Chlorazolic acid pharmaceutical composition

Abstract

The present invention provides a pharmaceutical composition, which is a tablet comprising free chlorbuconazole, one or more diluents, 7-9% (w / w%) disintegrant, and lubricant. A representative embodiment is comprising about 11.6% (w / w%) of free chloroazolate; about 53.1% (w / w%) microcrystalline cellulose; about 26.55% (w / w%) lactose monohydrate; tablets of about 8.0% (w / w%) type b cross-linked povidone and about 0.75% (w / w%) magnesium stearate.

Description

[0001] Transthyretin (ATTR) amyloidosis is a rare, progressive disease characterized by the abnormal accumulation of amyloid deposits composed of misfolded thyroxine transporter proteins in organs and tissues of the body. ATTR amyloidosis can affect many organs and tissues in 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 causes restrictive cardiomyopathy and progressive heart failure. There are two subtypes of ATTR-CM: the hereditary type, which is caused by mutations in the thyroxine transporter gene and can appear as early as in people's 50s and 60s; or the wild type, which is associated with aging and is considered more common, usually affecting men after the age of 60. ATTR-CM is often diagnosed only after symptoms have become severe. ATTR-PN is caused by genetic mutations in the thyroxine transporter gene, which causes amyloid fibrils to form in peripheral and autonomic nerves. ATTR-PN generally presents in active adulthood, with onset as early as the 30s in some patients, followed by disease progression that reaches a terminal stage within an average of approximately 10 years from disease onset.

[0002] Trademark name and Tafamidis, which is sold, is an oral thyroxine transporter stabilizer drug for treating adults with certain forms of thyroxine transporter amyloidosis. Tafamidis can be used to treat hereditary and wild-type thyroxine transporter amyloidosis. Tafamidis works by selectively binding to thyroxine transporter and stabilizing the quaternary structure of tetrameric thyroxine transporter and slowing down the formation of amyloid. Tafamidis free acid can be prepared by methods such as those described in U.S. Patents 7,214,695, WO04056315, US 9,770,441 and WO 2016 / 038500. Summary of the invention

[0003] The present invention provides an oral pharmaceutical composition comprising tamiprofen free acid. The oral pharmaceutical composition comprises tamiprofen free acid in an oral tablet dosage form. The present invention particularly provides an immediate release tablet formulation of tamiprofen free acid, wherein the tablet may be film-coated. Tamiprofen is formulated as a common blend to make an immediate release tablet core, which is then film-coated to make a film-coated tablet, such as 12.2 mg tamiprofen free acid and 61 mg tamiprofen free acid tablet drug products.

[0004] Tamiflu 12.2 mg and 61 mg film-coated tablets have been formulated for immediate release for oral treatment of transthyretin amyloidosis (such as ATTR-CM and ATTR-PN). The core is made from a common blend using a dry granulation process and can then be film coated by a batch process to provide a film-coated tablet drug product.

[0005] The following are representative embodiments of the present invention and should not be construed in a limiting manner.

[0006] E1 is a pharmaceutical composition which is a tablet comprising tamiflu acid free acid, one or more diluents, 7-9% (w / w%) of a disintegrant, and a lubricant.

[0007] E2 is the pharmaceutical composition of E1, which is a tablet, wherein the disintegrant is crospovidone.

[0008] E3 is the pharmaceutical composition of E1 or E2, which is a tablet, wherein the disintegrant is type b crospovidone.

[0009] E4 is the pharmaceutical composition of any one of E1 to E3, which is a tablet, wherein the one or more diluents are selected from microcrystalline cellulose and lactose monohydrate.

[0010] E5 is the pharmaceutical composition of any one of E1 to E4, which is a tablet, wherein the lubricant is magnesium stearate.

[0011] E6 is the pharmaceutical composition of any one of E1 to E5, which is a tablet comprising about 8% (w / w%) crospovidone type b.

[0012] E7 is the pharmaceutical composition of any one of E1 to E6, which is a tablet comprising about 11.6% (w / w%) tamiflu acid free acid.

