Pharmaceutical combination preparation comprising telmisartan, (s)-amlodipine, and chlorthalidone

Abstract

The present invention relates to a pharmaceutical combination preparation comprising telmisartan, (S)-amlodipine, and chlorthalidone as active pharmaceutical ingredients. The present invention provides a pharmaceutical combination preparation capable of alleviating quality deterioration problems such as layer separation and content uniformity problems during the manufacturing or storage process due to the characteristics of three active pharmaceutical ingredients and the granular properties of each layer by using a pharmaceutical additive and controlling particle size of granules.

Description

PHARMACEUTICAL COMBINATION PREPARATION COMPRISING TELMISARTAN, (S)-AMLODIPINE, AND CHLORTHALIDONE

[0001] The present invention relates to a pharmaceutical combination preparation comprising telmisartan, (S)-amlodipine, and chlorthalidone as active pharmaceutical ingredients. The present invention provides a pharmaceutical combination preparation capable of alleviating quality deterioration problems such as layer separation and content uniformity problems during the manufacturing or storage process due to the characteristics of three active pharmaceutical ingredients and the granular properties of each layer by using a pharmaceutical additive as a layer separation prevention agent and controlling particle size of granules.

[0002] Hypertension refers to a condition in which blood pressure continues to remain above the normal range. Hypertension may cause various complications and eventually lead to death. Hypertension is classified into primary hypertension and secondary hypertension according to the cause of blood pressure increase. Primary hypertension is essential hypertension in which the cause of blood pressure increase is unknown, and secondary hypertension is hypertension in which blood pressure increase occurs as a result of a specific disease or illness. Secondary hypertension may be treated by identifying the cause of blood pressure increase, but primary hypertension, which accounts for approximately 95% of all hypertension, has an unknown cause, so treatment for patients with primary hypertension is performed with drug therapy based on several blood pressure lowering mechanisms.

[0003] Drugs commonly used for the treatment of hypertension include angiotensin converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARB), calcium channel blockers (CCB), and diuretics (DU), according to the mechanism of action of the drugs, and it has been reported that when two or more drugs are administered in combination, an effective hypertension treatment effect can be obtained.

[0004] ARB is the most commonly used single antihypertension therapy, and when blood pressure control with a single drug fails, a combination formulation of ARB and CCB, which have different mechanisms of action in the human body, is preferentially selected. When blood pressure is not adequately controlled with two-drug antihypertension regimen, three-drug regimen is used, and major academic societies in the field of hypertension, such as the European Society of Hypertension (ESH), the European Society of Cardiology (ESC), and the Japanese Society of Hypertension (JSH), recommend triple combination therapy of ARB, CCB, and DU as three-drug regimen.

[0005] Telmisartan, one of the ARBs, is sold under the trade name Micardis in 40 mg and 80 mg doses. Its chemical name is 4'-[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-ylmethyl]-biphenyl-2-carboxylic acid, and it has the structure represented by Chemical Formula 1 below.

[0006] [Chemical Formula 1]

[0007]

[0008] Telmisartan is prescribed for essential hypertension, and it inhibits the binding of angiotensin II and angiotensin receptor 1 (AT 1 receptor) in the renin-angiotensin-aldosterone system, thereby inhibiting aldosterone secretion and vasoconstriction and lowering blood pressure. In addition, the blood pressure-lowering effect lasts for 24 hours, so it is capable of stably controlling blood pressure until the morning when blood pressure rises sharply and stroke and cardiac arrest occur frequently. In addition, it has a low renal excretion rate, so it has the advantage of not requiring dose adjustment in patients with mild to severe renal impairment.

[0009] Amlodipine, one of the CCBs, is sold under the trade name Norvasc in 5 mg and 10 mg doses. Its chemical name is 3-O-ethyl 5-O-methyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate, and it has the structure represented by Chemical Formula 2 below.

[0010] [Chemical Formula 2]

[0011]

[0012] Amlodipine is a drug that lowers blood pressure by blocking calcium influx into vascular smooth muscles, thereby inducing peripheral arterial dilatation, and it is also effective in treating angina pectoris caused by spastic vasoconstriction. When administered orally, it is absorbed in the small intestine, and more than 40% is metabolized in the liver by the drug-metabolizing enzyme cytochrome P450 3A4, and only the remaining 60% is released into the blood, exerting a sufficient blood pressure-lowering effect.

[0013] This amlodipine is a chiral compound with an asymmetric carbon (chiral center), and the S-(-)-isomer of amlodipine is a compound represented by Chemical Formula 2-1 below and is known to exhibit higher activity than the isomer mixture (racemic form) as a potent CCB (Arrowsmith et al., J. Med. Chem., 29, 1696 (1986)). The (R)-enantiomer is 1000 times less active than the (S)-enantiomer and exhibits a kinin-mediated nitric oxide mechanism, which is thought to be related to side effects (Hintze et al., J. Cardiovasc. Pharmacol., 39(2):208-14 (2002)). Therefore, when the pure optical isomer, (S)-amlodipine, is separated and administered, it has the advantage of increasing the selectivity of receptor binding that shows the drug effect compared to the racemic amlodipine, and reducing the administration dose by about half, thereby reducing the possibility of drug interactions and side effects such as peripheral edema and fatigue. However, in terms of stability, (S)-amlodipine is considerably more unstable than its racemic counterpart, and it is experimentally known that (S)-amlodipine decomposes faster than the racemic counterpart and the amount of related substances due to the increase in decomposition products also increases. This is because the separated optical isomer form is thermodynamically unstable (Hadzidedic et al., J. Pharm. Dev. Technol., 19(8): 930.941 (2014)).

[0014] [Chemical Formula 2-1]

[0015]

[0016] Chlorthalidone is a DU, and it is currently sold under the trade name Hygroton. Its chemical name is benzenesulfonamide-2-chloro-5(2,3)-dihydro-hydroxy-3-oxo-1H-isoindol-1-yl), and it has the structure represented by Chemical Formula 3 below.

[0017] [Chemical Formula 3]

[0018]

[0019] Chlorthalidone is a thiazide-like drug that has demonstrated improved efficacy and duration of action with a longer half-life than that of the original diuretic thiazide drug. Chlorthalidone blocks the Na+ / Cl-cotransporter in the distal convoluted tubule, inhibits the absorption of Na+and Cl-, and increases the excretion of K+, thereby retaining water in the urine. Hypertension guidelines in Korea and other countries and the 2023 American Diabetes Association guidelines recommend chlorthalidone over the thiazide drug hydrochlorothiazide (HCTZ or HCT) when selecting a DU.

