvate thereof in a biological environment, the inventors investigated pH adjusters with the aim of adjusting the pH when dissolving pharmaceutical compositions of lenvatinib, a salt thereof, or a solvate thereof to a near-neutral pH. As a result, it was found that the use of a pH adjuster as an additive can sufficiently improve the dissolution of pharmaceutical compositions containing a medicinal ingredient consisting of lenvatinib, a salt thereof, or a solvate thereof under near-neutral pH conditions, as well as under acidic conditions.

[0022] A pharmaceutical composition according to one embodiment of the present invention comprises a medicinal ingredient consisting of lenvatinib, a salt thereof, or a solvate thereof, or a granule containing the medicinal ingredient, and when the pharmaceutical composition is suspended in 15 mL of water, the pH is 6.0 to 8.0, preferably 6.0 to 7.5, and most preferably 6.3 to 7.1. By suspending the pharmaceutical composition in water at a pH close to neutral, the dissolution properties of the pharmaceutical composition containing the medicinal ingredient consisting of lenvatinib, a salt thereof, or a solvate thereof are improved not only under acidic conditions but also under neutral or near-neutral conditions.

[0023] Lenvatinib, its salt, or solvate thereof includes lenvatinib (4-{3-Chloro-4-[(cyclopropylcarbamoyl)amino]phenoxy}-7-methoxyquinoline-6-carboxamide), lenvatinib mesylate (4-{3-Chloro-4-[(cyclopropylcarbamoyl)amino]phenoxy}-7-methoxyquinoline-6-carboxamide monomethanesulfonate), or a solvate thereof. The amount of lenvatinib can be selected appropriately depending on the desired therapeutic effect, but is 4 mg or 10 mg of lenvatinib per pharmaceutical composition.

[0024] Lenvatinib is preferably a salt of lenvatinib or a solvate thereof. For example, lenvatinib is an anhydrate or dihydrate of lenvatinib mesylate hydrochloride. Lenvatinib exhibits similar effects in terms of dissolution regardless of whether it is a solvate, for example, a hydrate.

[0025] One embodiment of the present invention relates to a pharmaceutical composition comprising a pH adjuster that adjusts the pH of a 5% (W / W) aqueous solution or suspension to 7.0 or more and less than 8.0, preferably 7.0 to 7.5. By including a pH adjuster that adjusts the pH of a 5% (W / W) aqueous solution or suspension to 7.0 or more and less than 8.0, preferably 7.0 to 7.5, the pH of a suspended pharmaceutical composition containing a medicinal ingredient consisting of lenvatinib, a salt thereof, or a solvate thereof can be adjusted to near neutral.

[0026] In one embodiment of the present invention, the pH adjuster that adjusts the pH of a 5% (w / w) aqueous solution or suspension to between 7.0 and 8.0 is, for example, one or more selected from the group consisting of buffers, pH regulators, excipients, disintegrants, fluidizers, and lubricants. Examples of pH adjusters include sodium chloride (NaCl), calcium gluconate hydrate, sodium L-glutamate, disodium succinate hydrate, sodium tartrate, calcium lactate hydrate, dried aluminum hydroxide gel, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, sodium alginate, sodium lauryl sulfate, titanium oxide, calcium hydrogen phosphate granules, hydrogenated oil, and calcium sulfate hydrate. Two or more pH adjusters may be used in combination in a mixture or granule.

[0027] In one embodiment, the content of the pH adjuster is, for example, 15 to 60 wt %, preferably 33 to 45 wt %, and most preferably 33 to 39 wt %, based on the total weight of the pharmaceutical composition. Varying the content of the pH adjuster within this range also improves the dissolution property of the pharmaceutical composition. Furthermore, varying the content of the pH adjuster within this range also improves the dissolution property of the pharmaceutical composition under acidic to near-neutral conditions.

[0028] In one embodiment, when two or more pH adjusters are used in a mixture or granulation product, the content of the second pH adjuster in the pharmaceutical composition is preferably smaller than the content of the first pH adjuster. For example, the weight ratio of the first pH adjuster to the second pH adjuster in the total weight of the pharmaceutical composition is preferably 1.00:0.02-0.04. Dissolution can be improved by adding a small amount of a different second pH adjuster to the pharmaceutical composition in addition to the first pH adjuster.