[0013] E8 is the pharmaceutical composition of any one of E1 to E7, which is a tablet comprising 12.2 mg of clofazodone free acid.

[0014] E9 is the pharmaceutical composition of any one of E1 to E7, which is a tablet comprising 61 mg of clofazodone free acid.

[0015] E10 is the pharmaceutical composition of any one of E1 to E9, which is a tablet comprising about 79.65% (w / w%) of one or more diluents selected from microcrystalline cellulose and lactose monohydrate.

[0016] E11 is the pharmaceutical composition of any one of E1 to E10, which is a tablet comprising about 53.1% (w / w%) microcrystalline cellulose and about 26.55% lactose monohydrate.

[0017] E12 is the pharmaceutical composition of any one of E1 to E11, which is a tablet comprising about 0.75% (w / w%) magnesium stearate.

[0018] E13 is the pharmaceutical composition of any one of E1 to E12, wherein the tablet is film-coated.

[0019] E14 is the pharmaceutical composition of E13, wherein the tablet film coating comprises hydroxypropylmethylcellulose and lactose.

[0020] E15 is the pharmaceutical composition of E13 or E14, wherein the tablet film coating is about 4% (w / w) of the total weight of the film-coated tablet.

[0021] E16 is a pharmaceutical composition, which is a tablet comprising about 11.6% (w / w%) clofazodone free acid, about 53.1% (w / w%) microcrystalline cellulose; about 26.55% (w / w%) lactose monohydrate; about 8.0% (w / w%) crospovidone type b and about 0.75% (w / w%) magnesium stearate.

[0022] E17 is a pharmaceutical composition, which is a tablet comprising 11.6%±0.1% (w / w%) clofazodone free acid, 53.1%±0.1% (w / w%) microcrystalline cellulose; 26.55%±0.1% (w / w%) lactose monohydrate; 8.0%±0.1% (w / w%) type b cross-linked polyvidone and 0.75%±0.1% (w / w%) magnesium stearate.

[0023] E18 is the pharmaceutical composition of E16 or E17, wherein the tablet is film-coated.

[0024] E19 is the pharmaceutical composition of any one of E16 to E18, wherein the tablet film coating comprises hydroxypropylmethylcellulose and lactose.

[0025] E20 is the pharmaceutical composition of E18 or E19, wherein the tablet film coating is 4.0%±0.1% (w / w%) of the total weight of the film-coated tablet.

[0026] E21 is a pharmaceutical composition which is a tablet comprising about 12.20 mg tamiflu acid free acid, about 55.85 mg microcrystalline cellulose, about 27.92 mg lactose monohydrate, about 8.42 mg crospovidone type b, and about 0.79 mg magnesium stearate.

[0027] E22 is the drug of E21, which is a tablet comprising 12.20 mg of tamiflu acid 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.

[0028] E23 is the pharmaceutical composition of E21 or E22, wherein the tablet is film-coated.

[0029] E24 is the pharmaceutical composition of E23, wherein the tablet film coating comprises hydroxypropylmethylcellulose and lactose.

[0030] E25 is the pharmaceutical composition of E23 or E24, wherein the tablet film coating weighs 4.21 mg.

[0031] E26 is a pharmaceutical composition which is a tablet comprising about 61.00 mg tamiflu acid free acid, about 279.25 mg microcrystalline cellulose, about 139.6 mg lactose monohydrate, about 42.10 mg crospovidone type b, and about 2.95 mg magnesium stearate.

[0032] E27 is the pharmaceutical composition of E26, which is a tablet comprising 61.00 mg tamiflu acid free acid, 279.25 mg microcrystalline cellulose, 139.6 mg lactose monohydrate, 42.10 mg crospovidone type b and 2.95 mg magnesium stearate.

[0033] E28 is the pharmaceutical composition of E26 or E27, wherein the tablet is film-coated.

