Tafamidis pharmaceutical composition

Abstract

The present invention provides a pharmaceutical composition which is a tablet containing tafamidis free acid, one or more diluents, a disintegrant of 7 - 9% (w / w%) and a lubricant. A typical example is a tablet containing about 11.6% (w / w%) of tafamidis free acid; about 53.1% (w / w%) of microcrystalline cellulose; about 26.55% (w / w%) of lactose monohydrate; about 8.0% (w / w%) of crospovidone type b and about 0.75% (w / w%) of magnesium stearate. 【Figure 1】 TIFF2025524085000013.tif161105

Description

Technical Field

[0001] Transthyretin (ATTR) amyloidosis is a rare progressive disease characterized by the abnormal accumulation of amyloid deposits composed of misfolded transthyretin protein in body organs and tissues. ATTR amyloidosis can affect multiple organs and tissues of the body, including the peripheral nervous system and organs such as the heart, kidneys, gastrointestinal tract, and eyes. Transthyretin cardiomyopathy (ATTR-CM) and transthyretin polyneuropathy (ATTR-PN) are two manifestations of the disease. ATTR-CM affects the heart and leads to restrictive cardiomyopathy and progressive heart failure. There are two subtypes of ATTR-CM: hereditary, caused by mutations in the transthyretin gene and occurring in humans in the early 50s and 60s; or wild-type, associated with aging, more common, and usually affecting men over 60. In many cases, ATTR-CM is diagnosed only after the symptoms have become severe. ATTR-PN results from genetic mutations in the transthyretin gene that cause the formation of amyloid fibrils in the peripheral and autonomic nerves. ATTR-PN typically occurs during active adulthood, with some patients developing the disease in the early 30s, and subsequently, the disease progresses and can reach the end stage approximately 10 years on average from disease onset.

Background Art

[0002] Tafamidis, sold under the trademark names Vyndaqel® and Vyndamax®, is an oral transthyretin stabilizer used to treat adults with a specific type of transthyretin amyloidosis. Tafamidis can be used to treat both hereditary and wild-type transthyretin amyloidosis. Tafamidis acts by selectively binding to transthyretin, stabilizing the quaternary structure of the tetrameric transthyretin protein, and slowing the formation of amyloid. Tafamidis free acid can be prepared by methods such as those described in U.S. Patent No. 7,214,695, WO04056315, U.S. Patent No. 9,770,441, and WO2016 / 038500. SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION

[0003] MEANS FOR SOLVING THE PROBLEMS

[0004] The present invention provides an oral pharmaceutical composition containing tafamidis free acid. The oral pharmaceutical composition contains tafamidis free acid in an oral tablet dosage form. Specifically, the present invention provides an immediate-release tablet formulation of tafamidis free acid, which may be film-coated. Tafamidis is formulated as a common blend for making an immediate-release tablet core, which is then film-coated to produce film-coated tablets such as 12.2 mg tafamidis free acid and 61 mg tafamidis free acid tablets.

[0005] 12.2 mg and 61 mg film-coated tablets of tafamidis are formulated for immediate release for the oral treatment of transthyretin amyloidosis diseases such as ATTR-CM and ATTR-PN. When the tablet core is made from a common blend using a dry granulation process and then film-coated by a batch process, a film-coated tablet pharmaceutical can be obtained.

[0006] Next is a representative embodiment of the present invention, but it should not be construed in a limiting manner.

[0007] E1 is a pharmaceutical composition which is a tablet containing tafamidis free acid, one or more diluents, 7 - 9% (w / w%) of a disintegrant and a lubricant.

[0008] E2 is the pharmaceutical composition according to E1, which is a tablet in which the disintegrant is crospovidone.

[0009] E3 is the pharmaceutical composition according to E1 or E2, which is a tablet in which the disintegrant is crospovidone type b.

[0010] E4 is the pharmaceutical composition according to any one of E1 to E3, which is a tablet in which the one or more diluents are selected from microcrystalline cellulose and lactose monohydrate.

[0011] E5 is the pharmaceutical composition according to any one of E1 to E4, which is a tablet in which the lubricant is magnesium stearate.

[0012] E6 is the pharmaceutical composition according to any one of E1 to E5, which is a tablet containing about 8% (w / w%) of crospovidone type b.

[0013] E7 is the pharmaceutical composition according to any one of E1 to E6, which is a tablet containing about 11.6% (w / w%) of tafamidis free acid.

