Tablet containing pazopanib as active ingredient, and preparation method thereof

Abstract

To provide: a pazopanib tablet capable of exhibiting dissolution and pharmacodynamic properties comparable to or better than those of conventional tablet products and, simultaneously, exhibiting uniform internal absorption by having a small deviation in disintegration time; and a preparation method thereof.SOLUTION: A pazopanib tablet comprises: granules containing pazopanib or a pharmaceutically acceptable salt thereof, a diluent, a disintegrant and a binder; a core tablet containing one or more pharmaceutically acceptable additives; and a coating layer formed on the core tablet. The granules do not contain alcohol. The bulk density of the granules is from 0.4 g / mL to 0.5 g / mL inclusive. The tap density of the granules is from 0.51 g / mL to 0.6 g / mL inclusive. The standard hardness of the core tablet is 160 N to 200 N. The disintegration time in a pH 1.0-1.4 solution at 37±2°C is at least 3 minutes.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a tablet containing the poorly soluble drug pazopanib as an active ingredient, and more specifically to a pazopanib tablet that exhibits dissolution characteristics and pharmacokinetic characteristics equivalent to or superior to those of conventional tablet products, while at the same time having little deviation in disintegration time and exhibiting uniform absorption in the body, and a method for producing the same. [Background technology]

[0002] Pazopanib is a multi-target receptor tyrosine kinase inhibitor that blocks tumor growth and suppresses angiogenesis. It selectively blocks vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3, c-kit, and platelet derived growth factor receptor (PDGF-R), and inhibits pazopanib. It is marketed in the form of cyclosporine hydrochloride. Its molecular weight is 473.98 g / mol and its molecular formula is C 21 H 23 N7O2S·HCl, IUPAC name is 5-[[4-[(2,3-dimethylindazol-6-yl)-methylamino]pyrimidin-2-yl]amino]-2-methyl It is a benzenesulfonamide hydrochloride salt. Its solubility in water is predicted to be 3.3 mg / L, but it is poor and varies depending on the pH, with the solubility tending to decrease rapidly as the pH increases. Its melting point is known to be around 301-313°C. Its known bioavailability in the human body is low at 14-21%, but it can be increased by dieting with low or high fat foods. It should be taken on an empty stomach, as the effects can be approximately twice as high depending on the dose.

[0003] Pazopanib, even in the form of hydrochloride, is not highly soluble in aqueous solutions and has a solubility characteristic that is highly dependent on pH, but according to FDA documents provided by Novartis, the manufacturer of the commercial product VOTRIENT® tablets, it is known to be "very slightly soluble" at pH 1 and "practically insoluble" at pH 4 or higher. Therefore, while it dissolves to some extent in the stomach with a pH of 2 or less in the fasting state, its solubility drops sharply in the duodenum, small intestine, etc., where the pH is 4 or higher.

[0004] Due to these characteristics, the bioavailability in the human body is only 14-21%, and the deviation in absorption is very large. In particular, in the case of tablets, this deviation is likely to be even larger, so it is very difficult to develop a formulation that can adjust the disintegration time to a uniform and narrow range. Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention is intended to solve the problems of conventional pazopanib formulations, which have poor solubility and large differences in in vivo absorption caused by their property of rapidly changing depending on pH, as described above. The object of the present invention is to provide a pazopanib tablet and a manufacturing method thereof, which exhibits dissolution characteristics and pharmacokinetic characteristics equivalent to or better than those of conventional tablet products, while having small deviation in disintegration time and uniform absorption in the body, and which can facilitate quality control due to the reduced deviation in disintegration time and absorption in the body. [Means for solving the problem]

[0006] In order to solve the above-mentioned technical problems, one aspect of the present invention provides a pazopanib tablet comprising: pazopanib or a pharma- ceutically acceptable salt thereof; a diluent; a disintegrant; and a binder, and produced without using alcohol; and one or more pharma- ceutically acceptable additives; and having a standard uncoated tablet hardness of 160N to 200N.

