Solid dosage forms of tafamidis and its pharmaceutically acceptable salt thereof.

Abstract

The present disclosure provides a solid pharmaceutical composition comprising of tafamidis, a solubilizer, and one or more pharmaceutically acceptable excipients; and process of making such compositions. The present disclosure also provides a solid pharmaceutical composition comprising of tafamidis indicated for the treatment of the cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization.

Description

[0001] FIELD OF INVENTION

[0002] The present invention is directed to a pharmaceutical composition comprising of tafamidis or its pharmaceutically acceptable salt, and a process of preparation thereof.

[0003] The present invention is directed to solid pharmaceutical compositions comprising of tafamidis, Hydroxypropyl methylcellulose as a solubilizer, and one or more pharmaceutically acceptable excipients. The present invention is also directed to a process of making such compositions.

[0004] BACKGROUND OF THE INVENTION

[0005] Tafamidis is a selective stabilizer of transthyretin. Tafamidis is chemically known as 2- (3,5-dichlorophenyl)-l,3-benzoxazole-6-carboxylic acid with a molecular weight of 308.12 g / mol. Tafamidis meglumine is chemically known as 2-(3, 5-dichlorophenyl)-l,3- benzoxazole-6-carboxylic acid mono (1-deoxy-l-methylamino-D-glucitol) with a molecular weight of 503.33 g / mol.

[0006] Synthetic routes for 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole (hereinafter “the compound of Formula I”) are described in U.S. Pat. No. 7,214,695 and solid forms of the meglumine salt of the compound of Formula I are described in U.S. patent application Ser. No. 14 / 345,111, which is the U.S. national phase of International Application No. PCT / IB2012 / 054748, all of which are hereby incorporated herein by reference in their entireties for all purposes, and has the structure shown below. The compound of Formula I stabilizes the protein transthyretin (TTR), dissociation of which is implicated in TTR amyloidosis (i.e., the compound of Formula I prevents dissociation of the native TTR tetramer into monomers, which results in the inhibition of TTR amyloid fibril formation) and is being developed for use in the treatment of transthyretin amyloid diseases. Tafamidis and Tafamidis meglumine are available as soft gelatin capsule form in United States, Europe and other markets. Tafamidis is marketed as Vyndamax®, while Tafamidis meglumine is marketed as Vyndaqel® in USA. However, it is marketed under Vyndaqel® (Tafamidis & Tafamidis meglumine) in Europe.

[0007] According to the Vyndaqel® European Public assessment report “[t]he chosen excipients in the capsule fill solution are: polyethylene glycol (suspending vehicle), sorbitan monoleate (surfactant / wetting agent), polysorbate 80 (surfactant / wetting agent),” while “[t]he excipients in the capsule shell are: gelatin, propylene glycol, purified water, ‘Sorbitol special-glycerin blend’ (d-sorbitol, 1,4 sorbitan, mannitol and glycerin) and titanium dioxide (E 171) and black printing ink.”

[0008] Certain solid forms may also exhibit enhanced stability or may be more readily manufactured in high purity in large quantities, and thus are more suitable for inclusion in pharmaceutical formulations. U.S. Pat. No. 9,770,441 claims Form 1 wherein said form (i) has a powder X-ray diffraction pattern comprising peak at diffraction angles (29) of 28.6+0.2; (ii) has a NMR spectrum comprising 13C chemical shifts (ppm) at 120.8+0.2 and 127.7+0.2 and (iii) Raman shift peaks (cm1) at 1292+2 and 1615+2. U.S. Pat. No. 9,770,441 provides disclosure of different forms (Form 2, Form 4, Form 6 or Amorphous).

[0009] U.S. Pat. No. 11,878,081 claims an unit-dose formulation comprising 1% w / w to 20% w / w of a tafamidis-organic acid (such as adipic acid, glutaric acid, or fumaric acid) cocrystal; from 0.25% w / w to 2.5% w / w of an organic acid dissolution enhancer. Such formulations release, within 15 minutes in % strength fed state simulated intestinal fluid pH 5.8 or in fasted state simulated intestinal fluid +0.1% polysorbate 80 pH 6.5, at least 85% of the total tafamidis of the formulation.