[0014] E8 is the pharmaceutical composition according to any one of E1 to E7, which is a tablet containing 12.2 mg of tafamidis free acid.

[0015] E9 is the pharmaceutical composition according to any one of E1 to E7, which is a tablet containing 61 mg of tafamidis free acid.

[0016] E10 is a pharmaceutical composition according to any one of E1 to E9, which is a tablet containing about 79.65% (w / w%) of one or more diluents selected from microcrystalline cellulose and lactose monohydrate.

[0017] E11 is a pharmaceutical composition according to any one of E1 to E10, which is a tablet containing about 53.1% (w / w%) of microcrystalline cellulose and about 26.55% of lactose monohydrate.

[0018] E12 is a pharmaceutical composition according to any one of E1 to E11, which is a tablet containing about 0.75% (w / w%) of magnesium stearate.

[0019] E13 is a pharmaceutical composition according to any one of E1 to E12, wherein the tablet is film-coated.

[0020] E14 is a pharmaceutical composition according to E13, wherein the tablet film coating contains hydroxypropyl methylcellulose and lactose.

[0021] E15 is a pharmaceutical composition according to E13 or E14, wherein the tablet film coating is about 4% (w / w) of the total weight of the film-coated tablet.

[0022] E16 is a pharmaceutical composition which is a tablet containing about 11.6% (w / w%) of tafamidis free acid; about 53.1% (w / w%) of microcrystalline cellulose; about 26.55% (w / w%) of lactose monohydrate; about 8.0% (w / w%) of crospovidone type b and about 0.75% (w / w%) of magnesium stearate.

[0023] E17 is a pharmaceutical composition which is a tablet containing 11.6% ± 0.1% (w / w%) of tafamidis free acid; 53.1% ± 0.1% (w / w%) of microcrystalline cellulose; 26.55% ± 0.1% (w / w%) of lactose monohydrate; 8.0% ± 0.1% (w / w%) of crospovidone type b and 0.75% ± 0.1% (w / w%) of magnesium stearate.

[0024] E18 is the pharmaceutical composition according to E16 or E17, wherein the tablet is film-coated.

[0025] E19 is the pharmaceutical composition according to any one of E16 to E18, wherein the tablet film coating contains hydroxypropyl methylcellulose and lactose.

[0026] E20 is the pharmaceutical composition according to E18 or E19, wherein the weight of the tablet film coating is 4.0% ± 0.1% (w / w%) of the total weight of the film-coated tablet.

[0027] E21 is a pharmaceutical composition which is a tablet containing about 12.20 mg of tafamidis free acid, about 55.85 mg of microcrystalline cellulose, about 27.92 mg of lactose monohydrate, about 8.42 mg of crospovidone type b and about 0.79 mg of magnesium stearate.

[0028] E22 is the medicine according to E21, which is a tablet containing 12.20 mg of tafamidis free acid, 55.85 mg of microcrystalline cellulose, 27.92 mg of lactose monohydrate, 8.42 mg of crospovidone type b and 0.79 mg of magnesium stearate.

[0029] E23 is the pharmaceutical composition according to E21 or E22, wherein the tablet is film-coated.

[0030] E24 is the pharmaceutical composition according to E23, wherein the tablet film coating contains hydroxypropyl methylcellulose and lactose.

[0031] E25 is the pharmaceutical composition according to E23 or E24, wherein the weight of the tablet film coating is 4.21 mg.

[0032] E26 is a pharmaceutical composition that is a tablet containing approximately 61.00 mg of tafamidis free acid, approximately 279.25 mg of microcrystalline cellulose, approximately 139.6 mg of lactose monohydrate, approximately 42.10 mg of crospovidone type b, and approximately 2.95 mg of magnesium stearate.

[0033] E27 is the pharmaceutical composition according to E26, which is a tablet containing 61.00 mg of tafamidis free acid, 279.25 mg of microcrystalline cellulose, 139.6 mg of lactose monohydrate, 42.10 mg of crospovidone type b, and 2.95 mg of magnesium stearate.

[0034] E28 is the pharmaceutical composition according to E26 or E27, in which the tablet is film-coated.

[0035] E29 is the pharmaceutical composition according to E28, in which the tablet film coating contains hydroxypropyl methylcellulose and lactose.

[0036] E30 is the pharmaceutical composition according to E28 or E29, in which the weight of the tablet film coating is 21.05 mg.