[0034] E29 is the pharmaceutical composition of E28, wherein the tablet film coating comprises hydroxypropylmethylcellulose and lactose.

[0035] E30 is the pharmaceutical composition of E28 or E29, wherein the tablet film coating weighs 21.05 mg.

[0036] E31 is the pharmaceutical composition of any one of E1 to E7, 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 tamiflu acid free acid.

[0037] E32 is a pharmaceutical composition of E31, 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 tamiflu acid free acid.

[0038] E33 is the pharmaceutical composition of E32, which is a tablet comprising 13.0 mg of tamiflu acid free acid.

[0039] E34 is the pharmaceutical composition of E33, which is a tablet comprising 13.0 mg of tamiflu acid 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.

[0040] E35 is a pharmaceutical composition of E32, which is a tablet comprising 13.5 mg of tamiflu acid free acid.

[0041] E36 is the pharmaceutical composition of E35, which is a tablet comprising 13.5 mg tamiflu acid free acid, 61.80 mg microcrystalline cellulose, 30.89 mg lactose monohydrate, 9.32 mg crospovidone type b and 0.88 mg magnesium stearate.

[0042] E37 is a pharmaceutical composition of E32, which is a tablet comprising 14.0 mg of tamiflu acid free acid.

[0043] E38 is the pharmaceutical composition of E37, which is a tablet comprising 14.0 mg tamiflu acid free acid, 64.09 mg microcrystalline cellulose, 32.04 mg lactose monohydrate, 9.66 mg crospovidone type b and 0.91 mg magnesium stearate.

[0044] E39 is the pharmaceutical composition of E32, which is a tablet comprising 14.5 mg of tamiflu acid free acid.

[0045] E40 is the pharmaceutical composition of E39, which is a tablet comprising 14.5 mg tamiflu acid free acid, 66.38 mg microcrystalline cellulose, 33.18 mg lactose monohydrate, 10.00 mg crospovidone type b and 0.94 mg magnesium stearate.

[0046] E41 is a pharmaceutical composition of E32, which is a tablet comprising 15.0 mg of tamiflu acid free acid.

[0047] E42 is the pharmaceutical composition of E41, which is a tablet comprising 15.0 mg tamiflu acid free acid, 68.69 mg microcrystalline cellulose, 34.33 mg lactose monohydrate, 10.36 mg crospovidone type b and 0.97 mg magnesium stearate.

[0048] E43 is a pharmaceutical composition of E32, which is a tablet comprising 15.5 mg of tamiflu acid free acid.

[0049] E44 is the pharmaceutical composition of E43, which is a tablet comprising 15.5 mg tamiflu acid free acid, 70.96 mg microcrystalline cellulose, 35.47 mg lactose monohydrate, 10.70 mg crospovidone type b and 1.00 mg magnesium stearate.

[0050] E45 is a pharmaceutical composition of E32, which is a tablet comprising 59.0 mg of tamiflu acid free acid.

[0051] E46 is a pharmaceutical composition as E45, which is a tablet comprising 59.0 mg tamiflu acid free acid, 270.09 mg microcrystalline cellulose, 135.02 mg lactose monohydrate, 40.72 mg crospovidone type b and 3.82 mg magnesium stearate.

[0052] E47 is a pharmaceutical composition of E32, which is a tablet comprising 60.0 mg of clofazodone free acid.

[0053] E48 is the pharmaceutical composition of E47, which is a tablet comprising 60.0 mg tamiflu acid free acid, 274.67 mg microcrystalline cellulose, 137.31 mg lactose monohydrate, 41.40 mg crospovidone type b and 3.89 mg magnesium stearate.

[0054] E49 is a pharmaceutical composition of E32, which is a tablet comprising 62.0 mg of tamiflu acid free acid.

[0055] E50 is the pharmaceutical composition of E49, which is a tablet comprising 62.0 mg tamiflu acid free acid, 283.83 mg microcrystalline cellulose, 141.89 mg lactose monohydrate, 42.80 mg crospovidone type b and 4.01 mg magnesium stearate.

