KR20180053044A - A pharmaceutical composition in a monolithic matrix tablet form comprising chlorthalidone or its salt and amlodipine or its salt and a process for preparing the same - Google Patents

Abstract

The present invention relates to a pharmaceutical composition in a monolithic matrix tablet form comprising chlorthalidone or salt thereof and amlodipine or salt thereof, and a production method of the same. Additionally, the present invention relates to a pharmaceutical composition in a bilayer tablet form comprising a first layer in a monolithic matrix tablet form and a second layer including telmisartan or salt thereof, and a production method of the same. According to the present invention, the uniformity of contents can be ensured.

Description

FIELD OF THE INVENTION The present invention relates to a pharmaceutical composition in the form of a single matrix tablet comprising chlortalidone or a salt thereof and amlodipine or a salt thereof and a process for preparing the same. the same}

The present invention relates to a pharmaceutical composition in the form of a single matrix tablet comprising chlortalidone or a pharmaceutically acceptable salt thereof and amlodipine or a pharmaceutically acceptable salt thereof and a process for the preparation thereof. The present invention also relates to a pharmaceutical composition in the form of a bilayer tablet comprising a first layer in the form of a single matrix tablet and a second layer comprising a salt of telmisartan or a salt thereof, and a process for its preparation.

Hypertension is caused by a variety of causes. Therefore, a variety of studies have been conducted on a combination of two or more different antihypertensive drugs for the treatment of hypertension. For example, when a diuretic such as hydrochlorothiazide or chlortalidone, an angiotensin II receptor antagonist such as olmesartan medoxomil or telmisartan, and / or a calcium channel blocker such as amlodipine are administered in combination with each other, effective hypertension It has been reported that a therapeutic effect can be obtained.

As a preparation in a single dosage form containing two or more antihypertensive drugs, for example, International Patent Publication No. WO 2003/059327 discloses a bilayer tablet comprising telmisartan and hydrochlorothiazide There is a bar. Korean Patent Laid-Open No. 10-2011-0012732 also discloses a first layer comprising an angiotensin II receptor antagonist or a calcium channel blocker; A disintegrable second layer that is completely disintegrated within one minute in an aqueous medium; And a third layer comprising a diuretic agent. In addition, U.S. Patent Publication No. 2007/0237815 discloses tablets containing amlodipine and chlortalidone in a certain amount, which tablets have a multi-segment structure comprising an inactive segment .

On the other hand, when a pharmaceutical composition is formulated in a single dosage form containing three active ingredients of a diuretic, angiotensin II receptor antagonist, and calcium channel blocker, it is necessary to minimize drug interaction and also to have a single preparation for each drug Biologically equivalent is required. As a method for avoiding drug interactions, a multi-layered tablet form preparation in which three active ingredients are separately formed as separate layers, and an inactive layer is inserted between each of the layers as required (see, for example, U.S. Patent Publication No. 2007 / RTI > < RTI ID = 0.0 > / 0237815). ≪ / RTI > However, such a multi-layer tablet has a problem in that it is difficult to apply it in a production site due to the complicated manufacturing process, and it is difficult to secure bioequivalence due to the elution of each drug due to a complicated multi-layer structure.

Thus, when formulating a pharmaceutical composition in a single dosage form comprising three active ingredients of a diuretic, an angiotensin II receptor antagonist, and a calcium channel blocker, at least two active ingredients, for example, It is required to formulate chlortalidone and amlodipine in the form of a monolithic matrix. However, to date, no single-matrix formulations have been developed which contain chlortalidone or a salt thereof and amlodipine or a salt thereof, and a single matrix comprising chlortalidone or a salt thereof and amlodipine or a salt thereof and a telmisartan, A single dosage form in which a calcium channel blocker such as a salt thereof is formulated together has not yet been developed.

Therefore, it can be easily applied as a complex preparation comprising a diuretic agent, an angiotensin II receptor antagonist, and three components of a calcium channel blocker, in particular chlortalidone or its salt, amlodipine or its salt, and telmisartan or its salt There is a need in the art to develop a single dosage form that is biologically equivalent to each single formulation.

The present inventors have found that a single monolithic matrix form of formulation comprising chlortalidone or a salt thereof and amlodipine or a salt thereof; And a variety of studies have been carried out to develop a single dosage form formulation in which the single matrix is combined with telmisartan or a salt thereof.

Chlortalidone or a salt thereof is low in density, large in acidity, has electrostatic characteristics, and has a characteristic of coagulating with each other or sticking well to the wall. In addition, the content per unit of chlortalidone or its salt is about 25 mg as a free base, while the content per unit of amlodipine or its salt (e.g., amlodipine besylate) is about 5 mg as a free base, amlodipine Since it is about 6.9 mg as the behenylate, it is very difficult to formulate it into a single matrix form by a conventional formulation method because the weight ratio and the density difference of the active ingredient are large and the ratio thereof per unit substance is small. That is to say, it is possible to mix and titrate the chlortalidone or its salt with amlodipine or a salt thereof, which has not only acidic and cohesive properties but also the content of active ingredient which is significantly higher than that of amlodipine or its salt, It has been found by the present invention that, when molding, not only a tableting trouble such as capping or sticking occurs but also uniform mixing is very difficult and it is difficult to secure uniformity of contents. Since amlodipine is known to be unstable by water (Pharm. Dev. Technol. 2004, 9, (1): 15-24.), Granulation will affect the stability of the active ingredient, It can be very difficult. The present inventors have conducted various studies in order to avoid the maltreating disorder and to secure the uniformity of the contents. Surprisingly, granulating the chlortalidone or a salt thereof and then blending the salt with amlodipine or its salt with additives, It has been found that not only the problem of the tableting disorder can be solved but also the homogeneity of the content can be secured and the bioequivalence with each single preparation and the stability of each active ingredient can be ensured.

In addition, when a layer containing telmisartan is formed on the single matrix and formulated into a single dosage form in the form of a bilayer tablet, it can be easily applied at the production site as compared with a multi-layered tablet, and each single preparation Lt; RTI ID = 0.0 > bioequivalence. ≪ / RTI >

Accordingly, it is an object of the present invention to provide a pharmaceutical composition in the form of a single matrix comprising granulating chlortalidone or a salt thereof and then tableting a mixture obtained by blending and mixing amlodipine or a salt thereof with an additive and a process for producing the same. .