[0037] E31 is the pharmaceutical composition according to any one of E1 to E7, which is a tablet containing approximately 13.0 mg, approximately 13.5 mg, approximately 14.0 mg, approximately 14.5 mg, approximately 15.0 mg, approximately 15.5 mg, approximately 59.0 mg, approximately 60.0 mg, or approximately 62 mg of tafamidis free acid.

[0038] E32 is the pharmaceutical composition according to E31, which is a tablet containing 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 59.0 mg, 60.0 mg, or 62.0 mg of tafamidis free acid.

[0039] E33 is the pharmaceutical composition according to E32, which is a tablet containing 13.0 mg of tafamidis free acid.

[0040] E34 is the pharmaceutical composition according to E33, which is a tablet containing 13.0 mg of tafamidis free acid, 59.51 mg of microcrystalline cellulose, 29.75 mg of lactose monohydrate, 8.98 mg of crospovidone type b, and 0.85 mg of magnesium stearate.

[0041] E35 is the pharmaceutical composition according to E32, which is a tablet containing 13.5 mg of tafamidis free acid.

[0042] E36 is the pharmaceutical composition according to E35, which is a tablet containing 13.5 mg of tafamidis free acid, 61.80 mg of microcrystalline cellulose, 30.89 mg of lactose monohydrate, 9.32 mg of crospovidone type b, and 0.88 mg of magnesium stearate.

[0043] E37 is the pharmaceutical composition according to E32, which is a tablet containing 14.0 mg of tafamidis free acid.

[0044] E38 is the pharmaceutical composition according to E37, which is a tablet containing 14.0 mg of tafamidis free acid, 64.09 mg of microcrystalline cellulose, 32.04 mg of lactose monohydrate, 9.66 mg of crospovidone type b, and 0.91 mg of magnesium stearate.

[0045] E39 is the pharmaceutical composition according to E32, which is a tablet containing 14.5 mg of tafamidis free acid.

[0046] E40 is the pharmaceutical composition according to E39, which is a tablet containing 14.5 mg of tafamidis free acid, 66.38 mg of microcrystalline cellulose, 33.18 mg of lactose monohydrate, 10.00 mg of crospovidone type b, and 0.94 mg of magnesium stearate.

[0047] E41 is the pharmaceutical composition according to E32, which is a tablet containing 15.0 mg of tafamidis free acid.

[0048] E42 is the pharmaceutical composition according to E41, which is a tablet containing 15.0 mg of tafamidis free acid, 68.69 mg of microcrystalline cellulose, 34.33 mg of lactose monohydrate, 10.36 mg of crospovidone type b, and 0.97 mg of magnesium stearate.

[0049] E43 is the pharmaceutical composition according to E32, which is a tablet containing 15.5 mg of tafamidis free acid.

[0050] E44 is the pharmaceutical composition according to E43, which is a tablet containing 15.5 mg of tafamidis free acid, 70.96 mg of microcrystalline cellulose, 35.47 mg of lactose monohydrate, 10.70 mg of crospovidone type b, and 1.00 mg of magnesium stearate.

[0051] E45 is the pharmaceutical composition according to E32, which is a tablet containing 59.0 mg of tafamidis free acid.

[0052] E46 is the pharmaceutical composition according to E45, which is a tablet containing 59.0 mg of tafamidis free acid, 270.09 mg of microcrystalline cellulose, 135.02 mg of lactose monohydrate, 40.72 mg of crospovidone type b, and 3.82 mg of magnesium stearate.

[0053] E47 is the pharmaceutical composition according to E32, which is a tablet containing 60.0 mg of tafamidis free acid.

[0054] E48 is the pharmaceutical composition according to E47, which is a tablet containing 60.0 mg of tafamidis free acid, 274.67 mg of microcrystalline cellulose, 137.31 mg of lactose monohydrate, 41.40 mg of crospovidone type b, and 3.89 mg of magnesium stearate.

[0055] E49 is the pharmaceutical composition according to E32, which is a tablet containing 62.0 mg of tafamidis free acid.

[0056] E50 is the pharmaceutical composition according to E49, which is a tablet containing 62.0 mg of tafamidis free acid, 283.83 mg of microcrystalline cellulose, 141.89 mg of lactose monohydrate, 42.80 mg of crospovidone type b, and 4.01 mg of magnesium stearate.

[0057] E51 is the pharmaceutical composition according to any one of E31 to E50, wherein the tablet is film-coated.

