Amorphous tolvaptan tablet formulation with micronized particle size.

Abstract

This invention relates to a tablet formulation containing amorphous tolvaptan and at least one pharmaceutically acceptable excipient, where the particle size of amorphous tolvaptan d(0.9) is less than 40 µm and the formulation is obtained using a solvent-free process.

Description

Amorphous tolvaptan tablet formulation with micronized particle size. THE FIELD OF INVENTION This invention describes a chemical formula containing amorphous tolvaptan and at least one pharmaceutically acceptable excipient. amorphous tolvaptan d (0.9) particle size less than 40 µm and formulation without solvent It relates to a tablet formulation obtained using a process. Background of the Invention Tolvaptan is an oral, selective arginine vasopressin that can be used to treat hyponatremia. It is a receptor 2 (V2, AVPR2) antagonist. Upon oral administration, tolvaptan selectively and competitively inhibits receptor 2 (V2, AVPR2). to the V2 receptor found in the blood vessel walls and luminal membranes of the renal collecting ducts It binds to and blocks vasopressin, thus preventing it from binding to the V2 receptor. This prevents water from reaching the kidneys. It prevents absorption and increases the excretion of electrolyte-free water through the kidneys. This increases intravascular volume. It reduces and increases serum sodium concentrations and osmolality. Tolvaptan is chemically N-(4-(7-Chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carbonyl)- It is identified as 3-methylphenyl)-2-methylbenzamide. Its empirical formula is C ClN, and its structural formula is... (26) H25 (2) O3 It is as follows: Formula I: Tolvaptan Tolvaptan is used by Otsuka for the treatment of clinically significant hypervolemic and euvolemic hyponatremia. SAMSCA®, an oral medication containing 15 mg and 30 mg of tolvaptan, is manufactured by America Pharmaceutical. It is available in tablet form. There is also a product called JINARC, manufactured by Otsuka pharmaceutical company. JINARC, patients with autosomal dominant polycystic kidney disease (ADPKD) at the start of treatment, progressing from stage 1 to stage... Cyst development in adult patients with rapidly progressing chronic kidney disease (CKD) up to grade 4 and It is indicated to slow the progression of kidney failure. 2 Tolvaptan is a class IV drug in the BCS classification, meaning it is a low-solubility and hypotonic drug. For soluble drugs, dissolution is the rate-limiting process of absorption and often affects their bioavailability. It is the most important factor. US Pat. No. 5,258,510 describes tolvaptan. CN102366412 (A) describes a method for preparing tolvaptan tablets. The method involves wet preparation of tablets without water. It is granulation. WO2008156217 (A2) tolvaptan and 50% or more by weight of hydroxypropoxyl group It describes a pharmaceutical solid preparation containing hydroxypropylcellulose. Furthermore, it describes a pharmaceutical solid. A method for preparing the preparation is described. The method is wet or dry granulation. In the previous technique, several new approaches were developed to address the solubility problems of tolvaptane. However, while these methods successfully improve resolution, they often suffer from instability and poor performance. This also brings with it other formulation challenges such as flow characteristics and insufficient compressibility. This results in acceptable stability, fluidity, and content in the final pharmaceutical formulation. a comprehensive approach that addresses the simultaneous increase in solubility while maintaining homogeneity levels It is needed. There is still a need to overcome these challenges in art; the current invention addresses those larger than 40 µm. an amorphous tolvaptan tablet formulation with a small particle size d (0.9) and also solvent-free The formulation obtained using the process provides this. This approach only increases the solubility of tolvaptan. Not only does it increase efficiency, but the tablet also has improved stability, fluidity, and content homogeneity. It provides the formulation. Detailed Description of the Invention The main purpose of this invention is to produce the desired amorphous tolvaptan containing a particle size d (0.9) smaller than 40 µm. excellent dissolution rate and high stability, as well as fluidity and homogeneity of content. possessing physicochemical properties, overcoming the problems described above in the previous technique, and The goal is to provide a tablet formulation that offers additional advantages. Another objective of the present invention is to develop a process for a tablet formulation containing amorphous tolvaptan. The goal is to provide a simple, fast, cost-effective, time-saving, and industrially viable process. It is a method. 