It is another object of the present invention to provide a pharmaceutical composition in the form of a bilayer tablet comprising forming a layer containing telmisartan or a salt thereof in the single matrix and a method for producing the same.

According to one aspect of the present invention there is provided a pharmaceutical composition in the form of a single matrix tablet comprising granules and amlodipine or a pharmaceutically acceptable salt thereof comprising chlortalidone or a pharmaceutically acceptable salt thereof.

According to another aspect of the present invention there is provided a pharmaceutical composition comprising a first layer in the form of a single matrix comprising granules and amlodipine or a pharmaceutically acceptable salt thereof comprising chlortalidone or a pharmaceutically acceptable salt thereof; And a second layer comprising telmisartan or a pharmaceutically acceptable salt thereof, in the form of a bilayer tablet.

According to a further aspect of the present invention there is provided a process for preparing a pharmaceutical composition in the form of a single matrix tablet comprising chlortalidone or a pharmaceutically acceptable salt thereof and amlodipine or a pharmaceutically acceptable salt thereof, Granulating the money or a pharmaceutically acceptable salt thereof to prepare granules; (b) blending and mixing amlodipine or a pharmaceutically acceptable salt thereof, the granulate obtained in step (a) and a pharmaceutically acceptable additive; And (c) titrating the mixture obtained in step (b) in the form of a single matrix tablet.

According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of chlortalidone, or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt of telmisartan or a pharmaceutically acceptable salt thereof CLAIMS What is claimed is: 1. A method for preparing a pharmaceutical composition comprising: (a ') granulating chloraltidalin or a pharmaceutically acceptable salt thereof to prepare granules; (b ') amlodipine or a pharmaceutically acceptable salt thereof, a step of blending the granules obtained in step (a') and a pharmaceutically acceptable additive; (c ') depositing the mixture obtained in step (b) in the form of a single matrix layer to form a first layer; And (d ') forming a second layer comprising telmisartan or a pharmaceutically acceptable salt thereof in the first layer obtained in step (c').

The pharmaceutical composition according to the present invention may be prepared by granulating chlortalidone and then blending and mixing amlodipine or a salt thereof with an additive and then kneading the resulting mixture to form a single matrix form so that chlortalidone or a salt thereof and amlodipine or a salt thereof It is possible not only to avoid the penile disorder caused in the formulation by the conventional method but also to ensure the uniformity of the content and to secure the bioequivalence and stability with each single preparation. In addition, the pharmaceutical composition of the present invention can be easily applied on a production site as compared to a multi-layered tablet form by forming a layer containing telmisartan on the single matrix and formulating it into a single dosage form in the form of a bilayer tablet In addition, bioequivalence and stability with each single preparation can be ensured. Accordingly, the pharmaceutical compositions of the present invention, which are obtained in the form of a single matrix tablet and the pharmaceutical composition in the form of a bilayer tablet, can remarkably improve the convenience of taking a patient.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a blood concentration profile of chlortalidone obtained by oral administration of a bilayer tablet prepared according to the present invention and a comparative preparation (higrotonontje) to a beagle dog.
2 is a blood concentration profile of amlodipine obtained by oral administration of a bilayer tablet prepared according to the present invention and a comparative preparation (Twins tablet) to a beagle dog.
3 is a blood concentration profile of telmisartan obtained by oral administration of a bilayer tablet and a comparative preparation (Twins tablet) prepared according to the present invention to a beagle dog.
Figure 4 shows the properties of tablets of Comparative Example prepared by increasing the static pressure.

The present invention provides a pharmaceutical composition in the form of a single matrix tablet comprising granules and amlodipine or a pharmaceutically acceptable salt thereof containing chlortalidone or a pharmaceutically acceptable salt thereof.

The present invention also relates to a pharmaceutical composition comprising a first layer in the form of a single matrix comprising granules and amlodipine or a pharmaceutically acceptable salt thereof comprising chlortalidone or a pharmaceutically acceptable salt thereof; And a second layer comprising telmisartan or a pharmaceutically acceptable salt thereof.

The present invention also relates to a process for the preparation of a pharmaceutical composition in the form of a single matrix tablet comprising chlortalidone or a pharmaceutically acceptable salt thereof and amlodipine or a pharmaceutically acceptable salt thereof, which comprises (a) ≪ / RTI > to produce a granulate; (b) blending and mixing amlodipine or a pharmaceutically acceptable salt thereof, the granulate obtained in step (a) and a pharmaceutically acceptable additive; And (c) titrating the mixture obtained in step (b) into a single matrix tablet form.

The present invention also relates to a method for the preparation of a pharmaceutical composition in the form of a bilayer tablet comprising chlortalidone or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, and telmisartan or a pharmaceutically acceptable salt thereof (A ') granulating the chlortalidone or a pharmaceutically acceptable salt thereof to prepare granules; (b ') amlodipine or a pharmaceutically acceptable salt thereof, a step of blending the granules obtained in step (a') and a pharmaceutically acceptable additive; (c ') depositing the mixture obtained in step (b) in the form of a single matrix layer to form a first layer; And (d ') forming a second layer comprising telmisartan or a pharmaceutically acceptable salt thereof in the first layer obtained in step (c').

In a pharmaceutical composition in the form of a single matrix tablet according to the present invention and a process for the preparation thereof, the chlorthalidone or a pharmaceutically acceptable salt thereof may be used in a therapeutically effective amount, preferably chlortalidone The free base may be used to contain a content of 12.5 mg to 25 mg per unit tablet. The amlodipine or a pharmaceutically acceptable salt thereof may be used, for example, in the form of amlodipine besylate, preferably as free base in a content of 5 mg per unit tablet (about 6.9 mg of amlodipine in the case of amlodipine besylate) ). ≪ / RTI >

In addition, in the pharmaceutical composition in the form of a bilayer tablet according to the present invention and its preparation method, chlortalidone or a pharmaceutically acceptable salt thereof and amlodipine or a pharmaceutically acceptable salt thereof may be used in the above- Telmisartan or a pharmaceutically acceptable salt thereof may be used in a therapeutically effective amount and may preferably be used to contain a content of from 40 mg to 80 mg per unit tablet as a telmisartan free base . For example, chlortalidone or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, telmisartan, or a pharmaceutically acceptable salt thereof, is used as a free base in an amount of 12.5 / 5/40 mg, 12.5 / 5/80 mg, 25/5/40 mg, 25/5/80 mg, but is not limited thereto.