[0010] US Publication No. US20250009670 claims an oral pharmaceutically acceptable formulation comprising: an effective amount of at least one of tafamidis, a pharmaceutically acceptable salt thereof, and a tafamidis co-crystal, having a D90 particle size of about 20 microns or less; atleast one solubilizing agent selected from cyclodextrins, substituted cyclodextrin derivatives, and mixtures thereof; and at least one excipient selected from diluent, disintegrant and lubricant; wherein the formulation is provided in a form of a powder filled hard gelatin capsule.

[0011] WO2025 166343 claims a pharmaceutically acceptable tablet formulation comprising; an effective amount of at least one of tafamidis, a pharmaceutically acceptable salt thereof, and a tafamidis co-crystal; at least one solubilizing agent selected from cyclodextrin, substituted cyclodextrin derivatives, and mixtures thereof; and at least one excipient selected from diluent, disintegrant and lubricant.

[0012] U.S. Pat. No. 11,523,993 claims a tablet composition comprising a) Tafamidis or Tafamidis meglumine; b) at least one acidifier, wherein the at least one acidifier is present in an amount of from about 0.1% w / w to about 10% w / w based on the total weight of the composition; and c) at least one pharmaceutically acceptable excipient; wherein the tablet comprises 61 mg of Tafamidis or 20 mg of Tafamidis meglumine. The composition exemplified from Example 10 -12 is related to Tafamidis meglumine and Hydroxypropyl P-cyclodextrin at 1: 1 ratio with and without surfactant shows poor dissolution rate and rigid gel formation. Whereas Tafamidis meglumine and Hydroxypropyl P-cyclodextrin at 1:5 ratio without surfactant shows good dissolution rate and no gel formation was observed.

[0013] The organic acidifier used in US Pat. No. 11,523,993 (US’993) is preferably citric acid anhydrous that may cause increased inflammatory symptoms after consuming foods or medications with manufactured citric acid. Since manufactured citric acid is a product of Aspergillus niger. there are contaminants from the production process that remain in the final product. Ingestion of the manufactured citric acid leads to an inflammatory cascade which manifests differently in different individuals based on their genetic predisposition, susceptibility and underling medical history, as well as the degree of stress exerted by environmental factors. Therefore, there is an unmet need for developing simple tafamidis tablet compositions free of acidifiers and such compositions should have desired dissolution and pharmacokinetic profiles. SUMMARY OF THE INVENTION

[0014] The present invention provides a solid pharmaceutical composition comprising of tafamidis, a solubilizer, and one or more pharmaceutically acceptable excipients.

[0015] The present invention provides solid pharmaceutical compositions comprising of tafamidis, Hydroxypropyl methylcellulose, and one or more pharmaceutically acceptable excipients, and process of making such compositions.

[0016] The present invention provides solid pharmaceutical compositions comprising of tafamidis; Hydroxypropyl methylcellulose; atleast one surfactant; one or more pharmaceutically acceptable excipients selected from diluents, disintegrants, glidants, lubricants, adsorbents; and process of making such compositions.

[0017] The present invention provides a solid pharmaceutical composition comprising of tafamidis; Hydroxypropyl methylcellulose; and one or more pharmaceutically acceptable excipients; wherein the tafamidis composition is indicated for the treatment of cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization.

[0018] DETAILED DESCRIPTION OF THE INVENTION

[0019] The information that follows illustrates various embodiments of the compositions disclosed herein. For the avoidance of doubt, it is specifically intended that any particular feature(s) described individually in any one of these paragraphs (or part thereof) may be combined with one or more other features described in one or more of the remaining paragraphs (or part thereof). In other words, it is explicitly intended that the features described below individually in each paragraph (or part thereof) represent important aspects of the invention that may be taken in isolation and also combined with other important aspects of the invention described elsewhere within this specification as a whole and including the examples and figures. The skilled person will appreciate that the compositions claimed herein extends to such combinations of features and that these have not been recited in detail here in the interests of brevity.

[0020] Definitions of some of the terms used herein are detailed below. The use of the terms “a” and “an” and “the” and similar references in the context of describing the composition described herein (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The term “about” as used herein embodies standard error associated with a physicochemical observable. As used herein, the term “about” means a slight variation of the value specified, for example, within 10% of the value specified. A stated amount for a compositional ingredient that is not preceded by the term “about” does not mean that there is no variance for the stated term, as one of ordinary skill would understand that there may be the possibility of a degree of variability generally associated with experimental error.

