Method for producing tablet of pharmaceutical composition containing triazolopyrazine derivative compound as active ingredient

Abstract

The present invention provides a tablet-type composition including granules prepared from a triazolopyrazine derivative represented by Chemical Formula 1, which is a raw drug, an excipient, a binder and a disintegrant, and a method for preparing the same. [Solution] The invention solves the problems in drug manufacturing caused by the poor flowability and tableting properties of the triazolopyrazine derivative represented by Chemical Formula 1, and is characterized by a tablet-type composition with improved safety, which is formed by containing mannitol as an excipient and low-substituted hydroxypropylcellulose as a binder, and a method for producing the same.

Description

[Technical field]

[0001] The present invention relates to a method for preparing a pharmaceutical composition in tablet form, the pharmaceutical composition comprising a triazolopyrazine derivative represented by the following formula 1 as an active ingredient. [Background technology]

[0002] The present invention relates to a method for preparing a pharmaceutical composition in tablet form, the pharmaceutical composition comprising a triazolopyrazine derivative (ABN401) represented by the following Chemical Formula 1 as an active ingredient. [Chemical formula 1] JPEG0007648238000001.jpg82168

[0003] The present inventors have made research efforts to discover compounds having inhibitory activity against tyrosine kinases, thereby developing compositions for effectively preventing or treating various hyperproliferative disorders induced by abnormal tyrosine kinase activity.

[0004] Drug delivery system (DDS) refers to technology to design drug dosage forms or drug delivery methods to minimize side effects and maximize pharmacological effects by selectively delivering drugs to necessary or specific diseased parts of the human body. Such DDS can be classified into sustained release (SR) systems, immediate release (IR) systems, controlled release (CR) systems, targeted DDS, etc. The SR system is a dosage form designed to minimize problems such as low bioavailability, very slow drug absorption, or high drug elimination rate by slowing down the drug release rate. The IR system has a relatively short drug release duration compared to the SR system, but is designed for cases where high drug efficiency is required in a short period of time by increasing the release rate per unit time and increasing bioavailability.

[0005] The inventors of the present invention have discovered triazolopyrazine and its derivatives, which are compounds having inhibitory activity against tyrosine kinase, and have revealed that various hyperproliferative disorders induced by abnormal tyrosine kinase activity can be effectively prevented or treated by using the triazolopyrazine and its derivatives. However, as a result of investigating the physical properties of the triazolopyrazine and its derivatives, it was found that the flowability and tabletability are very poor due to the high content and the large amount of fine powder. When the triazolopyrazine and its derivatives are prepared into a quick-release capsule composition, problems such as tableting failure and non-uniform content occur due to the poor flowability and tabletability. In response to this, the researchers of the present invention have confirmed the improvement effects of the flowability, gushing speed and mixing uniformity of the drug when a tablet is manufactured using the triazolopyrazine derivative compound represented by Chemical Formula 1, micro crystalline cellulose (MCC) as a binder as a main component, low-substituted hydroxypropyl cellulose (LH21) as a disintegrant, and mannitol, poloxamer (Kolliphor (registered trademark) P188) and the like as additives, and have completed the present invention.

[0006] According to the present invention, the compound of Chemical Formula 1 (ABN401) is known to bind to hepatocyte growth factor (HGF) and inactivate phosphorylation, thereby significantly inhibiting the activity of c-Met kinase, which catalyzes cell proliferation, migration, and angiogenesis.

[0007] As used herein, the term "hyperproliferative disorder" refers to a pathological condition caused by excessive cell growth, division and migration that is not controlled by normal restrictive means in the body of an animal during normal growth. Hyperproliferative disorders that can be prevented or treated with the composition of the present invention include, but are not limited to, cancer, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma, retinopathy, proliferative retinopathy, psoriasis, rheumatoid arthritis, osteoarthritis, autoimmune diseases, Crohn's disease, restenosis, atherosclerosis, intestinal adhesion, ulcer, liver cirrhosis, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy, organ transplant rejection and neoglomerulopathy, and include all hyperproliferative disorders caused by abnormal cell proliferation and excessive generation of new blood vessels.