3 Tolvaptan is sparingly soluble in water. This leads to issues with its solubility profile and bioavailability. In the current invention, some work has been done to prevent these problems from arising. Amorphous tolvaptane has been shown to have better solubility than crystalline tolvaptane. Pharmaceutical In addition to solubility, stability is also very important in the composition. Amorphous tolvaptane does not transform into crystals. The fact that it can be produced and remains amorphous throughout its shelf life is crucial for its stability. Using the amorphous form can increase the solubility of tolvaptan within the physiological pH range. With this... Together, amorphous tolvaptan is unstable and overcoming fluidity and content homogeneity is very difficult. It's difficult. In this invention, any stage of tablet formulation, mixing, granulation or compression is avoided. using a dry or non-aqueous production process in which no solvent or liquid medium is used It is produced. Tablet production involves a dry process (dry granulation or direct compression) Adopting this approach yields advantageous results. One of these is the use of water or solvents during the process. elimination of active pharmaceuticals that are susceptible to hydrolysis or degradation in the presence of moisture. Significantly improves the chemical and physical stability of components (APIs) and excipients. It is about increasing efficiency. Furthermore, such processes involve easy and cost-effective process steps. Accordingly, here... The described dry production process is particularly suitable for high-efficiency applications involving moisture-sensitive or thermolabile components. It offers significant technical and economic advantages in the context of pharmaceutical tablet production. Furthermore... However, some fluidity and content homogeneity problems have been observed in these solvent-free processes. D (0.9) Amorphous tolvaptan with particle size less than 40 µm is very important for the formulation We found that the dissolution properties, powder homogenization, and desired fluidity were particularly positive. It has an effect in this direction. Tablets obtained from a more homogeneous powder have a more ideal homogeneity of content. As used here, "particle size distribution" refers to the Malvern Mastersizer 2000 laser diffraction. The conventional method is laser diffraction, which is determined by particle size analysis instrument equipment. It is defined by the cumulative volume size distribution tested by a method accepted as "D (0.9)". or "d90" dimension where 90% of the particles are finer by volume, d (0.1) particles by volume The dimension where 10% of the particles are finer and the dimension where 50% of the particles are finer by volume d (0.5) It expresses. According to this arrangement of the invention, amorphous tolvaptan and at least one pharmaceutically acceptable substance A tablet formulation containing excipient, where amorphous tolvaptan d (0.9) particle size 40 It is smaller than µm and the formulation is obtained using a solvent-free process. 4 According to this arrangement of the present invention, the dry granulation method, which is a solvent-free process, or It is direct compression. According to this arrangement of the invention, amorphous tolvaptan and at least one pharmaceutically acceptable substance A tablet formulation containing excipient, where amorphous tolvaptan d (0.9) particle size 40 It is smaller than µm and the formulation is obtained using the dry granulation method or direct compression. It is done. According to this arrangement of the present invention, the formulation is obtained using the dry granulation method. It is done. According to this arrangement of the present invention, the formulation is obtained using direct compression. According to this arrangement of the