[0021] The term “therapeutically effective amount” or effective dose” as used herein refers to the amount or dose of Tafamidis that is sufficient to initiate therapeutic response in a patient. The present invention compositions typically contain 40mg to 61mg of tafamidis.

[0022] A first embodiment of the present invention relates to a solid pharmaceutical composition comprising of tafamidis, a solubilizer, and one or more pharmaceutically acceptable excipients .

[0023] In one aspect of the first embodiment, it relates to a solid pharmaceutical composition comprising of tafamidis, Hydroxypropyl methylcellulose, and one or more pharmaceutically acceptable excipients. In the present invention Hydroxypropyl methylcellulose (HPMC) functions as a solubilizer and preferably HPMC E3 grade is useful in making the invention compositions. The solid pharmaceutical composition can be a tablet or a hard gelatin capsule encapsulated with powder, granules, mini-tablets or combinations thereof.

[0024] In another aspect of the first embodiment, it relates to a solid pharmaceutical composition comprising of tafamidis, Hydroxypropyl methylcellulose, and one or more pharmaceutically acceptable excipients selected from surfactants, diluents, disintegrants, glidants, adsorbents, lubricants and combinations thereof; wherein the weight ratio of tafamidis and Hydroxypropyl methylcellulose is from 1:0.1 to 1: 10. Preferably, the weight ratio of tafamidis and Hydroxypropyl methylcellulose is from 1:0.25 to 1:5. More preferably, the weight ratio of tafamidis and Hydroxypropyl methylcellulose is from 1:0.25 to 1: 1.

[0025] Examples of surfactants include but are not limited to sodium lauryl sulfate (SLS), poloxamer, glyceryl monostearate, glyceryl monolaurate, sorbitan monolaurate, sorbitan monostearate, polyethylene glycols, Caprylocaproyl Polyoxyl-8 glycerides, Polyoxyl 40 Hydrogenated castor oil, Polysorbate 80, Medium-chain triglycerides with fatty acids typically having 6-12 carbon atoms (MCFAs), long-chain triglycerides with having 14- 18 fatty acids (LCFAs), or combinations thereof. Observations made during development work shown that the at least one surfactant may influence or increase invivo bioavailability upon oral administration of a composition disclosed herein. The preferred surfactants are selected from Poloxamer 188, Caprylocaproyl Polyoxyl-8 glycerides, Polyoxyl 40 Hydrogenated castor oil, Polysorbate 80, Medium-chain triglycerides with fatty acids typically having 6-12 carbon atoms (MCFAs), long-chain triglycerides with having 14-18 fatty acids (ECFAs), or combinations thereof. Caprylocaproyl Polyoxyl-8 glycerides is a non-ionic water dispersible surfactant well known under the brand name Eabrasol® by Gattefosse company. Polyoxyl 40 Hydrogenated castor oil is a nonionic surfactant well known under the brand name Kolliphor® by BASF company. The weight of surfactants may vary from about 0.1% w / w to about 30% w / w based on the total weight of the composition. The weight selection of surfactant depends on manufacturing process feasibility and its impact on tafamidis invitro drug release and / or tafamidis invivo bioavailability.

[0026] Examples of diluents include, but are not limited to lactose, microcrystalline cellulose (MCC), Silcified microcrystalline cellulose, starch, dicalcium phosphate, mannitol, Dextrates, xylitol, sorbitol, dextrose, fructose, sucrose, maltodextrin, or a combination thereof. The preferred diluents are Microcrystalline cellulose, Silcified microcrystalline cellulose, Dextrates, Mannitol, Eactose anhydrous and combinations thereof.

[0027] Examples of disintegrants include, but are not limited to, crospovidone, croscarmellose sodium, low substituted hydroxypropyl cellulose, starch, sodium starch glycolate, microcrystalline cellulose, alginic acid, polacrillin potassium, or a combination thereof. Preferred disintegrant is Croscarmellose sodium. The invention composition may comprise at least one disintegrant from about 0% w / w to about 10% w / w based on the total weight of the composition, including all values in between, such as, for example, about 0.05% w / w, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 1.0% w / w, about 1.5% w / w, about 2.0% w / w, about 2.5% w / w, about 3.0% w / w, about 3.5% w / w, about 4.0% w / w, about 4.5% w / w, about 5.0% w / w, about 5.5% w / w, about 6.5% w / w, about 7.0% w / w, about 7.5% w / w, about 8.5% w / w, about 9.0% w / w, and about 9.5% w / w.