[0007] Another aspect of the present invention provides a method for producing pazopanib tablets, comprising: (1) mixing pazopanib or a pharma- ceutically acceptable salt thereof, a diluent, a disintegrant, a binder and a solvent; (2) removing the solvent from the mixture obtained in the step (1) and granulating the mixture; and (3) mixing the granules obtained in the step (2) with one or more pharma- ceutically acceptable additives and compressing the mixture into tablets, wherein the solvent used in the step (1) does not contain alcohol, and the uncoated tablet standard hardness of the tablets produced in the step (3) is 160N to 200N. Effect of the Invention

[0008] The oral pazopanib tablet provided by the present invention exhibits physicochemical equivalence to conventional pazopanib formulations, and equivalence has been confirmed in non-clinical trials and bioequivalence tests. It exhibits equivalent pharmacological therapeutic effects, while having less deviation in disintegration time and reduced deviation in systemic absorption, allowing for stable pharmacological efficacy and making quality control easier. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] Meaning of the term Unless expressly stated otherwise, several terms used throughout this specification can be defined as follows.

[0010] Unless otherwise stated throughout this specification, "comprise" or "contains" means the inclusion of any element or component without specific limitation, and is not to be interpreted as excluding the addition of other elements or components.

[0011] The pazopanib tablet according to the present invention comprises a granule containing pazopanib or a pharma- ceutically acceptable salt thereof, a diluent, a disintegrant and a binder, the granule being produced without the use of alcohol; and one or more pharma- ceutically acceptable excipients.

[0012] In the present invention, the "pazopanib" may be a free base of pazopanib (a base drug without a separate salt), or an isomer thereof, or a mixture thereof. In addition, it may form various hydrates in each case, and various crystal forms in each case. For example, the pazopanib may be in the form of various hydrates or various solvates such as pazopanib anhydrate, hemihydrate, monohydrate, dihydrate, trihydrate, or mixtures thereof. In addition, the pharmaceutically acceptable salt of pazopanib may be, for example, hydrochloride.

[0013] In one embodiment of the present invention, the "pazopanib or a pharma- ceutically acceptable salt thereof" may be pazopanib hydrochloride.

[0014] The pazopanib or a pharma- ceutically acceptable salt thereof may be micronized. The term "micronized" means that the powder is pulverized to a very small size, for example, a size of an average diameter in micrometers or nanometers. The average particle size (X50) of the micronized pazopanib or a pharma- ceutically acceptable salt thereof may be, for example, less than 100 μm, preferably less than 50 μm, more preferably less than 30 μm, even more preferably less than 15 μm, and even more preferably less than 10 μm. The average particle size (X50) of the micronized pazopanib or a pharma- ceutically acceptable salt thereof may be, for example, 0.1 μm or more, preferably 0.2 μm or more, more preferably 0.5 μm or more, more preferably 1 μm or more, and even more preferably 2 μm or more. When pazopanib or a pharma- ceutically acceptable salt thereof in a range that deviates from the above-mentioned average particle size is used, there is a risk of a decrease in dissolution rate or a process failure. The average particle size (X50) refers to the average particle size of the bottom 50% of all particles, and can be measured, for example, using a light diffraction particle sizer.

[0015] In one embodiment, the diluent contained in the granules contained in the pazopanib tablet of the present invention can be selected from the group consisting of sugars, sugar alcohols, cellulose, starch, inorganic salts, and mixtures thereof. Non-limiting examples include lactose (anhydrous or hydrated, e.g., monohydrate), cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, starch, pregelatinized starch, gelatinized starch, calcium carbonate, cyclodextrin, calcium sulfate, calcium silicate, magnesium carbonate, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, potassium chloride, sodium chloride, calcium hydrogen phosphate dihydrate, tricalcium phosphate, kaolin, magnesium carbonate, magnesium oxide, mannitol, maltitol, sorbitol, xylitol, lactose, dextrose, maltose, sucrose, glucose, fructose, maltodextrin, dextrates, dextrin, and mixtures thereof. More specifically, microcrystalline cellulose can be used.

[0016] In one embodiment, the granules contained in the pazopanib tablet of the present invention may contain 0.05 or more, 0.1 or more, 0.15 or more, or 0.2 or more parts by weight of the diluent per part by weight of pazopanib or a pharma- ceutically acceptable salt thereof, and may contain 0.5 or less, 0.45 or less, 0.4 or less, 0.35 or less, or 0.3 or less parts by weight of the diluent. If the diluent content in the granules is too low, tableting problems may occur when tablets are produced using such granules, and conversely, if the diluent content in the granules is too high, the weight per tablet may increase, resulting in a size that is burdensome to take.

