Pharmaceutical composition of resmetirom and process thereof

Abstract

The present invention relates to a solid, orally administrable pharmaceutical composition of resmetirom with one or more pharmaceutically acceptable excipients. More specifically a solid, orally administrable pharmaceutical composition may be prepared by a wet granulation process for preparing granules that are subsequently converted into solid oral dosage forms of resmetirom.

Description

[0001] PHARMACEUTICAL COMPOSITION OF RESMETIROM AND PROCESS THEREOF

[0002] CROSS REFERENCE

[0003] This application claims the benefit of priority of our Indian patent application IN202411034308 filed on 30 April 2024, which is incorporated herein by reference.

[0004] FIELD OF THE INVENTION

[0005] The present invention relates to a solid, orally administrable pharmaceutical composition of resmetirom with one or more pharmaceutically acceptable excipients. More specifically a solid, orally administrable pharmaceutical composition may be prepared by a wet granulation process for preparing granules that are subsequently converted into solid oral dosage forms of resmetirom.

[0006] BACKGROUND OF INVENTION

[0007] Resmetirom (MGL-3196) is a potent and selective thyroid hormone receptor [THR] 0 agonist for the treatment of non-alcoholic steatohepatitis (NASH) which is the most severe form of non-alcoholic fatty liver disease (NAFLD) by increasing hepatic fat metabolism and reducing lipotoxicity. Specifically, resmetirom, chemically known as 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6- dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-l,2,4-triazine-6-carbonitrile is selective THR0 agonist in vitro, reduced hepatic steatosis in preclinical NASH models in vivo.

[0008] As of before, there was no approved treatment for non-alcoholic steatohepatitis (NASH) which can lead to progressive liver diseases like fibrosis, cirrhosis and hepatocellular carcinoma. On 14thMarch 2024, U.S. Food and Drug Administration (FDA) have approved Rezdiffra (resmetirom) for the treatment of adults with noncirrhotic non-alcoholic steatohepatitis (NASH) with moderate to advanced liver scarring (fibrosis), to be used along with diet and exercise. Resmetirom has low aqueous solubility at below pH 6 and higher solubility at above pH 7.

[0009] The synthesis of resmetirom and its pharmaceutical compositions have been first time described in patent family [WO 2007 / 009913] by Hoffman-La-Roche. The said compositions comprising resmetirom and a pharmaceutically acceptable carrier and / or adjuvant. The patent discloses several dosage forms along with their preparation such as tablet, hard gelatin capsules, soft gelatin capsules, injection solutions and sachets of resmetirom. However, the said publication is silent about the purity of the resmetirom. It has been observed by the present inventors that upon repetition of the process, the residual solvent content in the final product obtained was quite high than the permissible limits as specified in International Conference for Harmonization (ICH) guidelines, thereby making material of low purity and high residual content that is not suitable for pharmaceutical formulations and therapeutic use thereof.

[0010] Another PCT publication WO 2014 / 043706 discloses resmetirom anhydrous form I, hydrate, methyl isobutyl ketone (MIBK) solvates and dimethylacetamide solvate. The publication broadly discloses various possible dosage forms comprising of the active pharmaceutical ingredient (API). However, the said publication does not provide any specific example for resmetirom composition by using any of the polymorphic forms either anhydrous, hydrate or solvate disclosed herein.

[0011] In one another PCT publication WO 2020 / 010068 discloses a crystalline salt of resmetirom having counter-ions like L-lysine, L-arginine, 2-hydroxy-N,N,N-trimethylethan-l-aminium, diethylamine, ethanolamine, ethanol-2-diethylamine, Na+, Mg2+, K+, Ca2+, diethanolamine, triethanolamine, L- histidine, and meglumine. The said publication also discloses a amorphous solid dispersion of resmetirom, wherein the amorphous solid dispersion comprises a polymer. However, the said publication does not disclose any specific example of resmetirom composition by using any of the crystalline salt of resmetirom.

[0012] Several PCT publications WO 2021 / 063367 and WO 2021 / 129465 unveil different crystalline forms of resmetirom such as CSI and CSIV / CSV respectively. However, the said publications do not disclose any specific example of resmetirom composition by using any of said crystalline forms of resmetirom.

[0013] Another PCT publication WO 2022 / 052822 discloses a crystal form CSVI of resmetirom. The publication also discloses the pharmaceutical composition of form CSVI and its preparation thereof. The composition comprises microcrystalline cellulose as a diluent, povidone as a binder, sodium carboxymethyl starch as a disintegrant and magnesium stearate as lubricant.

[0014] One another PCT publication WO 2022 / 171200 discloses a resmetirom crystalline form 3 and its pharmaceutical composition thereof. The capsule composition comprises lactose, corn starch and talc.

