Tafamidis-containing pharmaceutical composition, and formulation containing the same

Abstract

To provide a tafamidis-containing pharmaceutical composition that suppresses crystal transition from the form 4 to the form 1, and stably maintains the form 4.SOLUTION: Provided is a tafamidis-containing pharmaceutical composition containing tafamidis of the form 4, and one or more additives selected from the group consisting of glycerine, concentrated glycerin, glycerol fatty acid ester, polyethylene glycol fatty acid ester, vegetable oil, soybean lecithin and liquid paraffin. In the tafamidis-containing pharmaceutical composition, the glycerol fatty acid ester may be decaglyceryl trioleate or decaglyceryl decaoleate, and the vegetable oil may be soybean oil or castor oil.SELECTED DRAWING: Figure 5

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical compositions containing tafamidis. [Background technology]

[0002] Tafamidis (2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid) is a therapeutic agent for transthyretin familial amyloid polyneuropathy (TTR-FAP) that binds to the thyroxine-binding site of the transthyretin (TTR) tetramer, stabilizing the TTR tetramer and inhibiting its dissociation into monomers, thereby suppressing amyloid formation and deposition in tissues. An example of a soft capsule formulation containing tafamidis is Vynmac® Capsules (Non-Patent Document 1). Vynmac® Capsules is a soft capsule formulation in which tafamidis free acid, the active ingredient of tafamidis meglumine, is dispersed in macrogol 400, polysorbate 20, povidone (K-90), and dibutylhydroxytoluene, and then encapsulated.

[0003] Several crystalline forms of tafamidis are known. Generally, different crystalline forms are known to have different stability and physical properties. For example, Patent Document 1 discloses the properties of tafamidis forms 1, 2, 4, and 6, which are more suitable for mass preparation and handling than amorphous forms. Patent Document 2 also discloses the properties of tafamidis forms S, N, and R. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Application Publication No. 2023-134645 [Patent Document 2] International Publication No. 2021 / 001858 [Non-patent literature]

[0005] [Non-Patent Document 1] Binmac (registered trademark) Capsules Pharmaceutical Interview Form Revised March 2023 (3rd edition) Summary of the Invention [Problem to be solved by the invention]

[0006] As a result of studies by the present inventors, it has been revealed that tafamidis is susceptible to crystal transition from Form R and Form N to Form 4, and from Form 4 to Form 1, depending on the temperature and humidity during storage. One object of the present invention is to provide a pharmaceutical composition containing tafamidis that inhibits the crystal transition from Form 4 to Form 1 and stably maintains Form 4. [Means for solving the problem]

[0007] According to one embodiment of the present invention, there is provided a pharmaceutical composition containing tafamidis, characterized by comprising Form 4 of tafamidis and one or more additives selected from the group consisting of glycerin, concentrated glycerin, glycerin fatty acid esters, polyethylene glycol fatty acid esters, vegetable oils, soybean lecithin, and liquid paraffin.

[0008] The glycerin fatty acid ester may be decaglyceryl trioleate or decaglyceryl decaoleate.

[0009] The polyethylene glycol fatty acid ester may be polyethylene glycol monooleate.

[0010] The vegetable oil may be soybean oil or castor oil.

[0011] The vegetable oil may be soybean oil.

[0012] Form 4 of tafamidis may have characteristic peaks at 16.87°±0.2° and 27.23°±0.2° 2θ in powder X-ray diffraction (XRD) analysis.

[0013] Form 4 of tafamidis may not exhibit detectable peaks at 5.07°±0.2°, 8.01°±0.2°, and 20.24°±0.2° 2θ in powder X-ray diffraction (XRD) analysis.

[0014] The formulation may comprise a pharmaceutical composition containing tafamidis. [Effects of the Invention]

[0015] According to one embodiment of the present invention, there is provided a pharmaceutical composition containing tafamidis that inhibits the crystal transformation from Form 4 to Form 1 and stably maintains Form 4. [Brief explanation of the drawings]

