Coated tablet composition comprising trimetazidine and method for preparing same

Abstract

The present invention relates to a coated tablet composition comprising trimetazidine (KN713), and to a method for preparing same. In the present invention, in order to improve the flowability of trimetazidine, which is the main ingredient of KN713 tablets (30 mg), a tablet composition was designed using silicified microcrystalline cellulose, mannitol, and colloidal silicon dioxide, and magnesium stearate is added to solve the filming phenomenon occurring during tableting. In addition, it was confirmed that when KN713 tablets (30 mg) are prepared using the coated tablet composition of the present invention, it is possible to prepare tablets suitable for disintegration, dissolution, and friability criteria and the increase in flexible substances is significantly reduced. Therefore, the tablet composition of the present invention can be effectively used for anticancer tablets.

Description

Coated tablet composition containing trimetazidine and method for preparing the same

[0001] The present invention relates to a coated tablet composition comprising trimetazidine (KN713) and a method for producing the same, and more particularly, to a coated tablet composition comprising trimetazidine with improved flowability and a method for producing the same.

[0002]

[0003] Trimetazidine, a 3-ketoacyl CoA thiolase (ACAA) inhibitor, is known to be an anti-ischemic (antianginal) metabolic agent or fatty acid oxidation inhibitor that improves myocardial glucose utilization by inhibiting fatty acid metabolism, and omeprazole, a carnitine acylcarnitine carrier (CAC) inhibitor, is a proton pump inhibitor that is known to be effective in treating gastroesophageal reflux disease, peptic ulcers, erosive esophagitis, or eosinophilic esophagitis.

[0004] Regarding the manufacture of tablets for use as pharmaceuticals using trimetazidine, International Publication Nos. WO2013-114053~ discloses a pharmaceutical form for long-term release, and International Publication No. WO2022-005926 discloses a modified release formulation of trimetazidine. However, trimetazidine has poor flowability, making it difficult to manufacture pharmaceuticals in tablet form.

[0005]

[0006] In the present invention, it was confirmed that trimetazidine, the main ingredient of KN713 tablet 30 mg, had poor flowability, causing problems in tablet manufacturing. Accordingly, the present invention made extensive efforts to develop a tablet composition that improves the flowability of trimetazidine, and as a result, a coated tablet suitable for disintegration, dissolution, and friability standards was manufactured. As a result of a simple stability test on the manufactured tablet, it was confirmed that the increase in soluble substances was significantly reduced, and the present invention was completed.

[0007]

[0008] Accordingly, an object of the present invention is to provide a coated tablet composition comprising trimetazidine or a pharmaceutically acceptable salt thereof and a coated tablet comprising the composition.

[0009] Another object of the present invention is to provide a method for manufacturing the above-mentioned coated tablet.

[0010]

[0011] To achieve the above-mentioned purpose,

[0012] The present invention relates to a tablet composition comprising trimetazidine (KN713, Trimetazidine Dihydrochloride) or a pharmaceutically acceptable salt thereof as a main ingredient, silicified microcrystalline cellulose and mannitol as excipients, colloidal silicon dioxide as a fluidizing agent, and talc and magnesium stearate as lubricants.

[0013] A composition for film coating comprising polyvinyl alcohol (PVA),

[0014] Provided is a coated tablet composition comprising trimetazidine (KN713, Trimetazidine Dihydrochloride), characterized in that it comprises 24 mg to 36 mg of trimetazidine or a pharmaceutically acceptable salt thereof, 40 mg to 60 mg of silicified microcrystalline cellulose, 30 mg to 45 mg of mannitol, 0.5 mg to 0.7 mg of colloidal silicon dioxide, 0.95 mg to 1.5 mg of talc, and 0.95 mg to 1.5 mg of magnesium stearate.

[0015]

[0016] In a preferred embodiment of the present invention, 30 mg of trimetazidine or a pharmaceutically acceptable salt thereof may include 50 mg of silicified microcrystalline cellulose, 37.6 mg of mannitol, 0.6 mg of colloidal silicon dioxide, 1.2 mg of talc, and 1.2 mg of magnesium stearate.

[0017] In another preferred embodiment of the present invention, the film coating composition may contain 2.8 mg to 4.5 mg per 24 mg to 36 mg of trimetazidine or a pharmaceutically acceptable salt thereof, preferably 3.6 mg per 30 mg of trimetazidine or a pharmaceutically acceptable salt thereof.

