AVATROMBOPAG-CONTAINING FILM-COATED TABLET FORMULATION

Abstract

The present invention relates to a film-coated tablet formulation containing avatrombopag maleate or a pharmaceutically acceptable salt, in amorphous or crystalline form, and at least one filler in which avatrombopag maleate is crystalline form B. The present invention also relates to a simple, rapid, cost-effective, time-saving and industrially feasible method for preparing the formulation.

Description

AVATROMBOPAG-CONTAINING FILM-COATED TABLET FORMULATION Meeting Area The present invention relates to avatrombopag maleate or a pharmaceutically acceptable salt, amorphous or This relates to film-coated tablet formulations in crystalline form and containing at least one filler, Here, avatrombopag maleate is crystalline form B. The present invention also includes preparing the formulation. a simple, fast, cost-effective, time-saving and industrially viable method It is related. Background of the Invention Avatrombopag, sold under the brand name Doptelet, is for those undergoing a planned medical or dental procedure. thrombocytopenia, such as thrombocytopenia associated with chronic liver disease in adults Avatrombopag maleate is a medication used for certain conditions that cause low platelet count. The molecular formula is CH Cl NOS .CHO and the structural formula (I) is as follows: 29 34 2 6 3 2 4 4 4 Formula I Avatrombopag is a white to off-white powder with a non-chiral structure. The compound is practical. It is insoluble in water and is not hygroscopic. However, avatrombopag maleate is soluble in water and It is virtually insoluble in 0.1M hydrochloric acid and operates within the pH range of all systems in the body. It is almost insoluble. Avatrombopag maleate is a compound that can simulate the biological effect of TPO, stimulating platelet production. An oral, small-molecule thrombopoietin that increases platelet count and is a clinical emergency drug. It is a TPO receptor (c-Mpl) agonist. Patent CN112022825A describes avatrombopag maleate tablets and preparation method. It is explained in this patent that the crystalline form of Avatrombopag maleate is Form C. 2 In the patent CN118453530A, an avatrombopag maleate tablet and avatrombopag maleate tablet The preparation method is described. Avatrombopag maleate tablets consist of a tablet core and a film. It contains a coating layer; the tablet core contains avatrombopag maleate (particle). The size D90 is equal to or less than 85.6 mm), a filler containing anhydrous lactose and lactose (4.6: 1)-(3: 1), adopts two internal and external addition modes, one dispersing agent and one sliding agent, the ratio of the particle dispersing material to the inner and outer addition (2:1)-(4:1) and the ratio of the lubricant to the inner and outer The addition ratio is (1:1)-(1:2.4). In this patent, the crystalline form of Avatrombopag maleate is Form C. Avatrombopag is generally used in solid form in formulations; drug polymorphism affects drug quality. and is one of the important factors affecting the clinical therapeutic effect, therefore the crystalline form It has very important implications for research. There are many patent applications for the avatrombopag technique from the previous era. It is still new and simple. A formulation and process are needed to overcome the low solubility of the active substance. To achieve this, the crystalline B form of avatrombopag maleate was used. Avatrombopag maleate B When this form is used, a high-resolution formulation is obtained, and therefore the desired result is achieved. A dissolution profile has been obtained. Detailed description of the invention The main objective of the present invention is to create a film containing avatrombopag maleate with the desired dissolution profile. The goal is to provide a coated tablet formulation. Another objective of the present invention is to create avatrombopag with uniform and fluid content. The goal is to provide a film-coated tablet formulation containing maleate. Another aim of this invention is to produce avatrombopag maleate, which is a simple and cost-effective process. The aim is to provide the process for preparing film-coated tablet formulations. Avatrombopag maleate exhibits low solubility in water, which necessitates techniques to improve its solubility. formulated in oral solid dosage forms such as tablets or capsules without being used This can make things more difficult. Since avatrombopag maleate is sparingly soluble in water, the dissolution rate is slow. That's possible. Therefore, there is still a need to develop a new formulation with high solubility. there are. In our studies, we identified various crystalline forms of avatrombopag maleate, namely A, B, and C. We tried it. However, when we used form B of avatrombopag maleate, the solubility was higher than that of forms A and C. We observed that it gave better results according to its forms. Therefore, avatrombopag maleate B By using this form, we obtained a high-resolution formulation. Thus, the formulation It had the desired dissolution profile. 