[0058] E52 is the pharmaceutical composition according to E51, wherein the film coating of the tablet contains hydroxypropyl methylcellulose and lactose.

[0059] E53 is the pharmaceutical composition according to E52, wherein the film coating of the tablet is about 4% (w / w) of the total weight of the film-coated tablet.

[0060] E54 is a method for treating transthyretin amyloidosis in a patient, which comprises administering to the patient the pharmaceutical composition according to any one of E1 to E53.

[0061] E55 is the method according to claim 54, wherein the transthyretin amyloidosis is transthyretin cardiomyopathy (ATTR-CM) or transthyretin polyneuropathy (ATTR-PN).

[0062] E56 is the use of the pharmaceutical composition according to any one of E1 to E53 for treating transthyretin amyloidosis.

[0063] E57 is the use according to E56, wherein the transthyretin amyloidosis is transthyretin cardiomyopathy (ATTR-CM) or transthyretin polyneuropathy (ATTR-PN).

Brief Description of the Drawings

[0064]

Figure 1

Mode for Carrying Out the Invention

[0065] The additives used in the tafamidis tablets or film-coated tablets are globally acceptable, and all except crospovidone are present at pre-exemplified levels in the formulation. The amounts of tablet ingredients can be expressed as weight percentages of the tablet (i.e., w / w%). The term "about" should be used as being plus or minus 0.2% or alternatively 0.1% (i.e., ±0.2% or ±0.1%). Crospovidone is typically used at 1 - 5% (w / w%) levels, and an advantageous embodiment of the tafamidis common blend used to prepare the tablet core of the present invention contains 8% crospovidone. Crospovidone was evaluated during development at 4, 6, 8, and 10% (w / w%) levels, and accordingly the microcrystalline cellulose / lactose monohydrate diluent was adjusted to manage the tablet core weight. Optimal release characteristics to achieve bioequivalence (BE) when compared to the currently marketed 20 mg tafamidis meglumine soft gelatin capsule product, based on biopharmaceutics modeling (in-vitro) associated with the use of the differential dissolution method, were achieved at a crospovidone level of 8% (w / w%). Alternative formulations evaluated at a crospovidone disintegrant level reduced to 6% (w / w%), presented in Table 2, failed bioequivalence when compared to the 20 mg tafamidis meglumine soft gelatin capsule during batch evaluation. This data demonstrates the importance of the crospovidone disintegrant level required to achieve bioequivalence to the 20 mg tafamidis meglumine gel capsule.

[0066] Modifications to the formulation to achieve bioequivalence (BE) when compared to an alternative formulation include increasing the disintegrant level, changing the crospovidone particle size, and eliminating the dry binder (commonly known as vinyl pyrrolidone-vinyl acetate copolymer or copovidone). The use of crospovidone with a reduced particle size for a formulation containing crospovidone in the extra-granular portion of the manufacturing process acts as a disintegrant / dry binder and is hypothesized to eliminate the in-vivo residual of the active pharmaceutical ingredient within the tablet, which could be the root cause of BE failure of an alternative formulation as noted for a vinyl pyrrolidone-vinyl acetate copolymer (dry binder) without disintegration properties. Studies have been conducted to evaluate the impact of additives on pharmaceutical manufacturing and performance. Microcrystalline cellulose and lactose monohydrate are the diluents used in this tavamidis formulation and have precedence at the proposed levels in oral tablets. These components are used in a 2:1 ratio to facilitate powder flow and compressibility during tablet compression. Crospovidone is included in the tablet core formulation as a disintegrant in oral tablets. The addition of the disintegrant promotes tablet disintegration, and addition to the extra-granular portion after roller compression acts as a disintegrant and further as a dry binder. Magnesium stearate is included in the tablet core formulation as a lubricant in tablets. Magnesium stearate is used as a lubricant in the tablet core formulation to assist in tablet compression. Opadry® II Yellow and Opadry® II White are patented film coating systems used for 12.2 mg and 61 mg tablets, respectively.

[0067] Estimation of Dose Adjustment for Low-Dose Tavamidis Free Acid Tablets To estimate the possible dose adjustment range (equivalent to 1 20 mg meglumine salt (MS) capsule) for low-dose tavamidis free acid (FA) tablets, the C max and AUC inf ratio of the 12.2 mg FA tablet and the 20 mg tavamidis MS capsule obtained in Study B3461103 was used. The C max and AUC infis assumed to increase proportionally as the dose increases from 12.2 mg to 17 mg. The estimated C max and AUC inf ratios of tafamidis FA tablets with various concentrations and 20 mg tafamidis MS capsules are listed in Table A.