[0029] A pharmaceutical composition according to one embodiment of the present invention comprises a granulated product, and the granulated product contains an active ingredient. The granulated product may contain a first pH adjuster that adjusts the pH of a 5% (W / W) aqueous solution or suspension to between 7.0 and 8.0. The first pH adjuster is included in the pH adjuster.

[0030] In one embodiment, the first pH adjuster may be the same as the pH adjuster described above. In one embodiment, the first pH adjuster is preferably sodium chloride, sodium tartrate, calcium lactate hydrate, dry aluminum hydroxide gel, anhydrous calcium hydrogen phosphate, or calcium hydrogen phosphate hydrate, among the pH adjusters described above. In one embodiment, the first pH adjuster is more preferably anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, or calcium lactate hydrate. The first pH adjuster may be used in combination with these agents.

[0031] In one embodiment, the content of the first pH adjuster is, for example, 15 to 60 wt %, preferably 33 to 45 wt %, and most preferably 33 to 39 wt %, based on the total weight of the pharmaceutical composition. Varying the content of the first pH adjuster within this range also improves the dissolution property of the pharmaceutical composition. Furthermore, varying the content of the first pH adjuster within this range also improves the dissolution property of the pharmaceutical composition under acidic to near-neutral conditions.

[0032] Here, the pH of a 5% (W / W) aqueous solution or suspension of 7.0 or more but less than 8.0 refers to the pH value measured with a pH meter after, for example, weighing out 5 g of the first pH adjuster, adding water to make the total volume 100 ml, stirring, and then measuring the pH value with a pH meter.

[0033] A pharmaceutical composition according to one embodiment of the present invention further contains an additive other than the granulated material, and the additive contains a second pH adjuster that adjusts the pH of the 5% (W / W) aqueous solution or suspension to 7.0 or more and less than 8.0.

[0034] The second pH adjuster that adjusts the pH of the 5% (W / W) aqueous solution or suspension according to one embodiment of the present invention to 7.0 or more and less than 8.0 can be the same as the first pH adjuster.

[0035] In one embodiment, it is preferred to use dry aluminum hydroxide gel as the second pH adjuster.

[0036] In one embodiment, the content of the second pH adjuster in the pharmaceutical composition is preferably smaller than the content of the first pH adjuster. For example, the weight ratio of the first pH adjuster to the second pH adjuster in the total weight of the pharmaceutical composition is preferably 1.00:0.02-0.04. Adding a small amount of the second pH adjuster to the pharmaceutical composition in addition to the first pH adjuster can improve dissolution properties.

[0037] In addition to the additives described above, the pharmaceutical composition of the present invention may further contain one or more pharmaceutically acceptable additives, such as disintegrants, excipients, binders, lubricants, antioxidants, flavoring agents, colorants, and fragrances.

[0038] The disintegrant can be selected from known disintegrants, including, but not limited to, one or more selected from the group consisting of corn starch, partially pregelatinized starch, hydroxypropyl starch, carmellose, carmellose sodium, carmellose calcium, carboxymethyl starch sodium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, and crospovidone.

[0039] The excipient can be selected from known excipients, for example, one or more excipients selected from the group consisting of lactose, sucrose, glucose, fructose, starch, potato starch, corn starch, wheat starch, rice starch, crystalline cellulose, microcrystalline cellulose, licorice powder, mannitol, erythritol, maltitol, sorbitol, trehalose, anhydrous silicic acid, calcium silicate, sodium bicarbonate, calcium phosphate, anhydrous calcium phosphate, and calcium sulfate, but is not limited thereto.

[0040] The binder can be selected from known binders, for example, one or more binders selected from the group consisting of gelatin, starch, gum arabic, tragacanth, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, methyl cellulose, partially pregelatinized starch, pregelatinized starch, polyvinyl alcohol, sodium alginate, pullulan, and glycerin, but is not limited thereto.