[0018] In another preferred embodiment of the present invention, the film coating composition comprising polyvinyl alcohol may be Opadry® 85F 12380 or Opadry® Ⅱ White 85F18422.

[0019] In another preferred embodiment of the present invention, the coated tablet composition comprising trimetazidine (KN713, Trimetazidine Dihydrochloride) may be a pharmaceutical composition for preventing or treating cancer.

[0020]

[0021] The present invention also provides a tablet comprising a core (tablet) comprising trimetazidine (KN713, Trimetazidine Dihydrochloride) or a pharmaceutically acceptable salt thereof as a main ingredient, silicified microcrystalline cellulose and mannitol as excipients, colloidal silicon dioxide as a fluidizing agent, and talc and magnesium stearate as lubricants; and

[0022] A coating tablet comprising a film coating layer comprising polyvinyl alcohol (PVA) and arranged to surround the above-mentioned core;

[0023] Provided is a coated tablet comprising trimetazidine (KN713, Trimetazidine Dihydrochloride), characterized in that each unit tablet of the above-mentioned core contains 24 mg to 36 mg of trimetazidine or a pharmaceutically acceptable salt thereof, 40 mg to 60 mg of silicified microcrystalline cellulose, 30 mg to 45 mg of mannitol, 0.5 mg to 0.7 mg of colloidal silicon dioxide, 0.95 mg to 1.5 mg of talc, and 0.95 mg to 1.5 mg of magnesium stearate.

[0024] In a preferred embodiment of the present invention, when the coated tablet is rotated at a rotation speed of 100 rpm for 15 minutes in 900 ml of a pH 6.8 dissolution test solution, the dissolution rate of trimetazidine or a pharmaceutically acceptable salt thereof may be 95 wt% to 100 wt%.

[0025] In another preferred embodiment of the present invention, the core may have a hardness of 7.5 to 8.5 kp, a disintegration time of 30 minutes or less, a wear rate of 0 to 1 wt%, and an average mass of 114 mg to 125 mg.

[0026] In another preferred embodiment of the present invention, the coated tablet containing trimetazidine (KN713, Trimetazidine Dihydrochloride) may be a pharmaceutical product for preventing or treating cancer.

[0027]

[0028] To achieve other purposes described above,

[0029] The present invention comprises the steps of: (a) mixing trimetazidine (KN713, Trimetazidine Dihydrochloride) or a pharmaceutically acceptable salt thereof, silicified microcrystalline cellulose, mannitol, and colloidal silicon dioxide through a 22 to 27 mesh sieve, and then performing bag mixing;

[0030] (b) A step of adding talc and magnesium stearate sieved through 22 to 27 mesh to the mixture of step (a), and then performing bag mixing;

[0031] (c) a step of manufacturing a tablet core (tablet) by pressing the mixture of step (b); and

[0032] (d) a step of manufacturing a coated tablet by coating the core of step (c) with a film coating solution containing polyvinyl alcohol (PVA);

[0033] The present invention provides a method for manufacturing a coated tablet comprising trimetazidine (KN713, Trimetazidine Dihydrochloride), characterized in that the tablet comprises 24 mg to 36 mg of trimetazidine or a pharmaceutically acceptable salt thereof, 40 mg to 60 mg of silicified microcrystalline cellulose, 30 mg to 45 mg of mannitol, 0.5 mg to 0.7 mg of colloidal silicon dioxide, 0.95 mg to 1.5 mg of talc, and 0.95 mg to 1.5 mg of magnesium stearate per unit tablet of the core of the above step (c).

[0034] In a preferred embodiment of the present invention, the coating solution of step (d) may be included in an amount of 2.8 mg to 4.5 mg per unit tablet of the Najeong core.

[0035] In another preferred embodiment of the present invention, the coating in step (d) can be performed under the conditions of a coating pan of 3 to 15 rpm, a coating liquid spray amount of 5 to 25 rpm, an exhaust temperature of 35°C to 55°C, and an exhaust fan of 2500 to 3500 rpm.