[0068]

Table 1

[0069] Estimated C max and AUC inf Since the ratio is within 0.8 to 1.25, the possible dose adjustment range (equivalent to 20 mg tafamidis MS capsules) with low-dose tafamidis FA tablets is estimated to be 12.2 mg to 16 mg. Estimated C max and AUC inf Since the ratio is within 0.85 to 1.20, a more conservative estimated value would be set in the dose range between 13 mg and 15.5 mg.

[0070] Estimation of dose adjustment for high-dose tafamidis free acid tablets To estimate the possible dose adjustment range (equivalent to 4 × 20 mg meglumine salt capsules) with high-dose tafamidis FA tablets, the C max and AUC inf ratios of 48.8 mg or 58 mg tafamidis FA tablets and 4 × 20 mg tafamidis MS capsules obtained in Study B3461030 and Study B3461051 were used. The C max and AUC inf of tafamidis FA tablets are assumed to increase proportionally as the dose increases from 48.8 mg to 71 mg.

[0071] Estimated C max and AUC infThe ratio can be calculated using the clinical data obtained in Study B3461030 (48.8 mg tafamidis FA tablets vs. 4 x 20 mg tafamidis MS capsules) and Study B3461051 (48.8 mg tafamidis FA tablets or 58 mg tafamidis free acid tablets vs. 4 x 20 mg tafamidis MS capsules). The estimated C max and AUC inf ratios for tafamidis FA tablets with various concentrations and 4 x 20 mg tafamidis MS capsules are listed in Table B.

[0072] Based on the observed rBA data of the 48.8 mg tafamidis FA tablets in Study B3461030 (Table B2), the estimated C max and AUC inf ratios are within 0.8 - 1.25, so the dose adjustment range for high-dose tafamidis FA tablets (equivalent to 4 x 20 mg meglumine salt capsules) is estimated to be 51 mg - 70 mg. Using the same acceptance criteria, the dose adjustment range is estimated to be 53 mg - 67 mg when using the observed rBA data of the 48.8 mg tafamidis FA tablets in Study B3461051 (Table B2), and 56 mg - 65 mg when using the observed rBA data of the 58 mg tafamidis FA tablets in Study B3461051 (Table B3).

[0073] To estimate the dose adjustment range with a more conservative approach, the acceptance criteria for the C max and AUC inf ratios can be set to 0.85 - 1.20. In this case, the possible dose adjustment ranges are estimated to be 51 - 67 mg when using the 48.8 mg tafamidis FA tablet rBA data from Study B3461030 (Table B), 56 - 64 mg when using the 48.8 mg tafamidis FA tablet rBA data from Study B3461051 (Table B2), and 59 - 62 mg when using the 58 mg tafamidis FA tablet rBA data from Study B3461051 (Table B3). Since all calculation ranges cover 59 - 62 mg, this dose adjustment range (59 - 62 mg) would be preferred.

[0074] In summary, the observed clinical data suggest that the dosage adjustment range of high-dose tafamidis FA tablets may be between 51 mg and 70 mg. This dosage range includes all of the estimated ranges calculated by the above method. Within this dosage adjustment range, since it is the common part of all the estimated ranges, 59 mg to 62 mg is preferred.

[0075] [Table 2]

[0076] [Table 3]

[0077] [Table 4]

[0078] Formulation Tafamidis is formulated as a common blend for making immediate-release tablet cores such as 12.2 mg and 61 mg immediate-release tablet cores. The formulations presented in Table 1 are composed of microcrystalline cellulose and lactose monohydrate (diluent), crospovidone (disintegrant), and magnesium stearate (lubricant). Commercially available tafamidis tablets are manufactured using a dry granulation manufacturing platform, followed by a film coating step. The tablets are film coated with a suitable coating. For example, the tablets can be coated with a hydroxypropylmethylcellulose / lactose-based Opadry® II formulation that has a yellow color for 12.2 mg tablets and a white color for 61 mg tablets. [Examples]

[0079] General procedure for tablet preparation Add microcrystalline cellulose (Item 2), crospovidone (Item 4), tafamidis free acid (Item 1), and lactose monohydrate (Item 3) to an intermediate bulk container (IBC) of appropriate size, and blend at 12 ± 1 revolutions per minute (rpm) for 20 ± 1 minutes to obtain a first blend [referred to as Blend 1 / 4].