The granulation of step (a) and step (a ') may be carried out by a granulation process commonly used in the pharmaceutical industry, preferably by wet granulation using a binding liquid . For example, the granulation of step (a) and step (a ') can be carried out using chlortalidone or a pharmaceutically acceptable salt thereof, with suitable excipients, disintegrants, and binders.

The excipient is selected from the group consisting of microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylethylcellulose, Hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate, cellulose acetate phthalate, calcium hydrogenphosphate or a hydrate thereof, lactose, polyethylene oxide, polyvinyl acetate, polyvinyl alcohol, povidone, corn starch, potato starch , Starch starch, hydroxyethyl starch, dextrin, dextran, maltodextrin, polydextrose, guar gum, locust bean gum, xanthan gum, cyclodextrin, gum arabic, gellan gum, But are not limited to, gum tragacanth, gum tragacanth gum, tamarind gum, tragacanth gum, ghatti gum, gelatin, collagen, protamine, carbomer, polyacrylamide, carnauba wax, non- wax, sucrose, liquid sucrose, polyvinylacetate, diethylaminoacetate, , Chitin, agar, pectin, carrageenan, shellac, microcrystalline cellulose, sodium citrate, calcium phosphate, glycine, starch, mannitol, carboxymethylcellulose, erythritol, isomalt, maltitol, xylitol, sorbitol, trehalose, dextrose and Low-substituted hydroxypropylcellulose, and microcrystalline cellulose may be preferably used.

Wherein said disintegrant is selected from the group consisting of crospovidone, copovidone, croscarmellose sodium, sodium starch glycolate, low substituted hydroxypropylcellulose, formalin-casein, chitin, chitosan, polymerized agar acrylamide, xylan, at least one selected from the group consisting of alginic acid or its salt, hydroxypropylcellulose, polacrilin potassium, starch, pregelatinized starch, and carboxymethyl starch, And preferably sodium starch glycolate can be used.

The binder is selected from the group consisting of polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, sucrose, gelatin, acacia gum, povidone, hypromellose, hydroxypropylcellulose, copovidone, starch, glucose syrup, polyethylene glycol 6000 , Methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxyethylcellulose, low-substituted hydroxypropylcellulose, and methylcellulose. Rice, preferably povidone, may be used. The binder may be used in the form of a binding liquid in which water, an organic solvent (for example, ethanol, isopropanol, methylene chloride, etc.) or a mixed solvent of water and an organic solvent is dissolved.

The granules obtained in step (a) and step (a ') preferably have an appropriate particle size, for example, such that the average diameter of d _(0.9) of the granules ₍ i.e., 90% granules ₎ . The particle size control can be performed by a sizing process using a device such as a Fitz mill (Fitz patrick, USA).

In addition, the granules obtained in steps (a) and (a '), that is, the granules containing the chlortalidone or a pharmaceutically acceptable salt thereof, Is preferably in the range of 20 to 80% by weight based on the total weight of the single matrix tablet or the total weight of the first layer of the single matrix type.

The pharmaceutically acceptable additives used in step (b) and step (b ') are selected from the group consisting of microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, Hydroxypropyl methylcellulose, hydroxypropylethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate, cellulose acetate phthalate, calcium hydrogenphosphate or a hydrate thereof, lactose, polyethylene Polyvinyl acetate, polyvinyl alcohol, povidone, corn starch, potato starch, pregelatinized starch, hydroxyethyl starch, dextrin, dextran, maltodextrin, polydextrose, guar gum, locust bean gum, xanthan gum, Gelatin, collagen, protamine, carbomer, polyacrylamide, carnauba wax, non-wax, sucrose, gum arabic, gum arabic, gellan gum, karaya gum, casein, tara gum, tamarind gum, tragacanth gum, , Liquid sucrose, polyvinylacetate, diethylaminoacetate, chitosan, chitin, agar, pectin, carrageenan, shellac, microcrystalline cellulose, sodium citrate, calcium phosphate, glycine, starch, mannitol, carboxymethylcellulose, erythritol, iso At least one excipient selected from the group consisting of malt, maltitol, xylitol, sorbitol, trehalose, dextrose, and low substituted hydroxypropylcellulose; But are not limited to, crospovidone, copovidone, croscarmellose sodium, starch glycolate sodium, low-substituted hydroxypropylcellulose, formalin-casein, chitin, chitosan, polymerized agar acrylamide, xylan, smecta, At least one disintegrant selected from the group consisting of Tapioca modified starch, alginic acid or its salt, hydroxypropylcellulose, polacrilin potassium, starch, pregelatinized starch, and carboxymethyl starch; 1, 2, 3, 4, 5, or 6 members from the group consisting of stearic acid or its salts, talc, light anhydrous silicic acid, magnesium oxide, magnesium silicate, magnesium aluminosilicate, titanium oxide, stearyl sodium fumarate, aluminum silicate, colloidal silicon dioxide, Selected lubricants over the species; And a colorant. In one embodiment, the pharmaceutically acceptable excipients used in step (b) and step (b ') include microcrystalline cellulose, calcium hydrogen phosphate, sodium starch glycolate, pregelatinized starch, colloidal silicon dioxide, magnesium stearate, And a colorant.

The blending mixture of step (b) and step (b ') is prepared by mixing the granules, amlodipine or a pharmaceutically acceptable salt thereof obtained in step (a) and step (a') and the above- Is not particularly limited as long as a uniform mixture can be obtained. In one embodiment, the batting mix comprises: (i) mixing a starch glycolate, amlodipine or a pharmaceutically acceptable salt thereof to obtain a first mixture, (ii) mixing the first mixture, pregelatinized starch, colloidal (Iii) mixing the granules obtained in step (a) or step (a ') to obtain a tertiary mixture, (iv) mixing the granules obtained in step (a) Mixing the first mixture and the magnesium stearate to obtain a final mixture, and (v) mixing the fourth mixture and magnesium stearate to obtain a final mixture.