[0028] Examples of glidants include, but are not limited to, colloidal silicon dioxide, magnesium trisilicate, starch, talc, or a combination thereof. Preferred glidant is colloidal silicon dioxide. The invention composition may comprise at least one glidant from about 0% w / w to about 2% w / w based on the total weight of the composition, including all values in between, such as, for example, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1.0% w / w, about 1.1% w / w, about 1.2% w / w, about 1.3% w / w, about 1.4% w / w, about 1.5% w / w, about 1.6% w / w, about 1.7% w / w, about 1.8% w / w, and about 1.9% w / w.

[0029] Examples of lubricants include, but are not limited to, calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil type I, light mineral oil, magnesium lauryl sulfate, magnesium stearate, medium-chain triglycerides, mineral oil, myristic acid, palmitic acid, poloxamer, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, zinc stearate, or a combination thereof. Preferred lubricant is magnesium stearate. The invention composition may comprise at least one lubricant from about 0% w / w to about 2% w / w based on the total weight of the composition, including all values in between, such as, for example, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1.0% w / w, about 1.1% w / w, about 1.2% w / w, about 1.3% w / w, about 1.4% w / w, about 1.5% w / w, about 1.6% w / w, about 1.7% w / w, about 1.8% w / w, and about 1.9% w / w. In yet another aspect of the first embodiment, it relates to a process of making solid oral pharmaceutical composition of tafamidis comprising of the following steps:

[0030] Step-1: Tafamidis, solubilizer, and atleast one surfactant were mixed;

[0031] Step-2: Step-1 material was dry mixed and granulated with one or more pharmaceutically acceptable excipients in a granulator;

[0032] Step-3: Step-2 wet granules were dried;

[0033] Step-4: Step-3 material was optionally mixed with a glidant, a disintegrant or the combinations thereof.

[0034] Step-5: Step-4 material was lubricated with a lubricant; Step-6: The lubricated blend was compressed into tablets or encapsulated into a hard gelatin capsule.

[0035] In yet another aspect of the first embodiment, it relates to a solid pharmaceutical composition comprising of Tafamidis; Hydroxypropyl methylcellulose; Poloxamer 188, croscarmellose sodium; colloidal silicon dioxide and magnesium stearate.

[0036] A second embodiment of the present invention it relates to a solid pharmaceutical composition comprising of tafamidis; a solubilizer; atleast one surfactant; an adsorbent; and one or more pharmaceutically acceptable excipients.

[0037] Examples of adsorbents include, but are not limited to, Magnesium aluminometasilicate and Microcrystalline cellulose.

[0038] In one aspect of the second embodiment, it relates to a solid pharmaceutical composition comprising of tafamidis; Hydroxypropyl methylcellulose; atleast one surfactant selected from Poloxamer 188, Caprylocaproyl Polyoxyl-8 glycerides, Polyoxyl 40 Hydrogenated castor oil, Polysorbate 80, Medium-chain triglycerides with fatty acids typically having 6-12 carbon atoms (MCFAs), long-chain triglycerides with having 14-18 fatty acids (LCFAs), or combinations thereof; Magnesium aluminometasilicate; and one or more pharmaceutically acceptable excipients selected from diluents, disintegrants, glidants, lubricants and combinations thereof. Preferred diluents of such compositions are selected from Microcrystalline cellulose, Silcified microcrystalline cellulose, Dextrates, Mannitol, Lactose anhydrous and combinations thereof. Preferred glidant of such compositions is colloidal silicon dioxide. Preferred lubricant of such compositions is magnesium stearate.

[0039] In one aspect of the second embodiment, it relates to a solid pharmaceutical composition comprising of tafamidis; Hydroxypropyl methylcellulose; atleast one surfactant selected from Poloxamer 188, Caprylocaproyl Polyoxyl-8 glycerides, Polyoxyl 40 Hydrogenated castor oil, Polysorbate 80, Medium-chain triglycerides with fatty acids typically having 6-12 carbon atoms (MCFAs), long-chain triglycerides with having 14-18 fatty acids (LCFAs), or combinations thereof; Magnesium aluminometasilicate; and one or more pharmaceutically acceptable excipients selected from diluents, disintegrants, glidants, lubricants and combinations thereof; wherein such compositions comprising of weight ratio of tafamidis and Caprylocaproyl Polyoxyl-8 glycerides is from 1: 1 to 1:2; weight ratio of tafamidis and Magnesium aluminometasilicate is from 1: 1 to 1:2.

