Coated tablet composition comprising omeprazole with increased stability and manufacturing method therefor

Abstract

The present invention relates to a coated tablet composition comprising an omeprazole (KN510) with improved stability, and a manufacturing method therefor, and more specifically, to a double coated tablet composition comprising omeprazole, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, and a method for manufacturing same. In the present invention, in order to increase the stability of KN510 tablets (30 mg) containing omeprazole, a tablet composition was designed using calcium carbonate. When mannitol and lactose are contained as excipients, it was confirmed that tablets suitable for disintegration, elution, and friability criteria can be manufactured, and the increase in related substances is significantly reduced.

Description

Coated tablet composition containing omeprazole with increased stability and method for preparing the same

[0001] The present invention relates to a coated tablet composition comprising omeprazole (KN510; Omeprazole) with increased stability and a method for preparing the same, and more particularly, to a double-coated tablet composition comprising omeprazole, an enantiomer thereof or a pharmaceutically acceptable salt thereof and a method for preparing the same.

[0002]

[0003] Omeprazole, a carnitine acylcarnitine carrier (CAC) inhibitor, is a proton pump inhibitor known to be effective in treating gastroesophageal reflux disease, peptic ulcers, erosive esophagitis, and eosinophilic esophagitis. Recently, a study was published showing that PPIs, including omeprazole, inhibit the activity of fatty acid synthase (FASN), an enzyme that helps produce fatty acids, which are essential for cancer cell survival, and induce cancer cell death while minimizing the effects on non-cancerous cells (Walshet et al., Journal of Experimental & Clinical Cancer Research, 34:93, 2015).

[0004] Omeprazole or its pharmaceutically acceptable salts are highly effective in suppressing gastric acid secretion, but are known to be highly unstable in the presence of moisture, heat, and acid. In particular, when omeprazole or its pharmaceutically acceptable salts are administered orally, they are rapidly degraded by gastric acid and are barely absorbed. Therefore, active research is being conducted to improve the stability of stable omeprazole-based drug formulations (Korean Patent Registration No. 10-2080023, Korean Patent Registration No. 10-2006777, and Korean Patent Publication No. 10-2020-0023185).

[0005] To prevent drug degradation by gastric juice, drugs using formulation technologies such as enteric coating or enteric pellets are commercially available. However, when products using technologies such as enteric coating or enteric pellets are administered orally, the drug passes through the stomach and is released in the intestine, which has the disadvantage of significantly delaying the time it takes for the drug to take effect.

[0006] To address these shortcomings, Korean Patent No. 10-679767 proposes a method of using a buffering agent such as sodium bicarbonate with omeprazole. However, using large amounts of sodium bicarbonate has the disadvantage of reducing the efficacy of omeprazole and causing side effects. Specifically, administering large amounts of sodium bicarbonate can cause stomach distension, which can increase pain in critically ill patients. In addition, the absorption of sodium bicarbonate can cause burping, which can cause upward movement of stomach acid and potentially worsen gastroesophageal reflux disease. Furthermore, there is a concern that excessive sodium intake can cause electrolyte imbalances and side effects such as hypertension, heart failure, and renal failure.

[0007]

[0008] In the present invention, it was confirmed that since omeprazole, the main ingredient of KN510 tablet 30 mg, is sensitive to temperature and humidity, simply applying a moisture-proof coating alone cannot prevent a decrease in content and an increase in volatile substances. Accordingly, in the present invention, as a result of diligent efforts to develop a tablet composition capable of increasing the stability of omeprazole, a coated tablet suitable for the standards of disintegration, dissolution, and friability was manufactured, and as a result of a simple stability test on the manufactured tablet, it was confirmed that the increase in volatile substances was significantly reduced, thereby completing the present invention.

[0009]

[0010] Accordingly, an object of the present invention is to provide a double-coated tablet composition comprising omeprazole, an enantiomer thereof or a pharmaceutically acceptable salt thereof, and a double-coated tablet comprising the composition.

[0011] Another object of the present invention is to provide a method for manufacturing the double-coated tablet.

[0012]

[0013] To achieve the above-mentioned purpose,

[0014] The present invention provides a tablet composition comprising omeprazole (KN510, Omeprazole) as a main ingredient, an enantiomer thereof or a pharmaceutically acceptable salt thereof, lactose monohydrate and mannitol as excipients, hydroxypropylcellulose as a binder, precipitated calcium carbonate as a pH adjuster, sodium laruyl sulfate as a solubilizer, sodium starch glycolate as a disintegrant, and magnesium stearate as a lubricant;

[0015] A composition for primary film coating comprising hydroxypropyl methylcellulose (HPMC); and

[0016] A double-coated tablet composition comprising a composition for secondary film coating comprising polyvinyl alcohol (PVA) is provided.

[0017]

[0018] In a preferred embodiment of the present invention, 24 mg to 36 mg of the omeprazole, its enantiomer or its pharmaceutically acceptable salt may include 60 mg to 90 mg of lactose, 60 mg to 90 mg of mannitol, 4.8 mg to 7.2 mg of hydroxypropyl cellulose, 120 mg to 180 mg of precipitated calcium carbonate, 2.4 mg to 3.6 mg of sodium lauryl sulfate, and 24 mg to 36 mg of sodium starch glycolate.