[0016] [Figure 1] FIG. 1 shows the powder X-ray diffraction pattern of Form 1 of tafamidis. [Figure 2] FIG. 1 shows the powder X-ray diffraction pattern of Form 4 of tafamidis. [Figure 3] FIG. 1 shows the powder X-ray diffraction pattern of Form N of tafamidis. [Figure 4] FIG. 1 shows the powder X-ray diffraction pattern of Form R of tafamidis. [Figure 5] FIG. 1 shows the results of evaluation of the crystal form of the tafamidis-containing pharmaceutical compositions according to Examples 1 to 9 of the present invention and Comparative Examples 1 to 9 before and after storage at 40°C and 75% RH for one month (40°C, 1M) or at 60°C and 60% RH for two weeks (60°C, 2W). [Figure 6] FIG. 1 shows the powder X-ray diffraction pattern of the tafamidis-containing pharmaceutical composition according to Example 6 of the present invention after storage at 60° C. and 60% RH for 2 weeks (60° C., 2W). [Figure 7]FIG. 1 shows the powder X-ray diffraction pattern of the tafamidis-containing pharmaceutical composition according to Comparative Example 2 of the present invention after storage under conditions of 60° C. and 60% RH for 2 weeks (60° C., 2W). [Figure 8] FIG. 1 shows the powder X-ray diffraction pattern of the tafamidis-containing pharmaceutical composition according to Comparative Example 9 of the present invention after storage under conditions of 60° C. and 60% RH for 2 weeks (60° C., 2W). [Figure 9] FIG. 1 shows the powder X-ray diffraction pattern of the tafamidis-containing pharmaceutical composition according to Comparative Example 7 of the present invention after storage at 40° C. and 75% RH for one month (40° C., 1M). DETAILED DESCRIPTION OF THE INVENTION

[0017] The tafamidis-containing pharmaceutical composition of the present invention will be described in detail below, but the tafamidis-containing pharmaceutical composition of the present invention should not be construed as being limited to the description of the following embodiments and examples.

[0018] As a result of studies conducted by the present inventors, it was found that tafamidis is susceptible to crystal transition from Forms R and N to Form 4, and further from Form 4 to Form 1, depending on the temperature and humidity during storage. On the other hand, it was found that Form 4 tafamidis drug substance alone did not undergo crystal transition to Form 1 even after 2 weeks of storage under conditions of 60°C and 60% RH. Furthermore, Form 4 does not undergo crystal transition to Form 1 even after a milling process, making particle size control possible. However, it was found that the use of excipients commonly used in soft capsules, such as macrogol 400 and polysorbate 20, which are used in Vynmac® Capsules to formulate Form 4 tafamidis, results in crystal transition of tafamidis from Form 4 to Form 1. Therefore, excipients were screened to find a method for inhibiting the crystal transition from Form 4 to Form 1. Surprisingly, it was found that the use of one or more additives selected from the group consisting of glycerin, concentrated glycerin, glycerin fatty acid esters, polyethylene glycol fatty acid esters, vegetable oils, liquid paraffin, and soybean lecithin in a pharmaceutical composition containing tafamidis inhibits the crystal transformation from Form 4 to Form 1 in stability tests in which the composition was stored at 60°C and 60% RH for two weeks or at 40°C and 75% RH for one month.

[0019] [Pharmaceutical composition containing tafamidis] In one embodiment of the present invention, the tafamidis-containing pharmaceutical composition comprises tafamidis Form 4 and one or more additives selected from the group consisting of glycerin, concentrated glycerin, glycerin fatty acid esters, polyethylene glycol fatty acid esters, vegetable oils, liquid paraffin, and soybean lecithin.

[0020] The tafamidis of this embodiment is 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid in Form 4. Alternatively, instead of tafamidis in Form 4, a drug substance in a crystalline form that can be transformed into tafamidis in Form 4 may be used. Drug substances in a crystalline form that can be transformed into tafamidis in Form 4 include, but are not limited to, tafamidis in Form R and Form N.

[0021] Form 1 of tafamidis has a characteristic peak at 20.24°±0.2° 2θ in powder X-ray diffraction (XRD), which can be used to identify the crystalline form of tafamidis in the composition. Preferably, no peaks are detected at 5.07°±0.2°, 8.01°±0.2°, 16.87°±0.2°, and 27.23°±0.2°.

[0022] Form 4 of tafamidis has characteristic peaks at 16.87°±0.2° and 27.23°±0.2° 2θ in powder X-ray diffraction (XRD), which can be used to identify the crystalline form of tafamidis in the composition. Preferably, no peaks are detected at 5.07°±0.2°, 8.01°±0.2°, and 20.24°±0.2°.