[0020] When a pharmaceutical composition in a single dosage form comprising three active pharmaceutical ingredients is formulated as described above, there is a problem that quality deterioration problems such as layer separation and content uniformity problems are likely to occur during the manufacturing or storage process due to the characteristics of the active pharmaceutical ingredients and the granular properties of each layer.

[0021] [Prior Art Documents]

[0022] [Non-patent Documents]

[0023] (Non-patent Document 1) Arrowsmith et al., J. Med. Chem., 29, 1696 (1986)

[0024] (Non-patent Document 2) Hintze et al., J. Cardiovasc. Pharmacol., 39(2):208-14 (2002)

[0025] (Non-patent Document 3) Hadzidedic et al., J. Pharm. Dev. Technol., 19(8): 930.941 (2014)

[0026] An object of the present invention is to solve the above-described problems, and when a single dosage form pharmaceutical composition comprising three active pharmaceutical ingredients of telmisartan, (S)-amlodipine, and chlorthalidone is formulated, a specific technical problem to be solved is to provide a pharmaceutical combination preparation in the form of a triple-layered tablet form in which each layer is separated so as to minimize the interaction between drugs in order not to damage the unique characteristics of each drug.

[0027] In order to achieve the above-described object, a means through pharmaceutical additives and granule particle size control is proposed.

[0028] The pharmaceutical combination preparation of the present invention is a triple-drug combination drug against hypertension and can be expected to increase the convenience of taking the medication for patients and effectively and strongly lower blood pressure.

[0029] To solve the above-described problems, the present invention discloses the following.

[0030] In one aspect, the present invention discloses a pharmaceutical combination preparation in a triple-layered tablet form, comprising: a first layer comprising telmisartan or a pharmaceutically acceptable salt thereof; a second layer comprising (S)-amlodipine or a pharmaceutically acceptable salt thereof, or a hydrate thereof; and a third layer comprising chlorthalidone or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical combination preparation comprises microcrystalline cellulose and colloidal silicon dioxide as a layer separation prevention agent in the second layer.

[0031] In another aspect, the present invention discloses a pharmaceutical combination preparation in a triple-layered tablet form, comprising: a first layer comprising telmisartan or a pharmaceutically acceptable salt thereof; a second layer comprising (S)-amlodipine or a pharmaceutically acceptable salt thereof, or a hydrate thereof; and a third layer comprising chlorthalidone or a pharmaceutically acceptable salt thereof, wherein the chlorthalidone or the pharmaceutically acceptable salt thereof is comprised in a granule form, and the granule of the chlorthalidone or the pharmaceutically acceptable salt thereof has a d90particle size in a range of 180 to 700 μm.

[0032] The pharmaceutical combination preparation according to the present invention has the advantage of preventing layer separation by comprising microcrystalline cellulose and colloidal silicon dioxide in an (S)-amlodipine layer and of reducing or suppressing layer separation by controlling the d90particle size of granules comprising chlorthalidone.

[0033] The pharmaceutical combination preparation according to the present invention simultaneously comprises active pharmaceutical ingredients of telmisartan, (S)-amlodipine, and chlorthalidone, and the dissolution pattern and pharmacokinetic (PK) profile of each active pharmaceutical ingredient are similar to the dissolution pattern and PK profile of the commercial preparation, Truset tablet 80 / 5 / 25 mg, at a level of ±10%, so that it can exhibit the same pharmacological effect as the commercial preparation.

[0034] The pharmaceutical combination preparation according to the present invention has the advantage of exhibiting excellent ability to withstand breakage of tablets due to excellent wear resistance compared to the commercial preparation.

[0035] The pharmaceutical combination preparation according to the present invention has the advantage of exhibiting high appearance stability under accelerated conditions (40 ℃, 75RH%) compared to the commercial preparation.

[0036] The pharmaceutical combination preparation according to the present invention has high formulation stability because there is almost no change in content, related substances, and dissolution stability under long-term conditions (room temperature), accelerated conditions (40 ℃, RH70%), and severe conditions (60 ℃), so it can be utilized as an effective combination preparation for the prevention or treatment of hypertension.

[0037] The effects of the present invention are not limited to the above-mentioned effects, and various effects may be comprised within a range obvious to those skilled in the art from the contents described below.

[0038] FIG. 1 shows the results of an evaluation of in vivo drug behavior (Experimental Example 3) of the commercial preparation (Truset Tablet 80 / 5 / 25 mg) of Comparative Example and a pharmaceutical combination preparation (tablet) in a triple-layered tablet form according to Example 4. (In FIG.1, 'Reference' means the Comparative Example (control drug, Truset tablet 80 / 5 / 25 mg), and 'Test' means the triple-layered tablet form pharmaceutical combination preparation according to Example 4.)

[0039] FIG. 2 shows the results of a comparative test (Experimental Example 4) on the friability of the commercial preparation (Truset Tablet 80 / 5 / 25 mg) of Comparative Example and a pharmaceutical combination preparation (tablet) in a triple-layered tablet form according to Example 4.

[0040] FIG. 3 shows the results of a comparative test (Experimental Example 5) on the appearance of the commercial preparation (Truset Tablet 80 / 5 / 25 mg) of Comparative Example and a pharmaceutical combination preparation (tablet) in a triple-layered tablet form according to Example 4.

[0041] Hereinafter, the present specification will be described in more detail.

[0042] The present specification is described in more detail as follows. The terms used herein are selected as general terms that are currently widely used as much as possible while considering the functions in the present invention, but they may vary depending on the intention or precedent of those of ordinary skill in the art, the emergence of new technology, or the like. In addition, in certain cases, there are terms arbitrarily selected by the applicant, and in this case, the meaning will be described in the corresponding part of the detailed description of the invention. Therefore, the terms used in the present invention should be defined based on the meaning of the terms and the overall content of the present invention, rather than simply the names of the terms.

[0043] Unless otherwise defined, all terms, comprising technical and scientific terms used herein, have the same meaning as generally understood by one of ordinary skill in the art to which the present invention pertains. Terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and are not interpreted in an idealized or overly formal sense unless clearly so defined in the present invention.