[0080] Pass the contents of the IBC (Blend 1 / 4) through a Comil U20 equipped with a 032R or 024R screen and a circular edge impeller operating at 750 ± 50 rpm, or equivalent (e.g., Comil U10 / 197 S equipped with a 0.6 - 0.8 mm sieve operating at 1320 ± 80 rpm). Collect the resulting blend in the IBC. Pre-screen magnesium stearate (Item 5) (1 mm screen, US Sieve #20) and add it to the IBC. Blend at 12 ± 1 rpm for 3 ± 1 minutes to obtain a second blend [referred to as Blend 2 / 4]. Roller compress and micronize Blend 2 / 4 with a Gerteis 3W Macropactor or equivalent. Collect the resulting granules in the IBC.

[0081] Add extragranular crospovidone (Item 6) to the IBC while preparing for the required yield, and blend for 20 ± 1 minutes. Pre-screen magnesium stearate (Item 7) (1 mm screen, US Sieve #20) and add it to the IBC while preparing for the required yield. Blend at 12 ± 1 rpm for 3 ± 1 minutes [Blend 4 / 4], and blend at 12 ± 1 rpm for 1 ± 1 minute [referred to as Blend 3 / 4].

[0082] Use a rotary press to compress the tablets to a target average weight of 105.2 ± 5% (±5.2 mg) and a target hardness of 5 ± 2 kP (49 ± 19 N) using a 6.5 mm tool. The preceding sentence is for 12.2 mg tablets; a similar tablet compression process is used to prepare 61 mg tablets. After compression, dust the cores and pass them through a metal detector.

[0083] For the 12.2 mg tablets, use Opadry II Yellow (33G120011) (Item 8) and purified water (Item 9) to prepare a solid 18% w / w film coating suspension. This suspension should be prepared in excess taking into account processing losses. For the 61 mg tablets, use Opadry II White and purified water to prepare a similar film coating suspension. Fill a suitable coating pan with an appropriate amount of tablet cores. Apply sufficient film coating to give a minimum target weight increase of 4% relative to the average core tablet weight.

[0084] Using a similar approach to the preceding procedure, prepare tablet cores containing 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 59.0 mg, 60 mg or 62.0 mg of tafamidis and coat those cores at 4% by weight with film coating.

[0085] Examples 1 and 2 were prepared using the general procedure for tablet preparation as described above.

[0086]

Table 5

[0087] Comparative Example A

[0088]

Table 6

[0089] The above tablets were prepared in a manner similar to the general method described for Examples 1 and 2. In the study, this formulation was unable to show characteristics equivalent to those of the 20 mg tafamidis meglumine gel capsules and was therefore determined to be not feasible as a commercially acceptable formulation.

[0090] Comparative Example B

[0091] [Table 7]

[0092] Examples 3 to 12

[0093] [Table 8]

[0094] [Table 9]

[0095] [Table 10]

[0096] [Table 11]

[0097] All patents and publications mentioned above in this specification are hereby incorporated by reference in their entirety. Although the present invention has been described with respect to various preferred embodiments and specific examples, it should not be understood that the present invention is limited by the above detailed description, but rather should be understood to be defined by the appended claims and their equivalents.

Claims

1. A pharmaceutical composition which is a tablet containing tafamidis free acid, one or more diluents, 7-9% (w / w%) of a disintegrant and a lubricant.

2. The pharmaceutical composition according to claim 1, which is a tablet wherein the disintegrant is crospovidone.

3. The pharmaceutical composition according to claim 2, which is a tablet wherein the disintegrant is crospovidone type b.

4. The pharmaceutical composition according to claim 3, which is a tablet wherein the one or more diluents are selected from microcrystalline cellulose and lactose monohydrate.

5. The pharmaceutical composition according to claim 4, which is a tablet wherein the lubricant is magnesium stearate.

6. The pharmaceutical composition according to claim 5, which is a tablet containing about 8% (w / w%) of crospovidone type b.

7. The pharmaceutical composition according to claim 6, which is a tablet containing about 11.6% (w / w%) of tafamidis free acid.

