Film coated tablet formulations comprising ivacaftor

Abstract

The present invention relates to a film coated tablet formulation comprising a solid dispersion of ivacaftor and at least one pharmaceutical excipient wherein ivacaftor has a d (0.9) particle size between 5 µm and 25 µm. The present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient method of preparing the formulation.

Description

IVACAFTOR-CONTAINING FILM-COATED TABLET FORMULATIONS Meeting Area The present invention describes a solid dispersion of ivacaftor and at least one pharmaceutical excipient. This relates to a film-coated tablet formulation, where ivacaftor is present in a film-coated tablet form with a thickness between 5 µm and 25 µm. It has a particle size of (0.9). The present invention also applies to the preparation of the formulation. It is about a simple, fast, cost-effective, time-saving, and industrially viable method. Background of the Invention Also known as N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide ivakaftor has the following Formula (I): Formula I Ivacaftor is a white to off-white powder that is practically insoluble in water (<0.05 micrograms / mL). Ivacaftorun has low water solubility, is very lipophilic, and when administered with food... The bioavailability of ivacaftorun is significantly increased. Due to its poor aqueous solubility, extensive Formulation efforts were required, and ivacaftorun was found to be suitable as a spray-dried product for oral administration. This resulted in a dispersion. Ivakaftor is FDA approved and available orally at 150 mg. Vertex Pharma offers KALYDECO® brand tablets for the treatment of cystic fibrosis. It is marketed by Kalydeco®, CFTR (cystic fibrosis transmembrane conductivity). In patients aged 6 and older with a G55ID mutation in the (regulator) gene, for the treatment of cystic fibrosis. It is indicated. Ivacaftor is an enhancer of the CFTR protein. The CFTR protein is found in epithelial cells in multiple organs. It is a chloride channel found on the surface of cells. Ivacaphtor is the channel-opening mechanism of the CFTR protein. It strengthens the probability (or gating) of increased chloride transport, thereby facilitating increased chloride transport. Accordingly, a stable, bioavailable and suitable alternative could be used in the treatment of cystic fibrosis patients. High-resolution ivacaftor pharmaceutical formulations are needed. 2 Patent number IN201502628I4 describes novel compositions of ivacaphthora. More specifically, Unit solid oral formulations of crystalline ivacaftor and one or more pharmaceutical excipients. It is related to the fact that the particle size of ivacaftor d(0.9) is less than approximately 20 microns. Patent number US2015010628A1 concerns N-[2,4-Bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4- Oxoquinoline-3-carboxamide solid dispersion, solid dispersions in powder, granule and mini tablet form. formulations, methods for the production and processing of powders and mini-tablets and pharmaceuticals Methods for treating cystic fibrosis using this compound are described. It is known that the solubility of ivacaftor is poor in the previous technique, and it was written for this purpose. There are patent applications. However, it still requires both high stability and high resolution. A formulation with this feature is needed. In the present invention, a solid dispersion of ivacaftor with a thickness of 5 µm is used. By using a particle size of d(0.9) between µm, both high stability and high A formulation with sufficient solubility has been obtained. Detailed description of the invention The main objective of the present invention is to achieve high resolution, the desired resolution profile, and high... The aim is to provide a film-coated tablet formulation containing a homogeneous ivacaftor with stability. Another objective of the present invention is to provide a simple and effective film-coated tablet formulation containing ivacaftor. The goal is to provide a cost-effective preparation process. Ivacaftor