[0015] A Chinese publication CN115124515 unveils crystalline forms 4, 7 and 9 of resmetirom which are acetone, 1, 4-dioxane and butanone solvates respectively. However, this publication does not provide any specific example of resmetirom composition by using any of said crystalline forms of resmetirom.

[0016] In the present scenario, there is a need to provide an advantageously solid, orally administrable pharmaceutical composition of resmetirom using operationally simplified process thereof, wherein the composition is stable and substantially free of impurities. In particular, a pharmaceutical composition should be provided, having improved properties like solubility, dissolution profile, stability and bioavailability. Therefore, a stable pharmaceutical composition for oral administration is desired with enhanced technical formulation attributes such as a superior dissolution profile even after prolonged time of storage, stability, bioequivalence, and which is simple, reproducible and commercially viable at industrial scale.

[0017] OBJECT OF THE INVENTION

[0018] The principal object of the present invention is to provide a process for the preparation of a solid orally administrable pharmaceutical composition of resmetirom with desired dissolution profile.

[0019] Another object of the present invention is to provide a stable oral pharmaceutical composition of resmetirom with a solubility which is not substantially lowered, even when it is stored for a long period of time.

[0020] One another object of the present invention is to provide a stable oral pharmaceutical composition of resmetirom wherein the impurity profile and stability comply with the regulatory / ICH guidelines.

[0021] Yet another objective of the present invention is to provide a pharmaceutical composition by using a wet granulation process wherein the process provides homogeneity of the powder, better solubility and compressibility, and reduced dust formation during the processing.

[0022] Yet another object of the present invention is to provide a simple, efficient, industrially feasible and economical process for the preparation of pharmaceutical composition of resmetirom.

[0023] SUMMARY OF INVENTION

[0024] Accordingly, the present invention provides a solid orally administrable pharmaceutical composition of resmetirom and a process for preparation of the composition thereof. In one embodiment, the present invention provides a solid orally administrable pharmaceutical composition comprising resmetirom and one or more pharmaceutically acceptable excipients selected from the group comprising of diluent, binder, solubilizer, solvent, disintegrant, lubricant, optionally glidant and / or optionally coating agent for the compressed dosage forms.

[0025] In one another embodiment of the present invention provides a pharmaceutical composition comprising: resmetirom in an amount of 3.5% to 45% w / w; diluent ranging from 5% to 95% w / w; binder ranging from 0.5% to 10% w / w; solubilizer ranging from 0.5% to 20% w / w; disintegrant ranging from 1% to 15% w / w; lubricant ranging from 0.1% to 8% w / w; optionally, glidant ranging from 0 % to 12% w / w; and optionally, film coating agent ranging from 0.5% to 5% relative to the total weight of the pharmaceutical dosage form.

[0026] In another embodiment, the present invention provides a process for the preparation of a solid, orally administrable pharmaceutical composition of resmetirom, comprises the steps of: i. preparing an intragranular phase comprising a) blending one or more pharmaceutically acceptable excipients to form a blend, b) providing an active granulating liquid comprising resmetirom, one or more pharmaceutical excipients, and solvent, c) granulating the blend of step i (a) with the active granulating liquid of step i (b) to obtain granules, ii. blending the granules of intragranular phase of step (i) with the excipients of extragranular phase to obtain final blend, iii. converting the final blend of step (ii) into solid oral dosage forms. In one another embodiment, the present invention provides a wet granulation process for the preparation of a solid orally administrable pharmaceutical composition of resmetirom.

[0027] In yet another embodiment, a process for the preparation of solid orally administrable pharmaceutical composition of resmetirom by using wet granulation comprising: i. dissolving one or more pharmaceutical excipients in solvent to obtain solution, ii. adding resmetirom optionally with one or more pharmaceutical excipients in a solution obtained in step (i) to obtain active granulating liquid, iii. mixing of active granulating liquid obtained in step (ii) with one or more pharmaceutical excipients of intragranular phase to obtain granulated blend, iv. converting granulated blend obtained in step (iii) into solid dosage forms of resmetirom.

[0028] In another embodiment, the present invention provides an oral pharmaceutical composition comprising a therapeutically effective amount of resmetirom, at least one solubilizer, and optionally one or more pharmaceutically acceptable excipients.

[0029] DETAILED DESCRIPTION OF THE INVENTION

[0030] The present invention relates to a solid, orally administrable pharmaceutical composition of resmetirom comprising resmetirom and one or more pharmaceutically acceptable excipients, and a process for the preparation of the stable pharmaceutical composition thereof.

[0031] As used herein, the term “solid oral dosage forms” refers to tablet, capsule, powder, disc, caplet, granules, pellets, tablet in tablet, tablet in capsule, pellets in capsule, powder in capsule, granules in capsule and other like dosage forms suitable for oral administration.

[0032] As used herein, the term “intragranular phase” refers to the part which includes resmetirom, one or more pharmaceutical excipients, and solvent present in the composition forming granules. The pharmaceutical excipients herein can be selected from the group comprising of diluent, binder, solubilizer and solvent.