8. The pharmaceutical composition according to claim 7, which is a tablet containing 12.2 mg of tafamidis free acid.

9. The pharmaceutical composition according to claim 7, which is a tablet containing 61 mg of tafamidis free acid.

10. The pharmaceutical composition according to claim 8 or claim 9, which is a tablet containing about 79.65% (w / w%) of one or more diluents selected from microcrystalline cellulose and lactose monohydrate.

11. The pharmaceutical composition according to claim 10, which is a tablet containing about 53.1% (w / w%) of microcrystalline cellulose and about 26.55% of lactose monohydrate.

12. The pharmaceutical composition according to claim 11, which is a tablet containing about 0.75% (w / w%) of magnesium stearate.

13. The pharmaceutical composition according to any one of claims 12, wherein the tablet is film-coated.

14. The pharmaceutical composition according to claim 13, wherein the tablet film coating contains hydroxypropyl methylcellulose and lactose.

15. The pharmaceutical composition according to claim 14, wherein the tablet film coating is about 4% (w / w) of the total weight of the film-coated tablet.

16. A pharmaceutical composition which is a tablet containing about 11.6% (w / w%) of tafamidis free acid; about 53.1% (w / w%) of microcrystalline cellulose; about 26.55% (w / w%) of lactose monohydrate; about 8.0% (w / w%) of crospovidone type b and about 0.75% (w / w%) of magnesium stearate.

17. A pharmaceutical composition which is a tablet containing tavamidis free acid 11.6% ± 0.1% (w / w%); microcrystalline cellulose 53.1% ± 0.1% (w / w%); lactose monohydrate 26.55% ± 0.1% (w / w%); crospovidone type b 8.0% ± 0.1% (w / w%) and magnesium stearate 0.75% ± 0.1% (w / w%).

18. The pharmaceutical composition according to claim 16 or 17, wherein the tablet is film-coated.

19. The pharmaceutical composition according to any one of claims 18, wherein the tablet film coating contains hydroxypropyl methylcellulose and lactose.

20. The pharmaceutical composition according to claim 19, wherein the tablet film coating is 4.0% ± 0.1% (w / w%) of the total weight of the film-coated tablet.

21. A pharmaceutical composition which is a tablet containing about 12.20 mg of tavamidis free acid, about 55.85 mg of microcrystalline cellulose, about 27.92 mg of lactose monohydrate, about 8.42 mg of crospovidone type b and about 0.79 mg of magnesium stearate.

22. The medicine according to claim 21, which is a tablet containing 12.20 mg of tavamidis free acid, 55.85 mg of microcrystalline cellulose, 27.92 mg of lactose monohydrate, 8.42 mg of crospovidone type b and 0.79 mg of magnesium stearate.

23. The pharmaceutical composition according to claim 22, wherein the tablet is film-coated.

24. The pharmaceutical composition according to claim 23, wherein the tablet film coating contains hydroxypropyl methylcellulose and lactose.

25. The pharmaceutical composition according to claim 24, wherein the weight of the tablet film coating is 4.21 mg.

26. A pharmaceutical composition which is a tablet containing about 61.00 mg of tavamidis free acid, about 279.25 mg of microcrystalline cellulose, about 139.6 mg of lactose monohydrate, about 42.10 mg of crospovidone type b and about 2.95 mg of magnesium stearate.

27. The pharmaceutical composition according to claim 26, which is a tablet containing 61.00 mg of tavamidis free acid, 279.25 mg of microcrystalline cellulose, 139.6 mg of lactose monohydrate, 42.10 mg of crospovidone type b and 2.95 mg of magnesium stearate.

28. The pharmaceutical composition according to claim 27, wherein the tablet is film-coated.

29. The pharmaceutical composition according to claim 28, wherein the tablet film coating comprises hydroxypropyl methylcellulose and lactose.

30. The pharmaceutical composition according to claim 29, wherein the weight of the tablet film coating is 21.05 mg.

31. The pharmaceutical composition according to claim 7, which is a tablet comprising about 13.0 mg, about 13.5 mg, about 14.0 mg, about 14.5 mg, about 15.0 mg, about 15.5 mg, about 59.0 mg, about 60.0 mg or about 62 mg of tafamidis free acid.

32. The pharmaceutical composition according to claim 31, which is a tablet comprising 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 59.0 mg, 60.0 mg or 62.0 mg of tafamidis free acid.

33. The pharmaceutical composition according to claim 32, which is a tablet comprising 13.0 mg of tafamidis free acid.

34. The pharmaceutical composition according to claim 33, which is a tablet comprising 13.0 mg of tafamidis free acid, 59.51 mg of microcrystalline cellulose, 29.75 mg of lactose monohydrate, 8.98 mg of crospovidone type b and 0.85 mg of magnesium stearate.

