KR102595702B1 - Pharmaceutical composite formulation and method of preparing pharmaceutical composite formulation - Google Patents

Abstract

In the pharmaceutical combination preparation and method for producing the same according to the present invention, the pharmaceutical combination preparation includes a first layer containing fimasartan, a pharmaceutically acceptable salt thereof, a solvate or hydrate thereof, and additives as an active ingredient; and a second layer containing at least one active ingredient and an additive, and the difference in disintegration time between the first layer and the second layer is 1 minute and 30 seconds or more and less than 7 minutes. Accordingly, it is possible to provide a pharmaceutical combination preparation containing two or more active ingredients that has both effectiveness and safety and improved convenience of taking medication.

Description

Pharmaceutical complex preparation and manufacturing method {PHARMACEUTICAL COMPOSITE FORMULATION AND METHOD OF PREPARING PHARMACEUTICAL COMPOSITE FORMULATION}

The present invention relates to a pharmaceutical combination preparation and a manufacturing method, and more specifically, to a pharmaceutical combination preparation and a manufacturing method containing fimasartan as an active ingredient.

For high blood pressure, it is important to maintain blood pressure within a normal range rather than treating the blood pressure itself to prevent life-threatening cardiovascular complications such as coronary artery disease such as stroke, heart failure, and myocardial infarction, and renal failure. It is important to control blood pressure. Because blood pressure medications require long-term use, care must be taken when choosing a treatment drug. Therefore, in order to maintain constant blood pressure over a long period of time, it is necessary to reduce side effects that may occur due to long-term drug use by using drugs with different mechanisms in combination and reducing the amount of single drug used through combined administration rather than selecting one drug. there is.

In order to more effectively treat cardiovascular diseases, including high blood pressure, combination preparations with different mechanisms of action as described above can be considered. However, in this case, there is a problem affecting the dissolution of each active ingredient due to mutual interference of each ingredient. It can happen.

Fimasartan (Korean Patent No. 10-1058284), known as a blood pressure lowering agent of the Angiotensin II Receptor Blocker (ARB) series developed to treat high blood pressure and other medical conditions, is 2-n-butyl-5-dimethyl Aminothiocarbonylmethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidin-4(3H)-one, molecularly and chemically It is a non-peptide described, its empirical formula is C ₂₇ H ₃₀ N ₇ O _S and its molecular weight is 501.65.

Kanarb ^® , which is commercially available as a single fimasartan preparation with product approval, has low solubility at low pH (e.g., pH 1.2 to pH 1.4), but when it is combined with other pharmacologically active ingredients, the dissolution rate is lower than that of the single preparation. There is a problem that may result in a lower dissolution rate.

For the treatment of high blood pressure, a combination of amlodipine, a calcium channel blocker, and ARB class drugs is being actively studied, and many studies are being conducted on the combination treatment of ARB class drugs and hydrochlorothiazide, a diuretic, or two or more types of ARB class drugs. are in progress. In these two-component combination preparations, combination preparations that contain fimasartan as an ARB class drug and have confirmed efficacy and safety are being approved and sold. Fimasartan-based combination preparations approved and sold include Ducarb ^® tablets, which are a combination of fimasartan and amlodipine, and Tubero ^® tablets, a combination of fimasartan and rosuvastatin.

In order to effectively treat diseases and improve the convenience of taking medication, the development of two-component combination preparations combining fimasartan and new drug ingredients, and furthermore, complex preparations of various combinations of three and four components, is required. However, fimasartan If a new drug ingredient is combined with Sartan, or if another drug is added as a third ingredient even in a two-component combination drug whose effectiveness has already been confirmed, the dissolution rate of fimasartan may decrease due to another interaction. .

One object of the present invention is to provide a pharmaceutical combination preparation containing two or more active ingredients that exhibits excellent dissolution characteristics and pharmacological effects while improving medication convenience.

Another object of the present invention is to provide a method for producing the above pharmaceutical combination preparation.