[0017] In one embodiment, the disintegrant contained in the granules contained in the pazopanib tablet of the present invention can be selected from the group consisting of a swelling disintegrant, a moist disintegrant, and a mixture thereof. Non-limiting examples include starch, cellulose, cross-linked polymers, gums, polysaccharides, and a mixture thereof. More specifically, one or more selected from the group consisting of croscarmellose sodium, carboxymethylcellulose, crospovidone, L-HPC, starch, sodium carboxymethyl starch, sodium starch glycolate, alginic acid, sodium carboxymethylcellulose, agar, xylan, gellan gum, xanthan gum, partially hydrolyzed starch, and a mixture thereof can be used. More specifically, one or more selected from the group consisting of croscarmellose sodium, crospovidone, L-HPC, sodium starch glycolate, and a mixture thereof can be used. Even more specifically, sodium starch glycolate can be used.

[0018] In one embodiment, the granules contained in the pazopanib tablet of the present invention may contain the disintegrant in an amount of 0.01 or more, 0.02 or more, 0.03 or more, 0.04 or more, or 0.05 or more parts by weight, or 0.2 or less, 0.18 or less, 0.16 or less, 0.14 or less, or 0.12 or less parts by weight, per part by weight of pazopanib or a pharma- ceutically acceptable salt thereof. If the disintegrant content in the granules is too low, the disintegration rate of the tablet produced using such granules may be delayed to a satisfactory dissolution rate, and conversely, if the disintegrant content in the granules is too high, tableting problems, coating problems, etc. may occur during tablet production, resulting in low productivity.

[0019] In one embodiment, the binder present in the granules present in the pazopanib tablet of the present invention is povidone, polyvinylpyrrolidone, polyvinyl alcohol, carbopol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose, pullulan, carboxyvinyl polymers, polyethylene glycol or derivatives thereof, and mixtures thereof. The cellulose acetate hydrochloride may be selected from the group consisting of povidone, polyvinylpyrrolidone, hydroxypropyl cellulose, and mixtures thereof, and more specifically may be povidone.

[0020] In one embodiment, the granules contained in the pazopanib tablet of the present invention may contain the binder in an amount of 0.01 or more, 0.02 or more, 0.03 or more, 0.04 or more, or 0.05 or more parts by weight per part by weight of pazopanib or a pharma- ceutically acceptable salt thereof, and may contain the binder in an amount of 0.2 or less, 0.18 or less, 0.16 or less, 0.14 or less, or 0.12 or less parts by weight. If the binder content in the granules is too low, it may be impossible to achieve an appropriate granule density in the tableting process when tablets are produced using such granules. Conversely, if the binder content in the granules is too high, tableting problems may occur during tablet production, resulting in low productivity, and may cause delayed disintegration of the produced tablets or delayed dissolution rate due to excessive binding force.

[0021] In one embodiment, the granules contained in the pazopanib tablet of the present invention are produced by wet granulation, and water can be used as a solvent. Such a solvent can be used in an amount of 0.2 to 0.5 parts by weight, preferably 0.3 to 0.4 parts by weight, per part by weight of pazopanib or a pharma- ceutical acceptable salt thereof. If an excessive amount of solvent is used, related substances may be generated during the evaporation of the solvent, and if too little is used, it may be difficult to achieve a suitable hardness.

[0022] The granules contained in the pazopanib tablet of the present invention are produced without using alcohol, which may be an alcohol having 1 to 10 carbon atoms, including, but not limited to, methanol, ethanol, propanol, butanol, etc.

[0023] When preparing granules contained in pazopanib tablets, for example, when alcohol is used as a granulation solvent, even if a process for removing the solvent used in the granulation process or the subsequent tablet production is performed, there is a problem that the final tablet cannot achieve the desired level of disintegration time or dissolution rate because some of the solvent remains or the used solvent affects the binding of each excipient during the production process.

[0024] In one embodiment, the granules contained in the pazopanib tablet of the present invention may be produced without the use of organic solvents other than alcohol.

[0025] In one embodiment, the granules contained in the pazopanib tablet of the present invention may be prepared using an aqueous solvent (eg, water).

[0026] In one embodiment, the bulk density (unit: g / mL) of the granules contained in the pazopanib tablet of the present invention may be 0.34 or more, 0.35 or more, 0.36 or more, 0.37 or more, 0.38 or more, 0.39 or more, or 0.4 or more, and may be 0.5 or less, 0.49 or less, 0.48 or less, 0.47 or less, 0.46 or less, or 0.45 or less.

[0027] In one embodiment, the tapped density (unit: g / mL) of the granules contained in the pazopanib tablet of the present invention may be 0.45 or more, 0.46 or more, 0.47 or more, 0.48 or more, 0.49 or more, 0.50 or more, or 0.51 or more, or may be 0.6 or less, 0.59 or less, 0.58 or less, 0.57 or less, or 0.56 or less.