[0056] E51 is the pharmaceutical composition of any one of E31 to E50, wherein the tablet is film-coated.

[0057] E52 is the pharmaceutical composition of E51, wherein the tablet film coating comprises hydroxypropylmethylcellulose and lactose.

[0058] E53 is the pharmaceutical composition of E52, wherein the tablet film coating is about 4% (w / w) of the total weight of the film-coated tablet.

[0059] E54 is a method of treating transthyretin amyloidosis in a patient, the method comprising administering a pharmaceutical composition according to any one of E1 to E53 to the patient.

[0060] E55 is the method of claim 54, wherein the transthyretin amyloidosis is transthyretin cardiomyopathy (ATTR-CM) or transthyretin polyneuropathy (ATTR-PN).

[0061] E56 is the use of a pharmaceutical composition according to any one of E1 to E53 for the treatment of transthyretin amyloidosis.

[0062] 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

[0063] Figure 1 : Flow chart of the preparation process of clofazodone 12.2 mg and 61.0 mg film-coated tablets. DETAILED DESCRIPTION OF THE INVENTION

[0065] The excipients used in the tamiflu tablets or film-coated tablets are globally acceptable and all excipients except crospovidone are present in the formulation at precedent levels. The amounts of tablet ingredients may be expressed as a percentage of the weight of the tablet (i.e., w / w%). The term "about" should be used which may be plus or minus 0.2% or alternatively 0.1% (i.e., ±0.2% or ±0.1%). Crospovidone is generally used at a level of 1-5% (w / w%) and an advantageous embodiment of a common blend of tamiflu used to prepare the tablet core of the present invention contains 8% crospovidone. Crospovidone was evaluated at 4, 6, 8, and 10% (w / w%) levels during development and the microcrystalline cellulose / lactose monohydrate diluent was adjusted accordingly to manage the tablet core weight. Based on biopharmaceutical modeling combined with the use of a differential dissolution method (in vitro), the best release profile to achieve bioequivalence (BE) compared to the currently marketed tamiprofen meglumine 20 mg soft gelatin capsule product was achieved at an 8% (w / w%) crospovidone level. During batch evaluation, alternative formulations evaluated at a reduced 6% (w / w%) crospovidone disintegrant level as provided in Table 2 did not achieve bioequivalence compared to tamiprofen meglumine 20 mg soft gelatin capsules. This data demonstrates the criticality of the crospovidone disintegrant level required to achieve bioequivalence to tamiprofen meglumine 20 mg soft gelatin capsules.

[0066] Formulation modifications to achieve bioequivalence (BE) compared to alternative formulations include increasing disintegrant levels, changing crospovidone particle size, and eliminating dry binder (vinyl pyrrolidone-vinyl acetate copolymer or generally referred to as crospovidone). It is hypothesized that the use of reduced particle size crospovidone in the extragranular portion of the manufacturing process for crospovidone-containing formulations acts as a disintegrant / dry binder, thereby eliminating retention of the drug substance in the in vivo tablet, which is a potential root cause of BE failure of alternative formulations (as shown with vinyl pyrrolidone-vinyl acetate copolymer (dry binder) that does not have disintegrating properties). Studies have been conducted to evaluate the effects of excipients on drug product preparation and performance. Microcrystalline cellulose and lactose monohydrate are diluents used in the tamifluac formulations of the present invention and have precedents in oral tablets at the levels suggested. These ingredients are used in a 2:1 ratio to promote powder flow and compactness during tablet compression. Crospovidone is included in the core formulation as a disintegrant in oral tablets. Disintegrants are added to promote tablet disintegration and are added to the extragranular portion after roller compaction to act as a disintegrant as well as a dry binder. Magnesium stearate is included in the core formulation as a lubricant in the tablet. Magnesium stearate is used as a lubricant in the core formulation to assist tablet compression. II Huang He II White is a proprietary film coating system used for 12.2 mg and 61 mg tablets respectively.