A pharmaceutical combination preparation for one purpose of the present invention includes a first layer containing fimasartan, a pharmaceutically acceptable salt thereof, a solvate or hydrate thereof, and additives as an active ingredient; and a second layer containing at least one active ingredient and an additive, and the difference in disintegration time between the first layer and the second layer is 1 minute and 30 seconds or more and less than 7 minutes.

In the present invention, “disintegration time” means the time it takes for the solid preparation to completely disintegrate in the test solution. Disintegration time is measured according to the Korean Pharmacopoeia disintegration test method. The test liquid defining the disintegration time may be water.

In one embodiment, the difference in disintegration time between the first layer and the second layer may be 1 minute 30 seconds or more and 6 minutes 40 seconds or less.

In one embodiment, the disintegration time of the first layer may be more than 2 minutes and less than 7 minutes and 15 seconds. At this time, the disintegration time of the second layer may be 15 seconds or more and 30 seconds or less.

In one embodiment, the disintegration time of the first layer may be 2 minutes or more and 7 minutes or less. At this time, the disintegration time of the second layer may be 15 seconds or more and 30 seconds or less.

In the composite formulation of the present invention, the disintegration time difference between the first layer and the second layer is 1 minute and 30 seconds or more and less than 7 minutes, thereby providing a composite formulation that exhibits excellent dissolution characteristics of the active ingredient. Under the condition that the difference in disintegration time between the first layer and the second layer is 1 minute and 30 seconds or more but less than 7 minutes, an excellent final dissolution rate of fimasartan can be realized without the fimasartan of the first layer being interfered with by the active ingredient of the second layer. You can. Additionally, the difference in disintegration time between the first and second layers of the composite preparation according to the present invention does not affect the dissolution results of the active ingredient in the second layer. Accordingly, the combination preparation of the present invention exhibits excellent dissolution and pharmacological effects and has improved medication convenience.

In one embodiment, the content of the active ingredient in the first layer per unit dosage form of the pharmaceutical combination preparation may be 30 mg to 70 mg. For example, the content of the active ingredient in the first layer per unit dosage form of the pharmaceutical combination preparation may be 30 mg to 40 mg, or 60 mg to 70 mg. In one embodiment, the pharmaceutical combination preparation may contain 30 mg to 70 mg, 30 mg to 40 mg, or 60 mg to 70 mg of pimasartan potassium trihydrate per unit dosage form. For example, the pharmaceutical combination preparation may contain 30 mg or 60 mg of fimasartan potassium per unit dosage form.

Fimasartan according to the present invention may be a compound represented by the following formula (1).

<Formula 1>

The pharmaceutically acceptable salt of fimasartan according to the present invention refers to a salt commonly used in the pharmaceutical industry and is not particularly limited. For example, pharmaceutically acceptable salts include inorganic ionic salts made of calcium, potassium, sodium, or magnesium; Inorganic acid salts made from hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodic acid, perchloric acid, tartaric acid, or sulfuric acid; Acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, fumaric acid, manderic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, Organic acid salts prepared from ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, mandelic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, or succinic acid; Sulfonic acid salts made from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, or naphthalenesulfonic acid; Amino acid salts made from glycine, arginine, or lysine; Alternatively, it may include an amine salt prepared from trimethylamine, triethylamine, ammonia, pyridine, or picoline.

The hydrate of fimasartan or a pharmaceutically acceptable salt thereof according to the present invention may be monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, etc.

The solvate of fimasartan or a pharmaceutically acceptable salt thereof of the present invention may contain a stoichiometric or non-stoichiometric amount of solvent bound by intermolecular forces.

The first layer may include fimasartan potassium trihydrate.

Additives of the first layer may include excipients, binders, disintegrants, lubricants, coating agents, etc. In addition, the pharmaceutical complex preparation of the present invention can be formulated using various pharmaceutically acceptable additives selected from surfactants, emulsifiers, colorants, and flavorings, and the additives can be formulated to contain a dosage within the normal range by selection. You can.