[0028] The pazopanib tablet according to the present invention further comprises, in addition to the granules described above, one or more pharma- ceutically acceptable excipients;

[0029] In one embodiment, the one or more pharma- ceutically acceptable additives contained in the pazopanib tablet of the present invention may be a diluent, a disintegrant, a lubricant, or a combination thereof, and more specifically, the pazopanib tablet of the present invention may include all of a diluent, a disintegrant, and a lubricant as the one or more pharma- ceutically acceptable additives.

[0030] In one embodiment, the diluent contained in the pazopanib tablet of the present invention (hereinafter also referred to as "additional diluent") is additionally added to the tablet of the present invention separately from the diluent contained in the granules described above.

[0031] In one embodiment, such additional diluents can be selected from the group consisting of sugars, sugar alcohols, cellulose, starches, inorganic salts, and mixtures thereof, and non-limiting examples include lactose (anhydrous or hydrated, e.g., monohydrate), cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, starch, pregelatinized starch, gelatinized starch, calcium carbonate, cyclodextrin, calcium sulfate, calcium silicate, magnesium carbonate, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, potassium chloride, sodium chloride, calcium hydrogen phosphate dihydrate, tricalcium phosphate, kaolin, magnesium carbonate, magnesium oxide, mannitol, maltitol, sorbitol, xylitol, lactose, dextrose, maltose, sucrose, glucose, fructose, maltodextrin, dextrates, dextrin, and mixtures thereof, and more specifically, microcrystalline cellulose can be used.

[0032] In one embodiment, the pazopanib tablet of the present invention may contain 0.005 or more, 0.006 or more, 0.007 or more, 0.008 or more, 0.009 or more, or 0.01 or more parts by weight of the additional diluent per part by weight of pazopanib or a pharma- ceutically acceptable salt thereof contained therein, and may contain 0.1 or less, 0.09 or less, 0.08 or less, 0.07 or less, 0.06 or less, or 0.05 or less parts by weight of the additional diluent.

[0033] In one embodiment, the disintegrant contained in the pazopanib tablet of the present invention (hereinafter also referred to as "additional disintegrant") is additionally added to the tablet of the present invention separately from the disintegrant contained in the granules described above.

[0034] In one embodiment, such additional disintegrants can be selected from the group consisting of swelling disintegrants, wettable disintegrants, and mixtures thereof, and non-limiting examples include starch, cellulose, cross-linked polymers, gums, polysaccharides, and mixtures thereof, and more specifically, one or more selected from the group consisting of croscarmellose sodium, carboxymethylcellulose, crospovidone, L-HPC, starch, sodium carboxymethyl starch, sodium starch glycolate, alginic acid, sodium carboxymethylcellulose, agar, xylan, gellan gum, xanthan gum, partially hydrolyzed starch, and mixtures thereof can be used, and more specifically, one or more selected from the group consisting of croscarmellose sodium, crospovidone, L-HPC, sodium starch glycolate, and mixtures thereof can be used, and even more specifically, sodium starch glycolate can be used.

[0035] In one embodiment, the pazopanib tablet of the present invention may contain the additional disintegrant in an amount of 0.001 or more, 0.02 or more, 0.03 or more, 0.04 or more, or 0.05 or more parts by weight, and may contain 0.3 or less, 0.25 or less, 0.2 or less, or 0.15 or less parts by weight, per part by weight of pazopanib or a pharma- ceutically acceptable salt thereof.

[0036] In one embodiment, the lubricant contained in the pazopanib tablet of the present invention can be selected from the group consisting of soluble lubricants, insoluble lubricants and mixtures thereof, non-limiting examples of which include magnesium stearate, fumaric acid, stearic acid, calcium stearate, sodium stearyl fumarate, sucrose fatty acid esters, starch, talc, colloidal silica, magnesium oxide, magnesium carbonate, glyceryl behenate, glyceryl monostearate, silicon dioxide, calcium silicate, magnesium silicate, hydrogenated vegetable oil, hard liquid paraffin, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, sodium benzoate, polyoxyethylene monostearate, glyceryl triacetate, sucrose monolaurate and mixtures thereof, more specifically, it may be one or more selected from the group consisting of magnesium stearate, stearic acid, colloidal silica and mixtures thereof, and even more specifically, it may be magnesium stearate.