[0067] Dose Adjustment Estimation for Low-Dose Tamiflu Free Acid Tablets

[0068] To estimate the potential dose adjustment range for low-dose tamiflu acid free acid (FA) tablets (equivalent to one 20 mg meglumine salt (MS) capsule), the C values ​​of 12.2 mg FA tablets and 20 mg tamiflu acid MS capsules obtained in Study B3461103 were used. max and AUC inf Assuming that the C of clofazodone FA tablets max and AUC inf Increased proportionally with increasing doses from 12.2 mg to 17 mg. Estimated C of various strengths of tamiflu FA tablets and 20 mg tamiflu MS capsules max and AUC inf The ratios are listed in Table A.

[0069] Table A. Estimated C values ​​for dose-adjusted tamiflu acid free acid tablets (test) and 20 mg meglumine capsules (reference) calculated from observed clinical data in B3461103 max and AUC inf ratio.

[0070] Dosage (mg) <![CDATA[C max Ratio (FA tablets / MS capsules)]]> <![CDATA[AUC inf Ratio (FA tablets / MS capsules)]]> 12 79.67 91.65 12.2 (Observed) 81.00 93.18 13 86.31 99.29 14 92.95 106.39 15 99.59 114.57 15.5 102.91 118.38 16 106.23 122.20 17 112.87 129.84

[0071] When the estimated C max and AUC inf With a ratio of 0.8-1.25, the potential dose adjustment range for low-dose tamiflu FA tablets (equivalent to 20 mg tamiflu MS capsules) was estimated to be 12.2 mg to 16 mg. max and AUC inf With a ratio of 0.85-1.20, a more conservative estimate would place the dose range between 13 mg and 15.5 mg.

[0072] Dose Adjustment Estimation for High-Dose Tamiflu Free Acid Tablets

[0073] To estimate the potential dose adjustment range for high-dose tamiprofen FA tablets (equivalent to 4 x 20 mg meglumine salt capsules), the C values ​​of 48.8 mg or 58 mg tamiprofen FA tablets and 4 x 20 mg tamiprofen MS capsules obtained in Study B3461030 and Study B3461051 were used. max and AUC inf Assuming that the C of clofazodone FA tablets max and AUC inf Increases proportionally with increasing doses from 48.8 mg to 71 mg.

[0074] The estimated C was calculated using clinical data obtained in Study B3461030 (48.8 mg tamiflu FA tablets vs 4 x 20 mg tamiflu MS capsules) and Study B3461051 (48.8 mg tamiflu FA tablets or 58 mg tamiflu free acid tablets vs 4 x 20 mg tamiflu MS capsules). max and AUC inf Ratio. Estimated C of various strengths of tamiflu FA tablets to 4 x 20 mg tamiflu MS capsules max and AUC inf The ratios are listed in Table B.

[0075] Based on the observed rBA data for 48.8 mg tamifluamide FA tablets in Study B3461030 (Table B2), when the estimated C max and AUC infWith a ratio of 0.8-1.25, the dose adjustment range for high-dose tamiprofen FA tablets (equivalent to 4 x 20 mg meglumine salt capsules) was estimated to be 51 mg to 70 mg. Using the same acceptance criteria, using the observed rBA data for 48.8 mg tamiprofen FA tablets in Study B3461051 (Table B2), the dose adjustment range was estimated to be 53 mg to 67 mg; and using the observed rBA data for 58 mg tamiprofen FA tablets in Study B3461051 (Table B3), the dose adjustment range was estimated to be 56 mg to 65 mg.

[0076] In order to estimate the dose adjustment range in a more conservative way, C max and AUC inf The acceptance criteria for the ratio can be set at 0.85-1.20. In this case, using the 48.8 mg tamiprofen FA tablet rBA data from study B3461030 (Table B), the potential dose adjustment range is estimated to be 51-67 mg; using the 48.8 mg tamiprofen FA tablet rBA data from study B3461051 (Table B2), the potential dose adjustment range is estimated to be 56-64 mg; and using the 58 mg tamiprofen FA tablet rBA data from study B3461051 (Table B3), the potential dose adjustment range is estimated to be 59-62 mg. Because all calculated ranges cover 59-62 mg, this dose adjustment range (59-62 mg) is preferred.