Excipients may include microcrystalline cellulose, silicified microcrystalline cellulose, mannitol, sucrose, lactose, sorbitol, xylitol, glucose, precipitated calcium carbonate, or a combination of two or more thereof.

Binders include glucose syrup, polyvinylpyrrolidone, polyethylene glycol 6000, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, gelatin, povidone, starch. , pregelatinized starch (pregelatinized starch), or a combination of two or more of these.

Disintegrants include starches or modified starches such as sodium starch glycolate, corn starch, potato starch, or pregelatinized starch (pregelatinized starch); Clays such as bentonite, montmorillonite, or veegum; Cellulose such as low-substituted hydroxypropyl cellulose; Cross-linked cellulose such as croscarmellose sodium; Gums such as guar gum and xanthan gum; Cross-linked polymers such as crospovidone; It may contain effervescent agents such as sodium bicarbonate and citric acid, or a combination of two or more thereof.

Lubricants include calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate. , talc, or a combination of two or more of these.

The coating agent may include polyvinyl alcohol, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, polyvinyl acetate, polyethylene glycol, titanium dioxide, iron oxide, etc., brand name ^Opadry® , or a combination of two or more thereof.

In one embodiment, the additive of the first layer may include at least one selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, pregelatinized starch, and low-substituted hydroxypropylcellulose.

In one embodiment, the first layer may include fimasartan granules including fimasartan, a pharmaceutically acceptable salt thereof, a solvate or hydrate thereof, and a first disintegrant, and a second disintegrant. The first and second disintegrants may be the same or different from each other. The first and second disintegrants may each independently be at least one selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, pregelatinized starch, and low-substituted hydroxypropyl cellulose.

In one embodiment, the dissolution rate of the active ingredient in the first layer may be 30% or more and 70% or less.

In one embodiment, the dissolution rate of the active ingredient in the first layer may be 34% or more and 65% or less, and specifically, may be 34.6% or more and 64.6% or less. At this time, the dissolution rate may mean the final dissolution rate in a pH 1.2 test solution.

The active ingredient of the second layer may include a calcium channel blocker, an HMG-CoA reductase inhibitor, or a diuretic, and these may be used alone or in combination of two or more.

The calcium channel blockers include nifedipine, nimodipine, nilvadipine, manidipine, barnidipine, nitrendipine, benidipine, nicardipine, lercanidipine, amlodipine, nisoldipine, eponidipine, cilnidipine, and azelnidipine. , felodipine, aranidipine, or pranidipine, and may include pharmaceutically acceptable salts thereof, hydrates thereof, or solvates thereof, each of which may be used alone or in combination of two or more. can be used

At this time, each of the pharmaceutically acceptable salts, hydrates, and solvates of the calcium channel blocker is substantially the same as that described for each of the salts, hydrates, and solvates of fimasartan, so overlapping descriptions will be omitted.

Examples of the HMG-CoA reductase inhibitor include rosuvastatin, atorvastatin, pitavastatin, pravastatin, simvastatin, or lovastatin, and pharmaceutically acceptable salts, hydrates, or solvates thereof. It may include, and these may be used alone or in combination of two or more.

At this time, each of the pharmaceutically acceptable salts, hydrates, and solvates of the HMG-CoA reductase inhibitor is substantially the same as that described for each of the salts, hydrates, and solvates of fimasartan, so overlapping descriptions will be omitted.

The diuretics may include chlorothiazide, hydrochlorothiazide, chlorthalidone, indapamide, etc.

In one embodiment, the active ingredient of the second layer is amlodipine, a pharmaceutically acceptable salt thereof, or a hydrate thereof; Atorvastatin, a pharmaceutically acceptable salt or hydrate thereof; and hydrochlorothiazide, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

In one embodiment, the active ingredient of the second layer may include amlodipine, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

In one embodiment, the active ingredient of the second layer is amlodipine, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof; and hydrochlorothiazide.