Preferably, the mixture obtained in step (b) and step (b ') has a flowability suitable for carrying out the tabletting process. For example, the mixture preferably has a Carr's Index of 25% or less. The Carr's Index can be measured according to known methods (e.g., RL Carr., "Evaluating Flow Properties of Solids ", Chem. Eng. 72. 163-8, 1965) Is used. According to the present invention, the mixture obtained in step (b) and step (b ') has a Carr's Index of less than 25%, preferably in the range of about 14 to 25%, thus exhibiting excellent flowability, Lt; / RTI >

In the production process of the present invention, it is preferred that the tableting of step (c) and step (c ') is carried out such that a single matrix tablet or a single matrix layer has a hardness of 7 to 30 kp, . The static pressure varies depending on the type of tablet machine used, and can be appropriately adjusted so as to have a hardness in the above range. If the hardness is lower than the above range, the tablet may easily break or be damaged during transportation, storage and distribution. If the hardness exceeds the above range, disintegration and / or dissolution may be delayed.

In the pharmaceutical composition of the present invention in the form of a bilayer tablet, the formation of the second layer may be carried out according to a known method for producing a telmisartan-containing bilayer tablet (for example, the method disclosed in WO2003 / 059327) . In one embodiment, the formation of the second layer comprises dissolving (i ') telmisartan or a pharmaceutically acceptable salt thereof, sodium hydroxide, meglumine, and povidone in a mixed solvent of purified water and ethanol to form a binding solution Producing; (ii ') a step of spraying the binding liquid prepared in step (i') on mannitol to prepare granules, (iii ') mixing the granules, mannitol and glidant prepared in step (ii' And (iv) titrating the mixture obtained in step (iii ') into the first layer obtained in step (c').

The pharmaceutical composition in the form of a single matrix tablet obtained in accordance with the present invention and the pharmaceutical composition in the form of a bilayer tablet may contain an additional coating layer, for example, an additional film coating layer for the purpose of improving the appearance and the like, . ≪ / RTI >

Example  1 to 6: chlortalidone and Amlodipine  Containing Tablets

Matrix tablets containing chlortalidone and amlodipine were prepared according to the ingredients and contents in Table 1 below. The content in Table 1 means the content per unit tablet (mg).

Povidone was dissolved in purified water to prepare a binding solution. Cholesterol, sodium starch glycolate, and microcrystalline cellulose were added to a granulator (Bohle, VMA-10, Germany), and granules were prepared using the binding solution. The resulting granules were formulated using a 1.0 mm screen size Fitz mill (Bohle, BTM-300, Germany).

Sodium starch glycolate was sieved in a No. 40 sieve, mixed with amlodipine besylate, and the red iron oxide, pregelatinized starch, and colloidal silicon dioxide, which were applicated in a No. 60 sieve, were added to the mixture and mixed. The chlortalidone granules obtained above were put into the mixture and mixed. Then, microcrystalline cellulose and calcium hydrogenphosphate hydrate were added and mixed, and then magnesium stearate was added to the mixture in an amount of 40 by sieving. The amount of microcrystalline cellulose was adjusted so that the total weight was 200 mg. This mixture was tableted with a tablet machine (Oystar Manesty, Flexiteb, UK) to prepare tablets having a hardness of about 17 kp.

Ingredients Example One 2 3 4 5 6 In the granule Chlortalidone 25 25 25 25 12.5 12.5 Starch glycolate sodium One 2 3 4 2 One Microcrystalline cellulose 11 47 83 119 59.5 23.5 Binding liquid Povidone 3 6 9 12 6 3 water 19 38 57 76 38 19 sub Total 40 80 120 160 80 40 Granule et al Amlodipine besylate 6.935 6.935 6.935 6.935 6.935 6.935 Colloidal silicon dioxide 2 2 2 2 2 2 Starch glycolate sodium 4.5 4.5 4.5 4.5 4.5 4.5 Pregelatinized starch 20 20 20 20 20 20 Calcium hydrogen phosphate hydrate 40 40 40 40 40 40 Microcrystalline cellulose Suitable amount Suitable amount Suitable amount Suitable amount Suitable amount Suitable amount Red iron oxide 0.1 0.1 0.1 0.1 0.1 0.1 Magnesium stearate 3 3 3 3 3 3 sum 200 200 200 200 200 200

Example  7 to 10: hardness Different  Chlortalidone and Amlodipine  Containing Tablets

Same as Examples 1 to 6 except that the hardness at the time of tableting in Example 2 was fixed to 7 kp (Example 7), 10 kp (Example 8), 20 kp (Example 9) and 30 kp (Example 10) To prepare tablets.

Example  11 to 13: chlortalidone, Amlodipine , And Telmisartan  Containing Double layer  refine

Double-layer tablets containing chlortalidone, amlodipine, and telmisartan were prepared according to the ingredients and contents in Table 2 below. The content in Table 2 means the content per unit tablet (mg).

Telmisartan, sodium hydroxide, meglumine, and povidone were dissolved in a mixed solvent of purified water and ethanol to prepare a binding solution. The granules were prepared by spraying the binding solution while flowing mannitol in a fluidized bed granulator (Gratter, GPCG-1, Germany). The obtained granules were sieved using a No. 18 sieve. Mannitol was added to the granules, and magnesium stearate and sodium stearyl fumarate were applied to a No. 40 sieve and mixed.

Layer tablets having a hardness of about 17 kp were prepared by tabletting the telmisartan mixture of Table 2 below as a top layer and tablets using a tableting machine (Oystar Manesty, Flexiteb, UK).