[0033] As used herein, the term “extragranular phase” refers to the excipients present in the formulation which are out of the intragranular phase. The pharmaceutical excipients herein can be selected from the group comprising of disintegrant, lubricant, and optionally diluent and / or glidant. As used herein, the term “solubilizer” refers to a material which is able to solubilize or partially solubilize active pharmaceutical ingredient (API) and / or composition and also improves dissolution of the API. Moreover, solubilizers enhance the bioavailability of oral dosage forms by increasing the solubility of poorly soluble drugs.

[0034] As used herein, the term "wet granulation" as used herein refers to a process to form granules by using liquid solution. Granulation can also be carried out with water or organic solvent or mixture of organic solvent with water. Wet granulation can be carried out by fluidized bed granulation and rapid mixer granulation processes.

[0035] As used here the term “fluidized bed granulation” refers to a granulation process which involves suspending particles in an air stream and spraying a liquid from the top of the system down onto the fluidized bed (top-down spray).

[0036] As used herein the term “top spray” refers to the spray method comprising steps of spraying active granulating liquid as minute droplets using a nozzle or rotating disc and drying the droplets by blowing hot air.

[0037] As used herein, the term “stable” refers to the chemical stability of resmetirom in solid dosage forms wherein there is no significant change in assay, dissolution and related impurities when the dosage form is kept at 30°C / 75% RH and 40°C / 75% RH for 6 months.

[0038] As used herein the term "particle size distribution" refers to the relative percentages by volume of each of the different size fractions of a particulate matter.

[0039] In the first aspect, the present invention provides a solid, orally administrable pharmaceutical composition of resmetirom comprising of an intragranular phase wherein the composition comprises of resmetirom, at least one solubilizer and optionally one or more excipients and an extragranular phase, and optionally coating agent for the compressed dosage forms i.e., tablets.

[0040] In the first aspect, the present invention provides a solid, orally administrable pharmaceutical composition of resmetirom comprising of an intragranular phase having resmetirom and one or more pharmaceutically acceptable excipients selected from the group consisting of diluent, binder, solubilizer, solvent and an extragranular phase comprises of disintegrant, lubricant, optionally diluent, optionally glidant and optionally coating agent for the compressed dosage forms i.e., tablets. The solid orally administrable pharmaceutical composition of resmetirom of the present invention can be in the form of a tablet, a stock granulation (e.g., granules) and a capsule.

[0041] The active pharmaceutical ingredient (API) resmetirom contained in the solid pharmaceutical composition may be present, partially or completely, in different crystalline forms such as anhydrous, hydrates, solvates, desolvates, and amorphous or combination thereof.

[0042] The crystalline resmetirom can be anhydrous or hydrate such as, hemihydrate or monohydrate or dihydrate in nature. Anhydrous form may have contained water content less than 1 % by weight. The hydrate form may have contained water content either in less than 2% by weight for hemihydrate or less than 4% by weight for monohydrate and around 7% for dihydrate.

[0043] The intragranular phase in accordance with the first aspect of the present invention comprises resmetirom in an amount from 3.5 % to 45%, preferably from 6.4% to 40% by weight relative to the total weight of the solid pharmaceutical composition. The intragranular phase can be of pharmaceutically acceptable excipients which may include but not limited to diluent, binder, optionally disintegrant, solubilizer and solvent.

[0044] The "diluent" can be selected from starch, corn starch, potato starch, pregelatinized starch, dry starch, disaccharides, lactose, cellulose, maltodextrins, cellulose derivatives, such as silicified microcrystalline cellulose, microcrystalline cellulose, mannitol, sorbitol, xylitol, trehalose, colloidal silica, sucrose or other sugars or sugar derivatives, calcium hydrogen phosphate and dicalcium phosphate. Preferably the diluent contained in the intragranular phase is selected from dicalcium phosphate, mannitol sorbitol, xylitol. More preferably, the diluent contained in the intragranular phase is dicalcium phosphate and mannitol. The total amount of diluent in the pharmaceutical composition may be between 5% and 95%, preferably between 7% and 93%, more preferably between 10% and 90%. The same or different diluent can be used in the extragranular phase as used in the intragranular phase.

[0045] In a preferred composition of the present invention suitable “binder” may be selected from hydrophilic polymers wherein, hydrophilic polymers are selected from polyvinyl pyrrolidone (Povidone), polyvinyl alcohol, copolymers of vinylpyrrolidone with other vinylderivatives (Copovidone), hydroxypropyl methylcellulose, hydroxypropyl cellulose, powdered acacia, gelatin, guar gum, carbomer such as carbopol, polymethacrylates, pregelatinized starch and combination thereof. The binder may be present in the intragranular phase in an amount between 0.5% to 10%, preferably between 0.1% to 9.9%.