[0023] Form N of tafamidis has a characteristic peak at 5.07°±0.2° 2θ in powder X-ray diffraction (XRD) and can be used to identify the crystalline form of tafamidis in a composition.

[0024] Form R of tafamidis has a characteristic peak in powder X-ray diffraction (XRD) at 8.01°±0.2° 2θ, which can be used to identify the crystalline form of tafamidis in a composition.

[0025] The mixed crystal of tafamidis Form 1 and Form 4 has characteristic peaks at 16.87°±0.2°, 20.24°±0.2°, and 27.23°±0.2° 2θ in powder X-ray diffraction (XRD), which can be used to identify the crystalline form of tafamidis in the composition. Preferably, no peaks are detected at 5.07°±0.2° and 8.01°±0.2° 2θ.

[0026] The mixed crystal of tafamidis Form 4 and Form R has characteristic peaks at 8.01°±0.2°, 16.87°±0.2°, and 27.23°±0.2° 2θ in powder X-ray diffraction (XRD), which can be used to identify the crystalline form of tafamidis in the composition. Preferably, no peaks are detected at 5.07°±0.2° and 20.24°±0.2° 2θ.

[0027] The mixed crystal of tafamidis Form 4 and Form N has characteristic peaks at 5.07°±0.2°, 16.87°±0.2°, and 27.23°±0.2° 2θ in powder X-ray diffraction (XRD), which can be used to identify the crystalline form of tafamidis in the composition. Preferably, no peaks are detected at 8.01°±0.2° and 20.24°±0.2° 2θ.

[0028] In one embodiment, the tafamidis-containing pharmaceutical composition contains an additive. The additive contained in the tafamidis-containing pharmaceutical composition of this embodiment is, for example, one or more selected from the group consisting of glycerin, concentrated glycerin, glycerin fatty acid esters, polyethylene glycol fatty acid esters, vegetable oils, liquid paraffin, and soybean lecithin. The additive contained in the tafamidis-containing pharmaceutical composition of this embodiment is, for example, preferably one or more selected from the group consisting of glycerin, concentrated glycerin, glycerin fatty acid esters, vegetable oils, and liquid paraffin.

[0029] The glycerol fatty acid ester contained in the tafamidis-containing pharmaceutical composition of this embodiment is preferably decaglyceryl trioleate or decaglyceryl decaoleate.The glycerol fatty acid ester contained in the tafamidis-containing pharmaceutical composition of this embodiment may be decaglyceryl monopalmitate, decaglyceryl monooleate, decaglyceryl monomyristate, decaglyceryl monolaurate, tetraglyceryl monooleate, hexaglyceryl condensed ricinoleate, hexaglyceryl monomyristate, hexaglyceryl monolaurate, diglyceryl monooleate, decaglyceryl pentaoleate, glyceryl monocaprylate, glyceryl monoolivate, or glyceryl monoundecylenate.

[0030] The polyethylene glycol fatty acid ester contained in the tafamidis-containing pharmaceutical composition of this embodiment is preferably polyethylene glycol monooleate, and may also be polyethylene glycol monolaurate.

[0031] The vegetable oil contained in the tafamidis-containing pharmaceutical composition of this embodiment is preferably soybean oil or castor oil. The vegetable oil contained in the tafamidis-containing pharmaceutical composition of this embodiment is more preferably soybean oil. In this embodiment, the specific additive can suppress the crystal transition of tafamidis from Form 4 to Form 1 in the tafamidis-containing pharmaceutical composition.

[0032] The content of the additive in the tafamidis-containing pharmaceutical composition is not particularly limited, but is preferably 20% or more relative to tafamidis. In this embodiment, a specific amount of the additive can suppress the crystal transition of tafamidis from Form 4 to Form 1 in the tafamidis-containing pharmaceutical composition.

[0033] In one embodiment, the formulation comprises a tafamidis-containing pharmaceutical composition. In this embodiment, the specific additive can suppress the crystalline transition from Form 4 to Form 1 of tafamidis in the formulation comprising the tafamidis-containing pharmaceutical composition.

[0034] In this embodiment, the tafamidis-containing pharmaceutical composition can be produced according to a production method known in the pharmaceutical field. In this embodiment, the tafamidis-containing pharmaceutical composition is produced by first adding Form 4 tafamidis to one or more additives selected from the group consisting of glycerin, concentrated glycerin, glycerin fatty acid esters, polyethylene glycol fatty acid esters, vegetable oil, liquid paraffin, and soybean lecithin, and stirring to disperse the mixture.