The second layer may include amlodipine besylate and hydrochlorothiazide.

In one embodiment, the active ingredient of the second layer may include atorvastatin, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof as an HMG-CoA reductase inhibitor.

In one embodiment, the pharmaceutical combination preparation may contain 6 to 14 mg of amlodipine besylate as an active ingredient in the second layer per unit dosage form. Alternatively, per unit dosage form of the pharmaceutical combination preparation, the active ingredient of the second layer may include 5 mg to 10 mg of amlodipine.

For example, the pharmaceutical combination preparation may contain 12.5 mg to 25 mg of hydrochlorothiazide as an active ingredient in the second layer per unit dosage form.

For example, per unit dosage form of the pharmaceutical combination preparation, the active ingredient of the second layer may include 10 to 50 mg of atorvastatin calcium trihydrate. Alternatively, the pharmaceutical combination preparation may contain 10 to 40 mg of atorvastatin per unit dosage form.

Additives of the second layer may include excipients, binders, disintegrants, lubricants, coating agents, etc. Since the additives of the second layer are substantially the same as those described for the additives of the first layer, overlapping descriptions will be omitted. The additives included in the second layer may be the same as or different from the additives included in the first layer.

In one embodiment, the second layer comprises amlodipine, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, hydrochlorothiazide, microcrystalline cellulose, pregelatinized starch, hydroxypropylcellulose, sodium starch glycolate, and stearate. May contain magnesium acid.

In one embodiment, the second layer is atorvastatin, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof, precipitated calcium carbonate, lactose hydrate, microcrystalline cellulose, polysorbate 80, croscarmellose sodium, hydroxide. It may contain oxypropylcellulose and magnesium stearate.

A pharmaceutical combination preparation for one purpose of the present invention includes a first layer containing fimasartan, a pharmaceutically acceptable salt thereof, a solvate or hydrate thereof, and additives as an active ingredient; and a second layer comprising amlodipine, a pharmaceutically acceptable salt or hydrate thereof, hydrochlorothiazide, a pharmaceutically acceptable salt or hydrate thereof, and additives, wherein the first layer and the second layer include The difference in disintegration time is between 1 minute and 30 seconds and less than 7 minutes.

A pharmaceutical combination preparation for one purpose of the present invention includes a first layer containing fimasartan, a pharmaceutically acceptable salt thereof, a solvate or hydrate thereof, and additives as an active ingredient; and a second layer containing atorvastatin, a pharmaceutically acceptable salt or hydrate thereof, and additives, wherein the difference in disintegration time between the first layer and the second layer is 1 minute and 30 seconds or more and less than 7 minutes. .

The pharmaceutical combination preparation according to the present invention may be a solid preparation and may be in the form of tablets. At this time, the tablet refers to a compressed pharmaceutical dosage form of all shapes and sizes, and the pharmaceutical combination preparation according to the present invention may include a double-layer tablet. A double-layer tablet refers to a complex preparation in which the compartments are separated and each component exists independently in each layer without mixing. Double-layer tablets may be coated, and pharmaceutical combination preparations may include a coating layer.

The method for producing a pharmaceutical combination preparation according to the present invention,

(a) preparing a first mixture by mixing fimasartan, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, and additives;

(b) preparing a second mixture by mixing at least one active ingredient and additives; and

(c) comprising the step of preparing a composite preparation by compressing the first mixture and the second mixture into tablets,

The composite preparation includes a first layer containing the first mixture and a second layer containing the second mixture, and the difference in disintegration time between the first layer and the second layer is 1 minute and 30 seconds or more. Less than a minute.

Double-layer tablets can be coated. Conventional methods can be used as the coating method, examples of which include pan coating, induced layer coating, or compression coating.

The active ingredient of the second mixture may include an HMG-CoA reductase inhibitor, a calcium channel blocker, or a diuretic, and these may be used alone or in combination of two or more.