[0036]

[0037] In the present invention, in order to improve the flowability of trimetazidine, the main ingredient of KN713 tablets (30 mg), a tablet composition was designed using silicified microcrystalline cellulose, mannitol, and colloidal silicon dioxide, and magnesium stearate was added to solve the filming phenomenon that occurs during tableting. In addition, when manufacturing KN713 tablets (30 mg) using the coated tablet composition of the present invention, it was confirmed that it was possible to manufacture tablets that met the standards for disintegration, dissolution, and friability, and that the increase in flexible substances was significantly reduced. Therefore, the tablet composition of the present invention can be usefully utilized as an anticancer tablet.

[0038]

[0039] Figure 1 is a photograph showing the phenomenon of filming occurring when powder forms a film on the upper and lower parts of a punch during tablet manufacturing using a first formulation.

[0040] Figure 2 is a photograph of a punch observed after preparing 100 tablets with an improved prescription.

[0041] Figure 3 is data confirming the dissolution rate of the improved prescription tablets according to the tablet pressure.

[0042] Figure 4 is a schematic diagram showing the manufacturing process of KN713.

[0043]

[0044] Hereinafter, the present invention will be described in detail.

[0045]

[0046] The present invention, from a consistent perspective, comprises trimetazidine (KN713, Trimetazidine Dihydrochloride) or a pharmaceutically acceptable salt thereof as a main ingredient,

[0047] Silicified microcrystalline cellulose and mannitol as excipients;

[0048] Colloidal Silicon Dioxide as a fluidizing agent,

[0049] A tablet composition comprising talc and magnesium stearate as lubricants; and

[0050] A composition for film coating comprising polyvinyl alcohol (PVA);

[0051] The present invention relates to a coated tablet composition comprising trimetazidine (KN713, Trimetazidine Dihydrochloride), characterized in that it comprises 24 mg to 36 mg of trimetazidine or a pharmaceutically acceptable salt thereof, 40 mg to 60 mg of silicified microcrystalline cellulose, 30 mg to 45 mg of mannitol, 0.5 mg to 0.7 mg of colloidal silicon dioxide, 0.95 mg to 1.5 mg of talc, and 0.95 mg to 1.5 mg of magnesium stearate.

[0052]

[0053] More preferably, it may contain 50 mg of silicified microcrystalline cellulose, 37.6 mg of mannitol, 0.6 mg of colloidal silicon dioxide, 1.2 mg of talc, and 1.2 mg of magnesium stearate per 30 mg of trimetazidine or a pharmaceutically acceptable salt thereof.

[0054] In the present invention, the film coating composition may contain 2.8 mg to 4.5 mg per 24 mg to 36 mg of trimetazidine or a pharmaceutically acceptable salt thereof, preferably 3.6 mg per 30 mg of trimetazidine or a pharmaceutically acceptable salt thereof, and may additionally contain purified water as a solvent.

[0055] The tablet of the present invention can perform an aqueous film coating that protects against environmental moisture, which is an aqueous moisture barrier film coating system, and preferably, a composition for an aqueous film coating containing polyvinyl alcohol can be used. More preferably, Opadry® 85F 12380 or Opadry® Ⅱ White 85F18422 can be used, but is not limited thereto, and a film coating technique known in the art can be applied.

[0056]

[0057] Since trimetazidine, the main ingredient of KN713, has poor flowability, in a specific embodiment of the present invention, a prescription composition that can increase flowability by mixing with trimetazidine was designed. First, a primary prescription composition F1 was designed to add silicified microcrystalline cellulose and mannitol as excipients to improve flowability (Example 3). However, the F1 prescription caused a filming phenomenon during tableting. To improve this, an improved prescription composition F2 was designed to add magnesium stearate (Example 4). Although the F2 prescription improved the filming phenomenon, the flowability of the prescription mixture was still poor, so a pilot-scale improved prescription was designed to add colloidal silicon dioxide as a fluidizing agent. It was confirmed that the mixture, uncoated tablet, and coated tablet manufactured using this were suitable for process inspection, and as a result of a simple stability test on the manufactured tablet, it was confirmed that the increase in flexible substances was significantly reduced (Example 6).

[0058] Therefore, in the present invention, based on the coating tablet results for the pilot-scale improvement prescription, the final prescription was established as in Table 17, and a method for manufacturing a coated tablet (KN713 tablet 30 mg) containing trimetazidine was established as shown in Table 19 and Figure 4 (Example 7).