[0044] Numerical ranges are inclusive of the values defined therein. Every maximum numerical limitation given throughout the present specification includes every lower numerical limitation, as if such lower numerical limitations were expressly written. Every minimum numerical limitation given throughout the present specification includes every higher numerical limitation, as if such higher numerical limitations were expressly written. Every numerical limitation given throughout the present specification will include every better numerical range within the broader numerical range, as if the narrower numerical limitations were expressly written.

[0045] Hereinafter, each description and embodiment disclosed in the present invention may also be applied to other descriptions and embodiments for each. In other words, all combinations of various elements disclosed in the present invention fall within the scope of the present invention. In addition, the scope of the present invention may not be considered as being limited by the specific description described below.

[0046] Expressions such as "comprising" as used herein should be understood as open-ended terms implying the possibility of including other embodiments, unless specifically stated otherwise in the phrase or sentence in which the expression is included.

[0047] While performing research to develop a triple-combination preparation comprising telmisartan, (S)-amlodipine, and chlorthalidone as main ingredients, the present inventors recognized that quality deterioration problems such as layer separation and content uniformity problems occurred during the manufacturing or storage process due to the characteristics of the main ingredients and the granular properties of each layer.

[0048] In order to solve these problems, it was confirmed that layer separation can be prevented when microcrystalline cellulose and colloidal silicon dioxide, among various pharmaceutical additives, are used as layer separation prevention agents in the (S)-amlodipine layer, and layer separation can be reduced by controlling the d90particle size of granules comprising chlorthalidone. In addition, while resolving these problems, it was confirmed that the triple-combination preparation exhibits the same pharmacological effects as the commercial preparation by showing the dissolution pattern and pharmacokinetic (PK) profile of each active pharmaceutical ingredient at the level of ±10% of that of Truset tablet 80 / 5 / 25 mg, while exhibiting excellent ability to withstand breakage of the tablet by showing superior wear resistance compared to the commercial preparation, Truset tablet 80 / 5 / 25 mg, thereby completing the present invention.

[0049] Hereinafter, the present invention will be described in detail.

[0050] A telmisartan granule, an (S)-amlodipine granule, and a chlorthalidone granule are used herein with the same meanings as a telmisartan layer, an (S)-amlodipine layer, and a chlorthalidone layer.

[0051] Telmisartan herein may refer to telmisartan or a pharmaceutically acceptable salt thereof. Accordingly, a layer / granule comprising telmisartan herein may refer to a layer / granule comprising telmisartan or a pharmaceutically acceptable salt thereof.

[0052] (S)-amlodipine herein may refer to (S)-amlodipine or a pharmaceutically acceptable salt thereof, or a hydrate thereof. Accordingly, a layer / granule comprising (S)-amlodipine herein may refer to a layer / granule comprising (S)-amlodipine or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[0053] Chlorthalidone herein may refer to chlorthalidone or a pharmaceutically acceptable salt thereof. Accordingly, a layer / granule comprising chlorthalidone herein may refer to a layer / granule comprising chlorthalidone or a pharmaceutically acceptable salt thereof.

[0054] Pharmaceutical combination preparation

[0055] In order to solve the above problem, the present invention discloses the following means.

[0056] In one aspect, the present invention discloses a pharmaceutical combination preparation in a triple-layered tablet form, comprising: a first layer comprising telmisartan or a pharmaceutically acceptable salt thereof; a second layer comprising (S)-amlodipine or a pharmaceutically acceptable salt thereof, or a hydrate thereof; and a third layer comprising chlorthalidone or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical combination preparation comprises microcrystalline cellulose and colloidal silicon dioxide as a layer separation prevention agent in the second layer.

[0057] In another aspect, the present invention discloses a pharmaceutical combination preparation in a triple-layered tablet form, comprising: a first layer comprising telmisartan or a pharmaceutically acceptable salt thereof; a second layer comprising (S)-amlodipine or a pharmaceutically acceptable salt thereof, or a hydrate thereof; and a third layer comprising chlorthalidone or a pharmaceutically acceptable salt thereof, wherein the chlorthalidone or the pharmaceutically acceptable salt thereof is comprised in a granule form, and the granule of the chlorthalidone or the pharmaceutically acceptable salt thereof has a d90particle size in a range of 180 to 700 μm.

[0058] In the present invention, the term "telmisartan" refers to an angiotensin II receptor blocker (ARB) drug used for the treatment of essential hypertension represented by Chemical Formula 1 below. Its specific chemical name is 4'-[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-ylmethyl]-biphenyl-2-carboxylic acid.

[0059] [Chemical Formula 1]

[0060]

[0061] The telmisartan may be easily chemically synthesized and prepared by one of ordinary skill in the art using a known synthetic method and may also be purchased and used as a commercially manufactured product.

[0062] In the present invention, the term "(S)-amlodipine" refers to a compound represented by Chemical Formula 2-1 below, which is a calcium channel blocker (CCB) mainly used for the treatment of hypertension and angina pectoris. Its specific chemical name is 3-O-ethyl 5-O-methyl (4S)-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate.

[0063] [Chemical Formula 2-1]

[0064]

[0065] The (S)-amlodipine may be easily chemically synthesized and prepared by one of ordinary skill in the art using a known synthetic method and may also be purchased and used as a commercially manufactured product.

[0066] In the present invention, the term "chlorthalidone" refers to a compound represented by Chemical Formula 3 below, which is a thiazide-like drug that blocks the Na+ / Cl-cotransporter of the distal convoluted tubule, inhibits the absorption of Na+and Cl-, and increases the excretion of K+, thereby retaining water in the urine. Its specific chemical name is benzenesulfonamide-2-chloro-5(2,3)-dihydro-hydroxy-3-oxo-1H-isoindol-1-yl).

[0067] [Chemical Formula 3]

[0068]

[0069] The chlorthalidone may be easily chemically synthesized and prepared by one of ordinary skill in the art using a known synthetic method and may also be purchased and used as a commercially manufactured product.

[0070] In the present invention, the term "pharmaceutically acceptable salt" refers to a salt derived from a pharmaceutically acceptable acid or base. The pharmaceutically acceptable salt refers to any organic or inorganic addition salt that is relatively non-toxic and harmless to a patient at a therapeutically effective concentration, and whose side effects do not diminish the beneficial effects of the pharmacologically active pharmaceutical ingredient.