The first mixture may include fimasartan granules including fimasartan, a pharmaceutically acceptable salt thereof, a solvate or hydrate thereof, a first disintegrant, and a second disintegrant. The first and second disintegrants may be the same or different from each other.

Preparing the first mixture includes preparing fimasartan granules containing fimasartan, a pharmaceutically acceptable salt thereof, a solvate or hydrate thereof, and a first disintegrant; And it may include mixing the fimasartan granules with a second disintegrant. Other additives may be further mixed with the second disintegrant. The first and second disintegrants may each independently be at least one selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, pregelatinized starch, and low-substituted hydroxypropyl cellulose.

According to the pharmaceutical complex preparation and manufacturing method of the present invention, it is possible to provide a complex preparation showing excellent dissolution characteristics of the active ingredient by controlling the difference in disintegration time between the first layer and the second layer of the complex preparation. Under the condition that the difference in disintegration time between the first layer and the second layer is 1 minute and 30 seconds or more but less than 7 minutes, an excellent final dissolution rate of fimasartan can be realized without the fimasartan of the first layer being interfered with by the active ingredient of the second layer. You can. Additionally, the difference in disintegration time between the first and second layers of the composite preparation according to the present invention does not affect the dissolution results of the active ingredient in the second layer. Accordingly, the combination preparation of the present invention exhibits excellent dissolution and pharmacological effects and has improved medication convenience.

Hereinafter, embodiments of the present invention will be described in detail. Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by a person of ordinary skill in the technical field to which the present invention pertains. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with the meaning in the context of the related technology, and unless explicitly defined in the present application, should not be interpreted in an ideal or excessively formal sense. No.

Preparation Examples 1(1) to 1(37) - Preparation of granules containing fimasartan as an active ingredient

In each of Preparation Examples 1 (1) to 1 (37), fimasartan granules were manufactured by adjusting the amount of each ingredient included in the first layer per unit dosage form (mg/tablet) as shown in Table 1 below. The total amount of ingredients constituting the first layer per unit dosage form is 150 mg/tablet when using Preparation Examples 1 (1) to 1 (34), and 75 mg when using Preparation Examples 1 (35) to 1 (37). /tablet.

Specifically, fimasartan potassium trihydrate, lactose hydrate, microcrystalline cellulose, and the first disintegrant were mixed for about 5 minutes, then placed in a fluid bed granulator and mixed for about 2 minutes. Separately, hydroxypropyl cellulose was added to purified water to prepare a binding solution.

The prepared binding solution was wet-granulated using a fluidized bed granulator and then dried. The dried granules were sized using a sizing machine. A second disintegrant was added to the sized product and mixed in a bin-type mixer for about 10 minutes. , Magnesium stearate was added and mixed for about 5 minutes to prepare each fimasartan granule according to Preparation Examples 1 (1) to 1 (37).

In Table 1 below, among the first and second disintegrants, CCS refers to croscarmellose sodium, CP refers to crospovidone, SSG refers to sodium starch glycolate, and L-HPC refers to low-substituted hydroxypropyl. It means cellulose.

[Table 1]

Preparation Example 2 (1) and (2) - Preparation of granules containing amlodipine and hydrochlorothiazide as active ingredients

In Preparation Example 2, amlodipine/hydrochlorothiazide granules (1) and (2) were prepared by determining the amount (mg/tablet) of each component included in the second layer per unit dosage form as shown in Tables 2 and 3 below. .

Specifically, amlodipine besylate, hydrochlorothiazide, microcrystalline cellulose, pregelatinized starch, and sodium starch glycolate were mixed for 5 minutes, and then the mixture was placed in a high shear mixer and mixed for 5 minutes.

Separately, hydroxypropyl cellulose was added to purified water to prepare a binding solution.

The prepared binding solution was wet-granulated with the mixture prepared above using a high-speed granulator and then dried. The dried granules were sized using a sizing machine. Magnesium stearate was added to the sized product and mixed for about 5 minutes to form amlodipine. /Hydrochlorothiazide granules (1) and (2) were prepared, respectively.