[0040] In yet another aspect of the second embodiment, it relates to a process of making a tafamidis solid oral composition comprising of the following steps:

[0041] Step-1: Mixing tafamidis, Hydroxypropyl methylcellulose, and one or more surfactants;

[0042] Step-2: Adsorption of step-1 mixture onto adsorbent;

[0043] Step-3: Blending of step-2 blend with atleast one of diluent, disintegrant, glidant and combinations thereof;

[0044] Step-4: Lubrication of step-3 blend with a lubricant;

[0045] Step-5: Compression of lubricated blend into a tablet or encapsulation of lubricated blend into a hard gelatin capsule.

[0046] In yet another aspect of the second embodiment, it relates to a process of making a tafamidis solid oral composition comprising of the following steps:

[0047] Step-1: Mixing tafamidis, Hydroxypropyl methylcellulose, and one or more surfactants selected from Poloxamer 188, Caprylocaproyl Polyoxyl-8 glycerides, Polyoxyl 40 Hydrogenated castor oil, Polysorbate 80, Medium-chain triglycerides with fatty acids typically having 6-12 carbon atoms (MCFAs), long-chain triglycerides with having 14-18 fatty acids (LCFAs) or combinations thereof;

[0048] Step-2: Adsorption of step-1 mixture onto Magnesium aluminometasilicate or Microcrystalline cellulose;

[0049] Step-3: Blending of step-2 blend with atleast one of diluent, disintegrant, glidant and combinations thereof;

[0050] Step-4: Lubrication of step-3 blend with a lubricant;

[0051] Step-5: Compression of lubricated blend into a tablet or encapsulation of lubricated blend into a hard gelatin capsule.

[0052] In yet another aspect of the second embodiment, it relates to a solid pharmaceutical composition comprising of Tafamidis; Hydroxypropyl methylcellulose; one or more surfactants selected from Poloxamer 188, Caprylocaproyl Polyoxyl-8 glycerides, Polyoxyl 40 Hydrogenated castor oil, Polysorbate 80, Medium-chain triglycerides with fatty acids typically having 6-12 carbon atoms (MCFAs), long-chain triglycerides with having 14-18 fatty acids (LCFAs) or combinations thereof; Magnesium aluminometasilicate; croscarmellose sodium; colloidal silicon dioxide and magnesium stearate.

[0053] In first and second embodiments of the present invention it relates to a solid pharmaceutical composition comprising of tafamidis; wherein not less than 70% of tafamidis released at 45 minutes and / or at 60 minutes in 6.8 phosphate buffer.

[0054] In first and second embodiments of the present invention it relates to a solid pharmaceutical composition comprising of tafamidis indicated for the treatment of cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization.

[0055] The following examples are provided to illustrate the present invention. It should be understood, however, that the invention is not to be limited to the specific conditions or details described in these examples.

[0056] EXAMPLES: Example 1-5: Tafamidis tablets

[0057] Table- 1

[0058] Process for preparation of Example 1-3 & 5 Tafamidis formulations: The weighed batch quantities of Tafamidis, HP-B-Cyclodextrin, Salcaprozate Sodium, Tafamidis + HPpCD (1: 1) premix (in the form of solid dispersion), MCC (Avicel pH 102), MCC (Avicel 101), MCC (Avicel 112), Lactose Monohydrate (Flowlac 100), Croscarmellose Sodium, Sodium lauryl sulfate, Povidone K-30, Colloidal Silicon dioxide, Poloxamer 188 (as per the trial batches) was sifted together and blended. The pre-lubricated blend was lubricated with magnesium stearate. The lubricated blend was compressed into tablets.

[0059] Process for preparation of Example 4 Tafamidis formulations:

[0060] 1. Co-sifted the weighed quantities of Tafamidis, Salcaprozate sodium, MCC (Avicel 101), Lactose monohydrate and Croscarmellose sodium for granulation,

[0061] 2. Step-1 material was granulated with Purified water and Poloxamer 188 by rapid mixing granulator and wet granules were dried.