[0041] The lubricant can be selected from known lubricants, such as, but not limited to, one or more lubricants selected from the group consisting of stearic acid and macrogol.

[0042] The antioxidant can be selected from known antioxidants, such as, but not limited to, one or more antioxidants selected from the group consisting of sodium ascorbate, L-cysteine, sodium sulfite, tocopherol, and soybean lecithin.

[0043] The flavoring agent can be selected from known flavoring agents, for example, one or more selected from the group consisting of citric acid, ascorbic acid, tartaric acid, malic acid, aspartame, acesulfame potassium, thaumatin, sodium saccharin, dipotassium glycyrrhizinate, sodium glutamate, 5'-sodium inosinate, and 5'-guanylic acid, but is not limited thereto.

[0044] The coloring agent can be selected from known coloring agents, for example, one or more coloring agents selected from the group consisting of titanium oxide, iron sesquioxide, yellow iron sesquioxide, cochineal, carmine, riboflavin, food yellow no. 5, and food blue no. 2, but is not limited thereto.

[0045] The flavoring agent can be selected from known flavoring agents, such as, but not limited to, one or more flavoring agents selected from the group consisting of lemon oil, orange oil, menthol, peppermint oil, borneol, and vanilla flavor.

[0046] As described above, the pharmaceutical composition of the present invention contains an active ingredient consisting of lenvatinib, a salt thereof, or a solvate of the lenvatinib or a salt thereof, and one or more pH adjusters that adjust the pH of a 5% (W / W) aqueous solution or suspension to between 7.0 and 8.0. This results in a pH of 6.0 to 8.0 when suspended in 15 mL of water, which not only inhibits gelation under acidic conditions but also significantly improves dissolution properties in water or under near-neutral conditions such as pH 6.8.

[0047] [Method of manufacturing pharmaceutical composition] A known manufacturing method can be used for manufacturing the pharmaceutical composition of the present invention. For example, in one embodiment, a granule containing a medicinal ingredient consisting of lenvatinib, a salt thereof, or a solvate thereof, a first pH adjuster that adjusts the pH of a 5% (W / W) aqueous solution or suspension to 7.0 or more and less than 8.0, and the other additives described above can be mixed and granulated to produce a granule containing a medicinal ingredient consisting of lenvatinib, a salt thereof, or a solvate thereof, and a first pH adjuster that adjusts the pH of a 5% (W / W) aqueous solution or suspension to 7.0 or more and less than 8.0.

[0048] In addition, a second pH adjuster that adjusts the pH of a 5% (W / W) aqueous solution or suspension to 7.0 or more but less than 8.0, and the other additives mentioned above, can be added to the granules to produce pharmaceutical compositions such as tablets and capsules using conventional methods.

[0049] Alternatively, in one embodiment, the method for producing a pharmaceutical composition according to the present invention includes mixing the active ingredient consisting of lenvatinib, a salt thereof, or a solvate thereof, a pH adjuster that adjusts the pH of a 5% (W / W) aqueous solution or suspension to between 7.0 and 8.0, and the other additives described above, and compressing the resulting mixed powder into tablets to produce a tablet pharmaceutical composition containing the active ingredient consisting of lenvatinib, a salt thereof, or a solvate thereof, and a pH adjuster that adjusts the pH of a 5% (W / W) aqueous solution or suspension to between 7.0 and 8.0. The mixed powder may further contain a pH adjuster that adjusts the pH of a 5% (W / W) aqueous solution or suspension to between 7.0 and 8.0.

[0050] Alternatively, the resulting mixed powder may be filled into capsules without tableting to produce a pharmaceutical composition in the form of capsules. [Example]

[0051] [Study of acid dissociation constant] The suitability of pH for solubility was examined based on the acid dissociation constant (pKa) of lenvatinib, a salt thereof, or a solvate thereof.