[Table 2]

[Table 3]

Preparation Example 3 - Preparation of granules containing atorvastatin as an active ingredient

After mixing atorvastatin calcium trihydrate, precipitated calcium carbonate, lactose hydrate, microcrystalline cellulose, and polysorbate 80 for about 10 minutes, the mixture was placed in a high shear mixer and mixed for about 3 minutes.

Separately, hydroxypropyl cellulose was added to purified water to prepare a binding solution.

The prepared binding solution was wet-granulated with the mixture prepared above using a high-speed granulator and then dried, and the dried granules were sized using a sizing machine. Croscarmellose sodium was added to the sized product and mixed in a bin-type mixer for about 20 minutes. After mixing for 5 minutes, additional magnesium stearate was added and mixed for about 5 minutes to prepare atorvastatin granules.

In Preparation Example 3, atorvastatin granules were manufactured by determining the amount (mg/tablet) of each ingredient included in the second layer per unit dosage form as shown in Table 4 below.

[Table 4]

Example 1 - Preparation of bilayer tablet

The fimasartan granules obtained according to Preparation Example 1 (3) and the amlodipine/hydrochlorothiazide granules (1) obtained according to Preparation Example 2 (1) were placed in the punch die of a multi-layer tablet press (Korsch) for 5 to 15 minutes. Two-layer tablets were manufactured by tableting with a tableting pressure of kN to have a hardness of 5 to 20 kp. The contents of the components included in the double-layer tablet per unit dosage form are shown in Tables 1 and 2.

Examples 2 to 24 - Preparation of bilayer tablets

Two-layer tablets were prepared using fimasartan granules obtained according to Preparation Examples 1 (4) to 1 (25) and 1 (31) and amlodipine / hydrochlorothiazide granules (1) obtained according to Preparation Example 2 (1), respectively. did. The contents of the ingredients included in the double-layer tablets per unit dosage form are shown in Tables 1 and 2.

Example 25 - Preparation of bilayer tablet

A bilayer tablet was prepared using fimasartan granules obtained according to Preparation Example 1 (37) and amlodipine/hydrochlorothiazide granules (2) obtained according to Preparation Example 2 (2). The contents of the components included in the double-layer tablet per unit dosage form are shown in Tables 1 and 3.

Example 26 - Preparation of bilayer tablet

A double-layer tablet was prepared using fimasartan granules obtained according to Preparation Example 1 (4) and atorvastatin granules obtained according to Preparation Example 3. The contents of the components included in the double-layer tablet per unit dosage form are shown in Tables 1 and 4.

Comparative Examples 1 to 10 - Preparation of double-layer tablets

Two-layer tablets were prepared using fimasartan granules obtained according to Preparation Examples 1 (1), 1 (2), 1 (26) to 1 (30), and 1 (32) to 1 (34), respectively. The contents of the ingredients included in the double-layer tablets per unit dosage form are shown in Tables 1 and 2.

Comparative Examples 11 and 12 - Preparation of double-layer tablets

A bilayer tablet was prepared using fimasartan granules obtained according to Preparation Example 1 (35) and Preparation Example 1 (36), respectively, and amlodipine/hydrochlorothiazide granules (2) obtained according to Preparation Example 2 (2). The contents per unit dosage form of the ingredients contained in the double-layer tablets are shown in Tables 1 and 3.

Comparative Example 13 - Preparation of double-layer tablet

A double-layer tablet was prepared using fimasartan granules obtained according to Preparation Example 1 (29) and atorvastatin granules obtained according to Preparation Example 3. The content per unit dosage form of the ingredients contained in the double-layer tablets is shown in Tables 1 and 4.

Test example - disintegration test

A disintegration test was conducted on the double-layer tablets according to Examples 1 to 26 and Comparative Examples 1 to 13. The disintegration time was measured according to the disintegration test method described in the General Test Methods of the Korean Pharmacopoeia (test solution: water, auxiliary plate: not used). As a result, the disintegration time of each of the first layer and the second layer and the difference between their disintegration times are shown in Table 5 below.