present invention, amorphous tolvaptan is between 1 µm and 40 µm or between 3 µm and 35 µm. between or between 6 µm and 30 µm or between 9 µm and 25 µm with a particle size d (0.9) has. According to one arrangement of this invention, the amount of amorphous tolvaptan is relative to the weight of the total formulation. It is between 3.0% and 25.0%, between 4.0% and 25.0%, and between 4.0% and 19.0%. According to one arrangement of this invention, a tablet formulation may consist of binders, dispersants, fillers, pharmaceuticals selected from the group containing lubricants, colorants or mixtures thereof. It contains at least one excipient. Suitable binders include polyvinylpyrrolidone, sodium carboxymethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, starch, pregelatinized starch, sodium alginate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, methyl cellulose, gelatin, carrageenan, guar gum, polymethacrylates, methacrylate polymers, pectin, polysaccharides, carbomer, poloxamer, polyacrylamide, aluminum hydroxide, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide, or mixtures thereof It is selected from the group that includes. According to one arrangement of this invention, the binder is polyvinylpyrrolidone or pregelatinized starch. or mixtures thereof. The viscosity of a binder is a measure of its flow properties and the performance of a bituminous mixture. It is largely affected by its viscosity. In the present invention, binders with low viscosity are used. It is used. According to one arrangement of the present invention, the binder is polyvinylpyrrolidone. It has low viscosity. he The polymer is povidone, with a dynamic viscosity of approximately 10 mPa.s in a 10% aqueous solution at 25°C. Povidone is selected from K12, K17, K25, K30, VA 64 and mixtures thereof, with VA 64 and K25 being the most preferred. The use of binders surprisingly improves content homogeneity, desired fluidity, and the effectiveness of the active ingredient. We observed that it ensured homogeneity. According to one regulation, the binder is pre-gelatinized starch. According to one regulation of this invention, the amount of binder is between 1.0% and 1.0% of the total formulation weight. It is between 20.0%, or between 1.5% and 16.0%, or between 1.5% and 9.0%. Suitable dispersants include croscarmellose sodium, corn starch, starch, crospovidon, and low-substitution products. hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl from the group containing cellulose, sodium carboxymethyl starch, hydroxymethyl starch or mixtures thereof is selected. According to one arrangement of the present invention, the dispersant is croscarmellose sodium. According to one regulation of this invention, the amount of dispersing agent is 1.0% of the total formulation weight. between 2.0% and 15.0%, preferably between 2.0% and 9.0%, and even more preferably between 3.0% and 6.5%. 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, lactose, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium-chain sugars triglycerides, polydextrose, polymethacrylates, simethicone, sodium alginate, sodium chloride, sorbitol, sucrose, sugar spheres, sulfobytyrophosphate beta-cyclodextrin, talc, gum tragacanth, trehalose, xylitol or mixtures thereof It is selected from the group that includes. According to one arrangement of the present invention, the filler is microcrystalline cellulose or lactose monohydrate. or mixtures thereof. According to one arrangement of this invention, the amount of filler is 50.0% to 50.0% by weight of the total formulation. 88.0% is between 65.0% and 83.0%. Suitable lubricants include magnesium stearate, talc, colloidal silicon dioxide, calcium stearate, and sodium stearyl. fumarate, potassium stearate, stearic acid, sodium chloride, sodium benzoate, sodium acetate, sodium It is selected from the group containing oleates, polyethylene glycols, or mixtures thereof. 