has low water solubility, which inhibits its absorption in the gastrointestinal system. Ivacaphtor's solid dispersion formulation allows the drug to disperse within a hydrophobic matrix. It provides a larger surface area for resolution, while also offering resolutions ranging from 5 µm to 25 µm. A small particle size provides a larger surface area for better drug solubility. This results in low... This is critical for drugs that require solubility because the faster the drug dissolves, the better. It is rapidly absorbed and enters the bloodstream. Its larger surface area increases solubility. Ivacaphtorun The use of solid dispersion is also more advantageous compared to traditional ivakaftor formulations. It provides high stability. The small particle size allows for integration with the drug during the formulation process. It ensures better homogeneity with the help of the auxiliary substances used. As a result, ivakaftor solid dispersion and d(0.9) particle size between 5 µm and 25 µm were used Our formulation provides a homogeneous solution with the desired dissolution profile and high stability. This has resulted in the formulation. According to this arrangement of the invention, the solid dispersion of ivacaftor and at least one pharmaceutical This relates to a film-coated tablet formulation containing the excipient, ivakaftor 5 µm. It has a particle size of d (0.9) between µm. 3 According to this arrangement of the invention, the solid dispersion ivacaftor, hypromellose acetate succinate and It contains sodium lauryl sulfate. According to this arrangement of the invention, the solid dispersion contains between 70.0% and 80.0% by weight of dispersion. ivakaftor contains 20.0% to 25.0% hypromellose acetate by weight in dispersion. It contains 0.1% to 1.0% sodium lauryl sulfate by weight in succinate and dispersion. According to this arrangement of the invention, the amount of solid dispersion of ivacaphthor is the total It is between 25.0% and 45.0% by weight in the formulation. According to this arrangement of the present invention, the film-coated tablet formulation is a filler, dispersants, surfactants, glidants, lubricants, film coating agents or their derivatives at least one pharmaceutically acceptable excipient selected from a group containing a mixture includes. Suitable fillers include lactose monohydrate, microcrystalline cellulose, mannitol, lactose, and dibasic acid. calcium phosphate, spray-dried mannitol, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium from the group containing carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof is selected. According to this arrangement of the present invention, the filler is lactose monohydrate or microcrystalline. It is cellulose or mannitol or a mixture of both. According to this arrangement of the present invention, the amount of filler is a percentage of the total formulation. It is between 40.0% and 65.0% by weight, preferably 45.0% to 65.0% by weight of the total formulation. It is between 60.0%. More preferably, the amount of filler should be a percentage of the total formulation by weight. It is between 48.0% and 68.0%. Suitable dispersants include croscarmellose sodium, sodium starch glycolate, crospovidon, and low-substitution alternatives. hydroxypropyl cellulose, starch, calcium carboxymethyl cellulose, pre-gelatinized starch, sodium docusate, guar gum, sodium alginate, alginic acid, magnesium aluminum It is selected from the group containing silica, poloxamer, sodium glycine carbonate, or mixtures thereof. According to this arrangement of the present invention, the dispersing agent is croscarmellose sodium. According to this arrangement of the invention, the dispersant amount is 1.0% to 1.0% by weight of the total formulation. It is between 10.0%, preferably between 3.0% and 7.0% by weight of the total formulation. 