[0059]

[0060] In the present invention, the coated tablet composition containing trimetazidine (KN713, Trimetazidine Dihydrochloride) may be a pharmaceutical composition for preventing or treating cancer.

[0061] In a previous study (Korean Patent Publication No. 2022-0003475), the inventors of the present invention confirmed that the anticancer effect of trimetazidine, a 3-ketoacyl CoA thiolase (ACAA) inhibitor, significantly increased when administered in combination with omeprazole, a carnitine acylcarnitine carrier (CAC) inhibitor. Therefore, the coated tablet comprising trimetazidine (KN510) of the present invention can be utilized as a pharmaceutical composition for preventing or treating cancer.

[0062]

[0063] In another aspect, the present invention comprises trimetazidine (KN713, Trimetazidine Dihydrochloride) or a pharmaceutically acceptable salt thereof as a main ingredient.

[0064] Silicified microcrystalline cellulose and mannitol as excipients;

[0065] Colloidal Silicon Dioxide as a fluidizing agent,

[0066] A tablet core composed of talc and magnesium stearate as lubricants; and

[0067] A coating tablet comprising a film coating layer comprising polyvinyl alcohol (PVA) and arranged to surround the above-mentioned core;

[0068] The present invention relates to a coated tablet comprising trimetazidine (KN713, Trimetazidine Dihydrochloride), characterized in that each unit tablet of the above-mentioned core contains 24 mg to 36 mg of trimetazidine or a pharmaceutically acceptable salt thereof, 40 mg to 60 mg of silicified microcrystalline cellulose, 30 mg to 45 mg of mannitol, 0.5 mg to 0.7 mg of colloidal silicon dioxide, 0.95 mg to 1.5 mg of talc, and 0.95 mg to 1.5 mg of magnesium stearate.

[0069] In the present invention, when the coated tablet is rotated at a rotation speed of 100 rpm for 15 minutes in 900 ml of a pH 6.8 dissolution test solution, the dissolution rate of trimetazidine or a pharmaceutically acceptable salt thereof may be 95 wt% to 100 wt%.

[0070] In the present invention, the core may have a hardness of 7.5 to 8.5 kp, a disintegration time of 30 minutes or less, a wear rate of 0 to 1 wt%, and an average mass of 114 mg to 125 mg.

[0071] In the present invention, the film coating layer containing polyvinyl alcohol may preferably use Opadry® 85F 12380 or Opadry® Ⅱ White 85F18422, but an aqueous film coating composition containing polyvinyl alcohol that does not affect the dissolution rate of trimetazidine and can increase stability may be used without limitation.

[0072] In the present invention, the coated tablet containing trimetazidine (KN713, Trimetazidine Dihydrochloride) may be a pharmaceutical product for preventing or treating cancer.

[0073]

[0074] In another aspect of the present invention, (a) a step of mixing trimetazidine (KN713, Trimetazidine Dihydrochloride) or a pharmaceutically acceptable salt thereof, silicified microcrystalline cellulose, mannitol and colloidal silicon dioxide by sieving them through a 22 to 27 mesh, and then performing bag mixing;

[0075] (b) A step of adding talc and magnesium stearate sieved through 22 to 27 mesh to the mixture of step (a), and then performing bag mixing;

[0076] (c) a step of manufacturing a tablet core (tablet) by pressing the mixture of step (b); and

[0077] (d) a step of manufacturing a coated tablet by coating the core of step (c) with a film coating solution containing polyvinyl alcohol (PVA);

[0078] The present invention provides a method for manufacturing a coated tablet comprising trimetazidine (KN713, Trimetazidine Dihydrochloride), characterized in that the tablet comprises 24 mg to 36 mg of trimetazidine or a pharmaceutically acceptable salt thereof, 40 mg to 60 mg of silicified microcrystalline cellulose, 30 mg to 45 mg of mannitol, 0.5 mg to 0.7 mg of colloidal silicon dioxide, 0.95 mg to 1.5 mg of talc, and 0.95 mg to 1.5 mg of magnesium stearate per unit tablet of the core of the above step (c).