[0037] In one embodiment, the pazopanib tablet of the present invention may contain 0.005 or more, 0.006 or more, 0.007 or more, 0.008 or more, or 0.009 or more parts by weight of the lubricant per part by weight of pazopanib or a pharma- ceutically acceptable salt thereof, and may contain 0.1 or less, 0.08 or less, 0.06 or less, 0.04 or less, or 0.02 or less parts by weight of the lubricant. If the lubricant content in the tablet is too low, tableting problems may be induced during tablet production, resulting in low productivity. Conversely, if the lubricant content in the tablet is too high, delayed dissolution of the produced tablet may occur, resulting in problems with productivity.

[0038] In one embodiment, the pazopanib tablet of the present invention may be a coated tablet further comprising a coating layer.

[0039] The coating is included for the purpose of preventing loss of the drug. If necessary, a secondary coating can be applied after the primary coating. The thickness of the coating can be appropriately selected within a range that does not delay the dissolution of the drug.

[0040] In one embodiment, the coating base used in the coating layer may be selected from the group consisting of polyvinylpyrrolidone, hydroxypropylmethylcellulose, carboxymethylcellulose and its salts, ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose (L-HPC), polyvinyl alcohol, macrogol polyvinyl alcohol graft copolymer, polymers of acrylic acid and its salts, polymethacrylate, poly(butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymer, vinylpyrrolidone-vinyl acetate copolymer, gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan, and mixtures thereof. The solvent used in the coating layer may be an aqueous solvent.

[0041] In one embodiment, the content of the coating layer in the pazopanib tablet of the present invention may be 1 to 10 parts by weight, more specifically 1 to 8 parts by weight, and even more specifically 1 to 5 parts by weight, relative to 100 parts by weight of the uncoated tablet before coating. If the content of the coating layer in the tablet is too low below the above level, the entire uncoated tablet may not be sufficiently coated, and conversely, if it is too high above the above level, the dissolution rate of the tablet may be delayed.

[0042] The hardness of the pazopanib tablet of the present invention may be 160N to 200N, more specifically 165N to 195N, and even more specifically 170N to 190N, based on the uncoated tablet. The thickness of the tablet may be 6.0 mm to 6.5 mm, more specifically 6.2 mm to 6.4 mm, based on a 640 mg uncoated tablet.

[0043] If the hardness of the pazopanib tablet of the present invention is less than 160 N based on the uncoated tablet, it may cause tableting problems, coating problems, etc. during tablet production, resulting in low productivity. Conversely, if it exceeds 200 N, the disintegration rate of the tablet may be delayed, making it impossible to achieve a satisfactory dissolution rate.

[0044] In one embodiment, when the pazopanib tablet of the present invention is a coated tablet, it may have a disintegration time of 2 minutes 30 seconds to 5 minutes, preferably 3 minutes to 4 minutes, in a pH 1.0 to 1.4 solution at 37±2° C. The disintegration time is measured according to the disintegration test method specified in the 10th revision of the Korean Pharmacopoeia, and may be measured by dissolving 6 tablets in a solution of 2.0 g of water or sodium chloride to which 7.0 mL of hydrochloric acid and water have been added to make 1000 mL, and adjusting the pH to about 1.2, using a tester and an electric motor that reciprocates 29 to 32 times per minute in a thermostatic bath at 37±2° C. and moves up and down with an amplitude of 53 to 57 mm.

[0045] In one embodiment, when the pazopanib tablet of the present invention is a coated tablet, it can show a dissolution rate of 50% or less within 5 minutes in a pH 1.0-1.4 solution at 37±0.5°C, and a dissolution rate of 90% or more within 30 minutes. More specifically, the coated tablet can show a dissolution rate of 40% or more to 45% or less within 5 minutes, and a dissolution rate of 5% or more to 10% or less within 2.5 minutes. In addition, the coated tablet can achieve a dissolution rate of 70% or more, preferably 70% to 80%, within 10 minutes. The dissolution rate is measured according to the paddle method of the dissolution test method specified in the 10th revision of the Korean Pharmacopoeia, and is measured by paddle operation at 37±0.5°C and 50 rpm, and mixing 7.0 mL of hydrochloric acid and 2.0 g of water or sodium chloride with 2.0 g of water or sodium chloride. The solution may be dissolved in a solution containing 0.1% ethanol and made up to 1000 mL, and then six tablets are tested in 900 mL of the solution adjusted to a pH of about 1.2, followed by measurement using HPLC.