Ingredients Example 11 12 13 Binding liquid Telmisartan 80 40 40 Sodium hydroxide 6.72 3.36 6.72 Meglumine 24 12 24 Povidone 24 12 24 Purified water 240 120 240 ethanol 60 30 60 In the granule Mannitol 287.28 143.64 287.28 Granule et al Mannitol 40.4 20.2 80.4 Magnesium stearate 5.6 2.8 5.6 Sodium stearyl fumarate 12 6 12 sum 480 240 480

Comparative Example  1 and 2: chlortalidone with different weight ratios of chlortalidone granules and Amlodipine  Containing Tablets

The tablets were prepared in the same manner as in Examples 1 to 6 according to the ingredients and contents in Table 3 below.

Ingredients Comparative Example One 2 In the granule Chlortalidone 25 25 Starch glycolate sodium 0.5 4.5 Microcrystalline cellulose 2 127.5 Binding liquid Povidone 2.5 13 water 14 79 sub Total 30 170 Granule et al Amlodipine besylate 6.935 6.935 Colloidal silicon dioxide 2 2 Starch glycolate sodium 4.5 4.5 Pregelatinized starch 20 4 Calcium hydrogen phosphate hydrate 40 8 Microcrystalline cellulose Suitable amount Suitable amount Red iron oxide 0.1 0.1 Magnesium stearate 3 3 sum 200 200

Comparative Example  3 and 4: The particle size of the chlortalidone granules Different  Tablets containing chlortalidone and amlodipine

The tablets were prepared in the same manner as in Examples 1 to 6 except that the sizing process in Example 2 was used at 0.5 mm screen size (Comparative Example 3) and 1.5 mm screen size (Comparative Example 4), respectively.

Comparative Example  5: Redemption  Chlortalidone by mixing and Amlodipine  Containing Tablets

Sodium starch glycolate was sieved in a No. 40 sieve, mixed with amlodipine besylate, and the red iron oxide, pregelatinized starch, and colloidal silicon dioxide, which were applicated in a No. 60 sieve, were added to the mixture and mixed. Chlortalidone and povidone were added to and mixed with the above mixture, and then microcrystalline cellulose and calcium hydrogenphosphate hydrate were added thereto and mixed. Magnesium stearate was added to the above mixture by mixing in a No. 40 sieve. This mixture was tableted in the same manner as in Examples 1 to 6 to prepare tablets.

Ingredients Comparative Example 5 Chlortalidone 25 Colloidal silicon dioxide 2 Povidone 6 Starch glycolate sodium 6.5 Amlodipine besylate 6.935 Pregelatinized starch 20 Calcium hydrogen phosphate hydrate 40 Microcrystalline cellulose Suitable amount Red iron oxide 0.1 Magnesium stearate 3 sum 200.0

Comparative Example  6: simple mixing (non- Redemption  Mixed) Chlortalidone and Amlodipine  Containing Tablets

The granulation process of chlortalidone was carried out in the same manner and the tablets were tableted by the same method as in Examples 1 to 6 except that all the additives were added all at once without being mixed in the post-mixing step after the granules and mixed. .

Ingredients Comparative Example 6 In the granule Chlortalidone 25 Starch glycolate sodium 2 Microcrystalline cellulose 47 Binding liquid Povidone 6 water 38 sub Total 80 Granule et al Amlodipine besylate 6.935 Colloidal silicon dioxide 2 Starch glycolate sodium 4.5 Pregelatinized starch 20 Calcium hydrogen phosphate hydrate 40 Microcrystalline cellulose Suitable amount Red iron oxide 0.1 Magnesium stearate 3 sum 200

Comparative Example  7 and 8: Hardness Different  Chlortalidone and Amlodipine  Containing Tablets

The tablets were prepared in the same manner as in Examples 1 to 6 except that the hardness at the time of tableting in Example 3 was fixed to 6 kp (Comparative Example 7) and 32 kp (Comparative Example 8).

Test Example  1: of chlortalidone granule Particle size distribution test

The particle size distribution test on the chloraltidal granules obtained in Examples 1 to 4 and Comparative Examples 1 to 4 was carried out according to the US Pharmacopoeia. Specifically, the particle size distribution test was performed according to the "particle size distribution estimation by analytical sieving" method of USP Physical Tests, and the test was conducted using the ATM Sonic Sifter (L3P, ATM corporation, USA) model in Test Sieve Shaker Respectively. Based on the result of the particle size distribution test, the average diameter of 90% of the granules, i.e., d _(0.9) was calculated through cumulative distribution, and the results are shown in Table 6 below.

d _(0.9) Example 1 266 탆 Example 2 326 탆 Example 3 514 탆 Example 4 788 탆 Comparative Example 1 163 탆 Comparative Example 2 886 탆 Comparative Example 3 132 탆 Comparative Example 4 1156 탆

From the results shown in Table 6, it can be seen that the chlortalidone-containing granules of Examples 1 to 4 obtained according to the present invention can secure d _(0.9) in the range of about 250 to 800 μm. On the other hand, in Comparative Examples 3 and 4, the particle size of d _(0.9) was 132 탆 and 1156 탆, respectively, which were too large or small so that the particle size was large or small in the final mixture and the content uniformity and flow The quality of the product is adversely affected and the quality of the product is adversely affected. It can be confirmed that the particle size of the chlortalidone-containing granules obtained according to the present invention can be smoothly applied at the production site.

Test Example  2: Flowability evaluation

For the mixture just before tabletting in Examples 1 to 4 and Comparative Examples 1, 3, 5 and 6, R.L. Carr. Carr's Index (CI value) was measured based on the following equation according to the method of "Evaluating Flow Properties of Solids", Chem. Eng., 72. 163-8, 1965. The results are as follows.

Carr's Index = 100 x (Vb-Vt) / Vb

[Vb = bulk density, Vt = tapped density]

CI value Example 1 22.7 Example 2 14.4 Example 3 15.2 Example 4 16.8 Comparative Example 1 27.1 Comparative Example 3 32.1 Comparative Example 5 38.0 Comparative Example 6 27.5

From the results of Table 7, it can be seen that when the granulation process is not carried out (Comparative Example 5) and the sintering process is not carried out (Comparative Example 6), the CI value is high and low flowability is obtained, RTI ID = 0.0 > 25% < / RTI > In the case of Comparative Example 1, since the ratio of chlorthalidone granules was very small as 15% by weight with respect to the total composition weight, the improvement effect on the specific physical properties such as non-acidity, low density and static electricity was small, And showed low flow rate. In the case of Comparative Example 3, too, the flowability was low due to the generation of granules of relatively small particles. Generally, it is known that when the CI value is 25% or less, good flowability is exhibited. Thus, it can be seen that the mixtures of Examples 1 to 4 obtained according to the present invention exhibit excellent flowability, which makes them suitable for carrying out the tableting process at the production site.