4 Suitable surfactants include sodium lauryl sulfate, cetostearyl alcohol, and cetomacrogol emulsifier. exfoliating wax, gelatin, casein, docusate sodium, benzalkonium chloride, calcium stearate, polyethylene glycols, phosphates, polyoxyethylene sorbitan fatty acid esters, gum tragacanth, polyoxyethylene 20 stearyl ethers, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, pegylated hydrogenated castor oil oils, sorbitan esters of fatty acids, vitamin E or tocopherol derivatives, vitamin E TPGS, tocopheryl esters, lecithin, phospholipids and derivatives, poloxamers, stearic acid, oleic acid, oleic alcohol, cetyl alcohol, mono and diglycerides, propylene glycol esters of fatty acids, ethylene glycol palmitostearate, polyoxylglycerides, propylene glycol monocaprylate, propylene glycol monolaurate, alkyl It is selected from the group containing aryl polyether alcohols and polyglyceryl oleate or mixtures thereof. According to this arrangement of the present invention, the surfactant is sodium lauryl sulfate. According to this arrangement of the present invention, the amount of surfactant is a percentage of the total formulation. It is between 0.01% and 5.0% by weight, preferably between 0.1% and 5.0% of the total formulation by weight. It is between 2.0%. Suitable lubricants include sodium stearyl fumarate, glyceryl behenate, fatty acids, stearic acid, and magnesium. stearate, calcium stearate, sodium stearate, stearic acid, glyceryl monostearate, hydrogenated fats (e.g., hydrogenated vegetable oil), polyethylene glycol, fatty alcohol, fatty acid ester, glyceryl behenate, from the group consisting of mineral oil, vegetable oil, leucine, sodium benzoate or a mixture thereof is selected. According to this arrangement of the present invention, the lubricant is sodium stearyl fumarate or glyceryl behenate. or a mixture of these. According to this arrangement of the present invention, the amount of lubricant is a percentage of the total formulation by weight. It is between 0.01% and 8.0%, preferably between 0.1% and 5.0% by weight of the total formulation. It is among them. Suitable glidants include colloidal silicon dioxide, magnesium oxide, magnesium silicate, and hydrophobic adhesives. It is selected from a group consisting of colloidal silica, calcium phosphate, powdered cellulose, or a mixture thereof. According to this arrangement of the present invention, the glidant is colloidal silicon dioxide. According to this arrangement of the invention, the amount of glidant is between 0.01% and 1% by weight of the total formulation. It is between 8.0%, preferably between 0.1% and 5.0% by weight of the total formulation. Suitable film coating materials include polyvinyl alcohol (PVA), titanium dioxide, and macrogol (PEG 3350). Indigo carmine, aluminum lake, talc, carnauba wax, hydroxypropylmethylcellulose, polyethylene glycol (PEG), polyvinyl alcohol-polyethylene glycol copolymers, lecithin, polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), pigments, dyes, iron oxide or a mixture thereof. They are selected from the group. 5 According to this arrangement of the present invention, the amount of film coating agent is a percentage of the total formulation. It is between 1.0% and 8.0% by weight. In the present invention, the tablet is designed to protect the composition from moisture and light in order to maintain stability. Includes film coating. The process for preparing film-coated tablets containing ivacaftor involves the following steps: a) solid containing ivacaftor, fillers, disintegrating agent, surfactant and glidant weighing and mixing the dispersion, b) Sifting the mixture through a sieve, c) Finally, the slider is sifted through a sieve and added to the mixture. Example 1; Components by Weight (%) Ivacaphtor solid dispersion 25-45 Lactose monohydrate 11SD (Supertab) 10-40 Microcrystalline cellulose 200 15-40 Croscarmellose sodium 1-10 Sodium lauryl sulfate 0.01-5 Colloidal silicon dioxide 0.01-8 Sodium stearyl fumarate 0.1-8 TOTAL CORE TABLET WEIGHT 92-99 OPARDY II 85F505345 - POLYVINYL ALCOHOL - PART. HYDROLYZED (USP, (FCC, PhEur, JPE, ChP, GB) -TITANIUM DIOXIDE (USP, FCC, PhEur, JP, JSFA, (CHP, GB) 1-8 -MAKROGOL / PEG (USP, FCC, PhEur, JECFA, JP) -TALK (USP, FCC, PhEur, JP, JECFA, ChP) -FD&C