[0008] More preferably, the cancer, which is one of the abnormal proliferative diseases that can be prevented and treated by the composition of the present invention, is lung cancer, gastric cancer, pancreatic cancer, colon cancer, ovarian cancer, renal cell carcinoma, prostate cancer, or liver cancer. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] U.S. Patent Publication No. 8,507,487 Summary of the Invention [Problem to be solved by the invention]

[0010] The present inventors have developed suitable excipients, binders and disintegrants to efficiently solve problems such as tableting failure and non-uniform content caused by poor flowability and tableting properties of triazolopyrazine compounds, and have an object to provide a method for preparing a pharmaceutical composition containing the triazolopyrazine derivative represented by Chemical Formula 1 as an active ingredient in the form of a tablet. [Means for solving the problem]

[0011] The present inventors have been searching for suitable excipients, binders, diluents and disintegrants to efficiently solve problems such as tableting failure and non-uniform content caused by the poor flowability and tableting properties of the triazolopyrazine compound represented by Chemical Formula 1. The inventors have confirmed a revolutionary improvement effect in the flowability, release rate and uniformity of drug release when tablets are prepared using mannitol as an excipient, microcrystalline cellulose (MCC) and low-substituted hydropropyl cellulose (L-HPC) as binders, and poloxamer (Kolliphor P188) and sodium starch glycolate as disintegrants, thereby completing the present invention. Effect of the Invention

[0012] The present invention efficiently solves problems such as tableting failure and non-uniform content due to poor flowability and tableting properties of the triazolopyrazine derivative (ABN401) represented by Chemical Formula 1 by preparing tablets containing the additives provided by the present invention, thereby further improving the usefulness of the compound. [Brief description of the drawings]

[0013] [Figure 1] 1 is a schematic diagram of the manufacturing process of the drug tablet provided by the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited to the following examples.

[0015] The present invention relates to a method for preparing a pharmaceutical composition in tablet form, comprising as an active ingredient the compound of Formula 1 (ABN401), which can effectively prevent or treat various hyperproliferative disorders by inhibiting the activity of c-Met kinase. JPEG0007648238000002.jpg82168

[0016] The embodiments described below can be modified into many other forms, and the scope of the present invention is not limited to the embodiments described below. The embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.

[0017] The present invention relates to a method for preparing a tablet of a pharmaceutical composition containing the triazolopyrazine derivative (ABN401) represented by Chemical Formula 1 as an active ingredient, and a tablet prepared by the method.

[0018] The method for preparing a tablet of a drug containing the triazolopyrazine derivative as an active ingredient as provided by the present invention includes the following steps.

[0019] The method for producing tablets provided by the present invention is specifically as follows: A first step of blending and milling a triazolopyrazine derivative with a disintegrant, a binder and an excipient; A second step of preparing granules by adding a binder to the composition of the first step through a granulation process; A third step of adding a binder liquid to the composition prepared in the second step and mixing the composition; a fourth step of compressing the composition that has undergone the third step; A fifth step of coating the composition that has been subjected to the fourth step; include.

[0020] The binder used in the first and second steps of the present invention may include one or more components selected from microcrystalline cellulose, mannitol, low-substituted hydroxypropylcellulose (L-HPC, LH21), poloxamer (Kolliphor P188), sodium stearyl fumarate, lactose monohydrate, sobitol, and sucrose.

[0021] In the present invention, the weight ratio of the triazolopyrazine derivative to the binder may be 20:0.1 to 50:5.

[0022] In the second step, a binding liquid may be further added, and purified water may be used as the binding liquid.

[0023] The disintegrant of the present invention may be any one or more selected from the group consisting of methylcellulose, crospovidone, alginic acid, croscarmellose, sodium starch glycolate, and carboxymethylcellulose.

[0024] In the present invention, the weight ratio of the triazolopyrazine derivative to the disintegrant may be 20:0.1 to 50:5.

[0025] The tablet of the present invention may further contain an excipient other than the binder and disintegrant.

[0026] The excipient used in the present invention may include at least one selected from the group consisting of colloidal silicon dioxide, magnesium trisilicate, corn starch, talc, carboxymethyl cellulose sodium, croscarmellose sodium, povidone K30, povidone K90, polyethylene glycol, polyethylene oxide, polyethylene propylene glycol copolymer, glyceryl monostearate, glyceryl palmitostearin, glyceryl behenate, ethyl maltol, wax, sodium acetate, trihydrate, etc., which are additives used in the development of drug dosage forms, such as lubricants, surfactants, and flow agents.