Test Example  3: Content uniformity test

Ten tablets each of the tablets prepared in Examples 1 to 4 and Comparative Examples 1 to 6 were taken and subjected to a content uniformity test using HPLC. The analysis conditions of HPLC are as follows, and the results are shown in Tables 8 to 10 below. In Tables 8 to 10, A represents amlodipine and C represents the content of chlortalidone (HPLC area value).

<HPLC analysis conditions (amlodipine)>

- Detector: Ultraviolet absorptiometer (measuring wavelength 237 nm)

Column: A column packed with octadecylsilylated silica gel for liquid chromatography of 5 mu m in a stainless steel tube of 3.9 mm x 15 cm

- mobile phase: methanol and acetonitrile and mobile phase A = 31: 15: 30

(Mobile phase A was prepared by dissolving 7.0 mL of triethylamine in 900 mL of water, adding phosphoric acid to adjust to pH 3.0, and then adding water to make 1000 mL.)

- Flow rate: 1 mL / min

- Injection volume: 50 μL

<HPLC analysis conditions (chlortalidone)>

- Detector: Ultraviolet absorptiometer (measuring wavelength 254 nm)

- Column: A column packed with octylsilylated silica gel for a liquid chromatograph of 5 m in a stainless steel tube of 4.6 mm x 25 cm

- mobile phase: adjusted to pH 5.5 with phosphoric acid in methanol and 0.01 M ammonium dihydrogen phosphate = 40: 60

Flow rate: 1.0 mL / min

Injection amount: 25 μL

Example 1 Example 2 Example 3 Example 4 A (%) C (%) A (%) C (%) A (%) C (%) A (%) C (%) Average 100.7 102.1 100.4 98.9 97.6 99.7 96.6 98.2 Standard Deviation 3.1 3.1 1.5 0.5 2.8 3.0 1.9 3.1

Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 A (%) C (%) A (%) C (%) A (%) C (%) A (%) C (%) Average 99.7 98.3 97.3 101.3 98.1 102.0 94.6 96.9 Standard Deviation 7.4 7.3 11.3 1.2 8.3 10.2 12.3 9.6

Comparative Example 5 Comparative Example 6 A (%) C (%) A (%) C (%) Average 98.7 99.1 91.1 100.1 Standard Deviation 8.9 15.4 13.1 1.5

As can be seen from the results of Tables 8 to 10, the tablets of Comparative Example 5, which had not undergone the granulation process, showed very low content uniformity due to a very high content of the tablets, and the tablets of Comparative Example 6, The content of amlodipine was very high and the content uniformity was very low. In Comparative Example 1, in which the weight ratio of the chlortalidone granules was small, the effect of improving the physical properties of the chlortalidone raw material was not so good, and the flowability and the like were not so good, The amlodipine having a relatively low weight ratio was not mixed homogeneously, and the amount of the amlodipine was relatively large. In Comparative Example 3 in which the particle size of the chlortalidone granules was small and in Comparative Example 4 in which the particle size was large, a large difference in particle size occurred in the mixture, which was not homogeneously mixed, and the uniformity of contents of chlortalidone and amlodipine Sex was low. On the contrary, the tablets of Examples 1 to 4 obtained according to the present invention have good content uniformity.

Test Example  4: Hardness and Massono  exam

The hardness test, the shattering test, and the disintegration test were carried out according to the method described in the Pharmacopoeia 11 of the tablets obtained in Examples 2 and 7 to 10 and Comparative Examples 5, 7 and 8, Respectively.

Example Comparative Example 2 7 8 9 10 5 7 8 Hardness (kp) 17.5 7.8 10.0 20.8 30.4 6.8 6.5 32.8 Marson (%) 0.02 1.11 0.08 0.04 0.09 8.1 3.3 0.12 Disintegration (minute) 13 7 11 15 19 3 6 26

As can be seen from the results of Table 11, Examples 2 and 7 to 10 showed good results in terms of the degree of malleability. In Comparative Example 7, the degree of grinding was relatively high because of the low hardness. In Comparative Example 8, although the degree of grinding was low, since the static pressure was applied to the maximum value of the tabletting machine, mechanical overload was caused and the disintegration time was slow The elution may be delayed and the quality may be lowered. In Comparative Example 5, since chlortalidone was not subjected to the granulation process, the quality was very low due to its low hardness and high scratch resistance due to the influence of the main component properties. When the static pressure is increased to increase the hardness, a mechanical disorder such as capping and laminating phenomenon occurs, and mechanical overload is caused and smooth production is not achieved (see FIG. 4). On the contrary, Examples 2 and 7 to 10 obtained according to the present invention exhibited good hardness of about 7 to 30 kp and exhibited excellent productivity without a penile disorder.

Test Example  5: Dissolution test

The elution test was carried out on the double-layer tablets prepared in Example 11 under the following conditions.

&Lt; Dissolution condition >

Eluent: 900 mL of one solution (pH 1.2) of the disintegration test method of Korea Pharmacopoeia 11, two solutions (pH 6.8) 900 mL

Apparatus: Korean Pharmacopoeia 11 revision dissolution test method 2 (paddle method), 75 rpm

Temperature: 37 ° C

Elution time: 5, 10, 15, 30, 45, 60, 90, and 120 minutes

The content of amlodipine and chlortalidone in the sample obtained from the leaching test was measured by HPLC in the same manner as described in Test Example 3. [ In addition, the content of telmisartan in the sample was measured using HPLC under the following analysis conditions.