[0062] 3. Step-2 dried granules were sifted through sieve and retained granules were milled and sifted.

[0063] 4. The batch quantity of Croscarmellose sodium and Colloidal Silicon dioxide were sifted separately.

[0064] 5. Step-3 material and sifted Croscarmellose sodium of step-4 were co-sifted together and blended to obtain pre-lubricated blend.

[0065] 6. The pre-lubricated blend of step-5 was sifted with Magnesium stearate obtain lubricated blend.

[0066] 7. The lubricated blend was compressed into tablets. Example 1-5 Tafamidis tablets were subjected to dissolution testing under dissolution conditions of Sodium Phosphate, pH 6.8 with 1% Tween 80, Type II USP (paddle) with sinker, 75 RPM, 900 mL at temperature of 37°C±0.5°C.

[0067] Not less than 75% of Tafamidis released in 45 minutes. No gel formation observed Example 6-7: Tafamidis tablets

[0068] Table-2

[0069] Process for preparation of Example 6 & 7 Tafamidis formulations: The weighed batch quantities of granules of Tafamidis + Eudragit EPO (1: 1) or granules of Tafamidis + HPMC (1: 1), MCC (Avicel pH 102), Poloxamer 188, Lactose (Flowlac 100), Croscarmellose Sodium, Colloidal Silicon dioxide as sifted together and blended. The pre-lubricated blend was lubricated with magnesium stearate. The lubricated blend was compressed into tablets.

[0070] Dissolution data of Tafamidis tablets (Examples 6-7) in

[0071] 50 mM Sodium phosphate buffer pH 6.8, 900 mL, 75 rpm, USP II (Paddle): Not less than 75% of Tafamidis released in 45 minutes. No gel formation observed

[0072] Example 8A, 8B and 8C: Tafamidis tablets 61mg

[0073] Table-3 Process for preparation of Tafamidis formulations:

[0074] 1. Co-sifted the weighed quantities of Tafamidis, Poloxamer 188, HPMC E3.

[0075] 2. Microcrystalline cellulose, Lactose monohydrate, Croscarmellose sodium were sifted together 3. Mixed step 2 with step 1 and dry mixed in rapid mixer granulator.

[0076] 4. Step-3 material was granulated with water and wet granules were dried.

[0077] 5. Step-4 dried granules were sifted through sieve.

[0078] 6. The batch quantity of Croscarmellose sodium were sifted separately.

[0079] 7. Step-5 material and sifted Croscarmellose sodium of step-6 were co-sifted together and blended to obtain pre-lubricated blend.

[0080] 8. The pre-lubricated blend of step-7 was sifted with Magnesium stearate and Colloidal Silicon dioxide to obtain lubricated blend.

[0081] 9. The lubricated blend was compressed into tablets and tablet cores were film coated.

[0082] Dissolution study conducted in 50 mM Sodium phosphate buffer pH 6.8 and 1% Tween 80, 900 m , 75 rpm, USP II (Paddle):

[0083] 1. 8A Tablets (1: 1:0.1): 41% at 15 min, 85% at 30 min, 93% at 45 min, 96% at 60 min

[0084] 2. 8B Tablets (l:0.5:0.1): 72% at 15 min, 77% at 30 min, 80% at 45 min, 91% at 60 min

[0085] 3. 8C Tablets (1:0.25:0.1): 72% at 15 min, 77% at 30 min, 80% at 45 min, 80% at 60 min

[0086] It was concluded that tablets containing Tafamidis: HPMC: Poloxamer 188 in the weight ratio from l:0.5:0.1 and 1: 1:0.1 shown promising dissolution profile with not less than 70% drug release in 60 min. The extent of drug release of 1: 1:0.1 > l:0.5:0.1 > 1:0.25:0.1.

[0087] Example 9 A, 9B and 9C: Tafamidis tablets 61 mg

[0088] Table-4

[0089] Example 9 Tafamidis tablets were prepared similar to Example 8 and were subjected dissolution testing.