6 According to a regulation of the present invention, the lubricant is magnesium stearate or talc or colloidal silicone. These are dioxides or mixtures thereof. Preferably magnesium stearate. Suitable coloring agents include indigo carmine, aluminum lake dye, ferric oxide, titanium dioxide, Food grade. Pharmaceutical and Cosmetic (FD&C) dyes (e.g., FD&C blue, FD&C green, FD&C red, FD&C yellow, FD&CC) lakes), poncau, indigo Drug & Cosmetic (D&C) blue, indigotine FD&C blue, carmoisine indigotine (Indigo carmine); iron oxides (e.g., iron oxide red, yellow, black), quinoline yellow, flame red, It is selected from carmine, carmoisine, sunset yellow, or a mixture thereof. According to one arrangement of the present invention, the coloring agent is indigo carmine aluminum lake dye. This excipient is known as a redox indicator. It reacts with oxidative and reducing agents (stress factors). It prevents the degradation of the active substance by giving its own reversible reaction. The reaction is reversible. It is not completely depleted by its own degradation and is not protected from raw material stress factors (oxidative and (Reducing species) are preserved. This positively contributes to the shelf life of the product. This coloring agent It provides the desired stability. According to a regulation of the present invention, the tablet contains the following: − Amorphous Tolvaptan - Croscarmellose sodium − Polyvinylpyrrolidone VA 64 - Lactose anhydrous - Microcrystalline cellulose - Magnesium stearate According to this arrangement of the invention, the process for preparing a tablet formulation is as follows: It includes the following steps: a) Amorphous tolvaptan with at least one binder and d (0,9) particle size between 1 µm and 40 µm mixing and then sieving to 0.6 mm, b) Adding at least one dispersant and at least one filler, then mixing and then... Sieving to 0.6 mm, c) To obtain granulation, a compacting device is used to achieve a pressure range of 90 to 145 kP. applying compression pressure, d) Adding at least one filler and then mixing it, e) Addition and subsequent mixing of indigo carmine aluminum lake dye, f) Adding at least one slider and then mixing it, g) Compressing the mixture into tablets. 7 According to this arrangement of the invention, the process for preparing a tablet formulation is as follows: Includes: a) Polyvinylpyrrolidone VA 64 and d (0,9) amorphous with particle size between 1 µm and 40 µm Mixing the tolvaptan and then sifting it to 0.6 mm, b) Adding croscarmellose sodium and microcrystalline cellulose, then mixing and then sifting to 0.6 mm, c) To obtain granulation, a compacting device is used to achieve a pressure range of 90 to 145 kP. applying compression pressure, d) Addition of anhydrous lactose and subsequent mixing, e) Addition and subsequent mixing of indigo carmine aluminum lake dye, f) Magnesium stearate is added and mixed. g) Compressing the mixture into tablets. Compression pressure is used to bind powders or granules into a solid, cohesive tablet form during the tablet manufacturing process. It refers to the force applied for compression and ensures sufficient stiffness, homogeneity, and structural integrity. According to this arrangement of the present invention, in dry granulation method or direct compression The compression pressure used is between 90 kP and 145 kP. According to this arrangement of the present invention, in dry granulation method or direct compression The compression pressure used is between 115 kP and 140 kP. According to this arrangement of the present invention, in dry granulation method or direct compression The compression pressure used is between 245 kP and 300 kP. 8 Example 1: Total Total Total formulation formulation formulation % by weight % by weight % by weight D (0,9) particle size 1 µm between 3.0 - 25.0 15 7.5 and 40 µm amorphous Tolvaptan Polyvinylpyrrolidone VA 64 1.0 - 20.0 5 5 Croscarmellose Sodium 1.0 - 15.0 5 5 Anhydrous lactose 40.0 - 65.0 55 62.5 Microcrystalline cellulose 18.9 18.9 16.0 - 30.0 pH112 Magnesium stearate 0.5 - 4.0 1 1 Indigo Carmine Aluminum 0.1 0.1 0.05 - 1.0 Lake paint Total 100 100 100 A process for Example 1; a) Polyvinylpyrrolidone VA 64 and d (0,9) amorphous with particle size between 1 µm and 40 µm Mixing the tolvaptan and then sifting it through a 0.6 mm sieve, b) After adding and mixing croscarmellose sodium and microcrystalline cellulose, the mixture is strained through a 0.6 mm sieve. will be eliminated. c) To obtain granulation, a compacting device is used to achieve a pressure range of 90 to 145 kP. applying compression pressure, d) Addition of anhydrous lactose and subsequent mixing, e) Addition and subsequent mixing of indigo carmine aluminum lake dye, f) Magnesium stearate is added and mixed. g) Compressing the mixture into tablets.