[0071] In the present invention, the term "hydrate" refers to a compound of the present invention or a pharmaceutically acceptable salt thereof comprising a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0072] Specifically, the pharmaceutically acceptable salt or hydrate thereof of (S)-amlodipine may be used in the form of hydrochloride, hydrobromide, sulfate, phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, or besylate, preferably (S)-amlodipine besylate, and the hydrate may be (S)-amlodipine besylate dihydrate, but is not limited thereto.

[0073] In the present invention, the terms "first," "second," "third," and the like do not specifically indicate the order but are simply intended to indicate that the meanings of the terms described below are different from each other.

[0074] In the present invention, telmisartan or a pharmaceutically acceptable salt thereof comprised in the first layer may be comprised in an amount of 40 to 80 mg based on a unit dosage form, but is not limited thereto.

[0075] In the present invention, (S)-amlodipine or a pharmaceutically acceptable salt thereof, or a hydrate thereof comprised in the second layer may be comprised in an amount of 2.5 to 5.0 mg based on a unit dosage form, and specifically, the pharmaceutically acceptable salt or a hydrate thereof of (S)-amlodipine may be comprised in an amount of 2.5 to 5.0 mg based on a unit dosage form as (S)-amlodipine, but is not limited thereto.

[0076] In the present invention, chlorthalidone or a pharmaceutically acceptable salt thereof comprised in the third layer may be comprised in an amount of 12.5 to 25 mg based on a unit dosage form, but is not limited thereto.

[0077] In the present invention, the second layer comprises microcrystalline cellulose and colloidal silicon dioxide as layer separation prevention agents, an at this time, the "layer separation prevention agent" refers to a pharmaceutical additive that prevents the separation of layers of a multilayered tablet comprising two or more active pharmaceutical ingredients during a storage process.

[0078] Specifically, the second layer comprises microcrystalline cellulose and colloidal silicon dioxide as layer separation prevention agents, and when only microcrystalline cellulose is comprised, the degree of occurrence of layer separation may be reduced, but when microcrystalline cellulose and colloidal silicon dioxide are combined, the colloidal silicon dioxide fills the gap between the layers and increases the bonding strength, thereby having the advantage of completely preventing layer separation.

[0079] In the present invention, the amount of the microcrystalline cellulose may be 50% to 95% by weight based on the total weight of the second layer, specifically 55% to 95% by weight, more specifically 85% to 95% by weight, but is not limited thereto.

[0080] In the present invention, the amount of the colloidal silicon dioxide may be 0.3% to 3% by weight based on the total weight of the second layer, specifically 1% to 3% by weight, more specifically 1.5% to 2.5% by weight, but is not limited thereto.

[0081] In the present invention, the second layer may further comprise magnesium stearate, and the amount of the magnesium stearate may be 0.3% to 3% by weight based on the total weight of the second layer, specifically 0.5% to 2.0% by weight, but is not limited thereto.

[0082] Specifically, when the second layer comprising (S)-amlodipine or a pharmaceutically acceptable salt thereof, or a hydrate thereof comprises less than 0.3% by weight of magnesium stearate as a lubricant, there is a problem of the occurrence of sticking, and when the second layer comprising (S)-amlodipine or a pharmaceutically acceptable salt thereof, or a hydrate thereof comprises more than 3% by weight of magnesium stearate, there is a problem of increased layer separation.

[0083] In the present invention, telmisartan or a pharmaceutically acceptable salt thereof, (S)-amlodipine or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and chlorthalidone or a pharmaceutically acceptable salt thereof may each be a granule form, and the pharmaceutical combination preparation may have a triple-layered tablet form by tableting each granule. In other words, the dosage form of the pharmaceutical combination preparation according to the present invention may be in a tablet form.

[0084] In the present invention, the granules of chlorthalidone or a pharmaceutically acceptable salt thereof may have a d90particle size of 180 to 700 μm, but is not limited thereto.

[0085] Specifically, the granules of chlorthalidone or a pharmaceutically acceptable salt thereof may have a d90particle size of 200 to 650 μm, 200 to 350 μm, or 230 to 250 μm, but is not limited thereto.

[0086] Specifically, when the d90particle size of the granules of chlorthalidone or a pharmaceutically acceptable salt thereof is below a lower limit of the numerical range, sticking occurs due to the low particle size during tableting, and issues such as poor flowability leading to reduced tabletability arise. When the d90particle size exceeds an upper limit of the numerical range, content non-uniformity occurs due to a deviation in particle size distribution during tableting.

[0087] In the present invention, the term "d10" refers to the particle size at the point where a cumulative volume is 10% in a cumulative particle size distribution, which also represents the diameter of particles corresponding to the lower 10% of the cumulative volume in the cumulative particle size distribution measured by a particle size analyzer. In addition, the terms "d50" and "d90" refer to the particle sizes at the points where a cumulative volume is 50% and 90% in a cumulative particle size distribution, which also represent the diameters of the particles corresponding to the lower 50% and 90% of the cumulative volume in the cumulative particle size distribution measured by a particle size analyzer. The particle size of the granules of chlorthalidone or a pharmaceutically acceptable salt thereof in the present invention is measured using a QICPIC-OASIS / L (manufacturer: Sympatec, Germany) with the following parameters: a measurement range of 5 to 1705 μm, a RODOS disperser, a dry dispersion system, a dispersion pressure of 1.0 bar, a shooting speed of 450 Hz per second, and volume average. Particle size distribution measuring devices are also commercially available from various suppliers such as Sympatec or Malvern Instruments Ltd.

[0088] Therefore, in order to solve the problems of the present invention, a second layer comprising (S)-amlodipine or a pharmaceutically acceptable salt thereof, or a hydrate thereof comprises microcrystalline cellulose and colloidal silicon dioxide as layer separation prevention agents, and a third layer comprising chlorthalidone or a pharmaceutically acceptable salt thereof, the d90particle size of which is adjusted to 180 to 700 μm, is comprised.

[0089] In the present invention, the telmisartan granules and chlorthalidone granules may be prepared by a wet granulation method, and the (S)-amlodipine granules may be prepared by a dry granulation method, but are not limited thereto. At this time, the wet granulation method and the dry granulation method may be methods widely known in the art.

[0090] In the present invention, the first layer, the second layer, and the third layer may comprise a pharmaceutical additive.