[0046] In a preferred composition of the present invention suitable “solubilizer” may be selected from derivatives of cellulose (hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), preferably sodium or calcium salts thereof, polyvinylpyrrolidone, preferably having a weight average molecular weight of 10,000 to 60,000 g / mol, copolymers of polyvinylpyrrolidones, preferably copolymers comprising vinylpyrrolidone and vinylacetate units (e.g. Kollidon VA 64; BASF), preferably having a weight average molecular weight of 40,000 to 70,000 g / mol, polyoxyethylene alkylethers, polyethylene glycol, sugar alcohols like isomalt, sorbitol or mannitol, co-blockpolymers of ethylene oxide and propylene oxide (Poloxamer, Pluronic®), PEG 40 hydrogenated castor oil (Cremophor® RH 40** market by BASF), Cremophor RH 40, polysorbates including polysorbate 80, sodium lauryl sulphate and combination thereof. The solubilizing agent is present in an amount between 0.5% to 20%, and most preferably Cremophor RH 40 can be used.

[0047] The “solvent” may be selected from but not limited to water or organic solvent or mixture of organic solvent with water. The organic solvent can be selected from the group consisting of an alcohol such as methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, isobutanol, 1 -pentanol, 2- pentanol, 3-pentanol, 2-methyl-l -butanol, 3-methyl-l -butanol, 2-methyl-2-butanol, 3-methyl-2- butanol, 2,2-dimethyl- 1 -propanol, cyclohexanol, 1 -hexanol, 2-methyl-l -pentanol, 4-methyl-2- pentanol, 2-ethyl- 1 -butanol, 1 -octanol, 2-ethyl-l -hexanol, benzyl alcohol, m-creosol, 2-penten-l-ol, cis-2-buten-l-ol, propargyl alcohol, ethylene glycol, propylene glycol, trimethylene glycol, 1,3- butanediol, glycerin, methyl cellosolve, ethyl cellosolve, butyl cellosolve, diethylene glycol, triethylene glycol, 2-(2-methoxyethoxy) ethanol) and combination and / or mixture thereof. Preferably, water can be used for the preparation of an active granulating liquid.

[0048] The extragranular phase may include at least, disintegrant, lubricant and optionally diluent and / or optionally glidant.

[0049] The “disintegrant” for intragranular phase or extragranular phase may be selected from croscarmellose sodium, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone; (croscarmellose sodium) cross-linked sodium carboxymethylcellulose, cross-linked calcium carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxy methylcellulose, microcrystalline cellulose; sodium starch glycolate; ion-exchange resins includes polacrilin potassium (Kyron T 314); starch and modified starches including pregelatinized starch; formalincasein; alginates, gums; and combination thereof. The total amount of the disintegrant in the composition may be present in an amount between 1% and 15%. The same or different disintegrant can be used in the extragranular phase as used in the intragranular phase.

[0050] In a preferred composition the “lubricant” may be selected from calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, fumaric acid, sodium benzoate, sodium stearyl fumarate, stearic acid, talc, vegetable oil, zinc stearate, castor wax and combination thereof. In a preferred composition, lubricant can be used either alone or in a combination of at least one or more disintegrant. The lubricant contained in the pharmaceutical composition is present in an amount between 0.1% to 8%, and most preferably magnesium stearate.

[0051] In a preferred composition, the suitable “glidant” may be selected from calcium phosphate, calcium silicate, powdered cellulose, magnesium trisilicate, silicon dioxide, talc, colloidal silica, colloidal silica anhydrous, maize starch and combination thereof. The glidant used herein is preferably colloidal silicon dioxide and is present in amounts between 0% to 12%.

[0052] In a preferred composition the “coating material” can be selected from the group comprising film coating agents, plasticizer, anti-tacking agent, pigments, porosity agents and solvent may be used for coating of the composition, more specifically for granules or compressed tablets.

[0053] The film coating agents may be used in order to improve the appearance of the solid pharmaceutical composition and to facilitate handling during the packaging of said pharmaceutical composition. The film coating comprises a film forming agent, which can be any polymer appropriate for film coating. Examples of appropriate polymers / film forming agents may include but are not limited to cellulose derivatives such as methylcellulose (MC), ethyl cellulose (EC) carboxymethyl-cellulose (CMC), sodium carboxymethylcellulose, hydroxymethylcellulose (HMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), or hydroxypropyl methylcellulose (HPMC, hypromellose); acrylics such as methacrylate; or methylmethacrylate copolymers; vinyl such as polyvinyl alcohol; and mixtures thereof.

[0054] Preferably, the film forming agent, contained in the film coating, can be selected from a cellulose derivative or a vinyl; most preferable, the film forming agent is a cellulose derivative selected from methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, and mixtures thereof. More preferably, the film forming agent, contained in the film coating, can be either hydroxypropylmethyl cellulose or combination of hydroxypropylmethyl cellulose and ethyl cellulose.