[0046] It was confirmed that even if the disintegration rate and dissolution rate are the results obtained in vitro or the final measurement time point of 30 minutes, which is a dissolution rate of 90% or more, and an appropriate dissolution rate is achieved, a small difference in the disintegration rate and dissolution rate within 5 minutes, more preferably within 2.5 minutes, may significantly change the AUC and Cmax values ​​obtained by the actual measurement of the PK value in the body. Therefore, tablets showing the disintegration rate and dissolution rate in the above ranges are expected to show a more uniform effect and have the advantage of being less likely to induce toxicity. In addition, since this can be determined by the in vitro value, unnecessary in vivo experiments can be avoided, and as a result, the production cost can be reduced.

[0047] In one embodiment, the pazopanib tablet of the present invention may be alcohol-free. This means that no alcohol is used during the production of the pazopanib tablet. The alcohol may be an alcohol having 1 to 10 carbon atoms, including, but not limited to, methanol, ethanol, propanol, butanol, etc. When alcohol is used during the production of the pazopanib tablet, even if a process for removing the used solvent is performed later, there is a problem that the final tablet cannot achieve the desired level of disintegration time or dissolution rate because some of the solvent remains or the used solvent affects the binding of each excipient during the production process. More specifically, the pazopanib tablet of the present invention may be organic solvent-free.

[0048] According to another aspect of the present invention, there is provided a method for producing a pharmaceutical composition comprising the steps of: (1) mixing pazopanib or a pharma- ceutically acceptable salt thereof, a diluent, a disintegrant, a binder and a solvent; (2) removing the solvent from the mixture obtained in the step (1) and granulating the mixture; and (3) mixing the granules obtained in the step (2) with one or more pharma- ceutically acceptable additives and compressing the mixture into tablets. The method for producing a pazopanib tablet is provided, wherein the solvent used does not contain alcohol, and the tablet produced in the step (3) has a reference uncoated tablet hardness of 160N to 200N.

[0049] The step (1) of the method for producing pazopanib tablets of the present invention includes a step of primarily mixing pazopanib or a pharma- ceutically acceptable salt thereof, a diluent, a disintegrant, and a binder, and then adding an alcohol-free solvent (e.g., an aqueous solvent, more specifically, water (purified water)) to perform secondary mixing.

[0050] In one embodiment, the amount of the solvent used in step (1) may be, but is not limited to, 13 to 30 parts by weight per part by weight of pazopanib or a pharma- ceutically acceptable salt thereof.

[0051] In one embodiment, the step (2) may further include a step of sieving the produced granules, which may make the particle size of the mixture uniform and aid the flowability and compressibility of the mixture.

[0052] In one embodiment, the step (3) can be carried out using a single punch tablet press or a small rotary tablet press. When using a rotary tablet press, it may be preferable to rotate the tablet press at 12 rpm or less, preferably 10 rpm or less, and more preferably 8 rpm or less, but 5 rpm or more, in order to prevent the occurrence of weight deviation.

[0053] In one embodiment, the method for producing a pazopanib tablet of the present invention may further include (4) a step of coating the uncoated tablet compressed in the step (3) with a coating base.

[0054] In one embodiment, the method for producing pazopanib tablets of the present invention may not use alcohol, more specifically, an organic solvent. Therefore, it may be preferable that the solvent used to dissolve the coating base is also an aqueous solvent. The aqueous solvent may be, for example, water, specifically, purified water. In the process of producing coated tablets, various biologically inactive ingredients may be further used for further purposes such as coating efficiency, drug stability, appearance, color, protection, maintenance, binding, performance improvement, and manufacturing process improvement. The biologically inactive ingredients that may be further included in the coating layer may be one or more selected from the group consisting of plasticizers, lubricants, colorants, flavoring agents, surfactants, stabilizers, antioxidants, foaming agents, antifoaming agents, paraffin, wax, etc.

[0055] In one embodiment, the method for producing pazopanib tablets of the present invention may further include a step of measuring the bulk density, tap density or a combination thereof of the granules before tableting in the step (3); and optionally a step of measuring the disintegration time, dissolution rate or a combination thereof of the tablets produced in the step (3).

[0056] Examples are presented below to aid in understanding the present invention, but the following examples are merely for illustrating the present invention and are not intended to limit the present invention thereto. EXAMPLES

[0057] Example 1 Pazopanib hydrochloride 21.674 g and microcrystalline cellulose 5.9 g, starch glycolate 2.0 g of sodium and 1.6 g of povidone (k-30) were sieved and mixed, and then 16.0 g of water was added thereto, mixed, and dried at 50°C to volatilize the solvent, and then sieved to obtain granules. 0.5 g of microcrystalline cellulose and 2.12 g of sodium starch glycolate were added to the sieved granules and mixed, and then 0.21 g of magnesium stearate was added and further mixed ( Lubrication process. This mixture was compressed into tablets using rectangular punches based on a tablet weight of 640.0 mg. Coating was performed at a ratio of 3.0% (w / w) in total based on the total weight of the uncoated tablets. Opadry® (registered trademark) manufactured by Colorcon Corporation, which contains hydroxypropyl methylcellulose (HPMC) as the main component, was used as the coating base, and water was used as the coating liquid.