[0091] Specifically, the first layer comprising telmisartan or a pharmaceutically acceptable salt thereof may comprise 30% to 50% by weight of microcrystalline cellulose, 1.5% to 3% by weight of calcium silicate, 5% to 10% by weight of low-substituted hydroxypropyl cellulose, 7% to 14% by weight of dry sodium carbonate, 5% to 10% by weight of povidone, 0.5% to 1.5% by weight of colloidal silicon dioxide, and 0.5% to 1.5% by weight of magnesium stearate based on the total weight of the first layer, but is not limited thereto.

[0092] In addition, the second layer comprising (S)-amlodipine or a pharmaceutically acceptable salt thereof, or a hydrate thereof may further comprise sodium starch glycolate and pregelatinized starch in addition to microcrystalline cellulose and colloidal silicon dioxide as layer separation prevention agents and magnesium stearate as a lubricant, and the amount of sodium starch glycolate may be 0.3% to 3% by weight based on the total weight of the second layer, specifically 0.5% to 2.0% by weight, and the amount of pregelatinized starch may be 30% to 40% by weight based on the total weight of the second layer, but is not limited thereto.

[0093] In addition, the third layer comprising chlorthalidone or a pharmaceutically acceptable salt thereof may comprise 45% to 55% by weight of microcrystalline cellulose, 15% to 25% by weight of mannitol, 5% to 10% by weight of pregelatinized starch, 3% to 6% by weight of sodium starch glycolate, 2% to 10% by weight of povidone, 0.5% to 1.5% by weight of colloidal silicon dioxide, and 0.5% to 1.5% by weight of magnesium stearate based on the total weight of the third layer, and more specifically, 48% to 52% by weight of microcrystalline cellulose, 18% to 22% by weight of mannitol, 6% to 8% by weight of pregelatinized starch, 4% to 5% by weight of sodium starch glycolate, 2% to 4% by weight of povidone, 0.5% to 1.5% by weight of colloidal silicon dioxide, and 0.5% to 1.5% by weight of magnesium stearate based on the total weight of the third layer, but is not limited thereto.

[0094] In the present invention, the pharmaceutical combination preparation may be used for the prevention or treatment of hypertension, and the hypertension may be essential hypertension, but is not limited thereto.

[0095] Method of preventing or treating hypertension, comprising administering a therapeutically effective amount of the pharmaceutical combination preparation to a subject in need thereof

[0096] The present invention provides a method of preventing or treating hypertension, comprising administering a therapeutically effective amount of the pharmaceutical combination preparation to a subject in need thereof.

[0097] In the present invention, the hypertension may be essential hypertension but is not limited thereto.

[0098] The method of preventing or treating hypertension of the present invention comprises not only treating the disease itself before the onset of symptoms but also inhibiting or avoiding symptoms thereof by administering the pharmaceutical combination preparation. In managing a disease, the prophylactic or therapeutic dose of a particular active pharmaceutical ingredient may vary depending on the nature and severity of the disease or condition and the route of administration of the active pharmaceutical ingredient. The dose and the frequency of administration may vary depending on the age, weight, and response of the individual patient. Appropriate dose regimens may be easily selected by those skilled in the art who obviously take these factors into account. In addition, the method of preventing or treating hypertension of the present invention may further comprise administering a therapeutically effective amount of an additional active agent that is helpful in treating the disease together with the pharmaceutical combination preparation, and the additional active agent may exhibit a synergistic or adjuvant effect together with the pharmaceutical combination preparation.

[0099] Use of the pharmaceutical combination preparation for preparation of a drug for prevention or treatment of hypertension

[0100] The present invention provides use of the pharmaceutical combination preparation for the preparation of a drug for the prevention or treatment of hypertension.

[0101] The pharmaceutical combination preparation for the preparation of a drug may be mixed with acceptable adjuvants, diluents, carriers, and the like and may be prepared as a combination preparation with other active pharmaceutical ingredients to exhibit a synergistic effect of the active pharmaceutical ingredients.

[0102] Use of the pharmaceutical combination preparation for preparation of a pharmaceutical preparation having a preventive or treating effect on hypertension

[0103] The present invention provides a use of a pharmaceutical combination preparation for the preparation of a pharmaceutical preparation having a preventive or treating effect on hypertension.

[0104] All matters mentioned regarding the pharmaceutical combination preparation, the prevention or treatment method, and the use of the present invention equally apply unless they are inconsistent with each other.

[0105] Hereinafter, the present invention will be described in detail with reference to examples. However, the following examples are intended solely to illustrate the present invention and are not intended to limit the scope of the present invention.

[0106] Examples: Preparation of the pharmaceutical combination preparation

[0107] Example 1.

[0108] [Table 1]

[0109]

[0110] 1) Preparation of telmisartan granules (Reference Example 1)

[0111] ① Dry sodium carbonate, povidone, and telmisartan were added to purified water and heated to prepare binder solution A. Thereafter, calcium silicate was added to purified water and stirred to prepare binder solution B.

[0112] ② Microcrystalline cellulose was added to a fluid bed granulator, and binder solutions A and B were sprayed, dried, and sieved through a co-mill. Thereafter, low-substituted hydroxypropyl cellulose, colloidal silicon dioxide, and magnesium stearate were added and finally mixed to produce telmisartan granules.

[0113] 2) Preparation of (S)-amlodipine granules (Reference Example 2)

[0114] ① (S)-amlodipine besylate dihydrate, a portion of microcrystalline cellulose, a portion of sodium starch glycolate, and a portion of magnesium stearate were geometrically diluted in a mixing bowl and then slugged.

[0115] ② The slugged product was sieved through a co-mill, and then the remaining portion of microcrystalline cellulose, the remaining portion of sodium starch glycolate, the remaining portion of magnesium stearate, and colloidal silicon dioxide were added and finally mixed to prepare (S)-amlodipine granules.

[0116] 3) Preparation of chlorthalidone granules (Reference Example 3)

[0117] ① Povidone was added to purified water to prepare a binder solution. Thereafter, a mixture of chlorthalidone, a portion of microcrystalline cellulose, and a portion of pregelatinized starch was added and kneaded.

[0118] ② The kneaded product was granulated, then dried in a fluid bed granulation dryer, and subsequently sieved through a co-mill. The remaining portion of microcrystalline cellulose, the remaining portion of pregelatinized starch, mannitol, colloidal silicon dioxide, sodium starch glycolate, and magnesium stearate were added and finally mixed to prepare chlorthalidone granules.