Claims

1) Amorphous tolvaptan containing at least one pharmaceutically acceptable excipient. tolvaptan d (0.9) particle size is less than 40 µm and the formulation is solvent-free A tablet formulation obtained using a process. 2) Tablet formulation according to Claim 1, where solvent-free process dry granulation is used. This method is either compression or direct compression. 3) Tablet formulation according to claim 1, where amorphous tolvaptan is present in amounts between 1 µm and 40 µm or A d (0.9) between 3 µm and 35 µm or between 6 µm and 30 µm or between 9 µm and 25 µm It has a particle size. 4) Tablet formulation according to Claim 1, whereby binders, dispersants, fillers, pharmaceuticals selected from the group containing lubricants, colorants or mixtures thereof It contains at least one excipient that can be considered acceptable. 5) Tablet formulation according to claim 4, where the binders are polyvinylpyrrolidone, sodium carboxymethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, starch, pregelatinized starch, sodium alginate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, methyl cellulose, gelatin, carrageenan, guar gum, polymethacrylates, methacrylate polymers, pectin, polysaccharides, carbomer, poloxamer, polyacrylamide, aluminum hydroxide, from the group containing polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof is selected. 6) Tablet formulation according to claim 4, where the binder is polyvinylpyrrolidone or pre-containing These are gelatinized starches or mixtures thereof. 7) Tablet formulation according to claim 4, where the dispersants are croscarmellose sodium and cornelian cherry. starch, crospovidon, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, It is selected from the group containing hydroxymethyl starch or mixtures thereof. 8) Tablet formulation according to claim 4, where the dispersant is croscarmellose sodium. 9) Tablet formulation according to claim 4, where the fillers are microcrystalline cellulose and 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, lactose, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium-chain triglycerides, polydextrose, polymethacrylates, simethicone, sodium alginate, sodium chloride, sorbitol, sucrose, sugar spheres, sulfobytyrophosphate beta-cyclodextrin, talc, gum tragacanth, trehalose, xylitol or any of these It is selected from the group containing the mixtures. 10) Tablet formulation according to claim 4, where the lubricants are magnesium stearate, talc, colloidal silicon dioxide, calcium stearate, sodium stearyl fumarate, potassium stearate, stearic acid, sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols or It is selected from the group that contains mixtures of these. 11) Tablet formulation according to claim 4, where the coloring agents are indigo carmine. aluminum lake, ferric oxide, titanium dioxide, Food, Drug and Cosmetic (FD&C) dyes (for example; FD&C blue, FD&C green, FD&C red, FD&C yellow, FD&C lakes), poncau, indigo Drug & Cosmetic (D&C) blue, indigotine FD&C blue, carmoisine indigotine (indigo Carmine); iron oxides (e.g., iron oxide red, yellow, black), quinoline yellow, flame red, carmine, carmoisine, It is selected from the group that includes sunset yellow or mixtures thereof. 12) Tablet formulation according to claim 4, where the coloring agent is indigo carmine. It is aluminum lake paint. 13) The process for preparing a tablet formulation includes the following steps: a) Amorphous tolvaptan with at least one binder and d (0,9) particle size between 1 µm and 40 µm mixing and then sifting through a 0.6 mm sieve, b) Adding at least one dispersant and at least one filler, and then mixing it, and then sifted through a 0.6 mm sieve, c) To obtain granulation, a compacting device is used to achieve a pressure range of 90 to 145 kP. applying compression pressure, d) Adding at least one filler and then mixing it, e) Addition and subsequent mixing of indigo carmine aluminum lake dye, f) Adding at least one slider and then mixing it, g) Compressing the mixture into tablets. 14) A process for preparing a tablet formulation according to claim 13, whereby the following steps are performed: Includes: a) Polyvinylpyrrolidone VA 64 and d (0,9) amorphous with particle size between 1 µm and 40 µm Mixing the tolvaptan and then sifting it through a 0.6 mm sieve, b) After adding and mixing croscarmellose sodium and microcrystalline cellulose, a 0.6 mm mixture is formed. sifted through a sieve, c) To obtain granulation, a compacting device is used to achieve a pressure range of 90 to 145 kP. applying compression pressure, d) Addition of anhydrous lactose and subsequent mixing, e) Addition and subsequent mixing of indigo carmine aluminum lake dye, f) Magnesium stearate is added and mixed. 35 g) Compressing the mixture into tablets.