[0035] In this embodiment, the method for producing a pharmaceutical composition containing tafamidis involves adding tafamidis Form 4 to one or more additives selected from the group consisting of glycerin, concentrated glycerin, glycerin fatty acid esters, polyethylene glycol fatty acid esters, vegetable oil, liquid paraffin, and soybean lecithin, stirring, and dispersing the tafamidis, thereby suppressing the crystal transition of tafamidis Form 4 to Form 1 in the pharmaceutical composition containing tafamidis. [Example]

[0036] The above-described present invention will be described in detail by showing specific examples and test results.

[0037] [Reference example 1] The crystalline form of Form 1 tafamidis was evaluated by XRD. (XRD conditions) Powder X-ray diffractometer: D8 ADVANCE (Bruker) Measurement conditions: Tube: Cu, Tube voltage: 40 kV, Tube current: 40 mA, Measurement range: 2° to 40°, Scan speed: 1.0 sec / step, Step size: 0.015° A chart of the diffracted X-ray intensity at each diffraction angle (2θ) (powder X-ray diffraction pattern) is shown in FIG.

[0038] As shown in Figure 1, Form 1 of tafamidis exhibited a characteristic peak (dotted arrow) at 20.24°±0.2° 2θ in powder X-ray diffraction (XRD).

[0039] [Reference example 2] The crystalline form of Form 4 of tafamidis was evaluated by XRD in the same manner as in Reference Example 1. As shown in Figure 2, Form 4 of tafamidis showed characteristic peaks (arrows) at 16.87°±0.2° and 27.23°±0.2° 2θ in powder X-ray diffraction (XRD).

[0040] [Reference example 3] The crystal form of Form N of tafamidis was evaluated by XRD in the same manner as in Reference Example 1. As shown in Figure 3, Form N of tafamidis showed a characteristic peak (arrow) at 5.07°±0.2° in powder X-ray diffraction (XRD).

[0041] [Reference example 4] The crystal form of Form R of tafamidis was evaluated by XRD in the same manner as in Reference Example 1. As shown in Figure 4, Form R of tafamidis showed a characteristic peak (arrow) at 8.01°±0.2° in powder X-ray diffraction (XRD).

[0042] [Example 1] 0.1 g of Form 4 tafamidis was added to 2 ml of glycerin as an additive, and the mixture was stirred and dispersed to obtain the tafamidis-containing pharmaceutical composition of Example 1.

[0043] [Example 2] 0.1 g of Form 4 tafamidis was added to 2 ml of concentrated glycerin as an additive, and the mixture was stirred and dispersed to obtain the tafamidis-containing pharmaceutical composition of Example 2.

[0044] [Example 3] 0.1 g of Form 4 tafamidis was added to 2 ml of decaglyceryl trioleate (3-OVF) as an additive, and the mixture was stirred and dispersed to obtain the tafamidis-containing pharmaceutical composition of Example 3.

[0045] [Example 4] 0.1 g of Form 4 tafamidis was added to 2 ml of decaglyceryl decaoleate (10-OVF) as an additive, and the mixture was stirred and dispersed to obtain the tafamidis-containing pharmaceutical composition of Example 4.

[0046] [Example 5] 0.1 g of tafamidis Form 4 was added to 2 ml of soybean oil as an additive, and the mixture was stirred and dispersed to obtain the tafamidis-containing pharmaceutical composition of Example 5.

[0047] [Example 6] 0.1 g of Form 4 tafamidis was added as an additive to 2 ml of liquid paraffin, and the mixture was stirred and dispersed to obtain the tafamidis-containing pharmaceutical composition of Example 6.

[0048] [Example 7] 0.1 g of Form 4 tafamidis was added to 2 ml of polyethylene glycol monooleate (MYO-6V) as an additive, and the mixture was stirred and dispersed to obtain the tafamidis-containing pharmaceutical composition of Example 7.

[0049] [Example 8] 0.1 g of tafamidis Form 4 was added to 2 ml of castor oil as an additive, and the mixture was stirred and dispersed to obtain the tafamidis-containing pharmaceutical composition of Example 8.