[0079] The specific method for manufacturing a coated tablet is shown in Table 19 and Fig. 4, and the coating solution of step (d) may be included in an amount of 2.8 mg to 4.5 mg per unit tablet of the tablet core, and purified water may be additionally included as a solvent.

[0080] The film coating solution containing polyvinyl alcohol of the above step (d) can preferably use Opadry® 85F 12380 or Opadry® Ⅱ White 85F18422, and the coating can be performed under the conditions of a coating pan of 3 to 15 rpm, a coating solution spray amount of 5 to 25 rpm, an exhaust temperature of 35°C to 55°C, and an exhaust fan of 2500 to 3500 rpm.

[0081]

[0082] Hereinafter, the present invention will be described in more detail through examples. These examples are intended solely to illustrate the present invention, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples.

[0083]

[0084] Example 1:

[0085] Main ingredient information and raw pharmaceutical information

[0086] 1-1: Main ingredient information

[0087] - Name: KN713

[0088] - Ingredient name: Trimetazidine dihydrochloride

[0089] - Chemical name: 1-[(2,3,4-trimethoxyphenyl)methyl]piperazine dihydrochloride

[0090] - Chemical structure: C 14 H22 N2O3· 2HCl

[0091] [Chemical Formula 1]

[0092]

[0093] - Appearance: White fine powder

[0094] - Solubility of KN713 in water: Freely slouble (see Table 1 below)

[0095] - Solubility of KN713 in organic solvents: Slightly soluble in alcohol (see Table 1 below)

[0096]

[0097]

[0098]

[0099] 1-2: Flow Test for KN713

[0100] The flowability test was performed according to the apparent density and tap density measurement methods disclosed in the general information of the Korean Pharmacopoeia.

[0101]

[0102]

[0103]

[0104]

[0105]

[0106] As shown in Tables 2 and 3 above, the flowability analysis results confirmed that the flowability of KN5713 was very very poor.

[0107]

[0108] Example 2: Compatibility Test

[0109] A test was conducted to confirm the compatibility between additives commonly used in formulations and KN713.

[0110] First, KN713 and additives were mixed at a ratio of 1:1 or 10:1, and the samples were placed in HDPE bottles and stored in a stability chamber under accelerated conditions (temperature 40±2℃, humidity 75±5%) for 4 weeks in a sealed or open state. A mixing suitability test was conducted for a total of 4 weeks, and the trends in content and flexible substances were analyzed.

[0111] Because KN713 has poor flowability, a formulation that can increase flowability by mixing it with KN713 is needed. When KN713 was mixed with polyvinylpyrrolidone K-30 (PVP K-30) in a 1:1 ratio, the total flexible substance tended to increase slightly.

[0112] When mixed with croscarmellose sodium, used as a disintegrant, it was confirmed that the content was reduced (by approximately 70%) simply by mixing. In addition, when mixed with crospovidone, used as a disintegrant, it was confirmed that the amount of flexible substances in the mixture increased significantly under accelerated conditions.

[0113] Therefore, in the present invention, it was confirmed that the compatibility of KN713 with PVP K-30, croscarmellose sodium, and crospovidone was not good. However, because KN713 has excellent water solubility, it is believed that there will be no issues with dissolution if the disintegration time meets the pharmacopoeia (KP) standards (within 30 minutes). Furthermore, to enhance the long-term storage and stability of the formulation, the formulation was designed in a coated tablet form in subsequent studies.

[0114]

[0115] Example 3: Study on the first formulation composition

[0116] Based on the results of compatibility tests for the binder PVP K-30, the manufacturing process was designed to limit its use. Research was conducted to explore the possibility of manufacturing formulations through direct mixing and tableting.

[0117] Silicified microcrystalline cellulose (SMCC) was selected as an excipient to improve the flowability of the mixture containing KN713, which has poor flowability, and to ensure mixing uniformity. However, since the use of SMCC alone may cause swelling due to the water in the sprayed coating solution, mannitol was additionally prescribed.

[0118] Based on the above, a prescription was designed as shown in Table 4 below, and a tableting test was performed.

[0119]

[0120]

[0121]

[0122] The manufacturing process using the prescription in Table 4 above is as follows:

[0123] 1) A step of placing KN713 and excipients in a plastic bag and performing bag mixing 50 times;

[0124] 2) A step of placing the 25Mesh sieved lubricant into a plastic bag containing the above mixture and performing bag mixing 50 times;

[0125] 3) Step to check for disintegration, hardness, wear and tear after tableting and to check for tableting problems.