BLUE #2 / INDIGO CARMINE ALUMINUM LAKE (JECFA, JP MO, GB) -CARNAUBA WAX (NF, PhEur, JP, ChP, FCC) TOTAL WEIGHT OF COATED TABLETS: 100 A process for Example 1; a) Ivacaphthoron solid dispersion, lactose monohydrate 11SD, microcrystalline cellulose 200, Weighing of croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide and 10 Mixing for 6 minutes. b) Sifting the mixture through a 0.85 mm sieve, c) Finally, the sodium stearyl fumarate is sieved through a 0.425 mm sieve and added to the mixture. addition. Example 2; Components by Weight (%) Ivacaphtor solid dispersion 25-45 Lactose monohydrate 11SD (Supertab) 46-65 Croscarmellose sodium 1-10 Sodium lauryl sulfate 0.01-5 Colloidal silicon dioxide 0.01-5 Sodium stearyl fumarate 0.01-5 TOTAL CORE TABLET WEIGHT 92-99 OPARDY II 85F505345 - POLYVINYL ALCOHOL - PIECE. HYDROLYZED (USP, (FCC, PhEur, JPE, ChP, GB) -TITANIUM DIOXIDE (USP, FCC, PhEur, JP, JSFA, (CHP, GB) 1-8 -MAKROGOL / PEG (USP, FCC, PhEur, JECFA, JP) -TALK (USP, FCC, PhEur, JP, JECFA, ChP) -FD&C BLUE #2 / INDIGO CARMINE ALUMINUM LAKE (JECFA, JP MO, GB) -CARNAUBA WAX (NF, PhEur, JP, ChP, FCC) TOTAL WEIGHT OF COATED TABLETS: 100 A process for Example 2; a) Ivacaphthora solid dispersion, lactose monohydrate 11SD, croscarmellose sodium, sodium lauryl sulfate and colloidal silicon dioxide were weighed and mixed for 10 minutes. b) Sifting the mixture through a 0.85 mm sieve, c) Finally, the sodium stearyl fumarate is sieved through a 0.425 mm sieve and added to the mixture. addition. 7 Example 3; Components by Weight (%) Ivacaphtor solid dispersion 25-45 Lactose monohydrate 11SD (Supertab) 20-40 Microcrystalline cellulose 200 10-30 Croscarmellose sodium 1-10 Sodium lauryl sulfate 0.01-5 Colloidal silicon dioxide 0.01-5 Glyceryl behenate 0.5-8 TOTAL CORE TABLET WEIGHT 92-99 OPARDY II 85F505345 - POLYVINYL ALCOHOL - PIECE. HYDROLYZED (USP, (FCC, PhEur, JPE, ChP, GB) -TITANIUM DIOXIDE (USP, FCC, PhEur, JP, JSFA, (CHP, GB) 1-8 -MAKROGOL / PEG (USP, FCC, PhEur, JECFA, JP) -TALK (USP, FCC, PhEur, JP, JECFA, ChP) -FD&C BLUE #2 / INDIGO CARMINE ALUMINUM LAKE (JECFA, JP MO, GB) -CARNAUBA WAX (NF, PhEur, JP, ChP, FCC) TOTAL WEIGHT OF COATED TABLETS: 100 A process for Example 3; a) Ivacaphthoron solid dispersion, lactose monohydrate 11SD, microcrystalline cellulose 200, Weighing of croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide and 10 mixing for a few minutes, b) Sifting the mixture through a 0.85 mm sieve, c) Finally, glyceryl behenate is sieved through a 0.425 mm sieve and added to the mixture. 8 Example 4; Components by Weight (%) Ivacaphtor solid dispersion 25-45 Lactose monohydrate 11SD (Supertab) 45-65 Mannitol 1-20 Microcrystalline cellulose 200 10-30 Croscarmellose sodium 1-10 Sodium lauryl sulfate 0.01-5 Colloidal silicon dioxide 0.5-8 Sodium stearyl fumarate 0.5-8 TOTAL CORE TABLET WEIGHT 92-99 OPARDY II 85F505345 - POLYVINYL ALCOHOL - PIECE. HYDROLYZED (USP, (FCC, PhEur, JPE, ChP, GB) -TITANIUM DIOXIDE (USP, FCC, PhEur, JP, JSFA, (CHP, GB) 1-8 -MAKROGOL / PEG (USP, FCC, PhEur, JECFA, JP) -TALK (USP, FCC, PhEur, JP, JECFA, ChP) -FD&C BLUE #2 / INDIGO CARMINE ALUMINUM LAKE (JECFA, JP MO, GB) -CARNAUBA WAX (NF, PhEur, JP, ChP, FCC) TOTAL WEIGHT OF COATED TABLETS: 100 A process for Example 4; a) Ivacaftor solid dispersion, lactose monohydrate 11SD, mannitol, microcrystalline cellulose Weighing of 200 croscarmellose sodium, sodium lauryl sulfate, and colloidal silicon dioxide. mixing for a few minutes, b) Sifting the mixture through a 0.85 mm sieve, c) Finally, the sodium stearyl fumarate is sieved through a 0.425 mm sieve and added to the mixture. addition. 9 Example 5; A solid dispersion Solid distribution by weight % Ivacaftor 76 Hypromellose acetate succinate 23.5 Sodium lauryl sulfate 0.5 Total 100 A process for Example 5; a) Weigh ivacaftor, hypromellose acetate succinate, sodium lauryl sulfate and incubate for 10 minutes. mixing, b) Dissolving the mixture in water and drying it in a fluidized bed dryer at 50ºC, c) Passing the mixture through a 1 mm square sieve.