[0077] In summary, the observed clinical data suggest that the dose adjustment range of high-dose clofamide FA tablets may be between 51 mg and 70 mg. This dose range includes all estimated ranges calculated by the above method. Within this dose adjustment range, 59 mg to 62 mg is preferred because it is the intersection of all estimated ranges.

[0078] Table B. Estimated C between dose-adjusted tamiflu acid free acid tablets (test) and 4 x 20 mg meglumine capsules (reference) max and AUC inf ratio.

[0079] C calculated using rBA data between 48.8 mg tamiflu acid free acid tablets and 4 x 20 mg tamiflu acid meglumine salt capsules in Study 1030 max and AUC inf ratio.

[0080]

[0081]

[0082] Table B2: C calculated using rBA data between 48.8 mg tamiflu acid free acid tablets and 4 x 20 mg tamiflu acid meglumine salt capsules in Study 1051 max and AUC inf ratio.

[0083] Dosage (mg) <![CDATA[C max Ratio (FA tablets / MS capsules)]]> <![CDATA[AUC inf Ratio (FA tablets / MS capsules)]]> 48.8 (observed) 74.48 90.93 50 76.31 93.17 51 77.84 95.03 52 79.36 96.89 53 80.89 98.76 54 82.42 100.62 55 83.94 102.48 56 85.47 104.35 57 87.00 106.21 58 88.52 108.07 59 90.05 109.94 60 91.57 111.80 61 93.10 113.66 62 94.63 115.53 63 96.15 117.39 64 97.68 119.25 65 99.20 121.12 66 100.73 122.98 67 102.26 124.84 68 103.78 126.71 69 105.31 128.57

[0084] Table B3: C calculated using rBA data between 58 mg tamiflu acid free acid tablets and 4 x 20 mg tamiflu acid meglumine salt capsules in Study 1051 max and AUC inf ratio.

[0085] Dosage (mg) <![CDATA[C max Ratio (FA Tab / MS Cap)]]> <![CDATA[AUC inf Ratio (FA Tab / MS Cap)]]> 58 (observed) 83.68 111.15 55 79.35 105.40 56 80.79 107.32 57 82.24 109.23 58 83.68 111.15 59 85.12 113.07 60 86.57 114.98 61 88.01 116.90 62 89.45 118.82 63 90.89 120.73 64 92.34 122.65 65 93.78 124.56 66 95.22 126.48

[0086] preparation

[0087] Tamiflu is formulated as a common blend to make immediate release tablet cores, such as 12.2 mg and 61 mg immediate release tablet cores. The formulations provided in Table 1 consist of microcrystalline cellulose and lactose monohydrate (diluents), crospovidone (disintegrant), and magnesium stearate (lubricant). Commercially available tamiflu tablet cores are prepared using a dry granulation preparation platform followed by a film coating step. The tablets are film coated with a suitable coating. For example, the tablets may be based on II formulation (yellow for 12.2 mg tablets and white for 61 mg tablets) The tablets were coated with hydroxypropylmethylcellulose / lactose. Example

[0088] General procedure for tablet preparation

[0089] Microcrystalline cellulose (Item 2), intragranular crospovidone (Item 4), tamifluamide free acid (Item 1), and lactose monohydrate (Item 3) are added to an appropriately sized Intermediate Bulk Container (IBC) and mixed at 12 ± 1 revolutions per minute (rpm) for 20 ± 1 minutes to provide a first blend [designated Blend 1 / 4].