[0050] [Example 9] 0.1 g of Form 4 tafamidis was added to 2 ml of soybean lecithin (TOPCITHIN) as an additive, and the mixture was stirred and dispersed to obtain the tafamidis-containing pharmaceutical composition of Example 9.

[0051] [Comparative Example 1] 0.1 g of Form 4 tafamidis was added to 2 ml of medium-chain fatty acid triglyceride as an additive, and the mixture was stirred and dispersed to obtain a tafamidis-containing pharmaceutical composition of Comparative Example 1.

[0052] Comparative Example 2 0.1 g of Form 4 tafamidis was added to 2 ml of macrogol 400 as an additive, and the mixture was stirred and dispersed to obtain a pharmaceutical composition containing tafamidis of Comparative Example 2.

[0053] Comparative Example 3 0.1 g of tafamidis Form 4 was added to 2 ml of polysorbate 20 as an additive, and the mixture was stirred and dispersed to obtain a tafamidis-containing pharmaceutical composition of Comparative Example 3.

[0054] Comparative Example 4 0.1 g of tafamidis Form 4 was added to 2 ml of hydrogenated castor oil as an additive, and the mixture was stirred and dispersed to obtain a pharmaceutical composition containing tafamidis of Comparative Example 4.

[0055] Comparative Example 5 0.1 g of tafamidis Form 4 was added to 2 ml of propylene glycol as an additive, and the mixture was stirred and dispersed to obtain a pharmaceutical composition containing tafamidis of Comparative Example 5.

[0056] Comparative Example 6 0.1 g of Form 4 tafamidis was added to 2 ml of benzyl alcohol as an additive, and the mixture was stirred and dispersed to obtain a pharmaceutical composition containing tafamidis of Comparative Example 6.

[0057] Comparative Example 7 0.1 g of tafamidis Form 4 was added to 2 ml of lauromacrogol (BL-2 Kyoku) as an additive, and the mixture was stirred and dispersed to obtain a pharmaceutical composition containing tafamidis of Comparative Example 7.

[0058] [Comparative Example 8] 0.1 g of Form 4 tafamidis was added to 2 ml of propylene glycol fatty acid ester as an additive, and the mixture was stirred and dispersed to obtain a tafamidis-containing pharmaceutical composition of Comparative Example 8.

[0059] Comparative Example 9 0.1 g of tafamidis Form 4 was added to 2 ml of lactic acid as an additive, and the mixture was stirred and dispersed to obtain a pharmaceutical composition containing tafamidis of Comparative Example 9.

[0060] [Stability test conditions] Each of the tafamidis-containing pharmaceutical compositions obtained in Examples 1 to 9 and Comparative Examples 1 to 9 was placed in a bottle and sealed, and the sealed bottle was then sealed in an aluminum bag and stored at 40°C and 75% RH for one month (40°C, 1M) or at 60°C and 60% RH for two weeks (60°C, 2W).

[0061] [Additive Consideration] The tafamidis-containing pharmaceutical compositions of Examples 1 to 9 and Comparative Examples 1 to 9 were evaluated for tafamidis crystal form before and after storage by XRD under the same conditions as in Reference Example 1. The criteria for crystalline transition were as follows: when the peaks at 16.87°±0.2° and 27.23°±0.2° characteristic of Form 4 tafamidis were reduced and a peak at 20.24°±0.2° characteristic of Form 1 tafamidis was detected, it was determined that a transition from tafamidis Form 4 (Form IV) to tafamidis Form 1 (Form I) had occurred. The evaluation of the tafamidis crystal form before storage (INT) and after storage under each condition (40°C, 1M or 60°C, 2W) for Examples 1 to 9 and Comparative Examples 1 to 9 is shown in Figure 5. Regarding the evaluation of crystal form in Figure 5, compositions that met the above criteria were designated as Form I, regardless of the amount of Form 4 tafamidis remaining in the composition. Furthermore, charts of diffracted X-ray intensity (powder X-ray diffraction patterns) at each diffraction angle (2θ) for tafamidis in Example 6 and Comparative Examples 2, 7, and 9 after storage (40°C, 1M or 60°C, 2W) are shown in Figures 6 to 9.