[0090] 1. 9A Tablets (1: 1:0): 35% at 15 min, 80% at 30 min, 90% at 45 min, 92% at 60 min

[0091] 2. 9B Tablets (1: 1 :0.1 Poloxamer): 33% at 15 min, 72% at 30 min, 93% at 45 min, 96% at 60 min

[0092] 3. 9C Tablets (1: 1:0.1 SLS): 18% at 15 min, 39% at 30 min, 55% at 45 min, 77% at 60 min It was concluded that Tafamidis tablets with Hydroxypropyl methylcellulose as a solubilizer and with or without Poloxamer shown drug release of NLT 70% in 60 min. Tafamidis tablets with Hydroxypropyl methylcellulose as a solubilizer and with SLS has low drug release in comparison to Tafamidis tablets with Poloxamer. Hence, Poloxamer was found to have better results with HPMC as compared to SLS with HPMC. Example 10A, 1OB, IOC and 1OD: Tafamidis Tablets 61 mg

[0093] A- Tablets containing Tafamidis: Caprylocaproyl Polyoxyl-8 glycerides: Magnesium aluminometasilicate (1:2:2); Polyoxyl 40 Hydrogenated castor oil; Hydroxypropyl methylcellulose and Poloxamer 188 B- Tablets containing Tafamidis: Caprylocaproyl Polyoxyl-8 glycerides: Magnesium aluminometasilicate (1:2: 1); Polyoxyl 40 Hydrogenated castor oil; Hydroxypropyl methylcellulose and Poloxamer 188

[0094] C- Tablets containing Tafamidis: Caprylocaproyl Polyoxyl-8 glycerides: Magnesium aluminometasilicate (1:2:2); Polyoxyl 40 Hydrogenated castor oil and Poloxamer 188 D- Tablets containing Tafamidis: Caprylocaproyl Polyoxyl-8 glycerides: Magnesium aluminometasilicate (1:2:2); Polysorbate 80; Hydroxypropyl methylcellulose and Poloxamer 188

[0095] Table-5

[0096] Process for preparation of Example 10A Tafamidis tablet:

[0097] 1. Batch quantities of Tafamidis, Poloxamer 188, Hydroxypropyl methylcellulose were mixed 2. Caprylocaproyl Polyoxyl-8 glycerides and Polyoxyl 40 Hydrogenated castor oil were mixed together

[0098] 3. Step-1 and Step-2 material were mixed and adsorbed onto batch quantity of Magnesium aluminometasilicate

[0099] 4. Step-3 material was sifted together with batch quantity of Microcrystalline cellulose or Silcified microcrystalline cellulose; and Croscarmellose sodium

[0100] 5. Step-4 material was sifted together with batch quantity of Dextrates or Mannitol or Lactose anhydrous

[0101] 6. Step-5 material was blended to obtain homogeneous blend

[0102] 7. Step-6 material was blended with Colloidal silicon dioxide 8. Step-7 material was lubricated with magnesium stearate

[0103] 9. Step-8 material was compressed into tablets Example 10B, IOC and 1OD Tafamidis tablets were prepared with the same process of 10A tablets.

[0104] Example 11: Tafamidis Tablets 50mg

[0105] Table-6

[0106] Example 11 Tafamidis tablets were prepared with the same process of 10A tablets.

[0107] Dissolution study conducted in 50 mM Sodium phosphate buffer pH 6.8 and 1% Tween 80, 900 mL, 75 rpm, USP II (Paddle):

[0108] Dissolution study conducted in pH 1.2 0.1N Hcl and 1% Tween 80, 900 mL, 75 rpm, USP II (Paddle):

[0109] The unexpected findings observed from dissolution studies are summarized below:

[0110] 1. 10A and 10B:- Tablets comprising of Tafamidis: Caprylocaproyl Polyoxyl-8 glycerides: Magnesium aluminometasilicate (1:2:2) or Tablets containing Tafamidis: Caprylocaproyl Polyoxyl-8 glycerides: Magnesium aluminometasilicate (1:2: 1) shown identical drug release of not less than 70% drug release in phosphate buffer at 45min and 60 min.

[0111] 2. 10A and 10C:- Tablets comprising of Tafamidis: Caprylocaproyl Polyoxyl-8 glycerides: Magnesium aluminometasilicate (1:2:2) with or without Hydroxypropyl methylcellulose shown identical drug release of not less than 70% drug release in phosphate buffer at 45min and 60 min.