The disintegration time of the first layer and the disintegration time of the second layer refer to the time when both the first layer and the second layer are respectively disintegrated in the sample subject to the disintegration test.

[Table 5]

Characteristic evaluation - dissolution rate test of active ingredients

Each of the double-layer tablets according to Examples 1 to 26 was used to evaluate dissolution according to the dissolution test method described in the General Test Methods of the Korean Pharmacopoeia.

- Dissolution test solution: 1 solution (pH 1.2), 900 mL

- Test temperature: 37±0.5℃

- Test method: Korean Pharmacopoeia Dissolution Test Method 2 (Paddle Method), 50 revolutions per minute

- Dissolution test device: LABINDIA DS14000 SMART

- Sample collection time: 5, 10, 15, 30, 60 minutes

- Sample collection volume: 10 mL

- Filter: 0.45 um syringe filter

Experiment Result 1 - Final dissolution rate of fimasartan

The final dissolution rate of fimasartan in each of the two-layer tablets according to Examples 1 to 26 was measured in the dissolution test solution for 1 hour, and the results are shown in Table 6 below.

[Table 6]

Referring to Table 6, it can be seen that the final dissolution rates of fimasartan in each of Examples 1 to 26 were within the range of 30% to 70%. In particular, when compared to a composite formulation containing three or more active ingredients and having a final dissolution rate of fimasartan of 45% to 55%, specifically, a composite formulation having a fimasartan dissolution rate of 49% to 50%, it is better than this or is within a substantially equivalent range.

On the other hand, it can be seen that the final dissolution rate in Comparative Examples 3 to 10 and 13 is a significantly low level of only 20.8% at maximum. In addition, it can be seen that the dissolution rates of Comparative Examples 1, 2, 11, and 12 are very high, but this excessively high dissolution rate of fimasartan leads to safety problems, and the final dissolution rate of fimasartan is 45% to 55%, specifically 49%. Compared to complex preparations of % to 50%, it is not suitable as it corresponds to a pharmacologically different preparation.

In the case of a composite preparation containing 3 or more active ingredients and having a final dissolution rate of fimasartan of 45% to 55%, specifically 49% to 50%, the pharmaceutical equivalence test standards (No. 2020-91, 2020.09.22 , Article 7 Paragraphs 2 and 3), the dissolution test results of Examples 1 to 26 in Table 6 are comparative dissolution test results, and the final dissolution rate of fimasartan was 45% while containing 3 or more active ingredients. to 55%, specifically 49% to 50%, can be considered to have proven bioequivalence compared to complex preparations or are grounds for exemption from bioequivalence testing, while the preparations according to Comparative Examples 1 to 13 that deviate from the equivalence standard ultimately have It is a preparation that is not pharmacologically equivalent to a complex preparation with a final dissolution rate of fimasartan of 45% to 55%, specifically 49% to 50%, and is therefore unsuitable as a medicine.

Through Table 6, it can be seen that the final dissolution rate of fimasartan in the composite formulation does not depend on the disintegration time of the first layer, and the difference between the disintegration time of the first and second layers is 1 minute and 30 seconds or more. It was confirmed that an excellent final dissolution rate of fimasartan could be achieved without the fimasartan in the first layer being interfered with by the active ingredient in the second layer under conditions of less than a minute.

Experiment Result 2 - Dissolution rate of active ingredients in the second layer

In addition, from the results of the dissolution rate experiment, it can be seen that the final dissolution rate of amlodipine and hydrochlorothiazide in the double-layer tablet of Example 25 was 90% and 93.5%. In this way, it can be confirmed that the active ingredients of the second layer of the composite preparation according to the present invention also exhibit excellent dissolution characteristics. It was confirmed that the final dissolution rate of the active ingredients of the second layer in each of Comparative Examples 11 and 12 was at a similar level to that of the Examples. In other words, it can be confirmed that the difference in disintegration time between the first and second layers of the composite preparation according to the present invention does not affect the dissolution results of the active ingredient in the second layer.