[0027] In the present invention, the weight ratio of the triazolopyrazine derivative to the excipient may be 25:55 to 50:70.

[0028] Opadry® can be used as a coating agent in the coating step, which is the fifth step of the manufacturing method provided by the present invention. Opadry is a coating agent with proven safety that is widely used to coat solid drugs manufactured by Colorcon, and can improve the hygroscopicity and light safety of tablet tablets. Opadry is manufactured by mixing polyvinyl alcohol, polyethylene glycol, titanium oxide, indigo carmine aluminum cake, etc., and a colorant compound such as brilliant blue can be added in addition to the above ingredients depending on the surface color of the drug.

[0029] In the second granulation step, a Gerteis Minipactor® high shear granulator is used, and in the step of producing granules using the high shear granulator, the amount of binding liquid sprayed may be 25 μl / s to 75 μl / s at an impeller speed of 400 rpm to 12,000 rpm, and preferably the amount of binding liquid sprayed may be 50 μl / s to 250 μl / s at an impeller speed of 500 rpm to 12,000 rpm.

[0030] The step of drying the granules may be performed using a fluidized bed dryer. A fluidized bed dryer is used for drying and mixing powders, fine particles, and granules for pharmaceuticals, chemicals, food, etc., and is a device in which the material to be dried is loaded into a container, floated to the top with heated air, and dried while flowing.

[0031] In the fourth step, the compression step, a rotary tablet compression machine (Beta Press SADE) is used, and a pressure of 1 to 10 kN / cm can be applied.

[0032] The fifth step, the coating step, uses an O'Hara Technology Labcoat tablet coating system and can be performed at a fan speed of 10 to 30 rpm.

[0033] Hereinafter, preferred examples will be presented to aid in understanding the present invention. However, the following examples are provided only to facilitate the implementation of the present invention, and the contents of the present invention are not limited to the following examples.

[0034] Example 1: Preparation of various tablets containing ABN401 as the active ingredient ABN401, which is used as an active ingredient in the present invention, has a high content and a lot of fine powder. Therefore, when it is prepared as a tablet composition, ABN401 has a problem that it is difficult to tablet and the content is non-uniform. In order to solve the above problem, a screening experiment was first carried out to select an excipient that significantly affects the gushing rate using excipients (MCC, LM, LH21, CMC-Na) whose safety was ensured through a mutual safety test between ABN401 and excipients. Depending on the type and content of the excipient, binder, and excipient, ABN401, excipient, binder, and disintegrant were placed in a high-shear granulator and mixed for 5 minutes at a rotation speed of 500 rpm. The mixture was mixed at 800 rpm for 4 minutes, and purified water was added at 1 ml per 20 seconds until granules were produced, to produce granules. The produced granules were dried in a 60°C oven for about 1 hour and 30 minutes.

[0035] The dried granules were sieved through a No. 25 sieve, and the type and content of the disintegrant from the above mixture was added according to the amount of the mixture, and mixed for about 5 minutes. The surfaces of the solid pharmaceutical compositions prepared through the above process, which have ABN401 contents of 5 mg, 25 mg, 100 mg, and 200 mg, were coated with Opadry and the exact amount was measured and shown in the table below. Each number in the table below indicates the content per tablet, and 30 tablets were prepared for each content corresponding to each example.

[0036] The content of each of the above components is shown in Table 1 below. [Table 1] Experimental Example 1: Measurement of the ABN401 tablet gushing rate of Examples 1 to 4 In order to measure the release rate of ABN401 from the tablets of Examples 1 to 4, the following preparations were made.

[0037] The drug release rate of the tablet of the present invention was measured by HPLC. First, 900 ml of 0.1N hydrochloric acid solution was prepared as a release buffer solution by diluting 5N hydrochloric acid with distilled water and heating it at 37°C.

[0038] To measure the drug transport profile using the HPLA method, TEA was diluted in 20 mM ammonium carbonate solution at pH 9.4 and acetonitrile solvent to prepare 1 liter of 1% TEA solution, and then the ammonium carbonate solution and the TEA solution were mixed in a volume ratio of 600:400.