[0119] At this time, the d90particle size of the chlorthalidone granules is shown in Table 2 below.

[0120] 4) Tableting

[0121] The telmisartan granules, (S)-amlodipine granules, and chlorthalidone granules were tableted to produce a triple-layered tablet form pharmaceutical combination preparation (tablet).

[0122] Example 2.

[0123] A triple-layered tablet form pharmaceutical combination preparation (tablet) was produced in the same manner as in Example 1, except that the telmisartan granules and (S)-amlodipine granules were the same as in Example 1, the amount of povidone as a binder in the chlorthalidone granules was increased to 12 mg, and the amount of microcrystalline cellulose as an excipient was reduced to 95 mg.

[0124] At this time, the d90particle size of the chlorthalidone granules is shown in Table 2 below.

[0125] Example 3.

[0126] A triple-layered tablet form pharmaceutical combination preparation (tablet) was produced in the same manner as in Example 1, except that the telmisartan granules and chlorthalidone granules were the same as in Example 1, the amount of microcrystalline cellulose as an excipient in the (S)-amlodipine granules was reduced to 86.81 mg, and 55 mg of pregelatinized starch was added.

[0127] At this time, the d90particle size of the chlorthalidone granules is shown in Table 2 below.

[0128] Example 4.

[0129] A triple-layered tablet form pharmaceutical combination preparation (tablet) was produced in the same manner as in Example 1, except that the telmisartan granules and chlorthalidone granules were the same as in Example 1, the amount of the colloidal silicon dioxide in the (S)-amlodipine granules was increased to 3.0 mg, and the amount of microcrystalline cellulose as an excipient was reduced to 140.31 mg.

[0130] At this time, the d90particle size of the chlorthalidone granules is shown in Table 2 below.

[0131] Example 5.

[0132] A triple-layered tablet form pharmaceutical combination preparation (tablet) was produced in the same manner as in Example 1, except that the telmisartan granules and (S)-amlodipine granules were the same as in Example 4, the amount of povidone as a binder in the chlorthalidone granules was increased to 12 mg, and the amount of microcrystalline cellulose as an excipient was reduced to 95 mg.

[0133] At this time, the d90particle size of the chlorthalidone granules is shown in Table 2 below.

[0134] Particle size of chlorthalidone granulesExamples 1, 3, and 4Examples 2 and 5d1047.8 ± 0.5 μm51.9 ± 1 μmd5091.3 ± 2.4 μm133.8 ± 6.9 μmd90247.9 ± 63.2 μm615.7 ± 144.6 μm

[0135] Comparative Example: Control drug setting

[0136] The control drug for Comparative Example was Truset tablets 80 / 5 / 25 mg. Hereinafter, the terms "Comparative Example," "control drug," and "commercial preparation" are used interchangeably.

[0137] Experimental Examples.

[0138] Experimental Example 1: Layer separation comparison test

[0139] 1. Experimental method

[0140] A friability tester was used to measure the interlayer bonding strength of the triple-layered tablet form pharmaceutical combination preparations according to Examples 1 to 5. Specifically, each of ten tablets were placed in a friability tester (SVM-102 (Pharma Test Apparatebau, GmbH, Germany)) and rotated 100 times at 25 rpm to observe the degree of tablet damage. When no layer separation occurred, the test was repeated up to a maximum of 500 times. When layer separation occurred or the edges of the layers were clearly detached, the number of damaged tablets was recorded, and the test was terminated. The results are shown in Table 3.

[0141] 2. Experimental results

[0142] Referring to Table 3, when the triple-layered tablet form pharmaceutical combination preparations according to Examples 1 and 2 were compared, layer separation was observed in both formulations. Layer separation increased in the triple-layered tablet form pharmaceutical combination preparation according to Example 2, which included a higher proportion of binder in the chlorthalidone layer. When the particle sizes of the chlorthalidone layers of the two formulations were compared, the d90of Example 1 was approximately 248 μm, while that of Example 2 was approximately 616 μm. These results suggest that the larger particle size of the chlorthalidone layer granules in the triple-layered tablet form pharmaceutical combination preparation according to Example 2 increased layer separation.

[0143] When the triple-layered tablet form pharmaceutical combination preparations according to Examples 1 and 3 were compared, a trend toward reduced layer separation was observed in the triple-layered tablet form pharmaceutical combination preparation according to Example 1, which included only microcrystalline cellulose as an excipient in the (S)-amlodipine layer without the addition of pregelatinized starch.

[0144] When the triple-layered tablet form pharmaceutical combination preparations of Examples 1 and 4 were compared, no layer separation occurred when colloidal silicon dioxide was added to the (S)-amlodipine layer. These results indicate that colloidal silicon dioxide filled interlayer voids, thereby increasing the bonding strength.

[0145] When the triple-layered tablet form pharmaceutical combination preparations of Examples 4 and 5 were compared, the colloidal silicon dioxide in the (S)-amlodipine layer increased the interlayer bonding strength, but the smaller the d90particle size of the chlorthalidone layer granules, the less layer separation occurred (d90particle size of the chlorthalidone layer granules of Example 4: approximately 248 μm; d90particle size of the chlorthalidone layer granules of Example 5: approximately 616 μm).

[0146] (The d90particle size of the chlorthalidone layer granules in Experimental Example 1 was measured using the above-described method.)

[0147] Evaluation of friability(rotation count)Tablets with layer separation (number of tablets tested: 10 tablets)Example 1Example 2Example 3Example 4Example 5100 rotations00000200 rotations03400300 rotations2--00400 rotations---02500 rotations---0-

[0148] Through Experimental Example 1 above, it was confirmed that when colloidal silicon dioxide is included in the (S)-amlodipine layer and the d90particle size of the chlorthalidone layer granules is relatively small, layer separation could be prevented in the triple-layered tablet form pharmaceutical combination preparations.

[0149] Accordingly, the following experiment was performed based on the formulation confirmed as the optimal formulation in Example 4.