<HPLC analysis conditions (telmisartan)>

- Detector: Ultraviolet absorptiometer (measuring wavelength 298 nm)

Column: A column packed with octadecylsilylated silica gel for a liquid chromatograph of 5 mu m in a stainless steel tube of 4.0 mm x 4 cm

- mobile phase: methanol and mobile phase A = 70: 30

(Mobile phase A was prepared by dissolving 2.0 g of ammonium dihydrogenphosphate in 900 mL of water, adding 1 M phosphoric acid to adjust to pH 3.0, and then adding water to make 1000 mL.)

Flow rate: 0.7 mL / min

Injection volume: 5 μL

Column temperature: 40 ° C

Commercially available Twins tablet (Boehringer Ingelheim, amlodipine / telmisartan combination) and higrotonontje (Hanlim Pharmaceutical, chlortalidone single agent) were evaluated together as comparative agents, respectively. The results of the dissolution test are shown in Table 12 below.

time
(minute) Amlodipine
(pH 1.2) Chlortalidone
(pH 6.8) Telmisartan
(pH 1.2) Comparative formulation
(Twins hit) Example 11 Comparative formulation
(High gross tonnage) Example 11 Comparative formulation
(Twins hit) Example 11 0 0 0 0 0 0 0 5 29.1 24.9 42.7 54.2 12.1 9.0 10 52.8 49.7 64.1 71.1 22.9 16.0 15 72.0 67.6 75.4 79.2 31.5 23.7 30 98.1 87.2 90.0 88.7 50.6 45.4 45 99.5 92.0 95.4 91.8 63.9 62.8 60 99.2 94.1 97.6 93.7 74.5 74.9 90 - - - - 86.1 80.6 120 - - - - 91.0 88.6

From the results of Table 12, it can be seen that the tablets obtained according to the present invention exhibit an elution pattern equivalent to elution of amlodipine, telmisartan and chlortallidone with the comparative agent.

Test Example  6: Stability test

The tablets prepared in Example 2 and the double-layer tablets prepared in Example 11 were packed in Alu-Alu wrapping paper and packed in Alu-Alu wrapping paper under accelerated conditions (temperature 40 ° C., relative humidity 75%) and room temperature conditions (temperature 25 ° C., Each content test was carried out while storing, and the results are shown in Table 13 below.

Storage period Storage conditions content(%) Example 2 Example 11 Telmisartan Amlodipine Chlortalidone Telmisartan Amlodipine Chlortalidone Early Room temperature / acceleration - 94.9 97.0 98.1 96.0 96.7 1 month Room temperature - 95.7 98.2 98.7 95.9 97.2 Acceleration - 95.6 97.8 98.7 95.3 96.9 3 months Room temperature - 97.8 96.4 98.1 94.9 96.6 Acceleration - 98.0 96.5 98.7 95.0 96.7 6 months Room temperature - 96.8 95.18 98.5 95.6 96.6 Acceleration - 95.4 95.15 98.6 95.5 96.5 9 months Room temperature - 95.7 97.7 97.7 95.6 95.7 12 months Room temperature - 95.6 98.2 97.5 95.7 96.7

From the results in Table 13, it can be confirmed that the single matrix tablets and double-layer tablets obtained according to the preparation method of the present invention have excellent stability.

Test Example  6: Evaluation of bioavailability

Bioavailability of the tablets and comparative preparations prepared in Example 11 were evaluated in a Beagle dog. Sixteen beagle dogs weighing about 10 kg fasted for 12 hours were orally administered the comparative preparation and the tablet prepared in Example 9 at fasting. Blood was collected at 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, and 8 hours after the administration with heparinized syringes. The collected blood was placed in a centrifuge tube and centrifuged at 3000 rpm for 5 minutes. The separated plasma was taken and stored frozen at -20 ° C until analysis. The concentrations of telmisartan, amlodipine, and chlortalidone in plasma were quantified using LC / MS / MS, and the analysis conditions were as follows.

<LC / MS / MS conditions>

1. LC condition

- Guard column: Phenomenex C18 (4.0 x 3.0 mm I.D)

- Column temperature: about 40 ℃

* F.A: formic acid; A. F: Ammonium formate

2. MS / MS conditions

- Scan type: MRM (Multiple Reaction Monitoring) mode

- Polarity: Positive (telmisartan, amlodipine), Negative (chlortalidone)

- Ion source: Electrospray ionization

- Resolution Q1: Unit

- Resolution Q3: Unit

The blood concentration profiles of chlortalidone, amlodipine, and telmisartan obtained as described above are shown in FIGS. 1 to 3. The drug kinetic parameters and the T / R ratio (T / R ratio) Table 14 shows the results.

Telmisartan Amlodipine Chlortalidone AUC
(ng · hr / ml) Cmax
(ng / ml) AUC
(ng · hr / ml) Cmax
(ng / ml) AUC
(ng · hr / ml) Cmax
(ng / ml) Comparative formulation 21111.1 10557.28 130.636 23.513 3163.592 640.403 Example 11 22909.32 10964.33 131.98 24.043 2967.803 672.904 T / R ratio 1.085 1.038 1.01 1.022 0.938 1.05

As can be seen from the results of FIGS. 1 to 3 and Table 14, the double-layer tablets obtained according to the present invention exhibited the highest blood concentration (Cmax) and the lower curve (AUC) of the comparative preparations (Twins tablet and high- It does not show any statistically significant difference, and thus shows biological equivalence.

Claims (23)