[0055] In a preferred formulation of the present invention suitable “plasticizer” may include polyethylene glycol (PEG), propylene glycol, triethyl citrate, dibutyl sebacate, diethyl phthalate, dextrin, lecithin and triacetin or combination thereof. Most preferable, plasticizer used in the composition can be polyethylene glycol (PEG), and combination thereof.

[0056] In a preferred formulation of the present invention suitable “anti-tacking agent” can be talc, metal salts of fatty acids, magnesium stearate, stearic acid, glyceryl monostearate, colloidal silicon dioxide and combination thereof.

[0057] The “pigments” used in the above film coat may be selected from metals, metal oxides, metal hydroxides, metal chromates, metal sulfides, metal sulfates, metal carbonates, carbon black, talc, clay, and organic pigments and dyes, preferably including iron oxide red and / or yellow with or without a suitable opacifier like titanium dioxide.

[0058] The “porosity agent” in the film coat can be selected from lactose, fructose, polydextrose, sucrose, maltose and mixtures thereof; more preferably the filler is polydextrose, lactose or mixtures thereof; most preferably, the porosity agent is lactose. Additionally, the film coating may further comprise of opacifiers and colorants selected from titanium dioxide, calcium carbonate, iron oxides, aluminum lakes or mixtures thereof.

[0059] Optionally, suitable film coating can be present in an amount of 0.5% to 10% by weight relative to the total weight of the solid pharmaceutical composition of resmetirom. In a preferred embodiment, the film coating is in an amount of at least 0.5% to 5% by weight relative to the total weight of the solid pharmaceutical composition.

[0060] In second aspect, the present invention provides a process for the preparation of a solid, orally administrable pharmaceutical composition of resmetirom, wherein an intragranular phase may be prepared by blending one or more pharmaceutically acceptable excipients to form a blend. In parallel, an active granulating liquid comprising resmetirom, at least one solubilizer, one or more pharmaceutical excipients and solvent may be prepared. Thereafter, granulating the blend as prepared above with an active granulating liquid to obtain granules. Then granules of intragranular phase as prepared above may be blended with excipients of extragranular phase to obtain final blend, which may be converted into solid oral dosage forms.

[0061] The components used in the process according to the second aspect of the present invention, as defined above, can be sieved prior to the blending / mixing steps. The specific components used in the process for the preparation of the solid, orally administrable pharmaceutical composition of resmetirom, as well as their properties and amounts, are as described above for the first aspect of the invention.

[0062] In the preferred embodiment, the one or more pharmaceutical acceptable excipients can be mixed together to form a blend. The excipients can be selected from at least one or more diluent and / or disintegrant.

[0063] The active granulating liquid comprises of resmetirom, at least one solubilizer, one or more pharmaceutical excipients and solvent. It can be prepared by dissolving at least one solubilizer in solvent followed by addition of one or more pharmaceutical excipients such as at least one or more binder and then resmetirom to obtain active granulating liquid. The excipients can be selected from at least one or more binders.

[0064] The process for the preparation of a solid orally administrable pharmaceutical composition of resmetirom may be performed by using conventional wet granulation procedures, such as fluidized bed granulation.

[0065] In the wet granulation process, the active pharmaceutical ingredient i.e., resmetirom is subjected for granulation with excipients. The process can be carried out by granulating the blend of excipients with the active granulating liquid to obtain granules. These granules can be dried and sized by using sieves.

[0066] In the preferred embodiment, granulation of blend of excipients with granulating liquid can be carried out in fluidized bed granulator wherein the process involves spraying of active granulating liquid onto the blend of excipients by a top spray or bottom spray system.

[0067] Thereafter, dried granules can be subjected for blending with excipients of extragranular phase to obtain a final blend which can be used to prepare desired dosage forms, such as capsules, sachets and / or compressed to form tablets or film coated tablets. The dosage form used herein may be in the form of a tablet, a stock granulation (e.g., granules) and a capsule.

[0068] The extragranular phase in accordance with the second aspect of the present invention comprises of disintegrant, lubricant, optionally diluent and / or optionally glidant. The same or different disintegrant can be used in the extragranular phase as used in the intragranular phase. The dried granules can be blended with disintegrant, optionally diluent and / or optionally glidant then subjected for lubrication with a lubricant to obtain a final blend.

[0069] Optionally the tablets and / or granules can be coated with a film coat, to provide an aesthetic appeal, moisture protection, taste masking etc. The film coat may include a film forming agent, porosity agent, a plasticizer, an anti-tacking agent and optionally one or more pigments.

[0070] In another embodiment of the present invention, the pharmaceutical composition of resmetirom optionally has a functional or non-functional coating. The functional coating may include controlled release and / or delayed release coating and non-functional coating may include film coating.

[0071] In a preferred embodiment of the present invention, the pharmaceutical composition provides a stable product, with acceptable blend uniformity, content uniformity and bioavailability.