[0019] In another preferred embodiment of the present invention, the composition may additionally contain ethanol as a solvent.

[0020] In another preferred embodiment of the present invention, the composition for primary film coating comprising hydroxypropyl methylcellulose may be Opadray® White (Opadray® White 03B28796), and may contain 4.8 mg to 7.2 mg of omeprazole, its enantiomer, or a pharmaceutically acceptable salt thereof per 24 mg to 36 mg of omeprazole.

[0021] In another preferred embodiment of the present invention, the composition for secondary film coating comprising polyvinyl alcohol may be Opadry® amb Ⅱ (Opadry® amb Ⅱ 88A600013), and may contain 12.8 mg to 19.2 mg of omeprazole, its enantiomer or its pharmaceutically acceptable salt per 24 mg to 36 mg of omeprazole.

[0022] In another preferred embodiment of the present invention, the double-coated tablet composition may be a pharmaceutical composition for preventing or treating cancer.

[0023]

[0024] The present invention also provides a tablet comprising a core (tablet) comprising omeprazole (KN510, Omeprazole) as a main ingredient, an enantiomer thereof or a pharmaceutically acceptable salt thereof, lactose monohydrate and mannitol as excipients, hydroxypropylcellulose as a binder, precipitated calcium carbonate as a pH regulator, sodium laruyl sulfate as a solubilizer, sodium starch glycolate as a disintegrant, and magnesium stearate as a lubricant;

[0025] A first coating layer surrounding the above-mentioned core and comprising hydroxypropyl methylcellulose; and

[0026] A double-coated tablet is provided, comprising a second coating layer disposed on the first coating layer and containing polyvinyl alcohol.

[0027] In a preferred embodiment of the present invention, the unit tablet of the above-described core may contain 24 mg to 36 mg of omeprazole, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, 60 mg to 90 mg of lactose, 60 mg to 90 mg of mannitol, 4.8 mg to 7.2 mg of hydroxypropyl cellulose, 120 mg to 180 mg of precipitated calcium carbonate, 2.4 mg to 3.6 mg of sodium lauryl sulfate, 24 mg to 36 mg of sodium starch glycolate, and 1.6 mg to 2.4 mg of magnesium stearate.

[0028] In another preferred embodiment of the present invention, when the double-coated tablet is rotated at a rotation speed of 100 rpm in 900 ml of a pH 6.8 dissolution test solution for 15 minutes, the dissolution rate of omeprazole may be 91 wt% to 98 wt%.

[0029] In another preferred embodiment of the present invention, the core may have a hardness of 5 to 20 kp, a disintegration time of 30 minutes or less, a wear rate of 0 to 1 wt%, and an average mass of 359.9 mg to 382.1 mg.

[0030] In another preferred embodiment of the present invention, the double-coated tablet may be a pharmaceutical agent for preventing or treating cancer.

[0031]

[0032] To achieve other purposes described above,

[0033] The present invention comprises the steps of (a) preparing a binding solution by dissolving hydroxypropyl cellulose, which is a binding agent, in ethanol, which is a solvent;

[0034] (b) the main ingredient omeprazole (KN510, Omeprazole), its enantiomer or its pharmaceutically acceptable salt,

[0035] Excipients: Lactose Monohydrate and Mannitol;

[0036] Precipitated Calcium Carbonate, a pH adjuster

[0037] Sodium Laruyl Sulfate, a solubilizing agent, and

[0038] A step of mixing sodium starch glycolate, a disintegrating agent, and then mixing it with the binding solution prepared in step (a) to prepare a granule;

[0039] (c) A step of drying the granules of step (b) using a fluid bed drying (FBG) method and then sizing them to 15 to 20 meshes;

[0040] (d) a step of sieving sodium starch glycolate, a disintegrant, and magnesium stearate, a lubricant, through a 22 to 27 mesh, and then mixing them with the granules established in step (c);

[0041] (e) a step of manufacturing a tablet core (tablet) by pressing the mixture of step (d);

[0042] (f) a step of manufacturing a coated tablet by first coating the core of step (e) with a first coating solution containing hydroxypropyl methylcellulose; and

[0043] (g) A method for manufacturing a double-coated tablet is provided, comprising: a step of manufacturing a double-coated tablet by first coating the coated tablet of step (f) with a second coating solution containing polyvinyl alcohol;

[0044]

[0045] In a preferred embodiment of the present invention, the omeprazole, its enantiomer or its pharmaceutically acceptable salt may comprise 24 mg to 36 mg of lactose, 60 mg to 90 mg of mannitol, 4.8 mg to 7.2 mg of hydroxypropyl cellulose, 120 mg to 180 mg of precipitated calcium carbonate, 2.4 mg to 3.6 mg of sodium lauryl sulfate, and 24 mg to 36 mg of sodium starch glycolate.

[0046] In another preferred embodiment of the present invention, the step (c) may be performed under the conditions of an air supply temperature of 30°C to 70°C and an air supply amount of 40 ㎥ / h to 70 ㎥ / h.