A pharmaceutical composition in the form of a single matrix tablet comprising granules and amlodipine or a pharmaceutically acceptable salt thereof, wherein the composition comprises chlortalidone or a pharmaceutically acceptable salt thereof. A first layer in the form of a single matrix comprising granules and amlodipine, or a pharmaceutically acceptable salt thereof, containing chlortalidone or a pharmaceutically acceptable salt thereof; And a second layer comprising telmisartan or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 1, wherein the content of chlorptalidone or a pharmaceutically acceptable salt thereof is 12.5 mg to 25 mg per unit tablet as a free base, and the amount of the amlodipine or a pharmaceutically acceptable salt thereof is 5 units / mg. &lt; / RTI &gt; 3. The pharmaceutical composition according to claim 2, wherein the amount of chlortalidone or a pharmaceutically acceptable salt thereof is 12.5 mg to 25 mg per unit tablet as a free base, and the content of the amlodipine or a pharmaceutically acceptable salt thereof is 5 mg, and the content of said telmisartan or pharmaceutically acceptable salt thereof is from 40 mg to 80 mg per unit tablet as a free base. 3. The pharmaceutical composition according to claim 1 or 2, wherein the granule containing the chlortalidone or a pharmaceutically acceptable salt thereof is chlortalidone or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, sodium starch glycolate, and povidone &Lt; / RTI &gt; 3. The pharmaceutical composition according to claim 1 or 2, characterized in that the d _(0.9) of the granules containing the chlortalidone or a pharmaceutically acceptable salt thereof ranges from 250 to 800 mu m. The composition of claim 1 or 2, wherein the granulate containing the chlortalidone or a pharmaceutically acceptable salt thereof is present in an amount of from 20 to 80% by weight, based on the total weight of the single matrix tablet or the total weight of the first layer in the single matrix form Lt; RTI ID = 0.0 &gt; 1, &lt; / RTI &gt; 3. The method of claim 1 or 2, wherein the first matrix in the form of a single matrix tablet or the single matrix comprises microcrystalline cellulose, calcium hydrogen phosphate, sodium starch glycolate, pregelatinized starch, colloidal silicon dioxide, magnesium stearate, &Lt; / RTI &gt; further comprising a colorant. 3. The pharmaceutical composition according to claim 1 or 2, wherein the first matrix in the form of a single matrix tablet or the single matrix has a hardness of 7 to 30 kp. 3. The pharmaceutical composition according to claim 2, wherein said second layer further comprises sodium hydroxide, meglumine, povidone, mannitol, and a glidant. A process for the preparation of a pharmaceutical composition in the form of a single matrix tablet comprising chlortalidone or a pharmaceutically acceptable salt thereof and amlodipine or a pharmaceutically acceptable salt thereof,
(a) granulating chlortalidone or a pharmaceutically acceptable salt thereof to prepare granules;
(b) blending and mixing amlodipine or a pharmaceutically acceptable salt thereof, the granulate obtained in step (a) and a pharmaceutically acceptable additive; And
(c) titrating the mixture obtained in step (b) into a single matrix tablet form
&Lt; / RTI &gt; A process for the preparation of a pharmaceutical composition in the form of a bilayer tablet comprising chlortalidone or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, and telmisartan or a pharmaceutically acceptable salt thereof,
(a ') granulating clathalidone or a pharmaceutically acceptable salt thereof to produce granules;
(b ') amlodipine or a pharmaceutically acceptable salt thereof, a step of blending the granules obtained in step (a') and a pharmaceutically acceptable additive;
(c ') depositing the mixture obtained in step (b) in the form of a single matrix layer to form a first layer; And
(d ') forming a second layer comprising telmisartan or a pharmaceutically acceptable salt thereof in the first layer obtained in step (c')
&Lt; / RTI &gt; 12. The pharmaceutical composition according to claim 11, wherein the chlortalidone or a pharmaceutically acceptable salt thereof is used to contain a content of 12.5 mg to 25 mg per unit tablet as a free base, and the amlodipine or a pharmaceutically acceptable salt thereof is a free base Lt; RTI ID = 0.0 &gt; 5 mg &lt; / RTI &gt; per unit tablet. 13. The pharmaceutical composition according to claim 12, wherein the chlortalidone or a pharmaceutically acceptable salt thereof is used to contain a content of 12.5 mg to 25 mg per unit tablet as a free base, and the amlodipine or a pharmaceutically acceptable salt thereof is a free base Wherein the composition is used to contain a content of 5 mg per unit tablet and the telmisartan or a pharmaceutically acceptable salt thereof is used as a free base to contain a content of 40 mg to 80 mg per unit tablet. 13. Process according to claim 11 or 12, characterized in that the granulation of step (a) and step (a ') is carried out by wet granulation. 13. The method of claim 11 or 12, wherein said granulation of step (a) and step (a ') is carried out using chlortalidone or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, sodium starch glycolate, and povidone . &Lt; / RTI &gt; 16. The method according to claim 15, wherein the povidone is used in the form of a binding liquid in which water, an organic solvent, or a mixed solvent of water and an organic solvent is dissolved. The process according to claim 11 or 12, further comprising a step of setting the d _(0.9) of the granules obtained in step (a) and step (a ') to have a size of 250 to 800 탆. 13. The composition of claim 11 or 12 wherein the pharmaceutically acceptable excipients used in step (b) and step (b ') are selected from the group consisting of microcrystalline cellulose, calcium hydrogen phosphate, sodium starch glycolate, pregelatinized starch, colloidal silicon dioxide , Magnesium stearate, and a colorant. 13. The process according to claim 11 or 12, wherein said bubble mix of step (b) and step (b ') comprises (i) mixing starch glycolate, amlodipine or a pharmaceutically acceptable salt thereof to obtain a first mixture (Ii) obtaining a second mixture by mixing the first mixture, pregelatinized starch, colloidal silicon dioxide and a colorant; (iii) mixing the second mixture obtained in step (a) or step (Iv) mixing the tertiary mixture, microcrystalline cellulose and calcium hydrogen phosphate to obtain a fourth mixture, and (v) mixing the fourth mixture and magnesium stearate to obtain a second mixture, Lt; RTI ID = 0.0 &gt; 1, &lt; / RTI &gt; to obtain a final mixture. 13. The process according to claim 11 or 12, wherein the Carr's Index of the mixture obtained in step (b) and step (b ') is 25% or less. The process according to claim 11 or 12, characterized in that the tableting of step (c) and step (c ') adjusts the netting pressure so that the single matrix tablet or single matrix layer has a hardness of 7-30 kp. Way. 13. The method of claim 12, wherein the formation of the second layer comprises dissolving (i ') telmisartan or a pharmaceutically acceptable salt thereof, sodium hydroxide, meglumine, and povidone in a mixed solvent of purified water and ethanol, Lt; / RTI &gt; (ii ') a step of spraying the binding liquid prepared in step (i') on mannitol to prepare granules, (iii ') mixing the granules, mannitol and glidant prepared in step (ii' And (iv) titrating the mixture obtained in step (iii ') into the first layer obtained in step (c').

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