[0052] (Reference example 1) The pKa values ​​of lenvatinib mesylate anhydrate and lenvatinib mesylate dihydrate were measured and evaluated using UV and pH titration methods with an inForm (Pion). The pKa value of lenvatinib mesylate anhydrate measured using UV was 5.14. The pKa value of lenvatinib mesylate dihydrate was 5.09. The pKa value of lenvatinib mesylate anhydrate measured using pH titration was 4.96. The pKa value of lenvatinib mesylate dihydrate was 5.05. This indicates that, regardless of the presence or absence of a hydrate, lenvatinib mesylate exhibits a high proportion of the ionic form under acidic conditions of about pH 5 or less, whereas conversely, the molecular form (non-ionic form) exhibits a high proportion under conditions of about pH 5 or more.

[0053] The tendency for gelation to occur on the surface of pharmaceutical compositions containing lenvatinib mesylate has been thought to be due to the high solubility of the ionic form. However, it has been revealed that while pharmaceutical compositions containing additives at pH 8 or higher can improve dissolution by suppressing gelation under acidic conditions, dissolution is significantly reduced in water or under near-neutral conditions such as pH 6.8. In other words, it has been found that to suppress gelation on the surface of pharmaceutical compositions containing lenvatinib mesylate, the proportion of the ionic form must be low, but to improve dissolution, the pH at which lenvatinib mesylate dissolves must not be too high. Since the pKa of lenvatinib mesylate is approximately 5.0, the Henderson-Hasselbalch equation predicts that the molecular form (non-ionic form) of lenvatinib mesylate is approximately 10 times that of the ionic form. 2 It can be seen that the pH at which the proportion of the ionized form is sufficiently low that the dissolution rate is twice as high is about 7.0. These results demonstrate that gelation can be suppressed and dissolution properties can be improved by adjusting the pH at which a pharmaceutical composition containing lenvatinib mesylate is dissolved to about 7.0.

[0054] [Consideration of pH adjusters] The combination of lenvatinib, its salt, or a solvate thereof with a pH adjuster was investigated.

[0055] (Reference example 2) The pH of a 5% (W / W) aqueous solution or suspension of each pH adjuster was measured, as well as the pH of a solution prepared by mixing or dissolving 4.0 mg of lenvatinib mesylate dihydrate and 3.75 to 15 times the amount of lenvatinib in 15 mL of water. pH was measured using a pH meter (HORIBA). Details of the pH adjusters and the results of the neutralization test are shown in Table 1.

[0056] As shown in Table 1, when 4.0 mg of lenvatinib mesylate dihydrate, the active ingredient, was suspended in 15 ml of water, the pH was 3.60 to 3.64.

[0057] [Table 1]

[0058] The above pH adjusters can neutralize lenvatinib mesylate, which has a pH of 3.60 to 3.64, and it has been revealed that depending on the amount added and the combination, the pH of a pharmaceutical composition containing lenvatinib mesylate or a solvate thereof can be adjusted to neutral or near-neutral. Furthermore, Lenvima® Capsules, a commercially available formulation containing precipitated calcium carbonate and talc as additives, had a pH of about 9.

[0059] [Solubility of pharmaceutical compositions in formulations] Based on the above, pharmaceutical compositions containing lenvatinib, a salt thereof, or a solvate thereof were prepared, and the solubility of lenvatinib, a salt thereof, or a solvate thereof was investigated.

[0060] Example 1 Each pharmaceutical composition-containing tablet contained 5.24 mg of lenvatinib mesylate dihydrate, 15.76 mg of D-mannitol (Mannit P, Mitsubishi Corporation Foodtech), 10.0 mg of microcrystalline cellulose (Ceolas®, PH-101, Asahi Kasei Corporation), 33.0 mg of calcium hydrogen phosphate hydrate (Rika, Kyowa Chemical Industry Co., Ltd.), 25.0 mg of low-substituted hydroxypropyl cellulose (L-HPC®, LH-21, Shin-Etsu Chemical Co., Ltd.), and 3.0 mg of hydroxypropyl cellulose (HPC-L, Nippon Soda Co., Ltd.). The mixture was kneaded in a high-speed mixer using purified water as a granulation liquid. The kneaded mixture was dried in a fluidized bed dryer and then sized using a sieve (size sieve). The resulting granules were mixed with 5.0 mg of microcrystalline cellulose (PH-102, Asahi Kasei Chemicals), 2.0 mg of croscarmellose sodium (Ac-Di-Sol, FMC), and 1.0 mg of dried aluminum hydroxide gel (S-100, Kyowa Chemical Industry Co., Ltd.) to obtain a mixed powder. The resulting mixed powder was compressed using a rotary tablet press (Kikusui Seisakusho, VELA5) to obtain tablets with a curvature radius of 6 mm. The contents of each additive in the formulation are shown in Table 2.