[0047]

[0048] In the present invention, in order to increase the stability of KN510 tablets (30 mg) containing omeprazole, a tablet composition was designed using calcium carbonate, and it was confirmed that when mannitol and lactose were included as excipients, tablets suitable for disintegration, dissolution, and friability standards could be 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.

[0049]

[0050] Figure 1 shows data analyzing the particle size of KN510 (Omeprazole).

[0051] Figure 2 is a photograph showing the appearance of the F2 prescription tablet after measuring its wear resistance.

[0052] Figure 3 is data confirming the dissolution rate of F2 prescription tablets according to tablet pressure.

[0053] Figure 4 shows data confirming the dissolution rate of the uncoated and coated tablets of the pilot-scale F2 prescription.

[0054] Figure 5 is a schematic diagram showing the manufacturing process of KN510.

[0055]

[0056] Hereinafter, the present invention will be described in detail.

[0057]

[0058] The present invention, from a consistent perspective, comprises as a main ingredient omeprazole (KN510, Omeprazole), an enantiomer thereof or a pharmaceutically acceptable salt thereof,

[0059] Lactose Monohydrate and Mannitol as excipients,

[0060] Hydroxypropylcellulose as a binder,

[0061] Precipitated Calcium Carbonate as a pH adjuster

[0062] Sodium Laruyl Sulfate as a solubilizer,

[0063] Sodium Starch Glycolate as a disintegrant,

[0064] A tablet composition comprising magnesium stearate as a lubricant;

[0065] A composition for primary film coating comprising hydroxypropyl methylcellulose (HPMC); and

[0066] The present invention relates to a double-coated tablet composition comprising a composition for secondary film coating comprising polyvinyl alcohol (PVA).

[0067]

[0068] Omeprazole (KN510; Omeprazole) may be included, characterized in that it comprises 24 mg to 36 mg of the above omeprazole, its enantiomer or its pharmaceutically acceptable salt, 60 mg to 90 mg of lactose, 60 mg to 90 mg of mannitol, 4.8 mg to 7.2 mg of hydroxypropyl cellulose, 120 mg to 180 mg of precipitated calcium carbonate, 2.4 mg to 3.6 mg of sodium lauryl sulfate, and 24 mg to 36 mg of sodium starch glycolate.

[0069] More preferably, the composition may contain 30 mg of omeprazole, its enantiomer or its pharmaceutically acceptable salt, 75 mg of lactose, 75 mg of mannitol, 6 mg of hydroxypropylcellulose, 150 mg of precipitated calcium carbonate, 3 mg of sodium lauryl sulfate, 30 mg of sodium starch glycolate, and 2 mg of magnesium stearate.

[0070] In the present invention, the above-mentioned composition may additionally include ethanol as a solvent.

[0071] In the present invention, the composition for primary film coating comprising hydroxypropyl methylcellulose may contain 4.8 mg to 7.2 mg of omeprazole, its enantiomer, or its pharmaceutically acceptable salt per 24 mg to 36 mg of omeprazole, and may further contain ethanol and purified water as solvents. The composition for primary film coating comprising hydroxypropyl methylcellulose may preferably be Opadray® White (Opadray® White 03B28796), but is not limited thereto, and a hydroxypropyl methylcellulose film coating technology known in the art may be applied.

[0072] In the present invention, the secondary film coating composition comprising polyvinyl alcohol may contain 12.8 mg to 19.2 mg per 24 mg to 36 mg of omeprazole or a pharmaceutically acceptable salt thereof, and may further contain purified water as a solvent. The secondary film coating composition comprising polyvinyl alcohol may preferably be Opadry® amb Ⅱ (Opadry® amb Ⅱ 88A600013), but is not limited thereto, and a polyvinyl alcohol film coating technology known in the art may be applied.

[0073]

[0074] Omeprazole, the main ingredient of KN510, is sensitive to temperature and humidity, so in a specific embodiment of the present invention, primary formulations F1 and F2 were designed to increase the stability of omeprazole. The F1 formulation improved the flowability of the granules, but edge breakage occurred after measuring the friability. The F2 formulation showed suitable results in the granule flowability, friability, and dissolution tests even at a pilot scale, but an increase in flexible substances was confirmed in the simple stability test (Examples 3 to 5 of the present invention).

[0075] Therefore, in the present invention, it was confirmed that a simple moisture-proof coating alone cannot prevent a decrease in content and an increase in flexible substances, and a new tablet formulation was designed using calcium carbonate, and an optimization study was conducted to produce tablets that meet the standards for disintegration, dissolution, and friability. After conducting a double-coated tablet manufacturing test for the improved formulation on a pilot scale, it was confirmed as a result of a simple stability test on the manufactured tablets that the increase in flexible substances was significantly reduced (Examples 6 and 7 of the present invention). Based on the results of the double-coated tablets for the improved formulation on a pilot scale, the final formulation was established as shown in Table 23, and a method for manufacturing double-coated tablets (KN510 tablets 30 mg) was established as shown in Table 24 and Fig. 5.