[0058] Comparative Example 1 Granules were prepared in the same manner as in Example 1, using 7.5 g of water, and the other steps and excipient ratios were the same to obtain uncoated tablets and coated tablets. The hardness of the uncoated tablets was about 150N.

[0059] Comparative Example 2 Granules were prepared in the same manner as in Example 1, using 12.5 g of water, and the other steps and excipient ratios were the same to obtain uncoated tablets and coated tablets. The hardness of the uncoated tablets was about 153 N.

[0060] Comparative Example 3 Granules were produced in the same manner as in Comparative Example 1, using 16.0 g of water, and the other steps and excipient ratios were the same to obtain uncoated tablets and coated tablets. The hardness of the uncoated tablets was adjusted to about 150N.

[0061] Comparative Example 4 21.674 g of pazopanib hydrochloride, 5.9 g of microcrystalline cellulose, 2.0 g of sodium starch glycolate, and 1.6 g of povidone (k-30) were sieved and mixed, and then 5.0 g of ethanol was added thereto, mixed, and dried at 50°C to evaporate the solvent, and then sieved to obtain granules. The sieved granules were mixed with 0.5 g of microcrystalline cellulose and 2.12 g of sodium starch glycolate, and then mixed with 0.21 g of magnesium stearate. The mixture was compressed into tablets using a rectangular punch based on a weight of 640.0 mg per tablet. The hardness of the uncoated tablets was about 155 N. Coating was performed at a ratio of 3.0% (w / w) based on the total weight of the uncoated tablets (100% (w / w)). Opadry (registered trademark) manufactured by Colorcon Inc., which is mainly composed of HPMC, was used as the coating base, and water was used as the coating liquid.

[0062] Test Example 1: Measurement of granule properties Measurement of bulk and density (bulk density, tap density) Bulk and density were measured according to the method described in Bulk Density and Tapped Density of Powders, Method I of the United States Pharmacopoeia 616. 10.0 g of lubricated granules of each Example and Comparative Example was weighed and added to a 50 mL measuring cylinder while tilting it so as not to be pressed, and the volume was measured to calculate the bulk density (g / mL). The measuring cylinder containing the granules whose bulk density had been measured was tapped at a rate of 200 times per minute. Tapping was repeated 50 times until the difference between two consecutive measurements was less than 2% of the previous measurement, and the final volume at this time was measured to calculate the tap density (g / mL).

[0063] [Table 1]

[0064] Test Example 2: Measurement of tablet properties Tablet hardness and thickness The tablet hardness and thickness were measured for the plain tablets of each Example and Comparative Example. The number of tablets in each batch was n=6. Specifically, the hardness was measured based on the long axis of the tablet using an electric hardness tester (Tablet Tester 8M manufactured by DR. SCHLEUNIGER). The thickness was measured at the thickest central part of the tablet using a vernier caliper (CD-20APX manufactured by Mitutoyo). The measurement results are shown in Table 2 below.

[0065] [Table 2]

[0066] Disintegration test According to the disintegration test method of the Korean Pharmacopoeia, 10th Edition, a disintegration test was carried out in water for the coated tablets obtained in each Example and Comparative Example (n=3). Specifically, the disintegration rate was measured by adding one coated tablet to 1000 mL of water adjusted to about pH 1.2 with hydrochloric acid using a tester and motor that reciprocated 29-32 times per minute and moved up and down with an amplitude of 53-57 mm in a thermostatic bath at 37±2°C. The color of the test solution was transparent and the pH was about 1.2, and the results are shown in Table 3 below.

[0067] [Table 3]

[0068] Test Example 3: Dissolution test Dissolution tests were performed for each Example and Comparative Example and the control drug (VOTRIENT (registered trademark) tablet) using the paddle method of the Korean Pharmacopoeia, 10th Revised Edition, under the following conditions (n=3). The results are shown in Table 4 below.