Characterization evaluation - stability under accelerated conditions

The double-layer tablet according to Example 2 was prepared using 9.0 mg of Opadry (Colorcon), and the surface of the coated tablet was polished using 0.025 mg of carnaubanape. At this time, the obtained tablets were stored at 40 ± 2°C and relative humidity of 75 ± 5%, and the content of each active ingredient before and after was measured to compare changes in content. In addition, related substances were measured by analyzing with ultraviolet absorption spectroscopy using liquid chromatography (HPLC). The results are shown in Table 7 below.

[Table 7]

(ACB = 4-amino-6-chloro-1,3-benzenedisulfonamide)

Referring to Table 7, it can be seen that the double-layer tablet according to Example 2 of the present invention maintains the content of each ingredient even after 3 and 6 months, and generates almost no related substances. In other words, it can be confirmed that the double-layer tablet according to Example 2 of the present invention is stable against heat and moisture.

Although the present invention has been described above with reference to preferred embodiments, those skilled in the art can make various modifications and changes to the present invention without departing from the spirit and scope of the present invention as set forth in the following patent claims. You will understand that it is possible.

Claims (14)

A first layer containing fimasartan, a pharmaceutically acceptable salt thereof, a solvate or hydrate thereof, and additives as an active ingredient; and
As an active ingredient, amlodipine, a pharmaceutically acceptable salt or hydrate thereof; As an active ingredient, hydrochlorothiazide, a pharmaceutically acceptable salt or hydrate thereof; and a second layer comprising an additive,
The additive of the first layer includes at least one of croscarmellose sodium, crospovidone, sodium starch glycolate, pregelatinized starch, and low-substituted hydroxypropyl cellulose,
The additive of the second layer includes at least one of croscarmellose sodium, crospovidone, sodium starch glycolate, pregelatinized starch, and low-substituted hydroxypropyl cellulose,
The difference between the disintegration times of the first layer and the second layer in water is 1 minute and 30 seconds or more and less than 7 minutes,
refine. delete delete According to paragraph 1,
The dissolution rate of the active ingredient in the first layer is 34% or more and 65% or less in a pH 1.2 solution,
refine. According to paragraph 1,
The additives of the first layer are
Containing at least one of a disintegrant, a binder, an excipient, a lubricant, a coating agent, and mixtures thereof,
refine. delete According to paragraph 1,
The disintegration time of the first layer in water is more than 2 minutes and less than 7 minutes and 15 seconds,
The disintegration time of the second layer in water is 15 seconds or more and 30 seconds or less,
refine. delete delete (a) preparing a first mixture by mixing fimasartan, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, and additives;
(b) amlodipine, a pharmaceutically acceptable salt or hydrate thereof; Hydrochlorothiazide, a pharmaceutically acceptable salt or hydrate thereof; and mixing additives to prepare a second mixture; and
(c) comprising the step of compressing the first mixture and the second mixture into tablets,
The tablet comprises a first layer comprising the first mixture and a second layer comprising the second mixture,
The additive of the first layer includes at least one of croscarmellose sodium, crospovidone, sodium starch glycolate, pregelatinized starch, and low-substituted hydroxypropyl cellulose,
The additive of the second layer includes at least one of croscarmellose sodium, crospovidone, sodium starch glycolate, pregelatinized starch, and low-substituted hydroxypropyl cellulose,
The difference between the disintegration time of the first layer and the second layer in water is 1 minute and 30 seconds or more and less than 7 minutes,
Method of manufacturing tablets. In paragraph 1
the second layer comprising amlodipine besylate and hydrochlorothiazide,
refine. In paragraph 1
The tablet of claim 1, wherein the first layer comprises fimasartan potassium trihydrate. delete delete