[0076]

[0077] In the present invention, the double-coated tablet composition may be a pharmaceutical composition for preventing or treating cancer.

[0078] In a previous study (Korean Patent Publication No. 2022-0003475), the inventors of the present invention confirmed that the anticancer effect was significantly increased when omeprazole, a carnitine acylcarnitine carrier (CAC) inhibitor, and trimetazidine, a carnitine acylcarnitine carrier (CAC) inhibitor, were co-administered. Therefore, the double-coated tablet comprising omeprazole (KN510) of the present invention can be utilized as a pharmaceutical composition for the prevention or treatment of cancer.

[0079]

[0080] In another aspect, the present invention comprises as a main ingredient omeprazole (KN510, Omeprazole), an enantiomer thereof or a pharmaceutically acceptable salt thereof,

[0081] Lactose Monohydrate and Mannitol as excipients; Hydroxypropylcellulose as binder;

[0082] Precipitated Calcium Carbonate as a pH adjuster

[0083] Sodium Laruyl Sulfate as a solubilizer,

[0084] Sodium Starch Glycolate as a disintegrant,

[0085] Najeong core (tablet) containing magnesium stearate as a lubricant;

[0086] A first coating layer surrounding the above-mentioned core and containing hydroxypropyl methylcellulose (HPMC); and

[0087] It relates to a double-coated tablet comprising a second coating layer disposed on the first coating layer and containing polyvinyl alcohol (PVA).

[0088] In the present invention, the unit tablet of the above-described core may contain 24 mg to 36 mg of omeprazole, its enantiomer, or its pharmaceutically acceptable salt, 60 mg to 90 mg of lactose, 60 mg to 90 mg of mannitol, 4.8 mg to 7.2 mg of hydroxypropyl cellulose, 120 mg to 180 mg of precipitated calcium carbonate, 2.4 mg to 3.6 mg of sodium lauryl sulfate, 24 mg to 36 mg of sodium starch glycolate, and 1.6 mg to 2.4 mg of magnesium stearate.

[0089] In the present invention, when the double-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 omeprazole may be 91 wt% to 98 wt%.

[0090] In the present invention, the core may have a hardness of 5 to 20 kp, a disintegration time of 30 minutes or less, a wear rate of 0 to 1 wt%, and an average mass of 359.9 mg to 382.1 mg.

[0091] In the present invention, the double-coated tablet may be a pharmaceutical product for preventing or treating cancer.

[0092]

[0093] In another aspect, the present invention comprises the steps of: (a) preparing a binding solution by dissolving hydroxypropyl cellulose as a binding agent in ethanol as a solvent;

[0094] (b) the main ingredient omeprazole (KN510, Omeprazole), its enantiomer or its pharmaceutically acceptable salt,

[0095] Excipients: Lactose Monohydrate and Mannitol;

[0096] Precipitated Calcium Carbonate, a pH adjuster

[0097] Sodium Laruyl Sulfate, a solubilizing agent, and

[0098] A step of mixing sodium starch glycolate, a disintegrating agent, and then mixing it with the binding solution prepared in step (a) to prepare a granule;

[0099] (c) A step of drying the granules of step (b) using a fluid bed drying (FBG) method and then sizing them to 15 to 20 meshes;

[0100] (d) a step of sieving sodium starch glycolate, a disintegrant, and magnesium stearate, a lubricant, through a 22 to 27 mesh, and then mixing them with the granules established in step (c);

[0101] (e) a step of manufacturing a tablet core (tablet) by pressing the mixture of step (d);

[0102] (f) a step of manufacturing a coated tablet by first coating the core of step (e) with a first coating solution containing hydroxypropyl methylcellulose; and

[0103] (g) A method for manufacturing a double-coated tablet, comprising: a step of manufacturing a double-coated tablet by first coating the coated tablet of step (f) with a second coating solution containing polyvinyl alcohol;

[0104]

[0105] In the present invention, the omeprazole, its enantiomer or its pharmaceutically acceptable salt may comprise 24 mg to 36 mg of lactose, 60 mg to 90 mg of mannitol, 4.8 mg to 7.2 mg of hydroxypropyl cellulose, 120 mg to 180 mg of precipitated calcium carbonate, 2.4 mg to 3.6 mg of sodium lauryl sulfate, and 24 mg to 36 mg of sodium starch glycolate.

[0106] The specific method for manufacturing a double-coated tablet is shown in Table 25 and Fig. 5, and the step (c) can be performed under the conditions of an air supply temperature of 30°C to 70°C and an air supply amount of 40 ㎥ / h to 70 ㎥ / h.

[0107] The first coating solution of the above step (f) contains 24 mg to 36 mg of omeprazole, its enantiomer, or its pharmaceutically acceptable salt, 4.8 mg to 7.2 mg of Opadry White, 42 ml to 63 ml of ethanol, and 13.2 ml to 19.8 ml of purified water, and the first 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.

[0108] The secondary coating solution of the above step (g) contains 24 mg to 36 mg of omeprazole, its enantiomer, or its pharmaceutically acceptable salt, 12.8 mg to 19.2 mg of Opadry II Purple, and 51.2 ml to 76.8 ml of purified water, and the secondary coating can be performed under the following conditions: 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.