3 According to one arrangement of the invention, avatrombopag maleate can be considered a pharmaceutical. a film-coated tablet formulation containing a salt, its amorphous or crystalline form, and at least one dispersant It is related to, and here, avatrombopag maleate is crystalline form B. According to this arrangement of the invention, the amount of avatrombopag maleate in the total formulation It ranges from 1.0% to 20.0% by weight. Preferably, the amount of avatrombopag maleate is total. It is between 5.0% and 15.0% by weight in the formulation. Suitable fillers include microcrystalline cellulose, lactose monohydrate, ammonium alginate, and calcium. carbonate, calcium phosphate, calcium phosphate dehydrate, neutral pellets, calcium sulfate, cellulose, cellulose acetate, compressible sugar, dextrates, dextrin, dextrose, ethylcellulose, fructose, glyceryl palmitostearate, lactitol, mannitol, polymethacrylates, simethicone, sodium alginate, sodium chloride, sorbitol, sucrose, sugar spheres, sulfobutyrate beta-cyclodextrin, gum tragacanth, trehalose, xylitol or It is selected from the group that contains mixtures of these. According to one arrangement of the present invention, the filler material is microcrystalline cellulose or lactose. It is monohydrate or a mixture thereof. According to one arrangement of this invention, the amount of filler is by weight in the total formulation. It is between 70.0% and 90.0%. Preferably, the amount of filler is measured by weight in the total formulation. It is between 75.0% and 85.0%. This filling ratio is determined by the amount of powder mixture during the compression process. It ensures a smooth flow, resulting in a uniform tablet weight. Thus... It eliminates problems such as fluidity and content monotony. According to one arrangement of this invention, the film-coated tablet formulation also includes dispensers, selected from a group consisting of sliders / glidants, film coating agents or mixtures thereof. It contains at least one pharmaceutically acceptable excipient. Suitable dispersants include crospovidon, croscarmellose sodium, sodium starch glycolate, and low-substitution products. hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, polyacrylate potassium, sodium alginate, corn starch, alginic acid, alginates, ion exchange resins, magnesium aluminum silica, sodium dodecyl sulfate, poloxamer, sodium glycine carbonate, sodium lauryl sulfate or any of these It is selected from the group that includes the mixtures. According to one arrangement of the present invention, the dispersant is crospovidon. According to one arrangement of this invention, the dispersant amount is 0.1% by weight in the total formulation to... It is between 10.0%. Suitable sliders / glidants include magnesium stearate, colloidal silicon dioxide, talc, and calcium. stearate, zinc stearate, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium 4 lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fat acid, fumaric acid, glyceryl palmitosulfate, sodium stearyl fumarate, sodium lauryl sulfate or It is selected from the group that contains mixtures of these. According to one arrangement of the present invention, the sliding / glidant is magnesium stearate or colloidal. It is silicon dioxide or a mixture thereof. According to one arrangement of this invention, the amount of glider / slider is measured by weight in the total formulation. It ranges from 0.01% to 10.0%. Suitable film coating agents include opadry yellow, polyvinyl alcohol (PVA), titanium dioxide, and macrogol. (PEG 3350), iron oxide, talc, indigo carmine aluminum lake, carnauba wax, hydroxypropylmethylcellulose, polyethylene glycol (PEG), polyvinyl alcohol-polyethylene glycol copolymers, Lecithin, polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), pigments, dyes or their derivatives It is selected from the group that consists of the mixture. According to this arrangement of the present invention, the amount of film coating agent in the total formulation It ranges from 1.0% to 8.0% by weight. According to a regulation of this invention, avatrombopag maleate or pharmaceutically accepted a film-coated tablet formulation containing a usable salt, in amorphous and crystalline forms directly It is obtained by compression. In direct compression, film-coated tablet components It is not exposed to moisture, solvents, or heat. Therefore, this invention is not exposed to moisture, solvents, and / or heat. Direct compression is used for processing heat-sensitive avatrombopag. A process for preparing a film-coated tablet formulation containing avatrombopag. It includes the following steps; a) Avatrombopag Maleate form B, filler, dispersant and glidant mixing, b) Sieving the mixture from step (a), c) Adding a slider / glidant to the mixture in step (b), d) Each tablet of the resulting homogeneous mixture must have the specified characteristics. compression, e) Coating the core tablet with a film coating. 5 Example 1; Components (by weight %) (by weight %) Avatrombopag Maleate Form B (20 mg Avatrombopag 11.3 1-20 equivalent) Lactose Monohydrate 58.1 50-65 Microcrystalline cellulose 20 10-25 Crospovidon Type B 2.9 0.1-10 Colloidal Silicon Dioxide 2.9 0.1-10 Magnesium Stearate 1 0.01-5 Core tablet weight 96.2 92-99 Film Coating: (Polyvinyl) Alcohol, Talc, Macrogol, 3.8 1-8 Titanium dioxide, Iron Opadry Yellow TOTAL 100 100 A process for Example 1; a) Avatrombopag maleate form B, lactose monohydrate, microcrystalline cellulose, crospovidone Type B, mixing of colloidal silicon dioxide. b) Sieving the mixture from step (a) through a 630 mm sieve, c) Adding magnesium stearate to the mixture in step (b), d) Each tablet of the resulting homogeneous mixture must have the specified characteristics. compression, e) Coating the core tablet with a film coating.