[0090] The contents of the IBC (blend 1 / 4) are passed through a Comil U20 equipped with a 032R or 024R screen and a rounded impeller running at 750 ± 50 rpm, or through an equivalent device (e.g., a Comil U10 / 197S equipped with a 0.6-0.8 mm screen running at 1320 ± 80 rpm). The resulting blend is collected in an IBC. Prescreen (1 mm screen, US Sieve #20) intragranular magnesium stearate (item 5) and add to the IBC. Mix at 12 ± 1 rpm for 3 ± 1 minutes to provide a second blend [designated as blend 2 / 4]. Roll and grind the blend 2 / 4 on a Gerteis 3W Macropactor or equivalent device. Collect the resulting particles in the IBC.

[0091] Add extragranular crospovidone (item 6) (adjust for yield if necessary) to the IBC and mix for 20 ± 1 minutes. Prescreen (1 mm screen, US Sieve #20) extragranular magnesium stearate (item 7) and add to the IBC, adjust for yield if necessary. Mix at 12 ± 1 rpm for 3 ± 1 minutes [Blend 4 / 4], mix at 12 ± 1 rpm for ± 1 minute [designated as Blend 3 / 4].

[0092] Tablets were compressed using a rotary press using a 6.5 mm die to a target average weight of 105.2 ± 5% (± 5.2 mg) and a target hardness of 5 ± 2 kP (49 ± 19 N). The previous sentence was for the 12.2 mg tablets and a similar tablet compression procedure was used to prepare the 61 mg tablets. After compression, the cores were dusted and passed through a metal detector.

[0093] For the 12.2 mg tablets, prepare an 18% solids w / w film coating suspension using Opadry II yellow (33G120011) (Item 8) and purified water (Item 9). This suspension should be prepared in excess to compensate for processing losses. For the 61 mg tablets, prepare a similar film coating suspension using Opadry II white and purified water.

[0094] Fill a suitable coating pan with the appropriate amount of cores. Apply enough film coating to a minimum target weight gain of 4% based on average core weight.

[0095] 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 tamifluamide were prepared in a similar manner using the aforementioned procedure and those cores were coated with a 4 wt % film coating.

[0096] Examples 1 and 2 were prepared using the general procedure for tablet preparation as described above.

[0097] Table 1: Examples 1 and 2 - Composition of 12.2 mg and 61 mg film-coated tablets of tamiflu using 8% (w / w) disintegrant type B crospovidone

[0098]

[0099] a Intragranular

[0100] b Extragranular

[0101] c Non-cow

[0102] Comparative Example A

[0103] Table 2: Comparative Example A - Composition of 12.2 mg film-coated tablets of tamifluamide using 6% (w / w) disintegrant type A crospovidone

[0104]

[0105]

[0106] a Intragranular

[0107] b Extragranular

[0108] c Non-cow

[0109] The tablets described above were prepared in a manner similar to the general method described above for Examples 1 and 2. In studies, this formulation failed to demonstrate properties equivalent to the 20 mg tamifluan meglumine gel capsule and was therefore determined not to be a commercially acceptable formulation.

[0110] Comparative Example B

[0111] Table 3: Composition of 12.2 mg film-coated tablets of tamiflu using 4% (w / w) disintegrant type A crospovidone

[0112]

[0113]

[0114] a Intragranular

[0115] b Extragranular

[0116] c Non-cow

[0117] Example 3-12

[0118] Table 1A: Examples 3 and 4 - Composition of 13.0 mg and 13.5 mg film-coated tablets of tamifluamide using 8% (w / w) disintegrant copovidone type B

[0119]

[0120]

[0121] a Intragranular

[0122] b Extragranular

[0123] c Non-cow

[0124] Table 1B: Examples 5 and 6 - Composition of 14.0 mg and 14.5 mg film-coated tablets of tamiflu using 8% (w / w) disintegrant type B crospovidone

[0125]

[0126] a Intragranular

[0127] b Extragranular

[0128] c Non-cow

[0129] Table 1C: Examples 7 and 8 - Composition of 15.0 mg and 15.5 mg film-coated tablets of tamiflu using 8% (w / w) disintegrant type B crospovidone

[0130]