[0069] <Dissolution test method> Dissolution medium: Dissolution test No. 1 solution (pH 1.2 buffer solution) Rotational speed: 50 rpm Temperature: 37℃ Dissolution test sample collection times: 2.5 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes Analysis method: HPLC analysis method

[0070] [Table 4]

[0071] Study Example 4: Non-clinical PK study of pazopanib 1 A non-clinical pharmacodynamics (PK) study was conducted in beagle dogs to compare the in vivo pharmacodynamic properties of the pazopanib coated tablets (400 mg pazopanib) prepared in Comparative Example 2 with those of the control drug VOTRIENT (registered trademark) tablets (Novartis, 400 mg pazopanib). The experimental animals were divided into two groups, and each group was given the tablet of Example 2 or the control drug with water in a fasting state, and blood was collected at a set time interval up to 48 hours. The collected blood samples were frozen and stored after separating the plasma, and the concentration was analyzed by LC / MS / MS device to obtain the blood concentration over time. The AUC and Cmax were calculated from the corresponding data, and the results are summarized in Table 5 below.

[0072] [Table 5]

[0073] Study Example 5: Nonclinical PK study of pazopanib 2 A non-clinical PK study was conducted in beagle dogs to compare the in vivo pharmacodynamic properties of the pazopanib coated tablets (400 mg pazopanib) prepared in Example 1 with those of the control drug VOTRIENT (registered trademark) tablets (Novartis, 400 mg pazopanib). The experimental animals were divided into three groups, and each group was administered the tablet of Example 4 or the control drug with water in a fasting state, and blood was collected at a set interval up to 48 hours. The collected blood samples were frozen and stored after separating the plasma, and the concentration was analyzed by LC / MS / MS device to obtain the blood concentration over time. The AUC and Cmax were calculated from the corresponding data, and the results are summarized in Table 6 below.

[0074] [Table 6]

Claims

1. granules comprising pazopanib or a pharma- ceutically acceptable salt thereof, a diluent, a disintegrant and a binder; and one or more pharma- ceutically acceptable excipients; and A coating layer formed on the tablet, The granules are alcohol-free, The bulk density of the granules is 0.4 g / mL or more and 0.5 g / mL or less; The tap density of the granules is 0.51 g / mL or more and 0.6 g / mL or less; The standard hardness of the uncoated tablet is 160N to 200N; Pazopanib tablets exhibiting a disintegration time of 3 minutes or more in a pH 1.0-1.4 solution at 37±2°C.

2. 2. The tablet of claim 1, wherein the pazopanib or a pharma- ceutically acceptable salt thereof is pazopanib hydrochloride.

3. 2. The tablet of claim 1, wherein the diluent contained in the granules is selected from the group consisting of sugar, sugar alcohol, cellulose, starch, inorganic salts and mixtures thereof.

4. 2. The tablet according to claim 1, wherein the disintegrant contained in the granules is selected from the group consisting of a swelling disintegrant, a moist disintegrant, and a mixture thereof.

5. 2. The tablet of claim 1, wherein the binder contained in the granules is selected from the group consisting of povidone, polyvinylpyrrolidone, polyvinyl alcohol, carbopol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose, pullulan, carboxyvinyl polymer polyethylene glycol or derivatives thereof, and mixtures thereof.

6. The tablet according to claim 1, which has a disintegration time of 3 minutes or more and 5 minutes or less in a pH 1.0 to 1.4 solution at 37±2° C.

7. The tablet according to claim 1, which shows a dissolution rate of 40% to 45% within 5 minutes in a pH 1.0 to 1.4 solution at 37±0.5° C. and a dissolution rate of 90% or more within 30 minutes.

8. (1) mixing pazopanib or a pharma- ceutically acceptable salt thereof, a diluent, a disintegrant, a binder and a solvent; (2) removing the solvent from the mixture obtained in the step (1) and granulating the mixture; (3) mixing the granules obtained in the step (2) with one or more pharma- ceutically acceptable additives and compressing the mixture into tablets; and (4) A step of coating the plain tablet obtained in the step (3) with a coating base, The solvent used in the step (1) does not contain alcohol, The bulk density of the granules obtained in the step (2) is 0.4 g / mL or more and 0.5 g / mL or less; The tap density of the granules obtained in the step (2) is 0.51 g / mL or more and 0.6 g / mL or less; The uncoated tablet standard hardness of the tablet produced in the step (3) is 160N to 200N; A method for producing pazopanib tablets, wherein the tablets coated in step (4) exhibit a disintegration time of 3 minutes or more in a pH 1.0-1.4 solution at 37±2° C.

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