[0072] In another preferred embodiment of the present invention, resmetirom used herein can be milled and micronized to obtain the desired particle size. The particle size d90 of resmetirom is in the range of 1 pm to 300 pm.

[0073] In third aspect, the present invention provides a process for the preparation of solid orally administrable pharmaceutical composition of resmetirom by using wet granulation, wherein solubilizer may be dissolved in solvent to obtain solution. Thereafter, resmetirom optionally with one or more pharmaceutical excipients may be added in a solution to obtain active granulating liquid which further may be mixed with one or more pharmaceutical excipients of intragranular phase to obtain blend of granules. Then, the obtained blend may be converted into solid dosage forms of resmetirom.

[0074] The “solvent” may be selected from but not limited to water or organic solvent or mixture of organic solvent with water. The organic solvent can be selected from the group consisting of an alcohol such as methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, isobutanol, 1 -pentanol, 2- pentanol, 3-pentanol, 2-methyl-l -butanol, 3-methyl-l -butanol, 2-methyl-2-butanol, 3-methyl-2- butanol, 2,2-dimethyl- 1 -propanol, cyclohexanol, 1 -hexanol, 2-methyl-l -pentanol, 4-methyl-2- pentanol, 2-ethyl-l -butanol, 1 -octanol, 2-ethyl- 1 -hexanol, benzylalcohol, m-creosol, 2-penten-l-ol, cis-2-buten-l-ol, propargyl alcohol, ethylene glycol, propylene glycol, trimethylene glycol, 1,3- butanediol, glycerin, methyl cellosolve, ethyl cellosolve, butyl cellosolve, diethylene glycol, triethylene glycol, 2-(2-methoxyethoxy) ethanol) and combination and / or mixture thereof. Preferably, water can be used for the preparation of active granulating liquid.

[0075] In a preferred embodiment of the present invention, the pharmaceutical composition may be used one or more pharmaceutical excipients as defined above for the preparation of active granulating liquid and granulating blend.

[0076] In fourth aspect, the present invention provides an oral pharmaceutical composition comprising a therapeutically effective amount of resmetirom, at least one solubilizer, and optionally one or more pharmaceutically acceptable excipients.

[0077] In a preferred embodiment of the present invention, the pharmaceutical composition may contain a solubilizer and one or more pharmaceutical excipients as defined above for the preparation of oral composition.

[0078] In one embodiment, the solubilizer of the compositions described herein helps to increase the solubility of the active ingredient to enhance the product release profile and bioavailability.

[0079] In a further aspect, the ratio of resmetirom to solubilizer in compositions of the present invention ranges between 50:1 to 1.67: 1.

[0080] Nevertheless, the results obtained show that a resmetirom composition by using wet granulation process wherein specific ratio of resmetirom and solubilizer could effectively improve the drug’s solubility / oral bioavailability.

[0081] In a preferred embodiment of the present invention, a pharmaceutical composition is provided that is stable at 40°C and 75% relative humidity.

[0082] The present invention provides stable dosage form wherein known or unknown impurities are within the acceptable limit and drug assay is in the range of 90% to 110% as per regulatory guidelines throughout its shelf life or during in-use different stability conditions such as 40°C / 75% RH and 3Q°C / 15% RH. The level of impurities has been controlled within the composition as per guidelines. The following impurities have been monitored.

[0083] The dosage forms of different strength prepared as per the present invention have been kept at stability conditions of 30°C / 75% RH and 40°C / 75% RH, wherein all the impurities as defined above are below detection limit and drug assay within the range of 90% to 110% in the composition.

[0084] It has been found that all dosage forms are stable, and the level of all impurities as defined above have been found to be below the detection limit and drug assay within the range after 3 months and 6 months during stability studies.

[0085] In accordance with another embodiment of the present invention, the total weight of the composition can be in the range of 120 mg to 1500 mg, more preferably, the total weight of the composition can be in the range of 150 mg to 1200 mg.

[0086] In another embodiment, pharmaceutical composition of the present invention exhibits more than 90% of drug release within 30 minutes in 900 ml of pH 6.8 buffer +1% sodium lauryl sulphate using a USP dissolution apparatus II (paddle) at a temperature of 37±0.5° C and a rotation speed of 75 revolutions per minute and sinker is used in case of capsules.

[0087] In yet another embodiment, the stable formulation (tablet and / or capsules) of the present invention can be provided in the various packing materials like aluminum-polyvinyl chloride blister packing (Alu-PVC), aluminum-aluminum blister packing (Alu-Alu), aluminum foil / polyvinyl chloride (PVC) and polyvinylidene chloride (PVDC), high-density polyethylene (HDPE). More preferably, aluminum-aluminum blister packing (Alu-Alu) can be used as a packing material. In preferred embodiment, the present invention with packaging materials lead to provide an improved shelf life and stability to resmetirom composition.