[0061] Example 2 In Example 2, tablets with a curvature radius of 6 mm were obtained in the same manner as in Example 1, except that anhydrous calcium hydrogen phosphate (Carica, Kyowa Chemical Industry Co., Ltd.) was mixed in place of calcium hydrogen phosphate hydrate (Rika, Kyowa Chemical Industry Co., Ltd.). The contents of each additive in the formulation are shown in Table 2.

[0062] Example 3 In Example 3, tablets with a curvature radius of 6 mm were obtained in the same manner as in Example 1, except that calcium hydrogen phosphate hydrate (FF-100, Kyowa Chemical Industry Co., Ltd.) was mixed in place of calcium hydrogen phosphate hydrate (Rika, Kyowa Chemical Industry Co., Ltd.). The contents of each additive in the formulation are shown in Table 2.

[0063] (Comparative Example 1) As Comparative Example 1, a tablet having a curvature radius of 6 mm was obtained in the same manner as in Example 1, except that calcium hydrogen phosphate hydrate (Rika, Kyowa Chemical Industry Co., Ltd.) was not contained. The contents of each additive in the formulation are shown in Table 2.

[0064] Example 4 In Example 4, the mixed powder obtained in Example 1 was filled into capsules (hypromellose capsules, No. 4) to produce capsules.

[0065] Example 5 In Example 5, the mixed powder obtained in Example 2 was filled into capsules (hypromellose capsules, No. 4) to produce capsules.

[0066] Example 6 In Example 6, the mixed powder obtained in Example 3 was filled into capsules (hypromellose capsules, No. 4) to produce capsules.

[0067] (Comparative Example 2) In Comparative Example 2, the mixed powder obtained in Comparative Example 1 was filled into capsules (hypromellose capsules, No. 4) to produce capsules.

[0068] [Table 2]

[0069] [pH Rating 1] The preparations obtained in Examples 1 to 6 were suspended in water and the pH was evaluated. To evaluate the pH, one tablet or one capsule of the preparation obtained in Examples 1 to 6 was added to 15 mL of the test solution while stirring with a stirrer, and the pH of the test solution in which the preparation was suspended was evaluated using a pH meter (manufactured by HORIBA). Water was used as the test solution. The pH evaluation results are shown in Table 3.

[0070] [Table 3]

[0071] Table 3 reveals that by adding the first pH adjuster to the pharmaceutical composition, the pH of each formulation suspended in water is adjusted to a near neutral range of 6.34 to 7.05.

[0072] [Evaluation of dissolution 1] The dissolution properties of Examples 1 to 6, Comparative Examples 1 and 2, and the commercially available "Lenvima (registered trademark) Capsules 4 mg" were evaluated. Dissolution evaluation was performed in accordance with the dissolution test method of the Japanese Pharmacopoeia, Seventeenth Edition (paddle method, 50 revolutions per minute) at a dissolution time of 30 minutes or 120 minutes. The test fluids used were the first dissolution test fluid (pH 1.2) of the Japanese Pharmacopoeia, Seventeenth Edition, under acid-base conditions, and water, and the second dissolution test fluid (pH 6.8) of the Japanese Pharmacopoeia, Seventeenth Edition, under near-neutral conditions. Dissolution evaluation under near-neutral conditions was performed for Examples 1 and 4, and the commercially available formulation. The results of the dissolution evaluation using the first dissolution test fluid are shown in Figures 1 and 4. The results of the dissolution evaluation using water are shown in Figure 2. The results of the dissolution evaluation using the second dissolution test fluid are shown in Figures 3 and 5.