[0109]

[0110] 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.

[0111]

[0112] Example 1: Main ingredient information and raw pharmaceutical information

[0113] 1-1: Main ingredient information

[0114] - Name and ingredient name: KN510, Omeprazole

[0115] - Chemical name: 5-Methoxy-2-[[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulphanyl]-1H-benzimidazole

[0116] - Chemical structure: (C 17 H 19 N3O3S)

[0117] [Chemical Formula 1]

[0118]

[0119] - Appearance: White fine powder

[0120] - Solubility of KN510 in solvents: See Table 1 and Table 2 below.

[0121]

[0122]

[0123]

[0124]

[0125] 1-2: Flow Test for KN510

[0126] The flowability test was performed according to the apparent density and tap density measurement methods disclosed in the general information of the Korean Pharmacopoeia.

[0127]

[0128]

[0129]

[0130]

[0131] As shown in Tables 3 and 4 above, the flowability analysis results confirmed that the flowability of KN510 was very very poor.

[0132]

[0133] 1-3: Particle size analysis of KN510

[0134] The particle size was measured using a particle size analyzer (Mastersizer 3000).

[0135] As a result of particle size analysis, as shown in Fig. 1, it was confirmed that KN510 was in the form of fine particles of 10㎛ or less.

[0136]

[0137] 1-4: Stability-related characteristics of KN510

[0138] KN510 is known to be sensitive to moisture and acidic conditions.

[0139]

[0140] Example 2: Compatibility Test

[0141] A test was conducted to confirm the compatibility between additives commonly used in formulations and KN510.

[0142] First, KN510 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.

[0143] As a result, it was confirmed that polyvinylpyrrolidone K-30 (PVP K-30), which is mainly used as a binder, can reduce the content of the main component and induce an increase in flexible substances when mixed with KN510 under accelerated conditions.

[0144] Additionally, it was confirmed that crospovidone, which is mainly used as a disintegrant, significantly increases the amount of flexible substances in the sample when mixed with KN510.

[0145] It was confirmed that the flexible material tended to increase for all samples under open conditions.

[0146]

[0147] Example 3: Study on the first formulation composition

[0148] 3-1: Primary Prescription Design Process

[0149] To improve the flowability of the main ingredient, a granulation process was introduced, and hydroxypropyl cellulose (HPC) was selected as the binder. Anhydrous ethanol (hereinafter referred to as ethanol or ethanol) was selected as the binder to enable drying even at low temperatures. Additionally, sodium lauryl sulfate (SLS), a solubilizer that increases the solubility of the main ingredient, was included in the formulation.

[0150] Lactose was used as the main excipient, but corn starch or microcrystalline cellulose (MCC), which are excipients used in existing solid omeprazole formulations, were also prescribed (F1 and F2 prescriptions).

[0151]

[0152]

[0153] The ingredients and contents of the F1 and F2 prescriptions are shown in Table 5 above, and the manufacturing process is as follows:

[0154] 1) A step of preparing a binding solution by dissolving a binding agent in a solvent;

[0155] 2) Step of adding and mixing main ingredients, excipients, and solubilizers;

[0156] 3) Step of adding a binding solution to the mixture and granulating it using a granulator;

[0157] 4) Drying the formed granules and sieving them through an 18 mesh;

[0158] 5) A final mixing step after adding a disintegrant and a 25 mesh sieved lubricant; and

[0159] 6) After the final touch, a process inspection is performed to check wear, disintegration, hardness, etc.

[0160]

[0161] 3-2: Checking the flowability of granules for the F1 prescription

[0162] As a result of conducting the granulation process using the F1 prescription, it was confirmed that the flowability of the granules was improved.

[0163]

[0164]

[0165]

[0166] 3-3: Checking the wear and tear problem of F1 prescription tablets

[0167] The friability of F1 prescription tablets was evaluated according to the friability test method described in the general information of the Korean Pharmacopoeia.

[0168] As a result, as shown in Fig. 2, the tablets manufactured using the F1 prescription had a problem of breakage at the corners after the wear test.

[0169]

[0170] 3-4: Process inspection results for F2 prescription tablets

[0171] For the F2 prescription, the process was performed in the same manner as the F1 prescription.

[0172] As shown in Table 7 below, the flowability of the granules for the F2 prescription was Passable, indicating that there was no problem in supplying raw materials during mass production.

[0173]

[0174]

[0175]

[0176] After manufacturing the post-mixture, tablets were manufactured under different pressing pressures and then subjected to process inspection. As shown in Table 8 below, when the pressing pressure was 230 kgf or less, breakage at the edges occurred after measuring the degree of wear. At higher pressing pressures, no breakage at the edges occurred and the disintegration rate also satisfied the MP standard (standard disintegration time: within 30 minutes).

[0177]

[0178]

[0179]

[0180] 3-5: Results of dissolution test for F2 tablets by tablet pressure

[0181] The dissolution test for F2 tablets manufactured by different pressing pressures was performed under the conditions shown in Table 9 below (reference material for dissolution test settings: Omeprezole Delayed Capsule USP).