[0088] The following examples, which include preferred embodiments, will serve to illustrate the practice of the invention, it is to be understood that the examples are provided solely for purposes of illustration and should not be regarded as limiting the scope of the invention in any manner.

[0089] Example 1:

[0090] Procedure:

[0091] 1. Pregelatinized Starch and mannitol were co-sifted through a suitable sieve to form a blend.

[0092] 2. Cremophor RH 40 was dissolved in purified water. Then hydroxypropyl methylcellulose was added to get a solution. Further, resmetirom was added in the solution to obtain an active granulating liquid.

[0093] 3. The blend of step 1 was granulated with an active granulating liquid of step 2 in a fluidized bed granulator to obtain granules.

[0094] 4. The granules obtained in step 3 were blended with croscarmellose sodium and then lubricated with sodium stearyl fumarate to form the final blend.

[0095] 5. The final blend was filled into empty hard gelatin capsule shells, sachet or optionally compressed into tablets.

[0096] 6. The compressed tablets were further coated using a suitable coating material. Example 2: Capsules [60mg, 80mg and lOOmg]

[0097] Procedure:

[0098] 1. Pregelatinized Starch and mannitol were co-sifted through a suitable sieve to form a blend.

[0099] 2. Cremophor RH 40 was dissolved in purified water. Then hydroxypropyl methylcellulose was added to get a solution. Further, resmetirom was added in the solution to obtain an active granulating liquid.

[0100] 3. The blend of step 1 was granulated with an active granulating liquid of step 2 in a fluidized bed granulator to obtain granules.

[0101] 4. The granules obtained in step 3 were blended with croscarmellose sodium and then lubricated with sodium stearyl fumarate to form the final blend.

[0102] 5. The final blend was filled into empty hard gelatin capsule shells.

[0103] Stability studies of lOOmg capsules at 40° C / 75% RH

[0104] The composition of example 2 was stored at 40°C / 75% RH and was tested for drug assay. The results of example 2 are tabulated in Table 1. Table 1: lOOmg capsules (Example 2)

[0105] Dissolution studies of lOOmg capsules at 40° C / 75% RH

[0106] Dissolution studies of composition of example 2 were conducted in 900 ml of pH 6.8 buffer +1% sodium lauryl sulphate with USP dissolution apparatus II (paddle), and release of resmetirom at time point of 30 minutes on stability at 40° C / 75% RH are as follows in Table 2.

[0107] Table 2: lOOmg capsules (Example 2)

[0108] Example 3: Tablets [60mg, 80mg and lOOmg] Procedure:

[0109] 1. Pregelatinized Starch and mannitol were co-sifted through a suitable sieve to form a blend.

[0110] 2. Cremophor RH 40 was dissolved in purified water. Then hydroxypropyl methylcellulose was added to get a solution. Further, resmetirom was added in the solution to obtain an active granulating liquid.

[0111] 3. The blend of step 1 was granulated with an active granulating liquid of step 2 in a fluidized bed granulator to obtain granules.

[0112] 4. The granules obtained in step 3 were blended with croscarmellose sodium and then lubricated with sodium stearyl fumarate to form the final blend.

[0113] 5. The final blend was compressed into tablets.

[0114] 6. The compressed tablets were further coated using suitable coating material.

[0115] Stability Studies 60mg tablets at 40° C / 75% RH and 30° C / 75% RH

[0116] The composition of example 3 was stored at 40° C / 75% RH and 30° C / 75% RH and was tested for drug assay. The results of example 3 are tabulated in Table 3.

[0117] Table 3: 60mg tablets (Example 3)

[0118] Dissolution Studies at 40° C / 75% RH and 30° C / 75% RH

[0119] Dissolution studies of composition of example 3 were conducted in 900 ml of pH 6.8 buffer +1% sodium lauryl sulphate with USP dissolution apparatus II (paddle) and release of resmetirom at time point of 30 minutes on stability at 40° C / 75% RH / 30° C / 75% RH are as follows in Table 4.

[0120] TABLE 4: 60mg tablets (Example 3) Stability studies 80mg tablet at 40° C / 75% RH and 30°C / 75% RH

[0121] The composition of example 3 was stored at 40° C / 75% RH and 30°C / 75% RH and was tested for drug assay. The results of example 3 are tabulated in Table 5.

[0122] Table 5: 80mg tablets (Example 3)

[0123] Dissolution studies 80mg tablet at 40° C / 75% RH and 30°C / 75% RH

[0124] Dissolution studies of composition of example 3 were conducted in 900 ml of pH 6.8 buffer +1% sodium lauryl sulphate with USP dissolution apparatus II (paddle) and release of resmetirom at time point of 30 minutes on stability at 40° C / 75% RH / 30°C / 75% RH are as follows in Table 6.