[0131] a Intragranular

[0132] b Extragranular

[0133] c Non-cow

[0134] Table ID: Examples 9, 10 and 11 - Composition of tamiprofen 59.0 mg, 60.0 mg and 62.0 mg film-coated tablets using 8% (w / w) disintegrant type B crospovidone

[0135]

[0136] a Intragranular

[0137] b Extragranular

[0138] c Non-cow

[0139] All patents and publications mentioned above are incorporated herein by reference in their entirety.While the present invention has been described with respect to various preferred embodiments and specific examples, it should be understood that the invention is not limited by the foregoing detailed description but is defined by the appended claims and their equivalents.

Claims

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

2. The pharmaceutical composition of claim 1, which is a tablet, wherein the disintegrant is cross-linked polyvinylpyrrolidone.

3. The pharmaceutical composition of claim 2, which is a tablet, wherein the disintegrant is type b cross-linked polyvinylpyrrolidone.

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

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

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

7. The pharmaceutical composition of claim 6, which is a tablet comprising about 11.6% (w / w%) tamiflu acid free acid.

8. The pharmaceutical composition of claim 7, which is a tablet comprising 12.2 mg of clofazodone free acid.

9. The pharmaceutical composition of claim 7, which is a tablet comprising 61 mg of clofazodone free acid.

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

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

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

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

14. The pharmaceutical composition of claim 13, wherein the tablet film coating comprises hydroxypropyl methylcellulose and lactose.

15. The pharmaceutical composition of 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 comprising about 11.6% (w / w%) tamiflu acid free acid; about 53.1% (w / w%) microcrystalline cellulose; about 26.55% (w / w%) lactose monohydrate; about 8.0% (w / w%) crospovidone type b; and about 0.75% (w / w%) magnesium stearate.

17. A pharmaceutical composition comprising 11.6%±0.1% (w / w%) clofazodone free acid, 53.1%±0.1% (w / w%) microcrystalline cellulose; 26.55% ± 0.1% (w / w%) lactose monohydrate; Tablets of 8.0%±0.1% (w / w%) crospovidone type b and 0.75%±0.1% (w / w%) magnesium stearate.

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

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

20. The pharmaceutical composition of 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 comprising about 12.20 mg tamiflu acid free acid, about 55.85 mg microcrystalline cellulose, about 27.92 mg lactose monohydrate, about 8.42 mg crospovidone type b, and about 0.79 mg magnesium stearate.

22. The drug according to claim 21, which is a tablet comprising 12.20 mg of tamiflu acid 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 of claim 22, wherein the tablet is film-coated.

24. The pharmaceutical composition of claim 23, wherein the tablet film coating comprises hydroxypropyl methylcellulose and lactose.

25. The pharmaceutical composition of claim 24, wherein the tablet film coating weighs 4.21 mg.

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

27. The pharmaceutical composition of claim 26, which is a tablet comprising 61.00 mg of tamiflu acid 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 of claim 27, wherein the tablet is film-coated.

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

30. The pharmaceutical composition of claim 29, wherein the tablet film coating weighs 21.05 mg.

31. The pharmaceutical composition of 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 tamiflu acid free acid.

32. The pharmaceutical composition of 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 tamifluan free acid.

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

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

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

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

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

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

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

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

41. The pharmaceutical composition of claim 32, which is a tablet comprising 15.0 mg of tamiflu acid free acid.

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

43. The pharmaceutical composition of claim 32, which is a tablet comprising 15.5 mg of tamiflu acid free acid.

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

45. The pharmaceutical composition of claim 32, which is a tablet comprising 59.0 mg of tamiflu acid free acid.

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

47. The pharmaceutical composition of claim 32, which is a tablet comprising 60.0 mg of tamiflu acid free acid.

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

49. The pharmaceutical composition of claim 32, which is a tablet comprising 62.0 mg of tamiflu acid free acid.

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

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

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

53. The pharmaceutical composition of 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 of 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 the treatment of 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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