[0073] 1 to 5 reveal that the addition of a first pH adjuster to a pharmaceutical composition significantly improves the dissolution of a pharmaceutical composition containing lenvatinib or a salt thereof, or a solvate thereof, not only under acidic conditions but also under near-neutral conditions where commercially available formulations containing additives at a pH of 8 or higher exhibit poor dissolution. Furthermore, it was revealed that calcium hydrogen phosphate hydrate or anhydrous calcium hydrogen phosphate can be suitably used as the first pH adjuster, regardless of its grade.

[0074] [pH adjuster study 2] The amount of pH adjuster added was investigated.

[0075] Example 7 In Example 7, tablets with a curvature radius of 6 mm were obtained in the same manner as in Example 1, except that 8.5 mg of crystalline cellulose was mixed and 39.0 mg of calcium hydrogen phosphate hydrate (FF100, Kyowa Chemical Industry Co., Ltd.) was mixed instead of calcium hydrogen phosphate hydrate (Rika, Kyowa Chemical Industry Co., Ltd.). The contents of each additive in the formulation are shown in Table 4.

[0076] Example 8 In Example 8, tablets with a curvature radius of 6 mm were obtained in the same manner as in Example 1, except that 7.0 mg of crystalline cellulose was mixed and 45.0 mg of calcium hydrogen phosphate hydrate (FF100, Kyowa Chemical Industry Co., Ltd.) was mixed instead of calcium hydrogen phosphate hydrate (Rika, Kyowa Chemical Industry Co., Ltd.). The contents of each additive in the formulation are shown in Table 4.

[0077] Example 9 In Example 9, the mixed powder obtained in Example 7 was filled into capsules (hypromellose capsules, No. 4) to produce capsules.

[0078] Example 10 In Example 10, the mixed powder obtained in Example 8 was filled into capsules (hypromellose capsules, No. 4) to produce capsules.

[0079] [Table 4]

[0080] [pH Rating 2] The pH was evaluated when Examples 7 to 10 were suspended in water. The pH was evaluated using the same method as in Example 1. The pH evaluation results are shown in Table 5.

[0081] [Table 5]

[0082] Table 5 shows that even when the amount of pH adjuster was varied from 33 to 45% by weight relative to the total weight, the pH of each formulation when suspended in water was adjusted to 6.97 to 7.04, which was close to neutral.

[0083] [Evaluation of dissolution 2] The dissolution properties of Examples 3, 6 to 10, and the commercially available "Lenvima (registered trademark) Capsules 4 mg" as a comparative example were evaluated. The dissolution properties were evaluated using the same method as in Example 1. The results of the evaluation of dissolution properties using the first dissolution test fluid are shown in Figures 6 and 8. The results of the evaluation of dissolution properties using water are shown in Figure 7.

[0084] 6 to 8, it is clear that the dissolution property is improved even when the amount of pH adjuster is changed.

[0085] [Study of additives in encapsulation] Based on the above examples and comparative examples, an encapsulated formulation containing lenvatinib, a salt thereof, or a solvate thereof was investigated.

[0086] Example 11 In Example 11, capsules were produced in the same manner as in Example 6, except that 7.0 mg of microcrystalline cellulose was added instead of croscarmellose sodium. The contents of each additive in the formulation are shown in Table 6.

[0087] [Table 6]

[0088] [pH Rating 3] Example 11 was suspended in water and the pH was evaluated. The pH was evaluated using the same method as in Example 1. The pH evaluation results are shown in Table 7.

[0089] [Table 7]

[0090] [Evaluation of dissolution 3] The dissolution properties of Example 11 and the commercially available "Lenvima (registered trademark) Capsules 4 mg" as a comparative example were evaluated. The dissolution properties were evaluated using the same method as in Example 1. The results of the evaluation of dissolution properties using the first dissolution test fluid are shown in Figure 9. The results of the evaluation of dissolution properties using water are shown in Figure 10. The results of the evaluation of dissolution properties using the second dissolution test fluid are shown in Figure 11.