[0150] Experimental Example 2: Dissolution profile comparison test

[0151] 1. Experimental method

[0152] A dissolution test was performed on the triple-layered tablet form pharmaceutical combination preparation according to Example 4 in accordance with the Korean Pharmacopoeia's Dissolution Test Method 1 (rotating basket method) under the same conditions as described in Table 4 below. The dissolution test was performed in three media having pH 1.2, pH 4.5, and pH 6.8. To compare dissolution rates, Yuhan Corporation's Truset Tablet 80 / 5 / 25 mg, a commercially available combination preparation of telmisartan, amlodipine, and chlorthalidone, was used as a control, and the dissolution test was performed under the same conditions. The dissolution test conditions for telmisartan, amlodipine, and chlorthalidone are shown in Table 4, and the dissolution results are shown in Tables 5 to 7 below.

[0153] ItemConditionDissolution testerAgilentDissolution mediumpH 1.2, pH 4.5, pH 6.8Sample volume900 mLRotation speed50 rpmAnalyzerUPLCColumnC18 columnMobile phasebuffer:ACN:MeOH = 5:3:2

[0154] 2. Experimental results

[0155] The dissolution test results of telmisartan are shown in Table 5 below.

[0156] Telmisartan5 min10 min15 min30 min45 min1 hr1.5 hr2 hrpH 1.2Comparative Example7.112.417.128.738.146.460.770.5Example 41.46.914.731.242.650.962.372.4pH 4.5Comparative Example0.00.71.64.06.99.412.815.2Example 40.11.83.19.714.315.115.416.6pH 6.8Comparative Example16.134.252.283.595.896.496.596.3Example 40.54.115.149.771.084.190.992.5

[0157] The dissolution test results of amlodipine are shown in Table 6 below.

[0158] Amlodipine5 min10 min15 min30 min45 min1 hr1.5 hr2 hrpH 1.2Comparative Example82.388.691.795.295.296.596.997.0Example 483.194.495.797.096.296.897.397.0pH 4.5Comparative Example77.486.188.190.990.390.991.791.2Example 469.484.987.990.590.491.491.992.1pH 6.8Comparative Example37.950.652.850.152.552.855.256.8Example 414.232.345.954.359.162.467.770.1

[0159] The dissolution test results of chlorthalidone are shown in Table 7 below.

[0160] Chlorthalidone5 min10 min15 min30 min45 min1 hr1.5 hr2 hrpH 1.2Comparative Example14.227.433.241.747.151.558.764.0Example 47.922.640.352.956.161.367.271.0pH 4.5Comparative Example12.632.039.649.556.360.667.673.5Example 414.434.140.349.755.158.965.170.1pH 6.8Comparative Example22.130.035.240.643.846.349.852.5Example 413.127.439.849.652.554.657.560.0

[0161] Through Tables 5 to 7 above, it was confirmed that the dissolution profile of telmisartan, (S)-amlodipine, and chlorthalidone of the triple-layered tablet form pharmaceutical combination preparation according to Example 4 obtained according to the present invention was similar to that of the commercially available preparation (Truset tablet 80 / 5 / 25 mg) at the level of ±10%.

[0162] Experimental Example 3: Evaluation of in vivo drug behavior

[0163] 1. Experimental method

[0164] The in vivo absorption of the comparative example (control drug, Truset tablet 80 / 5 / 25 mg) and the triple-layered tablet form pharmaceutical combination preparation (test drug) according to Example 4 was evaluated through a clinical trial. The clinical trial design is shown in Table 8 below.

[0165] [Table 8]

[0166]

[0167] Blood samples were collected from healthy adults at equivalent times after single administration of the drug of Comparative Example (control drug, Truset tablet 80 / 5 / 25 mg) and the triple-layered tablet form pharmaceutical combination preparation (test drug) according to Example 4. The blood concentrations of telmisartan, (S)-amlodipine, and chlorthalidone were each quantified using LC-MS / MS. After quantification, the area under curve (AUC) values of telmisartan, (S)-amlodipine, and chlorthalidone after administration of the drug of Comparative Example (control drug, Truset tablet 80 / 5 / 25 mg) and the triple-layered tablet form pharmaceutical combination preparation (test drug) according to Example 4 were log-transformed, and the geometric mean was calculated. The 90% confidence interval for the ratio of the geometric means was calculated. The results are shown in Table 9 and FIG. 1 below.

[0168] ClassificationPK ParameterTelmisartan(S)-AmlodipineChlorthalidone90% CIT / RJudgment90% CIT / RJudgment90% CIT / RJudgmentExample 4AUCt0.94 ~ 1.040.99Equivalent0.90 ~ 0.980.94Equivalent0.98 ~ 1.031.00EquivalentCmax1.03 ~ 1.28*1.15Equivalent0.94 ~ 1.030.98Equivalent1.04 ~ 1.211.12Equivalent*Permissible range for Telmisartan Cmax90% CI: 0.7396 - 1.3520

[0169] 2. Experimental results

[0170] Referring to Table 9 and FIG. 1, Comparative Example (control drug, Truset tablet 80 / 5 / 25 mg) and the triple-layered tablet form pharmaceutical combination preparation (test drug) according to Example 4 showed similar levels of area under the blood concentration curve (AUCt) and maximum blood concentration (Cmax), confirming that Comparative Example (control drug, Truset tablet 80 / 5 / 25 mg) and the triple-layered tablet form pharmaceutical combination preparation (test drug) according to Example 4 had similar pharmacokinetic behavior.

[0171] Experimental Example 4: Friability comparison test with commercial preparation

[0172] 1. Experimental method

[0173] A friability tester was used to measure the physical strength of the commercial preparation of Comparative Example (Truset tablet 80 / 5 / 25 mg) and the triple-layered tablet form pharmaceutical combination preparation according to Example 4. Specifically, ten tablets were each placed in the friability tester and rotated in 100 rotations at 25 rpm for four minutes to measure the degree of tablet damage. This test is regarded as an assessment of a tablet's ability to withstand breakage during packaging and transportation.

[0174] To measure friability, ten tablets of the commercial preparation of Comparative Example (Truset tablet 80 / 5 / 25 mg) and the triple-layer pharmaceutical combination preparation prepared in Example 4 were each placed in the friability tester (SVM-102 (Pharma Test Apparatebau, GmbH, Germany)) and in 100 rotations at 25 rpm for four minutes to measure the degree of tablet damage. To compare the friability, the tablets were tested up to 300 rotations under more severe conditions than conventional testing, and the results were recorded every 100 rotations. The measurement results are shown in Table 10 and FIG. 2 below.