[0062] As shown in Figure 5, the tafamidis-containing pharmaceutical compositions of Examples 1 to 8 did not undergo crystal transition to Form 1 even after two weeks of storage at 60°C and 60% RH (60°C, 2W). The tafamidis-containing pharmaceutical compositions of Examples 1 to 6 and 9 did not undergo crystal transition to Form 1 even after one month of storage at 40°C and 75% RH (40°C, 1M). The tafamidis-containing pharmaceutical compositions of Comparative Examples 1 to 9 showed a crystal transition to Form 1, with a 20.24°±0.2° characteristic of Form 1 tafamidis, after two weeks of storage at 60°C and 60% RH (60°C, 2W) or one month of storage at 40°C and 75% RH. In particular, the tafamidis-containing pharmaceutical compositions of Comparative Examples 2, 6 and 7 underwent crystal transition to Form 1 immediately after preparation.

[0063] From the above, it was found that when stored for 2 weeks (60°C, 2W) under conditions of 60°C and 60% RH, tafamidis in Form 4 in the tafamidis-containing pharmaceutical compositions of Examples 1 to 8, which contain one or more additives selected from the group consisting of glycerin, concentrated glycerin, glycerin fatty acid esters, polyethylene glycol fatty acid esters, vegetable oils, and liquid paraffin, does not undergo crystallization to Form 1.

[0064] As shown in Figure 6, when the tafamidis-containing pharmaceutical composition of Example 6 was stored for 2 weeks (60°C, 2W) under conditions of 60°C and 60% RH, the peak at 20.24°±0.2° (dotted arrow) characteristic of Form 1 was not detected, and characteristic peaks (arrows) of 16.87°±0.2° and 27.23°±0.2° characteristic of Form 4 were detected, and Form 4 was maintained.

[0065] As shown in Figure 7, when the tafamidis-containing pharmaceutical composition of Comparative Example 2 was stored under conditions of 60°C and 60% RH for 2 weeks (60°C, 2W), both the characteristic peak at 20.24°±0.2° (dotted arrow) characteristic of Form 1 and the characteristic peaks at 16.87°±0.2° and 27.23°±0.2° (arrows) characteristic of Form 4 were detected, and the composition underwent a crystalline transition to a mixed crystal of Form 4 and Form 1.

[0066] As shown in Figure 8, when the tafamidis-containing pharmaceutical composition of Comparative Example 9 was stored under conditions of 60°C and 60% RH for 2 weeks (60°C, 2W), both the characteristic peak at 20.24°±0.2° (dotted arrow) characteristic of Form 1 and the characteristic peaks at 16.87°±0.2° and 27.23°±0.2° (arrows) characteristic of Form 4 were detected, and the composition underwent a crystalline transition to a mixed crystal of Form 4 and Form 1.

[0067] As shown in Figure 9, when the tafamidis-containing pharmaceutical composition of Comparative Example 7 was stored under conditions of 40°C and 75% RH for one month (40°C, 1M), a characteristic peak (dotted arrow) at 20.24°±0.2° characteristic of Form 1 was detected, and the composition underwent a crystalline transition to Form 1.

[0068] 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. Form 4 tafamidis and one or more additives selected from the group consisting of glycerin, concentrated glycerin, glycerin fatty acid ester, polyethylene glycol fatty acid ester, vegetable oil, soybean lecithin, and liquid paraffin; A tafamidis-containing pharmaceutical composition comprising:

2. The tafamidis-containing pharmaceutical composition according to claim 1, wherein the glycerin fatty acid ester is decaglyceryl trioleate or decaglyceryl decaoleate.

3. The tafamidis-containing pharmaceutical composition according to claim 1, wherein the polyethylene glycol fatty acid ester is polyethylene glycol monooleate.

4. The tafamidis-containing pharmaceutical composition according to claim 1, characterized in that the vegetable oil is soybean oil or castor oil.

5. The tafamidis-containing pharmaceutical composition according to claim 4, wherein the vegetable oil is soybean oil.

6. The pharmaceutical composition containing tafamidis according to claim 1, characterized in that Form 4 of tafamidis has peaks at 16.87°±0.2° and 27.23°±0.2° 2θ as measured by powder X-ray diffraction (XRD).

7. The pharmaceutical composition containing tafamidis according to claim 6, characterized in that no peaks are detected at 5.07°±0.2°, 8.01°±0.2°, and 20.24°±0.2° 2θ when measured by powder X-ray diffraction (XRD).

8. A formulation comprising the tafamidis-containing pharmaceutical composition according to any one of claims 1 to 7.

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