[0039] The HPLC migration measurement was carried out by adding 25 μl of each of the sample samples of Examples 1 to 4 to the mixed solution and using the paddle method specified in the Korean Pharmaceutical Standards for the Gushing Test. The amount of drug gushing out was quantitatively analyzed by measuring the absorbance at 282 nm using a UV-Visible Spectrophotometer (Jasco V-730) at a set time (5 min, 10 min, 20 min, 30 min, 45 min, infinity). The results of the gushing experiment are shown in Table 2. All of the tablets manufactured according to each Example showed almost 100% gushing out within 20 min after the start of gushing. Each number indicates the percentage gushing out rate. [Table 2]

[0040] From the above results, it can be seen that all of the tablets containing the triazolopyrazine derivative represented by chemical formula 1 prepared in the present invention as an active ingredient showed almost 100% release within 20 minutes after the start of release, and the tablets provided in the present invention are suitable for use as immediate release preparations. Experimental Example 2: Measurement of thickness and strength of ABN401 tablets of Examples 1 to 4

[0041] In order to confirm the physical safety of the tablets manufactured in Examples 1 to 4, the thickness and strength of each tablet were measured. The results are shown in Table 3. [Table 3]

[0042] From the above examples and experimental examples, it has been found that the tablet containing the triazolopyrazine derivative represented by Chemical Formula 1 provided by the present invention as an active ingredient is suitable as a fast-release drug formulation for oral administration, as confirmed by the drug release rate, thickness and strength.

[0043] It is obvious to those skilled in the art that the technical idea of ​​the invention is not limited to the above examples and experimental examples, and includes all scopes that do not change the technical idea of ​​the present invention.

[0044] The present invention is industrially applicable.

Claims

1. The present invention relates to a tablet-type composition for treating hyperproliferative diseases, comprising a triazolopyrazine derivative represented by the following formula 1, a binder, a disintegrant and an excipient: [Chemical formula 1] the binder is at least one selected from the group consisting of microcrystalline cellulose, mannitol, poloxamer, and sodium stearyl fumarate, and the weight ratio of the triazolopyrazine derivative to the binder is 20:0.1 to 50:5; the disintegrant is sodium starch glycolate, and the weight ratio of the triazolopyrazine derivative to the disintegrant is 20:0.1 to 50:5; A tablet-form composition, wherein the excipient is colloidal silicon dioxide, and the weight ratio of the triazolopyrazine derivative to the excipient is 25:55 to 50:

70.

2. 2. The tablet-form composition according to claim 1, wherein the hyperproliferative disease is any one selected from the group consisting of lung cancer, gastric cancer, splenic cancer, colon cancer, ovarian cancer, renal cell carcinoma, prostate cancer and liver cancer.

3. The present invention relates to a method for preparing a tablet-type composition for treating a hyperproliferative disease, comprising a triazolopyrazine derivative represented by the following formula 1, a binder, a disintegrant and an excipient, the method comprising the steps of: <Chemical formula 1> A first step of mixing and grinding the triazolopyrazine derivative of formula 1 with a disintegrant, a binder and an excipient; A second step of preparing granules by adding a binder to the composition of the first step and carrying out a granulation process at an impeller speed of 500 rpm to 12,000 rpm; A third step of further adding a disintegrant to the composition prepared in the second step and mixing the composition; A fourth step of compressing the composition that has been subjected to the third step at a pressure of 1 to 10 kN / cm; A fifth step of coating the composition from the fourth step at a fan speed of 10 to 30 rpm; the binder is at least one selected from the group consisting of microcrystalline cellulose, mannitol, poloxamer, and sodium stearyl fumarate, and the weight ratio of the triazolopyrazine derivative to the binder is 20:0.1 to 50:5; the disintegrant is sodium starch glycolate, and the weight ratio of the triazolopyrazine derivative to the disintegrant is 20:0.1 to 50:5; The method for preparing a tablet-form composition, wherein the excipient is colloidal silicon dioxide, and the weight ratio of the triazolopyrazine derivative to the excipient is 25:55 to 50:

70.

4. 4. The method for preparing a tablet-form composition according to claim 3, wherein the coating agent used in the fifth step, that is, the coating step, is Opadry.

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