[0126]

[0127] Example 4: Design of an improved prescription

[0128] 4-1: Prescription improvement measures due to the issue of tablets

[0129] When tableting was performed using the prescription designed in the above <Example 1>, it was confirmed that a filming phenomenon occurred in which powder formed a film on the upper and lower parts of the punch when manufacturing a large number of tablets (see Fig. 1).

[0130] Accordingly, in the present invention, the amount of mannitol, an excipient, was increased to improve the filming phenomenon. In addition, the conditions for smooth filming were confirmed by adding magnesium stearate together with talc as a lubricant. As a result, as shown in the improved recipe (F2 recipe) in Table 5 below, it was confirmed that when 1% of magnesium stearate was additionally added, tableting problems such as filming did not occur (the filming phenomenon did not occur even after manufacturing more than 100 tablets).

[0131]

[0132]

[0133]

[0134] 4-2: Results of content and dissolution tests for the improved prescription (F2 prescription)

[0135] The content uniformity of the mixture was evaluated using HPLC (High Performance Liquid Chromatography) analysis, and it was confirmed that the average content was 98.5% and the deviation was small (Table 6).

[0136]

[0137]

[0138]

[0139] Tablets were manufactured according to the tableting pressure that can affect the formation and dissolution rate of the tablets, and then subjected to process tests (disintegration, friability, and hardness tests) (Table 7). Process tests were performed using the analytical methods described in the General Information section of the Korean Pharmacopoeia.

[0140]

[0141]

[0142]

[0143] As a result, tablets meeting the KP standards (friction of 1% or less, disintegration within 30 minutes) were formed at a tableting pressure of 220 kgf or more, and it was confirmed that the disintegration rate was delayed as the tableting pressure increased.

[0144]

[0145] A dissolution test was conducted on the tablets manufactured by different pressing pressures, and the dissolution test method is shown in Table 8 below (reference material for dissolution test settings: Trimetazidine hydrochloride tablet JP).

[0146]

[0147]

[0148]

[0149] Each tablet was placed in a dissolution device, extracted, and then analyzed using HPLC analysis.

[0150] As a result, as shown in Fig. 3, the dissolution test results for each pressing pressure showed that all of them showed a dissolution rate of 90% or more within 30 minutes. However, when a pressing pressure of 300 kgf or more was applied, the dissolution rate tended to decrease in the 15-minute range.

[0151]

[0152] 4-3: Preparation uniformity test

[0153] As a result of checking the formulation uniformity of tablets manufactured with the above 220 to 240 kgf pressing pressure, it was confirmed that the tablets were manufactured uniformly with an average content of approximately 96% (Table 9).

[0154]

[0155]

[0156]

[0157] 4-4: Addition of a fluidizing agent to improve the flowability of the mixture.

[0158] The mixture flowability of the improved prescription (F2 prescription) was measured as Very Poor (Table 10; see Reference Table 3). Although it was improved compared to when the main ingredient KN713 was used alone, there is concern that problems may arise during mass production.

[0159]

[0160]

[0161]

[0162] Therefore, to improve the flowability of the F2 prescription mixture, colloidal silicon dioxide (trade name: Aerosil 200), a fluidizing agent, was gradually added starting from 0.5 wt% per total weight of the mixture, and it was confirmed whether flowability improvement was possible.

[0163]

[0164]

[0165]

[0166] When the amount of colloidal silicon dioxide, which is a fluidizing agent, was added at 0.5 wt% based on the total weight of the mixture, it was confirmed that the final mixture exhibited a fluidity that enabled the manufacture of tablets even on a large scale, as shown in Table 11 above.

[0167]

[0168] Example 5: Improved prescription and process setup at pilot scale

[0169] 5-1: Pilot-scale manufacturing of improved prescriptions

[0170] In the present invention, reflecting the flowability improvement results of the above <Example 4-4>, a prescription to be manufactured on a pilot scale (3,000T or more) was set as shown in Table 12 below.