Claims

1- Avatrombopag maleate or a pharmaceutically acceptable salt thereof, in amorphous or This relates to film-coated tablet formulations containing crystalline form and at least one dispenser, where avatrombopag maleate is crystal form B. 2- Film-coated tablet formulation according to Claim 1, where the amount of avatrombopag maleate is... It is between 1.0% and 20.0% by weight in the total formulation. 3- Film-coated tablet formulation according to Claim 1, where fillers are used. microcrystalline cellulose, lactose monohydrate, ammonium alginate, calcium carbonate, calcium phosphate, calcium phosphate dehydrate, neutral pellets, calcium sulfate, cellulose, cellulose acetate, compressible sugar, dextrates, dextrin, dextrose, ethylcellulose, fructose, glyceryl palmitostearate, lactitol, mannitol, polymethacrylates, simethicone, sodium alginate, sodium chloride, sorbitol, sucrose, sugar spheres, sulfobutyre beta-cyclodextrin, tragacanth, It is selected from the group containing trehalose, xylitol, or mixtures thereof. 4- Film-coated tablet formulation according to claim 1 or 3, where filler material It is microcrystalline cellulose or lactose monohydrate, or a mixture thereof. 5- Film-coated tablet formulation according to claim 3 or 4, where the amount of filler is specified. It is between 70.0% and 90.0% by weight in the total formulation. 6- According to Claim 1, the film-coated tablet formulation is used herein. also dispersants, sliders / glidants, film coating agents or their derivatives at least one pharmaceutically acceptable substance selected from the group consisting of the mixture Contains excipients. 7- Film-coated tablet formulation according to claim 6, where the dispersants are crospovidon, croscarmellose sodium, sodium starch glycolate, low-substitution hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, Docusate sodium, guar gum, polyacrylate potassium, sodium alginate, corn starch, alginic acid, alginates, ion exchange resins, magnesium aluminum silica, sodium dodecyl sulfate, poloxamer, sodium glycine carbonate, sodium lauryl sulfate or any of these It is selected from the group that includes the mixtures. 8- Film-coated tablet formulation according to claim 6 or 7, where the dispersant It is crospovidon. 9- Film-coated tablet formulation according to claim 7 or 8, where the amount of dispersant is total It is present in the formulation at a rate of 0.1% to 10.0% by weight. 10- Film-coated tablet formulation according to claim 6, where sliders / glidants magnesium stearate, colloidal silicon dioxide, talc, calcium stearate, zinc stearate, 35 waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fatty acid, 7 fumaric acid, glyceryl palmitosulfate, sodium stearyl fumarate, sodium lauryl sulfate or It is selected from the group that contains mixtures of these. 11- Film-coated tablet formulation according to claim 6 or 10, where the sliding agent / glidant It is magnesium stearate or colloidal silicon dioxide or a mixture thereof. 12- Film-coated tablet formulation according to claim 10 or 11, where the gliding agent / glidant Its amount ranges from 0.01% to 10.0% by weight in the total formulation. 13- A procedure for preparing a film-coated tablet formulation containing avatrombopag. It includes the following steps; a) Avatrombopag Maleate form B, filler, dispersant and glidant mixing, b) Sieving the mixture from step (a), c) Adding a slider / glidant to the mixture in step (b), d) Each tablet of the resulting homogeneous mixture must have the specified characteristics. compression, e) Coating the core tablet with a film coating. 35