[0182]

[0183]

[0184] Each tablet was placed in a dissolution device and dissolution was performed. Afterwards, the dissolution rate was confirmed by measuring the absorbance at 305 nm using a UV-spectrophotometer.

[0185] As a result, as shown in Fig. 3, more than 90% of the dissolution was observed within 15 minutes regardless of the tablet pressure (licensed product: at least 75% of the dissolution rate within 45 minutes under pH 6.8 conditions).

[0186]

[0187] Example 4: Primary formulation formulation_Pilot scale F2 formulation and process setup

[0188] 4-1: Pilot-scale F2 formulation manufacturing

[0189] In the present invention, the F2 prescription is used as the basic prescription, and a moisture-proof coating is added to enhance the stability of the main ingredient.

[0190]

[0191]

[0192]

[0193] The pilot-scale manufacturing process and evaluation method for the F2 prescription are as follows:

[0194] 1) A step of preparing a binding solution by dissolving a binding agent in a solvent;

[0195] 2) Step of adding and mixing main ingredients, excipients, and solubilizers;

[0196] 3) A step of granulating by adding a binding solution using a high-speed mixer;

[0197] 4) Step of drying granules using the fluid bed drying (FBG) method using Consigma-1 (at this time, the supply air temperature is set to 40℃ and the supply air volume is set to 60㎥ / h);

[0198] 5) Drying is performed until the LOD value is within 3%, and then sieving is performed through 18 Mesh;

[0199] 6) After adding the disintegrant and the lubricant sieved through 25 Mesh, the final mixing step is performed;

[0200] 7) A step of forming tablets of appropriate size and shape by adjusting the tableting pressure and filling depth using a rotary tableting machine (at this time, a process inspection is conducted to confirm whether tablets that meet the KP standards have been formed); and

[0201] 8) Step of manufacturing the final tablet by performing moisture-proof coating using a coating machine.

[0202]

[0203] The F2 prescription tablets manufactured through the above steps were tested for content, dissolution, and degree of flexible substances to confirm whether the tablets had appropriate quality characteristics.

[0204]

[0205] 4-2: Process test results for granules and tablets manufactured on a pilot scale

[0206] It was confirmed that the color of the granules manufactured on a pilot scale remained white, and the flowability of the sieved granules was also "Passable," confirming that they had flowability suitable for mass-production of tablets (Table 11).

[0207]

[0208]

[0209]

[0210] As a result of manufacturing tablets using a tablet machine (Rotary Tableting Machine) on a pilot scale, it was confirmed that the disintegration time and friability of the tablets met the standards of the Pharmacopoeia (KP) (Table 12).

[0211]

[0212]

[0213]

[0214] A formulation uniformity test (to determine the content uniformity of the formulation) was performed on the mixture, tablet, and coated tablet after the coating process. The content uniformity of the mixture and formulation was determined using HPLC (High Performance Liquid Chromatography) analysis, and it was confirmed that KN510 was uniformly distributed within the mixture and formulation (Table 13).

[0215]

[0216]

[0217]

[0218]

[0219] In addition, as a result of performing a dissolution test on the uncoated tablet and the coated tablet in the same manner as the F2 tablet dissolution evaluation method of the above <Example 3-5>, it was confirmed that the coating did not affect the dissolution, as shown in Fig. 4 (n=4, approved product: dissolution rate of 75% or more within 45 minutes under pH 6.8 conditions).

[0220]

[0221] Example 5: Confirmation of stability issues in the first formulation

[0222] In order to perform a simple stability test of the first prescription tablet in the present invention, the pilot-scale F2 prescription tablet manufactured in the above Example <4-1> was stored in an acceleration chamber (temperature 40±2℃, humidity 75±5%) for 1 month and 3 months, and then the content and flexible substances were analyzed.

[0223]

[0224]

[0225]

[0226] As a result, as shown in Table 14 above, the amount of flexible substances increased in the first month, and when stored under accelerated conditions for three months, the amount of flexible substances increased and the content decreased. In addition, when the tablets stored in the actual acceleration chamber for one month were ground and the inside was inspected, it was confirmed that the powder's appearance changed from white to pink.

[0227] In the present invention, it was confirmed that the properties of KN510 changed and the amount of flexible material increased under accelerated conditions despite the application of a moisture-proof coating. Therefore, it was determined that additional formulations of substances capable of enhancing the stability of KN510 were necessary.

[0228]

[0229] Example 6: Improved formulation formulation and process study

[0230] To address the issues of the first-line tablet formulation, the present invention conducted a study on the formulation using calcium carbonate, which can act as a pH regulator. Furthermore, mannitol and lactose were utilized as excipients for tablet formulation, establishing a set of formulation candidates, as shown in Table 15 below.

[0231]

[0232]

[0233]

[0234] The manufacturing process was performed in the same manner as the manufacturing process of <Example 3-1> above, except that a pH regulator was added into the granulator before the granulation process.