[0171]

[0172]

[0173]

[0174] The pilot-scale manufacturing process and evaluation method for the improved prescription are as follows:

[0175] 1) A step of sieving the main ingredient, excipients, and fluidizing agent through a 25 mesh sieve, placing them in a plastic bag, and then performing bag mixing;

[0176] 2) A step of placing the 25 Mesh sieved active agent into a plastic bag containing the above mixture and performing bag mixing 50 times;

[0177] 3) A step of manufacturing a pilot-scale tablet using a rotary tableting machine; and

[0178] 4) Step of manufacturing the final coated tablet by coating the tablet with a coating machine.

[0179]

[0180] 5-2: Process test results for mixtures, tablets, and coated tablets manufactured on a pilot scale

[0181] Process testing was performed on the final mixture, tablet, and coated tablet manufactured in the manufacturing process of the above <Example 5-1>.

[0182] The flowability evaluation result for the final mixture was Poor, similar to <Example 4-4> before the pilot scale, and it was confirmed that the raw material supply was proceeding without any problems during the tableting process (Table 13).

[0183]

[0184]

[0185]

[0186] As a result of conducting a process test on the manufactured tablets, it was confirmed that tablets having a disintegration time (standard: within 30 minutes) and a friability (standard: 1% or less) that met the KP standards were smoothly manufactured (Table 14).

[0187]

[0188]

[0189]

[0190] As a result of the dissolution test after manufacturing the coated tablet, it was confirmed that the tablet (coated tablet) was manufactured smoothly, showing 100% dissolution without significant deviation within 30 minutes (Table 15).

[0191]

[0192]

[0193]

[0194] 5-3: Simple stability test for improved prescription coated tablets (KN713 tablets 30 mg) manufactured on a pilot scale

[0195] The improved prescription coated tablets (KN713 tablets 30 mg) manufactured on a pilot scale were stored for 1 month and 3 months under accelerated conditions (temperature 40±2℃, humidity 75±5%), and then the content and flexible substances of the coated tablets were analyzed.

[0196]

[0197]

[0198]

[0199] As a result, as shown in Table 16 above, it was confirmed that the improved prescription of <Example 5-1> above did not induce a decrease in content or an increase in flexible substances.

[0200]

[0201] Example 6: Final formulation and manufacturing process

[0202] 6-1: Manufacturing the final prescription tablets

[0203] In the present invention, the final cleaning and manufacturing process was established based on the experimental results of the improved prescription of the above <Example 5> (Tables 17 to 19).

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211] 6-2: Production and results of tablets for stability testing for the final formulation

[0212] As a result of producing tablets for stability testing according to the final prescription and process, the finished product test results for the produced tablets for stability testing were judged to be acceptable, as shown in Table 20 below (Test No.: GR-22055).

[0213]

[0214]

[0215]

[0216] In the present invention, in order to improve the flowability of trimetazidine, the main ingredient of KN713 tablets (30 mg), a tablet composition was designed using silicified microcrystalline cellulose, mannitol, and colloidal silicon dioxide. When KN713 tablets (30 mg) are manufactured using the coated tablet composition of the present invention, it was confirmed that tablets meeting the standards for disintegration, dissolution, and friability were manufactured, and the increase in flexible substances was significantly reduced. Therefore, the tablet composition of the present invention can be usefully utilized as an anticancer tablet.

Claims

1. Trimetazidine (KN713, Trimetazidine Dihydrochloride) or a pharmaceutically acceptable salt thereof as the main ingredient; Silicified microcrystalline cellulose and mannitol as excipients; Colloidal Silicon Dioxide as a fluidizing agent, A tablet composition comprising talc and magnesium stearate as lubricants; and A composition for film coating comprising polyvinyl alcohol (PVA); A coated tablet composition comprising trimetazidine (KN713, Trimetazidine Dihydrochloride), characterized in that it comprises 24 mg to 36 mg of trimetazidine or a pharmaceutically acceptable salt thereof, 40 mg to 60 mg of silicified microcrystalline cellulose, 30 mg to 45 mg of mannitol, 0.5 mg to 0.7 mg of colloidal silicon dioxide, 0.95 mg to 1.5 mg of talc, and 0.95 mg to 1.5 mg of magnesium stearate.