35. The pharmaceutical composition according to claim 32, which is a tablet comprising 13.5 mg of tafamidis free acid.

36. The pharmaceutical composition according to claim 35, which is a tablet comprising 13.5 mg of tafamidis free acid, 61.80 mg of microcrystalline cellulose, 30.89 mg of lactose monohydrate, 9.32 mg of crospovidone type b and 0.88 mg of magnesium stearate.

37. The pharmaceutical composition according to claim 32, which is a tablet comprising 14.0 mg of tafamidis free acid.

38. The pharmaceutical composition according to claim 37, which is a tablet comprising 14.0 mg of tafamidis free acid, 64.09 mg of microcrystalline cellulose, 32.04 mg of lactose monohydrate, 9.66 mg of crospovidone type b and 0.91 mg of magnesium stearate.

39. The pharmaceutical composition according to claim 32, which is a tablet comprising 14.5 mg of tafamidis free acid.

40. The pharmaceutical composition according to claim 39, which is a tablet containing 14.5 mg of tafamidis free acid, 66.38 mg of microcrystalline cellulose, 33.18 mg of lactose monohydrate, 10.00 mg of crospovidone type b, and 0.94 mg of magnesium stearate.

41. The pharmaceutical composition according to claim 32, which is a tablet containing 15.0 mg of tafamidis free acid.

42. The pharmaceutical composition according to claim 41, which is a tablet containing 15.0 mg of tafamidis free acid, 68.69 mg of microcrystalline cellulose, 34.33 mg of lactose monohydrate, 10.36 mg of crospovidone type b, and 0.97 mg of magnesium stearate.

43. The pharmaceutical composition according to claim 32, which is a tablet containing 15.5 mg of tafamidis free acid.

44. The pharmaceutical composition according to claim 43, which is a tablet containing 15.5 mg of tafamidis free acid, 70.96 mg of microcrystalline cellulose, 35.47 mg of lactose monohydrate, 10.70 mg of crospovidone type b, and 1.00 mg of magnesium stearate.

45. The pharmaceutical composition according to claim 32, which is a tablet containing 59.0 mg of tafamidis free acid.

46. The pharmaceutical composition according to claim 45, which is a tablet containing 59.0 mg of tafamidis free acid, 270.09 mg of microcrystalline cellulose, 135.02 mg of lactose monohydrate, 40.72 mg of crospovidone type b, and 3.82 mg of magnesium stearate.

47. The pharmaceutical composition according to claim 32, which is a tablet containing 60.0 mg of tafamidis free acid.

48. The pharmaceutical composition according to claim 47, which is a tablet containing 60.0 mg of tafamidis free acid, 274.67 mg of microcrystalline cellulose, 137.31 mg of lactose monohydrate, 41.40 mg of crospovidone type b, and 3.89 mg of magnesium stearate.

49. The pharmaceutical composition according to claim 32, which is a tablet containing 62.0 mg of tafamidis free acid.

50. The pharmaceutical composition according to claim 49, which is a tablet containing 62.0 mg of tafamidis free acid, 283.83 mg of microcrystalline cellulose, 141.89 mg of lactose monohydrate, 42.80 mg of crospovidone type b, and 4.01 mg of magnesium stearate.

51. The pharmaceutical composition according to any one of claims 31 to 50, wherein the tablet is film-coated.

52. The pharmaceutical composition according to claim 51, wherein the tablet film coating comprises hydroxypropyl methylcellulose and lactose.

53. The pharmaceutical composition according to claim 52, wherein the tablet film coating is about 4% (w / w) of the total weight of the film-coated tablet.

54. A method of treating transthyretin amyloidosis in a patient, the method comprising administering to the patient a pharmaceutical composition according to any one of claims 1 to 53.

55. The method according to claim 54, wherein the transthyretin amyloidosis is transthyretin cardiomyopathy (ATTR-CM) or transthyretin polyneuropathy (ATTR-PN).

56. Use of a pharmaceutical composition according to any one of claims 1 to 53 for treating transthyretin amyloidosis.

57. The use according to claim 56, wherein the transthyretin amyloidosis is transthyretin cardiomyopathy (ATTR-CM) or transthyretin polyneuropathy (ATTR-PN).

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