[0235]

[0236]

[0237]

[0238] As a result of measuring the hardness, disintegration and friability of the tablets manufactured for each prescription, it was confirmed that the F'2 prescription, which mixed mannitol and lactose, formed a formulation that complies with the Pharmacopoeia (KP) standards, as shown in Table 16 above.

[0239]

[0240] Example 7: Improved formulation prescription_Pilot scale F'3 prescription and process setup

[0241] 7-1: Manufacturing of pilot-scale improved prescription (F'3)

[0242] In the present invention, a pilot-scale manufacturing test (F'3 formulation; 2,000 tablets or more) was conducted for the F'2 formulation containing calcium carbonate derived from the study of <Example 6-1> above. During the pilot-scale manufacturing test, a moisture-proof coating process was added to further enhance the stability of KN510 from external environments. The ingredients and contents of the improved pilot-scale formulation for the F'2 formulation are shown in Table 17 below.

[0243]

[0244]

[0245]

[0246] The pilot-scale manufacturing process for the F'2 formulation is as follows:

[0247] 1) A step of preparing a binding solution by dissolving a binding agent in a solvent;

[0248] 2) Step of mixing the main ingredient, excipients, pH regulator, solubilizer, and disintegrant in a high-speed mixer;

[0249] 3) A step of adding a binding solution to the mixture and performing granulation using a granulator;

[0250] 4) Step of drying granules using the fluid bed drying (FBG) method using Consigma-1 (at this time, the supply air temperature is set to 45℃ and the supply air amount is set to 60 ㎥ / h to 70 ㎥ / h);

[0251] 5) After drying, the LOD value is measured (LOD result: 0.46%), and then sieved through 18 Mesh;

[0252] 6) After adding the disintegrant and the lubricant sieved through 25 Mesh, the final mixing step is performed;

[0253] 7) A step of forming tablets (tablet shape: 8.5 mm round, concave) of appropriate size and hardness using a tablet machine (rotary tableting machine) (at this time, a process inspection is conducted to confirm whether tablets that meet the KP standards have been formed); and

[0254] 8) The step of manufacturing the final tablet by performing the first coating using a coating machine and then performing the second coating, which is a moisture-proof coating.

[0255]

[0256] The pilot-scale improved prescription (F'3 prescription) tablets for the F'2 prescription manufactured in the above steps were tested for content, dissolution, and degree of flexible substances to confirm whether the tablets had appropriate quality characteristics.

[0257]

[0258] 7-2: Process test results for granules and tablets manufactured on a pilot scale

[0259] As a result of conducting a process inspection on the tablets manufactured in step 7 of the manufacturing process of the above <Example 7-1>, it was confirmed that the disintegration time and friability of the tablets were within the standards of the Pharmacopoeia (KP) (Table 18).

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267] In addition, the results of the content test on the prepared coated tablets confirmed that uniform coated tablets were prepared with an average content of 100.46% (n=5; Table 19). The results of the dissolution test on the coated tablets confirmed that the average dissolution rate was 95% based on a dissolution time of 30 minutes, and the deviation value was also low (Table 20). Therefore, it was confirmed that the introduction of the coating process did not significantly affect the dissolution.

[0268]

[0269] 7-3: Simple stability test for improved prescription

[0270] Coated tablets with improved formulations were stored under accelerated conditions (temperature 40±2℃, humidity 75±5%) for 2 and 4 weeks, and then the content and flexible substances of the coated tablets were analyzed. As a comparison group, KN510 (Omeprazole) alone was stored under accelerated conditions (closed conditions), and the content and flexible substances were analyzed.

[0271]

[0272]

[0273]

[0274] As a result, as shown in Table 21 above, it was confirmed that similar flexible substances were exhibited as when KN510 was stored alone under accelerated conditions, and it was also confirmed that no problem of content deterioration occurred.

[0275]

[0276] Example 8: Final formulation and manufacturing process

[0277] 8-1: Manufacturing the final prescription tablets

[0278] In the present invention, the final formulation and manufacturing process were established based on the experimental results of the improved formulation of <Example 7> above (Tables 23 to 25).

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286] 8-2: Production and results of tablets for stability testing for final formulation

[0287] 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 26 below (Test No.: GR-22090).

[0288]

[0289]

[0290]

[0291] In the present invention, in order to increase the stability of KN510 tablets (30 mg) containing omeprazole, a tablet composition was designed using calcium carbonate, and it was confirmed that when mannitol and lactose were included as excipients, tablets suitable for disintegration, dissolution, and friability standards could be 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. Omeprazole (KN510, Omeprazole) as the main ingredient, its enantiomer or its pharmaceutically acceptable salt, Lactose Monohydrate and Mannitol as excipients, Hydroxypropylcellulose as a binder, Precipitated Calcium Carbonate as a pH adjuster Sodium Laruyl Sulfate as a solubilizer, Sodium Starch Glycolate as a disintegrant, A tablet composition comprising magnesium stearate as a lubricant; A composition for primary film coating comprising hydroxypropyl methylcellulose (HPMC); and A double-coated tablet composition comprising a composition for secondary film coating comprising polyvinyl alcohol (PVA).