2. In paragraph 1, A coated tablet composition comprising trimetazidine (KN713, Trimetazidine Dihydrochloride), characterized in that it comprises 50 mg of silicified microcrystalline cellulose, 37.6 mg of mannitol, 0.6 mg of colloidal silicon dioxide, 1.2 mg of talc, and 1.2 mg of magnesium stearate per 30 mg of trimetazidine or a pharmaceutically acceptable salt thereof.

3. In paragraph 1, A coating tablet composition comprising trimetazidine (KN713, Trimetazidine Dihydrochloride), characterized in that the film coating composition comprises 2.8 mg to 4.5 mg of trimetazidine or a pharmaceutically acceptable salt thereof per 24 mg to 36 mg of trimetazidine.

4. In paragraph 1, A coated tablet composition comprising trimetazidine (KN713, Trimetazidine Dihydrochloride), characterized in that the coated tablet composition comprising trimetazidine (KN713, Trimetazidine Dihydrochloride) is a pharmaceutical composition for preventing or treating cancer.

5. Trimetazidine (KN713, Trimetazidine Dihydrochloride) or a pharmaceutically acceptable salt thereof as the main ingredient; Silicified microcrystalline cellulose and mannitol as excipients; Colloidal Silicon Dioxide as a fluidizing agent, A tablet core composed of talc and magnesium stearate as lubricants; and A coating tablet comprising a film coating layer comprising polyvinyl alcohol (PVA) and arranged to surround the above-mentioned core; A coated tablet comprising trimetazidine (KN713, Trimetazidine Dihydrochloride), characterized in that each unit tablet of the above-mentioned core contains 24 mg to 36 mg of trimetazidine or a pharmaceutically acceptable salt thereof, 40 mg to 60 mg of silicified microcrystalline cellulose, 30 mg to 45 mg of mannitol, 0.5 mg to 0.7 mg of colloidal silicon dioxide, 0.95 mg to 1.5 mg of talc, and 0.95 mg to 1.5 mg of magnesium stearate.

6. In paragraph 5, A coated tablet containing trimetazidine (KN713, Trimetazidine Dihydrochloride), characterized in that when the coated tablet is rotated at a rotation speed of 100 rpm for 15 minutes in 900 ml of a pH 6.8 dissolution test solution, the dissolution rate of trimetazidine or a pharmaceutically acceptable salt thereof is 95 wt% to 100 wt%.

7. In paragraph 5, A coated tablet containing trimetazidine (KN713, Trimetazidine Dihydrochloride), characterized in that the above-mentioned core has a hardness of 7.5 to 8.5 kp, a disintegration time of less than 30 minutes, a friability of 0 to 1 wt%, and an average mass of 114 mg to 125 mg.

8. In paragraph 5, A coated tablet comprising trimetazidine (KN713, Trimetazidine Dihydrochloride), characterized in that the coated tablet comprising trimetazidine (KN713, Trimetazidine Dihydrochloride) is a pharmaceutical product for preventing or treating cancer. 9.(a) A step of mixing trimetazidine (KN713, Trimetazidine Dihydrochloride) or a pharmaceutically acceptable salt thereof, silicified microcrystalline cellulose, mannitol, and colloidal silicon dioxide by sieving them through a 22 to 27 mesh, and then performing bag mixing; (b) A step of adding talc and magnesium stearate sieved through 22 to 27 mesh to the mixture of step (a), and then performing bag mixing; (c) a step of manufacturing a tablet core (tablet) by pressing the mixture of step (b); and (d) a step of manufacturing a coated tablet by coating the core of step (c) with a film coating solution containing polyvinyl alcohol (PVA); A method for manufacturing a coated tablet comprising trimetazidine (KN713, Trimetazidine Dihydrochloride), characterized in that the unit tablet of the core of the step (c) above contains 24 mg to 36 mg of trimetazidine or a pharmaceutically acceptable salt thereof, 40 mg to 60 mg of silicified microcrystalline cellulose, 30 mg to 45 mg of mannitol, 0.5 mg to 0.7 mg of colloidal silicon dioxide, 0.95 mg to 1.5 mg of talc, and 0.95 mg to 1.5 mg of magnesium stearate.

10. In paragraph 9, A method for manufacturing a coated tablet containing trimetazidine (KN713, Trimetazidine Dihydrochloride), characterized in that the coating solution of the above step (d) is included in an amount of 2.8 mg to 4.5 mg per unit tablet of the core.

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