Claims

1- A film containing a solid dispersion of ivacaftor and at least one pharmaceutical excipient. coated tablet formulation where ivacaftor has a d (0.9) between 5 µm and 25 µm. It has a particle size. 2- Film-coated tablet formulation according to claim 1, where ivacaftor solid The amount of dispersion in the total formulation is between 25.0% and 45.0% by weight. 3- Film-coated tablet formulation according to Claim 1, where film-coated tablet is a filler. ingredients, dispersants, surfactants, glidants, lubricants, film coating agents or selected from a group consisting of a mixture of these, the most pharmaceutically acceptable It contains very few excipients. 4- Film-coated tablet formulation according to claim 3, where the filler material is lactose. monohydrate, microcrystalline cellulose, mannitol, lactose, dibasic calcium phosphate, by spray Dried mannitol, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextracts, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium containing carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof They are selected from the group. 5- Film-coated tablet formulation according to claim 3 or 4, where lactose is the filler. It is cellulose monohydrate or microcrystalline cellulose or mannitol or a mixture thereof. 6- Film-coated tablet formulation according to claim 4 or 5, where the amount of filler is specified. It constitutes between 40.0% and 65.0% by weight of the total formulation, preferably total. It is between 45.0% and 60.0% by weight of the formulation. 7- Film-coated tablet formulation according to claim 3, where the dispersant is croscarmellose. sodium, sodium starch glycolate, crospovidon, low-substitution hydroxypropyl cellulose, starch, calcium carboxymethyl cellulose, pregelatinized starch, docusate sodium, guar gum, sodium alginate, alginic acid, magnesium aluminum silica, Poloxamer is selected from the group containing sodium glycine carbonate or mixtures thereof. 8- Film-coated tablet formulation according to claim 3 or 7, where the dispersant is... It is croscarmellose sodium. 9- Film-coated tablet formulation according to claim 7 or 8, where the amount of dispersant is total The concentration of the formulation is between 1.0% and 10.0% by weight, preferably of the total formulation. It is between 3.0% and 7.0% by weight. 10- Film-coated tablet formulation according to claim 3, where the surfactants are sodium lauryl sulfate, cetostearyl alcohol, cetomacrogol emulsifying wax, gelatin, casein, 35 docusate sodium, benzalkonium chloride, calcium stearate, polyethylene glycols, phosphates, polyoxyethylene sorbitan fatty acid esters, gum tragacanth, polyoxyethylene 20 stearyl ethers, 11 polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, pegylated hydrogenated castor oil oils, sorbitan esters of fatty acids, vitamin E or tocopherol derivatives, vitamin E TPGS, tocopheryl esters, lecithin, phospholipids and derivatives, poloxamers, stearic acid, oleic acid, oleic alcohol, cetyl alcohol, mono and diglycerides, propylene glycol of fatty acids esters, ethylene glycol palmitostearate, polyoxylglycerides, propylene glycol monocaprylate, propylene glycol monolaurate, alkyl aryl polyether alcohols and polyglyceryl oleate or any thereof It is selected from the group that includes the mixtures. 11- Film-coated tablet formulation according to claim 3 or 10, where surfactant It is sodium lauryl sulfate. 12- Film-coated tablet formulation according to claim 10 or 11, where surfactant The amount is between 0.01% and 5.0% by weight of the total formulation, preferably total. It is between 0.1% and 2.0% by weight of the formulation. 13- Film-coated tablet formulation according to claim 3, where sodium stearyl is the lubricant. fumarate, glyceryl behenate, fatty acid, stearic acid, magnesium stearate, calcium stearate, sodium stearate, stearic acid, glyceryl monostearate, hydrogenated fats (e.g., hydrogenated vegetable oil), polyethylene glycol, fatty alcohol, fatty acid ester, glyceryl behenate, mineral oil, It is selected from the group containing vegetable oil, leucine, sodium benzoate, or mixtures thereof. 14- Film-coated tablet formulation according to claim 3 or 13, where sodium lubricating agent is used. It is stearyl fumarate or glyceryl behenate or a mixture thereof. 15- Film-coated tablet formulation according to claim 13 or 14, where the amount of lubricant is specified. It is between 0.01% and 8.0% by weight of the total formulation, preferably total. The concentration of the formulation is between 0.1% and 5.0% by weight.