[0112] 3. 10A and 10D:- Tablets containing Tafamidis: Caprylocaproyl Polyoxyl-8 glycerides: Magnesium aluminometasilicate, with either of Polyoxyl 40 Hydrogenated castor oil or Polysorbate 80 shown identical drug release of not less than 70% in phosphate buffer at 45min and 60 min.

[0113] 4. 10A and 10C:- Tablets comprising of Tafamidis: Caprylocaproyl Polyoxyl-8 glycerides: Magnesium aluminometasilicate with Polyoxyl 40 Hydrogenated castor oil and Hydroxypropyl methylcellulose shown drug release of 49% drug release in 0.1N HC1 at 60 min. However, 10C formulation with no Hydroxypropyl methylcellulose shown drug release of 40% drug release in 0.1N HC1 at 60 min. Surprisingly Hydroxypropyl methylcellulose exhibited good solubilizer property with an increase of 10% drug release in 0.1N HC1.

Claims

Claims:

1. A solid pharmaceutical composition comprising of tafamidis, Hydroxypropyl methylcellulose, and one or more pharmaceutically acceptable excipients.

2. A solid pharmaceutical composition of claim 1 wherein the weight ratio of tafamidis and Hydroxypropyl methylcellulose is from 1:0.1 to 1: 10.

3. A solid pharmaceutical composition of claim 1 is a tablet or a hard gelatin capsule comprising of 40mg to 61mg of tafamidis.

4. A solid pharmaceutical composition of claim 1 comprising of one or more pharmaceutically acceptable excipients selected from surfactants, diluents, disintegrants, glidants, adsorbents, lubricants and combinations thereof.

5. A solid pharmaceutical composition of claim 1 comprising of one or more diluents selected from Microcrystalline cellulose, Silcified microcrystalline cellulose, Dextrates, Mannitol, Lactose anhydrous and combinations thereof.

6. A solid pharmaceutical composition of claim 1 comprising of croscarmellose sodium.

7. A solid pharmaceutical composition of claim 1 comprising of colloidal silicon dioxide.

8. A solid pharmaceutical composition of claim 1 comprising of magnesium stearate.

9. A solid pharmaceutical composition of claim 1 comprising of surfactants selected from Poloxamer 188, Caprylocaproyl Polyoxyl-8 glycerides, Polyoxyl 40 Hydrogenated castor oil, Polysorbate 80, Medium-chain triglycerides with fatty acids having 6-12 carbon atoms, long-chain triglycerides with fatty acids having 14-18 carbon atoms or combinations thereof.

10. A solid pharmaceutical composition of claim 1 comprising of adsorbents selected from Magnesium aluminometasilicate and Microcrystalline cellulose11. A solid pharmaceutical composition of claim 1 comprising of tafamidis and Caprylocaproyl Polyoxyl-8 glycerides in the weight ratio from 1: 1 to 1:2; tafamidis and Magnesium aluminometasilicate in the weight ratio from 1: 1 to 1:2.

12. A solid pharmaceutical composition comprising of Tafamidis; Hydroxypropyl methylcellulose; Poloxamer 188, croscarmellose sodium; colloidal silicon dioxide and magnesium stearate.

13. A solid pharmaceutical composition comprising of Tafamidis; Hydroxypropyl methylcellulose; one or more surfactants selected from Poloxamer 188, Caprylocaproyl Polyoxyl-8 glycerides, Polyoxyl 40 Hydrogenated castor oil, Polysorbate 80, or combinations thereof; Magnesium aluminometasilicate; croscarmellose sodium; colloidal silicon dioxide and magnesium stearate.

14. A process of making a tafamidis solid oral composition comprising of the following steps:Step-1: Mixing tafamidis, Hydroxypropyl methylcellulose, and one or more surfactants;Step-2: Adsorption of step-1 mixture onto adsorbent;Step-3: Blending of step-2 blend with atleast one or more excipients selected from diluent, disintegrant, glidant and combinations thereof;Step-4: Lubrication of step-3 blend with a lubricant;Step-5: Compression of lubricated blend into a tablet or encapsulation of lubricated blend into a hard gelatin capsule.

15. A solid pharmaceutical composition of claim 1 to 14 wherein not less than 70% of tafamidis released at 45 minutes and / or at 60 minutes in 6.8 phosphate buffer.

16. A solid pharmaceutical composition of claim 1 to 15 wherein the tafamidis composition is indicated for the treatment of cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization.

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