[0125] TABLE 6: 80mg tablets (Example 3)

[0126] Stability Studies lOOmg tablets at 40° C / 75% RH and 30°C / 75% RH

[0127] The composition of example 3 was stored at 40° C / 75% RH and 30°C / 75% RH and was tested for drug assay. The results of example 3 are tabulated in Table 7.

[0128] Table 7: lOOmg tablets (Example 3) Dissolution Studies lOOmg tablets at 40° C / 75% RH and 30°C / 75% RH

[0129] Dissolution studies of composition of example 3 were conducted in 900 ml of pH 6.8 buffer +1% sodium lauryl sulphate with USP dissolution apparatus II (paddle), and release of resmetirom at time point of 30 minutes on stability at 40° C / 75% RH and 30°C / 75% RH are as follows in Table 8.

[0130] TABLE 8: lOOmg tablets (Example 3)

[0131] It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit and scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.

Claims

CLAIMS1. A pharmaceutical composition comprising: resmetirom in an amount of 3.5% to 45% w / w; diluent ranging from 5% to 95% w / w; binder ranging from 0.5% to 10% w / w; solubilizer ranging from 0.5% to 20% w / w; disintegrant ranging from 1% to 15% w / w; lubricant ranging from 0.1% to 8% w / w; glidant ranging from 0 % to 12% w / w; and optionally, film coating agent ranging from 0.5% to 5%; relative to the total weight of the pharmaceutical dosage form.

2. The pharmaceutical composition as claimed in claim 1, wherein diluent is selected from starch, corn starch, potato starch, pregelatinized starch, dry starch, disaccharides, lactose, cellulose, maltodextrins, silicified microcrystalline cellulose, microcrystalline cellulose, mannitol, sorbitol, xylitol, trehalose, colloidal silica, sucrose or other sugars or sugar derivatives, calcium hydrogen phosphate and dicalcium phosphate; binder is selected from polyvinyl pyrrolidone, polyvinyl alcohol, copovidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, powdered acacia, gelatin, guar gum, carbopol, polymethacrylates, pregelatinized starch and combination thereof.

3. The pharmaceutical composition as claimed in claim 1, wherein solubilizer is selected from hydroxypropylmethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidones, copolymers comprising vinylpyrrolidone and vinylacetate units, polyoxyethylene alkylethers, polyethylene glycol, isomalt, sorbitol, mannitol, co-blockpolymers of ethylene oxide and propylene oxide, PEG 40 hydrogenated castor oil, polysorbates, sodium lauryl sulphate and combination thereof.

4. The pharmaceutical composition as claimed in claim 1, wherein disintegrant is selected from croscarmellose sodium, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, croscarmellose sodium, cross-linked calcium carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxy methylcellulose, microcrystalline cellulose, sodium starch glycolate, ion-exchange resins; starch, pregelatinized starch, formalin-casein, alginates, gums and combination thereof; lubricant is selected from calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, fumaric acid, sodium benzoate, sodium stearyl fumarate, stearic acid, talc, vegetable oil, zinc stearate, castor wax andcombination thereof; glidant is selected from calcium phosphate, calcium silicate, powdered cellulose, magnesium trisilicate, silicon dioxide, talc, colloidal silica, colloidal silica anhydrous, maize starch and combination thereof; film coating agent is selected from the group comprising film coating agents, plasticizer, anti-tacking agent, pigments, porosity agents and solvent thereof.

5. A process for the preparation of a pharmaceutical composition of resmetirom, comprises the steps of: i. preparing an intragranular phase comprising a) blending one or more pharmaceutically acceptable excipients to form a blend, b) providing an active granulating liquid comprising resmetirom, one or more pharmaceutical excipients, and solvent, c) granulating the blend of step i (a) with the active granulating liquid of step i (b) to obtain granules, ii. blending the granules of intragranular phase of step (i) with the excipients of extragranular phase to obtain final blend, iii. converting the final blend of step (ii) into solid oral dosage forms.

6. The pharmaceutical composition as claimed in claim 5, wherein solvent is selected from water or organic solvent or mixture of organic solvent with water.

7. The pharmaceutical composition as claimed in claim 5, wherein intragranular phase excipients in step (i) comprising of diluent, binder and solubilizer; wherein extragranular phase excipients in step (ii) comprising of disintegrant, lubricant, and optionally diluent and / or glidant.

8. The pharmaceutical composition as claimed in claim 1, wherein resmetirom is present in an amount of 3.5% to 45% w / w of the total weight of the pharmaceutical composition having dissolution more than 90% within 30 minutes.

9. A solid orally administrable pharmaceutical composition comprising a therapeutically effective amount of resmetirom, at least one solubilizer, and optionally one or more pharmaceutically acceptable excipients.

10. The pharmaceutical composition as claimed in claim 9, wherein ratio of resmetirom to solubilizer in composition is 50: 1 to 1.67: 1.

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