[0091] 9 to 11, it was revealed that the formulation of Example 11 maintained the same level of dissolution property under acidic conditions compared to the commercially available formulation, but exhibited significantly higher dissolution property under near-neutral conditions.

[0092] [Consideration of manufacturing method] A method for producing a formulation containing lenvatinib, a salt thereof, or a solvate thereof was investigated.

[0093] Example 12 In Example 12, lenvatinib mesylate dihydrate was mixed with additives, and the resulting mixed powder was compressed without granulation to produce tablets.

[0094] Per tablet containing the pharmaceutical composition, 5.24 mg of lenvatinib mesylate dihydrate, 13.76 mg of D-mannitol (Granutol F, Freund Corporation), 33.0 mg of calcium hydrogen phosphate hydrate (FF-100, Kyowa Chemical Industry Co., Ltd.), 25.0 mg of low-substituted hydroxypropyl cellulose (L-HPC®, LH-21, Shin-Etsu Chemical Co., Ltd.), 3.0 mg of hydroxypropyl cellulose (HPC-L, Nippon Soda Co., Ltd.), 15.0 mg of microcrystalline cellulose (PH-102, Asahi Kasei Chemicals), 4.0 mg of croscarmellose sodium (Ac-Di-Sol, FMC), and 1.0 mg of dried aluminum hydroxide gel (S-100, Kyowa Chemical Industry Co., Ltd.) were mixed to obtain a mixed powder. The resulting mixed powder was compressed using a rotary tablet press (VELA5, Kikusui Seisakusho) to obtain tablets with a curvature radius of 6 mm. The content of each additive in the formulation is shown in Table 8.

[0095] [Table 8]

[0096] Example 13 The mixed powder obtained in Example 12 was filled into capsules (hypromellose capsules, No. 4) to produce capsules.

[0097] Even if there are other effects and advantages different from those brought about by the aspects of each of the above-mentioned embodiments, those that are clear from the description in this specification or that can be easily predicted by a person skilled in the art are naturally understood to be brought about by the present invention.

Claims

1. Contains a medicinal ingredient consisting of lenvatinib, a salt thereof, or a solvate thereof, A pharmaceutical composition having a pH of 6.0 to 8.0 when suspended in 15 mL of water.

2. Further comprising one or more pH adjusters that adjust the pH of the 5% (W / W) aqueous solution or suspension to 7.0 or more and less than 8.0; The pharmaceutical composition of claim 1.

3. The pH adjuster is at least one selected from the group consisting of sodium chloride, calcium gluconate hydrate, sodium L-glutamate, disodium succinate hydrate, sodium tartrate, calcium lactate hydrate, dry aluminum hydroxide gel, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, sodium alginate, sodium lauryl sulfate, titanium oxide, calcium hydrogen phosphate granules, hydrogenated oil, and calcium sulfate hydrate. The pharmaceutical composition of claim 2.

4. The pharmaceutical composition comprises a granulation product containing the active ingredient, the pH adjuster includes a first pH adjuster, The first pH adjuster is contained in the granules. The pharmaceutical composition according to claim 3.

5. Further containing additives other than the granules, The pH adjuster further comprises a second pH adjuster; The second pH adjuster is included in the additive. The pharmaceutical composition according to claim 4.

6. The first pH adjuster and the second pH adjuster are at least one selected from the group consisting of sodium chloride, calcium gluconate hydrate, sodium L-glutamate, disodium succinate hydrate, sodium tartrate, calcium lactate hydrate, dry aluminum hydroxide gel, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, sodium alginate, sodium lauryl sulfate, titanium oxide, calcium hydrogen phosphate granules, hydrogenated oil, and calcium sulfate hydrate. The pharmaceutical composition according to claim 5.

7. the first pH adjuster and the second pH adjuster are one or more selected from the group consisting of sodium chloride, sodium tartrate, calcium lactate hydrate, dry aluminum hydroxide gel, anhydrous calcium hydrogen phosphate, and calcium hydrogen phosphate hydrate; The pharmaceutical composition according to claim 6.

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