[0175] 2. Experimental results

[0176] Referring to Table 10 and FIG. 2, the triple-layered tablet form pharmaceutical combination preparation according to Example 4 exhibited superior friability compared to the commercial preparation of Comparative Example (Truset tablet 80 / 5 / 25 mg). After 300 friability measurements, it was confirmed that the commercial preparation of Comparative Example (Truset tablet 80 / 5 / 25 mg) exhibited visible damage to the tablets, while the triple-layered tablet form pharmaceutical combination preparation according to Example 4 exhibited no visible damage.

[0177] Evaluation of friability(rotation count)Degree of tablet damage (number of tablets tested: 10 tablets)Comparative ExampleExample 41000.28%0.02%2000.71%0.03%3001.31%0.05%

[0178] Experimental Example 5: Appearance comparison test of with commercial preparation

[0179] 1. Experimental method

[0180] To compare the appearance of the commercial preparation of Comparative Example (Truset tablet 80 / 5 / 25 mg) and the triple-layered tablet form pharmaceutical combination preparation according to Example 4, an experiment was performed under accelerated conditions (40 ℃, 75 RH%). The commercial preparation of Comparative Example (Truset tablet 80 / 5 / 25 mg) and the triple-layered tablet form pharmaceutical combination preparation according to Example 4 were placed in HDPE bottles and placed under accelerated conditions (40 ℃, 75 RH%) for 72 hours without capping. The appearance of Comparative Example (commercial preparation) and the triple-layered tablet form pharmaceutical combination preparation according to Example 4 was observed, and the results are shown in FIG. 3.

[0181] 2. Experimental results

[0182] Referring to FIG. 3, the triple-layered tablet form pharmaceutical combination preparation according to Example 4 exhibited higher appearance stability compared to the commercial preparation of Comparative Example (Truset tablet 80 / 5 / 25 mg), and any changes in the appearance of the triple-layered tablet form pharmaceutical combination preparation according to Example 4 were hardly observed visually.

[0183] Experimental Example 6: Formulation stability test

[0184] 1. Experimental method

[0185] Samples of the triple-layered tablet form pharmaceutical combination preparation according to Example 4 were stored under three different conditions: long-term conditions (room temperature), accelerated conditions (40 ℃, RH70%), and severe conditions (60 ℃) conditions (storage periods are listed in Table 15 below). The content, related substances, and dissolution stability of each were evaluated to confirm the formulation stability. The test conditions are as follows: Table 11 (Content test conditions), Table 12 (Related substances test conditions), Table 13 (Dissolution test conditions: telmisartan and chlorthalidone), and Table 14 (Dissolution test conditions: (S)-amlodipine). The test results are shown in Table 15.

[0186] ItemConditionAnalyzerHPLCDiluentSodium hydroxide aqueous solution:Methanol = 1:1ColumnC18 columnMobile phasebuffer:ACN:MeOH = 5:3:2

[0187] ItemConditionAnalyzerHPLCDiluentSodium hydroxide aqueous solution:Methanol = 1:1ColumnC18 columnMobile phaseA) pH6.8:buffer:ACN = 95:5B) pH6.8:buffer:ACN = 5:95

[0188] ItemConditionDissolution testerAgilentDissolution mediumpH 7.5 bufferTest solution temperature37 ℃Test solution volume900 mLRotation speed75 rpmSample collection timeTelmisartan - 60 minChlorthalidone - 45 minAnalyzerHPLCColumnC18 columnMobile phasebuffer:ACN:MeOH = 5:3:2

[0189] ItemConditionDissolution testerAgilentDissolution medium0.01 N HClTest solution temperature37 ℃Test solution volume900 mLRotation speed50 rpmSample collection timeS-Amlodipine - 30 minAnalyzerHPLCColumnC18 columnMobile phasebuffer:ACN:MeOH=5:3:2

[0190] 2. Experimental results

[0191] Referring to Table 15, telmisartan and chlorthalidone showed little change in the content, related substances, and dissolution stability under all conditions. In addition, (S)-amlodipine showed no change in stability under long-term conditions, but a decrease in the content and an increase in related substances were observed under accelerated 6-month and severe 1-month conditions. However, the results met the criteria, confirming that there were no stability problems across all items.

[0192] [Table 15]

[0193]

[0194] While the specific parts of the present invention have been described in detail above, it is obvious to those skilled in the art that these specific descriptions are merely preferred embodiments and that the scope of the present invention is not limited thereto. Therefore, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims

1.A pharmaceutical combination preparation in a triple-layered tablet form, comprising:a first layer comprising telmisartan or a pharmaceutically acceptable salt thereof;a second layer comprising (S)-amlodipine or a pharmaceutically acceptable salt thereof, or a hydrate thereof; anda third layer comprising chlorthalidone or a pharmaceutically acceptable salt thereof,wherein the pharmaceutical combination preparation comprises microcrystalline cellulose and colloidal silicon dioxide as a layer separation prevention agent in the second layer.2.The pharmaceutical combination preparation of claim 1, wherein the (S)-amlodipine or a pharmaceutically acceptable salt thereof, or a hydrate thereof, comprised in the second layer is comprised in an amount of 2.5 to 5.0 mg per unit dosage form.3.The pharmaceutical combination preparation of claim 1, wherein the microcrystalline cellulose is comprised in an amount of 50% to 95% by weight based on the total weight of the second layer.4.The pharmaceutical combination preparation of claim 1, wherein the colloidal silicon dioxide is comprised in an amount of 0.3% to 3% by weight based on the total weight of the second layer.5.The pharmaceutical combination preparation of claim 1, wherein the second layer further comprises magnesium stearate.6.The pharmaceutical combination preparation of claim 5, wherein the magnesium stearate is comprised in an amount of 0.3% to 3% by weight based on the total weight of the second layer.7.A pharmaceutical combination preparation in a triple-layered tablet form, comprising:a first layer comprising telmisartan or a pharmaceutically acceptable salt thereof;a second layer comprising (S)-amlodipine or a pharmaceutically acceptable salt thereof, or a hydrate thereof; anda third layer comprising chlorthalidone or a pharmaceutically acceptable salt thereof,wherein the chlorthalidone or the pharmaceutically acceptable salt thereof is comprised in a granule form, and the granule of the chlorthalidone or the pharmaceutically acceptable salt thereof has a d90particle size in a range of 180 to 700 μm.

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