2. In paragraph 1, A double-coated tablet composition comprising 24 mg to 36 mg of the above omeprazole, its enantiomer or its pharmaceutically acceptable salt, 60 mg to 90 mg of lactose, 60 mg to 90 mg of mannitol, 4.8 mg to 7.2 mg of hydroxypropyl cellulose, 120 mg to 180 mg of precipitated calcium carbonate, 2.4 mg to 3.6 mg of sodium lauryl sulfate, and 24 mg to 36 mg of sodium starch glycolate.

3. In the first paragraph, the composition for primary film coating comprising hydroxypropyl methylcellulose comprises 4.8 mg to 7.2 mg of omeprazole, its enantiomer or its pharmaceutically acceptable salt per 24 mg to 36 mg of omeprazole, A double-coated tablet composition, characterized in that the composition for secondary film coating containing the above polyvinyl alcohol contains 12.8 mg to 19.2 mg of omeprazole, its enantiomer or its pharmaceutically acceptable salt per 24 mg to 36 mg of omeprazole.

4. In paragraph 1, A double-coated tablet composition characterized in that the above double-coated tablet composition is a pharmaceutical composition for preventing or treating cancer.

5. Omeprazole (KN510, Omeprazole) as the main ingredient, its enantiomer or its pharmaceutically acceptable salt, Lactose Monohydrate and Mannitol as excipients, Hydroxypropylcellulose as a binder, Precipitated Calcium Carbonate as a pH adjuster Sodium Laruyl Sulfate as a dissolving agent, Sodium Starch Glycolate as a disintegrant, A tablet core containing magnesium stearate as a lubricant; A first coating layer surrounding the above-mentioned core and comprising hydroxypropyl methylcellulose; and A double-coated tablet comprising a second coating layer disposed on the first coating layer and containing polyvinyl alcohol.

6. In paragraph 5, A double-coated tablet characterized in that each unit tablet of the above-mentioned core contains 24 mg to 36 mg of omeprazole, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, 60 mg to 90 mg of lactose, 60 mg to 90 mg of mannitol, 4.8 mg to 7.2 mg of hydroxypropyl cellulose, 120 mg to 180 mg of precipitated calcium carbonate, 2.4 mg to 3.6 mg of sodium lauryl sulfate, 24 mg to 36 mg of sodium starch glycolate, and 1.6 mg to 2.4 mg of magnesium stearate.

7. In paragraph 5, The above double-coated tablet is characterized in that, when rotated for 15 minutes at a rotation speed of 100 rpm in 900 ml of a pH 6.8 dissolution test solution, the dissolution rate of omeprazole is 91 wt% to 98 wt%.

8. In paragraph 5, A double-coated tablet, characterized in that the above-mentioned core has a hardness of 5 to 20 kp, a disintegration time of less than 30 minutes, a degree of wear of 0 to 1 wt%, and an average mass of 359.9 mg to 382.1 mg.

9. In paragraph 5, A double-coated tablet characterized in that the above double-coated tablet is a pharmaceutical product for preventing or treating cancer. 10.(a) A step of preparing a binding solution by dissolving hydroxypropyl cellulose, a binding agent, in ethanol, a solvent; (b) the main ingredient omeprazole (KN510, Omeprazole), its enantiomer or its pharmaceutically acceptable salt, Excipients: Lactose Monohydrate and Mannitol; Precipitated Calcium Carbonate, a pH adjuster Sodium Laruyl Sulfate, a solubilizing agent, and A step of mixing sodium starch glycolate, a disintegrating agent, and then mixing it with the binding solution prepared in step (a) to prepare a granule; (c) A step of drying the granules of step (b) using a fluid bed drying (FBG) method and then sizing them to 15 to 20 meshes; (d) a step of sieving sodium starch glycolate, a disintegrant, and magnesium stearate, a lubricant, through a 22 to 27 mesh, and then mixing them with the granules established in step (c); (e) a step of manufacturing a tablet core (tablet) by pressing the mixture of step (d); (f) a step of manufacturing a coated tablet by first coating the core of step (e) with a first coating solution containing hydroxypropyl methylcellulose; and (g) A method for manufacturing a double-coated tablet, comprising: a step of manufacturing a double-coated tablet by first coating the coated tablet of step (f) with a second coating solution containing polyvinyl alcohol; 11. In paragraph 10, A method for manufacturing a double-coated tablet, characterized in that it comprises 24 mg to 36 mg of the above omeprazole, its enantiomer or its pharmaceutically acceptable salt, 60 mg to 90 mg of lactose, 60 mg to 90 mg of mannitol, 4.8 mg to 7.2 mg of hydroxypropyl cellulose, 120 mg to 180 mg of precipitated calcium carbonate, 2.4 mg to 3.6 mg of sodium lauryl sulfate, and 24 mg to 36 mg of sodium starch glycolate.

12. In paragraph 10, A method for manufacturing a double-coated tablet, characterized in that the step (c) is performed under the conditions of a supply air temperature of 30℃ to 70℃ and a supply air amount of 40 ㎥ / h to 70 ㎥ / h.

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